Asymmetric Synthesis of 3-Allyloxindoles and 3-Allenyloxindoles by Scandium(III)-Catalyzed Claisen Rearrangement Reactions

Article abstract of DOI:10.1002/cjoc.201700486

Scandium-catalyzed asymmetric Claisen rearrangement reactions of 2-allyloxyindoles and 2-propargyloxyindoles provide a novel approach to diverse 3-allyloxindoles and 3-allenyloxindoles in excellent yields (up to 99%) and enantioselectivity (up to 99% ee)

Full text of DOI:10.1002/cjoc.201700486

Asymmetric Synthesis of 3-Allyloxindoles and 3-Allenyloxindoles by
Scandium(III)-catalyzed Claisen Rearrangement Reactions
Zeng-Wei Lai1,2, Chuan Liu1, Hongbin Sun2*, and Shu-Li You1*
1State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China.
2State Key Laboratory of Natural Medicines and Center of Drug Discovery, China Pharmaceutical University, 24 T
ongjia Xiang, Nanjing 210009, China.
*
E-mail: slyou@sioc.ac.cn, or hbsun2000@yahoo.com; Tel.: telephone number ((optional)); Fax: (+86) 21-54925087
Received ((will be filled in by the editorial staff)); accepted ((will be filled in by the editorial staff)); published online XXXX, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.2013xxxxx or from the author. ((Please delete
if not appropriate.)).
Dedicated to … on the Occasion of … ((optional))
Scandium-catalyzed
asymmetric
Claisen
rearrangement
reactions
of
2-allyloxyindoles
and
2-propargyloxyindoles provide a novel approach to diverse 3-allyloxindoles and 3-allenyloxindoles in excellent
yields (up to 99%) and enantioselectivity (up to 99% ee) under mild reaction conditions. The scandium catalyst was
derived from Sc(OTf)3 and Pybox ligand.
Keywords allene, asymmetric catalysis, Pybox, rearrangement, scandium
Introduction
In 2008, Kozlowski and coworkers accomplished an
asymmetric version with good enantioselectivity
employing the [Pd(tBu-Phox)](SbF6)2 complex as Lewis
acid catalyst.13a,b As a substantial extension of the work,
The oxindoles that incorporate
a
quaternary
stereocenter at the C3 position exist widely in natural
products1 and bioactive compounds2 (Figure 1) which
show significant pharmaceutical properties. Therefore,
these motifs have attracted considerable attention and
have served as key intermediates for the synthesis of
indole alkaloids.3 The catalytic asymmetric construction
of a quaternary stereocenter is one of the most
challenging and dynamic research fields in modern
organic synthesis.4 Hence, the enantioselective synthesis
of 3,3’-disubstituted oxindoles bearing a tetrasubstituted
stereogenic center has been the most prevailing
synthetic subject in the past few years,5 and dozens of
methods (nucleophilic addition to isatins,6 direct
functionalization of oxindoles,7 Heck reaction,8
cyanoamidation,9 arylation,10 acyl migration11) have
been developed to construct different kinds of
3,3’-disubstituted oxindole motifs including all-carbon
and heteroatom-containing substituents. Although
significant advances have been achieved, there are only
two examples of asymmetric synthesis of
3-ester-3-allyloxindoles.12,13
they reported the same reaction using
a
substoichiometric Cu(II)-Box catalysts, but only
moderate enantioselectivities were obtained.13c Despite
the elegance of Kozlowski’s approach, two precious
metals (Ag and Pd) are needed and special care (in the
dark) should be taken during the preparation of the
catalyst. Based on the known Lewis acid mediated
Figure 1. Selected natural products and bioactive compounds
(The core structure or synthetic intermediate of these indole al-
kaloids is the 3,3’-disubstituted oxindole motif).
activation of Claisen rearrangements,15 we envisaged
that Sc(OTf)3-Box complex, prepared easily, might be a
In 2006, Trost and Brennan utilized the Pd-catalyzed
asymmetric allylic alkylation reaction to yield
3-ester-3-allyloxindoles, however, the substrates
required
a
multi-step
synthesis.
