Enantioselective dicarbofunctionalization of (: E)-alkenyloxindoles with pyridinium salts by chiral Lewis acid/photo relay catalysis

Article abstract of DOI:10.1039/d0cc05621a

A highly efficient enantioselective dicarbofunctionalization reaction of (E)-alkenyloxindoles with pyridinium salts was realized. The process includes the chiral N,N′-dioxide-Sc(iii) complex-catalyzed regio-, diastereo-, and enantioselective [3+2] cycloaddition reaction and the following photo-promoted aza-Norrish II type rearrangement. A series of 2-pyridyl substituted oxindole derivatives were obtained in good yields with moderate to good diastereo- and enantioselectivities. This journal is

Full text of DOI:10.1039/d0cc05621a

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S. J. Connon, M. O. Senge et al.
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Enantioselective dicarbofunctionalization of (E)-alkenyloxindoles
with pyridinium salts by chiral Lewis acid/photo relay catalysis
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
Dong Zhang, Shunxi Dong, Qianwen He, Yao Luo, Yun Liu, Xiaohua Liu* , Xiaoming Feng*
DOI: 10.1039/x0xx00000x
a) Enantioselective pyridine direct ortho-alkylation (Hou's work)ref 3
Sc/L*
A
highly efficient enantioselective dicarbofunctionalization
reaction of (E)-alkenyloxindoles with pyridinium salts was
realized. The process includes the chiral N,Nʹ-dioxide-Sc(III)
complex-catalyzed regio-, diastereo-, and enantioselective [3+2]
cycloaddition reaction and the following photo-promoted aza-
Norrish II type rearrangement. A series of 2-pyridyl substituted
oxindole derivatives were obtained in good yields with moderate
to good diastereo- and enantioselectivities.
R
alkyl
R
[Ph3C][B(C6F5)4]
N
H
N
H

alkyl
ref 4
b) Enantioselective pyridine N-oxides ortho-alkylation (Ge's work)

(
L)Cu-H
Ar
Ar

R
R
N
O
H
N
R

CuL*
Ar
c) Pyridinium ylide ortho-alkylation (Su's work)ref 6
Pyridine-heterocyclic structures are popular among drugs and
1
natural products. In the past few years, developing efficient
H
N
H
h
Br
R
N
R
N
R
methods for the selective ortho-alkylated modification of the
pyridine ring have attracted increasing interest. Among them,
most advances in the alkylation of pyridines only deliver
A
A
[3+2]
e
N
A
AH
R
A = Accepter
photosensitizer biradical species
2
racemic products, and protocols for asymmetric synthesis of
d) Enantioselective 2-pyridylation of (E)-alkenyloxindoles (this work)
chiral ortho-alkylated pyridine derivatives are meager. In 2014,
R
R
R2
R3
R1

Hou and co-workers developed
a Sc-catalyzed direct
N
Blue LEDs
L*-Sc(III)

R
N
enantioselective C−H carbo-2-pyridylation with terminal

Bz
Bz
R2
[3+2]

