Quinazolinone, 3-Alkyl

A still unresolved problem is the structure of the often used adducts from phosphorus trihalides and carboxylic acid amides, which might be described by the formulae (8) or (9). With the aid of in situ generated adducts of acid amides and PX3 amidines, isonitriles, quinazolinones, alkyl chlorides, aminomethylenediphosphonic acids, carbamoyl halides, triformylaminomethane, 1,3,4-oxadia-zoles, sulfides (from sulfoxides), nitriles (from primary nitro compounds)" and bromoqui-nolines (from methoxyquinolines)" have been prepared. 

Alkyl-3-aryl-4(3If)quinazolinones affect the nervous system in a... 

Quinazolines undergo many of the same reactions as pyrimidines, such as the modification of an amino group. Gangjee and co-workers reported the reductive alkylation of diaminoquinazolinones 141 with various aryl carbonyl compounds 142, which regioselectively produced quinazolinones 143 <00JHC1097>. 

Reductive alkylation of carboxamides 262 with sodium borohydride in the presence of an oxo compound furnished the carboxamides 265. In this process for the cis or trans isomers of 262 with acetone or cyclohexanone, the quinazolinone intermediates 266 [R = R = Me R, R = (CH2)s] of the reductive alkylation were also isolated and characterized [87-ACSA(B)228 91AX(C)2632]. 

JME3772, 2004JME871>, 7-fluoro-5-morpholino-4(3//)-quinazolinone 192 <2006JME6465>, and 4-(iV-alkyl-A -arylamino)-7-fluoro-6-methoxyquinazolines 193 <2005JME7560>. 

With 2-unsubstituted quinazolines 426 (X = O or S), organometallic addition occurs at the 2-position to give 2-alkyl-l,2-dihydroquinazolines 428 <2005JSF121, 2005S2951>, while with 2-alkoxyquinazolines addition of orga-nometallics occurs at the 4-position, as demonstrated by the addition of lithium phenylacetylide to the 2-methoxy-methyl quinazolinone 429 which gave a quantitative yield of a tautomeric mixture of the 3,4- and 1,4-dihydro derivatives 430 and 431 <2004JA5427>. 

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>. 

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>. 

The usual precursor is an appropriately orf/to-disubstituted benzene. Thus, quinazolines (290) can be prepared by the reaction of o-acylanilines (289 R = alkyl) with amides RCONH2. Heating anthranilic acid (289 R = OH) with amides or amidines yields 4-quinazolinones (291). The second nitrogen can be introduced into (289) before ring closure, as in (292) + HC(OEt)3 — (293). 

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. 

Hazarkhani, H. and Kamiri, B., A facile synthesis of new 3-(2-benzimidazolyl)-2-alkyl-4-(3H)-quinazolinones under microwave irradiation, Tetrahedron, 2003, 59, 4757-4760. 

The enantiopure 3-amino-2-(l-hydroxyethyl)quinazolinone 258 upon alkylation with cinnamyl bromide afforded O-alkylated product 259 as minor and N,0-dialkylated product as major (Scheme 58). Further iV-acetoxylation of 259 led to the formation of 260, which underwent intramolecular aziridination to give the 1,4,5-oxadiazepine 261 as a single diastereomer <1995J(P2)205>. 

Stephen and Stephen set out from 2-chloro-3,4,5,6-tetrahydropyridine and methyl anthranilate and obtained the pyrido[2,l-i>]quinazolinone 205 (R = R = H, n = 1) in 75% yield. Alkyl anthranilates were also treated with lactim ethers and lactams. ... 

The alkylation of the hexahydropyrido[2,l- >]quinazolinone (102) with coaminoalkyl chloride in dimethylformamide in the presence of sodium hydride and the reaction of the perhydropyrido[2,1 -6]quinazolinones 343 (R = H) and 346 (R = H) with methyl iodide in acetone in the presence of silver oxide " - led to products alkylated on the nonbridgehead nitrogen atom. 

Condensation of o-phenylenediamine with methylglyoxal, aldohexoses and aryl or alkyl acyloins gave the corresponding quinoxalines 76. Indoloquinoxalines were obtained from isatin. Carbethoxymethylation of isatin and then reaction with o-phenylenedimine gave the respective indoloquinoxalines 77, whereas hydrazide was condensed with aromatic aldehydes and monosaccharides. L-Ascorbic acid or D-isoascorbic acid were oxidized with iodine and then reacted with o-phenylenediamine and phenylhydrazine to give quinoxalinones 78, which were cyclized to pyrazolyl-quinazolinones . ... 

A series of quinazolinone inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) was prepared. It was shown that, in general, compounds linked with the cyclopentene 43 were more metabolically stable and had lower clearance rates than the corresponding compounds linked with linear alkyl linkers, as is 42. Being able to block the primary site of metabolism also translated into having more efficacious compounds in vivo with superior B/P ratios. Compound 42 had a B/P ratio of 0.4 after oral administration, while cyclopentene 43 had a B/P ratio of 4.1. 

When an anthranilic acid ester is heated with ammonium thiocyanate, 2-thioxo-4(3//)-quin-azolinones (629) are formed. When alkyl- or aryl-isothiocyanates are used, the corresponding N3-substituted 2-thioxo-4-quinazolinones (629) are formed . 

Methylation reactions (N versus S) of 2-thiophenobarbital under various conditions have been performed [94MI(68)117]. There is also a report on the ratio of N- and 6>-alkylation of 4(3/7)-quinazolinones depending on the nature of a substituent in position 2 [93CPB(41)1114].. Quinazoline-2,4(l//,3W)-d ones have been alkylated with l,4-dibromo-2-methylbut-2-ene under phase-transfer conditions to give dialkylated as well as monoalkylated products [93JHC(30)lil71. 

The indole-containing alkaloid rutaecarpine 126 has been synthesised via cyclisation of a 2-indolyl radical onto the 2-position of a 4-quinazolinone (070BC103). The radical precursor 124 was prepared by N-alkylation of the 3-position of the 4-quinazolinone followed by bromination of the 2-position of the indole ring. Slow addition of BusSnH gave 15% of rutaecarpine 126 and 57% of the reduced product 125. 

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