SYNTHESIS OF arylboronic acids

Organolithiums have rather limited applications due to their high reactivity with a number of functional groups, e.g. ester, nitrile, amide, etc. 

The use of triisopropyl borate is the most popular nowadays since it generally allows to carry out the reactions at common reaction temperatures, between -25 and 0 °C. The acid catalysed hydrolysis of the arylboronic esters is affected by adding dilute aqueous hydrochloric, acetic acid or even water, at 0 to room temperature, to the reaction mixture containing the crade arylboronic ester, to produce the corresponding 

The latter have been prepared in high yields by the transesterification of the cmde dialkyl arylboronates in refluxing two-phase ethyleneglycol / toluene mixture [147]. 

Except the metallation of aryl halides with the lithium metal and the Grignard reaction, the arylmetallics can be alternatively prepared by  

The reactions have been conducted in an excess of the arene to be borylated as the reaction medium [169,170], or in cyclohexane as an inert solvent [168]. For example, Miyaura s group [170] described a rather convenient method for borylation of simple arenes with 350 under mild reaction conditions. Table 10. 

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Perhaps most dramatically of all, for the first time, bis(carbene)-substituted iridium complexes, such as [Ir(cod)(NHC)2] (NHC = 1,3-dimethyl- or 1,3-dicyclohexylimidazolin-2-ylidene] were successfully used by Herrmann and coworkers as C—H-activation catalysts in the synthesis of arylboronic acids starting from pinacolborane and arene derivatives [46]. 

The log, lath-like molecular structure of most liquid crystalline compounds makes the cross-coupling protocol very important in syntheses [178,179]. The method based on arylboronic acids simplifies the procedure for liquid crystal materials of more complex substitution patterns [64,180,181] (Scheme 32). The synthesis of arylboronic acids via ortho-metalation of fiuoroarenes and the successive cross-coupling reaction readily extended the aryl units. The Pd/C-cat-alyzed reaction was also reported as an economical alternative [64]. Several liquid crystals having a biaryl unit are now an industrial process of Merck in Germany (ca. 3 tons/year) [182]. 

Murphy JM, Tzschucke CC, Hartwig JF (2007) One-pot synthesis of arylboronic acids and aryl trifluoroborates by Ir-catalyzed borylation of arenes. Org Lett 9 757... 

Synthesis of arylboronic acids via Grignard reaction of sluggishly reactive aryl halides Preparation of mesitylboronic acid (283) 1143]... 

Synthesis of arylboronic acids by in situ quench procedure with n-BuLi and triisopropyl borate Preparation of 3-thienylboronic acid (364) 11481... 

The ready availability of ortAo-functionalized arylboronic acids by a metallation-boronation sequence provides a s)mthetic link to the crosscoupling protocol, which allows syntheses of various polycyclic heteroaromatics via cyclization between two ortho functionalities. The synthesis of arylboronic acids having an CONl 2 OCONEt2, NH Boc, or and their coupling with various... 

The increasing importance of boronic acids as synthetic intermediates has justified the development of new, mild and efficient methods to provide access to a large pool. Of particular interest is the synthesis of arylboronic acids substituted with a wide range of other functional groups. As a consequence of their growing popularity and improvements in methods available for their preparation, many functionahzed boronic acids have become available from several commercial sources. Although several methods, like the oxidation or hydrolysis of trialkylboranes, have significant historical and fundamental relevance, this section is devoted mainly to modem methods of practical value to synthetic chemists. 

Figurel.18 Common methods for the synthesis of arylboronic acids (esters).

Kabalka, G. W, Sastry, U., Sastry, K. A. R., Knapp, F. R, Srivastava, P. C. 1983. Synthesis of arylboronic acids via the reaction of borane complexes with arylmagnesium halides. J. OrganometaL Chem. 259 269-274. 

One-pot Synthesis of Arylboronic Acids and Aryltrifluorobo-rates. Hartwig also reported the synthesis of arylboronic acids and aryltrifluoroborates in a one-pot sequence by Ir-catalyzed borylation of arenes followed by the oxidative cleavage of the boronate ester with NaI04 and the displacement of pinacol by KHF2, respectively (eq 4). These two-step sequences give products that are more reactive and selective in the subsequent chemistry, such as Suzuki coupling, than the initially formed pinacol-boronates. 

SCHEME 6.20 Synthesis of arylboronic acids using an I/MgBr exchange reaction [41]. 

A microwave-assisted tandem Ir-catalyzed C-H boronylation/Pd-catalyzed Suzuki-Miyaura cross-coupling reaction has been reported (Harrisson et al., 2009). This includes the synthesis of arylboronic acids, direct boronylation of arenes and alkanes, which provides access to synthetically useful compounds without relying on the accessibility of aryl or alkyl halides. They developed an elegant methodology for the direct C-H boronylation using a pinacoldiborane dimer under microwave irradiation at 80°C for 5-60 min. 

Arylation of alkynes via addition of arylboronic acids to alkynes represents an attractive strategy in organic synthesis. The first addition of arylboronic acids to alkynes in aqueous media catalyzed by rhodium was reported by Hayashi et al.89 They found that rhodium catalysts associated with chelating bisphosphine ligands, such as 1,4-Ws(diphenyl-phosphino)butane (dppb) and 1,1 -/ E(diphenylphospliino)fcrroccnc... 

