1m1
Chsm. Rev. 1993, 93, 1991-2005
The Chemistry of &Enaminonitriles as Versatile Reagents in Heterocyclic Synthesis Ayman Wahba Erian L%ptmnt of Umdsby. Faaiify of sdsnos. ce*o LhkamY~,W, Egypt
Recehd M y 29, 1001 iRm4sxl MatIuTUW Recehd Ap# 22. 1008)
conhts
4
1. Immductlon 1991 11. Molecular Sbuctures and Spectral Properties 1991 1992 111. Mahods of Preparation 1992 A. Reparam of &EnaminonMiles 1993 6. Reparam of Mamlnomaleonlblle 1993 C. Preparation of 3-Amino-2-Substttuted4.4.4-Trichlorocrotononitribs D. Preparation of 1993 2-Amino-l.1.3-Tricyanopropene IV. WlHy in Heterocyclic Synthesis and Symhesis 1993 Of
Monocyclic Azines
A. Synthesis of Pyridine% 6. Synthesis of Pyrimidines V. Synthesis of FiveMembered Rings with One
VI.
VII. VIII. IX.
f.
Heteroatom A. Pyrroles end Their Benzo Derhrathes Synthesis of FhncMembered Rings wim Two or More Heteroatoms A. Pyrazoles and Rloir Fused Six-or Five-Membered Heterocyclic Rings 6. Imidazoles and Their Fused Six-Membered Heterocyclic Rings Mlsceilaneous Conclusion and outlook References
1993 1997 1999 1999 2000 2000 2001 2002 2003
Dr.AymnnW.ErinnwasbominCako.Egypt,in 1961. Mareceived his B.Sc. in Chemistry at Cheti'dstry Depftmenl,Faculty of Science. Cairo University in 1982, wlth grade of "Distinction wim first Class
Honours". He was a graduate student in heterocyclic chemistry (MSc. 1986. Ph.D. 1989)atCahoUniversityunderdlrects~lon of Prof. Dr. M. H. Einagdi (Facultyof Science. Cairo University). He receivedafelbwshipofUwAiexanderVon HumboldtSWtung(l990 1992)and did postdoctoral work whh Prof. Dr. D. W p p at Duisburg University, FRG. His research work is in the area of heterocyclic synthesis and studies wlth photochemishy. He is currently an Assistant Professor of Chemistry at Cairo University. In addition to heterocyclic chemistry Dr. Erian's research interestsaisoinclude photochemisby and ultrasonic Chemistry in Cycloaddltlon Reactions.
2003
"I eC ,XCN N R
H2N
I. Inhoducllon
R
Much synthetic heterocyclic organic chemistry involves specially designed reagents which are readily generated and then used toprovide molecules withbuiltin functional moieties for further exploitation. Important examples of such reagents are @-enaminonitriles (j3-aminoalkenonitrile) which have proven to be valuable tools in the synthesis of a wide variety of unique heterocyclic systems such as pharmaceuticals, fungicides, and solvatochromatic dyes. Numerous reports in the literature concerning their applications attest to their growing importance. Although reviews covering thechemistryof enamines,'heterocyclic enamines? and heterocyclic @-enaminonitrile@ have appeared, it is hoped that this review will remedy the lack of a more comprehensive review by providing an up-to-date coverage of the recent literature. This review covers the literature up to 1992 and considers the properties, reactions and applications of open-chain @-enaminonitriles (1-4). 3-Aminocrotononitrile (1.2, R = CH3) and diaminomaleonitrile (DAMN) (3) are discussed in particular depth due to their frequent appearance in the literature as well as their potential biomedical and industrial importance. 00092665/93/0793-1991$12.00/0
NH2
(a4
(E)-* R = H. alkyl ff awl
3
4a: R = CCI,:
R' = CN. CO,EI. COP^
4 b R I CHSN: R' = CN
I I . Molecular Structures and Speclrel Pmpertles @-Enaminonitriles exist in two stereoisomers. In 2-form (2),the amino and cyano groups are in adjacent positions on the double bond. An intramolecular hydrogen bond makes the 2-form more stable than the E-isomer (l).' In thecaseof@-aminmotononitrile(1,2, R = CHs), it has been established that isomerization in either solution or the solid state can occur.8 A mixture of E- and 2-isomers, which are readily distinguishable by 'H NMR, is formed. Only the 2-isomer (2) has a coupling constant of 0.8 Hz for the CH3. In addition the 2-isomer absorbs in UV spectroscopp a t shorter wavelength and usually givesa more intense absorption (MeCN) = 254 nm, e = 11.77 X 10') than band at (A, does the E-isomer at (A- (MeCN) = 255 nm, c = 1.54 8 1993 A
n "
Chemical Soclay
Erlan
1002 Chemical Reviews, 1993, Voi. 93, No. 6
Table 1.
