Chiral N,N′-Dioxide/Scandium(III)-Catalyzed Asymmetric Alkylation of N-Unprotected 3-Substituted Oxindoles

Article abstract of DOI:10.1002/adsc.201800877

An efficient enantioselective alkylation of N-unprotected 3-substituted oxindoles was realized by using a chiral N,N′-dioxide/scandium(III) complex as the catalyst. A wide range of 3,3-dialkyl substituted oxindoles with quaternary stereocenters were obtained in high yields and ee values (up to 98% yield and 99% ee). (Figure presented.).

Full text of DOI:10.1002/adsc.201800877

Title: Chiral N,N'-Dioxide/Scandium(III)-Catalyzed Asymmetric
Alkylation of N-Unprotected 3-Substituted Oxindoles
Authors: Changqiang He, Weidi Cao, Jianlin Zhang, Shulin Ge, and
Xiaoming Feng
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10.1002/adsc.201800877
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Chiral N,N-Dioxide/Scandium(III)-Catalyzed Asymmetric
Alkylation of N-Unprotected 3-Substituted Oxindoles
Changqiang He,a Weidi Cao,a,* Jianlin Zhang,a Shulin Ge,a Xiaoming Fenga,*
a
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, People’s Republic of China
Tel: +86 28 85418249
Fax: +86 28 85418249
E-mail: wdcao@scu.edu.cn; xmfeng@scu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. An efficient enantioselective alkylation of N-
unprotected 3-substituted oxindoles was realized by using a
chiral N,N-dioxide/scandium(III) complex as the catalyst.
A wide range of 3,3-dialkyl substituted oxindoles with
quaternary stereocenters were obtained in high yields and
ee values (up to 98% yield and 99% ee).
Keywords: Asymmetric catalysis; Alkylation; Oxindole;
Quaternary carbon stereocenter; Scandium
The 3,3-dialkyl substituted 2-oxindole structural
motifs exist in a variety of natural products, clinical
pharmaceuticals and drug candidates.[1] Diverse
Scheme 1. The asymmetric alkylation of 3-substituted
oxindoles.
methods are continually sought to construct these
important skeletons.[2] The application of prochiral 3-
substituted oxindoles as nucleophiles is a widely
adopted strategy, including enantioselective aldol
method
for
palladium-catalyzed
asymmetric
reaction,[3] Mannich reaction,[4] Michael reaction,[5]
arylation or vinylation reaction[6] and alkylation
reaction.[7,8] Most of these well-developed asymmetric
reactions use N-protected 3-substituted oxindoles
because of the high reactivity resulting when
introducing a protecting group (methyl, benzyl, Boc,
etc.) Unfortunately, the introduction and removal of
the activating group are not atom-economic and may
render the potential of breaking the molecular
structure. Up to now, functionalization at the C3
position of N-unprotected 3-substituted oxindoles to
access 3,3-dialkyl substituted oxindoles containing a
chiral quaternary carbon center are still
challenging,[2a] because of the poor reactivity and the
side reaction of alkylation at the position of the
nitrogen moiety. Shibata’s, Zhou’s and Chen’s groups
reported the direct aldol reaction, Michael addition
and Mannich reaction of unprotected 3-substituted
[7b]
benzylation of 3-aryl oxindoles.
In recent years,
our group also realized the functionalizations of N-
unprotected 3-substituted oxindoles catalyzed by
[9,10]
chiral N,N-dioxide/metal complexes.
For
instance, N,N-dioxide/Sc(III) complexes-catalyzed
asymmetric -arylation[6b] and aldol reaction,
[10b,10c]
as well as N,N-dioxide/Nd(III) complexes-catalyzed
Michael addition[10e] could give efficient results.
On the other hand, the catalytic asymmetric
propargylation provides productive access to optically
active propargyl derivatives that are widely
distributed across medicinal agents and valuable
building blocks for various transformations. [11] To the
best of our knowledge, most of the reported alkylation
reactions of 3-substititued oxindoles focused on
asymmetric allylic alkylation (AAA) reactions, [8] only
one example of asymmetric alkylation of 3-
substituted oxindoles including propargylation was
reported by Ooi, a chiral 1,2,3-triazolium ion-based
phase transfer catalyst was used, giving the
corresponding propargylation product with 85% ee
oxindoles by using cinchona alkaloid derivatives as
[3a,4b,5g]
the catalysts, respectively.
Czabaniuk developed a
Trost and
1
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10.1002/adsc.201800877
Advanced Synthesis & Catalysis
Table 1. The optimization of the reaction conditions[a]
Entry
Metal salt
Ligand
Base
Yield (%)[b]
ee (%)[c]
1
2
3
4
5
6
7
8
Cu(OTf)2
Y(OTf)3
La(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
KHCO3
Na3PO4
K3PO4
K3PO4∙7H2O
K3PO4∙7H2O
K3PO4∙7H2O
NR[d]
trace
trace
60
35
70
68
68
23
70
-
0
0
L-RaPr2
L-RaPr2
L-RaPr2
L-RaPr2
L-PrPr2
L-PiPr2
L-PiEt2
L-PiMe2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
L-PiPr2
24
15
53
34
0
57
57
94
96
97
91
9
10
11
12
13[e]
14[f]
76
83
96
73
[a] Unless otherwise noted, the reaction was carried out with 3-benzylindolin-2-one 1a (0.10 mmol), 3-phenylpropargyl
chloride 2a (0.25 mmol), metal salt/ligand (1:1, 10 mol%) and base (0.40 mmol) in CHCl3 (1.0 mL) at 60 C for 16 h.