rearrangement
N


3
R1
R2 R3
alkenes (Scheme 1a). Afterward, Ge and co-workers reported
Bz
R1
a copper-catalyzed enantioselective alkylation of quinoline- or
tetrahydroindolizines
Key Int. (unstable)
Contiguous
stereocenters
R3
4
pyridine N-oxides with vinyl arenes (Scheme 1b). Although
Scheme 1. Representative ortho-alkylation of pyridine derivatives with alkenes.
these approaches have undergone extensive development, the
development of a new practical protocol for the synthesis of dearomative [3+2] cycloaddition of N-benzoyl pyridinium
chiral ortho-alkylated pyridines from readily accessible starting ylides with electron-deficient alkenes afford an intramolecular
7
materials is still highly desirable.
EDA (electron donor-acceptor) complex, which would
Recently, photocatalyzed radical ortho-alkylation of pyridine undergoes an aza-Norrish II type rearrangement to yield
5
has attracted considerable attention, and the direct addition carbo-2-pyridylation products enabled by the photo-induced
of photoexcited radical species to the pyridine ring represents electron transfer process. Previously, our research group have
a useful alternative, however, the pyridine scaffold contains developed an enantioselective [3+2] cycloaddition reaction
multiple reactive sites, and site selective functionalization in successfully to synthesize tetrahydroindolizines by generating
alkyl radical additions remains a longstanding challenge. In the N-acetate pyridinium ylides from -diazoacetate and
8
2
017, Su and co-workers reported a new type photocatalyzed pyridine in situ. Building upon these results, we reasoned that
ortho- alkylation reaction of pyridinium salt (Scheme 1c). A
6
if N-benzoylmethyl pyridinium ylide participates in the [3+2]
cycloaddition, the intramolecular EDA intermediate might be
generated and undergo similar rearrangement to yield 2-
pyridylation-3-benzoylation product as the final product upon
visible-light initiation (Scheme 1d). More importantly, regio-,
diastereo- and enantioselective synthesis of such
a. Key Laboratory of Green Chemistry & Technology Ministry of Education, College
of Chemistry Sichuan University, Chengdu 610064 (China). E-mail:
liuxh@scu.edu.cn; xmfeng@scu.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any dicarbofunctionalized products might be feasible for the
supplementary information available should be included here]. See DOI:
control of stereochemistry of the initial cycloaddition reaction
1
0.1039/x0xx00000x
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Journal Name
with proper chiral catalysts. Herein, we wish to disclose a new in situ were evaluated. Fortunately, the enantioselectivity was
View Article Online
DOI: 10.1039/D0CC05621A
(E)- greatly increased when K CO was used instead of Et N,
2 3 3
formal
asymmetric
dicarbofunctionization
of
alkenyloxindoles, which affords optically active 2-pyridyl providing 4a in 38% yield with 91:9 e.r. (entry 6). Remarkably,
substituted oxindole derivatives by chiral N,N'-dioxide- the reactivity was sharply improved with the slightly
9
scandium(III) complex and photo relay catalysis.
diminished e.r. value when the reaction was performed under
enhanced blue LED lamps from begining to end (entry 7).
Finally, changing the reaction procedure as initiating the
cycloaddition at lower temperature in dark for one day, and
then exciting with blue LED lamps at room temperature led to
significant improvements of both the yield and e.r. (entry 8).
