Preparation of Aryl Boronic Acids

Many methods have been developed for synthesizing alkenyl and aryl boronic acids. For example, an aryl Grignard reagent reacts with trimethoxyborane, B(OCH3)3, which is commercially available, to give a dimethoxyaryl borane, AtB(OCH3)2. Hydrolysis of the borane ves the aryl boronic acid, as shown below. 

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General Procedure for the Preparation of Aryl Boronic Acids... 

Alternative methods for the preparation of aryl boronic acids involve the well established metal-halogen exchange of aryl bromides, 53 52 54 and the less... 

The widespread use of aryl boronic acids or aryl boronates in various metal-catalysed C-C bond-forming reactions has created a substantial demand for these versatile nncleophiles. A general procedure for the preparation of these compounds, based on a NHC/Pd catalysed coupling, has been reported by Fiirtsner and co-workers nsing aryl chlorides and the tetraalkoxy diboron derivative 27 as conpling partners. Very good yields were obtained in several cases especially when electron poor aryls were employed [169]. Milder reaction conditions can be achieved when diazonium salts are used instead of chlorides [170] (Scheme 6.51). 

In recent years, a variety of aryl boronic acids are commercially available, albeit in some cases they may be expensive for large scale purposes. During our work in the mid-1990 s boronic acid (II) was not commercially available and so two different protocols were used to prepare this acid. The first approach involved the transmetallation with n-butyl lithium of aryl bromide (I) and trapping the lithio species generated with trialkyl borate followed by an acid quench. Aryl bromide (I) is easily prepared by reaction of o-bromobenzenesulfonyl chloride with 2-propanol in the presence of pyridine as a base. The second approach was a directed metallation of isopropyl ester of benzene sulfonic acid (VII), to generate the same lithio species and reaction with trialkyl borate. The sulfonyl ester is prepared by reaction of 2-propanol with benzenesulfonyl chloride. From a long-term strategy the latter approach is... 

Endothelin receptor antagonists 134 and 135 were prepared from the triflated oxicam derivative 136 (Scheme 18) <1998BMC1447>. Addition of aryl thiol 137 to the position gave product 134. Palladium-catalyzed Suzuki coupling of aryl boronic acid 138 and aryl triflate 136 affords the sulfonamide product 135. 

A long-standing reaction is the oxidation of aryl boronic acids to phenols by alkaline peroxide, usually in the work-up of a borate-organolithium reaction, without isolation of the boronic acid, i.e. an efficient ArBr ArOH conversion. A variant under milder conditions uses sodium perborate (for the conversion of 5-bromopyrimidines), and, using oxone, oxindoles can be prepared from 1-Boc indoles via direct... 

A closely related cross coupling reaction, the so-called Suzuki coupling of aryl-boronic acids with aryl halides leads to biphenyl groups under very mild conditions in the presence of a Pd catalyst. Due to the stability, ease of preparation and low toxicity of the boronic acid compounds, the reaction has attracted much attention. 

Recently, simple copper-catalyzed trifluoromethylation of aryl boronic acids under mild conditions was developed. Using (trifluoromethyl)trimethylsilane (McsSiCFs) [93], trifluoromethyldibenzothiophenium triflate [94], or Togni s reagent [95], 2-trifluoromethylbenzo[fc]thiophene 173 was prepared in 45-73 % yields. 

The use of potassium metabisulfite serves two roles (1) it serves as a source of SO2 and (2) it buffers the reaction solution so that decomposition of the intermediate sulfinate does not oeeur via disproportionation. Importantly, the intermediate sulfinate can also be reaeted with allg l halide electrophiles to produce sulfones in addition to aryl sulfonamides. The current methodology addresses the key limitation of the Buehwald protocol as it tolerates N-heterocycles. To demonstrate the rapid synthesis of analogues, sildenafil and ten sulfonamide analogues were prepared in a parallel fashion from a late stage intermediate. Potassium metabisulfite has also been utilised as a convenient SO2 source in the gold-eatalysed sulfonami-dation of aryl boronic acids." ... 

The use of expensive and unstable ZnPli2 in the preparation of chiral di-arylmethanol derivatives, with electronically and sterically similar aryl rings, made this approach less attractive for the enantioselective synthesis. In order to avoid this inconvenience, other alternative preparations of arylzinc reagents were evaluated.As a first choice, Yus et al. proposed the use of arylboronic adds as a viable source of phenyl (Scheme 4.19). Thus, the reaction of various boronic acids with an excess of ZnEt2 at 70 °C gave the corresponding arylzinc intermediates (probably aryl(ethyl)zincs), which were trapped by reaction with dif-... 

When the metallic additive to the intermediate 374 was zinc dihalide (or another Lewis acid, such as aluminum trichloride, iron trichloride or boron trifluoride), a conjugate addition to electrophilic olefins affords 381 . In the case of the lithium-zinc transmetallation, a palladium-catalyzed Negishi cross-coupling reaction with aryl bromides or iodides allowed the preparation of arylated componnds 384 ° in 26-77% yield. In addition, a Sn2 allylation of the mentioned zinc intermediates with reagents of type R CH=CHCH(R )X (X = chlorine, bromine) gave the corresponding compounds 385 in 52-68% yield. ... 

The resulting triazoles can be N-alkylated by treatment with alkyl halides (0.25 mol/L, 30 equiv., DMF, NaOH), but mixtures of the 1-alkylated and 2-alkylated triazoles are obtained [255]. 1,2,4-Triazoles have also been prepared from N-amino-amidines (amidohydrazones Entry 4, Table 15.20), which were prepared from resin-bound thioamides by S-alkylation with methyl triflate followed by treatment with hydrazine [256]. 1,2,4-Tri azoles undergo Michael addition to polystyrene-bound a-acetamido acrylates to yield triazole-derived a-amino acids (Entry 7, Table 15.20). Benzotriazoles have been N-arylated on insoluble supports by treatment with aryl-boronic acids in the presence of catalytic amounts of copper salts (Entry 8, Table... 

Aryl halides of many different types, including simple unsubstituted halides, may be conveniently converted into phenols by an indirect route involving the preparation of an arylboronic acid and its subsequent oxidation with hydrogen peroxide. The arylboronic acid (3) is normally prepared by reaction of the corresponding arylmagnesium halide with a borate ester (typically tributyl borate) at between —60 and — 80 °C, to yield the dialkyl boronate ester (2) which is then hydrolysed to the arylboronic acid (3). The latter may be isolated, purified and then oxidised with hydrogen peroxide as described in the preparation of m-cresol (Expt 6.101). Alternatively the crude reaction mixture from the preparation of (3) may be treated directly with hydrogen peroxide.36... 

The use of alkenyl boronic acid derivatives 50, which are readily prepared via hydroboration or bromoboration of alkynes, affords the corresponding p,y-unsaturated amino acids (e.g. 52-57) in a geometrically pure form [34], A variety of amines 48, including primary and secondary amines, anilines, amino alcohols and hydroxylamines can effectively participate in this process, while the alkenyl boronic acid can contain alkyl, aryl or bromo-substituents. Although the alkenyl amino acid side chain is introduced through the boronic acid component, the use of more substituted a-keto acids 49 allows the simultaneous incorporation of an additional a-substituent (e.g. 57). 

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