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. 2019 Feb 15;21(4):984-988.
doi: 10.1021/acs.orglett.8b03959. Epub 2019 Jan 29.

B(C6F5)3-Catalyzed C-H Alkylation of N-Alkylamines Using Silicon Enolates without External Oxidant

Jessica Z Chan  1 , Yejin Chang  1 , Masayuki Wasa  1
Affiliations

B(C6F5)3-Catalyzed C-H Alkylation of N-Alkylamines Using Silicon Enolates without External Oxidant

Jessica Z Chan et al. Org Lett. .

Abstract

An efficient method for the coupling of N-alkylamines with silicon enolates to generate β-amino carbonyl compounds is disclosed. These reactions proceed by activation of α-amino C-H bonds by B(C6F5)3, which likely generates a "frustrated" acid/base complex in the presence of large N-alkylamines. The transformation requires no external oxidant and releases hydrosilane as a byproduct. The utility of this method is demonstrated in the late-stage functionalization of bioactive molecules such as citalopram, atomoxetine, and fluoxetine.

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Figures

Figure 1.
Figure 1.
Coupling of N-Alkylamines and Silicon Enolates
Scheme 1.
Scheme 1.
Evaluation of N-Aryl Substituents a,b a Conditions: N,N-dimethylaniline (0.1 mmol), 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.2 mmol), B(C6F5)3 (20 mol %), dichloroethane (0.25 mL), under N2, 22 °C, 12 h. b Yields were determined by 1H NMR analysis of unpurified product mixtures with mesitylene as the internal standard. See the Supporting Information for details.
Scheme 2.
Scheme 2.
Evaluation of Different N-Alkylamines a,b a Conditions: N,N-dialkylaniline (0.2 mmol), 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (0.4 mmol), B(C6F5)3, solvent (0.5 mL), under N2, 22 °C, 12 h. b Yield of purified products. c B(C6F5)3 (5.0 mol %) was used. d Benzene (0.5 mL) was used. e THF (0.5 mL) was used. f B(C6F5)3 (10 mol %) and benzene (0.5 mL) were used and reaction was performed at 50 °C. g Benzene (0.5 mL) was used and reaction was performed at 70 °C. See the Supporting Information for details.
Scheme 3.
Scheme 3.
Evaluation of Various Silicon Enolates a,b a Conditions: N,N-dialkylaniline (0.2 mmol), silicon enolate (0.4 mmol), B(C6F5)3 (10 mol %), solvent, under N2, 22 °C, 12 h. b Yield of purified products. c Benzene (0.5 mL) was used. d THF (0.5 mL) was used. See the Supporting Information for details.
Scheme 4.
Scheme 4.
Scale-Up Synthesis and Late-Stage Functionalization of Bioactive Molecules a See the Supporting Information for details.
See this image and copyright information in PMC

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