Chelating Hydroxyalkyl NHC as Efficient Chiral Ligands for Room-Temperature Copper-Catalyzed Asymmetric Allylic Alkylation

Abstract

The application of chiral chelating hydroxy NHC in copper-catalyzed asymmetric allylic alkylation (Cu-AAA) involving various dialkylzincs and allylic phosphate substrates is reported here. From a library of 11 chiral chelating hydroxyalkyl NHC, a fine-tuning has been done to identify the best architectural features enabling to produce the expected γ-adducts in total regioselectivity, good isolated yields, and excellent enantioselectivities (ranging from 93% to >98% ee).

Key words

chiral chelating diaminocarbene - asymmetric allylic alkylation - copper dialkylzinc

References and Notes

• For recent books dealing with NHC in synthesis and catalysis, see:
• 1a N-Heterocyclic Carbenes in Synthesis   Nolan SP. Wiley-VCH; Weinheim: 2006. 
• 1b N-Heterocyclic Carbenes in Transition Metal Catalysis   Glorius F. Topics in Organometallic Chemistry, Springer; Berlin: 2006. 
• For recent reviews on chiral NHC, see:
• 1c Clavier H. Mauduit M. In N-Heterocyclic Carbenes in Synthesis   Nolan SP. Wiley-VCH; Weinheim: 2006.  p.183-222  
• 1d Bellemin-Laponnaz S. Gade L. In N-Heterocyclic Carbenes in Transition Metal Catalysis, In Topics in Organometallic Chemistry   Vol. 21:  Glorius F. Springer; Berlin: 2006.  p.117-157  
• 2 Wanzlick HW. Schönherr HJ. Angew. Chem., Int. Ed. Engl.  1968,  7:  141 
• 3 Öfele K. J. Organomet. Chem.  1968,  12:  42 
• 4 For the first isolation of stable NHC, see: Arduengo AJ. Harlow RL. Kline MJ. J. Am. Chem. Soc.  1991,  113:  361 
• 5 For a review on the design, the synthesis and applications of chiral chelating hydroxyalkyl and hydroxyaryl NHCs, see: Wencel J. Hénon H. Kehrli S. Alexakis A. Mauduit M. Aldrichimica Acta  2009,  42:  43 
• Applications in Cu-catalyzed asymmetric conjugate addition (Cu-ACA); for chelating hydroxyalkyl NHC L _alk , see:
• 6a Clavier H. Coutable L. Guillemin J.-C. Mauduit M. Tetrahedron: Asymmetry  2005,  16:  921 
• 6b Clavier H. Coutable L. Guillemin J.-C. Mauduit M. J. Organomet. Chem.  2005,  690:  5237 
• 6c Martin D. Kehli S. d’Augustin M. Clavier H. Mauduit M. Alexakis A.
  J. Am. Chem. Soc.  2006,  128:  8416 
• 6d Henon H. Mauduit M. Alexakis A. Angew. Chem. Int. Ed.  2008,  47:  9122 
• 6e Rix D. Labat S. Toupet L. Crévisy C. Mauduit M. Eur. J. Inorg. Chem.  2009,  1989 
• For chelating hydroxyaryl NHC L>A_r, see:
• 6f Lee KS. Brown MK. Hird AW. Hoveyda AH. J. Am. Chem. Soc.  2006,  128:  7182 
• For chelating hydroxyaryl NHC L _{A r} in Cu-catalyzed asymmetric allylic alkylation (Cu-AAA), see:
• 7a Larsen AO. Leu W. Nieto Oberhuber C. Campbell JE. Hoveyda AH. J. Am. Chem. Soc.  2004,  126:  11130 
• 7b Murphy KE. Hoveyda AH. Org. Lett.  2005,  7:  1255 
• 7c Van Veldhuizen JJ. Campbell JE. Guidici RE. Hoveyda AH. J. Am. Chem. Soc.  2005,  127:  6877 
• 7d Gillingham DG. Hoveyda AH. Angew. Chem. Int. Ed.  2007,  46:  3860 
• 7e Kacprzynski MA. May TL. Kazane SA. Hoveyda AH. Angew. Chem. Int. Ed.  2007,  46:  4554 
• For recent reviews on Cu-ACA and Cu-AAA, see:
• 8a Alexakis A. Benhaim C. Eur. J. Org. Chem.  2002,  3221 
• 8b Alexakis A. Backvall JE. Krause N. Pamies O. Dieguez M. Chem. Rev.  2008,  108:  2796 
• 10 Ethyl acetate is considered as a greener solvent, see: Alfonsi K. Colberg J. Dunn PJ. Fevig T. Jennings S. Johnson TA. Kleine HP. Knight C. Nagy MA. Perry DA. Stefaniak M. Green Chem.  2008,  10:  31 
• 11 Wang HMJ. Lin IJB. Organometallics  1998,  17:  972 

