Cu(I)/TEMPO-catalyzed aerobic oxidative synthesis of imines directly from primary and secondary amines under ambient and neat conditions

Article abstract of DOI:10.1016/j.tetlet.2013.03.098

By catalyst and condition screening, a simple Cu(I)/TEMPO-catalyst system was found to be an active and highly effective catalyst for the aerobic oxidation of amines to imines in open air at room temperature under neat conditions. This new method provided a mild, efficient, and practical alternative for the synthesis of the useful imines directly from primary and secondary amines.

Full text of DOI:10.1016/j.tetlet.2013.03.098

Tetrahedron Letters 54 (2013) 2861–2864
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cu(I)/TEMPO-catalyzed aerobic oxidative synthesis of imines directly from
primary and secondary amines under ambient and neat conditions
Bo Huang a, Haiwen Tian a, Shoushuai Lin a, Meihua Xie b, Xiaochun Yu a, , Qing Xu a,
⇑
⇑
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang 325035, PR China
b College of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
By catalyst and condition screening, a simple Cu(I)/TEMPO-catalyst system was found to be an active and
highly effective catalyst for the aerobic oxidation of amines to imines in open air at room temperature
under neat conditions. This new method provided a mild, efficient, and practical alternative for the syn-
thesis of the useful imines directly from primary and secondary amines.
Received 30 January 2013
Revised 16 March 2013
Accepted 22 March 2013
Available online 2 April 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Air
Amine oxidation
Copper
Imines
Room temperature
TEMPO
Because imines contain a reactive C@N double bond and can
readily undergo various types of transformations such as reduc-
tion, addition, cycloaddition, and multi-component reactions, they
are useful nitrogen sources and versatile intermediates in the syn-
thesis of biochemically and pharmaceutically active compounds
and natural products.1 Traditionally, imines were prepared by
dehydrative condensation of amines with carbonyl compounds,
especially the aldehydes.2 However, since aldehydes are reactive,
odorous, toxic, readily oxidized to carboxylic acids, and not easy
to handle and store, they usually require purification before use
and inert and harsh reaction conditions. Since aldehydes and
ketones are mostly obtained from corresponding alcohols via oxi-
dation reactions, several tandem processes have recently been
developed for preparation of imines from alcohols and amines.3–6
For example, the early methods used excess amounts of oxidants
such as MnO2.3 The dehydrogenative methods were conducted un-
der inert conditions at high temperatures, generating gas hydrogen
as the byproduct.4 The presently available aerobic methods gener-
ally require the use of pure oxygen at elevated temperatures.5
Worth noting is that, we recently developed two especially active
Pd and Cu catalysts, which can efficiently catalyze the aerobic reac-
tions of alcohols and amines in open air at room temperature to
afford the useful imines Eq. 1.6 To our knowledge, these may be
the mildest methods ever known for imine synthesis from alcohols
and amines.3–6
Pd(OAc)2/Et3N/TEMPO (1 mol% Pd)
or CuI/bipy/TEMPO (1 mol% Cu)
R2
+
OH
R2NH2
R1
R1
N
air, r.t.
previous work
ð1Þ
During studies, we found that both Pd and Cu catalysts can
selectively oxidize the alcohols to aldehydes and generate the cross
imines as the sole product Eq. 1,6 without detecting any other po-
tential byproducts derived from the oxidation reactions of
amines.7–9 On the contrary, when the Cu-catalyzed reaction was
accidentally conducted under similar conditions without adding
alcohol, it readily afforded 75% yield of the amine-derived imine
2a with 12% yield of benzonitrile 3a Eq. 2. In fact, various metal
catalysts have been used to catalyze the aerobic oxidation of
amines for the synthesis of nitriles,7 amides,8 and imines.9 Among
imine formation methods, most reactions still require the use of
noble metal catalysts under oxidant-free conditions at high
temperatures,10 or large excess amounts of oxidants that will also
generate large amounts of wastes,11 or using pure oxygen as the
oxidant at high temperatures.9a–h In contrast, practical methods
that can use air as the more economic and safer oxidant and those
which can be carried out under milder conditions are still rare up
to date,9i–m and are thus still highly desirable in the field.9n
⇑
Corresponding authors. Tel.: +86 13857745327; fax: +86 577 86689300.
