Highly effective and diastereoselective synthesis of axially chiral bis-sulfoxide ligands via oxidative aryl coupling

Article abstract of DOI:10.1021/ol100536e

Figure presented A series of axially chiral bis-sulfoxide ligands have been efficiently synthesized via oxidative coupling with high diastereoselectivities. The axial chirality is well controlled by the tert-butylsulfinyl or the p-tolylsulfinyl group. The

Full text of DOI:10.1021/ol100536e

ORGANIC
LETTERS
2010
Vol. 12, No. 9
1928-1931
Highly Effective and Diastereoselective
Synthesis of Axially Chiral Bis-sulfoxide
Ligands via Oxidative Aryl Coupling
Qing-An Chen,† Xiang Dong,‡ Mu-Wang Chen,† Duo-Sheng Wang,†
Yong-Gui Zhou,*,§ and Yu-Xue Li*,§
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China, Department of
Chemical Physics, UniVersity of Science and Technology of China, Hefei 230026, China,
and State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
ygzhou@dicp.ac.cn; liyuxue@mail.sioc.ac.cn
Received January 26, 2010
ABSTRACT
A series of axially chiral bis-sulfoxide ligands have been efficiently synthesized via oxidative coupling with high diastereoselectivities. The
axial chirality is well controlled by the tert-butylsulfinyl or the p-tolylsulfinyl group. These axially chiral bis-sulfoxides proved to be remarkably
efficient ligands for the rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to 2-cyclohexenone with 99% ee.
In the past decade, considerable efforts have been under-
taken for using enantiopure sulfinyl groups as efficient
chiral auxiliaries in asymmetric C-C and C-X bond
formations.1 The success and effectiveness of the sulfinyl
group as a chiral controller lie in three basic factors: (i)
its high optical stability, (ii) its efficiency as a carrier of
the chiral information, and (iii) its accessibility in both
enantiomeric forms. Therefore, much progress has been
achieved in asymmetric synthesis employing enantiopure
sulfoxides as chiral ligands.1d,j,k,2 Despite the fact that
axially chiral ligands are most commonly used for asym-
metric transformations, limited optically pure sulfoxide
ligands bearing axial chirality have hitherto been described.3
Recently, Dorta et al. disclosed that axially chiral bis-
sulfoxides, synthesized from racemic axial dibromides, can
† Dalian Institute of Chemical Physics.
(2) Recent works: (a) Tokunoh, R.; Sodeoka, M.; Aoe, K.-I.; Shibasaki,
M. Tetrahedron Lett. 1995, 36, 8035. (b) Kobayashi, S.; Ogawa, C.; Konishi,
H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 6610. (c) Massa, A.; Malkov,
A. V.; Kocˇovsky´, P.; Scettri, A. Tetrahedron Lett. 2003, 44, 7179. (d)
Rowlands, G. J.; Barnes, W. K. Chem. Commun. 2003, 2712. (e) Ferna´ndez,
‡ University of Science and Technology of China.
§ Shanghai Institute of Organic Chemistry.
(1) (a) Reggelin, M.; Zur, C. Synthesis 2000, 1. (b) Ellman, J. A.; Owens,
T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984. (c) Ellman, J. A. Pure
Appl. Chem. 2003, 75, 39. (d) Ferna´ndez, I.; Khiar, N. Chem. ReV. 2003,
103, 3651. (e) Zhou, P.; Chen, B. C.; Davis, F. A. Tetrahedron 2004, 60,
8003. (f) Senanayake, C. H.; Krishnamurthy, D.; Lu, Z. H.; Han, Z. X.;
Gallou, I. Aldrichimica Acta 2005, 38, 93. (g) Morton, D.; Stockman, R. A.
Tetrahedron 2006, 62, 8869. (h) Pellissier, H. Tetrahedron 2006, 62, 5559.
(i) Davis, F. A. J. Org. Chem. 2006, 71, 8993. (j) Pellissier, H. Tetrahedron
2007, 63, 1297. (k) Carren˜o, M. C.; Herna´ndez-Torres, G.; Ribagorda, M.;
Urbano, A. Chem. Commun. 2009, 6129. (l) Ferreira, F.; Botuha, C.;
Chemla, F.; Pe´rez-Luna, A. Chem. Soc. ReV. 2009, 38, 1162. (m) Mellah,
M.; Voituriez, A.; Schulz, E. Chem. ReV. 2007, 107, 5133.
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I.; Valdivia, V.; Gori, B.; Alcudia, F.; Alvarez, E.; Khiar, N. Org. Lett.
2005, 7, 1307. (f) Garc´ıa-Flores, F.; Flores-Michel, L. S.; Juaristi, E.
Tetrahedron Lett. 2006, 47, 8235. (g) Ferna´ndez, I.; Valdivia, V.; Leal,
M. P.; Khiar, N. Org. Lett. 2007, 9, 2215. (h) Chen, J. M.; Li, D.; Ma,
H. F.; Cun, L. F.; Zhu, J.; Deng, J. G.; Liao, J. Tetrahedron Lett. 2008, 49,
6921. (i) Fulton, J. R.; Kamara, L. M.; Morton, S. C.; Rowlands, G. J.
Tetrahedron 2009, 65, 9134. (j) Massa, A.; Acocella, M. R.; De Sio, V.;
Villano, R.; Scettri, A. Tetrahedron: Asymmetry 2009, 20, 202. (k) Wang,
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10.1021/ol100536e  2010 American Chemical Society
Published on Web 04/13/2010

