Synthesis of Pyrroles and Thiazolanes Promoted by N-Methylimidazole in Water

Abstract

A convenient and efficient approach to the synthesis of substituted pyrroles is reported based on three-component reaction of primary amines and alkyl propiolates in the presence of N-methyl­imidazole in water. A water-accelerated synthesis of thiazolane derivatives has also been established by employing the three-component reaction of primary amines, alkyl propiolates, and isothiocyanates in the presence of N-methylimidazole.

Increasing emphasis is being placed on the development of mild and green methodology to minimize waste and byproducts[1] and to prepare novel structures,[2] with the pharmaceutical industry being an important potential beneficiary.[3] Multicomponent reactions (MCR) have been ‎developed to create targets from bifunctional substrates that react ‎intramolecularly.[4] Five-membered, nitrogen-containing heterocycles are the principal building blocks in a wide number of biologically active structures.[5] Of these, ‎pyrroles are highly significant, occurring as structural subunits in natural ‎products such as heme, chlorophyl, vitamin B₁₂, and the cytochromes.[6] Recently, isolated pyrrole-containing marine natural products have been demonstrated to show substantial cytotoxicity and utility as agents against multidrug resistance.[7] Pyrroles also occupy a central position in materials ‎science[8] and have been used as antioxidants, as well as antibacterial, ionotropic, antitumor, ‎anti-inflammatory, and antifungal agents.[9] [10] [11] [12] [13] [14]

While there are many methods for the synthesis of pyrrole compounds,[15] [16] [17] [18] [19] [20] there is always scope for new methodology. As part of our studies on the expansion of new ways in heterocyclic synthesis, we describe herein the reaction of propiolates 1 and primary amines 2 in the presence of N-methylimidazole (3) to produce pyrrole derivatives of 4 in good yield (Table [1]).[21]

The structures of compounds 4a–f were assigned by IR, ¹H NMR, ¹³C NMR spectroscopic and mass spectrometric analysis. For example, the ¹H NMR spectrum of 4a exhibited one singlet for two methoxy protons at δ = 3.78 ppm, one singlet for NMe protons at δ = 3.58 ppm and one singlet for two methine groups at δ = 6.92 ppm. The ¹³C NMR spectrum exhibited nine distinct resonances which further confirmed the proposed structure of 4a. The IR spectrum of 4a displayed characteristic C=O bands. The mass spectrum displayed the appropriate molecular ion.

Table 1 Three-component reactions for the synthesis of pyrrole derivatives in water

Entry	Compd 1, 2, 4	R1	R2	Yield of 4 (%)
1	a	Me	Me	92
2	b	Me	Et	87
3	c	Me	n-Bu	85
4	d	Et	Me	80
5	e	Et	4-MeBn	78
6	f	Me	4-MeOBn	83

Presumably, the zwitterionic intermediate 6, formed from N-methylimidazole (X₃N) and alkyl propiolate 1, is generated in situ from primary amine 2 and alkylpropiolate 1. Proton transfer from 5 to 6 then leads to intermediates 7 and 8. Nucleophilic addition of the conjugate base of 7 to intermediate 8 leads to adduct 9, which undergoes two proton shifts to afford a new zwitterionic intermediate 10. After this, intramolecular cyclization reaction and loss of the N-methylimidazole group affords compound 11 that undergoes oxidative aromatization to give 4 (Scheme [1]).

Another class of five-membered heterocycles, the thiazoles, find use in agrochemicals,[22] and thiazole-based drugs have been developed for anti-inflammatory,[23] [24] antitumor,[25] antihyperlipidemic,[26] antihypertensive,[27] anti-HIV,[28] and other properties.[29] [30]

Thus, under similar conditions as for the pyrrole synthesis, we have employed the three-component reaction between alkyl propiolates, primary amines, and isothiocyanates in the presence of a catalytic amount of N-methylimidazole in water at room temperature to generate thiazolane derivatives 13 [31] in good yields (Table [2]).[32] [33]

Table 2 Three-component reaction for the synthesis of thiazolanes in water

Entry	Compd 1, 2, 12, 13	R1	R2	R3	Yield of 13 (%)
1	a	Me	Me	Ph	75
2	b	Me	Et	4-MeOC6H4	87
3	c	Et	n-Bu	4-MeOC6H4	70
4	d	Et	t-Bu	4-MeC6H4	75
5	e	Me	t-Bu	Ph	80

The structures of compounds 13a–e were apparently from the ¹H NMR, ¹³C NMR, and IR spectra which were in agreement with the proposed structures. For example, the ¹H NMR spectrum of 13a displayed two singlets for the NMe protons at δ = 3.24 ppm, the MeO protons appeared as a singlet at δ = 3.75 ppm, and the CH₂ and CH protons appeared as three double doublets at δ = 3.78 ppm, 4.12 ppm, and 4.78 ppm, respectively. The C=N and carbonyl-group resonances in the ¹³C NMR spectra of 13a appeared at δ = 163.2 (C=N) and 172.5 (C=O) ppm, and the mass spectrum displayed the appropriate molecular ion.