E-mail address: qing-xu@wzu.edu.cn (Q. Xu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.098

2862
B. Huang et al. / Tetrahedron Letters 54 (2013) 2861–2864
Therefore, the above interesting results Eq. 2 intrigued us to further
investigate the Cu-catalyzed aerobic amine oxidation reaction to
develop a mild and practical method for the synthesis of the useful
imines directly from amines. Besides, although several Cu-cata-
lyzed reactions have been reported,9b,k–m a mild and efficient
Cu(I)/TEMPO-catalyzed method was not known yet.12 Herein we
report a new method for imine synthesis by describing a mild
and efficient Cu(I)/TEMPO-catalyzed aerobic amine oxidation
reaction in open air at room temperature under ligand- and sol-
vent-free conditions.
Cu(I) catalysts such as CuBr (run 9) and CuCl (run 10), Cu(II) cata-
lysts such as CuBr2 (run 11),12 CuCl2ꢀ2H2O (run 12), Cu(OAc)2ꢀH2O,
CuSO4, Cu(NO3)2, etc., were all found to be less effective catalysts
than CuI for giving lower yields and/or lower selectivities of 2a.
In comparison with other Cu-catalyzed methods that require either
a high temperature,9k or using dioxygen as the oxidant,9b or using
higher loadings of catalysts, or large amount of solvents,9b,l,m or
using complex catalyst systems,9b,m the present method may be
a much simpler and more practical alternative since the reaction
can be readily conducted under ambient and neat conditions by
using lower loadings of the catalysts and air as the oxidant.
The optimized condition (Table 1, run 8) was then applied to
various primary amines to extend the scope of the method.13 As
shown in Table 2, the results revealed that the method is highly
tolerant of various functional groups. Thus, both electron-rich
and -deficient benzylamines (runs 1–14), even the sterically more
hindered ortho-substituted ones (runs 4, 7, 10, 13, 14), usually re-
acted efficiently at room temperature to give the target imines in
good to high isolated yields and high selectivities (up to 98:2).
Possibly due to the presence of two chloro groups, 2,4-dichloro-
benzylamine (1n) gave a lower yield and lower selectivity of the
product imine 2n (run 14). However, the fluoro- and chloro-substi-
tuted imines obtained from the corresponding halo-benzylamines
should be of potentially wide utility in synthesis due to the pres-
ence of the useful fluoro or chloro groups along with the reactive
C@N moiety in the molecule. Besides, according to GC analysis of
the reaction mixtures, no other byproducts (such as another poten-
tial byproduct, the corresponding aldehydes) were observed in the
reactions, which may be attributed to the mild and neat conditions
employed in the present method.
CuI/bipy/TEMPO (1/1/2 mol%)
Ph
NH2
PhCN
+
Ph
N
Ph
CH3CN, air, r.t., 10 h
2a/3a 86/14
1a
2a, 75%
3a, 12%
ð2Þ
Since considerable amounts of benzonitrile 3a was also gener-
ated as the byproduct Eq. 2, the conditions of the above reaction
were further optimized to enhance the yield and selectivity of
the target imine 2a (Table 1). We found the reaction was better
to be carried out under solvent-free conditions, for higher yield
and higher selectivity of 2a could be achieved without using the
solvent (run 1). Preliminary screening on the loadings of CuI and
bipy (2,20-bipyridine) revealed that more loading of the ligand
was ineffective to promote the reaction (run 2), but more loading
of CuI could slightly enhance the product yield (run 3). A detailed
screening on the loadings of CuI, bipy, and TEMPO (2,2,6,6-tetra-
methyl-1-piperidinyloxyl) was then carried out to investigate their
effects on the reaction. Thus, CuI alone, CuI/bipy, TEMPO alone, or
bipy/TEMPO were all found to be inefficient to catalyze the reac-
tion under similar conditions (runs 4–7). In contrast, CuI/TEMPO
was found to be most effective so that 2 mol % only could ensure
a high conversion of 1a (97%) and high yield and high selectivity
of 2a under the same condition (run 8), which is even better than
the reaction using bipy as the ligand (run 3). All the above contras-
tive results clearly showed that ligand bipy is unnecessary for the
reaction, as well as the high catalytic activity of CuI/TEMPO in the
reaction. Further condition screening showed that less loadings of
CuI and/or TEMPO were less effective and more loadings of them
were also unnecessary. During condition screening, we also inves-
tigated other Cu catalysts under the same condition. Thus, other
Similar to benzylamines, the reactions of heterobenzylamines
1o and 1p were also efficient under the same condition, but the
target imines 2o and 2p could not be isolated pure at present (runs
15, 16), because they easily hydrolyzed to give the corresponding
Table 2
Extension of the substrate scopea
CuI/TEMPO (2/2 mol%)
R
NH2
R
N
2
R +
RCN
3
air, neat, r.t.
