Copper N-Heterocyclic Carbene: A Catalyst for Aerobic Oxidation or Reduction Reactions

Article abstract of DOI:10.1021/acs.orglett.5b02756

Copper N-heterocyclic carbene complexes can be readily used as catalysts for both aerobic oxidation of alcohols to aldehydes and reduction of imines to amines. Our methodology is universal for aromatic substrates and shows versatile tolerance to potential cascade reactions. A one-pot tandem synthetic strategy could afford useful imines and secondary amines via an oxidation-reduction strategy.

Full text of DOI:10.1021/acs.orglett.5b02756

Letter
pubs.acs.org/OrgLett
Copper N‑Heterocyclic Carbene: A Catalyst for Aerobic Oxidation or
Reduction Reactions
Le-Wu Zhan,† Lei Han,‡ Ping Xing,‡ and Biao Jiang*,†,‡,§
†School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiaolingwei, Nanjing 210094, China
‡CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Copper N-heterocyclic carbene complexes can
be readily used as catalysts for both aerobic oxidation of
alcohols to aldehydes and reduction of imines to amines. Our
methodology is universal for aromatic substrates and shows
versatile tolerance to potential cascade reactions. A one-pot
tandem synthetic strategy could afford useful imines and
secondary amines via an oxidation−reduction strategy.
he oxidation of alcohols to carbonyl compounds is one of
Tthe most common classes of oxidation reactions in organic
chemistry. Widespread interest has been directed toward the
development of catalytic aerobic oxidation methods.1 Copper-
catalyzed aerobic organic reactions have become a burgeoning
field of research. Oxygen is a highly atom-economical,
environmentally benign, and abundant oxidant. Since oxygen
can serve as either a sink for electrons, a source of oxygen
atoms that are incorporated into the product, or both, the
chemistry of copper catalysis is increased exponentially when
combined with molecular oxygen. Such oxidations using oxygen
or air have been employed safely in numerous commodity
chemical continuous and batch processes.2 Similarly, significant
advances have been made over the last two decades since the
benefit of N-heterocyclic carbenes (NHCs) as ancillary ligands
in organometallic catalysis has been realized.3 Increasing
experimental evidence clearly shows that metal−NHC catalysts
can surpass their phosphine-based counterparts in both activity
and scope,4,5 and they are mainly known for their impact on
palladium-,6 ruthenium-,7 silver-,8,9and gold-catalyzed10 reac-
tions. Copper is much cheaper than many transition metals that
are commonly used in organometallic catalysis. In conjunction
with copper, the strong electron-donating properties of NHCs
yield catalysts that are often very robust, demonstrating air,
moisture, and thermal stability.5,11,12 In the past decade, NHC-
ligated copper complexes (examples of which are shown in
Figure 1) have been found to act as catalysts for
functionalization of carbonyls, alkenes, and alkynes.5
Figure 1. Selected Cu−NHC catalysts.
at 80 °C.14 In continuation of our interest in metal−NHC
chemistry,15 herein we report a Cu−NHC catalyst that was
found to be competent for both aerobic oxidation of alcohols to
aldehydes and reduction of imines to amines in excellent yields
under mild conditions. The aerobic oxidation and reduction
appear to be more advantageous and feasible methods because
of the use of dry oxygen and polymethylhydrosiloxane (PMHS)
as pollution-free reagents, safer and milder conditions, as well as
fewer byproducts. We also explored a one-pot tandem synthetic
strategy providing several greener and practical approaches for
the preparation of aldehydes, ketones, imines, or secondary
amines.
