Microwave-Assisted Addition of Pyrroles to Electron-Deficient Olefins: A Rapid Entry to C-Alkyl Pyrroles

Abstract

A general procedure for the Michael addition of pyrroles with electron-deficient olefins using silica gel supported reagent under microwave irradiation, has been developed. This new method is fast, efficient, environmentally benign and solvent-free. A catalytic amount of BiCl₃ is employed for moderately bulk electron-deficient olefins.

Key words

microwave irradiation - bismuth trichloride - pyrroles - electron-deficient olefins - Michael reaction

References

• 1a Sundberg RD. Pyrroles and their Benzo Derivatives: Synthesis and Applications, In Comprehensive Heterocyclic Chemistry   Vol. 4:  Katrizky AR. Rees CW. Pergamon; Oxford: 1984.  p.313-376  
• 1b Saxton JE. Nat. Prod. Rep.  1997,  14:  559 
• 1c Toyota M. Ihara N. Nat. Prod. Rep.  1998,  15:  327 
• 1d Leonid I. Belen K. Heterocycles  1994,  37:  2029 
• 2 Signaigo FK. Adkins H. J. Am. Chem. Soc.  1936,  58:  709 
• 3 Patterson JM. Soedigdo S. J. Org. Chem.  1968,  33:  2057 
• 4 Reinecke MG. Johnson HM. Sebastian JF. J. Am. Chem. Soc.  1963,  85:  2859 
• 5a Joule JA. Mills K. Smith GF. Heterocyclic Chemistry   3rd ed.:  Chapman and Hall; London: 1995.  p.231-232  
• 5b Schofield K. Hetero-Aromatic Nitrogen Compounds: Pyrroles and Pyridines   Plenum Press; New York: 1967.  p.3 
• N-Alkylpyrroles, however, are readily prepared by reaction of pyrryl salts with iodoalkanes, see:
• 5c Candy CF. Jones AR. J. Org. Chem.  1971,  36:  3990 
• 5d Hobbs CF. McMillin CK. Papadopoulos EP. VanderWerf CA. J. Am. Chem. Soc.  1962,  84:  43 
• 6 Yadav JS. Abraham S. Subba Reddy BV. Sabitha G. Tetrahedron Lett.  2001,  42:  8063 
• 7 Palomo C. Oiarbide M. Kardak BG. García JM. Linden A. J. Am. Chem. Soc.  2005,  127:  4154 
• 8 Paras NA. MacMillan DWC. J. Am. Chem. Soc.  2001,  123:  4370 
• 9a Poondra RR. Turner NJ. Org. Lett.  2005,  7:  863 
• 9b Kudrimoti S. Bommena VR. Tetrahedron Lett.  2005,  46:  1209 
• 9c Saxena I. Borah DC. Sarma JC. Tetrahedron Lett.  2005,  46:  1159 
• 9d Bengtson A. Hallberg A. Larhed M. Org. Lett.  2002,  4:  1231 
• 10a Kaval N. Dehaen W. Matyus P. Eycken EV. Green Chem.  2004,  6:  125 
• 10b Ju Y. Varma RS. Green Chem.  2004,  6:  219 
• 10c Miao G. Ye P. Yu L. Baldino CM. J. Org. Chem.  2005,  70:  2332 
• 10d Poondra RR. Fischer PM. Turner NJ. J. Org. Chem.  2004,  69:  6920 
• 11 Gabriel C. Gabriel S. Grant EH. Halstead BSJ. Mingos DMP. Chem. Soc. Rev.  1998,  27:  213 
• 13a Leonard NM. Wieland LC. Mohan RS. Tetrahedron  2002,  58:  8373 
• 13b Postel M. Dunach E. Coord. Chem. Rev.  1996,  155:  127 

12

Typical Experimental Procedure.
Catalyst-free: To a solution of pyrrole (2 mmol) or N-benzyl pyrrole (2 mmol) or 2-alkylpyrroles (1 mmol) in CH₂Cl₂ (1 mL) was added electron-deficient olefin (1 mmol for pyrrole and N-benzyl pyrrole, 1.2 mmol for 2-alkylpyrroles) and silica gel (0.25 g). Then the mixture was mixed thoroughly and dried under reduced pressure. The contents were taken in a 5 mL conical flask and was placed in a microwave oven (cooking type, Galanz WP 700P 21-6) and irradiated for 1-4 min at 680 W. After completion of the reaction indicated by TLC, the reaction mixture was allowed to cool, diluted with CH₂Cl₂ and passed through a short silica gel column using CH₂Cl₂ as eluent. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography to afford the corresponding 2-alkylpyrroles or 2,5-dialkylpyrroles.
Spectral data for selected compound. 4-(1 H -Pyrrol-2-yl)butan-2-one (a): yield 123 mg (90%). IR (film): 3377, 1707 cm^-1. ¹H NMR (500 MHz, CDCl₃):
δ = 2.17 (s, 3 H), 2.81 (t, J = 6.5 Hz, 2 H), 2.87 (t, J = 6.5 Hz, 2 H), 5.90 (s, 1 H), 6.10 (d, J = 3.0 Hz, 1 H), 6.66 (d, J = 3.0 Hz, 1 H), 8.54 (br, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.2, 30.0, 44.0, 105.1, 107.7, 116.6, 131.4, 209.6. ESI-MS: m/z (%) = 138 (100) [M + H⁺], 160 (48) [M + Na⁺]. Anal. Calcd for C₈H₁₁NO: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.02; H, 8.12; N, 10.07.
Using 5% mol BiCl₃ as catalyst: to a solution of BiCl₃ (0.05 mmol) in MeCN (1 mL) was added pyrrole (2 mmol) or N-benzyl pyrrole (2 mmol) or 2-alkylpyrroles (1 mmol), followed by electron-deficient olefins (1 mmol for pyrrole and N-benzyl pyrrole, 1.2 mmol for 2-alkylpyrroles) and silica gel (0.25 g). Then the mixture was mixed thoroughly and dried under reduced pressure. For the following work up see typical experimental procedure (a).

Spectral data for selected compound.
3-[5-(3-Oxo-3-phenylpropyl)-1 H -pyrrol-2-yl]cyclo-hexanone (f): yield 259 mg (88%). IR (film): 3373, 1708, 1677, 1595, 1579 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.72-2.69 (m, 8 H), 3.01 (t, J = 6.0 Hz, 2 H), 3.04-3.11 (m, 1 H), 3.33 (t, J = 6.0 Hz, 2 H), 5.79 (d, J = 2.5 Hz, 1 H), 5.83 (d, J = 2.5 Hz, 1 H), 7.44-8.04 (m, 5 H), 8.52 (br, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.5, 24.8, 31.6, 37.4, 39.4, 41.2, 47.4, 103.4, 105.2, 128.0, 128.6, 130.9, 133.4, 133.7, 136.6, 200.9, 210.9. ESI-MS: m/z (%) = 296 (100) [M + H⁺], 318 (95) [M + Na⁺]. Anal. Calcd for C₁₉H₂₁NO₂: C, 77.14; H, 7.05; N, 4.67. Found: C, 77.26; H, 7.17; N, 4.74.