1
Run
RCH2NH2 (1)
t (h)
2%, 2/3b
1
2
3
4
5
6
7
8
PhCH2NH2 (1a)
10
20
16
16
20
16
16
16
17
17
16
17
24
24
12
24
24
48
48
2a: 91 (85), 94/6
2b: 92 (82), 96/4
2c: 95 (89), 96/4
2d: 96 (87), 97/3
2e: 94 (86), 96/4
2f: 97 (88), 97/3
2g: 92 (84), 96/4
2h: 85 (75), 97/3
2i: 96 (88), 97/3
2j: 94 (81), 96/4
2k: 88 (82), 98/2
2l: 85 (77), 98/2
2m: 95 (86), 98/2
2n: 68 (51), 78/22
2o: 81, 81/19d
Table 1
4-FC6H4CH2NH2 (1b)
3-FC6H4CH2NH2 (1c)
2-FC6H4CH2NH2 (1d)
4-MeOC6H4CH2NH2 (1e)
3-MeOC6H4CH2NH2 (1f)
2-MeOC6H4CH2NH2 (1g)
4-MeC6H4CH2NH2 (1h)
3-MeC6H4CH2NH2 (1i)
2-MeC6H4CH2NH2 (1j)
4-ClC6H4CH2NH2 (1k)
3-ClC6H4CH2NH2 (1l)
2-ClC6H4CH2NH2 (1m)
2,4-Cl2C6H3CH2NH2 (1n)
(2-Furyl)methylamine (1o)
3-Picolylamine (1p)
Optimization of the reaction conditionsa
cat. [Cu]/bipy/TEMPO
Ph
NH2
+
Ph
N
2a
Ph
PhCN
3a
air, neat, r.t.
1a
Run
[Cu], [Cu]/bipy/TEMPO (mol %)
t (h)
2ab (%)
3ab (%)
2a/3ac
9
1
2
3
4
5
6
7
8
9
CuI, 1/1/2
CuI, 1/2/2
CuI, 2/2/2
CuI, 2/0/0
CuI, 2/2/0
CuI, 0/0/2
CuI, 0/2/2
CuI, 2/0/2
CuBr, 2/0/2
CuCl, 2/0/2
CuBr2, 2/0/2
CuCl2,e 2/0/2
10
10
10
31
12
10
10
10
12
12
12
12
80
79
82
9
6
6
8
93/7
93/7
91/9
—
—
—
10
11
12
13
14
15c
16c
17c
18c,e
19c,e
—
—
—
—
6
12
25
—
—
20
NRd
NR
91 (85)
81
—
2p: 88, 95/5
2q: 37, 77/23
94/6
87/13
73/27
—
4-Picolylamine (1q)
n-C8H17NH2 (1r)
PhCH2CH2NH2 (1s)
2r: 73, 86/14
2s: 49, 91/9f
10
11
12
68
15
2
a
Unless otherwise noted, the mixture of 1 (5.0 mmol), CuI (2 mol%), and TEMPO
—
(2 mol %) was directly stirred in open air at room temperature (ca. 30 °C), and was
a
The mixture of benzylamine 1a (5.0 mmol), Cu catalyst, bipy, and TEMPO was
then monitored by GC–MS and/or TLC.
b
directly stirred in open air at room temperature (ca. 30 °C), and was then monitored
GC yields (isolated yields in parenthesis) of 2 were based on 1. 2/3 ratios were
by GC–MS and/or TLC.
obtained by GC analysis.
b
c
GC yields (isolated yields in parenthesis) were based on 1a.
Compound 2a/3a ratios were obtained by GC analysis.
NR: no reaction.
The target imines could not be isolated pure at present (see Ref. 14).
The byproduct is the corresponding amide, 2-furancarboxamide.
CuCl/TEMPO (2/2 mol %), air, neat, 60 °C.
c
d
d
e
e
f
CuCl2ꢀ2H2O was used.
The byproduct is PhCH@NCH2CH2Ph (see also Ref. 9j).