Only one diastereomer 4a was isolated in 93% yield with 96:4
e.r.. It should be mentioned that in the absence of a chiral
Lewis acid catalyst, the racemic product 4a was obtained in
38% yield, revealing the existence of a strong background
reaction under the standard reaction conditions (entry 9).
Besides, trace amount of regioselective product 4a' was also
detected along with the major isomer 4a during the
optimization reaction process.
Table 1. Optimization of the reaction conditions.
Ph
tBuO2C
Ph
N
O
Ligand/Sc(OTf)3
1:1, 10 mol%)
Br
H
O
Br
(
t
N
CO2 Bu
O
+
O
base, solvent
N
H
N
H
+
4a
visible light, r.t.
Br
O
1a
2a
Br
n
n
Ph
N
N
N
N
N
O
O
O
O
H
O
O
O
O
N
N
R
N
R
N
t
H
H
H
H
CO2 Bu
R
R
O
N
H
i
i
4a'
L3-PrPr2: R = 2,6- Pr2C6H3, n = 1 L3-RaPr2: R = 2,6- Pr2C6H3
i
L3-PiPr2: R = 2,6- Pr2C6H3, n = 2 L3-RaAd: R = 1-adamantyl
Minor regioisomer
Entrya
Ligand
Solvent
DCM
Base
Yield (%)b
e.r.c
tBuO2C
Ph
Ph
1
2
3
4
5
6
L
L
L
L
L
L
L
L
3
3
3
3
3
3
3
3
-PrPr
-PiPr
-RaPr
2
Et
Et
Et
Et
Et
3
3
3
3
3
N
N
N
N
N
20
22
26
34
52
38
80
93
38
61:39
51:49
66:34
72:28
73:27
91:9
1. L3-RaAd/Sc(OTf)3
(1:1, 10 mol%)
K2CO3, HCO2Et, 30 °C
N
O
O
Br
Br
H
R1
N
O
t
CO2 Bu
DCM
N
R1
2
O
H
2. Blue LEDs, r.t.
N
Br
H
2
DCM
1a-1k
2a
4a-4k
Ph
Ph
Ph
H
-RaAd
-RaAd
-RaAd
-RaAd
-RaAd
DCM
N
O
N
O
N
O
Br
H
Br
H
Br
HCO
HCO
HCO
HCO
HCO
2
Et
2
Et
2
Et
2
Et
2
Et
Me
MeO
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
O
O
O
N
N
N
K
K
K
K
2
2
2
2
CO
CO
CO
CO
3
3
3
3
H
H
H
4a, 12 h, 93% yield
4b, 12 h, 83% yield
4c, 12 h, 86% yield
7d
87:13
96:4
>
19:1 dr, 96:4 e.r.
>19:1 dr, 95:5 e.r.
>19:1 dr, 95:5 e.r.
8e,f
Ph
Ph
N
O
N
O
2
3
Br
H
Br
H
9
--
50:50
t
2
t
CO2 Bu
3
CO2 Bu
O
O
aUnless otherwise noted, all reactions were carried out with 1a (0.10 mmol), 2a (0.12
N
N
H
MeO
H
mmol), base (0.12 mmol), ligand/Sc(OTf)
3
(1:1, 10 mol%) in solvent (0.1 M) under an
Me
4
>
d, 11 h, 83% yield
19:1 dr, 96:4 e.r.
4e, 26 h, 91% yield
>19:1 dr, 96:4 e.r.
rel-(2S, 3S)-4e
CCDC: 1984207
b
c
intensity of a 23 W LED lamp at room temperature for 10 h. Isolated product. The e.r.
value was determined by HPLC analysis on a chiral stationary phase and all dr values
Ph
Ph
Ph
d
e
were >19:1. At room temperature under blue LED lamps (4 × 20 W) for 10 h. At 30 °C
N
O
N
O
N
O
in dark for 24 h, then at room temperature under blue LED lamps (4 × 20 W) for 10 h.
Br
H
Br
H
Br
H
f
Me
Me
1
a:2a:K
2
CO
3
= 1:1:1.
t
MeO
MeO
t
Me
t
CO2 Bu
CO2 Bu
CO2 Bu
O
O
O
N
N
N
Initially,
the
(E)-alkenyloxindole
(1a)
and
N-
H
H
H
Me
benzoylmethylpyridinium bromide (2a) were selected as the
model substrates to optimize the reaction conditions. In the
4f, 45 h, 98% yield
4g, 45 h, 97% yield
>19:1 dr, 97:3 e.r.
4h, 24 h, 96% yield
>19:1 dr, 97:3 e.r.
>
19:1 dr, 96:4 e.r.
Ph
Ph
Ph
3 3 2
presence of 10 mol% of Sc(OTf) -L -PrPr complex with a 23 W
N
O
N
O
N
O
Br
H
Br
H
Br
H
LED lamp, the desired 2-pyridylation product 4a was formed
albeit with poor yield and enantioselectivity, but the
diastereoselectivity was high (20% yield, >19:1 dr, 61:39 e.r.;
Table 1, entry 1). Then, N,Nʹ-dioxides with varied amino acid
t
t
t
CO2 Bu
CO2 Bu
CO2 Bu
O
O
O
N
N
N
F
Cl
Br
H
H
H
4
>
i, 45 h, 90% yield
19:1 dr, 92:8 e.r.
4j, 12 h, 88% yield
>19:1 dr, 87:13 e.r.
4k, 45 h, 80% yield
>19:1 dr, 88:12 e.r.
3
backbones and amide units coordinated with Sc(OTf) were
examined (entries 2-4). It was found that the e.r. value of 4a 1 (0.10 mmol), 2a (0.10 mmol), L
Scheme 2. Substrate scope of (E)-alkenyloxindoles. All reactions were carried out with
-RaAd/Sc(OTf) (1:1, 10 mol%), K CO (0.10 mmol) in
3
3
2
3
