Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

A sequential strategy to access 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinones (DBDAPs) is disclosed in this article through a palladium and copper-catalyzed amination (Buchwald–Hartwig (B–H) or Chan–Lam (C–L)) followed by a palladium-catalyzed intramolecular aminocarbonylation with Mo(CO)6 as CO surrogate (to avoid toxic CO handling) of readily available o-phenylenediamines and either 1,2-dibromobenzene or 2-bromophenylboronic acid. The 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepinone could be synthezised in good yield using a sequential catalytic procedure, using both C–L and B–H approaches. Gratifingly, the use of the C–L reaction was more impressive, and afforded the dibenzodiazepinones in good yields (up to 45%; 2 steps) and much milder conditions using copper as the catalyst. The synthetic utility of this novel strategy was showcased by demonstrating a formal synthesis for the antipsychotic drug clozapine and to an anticancer triazole–DBDAP hybrid.

Aesar and were used as received.The solvents used were dried using standard laboratory techniques.The catalytic reactions were conducted in a Radley's 12-position carousel reactor under a nitrogen atmosphere or in round-bottomed flasks.Column chromatography was carried out on silica gel (Carlo Erba, 40-63 μm (flash) and 60-200 μm, 60A).Thin-layer chromatography (TLC) was carried out on aluminum-backed Kieselgel 60 F254 plates (Merck and Machery Nagel).
Plates were visualized either by UV light or with phosphomolybdic acid in ethanol.Melting points (mp) were determined with a Barnstead Electrothermal 9100 apparatus and are uncorrected.NMR spectra were recorded with a Bruker Avance III instrument (400 MHz) with a broad band probe.Chemical shifts are quoted in parts per million (ppm) relative to  = 0.0 ppm and were referenced to the appropriate non-deuterated solvent peak.Coupling constants (J) are reported in Hz and refer to apparent peak multiplicities.Splitting patterns are reported as s, singlet; d, doublet; t, triplet; m, multiplet; br, broad.
Low-resolution mass spectra (LRMS) were recorded with a quadrupole mass spectrometer Waters ZQ4000 and high-resolution mass spectra (HRMS) on a Thermo Orbitrap Q-exactive focus at a resolution of 70000 at the Chemistry Department, University of Salamanca (by Dr. César Raposo).ESI was used as ionization method, and the samples were dissolved in S2 methanol.In the case of the HRMS, an alternating method between positive and negative modes was applied and the mode with the best signal was used for the determination of the exact mass.
Data for compound 3b:

III -Kinetic study of the Molybdenum/Palladium Buchwald-Hartwig coupling reaction
In order to understand the role of the Molybdenum species in this reaction, and if it exerted a catalytic effect, a kinetic study was performed using the aforementioned model system described above with 5 mol % of Mo(CO)6.The standard reaction (benchmark) contained everything bar the Mo species.A 1 mL sample was collected every 10 min and the reaction progress was constantly monitored by 1 H NMR (Scheme S1).For practical reasons, the reaction was carried out at a larger scale than in the previous reactions, and the results are shown in Figure S1.At the larger scale, we observed the formation of the usual black precipitate in the presence of Mo(CO)6 which could be due to the complexation of the palladium with the molybdenum, which may lead to a reduction in the catalytic activity of that particular system.

S12
Palladium catalysts have a tendency for aggregation which often leads to the formation of a black precipitate and we believe this phenomenon can also take place at the larger scale used here [4].The Mo(CO)6 may also exert a reducing effect on the Pd(II) catalyst, producing Pd(0) as black precipitate.For practical reasons, the reaction was only monitored for 90 min.In all cases, except for the first 10 min, the reaction without Mo gave the best yields, this was particularly evident after 30 min.In a round-bottomed flask, aniline (0.45 mL, 5 mmol), o-bromobenzene (0.52 mL, 5 mmol) were dissolved in DMF (20 ml), then Pd(OAc)2 (56 mg, 0.25 mmol), DPEPhos (0.13 g, 0.25 mmol) and Mo(CO)6 (66 mg, 0.25 mmol) were added to the reaction mixture.The resulting mixture was allowed to stir at 130 °C under a nitrogen atmosphere.A sample (1 mL) was taken from the reaction mixture after 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 60 min, and 90 S13 min of reaction.The sample was filtered through a glass pipette with flash silica and washed with DCM.The solvent was evaporated under reduced pressure, and mesitylene (0.08 g, 0.48 mmol) was added as standard to each crude mixture and analyzed by 1 H NMR, the yields were determined afterwards.

Figure S1 :
Figure S1: Comparative study of the Pd and Pd/Mo-catalyzed B-H amination between bromobenzene and aniline (analysis conducted via 1 H NMR with a mesitylene standard).

Table S1 :
Kinetic study of the Pd/Mo catalyzed B-H coupling of aniline with bromobenzene.