be used successfully as ligands in the rhodium-catalyzed
asymmetric 1,4-addition of arylboronic acids to enones with
excellent enantioselectivties.3a,b Thus, development of a
simple and efficient method for the synthesis of optically
pure axially chiral sulfoxide ligands is highly desirable.
Herein, we report an efficient and highly diastereoselective
synthesis of axially chiral bis-sulfoxide ligands via oxidative
coupling.
Table 1. Atropo-diastereoselective Oxidative Coupling Reaction
with a tert-Butyl and a p-Tolylsulfinyl Group as Chiral
Auxiliary
On the basis of the preparation of chiral atropisomeric
biaryl diphosphines through oxidative coupling with iron(III)
chloride,4 enantiopure sulfoxides 1 were first synthesized
according to the literature procedure (Scheme 1).2h Standard
Scheme 1. Synthesis of Enantiopure Sulfoxides 1
a Mixture of both diastereomers. b Determined by 1H NMR on the crude
mixture. c The absolute configuration of major diastereomer of 2a was
determined by X-ray analysis. Other products’ absolute configurations were
assigned as (M,S,S) by analogy to 2a.
bromo-lithium exchange of bromo-arene derivatives pro-
ceeded at low temperature. After quench by thiosulfinate that
is commercially available, the desired products 1a-1c were
obtained in moderate to high yields (53-88% yields, eq 1).
The reaction of Grignard reagents (derived from aryl
bromides) with enantiopure (SS)-menthyl p-toluenesulfinate
delivered their corresponding enantiopure sulfoxides 1d-1f
in good yields (60-70% yields, eq 2).
ated intermediate, which could be oxidized by FeCl3 to
provide bis-sulfoxide 2a with high diastereoselectivity
(>95:5) and good yield (76%, entry 1). Recrystallization
from EtOAc and CH2Cl2 gave optically pure 2a as a
colorless crystalline solid, and its absolute configuration
was assigned as (M,S,S) by X-ray crystallographic analysis
(Figure 1).
Next, we studied the oxidative homocoupling reactions
of enantiopure sulfoxides 1 using FeCl3 as the oxidant (Table
1). Deprotonation of 1a with LDA generated the ortholithi-
(3) (a) Mariz, R.; Luan, X. J.; Gatti, M.; Linden, A.; Dorta, R. J. Am.
Chem. Soc. 2008, 130, 2172. (b) Bu¨rgi, J. J.; Mariz, R.; Gatti, M.; Drinkel,
E.; Luan, X. J.; Blumentritt, S.; Linden, A.; Dorta, R. Angew. Chem., Int.
Ed. 2009, 48, 2768. (c) Colobert, F.; Valdivia, V.; Choppin, S.; Leroux,
The oxidative coupling reaction was quite general.
Several aryl sulfoxides 1 bearing tert-butyl or p-tolyl
sulfinyl group all delivered their corresponding axially
chiral bis-sulfoxides 2b-2f in good yields with excellent
diastereoselectivities (entries 2-5). Fortunately, the minor
diastereomer (P,S,S)-2d was obtained after repeated re-
crystallization from mother liquor of 2d. Following the
nomenclature for MeO-Biphep, ligand 2a was named as
t-Bu-MeO-BipheSO [2,2′-dimethoxy-6,6′-bis(tert-butyl-
sulfinyl)biphenyl].
´
F. R.; Ferna´ndez, I.; Alvarez, E.; Khiar, N. Org. Lett. 2009, 11, 5130.
(4) (a) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264. (b) Duprat de Paule,
S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Geneˆt, J. P.; Champion, N.; Dellis,
P. Eur. J. Org. Chem. 2003, 1931. (c) Duprat de Paule, S.; Jeulin, S.;
Ratovelomanana-Vidal, V.; Geneˆt, J. P.; Champion, N.; Dellis, P. Tetra-
hedron Lett. 2003, 44, 823. (d) Duprat de Paule, S.; Jeulin, S.; Ratovelo-
manana-Vidal, V.; Geneˆt, J. P.; Champion, N.; Deschaux, G.; Dellis, P.
Org. Process Res. DeV. 2003, 7, 399. (e) Qiu, L. Q.; Wu, J.; Chan, S. S.;
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X. M. Tetrahedron Lett. 2009, 50, 5777.
To further understand the origin of the high diastereo-
selectivities during the oxidative coupling, a computational
Org. Lett., Vol. 12, No. 9, 2010
1929

