Schmidt Reaction on 2-Aryl-1,2,3,4-tetrahydro-4-quinolone

Synthesis and stereochemistry of 2-aryl-1,2,3,4-tetrahydro-5H-1,4-benzodiazepin-5-one and 2-aryl-2,3-dihydro-4H-tetrazolo [1,5-d]-1H-1,4-benzodiazepine is reported by the Schmidt reaction on 2-aryl-1,2,3,4-tetrahydro-4-quinolone.     

The synthesis of bicyclic 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones from 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxide precursors

Sulfinylation of o-nitrobenzamide and subsequent hetero Diels-Alder reaction gave a series of 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxides. The 2-(o-nitrobenzoyl)-1,2-thiazine-1-oxides undergo a ring opening reaction with phenyl magnesium bromide to give allylic sulfoxides, which, after [2,3]-sigmatropic rearrangement and desulfurisation, furnish unsaturated vicinal N-(o-nitrobenzoyl)-1,2-amino alcohols. Oxidation of the alcohol and reductive ring closure gave a series of bicyclic 1,2,3,4-tetrahydro-1,4-benzodiazepin-5-ones, a subset of the ‘privileged’ 1,4-benzodiazepine structure. A 4-hydroxy-1,2,5-benzothiadiazepin-1,1-dioxide was synthesised by the same route starting from o-nitrobenzenesulfonamide.     

Expedient one-pot synthesis of novel chiral 2-substituted 5-phenyl-1,4-benzodiazepine scaffolds from amino acid-derived amino nitriles

An efficient and stereocontrolled synthesis of phenylalanine- and tryptophan-derived 5-phenyl-1,4-benzodiazepines is described. This new methodology involves, as a key step, the synthesis of 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepines by a one-pot cyano reduction and reductive cyclization of the appropriate amino nitrile, which were obtained via a modified Strecker reaction of N-protected alpha-amino aldehydes with 2-aminobenzophenone and trimethylsilyl cyanide. The subsequent reduction of these 2,3-dihydro-1H-1,4-benzodiazepines, followed by regioselective alkylation or acylation at position 4, led to 2,4-disubstituted-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.     

1,5-Thione-thiol isomerization of 3-O-phosphorylated 1,4-benzodiazepine

Diphenylphosphinite, 1,4-benzodiazepine 3-O-derivative, was converted into the corresponding imides by the Staudinger reaction with azides of diphenylphosphinic, diphenylthiophosphinic, and diphenylphosphoric acids. The imide derived from azide of diphenylthiophosphinic acid undergoes the isomerization into the corresponding thiol when heated in the presence of catalytic amounts of a substituted 3-chloro-1,4-benzodiazepine.     

Methylation of 5-Phenyl-1,4-benzodiazepin-2-one derivatives with N,N-dimethylformamide-dimethyl acetal

A novel method for N-methylation of the cyclic amide in the 1,4-benzodiazepine ring system is presented. Methods traditionally used involve treatment of the 1,4-benzodiazepinone anion with an alkyl halide. It has been demonstrated that these derivatives can be methylated on the amide nitrogen atom by use of dimethyl-formamide dimethyl acetal which acts as both reagent and solvent for the reaction.     

2－异丙基－1，3－二氢－4（1H）异喹啉酮及其衍生物的合成

异喹啉酮（1）与羟胺反应得异喹啉酮肟（2），再经Schroeter重排合成得到 4-氨基异喹啉的盐（3），进而经催化加氢还原生成其脱烷基产物6.另外 ，异喹啉 酮与NaN3反应合成得到苯并二氮杂Zhuo酮（4），4经还原可生成苯并二氮杂Zhuo（ 5），合成得到的5个新化合物的结构经元素分析、红外、^1H NMR及质谱等方法所 证实。     

An anomalous reaction of 7-chloro-2-hydrazono-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine with sodium acetate and 1,1′-carbonyldiimidazole

The addition of 7-chloro-2-hydrazono-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine 3 to a mixture of sodium acetate and 1,1′-carbonyldiimidazole 1 at room temperature gave, in moderate yields, carbonyl-1,1′-bis[7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-ylidene hydrazone] 7 instead of the expected 2-acetylhydrazono-7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine 4 .     

