Efficient procedures for the synthesis of benzo-fluorinated dibenz[b,f]azepines (iminostilbenes) from fluorinated isatins or indoles using a number of ring-expansion reactions are described. A range of mono- and difluorinated analogues is accessible, and the syntheses can deliver gram quantities of the final products, which are precursors of fluoro analogues of the important anticonvulsant carbamazepine.

The anticonvulsant carbamazepine 1 is associated with adverse drug reactions (ADRs), including hepatotoxicity; oxidative metabolism of 1 has been implicated in the pathogenesis of the ADRs. We report the synthesis and evaluation of 2-monohalo and 2,8-dihalo analogues of 1 that were intended to minimize reactive metabolite formation via arene oxidation and 10,11-epoxidation. Halo analogues were obtained either by rearrangement of halogenated N-arylindoles or from specifically halogenated iminodibenzyl derivatives. In rat hepatocytes, none of the analogues underwent oxidative dehalogenation or glutathione adduction. Some formation of the 10,11-epoxide still occurred, but aromatic hydroxylation was not seen with the exception of 2-fluoro, which allowed minor monohydroxylation. Complete inhibition of aromatic hydroxylation required at least monochlorination or difluorination of 1. In human liver microsomes, difluoro analogue 5b underwent 10,11-epoxidation but gave no arene oxidation.

The dibenz[b,f]azepine heterocyclic system and related molecules with a single 10,11-bond are important templates for well-prescribed drug molecules, notably carbamazepine (anticonvulsant), clomipramine and imipramine (antidepressants). We synthesised a range of halogenated carbamazepine analogues, in connection with metabolic and immunological studies, as probes for structure-metabolism and hypersensitive effects and have published on their metabolic behaviour. While a number of synthetic routes to such analogues are possible, we naturally sought short and efficient methods for our target compounds. In the following report we present an effective two-step synthesis of a range of dibenz[b,f]azepines from appropriate indoles via N-arylation, then acid-catalysed rearrangement, with a critical analysis of other approaches. We showed earlier that this route was effective for fluoro analogues and here present a broader review of its scope. The 5-(carboxamido) side chain of carbamazepine may be added in various ways, affording overall a convenient access to drug molecules.

Convenient Syntheses of Halo-Dibenz[b,f]azepines and Carbamazepine Analogues via N-Arylindoles. -A two-step-approach to title compounds (IV) based on N-arylation of indole derivatives (I), followed by acid-catalyzed rearrangement is reported. -(ELLIOTT, E.-C.; MAGGS, J. L.; PARK, B. K.; O'NEILL, P. M.; STACHULSKI*, A. V.; Org. Biomol. Chem. 11 (2013) 48, 8426-8434, http://dx.doi.org/10.1039/c3ob41252k ; Dep. Chem., Univ. Liverpool, Liverpool L69 7ZD, UK; Eng.) -M. Paetzel

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Convenient Synthesis of Benzo-Fluorinated Dibenz[b,f]azepines: Rearrangements of Isatins, Acridines, and Indoles. -The direct fluorination of dibenzazepines with SelectFluor fails. A 5-step synthesis based on isatin provides precursors such as (V) on a gram scale. Starting from indoles a range of regioisomeric fluorinated products (IX) and (X) is generated in 2 steps. -(ELLIOTT, E.-C.; BOWKETT, E. R.; MAGGS, J. L.; BACSA, J.; PARK, B. K.; REGAN, S. L.; O'NEILL, P. M.; STACHULSKI*, A. V.; Org. Lett. 13 (2011) 20, 5592-5595, http://dx.doi.org/10.1021/ol202318w ; Dep. Chem., Univ. Liverpool, Liverpool L69 7ZD, UK; Eng.) -H. Simon