Biphenylene-substituted ruthenocenylphosphine for Suzuki-Miyaura coupling of sterically hindered aryl bromides

Article abstract of DOI:10.1021/jo900550g

(Chemical Equation Presented) A highly general, active, and stable catalytic system was realized in the palladium-catalyzed Suzuki-Miyaura reactions of sterically hindered aryl bromides with arylboronic acids using biphenylene-substituted di-tert-butylrut

Full text of DOI:10.1021/jo900550g

SCHEME 1. Suzuki-Miyaura Coupling of Aryl Chloride
Providing Tetra-Ortho-Substituted Biphenyl Using R-Phos
Biphenylene-Substituted Ruthenocenylphosphine
for Suzuki-Miyaura Coupling of Sterically
Hindered Aryl Bromides
Takashi Hoshi,*,† Ippei Saitoh,‡ Taichi Nakazawa,‡
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, 2009
times with low catalyst loadings (Scheme 1). In light of the
performance of this catalyst in the reactions of sterically
hindered aryl chlorides, we focused on the challenging reactions
of aryl bromides containing large ortho, ortho′-substituents. In
this paper, we report exceptional capabilities of this catalyst in
the Suzuki-Miyaura reactions of di-ortho-substituted aryl
bromides with arylboronic acids. This includes the high catalytic
activity in the reactions of very hindered 2,4,6-triisopropylbro-
mobenzene (1a) with ortho-substituted phenylboronic acids at
50 °C or even at room temperature, the first cross-coupling
syntheses of triortho-substituted biphenyls from 1a below
100 °C.5 The unprecedented low catalyst loading, short reaction
time, and broad scope of ortho-substituted arylboronic acids
were exhibited in the couplings with 2,6-dimethylbromobenzene
(1b) at 100 °C.6 In addition, at this elevated temperature, the
activity of this catalyst system showed a significant dependence
on the L/Pd ratio which furnished a much higher activity at a
3:1 ratio of R-Phos to Pd.7
A highly general, active, and stable catalytic system was
realized in the palladium-catalyzed Suzuki-Miyaura reac-
tions of sterically hindered aryl bromides with arylboronic
acids using biphenylene-substituted di-tert-butylruthenoce-
nylphosphine (R-Phos) as a supporting ligand.
In our initial study, we examined the performance of the
R-Phos-based palladium catalyst in the reactions of aryl
(2) For some recent examples, see: (a) Munday, R. H.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 2754. (b) Shen, Q.; Ogata, T.;
Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586. (c) Dreher, S. D.; Dormer,
P. G.; Sandrock, D. L.; Molander, G. A. J. Am. Chem. Soc. 2008, 130, 9257. (d)
Altman, R. A.; Hyde, A. M.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 9613. (e) Wolf, C.; Xu, H. J. Org. Chem. 2008, 73, 162. (f) So,
C. M.; Yeung, C. C.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2008, 73, 7803.
(g) Vo, G. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2008, 47, 2127. (h)
Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 4695. (i)
So, C. M.; Zhou, Z.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47,
6402. (j) So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47,
8059. (k) Fujihara, T.; Yoshida, S.; Ohta, H.; Tsuji, Y. Angew. Chem., Int. Ed.
2008, 47, 8310.
Over the past 10 years, extensive efforts aimed at reaching a
high degree of efficiency in palladium-catalyzed cross-coupling
processes have been devoted toward the development of new
ligands with the ability to provide excellent levels of catalytic
generality, activity, and longevity.1,2 Recently, we have also
reported the design, development, and high activity of biphe-
nylene-substituted di-tert-butylruthenocenylphosphine (R-Phos)
as a supporting ligand for palladium-catalyzed Suzuki-Miyaura
reactions of aryl chlorides with arylboronic acids.3,4 The catalyst
generated from R-Phos and Pd(dba)2 facilitates the couplings
even for the construction of highly hindered tetra-ortho-
substituted biaryls in good to excellent yields in short reaction
(3) Hoshi, T.; Nakazawa, T.; Saitoh, I.; Mori, A.; Suzuki, T.; Sakai, J.;
Hagiwara, H. Org. Lett. 2008, 10, 2063.
(4) For recent reviews on 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) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2008,
64, 3047. (f) See also ref 1e.
(5) (a) Su, W.; Urgaonkar, S.; McLaughlin, P. A.; Verkade, J. G. J. Am.
