Transmetalation Suzuki reaction

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. 

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... 

In 2007, negative-ion ESI-MS was used to detect the boron species responsible for transmetallation in the Suzuki reaction [PhB(OCH3)3] (Fig. 4D) [46]. Soon after, ESI-MS allowed the in situ observation of small catalytically active palladium clusters during a Suzuki reaction that could be precursors to catalytically active palladium nanoparticles. [(lL)sPd3(H20)], [(lL)3Pd3(H20)7] and the... 

The palladium-catalyzed coupling of boronic acids (as well as other boron derivatives) with aryl and vinyl halides and psendohalides is known as the Suzuki or Suzuki-Miyaura reaction. Because boron is nontoxic, this reaction has been used in pharmaceutical syntheses. In addition, hydroboration or borate substitution allows for the synthesis of virtually any desired coupling partner. For these reasons, as well as the high yields and functional group compatibility, the Suzuki reaction is the first reaction to consider for carrying out a cross coupling. Representative substrates and catalysts are shown in Scheme 17. The various bases are used to generate four-coordinate boron ate complexes that are more reactive in transmetalation. 

When the Stille reaction is carried out under a CO atmosphere, the carbonylative coupling proceeds in a manner similar to that described for the Suzuki reaction namely, carbonyl insertion into the Pd-C bond of the oxidative addition complex. Transmetalation, followed by ds-trans-isomerization and reductive elimination, generates the ketone product. " ... 

Electrospray MS studies provided circumstantial evidence for the commonly proposed catalytic cycle of the Suzuki reaction [48]. During the investigation of the reaction of 3-bromopyridine 136 with phenylboronic acids 137 to afford 138, molecular ion peaks were observed for species consistent with [(PyrHjPdfPPhjjjBr] or [(PyrjPdfPPhjjj]. Also consistently observed in the spectra was a peak that correlated with [(PyrH) (R, RjQH jPdfPPh,),]. Additionally observed, but at much lower levels, was [(R, RjC, ,) PdfPPh jj] that could have arisen from transmetalation with the catalyst directly. By definition, it is not possible to observe catalytic species so one must question the validity of these observations. 

The course of the Suzuki reaction can be redirected if the reaction is conducted under an atmosphere of carbon monoxide. In this modification of the reaction [82], the organo-paUadium intermediate is captured by carbon monoxide prior to the transmetalation step. The product from this is the carbonyl-inserted derivative. Application of this variation provided ready access to pyridyl ketones as exemplified in the conversion of 51 with 150 to 230. 

The presence of a small amount of water enhances the efficiency of these Suzuki reactions of alkyl bromides. Thus, if anhydrous K3PO4 rather than K3P04-H20 is used, the cross-coupling proceeds much more slowly. B NMR studies revealed that, in the presence of water, a hydroxy-bound boron ate complex is formed, which was suggested might be the species that participates in the transmetalation step of the catalytic cycle. 

Though both Suzuki and Stille reactions have been widely used to prepare conjugated polymers (including D-A copolymers), there are some subtle issues to consider when it comes to choose which reaction to use. For example, it is worth noting that the electron richness of stannyl aromatics decides whether these monomers are suitable for Stille-based polymerization or not. Mechanistically, relatively electron-rich thiophenes undergo the transmetalation step more readily than stannylbenzenes. Thus, stannylbenzenes experience low reactivity under Stille reaction conditions. Correspondingly, most thiophene-based aromatics are polymerized via Stille reactions, whereas a Suzuki reaction is a better option for benzene-based compounds. For example, fluorene and carbazole based polymers are usually prepared by Suzuki reaction, whereas polymers with cyclo-penta[2,l- ) 3,4-6 ]dithiophene, silolo[3,2- 4,5- ) ]dithiophene or benzo[l,2- 4,5-i Jdithiophene are often polymerized via Stille reaction. Due to its broader utilization over the Suzuki reaction in preparing D-A copolymers, Stille reaction-based polymerization will be the focus of this chapter, with a brief discussion on the Suzuki-based polymerization also included (Section 15.2.3). 

In 1994, Aliprantis and coworkers studied the catalytic intermediates in the Suzuki reaction by ESI-MS [1]. The currently accepted catalytic cycle involves oxidative addition, transmetalation, isomerization, and reductive elimination (Scheme 4.1). In order to form the protonated intermediates detectable by ESI-MS, pyridyl bromide and three phenylboronic acids were chosen for the reaction. Intermediate ions of [(pyrH)Pd(PPh3)2Br], diaryl Pd(II) species, and some other derivative palladium species were detected in the reaction mixture. 

Therefore, anionic bases, F, OH (when used as it or generated from COj " in the presence of water), do not play the role of bases but serve as ligands for aryl-Pd" complexes. In Suzuki reactions involving a fast oxidative addition (Arl and EAG-substituted ArBr), one needs to increase the rate of the rate-determining transmetallation. This requires (i) to select the best base OH >COj ",... 

Stille coupling of alkyl halides with alkenyl stannanes can be achieved using electron-rich alkyl phosphines ligands, combined with the addition of a fluoride source as a nucleophilic promoter (Scheme 2.69). ° This probably works by generating a stannate complex 2.201 that participates in transmetallation more readily than the original stannane, in a similar manner to the addition of Lewis bases to Suzuki reactions (Section 2.6). 

As in all C-C cross-coupling reactions, the Negishi reaction mechanism consists in three steps (Fig.4.1) oxidative addition, transmetalation, and reductive elimination. The former and the latter are common to all the other cross-coupling reactions, whereas the transmetalation step is particular of this reaction. Unfortunately, this transmetalation has been less studied compared to the ones in the Stille [12-17] or Suzuki reactions, [18-21] in spite of the fact that the transmetalation between organozinc and palladium complexes is also involved in other relevant processes, such as the hydroalkylation of styrenes, [22] the asymmetric allylation of aryl aldehydes, [23] the coupling propargylic benzoates and aldehydes, [24] or the double-transmetalation oxidative cross-coupling reaction [25, 26]. 

This reaction is far-reaching, because a wide variety of air- and thermally stable organoboron reagents are commercially available or easily synthesized, and it has indeed found extensive use in natural product synthesis. The Suzuki reaction allows the introduction of alkenes, alkynes and arenes in C-C coupling processes, the hydroboration of alkenes and alkynes being very well known. It is the addition of a base in the medium of the Suzuki reaction that leads to the transformation of a borane BR3 into a boronate BR3(OH) that is the active species for transmetallation towards Pd ... 

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