Vol. $4,N o . 2, February 1969 Florisil. Elution with chloroform gave 1.0 g of syrup which soon crystallized. Aft,er one recryst.allization from acetoneether, the product melted at, 142-143": ir (CHCl,) 1700 cm-' nnir (CDCl,) 7 2.5-2.9 (3, aromatic), 1.53 (indole N-C=O); (1, indole (211-H deshielded by C=O). Anal. Calcd for CleH~oN20: C, 77.10; H, 7.19; N , 9.99. Found: C,76.76; H, 7.27; N, 10.17.
1,2,3,4,6,7,7a,12,12a,l2b-Decahydro-7a,12-dihydroxy-l,l2 (7oxo) trimethyleneindolo~2,3-a~quinolizine (9) .-Further
development of t,he Florisil :olumn described above using acetone as eluent gave 0.8 g of material which was purified by recrystallization from acetone: mp 244-245"; ir (KC1) 1650 (amide C=O); uv (XeOH) 212 mfi ( E 9800), 257 (10,900); nmr (pyridine-ds), 7 3.40 (s, 1 , C'Z-OH), 3.92 (m, 1, CI,-OH); shaking the pyridine solution with D 2 0 caused almost complete removal of these signals. Anal. Calcd for ClnH&20a: C, 68.76; H, 7.05; N, 8.91. Found: C,68.61; H,7.23; S , 9-01. 1,2,3,4,6,7,12,12b-Octahydro-1-propyliidolo [ 2,3-a]quinolizine (7).--6 mixture of 2.82 g (0.010 mol) of 6a, 50 ml of ethylene glycol, 20 ml of hydrazine hydrate and 2 g of KOH was heated under a nitrogen atmosphere at 130-132" for 2 hr. The temperature was then raised to 180' and maintained for 1 hr. The thick solution was shaken with 500 ml of ether and the extract washed with 1 1. of cold water. The aqueous extracts were counterextracted with ether and the combined extract then concentrated in vacuo to give 2.9 g of thick syrup. The material was chromatographed on 100 g of neutral alumina using chloroform as eluent. The product (1.69 g) was a yellow syrup which failed to crystallize; ir (CHC13) 3480 cm-1 (indole N-H); uvmax (MeOH) 227 mfi (E 28,000), 283 (6400). Treatment of the free base with 0.6 g of oxalic acid in ether gave an ivory-colored salt (1.95 g) which after two recrystallizations from ether-methanol melted at, 177-178" (bubbling); the salt resolidified and melted again a t 244-245 O .
Anal. Calcd for C18H21Nl.(C0~H)~; S , 7.82. Found: N, 7.69. 1,2,~,6,11,12,13,14,15,15aDecahydro- 13-0xo-SH-benz[i]indolo[2,3-a]quinolizine (13).-To a stirred solution of 11.2 g (0.050 mol) of 2 in 100 ml of dry T H F was added a solution of 3.50 g (0.050 mol) of methyl vinyl ketone in 50 ml of benzene over a 30-min period. The solution was stirred for 5 hr, then the solvent was removed zn vacuo. The crude product (10.7 g) was dissolved in a little CHCL and chromatographed on 200 g of Florisil. Elution with USP ether and concentration of the fractions gave 3.9 g of material, which on stirring with anhydrous ether gave 1.4 g of crystalline product, m p 172-177'. Recrystallization from benzene-ether-hexane gave analytically pure 13: mp 175-176"; ir (CHCI,) 34'70 em-' (indole N-H), 1715 (ketone C=O), no bands in the 2700-2800-cm-' region; uv (MeOH, neutral) 226 mfi ( C 32,000), 283 (7900). Anal. Calcd for C19H22N20: C, 77.55; H, '7.55; N , 9.52. Found: C, 77.46; H, 7.53; N,9.43.
Acknowledgment.-The authors xish to thank Dr. Dale A. Stauffer and associates for the analytical services. Registry No.--2, 5912-12-9; 4a, 13039-47-9; 4b, 18039-48-0; 4c, 13067-03-3; 4d, 18039-49-1; 6a, 13031-30-6; 6b, 18031-31-7; 6b.HC1, 13031-32-8; 6c, 13031-33-9; 6ceHC1, 13031-34-0; 7, 13039-51-5; 7 oxalate, 18031-35-1; 8, 13031-36-2; 9, 13031-37-3; 10 oxalate, 13031-38-4; 11 oxalate, 13031-39-5; 12, 18039-50-4.
