Thieno thiophene-1,1 -dioxide

Compound 145 on lithiation <1999SM(102)987> and subsequent reaction with carbon dioxide afforded compound 146. Sandmeyer reaction of 2-bromodi thieno[3,2-A2, 3 -with copper(l)cyanide in hot iV-methyl pyrrolidine (NMP) gave the corresponding nitrile 148 which was then converted to the tetrazole 149 with a mixture of sodium azide and ammonium chloride in NMP in low overall yield (Scheme 14) <2001JMC1625>. 

Zwanenburg and Wynberg also proposed another route to the thienothiophene (112). 2,5-Dibromo-3,4-bisbromomethylthiophene (116) was cyclized with sodium sulfide to give 4,6-dibromo-l f,3/f-thieno[3,4-c]thiophene (117) in 60% yield 117 was then reduced to thienothiophene (112). l,3,7,9-Tetrabromo-4i/,67f,10.H, 12ff-dithieno-[3,4 C 3, 4 -/i][l,6]dithiecin (118) (18%) was also formed during the ring closure. Oxidation of thienothiophene (117) followed by reduction by zinc in acetic acid gave l/f,3H-thieno[3,4-c]thiophene 2,2-dioxide (119). ... 

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). 

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 et al oxidized dimethyl lH,3H-thieno[3,4-c]thiophene-4,6-dicarboxylate (115) with HjOj-HOAc to the dioxide 218 (55%) [Eq. (72)]. 

Similarly 4,6-dibromo-l/f,3H-thieno[3,4-clthiophcne (117) affords 90% of the 2,2-dioxide (219) the last can be debrominated to IHtiH-thieno[3,4-c]thiophene-2,2-dioxide (119) with zinc in acetic acid [Eq. (72)1. 

The 2-bromo-4,6-dihydrothieno[3,4-, ]thiophene-5,5-dioxide 211 was used in the synthesis of 5-(5,5-dioxo-5,6-dihydro-477-5A -thieno[3,4-, ]thiophen-2-yl)-3,3"-dipentyl[2,2 5, 2"]terthiophene 213 by Suzuki cross-coupling reaction with 5-bromo-3,3"-dipentyl-[2,2 5, 2"]terthiophene 212 (Scheme 20) <1998S1372>. 

Thieno[3,4-( ]-l,2,4-thiadiazine dioxide 33 and thieno[2,3-i ]-l,2,4-thiadiazine dioxide 34 (prepared as shown in Scheme 8 and Equation (10), Section 10.09.9.1.1) undergo electrophilic substitution on the thiophene ring regio-selectively as shown in Scheme 6 <1997H(45)1767>. 

In addition to procedures for pyridine ring closure based on the use of 3-amino-thiophene derivatives, there are alternative methods for the construction of thieno [3,2-Z>]pyridines. One approach made use of cyclic (3-keto sulfones, which proved to be convenient synthons for the modified Hantzsch synthesis of fused pyridines (1986KGS1563, 1990JHC1453, 2000MI1, 2002USP6191140). For example, the reactions of benzothiophene 1,1-dioxide 168 with enamines 169 or methylene-active compounds 170 in the presence of NH4OAc produced fused dihydropyridines 171 (1990JHC1453). 

Thermal decomposition of 3-azido-2-formylfuran, -thiophene, and -selenoles has also been used to prepare furo[3,2-c]isoxazole (97), thieno[3,2-c]isoxazole (4), and selenolo[3,2-c]isoxazoles (98) (Equation (27)) <76CS165>. In contrast, some azido ketones eliminate nitrogen at ambient temperature and cyclize as exemplified in the reactions of 2-chloro-3-acetylindole (99) (Equation (28)) and 3-chloro-2-benzoylbenzothiophene dioxide (101) (Equation (29)) with sodium azide (78CB1521, 92JOC2127). 

This methodology has been extended to the synthesis of new thieno[3,2-c][l,2,6]thiadia-zine 2,2-dioxides bearing substituents on the thiophene ring, for example compounds (29a) and (29b). 

