Evaluation of polymer-supported vinyltin reagents in the Stille cross-coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2007.01.028

The synthesis of two new vinyltin reagents grafted on an insoluble macroporous polymer is reported. These reagents were used in the palladium-catalyzed Stille cross-coupling reaction with aryl halides. In all reactions, the conversion of the starting aryl halide is high and the amount of organotin by-product is particularly low (at the end of the catalytic run, the amount of Sn is up to 16 ppm in the crude reaction mixture removed of the insoluble polymer, and it is less than 1 ppm in the product purified by chromatography on silica gel).

Full text of DOI:10.1016/j.tetlet.2007.01.028

Tetrahedron Letters 48 (2007) 1781–1785
Evaluation of polymer-supported vinyltin reagents
in the Stille cross-coupling reaction
a
a
a,
a
Jean-Mathieu Chretien, Aurelie Mallinger, Franc¸oise Zammattio, * Erwan Le Grognec,
´
´
Michae¨l Paris,b Gilles Montavonc and Jean-Paul Quintarda,*
a
`
Universite´ de Nantes, Nantes Atlantique Universite´s, CNRS, Laboratoire de Synthese Organique (LSO),
`
UMR 6513, 2 rue de la Houssiniere, BP 92208, 44322 Nantes cedex 3, France
bUniversite´ de Nantes, Nantes Atlantique Universite´s, CNRS, Institut des Mate´riaux Jean Rouxel,
`
UMR 6502, 2 rue de la Houssiniere, BP 32229, 44322 Nantes cedex 3, France
c
´
Universite´ de Nantes, Nantes Atlantique Universite´s, Ecole des Mines de Nantes, CNRS, Subatech,
UMR 6457, 4 rue Alfred Kastler, BP 20722, 44307 Nantes cedex 3, France
Received 15 November 2006; revised 21 December 2006; accepted 5 January 2007
Available online 10 January 2007
Abstract—The synthesis of two new vinyltin reagents grafted on an insoluble macroporous polymer is reported. These reagents were
used in the palladium-catalyzed Stille cross-coupling reaction with aryl halides. In all reactions, the conversion of the starting aryl
halide is high and the amount of organotin by-product is particularly low (at the end of the catalytic run, the amount of Sn is up to
16 ppm in the crude reaction mixture removed of the insoluble polymer, and it is less than 1 ppm in the product purified by chro-
matography on silica gel).
ꢀ 2007 Elsevier Ltd. All rights reserved.
The Stille cross-coupling of vinyltin reagents with a vari-
ety of organic electrophiles is a very useful method for
the formation of carbon–carbon bonds in organic syn-
thesis.1–5 Due to its versatility and functional group
compatibility, this reaction constitutes an invaluable
method for the formation of a r bond between two
sp2 carbon centers especially in the total syntheses of
complex natural molecules,6,7 but also for versatile syn-
theses of molecules of interest for material chemistry as
exemplified by previous work in our group.8,9 However,
the Stille reaction, which requires a stoichiometric
amount of tin, suffers from the difficulty of obtaining
products uncontaminated by organotin residues. In
order to minimize this problem, several improvements
have been suggested: (i) The use of monoorganotin re-
agents which lead to non-toxic tin by-products at the
end of the Stille reaction.10–13 (ii) The use of a catalytic
amount of organotin reagent through a reduction/addi-
tion/cross coupling sequence.14,15 In this case, low tin
contamination can be obtained using a resin-supported
organotin halide.16 (iii) The grafting of the reactive elec-
trophile on a solid support allowing the separation of
soluble organotin by-products from solid-supported
products of the reaction.17 (iv) The use of solid-sup-
ported organotin reagents which can be removed at
the end of a reaction by simple filtration, regenerated
and reused. However, to our knowledge, a limited num-
ber of applications of this type have been reported for
the Stille cross-coupling reaction.18–20
In our effort to develop polymer-supported organotin
reagents, we recently reported on their use both in the
halogenation reaction of aromatic amines21 and in the
allylation reaction of aldehydes.22 The efficiency of these
reagents was illustrated by the low level of organotin
residues in the corresponding synthesized products.
Herein, we wish to report our first results concerning
the Stille reaction involving polymer-supported vinyltin
reagents. In this work, we have chosen polymer-sup-
ported organotin reagents, bearing a vinyl or a
3,3-diethoxyprop-1-en-1-yl substituent, as target com-
pounds and we describe their synthesis and their use in
the palladium-catalyzed Stille cross-coupling reaction
Keywords: Polymer-supported vinyltins; Stille cross-coupling reaction;
Green chemistry; b-Formylvinylanion.
*
Corresponding authors. Tel.: +33 2 5112 5419 (F.Z.); tel.: +33 2 5112
5408; fax: +33 2 5112 5402 (J.-P.Q.); e-mail addresses: francoise.
zammattio@univ-nantes.fr; jean-paul.quintard@univ-nantes.fr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.028

