DHTP Ligands for the highly ortho-selective, palladium-catalyzed cross-coupling of dihaloarenes with grignard reagents: A conformational approach for catalyst improvement

Article abstract of DOI:10.1002/anie.200905544

(Chemical Equation Presentation) Palladium catalysts bearing dihydroxyter-phenylphosphine ligands (such as 1) are reported for the ortho-selective cross-coupling of Grignard reagents and dihaloarenes. The second hydroxy group onto the terphenylphosphine ligand dramatically improved the catalytic efficiency and expanded the scope of the reaction.

Full text of DOI:10.1002/anie.200905544

Communications
DOI: 10.1002/anie.200905544
Palladium Catalysis
DHTP Ligands for the Highly Ortho-Selective, Palladium-Catalyzed
Cross-Coupling of Dihaloarenes with Grignard Reagents:
A Conformational Approach for Catalyst Improvement**
Shunpei Ishikawa and Kei Manabe*
The site-selective cross-coupling of dihaloarenes is a useful
method for synthesizing substituted monohaloarenes, which
are an important class of compounds that are commonly
employed as drug frameworks and synthetic intermediates.[1]
To achieve their efficient site-selective cross-coupling, two
main problems must be addressed: First, the difficulty in
differentiating two reactive sites, particularly when the
desired coupling position is sterically and electronically
unfavorable, and second, the difficulty in suppressing unde-
sired doubly cross-coupled products.[2]
We recently developed the site-selective, palladium-
catalyzed cross-coupling of dibromobenzenes with Grignard
reagents.[3] The cross-coupling occurred site-selectively at the
positions ortho to the hydroxy or amino groups on the
substrate. In most cases, the reactions occurred at sterically
and electronically unfavorable sites. The key to this system
Scheme 1. Structures of terphenylphosphines (1 and 2; top left),
was the use of hydroxy-substituted terphenylphosphine
ligands (1 or 2; Scheme 1).[4] We assume that these phosphines
form bimetallic palladium/magnesium species in the presence
of palladium and Grignard reagents, and that the OMgX
moiety acts as a binding site for the substrate (which also
exists as the magnesium salt), and holds the ortho halo group
close to the palladium center (Scheme 1). In this mechanism,
oxidative addition to the palladium atom occurs preferen-
tially at the positions ortho to the OMg group of the substrate.
Whilst the ortho selectivity for substrates that have a strongly
electron-donating substituent is unique, and cannot be
achieved using other phosphine ligands, the selectivities
were often modest and the formation of doubly cross-coupled
products was a severe problem in many cases. Therefore,
improvement of the catalysts was necessary to expand the
applicability of this ortho-selective cross-coupling procedure.
dihydroxyterphenylphosphines (3–6; top right), and a mechanism for
the ortho-selectivity in the site-selective cross-coupling of dibromophe-
nol with a Grignard reagent.
Herein, we present dihydroxyterphenylphosphine (DHTP)
ligands 3–6 that improved the palladium-catalyzed ortho-
selective cross-coupling of dihaloarenes remarkably and
expanded the scope of the reaction.
The design of DHTPs was based on the following ideas.
The assumed catalytic species formed from 1 or 2 is
conformationally rigid owing to the para-terphenyl frame-
À
work but retains flexibility in rotation of the C C single
bonds. As shown in Scheme 2a, the conformation in which the
palladium and the magnesium oxido moieties are located
proximal to each other is in equilibrium with that in which
they are on opposing sides of the terphenyl group. In the latter
conformation, the cooperative effect of the palladium and
magnesium oxido groups cannot work (Scheme 1). Con-
versely, when DHTPs are used, there is always a magnesium
oxido group on the same face of the terphenyl structure as the
[*] Prof. Dr. K. Manabe
School of Pharmaceutical Sciences, University of Shizuoka
52-1 Yada, Suruga-ku, Shizuoka 422-8526 (Japan)
Fax: (+81)54-264-5754
À
palladium atom, even if C C bond rotation occurs (Sche-
me 2b).[5] Therefore, cooperation between the palladium and
magnesium oxido moieties would be more effective when
DHTP ligands are used, thus affording higher selectivities in
the ortho-selective cross-coupling reaction.