B. Huang et al. / Tetrahedron Letters 54 (2013) 2861–2864
2863
Table 3
cat. Cu(I)/TEMPO
cat. Cu(I)/TEMPO
Cu/TEMPO-catalyzed aerobic oxidation of secondary aminesa
R
NH2
R
R
C N
NH
air, - H2O
fast
air, - H2O
slow
1
6
byproduct 3
CuX/TEMPO (2/2 mol%)
R2
R1
N
H
4
R1
N
2 or 5
R2
air, neat, T, t
H2O
1, - NH3
R
1
2
N
2
R
R
O
- H2O
- NH3
path b
fast
7
Run
1
4
CuX, T, t
Product
Yieldb (%)
13
path a
Ph
N
Ph
CuI, rt, 48 h
2a
Scheme 1. Proposed simplified reaction path for Cu(I)/TEMPO-catalyzed aerobic
oxidation of primary amines to imines.
H
2
3
4
5
6
4a
4a
4a
4a
4a
CuBr, rt, 17 h
2a
2a
2a
2a
2a
25
13
28
73
CuCl, r.t., 17 h
CuI, 60 °C, 48 h
CuBr, 60 °C, 48 h
CuCl, 60 °C, 48 h
reactions.9 Since both Cu(I) and TEMPO are essential but a ligand
such as bipy is unnecessary for the reaction, the first step of the
reaction should be the Cu(I)/TEMPO-catalyzed aerobic amine oxi-
dation to give a reactive imine intermediate 6, during which the
reactant amine 1 may coordinate with Cu(I)6b and TEMPO to form
an active complex to facilitate the oxidation of 1 to imine 6.9 Dif-
ferent to Cu(II) catalysts12 that are ineffective under the present
conditions (Table 1), Cu(I) is a much active catalyst for the reaction
(Table 1), indicating that the Cu(I)-derived complexes should be
more active for aerobic amine oxidation than the Cu(II)-derived
complexes12 under the neat conditions. The generated imine 6
should then undergo a fast condensation with another amine 1
to give the target imine product 2 (path a). Since no or only trace
amounts of aldehydes were observed as the byproducts in the
above reactions (Tables 1 and 2), hydrolysis of 6 to give an alde-
hyde intermediate 7 followed by dehydrative condensation of 7
with 1 to give 2 (path b) should be an unfavorable path in the reac-
tion. As observed, small amounts of the byproduct nitriles 3 may be
generated via further aerobic oxidation of 6 under the Cu(I)/TEM-
PO-catalyzed aerobic oxidative conditions. However, possibly due
to the mild conditions of the present method, and different to
the nitrile synthesis reactions that use pure oxygen as the oxidant
under harsh conditions,7 oxidation of 6 to 3 should be more diffi-
cult and accordingly the selectivity of 3 can be as low as 2% in
the present reactions (Table 2).
In summary, by catalyst and condition screening, we developed
a mild and simple method for synthesis of the useful imines by di-
rectly using amines as the substrates via an efficient Cu(I)/TEMPO-
catalyzed aerobic amine oxidation method under ambient and neat
conditions. Due to the mild conditions, low loadings of the readily
available and economic catalysts, no solvents, and employing air as
the economic and safe oxidant, the present method may be a more
practical alternative for imine preparation directly from amines.
Further applications of the Cu-catalyzed aerobic oxidative method
and the Cu(I)/TEMPO-catalyzed aerobic oxidative imine synthesis
method are underway.
90 (83)
N
N
7
CuCl, 60 °C, 60 h
99 (91)
H
H
5b
5c
4b
4c
8
9
CuCl, 60 °C, 60 h
CuCl, 60 °C, 60 h
30 (25)c
88d (81)
N
H
N
NH
N
5d
4d
a
The mixture of 4 (4.0 mmol), CuX (2 mol %), and TEMPO (2 mol %) was directly
stirred in open air at room temperature (ca. 30 °C) or at 60 °C, and was then
monitored by GC–MS and/or TLC.
b
GC yields (isolated yields in parenthesis) of the products were based on 4.
Large amounts of the reactant 4c remained unreacted.