In the Cu−NHC−TEMPO aerobic oxidation of alcohols
reported by Chen,14 addition of base (tBuOK or Et3N) resulted
in an obvious decrease in yield, and the Cu−NHCs
[(IMes)CuBr] and [(IPr)CuBr] became totally inactive. We
reexamined the catalytic activities of Cu−NHCs for aerobic
oxidation of alcohols and found that base is necessary for the
aerobic oxidation. When the aerobic reaction was carried out
A remarkable number of transition-metal-catalyzed aerobic
oxidations of alcohols have been well-established, including
those using copper,2 such as copper salts in combination with
TEMPO and various N-ligands such as 2,2′-bipyridine,
DABCO,13 and TMDP. Recently, imidazolium salts bearing
TEMPO groups were shown to react with copper powder to
afford Cu−NHC−TEMPO complexes in situ as efficient
catalysts for aerobic oxidation of primary alcohols to aldehydes
t
with BuOK in the presence of 4 Å molecular sieves (MS) in
dichloromethane, high yields of aldehyde were obtained when
Received: October 11, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b02756
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a
Table 1. Studies of Aerobic Oxidative Reaction Conditions
Table 2. Study of Aerobic Oxidation of Alcohols to
Aldehydes
a
time
(h)
yield
b
entry
catalyst
solvent
additive
(%)
1
2
3
4
5
6
7
8
(IMes)CuCl
(SIMes)CuCl CH2Cl2 tBuOK (2 equiv)
CH2Cl2 tBuOK (2 equiv)
24
24
24
24
12
12
12
12
12
12
35
89
(IPr)CuCl
CH2Cl2 tBuOK (2 equiv)
CH2Cl2 tBuOK (2 equiv)
68
(SIPr)CuCl
95
(SIMes)CuCl toluene
KOH (2 equiv)
92
(SIPr)CuCl
(SIPr)CuCl
(SIPr)CuCl
(SIPr)CuCl
(SIPr)CuCl
CH2Cl2 KOH (2 equiv)
CH2Cl2 none
99
trace
58
CH2Cl2 KOH (1 equiv)
CH2Cl2 KOH (2 equiv)
CH2Cl2 KOH (2 equiv)
c
9
d
89
10
NR
a
Reaction conditions: the mixture of 1a, Cu−NHC catalyst, base, and
4 Å MS was stirred at ambient temperature in a pure oxygen
b
c
atmosphere. Isolated yields. The oxidation reaction was carried out
in a dry air atmosphere. The oxidation reaction was carried in an
d
argon atmosphere.
[(SIMes)CuCl] or [(SIPr)CuCl] was used as the catalyst
(Table 1, entries 2 and 4), whereas [(IMes)CuCl] and
[(IPr)CuCl] gave low yields (Table 1, entries 1 and 3),
because the saturated NHC ligands are slightly less electron-
donating than their unsaturated analogues.16 Further screening
of solvents and bases revealed that the reaction gave almost
quantitative yield with KOH as the base in dichloromethane
(Table 1, entries 5 and 6). When the amount of KOH was
reduced to 1 equiv or none, the yield of the product was
reduced to 58% or trace, respectively (Table 1, entries 7 and 8).
Changing oxygen to air reduced the yield of the product to 89%
(Table 1, entry 9). No product was detected when the reaction
was carried out in an argon atmosphere (Table 1, entry 10).
The Cu−NHC-catalyzed aerobic oxidation was then
extended to various alcohol substrates (Table 2). It seemed
that this method not only was suitable for benzylic alcohols
bearing electron-withdrawing groups (Table 2, entries 2−5) but
also afforded benzaldehydes substituted with electron-donating
groups in excellent yields (Table 2, entries 6−8). Our mild
oxidation strategy was also tolerant of heterocyclic substrates
such as pyridine- (1i) and thiophene-derived (1j) alcohols,
which are especially advantageous compared with their furan
counterpart (1k), which is sensitive to heat (Table 2, entries 9−
11). Besides, we have extended our alcohol substrates to
cinnamyl alcohol (1l) (Table 2, entry 12), and aromatic ketone
2m was also obtained in excellent yield (Table 2, entry 13). For
an aliphatic alcohol, we detected the aldehyde in only 9% GC−
MS yield (Table 2, entry 14).
a
Reaction conditions: the mixture of 1 (1 mmol), (SIPr)CuCl catalyst
(0.02 mmol, 2 mol %), KOH (2 mmol), 4 Å MS, and CH2Cl2 (10 mL)
was stirred at ambient temperature in a pure oxygen atmosphere for 12
b
c
h. Isolated yields. Reaction conditions: the mixture of 1n (1 mmol),
(SIPr)CuCl catalyst (0.02 mmol, 2 mol %), KOH (2 mmol), 4 Å MS,
and THF (10 mL) was stirred at 60 °C in a pure oxygen atmosphere
for 12 h, and the yield was determined by GC−MS.
