Rh/chiral sulfinylphosphine catalyzed asymmetric 1,4-addition of arylboronic acids to chalcones

Article abstract of DOI:10.1016/j.tet.2012.04.096

A general method to obtain enantioenriched 1,3,3-triarylpropan-1-ones bearing a diarylmethine stereocenter was developed using Rh/chiral sulfinylphosphine catalyzed 1,4-addition of arylboronic acids to chalcones. The catalysis progressed smoothly in the p

Full text of DOI:10.1016/j.tet.2012.04.096

Tetrahedron 68 (2012) 5908e5911
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Rh/chiral sulfinylphosphine catalyzed asymmetric 1,4-addition of arylboronic
acids to chalcones
,
b
,
,
b
,
,b,
*
Guihua Chen a c, Junwei Xing a c, Peng Cao b, Jian Liao a
a Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
c Graduate School of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method to obtain enantioenriched 1,3,3-triarylpropan-1-ones bearing a diarylmethine ster-
eocenter was developed using Rh/chiral sulfinylphosphine catalyzed 1,4-addition of arylboronic acids to
chalcones. The catalysis progressed smoothly in the presence of 2 mol % catalyst formed in situ from
[Rh(C2H4)2Cl]2 and chiral tert-butanesulfinylphosphine and gave the adducts with up to 99% yield and
98% ee.
Received 14 February 2012
Received in revised form 27 March 2012
Accepted 24 April 2012
Available online 10 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Chiral sulfinylphosphine
Chalcones
1,4-Addition
1. Introduction
of the diarylmethine motif inspired many groups to explore nu-
merous arylnucleophilic reagents for the 1,4-addition based on the
Diarylmethine-containing stereocenters are very important
substructure as they exist in many pharmaceuticals (such as tol-
terodine and sertraline) and natural products (such as cherylline
and podophyllotoxin) (Fig. 1). However, methods for the stereo-
selective synthesis of this structure motif are limited, due to the
little discrimination of two aryl groups. The most efficient approach
to the optically active 3,3-diarylalkanes is the addition of aryl nu-
linear unsaturated carbonyl compounds.2 The variant of asym-
metric addition mostly utilized arylboronic acid as reagents for the
arylation.
In 2005, Carreira employed Rh(I)-diene complexes to provide
access to valuable, optically enriched 3,3-diarylpropanals in
63e90% yields and 89e93% ees from readily available arylboronic
acids and substituted cinnamaldehydes. This was also effective for
tert-butyl cinnamates.3 Meantime, similar method to chiral 3,3-
diarylpropanals was developed by Hayashi and this system was
used in the synthesis of chiral methyl 3,3-diaryl-2-
cyanopropanoates, which was further converted to (R)-tolter-
odine.4 For the enantioselective synthesis of 3,3-diaryl ketones,
Miyaura found that the dicationic palladium (II)/chiral phosphine
complex was the efficient catalyst for the addition of arylboronic
cleophiles to
work of Miyaura and Hayashi, the rhodium-catalyzed asymmetric
1,4-addition of organometallic reagents to -unsaturated car-
b-aryl-a, b-unsaturated alkenes. Since the pioneering
a, b
bonyl compounds is considered as one of the most useful strategies
for the enantioselective construction of CeC bond.1 The significance
Cl
OMe
Cl
OH
MeO
OMe
acids to b-arylenones even at low temperature and catalyst load-
ings.5 Recently, the chiral binaphthols was also found to catalyze
the asymmetric 1,4-addition of arylboronates to chalcones at 120 ꢀC
with good yields and ees.6 Given our long-standing research in the
development of chiral sulfoxide-containing ligands for transition-
metal-catalyzed asymmetric reactions,7 many challenging olefins,
O
O
O
O
MeO
HO
N
N
HN
OH
Podophyllotoxin
OH
Cherylline
Tolterodine
Sertraline
such as chromenones7d,7h and
b
-nitrostyrenes,7i,7k underwent
Fig. 1. Selected bioactive compounds bearing diarylmethine stereocenters.