Full conversion of 4d and 12% yield of byproduct isoquinoline were observed.
c
d
aldehydes and amines during the purification process even by
using preneutralized silica gel.14 In the case of 1o, the formed
byproduct was not the nitrile, but the corresponding amide instead
(run 15).8 In contrast, the reactions of heterobenzylamine 1q and
aliphatic amines 1r and 1s were much less efficient under the stan-
dard condition. Only low yields of the target imines were detected
(run 17). Although the reactions of 1r and 1s could be promoted by
using CuCl as the catalyst at a higher temperature (runs 18, 19), the
products could not be isolated pure, either, due to their instability
and easy decomposition during the purification process (runs 17,
18).14
The Cu(I)/TEMPO-catalyzed aerobic amine oxidation method
was then applied to secondary amines (Table 3). Different to the
ready oxidation of primary amines to imines, the reactions of
dibenzylamine 4a were not efficient at room temperature by using
CuI, CuBr, or CuCl as the catalyst (runs 1–3). Further condition
screening revealed that the reaction was better to be conducted
at a higher temperature such as 60 °C with CuCl being the best cat-
alyst (runs 4-6), giving the target imine 2a in 83% isolated yield
(run 6).15 The same method could be applied to other secondary
amines such as indoline (4b), 1,2,3,4-tetrahydroquinoline (4c),
and 1,2,3,4-tetrahydroisoquinoline (4d). Thus, the reaction of ind-
oline (4b) readily gave the corresponding indole (5b) in a high
yield (run 7). The oxidation of 1,2,3,4-tetrahydroquinoline (4c)
was comparatively more difficult, and it gave the aromatized
quinoline (5c) in a low yield with a large amount of the substrate
remaining unreacted (run 8). In contrast, the reaction of 1,2,3,4-
tetrahydroisoquinoline (4d) was very efficient under the same con-
dition, giving 3,4-dihydroisoquinoline (5d) in a good yield (run 9).
Although the mechanism of this mild and efficient Cu(I)/TEM-
PO-catalyzed aerobic amine oxidation reaction has not been
investigated in detail and was not exactly clear at present, a
simplified reaction path was proposed (Scheme 1) based on all
the above results and the literature on aerobic amine oxidation
Acknowledgments
We thank NNSFC (No. 20902070), SRF for ROCS of SEM, ZJNSF
(No. Y4100579), ZJQJTP (No. QJD0902004), and Opening Founda-
tion of Zhejing Provincial Top Key Disciplines (No. 10006120
0133) for financial support.
Supplementary data
Supplementary data (detailed experimental procedures, prod-
uct characterization, and NMR spectra of the products) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.03.098.
References and notes
1. (a) Bloch, R. Chem. Rev. 1998, 98, 1407; (b) Yet, L. Angew. Chem., Int. Ed. 2001, 40,
875; (c) Ellman, J. A.; Owens, T. D.; Tang, T. P. Acc. Chem. Res. 2002, 35, 984; (d)

2864
B. Huang et al. / Tetrahedron Letters 54 (2013) 2861–2864
Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10; (e) Córdova, A.
11, 2327; (j) Lang, X.; Ji, H.; Chen, C.; Ma, W.; Zhao, J. Angew. Chem., Int. Ed.
2011, 50, 3934; (k) Patil, R. D.; Adimurthy, S. Adv. Synth. Catal. 2011, 353, 1695;
(l) Hu, Z.; Kerton, F. M. Org. Biomol. Chem. 2012, 10, 1618; (m) Largeron, M.;
Fleury, M. B. Angew. Chem., Int. Ed. 2012, 51, 5409; For a recent perspective: (n)
Largeron, M.; Fleury, M. B. Science 2013, 339, 43.
Acc. Chem. Res. 2004, 37, 102; (f) Ma, J.-A. Chem. Soc. Rev. 2006, 35, 630; (g)
Dömling, A. Chem. Rev. 2006, 106, 17; (h) Erkkilä, A.; Majander, I.; Pihko, P. M.
Chem. Rev. 2007, 107, 5416; (i) Gawronski, J.; Wascinska, N.; Gajewy, J. Chem.
Rev. 2008, 108, 5227; (j) Yamada, K.-I.; Tomioka, K. Chem. Rev. 2008, 108, 2874;
(k) Merino, P.; Marqués-López, E.; Herrera, R. P. Adv. Synth. Catal. 2008, 350,
1195; (l) Ordóñez, M.; Rojas-Cabrera, H.; Cativiela, C. Tetrahedron 2009, 65, 17;
(m) Martin, S. F. Pure Appl. Chem. 2009, 81, 195; (n) de Armas, P.; Tejedor, D.;
Garía-Tellado, F. Angew. Chem., Int. Ed. 2010, 49, 1013; (o) Li, C.-J. Acc. Chem. Res.