The reaction of 3,4-bis(halomethyl)thiophenes with sodium sulfide and primary amines gives l//,3//-thieno[3,4-c]thiophenes (103) and 5,6-dihydro-47/-thieno[3,4-c]pyrroles (104), respectively. Some of the cyclizations are adversely affected by ortho substituents (X) (69JOC333). The method has been used to prepare l,3,4,6-tetrahydrothieno[3,4-c]pyrrole 2,2-dioxides (73JHC785). 

Treatment of the sulfone 35 with three equivalents of butyllithium gave an intermediate selectively dimetalated at C-2 and the adjacent methyl group. Subsequent reactions of this species with aromatic or heteroaromatic esters, such as methyl thiophene-2-carboxylate, and final acid induced elimination of water, gave a series of thieno[ 3,2 -6] thiophene 1,1-dioxide systems, for example 36 <07S1827>. On the other hand, 3-methylthiophene undergoes selective deprotonation at C-5 upon treatment with lithium 2,2,6,6-tetramethylpiperidide (LiTMP), giving access to a 2,4-disubstituted thiophene derivatives <07JOC 1031>. 

Ab initio MO calculations on 3-formyl-(5 2-isoxazoline-BF3-complex suggests that s-trans conformation is preferred over s-cis conformation. Nucleophiles attack the stable s-trans conformer from the opposite side of the C-4 substituent, giving the respective anti adducts <93T7637>. The regioselectivity of the 1,3-dipolar cycloadditions of mesitonitrile oxide with benzo[b]thiophene S-oxide and S,S-dioxide yielding only 2,3-dihydrobenzo[b]thieno[2,3-d]isoxazolines, is discussed in terms of frontier MO interactions on the basis of photoelectron spectra and CNDO/S calculations <82JOC2461>. 

The preparation of two of the three possible isomeric thieno-1,2-thiazin-4-ones (Schemes 5 and 6)128 involved reactions reported12 for the corresponding benzothiazines (see Scheme 1 ). Thus, methyl 3-chlorosul-fonylthiophene-2-carboxylate (152) with sarcosine ethyl ester gave thiophene sulfonamide (153) which, with methanolic sodium methoxide, yielded 3-methoxycarbonyl-4-hydroxy-2-methyl-2H-thieno[2,3-c]-l,2-thiazine 1,1-dioxide (154). Heating 154 with 2-aminothiazole gave 155, a thieno-1,2-thiazine analog of sudoxicam (20) (Scheme 5). 

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. 

Methyl 4,5,6,7-tetrafiuorobenzo[h](hiophene-2-carboxylate is oxidized by trifluoroperacetic acid or m-CPBA to form a 2,3-epoxysulfbne reaction with chlorine or sulfuryl chloride produces a 2,3-dichIoride derivative <94JFCS1>. HOF MeCN is a novel oxidant which oxidizes a variety of thiophene derivatives to 3,5-dioxides <94CC1959>. Bromination of thieno[c]fused l,S-n hthyridines occurs with tetrabutylammonium perbromide <94H331> or with dibromoisocyanuric acid/sulfuric acid <94JHCS21>. 

Extrusion of sulfur dioxide from oxidized thiophene derivatives is an exceptional method to prepare cis-dienes as components for Diels-Alder reactions. An example of this approach utilizes the Diels-Alder reactivity of the furan ring in substituted 4//,6ff-thieno[3,4-c]furan-3,S-dioxides to react with a variety of dienophiles such as DMAD, dimethyl maleate and dimethyl fumarate which then lose SO2 to form another reactive diene (Eq. 17) <94H961>. A review of the preparation and use of 4i/,6f/-thieno[3,4-c]furan-S,5-dioxides as well as other heteroaromatic-fused 3-suIfolenes is report <94H1417>. The preparation of dihydrothienooxazole 80 requires the careful control of the reaction time and temperature as well as the reactants molar ratio <94JOC2241>. Specific control of the alkylation conditions for 81 (X = COCH3) allows for the preparation of either 1,4-disubstituted or 1,6-disubstituted 4, 6//-thieno[3,4-c]furan-S,S-dioxides. These molecules could be used as intermediates for the preparation of novel pentacyclic compounds <94JCS(P1)1371>. 

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