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Article

A Mild and Facile One-Pot Synthesis of N-Methyl-3-Acyl-Pyrroles

by
Hassan Valizadeh
* and
Ashraf Fakhari
Department of Chemistry, Faculty of Sciences, Azarbaijan University of Tarbiat Moallem, Tabriz, Iran
*
Author to whom correspondence should be addressed.
Molecules 2010, 15(5), 2972-2979; https://doi.org/10.3390/molecules15052972
Submission received: 28 February 2010 / Revised: 23 March 2010 / Accepted: 18 April 2010 / Published: 27 April 2010
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Abstract

:
N-Methyl-3-acylpyrroles were synthesized via a multicomponent reaction of dimethylacetylene dicarboxylate (DMAD), N-methylhydroxylamine and acylchlorides in the presence of KHCO3. For comparison both conventional and microwave protocols were examined in this procedure. The reaction is clean and gives the products in good to excellent yields under conventional heating conditions at 40 ºC in anhydrous dichloromethane.

1. Introduction

Pyrrole is one of the most important heterocyclic compounds, having become increasingly important in medicinal chemistry and organic synthesis [1,2,3,4,5]. Some of the recently isolated pyrrole-containing marine natural products have been found to exhibit considerable cytotoxicity and function as multi drug resistant (MDR) reversal agents. Many of these biologically active compounds have emerged as chemotherapeutic agents [6]. Heterocyclic compounds containing a 3-acylpyrrole fragment are of interest for making new pharmacological preparations. For example, the cannabinoid activity of 1-alkyl-3-(naphthoyl)pyrroles [7] and 1-alkyl-3-(naphthoyl)indoles [8] is known, as is the antibiotic activity of verrucarin E (3-acetyl-4-hydroxymethylpyrrole) isolated from Myrothecium verrucaria [9]. 3-Acylpyrroles and other 3-substituted pyrroles obtained from them are precursors of liquid crystal materials [10] and polypyrroles [11], possessing high electrical conductivity in comparison with their 1-substituted analogs [12]. Such conjugated polymers may be used, for example, to construct gas sensors [13], and also sensors capable of distinguishing DNA molecules [14]. Many methods for the synthesis of diversely substituted pyrroles have been developed [15]. Conjugate addition reactions [16], transition metal-mediated reactions [17], reductive couplings [18], aza-Wittig reactions [19], and other multistep operations [20] have all been performed for the synthesis of pyrroles. Despite these huge developments, the Paal-Knorr [21] reaction is still considered to be the most attractive method for the synthesis of pyrroles. In the present work, we describe a simple method for the KHCO3-catalyzed synthesis of 3-acylpyrroles in good yields starting from commercially available DMAD, N-methylhydroxylamine and various acylchlorides.