1782
J.-M. Chre´tien et al. / Tetrahedron Letters 48 (2007) 1781–1785
in order to evaluate the potential of these compounds
and to identify the possible limitations of their
application.
For this purpose, macroporous polymer-supported
triorganotin iodide was first prepared in three steps
according to the literature (Scheme 1).21,23–25 Treatment
of the lithiated Amberlite XE 305 with 1-bromo-4-chlo-
robutane gave resin 1, which was stannylated with
Bu2SnPhLi to afford stannylated polymer 2. Iododearyl-
ation of 2 with a solution of iodine in ethanol led to the
corresponding supported triorganotin iodide 3.
To highlight the case of unfunctionalized supported
vinyltin reagents, the vinylation procedure used in liquid
phase26 was subsequently applied to the polymer-sup-
ported triorganotin iodide 3 using two equivalents of
vinyl-magnesium chloride in THF for 16 h at 45 ꢁC
before workup and filtration (Scheme 2).
Figure 1. 119Sn MAS-NMR spectra: (a) resin 3: dSn = +81 ppm and
(b) resin 4: dSn = ꢀ51 ppm.
hydrostannation of alkynes as a possible route to poly-
mer-supported functionalized vinyltins reagents. Resin 3
was first reduced quantitatively in polymer-supported
tin hydride 5 with LiAlH4 (5 equiv) in dry THF for
150 min at 40 ꢁC. According to the literature,29 the so-
lid-state 119Sn MAS-NMR spectrum exhibits a single
signal indicative of the Sn–H function (dSn = ꢀ91 ppm,
Fig. 2) but no signal attributable to 3 or for bis-stannyl-
ated species when the reaction was carefully performed
in the dark and in the absence of dioxygen. In a second
step, the supported tin hydride was reacted with 3,3-
diethoxyprop-1-yne, in dry toluene at 110 ꢁC, with a cata-
lytic amount of AIBN (Scheme 3).
The polymer-supported vinyltin reagent 4 was succes-
sively washed with THF and absolute ethanol, before
being dried under vacuum. The FT-IR spectrum of
polymer 4 exhibits a well defined band around
1650 cmꢀ1, indicative of the C@C double bond of the
vinylic moiety. Chemical information on the tin environ-
ment was also obtained through solid-state 119Sn MAS-
NMR analysis allowing us to ascertain the level of
conversion of resin 3 to resin 4.27,28 Indeed, the complete
disappearance of the broad signal due to polymer 3
(dSn = + 81 ppm) and the presence of a unique sharp
signal (dSn = ꢀ51 ppm) typical of a Sn–Vinyl moiety
was considered as a proof of an almost quantitative con-
version (Fig. 1). Elemental analysis of resin 4 confirmed
the absence of iodine and allowed us to estimate a tin
The complete conversion of 5–6 was established by 119Sn
MAS-NMR spectroscopy. Thus, the spectrum clearly
highlights the disappearance of 5 and the formation of
polymer-supported vinyltin reagent 6 as a mixture
of two regioisomers a-6 and b-6 (Fig. 2). On the basis
of 119Sn NMR data in solution,30 the larger signal at
ꢀ47 ppm was assigned to a-6 and (E)-b-6 and the minor
signal near ꢀ61 ppm to (Z)-b-6. Accordingly, the iso-
meric ratio of a-6, (E)-b-6, and (Z)-b-6 given in Scheme
loading of 1.4 mmol gꢀ1
.
As the aforementioned synthesis is restricted to non-
functionalized vinyltin reagents, we then explored the
a, b
1
3 was determined indirectly by H NMR analysis of the
H
Cl
corresponding iododestannylation products (known to
occur with retention of configuration31). It is to be noted
1
Amberlite XE 305
c
SnBu2Ph
SnBu2I
2
3
d
Scheme 1. Reagents and conditions: (a) n-BuLi/TMEDA, cyclo-
hexane, 65 ꢁC; (b) Br–(CH2)4–Cl, THF, 0 ꢁC–rt; (c) Bu2SnPhLi,
THF, rt and (d) I2, EtOH, 60 ꢁC.
a
SnBu2I
SnBu2
3
4
Figure 2. 119Sn MAS-NMR spectra: (a) resin 5: dSn = ꢀ91 ppm and
(b) resin 6: dSn = ꢀ47 ppm: (E) + a isomers; dSn = ꢀ62 ppm: (Z)
isomer.
Scheme 2. Reagents and conditions: (a) VinylMgBr (2 equiv), THF,
45 ꢁC.

