Hiyama cross-coupling of chloro-, fluoro-, and methoxypyridyltrimethylsilanes: Room-temperature novel access to functional bi(het)aryl

Article abstract of DOI:10.1021/ol047482u

(Chemical Equation Presented) The incorporation of chloro, fluoro, or methoxy substituents on the pyridine ring of pyridyltrimethylsilanes allowed us to perform efficient Hiyama cross-coupling with various (het)aryl halides. The reactions proceeded smoothly at room temperature leading to the corresponding functional bis(het)aryl in fair to excellent yields. The presence of pyridine nitrogen α to the trimethylsilyl group was requisite to achieve the cross-coupling.

Full text of DOI:10.1021/ol047482u

ORGANIC
LETTERS
2005
Vol. 7, No. 4
697-700
Hiyama Cross-Coupling of Chloro-,
Fluoro-, and
Methoxypyridyltrimethylsilanes:
Room-Temperature Novel Access to
Functional Bi(het)aryl
Philippe Pierrat, Philippe Gros,* and Yves Fort
Synthe`se Organome´tallique et Re´actiVite´, UMR CNRS 7565,
UniVersite´ Henri Poincare´, Faculte´ des Sciences, BouleVard des Aiguillettes,
54506 VandoeuVre-le`s-Nancy, France
philippe.gros@sor.uhp-nancy.fr
Received December 8, 2004
ABSTRACT
The incorporation of chloro, fluoro, or methoxy substituents on the pyridine ring of pyridyltrimethylsilanes allowed us to perform efficient
Hiyama cross-coupling with various (het)aryl halides. The reactions proceeded smoothly at room temperature leading to the corresponding
functional bis(het)aryl in fair to excellent yields. The presence of pyridine nitrogen
cross-coupling.
r to the trimethylsilyl group was requisite to achieve the
The Hiyama cross-coupling of organosilanes with organo
halides and triflates has proved to be a powerful methodology
for preparation of biaryls and alkyl and vinyl aromatics.1
The organosilanes display many advantages compared to
other organometallic precursors: Organoboron reagents are
not always easily prepared and stable while organostannanes
release toxic tin halides upon coupling process. However,
the absence of polarization of the C-Si bond implies the
use of activated silicon moieties such as halosilanes,1b,2 sila-
nols,3 siloxanes,4 bis(catechol)silicates,5 or silacyclobutanes.1c,6
Although efficient in cross-coupling or aromatics, these
silicon species have been scarcely used in heterocyclic
chemistry especially in the important pyridine series for
which efficient coupling methodologies are still needed for
preparation of new ligands and pharmacophores.
From our knowledge, only two examples of activated
pyridylsilanes have been reported. Hiyama1b introduced an
instable dichloroethylsilyl group at C-2 of picoline which
had to be in situ cross-coupled while DeShong prepared a
biscatechol derivative from 2-methoxypyridine which was
coupled only with aryltriflates (Figure 1).5
(3) (a) Hirabayashi, K.; Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama,
T. Org. Lett. 1999, 1, 299-301. (b) Hirabayashi, K.; Mori, A.; Kawashima,
J.; Suguro, M.; Nishihara, Y.; Hiyama, T. J. Org. Chem. 2000, 65, 5342-
5349. (c) Denmark, S. E.; Neuville, L. Org. Lett. 2000, 5, 3221-3224.
(4) (a) Lee, H.-M.; Nolan, S. P. Org. Lett. 2000, 2, 2053-2054. (b)
McElroy, W. T.; DeShong, P. Org. Lett. 2003, 5, 4779-4782. (c) Lee,
J.-Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616-5617.
(5) Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 1137-1143.
(6) (a) Denmark, S. E.; Choi, J.-Y. J. Am. Chem. Soc. 1999, 121, 5821-
5822. (b) Denmark, S. E.; Wu, Z. Org. Lett. 1999, 1, 1495-1498. (c)
Denmark, S. E.; Wehrli, D.; Choi, J.-Y. Org. Lett. 2000, 2, 2491-2494.
(1) For reviews, see: (a) Hiyama, T. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Weinheim, Germany, 1998.
(b) Hiyama, T. J. Organomet. Chem. 2002, 653, 58-61. (c) Denmark, S.
E.; Sweiss, R. F. Acc. Chem. Res., 2002, 35, 835-846. (d) Spivey, A. C.;
Gripton, C. J. G.; Hannah, J. P. Curr. Org. Synth. 2004, 1, 211-226.
(2) (a) Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471-
1478. (b) Goda, K.-I.; Hagiwara, E.; Hatanaka, Y.; Hiyama, T. Tetrahedron
Lett. 1997, 38, 439-442. (c) Homsi, F.; Hosoi, K.; Nozaki, K.; Hiyama, T.
J. Organomet. Chem. 2001, 624, 208-216.
10.1021/ol047482u CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/22/2005