Figure 1. X-ray structure of chiral compound (M,S,S)-2a.
Figure 3. Possible mechanism of the chiral induction.
study concerning two diastereomers of 2a was performed
at the B3LYP/6-311+G** level (Figure 2). The calculation
Some potentially useful sulfur-based ligands could be
readily obtained by the reduction of axially chiral bis-
sulfoxides 2 (Scheme 2). The deoxygenation of sulfoxide
Scheme 2
.
Synthesis of Sulfur-Based Ligands from Chiral
Bis-sulfoxides 2
Figure 2. Optimized structures of (M,S,S)-2a and (P,S,S)-2a. The
calculations have been performed at the B3LYP/6-311+G** level,
and the relative free energies ∆G (298 K) are in kcal/mol.
results indicate that the major diastereomer (M,S,S)-2a is
more stable than (P,S,S)-2a owing to the absence of the
repulsion between two tert-butyl groups observed in
(P,S,S)-2a.
During the radical coupling reaction, the two tert-butyl
groups should point in opposite directions to avoid
repulsions (Figure 3). In addition, the lithium cation will
coordinate with oxygen atoms of the sulfinyl groups,
keeping the two SdO bonds on the same side, which may
also have some effects on the chiral induction.5 Therefore,
the chiral induction possibly originates from the repulsion
between the two tert-butyl groups and the coordination
of metal ion with the sulfinyl groups. Product (M,S,S)-2a
is a more favorable diastereoisomer with respect to
both thermodynamics and kinetics according to this
propose.
(M,S,S)-2b to the corresponding monosulfoxide (M,S)-3 and
disulfide (M)-4 was conveniently carried out at ambient
temperature by using trichloromethylsilane/sodium iodide in
acetonitrile.6 However, no semireduction product of (M,S,S)-
(6) Olah, G. A.; Husain, A.; Singh, B. P.; Mehrotra, A. K. J. Org. Chem.
1983, 48, 3667.
(7) For reviews on Rh-catalyzed asymmetric 1,4-addition reactions, see:
(a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829. (b) Fagnou,
K.; Lautens, M. Chem. ReV. 2003, 103, 169.
(5) Sugiyarna, S.; Kido, M.; Satoh, T. Tetrahedron Lett. 2005, 46, 6771.
1930
Org. Lett., Vol. 12, No. 9, 2010