J.-M. Chre´tien et al. / Tetrahedron Letters 48 (2007) 1781–1785
1783
a
SnBu2I
SnBu2H
Table 1.
OEt
OEt
3
5
Br
6, Pd(PPh3)4
OEt
OEt
toluene, 110 °C
OHC
OHC
OEt
OEt
SnBu2
7a
8a
β-6 (89% E:Z = 79/21)
Entry Pd(PPh3)4 (mol %) Reaction time (h) Conversiona (%)
b
OEt
1
2
3
4
2
2
5
5
18
40
18
40
77
79
83
SnBu2
OEt
α-6 (11%)
100
a Conversion determined by GC analysis of the crude product.
Scheme 3. Reagents and conditions: (a) LiAlH4, THF, 40 ꢁC and (b)
AIBN, toluene, 110 ꢁC.
Using these experimental conditions,32 further attempts
were achieved in Schlenk tubes by heating resin 4 or 6 in
toluene in the presence of the aryl iodide or bromide 7a–
e using an ellipsoidal stirring (Table 2). Good conver-
sions were obtained from the resins 4 and 6, regardless
of the nature of the functional group on the aryl halide
substrate.
that the presence of the regioisomer a-6 is not prejudicial
to a primary exploration of the reactivity of these vinyl-
tins since the regioisomer a-6 is known to be less reactive
than (E)-b-6 and (Z)-b-6.30 Elemental analysis indicated
a tin loading of 1.14 mmol gꢀ1 on this sample.
Having established the grafting degree and the nature of
the substituents around tin in supported vinyltins 4 and
6, we tested their reactivity in the palladium-catalyzed
Stille cross-coupling reaction with various aryl iodides
and bromides. In order to determine the appropriate
experimental conditions, the coupling of reagent 6 with
4-bromobenzaldehyde 7a was first examined in dry tolu-
ene at 110 ꢁC and the amount of palladium catalyst
(Pd(PPh3)4) as well as the reaction time were varied
(Table 1). At this temperature, the higher conversions
in 8a were obtained with 5 mol % of palladium catalyst
after 40 h of reaction.
ICP-MS analyses performed on 8a–d and 9a–d exhibited
very low amount of organotin residues in the products
(under 16 ppm when the analysis is performed on the
crude product and under 1 ppm when the analysis is
realized on the purified product). This very low contam-
ination by organotin by-products demonstrates the effi-
ciency of these polymer-supported vinyltin reagents as
non-polluting reagents. In this way, their use in the syn-
thesis of biologically active molecules may be considered
even in the late steps of the synthetic strategy. At this
Table 2. Stille cross-coupling reactions of aryl halides (7a–e) with polymer-supported organotin reagents 4 or 633,34
X
R
R
Pd(PPh3)4 (5% mol)
SnBu2
+
toluene, 110 °C
R'
R'
40 h
4 or 6
7a-e
8a-9d
Conversionb (%)
Entry
1
Resina
Ar–X
Product
Snc (ppm)
7.2d
OEt
OEt
Br
6: R = CH(OEt)2
100
OHC
OHC
7a
8a
OEt
I
OEt
2
3
4
6: R = CH(OEt)2
6: R = CH(OEt)2
6: R = CH(OEt)2
96 (92)
< 0.5e
MeO2C
MeO
MeO2C
7b
8b33
OEt
OEt
I
f
80
—
MeO
MeO
7c
8c
8c
OEt
OEt
Br
f
78
—
MeO
7d
(continued on next page)