E-mail: manabe@u-shizuoka-ken.ac.jp
Dr. S. Ishikawa, Prof. Dr. K. Manabe
Manabe Initiative Research Unit, RIKEN Advanced Science Institute
2-1 Hirosawa, Wako 351-0198 (Japan)
[**] This work was supported by the Society of Synthetic Organic
Chemistry (Japan), the Takeda Science Foundation, and by a Grant-
in-Aid for Scientific Research on Priority Areas “Advanced Molecular
Transformations of Carbon Resources” from the Ministry of
Education, Culture, Sports, Science and Technology (Japan).
DHTP=dihydroxyterphenylphosphine.
The magnesium oxido moiety of the catalytic species also
has conformational flexibility (Scheme 2c). Although it was
expected that controlling the spatial arrangement of the
magnesium atom should affect the catalytic performance, it
was unknown how that would affect the ortho-selective cross-
coupling. To control the position of the magnesium atom, we
introduced two types of substituents at the position ortho to
Supporting information for this article is available on the WWW
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product of cross-coupling at the position ortho to the hydroxy
group of the substrate (17%), although 9 and 10 were also
isolated in similar yields (Table 1, entry 6). To our delight, the
use of DHTPs as ligands was found to be remarkably
effective. When DHTP 3 was used, 8 was obtained in good
yield (79%; Table 1, entry 7), isomer 9 was not obtained at all,
and diarylated compound 10 was produced in only 6% yield.
Use of 4 further improved the reaction, giving 8 in 92% yield
(Table 1, entry 8). It should be mentioned that significant rate
acceleration was also observed, with the reaction nearly
proceeding to completion in 2 h.
DHTP ligands were also effective for other substrates
(Table 2). For example, 4 and 5 afforded the ortho-coupled
product from 2,4-dibromophenol in high yields with excellent
À
Scheme 2. Conformational rigidity of ligands and complexes. a) C C
Table 2: Ortho-selective cross-coupling of dibromobenzenes.[a]
Bond rotation for the species formed from 1 or 2. Y=anionic
substrate. b) from DHTPs. c) Conformation of the magnesium oxido
moiety. d) Steric control. e) Chelation control.
the Mg oxido: a methyl group that would direct the
magnesium position using steric hindrance (Scheme 2d),
and a 2-methoxyphenyl group that would chelate to the
magnesium center (Scheme 2e).
Entry Substrate
Ligand RMgBr
T
t
Yield [%]
ortho- isomer di-cou-
(equiv) [8C] [h]
product
pled
To demonstrate the effectiveness of the new DHTP
ligands, the cross-coupling of 7 with a 4-methoxyphenyl
Grignard reagent was investigated (Table 1). In all cases,
[Pd2(dba)3] was used as the palladium source. When PCy3 or
PPh3 was used as the ligand, cross-coupling occurred pre-
dominantly at the 6-position to give 9 as the major product
(Table 1, entries 1 and 2). DPPF gave 9 in high yield with
complete selectivity (Table 1, entry 3). Biphenylphosphine
11[4a] and methoxylated terphenylphosphine 12[3a] resulted in
selectivities similar to that obtained with PCy3 (Table 1,
entries 4 and 5). Use of 1 slightly increased the yield of 8, the
1
2
3
4
5
6
7
2,4-dibromo-
phenol
2,4-dibromo-
phenol
2,4-dibromo-
phenol
2,4-dibromo-
aniline
2,5-dibromo-
phenol
2,5-dibromo-
phenol
2,5-dibromo-
phenol
4
4
5
4
4
5
5
3.0
2.2
2.2
3.0
3.0
3.0
3.0
25
25
35
2
2
2
91
0
0
0
0
0
0
0
2
79
81
90
64
61
83
5
4
25 10
0
25
25
35
2
2
2
25
5
8
Table 1: Effect of the ligand in the cross-coupling of 7.[a]
[a] R=4-methoxyphenyl.
selectivities (Table 2, entry 1), even when the amount of the
Grignard reagent was lowered to 2.2 equiv (Table 2, entries 2
and 3). 2,4-Dibromoaniline also gave excellent results
(Table 2, entry 4). In the reaction of 2,5-dibromophenol
using ligand 4, a more significant amount of diarylation
occurred because oxidative addition at the 5-position is
electronically more favorable than at the 4-position (Table 2,
entry 5). In contrast, the use of methylated ligand 5 remark-
ably suppressed the diarylation (Table 2, entries 6 and 7). This
result demonstrates that the methyl groups significantly
improve this cross-coupling reaction.
