Substituted alkyl pyrimidine amines

With the knowledge that pyrimidine amines were among the most active sulfonylurea herbicides, we felt that a thorough exploration of more extended substitution on the pyrimidine nucleus was warranted in the search for sulfonylureas with improved crop selectivity. One direct approach to a variety of substituted pyrimidines was through metalation reactions on alkyl pyrimidine amine derivatives. 

One review of a synthetic nature covered new routes to pyridazino-fused ring systems <04SL1123>. In addition to this, there were two reviews focusing on specific medicinal applications of some diazines. One covered the design, synthesis and SAR of 5-[(l-substituted) alkyl (or vinyl)] pyrimidine nucleosides as potential inhibitors of herpes viruses <04MI2749>, and the other described 4-thiophenoxy-N-(3,4,5-trialkoxyphenyl)pyrimidine-2-amines as potent and selective inhibitors of the T-cell p561ck tyrosine kinase <04MI747>. 

The structures of the principal DNA and RNA bases are shown, along with the numbering scheme. Other subsitution products, either in the purine N9 or pyrimidine Nj position, or substitution of exocyclic amine hydrogen atoms by alkyl groups, are named in standard fashion. 

A mesoporous SBA-15-supported pyrimidine-substituted NHC-Ir " complex 132 was successfully applied to the N-alkylation of amines with alcohols. 

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

The reaction of the salt 308 with alkyl halides in base gave the corresponding 2-alkylthiothieno[3,4-d]pyrimidin-4(3//)-ones 369. Heating the latter with ammonia or amines afforded 2-amino(or substituted amino)thieno[3,4-d]pyrimidin-4(3//)-ones 370 (90EUP404356). When 2-methylthiothieno[3,4-d]pyrimidin-4(3//)-one 360 was heated with o-tolu-idine at 200°C, displacement of the 2-methylthio group afforded compound 372 (91MIP1). 

Villalgordo et al. [22, 23] as well as Gayo and Suto [25] developed a strategy to cleave pyrimidines from the solid support. After oxidation of the thioether-linkage 17, aromatic substitution of the sulfonyl unit was performed with different N-nucleophiles as amines and azides to give free amino- or azido-pyrimidines 19 (Scheme 16.5). To demonstrate the stability of the linker, the resin-bound derivatives were subjected to different reactions such as saponification, ester reduction, acid chloride formation or Mitsunobu alkylation. A similar approach was presented later on by Hwang and Gong in the SPOS of 2-aminobenzoxazoles [26]. 

Pyridine can become involved in nucleophilic substitution when very reactive trifiates are being synthesized. One approach to minimize this disadvantage is to replace it with sterically hindered bases, such as 2,6-di-f-butyl-4-methylpyridine, 2,4,6-trisubs-tituted pyrimidines, or nonnucleophilic aliphatic amines (usually W,W-diisobutyl-2,4-dimethyl-3-pentylamine). No salt formation appears to take place under these conditions. The triflic anhydride seems to be the direct triflating agent and the base only neutralizes the triflic acid formed. Numerous alkyl triflates have been prepared in the literature by the above method. Some recent examples of triflates prepared from alcohols are illustrated in eqs 2 and 3. As an exception, 2,6-dinitrobenzyl alcohol does not react with Tf20 although similar sulfonyl esters could be prepared. ... 

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