conjugate addition with arylboronic acids to give the adducts with
excellent yields and ees. We envisioned that chalcone might be
a good Michael acceptor for Rh-catalyzed asymmetric 1,4-addition
of arylboronic acids. Herein, we described our efforts toward the
construction of chiral 1,3,3-triarylpropan-1-ones using Rh/chiral
* Corresponding author. E-mail address: jliao@cib.ac.cn (J. Liao).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.096

G. Chen et al. / Tetrahedron 68 (2012) 5908e5911
5909
tert-butanesulfinylphosphine catalyzed 1,4-addition of boronic
acids to chalcones.
product gave rise to 92% (entries 9e12). In the same conditions, the
reaction failed with classical BINAP as the ligand, while the quan-
titative product could be obtained under the optimized condition8
but with moderate ee (entries 13e14).
In the examination of the effect of solvents and bases to the
reaction, we found the enantioselectivity was more consistent than
the reactivity and good to excellent ees could be kept in various
solvents and bases, as shown in Table 2. With the combination of 2-
propanol and aqueous KF was the best choice.
2. Results and discussion
In our previous work, we found that sulfoxideeolefins can give
modest enantioselectivity in rhodium-catalyzed conjugate addition
of phenylboronic acid to chalcone,7j bis-sulfoxide is good for linear
aliphatic enones,7d and SO-Ps are efficient ligands for electronic
deficient aryl-olefins (b
-nitrostyrenes).7i Hence, all above three
Table 2
Reaction condition optimizationa
classes of ligands were evaluated in this work. Using the optimal
reaction conditions developed in our previous work,7j 1.0 mol % of
[Rh(C2H4)2Cl]2, 2.4 mol % of ligand, 50 mol % aqueous KF in meth-
anol at 40 ꢀC for 3 h, various ligands including chiral sulfoxide-enes
1, chiral disulfoxide 2, chiral sulfinylphosphines 3 and (R)-BINAP 4
were tested in the addition of pheylboronic acid 6a to (E)-1-phenyl-
3-(p-tolyl)prop-2-en-1-one 5b. As shown in Table 1, chiral
sulfoxide-enes with branched olefin (1a, 1b, 1c, 1d, 1g) afforded the
adducts in good yields but poor ees (entries 1e5), the linear olefin
1e, 1f and disulfoxide 2 gave very poor results (entries 6e8).
Pleasingly, chiral tert-butanesulfinylphosphines 3ae3d showed
both good reactivities and enantioselectivities. With 3d in-
corporating two electron-donating CH3O group, the ee value of the
Entry
Solvent
Base
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Dioxane
THF
MTBE
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
K2CO3
K3PO4
KOH
TEA
93
Trace
68
61
89
93
69
nr
98
96
98
92
94
95
82
93
nd
93
86
88
94
92
nd
92
94
95
95
95
95
88
DCM
Acetone
Toluene
Hexane
Acetonitrile
MeOH
EtOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
9
Table 1
10
11
12
13
14
15d
Rh-catalyzed asymmetric 1,4-addition of phenylboronic acid to chalconea
a
Reactions were performed with 5b (0.3 mmol), 6a (0.6 mmol), [Rh(C2H4)2Cl]2
(1.2 mg, 0.003 mmol), 3d (0.0072 mmol), base (0.15 mL, 1.0 mol/L in H2O,
0.15 mmol), solvent (0.6 mL) at 40 ꢀC for 3 h.
b
Yield of the isolated product.
Determined by HPLC analysis on a chiral stationary phase.
