Heterocyclizations of functionalized heterocumulenes with C,N-, C,O-, and C,S-binucleophiles: XIII. Synthesis of dialkyl 2-oxo-3-allyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates and their reaction with arylhydroxymoyl chlorides

Abstract

Dialkyl 2-oxo-3-allyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates obtained by condensation of 1-chlorobenzyl isocyanates with N-allylfumarates reacted regioselectively with arylhydroxymoyl chlorides with the formation of dialkyl 6-aryl-3-[(3-aryl-4,5-dihydro-5-isoxazolyl)methyl]-2-oxo-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates.3,4-Dihydropyrimidine ring is the structural fragment governing the biological activity of many organic compounds [2][3][4]. Therewith the useful properties of 3,4-dihydropyrimidine derivatives are essentially affected by the character of substituents at the carbon atoms of the ring. Yet the effect of the substituents at nitrogen atoms remains practically nonstudied to a certain extent because of the lack of methods of the selective functionalization of the nitrogen atoms with biophore moieties. To the latter the isoxazoline heterocycle certainly belongs for among its derivatives substances are found with a wide range of the biologic action [5][6][7][8].The analysis of publications [9-11] reveals a limited number of isoxazoline derivatives linked to the other heterocycles by a methylene bridge. It was therefore feasible to extend our method [12] of 3-arylpyrimidinedicarboxylates synthesis on their 3-allyl analogs and to use the latter for building up an isoxazoline ring. ___________________ * For Communication XII, see [1].It was established that 1-chlorobenzyl isocyanates Іа-Ie reacted with previously unknown dialkyl N-allylaminofumarates ІІа, IIb in toluene solution at room temperature giving dialkyl 2-oxo-3-allyl-6-aryl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylates ІІІа-IIIh in 45-83% yields. The structure of the latter is confi rmed by 1 Н and 13 С NMR spectra containing typical doublets of protons Н 6 in the range 5.23-5.42 ppm and signals of atoms С 6 in the range 51.86-53.02 ppm. The presence of the asymmetric carbon center in the position 6 of the heterocycle results in the diastereotopic character of the methylene group of the allyl substituent leading to the complex multiplicity of the signal of allyl protons in the 1 Н NMR spectrum.Among the versatile procedures for the preparation of isoxazoline derivatives the version should be specially indicated of 1,3-dipolar addition of nitrile oxides to alkenes, in particular, to functionalized ones, which is characterized by high regioselectivity [13,14]. We demonstrated that 3-allylpyrimidin-2-ones ІІІb, IIId, IIIe-IIIh also reacted regioselectively with hydroxymoyl chlorides IVа-IVb in the presence of triethylamine, i.e.,

Nitrile Oxide, Alkenes, Dipolar Cycloaddition, Isomerization and Metathesis Involved in the Syntheses of 2-Isoxazolines

“…3,5-disubstituted 2-isoxazolines possessing substituted oxopyrimidine motifs in position 5 can also be obtained using 1,3-DP cycloaddition of in situ-generated ArCNO to N -allylpyrimidine derivatives, as presented in work by Kushnir, Mel’nichenko, and Vovk— Scheme 78 [ 84 ].…”

“… Syntheses of 3,5-disubstituted 2-isoxazolines equipped with oxo-pyrimidine motifs in position 5 [ 84 ]. Ar 1 , Ar 2 = Ph, m -BrC 6 H 4 , m -NO 2 C 6 H 4 , p -NO 2 C 6 H 4 , 3,4-Cl 2 C 6 H 3 , 3,4-Cl 2 C 6 H 3 , p -FC 6 H 4 , p -MeOC 6 H 4 ; Alkyl = Me, Et; a = Et 3 N, CH 2 Cl 2 , from −15 °C to rt, 12 h; 75% yield.…”