Bioinspired organocatalytic aerobic C-H oxidation of amines with an ortho -quinone catalyst

Article abstract of DOI:10.1021/acs.orglett.5b00351

A simple bioinspired ortho-quinone catalyst for the aerobic oxidative dehydrogenation of amines to imines is reported. Without any metal cocatalysts, the identified optimal ortho-quinone catalyst enables the oxidations of α-branched primary amines and cyclic secondary amines. Mechanistic studies have disclosed the origins of different performances of ortho-quinone vs para-quinone in biomimetic amine oxidations.

Full text of DOI:10.1021/acs.orglett.5b00351

Letter
pubs.acs.org/OrgLett
Bioinspired Organocatalytic Aerobic C−H Oxidation of Amines with
an ortho-Quinone Catalyst
Yan Qin,†,§ Long Zhang,†,‡,§ Jian Lv,†,‡ Sanzhong Luo,*,†,‡ and Jin-Pei Cheng†,‡
†Beijing National Laboratory for Molecular Sciences (BNLMS) CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, The Chinese Academy of Sciences, Beijing 100190, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A simple bioinspired ortho-quinone catalyst for
the aerobic oxidative dehydrogenation of amines to imines is
reported. Without any metal cocatalysts, the identified optimal
ortho-quinone catalyst enables the oxidations of α-branched
primary amines and cyclic secondary amines. Mechanistic
studies have disclosed the origins of different performances of
ortho-quinone vs para-quinone in biomimetic amine oxidations.
he enormous potential of oxidative C−H functionalization
Thas spurred significant research efforts in search of highly
efficient catalytic systems in synthetic chemistry. In nature, a
large portion of enzymatic processes involve C−H activation
and functionalization as key steps. The high efficiency and
exquisite stereocontrol of enzymatic C−H transformations have
inspired chemists to develop small molecule analogues for
synthetic applications.1 Quinone-based enzymes are a class of
important metalloenzymes containing Cu2+ and quinone
cofactors, which can promote aerobic oxidation of primary
amines coupled with the reduction of O2.2 Mechanistic
understanding of this transformation developed by Klinma-
n,2a−e,3a−k Sayre,3l−o and others3p−r has disclosed quinone
cofactors as real active centers in mediating C−H oxidation of
amine,3j,o which underlies the pursuit of biomimetic quinone
catalysts, particularly, pure organocatalysts, with an aim to
achieve sustainable aerobic amine oxidation reactions.
Recently, notable advances have been developed in the
explorations of p-Q14a and o-Q15b (Figure 1A) in the catalytic
oxidative dehydrogenation of linear primary amines to imines.
However, these quinone catalysts did not work with α-
branched primary and secondary amines, consistent with the
known biocatalytic behaviors of quinone cofactors, e.g., TPQ.
Breakthroughs to this limitation have been made with ortho-
quinones in concert with transition metal cocatalysts.4−7 In this
regard, Kobayashi6 reported a successful example of secondary
amine dehydrogenation3p,8 by using a cooperative catalytic
system of Pt/Ir nanocluster and 4-tert-butylcatechol (o-Q2-H).
Stahl4b,c and co-workers reported that a simple ortho-quinone,
1,10-phenanthroline-5,6-dione (o-Q3), could promote effective
secondary amine oxidation by the combination of different
metals such as ZnI2 and [Ru]/[Co].
Figure 1. Biomimetic quinone-based catalysts.
quinone catalysts, stoichiometric amount of base4a or electro-
catalytic system5c are needed in the aerobic oxidation of α-
branched primary amines. In our studies, we sought to develop
quinone-type catalysts focusing on the challenging oxidative
dehydrogenation of α-branched amines. A simple ortho-
quinone, e.g., o-Q4,3g,h was identified as a viable catalyst and
this bioinspired quinone catalyst turned out to be quite general
promoting aerobic oxidation unprecedentedly of both primary
amines and secondary amines without the use of any metal
Thus, to achieve an organocatalytic aerobic oxidation of α-
branched primary amine remains elusive despite tremendous
efforts in this direction.9 Previous protocols required metal
cocatalysts or were of limited scope with low activity. For
Received: February 3, 2015
Published: March 11, 2015
© 2015 American Chemical Society
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Letter
cocatalysts or additives (Figure 1).We chose 1-phenylethan-
amine as the model substrate and a number of quinone-based
catalysts10 were synthesized and tested (Figure 1B). To our
delight, a simple ortho-quinone, o-Q4 with a methoxyl group
was eventually identified to give a promising result with 62%
yield of the desired imine in 36 h. In sharp comparison, the
known quinone catalysts such as p-Q1, o-Q2, and o-Q3, which
were effective for linear primary or secondary amine oxidation,
showed negligible activity with only trace or no products
(Figure 1B). Seeing the critical roles of methoxy group (o-Q2
vs o-Q4), variations on this moiety was probed. Ethoxyl (o-
Q5), iso-propoxyl (o-Q6) and aryloxyl(o-Q7) were less effective
(Figure 1B). By removing tert-butyl group (o-Q8), no imine
product was detected and the poor solubility of o-Q8 may be
one of the reasons of its low activity under the present
conditions (Figure 1B). We also tested Corey’s reagent, ortho-
Q9, and only 5% product was observed at ambient temperature
(Figure 1B). By increasing the catalyst (o-Q4) loading to 10
mol %, the yield was further improved with complete
transformation. Further optimizations in terms of additives,
such as metal cocatalysts and Lewis/Brønsted acids, did not
lead to improvement on activity and in many cases inhibitions
of the oxidation reactions were observed.
