Pyrimidinones alkylation

Similar intermediates including o-ethoxycarbonyl-, o-cyano- and o-dimethyl-aminomethylene-piperidones or their imines have been used to give partially reduced analogues, e.g. (244), in the [2,3-. 

Pyrimidine-4(3H)-thione, 6-methoxy-5-nitro-reduction, 3, 88 Pyrimidinethiones acidic pK, 3, 60 S-acylation, 3, 95 N-alkylated synthesis, 3, 139 aminolysis, 3, 94 desulfurization, 3, 93 electrophilic reactions, 3, 69 hydrolysis, 3, 94 oxidation, 3, 94, 138 pyrimidinone synthesis from, 3, 133 reactions... 

Electrophilic substitution at ring nitrogen atoms has been limited to protonation and iV-alkylation of the anion derived from a pyrido-pyrimidinone.i - Thus, the sodium salt of pyrido-[2,3-d]pyrimidine-2,4-(l//,3ir)-dione and dimethylsulfate yield the 1,3-dimethy] derivative (176). 

The use of more polar solvents (acetonitrile, DMF) improved the N 0 ratio in the Mitsunobu alkylation of 3-benzoyl thymine with cyclopentanol <06SL324>. N vs. O-selectivity in the alkylation of 2-pyrimidinones has been investigated and the results rationalised on the HSAB principle <06T6848>. 

N-Alkylation is promoted by prior conversion of the pyrimidinones into their respective silyl ethers. Besides selectivity in the alkylation reactions, silylation confers solubility on molecules which otherwise may be difficult to dissolve in nonhydroxylic organic solvents. Selective N-3-alkylation of uracils requires initial protection of N-1. The alkylation of tautomeric thiones invariably proceeds to give an A-alkyl derivative any N-, 0-, or C-alkylation is less rapid and can be avoided. 

The C-5 protons in reduced 4-pyrimidinones are acidic and can be removed by strong bases. The resulting enolate can then be alkylated by a variety of different electrophiles. This alkylation can occur diastereoselectively... 

Alkylation at the 6-position can also be achieved with N -unsubstituted 4-pyrimidinones, via a dianion, when there is an electron-withdrawing group also present at the 6-position. Thus, alkylation of the chiral pyrimidinone 514 (At = -chlorophenyl) gave a 54% yield of the enantiomerically pure methyl derivative 516 via the dianion 515 <1999JOC7885>. 

After selective generation of the syn- or anH -enolate of an amide, it is usually reacted with a haloalkane, often the iodide. Allylic and benzylic bromides also react satisfactorily, and dimethyl and diethyl sulfate have also been used in some cases. A solution of the alkylating agent in an ethereal solvent, usually tetrahydrofuran, is added to the enolate, usually at low temperature. A polar, aprotic cosolvent, such as hexamethylphosphoric triamide, is frequently used as an additive in the alkylation step. The use of this suspected carcinogen is prohibited in some countries, which limits the usefulness of many of the reactions described below. However, similarly effective in many cases are some ureas, such as the commercially available 1,3-dimethyl-3,4,5,6-tetrahydro-2(l//)-pyrimidinone (DMPU)12. 

The possibility of preparing /3-amino acids in a similar way to the a-amino acids (vide supra) has been explored14. Thus, the six-membered, racemic tetrahydro-4(3//)-pyrimidinone 1 forms the enolatc with lithium diisopropylamidc at —78 CC. Subsequent alkylation with a number of halides gives excellent diastereoselectivities in favor of the trara-isomer 2. 

The enantiomerically pure substituted 1,2-dihydro-4(3//)-pyrimidinone 11 has been employed as a chiral auxiliary for diastereoselective alkylation reactions2. Thus, acylation, followed by enolate formation and alkylation with reactive halides such as halomethanes. (balomethyl)benzenes, 3-halopropenes and 3-halopropynes, affords the alkylation products with high diastereoselectivity (d.r. 93 7 to 99 1) . 

Cyclization of 2-hydrazinocyanopyrimidinone 392 with triethyl orthoformate afforded the triazolopyrimidin-5-one 394 rather than 396, together with its A-ethylated derivative 395, whose amount increased with time. Here the orthoester acts as a novel alkylating agent. The products from reaction with N-substituted pyrimidinones (393) were the triazolopyrimidin-7-ones 146 (98UP1) (Scheme 74). 

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