Biphenylene-Substituted Ruthenocenylphosphine for Suzuki-Miyaura Coupling of Aryl Chlorides

Article abstract of DOI:10.1021/ol800567q

High activity in the palladium-catalyzed Suzuki-Miyaura reactions of aryl chlorides with arylboronic acids was furnished using biphenylene-substituted di-tert-butylruthenocenylphosphine (R-Phos) as a supporting ligand. Substrate combinations even for the construction of highly hindered tetra-ortho- substituted biaryls can be achieved in good to excellent yields with low catalyst loadings in short reaction times.

Full text of DOI:10.1021/ol800567q

ORGANIC
LETTERS
2008
Vol. 10, No. 10
2063-2066
Biphenylene-Substituted
Ruthenocenylphosphine for Suzuki–
Miyaura Coupling of Aryl Chlorides
Takashi Hoshi,*,† Taichi Nakazawa,‡ Ippei Saitoh,‡ Ayako Mori,† Toshio Suzuki,†
Jun-ichi Sakai,† and Hisahiro Hagiwara*,‡
Faculty of Engineering and Graduate School of Science and Technology, Niigata
UniVersity, 8050, 2-Nocho, Ikarashi, Nishi-ku, Niigata 950-2181, Japan
hoshi@gs.niigata-u.ac.jp; hagiwara@gs.niigata-u.ac.jp
Received March 12, 2008
ABSTRACT
High activity in the palladium-catalyzed Suzuki-Miyaura reactions of aryl chlorides with arylboronic acids was furnished using biphenylene-
substituted di-tert-butylruthenocenylphosphine (R-Phos) as a supporting ligand. Substrate combinations even for the construction of highly
hindered tetra-ortho-substituted biaryls can be achieved in good to excellent yields with low catalyst loadings in short reaction times.
The use of bulky and electron-rich phosphines and N-
heterocyclic carbenes (NHCs) as supporting ligands is now
a well-recognized strategy for generating active palladium
catalysts for cross-coupling reactions.1 Excellent phosphine
ligands have also been realized using a biaryl backbone
involving the lower arene ring ortho to phosphine as the key
structural element.2,3 X-ray crystallographic and/or compu-
tational studies of palladium complexes bearing such active
biaryl-based monophosphine ligands showed that these
ligands serve as unique bidentate phosphine-arene ligands
and not as simple monodentate phosphine ligands resulting
from an interaction between the lower arene ring and the
phosphine-ligated palladium center.3 Buchwald proposed
the importance of such the Pd-arene interaction to assist the
generation of monophosphine-Pd0 complexes believed to
be catalytic species in the oxidative addition step, with
concomitant improvement of their inherent instability as-
sociated with the highly coordinatively unsaturated palladium
center. In this paper, we describe the development of a
(2) For some recent examples of active biaryl-based monophosphine
ligands, see: (a) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 3358. (b) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3844. (c) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
5096. (d) Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 10354.
(e) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am. Chem.
Soc. 2007, 129, 13001. (f) Barder, T. E.; Buchwald, S. L. Org. Lett. 2007,
9, 137. (g) Molander, G. A.; Vargas, F. Org. Lett. 2007, 9, 203. (h)
Barluenga, J.; Morlel, P.; Aznar, F.; Valdes, C. Org. Lett. 2007, 9, 275. (i)
Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597. (j) McNeill,
E.; Barder, T. E.; Buchwald, S. L. Org. Lett. 2007, 9, 3785. (k) Molander,
G. A.; Jean-Ge´rard, L. J. Org. Chem. 2007, 72, 8422. (l) Biscoe, M. R.;
Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7232. (m)
Mart´ın, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7236. (n)
Zheng, N. Z.; Anderson, K, W.; Huang, X.; Nguyen, H. N.; Buchwald,
S. L. Angew. Chem. Int. Ed. 2007, 46, 7509.
† Faculty of Engineering.
‡ Graduate School of Science and Technology.
(1) For recent reviews on effective ligands for palladium-catalyzed cross-
coupling reactions, see: (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176. (b) Miura, M. Angew. Chem., Int. Ed. 2004, 43, 2201. (c)
Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44, 366.
10.1021/ol800567q CCC: $40.75
Published on Web 04/19/2008
2008 American Chemical Society

