Chiral scandium(III)-catalyzed enantioselective α-arylation of N-unprotected 3-substituted oxindoles with diaryliodonium salts

Article abstract of DOI:10.1002/anie.201303602

Catalytic asymmetric α-arylation of N-unprotected 3-substituted oxindoles with diaryliodonium salts has been realized by a chiral Lewis acid promoted electrophilic addition and aryl-rearrangement process. Single C3-arylated products containing a quaternary carbon center were generated in high enantioselectivity and reactivity. Copyright

Full text of DOI:10.1002/anie.201303602

Angewandte
Chemie
DOI: 10.1002/anie.201303602
Asymmetric Catalysis
Chiral Scandium(III)-Catalyzed Enantioselective a-Arylation of N-
Unprotected 3-Substituted Oxindoles with Diaryliodonium Salts**
Jing Guo, Shunxi Dong, Yulong Zhang, Yulong Kuang, Xiaohua Liu, Lili Lin, and
Xiaoming Feng*
Dedicated to Professor Xiao-Zeng You on the occasion of his 80th birthday
The catalytic asymmetric a-arylation of carbonyl compounds
is of high interest, because it provides an efficient access to
optically active a-aryl compounds regarded as essential
motifs in many biologically active natural products and
pharmaceutically active compounds.[1] Significant efforts
have been directed towards the development of metal-
catalyzed a-arylation of carbonyl compounds with aryl
halides, aryl triflates, or aryl organometallic reactants.[2]
Diaryliodonium salts are mild, selective, and non-toxic
reagents, and are alternative arylation partners for a variety
of nucleophiles.[3] The MacMillan group[4] provided earily
enantioselective enolate a-arylation employing diaryliodo-
nium salts, such as a metal–organocatalysis merger for a-
arylation of aldehydes,[4a] and chiral copper catalysis of
silylkene acetals.[4b] The Gaunt group realized chiral copper-
catalyzed a-arylation of N-acyloxazolidiones.[5] In these cases,
a CuIII–aryl process followed by reductive elimination was
postulated (Scheme 1a). Furthermore, the involvement of
electrophilic addition and aryl moiety in rearrangement was
also proposed.[6] A recent computational study by Olofsson
and co-workers confirmed that the reaction could follow
associative or dissociative ligand-exchange pathways.[6b] It
suggests that the addition of diaryliodonium salts to the
Scheme 1. Possible mechanism for a-arylation of carbonyl compounds.
enolate results in almost isoenergetic oxygen–iodine and
carbon–iodine bonded isomers. The [2,3]-rearrangement
pathway was favored over the [1,2]-process (Scheme 1b).
An interesting perspective is that the asymmetric version
could be obtained either based on covalently linked auxil-
iaries, or chiral Lewis acid catalysis.[6b] Chiral diaryliodonium
salts,[7] such as Ochiaiꢀs salt,[7b] show the success of the former
strategy. A direct asymmetric a-arylation of cyclohexanones
organocatalytic arylation is of considerable interest. If
a chiral Lewis acid with strong oxygen affinity was introdu-
ced,[6b] the association would benefit the formation of C-
linked intermediate enantiotopically, overwhelming incorpo-
À
ration of the O I process (Scheme 1c).
À
by shifting the enantiodifferentiation away from the C C
Given our long-term endeavor in the development of
chiral catalysts derived from rare-earth metal/N,N’-dioxide
complexes,[8] we envision that this kind of useful catalyst could
provide new route for the asymmetric a-arylation of carbonyl
compounds. Herein, we present a chiral Lewis acid catalyzed
asymmetric a-arylation of N-unprotected 3-substituted oxin-
doles with diaryliodonium salts. The scandium(III) complex
of chiral N,N’-dioxide bearing tetrahydroisoquinoline back-
bones exhibited excellent performance under mild reaction
conditions, generating oxindole derivatives with quaternary
carbon centers in high enantioselectivity and reactivity (up to
99% ee and 99% yield). The process also facilitated the
synthesis of an antiproliferative agent for the treatment of
cancer.
