Development in dihydropyridine chemistry - American Chemical

I&. Eng. Chem. Prod Res. Dev. 1882. 21. 191-261

191

REVIEW SECTION Development In Dihydropyridine Chemistry Jwef Kuthan' and A. Kurfirrst Dsperfmsnf of Orwnlc Ctmmisw, Ragw InstlMe of chemical Techmk?g)

This review includes developments in the recent period 1972 to 1980 under the same limitations as the authors' 1972 review (ref 251). It includes 1197 references. Pyridine methenes. dihydropyridones. pyrkione imines, benzodihydropyridines. quinoiizidines. and special biochemical aspects regarding NADH are not induded. Along wim synthesis. sbucture. reactivity. and

properties, expanding practical applications of dihydropyridine derivatives are discussed

I. Introduction Dihydropyridine chemistry is of interest not only from the point of view of pure research on heterocyclic compounds but especially because of expanding practical applications of dihydropyridine derivatives as pharmaceutics (seethe Appendix), anticorrosion agents (90%911),plating bath components (193, 328), photographic materials (3, 858,875,890, 903, 1150), scintillators (312).rocket fuels (354).and different antioxidants and stabilizers of unstable organic substances (71,241-243,387,388-391,393,396, 548-550, 553, 654, 866, 874, 1037, 1040, 1103-1105, 1143-1145). Certain dihydropyridine derivatives appear to be effective, such as fertility, milk productivity and growth stimulators for cows (1039, 1187), stabilizers of fishmeal for broiler chicks (246,1058),ingredients in hog, calf, and cattle feed (1036, 1038, 1123, 1186), as well as agents for antiradiation protection of plants (397). Dihydropyridme compounds are important intermediates in the synthesis of benmmorphane (46-50,299,300,484,513, 519,524,845, 9021, thienomorphane (323-326, 6 0 W 0 3 ) . azocine (37, 708) and cephalosporine (774-776,1041) derivatives, in the biosynthesis of indole alkaloids (591,592, 985,%6), of nicotine (6131,and in the biotransformations of elastine (863). Two alkaloids possessing a dihydropyridine skeleton were identified (619,894). It is generally well known that the reduced coenzyme forms of NAD(P)H are dihydropyridine derivatives (255,256,372, 442, 516, 544, 653, 731, 796, 1025, 1097, 1176, 1180) and through these compounds dihydropyridine chemistry in all living organisms enters fundamental biochemical processes. In contrast to other branches of heterocyclic chemistry, most of the potential practical usages have still not been explored in the field of dihydropyridines. Hence, for practical chemists novel developments in dihydropyridine chemistry could be stimulating to the planning of new experiments. In the literature, besides one complete review (251) covering the period 1882 to 1972, other excellent less extended surveys (11,255,516,643,796,1025,1097) on special topics of dihydropyridine chemistry are available. This review covers the recent period 1972 to 1980 under 0198-4321/82/1221-0191$01.25/0

J o s e f K u t h was born in 1934 in Prague, Czechoslovakia. He attended the Prague Institute of Chemical Technology, where he received the degree of chemical engineer in 1956, a Ph.D. degree in 1961, and a DSc. degree in 1973. He was promoted to Associate Professor in 1965, to Professor of' Organic Chemistry in 1977, and elected Vice President of the Institute for the period 1971 to 1976. Dr. Kuthan's research interests and activities have concerned predominantly heterocyclic chemistry and chemical spectroscopy as well as quantum and physical organic chemistry, in the field of which he has published more than a hundred papers and about thirty patents. He is an active member of the Czechoslovak Chemical and the Czechoslovak Spectroscopic Societies. He visited the United States in 1972 as a UNESCO expert. Antonk K u r f u r s t was born in 1951 in Gottwaldou, Czechoslovakia. He attended the Prague Institute of Chemical Technology where he received the degree of chemical engineer in 1975. He has been cooperating with Professor Kuthan. the same limitations as in ref 251; e.g., only isolable or spectroscopically identifiable dihydropyridines without exocyclic double bonds are considered. Consequently, all pyridine methenes, dihydropyridones, pyridone imines as well as benzodihydropyridines and quinolizidines are excluded. Special biochemical aspects regarding NADH also are not mentioned. 11. S t r u c t u r e

A. Constitution a n d Stability. The structural classification of dihydropyridine derivatives is based on the five parent 1,2-, 1,4-, 2.3-, 3,4-, and 2,5-dihydro types 1-5. Only 1,Cdihydro isomer 6 was prepared (211,536)as an unstable substance, although all compounds 1-5 were studied theoretically (109,114,283). MIND0/3 (109)as well 89 ab initio 4-31G calculations (114)predict compound 6 to be the most stable isomer. For simple 1-methyl derivatives of l and 2 it was really found (283)that the energy preference of 2 is 9.57 + 0.04 kJ mol-'. In addition, it has been further suggested (89, 114) that for unsubstituted structures 1-5 tautomerisms 3 > 1 > 5 and 2 > 4 come into 0 1982 American Chemical Society

192

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982

I

I

1

2

etry of R shows slight deviations from the full planarity of ring system 1 as well as a certain important degree of conjugation between double bonds and nitrogen lone pair. Similar features follow from the X-ray studies (2, 780, 781) on the more complex 1,2-dihydropyridine derivatives 13 (see Table I).

4

3

R2

5

account. According to this suggestion types 3-5 may spontaneously isomerize to thermodynamicallymore stable 1 or 2 by proton transfer from position 3 or 5 to position 1. As a matter of fact, easily isolable 2,3-dihydropyridines of 7a-c types as well as 2,5-dihydropyridinesof 8a-d types exhibit geminal 2,2-, 3,3-, or 5,5-disubstitution preventing them from the above-mentioned isomerizations. The existence of some further 2,3-types (332,363,638,869,870) and 2,Mypes (288, 870, 967) was correctly proved by spectroscopic methods. On the other hand, in some cases (206,470,623,897,918,936)no conclusive arguments in favor of the 2,3-dihydro structures were given and reinvestigations of the results would be desirable. Among 3,bdihydropyridines 4 only compounds possessing fragmenta 9 have been prepared as well (292-294,677,679,680, 684,6914393,698,699,942,1159)where the amino group probably stabilizes structure 4 with respect to other tautomers. Similar effects are apparently responsible for 2,5-structure 5 of compounds 10 (925). It can be generally postulated that the predominant number of known dihydropyridine derivatives are still 1,2and 1,4-dihydro types 1 and 2 in agreement with theoretical considerations (109, 114). Every 3,5-disubstitution at skeletons 1 and 2 by electron-withdrawing substituents X and Y as COR, C02R, CN, and NO2 enhances their chemical stability. This effect leads in combination with 2 to the most popular "Hantzsch dihydropyridines" (251, 358) of the general formula 11. Derivatives 11 have the best chances m applied chemistry.

Me

12a: R' = R3 = H, R2 = M e b: R' = Et, R2 = R3 = H c : R' = R2 = H, R3 = E t COZMe

13a: b: c: d:

R' R', R', R',

= R4 = o-SC,H,-, R2 = H, R3 = C0,Me R2 = o-SC,H,-, R3 = CO,Me, R4 = H R 2 = -SCH=C(Me)-, R3 = Me, R4 = C0,Me R2 = -SCH=CH-, R3 = C02Me, R4 = Me

The molecular geometry of Hantzsch 1,Cdihydropyridines 14-18 was determined (153,373,421,551,552, 617,714,1133) by X-ray crystallography which has shown ring 2 to be planar in 14a (617,1133),boat-like in 14b, 15, 17, 18, and 19 (153,373,551,552, 714,898, 1133), or enEt-0

hl e

Me

H

14a: R = H ( 6 1 7 ) b: R = Ph (373, 714) c : R = 3-pyridyl (552)

15: R = 3-pyridyl(531)

I,

6

7 a : R' = Me, RZ = R3 = H ( 2 5 1 ) b: R' = H, R2 = R3 = alkyl (8, 251, 262, 298) c : R' = R2 = R3 = F (173, 174, 417)

18 (153)

17 (1133) 9

8a: R' = R2 = R3 = M e (837) b: R' = Me, R2 = H, R3 = aryl (273) c : R' = PhS, R2 = H, R3 = Me (262) d : R' = R2 = R3 = F ( l 7 4 , 417)

NCjX& R'

I

R3

1 6 (421)

I 10

11

B. Molecular Geometry and Conformation. In the crystallic chromium complexes RCr(C0)3 some simple l,2-dihydropyridine molecules 12 as ligands R were studied (79,80,423)by X-ray diffraction. The determined geom-

CMe3

19 (898)

velope-like in 16 (421) having R' = R2= Me and R3 = Et. Except 14a, all other molecules possess nonequivalent bonds at the 4-carbon atom with axial groups Me, R, or COzK and equatorial H or Me. Different anti-syn conformations of functional groups in 14b, 14c, and 15 lead to the interesting origin of 4-carbon atom asymmetric


103

Table I. Bond Lengths in Some Dihydropyridines Determined by X-Ray Diffraction

12a ( 4 2 3 ) 13b (780) 14a (61 7 ) 14b ( 7 1 4 ) 16 (421 ) 23 ( 8 6 9 ) 110 ( 4 0 % ) 110 ( 4 0 % )

1 1 2 2 2 3 3a 3b a

R1 = H a n d R2 = Me.

149.4 151.4 134.5 135.8 135.3 154.0 154.4 152.3

147.7 148.7 136.4 138.4 138.8 148.0 145.2 145.8

R R

I R

/

0

20

136.0 134.2 135.4 135.3 146.0 145.9 147.5

135.4 137.6 138.6 138.8 125.0 128.2 126.9

R' = Me and RZ = H.

centers in the solid state. The typical interatomic distances shown in Table I demonstrate double bond locations as well as the conjugation of 3,5-functional groups with the entire unsaturated sytem 2 in Hantzsch dihydropyridines. Tetrameric structure 20 has been confirmed (661)by the diffraction method for a condensate from quaternary salts of nicotinamide. The found envelope-like ring conformations of 1,Cdihydropyridine fragments in 20 are remarkable and may be due to steric effects of the whole macrocyclic system. In this connection somewhat contradictory results (556,579,581) of semiempirical MO methods regarding the ring conformations of l-methyl1 , 4 d i h y d r o n i c o t i d e 21a (R = Me) are of interest. The EHT calculations (556)predict an envelope-like conformation to be the most stable form while the analogous CNDO/2 treatment (579)prefers a planar form of ring. In addition, the rarely found nonequivalence of both 4protons in the N M R spectra of certain 1,4-dihydropyridine derivatives 21 has been unambiguously proved to be due

R

145.5 150.4 153.5 151.2 134.0 131.1 131.1

135.5 151.7 152.4 151.2 150.0 149.7 148.2

R

21a: R = Me

b: R = 4-MeOC6H,CH,C*H (t-Bu) C : R = nucleotide residue d : R = monosaccharide group

either to special orientations of a chiral substituent R in 21b (1138)and in NADH 21c (828)or to 3,bbridge substituents in 22 (924) blocking one face of the ring. Hence, the ring conformation of this biologically important dihydropyridines seems to be still an open question. On the other hand, the syn-conformation of 3-carboxamide group shown in formula 21 appears to be clear according to all 579,581). performed MO calculations (198,408,409, Further limited information is available regarding the conformation of 1,Cdihydro ring 2 in solution. A broadening of Cmethyl signals in low-temperature proton NMR spectra of compounds 16 has been incorporated (987) to be due to equilibria between boat-like and planar conformers. On the other hand, the existence of two conformers was unambiguously proved (989)by the identification of a coalescence behavior of N-methyl signals in 13C NMR spectra of the spirocyclic derivative 19. The corresponding conformational barriers were calculated (898,987) on the basis of experimental data.

The geometry of a 2,3-dihydro ring 3 was recognized (402u,869)in the X-ray diffraction study of the complex derivative 23 indicating a full double bond location and a nonplanarity of a ring arrangement (see Table I).

I

23a: X = C0,Et b: X = CH,OCOMe

CH2Ph

22

C. Electronic Structure. Modern sophisticated MO methods have been applied in the calculations of different dihydropyridines in the last decade. An extensive MIND 0 / 3 study (109)reports atomic charges for all unsubstituted dihydropyridines, their ionized forms and some 1-methyl derivatives. Their comparison with the results of recent ab initio STO-3G and 4-31G calculations (114) suggests, however, certain unimportant discrepancies among atomic charges at least for some positions (see Table 11). Different semiempirical MO methods at the all-valence electrons level have been used to calculate electron distribution in the series of dihydropyridine derivatives. MIND0/3 calculations were performed (864)on biologically interesting aldoximes 24 and 25. All NDO (408,579, 5811, PCILO (1981,and EHT (580)calculations on the trivial NADH model 21 (R = Me) appear to be in agreement with a full conservation of double bond character in the dihydropyridine ring and the 3-carboxamide group. All valence electron distribution of a number of 3,5-diformyl-1,4-dihydropyridines26 (1174)by the CNDO/S C=CH I

1

I

Me

Me

24

25

26

method lead to analogous conclusions. r-Electron distributions of different 3,5-dicyano dihydropyridinesin their ground and excited states obtained by the HMO and PPP treatments are also available (588,739,1028,1030). 111. Syntheses A. Preparations from Pyridine Derivatives. (1) Reactions with Nucleophiles. (a) Reductions with

194


Table 11. Comparison of Some Atomic Charges Calculated (109, 114)for 1,2- and 1,4-DihydropyridineMolecules 1,2-dihydropyridine 1,4-dihydropyridine positiona MIND0/3 4-31G MIND0/3 4-31G -0.974 -0.923 -0.067 N(1) -0.117 +0.058 +0.191 -0.003 C(2) +0.258 -0.092 -0.246 -0.225 C(3) -0.116 -0.329 -0.139 -0.094 C(4) t0.091 -0.089 -0.245 -0.320 -0.168 C(5) t0.056 +0.191 C(6) +0.167 +0.220 a For numbering of the rings, see formulas 1 and 2.

OH 'ErzH

CI

H

CI

I

30

R

31a: R = C0,Me U

b: R = C0,Ph c: R = Me d: R = CHPh, e : R = CPh, f : R = CH=CH, g : R = CH=CHPh h: R = saccharide residue

"

I

R

Table 111. Products Ratio Reaction 1; See Ref 11 6 substituent %of %of x reagent/medium 28 29 CO,H NaCNBHJAcOH 77

a

C0,Me

NaBH,/MeOH

37

CO ,Et

NaBH,/C,H,N NaBHJMeCN

50 13 63

NaCNBHJAcOH B,H,/THF"

32a: R = C0,Me b: R = S0,Ph c: R = S0,Me d: R = CPh, e : R = saccharide residue

63 74 50 87 37 77 21

NaCNBHJAcOH B,H,/THFa 79 The reaction mechanism is not clear.

R'

33

Complex Hydrides. The preparation of dihydropyridine derivatives by the complex hydride reductions of pyridines and pyridinium salts (251) is of practical importance. The reduction procedures for 3,5-disubstituted pyridines 27 were enriched (116)by the introduction of new agents and reaction media as illustrated in eq 1 and Table 111. 3-

R' = OMe, OCHMe,, CN, CO,Me, CO,CH,Ph, CH( OCH,),, CCH,(OCH,), R2 = Me, CHCCI,, OMe, OCH,Ph R'

I HC

II

27

ii

ti

28

29

Cyanopyridine reacts with NaBH, in pyridine to give 3cyano-1,4-dihydropyridine in 52% yield (514,515). Similarly, Hantzsch lP-dihydropyridine 14a (116,515)and a number of 3,5-dicyano-1,4-dihydropyridines(589, 1028, 1030) were obtained. On saturation of a reaction mixture of pentachloropyridine with LiAlH, in ether with carbon dioxide 10% of 3,4-dihydropyridine 30 was isolated (101). The second approach to dihydropyridines consists of the complex hydride reduction of different pyridinium salts. In certain cases pyridine is reduced in the presence of acylating agents to give the corresponding l-acyldihydropyridines via the more or less stable 1-acylpyridinium cations. Thus, at -10 "C, it reacts with NaBH, in T H F and in the presence of methyl chloroformate to give the mixture of 31a and 32a, while at -70 OC in methanol only 1,4-isomer 32a was isolated (284). Similarly, 1-(alkylsulfony1)pyridinium salts were reduced to 31b, 32b, and 32c, respectively (533). In the 4-substituted series the formation of only 1,2-dihydro isomers 33 was observed (752,905). Some didehydro-aza[l7]annulenesof the type 34 (R2= H) and their acyclic precursors were prepared (85-87) after acylation of the starting pyridine derivatives by the LiA1H4 reduction. A number of 1-alkyl or 1-arylpyridinium salts were reduced by complex hydrides. Thus, during the reaction of 1-methylpyridinium iodide with LiAlH, in ether very unstable l-methyl-1,2-dihydropyridine31c is formed (1171). The 1,2-dihydropyridines 31d, 31f, and 31g were prepared analogously by the reaction with NaBH, (657,

34

658). On the other hand, 1-tritylpyridinium tetrafluoroborate with NaBH, gave (644)a mixture of 31e (73%) and the corresponding 1,Cisomer 32d (23%). The formation of the latter may be due to the steric effect of 1-trityl group blocking partly the reaction at position 2. In apparent agreement with this suggestion some disaccharide 1,4-dihydro derivatives 32e were reported (876) to be formed exclusively by the reduction of the corresponding pyridinium salts possessing very voluminous 1-substituents; however, the formation of both isomers 31h and 32e was found (250) in a monosaccharide series. 1,2- and 1,Cdisubstituted pyridinium salts reduced to the corresponding 1,6- or 1,2-dihydropyridines, respectively. Thus, methiodides of 2-pyridine-aldehyde derivatives react with NaBH, in a simple way or on using an addition-elimination mechanism under hydrogen cyanide participation ( 111,112,385,386)to give biologically active hydrochloride of 25 or the analogous diethyl acetal. 1Benzyl-Cmethy1-1,2-dihydropyridine was prepared (16) by the reduction of the corresponding pyridinium salt with NaBH, in NaOH. If 2- or 4-substituents are strongly electron-withdrawing the originally arisen 1,6- or 1,2-dihydro produds 35 (621) and 36 (39,331,622,1192)undergo more or less rapidly Diels-Alder-type dimerizations. The reduction of l,&disubstituted pyridinium salts 37 may lead to more complicated mixtures of dihydro isomers according to eq 2. Table IV shows that the composition

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 195

H QCN

I

I

R

Me

36: X = CN, benzoxazol-2-yl, benz thiazol-2-yl R = alkyl

35

qX -a i I

I

R

R

37

u

Me,

u

''W I

I

R

R

39

38

,Me

(2)

t

f

lithio-2-alkyl(aryl)-1,2-dihydropyridines.4,CDimethyloxazolin-2-yl derivative 44 reacts with different lithium reagents RLi (R = Me, n-Bu, and Ph) to give the corresponding 4-substituted 1,Cdihydropyridines (307) after hydrolysis, while the use of an analogous tert-butyl organometallic reagent leads to a mixture of the appropriate 1,4-dihydro compound together with its 6-substituted 1,Bdihydro isomer (704). 2,6-Unsubstituted Hantzsch dihydropyridines 45a,b were prepared (629, 632) by the

44

45a: R' = RZ = ( 6 3 2 ) b: R' = Et, RZ = Ph (629)

40

of products depends upon the reaction conditions as well as on the structure of 1,3-substituents. The l,&dialkylated products 38 and 40 (R = Me, X = Et) exhibit low stabilities and may be advantageously isolated via their tricarbonyl-chromium complexes (79, 594,921) from which they are eliminated by the action of pyridine. The isolation of all isomers 38,39, and 40 has been usually performed by different chromatographic techniques. 2,4,6-Triphenyl-l,2-dihydropyridines 4la,b,c were prepared by the NaBH4 reduction of the corresponding 1,2,4,6-tetrasubstituted pyridinium salts in DMF (975) or in a MeCN-MeOH mixture (145,492)while the analogous perchlorate 42 gave only the 1,4-dihydro product (489), probably due to the steric effect of the 1-substituent. On the other hand, the similar 1,Creductions (488, 492) of 1-substituted 2,3,5,6-tetraphenylpyridiniumtetrafluoroborates 43 are easily understandable because of the,lack of a 4-substituent.

addition of reagents R2MgXto methyl or ethyl 3,5-pyridine dicarboxylates, respectively. Similarly, didehydro-aza[17]annulenes 34 were isolated (84) after the reaction of R2Li with appropriate pyridines and after 1-methylation of crude 1,Cadducts with methyl iodide. 2-Alkyl-2-lithio-l,3-dithianes with pyridine gave 1,4adducts which were acylated with acetyl chloride to dihydropyridines 46 (1074). Similar transformations using reagents RCuLi (R = alkyl or aryl) and methyl chloroformate afforded (871)mixtures of isomers 47b (2 to 11%) and 48 (89 to 98%) while 4-alkylated pyridines gave exclusively 2-substituted 1,2-dihydro isomers (285, 645). Thus, 1,2-dihydropyridines 49 were obtained in 55-71 %

I cox

46

Ph

I PhO

P

47a: X = Me b: X = OMe c : X = OEt

Hh

I

I

COeMe

48

R'

R

41a: R = Me, NMe, ( 9 7 5 ) b: R = Ph, 2-pyridyl ( 1 4 5 ) c : R = Ph(CH,), ,, 4-CIC6H, (CH,),, 4 H , , (921 1

I

b

2H

.

I

cox 49a: R' = X = Me, R2 = Ph b: R' =Me, R2 = Ph, X = OEt C : R' R2 f-Bu, X = OEt

I R

BF4-

43 42

Although the NaBH4 reduction of pyridinium salts is generally believed to be nucleophilic (1193, a surprising suggestion assuming an alternative radical mechanism has been published (1122). (b) Addition of Organometallic Compounds. New examples of the known origin (251, 643) of dihydropyridines by the reaction of organometallics with pyridines, pyridinium salts, or pyridine-N-oxides have been described. The reactions of pyridine (289)and its alkyl derivatives (7, 306) with alkyl- or aryllithium lead to unstable 1-

yields by the addition of phenylmagnesium bromide or diphenylcadmium to 4-methylpyridine (645)and tert-butylmagnesium bromide to 4-tert-butylpyridine (285)after acylations of 1,Zadducts with appropriate acyl chlorides. 3-Benzoylpyridinewas analogously transformed (645)into 1,3-dibenzoyl-1,4-and 1,6-dihydropyridines according to eq 3. -C@Ph

Ph

H

,C@Ph

I

C@Ph

19%

I

COPh

61%

Remarkable spirocyclic 1,Qdihydropyridines 50 was prepared (285) after intramolecular addition of organo-

196


Table IV. Composition of Reaction Roducts in Eq 2 R

reagent /solvent

%of38

%of39

%of 40

ref

NaBH,/NaOH + H,O NaBH,/NaOH + MeOH NaBH,/EtOH NaBH,/DMF NaBH,/H,O + CHCl, NaBH,/H,O + MeOH NaBH,/MeOH NaBH,/MeOH NaBH,/H,O NaBH,/NaOH + H,O NaBH,/H,O + MeOH Bu,NBH,/MeCN NaBH,/H,O + C,H, NaBH,/H,O + C,H, NaBH,/Na,CO, + H,O

62 86 35

11

11

90

5

5

171 593 515 9 75 9 75

60 33

40 67 29 50 33 33' 33' 49 90 75b

X

Me Me Me

Me Et CN

Me Ph

CONH, CONH,

CH,Ph

CONH,

Me Me -CH,OCH,-

CON-i-Pr, CONEt, CONH, b

a Isolated 1 min after the starting of reaction. of NAD, see ref 320.

Mn

(4) CHzM

M = Li, MgCl or Hg

50

R = Ac, COPh, CO,Me, CO,Et, SiMe,

Quaternary pyridinium salts react with organolithium reagents with formation of 1-substituted dihydropyridines whose structures depend on substitution patterns in both reactants. Thus, 1-methylpyridinium iodide 51 as well as 1-benzylpyridinium chloride with phenyllithium gave 1methyl(benzyl)-2-phenyl-l,2-dihydropyridinesin 41% and 63% yields (95) while the reaction of 51 with n-butyllithium afforded a mixture of 2-n-butyl-1,2- and 4-n-butyl-1,4-dihydro products (95). On the other hand, similar reactions of more voluminous lithium carboranes (1188) with 51 proceed exclusively at the 4-position to give 1,4dihydropyridyl carboranes 52; see eq 5 . Phenyllithium

h o Hio

51

33 67' 67' 10

t LlCl ( 5 )

CR

M e N 2 H C-

\-I:

16 16 16 16 79 7 79 7 9 75 9 75 34 7

way 1,2-dihydropyridines 47a,c (R = Ph) and 49a,b were prepared (645)in yields 5% to 83% being strongly affected by the used reagents in the order PhMgBr > PhzCd > PhLi. l-Ethoxycarbonyl-2,4-dimethylpyridinium chloride with PhMgBr or PhzCd gave (645) under the same conditions both 1,2- and 1,Gdihydroisomers in the ratios 22:78 or 17:83, respectively. The reaction of 1,3-dibenzoylpyridinium chloride with PhMgBr afforded (645) a similar reaction mixture to that shown in eq 3. Little is still known of the reactions of organometallic compounds with pyridinium cations possessing N-O, N-N, or N-P bonds. 1,2-Adductsof type 53 were believed (100, 1071) to be intermediates in the reaction of polyhalogenopyridine-N-oxideswith Grignard reagents RMgX. On the other hand, the existence of 2,5-dihydropyridines 54 arising from pyridine-N-oxide and PhMgX (967,968) has been proved spectroscopically (967). 1,4-Dihydropyridines 55 (R1 = alkyl and R2 = Me) being evidently CI

R

OMgX

0

54: R = H or Me

53

R = Me or Ph

-

71 50 33

3 02

Reduction of both rings in a bis-quaternary salt; for analogous reduction

metallic pyridines followed by 1-acylation or by 1-silylation of primary intermediates; see eq 4.

re

100

:I/

Bio Hl0

52

with 1,2-dimethylpyridinium iodide yields 80% of 1,2dimethyl-1,6-dihydropyridinewhile in the case of 1,2,6trimethylated salt a mixture of 1,2- and 1,4-dihydro products is formed (95). Alkyl and aryl Grignard reagents can be added to 1,4dialkylpyridinium salta (1100) to give 1,2,4-trisubstituted 1,2-dihydropyridines. The reaction of further 1,4-dialkylpyridinium salts (323,324,600,602,603, 708) as well as of 1,3,4-trialkylpyridiniumsalts (29,37,46-50,325,326, 484,513,519,524,601,845,902,1120) with organometallic compounds have been frequently used as starting steps in the syntheses of different benzomorphane derivatives. The reactions of organometallic compounds with free or in situ prepared 1-acylpyridinium salts seem to be an alternative approach to 1-acyldihydropyridines. In this

0 55

formed from the corresponding pyridinium cation and Grignard reagents undergo a spontaneous decomposition to 4-alkylpyridine and 2,6-dimethyl-4-pyridone(486,487). Certain information concerning the preparation of 1,2dihydropyridine-1-phosphonates from pyridine, organometallics, and dialkylphosphoric chloride is to be found in the patent literature (910, 911). (c) Dithionite Reduction. The transformation of quaternary pyridinium salts with sodium dithionite to the corresponding 1,4dihydropyridines is the well-known (251) preparative procedure. The first described (1043) reduction of a free pyridine base giving tricyclic 1,Cdihydro derivative 56 might be of interest in this connection.

Me

Me Me

0

56


Table V. Composition of Sodium Dithionite Reduction Products in Eq 2 R

X

CH,CONH, CH,Ph Me

COMe CO ,Me CH,CO,Me CN CN CONH, CONH, CONH, CONH, CONH, CONEt, CONEt,

Me CH,Ph Me CH,Ph Ph CH,OMe CH,CONH, Me CH,Ph

ref

%of 39 %of 40

-

64 340 7

100 71 75

99.9 65

0.1

-

70

773 24 426

975 225, 631

773

(862, 860) spectrophotometrically and charge-transfer complex between reactants as important intermediate has been considered (862). On the other hand, the application (106) of the "stopped flow" technique for the reductions cation and for NAD+ of 1-methyl-3-carbamoylpyridinium made it possible to detect anions of type 59 as key intermediates and to formulate their decomposition according to eq 7.

797 16 773

773

66 90

10

975

95

5

975

Isolated product with X = C0,H.

1-Monosubstituted and 1,3-disubstituted pyridinium salts 37 being studied as NAD models usually react with sodium dithionite to give 1,Cdihydropyridines 32e (250) or 39 (16,24,54,106,148,225,257,426,631,633,659, 745, 773, 797,801,827,965,975),respectively, and only in rare cases additional small amounts of 1,gdihydro isomers 40 (797, 975). Table V shows some illustrative yields of reaction products obtained by different investigators. Polymeric bound 1,4-dihydronicotinamides(260, 366, 848,935,1014) as well as further 1,Cdihydro derivatives (90,96, 405a, 634-636, 799, 806, 924, 943, 1132) were prepared in the same way. The reduction shown in eq 6 is believed (943) to proceed by an intramolecular mechanism.

I

R

R

R = 2,6-dichlorobenzyl

3,5-Diamides 57 (832,223),1,Cdihydropyridine crowns of type 58 (221a, 509, 11301, and didehydro-aza[l7]-

R

R

59

(d) Addition of Cyanide Ion. The cyanide anion having a lower nucleophility does not react with free pyridines. However, its reactions with quaternary pyridinium salts take place easily and predominantly at the 4-position giving the corresponding 4-cyano-1,4-dihydropyridines. Thus,compounds 60a are formed in 24 to 92% yields (919,920). The origin of 1-aryl derivatives 60b was studied (500) by means of the chemical kinetics, and the reversibility of the process was demonstrated. The rate constants correlate well with u parameters of substituents X and the cyanide addition seems to be inhibited by the presence of free hydrogen cyanide. l,4-Dihydro derivative 55 (R = CN) and its homologues can be isolated (618) after the cyanide addition to appropriate pyridinium salts. The lack of both methyl groups in 1-substituent causes l,4-dihydro adducts to be unstable and they undergo a spontaneous decomposition to cyanopyridines (618). 1,3-Disubstituted pyridinium salts 61 (NAD+ models) CN

H

M

CN

Y

Y N 2

I

R

60a: R = alkyl b: R = mlpa-

X-C, H,CH ,

I

R'

57a: R' = CH,Ph. RZ = R3 = n-Pr b: R' = 2,6k12'C6H,CH,; R2, R3 = (CH,), C : R' = 2,6-C12C6H,CH,; R2, R3 = (CH,),CO(CH,),

I

I

R

61a: R = CH,Ph, X = CN (631) b : R = alkyl, X = CONH, (73, 74, 1007, 1 0 1 7 ) c : R = Z-(adenin-g-yl)-ethyl,

Me

X = CONH, (816, 815)

58

d : R = -CH,-, C,H,-AH-CH,-, X = CONH, (1016)

annulene 34 having R' = Me and R2 = H (85)were isolated after the dithionite reductions of the corresponding pyridinium salts. In some cases hydrogen sulfite (54) as well as compound +NH2=C(S02-)NH2 (797) were used as reducing agents instead of sodium dithionite. Some novel aspects regarding the mechanism of dithionite reductions have been discussed. The reduction of 1-benzyl-3-carbamoylpyridinium cation has been studied

react with alkali cyanide in the same way (73, 74,631,815, 816,1007,1016,1017)as 60. In the case of 61a where R = (CH,)fle (n = 7,9,11,13,15) an enhancement of reaction rate caused by micellar catalysis with salts Me,RN+Br- as well as an inhibition by pyridinium salts anions in order Br- > C1- > NO2- > F- were observed (73, 74). The formation of 1,Cdihydropyridines 61b-d appears to be in agreement with the electron energy of intra-reacting system 62 calculated (1029) by EHT method. The similar cyanide ion 1,4-addition to the structurally more complex salts 63a,c (231,232)may be expected but in the case of 63b an additional formation of the corre-

198


I

’ N

Me Me

62

‘CG~H

63a: R = X = H

b: R = H,X = 0 c : R = Ac, X = 0

sponding 2-cyano-1,2-dihydroadduct was observed (231). The exclusive formation of l-(benzoxazol-2-yl)-2-cyano1,2-dihydropyridines is also reported in the patent literature (719). The latter cases of 1,Zaddition might account for a kinetic control of reaction mechanism (251) under conditions used in ref 719 and 806. An interesting course of discussed chemical transformations was found (443,359) in the case of cyanide ion addition to 1,3,5-trimethylpyridiniumchloride. As shown in eq 8 an excess of cyanide anion causes the 4-deprotonMewMe

CN-

A

M

H e

e

I I

M

e

-HCN

Me

,

70

has been elucidated (713) by 13C NMR for a product from the same starting salt after treatment with sodium hydroxide in water. It may be noted that other artificial products were isolated somewhat later (728). Another more complex picture represents the reaction of hydroxide ion with 1-methyl-3-cyanopyridiniumiodide 71 (724, 728). As shown in eq 9 three simple dihydro derivatives, two pyridones, and two aldehydes can be isolated (728).