biphenylene-substituted di-tert-butylruthenocenylphosphine
1 (R-Phos) designed as a novel phosphine-arene ligand and
its high ability to activate the palladium catalyst for
Suzuki-Miyaura reactions of aryl chlorides with arylboronic
acids,4 even for the construction of highly hindered tetra-
ortho-substituted biaryls.
geometry, and (2) the three phenyl rings incorporated on the
lower Cp ring whose steric bulk would control the phosphine-
ligated palladium atom to locate on the less sterically
demanding biphenylene group. R-Phos can be readily
prepared starting from bromocyclopentadiene 25 (Scheme
2). As a metallocene scaffold, we chose ruthenocene, rather
The suggested process leading to the development of
R-Phos is illustrated in Scheme 1. The ligand architecture
Scheme 2. Synthesis of R-Phos
Scheme 1. Ligand Design Leading to R-Phos
of R-Phos is based on 1,1′-bis(phosphino)metallocene, a well-
established bidentate bisphosphine ligand. We anticipated that
a phosphine-arene ligand derived from a bidentate bispho-
sphine ligand by replacement of one phosphino group with
an arene group (e.g., the biphenylene group in this study)
would have the ability to adopt the chelate geometry in the
complex, as has the parent ligand, and therefore would serve
as a bidentate ligand for realizing the interaction between
the arene ring and the phosphine-ligated palladium center.
Furthermore, R-Phos may possess at least two structural
advantages for the Pd-arene interaction: (1) the plane
biphenylene group fixed parallel to the lower Cp ring, which
would be the most preferable conformation for the chelate
than ferrocene, in view of the ready accessibility of its
precursor, the bromodicarbonyl ruthenium complex 3.6
In the initial investigation of the performance of R-Phos,
we evaluated the Suzuki-Miyaura reactions of aryl chlorides
in the presence of 0.1 mol % Pd.7–9 For a test reaction, we
chose 2-chloro-1,3-dimethylbenzene (5a) and 2-methylphe-
nylboronic acid (6a) as a moderately hindered substrate
combination. Actually, there have been only a few ligands
found to be effective for this substrate combination with less
than 0.1 mol % of Pd.3e,4g To obtain a larger proportion of
the coordinatively unsaturated active palladium catalyst, a
1:1 ratio of Pd/R-Phos was chosen for preparing the catalyst
system.10 However, under this condition, the cross-coupling
product 7a was obtained in only modest yield (Table 1, entry
1). Even at an early stage of the reaction, the formation of
Pd black was observed, indicating decomposition of the
active catalyst. Thus, to improve the longevity of the active
catalyst, we increased the Pd/R-Phos ratio.11 As expected,
with a 1:2 ratio of Pd/R-Phos, the amount of Pd black was
effectively decreased and the yield was clearly improved
(Table 1, entry 2). Then, we further increased the Pd/R-Phos
(3) (a) Kocˇovsky´, P.; Vyskocˇil, S.; C´ısaˇrova´, I.; Sejbal, J.; Tisˇlerova´,
I.; Smrcˇina, M.; Lloyd-Jones, G. C.; Stephen, S. C.; Butts, C. P.; Murray,
M.; Langer, V. J. Am. Chem. Soc. 1999, 121, 7714. (b) Yin, J.; Rainka,
M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162.
(c) Reid, S. M.; Boyle, R. C.; Mague, J. T.; Fink, M. J. J. Am. Chem. Soc.
2003, 125, 7816. (d) Wang, Y.; Li, X.; Sun, J.; Ding, K. Organometallics
2003, 22, 1856. (e) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald,
S. L. Angew. Chem., Int. Ed 2004, 43, 1871. (f) Christmann, U.; Vilar, R.;
White, A. J. P.; Williams, D. J. Chem. Commun. 2004, 1294. (g) Faller,
J. W.; Sarantopoulos, N. Organometallics 2004, 23, 2008. (h) Barder, T. E.;
Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 4685. (i) Barder, T. E. J. Am. Chem. Soc. 2006, 128, 898. (j)
Christmann, U.; Pantazis, D. A.; Benet-Buchholz, J.; McGrady, J. E.;
Maseras, F.; Vilar, R. J. Am. Chem. Soc. 2006, 128, 6376. (k) Iwasawa, T.;
Komano, T.; Tajima, A.; Tokunaga, M.; Obora, Y.; Fujihara, T.; Tsuji, Y.
Organometallics 2006, 25, 4665. (l) Billingsley, K. L.; Barder, T. E.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 5359. (m) Barder, T. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 12003. (n) Barder, T. B.;
Biscoe, M. R.; Buchwald, S. L. Organometallics 2007, 26, 2183.
(4) For recent examples of metallocene-based monophosphine ligands
for palladium-catalyzed cross-coupling reactions, see: (a) Shelby, Q.;
Kataoka, N.; Mann, G.; Hartwig, J. J. Am. Chem. Soc. 2000, 122, 10718.
(b) Liu, S.-Y.; Choi, M. J.; Fu, G. C. Chem. Commun. 2001, 2408. (c)
Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002,
67, 5553. (d) Pickett, T. E.; Roca, F. X.; Richards, C. J. J. Org. Chem.
2003, 68, 2592. (e) Jensen, J. F.; Johannsen, M. Org. Lett. 2003, 5, 3025.
(f) Pickett, T. E.; Roca, F. X.; Richards, C. J. J. Org. Chem. 2003, 68,
2592. (g) Kwong, F. Y.; Chan, K. S.; Yeung, C. H.; Chan, A. S. C. Chem.
Commun. 2004, 2336. (h) Baille, C.; Zhang, L.; Xiao, J. J. Org. Chem.
2004, 69, 7779. (i) Weng, Z.; Teo, S.; Koh, L. L.; Hor, T. S. A.
Organometallics 2004, 23, 4342. (j) Teo, S.; Weng, Z.; Hor, T. S. A.
Organometallics 2006, 25, 1199. (k) Thimmaiah, M.; Fang, S. Tetrahedron
2007, 63, 6879.
(5) Dennis, G. D.; Edwards-Davis, D.; Field, L. D.; Masters, A. F.;
Maschmeyer, T.; Ward, A. J.; Buys, I. E.; Turner, P. Aust. J. Chem. 2006,
59, 135.
(6) We could not prepare the iron analogue according to similar
procedure using Fe2(CO)9 or Fe3(CO)12.
(7) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 36,
3437
.
(8) For recent reviews on the Suzuki-Miyaura reaction, see: (a) Miyaura,
N. Top. Curr. Chem. 2002, 219, 11. (b) Hassan, J.; Sevignon, M.; Gozzi,
C.; Schulz, E.; Lemaire, M. Chem. ReV. 2002, 102, 1359. (c) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633. (d) Bellina, F.;
Carpita, A.; Rossi, R. Synthesis 2004, 15, 2419. (e) Molander, G. A.; Ellis,
N. Acc. Chem. Res. 2007, 40, 275
(9) For a review on palladium-catalyzed cross-coupling reactions of aryl
chlorides, see ref 1a
(10) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000, 122,
4020.
(11) Littke, A. F.; Fu, G. C. J. Org. Chem. 1999, 64, 10.
.
.
2064
Org. Lett., Vol. 10, No. 10, 2008

