Cyanopyrimidines

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]. 

The reaction of 2-mercapto-4-(2, 4 -dichlorophenyl)-5-cyanopyrimidin-6(l//)one 421 (obtained by stirring ethyl cyanoacetate and thiourea with 2,4-dichlorobenzaldehyde in sodium ethylate at room temperature, in 70% yield), with a solution of monochloroacetic acid and />-cholorobenzaldehyde in glacial acetic acid, in the presence of sodium acetate, affords 2-[(/>-chlorophenyl)methylene]-6-cyano-7-(2, 4 -dichlorophenyl)thiazolo[3,2-tf]pyrimidin-3,5-dione 422. Finally, the reaction of compound 422 with hydrazine hydrate converts it into product 423 (Scheme 49) < 1996PS( 116)39>. 

After isolation of the radioactive 6-amino-5-cyanopyrimidine (26) and hydrolysis of 26 with acid into 4-phenylpyrimidin-6-one and carbon dioxide (the last being derived from the cyano function. Scheme 11.17), the... 

The ketene dithioacetal method group has proved useful for the synthesis of a number of biologically interesting molecules <2000BML703, 2004EJM969>, including 5-cyanopyrimidine derivatives which are orally active inhibitors... 

The above reactions are relatively straightforward in terms of mechanism. There are, however, a number of important transformations based on 1,3,5-triazine as starting material, and which result in formation of either pyridine or pyrimidine derivatives. 1,3,5-Triazine reacts very readily with nucleophiles, probably as outlined in equation (197) if X in (31) is a suitable electrophile, cyclization can take place. Thus, when X = CN, 4-amino-5-cyanopyrimidine is obtained, and other illustrative examples are shown in equation (198). This procedure is particularly useful for the preparation of 2-unsubstituted pyrimidines, a class of compound which is not readily accessible by other types of ring formation. The reverse type of transformation, i.e. of pyrimidines to 1,3,5-triazines, is also an important synthetic method, and one which has been studied in detail. Two types of substituted... 

Recent examples of the methods described in CHEC(1984) and CHEC-II(1996), and involving condensation of a substituted pyrimidine with a Ci unit, include the condensation of 3-amino-4-cyanopyrimidines with orthoformates <1995W095/19774> and a variety of carboxylic acid derivatives <1995EJM525, 1996JIC698, 1998JRM2880, 2002EJC995>. 

Synthetic routes to pyrimidines through HCN trimers are listed in Section Another route is through reaction of DAMN with cyanoformimi-dates. l-Amino-2-aminoalkoxymethyleneamino)maleonitrile (134) is first formed. This rear-ranges to the ( )-isomer, which cyclizes to the 2-alkoxy-4,5-diamino-6-cyanopyrimidine (135) in a second step (Scheme 49) (75USP3883532). 

AND 2-MERCAPTO-4-HYDRO XY-5-CYANOPYRIMIDINE (5-Pyrimidinecarbonitrile, 4-hydroxy-2-mercapto-,)... 

B. 2-Mercapto-4-hydroxy-5-cyanopyrimidine. The aqueous filtrate from which the crude 2-mercapto-4-amino-5-carbethoxy-pyrimidine separated is cooled overnight at 0°, and the cyano-pyrimidine that precipitates is collected on a suction filter. The crude product is recrystallized from about 200 ml. of 10% acetic acid with 1 g. of decolorizing charcoal added. Two additional recrystallizations done similarly give the pure cyanopyrimidine as faintly yellow crystals, m.p. 265-272° (dec.) (Note 3). The yield is 10-18 g. (7-12%). 

The most popular preparations of pyrimido[4, 5 ]pyrimidi nes are based on cyanoethylene or cyanomethylene derivatives. In many of these preparations the appropriate acid chloride (R1 = alkyl, aryl) is reacted with malononitrile to give an enol (250), which is readily alkylated to the enol ether (251). This can be condensed with guanidine or a variety of amidines (R2 = H, alkyl, aryl) to yield the key intermediate 4-amino-5-cyanopyrimidines (252) (81S955). Reaction with a second mole of guanidine or amidine is a convenient preparation of a variety of pyrimido[4,5 ]pyrimidines. Under the appropriate conditions the final ring system can be obtained from the enol ether in one step (68JMC568). 

The 5,7-dioxopyrimido[4,5-rf]pyrimidine-5,7-dione (254) can be obtained by fusion of the amide (253) with urea (68JMC568). This amide is prepared by hydrolysis of the corresponding cyanopyrimidine in concentrated sulfuric acid. 4-Aminopyrimidine-5-carboxamides can also be condensed with alkyl and aryl esters to give pyrimido[4,5-d]pyrimidin-4-ones... 

In addition, the reaction was extended to the 4-unsubstituted tetrahydro-pyrimidines 60. Here the same reaction pattern as before was observed The 1-unsubstituted derivative led to the 6-cyanopyrimidine 61, whereas the 1-methyl derivative afforded the geminal diazide 62 [90LA505],... 

The hydrazone of a 5-formylpyrimidine (114) when treated with sodium hydride and then heated to 150°C also results in formation of a pyrrolopyrimidine (115) (Equation (36)) <89H(29)1993>. In a related reaction, treatment of 2,4-diamino-6(l//)-oxopyrimidine (116) with methyl chloro-formylacetate gives both the pyrrolopyrimidine (117), and the furopyrimidine (118) (Equation (37)) <89JCS(Pl)2375>. The latter can be converted into pyrrolopyrimidine products. Pyrrolopyrimidines with 5-amino substituents can be prepared from 5-cyanopyrimidines utilizing similar chemistry <88LA633>. 

Azine approach. Cyclization of the oxime (48) (73G219) corresponds to a common method for the preparation of isoxazoles, viz. the reaction between 1,3-dicarbonyl compounds and hydroxylamine. Similarly a cyano group reacts with hydroxylamine to form an N-hydroxyamidine which can be cyclized to an isoxazole if the vicinal carbon is activated and carries a leaving group. The 5-cyanopyrimidine (49) perhaps behaves unexpectedly in that it is a trichloromethyl substituent which is the leaving group in the cyclization (79JHC11-09). This behavior may be attributed to its location in the activated pyrimidine 4-position. 

Cyclization of 5-cyano-6-methylpyrimidine-2,4(l//,3H)-diones 136 with elemental sulfur generated the corresponding 5-aminothieno[3,4-d]-pyrimidine-2,4(l//,3//)-diones 137 (90MI1 91MI2). Similarly, cyclization of 5-cyanopyrimidine-4(3H)-thiones 138 with sulfur afforded the 5-amino-4-thioxo derivative 139 (90LA1215). 

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