Stereoselective in-vitro aromatic-ring oxygenations of chiral 1,4-benzodiazepin-2-ones

Biological N(1)-demethylation and C(3)-hydroxylation of two enantiomeric 1,4-benzodiazepin-2-ones 1 and 2 (cf. scheme 2) were found to be nonstereoselective. Aromatic-ring hydroxylation, however, took place in the (S)-series only, leading to 3′- and 4′-hydroxylated, N(1)-demethylated, metabolites ( 54 and 56 , cf. scheme 5: these structures were unambiguously confirmed by comparing their UV., CD., and mass spectra with those of authentic specimens). Several compounds, theoretically conceivable as products of hydroxylation in the aromatic A-ring of 1 and 2 by mechanisms including the NIH-shift (cf. scheme 3), were synthesized but none of these compounds was yet isolated from in vitro incubation mixtures.     

Comparative study on the preparation of C(3)-hydroxy-1,3-dihydro-2H-1,4-benzodiazepin-2-ones

C(3)-Hydroxy-1,4-benzodiazepin-2-ones 1–3 have been prepared in high yields using a new, two step approach. In the first step, the 3-deoxy-precursors 4–6 were acetylated at C(3) using the redox-system lead tetraacetate and iodine, or potassium iodide, in acetic acid. The intermediary acetates 9–11 were quantitatively hydrolyzed into 1–3 in non-aqueous conditions, i.e. in a methanol-methylene chloride solvent mixture in the presence of sodium methoxide. Another route to the title compounds has been improved as follows. The yields of C(3)-bromination of compounds 4–6 has been significantly augmented in relation to the known methods using the strong trifluoroacetic acid in very dilute carbon tetrachloride solutions as a catalyst for NBS mediated bromination. The intermediary C(3)-bromo derivatives have been acetoxylated in situ, and compounds 9–11 have been isolated in over 80% yield. These compounds were solvolyzed into 1–3 as described above. The third part of this paper describes the search for feasible reaction conditions in the synthesis of 3 according to a known method (Scheme 1.); optimization of the yields in all steps was performed.     

An efficient approach to chiral C8/C9-piperazino-substituted 1,4-benzodiazepin-2-ones as peptidomimetic scaffolds

A promising way to interfere with biological processes is through the modulation of protein-protein interactions by means of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways to C6-8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9 have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate protein-protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the substrates.     

Synthesis of some 7-α-carboxyethyl-1,3-dihydro-(2H)-1,4-benzodiazepin-2-ones

1,4-Benzodiazepin-2-ones possessing an α-carboxyethyl group in 7-position (21-25) were prepared from a key compound, 2-amino-5-α-carboxyethylbenzophenone (8) or from its O-benzyl derivative 14 , using methods developed previously. An optimized route to 8 starting from 2-nitro-5-chlorobenzophenone ( 1 ), as well as some unsuccessful attempts are described. Compound 8 was deaminated into racemic α-(3-benzoyl)-phenylpropionic acid ( 9 ), a well-known antiinflammatory agent.     

New synthesis of 1,3-dihydro-1,4-benzodiazepin-2(2H)-ones and 3-amino-1,3-dihydro-1,4-benzodiazepin-2(2H)-ones: Pd-catalyzed cross-coupling of imidoyl chlorides with organoboronic acids

A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic reagent as the key step, is described. A five-step synthesis of a key intermediate is described and it is shown that in only four further steps (three couplings and a TFA-mediated BOC-deprotection) a wide variety of N1-, C3-amino-, C5-carbon-, or nitrogen-substituted 1,4-benzodiazepines can be synthesized.     

Solid phase synthesis of tetrahydro-1,4-benzodiazepin-2-ones

A novel solid phase route to tetrahydro-1,4-benzodiazepin-2-ones is described which involves construction of a core template in solution followed by diverse derivatization on solid phase.     

Mass spectra of 3-arylidene-1H-2,3-dihydro-1,4-benzodiazepin-2-ones

The scheme of the fragmentation of arylidene derivatives of 5-phenyl-1,4-benzodiazepin-2-ones was established by means of high-resolution mass spectrometry. One of the principal fragmentation pathways of these compounds is cleavage of the 2C-3C and 4N-5C bonds to give two fragments. Depending on the substituents in the arylidene portion of the molecule, the charge is localized primarily on one or the other of these fragments. The mechanism of the formation of the [ArCH₂]⁺ ions observed in the mass spectra of all of the investigated compounds was established on the basis of the mass spectrum of the 1N-deuterium-labeled compound. The specific fragmentation pathways due to the ortho effect of the nitro group are discussed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1690–1696, December, 1976.     

Synthesis of imidazolidin-4-ones and their conversion into 1,4-benzodiazepin-2-ones

α-Haloacetanilides Ia-e react with hexamine in ethanol giving the bisimidazolidin-4-one derivatives IIa-e, which hydrolize, in acidic media into the corresponding mono-imidazolidin-4-ones IIIa-e. The compounds IIa-d were converted into 1,4-benzodiazepin-2-ones, under different conditions and in the presence of a variety of agents. The yields were between 50 and 100%.     

Configurational and conformational aspects of some 5-methylenedisubstituted-3-pyrrolin-2-ones

The influence of the disubstitution at the exocyclic carbon atom of 5-methylene-3-pyrrolin-2-ones upon the configurational and conformational equilibria is studied. The results obtained confirm and extend the observations reported in the literature about the factors determining the configurational and conformational equilibria in monosubstituted systems, i.e.: 5-arylmethylene-3—pyrrolin-2-ones and 5(1H)-pyrromethenones.

