Polymer-supported organotin reagents in the catalytic Stille reaction

Article abstract of DOI:10.1016/j.tetlet.2003.09.143

Polymer-supported dibutyltin chloride and dimethyltin chloride resins were synthesised and used in Maleczka's catalytic Stille reaction.

Full text of DOI:10.1016/j.tetlet.2003.09.143

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8601–8603
Polymer-supported organotin reagents in the catalytic
Stille reaction
Alejandro G. Herna´n, Vincent Guillot, Alexander Kuvshinov and Jeremy D. Kilburn*
Combinatorial Centre of Excellence, Department of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
Received 24 July 2003; revised 5 September 2003; accepted 12 September 2003
Abstract—Polymer-supported dibutyltin chloride and dimethyltin chloride resins were synthesised and used in Maleczka’s catalytic
Stille reaction.
© 2003 Elsevier Ltd. All rights reserved.
The palladium-catalysed Stille coupling of a vinyl stan-
nane to an organic halide is a widely used car-
bonꢀcarbon bond forming reaction, but suffers from
the formation of stoichiometric tin by-products.1
Recent work by Maleczka has demonstrated that for-
mation of a vinyl stannane coupling partner, by in situ
hydrostannylation of an alkyne, allows the reaction to
be carried out with as little as 5 mol% of trimethyltin
chloride (which gave significantly better yields than
tributyltin chloride) as the precursor tin reagent.2 The
catalytic cycle developed by Maleczka raises the possi-
bility of using a solid supported tin reagent, which can
be removed by filtration at the end of the reaction and
potentially giving coupled products completely free of
residual tin impurities. In this communication we
not been reported. In order to investigate the potential
of resin bound tin reagents in Maleczka’s catalytic Stille
protocol we prepared both dibutyltin chloride and
dimethyltin chloride resins 3 and 4.
The resins 3 and 4 were prepared by hydrostannylation
of resin-bound allyl ether 2, prepared from Merrifield
resin 1 (1.6 mmol/g, 1% DVB).3f,g,i Hydrostannylation
of the alkene was accomplished using Neumann’s
procedure3a with Bu2SnHCl, prepared in situ from a 1:1
mixture of Bu2SnH24 and Bu2SnCl2, and gave dibutyltin
chloride resin 3 as a white solid (Scheme 1).
Dimethyltin chloride resin 4 was prepared by an
analogous procedure. Me2SnH2 was most conveniently
prepared on a small scale by reduction of Me2SnCl2
using Bu3SnH, followed by distillation, according to
Kuivila’s method.5 The Me2SnH2, which decomposed
rapidly,6 was mixed immediately with Me2SnCl2 to
produce Me2SnHCl and used for the hydrostannylation
of resin 2. The excess of Me2SnHCl used in the synthe-
sis of 4 decomposed during the reaction forming a grey
precipitate (presumably metallic tin). An acidic wash
(1:1 1N HCl/MeOH) removed the impurities to give 4
as a white solid. Both polymers 3 and 4 were character-
describe the synthesis of
a
polymer-supported
dimethyltin chloride reagent, which has been success-
fully used in the Maleczka catalytic Stille coupling.
Several examples of resin-bound dibutyltin chloride and
hydride reagents have been previously described3 and
have been investigated extensively in tin hydride medi-
ated radical reactions3a,d and stoichiometric Stille cou-
plings,3b,e but to our knowledge the analogous resin
bound dimethyltin chloride and hydride reagents have
Scheme 1.
Keywords: Stille reaction; polymer-supported; tin chloride.
* Corresponding author. Tel.: +44-23 80593596; fax: +44-23 80596805; e-mail: jdk1@soton.ac.uk
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.143

