Mendeleev Communications Electronic Version, Issue 1, 2002 1 A novel transformation of 2-acetylthiophene and its halogen derivatives under Vilsmeier reaction conditions Valerii Z. Shirinian,* Leonid I. Belen¡�kii and Mikhail M. Krayushkin N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 095 137 6939; e-mail: shir@ioc.ac.ru 10.1070/MC2002v012n01ABEH001529 Under conditions of the Vilsmeier reaction either ¥â-chloro-¥â-(2-thienyl)acrylic aldehydes or N,N-dimethyl-2-thiophenecarboxamides can be synthesised from 2-acetylthiophenes depending on the reaction temperature and time.The Vilsmeier reaction is a general procedure for introducing an aldehyde group into activated aromatic rings.1.3 This method has been widely used for the synthesis of various aldehyde derivatives of benzene, thiophene, furan, pyrrole etc., via a complex derived from DMF and POCl3, SOCl2 or COCl2.The Vilsmeier complex is also used as a halogenating and dehydrating agent.4.6 In particular, the dehydration of N-monosubstituted formamides by DMF.POCl3 is a simple procedure for the synthesis of isonitriles.4 Specific transformations under the action of Vilsmeier¡�s reagent are known, e.g., the synthesis of previously unknown amidomercaptals from the 2-thienyl sulfides or alkanethiols. 5,6 Interesting synthetic possibilities are offered by the joint action of Vilsmeier¡�s reagent and hydride reductants.7 In addition to the electrophilic formylation of aromatic compounds, Vilsmeier¡�s reagent has been also widely used in reactions with carbonyl compounds.8 Arnold and Zemlicka9,10 found that the reaction of Vilsmeier¡�s reagent with ketones containing methyl or methylene groups adjacent to the carbonyl group affords substituted ¥â-chloroacrylaldehydes. The reaction can be used for the preparation of ¥â-chloroacrylaldehydes from ketones including aryl alkyl ketones.8 The reaction proceeds on the addition of a ketone to Vilsmeier¡�s reagent at 5.10 ¡ÆC followed by heating the reaction mixture at 60 to 100 ¡ÆC up to the complete transformation into ¥â-chloroacrylaldehyde.However, we found that 2-acetylthiophenes 1a.c heated with Vilsmeier¡�s reagent above 120 ¡ÆC afforded N,N-dimethylthiophene- 2-carboxamides 3a.c rather than expected ¥â-chloroacrylaldehydes 2a.c (Scheme 1).¢Ó The structures of amides 3a.c were found from spectroscopic data and the results of elemental analyses,¢Ô in the case of 3a the characteristics were compared with published data.The structure of amide 3b was found by spectrometric techniques, elemental analysis and through its independent synthesis from known 4-bromothiophene-2-carboxylic acid.15 As to the replacement of bromine by a chlorine atom on the interaction of 2-acetyl- 4,5-dibromothiophene 1c with Vilsmeier¡�s reagent, the preparation of 5-chlorothiophene-2-carbaldehyde by the reaction of 2-bromothiophene with N-methylformanilide and POCl3 at 100 ¡ÆC should be mentioned.16 Note that there is a weak parent peak (m/z 313) of N,N-dimethyl-4,5-dibromothiophene-2-carboxamide in the mass spectrum of unpurified amide 3c.The mechanism of this novel transformation remains unclear. The reaction likely involves many steps (Scheme 2) and includes the formation of intermediate 6, which is analogous to key compounds yielding ¥â-chloroacrylaldehydes.8 The formation of ¥â-chloroacrylaldehydes from acetylthiophenes and Vilsmeier¡�s reagent at 60.100 ¡ÆC was described.8,17,18 In particular, 3-chloro- 3-(2-thienyl)propenal was obtained in 11% yield by treatment of 2-acetylthiophene with Vilsmeier¡�s reagent