Unprecedented synthesis of a 14-membered hexaazamacrocycle.

The transformation of 3-[(ethoxymethylene)amino]-1-methyl-1H-pyrazole-4-carbonitrile into the 14-membered macrocycle, 2,10-dimethyl-2,8,10,16-tetrahydrodipyrazolo[3,4-e:3',4'-l][1,2,4,8,9,11]hexaazacyclotetradecine-4,12-diamine, by the reaction with excess hydrazine under various conditions was studied in detail. The reaction proceeded through the initial formation of 4-imino-2-methyl-2,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-amine followed by dimerization to give the final macrocycle. A convenient synthesis of the latter starting from 4-imino-2-methyl-2,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-amine was developed. A plausible pathway for the macrocycle self-assembly is discussed. Some features of the structure and reactivity of the obtained macrocycle are outlined.

Different Modes of Acid-Promoted Cyclooligomerization of 4-(4-Thiosemicarbazido)butan-2-one Hydrazone: 14-Membered versus 28-Membered Polyazamacrocycle Formation.

Unprecedented self-assembly of a novel 14-membered cyclic bis-thiosemicarbazone or/and a 28-membered cyclic tetrakis-thiosemicarbazone upon acid-promoted cyclooligomerization of 4-(4-thiosemicarbazido)butan-2-one hydrazone has been discovered. A thorough study of the influence of various factors on the direction of macrocyclization provided the optimal conditions for the highly selective formation of each of the macrocycles in excellent yields. Plausible pathways for macrocyclizations have been discussed. The macrocycle precursor was prepared by the reaction of readily available 4-isothiocyanatobutan-2-one with an excess of hydrazine.

A general and stereoselective approach to 14-membered cyclic bis-semicarbazones involving BF3-catalyzed amidoalkylation of 2-(trimethylsilyloxy)propene.

A general and stereoselective five-step approach to 14-membered cyclic bis-semicarbazones, 5,12-diaryl-7,14-dimethyl-1,2,4,8,9,11-hexaazacyclotetradeca-7,14-diene-3,10-diones, starting from aldehyde semicarbazones has been developed. The key intermediates, 4-(3-oxobut-1-yl)semicarbazones, were prepared by BF3-catalyzed amidoalkylation of 2-(trimethylsilyloxy)propene with 4-[(aryl)(methoxy)methyl]- or 4-[(aryl)(tosyl)methyl]semicarbazones. Treatment of these intermediates with excess of hydrazine gave hydrazones of 4-(3-oxobut-1-yl)semicarbazones or 4-(3-oxobut-1-yl)semicarbazides, which in the presence of TsOH were converted into the target macrocycles. All steps of this approach could be scaled up easily to the multi-gram level.

A convenient stereoselective access to novel 1,2,4-triazepan-3-ones/thiones via reduction or reductive alkylation of 7-membered cyclic semicarbazones and thiosemicarbazones.

A general stereoselective approach to previously unknown 1,2,4-triazepane-3-thiones/ones based on reduction or reductive alkylation of readily available 2,4,5,6-tetrahydro-3H-1,2,4-triazepine-3-thiones/ones has been developed. The approach involved the treatment of tetrahydrotriazepines with sodium cyanoborohydride in MeOH at pH 3 or with sodium borohydride and excess of carboxylic acid in THF to give 1-unsubstituted or 1-alkyl-substituted 1,2,4-triazepane-3-thiones/ones, respectively. The latter were also prepared by the reaction of 1-unsubstituted 1,2,4-triazepane-3-thiones/ones with sodium cyanoborohydride and an aldehyde in MeOH in the presence of AcOH. The stereochemistry of the triazepane-3-thiones/ones obtained was established in DMSO solution and in the solid state using NMR spectroscopy and single-crystal X-ray diffraction. These data and DFT B3LYP/6-311++G(d,p) calculations show that the gauche effect plays a significant role in stabilization of preferred conformations of 1-unsubstituted 1,2,4-triazepane-3-thiones/ones.

