Copper-catalyzed enantioselective Friedel-Crafts alkylation of pyrrole with isatins

Article abstract of DOI:10.1021/ol501086q

The highly enantioselective Friedel-Crafts alkylation of pyrrole with isatins catalyzed by the tridentate Schiff base/Cu catalyst was developed. Hexafluoroisopropanol (HFIP) was used as a crucial additive to improve the enantioselectivity. In the case of N-unprotected isatins, an innovative substrate slow-releasing strategy was applied by virtue of a Henry/retro-Henry reaction.

Full text of DOI:10.1021/ol501086q

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Enantioselective Friedel−Crafts Alkylation of
Pyrrole with Isatins
†
†
Chong Li, Fengfeng Guo, Kun Xu, Sheng Zhang, Yanbin Hu, Zhenggen Zha, and Zhiyong Wang*
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry & Collaborative
Innovation Center of Suzhou Nano Science and Technology, University of Science and Technology of China, Hefei, 230026, P. R.
China
*
S Supporting Information
ABSTRACT: The highly enantioselective Friedel−Crafts alkyla-
tion of pyrrole with isatins catalyzed by the tridentate Schiff base/
Cu catalyst was developed. Hexafluoroisopropanol (HFIP) was
used as a crucial additive to improve the enantioselectivity. In the
case of N-unprotected isatins, an innovative substrate slow-
releasing strategy was applied by virtue of a Henry/retro-Henry
reaction.
ptically active 3-substituted 3-hydroxy-2-oxindole is an
important structural unit which exists in a vast array of
achieve the construction of chiral 3-substituted 3-hydroxy-2-
oxindoles, chiral tridentate Schiff base/metal complex catalyzed
Friedel−Crafts alkylation of pyrrole with isatins was inves-
tigated in our laboratory.
O
natural products and drug candidates, such as Dioxibrassinine,
1
Maremycin B, and SM-130686 (Figure 1). A number of
Initially, N-methylisatin 1a and pyrrole 2a were chosen as
reaction substrates (Table 1), with our previously established
5a
Schiff base/Zn complex (catalyst A) or Schiff base/Cu
5b
complex (catalyst B) as chiral catalysts. Different solvent
systems were tested for this reaction (Table 1, entries 1−5).
When catalyst A was used, THF was the best solvent to afford
product 3a in 90% yield with 70% ee, while, in the case of
catalyst B, dichloromethane was the best choice with a yield of
9
6% and an enantiomer excess of 77% respectively. To further
Figure 1. 3-hydroxy-2-oxindole structural motif in natural products
and drug candidates.
improve the enantioselectivity of this reaction, 1,1,1,3,3,3-
hexafluoro-2-propanol (HFIP) was selected as an additive for
this reaction (Table 1, entries 6−8). When 20 μL of HFIP
were added to the reaction mixture and catalyst B was
employed, the ee value could be significantly enhanced to 99%
6
elegant synthetic strategies have been reported for the
2
construction of these useful structures, of which catalytic
asymmetric addition of isatins with various nucleophiles has
emerged as one of the most attractive methods since isatins are
(
Table 1, entry 6). Notably, this reaction proceeded at the C2-
position of pyrrole exclusively to give the corresponding
optically active 3-substituted 3-hydroxy-2-oxindoles.
3
readily available substrates in organic synthesis. Recent
publications indicated that asymmetric Friedel−Crafts alkyla-
tion of isatins with electron-rich aromatic compounds could
give biologically interesting chiral 3-aryl-3-hydroxy-2-oxindoles
efficiently with high ee values. However, successful catalysts are
limited to chiral metal−pybox complexes and cinchona alkaloid
With the optimal conditions in hand, the scope of this
reaction was investigated (Table 2). N-Methylisatins with
different substituents at the 5-, 6-, or 7-positions could react
with pyrrole smoothly to give the corresponding products in
over 90% ee’s with almost quantitative yields (Table 2, entries
4
derivatives, and the results were not always satisfactory. As far
1
−9). In a previous report, shifting the substituent group to the
as we know, only one successful example of asymmetric
4
-position of N-methyl isatin had an unfavorable effect on the
Friedel−Crafts alkylation of isatins with pyrroles has been
4d
4d
reactivity, even to the extent no reaction occurred. Now
under our catalytic system, 3k could be isolated in 94% yield
with 82% ee after 24 h (Table 2, entry 11). When N-benzyl
isatin was used instead of N-methyl isatin, it reacted readily
reported by the Franz group. As a result, developing new
catalytic systems with a broad substrate scope and simple
manipulations is still highly required.
