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Solid-phase organik syntheses - Burdges K.

Burdges K. Solid-phase organik syntheses - John Wiley & Sons, 2000. - 283 p.
ISBN 0-471-22824-9
Download (direct link): phaseorganicsynthesis2000.pdf
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-SiMe^
N-N
Pd2(dba)3 Cul, PPh3 NEt3, 65C
"N'" // ~~ \ // ~ SiM<%
N-N xx x f/
f
R
Scheme 1.
within 5 min. Triazene unmasking involves placing the support in neat methyl iodide in a sealed tube and heating to 110C for 12 h. Yields of this reaction are generally high, although a few instances have been encountered when by-products were formed. The mechanism of this reaction has not been carefully studied, but the following is known: The reaction rate is increased by electron-donating substituents on the aromatic ring.30 In the cleavage of a hexamer from solid support, a side product was formed and determined to be the 1-iodo-olefinic hexamer derivative (Figure 4.3).15 Further characterization indicated that the by-product was a result of the trimethylsilyl acetylene moiety reacting with HI produced under cleavage conditions. Attempts to quench HI in situ (by the addition of propylene oxide or potassium carbonate) resulted in slow or no reaction. This observation suggests an acid-catalyzed mechanism for the decomposition of aryl triazenes and iodomethane. The reaction may also involve radical interme-
124 SOLID-PHASE SYNTHESIS OF SEQUENCE-SPECIFIC PHENYLACETYLENE OLIGOMERS
Figure 4.3. 1-lodoarylalkyne impurity produced during the cleavage of the corresponding hexamer.
diates; hence, functional groups that are sensitive to radicals may need to be avoided.
The final reaction in the triad, a palladium-catalyzed cross-coupling, features a catalyst cocktail solution. This is stable for up to one month and hence is particularly convenient for repeated use in solid-phase syntheses; the supernatant is added via cannula in the cross-coupling of aryl halides and terminal alkynes. The procedure for cocktail generation is also included at the end of this chapter. The generally accepted mechanism of palladium-catalyzed cross-coupling of aryl halides to terminal alkynes is shown in Scheme 2.31 Palladium starts out in the zero oxidation state. Triphenylphosphine is added to replace the highly labile dibenzylideneace-tone (dba) ligands on palladium. The catalyst converts to the more robust Pd(II) state upon oxidative addition into the aryl halide bond. A slight excess of aryl halide (1.1 equiv) is used to maintain palladium in this more durable state. This also helps to prevent diacetylenes formed by oxidative dimeri-zation. In the next step of the catalytic cycle, triethylamine removes the acidic terminal acetylene proton, producing copper acetylide and triethy-lammonium iodide. Transmetallation then occurs between this species and the Pd(II) complex, regenerating copper halide. Finally, the palladium complex rearranges to accommodate reductive elimination of the aryl acetylene, palladium returns to its zero oxidation state, and the cycle continues.
Catalyst levels necessary for the reactions outlined above usually do not exceed 5 mol %. Bromoiodoaryl monomers can also be used for selective displacements: The iodide functionality reacts much faster than bromides.34
4.3. SYNTHETIC TACTICS 125
Scheme 2.
The reaction also can be used to synthesize TMS-acetylated monomers from aryl halides (the terminal acetylene is simply trimethylsilylacetylene) and to mono-TMS-acetylate meta-di-halides. Work-up involves filtration to remove inorganic salts followed by separation via column chromatography. With the use of triphenylphosphine in this reaction, the opportunity for phenyl-aryl interchange in the palladium complex does exist, as seen in Scheme .35 Coupling yields are typically high for smaller oligomers, suggesting that ligand-monomer interchange is not a significant side reaction. As the oligomer length increases, yields tend to decrease, which is an indication that the rate of this side reaction may become competitive.
PhPPh2 ArPPh2
Ar-Pd-X ^ -.......-- Ph-Pd-X
PPh3 PPh3
Scheme 3.
126 SOLID-PHASE SYNTHESIS OF SEQUENCE-SPECIFIC PHENYLACETYLENE OLIGOMERS
4.3.2. Tethers
Triazene linkers facilitate removal of oligomers from solid supports in one step.14,15 Triazene masking groups have been tested in solution-phase synthesis of phenylacetylene oligomers.30 Triazenes are stable to many of the reagents commonly encountered in monomer synthesis, as seen in Table 4.1, though the stability of triazenes is lowered by electron-releasing groups or sterically bulky ortho substitutes.30 Electron-deficient aromatic systems lend stability by making the lone pair on the amino nitrogen less nucleo-philic and, therefore, less reactive. On the other hand, electron-rich rings tend to increase the reactivity of the triazene. At the bench, triazenes must be handled with care due to their suspected carcinogenicity.36 Most triazenes are stable to air and can be stored for months at a time. Triazene monomers are thermally stable and can be distilled under vacuum below 140C.
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