In
2000,
Booker-Milburn, Fedouloff and their coworkers
developed a Claisen rearrangement of 2-allyloxyindoles
suitable catalyst. Herein, we report
a
highly
enantioselective synthesis of 3-allyl oxindoles and
3-allenyl oxindoles via scandium-catalyzed Claisen
rearrangement reactions of 2-allyloxyindoles and
and
2-propargyloxyindoles
to
synthesize
3-allyloxindoles and 3-allenyloxindoles respectively.14
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2-propargyloxyindoles, respectively.
13-14, Table 1). Lowering the catalyst loading led to a
decline in both yield and enantioselectivity (51% yield,
80% ee, entry 15, Table 1). Interestingly, we found that
substrate concentration could also affect the reactivity
and enantioselectivity significantly (entries 16-18, Table
1). Finally, the best conditions were obtained as the
following: 1a in DCE (0.05 M), 30 mol % of Sc(OTf)3,
33 mol % of L7, 200 mg 4Å MS at rt. Under the
optimization conditions, product 2a was obtained in 92%
yield and 91% ee (entry 17, Table 1). The absolute
configuration of the product was assigned as (R) by
comparing the sign of the optical rotation with that
reported in the literature. 13a
Experimental
General Procedure for Asymmetric Rearrangement
Reaction of Allyloxy- and Propargyloxy Indoles:
To a flame-dried Schlenk tube were added 4Å MS
(200 mg), Sc(OTf)3 (22.1 mg, 0.045 mmol), L7 (19.5
mg, 0.0495 mmol) and DCE (2 mL). After stirring the
suspension at rt for 1 h, a solution of 1a (36.8 mg, 0.15
mmol) in DCE (1 mL) was added. The mixture was
stirred at rt for 12 h prior to quenching with saturated
NaHCO3 (5 mL) and extracting with EtOAc (3 x 10
mL). The combined organic phases were washed with
brine, dried over anhydrous Na2SO4, filtered and con-
centrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography
(PE/EtOAc=30:1) to afford 2a as a white solid (33.9 mg,
92% yield).
Table 1 Optimization of the reaction conditions.a
General Procedure for Asymmetric Rearrangement
Reaction of Propargyloxy Indoles:
To a flame-dried Schlenk tube were added 4Å MS
(200 mg), Sc(OTf)3 (3.69 mg, 0.0075 mmol), L7 (3.24
mg, 0.008 mmol) and DCE (2 mL). After stirring the
suspension at rt for 1 h, a solution of 3g (45.8 mg, 0.15
mmol) in DCE (1 mL) was added. The mixture was
stirred at rt for 60 min prior to quenching with saturated
NaHCO3 (5 mL) and extracting with EtOAc (3 x 10
mL). The combined organic phases were washed with
brine, dried over anhydrous Na2SO4, filtered and con-
centrated under reduced pressure. The residue was puri-
fied by silica gel column chromatography (PE/ EtOAc
=30:1) to 4g as a white solid (43.9 mg, 96% yield).
temp time
(oC) (h)
yield
(%)b
50
entry ligand additive
sol. con.(M)
ee (%)c
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L7
L7
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
3Å MS
5Å MS
rt
rt
rt
rt
rt
rt
rt
rt
rt
48
48
15
48
48
48
24
24
24
DCE 0.017
DCE 0.017
DCE 0.017
DCE 0.017
DCE 0.017
DCE 0.017
DCE 0.017
DCE 0.017
DCE 0.017
DCM
0
52
2
85
47
31
13
2
51
50
Results and Discussion
57
78
86
79
77
At the outset, we utilized the well-developed
Sc-complex including Sc(OTf)3 and the Box ligand as
catalyst16 and chose 1a as a substrate to investigate the
reaction conditions (Table 1). In the presence of 30 mol %
Sc(OTf)3, 33 mol % L1 and 4 Å molecular sieves (MS)
in DCE at room temperature, the reaction proceeded
smoothly to afford the desired rearrangement product 2a
in 50% yield within 48 hours but with no
enantioselective control (entry 1, Table 1). To improve
the enantioselectivity of the reaction, various chiral
ligands were tested. As illustrated in Table 1, ligands L2
and L6 could be used to promote the reaction with
moderate conversions, but with poor enantioselective
control. With ligands L3, L4 and L5, the reaction
occurred smoothly with moderate enantioselectivity
(13-47% ee, entries 3-5, Table 1). To our great delight,
when inda-pybox (L7) was employed, the reaction gave
the best enantioselectivity (86% ee, entry 7, Table 1).
