Preparation of thiophen esters by the Hinsberg reaction

摘要

1972 2079Preparation of Thiophen Esters by the Hinsberg ReactionBy D. J. Chadwick, J. Chambers, G. D. Meakins," and R. L. Snowden, Dyson Perrins Laboratory, OxfordThe Hinsberg reaction (interaction between an a-diketone and a dialkyl thiodiacetate) has been used to prepare aseries of 3.4-disubstituted thiophen-2-carboxylates and -2.5-dicarboxylates.University, South Parks Road, Oxford OX1 3QYFOR spectrometric investigations of heterocyclic com- (I) : these had not been detected in the earlier work,pounds with carbonyl groups a t the a-position(s), we which involved saponification as part of the generalrequired a series of thiophen mono- and di-esters of procedure. Since the half-esters can be decarboxylated,3types (111) and (V). The Hinsberg2 reaction has been the Hinsberg reaction appeared well suited to ourused fairly extensively for obtaining the 2,5-diacids (11) purpose (see Scheme).R ' R ''c-c'II It0 0R1 R1I vNaO ' ONaoMe J Me02 c c j c 0 2 M eM e 0'c-c'II II0 0Reagents: (i), KOBut; (ii), NaOH; (iii), Cu-heat;IY)tl v i )(for E la ; R2=Meb ; R * = E tC ; R~=BJSCHEME(iv), H,SO,-MeOH, or EtOH, or Me,CH:CH,; (v), NaOMe; (vi) PhCH,Cland their derivatives.Mechanistic studies by Wynberget aZ.3 established that the initial products from a-diketones and dialkyl thiodiacetates are the half-esters1 D. J. Chadwick, J. Chambers, G. D. Meakins, and R. L.Snowden, in the press.Although most of the condensations shown in theScheme have been reported previously (references in theExperimental section), there is considerable variation(a) H.Wynberg and H. J. Kooreman, J. Amer. Chem. SOC.,1965, 87, 1739; (b) H. Wynberg and D. J. Zwanenburg, J . Org.Chem., 1964, 29, 1919. 0. Hinsberg, Ber., 1910, 43, 9012080 J.C.S. Perkin IC,,H,,O,S requires C, 67-8; H, 5.1; S, 9-0), z (CC1,)2-61 (lH, s, 5-H), cu. 3-22 (SH, m, ArH), 6.20 (3H, s, 3-ArOMe), 6.27 (3H, s, 4-ArOMe), and 6.29 (3H, s, CO,Me),m/e 354 (M', 100). The 5-ethoxycarbonyl acid (ICb)(3 g), on heating with Cu bronze (1 g) a t 250 "C for 20 min,gave the ethyl ester (IIICb) (1.2 g), m.p. 83-84' (fromMeOH) (Found: C, 68.7; H, 5.3; S, 8.5. C,,H,,O,Srequires C, 68-5; H, 5.5; S, 8.7).Saponification of the half-ester (ICb) by heating underreflux with 20 aqueous NaOH for 2 h followed by thestandard work-up gave 3,4-di- (+-methoxyphenyl) thiophen-2,5-dicarboxylic acid (IIC) (75), m.p.273-274" (lit.,6269-270"), A,, (EtOH) 235 (E 18,200) and 259 nm (12,400).Similarly the ethyl ester (IIICb) gave 3,4-di-(p-methoxy-~henyZ)thio~hen-2-curboxyZic acid (IVC) (72), m.p. 205-215' (decomp.) (from MeOH) (Found: C, 67-3; H, 5.0.Ct,,O4S requires C, 67.05; H, 4.75), 7 (Me2SO) 2-28Isobutene (20 ml) was added to the 2-acid (IVC) (500 mg)in dry Et,O (40 m1)-H,SO, (2 ml) which was cooled to-30" in a thick-walled flask fitted with a magnetic stirrer.A well-fitting rubber bung was securely wired into positionand the mixture was left to reach 20" with stirring. After3 d the flask was cooled to -3O", opened cautiously, andthe solution was poured slowly, with stirring, into cold 5aqueous KOH (250 ml).Isolation with Et,O and p.1.c.l large plate, 4 x petrol-Me,CO (4: l) afforded t-butyZ3,4-di-(p-methoxyphenyZ)thiophen-2-carboxyZate (IIICc) (325mg), m.p. 123-125" (from MeOH) (Found: C, 69.8; H, 6.1.C,,H,,O,S requires C, 69.7; H, 6*ly0), T (CCI,) 2.72 (lH, s,5-H) and 8-65 (9H, s, CO,But), m/e 396 (M', 35) and 340Products from BiucetyZ.