[b] Isolated yield.
[c] Determined by chiral HPLC analysis.
[d] NR = no reaction
[e] Sc(OTf)3/L-PiPr2 (1:1.2, 10 mol%).
[f] Sc(OTf)3/L-PiPr2 (1:1.2, 5 mol%).
(Scheme 1a). [12] Based on long-term endeavor in the of L-PiPr2 were beneficial to achieve higher
development of chiral N,N-dioxide/metal complexes enantioselectivity (Table 1, entry 6 vs entries 7 and 8).
and our previous studies of the oxindole derivatives, It was worthy to note that the bases had a significant
we envisioned that this kind of effective catalyst influence on both the reactivity and enantioselectivity.
system could provide a new route for the asymmetric The product 3aa could be obtained in 76% yield and
alkylation of N-unprotected 3-substituted oxindoles, 94% ee when K3PO4 was selected as the base (Table 1,
including propargylation, allylation and benzylation entry 11). The trace amount of crystal water had a
reactions (Scheme 1b).
little effect on the yield and enantioselectivity, maybe
In our preliminary investigation, N-unprotected 3- because of the higher solubility of K3PO4∙7H2O in
substituted oxindole 1a and 3-phenylpropargyl CHCl3 than K3PO4 (Table 1, entry 12). Adjusting the
chloride 2a were selected as the model substrates to ratio of Sc(OTf)3/L-PiPr2 from 1:1 to 1:1.2, the yield
optimize the reaction conditions. Firstly, various was further improved to 96% (Table 1, entry 13).
metal salts were screened by coordinating with L- However, decreasing the catalyst loading to 5 mol%,
RaPr2 in the presence of K2CO3 in CHCl3 at 60 C the enantioselectivity and reactivity decreased (Table
(Table 1, entries 1-4), only the Sc(OTf)3/L-RaPr2 1, entry 14). Thus, the optimized conditions were
complex could promote the reaction, giving the established, Sc(OTf)3/L-PiPr2 (1:1.2, 10 mol%) as the
desired product 3aa in 60% yield with 24% ee (Table catalyst with K3PO4∙7H2O (4 equiv.) in CHCl3 at 60
1, entry 4). The examination of the chiral ligands C for 16 h.
indicated that the L-pipecolic acid derived L-PiPr2
Under the optimized reaction conditions, the
was superior to L-ramipril derived L-RaPr2 and L- substrate scope was explored. A series of N-
proline derived L-PrPr2 in terms of the yield and unprotected 3-substituted oxindoles could react with
enantioselectivity (Table 1, entry 6 vs entries 4-5). 3-phenylpropargyl chloride smoothly and gave the
More sterically hindered ortho-substituents on aniline corresponding propargylated products 3aa−3oa in
2
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10.1002/adsc.201800877
Advanced Synthesis & Catalysis
Table 2. The scope of 3-substituted 2-oxindoles[a]
Table 4. The scope of allyl and benzyl chloride
derivatives[a]
Entry R1
Yield
(%)[b]
ee
(%)[c]
1
2
3
4
5
6
7
8
Bn
96 (3aa)
91 (3ba)
94 (3ca)
91 (3da)
96 (3ea)
96 (3fa)
95 (3ga)
88 (3ha)
95 (3ia)
96 (3ja)
96 (3ka)
92 (3la)
96 (3ma)
95 (3na)
96 (3oa)
97
98
98
98
98
98
99
99
99
98
97
97
96
98
97
4-FC6H4CH2
4-ClC6H4CH2
4-BrC6H4CH2
3-BrC6H4CH2
2-BrC6H4CH2
4-O2NC6H4CH2
4-F3CC6H4CH2
4-NCC6H4CH2
2,4-Cl2C6H3CH2
4-MeOC6H4CH2
4-MeC6H4CH2
3-MeC6H4CH2
2-MeC6H4CH2
9
10
11
12
13
14
15
[a] Unless otherwise noted, the reaction was carried out with
3-benzylindolin-2-one 1a (0.10 mmol), allyl and benzyl
chloride derivatives 4 (0.25 mmol), Sc(OTf)3/L-PiPr2 (1:1,
10 mol%) and K3PO4∙7H2O (0.80 mmol) in CHCl3 (1.0
mL) at 60 C. Yield is that of isolated product. The ee
values were determined by HPLC analysis on a chiral
stationary phase.
