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Synlett 2014; 25(10): 1461-1465
DOI: 10.1055/s-0033-1341281
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© Georg Thieme Verlag Stuttgart · New York

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

Wei Yang
a   College of Material Chemistry and Chemical Engineering, and Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, P. R. of China   Fax: +86(571)28868918   Email: licpxulw@yahoo.com   Email: liwenxu@hznu.edu.cn
,
Yu-Ming Cui
a   College of Material Chemistry and Chemical Engineering, and Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, P. R. of China   Fax: +86(571)28868918   Email: licpxulw@yahoo.com   Email: liwenxu@hznu.edu.cn
,
Wei Zhou
a   College of Material Chemistry and Chemical Engineering, and Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, P. R. of China   Fax: +86(571)28868918   Email: licpxulw@yahoo.com   Email: liwenxu@hznu.edu.cn
,
Li Li*
a   College of Material Chemistry and Chemical Engineering, and Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, P. R. of China   Fax: +86(571)28868918   Email: licpxulw@yahoo.com   Email: liwenxu@hznu.edu.cn
,
Ke-Fang Yang
a   College of Material Chemistry and Chemical Engineering, and Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, P. R. of China   Fax: +86(571)28868918   Email: licpxulw@yahoo.com   Email: liwenxu@hznu.edu.cn
,
Zhan-Jiang Zheng
a   College of Material Chemistry and Chemical Engineering, and Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, P. R. of China   Fax: +86(571)28868918   Email: licpxulw@yahoo.com   Email: liwenxu@hznu.edu.cn
,
Yixin Lu
b   Department of Chemistry and Medicinal Chemistry Program, Life Sciences Institute, National University of Singapore, 3 Science Drive 3, 117543 Singapore, Republic of Singapore
,
Li-Wen Xu*
a   College of Material Chemistry and Chemical Engineering, and Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 310012, P. R. of China   Fax: +86(571)28868918   Email: licpxulw@yahoo.com   Email: liwenxu@hznu.edu.cn
c   State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics and University of Chinese Academy of Sciences, Chinese Academy of Sciences, Lanzhou 730000, P. R. of China
› Author Affiliations
Further Information

Publication History

Received: 22 February 2014

Accepted after revision: 07 April 2014

Publication Date:
20 May 2014 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/products/ejournals/journal/ 10.1055/s-00000083.
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  • References and Notes

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    • 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.