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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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h2n^0
Rink amide ^  BnBr> 'Pr2NEt
DCC, HOBt, DMF DMF, 80 把
25 把, 24 h "
(i) cat. PdCI2(PPh3)2, Bu4NCI Et3N, DMF-H20 (9:1), 80 把, 24 h
------------------------------>
(ii) 30% TFA/CH2CI2, 25 把, 2 h
Scheme 10.
2.2. HECK REACTION 35
bond migration to allow formation of the more thermodynamically stable endocyclic indole.
A common goal of library synthesis is to maximize diversity around a core, so the synthetic route described above was extended to accommodate a variety of substituted aryl groups. The modified route is shown in Scheme 11. The solid-phase starting material was Rink amide resin,36 which had been loaded with y-bromocrotonic acid (attempts to load with other suitable fragments, such as fumaraldehydic acid, or the pentafluorophenol-activated ester, failed). Substituted ortho-iodoanilines could then be used to alkylate
H
0^v/N\
N 'Pr2NEt, DMF ] I Pr2NEt
" DMF, 80 把
(i) PdCI2(PPh3)2, Bu4NCI Et3N, DMF/H20 (9:1), 80 把
(ii) 30% TFA/CH2CI2, 25 把, 2 h
Br
Scheme 11.
36 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
this resin to give the support-bound precursor 8. As before, the nitrogen could then be alkylated, providing additional diversity, before the cycliza-tion step was performed to give the desired indoles after cleavage in high purity and 67-88% yields overall based on the loading of the initial resin. Both electron-withdrawing and electron-donating substituents were tolerated as R1. A small (18-member) library was prepared where the methyl ester functionality incorporated as R1 was cleaved (with potassium trimethylsilanolate)37 and then coupled to a peptide fragment to give compounds of type 9. Adaptation of this work to the benzofuran nucleus, that is, the replacement of the NH with O, was also shown for two cases, with similar yields and purities; this followed from the solution-phase studies by
Et3N, DMA, 85 把, 6 h
(ii) TFA
p-elimination
I (3-elimi
elimination
12, 55% desired
Pd-catalyzed
rearrangement
13, 23% undesired
Scheme 12.
2.2. HECK REACTION 37
Larock.38 The method allows for variation in the aromatic ring component. An interesting feature of this work, probably influenced by the ease of cleavage of the Rink linker, is that all characterization and yield calculations were done off-bead.
The same exo to endo bond migration shown above was postulated earlier by Yun and Mohan in their studies on the synthesis of indole analogues.39 The precursor species 10, assembled principally in solution, then deriva-tized on resin, was subjected to Heck conditions at elevated temperature, as shown in Scheme 12. The progress of the reaction was monitored by HPLC of cleaved product. It was claimed that an inert atmosphere was essential to the reaction owing to the oxidation of Pd(0) at elevated temperatures; this catalyst oxidation was associated with unwanted reductive debromination of the starting material, though the mechanism for this is unclear. Eight different indoles were produced, using 50 mol % palladium catalyst for the cyclization, in good to excellent yields based on the initial loading of the polymer; poor purities were obtained in some cases, however. An interesting by-product was formed in the case of the indole shown in Scheme 12. At the stage of (-elimination from 11, the sterically less hindered path appears to have been taken to generate the terminal alkene 12 rather than that to give the desired indole 13.
Steric influences were proposed to account for the result shown above, but other observations suggest that it is the phenyl group that is important
HO
O'
84%
jPr
14
HO
O'
15
34%
Scheme 13.
38 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT
and that it somehow disfavors endo elimination. Thus Scheme 13 indicates the case of amide 14 wherein an iso-propyl group (rather than a phenyl) is present. This cyclization proceeds well. Conversely, the yield for the cycli-zation is low when there is no alternative elimination possible, but again a phenyl group is attached to the amide, that is, for substrate 15.
2.2.3. Polymer Construction on Solid Support
In a study of syntheses of polymers on solid support, Tour et al. found they could rapidly produce oligo(l,4-phenyleneethynylene)s of defined lengths.40 This area will not be discussed in detail, but since a report by Moore in 1994, much elegant and efficient solid-phase chemistry has been developed (see Chapter 4) 41,42 Solution-phase chemistry used for the present example is shown in Scheme 14. Central to this are a palladium/copper co-catalyzed coupling reaction and a doubly protected monomer unit 16 having a silylated alkyne and a diethyltriazene group. The former may be protodesilylated to generate a terminal alkyne for the coupling, and the
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