Advantageous use oftBu2P-N=P(iBuNCH 2CH2)3N in the hiyama coupling of aryl bromides and chlorides

Article abstract of DOI:10.1021/jo902338w

(Chemical Equation Presentation) An efficient catalytic route to biaryls by employing (generally) only 0.25 mol % of Pd(OAc)₂ and 0.5 mol % of 1 in the Hiyama coupling reaction is reported. High yields for electron-rich, -neutral, and -deficient aryl chlorides are obtained. A variety of phenylsiloxanes undergo coupling with aryl bromides and chlorides with low Pd(OAc)₂/1 loadings.

Full text of DOI:10.1021/jo902338w

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e.g., Pd-catalyzed Suzuki,1 Negishi,2 Kumada,3 Hiyama,4
Advantageous Use of tBu2P-NdP(iBuNCH2CH2)3N
in the Hiyama Coupling of Aryl Bromides and
Chlorides
and Stille5 reactions. Despite the toxicity and relatively
expensive organotin reagents, the Stille reaction remains a
popular approach, especially because of its utility in the
stereoselective coupling of vinyl- and alkenylstannanes.6
The potentially most attractive of the aforementioned
methodologies is Hiyama cross-coupling because organosi-
licon reagents are commercially available at relatively low
cost or can be easily prepared. These reagents are also
nontoxic and quite stable to the presence of other function-
alities and to a variety of reaction conditions. However,
because organosilanes are comparatively unreactive nucleo-
philes, Hiyama coupling has not yet replaced Stille and
Suzuki methodologies.1,4,5 For example, in contrast to Suzuki,
Kumada, and Stille methodologies, there is presently no
general method for cross-coupling considerably cheaper,
more widely available aryl chlorides with organosilicon com-
pounds.
Steven M. Raders, Jesudoss V. Kingston, and
John G. Verkade*
Department of Chemistry, Iowa State University,
Ames, Iowa 50011
jverkade@iastate.edu
Received November 1, 2009
Hiyama and co-workers showed that aryl(ethyl)dichloro-
silanes could be coupled with activated aryl chlorides to give
good yields of coupled product after 24-48 h at 120 °C in
DMF.4b Deshong and Mowery developed a useful protocol
for coupling aryl bromides and iodides with siloxane deriva-
tives, which have been touted as the most convenient organo-
silanes for Hiyama cross-coupling.4c However, challenges
with aryl chlorides were encountered in that work. Recently,
an efficient method for producing biaryls from mesityl-pro-
tected aryl alcohols and aryl siloxanes using 2 mol % of
Pd(OAc)2 and 8 mol % of CM-phos was reported.7 Ligands
such as PPh3, Bu3P, and Bu2P-biphenyl were completely
ineffective. Even Cy2P-biphenyl/Pd2dba3 (the most effective
catalyst utilized by Buchwald for a range of aryl chloride
cross-couplings4c) produced only a 47% yield of product in
the cross-couplingofPhSi(OMe)3 with4-chloroacetophenone
using 10 mol % of Pd2dba3.4c It has been reported that an
imidazoliumchloride/Pd(OAc)2 catalystwasmoreusefulthan
Cy2P-biphenyl/Pd2dba3 for three activated aryl chlorides, but
unactivated substrates such as 4-chloroanisole gave poor
yields.4f PdCl2(CH3CN)2 in the presence of β-diimine ligands
for the coupling of 4-chloroacetophenone with PhSi(OMe)3
afforded only a 62% yield of product.8
Recently, we reported the first synthesis of the bulky
phosphine 1 (Figure 1) and showed it to be effective in
Suzuki-Miyaura cross-coupling reactions, giving high
yields of desired biaryls in the presence of 1 mol % of
Pd(OAc)2 and 2 mol % of 1.9 Ligand 1 features a bulky
iminoproazaphosphatrane moiety that provides electron
richnesstothetBu2P group via donation from the “equatorial”
iBuN substituents and via potential transannulation from the
basal planar N.9 Here we show the usefulness of 1 in the
Hiyama coupling of a variety of aryl bromides and chlorides
to obtain high yields of biaryls with low loadings of Pd
(0.25-1.0 mol %) and 1 (0.5-2.0 mol %).