8602
A. G. Herna´n et al. / Tetrahedron Letters 44 (2003) 8601–8603
ised by tin and chlorine microanalysis and by gel-phase
13C and 119Sn NMR.7 The NMR data was consistent
with the literature.3c,8 Confident in the structure of both
polymers we tested them in the catalytic Stille protocol
described by Maleczka.
The dimethyltin chloride resin 4 also gave much better
results than the dibutyltin chloride resin 3 which is in
good agreement with the superiority of Me3SnCl in
comparison with Bu3SnCl in Maleczka’s cycle.
Maleczka reported that the catalytic cycle suffers from
deactivation of the organotin hydride intermediates by
oxidative coupling to give distannane species. We had
thought that the catalytic cycle might be more tolerant
to various reaction conditions using polymer-supported
organotin reagents since the effective isolation of the
reactive sites might result in the suppression of the
oxidative coupling.11 However, a dramatic decrease in
yield was observed when changing to other solvents
(DMF) or catalytic systems (Pd(PhCN)2Cl2/Ph3As)
routinely used in Stille couplings. Reaction optimisa-
tion using the less reactive Stille coupling partner bro-
mobenzene was also unsuccessful.
In a typical procedure the tin chloride resin (6–100
mol%) was suspended in an aqueous Na2CO3/THF
mixture (1:20), with an alkyne 6, palladium catalyst
system (1 mol% Pd2dba3, 1 mol% PdCl2(PPh3)2 and 4
mol% tri-2-furylphosphine) and polymethylhydrosilox-
ane (PMHS) (1.5 equiv.). Aryl iodide or bromide 5 (1.5
equiv.) was added over 15 h by syringe pump. Using
these optimised conditions, as reported by Maleczka
with trimethyltin chloride, the coupling of b-bro-
mostyrene and o-iodoanisole with various alkynols9
proceeded in good yield (Table 1) despite the multiple
phases in which the catalytic cycle has to take place
(aqueous, organic and polymeric). Substoichiometric
(30 mol%) amounts of the dimethyltin chloride resin 4
could be used satisfactorily, but lower amounts of resin
(6 mol%) did give significantly reduced yields. Clearly
the reducing agent PHMS is able to regenerate the
polystyrene bound R(Me)2SnH in contrast to its
reported ineffectiveness for the regeneration of
R(Bu)2SnH in the polymer supported catalytic Barton–
McCombie deoxygenation of secondary alcohols.3h
In summary, we report the use of catalytic amounts of
polymer-supported organotin reagents in a Stille reac-
tion. The polystyrene-based reagents present similar
chemical limitations to the soluble tin chloride reagents
in the same catalytic cycle. Work is currently underway
to improve the performance of the reagent and to
exploit the potential technical advantages of this
method.
After chromatographic purification the reaction prod-
ucts were obtained microanalytically pure and tin analy-
sis showed low or insignificant tin content (<5–60
ppm).10 In comparison, using the same chromato-
graphic purification of reactions conducted using solu-
ble trimethyltin chloride, gave products with tin
impurities >500 ppm.
Acknowledgements
The authors acknowledge the supporting partners of
the Southampton Combinatorial Centre of Excellence
for financial support. The funding partners are Amer-
sham Health and Amersham Biosciences, AstraZeneca,
Table 1.
R1-X
Alkyne
Resin
Resin (equiv.)
Conditions
Yield of 7 (%)
4-Iodoanisole
4-Iodoanisole
4-Iodoanisole
4-Iodoanisole
4-Iodoanisole
4-Iodoanisole
4-Iodoanisole
4-Iodoanisole
4-Iodoanisole
b-Bromostyrene
b-Bromostyrene
b-Bromostyrene
b-Bromostyrene
b-Bromostyrene
Bromobenzene
Bromobenzene
R2=Ph
R2=Ph
R2=Ph
R2=Ph
R2=Ph
R2=Ph
R2=Me
R2=Me
R2=C6H11
R2=Ph
R2=Ph
R2=Me
R2=Me
R2=Ph
R2=Ph
R2=Ph
4
4
4
3
4
4
4
4
4
4
3
4
4
4
4
4
1.0
0.3
0.06
1.0
1.0
1.0
0.3
0.3
0.3
0.3
1.0
0.3
0.3
0.3
0.3
1.0
a
a
a
a
b
c
63
60
21
20
5
0
a
c
57
10
55
50
15
67
7
60
9
0
a
a
a
a
c
a
a
b
Conditions: (a) 1 mol% Pd2Cl2(PPh3)2, 1 mol% Pd2dba3, 4 mol% (2-furyl)3P, 1.5 equiv. PMHS, Na2CO3, H2O/THF, reflux; (b) 1 mol%
Pd(PhCN)2, Ph3As, 1.5 equiv. PMHS, Na2CO3, H2O/THF, reflux; (c) 1 mol% Pd2Cl2(PPh3)2, 1 mol% Pd2dba3, 4 mol% (2-furyl)3P, 1.5 equiv.
PMHS, Na2CO3,H2O/DMF, reflux.

A. G. Herna´n et al. / Tetrahedron Letters 44 (2003) 8601–8603
8603
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27.8, 40.3 (br), 71 (br), 73.1; 119Sn NMR (C6D6; 112
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