Thieno thiophene-2-carboxylates

The use of thienyl Grignard reagents, and more recently lithiated thiophenes, has been extensive and can be illustrated by citing formation of oxythiophenes, either by reaction of the former with f-butyl perbenzoate or the latter directly with bis(trimethylsilyl) peroxide or via the boronic acid, the synthesis of thiophene carboxylic acids by reaction of the organometallic with carbon dioxide, the synthesis of ketones, by reaction with a nitrile, or alcohols by reaction with aldehydes, by the reaction of 2-lithiothiophene with A -tosylaziridine, and by syntheses of thieno[3,2- ]thiophene and of dithieno[3,2- 2, 3 - /]thiophene. Some of these are illustrated below. 

Earlier, cyclization of a-mercaptoacrylic acids in the presence of iodine was shown to yield fused thiophenes, which was utilized by Schneller and Petru [12] to synthesize thieno[23-h] thiophene carboxylic acid, which on decarboxylation yielded T23bT, an overall 60% yield (Scheme 11.3). 

The preparation of thieno[3,2-fc]thiophene was reported by Iddon and co-workers [76, 77] and it is readily prepared in four steps from commercially available 3-bromothiophene (Scheme 17.1). Thus 3-bromo-thiophene can be lithiated in the 2-position with a bulky non-nucleophilic base such as lithium diisopropylamine. Quenching of the resulting thiophene anion with dimethylfonnamide or tV-formylpiperidine afforded the thiophene aldehyde. Treatment of this o-bromoaldehyde with ethyl 2-sulfanylacetate in the presence of base afforded thieno[3,2-fc]thiophene carboxylate ester in good yield. Hydrolysis of the ester group, followed by thermal decarboxylation of the resulting acid with quinoline in the presence of copper, afforded the unsubstituted thieno[3,2-f>]thiophene in overall yields of approximately 60 % over the four steps. 

In contrast to 6-azidobenzo[/)]thiophene, which yields only benzo[i]thiophen-6-amine (9 %) and JVh,Ar(1-diethylbenzo[/)]thiopheiie-6,7-diamine (25 % bp 175-177 C/0.7 Torr), 6-azido-2,3-dibromobcnzojhjthiophene (1 a, R = R2 = Br) on irradiation in diethylamine in the presence of pyrene, a triplet nitrene quenching agent, yields a mixture of 2,3-dibromo-./V6,./V6-diethyl-benzo[5]thiophene-6,7-diamine (2a, R1 = R2 = Br 13%) and the 8W-thieno[2,3-r]azepine 3a.14<1 Likewise, methyl 6-azidobenzo[6]thiophene-2-carboxylate (lb, R1 = C02Me R2 = H) yields the thienoazepine ester 3b.147... 

Thieno[3,4- ]pyrrolizin-8-one 4 <2004JEZ585> has been synthesized from 4-amino-thiophene-3-carboxylate 268 (Scheme 48). This useful starting material was converted into ester 269 and the amide 270, to afford 4 (Scheme 48). 

Unsubstituted thieno[3,4-6]thiophene (3) (see Litvinov and Fraenkel ), was prepared by Cava and Pollack s method for benzo[c]-thiophene i.e., thermal decomposition of H, 3 -benzo[c]thiophene sulfoxide. By refluxing 4/f,6/f-thieno[3,4-ft]thiophene-2-carboxylic acid 5-oxide (91) with acetic anhydride (the synthesis of dihydrothieno-thiophenes will be described below), Wynberg et a/." obtained the mixed anhydride 92 in 95% yield. Hydrolysis gave thieno[3,4-6]-thiophene-2-carboxylic acid (93) (88%). Decarboxylation of the acid (93) gave thienothiophene 3, unstable at room temperature [Eq. (29)]. 

In 1972 Wright prepared 3-chlorothieno[3,2-6]thiophene-2-carbonyl chloride (94) in 11-13% yield by heating 3-(2-thienyl)acrylic acid, thionyl chloride, and pyridine, a method of synthesis of benzo[6]-thiophene-2-carbonyl chloride derivatives. " Methyl 3,5-dichloro-thieno[3,2-6]thiophene-2-carboxylate (95) and methyl 2-chloro-3-(5-chloro-2-thienyl)acrylate were also isolated. When fte reaction was carried out in refluxing toluene or chlorobenzene, the acid chloride (94)... 

Later Gronowitz and Maltesson reported the extension of this method to the preparation of thieno[2,3-6]thiophene (1) derivatives. A mixture of 3-(3-thienyl)acrylic acid, thionyl chloride, and pyridine was heated for 24 hours. 2-Chloro-3-(3-thienyl)-acrylic acid (4.5%), 3,5-dichlorothieno[2,3-6]thiophene-2-carbonyl chloride (99) (9.5%), 3-chlorothieno[2,3-Z)]thiophene-2-carbonyl chloride (100) (79.1%), and other compounds were detected by GLC among the reaction products [Eq. (31)]. Hydrolysis of the reaction mixture gave 3-chlorothieno[2,3-Z>]thiophene-2-carboxylic acid in 63% yield dechlorination of the latter by copper in propionic acid converted it into thieno[2,3-6]thiophene-2-carboxylic acid. 