NMR Spectra of Enaminonitriles H
CN
R3$N
-
-
€-isomer
nitrile
A
B
c D
E F
R2
R3 H
E (100)
c&6
a ‘J(HC=CCHs) < 0.1 Hz. 4J(HC=CCH3) = 0.75 further examples and details, see ref 25.
* 0.2 Hz.
X lo4). The position of the photoequilibrium, as established by UV absorption data, is at (75 %) 2 form and (25%) E form.1° Spectroscopic studies of enaminonitriles also showed that the enamine tautomeric structure 5 is preferred over the imino structure 6.7J1-17 CN
CN
h-
HC-
I
C-
I
NHZ 5
’
CN
R’INpR3
2-isomer
prevailing isomer solvent (relative population, %) H (CDs)zSO E z (70) CDC13 CeH6 E (60) CH3 CH3 H CDCls E (85) CeDe E (95) CH3 CeH6 H CDCl3 E (90) E (95) CsH6 Z (85) C~H.F,H H CDCl3 C&6 z (100) CH3 C~H&HZ H CDCls E (100) c&6 E (100) CH3 CzH6 C2H6 CDCls E (100) R‘ CH3
H
chemical shifts in isomers H3CC= R2 R3=H E Z E Z E z (NH) 3.94” 1.94O 6.48 6.48 4.10 3.8gb 2.09 1.92* 4.68 4.68 3.490 3.22b 1.37 0.90b 3.65 3.39 2.03 1.70 2.62 (d)c 2.96 (d)c 5.42 3.51 3.44b 1.86 1.36b 2.21 (d)c 2.52 (d)c 4.35 3.93 2.17 1.90 6.9-7.4 (m) 6.65 4.06 1.50 1.09 6.4-6.9 (m) 4.70 4.35 4.14 5.12 5.12 3.90 4.52 4.52 3.80 2.07 4.10 (d)c,d 4.81 3.44 2.43 3.26 (d)O 3.70 2.14 1.02 (t)* 3.22 (q)e 3.58 1.85 0.78 (t)’ 2.70 (q)e HC=
CeH6 proton multiplet around 6 = 7.3. e 3J(HCCH) = 7
and C=C bonds at the same time as increasing the 7r-bond orders of the C-CN bonds. The 7r-electron distribution and densities of j3-aminocrotononitrileare given in structure 7. CH3
0808
1878
i6
Two absorption bands found in the NH-stretching region of the IR are compatible with a primary amine groups (NH2).16 Furthermore, the lack of two IR absorption nitrile stretching bands led to the conclusion that enaminonitriles exist solely in form 5 rather than in an equilibrium mixture of 5 and 6. lH NMR appears to support this conclusion, since the NH signal appears in a position typical for an amino group.8J8Jg 13CNMR has also been used to study the structure of enaminonitriles in order to obtain information on the transmission of electronic effects of the amino group and their influence on the reactivity of the enaminonitrile system.20 In cases where a considerable variation was observed in the contribution of the amino moiety to the chemical shift of the olefinic carbons this was attributed principally to a variation in the mesomeric contribution to the electron d e n ~ i t y . ~ lSimilarly -~~ lH NMR and nuclear Overhauser effects (NOE) studies of a series of 3-substituted 3-aminoacrylonitrilesshow that the olefinic proton is more shielded and that the protonproton long-range coupling constants J (HC=CH3) and J (HC=CNH2) are larger in the 2-isomer (2) than in the isomer (1) (Table 1).26 Huckel’s LCAO-MO method has been used to study the 7r-electronic structures of some enaminonitriles.26 It was shown that conjugation of the electrons with the cyano group decreases the ?r-bondorders of the C-NH
1936
02751 07% HzN-C-C-C-N 0377
I I
NH
* 1 Hz. For
0455
1222
0866
0859
1296
7
It should also noted that the resonance hybrid enamine structure (cf. I, 11, 111) imparts certain nucleophilic character to some atoms while other atoms are electrophile,7 since the Michael addition features so prominently.
