Abstract
The development of green Buchwald–Hartwig aminations has long been considered challenging, due to the high sensitivity of the reaction to the environment. Here we show that food-grade and waste vegetable oils, triglycerides originating from animals, and natural waxes can serve as excellent green solvents for Buchwald–Hartwig amination. We further demonstrate that amphiphiles and trace ingredients present in triglycerides as additives have a decisive effect on the yields of Buchwald–Hartwig aminations.
Highlights
IntroductionAccording to a recent study, over 62% of bioactive molecules described in the medicinal chemistry literature possess a C−N bond in the form of primary, secondary, or tertiary amines.[1] While different variations of C(sp3)−N bond forming reactions were invented over a century ago, C(sp2)−N bond construction was quite challenging until the late 1990s but was effectively resolved by the invention of the Buchwald−Hartwig amination.[2,3] The significance of the Buchwald−Hartwig amination was demonstrated by Brown et al in their study on past and present synthetic methodologies used in medicinal chemistry, where the Buchwald−Hartwig amination was found to be among the top 20 most frequently used reactions.[4] Similar surveys by Schneider et al.[5] on the methodologies used in pharmaceutical patents and Gillet et al.[6] on an analysis of Electronic Lab. Notebooks of a major pharmaceutical company further evidenced the importance of Buchwald−Hartwig amination for the pharmaceutical industry
C−N bonds are omnipresent in natural products and pharmaceuticals
We were interested in the development of conditions suitable for Buchwald−Hartwig amination in vegetable oils
Summary
According to a recent study, over 62% of bioactive molecules described in the medicinal chemistry literature possess a C−N bond in the form of primary, secondary, or tertiary amines.[1] While different variations of C(sp3)−N bond forming reactions were invented over a century ago, C(sp2)−N bond construction was quite challenging until the late 1990s but was effectively resolved by the invention of the Buchwald−Hartwig amination.[2,3] The significance of the Buchwald−Hartwig amination was demonstrated by Brown et al in their study on past and present synthetic methodologies used in medicinal chemistry, where the Buchwald−Hartwig amination was found to be among the top 20 most frequently used reactions.[4] Similar surveys by Schneider et al.[5] on the methodologies used in pharmaceutical patents and Gillet et al.[6] on an analysis of Electronic Lab. Notebooks of a major pharmaceutical company further evidenced the importance of Buchwald−Hartwig amination for the pharmaceutical industry. Among Pd-catalyzed cross-coupling reactions, the Buchwald−Hartwig amination was invented and established most recently (Figure 1A). One reason for the slow development may be that the Buchwald−Hartwig amination is very sensitive to the reaction conditions, including the Pd precatalyst, the ligand, the additives, and the solvent. The reproducibility of previously developed methodologies can vary drastically depending on the origin and quality of the reagents used, the Pd source, and solvents.2a,7 This was well illustrated by Richardson et al, who performed a model Buchwald−
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