Direct one-pot reductive imination of nitroarenes using aldehydes and carbon monoxide by titania supported gold nanoparticles at room temperature

Article abstract of DOI:10.1039/c1gc15307b

The direct one-pot reductive imination of nitroarenes with various aldehydes by a titania supported gold catalyst at room temperature using CO/H₂O as a reducing agent is illustrated. This method is simple, economic, general and environmentally benign, thus resulting in practical advantages for the synthesis of imines and their derivatives.

Full text of DOI:10.1039/c1gc15307b

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COMMUNICATION
Direct one-pot reductive imination of nitroarenes using aldehydes and
carbon monoxide by titania supported gold nanoparticles at room
temperature†
Jun Huang, Lei Yu, Lin He, Yong-Mei Liu, Yong Cao* and Kang-Nian Fan
Received 21st March 2011, Accepted 6th July 2011
DOI: 10.1039/c1gc15307b
The direct one-pot reductive imination of nitroarenes with
various aldehydes by a titania supported gold catalyst
at room temperature using CO/H2O as a reducing agent
is illustrated. This method is simple, economic, general
and environmentally benign, thus resulting in practical
advantages for the synthesis of imines and their derivatives.
methodologies that afford high chemo- and regio-selectivity
under mild reaction conditions is still a challenging problem.8
As for the synthesis of imines, the direct use of nitroarenes as
starting materials is highly attractive, especially when an efficient
and reusable catalytic system can be employed. Compared to
the great progress being made in the imination of amines with
aldehydes or ketones,9 there are scarcely any available reports
dealing with the direct reductive imination of nitroarenes with
carbonyl compounds. A number of transition-metal-catalyzed
carbonylative reductions of nitroarenes and aldehydes with CO
and water to afford imines have been reported since the early
1970s.10a–e However, these homogeneous systems are problematic
in terms of the recovery/recycling of the catalyst and the special
handling of metal complexes. Recently, the direct synthesis of
imines from nitroarenes and carbonyl compounds was realized
The formation of carbon–nitrogen bonds is one of the most
important transformations in organic chemistry.1 In particular,
imines are highly desirable, owing to their versatile applica-
tions as electrophilic reagents in many organic reactions, such
as reductions, additions, condensations, and cycloadditions.2,3
Traditionally, imines are synthesized from the dehydrative
condensation of amines and carbonyl compounds in the
presence of an acid catalyst.4 Imines can also be prepared
by a number of catalytic and non-catalytic procedures, such
as the self-condensation of amines upon oxidation,5a,5b the
oxidation of secondary amines5c,5d or directly from alcohols
and amines via several tandem catalytic processes,5e,5f ,6 mostly
with homogeneous systems. However, many of these methods
entail important practical drawbacks regarding the difficulty
for resue, the use of expensive amines as starting materials,
long reaction time, low selectivities, high temperature, tedious
work-up procedures, and/or concomitant formation of large
amounts of wasteful salts. In these regards, there is a strong
incentive to develop an alternative heterogeneous-based method
that can employ simpler starting materials, as well as mild and
environmentally benign conditions.
11a
11b
using Au/TiO2 or Ni/SiO2 as a catalyst in the presence of
molecular H2, or using the hydrogen gas produced from the
aqueous-phase reforming of methanol as an in situ reductant
11c
over a bimetallic Au–Pd/Al2O3 catalyst. Despite their utility,
clear drawbacks of these methods are the requirement ◦of harsh
reaction conditions, such as high temperatures (>110 C), ele-
vated pressures and prolonged reaction times, which made them
far from ideal for both synthetic and large-scale applications.
In this respect, the development of a new practical and efficient
one-pot process that can allow the direct synthesis of imines from
aromatic nitro compounds under mild conditions still remains
a major challenge.