Steric Inhibition of Intramolecular Cyclizations by ortho Substituents. The Synthesis of lH,SH-Thien0[3,4-c]thiophene,Its 2,2-Dioxide, and 5-Ethyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole' D. J. ZWANENBURGAND HANSWYNBERG Department of Organic Chemistry of the University, Bloemsingel 10,Groningen, The Netherlands Received July E?, 1968 During clur study of the synthesis of anellated five-membered rings on thiophene, we discovered that some intramoleclilar cyclizations are adversely affected by ortho substituents in the aromatic ring. Reaction of 2,5-dibromo-3,4-bis(bromomethyl)thiophene with sodiiim sdfide furnished 4,6-dibromo-1H13H-thieno[3,4-c]thiophene with sodium sulfide gave the 4,Gdichloro derivaand ring closure of 2,5-dichloro-3,4-bis(chloromethyl)thiophene tive. On the other hand, reaction of 2,5-dichloro-3,4bis(chloromethyl)thiophenewith ethylamine in acetonitrile pyrrole was does not form a thienopyrrole derivative, while cyclization to 3-ethyl-5,6-dihydro-4H-thieno[3,4-c] successful when the chlorine atoms on the thiophene nucleus of the tetrachloride were removed prior to the reaction with ethylamine. Our explanation of the steric inhibition of intramolecular cyclization by ortho snbstituents is given.
In an earlier publication2 me have described the synthesis of 1H,3H[-thieno[3,4-c]thiophene (4) by ring closure of dimethyl 3,4-bis(bromomethyl)thiophene2,5-dicarboxylate with sodium sulfide, followed by removal of the carbomethoxy groups. In view of the we wish to current interest in thienothiophene~,~.~ describe here an improved preparation of thienothiophene 4. Cyclization of 2,5-dibromo-3,4-bis(bromo(1) Abstracted in part from the Doctoral Thesis of D. J. Z., Groningen, 1967. (2) H. Wynherg and D. J. Zmanenburg, J. Ow. Chem., 29, 1919 (1964). (3) H.Wynberg and D. J. Zwanenburg, Tetrahedron Lett., 761 (1967). ( 4 ) M. P. Cava and N. M. Pollack, J . Amer. Chem. Soc., 89,3639 (1967).
methyl) thiophene ( 1)5 with sodium sulfide gave 4,6dibromo-lH,3H-thieno [3,4-c]thiophcne (2) in 60% yield; the latter could be reduced to lH,3H-thieno[3,4-c]thiophene (4) in 75y0 yield (Scheme I). The cyclization reaction also yielded the dimeric compound 1,3,7,9-tetrabrom0-4H,GH, 10H, 128,dithieno [3,4-c:3', 4'-h] [1,6]dithiecin (3) in 18% yield. Oxidation of sulfide 2, followed by zinc in acetic acid reduction, furnished 1H,3H-thieno [3,4-c]thiophene 2,2-dioxide (6) in 60% over-all yield. As we have described, reaction of methyl 2,3-his( 5 ) D. J . Zwanenburg and I i . Kynberg. Rec. T r m . Chim. Paus-Bns. in pres?.
The Journal of Organic Chemistry
334 ZWANENBURGAND WYNBERG SCHEME I S.
Br
Ri.
2
Br
Br
XaS
Br
Hr
0
1
z
n
,
c
y
pJ
CH,CO?H
3
dioxaoe
4
5
(chloromethyl) t,hiophene-5-carboxylate (7) with sodium sulfide in methanol or with ethylamine in acetonitrile gives the thienothiophene g6 and the thienopyrrole 9,7 respectively.
H C0.C
C,H.NH, CH,CN
H iCO,C 8
,
7
6
of the ditosylate after reaction with p-tolylsulfonylchloride. Whereas reacttion of the tetrachloride 10 with ethylamine did not furnish a thienopyrrole derivative, ring closure of the tetrachloride 10 with p-toluenesulfonamide in dimethylformamide and potassium carbonatelOJ1 as base did furnish 1,3-dichloro-5-tosyl-5,6dihydro-4H-thieno [3,4-c]pyrrole (15). Subsequent catalytic dechlorination furnished 5-tosyl-5,6-dihydro4H-thieno [3,4-c]pyrrole (16).
