Enantioselective Primary Amine Catalyzed Aldol-Type Construction of Trifluoromethylated Tertiary Alcohols

Abstract

It was found that the cinchona-derived primary amines and their combined catalyst systems with chiral organic acid or Lewis acid have been successfully applied in the cross-aldol reaction of trifluoromethyl ketones and aliphatic ketones. Excellent yields and good enantioselectivities (up to 89% ee) of the resulting β-trifluoromethyl-β-hydroxy ketones were obtained in the chiral primary amine catalyzed cross-aldol reaction under different conditions, which also led to both enantiomers of the desired products. This study also demonstrated the importance of synergistic effect of chiral organic acid on the primary amine catalysis.

Key words

tertiary alcohol - primary amine - organofluorine - organocatalysis - cross-aldol reaction

• References and Notes

• 1a Kirsch P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Application. Wiley-VCH; Weinheim: 2004
• 1b Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
• 1c Fustero S, Sanz-Cervera JF, Aceña JL, Sánchez-Rosslló M. Synlett 2009; 525
• 2a Ritter KS. Chem. Eng. News 2012; 90 (9): 10
• 2b Zhang P, Wolf C. J. Org. Chem. 2012; 77: 8840
• 3a Ma JA, Cahard D. Chem. Rev. 2004; 104: 6119
• 3b Ma JA, Cahard D. Chem. Rev. 2008; 108: PR1
• 3c Shibata N, Mizuta S, Kawai H. Tetrahedron: Asymmetry 2008; 19: 2633
• 3d Nie J, Guo HC, Cahard D, Ma JA. Chem. Rev. 2011; 111: 455
• 4 List B, Lerner RA, Barbas III C. F. J. Am. Chem. Soc. 2000; 122: 2395

For selected recent reviews, see:
• 5a Scheffler U, Mahrwald R. Chem. Eur. J. 2013; 19: 14346
• 5b Hong L, Wang R. Adv. Synth. Catal. 2013; 355: 1023
• 5c Avila EP, Amarante GW. ChemCatChem 2012; 4: 1713
• 5d Pellissier H. Adv. Synth. Catal. 2012; 354: 237
• 5e Pansare SV, Paul EK. Chem. Eur. J. 2011; 17: 8770
• 5f Xu LW, Li L, Shi ZH. Adv. Synth. Catal. 2010; 352: 243
• 6a Cergol KM, Jensen P, Turner P, Coster MJ. Chem. Commun. 2007; 1363
• 6b Xu LW, Li L, Cai YF. Aldol Reaction–Homogeneous. In Encyclopedia of Catalysis [Online] . John Wiley and Sons; New York: 2011. DOI: 10.1002/0471227617.eoc219
• 6c Bisai V, Bisai A, Singh VK. Tetrahedron 2012; 68: 4541
• 7 Qiu LH, Shen ZX, Shi CQ, Liu YH, Zhang YW. Chin. J. Chem. 2005; 23: 584
• 8 Hara N, Tamura R, Funahashi Y, Nakamura S. Org. Lett. 2011; 13: 1662
• 9 Kokotos CG. J. Org. Chem. 2012; 77: 1131
• 10 Duangdee N, Harnying W, Rulli G, Neudörfl JM, Gröger H, Berkessel A. J. Am. Chem. Soc. 2012; 134: 11196
• 11 Luo S, Xu H, Chen L, Cheng JP. Org. Lett. 2008; 10: 1775
• 12a Zheng Y, Xiong HY, Nie J, Hua MQ, Ma JA. Chem. Commun. 2012; 48: 4308
• 12b Li XJ, Xiong HY, Hua MQ, Nie J, Zheng Y, Ma JA. Tetrahedron Lett. 2012; 53: 2117

For recent reviews, see:
• 13a Adachi S, Harada T. Eur. J. Org. Chem. 2009; 3661

For selected examples of organocatalytic ketone–ketone aldol reactions, see:
• 13b Chen JR, Liu XP, Zhu XY, Li L, Qiao YF, Zhang JM, Xiao WJ. Tetrahedron 2007; 63: 10437
• 13c Malkov AV, Kabeshov MA, Bella M, Kysilka O, Malyshev DA, Pluháčková K, Kočovskŷ P. Org. Lett. 2007; 9: 5473
• 13d Liu J, Yang ZG, Wang Z, Wang F, Chen XH, Liu XH, Feng XM, Su ZS, Hu CW. J. Am. Chem. Soc. 2008; 130: 5654
• 13e Zheng CW, Wu YY, Wang XS, Zhao G. Adv. Synth. Catal. 2008; 350: 2690
• 13f Guo Q, Bhanushali M, Zhao CG. Angew. Chem. Int. Ed. 2010; 49: 9460
• 13g Allu S, Molleti N, Panem R, Singh VK. Tetrahedron 2011; 52: 4080
• 13h Lu Y, Ma Y, Yang S, Ma M, Chu H, Song C. Tetrahedron: Asymmetry 2013; 24: 1082
• 13i Xu B, Li L, Gou SH. Tetrahedron: Asymmetry 2013; 24: 1556