2. Results and Discussion

Our research group has reported several studies directed toward the synthesis of some heterocyclic compounds under solvent-free conditions [22,23,24,25,26,27]. Because of the biological activities of pyrrole derivatives, we became interested in the one-pot synthesis of N-methyl-3-acylpyrroles under mild and solvent-free conditions.
Electrophilic substitution in pyrrole occurs predominantly at the C2-position [28,29,30]. Thus, the investigation of efficient methods for preparing C3-substituted pyrroles is one of the important goals in pyrrole chemistry because of their frequent use for obtaining various biologically active compounds like porphyrins. For the substitution on β-(C3) position, Friedel-Crafts acylation or alkylation on pyrrole bearing an electron withdrawing substituent at C2 [31,32] or N1 [33,34] has been widely investigated. Direct Friedel-Crafts acylation on 2,5-dimethylpyrrole also gives 3,4-symmetric acyl compounds, but normally the yields are very low ( < 5%) when no electron withdrawing groups are on the substituted pyrroles [18]. Very recently we prepared pentasubstituted pyrroles via the reaction of DMAD with N-methylhydroxylamine under mild solvent-free conditions, so we studied the possibility of synthesizing N-methyl-3-acylpyrroles 4a-e using a multicomponent reaction in anhydrous dichloromethane of DMAD (1), N-methylhydroxylamine (2) and various acylchlorides 3a-e in the presence of KHCO3 (Scheme 1).
Molecules 15 02972 g001 550
Scheme 1. One-pot synthesis of N-methyl-3-acylpyrroles.
Scheme 1. One-pot synthesis of N-methyl-3-acylpyrroles.
Molecules 15 02972 g001
We tried several different reaction conditions under microwave irradiation and conventional heating, and found that the reaction took place efficiently and in good yield at 40 ºC in CH2Cl2. Firstly, benzoyl chloride (3a) was chosen as a model for the reaction with DMAD and N-methylhydroxylamine to optimize reaction conditions. It was observed that a low yield of 4a was obtained in the absence of KHCO3 when the reaction was stirred at room temperature for 10 h. The reaction in the presence of the KHCO3 at room temperature in CH2Cl2, afforded the corresponding product in 61% yield (Table 1, entry 1). The reaction was also examined at 40 ºC and found to be faster and to give higher yield (81%) than at room temperature (Table 1, entry 2). The procedure was examined under microwave-assisted conditions and found that the yield of product was very low in comparison with conventional heating in anhydrous CH2Cl2 (Table 1, entries 7-8). In another experiment, for the same reaction, several common solvents were examined in the presence of KHCO3at 40 ºC. The results showed that the reaction in CH2Cl2 resulted in higher yields in comparison with the other tested solvents (Table 1, entries 2-5). There is no significant difference in the results using different bases such as Na2CO3, K2CO3, KHCO3, NH4OAc, NaOH, and NH4Cl as the catalyst in this procedure. The reaction of enamine, derived from addition of an N-methylhydroxylamine to DMAD, and benzoylchloride proceeds by a smooth 1:1:1 addition reaction in anhydrous dichloromethane at 40ºC to produce N-mehyl-3-benzoylpyrrole (4a) in 81% yield.
Table
Table 1. Study of the synthesis of 3-benzoylpyrrole 4a under different conditions.
Table 1. Study of the synthesis of 3-benzoylpyrrole 4a under different conditions.
EntrySolvent/Solid supportMode of heatingTemperature (ºC)Time (h)Yielda(%)
1CH2Cl2Conventional25361
2CH2Cl2Conventional402.581
3CHCl3Conventional40363
4DioxaneConventional402.560
5THFConventional402.563
6NeatConventional40353
7NeatMWNot detected10 min<30
8Basic aluminaMWNot detected10 min<30
a Isolated yields after column chromatography.
Having established the reaction conditions, various acyl chlorides were examined in this procedure to investigate the reaction scope, and several representative examples are summarized in Table 2. The reaction was clean and proceeded smoothly to give the corresponding 3-acylpyrroles in good to excellent yields. There were no remarkable differences in yields and reaction times between aromatic and aliphatic acyl halides in this procedure.
Table
Table 2. One-pot synthesis of 3-acylpyrroles.
Table 2. One-pot synthesis of 3-acylpyrroles.
EntryProductTime (h)Yielda(%)
14a2.581
24b383
34c373
44d3.578
54e2.576
a Isolated yields after column chromatography.
The structures of compounds 4a–4e were deduced from their elemental analyses and their IR, 1H- NMR, and 13C-NMR spectroscopic data and no side products were identified. For example, the 1H- NMR spectrum of 4a exhibited one singlet identified as the N-methyl moiety (δ 3.50), phenyl proton multiplets (δ 7.30, 3H and δ 7.41, 2H), along with multiplets [δ 7.51, 1H, δ 7.60, 1H and δ 7.81, 1H), for the pyrrole protons. The 1H-decoupled 13C-NMR spectrum of 4a showed 10 distinct resonances that confirm the proposed structure. The IR spectrum of 4a displayed a characteristic carbonyl (1,732 cm-1) stretching vibration.
Although the mechanistic details of the reaction are not known, a plausible rationalization may be advanced to explain the product formation. Presumably, the enamine 5 formed from N-methyl-hydroxylamine and DMAD attacked to acyl chloride to furnish intermediate 6, which is converted to intermediate 7. Subsequent reaction of 7 with DMAD yields intermediate 8, which undergoes an intramolecular cyclization reaction to generate 9. Finally, products 4a-e were formed from intermediate 9.
Molecules 15 02972 g002 550
Scheme 2. Plausible mechanism for the formation of the products 4a-e.
Scheme 2. Plausible mechanism for the formation of the products 4a-e.
Molecules 15 02972 g002