HCO
2
Et (0.1 M) at 30 °C in dark for the indicated time, then under blue LED lamps (4 ×
3
could be increased to 72:28 with the use of L -RaAd (entry 4).
1
2
0 W) at room temperature for 10 h. The dr value was determined by H NMR
Various other common ligands were explored as well to
spectroscopy and the e.r. was determined by HPLC analysis on a chiral stationary
promote this reaction, but poor results were gained (for phase.
details,
With the optimized reaction conditions in hand, the
substrate scope with respect to (E)-alkenyloxindoles was then
investigated (Scheme 2). Oxindole substrates with electron-
donating substituents (R ) on the 5- to 7-positions of the oxindole
were converted to the corresponding products (4b-4h) in good
see Table S2). The reactivity was slightly improved by switching
the reaction medium from DCM to HCO Et, affording the
product in 52% yield with 73:27 e.r. (entry 5). Subsequently,
various bases which was used to generate the pyridinium ylide
2
1
2
| J. Name., 2012, 00, 1-3
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yields with excellent diastereoselectivities and e.r. values. The could be obtained in these cases under the current catalytic
View Article Online
DOI: 10.1039/D0CC05621A
relative configuration of the major diastereomer of the product 4e system (see ESI for details).
1
0
Ph
Ph
was determined to be (2S,3S) by X-ray crystal diffraction analysis.
tBuO C
2
O
1. L3-RaAd/Sc(OTf)3
1:1, 10 mol%)
K CO , HCO Et, 30 C
N
O
Oxindole substrates with electron-withdrawing substituents
provided the products (4i-4k) in good yields with excellent
diastereoselectivities, but lower e.r. values, which might be
attributed to the competition of racemic background reaction.
Br
Br
H
(
N
a)
O
CO2tBu
2
3
2
N
O
H
Br
2. Blue LEDs, r.t.
N
H
1a
2a
4a, 1.25 g, 80% yield
3
.0 mmol, 0.73 g 3.0 mmol, 1.07 g
> 19:1 dr, 94:6 e.r.
The scope of pyridinium salts was next examined under the
optimal reaction conditions. The substituents on pyridine
moiety had a great effect on the nucleophilicity of the
corresponding pyridinium ylides, raising a challenge for
asymmetric induction. As shown in the test results presented
in Scheme 3, halogen-substituted pyridine moieties including
NC
Ph
tBuO2C
3
1. L -RaAd/Sc(OTf)
3
N
O
NC
N
H
(1:1, 10 mol%)
t
Fe(TPP)Cl (5 mol%)
HCO2Et, 30 °C, dark
2. Blue LEDs, r.t.
CO2 Bu
b)
O
O
O
N
N2
N
H
Ph
H
1
a
4n, 43% yield
H
>
19:1 dr, 82:18 e.r.
Ph
H
Ph
4
H
3
-fluoro-, and 3-chloro-substituent were tolerated in this
N
O
N
OH
catalytic system, affording the desired products 4l, and 4m in
good yields, excellent diastereoselectivities, but with slightly
decreased e.r. values. The 4-cyano pyridine derived ylide 2d
underwent the reaction efficiently, providing 4n in 83% yield,
Br
2
NaBH4
MeOH
Br
2
H
3
3
t
t
CO2 Bu
CO2 Bu
c)
O
O
0
°C, 1 h
N
H
N
H
(
2S, 3S, 4S)-5a, 97% yield
CCDC:
2010306
(2S, 3S)-4a, 99:1 e.r.
91/9 dr, 99:1 e.r.
>
19:1 dr and 93:7 e.r.. On the other hand, the substituents on
Ph
5
H
the benzoyl unit of the pyridinium salts have influence on the
reactivity rather than the enantioselectivity. Ylides with
electron-donating or withdrawing substituents at different
position of the benzoyl ring still converted into the
corresponding products smoothly under the standard reaction
conditions, giving the expected
N
3
Br
H
O
3
'
p-TSA
O O
Toluene
0 °C, 3 h
N
6
H
(
3S, 3'S, 5S)-6a
(3S, 3'S, 5S)-6a, 80% yield
CCDC
:
1921882
87/13 dr, 99:1 e.r.
Scheme 4. a) Gram-scale reaction; b) One-pot three-component reaction for the