9

Other copper sources have been evaluated such as Cu(OTf)₂, CuTC (TC = thiophene 2-carboxylate) or (CuOTf)₂-toluene, however, lower yields and enantioselectivities were observed.

12

Azolium salts L1-11 are easily accessible in four steps from enantiopure β-amino alcohols, see ref. 6b and 6e.

13

Analytical and Spectral Data of L8
^¹H NMR (400 MHz, CD₂Cl₂): δ = 7.73 (s, 1 H), 7.40 (t, J = 7.8 Hz, 1H), 7.22-7.19 (m, 2 H), 4.31-4.10 (m, 4 H), 3.93 (dd, J = 11.9, 3.8 Hz, 1 H), 3.73 (dd, J = 1.09, 10.4 Hz, 1 H), 3.62 (dd, J = 10.4, 3.8 Hz, 1 H), 2.86-2.73 (m, 2 H), 2.03 (s, 1 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.20 (d, J = 6.8 Hz, 3 H), 1.13 (d, J = 5.2 Hz, 3 H), 1.11 (d, J = 5.2 Hz, 3 H), 0.99 (s, 9 H). ^¹³C NMR (100 MHz, CD₂Cl₂): δ = 159.9 (CH), 147.1 (C), 146.8 (C), 131.7 (CH), 129.9 (C), 125.4 (CH), 125.2 (CH), 70.7 (CH), 57.6 (CH₂), 48.5 (CH₂), 37.8 (CH₂), 31.0 (C), 29.2 (CH), 29.0 (CH), 27.4 (3 CH₃), 24.9 (CH₃), 24.8 (CH₃), 24.0 (CH₃), 23.9 (CH₃). ^³¹P NMR (162 MHz, CD₂Cl₂): δ = -144.5 (sept, J = 711 Hz, 1 P). ^¹9F NMR (376 MHz, CD₂Cl₂): δ = -71.53 (d, J = 711 Hz, 6 F). [α]_D ^²0 +5.4 (c 1, acetone). Anal. Calcd (%) for C₂₁H₃₅F₆N₂OP (476.24): C, 52.94; H, 7.40; N, 5.88. Found: C, 52.97; H, 7.54; N, 5.89.

14

Representative Procedure for the Copper-Catalyzed Allylic Alkylation of Dialkylzinc Reagents to Allylic Phosphates
A dried Schlenk tube, under an argon atmosphere, was charged with (CuOTf)₂˙C₆H₆ (0.005 mmol) and ligand L8 (0.01 mmol). Then, 0.5 mL of freshly distillated EtOAc was added, followed by the addition of n-BuLi (0.025 mmol). After stirring at r.t. for 10 min, the dialkylzinc reagent (3.0 mmol) was added dropwise at this temperature. After cooling the reaction vessel to 0 ˚C, the phosphate (1 mmol) was added. As soon as the addition of the substrate was completed, the ice bath was removed, and the reaction mixture was stirred at r.t. Upon completion of the reaction, 1 N HCl was added, and the compound was extracted with Et₂O. The combined organic layers were then washed with sat. NaHCO₃ aq solution, brine, and dried over MgSO₄. The solvents were carefully removed under vacuo. The crude product was purified by silica gel chromatography (100% pentane) to afford the corresponding product as a colorless oil.