Selective formation of imines by aerobic photocatalytic oxidation of amines on TiO2

Article abstract of DOI:10.1002/anie.201007056

An oxygenation pathway: The title transformation involves a two-step process: a selective oxygenation step to generate aldehyde intermediates and a subsequent condensation step to afford the imine products (see scheme).

Full text of DOI:10.1002/anie.201007056

Communications
DOI: 10.1002/anie.201007056
Photocatalysis
Selective Formation of Imines by Aerobic Photocatalytic Oxidation of
Amines on TiO **
2
Xianjun Lang, Hongwei Ji, Chuncheng Chen, Wanhong Ma, and Jincai Zhao*
Imine derivatives are important
building blocks for the synthesis of
fine chemicals and pharmaceuti-
[
1]
cals. Generally, their synthesis
involves condensation of an amine
and a carbonyl compound. To cir-
cumvent the problem caused by the
excessively active nature of ketones
or aldehydes, an alternative strategy for the direct oxidation
in TiO photocatalysis in the presence of dioxygen, and hence
2
[2]
of amines has attracted much interest. Dioxygen, or more
preferably dioxygen in the air, embodies the quintessential
oxidant for chemical synthesis. Unfortunately, the reactivity
of dioxygen is difficult to control; it typically reacts under
harsh conditions with poor selectivity. Recently, much atten-
tion has been paid to organic synthesis photocatalyzed by
should lead to high selectivity in the photocatalytic oxidation
of alcohols. This mechanistic insight can direct us to envision
new reactions. Herein, we report our findings on a series of
benzylic amines that were selectively transformed into the
corresponding imines using 1 atm of air as the oxidant by TiO2
photocatalysis in acetonitrile. The formation of imines
involves a two-step process: a selective oxygenation step to
generate the aldehydes and a subsequent condensation step to
afford the imines. The high selectivity for the formation of
imines is attributed to both the highly selective formation of
aldehydes from amines [Eq. (2)] via a similar mechanism to
[3]
TiO2. In H O, the selectivity of TiO photocatalysis is
2
2
especially poor, so that, it is efficient in the degradation of
[4]
organic pollutants. Even when the reactions are performed
in inert organic solvent to prevent generation of OH radicals,
the selectivity is usually very low owing to the unselective
autooxidation of the photogener-
ated radicals. However, it has been
shown that high selectivity can be
realized in the TiO photocatalytic
2
system when both generation of
the OH radical and unselective
[
5]
autooxidation are avoided.
1
8
By using O-labeling experi-
ments, our research group has
discovered that an oxygen-atom
transfer dominates the photocata-
lytic transformation of alcohols
into the corresponding carbonyl compounds on TiO2 in
benzotrifluoride. This transformation has a different mecha-
nism than that of noble-metal/transition-metal complex
catalysis. All the experimental results support a mechanism
as shown in Equation (1). Such a mechanism avoids the
unselective autooxidation processes, which commonly occur
that which governs the aerobic oxidation of alcohols [Eq. (1)],
and the easy nucleophilic attack of such nascent aldehydes by
the unreacted amines to yield the corresponding imines.
Control experiments (see Table S1 in the Supporting
[6]
Information) revealed that TiO , dioxygen, and UV irradi-
2
ation are all necessary for these reactions. It was found that
the selectively oxidative coupling proceeds smoothly using
1 atm of air as the terminal oxidant. The pressure of O2
(Table S1, entry 4) did not influence the reaction significantly,
[*] Dr. X. Lang, Dr. H. Ji, Prof. C. Chen, Prof. W. Ma, Prof. J. Zhao
Key Laboratory of Photochemistry
Beijing National Laboratory for Molecular Sciences
Institute of Chemistry, Chinese Academy of Sciences
Beijing 100190 (China)
Fax: (+86)10-8261-6495
E-mail: jczhao@iccas.ac.cn
thus suggesting that the participation of O is not involved in
2
the rate-determining steps. The cutoff light below 350 nm
instead of 300 nm did not improve the selectivity (Table 1,
entry 2) and therefore excludes the involvement of a back-
ground photochemical reaction. Acetonitrile was found to be
the best solvent among those examined (Table S2). Table 1
summaries the results of the photocatalytic oxidation of
various amine derivatives. The transformation of all the
benzylic amines examined showed high selectivity and gave
[
**] Financial support from the 973 project (nos. 2010CB933503 and
2
2
007CB613306), the NSFC (nos. 20920102034, 21077110, and
0877076,) and the CAS are gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007056.
3
934
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Angew. Chem. Int. Ed. 2011, 50, 3934 –3937