Nucleophile-Mediated Ring Expansion of 5-Acyl-substituted 4-Mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-ones in the Synthesis of 7-Membered Analogues of Biginelli Compounds and Related Heterocycles.

A general six-step approach to alkyl 2-oxo-2,3,6,7-tetrahydro-1H-1,3-diazepine-5-carboxylates and 5-acyl-2,3,6,7-tetrahydro-1H-1,3-diazepin-2-ones based on the nucleophile-mediated ring expansion reaction of 5-functionalized 4-mesyloxymethyl-1,2,3,4-tetrahydropyrimidin-2-ones has been developed. Synthesis of the latter involved nucleophilic substitution of tosyl group in readily available N-[(2-benzoyloxy-1-tosyl)ethyl]urea with sodium enolates of ß-oxoesters or 1,3-diketones, followed by dehydration or heterocyclization-dehydration of resulting products, removal of benzoyl protection, and conversion of hydroxymethyl group into mesyloxymethyl group. Conformations of the obtained tetrahydro-1H-1,3-diazepin-2-ones in solid state and solutions were established using X-ray diffraction and NMR spectroscopy. A plausible mechanism of tetrahydropyrimidine ring expansion based on DFT calculation at B3LYP/6-31+G(d,p) level and NMR monitoring experiments was discussed. The ring contraction reaction of methoxy- or phenylthio-diazepinones under acidic conditions resulted in the corresponding 3-functionalized 1-carbamoyl-1H-pyrroles.

Synthesis of γ-azido-ß-ureido ketones and their transformation into functionalized pyrrolines and pyrroles via Staudinger/aza-Wittig reaction.

A simple two-step procedure yielding γ-azido-ß-ureido ketones or/and their cyclic isomers, 6-(1-azidoalkyl)-4-hydroxyhexahydropyrimidin-2-ones, has been developed. The synthesis includes three-component condensation of acetals of 2-azidoaldehydes with urea or methylurea and p-toluenesulfinic acid in aqueous formic acid followed by reaction of the obtained N-[(2-azido-1-tosyl)alkyl]ureas with sodium enolates of α-functionalized ketones. The azido ketones or their cyclic isomers are transformed into ureido-substituted Δ(1)- or/and Δ(2)-pyrrolines via Staudinger/aza-Wittig reaction promoted by PPh(3). The obtained pyrrolines are converted into 3-functionalized 1H-pyrroles via elimination of urea under acidic conditions. Convenient one-pot syntheses of 1H-pyrroles starting from N-[(2-azido-1-tosyl)alkyl]ureas or γ-azido-ß-ureido ketones have been also developed.

Synthesis of functionalized tetrahydro-1,3-diazepin-2-ones and 1-carbamoyl-1H-pyrroles via ring expansion and ring expansion/ring contraction of tetrahydropyrimidines.

A general approach to 6-phenylthio-substituted 2,3,4,5-tetrahydro-1H-1,3-diazepin-2-ones based on the ring expansion reaction of 1,2,3,4-tetrahydropyrimidin-2-ones under the action of nucleophiles has been developed. The first step of the synthesis was preparation of N-[(2-benzoyloxy-1-tosyl)ethyl]urea by three-component condensation of 2-benzoyloxyethanal, urea and p-toluenesulfinic acid. Nucleophilic substitution of the tosyl group in the obtained sulfone with sodium enolates of α-phenylthioketones followed by cyclization-dehydration, and debenzoylation gave 4-hydroxymethyl-5-phenylthio-1,2,3,4-tetrahydropyrimidin-2-ones which were transformed into the 4-mesyloxymethyl-derivatives. Treatment of the latter with nucleophilic reagents, such as NaCN, sodium diethyl malonate, PhSNa, MeONa, NaBH(4), sodium succinimide, or potassium phthalimide, afforded the target multi-functionalized diazepinones. The obtained 6-phenylthio-diazepinones and their 6-tosyl-substituted analogues were converted into 3-substituted 1-carbamoyl-1H-pyrroles under acidic conditions as a result of ring contraction. Effective one-pot synthesis of the latter from 4-mesyloxymethyl-pyrimidines was realized using a ring expansion/ring contraction sequence.