Synthesis of Quinazolines and Quinazolinones

A considerable number of quinazolines and quinazolinones are still being prepared by conventional and well known syntheses, but only new and unusual modifications of known synthesis are described in this section. The section is divided into four parts. The first is on the synthesis of quinazolines in which the pyrimidine ring retains its complete aromatic character (i.e., three conjugated double bonds), and the other three parts are on the synthesis of quinazolines with oxygen, and/or sulfur atoms at the 2-, 4-, and 2,4-positions. 

The oxygen atom in the aromatic pyrylium salts is known to be readily exchanged (e.g., with ammonia) to provide the respective nitrogen hetero-cycle. This substitution in the nucleus is also successful for the quinazoline series and a few 2-substituted-4-phenylquinazolines were prepared by treating 2-substituted-4-phenyl-3,l-benzoxazin-3-ium perchlorates (11) with ammonia.  

Irradiation of aqueous solutions of (5)-tryptophan at pH 6-9 containing a photosensitizer (e.g., eosin) caused destruction of the amino acid and formation of N -formylkynurenine as the major product. Similar irradiation in dilute ammonia at pH 8-9 gave an optically active compound in 13% yield, which was shown to be 4-(2 -amino-2 -carboxyethyl)quinazoline (12). 

Racemic tryptophan similarly gave 4,/-12, the methyl ester and 2-methyl derivatives gave the corresponding quinazolines, but the JV-acetyl derivative failed to yield a quinazoline and gave AT-acetyl-iV -formylkynurenine. Clearly the pyrrole ring was cleaved, and then reaction with ammonia followed by ring closure, gave the quinazoline. This is probably how the metabolism of tryptophan takes place in the quinazoline pathway in Pseudomonas (see Section VIII). 

A study of all the stages in the synthesis of 4-aminoquinazolines from isatoic anhydride, via anthranilamide and o-aminobenzonitrile, made possible the preparation of these compounds by a one-pot synthesis. The anhydride was treated with ammonia in dimethylformamide, nitrogen was then bubbled through the solution to remove excess of ammonia, phosphoryl chloride was added and heated at 40°-60°C for conversion into the nitrile, and finally the respective amine was added to yield the 4-(substituted-amino)-quinazolines in 44-79% yields.  

In a novel transformation the /1-oximes of isatins gave oN, Af -dimeth-ylaminomethyleneaminobenzonitriles (13) with the Vilsmeier reagent (Me2NCHO—POCl3). The nitriles were cyclized to 4-aminoquinazolines with ammonium acetate in 70-80% yields.75 

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The Bischler and Niementowski syntheses are the most important methods for the synthesis of quinazolines and quinazolinones, with the latter and more well-known reaction being m improvement on the Bischler synthesis. Additional methods for the synthesis of quinazoline and quinazolinone ring systems involve various rearrangement reactions and metal-mediated processes. Examples of these reactions are illustrated below. 

The Niementowski synthesis is still used today to prepare a host of quinazolines and quinazolinones of biological significance. For example, the original Niementowski synthesis was used as a key step in the synthesis of gefitinib (Iressa) by Richards and co-workers. ° Fusion of 4,5-dimethyoxyanthranilic acid and formamide fiimished the desired quinazolinone in 20% yield. This yield was significantly improved in later work by Orfi and co-workers using formadine acetate and formamide under microwave conditions to provide the product in quantitative yield. 

Transition metal-promoted reactions have recently become important in the synthesis of the basic core structures of quinazolines and quinazolinones. While many of the examples below are not necessarily biologically relevant in and of themselves, they highlight important areas of development in the synthesis of these ring classes that can be employed in the future synthesis of compounds with greater biological significance. 

The same methodology can be applied to the synthesis of pharmaceutically relevant quinazolines and quinazolinones containing a fused alicyclic ring [45,46]. 

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>. 

As stated above, the synthesis of quinazoline derivatives can also be conducted in two stages, i.e., by the reaction of isatoic anhydrides with ammonia, amides, and various compounds containing the NH2 group followed by cyclization of the obtained anthranilic acid derivatives. Thus, the amino amides 157, formed during the action of aqueous ammonia on the anhydrides 61 (yields 61-73%), were brought into reaction with orthoformic ester, and this led to the quinazolinones 158 (yields 53-78%) [79],... 

The Bischler synthesis is still practical today for the synthesis of 2-substituted quinazolines and quinazolinones. However, it has been largely replaced by the Neimentowksi reaction, which can be conducted under milder conditions and is therefore more practical for synthesis highly functionalized quinazolines and quinazolinones. 

The Niementowski synthesis, first described in 1895, remains one of the most important methods for synthesizing quinazolines and quinazolinones. This reaction involves condensation of anthranilic acids with formamide or acetamide derivatives to form the intermediate quinazoline-4(3//)-ones under thermal conditions. 

The synthesis of several commercially available and biologically significant quinazolines and quinazolinones are illustrated below. In most cases, the quinazoline or quinazolinone ring system is constructed from acyclic precursors and then functionalized accordingly. 

Since Watanabe s synthesis of 4(3H)-quinazolinones in 1993 via transition-metal catalyzed reductive N-heterocychzation [ 181 ], several catalytic methods for quinazoline synthesis have been developed [182-186]. For example, palladium-catalyzed cyclocarbonylations of halides with appropriate reactants provided regioselective synthesis of 4(3H)-quinazolinone derivatives [182] and indoloquinazolines [184]. Also selenium-catalyzed reductive N-heterocyclization to quinazolinones has been developed by Sonoda et al. [183]. Copper-catalyzed heteroannulation with alkynes has been developed as highly region- and stereoselective route to 2-(2-arylvinyl)-l,2,3,4-tetrahydroquinazolin-4-ones 64 by Kimdu et al. [ 185] (Scheme 12). Recently, condensation of anthranylamide with various aldehydes to 4-quinazotinones has been found to give excellent yields in the presence of cupric chloride [186]. 

