TETRAHEDRON LETTERS Tetrahedron Letters 44 (2003) 6253–6255 Pergamon A versatile one-pot synthesis of 2,3,5-tri-substituted thiophenes from thiomorpholides Firouz Matloubi Moghaddam* and Hassan Zali-Boinee Sharif University of Technology, Department of Chemistry, PO Box 11365 -9516 Tehran, Iran Received 19 April 2003; revised 7 June 2003; accepted 20 June 2003 Abstract—An efficient method for the preparation of 2,3,5-trisubstituted thiophenes in a one-pot synthesis from thiomorpholides via the thio-Claisen rearrangement was developed. © 2003 Elsevier Ltd. All rights reserved. Highly substituted thiophenes have attracted a great deal of interest, due to their presence in natural prod- ucts, 1 as novel conducting polymers, 2 isosteric replace- ments for phenyl groups in medicinal chemistry 3 and as optical chromophores. 4 The thio-Claisen rearrangement has been an excellent method for the formation of CC bonds and is useful for the construction of heterocyclic ring system. 5 In continuation of our recent work on microwave-assisted Claisen rearrangement of propargyl naphthyl ethers to pyrans and furans, 6 here we report a simple and one-pot method for the preparation of substituted thiophenes. When the thiomorpholide 2a as a model was treated with propargyl bromide in the presence of anhydrous K 2 CO 3 in o -dichlorobenzene and heated at 120–130°C for about 4 h, the three-substituted thiophene 3a was obtained in 76% yield (Scheme 1). o -Dichlorobenzene was found to be a versatile solvent for conducting this type of Claisen rearrangement. A mechanism has been proposed for this type of transformation and is shown in Scheme 2. Thiomorpholides undergo an initial eno- lization, then S -propargylation followed by Claisen rearrangement. Several further examples have been investigated and Table 1 summarizes our results along with the melting points of the compounds. In conclusion, this is a facile one-pot synthesis of substituted thiophenes. The gener- ality of the method has been demonstrated by the successful conversion of six substrates (2a–f) into 2- morpholinothiophenes (3a–f) in good isolated yields. These materials have the potential to be used as drugs. 7 The methodology described here seems to be the sim- plest one for the synthesis of these compounds. Experimental The substrates (2a–f) were prepared from substituted styrenes 8 or arylketones 9 by our previously published procedures. General procedure for the one -pot preparation of substi - tuted thiophenes : To a stirred solution of thiomorpholide (2 mmol) in o -dichlorobenzene (4 ml), anhydrous K 2 CO 3 (0.552 g, 4 mmol) was added. Then, freshly distilled propargyl bromide (0.36 ml, 4 mmol) was added dropwise during about 15 min. The reaction mixture was heated to 60°C for 1 h and was then raised to 120–130°C for 4 h. The progress of the reaction was monitored by TLC. After the necessary time, the reac- tion mixture was filtered, washed with water (3×5 ml) and dried over anhydrous MgSO 4 . The solvent was removed and the crude reaction mixture was purified by Scheme 1. * Corresponding author. E-mail: matloubi@sharif.edu 0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved. doi:10.1016/S0040-4039(03)01548-X