2010, 43, 581; (p) Akhmetova, V. R.; Khabibullina, G. R.; Rakhimova, E. B.;
Vagapov, R. A.; Khairullina, R. R.; Niatshina, Z. T.; Murzakova, N. N. Mol. Divers.
2010, 14, 463; (q) Yin, B.; Zhang, Y.; Xu, L.-W. Synthesis 2010, 3583; (r)
Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626; (s)
Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Chem. Rev. 2011, 111, 1713; (t) Adrio, J.;
Carretero, J. C. Chem. Commun. 2011, 47, 6784; (u) Marques, C. S.; Burke, A. J.
ChemCatChem 2011, 3, 635; (v) Ramadhar, T. R.; Batey, R. A. Synthesis 2011,
1321; (w) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen, S.;
Jøgensen, K. A. Chem. Commun. 2011, 47, 632.
10. For oxidant-free dehydrogenation methods: (a) Muthaiah, S.; Hong, S. K. Adv.
Synth. Catal. 2012, 354, 3045; (b) Prades, A.; Peris, E.; Albrecht, M.
Organometallics 2011, 30, 1162; (c) Yi, C. S.; Lee, D. W. Organometallics 2009,
28, 947.
11. For reactions using stoichiometric amounts of oxidants or hydrogen acceptors:
(a) Murahashi, S.-I.; Naota, T.; Taki, H. Chem. Commun. 1985, 613; (b) Müller, F.;
Gilabert, D. M. Tetrahedron 1988, 44, 7171; (c) Orito, K.; Hatakeyama, T.; Takeo,
M.; Uchiito, S.; Tokuda, M.; Suginome, H. Tetrahedron 1998, 55, 8403; (d) Éll, A.
H.; Samec, J. S.; Brasse, C.; Bäckvall, J.-E. Chem. Commun. 2002, 1144; (e)
Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. Angew. Chem., Int. Ed. 2003, 42,
4077; (f) Nicolaou, K. C.; Mathison, C. J. N.; Montagnon, T. J. Am. Chem. Soc.
2004, 126, 5192; (g) Kim, S. S.; Thakur, S. S.; Song, J. Y.; Lee, K.-H. Bull. Korean
Chem. Soc. 2005, 26, 499; (h) Choi, H.; Doyle, M. P. Chem. Commun. 2007, 745;
(i) Fan, R.; Pu, D.; Wen, F.; Wu, J. J. Org. Chem. 2007, 72, 8994; (j) Chu, G.; Li, C.
Org. Biomol. Chem. 2010, 8, 4716.
2. (a) Schiff, H. Justus Liebigs Ann. Chem. 1864, 131, 118; (b) Sprung, M. M. Chem.
Rev. 1940, 26, 297; (c) Layer, R. W. Chem. Rev. 1963, 63, 489.
3. (a) Blackburn, L.; Taylor, R. J. K. Org. Lett. 2001, 3, 1637; (b) Yusubov, M. S.; Chi,
K.-W.; Park, J. Y.; Karimovc, R.; Zhdankinc, V. V. Tetrahedron Lett. 2006, 47,
6305.
4. (a) Gnanaprakasam, B.; Zhang, J.; Milstein, D. Angew. Chem., Int. Ed. 2010, 49,
1468; (b) Shiraishi, Y.; Ikeda, M.; Tsukamoto, D.; Tanaka, S.; Hiraia, T. Chem.
Commun. 2011, 47, 4811.
5. (a) Kwon, M. S.; Kim, S.; Park, S.; Bosco, W.; Chidrala, R. K.; Park, J. J. Org. Chem.
2009, 74, 2877; (b) Sun, H.; Su, F.-Z.; Ni, J.; Cao, Y.; He, H.-Y.; Fan, K.-N. Angew.
Chem., Int. Ed. 2009, 48, 4390; (c) Kang, Q.; Zhang, Y. Green Chem. 2012, 14,
1016; (d) Soulé, J.-F.; Miyamura, H.; Kobayashi, S. Chem. Commun. 2013, 49,
355.
6. (a) Jiang, L.; Jin, L.; Tian, H.; Yuan, X.; Yu, X.; Xu, Q. Chem. Commun. 2011, 47,
10833; (b) Tian, H.; Yu, X.; Li, Q.; Wang, J.; Xu, Q. Adv. Synth. Catal. 2012, 354,
2671.
