Microwave-Assisted Silyloxy-Cope Rearrangement of syn-Aldol Products in DMF: Enhancement of Rate and Diastereoselectivity

Abstract

Microwave-assisted Cope rearrangements of 1,5-dienes embedded in a syn-aldol structure proceed in substantially reduced reaction times and markedly increased diastereoselectivity when conducted in DMF as solvent.

Key words

aldol products - Cope rearrangement - diastereoselectivity - microwave irradiation

References and Notes

• Reviews:
• 1a Nubbemeyer U. Synthesis  2003,  961 ; and references cited therein
• 1b Enders D. Knopp M. Schiffers R. Tetrahedron: Asymmetry  1996,  7:  1847 
• 1c Frauenrath H. Stereoselective Synthesis, In Houben-Weyl (Methods in Organic Chemistry)   Vol. E21d:  Helmchen G. Hoffmann RW. Mulzer J. Schaumann E. Thieme; Stuttgart: 1995.  p.3301 
• 2a Schneider C. Rehfeuter M. Synlett  1996,  212 
• 2b Schneider C. Rehfeuter M. Tetrahedron  1997,  53:  133 
• 2c Schneider C. Synlett  2001,  1079 
• For related work see:
• 2d Black WC. Giroux A. Greidanus G. Tetrahedron Lett.  1996,  37:  4471 
• 2e Tomooka K. Nagasawa A. Wei Y. Nakai T. Tetrahedron Lett.  1996,  37:  8899 
• 3a Evans DA. Bartroli J. Shi TL. J. Am. Chem. Soc.  1981,  103:  2128 
• 3b Evans DA. Sjogren EB. Tetrahedron Lett.  1986,  27:  4957 
• 4 Doering WvE. Roth WR. Tetrahedron  1962,  18:  67 
• For the application of the Cope products in organic synthesis see:
• 5a Schneider C. Synlett  1997,  815 
• 5b Schneider C. Schuffenhauer A. Eur. J. Org. Chem.  2000,  73 
• 5c Schneider C. Börner C. Synlett  1998,  652 
• 5d Schneider C. Börner C. Schuffenhauer A. Eur. J. Org. Chem.  1999,  3353 
• 5e Schneider C. Eur. J. Org. Chem.  1998,  1661 
• 5f Schneider C. Rehfeuter M. Tetrahedron Lett.  1998,  39:  9 
• 5g Schneider C. Rehfeuter M. Chem. Eur. J.  1999,  5:  2850 
• 5h Schneider C. Reese O. Angew. Chem. Int. Ed.  2000,  39:  2948 ; Angew. Chem. 2000, 112, 3074
• 5i Schneider C. Reese O. Chem. Eur. J.  2002,  8:  2585 
• 5j Schneider C. Tolksdorf F. Rehfeuter M. Synlett  2002,  2098 
• 6 Davies et al. reported the microwave-assisted Cope rearrangement of a similar, but ester-derived aldol product in hexane (190 °C, 70 min) and an ionic liquid (240 °C, 45 min). Our results with the imide-based aldol products 1 compare favorably with these conditions. See: Davies HML. Beckwith REJ. J. Org. Chem.  2004,  69:  9241 
• 7 Excellent review: Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 ; Angew. Chem. 2004, 116, 6408

8

Typical Experimental Procedure.
A microwave reactor ‘microPREP A’ (MLS GmbH, Germany) with a single magnetron (max. 1200 W, pulsed irradiation, 2.45 GHz) terminal 320 controller, and easy CONTROL 06 software was used for the microwave experiments. A power of max. 500 W was used in all experiments and the temperature inside the reaction mixture was controlled with a ATC-FO 300 fiberoptic sensor inserted into the reaction vessel and automatically adjusted to the set temperature. The amount of 300 mg (0.70 mmol) of 1,5-diene 1a was dissolved in 25 mL dry DMF and placed in a microwave vessel, which was sealed. The sample was irradiated for 15 min at 180 °C whereupon the solvent was evaporated in vacuo. The crude product was analyzed by NMR to determine the diastereoselectivity (25:1) and subsequently purified by flash chromatography over silica gel with Et₂O and pentane (1:6) to furnish 275 mg of the Cope product 2a (91%) as a colorless solid. Mp 60-61 °C; [α]_D ²⁰ 13.0 (c 1.2, CHCl₃). IR (film): ν = 3027, 2956, 2858, 1782, 1681 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 0.13 (s, 6 H, TBS), 0.92 (s, 9 H, TBS), 1.02 (d, J = 7.0 Hz, 3 H, Me), 2.28-2.32 (m, 2 H), 2.79 (dd, J = 13.0, 9.8 Hz, 1 H, benzyl-H), 2.90 (m, 1 H), 3.34 (dd, J = 13.0, 3.0 Hz, 1 H, benzyl-H), 4.14-4.23 (m, 2 H), 4.31 (dd, J = 10.0, 8.7 Hz, 1 H, 6′-H), 4.72 (m, 1 H), 6.16 (dd, J = 6.0, 1.0 Hz, 1 H, 7′-H), 7.21-7.36 (m, 7 H, 2′-H, 3′H, phenyl-H). ¹³C NMR (75 MHz, CDCl₃): δ = -5.30, -5.22, 18.35, 20.94, 25.76, 28.46, 38.06, 40.63, 55.45, 66.18, 115.10, 121.20, 127.40, 129.10, 129.60, 135.60, 138.30, 151.10, 153.50, 165.10. MS (EI, 70eV): m/z = 429 (1), 414 (10), 372 (20), 185 (100), 91 (45), 73 (99). Anal. Calcd: C, 67.10; H, 8.21; N, 3.26. Found: C, 67.14; H, 8.39; N, 3.13.