In summary, we report a reaction involving alkyl propiolates and primary amines in the presence of catalytic amount of N-methylimidazole at 50 °C in water which affords a new route for the synthesis of functionalized pyrroles. By extending this 3-MCR, we found that the reaction of alkyl propiolates with isothiocyanates and primary amines in the presence of a of N-methylimidazole similarly leads to formation of the thiazolanes.

Acknowledgment

We gratefully acknowledge support from the Gonbad Kavous University.

• References and Notes

• 1 Anastas P, Williamson T. Green Chemistry, Frontiers in Benign Chemical Synthesis and Procedures . Oxford Science Publications; New York: 1998
  Search in Google Scholar
• 2 Cave GW. V, Raston CL, Scott JL. Chem. Commun. 2001; 2159
• 3 Sheldon RA. Chem. Ind. 1997; 12‎
• 4 Multicomponent Reactions . Zhu J, Bienayme H. Wiley-VCH; Weinheim: 2005
  CrossrefSearch in Google Scholar
• 5 Torok M, Abid M, Mhadgut SC, Torok B. Biochemistry 2006; 45: 5377
  CrossrefSearch in Google Scholar
• 6 Sundberg RJ In Comprehensive Heterocyclic Chemistry . Katritzky A, Rees CW, Scriven EF. V. Pergamon; Oxford: 1996
  Search in Google Scholar
• 7 Tao H, Hwang I, Boger DL. Bioorg. Med. Chem. Lett. 2004; 14: 5979‎
  CrossrefSearch in Google Scholar
• 8 Baumgarten M, Tyutyulkov N. Chem. Eur. J. 1998; 4: 987
  CrossrefSearch in Google Scholar
• 9 Lehuede J, Fauconneau B, Barrier L, Ourakow M, Piriou A, Vierfond JM. Eur. J. Med. Chem. 1999; 34: 991
  CrossrefPubMedSearch in Google Scholar
• 10 Burli RW, Jones P, McMinn D, Le Q, Duan JX, Kaizerman JA, Difuntorum S, Moser HE. Bioorg. Med. Chem. Lett. 2004; 14: 1259
  CrossrefSearch in Google Scholar
• 11 Jonas R, Klockow M, Lues I, Pruecher H, Schliep HJ, Wurziger H. Eur. J. Med. Chem. 1993; 28: 129
  CrossrefSearch in Google Scholar
• 12 Denny WA, Rewcastle GW, Baguley BC. J. Med. Chem. 1990; 33: 814
  CrossrefPubMedSearch in Google Scholar
• 13 Demopoulos VJ, Rekka E. J. Pharm. Sci. 1995; 84: 79
  CrossrefSearch in Google Scholar
• 14 Del Poeta M, Schell WA, Dykstra CC, Jones S, Tidwell RR, Czarny A, Bajic M, Kumar A, Boykin D, Perfect JR. Antimicrob. Agents Chemother. 1998; 42: 2495
  Search in Google Scholar
• 15 Khlebnikov AF, Golovkina MV, Novikov MS, Yufit DS. Org. Lett. 2012; 14: 3768
  Search in Google Scholar
• 16 Das B, Reddy GC, Balasubramanyan P, Veeranjaneyulu B. Synthesis 2010; 1625
  Thieme Connect
• 17 Liu W, Jiang H, Huang L. Org. Lett. 2010; 12: 312
  CrossrefPubMedSearch in Google Scholar
• 18 Morin MS. T, Arndtsen BA. Org. Lett. 2010; 12: 4916
  CrossrefPubMedSearch in Google Scholar
• 19 Herath A, Cosford ND. P. Org. Lett. 2010; 12: 5182
  CrossrefSearch in Google Scholar
• 20 Ciez D. Org. Lett. 2009; 11: 4282
  CrossrefSearch in Google Scholar
