Boronic acids cross-coupling with

Sphinx Pharmaceuticals101 patented successful Stille (with a resin-bound organostannane) and Suzuki (with a supported boronic acid) cross-couplings. In the same patent, they also reported a coupling of a phenylacety-lene with a resin-bound bromide wherein Pd(OAc)2 was the catalyst (Scheme 50). 

Nickel/carbene complexes have also been successfully employed in the Suzuki-Miyaura cross-coupling reaction. One of the first successful applications of this was demonstrated by Blakey and MacMillan, wherein boronic acids were coupled with aryltrimethylammonium salts [52]. It was found that the transformation could be accomplished using 10 mol % Ni(COD)2,... 

The most important palladium-catalyzed processes include Heck vinylation of halides and sulfonates and various cross-coupling reactions in which a nucleophilic intermediate (stannane, organo-zinc halide or boronic acid) is coupled with an electrophile (halide or sulfonate). These coupling reactions are usually restricted to arylation and vinylation because of the tendency of alkylpalladium species to undergo elimination. The pyrrole and indole rings can participate in cross-coupling as either the nucleophilic or electrophilic component. 

Since the early success of Decicco et al. [19] in extending the boronic acid cross-coupling to an intramolecular system, more examples of this approach have appeared in the literature (Scheme 5.5). Snapper and Hoveyda reported a total synthesis of the anti-HIV natural product chloropeptin 1 in which the crucial biaryl ether moiety was constructed via the Cu-mediated reaction (Scheme 5.5) [20]. Thus, treatment of the boronic ester 10 with NalO liberates the boronic acid, which then cyclizes under Cu(OAc)2 to give the biaryl ether 11, a precursor to the final target. In this case, the addition of 10 equiv. of methanol was critical for efficient intramolecular cross[Pg.210]

Lam et al. [23a] have also investigated the use of alkylboronk acids. Cydohexylboron-ic acid cross-couples with t-butylaniline in low yields (16% for TEA and 6% for pyridine) under standard conditions for 2 days at 70 °C in dichloroethane (Scheme 5.29). However, no reaction with phenols or anilines was observed using cyclopropyl-boronic acid [23a, cj. 

The first total synthesis of 87 was published in 1990 (90TL1523). 5-Hydroxyindole (88) was mesylated and then reduced with sodium cyanoborohydride to give an indoline which was brominated to afford the bromoindoline 89 in good yield (Scheme 33). Cross-coupling with ortho-formyl boronic acid under Suzuki conditions, followed by air oxidation of the resulting cyclized product, followed by reduction of the lactam formed with excess Red-Al gave the target compound 87. 

The authors used a synthesis of 9,9-spirobitluorenes 32 which was developed by Clarksen and Gomberg [60] and which includes the addition of biphenyl-2-yl-magnesium iodide to fluorenone and subsequent cyclization with protic acids. To obtain 2,2,, 7,7 -arylated 9,9-spirobifluorenes 33, 9,9-spirobifluorene (32) was tetrabrominated [58] to yield 34 followed by a Suzuki-type aryl-aryl cross-coupling with various oligoaryl and oligoheteroaryl boronic acids to obtain the 2,2, 7,7 -tetraarylated derivatives 33. 

Using Pd-mediated cross-coupling reactions, such as Suzuki, Heck, and Sonoga-shira- Hagihara reaction, researchers efficiently constructed a library of 151 coumarin derivatives from eight 3-bromocoumarins cross-coupled with ten aryl/heteroaryl boronic acids, ten alkenes, and ten alkynes (Fig. 4). 

There are only a few examples of displacement of a fluorine atom in a cross-coupling reaction. With tricarbonylchromium complexes of fluoroarenes as substrates, cross-coupling with both boronic acids and vinylstannanes has been realized. Interestingly, only PMe3 is effective as ligand in this reaction (89).2" See Section 9.6.3.4.10 for an example of the involvement of unactivated fluoroarenes in cross-coupling reactions. 

In this method, Furstner converts N-BOC protected pyrrole to the 2,5-dibromo compound (122) with NBS and this is followed by metalation and carbomethoxylation with t-butyl lithium in THF and subsequent trapping of the metalated species with methyl chloroformate to yield a pyrrole diester (123). Bromination of this diester at positions 3 and 4 with bromine in water followed by Suzuki cross-coupling with 3,4,5-trimethoxyphenyl boronic acid yields the symmetrical tetrasubstituted pyrrole (125). Base-mediated N-alkylation of this pyrrole with 4-methoxyphenethyl bromide produces the key Boger diester (126) and thereby constitutes a relay synthesis of permethyl storniamide A (120). 

In a simple strategy to biaryl formation, Han et al.89 showed that silicon-directed ipso-substitution and concomitant cleavage from supports could be used for formation of functionalized biphenyls. For this they used a tethered silyl aryl bromide in a Suzuki cross-coupling reaction, followed by the ipso-substitution/cleavage step (Scheme 39). A variety of boronic acids were coupled in this manner. The only difficulty occurred with electron-deficient nitrophenylboronic acid where the desired product was formed under anhydrous conditions in only 33% yield (the remainder being starting material). Reversion to the more usual conditions of aqueous base-DME (i.e., those used by Frenette and Friesen)70 improved the yield to 82%. 

In an application of the Suzuki process, 2-chloroquinoline (141) has been converted into the condensed heterocycle 197 (Scheme 58) (89JHC1589). Thus, metalation, trimethyl borate quench, and hydrolysis affords the stable 3-boronic acid 195 which, upon subjection to cross coupling with ortho-iodo aniline in the presence of Pd(0) catalyst and base, affords the 3-arylquinoline 196. Acid catalysis converts this material into the in-dolo[2,3-f ]quinoline (197) in 35% overall yield. 

The Suzuki cross-coupling reaction between 1,2,5-trisubstituted pyrrole halides 1443 and 2-A -(/-butoxycarbonyl)-aminophenyl boronic acid 1444 performed with benzyl[bis(triphenylphosphine)]palladium(ll) chloride (PdBnCl(PPh3)2)... 

Since this study, the addition of repeat units capable of a postsynthetic transformation have been investigated. Bo et al. investigated the incorporation of an aryl bromide functionality on the Frechet-type repeat unit, which could be modified by a Suzuki cross-coupling with an aryl boronic acid.521 Freeman et al. explored the attachment of an allyl ether functionality on the same repeat unit,522 while Schultz et al. incorporated an aromatic spacer with two allyl groups to enable internal cross-linking via olefin metathesis.523... 

Buchwald observed that using solubilizing functionality on the phosphine ligands allowed the Suzuki reaction to be executed under aqueous conditions [57]. This also obviated the need to protect free amino groups as no metal chelation was observed. Thus pyridyl derivative 164 was cross-coupled with boronic acid 165 using the modified ligand 166 to afford 167 in excellent yield. 

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