Mechanistic Studies on Bioinspired Aerobic C-H Oxidation of Amines with an ortho-Quinone Catalyst

Article abstract of DOI:10.1021/acs.joc.8b02948

We report herein our mechanistic studies of the ortho-quinone-catalyzed aerobic oxidation of primary, secondary, and tertiary amines. Two different catalytic pathways were discovered for the reductive half reactions: for primary amines, the reaction was found to proceed via a transamination pathway, while the reactions with secondary amines and tertiary amines proceeded via hydride transfer. We also found that the amine substrates could significantly promote the regeneration of the ortho-quinone catalyst in the oxidative half reaction, in which a proton transfer occurs between the amine substrates and catechol derivatives (the reduced form of the ortho-quinone catalyst).

Full text of DOI:10.1021/acs.joc.8b02948

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Article
Mechanistic Studies on Bioinspired Aerobic C-H
Oxidation of Amines with an ortho-Quinone Catalyst
Ruipu Zhang, Yan Qin, Long Zhang, and Sanzhong Luo
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 Feb 2019
Downloaded from http://pubs.acs.org on February 13, 2019
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The Journal of Organic Chemistry
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Mechanistic Studies on Bioinspired Aerobic C-H Oxidation of
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Amines with an ortho-Quinone Catalyst
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Ruipu Zhang,†,§ Yan Qin,†,§ Long Zhang,*,†, ‡,¶ and Sanzhong Luo*,†,‡,¶
†Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, The Chinese Academy of Sciences, Beijing
100190, China and University of Chinese Academy of Sciences, Beijing, 100049, China
‡Center of Basic Molecular Science (CBMS), Department of Chemistry, Tsinghua University, Beijing, 100084, China
¶Collaborative Innovation Center of Chemical Science and Engineering, Tianjin, 300071, China
Nu-H
N
tBu
O
O
NH2
Ar
MeO
Ar
NH
R
Transamination
Hydride Transfer
N
O2
Ar
N
Ar
R
N
Ar
Nu
ABSTRACT: We report herein our mechanistic studies of the ortho-quinone-catalyzed aerobic oxidation of primary, secondary, and
tertiary amines. Two different catalytic pathways were discovered for the reductive half reactions: for primary amines, the reaction
was found to proceed via a transamination pathway, while the reactions with secondary amines and tertiary amines proceeded via
hydride transfer. We also found that the amine substrates could significantly promote the regeneration of the ortho-quinone catalyst
in the oxidative half reaction, in which a proton transfer occurs between the amine substrates and catechol derivatives (the reduced
form of the ortho-quinone catalyst).
Introduction
Natural enzymatic transformations provide a great source of inspiration for developing new catalysts and reactions. The copper
amine oxidases (CuAOs), which are involved in the metabolism of amines,1 have been the basis for developing the biomimetic amine
oxidation process. In 1990, Klinman2 first identified the cofactor of CuAOs, isolated from bovine serum amine oxidase, as TPQ
(2,4,5-trihydroxyphenylalanine quinone). Similar cofactors can be found in all bacteria, yeasts, plants, and animals. Unlike the
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dissociable PQQ (pyrroloquinoline quinone) cofactors found in alcohol and glucose dehydrogenases from Gram-negative bacteria,3
which bind to the quinone proteins through ionic interactions, TPQ is generated directly from the Tyr side chain and hence is
covalently bound to the protein backbone (Scheme 1A). The aerobic oxidation catalyzed by CuAOs consists of two distinct half
reactions (based on the redox process of catalysts): in the reductive half reaction, TPQ gains two electrons to reach its reductive state,
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5
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8
+
oxidizing amines to aldehydes; in the oxidative half reaction, reductive TPQ is oxidized by oxygen to the resting state, releasing NH4
9
and H2O2 with the assistance of a cupric ion.1c The quinone cofactors are the only active species promoting amine oxidation; the
cupric ion simply assists oxygen to recycle the quinone cofactors. Mechanistic works reported by Klinman,1b-d, 2, 4 Sayre,5 and others6
demonstrated that the reductive half reaction proceeds through a transamination pathway (Scheme 1B). In a much earlier study,
Corey7 reported oxidation of primary amines to ketones using 3,5-di-t-butyl-1,2-benzoquinone via a transamination pathway.
Recently, notable advances have been made in the development of bioinspired ortho-quinone catalysts (Scheme 1C).8 For example,
Largeron9 achieved the oxidation of a large number of primary amines with o-iminoquinone recycled using electrochemical
conditions or air in the presence of cupric ions. A natural Purpurogallin-derived ortho-quinone catalyst has also been developed to
promote primary amine oxidation under air condition without the assistance of any metal cocatalysts. 9g Stahl and colleagues10 also
made a great contribution to this field by developing several quinone-based catalysts, which enabled efficient dehydrogenation of
primary amines, secondary amines, and even nitrogen heterocycles with the assistance of metal cocatalysts under mild reaction
conditions. Furthermore, they showed that secondary amines were oxidized by the ortho-quinone catalyst (1,10-phenanthroline-5,6-
dione, phd) via an “addition-elimination” pathway involving a hemiaminal intermediate.10b Kobayashi11 proposed the involvement of
hemiaminal intermediates in secondary amine oxidation reactions by a cooperative catalytic system of Pt/Ir nanoclusters and 4-tert-
butylcatechol. Oh and co-workers reported that an ortho-naphthoquinone could catalyze aerobic oxidation of primary and secondary
amines in the presence of trifluoroacetic acid or Cu(OAc)2.12 Recently, we developed a simple bio-inspired ortho-quinone catalyst
(Scheme 1, o-Q1) that enabled effective oxidative dehydrogenation of the difficult α-branched primary amines without any co-
catalyst.13a We13b and others14 reported oxidative C-H functionalizations of primary amines to afford aza-heterocycles via in-situ
formed imine intermediates. Further investigation showed that the oxidation of cyclic secondary amines and tertiary amines were also
viable using the same ortho-quinone catalyst. Herein, we report a full account of mechanistic studies on our ortho-quinone catalysis.
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COO-
A
B
O
-OOC
N
1
2
HN
O
3
OH
-OOC
O
O
4
5
OH
CuII
O
O
PQQ
TPQ
6
7
8
9
NH2
C
OH
O
H2O
R
O
O
HN
Ph
O
OH
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Largeron
Kobayashi
"o-iminoquinone"
"4-tBu-o-quinone"
NH3
O
O
O
O
H2N
R
CuII
N
OH
O
Stahl
R
N
N
OH
N
O
Stahl
"phd"
"TBHBQ"
Transamination
Mechanism
O
OH
OH
O
OH
OH
NH
CuII
CuII
OH
R
Ph
Oh
Largeron
"pyrogallol"
"o-naphthoquinone"
H2O
H2O2
OH
tBu
O
O
O2
R
H
RO
O
OH
CuII NH2
Luo
o-Q1, R = Me
o-Q2, R = Et
Scheme 1. (A) Structures of two quinone cofactors: PQQ (pyrroloquinoline quinone) and TPQ (2,4,5-trihydroxyphenylalanine
quinone). (B) Mechanism of amine oxidation mediated by CuAOs via a transamination pathway. (C) Recent biomimetic quinone-
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based catalysts developed by Largeron, Kobayashi, Stahl, Oh, and Luo.
Results and Discussion
α-Branched primary amine. In our previous reports, we developed a bioinspired ortho-quinone catalyst for the aerobic oxidation
of α-branched primary amines (Scheme 2).13b 1-Phenylethanamines bearing electron-donating or electron-withdrawing groups were
well tolerated and produced secondary imines with high to excellent yields and good E/Z ratio. Substrates with a bulky group such
as diphenylmethanamine also gave the desired imine. It should be mentioned that the catalytic reaction by using para-quinone
(TBHBQ) as catalyst was nearly inert, highlighting the unique catalytic ability of our ortho-quinone catalyst. Moreover, a higher
temperature would afford oxidative trimerization adducts, imidazolinones (Scheme 2). Control experiments showed that the quinone
catalyst was also involved in the later stages of oxidation, as no product was observed in the absence of catalyst when using imine as
the starting material. Overall, this oxidative trimerization provided a novel method for the synthesis of imidazolinones.
