Pyrimido-quinazolines

N-(Butyn-2-yl)isatoic anhydride (503) gave the pyrimido[l,2-a] quinazolinone (504) on cyclization with 3-allyl-2-methylthiopseudourea (76JOC825). 

This linear type of pyrimido-quinazoline was synthesized by (a) formation of the terminal pyrimidine ring, (b) formation of the middle pyrimidine ring, and (c) formation of both pyrimidine rings. 

Synthesis according to the first approach requires quinazoline precursors with an appropriate subtituent on position 2 or 3 which, upon cyclization, forms the terminal pyrimidine ring. Thus, 2-aminoquinazolin-4(3//)-one (505) underwent cyclization with a,j8-unsaturated acids (78KGS105 80MI1) or their chlorides (87KGS1527) to the pyrimido 

76USP3969506]. Reductive cyclization of 2-methylthio-l-(2-nitrobenzyl]-6-pyrimidines (515) with stannous chloride gave 6,1 l-dihydro-4//-pyrimido[2,l-fc]quinazolin-4-ones (516) (78JHC77). 

The two pyrimidine rings of 1,2,3,4-tetrahydro-6//-pyrimido[2,1-b]-quinazolin-6-one (517) were simultaneously formed when ethyl Ar-(2-methoxy-carbonylphenyl)thiocarbamate was cyclized with 1,3-diaminopropane (82JHC1117). The two heterocyclic rings of 1,2,3,4,5,6-hexahydropyrimido[2,l-6]quinazolin-2-ones (519) were also concomitantly formed when compounds 518 were cyclized with cyanogen bromide [73GEP(O)2305575 76USP3932407]. 

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Bond orders, charges on the atoms in 1 l//-pyrido[2,l-Z)]quinazolin-l 1-one and its protonated form were calculated by quantum chemical calculations by the semiempirical AMI method. According to the results, the equilibrium conformation of the ring in 1 l//-pyrido[2,l-Z)]quinazolin-l 1-one is planar, while l//-pyrimido[l,2-u]quinolin-1-one adopts a conformation close to a half-chair due to the unfavorable interactions between the oxygen atom of the carbonyl group and the ring C-10 atom in the pen-position (97MI22). 

The use of 1 l//-pyrido[2,l-Z)]quinazolin-l 1-ones in an organic electroluminescent device was patented (99JAP(K)99/74080). 2//-Pyrimido[2,l-n]isoquinolin-7-ols were patented as multi-functional fuel and lube additives (97USP5646098). 

Treatment of pyrimidine-2-thione 184 with A1C13 yielded 6-oxo-6,7-dihydro-4//-pyrimido[6,l-tf]isoquinolin-4-thione 185 (Equation 37) <1998MI337>. Cyclization of 6,7-diethoxy-2-propylaminocarbonyl-l,2,3,4-tetrahydroisoquinoline-l-acetonitrile using NaOMe afforded 9,10-diethoxy-2-imino-3-propyl-l,2,4,6,7,l lb-hexahydropyrimido[6,l-tf]isoquinolin-4-one <1995S863>. Cyclization of l-(2-carboxyethyl)-l,2,3,4-tetrahydroquinazoline-2,4-dione 186 in polyphosphoric acid (PPA) afforded l,2,3,5,6,7-hexahydropyrimido[3,2,T /]quinazoline-l,3,7-trione 187 (Equation 38) <1997CHE96>. 

A special class of synthesis is the utilization of retro-Diels-Alder (RDA) reactions. A double RDA sequence was used to prepare the pyrimido[l,2-A]pyridazin-3-one 118. In this versatile method both reactants of the parent compound were constructed from cyclopentadiene. The parent compound 117 contains two norbornene units and decomposes on heating in toluene in a double RDA reaction leaving two double bonds in the target heterocycle. Similarily, the parent compound 119 decomposes in a single RDA reaction to yield the benzologue, pyridazino[6,l-3]-quinazolin-10-one 120 (Scheme 13) <2000SL67>. 

The linearly fused benzologues, pyrimido[2,l-A]quinazolines, are most frequently synthesized from a 2-amino- or 2-iminoquinazoline. Synthesis from [6+0] atom fragments by bond formation 7 to the ring junction nitrogen takes place when the 2-aminoquinazoline bearing a suitable substituent at N-3 is cyclized. The 2-iminoquinazoline-3-propionates 197 cyclized on treatment with alkali to give 198 (Scheme 31) <1997EPP0778258>. 

The 2,3-dihydro-6/7-pyrimido[2,l-A]quinazolin-4(177)-ones 201 were obtained in a one-pot synthesis from the iminophosphorane 199 and isocyanate, through the 2-aminoquinazoline 200. Yields were good (R1 = H, Rz = c-hexyl) to excellent (R1 = Rz = Ph) (Equation 21) <1996TL9071>. 

The angularly condensed pyrimido[l,6- ]quinazoline 223 was prepared from [3+3] atom fragments by reacting 2,4,6-triaminopyrimidine and ethyl 2-oxo-cyclohexane-l-carboxylate under acidic conditions. The reaction also gave rise to the isomeric linear N-bridgehead tricycle, 224. The expected C-annelated product 225 was obtained under thermal conditions (Scheme 36) <1999JOC634>. 

In the other approach, the pyrimidine ring of the pyrimido[l,2-r]quinazolines 238 was formed from [4+2] atom fragments starting from 4-thioxoquinazolines 236 <1996CCC957, 2002PS( 177) 1349> or 4-chloroquinazolines 237 <1999IJH63> (Scheme 41). 

The 3.4-dihydro-17/,2//.6//-pyrimido[2,l - quinazolin-2-ones 198 are blood platelet reducing agents <1997EPP0778258>. 2-(2-Pyndazyl-amino)-6//-pyrimido[2,l-Z ]quinazolin-6-oncs have been claimed as protein... 

Reports concerning bridgehead nitrogen bicyclic systems containing four extra heteroatoms (3 1) are rare <1996CHEC-II(8)729>. Only four such ring systems, 1-4, have been reported previously. Related ring systems reported in the last decade are l,2-dihydropyrimido[l,2- ]-l,2,4,5-tetrazin-6-ones 5, 67/-[l,2,4,5]tetrazino[3,2- ] quinazolin-6-ones 6, thioxotetrazinoquinazoline 7, and pyrimido[l,2- ]-l,2,4,5-tetrazin-6-ones 8. 

The relevant heterocycles that belong to this type of ring system are the pyrimido[jc,y-z][l, 2,4]triazines and the [ 1,2,4]triazino[x,y-z]quinazolines. 

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