Ring-Expansion Reaction of Cyclic β-Keto Esters or α-Cyano Ketones via ­Conjugate Addition to Alkynyl Imines: The Synthesis of Functionalized ­Medium-Sized Carbocycles

Abstract

The ring-expansion reaction of cyclic β-keto esters or α-cyano ketones afforded two-atom-enlarged carbocyclic products in good yields via conjugate addition to alkynyl imines. On the other hand, the reaction of ethyl 2-oxocyclododecanecarboxylate with alkynyl imine proceeded smoothly to give bicyclo-2-pyridone in moderate yield.

carbocycles - conjugate addition - lactones - medium-sized-ring compounds - ring expansion

References and Notes

1 Illuminati G. Mandolini L. Acc. Chem. Res.  1981,  14:  95 

For reviews, see:

2a Petasis NA. Patane MA. Tetrahedron  1992,  48:  5757 

2b Roxburgh CJ. Tetrahedron  1993,  49:  10749 

2c Mehta G. Singh V. Chem. Rev.  1999,  99:  881 

2d Yet L. Chem. Rev.  2000,  100:  2963 

For recent examples of cycloadditions, see:

3a Nakamura H. Aoyagi K. Shim J.-G. Yamamoto Y. J. Am. Chem. Soc.  2001,  123:  372 

3b López F. Castedo L. Mascareñas JL. Org. Lett.  2005,  7:  287 

For recent examples of cyclizations, see:

4a Nagano H. Tada A. Isobe Y. Yajima T. Synlett  2000,  1193 

4b López F. Castedo L. Mascareñas JL. J. Am. Chem. Soc.  2002,  124:  4218 

4c Molander GA. Brown GA. Storch de Gracia IS. J. Org. Chem.  2002,  67:  3459 

4d Fillion E. Beingessner RL. J. Org. Chem.  2003,  68:  9485 

5 For a recent example of a cross-coupling reaction, see: Denmark SE. Yang S.-M. Tetrahedron  2004,  60:  9695 

For recent examples of a ring-closing metathesis, see:

6a Mascareñas JL. Rumbo A. Castedo L. J. Org. Chem.  1997,  62:  8620 

6b Marco-Contelles J. de Opazo E. J. Org. Chem.  2002,  67:  3705 

6c Rodriguez JR. Castedo L. Mascareñas JL. Chem. Eur. J.  2002,  8:  2923 

6d Rodriguez CM. Ravelo JL. Martin VS. Org, Lett.  2004,  6:  4787 

7a Clark JS. Bate AL. Grinter T. Chem. Commun.  2001,  459 

7b Rassu G. Auzzas L. Pinna L. Zambrano V. Zanardi F. Battistini L. Gaetani E. Curti C. Casiraghi G. J. Org. Chem.  2003,  68:  5881 

7c Ramesh NG. Hassner A. Synlett  2004,  975 

For recent examples of ring-expansion reactions, see:

8a Li C.-J. Chen D.-L. Lu Y.-Q. Haberman JX. Mague JT. Tetrahedron  1998,  54:  2347 

8b Amann CM. Fisher PV. Pugh ML. West FG. J. Org. Chem.  1998,  63:  2806 

8c Kakimoto Y. Ogasawara Y. Nishida A. Kawahara N. Nishida M. Takayanagi H. Tetrahedron  2000,  56:  7173 

8d Molander GA. Huerou YL. Brown GA. J. Org. Chem.  2001,  66:  4511 

8e Oh H.-S. Lee HI. Cha JK. Org. Lett.  2002,  4:  3707 

8f Oh H.-S. Cha JK. Tetrahedron: Asymmetry  2003,  14:  2911 

8g Michaut A. Miranda-Garcia S. Menéndez JC. Rodriguez J. Org. Lett.  2004,  6:  3075 

8h Murakami M. Kadowaki S. Fujimoto A. Ishibashi M. Matsuda T. Org. Lett.  2005,  7:  2059 

9 For a review, see: Weyerstahl P. Marschall H. In Comprehensive Organic Synthesis   Vol. 6:  Trost BM. Fleming I. Winterfeldt E. Pergamon; Oxford: 1991.  p.1041 

10a Hachiya I. Ogura K. Shimizu M. Org. Lett.  2002,  4:  2755 

10b Shimizu M. Nishi T. Yamamoto A. Synlett  2003,  1469 

10c Hachiya I. Ogura K. Shimizu M. Synthesis  2004,  1349 

Ring expansion of carbocyclic β-keto esters with acetylenic esters, see:

11a Lennon M. McLean A. McWatt I. Proctor GR. J. Chem. Soc., Perkin Trans. 1  1974,  1828 

11b Frew AJ. Proctor GR. J. Chem. Soc., Perkin Trans. 1  1980,  1245 

11c Abou-Elzahab MM. Ayyad SN. Zimity MT. Z. Naturforsch., B  1986,  363 

11d Ring expansion of cyclic β-keto esters with benzyne, see: Tambar UK. Stoltz BM. J. Am. Chem. Soc.  2005,  127:  5340 

11e Ring expansion of cyclic β-keto esters with acetylenes, see: Kuninobu Y. Kawata A. Takai K. J. Am. Chem. Soc.  2006,  128:  11368 

12

To sodium ethoxide (23.1 mg, 0.34 mmol) was added a solution of cyclic β-keto ester 1a (78.5 mg, 0.43 mmol) in 1,4-dioxane (2.0 mL) at r.t. The reaction mixture was stirred at r.t. for 10 min, and then a solution of alkynyl imine 2a (40.0 mg, 0.17 mmol) in 1,4-dioxane (2.0 mL) was added at r.t. The resulting reaction mixture was stirred under reflux for 18.0 h and then cooled to r.t. Brine (10 mL) was added to quench the reaction. The mixture was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were dried over Na₂SO₄. The solvents were evaporated in vacuo and then the residue was purified by preparative TLC on silica gel (n-hexane-EtOAc = 2:1) to give ring-expansion product 3a (61.9 mg, 87%) as a yellow solid; mp 132-134 °C. IR (CHCl₃): 3019, 2932, 1699, 1631, 1561, 1514, 1443, 1397, 1291, 1247, 1215, 1174, 1096, 1035, 826, 779, 766, 739, 703 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 12.13 (d, J = 12.5 Hz, 1 H), 7.22-7.30 (m, 6 H), 6.77-6,83 (m, 4 H), 3.88-4.02 (m, 2 H), 3.74 (s, 3 H), 2.85-2.96 (m, 2 H), 2.46-2.49 (m, 1 H), 2.34-2.40 (m, 1 H), 1.86-1.93 (m, 1 H), 1.25-1.73 (m, 5 H), 0.89 (t, J = 7.0 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 203.2, 170.9, 156.4, 145.9, 143.7, 142.7, 134.6, 133.3, 128.8, 128.0, 127.8, 118.1, 114.8, 112.7, 60.3, 55.5, 40.6, 32.7, 29.0, 25.8, 24.8, 13.6. MS (ESI): m/z = 420 [M + H]⁺.

13 For a recent example of the synthesis of bicyclic lactones, see: Nguyen R.-V. Li C.-J. J. Am. Chem. Soc.  2005,  127:  17184 ; and references therein