CN-

I

I

Me

Knowledge of the hydroxide and alkoxide ions additions to 1,3-disubstituted pyridinium salts 37 (NAD+ models) seems to be somewhat contradictory although some experimental arguments favoring the hydroxide ion attack at position 6 are reported (340). All attempts to isolate hydroxy adducts like 65 and 68a have failed because of their secondary transformations in alkali media. Thus, 1-benzyl-3-carbamoylpyridiniumchloride with alkali hydroxide or sulfide gave dimeric products the structures of which were believed (193,327,328) to be of a 1,Zdihydro type 69a,b. On the other hand, 1,kdihydro structure 70

I

I

I

IJe

Me

64

ation of primary formed 4-cyano-1,4-dihydropyridine derivative followed by its air oxidation to relatively stable radical 64 which was proved (359) by EPR. (e) Reaction with Water, Hydroxides, Alkoxides, and Their Thia Analogues. A further example of the addition of low nucleophilic water molecules to pyridinium salts was described (1092). Extremely electrophilic 3,5dinitro-1-methylpyridiniumfluorosulfate gave a relatively stable 2-hydroxy-1,Bdihydro derivative 65. An analogous pseudobase was obtained (1059) from 4-(2-indolyl)-lmethylpyridinium iodide. More nucleophilic hydroxide and alkoxide ions have been frequently added to certain electrophilic pyridines and to different pyridinium salts. Thus, the Meisenheimer complexes 66 and 67 (R = H or Me) were prepared (98, R

Me

bAe

hl e

71

Me

Me

Me

The last two products shown in reaction scheme 9 are apparently ring-opening, ring-reclosure,and isomerization artifacts, while the mentioned dihydro and oxo compounds are probably formed by a defined disproportional process. In favor of this assumption, an analogous transformation of bis-quaternary cation 72 yields (347) 91% oxodihydro derivative 73 according to eq 10.

[qCGNH2] ZOH-

i r

CH2

-0 -C H2

72 I

Me

66

67

65

99) by the action of sodium methoxide on 3,5-dinitro-

pyridine and its 4-methoxy derivative. The corresponding kinetic and thermodynamic investigations (178,1094) have shown that 66 is energetically preferred with respect to 67. A number of kinetic and substituent effect investigations on the hydroxide (503), methoxide (92,499), and ethoxide (499,1106) ion additions to 1-arylpyridinium salts leading to 1,2-dihydro adducts 68a-c have been described in the literature.

I

iH,-

2

I -c H2

73

As above mentioned, behavior similar to that shown in eq 9 exhibits 1-benzyl-3-cyanopyridiniumchloride (728). On the other hand, in the presence of ethanol the reaction

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 1QQ

of this salt with sodium hydroxide proceeds quite differently (224,713,792)leading to a product with a surprisingly assigned (792)trimeric structure in contrast to the tetrameric structure 20 (R = CH2Ph) proved by X-ray (661)for a reaction product from the starting salt after its treatment with alcoholate in a nonaqueous medium (341, 346). The formation of 20 seems, however, to be correctly generalized (1162)for a sufficient number of reactions of different 1-substituted 3-carbamoylpyridinium salts (NAD+ models) with ethoxylate ion (341,346,1162) and with other nucleophiles (346,1162).The course from the salts to tetramers 20 where R are different alkyl or aryl groups has been conclusively explained (1162)via the primary formed betaine 75.

a:I

XCeH&HO

&H7

n-C3H7

R = CO, or SO,, X = H, 343, 4-Me, 4-Me0, and 4-NMe,

The addition of alkyl- or arylthiolate anions to quaternary pyridinium salts occurs mainly at the 2- or 4-position affording dihydropyridines 78 or 79 (1197)and 80 (486). H

H

P H -L'A .r'

74: R = Me,

I

I

I -.

R

75

i-Pr or t-Bu,

Ar = Ph, 4-NO,C6H,, 4-ClC6H, or 2,6-C1,C6H,

76a-c

n

78: X = H, I, CN, 79: X = COMe, CO,Me, CONH, C0,Me or CONH,

3-Cyanopyridinium salts possessing benzyl and analogous residue were found (345)to react with sodium alkoxylates RONa to primary C-betaines which after their addition to the starting ions 37 at position 6 followed by the RO- addition and a five-membered ring closure gave 1,6-dihydropyridine derivatives 74. In contrast to the mentioned cases 68b,c (499,1106), some 1,3-disubstituted and 1,3,5-trisubstituted pyridinium salts (204)react with methoxide ions at both 2- and 4positions to give mixtures of isomers 76a,b and 77a,b ac-

R

SR

R

0

80

This might be in accordance with the fact that thiolate anions are softer nucleophiles than ita oxa analogues. In this connection a reinvestigation of reported structure 69b (327,328)would be desirable. ( f ) Reaction with Ammonia and Amines. Ammonia or some amines can be added to variable pyridinium cations. Thus, 2-amino-1,Zdihydropyridines81a, analogous 3-substituted compounds 81b-d or 6-amino-1,6-dihydropyridines 82a-d are exclusively formed (1196)in liquid ammonia at -40 "C from the corresponding pyridinium salts. Under the same conditions quaternary salt 71 gave (1196)a mixture of 1,2- and 1,6-dihydro isomers 81e and 82e in which the latter prevailed. On the other hand, the reactions with piperidine led (725)to only 1,6dihydro adducts 83. Substituent effects in the additions

77a,b

R = Me or CH,Ph, X = CN, Y = H b: R = Me or CH,PH, X = Y = c1 c : R = CH=CHCO,Me, X = Y = Me a:

cording to NMR. The ratio 76:77 is affected by an isomerization of 76 to 77 and therefore depends on reaction time (204).The route to similar 2-methoxy-1,2-dihydropyridine 76c arising after the action of dimethyl acetylenedicarboxylate on 3,5-dimethylpyridine in methanol (20) appears, however, to be of a more complex character. It seems, in the excess of alkoholate ions, that primary 2-alkoxy-l,2-dihydropyidine derivatives may undergo a further reduction to a dealkoxylated l,4-dihydropyridine derivative (499,791,1023,1024). For example, the presence of l-phenyl-l,Cdihydropyridinewas detected in addition to 6812 having X = H (499)in reaction mixtures. This type of reactions accompanying the attack of alkoxylate ion at pyridinium ring is of special interest as it resembles the action of alcohol dehydrogenases. As a matter of fact it has been found (1023,1024)that some lithium benzyl alcoholates can be oxidized by certain 1,3-disubstituted pyridinium salts according to eq 11. Contrary to the interpretation (791)of experiments with 0-deuterated alcohols, the authors (1023)have claimed that the addition of alcoholate anions at the 2- or 6-position of the pyridinium ring is not the first step of the transformations shown by eq 11.

R

R

81a: X = H, R = Me, CH,Ph,

OMe b: X = C1, R = Me c : X = I, R = Me, CH,Ph d: X = CONH, R = OMe e : X = CN, R = Me, CH,Ph, CH,C6H,-4-NO,

82a: X = CF,, R = Me b: X = COMe, R = CH,Ph c: X=CO,Me,R=Me d: X = CONH,, R = Me,

CH,Ph, CH,C6H,-4-NO e : X = CN, R = Me, CH,% CH,C6H,-4-N0,

,

"

P

N

flh

83: X = COMe, CONH, or CN and R = CH,Ph or Me

of aniline (498,504), methylaniline (498),and piperidine (91)to 1-arylpyridinium salts were studied kinetically. After a much more prolonged reaction time ammonia and some aliphatic amines were reported (783)to reduce 1benzyl-3-carbamoylpyidiniumperchlorate, but the reaction mechanism has not yet been clarified.

200


In protic solvents ammonia as well as amines may catalyze additions of other nucleophiles to pyridinium salts. For example, more reactive hydroxide ions are generated in water according to the reaction H20

pR

Me a F L C C O z M e

I

"M'

+ RBN * OH- + RSNH+

In agreement with this assumption the reactions of salts of type 71 with aqueous ammonia, methylamine, ethylamine, or diethylamine lead to the same and/or similar artificial products (725, 727) as those shown in eq 9 with alkali hydroxide. Analogously, in the presence of chloroform the addition of trichloromethyl anion to 1,3-disubstituted pyridinium salts can be induced (670). The additions of further anions N02CH2-(512,1197) and EtS(1197) proceed easily in liquid ammonia (1197) or in the presence of triethylamine (512). (g) Reaction with C-Anions and Other C-Species. This type of dihydropyridine formations usually consists in a predissociation of an appropriate C-acid to the corresponding carbanion being added to a given pyridinium cation in the next step. Dihydropyridines prepared by this method are often important synthetic intermediates and a remarkable number of them has been described in the past decade in addition to some cases reported earlier (251). Sometimes the dihydropyridine products are unstable (475) or undergo ring-opening reactions (723). Free pyridines are able to undergo the mentioned additions exclusively after their primary conversion.into the corresponding pyridinium cations. In this connection the acetylenic ketones or esters of type HC-CCOX are of special interest (2&22) because they are able to form (20) with pyridine bases certain N-betaines convertible by C-protonation with C-acids into quaternary cations 84. The latter then react with simultaneously arising carbanions -C==CCOX (20)or Y-(21,22)to give dihydropyridines 85 and 86. R

H

I

COPh

87a: R = Ph, Ar = 1-azulenyl b: R = Ph, Ar = 3-indolyl c : R = Me, Ar = 4-Me,NC6H,

Copt.

88

C0Ar

89: Ar = 4-pyridyl

react with pyridine in the presence of acetyl chloride (867) to give mixtures of Z and E isomers 90 after protonation of primary adducts as shown in eq 12. A substitution in

0

CR'=i-BR13

H

@

[R:BCECR'l-

I

-

I

COMe

COMe H

CR'==CR'BR'~

COMe

CRLCHR'

g j H

I

COMe

H

I CH=CHCO'Me

I X COCH=CH 84: R = H o r Me X = Me or OMe

85

(12)

90

R' = n-C,H,, w cyclo-C,H,, R2 = n-Bu, n-C6H1,,Ph

parent pyridine molecules may cause the occurrence of both 1,2- and 1,Caddition pathways. Thus, the reaction of two molecules of 2-methylpyridine with ethyl chloroformate was found (616) to lead to a mixture of isomers 91 and 92 in contrast to an earlier report (38). Miscellaneous nucleophilic C-species have been added I to individual quaternary pyridinium salts giving the corCH =CHCOX responding dihydropyridines. Thus, adducts 93,97d, and 86: X = Me or OMe 94a were obtained in agreement with HMO calculations Y = CH,NO,, CH(CN),MeCHNO,, (655) after the reaction of alkylated salts with haloforms CH( CN)CO,Me and CMe(COMe), (244, 342, 655) or with nitromethane (512, 1197) in the Different C-nucleophiles can be added to l-benzoylpresence of strong bases. Similarly, very electrophilic pyridinium cation, arising in situ from pyridine and ben1-nitro- and 1-(2,4-dinitrophenyl)pyridiniumsalts with zoyl chloride, in alkali medium. Thus, 4-substituted 1,4nitroalkanes (822,823)and with malonic acid derivatives dihydropyridine derivatives 87a,b and 88 were isolated (1088) gave readily analogous 1,Cadducts 94b and 95 exafter the reaction with azulene (991,992),indole (268)and cept in the case of 96. Further 1,6dihydro products of 2-methylpyrrolo[3,2-4]quinoline( 1060). Other chlorides type 55 were prepared (4'86) by the addition of nitroalkane as R2POCl (993),PhS02Cl (994),and PhCCl=NPh (995) and ketone anions to the corresponding salt. were successively used in the reaction with indole. On the Analogous reactions of 1-arylpyridinium salts with other hand, l-methyl-6,7-dimethoxy-3,4-dihydroiso- acetone, cyclohexanone (501), ethyl acetoacetate, ethyl quinoline was found (742) to react with two molecules of cyanoacetate, and dimethyl malonate (502)were studied isonicotinoyl chloride to give spirocyclic derivative 89. kinetically including the corresponding Hammett plots for Similar reactions with 5-phenyl-oxazolidine-2,4dione were substituent effects. The formation of 1-benzyl-Ccycloalso described (982). pentadienylidene- 1,4-dihydropyridine after the reaction Remarkable ambient C-nucleophiles used in the menof 1-benzylpyridiniwnchloride with cyclopentadiene in the tioned reaction appear to be trialkylalkinyl boranes which presence of sodium ethanolate (146)may be explained by

6

ti


(797)that 1,3-disubstituted cation 37 (X = CONHz and J & c H z R Me

, I

R = CH,Ph) reacts either with a formic acid-triethylamine mixture or with alkali formate in the presence of a “crown” ether to give isomeric 1,4- and 1,6-dihydro products 39 and

H($H2R

H

QEt

I

I

I

I

2,6-&& ‘H$H2

CQEt

91

93: R’ = 2,&Cl,C,H,CH,

92

or -CH,CH(OCH,), R2 to R6 = H or Me

R = 2-pyridyl

94a: R’ = Me or CH,Ph R’ = R3 = H b: R’ = NO,, R’ = R3 =

95: X = OEt or NH,

mio2 axRpJx NQ

H or Me

iHCONH2

02N

-Ht

CN

96

R

a spontaneous dehydrogenation of a primary 1,4-adduct. A remarkable number of 1,3disubstituted pyridinium salts including some NAD’ models have undergone the reactions with nucleophilic C-species. As shown in Table VI the reaction of cations 37 (R = Me or 2,6-Cl2C&,CH,) with chloroform in the presence of strong bases afforded mainly (344,670)1,2-dihydropyridines 97a (X = CONHJ H

40 in the ratio 41. On the other hand, the reaction of the same substrate 37 with acetone in alkali medium has not been clarified with certainty although a reaction route considering a participation of two molecules of ketone has been suggested (1121)on the basis of kinetic measurements. Cyclic nitrones have been found (1175)to react with electrophilic 1,3,5-trisubstitutedpyridinium salts to afford 1,d-dihydro derivatives of type 100. Analogous additions have been described (205)for carbanions derived from nitromethane and nitroethane. The readily proceeding intramolecular carbanion additions to pyridinium salts (251)have been extended by novel examples. The remarkable formations of bicyclic 1,2-dihydropyridines 101 (291)and 102 (877,929) are demonstrated by eq 13 and 14.

I

I

PhCOdH2

PhCOtH-

I

CH

CR’R2R3

XHCN

PhCO

101

C ‘Hf

ax

c

l

a

x

R = H or Me and X = H or CN R4

CI

R4

I

I

R

R

97a: R’ = R’ = R3 =

98

b:R’=R*=H R3 = NO, c : R’ = H, RZ = M e R3 = N O , d: R = alkyl R1 = Rz = R3 = Br br I X = HI I, Me, CF,, CN, COMe, C0,Me

R4

R6 R5%

?

CI

CH2CHCN

RZ

(14)

*‘COR’

102 102a: X = CH, R’ = Me or Ph, R’ = Ph, R3 to R6 = H or Me (877) b: X = N, R’ = OMe, R2 = CO,Me, R3 to R6 = H or Me (929)

99

R

100: R = 2,6-Cl,CkH,CH,

as well as bicyclic products of dichlorocarbene additions while 1-substituted pyridinium 98 and 99 (342,343,670) salta gave (355) no dihydropyridine products. On the other hand, merely 1,6dihydro adducts 97b,c (X= I, Me, CFs, COMe, C02Me, CONH2,and CN) being in the case of X = CN mixturea of stereoisomers were identified (205,1197) after the reactions of 37 with nitromethane in liquid ammonia or in triethylamine. It is well known that formate ion may exhibit reducing properties in the reaction with an electrophilic substrate: S + HC02- HS + COP In fact, it has really been found

-

1,2,6-Trisubstituted l,2-dihydropyridine 103 was prepared (948)by the reaction of 2,6-dimethyl-l-methoxycarbonyl-iminopyridiniumylide with dimethyl acetylenedicarboxylate, similarly, as tricyclic 1,6-dihydro derivatives 104 from the corresponding tricyanomethylpyridinium ylides and 1,2,3-triphenylcyclopropene(668,669). On the other hand, tetracyclic 1,Sdihydropyridine 105 was obtained (222)in 90% yield after the action of sodium bicarbonate on the corresponding 1-substituted %cyanopyridinium salt. (h) Reactions with Other Nucleophiles. Under favorable conditions strongly electrophilic pyridines or pyridinium salta undergo the reactions with weak nucleophiles although a simple heterolytic mechanism might be

202


Analogous bis-lithio adducts 11 lb from 4-methylpyridine had been reported (102)to undergo N-methylation to bis-derivative 11 IC, but an attempt (215)to repeat this experiment was unsuccessful. Similar reduction of 2,6di-tert-butylpyridine with lithium in liquid ammonia gave (209)monomeric dihydropyridines 112 and 113 in the ratio

CN

,

103: R = C0,Me

I ,

R'

104

I

t - Bu

I H

H 112

105

questioned in such cases. Apart from these theoretical aspects the following described examples have enriched the convenient procedures leading to dihydropyridines. Thus,perhalogenated 2,3- and 2,5-dihydropyridines 106 and 107 were isolated (172) after the reaction of 4chlorotetrafluoropyridine with a CoF3-CoF2 reagent at elevated temperature and the reaction pathway has been discussed (172)on the basis of CND0/2 calculations. Analogous reactions take place in the case of 4-isopropyl tetrafluoropyridine (174)or by the action of molecular fluorine on pentafluoropyridine (417). It is possible to add some quaternary pyridinium salts to dialkylphosphonate (907-909)and to sulfite (460,1010) ions. 1-Aminopyridinium iodide with 2-phenylaziridine afthe bicyclic 1,Zdihydro derivative 108. forded (467,468) Contrary to the similar 1,a-adducts 109 arising from pyridine-N-oxides and phenylisocyanate (401,403)seem to be spontaneously isomerized (8,402) into 2,3-isomers 110 CI

JAB" I

CI

I

0'

llla: R' = Na, R' = H b: R' = Li, R7 = Me c : R' = R' = M e d: R' = COMe, RZ = H e: R' = CH,CONMe,, Rz = H f:R'=Me,R'=H

t-BU

t - BU

113

3:2. Hantzsch dihydropyridine 14b was prepared (628)in 90% yield by the reduction of the corresponding pyridine derivative with aluminum amalgam. In the presence of acylating agents pyridines react with metals as corresponding 1-acylpyridinium ions to give N-acyldihydropyridine derivatives apparently via radical intermediates. Thus, in acetic anhydride pyridine itself with zinc gave (43,625)bis-acetyl derivative 11 Id while in the presence of indole (989) or dimethylaniline (990) compounds 114a and 114b were isolated. Under similar conditions 3-substituted (518)and 4-substituted (44,45, 458)pyridines gave exclusively monomeric 1,4-diacyl-1,4dihydro products of type 115. H

106

107

(jAr

Ph

108

I

COMe

114a: Ar = 3-indolyl b: Ar = 4-Me,NC6H,

109

110 R1,R' = H or Me

in accordance with their relative energies calculated (8)by the MIND0 method. 1,2-Dihydropyridines have been considered as intermediates in other similar reactions (9, 10, 608,1089). Some further transformations of pyridine-N-oxides are believed to occur via 1,2-dihydro (5,25, 184,187,210,471,520) or 2,3-dihydro (5,256,520) intermediates. (2) One-Electron Reduction. (a) Reduction with Metals. Treatment of pyridines or pyridinium salts with metals usually results in a one-electron transfer leading to radical intermediates which either dimerize to bis-dihydropyridyls or else undergo further reduction to monomeric dihydropyridines (251). Dimerization tends to occur largely in aprotic solvents, but protic media are required for formation of monomeric dihydropyridines. The Birch reduction of pyridines with alkali metals in ammonia led either to dimeric (102,160)or to monomeric (209) dihydropyridines. The formation of bis-sodio derivative l l l a was described in the patent literature (160).

115: R' and R3 = H or alkyl Rz = Me or OEt

Quaternary pyridinium salts have been reduced with individual metals as well as with their amalgams. A modified Birch reduction of 51 and i b 2-, 3-, and 4-methyl derivatives with lithium and liquid ammonia in the presence of ethanol was found (215)to give monomeric 1methyl-1,4-dihydropyridine32 (R = Me) or the corresponding homologues, respectively. In other cases the formation of dimeric producta were observed (97,192,675). Sodium amalgam was applied for the preparation of bisamide l l l e in the patent report (192)or for the reduction of 1,2,6-trimethyl-3,5-diethoxycarbonylpyridinium ion to 2,4'-dimer 116 (675).The latter isomerized readily to the corresponding 4,4'-dimer (675)at elevated temperature. On the other hand, the 4,4'-structure 117a was proved (97)

4 R

X

-

Me

x

gN

H

x

R

L Me

116: X = C0,Et R=HorMe

R

-

-~

H Hk -N

N

-

R

X

117a: R = PhCH,, X = CONH, b: R = Me, X = CN

by 13CNMR for the reduction product of 1-benzyl-3-car-

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, NO. 2, 1982 203

Table VI. Reaction Products from Cations 37, Chloroform and Bases R PhCH, 2, 6-C1,C6H,CH 2,6-CI,C6H,CH,

,

X

base

% o f 97a

CONH, CH=NOH CONH,

NH, t H,O WOH), &(OH), NaOH + PhCH,N+Et,CIBa( OH 1 2

19 1

15

loa

21 7 4

X,G-Cl,C,H,CH, a

CN

In addition to 1%of l,a-isomer.

ref 6 70 344 342 343 343

5 2 5 22

Group X was dehydrated to CN.

bamoylpyridinium chloride (NAD+ model) with zinc and copper(I1) sulfate in methanolic ammonia in accordance with calculated spin populations and HOMO properties in the correspondhig radical intermediates ( 1 0 2 9 ~but ) in disagreement with earlier incorrect structure assignments (251,476). A more detailed study (789) has shown later that the reaction mixture consists of two stereoisomeric pairs of 4,4’-adducts 117a and 4,6’-adducts 118a. Analogous 4,4’-dimer was found (97) after the NAD+ reduction performed under the same conditions.

R N x-*

226 27

% o f 9 8 % o f 99

/

R

118a : R = CH,Ph, X = CONH, b: R = Me, X = CN

(b) Electrolytic Reduction. Electrochemical formation of dihydropyridines seems to be almost limited to the electrolytic reductions of some quaternary pyridinium salts proceeding analogously under suitable conditions as those with metals. The first one-electron step of the reduction appears to be in all cases the origin of the corresponding pyridinium radical which either dimerizes or undergoes a secondary one-electron cathodic reduction together with proton addition. A number of the results of purely mechanistic or polarographic investigations on l-substituted (26,322,357, 772, 788,789,901,973,974,1098), 1,2-, 1,3-, and 1,4-disubstituted (167, 466) as well as on 1,2,4,6-tetrasubstituted(878) pyridinium salts have been interpreted on the basis of the above-mentioned assumptions but without consideration of preparative aspects. The reaction course seems to be considerably affected by substituents (466,878)or by solvents. Another suggestion on the possible formation of 2,3-dihydropyridine derivatives (623) from 1-methyl- or l-ethy1-2,3,4,6-tetraarylpyridinium salts appears to be lacking rigorous structure proof. Two excellent reviews (255,1097) concerning the electrochemical properties of dihydronicotinamides (NADH models) are available. In some cams the products of electrolysis were identified preparatively and/or by means of spectroscopic methods. Thus, the electrochemical preparation of dimeric 1,4-dihydropyridine l l l f has been patented (715, 716,998). A detailed composition of reaction mixtures after the cathodic reduction of salts 37 (X= CONH2or CONMe2)and 71 was ascertained (166,167, 726, 788, 789) for both oneelectron and two-electron pathways. The former process led to two stereoisomeric pairs of 4,4’- and 4,6‘-adducts, e.g., to 117a and 118a (167, 726,789) or to 117b and 118b (166),respectively. On the other hand, the two-electron reduction of 37 where X = CONHz gave mixtures of monomeric 1,4- and l,&dihydropyridines 39 and 40 in the ratios 9 1 (788) or 1:4 (167) for R = CH2Ph and 1:9 for R = Ph while in the case of 37 where X = CONMez and R = Ph only 1,Cisomer 39 was identified (788).

(c) Silylation and Related Reactions. Trimethylsilyl radicals being generated either by treatment of trimethylsilyl chloride with alkali metals or by thermal decomposition of bis(trimethylsily1)mercuryare able to react with pyridines to give the corresponding l-trimethylsilylpyridinium radicals as reactive intermediates. It has been observed that the latter mostly dimerize (82,763,980, 1065, 1067) or undergo further additions (251). Thus, treatments of pyridine with trimethylsilyl chloride and to formation of mixtures lithium or sodium led (1065,1067) of monomeric and dimeric dihydropyridines 119 and 120a (R = H) the ratios of which depended on the alkali metal used, e.g., 69:13 for Li or 16:63 for Na, respectively. The reaction with bis(trimethylsily1)mercury has been extended to a larger number of pyridine derivatives. Thus, pyridine, methylpyridine (82,980),and N,N-dimethylnicotinamide (763)gave exclusively 4,4’-dimers 120a with the mentioned reagent. Organometallic 4,4’-adducts 120d were prepared (717) in the same way while the formation of analogous compounds 120b (717) and further 3,3’-substituted derivatives 120c (763)was found to be accompanied by the origin of 2,2’-isomers 121b and 121c. On the other hand, the apparently exceptional formation of merely 2,2’-adducts 121a and 122 from 3-tert-butylpyridine (717), 4-

120a: X = H, 2-Me, 3-Me, 4-Me, and 3-CONEt, b: X = 3-SiMe3, 3-GeMe3, and 3-SnMe3 C : X = 3-CN and C0,Me d: X = 3-Sn(n-Bu), and 3 -Pb (n-Bu),

119

x - 5

M

?IMe3

4-3

/

e

-

N

SiMe3

121a : X = 4-Ph and 4-CMe3 b: X = 4-SiMe,, 4-GeMe,, and 4-SnMe3 c : X = 5-CN and 5 4 0 ,Me

SiMe3 Me d L s

Ac

H Me

Ac

M

e

/

SlMe3

122

phenylpyridine (763), and from 4-acetyl-3,Ei-dimethylpyridine (763) might be explained by steric factors. Some dimeric dihydropyridines 120a have been found (980) to undergo a thermal decomposition to relatively stable radicals. Bis-triethylgermanyl4,4’-dimer123a was isolated (159) in 60% yield after the reaction of pyridine with bis(triethylgermanyhadmium. (3) Photochemical Reactions. Novel reactions have been described in which dihydropyridines arise from pyridines or pyridinium salts and appropriate reagents under UV irradiation. Although a detailed mechanism is

204

Ind. Eng. Chem. Rod. Res. Dev., Vol. 21, No. 2, 1982

t!8 Y

88 00 "Q,

P W W

111 111

w"

0

Q,

h m


R3Ge-N w --

e

G

R

3

X

123a:X = H,R = Et b:X=CN,R=Me

mostly unknown, the frequent formation of dimeric dihydropyridine derivatives suggests an important role of radical species being generated from electronically excited states of starting pyridine compounds. Irradiation of methanolic solutions of pyridine itself led (1110) merely to unstable dihydro adducts while in the presence of bis(trimethyIsily1)mercurya photochemical reduction via the proposed (764) mechanism took place. The mentioned mercury reagent was found (763) to transform some cr,w-di-(4-pyridyl)alkanesinto the corresponding spirocyclic "dimeric" products 124. Methanol

124

e

h

s

was found (755) to be photochemically added to 3-cyanopyridine to give a mixture of monomeric isomers 125 and 126 in the ratio 1016 but analogous reaction with nicotinic acid afforded (755) unstable adducts only. On the other hand, the action of bis(trimethylgermany1)mercury on 3-cyanopyridine resulted (763) in the formation of both dimeric isomers 123b and 127. Dihydropyridines are also

6

Me3T

H CHzOH

NC - CN

H f l

N H

HOH$

125

N H

N

/

H

-

\

GeMe3

126

127

believed (170) to be intermediates in the photoinitiated substitution reactions of 2-cyanopyridine with benzophenone. The irradiation (476,477)of Hantzsch dihydropyridine 14a in the presence of ethylenediamine tetraacetic acid led to 2,4'-dimer 116 where R = H while a mixture of the corresponding 4,4'-dimer 128 and monomeric 1,2-dihydropyridine 129 was obtained in the presence of diethylamine. An extensive study (127) on the photochemical transformations of 4-alkylated dihydropyridines 14 (R = alkyl) with alcohols has shown that there arose different products of reduction and dimerization as well as of alcohols additions. The composition of obtained complex reaction mixtures was found (1127) to be considerably dependent on the structure of reactants. Bicyclic 3,4-dihydropyridine 130 was prepared (66,67) Me

X

X

Me

E

t

O

$

n

F

t

F

s

F Me Me

X

X

128

Me

N H

129

Me

F

F

130

by the photochemically induced addition of ethylene to pentafluoropyridine in addition to a tricyclic 2:l adduct of the reactants. A photochemical addition of methanol to l-phenylpyridinium chloride gave products too labile (1080) to be isolated.

