Bioinspired aerobic oxidation of secondary amines and nitrogen heterocycles with a bifunctional quinone catalyst

Article abstract of DOI:10.1021/ja411692v

Copper amine oxidases are a family of enzymes with quinone cofactors that oxidize primary amines to aldehydes. The native mechanism proceeds via an iminoquinone intermediate that promotes high selectivity for reactions with primary amines, thereby constraining the scope of potential biomimetic synthetic applications. Here we report a novel bioinspired quinone catalyst system consisting of 1,10-phenanthroline-5,6-dione/ZnI₂ that bypasses these constraints via an abiological pathway involving a hemiaminal intermediate. Efficient aerobic dehydrogenation of non-native secondary amine substrates, including pharmaceutically relevant nitrogen heterocycles, is demonstrated. The ZnI₂ cocatalyst activates the quinone toward amine oxidation and provides a source of iodide, which plays an important redox-mediator role to promote aerobic catalytic turnover. These findings provide a valuable foundation for broader development of aerobic oxidation reactions employing quinone-based catalysts.

Full text of DOI:10.1021/ja411692v

Article
pubs.acs.org/JACS
Bioinspired Aerobic Oxidation of Secondary Amines and Nitrogen
Heterocycles with a Bifunctional Quinone Catalyst
Alison E. Wendlandt and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: Copper amine oxidases are a family of enzymes with quinone
cofactors that oxidize primary amines to aldehydes. The native mechanism
proceeds via an iminoquinone intermediate that promotes high selectivity for
reactions with primary amines, thereby constraining the scope of potential
biomimetic synthetic applications. Here we report a novel bioinspired
quinone catalyst system consisting of 1,10-phenanthroline-5,6-dione/ZnI2 that
bypasses these constraints via an abiological pathway involving a hemiaminal
intermediate. Efficient aerobic dehydrogenation of non-native secondary
amine substrates, including pharmaceutically relevant nitrogen heterocycles, is
demonstrated. The ZnI2 cocatalyst activates the quinone toward amine
oxidation and provides a source of iodide, which plays an important redox-mediator role to promote aerobic catalytic turnover.
These findings provide a valuable foundation for broader development of aerobic oxidation reactions employing quinone-based
catalysts.
The function of quinone cofactors in nature is not limited to
primary amine oxidation. For example, pyrroloquinoline
quinone (PQQ)-dependent alcohol dehydrogenases (Figure
2) mediate alcohol oxidation via a mechanism that involves a
hemiacetal intermediate, resembling the addition−elimination
mechanism in Figure 1B.15−17 Identification of new quinone-
based catalysts that operate via an addition−elimination
mechanism could significantly enhance the synthetic scope of
such oxidation reactions. Kobayashi proposed the involvement
of hemiaminal intermediates in diverse amine oxidation
reactions that use Pt/Ir nanoclusters and 4-tert-butylcatechol
as cocatalysts.8 In this work, we have expanded this concept by
showing that 1,10-phenanthroline-5,6-dione (phd) (Figure 2) is
an effective catalyst for secondary amine oxidation. Funda-
mental studies have provided direct evidence for the addition−
elimination pathway, including spectroscopic characterization
of the hemiaminal intermediate. We further show that
coordination of the distal nitrogen atoms to Zn2+ enhances
the amine oxidation activity of phd and that a catalyst system
composed of phd and ZnI2 promotes efficient aerobic oxidation
of a variety of secondary amines and nitrogen heterocycles.
INTRODUCTION
■
Enzymatic transformations have provided the inspiration for
numerous advances in synthetic chemistry and catalysis. In
connection with the widespread interest in the development of
aerobic oxidation reactions, numerous researchers have turned
to metalloenzymes as a starting point for the development of
