Arylboron intermediates

S.M. Marcuccio etal, US Patent 6,559,310 (May 6, 2003) Assignee Commonwealth Scientific and Industrial Research Organization Utility Arylboron Intermediates... 

A fine example demonstrating the use of an arylboron intermediate was reported by Santaniello et al As part of a project aimed at evaluating the biological activity of 2-and 4-substituted estrogens a convenient synthesis of 2-hydroxyestradiol was needed. Classical electrophilic oxidations usually lead to equimolar amounts of 2- and 4-isomers which are not easy to separate, and thus a method for regioselective hydroxylation was required. 3-Methoxyestra-l,3,5(10)-trien-17p-yl acetate (12) reacted with mercury(II) acetate in dry acetonitrile, and the reaction mixture was then treated with saturated aqueous sodium chloride to give the 2-chloromercurio derivative (13) in 80% yield. This intermediate was then exposed... 

During the total synthesis of the proteosome inhibitor TMC-95A by S.J. Danishefsky et al., the biaryl moiety of the compound was assembled in good yield by the Suzuki cross-coupling of an aryl iodide and an arylboron intermediate. ... 

SYNTHESIS OF ORTHO SUBSTITUTED ARYLBORONIC ESTERS BY IN SITU TRAPPING OF UNSTABLE LITHIO INTERMEDIATES 2-(5,5-DIMETHYL-l,3,2-DIOXABORINAN-2-YL)BENZOIC ACID ETHYL ESTER... 

Arylboronic acids have traditionally been prepared via the addition of an organomagnesium or organolithium intermediate to a trialkyl borate. Subsequent acidic hydrolysis produces the free arylboronic acid. This limits the type of arylboronic acids one can access via this method, as many functional groups are not compatible with the conditions necessary to generate the required organometallic species, or these species may not be stable intermediates. 

The direct isolation of the well defined and stable neopentyl glycol arylboronic esters, without the need for an intermediate aqueous work-up. 

A closely related reaction that is currently receiving much attention is the palladium-catalysed Suzuki coupling of arylboronic acids with aryl halides (Fu and Littke, 1998). For example, this technology has recently been applied by Clariant workers for the production of o-tolyl-benzonitrile (Eqn. (13)), an intermediate to a series of so-called angiotensin-II antagonists, a new class of antihypertensive drugs (Bernhagen, 1998). 

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-... 

Recently, a rhodium-catalyzed tandem cyclization has been reported with an arylboronic ester bearing a pendant Michael-type acceptor olefin and acetylenic65 or olefinic66 derivatives. This transformation proceeds in a water-containing medium as solvent and proton source. This catalyst system is optimized with electron-rich and bulky ligands to stabilize the rhodium intermediate and decrease the protonolysis of boron derivatives in a protic solvent. 

Arylative or silylative cyclizations of allenyl aldehydes or ketones have been reported (Equations (101) and (102)).459,459a The intermolecular process, that is, three-component coupling reaction of aldehydes, allenes, and arylboronic acids, is catalyzed by palladium as well (Equation (103)).46O 46Oa These reactions are proposed to proceed through nucleophilic attack of the allylpalladium intermediates to the carbonyl groups. 

Three-component assembly of allenes, organic halides and arylboronic acids has been reported in which Suzuki coupling of a Jt-allylpalladium complex with an orga-noboronic acid is utilized (Scheme 16.26) [31], Addition of phosphorus ligands to the reaction mixture greatly decreases either the product yields or E/Z ratios. The decrease in E/Z ratio may be explained based on the fact that donor ligands readily promote anti-syn rearrangement of a Jt-allylpalladium species via a cr-allylpalladium intermediate. 

There are several different routes to carboxamides. In most of these reactions, a carboxylic acid is converted to a more reactive intermediate, e.g. the acid chloride, which is then allowed to react with an amine. For practical reasons, it is preferable to form the reactive intermediate in situ. Arylboronic acids with electron-withdrawing groups such as (3,4,5-trifluorophenyl)boronic acid act as highly efficient catalysts in the amidation between carboxylic acids and amines. (3-Nitrophenyl)boronic acid and [3,5-bis(trifluoromethyl)phenyl]boronic acid are also effective eimidation catalysts and commercially available. 