Table 1. Reaction Parameter Screening in Hiyama Coupling
of 1a
entry ArI (equiv)
catalyst
PR3 CuI T (°C) 1ab (%)
Figure 1. Activated pyridyl silanes of the literature.
1
2
3
4
5
6
7
8
0.8
0.8
0.8
0.8
0.6
0.5
0.5
0.5
PdCl2(PPh3)2 PPh3
120
120
120
120
120
120
20
c
c
c
27
52
80
d
Pd(OAc)2
Pd(OAc)2
PCy3
PtBu3
PdCl2(PPh3)2 PPh3
PdCl2(PPh3)2 PPh3
PdCl2(PPh3)2 PPh3
PdCl2(PPh3)2 PPh3
PdCl2(PPh3)2 PPh3
1
1
1
So, there was an evident lack of stable and easy to handle
pyridylsilanes suitable for the Hiyama coupling and we
investigated the reactivity of the trimethylsilyl group in this
reaction. Our first attempts to couple 2-trimethylsilylpyridine
under classical conditions remained unsuccessful and we
turned to chloropyridyltrimethylsilanes. The electron-
withdrawing effect of chlorine on pyridine ring was here
expected to increase polarization of the C-Si bond thus
favoring the formation of the intermediate ate complex by
reaction with fluoride ions. Chloropyridyltrimethylsilanes are
stable liquids easily prepared from chloropyridines via halo-
gen or hydrogen lithium exchanges and subsequent reaction
with chlorotrimethylsilane. Moreover, the C-Cl bond also
offers a potential source for further functionalizations.
Herein, we report the first use of chloropyridyltrimethyl-
silanes as reactive partners in the Hiyama cross-coupling,
thus providing an important scope extension for this reaction
in heterocyclic chemistry.7
1
20
82
a All reactions performed on 1 mmol of 1. b Isolated yield after column
chromatography. c GC analysis showed quantitative formation of [4-MeOPh]2.
d [4-MeOPh]2 formed in 50% yield.
product 1a in 27% yield. The amount of 4-iodoanisole was
also a key parameter. The best improvement was obtained
by introduction of 1 and ArI in a 2:1 ratio leading to 1a in
excellent yield (80%) while a 1.5:1 ratio led to lower yield
and homocoupling or the aryl iodide (entries 5 and 6).
Finally, we were pleased to observe that cross-coupling was
also efficient at room temperature (entry 8). Note that the
role of CuI was also crucial under these conditions since
homocoupling of aryl halide was formed in absence of this
salt (entry 7). As already observed by Hiyama,1b we also
found that 2 equiv of TBAF9 was necessary to achieve the
cross-coupling. Couplings were also performed in THF at
room temperature but only resulted in poor yields (22%).
This coupling of 1 was unprecedented and of particular
interest since we had not observed any Stille coupling of
the corresponding stannane in our previous works probably
due to steric hindrance generated by chlorine at C-3.10 The
above determined best conditions (Table 1, entry 8) were
then applied to investigate the cross-coupling of the other
chloropyridylsilanes 2-6 (Scheme 1). At room temperature,
silane 2 gave the cross-coupling product 2a in high yield
while silanes 3-6 only gave the desilylated pyridines
indicating the formation of unreactive ate complexes under
the conditions used. A moderate amount of 4 could therefore
be cross-coupled by performing the reaction at 120 °C for
48 h. A reaction with activated 4-iodofluorobenzene was also
unsuccessful at room temperature or upon heating where only
homocoupling of the halide was obtained. All our attempts
An array of chloropyridylsilanes 1-6 (Figure 2) was
prepared according to literature procedures8 and involved
Figure 2. Starting silanes for coupling investigation.
cross-coupling reactions with 4-iodoanisole under various
conditions. The investigation of reaction parameters was
performed with silane 1 (Table 1).
(8) For preparation of 1-3 with BuLi-LiDMAE, see: Choppin, S. Gros,
Ph. Fort, Y. Org. Lett. 2000, 2, 803-805. Choppin, S. Gros, Ph. Fort, Eur.
J. Org. Chem. 2001, 3, 603-606. For preparation of 5 and 6 with LDA or
LTMP, see: Gribble, G. W. Saulnier, M. G. Tetrahedron Lett. 1980, 21,
4137-4140. Comins, D. L.; Myoung, Y. J. Org. Chem. 1990, 55, 292-
298. Compound 4 was prepared by reaction of BuLi with 2-chloro-5-
bromopyridine in THF at -78 °C and quenching with TMSCl.
(9) Other fluoride sources (TMAF, CsF, polymer-supported fluoride) gave
low yields.
First attempts using classical coupling conditions of the
literature and various palladium catalysts only resulted in
homocoupling of 4-iodoanisole (entries 1-3). A significant
CuI effect was observed (entry 4) leading to cross-coupling
(7) Trimethylsilylthiazole has been coupled under copper catalysis by
Hosomi and co-workers. See: Ito, H.; Sensui, H.-O.; Arimoto, K.; Miura,
K.; Hosomi, A. Chem. Lett. 1997, 639-640.
(10) Choppin, S. Ph.D. Thesis, Nancy, 2000.
698
Org. Lett., Vol. 7, No. 4, 2005

