Late stage functionalization has emerged as an attractive strategy for the diversification of lead compounds in drug development, not only because of its step reducing nature but also as a means of accessing synthetically challenging compounds. Many of these rely on transition metal catalyzed C-H activation enabled by coordination to a directing group. Ideally such late stage functionalization protocols take advantage of the directing effect of functional groups that are already present in the biologically active compound in order to provide predictable selectivity for specific C-H bonds. At the same time, a high level of functional group tolerance is key to allow for the functionalization of unprotected complex molecules.<br/>Focusing our efforts on the installation of the smallest alkyl group, we have developed a cobalt catalyzed C-H methylation protocol. The chemistry is facilitated by a broad scope of directing groups commonly found in organic molecules and because it relies on a methyl source that has a low propensity for nucleophilic or electrophilic attack and is performed under mild conditions, an excellent functional group tolerance is observed. To highlight the applicability of the transformation, a diverse array of biologically active molecules was C-H activated and methylation in one simple step, thus avoiding the need for prefunctionalization or post-reaction deprotection.

Cobalt-catalyzed C-H methylation for late stage functionalization

2019 Spring National Meeting

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