Boronic acids, metal catalyzed coupling with

The optional site selective metallation of fluorotoluenes158 with the superbasic mixture of butyllithium and potassium fert-butoxide has been applied to the synthesis of the anti-inflammatory and analgesic drug Flurbiprofen.171 3-Fluorotoluene is selectively metallated in the 4-position with LIC-KOR in THF at — 75 °C to afford, after reaction with fluorodimethoxyborane and hydrolysis, the corresponding boronic acid in 78% yield. A palladium-catalyzed coupling with bromobenzene gives the 2-fluoro-4-methylbiphenyl in 84% yield. This four-step sequence can also be contracted to a one-pot procedure with an overall yield of 79%. A double metallation with the superbasic mixture lithium diisopropylamide/potassium tert-butoxide (LIDA-KOR)172 173 is then required to produce flurbiprofen. 

Several different transition metal-catalyzed reactions with the 2(li-f)pyrazinone template have been evaluated. The Suzuki-Miyaura coupling was efficient in introducing aryl groups to both the 3 and the 5-positions of the heterocycle. The 3-arylated product could be isolated in 75% yield by using 1.1 equivalents of boronic acid and sodium carbonate as base whereas use of 2.2 equivalents of boronic acid with cesium carbonate yielded the 3,5-disubstituted compound in 52% yield (Scheme 15.21) [56]. Efforts to widen the utility of this Suzuki-Miyaura reaction to include solid-phase reactions met with difficulties, because the reaction was problematic to drive to completion [57]. Other teams have also reported problems with Suzuki-Miyaura couplings on polymeric supports [44, 58]. 

The Suzuki-Miyaura cross-coupling reaction is a standard method for carbon-carbon bond formation between an aryl halide or triflate and a boronic acid derivative, catalyzed by a palladium-metal complex. As with the Mizoroki-Heck reaction, this cross-coupling reaction has been developed in ionic liquids in order to recycle and reuse the catalyst. In 2000, the first cross-coupling of a halide derivative with phenylboronic acid in [bmim] [BF4] was described. As expected, the reaction proceeded much faster with bromobenzene and iodobenzene, whereas almost no biphenyl 91 was obtained using the chloride derivative (Scheme 36). The ionic liquid allowed the reactivity to be increased, with a turnover number between 72 and 78. Furthermore, the catalyst could be reused repeatedly without loss of activity, even when the reaction was performed under air. Cross-coupling with chlorobenzene was later achieved - although with only a moderate yield (42%) - using ultrasound activation. 

Looking for other transition metal-catalyzed coupling reactions, the Mainz research group achieved an improved synthesis of poly(p-2,5-di-n-hexylphenylene) by using Pd catalysts. This procedure was adapted from the Suzuki [71] and Miller [72] reaction in which Pd catalysts are used to couple various bromobenzene derivatives with benzene boronic acid. This reaction was described in the literature as being highly selective and quantitative. The influence of substituents attached at the ortho position was reported to be negligible. 

Figure1.36 Transition metal-catalyzed coupling of boronic acids (esters) with carbon halides/triflates (Suzuki cross-coupling...

As for poly(p-phenylene), there are two important methods the Ni-catalyzed coupling of Yamamoto and Colon, on the one hand, and the Suzuki reaction based on the coupling of aromatic boronic acids with halogenated aromatic compounds in the presence of a Pd(0) catalyst, on the other. Besides these two main methods, a series of other metal-catalyzed couplings have been explored. 

Researchers fundamentally interested in C-C bond-forming methods for polyketide synthesis have at times viewed allylation methods as alternatives, and maybe even competitors, to aldol addition reactions. Both areas have dealt with similar stereochemical problems simple versus absolute stereocontrol, matched versus mismatched reactants. There are mechanistic similarities between both reaction classes open and closed transition states, and Lewis acid and base catalysis. Moreover, there is considerable overlap in the prominent players in each area boron, titanium, tin, silicon, to name but a few, and the evolution of advances in both areas have paralleled each other closely. However, this holds for an analysis that views the allylation products (C=C) merely as surrogates of or synthetic equivalents to aldol products (C=0). The recent advances in alkene chemistry, such as olefin metathesis and metal-catalyzed coupling reactions, underscore the synthetic utility and versatility of alkenes in their own right. In reality, allylation and aldol methods are complementary The examples included throughout the chapter highlight the versatility and rich opportunities that allylation chemistry has to offer in synthetic design. 

The transition metal catalyzed cross coupling of an organohalide with a boronic acid derivative, the Suzuki-Miyaura coupling, has become one of the most popular ways of preparing biaryls.3 The reaction is very robust and can easily be scaled to provide multigrams of material.4... 

No examples of such reactions have been disclosed. Displacement of halogens on the parent heterocycle through metal-catalyzed processes have surprisingly not been reported to our knowledge on the neutral heterocycle. Recently, Suzuki-Miyaura cross-coupling reactions of imidazolium bromide 113 with various boronic acids or esters were reported <2005T6207> to proceed in good yield, without deprotonation at the C-3 position (Scheme 35). 

Qudguiner s group enlisted a combination of directed metalation and a Pd-catalyzed cross-coupling reaction for the construction of heteroaryl natural products [49]. One example was the total synthesis of bauerine B (64), a fl-carboline natural product [50]. Ort/zo-lithiation of 2,3-dichloro-iV-pivaloylaminobenzene (61) was followed by reaction with trimethylborate to provide boronic acid 62 after hydrolysis. The Suzuki reaction between 62 and 3-fluoro-4-iodopyridine led to the desired biaryl product 63 contaminated with the primary amine (ca. 30%), both of which were utilized in the total synthesis of bauerine B (64). Another fl-carboline natural product, the antibiotic eudistomin T (65), and a few other hydroxy 3-carbolines have also been synthesized in the same fashion [3, 51]. 

For the synthesis of a cavitand functionalized with terpyridyl groups via rigid linkages, transition metal catalyzed cross-coupling reactions are especially well suited. Starting with the boronic acid ester 48 [65], attachment of the terpyridyl groups to the cavitand was realized by Suzuki-Miyaura reaction with the tetraiodo-cavitand 47 (Fig. 15). 

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