A polarographic study of the hydrolysis of 1,4-benzodiazepines and its analytical applications

The mechanism of hydrolysis of flurazepam (Dalmane) and six of its metabolites was investigated in mildly acidic solution (pH 0–2) by differential pulse polarography. Simultaneous determinations of the “parent” compound(s) and hydrolytic degradation product(s) are possible because of the different reduction potentials. The kinetic results can be explained if the hydrolytic reaction is considered reversible; this is important for evaluation of the hydrolysis and absorption of 5-(o-fluorophenyl)-1,4-benzodiazepines in the stomach. The rate constants and the pK_a values corresponding to protonation of the azomethine groups are shown to be correlated. Appropriate kinetic data for other 1,4-benzodiazepines make it possible to evaluate the effects of certain substituents on the rate of hydrolysis and on the peak potentials of the “parent” compounds and their hydrolytic degradation products. The results of the kinetic investigations can be used for the identification of an isolated 5-(o-fluorophenyl)-1,4-benzodiazepine or identification of any 1,4-benzodiazepine studied here which exhibits some degree of acid hydrolysis within 24 h.     

Synthesis of substituted 1,4-diazepines and 1,5-benzodiazepines using an efficient heteropolyacid-catalyzed procedure

An efficient and improved procedure for the synthesis of 1,4-diazepine and 1,5-benzodiazepine derivatives via the reaction of ketimine intermediates with aldehydes in the presence of Keggin-type heteropolyacids (HPAs) was developed. High yields and short reaction times were obtained for both electron-releasing and electron-withdrawing substituted 1,4-diazepine and 1,5-benzodiazepines derivatives.     

Synthesis of 5-amino-2,3-dihydro-1H-1,4-benzodiazepines

A number of 5-amino-2,3-dihydro-lH-1,4-benzodiazepines (II) have been prepared from the reaction of 5-methylmercapto-2,3-dihydro-1H-1,4-benzodiazepine (I) with amines. Another alternate approach based on the cyclodehydration of the ureic compounds (IV) was unsuccessful. The synthesis of I was accomplished by methylation of the 1,2,3,4-tetrahydro-5H-5-thioxo-1,4-benzodiazepine (VI) with dimethyl sulfate in methanol-dioxane. Another attempted method for the synthesis of I is also presented. J. Heterocyclic Chem., 14, 985 (1977)     

Versatile synthesis of chiral 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines as novel scaffolds for peptidomimetic building

The stereocontrolled synthesis of phenylalanine and tryptophan derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives is described. This new methodology involves a modified Strecker reaction of N-Boc protected amino aldehydes and methyl anthranilate, reduction of the resulting α-amino nitriles, and lactamization. The resulting 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines were further functionalized at position 4 by alkylation or acylation reactions. One of these new tryptophan-derived 1,4-benzodiazepines showed significant selective binding affinity at cholecystokinin CCK₁ receptors (IC₅₀=156.5±33.2 nM).     

Attack of S- vs N-Nucleophiles on 2-halomethylquinazoline 3-Oxides

A comparison is made of thiols with amines in their mode of reaction with different substituted 2-halomethylquinazoline 3-oxides. Whereas the reaction of some amines (particularly small primary ones), as has long been known, leads to ring-enlarging rearrangement under certain conditions, all thiol nucleophiles we have observed, ranging from small to large, lead without rearrangement to direct benzylic substitution only. Preformed aminomethylquinazoline 3-oxides are shown not to rearrange to the corresponding 1,4-benzodiazepine 4-oxides. The mechanistic implications of these and other observations are discussed. Data on over forty new compounds are presented.     

Diazepines I. A new synthesis of 6-phenyl-4H-imidazo[1,2-a] [1,4] benzodiazepines

6-Phenyl-4H-imidazo[1,2-a][1,4]benzodiazepines are obtained on reaction of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine with α-bromoketones. In the cases of 3-bromo-2-butan-one and of 3-bromo-2-pentanone, 2-alkylimidazobenzodiazepine but not 1,2-dialkyl compound is the major product. A mechanism for the imidazole ring formation is presented.     

Synthetic Strategies Applicable in the Synthesis of Privileged Scaffold: 1,4-Benzodiazepine

The development of new synthetic approaches to the 1,4-benzodiazepine ring system and their further elaboration have provided access to a broad range of functionalized derivatives. In this review an attempt has been made to summarize those synthetic strategies involved for the synthesis of privileged scaffold 1,4-benzodiazepine over time.     

