Benzophenone imine, ammonia surrogate

The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose. 

Benzophenone imine is commercially available and serves as an ammonia surrogate that reacts with aryl halides in high yields under standard palladium-catalyzed conditions. Catalysts based on both DPPF- and BINAP-ligated palladium gave essentially quantitative yields for reactions of aryl bromides. These reactions can be conducted with either Cs2C03 or NaO-/-Bu as base [137,138]. The products are readily isolated by chromatographic techniques or by crystallization. They can be cleaved to the parent aniline by using hydroxylamine, acid, or Pd/C [138]. 

Benzophenone imine (66) is another ammonia surrogate. Arylation of the imine 66 is carried out using BINAP and CS2CO3. Hydrolysis of the arylated imine 67 affords the aniline derivative 68 [53]. 

A number of other protocols for the application of benzophenone imine as ammonia surrogate have been reported using DPEPhos (12) [61], BINAP (1) [62,63], or DPPF (9) [64] as ligands. DPPF was used on a 5.3kg scale by Merck for the synthesis of a 2-aminopyridine derivative, rendering the potential for the synthesis of substituted heterocycles (Scheme 13.10) [64]. 

Despite the efficient utilization of benzophenone imine and metal amides as ammonia surrogates, the quest for the direct coupling of ammonia with aryl halides continued. The biggest challenge was to suppress the polyarylation of ammonia, which arises from the reaction of the corresponding anihne. Hartwig et al. [72] were the first to master this task and to report the Pd-catalyzed monoarylation of ammonia (Scheme 13.19). 

Like the use of the imine as an ammonia surrogate, the hydrazone of benzophenone can be used as a hydrazine surrogate (Scheme 2.165). The coupling product 2.564 may be diverted directly into a Fischer indole synthesis via hydrazone exchange with an added ketone. This pathway gives an indole 2.565 with a free N-H. Alternatively, the available nitrogen atom may be alkylated or coupled a second time, and then diverted into a Fisher indole synthesis. In this way, indoles with no nitrogen substituent, or an A-alkylated indole 2.566 or an iV-arylated indole 2.567 can be formed. 

Other authors presented methods based on surrogates of ammonia such as amidine hydrochlorides [241], 2,2,2-trifluoroacetamides [156], benzophenone imine [242] and sodium azide (cf. Sect. 2.4.1) [243-248]. Although efficient, these systems require an additional deprotection step to get anilines and sometimes the use of stoichiometric amounts of a copper precursor. 

---