ratio (2a−k). In general, electron-deficient substrates (2b−d,
2h,i and 2k) were oxidized slowly comparing to electron-rich
amines (2f,g, 2j). Especially, for 1e, it needed longer reaction
time or higher oxygen pressure to be consumed completely.
Bulkier substrate such as diphenylmethanamine also underwent
oxidative dimerization to produce an imine product as a white
solid (2l). The heterocycle amine 1m proceeded smoothly with
good outcome at higher temperature as well (2m).
Acetylnaphthalene was obtained from deamination of (1-
naphthyl)ethylamine with no imine product detected (2n).
Similar deamination product was also obtained with 1-
phenylpropan-1-amine (2o). Besides, simple benzylamine has
been tested and the reaction went to completion more quickly
than branched amines in 12 h (2p).
Unexpectedly, we observed further reaction of imine with 1a
to afford an oxidative trimerization adduct, imidazolinone 3a
when the reaction was conducted at a higher temperature (60
°C). o-Q5 was found to be an optimal catalyst for this
trimerization process (Figure 2, eq 1). The quinone catalyst
Under the optimized conditions, the scope of the biomimetic
quinone-based catalytic system was examined with a range of α-
branched primary amines (Table 1). 1-Phenylethanamines
substituted with electron-donating and withdrawing groups
were well-tolerated undergoing aerobic oxidation to produce
secondary imines with high to excellent yields and good E/Z
a
Table 1. Aerobic Oxidation of Primary Amines
Figure 2. Biomimetic quinone-based catalysts.
seems to be also involved in the late stage oxidation as no
desired adduct was observed in the absence of catalyst (Figure
2, eq 2).11 The use of less loading of catalyst was found to favor
the trimerization (Figure 2, eq 1), presumably as a result of
balancing the imine formation (e.g., 2a). The reaction can be
applied to a number of 1-phenylethanamines particularly those
bearing electron-donating substitutes with moderate yields,
providing a distinctive pathway for the synthesis of
imidazolinones (Scheme 1).
a
Scheme 1. Oxidative Trimerization
a
b
Isolated yield. Unseparated isomers.
Mechanistically, bioinspired oxidation of amines to imines
may occur via covalent pathways, either transamination
(I)3b,c,e−h,l−n or addition−elimination (II),3p,8 as previously
proposed, or noncovalent direct H-abstraction pathway (III)
(Figure 3). The possibility of amine oxidation by electron
transfer could be ruled out by the observed large KIE = 2.9 in
the stoichiometric reactions of o-Q4 with 2a and α-deuterated
2a, respectively (Figure 4, eq 1). The significant KIE was
supportive of the direct H-transfer pathways (I−III). Our DFT
a
b
c
Yield was determined by 1H NMR analysis. 1.0 mmol scale. For 72
d
e
f
h. For 5 atm O2. 60 °C. For 12 h.
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Letter
intramolecular O−H···N hydrogen bond which presets the α-
C−H in an unfavored geometry for H-transfers (Figure 5).
Figure 5. Calculated geometries of iminoquinone 4 and 9.
Indeed, our DFT calculations on α-H abstraction revealed that
both the substrate-assisted intermolecular H-transfer and the
intramolecular transfer are disfavored requiring ca. 30−33 kcal/
mol (see Supporting Information). Recently, Stahl4a reported
the oxidation of 1-phenylethanamine by p-Q1 required a
stoichiometric amount of base, pinpointing the difficulties of
the H-abstractions with p-Q1. In sharp contrast to the para-
quinone p-Q1, the internal O−H···N hydrogen bond is absent
in iminoquinone 4, the key intermediate in the oxidation with
o-Q4. Instead, a weak C−H···O was clearly noted (Figure 5),
setting the stage for facile H-transfer. In this case, the
intramolecular proton transfer process required only 23.3
kcal/mol (Figure 3, pathway I).