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A
B
NH2
R
R
o-Q1
(10 mol %)
1
2
3
4
5
6
Ar
R
Ar
N
2
Ar
CH3CN, rt, O2, 48 h
1
up to 99% yield
R
7
8
9
O
o-Q2
N
N
(2 mol %)
NH2
R
CH3CN (0.3 M), 60 o
O2, 48 h - 72 h
C
1
R
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R
3
up to 65% yield
Scheme 2. (A) Aerobic oxidation of primary amines. (B) Oxidative trimerization of 1-phenylethanamines.
Cyclic secondary amines. In previous work, biomimetic oxidative dehydrogenation of secondary amines usually required
transition metal salts as cocatalysts.10b, 10c, 11, 15 To our delight, we found that the ortho-quinone catalyst also promoted the oxidation
of tetrahydroisoquinoline to 3,4-dihydroisoquinoline under an oxygen atmosphere and slightly higher temperature, and no metal
additive was needed (Scheme 3; for full substrate scope see Table S1 in SI).13b 1-Phenyl-substituted tetrahydroisoquinolines bearing
halogen or alkyl groups worked well in this catalytic system. Meanwhile, 1-phenyl-substituted tetrahydro-β-carbolines exhibited good
reactivity under the same conditions.
o-Q1
(10 mol %)
Ar
Ar
NH
N
CH3CN, 60 oC, O2
R
R
5
4
up to 99% yield
14 examples
Scheme 3. Aerobic oxidation of secondary amines.
Cyclic tertiary amines. The direct oxidation of tertiary amines is widely used in cross-dehydrogenative coupling (CDC)
reactions.16 Besides the commonly used transition metal catalysis17 and photoredox procedure,18 small organic molecules such as
DDQ are able to catalyze the oxidation of tertiary amines.19 We wondered whether the ortho-quinone catalyst could also be applied
to tertiary amine oxidation. As an initial trial, the aerobic oxidation of N-phenyl-tetrahydroisoquinoline with o-Q1 was examined in
acetonitrile at 60 °C. An oxidative amide product 7a was isolated in 48% yield after 48 h; this was determined to be the side product
of the CDC reaction (Scheme 4).20 The addition of water showed no effect on the yield of amide product, indicating that the oxygen
atom might come from molecular oxygen. This observation prompted us to further examine CDC-type coupling in the presence of
nucleophiles. After condition optimization (see Table S2 in SI), 2-equivalent nitromethane and 10% ortho-quinone catalyst under
neat conditions were employed as the optimal conditions to test the substrate scope (Scheme 5). To our delight, the scope of the
bioinspired metal-free organocatalytic CDC reaction was tolerated with various tertiary amines and nitroalkanes (see Table S3 in SI).
A series of N-aryl 1,2,3,4-tetrahydroisoquinoline derivatives with electron-donating or electron-withdrawing groups on the phenyl
ring were tolerated to undergo the CDC reaction with nitroalkanes to form the desired coupling products in good to excellent yields.
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Other nucleophiles could also react smoothly with N-phenyltetrahydroisoquinoline 6a, affording another method for C–X bond
1
2
formation.
3
4
5
6
o-Q1
(10 mol %)
N
N
MeCN (0.1 M), O2
60 oC, 16 h
Ph
Ph
6a
O
7a
7
8
9
18% (48% within 48 h)
with H2O (1 eq.): 13%
with H2O (5 eq.): 19%
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Scheme 4. Aerobic oxidation of N-phenyltetrahydroisoquinoline with o-Q1.
R1
o-Q1
(10 mol %)
R1
+
R2
R1
R3 NO2
or Nu-H
N
60 oC, O2
or
R2
N
N
Ph
12 h or 24 h
O2N
R3
Nu
6
8
9
up to 89% yield
14 examples
up to 90% yield
12 examples
MeO
MeO
N
N
N
N
N
N
Ph
Ph
Ph
Me
NO2
NO2
OMe
NO2
83%
Cl
O2N
77%
NO2
86%
73%
67%
N
N
N
N
Ph
N
O
Ph
OMe
Ph
Ph
Ph
MeO
Ph
MeO
MeO
P
NH
64%
O
O
O
N
90%
42%
62%
63%
Scheme 5. Aerobic oxidation of tertiary amines.
Mechanism Studies. In 1995, Klinman investigated the mechanism of topaquinone-dependent amine oxidases by using model
systems, and a transamination reaction mechanism was verified.4f However, the oxidation of secondary amine and tertiary amine
could not proceed via the transamination pathway; therefore other possible reaction pathways should be considered. In general, four
possible pathways were proposed for the bioinspired oxidation (Scheme 6): noncovalent pathways including (1) direct hydride
transfer and (2) single electron oxidation, covalent pathways including (3) addition−elimination and (4) transamination. To elucidate
the catalytic mechanism with ortho-quinone, we carried out detailed experimental and theoretical studies.
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Noncovalent pathway
1
I: Direct Hydride Transfer
2
3
4
5
NH2
O
O
H
MeO
NH2
o-Q1
NH
NH Ph
Ph
Me
Ph
N
Ph
Ph
Me
H
Ph
Product
1a
6
7
8
9
II: Single Electron Oxidation
NH2
HAT
or PCET
NH2
O
MeO
o-Q1
NH2
NH
Ph
Me
+
Ph
N
Ph
Ph
Me
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SET
Ph
Ph
O
Product
1a
Covalent pathway
HO
H
N
o-Q1
tBu
tBu
N
Ph
tBu
N
O
Ph
NH2
Me
- H2O
Ph
H
H
H
Ph
O
MeO
MeO
O
MeO
1a
11
10
IV: transamination
Ph
HO
H
N
tBu
NH
Ph
Ph
tBu
MeO
N
H
Ph
N
Ph
NH2
Me
NH2
Me
O
MeO
OH
Product
Ph
Ph
12
III: addition-elimination
Scheme 6. Possible oxidation pathway of α-branched primary amine oxidation.
Exclusion of the single electron transfer process. Quinones such as DDQ (2,3-dichloro-5,6-dicynobenzoquinone) are widely
used as single electron oxidants in organic synthesis. The oxidation of tertiary amines with DDQ has also been reported in the past
few years.19 Recently, Todd and co-workers revealed that the DDQ oxidation of N-phenyltetrahydroisoquinolines proceeded via a
single-electron-transfer (SET) pathway.21 To verify whether o-Q1 oxidized amines via a SET procedure, we first investigated the
oxidation potential of the amine substrates and the reduction potential of the o-Q1 catalyst via cyclic voltammetry (Figure 1). The
oxidation potential of primary, secondary and tertiary amine were determined to be 1.47 V, 1.19 V, and 0.89 V (vs Ag/AgCl),
respectively, while the reduction potential of the ortho-quinone catalyst was found to be -0.45 V (vs Ag/AgCl), thus the energy gap
of these oxidative process was 1.92 V, 1.64 V, and 1.34 V, respectively. According to the general accepted criteria,22 an electron-
transfer-initiated process would occur if the energy gap was well below the empirical energy limit (1.0 V, i.e., 23.1 kcal/mol).
However, the gap between three amine compounds and quinone catalyst was much higher than the limit. Therefore, the single electron
transfer was likely unfavorable for the catalytic reactions. We also calculated the energy difference between the starting materials
and the radical ions by using Gaussian 0923 with the same computational methods as Todd described21 (Scheme 7), the free energy
changes were 44.1, 41.1, and 32.6 kcal/mol, respectively (corresponding to 1.91 V, 1.78 V, and 1.41 V), which were in agreement
with the experimental results above. The reason for the difference in the SET process between o-Q1 and DDQ could be ascribed to
the electron-rich nature of o-Q1, which led to an unstable quinone radical anion. In addition, kinetic isotope effect (KIE) experiments
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showed primary KIEs for all three types of amines (Scheme 8), indicating that C–H bond cleavage was involved in the rate-
determining step of these oxidation processes.24
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5
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Figure 1. Cyclic voltammetry of amines and ortho-quinone catalyst (1 mmol/L) in electrolyte solution (0.1 M TBAPF6 in CH3CN),
using glassy carbon as the working electrode, and Ag/AgCl (0.1 M) as counter and reference electrode at a 100 mV/s scan rate.
NH2
O
+
N
N
Ph
H
MeO
O
1a
0.0
4a
0.0
6a
0.0
o-Q1
NH2
O
O
+
N
N
Ph
H
MeO
32.6 kcal/mol
o-Q1
44.1 kcal/mol
41.1 kcal/mol
Scheme 7. Energy differences between starting materials and the corresponding radical ions (ΔG in kcal/mol. calculation method:
M06-2X/6-311+G(3df,2p)// B3LYP/6-31G(2df,p)).