Amines are important compounds that are prominent in
bioactive molecules and natural products and widely used in
agrochemicals, chemical industries, and pharmaceuticals.17,19
A
Scheme 1. Tandem Attempt To Afford Imine 4a
classical method for preparing N-alkylamines is the reaction of
an amine with an alkyl halide.18 However, it is difficult to get
the desired product as the reaction is prone to overalkylation.19
As an environmentally benign approach for the synthesis of
amines, widespread interest has been directed toward reductive
amination with alcohols as alkylating agents based on the
catalytic hydrogen transfer process.20 A corresponding aldehyde
or ketone is generated by this reaction sequence, which would
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Letter
formation of an imine intermediate, which would then be
followed by transfer hydrogenation, affording the desired N-
alkylamine.21 Tandem catalysis that enables a one-pot multistep
reaction shows great potential for increasing the efficiency of
chemical synthesis.15 Since mild conditions are used for the
selective oxidation of alcohols, a cascade reaction was
attempted for the one-pot oxidative tandem synthesis of
imine 4a from alcohol 1a and amine 3a, and we got the desired
imine in high yield (Scheme 1).
Table 3. Study of Cascade Oxidative and Reductive
Reactions To Afford Secondary Amines
a
Considering the catalytic activities in reduction reactions of
Cu−NHCs,22 we designed a one-pot process for the synthesis
of important secondary amines from alcohols and primary
amines via aerobic oxidation, amination, and reduction
catalyzed by [(SIPr)CuCl]. The aerobic oxidation of alcohols
by the [(SIPr)CuCl]/tBuOK/4 Å MS catalyst system was
performed, and the reaction was monitored by TLC. After
consumption of the alcohol, PMHS and additional [(SIPr)-
CuCl] catalyst (2 mol %) was added to the reaction mixture to
reduce the imine to the secondary amine. Thus, the reaction of
4-chlorobenzyl alcohol and aniline for 6 h followed by the
addition of PMHS and [(SIPr)CuCl] gave a high yield of 5a
(Table 3, entry 1).We found that no obvious electronic effect
contributed to the yield of secondary amine (Table 3, entries
1−3) when para-substituted amines bearing electron-deficient
or electron-rich groups were used as substrates. Comparative
experiments on p-, m-, and o-methoxyaniline identified that
steric hindrance influences the yield of the secondary amine
(Table 3, entries 3−5). Amine 3a likewise reacted with benzylic
alcohols bearing electron-donating or electron-withdrawing
substituents (Table 3, entries 2 and 6−9), and the comparative
experiments on p-, m-, and o-methoxybenzyl alcohols identified
that steric hindrance more or less influences the yield of the
secondary amine (Table 3, entries 9−11). The mild conditions
were also used for the furan counterpart, which is sensitive to
heat (Table 3, entry 12). For the aliphatic amine, we obtained
the imine in only 90% yield, and the amine reductive product
could not be detected (Table 3, entry 13).
In conclusion, a robust and effective Cu−NHC for aerobic
alcohol oxidation that is effective for a variety of alcohols was
discovered and studied. When KOH is used in the presence of
4 Å molecular sieves, the oxidation can be carried out under an
oxygen atmosphere to afford aldehydes and ketones selectively
in excellent yields. In addition, the one-pot synthesis of imines
from benzylic alcohols and primary amines was achieved using
the Cu−NHC catalyst. The one-pot process for the synthesis of
important secondary amines via aerobic oxidation, amination,
and reduction catalyzed by [(SIPr)CuCl] was found to be high-
yielding.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02756.
a
Reaction conditions: the mixture of 1 (1 mmol), 3 (1.1 mmol),
t
(SIPr)CuCl catalyst (0.02 mmol, 2 mol %), BuOK (2 mmol), THF
Full experimental details, spectroscopic data, and copies
(10 mL), and 4 Å MS was stirred at ambient temperature in pure
oxygen for 6 h before the addition of PMHS (0.24 mL, 4 mmol) and
(SIPr)CuCl catalyst (0.02 mmol, 2 mol %), after which the stirring was
1
of H and 13C NMR spectra (PDF)
b
continued at ambient temperature for 8 h. Isolated yields.