For recent reviews, see:
• 14a Peng F, Shao Z. J. Mol. Catal. A: Chem. 2008; 285: 1
• 14b Bartoli G, Melchiorre P. Synlett 2008; 1759
• 14c Chen YC. Synlett 2008; 1919
• 14d Xu LW, Lu Y. Org. Biomol. Chem. 2008; 6: 2047
• 14e Xu LW, Luo J, Lu Y. Chem. Commun. 2009; 1807
• 14f Melchiorre P. Angew. Chem. Int. Ed. 2012; 51: 9748
• 14g Zhang L, Luo S. Synlett 2012; 1575
• 14h Narayanaperumal S, Rivera DG, Silva RC, Paixão MW. ChemCatChem 2013; 5: 2756
• 14i Xu LW, Lu Y. Non-Proline Amino Acid Catalysts. In Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications. Dalko PI. Wiley-VCH; Weinheim: 2013: 51-68
• 14j Serdyuk OV, Heckel CM, Christina M, Tsogoeva SB. Org. Biomol. Chem. 2013; 11: 7051
• 14k Tsakos M, Kokotos CG. Tetrahedron 2013; 69: 10199

For recent examples, see:
• 15a Hack D, Enders D. Synthesis 2013; 45: 2904
• 15b Avila A, Chinchilla R, Gómez-Bengoa E, Nájera C. Eur. J. Org. Chem. 2013; 5085
• 15c Cui LY, Zhu YB, Luo SZ, Cheng JP. Chem. Eur. J. 2013; 19: 9481
• 15d Zhou Y, Liu Q, Gong Y. Tetrahedron Lett. 2013; 54: 3011
• 15e Lu Y, Zou G, Zhao G. ACS Catal. 2013; 3: 1356
• 15f Xu C, Zhang L, Zhou P, Luo S, Cheng JP. Synthesis 2013; 45: 1939
• 15g Su Z, Lee HW, Kim CK. Eur. J. Org. Chem. 2013; 1706
• 15h Zhao Q, Zhong NJ, Zhang T, Liu L, Wang D, Chen YJ. Eur. J. Org. Chem. 2013; 2140
• 15i Chen YM, Lee PH, Lin J, Chen K. Eur. J. Org. Chem. 2013; 2699
• 15j Kucherenko AS, Siyutkin DE, Nigmatov AG, Chizhov AO, Zlotin SG. Adv. Synth. Catal. 2012; 354: 3078
• 15k Desmarchelier A, Coeffard V, Moreau X, Greck C. Chem. Eur. J. 2012; 18: 13222
• 15l Tsakos M, Kokotos C, Christoforos G, Kokotos G. Adv. Synth. Catal. 2012; 354: 740
• 15m Zhao H, Lan YB, Liu ZM, Wang Y, Wang XW, Tao JC. Eur. J. Org. Chem. 2012; 1935
• 15n Zhou P, Zhang L, Luo S, Cheng JP. J. Org. Chem. 2012; 77: 2526
• 15o Tuchman-Shukron L, Miller SJ, Portnoy M. Chem. Eur. J. 2012; 18: 2290
• 15p Tsakos M, Kokotos CG. Eur. J. Org. Chem. 2012; 576
• 15q Xiong XF, Zhou Q, Gu J, Dong L, Liu TY, Chen YC. Angew. Chem. Int. Ed. 2012; 51: 4401
• 16a Yang W, Jiang KZ, Lu X, Yang HM, Li L, Lu YX, Xu LW. Chem. Asian J. 2013; 8: 1182