Scheme 1. Attempted Cross-Coupling of Silanes 2-6a
Scheme 2. Proposed Catalytic Cycle for Cross-Coupling of 1
and 2
a Key: (i) PdCl2(PPh3)2 (5%), PPh3 (10%), CuI (1 equiv), TBAF
(2 equiv), 4-iodoanisole (0.5 equiv), DMF, rt, 12 h; (ii) ibid at 120
°C for 48 h; (iii) 4-iodofluorobenzene as electrophile, rt, 24 h or
120 °C, 48 h.
to couple 3, 5, or 6 by increasing temperature, reaction time,
fluoride, and palladium amount remained unsuccessful.
From a mechanistic angle, the above experiments feature
the preeminent role of the pyridine nitrogen in the reaction
pathway. Indeed, quantitative cross-coupling was observed
only when pyridine nitrogen was present R to the trimeth-
ylsilyl group. This suggested the complexation of palladium
species by the pyridine nitrogen leading to a complex in
which the two partners are ideally placed for achievement
of the transmetalation step assisted by fluorine and copper1b
(Scheme 2). The catalytic cycle also explained that 2 equiv
of TBAF was necessary to perform the cross-coupling.
Since the complexation of palladium by pyridine nitrogen
should be dependent on electronegativity of this site, the
charges on nitrogen in ate complexes were calculated to get
a better understanding of the behavior of 1-6 in the reaction
(Figure 3).11
As shown, the more electronegative nitrogens were found
in ate complexes resulting from unreactive 4-6. So, these
substrates were expected to coordinate the palladium species
in a greater extent. The lack of a silyl group near the metallic
center then did not allow the transmetalation step to proceed.
Nitrogen in silane 3 displayed the lowest electronegativity
and thus weaker palladium complexation could be expected.
However coupling was obtained in 20% yield upon heating
(see Scheme 1). So, electronic effects were not the only factor
governing the reaction in this case. In contrast, substrates 1
and 2 ideally combined nitrogen electronegativity and a silyl
group at C-2 leading to efficient cross-coupling.
Figure 3. Calculated charges on nitrogen in ate complexes.
1 reacted smoothly in each case except with 2-iodoanisole
may be due to steric hindrance of both the chlorine and
methoxy groups. An increase of temperature to 120 °C was
necessary to form 1c in moderate 38% yield (Table 2).
Of particular interest was the efficient cross-coupling of
1 or 2 with 2-bromopyridine providing the corresponding
chlorinated 2,2′-bipyridines in good to excellent yields. 1
was also smoothly coupled with the less reactive bromo-
thiophene of 4-bromoacetophenone. In contrast, 2 showed a
(12) General Procedure for Cross-Coupling of Silanes 1 or 2. To a
stirred mixture of PdCl2(PPh3)2 (35 mg, 0.05 mmol), PPh3 (26 mg, 0.1
mmol), and CuI (188 mg, 1 mmol) in DMF (5 mL) at room temperature
were added successively (Het)ArX (0.5 mmol), silane 1 or 2 (185 mg, 1
mmol), and TBAF (2 mL of a 1 M solution in THF, 2 mmol). The reaction
medium became instantly dark. After 12 h of stirring at room temperature,
the mixture was filtered through a Celite pad. After successive washings
with NH4OH, H2O, THF and Et2O, the filtrate was extracted twice with
diethyl ether. After drying (MgSO4) of the organic layer, the solvents were
evaporated under reduced pressure and the crude product purified by column
chromatography.
We then focused on the reaction of silanes 1 and 2 in cross-
coupling reactions with a range of (het)aryl halides.12 Silane
(11) Mulliken charges calculated using semiempirical PM3 method.
Org. Lett., Vol. 7, No. 4, 2005
699

