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.

Pyrroles may demonstrate diverse biological properties such as antibacterial, antiviral, anti-inflammatory, antitumor, and antioxidant activities.[1] In addition, they have been used as useful intermediates in the synthesis of natural products[2] and in materials science.[3] There are important differences in properties of fluorinated analogues and the large number of publications and the high percentage of new fluorinated molecules underline the importance of this field of research.[4] At the present time, at least one fluorine atom is present in around 20% of pharmaceuticals, and 30–40% of agrochemicals.[4b] [5] With the exception of monofluorinated molecules, compounds that contain trifluoromethyl groups, especially at aromatic positions, play an important role in the design of new potential drugs and crop-protection agents.[6] The trifluoromethyl group is becoming more and more important in both of agrochemical[7] and pharmaceutical applications[8] because of the influence of fluorination on physical, chemical, and physiological properties, stability and lipophilicity of the molecule.[9] Furthermore, it has found that use of trifluoromethylated chromophores in the dye industry leads to increased light fastness[8] [9] and trifluoromethylated polymers exhibit high thermal stability and enhanced mechanical and electrical properties.[10] [11]

In 2014 we reported a new method for synthesis of trifluoromethylated tetrazoles by using N-aryl-2,2,2- trifluoroacetimidoyl chlorides as trifluoromethylating agents.[12] As part of an ongoing project to develop new synthetic methods for the preparation of trifluoromethylated heterocycles, we have focused on the synthesis of trifluoromethylated pyrroles. Herein we wish to report a new method for the synthesis of 5-(trifluoromethyl)-1H-pyrroles based on the three-component reaction of trifluoromethylimidoyl chlorides with the isocyanide–DMAD zwitter ion in dichloromethane in the absence of catalyst (Scheme [1]).

The trifluoromethylimidoyl chlorides were prepared according to the reported procedures[13] [14] in which a primary aromatic amine was added to a mixture of trifluoroacetic acid, triethylamine, and triphenylphosphine in carbon tetrachloride under reflux conditions. In a typical experiment, a solution of isocyanide 1a and trifluoromethylimidoyl chloride 2a in dry dichloromethane was treated with DMAD solution in dry dichloromethane at room temperature. After completion of the reaction, as indicated by TLC, the solvent was removed under reduced pressure and the residue was subjected to column chromatography to yield 3b [15] in 70% yield (Scheme [2]).

The structure of 3b was determined on the basis of its elemental analysis, ¹H NMR, ¹³C NMR, ¹⁹F NMR, and IR spectroscopic data. The IR spectrum of 3a displayed characteristic ester carbonyl and N–H absorptions at 1752, 1667, and 3473 cm^–1, respectively. The ¹H NMR spectrum of 3b exhibited two singlets corresponding to the aromatic protons (δ = 7.80 and 7.89 ppm), and two three-proton singlets corresponding to the methoxy groups (δ = 3.93 and 3.97), along with multiplets (δ = 3.82–3.85 and 1.16–1.64 ppm) for the cyclohexyl protons. The NH proton resonance at δ = 3.33 ppm disappeared after addition of D₂O. The ¹⁹F NMR spectrum of 3b showed two signals at δ = –63.03 and –55.33 ppm corresponding to the CF₃ groups.

We next explored the protocol with a variety of acetimidoyl chlorides, acetylene dicarboxylates, and isocyanides and the outcomes are listed in Table [1]. Acetimidoyl chlorides with electron-donating as well as electron-withdrawing groups on the aromatic ring reacted smoothly.

Table 1 Synthesis of 5-(Trifluoromethyl-1H-pyrrole Derivatives 3a–i

Entry	R1	R2	R3	Product
1	t-Bu	Me	3-CF3	3a
2	c-Hex	Me	3,5-CF3	3b
3	c-Hex	Me	4-F-3-NO2	3c
4	c-Hex	Me	2-CN	3d
5	t-Bu	Et	4-Cl	3e
6	t-Bu	Et	4-F-3-NO2	3f
7	c-Hex	Me	4-NO2	3g
8	c-Hex	Me	4-Cl	3h
9	c-Hex	Me	3-CF3	3i

A plausible mechanism is proposed in Scheme [3]. Firstly, the isocyanide undergoes nucleophilic addition to DAAD to produce zwitterion I. Then nucleophilic addition of the isocyanide–DMAD zwitterion to the imidoyl carbon leads to the formation of the intermediate II. Cyclization yields III, followed by elimination of chlorine, conceivably by attack of excess isocyanide present in the system as a nucleophile to yield pyrrole IV, which is protonated to give product V.

In conclusion, we have found a simple and efficient method for the synthesis of a new class of highly functionalized pyrrole containing a trifluoromethyl group at position 5. The reaction is performed under neutral and catalyst-free conditions.

No conflict of interest has been declared by the author(s).

Acknowledgment

We gratefully acknowledge the Vail-e-Asr University of Rafsanjan Faculty Research Grant for financial support.

