Quinazoline 1,2-dihydro— from

The least troublesome routes to 3,4-dihydro- and 1,2,3,4-tetrahydro-quinazoline are probably the reduction of quinazoline by sodium borohydride, in water for the former or in methanol for the latter. Both must be isolated as salts. The dihydroquinazoline may be formed also by reduction with LAH in ether (65JHC157). In contrast, 5,6,7,8-tetrahy-droquinazoline is best made by primary synthesis from 2-formylcyclohexanone and for-mamide (57CB942) or from cyclohexanone and trisformamidomethane (60CB1402). 

Dihydroquinazolines are normally stable compounds but they deteriorate on long standing. Some examples are known to oxidize to the corresponding 4(3H)quinazolinones. 3-Methyl-3,4-dihydroquin-azoline is converted to the 4-oxo compound after three recrystallizations from light petroleum. The most remarkable example is 3,4-dihydro-6-fluoro-3(p-fluorophenyl)quinazoline [(44), R = F] which oxidizes at its melting point (137°-I38°C), Other halogenated derivatives of (44) are more stable. ... 

Phenyl-5,6-dihydro-l//,7//-pyrido[3,2,l-//]quinazoline-7-one and 1,7-dione 179 (X = H2 and O) were prepared from tetrahydroquinolines 206 and 207 with A-(ethoxycarbonyl)thiobenzamide and PhCOCl, respectively (98EJM763). 

Treatment of l,3,4,6,7,llb-hexahydro[l,3]oxazino[3,4- ]quinazolin-l-one with LAH in boiling THF gave 2-(2-hydroxyethyl)-l-methylquinoline <2003T6785>. Pyrimidinone 107 was obtained from trequinsin 106 on the action of NaH, followed by the treatment with Mel (Equation 17) <1997IJB349>. The reaction of7-(benzotriazol-l-yl)-6,7-dihydro-l//,3/7,5//-pyrido[3,2,l-zy][3,l ]bcnzoxazine with PhMgBr led to ring-opened l-benzyl-4-(benzotriazol-l-yl)-8-hydroxymethyl-l, 2,3,4-tetrahydroquinoline < 1995JOC3993>. 

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 277,477-3-bromomethyl-3,4-dihydro-[l,3]thiazino[3,2- ]quinazolin-6-one 341 was formed from the 2-thioxo-quinazolinone 340 using Br2/AcOH (Equation 36) <2000S714>. 

Quinazolines 51 have been prepared by the condensation of A-aryl carbamates with hexamine, followed by aromatisation of the dihydro intermediate. A variety of mono- and di-substituted anilides were used, mefa-substituted starting materials giving 7-substituted quinazolines <06T12351>. Benzoquinazolines were also prepared similarly from naphthylamine carbamates <06OL255>. 

The triazine ring could be formed by reaction [82S853 83BSF(2)226] of alkyl (2-aryl-4-thioxo-3,4-dihydro-2//-quinazolin-3-yl)acetates 477, prepared from 476, with hydrazine to yield 6-aryl-2,4-dihydro[l,2,4]tria-zino[4,3-c]quinazolin-3-ones 478. 

In the United States, compound RGW-2938 (47) has been developed as a selective positive inotropic agent its synthesis and pharmacological actions have been reviewed [161]. Related compounds, in which the dihydro-pyridazinone system is replaced by a benzoxazinyl system instead of the quinazoline system, have recently been studied in India and in the United States [162,163]. From this series, bemoradan (48) was found to be a very potent orally active, long-acting inotropic vasodilator agent in canine models (i.v. ED5o = 5.4 //g/kg 24h duration of action) [163]. 

Dihydro-4-methyl-2//,6//-l, 3,4-thiadiazino[2,3-fc]quinazolines (655) were synthesized from isatoic anhydrides and 1-(2-hydroxymethyl)-1-methylhydrazine(79JHC1339). l,3,4-Thiadiazino[2,3- ]quinazolines(657) were also prepared by the reaction of 3-amino-2-mercaptoquinazolinones (656 with a-haloketones [81IJC(B)14 82M1145]. 

MI1, 84MI3). 6-[2-(4-Methyl-l-piperazinyl)acetamido]-ll//-pyrido[2,l-b]quinazolin-l 1-one (329) was isolated from a mixture of crude 11-chloroacetyl-5,11 -dihydro-6 7/-pyrido[2,3-b][l, 4]benzodiazepin-6-one (327, R = COCH2Cl)) and excess 1-methylpiperazine in boiling benzene as a byproduct with pirenzepine (328) (88CCC1820 89JHC1229). 

Cyclocondensation of anhydro-1 -hydroxythiazolo[3,2-a]quinazolinium hydroxides (334) with dipolarophiles (335) afforded 5-methyl-5,6-dihydro-1 //-pyrido[l, 2-n]quinazoline-l, 6-diones (337) (85JOC1666). Sometimes better yields were achieved when mesoionic compounds (334) were prepared in situ from S-(quinazolin-2-yl)thioglycolic acids (333, R = Ph) with acetic anhydride or DCC in the presence of the dipolarophiles (335). Cycloadducts 336 (R = H, Ph, R1 = R2 = CN) could be characterized in the case of fumaronitrile by IR and 1H NMR spectroscopy. 

Cyano-3-methyl-5,6-dihydro-l//-pyrido[l,2-a]quinazoline-l,6-dione and its 5-substituted derivatives were prepared from 2-cyano-3-methylpyrido[l,2-a][3,l]benzoxazin-6-one with ammonium acetate at 200°C for 4 h, with hy-droxylamine hydrochloride and (thio)ureas in a boiling mixture of pyridine and ethanol for 4-7 h, with hydrazine hydrate, phenylhydrazide, primary aliphatic and (hetero)aromatic amines in boiling ethanol for 3-6 h (93CCC1953). 

A highly effective method has been proposed for the synthesis of 6,12-dihydro-6,12-dioxoindolo[2,l-h]-quinazoline (179) - the alkaloid couropitine A (from the tropical tree Couropita guianensis), having the same structure as the antibiotic tryptanthrin (from the yeast Candida lipolytica Hegolus), by the reaction of isatin with phosphorus oxychloride followed by treatment of the reaction mixture with ice [198] ... 

Azole approach. Quinazolines can be prepared from isatoic anhydride and an amide. When the amide function is part of a cyclic structure such as in a 3-isoxazolidinone, the 2,3-dihydro-9//-isoxazolo[3,2-h]quinazolin-9-one (84) is formed (77AF766). 

Azole approach. A one-pot synthesis of substituted 2,3-dihydro-5-oxo-5H-oxazolo[2,3-b ]quinazolines (273) consists of reacting esters of anthranilic acid with a 2-chloro- or 2-bromoalkyl-isocyanate the initially formed urea (271) is cyclized to the acid salt of the oxazoline (272), which on addition of piperidine as base forms the pyrimidine ring (76S469). In a similar reaction the aziridinyl urea (274), which is available from aziridinyl isocyanate... 

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