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A general four-step transformation of alkyl, cycloalkyl, aryl, and heteroaryl methyl ketones via 3-(dimethylamino)-1-substituted-prop-2-en-1-ones, followed by microwave [2+2] cycloaddition of dimethyl acetylenedicarboxylate, cyclization of (2E,3E)-2-[(dimethylamino)methylene]-3-(2-substituted)succinates with ammonia or hydroxylamine hydrochloride into 2-substituted-pyridine-4,5-dicarboxylates and their N-oxides and final cyclization with hydrazine hydrate into of 7-substituted-2,3-dihydropyrido[3,4-d]pyridazine-1,4-diones and 1,4-dioxo-7-substituted-1,2,3,4-tetrahydropyrido[4,3-d]pyridazine 6-oxides is shown.

A library of 24 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxamides 10{1,2; 1–12} was prepared by a parallel solution-phase approach. The synthesis comprises a five-step transformation of itaconic acid (11) into 1-methyl and 1-phenyl substituted 6-(5-oxo-1-phenylpyrrolidin-3-yl)pyrimidine-5-carboxylic acids 17{1,2} followed by parallel amidation of 17{1,2} with a series of 12 aliphatic amines 18{1–12} to afford the corresponding carboxamides 10 in good overall yields and in 80–100% purity.

Regioselective copper(i) iodide-catalyzed cycloadditions of chiral pyrazolidin-3-on-1-azomethine imines 3a–j to ethyl propiolate 4 gave cycloadducts 5a–h and 5′i and 5/5′j as single regioisomers. In terms of facial selectivity, cycloadducts 5a–h and 5′i were obtained as single diastereomers, whereas the reaction of dipole 3j was less selective and gave a mixture of 5j and 5′j in a ratio of 15:85. Stereoselectivity of copper(i) iodide-catalyzed cycloadditions of ethyl propiolate 4 to azomethine imines 3 was controlled by the stereodirecting phenyl group at position 5 and by the ortho-substituents at the 1′–Arresidue. [ABSTRACT FROM AUTHOR]

Abstract   15N NMR chemical shifts of the exo- and endocyclic nitrogen atoms show how efficient is the ground-state intramolecular charge transfer between these sites in 4-dimethylamino-1-methylpyridinium cation (increased contribution of the quinoid resonance form results in a shielding and deshielding effect of their NMR signals, respectively). As it was anticipated, insertion of vinylene and/or 1,4-phenylene spacers to the cation considerably hinders the ground-state charge transfer. This hypothesis is further supported by an analysis of the C–NMe2 bond lengths (X-ray data show that spacers elongate this bond). The selected valence angles in the compounds studied are also linearly dependent on δ(15Nendo) and δ(15Nexo) values. Although the correlation coefficient for the δ(15Nendo) versus δ(15Nexo) dependence is equal to 0.983, decrease of the net charge on one nitrogen atom is not compensated entirely by its increase on another nitrogen atom. This shows that exocyclic nitrogen atom is not the only acceptor of the positive charge in the molecule. The natural population analysis shows that the positive charge is transferred not only to the exocyclic N but also to, e.g., 1- and N-methyl C as well as to C3 and C5 atoms in pyridine ring. Ground-state charge transfer through the p-phenylene moiety was found to be less effective than through the trans-vinylene bridge. [ABSTRACT FROM AUTHOR]

Microwaveassisted 2+2 cycloadditions of acetylene mono and acetylenedicarboxylates 2to 5Z5dimethylaminomethyleneimidazolidine2,4dione 4aor to the corresponding thioxo derivative 4bin MeCN furnished the highly functionalized imidazolidine2,4dione derivatives 5and 6or the corresponding thioxo derivatives 5–7as single isomers or mixtures of two isomers Schemes2and 3, Table1. When the reaction of 5Z5dimethylaminomethyleneimidazolidine2,4dione 4c with acetylenedicarboxylate 2awas performed in DMF, hydrolysis of the dimethylaminomethylene group took place to give 2E22,5dioxoimidazolidin4ylidenebutanedioate 11Scheme5. [ABSTRACT FROM AUTHOR]

