Isocyanide Cyclization Reactions: 4-Methylene-4H-benzo[d][1,3]oxazine, 3-Benzyl-4-methylene-3,4-dihydroquinazolines and 3-(4-Benzyl)-3H-quinazolin-4-ones - Experiment and Theory

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‐4H‐benzoxazine derivative 4, which could be characterized by NMR spectroscopy, was formed in situ by t...

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Veröffentlicht in:European journal of organic chemistry 2013-08, Vol.2013 (22), p.4944-4952
Hauptverfasser: Neue, Benedikt, Reiermann, Ralph, Fröhlich, Roland, Wibbeling, Birgit, Bergander, Klaus, Würthwein, Ernst-Ulrich
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container_title European journal of organic chemistry
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Reiermann, Ralph
Fröhlich, Roland
Wibbeling, Birgit
Bergander, Klaus
Würthwein, Ernst-Ulrich
description 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‐4H‐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. 2‐Isocyanoacetophenone (3a) cyclizes under acid catalysis to give unstable methylene‐4H‐benzo[d][1,3]oxazine (4). Treatment of compound 3a with benzylamines 5 gives 3‐benzyl‐4‐methylene‐3,4‐dihydroquinazolines 6, which are oxidized by air into 3‐(4‐benzyl)‐3H‐quinazolin‐4‐ones 9. The reaction mechanisms were studied computationally. A six‐membered N‐heterocyclic carbene intermediate or its protonated form is suggested.
doi_str_mv 10.1002/ejoc.201300293
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Thus, a hitherto unknown rather unstable 4‐methylene‐4H‐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. 2‐Isocyanoacetophenone (3a) cyclizes under acid catalysis to give unstable methylene‐4H‐benzo[d][1,3]oxazine (4). Treatment of compound 3a with benzylamines 5 gives 3‐benzyl‐4‐methylene‐3,4‐dihydroquinazolines 6, which are oxidized by air into 3‐(4‐benzyl)‐3H‐quinazolin‐4‐ones 9. The reaction mechanisms were studied computationally. A six‐membered N‐heterocyclic carbene intermediate or its protonated form is suggested.</description><identifier>ISSN: 1434-193X</identifier><identifier>EISSN: 1099-0690</identifier><identifier>DOI: 10.1002/ejoc.201300293</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>Cyclization ; Density functional calculations ; Isocyanides ; Nitrogen heterocycles ; Oxygen heterocycles ; Reaction mechanisms ; Theory</subject><ispartof>European journal of organic chemistry, 2013-08, Vol.2013 (22), p.4944-4952</ispartof><rights>Copyright © 2013 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim</rights><rights>Copyright © 2013 WILEY-VCH Verlag GmbH &amp; Co. 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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. 2‐Isocyanoacetophenone (3a) cyclizes under acid catalysis to give unstable methylene‐4H‐benzo[d][1,3]oxazine (4). Treatment of compound 3a with benzylamines 5 gives 3‐benzyl‐4‐methylene‐3,4‐dihydroquinazolines 6, which are oxidized by air into 3‐(4‐benzyl)‐3H‐quinazolin‐4‐ones 9. The reaction mechanisms were studied computationally. 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J. Org. Chem</addtitle><date>2013-08</date><risdate>2013</risdate><volume>2013</volume><issue>22</issue><spage>4944</spage><epage>4952</epage><pages>4944-4952</pages><issn>1434-193X</issn><eissn>1099-0690</eissn><abstract>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‐4H‐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. 2‐Isocyanoacetophenone (3a) cyclizes under acid catalysis to give unstable methylene‐4H‐benzo[d][1,3]oxazine (4). Treatment of compound 3a with benzylamines 5 gives 3‐benzyl‐4‐methylene‐3,4‐dihydroquinazolines 6, which are oxidized by air into 3‐(4‐benzyl)‐3H‐quinazolin‐4‐ones 9. The reaction mechanisms were studied computationally. A six‐membered N‐heterocyclic carbene intermediate or its protonated form is suggested.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><doi>10.1002/ejoc.201300293</doi><tpages>9</tpages></addata></record>
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subjects Cyclization
Density functional calculations
Isocyanides
Nitrogen heterocycles
Oxygen heterocycles
Reaction mechanisms
Theory
title Isocyanide Cyclization Reactions: 4-Methylene-4H-benzo[d][1,3]oxazine, 3-Benzyl-4-methylene-3,4-dihydroquinazolines and 3-(4-Benzyl)-3H-quinazolin-4-ones - Experiment and Theory
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