at 60 ¡ÆC.17 The formation of both 3-chloro-3-(2-thienyl)propenal and N,N-dimethylthiophene- 2-carboxamide in the ratio ~1:1 on the heating of 2-acetylthiophene with Vilsmeier¡�s reagent for 1 h instead of 3 h¡× may indirectly indicate that ¥â-chloroacrylaldehydes are inter- ¢Ó Preparation of N,N-dimethylthiophene-2-carboxamides 3a.c (general procedure).Phosphorus oxychloride (2.5 ml, 4.1 g, 0.027 mol) was added dropwise to DMF (8.5 ml, 8.2 g, 0.11 mol) cooled to 0.10 ¡ÆC. The mixture was kept for 15 min at this temperature, then for 15 min at 45.50 ¡ÆC and cooled again to 0.10 ¡ÆC; a starting 2-acetylthiophene (0.024 mol) was added.(2-Acetylthiophene was purchased from Aldrich, 2-acetyl- 4-bromothiophene 1b and 2-acetyl-4,5-dibromothiophene 1c were prepared according to the published procedure.11) The reaction mixture was gradually heated to 120.130 ¡ÆC and kept at this temperature for 2.5.3 h. After cooling, CH2Cl2 (50 ml) was added, and the organic layer was washed successively with concentrated AcONa and NaHCO3 solutions and finally with water.The residue after evaporation of the extract was recrystallised from a suitable solvent. ¢Ô N,N-Dimethylthiophene-2-carboxamide 3a: yield 41%, mp 44.45 ¡ÆC (from light petroleum, lit.,12 mp 44.45 ¡ÆC). 1H NMR [200 MHz, (CD3)2CO] d: 3.18 (br. s, 6H, Me2N), 7.09 (dd, 1H, 4-H), 7.43 (dd, 1H, 3-H), 7.62 (dd, 1H, 5-H); J45 4.8 Hz, J34 3.7 Hz, J35 1.1 Hz (cf.ref. 13). MS (EI, 70 eV), m/z (%): 155 (46) [M]+, 111 (100) [M . NMe2]+. N,N-Dimethyl-4-bromothiophene-2-carboxamide 3b: yield 39%, mp 98. 100 ¡ÆC (from heptane). 1H NMR (200 MHz, CDCl3) d: 3.21 (br. s, 6H, Me2N), 7.25 (s, 1H, 5-H), 7.38 (s, 1H, 3-H). 13C NMR (50 MHz, CDCl3) d: 30.85 (Me), 109.12 (C.Br), 126.36 [C(3)], 131.12 [C(5)], 139.21 [C(2)], 162.80 (C=O).MS (EI, 70 eV), m/z (%): 235 (59) [M]+, 191 (99) [M . NMe2]+. Found (%): C, 36.41; H, 3.83; Br, 33.78; S, 13.55; N, 6.24. Calc. for C7H8BrNOS (%): C, 35.91; H, 3.44; Br, 34.13; S, 13.7; N, 5.98. N,N-Dimethyl-4-bromo-5-chlorothiophene-2-carboxamide 3c: yield 47%, mp 75.76 ¡ÆC (from heptane). 1H NMR (200 MHz, CDCl3) d: 3.19 (br. s, 6H, Me2N), 7.13 (s, 1H, 3-H). 13C NMR (50 MHz, CDCl3) d: 34.74 (Me), 35.37 (Me), 98.92 (C.Cl), 107.48 (C.Br), 128.34 [C(3)], 133.96 [C(2)], 159.35 (C=O). MS (EI, 70 eV), m/z (%): 271 (11) [M]+, 269 (38) [M]+, 267 (24) [M]+, 227 (24) [M . NMe2]+, 225 (78) [M . NMe2]+, 223 (64) [M . NMe2]+. Found (%): C, 31.32; H, 2.52; Br, 30.32; Cl, 13.46; S, 12.17; N, 4.39. Calc. for C7H7BrClNOS (%): C, 31.22; H, 2.60; Br, 29.74; Cl, 13.19; S, 11.89; N, 5.24.Found (by the Schoniger14 method) (%): S, 10.81. Calc. for C7H7BrClNOS (%): S, 11.89. ¡× On the interaction of 2-acetylthiophene 1a with Vilsmeier¡�s reagent at 100.120 ¡ÆC for 1 h, the residue (2.06 g of a yellow oil) obtained after evaporation of the solvent was chromatographed on silica gel (light petroleum.EtOAc, 2.5:1, as an eluent) to give two substances. After recrystallization from light petroleum the following compounds were obtained: 3-chloro-3-(2-thienyl)propenal 2a, 0.75 g (yield 21%), mp 54. 55 ¡ÆC (lit.,17 55.57 ¡ÆC). 1H NMR (200 MHz, CDCl3) d: 6.55 (d, 1H, C=CH, J 3.6 Hz), 7.08 (dd, 1H, 4-H, J45 4.8 Hz, J34 3.7 Hz), 7.51 (dd, 1H, 5-H, J35 1.2 Hz), 7.61 (m, 1H, 3-H), 10.08 (d, 1H, CH=O, J 6.05 Hz). Amide 3a, 0.92 g (yield 25%), identical to the above substance mp and 1H NMR spectrum. 