Highly efficient synthesis of a class of novel chiral-bridged atropisomeric monophosphine ligands via simple desymmetrization and their applications in asymmetric suzuki-miyaura coupling reaction

Article abstract of DOI:10.1021/ol300721p

A series of novel chiral-bridged atropisomeric monophosphine ligands were synthesized via convenient and simple pathways. The prepared ligands, especially for ligand 7d, were found to be highly effective in the Pd-catalyzed Suzuki-Miyaura coupling reactio

Full text of DOI:10.1021/ol300721p

ORGANIC
LETTERS
2012
Vol. 14, No. 8
1966–1969
Highly Efficient Synthesis of a Class
of Novel Chiral-Bridged Atropisomeric
Monophosphine Ligands via Simple
Desymmetrization and Their Applications
in Asymmetric SuzukiꢀMiyaura Coupling
Reaction
Shouliang Wang,† Jinjin Li,† Tingting Miao,† Wenhao Wu,† Qing Li,† Yue Zhuang,†
Zhongyuan Zhou,‡ and Liqin Qiu*,†
School of Chemistry and Chemical Engineering, Guangdong Engineering Research
Center of Chiral Drugs, Sun Yat-Sen University, No. 135 Xingangxi Road,
Guangzhou 510275, P. R. China, and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China
qiuliqin@mail.sysu.edu.cn
Received January 15, 2012
ABSTRACT
A series of novel chiral-bridged atropisomeric monophosphine ligands were synthesized via convenient and simple pathways. The prepared
ligands, especially for ligand 7d, were found to be highly effective in the Pd-catalyzed SuzukiꢀMiyaura coupling reaction. The steric hindrance and
electronic effect of substrates on the reactivity and enantioselectivity were explored preliminarily.
Atropo-molecules, in which the chirality originates from
restricted rotation along a chiral axis rather than a stereo-
genic center, have received considerable attention since
they are key structural motifs found in a number of natural
products from various origins and have a wide range of
biological properties.1 Relevantatropisomersalsoproveto
be efficient ligands and show remarkable enantioselectivies
in a number of asymmetric catalyses.2 In 1991, Hayashi
and co-workers developed the first monophosphine ligand
that is a well-known MOP (2-(diphenylphosphino)-20-
methoxy-1,l0-binaphthyl) with oxygen as another coordi-
nating atom (O,P-ligand), and it was successfully used in
an asymmetric palladium-catalyzed hydrosilylation reac-
tion.3 Since then, MOP and its analogues4 have been
successfully employed in many types of catalytic asym-
metric reactions and exhibited excellent enantioselective
induction capability.5 Substrates used for asymmetric
† Sun Yat-Sen University.
‡ The Hong Kong Polytechnic University.
(3) (a) Hayashi, T.; Uozumi, Y. J. Am. Chem. Soc. 1991, 113, 9887.
(b) Uozumi, Y.; Tanahashi, A.; Lee, S.-Y.; Hayashi, T. J. Org. Chem.
1993, 58, 1945.
(4) Hayashi, T.; Iwamura, H.; Uozumi, Y.; Matsumoto, Y.; Ozawa,
F. Synthesis 1994, 5, 526.
(5) (a) Hayashi, T. Acc. Chem. Res. 2000, 33, 354. (b) Chen, C.; Li, X.;
Schreiber, S.-L. J. Am. Chem. Soc. 2003, 125, 10174. (c) Shi, M.; Chen,
L.-H.; Li, C.-Q. J. Am. Chem. Soc. 2005, 127, 3790. (d) Shintani, R.;
Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006, 45, 3353. (e) Hoshi,
T.; Sasaki, K.; Sato, S.; Ishii, Y.; Suzuki, T.; Hagiwara, H. Org. Lett.
2011, 13, 932.
€
(1) (a) Bringmann, G.; Gunther, G.; Ochse, M.; Schupp, O.; Tasler,
S. In Progress in the Chemistry of Organic Natural Products; Herz, W.,
Falk, H., Kirby, G. W., Moore, R. E., Tamm, C., Eds.; Springer: New York,
2001; Vol. 82, pp 1ꢀ249. (b) Rao, A. V. R.; Gurjar, M. K.; Reddy, K. L.;
Rao, A. S. Chem. Rev. 1995, 95, 2135. (c) Nicolaou, K. C.; Boddy,
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C. N. C.; Brase, S.; Winssinger, N. Angew. Chem., Int. Ed. 1999, 38, 2096.
