Convenient syntheses of halo-dibenz[b,f]azepines and carbamazepine analogues via N-arylindoles

Abstract

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.

Recent Progress Concerning the N-Arylation of Indoles

“…Ligands in the form of natural amino acids allow the N -arylation of indoles under similarly mild reaction conditions [ 103 ]. Unfortunately, the scope of the reaction is almost exclusively limited to the preparation of N -arylindoles ( Table 2 , entries 3 [ 104 ] and 4 [ 105 ]). The use of metformin as the ligand for N -arylation led to the formation of N -arylindoles, although the reactions were carried out in DMF at 130 °C ( Table 2 , entry 5) [ 106 ].…”

Application of a Dual Catalytic Nickel/Iridium-Based Photoredox Reaction to Synthesize 2-Alkyl-N-Arylindoles in a Continuous Flow

“…For example, N -arylindoles are of interest as angiotensin II-antagonists, MT1 melatonin receptor partial agonists, and antipsychotic agents . Direct N -arylation of indoles has been generally accomplished using Ullmann, Buchwald, , and Chan-Lam coupling reactions. Copper-catalyzed Ullmann or Buchwald conditions generally require prolonged heating of indoles with aryl halides in the presence of diamine ligands at higher temperatures (for example, >120 °C for 18 h).…”

Copper-catalyzed N-arylation of bis(indolyl)methanes: the first approach for the synthesis of unsymmetrical N-aryl bis(indolyl)methanes by C–N cross-coupling reaction

“…Over the past years, versatile synthetic procedures using transition metals-based catalytic systems such as CuI [20], CuFe 2 O 4 [21], CuO [22], Pd(OAc) 2 [23], and Pd/C [24] have been reported for C-N crosscoupling reaction of heterocyclic systems such as indole. In this regard, copper is one of the most interesting and important catalysts, which is used in Ullmann-type reactions of the current study.…”