Trifluoroborate Suzuki coupling

The Suzuki Coupling, which is the palladium-catalysed cross coupling between organoboronic acid and halides. Recent catalyst and methods developments have broadened the possible applications enormously, so that the scope of the reaction partners is not restricted to aryls, but includes alkyls, alkenyls and alkynyls. Potassium trifluoroborates and organoboranes or boronate esters may be used in place of boronic acids. Some pseudohalides (for example triflates) may also be used as coupling partners. 

Molander has published a series of papers demonstrating the utility of potassium alkyl, alkenyl-, alkynyl-, and aryltrifluoroborates in palladium coupling reactions. The crystallinity and air-stability of these trifluoroborate salts make the use of these an interesting alternative to the use of boronic acids or esters. Good yields have been obtained in several related palladium coupling processes, which are most easily classified as Suzuki couplings. The broad applicability of this process is demonstrated by the production of 58 [40], 59 [41], and 60 [42]. 

Instead of aryl halides, arenediazonium salts are also excellent arylating agents in the Suzuki coupling, although more hindered arylboronic acids did not react The reaction is catalysed by several sources of ligand-free palladium such as Pd(OAc)2, Pd2(dba)3 and Pd/C at room temperature in dioxane without any added base [98]. Use of potassium aryl trifluoroborate salts also allowed the introduction of more sterically hindered aryl groups [99]. 

PCy3 also proved to be the ligand of choice for a wide-ranging study of Suzuki couplings of heteroaryl chlorides and heteroarylboronic acids (Equation 2.18) where aryl boronate esters and aryl trifluoroborates could also be employed [33]. 

Another solution is to employ trifluoroborate salts 2.215, which can be prepared from the boronic acid by treatment with potassium hydrogen fluoride (Scheme 2.74). They can also be prepared from alkyl bo-ranes in a similar way (Scheme 2.75). These stable salts can be efficiently employed in Suzuki coupling reactions (Scheme 2.T6)P One application is in the synthesis of the unusual amino acid, trityrosine 2J26 (Scheme 2.77). In this synthesis an aryl diiodide 2.222 was coupled with a trifluoroborate salt 2.224 that had been formed by Miyaura borylation of iodide 2.223 followed by KHF2 treatment. Global debenzylation of coupling product 2.225 gave the product 2.226. Another example of the use of a trifluoroborate salt can be found in Scheme 2.88. 

The installation of a vinyl group by Suzuki coupling presents a particular problem because vinyl boronic acid is unstable, readily undergoing polymerization. In a smdy of vinylation in order to make a polymer precursor, the vinyl trifluoroborate salt was found to be effective, giving the cleanest product 2.228 on a 72 g scale (Scheme 2.78). ... 

The utility of potassium organotrifluroborate salts in natural product synthesis was demonstrated by Molander through a formal total synthesis of the macrolide oximidine II. Alkyne 68 was selectively hydroborated with di(isopropylprenyl)borane and then converted to the potassium trifluoroborate salt 69. Formation of the macrocyclic ring was achieved through intramolecular Suzuki coupling of 69, which generated 70 in a 42% yield. Intermediate 70 was transformed to 71 in two steps to complete the formal synthesis. 

Savall et al. [23] reported a simple and efficient method for the direct synthesis of unprotected 2-aryl benzimidazoles (xiv) using microwave-mediated Suzuki-Miya-ura cross coupling of readily available trifluoroborates and 2-chlorobenzimidazoles. 

Molander has effected a Suzuki reaction between 7-bromoindole and potassium trifluoroborates (e.g. 155) to give the corresponding coupled product 156 [163]. 

The use of trifluoroborate salts in couplings, which are very easily prepared from boronic acids by reaction with KHF2, is a useful variant of the Suzuki reaction. These salts have the advantage of enhanced (often considerably) stabihty compared to boronic acids and this is particularly notable for alkenyl compounds, which can be stored for a considerable time. The coupling conditions are very similar to those for boronates and are apphcable to a wide range of heterocyclic substrates, ... 

Scheme 2.25 Suzuki-Miyaura cross-coupling reactions of heteroaromatic trifluoroborates.

Utilized Pd(OAc)2 and SPhos 24 as the catalyst system to effectively catalyze Suzuki-Miyaura cross-couplings with only 1.1 equiv. of trifluoroborates [84e]. More recently, Molander and coworkers have developed a general cross-coupling system to many classes of heteroaromatic trifluoroborates employing Pd(OAc)2 and RuPhos 23 [84j]. Furan 135, thiophene 132, pyrrole 126, pyrazole 130, isoxazole 131, pyridine 127, pyrimidine 133, indole 129, benzothiophene 136, benzofuran 135, quinoline 128, and isoquinoUne could all be cross-coupled with only 1.04 equiv. of trifluoroborate salts, affording the corresponding cross-coupled products in good yield (Scheme 2.25). 

Recent innovations have involved the use of trifluoroborate [29], tetraarylborate [30], and trihydroxyborate [31] salts, some originating from DoM reactions, as coupling partners in the Suzuki-Miyaura cross-couplings. 

Scheme 3.13 Conversion into trifluoroborates and Suzuki-Miyaura coupling.

Few literature data allow a clear-cut comparison between different arylboronic esters under identical reaction conditions (Cu, Ni, Ru, Pd, ). Heise and coworkers tested the reactivity in Suzuki-Miyaura reactions of the three cyclic esters Bpin, Bhg, Bnpg under the same conditions. This reactivity clearly increases with decreasing steric hindrance (Scheme 3.35). For Ni-catalyzed Suzuki-Miyaura couplings also, the relative efficiencies of boronic esters of pinaeol and neopentylglycol, boronic acid and trifluoroborates were compared in a dedicated study. Parallel and competition experiments... 

Molander, G. A., Bernard , C. R. 2002. Suzuki-Miyaura cross-coupling reactions of potassium alkenyl-trifluoroborates. J. Org. Chem. 67 8424—8429. 

Typically, boronic acids/boronates, dialkylboranes, or trifluoroborates can all be used for Suzuki-Miyaura cross-coupling reaction. The following section details several protocols reported in the literature for the synthesis of these boron congeners. 

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