Masked acyl cyanide (MAC) reagents are useful moieties that demonstrate umpolung reactivity by serving as an oxidation state 3 nucleophilic equivalent. Their weakly acidic methine hydrogen can be activated by a mild base, such as a tertiary amine, which makes them compatible in organocatalyzed reactions. TBS-MAC is a silyl-protected MAC reagent that is synthesized in three steps: 1) acetylation of malononitrile to form the sodium enolate, 2) protonation of the enolate to form acetylmalononitrile, and 3) epoxidation of the enol, rearrangement to form an unstable alcohol, and finally TBS-protection to form the title compound. While the synthesis of TBS-MAC is published in the literature, we have found complications including difficult to remove by-products, water solubility during workup, and scalability issues. These factors contributed to inconsistent yields and reproducibility in our hands. We have reworked the first two steps completely to provide high yields at various scales by taking advantage of solubility differences and filtration, without requiring any purification. For the third step, we have scaled up and can reproducibly synthesize the unstable hydroxymalononitrile intermediate, which is then protected and purified resulting in consistent yields of 55-70% for TBS-MAC.

Three-step synthesis of the masked acyl cyanide TBS-MAC

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