Pyrimidine alkylation

Reactions of iV -alkylated or arylated azinium compounds with nucleophiles proceed more readily than those of the parent, uncation-ized azines, and the ring tends to open. The iV -substituent may bring into play an accelerative effect from the London forces of attraction. Increased displaceability of the substituent in iV -alkyl-azinium compounds has been noted for 2-halopyridinium (87) 1-haloisoquinolinium, 4-halopyrimidinium, 4-methoxypyrid-inium (88), 4-phenoxy- and 4-acetamido-quinazolinium (89), 3-methylthiopyridazinium, and 2-car boxymethylthiopyrimidi-nium salts (90). The latter was prepared in situ from the iV -alkyl-pyrimidine-2-thione. The activation can be effectively transmitted to... 

When an N(l)-H is avalable as in free-base systems, deprotonation at N( 1) speeds up the hydrolysis (Steenken and Jagannadham 1985). For example, the corresponding p-nitroacetophenone Ura adduct decays with 2.4 x 10s s-1 when deprotonated at N(l). The N(l)-alkylated pyrimidines also hydrolyze, but slower (e.g., k = 4.5 x 103 s-1 in the case of uridylic acid) when deprotonated at N(3). In neutral solution, the rate of hydrolysis must be considerably slower, possibly that slow that other reactions may compete. 

Oxidation of 3,4-dihydropyrimidin-2(l //)-oncs (DHPMs) with ceric ammonium nitrate (CAN) in acetic acid resulted in ethyl 2,4-dioxo-6-phenyltetrahydropyrimidin-5-carboxylates as the major product. However, DHPMs undergo a regioselective oxidation with CAN in the presence of sodium hydrogencarbonate in neutral aqueous acetone solution to yield ethyl 6-meihyl-4-aryl(alkyl)pyrimidin-2(l //)-one-5-carboxylates. A mechanism involving a nitrolic acid intermediate has been suggested.72... 

With readily hydrolyzed (generally fully alkylated) pyrimidines Dimroth rearrangements are possible. Thus 9-methyl-8-thioxo-7,8-dihydropurine results, as expected, from the pyrimidine (272) but also from (273 Scheme 92) (63JCS1276). 

All alkyl-diazines, with the exception of 5-alkyl-pyrimidines, undergo condensations that involve deprotonation of the alkyl group, " in the same way as a- and y-picolines. The intermediate anions are stabilised by mesomerism involving one, or in the case of 2- and 4-alkyl-pyrimidines, both nitrogens. 

Methyl ketones give 4-monosubstituted-pyrimidines when reacted with formamide at high temperature. Although the yields, apart from aryl-methyl-ketones, are not large, the method is extremely simple. Aryl higher-alkyl ketones also react in this way, giving 4-aryl-5-alkyl-pyrimidines. 

Condensation of an appropriately substituted malononitrile with guanidine yields a 5-alkyl-pyrimidine-2,4,6-triamine, 12, with a protected /1-formyl group.109 Deprotection of the aldehyde followed by ring closure and subsequent oxidation to give 13 is then achieved in dilute hydrochloric acid with air, with triphenylmethanol/trifluoroacetic acid, or with trifluoroperoxy-acetic acid.150... 

Ch. 10 The A -Alkylated Pyrimidines and Pyrimidine A40xides Ch. 11 The Pyrimidinecarboxylic Acids and Related Derivatives Ch. 12 The Reduced Pyrimidines Ch. 13 The Ionization and Spectra of Pyrimidines... 

The original Hilbert-Johns on reaction has been modified using trimethylsilyl protected pyrimidine as aglycons to condense with glycosyl acetate and has been applied extensively to the synthesis of a variety of nucleoside derivatives. In addition, the substitution of 2-alkyl pyrimidine for 2-methylthio-protected pyrimidine allows the preparation of 2-oxo, 2-thio, and 2-aminopyrimidine nucleosides. 

Li QY Ge ZM, Cheng TM, Li RT (2012) An efficient three-eomponent, one-pot synthesis of 2-alkylthio-4-amino-5-cyano-6-aryl(alkyl)pyrimidines in water. Mol Divers 16 431-439... 

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. 

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