Reactions Buchwald-Hartwig

In spite of their relatively young age palladium and nickel catalyzed carbon-heteroatom bond forming reactions, also known as the Buchwald-Hartwig reaction, have gained significant importance amongst synthetic 

The opening step of the Buchwald-Hartwig reaction, similarly to the previous cases, is the oxidative addition of an aryl halide or sulfonate onto a low oxidation state metal. Although the term Buchwald-Hartwig reaction is usually reserved for palladium catalyzed processes, carbon-heteroatom bond formation also proceeds readily with nickel and copper. The nickel catalyzed processes follow a similar mechanism, while the distinctly different copper catalyzed reactions will be discussed in Chapter 2.5. 

The final step of the process is the detachment of the product from the metal in reductive elimination. Unlike in most cross-coupling reactions, this step was the limiting factor in the early reports on the Buchwald-Hartwig reaction. The use of sterically demanding mono and bidentate ligands, however helped to overcome this difficulty by facilitating the closing step. 

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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 has also developed a route to enantiomerically pure 2,1-benzothiazines. The process involves the /V-arylation of sulfoximines using the Buchwald-Hartwig reaction conditions, <02MI3 99JOM(576)125> a reaction first reported by Bolm... 

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. 

Needless to say, the Buchwald-Hartwig reaction can also be usefully employed in ways other than the efficient preparation of diphenylamines. Given the respective substitution, it should be possible to bring about the phenazine skeleton by Pd-catalyzed ring formation as well. There are two ways to proceed either the substituent pattern required by the intramolecular Buchwald-Hartwig reaction is elaborated after the formation of the diphenylamine (121 124), or the starting material already contains the substituents necessary for the two JV-arylations. A reasonable starting point is the intermolecular JV-arylation of an o-haloaniline... 

Pyrazolo[3,4-c]pyridines can also be synthesized through an intramolecular Buchwald-Hartwig reaction in excellent yield (Equation 58) <2005JOC596>. 

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... 

The Buchwald-Hartwig reaction was performed under a variety of conditions starting with the model compounds and leading up to target substrate. The results are shown in Table 3. There was a 70 % yield obtained in the reaction of triflate 35 with the cyclic secondary amine morpholine using condition A (entry l),32 however the reaction fails with diphenethylamine (entry 2). Changing the base to sodium tert-butoxide (condition B) or the catalyst to Pd2(dba)3 and ligand (condition C) also resulted in no reaction (entries 3 and 4). 

Table 3. Conditions Applied to the Buchwald-Hartwig Reaction.

The side arms were introduced via a Buchwald-Hartwig reaction. While the yield of the reaction was low and the reaction was not reproducible, this was the first example of a Buchwald-Hartwig reaction on a macrocyclic system of this kind. In addition, this was the first example of a Buchwald-Hartwig reaction to di-arylate a diamine system. 

The synthesis of cyclophane 17 (9,10,ll,12,26,27,28,29-octahydro-3H,8H,16H,20H,25H, 33H-4,7 21,24- dimetheno -13,19,15 30,2,32-di[ 1 ]propane[ 1 ]yl[3Jylidine- 1H, 18H-dipyrimidino [l,2-a l ,6 -o] [l,8,15,22]tetraazacyclo-octacosine) is described. Both isomers of cyclophane 17 were synthesized over nine steps in 46 % overall yield from readily available starting materials. We designed and synthesized a side group for attachment to cyclophane 17, which we wish to use for the directed-complexation of the cyclophane with a specified aromatic guest. We had hoped to use the Buchwald-Hartwig reaction to attach this side arm to the secondary amines of 17, but despite our many efforts we were unable to achieve this goal in a reproducible manner. 

N-Aryl amination, or the Buchwald-Hartwig reaction, has proven to be a useful and versatile method to obtain aryl amines, which are of great synthetical and industrial interest [145]. The first examples of carbene/palladium-catalyzed amination of aryl halides showed that in situ-generated catalyst could efficiently mediate the coupling of aryl halides with primary and secondary amines, imines and indoles [ 146-148]. Even if most of these reactions could be carried out at room temperature with aryl iodides and bromides, elevated temperatures were required in order to couple aryl chlorides. 

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

Catalytic Cross Couplings of Aryl Halides to Nitrogen and Oxygen Nucleophiles, the Buchwald-Hartwig Reaction... 

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