Tetrahydro-1,4-benzodiazepines

Bhalay, G. Blaney, R Palmer, V. H. Baxter, A. D. Solid-Phase Synthesis of Diverse Tetrahydro-1,4-Benzodiazepine-2-ones, Tetrahedron Lett. 1997,38, 8375. 

The Michael-type addition of an aniline to an unsaturated ester, generated in situ, provided an example of a type a ring closure in which the electrophilic center is sp2-hybridized <2004BML4147>. This reaction represents a synthetically useful procedure to access tetrahydro-1,4-benzodiazepines. 

A large amount of activity on 1,4-benzodiazepine derivatives was reported in 2004. Tetrahydro-l,4-benzazepin-2-one derivatives are of interest as P-turn peptidomimetics and their solid-phase synthesis was reported by Kim et al. <04JC0207>. The diasteroselective synthesis of two enantiopure tetrahydro-l,4-benzodiazepin-5-ones was also achieved based on intramolecular azide cycloaddition and subsequent stereoselective reduction of the 1,4-benzodiazepinone products <04TA687>. A different approach to tetrahydro-1,4-benzodiazepin-5-ones 80 involves the 1,2-thiazine 1-oxides 77 as key intermediates. These intermediates were then converted to the nitroaryl amides 78 (R , R, R = H or Me) which could be cyclised to 80 after hydrogenation of the nitro group via the intermediates 79 <04T3349>. 

R. Mossetti, D. Saggiorato, G. C. Tron, J. Org. Chem. 2011, 76, 10258-10262. Exploiting the acylating nature of the imide-Ugi intermediate a straightforward synthesis of tetrahydro-1,4-benzodiazepin-2-ones. 

Figure 5.1. Four novel core skeletons extracted or designed structure from natural products and peptide mimic motif (a) diaza-bridged heterocycles, (b) tetrahydro-fi-carboline alkaloid, (c) A -2-oxopiperazines, and (d) tetrahydro-1,4-benzodiazepine.

Novel Application of the Leuckart-Wallach Reaction for the Synthesis of a Tetrahydro-1,4-benzodiazepin-5-one Library (Type V)... 

The series of compounds containing the tetrahydro-1,4-benzodiazepine scaffold are an important class of prototypical privileged structures associated with various biological... 

Figure 5.8. Reported methods and our synthetic strategy for the construction of tetrahydro-1,4-benzodiazepin-5-ones.

Scheme 5.6. Key transformation toward tetrahydro-1,4-benzodiazepin-5-onevia intramolecular Leuckart-Wallach reduction.

H-2,3-Benzodiazepine, 3,4-dihydro-synthesis, 7, 596, 599 5H-2,3-Benzodiazepine, 4-phenyI-acylation, 7, 602 photochemical reactions, 7, 600 5 H-2,3 - Benzodiazepine, 1,2,3,4-tetrahydro-synthesis, 7, 596... 

Chemical Name 7-Ch oro-5-phenyl-5 -methyltetrahydrooxazolo[54-b] -2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-2-one... 

The reaction of lithium aluminum hydride with l//-l,4-benzodiazepine-2,5(3//,4//)-dione (3) gives 2,3,4,5-tetrahydro-l//-l,4-benzodiazepinc (12).209... 

DUiydroxy-2,3,4,5-tetrahydro-l//-benzodiazepine-2,4-dione (441) gave 2,3-(l//,47/)-quinoxalinedione (443) (xylene, reflux, 4 h 17% after purification) or 3-oxo-3,4-dihydro-2-quinoxalinecarboxylic acid (444) (2M HCl, reflux, 15 min 58%) both products appear to have come from the intermediate... 

Ethyl l-(o-aminobenzoyl)-3-oxo-l,2,3,4-tetrahydro-2-quinoxalinecarboxylate (204) underwent thermal cyclization with loss of EtOH to give 6a,7-dfliydroquinoxalino[2,1 -c] [ 1,4]benzodiazepine-6,7,13(5//, 8//)-trione (205) (neat substrates, 200°C, vacuum, 30 min 60%). " ... 

