Diazepines and fused derivatives

A convenient and effective palladium-catalysed Suzuki-Miyaura cross coupling reaction of deactivated aryl chlorides with phenylboronic acid utilised the 1,3-diazepinium salts 107 as in situ precursors of the palladium ligands. These salts were prepared from the diamines 106 and cyclocondensation with triethyl orthoformate 05SL2394 . 

A new two-step route to chiral 3-substituted l,4-benzodiazepin-2-ones based on reaction of 2-nitrobenzylbromide with amino acids, followed by cyclisation on reaction with iron and hot acetic acid, has been reported 05S1881 . 

Highly functionalized l,4-benzazepin-5-one derivatives can be made by solid-phase synthesis incorporating aza-Wittig reactions 05MI2680 . 

The preparation of 2-substituted l,4-benzodiazepin-3-ones by highly diastereoselective alkylation (with n-BuLi as the base in THF) of the l,4-benzodiazepin-3-one 127 with an N-based chiral auxiliary has been described 05EJ01590 . The precursor 126 was assembled in a multi-step synthesis starting from o-nitrobenzaldehyde and proceeding via the chiral amino alcohol 122 to 123, 124, 125, and the bromoacetamide 126. Base-induced intramolecular nucleophihc displacement in 126 then gave 127 in fair yield. 

Two major complementary papers by Carlier and coworkers elaborate on the ring inversion of l,4-benzodiazepin-2-ones 05JOC1530 and memory of chirality trapping of enolates of l,4-benzodiazepin-2-ones with low inversion barriers 05TA2998 . In the former study, dynamic H NMR and 2D-EXSY NMR and DFT calculations were used to characterize the inversion barriers and, in the latter, calculations then highlighted the significant effect of the nature of the N1 substituent in determining the barrier. 

Although highly reactive, 2/7-azirines are of considerable synthetic interest and serve as a source of the 3-fluoro-4//-l, 3-diazepines 86. Reaction of 80 with difluorocarbene in the presence of furfural gave 86, rather than the expected furfural-derived products 83. Rearrangement of the initial 1,3-dipolar intermediate 81 to 84 and then cycloaddition of 84 with 80 are proposed as key steps in the reaction the intermediate cycloadduct 85 gave 86 on base-induced elimination of HF. Nucleophilic displacement of the fluoro group in 86 provided access to further substituted 1,3-diazepines 06TL639 . 

Reagents (i), CF2Br2, active Pb, Bu4NBr, furfural, CH2C12, 40-43 °C, 6 h 

4-diazepane 87 has been used as a neutral 6-electron ligand for the support of cationic Group 3 metal (Sc,Y) alkyl catalysts 06CC3320 . 

Parallel array synthesis was used to access the 3-aryl-tetrahydro-l,2-diazepines 90 (and other related compounds) by cyclisation of the chloro ketones 88 on reaction with hydrazine to give 89 followed by sulfonamide formation the Si-TrisAmine was added at the end as a scavenger to remove any unreacted arylsulfonyl chloride remaining 06MCL3777 . 

In an extension of previous work on conjugated enamine carbonyl derivatives, reaction of the pyrazolone 91 with IV.lV-disubstituted hydrazines on heating in an alcohol solvent afforded the hexahydropyrazolo[4,3- i][l,2]diazepine-8-carboxylates 92 in good yields. While the exact mechanism for the formation of 92 is not known, one possibility, namely a Michael-type addition of the alcohol to a pre-formed pyrazolo-diazepine, was excluded 06T8126 . 

3 SEVEN-MEMBERED SYSTEMS CONTAINING TWO HETEROATOMS 7.3.1 Diazepines and fused derivatives 

Hydrazines react with 6-chloro-l-hexynylphosphonates 74 to provide the corresponding azaheterocyclic phosphonates 75 in good yields and purity 07TL3213 , while pyrazolo[4,3-c]diazepine carboxylates 77 were prepared by heating the to-enamine 76 with 1,2-dimethylhydrazine in methanol or ethanol at reflux 07H(71)657 . 