With L7 as the optimal ligand, we examined molecular
sieves as the additive and found that 4 Å MS was the
best (entries 7-9, Table 1). Next, various solvents were
used, and DCE gave the best result (entries 10-12, Table
75
73
10
L7
4Å MS
rt
14
70
25
76
0.017
toluene 0.017
11
12
13
14
15d
16
17
18
L7
L7
L7
L7
L7
L7
L7
L7
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
4ÅMS
4 Å MS
rt
rt
48
24
16
48
24
24
10
24
31
33
60
82
80
89
91
85
CHCl3 0.017 60
50
0
DCE 0.017
DCE 0.017
DCE 0.017
DCE 0.033
DCE 0.05
DCE 0.067
80
15
51
85
92
rt
rt
rt
rt
71
a Reagents and conditions: 0.15 mmol 1a, 30 mol % Sc(OTf)3, 33
mol % ligand, 200 mg additive. b Isolated yield. Determined by
c
HPLC analysis. d With 20 mol % Sc(OTf)3 and 22 mol % L7.
Under the above optimized reaction conditions, the
substrate scope was explored to examine the generality
of the rearrangement process. As summarized in
Scheme 1, the method was general for different kinds of
2-allyloxyindoles (89-97% yield, 68-96% ee).
Substrates bearing various substituents on the different
positions of the indole core (5-F, 5-Br, 5-MeO, 5-Me,
6-Cl, 6-Br, 7-Me), regardless of their electronic nature,
o
o
1). Varying the reaction temperature to 0 C and 50 C
led to decreased yields and enantioselectivity (entries
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were well tolerated, providing the corresponding
rearrangement products in excellent yields and ee values
(93-97% yield, 90-96% ee). With respect to the C3 ester
group, excellent enantioselectivities were obtained
regardless of the size of the ester (methyl, ethyl and
isopropyl ester). Notably, enantioselectivities were
decreased when the methyl group at the allyl C2’
position was replaced with an H atom (2m and 2n, 68%
ee and 74% ee, respectively).
tolerated. In all cases, the reactions proceeded rapidly to
afford 3-allenyloxindole products in excellent yields and
enantioselectivity (95-99% yield, 94-99% ee) within 10
min to 12 h. It is worthy mentioned that the catalyst
loading could be reduced to 5 mol% from the original
30 mol%. Particularly, the rearrangement reaction of
substrate 4n afforded the desired product in 95% yield
and 87% ee even with only 1 mol% catalyst.
Scheme 2. Substrate scope for asymmetric rearrangement of
propargyloxy-substituted indoles. a
Scheme 1. Substrate scope for asymmetric rearrangement of
allyloxyindoles. a
Sc(OTf)3 (30 mol %)
COOR
O
ROOC
L7 (33 mol %)
4 Å MS
R1
X
R1
X
O
DCE (c = 0.05 M)
rt
N
N
H
2
H
1
MeOOC
EtOOC
iPrOOC
MeOOC
O
O
O
O
N
N
H
N
N
Cl
H
H
H
2a, 92% yield, 91% ee 2b
2c
2d, 96% yield, 94% ee
, 95% yield, 92% ee
, 95% yield, 92% ee
MeOOC
MeOOC
O
MeOOC
O
EtOOC
F
Br
O
O
N
N
N
N
Br
Br
H
H
H
H
2g, 94% yield, 92% ee 2h, 95% yield, 94% ee
MeOOC
EtOOC
2e
2f
, 94% yield, 95% ee
, 97% yield, 95% ee
MeOOC
O
MeOOC
MeO
O
O
O
N
N
N
N
H
H
H
H
2i, 94% yield, 92% ee
2j, 97% yield, 90% ee 2k
2l
, 93% yield, 95% ee
, 95% yield, 96% ee
iPrOOC
MeOOC
O
O
N
N
H
H
2n, 89% yield, 74% ee
2m, 91% yield, 68% ee
a
All reactions were performed on a 0.15 mmol scale of 1 with
Sc(OTf)3 (0.045 mmol), L7 (0.0495 mmol), 4 Å MS (200 mg), 3
mL DCE (0.05 M) at room temperature for 12 h. The yields are
those of the isolated products and the ee values were determined
by HPLC analysis.
