Disubstituted-pyrimidines

Pyrimido[5,4-d]pyrimidine, 4-amino-2,8-dihydroxy-3,8-disubstituted synthesis, 3, 365... 

Tetrahydroquinazolines are more conveniently classified as 4,5-tetramethylene pyrimidines and their reactions are accordingly typical of pyrimidines. 2,4-Disubstituted derivatives have been prepared by condensation of 1-ethoxycarbonyl cyclohexanones with ureas and thioureas (Scheme 9). For monosubstituted derivatives the... 

The usual syntheses of quinazolines make use of an o-disubstituted benzene structure (46) from which the quinazoline skeleton is completed by adding C-2 and N-3 in various ways. Substituents could either be in (a) the pyrimidine ring or (b) the benzene ring or in both rings. The syntheses will be described in this order and the methods used for (a) apply equally well to quinazolines substituted in both rings. 

The syntheses of pyrido[3,2-d]pyrimidines from pyridines utilize a 2,3-disubstituted pjrridine and insert the C-2 and N-3 atoms, either previously linked (route i) or in separate stages (route ii). 

Amino-4//-pyrido[],2-rz]pyrimidin-4-ones 184 were obtained from 3-(2,2-disubstituted ethenylamino) derivatives 183 with H2NNH2 H2O or HONH2 HCI m good yields, and from 183 (R = COOCH2Ph, R = acetyl) by treatment with NaBH4 in moderate yields (97H(45)2349,... 

The third and very valuable discovery that the new phthalazine (PHAL) and pyrimidine (PYR) ligand classes (32-35, Figure 2) out-perform the monomeric ligands under identical conditions emerged from a heuristic screening process. The PHAL class in particular has become the first choice for most olefin classes. The PYR class is usually superior for terminal olefins, while the IND class is ideally suited for cA-disubstituted olefins. These ligands are commercially available or can be made easily from relatively inexpensive starting materials. 

Canthine skeleton 52 Cardiotonic agent, heart failiu-e 3 Caspase-3 inhibitors, non-peptide 269 Catch and release , 2,4,5-trisubstituted pyrimidines 98 Chloro dehydroxylation 17 Click chemistry, 1,4-disubstituted triazoles 45... 

Substituted pyrimidine N-oxides such as 891 are converted analogously into their corresponding 4-substituted 2-cyano pyrimidines 892 and 4-substituted 6-cya-no pyrimidines 893 [18]. Likewise 2,4-substituted pyrimidine N-oxides 894 afford the 2,4-substituted 6-cyano pyrimidines 895 whereas the 2,6-dimethylpyrimidine-N-oxide 896 gives the 2,6-dimethyl-4-cyanopyrimidine 897 [18, 19] (Scheme 7.6). The 4,5-disubstituted pyridine N-oxides 898 are converted into 2-cyano-4,5-disubsti-tuted pyrimidines 899 and 4,5-disubstituted-6-cyano pyrimidines 900 [19] (Scheme 7.6). Whereas with most of the 4,5-substituents in 898 the 6-cyano pyrimidines 900 are formed nearly exclusively, combination of a 4-methoxy substituent with a 5-methoxy, 5-phenyl, 5-methyl, or 5-halo substituent gives rise to the exclusive formation of the 2-cyanopyrimidines 899 [19] (Scheme 7.6). The chemistry of pyrimidine N-oxides has been reviewed [20]. In the pyrazine series, 3-aminopyrazine N-ox-ide 901 affords, with TCS 14, NaCN, and triethylamine in DMF, 3-amino-2-cyano-pyrazine 902 in 80% yield and 5% amidine 903 [21, 22] which is apparently formed by reaction of the amino group in 902 with DMF in the presence of TCS 14 [23] (Scheme 7.7) (cf. also Section 4.2.2). Other 3-substituted pyrazine N-oxides react with 18 under a variety of conditions, e.g. in the presence of ZnBr2 [22]. 

Methyl-5-nitropyrimidin-4(3f/)-one reacts with ketones in the presence of ammonium salts to give 4,5-disubstituted pyrimidines or 5,6-disubstituted 3-nitro-2-pyridones depending on reaction conditions (Eq. 10.83).142... 

AJC287>. From a complex reaction mixture of BuCH(COCl)2 and 2- 4-[(4-hydroxy-3-carboxyphenyl)hydrazi-no]phenylsulfonylamino pyridine at elevated temperature, tf yr/r >-(3-butyl-2-hydroxy-4-oxo-4//-pyrido[l,2-tf]pyrimi-din-3-ylium)hydroxide was isolated <2001MI53>. Reaction of 2-aminopyridines and diethyl alkylidenemalonates at 175 °C yielded 3-(2,2-disubstituted vinyl)-2-hydroxy-4//-pyrido[l,2-tf]pyrimidin-4-ones from the initially formed... 

Chiral 4,7-disubstituted perhydropyrazino[l,2-f]pyrimidine-l,6,8-triones 170 were synthesized from [4+2] atom fragments by reacting separately, the four diastereomers of 169 with isocyanates in a base-catalyzed cyclization (Scheme 23) <2002TL4899>. 

Several studies deal with the reactivity of 2,4-disubstituted-6-aminopyrimidines, which have competing sites for ring formation with 1,3-biselectrophiles. Treatment of 2,4,6-triaminopyrimidine with ethyl acetoacetate in acetic acid formed the pyrimido[l,6-tf]pyrimidin-4-one 216, while the expected pyrido[2,3-r/]pyrimidin-7-one 217 was obtained under thermal conditions (Scheme 34) <1999JOC634>. 

Synthesis from pyrido[7,2-a/pyrimidines. Reaction of the disubstituted pyridopyrimidinone 416 with hydrazine gives the aminopyrazole-fused product 417 (Equation 153) <1996FA781, 2003JIC311, 2004IJB1561>. Similarly, substituent interaction in the pyridopyrimidine 418 with amines in toluene at reflux gives, in various proportions, diastereomeric mixtures of the pyrrolopyridopyrimidines 419 and 420 (Equation 154) <2003T4581>. 

Similarly, heterocyclic amines such as imidazole were added to pyrimidines 57 with moderate to high regioselectivity to produce mainly 4,5-disubstituted pyrimidines 58 after a 1,3-hydride shift along with small amounts of the 2,5-disubstituted isomers 59 . 

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