16
17
18
19
20
1-Naphthylmethyl
2-Thienylmethyl
2-Furylmethyl
CH3
98 (3pa)
87 (3qa)
84 (3ra)
62 (3sa)
90 (3ta)
98
93 (S)
85
81
95
tBuCH2
[a] Unless otherwise noted, the reaction was carried out with
1 (0.1 mmol), 3-phenylpropargyl chloride 2a (0.25 mmol),
Sc(OTf)3/L-PiPr2 (1:1.2, 10 mol%) and K3PO4∙7H2O (0.4
mmol) in CHCl3 (1.0 mL) at 60 C for 16 h.
[b] Isolated yield.
excellent yields and ee values, regardless of the
electronic nature and the position of substituents on
the phenyl group (88-96% yield, 96-99% ee, Table 2,
entries 1-15). 2-Oxindole with a naphthylmethyl
substituent 1p was suitable for this reaction, affording
the propargylated product 3pa in 98% yield and 98%
ee (Table 2, entry 16). Moreover, oxindoles
containing 2-thienylmethyl 1q and 2-furylmethyl 1r
were also tolerated and the absolute configuration of
3qa was determined to be S by using single-crystal X-
ray diffraction analysis (Table 2, entries 17 and
18).[13] The 3-methyl-2-oxindole 1s gave the desired
product 3sa with a decreasing yield and ee value
(62% yield, 81% ee, Table 2, entry 19). Nevertheless,
3-neopentyl-2-oxindole 1t could transform into 3ta in
90% yield and 95% ee (Table 2, entry 20).
Next, we turned our attention to the scope of
propargyl chloride derivatives (Table 3). The
substituents on the phenyl group had little effect on
this propargylation reaction. The corresponding 3,3-
dialkyl substituted 2-oxindoles could be achieved in
high yields with excellent ee values (83-94% yields,
91-98% ee, Table 3, entries 1-8). Naphthyl-
substituted propargyl chloride 2j and the terminal 3-
chloroprop-1-yne 2k were also compatible with this
transformation, affording 3aj and 3ak with good
results.
[c] Determined by chiral HPLC analysis.
Table 3. The scope of propargyl chlorides[a]
Entry
R2
Yield (%)[b] ee (%)[c]
1
2
3
4
5
6
7
8
4-FC6H4
93 (3ab)
93 (3ac)
94 (3ad)
87 (3ae)
90 (3af)
83 (3ag)
91 (3ah)
84 (3ai)
92 (3aj)
77 (3ak)
97
96
97
98
97
91
96
96
97
96
4-ClC6H4
4-BrC6H4
4-F3CC6H4
3,4-Cl2C6H3
4-MeC6H4
3-MeC6H4
2-MeC6H4
1-Naphthyl
H
9
10[d]
[a] Unless otherwise noted, the reaction was carried out with
3-benzylindolin-2-one 1a (0.10 mmol), propargyl chloride
derivatives 2 (0.25 mmol), Sc(OTf)3/L-PiPr2 (1:1.2, 10
mol%) and K3PO4∙7H2O (0.40 mmol) in CHCl3 (1.0 mL) at
60 C for 16 h.
Encouraged by the results of -propargylation, we
further tested the -allylation and -benzylation of N-
unprotected 3-benzyl-2-oxindoles (Table 4). The
corresponding oxindoles bearing chiral quaternary
[b] Isolated yield.
[c] Determined by chiral HPLC analysis.
[d]
Another portion of 2k (0.25 mmol) was added in the
middle of the reaction.
3
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10.1002/adsc.201800877
Advanced Synthesis & Catalysis
achieved through a simple Friedel−Crafts cyclization
reaction from the -propargyl product without loss of
enantioselectivity.
Experimental Section
L-PiPr2 (7.8 mg, 0.012 mmol or 6.5 mg, 0.010 mmol),
Sc(OTf)3 (4.9 mg, 0.010 mmol) and 3-substituted-2-
oxindole 1 (0.10 mmol) were added to an oven-dried
reaction tube. Then 1.0 mL anhydrous CHCl3 was added
and the solution was stirred at 35 °C for 30 mins.
Subsequently, propargyl, allylic or alkyl chloride 2 or 4
(0.25 mmol) and K3PO4·7H2O (0.40 mmol or 0.80 mmol)
were added and stirred at 60 °C with indicated time. The
reaction mixture was purified by silica gel column
chromatographic (petroleum ether/ethyl acetate = 6:1 or
9:1) to afford the desired products.
Scheme 2. a) Gram-scale version of the reaction. b)
Intramolecular Friedel−Crafts cyclization reaction of the
product 3aa.
Acknowledgements
We appreciate the National Natural Science Foundation of China
(No. 21432006 and 21772127) for financial support.
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Figure 1. The proposed catalytic model.
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and our previous works,10 a possible transition state
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stereoselectivity (Figure 1). The oxygen atoms of N-
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10.1002/adsc.201800877
Advanced Synthesis & Catalysis
COMMUNICATION
Chiral N,N'-Dioxide/Scandium(III)-Catalyzed
Asymmetric Alkylation of N-Unprotected 3-
Substituted Oxindoles
Adv. Synth. Catal. Year, Volume, Page – Page
Changqiang He,a Weidi Cao,a,* Jianlin Zhang,a
Shulin Ge,a Xiaoming Fenga,*
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This article is protected by copyright. All rights reserved.