The use of supported gold nanoparticles (NPs) as cata-
lysts for green organic transformations is an area of growing
interest.12 Recently, from our continuing studies on supported
gold NPs catalysis,5e,13 we have discovered an excellent Au-
catalyzed reduction strategy that can allow the rapid and
chemoselective reduction of polysubstituted nitro and carbonyl
compounds under very mild conditions.14 This process can
circumvent the limited hydrogen delivery rate that has plagued
previously reported Au-catalyzed hydrogenation processes.8a,15
The reductant used in this green alternative methodology was
CO and H2O (rather than H2), where the transient Au0–H
formed by the CO-induced H2O reduction is believed to be the
key active species for nitro reduction. An interesting feature
of the Au–CO/H2O-catalyzed reaction is that it tolerates a
Nitroarenes are inexpensive and readily available organic
compounds, and the reduction of nitro compounds is a key
step in the preparation of many pharmaceutical agents and
fine chemicals.7 Despite numerous established procedures for
the reduction of nitro compounds, the development of catalytic
Shanghai Key Laboratory of Molecular Catalysis and Innovative
Materials, Department of Chemistry, Fudan University, Shanghai,
200433, P. R. China. E-mail: yongcao@fudan.edu.cn; Fax: (+86-21)
65643774
† Electronic supplementary information (ESI) available: Experimental
section, elemental analysis, TEM, XPS and 1H NMR. See DOI:
10.1039/c1gc15307b
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Table 1 Synthesis of N-benzylidenebenzenamine from nitrobenzene and benzaldehyde in different solventsa
Sel.[%]c
Entry
Solvent
Water [equiv]b
Con. [%]c
Imine
Aniline
Nitroned
1
2
3
4
5
6
7
8
Ethanol/Water (v/v = 2 : 1)
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Acetonitrile
DMF
33
0
0.5
1
2
10
1
1
1
1
1
100
25
71
27
78
74
72
64
43
53
50
79
85
95
93
—
65
2
8
8
20
18
15
13
10
19
15
11
5
90
13
23
47
28
35
10
10
5
100
100
43
34
78
100
100
97
9
Toluene
10
11
12e
13f
Tetrahydrofuran
Triethylamine
Triethylamine
Triethylamine
0
0
—
1
1
7
—
n.r.
a Reaction conditions: 1 mmol nitrobenzene, 1 mmol benzaldehyde, Au/TiO2-VS (1 mol% Au), 2 mL solvent, 5 atm CO, 25 ◦C, 1 h. b Relative to that
of nitrobenzene. c GC conversion and selectivity obtained by using anisole as an internal reference. d Confirmed by GC/MS. e 1 atm CO, 5 h. f H2
(5 atm) as the hydrogen source, n.r. = no reaction.
diverse range of reducible functional groups, including alkenes,
alkynes, halogens, ketones, aldehydes, esters, and nitriles.14
Furthermore, this reaction can be carried out under atmospheric
CO at room temperature. In view of the prominent efficiency
of the gold system for chemoselective reduction of the nitro
functionality, we envisioned that the CO/H2O-mediated Au-
catalyzed reduction strategy could afford a green and efficient
protocol for the direct synthesis of substituted imines from
nitroaromatics under mild conditions.
Herein, we report for the first time that direct reductive
imination of nitroarenes with aldehydes via a simple CO-
mediated one-pot strategy could efficiently be promoted by
small gold NPs supported on titania (Au/TiO2-VS). With the
procedure presented here, nitroarenes are directly used as the
starting reactants and undergo a selective reduction process
to form anilines, which condense in situ with the aldehydes
to provide the final imines through a cascade-type reaction
(Scheme 1). Of note is that this particular transformation can
proceed very effectively at ambient temperature under 5 atm
CO atmosphere, these are the mildest reaction conditions ever
reported for the direct reductive transformation of nitroarenes
and aldehydes for the preparation of substituted imines. Thanks
to the chemoselectivity of the CO–Au/TiO2-VS system during
the reduction of nitro aromatics, this methodology is found to be
applicable to both aromatic and aliphatic aldehydes and a wide
range of nitroaromatics. Compared with the known protocols
from the literature,11 the present Au-catalyzed CO-mediated
one-pot direct reductive imination system has the following
advantages: i) unprecedentedly high activity under very mild
conditions; ii) high selectivity towards very sensitive competing
groups; and iii) the use of safe and easy-to-handle catalysts and
reducing reagents.