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X
o-Q1 (10 mol%)
1
2
3
4
5
6
X
NH2
X = H, or D
1a
X X
(eq. 1)
CH3CN, rt, O2
Ph
N
Ph
X = H or D
KIE = 6.5
X X
7
8
9
o-Q1 (10 mol%)
(eq. 2)
N
N
CH3CN
H
60 oC, O2
X X (> 95%)
X
10
11
12
13
14
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X = H, or D
4a
KIE = 2.6
(> 90%)
X X
X
X
o-Q1 (10 mol%)
(eq. 3)
N
N
Ph
Ph
MeNO2 (2.0 eq.)
60 oC, CH3CN
X
X X (> 95%)
NO2
X = H, or D
6a
KIE = 
Scheme 8. KIE experiments for primary, secondary, and tertiary amine oxidation.
Mechanism for the oxidation of α-branched primary amines. In situ electrospray ionization mass spectrometry (ESI-MS)
analysis of the oxidation of α-branched primary amines was conducted. Signals corresponding to hemiketal 10, substrate imine 11,
and product imine 12 could be clearly observed (Scheme 9A). An attempt to isolate the product imine 12 failed owing to
contamination of the final product and other intermediates; however, an aza-ortho-quinone side product 14 (Scheme 9B), an oxidized
product of the iminoquinone intermediate, was isolated and fully characterized by 1H and 13C nuclear magnetic resonance (NMR). In
addition, the isolation of reductive quinone catalyst 15 further supported the transamination pathway (Scheme 9C). These
experimental observations supported the transamination mechanism, in accordance with Klinman’s biomimetic studies.4e,4f Density
functional theory (DFT) calculations on the three possible H-transfer pathways were performed using Truhlar’s M06-2X method.25
For the direct hydride transfer process, the electronic differentiation of the two carbonyls on the quinone catalyst was evaluated (TS1
vs TS1a, Scheme 10, I). The results showed that the oxygen atom on the carbonyl meta to MeO group was more electron-rich, and
thus would preferentially bond with the positive N-H instead of C-H (see SI, S24 for details). A 29.2 kcal/mol energy barrier (vs 30.8
kcal/mol for TS1a) was obtained for this process. A much higher free energy barrier (46.2 kcal/mol, compared with 1a) was found
for the addition-elimination pathway, (Scheme 10, II). In comparison, the energy gap (TS3) for transamination was much lower, only
23.3 kcal/mol, consistent with an ambient-temperature reaction condition. Given that the substrate amine or additional base could
facilitate the hydrogen transfer of this transamination, we also calculated the intermolecular hydrogen transfer pathway for the
transamination of iminoquinone 11 (TS3a). Owing to the assistance of an additional amine, this process needed a lower energy barrier
than direct hydride transfer or addition-elimination, but it was still higher than that of intramolecular hydrogen transfer (TS3).
Kinetically, the reaction was determined to be first order for the α-branched primary amine 1a (Scheme 11), consistent with an
intramolecular transamination pathway (TS3, Scheme 10, III).
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A
Ph
HO
H
H
N
1
2
N
tBu
tBu
Ph
tBu
N
O
Ph
H
H
OH
MeO
3
4
MeO
O
MeO
11
12
10
5
6
Exact Mass: 316.19015
298.17972
298.18016
296.16542
296.16560
ESI-MS:
316.19072
7
8
9
B
MeO
O
N
CH3CN (0.5 mL)
rt, O2
MeO
O
O
CO2Et
+
NH2
10
11
12
13
14
15
16
17
18
19
20
70% yield
CO2Et
13
o-Q1
o-Q1
14
Ph
1 : 1
C
O
O
NH2
OH
N2
NH2
CH3CN
MeO
O
1b
15
Scheme 9. (A) ESI-MS analysis of the oxidation of α-branched primary amines. (B) Stoichiometric reaction of -branched amines
with quinone catalysts. (C) Synthesis of reductive quinone catalyst—aminophenol 15.
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
HO
H
N
tBu
Ph
O
O
tBu
O
O
H
MeO
H
46.2
H
NH
NH
O
MeO
TS2
MeO
H
Ph
TS2
tBu
H
Ph
TS1a
TS1
30.8
tBu
MeO
N
Ph
TS1a
G (kcal/mol)
H
Direct Hydride Transfer
Addition-elimination
Transamination
26.5
TS1
29.2
O
TS3a
N
H
TS3a
H
Ph
TS3
23.1
tBu
MeO
N
O
Ph
tBu
O
O
H
MeO
6.2
o-Q1
TS3
10
0
-0.2
11
tBu
NH2
o-Q1 + 1a
HO
H
N
Ph
N
Ph
Ph
1a
tBu
Ph
H
tBu
N
H
MeO
O
O
MeO
10
11
MeO
-23.1
OH
12
12
NH
tBu
MeO
OH
OH
Ph
Ph
N
2a
-55.7
18 + Int-0
Int-0
18
Scheme 10. Transition states of possible pathways in the oxidation of primary amines (calculation method: UM062x/6-
311++G(2df, 2pd)//UM06-2X/6-31G(d)). Energy relative to 1a/o-Q1 (kcal/mol).
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1
2
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7
8
9
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 11. Kinetic analysis of primary amine oxidation.
The para-quinone catalyst (TBHBQ), which was identified as an efficient catalyst for the oxidation of benzyl amines10a, was
inactive for α-branched primary amines. In a single case, the oxidation of α-branched primary amine was shown to proceed only in
the presence of a stoichiometric amount of inorganic base. To disclose the catalytic difference between ortho-quinone and para-
quinone, we analyzed the intrinsic properties of these two catalysts. Previously, Zhu and co-workers systematically investigated the
hydride affinities and one-electron reduction potentials of various p- and o-quinones.26 The hydride affinities of o-quinones were
found to be generally higher than those of p-quinones, indicating that o-quinones would be more suitable for hydride abstraction
processes. We calculated the hydride affinity of o-Q1 and TBHBQ based on Zhu’s method (Scheme 12A). The hydride affinity of o-
Q1 was found to be 3.5 kcal/mol higher than that of TBHBQ. The one-electron reduction potential calculations based on Zhu’s
equations also showed that o-Q1 was a stronger oxidant than TBHBQ. We also investigated the stoichiometric reaction of 1-
phenylethanamine with TBHBQ (Scheme 12B) by 1H NMR. Only the reactant imine 16 was formed; no oxidized product imine 17
was found. The DFT calculations revealed intramolecular O-H…N hydrogen bonding in the reactant imine intermediate TS4, which
prevented any further hydrogen-transfer process (Scheme 13). The energy barrier of this intermolecular hydrogen-transfer step
(Scheme 13, TS4) was determined to be 29.4 kcal/mol, indicating that a room-temperature reaction was unfavorable. On the other
hand, a C-H…O weak interaction was noted in the reactant imine intermediate 11 with o-Q1, facilitating 1,5-H transfer (Scheme 10,
III, TS3).
Structurally, p-quinone TBHBQ could equilibrate with an ortho-quinone derivative 16a and this equilibrium could be further driven
to ortho-quinone anion 16b in the presence of base (Scheme 13). The reactions of the latter two species with α-branched primary
amine 1a were explored by DFT. While the energy barrier was even higher for 16a via intramolecular hydrogen-transfer (TS4a, 34.2
kcal/mol), o-quinone 16b showed only a 27.2 kcal/mole barrier via a transition state TS4b (Using HCOO- as base and DMF as
solvent) (Scheme 13), similar to TS3 (Scheme 10, III). This result was consistent with the observed base effect.10a Clearly, the
presence of base equilibrated p-quinone TBHBQ to its o-quinone isomer, favoring a transamination pathway.
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The Journal of Organic Chemistry
A
O
O
1
2
3
4
5
6
7
8
GH-A = -71.1 kcal/mol
ENHE(Q/Q- = -0.27 V
GH-A = -67.7 kcal/mol
ENHE(Q/Q- = -0.45 V
O
OH
O
o-Q1
O
TBHBQ
O
OH
B
O
CD3CN (0,5 mL)
rt, N2
NH2
+
quant.
