Pyrimido pyrimidines, methylation

Pyrimido[4,5-d]pyrimidine, 3-aryl-1,2,3,4-tetrahydro- H NMR, 3, 338 (69JOC2760) Pyrimido[4,5-d]pyrimidine, 4-hydroxy-UV, 3, 338 (58JOC1451) Pyrimido[4,5-d]pyrimidine, 4-hydroxy-2-methyl-7-(methylmercapto)-UV, 3, 338 (60JA5711)... 

Pyrimido[4,5-d]pyrimidine, 4-mercapto-2-methyl-7-(methylmercapto)-UV, 3, 338 (60JA5711)... 

Cyclization of the 5-(A -arylcarboxamido)-4-hydrazino-6methylpyrim-idin-2-ones 104 with two molar equivalents of formaldehyde in the presence of pyridine caused the concomittant triazole and pyrimidine ring formation to yield the 4-aryl-l,3,4,10-tetrahydro-6-methyl-l,2,4-tria-zolo-[2,3,4-c,d]pyrimido[4,5-d]pyrimidine-5,8-diones 105 (89AP599)... 

Characteristic H NMR data of (4a/ ,55)- and (4n5,5R)-2-substituted 5- [A-(/e/ /-butoxycarbonyl)-L-tryptophyl]amino perhydropyrido[l,2-c]pyri-midine-l,3-diones were tabulated (01JMC2219). C CPMASS NMR data of 4-(4-methoxyphenyl)perhydropyrido[l,2-c]pyrimidine were reported (00JST73). C NMR data were reported for eight 4-aryl-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyrimidin-l,3-diones in the solid state and in CDCI3 solution (00JPO213). The structure of 4-aryl-3,4-dihydro-2//-pyrido [l,2-c]pyrimidine-l,3-diones and their 2,3,5,6,7,8-hexahydro derivatives were characterized by H and C NMR data (99JHC389). Conformational analysis of 6-methyl-2,3,4,6,7,ll/)-hexahydro-l//-pyrimido[6,l-n]isoquino-lin-2-ones 138 and 139 were carried out by H and C NMR studies (97LA1165). 

The bromine atom of 4-aryl-2-(4-bromobutyl)-2,3,5,6,7,8-hexahydro-177- ancj -perhydropyrido[l,2-c]pyrimidine-l,3-diones was displaced with 4-substituted piperazines <2002FES959, 2004APH139, 2004PHA99>. Heating 3-hydroxymethyl derivatives of epimeric 6-methyl-l,3,4,6,7,llb-hexahydro-277-pyrimido[6,l-,2]isoquinolin-2-ones 152 resulted in the formation of the 3-unsubstituted derivatives 153 by loss of CH20 (Equation 26) <1997LA1165>. 

Cyclization reactions of pyrimidines were studied, for instance, the reactivity of tetrahydropyrido[4,3-fc]pyrimidines with DMAD leading to dihydropyrimidinylethylamines <05TL1975> and pyrimido[4,5-rf]pyrimidines obtained efficiently by hetero Diels-Alder cycloaddition of methyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-... 

The cyclization ofthe2-(4-methylpiperazinyl) derivative of1046 (R = 4-methyl-1 -piperaziny 1) afforded pyrimido[2,3-c/]pyrimidine-6-carboxylate (1047, R = 4-methyl-l-piperazinyl, R1 = Et) in 82% yield when it was heated in polyphosphoric acid at 140°C for 20 min (74GEP2341146). 

A series of 6- and 7-aciylamide derivatives of 4-(phenylamino)-quinazoline and 4-(phenylainino)-pyridopyrimidine, classes of epidermal growth factor receptor (EGER) inhibitors, have been prepared from the corresponding amino compounds by reaction with actoyl chloride/base <99JMC1803>. Reaction of thionyl chloride with hexahydro-7-methyl-pyrimido[l,6-a]-pyrimidine-6,8-dione yields the corresponding 9,9 -thiobispyriiiudopyrimidine derivative <99JHC453>. 

MI33>. Covalent hydration of pyrimido[4,5- pyrimidines was reported in CHEC-II(1996) <1996CHEC-II(7)737> covalent hydration across the 7-8 bond of 6- and 8-methylated species 68 and 69 has been investigated in detail <2003EJM719>. 

