A catalytic route to dibenzodiazepines involving Buchwald–Hartwig coupling: reaction scope and mechanistic consideration

Abstract

We report a new synthetic method for the synthesis of a family of dibenzodiazepines (DBDAs), employing Pd-catalyzed C-N coupling of o-bromoaldimine, with o-bromoaniline as the key step. Eleven DBDAs were prepared, containing electron-withdrawing groups (CN, F, NO 2 ) and electron-donating groups (OMe). The reaction conditions were optimized (catalyst, phosphine, base and solvent) and best results were obtained with Pd(OAc) 2 , SPhos, Cs 2 CO 3 in THF. Due to the ambiguity of the mechanism at hand, various mechanistic studies were performed, that included DFT calculations. The oxidative addition process was studied in detail by DFT, and these studies supported the observed reaction regioselectivity. The adducts formed between the aldimine and the Pd(0) catalyst were calculated to be more stable than the ones formed with the amine, and the barrier for the oxidative addition at the C-Br bond of the aldimine was calculated to be lower than the one at the C-Br bond of the aryl amine. The formation of DBDA over the dibenzoaminopiperidine has been explained in the final cyclization step.

Metal‐Catalyzed Routes to Dibenzodiazepines (DBDAs) and Structural Analogues: Recent Advances

“…Scheme 4. [31] After very careful optimization studies, the best conditions were found to be Pd(OAc) 2 (2.5 mol-%), Cs 2 CO 3 (2 equiv. [29] The 2-aminobenzophenones 10 underwent a Buchwald-Hartwig reaction with 2-bromonitrobenzenes 11 in the presence of PdCl 2 (PPh 3 ) 2 and Cs 2 CO 3 in toluene at 110-120°C.…”

“…Alternative Pd-catalysed DBDA synthesis as described by Yin and co-workers. [31] Scheme 6. These conditions were obtained via careful optimization studies.…”

“…[29] The 2-aminobenzophenones 10 underwent a Buchwald-Hartwig reaction with 2-bromonitrobenzenes 11 in the presence of PdCl 2 (PPh 3 ) 2 and Cs 2 CO 3 in toluene at 110-120°C. [31] pling at the N atom is not unprecedented. This was followed by hydrogenation using 10 % Pd/C in methanol at room temperature for 30 minutes generating the corresponding amine intermediate (which was difficult to isolate due to its inherent lability), but underwent cyclization to the final DBDA 12 using a catalytic quantity of p-toluenesulfonic acid (pTsA).…”

“…These conditions were obtained via careful optimization studies. [31] A computational study using DFT calculations was employed to rationalize this unusual mechanism for the formation of the azepine unit. These workers demonstrated the scope of the reaction.…”

“…In 2015 our group reported a surprising alternative to the method of Tsvelikhovsky and Buchwald, in this approach (with a patent filed), o-bromoanilines 14 were reacted with o-bromoarylimines 13 to form simple DBDAs 15 lacking substituents in the DBDA iminic site (Scheme 5). [31] After very careful optimization studies, the best conditions were found to be Pd(OAc) 2 (2.5 mol-%), Cs 2 CO 3 (2 equiv. ), SPhos, (5 mol-%), THF, 100°C, 18 h. The aldimine 13 was synthesized from o-bromobenzaldehyde and some sulfonylamines via condensation with BF 3 -Et 2 O as catalyst.…”