Reagents (i) NH2NH2 or CH3NHNH2, Reagents (i) MeNHNHMe, ROH (R = Me or Et), reflux 

A new class of thiazole-fused diazepinones 79 was prepared by treatment of 2-arylamino-4-coumarinyl-5-formyl thiazoles 78 with hydrazine hydrate in refluxing ethanol to yield the rearranged products via ring-opening by attack of the intermediate hydrazone on the lactone of the coumarin 07SC99 . 

The novel /V-hcicrocyclic carbene (NHC) l,3-dicyclohexyl-l,3-diazepan-2-ylidene 80 and its 5,6-dioxolane derivative 81 were synthesised and their coordination chemistry with Rh(I), Ir(I), and Pt(0) explored. The coordinated carbene ligands display extremely large NCN bond angles in crystal structures 0704800 . The cyclic urea 82 was synthesised and fluorescent properties studied in a search for new DNA/RNA bioprobes 07JOC102 . 

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Benzodiazepines (1) are the 2,3-benzo-fused derivatives of the dihydrodiazepines of the previous Chapter. The reader should note that the numbering systems required (IUPAC Chemical Abstracts) for the benzo series and the dihydro compounds proceed in opposite directions about the diazepine rings. 

Many reactions of substituted diazepines and their fused derivatives frequently relate to a study of the functionality rather than being dependent on the presence of the azepine ring system, most particularly with reduced derivatives. Reaction of the unsymmetrical semicarbazones (110) <91JOC5203> gives the two selenodiazoles (111) and (112), the ratios of which show a solvent dependency (Equation (8)). 

Huge success of benzodiazepenes as pharmaceutical scaffolds has prompted preparation and evaluation of het-erocyde-annulated benzodiazepine derivatives. A tandem Michael addition-condensation sequence xmder MW irradiation was also proved to be useful for the synthesis of amino-substituted pyrimidine-fused diazepine derivatives of the type 96 from 4,5,6-triaminopyrimidine and chalcones [57]. Similarly, the pyridine-fused derivatives (97) were prepared xmder MW-assisted solvent and catalyst-free condition [58], Condensation of thiadiazole-annulated phen-ylene diamines with appropriate carbonyl compounds using sulfamic acid as organocatalyst led to the formation of corresponding diazepine derivatives 98 in excellent yields [59] (Figure 4). 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

Examples of seven-membered heterocycles with significant antiviral activity include imidazo[4,5-e][l,3]diazepine-4,8-diones with anti-hepatitis C virus (HCV) activity <07BMCL2225> <07BMC4933> and benzo(indolo)fused 1,4-oxazepine derivatives as HCV RNA polymerase inhibitors that show excellent replicon potency <07BMCL3181>. Novel 2-chloro-8-[(arylthio)methyl]dipyridodiazepinone derivatives show activity against HIV-1... 

In the same manner 2-phenylthiazole and 2,3-substituted thiophene derived imino-phosphoranes react with one eqivalent of aryl isocyanate to give fused 1,3-diazepines in 50-72 % yield, while with two equivalents aryl isocyanate the [2-1-2] cycloadducts are obtained in 50-61% yield. ... 

Vinyliminophosphoranes derived from 1,6-methanol[10]-annulenes react with isocyanates to give 1,6-methanol[10]-annulenopyridines. Bis(vinyliminophosphoranes) combine with isocyanates to provide azolofused l,3-diazepines. Differences on the periphery of the fused ring systems occur based on isocyanato (alkyl vs aryl) substituents. The thermal reaction of [(2-azulenyl)imino] phosphoranes on [(1-azaazulen-z-)imino]-phosphoranes with 2-bromotropone allow for the preparation of 6-aza- and 6,7-diazaazuleno[1,2-a]azulenes. °... 

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