Chem. Soc. 2004, 126, 16433. (b) Walker, S. D.; Barder, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871. (c) Barder, T. E.; Walker,
S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (d)
Liang, L.-C.; Chien, P.-S.; Huang, M.-H. Organometallics 2005, 24, 353.
(6) For Suzuki-Miyaura reactions of 1b or its mesityl analogue with 2b in
the presence of less than 0.1 mol % of Pd catalyst, see: (a) Feuersten, M.; Berthiol,
F.; Doucet, H.; Santelli, M. Synlett 2002, 1807. (b) See also ref 5d.
(7) For some examples of the beneficial effect of increasing the L/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.
† Faculty of Engineering.
‡ Graduate School of Science and Technology.
(1) For recent reviews, 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. (d) Marion,
N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440. (e) Martin, R.; Buchwald,
S. L. Acc. Chem. Res. 2008, 41, 1461. (f) Wu¨rtz, S.; Glorius, F. Acc. Chem.
Res. 2008, 41, 1523. (g) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (h) Fu,
G. C. Acc. Chem. Res. 2008, 41, 1555. (i) Surry, D. S.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2008, 47, 6338.
10.1021/jo900550g CCC: $40.75
Published on Web 04/24/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 4013–4016 4013

TABLE 1. Suzuki-Miyaura Coupling of Aryl Bromide at Room
TABLE 2. Suzuki-Miyaura Coupling of 1a with
Temperaturea
Ortho-Substituted Phenylboronic Acid under Mild Conditionsa
a Conditions: 1 equiv of aryl bromide, 1.5 equiv of arylboronic acid, 1
mol % of Pd(dba)2, 1 mol % of R-Phos, 3 equiv of K3PO4 ·H2O, THF,
50 °C. b 1 mol % of Pd(dba)2, 3 mol % of R-Phos, room temperature.
c
1H NMR yield. d 0.5 mol % of Pd(dba)2, 0.5 mol % of R-Phos.
a Conditions: 1 equiv of aryl bromide, 1.5 equiv of arylboronic acid, 1
mol % of Pd(dba)2, 1 mol % of R-Phos, 3 equiv of K3PO4 ·H2O, THF,
room temperature.
or above. The ability to undergo the reaction under milder
conditions is of great synthetic importance. Thus, we examined
the reactions of 1a with a series of ortho-substituted phenyl-
boronic acids at lower temperatures (Table 2). Initially, the
reaction with the most simple 2b was executed at room
temperature with 1 mol % of the catalyst, and we obtained the
desired biphenyl 3h in 52% yield after 18 h (Table 2, entry 1).
When heated at 50 °C, this transformation was dramatically
accelerated to afford a nearly quantitative yield in only 1 h with
0.5 mol % of Pd (Table 2, entry 2). By using 1 mol % of the
catalyst, more sterically hindered 2-ethylphenylboronic acid (2c)
and 2-methoxyphenylboronic acid (2d) could also be coupled
with 1a in excellent yields in short reaction times (Table 2,
entries 3 and 4). Although further sterically hindered 2-isopro-
poxyphenylboronic acid (2e) and 2-phenylphenylboronic acid
(2f) resulted in a significant loss in yield (Table 2, entries 5
and 6), a range of tri-ortho-substituted biphenyls from 1a could
be obtained at 50 °C with the catalyst based on R-Phos. We
also found that the coupling of 2,4,6-trimethylphenylboronic
acid (2g) with 1b, one of the most difficult Suzuki-Miyaura
substrate combinations,10 occurred at this low temperature.
Though full conversion was not observed, the corresponding
biphenyl with four o-methyl substituents 3m was obtained in
an acceptable yield (eq 1).
bromides at room temperature. As shown in Table 1, in the
presence of 1 mol % of the catalyst containing equimolar
amounts of R-Phos and Pd(dba)2, an array of sterically and
electronically different aryl bromides underwent efficient cou-
plings with phenylboronic acid (2a) or 2-methylphenylboronic
acid (2b) to afford the corresponding biphenyls in excellent
yields in short reaction times. Particularly noteworthy is the
ability of this catalyst to promote coupling reactions with a
comparable rate regardless of the steric character of the substrate
even for the construction of hindered tri-ortho-substituted
biphenyl 3g, indicating the high activity of this catalyst toward
sterically hindered aryl bromides even at room temperature.