OH
OH
Ph
OH
9
N
N
O
10
11
12
13
14
16
TBHBQ
Ph
Ph
17
no detected
Scheme 12. (A) The calculated hydride affinity of quinone catalysts (the energy and frequency in gas phase was calculated with
MP2/ 6-311++g(d,p)//B3LYP/6-31+G(d), the solvation energy in DMSO was calculated with HF/6-31+g(d,p)(IEFPCM)). (B) The
stoichiometric reaction of 1-phenylethanamine with TBHBQ.
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
G = 3.9 kcal/mol
(HCOO- as base
+ HCOOH
HO
O
O
in DMF)
G = 10.1 kcal/mol
Ph
H
N
N
N
O
O
O
H
H
H
Ph
Ph
iminoquinone 16a
iminoquinone 16
iminoquinone 16b
NH2
Ph
HO
O
Ph
O
H
Ph
H
H2N
N
N
N
O
H
O
O
H
H
Ph
Ph
TS4a
TS4
TS4b
Ga = 29.4 kcal/mol
Ga = 34.2 kcal/mol
Ga = 27.2 kcal/mol
- HCOO-
HO
Me
N
Ph
OH
product imine intermediate
Scheme 13. The reaction profile of primary amine oxidation using TBHBQ (calculation method: UM062x/6-311++G(2df,
2pd)//UM06-2X/6-31G(d)).
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1
2
3
4
5
6
Mechanism for the oxidation of secondary amines. Natural quinoproteins such as CuAOs do not work with secondary amines.5
The addition of secondary amines was found to deactivate the enzymes. Mechanistically, the transamination process was not feasible
with cyclic secondary amine substrates, leaving addition-elimination and direct hydride transfer as two possible pathways. Stahl and
7
8
Kobayshi proposed an addition-elimination pathway for the secondary amine oxidation by a p-quinone or o-quinone catalyst.10,11
A
9
hemiacetal intermediate was observed and proposed to support the addition-elimination mechanism by Stahl. We also observed this
hemiacetal intermediate Int-1 by high-resolution mass spectrometry (HRMS; see Figure S5 in SI). However, with the catalysis of o-
Q1, a much higher energy (Figure 2, TS6, 42.6 kcal/mol) had to be overcome for the addition-elimination procedure. It is likely that
Int-1 was an off-cycle parasite species that reversibly entered or exited the main cycle. By contrast, the reaction barrier for direct
hydride transfer (TS5) was only 25.7 kcal/mol, consistent with a facile reaction. Meanwhile, the kinetic study showed a first-order
reaction for the secondary amine substrate (Scheme 14). These results were supportive of a direct hydride transfer process. The
primary KIE of 2.2 was also in support of this conclusion.27 Previously, Lumb28 reported the coupling of ortho-quinone and
pyrrolidine leading to an N-heterocycle via a covalent pathway. In our case, when tetrahydroisoquinoline 4a was treated with a
stoichiometric amount of o-Q1 at 60 °C, the reaction proceeded smoothly to 3,4-dihydroisoquinoline 5a and no quinone-covalent
adduct was detected.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
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59
60
HO
N
O
tBu
NH
H
MeO
H
tBu
O
O
TS6
MeO
42.6
NH
(37.1)
TS5
+
25.7
(20.2)
tBu
O
MeO
O
tBu
OH
OH
-2.0
(-6.1)
-3.6
(-8.3)
MeO
+
N
HO
H
N
O
tBu
+
H
O
N
H
tBu
MeO
-20.2
(-22.5)
MeO
O
Int-1
Int-2
Figure 2. Reaction profile of aerobic oxidation of secondary amines (calculation method: UM062x/6-311++G(2df, 2pd)//UM06-
2X/6-31G(d). Values in Figure 2 are G (kcal/mol), values in parentheses are H (kcal/mol)).
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Scheme 14. Kinetic analysis of secondary amine oxidation.
Mechanism for the oxidation of tertiary amines. For tertiary amine oxidation, non-covalent pathways may usually be possible.
As single-electron oxidation can be excluded, direct hydride transfer might be responsible for this transformation. By DFT, we located
the direct hydride-transfer transition state using the B3LYP method and 6-31G(2df,p) basis set, and the activation free energy was
determined to be 27.3 kcal/mol. The iminium ion formed in situ then reacted with the nucleophiles to complete the CDC process
(Scheme 15).
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
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50
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53
54
55
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57
58
59
60
N
N
Ph
Ph
N
Nu
Ph
9
o-Q1
H
N
Ph
tBu
O
O
Nu
Nu
H
H
6a
O
tBu
MeO
OH
OH
tBu
OH
O
[O]
TS7
G = 27.3 kcal/mol
o-Q1
TS7
MeO
Scheme 15. The cross-dehydrogenative coupling of tertiary amines with nucleophiles (calculation method: M06-2X/6-
311+G(3df,2p)// B3LYP/6-31G(2df,p)).
Oxidative half reaction of the catalyst. In previous reports, the reduced ortho-quinone catalysts, including catechol derivatives
such as 18 (Scheme 16), could be re-oxidized by electrochemical conditions9b-c or metal-promoted9e,10b-c aerobic oxidation to complete
the catalytic cycle. To look into this oxidative half reaction (re-oxidation of the reduced catalyst), we investigated the stoichiometric
reaction with o-Q1 or its reduced analogue (e.g., 15 and 18) under a nitrogen or oxygen atmosphere, respectively. In the stoichiometric
reaction with the primary amine, the performance of an aminophenol 15/O2 combination showed much lower activity than o-Q1,
resulting in a 14% yield of homo-coupling imine along with 12% o-Q1 and 83% 1a in 0.5 h. Similar phenomena were observed for
the oxidation of secondary and tertiary amines mediated by a catechol 18/O2 system (Scheme 16). Significant amounts of o-Q1 were
detected in both cases. In the CDC reaction, the desired adduct was obtained in 17% yield (vs 30% yield with o-Q1) and the catechol
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was completely oxidized to o-Q1. These results suggest that the reductive half reaction (amine oxidation) was slower than the
1
2
oxidative half reaction (reduced catalyst re-oxidation) for all the three types of amines, consistent with the KIE results.
3
4
5
6
7
8
Condition B:
15 or 18
Condition A:
(1 eq.), O2
o-Q1
(1 eq.), N2
O
OH
O
O
Stoichiometric Amine Oxidation
9
XH
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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60
CH3CN, 0.5 h
NH2
2a
: 14%
o-Q1
N
2a
5a
: 87%
: 12%
rt
15
: 71%
1a
2a
CH3CN, 0.5 h
NH
5a
: 29%
o-Q1 :
N
: 70%
: 30%
60 o
C
67%
: 30%
18
4a
5a
CH3CN, 10 h
60 o
8a
o-Q1
18
: 17%
: 86%
+ CH3NO2
Ph
N
N
Ph
8a
C
no
detected
O2N
6a
8a
Scheme 16. Comparison of reaction outcomes in stoichiometric reaction when using quinone catalyst and reductive catalyst.
We next investigated the oxidative half reaction with catechol 18 as a model compound (Table 1). Surprisingly, oxidation of
catechol barely proceeded in acetonitrile under aerobic conditions, with only 6% yield after 12 h (Table 1, entry 1). When a catalytic
amount of amine was added, the oxidation was significantly accelerated to afford ortho-quinone o-Q1 at moderate to high yield
(Table 1, entry 2-5). In general, tertiary amines had the best outcomes compared with secondary and primary amines. Even the imine
adduct showed a promoting effect (Table 1, entry 7). The use of inorganic base Na2CO3 also accelerated the oxidation (Table 1, entry
6), indicating a general base catalysis in this oxidative process.29 We also investigated the amine effect on the oxidative half reaction
using aminophenol 15. With a catalytic amount of primary amine 1a, a trimerization side product 19 instead of o-Q1 was obtained,
along with many other unidentified products (Scheme 17). Increasing the loading of primary amine inhibited the self-condensation
and side product 19 was not detected under catalytic conditions (Scheme 17). No obvious base effect was observed in this case.30
Previously, it has been reported that aerobic oxidation of catechol proceeded via radical species (e.g., 20) with a superoxide anion
(Scheme 18).31 A similar base effect was noted in cobalt-catalyzed oxidation of catechol.32 Our experiments showed that amines could
effectively promote the aerobic oxidation of catechol 18 in a metal-free context. Mechanistically, the amine would serve as an organic
base to facilitate the deprotonation of either free catechol or its radical cation, thus promoting the oxidation. Taken together, the whole
aerobic ortho-quinone catalysis involves two mutually promoting cycles, wherein the ortho-quinone catalyzes the oxidation of amines,
and the amine (or its oxidized product) catalyzes the aerobic re-oxidation of the reduced ortho-quinone.