206


cy

2

cycycycycycycy cycycycycycycy I

Y

Y

Y

Y

I

I

0 In

m

c.1

omommom

(DmmInt-mm

c

R

2

k

9

m

t

ZP 0 ' 0 0

T*

z* u' 0


The irradiation of 1-benzyl-3-carbamoylpyridinium chloride (NAD+ model 37) in the presence of diethylamine (476,477)gave a mixture of 1,6-dihydropyridinederivatives 131 (9%)and 132a (19%) via a charge-transfer complex. R

E + 2 N G c o N H 2

-

N H

X&

H

\R

I

CH2Ph

132a: R = CH,F%, X = CONH, b: R = H, X = COPh

131

Another photochemical reduction of salt 37 with ascorbic acid in the presence of ammonia afforded (670)1,4-dihydropyridine 39 (R = CH2Ph and X = CONH2) and might be of biochemical interest. A radiolysis of similar cation 37 (R = Me and X = CONH2) led to a radical species which easily dimerized (546). (4) Miscellaneous. A number of addition reactions have been described leading to dihydropyridines which do not unambiguously belong to the above discussed cases. Some other nucleophiles have been added to pyridines and to pyridinium salts. Remarkable results have been achieved during the investigations (211,213,214) on the reactivity of pyridine bases toward zinc and magnesium hydrides. Thus, the former reagent was found (214)to be readily added as well as coordinated to give trimeric products of 133 type while after a prolonged reaction time tetrameric products of 134 type were identified (211).The

-

3

R

.-E 4

8E

2

8

H

g-3

H

H

H

\/

//

/ \

H H

133

134

exclusive formation of 1,6dihydro isomeric structures seems to be of particular interest in relation to nucleophility of the reagents. Some pyridinium salts possessing at 3- or 4-position an electron-withdrawingsubstituent as C02Hor CONH2were found to be able to react with alkali metal hydroxides to give the corresponding a-radicals which either dimerized to dimeric dihydropyridines (188,290) or underwent a disproportionation into mixtures of the starting salts and the corresponding 1,4-dihydro derivatives (547,761). In the case of 1-ethyl-4methoxycarbonylpyridiniumbromide the primary arisen radical was trapped (720)with 1,3-dinitrobenzene as bis-adduct 135. Dihydropyridine interMe02C,

P 2

?

Y

0 E v1

2

4 . I

0

f s 0

135

mediates, however, have been assumed after the reaction of pyridinium salt 42 with hydrogen peroxide (490)and after the oxidation of certain pyridinium ylides (103,1034).

208

Id. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982

Table IX. Hantzsch Dihydropyridines 1 4 3 (R' = R4 = H and R 3 = Me) Prepared b y Method B RZ Me OEt 0-n-Pr 0-i-Pr 0-n-Bu 0-i-Bu 0-t-Bu

a5 82 71 63

g1

o:?-c

% of 1 4 3

1

0 Z-C, I1 0-n-C, H,, 0-cyclohexy1 O-n-C,H,, 0 - n-C, H,, O-n-C,H,, O-n-C,,H,, 0 - n-CI l H,, O-n-C,,H,, O-n-C,,H,, O-n-C,,H,, 0-n-C,,H,, 0-n-C, H,, OCH,dO,Et OCH,CH,OH OCH,CH,OMe OCH,CH,OE t OCH,CH,O-n-Bu OCH,CH,O-n-C,H,, OCH,CH,OPh OCH,CH,Cl OCH,CH,CN 0CH,CH,OCH, CH C1 OCH ,CH= CH OCH,C=CH OCH - CH= CHPh O(CI~,),CH=CH(CH,),CH, OCH,Ph OCH;C,H4-4-OMe OPh OC,H4-3-OH OC,H4-3-OMe OC6H,-4-Me OCsH,-4-OH OC6H,-4-OMe OC,H,-I-Cl OC6H4-4-OCH,Ph OCsH,-4-NHCONH, OC6H3-2-Ph-5-Me

65, 58 61 65 51 53 47 57

60 50 60

66, 64 a2 82 65 76 78 76 59 49 IO 78, 6 5 82, 4 0 85 90, 55 37 59 79 86 75 73 92 79 75

63, 65 24 66, 68 61, 48, 48 32 49

4 32

34 14

ref 392 387, 392 1115 1115 872, 1115 1115 1115 1115 1115 1115 1115 1115 1115 1115 872, 1115 1115 392, 1115 8 72 1115 8 72 8 72

I115 1115 873. 1115 873: 1115 873, 1115 1115 873, 1115 834 834 8 73 8 73 8 73 1115 8 72 1115 8 73 180, 233, 872 180, 233 180 180, 233, 872 180, 233 180, 872 180, 233, 872 180 180 180

Yields not reported.

by treatment of primary adducts with ethanol. Three novel examples of the origin of polycyclic dihydropyridines by additional reactions have been reported. 1,2-Dihydro derivative 140 was found (1178,1179)to be formed during the polymerization of maleic anhydride in the presence of pyridine. 3-Methylpyridine was reported (19)to react with 1-phenylbut-1-in-3-oneto give 1,Zadduct 141. Structure 142 has been assigned (237)to a product

140 138a: R' = RZ = H b: R 1 = H, RZ = Me e : R1 = R2 = Me

141

139

bH

142: R = 2-pyridyl

of the isomerization of 1,4-diphenyl-1,4-di-(2-pyridyl)-2butin-1,4-diol on the basis of 13C NMR in contrast to an earlier report (1027).1,2-Dihydropyridine-2-derivative139 is believed (615)to be a product of the reaction of the corresponding 2-iodopyridinium iodide with potassium hydrogen sulfide in methanol. B. Hantzsch Synthesis a n d Related Cyclocondensations. Hantzsch synthesis is defined here (251) as the reaction of an aldehyde with an active methylene carbonyl compound and ammonia proceeding according to the general scheme, eq 15. Other similar cycloR'

I

In suitable cases a radical addition seems to be an alternative approach to dihydropyridines. Thus, acetyl radicals generated in situ by the action of di-tert-butyl peroxide on acetaldehyde gave (45)1,Cdihydropyridine 115 (R1 = R2 = Me and R3 = H) with 4-methylpyridine while the same reaction with 4-methylpyridinium ion led (711)to 2-acetyl-4-methylpyridineapparently via unstable 1,2-diacetyl-1,2-dihydroisomer of 115. Diphenylketyls generated by the reaction of benzophenone with lithium (934)or sodium in liquid ammonia (436,437,1057) were also found to attack pyridine ring. In the case of 4methylpyridine the formation of an 1,2-adduct has been assumed (934).On the other hand, the reaction with 3benzoylpyridine really afforded either monomeric 1,6-dihydropyridine 136 in 80% yield (437,1057) or dimeric 6,6'-adduct 132b (1057)in the presence or in the absence of ammonium chloride, respectively. Analogous but multi-step transformation of 3-bromopyridine led (437)to bicyclic 3,4-dihydropyridine 137. 1,ZDihydropyridine phosphonates 138a-c were prepared (113)by the PC13 addition to hydrochlorides of the corresponding quaternary pyridinium chlorides followed

137

136

I

.94

H

R'

A4

143

condensations may be considered as Hantzsch-like syntheses although any terminological distinctions among different modifications of the reaction seems to be of little importance in practice. (1) Hantzsch Synthesis. This well-known cyclization (15) has been widely used in the past decade. The preparatory procedures usually consist of the warming of the above-given reagenta in alcohol (method A), of using hexamethylenetetramine in place of formaldehyde and ammonia (method B)or of the application of ammonium acetate as well as primary amine salta together with acetic acid or pyridine as solvents (method C). To enable the reader orientation among newly prepared 1,4-dihydropyridines 143 a survey of their structures and yields is summarized in Tables VI1 to XI. As expected, the largest

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 209 Table X. Hantzsch Dihydropyridines 1 4 3 ( R 3 = Me and R4 = H ) Prepared by Method C. Yields Not Reported R2 R' Me

OMe

OEt

0-i-Pr OCH, CH ,SCH, CH ,

ref

2-0,NC,H4 2-N,C,H, 3-O;Nb,k4 3-N,C,H, 3 -NCC, H. 4-N3C,h42-N3-4-C1C,H, 2-MeOOCCH.OC,H, 2-Et o o c c H , 0 C , ~ 4 ~ 2-EtOOCCH,O- 5-0,NC,H, 3-EtOOCCH,O-4-MeOC6H, 2-i-PrOOCCH,0C6H, 3-EtOOCCH,0C,H4 2-EtOOCCHzO-5-BrC,H, 2-Et00CCH,O-5-0,NC6H, 3-EtOOCCH,0-4-MeOC,H3 2-EtOOCCH,OC,H, 2-E tOOCCH,O-5-0 ,NC,H, H

136 932 136 932 136 932 932 932 125 125 125 125 125 125 125 125 125 125 4

Table XI. Hantzsch Dihydropyridines 143 (Rz = Et, R4 = H) Prepared by Method A % of

R3

R'

143

ref

P-ClC,H,

75

142

3-C1C6H, 4-OzNC,H4 2-ClC,H, 2-F3CC,H4 4-MeSC6H, 3-Me0-4-HOC6H, 2-O,NC,H, 2-pyridyl

55 55 60 50 40 50 45

142 142 144 144 144 144 144 144

2-C1C,H4

60

142

Ph Me 3-pyridyl H, Me, Et, n-Pr,Ph 2-,4-0,NC,H4 2,3-pyridyl, 2-fury1 Et Et Me Me Me

10 71 61

629 62 62 65 65 65 873 873 873 873 873

0

acetoacetates (142,144) and different acylacetates (62,65, 629,873)were used in place of originally explored (358) ethyl acetoacetate. A large number of R4NH2has been 132-134,136,629,685, already used (122,124,125,130, 931,932,958,959,1149) in the Hantzsch synthesis. Bicyclic and tricyclic Hantzsch dihydropyridines 144a and 145a are available by the use of 1,3-cyclohexadione as a carbonyl component in methods A and C according to the patent literature (134,932). On the other hand, simple ketones as acetone, cyclopentanone as well as cyclohexanone were found (586)to react with benzoylacetonitrile and ammonium acetate (method C)with the formation of 1,6dihydropyridines 146a-c.

144a: R' = Ph, XC,H,(Cl, 145a: R' = XC,H,(N,, N O , OH, C0,Me); X, NH,, Me,N); 2-, Y-C,H,( Cl, OH, NO,) 3-pyridyl or or 2-thienyl 2-N,-4( 5)XC,H, R' = EtO, i-Pro, Rz = H or Me CH=CCH,O or R3 = H 2-furyloxy, R3 = H b: R' = H, Me or Ph b: R' = H, Me or Ph R' = H, R3 = Me RZ = Et, R3 = Me R'

Ncfic

0

CH ,OCH,

CH,OEt

80

0

COOEt CF3

Ph CH,Ph CH CH,CH= CH, CH ,CH,Ph n-C13H25

a


a

a

a 10 51 46 59 73

R2

Ph

H

Ph

146a: R' = R Z = M e b: R', R' = (CH,), C : R', R' = (CH,),

Further Hantzsch 5-keto-3-esters 147 similar to 144a were successively synthetized (453) for a biological screening.

Me

I Me

H

147: Ar = 3-N0,C,H4 or 3-CF,C,H4

(2) Use of Enamines. Enamino ketones, esters, and nitriles have been frequently used in place of usual methylene carbonyl and nitrogen components in the above-mentioned Hantzsch synthesis. Under suitable conditions such modified procedures lead to better yields of resulting 1,4-dihydropyridines 11 than process 15, especially in the series of cyano derivatives (Xand/or Y =

CN). variability was explored for substituents R', the mean one On using one enamine component together with an alfor R2, and the minimum one for both R3 and R4. Subdehyde or a ketone symmetrical ring closure (16) takes stituent R' may be further aliphatic (4,26,62,65,117,392, place and symmetrically substituted Hantzsch dihydroaromatic 586,599,774-776,834,872,873,926,1041,1132), pyridines 148 are formed (251). (62,117,122,124,125,13~136,142,144,179,234,238,239, 272,449,452,453,482,485,505,577,685,737,873,928, 931,932,957-959,984,1149) as well as heteroaromatic R' R2 group (62,117,122,124,130,134,135,144,238,239,452, 479,505,570,685, 762,959,1096).As for substituents R2 and R3 some l,&diketones (134,135,453,685,932), dif135,272, ferent esters (4,57,117,122,124,125,131-133, 449,452,453,479,482,505,599, 685,737,834,872,873, A4 928,931,957,959,1096,1149) and amides (130,238,239, 485) of acetoacetic acid as well as certain 4;substituted 148

R'YRZ

210


Table XII. Hantzsch Dihydropyridines 148 (RZ = H and R3 = Me) Prepared by Cyclocondensation 16

X COMe COOMe COOEt

COO-i-Pr COOCH,C(CH,), COOCH,Si( CH,), CONH. CN

R' 2-.3-.4-~vridvl 5-OzN-i-?uril CH,PO( OPr )( 0-i-Pr ) 2-0,NC6H, 8-chinolyl S-F,CC,H, 3-isochinol y 1 7-O2N-4-chinolyl 5-O2N-2-furyl CH,PO(OMe), CH,PO(OPr)(O-i-Pr) CH,PO( O-s-Bu)(OEt) 1-naphthyl 3-isochinolvl

H H Me H H H H €3 H H H

3-0,NC6H, Ph H Et n-Pr n-Pr i-Pr i-Pr

H H Me Et H Et H Et

R4 yield H H

a

76 24 a 57 16 68 43 78 23 17 18 60 74 49 52 22 a 46 56 46 44 13

H

~-o,Nc,H,*

H

Table XIII. Hantzsch Dihydropyridines 148 (X = CN) Prepared by Cyclocondensation 16

R3 Me

Ph

R' Me Me Me Me Me Me Me Me Me Me Et (CH2)4

(CHZ)4

(CH,),

(CH,), (CH2)4 (CH'),

(CH2)4

(CHZ), a

R' Me Me Me Me Me Me Me Et n-Pr n-Bu Et

R4

yield

ref

H Me Et n -Pr Ph CH,Ph cyclohexyl H H H H

40 40 68 46 22 25 2 45 40 35 50 a 50, 3 0 37 31

236 58 2 582 58 2 582 58 2 582 58 2 582 582 582 844 582, 629 586 58 6

H H


Table XIV. Hantzsch Dihydropyridines 149 (R2 = R 3 = Me) Prepared by Cyclocondensation 17 X Y R' yield ref CN

COOMe C0,Et C0,Et C0,Et COiEt C0,Et C0,Et C0,Et C0,Et C0,Et COO -n-Pr COO -i -Pr COO-t-Bu COOCH,CH,OEt CO0CH ,Ph COOCH2-2-pyridyl


2-0,NC,H4 Me,CCl, CH=CHMe CH.CH,OMe CHSCHiSMe CH,CH,Ph Ph,B-ClC,H, 3-,4-OzNC,H, 2-0,NC6H, 2-fury1 2-0,NC,H4 2-0,NC,H4 2-0,NC,H4 2-0,NC6H, 2-O,NC6H, 2-O,NC6H,

58 666 a 406 a 406 a 406 a 406 a 406 a 406 a 406 a 406, 666 a 406 42 665, 667 30 665 20 665 48 665 30 665 19 665

2-0,NC6H,

40 665

3-OZNC,H,

a

737

3-F3CC,H,

a

737

ref 748 63 906 736 685 629 685 685 747 906 906 906 685 685 1072 1072 485 584 739 739 739 739 739

X

R'

R4

CN

i-BU t-Bu subst. phenyl 2-0 ,N C,H, 3-HOC6H, 3-MeOC6H, 3-FC, H, 3-C1C6H, 3-0,NC6H, 3-NCC6H, 4-HOC,H4 4-MeOC6H, 4-FC6H, 4-C1C6H, 4-0,NC,H4 4-Me2NC,H, 4-MeOOCC6H, 4-NCC6H, CH,Ph 3-pyridyl 2,4-pyridyl 2-thienyl,2-furyl 2-pyrryl ferrocenyl

Et HCH,Ph H H H H H H H H H H H H H H H H H H H H H

yield 36 --

36 a a

48 76 62 74 75 86 49 59 66 74 45 70 93 51 52 71 a a a a

ref 7.19 . --

739 583 161 577 577 577 577 577 577 577 577 577 577 577 577 577 577 739, 546 1153 1153 1153 1153 817

Table XV. Ratios of Tautomeric Dihydropyridines 150 and 151 (Y= OEt) Estimated (859)by NMR R 150:151 R 150:151 Me Ph %O,NC,H, 3-0,NC6H, 1-naphthyl 4-pyridyl

50:50 73~27 0:100 1OO:O 0:lOO

1oo:o

2-F3CC,H, 3-F,CC,H4 2-MeC,H4 2-FC,H4 2-fury1

5~95 1OO:O 25:75 95: 5 65:35

Since the cyclocondensation (16) requires elimination of a basic molecule R4NH2(ammonia or a primary amine) the corresponding preparatory procedures have usually been accomplished in acidic media. A large number of newly prepared dihydropyridines 148 is demonstrated in Tables XI1 and XIII. It is evident that a considerable variability of substituents except R2 were explored. One may further note that process (16) siinilarly as (15) appears to be quite general for aldehydes R'CHO while ketones R1R2C0 give products 148 exclusively in the series of 3,5-dinitriles (see Table XIII) probably due to a steric hindrance in molecules of intermediates. The formation of 3,5-dicyano-1,4-dihydropyridines146a-c by cyclocondensation (16) with the corresponding ketones was found (586)to be accompanied by a yellow byproduct, the occurrence of which had been erroneously interpreted (941) in favor of the incorrect 1,2-dihydrostructure assignments for the products. The second version (17) of the Hantzsch-like synthesis

149

consists in the use of two different enamine components and leads to unsymmetrically substituted 1P-dihydropyridines 149 (251). All derivatives 149 thus newly prepared are summarized in Table XIV. A novel modification of HanWch-like syntheses (16) and (17) is baaed on the use of amidine or endiamine components, respectively. Thus, the reaction of ethyl 3,3-diaminoacrylate with aldehydes RCHO was found (680) to


Table XVI. Dihydropyridines 150 Isolated (734)after Cyclocondensation 17 (RZ= R4 = H, R 3 = NH,)

R

Y OEt

yield 61 59 67 33 72 49 56 70 63 76

Me Ph %MeC,H, 2-PhC,H, 2-MeOC6H, Z!-FC,H, 2-0 ,NC,H, 2-F 3CC,H, 3-0,NC6H, 4-pyridyl

0-i-Pr

Y

R

OCH,C=CH

3-NCC6H, 3-F3CC,H, 4-MeSC6H, 3-0 ,N-5-C1C6H, 1-naphthy1 2-pyridyl 4-chinolyl 4,6-(MeO),-5-pyrimidyl %fury1 3-O,NC6H,

OEt

Table XVII. Dihydropyridines 152 Isolated after Cyclocondensation 16 ( R 3 = H) Y

RZ

R'

yield

ref

~3

P-FC,H, 3-C1C6H, 3-0,NC6H, Me Ph 2-0,NC6H, 3-C1C6H, 3-0,NC6H, 3-NCC6H, 4-MeC6H, 4-C1C6H, 4-Et0,CC6H, 4-MeSC6H, 2,4-Cl, C,H, 2-C1-5-0,NC6H, 2-pyridyl 4-pyridyl 2-fury1 3-OZNC,H, 3-0,NC6H, 3-NCC6H, 4-pyridyl 3-0,NC6H, 2-pyridyl

59 78 71, 58 57,46 64, 51 59, 56 76, 26 68, 6 2 73 47, 27 56 33 52,42 68,30 65, 56 55,46 72,45 62 39 44 38 47 a a

684 684 677,684 677,684 677,684 677,684 677,684 677,684 677,684 677,684 684 677 677,684 677,684 677,684 677,684 677,684 684 691 691 691 691 680 680

Ph

a

680

OEt

3-0,NC6H,

45

684

OMe

OEt

OEt

OEt

SMe SEt NMe,

0-i-Pr a

give mixtures of 1,4- and 3,4-dihydro tautomers 150 and 151 (see Table XV), while the exclusive isolation of former isomers 150 had been reported in the patent (688);see Table XVI. On the other hand, all authors (684,691,677, 680)investigating the use of ethyl 3,3-diaminoacrylate as one of enamino components in cyclocondensation (17) have defined the products to be 3,4-dihydropyridines 152; see Table XVII.

COY

COY

NH,

NH,

H2N

H,N

151

150

152

The third successful version (18) of using enamines in

I

D 4

one aldehyde and one active methylene carbonyl component. Since two molecules of water are eliminated during the formation of 1,4-dihydropyridine 153 the cyclocondensation (18) resembles mostly the simple Hantzsch synthesis but offers a substantially extended variability of substituents as illustrated on broad experimental material in Tables XVIII to XX. I t is evident that procedure 18 has enabled the synthetization of a number of structurally more complex 1,4-dihydropyridines153 and 176 (see Table XXVII) which is of pharmaceutical interest and it further permitted the preparation of Hantzsch dihydropyridines 1 1 possessing unusual Substituents Y as SOZMeor SO& (142,309,1157, 1162,1163)and NOz (120).In addition, the first example of the Hantzsch-like synthesis of a 3,5-dinitro-1,4-dihydropyridine was reported (122)in the case of compounds 154.

154: Ar = 3-N0,C6H,

0 II


I

R4

153

Hantzsch-like syntheses includes an enamine together with

yield 55 56 48 48 52 74 58 56 74 59

155a: R' = H, Me or Ph, R' = Me X = CN, COMe, COPh, or C0,Et b: R'; see Table XXVII RZ = NH,, X = C0,Et

H\/R

156

157

A number of bicyclic dihydropyridines of 144 type (R1 = XC,H,) or different heteroaromatic residues and

Rz=

Me, OMe, OEt, or 0-i-Pr) as well as some of their Nmethyl derivatives have been reported (134,932) to be available by cyclocondensation (18) with 1,3cyclohexadione as one of reactants. Similar compounds 144b, 145b and 155a were also obtained (230,1042),in connection with a study of competing reactions with variable enamines in the process (18). Analogously, 1,4-dihydropyridines 155 and 156 as well as 157 were prepared on using the above mentioned diketone (679,687,1158) or 2,6-dimethyl-2,6-diaza-1,3,5-cyclohexatrione (121)as active methylene componenk, see Tables XXI and XXII. (3) Use of 1,5-Dialdehydes and 1,5-Diketones. Further examples of the Hantzsch-like syntheses using the cyclocondensation of different 1,5-dioxo precursors with an amino component (251)have been described. Thus, simple 1,Cdihydropyridine 6 was exploited (613)in a biomimetic synthesis of nicotine from glutaric dialdehyde. Analogously, 3,3-dialkylated 1,5-dialdehydes afforded 1,4-dihydropyridines 158a (287) or 158b (279)by the ring


212

closure with ammonia and amides XNH2,respectively; see eq 19. The mentioned dialdehydes have also been gen-

I

I -

CHO

CHO

-2Hy0

YHz X

X

158a:X=H,R=MeorR,R=(CH,), b: X = COMe, COPh or C0,Et and R = H, Me or R, R = (CH,),-,

erated in situ by the periodate oxidation of 4,4-disubstituted 1,2-cyclopentadiols (280,286). In contrast to above-given cases, the preparation of 1,Qdihydropyridines of 159 type by the reaction of glu4-X-C6H,COCHzH

CcD

I

I

4 - Y - A6H

x-yJ R‘ H

C02R2

2 -2Ho

(20)

Me

I

160

taconic dialdehyde dianiles with acetophenones (511) apparently involves a many-step addition-elimination mechanism. Various tricyclic l,4-dihydropyridines of 160 type were 374,380,559, 962)to be readily available shown (27,28, by the cyclocondensation of amines R1NH2with the corresponding diketone (method D)or their intramolecular “aldoles” (method E), respectively; see Table XXIII. Some Hantzsch dihydropyridines 11 were prepared via l,5-diketonic intermediates. Thus, bis-salts 161a with ammonium sulfate or dienediol 161b with amines RNH2 afforded (1173)3,5-diformyl-1,4-dihydropyridines 26 (R = H, alkyl or aryl) and the corresponding 3,5-diimines 162 (R # H), respectively. On using appropriate diketonic starting compounds with ammonia under elevated temperature (158)or with ammonium acetate-acetic acid mixtures (60,163,349) bis-lactone 163 (158)as well as 2,3,5,6-tetraesters 164a (163,349) and 164b (60)were prepared. Similarly, 3,bdiester 165 was obtained (491) CGCH

CECH

H

RN=CH

CHOM

I

R3

R4

166

AI

159: X = H, Br, C1, MeO, NO, Y = H, Br, Cl, Me, MeO, C0,Et

MOCH

I

\/

0

oHc*vo

R’

H R2

//

Y

after the reaction of N-aminophthalimide with the corresponding l,&diketonic derivative. (4) Use of cud-UnsaturatedAldehydes and Ketones. This Hantzsch-like approach consists in cyclocondensations of a,P-unsaturated aldehydic or ketonic derivatives with the mixture of an active methylene carbonyl component and an amino derivative or with the corresponding enamine. The latter version seems to be more popular and serves as an effective tool for syntheses of variously substituted dihydropyridines. This frequently used method (251)has been enriched in the past decade by introducing aldehydic and new ketonic starting compounds. The ring closure (20) in the original version may be

regarded as a part of the Hantzach synthesis (15) provided the aldolization of aldehyde RlCHO with one the active methylene components is the first step in the whole process as has been repeatedly demonstrated (349). As shown in Table XXIV a variety of substituents R1 and R2 as well as of functional groups X were exploited (124,126,130,349,441,682,737,1160) and especially case 166 having the unusual residue X = PO(OEt)2 (441)appears to be of particular interest. Free cY,&unsaturated aldehydes or their imino-enamino derivatives have been used in the synthesis of 1,4-dihydropyridines in combination with enamines. Thus, crotonaldehyde with ethyl 3-aminocrotonate was found (933)to give 2,3,4-trisubstituted product 167a while a similar reaction of dieneamine CH2=CHCH=CHNH2 with enamines Me(NH2)C=CHCOR yielded mixtures of 2,3,4- and 2,3,6-trisubstituted isomers 167b (ca. 93%) and 168 (ca. 7%). Analogously, Schiff bases ArN=CHCH= CHPh were reported (946) to react with ethyl acetoacetate or with acetylacetone in the presence of sodium ethanolate at an elevated temperature to 1,4-dihydropyridines 169, but a rigorous structure proof is lacking in these cases.

ficH=” I

161a: M = Na, K, or Ba

b:M=H

R

162: R = C,H, or C,H,X (2-Me0,

4-Me, 3-NMe,, 4-NMe,, 3-CO,Et

168: R = Me or Et

167a: R = OEt

b: R = M e o r E t

& Y ?h H

Me

Ar = XC,H, (2-, 3-, 4-Me, 4-Me0, 4-Cl), or 1-naphthy1

169: R = Me or Et, 163

164a: Ar = 3-NO,C6H, b: Ar = 4-pyridyl n

Me

165: X = C0,Et

X

Various asymmetrically substituted Hantzsch 3,5-diesters 170 (see Table XXV) and 171a-c (142,953,954-956) were prepared on using the corresponding enamines as the second component in the cyclocondensationsof type (21). A more general applicability of ring closures like (21) may be demonstrated by the successful syntheses of bi-


Eto2cfx CO,R~

42

'\Me

R2

Me-l

H

Me

NH2

I

R'

178

Similarly, bicyclic dihydropyridines 172 (X= NH, see Table XXVI)were prepared (678). On the other hand, cyclocondensation products obtained analogously from different N-substituted 3,3-diaminocrotonates (see Table XXX) or by the reaction of ketones R1CH=CHCOR2with 1-substituted 2-aminOindOleS (see Table XXXI)have been formulated (679,936) as 3,4-dihydro isomers 179 and 180, respectively.

170 H X C, H

H

l 7 l a : R' = Et, R2 = CH,OH, X = 2-Cl or 2 - N 0 2 b: R' Et, Rz = CH(OEt), and X = 2-N02 c: R' = CH,CH,N(Ivle)CH,€%, R2 = CN and X = 2-NO, d: R' Et, R2 = CH2NHz,X = 2-Cl(141)

H R'

cyclic and tricyclic Hantzsch dihydropyridines 172 (see Table XXVI where X = CH2)and 173 (6781, respectively (see eq 22 and 23) as well as by the preparation (497,

mtC2 I

179

A3

180

R' Et02C\C//CH

I

I MeACo

H

177

CH/C02R2

II

COzR2

2 -n o

Et

02cy3/x

(22)

(5) Use of Acetylenic Derivatives. The formerly known (251) cyclocondensation (24) of methyl acetylene+(

I

NH/'\X LCH2)>

MeO'c- li

172

173 173: R (yield) = Me(35), Ph(46), 2-C1C,H4(24), 3-ClC,H4(31)and 2-NCC6H,(30) 11474 of oligocyclic derivatives 174,175, and 176 in the

H

174: X (yield) = COMe( 50), COPh( 55), CO,Et(3O) or CN( 50)

CHO

LICH$

H

175: (yield: 20)

analogous way involving the corresponding derivatives of 2-methyleneindandione as one of the starting components. 2-Aminodihydropyridinesformulated (564,679) as 1,4dihydro isomers 177 and 178 were found to be available from ketones R1CH=CHCOR2 or from analogous ketonic components as those shown in eq 21 provided the appropriate 3,3-diaminocrotonateswere used in place of simple enamino esters; see Tables XXVIII and XXIX.

-cozMe

NH;

181

Ar (Yield): Ph( 79), 2-CIC,H4(56), 4-C1C6H,(72), 3-N0,C,H4( 57),4-MeC,H4(68), 4-MeOC,H,( 68), 4-HOC6H,(52)

carboxylate with aldehydes in an ammonium acetateacetic acid mixture was further extended (162, 181) for the preparation of the series of Hantmch dihydropyridines 181. Although the synthesis appears to be general for aromatic aldehydes, somewhat contradictory results have been reported (162,181) regarding the use of 3-nitrobenzaldehyde which gave either the expected l,4-dihydropyridine 181 having Ar = 3-N02C6H4(162) or merely a trimeric Schiff base-like compound (181). Dimethyl acetylenedicarboxylate was found (899) to undergo a remarkable cycloaddition (25) to heterocyclic

r---i r - 1NMe

176 (yields: see Table XXVII)

c

CH

CH

t 2Me02CCGCC02Me

-

(25)

k

182

183

X = NMe or S

Na'-disubstituted amidines 182 leading to spirocyclic 1,4-dihydropyridines 183. It is noteworthy that the producta 183 summarized in Table XXXII seem to be the first case of obtained 4,4-disubstituted 1,4-dihydropyridines having two voluminous ester residues in 3- and 5-positions.

