O-Naphthoquinone-Catalyzed Aerobic Oxidation of Amines to (Ket)imines: A Modular Catalyst Approach

Article abstract of DOI:10.1021/acs.orglett.6b02697

A modular aerobic oxidation of amines to imines has been achieved using an ortho-naphthoquinone (o-NQ) catalyst. The cooperative catalyst system of o-NQ and Cu(OAc)₂ enabled the formation of homocoupled imines from benzylamines, while the presence of TFA helped the formation of cross-coupled imines in excellent yields. The current mild aerobic oxidation protocol could also be applied to the oxidation of secondary amines to imines or ketimines with the help of cocatalyst, Ag₂CO₃, with excellent yields.

Full text of DOI:10.1021/acs.orglett.6b02697

Letter
pubs.acs.org/OrgLett
o‑Naphthoquinone-Catalyzed Aerobic Oxidation of Amines to
(Ket)imines: A Modular Catalyst Approach
Yogesh Goriya, 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 modular aerobic oxidation of amines to imines
has been achieved using an ortho-naphthoquinone (o-NQ)
catalyst. The cooperative catalyst system of o-NQ and Cu(OAc)2
enabled the formation of homocoupled imines from benzyl-
amines, while the presence of TFA helped the formation of
cross-coupled imines in excellent yields. The current mild
aerobic oxidation protocol could also be applied to the oxidation
of secondary amines to imines or ketimines with the help of
cocatalyst, Ag2CO3, with excellent yields.
and Klinman (butyl-2-hydroxy-1,4-benzoquinone)6 studied the
o-Quinone-catalyzed dehydrogenation of amines mimics the
oxidation of amines using biomimetic model o-quinones.
However, the first practical use of synthetic o-quinones in the
dehydrogenation of amines was explored by the laboratories of
Largeron7 and Stahl8 using IQox (o-iminoquinone) and
TBHBQ, respectively. In 2014, the laboratory of Stahl used
the PQQ model 1,10-phenanthroline-5,6-dione (phd) to
initiate the dehydrogenation of secondary amines and other
N-heterocycles in the presence of cocatalysts, ZnI2 and
pyridium p-toluenesulfonic acid.9 Such a modular catalyst
system has been applied to the dehydrogenation of 1,2,3,4-
tetrahydroquinolines by using a Ru/Co cocatalyst system.10
With the aim of identifying new o-quinone-based catalysts that
display tunable dehydrogenation activity for primary and
secondary amines,11 we examined substituted o-naphtho-
quinone derivatives as possible synthetic o-quinone cofactors.
In our recent synthetic studies of o-naphthoquinones, we found
that 4-substituted naphthalene-1,2-diols spontaneously undergo
aerobic oxidation to o-naphthoquinones in quantitative yields
(Scheme 1b).12 Motivated by the high redox activity of 4-
substituted o-naphthoquinone derivatives, we envisioned a new
biomimetic o-naphthoquinone-catalyzed dehydrogenation of
amines. Herein, we report a mild and tunable o-naphthoqui-
none-based dehydrogenation of primary amines to furnish
diverse homo- and cross-coupled imines. Importantly, the
current o-naphthoquinone-based dehydrogenation can be
applied to secondary amines to give imines and ketimines in
excellent yields.
copper amine oxidases (CuAOs) where redox-active organic
molecules skillfully utilize the green oxidants such as molecular
oxygen or air to promote the imine formation from primary
amines.1 The development of novel o-quinone cofactors in
CuAOs has received considerable attention from the synthetic
community for the past few years, culminating in the successful
identification of o-quinones for catalytic aerobic oxidation of
primary and secondary amines to imines.2 Taking initiative
from natural o-quinone cofactors with the two possible CuAOs
mechanisms (Scheme 1a), the laboratories of Bruice (pyrrolo-
quinonoline quinone),3 Itoh (methyl tryptophan tryptophyl-
quinone),4 Sayre (2,4,5-trihydroxy phenylalanine quinone),5
Scheme 1. Biomimetic o-Quinones for Dehydrogenation of
Amines
To evaluate the dehydrogenation activity of o-naphthoqui-
none derivatives, we chose p-methoxy benzylamine 1a as a
model substrate (Table 1). Upon stirring benzylamine 1a in the
presence of a catalytic amount of various o-naphthoquinones,
Received: September 8, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02697
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Letter
dehydrogenation protocol could be carried out under ambient
air conditions, but the reaction time increased to 60 h for
completion (entry 20).
