2- Methyl-A’-tetrahydropyrimidine

Lithiation of 2-(2-alkylphenyl)-l,2,3,4-tetrahydropyrimidines 427 with 1.3 M BuLi in the presence of A/, A/, A, A -tetramethylethylenediamine, then with 1.3 M -BuLi, followed by the addition of a carboxylic acid methyl ester, and treatment of the reaction mixture with pTSA afforded 3,4-dihydro-2/f-pyrimido[2,l-u]isoquinolines 428 after chromatographic work-up (98JMC1050). 

There are now a reasonable number of reactions in which derivatives of pyrimidine are converted into pyridines. The tetrahydropyrimidine (792) is converted into a dihydropyridine by heating with silica and alumina (48HCA612). It was assumed that hydrolysis gave a ketoimine (also obtained directly from acetone and ammonia), which recydized. Pyrimidine itself is converted by hot (190 °C) aqueous ammonia or methylamine into 2-methyl-5-ethylpyridine (793) (71RTC1246), while 2-methoxy-5-arylpyrimidines (794) with... 

In the case of 1,3-thiazine-2-ylidene compounds, hydrolysis of N-methylimino-5-ethoxycarbonyl-l,3-thiazine 188 (R = Me) is carried out in an acid medium. Formic acid does not react. Incorporation of water was found in the course of subsequent research (formic acid/aqueous triethyla-mine either formic acid or acetic acid/water 50-50 formic acid/aqueous formaldehyde) and resulted in the isolation of three compounds 5-ethoxy-carbonyl-2-oxo-2,3-dihydro-6//-l, 3-thiazine (189), 5-ethoxycarbonyl-l-methyl-2-thioxo-l,2,3,4-tetrahydropyrimidine (190) and 5-ethoxy-car-bonyl-3-methyl-2-thioxo-l, 2,3,4-tetrahydropyrimidine (191). The authors have proposed a mechanism involving cleavage of the C-6-S bond and reclosure of the six-membered ring by a Michael addition (Scheme 75). 

A solution of 6-hydroxy-6-methyl-2,4-diphenyl-1,4,5,6-tetrahydropyrimidine 3 (5.3 g, 0.02 mol) in glacial acetic acid (15-20 ml) was heated at 80°C, for approximately 48 h. After cooling, ice (20 g) was added followed by dichloromethane (40 ml). A 25% aqueous solution of ammonia (20-25 ml) was added slowly with constant stirring until the mixture became basic. The dichloromethane layer was separated and the upper layer was extracted with dichloromethane (3 x 50 ml). The organic layers were combined, dried with magnesium sulfate and the solvent was evaporated in vacuo. The residue of 2-methyl-2,4-diphenyl-1,4-dihydropyrimidine 4 was recrystallized from ethyl acetate. Yield 98%. Melting point 145°C. 

Rader et al. (1952) first found active protective fungicides among the tetra-hydropyrimidine derivatives later Nickell et al. (1961) also observed a systemic effect in some of the 2- -alkylmercapto-l,4,5,6-tetrahydropyrimidine derivatives used to combat rust. l- -Dodecyl-2-methyl-l,4,5,6-tetrahydropyrimidine (13) has also been applied in practice. It has proved efficient in orchards when used for the control of the disease caused by Erwinia amylovora which results in shoot withering and crown gall. 

To a stirred solution of 0.1 mmol (4R,VS)- and (45,l 5 )-4-(l -f rf-butoxycarbonyl-amino-2 -hydroxyethyl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester in 1 mL anhydrous CH2CI2 were added 29 mg (R)-Qf-methoxy-a -(trifluoro-methyl)phenylacetic acid (0.12 mmol), 25 mg 1,3-dicyclohexylcarbodiimide (0.12 mmol), and a catalytic amount of 4-A, A-(dimethylamino)pyridine. The mixture was stirred for an additional 12 h at room temperature, then concentrated. The residue was taken into EtOAc, washed with saturated aqueous NaHCOs and brine, dried over Na2S04, and concentrated. The residue was purified by preparative TLC, affording the corresponding Mosher ester in almost quantitative yield. 

Pseudodistamine (321) as well as 2-methyleudistomins D (30) and J (31) are rare examples of A-methyl P-carbolinium derivatives described from marine sources, while eudistomidins E (324) and F (325) are structurally unique, with a tetrahydropyrimidine ring fused to the P-carboline skeleton (Figure 38) [289]. 

A soln. of 2,3-dichloro-5,6-dicyanoquinone in abs. dioxane added to a soln. of ethyl l-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylate in the same solvent, and heated 1 hr. at 90° ethyl l-methyl-2-oxo-l,2-dihydropyrimidine-5-carboxylate. Y 80.2%. F. e. s. A. Takamizawa and K. Hirai, Ghem. Pharm. Bull. 12, 1418 (1964). 

In 1958 Hull and Swain synthesized 4-(5-nitrofuryl)-6-methyl-2-oxo-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid methylester (nitractin) XL) which Hurst and Hull described as a compound dxat protects mice from lymphogranuloma inguinale and related infections. 

N-(4-Chlorophenyl)-7-methyl-5-aryl-2,3-dihydro-5H-thiazolol[3,2-a]pyrimidine-6-carboxamides 41 (Scheme 18) were accomplished by cyclocondensation of l,2,3,4-tetrahydropyrimidine-2-thiones and 1,2-... 

A six-step approach to 6-phenylthio-substituted 2,3,4,5-tetrahydro-l,3-l//-diazepin-2-ones based on a ring-expansion reaction of 4-mesyloxymethyl-l,2,3,4-tetrahydropyrimidin-2-ones under the action of nucleophiles has been achieved. The thermal rearrangement of (6-oxo-l,6-dihydropyrimidin-2-yl)guanidines with triethyl orthoacetate to give 4-substituted-2-methyl-6//-pyrimido[l,2-a][l,3,5]triazm-6-ones has been reported (Scheme 16) ... 

Rana et al. (2011) synthesized (6-methyl-4- (substituted phenyl)-2-thioxo-l, 2, 3, 4-tetrahydropyrimidin-5-carboxylic acid ethyl ester by condensation of acetoace-tic ester, thiourea and substituted aromatic aldehydes using piperidine as catalyst with stirring for 4 h. While these were also obtained under microwave heating in five min using ethanol as a solvent and HCl as a catalyst. 

The condensation of 2-mercapto-3,4,5,6-tetrahydropyrimidine and ethyl a-bromopropionate at 160 C yields 2-methyl-4,5,6,7-tetrahydrothiazolo[3,2-a]pyrimidin-3(2H)-one (177) nearly quantitatively. 2-(2-Bromoethylthio)-... 

Pyrantel Pyrantel, l,4,5,6-tetrahydro-l-methyl-2-[trans-2-(2-thienyl)vinyl]-pyrimidine (38.1.22), a derivative of tetrahydropyrimidine, is made from 3-(2-thienyl)-acrylonitrile (38.1.19), which is made in a Knoevangel condensation of fnrfnral with cyanoacetic acid. Acidic hydrolysis of this makes 3-2(-thienyl)acrylamide (38.1.20). Reacting this with propansnUone gives an iminoester (38.1.21), which when reacted with A-methyltrimethyl-enediamine gives the desired pyrantel [20-23]. 

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