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

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

References and Notes

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Unpublished results: compound 5f exhibited activity against H37_Rv and RMPr (MIC = 12.5 µg/mL) and INHr (MIC = 50 µg/mL); 5h exhibited activity against H37_Rv and RMPr (MIC = 12.5 µg/mL) and INHr (MIC = 25.0 µg/mL); 5l exhibited activity against H37_Rv (MIC = 6.25 µg/mL) and RMPr and INHr (MIC = 12.5 µg/mL); 5m exhibited activity against H37_Rv 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.