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Phi or PhOTf ------------>
P(2-Fur)3 cat. Pd2(dba)3
5% TFA/CH2CI2 nh2
2.3. STILLE REACTION 47
(i) PhSnMe3 or PhSnBu3 cat. Pd2(dba)3, P(Fur)3 LiCI, NMP, 25 °Ñ
improved yield (21-33%) of desired biphenyl
these cases, and a more thorough study of these reactions would be needed to formulate definite conclusions.
This chemistry was repeated with a traceless photolabile linker.60 The desired biphenyl was formed, but the couplings gave side products, and all yields of the desired biphenyl were lower than 30%.
The Stille reaction was central to Ellman’s synthesis of 1,4-benzodiazepines from support-bound stannanes.61 The method features solid-phase syntheses of 2-aminoaryl intermediates; these are not as widely available as the other building blocks for the desired product, so the Stille step increases the diversity of accessible products (Scheme 26). The catalyst of choice was “ligandless” Pd2(dba)3 CHCl3. Elevated temperatures were required for this reaction to proceed with Pd(PPh3)4 as catalyst. To avoid any acid formed in the reaction initiating either carbamate deprotection or protodesilylation, potassium carbonate and Hunig’s base were added as scavengers. It is in this study that Ellman introduced a dilute KCN-DMSO wash to rid the resin of palladium black deposited during the coupling. The final, unpurified benzodiazepines were isolated in typically greater than 80% purity at the end of the sequence.
Chemistry similar to this was used in Ellman’s paper to promote application of a silicon-based traceless linker.62 The full report on this work63 shows that both aliphatic and aromatic acid chlorides may be used in the coupling step. The same,approach is also shown to be successful with a germanium-based linker in place of the silicon. The couplings were typically performed for 1 h only, with equilibration time of a few minutes
48 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
Î Pr2EtN, DMAP
aroyl or alkyl acid chloride
cat. Pd2(dba)3.CHCI3 THF, K2C03, 'Pr2EtN
allowed for the reagents to diffuse into the resin prior to the addition of the acid chloride. A KCN-DMSO wash was used as standard throughout.
The copper-catalyzed coupling of polymer-bound aryl iodides with stannanes has also been demonstrated.64
2.4. SUZUKI REACTION65
2.4.1. Early Work
Farrall and Frechet recognized the possibility of forming polymer-bound boronic acids in 1976.66 Supported /wa-benzeneboronic acid groups were generated by direct lithiation of polystyrene, giving a para-lithio intermediate that could be used to generate a host of other resins also (Scheme 27). Conversion to the boronic acid was one of the more successful transformations. The purpose of this transformation was to allow the attachment of sugars to the solid phase via the boronate.
2.4. SUZUKI REACTION 49
The Suzuki reaction was used in liquid crystal syntheses67 to modify the properties of a polymer by the introduction of aromatic groups to a boronic acid functionalized backbone. Palladium-catalyzed couplings have found wide use in this field.68,69
One of the earliest investigations into the utility of the Suzuki reaction on solid support for combinatorial chemistry was that carried out by Frenette and Friesen70 to form the biaryl subunit, which is an important pharmacophore in its own right. A number of polymer-supported aryl halides were generated by the cesium carbonate-mediated loading of o-, m-, and p-substituted haloaromatic carboxylic acids onto Merrifield resin, and these were then coupled with a small number of commercially available boronic acids bearing both electron-withdrawing and donating groups (Scheme 28). Cleavage of such products from the resin was achieved by a facile transesterification reaction with methoxide. A number of catalysts were tested for the couplings, with all except Pd2allyl2Cl2 giving good results. Eventually Pd(Pph3)4 was used and gave excellent yields of products in >90% purities, more or less devoid of any unreacted starting materials or by-products. Interestingly, the coupling reactions were performed using
50 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
Pd(0), 2 M Na2C03 DME, reflux, 12 h
Cs2C03, Kl, DMF
0.1 eq. NaOMe Me0
X = OMe, H, Me, N02, F
degassed DME, which is a common solvent for Suzuki reactions but is not frequently used in solid-phase chemistry. DME was identified as a solvent of choice for the Suzuki protocol in 1984.71