Highly diastereoselective oxa-[3+3] cyclization with C,N-cyclic azomethine imines: Via the copper-catalyzed aerobic oxygenated CC bond of indoles

Article abstract of DOI:10.1039/c7cc09640b

Herein, a copper-catalyzed highly diastereoselective aerobic oxygenated [3+3] cyclization of 3-substituted indoles with C,N-cyclic azomethine imines using oxygen as the sole oxidant under mild conditions has been developed. This protocol provides a simple and convenient approach for constructing [2,3]-fused indoline O-heterocycles bearing two pharmaceutically intriguing parts, tetrahydroisoquinoline and indoline. Good yields and excellent diastereoselectivity under mild reaction conditions were observed.

Full text of DOI:10.1039/c7cc09640b

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Highly Diastereoselective Oxa-[3+3] Cyclization with C, N-Cyclic
Azomethine Imines via Copper-Catalyzed Aerobic Oxygenated C=C
Bond of Indoles
Received 00th January 20xx,
Accepted 00th January 20xx
Lemao Yu,a Yuan Zhong, ab Jicong Yu,a Lu Gan,a Zhengjun Cai,a Rui Wang b and Xianxing Jiang*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein,
a copper-catalyzed highly diastereoselective aerobic
oxygenated [3+3] cyclization of 3-substituted indoles with C,N-
cyclic azomethine imines using oxygen as the sole oxidant under
mild condition has been developed. This protocol provides a
simple and convenient approach for constructing [2,3]-fused
indoline O-heterocycles bearing the two pharmaceutically
intriguing parts, tetrahydroisoquinoline and indoline. Good yield
and excellent diastereoselectivity under mild reaction conditions
were observed.
Indolines and tetrahydroisoquinolines (THIQs) have drawn
much attention in industrial and academic research due to
their privileged structural motifs in bioactive natural products
and pharmaceuticals.1-4 As a consequence, a considerable
number of catalytic strategies dedicated to the preparation of
either
polycyclic
indolines5
or
C1-functional
tetrahydroisoquinolines have been reported.6 Among them,
the cyclization of indoles, including catalytic [2+2],7 [2+3],8
[2+4]9 cycloaddition and other annulation10 reaction, provides
an efficient method for constructing polycyclic structure of
indoline derivatives (Scheme 1a).
Herein, we report an aerobic oxygenation of indoles and oxa-
[3+3] cyclization cascade with C,N-cyclic azomethine imines via
oxygenation of the C=C bond of indole framework using
copper catalysis under mild condition. The reaction provides a
concise route to polycyclic [2,3]-fused indoline and C1-
The copper-catalyzed aerobic oxygenated strategy has
emerged as an attractive and useful methodology for
constructing C-C bond and C-heteroatom bond.12 Recently,
several copper-catalyzed aerobic oxygenation reactions on the
cyclization of indoles have been developed via copper-
catalyzed oxygenation of C3 C-H bond of indole by the groups
of Li,13 and Deng,14 using TBHP and dioxygen as oxygen source,
respectively (Scheme 1b). These reactions provide various
polycyclic indolin-3-one derivatives with oxygen-atom
incorporated. Although these elegant work for the
construction of polycyclic indolines have been well-established,
however, the [2,3]-fused indoline skeletons via copper-
catalyzed aerobic oxygenation have not been discovered.
functional tetrahydroisoquinoline derivatives in
diastereoselective manner.
a highly
At the outset of our investigation, we began by carrying out
this oxidation/1,3-dipolar cyclization cascade of idoles applying
N-benzyl-3-methyl indole 1a and C,N-cyclic azomethine imines
3a as the model system in the presence of 10 mol%
Cu(CH3CN)4BF4 and dichloromethane at room temperature in
air, after the complete consumption of 1a in 24 h, the desired
adduct 4a was successfully isolated in 46% yield (Table 1, entry
1), meanwhile a byproduct
5 was isolated in only 3% yield. To
our delight, the yield of adduct 4a was improved to 70% yield
when an oxygen balloon was employed (Table 1, entry 2).
Subsequently, other transition metal catalysts were also
evaluated with dioxygen as the oxidant, including AgN(OTf)2,
AgSbF6, and Pd(OAc)2, and Pd(CH3CN)4(OTf)2 (Table 1, entries
3, 4; Table S1). However, they were found to be less efficient
than copper salts.
A survey of solvent effect using
Cu(CH3CN)4BF4 as the catalyst concluded that CH2Cl2 was the
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Table 1 Optimization of reaction conditionsa
Table 2 Scope of this aerobic oxidative cyclizationa
R3
R
R1
10 mol% Cu2(OH)2CO3
5 mol% Cu(OAc)2, O2
O
R
N
+
N
Ts
N
CH2Cl2, 24 h, rt
N
R2
N
R3
Ts
R1
H
N
R2
3
1
4
Yield (%)b
Entry
Structure
Product(4)
Yield (%)b
Entry
Oxidant
Cat.
