Cu/nitroxyl-catalyzed aerobic oxidation of primary amines into nitriles at room temperature

Article abstract of DOI:10.1021/cs400360e

An efficient catalytic method has been developed for aerobic oxidation of primary amines to the corresponding nitriles. The reactions proceed at room temperature and employ a catalyst consisting of (4,4′-^tBu ₂bpy)CuI/ABNO (ABNO = 9-azabicyclo[3.3.1]nonan-3-one-N-oxyl). The reactions exhibit excellent functional group compatibility and substrate scope and are effective with benzylic, allylic, and aliphatic amines. Preliminary mechanistic studies suggest that aerobic oxidation of the Cu catalyst is the turnover-limiting step of the reaction.

Full text of DOI:10.1021/cs400360e

Letter
pubs.acs.org/acscatalysis
Cu/Nitroxyl-Catalyzed Aerobic Oxidation of Primary Amines into
Nitriles at Room Temperature
Jinho Kim and Shannon S. Stahl*
Department of Chemistry, University of Wisconsin−Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: An efficient catalytic method has been developed
for aerobic oxidation of primary amines to the corresponding
nitriles. The reactions proceed at room temperature and employ
a catalyst consisting of (4,4′-tBu2bpy)CuI/ABNO (ABNO = 9-
azabicyclo[3.3.1]nonan-3-one-N-oxyl). The reactions exhibit
excellent functional group compatibility and substrate scope
and are effective with benzylic, allylic, and aliphatic amines.
Preliminary mechanistic studies suggest that aerobic oxidation of
the Cu catalyst is the turnover-limiting step of the reaction.
KEYWORDS: aerobic oxidation, copper, nitroxyl, nitrile, amine oxidation
omogeneous (bpy)Cu/TEMPO and related catalyst
that enables selective formation of nitriles from diverse primary
amines. The room temperature reaction conditions are very
convenient and much more mild than other catalytic methods
for oxidation of primary amines to nitriles,8,9 and the results
highlight the ability to tune product selectivity by variation of
the catalyst components. Preliminary mechanistic studies
provide insights into the catalytic reactions.
H
systems have emerged as some of the most effective
catalysts for aerobic oxidation of alcohols and amines.1,2
Catalyst systems of this type can be traced to the 1960s,3 but
they have become the focus of extensive investigation and
development in recent years.4−6 In 2011, we reported a
(bpy)CuI/TEMPO catalyst system that mediates efficient
aerobic oxidation of primary alcohols to aldehydes (eq 1).4i,j
We initiated the present study with 4-methoxybenzylamine
as a model substrate using 5 mol % of Cu and a nitroxyl radical
source in acetonitrile (Table 1). Our previously reported
alcohol oxidation conditions gave only 25% of nitrile 2a with
50% of homocoupled imine 3a (entry 1). Use of CuI led to
better selectivity for 2a (entry 2), albeit with lower yield.
Replacement of TEMPO with the sterically less hindered
nitroxyl species, such as ABNO and AZADO, resulted in a
significantly improved yield and selectivity of the nitrile 2a
(entries 3 and 4).10 Use of ketoABNO, which is a stronger
oxidant but sterically the same as ABNO, led to inferior results
(entry 5). Extensive screening of ligands and bases was carried
out (Table 1, entries 6−9; for full screening data, see
Supporting Information Table S2), and the best yield and
selectivity for 2a was achieved with reactions containing
4,4′-tBu2bpy (4,4′-di-tert-butyl-2,2′-bipyridyl) and DMAP (4-
dimethylaminopyridine) (entry 9). This optimized catalyst
system was evaluated in solvents other than acetonitrile. Good
substrate conversion was observed in THF, dioxane, DMF, and
toluene; however, the selectivity for nitrile 2a was significantly
lower (Supporting Information Table S1). Use of air as the
oxidant led to lower yield and selectivity (entry 10).
