1.2.4- Triazolo benzodiazepines synthesis

New synthetic methods for benzodiazepine synthesis involving Ugi-type multicomponent/post-Ugi cyclization reactions continue to be of interest. Ugi reactions of indole-2-carboxaldehydes, isocyanides, amines, and 2-iodobenzoic acid derivatives led to intermediates which, with copper(I) catalysis, underwent intramolecular indole N-arylation to produce indolo-fused benzodiazepinones, such as 134 (13CC2894). 2-Azido-benzaldehyde, isocyanides, propargylamines, and nitrophenols underwent Ugi-type reaction, Smiles-type rearrangement, and intramolecular azide-alkyne cyclization to afford triazolo-fused benzodiazepinones such as 135... 

A particularly interesting example of this method of synthesis is the cy-clrzation of the 4-amino-3-(2-aminophyenyl)-l,2,4-triazoloes 73 with cyanogen bromide. Primarily, this reaction was applied to synthesize the 6-amino-l,2,4-triazolo[4,3-d]benzodiazepine hydrobromides 74 the obtained products, however, were found to be the l,5-diamino-l,2,4-triazolo-[l,5-c]quinazolin-ium bromides 77. Structure elucidation of 77 was accomplished by direct... 

In contrast to the relatively limited number of non-fused 1,2,4-triazole syntheses that were reported in 1996, the preparation of several ting-fused 1,2,4-triazole-containing structures were published. For example, the frrst practical synthesis of fused[a]triazolo[l,4]benzodiazepine-5,11-diones 16 via the hydrazone IS was reported (Y = H, Cl, Me R = H, Me, Ph X = O, S) <96JHC275>. Oxidative cyclization of N-heteroarylamidines allowed the preparation of... 

Garanti et al. (30a) reported a synthesis of the l,2,3-triazolo[l,5-a][4.1]benzox-azepine 149 via an intramolecular cycloaddition of an aryl azide with an acetylene (Scheme 9.30). By using a similar strategy, the l,2,3-triazolo[l,5-a][l,4-l ]benzo-diazepine 150, an analogue of Flumazenil, was also reported (30b,c). As an extension of this method, the l,2,3-triazolo[l,5-a][l,4]benzodiazepine-6-one 153 was synthesized using an intramolecular 1,3-dipolar cycloaddition of an azide with a cyano group (30d). 

In an exploration of multi-component reactions for the synthesis of a diverse array of heterocyclic scaffolds Martin et al. demonstrated a cascade reaction involving the imine, formed from the condensation of 2-azidobenzaldehyde 97 with propargylamine, acetyl chloride and ketene acetal 98 to furnish the triazolo-fused benzodiazepine 99 via an intramolecular [3+2] cycloaddition <07OL4223>. 

A methodology for the synthesis of analogs of asmarine, marine alkaloids with a unique tetrahydro[l,4]diazepino[l,2,3-g,h]purine 120 (THDAP) strueture has been developed. Three cyclization methods were applied for the preparation of the 9,9-disubstituted 10-hydroxy-THDAP system aminomereurization, iodocyclization and acid-catalyzed cychzation <05JOC199>. A series of 2-phenyl[l,2,3]triazolo[l,2-a][l,2,4]benzotriazin-l,5-diones 121 have been synthesized and identified as affinity central benzodiazepine-receptor ligands <05JMC2936>. 

Diastereoselective intramolecular 1,3-dipolar cycloaddition reactions were deftly exploited in the synthesis of a number of enantiopure pyrazolo-pyrrolo- and triazolo-pyrrolo-fused 1,4-benzodiazepine systems <05S2246>. 

Synthesis of 13C- and uC-labelled Alprazolam , Q-chloro-1 -(2-dimethylamino)-ethyl-6-phenyl-4H-S-triazolo [4,3-a] [1,4] benzodiazepine (178) and of its tosylate (178 los OH)... 

This reaction principle has considerable scope, as shown by the synthesis of various heterocyclic annu-lated 1,4-benzodiazepines. [l,2,3]Triazolo[l,5-fl][l,4]benzodiazepines 23 are prepared from triazole derivatives 22 which are accessible by a 1,3-dipolar cycloaddition of o-azidobenzophenones with (aminomethyl)alkines pyrrolo[2,l-c][l,4]benzodiazepines 25 are formed from l,2-dihydro-3,l-benzoxazinediones 24 and proline ... 

Tennant [204], Smalley et al. [205], and Jones et al. [206]. For example, l,2,3-triazolo[l,5-a]qninazolines 70 were obtained in moderate yields by base-catalyzed cycloaddition/condensation reaction (Scheme 14) [205]. Synthesis of 4(3H)-qninazolinones and -imines via 1,3-dipolar cycloaddition has been reported also [207,208]. Novel formation of quinazoUnes via thermal ring contraction of 3H-1,4-benzodiazepines is found by Sashida et al. [209]. Synthesis of quinazoline alkaloids by cycloadditions is discussed in Sect. 3. 

This reaction principle has considerable scope, as shown by the synthesis of various hetero-annulated 1,4-benzodiazepines. For example, [l,2,3]triazolo[l,5-a]... 

Benzodiazepines are often bioactive compounds, widely used as anticonvulsants, antianxiety, hypnotic agents, analgesics, antidepressives, and anti-inflammatory drugs (Figure 19) [159]. For instance, 1,5-benzodiazepines are useful precursors for the synthesis of some benzodiazepine derivatives with pharmacological properties, such as tri-axolo-, triazolo-, oxadiazolo-, oxazino-, or furano-benzodiazepines. In particular, the application of these compoxmds has been also extended to various diseases, such as cancer, viral infection, and cardiovascular disorders. 

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