Microwave-Assisted Solution- and Solid-Phase Synthesis of 2-Amino-4-arylpyrimidine Derivatives

Abstract

An efficient and rapid microwave-assisted solution-phase method for the synthesis of 2-amino-4-arylpyrimidine-5-carboxylic acid derivatives has been developed. The five-step linear protocol involves an initial Biginelli multicomponent reaction leading to dihydropyrimidine-2-thiones which are subsequently S-alkylated with methyl iodide. The resulting 2-methylthiodihydropyrimidines are sequentially oxidized first with manganese dioxide and then with Oxone to provide 2-methylsulfonyl-pyrimidines which serve as excellent precursors for the generation of a variety of 2-substituted pyrimidines via displacement of the reactive sulfonyl group with nitrogen, oxygen, sulfur, and carbon nucleophiles. A modified protocol using a solid-phase method has also been developed.

Synthetic Studies on Novel 1,4-Dihydro-2-methylthio-4,4,6-trisubstituted Pyrimidine-5-carboxylic Acid Esters and Their Tautomers

“…Furthermore, no such threecomponent reaction took place to afford ethyl 1,4-dihydro-4,6,6-trimethyl-2-methylthiopyrimidine-5-carboxylate 12 or its 1,6-dihydro tautomer 13 when 9 (3-10 eq) and 10 (1.0 eq) were exposed to 3 (1.2 eq) instead of 8 in DMF in the presence of NaHCO 3 (4.0 eq) at 65°C for 12 h. [12][13][14] In contrast, when ethyl 2-benzylidene-3-oxobutanoate 14 [E/Z (1 : 3.0)], 15) a typical 2-(monosubstituted)methylene-3-oxoester prepared under the conventional Knoevenagel reaction conditions, was subjected to Atwal-Biginelli conditions [3 (1.2 eq), NaHCO 3 (4.0 eq), DMF, 60°C for 5 h], the cyclocondensation reaction proceeded uneventfully to provide ethyl 1,4-dihydro-2-methylthio-4,6-disubstituted pyrimidine-5-carboxylate 15 and its tautomeric isomer 16 as an inseparable mixture [15/16 (2.2 : 1)] in a combined yield of 67% (Chart 2). 16,17) Structural assignments for 15 and 16 were made by the following nuclear Overhauser enhancement spectroscopy (NOESY) experiment. With the major component 15, its 6-methyl protons exhibited a significant nuclear Overhauser effect (NOE) when the 1-NH proton was irradiated; hence, its structure was determined to be 1,4-dihydropyrimidine 15 as depicted in Chart 2.…”

Regioselective addition reactions at C-2 of 3,4-dihydropyrimidinones. Synthesis and evaluation of multifunctionalized tetrahydropyrimidines

“…A survey of recent literature revealed different approaches to access pyrimidines from pyrimidinone derivatives. 22,23 For example, pyrimidines bearing a sulfone moiety at C-2, obtained through treatment of 2-thioxopyrimidines with oxone can react with nucleophiles 23 to obtain 2-substituted pyrimidines. Alternatively, a palladium(0)-catalyzed copper(I)-mediated coupling of boronic acids with cyclic thioamides has been used.…”

Synthesis of Tri‐ or Tetrasubstituted Pyrimidine Derivatives through the [5+1] Annulation of Enamidines with either N,N‐Dimethylformamide Dialkyl Acetals or Orthoesters and Their Application in a Ring Transformation of Pyrimidines to Pyrido[2,3‐d]pyrimidin‐5‐one Derivatives

“…A variety of approaches for the synthesis of pyrimidine derivatives have been developed by a number of organic and pharmaceutical chemists. [1,[8][9][10][11] Most general synthetic routes to the pyrimidine framework utilize one of the following procedures (Scheme 2): i) [3+3] annulation between an N À C À N and a C À C À C fragment (known as the Pinner-type synthesis; [12] path a), [13,14] or between a C À C À N and a C À N À C fragment (path b); [15] ii) [4+2] annulation of a C À C À N À C fragment with a C À N fragment (path c), [16] a C À C À C À N fragment with a C À N fragment (path d), [17] or a C À NÀCÀN fragment with a CÀC fragment (path e); [18] and iii) [5+1] annulation of a NÀCÀCÀCÀN fragment with a C1 unit (path f), [19] or of a CÀNÀCÀCÀC fragment with an N1 unit (path g). [20] To our knowledge, the [5+1] annulation of a C À C À N À C À N fragment with a C1 unit has not yet been studied (path h).…”