A Merged Aldol Condensation, Alkene Isomerization, Cycloaddition/Cycloreversion Sequence Employing Oxazinone Intermediates for the Synthesis of Substituted Pyridines

Abstract

A domino reaction sequence has been evaluated that begins with union of novel dihydrooxazinone precursors with 2-alkynyl-substituted benzaldehyde components through aldol condensation. Ensuing operations, including alkene isomerization, Diels–Alder, and retrograde Diels–Alder with loss of CO₂ occurs in the same reaction vessel to provide polysubstituted tricyclic pyridine products.

Key words

cycloaddition - cycloreversion - pyridine synthesis - domino reactions - Diels–Alder - oxazinone

• References and Notes

• 1 Present address: J. B. Williamson, Department of Chemistry, The University of North Carolina, Chapel Hill, NC 27599, USA.
• 2a Tietze LF, Brasche G, Gericke KM. Domino Reactions in Organic Synthesis . Wiley-VCH; Weinheim: 2006
• 2b Tietze LF, Modi A. Med. Res. Rev. 2000; 20: 304-304
• 2c Tietze LF. Chem. Rev. 1996; 96: 115-115
• 3 Gaich T, Baran PS. J. Org. Chem. 2010; 75: 4657-4657
• 4a Margrey KA, Chinn AJ, Laws SW, Pike RD, Scheerer JR. Org. Lett. 2012; 43: 2458-2458
• 4b Laws SW, Scheerer JR. J. Org. Chem. 2013; 78: 2422-2422
• 5a Margrey KM, Hazzard AD, Scheerer JR. Org. Lett. 2014; 16: 904-904
• 5b Leibowitz MK, Winter ES, Scheerer JR. Tetrahedron Lett. 2015; 56: 6069-6069
• 6a Rogiers J, Wu XJ, Toppet S, Compernolle F, Hoornaert GJ. Tetrahedron 2001; 57: 8971-8971
• 6b De Borggraeve W, Rombouts F, Van der Eycken E, Hoornaert GJ. Synlett 2000; 713-713
• 6c Wu XJ, Dubois K, Rogiers J, Toppet S, Compernolle F, Hoornaert GJ. Tetrahedron 2000; 56: 3043-3043
• 6d Van der Eycken E, Deroover G, Toppet SM, Hoornaert GJ. Tetrahedron Lett. 1999; 40: 9147-9147
• 6e Medaer BP, Hoornaert GJ. Tetrahedron 1999; 55: 3987-3987
• 6f Medaer BP, Vanaken KJ, Hoornaert GJ. Tetrahedron 1996; 52: 8813-8813
• 6g Medaer B, Vanaken K, Hoornaert G. Tetrahedron Lett. 1994; 35: 9767-9767
• 6h Vanaken KJ, Lux GM, Deroover GG, Meerpoel L, Hoornaert GJ. Tetrahedron 1994; 50: 5211-5211
• 6i Fannes C, Meerpoel L, Toppet S, Hoornaert G. Synthesis 1992; 705-705
• 6j Fannes CC, Hoornaert GJ. Tetrahedron Lett. 1992; 33: 2049-2049
• 6k Tutonda MG, Vandenberghe SM, Vanaken KJ, Hoornaert GJ. J. Org. Chem. 1992; 57: 2935-2935
• 6l Vanaken KJ, Meerpoel L, Hoornaert GJ. Tetrahedron Lett. 1992; 33: 2713-2713
• 6m Meerpoel L, Hoornaert G. Tetrahedron Lett. 1989; 30: 3183-3183
• 7a Roughley SD, Jordan AM. J. Med. Chem. 2011; 54: 3451-3451
• 7b Michael JP. Nat. Prod. Rep. 2005; 22: 627-627
• 7c Henry GD. Tetrahedron 2004; 60: 6043-6043
• 7d Joule JA, Mills K. Heterocyclic Chemistry . Blackwell Publishing; Oxford: 2000. 4th ed. 63

Selected reviews:
• 8a Varela JA, Saá C. Chem. Rev. 2003; 103: 3787-3787
• 8b Gulevich AV, Dudnik AS, Chernyak N, Gevorgyan V. Chem. Rev. 2013; 113: 3084-3084
• 8c Hill MD. Chem. Eur. J. 2010; 16: 12052-12052
• 8d Bull JA, Mousseau JJ, Pelletier G, Charette AB. Chem. Rev. 2012; 112: 2642-2642
• 8e Nakao Y. Synthesis 2011; 3209-3209
• 9a Allais C, Grassot JM, Rodriguez J, Constantieux T. Chem. Rev. 2014; 114: 10829-10829
• 9b Kral K, Hapke M. Angew. Chem. Int. Ed. 2011; 50: 2434-2434
• 10 See Supporting Information for procedures that accompany Scheme 2 and the spectra and corresponding characterization data for all new compounds (including 5a–c, 13b,c, 14a–c, 15a–c).
• 11 Representative Procedure for the Domino Reaction Leading to Tricyclic Pyridine Product 13a Dihydrooxazinone 5a (50 mg, 0.38 mmol) was dissolved in toluene (3.0 mL, 0.12 M) and DBU (85 μL, 0.57 mmol, 1.5 equiv) was added. The reaction vessel was heated in an oil bath to a gentle reflux (110 °C) and 2-alkynyl benzaldehyde 10 (74 mg, 1.5 equiv) in toluene (1.0 mL) was introduced slowly to the reaction over 2 h (using a syringe pump). After stirring for 18 h at 110 °C, the reaction was cooled to r.t., transferred to a separatory funnel, and partitioned between sat. aq NH₄Cl (10 mL) and EtOAc (10 mL). The organic layer was removed, and the aqueous portion was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried (Na₂SO₄), filtered through Celite, and concentrated in vacuo. The resulting residue (82 mg) was purified by flash column chromatography on silica gel (gradient elution: 20% → 80% of CHCl₃ in hexane) to afford compound 13a (57 mg, 77% yield) as a light yellow oil; R_f  = 0.20 (50% CHCl₃–Hex). IR (film): 1586, 1463, 1307, 1029, 772 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.88 (d, J = 8.6 Hz, 1 H), 7.62 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 7.4 Hz, 1 H), 7.34 (t, J = 7.4 Hz, 1 H), 7.26 (t, J = 7.4 Hz, 1 H), 4.00 (s, 3 H), 3.87 (s, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 163.9, 162.5, 140.4, 139.8, 130.0, 128.4, 126.9, 126.0, 125.0, 119.2, 108.7, 53.7, 38.6. HRMS: m/z calcd for C₁₃H₉NONa [M + Na]⁺: 198.0913; found: 198.0913.