Table 1. Additive effect on the oxidative half reactiona.
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OH
OH
O
O
CH3CN, O2
1
2
3
Amine (10 mol %)
12 h, rt
O
O
18
o-Q1
4
5
6
7
Entry
1
Amine
Yield (%)
--
5
8
9
2
3
4
43
50
83
Ph
Ph
NH2
NH2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
N
H
5
91
N
6
7
Na2CO3
85
56
Ph
N
Ph
aGeneral conditions: 18 (0.05 mmol), amine (10 mol %), and CH3CN (0.5 mL) with O2 balloon at room temperature for 12 h. Yield
determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard.
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
N
N
O
OMe
tBu
tBu
tBu
O
O
tBu
NH2
OH
1a
(1 eq.)
Amine (10 mol %)
Ph
N
Ph
CH3CN, rt, O2
0.5 h
CH3CN, rt, O2
12 h
MeO
tBu
MeO
MeO
15
14%
28%
OMe
19
8% NMR yield
Scheme 17. The re-oxidation of aminophenol 15.
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NH2
Ph
1
2
1a
tBu
X
3
4
MeO
O
tBu
N
O
Ph
5
6
7
8
H2O2
MeO
NH
11
HO2
H
tBu
N
O
Ph
tBu
X
tBu
O
O
9
H
MeO
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeO
MeO
O
TS5
TS3
20
or
H2
N
O2
R'
R
N
Ph
H
Ph
H
N
tBu
O
O
tBu
MeO
N
O2
R'
R
MeO
tBu
XH
OH
TS7
OH
12
MeO
1a
Primary Amine
15 18
or
X = NH, O
Secondary&Tertiary Amine
Scheme 18. A proposed cycle of ortho-quinone catalysis.
Conclusion
In summary, we have disclosed the mechanism of aerobic oxidation of α-branched primary amines, cyclic secondary amines, and
cyclic tertiary amines with a simple bioinspired ortho-quinone catalytic system. The transamination pathway was responsible for the
oxidation of α-branched primary amines, while secondary and tertiary amines oxidation underwent hydride transfer process. Amine
substrate as a return was found to promote the oxidative half reaction via base catalysis of the aerobic oxidation of catechols.
Experimental Section
General information. Commercial reagents were used as received unless otherwise indicated. All manipulations were conducted
with a standard Schlenk technique. H, and 13C NMR spectra were measured on a NMR instrument (300 MHz, 400 MHz, or 500
1
MHz for H NMR; 75 MHz, 101 MHz, or 126 MHz for 13C NMR). Chemical shifts of H NMR spectra were recorded relative to
TMS (δ 0.00) or residual protonated solvents (CDCl3: δ 7.26; CD3CN: δ 1.94). 13C NMR spectra were obtained at 101 or 126 MHz
using a proton-decoupled pulse sequence and were tabulated by the observed peak. Chemical shifts were reported in parts per million
(ppm) and referenced to 77.16 ppm. Nuclear Overhauser effect spectroscopy (NOESY), heteronuclear multiple-bond correlation
spectroscopy (HMBC), and heteronuclear single-quantum correlation spectroscopy (HSQC) were used to determine the structures of
products. The following abbreviations are used to express the multiplicities: s = singlet; d = doublet; t = triplet; q = quartet; m =
multiplet; br = broad. Silica gel (300–400 mesh) was used for column chromatography. Unless otherwise noted, reagents obtained
1
1
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The Journal of Organic Chemistry
from commercial suppliers were used without further purification. Infrared spectroscopy was conducted on a Thermo Fisher Nicolet
6700 instrument. HRMS was recorded on a commercial apparatus (ESI and APCl Source). Cyclic voltammograms were collected
with a Shanghai Chenhua CH1600D potentiostat. Melting points are uncorrected.
1
2
3
4
5
6
7
8
Materials. All ortho-quinone catalysts were prepared according to the relevant literature.13 Tetrahydroisoquinolines and 1,2,3,4-
tetrahydro-β-carbolines were prepared by a Pictet-Spengler reaction in two steps according to the method of Stahl,10b from
commercially available 3,4-dimethoxyphenethylamine and 2-(1H-indol-3-yl)ethanamine, whose spectroscopic data matched those
previously reported.10b,33 Other cyclic secondary amines were obtained from commercial sources and used without further purification.
N-aryltetrahydroisoquinolines were prepared according to the method of Li.17b Nucleophiles were obtained from commercial sources
and used without further purification. 1-Phenylethylamine-d1,34 3,4-dihydro-2H-isoquinoline-d2,35 and N-phenyl-1,2,3,4-
tetrahydroisoquinoline-d436 were prepared according to previously described methods.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General procedure for secondary amines oxidation. A flame-dried 10 mL flask was flushed with O2 and equipped with an O2
balloon. o-Q1 (3.88 mg, 0.02 mmol, 10 mol%) in 1.0 mL of CH3CN and secondary amine (0.2 mmol) were added to the flask. The
reaction was stirred at 60 °C for 48–72 h. After the reaction was completed, the mixture was concentrated. The yield was determined
by 1H NMR analysis by using 1,3,5-trimethoxybenzene as an internal standard. Then the crude reaction product was purified though
an Et3N-washed silica gel using 1:10–1:4 EtOAc/petro ether to give a pure product. For known compounds: 3,4-Dihydroisoquinoline
(5a)10b, white solid, 19.7 mg, 75% yield; 6,7-Dimethoxy–3,4-dihydroisoquinoline (5b)10b, white solid, 36.3 mg, 95% yield; 1H–
indole (5c)10b, yellow solid, 11.7 mg, 50% yield; Quinoline (5d)10c, yellow solid, 9.8 mg, 38% yield; 6,7-Dimethoxy–1–phenyl–3,4-
dihydroisoquinoline (5e)10b, white solid, 47.6 mg, 89% yield; 1–(4-Chlorophenyl)–6,7-dimethoxy–3,4-dihydroisoquinoline
(5f)10b, white solid, 56.1 mg, 93% yield; 1–(4-Bromophenyl)–6,7-dimethoxy–3,4-dihydroisoquinoline (5g)37, yellow solid, 60.9
mg, 88% yield; 6,7-Dimethoxy–1–(p-tolyl)–3,4-dihydroisoquinoline (5h)37, white solid, 54.0 mg, 96% yield; 1–Phenyl–4,9–
dihydro-3H–pyrido[3,4-b]indole (5i)10b,white solid, 46.3 mg, 94% yield; 1–(4-Chlorophenyl)–4,9–dihydro-3H–pyrido[3,4-
b]indole (5j) 0b, white solid, 47.1 mg, 84% yield; 1–(4-Bromophenyl)–4,9–dihydro-3H–pyrido[3,4-b]indole (5k)33, yellow solid,
57.2 mg, 88% yield; 1–(p-Tolyl)–4,9–dihydro-3H–pyrido[3,4-b]indole (5l)38, yellow solid, 44.3 mg, 85% yield.
1-(Thiophen-3-yl)-4,9-dihydro-3H-pyrido[3,4-b]indole (5m): yellow solid, 47.8 mg, 95%. Mp: 231-234 oC. 1H NMR (300 MHz,
CDCl3) δ 8.41 (br, 1H), 7.76 – 7.75 (m, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.55 – 7.53 (m, 1H), 7.44 – 7.38 (m, 2H), 7.33 – 7.30 (m, 1H),
7.21 – 7.16 (m, 1H), 4.03 – 3.97 (m, 2H), 2.97 – 2.92 (m, 2H). 13C {1H} NMR (75 MHz, CDCl3) δ 154.7, 139.9, 136.7, 127.3, 126.7,
126.0, 125.8, 124.7, 120.6, 120.1, 118.2, 112.8, 77.5, 77.1, 76.7, 48.6, 19.3. IR (KBr, cm-1): 2931, 1541, 1276, 746, 726. HRMS (ESI-
Orbitrap) m/z: [M + H]+ Calcd for C15H13N2S 253.0794; Found 253.0792.