A one-pot process to form 1,3,4-substituted pyrazoles 25 by Suzuki coupling of arylboronic acids to chromone 24, followed by condensation with hydrazine has been reported <06JCO286>. The synthesis of 3 or 5-o-hydroxyphenol-4-benzylpyrazoles has been accomplished by treatment of 3-benzylchromones, 3-benzylflavones and their 4-thiochromone analogs with hydrazine hydrate in hot pyridine <06EJO2825>. 

Palladium catalyzed cross coupling of arylboronic acid to nonracemic trifluoromethylsulfonyl and fluorosulfonyl enol ethers is one of the key steps in the synthesis two endothelin receptor antagonists, SB 209670 and SB 217242, which have been clinically evaluated for several illnesses including hypertension, ischemia, stroke and others [37] (Scheme 6.14). 

Trialkylaryltin derivatives 30 are converted into fluoro-substituted derivatives 31. 37-38 (4-Mcth-oxyphenyl)trimethylsilane (32) in acetonitrile gives 4-fluoroanisole and (3-fluoro-4-meth-oxyphenyl)trimethylsilane in the ratio 1 2. A -Methyldiethanol esters of arylboronic acids 33 (l-aryl-5-methyl-2,8-dioxa-5-azonia-l-boranuidabicyclo[3.3.0]octanes) are converted into tluoroaromatic compounds with cesium fluoroxysulfate in acetonitrile in the presence of 1,3-dinitrobenzene at room temperature.39-40 Regiospecific synthesis of 2-fluoro-3-0-methyles-trone in 27 % yield occurs upon fluorination of the corresponding arylboronic acid with cesium fluoroxysulfate.41... 

The Suzuki coupling of arylboronic acids to the solid-supported arylha-lide 4 was initially performed by conventional heating methods, DMF at 85° in an oil bath for 16 h, to provide the desired products 6 after TFA cleavage. Due to the extended heating times necessary for the Suzuki reaction, full optimization of the reaction conditions were not investigated prior to compound library synthesis. Reaction conditions sufficient for the library synthesis were determined within a couple of weeks affording moderate yields of the desired oxazolidinones. Libraries of hundreds of... 

Asymmetric synthesis of diarylmethanols can be achieved via rhodium-catalysed addition of arylboronic acids to benzaldehydes, using chiral mono- or bi-dentate phos- ... 

The processes involving the aziridine cycle are very diverse. For instance, reactions of alkylation by alkyl halogenides [63], bromoacetic acid derivatives [29, 30] and acetoxypropene [64], are known. The use of arylboronic acids for synthesis of TV-alkyl derivatives, e.g., compound 45, is described in [63] (Scheme 1.13). The one-step reaction at room temperature of aziridinyl ketones 46 with chloroacetamides 47 and sulfur in the presence of Et3N yields mono-thio-oxamidines 48 [65]. 

Watanabe, T. Miyaura, N. Suzuki, A. Synthesis of sterically hindered biaryls via the Pd-cat-alyzed cross-coupling reaction of arylboronic acids or their esters with haloarenes. Synlett 1992, 207-210. 

An asymmetric 1,4-addition of arylboronic acids to coumarins such as 220 catalyzed by rhodium has been achieved in greater than 99% ee (Equation 21) <2005OL2285>. This method should prove useful for the synthesis of enantiomerically enriched compounds that contain a stereogenic center between two aryl groups. This methodology was used in the total synthesis of (R)-tolterodine. 

Arylboronic esters (Figure 5.48) can be oxidized with H202 in acetic acid to give aryl borates, which can then be hydrolyzed to provide phenols. The mechanism for this oxidation is similar to that for the OOH oxidation of trialkylboranes and is discussed in Section 14.4.3. In combination with the frequently simple synthesis of arylboronic esters one can thus achieve the overall conversions Ar—H —> Ar—OH or Ar—Br —> Ar-OH in two or three steps. 

N. Miyaura, Synthesis of Biaryls via the Cross-Coupling Reaction of Arylboronic Acids, in Advances in Metal-Organic Chemistry (L. S. Liebeskind, Ed.), JAI Press, Greenwich, 1998, 6, 187-243. 

Rhodium complex 27 has also been successfully applied in the enantio-selective conjugate addition of arylboronic acids [59]. In the synthesis of the 4-amino-3-aryl-butyric acid derivative 28, Helmchen et al. found that the addition product was obtained in > 99% ee (59% yield) within 2 h at 65 °C, whereas previous attempts with (S)-BINAP and [Rh(acac)(C2H4)2]... 

The biaryl coupling of arylboronic acid furnished a one-pot, two-step procedure for the synthesis of the angiotensin II receptor antagonist losartan 462, which played a critical role in the regulation of blood pressure,827 the AB biaryl ring of vancomycin aglycon 464, S/R= 1/1.3),828 bisporphyrin-based synthetic receptors 463 via a sequential double... 

Scheme 33 Cross-coupling of arylboronic acids or esters for synthesis of biaryls.

The use of microwaves was first reported in 1996 for both homogeneous883 and solid-phase coupling reactions of arylboronic acids (Equation (208)).884 Microwave irradiation significantly increases the efficiency of ligandless palladium acetate, solid-phase coupling for combinatorial synthesis, solid-phase coupling using KF-y-alumina,... 

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