4.5- Dihydrothieno

Dihydrothieno[2,3-6][l,5]benzothiazepines (42) were synthesized from 2-(2-thienylthio)aniline (40). Compound 40 was acylated by treatment with acetic anhydride or benzoyl chloride to give N-acyl derivatives (41), which afforded compounds 42 by cyclization with phosphorus oxychloride and subsequent reduction with sodium borohydride or Zn/HCl. N-Dimethylaminopropyl derivatives 43 were prepared by reaction with di-methylaminopropyl chloride in the presence of sodium amide (Scheme 13) (67CZP124935 68CCC1846). 

Related compound (B) has the systematic name methyl-( )-(o-chloro-phenyl)-4,5-dihydrothieno[2,3-c]pyridine-6-(7H)-acetate, hydrogen sulfate salt [2], and is a racemic residue formed during the manufacturing process. This compound may appear as a racemic mixture in samples of bulk drug substance as impurities (la) and (lb) [6, 7]. 

Dihydrothieno[2,3-t/]-1,2,3-thiadiazole (99) was obtained by treatment of the hydrazone (100) with SOCl2 <89TL7249). The polysubstituted thiophene (101) upon treatment with NaN02 in concentrated HC1 yielded 5-ethoxycarbonyl-6-methylthieno[2,3-<7]-1,2,3-thiadiazole (102) in 70% yield... 

As part of an effort to synthesize novel organic conductors based upon tetrathiafulvalene, 4,6-dihydrothieno[3,4-rf]-1,2,3-thiadiazole (70) was prepared from the hydrazone (100), together with an appreciable amount of 4,5-dihydrothieno[2,3-c/]-l,2,3-thiadiazole (99) (89TL7249). 

Isatins 307 on reaction with l,3-dimethyl-6,7-dihydroisothiophene-4(5//)-one 322 gave 2,3-dimethyl-4,5-dihydrothieno[3,4-c]acridine-6-car-boxylic acids 323 (Scheme 64) (50RTC1053). 

Thiophen Analogues of Isoquinoline. - Several derivatives of thienol3,2-c]pyridine, such as 4-allyl-5-methyl-4,5-dihydrothieno-... 

Remers et al. (71JMC1127) have used a quite different approach, which involves the Vilsmeier-Haack formylation of 6,7-dihydrobenzothiophen-4(5//)-one 306 (R = H) followed by cyclocondensation with aniline to give 4,5-dihydrothieno[2,3-c]acridine 311 (Scheme 59). 

Reaction with Organolithium Reagents. Organolithium derivatives of a variety of heteroaromatics have been fluorinated with NFSi. The direct C-H lithiation at the most reactive position of heteroarene compounds was conducted at low temperature with either t-BuLi, w-BuLi, or LDA in the presence of NFSi to provide regioselective fluorination. This way, oxazoles (eq 34), benzo[i>]thiophene-5,6-dicarbaldehyde, spiro[4,5-dihydrothieno[2,3-c]pyran-7,4 -piperidine, dibenzo-... 

Urothione 7-Amino-2-(r,2 -dihydroxyethyl)-3-methylthio-5-oxo-5,6- dihydrothieno[3,2-g]pteridine (70)... 

Similar transformations were also found on heating of 2-(but-3-ynylthio)pyrimidine (X = S) and 2-(but-3-ynylsulfonyl)pyrimidine (X = S02), 2,3-dihydrothieno[2,3-h]pyridine and l,l-dioxo-2,3-dihy-drothieno[2,3-h]pyridine, respectively being obtained (Scheme 35). 

Whereas in all previously mentioned inverse cycloaddition reactions [h]-fused pyrido annelated systems are formed, some reactions are described which lead to [c]-pyridine annelated bicyclic systems. 5-(Butynylthio)pyrimidines (R = Ph, NHCOCH3) give on heating at 180°C in nitrobenzene 5-R-2,3-dihydrothieno[2,3-c]pyridines (89T803). 5-Propynyloxymethylpyrimidines also readily undergo cycloaddition into l,3-dihydrofuro[3,4-c]pyridines (89T5151) (Scheme 39). Considerable rate enhancements were observed with quaternized pyrimidinium salts. Whereas... 

Klemm and coworkers18a prepared some isomeric chlorinated 2,3-dihydrothieno-[2,3-b]pyridine 1-oxides and reported their El mass spectra at 70 eV. Only one isomer (30) was isolated in the case of the 5-ethyl derivative the mass spectrum of which... 

