Practical and convenient Suzuki-Miyaura coupling reaction and α-arylation using diphenylcyclopropylphosphine ligands

Article abstract of DOI:10.1055/s-2008-1078525

A new ligand, diphenylmethylcyclopropylphosphine, has successfully been applied in the palladium-catalyzed Suzuki-Miyaura coupling and α-arylation of ketones with aryl chlorides in moderate to high yields. An asymmetric coupling between anisyl chloride and 2-methylindan-1-one was also tested as the first trial, giving 80% yield and 41% ee with 1 mol% of Pd. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078525

LETTER
1809
Practical and Convenient Suzuki–Miyaura Coupling Reaction and
a-Arylation Using Diphenylcyclopropylphosphine Ligands
a-Arylation
Using
e
D
iphenylcy
n
clopropylphosphin
S
e
L
igands uzuki,* Tomoya Sawaki, Yoji Hori, Tohru Kobayashi
Takasago International Corporation, Corporate Research & Development Division,
1-4-11 Nishi-yawata, Hiratsuka, Kanagawa 254-0073, Japan
Fax +81(463)252093; E-mail: ken_suzuki@takasago.com
Received 1 April 2008
Abstract: A new ligand, diphenylmethylcyclopropylphosphine,
has successfully been applied in the palladium-catalyzed Suzuki–
Me
P
Me
Miyaura coupling and a-arylation of ketones with aryl chlorides in
moderate to high yields. An asymmetric coupling between anisyl
chloride and 2-methylindan-1-one was also tested as the first trial,
giving 80% yield and 41% ee with 1 mol% of Pd.
P
2
Key words: cross-coupling, halides, ligands, palladium
1
Figure 1 Structures of phosphine ligands
Palladium-catalyzed coupling reactions of aryl halides
provide a general route to a wide range of substituted
arenes and have often been used as a key reaction for con-
structing carbon–carbon bonds due to the versatility and
reliability.1 Therefore, much work has been devoted to the
development of the coupling reactions.2–13,15 The previous
work has mainly focused on enhancing reactivity toward
aryl halides to employ aryl chlorides and sulfonates as
coupling partners, and also milder reaction conditions in
the various coupling reactions such as Buchwald–Hartwig
amination,2 Suzuki–Miyaura coupling,3 and a-arylation.4
Initial work by Hartwig,5 Buchwald,6 Fu,7 Beller,8 and
Nolan9 showed effective catalyst systems incorporating
sterically hindered alkylphosphines or carbene ligands in
the coupling reactions. Li,10 Verkade,11 and Koie12 as well
as other groups13 have also studied the coupling reactions
with their new systems. Recently, we reported amination
of various aryl chlorides using a new diphenylmethylcy-
clopropylphosphine (1)14 as the ligand, which was de-
signed based on combining two structural characteristics
that new phosphine ligands have in common.15 As part of
our continuing efforts to aim at developing practical and
convenient coupling reactions, Suzuki–Miyaura coupling
and a-arylation of aryl chlorides were attempted. We
herein report that ligand 1/palladium catalyst catalyzes
Suzuki–Miyaura coupling and a-arylation. We also report
an initial study of asymmetric a-arylation of ketone with
aryl chloride using optically pure ligand 2 (Figure 1).
were exposed to air for several months, no change was ob-
served. In addition, the purity of a solution of phosphine 1
in toluene was >99% after the solution was stirred at 30 °C
for 16 hours, although a trace amount of the phosphine ox-
ide was detected by HPLC (<0.3%). In the case at 50 °C,
the purity was >98%.
We next examined Suzuki–Miyaura coupling and a-aryl-
ation with ligand 1. As shown Table 1, the ligand 1/Pd
system was effective in the cross-coupling of various aryl
chlorides. For the Suzuki–Miyaura coupling, electron-
rich and electron-poor aryl chlorides coupled with arylbo-
ronic acids in high yields. In the presence of 0.5 mol% of
[(p-allyl)PdCl]2 and 2 mol% of ligand 1, reaction of 4-ani-
syl and 2,5-dimethoxyphenyl chlorides with arylboronic
acids afforded the corresponding biaryls in 96% and 93%
yields, respectively (entries 3 and 4). An aryl chloride
with an ester group was also a suitable coupling partner
(entry 2). In the reaction of sterically hindered substrates,
2,6-dimethylphenyl chloride and 2-tolylboronic acid, al-
though bulky ligand 1 was less effective, use of ligand 2
that had less bulkiness gave a better result with a longer
reaction time (entry 5). In the case of phenyl tosylate, the
isolated yield was moderate and further optimization of
the reaction conditions was needed (entry 6). The catalyst
system was also applicable for the reaction of electron-
rich aryl chlorides with ketones. The reaction of 4-chloro-
anisole and 2-chlorotoluene with propiophenones using 1
mol% of Pd selectively proceeded to give the correspond-
ing monoarylated products in 90% and 81% yields, re-
spectively (entries 7 and 8). In the case of 2-methylindan-
1-one, the coupling product was obtained in 91% yield
(entry 9). However, for arylation of phenyl tosylate, the
product was not observed under these conditions (entry
10).