(2) For reviews, see: (a) Bringmann, G.; Price, Mortimer, A. J.; Keller,
P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005,
44, 5384. (b) McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809. (c)
Brunel, J. M. Chem. Rev. 2005, 105, 857. (d) Eliel, E. L.; Wilen, S. H.
Stereochemistry of Organic Compounds; Wiley: New York, 1994.
r
10.1021/ol300721p
Published on Web 04/06/2012
2012 American Chemical Society

catalysis are highly diverse, and this results in great de-
mands for different chiral ligands and corresponding
catalysts. However, good monophosphine ligands are still
scarce in comparison with the biaryl diphosphine ligand
family.6 Thus, one of the most exciting and challenging
subjects in the research of catalytic asymmetric synthesis is
the development of highly effective chiral phosphine li-
gands suitable for different substrates and reaction types.
In 2000, Harada reported a method for asymmetric
synthesis of axially chiral 2,20-biphenyldiols via desym-
metrization of prochiral tetrahydroxybiphenyl.7 How-
ever, applications of these chiral biaryldiols are not
widespread to date.8 As part of our continuing effort in
designing chiral ligand scaffolds using a diastereose-
lective synthesis technique,9 we herein demonstrate two
simple and practical strategies for the preparation of a
series of novel chiral-bridged atropisomeric monopho-
sphine ligands 7aꢀ7g (Figure 1) via an asymmetric
desymmetrization and annulation reaction. The synthesized
ligands are highly effective in the asymmetric Suzukiꢀ
Miyaura coupling reaction.
Our approach started with achiral 2,20,6,60-tetrahydroxy-
biphenyl through two anchored hydroxy groups of the
biphenyl by (R,R)-2,3-butanediol bis(mesylate) through a
Williamson synthesis.7 A dsymmetrization reaction was com-
pleted, and annulation product 3 was afforded in 53% yield.
The (R,R)-configuration from the central chirality of 2 was
changed into the (S,S)-form via an SN2 substitution reaction.
At the same time, perfect chirality transfer from central to
axial chirality and complete diastereoselectivity were attained.
This overcomes the limitation of the maximum 50% yield for
the desired atropisomer via the traditional resolution step.
Monomethylation of 3 using methyl iodide provided 4 in
91% yield. Then trifluoromethanesulfonic anhydride was
added to a solution of 4 in pyridine at 0 °C, and the reaction
system was stirred at room temperature for 12 h and gave
product 5. An aryl phosphine oxide moiety was introduced by
reacting 5 with Ar2P(O)H in DMSO at 110 °C for 16 h in a
palladium acetate, 1,4-bis(diphenylphosphino) butane, and
i-Pr2NEt catalyst system, and monophosphine oxides 6aꢀ6d
were yielded. Ligands 7aꢀ7d were finally prepared via
subsequent reductions of 6aꢀ6d with trichlorosilane and
i-Pr2NEt. The molecular structure of 7a was confirmed by
single-crystal X-ray diffraction. It is noteworthy that only five
steps are needed in this synthetic process, which is less than the
case for the synthesis of MeO-MOP.3a
Another pathway was adopted for the synthesis of
ligands 7eꢀ7g. Detailed information is given in the Sup-
porting Information. It diverged from compound 3, and
the subsequent synthetic steps were similar to those in the
preparation of MOP.3b In the above-mentioned two syn-
thetic protocols, no resolution step is necessary. The chiral
bridge not only performs the function of chiral induction
but also becomes a part of the ligand skeleton.
SuzukiꢀMiyaura coupling has gained popularity as a
versatile and powerful synthetic tool for carbonꢀcarbon
bond formation;10 some achiral monophosphine ligands
were developed and displayed good efficiency in this kind
of reaction.11 However, successful asymmetric versions of
the reaction merely emerged in recent years. Limited
results were disclosed,12 and deep explorations are warmly
Figure 1. MeO-MOP, KenPhos, and our ligands.