10
In view of the results of the ring-closure reactions Tos with sodium sulfide, and of the formation of a thienoI pyrrole derivative in the reaction of 7 with ethylamine, we tried to synthesize 1,3-dichloro-5-ethyl-5,6-dihydro4H-thieno [3,4-c]pyrrole by ring closure of 2,bdichloro3,4-bis(chloromethyl) thiophene (10)889 with ethylh 15 amine in acetonitrile, using about the same conditions 16 as were used in the synthesis of the thienopyrrole 9. The attempts to prepare a thienopyrrole derivative by cyclization of tetrachloride 10 with ethylamine were Discussion unsuccessful, however. Two products were isolated, namely, 1,3,7,9-tetrachloro-5,11-diethyl-5~6,11,12-tetraThe striking differences in the behavior of tetrahydro-4Hll0H-dithieno [3,4-c:3’,4’-h] [1,6]diazecine(11) 10 and dichloride 7 toward ethylamine can be chloride and the open compound 2,5-dichloro-N,N‘-diethylrationalized by a working hypothesis in which a S N ~ 3,4-bis(aminomethyl) thiophene (12) (Scheme 11). t’ransition ~ t a t e ’ ~ leads - * ~ to the t’hienopyrrole ring Similar results were found for the reaction of 2,5-dichloro-3,4-bis(iodomethyl) thiophene (13) and ethylamine in acetonitrile. The bis(iodomethy1) compound (10) This reaction was first carried out in ethanol with sodium hydroxide as base, in analogy with t h e reaction of o-xylylene dibromide and p-toluene13 was prepared from the reaction of the tetrachloride sulfonamide giving 2-tosyl-1,3-dihydroisoindole~~ in 48% yield. Under these 10 with sodium iodide in acetone. The open comconditions thienopyrrole 16 was obtained in only 6% yield. From the n m r pound 12 was further characterized by the formation spectrum of the reaction mixture it appeared t h a t a reaction had taken place (6) D. J. Zwanenburg, H. d e Haan, and H. Wynberg, J . 079. Chem., $1, 3363 (1966). . . (7) D. J. Zwanenburg, J. Fsyen, and H. Wynberg, Rrc. Trat.. Chim.. 86, 589 (1907). (8) 2.5-Dichloro-3,4-bis~chloromethyl)thioplrene(10) \vas synthesized in 75% yield from 2,5-dichlorothiophene using chloromethyl methyl ether and stannic chloride (see Experimental Section). (9) Cyclization of tetrachloride 10 with sodium sulfide in methanol furnished in 48% yield the 4,6-dichloro analog of 8 .
between tetrachloride 10 a n d t h e solvent. (11) J. Bornstein, 9. C . Lashua, and A. P. Boiselle, J. OTg. Chem., 88, 1255 (1957). (12)6stman18 has provided strong experimental evidence for t h e SN2 character of the reaction of 2- and 3-thenyl chloride with lithium chloride in dimethylformamide. Naturs!ly our working hypothesis-namely, whether all of these cyclization reactio::s are truly S N ~or , whether a n SN1-type mechanism also plays a r o l e n e e d s further investigation. Preliminary experiments indicate that t h e polarity of the solvent plays a role in some of these reactions, suggesting t h e need f t r detailed kinetic work. (13) B. Ostman, J . Amar. Chem. Soc., 87, 3163 (1965).
VoE. 234, No. 2, February 1969 SCHEME I1
10
I
Sal CH,COCH,
IHLC 14 13
the -CH2C1 group from above and below. The energy of activation in the dimerization reaction consequently will be smaller than those in the cyclization reaction
A
B
Figure l.--An approximation of the transition states for the reactions of ethylamine with 2,5-dichloro-3,4-bis(chloromethyl)thiophene (10) and methyl 2,3-bis(chloromethyl)thiophene-5carboxylate (7), respectively, to the corresponding thienopyrrole derivatives. The angles and distances of the thiophene nucleus are of Bak and coworkers.1s For the distances CA,-Cl, C A ~ C, C-Cl, C-N and the angles CCN, CCCl are taken the values16 of chlorobenzene, toluene, l,Zdichloroethane, diethylamine diethylamine and 1,2-dichloroethane, respectively. The solid circles are the covalent radii of C1 and H respectively, and the dotted circles are the van der Waals radii of these atoms.