Allenes have been demonstrated as extremely im-
portant intermediates in organic synthesis.17,18 To further
broaden the application of the catalytic system,
2-propargyloxyindole substrates were also tested to af-
ford the corresponding 3-allenyloxindole products
(Scheme 2). Under the above reaction conditions, the
substrates with H- and TMS-substituted alkyne dis-
played low reactivity. However, moderate conversions
and ee values were obtained even after several days at
a
All reactions were performed on a 0.15 mmol scale of 3, 4 Å
a
MS (200 mg), 3 mL DCE (0.05 M). 30 mol % Sc(OTf)3 , 33
mol % L7, 40 C. 30 mol % Sc(OTf)3 , 33 mol % L7, rt.
mol % Sc(OTf)3 , 5.5 mol % L7, rt. 20 mol % Sc(OTf)3 , 22
mol % L7, rt. e 1 mol % Sc(OTf)3 , 1.1 mol % L7, rt.
o
b
c
5
d
To evaluate the practicality of the catalytic process, a
gram-scale reaction was carried out. As shown in
Scheme 3, product 4g could be obtained in 98% yield
and 99% ee.
o
40 C (4a, 4b, 67-72% yield, 30-72% ee). In general,
the enantioselectivity and reactivity steadily increased
as the size of the alkyl groups at R2 increased (4c-4e, 89%
ee to 93% ee). However, the substrate bearing a t-Bu
substituent resulted in a slightly lower enantioselectivity
(4f, 79% ee). To be noted, substrate (3e) with the cyclo-
propyl substituent displayed the best reactivity, along
with rapid conversion (2 h) under low catalyst loading
(from 30 mol % to 5 mol %). For the aryl-substituted
alkynes, with methyl or bromide group at the different
Scheme 3. A gram-scale synthesis of 4g.
positions of the indole core or phenyl ring were well
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Several transformations were carried out to
demonstrate the utility of the 3-allyloxindoles products.
For example, oxidative cleavage of the double bond of
2a with ozone afforded 5, furnishing a carbonyl
functional group (Scheme 4, a). The enantioenriched
product 2i was converted into 6 after Pd/C mediated
hydrogenation reaction (Scheme 4, b). The
bromo-containing product 2g underwent the Suzuki
coupling reaction with PhB(OH)2 in the presence of 5
mol % Pd(OAc)2, 10 mol % SPhos and 2 equiv of
K3PO4 (Scheme 4, c).
Scheme 4. Transformation of the rearrangement products.
Conclusions
In conclusion, an efficient enantioselective synthesis
of 3-allyloxindole and 3-allenyloxindole via scandi-
um-catalyzed Claisen rearrangement of 2-allyloxyindole
and 2-propargyloxyindole derivatives, respectively, has
been developed. The notable features of these reactions
include simple operational procedure, mild reaction
conditions, high reactivity and enantioselectivity, and
broad functional group compatibility. Moreover, the
enantioenriched rearrangement products can be used as
versatile precursors to construct useful chiral building
blocks. Further application of the products obtained here
is underway in our laboratory.
Acknowledgement ((optional))
We thank the National Key R&D Program of China
(2016YFA0202900), National Basic Research Program
of China (2015CB856600), the NSFC (21332009,
21421091), Program of Shanghai Subject Chief Scien-
tist (16XD1404300), and the CAS (XDB20000000,
QYZDY-SSW-SLH012) for generous financial support.
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Entry for the Table of Contents
Page No.
Asymmetric
3-Allyloxindoles
3-Allenyloxindoles
Synthesis
by
of
and
Scandi-
um(III)-catalyzed Claisen Rearrange-
ment Reactions
Zeng-Wei Lai, Chuan Liu,
Hongbin Sun*, and Shu-Li
You*
This article is protected by copyright. All rights reserved.