Synthesis of Pyrimidinones

Cui and coworkers reported a Rh(III)-catalyzed C-H activation/cyclization of indoles and pyrroles at the C2 position with various alkyne and alkene substrates to give pyrimidin-2(l//)-ones and 3,4-dihydropyrimidin-2(l//)-ones 101 (Eq. (5.98)) [51]. The reaction tolerates a wide range of substituents on the aromatic rings. Moreover, both symmetrical and unsymmetrical alkynes/alkenes with various functional groups, such as hydroxyl, nitrile, and ester, also react efficiently to provide the expected JV-heterocycles in good to excellent yields. 

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Sundaram and co-workers [90TL(31)7357] prepared 1-methoxycarbonyl-substituted diene 354 and reported its reaction with dimethyl acet-eylenedicarboxylate in refluxing benzene affording cycloadduct 355 in 72% yield (Scheme 78) there is no comment in the report on the aromatiza-tion step, which should imply loss of both dimethylamino and methoxycar-bonyl groups. Similarly, the synthesis of pyrimidinone 356 (96% yield) was described to occur when 354 was stirred with phenylketene at room temperature. 

SCHEME 78 Synthesis of pyrimidinones using Bi(N03)3-5H20 and TBAB. 

SCHEME 86 Synthesis of pyrimidinone derivatives using [TEBSAJPSOJ. 

A.R. Hajipour, Y. Ghayeb, N. Sheikhan, A.E. Ruoho, Bronsted acidic ionic liquid as an efficient and reusable catalyst for one-pot three-component synthesis of pyrimidinone derivatives via BiginelH-type reaction under solvent-free conditions, Syn. Commrm. 41 (2011) 2226-2233. 

Pyrimidines and Quinazolines. Acid-catalysed condensation of urea and propiolic acid in boiling benzene has been proposed as a new, viable, commercial process for the production of uracil. Also new is the synthesis of pyrimidinones and pyrimidines from a mixture of amides as outlined in Scheme 47. Isolation of the pyrimidinone (210) is dependent on the nature of R . Generally, if this substituent... 

This drug also is reported to activate macrophages, to iaduce polyclonal B-ceU activation as well as enhance specific antibody production m vivo, and to iaduce the synthesis of iaterferon and interleukin 1 (52). The iaduction of these important cytokiaes (and others) largely accounts for the profile of biological activity displayed by the pyrimidinones. Bropirimine is currentiy ia clinical evaluation for cancer, arthritis, and immunorestoration ia AIDS patients. 

Chander Mohan was born in 1975 at Dhariwal, Punjab, India. He received his B.Pharm. and M.Tech.(Pharm.) in bulk drugs from Guru Nanak Dev University and the National Institute of Pharmaceutical Education and Research (NIPER), Mohali. After that he worked as senior chemist at Dr. Reddy s Research Foundation, Hyderabad. He then joined Professor M. P. Mahajan s research group in 2002 for his doctoral studies. His research is focused on the synthesis and chemical transformation of C-5/C-6-substituted pyrimidinones. His research interests include synthesis of medicinally important molecules, transition metal-induced transformations in organic synthesis, reaction mechanism and total synthesis of natural products. 

A similar strategy has been used for the Biginelli condensation reaction to synthesize a set of pyrimidinones (65-95%) in a household MW oven [152]. This MW approach has been successfully applied to combinatorial synthesis [153]. Yet another example is the convenient synthesis of pyrroles (60-72 %) on silica gel using readily available enones, amines and nitro compounds [154]. 

Synthesis of Enantiomerically Pure p-Amino Acid from 2-tert-Butyl-1-carbomethoxy-2,3-dihydro-4(1 H)-pyrimidinone (S)-p-Tyrosine-O-methyl Ether. 

There are few cases in which free /3-aldehydo esters have been condensed successfully with ureas. Commonly, alkoxymethylene esters are used. The initial reaction leads to an acyclic intermediate that may require a separate treatment to induce ring closure. The reaction of a /3-keto ester with urea may be a two-step process in which case acid catalysis can be used in the formation of an acyclic intermediate, with ring closure effected by strong alkali. When the ester component is a lactone or chromone, the product contains a hydroxyalkyl <2000JME3837> or 2-hydroxyphenyl substituent <2004S942>, as shown by the synthesis of the 5-(2-hydroxyethyl)-4-pyrimidinone 657 and the 6-(2-hydroxyphenyl)-pyrimidine 659. 

Factors influencing the choice of synthetic routes to pyrimidines depend very much upon the substitution pattern of the desired product. For pyrimidines unsubstituted at the 4- and 6-positions, a two-component ring synthesis reaction involving a 1,3-dialdehyde and a urea or amidine derivative is the most straightforward route, but only if the dialdehyde is readily available. For example, synthesis of 2-chloro-5-(2-pyridyl)pyrimidine 989, an intermediate in the synthesis of a selective PDE-V inhibitor, was achieved in two steps in 40% overall yield by condensation of 2-(2-pyridyl)malondialdehyde 987 with methylurea, followed by demethylation/chlorination of the pyrimidinone 988 with a mixture of POCI3 and PCls <20070PD237>. 

A rapid and high yielding synthesis of pyrazolo[3,4- pyrimidinones by reaction of aromatic aldehydes with 4-amino-l-methyl-3-propyl-177-pyrazole-5-carboxamide intermediates in the presence of copper chloride has recently been reported for the synthesis of Viagra analogues <2005H(65)1821>. 

The synthesis of the pyrimidine ring represents a well-studied group of heterocyclization reactions based on enamines. One of the important approaches involves the reaction of enamines with assorted isocyanates and isothiocyanates. Thus, a reaction of enaminonitriles with benzyl isocyanate or phenyl isocyanate gives C- and N-adducts (190a and 190b, respectively) or their mixtures, which are transformed in a single step into 4-pyrimidinone (191) and 2-pyrimidinone (192) derivatives (94JHC329). The... 

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