Cycloaddition of methyl orotate or its 1,3-dimethyl derivative with 2,6-dichlorobenzonitrile oxide (generated in situ Scheme 79), or with the corresponding isocyanate, gives an oxazolo[4,5-d]pyrimidine. This intermediate undergoes ring opening under the reaction conditions, and recyclization occurs to provide a pyrimido[5,4-r/][l,2]oxazine <1992H(34)1423>. 

Dimethyl-3-(2-oxo-2-phenyl-ethyl--bromid lagert sich beim Kochen mit Triethylamin in Acetonitril in 2-(2-Imino-5-phenyl-2,3-dihydro-oxazol-3-yl)-4,6-dimethyl-pyrimidin um. Aus diesem werden durch Kochen in Alkoholen mit 4-Methyl-benzolsulfonsaure als Katalysator 2-Alkoxy-l-(4,6-dimethyl-2-pyrimidyl)-4-phenyl-imidazole oder durch Erhitzen mit primaren oder sekundaren Aminen ebenfalls in Gegenwart von 4-Methyl-benzolsulfonsaure 2-Alkylamino-l-(4,6-dimcthyl-2-pyrimidyl)-4-phe-nyl-imidazole erhalten374 ... 

An X-ray crystal structure determination of the [f-Bu3Zn] anion present in 21 has an almost perfect trigonal planar arrangement [Zn—C bond distances 2.080(7), 2.059(7) and 2.057(8) A C-Zn-C angles 118.1(2), 120.7(3) and 120.6(3)°]. Compound 21 was prepared by reacting l,3,4,6,7,8-hexahydro-2//-pyrimido[l,2]pyrimidine, Me2Zn and f-BuLi (equation 9). It is notable that the methyl groups initially bound to zinc all become... 

In contrast, the 7,8-benzo-fused perhydropyridol[l,2-c]pyrimidine 2-methyl-2,3,4,4a,5,6-hexahydro-l//-pyrimido[3,4-a]quinoline exists in solution as 80% equatorial N-methyl trans conformer 365 in equilibrium with 20% of the axial N-methyl trans conformer 366.303 H-NMR studies303 on three diastereoisomeric 7-methyl-6,7,8,9,10,l 1,1 la,l 16,12,13-decahydro-7a W-quino [ 1,2-c] quinazolines 367-369 indicate the almost exclusive existence of 367 in the trans-fused conformation 370, of 368 as 56% 371 44% 372 and of 369 as 80% 373 20% 374. The conformational preferences... 

Pyrimido[4,5-d]pyrimidine-4-thiones are also formed by reaction of pyrimido[4,5-d]-pyrimidin-4-ones with phosphorus pentasulfide. Methylation of these thiones with dimethyl sulfate or methyl iodide gives the corresponding methylthio derivatives (60JA5711). 5-Amino-l,3-dimethyl-7-methylthiopyrimido[4,5-d]pyrimidine-2,4(l//,3iy,)-dione (121) undergoes... 

Most derivatives of this ring system are prepared from 2-aminopyrimidines. Ethoxy-methylenemalonic ester (220) is a versatile synthon which can be reacted with 2-aminopyrimidines to give pyrimido[l,2-a]pyrimidine precursors. Reaction of 2-aminopyrimidine (219) with this ester gives the aminomethylenemalonic ester (221), which can be thermally cyclized to the heterocyclic ester (222). The enamine analogous to (221) which is derived from 2-amino-4,6-dimethylpyrimidine cannot be cyclized under these conditions. Presumably this cyclization fails due to steric hindrance of the methyl groups (72JMC1203). 

A number of 1,2,4-triazines are of interest owing to their biological activity. 1,2,4-Triazine-3,5-diones (6) represent aza analogues of pyrimidine nucleic acid bases, a number of natural antibiotics are derivatives of pyrimido[5,4-e][l,2,4]triazine (7), and 4-amino-6-r-butyl-3-methylthio-l,2,4-triazin-5-one (8) and 4-amino-3-methyl-6-phenyl-l,2,4-triazin-5-one (9) are used as herbicides. 

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