214


Table XVIII. Hantzsch Dihydropyridines 153 (RZ= R 3 = Me and R4 = H) Prepared by Cyclocondensation 18 X Y R yield COMe COOMe

S0,Ph COOMe COOEt

COO-n-Pr COOCH ,CH= CH , COOCH,C=CH COOCH2-2-pyridyl

COOCH,CH2-2-pyridyl COOCH,CH,NCH,Ph I Me COOCH,N-morpholyl COOCH,CH,N-morpholyl

S0,Me

S0,Ph SO,C,H,-Q-CI SO,C6H,-4-Me SO C H -4-OMe NO’,

C0,Et

COOMe

COOCH,CH=CH , COOCH,CH,OPr COO CH ,CH ,CN COOCH,CH,N-morpholyl CO,CH, CH ,NCH,Ph I Me

Ph 2-N0,C6H, 2-CIC6H, 3-0,N-6-C1C6H, 1-naphthyl 4-chinolyl 2-0,NC6H, 2-thienvl 2-FC6H, 3-0,NC,H4 Ph 2-ClC,H, 2-0,NC6-H4 2-N3C,H, 2-F3CC,H, 4-O,NC6H, 4-AcNHC6H4 2-F3C-4-0,NC,H3 5-Br-2-fury1 4,6-{MeO),-5-pyrimidyl 3-0,NC6H, Ph,2-MeSC6H,

52 a

69 65 48 58 54 53 60 68 85 85 65 15 15 15 15 55

IO 75 84 a a

ref 1163 735

6 76 6 76 6 76 6 76 6 76 6 76 6 76 6 76 124 124 124 124 124 124 124 124 124 124 124 445 450

2,4-0,NC6H, 2,3-F,CC,H4 3-F-4-MeOC6H, 3-O2NC,H, 4-MeSC6H, 2-pyridyl

a a

90

450 44 7 124 124 124 124

PhCH=CH

IO

124

PhCH,CH, Ph

55 90

124 124

2-C1C6H,

75

124

2-O,NC6H, 2-F3CC,H, 3-MeOC6H, 3-O,NC6H, 1-naphthyl 4-chinolyl 2 - 0,NC,H, 2-F3CC,H, 2-Me,N0,SC6H, 2-pyridyl 3-pyridyl 2-02NC,H, 3-pyridyl 3-pyridyl 3-pyridyl 2 - 0,N C, H, 2-F3CC,H, Ph 3-0,NC6H, 3-F,CC6H, 3-NCC6H, 4-MeSC6H, 3-pyridyl 2-MeC,H4 2-F3CC,H, 2-NCC, H, 2-MeOC6H, 3-0,NC6H, 2-CF3C, H, Ph 3-F3CC,H,

75 15 45 65 60 65

a

124 124 124 124 124 124 348 348 348 1162 1162 348 1162 1162 1162 120 120 6 76 6 76 6 76 6 76 6 76 6 76 6 76 6 76 6 76 6 76 6 76 1164 124 44 7

80

130

%ClC,H,

15 90 85

a

a a

68 65 a

61 58 62 31

36 74 15 65 66 61 72 52 51

42 43 51 55 80


Table XVIII (Continued) X

Y S0,Me S0,Ph !%Et COOMe

COO-n-Pr CO 0-i-Pr

R

-

3-0,NC,H4 P-O,NC,H, 2-pyridyl 3-pyridyl 3-pyridyl 3-pyridyl 3-0,NC6H4 2-0,NC6H, 2-p yridyl

COOEt COOPr COOCH ,CH= CH,

COO-~-Bu COO-t-Bu COO -cyclopenty 1

COO-cyclohexyl COO CH, CH= CH ,

COOCH,CH,OCH,CH,CH, COOCH,-%pyridyl S0,Me S0,Ph S0,Me S0,Me S0,Me S0,Me

2-MeOC,H4 2-NCC,H, %F,CC,H, 3-0,NC6H4 Ph 3-0,NC,H4 3-0,KC,H4 S-O,NC,H, 3-pyridyl 3-pyridyl

COOEt S0,Me S0,Ph

COO CH ,=CH COOCH,Ph COOCH,C6H4F-4 COOCH,C,H,C1-4 COOCH,C6H,C1,-3,4 COOCH2-2-pyridyl CO0CH ,OPh COOCH,Si( CH,), COOCH,CH,Ph

,

COOCH CH, C1 COOCH,CH,OMe

COOEt COOCH,CH,NMe, S0,Me S0,Ph

COOCH,CH,OPh COOCH,CH,NMe,

COOCH,CH,N

/

\ I

COOCH,CH,N'

\

ref

70

61

130 348 1162 1162 1162 120 6 76 6 76 6 76 6 76 6 76 6 76 6 76 6 76 6 76 1160 124 1162 1162 1162 348 1163 1163 1109 1162 6 76 1163 1162 1163 1163 6 76 445 1162 1163 1163 1163 1163 1163 1163 1163 1162 1163 1163 1072 1163 1162 453 453 453 6 76 124 1163 1162 1163 1163 1163 1160 445 1163 1162 453 453 453 453 453 453 453 1162

a

60 72 75 34 65 52 70 61 51 59 59 62 64 58 70 71 77 66 a 57 65 60 79 43 54 63 50 47 51 a

68 51 52 55 51 48 55 45 45 69 65 77 49 55 a

S0,Ph S0,Me S0,Ph S0,Ph SO ,Ph COOCH,C( CH,), S0,Ph S0,Me COOMe COOEt COO-i-Pr COOEt COOCH2-2-pyridyl S0,Me

a

a 49 55 60 59 50 51 55 49

S0,Ph COOCH,CH,O-n-Pr

yield

COO-i-Pr COOCH,CH,NMe, S0,Me S0,Ph COOMe COOEt COO-i-Pr COO-i-Bu COO-t-BU COOCH,Ph COOCH,CH,O-n -Pr S0,Me

a

48 68 a a

a a a a a

Et COO-i-Pr

3-0,NC6H,

a

453

COOMe

3-O2NC,H,

a

453

Me Me Ph

216


Table XVIII (Continued)

x COO CH ,CH ,N

/

R

Y

yield

ref

Me COOMe

Ph

a

453

COOEt

2-,3-F3CC, H, 2-,3-,4-0,NC6H, 3-0,NC6H, 3-F,CC6H, 2-,3-0,NC6H,

a a a a a

453 453 453 453 453

3-0,NC,H4

a

453

3-0,NC,H4

a

453

S0,Me

3-pyridyl

56

1162

COOMe

3-F,CC6H,

a

453

COOEt,i-Pr

3-0,NC6H,

a

453

COOEt

3-0,NC, H,

a

453

CH,C6H,C1-4 COO CH CH,N( CH ,Ph ), Me

COO-i-Pr

3-0,NC,H,

a

453

COOCH,CH,CH,N'

COO-i-Pr

3-0,NC6H,

a

453

S0,Me

2-0,NC6H,

a

348

COOMe

2-ClC,H, 2-MeOC6H, 2-NCC,H, %F,CC,H, P-O,NC,H, 3-MeC6H, 2-pyridyl 3-pyridyl 2-0 ,NC, H, 3-0,NC6H, 3-0,NC6H, 3-O,NC6H4 3-0,NC6H, 3-0,NC6H, 3-0,NC, H, 3-0,NC6H, 3-0,NC,H4 3-0,NC6H, 3-0,NC6H, 3-0,NC6H, 3-0,NC,H, Ph 2-O,NC,H, 3-0,NC,H, 3-0,NC6H, 3-0,NC6H, 3-0,NC,H4

42 41 33 35 58 58 66 62 47 54 49 42 48 40 33 43 45 40 40 46 32 26 16 24 37 36 41

1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 120 120

\

CH,Ph

COO-i-Pr COO CH ,CH,N

COOCH,CH,N

COOCH,CH,N

COOCH,CH,N

I \

I

I \

I \

Me Me Me CH,Ph

Me CH,C,H,Me-4 Me

\

,

I

." CN

\

CH,Ph

COOEt COOEt COO-i-Pr COO-n-Bu COO-cyclopentyl COOCH,CH=CH, COOCH,C,H,C1-2 COOCH,CH,OMe COOCH ,CH ,O-n-Pr COOCH,CH,O-n-Bu COOCH,CH,OPh COOCH ,CH2O-3-pyridyl COOCH,CH,NMe, S0,Ph NO,

a

COOEt COO-cyclopentyl COOCH,CH,OEt COOCH,CH,O-n-Pr

120

120


been employed. On the other hand, primary amines (27, (6) Source of Nitrogen. The source of heterocyclic 28,122,124,126,130,133,134,179,491,559,629,737,808, nitrogen in the Hantzsch synthesis (see eq 15) or in 931,932,959,962,963,1149)or their hydrochlorides (125, Hantach-like syntheses (seeeq 20 and 21) has been usually 132,133,135,136,234,449,685,958)have been frequently ammonia or ammonium acetate. Occasionally, hexamethylenetetramine (180,233,239,387,392,834,872,873),used in the past decade. Some imines supplied both nitrogen sources and carbonyl components (511,899,946). another aldehydeammonia compound (834),ammonium ( 7 ) The Carbonyl Component. Aliphatic, aromatic, chloride (125), ammonium sulfate (1173), ammonium and heteroaromatic aldehydes were still the most frecarbamate (4), ethyl carbamate (279),different amides quently used carbonyl components in the original and in (279),or derivatives of a-amino acids (774-776,1041) have

Ind. Eng. Chem. Prod. Res. Dev., Voi. 21, No. 2, 1982

related versions of the Hantzsch synthesis. 2-(Diacetoxymethyl)-5-nitrofuran(747) and tri-morpholyl derivative 184 (240) or 2-nitrobenzylidene chloride (733, 734, 940) were used as sources of the corresponding aldehydes. The use of ketones instead of aldehydes is rare and appears to be mainly limited for the synthesis of 3,5-dicyano-1,4-dihydropyridines of types 16 and 146 involving enaminonitriles as the second component (236,582,584,586,629, 844,1153). However, acenaphthoquinone was found (235) to be an effective carbonyl component in its cyclocondensation of type 15 with two molecules of 1,3indandione leading to octacyclic 1,4-dihydropyridine185.

217

189a : X = Ph A r = Ph, 3-,4-NO,C,H,, 2,3,4-pyridyl b: X = CN Ar = 4-Me, 443, 4-MezN

ponenta and afforded other 3,4-dihydropyridines 190 according to eq 27. It might be noted that detail structures of molecules 189 and 190 have not been elucidated with certainty. Ph MeSOz\C/CH

I

CN

L J

(8) Reaction Mechanism. Current views concerning the mechanism of the Hantzsch synthesis (15) have been mentioned in ref 251 and have not been developed significantly in the past decade. C. Miscellaneous Synthesis. (1) Cyclization of Nitriles a n d Amides. Malononitrile appears to be the most popular nitrile component used in cyclizations with a,@-unsaturatedketones or cyanides affording as a rule 3,4-dihydropyridines of type 4 accompanied by artificial and/or byproduck Thus, 3-phenyl-2-propen-1-ylideneacetophenone with malononitrile in the presence of ammonium acetate gave (944) a mixture containing 3,4-dihydro products 186 and the corresponding aromatized pyridine derivative. If mixtures of simple aldehydes or ketones R2CH2COR3and 3-substituted 2-hydroxybenzaldehydes were used in place of appropriate a,@-unsaturated components only 8 to 28% yields of dihydro products formulated as 187 were obtained (942) under similar conditions. Bis-2,5-benzylidenecyclopentanonewith malononitrile under basic catalysis was converted (829) into a product regarded to be either 3,4-dihydropyridine 188 or its l,4-isomer.

187: R' = H o r Me R* = H,Me, Et or n-Pr R3 = Me or Et

C/COzMe

II

-

HZN

NHZ/'\NMez

(27)

Mesozfi~OzMe NMe,

190 Y = H, 4-Me, 443, 4-MezN Ar = Ph, 3-NO,C6H,, 4-XC6H,(Me,N, Cl, MeO, Me) or 2,4-(Me0),C6H,

185 184

186

I

!HPh

188

The cyclization of malonitrile with a,P-unsaturated nitriles in methanol under the conditions of the Michael addition was found (292, 294) to be accompanied by methanolysis according to 26. Dihydropyridines 189a were isolated (292) while analogous derivatives 189b underwent (294) aromatization with the second molecule of a given benzylidenemalononitrile under the simultaneous origins of the corresponding pyridines and benzylmalononitriles. The latter were found (293,294)to react with the starting a,@-unsaturatedcom-

Some Hantzsch-like l,4-dihydro 3,5-diesters 178 where R' = 3-pyridyl and R3 = Et have been reported (64) to be available from ethyl 3-aminocrotonate and the corresponding 3-pyridyl-2-cyanoacrylatevia cycloaddition analogous to cyclization (26) but not accompanied by alcoholysis. On the other hand, methyl 2-dimethylamino2-iminopropriate with l-benzylidene-l-cyano-dimethylsulfone gave (1159) 3,4-dihydroderivative 191; see eq 28.

MeSOz\CficH

I

CH/COzMe

II

CN NHZHC\NMez

-

(28)

Mesozfi~OzMe H2N

NMez

191

A remarkable formation of 2,5-dihydropyridines 192 after the cycloaddition of arylidenemalononitriles with appropriate amidine derivatives of arylacetic acids (925) may be explained by differently orientated molecules of the starting compounds shown in eq 29.

192: cis and trans isomers Ar' and Arz = XC,H, (2-Me0, 2-Et0,4-C1, 4-iPr) or 1-naphthyl Rz = Ph or 2-MeC6H, and R* = Me or Et

The series of products formulated (469) as dihydropyridines 193 was isolated in preparatory yields (see Table XXXIII) after a less lucid cyclization of substituted ethyl cinnamates with ethyl thioglycolate in the presence of triethylamine (469). 2,3-Dihydropyridine derivative 23a was obtained (869) by a photochemically induced intramolecular cycloaddition of tetracyano derivative 194. A reductive cyclization of 1,2-dichloro-2,4dicyanobutaneinto 3-chloro-3-cyano-2,3-dihydropyridine has been patented (360). A 3,5-dicyano-l,4-dihydropyridineintermediate was considered (741) in the course of the Guareschi reaction between ethyl cyanoacetate and benzaldehyde.

218

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 ii 4r \ /

198 197a : X = SMe b: X = H

194

The extention (251)of the Bischler-Napieralski reaction to the pyridine series seems to be still rare. A further example (470)yielded 75% of 2,3-dihydropyridine 195 as shown by eq 30.

1' MeHCHC\CH2

0

I

+ PCI,

H

Me02C&&-CR'

R2R3

Ph

199 R' = H,Me, Et, Ph or PhCH,, RZ = H, Me, Et, C,H,,, or C,,H,, and R3 = H, Me, C,H,,, C,,H,,, PhCH, or Ph

-

in the photochemically induced multiple reaction of cyclopentene with N-substituted methyl 3-amino-2-formylacrylates resulting in the formation of l,4-dihydropyridine 200 according to eq 32.

ArCH,

M

e

d f POCI,

t HCI

(30)

ArCH,

195: Ar = 4-PhCH,OC6H,

A low-temperature degradation of polyacrylonitrile led to a polymer material for which 1,Cdihydropyridine structure 195a has been proposed (891). r

-,

b02Me NC

200 195a

(2)Other Cycloadditions. The known (251)procedure for the preparation of relatively stable 1,2-dihydropyridines 196 according to aq 31 has been enriched by introducing

A newly described (269)synthesis of some 1,Bdihydropyridines 203 from imino ylides 201 and acetylenic 1,3dicarbonyl electrophiles belongs to the second type of cycloadditions and seems to be a little more general. The corresponding pathway probably involves several elementary cycloadditions [3.2]sigmatropic as well as elimination steps demonstrated in eq 33. A success (269)in MeSO + / c H Z H C f r

I

R3

I

R3

196

novel Schiff bases (221,333,939) as well as on using imino ethers (51);see Table XXXIV. An analogous reaction with 2-methylthioimidazoleafforded (1112)cycloadduct 197a which can be desulfurated on Raney nickel into 1,2-dihydropyridine 197b. Another photochemically induced addition of dimethyl acetylenedicarboxylate to 1,Zdihydropyrazine derivatives 198 was found (637,638) to yield 72 to 91% of bicyclic 2,3-dihydropyridines 199 possessing different secondary or tertiary R1R2R3C residues with certain possible combinations of substituents R', R2,and R3 including optically active species. The mechanism of this pericyclic reaction seems to be rather complex and has been interpreted (638) in terms of orbital symmetry control. The formation of 4,5,6-trisubstituted dimethyl 2,3pyridinedicarboxylates after the reactions of dimethyl acetylenedicarboxylates with some l,&diimines has been convincingly explained (68)by decomposition of primary arisen 1,4-dihydropyridine cycloadducts. Two components cycloadditions leading to dihydropyridines may involve alkene-oxoenamine, alkine-iminoylide, and alkene-azirine couples, respectively. A remarkable process of the first type was recognized (1102)

C \ H-?

CCOR

Ph&Ar

201 H

COR

I

Ar

202

FOR Ph

I Ar

203 Ar,R (Yield of 208): Ph,Ph( 59), 4-N0,C6H,,Ph( 57), Ph,MeO( 54) and 4-NO2C,H,,Me0(62)

thermal transforming of independently prepared intermediate 202 having X = H and R = OMe into the corresponding 1,2-dihydropyridine203 supports the postulated


mechanism. Three-membered ring in azirines can be thermally split into reactive species which are as a rule easily added to suitable unsaturated substrates. Thus, 3,3-dimethyl-2phenylazirine with dimethylfulvene were found (837) to give a mixture of 2,bdihydropyridines 205 and 206 in the ratio 1O:l via intermediate 204, according to eq 34 in addition to a dihydropyrrole derivative.

Similar thermal cycloaddition proceeds apparently in the case of allyhino derivative 210 under sodium catalysis (207),see eq 37, and spirocyclic 1,Cdihydropyridine 211 was the isolated product.

210 I Ph

204

21 1 205

206

l-Dimethylamino-3-methyl-2-aza-1,3-butadiene generated by thermolysis of 3,3-dimethyl-2-dimethylaminoaziridine was found (217 ) to undergo a cycloaddition to dimethyl maleate accompanied by a dimethylamine elimination under the formation of 1,Cdihydropyridine 207; see eq 35. C0,Me

I

H,

(3) From Tetrahydropyridines and Hexahydropyridine Derivatives. A possibility of preparing dihydropyridines by partial dehydrogenation of tetrahydropyridines seems to be questioned because of the known tendency of the latter to undergo further aromatization. In this connection a report (945) on the conversion of tetrahydropyridine derivative 212 into the corresponding free 1,2-dihydroderivative on using sodium nitrite in acidic medium appears to be unexpected. On the other hand, relatively stable dihydropyridinium salts 213, 214, and 215 were prepared by oxidation of 1,2,3,6Ph

Jy;;

R3

C0,Me

Me

4

M e b c o z M e

-

,.rr C0,Me

212: R = 4-MeOC,H4

C0,Me

Me

(35)

207

Intramolecular thermolysis of unsaturated azirine derivatives was observed to lead to easily oxidizable dihydropyridines 208 (838) or 209 (835,836);see eq 36.

213: R’,RZ,R3, and R4 are some combinations of H, Me, Et or PhCH,

(-p I I

x

Me

SMe

phflco2Et 215: R = allyl, i-Bu, Ph, CH,CH,Ph, 2X1, Me, R’ = H, Me, PhCH, 214: M e 0 or 4-MeOC6H, RZ = Me, PhCH, X = Br or I R‘

p

h

~

z

c

o

z

E

t

N ‘H,

Hz C02R‘

Ph

208

R’ = Me, R2 = H, R3 = Ph or R’ = Me,RZ = Ph, R3 = Me

Me

phu tox

C0,Me

Me

209

\ Ph

C0,Me

tetrahydropyridines with hydrogen peroxide in trifluoroacetic anhydride (332) and by the action of alkylating ?gents on some 1,2,3,4-tetrahydropyridinelactones (370) or on 1,6-dihydro-2-thiopyridones( 1195): respectively. Hydroxy or alkoxytetrahydropyridines tend to eliminate water or alcohol molecules easily giving the corresponding dihydropyridines. Thus, tetrahydropyridines 216 being formed by cycloadditions of l-alkoxy-l,3-butadienes with methyl-3-trichloromethyl-2-aza-acrylate were found (650) to be labile and underwent a facile methanol or ethanol elimination to 83% of 1,2-dihydropyridine 217 in contrast to earlier reports (431). Similarly, 1,4-dihydropyridine218 was prepared (149) by dehydration of the appropriate 2-hydroxy-1,2,3,4-tetrahydro derivative. A remarkable 1,4-dihydropyridinebis-perchlorate 219 was obtained (263, 11 70) analogously by the action of perchloric acid on the corresponding 2,6-dihydroxy-hedydropyridine derivative.

220

Id. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982

Table XIX. Hantzsch Dihydropyridines 153 (R4= H) Prepared b y Cyclocondeneation 18 X Y RZ R3 R' Me Ph COPh COOEt NH, COOMe COOMe Me cyclopropyl 2-O,NC,H, CH,CO,Me CH,CO,Me 3-O2NC6H, COOEt Me CH,SMe 2-F3CC,H, 2-MeSC6H, CH,OCOCH, 2-0,NC6H, 3-C1C6H,

COOEt

Me Me Ph 3-pyridyl

Ph CH,OMe Me Me

4-pyridyl

Me

COOMe

4-pyridyl

Me

COOEt

Me

CH,OMe

S0,Me COOMe

CH,SMe

CH,OEt

CH,O-i-Pr CH,OCOCH,

CH,COOCH, CH,COOEt

cH2N*

ref

85 45 45 65

701 952 126 142 142 142 142

2-0,NC6H,

55

142

2-MeOC6H, 3 -ClC,H, 3-O2NC6H, 2-O,N-3-MeC6H3 2-0,NC6H, 3-E tO,CC,H, Ph Ph 2-MeSC6H, 3-0,NC6H, 3-pyridyl 2-C1C6H, 2-MeOC6H, 2-MeSO2C,H, 3-F3CC,H, 3-0,NC6H, 4-O2NC,H, 2-Et0,CCH,-3-MeOC6H, 3-F-4-MeC6H, 3,4,5-(MeO),C,H, 4-pyridyl 2-O2NC,H, 4-MeO2SC,H, 2-MeOC6H, 3 -NCC, H, 2-pyridyl 3-pyridyl 4-pyridyl Ph 2-C1C6H, O-F,CC,H, 3-IC6H, 3-0,NC,H4 3-NCC6H, 3-F-4-MeOC6H, 2-pyridyl 2-Me2N-6-pyrimidyl 2-pyridyl Ph 2-ClC,H, 2-MeOC6H, 2-F CC, H, 3-C1C6H, 3-FC6H, 3-MeOC6H, 3-O,NC6H4 4-MeOC6H, 2-pyridyl 3-pyridyl 2-pyridyl

65 65 65 85 a 60 56 55 80 a a 85 45 55 75 80 75 62 55 65 50 45 65 35 30 50 55 45 65 55 55 60 70 42 35 35 40 35 50 40 30 55 65 60 40 45 45 60

3-pyridyl

57 35 60

142 142 142 142 348 144 6 76 121 121 121 121 121 121 121 121 121 121 121 121 121 121 144 144 142 142 142 142 142 144 144 144 144 144 144 144 144 144 144 142 142 142 142 142 142 142 142 142 142 142 126 126 126

Ph

75

142

2-ClC,H, 2-MeSC6H, 3-ClC6H, 3-NCC6H, 4-FC6H,

50 35 55

142 142 142 142 142

cH*NB

COOEt

yield

2-p yridyl

a a a

55

0

90

80

Ind. Eng. Chem. Rod. Res. Dev., Vol. 21, No. 2, 1982 221 Table XIX (Continued) X

R3

R'

Y

R'

COOEt

i -Pr COOEt CH,COOEt

CH,OMe CH,OMe Me CH ,OMe CH,SMe

CH,SMe 3-pyri dyl

Me Me

4-pyridyl

Me

2-p yridyl

C0,-n-Pr

4-pyridyl

Et Me

C0,-i-Pr

4-pyridyl

Me

CO, - ~ - B u CO,CH,Ph CO,CH,CH=CH,

4-pyridyl 4-pyridyl 4-pyridyl

Me Me Me

CO ,CH,OMe

c0,-n-Pr

CO ,CH2CH,OMe CO,CH,CH,O-n-Pr COMe COOEt

3-pyridyl 4-pyridyl 4-pyridyl NH, CH3

Me Me Me Me CH,SMe CH20COCH

CO ,+Pr

COOEt

CH3

CH ,OCOCH

CO,CH,CH,OMe

COOEt

CH3

CH ,OCOCH

4 - 0 ,NC6H4 2-pyridyl 3-pyridyl 4-pyridyl 2-0,NC6H, 2-F3CC,H, 3-O,NC6H4 3,4,54Me0)3C6H2 1-naphthyl 2-pyridyl 3-pyridyl 4-pyridyl 2-pyridyl 3-0,NC6H, 2-pyridyl 3-pyridyl 3-0,NC6H, 2-pyridyl 3-pyridyl 2-MeOC6H, 3-O,NC6H4 4-i-PrOC6H, 2-pyridyl 2-MeSC6H, 4-MeSC6H, 4-EtO,SC6H, S4 ,54Me0)3C6H, 3-0,NC6H, 2-C1C H, 2-MedC6H, 3-0,NC6H, 1-Me-2-pyrryl 3-0,NC6H, 2-0,NC6H, %O,NC,H, 3-CIC6H 3-0,NC6k, 3-02NC6H, 3-O,NC,H, 3-0,NC6H, %O,NC,H, 3-C1C6H, 3-0,NC H, 3-C1C6d4 S-O,NC,H, 3-ClC,H4 3-0,NC6H,

yield

ref

45 75 65 65 58 55 62 40 65 75 75 50 60

142 142 142 142 126 126 126 126 126 126 126 126 144 144 126 144 142 142 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 121 687 142 142 142 142 142 142 142

a

60 65 35 30 45 62 65 55 65 55 70

80 80 65 85 75 55 40 50 80 50 65 75 75 60 48 40 60 65 60 65 45 60

Yields not reported. Table XX. Hantzsch Dihydropyridines 153 (R' = Me) hepared by Cyclocondensation 18

Y

R4

R'

R'

yield

ref

COOEt

COOMe COOE t COOEt CO, -i-Pr

Me 4-pyridyl Me Me Me

3-pyridyl I-O,NC,H, I-O,NC,H, 2-0,NC6H, P-O,NC,H,

70 70 40

CO,CH,CH,NMe,

4-MeOC6H, Me 4-E tOC,H, Me Me

122 121 122 453 453

X

a

a (I


Table XXI. Dihydropyridinea 155 and 156 Prepared by l8-Like Cyclocondensation R % of 155b ref R Me Ph 2-PhC,H P-O,NC,h, 2-NCC6H, 3-C1C6H, 3-0 ,NC,H, 3-EtOOCC, H, 2-F,C-4-0,NC6H3 2-02N-4,5-(MeO),C6H,

53, 25 24

35,20 69 49 66, 54 61,66 35 62,32 52

6 79, 68 7 6 79 6 79, 68 7 679, 68 7 68 7 679, 68 7 679, 68 7 6 79 679, 687 68 7

2-0,NC6H, 2-F,CC H, 3-C1C6€f, 3-02NC6H, 2-pyridyl

% of 156

ref

80

121 121 121 121 121

60

55 85

70

222

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 ,CH2CN

ti,

I

=

C02Me

CHzPh

217

21 8

Me or Et

Me Et

I

I

C02Me

216: R

Table XXII. Dihydropyridines 157 Prepared (641 ) by Cyclocondensation of Type 1 8 RZ R' n X yield 3-0,NC6H,

4 2 2 2

3-C1C,H4

CH, s NH

50 46 72 59

Table XXIII. A Survey of Prepared 1,4-Dihydropyridines 160

RZ

R'

H 220: R' = Me, Ph, CH,Ph, RZ = Me or R', R' = (CH,), or (CH,),

219

A preparative procedure for the synthesis (251) of 1,4dihydropyridines 220 from 4,4-disubstituted 3,5-dibromo-3,5-dicyanoglutarimidesand triphenyl phosphite as well as similar phosphonites was reported (176). (4) From Other Heterocycles. Some new examples of 4H-pyrans conversion into l,4-dihydropyridines (251) have been described. Several 3,5-diformyl-1,4-dihydropyridines 26 (R = H or aryl residues) were prepared by the reaction of 4H-pyran 221 with ammonium acetate (1172) and with arylamines (1173, 1174), respectively. 4H-Pyran bis-lactone 222 gave (158) the corresponding 1,4-dihydropyridine 163 in the same way. H, , C a C H

Me

Et Ph

0

221

222

The known (251) approach to simple dihydropyridines consisting in thermolysis of their oligocyclic strained isomers has been further developed. Thus, variable 1,2-dihydropyridines 31a and 223 were found to be available either from precursors 224 (1091)or 225 (88,115,362,363) by pyrolysis. The lithiumaluminum hydride reduction of 224 led (1091) directly to 70% of simple 1-methyl derivative 31c. 2,3-Dihydropyridine 226 was obtained (262) by the action of acetic acid on a chloroform solution of the bicyclic precursor 227.

4-MeOC6H, 4-Me,NC6H, 2-fury1 a

223

R' = R2 = H, R3 = C0,Me R1 = H, Rz = D, R3 = C0,Me R' = H, RZ = CO,Et, R3 = C0,Me R' = D, R2 = CO,Et, R3 = C0,Me

H

,CO,R'

228 224a: b: c: d:

a a a

D D D

34

D

a a

D D

34

D D, E D, E D E E E E E E E D D D D D D D D D D D D D E

a a

80 a a a a a 88 a 58 60 a a 14 62 35 66 20 54 37 68 67 54

962 962 962 559,962 27,28 27,28 559 27,28 27,28 559 28 28 962 962 962 963 962 559 559 27 27 559 559 559 559 559 559 559 559 559 963

A general synthesis (416, 705,1050,1051) starting from easily available bicyclic diaza-diesters 228 proceeds probably also via tricyclic strained intermediate 229; see eq 38.

6

I

Me CH2CH20H CH,COOEt CH,Ph C6H,-2-OH 2-H,NC6H, CH,Ph 2-HOC6H, 2-H,NC6H, 4-MeOOCC6H, 2-HOC6H, %-H,NC,H, Me CH,CH,OH CH,COOEt Ph CH,Ph cyclohexyl 2-MeOC6H, 2-HOC6H, 2-H2NC,H, 3-BrC6H, I-HOC,H, 4-EtOC6H, 4-0,NC6H, 4-Et,NC6H, Ph CH,Ph 4-Et,NC6H, Ph Ph

ref


R'OzC,

R3

yield method

----several steps +

9-

\/"

oxidation

N

I

R2

(38) k2

229: R' = Et or t-Bu, RZ = Me. Ph. 4-XC6H,(Me,Br,CN), Ph( CH,) ,, MeSO,, or PhSO,

k3

225: R' = RZ = H, R3 = Me, (CH,),-,Ph, (CH,),,,CH=CH,, CO,Me, CH,CO,Et, (CH,),COMe, (CH,),, ,CO,Me, (CH,) ,-( 3-indolyl)

226: Ar = 4-C1C,H,

221

A similar feature may be recognized in the formation of l,.i-dihydropyridine 230 after the cyclocondensation of triphenylpropene with certain 1,3-oxazoles (660)or 1,3thiazolones (892,893) shown in eq 39. The formation of 1,Pdihydropyridine 231 after the reaction of 3-aminopropionitrile with tris-tert-butylthiocyclopropenium salts in the presence of potassium tertbutanolate reported in the patent source (1184) might be

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 223 H

I

I

235a : R = H b: R = M e

Me

Me

X=OorS H.