2d was observed under the above conditions even with a
reduced amount of trichloromethylsilane/sodium iodide.
With ligands 2-5 in hand, their catalytic performance in
the asymmetric 1,4-addition of arylboronic acids to 2-cy-
clohexenone was investigated using [Rh(C2H4)2Cl]2 as the
metal precursor (Table 2).7,8 Surprisingly, ligands (M,S,S)-
3-5 were not effective (entries 8-10). After the evaluation
of the ligands, the scope of asymmetric 1,4-addition of
arylboronic acids to 2-cyclohexenone was explored using
[Rh(C2H4)2Cl]2/(M,S,S)-2e as the catalyst. In general, aryl-
boronic acids bearing either electron-withdrawing or electron-
donating groups at the para-position all delivered the addition
products in excellent enantioselectivities (up to >99% ee)
and high yields (entries 11-13). The use of 3-methoxyben-
zene-boronic acid 6e resulted in a decrease of yield (59%)
but the retention of enantioselectivity (99% ee, entry 14).
In conclusion, we have developed an efficient and highly
diastereoselective synthesis of axially chiral bis-sulfoxide
ligands via oxidative coupling. The axial chirality is well
controlled by the tert-butylsulfinyl or the p-tolylsulfinyl
group. This methodology provides easy access to various
potentially useful sulfur-based ligands. These axially chiral
bis-sulfoxides proved to be remarkably efficient ligands for
the rhodium-catalyzed asymmetric 1,4-addition of arylbo-
ronic acids to 2-cyclohexenone with up to >99% ee. Further
exploration of the applications of these ligands in various
asymmetric reactions is currently underway, and related
results will be reported in due course.
Table 2. Asymmetric 1,4-Addition of Boronic Acids to
2-Cyclohexenone Catalyzed by Rhodium Complexesa
entry
Ar in 6
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
Ph (6a)
4-CF3C6H4 (6b)
4-MeC6H4 (6c)
4-MeOC6H4 (6d)
3-MeOC6H4 (6e)
ligand
yield (%)b
ee (%)c
1
2
3
4
5
6
7
(M,S,S)-2a
(M,S,S)-2b
(M,S,S)-2c
(M,S,S)-2d
(M,S,S)-2e
(M,S,S)-2f
(P,S,S)-2d
(M,S)-3
(M)-4
(M)-5
(M,S,S)-2e
(M,S,S)-2e
(M,S,S)-2e
(M,S,S)-2e
trace
trace
trace
98
89
87
trace
trace
trace
trace
96
N/A
N/A
N/A
99
99
99
N/A
N/A
N/A
N/A
>99
97
Acknowledgment. We gratefully acknowledge the finan-
cial support of National Natural Science Foundation of China
(20921092 and 20872140), National Basic Research Program
of China (2010CB833300), and Chinese Academy of Sci-
ences.
8d
9d
10d
11
12
13
14
95
82
59
96
99
Supporting Information Available: Experimental, spec-
troscopic, computational, and crystallographic details includ-
ing CIF file. This material is available free of charge via the
Internet at http://pubs.acs.org.
a The reaction was carried out with 2-cyclohexenone (0.30 mmol),
arylboronic acid (0.45 mmol), [Rh(C2H4)2Cl]2 (0.003 mmol), ligand (0.0066
mmol, 1.1 equiv to Rh), and 0.75 M aq KOH (0.20 mL) in toluene (2.0
mL)atroomtemperaturefor3-6h.b Isolatedyieldbasedon2-cyclohexenone.
c Determined by HPLC analysis. d At 40 °C.
OL100536E
(8) For recent literatures on Rh-catalyzed asymmetric 1,4-addition
reaction of arylboronic acids to enones, see: (a) Takaya, Y.; Ogasawara,
M.; Hayashi, T.; Sakai, M.; Miyaura, N. J. Am. Chem. Soc. 1998, 120,
5579. (b) Kuriyama, M.; Nagai, K.; Yamada, K.; Miwa, Y.; Taga, T.;
Tomioka, K. J. Am. Chem. Soc. 2002, 124, 8932. (c) Hayashi, T.; Ueyama,
K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. (d)
Ma, Y. D.; Song, C.; Ma, C. Q.; Sun, Z. J.; Chai, Q.; Andrus, M. B. Angew.
Chem., Int. Ed. 2003, 42, 5871. (e) Shintani, R.; Duan, W. L.; Nagano, T.;
Okada, A.; Hayashi, T. Angew. Chem., Int. Ed. 2005, 44, 4611. (f) Duan,
W. L.; Iwamura, H.; Shintani, R.; Hayashi, T. J. Am. Chem. Soc. 2007,
129, 2130. (g) Feng, C. G.; Wang, Z. Q.; Shao, C.; Xu, M. H.; Lin, G. Q.
Org. Lett. 2008, 10, 4101. (h) Gendrineau, T.; Chuzel, O.; Eijsberg, H.;
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K.; Hayashi, T.; Rawal, V. H. Org. Lett. 2008, 10, 4387. (j) Hu, X. C.;
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2a, -2b, and -2c bearing tert-butylsulfinyl groups showed
no activity toward the enantioselective addition of phenyl-
boronic acid 6a to 2-cyclohexenone (entries 1-3), whereas
(M,S,S)-2d, -2e, and -2f with p-tolylsulfinyl groups emerged
as efficient ligands for this addition with respect to yields
and enantioselectivites (99% ee, entries 4-6). This interesting
phenomenon was probably ascribed to a mismatched binding
mode of (M,S,S)-2a, -2b, and -2c with the dimeric rhodium
precursor, which was supported by the inertness of (P,S,S)-
2d in this reaction (entry 7).3b To our disappointment, ligands
Org. Lett., Vol. 12, No. 9, 2010
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