Buchwald reactions

As a natural development of the intense activity in CH activation see Alkane Carbon-Hydrogen Bond Activatiori since the 1970s, interest has arisen more recently in the closely allied area of CC activation. This process is much more difficult than CH activation and has so far been studied for its mechanistic interest rather than for any practical benefit. CX activation, on the other hand, is a major area of study because it is an initial step in many important and commercially valuable homogeneous catalytic reactions, such as Mizoroki-Heck, Suzuki-Miyaura, and Hartwig-Buchwald reactions. Here, an important practical goal is to avoid having to use the expensive iodides and bromides as ArX reagents in catalytic reactions and to work instead with chlorides and tosylates. 

C-N Bond-Forming Reactions the Hartwig-Buchwald Reaction.260... 

Scheme 3.1 Components and reactions used to prepare nitrogen-linked nanoporous networks of aromatic rings and representative structures thereof (top) Ullman reaction catiyzed by insoluble CuBr, (middle) Ullman reaction catalyzed by soluble Cu(PPh3)3Br and (bottom) Buchwald reaction catalyzed by soluble Pd(dba)2-...

Although comparable with the Heck reaction in terms of the catalytic cocktail, the recently developed conversions of aryl bromides to arylamines (the Hartwig-Buchwald reactions) proceed by a different mechanism (Chapter 13). 

D.v.a. Formation of C—N Bonds. Though Pd-catalyzed amination— the Hartwig-Buchwald reaction—is normally performed in anhydrous media in the presence of strong bases, no steps of the mechanism of this reaction strictly require the absence of water. Moreover, it has been shown that amido complexes of Pd, the key intermediates of this reaction, can easily form by ligand exchange of water or hydroxyl (Scheme 56). ... 

Besides the Hartwig-Buchwald reaction, amination can be achieved by a Pd-catalyzed variant of the Ullmann reaction in the presence of copper salts. Though the scope of this reaction is much narrower, it does not require expensive phosphine ligands and thus is more economical. The arylation of diphenylamine with water-insoluble aryl iodides can be achieved in aqueous microemulsions in the presence of phosphine-free palladium catalyst and copper(I) iodide (Scheme 58). 

The fluorenylidene linker concept was also applied to the synthesis of triarylamine segmented polymers via a Hartwig Buchwald reaction [132] (Scheme 48). 

The Heck cyclization proceeds via methylene indolenines (83) (isolable in the presence of Ag salts) and migration of their exocyclic double bond to the internal enamine position under the reaction conditions. A variety of 3-methylindoles (84) is accessible directly from 2-bromoiodobenzenes by a Pd-catalyzed aryl amination (Hartwig-Buchwald reaction)/Heck cyclization cascade [172]. 

Finally, it is worth highlighting that it is not always necessary to turn to a Pd-catalyzed reaction for a given synthetic target. For example, a critical comparison of a Pd-catalysed cross-coupling approach (Hartwig-Buchwald reaction) with a classical SnAt reaction for the amination of certain heteroaromatic chlorides revealed that the latter approach was highly attractive. ... 

Palladium-catalyzed cross coupling of resin bound iodopyridine with a boronic acid (Suzuki reaction) (12) or with an alkenyl-, alkynyl-, or arylstannane (Stille reaction) (13) was effected by treatment of resin 5 with 4 equivalents of the boronic acid or stannane, 8 equivalents of K2CO3 (Suzuki reaction only), and catalytic Pd(PPh3)4 in DMF at 50 C for 20 hours. (14) Best results were achieved by running each reaction twice, with an intermediate wash of the resin, in order to drive the reaction to conq>letion. The corresponding Pd-catalyzed amination (Buchwald reaction) (15) worked well in protocol development but the reaction failed with the 3 amines attenpted during actual library preparation. 

A one-pot synthesis of acridine 110 from 108 and 109 was developed employing a Buchwald reaction as the key step without purification of intermediates (Scheme 38). The sequence involved an ester hydrolysis that also avoids aqueous workup (eight examples) (2004SL2391). Barium hydroxide, which is soluble in methanol, is used in this procedure. 

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