The Chemistry of Benzodiazepines

Synthesis of 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones by addition of Grignard reagents to derivatives of o-aminobenzonitrile

“…Compounds containing the 1,4-benzodiazepine (Bzp) core (4) have been known for their anxiety-relieving and sedative properties for a long period of time (Figure 1.2). 5 Valium (diazepam) (5) is perhaps the most renowned example but other variants, such as Xanax (6) (alprazolam) and Ativan (7) (lorazepam) are more commonly prescribed today. 6 The first synthetic benzodiazepine, chlorodiazepoxide (8), was serendipitously discovered in the mid 1950's by researchers at Hoffman LaRoche searching for new tranquilizers (Scheme 1.1).…”

“…60 In addition, properties such as cholesterol-lowering and hormone-like activities have been reported. 61 In recent times, material chemists have explored the electrochemical properties of diaryldibenzo [b,f] [1,5]-diazocines (72) which were found useful as a basis for molecular machines and artificial muscles. 62 In general, eight membered rings are difficult to prepare since their formation is usually hampered by unfavourable entropic factors and transannular interactions.…”

“…aza-Wittig cyclization, 65 intramolecular dehydration, 66 and ring expansion reactions, 67 however special conformational restrictions are usually required in order to obtain reasonable yields from direct cyclization of acyclic precursors. 63,68 For example, Banfi Tröger's base (75), a bridged variant of a dibenzo [b,f] [1,5]diazocine, has a chiral aromatic cleft structure with a unique ability to host guests and as a result act as a supramolecular receptor (Figure 1.11). 71 Although most applications of Tröger's base are within the field of supramolecular chemistry, pharmacological applications have also been reported.…”

“…125 In an interesting study by Stefanovic Further investigation of the diazocine 153 showed that addition of acetic acid induced ringopening to give the symmetrical dihydroxy derivative 157 (Scheme 4.6.). There is no general procedure for preparation of 2,6-dialkyldibenzo [b,f] [1,5]diazocines, e.g. 158, and attempts to obtain this compound from 153 failed.…”

“…126 The isolated product was identical to the unstable compound 159 previously obtained from 153. According to literature, treating 160b with various nucleophiles have resulted in 2,6disubstituted dibenzo [1,5]diazocines. 127 Consequently, dichloride 160b, prepared from diamide 161 and PCl 5 , was treated with MeMgBr.…”