Enantioselective Protonation in the Aza-Michael Reaction Using a Combination of Chiral Pd-µ-Hydroxo Complex with an Amine Salt

Abstract

A highly enantioselective protonation of enolate intermediates in aza-Michael reaction was achieved by using the combination of a bifunctional chiral Pd-µ-hydroxo complex with aromatic amine salts. The reaction proceeded smoothly to give the desired β-amino carbonyl compounds bearing a stereogenic carbon center at the α-position in good yield with excellent enantioselectivity (up to 97% ee). Although reactions with salts of electron-deficient amines were slow, the introduction of free amine as an additive promoted the reaction to a synthetically useful level.

Key words

asymmetric catalysis - protonations - palladium - aza-Michael additions - β-amino acids

References and Notes

• 1a Duhamel L. Duhamel P. Plaquevent J.-C. Tetrahedron: Asymmetry  2004,  15:  3653 
• 1b Yanagisawa A. Yamamoto H. In Comprehensive Asymmetric Catalysis   Vol. 3:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Berlin: 1999.  p.1295 
• 1c Yanagisawa A. In Comprehensive Asymmetric Catalysis   Suppl. 2:  Jacobsen EN. Pfaltz A. Yamamoto H. Springer; Berlin: 2004.  p.125 
• For recent examples of protonation of preformed enolates, see:
• 2a Nakamura S. Kaneeda M. Ishihara K. Yamamoto H. J. Am. Chem. Soc.  2000,  122:  8120 
• 2b Vedejs E. Kruger AW. Lee N. Sakata ST. Stec M. Suna E. J. Am. Chem. Soc.  2000,  122:  4602 
• 2c Cheon CH. Yamamoto H. J. Am. Chem. Soc.  2008,  130:  9246 
• 2d Yanagisawa A. Touge T. Arai T. Angew. Chem. Int. Ed.  2005,  44:  1546 
• 2e Poisson T. Dalla V. Marsais F. Dupas G. Oudeyer S. Levacher V. Angew. Chem. Int. Ed.  2007,  46:  7090 
• 2f Fehr C. Angew. Chem. Int. Ed.  2007,  46:  7119 ; added in revision: after submission of our manuscript, the paper cited in ref. 2g was reported
• 2g Morita M. Drouin L. Motoki R. Kimura Y. Fujimori I. Kanai M. Shibasaki M. J. Am. Chem. Soc.  2009,  131:  3858 
• Reactions starting from ketenes:
• 3a Hodous BL. Fu GC. J. Am. Chem. Soc.  2002,  124:  10006 
• 3b Wiskur SL. Fu GC. J. Am. Chem. Soc.  2005,  127:  6176 
• 3c Schaefer C. Fu GC. Angew. Chem. Int. Ed.  2005,  44:  4606 
• Decarboxylative protonation starting from β-keto esters:
• 3d Baur MA. Riahi A. Hénin F. Muzart J. Tetrahedron: Asymmetry  2003,  14:  2755 
• 3e Marinescu SC. Nishimata T. Mohr JT. Stoltz BM. Org. Lett.  2008,  10:  1039 
• Reactions using a chiral carbene catalyst:
• 3f Reynolds NT. Rovis T. J. Am. Chem. Soc.  2005,  127:  16406 
• 4a Emori E. Arai T. Sasai H. Shibasaki M. J. Am. Chem. Soc.  1998,  120:  4043 
• 4b Nishimura K. Ono M. Nagaoka Y. Tomioka K. Angew. Chem. Int. Ed.  2001,  40:  440 
• 4c Leow D. Lin S. Chittimalla SK. Fu X. Tan C.-H. Angew. Chem. Int. Ed.  2008,  47:  5641 
• 5a Navarre L. Darses S. Genet J.-P. Angew. Chem. Int. Ed.  2004,  43:  719 
• 5b Moss RJ. Wadsworth KJ. Chapman CJ. Frost CG. Chem. Commun.  2004,  1984 
• 5c Sibi MP. Tatamidani H. Patil K. Org. Lett.  2005,  7:  2571 
• 5d Nishimura T. Hirabayashi S. Yasuhara Y. Hayashi T. J. Am. Chem. Soc.  2006,  128:  2556 
• 5e Frost CG. Penrose SD. Lambshead K. Raithby PR. Warren JE. Gleave R. Org. Lett.  2007,  9:  2119 
• 5f Navarre L. Martinez R. Genet J.-P. Darses S. J. Am. Chem. Soc.  2008,  130:  6159 
• 6 Sibi MP. Coulomb J. Stanley LM. Angew. Chem. Int. Ed.  2008,  47:  9913 
• 7a Hamashima Y. Somei H. Shimura Y. Tamura T. Sodeoka M. Org. Lett.  2004,  6:  1861 
• 7b Hamashima Y. Sasamoto N. Hotta D. Somei H. Umebayashi N. Sodeoka M. Angew. Chem. Int. Ed.  2005,  44:  1525 
• 7c Sasamoto N. Dubs C. Hamashima Y. Sodeoka M.
  J. Am. Chem. Soc.  2006,  128:  14010 
• 8a Enantioselective Synthesis of β-Amino Acids   Juaristi E. Wiley-VCH; New York: 1997. 
• 8b Liu M. Sibi MP. Tetrahedron  2002,  58:  7991 
• 8c Ma J.-A. Angew. Chem. Int. Ed.  2003,  42:  4290 
• A short review:
• 9a Xu L.-W. Xia C.-G. Eur. J. Org. Chem.  2005,  633 
• For more recent examples:
• 9b Yamagiwa N. Qin N. Matsunaga S. Shibasaki M. J. Am. Chem. Soc.  2005,  127:  13419 
• 9c Chen YK. Yoshida M. MacMillan DWC. J. Am. Chem. Soc.  2006,  128:  9328 
• 9d Sibi MP. Itoh K. J. Am. Chem. Soc.  2007,  129:  8064 
• 9e Lu X. Deng L. Angew. Chem. Int. Ed.  2008,  47:  7710 
• 10a Sodeoka M. Hamashima Y. Bull. Chem. Soc. Jpn.  2005,  78:  941 
• 10b Sodeoka M. Hamashima Y. Pure Appl. Chem.  2006,  78:  477 
• 11 We previously reported one example (entry 1, Table 1) in ref. 7a. Recently, Hii et al. also reported partially successful results related to our reaction using a chiral cationic Pd complex. See: Phua PH. Mathew SP. White AJP. de Vries JG. Blackmond DG. Hii KK. Chem. Eur. J.  2007,  13:  4602 
• 12 The synthesis of the starting material was carried out based on the reported procedure. See: Liu X. Hu XE. Tian X. Mazur A. Ebetino FH. J. Organomet. Chem.  2002,  646:  212 
• Several practical aminomethylation reactions of aldehydes using organocatalysts have been reported. See:
• 14a Chi Y. Gellman SH. J. Am. Chem. Soc.  2006,  128:  6804 
• 14b Ibrahem I. Dziedzic P. Córdova A. Synthesis  2006,  4060 
• Asymmetric three-component classical Mannich reactions:
• 15a Ibrahem I. Casa J. Córdova A. Angew. Chem. Int. Ed.  2004,  43:  6528 
• 15b Hamashima Y. Sasamoto N. Umebayashi N. Sodeoka M. Chem. Asian J.  2008,  3:  1443 

