Rh(I)-catalyzed asymmetric 1,2-addition to α-diketones with chiral sulfur-alkene hybrid ligands

Article abstract of DOI:10.1021/ol203238j

This paper describes a Rh(I)-catalyzed highly efficient and enantioselective 1,2-addition of arylboronic acids to α-diketones with the use of a simple sulfur-alkene hybrid ligand. With as low as a 0.1 mol % catalyst loading, a variety of optically active

Full text of DOI:10.1021/ol203238j

ORGANIC
LETTERS
2012
Vol. 14, No. 2
624–627
Rh(I)-Catalyzed Asymmetric 1,2-Addition
to r-Diketones with Chiral SulfurꢀAlkene
Hybrid Ligands
Xiangqing Feng,† Yanzhao Nie,‡ Jing Yang,*,‡ and Haifeng Du*,†
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular
Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
100190, China, and State Key Laboratory of Chemical Resource, College of Life Science
and Technology, Beijing University of Chemical Technology, Beijing 100029, China
haifengdu@iccas.ac.cn; yangjingbuct@gmail.com
Received December 6, 2011
ABSTRACT
This paper describes a Rh(I)-catalyzed highly efficient and enantioselective 1,2-addition of arylboronic acids to R-diketones with the use of a
simple sulfurꢀalkene hybrid ligand. With as low as a 0.1 mol % catalyst loading, a variety of optically active R-hydroxyketones can be furnished in
high yields with excellent ee’s.
The transition-metal-catalyzed nucleophilic addition of
organometallic reagents to carbonyl compounds has be-
come an extremely useful method for alcohol synthesis.1
Especially, when using vicinal dicarbonyl compounds
as substrates, such as R-ketoesters,2 isatins,3 and R-
diketones,4 nucleophilic addition will produce tertiary
R-hydroxy carbonyl compounds which are very important
moieties contained in a number of biologically active
compounds and which also have a wide application in
synthetic chemistry.5,6 The catalytic asymmetric version of
such a transformation will furnish highly desirable opti-
cally active tertiary R-hydroxy carbonyl compounds, and
some important progress has already been achieved: for
example, the Rh(I)-catalyzed asymmetric addition of or-
ganoboronic acids to R-ketoesters using spriophosphite
† Chinese Academy of Sciences.
‡ Beijing University of Chemical Technology.
(1) For leading reviews, see: (a) Fagnou, K.; Lautens, M. Chem. Rev.
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2829. (c) Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Chem. Rev. 2011,
111, 7774.
(5) For examples on Lewis acid catalyzed addition to vicinal dicar-
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4, 3451. (b) DiMauro, E. F.; Kozlowski, M. C. J. Am. Chem. Soc. 2002,
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(6) For a leading review, see: (a) Coppola, G. M.; Schuster, H. F. R-
Hydroxy Acids in Enantioselective Synthesis; Wiley-VCH: Weineim, 1997.
For selected examples, see: (b) Kiesewetter, D. O.; Silverton, J. V.; Eckelman,
W. C. J. Med. Chem. 1995, 38, 1711. (c) Tokunaga, T.; Hume, W. E.;
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r
10.1021/ol203238j
Published on Web 01/10/2012
2012 American Chemical Society