small-molecule transition-metal catalysts. Organic cofactors are
also common in naturally occurring oxidases and oxygenases,
but these have been less extensively developed for use in
synthetic applications. Copper amine oxidases promote aerobic
oxidation of primary amines to aldehydes in nature (Figure 1).1
Copper is present in the enzyme, but substrate oxidation is
promoted exclusively by a quinone cofactor in the active site.
The mechanism of the reaction was the subject of considerable
historical debate that focused on two possible pathways:2,3
a
“transamination” pathway involving the formation and
oxidation of an iminoquinone intermediate (Figure 1A) and
an “addition−elimination” pathway involving substrate oxida-
tion via a hemiaminal intermediate (Figure 1B). Extensive
mechanistic studies of the enzyme and model systems by
Klinman, Sayre, and others convincingly demonstrated that the
reaction proceeds via the transamination pathway.4,5
Recently, several groups have begun to explore quinone-
based catalysts6−9 as alternatives to metal-based catalysts for
amine dehydrogenation.10−12 The use of quinones Q16 and
Q27 (Scheme 1) enables efficient and selective production of
homo- and heterocoupled imines under mild reaction
conditions (Scheme 1). These catalysts show exquisite
selectivity for primary amines, similar to the native enzymes.
Secondary amines are not compatible with the transamination
mechanism, and they often serve as inhibitors via the formation
of irreversible covalent adducts.13,14
RESULTS AND DISCUSSION
■
Stoichiometric Secondary Amine Oxidation and
Characterization of a Hemiaminal Adduct. In an effort
to expand upon our earlier studies of quinone-mediated amine
oxidation,6 we were drawn to the structure of phd as a potential
catalyst because of its bifunctional character associated with the
o-quinone moiety and the distal chelating nitrogen atoms
Received: November 16, 2013
© XXXX American Chemical Society
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Figure 1. Mechanism of aerobic amine oxidation mediated by copper amine oxidase enzymes. (A) “Transamination” mechanism involving covalent
imine intermediates. (B) “Addition−elimination” mechanism involving a hemiaminal intermediate.
PQQ, and they observed stoichiometric oxidation of various
amines, including the secondary amine morpholine. No
catalytic reactivity was observed, however, and the reaction
with morpholine led to the formation of an irreversible covalent
adduct.14,22 Catalytic dehydrogenation of secondary amines is
also an important target because the unsaturated heterocyclic
products are prevalent in pharmaceuticals and other biologically
active molecules.23
Scheme 1. Biomimetic Precatalysts Q1 and Q2 and Their
Synthetic Application to Oxidative Homo- and Cross-
Coupling of Primary Amines
Our initial studies probed the stoichiometric reaction of
1,2,3,4-tetrahydroisoquinoline (1) with phd in MeCN. The
reaction proceeded quantitatively at room temperature within
18 h to afford 3,4-dihydroisoquinoline (2) and 1,10-
phenanthroline-5,6-diol (phd-H2) as a yellow-green precipitate
(eq 1). The effectiveness of this reaction was better than
expected in light of Bruice’s precedent showing that secondary
amines could form irreversible covalent adducts with phd
analogues.14
1
The reaction of 1 with phd was monitored by H NMR
spectroscopy to determine whether intermediates could be
observed. Upon addition of 6 equiv of 1 in MeCN-d3 at room
temperature, the characteristic phd resonances disappeared
with the concomitant formation of new broad peaks. Variable-
temperature studies demonstrated these broad peaks to be
associated with an equilibrium exchange process occurring on
the NMR time scale. The broad peaks were resolved at lower
temperature (Figure 3 and Figure S1 in the Supporting
Information) to reveal the presence of a new species, and the
chemical exchange process was sufficiently slow at −40 °C to
enable full characterization of this intermediate by NMR