..
H$
R
I
-
“I
H2i‘ Hx=N:-
/
II
m I I I . Methods of Preparation Several methods have been reported for the synthesis of j3-enaminonitriles, most of these involve the dimerization of substituted nitriles. A. Preparation of @-Enaminonitriles
The dimerization of acetonitrile using sodium in organic solvents is the most common approach for the synthesis of j3-amino~rotononitriles.7~~~-~~ Treatment of acetonitrile with sodium gave j3-aminocrotononitrile (1,2, R = CH3) in quantitative yield. The reaction is processing via a free-radical mechanism (Scheme l).7
Chemical Reviews, 1993, Vol. 93,No. 6
&Enaminonitriles as Versatile Reagents
-
Scheme 1
CH$N
CH3CN CH3CN +'CH2CN
+ Na' + 'CH3
NaCN CH4
1993
tonitrile (11) using a base catalyst gives the title compound in good yields after only short reaction times.46~~~
+ 'CH3
+ 'CH2CN
CC13CN 11
+
XCHzCN S, 12: X = CN, C O ~ C ~ HCOCsHs
x
c13c 4a
H2'N'
CH3
This is only reported mechanism for such a reaction and looks least likely in view of lack of evidence as isolation of other products that should be formed in such radical reactions. A mechanism including formation of carbanion Na+ -CH2CN looks more logical. Cross condensation between acetonitrile and aromatic nitriles37-99or higher aliphatic nitriles leads to substitute P-enaminonitriles (1,2, R = alkyl or aryl).4o B. Preparation of Diaminomaieonitriie Diaminomaleonitrile (3) is readily formed in dilute aqueous solutions of HCN at room temperature (Scheme 2).34*41The initial step is the dimerization of
D. Preparation of 2-Amino-l,l,3-Tricyanopropene Although the self-condensation of malononitrile can produce dimers, trimers, or, in certain cases, polymel.48 the reaction may be controlled to give the dimer as the main product. The reaction can be catalyzed by a base, acid, or a Lewis acid. The a-methylene group in malononitrile is sufficiently acidic to afford a carbanion in the presence of a base catalyst; the carbanion can then react further to produce the dimer (Scheme 4).48 Scheme 4
C ' N 13
Scheme 2 PHCN HCN
+
-
fN8-
H2C,
,F N
IN€-EH-CN]
+
CN
NCxCN
e HNZCH-CEN H2N
HN=CH-C=N
,CN
NCH2C
\CH
I
14
CN
HCN
HzC,
H2N
,CN \CH
I
CN
NH2
4b
A -- H2NIcN 4b HzN
Thorpe condensation of two malononitrile molecules yields the dimer which exists mainly in the enamine f0rm.137493~
CN
3
HCN to iminoacetonitrile which combines with another molecule of HCN to give the aminomalononitrile. The latter reacts with another HCN molecule to give the isolable product diaminomaleonitrile (DAMN) (3). DAMN is the lowest oligomer isolable from an aqueous solution of HCN, and ita formation can be readily assayed by using its characteristic UV absorption band (Ama = 296 nm, ?r = 13 500).34 The postulated stepwise condensation of hydrogen cyanide to form DAMN is supported by the formation of the maleonitrile derivatives 10 via the intermediate 9 (Scheme 3).42 Addition of formaldehyde, acetaldeScheme 3
I V. Utlllty In Heterocyclic Synthesis and Synthesis of Monocyclic Azines A. Synthesis of Pyridines It has been reported that the dimerization of 0-aminocrotononitrile (1) under various reaction conditions produces 2,4-lutidine Satosg has reported a convenient method for the preparation of 19 by means of the polyphosphoric acid (PPA) catalyzed selfcondensation of 1. In contrast, under milder conditions 1 gave dienaminonitrile 17 (13% yield), in addition to the 2,4-lutidine (19). Intramolecular cyclization of the dienaminonitrile 17 when heated in PPA or an alkaline solution gave its isomer 19 (Scheme 5). Scheme 5