The reactions exhibit broad substrate scope and are compatible
with benzylic, allylic, and aliphatic alcohols bearing diverse
functional groups. We envisioned that amine oxidation (i.e., C−
N dehydrogenation) could be achieved using a similar Cu/
nitroxyl-based catalyst system. Several other groups recently
reported important progress in this area. For example,
Kerton,5b Kanai,5c and Xu5d demonstrated that various Cu/
nitroxyl catalyst systems promote aerobic oxidation of primary
amines to the corresponding homocoupled imines 3 (Scheme
1).7 The production of homocoupled imines suggests that
condensation of a second amine with the primary imine
intermediate A is more facile than oxidation of A to the
corresponding nitrile 2. Here, we report a Cu/nitroxyl system
Scheme 1. The Selectivity of Cu/Nitroxyl Catalyzed Primary
Amine Oxidation
The optimized reaction conditions (Table 1, entry 9) were
applied to diverse substrates to assess the reaction scope and
Received: May 15, 2013
Revised: June 13, 2013
© XXXX American Chemical Society
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Letter
Table 1. Optimization of Cu/Nitroxyl Catalyzed Aerobic
Oxidation of Primary Amine to Nitrile
Table 2. Substrates Scope of CuI/ABNO Catalyzed Aerobic
Oxidation of Primary Amine to Nitrile
a
a,b
b
yield (%)
entry
Cu
ligand
nitroxyl
base
2a
3a
1
2
3
4
5
6
7
8
9
CuOTf
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
bpy
bpy
bpy
bpy
bpy
4,4′-tBu2bpy
4,4′-Me2bpy
4,4′-OMe2bpy
4,4′-tBu2bpy
4,4′-tBu2bpy
TEMPO
TEMPO
ABNO
NMI
NMI
NMI
NMI
NMI
NMI
NMI
NMI
DMAP
DMAP
25
27
78
77
53
87
80
74
90
75
50
34
22
23
46
13
14
26
4
AZADO
ketoABNO
ABNO
ABNO
ABNO
ABNO
c
10
ABNO
24
a
Conditions: 1a (0.5 mmol), Cu, ligand, nitroxyl, and base in CH3CN
b
(2.0 mL) under O2 balloon at room temperature for 15 h. Yield
determined by 1H NMR (internal standard: 1,1,2,2-tetrachloroethane).
c
Carried out under air.
limitations (Table 2). Primary benzylic amines with a variety of
substituents (1a−1o) reacted to afford the corresponding
nitriles in good to excellent yields. Electron-donating and
electron-withdrawing groups, ranging from −OMe to −CF3
and −NO2 groups, were all well tolerated in the reactions, and
the method was compatible with aryl chlorides, bromides, and
iodides that can be used in subsequent coupling reactions.
Polycyclic or heteroaromatic methylamines, such as 1-
naphthylmethylamine (1m) and 2-furyl-methylamine (1n),
underwent effective conversion into the nitriles, and oxidation
of m-xylenediamine (1o) afforded 1,3-dicyanobenzene in high
yield. The allylic amines, cinnamylamine (1p) and geranyl-
amine (1q), afforded α,β-unsaturated nitriles in good yields. As
has been observed in alcohol oxidation reactions, aliphatic
substrates were less reactive, but good yields of the
corresponding nitriles (2r−2v) were obtained by increasing
the CuI/ABNO catalyst loading to 10 mol %. A reduced yield
of the nitrile was observed from oxidation of tetrahydrofurfuryl-
amine (1w), possibly reflecting inhibition by chelation of the
adjacent ether group. This amine oxidation method was
effective on a larger scale (eq 2): amine 1l underwent efficient
oxidation on a 10 mmol scale, resulting in a 70% yield of the
nitrile, even with decreased catalyst loading (3 mol %).
a
Conditions: 1 (0.5 mmol), CuI, 4,4′-tBu2bpy, ABNO, and DMAP in
CH3CN (2.0 mL) under O2 (balloon) at room temperature for 15 h.
b
c
d
Isolated yield. Yield determined by 1H NMR spectroscopy. 10 mol
% of CuI, 4,4′-tBu2bpy, ABNO, and 20 mol % of DMAP were
employed. Carried out at 40 °C
e
Some limitations of substrate scope were observed in the
oxidation of 4-bromophenethylamine, which formed a complex
mixture of products, and 4-hydroxybenzylamine, which
produced no 4-hydroxybenzonitrile (Figure 1). These
Figure 1. Problematic substrates for CuI/ABNO-catalyzed amine
oxidation.
limitations resemble those of analogous alcohol oxidation
reactions in which homobenzylic alcohols afford complex
product mixtures and phenols inhibit catalytic turnover.
Overall, these amine oxidation reactions exhibit a broad scope
that closely resembles the alcohol oxidation reactions.
The reaction profile for the oxidation of p-methoxybenzyl
amine, monitored by gas uptake methods and 1H NMR analysis
of the nitrile product, revealed an O2/product stoichiometry of
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1:1 (Figure 2).11 This ratio is consistent with that expected for
four-electron oxidation of a primary amine to a nitrile with
TEMPO-catalyzed alcohol oxidation,12 are consistent with a
two-stage catalytic mechanism consisting of (i) aerobic
oxidation of the reduced catalyst, (tBu2bpy)CuI and ABNO−
H, and (ii) dehydrogenation of the amine substrate by
(tBu2bpy)CuII species and ABNO (Scheme 2). Both the
Scheme 2. Simplified Catalytic Cycle for (tBu2bpy)CuI/-
ABNO-Catalyzed Aerobic Amine Oxidation
Figure 2. Reaction time course, monitored by gas uptake (O2) and 1H
NMR analysis of the organic products (nitrile and imine), showing the
1:1 relationship between O2 consumption and nitrile formed. See the
Supporting Information for details.
concomitant four-electron reduction of O2 to 2 equiv of water.
Only a small amount of the homocoupled imine 3a is detected,
with the majority formed early in the reaction when the amine
substrate concentration is highest.
