Buchwald—Hartwig amine arylation

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

Independently, Antane reported that arylisonipecotic acids were obtained from aryl bromides in a two-step process involving microwave-assisted palladium-catalyzed amination with ethyl isonipecotate followed by ester hydrolysis with KOH (Scheme 91) [96]. Interestingly, toluene, which is the standard solvent for Buchwald-Hartwig aminations under conventional heating, was used as the sole reaction medium, although it is a very weak... 

More challenging are the (hetero)aryl chlorides, since they are cheaper and more widely available than the corresponding bromides and iodides. Maes et al. published the first examples of microwave-assisted Buchwald-Hartwig aminations on (hetero)aryl chlorides in a commimication in 2003 [99]. The substrates 2- and 3-chloropyridine as well as 2-chloroquinoline were smoothly coupled with N-methylaniline and p-toluidine within only 10 min using a catalyst loading of only 1 mol% (Schemes 96 and 97). The diazine... 

The coupling between an aryl halide or triflate and an amine is known as the Buchwald-Hartwig amination [138]. Originally it was described using a tributyltin amine [139,140] and was thus considered to be a coupling reaction. Subsequently, tributyltin amine was replaced by a standard amine and a strong base. It is a reaction of great academic and industrial interest [11]. 

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]. 

Scheme 6.61 Buchwald-Hartwig amination reactions of aryl chlorides.

A more recent publication by Weigand and Pelka has disclosed a polymer-bound Buchwald-Hartwig amination [40], Activated, electron-deficient aryl halides were coupled with conventional PS Rink resin under microwave irradiation. Subsequent acidic cleavage afforded the desired aryl amines in moderate to good yields (Scheme 7.22). Commercially available Fmoc-protected Rink amide resin was suspended in 20% piperidine/N,N-dimethylformamide at room temperature for 30 min to achieve deprotection. After washing and drying, the resin was placed in a silylated microwave vessel and suspended in dimethoxyethane (DME)/tert-butanol... 

A synergistic combination of Pd-catalyzed amination and arylation was the central operation of Sakamoto s synthesis of carbolines [147]. Diarylamine 187 was first installed via the Buchwald-Hartwig amination protocol. Subsequent intramolecular Heck-like arylation of 187 provided a novel route to a-carboline 188. 

The double N-arylation of primary amines or ammonia equivalents 592 with 2,2 -biphenylylene ditriflate (591) under Buchwald-Hartwig N-arylation conditions gave the unsymmetrically multi-substituted carbazoles 593. Among the various... 

The dehydrohalogenation approach outlined in Scheme 1 reduces problems of selectivity in the synthesis of carbazoles. The method can be improved further by producing the N-aryl-2-haloaniline starting materials in the same pot as the subsequent carbazole product. This is achieved by Buchwald-Hartwig amination of 2-chloroanilines with aryl bromides [13], An illustrative example of this one-pot procedure is shown in Scheme 4. 

A fluorous imine reagent (3), also commercially available, was introduced by Herr as an ammonia equivalent in the Buchwald-Hartwig amination of aryl bromides, iodides, and triflates (Reaction Scheme 9)3 In this case, the problem of introducing a primary amine was solved by the use of (3) as a synthon for ammonia. 

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 Buchwald-Hartwig amination reaction has become a most efficient method for forming a new C-N bond, and it is mediated by a Pd catalyst. Onr group reported on the nse of 1 to catalyze amination reactions of aryl triflates with very good results (Table 14.5). ... 

Buchwald-Hartwig Amination Reactions with Aryl Triflates Using 1... 

The Buchwald-Hartwig amination is an exceedingly general method for generating any type of aromatic amine from an aryl halide or aryl sulfonates.1,2 The key feature of this methodology is the use of catalytic palladium modulated by various electron-rich ligands. Strong bases, such as sodium ferf-butoxide, are essential for catalyst turnover. 

Verkade s P,N-ligand L13 also catalyzes the Heck reaction of aryl iodides. It was thus shown that the Buchwald-Hartwig amination could be appended to a Heck reaction using Pd/L13.47 The operation is performed by first adding an aryl iodide to the catalyst solution and an aminostyrene 10 at 60 °C. This gives an intermediate N-aryl aminostyrene 11 to which 2 equiv of a second aryl iodide is added at 110 °C. This gives a second aryiation of the aminostyrene as well as the Heck arylation of the olefin (12). 

As stated previously, Q-phos shows perhaps the broadest scope for the Buchwald-Hartwig amination.45 Aryl chlorides are efficiently animated by all amine classes. The only coupling which gave poor yields was between ortho substituted aryl chlorides and acyclic secondary aliphatic amines. Typically, reaction temperatures of 70-100 °C are required and base sensitive aryl chlorides can be animated by replacing NaO/-Bu with K3PO4. 

Many other examples from the literature have used the Buchwald-Hartwig amination to rapidly access bioactive anilines. S. Morita formed aripiprazole 32 and its metabolite by distinguishing between an aryl chloride and bromide during the amination... 

---