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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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Several triazene tethers for solid-phase synthesis have been investigated to optimize preparation and cleavage steps. Initially, a Merrifield resin with a piperdinemethyl ether triazene tether was made, but under rather inconvenient conditions (NaH at 70°C in a sealed tube for 96 h). In a similar fashion, a monomer attached to a (2-hydroxyethyl)-3-ethyl-triazene linkage was also prepared.16 A tether featuring an amide linkage was also synthesized by coupling the triazene monomer to the tether under mild conditions (25°C for 1.5 h) via dicyclohexylcarbodiimide (DCC) activation. These tethers proved to be problematic for several reasons. First, they had to be synthesized separately, and activating agents were required for the coupling. Second, they produce oligomer sequences that are end capped with an iodobenzene lacking a side chain, which is unfortunate if homooligomers are the desired targets. A more versatile tether, and one that could be made directly from the monomer, was prepared by converting Merrifield resin
TABLE 4.1. Reactivity of Triazenes
Triazene Stability Triazene Lability
Aqueous NaOH Mel (110°C)
Methoxide Acids (e.g., acetic acid, TFA)
Pd cross-coupling reactions Lewis acids (e.g., A1C13, BC13, TfOH)
Butyllithium Br2
Grignard reagents Me3SiI
Catechol borane Strong alkylating reagents
4.3. SYNTHETIC TACTICS 127
Scheme 4.
end groups into a w-propylaminomethylated functionality, then reacting with a diazonium salt to create the triazene tether (Scheme 4).
Procedures for the preparation of propylaminomethylated resin and the corresponding tethered monomers are found at the end of this chapter.
The ^-propylaminomethylated tether is the best identified to date because of its versatility and ease of synthesis. Although yields tend to vary depending on the side chain, the advantage of this route is that the tether is created directly from the desired monomer; thus the oligomer does not have an unsubstituted capping monomer. A protocol was developed to test that all the amino sites on the bead are converted to triazenes.15 The diazonium salt was added portionwise to the DMF-resin suspension and an aliquot was removed and quenched with diethylamine to form the 3,3-diethyltriazene. If any excess of the diazonium remained, the corresponding triazene was formed and detected by gas chromatography (GC). The reaction was complete
50 100 150 200 250
Added Diazonium (mg)
Figure 4.4. Attachment of benzenediazonium salts to n-propylaminated Merrifield's resin monitored by gas chromatography. Completion of the reaction corresponds to increased concentration of triazene.
128 SOLID-PHASE SYNTHESIS OF SEQUENCE-SPECIFIC PHENYLACETYLENE OLIGOMERS
when a significant amount of triazene had been observed (Figure 4.4). Altogether, the /ă-propylaminomethylated linkage is the tether of choice and can be extended beyond phenylacetylene oligomers.
4.4. ILLUSTRATIVE APPLICATIONS
4.4.1. Oligomers
A comparative study of phenylacetylene oligomer synthesis on a solid support14 with solution-phase approaches has been undertaken.37 Results from syntheses featuring a “free” and “bound” terminal acetylene are shown in Scheme 5. (For clarity, substituted arene units are symbolized as a filled circle throughout the rest of this chapter.)
,N3Et2
N3Et2 N3Et2
^ deprot". Î coupling
form".
iodide
SiMeg H
SiMeg
SiMes
V
Bu
SiMe^
Scheme 5.
4.4. ILLUSTRATIVE APPLICATIONS 129
In both cases, a similar r-butyl aryl halide was coupled to a terminal acetylene. Oligomer growth in solution can occur from either end of the oligomer, whereas the bound oligomer can only grow from one end. The solution yield for the reaction triad of the free dimer was 80% whereas the yield of the “supported” dimer was 89%. Figure 4.5 shows the yields for the reaction triad of higher oligomers from the dimer using the fragment condensation method.
Several comparisons can be made between the solution- and solid-phase approaches. Yields of oligomers formed on the solid phase fluctuate more than solution methods, though both are similar. Solution yield calculations were compiled from isolated yields for each of the three transformations,
Oligomer Length (n)
Figure 4.5. Solution- and solid-phase oligomer yields versus length for the indicated oligomer series.
130 SOLID-PHASE SYNTHESIS OF SEQUENCE-SPECIFIC PHENYLACETYLENE OLIGOMERS
and solid-phase yields were determined by the amount of isolated material obtained after deprotection, coupling, and cleavage. Ease of purification is the main advantage of the solid-phase approach. In solution methods, difficulties with purification increase with oligomer lengths. For instance, when making the dodecamer, it is necessary to separate unreacted hexamer and the catalyst from the product. For supported methods, however, the unreacted hexamer is washed away with the catalyst. Once the oligomer has been cleaved from the bead, chromatography allows for facile separation of the dodecamer from higher molecular weight oligomers (e.g., those occurring from intramolecular reactions on the bead). The bound hexadecamer was further reacted via the fragment condensation approach to make the 32-mer in 95% yield and 5% unreacted hexadecamer. At this point, it was increasingly difficult to separate the higher oligomers from the cleaved 32-mer. Furthermore, solubility problems arose. The bound 32-mer could be further reacted to obtain the 64-mer along with the lower analogues present. Although this sequence-doubling strategy has its limitations, it is evident that free oligomers up to the hexadecamer can be obtained readily using this method.
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