Download (direct link):
In addition to the synthetic route shown in Scheme 32, Armstrong approached the synthesis from the other direction, by converting the initial resin-bound iodide to a supported pinacolatoboronate 30 under platinum catalysis (Scheme 33). This was then coupled in the usual way with a solution-phase aryl iodide in high yield, and with much more satisfactory results than were obtained with the vinylboronates 29. This chemistry was later shown to be useful in solution for one-pot biaryl synthesis by genera-
Pd(PPh3)4, DMF, 80 °Ñ (ii) 30% TFA/CH2CI2
aryl boronates appear to be more stable than vinylboronates on the solid phase
2.4. SUZUKI REACTION 55
tion of the boronate in situ, where the competition of boronate formation and aryl cross-coupling is finely controlled by the base.79
The work by Armstrong was extended to include the room temperature resin capture of trisubstituted ethenes with a pendant boronate group.80 Modification of the amide linker above to a novel silyl-based one allowed for the traceless cleavage of superior analogues.
A similar sequence was performed later by others,81 in which the formation of the boronate was performed using palladium (PdCl2(dppf)), rather than platinum, catalysis,82 and ortho-, meta-, and para-boronates were formed. These were then coupled with a variety of aryl iodides and bromides under almost identical conditions to those used by Armstrong to generate, after cleavage, the biaryls in good yield. The reaction was markedly slower when support-bound ortho-substituted boronates were used in the coupling reaction. Both the initial formation of the boronate and the subsequent coupling reaction were allowed 20 h each to run to completion.
Using related chemistry, we have found these repetitive couplings to be facile and have used aromatic diboronic acids83 to generate simple terphenyl structures on solid support.84 We used gel-phase fluorine NMR spectroscopy85 to observe the incorporation of the appropriate groups (Scheme 34) in repeated palladium-catalyzed reactions at slightly elevated temperature (55°C). This unoptimized two-step process was complete in essentially 24 h.
2.4.3. Tropane Synthesis
Ellman reported two palladium-catalyzed reactions as part of a process to generate tropane derivatives on solid support.86 The first step (Scheme 35) was a Heck-type addition of an arylpalladium species, generated in situ, across the double bond present in the starting material. What is striking is that the reactive r|2 organopalladium intermediate 31 is treated as a discrete, isolated species, seemingly stable to (i-elimination (some related intramolecular complexes have been isolated in solution).87 Here the (3-hydrogens are not periplanar with the palladium, giving the observed stability. The first stage of the reaction, the oxidative addition across the double bond, is favored by the use of electron-rich aryl bromides. Formal split-and-mix approaches feature isolation of this intermediate; the palladium is consequently not used catalytically.
A Suzuki reaction is then performed on 31 in THF with carbonate as base and also with added triphenylphosphine, which complexes to the Pd(0) and
56 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
DMF, EtOH, 55 °Ñ, 14 h
pp* *<5 ' ' ' -lo * ' ’ -SS ' ' ' -40 ' ' -²5 ' ' -70 ’
prevents formation of palladium black. The suspension is refluxed for 48 h. Complete conversion at this stage was observed using either electron-poor or electron-rich boronic acids. Alternatively, formic acid treatment gave replacement with hydrogen. Another option that was also shown to proceed well was to carry out a coupling to an alkyne using Cu(I) as a co-catalyst.
2.4.4. p-Lactam Synthesis
Ruhland et al. used both the Suzuki and Heck (see above) reactions on solid support in their generation of libraries of biaryl- and styryl-substituted (3-lactams.45 A preliminary investigation was performed into the most generally suitable catalytic system for preparation of their libraries. This featured coupling of phenylboronic acid with a resin-bound iodophenyl (3-lactam 32 (Scheme 36); the latter compound had been formed from a
2.4. SUZUKI REACTION 57
X = H, Me, MeO
Ar B(OH)2, Na2C03, PPh3
THF or anisole, 66 °Ñ
[2+2] cycloaddition of a phenoxy ketene with a resin-bound aldimine ester. Ambient temperature coupling reactions with these systems would be attractive, but attempts to perform the trial coupling at room temperature with a variety of catalysts failed to reproduce the successful results obtained by Guiles et al. for similar reactions.75 Successful couplings were achieved with the more usual conditions of heating in DMF with Pd(PPh3)4, but a tetraarylphosphonium (3-lactam resulting from quaternization by the iodo-