Quinazolines solid-phase synthesis

The same approach was readily adaptable to solid-phase synthesis. A small library of unnatural derivatives of 140 was prepared with variation of the configuration and nature of R1 and R4 and with substitution on the benzene ring <2000JC0186>. Three natural alkaloids, Verrucine A, B, and Anacine, were synthesized by a similar pathway and the pyrazino[2,l- ]quinazoline as opposed to the benzodiazepine structure of Anacine was proved <2001JNP1497>. Fiscalin B and other derivatives were prepared by solid-phase synthesis using polyethylene glycol (PEG) resin <2002USP6376667>. 

Tripeptides with N-terminal anthranilic acid part were used as starting materials in the solid-phase synthesis carried out on TentaGel resin to prepare 1,4,11,1 l -tetrahydro-2//-pyrazino[2,l-3]quinazoline-3,6-diones with various N-l and N-3 substituents <2003EPP1471066>. Tandem cyclization from [6+0] atom fragments took place in the solid-phase synthesis of 143 from 142. Intermediate 141 was built on bromoacetal resin (Scheme 17) <1998JOC3162>. 

In analogous fashion to isocyanate chemistry, isothiocyanates like 125 can be utilized to produce the corresponding quinazoline-2-thioxo-4-ones. Makino and co-workers reported the solid phase synthesis of quinazoline derivatives 126 through the reaction of polymer-bound primary amines 124 with isothiocyanates 125 <00TL8333>. 

The solid phase synthesis of quinazoline 114 was reported by Abell and co-workers, in which a traceless linker was utilized <99TL1045>. The key step in this procedure was the removal of the desired quinazoline from the resin with concurrent decarboxylation to produce 114 in 69% yield from 113. 

An efficient microwave-assisted multi-step synthesis of8//-quinazolino [4,3-b] quina-zolin-8-one has been investigated by Besson and co-workers77. The synthesis involved two Niementowski condensations starting from substituted anthranilic acids (Scheme 3.49). Both homogeneous and heterogeneous conditions were studied in an effort to develop a convenient synthesis of the desired compounds. The solventless procedure allowed easier access to the quinazolino[4,3-fi]quinazolin-8-ones and gave better yields than the method performed in the presence of solvents. However, the procedure with solvents would offer the possibility of investigating the microwave-assisted solid-phase synthesis of these quinazolinones, which would faciltate purification of the final products. 

Gordeev MF, Hui HC, Gordon EM, Patel DV, A general and efficient solid phase synthesis of quinazoline-2,4-diones, Tetrahedron Lett., 38 1729-1732, 1997. 

Solid-phase syntheses of pyrimidines continue to appear at a rapid pace. Solid-phase syntheses of olomoucine from 4,6-dichloro-2-(methylthio)-5-nitropyrimidine <02TL8071> and of 2,6-disubstituted 4(3//)-quinazolinones from 2,4-dichloro-6-hydroxyquinazoline <02TL2971> have been developed. 2-(Arylamino)quinazolinones 83 were accessed by a traceless parallel solid-phase route from 2-nitrobenzamides 82 <02JOC5831>. A solid-phase synthesis of quinazolin-4(3W)-ones with 3-point diversity relied on the use of immobilized arylguanidines <02TL5579>. 

Keywords Aza-Wittig reaction Quinazolinone annelation Quinazoline alkaloids -Microwave-assisted synthesis Solid-phase synthesis... 

The topical synthetic methodologies such as iminophosphorane mediated synthesis (aza-Wittig methodology), microwave-assisted synthesis, solid-phase synthesis, and application of organometalUc reagents, etc., will be discussed retrospectively focusing on the pathways to quinazoline, quinazoline-4-one and their derivatives. 

Castelhano et al. described the solid-phase synthesis of quinazoline-2,4-diones 313 based on the chemistry of acyl azides. Phthalic acid was immobilized on a PEG4-PS resin and converted into acyl azide 310 with DPPA and triethylamine in toluene. Curtius rearrangement, followed by reaction with a primary amine and subsequent cyclocleavage with K2CO3 gave quinazoline-2,4-diones 313 in good yield (Scheme 3.48). 

Gorl997b Gordeev, M.F., Hui, H.C., Gordon, E.M. and Patel, D.V., A General and Efficient Solid Phase Synthesis of Quinazoline-2,4-diones, Tetrahedron Lett., 38 (1997) 1729-1732. 

Goul996 Gouilleux, L., Fehrentz, J.-A., Wintemitz, F. and Martinez, J., Solid Phase Synthesis of Chiral 3-Substituted Quinazoline-2,4-diones, Tetrahedron Lett., 37 (1996) 7031-7034. 

Related quinazoline alkaloids have also been prepared using SPOS. For example, in 2001, Wang and Sim reported on the solid-phase synthesis of verrucine A 18 and its... 

Eguchi S (2006) Quinazoline Alkaloids and Related Chemistry. 6 113-156 Erd lyi M (2006) Solid-Phase Methods for the Microwave-Assisted Synthesis of Heterocycles. 1 79-128... 

A recent example of the parallel synthesis of different quinazoline-2,4-dione derivatives (46) demonstrates how to combine the advantages of fluorous synthesis with those of solid-phase chemistry without using expensive perfluorinated solvents [22] (Scheme 3.22). In the beginning, a fluorous benzyl alcohol (47) is adsorbed on fluorous reversed-phase silica gel (FRPSG). Then, in a sequence of splits and reactions, the linker group, which remains bound to the FRPSG by fluorophilic interactions, is converted into a library of differently substituted carboxamido-urethanes (48). These are cyclized and the liberated quinazoline-2,4-diones (46) are eluted from the support with the fluorophobic solvents water and CHjCN/... 

Fused pyrimidine-2,4-diones are important heterocyclic pharmacophores examples include natural purine bases, alkaloids, and pteridines. Benzo derivatives in this series (quinazoline-2,4-diones) bear ample precedence as potent ligands and inhibitors of receptors and enzymes of pharmaceutical interest. Based on these precedents, Gordeev et al. reported a solid-phase protocol for the synthesis of fused pyrimidine-2,4-diones. 

The fourth chapter Quinazoline Alkaloids and Related Chemistry by Shoji Eguchi provides a perspective review focusing on developements of the synthetic methodologies and their synthetic applications. A brief historical background, aza-Wittig methodology, microwave-assisted synthesis, solid-phase... 

Smil996a Smith, A.L., Thomson, C.G. and Leeson, P.D., An Efficient Solid Phase Synthetic Route to 1,3-Disubstituted (1H,3H)-Quinazoline-2,4-diones Suitable for Combinatorial Synthesis, Bioorg. Med. Chem. Lett., 6 (1996) 1483-1486. 

---