Ph

230

also explained via a strained bicyclic intermediate in accordance with eq 40. X

NCCH2

I

X

n

H

l

231: X = t-Bus and R = t-Bu 2,2,3,5-Tetraalkylated 1,2-dihydropyridine 232 was reported to be available in a mixture with 3,5-diethyl-2propylpyridine on heating of heterocyclic derivatives 233 (831)and 234 (830)with acetic acid. P,

I

Bu

233

234

232

Different 1,2-, 1,4-, and 2,3-dihydropyridine intermediates were found or assumed during a high-temperature aminolysis of 2-furoic acid (330)and after the reactions of some 1,3-oxazoloneswith acetic anhydrides in pyridine (1047)or with allyl bromide in the presence of bases (321). (5) Miscellaneous. 2,3-Dihydropyridine 235a was found (206)to be one the products being formed by the reaction of diallylamine and diisopropylamine in the presence of sodium. A similar compound 235b was identified (175)by NMR after a 30-min heating of n-butanal with ammonium acetate. The preparation of an unspecified dimethylethyldihydropyridineby the reaction among ethylene, carbon monoxide, water, rhodium(II1) chloride, and triphenylphosphine was patented (271). Thermolysis of the substituted alleneamidine 236 yielded (298)90% of 2,3-dihydropyridine 237 while 2,6diaryl-3,5-dimethyl-l,4-dihydropyridines being formed during pyrolitic rearrangements of some ketone quaternary hydrazones were found (765,766)to interact with other intermediates to the corresponding pyridines. Intramolecular dehydration of some 2-acyltryptophans to dihydro derivatives 238 on heating with hydrochloric acid was also found (897)to be a useful method for identification of the appropriate residues in proteins. Cyclo-

238

,C(Me)t-Bu

236

Me

Me

237

condensation of 2-benzoylethylamine with ethyl acetoacetate was reported (918)to give easily oxidizable 3-ethoxycarbonyl-2-methyl-4-phenyl-5,6-dihydropyridine. A 1,Qdihydropyridine derivative isomeric with 5-anilino-lphenyl-2,4-pentadienylideneiminiumchloride is assumed (662,663) to be an intermediate during the conversion of the latter into 1-phenylpyridinium chloride. IV. Chemical Reactivity A. Aromatization. Conversion of nonaromatic T electron dihydropyridine systems into heteroaromatic pyridines appears to be a typical feature of dihydropyridine chemistry. A classification of the corresponding processes might seem somewhat arbitrary as mentioned in ref 251. Such reactions, the principal aim of which is the preparation of a pyridine, are listed here under the “Aromatization” heading. “Hydrogen transfer”, on the other hand, includes studies designed to investigate the mechanism of the process where the nature of reduced products is of greater importance than the pyridine. (1) Chemical Oxidation. Oxidation with chemical reagents is probably still the most universal procedure for aromatization of dihydropyridines. It is well known (251) that variable oxidating agents can be applied for this purpose. A list of the reactants used in the past decade is given in Table XXXV. Newly introduced reagents appear to be especially organic peroxides, tetrachloromethane, nitrosobenzene, phenylpicrylhydrazyl, ozone, potassium permanganate, mercury(I1) acetate, and diazonium salts. 1,4-Dihydropyridines 119 and 120a (R = 2-Me) possessing trimethylsilyl residues were readily converted into pyridines 239 and 240 with oxygen (1065,1067)or potassium permanganate (82)evidently due to an easily oxidative splitting of Si-N bonds. Analogous oxidation of another dimeric 1,4-dihydropyridines 11If to the corresponding bis-pyridinium salts were patented (78,168,188, 190,191). The readily oxidation of l,&dihydropyridines 239 with triphenylcarbonium tetrafluoroborate into labile pyridinium salts 240a was successfully explored (671)as an effective phosphorylating method for hydroxy derivatives ROH in the sense of the equation: ROH + 240a ROPO(OAI-)~ 240b. Structural effects on the oxidation of Hantzsch dihydropyridines 241 and 242 with chloranil were investigated (1116).It has been found that the oxidation rate decreases in dependence on substituents R and X in the orders H > Me > Ph for X = COzEt and COMe > COzEt > COPh > CN in series 241a while in the order CONHPh > COPh > COMe > C02Et > CN in series 241b and 242, respectively. Similar effects were stated in polarographic (571,1054) and fermentative (237)oxidations. Further examples of loss of a substituent during dihydropyridine oxidations were described (58,568,570).

+

-

224


- "aN "yJCN (42)

- 2- He *

Me

241a: R = H

242

Hantzsch diester 243 was found (58) to eliminate 4-dimethylaminophenyl residue at the 4-position quantitatively according to eq 41. NMe,

I

EtO2CfiCO2Ei

Ll Me

NH

Me

Me

NH

Me

X = I, NO, SCN, HgOAc or 4-HS0,C6H,N,

243

Me

Me

246b

b: R = Me

EtO2C&CO2Et

Me

The oxidizing electrophiles X+ were generated in situ from the appropriate precursors (58). On the other hand, no elimination of the same 4-substituent was observed (990)during the oxidation of lP-dihydropyridine 87c with triphenylcarbonium perchlorate while similar l-tosyl-4(3-indolyl)-l,4-dihydropyridine was found (1062) to eliminate completely its 4-substituent as 3-triphenylmethylindole. Oxidation of Hantzsch esters of 14 type with pyridine-N-oxide at 210 "C (568,570)may be attributed to a side thermolysis of the starting compounds (see later) rather than to an oxidation process. Sodium 1-benzyldihydronicotinamide-4-sulfinate 244 was observed (433-435)to reduce some organic substrates under a complete elimination of 4-substituent leading to corresponding pyridinium ion 245.

ester 14a and its N-methyl homologue with dialkyl and diacyl peroxides on the basis of kinetic (361, 424) and proton NMR (1114) data. A positive isotopic kinetic effects in the oxidation of N-deuterated 14a was observed (425)on using di-tert-butyl peroxide but not in the case of diacetyl peroxide. A similar radical route for the ferricyanide oxidation of dihydronicotinamide 21 having R = CH2Ph and of compound 14a has been postulated (334, 335) also on the basis of kinetic experiments. Antioxidant properties of certain l,4-dihydropyridine derivatives were interpreted (1104, 1145) as their reactions with suitable radicals. A dehydrogenation of 3,4-dihydropyridines of 189 type having been frequently observed (292) during their syntheses according to eq 26 from 2-phenyl-3-arylacrylonitriles may be explained by the reduction of the latter with 189. An 1,2-dihydropyridine radical cation being formed after an attack of propionyl radical at 4-cyanopyridinium ion was assumed (169) to be readily oxidized with Fe(II1) salts to heteroaromatic 4-cyano-2-propionylpyridinium ion. (2) Simple Elimination Reaction. 1-Hydroxy and l-acyloxy-1,2-dihydropyridinesundergo as a rule a spontaneous dehydration or elimination of appropriate carboxylic acid. Thus, 1,2-dihydropyridine intermediates 247a-d were explored (187,471,962,966)in the synthesis of pyridine derivatives 248a-d according to eq 43. R'

247a: R1, R2 = (CH,),, R' = R4 = R5 = H (969) b: R' = R3 = Me, R2 = R5 = H, R4 = Ph (966) c : R1 = Rz = R3 = H, R4 = MeOC,H, or NCC,H,, R 5 = COMe ( 1 8 7 ) d: R1 = COMe, Rz = R3 = H, R4 = 3-indolyl, R 5 = COPh (471)

$jCONti2 S02Na

H

I

CtizPh

@CO""'

I

CH2Ph

245

A remarkable course of the oxidation of 4-ferrocenyl1,4-dihydropyridine 246a was discovered (817). On using dichlorodicyanobenzoquinoneas oxidizing agent, a radical cation 246b proved by ESR is formed as an intermediate followed by aromatization of 1,4-dihydropyridine system; see eq 42. Another mechanism involving radical intermediates was proposed (361, 424, 425) for the oxidations of Hantzsch

248a-d

The formation of 2-phenylaminopyridines 250 after the reaction of bicyclic 1,2-dihydropyridines109 with hydroxy ions (401,403)may be explained in a similar way via the acid 249 according to eq 44. A spontaneous aromatization in a l,4-dihydropyridine series was observed (908) in the case of 1-triphenylmethyl


A large number of 1-metalodihydropyridineshave been aromatized thermally. l-Lithio-1,2-dihydropyridinesbeing formed by the addition of organolithium reagents to pyridines (see section 1II.A.l.b) tend to eliminate lithium hydride at elevated temperatures and afford the corresponding pyridines (308-311,529,530,642). Spirocyclic 1-lithio-l,4-dihydropyridine 254 was found (285) to aromatize spontaneously according to eq 46, which resembles the process 4 proceeding in an opposite direction. -

I

250

Ph

2 49

R1 and R' = H, Me,Et, or CN derivative 151 which eliminates triphenylmethane in agreement with eq 45.

I

CPh3

Other dihydropyridines having C-N' bonds are usually decomposed into pyridines at temperatures exceeding as a rule 200 "C. Thus,1,4dihydro derivative 57c is reported (108,223)to afford pyridine derivative 252 on heating. Thermolysis of dihydropyridines 41 and 253 where R are

I'

LI+ LI

254

Metallic l,4-dihydropyridine derivatives 134 (M = Mg or Zn) underwent a thermolysis (211) into two molecules of pyridine in addition to one equivalent of magnesium, hydride or zinc with hydrogen, respectively. No systematic work has been done on catalytic dehydrogenation of dihydropyridines. l-Benzoyl-4-(3indoly1)-l,4-dihydropyridineis reported (268)to give the correspondingCsubstituted pyridine 255a on heating with a palladium-charcoal catalyst in diphenyl oxide at 200 "C. A similar formation of pyridine derivative 2558 having been observed (990)after the action of ethanolic potassium hydroxide on lP-dihydropyridine 87c might be explained by a disproportion (see later) rather than by a pure dehydrogenation process. On the other hand, catalytic dehydrogenations of 1,2-dihydropyridines 101 and 102b on Pd-charcoal were found to proceed smoothly in fivemembered rings of both reactants to afford the products 256 (291) and 257 (949),respectively.

YH(CH2 )3CO(CH2)3NH I

J

p

N

PhCO

252

I

R

253

alkyl, benzyl, or heteroarylmethyl residues gave (488,489, 492) some hydrocarbons and heteroaromatics of general formula RH in addition to 2,4,6-triphenyl- and 2,3,5,6tetraphenylpyridine, respectively. Analogously, tricyclic l,4-dihydropyridines 160 (R' = H or Ph and R2 = CHzPh or CH2CH20H)were converted (962)into the appropriate 4-substituted pyridines at temperatures between 240 and 280 OC. As already mentioned above, the oxidation of Hantzsch esters of type 14 with pyridine-N-oxide a t elevated temperatures is accompanied by a loss of 4-substituents which were found (568,570)to be trapped with pyridine as its 2- and 4-substituted derivatives, thus indicating a radical mechanism of the thermolysis. 1,4-Dihydropyridine derivatives possessing N'-N or N1-S bonds seem to undergo aromatization already at somewhat elevated temperatures. Such a decomposition of 1-(4pyridonyl) derivatives 55, where R' = certain alkyls, acylalkyls, CN, or P h and R2 = H or Me, was used (486, 487, 618) for the preparation of variable 4-substituted pyridines. Success in catalyzing the process with azobisisobutyronitrile (486) suggests a radical mechanism. 1,4Dihydropyridines 32b,c are reported (1050) to be easily convertable into pyridine and the corresponding potassium sulfinates (R = Me or Ph) by the action of potassium tert-butanolate.

255a : Ar = 3-indolyl

b: Ar = 4-Me2NC,H,

H

256: R = H, Me

X - H, CN R3

R' t o R" = H o r Me (3) Complex Elimination Reactions. In some cases a final elimination reaction step leading to products of dihydropyridine aromatization is undoubtedly preceded by a number of foregoing additions or substitution elementary reactions. Consequently, the whole aromatization process proceeds as multi-stepped conversion of a given dihydropyridine into a pyridine the structure of which may differentiate more or less in comparison to that of the starting compound. Thus, 2-methoxy-l,2-dihydro derivative 76a was found (20) to be readily aromatized with perchloric acid apparently via the addition-elimination mechanism proposed in eq 47. Sodium 1,4-dihydronicotinamide-4-sulfinate244 was found (433)to react with some arylalkyl bromides probably via substitution-addition intermediates 258 and 259 giving pyridinium ion 245 and the corresponding sulfones according to eq 48. 257:

226

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 H

H

76a

-

M

e

H+

a

t

MeQ“’

e and/or

\+

H

\+

OMe

I

-

OMe

I

R

R

(y! I

(47)

:e

R

R = CH=CHCO,Me ERBr

244

ONH,

I

Br I

I

I

I

PhCH(CH2)ZBr

CHZPh

- NO+- 28

258

R = PhCH, or PhCH=CHCH,

N-aryloxy-2-pyridones into pyrido-[2,3-b]-benzofurans262 caused by the action of thionyl chloride or phosphoroxy chloride, respectively. (4) Disproportionations. Such aromatizations in which a dihydropyridine is both the donor and the acceptor of hydrogen are considered to be disproportionations here. Dihydropyridines often tend to undergo disproportionations by heat or by catalysis with different agents as, e.g., palladium or hydrochloric acid (251). Some of those transformations have not been so far recognized experimentally and may be erroneously interpreted as different reaction types (see above). Hence, a disproportionation process need not be without importance in all cases of dihydropyridine aromatizations where yields of obtained pyridines do not exceed 50%. Several examples of the disproportionations were fully recognized in the past decade. Thus, l,2-dihydropyridines 263a,b formed by methanolysis of the corresponding 1lithio derivatives were found (7, 289) to give exclusively products of disproportionation 50 under the reaction conditions used.

Ph

I

R2 = t-Bu (289) b: R’ = Me and R2 = 2-MeC6H, ( 7 )

263a: R’ = H and

+

I

U

245

CH2Ph

259

In the case of the reaction of 244 with benzyl the intermediate 260 was isolated (434). The latter eliminates after protonation one benzoin molecule to give ion 245 slowly in aqueous methanol but very rapidly in the presence of magnesium chloride. As expected, the decomposition of 260 involving a proton addition, see eq 49, can be retarded by hydroxide ions (434).

“GoHO,

,Ph

)(,N6h

244

+ ‘OI Ph COPh

H20 -No

HSO;

-so32-

t&J I CHZPh C(OH )Ph

245

The origin of 2,3-dihydropyridine 235a from aliphatic amines and metallic sodium was always accompanied (206) by its disproportionation products. 2,BDihydropyridines 294a-e and 265 were also found (288,454)to disproportionate thermally into appropriate pyridines and tetrahydropyridines. 2,5-Dihydropyridine-N-oxides 264, however, underwent disproportionation 51 somewhat at already lower temperatures (967,968).

-k Ph(HO)C4

bH

264: R = Me or Ph

e PhCOCH(0H)Ph

(49)

1,4-Dihydropyridine260 (X= 4-Br and Y = 4Me0) was

An intramolecular disproportionation process may probably take place under suitable conditions. In favor of this assumption 3-pyridyl-tetrahydropyridine267 was

C H t C O C 6 HqX’

&l

ANI

phflNHAPh

R~SO?

I C6H4X

260

I

262: X = C1 or NO,

C6H4Y

261a: R = CH,COC,H,X

R2 = H. Me R 3 ’ = CH,Ph, 4-MeC,H4, or 1-adamantyl

265: R’.

-

H

266

Z = Br b: R = H, Z = C1

described (511) to be aromatized into the corresponding pyridinium salt 261a with gaseous hydrogen bromide while hydrochloric acid gave a mixture of salt 261b and p bromoacetophenone. These unsufficiently clarified findings (511) may probably be associated with a complex disproportionation mechanism. 1,2-Dihydropyridine derivatives are believed (6) to be key intermediates in complex rearrangements of some

267

isolated (309)instead of expected dimeric dihydropyridine 266 after the reaction of l-lithio-2-phenyl-l,2-dihydropyridine with 2-phenylpyridine.


Table XXIV. Hantzsch Dihydropyridines 166 hepared by Cyclocondensation 20

X PO( OEt) CONH, CONMe, COOMs

R3

R4 H H H H

I

I ‘

R2

Me Me Me Me

R’

yield

ref

Ph 3-O,NC6H, 3-0,NC6H, 2-FC6H, 2-F,CC,H4

29 58 70 61 49

441 130 130 682 682

3-O2NC,H,

a

73 7

CH2-2-pyridyl

3-0,NC6H,

76

124

( C HZ)3NnNMe

3-O,NC6H,

27

124

3-O,NC6H,

a

73 7

45

126 349 682 682 682 535, 536 1160 1160 73 7

Et

Et Et CH,CH=CH, CH,C=CH CHZCHZNCHzPh

I

Me

Me

Me

W

C H 2 CHz NC HZPh

I

Me

COO-i-Pr COOCH,CH,O-n-Pr COOCH,CH,(Me)CH,Ph a

COOEt Me

H

COOEt

COOEt Me

H H H

Ne Me

Et Et CH ,CH=CH

3-0,NC,H4 2-NCC6H, 2-MeC6H, 2,3,4-( MeO),C,H, 2-Me0 C, H, 3-0,NC,H4 3-0,NC6H, 3-0,NC6H, 3-F,CC,H4

,

CH,CH,O-n-Pr Et CH,CH,O-n-Pr i-Pr Me

a

54 58 41 a 41 40 a


A similar product like 267 was also isolated (614) after the hypochloride oxidation of simple dihydropyridines generated in situ. (5) Hydrogen Transfer. A major number of papers has been focused on the study of different biomimetic reactions with simple NADH models, e.g., certain 1,4-dihydropyridine derivatives, which resemble with more or less perfection real biochemical reductions preceeding in living organisms. Several reviews on this topic were published (372,442,516,544, 796,1025) in the past decade. Although different model investigations have concluded a hydride or a one-electron mechanism to be correct for a given reaction (see ref 475 and 7%), no convincing proof is available for the corresponding enzymatic systems. It may be noted that within model chemical systems involving simple 1,Cdihydropyridines the problem may be more clearly formulated as a question of whether a given oxidation of dihydropyridine P H into pyridine P coupled with the reduction of substrate S into its reduced form SH proceeds either by a one-step (52) or two-step (53) mechanism

- ... ... - + - ... - + - ... + PH

or PH

+S

+S

[PH S]*

[P H- SI* PH+.

S-.

P

SH

(52)

[P SH]* P SH (53)

Attempts (575)to distinguish both mechanisms 52 and 53 on the basis of a quantitative comparison of rate constants for 1,Cdihydropyridine reductions with 1,4-dihydropyridine reduction potentials did not lead to unambiguous conclusions. Nevertheless certain inspiring views regarding the mechanistic problem might be stimulated on the basis of the novel material on non-enzymatic catalysis and on further environmental effects recognized during different dihydropyridine aromatizations (see later). Some arguments in favor of charge-transfer interactions between NADH and p-substituted 2,6-dinitrobenzene-1sulfonate ions are available on the basis of the kinetic experiments (574)including the corresponding Hammett plots. 1-Propyl- and l-benzyl-l,4dihydronicotinamides268a,b and Hantzsch ester 14a seem to be the most popular

NADH models, probably because of their easy availability and sufficient stability under laboratory conditions. Novel reductions performed with those 1,Cdihydropyridines are summarized in Tables XXXVI and XXXVII. Similar models immobilized at a polymer matrix were used (260, 806,848, 1018), too. In agreement with earlier results (251) on other substrates, protonated Schiff bases were found (1013) to undergo a reduction with 268b in 0-deuterioethanol without deuterium transfer. As expected, the latter was proved after the reductions of trifluoroacetophenone (183,1045), a-keto esters (769),activated C=C bonds (305,850)as well as of iminium salts (57) with 268a,b or Hantzsch ester 270. A kinetic isotopic effect was observed (462, 769,810,813, 850,1005,1045) during the reductions with 269 and 270. D.

9

.D

,D COZEt

I

I

I

I

R

268a: R = n-Pr b: R = PhCH, c : R = (CH,),,Me d: R = (CH,),NEt,

“ozcJYJ Me

CHzPh

Me

27 0

269

Substituted benzaldehydes were reduced (790) with 268b as well as with the analogous N,N-dimethylamide to the corresponding benzyl alcohols. The reductions using 1heptyl-3-morpholinosulfonyl-1,Cdihydropyridine failed to be accomplished (790) contrary to earlier reports (1023, 1024). As expected, the reductions of some steroid iminium salts 14a was found (847)to proceed stereospecifically with respect to the substrates. The rates of the reduction of bis(4-dimethylaminopheny1)phenylcarboniumsalts with 268b were ascertained (107)to be dependent on the appropriate counterions and to decrease in the order Cl- > Br- > C10, > I-. A number of investigations were engaged (879-884, 889) in the kinetics and the mechanism of triphenylverdazyl radicals or anions dehydrogenations with 14a or 26813. On using a series of Hantzsch esters 143 having at the 4-position para X-substituted phenyl residues in place of 14a a remarkable

228


Table XXV. Hantzsch Dihydropyridines 170 Prepared by Cyclocondensation 21

R2 H

X

Y COMe COMe COOMe

R'

COMe S0,Ph COOEt

COO-i-Pr CO 0-i-Bu COOCH, CH=CH, COOCH,CH.OMe COOCH;CH;N(Me)CH,Ph COOEt

COOMe

COOEt

COOCH,CH,Cl COOCH,CH=CH

,

COPh CO-n-morpholyl PO( OEt), COOCH,CF, COOPr coo-i-Pr

NO, COOEt COOMe COOEt coo-i-Pr COOMe

COOEt

COOCH,CH=CH,

COOCH,CH,O-n-Pr COOMe COOEt

COOCH,CH,OMe

S0,Ph

COOCH,CH,OEt COOCH,CH,O-n-Pr

NO, COOEt coo-i-Pr S0,Me COOMe COPh CONHPh COOEt COOMe

COOCH,CH,OPh COOCH,CH,SEt COOCH,CH,NMe, COOCH,CH,CN CN

COOEt coo-i-Pr COO-n-Bu COOCH,CH=CH,

5-O2N-2-furyl Ph 2-NCC6H, 3-0,NC6H, 4-O,NC6H, 3-0,N-6-C1C6H, 1-naphthyl 2-pyridyl 2-NCC6H, 3-pyridyl 2-0 ,NC,H, 3-0,NC6H, 3-O,NC6H, 3-O,NC6H, 3-F,CC6H, 3-NCC6H, 4-MeSC6H, 2, 3 4 4 C, H 3-pyridyl 4-chinolyl 2-PYrrYl 2-thienyl 2-pyridyl 3-pyridyl 4-pyridyl 5-OzN-2-fury1 Me 2-CIC6H, 2-F,CC6H, 2-C1C6H, 2-NCC,H, 3-C1C6H,

Ph 4-MeOC6H, 3-C1C6H, 3-0,NC6H, 2-0,NC6H, 3-0,NC6H, 3-0,NC,H, 2 - 0 ,NC,H, 3-0,NC,H, 3-0,N-6-ClC6H, 2-pyridyl 2-thienul 2-NCC6H, 2-NCC6-H. 3-0,NC6H, 3-0,NC,H4 3-NCC,H , 3-0,N-6-C1C6H, 1-naphthyl 3-02NC,H, 3,4-(Me0),-5-BrC6H, 2-MeC6H, 2-NCC6H, 3-OzNC,H, 2-0,NC6H, 3-0,NC6H, 3-0,NC6H, 3-0,NC6H, 3-0,NC6H, 2-0,NC6H, 3-0,NC6H, 2-C1C6H, 2-ClC,H, 2-CF,C, H, 2-C1C,H4 2-MeOC6H, 2-NCC,H4 2-F ,CC,H, 2-0,NC6H, 3-MeC6H, 2-pyridyl 3-pyridyl 2-O,NC,H, S-O,NC,H, 3-0,NC6H, 3-0,NC,H4 3-0,NC,H4

yield Q

61 65 67 85 40 45 63 51 52 78 63 51 Q (I

68 60 75 36 74 36 45 90 90 90 Q

60 40 57 (I

77 75 50 57 52 Q

54 49 54 48 70 54 40 41 49 60 55 41 38 60 62 46 24 55 65 62 48

46 65 62 70 Q Q

66 47 32 43 42 64 63 55

60 58

61 55 52 49

ref 63 790 681 681 681 681 68 1 681 681 681 1158 681 68 1 7 37 7 37 681 681 94 681 681 681 68 1 748 748 748 63 834 682 682 56 0 130 130 441 441 120 415 681 681 681 681 681 681 681 681 681 681 681 681 681 1160 682 682 681 681 1162 1162 120 681 1160 1162 1156 561 562 1164 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157 1157


Table XXV (Continued)

X

Y

R2

COO-c-C,H,, COOCH,C6H4-2-Cl COOCH .CH,OMe COOCH CH O P ~ COOCH,CH,OBu COOCH,CH,OPh COO-i-Pr S0,Me S0,Ph

COOCH,CH=CH,

COOCH,C=CH

COOMe COOEt

COO-c-C,H,

coo-i-Pr S0,Me S0,Ph

COO-C-C~H,, COOCH,Ph

NO, COOEt COOMe S0,Ph

COOCH,C, H,-4-F

S0,Ph

COOCHZC,H,-4-Cl COOCH,C6H,-3,4-Cl,

S0,Ph S0,Me S0,Ph SO ,Ph S0,Ph COOEt S0,Me

COOCH2-2-pyridyl COOCH,CH,F'h COOCH,CH,CN COOCH,CH,OMe CN

R'

yield

ref

3-0,NC6H, 3-0,NC6 H, 3-0.NC.H. 3-O;NC;H; 3-O2NC,H, 3-0,NC,H, 3-0,NC6H, 2-0 ,NC,H, 2-0,NC6H, 3-0,NC6H, 3-O,NC6H, 2-pyridyl 2-F, CC, H, 3-O2NC,H, 3-O,NC6H, 2-0,NC6H, 2-0,NC6H, 3-O,NC6H, 3-0,NC6H, 3-0,NC,H, BO,NC,H, 2-ClC6H, 2-O,NC,H, 3-02NC,H, 2-C1C6H, 2-0,NC6H, 3-O,NC6H, 2 - 0,NC, H, 2-0,NC6H, 2-0,NC6H, 2-0,NC6H, 2-O,NC,H, 2-F ,CC, H, 2 - 0 ,NC,H, 2-C1C6H, 3-O,NC6H, 3-0,NC6H,

54 42 55 53 50 47 58 62 55 58 70 42 49 54 59 65 70 68 48 44 70 58 79 76 60 60 68 61 55 68 54 59 66 68 59 45 43 32 22 47 52 48 28 47 61 49 57 61 59 38 46

1157 1157 1157 1157 1157 1157 681 1162 1162 1162 681 681 682 681 681 1162 1162 1162 120 681 143 1162 1162 1162 1162 1162 1162 1162 1162 1162 1162 1162 1239 1162 1162 1157 1157 1157 1157 120 120 120 120 120 686 686 686 686 686 686 686

Ph COOMe

Me

COOMe COOEt

COOEt COOCH ,CF NO, COOEt COOMe

coo-i-Pr COOCH,CH=CH, COOCH,C=CH

COOMe COOEt COOEt

2-0,NC6H, 2-F3CC,H, 3-0,NC6H, 3-C1C6H, 3-0,NC6H, 3-0,NC6H, 2-0,NC6H, 3-0,NC6H, 3-O1N-6-C1C,J-4 2-fury1 3-0,NC6H, 3-0,NC6H, 2-NCC6H,

Yields not reported. Table XXVI. Bicyclic 1,4-Dihydropyridines 17 2 Prepared by Cyclocondensation 22. See Ref 641 R2 R' X n yield Me Et

2-MeC6H, 2-NCC6H, 3-0,NC6H, 2-MeC6H,

CH, CH, CH, CH,

2-ClC6H, 2-F,CC6H, Me 2-MeC6H,

CH, CH, NH 0 S NH 0 S NH

2-O,NC,H, 3-ClC6H,

4 4 4 2 3 4 4 2 2 2 2 2 2 2

74 54 79 77 66 79 46 53 41 75 52 44 66 71

kinetic substitution effect of X was observed (882).Further effeds were studied kinetically for the redox couples trifluoroacetophenone-l-carbamoylmethyl-1,4-dihydro-

nicotinamide (1048)and o- or p-substituted l-benzyl-1,C dihydronicotinamide-N-methylacridinium ion (351,352). In the latter case an additional catalytic effect of ortho substituents was reported (351). Some structural effecta influencing the ability of 1,kdihydropyridines 160 to reduce methylene blue, brilliant green as well as indigocarmine, were investigated (559),too. The reduction of immobilized tetra-o-acetylriboflavinewith NADH 21c was found (1020) to proceed much faster than with 3methyl-tetra-0-acetylriboflavine. Contrary to the behavior of 21c simple model 26813 exhibited (1019,1020)practically the same reaction in the both cases. The mechanisms of some oxidative aromatizations of 1,4-dihydropyridines have been discussed in connection with experimentally followed environmental effects. Thus, the findings that the rate of ferricyanide oxidation of 2688 was increased (814)in the presence of monucharged cations in the order of their polarizabilities, e.g., Cs+> Rb+ > K+ > Na+ > Li+ N Et,N+, were interpreted in favor of the


230

Table XXVII. 1,4-Dihydropyridine Derivatives 176 Prepared from 2-Methylene-Indandione Precursors. See Ref 1161a R' R2 yield H

EtS n-PrS PhCH,S EtS n -PrS n-Pro PhCH,O EtS n-PrS PhCH,S EtS PhCH,S EtS EtS EtS PhCH,S EtS PhCH,S EtS PhCH,S

Me Ph

2-HOC6H, 2-0,NC6H, 4-0,NC6H, 4-BrC6H, 2,3-(MeO),C,H, 2,4-C1,C6H,

100 15a 11a

18a 19a 82

85 87 59 70 79 80 82 69 79 69 63 73 65 79

a Obtained from indandione and the corresponding aldehyde.

