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.

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.