13

General Procedure
The starting material 9 (0.1 mmol), amine salts 7 (0.15 mmol), and the Pd complex 1 (5 mol%) were dissolved in THF (0.2 mL). In the case of 7c, the additive 15 (0.05 mmol) was included. The resulting solution was stirred at ambient temperature for the time shown in Tables  [¹] -  [³] . For quench-ing, cold sat. aq NaHCO₃ (2 mL) was added under ice-bath cooling. Usual workup, followed by flash column chromato-graphy (Si₂O, hexane-EtOAc system) gave the pure products.
Analytical Data of 10ca
^¹H NMR (400 MHz, CDCl₃): δ = 3.38 (dd, J = 5.5, 13.0 Hz, 1 H), 3.74 (s, 3 H), 3.84 (dd, J = 8.7, 13.0 Hz, 1 H), 4.48 (br s, 1 H), 5.08 (s, 2 H), 6.58 (d, J = 8.8 Hz, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 7.26-7.39 (m, 10 H), 7.55 (br s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 48.0, 51.2, 55.7, 67.9, 114.7, 115.0, 128.0, 128.4, 128.5, 128.6, 128.7, 129.1, 134.7, 136.0, 141.2, 150.6, 152.5, 172.4. LRMS-FAB (mNBA): m/z = 404 [M⁺], 405 [M + H]⁺. HRMS (PEG 400/mNBA): m/z calcd for C₂₄H₂₄N₂O₄ [M]⁺ 404.1736; found: 404.1739. [α]_D ^²5 +64.6 (c 0.82, CHCl₃; 93% ee). HPLC (DAICEL CHIRALPAK AD-H, hexane-2-PrOH = 3:1, 1.0 mL/min, 254 mn): t _R(minor) = 17.2 min, t _R(major) = 20.9 min.