Dihydrothieno[3,4-Z ]thiophene (131) was prepared by two methods. In the first (Scheme 8), chloromethylation of methyl thiophene-2-carboxylate (132) forms methyl 2,3-bischloromethyl-thiophene-5-carboxylate (133) (85%) cyclization of 133 with sodium sulfide in methanol yields (66%) methyl 4,6-dihydrothieno[3,4-i]-thiophene-2-carboxylate (134). Peroxide oxidation of 134 gives 2-methoxycarbonyl-4,6-dihydrothieno[3,4-h]thiophene 5,5-dioxide (135) and hydrolysis of 134 followed by metaperiodate oxidation furnishes the sulfoxide (91). Thienothiophene (131) was produced by hydrolysis and decarboxylation of 134. As indicated above, the sulfoxide (91) was used for the synthesis of thieno[3,4-6]thiophene (3). 

Fiessdmann and Pfeiffer" passed HCl at 0° through acetoacetic ester and thioglycolic ester in dcohol to obtain triethyl y3, -bis(carbo-methoxymethylthio)butyrate (169) Dieckmann condensation reportedly furnish ethyl 3,4-dihydroxy-6a-methyl-3a,6a-dihydro-thieno(2,3-b]-thiophene-2-carbOxylate (170) [Eq. (48)]. 

Similarly, acetylation of thieno[3,2-6]thiophene (2) afforded 2-acetyl-thieno[3,2-6]thiophene, which was converted into methyl n-hexyl ketone by desulfurization with Raney nickel. Oxidation of 2-acetylthieno-[3,2-i]thiophene followed by nitration gave 5-nitrothieno[3,2-6]-thiophene-2-carboxylic acid. Decarboxylation of the latter furnished 2-nitrothieno[3,2-ft]thiophene identical with the compound obtained by direct nitration of thienothiophene 2 [Eq. (60)]. 

Unsubstituted thienothiophenes 1 and 2 are smoothly formylated in the 2-positions by DMF-phosphorus oxychloride in dchloro-ethane. The site of substitution in thienothiophene 2 was confirmed by preparing the corresponding formyl derivative from 2-lithiothieno-[3,2-6]thiophene and DMF, and in the case of 1, by oxidizing the formyl derivative to thieno[2,3-h]thiophene-2-carboxylic acid, as well as the NMR spectra [Eqs. (66) and (67)]. 

Wynberg and Feijen studied thieno[3,4-6]thiophene (3) formylation and found that both positions 4 and 6 are attacked. This is in accordance with theoretical predictions. The reaction produces a mixture (7 3) of 4-formyl- (194) and 6-formylthieno[3,4-6]thiophene (195) in 56% total yield after separation and purification. The formyl derivatives obtained were oxidized to the corresponding carboxylic acids 196 and 197, which were converted into 3-ethylpentanoic 198 and 4-methylhexanoic (199) acids by desulfurization with Raney nickel [Scheme 15]. 

More vigorous conditions were required for the formylation of thienothiophene 3 with an electron acceptor group in the molecule. Thus, refluxing methyl thieno[3,4-6]thiophene-2-carboxylate, iV-methyl-formanilide and phosphorus oxychloride for 1 hour gave a mixture (1 1)... 

Bugge brominated thienothiophenes 1 and 2 with IV-bromo-succinimide in glacial acetic acid to 2-bromothieno[2,3-6]thiophene (66%) and 2-bromothieno[3,2-6]thiophene (55%). The structure of 2-bromothieno[2,3-6]thiophene was confirmed by the replacement of bromine by lithium at —70° followed by carbonation to thieno[2,3-6j-thiophene-2-carboxylic acid 2-bromothieno[3,2-fe]thiophene was independently prepared by the treatment of 2-lithiothieno[3,2-6]thiophene with one equivient of bromine at —70°. The 2-bromo derivatives of thienothiophenes 1 and 2 decompose within several hours at 20°, but remain uncWged for weeks at —15°. 

Oxidation of acetyl- and acetylnitro-substituted thienothiophenes 1 and 2 with ferricyanide or hypoiodite to the corresponding acids was used primarily to confirm the site of electrophilic substitution at position 2 in the thienothiophenes. " Permanganate degrades the thieno[3,2-A]-thiophene (2) ring system, while potassium hypobromite produced bromo derivatives of thieno[2,3-6]thiophene-2-carboxylic acid. ... 