A complex sequence of pericyclic reactions, intramolecular and intermolecular cycloadditions and cycloreversions, was studied in an attempt to readily achieve bicyclic five-membered heterocycles, the methyl 4,6-dihydrothieno- and methyl-... 

CN (5 )-.a-(2-Chlorophenyi)-6,7-dihydrothieno[3,2-c]pyridine-5(4//)-acetic acid methyl ester sulfate (1 1)... 

The preparation of 1-substituted 4//,6//-dihydrothieno[3,4-c]fiu an 5,5-dioxide and some intermolecular Diels-Alder reactions with typical dienophiles (e.g., DMAD) were reported (Scheme 3, <96JCS(P1)2699>). 

Additional studies featuring reactions of thiophene derivatives detail biohydrolysis of (S)-3-(thiophen-2-ylthio)butanenitrile <06TL8119>, lipase catalyzed resolution of thiotetronic acids <06TL7163>, enzymatic kinetic resolution of l,l-dioxo-2,3-dihydrothiophen-3-ol <06TL5273>, and efficient synthesis of 6-methyl-2,3-dihydrothieno[2,3-c]furan 55, a coffee... 

Dipolar cycloaddition of 2,4-(trimethylsilyl)- and 2,4-(trimethylgermyl)-substituted thiophene-1,1-dioxides as well as silylated 2,2 -bithiophene-1,1-dioxides was investigated. It was shown that only the C(4)=C(5) double bond of 2,4-disubstituted thiophene-1,1-dioxides interacts with acetonitrile oxide to give thienoisoxazoline dioxides. Bithiophene derivatives were inactive or their reaction with nitrile oxide was accompanied by desilylation. Cycloaddition of benzonitrile oxide with all mentioned sulfones did not occur. The molecular structure of 3a-methyl-5.6a-bis(trimethylgermyl)-3a,6a-dihydrothieno 2.3-c/ isoxazole 4,4-dioxide was established by X-ray diffraction (263). ... 

Dihydrothieno[2,3-/]-l,4-thiazepin-5(2//)-thione (514) was reacted with diethyl 2-bromomalonate in methylene chloride under argon for 2.5 hr. The reaction mixture was then treated with a 10% aqueous solution of potassium hydrogen carbonate for 30 min to give (thienothiazepinylide-ne)malonate (515) (86EUP183994). 

Challenger and Harrison found both thienothiophene 1 and its isomer 2 in the products of the reaction between acetylene and sulfur. To identify these compounds, Challenger et developed syntheses of unsubstituted and 2-alkyl-substituted thieno[3,2-f>]thiophene (2) from thiophene derivatives. Cyclization of (3-thienylthio)acetic acid in the presence of sulfuric acid gave 2,3-dihydrothieno[3,2-6]thiophen-3-one (22) (R = H) in 14% yield reducing the latter with lithium aluminum hydride resulted in thienothiophene (2) formation in 80% yield [Eq. (9)]. Similarly 2-methyl- and 2-ethyl-2,3-dihydrothieno[3,2-/>]thiophen-3-one were obtained from a-(3-thienylthio)propionic and a-(3-tWenylthio)-butyric acids in 30% and 27% yields, respectively their reduction yielded 2-methyl (32%) and 2-ethylthieno[3,2-6]thiophenes (52%). The parent acids were prepared from 3-mercaptothiophene. ... 

Gronowitz et observed a similar isomerization of (2-pyrrolyl-thio)acetic acid to (3-pyrrolylthio)acetic acid by polyphosphoric acid followed by cyclization to 2,3-dihydrothieno[3,2-h]pyrrol-3-one. 

Rearrangement of allyl 3-thienyl sulfide (45) gives 2-methyl-2,3-dihydrothieno[3,2- >]thiophene (46) [Eq. (21)]. 

The rearrangement of crotyl 2-thienyl sulfide (47) at 200° gave only 48, 49, and 2,3-dimethyl-2,3-dihydrothieno[2,3-6]thiophene (50) out of numerous possibilities. 

Dialkylamino-2,3-dihydrothieno[2,3-6]thiophenes are assumed intermediates as in Scheme 4. Such thiophenes are also formed in the reaction between thione (85) and dimethylsulfonium methylide (Scheme 5). ... 

