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Synlett 2009(5): 755-758  
DOI: 10.1055/s-0028-1087821
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Convenient One-Pot Synthesis of N-Substituted 3-Trifluoroacetyl Pyrroles

Nilo Zanatta*a, Ana D. Woutersa, Leonardo Fantinela, Fabio M. da Silvaa, Rosemário Barichelloa, Pedro E. A. da Silvab, Daniela F. Ramosb, Helio G. Bonacorsoa, Marcos A. P. Martinsa
a Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, Brazil
Fax: +55(55)32208756; e-Mail: zanatta@base.ufsm.br;
b Departamento de Patologia, Fundação Universidade Federal de Rio Grande, Rio Grande, RS, Brazil
Further Information

Publication History

Received 1 December 2008
Publication Date:
24 February 2009 (online)

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Abstract

A new one-pot strategy for the synthesis of a series of new N-substituted 3-trifluoroacetyl pyrroles is presented. These compounds were obtained by the reaction of 3-trifluoroacetyl-4,5-dihydrofuran with primary amines, which generated 1,1,1-trifluoro-3-(2-hydroxyethyl)-4-alkylaminobut-3-en-2-one intermediates. In most cases these intermediates were not stable enough to be isolated. Thus, in the same reaction vessel they were directly submitted to oxidation with PCC (Corey’s reagent) to furnish 1,1,1-trifluoro-3-(2-ethanal)-4-alkylaminobut-3-en-2-ones, which under reflux underwent intramolecular cyclization to give the desired N-substituted 3-trifluoroacetyl pyrroles, in moderate yields. All of these pyrroles were tested against pan-susceptible Mycobacterium tuberculosis H37Rv and clinical isolates INH- and RMP-resistant strain and some of these compounds showed significant in vitro antimicrobial activity.

Key words

pyrroles - 3-trifluoroacetylpyrroles - dihydrofuran - N-substituted pyrroles - antimicrobial activity

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Unpublished results: compound 5f exhibited activity against H37Rv and RMPr (MIC = 12.5 µg/mL) and INHr (MIC = 50 µg/mL); 5h exhibited activity against H37Rv and RMPr (MIC = 12.5 µg/mL) and INHr (MIC = 25.0 µg/mL); 5l exhibited activity against H37Rv (MIC = 6.25 µg/mL) and RMPr and INHr (MIC = 12.5 µg/mL); 5m exhibited activity against H37Rv and RMPr (MIC = 6.25 µg/mL) and INHr (MIC = 12.5 µg/mL).

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Synthesis of N-Substituted 3-Trifluoroacetyl Pyrroles 5 - General Procedure
To a solution of 3-trifluoroacetyl-4,5-dihydrofuran 1 (0.50 g, 3.0 mmol) in CH2Cl2 (5 mL), amines 2a,b (approx. 6.0 mmol), amines 2c-r (3.0 mmol), and amines 2s-u (1.5 mmol) were added under magnetic stirring, and the reaction was stirred for 30 min at r.t. After this period, PCC (4.5 mmol) in CH2Cl2 (5 mL) was added, and the reaction mixture was refluxed for 3 h. For amines 2a,b, before the addition of PCC, the reaction was extracted with CH2Cl2 (3 × 15 mL) and dried with MgSO4. The solvent was evaporated by rotary evaporator, and the reaction residue was treated with 1 M solution of NaOH and extracted with Et2O (3 × 50 mL). The combined organic layers were washed with 1 M NaOH solution (2 × 50 mL) and distilled H2O (1 × 50 mL). The organic phase was dried with anhyd MgSO4, evaporated, and purified by column chromatography using basic alumina (60 g) with a plug of active charcoal and eluted with Et2O (50 mL).

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Spectroscopic Data of Selected Compounds1-Methyl-3-trifluoroacetylpyrrole (5b) ¹H NMR (200 MHz, CDCl3): δ = 7.4 (s, 1 H), 6.7 (s, 1 H), 6.6 (s, 1 H), 3.7 (s, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 175.0 (q, ² J CF = 35.3 Hz), 130.1, 124.3, 117.8, 116.9 (q, ¹ J CF = 288.7 Hz), 110.9, 36.8. GC-MS (IE, 70eV): m/z (%) = 117 (68) [M+], 108 (100), 80 (30). ESI-HRMS: m/z calcd for C6H4F3NO [M + H]+: 178.0479; found: 178.0471.
1-(Ethan-1-ol-2-yl)-3-trifluoroacetylpyrrole (5g)
¹H NMR (400 MHz, CDCl3): δ = 7.5 (s, 1 H), 6.7 (m, 2 H), 4 (t, 1 H, J = 9.2 Hz), 3.9 (t, 1 H, J = 9.2 Hz). ¹³C NMR (100 MHz, CDCl3): δ = 175.4 (q, ² J CF = 35.7 Hz), 130.1, 123.8, 117.8, 116.9 (q, ¹ J CF = 288.8 Hz), 110.9, 61.8, 52.5. GC-MS (IE, 70eV): m/z (%) = 207 (25) [M+], 138 (100), 94 (57). ESI-HRMS: m/z calcd for C9H8F3NO [M + H]+: 208.0585; found: 208.0576.
1-(2,2-Dimethyl-etan-1-ol-2-yl)-3-trifluoroacetylpyrrole (5k)
¹H NMR (400 MHz, CDCl3): δ = 7.6 (s, 1 H), 6.9 (m, 1 H), 6.7 (m, 2 H), 3.6 (s, 2 H), 1.5 (s, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 175.4 (q, ² J CF = 35 Hz), 127.5, 121, 117.3, 116.9 (q, ¹ J CF = 289 Hz), 110.5, 70.4, 60.2, 24.5. GC-MS (IE 70eV): m/z (%) = 235 (30) [M+], 204 (97), 94 (100). ESI-HRMS: m/z calcd for C10H12F3NO2 [M + H]+: 236.0898; found: 236.0891.
1-(Ethan-2-dimethylamino-1-yl)-3-trifluoroacetyl-pyrrole (5q)
¹H NMR (400 MHz, CDCl3): δ = 7.55 (s, 1 H), 6.74 (m, 2 H), 4.01 (t, 2 H, J = 3.2 Hz) 2.67 (t, 2 H, J = 3.1 Hz), 2.27 (s, 6 H). ¹³C NMR (100 MHz, CDCl3): δ = 175.2 (q, ² J CF = 35 Hz), 129.6, 123.5, 117.8, 116.9 (q, ¹ J CF = 288 Hz), 110.7, 59.6, 48.5, 45.4. GC-MS (IE, 70eV): m/z (%) = 235 (100) [MH+], 165 (20). ESI-HRMS: m/z calcd for C10H13F3N2O [M + H]+: 235.1058; found: 235.1058.
1,2-Bis-3-trifluoroacetylpyrrole-1-yl-ethane (5s)
¹H NMR (400 MHz, CDCl3): δ = 7.14 (s, 1 H), 6.77 (s, 1 H), 6.50 (m, 1 H), 4.30 (s, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 175.2 (q, ² J CF = 35 Hz), 128.8, 122.8, 118.8, 116.7 (q, ¹ J CF = 288 Hz), 111.9, 52.1. GC-MS (IE, 70eV): m/z (%) = 352 (31) [M+], 283 (100), 176 (26), 107 (25). ESI-HRMS: m/z calcd for C14H10F6N2O2 [M + H]+: 367.0881; found: 367.0876.