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58 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
phenyl p-lactam of triphenylphosphine was a major by-product. Indeed, this was isolated quantitatively when boronic acid was excluded from the reaction mixture. Use of 20 mol % PdCl2(dppf) in the presence of excess triethylamine circumvented this problem, and provided an effective system for the coupling of the resin-bound bromide analogue of 32. Subsequently, six different boronic acids were coupled with the same resin-bound aryl iodide to show tolerance to several functional groups; electron-rich (methoxy-) and electron-poor (nitro-) aryl boronic acids both gave good yields. Different boronic acid regiochemistries were also well tolerated since all three isomers (î-, m-, and p-) of methoxyphenyl boronic acid gave product yields within the range 65-80%. 3-Acetamidophenyl- and 2-thienyl boronic acids were also shown to couple with similar efficacy. Preparative HPLC was used to purify all compounds after cleavage in this study.
A drawback with the strategy depicted in Scheme 36 is the limited commercial availability of boronic acids and esters compared to the corresponding availability of iodides. The synthetic strategy was easily reversed, however, by generating the resin-bound boronic acid 33 by the method shown in Scheme 37. This reaction was observed to proceed with higher yield on ArgoGel-MB-OH, a poly(ethylene glycol)-grafted resin, than on polystyrene-based supports. Polyethylene graft resins presumably facilitate penetration of the polar phenoxyacetyl-chloride-derived ketene intermediate into the resin.
Application of the conditions previously used for the Suzuki coupling of 32 [20 mol % PdCl2(dppf)/NEt3] gave poor results, while addition of water drove the reaction to completion. Catalyst systems based upon PdCl2(dppf)-NEt3-DMF-H20 were found to give good to excellent yields of coupled products when both electron-deficient and electron-rich aryl iodides were used. This reaction could even be performed in the air, a distinct advantage
(i) 30% piperidine/DMF
(ii) 4-CHOC6H4B(OH)2 DMF, 40 °Ñ, 16 h, 4 A MS
(iii) phenoxy acetyl chloride NEt3, 25 °Ñ, 16 h
2.4. SUZUKI REACTION 59
for automated synthesis. Perhaps unsurprisingly for a solvent system that includes water, the yields were somewhat dependent upon the choice of solid support. The usual polystyrene supports suffered presumably due to the shrinking effect caused by aqueous mixtures. The overall findings support the intuitive idea that a reversal of polarity in the Suzuki coupling (and indeed any of the organometallic coupling processes) does not necessarily mean a decrease in yield of the reaction. The further use of these same catalyst systems for the Heck reaction has been described above.
2.4.5. Silyl-Based Synthesis
Veber et al.88 used Suzuki couplings on a solid support to generate simple biphenyls (Scheme 38), in the presence of a silyl linker, which was cleaved to release these structures without trace of the linkage position.
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%.
60 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
Br PhB(OH)2, Et3N/DMF 3 mol% Pd(PPh3)4
80-90 °Ñ, 24 h
3 eq. ICI CH2CI2
Ellman used silyl chemistry for the direct linkage of aromatics onto the solid support by converting an aryl bromide to aryl lithium and reacting this with a silyl resin.90 It is the production of the silyl resin that is of interest in the context of this review, since an in situ Suzuki coupling was used to link the allyl silane to bromomethyl polystyrene resin (Scheme 40). 9-BBN is used to carry out the regioselective hydroboration, and this is linked to the resin with palladium catalysis in the usual way. After brief exposure of this
2.4. SUZUKI REACTION 61
resin to an HC1 solution in dichloromethane, the resin 34 is activated and ready for loading with lithiated aryls. This chemistry is far simpler than that used by the same group in an earlier paper62 wherein a similar alkene is hydroxylated using 9-BBN, and then linked to the resin via cyanomethyl 4-hydroxyphenoxyacetate. This direct in situ Suzuki coupling provides a more direct strategy for the attachment process.