TEA was used as neat.
c
d
Under the optimal reaction conditions, the scope of the sub-
strates was examined (Table 3). A number of arylboronic acids 6,
with electron-donating groups in the para-, meta-positions, reacted
with (E)-chalcone 5a to give adducts in excellent yields and ees
(entries 1e4), while o-methoxylphenylboronic acid showed trace
product. The lower ees were obtained when the rather electron-
deficient arylboronic acids were used (entry 8). For chalcones,
electron-donating substituents on 1- or 3-phenyl groups are ben-
efit for the reaction (entries 10e13 and 16), while electron-
withdrawing groups decreased the yield or ee of the product,
even inhibit the reaction, and the substrates were recovered un-
changed. Finally, the 3-heteroaryl groups of chalcones were also
found to interfere to the catalytic reaction with moderate re-
activities and stereoselectivities (entries 18e20). The aliphatic
chalcone 5n also gave very good results (entry 21).
This methodology could also provide an approach to the access
to the reversal enantiomer through the exchange of 3-aryl group of
the chalcone and aryl moiety of the boronic acid (Table 2, entry 11
vs Table 3, entry 1; Table 3, entry 3 vs entry 10; entry 4 vs entry 11).
This is especially practical as there are various arylboronic acids
available as well as chalcones can be synthesized easily while in
some cases the isomers of catalysts are difficult to obtain.
Entry
L
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1g
1e
1f
2
3a
3b
3c
3d
4
94
95
98
97
94
17
15
8
96
96
97
98
Trace
98
14
58
ꢁ52
ꢁ44
ꢁ22
ꢁ23
ꢁ15
ꢁ7
9
91
89
82
92
nd
ꢁ75
10
11
12
13
14d
4
3. Conclusion
a
Reactions were performed with 5b (0.3 mmol), 6a (0.6 mmol), [Rh(C2H4)2Cl]2
(1.2 mg, 0.003 mmol), L (0.0072 mmol), KF (0.15 mL, 1.0 mol/L in H2O, 0.15 mmol),
MeOH (0.6 mL) at 40 ꢀC for 3 h.
In conclusion, an efficient route to the synthesis of 1,3,3-
triarylpropan-1-ones bearing a chiral diarylmethine stereocenter
was developed through the asymmetric addition of arylboronic acids
to chalcones catalyzed by Rh(I)-chiral tert-butanesulfinylphosphine
b
Yield of the isolated product.
Determined by HPLC analysis on a chiral stationary phase.
3 Mol % Rh/4, KOH (30 mol %), dioxane/H2O (10:1), 40 ꢀC, 9 h.
c
d

5910
G. Chen et al. / Tetrahedron 68 (2012) 5908e5911
Table 3
4.2. General procedure for the catalytic asymmetric 1,4-
additions
Addition of arylboronic acids to chalconesa
Under argon atmosphere, to a 10-mL Schlenk tube was added
[Rh(C2H4)2Cl]2 (1.2 mg, 0.003 mmol), tert-butanesulfinylphos-
phine ligand (0.0072 mmol), followed by 0.5 mL dichloromethane,
the mixture was stirred at rt for 30 min, then solvent was removed
and chalcone (0.3 mmol) and arylboronic acid (0.6 mmol) were
added, after purging with argon, 2-propanol (0.6 mL) and KF
(0.15 mL, 1.0 M in H2O, 0.15 mmol) were added sequentially. The
mixture was stirred at 40 ꢀC for 3 h, then the solvent was removed
in vacuo and the residue was purified by flash chromatography on
silica gel with petroleum ether/ethyl acetate 20/1 as eluent to
afford the adducts.
Entry R1
R2
R3
Yield (%)b ee (%)c
1
H
H (5a)
H (5a)
H (5a)
H (5a)
H (5a)
H (5a)
4-Me (6b)
3-Me (6c)
4-MeO (6d) 98
3-MeO (6e) 97
2-MeO (6f) Trace
3, 5-Me (6g) 99
92
97
ꢁ97
95
2
H
3
H
98
4
H
89 (S)d
nd
5
H
6
H
97
4.2.1. 1,3-Diphenyl-3-(p-tolyl)propan-1-one (7ba).2,5a,6 Yield 98%,
7
8
9
H
H
H
H
H
H
H
H
H (5a)
H (5a)
H (5a)
4-Cl (6 h)
4-F3C (6i)
2-Naph (6j) 99
96
95
81
25
94
ꢁ97
ꢁ93 (R)d
92
97
nd
nd
95
97
81
white solid, mp 77e78 ꢀC, ½a D20
ꢂ ꢁ11 (c 0.110, CHCl3) for 95% ee.
