2-substituted-4 quinazolinones

The first attempts to hydroformylate quinazolinone-substituted allyl amines under smooth conditions (10-40bar, 60-80°C) led to hydrogenation [100]. Only higher temperature and a syngas composition not equal to 1 produced the desired product. Similar conditions also allowed HAM of this substrate with phenylhydrazine derivatives (Scheme 5.116). By this protocol, other aminobutyl-substituted quinazolin-4(3//)-ones with biological activity in the central nervous system could also be prepared. 

Scheme 5.116 Hydroaminomethylation of quinazolinone-substituted allyl amines with phenylhydrazine and some products with pharmaceutical relevance.

Methyl-4-hydroxyquinazoline reacts with organic halides, in the presence of sodium methoxide, to give 3-substituted 2-methyl-4(3i/)-quinazolinones. The 0-acetyl derivative of 4-hydroxyquinazoline has been prepared under anhydrous conditions and gives the hydroxy compound with water or with lithium aluminum hydride. The N-3 acetyl derivative, however, is more stable and gives 3-methyl-4(31/)-quinazolinone with lithium aluminum hydride. ... 

Hydroxyquinazolines react with primary amines or hydrazines to form 3-substituted 4(3//)quinazolinones (15). > The mechanism was shown to involve ring opening because with secondary amines (where ring closure is not possible) A-disubstituted benzamides are formed. Grignard reagents do not always react in the normal way with... 

Substituted 2-mercapto-4(3i/)quinazolinones were prepared by condensing methyl anthranilate with isothiocyanates (see 7c). 

When the quinazolinones or thiones 251 (X = O, S R = H, Me, CHaPh) were reacted with 2,4- or 2,6-dimethylphenol, an addition took place, resulting in the 8a-(2-hydroxy-3,5-dimethylphenyl)- or the 8a-(4-hydroxy-3,5-dimethylphenyl)-substituted quinazolinone 252 (70M1745). The stereochemistry of 252 was not investigated. 

The 2-aminoquinazolines 259 were prepared in two independent ways. The 2-quinazolinone 258 was transformed to 2-aminoquinazoline 259 by treatment with phosphorus oxychloride and subsequently with sodium amide in liquid ammonia, or with phosphorus pentachloride under carefully controlled conditions [75JCS(P1)1471]. Attempts to prepare the N-substituted derivatives failed, but the reaction was successful with the unsubstituted cis cyclopentane-fused homolog [76JCS(P1)1415]. 

When the 6-position of the 4(377)-quinazolone is blocked, nitration occurs at the 5-position <1975JOC363>, but when the 7-position is also substituted, as with 6-bromo-7-chloro-4(3/7)-quinazolinone 44, the 8-substituted product 45 is obtained as the sole product <1996JME918>. 

Direct lithiation of 2-/r t/-butyl-4(3//)-quinazolinone 76 with jr f-butyllithium and bis(dimethylamino)ethane (TMEDA) followed by quenching with diphenyldisulfide gave the 5-phenylthio derivative 77 in moderate yield, although a mixture of 5- and 8-substituted products was obtained on quenchinq with di-fetZ-butyldisulfide <2004T7983>. 

Z- and 4-alkoxyquinazolines are readily prepared by nucleophilic substitution reactions, and 2,4-dialkoxyquinazolines can simply be prepared by boiling 2,4-dichloroquinazolines with 2 equiv of an alkoxide in the appropriate alcohol solvent <1996HC(55)1>. The first substitution is in the more reactive 4-position, so it is possible to isolate both 4-alkoxy and 4-phenoxy monosubstitution products <1977EJM325, 2005BMC3681>, and this selectivity has been used to attach both 2,4,6- and 2,4,7-trichloroquinazoline to a solid support, via the 4-position, for subsequent solid-phase synthesis of 2,6- and 2,7-diamino-4(377)-quinazolinones <2003TL7533>. 

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>. 

The lithiation of 3-substituted 4-quinazolinones 315 occurs at the 2-position, with a variety of 3-substituents such as acetylamino and pivaloylamino <1996JOC647>, aryl <1999TA25>, and BOC <2002H(57)323> having been found acceptable. 

The hydrogenation of 3-substituted 4(377)-quinazolinones 402 has been performed with both palladium and platinum oxide to give the 1,2-dihydro derivatives 403 <2001JME1971, 2004H(63)2019>, while the reduction of 2(1//)-quinazolinones 404 is readily performed with sodium borohydride in methanol <1990H (30)493 >. 

The PMB-substituted 2(177)-quinazolinone 436 underwent addition at the 4-position with lithium cyclopropyl-acetylide <2003JOC754>, while the more reactive 3-substituted 2(377)-quinazolinone 438 underwent a diasterose-lective addition with cyclopropylacetylenemagnesium chloride to give the 1,4-addition product 439 <2000TL3015, 2003JOC754>. 

The double lithiation and subsequent substitution of 2-alkyl-4(3//7-quinazolinethiones has also been performed <2004S363>, and a number of 3-amino- and 3-acylamino-2-alkyM(3//)-quinazolinones 570 have also been deriva-tized via their dianions <1995J(P1)1029, 1996JOC647, 1996JOC656, 2000H(53)1839, 2004S2121>. 

Due to the electron-withdrawing nature of the pyrimidine ring, alkenylpyrimidines can undergo addition reactions at the /3-carbon, and while this is a well-established route to substituted pyrimidine derivatives <1994HC(52)1, 1996CHEC-II(6)93>, it has also been used to prepare quinazolinone derivatives 578 from 2-alkenyM(3//)-quinazo-linones 577 <2000T7245>. 

Cyclization of o-acylaminobenzamides 759 leads to 2-substituted 4(3//)-quinazolinones 760. The benzamide may be generated in situ from an ester and an amine, and the ring closure can be performed under either acidic or basic conditions <1996HC(55)1, 1997IJH101, 2002JHC351, 2004808(16)573, 2006JOC382, 2007TL3243>. 

When 2-substituted 4(3//)-quinazolinones 852 are desired, the reaction of anthranilic acids with imidates 851 provides a good route to this class of compound <1996JME695, 2001SL1707, 2004JOC6572, 2005T9808>. 

N-3-Substituted 2-thioxo-4-quinazolinones 859 are formed when alkyl or aryl isothiocyanates are reacted with anthranilic acids or esters 857, <2001JME1710, 2002AP556, 2004JC0584, 2006JME2440>. The intermediate di-substituted thiourea 858 is normally not isolated, but is directly ring-closed in situ to the thioxoquinazolinone product 859. When 3-unsubstituted products are required, benzoyl isocyanate can be used <20008714>. 

In a related organometallic approach, treatment of the diiodoarylformamidine 878 with isopropylmagnesium bromide gave an organomagnesium intermediate which reacted with a variety of alkyl, allyl, and aryl isocyanates to give 3-substituted-8-iodo-4(37/)-quinazolinones 879 <20020L1819>. 

Numerous solid-phase preparations of quinazolinones have been reported. The main synthetic strategies used are summarized in Figure 15.16. Quinazolin-2,4-diones can be prepared from anthranilic acid derived ureas or from N-(alkoxycarbonyl)-anthranilamides. These reactions have been performed on insoluble supports either in such a way that the cyclized product remains linked to the support, or such that it is simultaneously cleaved from the support upon ring formation. Quinazolin-4-ones can be prepared by cyclocondensation of anthranilamides with aldehydes, orthoesters [342], or other carboxylic acid derivatives [343]. The selection of examples listed in Table 15.29 illustrates the variety of substitution patterns accessible by means of these cyclizations. 

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. 

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