Given the high catalytic activity toward sterically hindered
aryl bromides, we explored the possibility of carrying out the
coupling reaction of 1a, the quite difficult aryl bromide substrate
for the cross-coupling reactions due to its extremely increased
steric hindrance imparted by two large o-isopropyl groups.5,8,9
In fact, to the best of our knowledge, Buchwald’s S-Phos has
been reported as the only successful ligand for the Suzuki-
Miyaura couplings of 1a with ortho-substituted arylboronic acids
to date.5b,c In addition, previous cross-coupling syntheses of tri-
ortho-substituted biphenyls from 1a were carried out at 100 °C
(8) For Suzuki-Miyaura reactions of 1a with ortho-unsubstituted arylboronic
acid, see: (a) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2002,
42, 6667. (b) Kwong, F. Y.; Chan, K. S.; Yeung, C. H.; Chan, A. S. C. Chem.
Commun. 2004, 2336. (c) Lipshutz, B. H.; Petersen, T. B.; Abela, A. R. Org.
Lett. 2008, 10, 1333. (d) See also refs 5b and 5c.
(9) For Mizoroki-Heck reactions of 1a, see: (a) Feuerstein, M.; Doucet,
H.; Santelli, M. Synlett 2001, 1980. (b) Feuerstein, M.; Doucet, H.; Santelli, M.
Tetrahedron Lett. 2002, 43, 2191. (c) Battace, A.; Zair, T.; Doucet, H.; Santelli,
M. Tetrahedron Lett. 2006, 47, 459. (d) Berthiol, F.; Doucet, H.; Santelli, M.
Appl. Organometal. Chem. 2006, 20, 855. (e) Battace, A.; Zair, T.; Doucet, H.;
Santelli, M. Synthesis 2006, 3495. (f) Lemhadri, M.; Doucet, H.; Santelli, M.
Synlett 2006, 2935. (g) Battace, A.; Feuerstein, M.; Lemhadri, M.; Zair, T.;
Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2007, 3122. (h) Kantchev, E. A. B.;
Peh, G.-R.; Zhang, C.; Ying, J. Y. Org. Lett. 2008, 10, 3949.
The catalyst generated from R-Phos and Pd(dba)2 demon-
strated a beneficial effect of increasing the L/Pd ratio on the
catalyst activity at 100 °C, as previously reported in the reaction
(10) (a) Yin, J.; Rainka, M. P.; Zhang, X.-X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 1162. (b) Altenhoff, G.; Goddard, R.; Lehmann, C. W.; Glorius,
F. J. Am. Chem. Soc. 2004, 126, 15195. (c) Demchuk, O. M.; Yoruk, B.;
Blackburn, T.; Snieckus, V. Synlett 2006, 2908. (d) See also refs 5b and 5c.
4014 J. Org. Chem. Vol. 74, No. 10, 2009

TABLE 3. Effect of R-Phos/Pd Ratio on Suzuki-Miyaura
TABLE 4. Suzuki-Miyaura Coupling of Sterically Hindered Aryl
Coupling of Aryl Bromide and Arylboronic Acida
Bromide and Arylboronic Acid with 0.01 mol % of Pda
entry ArBr Pd (mol %) R-Phos/Pd T (°C) time product yield (%)
1b, c 1b
2b,d 1b
3b,e 1b
4b,g 1b
5b,h 1b
0.1
0.1
0.01
0.01
0.001
1
1
1
1
1:1
3:1
1:1
3:1
3:1
1:1
3:1
1:1
3:1
100 45 min
100 15 min
100 4.5 h
100 30 min
100 2 h
3g
3g
3g
3g
3g
3g
3g
3h
3h
94
98
11f
97
83
97
87
88
92
6i,j
7i,k
8j,l
9k,l
1b
1b
1a
1a
rt
2 h
2 h
1 h
1 h
rt
50
50
a Conditions: 1 equiv of aryl bromide, 1.5 equiv of arylboronic acid, 3
equiv of K3PO4 ·H2O. b Dioxane, 100 °C. c 0.1 mol % of Pd(dba)2, 0.1
mol % of R-Phos. d 0.1 mol % of Pd(dba)2, 0.3 mol % of R-Phos. e 0.01
f
mol % of Pd(dba)2, 0.01 mol % of R-Phos. 1H NMR yield. g 0.01 mol
% of Pd(dba)2, 0.03 mol % of R-Phos. h 0.001 mol % of Pd(dba)2, 0.003
mol % of R-Phos. i THF, room temperature. j 1 mol % of Pd(dba)2, 1
mol % of R-Phos. k 1 mol % of Pd(dba)2, 3 mol % of R-Phos. l THF,
50 °C.
