Aerobic Oxidation Approaches to Indole-3-carboxylates: A Tandem Cross Coupling of Amines-Intramolecular Mannich-Oxidation Sequence

Article abstract of DOI:10.1021/acs.orglett.9b02348

A tandem aerobic oxidation protocol has been developed for the facile synthesis of indole-3-carboxylates. Two readily available starting materials, anilines and benzylamines, were efficiently cross-coupled under the o-naphthoquinone-catalyzed aerobic oxid

Full text of DOI:10.1021/acs.orglett.9b02348

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Aerobic Oxidation Approaches to Indole-3-carboxylates: A Tandem
Cross Coupling of Amines−Intramolecular Mannich−Oxidation
Sequence
Kyeongha Kim, Hun Young Kim,* and Kyungsoo Oh*
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic
of Korea
S
* Supporting Information
ABSTRACT: A tandem aerobic oxidation protocol has been
developed for the facile synthesis of indole-3-carboxylates.
Two readily available starting materials, anilines and benzyl-
amines, were efficiently cross-coupled under the o-naphtho-
quinone-catalyzed aerobic oxidation conditions to the
corresponding 2-arylmethyleneaminophenylacetates that in
turn smoothly underwent the Cu(II)-catalyzed intramolecular
Mannich reaction. The resulting indoline derivatives were aerobically oxidized to indole-3-carboxylates, providing a ready access
to indole derivatives from two simple amine derivatives.
Scheme 1. Aerobic Oxidation Approaches to Indole
Derivatives
direct access to indole derivatives from readily available
starting materials significantly improves the overall
A
synthetic efficiency without having to isolate the synthetic
intermediates.1 The recent development of transition-metal-
catalyzed C−H activation strategies has further strengthened
the late-stage installation of an indole moiety in a target-
oriented synthesis.2 While numerous synthetic methods to
indole derivatives boast diverse starting materials and rationally
designed catalyst systems,3 it is highly practical to develop the
aerobic oxidation protocol to indole derivatives from two
readily available starting materials given that the structural
diversity of indoles can be achieved. In 2012, Yoshikai et al.
disclosed the Pd(II)-catalyzed aerobic oxidative cross-dehy-
drogenative coupling of imines,4 in contrast to the previous
Pd(II)-catalyzed oxidative cyclization of N-aryl enamines with
stoichiometric amounts of Cu(OAc)2 as the oxidant (Scheme
1a).5 Previously, we developed the o-naphthoquinone (o-NQ)-
catalyzed deaminative cross-coupling of amines, where two
different amines were condensed under aerobic conditions to
give imines (Scheme 1b).6 Since the access to N-
benzylideneaniline derivatives could be secured under the
aerobic oxidation conditions, we envisioned an intramolecular
Mannich reaction to indolines that could be aerobically
oxidized to indole derivatives (Scheme 1c). The reaction
design was partially supported by the work of Hodges et al.
where the intramolecular Mannich reaction did provide the
desired indoline in 37% yield.7 While this result contradicted
the earlier works of Speckamp et al., who reported the failure
of the reaction under a variety of solvent and base
combinations,8 the challenge poised by the precarious
experimental results did not deter us from verifying our
reaction design.9 The use of N-benzylideneanilines as the
cyclization precursor is clearly beneficial since the isomer-
ization of substituted imines to N-aryl enamines does require a
stoichiometric amount of oxidants, not suitable under
Yoshikai’s aerobic oxidation conditions.4 In addition, the
aerobic oxidation of indolines to indoles implies the
dehydrogenative oxidation of amines, a valuable oxidation
protocol from the viewpoint of green chemistry.10
With the aim of developing a direct access to indole-3-
carboxylates from simple two-amine starting materials, the o-
NQ-catalyzed aerobic cross-coupling of tert-butyl 2-(2-
aminophenyl)acetate 1a and benzylamine 2a was examined
(Table 1). The use of o-NQ1 in THF at ambient temperature
provided the imine 3a, a homocoupling product of 2a, as a
Received: July 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02348
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 1. Optimization of o-NQ-Catalyzed Aerobic Cross-
Coupling of Amines
Table 2. Optimization of Intramolecular Mannich
Reaction−Aerobic Oxidation
a
a
b
entry
additive (mol %)
t-BuOK (equiv)
T (°C)
yield (%)
1
2
3
4
5
6
7
8
0.1
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
23
23
23
0
20
48
60
60
60
70
60
66
50
78
70
66
71
56
64
b
entry
cat. (mol %)
o-NQ1 (10)
solvent
T (°C)
yield (%)
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
23
23
23
23
23
23
23
80
80
80
80
80
27
45
40
45
4
46
66
73
70
79
85
87
o-NQ1 (10)/TFA (20)
o-NQ2 (10)/TFA (20)
o-NQ3 (10)/TFA (20)
o-NQ4 (10)/TFA (20)
o-NQ1 (10)/TFA (20)
o-NQ1 (10)/TFA (20)
o-NQ1 (10)/TFA (20)
o-NQ1 (15)/TFA (20)
o-NQ1 (10)/TFA (30)
o-NQ1 (10)/TFA (20)
o-NQ1 (10)/TFA (20)
−78
23
23
23
23
23
23
23
23
23
23
Zn(OTf)2 (10)
In(OTf)2 (10)
Sc(OTf)2 (10)
Ti(Oi-Pr)2 (10)
Cu(OTf)2 (10)
Cu(OAc)2 (10)
CuOTf (10)
CuI (10)
Cu(OTf)2 (5)
Cu(OTf)2 (15)
THF
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
12
13
14
15
10
11
12
c
d
a
Reaction using 1a (0.20 mmol), 2a (0.24 mmol), o-NQ in solvent
a
Reaction using 4a in THF (0.2 M) under Ar → O2 balloon for 1 h.