1784
J.-M. Chre´tien et al. / Tetrahedron Letters 48 (2007) 1781–1785
Table 2 (continued)
Entry
Resina
Ar–X
Product
Conversionb (%)
100 (95)
Snc (ppm)
<0.5e
OEt
OEt
I
5
6: R = CH(OEt)2
O2N
O2N
7e
7a
8d34
Br
6
4: R = H
4: R = H
4: R = H
4: R = H
4: R = H
100
100
81
4.2d
OHC
OHC
9a
I
7
9.0d
MeO2C
MeO2C
9b
7b
I
8
8.1d
MeO
MeO
O2N
MeO
MeO
O2N
9c
9c
7c
7d
7e
Br
9
83
16.4d
I
10
100
10.2d
9d
a Resin 6 was used as a mixture of a-6 + (E/Z)-b-6. 1.12 equiv were used in order to take into account the presence of nearly unreactive a-6.
b Conversion determined by GC analysis of the crude product, the E/Z ratio is similar to those observed in b-6. For entries 2 and 5, isolated yields are
in brackets. It has to be noted that no homo-coupling by-product has been observed.
c Quantification of tin residues in the products determined by ICP-MS.
d These quantities have been measured on the crude product without any purification.
e These quantities have been measured on the purified product after chromatography on silica gel (eluent: petroleum ether–AcOEt 80:20).
f Not determined.
stage, the complete validity of the method required the
possibility of recycling polymer-supported tin reagents
recovered at the end of the cross-coupling reaction.
For this purpose, the resin recovered at the end of the
Stille process was washed with THF, absolute ethanol,
dried under vacuum and characterized by FT-IR and
119Sn MAS-NMR spectroscopy before being regener-
ated and reused. Thus, in the 119Sn MAS-NMR spectra
of the recovered resins, the signals at +133 ppm or
+81 ppm are characteristic of the regeneration of the
polymer-supported tin halides Sn–Br or Sn–I. The resin
recovered after reaction of resin 4 with aryl halide 7e
was successfully regenerated, utilizing the aforemen-
tioned procedure for its synthesis, and reacted again
with 7e with a similar efficiency as in the course of the
first coupling. However, at the end of this cycle, a
grey-black color is observed on the polymer, possibly
due to a palladium deposit during the reaction.
reaction in order to limit organotin pollution at very low
levels. However, the observed palladium deposit, which
is not prejudicial to the first cycle, should be taken into
account if regeneration and reuse of this reagent is de-
sired. For discovery research, this regeneration is not
imperative but, regio and stereoselective syntheses of
functional polymer-supported vinyltin reagents have to
be achieved (as it has been done in solution35,36) so as
to transfer organic units with fixed configuration to
organic substrates without the drawbacks of metallic
pollution. Work is in progress in order to deliver various
vinyltin reagents in a context of green chemistry, a
concept which can be also applied to functional aryltin,
heteroaryltin or allyltin reagents.
Acknowledgements
´
We gratefully acknowledge ‘Nantes Metropole’ for a
In conclusion, these preliminary experiments support
strongly the fact that polymer-supported vinyltin re-
agents can be used efficiently in the Stille cross-coupling
grant (J.-M.C.) as well as the CNRS and the University
of Nantes for financial support. We are indebted to
Katy Perrigaud from Subatech, UMR CNRS 6457,

J.-M. Chre´tien et al. / Tetrahedron Letters 48 (2007) 1781–1785
1785
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the gift of dibutyltin dichloride.
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