Suzuki transmetallation

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

Since the C—B bond is almost completely covalent, transmetalation of an organoboron reagent to transfer the organic group will not occur without coordination of a negatively charged base or a F to the boron atom. As a consequence, the Suzuki reaction normally needs to be carried out in a basic solution, which poses some limitations to base-sensitive substrates. 

Li and Yue observed an ethyl transmetalation during the Suzuki coupling of diethyl (3-pyridyl)borane and 3-bromoquinoxaline 44 [35]. In the presence of a strong base (NaOH), the Suzuki reaction of diethyl (3-pyridyl)borane with 3-bromo-6,7-dichloroquinoxalin-2-ylamine (44) proceeded to give 52% of the 3-pyridylquinoxaline 45 accompanied by 21% of 3-ethylquinoxaline 46. 

Some of the reactions (e.g., that of dimethylaluminum chloride in Table 2) involve redistribution of alkyl and halide groups between the metals. The boronic acids, ArB(OH>2, prepared by Sn/B transmetallation, have been used in Suzuki coupling reactions. It is remarkable that the bistributyltin derivative of 1,1 -binaphthyl undergoes... 

The palladium catalyzed cross-coupling of organosilicon compounds and aryl halides found only limited application with azines compared to the Suzuki or Negishi coupling. In a recent paper DeShong reported the efficient coupling of bromopyridine derivatives with aryl siloxanes (7.44.) 62 The transmetalating ability of the siloxane was enhanced by the addition of tetrabutylammonium fluoride. 

Stille coupling was also developed in tlie early 1980s and is similar to Suzuki coupling in its sequence. It is used to couple aryl or vinyl halides or triflates with organotin compounds via oxidative addition, transmetallation, and reductive elimination. The oxidative addition reaction has tlie same requirements and preferences as discussed earlier for tlie Heck and Suzuki reactions. The reductive elimination results in formation of tlie new carbon-carbon bond. The main difference is that tlie transmetallation reaction uses an organotin compound and occurs readily without the need for an oxygen base. Aryl, alkenyl, and alkyl stannanes are readily available. Usually only one of tlie groups on tin enters into... 

Early findings by Suzuki and co-workers [109] showed that the palladium-catalyzed iminocarbonylative cross-coupling reaction between 9-alkyl-9-BBN derivatives, t-butylisocyanide, and arylhalides gives access to alkyl aryl ketones 132 after hydrolysis of the corresponding ketimine intermediates 131. Presumably, the concentration of free isocyanide is kept to a minimum by its coordination with the borane. Formation of an iminoacylpalladium(II) halide 130 by insertion of isocyanide to the newly formed arylpalladium complex followed by a transmetallation step afford the ketimine intermediates 131 (Scheme 8.52). 

One difference between the Suzuki mechanism and that of the Stille Coupling is that the boronic acid must be activated, for example with base. This activation of the boron atom enhances the polarisation of the organic ligand, and facilitates transmetallation. If starting materials are substituted with base labile groups (for example esters), powdered KF effects this activation while leaving base labile groups unaffected. 

Arylboronic acids are readily available via transmetalation between ArSnMe3 and borane in THF. Consequently, a variety of arylpolyboronic acids is achievable from the stannanes previously synthesized by the SRN1 mechanism from ArCl or ArOH in around 80% yields [50, 51]. These arene di- and tri-boronic acids can be used as starting materials for the synthesis of polycyclic aromatic systems via double or triple Suzuki crosscoupling reactions [50, 51], as shown in Scheme 10.34 [51],... 

Bedford and coworkers disclosed iron-catalyzed Suzuki-Miyaura-type coupling reactions of benzyl bromides with sodium tetraphenylborate in the presence of 5 mol% 15 as the catalyst and 10 mol% of dianisylzinc as a promoter. No reaction occurred in its absence. The coupling furnished 38-88% yield of 3 (entry 26) [66]. The transformation proceeds probably by initial B-Zn transmetalation. The resulting arylzinc transfers the aryl group to the iron catalyst as in the Negishi couplings above. An aryliron(I) complex was proposed to be formed initially. 

Iron-catalyzed Suzuki-Miyaura coupling reactions were also reported by Nakamura and colleagues (entry 27) [67]. Alkyl halides 1 and mixed pinacol aryl(butyl)borates, generated in situ from arylboronates and butyllithium, were used as the reagents and 10 mol% of the iron complexes 16a or 16b as the catalysts. The addition of 20 mol% of MgBr2 was essential for the success of the reaction. Products 3 were isolated in 65-99% yield. The methodology tolerates ester and nitrile functions. The reaction starts probably by initial boron-iron transmetalation to generate a diaryliron(II) complex. 

The mechanism is very similar to that of the Stille coupling. Oxidative addition of the vinylic or aromatic halide to the palladium(O) complex generates a palladium(II) intermediate. This then undergoes a transmetallation with the alkenyl boronate, from which the product is expelled by reductive elimination, regenerating the palladium(O) catalyst. The important difference is the transmetallation step, which explains the need for an additional base, usually sodium or potassium ethoxide or hydroxide, in the Suzuki coupling. The base accelerates the transmetallation step leading to the borate directly presumably via a more nucleophilic ate complex,... 

However, studies on the scope of this sequence revealed that the substrate has to be an N-tosyl sulfonamide and that certain boronic acids are not trans-metallated but rather give rise to the formation of the pyrrole 21 or a pyridine derivative 22 (Scheme 7). The peculiar outcome as a carbopalladation-Suzuki sequence is rationalized by co or dinative stabilization of the insertion intermediate 18 by the sulfonyl oxygen atom, as represented in structure 19, now suppressing the usual /3-hydride elimination. If the transmetallation is rapid the Suzuki pathway is entered leading to product 17. However, if the transmetallation is slow, as for furyl or ferrocenyl boronic acid, either /i-hydride elimination or a subsequent cyclic carbopalladation occurs. The former leads to the formation of the diene 20 that is isomerized to the pyrrole 21. The latter furnishes the cyclopropylmethyl Pd species 23, which rearranges with concomitant ring expansion to furnish piperidyl-Pd intermediate 24 that suffers a -hydride elimination to give the methylene tetrahydro pyridine 22. 

Based upon this principle, aryl Pd species like 34 can also terminate in a transmetallation with boronic acids (i.e., in a Suzuki coupling) where the biphenyl 35 was obtained in 90% yield (Scheme 11) and the terphenyl derivative 36 was isolated in 93% yield (Scheme 12) [69]. 

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