spectroscopy.24 It was identified as hemiaminal A (Figure 3A)
Figure 2. (left) Pyrroloquinoline quinone (PQQ) and (right) phd, a
modular, bifunctional catalyst for amine oxidation. The o-quinone
moiety is responsible for substrate oxidation, while the remote metal-
binding sites can be used to tune the quinone reactivity.
(Figure 2). Independently, the coordination chemistry of phd
with a number of different metals has been investigated.18−20
We speculated that these two features could be combined to
achieve unique amine oxidation reactivity.21 The dehydrogen-
ation of cyclic secondary amines was targeted because these
substrates have been ineffective with traditional amine oxidase
mimics. For example, Bruice and co-workers studied isomeric
phenanthroline-derived o-quinones as models of the cofactor
1
1
on the basis of H−13C and H−15N gradient heteronuclear
single-quantum coherence (gHSQC) and gradient hetero-
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1
Figure 3. Observation of hemiaminal intermediate A by variable-temperature H NMR spectroscopy.
nuclear multiple-bond correlation (gHMBC) data as well as 1D
nuclear Overhauser effect spectroscopy (NOESY) data (see
Figures S2−S6 in the Supporting Information).
NMR titration studies of phd with 1 in MeCN-d3 (Figure S7
in the Supporting Information) were used to establish the
equilibrium constant for hemiaminal formation as K = 0.10
mM−1 at −40 °C. Exchange spectroscopy (EXSY) experiments
carried out with 6 equiv of 1 revealed exchange between 1 and
the hemiaminal and between the hemiaminal and free phd
(Figures S8 and S9 in the Supporting Information).
Zn2+-Promoted Amine Oxidation and Characteriza-
tion of Zn−phd Complexes. The prospect that metal ions
could promote phd-mediated amine oxidation was tested by
adding various quantities of Zn(OTf)2 to the reaction mixture.
The most significant rate enhancement was observed with 0.5
equiv of Zn(OTf)2 (i.e., phd/Zn2+ = 2:1), which led to an 11-
fold increase in the initial rate of the oxidation of 1 by phd
(Figure 4). The formation of large quantities of a precipitate,
presumably corresponding to a Zn2+/phd-H2 coordination
polymer, slowed the reaction after approximately 40−50%
conversion under these conditions.
Figure 4. Rates of the stoichiometric reaction of 1 with phd at −10 °C
in acetonitrile with and without 0.5 equiv of Zn(OTf)2. Reaction
conditions: [phd] = 19 mM (0.019 mmol), [1] = 114 mM (0.114
mmol), [Zn(OTf)2] = 9.5 mM (0.095 mmol), MeCN (1 mL), −10
°C.
NMR titration studies of Zn(OTf)2 and phd in MeCN-d3
revealed the sequential formation of three discrete species in
solution, corresponding to [Zn(phd)3]2+, [Zn(phd)2]2+, and
[Zn(phd)]2+ (Figure 5 and Figure S10 in the Supporting
Catalytic Aerobic Oxidation of Secondary Amines.
The oxidation of tetrahydroisoquinoline 1 to dihydroisoquino-
line 2 was then tested with catalytic quantities of phd (5 mol %)
and different Zn2+ sources (2.5 mol %) under O2 (1 atm)
(Table 1). Negligible catalytic turnover was observed in the
oxidation of 1 by phd in the absence of Zn2+ ions (7% yield),
and little improvement was achieved by including Zn(OTf)2,
Zn(OAc)2, ZnCl2, or ZnBr2 (Table 1, entries 1−5). Use of
ZnI2, however, resulted in significant catalytic turnover (55%
yield; entry 6). The yield further improved upon the addition of
1
Information). H−15N HMBC experiments revealed that the
phd 15N resonances shifted from 313 to 251 ppm in the
presence of Zn(OTf)2 (Figures S11 and S12 in the Supporting
Information), consistent with coordination of the pyridyl
nitrogen atoms to Zn. X-ray-quality crystals of a [Zn(phd)2]2+
species were obtained from a 2:1 phd/Zn(OTf)2 mixture in
MeCN, confirming the coordination of phd to Zn (Figure 6).
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Table 1. Optimization of the Reaction Conditions for the
Catalytic Aerobic Oxidation of Tetrahydroisoquinoline (1)
a
entry
quinone
additive
additive
yield of 2 (%)
1
2
5% phd
5% phd
5% phd
5% phd
5% phd
5% phd
5% phd



