The Suzuki Coupling

23) provides convenient access to ( vinylboranes [see ( 88] by a syn addition of the B-H bond to the alkyne. Stereoisomeric (Z)-vinylboranes [see (Z 91], on the other hand, can be smoothly prepared by a two-step sequence that commences with the hydroboration of a 1-halo-1-alkyne (see 89— 90). The desired (Z)-vinyl-borane (Z)-91 can then be formed upon exposure of the halo-genated hydroboration product 90 to the action of f-butyllithium. 

24) is especially interesting because it provides an efficient and elegant path for the synthesis of the indole nucleus. Exposure of the Suzuki coupling product 102 to the action of a mild acid induces 

A stereospecific Suzuki coupling is also the key step in the synthesis of trisporol B benzyl ether (111) by Suzuki et al. (see 

The late Professor J. K. Stille pioneered the development of a very effective and versatile palladium-mediated C-C bond forming method - the palladium-catalyzed cross-coupling of organic electrophiles with organostannanes.48 This process continues to enjoy much success in organic synthesis because it proceeds in high yields under mild reaction conditions and because it tolerates a 

Our general survey of palladium in organic synthesis must now come to an end. At the very least, we hope that our brief foray into this fascinating area conveys some of the vitality that characterizes research in this area. The remainder of this chapter will address the first total synthesis of rapamycin by the Nicolaou group. This work is predicated on a novel variant of the Stille reaction. 

Since first being reported in 1979, the Suzuki coupling has come to represent an important class of cross-coupling reactions, totalhng 25% of all palladiiun-catalysed cross-coupling reactions in 1992. The original report showed the reaction of an alkyl acetylene with catecholborane 18, followed by coupling with an aromatic iodide or bromide. 

The mechanism is very similar to that of the Stille coupling. Oxidative addition of the vinylic or aromatic halide to the palladium(0) complex generates a palladium(II) intermediate. This then imdergoes a transmetalatinn with the alkenylboronate, from which the product is expelled by reductive elimination, regenerating the palladium(O) catalyst. 

The importance of the reaction stems from the ability to preserve alkene geometry in both starting materials. A good example of this forms the basis for Protocol 4. Thus, the ( )-alkenylboronate 19 synthesised from 1-octyne couples with the (Z)-alkenylbromide 20, leading to (E) and (Z) double bonds in the product. 

Sterically demanding substrates such as 21 are tolerated well, and the methodology has been used in a wide range of aryl-aryl cross-couplings. 

Similarly, the reaction of substrates under normal coupling conditions, but in the presence of an atmosphere of CO, gives excellent yields of the ketones directly, without the need for hydrolysis of an intermediate species.  

Recently, iodobenzoates anchored onto an ionic liquid support (6.4) were coupled to various aryl boronic acids (6.5) in aqueous media using Pd(OAc)2 as the catalyst at 80°C to give the coupled product 

Sterically demanding, water-soluble alkylphosphines 6.10 and 6.11 as ligands have been found to have a high activity for the Suzuki coupling of aryl bromides in aqueous solvents (Eq. 6.35). Turnover numbers up to 734,000 mmol/mmol Pd have been achieved under such conditions. Glucosamine-based phosphines were found to be efficient ligands for Suzuki cross-couphng reactions in water.  

Recently, Suzuki-type reactions in air and water have also been studied, first by Li and co-workers. They found that the Suzuki reaction proceeded smoothly in water under an atmosphere of air with either Pd(OAc)2 or Pd/C as catalyst (Eq. 6.36). Interestingly, the presence of phosphine ligands prevented the reaction. Subsequently, Suzuki-type reactions in air and water have been investigated under a variety of systems. These include the use of oxime-derived palladacycles and tuned catalysts (TunaCat). A preformed oxime-carbapalladacycle complex covalently anchored onto mercaptopropyl-modified silica is highly active ( 99%) for the Suzuki reaction of p-chloroacetophenone and phenylboronic acid in water no leaching occurs and the same catalyst sample can be reused eight times without decreased activity.  

By utilizing a solid support-based tetradentate A/ -heterocyclic carbene-palladium catalyst, cross couplings of aryl bromides with phenylboronic acid were achieved in neat water under air. A high ratio of substrate to catalyst was also realized. 

In SPOC, either the aryl or vinyl halide or the boronate can be bound to the polymeric support. In most cases however, the aryl halide is bound to the polymer. A wide range of coupling conditions were developed within recent years, which are compatible with many polymeric supports (polystyrene, polyacrylamide, PEG, etc.) and are tolerated by many functional groups. 

The reaction usually requires palladium catalysis. In the case of aromatic tosylates [23] or arylchlorides, Ni-catalysts [20, 21] or Pd-imidazole-2-ylidene complexes had to be employed ]33]. The latter catalyst is generated in situ from 1,3-bisaryl or 1,3-bisalkyl imidazolidinium chloride ]34, 35] and a base, such as CS2CO3 or KOtBu ]36]. 

Benzylic boronic esters [52]can be obtained from bromomethyl boronic esters and aryl or vinyl stannanes [53]. Alkyl and vinyl boronic esters are accessible through hydroboration of alkynes with dialkylboranes followed by oxidation with acetaldehyde [43]. Alternatively, vinylboronates can be obtained directly from alkynes in a reaction -with catecholborane without a subsequent oxidation step [53]. Further diversification in the boronic acid derivatization is achieved by binding the boronic acids bearing another derivatizable functional group (for instance an amine) to suitable polymeric supports. The modified boronic acid may then be 

Purbaix et al. employed a similar hnkage system without a nitrogen atom to bind the boronic acids [55, 56, 58]. 