In our previous studies, we found that chiral tridentate Schiff
base/metal complexes could successfully catalyze the Friedel−
5
Crafts alkylation of indoles or pyrroles with nitroalkenes. To
Received: April 15, 2014
further explore the catalytic potential of these complexes and
©
XXXX American Chemical Society
A
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Organic Letters
Letter
Table 1. Optimization of Reaction Conditions for the
Friedel−Crafts Alkylation of Pyrrole with N-Methylisatin
with pyrrole to give the product 3l in excellent yield with
excellent enantioselectivity (Table 2, entry 12).
However, when unprotected isatins were used as substrates
under the optimal reaction conditions, the reactions were
completed within 3 h, only giving moderate enantioselectivity
a
(
Table 2, entries 13−15). The poor enantioselectivity was
probably due to the severe background reactions with
unprotected isatins. The conventional strategy of lowering
7
the temperature led to a diminished enantioselectivity under
our catalytic system (Scheme 1). This is perhaps due to the
Scheme 1. Asymmetric Friedel−Crafts Alkylation of Isatin
a
with Pyrrole at Different Temperatures
b
c
catalyst A
catalyst B
d
e
d
e
entry
solvent
toluene
yield (%)
ee (%)
yield (%)
ee (%)
1
2
3
4
5
80
93
90
98
96
99
97
98
56
34
70
39
60
18
5
85
96
90
97
98
96
99
99
60
77
25
58
−7
99
78
33
CH Cl2
2
THF
CH CN
3
i-PrOH
a
f
The reactions were carried out with isatin (0.3 mmol), pyrrole (0.45
6
toluene
f
mmol), catalyst B (5 mol %), and HFIP (20 μL) in 1.0 mL of toluene
at room temperature for 12 h. The yields were isolated yields, and the
ee values were detected by HPLC analysis on chiral stationary phase.
7
CH Cl2
2
f
8
THF
10
a
The reactions were carried out with 1a (0.3 mmol) and 2a (0.45
b
mmol) in 1.0 mL of solvent at room temperature for 12 h. Catalyst A:
in situ generated from Zn(OTf) (0.03 mmol), ligand (0.03 mmol),
and piperidine (0.09 mmol). Catalyst B: preformed catalyst from
2
lower temperature making the dimer catalyst more difficult to
dissociate into an active monomeric catalyst. To avoid the
racemic background reaction, we decided to employ a substrate
slow-releasing strategy, in which isatin can first react with a
reagent to afford an intermediate, and then the intermediate
can release isatin slowly to give a low concentration of isatin.
How to realize this strategy and control the concentration of
isatin in situ? With this question in mind, the Henry reaction
c
CuBr2 (0.015 mmol), ligand (0.015 mmol), and piperidine (0.03
d
e
mmol). Isolated yield. Detected by chiral HPLC analysis on chiral
f
stationary phase. Performed with HFIP (20 μL).
Table 2. Reaction Scope of the Enantioselective Friedel−
a
Crafts Alkylation of Isatins with Pyrrole
8
entered into our consideration. Under acidic or basic
conditions, aldehydes or ketones can react with nitromethane
to form the corresponding nitroalcohols. On the other hand,
several studies disclosed that this process was reversible under
appropriate conditions. As a result, aldehydes or ketones could
R1
R2
b
c
6d
entry
product
yield (%)
ee (%)
also be released from the corresponding nitroalcohols.
1
2
3
4
5
6
7
8
9
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Bn
3a
3b
3c
3d
3e
3f
96
97
99
95
97
98
98
97
96
96
94
97
99
91
95
99
98
99
98
91
94
99
99
99
88
82
95
69
63
56
By virtue of this Henry/retro-Henry process, we elaborated a
retro-Henry reaction to modulate the concentration of the
isatin in the reaction. In our experiment, we added a catalytic
amount of diethylamine to a solution of isatin in nitromethane.