General procedure for cross-dehydrogenative coupling reaction. A flame-dried 10 mL flask was flushed with O2 and equipped
with an O2 balloon. o-Q1 (4.85 mg, 0.025 mmol, 10 mol%), nucleophile (0.50 mmol), and N-aryltetrahydroisoquinoline (0.25 mmol)
were added to the flask. The reaction was stirred at 60 °C for 12–24 h. After the reaction was completed, the crude reaction product
was purified though a silica gel using 1:20–1:1 EtOAc/petro ether to give a pure product. For known compounds: 1–(Nitromethyl)–2–
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phenyl–1,2,3,4-tetrahydroisoquinoline (8a)39, yellow oil, 57.7 mg, 86%; 1–(1–Nitroethyl)–2–phenyl–1,2,3,4-
tetrahydroisoquinoline (8b)39, yellow oil, 62.8 mg, 89%; 1–(1–Nitropropyl)–2–phenyl–1,2,3,4-tetrahydroisoquinoline (8c)39,
yellow oil, 62.8 mg, 83%; 1–(Nitromethyl)–2–(m–tolyl)–1,2,3,4-tetrahydroisoquinoline (8d)40, yellow oil, 51.5 mg, 73%; 1–(1–
Nitroethyl)–2–(m–tolyl)–1,2,3,4-tetrahydroisoquinoline (8e)40, yellow oil, 49.6 mg, 67%; 1–(Nitromethyl)–2–(p-tolyl)–1,2,3,4-
tetrahydroisoquinoline (8f)39, yellow oil, 60.7 mg, 86%; 1–(Nitromethyl)–2–(p-tolyl)–1,2,3,4-tetrahydroisoquinoline (8g)39,
yellow oil, 63.7 mg, 86%; 2–(4-Methoxyphenyl)–1–(nitromethyl)–1,2,3,4-tetrahydroisoquinoline (8h)39, yellow solid, 54.4 mg,
73%; 2–(4-Methoxyphenyl)–1–(1–nitroethyl)–1,2,3,4-tetrahydroisoquinoline (8i)40, yellow solid, 57.8 mg, 74%; 2–(4-
Chlorophenyl)–1–(nitromethyl)–1,2,3,4-tetrahydroisoquinoline (8j)39, yellow solid, 62.8 mg, 83%; 2–(4-Chlorophenyl)–1–(1–
nitroethyl)–1,2,3,4-tetrahydroisoquinoline (8k)41, yellow solid, 64.1 mg, 81%; 2–(4-Bromophenyl)–1–(nitromethyl)–1,2,3,4-
tetrahydroisoquinoline (8l)39, yellow solid, 73.8 mg, 85%; 2–(4-Bromophenyl)–1–(1–nitroethyl)–1,2,3,4-tetrahydroisoquinoline
(8m)39, yellow solid, 65.0 mg, 72%; 2–(3-Methoxyphenyl)–1–(1–nitroethyl)–1,2,3,4-tetrahydroisoquinoline (8n)42, yellow oil,
58.2 mg, 78%; 2–(2–Methoxyphenyl)–1–(nitromethyl)–1,2,3,4-tetrahydroisoquinoline (8o)39, yellow oil, 27.6 mg, 37%; 6,7-
Dimethoxy–1–(nitromethyl)–2–phenyl–1,2,3,4-tetrahydroisoquinoline (8p)39, yellow oil, 63.2 mg, 77%; Dimethyl 2–(2–phenyl–
1,2,3,4-tetrahydroisoquinolin–1–yl)malonate (9a)39, colorless oil, 76.4 mg, 90%; Diethyl 2–(2–phenyl–1,2,3,4-
tetrahydroisoquinolin–1–yl)malonate (9b)43, colorless oil, 75.3 mg, 82%; 1–(1H–Indol–3-yl)–2–phenyl–1,2,3,4-
tetrahydroisoquinoline (9c)41, yellow solid, 51.9 mg; 1–(5-Methyl–1H–indol–3-yl)–2–phenyl–1,2,3,4-tetrahydroisoquinoline
(9d)44, yellow solid, 53.3 mg, 63%; 1–(1–Methyl–1H–indol–3-yl)–2–phenyl–1,2,3,4-tetrahydroisoquinoline (9e)41, yellow solid,
35.5 mg, 42%; Dimethyl (2–phenyl–1,2,3,4-tetrahydroisoquinolin–1–yl)phosphonate (9f)43, colorless oil, 49.2 mg, 62%; Diethyl
(2–phenyl–1,2,3,4-tetrahydroisoquinolin–1–yl)phosphonate (9g)19b, colorless oil, 52.7 mg, 61%; Diisopropyl (2–phenyl–1,2,3,4-
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tetrahydroisoquinolin–1–yl)phosphonate (9h)19b
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colorless oil, 53.2 mg, 57%; 1–Phenyl–2–(2–phenyl–1,2,3,4-
tetrahydroisoquinolin–1–yl)ethanone (9i)19b, colorless oil, 51.6 mg, 63%.
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9–Methyl–1–(nitromethyl)–2–phenyl–2,3,4,9–tetrahydro-1H–pyrido[3,4-b]indole (8q): yellow oil, 54.0 mg, 67% yield. H
NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.9 Hz, 1H), 7.32 – 7.19 (m, 4H), 7.14 – 7.10 (m, 1H), 7.00 (d, J = 7.9 Hz, 2H), 6.86 (t, J =
7.3 Hz, 1H), 5.61 (dd, J = 10.2, 3.3 Hz, 1H), 4.92 (dd, J = 12.5, 10.3 Hz, 1H), 4.65 (dd, J = 12.5, 3.4 Hz, 1H), 3.97 (dd, J = 14.7, 5.6
Hz, 1H), 3.75 (s, 3H), 3.65 –3.62 (m, 1H), 3.03 – 2.98 (m, 1H), 2.69 (dd, J = 15.9, 3.9 Hz, 1H). 13C {1H} NMR (101 MHz, CDCl3) δ
149.6, 137.6, 130.1, 129.4, 126.6, 122.6, 121.0, 119.7, 118.7, 118.1, 110.8, 109.2, 54.9, 42.1, 29.9, 18.8. IR (KBr, cm-1): 3057, 2942,
1601, 1557, 747. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C19H20N3O2 322.1550; Found 322.1548.
Kinetic isotope effect studies for amine oxidation. Kinetic isotope effect studies for amine oxidation. (a) Primary amine: To
a solution of o-Q1 (7.76 mg, 0.04 mmol) and 1,3,5-trimethoxybenzene (11.2 mg, 0.06 mmol) in 1 mL of CD3CN in a NMR tube was
added 1-phenylethanamine (48.4 mg, 0.4 mmol) or α-d-1-phenylethanamine (48.8 mg, 0.4 mmol). The NMR tube was flushed with
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O2. The reaction was monitored by H NMR analysis for 0.5 h (<10% conversion). The initial rates of varied concentration of 1-
phenylethanamine 1a or d-1a (0.25 mol/L, 0.33 mol/L, 0.40 mol/L, 0.56 mol/L, 0.60 mol/L) were measured, respectively. The rate
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constant was determined by plotting initial rates vs concentrations. The KIE was determined to be 6.5 based on the comparison of
rate constant (kH/kD). (b) Secondary amine: To a mixture of o-Q1 (3.88 mg, 0.02 mmol) and 1,3,5-trimethoxybenzene (11.2 mg, 0.06
mmol) or dimethyl sulfone (9.41 mg, 0.10 mmol) in 1.0 mL of CD3CN in a NMR tube was added 4a (26.6 mg, 0.20 mmol) or d4-4a
(27.7 mg, 0.20 mmol). The NMR tube was flushed with O2. The reaction was conducted at 60 °C and monitored by 1H NMR analysis
for 1 h (<10% conversion). The initial rates of different concentration of 4a or d4-4a (0.10 mol/L, 0.15 mol/L, 0.22 mol/L, 0.25 mol/L,
0.30 mol/L) were measured respectively. The rate constant was determined by plotting initial rates vs concentrations. The KIE was
determined to be 2.6 based on the comparison of rate constant. (c) Tertiary amine: To a mixture of o-Q1 (4.85 mg, 0.025 mmol),
nitromethane (30.6 mg, 0.50 mmol) and 1,3,5-trimethoxybenzene (11.2 mg, 0.06 mmol) in 0.4 mL of CD3CN in a NMR tube was
added N-phenyltetrahydroisoquinoline 6a (52.5 mg, 0.25 mmol) or d4-6a (53.5 mg, 0.25 mmol). The NMR tube was flushed with O2.
