Quinazoline electrophilic substitution

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]. 

Electrophilic substitution in quinazolines takes place in the benzene ring, although mixtures of products are often obtained <1996CHEC-II(6)93, 1996FIC(55)1>. Eor example, the bromination of quinazoline 65 with NBS in sulfuric acid at room temperature gave only a 27% yield of 6-bromoquinazoline 66, in addition to a mixture of other products which included tri- and tetrabrominated compounds < 2002883 >. 

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. 

Tin, zinc, boron, and mercury metallopyrimidines in alkylation and arylation reactions Acylation by electrophilic substitution Acylation by palladium-catalyzed reactions with stannanes Tin metallopyrimidines in acylation reactions Coupling reactions in quinazolines and perimidines Alkylation and arylation by organometallic adduct formation... 

Electrophilic substitution in quinazoline takes place in the benzene ring theoretical prediction of positional reactivity is 8 > 6 > 5 > 7 4. 4(3//)-Quinazolinone was converted into a mixture of 6-and 8-chloro, and 6,8-dichloro products <57JCS252I>. Initial bromination of 4(3/7)-quinazolinone and its 3-methyl derivative is in the 6-position with slow formation of the 6,8-dibromoquinazolinone. Below pH 2, when the former substrate and its A3-methyl derivative exist mainly as cations, the latter was brominated slightly faster. The pathway is believed to involve bromine attack on covalent hydrates <76JOC838, 93AHC(58)27I>. 

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. 

Kinetic studies have been carried out on the displacement reactions of various chloroazanaphthalenes with ethoxide ions and piperi-dine. - 2-Chloroquinoxaline is even more reactive than 2-chloro-quinazoline, thus demonstrating the powerfully electrophilic nature of the -carbon atoms in the quinoxaline nucleus. The ease of displacement of a-chlorine in the quinoxaline series is of preparative value thus, 2-alkoxy-, 2-amino-, - 2-raethylamino-, 2-dimethyl-amino-,2-benzylamino-, 2-mercapto-quinoxalines are all readily prepared from 2-chloroquinoxaline. The anions derived from substituted acetonitriles have also been used to displace chloride ion from 2-chloroquinoxaline, ... 

El-Hiti reported an in-depth study of the regioselective Iithiation of numerous substituted quinazolines and subsequent trapping of these nucleophiles with an array of electrophiles <00H1839>. As a representative example, Iithiation of dichloroquinazoline 150 gave rise to further substituted quinazolines 151. 

The high electrophilic character of the 2- and 4-positions in quinazoline makes hydrolysis to oxo derivatives relatively easy, and both 2- and 4-chloro substituents can be hydrolyzed in either alkaline or acid solution. The significantly higher reactivity in the 4-position simplifies stepwise substitutions, and the synthesis of 2-chloro-4(3//)-quinazoli-nones 173 is readily performed from the dichloro compounds 172 with sodium or potassium hydroxide at room temperature <2003BMC2439, 20050PD80, 2006H(67)489, 20060PD391>. 

Apart from early reports on the bromination of quinazolinones which gave undefined products, reports dealing with the direct introduction of a halogen into a quinazoline nucleus via the electrophilic reaction are scarce, probably because these derivatives are more easily accessible by cyclization of appropriate halogen-substituted precursors (cf. Section 6.3.1.1.1.). Quinazolin-4(3//)-one can be brominated by bromine in aqueous potassium bromide solution... 

Regioselective lithiation on the benzene moiety of 4-substituted quinazolines occurs at position peri to the N1 ring nitrogen. Thus, treatment of 4-methoxyquinazolines 8 with an excess of lithium 2,2,6,6-tetramethylpiperidide (LTMP) at — 78 to 0 X followed by reaction with various electrophiles affords 8-substituted quinazoline derivatives 9. This regioselective lithiation provides easy access to a large range of substituted quinazolines which are not easily synthesized by other routes. ... 

With 2-unsubstituted quinazolines, in some exceptional cases, lithiation at position 2 is observed. When position 8 in the benzene ring is blocked by a substituent, metalation with lithium 2,2,6,6-tetramethylpiperidide followed by reaction with various electrophiles affords only 7-substituted quinazolines in very good yields. All attempts to functionalize the C5 position via the metalation reaction have failed. 

Alkoxy derivatives in the electrophilic positions are readily available by nucleophilic substitution reactions as discussed for the oxo derivatives above. 2,4-Dialkoxyquinazolines can be prepared by boiling 2,4-dichloroquinazolines with two equivalents of alkali alkoxide in the appropriate alcohol. Mixed ethers (137) are possible because of the great difference in positional reactivity the first substitution is in the 4-position (136). 4-Chloro- and 2,4-dichloro-quinazoline very readily suffer alcoholysis in the 4-position with acid catalysis, presumably via 4-adduct formation as in the facile hydrolysis discussed above. 

The high electrophilicity of the 4-position in quinazoline makes this position very reactive towards nucleophilic additions such as in alkylation by acetophenone, acetone, 2-butanone, or cyclohexanone, which all have been reported to add across the 3,4-double bond (283) (Scheme 45). Alkyl-and arylmagnesium halides and phenyllithium add similarly to give the corresponding 4-substituted 3,4-dihydroquinazolines (284) . 

Reactions of benzodiazines show no exceptional features compared with the simple diazines. Reactivity towards electrophiles is less than in quinoline and isoquinoline. If S Ar reactions take place, they lead to substitution of the benzene ring. As a rule, nucleophilic substitution of benzodiazines occur in the diazine ring, particularly if substituted by halogen. The quinazoline system displays C-4 regioselectivity, e.g. in the reactions of 2,4-dichloroquinazoline with amines or alcohols ... 

Chen and collaborators developed an efficient, regioselective, Cu(II)-catalyzed one-pot synthesis of substituted quinazolines via a [2 + 2 + 2] cascade annulation of diaryliodonium salts with two nitriles. The authors proposed the following mechanism (Scheme 34) (13CC6752). The first nitrile reacts with the diaryliodonium salt to form A/-arylnitrilium intermediate 72, which is treated with the second nitrile to give an intermediate 73. Subsequent electrophilic aromatic substitution yielded the desired multi-substituted quinazolines 74 in moderate-to-good yields. 

The copper-catalyzed cascade annulation of nitriles, diaryliodonium salts, and alkynes was recently described by Chen and coworkers. N-Arylation of the nitrile resulted in an V-arylnitrilium intermediate, which was trapped by the aUcyne and subsequently underwent electrophilic annulation to yield substituted quinolines (Scheme 6d) [107]. The concept was later varied to reach polycyclic quinolines, quinazolines, quinazolinimine, and acridine scaffolds [108—110], A similar cascade reaction delivered iminobenzoxazines by N-aiylation of ort/io-cyanoanilides followed by C-O cyclization [111], and the reactimi of nitriles with [1,1-biphenyl]-derived iodonium salts resulted in phenanthiidines [112]. The corresponding C-arylation cascade reactions are discussed in Sect. 4.3. 

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