Incorporating an electron-donor alkyl group into position 2 of 2 was shown by foe present authors to facilitate S-oxidation thus, 2-efoyl-thieno[3,2-6]thiophene-l,1-dioxide (214) was prepared at40°-45° from 2-ethylthieno[3,2-6]thiophene, hydrogen peroxide and acetic acid. The thieno[3,2-6]thiophene system undergoes oxidation even if foe second a-position is carboxy-substituted oxidation of 5-efoylthieno[3,2-6]-thiophene-2-carboxylic acid furnished foe 4,4-dioxide (215) subsequently decarboxylated to sulfone (214) [Eq. (70)]. The [2,3-6] isomers, 20 and 55, with foe sulfur atoms bound to foe same carbon atom, do not form sulfones under similar conditions. 

Wynberg and Feijen prepared d-methylhexanoic acid (236) by desulfurization of thieno[3,4-6]thiophene-2-carboxylic (93) and 6-carboxylic (197) acids [Eq. (80)]. The analogous reaction with thieno-[3,4-A]thiophene-4-carboxylic acid (196) produce 3-ethylpentanoic acid (237) [Eq. (81)]. 

Annelation of a furan ring onto a thiophene is also possible by flash vacuum pyrolysis at 650 °C of the acrylate 368 and malonate 369, which gave 2-(methylthio)thieno[3,2-/ ]furan 370 and methyl-5-(methylthio)thieno[3,2- ]furan-2-carboxylate 371, respectively, in yields of 21% and 22% <1997J(P1)2483>. 

As in the synthesis of thieno[2,3-,7]-l,2,3-thiadiazoles, thieno[3,2-.7 -l,2,3-thiadiazoles are made using diazotization of aminothio-substituted thiophenes and by Hurd-Mori reaction of hydrazones. Diazotization of compound 134 with NaN02 in AcOH/HCl at 0°C produced methyl thieno[3,2- / -l,2,3-thiadiazole-5-carboxylate 135 but in only low yield. Hydrazone tautomer 136 treated with excess SOCI2 in CH2CI2 at room temperature gave dimethyl thieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 137 and dimethyl 5,6-dihydrothieno[3,2- / -l,2,3-thiadiazole-5,6-dicarboxylate 138 in a ratio of 3 2 (Equations 20 and 21) <1998H(48)259>. 

Lithium 2-thiophenethiolate, readily prepared from thiophene, -butyllithium, and sulfur, reacts with / -butryo-lactone to give carboxylate derivative 98 which can be readily acidified to the free acid. Cyclization in the presence of trifluoroacetic anhydride gives thieno[2,3-3]thiopyran (Scheme 27) <1996TA2721>. 

It is not necessary for the carbonyl functionality on the thiophene ring to be an ester. The carboxylic acid 399, shown in Scheme 32, is converted by reaction with a variety of acid chlorides (or acid anhydrides) into thieno-oxazinones 400. Reaction of 400 with dry ammonia generates 401 in average yields <2002JCM5>. 

A simple two-step synthesis of 4-arylthieno[3,2-c]pyridine-6-carboxylic acids has recently been presented by Eweiss (Scheme 74) (B-81MI31703). The condensation of thiophene-2-carbaldehyde with an N -aroylated a-amino acid yields a thienylidene azlactone (281) which on treatment with AICI3 is converted to a thieno[3,2-c]pyridine (283). A nitrilium ion (282) resulting from a vinyl-oxygen fission is probably involved as an intermediate. Sandberg s method already mentioned in the previous section has also been applied to the synthesis of thieno[3,2-c]pyridines (Scheme 75). 

Nielsen (81CS(18)135) prepared thieno[2,3-4]pyrimidin-4(3//)-ones in 43-90% yield by heating 2-acylaminothiophene-3-carboxylates (330) with phosphorus pentoxide, N,N -dimethylcyclohexylamine and an amine hydrochloride at 180 °C. By raising the temperature to 240 °C, thieno[2,3-4]pyrimidin-4-amines (331) were obtained in 27-34% yield (Scheme 92). Phenyl N,N -dimethylphosphorodiamidate [(MeNH)2P(0)OPh], a well-known reagent for the synthesis of 3-methyl-4-oxo-3,4-dihydroquinazolines (77S180), reacts with thiophene derivatives of type (330) to give 3-methylthieno[2,3-4]pyrimidin-4(3/f)-ones (78ACS(B)303). 

Another interesting derivative of benzo[c]thiophene which may be useful for preparative purposes has been described by Castro and coworkers. Strictly analogous to a synthetic sequence outlined in Section 3.17.2.1.1, 3-iodothiophene-4-carboxylic acid reacts with a copper(I) acetylide in DMF at 125 °C to give a l//-thieno[3,4-c]pyran-2-one (equation 53) (68JHC227). 

Reaction of thieno[3,4-6]thiophene (8) with DMF/POCl3 gave a 7 3 mixture of C-4 and C-6 formyl derivatives (58) and (59), respectively (76AHC(19)123). The substitution pattern was ascertained by oxidation to the carboxylic acids (60) and (61) and subsequent reductive desulfurization. The C-4 substituted isomer (60) yielded 3-ethylpentanoic acid (62) while the C-6 isomer led to 4-methylhexanoic acid (63 Scheme 14). 

---