Boronic acids cross-coupling

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). 

Savarin, C. Srogl, J. Liebeskind, L. S. Thiol ester-boronic acid cross-coupling. Catalysis using alkylative activation of the Pd thiolate intermediate. Org. Lett. 2000, 2, 3229-3231. 

Key words purines, nucleobases, boronic acids, cross-coupling, palladium... 

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]

Prokopcova et al. (2005) performed thioether-boronic acid cross-coupling (Liebeskind-Srogl reaction) using microwave heating involving C-C cross-coupling... 

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%. 

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. 

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. 

Vinylation can also be done by Pd-catalysed cross-coupling in which one component is used as a halide or triflate and the other as a stannane (Stille reaction) or boronic acid (Suzuki reaction). Entry 9, Table 11.3, is an example of the use of a vinylstannane with a haloindole. lndole-3-boronic acids, which can be prepared by mcrcuration/boration, undergo coupling with vinyl triflates (Entry 10). 

Moderate yields of acids and ketones can be obtained by paHadium-cataly2ed carbonylation of boronic acids and by carbonylation cross-coupling reactions (272,320,321). In an alternative procedure for the carbonylation reaction, potassium trialkylborohydride ia the presence of a catalytic amount of the free borane is utilized (322). FiaaHy, various tertiary alcohols including hindered and polycycHc stmctures become readily available by oxidation of the organoborane iatermediate produced after migration of three alkyl groups (312,313,323). 

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. 

The transition metal catalyzed cross coupling of an organohalide with a boronic acid derivative, the Suzuki-Miyaura coupling, has become one of the most popular ways of preparing biaryls.3 The reaction is very robust and can easily be scaled to provide multigrams of material.4... 

FuNn iONAL Group Tolerance of PdildbrO VIMes.HCI Catalyzed Suzuki Cross-Coupling Reactions of Aryl Chlorides with Phenyi.boronic Acid Derivatives... 

A drawback of the Heck-type reaction is that it is not strictly regioselective [119]. Depending on the substituents >1% of 1,1-diarylation is observed. Soluble 2,5-dialkoxy-PPVs 63 or 2-phenyl-PPV PPPV 93, without 1,1-diarylated moieties, were synthesized by Heitz et al. in a Suzuki-type cross coupling of substituted 1,4-phenylenediboronic acids and fran5-l,2-dibromoethylene, catalyzed by Pd(0) compounds [120]. However, about 3% of biaryl defect structures are observed in the coupling products (M up to 12,000), resulting from homocoupling of boronic acid functions. 

The medicinal chemists subsequently discovered an improved route to racemic acid 9 that started with 2-bromo-2-cyclopente-l-one 11 (Scheme 7.2) [5]. Suzuki-Miyaura cross-coupling of 11 with 4-fluorophenyl boronic acid 12 provided 13 in 67% yield. Conjugate addition of cyanide furnished ketone 14 in 71% yield. Reduction of 14 with NaB H4 gave a 2.8 1 mixture of desired 15 and undesired 16 which were separated by silica gel chromatography. The observed diastereoselec-tivity with the cyano group was similar to ester 6. Hydrolysis of 15 with 5 M NaOH in MeOH gave racemic acid 9 in 91% yield, which was resolved as outlined in Scheme 7.1. 

Our third approach to 27 addressed the unavailability of 3-methoxy-2-cyclopentenone (31) in bulk quantities which necessitated the discovery of an alternative route (Scheme 7.7). Fortunately, the precursor to 31,1,3-cyclopentandione (35), was available in the required quantities and our efforts shifted to the use of this reagent Bromination of 35 with NBS, employing either KHC03 or KOH as the base, gave brominated dione 36 in 85% isolated yield. Unfortunately, direct cross-coupling of alkyl bromide 36 with boronic acid 12 under a variety of Suzuki-... 

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