The synthetic route to ligands 7aꢀ7d was shown in
Scheme 1.
Scheme 1. Synthesis of Ligands 7aꢀ7d
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Chan, A. S. C. Org. Lett. 2002, 4, 4599. (b) Qiu, L.; Wu, J.; Chan, S.; Au-
Yeung, T. T.-L; Ji, J.-X.; Guo, R.; Pai, C.-C.; Zhou, Z.; Li, X.;Fan, Q.-H.;
Chan, A. S. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5815. (c) Qiu, L.;
Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.; Yu, W.-Y.; Li, Y.-M.; Guo,
R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2006, 128, 5955.
(10) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b)
Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M. J.; Garner,
J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384.
(11) (a) Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
5096. (b) So, C. M.; Kwong, F. Y. Chem. Soc. Rev. 2011, 40, 4963.
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(12) (a) Cammidge, A. N.; Crepy, K. V. L. Chem. Commun. 2000,
1723. (b) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 12051. (c)
Shen, X.; Jones, G. O.; Watson, D. A.; Bhayana, B.; Buchwald, S. L.
J. Am. Chem. Soc. 2010, 132, 11278. (d) Uozumi, Y.; Matsuura, Y.;
Arakawa, T.; Yamada, Y. M. A. Angew. Chem., Int. Ed. 2009, 48, 2708.
(6) (a) Miyashita, A.; Yasuda, A.; Takaya, H.; Toriumi, K.; Ito, T.;
Souchi, T.; Noyori, R. J. Am. Chem. Soc. 1980, 102, 7932. (b) Schmid,
R.; Cereghetti, M.; Heiser, B.; Schonholzer, P.; Hansen, H. J. Helv.
Chim. Acta 1988, 71, 897. (c) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen,
C.-C.; Chan, A. S. C. J. Am. Chem. Soc. 2000, 122, 11513.
(7) (a) Tuyet, T. M. T.; Harada, T.; Hashimoto, K.; Hatsuda, M.;
Oku, A. J. Org. Chem. 2000, 65, 1335. (b) Harada, T.; Tuyet, T. M. T.;
Oku, A. Org. Lett. 2000, 2, 1319.
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(f) Bermejo, A.; Ros, A.; Fernandez, R.; Lassaletta, J. M. J. Am. Chem.
Soc. 2008, 130, 15798. (g) Zhang, S.-S.; Wang, Z.-Q.; Xu, M.-H.; Lin,
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M. Chem. Commun. 2004, 2082. (i) Baudoin, O. Eur. J. Org. Chem. 2005,
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Chem., Int. Ed. 2008, 47, 6917.
Org. Lett., Vol. 14, No. 8, 2012
1967

expected. Buchwald and co-workers found that the reac-
tion of aryl halides bearing an ortho phosphonate group
and boronic acid possessing an o-alkyl substituent could
proceed with high enantioselectivities.12b,c Coupling of the
same naphthyl bromide with 2-methoxy-1-naphthylboro-
nic acid was carried out by Uozumi et al. using a chiral
imidazoindole phosphine supported onanamphiphilicPS-
PEG resin as the ligand, and 99% ee was obtained for the
product only after crystallization.12d During the prepara-
tion of this paper, Suginome reported a class of helically
chiral PQXphos ligands for the coupling reaction to form
axially chiral biarylphosphinic esters with excellent
enantioselection.13 Importantly, the phosphonate moiety
in these compounds is suitable for further functionaliza-
tion to prepare various atropisomeric monophosphine
ligands. Thus, the asymmetric SuzukiꢀMiyaura coupling
between diethyl 1-bromo-2-naphthylphosphonate and
naphthyl boronic acid was selected as the model reaction
to examine the chiral catalytic efficiency for our ligands.
Various solvents, Pd sources, bases, and ligands were
screened at first, and the results are outlined in Table 1.