Table 2. Preparation of Chlorinated Bis(het)aryl Derivativesa
Scheme 3. Cross-Coupling of Methoxy- and
Fluoropyridylsilanesa
a Key: (i) PdCl2(PPh3)2 (5%), PPh3 (10%), CuI (1 equiv), TBAF
(2 equiv), 4-iodoanisole (0.5 equiv), DMF, rt, 12 h.
cleanly the expected products. The replacement of chlorine
by fluorine led to impressive improvement of the cross-
coupling. Indeed 8 was coupled in 64% yield while we were
unable to react 3. For comparison with reaction of 1, a coup-
ling was attempted between 9 and 2-iodo-anisole. Unfortu-
nately, the expected coupling product was obtained only in
trace amount. Thus, steric effect of the halogen at C-3 in
pyridyl silane was not the limiting factor for cross-coupling
here.
a All reactions performed on 1 mmol of 1 or 2. b Isolated yield after
column chromatography. c Reaction performed at 120 °C. d 4,4′-Dichloro-
2,2′-bipyridine (Cl2bpy) formed in 40% yield. e GC yield. 2g could not be
separated from Cl2bpy.
strong tendency to homocouple in the presence of these less
reactive halides as indicated by formation of 4,4′-dichloro-
2,2′-bipyridine in notable amount (typically 40%). Homo-
coupling of silanes has been reported to be catalyzed by
copper halides.13 The CuI present in our reaction medium
was thus assumed to catalyze this reaction via formation of
a pyridylcopper intermediate rapidly decomposed into the
corresponding bipyridine upon workup.13,14 With 1, homo-
coupling was probably prevented by steric hindrance gener-
ated by chlorine at C-3.
Finally, we investigated the reaction with other electron-
withdrawing groups on the pyridine ring. We examined the
effect of methoxy and fluorine moieties (Scheme 3). The
more electronegative and less hindered fluorine atom was
convenient to evaluate stereoelectronic effects. We were
pleased to observe that methoxy- and fluoropyridines gave
In summary, we have shown that the introduction of
electron-withdrawing substituents on the pyridine ring of
2-trimethylsilylpyridines led to efficient activation of the
trimethylsilanes making them useful reactive partners in
the Hiyama cross-coupling. The coupling can be performed
cleanly at room temperature giving a novel access to
functional bi(het)aryl.
Acknowledgment. We thank Prof. T. Hiyama for kindly
providing data about coupling of dichloroethylsilylpyridines
and J. Defaux for careful preliminary experiments.
Supporting Information Available: Experimental pro-
cedure for Hiyama cross-coupling and spectroscopic data for
all compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL047482U
(13) Ikegashira, K.; Nishihara, Y.; Hirabayashi, K.; Mori, A.; Hiyama,
T. Chem. Commun. 1997, 1039-1040.
(14) Normant, J. F. Synthesis 1972, 63.
700
Org. Lett., Vol. 7, No. 4, 2005