7
2.5% ZnOTf2
2.5% ZnOAc2
2.5% ZnCl2
2.5% ZnBr2
2.5% ZnI2
2.5% ZnI2
2.5% ZnI2


7
3

7
4

7
5

10
55
75
NR
7
6

7
15% PPTS
15% PPTS
15% PPTS
15% PPTS
8
9
5% phd
5% phen
10
2.5% ZnI2
NR
a
Reaction conditions: 1 (0.130 mmol), MeCN (0.5 mL), O2
atmosphere, 24 h. PPTS, pyridinium p-toluenesulfonic acid, phen,
1
1,10-phenanthroline. Yields were determined by H NMR spectros-
copy.
Table 2. Beneficial Effect of Zn2+ and Iodide on Catalytic
a
Aerobic Amine Oxidation
Figure 5. (A) 1H NMR titration data and (B) speciation plot at
different Zn(OTf)2/phd ratios. Lines in (B) do not represent fits but
are included to guide the eye.
yield (%)
entry
quinone
additive
additive
2
4
1
2
3
4
5% phd
5% phd
5% phd

2.5% ZnI2
5% Bu4NI
2.5% I2
15% PPTS
15% PPTS
15% PPTS
15% PPTS
75
61
52
2
80
6
8
2.5% I2
3
a
Reaction conditions: amine (0.130 mmol), MeCN (0.5 mL), O2
atmosphere, 24 h. PPTS, Pyridinium p-toluenesulfonic acid. Yields
1
were determined by H NMR spectroscopy.
Figure 6. X-ray crystal structure of [Zn(phd)2(MeCN)(OTf)]+ shown
with 50% probability ellipsoids. All H atoms and disorder have been
omitted for clarity (see the Supporting Information for details).
the absence of phd led to negligible reactivity, even in the
reaction of 1 (entry 4).
The unique beneficial effect of iodide counterions raised the
possibility of a catalytic redox role for iodide, and the use of a
starch−iodine test provided evidence for the formation of I3− in
the absence of substrate under the standard reaction conditions.
On the basis of this result, at least two reasonable mechanisms
could be considered for the amine oxidation reactions (Scheme
2). Mechanism A involves phd-mediated amine oxidation,
similar to the stoichiometric reactivity shown in eq 1 and Figure
4. Catalytic turnover involves an iodide/triiodide cycle25 that
mediates aerobic reoxidation of phd-H2 (Scheme 2A).
Mechanism B reflects literature precedents for stoichiometric
oxidation of certain amines by molecular iodine,26 and the
catalytic quantities of a Brønsted acid [75% yield with 15 mol %
pyridinium p-toluenesulfonic acid (PPTS); entry 7]. Control
experiments showed that no amine oxidation occurred in the
absence of phd under these conditions (entry 8), and removal
of the ZnI2 led to only stoichiometric oxidation (7%; entry 9).
Replacement of phd with 1,10-phenanthroline also resulted in
no substrate oxidation (entry 10).
Further studies of the oxidation of 1 to 2, as well as the
oxidation of dibenzylamine (3) to N-benzylidene benzylamine
(4), revealed that both Zn2+ and iodide are important to the
success of the catalytic reactions. Oxidation of 3 under the
optimized reaction conditions resulted in an 80% yield of 4
(Table 2, entry 1). Upon replacement of ZnI2 with
tetrabutylammonium iodide (Bu4NI), significant catalytic
activity was retained in the oxidation of 1, but only
stoichiometric reactivity was observed in the oxidation of 3
(entry 2). A similar observation was made when ZnI2 was
replaced with molecular iodine (entry 3). Use of catalytic I2 in
−
catalytic cycle involves I2/I3 -promoted amine oxidation
coupled to a phd-based redox cycle that mediates aerobic
reoxidation of iodide (Scheme 2B). The latter pathway
resembles metal-catalyzed oxidation reactions in which
quinones have been used to facilitate aerobic oxidation of the
reduced catalyst.27
Kinetic isotope effect (KIE) experiments were carried out in
order to distinguish between these possibilities (Scheme 3).
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a
Scheme 2. Two Proposed Reaction Mechanisms
Table 3. Substrate Scope and Synthetic Applications
Scheme 3. Intramolecular Competition Kinetic Isotope
Effect Experiments
The reaction of 1-d1 was performed under three different sets
of reaction conditions: (a) use of stoichiometric phd as the
oxidant under anaerobic conditions; (b) use of stoichiometric
iodine as the oxidant under anaerobic conditions; and (c) the
optimized catalytic conditions with 5 mol % phd/2.5 mol %
ZnI2 under aerobic conditions. Comparison of the KIEs from
these experiments showed that the KIE obtained under catalytic
conditions matched that obtained with stoichiometric phd (KIE
= 6.4 in both cases) and differed from that observed with I2 as
the oxidant (KIE = 3.8). These results provide strong support
for the quinone-mediated amine oxidation pathway associated
with mechanism A in Scheme 2.
Substrate Scope and Synthetic Applications. The
optimized catalytic conditions were tested with a number of
different substrates (Table 3), ranging from simple dibenzyl