Conditional experiments showed that toluene, Pd2(dba-
)3, and K3PO4 were the best combination for this reaction
(Table 1, entries 1ꢀ11). This exactly matches the result
with KenPhos as the ligand. Under the optimal reaction
conditions, much better enantioselectivities were achieved
using our ligands 7aꢀ7g instead of KenPhos and MeO-
MOP although a small decrease in conversions occurred
(Table 1, entries 1 and 14ꢀ19 vs entries 12 and 13). Ligand
7d with a bulky 3,5-di-tert-butylphenyl group attached to
the phosphine atom afforded the best ee. The correspond-
ing ligands 7bꢀ7c possessing less bulky aryl groups such as
4-methylphenyl and 3,5-dimethylphenyl obtained similar
results as ligand 7a (Table 1, entries 14 and 15). The
influence of the alkyl group linked to the oxygen atom of
the ligands on the enantioselectivity of the model reaction
was also investigated. The best conversion and enantios-
electivity were obtained when the alkyl group was methyl.
In contrast, a negative effect was observed using other
counterparts (Et-, iPr-, Bn-) instead of the small CH3
(Table 1, entry 1 vs entries 17ꢀ19). Different mole ratios
of metal vs ligand (2:1, 5:4, 1:1, 4:5, 1:2) were tested; no
variation on the ee value was observed. However, the
activity of the catalyst dropped when the ratio was less
than 1. This indicates that the central metal palladium
complexed with the ligand at a ratio of 1:1. In Suginome’s
report, PQXphos was employed as the ligands to the
coupling between dimethyl 1-bromo-2-naphthylphospho-
nate and naphthyl boronic acid and it afforded the product
with94%ee, whereastheyield decreased sharply to42%.13
Encouraged by these results, we expanded the reaction to a
broader substrate scope employing 7d as the ligand. In
Buchwald’s and Suginome’s research, o-alkyl substituted
boronic acids were mainly focused.12b,c,13 But the alkyl
groups are difficult for further functionalization. Widely
used ligands such as MOP’s analogues can only been
Table 1. Optimization Experiments
conversionb eec
entrya
L*
7a
Pd
solvent
base
(%)
(%)
1
2
3
4
5
6
Pd2(dba)3 toluene K3PO4
Pd2(dba)3 DMF K3PO4
Pd2(dba)3 DMSO K3PO4
90
20
23
90
88
84
85
72
16
81
81
81
7a
7a
7a
7a
7a
Pd2(dba)3 DME
Pd2(dba)3 THF
K3PO4
K3PO4
Pd2(dba)3 DMEþ K3PO4
H2Oe
7
7a
7a
7a
7a
7a
Pd(OAc)2 toluene K3PO4
92
90
70
46
50
75
83
82
82
83
83
46
8
PdCl2
toluene K3PO4
9
Pd2(dba)3 toluene CsF
Pd2(dba)3 toluene CsCO3
Pd2(dba)3 toluene Ba(OH)2
10
11
12
MeO- Pd2(dba)3 toluene K3PO4
MOP
13
Ken
Phos
7b
Pd2(dba)3 toluene K3PO4
97
57d
14
15
16
17
18
19
Pd2(dba)3 toluene K3PO4
Pd2(dba)3 toluene K3PO4
Pd2(dba)3 toluene K3PO4
Pd2(dba)3 toluene K3PO4
Pd2(dba)3 toluene K3PO4
Pd2(dba)3 toluene K3PO4
88
90
62
88
87
65
84
84
88
77
71
77
7c
7d
7e
7f
7g
a Conditions: 1 equiv of aryl bromide, 2 equiv of naphthyl boronic
acid, 4% Pd, 4.8% of ligand, 3 equiv of base, solvent, 40 °C, 40 h.
b Determined by GC, NMR analysis. c Determined by HPLC with a
Chiralcel OD-H column. d Cited in the literature.12b e The ratio of DME
and H2O was 10:1.
synthesized by o-alkyloxy boronic acids. Introduction of
some functionalized substituents at the ortho position is no
doubt significant for the development of useful ligand
precursors. On the other hand, different kinds of aryl
boronic acids can also be used to test substrate tolerance
for the catalyst system. The results are summarized in
Table 2.
