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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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5.12. POLYMER-ASSISTED TECHNOLOGIES
183
Scheme 10.
product in 48% yield, compared with a 42% overall yield when each of the three steps was performed separately.
5.12. POLYMER-ASSISTED TECHNOLOGIES IN MULTISTEP SOLUTION-PHASE SYNTHESES
Polymer-assisted methodology has been used several times for parallel-ar-ray synthesis of libraries involving three to five synthetic steps. Scheme 11 shows a three-step solution-phase synthesis of 2-thioxo-4-dihydro-pyrimid-inones wherein the key purification step involved amine resin 1 to sequester excess aldehydes and isot;hiocyanates from upstream transformations. Thermal cyclization of the purified intermediates gave the desired 2-thioxo-4-dihydropyrimidinones in excellent yields and purities.85
184 POLYMER-ASSISTED SOLUTION-PHASE METHODS
r2 R3CHO R2
MeCyxXMU NaBH(OAc)3
Ji 2 R1
aqueous wash R4NCS r2
NEt3 __ MeCfeC^XN^R3
NH* rs^nh R2
1 R4
Scheme 11.
OMe
(i) Yb(OTf)3 ^^R1
1 U)YDiUIT)3
-R (iB resin 3 I v
N'R ', (ii) resin 3
r2AH + A OTMS (i'O HCI/EtOAc R
,2
() H2P2 (aq extraction)
(ii) R3NH2, MeOH
R3NH
BH4
63
H4\

64
1
.R1
(i) R COCI
N

10
(ii) resin 3
NHo
Scheme 12.
5.12. POLYMER-ASSISTED TECHNOLOGIES 185
A four-step solution-phase synthesis of 4-aminopiperidines containing four sites of diversity is shown in Scheme 12.23 Polymer-assisted steps involved
polyamine resin 3 to sequester residual imine reactant and unwanted enone byproduct generated from Danishefskys diene;
supported borohydride reagent 63;
aldehyde resin 64 to sequester excess amine reactants;
polymer-supported tertiary amine base 10 to mediate amine acylations; and,
polyamine resin 3 to sequester excess acylating reactants.
Bifunctionally tagged Mitsunobu reagents 21 and 22, quaternary ammonium carbonate resin 65, tetrafluorophthalic anhydride (as a solution-phase linking reagent), and amine-functionalized resin 2 were used in a three-step solution-phase synthesis of a series of substituted hydroxypiperidines.39 No further purification (e.g., liquid-phase extraction or chromatography) was required, and products were isolated in good yields and purities.
A four-step synthesis of a series of 4-hydroxyquinolinones starting from anthranilates is shown in Scheme 13.86 Resin capture of the Dieckmann cyclization intermediates was used as the main purification technique for this synthesis. Rinsing of the resin-captured adducts removed neutral and
186 POLYMER-ASSISTED SOLUTION-PHASE METHODS
R
(i) R CHO , c2Me (ij) NaBH(OAc)3 R
NHo
(iii) R4CH2COCI Na2C03, CH2CI2
j
C02Me ,
n^-r4
N+Me3 OH' 6
resin capture
TFA
basic impurities from the first three steps. The TFA-mediated resin release led to the isolation of the desired 4-hydroxyquinolinones in excellent purities and good overall yields.
Finally, a five-step solution phase synthesis of benzoxazinones used a combination of reactant- sequestering resins, a bifunctional linking reagent, a polymer-supported reagent, and solid-phase quench for synthesis and purification (Scheme 14)22: This features
tetrafluorophthalic anhydride and electrophile-sequestering resin 2 in the first step;
electrophile-sequestering resin 2 for purification in step 3;
TBAF-quenching calcium sulfonate resin 4 and acidic-quench resin 51 in step 4; and
polymeric EDCI reagent 65 in step 5 to mediate the cyclodehydration.
5.13. CONCLUSION 187
R2COCI or R2NCO ------------------>
tetrafluorophthalic anhydride, resin 2
(i) HCI/dioxane
----------------------->
(ii) R3COCI or R3OCOCI or
R3NCO or R3S02CI resin 2
C02CH2CH2TMS
NHCOR2
TBAF/THF
resins 4 and 51
R1 R1
R3nh 4^C02h resin65 R3nh

NHCOR2
N 65
Scheme 14.
5.13. CONCLUSION
Polymer-assisted solution-phase synthesis offers strategies for chemical library construction that complement solid-phase methods. Tools now available include chemoselective sequestering resins, bifunctional solution-phase linking reagents, bifunctional chemically tagged reagents, and an
188 POLYMER-ASSISTED SOLUTION-PHASE METHODS
expanded range of available polymer-supported reactants, reagents, and catalysts. Applications such as resin capture/resin release and polymer-assisted use of nonvolatile reagents for SPOS release protocols are now blurring the boundary between polymer-assisted solution-phase and solid-phase synthesis. Finally, polymer-assisted solution-phase technologies are now sufficiently mature to enable multistep library synthesis.
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