title: Secondary Interactions Arrest the Hemiaminal Intermediate To Invert the Modus Operandi of Schiff Base Reaction: A Route to Benzoxazinones.
abstract: Discovered by Hugo Schiff, condensation between amine and aldehyde represents one of the most ubiquitous reactions in chemistry. This classical reaction is widely used to manufacture pharmaceuticals and fine chemicals. However, the rapid and reversible formation of Schiff base prohibits formation of alternative products, of which benzoxazinones are an important class. Therefore, manipulating the reactivity of two partners to invert the course of this reaction is an elusive target. Presented here is a synthetic strategy that regulates the sequence of Schiff base reaction via weak secondary interactions. Guided by the computational models, reaction between 2,3,4,5,6-pentafluoro-benzaldehyde with 2-amino-6-methylbenzoic acid revealed quantitative (99%) formation of 5-methyl-2-(perfluorophenyl)-1,2-dihydro-4H-benzo[d][1,3]oxazin-4-one (15). Electron donating and electron withdrawing ortho-substituents on 2-aminobenzoic acid resulted in the production of benzoxazinones 9-36. The mode of action was tracked using low temperature NMR, UV-vis spectroscopy, and isotopic (18O) labeling experiments. These spectroscopic mechanistic investigations revealed that the hemiaminal intermediate is arrested by the hydrogen-bonding motif to yield benzoxazinone. Thus, the mechanistic investigations and DFT calculations categorically rule out the possibility of in situ imine formation followed by ring-closing, but support instead hydrogen-bond assisted ring-closing to prodrugs. This unprecedented reaction represents an interesting and competitive alternative to metal catalyzed and classical methods of preparing benzoxazinone.
authors.affiliation: Polyolefin Lab, Polymer Science and Engineering Division, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Ketan
authors.initials: K
authors.lastname: Patel
authors.affiliation: Polyolefin Lab, Polymer Science and Engineering Division, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Satej S
authors.initials: SS
authors.lastname: Deshmukh
authors.affiliation: Polyolefin Lab, Polymer Science and Engineering Division, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Dnyaneshwar
authors.initials: D
authors.lastname: Bodkhe
authors.affiliation: Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Manoj
authors.initials: M
authors.lastname: Mane
authors.affiliation: Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Kumar
authors.initials: K
authors.lastname: Vanka
authors.affiliation: Central NMR Facility, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Shinde
authors.affiliation: Central NMR Facility, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Pattuparambil R
authors.initials: PR
authors.lastname: Rajamohanan
authors.affiliation: Department of Chemistry, Indian Institute of Science, Education and Research , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Shyamapada
authors.initials: S
authors.lastname: Nandi
authors.affiliation: Department of Chemistry, Indian Institute of Science, Education and Research , Dr. Homi Bhabha Road, Pune 411008, India.
authors.forename: Ramanathan
authors.identifier: 0000-0003-4490-4397
authors.initials: R
authors.lastname: Vaidhyanathan
authors.affiliation: Polyolefin Lab, Polymer Science and Engineering Division, CSIR-National Chemical Laboratory , Dr. Homi Bhabha Road, Pune 411008, India.|Academy of Scientific and Innovative Research (AcSIR) , Anusandhan Bhawan, 2 Rafi Marg, New Delhi 110001, India.
authors.forename: Samir H
authors.identifier: 0000-0002-8442-1480
authors.initials: SH
authors.lastname: Chikkali