3. Experimental

3.1 General

All reagents were purchased from Merck and used without further purification. 1H- and 13C-NMR spectra were recorded on a Bruker Avance AC-400 MHz instrument using CDCl3 as the deuterated solvent and TMS as internal standard. Elemental analyses were carried out on a Perkin-Elmer 240C elemental analyzer and are reported in percent atomic abundance. All melting points are uncorrected and measured in open glass-capillaries using Stuart melting point apparatus. Microwave experiments were conducted in a Milestone MicroSYNTH apparatus.

3.2. General procedure for preparation of 3-acylpyrroles 4a-e

Dimethylacethylene dicarboxylate (2 mmol) was added to a stirred solution of N-methyhydroylamine hydrochloride (2 mmol) and KHCO3 (3 mmol) in anhydrous CH2Cl2 (10 mL). The mixture was stirred for 15 min, and then a solution of an acyl chloride (2 mmol) and dimethylacethylene dicarboxylate (2 mmol) in CH2Cl2 (5 mL) was added slowly at 40 ºC. After completion of the reaction (2.5–3.5 h) as indicated by TLC on silica gel F254 (n-hexane/EtOAc 6:1), the solvent from the reaction mixture was evaporated under reduced pressure to leave a residue that was purified by column chromatography (n-hexane/EtOAc 6:1) to afford pure desired products 4a-e.
N-Methyl-3-benzoyl pyrrole (4a): IR (KBr) (νmax, cm-1): 1732 (C=O); 1H-NMR δH (ppm): 7.81 (m, 1H), 7.60 (m, 1H), 7.51 (m, 1H), 7.41 (m, Ph-H, 2H), 7.30 (m, Ph-H, 3H), 3.50 (s, 3H, N-Me); 13C-NMR δC (ppm): 163.32, 133.14, 132.24, 129.92, 128.77, 127.62, 127.10, 126.84, 125.75, 36.24; Anal. Calcd (%) for C12H11NO: C, 77.81; H, 5.99; N, 7.56. Found (%): C, 77.90; H, 5.91; N, 7.48.
N-Methyl-3-acetyl pyrrole (4b): IR (KBr) (νmax, cm-1): 1727 (C=O); 1H-NMR δH (ppm): 7.75 (m, 1H), 7.48-7.55 (m, 2H), 3.53 (s, 3H, N-Me), 2.09 (s, 3H, COMe); 13C-NMR δC (ppm): 160.22, 131.33, 129.12, 126.12, 124.78, 33.45, 27.50; Anal. Calcd (%) for C7H9NO: C, 68.27; H, 7.37; N, 11.37. Found (%): C, 69.05; H, 7.29; N, 11.31.
N-Methyl-3-(4-chlorobenzoyl)-pyrrole (4c): IR (KBr) (νmax, cm-1): 1720 (C=O); 1H-NMR δH (ppm): 7.77 (m, 1H), 7.51-7.58 (m, 2H), 7.38 (d, J=7.56Hz, 2H), 7.31 (d, J=7.56Hz, 2H), 3.47 (s, 3H, N-Me); 13C-NMR δC (ppm): 164.56, 135.66, 134.32, 131.11, 129.32, 128.09, 127.99, 126.25, 126.15, 33.36; Anal. Calcd (%) for C12H10ClNO: C, 65.61; H, 4.59; N, 6.38. Found (%): C, 65.65; H, 4.53; N, 6.34.
N-Methyl-3-(2-methoxybenzoyl)-pyrrole (4d): IR (KBr) (νmax, cm-1): 1721 (C=O); 1H-NMR δH (ppm): 7.83 (m, 1H), 7.49-7.54 (m, 2H), 7.31-7.38 (m, Ph-H, 4H), 3.87 (s, 3H, OMe), 3.50 (s, 3H, N-Me); 13C-NMR δC (ppm): 162.21, 137.62, 136.54, 135.66, 134.10, 133.22, 132.20, 130.34, 129.79, 127.40, 126.15, 67.71, 34.16; Anal. Calcd (%) for C13H13NO2: C, 72.54; H, 6.09; N, 6.51. Found (%): C, 72.58; H, 5.98; N, 6.48.
N-Methyl-3-(4-nitrobenzoyl)-pyrrole (4e): IR (KBr) (νmax, cm-1): 1717 (C=O); 1H-NMR δH (ppm): 7.70 (m, 1H), 7.66 (d, J=7.87Hz, 2H), 7.45-7.53 (m, 2H), 7.37 (d, J=7.87Hz, 2H), 3.54 (s, 3H, N-Me); 13C-NMR δC (ppm): 160.06, 133.06, 133.02, 131.21, 129.70, 128.56, 127.65, 127.05, 126.55, 37.09; Anal. Calcd (%) for C12H10N2O3: C, 62.60; H, 4.38; N, 12.17. Found (%): C, 62.80; H, 4.35; N, 12.08.