• 21 General Procedure for the Preparation of Compounds 4 To a stirred mixture of alkyl propiolate 1 (2 mmol) and primary amine 2 (2 mmol) in H₂O (5 mL) was added a mixture of alkyl propiolate 1 and N-methylimidazole (3, 5 mol%) in H₂O (5 mL). The reaction mixture was then stirred for 1.5 h at 50 °C. After completion of the reaction (1.5 h; TLC; EtOAc–hexane = 1:4), the solid residue was filtered and washed with cold Et₂O to give pure product 4. Dimethyl 1-Methyl-1H-pyrrole-3,4-dicarboxylate (4a) Pale yellow powder, yield 0.36 g (92%). IR (KBr): 1735, 1729, 1587, 1435, 1295, 1126 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.58 (3 H, s, NMe), 3.78 (6 H, s, 2 MeO), 6.92 (2 H, s, 2 CH) ppm. ¹³C NMR(125.7 MHz, CDCl₃): δ = 35.8 (NMe), 51.8 (2 MeO), 137.2 (2 C), 138.3 (2 CH), 165.4 (2 C=O) ppm. MS (EI): m/z (%) = 197 (15) [M⁺], 135 (85), 79 (64), 31 (100). Anal. Calcd for C₉H₁₁NO₄ (197.19): C, 54.82; H, 5.62; N, 7.10. Found: C, 54.93; H, 5.74; N, 7.22.
• 22 Breslow R. J. Am. Chem. Soc. 1958; 80: 3719
  Search in Google Scholar
• 23 Miwatashi S, Arikawa Y, Kotani E, Miyamoto M, Naruo KI, Kimura H, Tanaka T, Asahi S, Ohkawa S. J. Med. Chem. 2005; 48: 5966
  CrossrefSearch in Google Scholar
• 24 Papadopoulou C, Geronikaki A, Hadjipavlou-Litina D. Il Farmaco 2005; 60: 969
  CrossrefSearch in Google Scholar
• 25 Kumar Y, Green R, Borysko KZ, Wise DS, Wotring LL, Townsend LB. J. Med. Chem. 1993; 36: 3843
  CrossrefSearch in Google Scholar
• 26 Pereira R, Gaudon C, Iglesias B, Germain P, Gronemeyer H, de Lera AR. Bioorg. Med. Chem. Lett. 2006; 16: 49
  CrossrefSearch in Google Scholar
• 27 Tsurumi Y, Ueda H, Hayashi K, Takase S, Nishikawa M, Kiyoto S, Okuhara M. J. Antibiot. 1995; 48: 1066
  CrossrefSearch in Google Scholar
• 28 Bell FW, Cantrell AS, Hoberg M, Jaskunas SR, Johansson NG, Jordon CL, Kinnick MD, Lind P, Morin JM. J. Med. Chem. 1995; 38: 4929
  CrossrefPubMedSearch in Google Scholar
• 29 Millan DS, Prager RH, Brand C, Hart PH. Tetrahedron 2000; 56: 811
  CrossrefSearch in Google Scholar
• 30 Wang WL, Yao DY, Gu M, Fan MZ, Li JY, Xing YC, Nan FJ. Bioorg. Med. Chem. Lett. 2005; 15: 5284
  CrossrefSearch in Google Scholar
• 31 Hossaini Z, Rostami-Charati F, Eslami Moghadam M, Moghaddasi-Kochaksaraee F. Chin. Chem. Lett. 2014; 25: 794
  CrossrefSearch in Google Scholar
• 32 General Procedure for the Preparation of Compounds 13 To a magnetically stirred mixture of acetylene 1 (2 mmol) and N-methylimidazole (3, 5 mol%) in H₂O (5 mL) was added a mixture of isothiocyanate 12 and primary amine 2 (2 mmol) in H₂O (5mL) at r.t. The reaction mixture was then stirred. After the completion of the reaction (6 h; TLC; EtOAc–hexane = 1:7), the solid residue was filtered and washed with cold Et₂O to afforded pure compounds 13. Methyl 2-(Methylimino)-1,3-thiazolane-5-dicarboxylate (13a) Yellow powder, mp 164–166 °C, yield 0.26 g (75%). IR (KBr) ν_max = 1738, 1567, 1456, 1385, 1257 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.24 (3 H, s, NMe), 3.75 (3 H, s, MeO), 3.87 (1 H, dd, ² J _HH = 16 Hz, ³ J _HH = 7 Hz, CH), 4.12 (1 H, dd, ² J _HH =16 Hz, ³ J _HH = 3 Hz, CH), 4.78 (1 H, dd, ³ J _HH = 7 Hz ³ J _HH = 3 Hz, CH), 6.14 (1 H, br, NH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 35.8 (NMe), 39.4 (CH), 47.5 (CH₂), 52.4 (MeO), 163.2 (C=N), 172.5 (C=O) ppm. MS: m/z (%) = 174 (15) [M⁺], 143 (84), 31 (100). Anal. Calcd (%) for C₆H₁₀N₂O₂S (174.22): C, 41.36; H, 5.79; N, 16.08. Found: C, 41.24; H, 5.62; N, 15.96.
• 33 Yavari I, Souri S, Sirouspour M. Synlett 2008; 1633
  Thieme Connect

