Aromatic Ring Opening of Fused Thiophenes via Organolithium Addition to Sulfur

Abstract

Organolithium reagents can add to the sulfur atom of thiophenes that are substituted by a chlorine atom and fused to another aromatic system, at -78°C, to give ortho-substituted aryl sulfides.While working on thieno[3,2-d]thiazole 1 1 , we encountered an unexpected reaction. Treatment of 1 with butyllithium at -100°C and addition of N-chlorosuccinimide yielded a product containing a butyl group and an extra chlorine atom. This unknown compound was then oxidized to the sulfone 4, which was identified by X-ray crystallography (scheme 1 and figure 1). This addition product could be explained by the addition reaction of the butyl group to the sulfur atom of the thiophene, with subsequent ring opening and trapping of the vinylic anion 2 with N-chlorosuccinimide. Scheme 1Although addition of alkyllithiums to sulfur in thioethers 2 , disulfides 3 and dithioketals 4 is known, there are few reports on addition to a sulfur atom included in an aromatic heterocycle with subsequent ring cleavage; known heterocycles reacting this way are imidazo[2,1-b]benzothiazoles 5 , 1,4-dithiins 6 and isothiazoles 7 . Evidences for the addition of butyl-and phenyllithium to thiophenes were reported for 3,4-dichloro-2,5-dimethoxythiophene at room temperature, but the only products of the reaction were dibutyl and diphenyl sulfides respectively 8 . We wish to report in this paper examples of this addition reaction of organolithiums to thiophenes, at -78°C or below, and evidence supporting the proposed mechanism.We first tried to determine what are the structural features that can promote such ring cleavage on a thiophene. Scheme 2 lists all the heterocycles that failed to give any addition of BuLi to the sulfur. In most cases, side reactions such as proton abstraction (thiophenes 5-9, 12, 14 and 15) and lithium-chlorine exchange (10, 16) compete effectively with the ring opening. In the absence of a chlorine substituent or an "acidic" proton, as in compounds 13 and 17, there is no reaction at all, even in ether at room temperature. 2,5-Dichloro-3,4-dinitrothiophene 18 gave only decomposition products and the acid 11 is attacked to give the butyl ketone at -78°C. Scheme 2The only thiophenes we have found that react with BuLi by addition to the sulfur are represented by the two 2-chlorothieno[3,2-d]thiazoles 1 and 19 9 (scheme 1 and table 1) and the fused thiophenes substituted by a chlorine atom in position 3 (table 2). In the case of the two 2-chlorothieno[3,2-d]thiazoles 1 and 19, the intermediate anion 2 obtained after addition of an organolithium salt can be trapped with the more reactive electrophiles to yield substituted (E)-chloroalkenes 20 with retention of configuration. As shown in table 1, this anion is not nucleophilic enough to react with ethyl iodide and benzyl bromide.Downloaded by: Nanyang Technological University NTU. Copyrighted material. LETTERS SYNLETTFor the thiophenes of table 2, a slightly different pathway is followed by the reaction. The electron withdrawing effect of the 3-chloro substituent, along with its easy elim...

Synthesis and DNA-binding affinity studies of glycosylated intercalators designed as functional mimics of the anthracycline antibiotics

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