Scheme 11. Buchwald-Hartwig Reaction

However, the Buchwald-Hartwig reaction with NHCs as hgands is not limited to palladium. Nickel has also been successfully employed in this catalytic amination. In situ procedures have been described for the coupling of aryl chlorides [163] and tosylates [164] and, more interestingly, anisoles [165]. The use of well-defined Ni(0) catalysts has also been studied [166] (Scheme 6.49). 

The Harmata group s initial report concerned a one-pot, one-operation procedure <99AG(E)2419> for the synthesis of enantiomerically pure 2,1-benzothiazines via the Buchwald-Hartwig reaction reported by Bolm <98TL5731 OOJOC169> for sulfoximine N-arylation. For example, treatment of ortho-bromobenzaldehyde 78 with enantiomerically pure N-H sulfoximine 77a in the presence of a palladium catalyst and base afforded the benzothiazine 79 in 78% yield (Scheme 22). Both C-N bond formation and condensation occurred during the reaction, a phenomenon that appears general for aldehydes like 78. 

The Harmata group also found that certain ort/w-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (7 )-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the p-carbon of the a,P-unsaturated ester, thus favoring cyclization. 

It was envisioned that the attachment of a functionalized aromatic group could be done via a Buchwald-Hartwig reaction (Scheme 11). This reaction was first studied using diphenethylamine with aryl triflates and halides as model compounds. Diphenethylamine was... 

Ar = 2,6-diisopropylphenyl Scheme 16 A palladacycle-mediated Buchwald-Hartwig reaction... 

An amine can be coupled with an aryl bromide, iodide or triflate in the presence of a palladium catalyst, a base, typically KOBu or CSCO3, and a ligand such as the bidentate phosphine BINAP. These reactions are known as Buchwald or Buchwald-Hartwig reactions (Scheme 10.24). A catalytic cycle is again involved, with the amine displacing X from Ar-Pd -X to form Ar-Pd -NHR2. Abstraction of a proton by the base produces Ar-Pd -NRj, which undergoes a reductive elimination. 

In 2012, T2ik2ihashi et al. [30] reported the catalytic enantioselective synthesis of atropisomeric 2-aryl-4-quinolinone derivatives using the Buchwald-Hartwig reaction with a (i )-MOP-Pd2(dba)3 catalyst. This reaction involved the 1,4-addition of aniline to an ynone, followed by an intramolecular Buchw2ild-Hartwig amination. An enantioselectivity as high as 72% ee could be achieved (Scheme 2.4). 

Scheme 2.4 Application of an asymmetric Buchwald-Hartwig reaction for atropisomeric 2-aryl-4-quinolinone synthesis by Takahashi ef al. [30].

Many other industrial applications at large scale are known. This subject has been comprehensively reviewed by Busacca et al. [37], and we will highlight one example here, the case of torcertrapib - which is a powerful cholesteryl ester transfer protein (CETP) inhibitor invented by Pfizer [38]. The key step in this synthesis - which can be scaled-up to multi-kilograms - is a Buchwald-Hartwig reaction involving very cheap l-chloro-4-trifluoromethylbenzene and a chiral amine in the presence of PdfOAcj and DavePhos (Scheme 2.8). Interestingly, PhB(OH)2 was added in order to activate the catalyst. 

Scheme 2.6 Application of a Buchwald-Hartwig reaction for the synthesis of the 5-HT,g receptor antagonist by Federsel and coworkers [35].

Scheme 2.10 Synthesis of olanzapine (Zyprexa) using a Buchwald-Hartwig reaction as the key step, under flow conditions using high-frequency inductive conditions, as reported by Kirschning and...

Scheme 11.13 Macrocycles from Buchwald-Hartwig reactions.

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... 

Indole systan 168 has been prepared from a ring closure reaction of dihydroisoqui-noline derivative 167 catalysed by a NHC-Pd system (Scheme 5.44) [49], The product 168 was prepared from an intramolecular Buchwald-Hartwig coupling and was used in the total synthesis of rac-mangochinine 169. 

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 6.58 Palladium-catalyzed amination reactions (Buchwald-Hartwig).

Scheme 6.61 Buchwald-Hartwig amination reactions of aryl chlorides.

This transformation avoids problems with the change of polarity during the reaction, which occurred in the telomerization, because two aromatic compounds react with each other to form a new aromatic product. The synthesis of 4-nitrodiphenylamine via a Pd-catalyzed Buchwald-Hartwig-type amina-tion from 4-chloronitrobenzene and aniline was chosen as the next test reaction in a cooperation with Lanxess as industrial partner of the network (Scheme 5). 

Scheme 4.29 Pd(O)-mediated Buchwald-Hartwig and Suzuki cross-coupling reactions.

The reaction of an orf/io-ester, e.g., HC(OEt)3, with a secondary bisamine in the presence of an anunonium salt yields imidazolidinium salts (Scheme The necessary secondary diamines can be generated by a classical condensation-reduction sequence or by applying the palladium-catalyzed Buchwald-Hartwig amination." The latter reaction offers convenient access to imidazolidinium salts with chiral backbones starting from chiral diamines, a number of which are commercially available. ... 

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