To investigate the performance of phosphine 1, we first
examined its stability, because it is important that it is sta-
ble to molecular oxygen and moisture, especially from the
industrial perspective. Phosphines 1 and 2 were stable
enough to be treated under air. When the solid phosphines
SYNLETT 2008, No. 12, pp 1809–1812
Advanced online publication: 19.06.2008
DOI: 10.1055/s-2008-1078525; Art ID: U02808ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8
Asymmetric coupling reactions of aryl halides to produce
new chiral quaternary carbon centers such as arylation of
ketones has attracted much attention. Buchwald’s group

1810
K. Suzuki et al.
LETTER
Table 1 Coupling Reactions of Aryl Chlorides and Tosylates with Arylboronic Acids and Ketones20,21
Entry
1
Aryl halide
Coupling partner
Conditionsa
A
Product
Yield (%)b
94
Cl
Me
(HO)2B
Me
CO2Me
CO2Me
Cl
2
3
A
A
96
96
(HO)2B
(HO)2B
Cl
Me
MeO
MeO
Me
MeO
MeO
OMe
OMe
Cl
4
A
93
OMe
(HO)2B
OMe
Me
Me
Me Me
Me
5c
6
A
A
B
87
Cl
(HO)2B
Me
41d
90
OTs
Me
(HO)2B
Me
OMe
O
O
7
MeO
Cl
Me
Me
O
Me
O
8
9
B
B
B
81
Cl
Me
OMe
O
O
91
MeO
Cl
Me
Me
O
O
10
NR
OTs
Me
a Conditions A: aryl halide (1.0 equiv), arylboronic acid (1.5 equiv), [(p-allyl)PdCl]2 (0.5 mol%), ligand 1 (2 mol%), K2CO3 (2 equiv), toluene,
80 °C, 3 h. Conditions B: aryl halide (1.0 equiv), ketone (1.1 equiv), [(p-allyl)PdCl]2 (0.5 mol%), ligand 1 (2 mol%), NaOt-Bu (1.2 equiv),
toluene, 80 °C, 16–18 h.
b Isolated yield.
c Reaction was conducted with ligand 2 as ligand for 8 h.
d GC conversion was 47%.
reported asymmetric arylation by an atropoisomeric bi- danone gave the coupling product in 80% yield and with
naphthylphosphine/Pd system, which enjoyed high enan- 41% ee (Equation 1). Although the high yield was ob-
tioselectivity.16 However, the reaction was mainly limited tained, it was ineffective for good enantioselectivity. We
to the reaction of aryl bromides. Ligands 117 and 218 orig- believe this study would lead to the next step of these
inally have chiral carbons next to the phosphorus in con- ligands.
trast to achiral phosphine ligands specially designed for
In conclusion, we demonstrated that, with diphenylmeth-
coupling reactions of less active aryl halides. We also
ylcyclopropylphosphines as the ligand, practical and ef-
tried asymmetric arylation with optically pure ligand 2,19
fective Suzuki–Miyaura coupling and a-arylation of
which was obtained by optical resolution of the racemic
ketones including asymmetric reaction can take place.
oxide by HPLC and subsequent reduction. Under the
Further improvements are now under investigation.
same conditions, the reaction of 4-anisyl chloride with in-
Synlett 2008, No. 12, 1809–1812 © Thieme Stuttgart · New York

LETTER
a-Arylation Using Diphenylcyclopropylphosphine Ligands
1811
D.; Naud, F.; Studer, M.; Nolan, S. P. Org. Lett. 2003, 5,
1479.
(10) (a) Li, G. Y. Angew. Chem. Int. Ed. 2001, 40, 1513. (b) Li,
G. Y. J. Org. Chem. 2002, 67, 3643.
O
OMe
O
Me
Pd/L
+
(11) (a) Urgaonkar, S.; Nagarajan, M.; Verkade, J. G.