bond-forming step was realized by Aggarwal.[7c] Nevertheless,
the development of non-oxidative metal-participated or
[*] J. Guo, S. X. Dong, Y. L. Zhang, Y. L. Kuang, Prof. Dr. X. H. Liu,
Dr. L. L. Lin, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology, Ministry of
Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
E-mail: xmfeng@scu.edu.cn
[**] We appreciate the National Basic Research Program of China (973
Program: No. 2010CB833300), the National Natural Science
Foundation of China (Nos. 21021001, 21290182, and 21172151),
and the Ministry of Education (No. 20110181130014) for financial
support.
We chose N-unprotected 3-substituted oxindoles as the
model substrates, considering that oxindole derivatives are
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201303602.
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a ubiquitous structural motif in a variety of natural products
and biologically active drug candidates.[9] The Buchwald
group has utilized enantioselective Pd-catalyzed intermolec-
ular coupling of N-Me oxindoles with aryl and vinyl bromides
to construct 3-substituted oxindoles with chiral quaternary
centers.[2f] Moreover, 3-substituted oxindole[10] is a acidic
carbon nucleophile that could react well with electrophilic
diaryliodonium salts. Initially, the study focused on the
reaction of N-unprotected 3-benzyl-2-oxindole 1a and com-
mercially available diaryliodonium salt 2a in the presence of
chiral N,N’-dioxide–metal complex and K2CO3. Investigation
of different Lewis acids coordinated to ligand L1 derived from
l-piperic acid showed that only Sc(OTf)3 gave promising
reactivity (Table 1, entry 4), while metal sources as CuBr,
various amino acid backbones and amide substituents
screened, N,N’-dioxide L6 bearing tetrahydroisoquinoline
units and (S)-phenylethanamine modifies exhibited the best
enantioselectivity (50% yield and 80% ee; Table 1, entry 9
versus entries 6–8). Chiral match among the subunits in the
ligands was found. Using ligand L7, the diastereomer of the
optimal ligand L6, resulted in dramatically reduced enantio-
selectivity and yield (Table 1, entry 10). Changing the anion of
diaryliodonium salt from tetrafluoroborate to triflate made
the reaction more applicable, and the desired a-arylation
product 3aa was given in 63% yield and 90% ee (Table 1,
entry 11). A further survey of other bases (see the Supporting
Information for details) showed that a slightly improved
enantioselectivity (93% ee) was achieved using NaHCO3
(Table 1, entry 12). Moreover, both the yield and the enan-
tioselectivity increased by the addition of 3 ꢁ molecular
sieves (Table 1, entry 13). Gratifyingly, when the ratio of
oxindole 1a, diaryliodonium triflate 2b and NaHCO3 was
fixed to 1:1.5:3, the desired 3-benzyl-3-phenylindolin-2-one
3aa was generated in 89% yield and 95% ee (Table 1,
entry 14). Attempts to decrease the catalyst loading resulted
in lower yield, albeit with slightly decreased enantioselectivity
(Table 1, entry 15).
Table 1: Optimization of the reaction conditions.[a]
With the optimized reaction conditions in hand (Table 1,
entry 14), the substrate scope of 3-substituted oxindoles was
investigated (Table 2). The reactions performed well with
a series of 3-benzyl substituted oxindoles, giving the corre-
sponding a-arylated products in 80–99% yields with 91–99%
ee, regardless of the electronic nature and the position of
substituents on the aromatic ring of the benzyl group (Table 2,
entries 1–18). In general, 3-benzyl oxindoles with a meta-
substituent on the aromatic ring gave slightly higher enantio-
selectivities than those with ortho- or para-substituents
(Table 2, entries 3, 6, 9, 11 and 13). 3-Benzyl oxindoles with
two substituents also gave out satisfying results, of which the
major product 3qa was unambiguously determined to be R
configuration by X-ray analysis[11] (Table 2, entries 17,18).
