Transnitrilation from Dimethylmalononitrile to Aryl Grignard and Lithium Reagents: A Practical Method for Aryl Nitrile Synthesis

Jonathan T. Reeves; Christian A. Malapit; Frederic G. Buono; Kanwar P. Sidhu; Maurice A. Marsini; C. Avery Sader; Keith R. Fandrick; Carl A. Busacca; Chris H. Senanayake

doi:10.1021/jacs.5b06136

Transnitrilation from Dimethylmalononitrile to Aryl Grignard and Lithium Reagents: A Practical Method for Aryl Nitrile Synthesis

Jonathan T. Reeves^*, Christian A. Malapit, Frederic G. Buono, Kanwar P. Sidhu, Maurice A. Marsini, C. Avery Sader, Keith R. Fandrick, Carl A. Busacca, Chris H. Senanayake

^*Corresponding author for this work

Chemistry

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Abstract

An electrophilic cyanation of aryl Grignard or lithium reagents, generated in situ from the corresponding aryl bromides or iodides, by a transnitrilation with dimethylmalononitrile (DMMN) was developed. DMMN is a commercially available, bench-stable solid. The transnitrilation with DMMN avoids the use of toxic reagents and transition metals and occurs under mild reaction conditions, even for extremely sterically hindered substrates. The transnitrilation of aryllithium species generated by directed ortho-lithiation enabled a net C-H cyanation. The intermediacy of a Thorpe-type imine adduct in the reaction was supported by isolation of the corresponding ketone from the quenched reaction. Computational studies supported the energetic favorability of retro-Thorpe fragmentation of the imine adduct. (Chemical Equation Presented).

Original language	English (US)
Pages (from-to)	9481-9488
Number of pages	8
Journal	Journal of the American Chemical Society
Volume	137
Issue number	29
DOIs	https://doi.org/10.1021/jacs.5b06136
State	Published - Jul 29 2015

ASJC Scopus subject areas

General Chemistry
Biochemistry
Catalysis
Colloid and Surface Chemistry

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Reeves, J. T., Malapit, C. A., Buono, F. G., Sidhu, K. P., Marsini, M. A., Sader, C. A., Fandrick, K. R., Busacca, C. A., & Senanayake, C. H. (2015). Transnitrilation from Dimethylmalononitrile to Aryl Grignard and Lithium Reagents: A Practical Method for Aryl Nitrile Synthesis. Journal of the American Chemical Society, 137(29), 9481-9488. https://doi.org/10.1021/jacs.5b06136

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title = "Transnitrilation from Dimethylmalononitrile to Aryl Grignard and Lithium Reagents: A Practical Method for Aryl Nitrile Synthesis",

abstract = "An electrophilic cyanation of aryl Grignard or lithium reagents, generated in situ from the corresponding aryl bromides or iodides, by a transnitrilation with dimethylmalononitrile (DMMN) was developed. DMMN is a commercially available, bench-stable solid. The transnitrilation with DMMN avoids the use of toxic reagents and transition metals and occurs under mild reaction conditions, even for extremely sterically hindered substrates. The transnitrilation of aryllithium species generated by directed ortho-lithiation enabled a net C-H cyanation. The intermediacy of a Thorpe-type imine adduct in the reaction was supported by isolation of the corresponding ketone from the quenched reaction. Computational studies supported the energetic favorability of retro-Thorpe fragmentation of the imine adduct. (Chemical Equation Presented).",

author = "Reeves, {Jonathan T.} and Malapit, {Christian A.} and Buono, {Frederic G.} and Sidhu, {Kanwar P.} and Marsini, {Maurice A.} and Sader, {C. Avery} and Fandrick, {Keith R.} and Busacca, {Carl A.} and Senanayake, {Chris H.}",

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AU - Buono, Frederic G.

AU - Sidhu, Kanwar P.

AU - Marsini, Maurice A.

AU - Sader, C. Avery

AU - Fandrick, Keith R.

AU - Busacca, Carl A.

AU - Senanayake, Chris H.

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N2 - An electrophilic cyanation of aryl Grignard or lithium reagents, generated in situ from the corresponding aryl bromides or iodides, by a transnitrilation with dimethylmalononitrile (DMMN) was developed. DMMN is a commercially available, bench-stable solid. The transnitrilation with DMMN avoids the use of toxic reagents and transition metals and occurs under mild reaction conditions, even for extremely sterically hindered substrates. The transnitrilation of aryllithium species generated by directed ortho-lithiation enabled a net C-H cyanation. The intermediacy of a Thorpe-type imine adduct in the reaction was supported by isolation of the corresponding ketone from the quenched reaction. Computational studies supported the energetic favorability of retro-Thorpe fragmentation of the imine adduct. (Chemical Equation Presented).

AB - An electrophilic cyanation of aryl Grignard or lithium reagents, generated in situ from the corresponding aryl bromides or iodides, by a transnitrilation with dimethylmalononitrile (DMMN) was developed. DMMN is a commercially available, bench-stable solid. The transnitrilation with DMMN avoids the use of toxic reagents and transition metals and occurs under mild reaction conditions, even for extremely sterically hindered substrates. The transnitrilation of aryllithium species generated by directed ortho-lithiation enabled a net C-H cyanation. The intermediacy of a Thorpe-type imine adduct in the reaction was supported by isolation of the corresponding ketone from the quenched reaction. Computational studies supported the energetic favorability of retro-Thorpe fragmentation of the imine adduct. (Chemical Equation Presented).

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Transnitrilation from Dimethylmalononitrile to Aryl Grignard and Lithium Reagents: A Practical Method for Aryl Nitrile Synthesis

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