or allene-containing phosphine ligands by Zhou2c (up
to 93% ee) or Reddy2e (up to 95% ee), and the Rh(I)-
catalyzed addition to isatins using MeO-mop ligands
by Hayashi3a (up to 93% ee). However, to the best
of our knowledge, no successful examples of transition-
metal-catalyzed asymmetric addition of organometallic
reagents to R-diketones are known,7 although the nona-
symmetric version with arylstannanes or arylboronic acids
has already been reported in 2003 and 2007, respectively.4
Searching for an effective chiral catalyst to overcome the
challenge remaining in this asymmetric transformation is
therefore of great importance.
To realize the challenging asymmetric 1,2-addition to R-
diketones, a suitable chiral ligand is thus essential. As part
of our ongoing project on the development of novel alkene
ligands,8ꢀ11 recently, we found that simple sulfurꢀalkene
hybrid ligands derived from chiral tert-butanesulfinamide12
were effective for Rh(I)-catalyzed asymmetric 1,4-addition
of arylboronic acids to R,β-unsaturated carbonyl com-
pounds.13ꢀ15 To our pleasure, we found that chiral sulfurꢀ
alkene hybrid ligands were also highly effective for Rh(I)-
catalyzed 1,2-additions to R-diketones with as low as a
0.1 mol % catalyst loading to afford optically active tertiary
R-hydroxyketones. Herein, we report our preliminary
results on this subject.
Table 1. Optimization of Reaction Conditions for Rh(I)-
Catalyzed Asymmetric Addition of 4-Methoxyphenylboronic
Acid (2a) to Benzil (1a)a
cat. loading
(mol %)
time
(h)
temp
conv
(%)b
ee
(%)c
entry
base
(°C)
1
5.0
1.0
1.0
1.0
1.0
1.0
0.1
0.1
0.05
0.01
KOH
KOH
Et3N
K3PO4
K2CO3
KF
4
2
50
25
25
25
25
25
25
50
50
80
>99
>99
55
99
99
99
99
99
99
99
98
98
95
2
3
2
4
2
>99
86
5
2
6
2
75
7
KOH
KOH
KOH
KOH
24
3
51
8
9
>99
59
17
16
10
12
a All reactions were carried out with 1a (0.20 mmol), 2a (0.30 mmol),
catalyst loading as indicated (Rh/4a = 1/1.2), and base (1.5 equiv of Rh)
in dioxane/H2O (v/v = 2/1) (1.5 mL) unless other noted; for entries
7ꢀ10, reactions were run with 1a (2.0 mmol) and 2a (3.0 mmol) in
dioxane/H2O (v/v = 2/1) (3.0 mL). b The conversion was determined by
crude 1H NMR. c The ee was determined by chiral HPLC.
Under previously reported reaction conditions,15 ligand
4a was initially subjected to the Rh(I)-catalyzed asym-
metric addition of 4-methoxyphenylboronic acid (2a) to
benzil (1a). We were pleased to find that the reaction went
smoothly to afford the desired product 3a in quantitative
conversion with 99% ee (Scheme 1). This promising result
encouraged us toward further optimization of the reaction
conditions. As shown in Table 1, bases were found to have
some impact on reactivity but not on enantioselectivity
(entries 2ꢀ6). The activity of the Rh/4a catalyst proved to
Scheme 1. Initial Study on Rh(I)-Catalyzed Asymmetric Addi-
tion of 4-Methoxyphenylboronic Acid (2a) to Benzil (1a)
€
€
46, 3139. (h) Maire, P.; Breher, F.; Schonberg, H.; Grutzmacher, H.
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Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 1143.
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Hu, X.; Zhuang, M.; Cao, Z.; Du, H. Org. Lett. 2009, 11, 4744. (b) Hu,
X.; Cao, Z.; Liu, Z.; Wang, Y.; Du, H. Adv. Synth. Catal. 2010, 352, 651.
(c) Cao, Z.; Du, H. Org. Lett. 2010, 12, 2602. (d) Wang, Y.; Hu, X.; Du,
H. Org. Lett. 2010, 12, 5482. (e) Liu, Z.; Du, H. Org. Lett. 2010, 12, 3054.
(f) Cao, Z.; Liu, Y.; Liu, Z.; Feng, X.; Zhuang, M.; Du, H. Org. Lett.
2011, 13, 2164. (g) Cao, Z.; Liu, Z.; Liu, Y.; Du, H. J. Org. Chem. 2011,
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T. P. Acc. Chem. Res. 2002, 35, 984. (b) Ellman, J. A. Pure Appl. Chem.
(7) During our preparation of the current manuscript, Xu and co-
workers reported a similar work using 3.0 mol % catalyst; see: Zhu, T.-S.;
Jin, S.-S.; Xu, M.-H. Angew. Chem., Int. Ed. DOI: 10.1002/anie.201106972.
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Hayashi, T. Aldrichimica Acta 2009, 42, 31. (e) Feng, C.-G.; Xu, M.-H.;
Lin, G.-Q. Synlett 2011, 1345.
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T.; Ueyama, K.; Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125,
11508. (b) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am.
Chem. Soc. 2004, 126, 1628.
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5336. (b) Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses,
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H. W. J. Am. Chem. Soc. 2010, 132, 14373. (e) Maire, P.; Deblon, S.;
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625

