Benzophenone imine, ammonia

Since the use of ammonia is not practical in transition metal catalyzed processes, the identification of its synthetic equivalents is of major importance. Benzophenone imine was found to couple with 3-bromopyridine readily under the above mentioned conditions (7.72.), The masking benzophenone was removed in transamination with hydroxylamine, which gave the desired 3-aminopyridine in 81% overall yield.92 Allylamine was also successfully employed as ammonia equivalent93... 

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 inline or allylamine can be used as ammonia equivalents in the CN coupling reactions of halopyr-idines <1996JOC7240,1998TL1313>. Primary S-aminopyrimidines can also be prepared using benzophenone imine as the amine source, as demonstrated by the synthesis of 970 from 968 via 969 <20060PD70>. Aromatic amines also efficiently aminate S-bromopyrimidine (Scheme 115) <2005OL3965>. 

Representative Procedure for the Use of Benzophenone Imine as an Ammonia Equivalent (Excerpted with permission from [108]. 1996 Pergamon Press) A Schlenk tube was charged with sodium tert-butoxide (1.4 mmol), Pd2(dba)3 (0.00125 mmol), and BINAP (0.00375 mmol). The Schlenk tube was fitted with a septum and attached to a Schlenk line. After the air atmosphere was replaced with argon, toluene (4 ml), 4-tert-butylbromobenzene (1.0 mmol), and benzophenone imine (1.2 mmol) were added by syringe. After the septum was replaced with a teflon valve, the reaction was sealed and heated to 80 °C with stirring until starting material was consumed as judged by GC analysis. The reaction mixture was cooled to room temperature, diluted with ether (40 ml), filtered, and concentrated. The crude reaction mixture was then recrystallized from MeOH to furnish the desired product in 90% yield. 

The DPPF-catalyst system is also useful in the arylation of the benzophenone-based ammonia equivalent [109]. The coupling of 4-bromoanisole and benzophenone imine proceeded in excellent yield with only 0.5 mol% palladium, Eq. (128). 

Several groups have utilized benzophenone imine as an ammonia equivalent in the palladium-catalyzed cross coupling. For example, Mullen and co-workers prepared a new thermotropic dye via the BINAP/Pd-coupling of the corresponding bromide, Eq. (130) [110]. Similarly, Basu reported the amination of a mixture of bromopyrene derivatives [111]. 

Benzophenone imine may be used as an ammonia equivalent with halopyridines as well. The coupHng of the bromopyridine below, followed by deprotection via transamination with hydroxylamine, proceeded in 81% yield over the two steps, Eq. (158) [ 128]. Analogously, Puttman found that allylamine could also be used as an ammonia equivalent in the C-N coupling reactions of halopyridines [114]. 

An alternative way to prepare aminopyridazin-3(2//)-ones such as 266 was also described using benzophenone imine as an ammonia equivalent [100]. 

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]. 

Benzophenone imine was used extensively as an ammonia equivalent by various research groups [49,174], mostly with BINAP or dppf as ligands [2]. Diallylamine... 

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). 

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. 

Benzophenone Process. Benzophenone, (CgH5 )2C=0, reacts with ammonia to form diphenylmethanimine, (CgHg )2C=NH. In the presence of copper catalysts, this is oxidized with oxygen to benzophenone azine, (CgHg )2C=N—N=C(CgHg The formation of the imine and its... 

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. 

A polarogram of a ketimine was first obtained by Zuman [6], who showed that the imine was reduced when acetone was dissolved in ammonium - ammonia buffer solution. The limiting current here corresponded to the equilibrium concentration in the body of the solution. Zuman then proposed the use of the less volatile primary amines in place of ammonia. He also discovered the first limitations of the method — benzophenone and acetoacetic ester could not be determined in this way [7]. There thus was available a very simple and convenient method for determining carbonyl compounds, and its details are still being developed to this day [8-13]. The method can also be used to detect aliphatic amines [12, 14, 15]. 

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