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

Nilo Zanatta; Ana D. Wouters; Leonardo Fantinel; Fabio M. da Silva; Rosemário Barichello; Pedro E. A. da Silva; Daniela F. Ramos; Helio G. Bonacorso; Marcos A. P. Martins

doi:10.1055/s-0028-1087821

LETTER

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

Nilo Zanatta*^a, Ana D. Wouters^a, Leonardo Fantinel^a, Fabio M. da Silva^a, Rosemário Barichello^a, Pedro E. A. da Silva^b, Daniela F. Ramos^b, Helio G. Bonacorso^a, Marcos A. P. Martins^a
^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

Abstract

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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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References and Notes

<A NAME="RS12108ST-1">1</A> Morales GO. Méndez F. Miranda DL. Tetrahedron Lett. 2007, 48: 4515

<A NAME="RS12108ST-2">2</A> Das B. Chowdhury N. Damodar K. Tetrahedron Lett. 2007, 48: 2867

<A NAME="RS12108ST-3">3</A> Misra NC. Panda K. Ila H. Junjappa H. J. Org. Chem. 2007, 72: 1246

<A NAME="RS12108ST-4">4</A> Pridmore SJ. Slatford PA. Aurélie D. Whittlesey MK. Williams JMJ. Tetrahedron Lett. 2007, 48: 5115

<A NAME="RS12108ST-5">5</A> Marcotte FA. Lubell WD. Org. Lett. 2002, 4: 2601

<A NAME="RS12108ST-6A">6a</A> Kawase M. Hirabayashi M. Koiwai H. Yamamoto K. Miyamae H. Chem. Commun. 1998, 641

<A NAME="RS12108ST-6B">6b</A> Bray BL. Mathies PM. Naef RN. Solas DR. Tidwell TT. Artis DR. Muchowski JM. J. Org. Chem. 1990, 55: 6317

<A NAME="RS12108ST-6C">6c</A> Wynne JH. Lloyd CT. Jensen SD. Boson S. Stalick WM. Synthesis 2004, 2277

<A NAME="RS12108ST-7A">7a</A> Okada E. Masuda R. Hojo M. Heterocycles 1992, 34: 791

<A NAME="RS12108ST-7B">7b</A> Druzhinin SV. Balenkova ES. Nenajdenko VG. Tetrahedron 2007, 63: 7753

<A NAME="RS12108ST-8A">8a</A> Andrew RJ. Mellor JM. Tetrahedron 2000, 56: 7267

<A NAME="RS12108ST-8B">8b</A> Okada E. Kinomura T. Takeuchi H. Hojo M. Heterocycles 1997, 44: 349

<A NAME="RS12108ST-8C">8c</A> Soufyane M. Mirand C. Levy J. Tetrahedron Lett. 1993, 34: 7737

<A NAME="RS12108ST-9A">9a</A> Rudenko AP. Aristov SA. Vasilyev AV. Russ. J. Org. Chem. 2004, 40: 1221

<A NAME="RS12108ST-9B">9b</A> Aristov SA. Vasilyev AV. Rudenko AP. Russ. J. Org. Chem. 2006, 42: 66

<A NAME="RS12108ST-10">10</A> Nenajdenko VG. Statsuk AV. Balenkova ES. Chem. Heterocycl. Compd. 2003, 5: 598

<A NAME="RS12108ST-11">11</A> Peng W.-M. Zhu S.-Z. J. Fluorine Chem. 2002, 116: 81

<A NAME="RS12108ST-12">12</A> Matsumoto N. Takahashi M. Tetrahedron Lett. 2005, 46: 5551

<A NAME="RS12108ST-13A">13a</A> Okada E. Masuda R. Hojo M. Yoshida R. Heterocycles 1992, 34: 1435

<A NAME="RS12108ST-13B">13b</A> Elguero R. Jacquier B. Shimizu B. Bull. Soc. Chim. Fr. 1967, 2996

<A NAME="RS12108ST-13C">13c</A> Elguero R. Jacquier B. Shimizu B. Bull. Soc. Chim. Fr. 1970, 1585

<A NAME="RS12108ST-13D">13d</A> Shaitanova EN. Gerus II. Kukhar VP. Tetrahedron Lett. 2008, 49: 1184

<A NAME="RS12108ST-14">14</A> Jones RA. Bean GP. In The Chemistry of Pyrroles Academic Press; London: 1977 and references cited therein.

