Synthesis of Trifluoromethylated Pyrroles via a One-Pot Three-Component Reaction

Abstract

A novel synthesis of trifluoromethylated pyrroles is described from a one-pot, three-component reaction between N-aryl-2,2,2-trifluoroacetimidoyl chlorides, dimethyl or diethyl acetylene dicarboxylate, and isocyanides in dry dichloromethane without catalyst in good yields.

Key words

N-aryl-2,2,2-trifluoroacetimidoyl chloride - trifluoromethylated pyrrole - isocyanide

• References and Notes

• 1a Jacobi PA, Coults LD, Guo JS, Leung SI. J. Org. Chem. 2000; 65: 205-205
• 1b Fürstner A. Angew. Chem. 2003; 115: 3706-3706
• 2 Boger DL, Boyce CW, Labrili MA, Sehon CA, Jin Q. J. Am. Chem. Soc. 1999; 121: 54-54
• 3a Groenendaal L, Meijer EW, Vekemans JA. J. M. In Electronic Materials: The Oligomer Approach. Müllen K, Wegner G. Wiley-VCH; Weinheim: 1997
• 3b Domingo VM, Aleman C, Brillas E, Julia L. J. Org. Chem. 2001; 66: 4058-4058
• 4a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881-1881
• 4b Kirsch P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity and Applications. Wiley-VCH; Weinheim: 2004
• 4c Hiyama T. Organofluorine Compounds: Chemistry and Applications. Springer; Berlin: 2000
• 5a Large S, Roques N, Langlois BR. J. Org. Chem. 2000; 65: 8848-8848
• 5b Thayer A. Chem. Eng. News 2006; 23: 15-15
• 6 Wiehn MS, Vinogradova EV, Togni A. J. Fluorine Chem. 2010; 131: 951-951
• 7a Filler R, Kobayashi Y. Biomedicinal Aspects of Fluorine Chemistry . Kodansha; Tokyo: 1982
• 7b Kumadaki I. J. Synth. Org. Chem., Jpn. 1984; 42: 786-786
• 7c Welch JT. Tetrahedron 1987; 43: 3123-3123
• 7d Welch JT, Eswarakrishnan S. Fluorine in Bioorganic Chemistry . John Wiley and Sons; New York: 1991
• 7e Filler R, Kobayashi Y, Yagupolskii LM. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications. Elsevier; Amsterdam: 1993
• 8 Yoshika H, Nakayama C, Matsuo N. J. Synth. Org. Chem., Jpn. 1984; 42: 809-809
• 9 Banks RE, Smart BE, Tatlow JC. Organofluorine Chemistry, Principles and Commercial Applications 1994-1994
• 10 Banks RE. Preparation, Properties and Industrial Applications of Organofluorine Compounds. Ellis Harwood; Chichester: 1982
• 11 Dickey JB, Towne EB, Bloom MS, Taylor GJ, Hill HM, Corbitt RA, McCall MA, Moore WH, Hedberg DG. Ind. Eng. Chem. 1953; 45: 1730-1730
• 12 Rahmani F, Darehkordi A, Notash B. J. Fluorine Chem. 2014; 31: 84-84
• 13 Darehkordi A, Khabazzadeh H, Saidi K. J. Fluorine Chem. 2005; 126: 1140-1140
• 14 Tamura K, Mizukami H, Maeda K, Watanabe H, Uneyama K. J. Org. Chem. 1993; 58: 32-32
• 15 General Procedure To a magnetically stirred solution of the requisite isocyanide (1 mmol) and 2,2,2-trifluoroacetimidoyl chloride (1 mmol) in CH₂Cl₂ (10 mL) was added a mixture of acetylene dicarboxylate (1 mmol) in CH₂Cl₂ (5 mL) at r.t. The reaction mixture was then allowed to stir for 24 h. The solvent was removed under reduced pressure, and the residue was purified by silica (Merck 230–400 mesh) column chromatography using hexane–EtOAc mixture as eluent. Dimethyl 2-(tert-Butylamino)-5-(trifluoromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3,4-dicarboxylate (3a) Mp 118–119 °C (yield: 73%). IR (neat): 3422, 1733, 1670 cm^–1. ¹H NMR (300 MHz, DMSO): δ = 7.62–7.45 (m, 4 H), 3.64 (s. 3 H, OMe), 3.57 (s, 3 H, OMe), 3.34 (br s, 1 H, NH), 0.90 (s, 9 H). ¹³C NMR (75 MHz, DMSO): δ = 171.51, 170.87, 166.69, 163.74, 141.61, 132.99, 130.31, 126.01, 125.35, 123.98, 122.40, 121.32, 93.79, 85.20, 54.61, 53.29, 50.67, 29.97. ¹⁹F NMR (282 MHz, DMSO): δ = –78.18, –61.02 ppm. Anal. Calcd (%) for C₂₀H₂₀F₆N₂O₄: C, 51.51; H, 4.32; N, 6.01. Found: C, 51.34; H, 4.25; N, 5.97.Dimethyl 1-[3,5-Bis(trifluoromethyl)phenyl]-2-(cyclohexylamino)-5-(trifluoromethyl)-1H-pyrrole-3,4-dicarboxylate (3b) Mp 103–104 °C (yield: 70%). IR (neat): 3473, 1752, 1667 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.89 (s, 1 H), 7.80 (s, 2 H), 3.97 (s. 3 H, OMe), 3.93 (s, 3 H, OMe), 3.82–3.85 (m, 1 H, CH), 3.33 (br s, 1 H, NH), 1.16–1.64 (m, 10 H, 5 CH₂ c-Hex). ¹³C NMR (75 MHz, CDCl₃): δ = 169.41, 167.97, 166.85, 164.81, 164.59, 149.41, 148.67, 133.70, 131.81, 124.17, 123.46, 121.79, 120.55, 96.22, 54.82, 52.96, 51.59, 33.57, 28.12, 26.13, 25.09, 24.35. ¹⁹F NMR (282 MHz, CDCl₃): δ = –63.03, –55.33 ppm. Anal. Calcd (%) for C₂₃H₂₁F₉N₂O₄: C, 49.29; H, 3.78; N, 5.00. Found: C, 49.12; H, 3.65; N, 4.88.