Remarkably, substrates bearing a condensed ring or hetero-
aromatic ring in the R1 substituents were also suitable
substrates for the reaction, affording the corresponding
products with good yields and excellent enantioselectivities
(81–90% yields, 91–96% ee; Table 2, entries 19–21). The 3-
tert-butyl-2-oxindole 2u reacted smoothly under the optimal
conditions (71% yield, 84% ee; Table 2, entry 22). Moreover,
oxindole 2v with an allyl group at the C3 position was
compatible with this catalytic system, giving a moderate yield
with 72% ee (Table 2, entry 23). Excellent results were
achieved for 6-chloro-substituent on the oxindole structure,
and the a-arylation of oxindole 2w and 2x generated the
corresponding products in 89% yield, 90% ee, and 90% yield,
98% ee, repectively (Table 2, entries 24 and 25). Furthermore,
3,3-diaryloxindoles are widely used as effecient mineralocor-
tocoid receptor antagonists[9e] and anticancer agents.[9f] How-
ever, there are limited asymmetric synthetic methods avail-
able. We achieved the asymmetric synthesis of 3,3-diary-
loxindole 3ya, albeit in moderate yield and enantioselectivity
(Table 2, entry 26).
Entry Ligand Metal
Base
2
Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L6
L6
L6
L6
L6
CuBr
Cu(OTf)2
Pd(OAc)2 K2CO3
K2CO3
K2CO3
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
trace
0[d]
n.r.[e]
18
–
–
–
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaHCO3 2b
NaHCO3 2b
NaHCO3 2b
NaHCO3 2b
5
16
18
17
17
30
9
10
50
25
63
55
67
89
75
17
80
17
90
93
94
95
91
9
10
11
12
13[f]
14[f,g]
15[f,h]
[a] Unless otherwise noted, all reactions were performed with metal/
ligand (1:1, 10 mol%), base (0.11 mmol), 1a (0.1 mmol), and diary-
liodonium salt 2 (0.1 mmol) in CH2Cl2 (0.8 mL) under N2 at 358C for
48 h. [b] Yield of isolated product. [c] Determined by HPLC analysis using
a Chiralcel IA column. [d] A complicated mixture was observed.
[e] n.r.=no reaction. [f] 3 ꢀ M.S. (2.0 mg) was added. [g] The ratio of 1a/
2b/NaHCO3 was 1:1.5:3. [h] L6-Sc(OTf)3 (1:1, 5 mol%).
Cu(OTf)2, and Pd(OAc)2, which were popular in a-arylation,
resulted in poor yields or complicated mixtures (Table 1,
entries 1–3). Following the survey of ligands complexed with
Sc(OTf)3, we found that the ligands bearing (S)-phenylethan-
amine modifies exhibited superior results (18% yield, 30%
ee; Table 1, entries 4–6). Interestingly, of all the ligands with
Next, a range of diaryliodonium triflates was employed.