The rate acceleration caused by the DHTP ligands
enabled the successful cross-coupling of the dihaloarene
with an ester-substituted Grignard reagent because it could be
conducted at lower temperatures. The cross-coupling of a tert-
butoxycarbonyl-substituted Grignard reagent, which was
prepared from tert-butyl 4-iodobenzoate using a literature
Entry
Ligand
t [h]
Yield [%]
8
9
10
1
2
3
4
5
6
7
8
PCy3
PPh3
DPPF
11
12
1
8
8
8
8
8
2
2
2
0
8
0
0
2
17
79
92
34
28
94
37
39
22
0
2
2
0
2
1
20
6
2
3
4
0
[a] R=4-methoxyphenyl.
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Communications
Table 4: Competitive cross-coupling of two substrates.
Entry
1
Substrates
PhMgBr (equiv) t [h] Products and Yields
4.0
4.0
3.0
2
2
2
2
3
Scheme 3. The site-selective cross-coupling reaction of 2-bromophenol
using dihydroxyterphenylphosphine ligand 4.
4
4.0
15
method,[6] proceeded at 158C to give 13 in good yield with
only 2% of diarylated by-product (73%; Scheme 3).
In our previous work with hydroxyterphenylphosphine
ligand 2, some selectivity between ortho-chloro and para-
bromo groups was observed in the reaction of 14, but a small
amount of 16 and a significant amount of 17 were still isolated
(Table 3, entry 2).[3c] However, the use of DHTP ligand 4 did
The cross-coupling reaction involving a 1:1 mixture of 2-
bromophenol and 4-bromophenol exhibited complete selec-
tivity to give the ortho-cross-coupled product (Table 4,
entry 1). When the same reaction was carried out at 408C
using DPPF instead of 4, the para-cross-coupled product was
obtained in 80% yield, with only 10% of the ortho-cross-
coupled product observed. Therefore, the palladium / ligand 4
catalyst completely reversed the substrate preference. High
selectivity was also observed in the competitive cross-
coupling reaction of a mixture of 2-bromo- and 3-bromo
substrates (Table 4, entry 2). This catalytic system also
favored the 2-bromophenol substrate over 4-bromoanisole
(Table 4, entry 3). In traditional cross-coupling chemistry,
electron-donating substituents are known to retard the
oxidative addition. However, in this case, the oxido moiety
that is formed in situ from the hydroxy substrate, and is more
electron-donating than the methoxy group, reacted preferen-
tially. Even more surprisingly, 2-bromoaniline, which was
converted into the highly electron-rich anion in the presence
of a Grignard reagent, preferentially reacted over 4-bromo-
phenol (Table 4, entry 4). These results emphasize the effec-
tiveness of this catalyst for 2-bromophenols and anilines.
In summary, a new catalytic system comprising DHTP
ligands and palladium is effective for the ortho-selective
cross-coupling of dihaloarenes with Grignard reagents. Intro-
ducing the second hydroxy group onto the terphenylphos-
phine ligand dramatically improved the catalytic efficiency
and expanded the scope of the reaction. Although this
improvement was caused by a conformational approach
based on a hypothesis that is currently under investigation
(Scheme 2), the reason for the improvement is still unknown.
Further studies to clarify the catalytic species and the origin of
the selectivity are underway.
Table 3: Effect of the ligand in the cross-coupling of 14.[a]
Entry
Ligand
Yield [%]
15
16
17
1[b]
2[b]
3
PCy3
5
34
4
0
13
22
5
2
4
6
58
80
91
4
0
7
[a] R=4-methoxyphenyl. [b] See Ref. [3c].
not afford any of side product 16, and gave 15 in good yield
(80%; Table 3, entry 3). The use of 6, which had two 2-
methoxyphenyl substituents, further improved the cross-
coupling to give 15 in 91% yield (Table 3, entry 4). It is
noteworthy that the ortho selectivity induced by DHTP
ligands superceded the intrinsic reactivity order (Br> Cl) of
the halo groups.[7]
We also attempted the competitive cross-coupling
between two substrates to demonstrate substrate specificity.