a Conditions: 1 equiv of aryl bromide, 1.5 equiv of arylboronic acid,
0.01 mol % of Pd(dba)2, 0.03 mol % of R-Phos, 3 equiv of K3PO4 ·H2O,
dioxane, 100 °C.
of aryl chlorides in which the exceptionally higher activity could
be induced at a 3:1 ratio of R-Phos to Pd(dba)2 (Table 3).3 When
the coupling of 1b with 2b was conducted in the presence of
0.1 mol % of Pd, the reaction proceeded about 3 times faster at
a 3:1 ratio than at a 1:1 ratio (Table 3, entries 1 and 2). This
L/Pd ratio-dependent catalytic activity was observed more
clearly with more than 1 order of magnitude lower catalyst
loadings. In actuality, when the palladium loading was reduced
to 0.01 mol %, the catalyst system containing equimolar amounts
of R-Phos and Pd(dba)2 resulted in only 11% yield (Table 3,
entry 3). In contrast, increasing the L/Pd ratio to 3:1 furnished
an excellent yield of the same coupling product in only 30 min
(Table 3, entry 4). Furthermore, the exceptionally low catalyst
loading of 0.001 mol % of Pd was also sufficient to induce this
transformation in 83% yield after 2 h, corresponding to a
turnover number (TON) and a turnover frequency (TOF) of
83000 and 41500 h-1, respectively (Table 3, entry 5).6 To the
best of our knowledge, this result represents more than 10 and
100 times higher TON and TOF than any of these observed for
this sterically difficult transformation to date. In contrast, there
was no observation of the influence of the L/Pd ratio on the
catalytic activity below 50 °C (Table 3, entries 6-9).
The ability to operate for a range of substrates at low catalyst
loading is of great importance in metal-catalyzed processes.
Thus, we proceeded to assess the efficiency of this catalyst
system in the couplings of 1b with a sterically diverse set of
ortho-substituted arylboronic acids in the presence of 0.01 mol
% of Pd (Table 4). 2-Ethylphenylboronic acid (2c), 2-methox-
yphenylboronic acid (2d), and 1-naphthylboronic acid (2h) also
underwent couplings with 1b in excellent yields in less than 30
min (Table 4, entries 1-3). Further sterically demanding
isopropoxyphenylboronic acid (2e) and 2-phenylphenylboronic
acid (2f) slightly retarded the rates of the reactions, whereas
coupling products could also be obtained in good to excellent
yields within 1 h (Table 4, entries 4 and 5). This catalyst system
was also effective for generating tri-ortho-substituted biaryls
from other hindered aryl bromides with only this low catalyst
loading. For example, 9-bromoanthracene (1g) underwent the
facile coupling even with 2f in quantitative yield in 30 min
(Table 4, entry 6). Furthermore, although a longer reaction time
was required, extremely hindered 1a could also be coupled with
2b in acceptable yield (Table 4, entry 7).
In summary, we have demonstrated the excellent generality,
activity, and stability of the catalyst generated from R-Phos and
Pd(dba)2 for the sterically difficult Suzuki-Miyaura reactions
of di-ortho-substituted aryl bromides with arylboronic acids. The
catalyst works well even for the couplings of extremely hindered
2,4,6-triisopropylbromobenzene (1a) with ortho-substituted phe-
nylboronic acids not just with the most simple 2-methyl
derivative to provide tri-ortho-substituted biphenyls in excellent
yields under mild conditions. When heated at 100 °C, 2,6-
dimethylbromobenzene (1b) couples with a sterically diverse
set of ortho-substituted arylboronic acids in good to excellent
yields and short reaction times in the presence of only
0.001-0.01 mol % of this catalyst. The operational simplicity
of our process without the need of special handling such as the
use of a glovebox is also noteworthy.
Experimental Section
General Procedure
A for Suzuki-Miyaura Couplings
below 50 °C. A flame-dried two-necked flask was charged with
R-Phos, arylboronic acid, Pd(dba)2, and K3PO4 ·H2O, capped with
a rubber septum, and then evacuated and backfilled with argon
J. Org. Chem. Vol. 74, No. 10, 2009 4015

(three cycles). To the flask were sequentially added aryl bromide
and THF via syringe through a septum, and then the reaction
mixture was stirred at the indicated temperature for the indicated
amount of time.
amount of a catalyst solution composed of R-Phos, Pd(dba)2, and
dioxane via syringe through a septum, and then the reaction mixture
was stirred at 100 °C for the indicated amount of time.