The symmetric diaryliodonium triflates[12] containing elec-
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Table 2: Substrate scope of substituted oxindoles.[a]
Table 3: Substrate scope of diaryliodonium triflates.[a]
Entry
R1
R2 Time [h] Yield (3) [%][b] ee [%][c]
1
2
3
4
5
6
C6H5CH2
2-MeC6H4CH2
3-MeC6H4CH2
4-MeC6H4CH2
2-ClC6H4CH2
3-ClC6H4CH2
3-ClC6H4CH2
4-ClC6H4CH2
3-FC6H4CH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
48 89 (3aa)
72 99 (3ba)
48 80 (3ca)
48 98 (3da)
48 93 (3ea)
24 99 (3 fa)
24 95 (3 fa)
35 84 (3ga)
48 95 (3ha)
48 92 (3ia)
48 99 (3ja)
35 82 (3ka)
48 99 (3la)
48 98 (3ma)
48 97 (3na)
48 95 (3oa)
48 90 (3pa)
48 89 (3qa)
95
91
95
94
92
99
96
96
97
95
99
97
98
95
97
95
95
92 (R)
Entry
Ar
R3
Time [h]
Yield (3) [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
4-FC6H4
4-ClC6H4
4-BrC6H4
4-tBuC6H4
4-MeC6H4
Mes
4-F
4-Cl
4-Br
4-tBu
4-Me
H
4-Cl
4-Br
4-Ph
48
24
48
72
72
120
120
120
120
65 (3ab)
79 (3ac)
82 (3ad)
80 (3ae)
76 (3af)
80 (3aa)
79 (3ac)
65 (3ad)
55 (3ag)
94
96
98
92
96
92
94
94
90
7[d]
8
9
Mes
Mes
Mes
10
11
12
13
14
15
16
17
18
4-FC6H4CH2
3-BrC6H4CH2
4-BrC6H4CH2
3-O2NC6H4CH2
4-O2NC6H4CH2
4-NCC6H4CH2
4-MeOC6H4CH2
2,4-Cl2C6H3CH2
2,6-Cl2C6H3CH2
[a] All reactions were performed with 1a (0.1 mmol), L6-Sc(OTf)3 (1:1,
10 mol%), 3 ꢀ M.S. (2.0 mg), NaHCO3 (0.3 mmol), and diaryliodonium
salt 2 (0.15 mmol) in CH2Cl2 (0.8 mL) at 358C for the indicated time.
[b] Yield of isolated product. [c] Determined by HPLC analysis.
19
H
48 90 (3ra)
96
20
21
22
23
24
25
26
2-naphthylmethyl
2-thienylmethyl
tBuCH2
H
H
H
H
48 81 (3sa)
48 82 (3ta)
48 71 (3ua)
120 60 (3va)
48 89 (3wa)
48 90 (3xa)
120 47 (3ya)
96
91
84
72
90
98
57
allyl
C6H5CH2 6-Cl
3-ClC6H4CH2 6-Cl
4-ClC6H4
H
[a] Unless specified, the reactions were performed with 1 (0.1 mmol), L6-
Sc(OTf)3 (1:1, 10 mol%), 3 ꢀ M.S. (2.0 mg), NaHCO3 (0.3 mmol), and
diaryliodonium salt 2b (0.15 mmol) in CH2Cl2 (0.8 mL) at 358C for the
indicated time. [b] Yield of isolated product. [c] Determined by HPLC
analysis. [d] L6-Sc(OTf)3 (1:1, 5 mol%).
Scheme 2. a) Gram version of the reaction; b) asymmetric synthesis of
the antiproliferative agent.
tron-rich or electron-deficient aryl groups could be success-
fully transferred to 3-benzyl-2-oxindole 1a with high enan-
tioselective levels (92–98% ee), and moderate to good yields
(65–82%; Table 3, entries 1–5). Pleasingly, the reaction of
diaryliodonium triflate with n-butyl substituents performed
well within a longer reaction time (80% yield, 92% ee;
Table 3, entry 4). It is important to note that the unsymmetric
salts[13] bearing nontransferring mesityl ligand could also be
readily exploited, and the electron-poor aryl moiety is
preferably transferred in enolate arylation. Aryl groups with
halogen substituents on the phenyl substituents could be
introduced in satisfying results under mild reaction conditions
(Table 3, entries 7–9). Unfortunately, a-vinylation[2f] by using
vinyliodonium salts failed.
3xl.[14] The arylation process between oxindole 1x and
unsymmetric salt 2l was conducted to afford the enantiomeric
enriched product 3xl in 71% yield and 94% ee (Scheme 2b).
This provides a useful and concise route to construct such an
important chiral molecules for the purposes of medicinal
agent testing.
