Direct and mild palladium-catalyzed aerobic oxidative synthesis of imines from alcohols and amines under ambient conditions

Article abstract of DOI:10.1039/c1cc14242a

By ligand, TEMPO, and base screening, we developed a mild and green one-pot imine synthesis from alcohols and amines via a low-loading palladium-catalyzed tandem aerobic alcohol oxidation-dehydrative condensation reaction that can be readily carried out in open air at room temperature.

Full text of DOI:10.1039/c1cc14242a

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COMMUNICATION
Direct and mild palladium-catalyzed aerobic oxidative synthesis of imines
from alcohols and amines under ambient conditionsw
Lan Jiang, Luolu Jin, Haiwen Tian, Xueqin Yuan, Xiaochun Yu* and Qing Xu*
Received 14th July 2011, Accepted 9th August 2011
DOI: 10.1039/c1cc14242a
By ligand, TEMPO, and base screening, we developed a mild
and green one-pot imine synthesis from alcohols and amines via a
low-loading palladium-catalyzed tandem aerobic alcohol
oxidation–dehydrative condensation reaction that can be readily
carried out in open air at room temperature.
protection and produce water as the byproduct, they usually
require the use of dioxygen as the oxidant and moderate to high
temperature heating.6f–h In comparison, a room temperature
reaction catalyzed by a heterogeneous Au catalyst was not
effective, giving only low yields of the products.6i The only
reaction using air as the economic oxidant is catalyzed by
OMS-2, but it requires both a high temperature and the use of
excess amounts of the amines.6j Therefore, developing highly
active catalysts that can lead to more efficient reactions under
milder conditions is still a challenging task in the area. We now
report a low-loading palladium-catalyzed mild and one-pot
method that can be readily carried out under solventless
conditions in open air at room temperature (Scheme 1, right).
We recently focused on amine derivatives and developed a
general and advantageous air-promoted metal-catalyzed
N-alkylation methodology (Scheme 1, left).7 During the research
we also noticed that imines could be obtained in moderate
amounts with excess air7 and that the Pd catalysts that had
never been successfully used in the N-alkylations are in effect
very active catalysts if employing the aerobic protocol.7c Since
the readily available Pd catalysts are known as good catalysts in
Imines are an important class of nitrogen compounds due to their
high reactivity.1–3 They have been used as nitrogen sources in
different types of transformations that can be further utilized in
synthetic, biological, pharmaceutical and industrial applications.2
Imines or iminium ions containing the reactive CQN moiety are
also key intermediates in multi-component reactions, asymmetric
organocatalysis, cross-dehydrogenative couplings, and so on.2,3
Therefore, synthesis and applications of imines are essentially
ever-appealing topics in chemistry.
Although several new methodologies have been developed
for imine synthesis in recent years,4 the traditional condensation
of aldehydes or ketones with amines is still the most simple way
to obtain the target imines.1 Because alcohols are much greener
chemicals in many aspects than the carbonyl compounds,5
a potentially more general and more advantageous protocol
would be the one-pot oxidative tandem synthesis from alcohols
and amines. Several methods are available at present, but, to
the best of our knowledge, severe drawbacks still remain.6 For
example, an in situ oxidative method requires the use of a large
excess of MnO2 (10 equiv.) as the oxidant and 4 A molecular
sieves as the dehydrating agent, which results in workup and
waste disposal problems.6a Two recent anaerobic catalytic reactions
not only require the usually unavailable Ru6b or Os6c pincer
complexes, but also organic solvents, inert atmosphere protection
and high temperatures (up to 150 1C), and the former method
seems to be limited to aliphatic amines only. A new report
using a heterogeneous Ru catalyst is even less effective as it
requires high temperature, long reaction time and high base
loading.6d In addition, another heterogeneous Pt-catalyzed
anaerobic reaction requires a thousand fold excess of alcohol
and UV irradiation.6e As to the aerobic methods, although a
good alternative as they do not require inert atmosphere
aerobic alcohol oxidations,8
a direct Pd-catalyzed imine
preparation from alcohols and amines using air as the greener,
safer, and more economic oxidant was anticipated.
The most often used catalyst, Pd(OAc)2,8 was employed in
the model reaction of benzyl alcohol 1a and benzyl amine 2a
(Table 1). Initially the reaction was heated at 120 1C. Toluene
was found to be a better solvent, giving moderate yield of
imine 3aa (run 1). With K2CO3 added as the base, the product
yield improved to 87% (run 2). When bipyridine and TEMPO
were added as the ligand and oxidation co-catalyst, the reaction
time was shortened to only 6 h (run 3). Realizing that the
ligand, TEMPO and base were all key factors for the reaction,
effects of these additives and their loadings were examined to
optimize the conditions. In ligand screening (PPh3, TMEDA,
pyridine, bipyridine, pyrrolidine, and o-phenanthroline), the
economic and air-stable Et3N was found to be the best one (runs
4 and 5). Thus, catalyst and additive loadings could be reduced
but still maintaining similarly high reaction efficiency (run 5).
College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou 325035, China. E-mail: qing-xu@wzu.edu.cn;
