Solid-Phase Synthesis of 3H-Quinazolin-4-ones Based on an Aza Wittig-Mediated annulation Strategy

Abstract

Aza Wittig-mediated annulation provides a highly efficient and straightforward strategy for the parallel synthesis of 3H-quinazolin-4-ones on solid support. The products were recovered in good yields and exhibited excellent purities.Combinatorial chemistry and related multiple synthesis technologies toward the synthesis of small organic molecules have recently emerged as powerful tools for lead structure identification. Thus, numerous protocols have already been disclosed for the construction of various heterocyclic and other compound libraries 1-8 . For most of these protocols, the use of solid phase methods has been the technique of choice 9-11 . As a part of our ongoing project devoted toward the development of efficient solid phase methodologies for the combinatorial and parallel synthesis of diverse heterocyclic systems 11,12 we have focused our attention on the benzopyrimidone (quinazoline) nucleus 1. (Figure 1) Figure 13H-Quinazolin-4-ones of type 1 represent an interesting pharmacophore that displays a wide rage of biological properties [13][14][15] . Therefore, an efficient strategy for the combinatorial and parallel synthesis of this interesting target, that allows the introduction of a high degree of molecular diversity, would be of interest.Herein, we report a highly versatile solid phase synthesis of quinazolinones 1, which efficiently combines the aza Wittig reaction with a multidirectional cleavage process. As recent literature has discussed in depth, [16][17][18][19][20][21][22] iminophosphoranes have been shown to be useful intermediates in organic synthesis, particularly for the preparation of different heterocyclic systems containing an endocyclic C,N double bond. In these cases, an aza Wittig-mediated annulation reaction was involved as the key step. Our working hypothesis began with the idea that a benzoic acid derivative containing an ortho-azido 2, or an ortho-amino group 3 would be tethered to the Merrifield resin and would provide the starting point for the formation of the corresponding phosphorylimine derivative 4 via a Kirsanov 19 or a Staudinger 23 reaction respectively.Division of the polymer bound iminophosphorane beds 4, followed by suitable manipulations and a cyclative cleavage process from the resin, would produce various heterocycles. We envisioned that this strategy could be applied efficiently to create compound libraries of diverse fused pyrimidones 5. (Scheme 1).To prove the above mentioned hypothesis, easily available ortho-azido benzoic acid 24 6 was selected as a model case. Thus, alkylative esterification of 6, via the corresponding cesium salt 25 , with high loaded Merrifield resin (3.4 mmol/g) resulted in polymer-bound ortho-azido Scheme 1 Scheme 2Downloaded by: National University of Singapore. Copyrighted material. 1406LETTERS SYNLETT ester 7. Treatment of 7 with a 5-fold excess PPh 3 in THF at room temperature produced the corresponding iminophosphorane 8 attached to the resin (evolution of N 2 clearly detected). Division of the resin beads and subsequent aza Witti...

Recent Advances in the Solid-Phase Combinatorial Synthetic Strategies for the Quinoxaline, Quinazoline and Benzimidazole Based Privileged Structures

“…Another approach [57] based on an aza-Wittig mediated annulation has also been developed. Makino and co-workers [58] have synthesized a variety of quinazolinones by cyclocondensation of anthranilamides with a variety of orthoformates on solid-support.…”

Wahre Spurlosigkeit: eine Nomenklatur für Linker

“…Eine an die lineare Produktvorstufe angehängte NH-Funktion bewirkt folglich die intramolekulare Spaltung der Esterbindung unter Bildung der Amidspur (PACT-NÀC(O)). [ 34 [58] AUFS¾TZE A. C. Comely und S. E. Gibson ben Matthews und Rivero Synthesen von 1,3,5-trisubstituierten Hydantoinen, deren Vorteil die Vielzahl der dafür benötigten kommerziell erhältlichen Aminosäuren, primären Amine und Aldehyde ist. [58] Ein repräsentatives Beispiel für das allgemeine Verfahren ist in Schema 20 genauer wiedergegeben.…”

A facile and efficient one-pot three-step protocol for synthesis of 6-aryl-7-oxo-5-aryoxy/alkoxy-1-(p-tolyl)-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidine-3-carbonitrile

“…16 This method, which is called Eguchi aza-Wittig protocol, 17 is known as tandem aza-Wittig heterocumulene-mediated annelation, and is recently classified as reaction. 18 Although annelation of ring systems with quinazolinones by means of an aza-Wittig reaction has been developed, 19 synthesis of pyrazolo [4,3-d]pyrimidin-7-ones by means of tandem aza-Wittig reactions of iminophosphorane with aryl isocyanates and nucleophiles has received less attention. In connection with our ongoing studies on fused nitrogen-containing heterocyclic construction synthesis and drug discovery project, we have focused on the synthesis of quinazolinones and other fused heterocyclic pyrimidinones.…”