Tetrahedron Lett. 2002, 43, 8921. (b) Urgaonkar, S.;
Nagarajan, M.; Verkade, J. G. Org. Lett. 2003, 5, 815.
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Lett. 1998, 39, 617. (b) Yamamoto, T.; Nishiyama, M.;
Koie, Y. Tetrahedron Lett. 1998, 39, 2367.
*
Me
Cl
OMe
Equation 1 Asymmetric coupling of 2-methylindanone and 4-ani-
syl chloride
(13) (a) Colacot, T. J.; Shea, H. A. Org. Lett. 2004, 6, 3731.
(b) Brenstrum, T.; Clattenburg, J.; Britten, J.; Zavorine, S.;
Dyck, J.; Robertson, A. J.; McNulty, J.; Capretta, A. Org.
Lett. 2006, 8, 103. (c) So, C. M.; Lau, C. P.; Kwong, F. Y.
Org. Lett. 2007, 9, 2795. (d) Bei, X.; Crevier, T.; Guram, A.
S.; Jandeleit, B.; Powers, T. S.; Turner, H. W.; Uno, T.;
Weinberg, W. H. Tetrahedron Lett. 1999, 40, 3855. (e) Bei,
X.; Uno, T.; Norris, J.; Turner, H. W.; Weinberg, W. H.;
Guram, A. S.; Petersen, J. L. Organometallics 1999, 18,
1840. (f) Feuerstein, M.; Doucet, H.; Santelli, M.
Tetrahedron Lett. 2001, 42, 5659. (g) Feuerstein, M.;
Berthiol, F.; Doucet, H.; Santelli, M. Synlett 2002, 1807.
(h) Gstöttmayr, C. W. K.; Böhm, V. P. W.; Herdtweck, E.;
Grosche, M.; Herrmann, W. A. Angew. Chem. Int. Ed. 2002,
41, 1363.
(14) As a series of BRIDPs, ligands 1 and 2 are commercially
available from Strem Chemicals, Inc. and Sigma-Aldrich.
(15) (a) Suzuki, K.; Hori, Y.; Kobayashi, T. Adv. Synth. Catal.
2008, 350, 652. (b) Suzuki, K.; Hori, Y.; Nishikawa, T.;
Kobayashi, T. Adv. Synth. Catal. 2007, 349, 2089.
(c) Suzuki, K.; Fontaine, A.; Hori, Y.; Kobayashi, T. Synlett
2007, 3206.
Acknowledgment
We thank Prof. Dr. T. Nakai and Dr. T. Hagiwara for helpful sug-
gestions and useful discussion.
References and Notes
(1) (a) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41,
4176. (b) Zapt, A.; Beller, M. Chem. Commun. 2005, 431.
(c) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U.
Adv. Synth. Catal. 2006, 348, 23.
(2) (a) Hartwig, J. F. Angew. Chem. Int. Ed. 1998, 37, 2046.
(b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125.
(3) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Miyaura, N. Top. Curr. Chem. 2002, 219, 11.
(4) (a) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 1360. (b) Culkin, D. A.; Hartwig, J.
F. Acc. Chem. Res. 2003, 36, 234.
(5) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998,
120, 7369. (b) Kataoka, N.; Shelby, Q.; Stambuli, J. P.;
Hartwig, J. F. J. Org. Chem. 2002, 67, 5553. (c) Stambuli,
J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem. Int. Ed.
2002, 41, 4746. (d) Hama, T.; Culkin, D. A.; Hartwig, J. F.
J. Am. Chem. Soc. 2006, 128, 4976. (e) Shen, Q.; Hartwig,
J. F. J. Am. Chem. Soc. 2006, 128, 10028.
(16) (a) Åhman, J.; Wolfe, J. P.; Troutman, M. V.; Paluchi, M.;
Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918.
(b) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 1261. (c) Liu, X.; Hartwig, J.
F. J. Am. Chem. Soc. 2004, 126, 5182.
(17) For optically pure phosphine 1, it is now under investigation.