AUTHOR INFORMATION
■
Corresponding Author
be kicked off by the dehydrogenation of an alcohol.
Subsquently, dehydrative condensation would cause the
*jiangb@mail.sioc.ac.cn
C
DOI: 10.1021/acs.orglett.5b02756
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Present Address
§B.J.: Shanghai Institute of Organic Chemistry.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Science and Technology
Commission of Shanghai Municipality (12DZ1930902) and the
Knowledge Innovation Program of the Chinese Academy of
Sciences.
REFERENCES
■
(1) (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalysed Oxidations of
Organic Compounds; Academic Press: New York, 1981. (b) Ley, V.;
Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 1994, 639.
(c) Hudlicky, M. Oxidations in Organic Chemistry; American Chemical
Society: Washington, DC, 1990.
(2) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C.
Chem. Rev. 2013, 113, 6234.
(3) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290.
(4) Diez-Gonzalez, S.; Nolan, S. P. Aldrichimica Acta 2008, 41, 43.
(5) Egbert, J. D.; Cazin, C. S. J.; Nolan, S. P. Catal. Sci. Technol. 2013,
3, 912.
(6) Navarro, O.; Viciu, M. S. Annu. Rep. Prog. Chem., Sect. B: Org.
Chem. 2010, 106, 243.
(7) Bantreil, X.; Broggi, J.; Nolan, S. P. Annu. Rep. Prog. Chem., Sect.
B: Org. Chem. 2009, 105, 232.
(8) Garrison, J. C.; Youngs, W. J. Chem. Rev. 2005, 105, 3978.
(9) Lin, I. J. B.; Vasam, C. S. Coord. Chem. Rev. 2007, 251, 642.
(10) Corberan, R.; Ramirez, J.; Poyatos, M.; Peris, E.; Fernandez, E.
Tetrahedron: Asymmetry 2006, 17, 1759.
(11) Langlois, J. B.; Alexakis, A. Copper-catalyzed Enantioselective
Allylic Substitution. In Transition Metal Catalyzed Enantioselective
Allylic Substitution in Organic Synthesis; Springer: Berlin, 2011; p 235.
(12) Zhang, L.; Hou, Z. Pure Appl. Chem. 2012, 84, 1705.
(13) Mannam, S.; Alamsetti, S. K.; Sekar, G. Adv. Synth. Catal. 2007,
349, 2253.
(14) Liu, X.; Xia, Q.; Zhang, Y.; Chen, C.; Chen, W. J. Org. Chem.
2013, 78, 8531.
(15) Han, L.; Xing, P.; Jiang, B. Org. Lett. 2014, 16, 3428.
(16) Dorta, R.; Stevens, E. D.; Scott, N. M.; Costabile, C.; Cavallo,
L.; Hoff, C. D.; Nolan, S. P. J. Am. Chem. Soc. 2005, 127, 2485.
(17) Pham, P. D.; Bertus, P.; Legoupy, S. Chem. Commun. 2009,
6207.
(18) Smith, M. B.; March, J. Advanced Organic Chemistry, 5th ed.;
Wiley: New York, 2001; p 499.
(19) Li, J. Q.; Andersson, P. G. Chem. Commun. 2013, 49, 6131.
(20) (a) Guillena, G.; Ramon, D. J.; Yus, M. Chem. Rev. 2010, 110,
1611. (b) Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010, 110,
681. (c) Yamaguchi, R.; Fujita, K.; Zhu, M. Heterocycles 2010, 81,
1093. (d) Nixon, T. D.; Whittlesey, M. K.; Williams, J. M. J. Dalton
Trans. 2009, 753. (e) Hamid, M. H. S. A.; Slatford, P. A.; Williams, J.
M. J. Adv. Synth. Catal. 2007, 349, 1555. (f) Naota, T.; Takaya, H.;
Murahashi, S.-I. Chem. Rev. 1998, 98, 2599.
(21) Kawahara, R.; Fujita, K.-i.; Yamaguchi, R. Adv. Synth. Catal.
2011, 353, 1161.
(22) Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan, S. P.
Organometallics 2004, 23, 1157.
D
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