[
a]
Table 1: Oxidation of amines photocatalyzed by TiO2.
further verified by the oxidation of
-phenylethylamine and 1-phenyl-
ethylamine (Table 1, entries 15 and
6) in which some of the products
2
Entry
Substrate
Product
t [h]
Conv.
mol%]
Select.
[mol%]
[
b]
[b]
[
1
1
9
5
5
99
93
99
85
87
91
(2, 4, and 5) result from unselective
autooxidation at multiple reactive
sites.
[
c]
2
There may be doubts that the N-
benzylidenebenzylamine might be
generated via an oxidative dehy-
drogenation of the amines [Eq. (4)].
This pathway is usually proposed
3
4
5
6
8
99
99
92
88
[
7]
for the oxidation of amines. Low
selectivity is associated with these
systems under homogenous photo-
chemical conditions. However, the
single issue of the high selectivity
6
7
8
9
1
15
6
77
99
99
99
99
71
90
86
90
84
for
N-benzylidenebenzylamine
could not unequivocally confirm
that the oxygenation pathway
10
10
5
[
Eq. (3)] is the main pathway to
contribute the formation of the final
imines in the present system. We
could not completely exclude the
possibility that there might be some
unknown factors that would lead to
a high selectivity via a dehydrogen-
0
1
1
1
2
6
6
78
81
77
33
ation pathway in TiO photocataly-
2
[
d]
d]
1
1
3
4
5
5
80
6
–
sis. In that case, benzylimine is
[
susceptible to H O (the concomi-
–
quant.
2
tant product of oxidation) to gen-
erate benzaldehyde. Therefore, this
renders it impossible to distinguish
these two pathways [Eqs. (3) and
[
d]
d]
1
5
6
8
5
65
73
–
–
(4)] for those substrates such as
[
1
benzylamine and its derivatives in
Table 1. As a result, additional
proof was needed to confirm that
the mechanism is via an oxygen-
ation process to generate the alde-
[
3
a] Reaction conditions: 0.1 mmol of amine, 10 mg of TiO (Degussa P25), 100 W Hg lamp cutoff below
00 nm, 5 mL of acetonitrile, 1 atm of air. [b] Determined by GC analysis using bromobenzene as the
internal standard. [c] 500 W Xe lamp cutoff below 350 nm. [d] Data in the parentheses is the selectivity
based on the initial amine.
2
the imine products (Table 1, entries 1–9). In addition, sub-
stituents on the benzylic amines did not affect the selectivity
significantly, but slightly changed the conversion rates. It
should be mentioned that this approach was also applicable to
heteroatom-containing substrates (Table 1, entries 10–12),
whose products are usually inaccessible by transition-metal
complex catalysis owing to deactivation of the catalysts
caused by the strong coordination of these amines to the
metal center. The relatively low selectivity for furfurylamine
hyde [Eq. (3)]. We chose dibenzylamine rather than benzyl-
amine as the substrate to synthesize N-benzylidenebenzyl-
amine. Thus, product analysis can be an important method to
distinguish these two mechanisms [Eqs. (3) and (5)] vs.
[Eqs. (4) and (6)]. If the reaction proceeds via a dehydrogen-
ation pathway, which ensures a high selectivity for benzyl-
amine as the substrate [Eq. (4)], an equal or even better
selectivity should be realized for dibenzylamine because it is a
(
Table 1, entry 12) might result from the instability of the
afforded imine. When nonbenzylic amines such as cyclo-
hexylamine and n-hexylamine were chosen as the substrates
(
Table 1, entries 13 and 14), no imines were formed and only
fragmentation products were detected. This finding is in line
with poor selectivity for the oxidation of these substrates with
dioxygen resulting from the unselective autooxidation caused
by the activation of multiple reactive sites. This notion is
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3935