An efficient catalytic route to biaryls by employing
(generally) only 0.25 mol % of Pd(OAc)2 and 0.5 mol %
of 1in the Hiyama coupling reaction is reported. High yields
for electron-rich, -neutral, and -deficient aryl chlorides are
obtained. A variety of phenylsiloxanes undergo coupling
with aryl bromides and chlorides with low Pd(OAc)2/1
loadings.
t
t
Palladium-catalyzed C-C bond-forming reactions are
exceedingly useful in modern organic synthesis. Biaryls
(constituents of aromatic polymers, liquid crystals, natural
products, and pharmaceuticals) can be synthesized using,
(1) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979,
3437. (b) Stanforth, S. P. Tetrahedron 1998, 54, 263. (c) Suzuki, A. Pure Appl.
Chem. 1991, 63, 419. (d) Wolfe, J. P.; Buchwald, S. P. Angew. Chem., Int. Ed.
1999, 38, 2413. (e) Zapf, A.; Beller, M. Chem.;Eur. J. 2000, 6, 1830.
(f) Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.;
Hursthouse, M. B.; Light, M. E. Organometallics 2003, 22, 987.
(2) (a) Baba, S.; Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729. (b) Dai, C.;
Fu, C. J. Am. Chem. Soc. 2001, 123, 2719.
(3) (a) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972, 94,
4374. (b) Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C. J. Organomet.
Chem. 1999, 576, 23.
(4) (a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 920. (b) Gouda,
K.; Hagiwara, E.; Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1996, 61, 7232.
(c) Mowery, M. E.; DeShong, P. Org. Lett. 1999, 1, 2137. (d) Lee, J.; Fu, G. C.
J. Am. Chem. Soc. 2003, 125, 5616. (e) Riggleman, S.; DeShong, P. J. Org.
Chem. 2003, 68, 8106. (f) Lee, H. M.; Nolan, S. P. Org. Lett. 2000, 2, 2053.
(5) (a) Stille, J. K. Pure Appl. Chem. 1985, 57, 1771. (b) Stille, J. K. Angew.
Chem., Int. Ed. 1986, 25, 508. (c) Farina, V.; Krishnamurthy, V.; Scott, W.
J. Org. React. 1997, 50, 1. (d) Hassa, J.; Svignon, M.; Gozzi, C.; Schulz, E.;
Lemaire, M. Chem. Rev. 2002, 102, 1359. (e) Littke, A. F.; Fu, G. C. Angew.
Chem., Int. Ed. 2002, 41, 4176.
(6) (a) Nakao, N.; Satoh, J.; Shirakawa, E.; Hiyama, T. Angew. Chem.,
Int. Ed. 2006, 45, 2271. (b) von Zezschwitz, P.; Petry, F.; de Meijere, A.
Chem.;Eur. J. 2001, 7, 4035. (c) Paley, R. S.; de Dios, A.; Estroff, L. A.;
Lafontaine, J. A.; Montero, C.; McCulley, D. J.; Rubio, M. B.; Ventura, M.
P.; Weers, H. L.; Fernandez de la Pradilla, R.; Castro, S.; Dorado, R.;
Morente, M. J. Org. Chem. 1997, 62, 6326. (d) Chu, K. H.; Wang, K. K.
J. Org. Chem. 1986, 51, 767.
(7) So, C. M.; Lee, H. W.; Lau, C. P.; Kwong, F. Y. Org. Lett. 2009, 11,
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€
(8) Domin, D.; Benito-Garagorri, D.; Mereiter, K.; Frohlich, J.; Kirchner,
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1744 J. Org. Chem. 2010, 75, 1744–1747
Published on Web 02/02/2010
DOI: 10.1021/jo902338w
r
2010 American Chemical Society

Raders et al.
JOCNote
TABLE 2. Scope of Aryl Bromides
FIGURE 1. Electron-rich phosphines synthesized in our laboratory.
TABLE 1. Optimization Study
aAverage of two runs. Yields are isolated yields. bReaction condi-
tions: 2 mmol of aryl bromide, 4 mmol of siloxane, 3 mmol of
aryl
halide
Pd(OAc)2
(mol %)
ligand
(mol %)
yielda
(%)
TBAF xH2O. c0.5 mol % of Pd(OAc)2, 1 mol % of 1, neat. d1 mol %
3
entry
solvent
of Pd(OAc)2, 2 mol % of 1, 5 mL of dioxane. e0.5 mol % of Pd(OAc)2, 1
mol % of 1, 5 mL of dioxane. f0.25 mol % of Pd(OAc)2, 0.5 mol % of 1, 5
mL of dioxane. g1 mol % of Pd(OAc)2, 2 mol % of 1, neat.