Synthesis and regioselectivity of the [3,3]-sigmatropic rearrangement of substituted 2-allylthio- and 2-allylseleno-1,4-dihydropyridines

The reaction of 3-cyano-1,4-dihydropyridine-2-thiolates and the corresponding selenolates with allyl bromide gave 2-allylthio- and 2-allylseleno-3-cyano-1,4-dihydropyridines, which, upon heating in various solvents or in the solid state, undergo [3,3]-sigmatropic rearrangement to give 3-cyano-3-allyl-1,2,3,4-tetrahydropyridine-2-thiones and the corresponding selenones. The resultant pyridinethiones are alkylated by alkyl halides at the sulfur atom and are oxidized by iodine to give disulfides.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1888–1895, August, 1991.     

Attempted synthesis of 1,4-benzodiazepine comprising an additional ring at the 1–3 position

Two possible synthetic routes leading to 1,4-benzodiazepine derivatives comprising an additional heterocyclic ring at position 1–3 have been studied. The first approach (scheme 1) consisted in subjecting intermediates VII and XII to the Bischler-Napieralski reaction while the second one (scheme 2) was based on intramolecular dehydration of amino ketone (XIX); both routes did however fail to yield the expected product XIII.     

1,4-Benzodiazepines and their cyclic homologs and analogs

The dependence of the IR and PMR spectral characteristics of 12 compounds of the 1,2-dihydro-3H-1,4-benzodiazepine series on structural and sterochemical factors was studied. Information in favor of concepts regarding the pseudoboat conformation as the primary one for this type of 1,4-benzodiazepine derivative was obtained.     

A new simple synthesis of 1,4-benzodiazepines

A convenient synthesis of 1,4-benzodiazepines starting from secondary-2-aminobenzhydrols, which are easily obtained from secondary anilines and benzaldehydes, is described. 7-Nitro-1-methyl-1,4-benzodiazepine 1d can be formed from 5-nitro-2-methylaminomethylacylaminobenzo-phenone 10b and c by using ammonium carbonate instead of ammonia, which gives only the Smiles-rearranged product 11 .     

Reaction of α,α-, α,α′-dihalothiones with 8-mercaptoquinolinium halides as a route to tetrahydro-1,4-thiazinoquinolinium halides

The reaction of 8-mercaptoquinolinium bromide with 1,3-dibromopropane-2-thione or 3,3-dibromobutane-2-thione in methanol gave the 2-bromomethyl-2-mercaptotetrahydro-1,4-thiazino[2,3,3,4-i,j]quinolinium and 3-bromo-2-mercapto-2,3-dimethyltetrahydro-1,4-thiazino[2,3,3,4-i,j]quinolinium bromides which readily exchanged the Br⁻ anion for ClO ₄ ⁻ upon treatment with sodium perchlorate in methanol. Oxidation of the 3-bromo-2-mercapto-2,3-dimethyltetrahydro-1,4-thiazino[2,3,3,4-i,j]-quinolinium bromide by selenium dioxide gave 2,2-dithiobis(3-bromo-2,3-dimethyltetrahydro-1,4-thiazino[2,3,3,4-i,j]quinolinium) bromide. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1720–1723, November, 2006.     

1,4-Benzodiazepines III . Cyclization paths of hexaminium salts of 2-chioroacetamido-5-ehlorobenzophenone and its N-methyl derivative

This study reports the isolation and characterization of hexaminium salts of 2-chloroacetamido-5-chlorobenzophenone (I) and of 2-(N-methyl)chloroacetamido-5-chlorobenzophenone (II). The 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (VI) and 7-chloro-1,3-dihydro-1-meth-yI-5-phenyl-2H-1,4-benzodiazepin-2-one (VII), respectively are of pharmacodynamic importance. Based on chromatographic separation of some intermediates, and on spectrophotometric monitoring of cyclizations I → VI and II → VII, respectively, two different pathways for these reactions have been proposed. Since the slowest step in the reaction sequence II → VII follows the quasi first order rate law, intramolecular nucleophilic attack of the benzophenone carbonyl group on the hexamine moiety proved to be decisive for the cyclization (scheme II). However, cyclization I → VI seems to incorporate quite different solvolytic pathways in addition to one corresponding to the sequence II → VII. Isolated 4-imidazolidinone intermediates N,N' -methylene-bis[3-{2 -benzoyl-4-chIoro)phenyI]-4-imidazolidinone(III), and 3-(2 -benzoyl-4′-chlorophenyI)-4-imidazolidinone hydrochloride (IV) recyclize into the 1,4-benzodiazepine VI. The optimal reaction conditions have been found to be between pH 6-7.