7. (a) Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2003, 42, 1480; (b) Maeda,
Y.; Nishimura, T.; Uemura, S. Bull. Chem. Soc. Jpn. 2003, 76, 2399; (c) Enkatesan,
S.; Kumar, A. S.; Lee, J.-F.; Chan, T.-S.; Zen, J.-M. Chem. Eur. J. 2012, 18, 6147.
8. (a) Kim, J. W.; Yamaguchi, K.; Mizuno, N. Angew. Chem., Int. Ed. 2008, 47, 9249;
(b) Xu, W.; Jiang, Y.; Fu, H. Synlett 2012, 801.
9. Selected examples: (a) Yuan, H.; Yoo, W.-J.; Miyamura, H.; Kobayashi, S. J. Am.
Chem. Soc. 2012, 134, 13970; (b) Sonobe, T.; Oisaki, K.; Kanai, M. Chem. Sci.
2012, 3, 3249; (c) Wendlandt, A. E.; Stahl, S. S. Org. Lett. 2012, 14, 2850; (d) Liu,
L.; Zhang, S.; Fu, X.; Yan, C. Chem. Commun. 2011, 47, 10148; (e) Aschwanden,
L.; Mallat, T.; Maciejewski, M.; Krumeich, F.; Baiker, A. ChemCatChem 2010, 2,
666; (f) Kodama, S.; Yoshida, J.; Nomoto, A.; Ueta, Y.; Yano, S.; Ueshima, M.;
Ogawa, A. Tetrahedron Lett. 2010, 51, 2450; (g) Liang, G.; Chen, J.; Huang, J.-S.;
Che, C.-M. Org. Lett. 2009, 11, 4568; (h) Grirrane, A.; Corma, A.; Garcia, H. J.
Catal. 2009, 264, 138; (i) Samec, J. S.; Éll, A. H.; Bäckvall, J.-E. Chem. Eur. J. 2005,
12. During the progress of our present work, Kerton and co-workers reported a
CuBr2/TEMPO-catalyzed method that requires more loadings of the catalysts
and large amounts of solvent (9 mL per 2 mmol substrate, see Ref. 9l). In
contrast, their Cu(II) catalyst is ineffective under the present neat conditions
as we observed (Table 1, run 11). The reason for these differences between
the two catalytic systems is still unclear at present and remain to be
clarified.
13. Typical Procedure for Cu(I)/TEMPO-catalyzed aerobic oxidation of primary amines
to imines. The mixture of benzylamine 1a (5.0 mmol), CuI (0.0190 g, 0.1 mmol,
2 mol %), and TEMPO (0.0156 g, 0.1 mmol, 2 mol %) was directly stirred in open
air at room temperature (ca. 30 °C) in a reaction tube. After completion of the
reaction as monitored by GC–MS and/or TLC, the mixture was then directly
purified, without any workup, through a Et3N-washed silica gel column using
ethyl acetate and petroleum ether as the eluent, affording N-
benzylidenebenzylamine 2a in 85% isolated yield.
14. Despite many attempts, these imines cannot be isolated pure at present due to
their easy decomposition during purification. (a) See: Ref. 9.; (b) Burland, P. A.;
Coisson, D.; Osborn, H. M. I. J. Org. Chem. 2010, 75, 7210; (c) Lee, A. V.; Schafer,
L. L. Organometallics 2006, 25, 5249; (d) Li, C.; Thomson, R. K.; Gillon, B.; Patrick,
B. O.; Schafer, L. L. Chem Commun. 2003, 2462; (e) Monnereau, L.; Sémeril, D.;
Matt, D. Green Chem. 2010, 12, 1670.
15. Typical procedure for Cu(I)/TEMPO-catalyzed aerobic oxidation of secondary
amines to imines. The mixture of dibenzylamine 4a (4 mmol), CuCl (0.0079 g,
0.08 mmol, 2 mol %), and TEMPO (0.0125 g, 0.08 mmol, 2 mol %) was directly
stirred in open air at 60 °C for 48 h in a reaction tube. The mixture was then
directly purified, without any workup, through
a Et3N-washed silica gel
column using ethyl acetate and petroleum ether as the eluent, affording N-
benzylidenebenzylamine 2a in 83% isolated yield.