title: Revisiting a Classic Transformation: A Lossen Rearrangement Initiated by Nitriles and "Pseudo-Catalytic" in Isocyanate.
abstract: The direct conversion of a hydroxamic acid to an amine has been accomplished in a single step in the synthesis of HIV drug candidate BMS-955176. This process utilizes catalytic base and proceeds under mild conditions (CH3CN, cat. DBU, 60 °C), without the need for strong electrophiles required for typical Lossen rearrangements, and can be applied to aliphatic and aromatic hydroxamic acids. Through investigation of the kinetics of this transformation, a mechanism was revealed involving a novel initiation pathway and a self-propagation cycle. The initiation pathway involves activation of hydroxamic acid by nitriles and subsequent Lossen rearrangement to generate the corresponding isocyanate. The isocyanate functions as a "pseudo-catalyst" for this system, leading to generation of product through a second Lossen rearrangement and regeneration of a new isocyanate molecule. Thorough mechanistic understanding allowed for this highly efficient process to be implemented on a 55 kg scale in 95.5% isolated yield.
authors.affiliation: Chemical and Synthetic Development, Bristol-Myers Squibb , One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Neil A
authors.identifier: 0000-0002-5350-8735
authors.initials: NA
authors.lastname: Strotman
authors.affiliation: Chemical and Synthetic Development, Bristol-Myers Squibb , One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Adrian
authors.identifier: 0000-0001-5273-9024
authors.initials: A
authors.lastname: Ortiz
authors.affiliation: Chemical and Synthetic Development, Bristol-Myers Squibb , One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Savage
authors.affiliation: Chemical and Synthetic Development, Bristol-Myers Squibb , One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Wilbert
authors.affiliation: Chemical and Synthetic Development, Bristol-Myers Squibb , One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Sloan
authors.initials: S
authors.lastname: Ayers
authors.affiliation: Chemical and Synthetic Development, Bristol-Myers Squibb , One Squibb Drive, New Brunswick, New Jersey 08903, United States.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kiau