Arylation ammonia surrogates

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]. 

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. 

An intermolecular version of the arylation of carbamates has been recently published by Hartwig et al. (Eq. (21)) [132]. His group showed that reactions catalyzed by a combination of Pd(OAc)2 and P( -Bu)3 formed /V-aryl carbamates from aryl bromides or chlorides and f-butylcarbamate as substrate. Again, the reaction conditions were not as mild as those for amination, but were similar to those of the intramolecular reactions. For the intermolecular reactions, the use of sodium phenox-ide as base was crucial. Reactions using Cs2C03 showed low conversions. Those involving NaO-r-Bu as base rapidly formed a gel, presumably from the deproto-nated carbamate, and also showed little or no conversion. The products of these reactions serve as conveniently protected anilines, and r-butylcarbamate can be considered one type of ammonia surrogate. In addition, the products of these reactions are suitable for subsequent directed metalation procedures [100]. 

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]. 

Recently, Fu and coworkers reported an alternative method for assembly of primary aryl amines [17]. In their reaction amidine hydrochlorides were used as the ammonia surrogates (Scheme 9.3). The ligand was also L-proUne (LI) and heating (110°C) was required for good yields. 

So far no arylation of ammonia has been reported, and it is difficult to prepare aniline derivatives directly by the Pd-catalyzed reaction of aryl halides with ammonia. Aniline derivatives are prepared indirectly by the reaction of ammonia surrogates (ammonia equivalents). The reaction of the ammonia surrogates with aryl halides, followed by deprotection affords aniline derivatives. As one of them, LiN(TMS)2 (61) reacts with aryl bromides and chlorides. P(t-Bu)3 is the best ligand, and the coupled products are converted easily to anilines by treatment with aq. HCl. 

Synthesis of 62 from 60 is an example [51], Use of LiN(TMS)2 as the ammonia surrogate is problematic for aryl bromides containing an amide group, but the reaction of p-bromoacetanilide (63) proceeds smoothly using 2.2 equivalents of 61 [29],... 

No smooth reaction of LiN(TMS)2 was observed with sterically congested ortho-substituted aryl halides. In such a case, Ph3SiNH2 can be used as an ammonia surrogate and the coupled product 64 was converted to 65 [52]. 

The passionate search for ammonia surrogates also suggested the use of metal amides as nucleophiles. Hartwig [69] reported LiHMDS as an ammonia equivalent for the coupling ofmeta- or para-substituted aryl halides (Br and Cl). Here, P(tBu)j (26) proved to be an effective ligand facilitating the coupling at room temperature (Scheme 13.15). 

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. 

Ureas and sulfonamides have occasionally been employed as ammonia surrogates. For example, 2-(trimethylsilyl)ethanesulfonyl amide (SES-NH2) can be arylated with electron-poor or electron-neutral aiyl haUdes in the presence of CS2CO3 and a catalyst composed of Pd(OAc)2/Xantphos (Elq. 37) [227], The SES group can subsequently be cleaved with CsF, which allows other sensitive functitmal groups to remain intact. Beletskaya has reported use of urea as an NH3 equivalent in the generation of symmetrical di- and triarylamines [228, 229], The authors found that para- and /Meta-substituted aiyl halides afforded triaiylated products, whereas diarylated anilines were generated when ortho substituted aryl halides were employed (Eq. 38). These results are similar to those reported by Buchwald for iV-aiylation reactions of lithium amide [230],... 

Using amidine hydrochloride as the ammonia surrogates, the Fu group developed an efficient entry to 1//-benzimidazoles 50. In their reaction, Cu-catalyzed coupling of o-haloacetanilides with amidine hydrochlorides 58 proceeded at 60-90°C to afford arylation products 59, which underwent hydrolysis and isomerization upon further heating to provide intermediates 60. Intramolecular condensation of 60 produced benzimidazoles 50 (Scheme 21) [51]. 

The utilization of in sim generated aryl azides is not restrictive to [3+2] Huisgen condensation-type reactions. These compounds could also play the role of ammonia surrogate for the synthesis of aniline derivatives. Thus in 2004 Fu, Qiao and co-workers described conditimis involving Cul with or without DMEDA L26... 

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