Solvent
1
2
3
4
5
6
7
R1 = H
4a
4b
4c
4d
4e
4f
88
70
60
66
67
86
83
1
2
air
O2
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
AgSbF6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
46
70
R1 = 5-Br
R1 = 5-F
R1 = 6-F
R1 = 6-Cl
R1 = 6-Me
R1 = 7-Me
3
O2
50
4
O2
Pd(OAc)2
63
5
O2
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4PF6
CuI
67
6
O2
DCE
69
4g
7
O2
toluene
Et2O
50
R1 = 6-OMe
4h
64
8
O2
trace
48
8
9
O2
THF
9
R = Et
4i
4j
83
82
81
80
70
80
73
64
42
90
45
83
81
10
11
12
13
14c
15
16d
17e
18 f
19g
20h
21i
O2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
45
10
11
12
13
14
15
16
17
18
19
20
21
R = Pr
O2
73
R = i-Pr
4k
4l
O2
69
R = n-hexane
R = hexane
R = -CH2CN
R = -CH2CH=CH2
R = -Bn
O2
Cu(OAc)2
81
4m
4n
4o
4p
4q
4r
O2
Cu2(OH)2CO3
79
.
O2
CuSO4 5H2O
77
O2
Cu2(OH)2CO3 + Cu(OAc)2
Cu2(OH)2CO3 + Cu(OAc)2
Cu2(OH)2CO3
88
O2
84
R
R2 = Me
m-CPBA
H2O2
t-BuOOH
O2
46
R2
4s
4t
Cu2(OH)2CO3
N.D.
N.D.
56
R2 = -Bn(2-CN)
R2 = -Bn(4-Cl)
Cu2(OH)2CO3
----
4u
a Unless otherwise stated, reactions were conducted on a 0.2 mmol scale with 1a
(1.0 equiv), 3a (1.5 equiv), and catalyst (0.1 equiv) in CH2Cl2 (1.0 mL) solvent at
22
R2 = H
6
14
b
room temperature for 24 h. For all of cases, >99:1 dr values was detected.
Isolated yield. c 3a (1.1 equiv) was used. d Cu2(OH)2CO3 (10 mol%) + Cu(OAc)2 (5
mol%) was used. eCu2(OH)2CO3 (5 mol%) + Cu(OAc)2 (2.5 mol%) was used. f For 2 h.
gH2O2 (30% in water) or ht-BuOOH (70% in water) was used. iFor 36 h.
23
24
25
26
R3 = 4-Cl
R3 = 4-F
R3
4v
4w
4x
78
73
85
66
R3 = 6-F
4y
preferred medium for the reaction (Table 1, entries 5−10). We
then employed a selection of copper salts as catalysts for the
optimization of reaction conditions (Table 1, entries 11−17). It
was shown a mixture of 5-mol% Cu(OAc)2 and 10-mol%
Cu2(OH)2CO3 was able to increase the reaction yields to 88%
(Table 1, entry 16). Furthermore, using basic Cu2(OH)2CO3 as
the catalyst seemed to be able to block the dimerization of
1,3-dipole substrate 3a, which allowed for decreasing the
utilization of 3a from 1.5 equivalents to 1.1 equivalents. Lastly,
27
R3 = 4-Me
4z
86
a
number of common oxidants were also used with
Cu2(OH)2CO3 as the catalyst. It was shown that the choice of
oxidants is critical for this cascade process (Table 1, entries
18−20). Replacing dioxygen with m-CPBA resulted in
a
significant decrease of reaction yields (Table 1, entry 18).
There was no product formed when H2O2 (30% in H2O) or t-
BuOOH (70% in H2O) was applied to this reaction (Table 1,
entries 19−20). In addition, without any catalyst, this reaction
could also be carried out, but longer time and decrease in yield
were shown (Table 1, entry21). The results indicated that
copper-catalyst and increasing the amount of catalyst could
a Unless otherwise stated, reactions were conducted on a 0.2 mmol scale with
1a (1.0 equiv), 3a (1.1 equiv), and catalyst (0.1 equiv) in CH2Cl2 (1.0 mL) solvent
at room temperature for 24 h. For all of cases, >99:1 dr values was detected. b
Isolated yield. Note: a relative configuration of product was exhibited.
accelerate this oxygenation reaction and improve isolated
yield of 4a (Table 1, entries 16−17, entry21).
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With the established optimal reaction conditions in hand,
the substrate scope of the oxidation/cyclization cascade
reaction was investigated by using various indole substrates
1
and C,N-cyclic azomethine imine 3 (Table 2). Both electron
donating and electron-withdrawing substituents in the C5-, C6-
, and C7-position of 1 were all compatible with the standard
reaction conditions (4b−4h) in yields ranging from 60% to 83%.