synthesis of 4a; c) Further transformation of 4a.
Ar
tBuO2C
Ar
R
N
O
To evaluate the synthetic potential of the catalytic system,
gram-scale synthesis of 4a was performed. The (E)-
alkenyloxindole (1a) (3.0 mmol) reacted smoothly with N-
benzoylmethylpyridinium bromide (2a) (3.0 mmol) under the
optimized reaction conditions, supplying the corresponding
product 4a in 80% yield (1.25 g) with >19:1 d.r. and 94:6 e.r.
Scheme 4a). To further show the simplicity and convenience
for synthesis the chiral ortho-alkylated pyridine derivatives, a
bimetallic/photo cascade catalytic system was also introduced
to synthesize the product 4n. As shown in Scheme 4b, in the
presence of a catalytic amount of Fe(TPP)Cl, (TPP =
tetraphenylporphyrin), and chiral N,N'-dioxide-scandium(III)
complex catalyst, one-pot three-component cascade reaction
also worked well. Initially, pyridinium ylide can be generated
in-situ by the reaction of commercially available -
diazoacetophenone and 4-cyanopyridine. Subsequently,
cyclization and rearrangement to afford the product 4n in 43%
yield with >19:1 dr and 82:18 e.r.. Furthermore, the
1
. L3-RaAd/Sc(OTf)3
1:1, 10 mol%)
K2CO3, HCO2Et, 30 °C
. Blue LEDs, r.t.
H
O
Br
(
(s)
O
t
CO2 Bu
O
N
(s)
N
R
N
H
H
2
1a
2b-2j
4l-4t
Ph
H
EtO C
2
4
l, R = 3-F, 60 h
R
N
O
86% yield, >19:1 dr, 89:11 e.r.
tBuO2C
N
4m, R = 3-Cl, 38 h
(
t
94% yield, >19:1 dr, 91:9 e.r.
4n, R = 4-CN, 48 h
83% yield, 90:10 dr, 93:7 e.r.
CO2 Bu
H
O
O
Br
N
N
H
H
3
>
u, 24 h, 91% yield
19:1 dr, 54:46 e.r.
4
9
4
7
4
o, X = 4-Me, 60 h
2% yield, >19:1 dr, 93:7 e.r.
p, X = 4-OMe, 60 h
5% yield, >19:1 dr, 91:9 e.r.
q, X = 4-OEt, 60 h
11
X
O
PhOC
N
N
Ph
N
O
71% yield, >19:1 dr, 91:9 e.r.
r, X = 4-OBn, 60 h
Br
H
4
O
t
81% yield, 10:1 dr, 93:7 e.r.
4s, X = 4-F, 60 h
73% yield, 10:1 dr, 90:10 e.r.
CO2 Bu
Br
O
N
H
4v, 24 h, 53% yield
>19:1 dr, 50:50 e.r.
4t, X = 3-Cl, 60 h
84% yield, >19:1 dr, 89:11 e.r.
Scheme 3. Substrate scope of pyridinium salts. All reactions were carried out
with 1a (0.10 mmol), 2b-2j (0.10 mmol), L -RaAd/Sc(OTf) (1:1, 10 mol%), K CO
0.10 mmol) in HCO
Et (0.1 M) at 30 °C in dark for the indicated time, then dicarbofunctionalized product 4a could be readily reduced
3
3
2
3
(
2
under blue LED lamps (4 × 20 W) at room temperature for 10 h. The dr value was
determined by H NMR spectroscopy and the e.r. value was determined by HPLC
10
4 3
upon treatment with NaBH in CH OH, providing 5a in 97%
1
yield with maintained enantioselectivity. And then the lactone
derivative 6a was isolated in 80% yield with 87:13 d.r. and
good e.r. after the treatment with TsOH (Scheme 4c). The
absolute configuration of the major isomer 6a was
unambiguously determined to be (3S,3'S,5S) by X-ray
analysis on a chiral stationary phase.
products 4o-4t in 71‒92% yields with 89:11 to 93:7 e.r..
Remarkably, when the benzoyl group of pyridinium salt was
place of an ester group, the desired product cannot be
detected, only the cycloadduct 3u was isolated in 91% yield
with low e.r., implying the benzoyl group is essential for the
late stage rearrangement. It should be mentioned that N-
phenylmaleimide and some other pyridinium salts were also
proved to be suitable in this reaction, however, only racemates
1
0
crystallographic analysis.
Therefore, the absolute
configuration of 4a was assigned to be (2S,3S), whose relative
1
0
configuration is in consist with the racemic product.
To gain insight the process of the cascade reaction, some
control experiments were conducted. Firstly, the unstable