1
2
3
4
5
6
7
8
9
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
dioxane
THF
1.0
1.0
0.5
0.25
0.5
0.5
0.5
0.5
0.5
0.5
0.25
1 (2.0)
1 (2.0)
1 (1.0)
1 (0.5)
2 (1.0)
3 (1.0)
4 (1.0)
1 (0.5)
1 (1.0)
1 (1.0)
1 (0.5)
86
64
81
56
6
42
0
70
81
93
87
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
neat
TABLE 3. Scope of Aryl Chlorides
10
11
neat
neat
aReaction conditions: 2 mmol of 4-chloroanisole, 4 mmol of tri-
methoxyphenylsilane, 3.5 mmol of TBAF xH2O, 5 mL of solvent, 2.5 h.
3
4-Chloroanisole is the most recalcitrant aryl halide sub-
strate in Hiyama coupling with PhSi(OMe)3. A 40% product
yield was obtained using 10 mol % of PdCl2(CH3CN)2 and
20 mol % of P(o-tol)3 in toluene at 80 °C.10 In the presence of
3 mol % of Pd(OAc)2 and 6 mol % of DABCO, only 20% of
the desired product was obtained after 24 h at 80 °C.11 The
highest reported yield (93%) was achieved using microwaves
at 120 °C for 10 min in the presence of 1 mol % of an oxime-
derived palladacycle.12 Under the conditions in entry 1 of
Table 1, we received an 87% yield of product using ligand 1.
Using Pd2dba3 or Pd(dba)2 decreased the product yield,
owing to the formation of Pd black. Increasing the tempera-
ture accelerated the formation of Pd black and also de-
creased product yield. Lower temperatures decreased the
amount of Pd black, but decreased product yields were also
observed.
Other fluoride sources (e.g., CsF and Bu3SnF) were
ineffective in our protocol. Only low product yields were
obtained with phosphine analogues 2 and 3 (Table 1, entries
5 and 6), and 4 was completely ineffective (entry 7). Changing
the Pd/L ratio from 1:2 to 1:1 gave a moderate product yield
of 70% (Table 1, entry 8). When both reactants are liquids,
the reaction could be carried out in the absence of solvent
to achieve the same yield as in entry 3 (entry 9). When
4-bromoanisole was coupled, an excellent yield of desired
biaryl was achieved (entry 10). Decreasing the palladium
loading to 0.25 mol % decreased product yield by only 6%
(entry 11).
aAverage of two runs. Yields correspond to isolated yields. bReaction
conditions: 2 mmol of aryl chloride, 4 mmol of siloxane, 3 mmol of
TBAF 3H2O, neat, time: 0.5-2 h. c0.5 mol % of Pd(OAc)2, 1 mol % of 1,
3
neat. d1 mol % of Pd(OAc)2, 2 mol % of 1, neat. e0.5 mol % of Pd(OAc)2,
1.0 mol % of 1, 5 mL of dioxane.
With the low catalyst loading in Table 1, entry 11, we
investigated a variety of aryl bromides (Table 2). All the
products in Table 2 have been reported previously using
other coupling approaches, although the products in
Table 2, entries 1 and 3-6, those in Table 3, entries 1 and
5, and the product in Table 4, entry 2, have also been
reported earlier via Hiyama coupling (see the correspond-
ing references in the last column of these tables). Pleasingly,
a wide range of aryl bromides can be coupled with a variety
of siloxanes. For example, electron-donating aryl bromides
bearing OMe or NMe2 substituents are coupled with
p-tolyltrimethoxysilane in moderate to excellent product
yields (Table 2, entries 1 and 2). Electron-withdrawing aryl
bromides containing CF3, NO2, COMe, or CN substituents
are also easily coupled with PhSi(OMe)3 in good to excel-
lent yields (Table 2, entries 3-6). Surprisingly, methyl
3-bromobenzoate was coupled to p-methoxyphenyltri-
methoxysilane in 87% yield in the presence of only
0.25 mol % of Pd(OAc)2 and 0.50 mol % of 1 (Table 2,
entry 7).