Mellors JW, Im G-J, Tramontano E, Winkler SR, Medina DJ, Dutschman GE, Bazmi HZ, Piras G, Gonzalez CJ, Cheng Y-C. A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to ( + )- (5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,l-y ][l,4]benzodiazepin-2(lH)-thione (TIBO R82150). Mol Pharmacol 1993 43 11-16. 

Cycloreversion with nitrile oxide formation is known not only in furoxans but also in isoxazolines, 1,2,4-oxadiazoles, furazans, and some other live-membered heterocycles (76). Such process, eliminating nitrile oxide fragment 3-R CeHiC N+Cr ", was observed mass spectrometrically in 3a,4,5,6-tetrahydro-[ 1,2,4 oxadiazolo[4,5-a J [ 1,5 benzodiazepine derivatives 11 (83). 

Tetrahydro pyrrolo-benzodiazepine 232 is a product of a two-step sequence starting from nitrile 231 (Scheme 49 (2005BMCL3453)). 

Tetrahydro pyrrolo-benzodiazepine 232 can be oxidized with manganese (IV) oxide to imino analog 233 (Scheme 49, Section 3.1.1.3 (2005BMCL3453)). 

Cyclic secondary amines with pyrrolo[2,l-c][l, 4]-benzodiazepine rings were oxidised with TPAP/NMO/PMS/CH3CN to the corresponding imines. Thns (llaS)-1,2,3,10,ll,lla-hexahydro-5H-pyrrolo[2,l-c][l, 4]-benzodiazepine-5-one gave (llaS)-l,2,3,lla-tetrahydro-5H-pyrrolo[2,l-c][l, 4]benzo-diazepine-5-one [23]. 

Carbonylation of the urea 27 in the presence of Pd(0) and KOAc as base is a useful route to 4-butyl-2-phenyl-23,44-tetrahydro-l/f-2,4-benzodiazepine-13-dione (28) <99TL2623>. Also isolated from this reaction as secondary product is IV-n-butylisoindoline. Pyrolysis of the cyclobutenones 29 afford the diazepines 30 in moderate yield <99JOC707>. 

Figure 17. Enantiomer separation by supercritical fluid chromatography of 7-chloro-2,3.4,5-tetrahydro-l-methyl-5-phenyl-1,4-benzodiazepin-2(l//)-one (dihydrodiazepam) on a 2.5 m x0.05 mm (i.d.) fused silica capillary column, containing immobilized octamethylenc-Chirasil-Dex [carbon dioxide at 90CC. density programmed from 0.31 g/mL (130 atm) at 0.0029 g/mL min 1 after an initial 2.0-min period at 0.31 g/ mL]130.

The iV-4-(benzotriazolylmethyl)-tetrahydro-l,4-benzodiazepine 59 reacted smoothly with Grignard reagents in THF to provide convenient access to substituted homologues in good yield (Scheme 25) <2002J(P1)592>. The benzo-triazole moiety can be removed reductively with NaBFLr to provide the simple jV-methyl compound, while reaction with triethyl phosphite and ZnBr2 in dry THF gave the diethylphosphonate derivative. 

The most common form of the type e ring-closure reaction to afford 1,4-benzodiazepines is a l-endo-trig--ptoce,ss in which a substituted iminium derivative, typically generated in situ, is captured by the aryl ring. Cyclization of the A,iV -(bis-l,2,3-benzotriazol-l-ylmethyl)amine 104 by a Friedel-Crafts-type ring closure afforded the tetrahydro-1,4-... 

Reduction of 2,-4-diphenyl-2,3-dihydro- 1H-1,5-benzodiazepine 103 (R is H, Ar is Ph) by sodium borohydride leads to an equimolar mixture of the diaster-eomeric tetrahydro derivatives 105 (Scheme 4.34), whereas under analogous... 

---