1H NMR (300 MHz, CDCl3):
d
¼2.34 (s, 3H), 3.78 (d, J¼7.32 Hz,
10
11
12
13
14
15
16e
17
18e
19e
20e
21
4-MeO (5c)
3-MeO (5d)
3, 5-MeO (5e)
3-OH (5f)
4-Br (5g)
4-MeO (5h)
4-MeO (5i)
4-MeO (5j)
2-Th (5k)
2-Furyl (5l)
2-Pyr (5m)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
H (6a)
93
99
99
99
nr
2H), 4.86 (t, J¼7.31 Hz, 1H), 7.14 (d, J¼7.94 Hz, 2H), 7.23 (d,
J¼7.96 Hz, 3H), 7.32e7.33 (m, 4H), 7.45e7.50 (m, 2H), 7.56e7.61 (m,
1H), 7.98e8.00 (m, 2H). 13C NMR (75 MHz, CDCl3):
d
¼20.9, 44.7,
45.5, 126.2, 127.6, 127.7, 128.0, 128.46, 128.50, 129.2, 133.0, 135.8,
137.0, 141.1, 144.3, 198.0.
4-Br
4-MeO
4-NO2
H
H
H
nr
98
31
83
94
34
98
HPLC: Daicel Chiralcel OJ-H, n-hexane/2-propanol¼70/30,
1.0 mL/min, 254 nm, retention time: 13.5 min (minor), 16.2 min
(major).
66
48
(E)-CH3COCH]CHC6H4-p-OCH3 (5n) H (6a)
90 (R)f
a
Acknowledgements
Reactions were performed with 5 (0.3 mmol), 6 (0.6 mmol), [Rh(C2H4)2Cl]2
(1.2 mg, 0.003 mmol), 3d (0.0072 mmol), KF (0.15 mL, 1.0 mol/L in H2O, 0.15 mmol),
2-propanol (0.6 mL) at 40 ꢀC for 3 h.
We thank the NSFC (No. 21072186 and 20872139), the West
Light Foundation of CAS, Chengdu Institute of Biology of CAS
(Y0B1051100), the Major State Basic Research Development Pro-
gram (973 program, 2010CB833300) for financial support.
b
Yield of the isolated product.
c
Determined by HPLC analysis on a chiral stationary phase.
d
Determined by comparison of the specific optical rotation with literature5a and
the others were assigned by analogy.
e
For 10 h.
f
Determined by comparison of the specific optical rotation with literature.9
Supplementary data
Full experimental details for all compounds, as well spectral
data can be founded in the Supplementary data. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.tet.2012.04.096.
complex. The adducts were readily obtained in up to 99% yield and
98% ee. The application of this methodology to other linear un-
saturated carbonyl compounds is underway in our laboratory.
References and notes
4. Experimental section
4.1. General method
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were used as received without further purification. Solvents used
in catalysis were distilled from appropriate drying agents and
bubbled with argon for 30 min prior to use. Solutions used in the
catalysis were made by dissolving the salt in distilled water then
bubbled with argon for 30 min prior to use. Flash column
chromatography was performed on silica gel H (HG/T2354-92,
Qingdao Haiyang Chemical Co. Ltd.); analytical TLC was per-
formed on HSGF 254 glass plates precoated with 0.15e0.20 mm
thickness of silica gel (Yantai Jiangyou Silica Gel Development Co.
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300 spectrometer (300 MHz for 1H and 75 MHz for 13C) in CDCl3.
Chemical shifts were recorded in parts per million (d) relative to
CHCl3 at 7.26 for 1H NMR and 77.0 for 13C NMR. Electrospray
ionization high-resolution mass spectra (ESI-HRMS) were recor-
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rotation was recorded on PE Model 341 polarimeter. Enantio-
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