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Synlett 2014; 25(10): 1461-1465
DOI: 10.1055/s-0033-1341281
DOI: 10.1055/s-0033-1341281
letter
Enantioselective Primary Amine Catalyzed Aldol-Type Construction of Trifluoromethylated Tertiary Alcohols
Weitere Informationen
Publikationsverlauf
Received: 22. Februar 2014
Accepted after revision: 07. April 2014
Publikationsdatum:
20. Mai 2014 (online)
![](https://www.thieme-connect.de/media/synlett/201410/lookinside/thumbnails/10.1055-s-0033-1341281-1.jpg)
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 reactionSupporting Information
- for this article is available online at http://www.thieme-connect.com/products/ejournals/journal/ 10.1055/s-00000083.
- Supporting Information
-
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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.
For selected recent reviews, see:
For recent reviews, see:
For selected examples of organocatalytic ketone–ketone aldol reactions, see:
For recent reviews, see:
For recent examples, see:
And for recent examples of the Michael reaction of aliphatic aldehydes with maleimides reported by other groups, see:
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: