Copper(I)-promoted palladium-catalyzed cross-coupling of unsaturated tri-n-butylstannane with heteroaromatic thioether

Article abstract of DOI:10.1021/ol027453o

(Matrix presented) Palladium-catalyzed cross-coupling of vinyl- and arylstannanes with π-electron-deficient heteroaromatics was performed in good yields. This Stille-type reaction was carried out with a methylthioether function as an electrophile in the presence of a copper(I) bromide-dimethyl sulfide complex.

Full text of DOI:10.1021/ol027453o

ORGANIC
LETTERS
2003
Vol. 5, No. 6
803-805
Copper(I)-Promoted Palladium-Catalyzed
Cross-Coupling of Unsaturated
Tri-n-butylstannane with Heteroaromatic
Thioether
France-Aime´e Alphonse,†,‡ Franck Suzenet,† Anne Keromnes,‡ Bruno Lebret,‡ and
,†
Ge´rald Guillaumet*
Institut de Chimie Organique et Analytique, UMR-CNRS 6005,
UniVersite´ d’Orle´ans, rue de Chartres, BP 6759, 45067 Orle´ans Cedex 2, France, and
Commissariat a` l’Energie Atomique, CEA/Le Ripault, B.P.16, 37260 Monts, France
gerald.guillaumet@uniV-orleans.fr
Received December 12, 2002
ABSTRACT
Palladium-catalyzed cross-coupling of vinyl- and arylstannanes with π-electron-deficient heteroaromatics was performed in good yields. This
Stille-type reaction was carried out with a methylthioether function as an electrophile in the presence of a copper(I) bromide-dimethyl sulfide
complex.
The discovery of new, efficient methods for the construction
of carbon-carbon bonds represents an ongoing, central
theme of research in the area of organic synthesis. In this
context, the palladium-catalyzed cross-coupling of organo-
metallic reagents with aryl or vinyl halides and triflates has
become an attractive method.1 Unfortunately, halides or
triflates might be of limited availability and/or stability,
especially in the heteroaromatic series. Consequently, recent
reports have dealt with the discovery of new electrophiles
for this type of reaction:2 Liebeskind and Srogl have
developed a palladium-catalyzed boronic acid-thioether
cross-coupling protocol mediated by copper(I) carboxylate.3
Extension of this method has been reported for heteroaro-
matic derivatives.4
Considering the advantages of using trialkylorganotin
species [for example, they are readily available (especially
alkenyl and heteroaromatic stannanes)],5 we investigated a
(2) (a) Malleron, J.-L.; Fiaud, J.-C.; Legros, J.-Y. Handbook of Pal-
ladium-Catalysed Organic Reactions; Academic Press: London, 1997. (b)
Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1997, 119,
12376-12377. (c) Srogl, J.; Liu, W.; Marshall, D.; Liebeskind, L. S. J.
Am. Chem. Soc. 1999, 121, 9449-9450. (d) Darses, S.; Geneˆt, J.-P.; Brayer,
J.-L.; Demoute, J.-P. Tetrahedron Lett. 1997, 38, 4393-4396. (e) Kikukawa,
K.; Kono, K.; Wada, F.; Matsuda, T. J. Org. Chem. 1983, 48, 1333-1336.
(f) Pridgen, L. N. J. Org. Chem. 1981, 46, 5402-5404.
(3) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260-
11261. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91-
93. (c) Savarin, C.; Liebeskind, L. S. Org. Lett. 2001, 3, 2149-2152. (d)
Kusturin, C. L.; Liebeskind, L. S.; Neumann, W. L. Org. Lett. 2002, 4,
983-985.
(4) (a) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.; Guil-
laumet, G. Synlett 2002, 3, 447-450. (b) Liebeskind, L. S.; Srogl, J. Org.
Lett. 2002, 4, 979-981.
† Universite´ d’Orle´ans.
‡ Commissariat a` l’Energie Atomique, CEA/Le Ripault.
(1) For reviews, see: (a) Heck, R. F. Palladium Reagents in Organic
Synthesis; Academic Press: New York, 1985. (b) Tsuji, J. Palladium
Reagents and Catalysts: InnoVations in Organic Synthesis; Wiley & Sons:
New York, 1995. (c) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25,
508-524. (d) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(e) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211.
(f) Angiolelli, M. E.; Casalnuovo, A. L.; Selby, T. P. Synlett 2000, 6, 905-
907.
(5) (a) Pereyre, M.; Quintard, J.-P.; Rahm, A. Tin in Organic Synthesis;
Butterworth: London, 1987. (b) Lee, A. S.-Y.; Dai, W.-C. Tetrahedron
1997, 53, 859-868 and references therein. (c) Smith, N. D.; Mancuso, J.;
Lautens, M. Chem. ReV. 2000, 100, 3257-3282.
10.1021/ol027453o CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003