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J. Name., 2013, 00, 1-3 | 3
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Journal Name
cycloadduct 3a was isolated successfully at a low temperature to elucidate the obtained stereochemistry. Further studies
View Article Online
DOI: 10.1039/D0CC05621A
and its relative configuration was identified to be
PhOC
about chiral Lewis acid/photo relay catalysis are undergoing in
our lab.
Ph
tBuO2C
N
Br
N
O
H
8a'
3
HCO2Et
r.t.
3'
2'
Conflicts of interest
t
CO2 Bu
H
O
O
Br
N
H
N
H
There are no conflicts to declare.
3a
4a
(
a) 0.10 mmol, 50:50 e.r.
Dark, 10 h: < 3% yield, 50:50 e.r.
Acknowledgements
(b) 0.10 mmol, 50:50 e.r.
Blue LEDs, 10 h: 92% yield, 50:50 e.r.
rel-(2'R,3S,3'R,8a'R)-3a
CCDC: 2009353
We appreciate the National Natural Science Foundation of
China (Nos. 21772127, and 21890723) for financial support.
(c) 0.10 mmol, 95:5 e.r.
Blue LEDs, 10 h: 90% yield, 94:6 e.r.
Notes and references
Br
H
Br
O
O
N
N
1
a) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem.
2014, 57, 5845; b) E. Vitaku, D. T. Smith, J. T. Njardarson, J.
Med. Chem. 2014, 57, 10257.
Ph
N
H
H
H
1
a+2a
K2CO3
O
H
PhOC
H
t
NH
CO2 Bu
tBuO2C
2
For selected reviews on ortho-alkylation of pyridines, see: a)
Y. Nakao, Synthesis 2011, 2011, 3209; b) M. A. J. Duncton,
Med. Chem. Commun. 2011, 2, 1135; c) D. E. Stephens, O. V.
Larionov, Tetrahedron 2015, 71, 8683; for selected examples,
see: d) R. Loska, M. Makosza, Mendeleev Communications
2006, 16, 161; e) R. Loska, M. Makosza, Chemistry 2008, 14,
L-RaAd/Sc(OTf)3
CCDC: 1833190
Ph
anti-ylide
-Si-face attack
ring closure
-Re-face attack
3
a
OH
Ph
O
hv
Ph
N
O
H
Br
cleavage
tBuO2C
N
1,5-H
tBuO2C
N
2
t
3
CO2 Bu
transfer
O
N
H
H
O
Br
Br
N
H
O
N
H
(
2S,3S)-4a
2
1
8
577; f) B. T. Guan, Z. M. Hou, J. Am. Chem. Soc. 2011, 133,
8086; g) X. S. Ma, S. B. Herzon, J. Am. Chem. Soc. 2016, 138,
718; h) W. Zhou, T. Miura, M. Murakami, Angew. Chem. Int.
Scheme 5. Control experiments and the plausible reaction process.
(
2'R,3S,3'R,8a'R) based on the X-ray crystallographic analysis.10
When racemic 3a was stirred in the dark, the desired product
a was formed in only a trace amount as determined by NMR
Ed. 2018, 57, 5139; i) A. Kundu, M. Inoue, H. Nagae, H.
Tsurugi, K. Mashima, J. Am. Chem. Soc. 2018, 140, 7332.
G. Y. Song, W. W. N. O, Z. M. Hou, J. Am. Chem. Soc. 2014,
4
3
4
5
analysis. But when the racemic or enantioenriched 3a was
stirred under Blue LEDs, the product 4a could be isolated in
high yield with the e.r. maintained. These results confirmed
that the cycloadduct was the key intermediate and the late-
stage rearrangement could occur smoothly without the
participation of the chiral Lewis acid. Based on previous
1
36, 12209.
S. J. Yu, H. L. Sang, S. Z. Ge, Angew. Chem. Int. Ed. 2017, 56,
5896.
1
a) J. Jin, D. W. C. MacMillan, Angew. Chem. Int. Ed. 2015, 54,
1565; b) T. McCallum, L. Barriault, Chem. Sci. 2016, 7, 4754;
c) G. X. Li, C. A. Morales-Rivera, Y. X. Wang, F. Gao, G. He, P.
Liu, G. Chen, Chem. Sci. 2016, 7, 6407; d) R. A. Garza-
Sanchez, A. Tlahuext-Aca, G. Tavakoli, F. Glorius, ACS Catal.
6
,8
reports , control experiments, the structural information of
the product and the chiral catalyst, a possible mechanism was
proposed to describe the process (Scheme 5). Mechanistically,
a stepwise mechanism via zwitterionic intermediates was
involved in the [3+2] cycloadditions of pyridinium ylides with
2
017, 7, 4057; e) J. K. Matsui, D. N. Primer, G. A. Molander,
