Synthesis and biological evaluation of benzodiazepines containing a pentafluorosulfanyl group

The widely used pentafluorosulfanyl group (SF5) was deployed as a bioisosteric replacement for a chlorogroup in the benzodiazepine diazepam (Valium (TM)). Reaction of 2-amino-5-pentafluorosulfanyl-benzophenone with chloroacetyl chloride followed by hexamethylenetetramine, in the presence of ammonia, led to 7-sulfurpentafluoro-5-phenyl-H-1-benzo[1,4]diazepin-2(3H)-one (2c). The latter was able to undergo a Pd-catalysed ortho-arylation, demonstrating that these highly fluorinated benzodiazepines can be further modified to form more complicated scaffolds. The replacement of Cl by the SF5 group, led to a loss of potency for potentiating GABA(A) receptor activation, most likely because of a lost ligand interaction with His102 in the GABA(A) receptor alpha subunit. Dedicated to Professor Jonathan Williams, an inspirational and humble pioneer, a colleague and mentor in chemistry. (C) 2021 Elsevier Ltd. All rights reserved.