amines (A) to various nitrogen heterocycles such as
tetrahydroisoquinolines (B), tetrahydro-β-carbolines (C), and
tetrahydroquinazolines (D), as well as indolines (E). Substrate
classes B−D are particularly appealing because the saturated
heterocycles may be accessed readily via simple condensation
and Pictet−Spengler reactions (Table 3B−D).
Substituted tetrahydroisoquinolines were smoothly con-
verted to 3,4-dihydroisoquinolines under these conditions
(Table 3B). Electron-donating groups improved the reaction
yield and diminished the reaction time. 6,7-Dimethoxytetrahy-
droisoquinoline was oxidized to dihydrobackebergine (6) in
91% isolated yield, and the reaction proceeded more rapidly
than that of the parent substrate 1. Aryl and alkyl substitution at
the 1-position was well-tolerated: 1-phenyl- and 1-cyclohexyl-
substituted 6,7-dimethoxy-3,4-dihydroisoquinolines were iso-
lated in excellent yields (98% yield of 7 and 90% yield of 8,
a
Reaction conditions: substrate amine (1.0 mmol), phd (0.05 mmol),
ZnI2 (0.025 mmol), PPTS (0.15 mmol), MeCN (4.0 mL), O2 balloon,
24−48 h. The reported yields are isolated yields; numbers in
b
parentheses indicate NMR yields. 48 h reaction time.
respectively). The 3,4-dihydroisoquinoline products of these
reactions have been widely used as precursors to chiral
tetrahydroisoquinolines, which are widely represented in
natural products and pharmaceuticals. For example, 1-(4-
chlorophenyl)-3,4-dihydro-6,7-dimethoxyisoquinoline (9),
which was obtained in 94% yield under our aerobic oxidation
conditions, is an intermediate to the phase III antiepileptic
AMPA receptor agonist 10.28
E
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Notes
Substituted tetrahydro-β-carbolines were readily converted to
3,4-dihydro-β-carbolines using the same optimized conditions
(Table 3C). Aryl substitution in the 1-position was again
tolerated, with slightly improved yields for substrates containing
electron-rich substituents (13, R = OMe, 88% yield) relative to
those containing electron-deficient substituents (11, R = Cl,
70% yield). o-Methyl substitution was also well-tolerated (14,
91% yield), and the natural product isoeudistomin U (15) was
obtained in 63% isolated yield (85% NMR yield).
Quinazolines were formed in good yields from tetrahy-
droquinazolines (Table 3D). Unlike other substrate classes,
wherein electron-donating substituents improved the yield,
quinazoline products containing electron-withdrawing substi-
tution at the 2-position were better substrates. Ring−chain
tautomerism in 2-substituted tetrahydroquinazolines could
occur, and the improved yields for electron-deficient quinazo-
lines may reflect the stabilization of the ring tautomer in the
respective tetrahydroquinazoline substrates.
With a slight modification of the reaction conditions (5 mol
% phd, 1.0 mol % ZnI2, and 1.0 mol % PPTS), indoline could
be converted to indole (25) in 81% isolated yield (Table 3E).
3-Methyl- and 2-methylindolines were also oxidized to the
corresponding indoles in good yields (80% and 73% isolated
yields for 26 and 27, respectively). Even the tertiary amine
substrate N-methylindoline afforded the indole product 28 in
48% yield (Table 3E); however, electron-deficient N-tosylindo-
line (29) was not oxidized under these conditions. Bruice
previously demonstrated stoichiometric oxidation of tertiary
amines with phenanthroline-derived o-quinones, and he
proposed a mechanism analogous to the addition−elimination
mechanism in Figure 1B involving an ammonium−hemiaminal
intermediate.14 Further studies to develop improved quinone-
based catalysts for tertiary amine oxidation are ongoing.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr. Paul White for helpful discussions and assistance
with NMR studies and Brian S. Dolinar and Dr. Ilia A. Guzei
for X-ray crystallographic determination. We are grateful for
financial support from the National Institutes of Health (R01-
GM100143). Analytical instrumentation was partially funded
by the National Science Foundation (CHE-1048642, CHE-
9208463, CHE-0342998, CHE-9974839, CHE-9304546) and
the National Institutes of Health (NIH 1 S10 RR13866-01)
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CONCLUSION
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ASSOCIATED CONTENT
■
S
* Supporting Information
Full experimental procedures and characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
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56, 6857.
stahl@chem.wisc.edu
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