Synthesis of 2,3-disubstituted thiophenes from 2-aryl-3-nitro-cyclopropane-1,1-dicarboxylates and 1,4-dithiane-2,5-diol

Abstract

A two-step synthesis of 2,3-disubstituted thiophenes from trans-2-aryl-3-nitrocyclopropane-1,1dicarboxylates and 1,4-dithiane-2,5-diol is described. Ar NO 2 CO 2 Et EtO 2 C 1) BF 3 OEt 2 , CH 2 Cl 2 , rt S CO 2 Et EtO 2 C OH Ar O 25-87% S S HO OH 2) Et 3 N p-TsOH PhMe, 90 C°S EtO 2 C O Ar 61-88%were aromatised to target thiophenes using p-toluenesulfonic acid. To prove the synthetic utility of the synthesised thiophenes, one of the thiophenes was transformed into a bis(thiophene) by a palladium-mediated homocoupling. Further scope of the methodology is under investigation.

Synthetic Applications of Aroyl‐ and Nitro‐substituted 2‐Aryl‐Cyclopropane‐1,1‐Dicarboxylates

“…On the other hand, the nitro‐substituted D‐A cyclopropanes 2 did not react with 1,4‐dithiane‐2,5‐diol ( 19 ) under the reaction conditions ( 2 gave mixtures of ring‐opened products and 19 did not undergo any change). Hence, we modified the reaction conditions, which led to the development of a sequential one‐pot strategy for the synthesis of tetrahydrothiophenes (Scheme ) . Accordingly, the treatment of nitrocyclopropanes 2 with BF 3 ⋅OEt 2 formed aroylmethylidene malonates 9 in situ , and subsequent addition of 19 in the presence of excess triethylamine (Et 3 N) (for neutralizing the Lewis acid as BF 3 ⋅OEt 2 ‐Et 3 N complex and generating mercaptoacetaldehyde in situ ) furnished tetrahydrothiophenes 22 (as diastereomeric mixtures).…”

“…Hence,w e modified the reaction conditions, which led to the development of as equential one-pot strategy for the synthesis of tetrahydrothiophenes (Scheme 20). [31] Accordingly,t he treatment of nitrocyclopropanes 2 with BF 3 ·OEt 2 formed aroylmethylidene malonates 9 in situ,a nd subsequent ad-dition of 19 in the presence of excess triethylamine (Et 3 N) (for neutralizing the Lewis acid as BF 3 ·OEt 2 -Et 3 N complex and generating mercaptoacetaldehyde in situ) furnished tetrahydrothiophenes 22 (as diastereomeric mixtures). Ther eaction takesp lace through at andem conjugatea ddition/intramolecular aldol reaction between 9 and 19'.T he products could serve as potential precursors for 2,3-disubstituted thiophenes,w hich are difficult to prepare by conventional methods.…”

1,4‐Dithiane‐2,5‐diol: An Attractive Platform for the Synthesis of Sulfur‐Containing Functionalized Heterocycles

“…[50] Srinivasan and co-workers described a one-pot method for the synthesis of tetrasubstituted thiophenes 66 from tetrahydrothiopyranols 65, in turn obtained through [3+3] annulation between trans-2aroyl-3-arylcyclopropane-1,1-dicarboxylates 64 and 1 in the presence of stoichiometric amounts of AlCl 3 (Scheme 22). Cycloaddition reactions of donoracceptor cyclopropanes represent powerful tools for the construction of various carbocycles and heterocycles and have been intensively studied in recent decades.…”

“…This strategy was first devised by Sathishkannan and Srinivasan for the synthesis of tetrasubstituted thiophenes 66 through AlCl 3 -mediated [3+3] annulation of 1,3-zwitterionic intermediates -derived from cyclopropanes 64 -with mercaptoacetaldehyde (generated in situ), followed by DBU-induced rearrangement of the resulting tetrahydrothiopyranols 65, providing the target thiophenes in 55-82 % yields (Scheme 22). [49,50] Scheme 22. Employment of 1 as a two-atom component in thiophene synthesis.…”

“…The reactions between trans-2-aryl-3-nitrocyclopropane-1,1dicarboxylates 79 and 1 were utilized by Selvi and co-workers (Scheme 29) [50] to prepare 2,3-disubstituted thiophenes 81. The two-step synthesis involved the formation of aroylmethylidene Kumar and co-workers reported reactions between α-nitroketene N,S-aryl/alkylaminoacetals 82 and 1 in the presence of K 2 CO 3 in ethanol at reflux as a way to form 3-nitro-N-aryl/alkylthiophen-2-amines 83 in good yields; it is worth noting that this efficient protocol generates two carbon-carbon bonds in a single operation (Scheme 30).…”