For synthesis of quinazoline derivatives, various coupling reactions have been utilized after synthesis of quinazoline-2,4(lH,3H)-diones via palladium-catalyzed oxidative coupling by Hirota et aL [187]. For example, synthesis of diarylquinazolines by iron-catalyzed cross-coupling reaction [188], and diamino quinazolinones by palladium-catalyzed amination [171] have been developed Synthetic applications to quinazoline alkaloids are given in Sect. 3. 

Scheme 60 Synthesis of 2-substituted quinazolinones and quinazolines via Cul-catalyzed N-arylation of amidines...

The synthesis of substituted quinazolin-4(. 7/)-ones and quinazolines via directed lithiation has been reviewed <2000H(53)1839>, and the topic has also been briefly discussed in a more general review on the synthesis of quinazolinones and quinazolines <2005T10153>. For example, the lithiation of 4-methoxyquinazoline 312 with LiTMP followed by reaction with acetaldehyde gave only a minor amount of the 2-substituted product 313, with the major product 314 being the result of lithiation at the 8-position in the benzene ring <1997T2871>. 

However, perhaps the simplest route to quinazoline derivatives involves the heating of 2-aminobenzamides with formic acid to give 4(3//)-quinazolinones, where the formic acid provides the solvent, the C-2 synthon, and the acid catalysis of the ring-closure step. For example, in the synthesis of the imidazoquinazolinone 798, both the imidazo and pyrimidine rings were formed simply by heating the triamino amide 797 in formic acid for 2h <1996JME918>. 

A similar rapid microwave one-pot synthesis of substituted quinazolin-4-ones was also reported, which involved cyclocondensation af anthranilic acid, formic acid (or an orthoester) and an amine under solvent-free conditions (Scheme 3.37)61. A complimentary approach was adopted to synthesise 4-aminoquinazolines in very good yields, involving the reaction of aromatic nitrile compounds with 2-aminobenzonitrile in the presence of a catalytic amount ofbase (Scheme 3.38)62. The reactions were performed in a domestic microwave oven and required only a very short heating time. A microwave-assisted synthesis of a variety of new 3-substituted-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters has also been described (Scheme 3.38)63. 

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. 

Nitrogen Heterocycles.- Reactions of iminophosphoranes have been used to prepare a wide range of heterocycles. Examples of compounds prepared by intramolecular aza-Wittig reactions include 3,4-dihydroquinazolines (191) and quinazolines (192), quinazoline derivatives (e.g. 193),pyrrolo( 1,2-a)quinoxalines (194), indolo[3,2-clquinolines (195), and indolo[l,2-c]quinazolines (196),"8 imidazolinones (197),"9 quinazolinones (198),"9, 120 pyrido[2,3-d]pyrimidine derivatives (199), 21 and 4,5-dihydropyrazolo(3,4-d]pyrimidine derivatives (200). 22 Tributyl(cyclohepta-1,3,5-trienylimino)phosphorane (201), prepared by thermal isomerization of the 2,4,6-derivative, reacts with a,p-unsaturated ketones to give 9H-cyclohepta[b]pyridine derivatives (202). 23 a synthesis of (2,4)pyridinophanes (204) by the reaction of N-vinyliminophosphoranes (203) with a,P-unsaturated ketones has been reported. 24... 

Chakraborty et al. (26) synthesized 1 by cyclization of the < -acyl-aminobenzamide 13 with diphosphorus pentoxide. Kametani et al. have developed a one-step synthesis of quinazolinone derivatives by condensation of sul-phinamide anhydrides generated from anthranilic acids and thionyl chloride with amides (27,28), imines (29,30), or thioamides (31). This reaction was applied to the synthesis of 1 (28,31,32), glycosminine (6) (28,31), glomerin (2) (27,31), homoglomerin (27), glycerine (3) (27), chrysogine (7) (27), and other quinazoline alkaloids (Scheme 1). 

In the synthesis of 2-alkylthio-3-quinazolin-4-ones 76 reported by Powers, treatment of isatoic anhydride (74), derived from anthranilic acid, with aminoacetonitrile followed by reaction with thiophosgene provided the quinazolinone 75 <01JHC419>. Alkylation of 75 led to the thioethers 76 in good to excellent yields. A very similar compound, quinazolin-2.4-dione 78, was synthesized from 77 and aminoacetonitrile bisulfate <01JOC4723>. 

Kametani and co-workers have applied their preparation of quinazolines from sulphinamide anhydrides cf. Vol. 8, p. 83) to the synthesis of the alkaloids glycorine (33 R = Me, R = H), glomerine (33 R = R = Me), and homo-glomerine (33 R = Me, R = Et). The reaction of the sulphinamide anhydride derived from anthranilic acid with O-benzyl-lactic acid amide furnished the quinazolinone [34 R = CH(OBz)Me], which was converted into the alkaloid crysogine [34 R = CH(OH)Me] by acid hydrolysis. 

Independently, Zhou and co-workers used the same approach in their synthesis of highly functionalized quinazolines as potential anti-cancer therapeutics. In one example, fusion of 2-amino-3,4,5-trimethoxybenzoic acid with formamide under thermal conditions gave the desired quinazolinone in 25% yield. A dibenzofliran quinazoline derivative produced using this process exhibited anti-proliferative properties against several tumor types, including Bcap-37, PC3, A431, and BGC823 cell lines. 

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