Table 1. Optimization of the Dehydrogenation of Benzyl
Amine
The optimized dehydrogenation conditions were further
evaluated using various benzyl amines (Scheme 2). In general,
Scheme 2. Scope of o-NQ3-Catalyzed Aerobic
Dehydrogenation of Benzyl Amines
b
entry
cat. (mol %)
add. (mol %)
solvent, t (h)
yield (%)
1
o-NQ1 (10)
o-NQ2 (10)
o-NQ3 (10)
o-NQ4 (10)
o-NQ5 (10)
o-NQ6 (10)
o-NQ7 (10)
o-NQ3 (10)
o-NQ3 (10)
o-NQ3 (10)
o-NQ3 (10)
o-NQ3 (20)
o-NQ3 (5)
o-NQ3 (5)
o-NQ3 (2)
o-NQ3 (1)
o-NQ3 (0.5)
o-NQ3 (2)
o-NQ3 (1)
o-NQ3 (2)
−
−
−
−
−
−
−
−
−
−
−
−
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
PhCH3
THF
48
48
48
48
48
48
48
48
48
48
48
24
48
18
18
60
60
18
18
60
39
64
69
47
63
9
2
3
4
5
6
7
29
25
22
50
28
91
33
99
99
80
65
83
43
81
8
9
10
11
12
13
14
a
b
c
EtOH
2 mol % catalysts. 5 mol % catalysts. Yields using internal standard.
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
−
benzyl amines with an electron-donating substituent provided
excellent yields of imines in the presence of 2 mol % o-NQ3
and Cu(OAc)2 (2a, 2c−e, 2k). However, electron-deficient
benzyl amines required 5 mol % of catalysts for comparable
dehydrogenation activities (2b, 2f−j). In cases of heteroatom-
containing amine substrates, the isolated yields of imines (2l−
m) were in 51−56% yields, possibly due to the facile imine
decomposition upon isolation and coordination to the metal
center.
Since the current dehydrogenation conditions using o-NQ3
were not applicable to aliphatic primary amines and sec-primary
amines,14 we examined the cross-coupling between primary
benzyl amines and other unreactive amines. After some
optimization studies (see the Supporting Information for
detail), we identified optimal conditions for the cross-coupling
using 10 mol % o-NQ3 and 20 mol % TFA with 2 equiv of
nonoxidizing amines. The result of the o-NQ3/TFA-catalyzed
aerobic cross-coupling of primary amines is illustrated in Table
2. The reaction is quite effective for various sec-primary amines
(3a−k), aliphatic primary amines (3l), tert-primary amines
(3m), anilines (3n).
Motivated by the fact that the dehydrogenation of amines
was strongly influenced by the additional promoters such as
Cu(OAc)2 and TFA, we further investigated the cross-coupling
using o-aminoaniline (Scheme 3). The synthesis of benzimida-
zole 4 was accomplished in 86% yield. Additionally, secondary
amines such as tetrahydroisoquinoline derivatives were
dehydrogenated in the presence of cocatalyst Ag2CO3 in
excellent yields to give 5a−c.15 The dehydrogenation of 9,10-
dihydroacridine to acridine 6 was also effected under mild
reaction conditions. However, aliphatic amines such as
tetrahydroquinoline and indoline were inert under various
reaction conditions.16
While more studies are needed to cast mechanistic insights
into the cooperative catalyst activities between o-NQ3 and
cocatalysts (metallic copper(II) salt, acidic TFA, and basic
Ag2CO3), the current cooperative catalyst system displays the
both features of “transamination”6a,b and “addition−elimina-
tion”4b,5e,f mechanistic pathways. Thus, the homocoupling and
cross-coupling of primary benzyl amines collectively illustrate
Cu(OAc)2 (5)
Cu(OAc)2 (2)
Cu(OAc)2 (1)
Cu(OAc)2 (0.5)
Cu(OAc)2 (1)
Cu(OAc)2 (2)
Cu(OAc)2 (2)
c
15
16
17
18
19
d
20
a
Reaction conditions: 1a (0.4 mmol) in CH3CN (1 mL) under O2
b
balloon. Isolated yield of products after column chromatography.