• References and Notes

• 1 Anastas P, Williamson T. Green Chemistry, Frontiers in Benign Chemical Synthesis and Procedures . Oxford Science Publications; New York: 1998
  Search in Google Scholar
• 2 Cave GW. V, Raston CL, Scott JL. Chem. Commun. 2001; 2159
• 3 Sheldon RA. Chem. Ind. 1997; 12‎
• 4 Multicomponent Reactions . Zhu J, Bienayme H. Wiley-VCH; Weinheim: 2005
  CrossrefSearch in Google Scholar
• 5 Torok M, Abid M, Mhadgut SC, Torok B. Biochemistry 2006; 45: 5377
  CrossrefSearch in Google Scholar
• 6 Sundberg RJ In Comprehensive Heterocyclic Chemistry . Katritzky A, Rees CW, Scriven EF. V. Pergamon; Oxford: 1996
  Search in Google Scholar
• 7 Tao H, Hwang I, Boger DL. Bioorg. Med. Chem. Lett. 2004; 14: 5979‎
  CrossrefSearch in Google Scholar
• 8 Baumgarten M, Tyutyulkov N. Chem. Eur. J. 1998; 4: 987
  CrossrefSearch in Google Scholar
• 9 Lehuede J, Fauconneau B, Barrier L, Ourakow M, Piriou A, Vierfond JM. Eur. J. Med. Chem. 1999; 34: 991
  CrossrefPubMedSearch in Google Scholar
• 10 Burli RW, Jones P, McMinn D, Le Q, Duan JX, Kaizerman JA, Difuntorum S, Moser HE. Bioorg. Med. Chem. Lett. 2004; 14: 1259
  CrossrefSearch in Google Scholar
• 11 Jonas R, Klockow M, Lues I, Pruecher H, Schliep HJ, Wurziger H. Eur. J. Med. Chem. 1993; 28: 129
  CrossrefSearch in Google Scholar
• 12 Denny WA, Rewcastle GW, Baguley BC. J. Med. Chem. 1990; 33: 814
  CrossrefPubMedSearch in Google Scholar
• 13 Demopoulos VJ, Rekka E. J. Pharm. Sci. 1995; 84: 79
  CrossrefSearch in Google Scholar
• 14 Del Poeta M, Schell WA, Dykstra CC, Jones S, Tidwell RR, Czarny A, Bajic M, Kumar A, Boykin D, Perfect JR. Antimicrob. Agents Chemother. 1998; 42: 2495
  Search in Google Scholar
• 15 Khlebnikov AF, Golovkina MV, Novikov MS, Yufit DS. Org. Lett. 2012; 14: 3768
  Search in Google Scholar
• 16 Das B, Reddy GC, Balasubramanyan P, Veeranjaneyulu B. Synthesis 2010; 1625
  Thieme Connect
• 17 Liu W, Jiang H, Huang L. Org. Lett. 2010; 12: 312
  CrossrefPubMedSearch in Google Scholar
• 18 Morin MS. T, Arndtsen BA. Org. Lett. 2010; 12: 4916
  CrossrefPubMedSearch in Google Scholar
• 19 Herath A, Cosford ND. P. Org. Lett. 2010; 12: 5182
  CrossrefSearch in Google Scholar
• 20 Ciez D. Org. Lett. 2009; 11: 4282
  CrossrefSearch in Google Scholar
• 21 General Procedure for the Preparation of Compounds 4 To a stirred mixture of alkyl propiolate 1 (2 mmol) and primary amine 2 (2 mmol) in H₂O (5 mL) was added a mixture of alkyl propiolate 1 and N-methylimidazole (3, 5 mol%) in H₂O (5 mL). The reaction mixture was then stirred for 1.5 h at 50 °C. After completion of the reaction (1.5 h; TLC; EtOAc–hexane = 1:4), the solid residue was filtered and washed with cold Et₂O to give pure product 4. Dimethyl 1-Methyl-1H-pyrrole-3,4-dicarboxylate (4a) Pale yellow powder, yield 0.36 g (92%). IR (KBr): 1735, 1729, 1587, 1435, 1295, 1126 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.58 (3 H, s, NMe), 3.78 (6 H, s, 2 MeO), 6.92 (2 H, s, 2 CH) ppm. ¹³C NMR(125.7 MHz, CDCl₃): δ = 35.8 (NMe), 51.8 (2 MeO), 137.2 (2 C), 138.3 (2 CH), 165.4 (2 C=O) ppm. MS (EI): m/z (%) = 197 (15) [M⁺], 135 (85), 79 (64), 31 (100). Anal. Calcd for C₉H₁₁NO₄ (197.19): C, 54.82; H, 5.62; N, 7.10. Found: C, 54.93; H, 5.74; N, 7.22.