425) including isotopic effect (425),aswell as intermediates NMR spectra (1111) measurements seemed to be in

agreement with a radical mechanism of the process. On the other hand, the reduction of quinone with 268b was concluded (760) to proceed either in radical or in ionic pathways on the basis of a study of kinetic solvent effects. Some effects of polyelectrolytes on the reduction of methylene blue with 268b were also mentioned (1021). Simultaneous interconversions of phenylglyoxal, hydrogen peroxide, and 268b molecules at different pHs and in the eventual presence of air oxygen, nitrobenzene, and Cu2+ions as models of speculative biological systems were investigated (885-888,1182,1183) spectrophotometrically and the reaction mechanism was discussed. Some organic redox systems, interesting from the point of view of biochemistry of the NADH-NAD couple, have been investigated. Thus, hydride transfers from 268b (1135, 1137) or from Hantzsch diesters of type 14 (1132) to corresponding pyridinium salts were investigated including isotopic effect considerations. The first example of a system capable of mimicking the stereoselectivity within NADH-NAD enzymatic interactions was recognized (924) in the finding that bridged pyridinium ion 271 re-

Table XXVIII. 2-Amino-1,4-dihydropyridines177 Prepared from Alkyl 3,3-Diaminocrotonates

R3

R2

R'

yield

ref

yield

ref

Et

Me

Ph 2-MeC6H, 2-C1C6H, 3-C1C,H4 4-MeOC6H, Ph 2-C1C6H, 3-C1C6H, 3-O2NC,H, 2-CIC6H,

73 61 62 56 52 69 68 73 71 51

690 690 690 690 690 690 690 690 690 690

58

679

52 30 58 63 62 94 62 21

679 679 679 679 679 679 679 679

R'

yield

ref

2-02NC,H, 2-NCC. H, 2421-5-& h C H, Me Ph 2-MeC6H, 2-PhC6H, 3-C1C6H, 3-O,NC6H, 2-fury1 3-02NC,H, 3-O2NC,H,

39 34 78 52 74 54 32 48 60 82 80 a

679 679 679 679 679 679 679 679 679 679 679 563.564

69 77

679 679

Ph

Me

i-Pr

Table XXIX. Hantzsch-Like 2-Amino-1,4-dihydropyridines 17 8 Prepared from Alkyl 3,3-Diaminocrotonates

R3 Et

R2 Me Et

i-Pr CH,CH,NCH,Ph I

Me n-Pr

i-Pr a

i-Pr Et

3-O,NC6H,

3-0,NC6H,

Yield not reported.

mechanism involving one-electron transfer followed by a proton transfer. The kinetics of the oxidation of 14a and 26813 with the same agent were also studied (334,335) and exhibited a positive catalytic effect of glycine. A negative effect due to coordinating cations was, however, observed for some reductions with 1,4-dihydropyridine crowns (1129) as well as with a crown having four 1,4-dihydronicotinamide substituents (90). The kinetic investigations on the reaction of 14a and of its 1-methyl derivative with organic peroxides (361,424,

I

CH2Ph

27 1

acted with 269 to give the corresponding 1,4-dihydro derivative 22 stereospecifically deuterated at position 4. In this connection it may be noted that the reduction of l,&disubstituted pyridinium salts 37 (NAD+models) with NADH into the corresponding 1,Cdihydropyridines 39 (NADH models) really takes place (463). Some hydrogen transfer reactions of 268a and 268b with hexachloracetone, trifluoroacetophenone,or with activated C==C bonds were found (1011,1134) to be catalyzed with acids. The reduction of Schiff bases was accelerated (1013) in the presence of amine hydrochlorides. p-tert-Butylcatechol exhibits a similar effect on the reductions of aketo esters with 14a (769, 770). Phase-transfer catalysis with benzyltrimethylammonium chloride in a water-methylene chloride two-phase system was found (745) to be very effective for the hydrogen transfer from 268b to pivalophenone. The same procedure involving deuterium oxide enabled (745) also a high yield preparation of 269. Micellar catalysis in the reactions of 268b,c with some pyridinium salts (1015), l-methylacridinium ion (1006),isoalloxazine (1006),malachite green (155) with tris-p-anisylcarbonium ion (155) as well as with some flavine derivatives (1016) was studied in detail. Asymmetric reductions of trifluoroacetophenonewith 268a were observed (55) in the presence of cholate micelle, pcyclodextrine, and bovine serum albumine. The catalytic effects of different metal ions seem to be examined in detail, especially in the cases of magnesium (257,303-305,309,313,525,648, 784, 786, 787, 790, 799, 800-802,804,807,809-812,846,849,852,950,1005,1011, 1018,1139) and zinc (200,201,303-305,313,411,418-420, 786,849,950,1073,1154). The effect of variable ions M2+

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 231 Table XXX. Dihydropyridines 179 Prepared from Endiamino Ketones. R4R*NC(NH,) = CHCOR' RS R4 R3 R2 R' yield H Me

H Me

(CH2)6

OEt OMe OEt

Et Et Et

OMe OEt

Et Et

i-OPr Me OMe OEt

i-Pr Et Et Et i-Pr Et

CH=CCH,O OEt

Et Me

H

Me

H

Ph

R' Ph 2-fury1 H

yield 76 85 52, 5

R3 H

R2

R'

Ph

Me

Ph

Me Ph Ph

yield 85 94 98

Table XX XI I. 1,4-Dihy dropy rid ines 183 Prepared by Cycloaddition 24. See Ref 481

R

amidine 1 8 2 Me Ph

Ph

19

3-C1C.H. 3 - 0 ,I'k,.H, 2-MeOC,H4 2-CIC6H, 2-F,CC,H4 2-NCC6H, 3-C1C,H4 3-O,NC6H, 3-O,NC6H, Me Ph 2-MeOC,H4 2-CIC,H4 2-OzNC,H, 2-F,CC,H, 2-NCC,H, 3 - 0 ,NC,H, 4-MeSC6H, 1-naphthyl 2-F,CC6H, 3-0,NC,H, 3-O,NC6H, 3-0,NC6H, 3-0,NC6H, Ph 2-MeC6H, 2-F CC, H, 2-NCC,H4 3-OzNC,H, 3-02NC,H, 3 - 0 ,NC,H,

6 79 679 679,689 6 79 689 68 9 689 679,689 6 79 679,689 6 79 689 689 689 679,689 689 689 679,689 689 689 689 689 689 679,689 689 689 689 679,689 689 679,689 679

56 67,44 58 62 56 59 76,66 65 42, 30 31 61 53 53 61,64 67 74 54,59 42 55 64 44 76 59, 63 47 47 81 58,43 68 77,74 37

Table XXXIII. Preparative Yields of Dihydropyridinea 193. See Ref 371

Table XXXI. Oligocyclic Dihydropyridines 180 Prepared from 1,2-Aminoindoles. See Ref 603