Besides, azomethine imine with methyl group substituent on
aryl ring exhibited relatively higher reactivity than that of with
halogen substituents. It appeared that the electronic effect of
the C3-position of
1 had significant influence on the reaction
process. Substrates with electron-neutral substituents or weak
electron-withdrawing substituents at the C3-position gave 42%
to 83% yields (4i
−4q). In addition, the N-substituent of indoles
seemed to be crucial for reaction yields and product stability,
substrates with an electron-neutral group at N-position of
4r 4u) gave 45% to 90% yields. Otherwise, only 14% yield of
1
6
(
−
and N1-substitued product in moderate yield have been
obtained when hydrogen atom at N-position of (see the
Supporting Information); however, there was no desired
product formed when R group of was changed to acyl or
1
1
ester group. We inferred that electrophilic effect of protecting
groups block the electron transfer from lone pair. Lastly,
various structurally diverse C,N-cyclic azomethine imines
3
azomethine imines played roles in this oxygenation/cyclization.
The relative configurations of the adduct products were
unambiguously determined by X-ray crystallography (4u and
4y; see the Supporting Information). For all cases, the values of
diastereoselectivities were above 99:1.
were synthesized to further explore the generality of this
reaction. The substitution impact on aryl groups of appeared
to be limited (4v−4z) with 66%−86% yields. It is worth noting
that azomethine imine 3x with condensed-ring system also
could be tolerated, and converted into the desired product 4x
with a satisfactory yield. However, the reaction didn’t work
when p-methylbenzene sulfonyl was replaced with benzoyl or
with other 1,3-dipolrs such as nitrone, azomethine ylides etc..
This is due to strong electrical absorption of Ts group was
more favourable to forming active 1,3-dipoles, and C,N-cyclic
For studying the mechanism of this oxidative
transformation, a series of control experiments have been
conducted. The isotope labelling experiment with 18O2
revealed that oxygen would be involved in the indole
oxygenation (Scheme 2a). Compound
5 as the by-product in
model reaction was found to be dominating when 2, 2, 6, 6-
Tetramethyl-1-oxylpiperid-ine (TEMPO) was used, and the
steric hindrance of methyl group at 3-position of indole could
give the best explain for this result. Introducing the radical
scavenger-butylated hydroxytoluene (BHT), the transformation
was prevented completely (Scheme 2b). These observations
support a probably radical mechanism. To further understand
the mechanism of this aerobic oxygenated cyclization, we also
performed this reaction process with dimethyldioxirane
(DMD), which could oxidize indole into oxireno[2,3-b]indole.15
The results showed that 1a can be transformed to
intermediate 2a by DMD as the oxidant under -20 oC,
moreover, the intermediate 2a can interact with 3a, giving the
desired adduct 4a in high yield without any metal catalysis in
total 2 h (Scheme 2c), and the similar results have been found
with m-CPBA as the oxidant. These results indicated that this
transformation maybe progress via intermediate
copper-based catalytic system.
2 under
On the basis of above results from the mechanistic studies,
a plausible mechanism of this aerobic oxygenation/cyclization
have been proposed (Scheme 3). Originally, copper (II) is
oxidized by molecular oxygen to afford a higher valence
copper (III) with the generation of the oxygen radical anion.
Subsequently, an electron of nitrogen on indole ring of
1 is
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cyclization between dipolar intermediate and enables the
formation of adduct in a high diastereoselectivity due to π-π
stacking and steric hindrance effect between -Ts group and N-
protected group (Scheme 3), this point was further
supported by the control experiment without any catalyst.
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proton transformation and tautomerism of enol form to offer
byproduct
3
2
3
4
,
R
7
8
2
5.
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In conclusion, we have reported a novel copper-catalyzed
aerobic oxidative 1,3-dipolar cyclization for efficiently
introducing indole- and THIQ-based substructures into
complex molecules. This protocol represents an elegant
example of aerobic oxygenation and 1,3-dipolar cyclization of
indoles in good yields and excellent diastereoselectivities
under mild reaction conditions. A diverse range of complex
alkaloid-type pentacycles for diversity-oriented synthesis and
drug discovery could be constructed in one single step.
9
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We greatly appreciate the financial support from the
Program for Guangdong Introducing Innovative and
Entrepreneurial Teams (2016ZT06Y337), and X. J. thanks the
Thousand Young Talents Program for financial support.
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4 | J. Name., 2012, 00, 1-3
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R3
R
R
O
R
oxa-[3+3]
cyclization
N
O
[Cu]/O2
R1
R1
R1
N
C=C bond
oxygenation
Ts
N
R2
N
N
R2
R3
Ts
R2
N
N
27 examples
up to 90% yield; >99:1 dr
Key features
1. C=C bond oxygenation 2. Oxa-[3+3] cyclization
3. High diastereoselectivity 4. Mild condition
5. Absolute atom economy without any by-product
6. Five-ring-[2,3]-fusedindoline featuring an THIQs scaffold
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J. Name., 2013, 00, 1-3 | 5
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