Transnitrilation

The preparation of nitrile-containing organic molecules has garnered attention from synthetic chemists for over a century due to their prevalence in pharmaceuticals and their versatile nature as synthetic intermediates. We have developed new synthetic methods that use non-toxic, bench-stable nitrile-transfer reagents for the synthesis of nitriles.

Ni Catalyzed Reductive Cyanations

We have reported the synthesis of benzonitriles from aryl (pseudo)halides via a Ni-catalyzed reductive cyanation using 2-methyl-2-phenylmalononitrile (MPMN) as the transnitrilation reagent (Scheme 5a). The mild reaction conditions, which are typical of reductive cross couplings, lead to a broad reaction scope, including a range of heteroaryl halides and various base-sensitive functional groups. In this report, we also demonstrate that soluble bromide salts act as an “on/off” switch for oxidative addition of more challenging aryl chloride and phenol-derived electrophiles. We have also reported that alkenyl nitriles can be prepared from alkenyl triflates and tosylates in the presence of TBABr (Scheme 5b). These C(sp2)–OR electrophiles are derived from readily available ketones while the corresponding alkenyl halides are more challenging to prepare.

We are continuing to develop new Ni-catalyzed reductive cross-couplings that involve transnitrilation. This includes a three-component reductive hydrocyanation of alkynes (Scheme 5c), which uncovered that trace amounts of formaldehyde, resulting from oxidized impurities in N,N-dimethylacetamide (DMA), played a critical role in the transformation. This study also revealed a new mechanistic manifold for MPMN in the presence of low-valent Ni, involving reductive coupling of MPMN and formaldehyde to slowly release glycolonitrile in situ. Overall, these findings have significant impacts beyond transnitrilation, since DMA is a commonly employed solvent in Ni-catalyzed reductive couplings.

Key References:
1) Mills, L. R.; Graham, J. M.; Patel, P.; Rousseaux, S. A. L. J. Am. Chem. Soc. 2019, 141, 19257–19262.
2) Graham, J. M.; Rousseaux, S. A. L. Chem. Commun. 2025, 61, 893–896.
3) Palermo, A. F.; Chiu, B. S. Y.; Patel, P.; Rousseaux, S. A. L. J. Am. Chem. Soc. 2023, 145, 24981–24989.

Malononitrile Desymmetrization Reactions

Inspired by our work using MPMN as a transnitrilation reagent, we have explored malononitrile (MN) decyanation as a platform to further valorize MN in synthesis. MN is an inexpensive building block that can be easily functionalized due to its relative acidity compared to acetonitrile. The ability to desymmetrize these products via decyanation is an exciting yet nearly unexplored strategy for the synthesis of nitriles.

We have developed two complementary approaches to access valuable α-(hetero)aryl nitriles from malononitrile derivatives. Our first approach proceeds via decyanation, mediated by MeMgBr, and subsequent SNAr reaction with electron-poor aryl electrophiles (Scheme 6, top path). Our second approach involves a Ni-catalyzed arylation (post-transnitrilation) (Scheme 6, lower path). The development of benzonitrile ligand L1 was crucial for the success of this reaction; L1 favours a challenging reductive elimination to form a quaternary center over competing β hydride elimination (when R1 or R2 = alkyl).

Key References:
1) Mills, L. R.; Patel, P.; Rousseaux, S. A. L. Org. Biomol. Chem. 2022, 20, 5933–5937.
2) Mills, L. R.; Edjoc, R. K.; Rousseaux, S. A. L. J. Am. Chem. Soc. 2021, 143, 10422–10428.