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Isocyanide Cyclization Reactions: 4‐Methylene‐4 H ‐benzo[ d ][1,3]oxazine, 3‐Benzyl‐4‐methylene‐3,4‐dihydroquinazolines and 3‐(4‐Benzyl)‐3 H ‐quinazolin‐4‐ones – Experiment and Theory
Author(s) -
Neue Benedikt,
Reiermann Ralph,
Fröhlich Roland,
Wibbeling Birgit,
Bergander Klaus,
Würthwein ErnstUlrich
Publication year - 2013
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201300293
Subject(s) - chemistry , methylene , isocyanide , protonation , carbene , medicinal chemistry , nuclear magnetic resonance spectroscopy , reaction mechanism , stereochemistry , combinatorial chemistry , organic chemistry , catalysis , ion
2‐Isocyanoacetophenone ( 3a ) was found to be an easily accessible starting material for the unexpected formation of various heterocyclic systems. Thus, a hitherto unknown rather unstable 4‐methylene‐4 H ‐benzoxazine derivative 4 , which could be characterized by NMR spectroscopy, was formed in situ by the reaction of 3a in the presence of weak acids. In the presence of benzylamines, a new class of 3,4‐dihydroquinazoline derivatives 6 and their oxidation products, quinazolin‐4‐ones 9 , were obtained. The starting materials and products were completely characterized by spectroscopic and X‐ray analysis. The scope and limitations of these cyclization reactions were investigated under various reaction conditions. High‐level quantum chemical calculations were carried out to elucidate the mechanisms leading to scaffolds 4 and 6 . The calculations suggest that the formation of 4 and 6 involves the generation of an unusual six‐membered N ‐heterocyclic carbene or its C ‐protonated form as a reaction intermediate, followed by tautomerisation. This mechanism might also be applicable to other isocyanide cyclization reactions.