be high, and the reaction can still proceed efficiently to give
product 3a in quantitative conversion and 98% ee when
the catalyst loading was reduced to 0.1 mol % (Table 1,
entry 8). Even though the amount of catalyst was further
reduced to 0.05 mol %, R-hydroxyketone 3a can be still
obtained in a reasonable yield without the loss of ee
(Table 1, entry 9).
Table 2. Rh(I)-Catalyzed Asymmetric Addition of Arylboronic
Acids to R-Diketonesa
Figure 1. Evaluation of representative chiral sulfurꢀalkene
ligands for Rh(I)-catalyzed asymmetric addition to benzil (1a).
A variety of representative chiral sulfurꢀalkene hybrid
ligandswere subsequently evaluated in the Rh(I)-catalyzed
1,2-additions to benzil (1a) under the optimal conditions
(Table 1, entry 8). As shown in Figure 1, all these ligands
proved to be effective for this enantioselective transforma-
tion. The chirality of carbon of 4a affected the activity and
selectivity slightly. Ligand 4b15b derived directly from the
condensation of chiral tert-butanesulfinamide with chal-
cone showed reasonable activity and selectivity. Ligand
4c15a bearing a terminal alkene gave 95% conversion and
94% ee. Ligand 4f15c was found to be almost as effective as
ligand 4a.7
Encouraged by the aforementioned excellent results, the
scope of arylboronic acids and R-diketones was subse-
quently investigated. As shown in Table 2, a variety of
arylboronic acids were well tolerated for Rh(I)-catalyzed
additions to benzil (1a) to give tertiary R-hydroxyketones
in 56ꢀ99% yields with 96ꢀ99% ee’s (entries 1ꢀ11). While
only a 40% yield and 88% ee were obtained when using
(E)-styrylboronic acid as a substrate (Table 2, entry 12), it
was found that substituted diketones were also suitable
substrates giving satisfactory results (Table 2, entries 13
and 14). 1,2-Di-(2-furyl or thienyl)-1,2-ethanedione exhib-
ited excellent reactivity but gave poor ee’s which might be
partially due to the coordination of heteroatoms to rhodium
(Table 2, entries 15 and 16). However, 2,20-dichlorobenzil
(5a) and cyclic R-diketones 5b and 5c were not suitable
substrates for this addition (Scheme 2). To our delight, we
found that the current catalytic system was also effective for
the addition of phenylboronic acid to isatin 6 although the
activity and selectivity still await further improvement
(Scheme 2).
a Reactions were carried out in 2.0 mmol scale and 3.0 mL of solvent
for a 0.1 mol % catalyst loading and in 0.4 mmol scale and 1.5 mL of
solvent for a 1.0 and 3.0 mol % catalyst loading at 50 °C. b Isolated yield.
c The ee was determined by chiral HPLC.
626
Org. Lett., Vol. 14, No. 2, 2012

and enantioselective Rh(I)-catalyzed asymmetric addi-
tion of arylboronic acids to R-diketones with as low as a
0.1 mol % catalyst loading. Our study provides a useful
method for the synthesis of important optically active
tertiary R-hydroxyketones with high yields and ee’s.
Further application of the chiral sulfurꢀalkene ligand in
other transition-metal-catalyzed enantioselective reactions
is underway in our laboratory.
Scheme 2. Rh(I)-Catalyzed Asymmetric Addition to Other
R-Diketones or Isatins
Acknowledgment. The authors are thankful for the
financial support from the National Science Founda-
tion of China (21072194, 21172222) and 973 program
(2010CB833300).
Supporting Information Available. The procedure for
rhodium-catalyzed additions, characterization of pro-
ducts, and data for the determination of enantiomeric
excesses. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, using a simple chiral sulfurꢀalkene hybrid
ligand, we have successfully developed a highly efficient
Org. Lett., Vol. 14, No. 2, 2012
627