Yields after column chromatography.
b
(0.2 M) under O2 balloon for 24 h. Yields of 4a based on internal
standard. Use of 2a (0.30 mmol, 1.5 equiv). Use of 2a (0.40 mmol,
b
c
d
2.0 equiv).
introduced to the reaction mixture immediately after the
addition of t-BuOK. In this way, the direct formation of indole
6a was accomplished. The use of substoichiometric amounts of
t-BuOK provided the indole 6a in 20−48% yields after the
aerobic oxidation (entries 1 and 2). While the use of 1 equiv of
t-BuOK improved the yield of 6a to 60% (entry 3), the
reaction temperature did not exert any influence to the
reaction efficiency (entries 4 and 5). Next, we screened various
Lewis acids for the intramolecular Mannich reaction to further
optimize the yields (entries 6−10).11 Among them, Cu(OTf)2
was identified as an optimal Lewis acid, providing the desired
product 6a in 78% yield (entry 10). The use of other copper
salts was effective but less efficient compared to Cu(OTf)2
(entries 11−13). The different amounts of Cu(OTf)2 provided
6a in 56−64% yields (entries 14 and 15), suggesting the
optimal loading of Cu(OTf)2 as 10 mol %.
Analyzing our experimental findings of the o-NQ1-catalyzed
aerobic oxidation and the Mannich cyclization followed by the
aerobic oxidation, it was necessary to switch the reaction
solvent from CH3CN to THF. Thus, after the o-NQ1-
catalyzed aerobic oxidation, the reaction solvent, CH3CN,
was evaporated, and then THF was reintroduced into the
reaction mixture. This simple solvent change did not affect the
following Mannich cyclization−aerobic oxidation sequence,
where the overall yields of indole-3-carboxylates were identical
between the stepwise and tandem reactions. The substrate
scope of thus combined tandem reaction procedure to indole-
3-carboxylates from tert-butyl 2-(2-aminophenyl)acetate 1a
and substituted benzylamines 2 is presented in Scheme 2. A
structurally diverse array of indole-3-carboxylates 6b−6q was
prepared in 20−67% yields. Considering the three reactions in
a tandem sequence, the average chemical yield for each step is
estimated around 80−85% yields. Of note, the electronic and
steric features of benzylamines 2 did not have significant
influence to the overall reaction sequence; however a furan
moiety 6p and other alkyl amines presented the substrate
major product, along with the desired cross-coupled product
4a in 27% yield (entry 1). The presence of cocatalyst TFA
facilitated the formation of 4a to 45% yield (entry 2). The
structure−activity relationship of o-NQ catalysts revealed a
minimal electronic effect of the phenyl moiety at the C-4
position of o-naphthoquinone (entries 3 and 4), while the
steric hindrance was exerted by the substituent at the C-3
position of o-naphthoquinone (entry 5). A brief survey of
solvents suggested that other solvents were comparable, but
CH3CN was the optimal solvent for the current cross-coupling
of two amines (entry 7). Further improvement of the reaction
was achieved by elevating the reaction temperature to 73%
yield (entry 8). The final tuning of the reaction conditions
involved the use of 2.0 equiv of benzylamine 2a, where the
formation of the cross-coupled imine 4a was obtained in 87%
yield (entry 12).
With the optimized cross-coupling reaction of amines, the
projected intramolecular Mannich reaction of 4a was
investigated (Table 2). Our initial attempts using various
bases such as Et3N, DBU, NaOMe, and KOH failed to provide
the desired cyclized product. These results were in line with
the previous observation by Speckamp.8 Upon use of t-BuOK,
the formation of Mannich product 5a was observed in 5−10%
yields.7,9 To our surprise, the indoline 5a was not stable under
the reaction conditions and thus rapidly decomposed to a
mixture of unidentifiable products. Upon a close look at the
reaction course, we found that the intramolecular Mannich
cyclization of 4a by t-BuOK happened instantaneously, and
then the indoline 5a immediately decomposed in the next few
minutes. Thus, it was crucial to minimize the exposure of 5a
under the reaction conditions. After some experimentation, it
was found that the in situ formed indoline 5a could be oxidized
to the corresponding indole 6a under an oxygen balloon. Thus,
while the t-BuOK addition stage of the reaction required an
inert atmosphere of argon, the aerobic oxygen was directly
B
DOI: 10.1021/acs.orglett.9b02348
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
carboxylates was achieved from readily available amines in a
tandem sequence of aerobic oxidation processes.