4. Conclusions

In summary, we have described a highly efficient one-pot procedure for the preparation of N-methyl-3-acylpyrroles by a three component reaction in CH2Cl2 using KHCO3 as catalyst. The reaction products were prepared in moderate to good yield, even with different substituted acyl halides. We believe that this procedure provides a valuable addition to current methodologies.

Acknowledgements

The partial financial assistance from the Research Vice Chancellor of Azarbaijan University of Tarbiat Moallem is gratefully acknowledged.
  • Sample Availability: Samples of compounds 4a-e are available from the authors.

References and Notes

  1. Lehuedu, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou, A.; Vierfond, J.M. Synthesis and antioxidant activity of new tetraarylpyrroles. Eur. J. Med. Chem. 1999, 34, 991–996. [Google Scholar]
  2. Raimondi, M.V.; Cascioferro, S.; Schillaci, D.; Petruso, S. Synthesis and antimicrobial activity of new bromine-rich pyrrole derivatives related to monodeoxypyoluteorin. Eur. J. Med. Chem. 2006, 41, 1439–1445. [Google Scholar] [CrossRef]
  3. Cara, L.C.L.; Camacho, M.E.; Carrión, M.D.; Tapias, V.; Gallo, M.A.; Escames, G.; Acuña-Castroviejo, D.; Espinosa, A.; Entrena, A. Phenylpyrrole derivatives as neural and inducible nitric oxide synthase (nNOS and iNOS) inhibitors. Eur. J. Med. Chem. 2009, 44, 2655–2666. [Google Scholar] [CrossRef]
  4. Abu-Rabeah, K.; Marks, R.S. Impedance study of the hybrid molecule alginate–pyrrole: Demonstration as host matrix for the construction of a highly sensitive amperometric glucose biosensor. Sens. Actuat. B. Chem. 2009, 136, 516–522. [Google Scholar] [CrossRef]
  5. Liu, J.-H.; Yang, Q.-C.; Mak, T.C.W.; Wong, H.N.C. Highly regioselective synthesis of 2,3,4-trisubstituted 1H-pyrroles: A formal total synthesis of lukianol A. J. Org. Chem. 2000, 65, 3587–3595. [Google Scholar]
  6. Tao, H.; Hwang, I.; Boger, D.L. Multidrug resistance reversal activity of permethyl ningalin B amide derivatives. Bioorg. Med. Chem. Lett. 2004, 14, 5979–5981. [Google Scholar] [CrossRef]
  7. Lainton, A.H.; Huffman, J.W. 1-Alkyl-3-(1-naphthoyl)pyrroles: A new class of cannabinoid. Tetrahedron Lett. 1995, 36, 1401–1404. [Google Scholar] [CrossRef]
  8. Huffman, J.W.; Dai, D.; Martin, B.R.; Compton, D.R. Design, synthesis and pharmacology of cannabimimetic indoles. Bioorg. Med. Chem. Lett. 1994, 4, 563–566. [Google Scholar]
  9. Pfäffli, P.; Tamm, C. Revidierte struktur von verrucarin E. Eine synthese des antibioticums und verwandter β-acetyl-pyrrol-derivate. Verrucarine und roridine. Helv. Chim. Acta 1969, 52, 1911–1920. [Google Scholar] [CrossRef]
  10. Langley, P.J.; Davis, F.J.; Mitchell, G.R. Approaches to 1,1-disubstituted cinnolin-3-ylio oxides: synthesis and reactivity of a new class of heterocyclic betaines. J. Chem. Soc. Perkin. Trans. 1997, 2, 2229–2236. [Google Scholar]