(18) Phosphine ligand 2 was prepared with the same manner as
ligand 1, see ref. 15a. 1H NMR (500 MHz, CDCl3): d = 0.99–
1.40 (m, 11 H), 1.01 (d, J = 1.7 Hz, 3 H), 1.55–1.93 (m, 13
H), 7.00 (t, J = 7.6 Hz, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 7.12
(t, J = 7.6 Hz, 2 H), 7.19 (d, J = 7.6 Hz, 2 H), 7.28–7.37 (m,
4 H). 13C NMR (125 MHz, CDCl3): d = 20.4 (d, J = 4.4 Hz),
23.9 (d, J = 17.1 Hz), 26.52, 26.54, 27.0 (d, J = 12.6 Hz),
27.36, 27.44 (d, J = 3.9 Hz), 27.9 (d, J = 4.0 Hz), 28.3 (d,
J = 15.5 Hz), 29.5, 30.1 (d, J = 8.9 Hz), 31.8 (d, J = 20.1
Hz), 32.7 (d, J = 15.5 Hz), 34.2 (d, J = 25.3 Hz), 34.6 (d,
J = 15.8 Hz), 40.6 (d, J = 10.9 Hz), 125.9, 126.1, 127.9,
128.2, 129.8 (d, J = 2.5 Hz), 130.3 (d, J = 1.3 Hz), 143.8 (d,
J = 8.8 Hz), 143.9. 31P NMR (202 MHz, CDCl3): d = 11.21.
ESI-HRMS: m/z calcd for C28H37P [M + Na]+: 427.2531;
found [M + Na]+: 427.2534.
(6) (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem. Int. Ed.
1999, 38, 2413. (b) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.;
Yin, J.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1158.
(c) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(d) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2003, 125, 11818. (e) Walker, S. D.; Barder, T. E.;
Martinelli, J. R.; Buchwald, S. L. Angew. Chem. Int. Ed.
2004, 43, 1871. (f) Barder, T. E.; Walker, S. D.; Martinelli,
J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
(7) (a) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 1998, 37,
3387. (b) Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc.
2000, 122, 4020. (c) Liu, S.-Y.; Choi, M. J.; Fu, G. C. Chem.
Commun. 2001, 2408. (d) Littke, A. F.; Schwarz, L.; Fu, G.
C. J. Am. Chem. Soc. 2002, 124, 6343.
(8) (a) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem. Int.
Ed. 2000, 39, 4153. (b) Ehrentraut, A.; Zapf, A.; Beller, M.
Adv. Synth. Catal. 2002, 344, 209. (c) Zapf, A.; Jackstell,
R.; Rataboul, F.; Riermeier, T.; Monsees, A.; Fuhrmann, C.;
Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun.
2004, 38. (d) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.;
Riermeier, T.; Monsees, A.; Dingerdissen, U.; Beller, M.
Chem. Eur. J. 2004, 10, 2983.
(19) Optically pure phosphine 2 was prepared by oxidation of
phosphine with H2O2, HPLC resolution and the following
reduction by Cl3SiH.
Oxidation of Phosphine Ligand 2
H2O2 (30% in H2O, 1.26 g, 11.1 mmol) was added dropwise
to a solution of phosphine 2 (3.00 g, 7.42 mmol) in toluene
(15 mL) at 0 °C. After the mixture was stirred at 35 °C for 2
h, an organic phase was separated, washed with 20% aq
Na2SO3 and H2O, dried over anhyd MgSO4, and
concentrated under reduced pressure to give a crude oxide
(3.14 g, quantitative yield) as a white solid. The crude was
used for chiral resolution without further purification. 1H
(9) (a) Zhang, C.; Huang, J.; Trudell, M. L.; Nalan, S. P. J. Org.
Chem. 1999, 64, 3804. (b) Grasa, G. A.; Viciu, M. S.;
Huang, J.; Nolan, S. P. J. Org. Chem. 2001, 66, 7729.
(c) Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem. Soc.
2003, 125, 16194. (d) Viciu, M. S.; Kelly, R. A.; Stevens, E.
Synlett 2008, No. 12, 1809–1812 © Thieme Stuttgart · New York

1812
K. Suzuki et al.
LETTER
NMR (500 MHz, CDCl3): d = 1.09 (d, J = 11.8 Hz, 3 H),
1.15–1.32 (m, 7 H), 1.33–2.23 (m, 16 H), 2.52 (dd, J = 4.7,
12.9 Hz, 1 H), 7.07 (t, J = 7.3 Hz, 1 H), 7.14–7.21 (m, 3 H),
7.24–7.32 (m, 2 H), 7.39–7.50 (m, 4 H). 13C NMR (125
MHz, CDCl3): d = 19.9, 20.0, 23.51, 23.53, 23.9, 24.5,
25.36, 25.40, 25.91, 25.95, 25.98, 26.11, 26.12, 26.25, 26.3,
26.6, 26.7, 27.28, 27.34, 27.37, 27.44, 27.53, 27.55, 28.37,
28.39, 35.4, 35.9, 38.8, 39.3, 40.46, 40.48, 126.1, 126.4,
127.6, 128.5, 129.6, 129.9, 141.64, 141.66, 143.4 (observed
complexity due to P–C splitting). 31P NMR (202 MHz,
CDCl3): d = 49.88. ESI-HRMS: m/z calcd for C28H37PO [M
+ H]+: 241.2660; found [M + H]+: 241.2656.