system. I n Figure 1, an approximation of the transition states is given.I4 The figure clearly suggests that in the ring closure of tetrachloride 10 with ethylamine the leaving chloride anion suffers considerable steric hindrance from the chlorine atom attached to the thiophene nucleus. Crucial to our argument is the reasonable assumption that the entire ring-closure sequence must occur in the plane of the aromatic ring. Steric factors of this nature are not involved in the case of dichloride 7; the hydrogen atom in this case is so small that there is no steric hindrance for the leaving chloride anion. The energy of activation in case A mill be much greater, due to the steric hindrance, than in case B. On the other hand, in the transition state of the reaction of the -CHzNHCzHs group in the intermediate C with a -CHzC1 group of a second molecule, there will be less steric hindrance, because in this case the nitrogen has the opportunity also to attack (14) T h e assumption of the transition state B, in which the clilorometliyl group in the 2 position has reacted with ethylamine prior to that in i\hich the qhloromethyl group in the 3 position has reacted, is based on the work of O s t m a n . 1 ~ B. Bak, D. Christensen, L. Hansen-Pu'ygaard, and J. RastrupAnderson, J . Mol. Spectrosc.. 7, 58 (1981). "Tables of Interatomic Distances and Configuration in Mo1ec:ules and Ions," L. E. Sutton, Ed., T h e Chemical Society, Burlington House, W.1., London, 1958.
C
D
to a five-membered ring. Likewise, the energy of activation for the reaction of intermediate C with a molecule of ethylamine will be smaller than those for the cyclization reaction to a five-membered ring. Also, the intramolecular cyclization of the intermediate C to a five-membered ring does not occur by reason of the high energy of activation. The fact that a reaction between tetrachloride 10 and p-toluenesulfonamide furnished a thienopyrrole derivative is not in contradiction with the given explanation, for the nucleophilicity of the anion of the -NHSO2C~H&H3 group in intermediate D is considerably greater than the nucleophilicity of the -YHCtH j group in the intermediate C.'6 For the same reason the reaction of tetrachloride 10 with sodium sulfide does furnish a five-membered ring, for the -CH*Sgroup is also a strong nucleophile. Evidence from the Literature.-In the literature several ring-closure reactions, which support our explanation of steric inhibition of intramolecular cyclizations, are described. Rosen and c ~ r n ~ r l i eobtained r~'~ only a 5% yield of the isoindoline derivative 18 (X = Cl) in the reaction of 1,2-bis(bromomethyl)-3,4,5,6tetrachlorobenzene (17, X = Cl) with methylamine. The main product (52%) in this reaction W:LS the diazecine derivative 19 (X = Cl). -4reactioii of 1,2bis(bromomethy1)benzene (17, X = H) with methylamine, however, gives isoindole 18 (X = H) in 50% yield. l7 (15) For a discussion on nucleophilicity and activation parameters see J. E. Leffler and E . Grunwald,"Rates and Ecluilibria of Organic Reactions," John Wiley 8: Sons, Inc., New York, N. T.,1963, pp 62, 2-13. (16) W. E. Rosen, V. P. Toohey, and A. C . Sllabioa, J . A v t e r , C/teiii. Soc., 80, 935 (1958). (17) G. Wittig. H. Tenhseff, W. Scliock, and C . lioenip, A t t ~ i . , 612, I (1951).
336 ZWANENBURGAND WYNBERG
T h e Joiirnal of Organic Chemistry matic systems was found in the observation that cyclization was successful when the chlorine atoms on the thiophene nucleus in 10 were removed prior to the reaction with ethylamine. Thus reaction of 3,4-bis(chloromethy1)thiophene (27)with ethylamine furnished 5-ethyl-5,6-dihydro-4H-thieno [3,4-c]pyrrole (28) in 49% yield (Scheme IV). The formation of thieno-
x 17
X
SCHEME IV HOH,C,
k
x
I
CH3
IS
x
,CH,OH
10
Ii.. Pd/C CH OH KOH
C1
19
25
Gol'dfarb and I