• 22 Breslow R. J. Am. Chem. Soc. 1958; 80: 3719
  Search in Google Scholar
• 23 Miwatashi S, Arikawa Y, Kotani E, Miyamoto M, Naruo KI, Kimura H, Tanaka T, Asahi S, Ohkawa S. J. Med. Chem. 2005; 48: 5966
  CrossrefSearch in Google Scholar
• 24 Papadopoulou C, Geronikaki A, Hadjipavlou-Litina D. Il Farmaco 2005; 60: 969
  CrossrefSearch in Google Scholar
• 25 Kumar Y, Green R, Borysko KZ, Wise DS, Wotring LL, Townsend LB. J. Med. Chem. 1993; 36: 3843
  CrossrefSearch in Google Scholar
• 26 Pereira R, Gaudon C, Iglesias B, Germain P, Gronemeyer H, de Lera AR. Bioorg. Med. Chem. Lett. 2006; 16: 49
  CrossrefSearch in Google Scholar
• 27 Tsurumi Y, Ueda H, Hayashi K, Takase S, Nishikawa M, Kiyoto S, Okuhara M. J. Antibiot. 1995; 48: 1066
  CrossrefSearch in Google Scholar
• 28 Bell FW, Cantrell AS, Hoberg M, Jaskunas SR, Johansson NG, Jordon CL, Kinnick MD, Lind P, Morin JM. J. Med. Chem. 1995; 38: 4929
  CrossrefPubMedSearch in Google Scholar
• 29 Millan DS, Prager RH, Brand C, Hart PH. Tetrahedron 2000; 56: 811
  CrossrefSearch in Google Scholar
• 30 Wang WL, Yao DY, Gu M, Fan MZ, Li JY, Xing YC, Nan FJ. Bioorg. Med. Chem. Lett. 2005; 15: 5284
  CrossrefSearch in Google Scholar
• 31 Hossaini Z, Rostami-Charati F, Eslami Moghadam M, Moghaddasi-Kochaksaraee F. Chin. Chem. Lett. 2014; 25: 794
  CrossrefSearch in Google Scholar
• 32 General Procedure for the Preparation of Compounds 13 To a magnetically stirred mixture of acetylene 1 (2 mmol) and N-methylimidazole (3, 5 mol%) in H₂O (5 mL) was added a mixture of isothiocyanate 12 and primary amine 2 (2 mmol) in H₂O (5mL) at r.t. The reaction mixture was then stirred. After the completion of the reaction (6 h; TLC; EtOAc–hexane = 1:7), the solid residue was filtered and washed with cold Et₂O to afforded pure compounds 13. Methyl 2-(Methylimino)-1,3-thiazolane-5-dicarboxylate (13a) Yellow powder, mp 164–166 °C, yield 0.26 g (75%). IR (KBr) ν_max = 1738, 1567, 1456, 1385, 1257 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.24 (3 H, s, NMe), 3.75 (3 H, s, MeO), 3.87 (1 H, dd, ² J _HH = 16 Hz, ³ J _HH = 7 Hz, CH), 4.12 (1 H, dd, ² J _HH =16 Hz, ³ J _HH = 3 Hz, CH), 4.78 (1 H, dd, ³ J _HH = 7 Hz ³ J _HH = 3 Hz, CH), 6.14 (1 H, br, NH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 35.8 (NMe), 39.4 (CH), 47.5 (CH₂), 52.4 (MeO), 163.2 (C=N), 172.5 (C=O) ppm. MS: m/z (%) = 174 (15) [M⁺], 143 (84), 31 (100). Anal. Calcd (%) for C₆H₁₀N₂O₂S (174.22): C, 41.36; H, 5.79; N, 16.08. Found: C, 41.24; H, 5.62; N, 15.96.
• 33 Yavari I, Souri S, Sirouspour M. Synlett 2008; 1633
  Thieme Connect