2-Substituted hexahydropyrimidines

Tautomerism of 2-substituted hexahydropyrimidines has been studied (980PP53), and free energies, enthalpies, and entropies of activation for this ring-chain tautomeric equilibrium have been measured [97JCS(P2)169]. 

Zohdi HF, Rateb NM, Elnagdy SM (2011) Green synthesis and antimicrobial evaluation of some new trifluoromethyl-substituted hexahydropyrimidines by grinding. Eur J Med Chem 46 5636-5640... 

Primary nitroparaffins react with two moles of formaldehyde and two moles of amines to yield 2-nitro-l,3-propanediamines. With excess formaldehyde, Mannich bases from primary nitroparaffins and primary amines can react further to give nitro-substituted cycHc derivatives, such as tetrahydro-l,3-oxa2iaes or hexahydropyrimidines (38,39). Pyrolysis of salts of Mannich bases, particularly of the boron trifluoride complex (40), yields nitro olefins by loss of the amine moiety. Closely related to the Mannich reaction is the formation of sodium 2-nitrobutane-1-sulfonate [76794-27-9] by warming 1-nitropropane with formaldehyde and sodium sulfite (41). 

Putilova ES, Troitskii NA, Zlotin SG, Khudina OG, Burgart YV, Saloutin VI, Chupakhin ON (2006) One-step solvent-free synthesis of fluoroalkyl-substituted 4-hydroxy-2-oxo(thioxo) hexahydropyrimidines in the presence of l-butyl-3-methylimidazolium tetrafluoroborate. Russ J Org Chem 42 1392-1395... 

Halogen displacement from 2-halo-tetrahydropyrans and -hexahydropyrimidines is extremely easy, being assisted, in the SnI process, by the electron pairs on the heteroatom (equation 124). 3-Halohexahydropyridines can also show accelerated halogen displacement (anchimeric assistance from nitrogen equation 125). Apart from these and other (normal) substitutions, eliminations of H—Hal are also commonly found. 

Emphasis is placed on simply substituted free bases. The problems of conformational equilibria in /V-alkylpiperidinium salts and N-quaternization reactions and the relationships of these to conformational equilibria in the free bases are not covered, since this area is a large one requiring separate treatment. In other relevant previous reviews, the topics include heterocyclic conformational analysis,3-7 interactions in azacyclic systems,8 the conformational analysis of piperidine,9 hexahydropyrimidines,10,11 hexahydropyri-dazines,12 quinolizidines,13 the conformational analysis of bi- and polycyclic... 

Cyclic ketene acetals can also react with amines to give 1,1-enediamines with elimination of ethylene glycol76. Treatment of 2-[(methoxycarbonyl)cyanomethylene]-1,3-dioxolane (38) with 1,3-diaminopropane or with 4,5-dimethyl-1,2-phenylenediamine gives the hexahydropyrimidine and the benzimidazoline derivatives 39 and 40, respectively (equation 11). Similarly to the reaction of ketene dithioacetals with amines, the reaction between ketene acetals and amines proceeds via monoamino-substituted intermediates and ketene 7V,Oacetals can be isolated when one molar amine is used72. 

Hexafluoroacetylacetone reacts with urea and thiourea to yield 4,6-bis(hydroxy)-4,6-bis(trifluoromethyl)hexahydropyrimidine-2-one and -2-thione (01ZOR915, 00JFC(103)17), respectively (Scheme 54). The dehydration of the products and also the reaction of unsymmetric fluoroalkylcontaining 1,3-diketones with urea and thiourea afford substituted pyrimidines. 

The hexahydropyrimidines are prepared almost exclusively by the condensation of substituted propane-1,3-diamines with aldehydes and ketones . 

Hexahydropyrimidines have also been used as carriers for the nitrogen mustard function. Compounds of type (CIV), prepared by the condensation of substituted 1,3-diaminopropanes with substituted benzaldehydes containing a p-bis( -chloroethyl)amine moiety, exhibit tumour-inhibitory activity against Walker 256 carcinoma in rats [543,544]. The degree of activity of these compounds is believed to be dependent on the electron-donating ability of the substituents on the aryl moiety [543]. 

Polarographic methods were used by Frost et al. ° to determine the cumulative stability constants (/ four ligands would be represented as Pt) of substituted thiourea derivatives with Cu(l) in acid. Values for p4 that were greater than 10 were determined for thiourea, hexahydropyrimidine-2-thione, and several other complexes with Cu(l). These very high stability coefficients in acid explain the abiiity of these iigands to prevent copper from plating onto steel in HCI at acid concentrations >1 M. 

DMPU is an acronym derived from A -dimethyl-N -propylene-urea= l,3-dimethyl-2-oxo-hexahydropyrimidine, a noncarcinogenic substitute for HMPA [49]. 

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