We began our study by examining the direct coupling of
nitrobenzene and benzaldehyde at 25 ◦C, as this is expected
to represent the easiest scheme for the proposed reductive
imination. First of all, the direct imination of nitrobenzene
with an equimolar amount of benzaldehyde under 5 atm of
CO in aqueous ethanol (ethanol/water 2 : 1) in the presence
of Au/TiO2-VS (1% mol of Au) was investigated. In line with
our previous results in CO/H2O-mediated Au-catalyzed nitro
reduction, the initial reduction of the nitro functionality was
complete after 1 h of the reaction.14a However, only very small
amounts of N-benzylidenebenzenamine could be detected in this
case (Table 1, entry 1), probably due to the lack of conversion in
the consecutive imine formation step. As a result of the presence
of a large excess of water in the reaction system, there still was
an appreciable amount of aniline left in the reaction mixture.
Surprisingly, a significant amount of nitrone was also observed
as a by-product. Nitrones are highly versatile and valuable
synthetic intermediates in organic synthesis and are extensively
used in the synthesis of biologically active compounds.16 The
most frequent routes to prepare nitrones include the con-
densation of carbonyl compounds with N-monosubstituted
hydroxylamines or the oxidation of hydroxylamines or imines.17
As the chemoselective reduction of nitroaromatics catalyzed by
supported gold catalysts is believed to involve the formation
of hydroxylamine as the key intermediate species,8d,18 it is likely
that the transient hydroxylamine thus formed might then react
further with benzaldehyde, giving rise to the corresponding
nitrones product.
In an attempt to facilitate the desired consecutive imine
formation, a systematic study of the reductive imination was
then accomplished in aqueous ethanol with decreasing water
content. As expected, the reaction run using standard non-dry
ethanol as the solvent (under otherwise the same conditions
as the preliminary experiment) led to significantly improved
imine selectivity but had the opposite effect on the conversion
of nitrobenzene (Table 1, entry 2). This latter result can
be rationalized by assuming that the formation of transient
Scheme 1 The imination of nitroarenes using aldehydes and carbon
monoxide by supported gold nanoparticles at room temperature.
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Au0–H species,19 which are responsible for the superior ac-
tivity of the CO/H2O-mediated Au-catalyzed nitro reduction,
is severely limited under water-deficient conditions.20 Upon
increasing the water content from 0.5 to 10 equiv (relative
to that of nitrobenzene), the reaction proceeds to completion
along with a progressive decrease in the selectivity of the desired
product (Table 1, entry 3–6). Thus, of the various conditions
examined here, the use of 1 equiv of H2O affords the optimal
catalytic performance (entry 4). In light of these results, the
use of 1 equiv of H2O was chosen as the suitable parameter to
study the influence of the nature of the solvent on this particular
transformation. Whereas changing the solvent to acetonitrile
and DMF significantly lowered the imine selectivity to a level
of ca. 50% (Table 1, entries 7 and 8), the use of toluene, THF
and triethylamine as the solvents can afford the formation of
imine with an excellent selectivity up to 95% (Table 1, entries 9–
11). Of particular note is the lack of formation of nitrone when
triethylamine was used as the solvent.21 Thus, of the various
solvents screened for this reaction, triethylamine is shown to be
the solvent of choice (Table 1, entry 11).22
Fig. 1 Time course of N-benzylidenebenzenamine formation from
nitrobenzene and benzaldehyde. (ꢀ) conversion of nitrobenzene, (
)
᭹
selectivity of aniline, (᭡) selectivity of imine, (᭢) selectivity of nitrone.
Reaction conditions: 1 mmol nitrobenzene, 1 mmol benzaldehyde,
Au/TiO2-VS (1 mol% Au), 2 mL triethylamine, 1 mmol H2O, 5 atm
CO, 25 ◦C.