Table 1. Effect of the Pd/R-Phos Ratio on Suzuki-Miyaura
Table 2. Suzuki-Miyaura Coupling with 0.1 mol % of Pd
Couplinga
Catalysta
entry Pd/R-Phos
t
Pd black yieldf (%) TOF (h-1
)
1b
2c
3d
4e
1:1
1:2
1:3
1:5
4.5 h
4 h
35 min
4 h
+++
+
-
36
80
163
1662
65
97 (3g)
-
96 (3g)
240
a Conditions: 1.0 mmol of aryl chloride 5a, 1.5 equiv of arylboronic
acid 6a, 0.1 mol % Pd(dba)2, 3 equiv of K3PO4·H2O, dioxane, 100 °C.
b 0.1 mol % of R-Phos. c 0.2 mol % of R-Phos. d 0.3 mol % of R-Phos.
e 0.5 mol % of R-Phos. f 1H NMR yield. g Yield of homocoupling product
(2,2′-dimethylbiphenyl).
ratio to 1:3 and found that the formation of Pd black was
completely suppressed and the reaction was dramatically
accelerated to provide the desired coupling product in 97%
yield in less than 35 min (Table 1, entry 3), which was
exemplified by 20 and 10 times higher TOF than those of
entries 1 and 2.12 It is noteworthy that a further slight increase
in the Pd/R-Phos ratio (1:5) resulted in an extremely slow
reaction; however, no Pd black and decrease in the yield
were observed (Table 1, entry 4).
a Conditions: 1.0 mmol of aryl chloride 5, 1.5 equiv of arylboronic acid
6, 0.1 mol % of Pd(dba)2, 0.3 mol % of R-Phos, 3 equiv of K3PO4·H2O,
dioxane, 100 °C. b THF, reflux.
Under the optimized conditions, an electronically broad
spectrum of aryl chlorides 5b-h also efficiently cross-
coupled with arylboronic acids in the presence of only 0.1
mol % of Pd in good to excellent yields in short reaction
times (Table 2). On the other hand, in contrast to the success
in the coupling of 5a and 6a (Table 1, entry 3), the
combination of sterically hindered 2,6-dimethylphenylboronic
acid (6d) and 2-chlorotoluene (5f) gave the same product in
only modest yield after 5 h under the same conditions (Table
3, entry 1). Even with 0.5 mol % of Pd, the yield was only
slightly improved (Table 3, entry 2). GC monitoring of the
reaction showed the formation of a significant amount of
m-xylene, suggesting the serious competition of the
undesired protodeboronation, a well-known drawback as-
sociated with sterically hindered arylboronic acids.13 In fact,
this transformation with excess boronic acid afforded nearly
quantitative yield in only 40 min (Table 3, entry 3). Thus,
to decrease the extent of protodeboronation, we reduced the
amount of the proton source in the reaction system by
replacing K3PO4·H2O with an anhydrous one.14 As expected,
with this modified method, 1.5 equiv of boronic acid was
sufficient to effect this coupling in good yield (Table 3, entry
4).
To evaluate the versatility of our catalytic system further,
we examined the construction of tetra-ortho-substituted
biaryls from aryl chlorides, which has emerged as an
Table 3. Suzuki–Miyaura Coupling of Sterically Hindered
Arylboronic Acid 6da
entry
Pd (mol %)
base
t
yield (%)
1b
0.1
0.5
0.5
0.5
K3PO4·H2O
K3PO4·H2O
K3PO4·H2O
K3PO4
5 h
5 h
40 min
4 h
27
56
95
80
2c
3c,d
4c
a Conditions: 1.0 mmol of aryl chloride 5f, 1.5 equiv of arylboronic
acid 6d, 3 equiv of base, dioxane, 100 °C. b 0.1 mol % of Pd(dba)2, 0.3
mol % of R-Phos. c 0.5 mol % of Pd(dba)2, 1.5 mol % of R-Phos. d 3 equiv
of arylboronic acid 6d.
extremely difficult task in Suzuki-Miyaura reactions.3b,14,15
In our initial investigation, the reaction of 5a with 3 equiv
of 2,4,6-trimethylphenylboronic acid (6e) was executed in
the presence of 1.0 mol % of Pd, and we found that the
(12) For some examples of the beneficial effect of increasing the ligand/
Pd ratio on catalytic activity, see: (a) Wolfe, J. P.; Singer, R. A.; Yang,
B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550. (b) Altenhoff,
G.; Goddard, R.; Lehmann, C. W.; Glorius, F. Angew. Chem., Int. Ed. 2003,
42, 3690.
(13) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(14) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius, F. J. Am.
Chem. Soc. 2004, 126, 15195.
(15) Song, C.; Ma, Y.; Chai, Q.; Ma, C.; Jiang, W.; Anders, M.
Tetrahedron 2005, 61, 7438
.
Org. Lett., Vol. 10, No. 10, 2008
2065