As Stated above, one of the routes to thienothiophene 2 is cyclization of (3-thienylthio)acetic acid in the presence of concentrated sulfuric acid followed by action of the 2,3-dihydrothieno[3,2-2>]thiophen-3-one (22, R = H) formed with lithium aluminum hydride.Attempts by the present authors as well as those of Gronowitz and Moses to obtain... 

Dann and Dimmling showed that (2,5-dimethyl-3-thienylthio)acetic acid (86) may by cyclized to 4,6-dimethyl-2,3-dihydrothieno[3,4-6]-thiophen-3-one (87) by anhydrous hydrogen fluoride, and then reduced to 4,6-dimethylthieno[3,4-b]thiophene (88). The latter was obtained by cyclization of acetal (89) synthesized from 3-mercapto-2,S-c ethylthiophene (90) and bromoacetaldehyde dimethylacetd using hydrogen fluoride at 70°-80°. The synthetic route is illustrated by Scheme 6. 

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)]. 

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). 

PMR spectroscopy has found wide application in studies of unsubstituted tWenothiophenes, " enophenothiophenes (Table I), > 9 carboxy-, formyl-, bromo-, and adkyl- thienothiophenes, and carboxy- selenopheno-thiophenes. The PMR meAod has also been used to study alkylthieno-[3,2-h]thiophene sulfones and 4,6-dihydrothieno[3,4-h]tMophene (131)9 analyze the mixture of products of the thio-Claisen ... 

Analogous oxidation of methyl 4,6-dihydrothieno[3,4-i]thiophene-2-carboxylate (134) leads to the 5,5-dioxide (135) (70%) hydrolysis and subsequent oxidation with sodium metaperiodate at 0° (cf. Leonard and Johnson ) results in 2-carboxy-4,6-dihydrothieno[3,4-i]thiophene-5-oxide (91) (74%). ... 

Reduction by UAIH4 of 2,3-dihydrothieno[3,2-6]thiophen-3-one (22) and its 2-methyl- and 2-ethyl-derivatives afforded the appropriate thienothiophene Similarly, Gronowitz and co-workers ... 

Quinoxalinethione carrying 2-hydroxyethyl substituent at C-3 carbon cyclizes by trifluoroacetic anhydride to produce 2,3-dihydrothieno[2,3- ]quinoxalines 123 (Equation 24) <2003S2799>. 

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>. 

The cycloaddition of the 4,6-dihydrothieno[3,4-, ]furan-5,5-dioxide 214 with NPMI in toluene at 150-160 °C gave product 215 (Scheme 21) <1997MI299>. 

A series of 4,6-disubstituted-l,3-dihydrothieno[3,4- ]thiophene-2,2-dioxides (sulfolenes) 477-480 was obtained <2002JOC9267> from 5,7-disubstituted l,4-dihydrothieno[3,4-7l[2,3]oxathiin-3-oxides (thienosultines) 476a-d by heating in benzene in sealed tube (Equation 15). 

Thieno[3,4-3]thiophenes 500 were prepared from thiophen-3-yl-substituted [l,3]dithiol-2-ones 496 in good yields <2003JOG7115>. The photochemical irradiation of 496 leads to thieno[3,4-f]dithiines 497 via a unique ring cleavage reaction and subsequent reductive treatment of dithiines 497 proceeds to give 2,3-dihydrothieno[3,4-/ ]thiophenes 498 and 499. Heating of 499 in the presence of further iodomethane leads to the formation of the thieno[3,4-/ ]-thiophenes 500 (Scheme 63). 

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>. 

Hurd-Mori reaction on hydrazone 147 produced methyl thieno[3,4-r/ -l,2,3-thiadiazole-6-carboxylate 148 along with methyl thieno[3,2-r7 -l,2,3-thiadiazole-5-carboxylate 135 and methyl 5,6-dihydrothieno[3,2-r7 -l,2,3-thiadiazole-5-carboxylate 149 in a ratio of 1 2.6 0.5 (72% combined yield). Conversion of compound 149 to the fully aromatized 135 is accomplished by treatment with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) in refluxing benzene for 10 days (Scheme 15). A modified reaction mechanism for the Hurd-Mori reaction is also presented here <1998H(48)259>. 

Quantum-mechanical calculations using the AMI method for a series of dihydrothieno[2,3- ]pytidines, 27, have been carried out. The calculations suggest that the dihydropyridine ring is in a flattened boat conformation while there is planar geometry at the thieno portion of the molecule <1997JHC931>. 

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