At this point it is interesting to note that the direct reductive
coupling of nitrobenzene and benzaldehyde to afford imine with
Au/TiO2-VS in triethylamine could be carried out smoothly
even under 1 atm of CO (Table 1, entry 12), although a much
longer reaction time is required for reaction completion. Such
mild reaction conditions had never been demonstrated for
the direct synthesis of imines from nitroarenes and carbonyl
compounds. As the choice of the support plays an important
role in gold catalysis, we also evaluate gold supported on Fe2O3
(Au/Fe2O3), CeO2 (Au/CeO2), silica (Au/SiO2) and activated
carbon (Au/C). However, all these catalysts were significantly
less active for the reductive imination reaction under similar
reaction conditions (see Table S3†). Note that this fact is in
complete agreement with our previous study about the role
of support for the Au-catalyzed reduction of nitroarenes with
CO/H2O.14a Therefore, among the various catalysts examined
here, TiO2 supported Au (Au/TiO2-VS) affords, by far, the best
catalytic performance.
To examine the reaction performed in triethylamine in detail,
a kinetic experiment for the reaction of nitrobenzene with
benzaldehyde was monitored by utilizing continuous sampling
by gas chromatography. As can be seen in Fig. 1, it is possible
to obtain N-benzylideneaniline with 95% selectivity at complete
nitrobenzene conversion after 1 h of reaction by using Au/Ti O2-
VS as the catalyst. The high yield of the desired product obtained
shows that both the carbonyl group of benzaldehyde and the
Lewis or Brønsted acids.4a,11c By using the direct condensation
between benzaldehyde and aniline in triethylamine as a standard
reaction, several control experiments were performed with both
the presence/absence of Au/TiO2-VS or in the presence of bare
TiO2 for comparative purposes (other conditions were the same
as those given in entry 11 of Table 1). As can be seen from Table
S1†, the best result was obtained with Au/TiO2-VS. Whereas
the catalytic performance of Au-free TiO2 closely resembles that
using Au/TiO2-VS as the catalyst, a substantially lower yield of
the desired imine has been observed for the case without using
any catalyst. Therefore, it seems that the mild acidity of the
TiO2 support surface11a,24 plays a significant role in accelerating
the subsequent imine formation step during the present one-pot
reductive imination process.
Under the optimized reaction conditions (Table 1, entry 11),
the scope of the reaction was explored with structurally and elec-
tronically diverse aldehydes with a wide range of nitroarenes. As
revealed in Table 2, various aldehydes were reductively iminated
with nitrobenzene under 5 atm of CO. The aldehydes used for
this study included aromatic and aliphatic examples. Irrespective
of the electronic nature of the substituent, aromatic aldehydes
reacted smoothly to give the desired imine products in excellent
yields (Table 2, entries 2–5). For instance, mixing nitroben-
zene with 4-methylbenzadlehyde, or 4-chlorobenzaldehyde, in
◦
triethylamine at 25 C for 1 h resulted in the formation of the
C
N group of the product imine remain unaffected during
corresponding imines in 97 and 96% yields, respectively (Table 2,
entries 2 and 3) and no dehalogenation of the chloride group is
observed. Substituted 4-methoxy and 4-hydroxybenzaldehydes
also gave the corresponding products in high yields (Table 2,
entries 4 and 5). Notably, all the aromatic aldehydes generated
the corresponding imines as the primary products. However,
alphatic aldehydes (Table 2, entries 6–8) were more difficult to
convert with aniline to form imines. For example, a much longer
reaction time is required to gain good yields. The reaction of
furfural with nitrobenzene led to the corresponding imine in
good yield (Table 2, entry 6). GC analysis showed that 13%
of the intermediate aniline was unreacted. Lower conversion
of the intermediate aniline was observed in the reaction of
the reduction of nitrobenzene.23 The most important finding,
however, is the lack of formation of N-phenylbenzylamine, even
after prolonged reaction times, inferring that the undesirable
imine reduction pathway is practically inhibited in this case.
Note that this behavior is much better in terms of conversion
and selectivity than those recently reported through a Au/TiO2-
catalyzed sequential nitro-hydrogenation-condensation path-
way using H2 as the reductant,11a in which a strict monitoring of
the hydrogen uptake to avoid over-reduction of imine is required.
