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5.10. COMBINATIONS OF SOLID- AND SOLUTION-PHASE TECHNIQUES 175
RCHO + ^\^Sn(CH2CH2C6F 13)3
nique in a synthesis of diamine-funetionalized triazines. Filtration of the crude mixtures from sequential S^Ar reactions through columns of acid-treated diatomacious earth led to sequestration of excess amine R3-NH2 and the amine hydrochloride byproducts. The end products were isolated in excellent yields and purities.
Fluorous-tagged reagents, coupled with post-reaction fluorous liquid-phase extraction, has been reported as a synthetic strategy for solution-phase chemical library synthesis.14,15 A polymer-supported fluorous-phase has recently been developed as an extension of this methodology.72 Scheme 4 illustrates how the fluorous chromatographic support 49 was used to separate homo-allylic alcohols from fluorous-tagged allyl stannanes and their byproducts. Filtration of crude reaction mixtures through the fluorous-phase bonded silica gel support led to efficient sequestration of the fluorous-tagged stannane reagents and byproducts. This polymer-fluorous-phase quench technique should widely expand the scope of reactions that can be handled efficiently in a robotic laboratory environment when avoidance of liquid-phase extraction is desired.
5.10. COMBINATIONS OF SOLID- AND SOLUTION-PHASE TECHNIQUES IN ORGANIC SYNTHESIS
5.10.1. Resin Capture of Products from Soiution-Phase Syntheses
Solid- and solution-phase organic syntheses are no longer distinct branches of chemistry, and several reports of combined technology applications have
176 POLYMER-ASSISTED SOLUTION-PHASE METHODS
emerged. One such application is now referred to as “resin capture” of solution-phase library products.
The first report of resin capture in solution-phase chemical library synthesis involved the covalent capture of solution-phase Ugi reaction products onto a functionalized polystyrene resin.73 Excess reactants, reagents, and reagent byproducts were washed away from the resin-captured intermediates. Further manipulation and release afforded purified solution-phase products for screening. More recently the same group reported on resin capture as a technique for the preparation of tetrasubstituted olefin libraries.74’75 As illustrated in Scheme 5, c/s-vinyl di-boryl esters were reacted with aryl halides (R3ArX) in parallel Suzuki reactions, leading to solution-phase intermediates. Another Suzuki reaction, this time with the
5.10. COMBINATIONS OF SOLID- AND SOLUTION-PHASE TECHNIQUES 177
polymer-supported aryl iodide 50, led to resin-captured intermediates. Excess of solution-phase reactants, reagents, palladium catalyst and any undesired bis-Suzuki side products (from solution-phase reaction of excess R3ArX at the second boryl ester site) were rinsed away from the captured intermediates. Finally, trifluoroacetic acid-mediated release (protodesily-lation) led to the isolation of purified tetrasubstituted alkenes.
In addition to these reports of covalent resin capture, several groups have used reversible ion pairing as a resin-capture/resin-release technique. In one report, the parallel-array reactions of excess epoxides with trimethylsilyl-protected primary amines gave crude ethanolamines (reaction 20).76 Cationic resin capture of the ethanolamines was mediated by the strongly acidic sulfonic acid ion exchange resin 51. Rinsing and subsequent release by ammonia/methanol cationic exchange afforded purified ethanolamines. A similar report described the resin capture of tertiary amine products by a strongly acidic sulfonic acid cation exchange resin (reaction 21).31 A solution-phase synthesis of amino-imidazopyridines, formed in a multicomponent reaction involving aminopyridines, aldehydes, and isocyanides, was described. A similar cationic resin-capture/ammonia-release strategy was employed (reaction 22).77
H ^ All
M R3 î (resin capture) Vě H
Me3srNX + Xŕ --------------------------- r4-^nVr (20)
R1 R2 R4 (ii) ammonia ni\,2
MeOH H R
(i) DIC, HOBT
(iii) ammonia/MeOH (resin release)
178 POLYMER-ASSISTED SOLUTION-PHASE METHODS
NH* m Q-HX
R2NC (iii) ammonia/MeOH
An interesting variant of cationic-resin capture has recently been reported wherein a strongly acidic cation exchange resin mediated sequential amine deprotection and resin capture (Scheme 6).78 Protected aminoalco-hols were reacted with an excess of isocyanates to form iV-BOC-amine carbamates in solution phase. Methanol was subsequently added to quench excess isocyanates as the neutral methyl carbamate byproducts. Sulfonic acid resin 51 was then used to affect amine-BOC group deprotection and resin capture of the deprotected amines. Washing of the resin bed and release (ammonia/methanol) afforded purified amine carbamate products.