Chem. Sci. 2017, 8, 3512; f) J. Jeon, Y. T. He, S. Shin, S. Hong,
Angew. Chem. Int. Ed. 2020, 59, 281; g) G. R. Mathi, Y. Jeong,
Y. Moon, S. Hong, Angew. Chem. Int. Ed. 2020, 59, 2049; h) Y.
Moon, W. Lee, S. Hong, J. Am. Chem. Soc. 2020, 142, 12420.
R. B. Hu, S. Sun, Y. J. Su, Angew. Chem. Int. Ed. 2017, 56,
1
2
electron-deficient alkenes. In the first asymmetric cyclization
step, the ylide and (E)-alkenyloxindole bond to Sc(III) center of
the chiral catalyst with their carbonyl groups, one positioned
above the other. Due to the steric hindrance, the nucleophilic
moiety of pyridinium ylide could only attacked from the -Si
face of 1a with its -Re-face, followed by ring closing to
provide the key intermediate 3a with four stereogenic centers.
And then, a radical process might be involved in the next
rearrangement. 3a absorbs blue light to generate a biradical
intermediate though an intramolecular SET process, followed
6
7
1
0877.
a) M. Nappi, G. Bergonzini, P. Melchiorre, Angew. Chem. Int.
Ed. 2014, 53, 4921; b) E. Arceo, A. Bahamonde, G.
Bergonzini, P. Melchiorre, Chem. Sci. 2014, 5, 2438.
D. Zhang, L. L. Lin, J. Yang, X. H. Liu, X. M. Feng, Angew.
Chem. Int. Ed. 2018, 57, 12323.
8
9
For selected examples on N,N'-dioxide-scandium(III)
complex, see: a) Y. Xia, X. H. Liu, H. F. Zheng, L. L. Lin, X. M.
Feng, Angew. Chem. Int. Ed. 2015, 54, 227; b) Y. Xia, L. L. Lin,
F. Z. Chang, Y. T. Liao, X. H. Liu, X. M. Feng, Angew. Chem. Int.
Ed. 2016, 55, 12228.
1
3
by
a
formal aza-Norrish II cleavage , keto-enol
1
0 CCDC 1984207 (4e); 2010306 (5a); 1921882 (6a); 1992675
tautomerization to afford the final product 4a. The
stereochemistry of the product 4a depends on the first
asymmetric cycloaddition of 1a with pyridinium ylide. The
stereogenic centers generated from the ylide unit depleted,
and the other two from (E)-alkenyloxindole addition
transferred to the final dicarbofunctionalized product.
In summary, dicarbofunctionalization reactions of (E)-
alkenyloxindoles with pyridinium ylides was presented via
regio-, diastereo- and enantioselective [3+2] cycloaddition and
visible-light-initiated rearrangement sequence. Chiral N,Nʹ-
(4a); 2009353 (3a) contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre.
1
1
1 J. Li, L. L. Lin, B. W. Hu, P. F. Zhou, T. Y. Huang, X. H. Liu, X. M.
Feng, Angew. Chem. Int. Ed. 2017, 56, 885.
2 a) D. S. Allgäuer, P. Mayer, H. Mayr, J. Am. Chem. Soc. 2013,
135, 15216; b) D. S. Allgäuer, H. Mayr, Eur. J. Org. Chem.
2013, 28, 6379.
3 a) J. Mal, R. V. Venkateswaran, J. Org. Chem. 1998, 63, 3855;
b) P. J. Hickford, J. R. Baker, I. Bruce, K. I. Booker-Milburn,
Org. Lett. 2007, 9. 4681; c) D. Alvarez-Dorta, E. I. Leon, A. R.
Kennedy, C. Riesco-Fagundo, E. Suarez, Angew. Chem. Int.
Ed. 2008, 47, 8917.
1
dioxide/Sc(OTf)
3
complex has been shown to be an effective
catalyst for the synthesis of ortho-pyridylated derivatives in
moderate to good results (up to 97% yield, >19:1 dr and 97:3 14
e.r.). A possible stepwise reaction process was also proposed
4
| J. Name., 2012, 00, 1-3
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R3
DOI: 10.1039/D0CC05621A
R3
Br
R2
tBuO2C
N
O
1
. L3-RaAd/Sc(OTf)3
2
H
O
N
N
3
t
O
(
s)
CO2 Bu
O
R1
O
O
(1:1, 10 mol%)
K2CO3, HCO2Et
dark, -30 °C
R1
(s)
O
O
+
N
N
N
N
N
R
H
H
R
H
R2
H
2. Blue leds, r.t.
20 examples
up to 97% yield
19:1 dr, up to 97:3 e.r.
L3-RaAd: R = 1-adamantyl
>
A highly efficient asymmetric dicarbofunctionalization reaction of (E)-alkenyloxindoles with
pyridinium salts was developed under mild conditions.