Pyrimidine-2-carboxylic esters, synthesis

The synthesis of pyrimidine carboxylic esters can be achieved by palladium-catalyzed carbonylation of halopyrimi-dines with carbon monoxide and an alcohol < 1999T405, 2001S1098>, as shown by the formation of a variety of esters 271 from 2-chloro-4,6-dimethoxypyrimidine 270 <1999T405>. 

The only way to realize an enantioselective Biginelli reaction is to conduct it intramolecularly where the enantiopure urea and aldehyde portions are tethered. This reaction was the key step in L.E. Overman s total synthesis of guanidine alkaloid 13,14,15-lsocrambescidin 800. An optically active guanidine aminal was reacted with an enantiopure (3-keto ester in trifluoroethanol to afford 1-iminohexahydropyrrolo[1,2-c]pyrimidine carboxylic ester with a 7 1 trans selectivity between CIO and Cl3 positions. 

Primary synthesis has limited application in making pyrimidine-carboxylic acids or even their esters. However, some pyrimidine-4(and 5)-carboxylic acids can be effectively so made. For example, bromomucic acid (785) reacts as an aidehydo ketone with S-methyl-thiourea to give 5-bromo-2-methylthiopyrimidine-4-carboxylic acid (786) directly (53JCS3129) while the Whitehead synthesis (Section 2.13.3.1.2<7) can give, for instance, 3-methylcytosine-5-carboxylic acid (787) (55MI21300). 

Pyrimidine-5-carboxylic acid, 4-amino-2-methyl-ethyl ester synthesis, 3, 111... 

Pyrrolo[2,3-d]pyrimidine, 5-cyano-bromination, 4, 506 Pyrrolo[2,3-d]pyrimidine, 5-nitroso-nucleophilic reactions, 4, 507 Pyrrolo[l, 2- c]pyrimidine-3-carboxylic acids methyl ester synthesis, 4, 293 Pyrrolopyrimidine-2,4-diones Mannich reaction, 4, 504 Vilsmeier reaction, 4, 505 Pyrrolopyrimidines synthesis, 4, 514, 517, 524, 527 Pyrrolopyrimidines, chloro-nucleophilic attack, S, 312 Pyrrolo[2,3-d]pyrimidines NMR, 4, 500... 

Enolates can also function as masked aldehydes or ketones and a new synthesis of 2-substituted pyrimidine-5-carboxylic esters 652 used a doubly masked dialdehyde 651, where one aldehyde was protected as an acetal and the other was used in the form of its sodium enolate <2002S720>. 

REMFRY-HULL Pyrimidine Synthesis Synthesis of pyrimidines by condensation of malon diamides with carboxylic esters. 

Pyrimidine syntheses based on 1,3-diaminopropenes or propanes are less important. The base-catalysed cyclocondensation of malonamides with carboxylic esters leads to 6-hydroxypyrimidin-4(3//)-ones 15 Remfry-Hull synthesis) ... 

A method for the synthesis of 2-substituted pyrimidine-5-carboxylic esters is described based on the similar concept of condensation of amidine... 

In fact, most pyrimidinecarboxylic acids are made by hydrolysis of the corresponding esters, nitriles or sometimes amides, many of which can be made more easily by primary synthesis than can the acids themselves. Thus, pyrimidine-5-carboxylic acid may be made by alkaline hydrolysis of its ethyl ester (62JOC2264) and pyrimidin-5-ylacetic acid (789 ... 

Hydroxy-L-prolin is converted into a 2-methoxypyrrolidine. This can be used as a valuable chiral building block to prepare optically active 2-substituted pyrrolidines (2-allyl, 2-cyano, 2-phosphono) with different nucleophiles and employing TiQ as Lewis acid (Eq. 21) [286]. Using these latent A -acylimmonium cations (Eq. 22) [287] (Table 9, No. 31), 2-(pyrimidin-l-yl)-2-amino acids [288], and 5-fluorouracil derivatives [289] have been prepared. For the synthesis of p-lactams a 4-acetoxyazetidinone, prepared by non-Kolbe electrolysis of the corresponding 4-carboxy derivative (Eq. 23) [290], proved to be a valuable intermediate. 0-Benzoylated a-hydroxyacetic acids are decarboxylated in methanol to mixed acylals [291]. By reaction of the intermediate cation, with the carboxylic acid used as precursor, esters are obtained in acetonitrile (Eq. 24) [292] and surprisingly also in methanol as solvent (Table 9, No. 32). Hydroxy compounds are formed by decarboxylation in water or in dimethyl sulfoxide (Table 9, Nos. 34, 35). 

Pd-catalyzed alkoxycarbonylation enables synthesis of a variety of heterocyclic esters that are otherwise not easily prepared. 5-Bromopyrimidine was transformed into 5-ethoxycarbonyl-pyrimidine in quantitative yield employing the Pd-catalyzed alkoxycarbonylation. The alkoxycarbonylation of 2-chloro-4,6-dimethoxypyrimidine, in turn, led to benzyl 4,6-dimethoxypyrimidine-2-carboxylate (112), whereas alkoxycarbonylation of 2-(chloromethyl)-4,6-dimethoxypyrimidine provided pyrimidinyl-2-acetate 113 [79]. 4,6-Dimethoxypyrimidines 112 and 113 are both important intermediates for the preparation of antihypertensive and antithrombotic drugs. 

Bahrami K, Khodaei MM, Farrokhi A (2009) Highly efficient solvent-free synthesis of dihydropyrimidinones catalyzed by zinc oxide. Synth Commun 39 1801-1808 74. Gross GA, Wurziger H, Schober A (2006) Solid-phase synthesis of 4,6-diaryl-3,4-dihydro-pyrimidine-2(lH)-one-5-carboxylic acid amide derivatives a Biginelli three-component-condensation protocol based on immobilized beta-ketoamides. J Comb Chem 8 153-155 Desai B, Dallinger D, Kappe CO (2006) Microwave-assisted solution phase synthesis of dihydropyrimidine C5 amides and esters. Tetrahedron 62 4651 664 Kumar A, Maurya RA (2007) An efficient bakers yeast catalyzed synthesis of 3,4-dihydro-pyrimidin-2-(lH)-ones. Tetrahedron Lett 48 4569-4571 77. Zalavadiya P, Tala S, Akbari J, Joshi H (2009) Multi-component synthesis of dihydropyrimidines by iodine catalyst at ambient temperature and in-vitro anti mycobacterial activity. Arch Pharm 342 469-475... 

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