  11. Ruhe, J.; Ezquerra, T.A.; Wegner, G. New conducting polymers from 3-alkylpyrroles. Synth Met. 1989, 28, 177–181. [Google Scholar]
  12. Delabouglise, D.; Roncali, J.; Lemaire, M.; Garnier, F. Control of the lipophilicity of polypyrrole by 3-alkyl substitution. J. Chem. Soc. Chem. Commun. 1989, 475–477. [Google Scholar]
  13. de Lacy Costello, B.P.J.; Evans, P.; Guernion, N.; Ratcliffe, N.M.; Sivanand, P.S.; Teare, G.C. The synthesis of a number of 3-alkyl and 3-carboxy substituted pyrroles; their chemical polymerisation onto poly(vinylidene fluoride) membranes, and their use as gas sensitive resistors. Synth. Met. 2000, 114, 181–188. [Google Scholar] [CrossRef]
  14. Garnier, F.; Korri-Youssoufi, H.; Srivastava, P.; Mandrand, B.; Delair, T. Toward intelligent polymers: DNA sensors based on oligonucleotide-functionalized polypyrroles. Synth Met. 1999, 100, 89–94. [Google Scholar]
  15. Gilchrist, T.L. Synthesis of aromatic heterocycles. J. Chem. Soc. Perkin. Trans. 1998, 1, 615–628. [Google Scholar] [CrossRef]
  16. Dieter, R.K.; Yu, H. A facile synthesis of polysubstituted pyrroles. Org. Lett. 2000, 2, 2283–2286. [Google Scholar] [CrossRef]
  17. Iwasawa, N.; Maeyama, K.; Saitou, M. Reactions of propargyl metallic species generated by the addition of alkynyllithiums to fischer-type carbene complexes. J. Am. Chem. Soc. 1997, 119, 1486–1487. [Google Scholar] [CrossRef]
  18. Furstner, A.; Weintritt, H.; Hupperts, A. A new, titanium-mediated approach to pyrroles: First synthesis of lukianol A and lamellarin O dimethyl ether. J. Org. Chem. 1995, 60, 6637–6641. [Google Scholar]
  19. Katritzky, A.; Jiang, J.; Steel, P.J. 1-Aza-1,3-bis(triphenylphosphoranylidene)propane: A Novel :CHCH2N: Synthon. J. Org. Chem. 1994, 59, 4551–4555. [Google Scholar] [CrossRef]
  20. Periasamy, M.; Srinivas, G.; Bharati, P. Conversion of aryl methyl ketimines to 2,5-diarylpyrroles using TiCl4/Et3N. J. Org. Chem. 1999, 64, 4204–4205. [Google Scholar] [CrossRef]
  21. Chen, J.; Wu, H.; Zheng, Z.; Jin, C.; Zhang, X.; Su, W. An approach to the Paal–Knorr pyrroles synthesis catalyzed by Sc(OTf)3 under solvent-free conditions. Tetrahedron Lett. 2006, 47, 5383–5387. [Google Scholar]
  22. Valizadeh, H.; Shockravi, A. An efficient procedure for the synthesis of coumarin derivatives using TiCl4 as catalyst under solvent-free conditions. Tetrahedron Lett. 2005, 46, 3501–3503. [Google Scholar] [CrossRef]
  23. Valizadeh, H.; Mamaghani, M.; Badrian, A. Effect of microwave irradiation on reaction of arylaldehyde derivatives with some active methylene compounds in aqueous media. Synth. Commun. 2005, 35, 785–790. [Google Scholar] [CrossRef]
