Metal-Free Bifunctional Catalysis of the Asymmetric Baylis-Hillman Reaction

Abstract

The Sharpless ligand (DHQD)₂AQN acts a bifunctional catalyst for the asymmetric Baylis-Hillman reaction. Enantioselectivities up to 77% have been observed.

Key words

(DHQD)₂AQN - bifunctional catalysis - asymmetric Baylis-Hillman reaction

References

• 1a Hamashima Y. Sawada D. Kanai M. Shibasaki M. J. Am. Chem. Soc.  1999,  121:  2641 
• 1b Shibasaki M. Kanai M. Funabashi K. Chem. Commun.  2002,  1989 
• 2 Baylis AB, and Hillman MED. inventors; German Patent  2,155,113.  ; Chem. Abstr. 1972, 77, 34174q
• For reviews of the Baylis-Hillman reaction, see:
• 3a Drewes SE. Roos GHP. Tetrahedron  1988,  44:  4653 
• 3b Basavaiah D. Rao DP. Hyma RS. Tetrahedron  1996,  52:  8001 
• 3c Ciganek E. Org. React.  1997,  51:  201 
• 3d Langer P. Angew. Chem. Int. Ed.  2000,  39:  3049 
• 3e Basavaiah D. Rao AJ. Satyanarayana T. Chem. Rev.  2003,  103:  811 
• For mechanistic studies, see:
• 4a Hill JS. Isaacs NS. J. Phys. Org. Chem.  1990,  3:  285 
• 4b Bode ML. Kaye PT. Tetrahedron Lett.  1992,  32:  5611 
• 4c Fort Y. Berthe MC. Caubere P. Tetrahedron  1992,  48:  6371 
• 5a Gilbert A. Heritage TW. Isaacs NS. Tetrahedron: Asymmetry  1991,  2:  965 
• 5b Roos GHP. Rampersadh P. Synth. Commun.  1993,  23:  1261 
• 5c Kundu MK. Mukherjee SB. Balu N. Padmakumar R. Bhat SV. Synlett  1994,  444 
• 5d Rafel S. Leahy JW. J. Org. Chem.  1997,  62:  1521 
• 5e Aggarwal VK. Mereu A. Tarver GJ. McCague R. J. Org. Chem.  1998,  63:  7183 
• 5f Kawamura M. Kobayashi S. Tetrahedron Lett.  1999,  40:  1539 
• 6a Drewes SE. Freese SD. Emslie ND. Roos GHP. Synth. Commun.  1988,  18:  1565 
• 6b Bailey M. Marko IE. Ollis D. Rasmussen PR. Tetrahedron Lett.  1990,  31:  4509 
• 7a Oishi T. Oguri H. Hirama M. Tetrahedron: Asymmetry  1995,  6:  1241 
• 7b Brzezinski LJ. Rafel S. Leahy JW. Tetrahedron  1997,  53:  16423 
• 7c Hayase T. Shibata T. Soai K. Wakatsuki Y. Chem. Commun.  1998,  1271 
• 7d Marko IE. Giles PR. Hindley PJ. Tetrahedron  1997,  53:  1015 
• 7e Barrett AGM. Cook AS. Kamimura A. Chem. Commun.  1998,  2533 
• 8 Iwabuchi Y. Nakatani M. Yokoyama N. Hatakeyama S. J. Am. Chem. Soc.  1999,  121:  10219 
• Other reports of catalytic asymmetric Baylis-Hillman reactions include:
• 9a Shi M. Xu Y.-M. Angew. Chem. Int. Ed.  2002,  41:  4507 
• 9b Walsh LM. Winn CL. Goodman JM. Tetrahedron Lett.  2002,  43:  8219 
• 9c Balan D. Adolfsson H. Tetrahedron Lett.  2003,  44:  2521 
• 9d Iwabuchi Y. Nakatani M. Yokoyama N. Hatakeyama S. Org. Lett.  2003,  3:  3103 
• 10a Sharpless KB. Amberg W. Bennani YL. Crispino GA. Hartung J. Jeong K.-S. Kwong H.-L. Morikawa K. Wang Z.-M. Xu D. Zhang X.-L. J. Org. Chem.  1992,  57:  2711 
• 10b Crispino GA. Jeong K.-S. Kolb HC. Wang Z.-M. Xu D. Sharpless KB. J. Org. Chem.  1993,  58:  3785 
• 10c Becker H. Sharpless KB. Angew. Chem., Int. Ed. Engl.  1996,  35:  449 
• 11 Shi M. Jiang J.-K. Tetrahedron: Asymmetry  2002,  13:  1941 

12

Experimental Procedure for the (DHQD) ₂ AQN-Catalysed BH Reaction: Compound ( R )-4: Methyl acrylate (45 µL, 0.5 mmol) was added to a stirred solution of p-nitrobenzaldehyde (76 mg, 0.5 mmol) and (DHQD)₂AQN (43 mg, 10 mol%) in 0.5 mL of a solution of propionic acid in THF (0.1 M, 10 mol%). The reaction was carried out at r.t. for 17 d. The crude mixture was then purified by flash chromatography eluting with 3:7 EtOAc-Petrol (40-60), to give the Baylis-Hillman product ( R )-4 (7 mg, 6%, 60% ee) as a light yellow oil. IR (film): 3493, 1716, 1521, 1349
cm^-1. ¹H NMR (500 MHz, CDCl₃,): δ = 8.19 (d, 2 H, J = 8.7 Hz, o-NO₂-ArH), 7.58 (d, 2 H, J = 8.7 Hz, m-NO₂-ArH), 6.40 (s, 1 H, =CH _cis H_trans), 5.88 (s, 1 H, =CH_cis H _trans ), 5.64 (d, 1 H, J = 6.2 Hz, CHOH), 3.75 (s, 3 H, OCH₃), 3.37 (d, 1 H, J = 6.2 Hz, OH). ¹³C NMR (75 MHz, CDCl₃): δ = 166.4 (C=O), 148.6 (NO₂-ArC), 147.4 (p-NO₂-ArC), 140.9 (C=CH₂), 127.3 (C=CH₂, m-NO₂-ArC), 123.6 (o-NO₂-ArC), 73.0 (COH), 52.3 (OCH₃). MS (EI): m/z (%) = 236 (32) [M - H]⁺, 220 (67), 205 (57), 190 (31), 177 (98), 150 (100), 115 (37), 83 (34), 55 (61). Daicel Chiralcel OD, 2-propanol:hexane = 2:98 to 4:96 for 40 min, 4:96 for 20 min, 4:96 to 10:90 for 30 min (0.5 mL/min), t _R = 65.60 (R) and 70.77 (S).

13

The low solubility of cinchona alkaloids limited the range of solvents. The rate of the reaction increased at 40 °C, but no reaction occurred at -20 °C.

14

Aliquots of acetic-d ₃ -acid-d (0.494 µL, 0.25 equiv) were added consecutively (up to 5 equiv) to a solution of (DHQD)₂AQN (30 mg, 0.035 mmol) in CDCl₃. The protonation process was monitored by ¹H NMR (500 MHz, CDCl₃).