<A NAME="RS12108ST-15A">15a</A> Pavri NP. Trudell ML. J. Org. Chem. 1997, 62: 2649

<A NAME="RS12108ST-15B">15b</A> Chen N. Lu Y. Gadamasetti K. Hurt CR. Norman MH. Fotsch C. J. Org. Chem. 2000, 65: 2603

<A NAME="RS12108ST-15C">15c</A> Marcotte F.-A. Rombouts FJR. Lubell WD. J. Org. Chem. 2003, 68: 6984

<A NAME="RS12108ST-15D">15d</A> Kagoshima H. Akiyama T. J. Am. Chem. Soc. 2000, 122: 11741

<A NAME="RS12108ST-15E">15e</A> Wasserman HH. Power P. Petersen AK. Tetrahedron Lett. 1996, 37: 6657

<A NAME="RS12108ST-16A">16a</A> Nunomoto S. Kawakami Y. Yamashita Y. Takeuchi H. Egushi S. J. Chem. Soc., Perkin Trans. 1 1990, 111

<A NAME="RS12108ST-16B">16b</A> Bourak M. Gallo R. Heterocycles 1990, 31: 401

For recent examples, see:

<A NAME="RS12108ST-17A">17a</A> Salamone SG. Dudley GB. Org. Lett. 2005, 7: 4443

<A NAME="RS12108ST-17B">17b</A> Song G. Wang B. Wang G. Kang Y. Yang T. Yang L. Synth. Commun. 2005, 35: 1051

<A NAME="RS12108ST-17C">17c</A> Dieltiens N. Stevens CV. De Vos D. Allaert B. Drozdzak R. Verpoort F. Tetrahedron Lett. 2004, 45: 8995

<A NAME="RS12108ST-17D">17d</A> Tracey MR. Hsung RP. Lambert RH. Synthesis 2004, 918

<A NAME="RS12108ST-17E">17e</A> Wang B. Gu Y. Luo C. Yang T. Yang L. Suo J. Tetrahedron Lett. 2004, 45: 3417

<A NAME="RS12108ST-17F">17f</A> Dhawan R. Arndtsen BA. J. Am. Chem. Soc. 2004, 126: 468

<A NAME="RS12108ST-17G">17g</A> Abdelrazek F. Synth. Commun. 2005, 35: 2251

<A NAME="RS12108ST-17H">17h</A> Delayen A. Goossens L. Houssin R. Henichart JP. Heterocycles 2005, 65: 1673

<A NAME="RS12108ST-18">18</A> Black BC. Hollingworth RM. Ahammadsahib KY. Kukel CD. Donovan S. Pestic. Biochem. Physiol. 1994, 50: 115

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).

<A NAME="RS12108ST-20">20</A> Colla A. Martins MAP. Clar G. Krimmer S. Fisher P. Synthesis 1991, 483

<A NAME="RS12108ST-21A">21a</A> Corey EJ. Sugs JW. Tetrahedron Lett. 1975, 32: 2647

<A NAME="RS12108ST-21B">21b</A> Hunsen M. Tetrahedron Lett. 2005, 46: 1651

<A NAME="RS12108ST-21C">21c</A> Dugger RW. Ragan JA. Brown DH. Org. Process Res. Dev. 2005, 9: 253

<A NAME="RS12108ST-21D">21d</A> Rauter AD. Piedade F. Almeida T. Ramalho R. Ferreira MJ. Resende R. Amado J. Perreira H. Justino J. Neves H. Silva FVM. Canda T. Carbohydr. Res. 2004, 339: 1889

<A NAME="RS12108ST-21E">21e</A> Li SH. Li TS. Steroids 1998, 63: 76

<A NAME="RS12108ST-21F">21f</A> Rauter AP. Fernandes AC. Czernecki S. Valery JM. J. Org. Chem. 1996, 61: 3594

<A NAME="RS12108ST-21G">21g</A> Rauter A. Ferreira M. Borges C. Duarte T. Piedade F. Silva M. Santos H. Carbohydr. Res. 2000, 325: 1

<A NAME="RS12108ST-22">22</A> Choudary BM. Prosad AD. Bhuma V. Swapna V. J. Org. Chem. 1992, 57: 5841

<A NAME="RS12108ST-23A">23a</A> Corey EJ. Schmidt G. Tetrahedron Lett. 1979, 20: 399

<A NAME="RS12108ST-23B">23b</A> Czernecki S. Georgoulis C. Stevens CL. Vijayakumaran K. Tetrahedron Lett. 1985, 26: 1699

<A NAME="RS12108ST-24">24</A> Aydin F. Turunc E. J. Serb. Chem. Soc. 2007, 72: 129

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).

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.

<A NAME="RS12108ST-27">27</A> Zanatta N. Barichello R. Pauletto MM. Bonacorso HG. Martins MAP. Tetrahedron Lett. 2003, 44: 961

<A NAME="RS12108ST-28">28</A> Zanatta N. Schneider MFM. Schneider PH. Wouters AD. Bonacorso HG. Martins MAP. Wessjohann LA. J. Org. Chem. 2006, 71: 6996