02509nas a2200241   4500008004100000245014200041210006900183260000800252300001400260490000700274520163100281100001701912700002401929700002401953700001601977700001701993700001902010700003502029700002202064700003002086700002402116856012702140       2017                        eng d00aSecondary interactions arrest the hemiaminal intermediate to invert the modus operandi of schiff base reaction: a route to benzoxazinones0 aSecondary interactions arrest the hemiaminal intermediate to inv  cAPR  a4342-43510 v823 aDiscovered 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-6methylbenzoic acid revealed quantitative (99%) formation of 5-methyl-2-(perfluoropheny01,2-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 936. The mode of action was tracked using low temperature NMR, IN vis spectroscopy, and isotopic (O-18) 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.1 aPatel, Ketan1 aDeshmukh, Satej, S.1 aBodkhe, Dnyaneshwar1 aMane, Manoj1 aVanka, Kumar1 aShinde, Dinesh1 aRajamohanan, Pattuparambil, R.1 aNandi, Shyamapada1 aVaidhyanathan, Ramanathan1 aChikkali, Samir, H.  uhttps://library.ncl.res.in/content/secondary-interactions-arrest-hemiaminal-intermediate-invert-modus-operandi-schiff-base