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2.4.9. Miscellaneous Uses of the Suzuki Reaction
Sarkar et al.94 constructed the relatively complicated structure 40 (Scheme 45) on a solid support by using a Suzuki coupling. The objective of this work was to demonstrate the efficacy of spin echo MAS !H NMR spectroscopy for gauging reactions on solid supports. The coupling was performed successfully under standard conditions, and a KCN in DMSO wash was used to remove adsorbed palladium after the reaction.
Grignard reactions of a resin-bound 1,3-cyclohexanedione have been shown to proceed in good to moderate yields (Scheme 46).95 Moreover, the purity of the TFA-cleaved product was excellent, possibly because the addition product 41 is more sensitive to acid than the starting dione. Lower yields were produced from secondary organometallic reagents, however. This led to the investigation of the effectiveness of Suzuki couplings of the resin-bound vinyl triflate with a range of commercially available boronic acids to produce similar products. The Suzuki reaction is therefore used here as an alternative to Grignard-type processes for carbon-carbon bond formation. This work included an early example of the use of vinyl triflates
(³) ArB(OH)2, Pd(PPh3)4 Na2C03, H20, EtOH DME, 3.8 min, 45 W >
X= I, Br
86 - 98%
Ar= Ph, 2-MeOC6H4OMe 2-thienyl
2.4. SUZUKI REACTION 65
Pd(PPh3)4, K2C03, PhH/EtOH, 80 °Ñ, 24 h OMe
RMgBr or RLi ---------->
THF, 0 °Ñ
KN(TMS)2 Tf2NPh, THF -78 °Ñ
ArB(OH)2, Pd(PPh3)4 Na2C03, dioxane
3% TFA/CH2CI2 ------------->
90 °Ñ, 2.5 h
5% TFA/ acetone
66 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
in solid-phase Suzuki reactions. Deoxygenated dioxane was used with Pd(PPh3)4, and the boronic acids were used in sevenfold excess under an inert atmosphere at 90°C for only 2.5 h. While the yields of these processes were only good to poor, the purities of the cleaved material was greater than 95% as judged by HPLC. Thus both methods can be used, but their applicability with respect to different coupling partners (e.g., alkyl vs. aryl/vinyl) varies.
The Suzuki reaction was used in Ellman’s report of a safety-catch linker based around Kenner’s acylsulfonamide,96 to introduce an aromatic site of diversity in a library based on the phenylacetic acid skeleton. The products were used for the generation of compounds useful in the inhibition of cyclooxygenase (Scheme 47). Mildly basic reaction conditions in the Suzuki reaction are well suited to this transformation since this prevents the protonation of the safety-catch linker. Good yields were seen in all cases using both arylboronic acids and also alkyl 9-BBN derivatives. Interestingly, whereas THF gave good results, DME enhanced the precipitation of palladium black in the resin. This was a significant concern because Pd(0) catalytically decomposes diazomethane, and this was the reagent used for activation of the linker prior to cleavage.
Raju and Kogan demonstrated the synthesis of simple, diverse sulfonamides using a new carbamate linker.44 They also showed that the Suzuki reaction could be used for convenient introduction of diversity in their solid-phase synthesis. The three-step sequence is shown in Scheme 48. The purities of the cleaved compounds are good, but the sequence yields are low (32-33%).
Yoo et al.97 used the solid support not only as a tether for the synthesis of biphenyltetrazole derivatives, but also as a protecting group for the acidic tetrazole moiety. The latter functionality was prevented from interfering with subsequent chemistry. Specifically, a support-bound dihydropyran was
R2-9-BBN or R2B(OH)2, Pd(PPh3)4, Na2C03, THF
65 °Ñ, 24-40 h
2.5. MISCELLANEOUS REACTIONS 67
(³) Pd(PPh3)4, DME, ArB(OH)2
I Na2C03, 90 °Ñ, 24 h
(ii) NaH, DMA, 25 °Ñ, 8 h
THF, 25 °Ñ, 2 d
(i) ArB(OH)2 5 mol% Pd(PPh3)4 Na2C03, DME
80 °Ñ, 24 h Ä.
(ii) 3% HCI in MeOH N^^NH Ar
used which is carboxylate reminiscent of Ellman’s THP linker for the immobilization of alcohols.98 The palladium-catalyzed reaction (Scheme 49) coupled a tethered ortho-bromo tetrazole and phenyl or tolyl boronic acid. After cleavage, the yield was 53-57% for the two steps. Biphenyltetra-zole is a pharmacophore of interest in the field of angiotensin II receptor antagonists.99,100
2.5. MISCELLANEOUS REACTIONS
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).