The corresponding nitroalcohol was obtained in a quantitative
yield in less than 5 min. Diethylamine and excess nitromethane
were removed under reduced pressure. The nitroalcohol was
further dissolved in toluene, and then catalyst B, HFIP, and
pyrrole were added into the nitroalcohol solution subsequently.
As expected, a retro-Henry reaction proceeded smoothly to
release isatin slowly, which was used as the substrate for the
consequent enantioselective Friedel−Crafts alkylation with
pyrrole. To our delight, by using this strategy, the ee values
of 3m−3o could be enhanced to 93%−99% after 36 h (Scheme
2). It was worth mentioning that these processes were carried
out in one pot starting from isatins.
5-F
5-Cl
5-Br
5-I
5-NO2
5-CH3
6-Br
3g
3h
3i
7-Br
10
11
12
13
14
15
7-CF3
4,7-dichloro
H
3j
d
e
f
3k
3l
H
H
3m
3n
3o
f
5-CH3
5-Br
H
f
H
a
The reactions were carried out with 1 (0.3 mmol), 2a (0.45 mmol),
HFIP (20 μL) in 1.0 mL of toluene at room temperature for 12 h.
Isolated yield. Detected by HPLC analysis on chiral stationary phase.
The reaction time is 24 h. The reaction time is 1 h. The reaction
time is 3 h.
To further investigate the substrate scope and the reaction
mechanism, a few other electron-rich heteroaryls were tested
b
c
d
e
f
(
Scheme 3). The reaction of N-methylisatin with indole could
gave the adduct 3p in 96% yield with 45% ee. 3,4-Disubstituted
pyrrole 2q was also an applicable substrate for this
enantioselective alkylation, which could give 5-alkylated
B
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Organic Letters
Letter
Scheme 2. Slow Release of Isatin by Using Henry/retro-
a
Henry Strategy
Figure 2. A hypothetical action mode of the transition state of the
asymmetric Friedel−Crafts alkylation of N-methylisatin with pyrrole.
a
pyrrole with isatins. A variety of 3-substituted 3-hydroxy-2-
oxindoles were synthesized in high yields and excellent
enantioselectivities under mild conditions. For N-unprotected
isatins, a novel and efficient substrate slow-releasing strategy
was employed to achieve high enantioselectivities. Applications
of this catalytic system as well as the substrate slow-releasing
strategy to other asymmetric reactions are ongoing in our
group.
The reactions were carried out with 5-substituted isatins (0.3 mmol),
diethylamine (25 μL) in nitromethane (3 mL) for 5 min. Then the
reactions were performed with the corresponding nitroalcohols,
catalyst B (5 mol %), and HFIP (20 μL) in 1.0 mL of toluene at
room temperature for 36 h.
Scheme 3. Scope of the Asymmetric Friedel−Crafts
Alkylation of N-Methylisatin with Other Heteroaryls
ASSOCIATED CONTENT
Supporting Information
■
*
S
Details of experimental procedures, spectroscopic data, and
physical properties of new compounds can be found in this
material. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: zwang3@ustc.edu.cn.
Author Contributions
†
These authors contributed equally.
Notes
The authors declare no competing financial interest.
a
The reaction was carried out with 1a (0.3 mmol), indole (0.45
ACKNOWLEDGMENTS
■
mmol), catalyst B (5 mol %), and HFIP (20 μL) in 1.0 mL of toluene
at room temperature for 8 h. The yield was isolated yield, and the ee
value was detected by HPLC analysis on chiral stationary phase. The
reactions were carried out with 1a (0.3 mmol), 2b or 2c (0.45 mmol),
catalyst B (5 mol %), and HFIP (20 μL) in 1.0 mL of toluene at room
temperature for 8 h. The yields were isolated yields, and the ee values
were detected by HPLC analysis on chiral stationary phase.
The authors are grateful to the National Nature Science
Foundation of China (2127222, 91213303, 21172205,
J1030412).
b
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Letter
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D
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