new type of electrophile for the Stille reaction. In this
communication, we present our first results of a palladium-
catalyzed coupling reaction between stannanes and electron-
poor heteroaromatic derivatives bearing a thiomethyl ether
function as a leaving group.
Table 2. Copper(I)-Promoted Palladium-Catalyzed
Cross-Coupling of Organostannanes with Heteroaromatic
Thioethersa
Initially, we examined the cross-coupling of 3-methyl-
thiotriazine 1a6 with the commercially available 2-tributyl-
stannylfuran 2a. A series of experiments was performed to
evaluate the feasibility of the carbon-carbon bond formation
and to identify the best coupling agents. The results are
shown in Table 1. By analogy with the cross-coupling
Table 1. Influence of Copper Cofactor and Palladium Catalyst
on the Cross-Coupling Reaction
Pd catalyst
(5 %)
reaction time yield
entry
cofactor/equiv
(h)
(%)
1
2
3
4
5
6
7
8
CuMeSal/2.2
CuI/2.2
CuBr‚Me2S/2.2 Pd(PPh3)4
CuBr‚Me2S/0.2 Pd(PPh3)4
CuBr/2.2
CuBr/2.2
Pd(PPh3)4
Pd(PPh3)4
24
48
16
48
9
48
48
48
60
50
90
15
60
0a
Pd(PPh3)4
Pd(PPh3)4
0a
CuBr‚Me2S/2.2 PdCl2(PPh3)2
74
a Only starting material was recovered.
reaction between thioether and boronic acids,4 we first used
copper(I) methylsalicylate as a cofactor in the presence of
Pd(PPh3)4 in boiling THF. Thus, we isolated the coupled
product in 60% yield. In the mechanism proposed by
Liebeskind and Srogl, the carboxylate counterion of the
copper is clearly important in facilitating transmetalation
from boron, possibly through direct coordination to triValent
boron.3b In the Stille mechanism, it is not essential (even if
it can be helpful)1e,7 to go through a pentacoordinate tin
intermediate for the transmetalation step.8 Indeed, in the
presence of 2.2 equiv of CuBr‚Me2S (or CuBr, entry 3 or
5), compound 3a was obtained in 90% (or 60%) yield. Using
CuI made the cross-coupling less effective. Compound 3a
was isolated in only 50% yield, and starting triazine 1a was
recovered in 10% yield (entry 2). Palladium catalyst and a
stoichiometric amount of copper(I) are essential for the
success of the reaction (entries 4, 6, and 7). Another source
of palladium catalyst [PdCl2(PPh3)2] was used, but the
reaction was slightly slower (entry 8).
a Thioether (0.78 mmol), organostannane (1.7 mmol), and CuBr‚Me2S
(1.7 mmol) were dissolved in THF (6 mL). After the vessel was flushed
with argon, Pd(PPh3)4 (5 mol %) was added and the reaction mixture was
stirred at reflux. b Reaction was performed in boiling DME instead of THF.
c Used 10 mol % Pd(PPh3)4. d Compound 2g was prepared regio- and
stereospecifically by reacting Bu3Sn(Bu)CuCNLi2 with phenylacetylene in
THF at -78 °C. e Low yield was obtained because of the instability of
compound 3l.
rapidly with electron-poor arylstannanes 2b and 2c to give
compounds 3b and 3c, respectively, in high yields (entries
1 and 2). With less reactive stannanes, reaction was
completed within 48 h in boiling DME, and for the electron-
rich arylstannane 2e, 10 mol % Pd(PPh3)4 was necessary
(entry 4). This method was successfully applied to vinyl-
stannane 2g to produce 3g in good yield with total retention
of stereochemistry of the organostannane (entry 6). Extension
of the reaction to methylthiopyrimidine 1b and methyl-
thiobenzothiazole 1c was successful, and compounds 3h-j
Results for different stannanes and π-deficient heteroaro-
matics are depicted in Table 2. Methylthiotriazine 1a reacted
(6) Paudler, W. W.; Chem, I. K. J. Heterocycl. Chem. 1970, 7, 767-
771.
(7) Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119-122.
(8) Casado, A. L.; Espinet, P. J. Am. Chem. Soc. 1998, 120, 8978-
8985 and references therein.
804
Org. Lett., Vol. 5, No. 6, 2003

