Phenylboronic acid synthesis

Figure 11.12 Temperature profile of the phenylboronic acid synthesis along the major steps of the process flow scheme (AT, ambient temperature TH F, tetrahydrofuran). The difference in temperatures of the conventional...

For the synthesis of a suitable arylboron compound, usually an aryl halide is converted to an aryllithium or aryl Grignard derivative, and then reacted with a trialkoxyborane to yield an arylboronic ester, e.g. the phenylboronic acid diisopropyl ester 13 from bromobenzene 11 ... 

The Suzuki-Miyaura synthesis is one of the most commonly used methods for the formation of carbon-to-carbon bonds [7]. As a palladium catalyst typically tetrakis(triphenylphosphine)palladium(0) has been used, giving yields of44—78%. Recently, Suzuki coupling between aryl halides and phenylboronic acid with efficient catalysis by palladacycles was reported to give yields of 83%. 

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

A parallel synthesis of a library of 2-aryl-6-chlorobenzothiazoles 112 involves a regioselective palladium-catalyzed Suzuki coupling reaction of 2,6-dichlorobenzothiazole 111 with arylboronic acids (1.1 equiv) under microwave irradiation <06TL3091>. When excess phenylboronic acid is used, Pd(PPh3)4 still provides 2-phenyl-6-chlorobenzothiazole exclusively, while 2-dicyclohexylphosphinobiphenyl 113 generates 2,6-diphenylbenzothiazole as the major product. 

Zhang et al. reported the use of densely functionalized molecules through Suzuki cross-coupling reactions [65]. This synthesis involves the reductive amination of mucaholic acids to form the unexpected lactone (e.g., 82). Compound 82 can then be reacted with phenylboronic acid (83) to form the 2,3-diaryl-a, /J-unsaluralcd-y-lactone 84 as outlined in Scheme 19 in a 78% yield. A similar procedure is outlined in the work of Beilina et al. [66]. 

Martin effected the synthesis of several 3,5-diarylated indoles by a tandem Stille-Suzuki sequence [131]. The latter reaction involves exposure of 3-(3-pyridyl)-5-bromo-l-(4-toluenesulfonyl)indole with arylboronic acids (aryl = 3-thienyl, 2-furyl, phenyl) under typical conditions to give the expected products in 86-98% yield [131], Carrera engaged 6- and 7-bromoindole in Pd-catalyzed couplings with 4-fluoro- and 4-methoxyphenylboronic acids to prepare 6- and 7-(4-fluorophenyl)indole (90% and 74% yield) and 6-(4-methoxyphenyl)indole (73% yield) [29]. Banwell and co-workers employed 7-bromoindole in a Suzuki coupling with 3,4-dioxygenated phenylboronic acids en route to the synthesis of Amaryllidaceae alkaloids [132], Yields of 7-arylated indoles are 93-99%. Moody successfully coupled 4-bromoindole... 

Debache A, Boulcina R, Belfaitah A, Rhouati S, Carboni B (2008) One-pot synthesis of 1,4-dihydropyridines via a phenylboronic acid catalyzed Hantzsch three-component reaction. Synlett 509-512... 

The synthesis by K. C. Nicolaou and co-workers is summarized in Scheme 13.43. Diels-Alder reactions are prominent in forming the early intermediates. The formation of the A ring in steps A and B involves use of z-cli loroacrylonitrile as a ketene synthon. In step C, the pyrone ring serves as diene. This reaction is facilitated by phenylboronic acid, which brings the diene and dienophile together as a boronate ester, permitting an intramolecular reaction. 

A phenylboronic acid-mediated synthesis of chromenes from naphthols and 3-methylbut-2-enal features in two short routes to 3-lapachone <99S1875>. 

A more recent synthesis for (14-9) takes quite a different course. The first step comprises the displacement of one of the halogens in 1,4-dibromobenzene by the alkoxide from A-2-hydroxyethylpyrrolidine (15-2) in the presence of 18-crown ether to afford (15-3). Condensation of the lithium salt from (15-3) with 6-methoxy-tetralone (15-4) followed by dehydration of the initially formed carbinol give the intermediate (15-5), which incorporates the important basic ether. Reaction of that compound with pridinium bromide perbromide leads to the displacement of the vinylic proton by halogen and the formation of bromide (15-6). Condensation of that product with phenylboronic acid in the presence of a tetrakistriphenyl-phosphine palladium catalyst leads to the coupling of the phenyl group by the formal displacement of bromine. The product (14-9) is then taken on to lasoxifene (14-11) as above [16]. 

Phenylazopyridines, with trinuclear Os clusters, 6, 731 Phenylbismuth amides, synthesis, 3, 918 9-Phenyl-9-borata-anthracenes, with Zr(IV), 4, 980 Phenylboronic acids, in carbonylative cross-coupling, 11, 416 4-Phenyl-3-buten-2-one, diboration, 10, 731-732... 

Synthesis and Cytostatic Activity of Substituted 6-Phenylpurine Bases and Nucleosides Application of the Suzuki—Miyaura Cross-Coupling Reactions of 6-Chloropurine Derivatives with Phenylboronic Acids... 

In conclusion, the application of the Suzuki—Miyaura reaction of 6-chloropurine derivatives with substituted phenylboronic acids is a facile and effective approach for the synthesis of a series of specifically substituted 6-phenylpurine bases and nucleosides. In comparison with the previously known methods25-30 using other types of organometallic reagents or photochemistry, this method is more effective and selective, and therefore, further applications in the synthesis of 6 C-substituted purine derivatives may be expected. 

Thus, for our present purposes a similar approach was followed using Suzuki cross-coupling reactions as the key steps in the synthesis of our target compounds. Symmetrically substituted compounds were synthesized in a twofold Suzuki crosscoupling reaction from commercially available p-substituted phenylboronic acids or esters and 4,4 -dibromobiphenyl or 4,4 -biphenyl-bis-boronic acid ester and a p-substituted arylhalide, respectively, using tetrakis (triphenylphosphino) palladium as catalyst together with cesium fluoride as base in dry tetrahydrofurane as shown in Scheme 8.1. The desired products were obtained in respectable yields after heating at reflux for 50 h. 

A similar Suzuki cross-coupling reaction has also been employed by Gill and Lubell in a synthesis of an unsaturated kainoid analogue.50 Vinyl triflates 97 and 98 were cross-coupled with phenylboronic acid using tetrakis(triphenylphosphine)palladium(0) to give the corresponding coupled products 99 and 100 with high efficiencies (Scheme 42). 

Leadbeater and Griffiths developed palladium catalysts for the Suzuki cross-coupling of aryl halides bearing two ortho substituents with phenylboronic acid, and used them in the synthesis of sterically hindered biaryls [83]. 

The reactivity and selectivity of cycloaddition can be considerably increased in intramolecular versions. The protocol was first demonstrated in the Diels-Alder reaction between anthrone 253416,417 and 4-hydroxy-2-butenoate mediated by phenylboronic acid (Equation (73)).418,419 Another method developed for the intramolecular cycloaddition is the synthesis of trienylboranes 256 by hydroboration of terminal alkynes (Equation (74)).419-422... 

The copper acetate-mediated inter- and intramolecular O-arylation of phenols with phenylboronic acid was the key step in the preparation of natural or macrocyclic biphenyl ethers. The intramolecular macrocyclization was mild and tolerant of chemical functionality (Equation (238)). The protocol has been used for the synthesis of (—)-teje-... 

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