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7‐Chloro‐5‐phenyl‐d5‐3(S)‐methyldihydro‐1,4‐benzodiazepin‐2‐one (1a) was synthesized and its conformation in solution determined using a computer assisted LIS‐NMR method. It was found, with Fr(fod)‐d27 as a shift reagent, that a lanthanide coordinates to a carbonyl oxygen at a 2.02 Å distance (bond angle 158.07°, torsional angle 39.53°), while the substrate 1a adopts an expected quasi‐boat conformation with a C(3)‐methyl group exposed in a quasi‐equatorial position.

New synthesis of 11‐acyl‐5,11‐dihydro‐6H‐pyrido[2,3‐b][1,4]benzodiazepin‐6‐ones (42‐44) is reported. The crucial steps (Scheme VI) represented N‐oxydation of 1 (1A) to 35 (35A), facilitated ring‐closure of 36 into 37, its subsequent N‐α‐chloroacetylation to 38, aminolysis to 39‐41 (involving N‐O anchimeric assistance as depicted in 38A) and deoxygenation to 42‐44 (Scheme VII). The central intermediate 37 is also obtained on oxygenation of 2, a new synthesis of which was reported in the previous paper of this series [3]. Other attempts of cyclisation “from the top” or “from the bottom” (Scheme I) are described. Thus, interaction of 1 with acetamide afforded 3 and 4 instead of the expected 2A. Compound 5 cyclised into 3‐pyridoquinazolone 6 while its 2‐(4′‐methylpiperazin‐1′‐yl analogue 9 was observed to be unstable for the attempted ring‐opening and reclosure to 42. “From the bottom” cyclisations of 10A‐10C, via intermediary amines 11A‐11C failed and pyridoquinazolinone 13 was isolated (Scheme V). The attempted oxidative cyclisation of the compounds 15 and 18 into 2 and 42, respectively, 13 afforded imidazolo[5,4‐b]pyridine derivative (18–19), while 15 remained unchanged. 3‐Acylamino‐2‐arylaminopyridines (21‐24), cyclised into imidazolopyridines 29‐30. Model compounds 45‐50 were prepared to study selective aminolysis of the chlorine atoms in 2‐chloro‐3‐(2′‐chlorobenzoyl)aminopyridine 1, and its N‐oxide 35.

C(3)‐Hydroxy‐1,4‐benzodiazepin‐2‐ones 1–3 have been prepared in high yields using a new, two step approach. In the first step, the 3‐deoxy‐precursors 4–6 were acetylated at C(3) using the redox‐system lead tetraacetate and iodine, or potassium iodide, in acetic acid. The intermediary acetates 9–11 were quantitatively hydrolyzed into 1–3 in non‐aqueous conditions, i.e. in a methanol‐methylene chloride solvent mixture in the presence of sodium methoxide. Another route to the title compounds has been improved as follows. The yields of C(3)‐bromination of compounds 4–6 has been significantly augmented in relation to the known methods using the strong trifluoroacetic acid in very dilute carbon tetrachloride solutions as a catalyst for NBS mediated bromination. The intermediary C(3)‐bromo derivatives have been acetoxylated in situ, and compounds 9–11 have been isolated in over 80% yield. These compounds were solvolyzed into 1–3 as described above. The third part of this paper describes the search for feasible reaction conditions in the synthesis of 3 according to a known method (Scheme 1.); optimization of the yields in all steps was performed.

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