(10) Li, J.; Deng, C.; Xie, Y. Synthesis 2006, 969.
(11) Li, J.; Deng, C.; Liu, W.; Xie, Y. Synthesis 2005, 3039.
ꢀ
(12) Alacid, E.; Najera, C. Adv. Synth. Catal. 2006, 348, 945.
With some Hiyama catalyst systems, aryl bromides bearing
an ortho methyl or phenyl group have provided only low to
J. Org. Chem. Vol. 75, No. 5, 2010 1745

Raders et al.
JOCNote
TABLE 4. Scope of Heterocyclic Chlorides
SCHEME 1. Reaction of Aryl Chlorides with Aryl Siloxanes
entry
heterocyclic chloride
time (h)
yielda,b (%)
1
2
3
2-pyridyl
3-pyridyl
2-thiopheneyl
2
1.5
1
81c
82d (lit: 63-92)
95c
aAverage of two runs. Yields are isolated yields. bReaction condi-
tions: 2 mmol of aryl chloride, 4 mmol of siloxane, 0.5 mol % of
Pd(OAc)2, 1 mol % of 1, 3 mmol of TBAF, time 0.5-2 h. cNeat
conditions. d5 mL of dioxane.
Sterically demanding aryl bromides are difficult substrates
in some catalytic Hiyama approaches, leading to only mod-
erate yields of the corresponding coupled products.7,8,10,11,13
Thus, sterically encumbered aryl chlorides might be pre-
dicted to be even more problematic in this respect. However,
using only 1 mol % of Pd(OAc)2/2 mol % of 1, 2-chloroto-
luene and 1-chloronaphthalene were coupled with PhSi-
(OMe)3 in good yields (87% and 83%, respectively,
Table 3, entries 7 and 8). Even 1-chlorocyclopentene was
coupled with PhSi(OMe)3 using only 0.5 mol % of Pd(OAc)2/
1 mol % of 1, producing a 91% product yield (entry 9). To the
best of our knowledge, this is the first time 1-chlorocyclopentene
has been used for Hiyama coupling.
The usefulness of our catalytic system also applies to the
coupling of 4-chloroanisole and 2-chloropyridine which
were coupled with p-methoxyphenyltrimethoxysilane and
p-tolyltrimethoxysilane in the presence of 1 mol % of Pd-
(OAc)2 and 2 mol % of 2 to give moderate to good product
yields (Scheme 1).
Next, we turned our focus to heterocyclic aryl chlorides
(Table 4). Only a few literature reports on the use of
heterocyclic aryl chlorides in Hiyama coupling have
appeared.12,15c Here, we show that such substrates couple
well with PhSi(OMe)3, in the presence of 0.5 mol % of
Pd(OAc)2/1 mol % of 1. Thus, 2-chloropyridine and
2-chlorothiophene underwent coupling to give an 81 and
95% isolated product yield, respectively, in the absence of
solvent (Table 3, entries 1 and 3). When dioxane was used as
solvent, GC revealed very low conversion to product. To
the best of our knowledge, this is the first time these
products have been made from a heterocyclic aryl chloride
via Hiyama coupling. When 3-chloropyridine was coupled
with PhSi(OMe)3, dioxane was required to suppress the rate
of Pd black production until the starting material was
consumed. After 1.5 h, an 82% yield of the desired biaryl
was isolated (Table 3, entry 2). The highest reported
literature yield for this reaction was 92%, which was
obtained using 1 mol % of an oxime-derived palladcycle
under microwave conditions at 120 °C.12
moderate yields of products.7,8,10,11,13 Here, sterically hindered
2-bromo-m-xylene coupled with p-methoxyphenyltrimethox-
ysilane to give an 89% product yield (Table 2, entry 8).
R-Bromostyrene coupled well with p-tolyltrimethoxysilane in
the absence of solvent to produce a 78% product yield
(Table 2, entry 11).
We next focused on aryl chloride substrates (Table 3).