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The reaction was conducted at 60 °C and monitored by H NMR analysis for 3 h (<10% conversion). The initial rates of different
concentration of 6a or d4-6a (0.38 mol/L, 0.43 mol/L, 0.50 mol/L, 0.55 mol/L, 0.75 mol/L) (the amount of nitromethane unchanged)
were measured, respectively. The rate constant was determined by plotting initial rates vs concentrations. The KIE was determined
to be 6.0 based on the comparison of rate constant.
Kinetic measurements of the oxidation of α-branched primary amines. To a solution of o-Q1 (7.76 mg, 0.04 mmol) and 1,3,5-
trimethoxybenzene (8.41 mg, 0.05 mmol) in 1.0 mL of CD3CN in a NMR tube was added 1-phenylethanamine (48.4 mg, 0.4 mmol).
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The reaction was monitored by H NMR analysis for 0.5 h. Experiments with different substrate concentrations were conducted
independently.
In-situ HRMS analysis for primary amine oxidation. To a solution of o-Q1 (9.70 mg, 0.05 mmol) in 0.5 mL of CH3CN in a
flask was added 1-phenylethanamine (12.1 mg, 0.1 mmol). After stirring for 30 min at room temperature, the reaction solution was
diluted by CH3CN, taking 5 µL of the diluted solution for ESI-MS analysis.
Stoichiometric reaction of phenylalanine ethyl ester with o-Q1. To a solution of o-Q1 (19.4 mg, 0.1 mmol) in 0.5 mL of CH3CN
was added phenylalanine ethyl ester (19.3 mg, 0.1 mmol). The tube was then flushed with O2 and equipped with an O2 balloon. The
reaction was stirred for 24 h at room temperature. After the reaction had been completed, the reaction mixture was concentrated.
Then, the reaction crude product was purified though an Et3N-washed silica gel using 1:10 EtOAc/petro ether to give pure product
14 as a yellow oil (26 mg, 70%). The spectroscopic data for 14 matched those described in the literature.13a 1H NMR (400 MHz,
CDCl3) δ 7.47 (s, 1H), 7.34 – 7.30 (m, 5H), 6.34 (s, 1H), 6.25 (s, 1H), 4.40 – 7.34 (m, 2H), 3.78 (s, 3H), 1.36 – 1.33 (m, 13H). 13
C
{1H} NMR (101 MHz, CDCl3) δ 163.41, 161.80, 147.73, 145.15, 136.62, 132.87, 129.30, 128.99, 128.32, 127.52, 125.19, 99.73,
72.68, 62.31, 55.42, 34.64, 29.94, 14.33. IR (KBr, cm-1): 2961, 1741, 1616, 1205, 756. HRMS (ESI-Orbitrap) m/z: [M + H]+
C22H26O4N Calcd for 368.1856; Found 368.1851.
Synthesis of reductive quinone catalyst—aminophenol 15. A flame-dried 10 mL flask was charged with o-Q1 (194.1 mg, 1.00
mmol). Benzylamine (214.0 mg, 2.00 mmol) and MeCN (2.0 mL) were added to the flask, and then it was degassed three times by a
standard freeze–thaw method. The reaction was stirred at room temperature. After 3 h, the reaction mixture was concentrated, and
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filtrated. The residue was washed with ether, and dried under vacuum to obtain aminophenol 15 as a light green solid (137 mg ,70%).
Mp: 159-161 oC. 1H NMR (500 MHz, DMSO-d6) δ 8.69 (br, 1H), 6.51 (s, 1H), 6.37 (s, 1H), 3.99 (s, 3H), 1.24 (s, 9H). 13C {1H} NMR
(125 MHz, DMSO-d6) δ 150.1, 142.8, 129.1, 128.5, 102.1, 56.2, 34.1, 30.6. IR (KBr, cm-1): 3387, 3312, 2957, 1508, 1462, 1326,
1208, 1187, 1074, 849. HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C11H18O2N 196.1332; Found 196.1331.
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Stoichiometric reaction of 1-phenylethanamine with TBHBQ. To a solution of TBHBQ (9.0 mg, 0.05 mmol) in 0.5 mL of
CD3CN was added 1-phenylethanamine (6.1 mg, 0.05 mmol). The tube was then flushed with N2. The reaction was stirred for 5 h at
room temperature. After the reaction had been completed, the reaction mixture was concentrated. The reaction crude product was
purified though an Et3N-washed silica gel ether to give pure product 16 as a yellow oil (14 mg, 99%). The spectroscopic data for 16
matched those described in the literature.13a 1H NMR (300 MHz, CDCl3) δ 7.38 – 7.27 (m, 5H), 6.99 (s, 1H), 5.88 (s, 1H), 5.19 (q, J
= 6.5 Hz, 1H), 1.62 (d, J = 6.6 Hz, 3H), 1.28 (s, 9H). 13C {1H} NMR (75 MHz, CDCl3) δ 188.05, 157.61, 153.88, 152.25, 143.81,
128.99, 127.71, 126.61, 116.97, 106.85, 59.43, 35.94, 29.71, 25.11. IR (KBr, cm-1): 3391, 2963, 1668, 1615, 1495, 758. HRMS (ESI-
Orbitrap): m/z: [M - H]- Calcd for C18H20O2N 282.1500; Found 282.1499.
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Kinetic measurements of the oxidation of secondary amines. To a mixture of o-Q1 (3.88 mg, 0.02 mmol) and 1,3,5-
trimethoxybenzene (11.2 mg, 0.06 mmol) or dimethyl sulfone (9.41 mg, 0.10 mmol) in 1.0 mL of CD3CN in a NMR tube was added
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4a (26.6 mg, 0.20 mmol). The NMR tube was flushed with O2. The reaction was conducted at 60 °C and monitored by H NMR
analysis for 1 h. Experiments with different substrate concentration were conducted independently.
Synthesis of reductive quinone catalyst (4-(tert-Butyl)-5-methoxybenzene-1,2-diol, 18). This compound was prepared in one
step according to a previously reported method and the spectroscopic data for 18 matched those described in the literature.45 To a
solution of 1.94 g (10 mmol) of o-Q1 in 25 mL of ethanol was added slowly a solution containing 2.0 g (11.5 mmol) of sodium
hydrosulfite in 30 mL of water and 15 mL of ethanol at room temperature. The addition was completed in 30 min, and the stirring
was continued for an additional 20 min. The reaction mixture was diluted with 100 mL of water and extracted with 200 mL of ether.
The aqueous layer was extracted twice with 50 mL of ether. The ether layer was dried over anhydrous MgSO4, and the solvent was
removed under reduced pressure. The product was crystallized from hexane to give 1.3 g (66%) of 18 as a white solid. Mp: 76-78 oC.
1H NMR (300 MHz, CDCl3) δ 6.80 (s, 1H), 6.49 (s, 1H), 5.18 (br, 1H), 4.61 (br, 1H), 3.74 (s ,3H), 1.31 (s ,9H). 13C {1H} NMR (75
MHz, CDCl3) δ 153.2, 142.2, 135.6, 131.0, 114.7, 101.2, 55.8, 34.3, 30.0. IR (KBr, cm-1): 3322, 2956, 1617, 1510, 1484, 1197.
HRMS (ESI-Orbitrap): m/z: [M - H]- Calcd for C11H15O3 195.1027; Found 195.1020.
General procedure for stoichiometric amine oxidation. (a) α-Branched primary amine: A flame-dried 10 mL flask was flushed
with O2 and equipped with an O2 balloon. 1a (12.1 mg, 0.10 mmol), o-Q1 or aminophenol 15 (0.05 mmol) and MeCN (0.5 mL) were
added to the flask. The reaction was stirred at room temperature. After 0.5 h, the reaction mixture was concentrated, and the yield of
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products and conversion of catechol were determined by H NMR of the crude mixture versus 1,3,5-trimethoxybenzene. (b)
Secondary amine: A flame-dried 10 mL flask was flushed with O2 and equipped with an O2 balloon. 4a (6.7 mg, 0.05 mmol), o-Q1
or catechol 18 (0.05 mmol) and MeCN (0.5 mL) were added to the flask. The reaction was stirred at 60 °C. After 0.5 h, the reaction
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mixture was concentrated, and the yield of 5a and conversion of catechol were determined by 1H NMR of the crude mixture versus
1,3,5-trimethoxybenzene. (C) Tertiary amine: A flame-dried 10 mL flask was flushed with O2 and equipped with an O2 balloon. 6a
(10.5 mg, 0.05 mmol), nitromethane (12.2 mg, 0.1 mmol), o-Q1 or catechol 18 (0.05 mmol) and MeCN (0.1 mL) were added to the
flask. The reaction was stirred at 60 °C. After 10 h, the reaction mixture was concentrated, and the yield of 8a and conversion of
catechol were determined by 1H NMR of the crude mixture versus 1,3,5-trimethoxybenzene.