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K. Manabe, Org. Lett. 2007, 9, 5593; d) K. Manabe, S. Ishikawa,
Chem. Commun. 2008, 3829; e) S. Ishikawa, K. Manabe, Synthesis
2008, 3180.
Experimental Section
Procedure for the cross-coupling of 7 (Table 1): A 0.5 molLÀ1 solution
of 4-methoxyphenylmagnesium bromide in tetrahydrofuran
(2.51 mL, 1.26 mmol) was added to a solution of 1,6-dibromo-2-
naphthol (7) (126 mg, 0.419 mmol), [Pd2(dba)3] (3.8 mg, 4.2 mmol),
and 4 (4.5 mg, 10.0 mmol) in tetrahydrofuran (0.42 mL) under argon
at À788C. After 10 min, the mixture was warmed to 258C and stirred
for 2 h. The reaction was quenched by the addition of an aqueous
solution of HCl (10%; 5 mL), and the mixture was extracted three
times with ethyl acetate (5 mL). The combined organic layers were
washed with brine (5 mL), dried over Na2SO4, and concentrated.
Purification by preparative TLC (silica gel, CH2Cl2/hexane = 1:1)
gave the desired product as a slightly yellow solid in 92% yield
(126 mg).
[4] The design of the phosphines reported herein was based on
reported biphenylphosphines: a) D. S. Surry, S. L. Buchwald,
Angew. Chem. 2008, 120, 6438; Angew. Chem. Int. Ed. 2008, 47,
6338. For other examples of phosphines bearing a hydroxy group,
see: b) T. Hayashi, T. Mise, M. Kumada, Tetrahedron Lett. 1976,
17, 4351; c) Y. Hatanaka, K. Goda, F. Yamashita, T. Hiyama,
Tetrahedron Lett. 1994, 35, 7981; d) K. Matsui, S. Takizawa, H.
Sasai, Synlett 2006, 761; e) X. Meng, Y. Huang, R. Chen, Chem.
Eur. J. 2008, 14, 6852; f) N. Yoshikai, H. Matsuda, E. Nakamura, J.
Am. Chem. Soc. 2009, 131, 9590.
[5] Similar conformational effects of 2,6-dihydroxyphenyl groups
have been reported for artificial receptors: K. Manabe, K.
Okamura, T. Date, K. Koga, J. Org. Chem. 1993, 58, 6692.
[6] L. Boymond, M. Rottlꢁnder, G. Cahiez, P. Knochel, Angew.
Chem. 1998, 110, 1801; Angew. Chem. Int. Ed. 1998, 37, 1701.
[7] Reversal of the reactivity order of halo groups in transition-metal-
catalyzed cross-coupling has been reported: a) J. Blum, O. Berlin,
D. Milstein, Y. Ben-David, B. C. Wassermann, S. Schutte, H.
Schumann, Synthesis 2000, 571; b) J. Terao, A. Ikumi, H.
Kuniyasu, N. Kambe, J. Am. Chem. Soc. 2003, 125, 5646; c) X.
Mei, A. T. August, C. Wolf, J. Org. Chem. 2006, 71, 142; d) I. N.
Houpis, J.-P. V. Hoeck, U. Tilstam, Synlett 2007, 2179; e) T. Wang,
B. J. Alfonso, J. A. Love, Org. Lett. 2007, 9, 5629; f) M. Arisawa, T.
Suzuki, T. Ishikawa, M. Yamaguchi, J. Am. Chem. Soc. 2008, 130,
12214. We have also reported nickel-catalyzed cross-coupling of
12. However, in that case, only alkyl Grignard reagents worked
well, and aryl Grignard reagents resulted in very low yields. See:
g) J.-R. Wang, K. Manabe, Org. Lett. 2009, 11, 741.
Received: October 5, 2009
Revised: November 20, 2009
Published online: December 16, 2009
Keywords: cross-coupling · Grignard reagents ·
.
homogeneous catalysis · phosphines · regioselectivity
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