Concise synthesis of indole-fused 1,4-diazepines through copper(I)-catalyzed domino three-component coupling-cyclization-N-arylation under microwave irradiation

Indole-fused benzo-1,4-diazepines were synthesized by copper-catalyzed domino three-component coupling-indole formation- N-arylation under microwave irradiation from a simple N-mesyl-2-ethynylaniline. This method was also applicable to the formation of heterocycle-fused 1,4-diazepines.     

Aza-di-π methan-umlagerungen ?

2,6-Diazabicyclo[3.2.o]hepta-2,6-dienes 3 are isolated as intermediates in the phototransformation of 4H-1,2-diazepines 1 to 6H-1,4-diazepines 4/5.★★)     

Solvent-Free one pot synthesis of benzo-[b]-1,4-diazepines using reusable sulfamic acid catalyst

α-β-Unsaturated carbonyl compounds on condensation with o-phenylenediamine in the presence of catalyst sulfamic acid under solvent free conditions, resulted in the formation of corresponding benzo-[b]-1,4-diazepines in excellent yields.     

Cyclization of fluoroalkyl-containing 1,3-dicarbonyl compounds with ethylenediamine hydroperchlorate to 1,4-diazepines

2,3-Dihydro-1H-1,4-diazepines and 1,2,3,4-tetrahydro-1,4-diazepin-5-ones were obtained by direct condensation of fluorine-containing 1,3-diketones and 1,3-keto ethers, respectively, with ethylenediamine monohydroperchlorate. The structure of the compounds was confirmed by¹H NMR, mass spectrometry and molecular weight determination.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 4, pp. 890–896, April, 1991.     

An efficient synthesis of substituted 1,4-diazepines by a Pd catalyzed amination and sequential hydrogenation condensation

An efficient synthesis of substituted 1,4-diazepines is developed.The accessible intermediates have been obtained via Pd-catalyzed amination.The subsequent hydrogenation and intramolecular condensation sequences could be conducted successively in one pot without special operation.The mild and general strategy enables the synthesis of various substituted 1,4-diazepines in high yields.     

Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives,novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist

In search of a dopamine D2 and serotonin 5-HT3 receptors dual antagonist as a potential broad antiemetic agent, a number of benzamides were prepared from 4-amino-5-chloro-2-methoxybenzoic acid derivatives and 6-amino-1,4-dialkylhexahydro-1,4-diazepines and evaluated for their binding affinity for the dopamine D2 and the serotonin 5-HT3 receptors using rat brain synaptic and rat cortical membranes, respectively. From the results of both in vitro receptor binding and in vivo biological assays for the dopamine D2 receptor, 1-ethyl-4-methylhexahydro-1,4-diazepine ring was selected as an optimum amine moiety. Introduction of one methyl group on the nitrogen atom at the 4-position and/or modification of the substituent at the 5-position of the 4-amino-5-chloro-2-methoxybenzoyl moiety caused a marked increase in the dopamine D2 receptor binding affinity along with a potent 5-HT3 receptor binding affinity. Among the compounds, 5-chloro-N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-methoxy-4-methylaminobenzamide (82), 5-bromo (110), and 5-iodo (112) analogues exhibited a much higher affinity for the dopamine D2 receptor than that of metoclopramide (IC50=17.5-61.0 nM vs. 483 nM). In particular, 82 showed a potent antagonistic activity for both receptors in vivo tests. Optical resolution of the racemate 82 brought about a dramatic change in the pharmacological profile with the (R)-enantiomer exhibiting a strong affinity for both the dopamine D2 and the 5-HT3 receptors, while the corresponding (S)-enantiomer had a potent and selective serotonin 5-HT3 receptor binding affinity.     

Polyfunctional fluoroalkyl-containing carbonyl compounds in the synthesis of heterocycles

Efficient procedures for the regioselective synthesis of fluoroalkyl-containing threefive-, six-, and seven-membered heterocycles as well as of related fused compounds, namely, α,β-epoxyketones, α,β-aziridinylketones, pyrazoles, pyrazolines, isoxazolines, 1,2-dithiolenes, amino- and mercaptopyrimidines, Δ^3,5-2-thioxo-1,3,2-thiazaphosphorines, Δ^3,5-2-thioxo-1,3,2-oxazaphosphorines, 2,3-dihydro-1,4-diazepines, azirino[1,2-a]quinoxalines, benzo[b]-and naphtho[2,3-b]-1,4-diazepines, and triazolopyridazines, which have been developed by the authors and coworkers, are summarized. The α- and β-functionalized fluoroalkylcontaining carbonyl compounds (β-diketones, β-ketoesters, their salts, regioisomeric β-aminovinyl ketones, β-aminovinylthiones, β-hydroxyketones, α,β-enones, and their halogen derivatives) were used as synthons in the processes of formation of the above-mentioned heterocycles. Dedicated to the memory of Academician I. Ya. Postovskii on his 100th birthday. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1279–1286, July, 1998.     

