Thiophene synthesis elaboration

Fluorinated thiophene derivatives have found a broad application as biologically intriguing molecules and especially as modem organic materials. However, methods for their synthesis are still limited. The direct fluorination or trifluoromethylation of thiophene is either not selective or proceeds in low yields. The most convenient approach to fluorothiophenes and their benzoanalogues involves Uthiation-fluorination reactions. Other common methods are based on heterocycUzations with participation of methyl thioglycolate, or cycloaddition reactions. The scarce methods for fluorinated thiophenes synthesis give a chance for synthetic chemists to elaborate new, better pathways to these intriguing and useful compounds. 

There have been a number of different synthetic approaches to substituted PTV derivatives proposed in the last decade. Almost all focus on the aromatic ring as the site for substitution. Some effort has been made to apply the traditional base-catalyzed dehydrohalogenation route to PTV and its substituted analogs. The methodology, however, is not as successful for PTV as it is for PPV and its derivatives because of the great tendency for the poly(u-chloro thiophene) precursor spontaneously to eliminate at room temperature. Swager and co-workers attempted this route to synthesize a PTV derivative substituted with a crown ether with potential applications as a sensory material (Scheme 1-26) [123]. The synthesis employs a Fager condensation [124] in its initial step to yield diol 78. Treatment with a ditosylate yields a crown ether-functionalized thiophene diester 79. This may be elaborated to dichloride 81, but pure material could not be isolated and the dichloride monomer had to be polymerized in situ. The polymer isolated... 

In contrast, synthesis of 3,4-diphosphorylthiophenes requires more elaboration because of low reactivity of 3,4-positions of thiophene and unavailability of 3,4-dihalo or dimetallated thiophenes. Minami et al. synthesized 3,4-diphosphoryl thiophenes 16 as shown in Scheme 24 [46], Bis(phosphoryl)butadiene 17 was synthesized from 2-butyne-l,4-diol. Double addition of sodium sulfide to 17 gave tetrahydrothiophene 18. Oxidation of 18 to the corresponding sulfoxide 19 followed by dehydration gave dihydrothiophene 20. Final oxidation of 20 afforded 3,4-diphosphorylthiophene 16. 3,4-Diphosphorylthiophene derivative 21 was also synthesized by Pd catalyzed phosphorylation of 2,5-disubstituted-3,4-dihalothiophene and converted to diphosphine ligand for Rh catalysts for asymmetric hydrogenation (Scheme 25) [47],... 

The thiophene can be considered a four-carbon synthon via reductive desulfurization with Raney nickel. A strategy using the thiophene as a lynch-pin for the construction of complex building blocks was utilized in a total synthesis of the cytotoxic sponge metabolite haliclamine A <02JOC6474>. Thienyl cyclopropyl ketone (108) was elaborated into 109. Reduction of 109 with Raney Ni gave 110 which was taken on to haliclamine A. 

The use of lithiated thiophenes for the introduction of substituents on the ring through C-C bond formation is now a standard tool in organic synthesis. This has been covered exhaustively in CHEC(1984) and CHEC-II(1996) <1984CHEC(4)741, 1996CHEC-II(2)491>. Further elaboration of this topic is therefore not necessary. 

A one-pot synthesis of 4-substituted 3-amino-2-cyanothiophenes involving o-ethyl thioformate was reported (140L2522). The thiophene core in these 4-subsitututed 2-cyanothiophenes can be readily incorporated into more elaborate pharmaceutically relevant structures as... 

DeBoef demonstrated the utility of the C2-selective oxidative cross-coupling of indole and benzene previously reported by his group in the expedient synthesis of a botulinum neurotoxin inhibitor (Scheme 10) [53]. The streamlined synthesis featured an oxidative cross-coupling of methyl-AT-SEM-indole-6-carboxylate with benzene, and after further elaboration, a direct arylation of a thiophene moiety that had been incorporated into the molecule. This formal synthesis highlights the efficiency of transition metal catalyzed reactions at C-H bonds in the planning of synthetic routes. 

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