Taming a carbene with a single substituent

By designing a right substituent, we have shown that aminomethylene, otherwise believed to be stable only in vacuo, can be tamed in vitro.

Go to the profile of Ryo Nakano
Oct 16, 2018

For a long time, carbenes were regarded as fleeting intermediates, but every chemistry-major student learns that the high reactivity of transient carbenes has allowed for spectacular synthetic developments. Since the isolation of the first stable disubstituted carbenes, (phosphino)(silyl)carbene I by us in 1988 and imidazol-2-ylidenes II by Arduengo in 1991, these historically believed to be transient species have evolved from simple laboratory curiosities to unavoidable actors of modern chemistry. In fact, no one would have expected that in the last 30 years these species would be extended their reach beyond organic and organometallic chemistry, to find applications even in medicinal and materials science.  

The Bertrand group continued interested in understanding the ambiphilicity of stable carbenes, lead to the discovery of the mono(hetero)substituted cyclic and acyclic alkyl(amino)carbenes III, which have been shown to exhibit more electrophilic and nucleophilic characters than di(heteroatom)substituted carbenes.

To further advance this field, we naturally set out on a project to synthesize the first stable monosubstituted carbene IV, which constitutes the missing link between the stable disubstituted carbenes I­–III and transient parent methylene V. Theoretically, the mono(amino)substituted IV should possess a large enough singlet-triplet gap to allow for its isolation using standard laboratory techniques. However, capitalizing on our long experience in this field, we also rationalized that without kinetic protection (steric) the free carbene should naturally dimerize.

The answers to this synthetic challenge are provided in our report. Herewith we show for the first time that a monosubstituted carbene IV can be isolated and stored at room temperature. The synthesis of the monosubstituted carbene was achieved in just three steps. Bulky benzo[c]pyrrolidine backbones were constructed by one-pot Grignard additions on N-methylphthalimide, an extrapolation of the method of Heidenbluth and Scheffler. Then, the N-methyl was converted into the N-methylene iminium by alpha-oxidation using nitrosonium cation (NO+), and finally deprotonated by a strong base to yield the monosubstituted carbene. The monosubstituted carbene features a highly electrophilic nature and is reactive enough to undergo cyclopropanation reactions with unactivated alkenes. The latter reaction was, so far, only known for non-isolable transient carbenes, and thus clearly shows that the isolable monosubstituted carbene lies between stable disubstituted carbenes and transient carbenes. With the synthetic simplicity of the benzo[c]pyrrolidine backbone, we believe that the bulky amino substituents developed here will be a suitable platform for the stabilization and isolation of other fleeting organic and organometallic species.



Go to the profile of Ryo Nakano

Ryo Nakano

Research Associate, Nagoya University

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