Fax: +86-577-88373111; Tel: +86-13857745327
w Electronic supplementary information (ESI) available: Experimental
and characterization of products. See DOI: 10.1039/c1cc14242a
Scheme 1 Meal-catalyzed aerobic reactions of alcohols and amines.
Chem. Commun., 2011, 47, 10833–10835 10833
c
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Table 1 Condition screening and optimizationa
Table 2 Pd-catalyzed aerobic oxidative imine preparation from
alcohols and aminesa
Conditions (mol%): Pd, L,
TEMPO, base
3b (%)
Run
T, t
3aab (%)
Run
1
2
1c,d
2c,d
3c,d
Pd(2)
120 1C, 24 h
120 1C, 24 h
120 1C, 6 h
51
87
77
1
2
3
4
5
6
7
8
PhCH2OH (1a)
1a
1a
1a
1a
p-CH3C6H4CH2OH (1b)
p-CH3OC6H4CH2OH (1c) 2a
PhCH2NH2 (2a)
n-C4H9NH2 (2b)
(CH3)2CHCH2NH2 (2c) 94
n-C8H17NH2 (2d)
cyclo-C6H11NH2 (2e)
2a
99
99
Pd(2), K2CO3(20)
Pd(2), bipy(2), TEMPO(4),
K2CO3(20)
Pd(2), Et3N(30), TEMPO(4),
K2CO3(20)
Pd(1), Et3N(15), TEMPO(2),
K2CO3(20)
Pd(1), Et3N(15), TEMPO(6),
t-BuOK(20)
99
99
76
98
99
81
99
99
4c,d
5c,d
6c,d
7c,d
8c
120 1C, 6 h
120 1C, 6 h
80 1C, 24 h
80 1C, 24 h
90
77
90
89
1c
1c
2b
2d
2b
2b
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
p-ClC6H4CH2OH (1d)
p-NO2C6H4CH2OH (1e)
m-CH3OC6H4CH2OH (1f) 2b
o-CH3OC6H4CH2OH (1g) 2b
2-Pyridinemethanol (1h)
2-Furanmethanol (1i)
2-Thiophenemethanol (1j) 2b
1c
1a
1c
1a
1c
1a
1a
1c
1a
1a
1a
1a
1a
Pd(1), Et3N(15), TEMPO(6),
KOH(20)
99
23 (92)c
99
94
Pd(1), Et3N(15), TEMPO(4),
t-BuOK(20)
50 1C, 2 days 73
2b
2d
9e
Pd(1), Et3N(15), TEMPO(4), r.t.,f 3 days
t-BuOK(20)
99(87)g
99
67
10e,h
11e,i
Pd(1), Et3N(15), TEMPO(4), r.t., 3 days
t-BuOK(20)
Pd(1), Et3N(15), TEMPO(4),
t-BuOK(20)
2-Furanmethylamine (2f) 91
PhNH2 (2g)
2g
p-CH3C6H4NH2 (2h)
2h
75 (83)c
67 (84)c
41 (81)d
91
r.t., 3 days
48
a
The mixture of 1a (1–2 equiv.), 2a (2 mmol), Pd catalyst, ligand and
base was stirred under air and then monitored by GC-MS. Pd(OAc)2
p-C2H5OC6H4NH2 (2i)
p-ClC6H4NH2 (2j)
2j
70 (86)d
35 (84)d
43 (86)d
b
was used as the catalyst unless otherwise noted. GC yields based on
f
2a. 1 equiv. of 1a. In 0.5 mL toluene. 2 equiv. of 1a. Room
c
d
e
m-CH3OC6H4NH2 (2k) 37 (84)d
g
h
m-ClC6H4NH2 (2l)
o-CH3C6H4NH2 (2m)
o-CH3OC6H4NH2 (2n)
o-ClC6H4NH2 (2o)
(66)d
(43)c
(36)c
(21)d
97
temperature: ca. 30 1C. Isolated yield in parenthesis. PdCl2.
Pd(PPh3)2Cl2.
i
PhCHQCHCH2OH (1k) 2b
1k
1k
Then, base screening showed that t-BuOK and KOH were
better than the others (K2CO3, t-BuONa, NaOH, etc.), leading
to a reduced reaction temperature (runs 6 and 7). Without a
solvent, the reaction could even be conducted at lower
temperatures in the presence of t-BuOK (runs 8 and 9). With
2 equiv. of 1a, the temperature was further reduced to room
temperature, affording almost quantitative yield of the
product in open air (run 9). However, further attempts to
optimize the conditions by tuning the Pd/Et3N ratios failed,
implying that an active catalytic species that is related to the Pd/
Et3N ratio must be involved. Under the optimized conditions,
product yields also decreased in degrees without TEMPO
(85%) or without base (13%). The catalytic activities of other
Pd catalysts were also examined. PdCl2 showed similarly high
activity as Pd(OAc)2 (run 10); while Pd(PPh3)2Cl2 was less
effective (run 11).
2d
2g
70
(46)c
a
b
See Table 1 for conditions. Reactions monitored by GC-MS and
c
d
GC yields based on 2a. 50 mol% t-BuOK added. 100 mol%
t-BuOK added.
and a heterobenzylic amine 2f (run 17) reacted efficiently to
afford moderate to high yields of the heteroaromatic imines
under the standard conditions.
As to the aromatic amines 2g–l, most of the reactions were
less efficient (runs 18–26) than those of the aliphatic amines. In
these cases, variant amounts of the unreacted aldehydes (5–29% by
GC) were detected in the reaction mixtures, possibly because
aromatic amines are less basic and nucleophilic than the aliphatic
ones, which may result in less efficient condensation reactions.
With this in mind, we increased the base loadings and were
pleased to see that the product yields could be enhanced greatly,
revealing the base’s facilitating effect on the condensation step.
The reactions of ortho-substituted aromatic amines 2m–o were
also investigated, but were found to be less efficient than those
of the para- and meta-substituted ones, even with higher base
loadings (runs 27–29). This is most possibly due to the steric
hindrance derived from the ortho-groups on the benzene ring.
Moreover, an allylic alcohol, cinnamyl alcohol 1k, also
reacted efficiently with aliphatic amines to give high yields of
the a,b-unsaturated imines (runs 30 and 31). The reaction of
1k with aniline 2g was less effective, but still afforded moderate
yield of the product with 50 mol% t-BuOK (run 32).
The optimized conditions were then applied to various
alcohols and amines to test the scope of the reaction
(Table 2). These results revealed the potential and generality
of the Pd-catalyzed aerobic method. Thus, 1a reacted efficiently
with aliphatic amines 2a–e to afford almost quantitative yields
of the imines (runs 1–5). So are the reactions of the aliphatic amines
with both electron-rich and electron-deficient para- and meta-
substituted benzylic alcohols 1b–f (runs 6–12). In comparison,
the reaction of an ortho-substituted alcohol 1g was not
effective under the standard conditions (run 13), but high
product yield could be obtained by increasing the base loading
(run 13, result in parenthesis). Like benzylic alcohols and
aliphatic amines, heterobenzylic alcohols 1h–j (runs 14–16)
c
10834 Chem. Commun., 2011, 47, 10833–10835
This journal is The Royal Society of Chemistry 2011

