Asymmetric Synthesis of Chromanones via N-Heterocyclic Carbene Catalyzed Intramolecular Crossed-Benzoin Reactions

Abstract

The enantioselective synthesis of 3-hydroxy-4-chromanones bearing a quaternary stereocenter via an N-heterocyclic ­carbene catalyzed intramolecular crossed-benzoin reaction is described.

Key words

organocatalysis - N-heterocyclic carbenes - asymmetric synthesis - benzoin reaction - chromanones

References and Notes

• 1a Arduengo AJ. Herlow RL. Kline M. J. Am. Chem. Soc.  1991,  117:  361 
• 1b Review: Arduengo AJ. Krafczyk R. Chem. Unserer Zeit  1998,  32:  6 
• 1c Enders D. Breuer K. Raabe G. Runsink J. Teles JH. Melder J.-P. Ebel K. Brode S. Angew. Chem. Int. Ed.  1995,  34:  2021 
• 1d Review: Canac Y. Soleilhavoup M. Conejero S. Bertrand G. J. Organomet. Chem.  2004,  689:  3857 
• Reviews:
• 2a Enders D. Balensiefer T. Acc. Chem. Res.  2004,  37:  534 
• 2b Zeitler K. Angew. Chem. Int. Ed.  2005,  44:  7506 
• 2c Enders D. Balensiefer T. Niemeier O. Christmann M. Nucleophilic N-Heterocyclic Carbenes in Asymmetric Synthesis In Enantioselective Organocatalysis - Reactions and Experimental Procedures   Dalko P. Wiley-VCH; Weinheim: 2006. in press
• 3a Burstein C. Glorius F. Angew. Chem. Int. Ed.  2004,  43:  6205 
• 3b Sohn SS. Rosen EL. Bode JW. J. Am. Chem. Soc.  2004,  126:  14370 
• 3c He M. Bode JW. Org. Lett.  2005,  7:  3131 
• 3d Mattson AE. Zuhl AM. Reynolds TE. Scheidt KA. J. Am. Chem. Soc.  2006,  128:  4932 
• 4 Singh R. Kissling RM. Letellier M.-A. Nolan SP. J. Org. Chem.  2004,  69:  209 
• 5 Coulembier O. Dove AP. Pratt RC. Sentman AC. Culkin DA. Mespouille L. Dubois P. Waymouth RM. Hedrick JL. Angew. Chem. Int. Ed.  2005,  44:  4964 
• 6 Fischer C. Smith SW. Powell DA. Fu GC. J. Am. Chem. Soc.  2006,  128:  1472 
• 7 Chan A. Scheidt KA. J. Am. Chem. Soc.  2006,  128:  4558 
• 8 Song JJ. Tan Z. Reeves JT. Gallou F. Yee NK. Senanayake CH. Org. Lett.  2005,  7:  2193 
• 9a Mattson AE. Bharadwaj AR. Scheidt KA. J. Am. Chem. Soc.  2004,  126:  2314 
• 9b Bharadwaj AR. Scheidt KA. Org. Lett.  2004,  6:  2465 
• 9c Mattson AE. Scheidt KA. Org. Lett.  2004,  6:  4363 
• 10 Enders D. Kallfass U. Angew. Chem. Int. Ed.  2002,  41:  1743 
• 11a Enders D. Breuer K. Runsink J. Teles JH. Helv. Chim. Acta  1996,  79:  1899 
• 11b Kerr MS. de Alaniz JR. Rovis T. J. Am. Chem. Soc.  2002,  35:  10298 
• 11c Kerr MS. Rovis T. J. Am. Chem. Soc.  2004,  126:  8876 
• 11d de Alaniz JR. Rovis T. J. Am. Chem. Soc.  2005,  127:  6284 
• 11e Liu Q. Rovis T. J. Am. Chem. Soc.  2006,  128:  2552 
• 11f Short review: Christmann M. Angew. Chem. Int. Ed.  2005,  44:  2632 
• 12a Mennen SM. Gipson JD. Kim YR. Miller SJ. J. Am. Chem. Soc.  2005,  127:  1654 
• 12b Murry JA. Frantz DE. Soheili A. Tillyer R. Grabowski EJJ. Reider PJ. J. Am. Chem. Soc.  2001,  123:  9696 
• 13a Linghu X. Johnson JS. Angew. Chem. Int. Ed.  2003,  42:  2534 
• 13b Linghu X. Potnick JR. Johnson JS. J. Am. Chem. Soc.  2004,  126:  3070 
• 13c Linghu X. Bausch CC. Johnson JS. J. Am. Chem. Soc.  2005,  127:  1833 
• Enzymatic cross-coupling:
• 14a Iding H. Dünnwald T. Greiner L. Liese A. Müller M. Siegert P. Grötzinger J. Demir AS. Pohl M. Chem. Eur. J.  2000,  6:  1483 
• 14b Dünkelmann P. Kolter-Jung D. Nitsche A. Demir AS. Siegert P. Lingen B. Baumann M. Pohl M. Müller M. J. Am. Chem. Soc.  2002,  124:  12084 
• 14c Pohl M. Lingen B. Müller M. Chem. Eur. J.  2002,  8:  5289 
• 15a Hachisu Y. Bode JW. Suzuki K. J. Am. Chem. Soc.  2003,  125:  8432 
• 15b Enders D. Niemeier O. Synlett  2004,  2111 
• 15c Hachisu Y. Bode JW. Suzuki K. Adv. Synth. Catal.  2004,  346:  1097 
• 16a Enders D. Niemeier O. Balensiefer T. Angew. Chem. Int. Ed.  2006,  45:  1463 
• 16b For a related study, see: Takikawa H. Hachisu Y. Bode JW. Suzuki K. Angew. Chem. Int. Ed.  2006,  45:  3492 
• Reviews:
• 17a Fuji K. Chem. Rev.  1993,  93:  2037 
• 17b Corey EJ. Guzman-Perez A. Angew. Chem. Int. Ed.  1998,  37:  388 
• 17c Christoffers J. Mann A. Angew. Chem. Int. Ed.  2001,  40:  4591 
• 17d Denissova I. Barriault L. Tetrahedron  2003,  59:  10105 
• 18a Heller W. Tamm C. Fortschr. Chem. Org. Naturst.  1981,  40:  105 
• 18b Davies FA. Weismiller MC. J. Org. Chem.  1990,  55:  3715 
• 19a Böhler P. Tamm C. Tetrahedron Lett.  1967,  36:  3479 
• 19b Crouch NR. Bangnai V. Mulholland DA. Phytochemistry  1999,  51:  943 