Scheme 2. Substrate Scope of Aerobic Oxidation to Indoles
To provide mechanistic insight into the intramolecular
Mannich process, we isolated the indoline intermediate 5a.12
Under our control experiments as shown in Scheme 4a, the
Scheme 4. Plausible Reaction Mechanism for Aerobic
Oxidation and Access to Functionalized Indole-3-
carboxylates
a
Reaction using o-NQ3 (10 mol %).
limitation during the o-NQ-catalyzed aerobic cross-coupling of
amines (vide infra).
Further substrate scope was investigated using substituted
anilines 1 and benzylamines 2 (Scheme 3). In general, the
observed yields were slightly lower for bromide-substituted
anilines (6t, 6ab, 6af, 6aj, 6an), some methoxy-substituted
anilines (6u, 6ac, 6ag), and naphthyl amines (6at−6az).
Nevertheless, the ready access to a large number of indole-3-
solid indoline 5a as well as the indoline 5a THF solution was
stable under air and under inert atmosphere in the absence of
t-BuOK. The use of t-BuOK and molecular oxygen was needed
for the rapid oxidation of indoline 5a to indole 6a.13 The
addition of Cu(OTf)2 did not have much effect to the
oxidation of indoline 5a to indole 6a; thus, the role of
Cu(OTf)2 in the reaction could be assigned as a promoter for
the intramolecular Mannich reaction.11 The indoline 5a was
rapidly decomposed to unidentifiable products in the presence
of t-BuOK, demonstrating the crucial role of molecular oxygen
in the oxidation of 5a to indole 6a. While further studies are
needed for the precise reaction mechanism for the observed
aerobic oxidation of indolines to indoles, given the direct
electron transfer capability of t-BuOK14 one possible
mechanistic explanation would be the abstraction of hydrogen
radical from the indoline N−H bond, followed by the benzylic
H radical abstraction and aromatization to indoles (Scheme
4a). The current aerobic oxidation method utilizes the imine
intermediates from the o-NQ-catalyzed cross imination of two
amines. While the imine intermediates can be obtained
through the condensation reactions between aldehydes and
anilines, the use of protic solvents15 or acid catalysts16 typically
requires the purification of imines for the subsequent reactions.
While the use of the unpurified imines in our control
experiments could provide the comparable yields of products
in 50−60% yields after the t-BuOK-promoted intramolecular
Mannich−aerobic oxidation protocol, the aldehyde condensa-
tion approaches lacked the substrate generality due to the
residual protic solvents and catalysts. Thus, the functional
group tolerance for the Mannich cyclization followed by
aerobic oxidation was further demonstrated using the purified
Scheme 3. Further Substrate Scope for Tandem Reactions
to Indoles
a
Reaction using o-NQ3 (10 mol %).
C
DOI: 10.1021/acs.orglett.9b02348
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imines 4b−d for consistent reproducibility (Scheme 4b). In
this way, the indole-3-carboxylates 6p, 7a, and 7b could be
accessed in synthetically useful yields, providing a convenient
synthetic route to highly functionalized indole derivatives.
In summary, we have developed a tandem aerobic oxidation
sequence to indole-3-carboxylates from readily available amine
derivatives. The key finding of the current synthetic access to
indole derivatives is the successful Mannich cyclization of 2-(2-
aminophenyl)acetates by t-BuOK in the presence of a catalytic
amount of Cu(OTf)2. The subsequent aerobic oxidation of
indolines to indoles is also noteworthy, where the stability and
reactivity of indoline intermediates were thoroughly examined.
The current tandem aerobic oxidation reactions should find
wide synthetic utility in organic synthesis. Our current research
efforts are directed to further broadening the tandem aerobic
oxidation sequence to other heterocycles.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02348.
Experimental procedures and characterization data for
all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kyungsoooh@cau.ac.kr.
*E-mail: hunykim@cau.ac.kr.
ORCID
Hun Young Kim: 0000-0002-8461-8910
Kyungsoo Oh: 0000-0002-4566-6573
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) grants funded by the Korean
government (MSICT) (NRF-2015R1A5A1008958 and NRF-
2018R1D1A1B07049189).
̈
Chem. 2007, 2007, 3977−3980. (k) Soderberg, B. C. G.; Banini, S. R.;
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DOI: 10.1021/acs.orglett.9b02348
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