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Notes and references
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Scheme 2 Proposed reaction path for the Pd-catalyzed aerobic
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oxidative imine preparation from alcohols and amines.
a,b-Unsaturated imines are also a class of versatile intermediates
that have been widely used in synthesis.9
As shown in eqn (1), Pd-catalyzed aerobic alcohol oxidation
under the standard conditions efficiently afforded 86% yield of
benzaldehyde 4a (based on 2 mmol 2a, although not added in
the reaction, run 1). In contrast, 4a yields decreased without
either the base or TEMPO (runs 2 and 3). These results, well
consistent with those obtained in condition screening, revealed
the facilitating effect of these additives on the alcohol oxidation
step. Therefore, although the active catalytic Pd species and the
reaction mechanism still remain to be fully clarified, the reaction
surely proceeds via the sequence of Pd-catalyzed aerobic alcohol
oxidation8 and dehydrative condensation of the generated
aldehydes with the amines1 (Scheme 2).6 In the oxidation step,
the base may act to facilitate the deprotonation of the alcohol
to give the alcoholate, promoting its coordination with Pd.8
According to our present results (Table 2, runs 19–30, 33) and
previous findings,7 the base may also promote the condensation
step by making the aromatic amines more basic and more
nucleophilic. The role of TEMPO, which is known to be
capable of oxidizing alcohols to aldehydes and TEMPOH,10
is not clear yet, but may be explained by that TEMPOH is
reoxidized by the oxidative Pd–O2 or Pd(II) species8 to regenerate
TEMPO. In addition, although condensation of aldehydes and
amines usually occurs easily under mild conditions, metal
catalysts were found to promote this step in some degree7 as
was predicted.5a Thus, Pd’s effect to promote the condensation
cannot be excluded completely.
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ð1Þ
In summary, we developed a direct and mild one-pot
synthesis of the useful imines via a low-loading Pd-catalyzed
aerobic oxidative tandem reaction of alcohols and amines. To
our knowledge, this is the first convenient, practical and green
method for imine synthesis from alcohols and amines.6 The
present results also support the proposed reaction path in the
metal-catalyzed aerobic N-alkylation reactions and that
metal-catalyzed aerobic alcohol oxidation should be a useful
and practical alcohol activation alternative.7 Deeper mechanistic
studies, scope and further extension of this Pd-catalyzed aerobic
method are underway.
This work was supported by National Natural Science
Foundation of China (No. 20902070), Natural Science
Foundation (No. Y4100579) and Qianjiang Talents Program
(No. QJD0902004) of Zhejiang Province. L. Jin thanks the
Science and Technology Department of Zhejiang Province
(No. 2010R424009).
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10833–10835 10835