1.3: a R1 = R2 = H b R1 = H, R2 = Br 1c, 2c R1 = R2 = Br 3c R1 = Cl, R2 = Br Scheme 1 S R2 R1 O S R2 R1 Cl O S R2 R1 N O 1a.c 2a.c 3a.c 60.100 ¡ÆC > 120 ¡ÆC DMF/POCl3Mendeleev Communications Electronic Version, Issue 1, 2002 2 mediates in the formation of the carboxamides. However, compound 3 cannot be obtained from aldehyde 2 under these conditions: the heating of 3-chloro-3-(2-thienyl)propenal under Vilsmeier reaction conditions leads to decomposition and tar formation.On the assumption that aldehydes 2 are formed from intermediates 6 on the treatment of the reaction mixture, the transformation of compounds 6 into amides 3 can be considered as a process including the formation of enamines 7 by the interaction DMF) with 6 like the synthesis of N,N-dimethylcarboxamides from DMF and acyl chlorides at 140–150 °C.19 Since intermediate 7 is a vinylog of amidines, a further transformation into N,N-dimethylamide 3 may be similar to the formation of amides from amidines on hydrolysis.It is also similar to the acidic cleavage of â-dicarbonyl compounds.The transformation 7 ® 3 is likely to proceed via amidinium salt 8. In conclusion, we found a new transformation under Vilsmeier reaction conditions, which is promising for the one-step preparation of N,N-dimethylthiophenecarboxamides from 2-acetylthiophenes. The heating of acetylthiophenes with Vilsmeier’s reagent can lead to both â-chloro-â-(2-thienyl)acrylaldehydes and N,N-dimethylthiophene- 2-carboxamides depending on the heating temperature and reaction time.Vilsmeier’s reagent can also be used as a transhalogenating agent. This work was supported by the Russian Foundation for Basic Research (grant no. 01-03-33150). References 1 L. Fieser and M. Fieser, Reagents for Organic Synthesis, Wiley, New York, 1967, p. 284. 2 H. Eilingsfeld, M. Seefelder and H.Weidingen, Angew. Chem., 1960, 72, 836. 3 J.C.Thurman, Chem. Ind., 1964, 752. 4 H. M. Walborsky and G. E. Niznik, J. Org. Chem., 1972, 37, 187. 5 B. P. Fedorov and F. M. Stoyanovich, Izv. Akad. Nauk SSSR, Otdel. Khim. Nauk, 1960, 1828 (Bull. Acad. Sci. USSR, Div. Chem. Sci., 1960, 9, 1700). 6 F. M. Stoyanovich, B. P. Fedorov and G. M. Andrianova, Dokl. Akad. Nauk SSSR, 1962, 145, 584 [Dokl.Chem. (Engl. Transl.), 1962, 640]. 7 D.Burn, Chem. Ind. (London), 1973, 870. 8 Ch. M. Marson, Tetrahedron, 1992, 48, 3659. 9 Z. Arnold and J. Zemli ka, Collect. Czech. Chem. Commun., 1959, 24, 2385. 10 Z. Arnold and J. Zemli ka, Proc. Chem. Soc., 1958, 227. 11 Ya. L. Gol’dfarb and Yu. B. Vol’kenshtein, Dokl. Akad. Nauk SSSR, 1959, 128, 536 [Dokl. Chem. (Engl.Transl.), 1959, 767]. 12 M. Davis, R. Lakhan and A. Ternai, J. Org. Chem., 1976, 41, 3591. 13 F. Fringuelli, S. Gronowitz, A.-B. Hornteldt, I. Jonson and A. Taticchi, Acta Chem. Scand., Ser. B, 1976, 30, 605. 14 Metody kolichestvennogo organicheskogo elementnogo mikroanaliza (Quantitative Methods for Organic Elemental Analysis), eds. N. E. Gel’man and E. A. Terent’eva, Nauka, Moscow, 1987, pp. 149–154 (in Russian). 15 Ya. L. Gol’dfarb, Yu. B. Vol’kenshtein and B. V. Lopatin, Zh. Obshch. Khim., 1964, 34, 969 [J. Gen. Chem. USSR (Engl. Transl.), 1964, 34, 961]. 16 W. J. King and F. F. Nord, J. Org. Chem., 1948, 13, 635. 17 K. Bodendorf and R. Mayer, Chem. Ber., 1965, 98, 3554. 18 Z. Vegh and D. Vegh, 17th International Congress of Heterocyclic Chemistry, Book of Abstracts, Vienna, 1999, p. 571. 19 G. M. Copinger, J. Am. Chem. Soc., 1954, 76, 1372. S R2 R1 O S R2 R1 Cl O S R2 R1 N O 1a–c 2a–c 3a–c HCl S R2 R1 OH – 2HCl DMF–POCl3 S R2 R1 O N 4 S R2 R1 O N 5 2Cl– DMF–POCl3 < 120 °C S R2 R1 Cl N Cl– N 6 NaOAc aq > 120 °C S R2 R1 N N Cl– S R2 R1 N N Cl– 7 S R2 R1 N N Cl– 8 Scheme 2 DMF c c Received: 1st November 2001; Com. 01/1855