• References and Notes

• 1a Jacobi PA, Coults LD, Guo JS, Leung SI. J. Org. Chem. 2000; 65: 205-205
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• 1b Fürstner A. Angew. Chem. 2003; 115: 3706-3706
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• 2 Boger DL, Boyce CW, Labrili MA, Sehon CA, Jin Q. J. Am. Chem. Soc. 1999; 121: 54-54
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• 3a Groenendaal L, Meijer EW, Vekemans JA. J. M. In Electronic Materials: The Oligomer Approach. Müllen K, Wegner G. Wiley-VCH; Weinheim: 1997
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• 3b Domingo VM, Aleman C, Brillas E, Julia L. J. Org. Chem. 2001; 66: 4058-4058
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• 4a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881-1881
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• 4b Kirsch P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity and Applications. Wiley-VCH; Weinheim: 2004
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• 4c Hiyama T. Organofluorine Compounds: Chemistry and Applications. Springer; Berlin: 2000
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• 5a Large S, Roques N, Langlois BR. J. Org. Chem. 2000; 65: 8848-8848
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• 5b Thayer A. Chem. Eng. News 2006; 23: 15-15
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• 6 Wiehn MS, Vinogradova EV, Togni A. J. Fluorine Chem. 2010; 131: 951-951
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• 7a Filler R, Kobayashi Y. Biomedicinal Aspects of Fluorine Chemistry . Kodansha; Tokyo: 1982
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• 7b Kumadaki I. J. Synth. Org. Chem., Jpn. 1984; 42: 786-786
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• 7c Welch JT. Tetrahedron 1987; 43: 3123-3123
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• 7d Welch JT, Eswarakrishnan S. Fluorine in Bioorganic Chemistry . John Wiley and Sons; New York: 1991
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• 7e Filler R, Kobayashi Y, Yagupolskii LM. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications. Elsevier; Amsterdam: 1993
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• 8 Yoshika H, Nakayama C, Matsuo N. J. Synth. Org. Chem., Jpn. 1984; 42: 809-809
  CrossrefSearch in Google Scholar
• 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
  Search in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 12 Rahmani F, Darehkordi A, Notash B. J. Fluorine Chem. 2014; 31: 84-84
  Search in Google Scholar
• 13 Darehkordi A, Khabazzadeh H, Saidi K. J. Fluorine Chem. 2005; 126: 1140-1140
  CrossrefSearch in Google Scholar
• 14 Tamura K, Mizukami H, Maeda K, Watanabe H, Uneyama K. J. Org. Chem. 1993; 58: 32-32
  CrossrefSearch in Google Scholar
• 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.

• References and Notes

• 1a Jacobi PA, Coults LD, Guo JS, Leung SI. J. Org. Chem. 2000; 65: 205-205
  CrossrefPubMedSearch in Google Scholar
• 1b Fürstner A. Angew. Chem. 2003; 115: 3706-3706
  CrossrefSearch in Google Scholar
• 2 Boger DL, Boyce CW, Labrili MA, Sehon CA, Jin Q. J. Am. Chem. Soc. 1999; 121: 54-54
  CrossrefSearch in Google Scholar
• 3a Groenendaal L, Meijer EW, Vekemans JA. J. M. In Electronic Materials: The Oligomer Approach. Müllen K, Wegner G. Wiley-VCH; Weinheim: 1997
  Search in Google Scholar
• 3b Domingo VM, Aleman C, Brillas E, Julia L. J. Org. Chem. 2001; 66: 4058-4058
  CrossrefPubMedSearch in Google Scholar
• 4a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881-1881
  CrossrefPubMedSearch in Google Scholar
• 4b Kirsch P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity and Applications. Wiley-VCH; Weinheim: 2004
  Search in Google Scholar
• 4c Hiyama T. Organofluorine Compounds: Chemistry and Applications. Springer; Berlin: 2000
  Search in Google Scholar
• 5a Large S, Roques N, Langlois BR. J. Org. Chem. 2000; 65: 8848-8848
  CrossrefPubMedSearch in Google Scholar
• 5b Thayer A. Chem. Eng. News 2006; 23: 15-15
  Search in Google Scholar
• 6 Wiehn MS, Vinogradova EV, Togni A. J. Fluorine Chem. 2010; 131: 951-951
  CrossrefSearch in Google Scholar
• 7a Filler R, Kobayashi Y. Biomedicinal Aspects of Fluorine Chemistry . Kodansha; Tokyo: 1982
  Search in Google Scholar
• 7b Kumadaki I. J. Synth. Org. Chem., Jpn. 1984; 42: 786-786
  CrossrefSearch in Google Scholar
• 7c Welch JT. Tetrahedron 1987; 43: 3123-3123
  CrossrefSearch in Google Scholar
• 7d Welch JT, Eswarakrishnan S. Fluorine in Bioorganic Chemistry . John Wiley and Sons; New York: 1991
  Search in Google Scholar
• 7e Filler R, Kobayashi Y, Yagupolskii LM. Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications. Elsevier; Amsterdam: 1993
  Search in Google Scholar
• 8 Yoshika H, Nakayama C, Matsuo N. J. Synth. Org. Chem., Jpn. 1984; 42: 809-809
  CrossrefSearch in Google Scholar
• 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
  Search in Google Scholar
• 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
  CrossrefSearch in Google Scholar
• 12 Rahmani F, Darehkordi A, Notash B. J. Fluorine Chem. 2014; 31: 84-84
  Search in Google Scholar
• 13 Darehkordi A, Khabazzadeh H, Saidi K. J. Fluorine Chem. 2005; 126: 1140-1140
  CrossrefSearch in Google Scholar
• 14 Tamura K, Mizukami H, Maeda K, Watanabe H, Uneyama K. J. Org. Chem. 1993; 58: 32-32
  CrossrefSearch in Google Scholar
• 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.

• Supplementary Material