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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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H
bocxn^^oh (') RNQ
H (ii) MeOH
H 6
H

() S03H
51
(resin capture)
H
(ii) ammonia/MeOH (resin release)

purified
Scheme 6.
5.10. COMBINATIONS OF SOLID-AND SOLUTION-PHASE TECHNIQUES 179
TFA resin release
Anionic resin capture of solution-phase library products has also been reported. The anion exchange resin A-26 hydroxide 6 was used in a dual capacity to mediate Dieckmann condensations of solution-phase library intermediates and also to affect resin capture of the formed tetramic acids as polymer-bound intermediates (Scheme 7).79 Rinsing, followed by tri-
R2NH2
+ -----------------
or R2OH
SOgNHCOXR?
or 2 (resin capture)
jQ>~CONHCOXFf
(resin release)
X = or NH
Scheme 8.
polymer-
trapped
salts
R3 /?
R. // R2
N-
HO^
R1
Scheme 7.
180 POLYMER-ASSISTED SOLUTION-PHASE METHODS
fluoroacetic acid-mediated resin release, afforded purified tetramic acids. Anionic resin capture has also been reported to purify a series of acidic A^-sulfonylureas, /V-sulfonylcarbamates, /V-acylureas, and N-acyl carbamates (Scheme 8). The basic polyamine resin 2 affected ionic resin capture of these intermediates. Rinsing, followed by acetic acid-mediated release, afforded purified products.32
5.10.2. Use of Solution-Phase Technologies to Expand the Scope of Solid-Phase Organic Synthesis
Polymer-assisted solution-phase technology has expanded the range of reactions that can efficiently be used to release products from polymer supports. Prior to this combined technology approach, only volatile reagents (e.g., HF, TFA) were typically used in release steps; however, polymer-assisted solution-phase techniques are now enabling the use of nonvolatile reagents. Scheme 9 illustrates how the carboxy-tagged phosphine 52 was used to mediate the release of sulfides from solid-phase supported disulfides.80 The tetramethylguanidine-functionalized resin 53
Scheme 9.
5.10. COMBINATIONS OF SOLID-AND SOLUTION-PHASE TECHNIQUES 181
was then added to the reaction mixtures to sequester carboxy-tagged phosphine and the corresponding phosphine oxide and also to mediate the solution-phase cyclization to the desired (-turn mimetics.
The nonvolatile oxidant (DDQ) was used to mediate the release of alcohols from solid-phase Wang-type ethers 54.81 Purification of the released alcohols was affected by the use of a mixed-resin bed containing Amberlyst A-26 ascorbate 55 (to reduce excess DDQ to its hydroquinone byproduct) and also Amberlyst A-26 bicarbonate 56 (to sequester the acidic hydroquinone byproducts). Filtration afforded purified alcohols in excellent yields and purities.
Release of substrates from polymer supports can sometimes provide an opportunity to increase diversity. For instance, excess secondary amines were used to release tertiary amines from a series of polymer-bound alkyl sulfonates 57 (see the diagram below).82 Phthalic anhydride was then used as a solution-phase linking reagent to transform the excess secondary amines into their phthalate half acids, which in turn were sequestered by the amine-functionalized ion exchange resin IRA-400 58. Similarly, excess amines were used to mediate diversifying release from polymer-bound pyrimidin-2-yl sulfones 59, forming the desired 2-aminopyrimidines (reaction 23).83The strongly acidic sulfonic acid ion exchange resin 51 was then added to sequester excess amines from the solution phase.

OH

OH
ROH
OR
54
N+Me3 ascorbate
55
56
182 POLYMER-ASSISTED SOLUTION-PHASE METHODS
o^
excess
57
^ IRA400 58
NHR1R2
CONR1R2
C02H
Qf
N^n
(i) r3nh2 (ii) " O-SO3H 51
(23)
NHR'3
59
5.11. MULTISTEP/ONE-CHAMBER SOLUTION-PHASE SYNTHESIS
One research group has exploited the concept of polymer site-isolation in a multistep/one-chamber solution-phase synthesis in which all the reagents, catalysts, and downstream reactants required for a multistep synthesis were combined in one reaction chamber. For instance, a one-chamber/three-step synthesis of substituted acetophenones has been reported (Scheme 10).84 An oc-phenethyl alcohol was introduced into a reaction chamber containing the polymer-supported reagents and reactants necessary to accomplish oxidation by polymer-supported pyridinium di-chromate 60; bromination by the A-26 perbromide resin 61; and nucleophilic displacement by the A-26 phenoxide resin 62. Filtration afforded the
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