desired biphenyl 7h was obtained in 94% yield in 2 h (Table
4, entry 1). The same coupling product 7h could also be
phosphine, R-Phos, as a supporting ligand for palladium-
catalyzed Suzuki-Miyaura reactions of aryl chlorides with
arylboronic acids. In particular, at a 1:3 Pd/R-Phos ratio,
substrate combinations even for the construction of highly
hindered tetra-ortho-substituted biaryls can be achieved in
good to excellent yields with low catalyst loadings in short
reaction times. Taking these results together with the high
activity of the catalyst, our catalytic system is operationally
simple and practical and requires no special handling such
as the use of a glovebox. In actuality, R-Phos in the solid
state can be handled in air at least during catalyst preparation.
Furthermore, commercially available aryl chlorides, arylbo-
ronic acids, and bases can be used without further purifica-
tion. Further work to expand the scope of substrates and
understand the origin of the activation ability of R-Phos for
Suzuki-Miyaura reactions is underway in our laboratory.
Studies toward the application of our catalyst system to
additional palladium-catalyzed cross-coupling processes are
also ongoing.
Table 4. Suzuki-Miyaura Coupling for the Construction of
Tetra-ortho-substituted Biarylsa
a Conditions: 1 mol % of Pd(dba)2, 3 mol % of R-Phos, 1 equiv of aryl
chloride 5, 3 equiv of arylboronic acid 6, 3 equiv of K3PO4, dioxane, 100
d
°C. b 1.0 mmol of aryl chloride. c 0.5 mmol of aryl chloride. 1H NMR
Acknowledgment. This work was supported financially
by Grants-in-Aid for Scientific Research (18550091 for
T.H., 17073007 for H.H. and T.H.) from MEXT and a Grant
for Promotion of Niigata University Research Projects (for
T.H.).
yield. e Yield of homocoupling product (2,2′,4,4′,6,6′-hexamethylbiphenyl).
f Yield of homocoupling product (2,2′,6,6′-tetramethylbiphenyl).
furnished from the alternative substrate combination in good
yield under the same condition (Table 4, entry 2). The
reaction of 9-chloroanthracene (5j) proceeded much more
rapidly to furnish the coupling product 7i in 85% yield within
20 min (Table 4, entry 3).
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we described the design, development, and
high activity of a biphenylene-substituted ruthenocene-based
OL800567Q
2066
Org. Lett., Vol. 10, No. 10, 2008