be the cause of the intramolecular oxidative coupling of
alkenyltrimethylstannane functions.11
Scheme 1. Possible Palladium Catalytic Coupling Cycle
Surprisingly, in our case we never observed this rapid (less
than 1 h) oxidative homocoupling reaction between stan-
nanes. This observation was, a priori, in contrast with the
transmetalation of tin to copper postulated by Piers.11 In fact,
when treating 2-tributylstannylthiophene 2b with 2.5 equiv
of CuBr‚Me2S in DMF for 5 h (Piers’ conditions), we have
observed the formation of the homocoupled product in 62%
yield. When performing the same reaction with CuBr‚Me2S
in DME, no homocoupled product was detected after 18 h,
showing that DME does not contribute to the oxidative
coupling of heteroarylstannanes. However, at this stage we
were unable to recover the starting 2-stannylthiophene and
mainly observed by GC analyses the protiodestannylated
compound suggesting the transmetalation from tin to copper
had really occurred (III, Scheme 1).
In summary, we have shown that π-electron-deficient
heteroaromatics bearing a methylthio group were coupled
with vinyl- and arylstannanes in the presence of copper(I)
and a catalytic amount of Pd(PPh3)4. Copper is not essential
for the oxidative addition of arylthioether to palladium but
plays a role at two stages: transmetalation from tin to copper
and probably activation of the Pd-S bond to ease the
transmetalation step in the palladium catalytic coupling cycle.
(from arylstannanes, entries 7-9) as well as compounds 3k,l
(from vinylstannanes, entries 10 and 11) were obtained in
good yields. From a mechanistic point of view, copper could
take part at two stages as reported in Scheme 1.
First, we believe that the oxidative addition of heteroaryl-
methylthioether to palladium is enhanced in weaker Csp2-S
bonds3c,4,2f independent of the presence of copper(I) (I,
Scheme 1). Indeed, when 5-furyl-3-methylthio-1,2,4-triazine
was treated with p-methoxyphenylmagnesium bromide in
THF with 5 mol % PdCl2(dppf) for 24 h, we isolated 30%
of 5-furyl-3-p-methoxyphenyl-1,2,4-triazine suggesting that
copper was not essential for the oxidative addition of
arylthioether to palladium.9 However, as suggested by
Liebeskind3c in the palladium-catalyzed cross-coupling reac-
tion between boronic acids and sulfur-containing species,
copper could polarize the Pd-S bond through Cu(I) coor-
dination to S (II, Scheme 1) to ease the rate-determining
transmetalation step.
Acknowledgment. We thank the Commissariat a` l’Energie
Atomique and the Conseil Re´gional de la Re´gion Centre for
financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data for 2g and 3a-l. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL027453O
(10) (a) Liebeskind, L. S.; Fengl, R. W. J. Org. Chem. 1990, 55, 5359-
5364. (b) Farina, V.; Kapadia, S. Krishnan, B.; Wang, C.; Liebeskind, L.
S. J. Org. Chem. 1994, 59, 5905-5911. (c) Allred, G. D.; Liebeskind, L.
S. J. Am. Chem. Soc. 1996, 118, 2748-2749. (d) Falck, J. R.; Bhatt, R. K.;
Ye, J. J. Am. Chem. Soc. 1995, 117, 5973-5982.
(11) (a) Piers, E.; Yee, J. G. K.; Gladstone, P. L. Org. Lett. 2000, 2,
481-484. (b) Piers, E.; McEachern, E. J.; Romero, M. A. J. Org. Chem.
1997, 62, 6034-6040. (c) Piers, E.; Romero, M. A. J. Am. Chem. Soc.
1996, 118, 1215-1216. (d) Piers, E.; Wong, T. J. Org. Chem. 1993, 58,
3609-3610.
Second, since 1990, the beneficial influence of cocatalytic
Cu(I) on the cross-coupling reaction has been extensively
used and mechanistic studies suggest the partial transmeta-
lation from tin to copper.10 This transmetalation would also
(9) Blank reaction performed without palladium catalyst gave no coupled
compound, and starting material was mainly recovered, suggesting that
palladium is essential in the coupling process.
Org. Lett., Vol. 5, No. 6, 2003
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