--B-Ethoxycarbonyl-3,4-dimethyl-thiophen-2-carboxylic acid 3b (IAb) (2 g) was heated withCu bronze (1 g) a t 300" for 1 h to give ethyl 3,4-dimethyZ-thiophen-2-carboxylate (IIIAb) (1.2 g), b.p. 98-102" (bath)a t 0.02 mmHg (Found: C, 58-95; H, 6.7. C,H,,O,Srequires C, 58.7; H, 6.6), nD20 1.5294. Saponification ofthis ester afforded the 2-acid (IVA), m.p.184-186" (Iit.,7187-1 88") , which was converted into t-butyZ 3,4-dimethyZ-thiophen-2-carboxyZate (IIIAc) (81y0), b.p. 100-105" (bath)a t 0.04 mmHg, m.p. 50-52" (Found: C, 62.5; H, 7-35;S, 15.25. C,lHl,O,S requires C, 62.25; PI, 7-6; S, 15.1).(500 mg), EtOH (20ml), and H,SO, (1-5 ml) was boiled under reflux for 2 h.Work-up gave diethyl 3,4-dirnethyZthiophen-2,5-dicarboxyEute(VAb) (505 mg), m.p. 79-80' (from MeOH) (Found: C,56.2; H, 6.3. C1,H,,04S requires C, 56.2; H, 6.3).The diacid (IIA) was also converted into di-t-butyZ 3,4-di~netlzyZthiophen-2,5-dicarboxyZate (VAc) (78 ), m.p. 167-168" (from MeOH) (Found: C, 61.4; H, 7.8; S, 10-1.C1,H,,04S requires C, 61-5; H, 7.75; S, 10-2y0).Products from Ben.-Isobutene (50 ml) , thiodiaceticacid (15 g), and Et,O (100 m1)-H,SO, (3 ml) were used asdescribed earlier to give di-t-butyZ thiodiacetate (19.5 g), b.p.121-122" a t 1-5 mmHg (Found: C, 55.2; H, 8.5; S, 12.1.C1,H,,O,S requires C, 54-95; H, 8-45; S, 12.2), T (CCl,)6-79 (s, S-CH,) and 8-35 (s, CO,But).Reaction of thisester (2 g) with benzil (1 g) at 30" for 15 min in a solutionprepared from K (1.4 g) and ButOH (30 ml) gave 2-t-butoxycarbonyl-3,4-d~~henylthio~hen-5-carboxyZ~c acid (IBc)6 0. Dann and G. Hauck, Arch. Pharm., 1960, 293, 187.7 H. Fiesselmann and H. Habicht, G. P. 1,092,929 (Cl. 2q)1960 (Chew. Abs., 1962, 57, 5894).8 R. Seka, Ber., 1925, 58, 1783.(lH, S , 5-H).(100).A mixture of the 2,5-diacid (IIA)in the extent to which they have been studied.Forexample, only one derivative, the diacid (IID),2 ofphenanthraquinone is recorded. All the t-butyl esters,which are especially important for the spectrometricwork, are new. With one exception, the half-esters (I)were smoothly decarboxylated by heating with copperbronze : the t-butyl ester (IBc), obtained from benziland di-t-butyl thiodiacetate, gave mainly 3,4-diphenyl-t hiophen .4When oxalic esters rather than a-diketones are usedin the Hinsberg reaction, the products are the salts of3,4-dihydroxy-2,5-diesters, e.g., the salt (VI) fromdimethyl oxalate and dimethyl thiodiacetate. Pre-sumably the first negatively-charged adduct losesmethoxide anion rather than forming a a-lactone as inthe case of the adduct from an a-diket~ne.~EXPERIMENTALPreparative details are given for the series of compoundsderived from one a-diketone; with the other series, pro-cedures are described only if they were not used in, or ifthey differ from those of the first series. The n.m.r.andmass spectra of the products were as expected, and only afew are reported. U.V. spectra were obtained for EtOHsolutions.Products from 4,4'-Dimethoxybenzil.