It is delightful that ligand 7d exhibited much higher
enantioselection than Buchwald’s KenPhos for the cou-
pling using 2-biphenylboronic acid (85% ee vs 74% ee,12b
Table 2, entry 2). The increase of the enantioselectivity was
more significant for (4-methoxy-1-naphthalenyl)-boronic
acid (97% ee vs 71% ee,12b Table 2, entry 3). The reaction
activities are alsocomparable tothose withKenPhos as the
ligand. Further, some aryl boronic acids were first selected
as the substrates to construct new biaryls containing a
phosphonate moiety (Table 2, entries 4ꢀ10). In general, all
the reactions for the aryl boronic acids with an electron-
donating group achieved satisfactory yields. However, the
eevalues changed from 78% to97% (Table 2, entries 4ꢀ9).
This may be caused by a steric hindrance effect at both the
ortho and meta positions. A small group such as OMe at
the ortho position of phenylboronic acid gave only 78% ee
(13) Yamamoto, T.; Akai, Y.; Nagata, Y.; Suginome, M. Angew.
Chem., Int. Ed. 2011, 50, 8844.
1968
Org. Lett., Vol. 14, No. 8, 2012

route for direct enantioselective synthesis of MOP’s
analogues. When 2-chlorophenylboronic acid was em-
ployed as the substrate, the reactivity slightly de-
creased. By raising the reaction temperature to 50 °C,
excellent enantioselectivity (90% ee) was obtained de-
spite a moderate yield for the product (Table 2, entry 10).
This product may be a very important intermediate
because it can be used for the synthesis of more compli-
cated biaryls via general coupling reactions. These results
suggest that the yields of this kind of reaction are sensitive
to the electronic effect of the substrate. Generally, aryl
boronic acids with an electron-withdrawing group are
quickly deboronated during the reaction, whereas aryl
boronic acids with an electron-donating group are more
stable which is beneficial to the increase of the reactivity
and yield.14
Table 2. Asymmetric SuzukiꢀMiyaura Coupling
In summary, a series of new chiral-bridged atropiso-
meric monophosphine ligands were successfully synthe-
sized via an asymmetric desymmetrization of 2,20,6,60-
tetrahydroxybiphenyl through central-to-axial chirality
transfertoobtaina versatilechiralbiaryldiol with exclusive
diastereoselectivity. Particularly noteworthy is that the
traditional resolution step was not necessary in the ligand
synthetic processes. This strategy of high atom economy
provided a convenient and simple pathway for the design
and development of atropisomeric monophosphine li-
gands. The newly developed ligands, especially for 7d,
were found to be highly effective in the palladium-catalyzed
SuzukiꢀMiyaura coupling reaction. Further exploration
of their applications in asymmetric catalysis are underway
in our group.
a Conditions: 1.0 equiv of aryl bromide, 2 equiv of boronic acid, 2%
Pd2(dba)3 (4% Pd), 4.8% of ligand 7d, 3 equiv of K3PO4, toluene. b Yield
of isolated product. c Determined by HPLC with a Chiralcel OD-H or
AD-H column. d Cited in the literature.12b
Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(NSFC) (20972196, J1103305), Doctoral Fund of Ministry
of Education of China (RFDP) (200805580009) and
Guangdong Provincial Natural Science Foundation
(S201101000130).
(Table 2, entries 5 and 9). In contrast, phenylboronic acids
with large groups at the ortho position provided higher
enantioselectivities (92% ee for EtO- and nPrO-, and 93%
ee for iPrO-, Table 2, entries 11ꢀ16). The bulky naphthyl
boronic acids obtained much higher enantioselectivities
(88%ꢀ97% ee, Table 2, entries 1, 3, and 4). It is noted that
our catalyst system is quite active so that the reactions
could proceed at room temperature. This supplies a new
Supporting Information Available. Experimental de-
tails, spectroscopic data, and analytical data for ligands
7a-7g and some intermediates and model reaction and
crystallographic data for compound 7a (CIF format).
This material is available free of charge via the Internet
at http://pubs.acs.org.
(14) (a) Kuivila, H. G.; Reuwer, J. F.; Mangravite, J. A. J. Am. Chem.
Soc. 1964, 86, 2666. (b) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am.
Chem. Soc. 2010, 132, 14073.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
1969