New synthetic equivalent of nitromalonaldehyde treatable in organic media

beta-Nitroenamines having a formyl group at the beta-position behave as the synthetic equivalent of unstable nitromalonaldehyde, which is a useful synthon for syntheses of versatile nitro compounds. High solubility of the nitroenamines into general organic solvents enables us to conduct reactions in the organic media accompanied by easy experimental manipulations and considerable safety. When nitroenamines are treated with 1,2-bifunctional nucleophiles such as hydrazines, hydroxylamine and glycine ester, nitrated pyrazoles, isoxazole and pyrrole-2-carboxylate were readily prepared. This methodology was also applicable to guanidines and 1,2-diamines, leading to pyrimidines and 1,4-diazepines, respectively.     

Reactions of β-sulfenyl α,β-unsaturated ketones with guanidine,Amidines, and diamines

β-Sulfenyl α, β-unsaturated ketones 1a-c reacted with guanidine or amidines to give pyrimidine derivatives 3 in 14-76% yields. Treatment of ketones 1 with diamines such as ethylenediamine and o -phenylenediamine afforded the seven-membered heterocycles, 2,3-dihydro-1,4-diazepine 5 and 2,3-benzo-1,4-diazepines 8a-c .     

Ring closure reactions of methyl N-(haloacetyl)anthranilates with ammonia

In the presence of ammonia, methyl N-(bromoacetyl)anthranilate ( 4 ) is cyclized into 3H-1,4-benzodiaze-pine-2,5(1H,4H)-dione ( 1 ). However, when 4 is replaced with methyl N-(chloroacetyl)anthranilate ( 6 ), the only heterocyclic product formed in the reaction is 2-(chloromethyl)quinazoline-4(3H)-one ( 7 ). Under analogous conditions, 3-haloacetamidocrotonates (9, 10) do not yield any heterocyclic products and no 1,4-diazepines can be obtained.     

Template reactions of fluorine-containing 1,3-diketones with ethylenediamine

Depending on the nature of the dicarbonyl fragment, the reaction of fluorinated copper(II) bis(1,3-diketonates) with ethylenediamine and its monoprotonated salts under mild conditions gives N,N-ethylenebis(aminovinyl ketones) and/or 1,4-diazepines. In excess ethylenediamine, copper(II) and nickel(II) N,N-ethylenebis(aminovinyl ketonates) undergo cyclization to 1,4-diazepines.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 2088–2092, September, 1991.     

Cycloaddition reactions of 2,3-dihydro-1H-1,4-diazepines with nitrile oxides and imines. Synthesis of bis[1,2,4]oxadiazolo-and bis[1,2,4]triazolo[1,4]diazepine derivatives

New heterotricyclic systems, 6,10a,11,11a-tetrahydro-5H-bis[1,2,4]oxadiazolo[4,5-d:5′,4′-g][1,4]diazepines 6,7,9-11 and 5,6,10,10a,11,11a-hexahydro-1H-bis[1,2,4]triazolo[4,3-d:3′,4′-g][1,4]diazepines 8,12 have been obtained by double site- and regie-specific 1,3-dipolar cycloaddition of mesitylnitrile oxide ( 1 ) or diphenylnitrile imine ( 2 ) to 5,7-disubstituted 2,3-dihydro-1H-1,4-diazepines 3-5. The structure of the synthesized bis-adducts 6-12 shows that the hetero double bonds are much more reactive than the olefinic ones in the dipolarophiles under study. No evidence for the formation of mono-adducts was obtained.     

1H-1,3-diazepines, 5H-1,3-diazepines, 1,3-diazepinones, and 2,4-diazabicyclo[3.2.0]heptenes

