One-Pot Synthesis of Pyridines or Pyrimidines by Tandem Oxidation-Heteroannulation of Propargylic Alcohols

Abstract

Pyridines and pyrimidines are prepared in a single step from propargylic alcohols by in situ oxidation with o-iodoxybenzoic acid or manganese dioxide and reaction with enamines or amidines, respectively, under either thermal or microwave-assisted conditions in a new one-pot tandem oxidation-heteroannulation procedure. The reaction of α β-ketoester, propargylic alcohol and ammonium acetate, with in situ oxidation, constitutes a highly facile three-component reaction for the synthesis of pyridines that accomplishes four distinct synthetic operations in one-pot, good yield and with total regiocontrol.

Key words

heterocycles - pyridines - pyrimidines

References

• 1a Foot JS. Kanno H. Giblin GMP. Taylor RJK. Synthesis  2003,  1055 
• 1b Blackburn L. Kanno H. Taylor RJK. Tetrahedron Lett.  2003,  44:  115 
• 1c Runcie KA. Taylor RJK. Chem. Commun.  2002,  974 
• 1d Blackburn L. Pei C. Taylor RJK. Synlett  2002,  215 
• 1e Blackburn L. Taylor RJK. Org. Lett.  2001,  3:  1637 
• 1f Wei X. Taylor RJK. J. Org. Chem.  2000,  65:  617 
• 1g Blackburn L. Wei X. Taylor RJK. Chem. Commun.  1999,  1337 
• 1h Wei X. Taylor RJK. Tetrahedron Lett.  1998,  39:  3815 
• 2 Crich D. Mo X.-S. Synlett  1999,  67 
• 3 Barrett AGM. Hamprecht D. Ohkubo M. J. Org. Chem.  1997,  62:  9376 
• 4 Shuto S. Niizuma S. Matsuda A. J. Org. Chem.  1998,  63:  4489 
• 5a Bagley MC. Brace C. Dale JW. Ohnesorge M. Phillips NG. Xiong X. Bower J. J. Chem. Soc., Perkin Trans. 1  2002,  1663 
• 5b Bagley MC. Lunn R. Xiong X. Tetrahedron Lett.  2002,  43:  8331 
• 6 Bagley MC. Dale JW. Bower J. Chem. Commun.  2002,  1682 
• 7 Collins I. J. Chem. Soc., Perkin Trans. 1  2002,  1921 
• 8 Bagley MC. Hughes DD. Taylor PH. Synlett  2003,  259 
• 10 Müller TJJ. Braun R. Ansorge M. Org. Lett.  2000,  2:  1967 
• 11 Bohlmann F. Rahtz D. Chem. Ber.  1957,  90:  2265 

9

Typical Procedure for the One-Pot Synthesis of Pyrimidines 4. A mixture of 1-phenyl-2-propyn-1-ol (1a) (0.13 g, 1.0 mmol), benzamidine hydrochloride salt (2a˙HCl) (0.19 g, 1.2 mmol), Na₂CO₃ (0.25 g, 2.4 mmol) and activated MnO₂ (0.87 g, 10 mmol) in acetonitrile (5 mL) was irradiated for 40 min in a self-tunable CEM microwave synthesizer at 120 °C (initial power 90 W) and then allowed to cool. The solution was filtered through Celite^® and evaporated in vacuo. Purification by flash chromatography on silica gave pure 2,4-diphenylpyrimidine (3a) [8] as a pale yellow solid (0.19 g, 84%).

12

Typical Procedure for the One-Pot Synthesis of Pyridines 6 from Enamines 5. A solution of IBX (0.56 g, 2.0 mmol) in DMSO-HOAc (5:1) (18 mL) was stirred at 65 °C until homogeneous. A solution of 1-phenyl-2-propyn-1-ol (1a) (0.26 g, 2.0 mmol) and ethyl β-aminocrotonate (5a) (0.13 g, 1.0 mmol) in DMSO (1 mL) was added and the resulting solution was stirred at 65 °C overnight. Water (10 mL) was added and the mixture was stirred for 10 min, allowed to cool, diluted with water (40 mL) and extracted with EtOAc (2 × 30 mL). The organic extracts were combined, washed sequentially with sat. aq NaHCO₃ solution (20 mL) and brine (20 mL), dried (Na₂SO₄) and evaporated in vacuo. Purification by flash chromatography on silica gave pure ethyl 2-methyl-6-phenylpyridine-3-carboxylate (6a) [5a] as a pale yellow solid (169 mg, 70%).

13

Typical Procedure for the One-Pot Synthesis of Pyridines 6 from β-Ketoesters 7. A solution of ethyl acetoacetate (7a) (39 mg, 0.3 mmol), 1-(4-chloro-phenyl)prop-2-yn-1-ol (1d) [5a] (100 mg, 0.6 mmol), ammonium acetate (0.46 g, 6.0 mmol)) and activated MnO₂ (0.52 g, 6.0 mmol) in toluene-glacial acetic acid (5:1)
(5 mL) was heated at reflux overnight. The mixture was allowed to cool, filtered through Celite^®, partitioned between sat. aq NaHCO₃ solution (30 mL) and EtOAc
(30 mL) and the aqueous layer was further extracted with EtOAc (20 mL). The combined organic layers were washed sequentially with sat. aq NaHCO₃ solution (20 mL) and brine (20 mL), dried (Na₂SO₄) and evaporated in vacuo. Purification by flash chromatography on silica gave pure pyridine 6d [5a] as a pale yellow solid (80 mg, 96%).