Suzuki Coupling to Displace the Remaining Chloro Atom on C2 with Aryl Groups (Fig. 10).15 To a 10-ml flame-dried Schlenk flask containing the solid supported intermediate 61 (0.10 mmol, 1.0 equiv.) are added an arylboronic acid (0.50 mmol, 5.0 equiv.), Pd2(dba)3 (0.007 mmol, 0.07 equiv.), l,3-bis(2,6-diisopropylphenyl)-lH-imidazol-3-ium chloride (carbine ligand, 0.014 mmol, 0.14 equiv.), and Cs2C03 (0.60 mmol,... 

Reactions between a representative range of alkyl- and aryl-amines and of aliphatic and aromatic acids showed that the direct formation of amides from primary amines and carboxylic acids without catalyst occurs under relatively low-temperature conditions (Scheme 1). The best result obtained was a 60% yield of N-bcnzyl-4-phenylbutan-amide from benzylamine and 4-phenylbutanoic acid. For all these reactions, an anhydride intermediate was proposed. Boric and boronic acid-based catalysts improved the reaction, especially for the less reactive aromatic acids, and initial results indicated that bifunctional catalysts showed even greater potential. Again, anhydride intermediates were proposed, in these cases mixed anhydrides of carboxylic acids and arylboronic acids, e.g. (I).1... 

Asymmetric hydroarylation of diphenylphosphinylallenes [Ph2P(0)]C(R)=C=CH2 with arylboronic acids ArB(OH)2, catalysed by an Rh-BINAP complex, has been shown to proceed in high yields with high regio- and enantio-selectivity to afford chiral allylphosphine oxides [Ph2P(0)]CH(R)C(Ar)=CH2 of up to 98% ee. A Tr-allylrhodium complex has been identified as the key intermediate.109... 

Formation of secondary alcohols, RCH(OH)Ar, from aldehydes and arylboronic acids, ArB(OH)2, is catalysed by a range of palladium(O) complexes, but chloroform is required.251 Palladium-chloroform complexes are equally effective, and evidence for (Ph3P)2Pd being converted to palladium(II) intermediates, (Ph3P)2Pd(X)-CHCl2, is presented (X = Cl, then OH). 

In a process developed by Myers et al., aromatic carboxylic acids were directly employed as substrates for Heck olefinations, albeit in the presence of a large excess of silver carbonate [38]. This base both facilitates the decarboxylation step and acts as an oxidant, generating arylpalladium(II) intermediates. In related processes, arylphosphonic [39] and arylboronic acids [40] were used as aryl sources in the presence of an oxidant. 

Fig. 16.19. Palladium-cata lyzed, stereoselective alkenylation of an arylboronic acid (preparation according to Figure 5.39) with a variety of iodoalkenes. The boronic acid is converted into the boronate anion A. The ion A reacts with the Pd(II) intermediate B via transmetalation subsequent reductive elimination leads to the coupling products.

Arylalkenes are accessible not only by way of an arylation of alkenylboron compounds (example in Figure 13.14) but also via an alkenylation of arylboron compounds. Figure 13.15 exemplifies this for a Pd-catalyzed reaction of an arylboronic acid with iodoalkenes with widely variable substitution patterns. The addition of KOH increases the reactivity of the arylboronic acid in this coupling and in similar ones. The base converts the boronic acid into a negatively charged boronate ion A. This ion A is transmetallated faster than the neutral boronic acid by the Pd(II) intermediate the boronate ion is a superior nucleophile and replaces the iodide ion in the Pd(II) complex particularly fast. 

Bromo- and iodoimidazoles are useful intermediates for further functionalization. 4(5)-Aryl- I //-imidazoles 57 can be efficiently and selectively prepared by palladium-catalyzed Suzuki-Miyaura reaction of commercially available 4(5)-bromo-l//-imidazole 56 with arylboronic acids under phase-transfer conditions, which then underwent highly selective palladium-catalyzed and copper(I) iodide mediated direct C-2-arylation with a variety of aryl bromides and iodides under base-free and ligandless conditions to produce 2,4(5)-diaryl-l//-imidazoles 58 in modest to good yields <07JOC8543>. A new procedure for the synthesis of a series of substituted 2-phenylhistamines 60 utilizing a microwave-promoted Suzuki... 

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