Figure 3. Possible pathways leading to product imine.
We also challenged this ortho-quinone catalyst in the
oxidation of cyclic secondary amines, for which previous
examples normally required metal cocatalysts for effective
conversions.4b,c To our delight, o-Q4 smoothly promoted the
oxidation of tetrahydroisoquinoline 10a to dihydroisoquinoline
under standard condition and slightly above ambient temper-
ature (60 °C) was applied to facilitate complete conversion
(Scheme 2, 11a). The reactions worked well with substituted
tetrahydroisoquinolines (11b and 11c).
Figure 4. Stoichiometric reactions of α-branched amines with quinone
catalysts.
studies on the three possible H-transfer pathways I−III
revealed that the transamination pathway (I)3g,h is favored
over pathways II and III by >5.0 kcal/mol (Figure 3). The in
situ NMR identifications and characterizations of intermediates
in reactions of o-Q4 and 2a has not been very successful;
however, we could observe those signals ascribing to
iminoquione 4/5 as well as the reduced-Q4 by high resolution
ESI-MS (see Supporting Information for details). In addition,
the isolation of a stable aza-ortho-quinone 8 (Figure 4, eq 2), an
oxidized product of the iminoquinone intermediate (e.g., 7,
Figure 3, pathway I) in the reactions of aminoester 7, added
further support to the transamination pathway.
a
Scheme 2. Aerobic Oxidation of Cyclic Secondary Amines
a
1
Yield was determined by H NMR analysis.
In summary, we have developed a simple bioinspired ortho-
Recent theoretical studies by Zhu12 have revealed that ortho-
quinone generally has larger hydride affinity than its para-
quinone derivative. Our calculations based on Zhu’s empirical
equation (see Supporting Information) gave ΔGHA(p-Q1) ≈
61.4 kcal/mol and ΔGHA(o-Q4) ≈ 73.9 kcal/mol, indicating the
ortho-quinone Q4 has stronger ability to abstract H atom, in
line with the observed catalytic behaviors. To gain more insight
into the origins of different performance of para-quinone Q1
and ortho-quinone Q4, we have also investigated the
stoichiometric experiments with p-Q1 in MeCN-d3 monitored
quinone catalyst for the aerobic oxidation of amines. The
current organocatalyst enables effective oxidations of α-
branched primary amines and cyclic secondary amines without
any metal cocatalysts. Mechanistic studies verified that the
transamination pathway, plausible only for α-unbranched
amines in nature,2 would also work for the oxidation of more
challenging α-branched primary amines with our bioinspired
small molecular catalyst, and these efforts disclosed the origins
of different performance of para-quinone and ortho-quinone in
biomimetic amine oxidations.
1
by H NMR (Figure 4, eq 3). 1-Phenylethanamine 1a was
ASSOCIATED CONTENT
* Supporting Information
■
consumed quickly, but no oxidized iminie product was
observed, consistent with the known inert nature of p-Q1 in
branched amine oxidations. Instead, the reaction was stopped at
the initial imine formation stage and the corresponding imine 9
was quantitatively formed and could be isolated and fully
characterized by NMR spectroscopy (see Supporting Informa-
tion). The structural optimization of 9 indicated a strong
S
Experimental procedures, detailed characterization data of
substrates, catalysts and products, X-ray crystal structure,
computational details and H and 13C NMR spectra. This
1
material is available free of charge via the Internet at http://
pubs.acs.org.
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Letter
(7) For recently selected reviews about imine synthesis, see:
AUTHOR INFORMATION
■
(a) Schumperli, M. T.; Hammond, C.; Hermans, I. ACS Catal.
̈
Corresponding Author
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(d) Lang, X.; Ma, W.; Chen, C.; Ji, H.; Zhao, J. Acc. Chem. Res. 2014,
47, 355.
*E-mail: luosz@iccas.ac.cn.
Author Contributions
§Y.Q. and L.Z. contributed equally to this work
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L. M. J. Am. Chem. Soc. 2006, 128, 6206. (b) Lee, Y.; Huang, H.; Sayre,
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the Ministry of Science and Technology
(2012CB821600), the Natural Science Foundation of China
(NSFC 21390400, 21202170, 21202171 and 21025208), and
the Chinese Academy of Sciences. S.L. is supported by the
National Program of Top-notch Young Professionals and the
CAS Youth Innovation Promotion Association.
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