20

Aldehyde ketones of type 5 can be synthezised by the reaction of the corresponding salicyl aldehydes, K₂CO₃ and α-bromo ketones in DMF at r.t.

21

CCDC 607797 (6a) and CCDC 607796 (6f) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

22

All new compounds were fully characterized (IR, NMR, MS, elemental analysis, optical rotation, and melting point).
Enantioselective Intramolecular Crossed-Chromanone Cyclization to 6a; Typical Procedure
In a Schlenk tube under argon at r.t. the pre-catalyst 1 (39.0 mg, 0.104 mmol, 20 mol%) was suspended in anhyd THF (9.5 mL). KHMDS (0.5 M in toluene; 198 µL, 0.099 mmol, 19 mol%) was added slowly, and the solution stirred for 15 min. The yellow solution was cooled to 5 °C and the aldehyde ketone 5a (100 mg, 0.520 mmol) dissolved in anhyd THF (1.0 mL) was added to the carbene solution. The reaction mixture was stirred for 48 h, diluted with CH₂Cl₂, quenched with H₂O, extracted twice with CH₂Cl₂, and dried over MgSO₄. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel (Et₂O-n-pentane, 1:8) to yield 6a (88 mg, 88%) as a colorless solid; mp 48 °C; ee 94% [determined by chiral stationary phase GC (Lipodex E)]; [α]_D ²³ -10.3 (c 1.2, CHCl₃). IR (KBr): 3853, 3742, 3482, 2973, 2361, 2340, 1837, 1690, 1610, 1558, 1465, 1382, 1311, 1215, 1134, 1021, 942, 862, 758, 670, 533. ¹H NMR (300 MHz, CDCl₃, TMS): δ = 0.95 (t, 3 H, J = 7.4 Hz, CH₃), 1.81 (q, 2 H, J = 7.5 Hz, CH₃CH₂), 3.68 (s, 1 H, OH), 4.17 (d, 1 H, J = 11.4 Hz, CHH), 4.40 (d, 1 H, J = 11.4 Hz, CHH), 6.96-7.08 (m, 2 H, Ar), 7.48-7.54 (m, 1 H, Ar), 7.86-7.89 (m, 1 H, Ar). ¹³C NMR (75 MHz, CDCl₃): δ = 6.8 (CH₃), 27.6, 72.8 (CH₂), 73.0 (C), 117.9 (CH), 118.4 (C), 127.5, 136.5 (CH), 161.4 (C), 196.8 (CO). MS (EI): m/z (%) = 192 (M⁺, 11), 122 (7), 121 [(M⁺ + 1) - 72, 100], 120 (11), 93 (7), 92 (18), 77 (5), 65 (6). Anal. Calcd for C₁₁H₁₂O₃: C, 68.75; H, 6.29. Found: C, 68.69; H, 6.28.