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Zur Konfiguration und Konformation von einigen 5-Methylen-disubstituierten-3-pyrrolin-2-onen

Zusammenfassung Es wird der Einfluß der Disubstitution des exocyclischen C-Atoms von 5-Methylen-3-pyrrolin-2-onen auf das Konfigurations- und Konformationsgleich-gewicht untersucht. Die erhaltenen Resultate stehen im Einklang mit der Literatur, die sich auf monosubstituierte Verbindungen [5-Arylmethylen-3-pyrrolin-2-one, 5 (1H)-Pyrromethenone und strukturverwandte Gallenpigmente] beziehen, und vertiefen das Verständnis der Faktoren, die für diese Gleichgewichte maßgebend sind.

     

Rearrangement of 1,4-benzodiazepin-2,4-diones to 3,l-benzoxazin-4-ones

Treatment of 7-chloro-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione (Ia) with refluxing acetic anhydride in the presence of pyridine afforded 6-chloro-2-methyl-4H-3,1-benzoxazin-4-one (IIa). A plausible reaction path for this novel rearrangement reaction is described: Ia → 4-acetyl-7-chloro-3,4-dihydro-lH-1,4-benzodiazepin-2,5-dione → 7-chloro-1,4-diacetyl-3,4-dihydro-lH-1,4-benzodiazepin-2,4-dione → IIa. When 7-chloro-3,4-dihydro-4-methyl-lH-1,4-benzodiazepin-2,5-dione (Ib), 3,4-dihydro-4-methyl-1H-1,4-benzodiazepin-2,5-dione (Id) and 3,4-dihydro-1-methyl-1H-1,4-benzodiazepin-2,5-dione (Ie) were allowed to react with acetic anhydride under conditions similar to those used for the rearrangement reaction, only acetylation occurred.     

Configurational stability in some 3-coordinate phosphorus compounds

PMR spectra of a variety of 4,4,5,5-tetramethyl-1,3,2-dioxaphospholanes, bearing different substituents at phosphorus, have been determined at different temperatures. There is no inversion at phosphorus detectable. The P-chloro compound undergoes a chemical exchange process the rate of which is concentration dependent.     

Enantioselective synthesis of diversely substituted quaternary 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones

Benzodiazepines are privileged scaffolds in medicinal chemistry, but enantiopure examples containing quaternary stereogenic centers are extremely rare. We demonstrate that installation of the di(p-anisyl)methyl (DAM) group at N1 of 1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones derived from enantiopure proteinogenic amino acids allows retentive replacement of the C3-proton via a deprotonation/trapping protocol. A wide variety of carbon and nitrogen electrophiles function well in this reaction, providing the corresponding quaternary benzodiazepines with excellent enantioselectivity. Deprotonation/trapping experiments on a pair of diastereomeric 1,4-benzodiazepine-2,5-diones provide evidence for a key role of conformational chirality in these enantioselective reactions. Acidic removal of the DAM group is fast and high-yielding and can be performed selectively in the presence of a N-Boc indole. Thus the synthesis of quaternary benzodiazepines with diverse N1 functionality can now be accomplished.     

Nitration products of substituted 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones

Highly substituted, novel, 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones were obtained by direct nitration of the corresponding mono- or di-substituted 5-phenyl-1,4-benzodiazepines. Substituent effects and the orientation of aromatic substituents in the nitration products are discussed. The single-crystal X-ray structural data for one of these products, 18 , is given.     

Facile synthesis of 4-substituted 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones by reductive cyclization of 2-chloro-N-(2-nitrobenzyl)acetamides

A facile and efficient method was developed for the synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones from 2-chloro-N-(2-nitrobenzyl)acetamides through a reductive cyclization using iron-ammonium chloride in ethanol–water in good yields. This method provides a simple approach to these benzodiazepine-3-ones which are of high value in the field of medicinal chemistry research.     

Synthesis of 2-alkyl-1,2,4-benzotriazin-3(2h)-ones and 2-alkyl-1,4-dihydro-1,2,4-benzotriazin-3(2h)-ones

A preparative method for the synthesis of 2-alkyl-1,2,4-benzotriazin-3(2H)-ones 3 was developed. The method involves treatment with sodium cyanate of 2-alkylbenzotetrazinium tetrafluoroborates, which exist in solutions in equilibrium with o-(alkylazo)aryldiazonium tetrafluoroborates. Reduction of compounds 3 with zinc in acetic acid afforded 2-alkyl-1,4-dihydro-1,2,4-benzotriazin-3(2H)-ones. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 346–349, February, 2006.     

3-Phenylazo-4-methyl-2,3-dihydro-1,5-benzodiazepin-2-ones

The corresponding azo derivatives, which exist primarily in the azo form, are formed in the reaction of 2,3-dihydro-1,5-benzodiazepin-2-ones with diazonium cations. The hydrazone form of these compounds is possible in solutions of acids.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1558–1560, November, 1978.     

A tandem one-pot, microwave-assisted synthesis of regiochemically differentiated 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones

A one-pot, two-step synthesis of the title compounds employs a multicomponent Ugi condensation reaction, microwave irradiation, and Fe(0) as a reductant. Two pathways are accessible; both routes utilize bifunctional, o-nitro-substituted arenes leading to either C2, N4, C5 substitution (A) or C2, N4 substitution (B).