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(Table 4.6). Specifically, the methods used were to (1) add a tag (type of atom or physical change tracked in these calculations); (2) remove a tag element from the resin during reaction; or (3) use a tag element unique to the resin before and after reaction. Error was estimated by accessing limitations of elemental analyses and known resin functionalization error. While the third case listed could not be applied to the phenylacetylene
120 -j ? 100 -ô 80 -
3 40 -
° 20 -0 -
0 2 4 6 8
—•—case 1 case 2
Figure 4.8. Cases 1 and 2 (Table 4.6) calculated yields for n-propylamination of Merrifield's resin versus chronological reaction attempt.
140 SOLID-PHASE SYNTHESIS OF SEQUENCE-SPECIFIC PHENYLACETYLENE OLIGOMERS
oligomer system, cases (1) and (2) were applicable to transformation of MerrifielcTs resin to the /³-propylaminomethyl-substituted resin. Figure 4.8 shows calculated yields using both cases 1 and 2 for this transformation. Yields were variable for even this simple starting transformation. Taking error into consideration, as well as low detection limits for nitrogen and chlorine in elemental analyses, the stated yields are quite liberal. In addition, their irregularity over eight reaction attempts (given in chronological order) highlights the unreliability. Since it is extremely difficult to estimate a dependable degree of substitution because the resin comprises a vast majority of the mass, yield calculations are inherently variable.
Despite the obstacles discussed above, solid-phase syntheses of oligomers do have two significant advantages over solution techniques. First, purifications in solid-phase techniques are easier and faster than in solution and are more likely to be amenable to automation. Second, hetero-oligomerizations are relatively easy to arrange if one component is anchored to a solid phase. Overall, the advantages of solid-phase syntheses of oligomers, as well as other products, can be appreciable for reproducible, reliable, and easily monitored reaction schemes.
Solid-phase methods are applicable to syntheses of sequence-specific oligomers and dendritic structures. The triazene chemistry developed for this specific purpose may also be useful in other types of syntheses. Further development of solid-phase syntheses of this type into combinatorial synthesis of oligomers is the next logical step. Solid-phase methods will never completely replace solution-phase approaches to oligomers, but either technique should be considered with respect to the special characteristics and requirements for the system under investigation.
4.7. REPRESENTATIVE PROCEDURES44
4.7.1. Trimethylsilyl Deprotection
To a suspension of the polymer-supported trimethylsilyl (TMS) protected acetylene tetramer (241 mg, 0.0757 mol) in THF (2 mL) was added a solution of tetrabutylammonium fluoride (TBAF) in wet THF (0.15 mL, 1.0
4.7. REPRESENTATIVE PROCEDURES 141
M) (Scheme 9). The suspension was agitated periodically for 5 min. The polymer beads were transferred to a fritted filter using THF and washed sequentially (7.2 mL) with THF and then methanol. The polymer beads were dried in vacuo to a constant mass to give polymer-supported terminal acetylene as light yellow beads.
4.7.2. Cleavage of Oligomers from the Polymer Support
A suspension of the polymer-supported TMS-protected acetylene hexamer (2.71 g, 0.279 mequiv/g) and iodomethane (27.0 mL) were degassed and heated at 110°C in a sealed tube for 12 h (Scheme 10). After the iodomethane was removed in vacuo, the product was extracted from the resin using hot CH2C12. The resulting solution was cooled and filtered through a plug of silica gel, and the CH2C12 was removed in vacuo to give an oily brown residue. The residue was purified by filtration through a plug of silica gel in CH2C12 to give 459.8 mg (0.44 mmol, 58%) of iodo-terminated hexamer as a white powder.
142 SOLID-PHASE SYNTHESIS OF SEQUENCE-SPECIFIC PHENYLACETYLENE OLIGOMERS
4.7.3. Preparation of a Soluble Pd(0) Coupling Solution
Under a nitrogen atmosphere, a mixture is prepared consisting of tris(diben-zylideneacetone)-dipalladium(O) (34.5 mg, 60 umol). Cu(I) iodide (11.4 mg, 60 |J.mol), triphenylphosphine (78.7 mg, 0.30 mmol), and dry, degassed triethylamine (15 mL) as solvent. The mixture is degassed and filled with nitrogen two more times, then stirred at 70°C for 2 h. After standing overnight, the supernatant from this solution can be transferred via cannula in the amount of 6 mL/g (0.7 mequiv/g) resin to another flask for use in the palladium-catalyzed cross-coupling reaction of an aryl halide and a terminal acetylene.
4.7.4. Palladium-Catalyzed Coupling
To a heavy-walled flask equipped with a nitrogen inlet side arm was added resin-bound terminal acetylene (684.4 mg resin, 0.274 mmol, 0.448 mequiv/g resin) and aryl iodide (120.6 mg, 0.3011 mmol) (Scheme 11). The flask was evacuated and back-filled with nitrogen a minimum of three times. The supernatant of a separate 0.2 M catalyst cocktail solution (previously prepared) was added via cannula (5 mL, 3.0 mmol) to the reaction flask. The flask was kept sealed at 65 °Ñ for 12 h and agitated periodically to remix polymer beads stuck on flask walls. The beads were then transferred to a fritted filter using methylene chloride and washed with methylene chloride (21 mL). Excess aryl iodide can be recovered from the first methylene chloride wash. All further washes were carried out in the ratio of 30 mL/g resin. The resin was washed sequentially with DMF, 0.05 M solution of sodium diethyl dithiocarbamate in 99 : 1 DMF-diisopropylethylamine,