  24. Valizadeh, H.; Vaghefi, H. One-pot Wittig and Knoevenagel reactions in ionic liquid as convenient methods for the synthesis of coumarin derivatives. Synth. Commun. 2009, 39, 1666–1678. [Google Scholar] [CrossRef]
  25. Shockravi, A.; Shargi, H.; Valizadeh, H.; Heravi, M.M. Solvent free synthesis of coumarins. Phosphorus, Sulfur, Silicon Relat. Elem. 2002, 177, 2555–2559. [Google Scholar]
  26. Valizadeh, H.; Amiri, M.; Gholipur, H. Efficient and convenient method for the synthesis of isoxazoles in ionic liquid. J. Heterocycl. Chem. 2009, 46, 108–110. [Google Scholar] [CrossRef]
  27. Valizadeh, H.; Heravi, M.M.; Amiri, M. Unexpected synthesis of N-methylbenzo[d]isoxazolium hydroxides under microwave irradiation conditions. Mol. Divers. 2009. [Google Scholar] [CrossRef]
  28. Jones, R.A. Advances in Heterocyclic Chemistry; Katritzky, A.R., Boulton, A.J., Eds.; Academic Press: New York, NY, USA, 1970; Volume 11, p. 383. [Google Scholar]
  29. Marino, G. Advances in Heterocyclic Chemistry; Katritzky, A.R., Boulton, A.J., Eds.; Academic Press: New York, NY, USA, 1970; Volume 13, p. 235. [Google Scholar]
  30. Bird, C.W.; Cheesman, G.W.H. Comprehensive Heterocyclic Chemistry; Katritzky, A., Ress, C.W., Eds.; Pergamon Press: Oxford, UK, 1984; Volume 4, p. 39. [Google Scholar]
  31. Cooper, G. Cyclopropyl 2-pyrrolyl ketone. J. Org. Chem. 1971, 36, 2897. [Google Scholar] [CrossRef]
  32. Tani, M.; Ariyasu, T.; Nishiyama, C.; Hagiwara, H.; Watanabe, T.; Yokoyama, Y.; Murakami, Y. β-Acylation of ethyl pyrrole-2-carboxylate by Friedel-Crafts acylation : Scope and limitations (synthetic studies on indoles and related compounds. XXXVIII). Chem. Pharm. Bull. 1996, 44, 48–54. [Google Scholar] [CrossRef]
  33. Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J. Regioselective synthesis of acylpyrroles. J. Org. Chem. 1983, 48, 3214–3219. [Google Scholar] [CrossRef]
  34. Anderson, H.J.; Loader, C.E.; Xu, R.X.; Le, N.; Gogan, N.J.; McDonald, R.; Edwards, L.G. Pyrrole chemistry. XXVIII. Substitution reactions of 1-(phenylsulfonyl)pyrrole and some derivatives. Can. J. Chem. 1985, 63, 896–902. [Google Scholar] [CrossRef]

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MDPI and ACS Style

Valizadeh, H.; Fakhari, A. A Mild and Facile One-Pot Synthesis of N-Methyl-3-Acyl-Pyrroles. Molecules 2010, 15, 2972-2979. https://doi.org/10.3390/molecules15052972

AMA Style

Valizadeh H, Fakhari A. A Mild and Facile One-Pot Synthesis of N-Methyl-3-Acyl-Pyrroles. Molecules. 2010; 15(5):2972-2979. https://doi.org/10.3390/molecules15052972

Chicago/Turabian Style

Valizadeh, Hassan, and Ashraf Fakhari. 2010. "A Mild and Facile One-Pot Synthesis of N-Methyl-3-Acyl-Pyrroles" Molecules 15, no. 5: 2972-2979. https://doi.org/10.3390/molecules15052972

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