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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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Scheme 18.
cat. PdCI2(PPh3)2 TsN
Cul, Phi, Et3N -
ch2ci2 Qf
/ = Ph

One of the most striking demonstrations of the Heck reaction on solid phase was an efficient macrocyclization reaction by Hauske et al. They cyclized the resin-bound species 19 under mild conditions and obtained products with high post-cleavage purity (Scheme 19).49 The efficiency of these reactions for a variety of structural modifications in the ring seems to suggest that the pseudodilution effects of site isolation on resin are important.
Magic angle spinning (MAS) NMR spectroscopy has been used to monitor reactions on solid support,50,51 as demonstrated for a three-step process involving a Heck transformation.52 The key step involves the simple coupling of ethyl acrylate to an aryl iodide bound to a Wang Lys(Boc) resin (Scheme 20). Examining the resin with TOCSY NMR spectroscopy facilitated observation of the appearance of ethyl acrylate peaks on resin; it was also possible to deduce the trans nature of the resultant double bond. Cleavage of the resin with 90% TFA in DCM resulted in a single peak on HPLC analysis, and from this the authors concluded that the reactions in the sequence had proceeded quantitatively.
zx
2.2. HECK REACTION 43
QO
Pd(OAc)2, PPh3, Bu4NCI
----------------------->
DMF/H20/Et3N, 25 , 12 h
0
78% Scheme 19.
^C02Et --------------->
Pd(OAc)2, P(o-Tol)3 DMF, 60 , 19 h
a'
Ck
44 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT

20
=^~SiMe3 10mol%Cul/Pd(PPh3)4 H
THF, Et3N, 25 , 40 h
H (i) R2CHO, 10 mol% CuCI
N N-R
Scheme 21.
NH
12 + ¥
.OH
DIC, DMF
25
HISL
RNHo
vBr
DMSO, 25
HNk

"NHR
(i) Pd(PPh3)4, PPh3 NaOAc, DMA, 85 , 5 h
(ii) TFA/H20
Scheme 22.
2.3. STILLE REACTION 45
A more recent use of the palladium/copper co-catalyzed Sonogashira reaction is the solid-phase synthesis of propargylamines (Scheme 21).53 The coupling was used at the outset of a library synthesis to convert the resin-bound aryl iodide 20 to terminal acetylene 21. The product was substrate for a Mannich reaction with an aldehyde and substituted piperazine in solution to yield, after cleavage, propargylamines 22 in good yields and purities. Various secondary amines were shown to be successful in the Mannich step, but ortho- and meta-substituted iodobenzoic acids initially could not be substituted for the para-isomer. The reactions were successfully performed by changing from a polystyrene- to a PEG-based support (with the same linker); no details were given, however.
In the final example of the Heck reaction on solid support, a Chiron group54 55 used a palladium-catalyzed cyclization step to prepare heterocycles. An example of their work, the production of l-(2H)-isoquinolinones, is shown in Scheme 22.
2.3. STILLE REACTION56
An early attempt to use the Stille reaction on solid support is detailed in a paper from 1994 by Deshpande.57 In this, an aryl iodide linked to Rink amide or Wang resin is coupled to a number of vinyl and one arylstannanes (Scheme 23). The protocol used only 5 mol % Pd^dba^ and proceeded in typically 90% yield at 45C. Interestingly, the reactions were simply left to stand (rather than being shaken) overnight.
In a subsequent paper on the use of the Stille reaction to form biaryls,58 the reaction was carried out under ambient conditions to allow robotic automation of the process. Attachment of the tin species to resin was very straightforward, in that 4-tn--buty 1st an nyl phenyl acetic acid was linked to Rink amide resin simply using a DIC coupling. Loading of this species was determined by tin elemental analysis and correlated with a quantitative ninhydrin test of free amines remaining on the support (Scheme 24).
One of the earliest examples of gel phase carbon NMR spectroscopy facilitated detection of support-bound tin species. When the Stille couplings were attempted using triphenylphosphine and PdCl2(PPh3)2, no products were observed on cleavage from the resin. However, when the conditions developed by Farina59 were used [tri-2-furylphosphine and Pd2(dba)3], biphenyl was produced in low yield, with iodobenzene giving a higher yield of product (15%) than benzene triflate (3%). Having shown partial conver-
46 PALLADIUM-CATALYZED CARBON-CARBON BOND FORMATION ON SOLID SUPPORT

(i) 5 mol% Pd2(dba)3 20 mol% AsPh3 NMP, 45 , 16 h
(ii) 5 % TFA/CH2CI2
h2noc
85%
H2NOC
Scheme 23.
sion at room temperature in 12 h, the polarity of the reaction was switched using 4-iodophenylacetic acid bound to the resin (Scheme 25). This reacted with trimethylphenyl tin under Farina conditions and formed the biphenyl product in 21% yield. Using tributylphenyl tin, the yield increased to 33%. However, other products were also formed, such as 23 and 24, the latter arising from alkyl transfer from the tin species. It was suggested that the polymer-bound tin species might adversely affect the swelling properties of the resin. However, the differences in the yields are really quite small in
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