R3 R2

ref

yield of 183

R

Ar

7

Me t-Bu Ph

26 43 63

Ph C,H4-4-C1

11 27

t-Bu

27

Me

R

Ar

yield ~~

Me

Ph 4-ClC,H4 4-MeC,H4 4-MeOC,H4 4-0,NC6H,

32 28 27 25 15

Et

~~~

35 24 30 27 17

Ph 4-ClC6H, 4-MeC,H4 4-MeOC6H, 4-0,NC6H,

Table XXXIV. 1,2-Dihydropyridines 196 Prepared by Cycloaddition ( 2 9 ) R3

6 16

yield

R2

H 4-MeC6H, Ph 4-MeOC,H4 Me Ph Me H Me H Me i-Pr Me Ph t-Bu H t-Bu H t-Bu OMe t-Bu OEt CH(Me)CO,Me Ph CH(i-Pr)CO,Me Ph CH( Ph)CO,Me Ph H CH,CH,Ph H CH,CH,Ph H CH,CH,Ph H CH,CH,Ph H 4-MeC6Y, H 4-BrC,H4 Ph Ph

Not reported.

R' H H H Ph i-Pr Ph Ph Ph OMe OEt H H H H H Ph 4-MeC6H, 4-MeOC6H, I-ClC,H, i-Pr i-Pr

yield ref 52 34 42 a

41 42 45 46 50 67 50 67 b b b 52 39 43 45 37 40

939 939 939 221 221 221 221 221 51 51 51 51 333 333 333 939 939 939 939 221 221

Small amounts only.

Me

on the reduction of pyridoxal phosphate with 14a was found (849,1002) to decrease in the order Ni2+> Co2+> Mn2+> Mg2+while in the orders Cu2+> Zn2+> Pb2+> Cd2+and NO2- > Br- > Cl- > OAc- for the corresponding

counterions in the reduction of pyridine-2-carboxaldehyde with 268b. The yields of products after the reduction of methyl benzoylformate with 272a was found (804) to be strongly dependent on the coordination ability of the cations: 100% for Mg2+,60 to 70% for Li+, and 0% for

232 Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 Table XXXV. Agents Used for Aromatization of Dihydropyridines agent references 0, or air oxygen

HNO, QO,

CCl, PhNO 4-HS03C,H,N,+XPh,C+ClO,-, Ph,C+BF, chloranil quinones methylene blue diphenylpicrylhydrazyl phenazine K , W CN), KMnO, &NO, Hg( OAc), Pd-charcoal a biological oxidation a Dehydrogenation, mitochondria.

273, 353, 363, 509, 61 3, 704, 835, 838, 867, 936, 1087, 1184 777 885, 886, 888, 1183 237, 1107 424, 1107 361, 425, 1114 58, 113, 466, 1188 58 54, 235, 240, 381, 479, 570, 632, 1030, 1132, 11610, 1170 60, 162, 163, 164 165, 181, 933, 1185 158, 51 8 28 1087 58 244, 491, 671, 990, 1062 180, 188, 227, 704, 748, 1067, 1115 190, 704, 760, 81 7, 1057, 1074, 1086, 1087 189 253 191 188, 334, 335, 1181 307, 455 596, 1096, 1100 58 366, 485, 755, 925 571, 1035 ~~~

Microsomal system or

Et4N+,respectively. The presence of Mg2+or Zn2+ions was found to enhance yields (784,786,787,794)or to be necessary for the Occurence (304,305,411,786,101 1,1154) of reductions. Asymmetric inductions due to chiral NADH models have also been studied in detail, as is partly reviewed (798) in Japanese. Thus, 1,4-dihydronicotinamides272a (784, 786,793,802,804,809,812), 272b (801),272c (799,800), 272d (648),273 (807)as well as 274a-c (818)possessing

R' R' R' R'

acetylpyridines acridinium salts activated double bonds alkylthallium( 111) compounds alloxan alloxanthin benzaldehydes substituted 2-benzoylpyridine a-bromonitro compounds a-chlorodeoxybenzoin copper( 11)salts N,N-dichlorodiiminosuccinonitrile a-diketones ferricyanide ions ferrocene carboxaldehyde flavopapaine hemine complexes hexachloroacetone imines iminium salts isoalloxazines a-keto alcohols a-keto carboxylic acid, esters, salts ketones a,p-unsaturated nicotinamide-adenine dinucleotide ninhydrin nitro compounds aliphatic pyridine-2-carboxaldehyde pyridinium salts pyridoxal phosphate pivalophenone quinone quinolinium salts 7,7,8,84etracyanoquininedimethide thiobenzophenone thiol esters thiopivalophenone triarylcarbonium ions triphenyl verdazyl radical and cation trifluoroacetophenone 1,3,5-trinitrobenzene 2,4,6-trinitro benzene1-sulfonate

= H, R' = Me, R3 = Ph = H, R Z = Me, R3 = 1-naphthyl = R2 = Me, R3 = Ph = H, R2 = CH,OH, R3 = CH*(Ph)OH

/Pr

258, 259, 260 258, 259 790 303 51 7 432 157 52 7 525, 787, 795, 1018 813, 814, 1181 1154 620 367 225, 1009 1004 851, 1008 1006 78 7 31 3, 525, 786, 81 2, 950 304 1092 258, 259 825 41 1, 412, 418, 419, 420, 1022, 1073, 1136, 1154 924, 1135, 1137 1002, 1003 745 760 56 93 7 805 849 811, 812 107, 154, 155, 1021 880, 881, 889 55, 81 0, 1045, 1134 808, 895 148

Table XXXVII. Substrates Reduced with Hantzsch Ester 14a substrate activated double bonds benzophenone hydrazones LY -brom oa ce top he n on e 1,4-cyclopentadiene-Pd ferricyanide ion imines, a +-imino esters iminium salts

I

Pr

27 3

525 351, 352, 1005, 1006 785, 1011, 1152 573

a Reduction with 268b. Reduction with 268a. Reductions with 268a as well as 26813.

I Pr

272a: b: c: d:

Table XXXVI. Substrates Reduced with Simple l-Alkyl-l,4-dihydronicotinamides 268a,b substrate a references

274a: R' = RZ = Me b: R' = H a n d R* = Me c : R' = Meand R2 = H

a chiral substituent a t amide group and 21 (1139,56,57) having the chiral residue a t heterocyclic nitrogen and Hantzach 3,5-bis(-)menthoxymbonylester of 143 type (57, 770)were used for the enanthiospecific reductions of 2-

a-keto carboxylic esters nicotinamide N-oxide peroxides and hydroperoxides pyridine-N-imines pyridine N-oxides sulfonium salts triphenylverdazyl radical and cation

references 850 302

379,1128 248 1181 744, 852, 858, 1026 57, 21 8, 21 9, 220, 846, 847, 851 648, 744, 769, 770 566 361, 424, 425, 743 567, 522, 379, 880,

1189, 1190 523, 569 1126, 1128 882, 883, 884, 879


acetylpyridine (793),a-keto esters (257,648,770,786,799, 800-802,804,807,809,812,1139), quinolinium salts (56) as well as some activated olefines (784). 3,3,5-Tri-

methyl-Qcyclohexenylidene iminium salts were reduced (54)with 21d to 3,3,5-trimethylcyclohexanonein 3 to 31% optical yields. On the other hand, sterically "hindered" 1,4-dihydronicotinamide 272c exhibited (799,800)more than 95% enanthiospecifity in its reaction with methyl mandelate. Chiral 1,Qdihydropyridine crown derivative ) reduce 2-benzoylpyridine, ben275 was found ( 2 2 1 ~to zoylformamide, ethyl benzoylformate, N-phenylbenzoylformamide as well as trifluoroacetophenone to the corresponding optically products exhibiting 64 to 86% of Sisomers. Simultaneously operating chirality and effects of coordination have been investigated, too. Thus, the reaction of trifluoroacetophenone with enanthiomeric 272a in the presence or in the absence of Mg2+ ions gave (794)optically active or racemic phenyltrifluoromethylmethanol, respectively. The effect of asymmetric induction during the reduction of ethyl benzoylformate with 272d or 268a in the presence of additional chiral compounds having or not having hydroxy residues was observed (648, 649) to be dependent on the Mg2+chelation to a given chiral component. In accordance with those findings the optical purity of methyl mandelate obtained after the reaction of the mentioned substrate with 272a was found (802)to be sensitive to used Mg2+/272a molar ratio as well as to a conversion stage of the reaction. It is noteworthy that the absolute configuration of methyl mandelate isolated at an early stage of the reduction was opposite to that found after a full completion of the process (802). Similarly, the enanthioselectivity of the reduction of 2-acetylpyridine with 272a or 273 (793)to be dependent on the molar ratio Mg2+/NADHmodel. On grounds of related experimental findings it has been suggested that the mentioned metallic ions activate (784, 807) the corresponding 1,Cdihydropyridine reducing agent so as to facilitate (809) a oneelectron release and enhance (305, 784,807) the stereospecifity of the interaction. Kinetic and isotopic effect investigations on the reaction of thiopivalophenone with 268b in the presence or absence of Mg2+ions enabled us to conclude (812) a retardation of the reduction by an intermediate metal coordination. On the other hand, analogous results obtained for the reduction of methyl mandelate with 272a were interpreted (812) assuming a transition state stabilization with Mg2' ions and consequently as an acceleration of the reduction. Similarly, the kinetic experiments (810) on the reaction of trifluoroacetophenonewith 268a led to a conclusion that Mg2+ions catalyze the initial electron-transfer process. The importance of a reduced substrate coordination has also been stated. Thus, the reduction N,N'-bisbenzylidenoligomethylenediamineswith Hantzsch ester 14a in the presence of Mg2+ions was found (852) to be remarkably facilitated in two cases where five- or sixmembered chelates 276 could be formed. Pyridine-2carboxaldehyde was easily reduced with 268a (420)or with 268b (418,420)via a Zn2+chelate formulated (420)as 277 while isomeric pyridine-3- and 4-carboxaldehydes incapable of the chelation did not react (430) under the same conditions. Some arguments in favor of simultaneous coordination of Zn2+,Mg2+,or Ni2+ions to both substrate as well as to amide oxygen in NADH model molecules were given on the basis of NMR (411,418-420),other spectrophotometrical ( 1154), and electrochemical (525, 950) measurements. In the case of polymeric NADH models the effect of Zn2+and Ni2+ions was found (1018)to depend

27 6

I

Me

275:

R = Me, i-Pr

277

on a number of 1,4-dihydronicotinamide units. A coordination of reduction products was observed (795) during the reaction of substituted benzils with 26813 where the formation of Mg2+complex with the corresponding radical anions was proved by means of ESR. Two probable mechanisms of the mentioned ions participation in the process of the hydrogen transfer have been proposed (303, 794). The first one involves the Mg2+coordination to the corresponding 1,4-dihydronicotinamide in such a way that its conformation becomes chiral and of an enhanced reactivity only at position 4. The second version presumes the formation of a ternary Mg2+complex with both substrate and NADH model molecules which may be either of a charge-transfer (199, 1045) or of an ion-pair (200, 432, 527, 804, 805) nature. The chargetransfer mechanism was concluded (1005)to be improbable on the basis of the isotopic effect investigations on the reduction of N-methylacridinium ion with 269 in the presence or in the absence of Mg2+ ions, respectively. Nevertheless, an unambiguous proof in favor of some alternate mechanisms is lacking. The reduction of chlorodeoxybenzoines with 268b was found (432) to be catalyzed by phtalocyanine metallic complexes. The catalysis by flavines was also observed (151,462,526,772,803,1177)and the substituent effects were investigated (772,1049) by means of empirical correlation analysis. A porphyrin skeleton was reduced (364) with poly(l-ethyl-4-vinyl-1,2-dihydropyridine). A formation of primary 1,4-dihydropyridine radical cations has been sometimes assumed (517,528,805)to be the early stage of the hydrogen transfer process. In favor of this assumption the appropriate nitro radical anions being formed during the reduction of aliphatic a-halogeno nitro compounds with 268b were detected (517) by means of ESR. On the other hand, an analogous report (805) concerning the formation of a substrate radical anion during the reaction of thiobenzophenone with the same NADH model 268b was later found (412) to be erroneous and the probability of one-electron transformations was also questioned (664) on the basis of kinetically followed quenching effects on 268b fluorescence. Another radical cation-radical intermediate was suggested ( 1136) for the reaction of 268b with pyridine-2-carboxaldehyde. Radical pair intermediates in the reactions of carbonium ions with l-methyl-1,4-dihydronicotinamide 21a were identified (438) by means of CIDNP technique. Antioxidant properties of certain 1,4-dihydropyridines were interpreted (1145) as their reactions with suitable radicals. Some of the reactions with NADH models are evidently multi-stepped as was already demonstrated in eq 48 and

234


49 and as followed from the investigations (435)on the reduction of acridine derivatives 278a-d with 268b and with 244. 9-Cyano derivative 278d with 268b gave acridane 280a probably via two intermediates in the sequence shown in eq 54a. 268b

280d 3 278a

278d-

- 280a 268b

A biochemically interesting complex oxidation of NADH model 268a converting adenosine diphosphate (ADP)into adenosine triphosphate (ATP) was described (81)in agreement with eq 55.

(54a) Pr

278a: X = H b: X = OMe c : x = c1 d: X = CN

279a-d

H

\ /x

280a-d

On the other hand, 1,4-dihydronicotinamide-4-sulfiiate 244 with 278a-d gave dimeric compounds 279a,b,d as major products except 279c, which underwent a spontaneous dehydrochlorination under the conditions used. An explanation of the formation of the mentioned as well as the additional 280a side product involving radical intermediate 281 is given in eq 54b. H I

i

268b

Pr

Pr

281

- 280 -278 - 280a 278

268b

___+

On the other hand, benzophenone was observed (435) to react with 244 at enhanced temperature only and yielded exclusively diphenylmethanol probably via intermediate 26813.

&

CONH,

(54b)

The reduction of 1-methylacridinium chloride with 244 proceeded analogously (435)leading to 1-methylacridane and the N,N’-dimethyl derivative of 279a in 13% and 69% yields, respectively. The major product of the reduction of fluorenone with 244 was found (434)to be the 1,4-dihydro derivative 282, the formation of which may be also explained by a one-electron pathway involving radicals 281 and ketyle 283 as follows. 28 1 281 + H+ fluorenone 283 282 +

Some photochemical reductions with NADH models were reported. Thus, lP-dihydropyridine 14a (379,785, 1026,1126)and 268b (785,825)reacted in electronically excited states with nitro compounds (825),alkenes (785), imines (1026),and sulfonium sdts (379,1126).In the case of aliphatic nitro compounds the photoactivated 26813 gave rise (825)to the substitution of the nitro group to hydrogen. (6) Electrolytic Oxidation. Some 1,4-dihydropyridine derivatives have been aromatized electrolytically on platinum, graphite, or glass anodes while no reports are yet available on the behavior of other dihydropyridine types. NADH (105,492,973) as well as its models like 21a and 268a,b (611,612,950,973) were subjected to extensive voltamperommetric investigations with the aim to understand possible similarities between biochemical and electrochemicaloxidations. The most probable mechanism of the aromatization proposed (611,612)on the basis of the behavior of 268a,b on a platinum electrode is shown in eq 56.

26813 -c

-H+

281

-e 245

(56)

I

CH2Ph

284

A catalysis with magnesium cations in the charge transfer between 268b and several aromatic compounds was also studied (950)by electrochemical techniques in acetonitrile in connection with the modelling of biochemical reductions. Hantzsch dihydropyridines of types 145 (1054),241 (1031, 1052-IO%), 242 (1054),243 (958,961),and 285

NH

285 CONH, ,-

LN’

I

R

286: R = H, Me, CH,C,H,X ( X = 4431, 4 - N 0 2 ,4-OMe)

0

283 282

Pyridine-N-oxide and its derivatives were converted (522,523,568-570) into pyridine or substituted pyridines by the reaction with Hantzsch esters of type 14.

(1054),all having at least one hydrogen atom at the 4position, exhibited an analogous two-electron aromatization like (56) at platinum microelectrodes (1031,1052). The corresponding half-wave potentials Ellz were found (1031,1052-1055)to be affected by substitution patterns. In the case of variable 4-substituents quantitative correlation analysis treatments of the substituent effects were

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21,No. 2,1982 235

successful (1053) while a simple HMO quantum chemical approach was shown (1031) to be more effective for the interpretation of the effects of 3,bsubstituents. Dimeric 1,4dihydropyridines like 117 were found (973)to be more easily oxidized than their monomeric analogues 14. Radical cations like 284 seem to be key intermediates of the electrolytic aromatization owing to the fact that any one-electron abstraction from the parent 1,4-dihydropyridine molecule 21 leads to a sufficient weakness of CH bonds in the 4-position as followed from the calculated (579, 580) character of HOMO. In accordance to this assumption 4,bdialkylated 3,5-dicyano-1,4-dihydropyridines of type 16 were observed (1031) to be oxidized on a platinum electrode with a one-electron mechanism only and forming radical cations 286 were identified by ESR (528). Variable Hantzsch dihydropyridines of 14 types and 148 (R2 = H) were electrolytically aromatized (93,1032) on a preparative scale. B. Reduction. (1) Catalytic Hydrogenation. Several examples of partial as well as total hydrogenations of dihydropyridines have been described in the past decade. It seems that partial hydrogenation has been observed only in cases where one of the double bonds is capable of conjugation with a substituent bearing ?r-electronsor electron pairs. Thus, enamino derivatives 287a+ were isolated ( 16, H

R'

%?fx H

6 \ ~ ) l 2

I A3

287a: R' = RZ = H, R 3 = Ph, X = CONH, (16) b: R', RZ = (CH,),, R 3 = Bu or CH(Me)Ph, X = CO,Me (1102) C : R' = CH,CN, R' = Et, R3 = CH,Ph. X = C0,Me' (149) . d : R' = R2 = H, R3 = Me or CH,Ph, X = CN. C0,Me or CONH, (8391

X = CONH, (1i11) R2 = (4-chloro-3-indolyl)methyl, R 3 = M e , X = CONH, (1111)

f : R' = H, H

R'

289 288a,b,f

149,839,1102,1111) after the hydrogenation of the corresponding 1,4-, 1,6-,or 4,ij-dihydropyridinederivatives on palladium. A mixture of tetrahydro derivative 287f and both stereoisomeric hexahydro derivatives 288f was obtained ( 111 1 ) under similar conditions. On using acetic acid as solvent 28713 was found (1102) to undergo further hydrogenation to hexahydro derivative 288b. Similarly, hexahydro derivative 288a was obtained (16) from the appropriate 1,2-dihydropyridine in addition to 1,4,5,6tetrahydro derivative 287a. The formation of the latter is probably due to a double bond isomerization on the surface of the catalyst. As expected, 2,3-dihydropyridine 237 was hydrogenated (298) on platinum to tetrahydro derivative 289 owing to the relative stability of the amidine part of its molecule. 1,4-Dihydropyridine 115 (R' = R2 = Me and R3 = H) and 120a (X= H)lacking stabilizing substituents in suitable positions were converted (45, 1067) with hydrogen on a palladium-charcoal catalyst smoothly into the corre-

sponding hexahydro derivatives. Hydrogenations of various 1,Zdihydropyridines or their mixtures with 1,4-dihydro isomers obtained after the reaction of quaternary pyridinium salts with organolithium reagents led (95) to the corresponding tetrahydropyridines and their mixtures, respectively. A selective hydrogenation of nitro groups in 1,4-dihydropyridine 147 (Ar = 3-N02C6H6)and in similar nitrophenyl substituted Hantzsch esters on palladium catalysts was patented (122, 631). (2) Miscellaneous Reductions. Some dihydropyridines have been reduced with complex hydrides or sodium dithionite as well as electrochemicallyto different tetrahydropyridines. Complex hydrides are apparently able to reduce conjugated enamino group -C=CN- in 1,2- and 1,Cdihydropyridines of 1 and 2 types as well as C=N bonds in other types, i.e., 3, 4, and 5. Thus, the borohydride reduction of various 1,2-dihydropyridines to the corresponding 1,2,5,6-tetrahydropyridines was widely used as a part in the syntheses of benzomorphane (29,46-50,323-326,484, 513, 519,524, 600-603, 845,902,1120) and azocine (37) derivatives. It has been repeatly shown (16, 594) or assumed (422,818)that 1,2- and 1,Cdihydro derivatives are intermediates in the complex hydride reductions of quaternary pyridinium salts to tetrahydro- and hexahydropyridines (251). The structure of the reduction products is usually affected by substitution patterns in the starting dihydropyridine molecules. Thus, 1,2,4-trisubstituted 1,2-dihydropyridines gave (1099)sodium borohydride mixtures of the appropriate 1,2,3,6- and 1,2,5,6-tetrahydropyridines in which the latter prevailed. Similarly, 1,3,6-trisubstituted 116-dihydropyridineswere reduced (596) into mixtures of 1,2,3,6- and 1,2,5,64etrahydropyridineswhile isomeric 1,2-dihydropyridines afforded (595, 596) exclusively 1,2,5,6-tetrahydro products. As expected, the 4-acetyl group in 1,4-diacetyl-4methyl-l,4-dihydropyridine115 (R' = R2= Me) was preferrably reduced (687) with sodium borohydride instead of the heterocyclic skeleton. Sometimes the borohydride reductions are facilated by a preceding electrophilic attack. Thus, hydrogen chloride was added to 2-cyanel,6-dihydropyridine35 (R = Me) and the intermediate 290 underwent (621) the following reduction into 1,2,3,6-tetrahydro derivative 291 as well as a side hydrolysis into l-methyl-3,6-dihydro-2-pyridone. Another example is the reaction of 1,2-dihydropyridine292 with benzyl bromide and sodium borohydride which yielded (594) 46% of 293a and 17% of 293b apparently via the dihydropyridine quaternary ions and with a partial electrophilic substitution at position 5 with benzyl bromide.

vE+

Me

290

Me

291

I

Me

292

293a: R = H b: R = CH,Ph

The borohydride reductions of 2,3-dihydropyridines110 (8) and 195 (470) gave the corresponding tetrahydropyridines as the only products. Similarly, the series of 2,fi-dihydropyridines 294a-e was found (288) to be convertible with lithium aluminum hydride easily into tetrahydro derivatives 295a-e. The kinetics of the conversion of 268b with sodium dithionite into tetrahydro product 296a (862) was inter-

236 Ind. Eng. Chem. Prod.Res. Dev., Vol. 21, No. 2, 1982 R'

294a-e a : R' = Me, RZ = t-Bu b: R1 = Et, R2 = t-Bu c: R' = Bu, R2 = Me

295a-e

I

d: R1 = Ph, R2 = M e e : R' = Ph, R2 = Et

R4

preted (860-862) as a complex transformation proceeding via adduct 296b and cation 297b. C O Y / . .-/ ,

R'

299

298: R', R3 = H o r Me, RZ = H, Me or Et, R4 = Me or PhCH, and X = CN

CONH2

H

"AJ X

I

I

R

296a: X = H, Y = NH,, R = CH,Ph b: X = SO,-, Y = NH,, R = PhCH, c : X = S O , ' , Y = N H , orMe R = F'r or PhCH, d: X = OH, Y = NH,, R = CH,Ph, Pr o r (CH,)', Me e : X = OP0,H-, Y = NH,,

ri 297a: R = Pr b: R = PhCH, c : R = (CH,),,Me d : R = (CH,),NEt,

300: R' = R3 = H, R2 = Et R4 = Me and X = PhS, PhCH,S or Me2N

In the connection the formation of 5-substituted 1,4,5,6-tetrahydronicotinamides303 found (965) after the

R = F'r The electrochemical reduction of Hantzsch 1,4-dihydropyridines of 148 type was investigated on mercury electrodes polarographically (464,587,590) as well as on a micropreparative scale (590). Substituents X were found (587,590) to facilitate the reduction in the order COMe > CN >> C0,Et and consequently the corresponding 3,5diesters underwent (464)the reduction only at considerably negative potentials. Tetrahydro derivatives appeared (590) to be the major reduction products from 148 where X = COMe. The relative polarographic reducibility of similar 1,2- and l,4-dihydropyridine derivatives seems to be somewhat contradictory (587,590) in dependence on the choice of compounds compared. C. Addition Reactions. (1) Nucleophilic Addition to Protonated Dihydropyridines and Analogous Cations. It is well known (251) that variable nucleophiles may be added smoothly to dihydropyridine cations affording structurally interesting tetrahydropyridine derivatives. Another reaction path is the dimerization observed (251) in cases where a fraction of unprotonated dihydropyridine molecules become the appropriate nucleophilic species. A number of novel examples of the mentioned reactions as well as similar transformations of further dihydropyridine cations has been reported in the past decade. Variably substituted 2,3-dihydropyridinium trifluoroacetates 299 were converted (332)with nucleophilic species X- or HX into tetrahydropyridines 298 or 300, respectively; see eq 57. The addition of nucleophilic reagents to 5,6-doublebond in NADH 21c and in its models of types 21 and 268 is z HNOC generally accepted (251, 861, 965, 1000, 1001, 1126) to proceed via 4,5-dihydropyridine cations 297a-d giving 1,4,5,6-tetrahydro adducts 296b (861,862), 296c (1113), 296d (156, 772, 1001, 1113, 1136, 1137) and 296e (81). Analogously, tetrahydropyridines 301a,b were obtained either by the reaction of acidic methanol with the appropriate 1,Cdihydropyridine 272c (799) or by the same reaction with cation 302 formed from 268b and bromomalononitrile (1126,1128). Similar adducts were expected (183) on the basis of kinetic isotope effects investigations of the reaction between 268a,b and trifluoroacetophenone.

I R4

301a: R' = Me, R2 = CH(Me)Ph, R3 = H, R4 = Pr b: R' = R2 = H, R3 = CH(CN), R4 = CH,Ph

I

CH2Ph

302 303: R = Me or CH,CH( NH,)CO,Me

reaction of 1,Cdihydropyridine 268d with the corresponding indole derivatives may be explained by the electrophilic attack on the parent molecule 268d with the protonated indoles rather than by the assumed (965) nucleophilic attack on dihydropyridinium cation 297b with free indoles. The kinetic measurements (156,1001) have shown that the protonation of 1,4-dihydronicotinamides268 is the rate-determining step followed by a rapid addition of the appropriate nucleophile to intermediate ions 297. The effects of substituents R and X influencing the water addition catalyzed with acetic acid were investigated (772, 776) in the series 304 and 305 and interpreted by means ,

,

,

,

kN!J I I

CHZR

304: R = H, CH,OH, OMe, C0,-i-Pr, COMe, CN, C0,Me and CONH,

ex N (J!

I

I CHzCONH,

305: X = COMe, CN or F

of empirical correlation of LFER analysis. The findings seem to be in agreement with the above-mentioned mechanism proposed on the basis of first order kinetics.


The micellar effect investigations (156,1000,1001) involving influence of the long-chain 1-substituent in 268c as well as of external detergents have demonstrated a critical role of charge in hydrophobic residues. Thus, negatively charged substituted sulfates and phosphates enhance the rate constant up to one order while quaternary cations exhibit a quite opposite and more significant effect. The latter finding was concluded (1O00,1001) to be analogy to the stabilization of alcohol dehydrogenase NAD by a positive charged lysine group, thus inhibiting undesirable water addition to the nicotinamide fragment of the coenzyme. Under suitable conditions the nucleophilic attacks on dihydropyridinium cations occur intramolecularly leading to tetrahydropyridine derivatives of more complex structures. Thus, 1,2-dihydropyridine 306 gave (29) tricyclic product 307 after protonation followed by electrophilic substitution of the thiophene ring in the side chain; see eq 58.

R’

R‘

C02Me

C02Me

I

I

R3

R3

310: R’ = H or Me, RZ = H, CN, CONH, R3 = Me, Ph, CH,Ph, CH=CHPh, C0,Et

31 1

Ncy-$-Jo Q 2Me I,

Coil Me

I

C02Me

R

312: R = Me, CH,Ph

31 3

xYEX:R

Me I

RHN

314a : R = Me, X = CN and Y = H b: R = Me, X = H and Y = CN

+

306

307

Analogously, biologically interesting tetracyclic tetrahydropyridines 308 and 309 were prepared (88,636) by

isomeric [4 21 adduct 315a prevailed (331,622,1192) at higher temperatures. 1,2-Dihydropyridine 232 was also reported (831) to form a dimer on heating at 254 OC. Further [4 + 21 dimers 315b were obtained (622) in low yields in the same way except in the case having R = (CH2)2CH=CH2 where the [2 + 41 addition proceeded intramolecularly and led to monomeric product 316 according to eq 59. CN

Hs ,CH2C02Me

Meo2c&

308 (88)

309 (636)

intramolecular acidic catalyzed cyclizations of the corresponding 1-(3’-indolyl-2-ethyl)-1,2- and 1,4-dihydropyridine derivatives, respectively. A more complex polycyclic structure of a dimeric product being formed from 268b in acidic medium was elucidated (1046) in accordance to earlier reports (251). (2)Cycloadditions. Some 1,2- as well as 1,Cdihydropyridines possessing *-electron systems 1 and 2 are found to enter [2 + 21 cycloaddition reactions. Contrary to the behavior of both type 1 and 2 the [4 + 21 Diels-Alder-like cycloadditions involving a dihydropyridine diene component can be considered as a characteristic property of 1,2-dihydropyridine systems 1 only. Variable 1-substituted 1,2- and l,6-dihydropyridines of 31,36,and 40 types were found (15,18, 657, 658,1165, 1166) to undergo the [2 + 21 addition with methyl acetylenedicarboxylate affording 1,2-dihydroazocines 31l or their transformation products (14) apparently via unstable [2 21 adducts 310. Similar primary [2 21 adducts 312 were isolated (23,24)after the reaction of the same methyl ester with 3-cyano-1,4-dihydropyridines39 (X = CN). l-Methyl-l,2-dihydropyridine31c with methyl acrylate gave (1166) primary [2 + 21 adduct 313 or stereoisomeric [4 + 21 adducts. 1-Methyl-2-or -4-cyanodihydropyridines 35 and 36 were observed (621,622) to be extremely labile, spontaneously dimerizing to 314a,b. In the case of 36 (R = Me) the [2 + 21 dimer 314b was the major product at -33 “C while

+

+

316 31 5a : R = Me, X = CN or 2-benzoxazolyl b: R = CH,CH=CH,, CH,C(=CH,)CH=CH,, (CH,) ,CH=CH,, CH,CH=C(Me)CH=CH, X= H

New variations of the Diels-Alder [4 + 21 reactions involving different 1,2-dihydropyridines and maleic anhydride were published (284,910,911) in addition to earlier reports (251) and further dienophiles were successfully introduced: methyl and ethyl acrylates (300, 708, 1165, 1166, 1171), methyl methacrylate (1166), N-substituted ethyl 2-(3-indolyl)acrylates (1069, 1070, 1083, 1166), dimethyl maleate (1033), N-phenylmaleinimide (532, 644, 1,2,4-triazolin-3,5-dione 910), tetracyanoethylene (948, M), (531-533), and some other compounds with activated double bonds (299,656,1033,1068). The stereochemistry of obtained [4 21 adducts was elucidated in some cases (532,1166). The mentioned type of Diels-Alder reactions was further used during identification of unstable 1,2-dihydropyridines (910, 948, 966) or their separation from 1,4-dihydro isomers (284, 644). Some 1,3-disubstituted 1,6-dihydropyridines of 40 type were converted (17) with dimethyl acetylenedicarboxylate into 3-substituted phthalates 318 apparently via labile [4 + 21 adducts 317 and also into addition-substitution products 319,in the cases where X = CONH2and R = Me or Ph. The mechanism of the reaction of l-vinyl-1,2-dihydropyridine with dimethyl acetylenedicarboxylate leading to a mixture of tetramethyl 1,2,3,4- and 1,2,4,5-benzenetetracarboxylates (657) seems to be less clarified. The participation of l-methyl-l,2-dihydropyridine 31c as a dienophile was observed (1166) in two [2 + 41 addi-

+

mCozMe

238 Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 CO2Me

-RN=CH2

C02Me

X

H

R2

COZMe

X

31 8

317: R = Me, Ph, PhCH, X = CN, CONH,, C0,Me

Me

R'

Me

324

326

325

compounds were converted (819)with the same reagent into stereoisomeric mixtures of secondary isomerization produds 328 as well as into diazo derivative 329 in the case of R' = Bu and R2 = COMe. R

319: R = Me, Ph X = C0,Me

YICN

i;i

tions with methyl vinyl ketone and ethyl 24 l-methyl-2indoly1)acrylate affording products 320 and 321, respectively.

I

327: R = Bu, Ph

R2

328: R' = H. Bu. Ph R Z = COMe, C0,Me or S0,Me

Et02Cm

COMe

320

321

329

The photoinitiated reaction of singlet oxygen with variable 172-dihydropyridines322a leads to endoperoxidic and in further syntheses useful intermediates 322b (750-754,756-758). R2

R2

I

I

-Q I

I R'

kl

322a: R' = CO,Me, CO,CH,Ph RZ = H, CN, CO,Me, CO,CH,Ph, -CH(OCH,), -CMe( OCH,) ,

322b

"VI

LI

t-Bu+~

+t-Bu

H I H LI

323

(3) Other Addition Reactions. l-Lithio-2-tert-b~tyl-l,&dihydropyridine obtained after the reaction of tert-butyllithium with pyridine was found (289)to afford l,&dilithio tetrahydropyridine 323 with lithium hydride. The known (251)cyanide ion addition to variable dihydropyridines has been further used. Thus, tetrahydropyridine 324 was prepared (111,112,385,386) by the borohydride reduction of the corresponding l-methylpyridinium-2-aldoximein the presence of hydrogen cyanide apparently via 1,6-dihydropyridine intermediate 25. Product 324 after its N-protonation eliminated (111,112) hydrogen cyanide by means of hydrogen chloride in methanol to give dihydropyridinium salt 325. Tricyclic 174-dihydropyridines160 added two molecules of hydrogen cyanide to afford (28,559, 962)dicyano derivatives 326. 2-Substituted 1,Zdihydropyridines were found (820)to react with cyanogen azide N3CN to give primary bicyclic adducts 327 and nitrogen while 1-substituted starting

D. Substitution Reactions. (1) Ring Substitution Reaction. In many cases a substitution of hydrogen atoms or another groups bound to 1,2- or 174-dihydropyridinering has been accomplished by different reagents although the mechanism of the transformation may be also an addition to a given substrate. Nevertheless, all reactions of the above-mentioned types will be mentioned here. Variable electrophilic agents tend to attack 1-nitrogen and/or positions 3 and 5 of the heterocycles 1 and 2 in agreement with expected a-electron distribution (see section 1I.C). Thus, 2-substituted l-lithio-2-alkyl(aryl)172-dihydropyridinesobtained after the reaction of organolithium compounds with pyridine (see section 111. A.(l)) were found (288)to be alkylated at the 5-position with methyl iodide or ethyl bromide at 0 OC to give unstable 2,5-dihydropyridines 294a-e which underwent aromatization and/or disproportionation at higher temperatures. Further agents such as acyl chlorides (308), carboxylic esters (308),isocyanates (95,821), and diethyl chlorophosphate (821)gave a variety of the products of 1-substitution 330a-c, 5-substitution 331a,b, and 1,5-disubstitution 332, respectively. If diphenyl disulfide was used (273)instead of the mentioned agents a small amount of 5,5-disubstituted 2,Ei-dihydropyridinederivative 8c was trapped. More usually, the primary 5-substituted compounds of 331 type were further aromatized in the process of substitution with reacting electrophiles to afford 2,5-disubstituted pyridines 333a-d (306,308,309,312,529,530,821) in addition to 2,2'-dibutyl-5,5'-bipyridyl(5307821)probably due to radical side reaction. A simple aromatization of 1-unsubstituted or l-lithio1,Zdihydropyridines with electrophiles was also observed (530,642,821) while 1-alkylated starting compounds 334a (95)and 335a (244)gave exclusively 5-substituted products 34413 and 335b,c after treatment with phenyl isocyanate (95),bromosuccinimide (244),and tetracyanoethylene (244),respectively. Exceptional behavior was observed (244)in the case of voluminous triphenylcarbonium ion which converted 335a after the elimination of the chloro-

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21,

Electrophilic replacements of 3-hydrogen in l-methyl1,4-dihydronicotinamide 21a by 34ndolylmethyl residues were accomplished (1111) according to eq 60.

H

I x

No. 2, 1982 239

X

X I

I

330a: R = Ph, X = COMe, COPh, COCF,, C0,Et (308) b: R = Bu,Ph, X = R'NHCO (821 1 c: R = Bu, X = PO(OEt), (821)

Rocn; xocnR NH

& c H 2 ~ c o N H zN

H

I cox

331a: R = Ph, X = CF, (308) b: R = Bu, Ph, X = NHR (821)

X=HorCl

332: R = Bu or Ph, X = NHR' ( 8 2 1 )

333a: R = Bu,X = Me, Br,PhSe or MeSO, (530) b: R = Ph, X = R'CO, R',Si or R ' , G (308, 530, 642) c : R = Ph, X = Br, CF,, CHO ArNHCHR or PhCHCH,OH (309) d: R = Bu or Ph, X = R'NHCO or R'CO (821 )

In some cases the electrophilic substitution of 1,4-dihydropyridines takes place in the tetragonal 4-carbon atom. Thus, the easily releasing sodium sulfiiate 4-residue in 244 can be replaced by hydrogen as demonstrated in eq 49. Opposite replacements of 4-hydrogen atoms in 337c affording derivatives 337d,e were accomplished (244) with strong electrophiles as substituted carbenes and nitrenes. X

Y

I

I

R

form molecule from unstable intermediate 2,5-dihydropyridinium ion 336 into the corresponding 3-triphenylpyridinium salts. I

R'

k3

2,6-c1&

I

H 3 c H2

334a: R' = H, Me, R Z = Bu, Ph 335a: X = H b: X = Br R3 = Me,PhCH,, X = H C : X=-C(CN)=C(CN), b: R' to R3 see above X = CONHR' H

I

Me

xXLR

R' H Jyx

(60)

\/\\

I

2.6-CIzC6H3C H 2

336

Electrophilic substitutions in 1-nitrogen have also been described for 1,4dihydropyridines. Thus, the 1-hydrogen atom in 3,bdiester 337a was replaced (93513) by the corresponding alkenyl residues in 337b after the reactions of dimethyl acetylenedicarboxylate or methane sulfonyl chloride with 337a. More nucleophilic l-lithio-l,4-dihydropyridine obtained after the addition of methyllithium to 32a was easily converted (284) into parent heterocycle 6 by protodelithiation with water. Similarly, metallic complexes 134 (M = Mg or Zn) gave (212) N-acyl derivatives of 32 type (R = Ac or AcCO) after the acylations with ethyl acetate or pyruvate, respectively. On the other hand, N-deacylations of 1,bdihydropyridines 26 (R = CONH, or CSNH,) and 89 were accomplished (742,1174) by hydrolysis in the presence of alkali hydroxides at suitable conditions. Contrary to these findings treatment of Hantzsch l-acyl-2-amino-l,4-dihydropyridines 193 with hydrochloric acid did not give 1-deacylated products but led (469)to dihydroppidones by nucleophilic substitution of the 2-amino group.

CHXC6H5

337a:R=X=Y=H b: R = MeO,CC=CHCO,Me or SO,Me, X = Y = H c : R = Me, X = Y = H d: R = Me, X = H, Y = CHCl, e : R = Me, X = EtO, Y = NHC0,Et

338a: X = H b: X = D

Deprototrimethylsilylation and deprotomethylation of 1-methyl-l,4-dihydropyridine with trimethylsilylmethylpotassium and trimethylsilyl chloride or methyl iodide proceed analogously at the 4-position (970) accompanied in the second case by a 1,4 1,2 isomerization. On the other hand, deprototrimethylsilylation of 4-methyl-1,4dihydropyridine with potassium tert-butanolate and trimethylsilyl chloride occured (970) at position 2. Similarly, deprotodeuteration of 1-phenyl-l,4-dihydropyridine with butyllithium followed by the reaction with deuterium oxide gave (1051) the 2,6-dideuterated product. Deprotodeuteration and deprotomethylation of l,&disubstituted dihydropyridines 38, 39, and 40 (R = Me and X = CN, CONEt,, CON(i-Pr), or CON(CH,CH,),O) with lithium diisopropylamidefollowed by the action of deuterium oxide or methyl fluorosulfonate in 0-deuteriomethanol were found (975) to take place exclusively at the 4-position in 1,2-isomer 38 (X = CN) and at the 2-position in all the other 1,4- and 1,8dihydro derivatives 39 and 40. A different side chain deprotodeuteration of 1-benzyl derivative 338a into 338b was also observed and a possible formation of dihydropyridine anions in all mentioned cases has been questioned (975). A usual substitution of all types of heterocyclic hydrogen 37 (X = CN atoms in l-benzyl-3-cyano-1,4-dihydropyridine and R = CH,Ph) was observed (631) after ita reaction with 1,1,2-trifluoro-2-propanone proceeding via eliminationaddition intermediates according to eq 61. 1,4-Di-(trimethylsilyl)-l,4-dihydropyridine119 was found (1066) to react with acrylonitrile under 1,4 1,2 isomerization of heterocyclic rings as shown in eq 62. Further similar transformations of 119 were patented

-

-

(1068).


240

510) to react with bromine to give dibromoderivatives 341a

341a: X = H, Y = Br, R' = Me or Et, RZ = Me, Et, Pr or R ' , R2 = ( C H , ) , , R 3 = H o r M e b: X = Y = Br, R', R2 = Me, Me or (CHz)4-5 c : X = H, Y = I, N,, SCN, OMe, NEt , N( CH,) or N(CH,CH,),O, R', R2, and R3 see 341a

I

I SiMe3

SiMe3

113

61%

Nucleophilic substitution in dihydropyridine rings appears to take place either in tetragonal carbon atoms or in the 2- and/or 6-positions of systems 1 and 2 depending on the character of the leaving groups and reagents. Thus, trichloromethyl2-substituent in 1,2-dihydropyridine335a (244)and both 2,6-bromines in 1,Cdihydropyridines 220 (176) were replaced by methoxy groups with methanol or sodium methanolate, respectively. l-Methyl-S-ethyl-l,2dihydropyridine 292 as a ligand in its tricarbonylchromium(0) complex 341 was found (596) to undergo nucleophilic substitution with 24ithiocyanides at position 6 according to eq 63. Cc(COI3

I

I

I

Me

Me

341 R' and R' = H or Me, X = CR'R'CN

(2) Side Chain Substitution. The Mannich reaction of Hantzsch dihydropyridines of 170 type with paraformaldehyde and some tertiary amine hydrochlorides leading (40) to a variety of products 339 and 340a,b in dependence on reaction conditions used seems to be another example of prototropic replacements. R102.C.:&'

Me

CHzCHzNRz

I R3

2

339: X = H, 2-Me, 4-Me0, 4-NO,, 2-N02, R' = Me, Et, R3 = H or Me R'02C

ZYCH

Me

l6

NO;

(R' = R3 = Me RZ = Me, PhCH,)

I

R3

340a : Y = CH,NR2,, Z = H and other substituents the same as in 339 b: Y = 2 = CH,NMe,, X see 339, R' = R Z = Me, R3 = H

Polysubstituted 3,5-dicyanc-1,4-dihydropyridinesof 148 type (X = CN and R3 = Me) were found (481,493,495,

R

NcficN R = Me or PhCH, (64)

Me

I

CHzN02

R

Two nitro groups could also be introduced into molecules of substrates 16 (X = CN), but isomerization and other side-reactions accompanied the nitration in some cases (572). As expected, the acylation of Hantzsch dihydropyridine 171d with chloroacetyl chloride is reported (141)to proceed exclusivelyat a more nucleophilic side chain nitrogen atom. The aromatic hydroxy group in Hantzsch diesters of 143 type having R4 = 4-HOC6H4was alkylated (122) with 2ethoxyethyl chloride or 2-dimethylaminoethyl chloride in the presence of sodium ethanolate into the corresponding aryl ethers and other substitution reactions of hydroxy derivatives of ethers with primary amines were also reported (122). A number of nucleophilic side chain displacements leading to pharmaceutically interesting products have been patented. Thus, at 2-methyl substituted derivatives 342a and 342b were prepared (139, 140) by the successive reactions of the starting 2-(N-phthalimidoyl)methylderivative 342c with hydrazine and dimethylacetals of amides. Similarly, the preparation of derivatives 343a-c was based on the reactions of the appropriate chloro derivatives (X = C1) with corresponding amines (297, 448, 834, 1093). Further, formal substitution reactions of 1,Cdihydropyridines will be mentioned among consideration concerning the transformation of functional groups (see section IV. JJ. E. Acid-Base Properties. It is well known (251)that 1-unsubstituted 1,Cdihydropyridine derivatives are as a rule bases and acids. Thus, the NH group in Hantzsch ester 14a was easily deuterated (425) on heating its 1,2dimethoxyethane-deuterium oxide solution. The corresponding anions prepared by the heterolysis of NH bonds at position 1 by the action of strong bases seem to be, however, powerful nucleophiles reacting readily