Communications
aldehydes and amines. There should be only two imines
produced (Scheme S1) via a dehydrogenation pathway
[
Eq. (6)]. However, if the reaction proceeds via the oxygen-
ation pathway [Eq. (5)], there should be four different imines
produced and two accumulated aldehydes as the final
products. The molar ratios for the four imines should be
close to 1:1:1:1 (Scheme S2). As shown in Table 2, entries 6
and 7, we did observe four different imines with molar ratio
close to 1:1:1:1 and two accumulated aldehydes. The notion
was further supported by the oxidation of N-benzyl-4-
methoxyaniline (Table 2, entry 8) in which only benzaldehyde
and 4-methoxyaniline were detected as the products. The
difficulty of the condensation between benzaldehyde and 4-
methoxyaniline prevents the formation of the imine.
In an attempt to determine the parameters related to the
reaction rate, a series of kinetic experiments were conducted
for the photocatalytic oxidation of amines. Preliminary
kinetics measurements indicate that the reaction exhibits
pseudo-first-order kinetics (Figure S1). The oxidation of
benzylamine and its derivatives with both electron-donating
and -withdrawing substituents at the para-position were
examined to obtain a Hammett plot (Figure 1). The slope of
the linear plot gave a 1 value close to zero. This 1 value
indicates that the reaction is not sensitive to substituents and
one-step pathway [Eq. (6)] for the formation of N-benzylide-
nebenzylamine. In the case of the oxygenation pathway, a
detour for the aldehyde and benzylamine will occur
[
8]
[
Eq. (5)]. The benzylamine generated in situ could also
self-couple to give N-benzylidenebenzylamine under the
present conditions [Eq. (3)]. Thus, some accumulated alde-
hyde will be detected as the final product in addition to
imines. The results for the oxidation of dibenzylamine and its
derivatives are summarized in Table 2, entries 1–5. The
selectivity for the afforded imines (38–53%) dropped signifi-
cantly compared with the results shown in Table 1 (85–92%),
therefore indicating that an oxygenation pathway [Eqs. (3)
and (5)] is preferred rather than the dehydrogenation path-
way [Eqs. (4) and (6)]. The detection of significant amounts of
aldehydes for all these substrates (Table 2, entries 1–5) is a
clear indication that the reaction proceeded via an oxygen-
ation pathway [Eqs. (3) and (5)].
To further confirm the oxygenation pathway in the
formation of imines, we selected asymmetric dibenzylamine
derivatives as the probe substrates. There are almost equal
opportunities for the activation of C ÀH bonds on both sides
electronic perturbation does not occur in the C ÀH activation
a
a
[9]
adjacent to the nitrogen atom (see discussion below) and
equal reaction rates for the condensation between different
step.
Kinetic isotope effect experiments between C H CH NH
2
6
5
2
and C H CD NH showed a k /
6
5
2
2
H
k value of 1.3 Æ 0.1, which indi-
D
Table 2: Oxidation of secondary benzylic amines on TiO2.[a]
cates that cleavage of the C ÀH
a
bond is not involved in the rate-
determining step. These kinetic
data resemble those in the oxi-
Entry Substrate
Conv.
Product
[
b]
[b]
[mol%] (select. [mol%])
1
91
90
dation of alcohols on TiO , and
2
is important information for the
future design of photocatalyst in
order to improve the efficiency
of the photocatalytic system for
[
c]
2
3
4
5
95
72
70
[6]
the oxidation of amines.
In summary, we have ach-
ieved highly selective photoca-
talytic oxidation of amines on
TiO using 1 atm of air as the
2
oxidant. The oxidation of
amines involves a highly selec-
tive formation of aldehydes
whose further condensation
with the unreacted or in-situ
generated amines affords the
corresponding imines. These
findings further demonstrate
the generality of the reaction
by the involvement of a selec-
tive oxygenation pathway in
[
d]
6
86
[
d]
7
90
38
8
TiO photocatalysis with dioxy-
2
gen as the oxidant. Such funda-
mental insights could help us to
envision new reactions for the
oxidation of organic substrates
[
a] Reaction conditions: 0.05 mmol of amine, 2.5 mL of acetonitrile, 10 mg of TiO (Degussa P25), 100 W Hg
2
lamp cutoff below 300 nm, 1 atm of air, 8 h. [b] Determined by GC analysis using bromobenzene as the
internal standard. [c] 5 h reaction time. [d] 4 h reaction time.
3
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and pave the way to new synthetic method for synthesizing
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2
Received: November 10, 2010
Revised: January 17, 2011
Published online: March 4, 2011
2
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[
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Keywords: imines · photocatalysis · selective oxidation ·
titanium dioxide
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