halide (1.0 equiv) were added to the premixed solution. The
mixture was stirred at 80 °C for the time specified. After
cooling to r.t., the reaction solution was diluted with toluene,
washed with H2O, dried over MgSO4, and concentrated
under reduced pressure. Purification of the concentrate by
column chromatography on SiO2 gave the coupling product.
4-Methoxy-4¢-methylbiphenyl (Table 1, Entry 3)
Purification by flash chromatography (hexane–
toluene = 2:1) gave a white solid. 1H NMR (300 MHz,
CDCl3): d = 2.38 (s, 3 H), 3.84 (s, 3 H), 6.96 (d, J = 9.0 Hz,
2 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.50
(d, J = 9.0 Hz). 13C NMR (75 MHz, CDCl3): d = 21.0, 55.3,
114.1, 126.6, 127.9, 129.4, 133.7, 136.3, 138.0, 158.9.
(21) Typical Procedure for the Coupling Reaction of Aryl
Halides with Ketones
HPLC Resolution of Racemic Oxide of Phosphine 2
The optically pure oxide was obtained by HPLC resolution
with a Chiralcel OD-H column (250 mm × 20 mm, hexane–
2-PrOH = 96:4, flow rate = 10 mL/min).
A solution of NaOt-Bu (1.2 equiv), [(p-allyl)PdCl]2 (0.5
mol%) and ligand (2.0 mol%) in toluene (0.5 M) was stirred
for 15 min at r.t. Aryl halide (1.0 equiv) and ketone (1.1
equiv) were added to the solution. The mixture was stirred at
80 °C for the time specified. After cooling to r.t., the reaction
solution was diluted with toluene, washed with H2O, dried
over MgSO4, and concentrated under reduced pressure.
Purification of the concentrate by column chromatography
on SiO2 gave the coupling product.
Reduction of Oxide of Phosphine 2
Under a nitrogen atmosphere, SiCl3H (2.26 g, 16.7 mmol)
was added dropwise to a solution of optically pure phosphine
oxide (1.00 g, 2.38 mmol) and N,N-dimethylaniline (2.31 g,
19.0 mmol) in xylene (16 mL) at 85 °C. After stirring at
115 °C for 1.5 h, remaining SiCl3H was removed from the
reaction solution by distillation. The solution was washed
with 20% aq NaOH and H2O, dried over anhyd MgSO4, and
concentrated under reduced pressure. The concentrate was
purified by recrystallization from toluene (1.5 mL) and
MeOH (6 mL) to give the optically pure phosphine 2 as a
white solid (0.49 g, 51%).
2-(4-Methoxyphenyl)propiophenone (Table 1, Entry 7)
Purification by flash chromatography (hexane–
EtOAc = 8:1) gave a colorless oil. 1H NMR (300 MHz,
CDCl3): d = 1.50 (d, J = 6.9 Hz, 3 H), 3.75 (s, 3 H), 4.64 (q,
J = 6.9 Hz, 1 H), 6.82 (d, J = 8.7 Hz, 2 H), 7.20 (d, J = 8.7
Hz, 2 H), 7.33–7.41 (m, 2 H), 7.42–7.51 (m, 1 H), 7.90–7.98
(m, 2 H). 13C NMR (75 MHz, CDCl3): d = 19.5, 46.9, 55.2,
114.4, 128.4, 128.7, 128.8, 132.7, 133.5, 136.5, 158.5,
200.5.
(20) Typical Procedure for the Coupling Reaction of Aryl
Halides with Arylboronic Acids
A solution of powdered K2CO3 (2.0 equiv), [(p-allyl)PdCl]2
(0.5 mol%) and ligand (2.0 mol%) in toluene (0.5 M) was
stirred for 15 min at r.t. Arylboronic acid (1.5 equiv) and aryl
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