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

Abstract

This article deals with a general approach to synthesizing alkyl 1,4-dihydro-2-methylthio-4,4,6-trisubstituted pyrimidine-5-carboxylate 1 and its tautomeric isomer, alkyl 1,6-dihydro-2-methylthio-4,6,6-trisubstituted pyrimidine-5-carboxylate 2, which was achieved by applying the Atwal-Biginelli cyclocondensation reaction 1-3) of S-methylisothiourea hemisulfate salt 3 to 2-(gem-disubstituted)methylene-3-oxoesters 4 available by the Lehnert procedure 4,5) for the Knoevenagel-type condensation (Fig. 1). This synthetic study was conducted as part of our medicinal chemistry program to explore alkyl 3,4-dihydro-2-oxo-3,4,4,6-tetrasubstituted pyrimidine-5-carboxylates 5a and their 2-thioxo congeners 5b for novel therapeutic agents, 6) which was inspired by the two track records with the related 1,4-dihydro-4-monoaryl-6-methylpyrimidine derivatives that follow: (R)-SQ 32926 6, 7) a calcium channel blocker developed as an orally active antihypertensive agent, and monastrol 7, 8-10) a possible anticancer agent that inhibits mitotic cell division by blocking the activity of kinesin Eg 5, a motor protein causing spindle bipolarity. alkyl 1,4-dihydro-2-methylthio-4,4,6-trisubstituted pyrimidine-5-carboxylate 1 and its tautomeric isomer, alkyl 1,6-dihydro-2-methylthio-4,6,6-trisubstituted pyrimidine-5-carboxylate 2 is synthesized by the Atwal--Biginelli cyclocondensation reaction of S-methylisothiourea hemisulfate salt 3 with 2-(gem-disubstituted)methylene-3-oxoesters 4 that can be accessed by the Lehnert procedure for the Knoevenagel-type condensation. The structures of the tautomeric products of the Atwal-Biginelli cyclocondensation reaction, 1 and 2, which are inseparable from each other, are determined unambiguously by 1 H-NMR spectroscopy at various temperatures and nuclear Overhauser enhancement spectroscopy (NOESY) experiment. Because these dihydropyrimidine products are otherwise inaccessible and thus hitherto unavailable, the synthetic methods established in this study will help to expand the molecular diversity of their related derivatives.

Synthesis of 4,4-Disubstituted 3,4-Dihydropyrimidin-2(1<i>H</i>)-ones and -thiones, the Corresponding Products of Biginelli Reaction Using Ketone, and Their Antiproliferative Effect on HL-60 Cells

“…As a preliminary experiment for the synthesis of 5, 3-oxo-2-(2-propylidene)-butanoate 8a was prepared from ethyl 3oxobutanoate and acetone under Lehnert conditions using TiCl 4 in the presence of pyridine. 21) When 8a (1.0 equivalent (equiv.)) and 11 (1.2 equiv.)…”

“…Unlike aldehydes 2, ketones are not applicable to the reaction because of their inertness. 21) Therefore, 4,4-disubstituted 3,4-dihydropyrimidin-2(1H)-ones 5 and -thiones 6 (Chart 2), corresponding to the products of a Biginelli-type reaction using ketones, have long been inaccessible and hitherto unavailable for medicinal chemistry.…”

“…High-resolution spectroscopy (HRMS) was performed using a JEOL JMS-700 mass analyzer. Absorbance spectra were measured on an absorbance microplate reader, Wallac 1420 ARVOsx multilabel counter (PerkinElmer, Inc. Life Sciences, MA, U.S.A.).2-(gem-Disubstituted)methylene-3-oxoester (8a-i)The 2-(gem-disubstituted) methylene-3-oxoesters 8a-i, were all assembled under the conditions in our previous report 21). Ethyl 2-Methoxy-4,4,6-trimethyl-1,4-dihydropyrimidine-5-carboxylate (12a) and Ethyl 2-Methoxy-4,6,6-trimethyl-1,6-dihydropyrimidine-5-carboxylate (13a) Under an atmosphere of argon, a mixture of 11 (74 mg, 0.601 mmol), 8a (85 mg, 0.499 mmol), and NaHCO 3 (168 mg, 2.00 mmol) in dry DMF (1.0 mL) was heated at 65 °C for 12 h. To the reaction mixture was added EtOAc (20 mL) followed by water (10 mL), and the organic layer was separated.…”

Water-Tuned Tautomer-Selective Tandem Synthesis of the 5,6-Dihydropyrimidin-4(3H)-ones, Driven under the Umbrella of Sustainable Chemistry

“…In earlier published methods, a few examples of the 5,6-dihydropyrimidin-4-ones were observed as a mixture of prototropic tautomers with very unfavorable purity (see Scheme a) . In one variation of the Biginelli–Atwal reaction, poor selectivity has been achieved (see Scheme b) . Both protocols performed with solvents indicate that high tautomer purity (≥99%), in Atwal’s modification of the Biginelli reaction, was a very problematic synthetic challenge and, so far, it has not been achieved.…”

“…37 In one variation of the Biginelli− Atwal reaction, poor selectivity has been achieved (see Scheme 1b). 42 Both protocols performed with solvents indicate that high tautomer purity (≥99%), in Atwal's modification of the Biginelli reaction, was a very problematic synthetic challenge and, so far, it has not been achieved. Bearing in mind the aforementioned facts, our combined experiences and interest in green synthesis 43,44 and multicomponent synthesis 45−47 prompted us to explore and develop novel and, at the same time, green synthetic strategies for the synthesis of 6-aryl-5,6dihydropyrimidin-4(3H)-ones in a highly tautomer-selective manner.…”