Quinazoline, nitration

Coumarins undergo nitration readily in the 6-position, while bromination results in substitution at the 3-position as a consequence of an additionelimination sequence. Quinazolines nitrate in the benzene ring for example, 5-chloro-4 (3//)-quinazolinonc nitrates at C(8) <2005BMC5613> and 5-fluoro-4(3//)-quinazolinone gives a 4 1 mixture of the 6- and 8-nitro derivatives <1991JHC1459>. 

Little is known quantitatively about substituent effects in the nitration of derivatives of azanaphthalenes. In preparative experiments 4-hydroxy-quinoline, -cinnoline, and -quinazoline give the 6- and 8-nitro compounds, but with nitric acid alone 4-hydroxyquinoline and 2,4-di-hydroxyquinoline react at With nitric acid, 4-hydroxycinnoline... 

There are few reports on the reactivity of aryl substituents attached to pyrimidine or quinazoline. However, nitration may be carried out with some success. 

The sole known example of electrophilic substitution in quinazoline is nitration. Quinazoline gives 6-nitroquinazoline with fuming nitric acid in concentrated sulfuric acid. No oxidation of the heterocyclic ring can occur under these conditions because the hydrated cation (see Section IIA>4) is not present. This substitution is in agreement with theoretical calculation [see (2) and reference 36]. 

Nitration of 3,4-dimethoxypropiophenone (91) affords the nitro derivative 92, and catalytic reduction leads to the aminoketone (93). This is then converted to the corresponding formamide by means of formic-acetic anhydride. Treatment with ammonia Completes Construction of the quinazoline ring. 

Nitration of 6,7,8,9-tetrahydro-117/-pyrido[2,l-6]quinazolin-l 1 -one (7) with a 1 1 mixture of cone, nitric acid and cone, sulfuric acid at -5°C for... 

Reaction of 6-formyl-5,7,8,9-tetrahydro-ll//-pyrido[2,l-b]quinazolin-ll-one (135) with Clayfen [K-10 montmorillonite clay supported iron(III) nitrate] in boiling methylene chloride for 2.5 h gave a mixture of 6,6-dinitro-6,7,8,9-tetrahydro (136) and 6-formyl-8,9-dihydro-ll//-pyrido[2,l-6]-quinazolin-ll-ones (137) (90JOC6198). 

Little is known quantitatively about substituent effects in the nitration of derivatives of azanaphthalenes. In preparative experiments 4-hydroxy-quinoline, -cinnoline, and -quinazoline give the 6- and 8-nitro compounds, but with nitric acid alone 4-hydroxyquinoline and 2,4-di-hydroxyquinoline react at C(3).31 With nitric acid, 4-hydroxycinnoline still gives mainly 4-hydroxy-6-nitrocinnoline, but some of the 3-nitro compound can also be isolated.81 51 The change of orientation with reagent could be due to a change to free-base nitration in the more weakly acidic medium, or to the occurrence in nitric acid of nitration via nitrosation.31... 

Quinazoline (11.16) nitrates in the 6-position, and because theoretical calculations predict 8- > 6-substitution (the 5- and 7-positions are each conjugatively deactivated by both nitrogens), it has been assumed that reaction must involve the hydrated quinazolinium cation (11.93) (47JOC405 49JCS1367). However, these calculations may not take sufficient account of inductive deactivation of the 8-position the deficiency of the calculations in this respect will be particularly marked if no auxiliary inductive parameter is used for the bridgehead carbon between the 1- and 8-positions. 

Acridine 613, phenanthridine 614, cinnoline 615, and quinazoline 616 are nitrated as shown in Figure 3. 

Nitration is the most common electrophilic substitution reaction of quinazolines. Theoretical considerations predict that the order of reactivity for nitration in different positions is (8) > 6 > 5 > 7 (4) > (2). Values in parentheses are for positions where an accurate value of the reactivity could not be estimated (cf. p 3). Mononitration of quinazoline with fuming nitric acid in concentrated sulfurie acid yields h-nitroquinazoline. Nitrations of various quinazolines 1, quinazoliti-4(3/7)-ones 3, and quinazoline-2,4(l f,3Af)-diones 5 evidence this reactivity order with 6- and/or 8-substitution as the major feature. 

NO is less electrophilic than NO2 therefore, nitrosation of quinazolines is less efficacious than nitration and is used only rarely for introduction of substituents in the quinazoline nucleus. Nitrosation of quinazolin-6-ol with sodium nitrite in aqueous hydrochloric acid affords 5-nitro-soquinazolin-6-ol in 80% yield. ... 

Quinazoline is quantitatively converted into 2- ert-butylquinazolin-4(3//)-one by treating it in aqueous solution with an excess of pivalic acid and ammonium peroxydisulfate at pH 0-1 in the presence of a catalytic amount of silver nitrate. At pH 5 where the concentration of a covalent hydrate is too small to influence the course of the reaction, it is converted into a mixture of 2-rcrr-butylquinazoline, 4-rc-Tr-butylquinazoline, and 2,4-di-to7-butylquinazoline in a ratio of 4 3 2. ° ... 

Quinazolines bearing a hydroxy, alkoxy, or amino group at position 5 or positions 5 and 8 can be oxidized by various oxidizing agents [e.g., ammonium cerium(IV) nitrate (CAN)] to give quinazoline-5,8-dioncs 1 with loss of aromaticity. 

Binz and Rath reported in 1931 that nitration of the pyrido[2,l-i>]quin-azolinone 286 with 30% nitric acid in concentrated sulfuric acid at 30 Cgave the 2-nitropyrido[2,l- )]quinazoline 218, whereas with 67% nitric acid in concentrated sulfuric acid at 50°C the 2,8-dinitro derivative 372 (R = H) was obtained. (The structures originally suggested for the products were not correct.)... 

Nitration of the 8-nitropyrido[2,l-6]quinazoline 364 with nitric acid in concentrated sulfuric acid led to the 2,8-dinitro derivative 372 (R = H) at... 

Nitration of quinazoline is in the 6-position in the benzene ring. 2- and 4-Substituted quinazolines are likewise nitrated in the 6-position <49JCS1354), but 4-chloro-2-phenylquinazoline reacts with mixed nitrating acid at 0°C to yield the w-nitrophenyl derivative with concomitant loss of the chloro substituent, the product isolated being 2-w-nitrophenyl-4(3/f)-quinazolinone <91UP 602-01). 

Quinazolinamines with the amino groups in the heterocyclic ring are prepared by the same sort of reactions as reviewed for pyrimidines. Amination, by way of electrophilic substitution, for example, by nitration or nitrosation in the carbocyclic ring, is substituent dependent and may have to be carried out in a precursor before formation of the quinazoline ring system. 

A number of procedures for the preparation of 2-substituted quinazo-lines were reported in 2013. Wu and coworkers prepared 2-substituted quinazolines via a copper-catalyzed cascade synthesis by treating (2-ami-nophenyl) methanols 68 with aromatic aldehydes in the presence of copper(I) chloride, cerium nitrate hexahydrate, ammonium chloride, and potassium hydroxide in acetonitrile in moderate-to-high yields (Scheme 31) (13JOC11342). Electron-withdrawing substituents on either the (2-aminophenyl)methanol or the aromatic aldehyde resulted in a decrease in yield. 

---