Preliminary studies of the mechanism were carried out by
HRMS experiments. The coordination of N,N’-dioxide L6
with Sc(OTf)3 was confirmed by the ion peak at m/z 825.2388,
corresponding to the intermediate [Sc3+ + (L6-H)À + TfOÀ]+.
Peaks at m/z 898.3812 and 1048.3442 were assigned to [Sc3+
+
To show the utility of the current method, a gram-scale
synthesis of 3-benzyl-3-aryloxindole derivative was carried
out with oxindole 1 f and diaryliodonium triflate 2b. The
reaction proceeded smoothly to give the product 3 fa in 99%
yield and 99% ee (Scheme 2a). Oxindole derivative 3xl is
used as a antiproliferative agent for the treatment of cancer.
To date, there are few asymmetric methods for synthesizing
L6 + 1a-2HÀ]+ and [Sc3+ + L6 + 1a + TfOÀ-H]+, respectively,
which indicated the association of oxindole to the metal
center. Based on our previous study of chiral N,N’-dioxide-
metal complex promoted asymmtric reaction of oxindoles, as
well as the theoretical study of Olofsson, we postulated
a possible catalytic model to elucidate the stereocontrol (see
the Supporting Information). The formation of chiral scan-
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dium enolate from oxindole 1 reduced the electric-charge
density of oxygen, which was adverse to the electrophilic
addition of diaryliodonium salts. Meanwhile, severe steric
hindrance around the oxygen also hampered the generation
À
À
À
of O I bonded isomer and C I to O I isomerization
(Scheme 1b). The enantioselective arylation of enolate was
obtained by differentiation of its enantiopotic faces through
the shielding effect of the nearby amide moiety of the ligand.
With easily dissociated triflate counterion, it was likely that
cationic hypervalent iodine reagents prefered to attack the C3
atom of the enolate from the Re-face. The intermediate
reapidly performed [1,2] rearrangement to give the desired
(R)-product, which is in good agreement with the X-ray
analysis of 3qa.
In conclusion, we have developed a new asymmetric
catalytic strategy for a-arylation of carbonyl compounds.
Chiral Lewis acid catalysts of N,N’-dioxide-Sc(OTf)3 complex
performed well in the reaction of N-unprotected 3-substituted
oxindoles with diaryliodonium triflates under mild reaction
conditions. The desired oxindole derivatives with quaternary
carbon centers were afforded in high enantioselectivity and
reactivity (up to 99% ee and 99% yield). As one example, this
new procedure has been successfully applied to the enantio-
selective synthesis of an antiproliferative agent. Of our study,
this is the first example that N,N’-dioxide bearing tetrahy-
droisoquinoline backbones gave better enantiocontrol than
these derived from other amino acids. Further application of
C2-symmetric N,N’-dioxide amides to other asymmetric
transformations, as well as the study of the relationship
between the structure of the catalyst and its catalytic features
in reactions, are ongoing in our laboratory.
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Experimental Section
General procedure for the asymmetric a-arylation of 3-substituted
oxindoles: A dry reaction tube was charged with L6-Sc(OTf)3 (1:1,
10 mol%), 3 ꢁ M.S. (2.0 mg, activated at 3008C for 5 h before use),
and oxindole 1 (0.1 mmol) under N2 atmosphere. CH2Cl2 (0.5 mL)
was added, and the mixture was stirred at 358C for 0.5 h. Then,
diaryliodonium salt 2 (0.15 mmol), NaHCO3 (0.3 mmol), and CH2Cl2
(0.3 mL) were added under stirring. The reaction mixture was stirred
at 358C for 24–120 h. After complete consumption of the starting
materials, the mixture was direct purified by column chromatography
on silica gel (petroleum ether/ethyl acetate = 8:1 to 6:1) to afford 3 as
a white solid.
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Received: April 28, 2013
Revised: June 19, 2013
Published online: September 9, 2013
Keywords: asymmetric catalysis · diaryliodonium salts ·
.
N,N’-dioxide · scandium · a-arylation
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