A kinetic isotope effect (KIE) was obtained for oxidation of
p-methoxybenzylamine by comparing the rate of the protio
substrate with that of the deuterated derivative (Figure 3A).
primary amine and the primary imine can serve as substrates in
the second stage of the reaction. The kinetic data suggest that
catalyst oxidation by O2, not substrate dehydrogenation, is
turnover-limiting. These preliminary results, together with our
previous study of Cu/TEMPO-catalyzed alcohol oxidation,12
provide a foundation for a more thorough comparison of the
relative reactivity of alcohols and amines and similarities and
differences between the reaction mechanisms.
The time course in Figure 2 suggests that the homocoupled
imine 3a does not convert into the nitrile once it forms, and it
is obtained in ∼5% yield after completion of the reaction.
Control experiments were performed to assess the reversibility
of imine formation under the reaction conditions. Imine 3a was
independently prepared and subjected to the typical reaction
conditions. Some conversion of 3a into nitrile 2a could be
achieved by adding ammonia to the reaction mixture (Scheme
3), and increasing the ammonia equivalents increases the nitrile
Figure 3. Isotope effect (A) and Hammett (B) data from CuI/ABNO-
catalyzed aerobic oxidation of p-methoxybenzylamine to p-methox-
ybenzonitrile.
The small observed KIE, kH/kD = 1.18 0.02, indicates that
C−H bond cleavage is not turnover-limiting in this present
reaction. Similarly, a Hammett study with different p-
substituted benzylamines reveals the absence of a significant
electronic effect on the reaction rate (ρ = −0.07; Figure 3B).
On the other hand, the reaction rate exhibits a first-order
dependence on the oxygen pressure (Figure 4 and Supporting
Information Figure S3). These observations, together with
insights from our recently reported mechanistic study of Cu/
Scheme 3. Investigation of the Possiblities of Homocoupled
Imine Intermediates
yield. Nevertheless, the relatively slow rate and the quantity of
ammonia required to promote this reaction suggest that the
homocoupled imine will, at best, convert slowly into nitrile
under the amine oxidation reaction conditions. These
observations further suggest that nitrile formation with this
catalyst system primarily proceeds via direct oxidation of
primary imine A, without diverting to the homocoupled imine.
The compatibility of this catalyst system with aqueous
ammonia raised the possibility of converting alcohols to nitriles
via oxidative coupling with ammonia (Scheme 4). Upon
Figure 4. O2-dependence kinetic data from CuI/ABNO-catalyzed
aerobic oxidation of p-methoxybenzylamine to p-methoxybenzonitrile.
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Scheme 4. Complementary Pathways for the Preparation of
Nitriles from Primary Amines or Primary Alcohols/
Ammonia
ABBREVIATIONS
■
ABNO, 9-azabicyclo [3.3.1] nonane N-oxyl; bpy, 2,2′-bipyridyl;
DMAP, 4-dimethylaminopyridine; DTBNO, di-tert-butylnitr-
oxide; ketoABNO, 9-azabicyclo[3.3.1]nonan-3-one-N-oxyl;
NMI, N-methylimidazole; TEMPO, 2,2,6,6-tetramethyl-1-pi-
peridinyloxyl
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In conclusion, we have identified (tBu2bpy)CuI/ABNO as an
efficient catalyst system with broad substrate scope for oxidative
dehydrogenation of primary amines to nitriles. The identity of
the nitroxyl reagent and the solvent are key factors in achieving
selectivity for nitrile rather than the homocoupled imine.
Elucidation of the mechanistic origin of this nitroxyl-dependent
selectivity, together with characterization of the mechanistic
similarities and differences among reactions of alcohols and
amines is an important focus of ongoing work.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, kinetic data, and additional
experiment data are included. This material is available free of
charge via the Internet at http://pubs.acs.org.
(8) Cu-mediated oxidation of primary amines to nitriles in the
absence of a nitroxyl cocatalyst require stoichiometric Cu, more-
forcing reaction conditions, and/or promote competitive formation of
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Synthesis 1989, 453. (b) Capdevielle, P.; Lavigne, A.; Sparfel, D.;
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31, 3305. (c) Maeda, Y.; Nishimura, T.; Uemura, S. Bull. Chem. Soc.
Jpn. 2003, 76, 2399.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stahl@chem.wisc.edu.
Notes
The authors declare no competing financial interest.
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K.; Chen, X.; Hu, T.; Yu, Y.; Zhang, J.; Huang, J. Catal. Commun.
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ACKNOWLEDGMENTS
■
We are grateful to the NIH (R01-GM100143), together with a
consortium of pharmaceutical companies (Eli Lilly, Pfizer, and
Merck) for financial support of this work. NMR spectroscopy
facilities were supported in part by the NSF (CHE-1048642).
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(10) (a) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am.
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was consumed. For the detailed gas uptake procedure, see the
Supporting Information.
(12) Hoover, J. M.; Ryland, B. L.; Stahl, S. S. J. Am. Chem. Soc. 2013,
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