-A mixture of 4,4'-dimethoxybenzil (dried a t 80" in vacuo; 9.5 g) and dimethylthiodiacetate (freshly distilled ; 12 g) was added to a solution,which was stirred a t 60°, made from K (4-2 g) and ButOH(freshly distilled from CaH,; 100 ml). After 30 min themixture was cooled, acidified with ~ N - H C ~ (20 ml), and thesolvents were removed a t 40" and 10 mmHg.The residuewas extracted with portions (50 ml) of ~N-NH,OH untilacidification of a sample of the alkaline solution did notgive a precipitate. Acidification of the combined extracts,and isolation with Et,O gave 5-methoxycarbonyZ-3,4-di-(p-methoxyphenyZ)thiophen-2-carboxyZic acid (ICa) (6.8 g) , m.p.220-225" (decomp.) (from MeOH) (Found: C, 62.9; H, 4.6;S, 8.2. C2,H1,0,S requires C, 63.3; H, 4.55; S, 8.0y0),T (CD,),SO 2.99, 3.13, 3-22, 3.26 (8H, A,B2 resonances,ArH), 6-30 (6H, s, ArOMe), and 6.33 (3H, s, CO,Me), m/e398 ( M f , 100) and 354 (18). Diethyl thiodiacetate (14 g)similarly gave 5-ethoxycarbonyZ-3,4-di-( p-methoxyphenyl) thio-phen-2-curboxylic acid (ICb) (7.6 g), m.p.192-194" (de-camp.) (Found: C, 64.2; H, 4.9; S, 8.2. C,,H,,O,SrequiresC, 64.1; H, 4.9; S, 7.8).An intimate mixture of the 5-methoxycarbonyl acid(ICa) (2 g) and Cu bronze (1 g) was heated a t 300" for 1 h.The material extracted with Et,O was chromatographed onSiO, (75 g). Petrol-Me,CO mixtures eluted 3,4-di-(p-methoxypheny1)thiophen (250 mg), m.p. 107-108" (fromMeOH) (lit.,6 117-118"), and then methyl 3,4-di-(p-rnethoxyphenyZ)thiophen-Z-curboxyZate (IIICa) (850 mg) , m.p.126" (from MeOH) (Found: C, 67.7; H, 5-1; S, 9.2.Petrol refers to light petroleum, b.p. 60-80".H. J. Backer and W. Stevens, Rec. Trav. chirn., 1940, 59,423.5 E. W. Fager, J . Amer. Chem. SOL, 1945,67,22171972(1.3 g), m.p. 210-220" (decomp.) (from MeOH) (Found:C, 69.6; H, 5.2; S, 8.6.C,,H,,O,S requires C, 69-5; H,5-3; S, 8.4). The ester (IBc) (500 mg) and Cu bronze(500 mg) a t 240" for 10 min gave 3,4-diphenylthiophen(310 mg), m.p. 112-114" (lit.,4 114").With isobutene, the 2-acid (IVB) gave t-butyl 3.4-dipheylthiofihelz-2-carboxylate (IIIBc) (68), m.p. 90-91"(from MeOH) (Found: C, 74-8; H, 6.2. C,1H2,0,Srequires C, 75.0; H, 6.0), and the 2,5-diacid (IIB) gavedi-t-butyl 3,4-dipheizylthiophen-2,5-dicarboxylate (VBc)(67y0), m.p. 172-174" (from MeOH) (Found: C, 71.7; H,6.65; S , 7.55. C,,H,,O,S requires C, 71.5; H, 6.5; S,Pvoducts from Phenanthraquiizofze.-Reaction of phen-anthraquinone (8 g) with dimethyl thiodiacetate (12 g) at30" for 15 min in a solution prepared from K (4.2 g) andBu tOH ( 100 ml) gave 3-nzetlzo,vycarbonyZ~Jzenanthro9,1O-c-tJ~iopJzen-l-carboxyZic acid (IDa) (3.5 g), m.p.215-220"(decornp.) (from MeOH) (Found: C, 67.4; H, 3.7.C1,H120,S requires C, 67.85; H, 3.6y0), A,,,,. (EtOH) 250(E 21,900) and 267 nm (21,200). Decarboxylation of thisIialf-ester (1 g) gave methyl p,$enanthro9,lO-cthio;bhen-l-$.30/,).2081carboxylate (IIIDa) (620 nig), m.p. 151-152" (from MeOH)(Found: C, 73.9; H, 4.1. C,,H1,02S requires C, 74.0; H,4.176).3,4-Dibenzyloxythiophen-2,5-dicarboxylic Acid (IIE) andDimethyl 3,4-Dibenzyloxythiophen-2,5-dicarboxylate (VEa) .-A suspension of the disodium salt of dimethyl 3,4-dihydroxythiophen-2,5-dicarboxylate (VI) (13-5 g) inPhCH,Cl (100 m1)-hle,NCHO (250 ml) was stirred a t 100"for 2.5 h. The cooled mixture was filtered, the filtrate wasevaporated iiz vaczto, and the residue was crystallised fromMeOH to give the dimethyl ester (VEa) (15-1 g), m.p. 104-106" (Found: C, 63-9; €3, 5.2; S, 7.7. C,,H,,-,O,S requiresC, 64.1; H, 4.9; S, 7.8y0), Am=. 282 nm (E 8900), wz/e 412(M+, 1) and 91 (100). Hydrolysis of this ester by heatingunder reflux for 1 h with 3 aqueous NaOH gave thedicarboxylic acid (IIE) (80y0), m.p. 205-206" (from MeOH)(Found: C, 62.2; H, 4.3; S, 8-4. C,,H,,O,S requires C,62.5; H, 4.2; S, 8.3y0), A,, 281 nm (E 9900).We thank the S.R.C. for Studentships (to D. J. C., J. C.,and R. L. S.).2/637 Received, 20th March, 1972