Thermal transformations of 3-azido-4H-quinolizin-4-ones 4a,b and 3-azido-4H-azino[1,2?x]pyrimidin-4-ones 4c,d, available from the corresponding heteroarylamines 2a?d, were studied. The reaction products were mostly dependent on the solvent. Thus, heating of 3-azido-1-cyano-4H-quinolizin-4-one (4a) in toluene afforded 2-(pyridin-2-yl)fumaronitrile 5a, whereas 3-amino-1-cyano-4H-quinolizin-4-one (8) was obtained on treatment of 4a in a mixture of toluene and trifluoroacetic anhydride. However, heating of 4a in acetic anhydride and in acetic acid resulted in a ring contraction to produce 3-(diacetylamino)indolizine-1-carbonitrile 6a and 3-(acetylamino)indolizine-1-carbonitrile 7a, respectively. Similarly, ring contractions took place on heating ethyl 3-azido-4-oxo-4H-quinolizin-1-carboxylate 4b and 3-azido-4H-azino[1,2?x]pyrimidin-4-ones 4c,d in acetic anhydride or acetic acid to produce the N-acetylated 3-aminoindolizine derivatives 6b, 7b and 3-aminoimidazo[1,2?x]azine derivatives 6c,d in 30?89% yields. The structures of compounds 5?8 were determined by NMR spectroscopy and X-ray diffraction. [ABSTRACT FROM AUTHOR]

A simple and efficient synthesis of four new substituted pyrimidines, compounds 9a–d, from the title compound 3 is described. Conversion of 3 to methyl (E)-3-(dimethylamino)-2-(6-methoxy-2-phenylpyrimidin-4-yl)prop-2-enoate (4), followed by condensation with various dinucleophiles according to the ‘enaminone methodology’, afforded the target compounds 9 in medium-to-good yields. [ABSTRACT FROM AUTHOR]

Two variations of a parallel solution-phase synthesis of N-substituted dimethyl 4-oxo-1,4-dihydropyridine-3,5-dicarboxylates 4and methyl 3-oxo-3,5-dihydro-2H-pyrazolo[4,3-c]pyridine-7-carboxylates 9from dimethyl acetone-1,3-dicarboxylate (1) were developed. The first synthetic method comprises preparation of the bis-enaminone reagents 2and 8and their cyclization with primary amines 3via double substitution of both dimethylamino groups to give dihydropyridines (DHPs) 4and 9, respectively. Another variation consists of preparation of the monoenaminone reagents 5and 10, followed by substitution of the dimethylamino group with primary amines 3, and cyclization of the so formed intermediates 6with N,N-dimethylformamide dimethylacetal (DMFDMA). In this manner, a library of 46 analytically pure compounds, 24 intermediates 6, 11, and 13, and 22 final dihydropyridines 4and 9was obtained employing just a simple filtration workup. [ABSTRACT FROM AUTHOR]

Combinatorial solution-phase cycloadditions of (1Z,4R,5R)-4-benzoylamino-5-phenylpyrazolidin-3-on-1-azomethine imines 3to -keto esters 4afforded a library of 26 bicyclic pyrazolidinones 5in 6−89% yields and in 14−100% de. All products were isolated in >90% purity according to 1H NMR, and 25 of them were analytically pure. The structures of cycloadducts were confirmed by NMR and X-ray diffraction. Most of the products were isolated as mixtures of the major (1S,2S,3R,5R,6R)-epimers 5and the minor (1R,2S,3R,5R,6R)-epimers 6. Epimerization of cycloadducts 5/6at the anomeric position 1 in solution was confirmed by 1H NMR. [ABSTRACT FROM AUTHOR]

Solution-phase combinatorial synthesis of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides was studied. First, di-tert-butyl (2S,4S)-4-amino-5-oxopyrrolidine-1,2-dicarboxylate hydrochloride was prepared as the key intermediate in five steps from (S)-pyroglutamic acid. Acylation of the amino group followed by acidolytic deprotection gave (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxylic acids, which were then coupled with amines to furnish a library of (2S,4S)-4-acylamino-5-oxopyrrolidine-2-carboxamides. Four coupling reagents, BPC, EEDQ, TBTU, and PFTU, were tested for the amidation reactions in the final step. Amidations with EEDQ and TBTU led to the desired carboxamides. On the other hand, BPC and PFTU were not suited, since diketopiperazines were sometimes obtained instead of the desired carboxamides. [ABSTRACT FROM AUTHOR]