Such chlorides are generally quite refractory in palladium-
assisted coupling reactions owing to their reluctance to
oxidatively add to Pd(0).14 Hence, only aryl chlorides with
highly electron-withdrawing substituents tend to undergo
coupling with aryl siloxanes.8,10,11,13,15 Electron-donating
groups on aryl chlorides generally lead to low to moderate
yields.10,11,13,15a,b Here, ligand 1 effectively facilitates
coupling of not only electron-withdrawing aryl chlorides
under low catalyst loadings but also electron-donating and
sterically hindered aryl chlorides. Aryl chlorides with elec-
tron-withdrawing groups such as CF3, CN, CO2Me, and
COMe are efficiently coupled to PhSi(OMe)3 in excellent
yields in the presence of only 0.5 mol % of Pd(OAc)2 and
1 mol % of 1 (Table 3, entries 3-5). The coupling of
2-chlorotrifluorotoluene with PhSi(OMe)3 proceeded
smoothly with 1 mol % of Pd(OAc)2 and 2 mol % of 1 to
provide 82% of the desired product (entry 2). This is the first
time that the products in entries 2-4 have been made from an
aryl chloride via Hiyama coupling.
Electron-donating aryl chlorides were coupled with PhSi-
(OMe)3 with surprising efficiency. Thus, 3-chloroanisole un-
derwent coupling to give 87% of the biaryl product in 1.5 h
(Table 3, entry 1). This biaryl was made only once previously
in a Hiyama coupling in which only 25% of the desired
product was obtained via the reaction of 3-chloroanisole with
PhSi(OMe)3 inthe presence of 5 mol % of Pd(acac)2 and 5 mol
% of the phosphite [3-Me-2,6-t-Bu2C6H2OP(OCH2)2]2C in
p-xylene at 120 °C.13a The electron-rich aryl chloride 5-chloro-
1,3-benzodioxole underwent coupling in 90% isolated yield
(Table 3, entry 6).
Herein we have demonstrated the wide utility of low
loadings of Pd(OAc)2/1 (generally 0.25 mol % of Pd(OAc)2
and 0.5 mol % of 1) and relatively mild conditions (generally
80 °C for 0.5-3 h) for coupling a wide range of aryl bromides
and chlorides with phenylsiloxanes. These reactions are
characterized by generally good to excellent product yields.
Further work directed at further expanding the substrate
scope is currently underway.
(13) (a) Ju, J.; Nam, H.; Jung, H.; Lee, S. Tetrahedron Lett. 2006, 47, 8673.
(b) Shi, S.; Zhang, Y. J. Org. Chem. 2007, 72, 5927. (c) Murata, M.; Yoshida,
S.; Nirei, S.; Watanabe, S.; Masuda, Y. Synlett 2006, 118.
(14) (a) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047. (b) Grushin,
V. V.; Alper, H. In Activation of Unreactive Bonds and Organic Synthesis;
Murai, S., Ed.; Springer: Berlin, 1999; p 193. (c) Herrmann, W. A. In Applied
Homogenous Catalysis With Organometallic Compounds, A Comprehensive
Handbook; Cornils, B., Herrmann, W. A., Eds.; VCH: Weinheim, 1996; Vol. 1, p
722.
(15) (a) Wu, Z.; Yang, M.; Li, H.; Qi, Y. Synthesis 2008, 1415. (b) Pan, C.;
Liu, M.; Zhao, L.; Wu, H.; Ding, J.; Cheng, J. Catal. Commun. 2008, 9, 1685.
(c) Ackermann, L.; Gschrei, C. J.; Althammer, A.; Reiderer, M. Chem.
Commun. 2006, 1419.
Experimental Section
General Procedure for the Hiyama Coupling of Aryl Bromides
and Chlorides. A 10 mL vial was charged with 3 mmol of
TBAF xH2O (794 mg), 0.5 mol % of Pd(OAc)2 (2.24 mg),
and 1.0 mol % of ligand 1 (10.03 mg) in a glovebox. The vial was
3
1746 J. Org. Chem. Vol. 75, No. 5, 2010

Raders et al.
JOCNote
Acknowledgment. We thank the National Science Foun-
dation for a grant (07500463) in support of this work.
capped and brought outside the glovebox where 4 mmol of
arylsiloxane and 2 mmol of aryl halide were added under an
argon flow. The reaction vessel was heated to 80 °C for the
specified times given in the tables. The mixtures were then
purified by column chromatography (0-5% EtOAc) to obtain
pure biaryls.
Supporting Information Available: 1H and 13C NMR for all
compounds as well as experimental prodedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 5, 2010 1747