Tetrazolo[1,5-a]pyridines/2-azidopyridines 1 undergo photochemical nitrogen elimination and ring expansion to 1,3-diazacyclohepta-1,2,4,6-tetraenes 3, which react with alcohols to afford 2-alkoxy-1H-1,3-diazepines 4 (5), with secondary amines to 2-dialkylamino-5H-1,3-diazepines 16, sometimes via isolable 2-dialkylamino-1H-1,3-diazepines 15, and with water to 1,3-diazepin-2-ones 19. The latter are also obtained by elimination of isobutene or propene from 2-tert-butoxy- or 2-isopropoxy-1H-1,3-diazepines 4 or 5. 1,3-Diazepin-2-one 22B and 1,3-diazepin-4-one 24 were obtained from hydrolysis of the corresponding 4-chlorodiazepines. Diazepinones 19 undergo photochemical ring closure to diazabicycloheptenones 25 in high yields. The 2-alkoxy-1H-1,3-diazepines 4 and 5 interconvert by rapid proton exchange between positions N1 and N3. The free energies of activation for the proton exchange were measured by the Forsén-Hoffman method as DeltaG([double dagger])298= 16.2 +/- 0.6 kcal mol(-1) as an average for 4a-c in CD2Cl2, acetone-d6, and methanol-d4, and 14.1 +/- 0.6 kcal mol(-1) for in 4c acetone/D2O. The structures of 2-methoxy-5,6-bis(trifluoromethyl)-1H-1,3-diazepine 4k, 1,2-dihydro-4-diethylamino-5H-1,3-diazepin-2-one 22bB, and diazabicycloheptanone were 26 determined by X-ray crystallography. The former represents the first reported X-ray crystal structure of any monocyclic N-unsubstituted 1H-azepine.     

Quantum chemical investigation of the molecular structure of some 2,3-dihydro-1,4-diazepines and related molecules

Accurate ab-initio and semi-empirical molecular orbital calculations with full geometry optimization were performed on the various tautomeric forms of some 2,3-dihydro-1,4-diazepines and related molecules. The highly accurate ab-initio calculations at the HF/6–31G7 level with Möller-Plesset Second-Order Perturbation Theory (MP2) refinement clearly established the higher stability of the enamine tautomer of the 1,4-diazepine ring over the di-imine form by 27.786 kJ/mol, whereas the semi-empirical calculations at the NDDO level (AM1 and PM3) predicted comparable energies within reported errors of the two methods. However, both ab-initio and semi-empirical NDDO methods predicted similar geometries in agreement with observed geometrical parameters. The AM1 calculations predicted small energy differences among the three tautomeric forms of 2,3-dihydro-5-methyl 7-phenyl 1,4-diazepine with the more polar enamine tautomer being the more stable tautomer in the half-chair conformation which is likely to predominate in polar media through stabilizing intermolecular solute-solvent interactions.     

Interactions of aliphatic β-amino-β-trifluoromethylvinyl ketones with ethylenediamine

The reactions of aliphatic β-amino-β-trifluoromethylvinyl ketones with an excess of ethylenediamine at room temperature afforded the corresponding 2,3-dihydro-1H-1,4-diazepines or substituted 2-acetonyl-2-trifluoromethylimidazolidines (the latter were obtained when the approach to the carbonyl group was sterically hindered). Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2305–2308, November, 1998.     

Reactions of 2-polyfluoroalkylchromones with aliphatic diamines

2-Polyfluoroalkylchromones react with aliphatic 1,2-diamines to give 2,3-dihydro-1H-1,4-diazepines. A similar reaction with 1,3-diaminopropane yieldsN,N′-trimethylenebis(2-hydroxyacetophenomines) as a result of scission of the original chromones. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 817–819, April, 1999.     

Synthesis of 6-substituted 6-nitroperhydro-1,4-diazepines via novel tandem retro-Henry and Mannich/Michael reactions

N,N'-Dibenzyl-6-hydroxymethyl-6-nitroperhydro-1,4-diazepine was converted into a nitronate via retro-Henry reaction, followed by either Michael reaction with several acrylic derivatives or Mannich reaction with different amines, thus leading to 6-substituted 6-nitroperhydro-1,4-diazepines. The tandem retro-Henry/Mannich reaction was also carried out using benzylamine as base, solvent, and reagent at the same time. Selective hydrogenation of the nitro group and complete hydrogenolysis were also successfully achieved.     

Recherches en série azabenzodiazépine VII. Synthése de pyrazolo[3,4-b]diazépines-1,4

Condensation of ethyl acetoacetate or acetylacetone with 4,5-diaminopyrazoles are reported and discussed. They gave new pyrazolo[3,4-b]-1,4-diazepines or intermediates which can be cyclised.     

Synthesis of novel substituted diaryl-1,4-diazepines

In this paper a convenient route to new 2,3-diaryl-substituted 1,4-diazepines is described through cyclization of ethanedione derivatives and 1,3-propanediamine. The ethanedione derivatives required were synthesized by microwave-assisted oxidation from ethanones. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1042–1047, July, 2006.     

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone derivatives and the properties of the obtained products

N′-(4-Oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides and N′-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides were synthesized by reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone or 2-methyl-1,4-naphthoquinone. The alkylated analogues of the above products were obtained using ethyl iodide. The interaction of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 2,3-dichloro-1,4-naphthoquinone was followed by formation of N′-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides. All these compounds were characterized using ¹H, ¹³C NMR, IR and mass spectra. Some of the new compounds were tested for the antimicrobial and antifungal activity.