9
10
R = (CH3)3C-, (CHa),CH-, CcHiq-, CZHSI
hyde, or acetone was reported as accelerating the formation of diaminomaleonitrile, although the mechanism of this process is unclear.43 In addition, halogens or Cu2+ ions can catalyze the tetramerization of hydrogen ~ y a n i d e . ~ ~ ~ ~ C. Preparation of 3-Amino-2-Substituted4,4,4-Trichlorocrotononltrlles The condensation of active methylenecarbonitriles XCHzCN (X = CN, C02R, COPh) with trichloroace-
15
Me,
H2Y'
Me
,NH2
NcfE\cHz
Me
I CN
--,~JH, "'~C,N -Hi
Me
H-transier
NH2 17
16
r
Me
18
19
1994 Chemical Reviews, 1993, Vol. 93, No. 6
Erlan
Scheme 8
36
21
r
NC S
22
1
Me
c-c=c,
,CNI
-
GN N-y
23
Scheme 7 NC-CH,-C=N 13
+
NH
Ar
R
~ 25
XAIC13
NC-CH,--~=N-R X-
26
NHR
NHR
13
N
27
28
30
H
39
E E N
31
The antischistosomal agents pyridylpyridazines 24 were synthesized via the reaction of p-aminocrotononitrile (1) with malononitrile (13) to yield the pyridine derivative 22. 22 couples easily with suitable aryldiazonium salts to form 23 which after a Japp-Klingeman reaction yields the desired product 24 (Scheme 6).60 2,4-Bis(sec-alkylamino)pyridines31 were obtained from the reaction of malononitrile (13) with sec-alkyl halides 25 under Friedel-Crafts condition. The reaction is assumed to proceed via intermediate of enaminonitrile 28 (Scheme 7).61 One example of a large number of P-enaminonitriles of the general formula ArNHC(R')=C(X)CN which have been cyclized using ethyl phosphate (PPE), is 33 which was prepared from 32.62163
the reaction of aldehydes with P-enaminonitrile34 yields the benzylidene derivatives 36 which in turn reacts with 34, in acetic acid, to form the intermediate diamines 37. The latter was isolated from the reaction of 34 with the aldehyde 35 in ethanol at room temperature.78The diamines 37 are readily converted into the 1,4-dihydropyridines 40 in acetic acid solution. Evidence for Scheme 8 was found by O'Callaghan et al.77J8 who isolated the dihydropyridine 39 by trapping the intermediate 38 using excess aldehyde 35 in the reaction mixture. The effect of the basic reagents in nonhydroxylic solvents on the Hantzsch-type 1,4-dihydropyridine 40 has been discussed briefly by Tinker.79 Treatment of the dimedone 41 with aldehydes 42 and 6-aminocrotononitrile (1) gave 44. The reaction was initiated by the condensation of dimedone with the aldehyde to give the intermediate 43, followed by the addition of 1 and cyclization.80
PPE
Et 32
(O&co2Et 0
N I El 33
The first reported synthesis of dihydropyridines 40 involved the condensation of P-enaminonitrile 34 and aromatic aldehydes 35.6L 1,4-Dihydropyridines40 have had widespread use in recent years in medicinal The synthesis of 1,4-dihydropyridines 40 (Table 2) takes place according to (Scheme 8);76177
'0' ;;ac CHR
A
O
R
Me
Me 41
Me 43
H 44
Nucleophilic attack by 1 at the C-2 of the acylchromones 45 produces the benzopyranopyridines 47. The reaction is believed to involve the intermediate 46 (Scheme 9).81In a similar reaction, 1with the aldehyde 48 gave good yields of the product 49.82*83 The reaction of carbethoxymalonaldehyde (52) with tosyl chloride followed by treatment with 6-aminocrotononitrile (1) produce the biologically and medicinally important nicotinic acid derivatives 55. Scheme 10 ~ shows the mechanism proposed by Torii et a l . " ~ The first step of which involves the sulfonylation of 52 to form the P-tosyloxyacrylate53. In the subsequent step, the intermediate 53 undergoes a nucleophilic attack by the enamine 1 to give the intermediate 54. The latter