Yang et al. used catechol to immobihze borane and boronic acids [58], since support-bound boronic catachol ester hnkage is stable enough to perform amidation reactions. Custom-derivatized boronic acids could be obtained, which could be hberated from the support with THF/H2O/ACOH 90 5 5 (v/v/v). Hebei et al. reported Suzuki-mediated release of biaryls from polyglycerol esters of various boronic acids and aryl bromides [59]. 

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The Suzuki coupling of arylboronic acids and aryl halides has proven to be a useful method for preparing C-aryl indoles. The indole can be used either as the halide component or as the boronic acid. 6-Bromo and 7-bromoindolc were coupled with arylboronic acids using Pd(PPh3)4[5]. No protection of the indole NH was necessary. 4-Thallated indoles couple with aryl and vinyl boronic acides in the presence of Pd(OAc)j[6]. Stille coupling between an aryl stannane and a haloindole is another option (Entry 5, Table 14.3). 

Of particular synthetic importance is the coupling of aryl- and hetarylboronic acids to aryl- and hetaryl halides (or triflates), allowing for a convenient synthesis of biphenyls, even sterically demanding derivatives such as 14, hetaryl phenyls and Zj/ -hetaryls. With appropriately disubstituted aromatic substrates, the Suzuki coupling reaction can be applied in the synthesis of polyphenylene materials. 

The postulated steps that constitute the Suzuki coupling process are shown in Scheme 25. After oxidative addition of the organic halide to the palladium(o) catalyst, it is presumed that a metathetical displacement of the halide substituent in the palladium(ii) complex A by ethoxide ion (or hydroxide ion) takes place to give an alkoxo-palladium(ff) complex B. The latter complex then reacts with the alkenylborane, generating the diorganopalladium complex C. Finally, reductive elimination of C furnishes the cross-coupling product (D) and regenerates the palladium(o) catalyst. 

Using Kishi s modification of the Suzuki coupling procedure,45 Nicolaou et al. accomplished the convergent union of compounds 112 and 113 (see Scheme 28).38b 46 This coupling is the key step in a synthesis of (55,6/ )-dihydroxyeicosatetraenoic acid [(55,6/ )-diHETE] methyl ester (115). Importantly, the configurations of the two coupling partners are reflected in the Suzuki coupling product 114. 

At about die same time, die application of the Suzuki coupling, the crosscoupling of boronic acids widi aryl-alkenyl halides in die presence of a base and a catalytic amount of palladium catalyst (Scheme 9.12),16 for step-growth polymerization also appeared. Schliiter et al. reported die synthesis of soluble poly(para-phenylene)s by using the Suzuki coupling condition in 1989 (Scheme 9.13).17 Because aryl-alkenyl boronic acids are readily available and moisture stable, the Suzuki coupling became one of die most commonly used mediods for die synthesis of a variety of polymers.18... 

In a micro reactor, there is much more surface available than in standard reactors [18]. Thus, surface-chemistry routes may dominate bulk-chemistry routes. In this context, it was found sometimes micro-reactor routes can omit the addition of costly homogeneous catalysts, since the surface now undertakes the action of the catalyst. This was demonstrated both at the examples of the Suzuki coupling and the esterification of pyrenyl-alkyl acids. 

As it was shown before that conversions and selectivities can be increased, usually not at the expense of each other, it stand to reason that micro reactors provide high yields. For example, the Suzuki coupling of 4-bromobenzonitrile and phenylboronic acid gives a yield of 62% for micro-flow processing which is about six times higher than with batch processing (10%) at comparable process conditions [155]. 

Scheme 6.24 Selected pre-catalysts used for the Suzuki coupling between aryl bromides and iodides with boronic acids...

Scheme 6.25 Nolan conditions for the Suzuki coupling between aryl chlorides and boronic adds...

Palladium complexes of inexpensive, easily synthesized bis(phosphinite) PCP -pincer ligands show good activity in the Suzuki coupling of deactivated and sterically hindered aryl bromides.256... 

The biaiyl phenol (X) was the penultimate intermediate in the synthesis of this final drag substance. Thus after the Suzuki coupling reaction is performed to give the phenol, the levels of Pd have to be lowered to < 10 ppm. In the pharma industry this can be a significant problem. Additionally there is always batch to batch variability observed when catalysts like Pd2(dba)3 have been used in Suzuki couphng reactions. 

Polymer 163 (and similar alternating copolymers of 9,9-dioctylfluorene and oxadiazole <2002MM3474>) with blue-light-emitting activity were synthesized by the Suzuki coupling reaction and studied by GPC, MALDI-TOF MS, LJV spectroscopy, and several other techniques <2002ANC6252>. 

Bedford RB, Cazin CSJ, Hazelwood SL (2002a) Simple mixed tricyclohexyl-phosphane-triarylphosphite complexes as extremely high-activity catalysts for the Suzuki coupling of aryl chlorides. Angew Chem Int Ed 41 4120-4122... 

In addition, with respect to the Suzuki coupling, various alkylboron reagents have also been successfully coupled with electrophile partners. 

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