Thieno analogues

Furo- and thieno- analogues (187 X = O, S) of PQQ have been prepared via the cyclization of a 6-amino-5-hydroxybenzofuran or benzothiophene with the dimethyl ester of 4-ketoglutaconic acid, followed by oxidation (HN03) of the triesters (186) to the ort/to-quinones (Scheme 26) <94HCA100>. 

Thiophen Analogues of Anthracene and Phenantbrene.— The remaining member (237) of the thieno-analogues of anthrone-anthrol has been synthesized from the known (238) by reduction of one of the carbonyl groups to the ketal, followed by... 

Many analogues of saccharin have been synthesized since its discovery. With the exception of one compound, thieno[3,4-i/ isothiazolone dioxide [59337-79-0] lOOOX, this effort has not generated more potent compounds. Acesulfame-K could be considered a ring-modification derivative of saccharin, however. 

When thieno[2,3- ]pyrazine was chlorinated, the reaction resembled the corresponding pyridine and pyrimidine (152) analogues in that 13-substitution in the thiophene ring was observed (80JHC1019). 

New routes to pyrrolo[2,l-c][l,4]benzodiazepines and their thiazolo[4,3-c] analogues have been reported <96CC385, 96TL6803, 96JHC275>. A number of new routes to pyrrolo[l,2-a]thieno[3,2 [l,4]diazepines have also been published <96JHC75,96JHC87>. 

The furo[3,4- ]pyrroles 132, 133 <2002TL6983>, thieno[2,3-f]furan 134, <1996JOC6166>, and furo[2,3-f]pyrrole 135 <1995T193>, which are mostly less stable than the benzo-fused analogues, were trapped by Diels-Alder reactions with dienophiles followed by elimination of water to give the corresponding indoles 136-139, 140, 141, and benzothiephenes 142, 143, and 144 with good to excellent yields (Scheme 13). 

Since isoquinolinones are known to be very potent inhibitors of poly(ADP-ribose)polymerase (PARP), thieno[3,4-( ]pyridin-4-ones have been studied for their potential as PARP inhibitors <1999BMC297>. Early studies indicate that the sulfur analogues also act as potent PARP inhibitors. Thienopyridine diazonium salts can be converted into heterocyclic dyes that are useful as disperse dyes for polyester fabrics <2005DP(64)223, 2006DP(70)60>. 

An interesting analogue of the benzotropylium cation, 2,3-thieno-tropylium cation, is mentioned in Section III. 

Nitrations of pyridine 1-oxides in the 4-position take place on the neutral free base species. 2,6-Dimethoxypyridine 1-oxide is nitrated as the conjugate acid to yield the 3-nitro derivative a second nitration to give the 3,5-dinitro analogue takes place on the free base. Thieno[3,2-/ Jpyridine N-oxide is nitrated by HN03-H2S04 to produce (88) with 63% yield (96CHEC-II(7)199). 

The chemistry of thienoquinolines has been explored to a limited degree. Two types (378,379) will be described in this subsection. The pharmacological interest in thieno[2,3-Z>]quinoline (378) and derivatives thereof stems from their isosteric and isoelectronic resemblance to acridine furthermore, (378) constitutes the sulfur analog of furoquinoline (Section 3.17.2.1.5), which is the parent system of a number of alkaloids. Thieno[3,4-6]quinoline (379) is an o-quinonoidal heterocycle which is of interest both for theoretical reasons compared with its isoconjugate analogues and as a synthon in Diels-Alder reactions for the preparation of other condensed heterocycles. 

Dipole moment studies of some A,B-diheteropentalenes have been discussed <84CHEC-I(4)1037>. The dipole moments of symmetrical thieno[3,2-6]thiophene (12) and its selenium analogue (14) are 0.00 D (1 D = 3.336 x 10-30C m), whereas for selenolo[3,2-6]thiophene (13) the dipole moment is... 

The l-methylbenzo[A]thieno[2,3-/)]pyrrole (149) and benzo[6]selenolo[2,3-6]pyrrole (150) were prepared (83JHC49) and the influence of annelation and of the heteroatom upon the reactivity towards acetylation and lithiation was investigated <83JHC6l>. The sulfur and selenium analogues with [h,2-b (75)-(77) and [2,3-b (149) and (150) annelation were acetylated at C-2 and C-3. No reaction at all was observed with butyllithium except in the case of 1 -methylbenzo[6]selenolo[2,3-/ ]pyrrole (150), where the opening of the selenophene nucleus, after car-boxylation and the action of diazomethane, gave l-methyl-2-methoxycarbonyl-3-(2 -methyl-selenophenyl)pyrrole (151) and the positional isomer (152). 

Within a given series of heterocycles, differences in reactivity and stability are found compared to their corresponding benzo analogues (see Section 7.02.5). For example, 2,1-benzoisoxazoles are stable in mineral acids, while thieno[3,2-c]isoxazoles (1) and selenolo[3,2-c]isoxazoles (2) are not. Further, 2,1-benzoisoxazoles react with activated methylene synthons to afford quinoline V-oxides <67TL2337> whereas compounds (1) and (2) are inert. The isomer distribution from the pH dependent bromination of thieno[3,2-c]pyrazole (3) is similar to that found for indazole, while thieno[3,2-c]isoxazole (4) is relatively inert <76CS165,77CSi>. 

One study that could have synthetic utility is the electrochemical reduction of thieno[2,3-6]py-razines, such as the parent molecule (68) to the corresponding tetrahydro compound (69) (Equation (23)) <91JOC4840>. Thieno[3,4- ]pyrazine, as well as the oxygen analogues of both compounds, behave similarly. 

There has been considerable interest in the thienothiazine ring system from the pharmaceutical and pharmacological view point since 1976 when tenoxicam (4-hydroxy-2-methyl-7V-2-pyridinyl-2//-thieno[2,3-c]-l,2-thiazine-3-carboxamide-1,1-dioxide) (376) was patented by Hoffmann-La Roche as an antiinflammatory agent. Since then there have been hundreds of references to analogues, and to related compounds, and their pharmacological action, metabolism, and analytical methods for these compounds. It would be beyond the scope of this chapter to attempt to review these data. 

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