2-Chloro-3-nitrothiophenes

Nucleophilic aromatic substitution reactions of nitro-substituted thiophenes have been utilized to prepare biologically active thiophenes including reverse transcriptase <02H(57)97> and nitric oxide synthase <02JHC857> inhibitors. The addition-elimination reaction of 2-chloro-3-nitrothiophene (56) with metallated indole 57 afforded 58 which was transformed into the corresponding thiophene-fused azepino[5,4,3-cd]indoles 59 <02H(57)1831>. 

The reaction of 3,4-dinitrothiophenene 89 with Grignard reagents has been shown to give thienylphenols, as exemplified by the formation of 90. A mechanistic rationale was provided to account for this unusual transformation <04EJO3566>. Synthesis of a number of 2-thienylphosphonates has been achieved by treatment of 2-chloro-3-nitrothiophenes with triethyl phosphite via a Michaelis-Arbuzov type reaction <04S668>. 

Scheme 103 Nucleophilic substitutions of 5-acetyl-2-chloro-3-nitrothiophene [164]...

Nice examples of nucleophilic substitution on a thiophene ring are represented by nucleophilic substitutions of 5-acetyl-2-chloro-3-nitrothiophene (Scheme 103) [164], The acetyl group, as a second electron-withdrawing group, in addition to the nitro group, was necessary to support successful nucleophilic substitution. Various nucleophiles were effective, including aliphatic and aromatic V-nucleophiles, aliphatic 0-nucleophiles as well as aliphatic S-nucleophiles (Scheme 103) [164],... 

Pyrazole-, Thiazole-, and Imidazole-fused Thiophens and Related Systems.— The behaviour of thieno- and selenolo-t-3,2-i/]pyrazoles in formylation and bromina-tion reactions has been studied. In contrast to benzo[fe]thiophen, a substituent is directed into the a-position of the condensed thiophen ring. 2-Mercapto-thieno[3,2-prepared from 2-chloro-3-nitrothiophen and sodium disulphide followed by carbon disulphide. A benzo-fused system was prepared similarly from 3-bromo-2-nitrobenzo[6]thiophen. Derivatives of... 

Addition-elimination (for the chloro compound) and elimination-addition (via an intermediate haloalkyne, for the bromo and iodo compounds) mechanisms account for the activation parameters determined for reaction of 2-(/3,/3-dihalovinyl)-5-nitrothiophenes with MeONa-MeOH. °°... 

Another potential avenue for future development is extrapolation of these chemistries from benzofused to heteroanellated heterocycles. We have recently been able to show that thicno[2,3-/ ][ 1,4]thiazepine-5-ones (88)69 can be synthesized on solid support from resin-bound 5-chloro-4-nitrothio-phene-2-carboxylic acid (87) using essentially the same synthetic protocols developed in the carbocyclic series (Scheme 17 and Section 3.2.1).5 The starting material, 5-chloro-4-nitrothiophene-2-carboxylic acid, was synthesized in solution from commercially available 5-chlorothiophene-2-carbox-ylic acid. 

J-Chloro-a,/ -unsaturated aldehydes react with sodium sulfide and bromo-nitromethane to give 2-nitrothiophenes [Eq. (6)].24... 

In an extension of their synthesis of 2-nitrothiophenes, Cagniant and co-workers have prepared 2-nitroselenophenes and -tellurophenes by similar procedures.32,33 Thus, the / -chloro-a,/ -unsaturated aldehyde 38 (R = Ph R = H) reacts with bromonitromethane and sodium selenide to form the 2-nitroselenophene 39. Similarly, with sodium telluride and bromonitromethane, chlorovinylaldehydes yield 2-nitrotellurophenes (40). 

Nucleophilic substitution has been used for the preparation of many thiophenes. For instance, 2-phenylthio-3,4-dinitro-5-piperidino-thiophene (155) has been prepared " through stepwise reaction of (150) with different nucleophiles. Nitrothienols and derivatives of them have been obtained from halogenated nitrothiophenes. Allyl ethers have been prepared by the reaction of 5-chloro-4-nitro-2-acetylthiophene, 3-nitro-2-chlorothiophene, and 2-nitro-3-bromothio-... 

Spinelli and co-workers have shown that linear free-energy or/Ao-correlations can be successfully established for the nucleophilic displacement reactions on activated halogenothiophenes. This has been validated on the benzenethiolate debromination of 2-bromo-3-A -5-nitrothiophenes (557) <91JCR(S)270>, the chlorine-isotopic exchange between ClLi, and some 2-chloro-3-3T-5-nitro-thiophenes (558) <88JCR(S)198>, and the piperidino-debromination of some 2-bromo-3-A -4-methyl-5-nitrothiophenes (559) <85JCS(P2)519>. 

Using the electrochemical methodology, we have performed cyanation of 2-nitrothiophene [22], aminations of 5-nitrothiophene-2-carbonitrile and 2-chloro-2-nitropyridine [24], and C-arylation of ketones with 2-chloro-2-nitropyridine [25] (Scheme 27). 

Amongst other 1,3-dicarbonyl equivalents which will serve for interaction wifli thioglycolates are 3-chloro-enones [94] and 3-chloro-enals [95, 96] (illustrated in Schemes 61 and 62 - the latter also showing the use of a nitro group in lieu of an ester, leading to a 2-nitrothiophene), 3-amino-enones [94], 3-methoxy-acrylates [97] 3,3-bis(methylthio)-enones (producing 5-methylthio-products) [98] and 3-phenylthio-enones [99]. 

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