Aminations, of aryl chlorides

Independently, Caddick et al. reported microwave-assisted amination of aryl chlorides using a palladium-N-heterocyclic carbene complex as the catalyst (Scheme 99) [lOlj. Initial experiments in a domestic microwave oven (reflux conditions) revealed that the solvent is crucial for the reaction. The Pd source also proved very important, since Pd(OAc)2 at high power in DMF gave extensive catalyst decomposition and using it at medium and low power gave no reaction at all. Pd(dba)2/imidazohum salt (1 mol% catalyst loading) in DME with the addition of some DMF was found to be suitable. Oil bath experiments indicated that only thermal effects are governing the amination reactions. 

The first examples utilising A-heterocyclic carbenes as ligands in the Buchwald-Hartwig amination involved the in situ formation of the catalyst from the corresponding imidazolium salt and a Pd(0) source. Nolan reported IPr-HCl/PdjCdbalj as a catalytic system for the amination of aryl chlorides in excellent yields, using different types of amines, anilines, and also imines or indoles [142,143] (Scheme 6.46). Hartwig showed later that in some cases the reactions could be performed at room temperature and without anhydrous conditions even for aryl chlorides [ 144]. This was later shown for the less challenging bromides and iodides [145,146]. 

Activated aryl chlorides, which are close in reactivity to unactivated aryl bromides, underwent reaction with the original P(o-tol)3-ligated catalyst.58 Nickel complexes, which catalyze classic C—C bond-forming cross-couplings of aryl chlorides, 9-64 also catalyzed aminations of aryl chlorides under mild conditions.65,66 However, the nickel-catalyzed chemistry generally occurred with lower turnover numbers and with a narrower substrate scope than the most efficient palladium-catalyzed reactions. 

Di-tert,-butylphosphino)-biphenyl has been used by Buchwald [5] et al. as the most efficient ligand in the Pd-catalyzed amination of aryl chlorides. 2-Chloro-4-methyl-toluene can be aminated with pyrrolidine in 98% yield using sodium-tert.-butoxide [eq. (e)]. 

Lipshutz has reported nickel on carbon catalysts for the amination of aryl chlorides [173]. The reactions were conducted with added DPPF as the ligand. The scope of the process is similar to that seen with homogeneous nickel species. Secondary amines provide good yields with electron-poor or electron-rich aryl chlorides, and anilines are suitable for coupling with a range of aryl chlorides. 

Scheme 10. Two concurrent mechanisms for the amination of aryl chlorides catalyzed by P(tBu)3 complexes of palladium.

As was the case in the other coupling reactions, nonphosphine-based catalysts have also been applied in amination chemistry. In particular, N-heterocyclic carbenes such as (9) have provided successful results for a wide variety of amination transformations. Similarly, catalysts based upon phosphinous acid ligands (e g. (11)) have also found success in the amination of aryl chloride substrates. ... 

The amination of aryl chlorides was first accomplished utilizing the palladacycle catalyst (12). This initial success spurred a significant amount of research that has gone into the synthesis and study of various palladacycles in order to see if the activity of this type of catalyst could be improved further. Recently, systems that consist of a palladacycle plus an added ligand have proven to be some of the most active yet. The theory here is that these species act as precursors to the actual Pd-L catalysts in which, once again, the P Pd ratio is restricted to its optimal 1 1 value. ... 

Proazaphosphatrane ligands in combination with Pd2(dba)3 also generate highly active catalysts for Buchwald-Hartwig amination of aryl chlorides, e.g. (132) from (130) and (131). The PAP ligand with R = Bu was particularly effective and the catalyst performed extremely well with sterically hindered substrates. ... 

The dimeric palladium(I) complex [ PdBrL 2] (L = P(l-Ad)(Bu-t)2, P(Bu-t)3) catalyzed reactions of aryl chlorides under mild conditions. For example, the amination of aryl chlorides with cyclic or acyclic amines ran to completion at room temperature within 15 minutes10. 

FIGURE 7. Carbenes and complexes with carbene as ancillary ligands synthesized for amination of aryl chlorides... 

Catalysts based on bulky, electron-rich phosphine ligands have recently been developed that are effective for aminations of aryl chlorides, as well as aryl bromides and triflates.5f 9>j These catalysts also promote room temperature coupling reactions.5f i... 

Wolfe, J.P. Tomori, J. Sadighi, J.P. Yin, J. Buchwald, S.L. Simple, efficient catalyst system for the palladium-catalyzed amination of aryl chlorides, bromides, and triflates. J. Org. Chem. 2000, 65, 1158. 

The P.O-ligand developed by A. S. Guram (L9) is a versatile ligand for the amination of aryl chlorides as most classes of amines work well.43 Primary amines have a more limited scope and tend to couple best with electron neutral to rich aryl chlorides, especially those with ortho substitution. 

M. Beller reports an improved phosphine ligand for aryl chloride amination based on //-phenyl indoles, L16 or L17. This class of ligands allows for the catalytic amination of aryl chlorides with primary aliphatic amines and anilines. Secondary cyclic amines also couple, but secondary acyclic amines were not reported. 

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