And for recent examples of the Michael reaction of aliphatic aldehydes with maleimides reported by other groups, see:
• 16b Yu F, Jin ZC, Huang HC, Ye TT, Liang XM, Ye JX. Org. Biomol. Chem. 2010; 8: 4767
• 16c Xue F, Liu L, Zhang SL, Duan WH, Wang W. Chem. Eur. J. 2010; 16: 7979
• 16d Nugent TC, Sadiq A, Bibi A, Heine T, Zeonjuk LL, Vankova N, Bassil BS. Chem. Eur. J. 2012; 18: 4088
• 17a Bartoli G, Bosco M, Carlone A, Pesciaioli F, Sambri L, Melchiorre P. Org. Lett. 2007; 9: 1403
• 17b Yang HM, Li L, Jiang KZ, Jiang JX, Lai GQ, Xu LW. Tetrahedron 2010; 66: 9708
• 17c Cai YF, Yang HM, Li L, Jiang KZ, Lai GQ, Jiang JX, Xu LW. Eur. J. Org. Chem. 2010; 4986
• 17d Loh CC. J, Enders D. Chem. Eur. J. 2012; 18: 10212
• 17e Xu LW, Yang HM, Shao ZH. Multi-Catalyst Systems. In Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications. Dalko PI. Wiley-VCH; Weinheim: 2013: 1333-1357
• 17f Zhu L, Xi ZG, Lv J, Luo SZ. Org. Lett. 2013; 15: 4496
• 17g Shang JY, Li L, Lu Y, Yang KF, Xu LW. Synth. Commun. 2014; 44: 101

Although fluorine-containing compounds (such as CF₃-containing molecules) might generally be expected to show significant level of the self-disproportionation of enantiomers (SDE) via achiral chromatography, we found no such effect was observed in this work after column chromatography. In spite of this, special care should be taken in collecting the entire product after column chromatography. For such phenomena, see:
• 18a Sorochinsky AE, Aceña JL, Soloshonok VA. Synthesis 2013; 45: 141
• 18b Soloshonok VA, Roussel C, Kitagawa O, Solochinsky AE. Chem. Soc. Rev. 2012; 41: 4180
• 18c Han J, Nelson DJ, Sorochinsky AE, Soloshonok VA. Curr. Org. Synth. 2012; 8: 310
• 19a General Procedure for Aldol Reaction of Acetone with Trifluoroacetophenone (Method A): To a mixture of QD-NH₂ (10 mol%), (R)-mandelic acid (10 mol%) was added aluminium isopropoxide (10 mol%), then the solvent (mesitylene, 0.5 mL), α,α,α-trifluoroacetophenone (0.2 mmol), and acetone (10 equiv, 2.0 mmol) were added subsequently, and the resulting solution was stirred at 35 °C for 12 h and monitored by TLC. The crude mixture was directly purified by column chromatography (silica gel, petroleum ether–EtOAc mixtures) to obtain pure products. The products were characterized by NMR, GC–MS, and IR analysis. And the ee values of the aldol products were determined by chiral-phase HPLC analysis using a Chiralcel OD-H column and the indicated eluent systems. (b) General Procedure for Aldol Reaction of Acetone with Trifluoroacetophenone (Method B): In a typical experiment, to a solution of QN-NH₂ and (R)-mandelic acid (10 mol%) in mesitylene (0.5 mL), α,α,α-trifluoroaceto-phenone (0.2 mmol), and acetone (2.0 mmol) were added subsequently, and the resulting solution was stirred at 35 °C for 12 h and monitored by TLC. The crude mixture was directly purified by column chromatography (silica gel, petroleum ether–EtOAc mixtures) to obtain pure products. The products were characterized by NMR, GC–MS, and IR analysis. And the ee values of the aldol products were determined by chiral-phase HPLC analysis using a Chiralcel OD-H column and the indicated eluent systems. 5,5,5-Trifluoro-4-hydroxy-4-phenylpentan-2-one (3a): colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (m, 2 H), 7.29 (m, 3 H), 5.37 (s, 1 H), 3.20 (q, J = 17.2 Hz, 2 H), 2.11 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 208.9, 137.3, 128.7, 128.4, 126.1, 125.8 (q, J = 283.3 Hz), 76.1 (d, J = 29.0 Hz), 45.0, 32.0. ¹⁹F NMR (376.5 MHz, CDCl₃): δ = –80.35 (s). IR (KBr): 3442.06, 2925.93, 2854.48, 2361.57, 2344.25, 2069.04, 1704.18, 1630.33, 1497.43, 1451.38, 1401.52, 1337.98, 1164.09, 1061.96, 1000.83, 906.86, 765.69, 736.64, 709.62, 633.02, 573.40, 525.79 cm^–1. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₁F₃NaO₂: 255.0603; found: 255.0616. Method A: 42 mg, 90% yield, 81% ee; [α]_D ²⁰ 15.16 (c = 0.30, CHCl₃). HPLC analysis: Chiralcel OD-H column, i-PrOH–hexane, 5:95; flow rate = 1.0 mL/min, λ = 210 nm, t _major = 14.12 min, t _minor= 8.33 min. Method B: 32 mg, 70% yield, 81% ee; [α]_D ²⁰ – 21.89 (c = 0.80, CHCl₃). HPLC analysis: Chiralcel OD-H column, i-PrOH–hexane, 5:95; flow rate = 1.0 mL/min, λ = 210 nm, t _major = 7.91 min, t _minor = 13.76 min.