Radical reactions with 3H-quinazolin-4-ones: synthesis of deoxyvasicinone, mackinazolinone, luotonin A, rutaecarpine and tryptanthrin

Abstract

Alkyl, aryl, heteroaryl and acyl radicals have been cyclised onto the 2-position of 3H-quinazolin-4-one. The side chains containing the radical precursors were attached to the nitrogen atom in the 3-position. The cyclisations take place by aromatic homolytic substitution hence retain the aromaticity of the 3H-quinazolin-4-one ring. The highest yields were obtained using hexamethylditin to facilitate cyclisation rather than reduction without cyclisation. The alkaloids deoxyvasicinone 2, mackinazolinone 3, tryptanthrin 4, luotonin A 5 and rutaecarpine 8 were synthesised by radical cyclisation onto 3H-quinazolin-4-one.The 3H-quinazolin-4-one ring system is important to the biological activity of both naturally occurring alkaloids, biosynthesised from anthranilic acid, and pharmaceuticals. The alkaloids include vasicinone 1 and deoxyvasicinone 2, 1 mackinazolinone 3, 2 tryptanthrin 4, 3 luotonins A 5, B 6 and E 7 4 and rutaecarpine 8. 5 3H-Quinazolin-4-one alkaloids have been recently reviewed. 6 All the 3H-quinazolin-4-one natural products have interesting biological activity and have therefore been extensively investigated for useful pharmaceutical activity. The 3H-quinazolin-4-one ring is regarded as a 'privileged structure' in combinatorial synthesis. 7 These are structures which represent molecules that are capable of binding at multiple sites with high affinity and facilitate more rapid discovery of useful medicinally active compounds. 7Our study involved the development of protocols involving radical cyclisation for the synthesis of polycyclic 3H-quinazolin-3-ones (Scheme 1). The protocols have also been used for the synthesis of novel polycyclic quinazolinones including the natural Department of Chemistry, Loughborough University, Loughborough, Leics, UK LE11 3TU. E-mail: g.w.weaver@lboro.ac.uk; Fax: 44(0) 1509 223925; Tel: 44(0) All of the above cyclisations are 'oxidative' i.e. the intermediate p-radicals are not reduced by triorganometal hydrides [e.g. tributyltin hydyride (Bu 3 SnH)] as normally observed for these reagents. The cyclisations proceed by aromatic homolytic substitution with abstraction of hydrogen in a rearomatisation process. Aromatic homolytic substitution has been recently reviewed 27 and the mechanism of Bu 3 SnH mediated 'oxidative' cyclisation elaborated. 28 The pyrimidin-4-one ring of the quinazolin-4-ones has some aromaticity and therefore aromatic homolytic substitution could be predicted, and was observed in our studies, as shown in Scheme 1 (9 to 11 via the p-radical 10). However, the lower aromaticity could favour reductive cyclisation in which the intermediate p-radical 10 is intercepted by reagents such as Bu 3 SnH. Our prediction that radical cyclisation onto the quinazolin-4-one ring would be 'oxidative' was supported by the 'oxidative' radical cyclisation onto related ring systems, e.g. pyrimidine-2,4-diones, 23,24This journal is

Synthesis and Crystal Structure of 3-(4-Methoxyphenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one

“…The title compound was synthesized by slight modification of a reported method [11] according to the route depicted in Figure 1. 4-Methoxyaniline in DMSO was treated with carbon disulfide and aqueous sodium hydroxide to afford sodium 4-methoxyphenylcarbamodithioate (1) followed by reaction with dimethyl sulfate to furnish the methyl 4-methoxyphenylcarbamodithioate (2).…”

Synthesis of tryptanthrin and deoxyvasicinone by a regioselective lithiation-intramolecular electrophilic reaction approach

“…15 In view of the importance of tryptanthrin and its attractive in vitro properties, synthesis of tryptanthrin has been pursued intensively. It includes annulation of quinazolinone, 16 reductive Nhetero-cyclization, 17 acyl radical cyclization, 18 from isatin, 5 and from 2-indolinone. 19 Similarly, deoxyvasicinone has been synthesized using various methods.…”

“…19 Similarly, deoxyvasicinone has been synthesized using various methods. It includes intramolecular azaWittig reaction, 20 reductive N-heterocyclization, 21 azido-reductive cyclization, 14 solid-phase synthesis, 22 microwave-assisted domino reactions, 23 polymer-supported reagents, 24 radical cyclization, 18 and many other methods. 25 Among these none have employed the strategy of regioselective lithiation at C-2 of quinazolinone followed by reaction with an electrophile in an intramolecular fashion forming C-C bond to generate the cyclized product.…”

One-Pot Synthesis of Simple Alkaloids: 2,3-Polymethylene-4(3<i>H</i>)-quinazolinones, Luotonin A, Tryptanthrin, and Rutaecarpine

“…[38][39][40][41][42][43] As a part of our research on biologically important natural products, we herein described a simple one-pot procedure for the preparation of 1 as well as related alkaloids 3, 4 and 5 in multi-gram quantity.…”

“…10,12) Nevertheless, the biological importance of 4(3H)-quinazolinone and related compounds still spurred the development of a new and simple synthetic method for theses compounds. [38][39][40][41][42][43] As a part of our research on biologically important natural products, we herein described a simple one-pot procedure for the preparation of 1 as well as related alkaloids 3, 4 and 5 in multi-gram quantity.…”