2,6-Dimethyl-2′-ethylbiphenyl (3n). Following procedure B, a
mixture of 2-ethylphenylboronic acid (226.0 mg, 1.51 mmol), 2,6-
dimethylbromobenzene (181.3 mg, 0.98 mmol), K3PO4 ·H2O (693.3
mg, 3.01 mmol), and 10 µL of a catalyst solution composed of
R-Phos (11.6 mg, 15 µmol), Pd(dba)2 (2.9 mg, 5 µmol), and dioxane
(0.5 mL) in dioxane (2 mL) was stirred at 100 °C for 15 min. The
reaction mixture was diluted with n-hexane (5 mL), filtered through
a thin pad of silica gel (n-hexane), and concentrated under reduced
pressure. The crude material obtained was purified by flash
chromatography on silica gel (n-hexane) to provide the title
compound (200.0 mg, 0.95 mmol, 97%) as a colorless oil: 1H NMR
(CDCl3, 270 MHz) δ 1.05 (t, J ) 7.6 Hz, 3H), 1.96 (s, 6H), 2.28
(q, J ) 7.6 Hz, 2H), 6.99 (d, J ) 8.1 Hz, 1H), 7.08-7.18 (m, 2H),
7.20-7.28 (m, 2H), 7.30-7.35 (m, 2H); 13C NMR (CDCl3, 67.5
MHz) δ 14.6, 20.7, 25.8, 125.9, 126.8, 127.1, 128.1, 129.0, 135.9,
139.7, 140.8, 141.4; IR (CHCl3, cm-1) 3062, 3010, 2969, 2933,
2874, 1463, 1379, 1006; MS (EI), m/z 210 (M+, 68), 195 (100),
181 (40), 180 (39), 165 (52); HRMS found 210.1403, calcd for
C16H18 210.1409.
2,4,6-Triisopropyl-2′-ethylbiphenyl (3i). Following procedure
A, a mixture of R-Phos (3.8 mg, 5 µmol), Pd(dba)2 (3.0 mg, 5
µmol), 2-ethylphenylboronic acid (114.0 mg, 0.76 mmol), 2,4,6-
triisopropylbromobenzene (138.6 mg, 0.49 mmol), and K3PO4 ·H2O
(350.6 mg, 1.52 mmol) in THF (1 mL) was stirred at 50 °C for
1 h. The reaction mixture was diluted with n-hexane (5 mL), filtered
through a thin pad of silica gel (n-hexane), and concentrated under
reduced pressure. The crude material obtained was purified by flash
chromatography on silica gel (n-hexane) to provide the title
compound (141.5 mg, 0.46 mmol, 94%) as a white solid: mp )
1
79-81 °C; H NMR (CDCl3, 270 MHz) δ 1.00 (d, J ) 6.8 Hz,
6H), 1.07 (t, J ) 7.3 Hz, 3H), 1.11 (d, J ) 6.6 Hz, 6H), 1.31 (d,
J ) 6.8 Hz, 6H), 2.30 (q, J ) 7.6 Hz, 2H), 2.44 (sept, J ) 6.8 Hz,
2H), 2.94 (sept, J ) 6.8 Hz, 1H), 7.03-7.06 (m, 3H), 7.16-7.25
(m, 1H), 7.31-7.33 (m, 2H); 13C NMR (CDCl3, 67.5 MHz) δ 14.2,
23.3, 24.2, 25.2, 25.7, 30.4, 34.2, 120.5, 125.0, 126.8, 127.3, 130.1,
135.5, 139.4, 142.1, 146.2, 147.5; IR (CHCl3, cm-1) 3019, 2964,
2932, 2870, 1465, 1362; MS (EI) m/z 308 (M+, 72), 223 (61), 209
(81), 181 (100); HRMS found 308.2498, calcd for C23H32 308.2504.
General Procedure B for Suzuki-Miyaura Couplings at
100 °C. A flame-dried, two-necked flask was charged with
arylboronic acid and K3PO4 ·H2O, capped with a rubber septum,
and then evacuated and backfilled with argon (3 cycles). To the
flask were sequentially added aryl bromide (9-bromoanthracene (1g)
was added during the initial charge), dioxane, and the indicated
Supporting Information Available: Experimental proce-
1
dures and full spectroscopic data and copies of H NMR and
13C NMR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO900550G
4016 J. Org. Chem. Vol. 74, No. 10, 2009