fi;Hyz C02R'

Me

-NOp. 286

C,r [ CO )3

C,r(C0)5

Me

or tetrabromoderivatives 341b in chloroform at 30 "C or in boiling acetic acid, respectively. Compounds 341a were converted (480,481)into side chain substituted derivatives 341c and other similar products by displacement of Br residues with appropriate nucleophiles. Analogous side chain nitration was observed (572,576) to proceed very smoothly via radical-cation 286 according to eq 64.


Nc35tcN R3

344: R', R2 = Me, Me; Et, E t ; Me, Pr;

342a: R' = aryl, RZ = Me, Et,

Ph, H; (CH,), or (CH,CMe),NMe R3 = Me, Ph, or 4-Me0

CH,CH=CH,, C H , e C H , i-Pr, PhCH, or MeOCH,CH, X = NH, b: R' and RZ see 342a, X = N=CR3NHR4RS c : R' and R2 see 342n, X = N( CO) ,C,H, H

R3

d

346: M = Li, Na, K, MgX; R', R' = H, H; Me, 345: n = 3, 4, 5

343a: n = 0, R' = 3-N0,C6H,, R Z = Et

R3 = CH(OEt),, X = 4-C1C6H,N(Me) (297) b: n = 1, R' = Rz = Me, R Z = Et, or CH,CH,X, X = NEt,, N(CH,),, NHCH( Me)CH,Ph, N( CH,CH,) ,NMe or N(CH,CH,),NPh ( 8 3 4 ) c : n = 1, R1 = 3-N0,C6H,, R Z = R3 = Me, X = N(Me)CH,Ph (448)

with alkylating and other electrophilic agents. The alkylation procedure of variable 1,4dihydropyridines usually consists of their treatments with sodium hydride in dimethoxyethane (85,226),dimethylformamide (577,582, 585,739,840,841,844,928), tetrahydrofuran (386,446,451, 453,506,560,626, 738,958,961, 1083), dioxane (582),or hexametapole (961)followed by the reaction with a given alkyl halogenide. Chloromethylated styrene-divinylbenzene copolymers were also used (1193) in the reaction with 14a. Sodium ethanolate (172) as well as ethylmagnesium bromide (582)were also used instead of sodium hydride. In the case of more acidic 3,5-dicyano-1,4-dihydropyridines 344 the corresponding anions capable of alkylation could be generated with potassium hydroxide in boiling acetone (494,496) or more elegantly in a twophase system using phase-transfer catalysts (843). Analogously 3,5-diformyl-l,Cdihydropyridine 26 (R = H) gave potassium salt ( 1174) and was fully acylated (1172) after its treatment with potassium hydroxide. Oligocyclic Hantzsch dihydropyridines 176 (R' = Ph, 4-BrC6H4,or 2,4-C12C6H3and X = SEt, SPr, or SCH,Ph) were successfully 1-alkylated (1161a)with methyl or ethyl iodide in the presence of sodium hydroxide in yields 51 to 75%. Contrary to those findings all attempts to alkylate the sodium salt available from Hantzsch dihydropyridine crown 345 and sodium hydride failed (509) due to a powerful complexion of the cation. The ionization of 3,5-diacetyl-1,4-dihydropyridinein water at higher pH's was followed (570) spectrophotometrically and polarographically. Bonds N-Me in annulenes 34 possessing a 1,4-dihydropyridine skeleton were found (83) to be split with metallic potassium in tetrahydrofuran to give the corresponding potassium salt. On the other hand, the formation of analogous lithium salts from 1,3-disubstituted dihydroppidines 38 to 40 and lithium diisopropylamide has not been conclusively proved (975) as mentioned in the preceding section. Simple 4,4-dialkylated 1,4-dihydropyridines 158b (X = C0,Et) were converted (287, 923) with organometallic compounds into relatively stable products formulated (287) as salts 346 in which about 25% of the negative charge is located at the 3,5-positions and about 75% of nitrogen as followed from a spectral analysis.

Me or (CH 1) 1-6

A little progress has been achieved regarding the basicity of dihydropyridines. Dimeric l,4-dihydropyridines 111 (R' = Me and R2 = COMe) with hydrochloric acid gave dications in which N-protonation has been assumed (290). Other possible protonation sites in dihydropyridine molecules are discussed in section IV. C. (1). F. Ring-Opening Reactions. 1,2-Disubstituted 1,2dihydropyridines 347 (91,498,502,503,504,723)and 349 (723,967,968)were observed to be kinetically unstable and underwent spontaneously the electrocyclic conversion into dieneimines 348a,b shown in eq 65.

H &

I

348a: A =

A.

341:

8-J ArN

Ar = Ph, 3-MeC6H,, 3-C1C6H,, 3-NO ,C,H,, 4-MeC6H,, 4-BrC6H,, 4-N0,C6H,; X = OH, NHR, NHPh, N( CH,) or CH( CN)CO,Me

Ar. B = X

b:A=OH,B=R C : A = 2-HO-5-XC6H,, B = ONa

OH

349: R = Me, Ph

Similar ring-opening product 348c was obtained (1106) by the action of sodium hydroxide on 1,2-dihydropyridine derivatives 350 probably by the pathway shown in eq 66.

350: X = ArS0,NH

P l

y C H O N a

348c

New examples of the hydrolytic ring opening (251)were described. Thus, l,4-dihydropyridine derivative 89 was treated (742)with methanolic potassium hydroxide giving a tetrahydro 2-ppanone product. A mixture of isomeric

242


2,6-di(tert-butyl)-1,4- and -3,4-dihydropyridines 112 and 113 afforded (209) expected 1,5-di(tert-butyl)-l,5-pentadione after the treatment with 10% hydrochloric acid. An interesting acidolysis of 3,4-dihydropyridine derivatives 190 (Y = H) with trifluoroacetic acid in dimethyl sulfoxide leading (293)to mixtures of cyanoesters 351 and cyanoamides 352 may be explained by the route shown in eq 67.

A similar isomerization of 1,2-dihydroderivative 109 into its 2,3-isomer 110 proceeding spontaneously (8,402)was just mentioned (see section 111. 1. h). Both isomerizations appear to be kinetically controlled. 2,6-Di(tert-butyl)1,4-dihydropyridine 112 was reported (209) to give its 3,4-isomer 113on standing in a deuteriochloroform solution at 38 OC. A thermal 1,2 1,4 isomerization of 2-trichloromethyl derivative 335a into the corresponding 4-trichloromethyl-l,4-dihydro isomers 357 was accomplished (244,

-

H

Ph

CC13

I

I

2.6-CliCrjH3c H Z NC--CGCH

I

bOnMe

t CH-CN

I CONH2

(67)

351 352 X = CF,CO, Ar = Ph, p-Me,NC,H,, p-CIC,H,, p-MeOC,H,, m-NO,C,H,

Two examples of oxidational ring splitting are reported l-butyl-3,5-diethyl-2-propyl-1,2-dihydropyridine 232 with osmium tetroxide and periodate ion gave (208) P-keto amide 353. The ozonolysis of 1-substituted 1,Cdihydronicotinamides 21 afforded (732)diformyl derivatives 354.

358: X = C0,Et

359: R = Me or Et

342) on heating its acetonitrile or xylene solutions and the process could be followed kinetically (244). Analogously, 2,2’-dimeric 1,2-dihydro derivative 358 was found (476)to be transformed thermally into its 1,Cdihydro 4,4’-isomer 128 (X = C02Et) and a appropriate kinetic data were reported (675). An interesting 1,2 1,6 isomerization (69) catalyzed

-

4

X I

354

353

X

A more complex mechanism including a cyclodimerization has been proposed (778) for ozonolysis of Hantzsch ester 241b (X = COZEt). G. Isomerizations. As is known (251), dihydropyridines are capable of isomerizing via certain ionization, protonation, and oxidation-reduction processes as well as by the action of metals or their complexes. Further examples of isomerizations have been described in the past decade in addition to new spontaneous or thermal processes. Photoinitiated isomerizations will be mentioned in section IV. I. The composition of reaction mixtures depends on the appropriate physicochemical mechanism, e.g., whether a given isomerization is kinetically or thermodynamically controlled (251). It may be noted that only in the second case do isomers energetically preferred prevail. 1-Substituted 1,2-dihydropyridines 355 were converted (362) into 2,3-disubstituted 2,3-dihydro isomers 356 probably via ring-opening intermediates according to eq 68.

(CH2 )2R

CH2Ph

R

Bu

355: R = H or (CH 2 ) ,CH=CH

357

I

Me

(CH2 )zR

i;’

X = C0,Et and Y = OEt

with trifluoroacetic acid was followed (12)by NMR in the presence of a chiral shift reagent. The formation of 4-akoxy-l,4-dihydronicotinamides 359 after the addition of different lithium alkoxides to the corresponding cation 245 was attributed (791)to isomerizations of the primary 1,2- and 1,6-adducts, respectively. A rare 2,3 2,5 isomerization of tetracyclic 2,3-dihydropyridine 23b into compound 360 was achieved (870)with sodium methanolate. The isolation (942)of N,O-diacetyl-1,4-dihydro derivative 361 after the treatment of 3,4-dihydropyridine187 (R1 = R2 = H and R3 = Me) with acetic anhydride in pyridine might be due to a prototropic 3,4 1,4 isomerization during acetylation. The isomerizations catalyzed with quaternary pyridinium salts or radical compounds proceed evidently using an oxidation-reduction mechanism. Thus, the reaction of l-methyl-l,4-dihydronicotinamide 21a with a small amount of 1-methyl-3-carbamoylpyridiniumiodide led (712)to an equilibrium mixture of 21a and its 1,6-dihydro isomer 40 (R = Me and X = CONH2) in which the energetically preferred compound 21a prevailed. Analogously, the treatment of 1,bdihydropyridine 3,5-diester 337c with diphenylpicrylhydrazyl radical resulted (253)in a mixture

flMe (68)

-

-


'f

Me

I

360

361

R'O 2 C n T 2 R 1 N

I

d

he

362a:R' = R2 = M e , R3 = H b: R' = RZ = Et, R3 = Me c : R', R2 = CI~,CH,(OCH,CH,), R3=Me

of 337c (33%) and its 1,2-dihydro isomer 362a (15%). On the other hand, Hantzsch 1,4-dihydropyridines58 and 143 were stated (379, 1126, 1128, 1130-1132) to isomerize quantitatively rapidly into their 1,2-isomers262b,c in the presence of structurally analogous pyridinium cations. The formation of products 262b,c is apparently kinetically controlled. A mixture of tricarbonylchromium(0) complexes of isomeric 1,2-dihydropyridines 12b and 12c was observed (593)to equilibrate from starting ratio 65:35 to the final 1:l composition after 14 h. Tris-triphenyl phosphine complex of rhodium(I1) chloride was found (252)to induce 1,2 1,4 isomerizations of 1,2-dihydropyridines 28 (X = COMe or C02Me)and 31a into their 1,4-isomers 29 and 32a, respectively. Electrolytically generated 1,Cdihydronicotinamides 21a and 268b were believed (788) to be artefacts from primary formed 1,6-dihydro isomers isomerizing at a surface of platinum electrode. H. Rearrangements. Some dihydropyridine derivatives undergo spontaneous or thermal rearrangements or react under a change of the heterocyclic skeleton. As rearrangements, isomerizations leading to nondihydropyridine products are also considered. 1,2-Dihydropyridine intermediates 363a,b have been observed to react under rearrangements affording 1,2,3,5-tetrasubstitutedpyrroles (760a) or 1,6-dihydropyridazine derivatives ( 1034) according to eq 70.

-

Ph

I

KOH(X= Fe(CN16K31

Yh

he

be

Me

R2

243

365

364: R = H, Me X = C0,Me Y = CO,Me, C0,Et

Thus, 1,4-dihydropyridine tosylate 366 gave (45) 4methylene-4,5-dihydro derivative 367 while Hantzsch ester 368a afforded (329) 4-X-substituted 4,5-dihydroazepines 369a,b after treatments with potassium cyanide and methanolic triethylamine, respectively. In the case of the former reagent a dihydropyridine ring contraction into pyrrole derivative 370 took place as a by-process. On using more nucleophilic sodium ethanolate, a deprotonation occurred instead of the nucleophile addition to give azepine 371. Contrary to these findings dis-

I Ac

I

fi

366

Me

H

NH

Mffi

367

H

Me02C

Me

368a : X = C1 b: X = Br c : X = OMe

Ac

Me

H

e

NcnC02Me

Me

369a: X = CN b: X = OMe

Ofle

NH

Me

Me

370

37 1

placements of chlorine atoms in 368a with less nucleophilic potassium rhodanide (329) or in 372 with thiourea (152) proceeded without any rearrangement. It is worth mentioning that the opposite process, e.g., a ring contraction of dihydroazepines 369 into 1,4-dihydropyridines 368a-c, was observed (329)after treatment with hydrogen chloride or bromide, respectively. Novel 1,Cdihydropyridine rearrangements into tri-, tetra-, as well as penta-membered ring fragments were described (152,329). Thus,Hantzsch ester 368a gave (329) tricyclic trans-epoxide 373a or a mixture of cis-trans isomers of 373b after reaction with aqueous potassium carbonate and sodium hydrogensulfide, respectively. The formation (152) of bicyclic products 374 from 1,4-di-

363a: R = Ph, Y = alkyl or aryl NH

Me

372: X = Me, OMe or OEt

Bicyclic 1,2-dihydropyridines 364 were stated (948) to aromatize spontaneously into pyridine derivatives 365 after several days in the possible pathway (71). A ring extension in some 1,Cdihydropyridines of types 368a,b and 372 giving dihydroazepine derivatives is a known (251) procedure. In the past decade several new examples of such rearrangements have been reported.

373a: X = 0 b: X = S

374: X = Me, OMe or OEt

hydropyridines 372 and urea apparently-involved certain ring-opening and ring-closure elementary steps.

244


I. Photochemical Transformations. Some novel photochemical reactions of dihydropyridines, e.g., isomerizations, dimerizations, aromatizations, and disproportionations, have been described in the past decade in addition to cases reported earlier (251). A methylene dichloride solution of l-methoxycarbonyl-l,2-dihydropyridine31a was found (284,115)to undergo photoisomerization 223 225 (R1 = R2 = H and R3 = C02Me) after UV irradiation. In other cases photochemically induced ring-openings of 1,Zdihydropyridines were observed. Thus, 2-methoxy-l-phenyl-l,2-dihydropyridine underwent (1080) isomerization 347 348a (X = OMe and Ar = Ph). Analogous behavior was reported (339) for 1,2,3,5-tetraalkylated 1,2-dihydropyridine 232. 3,5-Di-(ethoxycarbonyl)- 1,6dihydropyridine 29 (X = C02Et) gave (718) dimer 375 on UV irradiation in the nitrogen atmosphere in contrast to the different behavior (476, 477) of 2,6-dimethyl derivative 14a mentioned in section 111. A. 3. On the other hand, similar Hantzsch 1,4-dihydropyridines of 143 type possessing R' = R4 = H were easily oxidized with free oxygen (718) into the corresponding pyridine derivatives 376a by the W irradiation

-

A

A

R

R = 2,6-dichlorobenzyl(943)

-

d

X

375: X = C0,Et

376a: R' = H, RZ = M e or Et R3 = H or Me b: R' = 2-NO,C6H,, R2 = OEt

R3 = Me

of ethanolic or acetonitrile solutions while N-substituted 1,4-dihydro derivatives 143 (R' = H and R4 = Me or CH2Ph)afforded only low yields of the same 376a pyridines together with further unidentified products (718). A side photoreduction of 3-acetyl group in 376a (R2= Me) was also observed (718) in ethanolic solutions. Two alternative routes of the photoaromatization were stated (249,1095)in the case of 143 (R' = 2-N02CeH4,R2 = OMe, R3 = Me and R4 = H) leading either to the corresponding pyridine 376b (1095)or to 2-nitroso derivative 376c (249,1095)on irradiation with short light wave or long UV light wave, respectively. The photoaromatization of l-phosphoryl-1,4-dihydropyridine 239 into 3,5-diacetylpyridine 376a (R1 = R2 = H and R3 = Me) with oxygen in the presence of alcohols ROH was found (671)to be accompanied by the phosphorylation of the alcohols into esters ROPO(OC6H4X)2. Another example of the photoinduced splitting-off of 1-substituent is the reaction shown in eq 72.

NiMe)Ac

X = 1-acetyl-3-indolyl( 2 3 2 )

An intramolecularly proceeding redox photoprocess is demonstrated in eq 73. The photoinduced ring-opening of perfluoro 2,3-dihydropyridine 379 led ( 1 73) to perfluoro enamine (380) in 70% yield. 1,2-Dihydropyridineperoxide 377 having been assumed (103) as key intermediate during the photooxidation of phenyl(2,4,6-triphenyl-l-pyridyl)iminewith oxygen was evidently further photodecomposed into pyrrole derivative 378 and nitrosobenzene.

37a

N-0

377 CF(CF3 12

C F (CF3 ) 2

I

379

380

J. Chemical Transformations of Functional Groups. 3-Carbamoyl group in 1,2-dihydropyridine 381a was dehydrated with dichlorocarbene generated under the conditions of phase-transfer catalysis (343) in agreement with the equation 318a + CC12 381b CO 2HCl to yield 32% of nitrile l8lb together with 20% of secondary 43- and 5,6-adducts 98 and 99 (R = 2,6-C12C6H3CH2 and X = CN). Diethyl acetal residue R2 in a Hantzsch ester of 171b type was transformed (953) into other functional groups. Increased attention has been paid to nucleophilic displacement of 3,5-functional groups in Hantzsch 1,4-dihydropyridines. Thus, both aldehydic groups in 3,5-diformyl-4-ethinyl-l,4dihydropyridine26 (R = H) was found (1174) to be reactive enough to afford bis-hydrazone 162 (R = H) as well as bis-oxime. On the other hand, l-unsubstituted bis-3,5-ethyl ester 14b exhibited a substantially lower reactivity toward ethanolic potassium hydroxide yielding only 2% of ester-acid 382a (628)while analogous 1-substituted starting Hantzsch esters gave (960) higher yields of ester-acids 382b under similar conditions. A selective hydrolysis of 1-ethoxycarbonylmethyl group in 383a with ethanolic sodium hydroxide affording diesteracid 383b was patented (1083). Another approach to ester-acids 382c consists of a selective hydrolytic splitting of the 2-cyanoethoxycarbonyl group in Hantzsch 1,4-dihydropyridines of 170 type where X = C02i-Prand Y = C02CH2CH2CNwas also patented (75, 1155). Analogous reesterification processes in the series of Hantzsch esters have been observed to occur at one as well as both ester functions. Thus, asymetrically substituted 3,5-diester 147 (Ar = 3-N02C6H4)was prepared (52,1191) by partial reesterification of the starting dimethyl ester with N-benzyl-N-methyl-2-aminoethanol in the presence of aluminum tris-2-propanolate in toluene. On the other hand, simple Hantzsch 3,bdiester 14a and similar 1,4dihydropyridines underwent ( 1147,1148) total reesterification with primary alcohols, e.g., methanol, 1-propanol, 1-butanol, 1-pentanol, 1-hexanol, or 1-decanol, in the presence of potassium hydroxide while the same experimenta with other isomeric butanols led (1147) exclusively to ester-acid 382d. In the case of Hantzsch 2,3,5,6-tetraesters 384 their reactions with hydrazine hydrate proceeding according to

-

+

+

Ind. Eng. Chem. Prod. Res. Dev., Vol. 21, No. 2, 1982 245 CH( Me)OAc

I

388

SiMe3

382a: R' = Ph, R' = H R3 = Et b: R' = Me, Ph or

381a: X = CONH,

b: X = CN

389

387 R'

Eto

4-MeOCLH.. R' = Me or Ph, R' :'Et

R'

C:

=

Me

3-NO2C,H,,

R2 = H, R3 = i-fi d: R' = R2 = H, R3 = Et 3-NO2CsH4

f

i

Me

I

M

I

I

Me

k2

C02Et

391: R' = Me,

390a: R' = R2 = H b: R' = H, R2 = C0,Et c : R' = R2 = C0,Et

CO2Et

Et02C

H

Ph

R' = Me,Ph, 4-MeOC6H,

e

CH2C02R

Me M

383a: R = Et

e

m

M

Mee

b:R=H

eq 74 (60)are evidently facilitated by heteroaromatic ring closures.

392a: X = CO,H

A simple decarboxylation of Hantzsch ester-acids of 382 type into lP-dihydropyridine 3-esters 391 was reported (960) while the analogous transformation of tricyclic 4carboxylic acid 392a into 1,4-dihydropyridines 3921, was found (380)to be accompanied by side disproportionation reactions leading to pyridines 393a-c and 394. A hydrolytic decomposition of 1,Cdihydropyridine 395 gave (177) glutarimide 396. A radical polymerization of 1-substituted 1,4-dihydronicotinamide 397 afforded (365) a polymeric NAD+ model exhibiting the molecular weight of about 3200.

Eto2cfico2Et -:!% 0

H

A r O

2NHzNHz -4EtOH

Et02C

AH H

C02Et

384

0

0 OH H

I

OH

Ar

=

\ /

A r OH

I

OH

MeW

M

Mee

eM &: ,

Me

2-, 3-, 4-pyridyl or 6-methyl-2-pyridyl Me

Similar factors may play a role in the additions of formamide to the 3-cyano group of trans-2,5-dihydropyridines 192 and guanidine to 5-cyano group in 3,4-dihydroderivatives 189a (X = R = Ph) followed by cyclocondensations with the participation of neighboring amino groups resulting in final heteroaromatic products 385 (925) and 386 (292),respectively.

I

Me

395: X =

385: R' = Ph,

2-MeC6H,, R' = Ph, 4-C1C6H,, R3 = Ph, 2-MeOC6H,, 4-PhC6H, or 4-CIC6H,, R4 = Me

386

or Et

K. Miscellaneous. Thermal decomposition of 4,4'dimeric l,4-dihydropyridines (42,44,980) consists of homolytic splitting5 of endocyclic CC and CN bonds and recombinations of the arising radicals. Bis-N,N'-trimethylsilyl derivative 120a (X= H)was found (980)to dissociate into relatively stable radicals 387 while bisN,N'-diacetyl analogue l l l d gave (42,44) acetate 388 besides pyridine and 3-acetylpyridine. On the other hand, bis-N,"-diester 389 afforded (44)a complex reaction mixture in which 1,4-dihydropyridines 390a-c were identified in addition to pyridine and ethyl 3-pyridinecarboxylate.

394

R' = R' = H b: R' = H, R' = OH c: R', R' = 0

393a:

I

Me

PO(Ph)OMe 396

397

A number of stable chromium(0) complexes were prepared (79, 593, 596) by the action of compound (MeCN)3Cr(CO), on variable 1,2- and l,&dihydropyridines. The free heterocycles could be recovered from the given coordination compounds by substitution with pyridine (596). An attempt to calculate interaction energies of variable l-methyl-1,4-dihydr0pyridine-CO(CN)~complexes by means of a modified CND0/2 procedure was reported (895).Similar nonbonding interactions of NADH model 21a with one acetaldehyde molecule were investigated (1131,1136) by EHT and CNDO/2 methods. Other quantum chemical calculations on a complex NAD model were also reported (1133). V. Physical Properties The investigation of dihydropyridines by means of different spectroscopic techniques mentioned in the review

246


Table XXXVIII. Long-Wave UV Absorption Maximum of Some Dihydropyridines substituent at position type 1

2

1

2

3

4

5

hmax,nma

log€

ref

Me CH=CH, C0,Me COzEt C0,Et COMe Me Ph C0,Et C0,Et CH,Ph CH,Ph CH,Ph CH,Ph CH,Ph CH,COPh H H H Me Me

H H

Et H H H H H H H H H CHO CO,H CONH, CN CN NO, CHO CO,H C0,Me C0,Me CI Me

H H H H H H H H H C0,W H H H H CN H Me H Me Ph OMe H

H H H H H H H H H H H H H H H H CHO CO,H CO ,Me CO ,Me

3 27 344 b 302 302 281 303 302 287 230 288 370 352 360 345 336 431 376 314 359 368 313 2 54

d d 3.58 d

594, 593 65 7 284 920 312 312 284 1051 44 44 148 24 148 148 24 462 1174 116 632 181 204 206

3 a

H

CN Ph Ph H H H H H H H H H H H H H H H Et

Methanolic or ethanolic solutions.

In chloroform.

c1

Me

In n-Hexane.

(251) have been further extended and some new types of physical measurements were introduced in this field. The structural interpretations of the new X-ray diffraction data were mentioned in section 11. B. A. Electronic Spectra. It is well known (251) that all dihydropyridines exhibit one to two or three absorption maxima in the region of 200 to 400 nm. PPP-MO-LCAO calculations on 3,5-dicyano-1,2- and 1,4-dihydropyridine chromophores have repeatedly demonstrated (588, 739, 1028) that individual absorption bonds in the mentioned K* character and the longest wave region are of the K absorption corresponds to a pure electron transition between frontier orbitals, e.g., HOMO and LUMO, respectively. The same conclusion followed from the CNDO/S calculations (554, 1174) on the l-methyl-l,4-dihydronicotinamide 21a and 3,5-diformyl-4-ethinyl-1,4-dihydropyridine 26 chromophores. The positions of the long wave maxima found as the most sensitive ones to structural factors are shown in Table XXXVIII for some typical cases. Further characteristics of the UV absorption of 2,3- and 2,5-dihydropyridine types (273,298, %7), more complex derivatives (45,51, 66, 79,

3.41 3.63 2.97 3.28 4.06 4.16 d d

3.85 d

4.64 d

3.95 3.80 d

3.83 d

3.30

Not reported.

285,312,594,631,650,1080,1100)and analogous 4-substitution in 1,Cdihydropyridines (21,44,45,95,181,204, 216,226,228,285,548,511,518,817,920,1174,1175) give

rise to blue shifts of the long wave absorption maximum. The quantitative treatment of the effect of variable substituents X on the UV absorption maxima were carried out in the series of Hantzsch aldehydes 398 (1174), esters 399 (228) as well as nitriles 400 (739) and 401 (739).

-

90,95,148,157,166,176,180,216,225,226,228,234,236, 244, 253, 329, 343, 344, 346, 347, 351, 403, 458, 476, 477, 493, 518, 582, 586, 595, 631, 634, 636, 650, 657, 677, 773, 801,817,827,876,893,899,920,933,935-937,939, 958, 961,1028,1043,1080,1092,1111,1112,1115,1175) as well as polycyclic dihydropyridine derivatives (1042,1043,1130, 1170) were reported. UV absorption spectrophotometry was widely used in different thermodynamic or kinetic

measurements and in product analysis of systems containing dihydropyridines species. The formation of a 1,Cdihydropyridine chromophore by the sulfite ion addition to NAD+ was explored (459) for similar investigations of the latter. Further information regarding the effects of variable substituents on the long-wave absorption maxima have been obtained. As is evident from Table XXXVIII, the effect of 3- and 5-substitution is in general dominant. A higher electronegativity of 1-substituents promote hypsochromic shifts of the absorption and vice versa as follows from further references (216,346,920,961,1051). It appears that any 2-substitution in 1,2-dihydropyridines (95,

I C6H4X

399

398 Me

Me

R

400

H

X

k 401:R = H o r Et

The corresponding Hammett plots have shown polar effects of X-groups to be dominant (228, 739, 1174) in series 399, 398, and 401 while steric factors operate more significantly (739) in compounds of 400 type. Reflectance UV absorption spectra were measured (582) in connection with optical investigation of the solid phase of derivatives 400. Some UV spectra of dihydropyridine ions were also reported. Thus, 2,3- and 2,5-dihydropyridine cations exhibit (252, 332) as a rule similar absorptions as analogous dihydropyridines while 1,2- and 1,4-dihydropyridine anions possess long wave bonds substantially red shifted (83,98, 178, 961) with respect to those in nonionized species. Intensified attention has been paid to luminiscence properties of l&dihydropyridine derivatives including special applications in organic analysis (70). 1,4-Dihydronicotinamides of 268 type (664, 935) and variable Hantzsch 1,Cdihydropyridines 148 as 3,5-diesters (216) as 3,5-diketones (216) as well as 3,5-diamides (216, 224),


(251): dihydropyridine ring CC and CN stretching vibrations (1500 to 1700 em-') were observed in all cases, especially in references 24,180,223,238,327,363,477,933, 939,1092, 1115,1175. Characteristic absorptions of variable substituents bound to dihydropyridine rings have been usually recognized in the region 1700 to 3100 cm-', except in nitro group (1092) and are generally shifted to somewhat lower wave numbers with respect to the analogous absorptions of substituents in pyridine ring (158,180, 81 7, 933, 1115). All N-unsubstituted dihydropyridines exhibit characteristic bonds of NH stretching vibrations in the region of 3100 to 3500 cm-l (56,158,176,180,181,

Table XXXIX. Fluorescence of

3,5-Dicyano-1,4-dihydropyridines 400 in Microcrystallinic State. See Ref 582 Amam nm

X

activation 375 380 395 395 37 5 380 360

H Me Et n-Pr CH,Ph Ph c-C,H,,

emission 404 408 418 417 402 402 396,445

re1 intens, % 69.9 56.4 100 32.7 15.1 1.2 1.0

228,238,441,493,586,679,817,933,1030,1042,1043,1115,

1170, 1172). No important quantitative correlations were found (228) between structural parameters and bond positions of skeletal vibrations of Hantzsch esters 399. IR spectroscopy Amam nm was successively used (227) for solid state kinetic invessubstituents actiemistigation of the reaction of Hantzsch ester 14a with chloR' RZ R3 R4 vation sion ranil. Standard IR measurements of variable dihydroH Me H H 396 480 pyridines are not mentioned. Me H Me H 409 512 C. Nuclear Magnetic Resonance. This spectroscopic Me Me H 381 479 Ph technique has been widely used in the field of dihydroEt0 H Me H 374 463 pyridines in the past decade. Enhanced attention has been Ph Me H 357 463 Et0 paid especially to the application of 13-carbon and 19H Me Me 359 476 Et0 MeNH H H 2,6-C1,C6H, a 445 tJ fluorine absorptions in addition to the extensive use of Me PhNH H H 370 471 earlier summarized (251) proton resonance. PhNH Ph Me H 347 451 Proton NMR has been a rutine tool for structural investigations and the corresponding spectral data can be Not reported; see ref 223. See ref 223. found practically in all papers dealing with new dihydropyridine compounds or any discussion regarding their 1,2-dihydro derivative 129 (476, 477) and dimeric dihydropyridines 358 and 128 (476,477) all exhibit blue or structures. More special applications included isotopically labelled compounds (99,284,290,305,341,631,841,975, green fluorescence of their solutions. On the other hand, 1051,1091). The effects of chiral europium and ytterbium analogous 3,5-dinitrile of types 400 and 401 was observed shift reagents on proton chemical shifts of chiral NADH (582) to display fluorescence in solid states only at room model 272a and on the product of the process 69 were also temperatures. Some typical fluorescence characteristics are demonstrated in Tables XXXIX and XL. . The APF investigated (12, 804). spectrum of 3,5-dicyano-l-ethyl-2,4,4,6-tetramethyl-1,4Proton NMR was also used for the quantitative analyses dihydropyridine was also measured (739). of dihydropyridine mixtures containing variable isomers (209, 680,827, 925) and diastereomers (205, 763). The quenching of the fluorescence of 268b was evoked (664) by the action of some electron acceptors and rate The generally interesting problem of the magnetic constants of the process were correlated by use of quencher equivalence of 4-methylene protons in NADH 21c (828) reduction potentials. and in some of its models (828,924,1138)was repeatedly B. Infrared Spectra. The structural effects on IR studied and a differentiation of the signals was observed under suitable conditions. A broadening of 4-methyl sigabsorption have been discussed in three spectral regions Table XL. Fluorescence of Hantzsch 1,4-Dihydropyridines 143 in Ethanolic Solutions. See Ref 216

~

Table XLI. Chemical Shifts of Ring I3C in Some 1.2- and 1,4-Dihydropyridines position type

2

3

4

5

6

compound

ref

1 (1,2)

52 47.0 75.6 55.6 55.9 127.3 123.7 123.2 120.1 120.6 137.1 138.3 138.1 137.8 138.1 141 144.15 143.66 144.88 140.4

111 109.1 103.9 140.7 92.7 95.3 105.9 113.9 114.8 114.3 103.0 101.8 96.7 100.3 101.6 109 104.11 104.35 103.14 114.1

122 122.5 138.8 161.1 143.9 22.3 22.5 18.7 41.3 33.9 30.1 29.1 20.6 22.3 38.9 26 39.67 38.34 40.28 86.0

99 99.2 110.3 100.8 77.6 95.3

148 144.9 141.7 161.3 145.2 127.3

C C C

C C C

c

c

C

C

c 101.0 101.8 102.2 108

127.9 129.5 130.2 127

404 404 13b 13a 405 6 390a 406a ( n = 2) 406a ( n = 4) 406a ( n = 5) 406b ( n = 4) 406b ( n = 5) 268a 268b 117a 21c (NADH) 399 (X = H) 399 (X = pMe,N) 399 (X = p-CN) 19

97 726 78 0 780 1112 21 1 279, 280, 923 280, 923 280, 923 280, 923 923 923 713 726 726 97 229 229 229 214

2(1,4)

All data in

6

with respect t o Me,Si.

c C C C

C

C C C C

Numbering see the formula 1.

Not shown because of the molecular symmetry.

248


nals in the temperature dependent proton spectra of 1,4dihydro derivatives 16 was attributed (987) to conformational changes of the dihydropyridine ring. Dynamic changes of spectral characteristic were used (1114) for the clarification of the mechanism of l,.l-dihydropyridine derivative oxidation with dibenzoyl peroxide. The CIDNP technique enabled us to demonstrate radical mechanisms of the thermal decomposition (44) of dimeric 1,4-dihydropyridine 111 (R1 = COzEt and R2 = H) as well as of the reaction of 1-methyl-3-cyanopyridiniumion 71 with triphenylmethyl halogenides and tropylium tetrafluoroborate (438). The formation of a complex of Hantzsch ester 14a with pyridine N-oxide was proved as well (522) by proton NMR. The quantitative empirical correlations of X-substituent effects were found in the chemical shifts of 4-methin protons in series 398 (1174),399 (229,ti77), 401 (7391, and 402 (577) as well as in 1-methylene protons in series 403 (577). H,

CsH4X

analogously (20, 21, 79, 403, 631) as in the case of their 1,4-dihydro analogues. 4,4-Spirosubstituted 1,4-dihydropyridines seemed to exhibit (236) two kinds of the 4-radical elimination as demonstrated in eq 75.

cI H21 (75)

Nc&cN

,

Me

Me

I

H

Contrary to discussed examples the exceptionally easy loss of 1-benzyl residue was found (264) to be the most important fragmentation process for 3-acetyl-5-alkyl-lbenzyl-1,4-dihydropyridinesas shown in eq 76.

402 403

Carbon-13 NMR appeared to be a very effective tool in the elucidation of different dihydropyridine structures (1, 2,97, 104,211,214,215,229,279,280, 303,320, 418,516, 633,657, 713, 726, 767, 780, 789, 792,870,899,923,1112).

Some typical values of carbon-13 chemical shifts for variable 1,2- and 1,4-dihydropyridines are shown in Table XLI. Dynamic changes of the shifts were successively explored (418,420) in the investigations of the reduction of 2-benzoylpyridine and 2-pyridinecarboxaldehyde with NADH model 268b in the presence of Mg2+and Zn2+ions. Both carbon-13 and proton NMR spectra were also applied (104) in the structural assignments for nucleotides 21c, e.g., NADH and NADPH, respectively. 19-Fluorine NMR

x

I

CHZPh

404

I

kzzzz=

t

405: X = C 0 , E t

I I

X

406a: X = C0,Et

b: X = Li

spectra are reported (174,417) for several perfluoro 2,3and 2,5-dihydropyridine derivatives. D. Mass Spectrometry. It follows from the earlier summarized (252) results on mass spectrometry of dihydropyridine compounds that the major fragmentation mechanism is usually an aromatization besides the less important loss of N-alkyl substituents cleavage of 3- and 5-substituents as well as the opening of the heterocyclic system. The mentioned character of the fragmentation has been repeatedly confirmed. Thus, the aromatization of 1,4dihydropyridine molecular ions were frequently observed to proceed with loss of hydrogen atom (20,21,264, 380, 426, 920) or by elimination of 4-alkyl radicals (236, 263, 841, 842) especially in the case of 4-alkylated Hantzsch esters (263) and 4,4-disubstituted 3,5-dicyano-1,4-dihydropyridines (841). The fragmentation of variable 1,2dihydropyridine radical cations was observed to proceed

CH2Ph

H

H

R*CoMe

Y$J -

(76)

R = Me, Et, n-Pr and i-Pr

Mass spectrommetry seems to be a reliable molecular mass determination method for dihydropyridines (51,285, 310,476,477,576,675,893,967,1028, 1175). A thermal decomposition of 4-cyano-l,4-dihydropyridines61b and analogous 3-acetyl derivatives was found (265) to accompany their mass spectrommetric fragmentation and a detailed mechanism of the processes has been considered (265). The evaporation of 1-phenylpyridinium salts in the mass spectrometer was found (254) to lead to l-phenyldihydropyridine radical cations via a redox process. E. Miscellaneous. Photoelectron spectra (536) of 1,Cdihydropyridine 6 and its 1-methyl derivative exhibiting ionization potentials lower than 8 eV have shown that the compounds are stronger a-electron donors with respect to 1,Ccyclohexadiene. Chiroptical properties of NADH models 272a,b and 273 (801) as well as of a Hantzsch 3,5-bis-(-)menthyl ester (57) were measured and discussed in connection with metal ions coordination (801). Electron spin resonance of electrolytically generated 3,5-dicyano-1,4-dihydropyridine radical cations 286 were interpreted (528) in confrontation to simmulated spectral data. The same type of l,4-dihydropyridine species was indirectly proved (896) by means of the electrogenerated secondary chemiluminiscence of some aromatics. Further photophysical properties of some dihydropyridines were also investigated (202). The polarographic reduction of nitro groups in side chain substituted 1,4-dihydropyridines shown in eq 64 was studied in detail (578) and the appropriate mechanic and analytic aspects were discussed as well. The experimental dipole moment 4.00 D for l-methyl1,4-dihydronicotinamide 268a was found (579) to be in


good agreement with the theoretical momenta calculated by the CND0/2 method but not by the EHT procedure. TLC analysis of Hantzsch ester 14a in the presence of 3,5-dicarbethoxycarbonyl-2,6-dimethylpyridine was worked out (853,854,855,856)for practical purposes. Acknowledgment The work on this review was undoubtedly enabled by my (J.K.) correspondence with my colleagues from different countries, especially with my prematurely deceased friend Dr. Ulli Eisner (Trend Polytechnic, Nottingham, England) as well as with Professor R. A. Abramovitch (Clemson University, South Carolina), Professor J. F. Biellmann (Universitb Louis Pasteur de Strasbourg, France), Professor N. Bodor (The University of Kansas, Lawrence, Kansas), Dr. G. Duburs (Institute of Organic Synthesis, Latvian Academy of Sciences, Riga, U.S.S.R.), Dr. A. J. de Koning (State University, Utrecht, The Netherlands), and Professor U. K. Pandit and Professor J. W. Verhoeven (University of Amsterdam, The Netherlands). The authors express their thanks to Mrs. Zuzana Donnerovl for her indispensable technical assistance in the preparation of the manuscript. Appendix. A List of References on Biological Activity of Dihydropyridines Reported Properties: (Citations). Patents concerning hypotensive activity: 40,52,61, 75, 94,117,120-122,127-129,131-136,139-141,143,161,297,

348,415,444-452,483,505,506,538,564,583,626,665-667, 676,681483, 691, 694-700, 733-736, 762, 928, 931,932, 952, 955, 957, 984, 1072, 1082, 1083, 1149, 1156, 1157, 1159-1161, 1191). Papers on hypotensive activity and related phenomena: (30-36, 41, 53, 59, 69, 72, 76, 77, 118, 119, 123-126, 130, 137,138,144,147,150,182,185,186,194-197,234,245, 261,266, 267,270, 274-278,281,282, 301, 314-316,336, 338, 350,356, 368,369,374-378,383,384,398-400,404, 405,407,410,413,414,427,428-430,439,440,453,456, 457, 461,472, 473,478,479,482,508,521,534,535,537, 539,541-543,558,597,604-606,609,610,613,624,627-630, 639,640,641,647,651,674,684490,692, 702, 703, 706, 707, 709, 710, 719, 729, 730, 737, 738, 740, 746, 749, 759, 768, 771, 779, 782,824,826,833,834,859,865,868,900, 904,912-91 7,927,929,930,938,947,951,954,959,964, 971, 972, 976, 977-979, 981, 983, 988, 999, 1044, 1056, 1076-1079,1081,1084,1085,1090,1101,1108,1109,1118, 1124,1125,1140-1142,1146,1158,1162,1163,1167-1169).

Structure of metabolites from dihydropyridine pharmaceutics: (245, 382, 455,540, 657, 707, 971, 1151). Toxicity (130,234,482,685,686,689,692,693,719, 737, 834, 11 94). Antiinflammatory effects: (561,562, 701). Mutagenic effects: (317, 318, 319, 598, 646). Cancerogenesis: (63, 565). Bactericides, fungicides: (910). Other effects: (110-112,385,386,394,395,652,996,997, 1035,1038,1143,1158). Properties of dihydropyridine pharmaceutics: (295,296, 507, 672,673,1063,1064,1117). Literature Cited (1) Abbott, P. J.; Acheson, R. M.; Elsner, U.; Watkin, D. J.; Carruthers, R. J. J. Chem. Soc.. Chem. Commun. 1975, 155. (2) Abbott, P. J.; Acheson, R. M.; Eisner, U.; Watkin, D. J.; Carruthers, R. J. J. Chem. Soc., Perkln Trans. 7. 1978. 1269. (3) Abele, W.; Orosse, M.; Pllz, 0. Ger. Otfen. 2758210, 1979 Chem. Abstr. 1980, 9 2 , 155, 899. (4) Abeler, G. A.: Maul, R. Eur. Pat. ADd. . . 2007. 1979: Chem. Abstr. 1980, 9 2 , 6420. (5) Abramovtch, R. A.; Orins. 0.; Rogers, R. 9.; Shinkai, I.J. Am. Chem. Soc. 1978. 9 8 , 5671.

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Receiued for review October 2, 1981 Accepted January 15, 1982

Lanthanide Diphthalocyanines. Electrochemlstry and Display Applications Margle M. Nlcholson Autonetics Strategic Systems Division, Rockwell International, Anaheim, California 92803

Electrode films of lanthanide diphthalocyanines undergo a series of reversible color changes that make them potentially very attractive as flat-panel color display materials. Research on these compounds has revealed a complex scheme of electrode processes that is not yet fully characterized. The solid organic phases within the faradaic system include new roomtemperature anion and cation conductors, as well as electronic semiconductors. Application of diphthalocyanine electrochromics to practical display products will depend on development of adequate cycle life and a technique for matrix addressing.

Diphthalocyanine complexes of the lanthanide rare earths were first prepared and investigated by Russian scientists. These relatively new members of the phthalocyanine family have a sandwich structure resembling that of the ferrocenes. Moskalev and Kirin (1970a) reported that a film of lutetium diphthalocyanine on a transparent conductive tin oxide electrode underwent a series of striking color changes as the applied potential was varied in aqueous potassium chloride solution. That observation has led others to evaluate the rare-earth diphthalocyanines as electrochromic display materials and to investigate their basic electrochemistry. This research has emphasized the lutetium compound, although the electrochromism is 0 196-4321 18211221-0261$01.25/0

known to occur in diphthalocyanines of all the lanthanide elements and of several other trivalent metals. An exceptional range of chemical behavior is found in these systems. The discrete organic phases, characterized by different oxidation states of the dye, include electronic conductors, solid anion and cation conductors, and presumably ion exchangers. They may also include hydrates and oxygen adducts. Because of their close relationship to the chlorophylls and porphyrins, the diphthalocyanines might serve as dimeric model compounds for research on natural products. This article provides a survey and critique of electrochemical investigations on the lanthanide diphthalocyanines. It then describes their characteristics and status in relation to liquid crystals and other flat-panel display technologies. With further development over the next several years, the multicolor diphthalocyanine electrochromics may be ready for application to military, industrial, and consumer products. Composition and S t r u c t u r e Lanthanide diphthalocyanines are synthesized by heating the rare-earth acetate or chloride with ophthalonitrile (Moskalev and Kirin, 1970b; Mackay et al., 1974). An exothermic reaction near 300 "C produces the 0 1982 American Chemical Society

Development in dihydropyridine chemistry - American Chemical

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