c
d
CuCl (7%), CuCl2 (23%), CuOAc (9%). Reaction under ambient
air.
the formation of homocoupled imine 2a was observed at
ambient temperature under O2 atmosphere. The electron-
donating substituent at C-4 of o-naphthoquinones o-NQ2
improved the dehydrogenation activity, resulting in the
formation of 2a in 64% yield (entry 2) as opposed to 39%
when 4-alkyl naphthoquinone o-NQ1 was used (entry 1). The
dehydrogenation activity was further improved with the use of
4-phenyl naphthoquinone o-NQ3 to a 69% yield. The
investigation into the electronic effect of the phenyl group
revealed that the electron-donating group (entry 5) was
beneficial as opposed to the electron-deficient group (entry
4). The substituent at C-3 of o-naphthoquinones significantly
reduced the dehydrogenation activity, possibly due to steric
reasons, providing 2a in 9−29% yields (entries 6−7). The
solvent screening revealed CH3CN as the optimal solvent for
the current dehydrogenation protocol (entries 8−11). Next, we
examined the catalyst loading. While the use of 20 mol % o-
NQ3 led to the desired product 2a in 91% yield in 24 h (entry
12), the reduced catalyst loading to 5 mol % provided 2a in
33% yield with a prolonged reaction time of 48 h (entry 13).
To improve the dehydrogenation activity of o-NQ3, we opted
for the use of additional promoters as cocatalysts. Gratifyingly,
the catalytic use of Cu(OAc)2 significantly enhanced the
dehydrogenation activity of o-NQ3,13 providing 2a in >99%
yield in the presence of 2 mol % of both o-NQ3 and Cu(OAc)2
(entries 14−17). The optimal ratio between o-NQ3 and
Cu(OAc)2 was 1:1 (entries 18−19). Finally, the current
B
DOI: 10.1021/acs.orglett.6b02697
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
possible involvement of hemiacetal intermediates that typically
requires basic conditions for the abstraction of a H atom as
shown in Scheme 1.10,11a
Table 2. o-NQ3-Catalyzed Aerobic Cross-Coupling of
Amines
In summary, we have developed the highly modular aerobic
dehydrogenation protocols for primary and secondary amines.
With the discovery of new biomimetic o-naphthoquinones, mild
and efficient homo- and cross-couplings of amines were
achieved with the help of cocatalysts such as acids and bases.
While there exists room for improvement in terms of amine
substrate scope to nonbenzylic amines and catalyst loading to
<5 mol %, the fact that the reactivity of o-NQ3 could be
modulated using cocatalysts makes the current method
attractive for the synthesis of various heterocycles. Our current
research efforts are directed to detailed mechanistic studies and
expanding the chemistry to other amine substrates.
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.6b02697.
Experimental procedures and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hunykim@cau.ac.kr.
*E-mail: kyungsoooh@cau.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) grants funded by the Korea government
(MSIP) (NRF-2015R1A5A1008958 and NRF-2015-
R1C1A2A01053504).
a
Reaction conditions: 1 (0.2 mmol), amines (0.4 mmol) in CH3CN (1
b
mL) under O2 balloon. Isolated yield of products after column
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D
DOI: 10.1021/acs.orglett.6b02697
Org. Lett. XXXX, XXX, XXX−XXX