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General procedure for additive effect on the oxidative half reaction. A flame-dried 10 mL flask was flushed with O2 and
equipped with an O2 balloon. 18 (0.05 mmol), amine or base (0.005 mmol, 10%) and MeCN (0.5 mL) were added to the flask. The
reaction was stirred at room temperature. After 12 h, the reaction mixture was concentrated, and the yield of o-Q1 was determined
by 1H NMR of the crude mixture versus 1,3,5-trimethoxybenzene.
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Amine effect on the re-oxidation of aminophenol 15. A flame-dried 10 mL flask was flushed with O2 and equipped with an O2
balloon. 15 (0.05 mmol), benzylamine (0.54 mg, 0.005 mmol) and MeCN (0.5 mL) were added to the flask. The reaction was stirred
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at room temperature. After 12 h, the reaction mixture was concentrated, and the yield of 19 was determined by H NMR of crude
mixture versus 1,3,5-trimethoxybenzene. Then the reaction crude product was purified though silica gel by using 1:5 EtOAc/petro
ether to give pure product 19 as a white solid. Mp: 247-252 oC. 1H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.40 (s, 1H), 6.78 (s, 1H),
6.69 (s, 1H), 6.52 (s, 1H), 4.85 (s, 1H), 3.91 (s, 3H), 3.77 (s ,3H), 3.70 (s, 3H), 1.41 (s ,9H), 1.39 (s ,9H), 1.25 (s ,9H). 13C {1H} NMR
(125 MHz, CDCl3) δ 173.9, 166.4, 158.9, 156.7, 154.9, 148.4, 146.9, 137.6, 134.8, 133.9, 125.0, 119.2, 118.8, 117.7, 106.3, 93.6,
92.7, 56.2, 55.6, 55.4, 36.2, 35.2, 35.1, 30.2, 30.1, 29.9. IR (KBr, cm-1): 1717, 1626, 1506, 1463, 1425, 1391, 1232, 1193, 1083, 988.
HRMS (ESI-Orbitrap) m/z: [M + H]+ Calcd for C33H43O5N2 547.3167; Found 547.3161.
ASSOCIATED CONTENT
Supporting Information
Substrate scope, mechanism details, computation section and 1H and 13C NMR spectra are available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: luosz@tsinghua.edu.cn
* E-mail: zhanglong@tsinghua.edu.cn.
Author Contributions
§R.Z. and Y.Q. contributed equally to this work.
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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We thank the Natural Science Foundation of China (21390400, 21572232 and 21521002) and the Chinese Academy of Science (QYZDJ-
SSW-SLH023) for financial support. S. L. is supported by National Program of Top-notch Young Professionals.
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REFERENCES
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Containing Copper Amine Oxidases. Biochemistry 2002, 41, 9269. (d) Rinaldi, A. C.; Rescigno, A.; Rinaldi, A.; Sanjust, E. Modeling Novel
Quinocofactors: An Overview. Bioorg. Chem. 1999, 27, 253.
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Eukaryotic Enzymes: 6-Hydroxydopa at the Active Site of Bovine Serum Amine Oxidase. Science 1990, 248, 981.
(3) Salisbury, S. A.; Forrest, H. S.; Cruse, W. B. T.; Kennard, O. A Novel Coenzyme from Bacterial Primary Alcohol Dehydrogenases.
Nature 1979, 280, 843.
(4) For selected examples, see: (a) Janes, S. M.; Klinman, J. P. An Investigation of Bovine Serum Amine Oxidase Active Site Stoichiometry:
Evidence for An Aminotransferase Mechanism Involving Two Carbonyl Cofactors Per Enzyme Dimer. Biochemistry 2002, 30, 4599. (b)
Janes, S. M.; Palcic, M. M.; Scaman, C. H.; Smith, A. J.; Brown, D. E.; Dooley, D. M.; Mure, M.; Klinman, J. P. Identification of
Topaquinone and Its Consensus Sequence in Copper Amine Oxidases. Biochemistry 1992, 31, 12147. (c) Hartmann, C.; Brzovic, P.;
Klinman, J. P. Spectroscopic Detection of Chemical Intermediates in the Reaction of Para-Substituted Benzylamines with Bovine Serum
Amine Oxidase. Biochemistry 1993, 32, 2234. (d) Mure, M.; Klinman, J. P. Synthesis and Spectroscopic Characterization of Model
Compounds for the Active Site Cofactor in Copper Amine Oxidases. J. Am. Chem. Soc. 1993, 115, 7117. (e) Mure, M.; Klinman, J. P. Model
Studies of Topaquinone-Dependent Amine Oxidases. 1. Oxidation of Benzylamine by Topaquinone Analogs. J. Am. Chem. Soc. 1995, 117,
8698. (f) Mure, M.; Klinman, J. P. Model Studies of Topaquinone-Dependent Amine Oxidases. 2. Oxidation of Benzylamine by Topaquinone
Analogs. J. Am. Chem. Soc. 1995, 117, 8707. (g) Plastino, J.; Green, E. L.; Sanders-Loehr, J.; Klinman, J. P. An Unexpected Role for the
Active Site Base in Cofactor Orientation and Flexibility in the Copper Amine Oxidase from Hansenula Polymorpha. Biochemistry 1999, 38,
8204. (h) Schwartz, B.; Olgin, A. K.; Klinman, J. P. The Role of Copper in Topa Quinone Biogenesis and Catalysis, as Probed by Azide
Inhibition of a Copper Amine Oxidase from Yeast. Biochemistry 2001, 40, 2954. (i) Mure, M.; Wang, S. X.; Klinman, J. P. Synthesis and
Characterization of Model Compounds of the Lysine Tyrosyl Quinone Cofactor of Lysyl Oxidase. J. Am. Chem. Soc. 2003, 125, 6113.
(5) For selected examples, see: (a) Lee, Y.; Sayre, L. M. Model Reactions for the Quinone-Containing Copper Amine Oxidases. Anaerobic
Reaction Pathways and Catalytic Aerobic Deamination of Activated Amines in Buffered Aqueous Acetonitrile J. Am. Chem. Soc. 1995, 117,
3096. (b) Lee, Y.; Sayre, L. M. Model Studies on the Quinone-Containing Copper Amine Oxidases. Unambiguous Demonstration of a
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Transamination Mechanism. J. Am. Chem. Soc. 1995, 117, 11823. (c) Ling, K.-Q.; Kim, J.; Sayre, L. M. Catalytic Turnover of Benzylamine
by a Model for the Lysine Tyrosylquinone (LTQ) Cofactor of Lysyl Oxidase. J. Am. Chem. Soc. 2001, 123, 9606. (d) Lee, Y.; Jeon, H.-B.;
Huang, H.; Sayre, L. M. Temporary Inactivation of Plasma Amine Oxidase by Alkylhydrazines. A Combined Enzyme/Model Study
Implicates Cofactor Reduction/Reoxidation but Cofactor Deoxygenation and Subsequent Reoxygenation in the Case of Hydrazine Itself. J.
Org. Chem. 2001, 66, 1925.
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(6) For selected examples, see: (a) Murakami, Y.; Yoshimoto, N.; Fujieda, N.; Ohkubo, K.; Hasegawa, T.; Kano, K.; Fukuzumi, S.; Itoh, S.
Model Studies of 6,7-Indolequinone Cofactors of Quinoprotein Amine Dehydrogenases. J. Org. Chem. 2007, 72, 3369. (b) Itoh, S.; Takada,
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Wu. L.-Z.; Tung, C.-H. Visible-Light-Promoted Asymmetric Cross-Dehydrogenative Coupling of Tertiary Amines to Ketones by Synergistic
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H
H
O
O
H
NH2
BDE = 67.5 kcal/mol
BDE = 88 kcal/mol
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http://ibond.nankai.edu.cn). Benzylamine: 9.39 (H2O); Diallylamine: 9.29 (H2O); α-Methylbenzylamine: 9.59 (H2O); Quinuclidine: 11.29
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Related to Butylated Hydroxyanisole. J. Pharm. Sci. 1988, 77, 393.
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