Given the observed high activity and selectivity, it is of interest
to clarify the essential role of Au/TiO2-VS in the final imine
formation step, which is known as a process promoted by soluble
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Table 2 Catalytic results of the synthesis of imines from nitrobenzene
Table 3 Catalytic results of synthesis of imines from benzaldehyde and
and different aldehydesa
different nitroarenesa
Entry Aldehyde
1
Time [h] Con. [%]b
Yield [%]b,c
95 (91)
Entry Nitro-compound
1
Time [h] Con. [%]b Yield [%]b,c
1
1
1
1
1
> 99
> 99
> 99
> 99
> 99
1
1
3
1
> 99
> 99
> 99
> 99
95 (91)
98 (95)
97
2
3
4
5
6
97
96 (92)
93
2
3
4
91 (88)
92 (89)
5
3
> 99
89 (84)
1
4
> 99
> 99
27
87 (80)
7
8
1
6
> 99
> 99
15
75
6
7
3.5
3.5
3.5
98
> 99
> 99
71
85
1
9
> 99
> 99
8
64
a Reaction conditions:
1
mmol nitrobenzene,
1
mmol aldehyde,
Au/TiO2-VS (1 mol% Au), 2 mL triethylamine, 1 mmol H2O, 5 atm
CO, 25 ◦C. b GC conversion and selectivity obtained by using anisole as
an internal reference. Numbers in parentheses refer to yields of isolated
products. c Aniline was the sole by-product.
8
9
91 (89)
1
6
> 99
> 99
35
65
2-phenylacetaldehyde with nitrobenzene, which led to the imine
in 64% yield by GC analysis (Table 2, entry 8).
10
1
> 99
> 99
85
The generality of this methodology has been extended to
various substituted aromatic nitroarenes and benzaldehyde to
produce corresponding imines under mild reaction conditions.
Table 3 compiles the conversion and selectivity results obtained
in the reductive imination of benzaldehyde and different nitro-
compounds. The electronic effect on the aromatic ring was not
significant; nitrobenzene substituted with electron-donating or
-withdrawing groups could undergo reductive coupling to the
corresponding imines with high yields (Table 3, entries 2–5, 8 and
11). For instance, coupling of benzaldehyde with 1-fluoro-4-nitro
benzene (Table 3, entry 2) or p-methyl-nitrobenzene (Table 3,
entry 8) gave the desired imines in excellent yields with 98 and
91%, respectively. Of note is that the reducible function groups,
such as alkene, ketone as well as the C N group, remained
intact during the reduction of nitrobenzene (Table 3, entries 4
and 5). In the transformation of methyl and chloronitroarenes,
the lower rate of o- and m-methyl and chloronitroarenes relative
to p-analogues indicated a steric effect (Table 3, entries 6–8
and entries 9–11). Again, no dehalogenation of the fluorine or
chloride group is observed. Notably, all these results showed
11
12
1
3
93 (90)
> 99
> 99
52
65
12
a Reaction conditions: 1 mmol nitro-compound, 1 mmol benzaldehyde,
Au/TiO2-VS (1 mol% Au), 2 mL triethylamine, 1 mmol H2O, 5 atm
CO, 25 ◦C. b GC conversion and selectivity obtained by using anisole as
an internal reference. Numbers in parentheses refer to yields of isolated
products. c The corresponding aniline was the sole by-product.
the high efficiency of the Au/TiO2-VS reductive coupling of
nitrocompounds and benzaldehyde mixtures to generate the
desired imines.
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The applicability of the Au/TiO2-VS-catalyzed one-pot re-
ductive imination reaction is highlighted by an aza Diels–
Alder reaction of the imine (Scheme 2). After the coupling
reaction of nitrobenzene and benzaldehyde under a CO at-
mosphere, the reactor was depressurized. Danishefsky’s diene
was then admitted into the reaction system to allow a reaction
with the resulting imine. Purification of the aza Diels–Alder
product by column chromatography provided 1,2-diphenyl-2,3-
dihydropyridin-4-one through desilylation in a good yield of
85%. Given that the dihydropyridone derivatives thus obtained
are prominent core scaffolds in biologically active compounds,25
this atom-economical strategy towards aza-cycles opens up new
possibilities for the application of ligand-free supported gold
catalysts to the green synthesis of pharmaceutically important
compounds.
In conclusion, we have demonstrated a simple and efficient
heterogeneous TiO2 supported gold-catalyzed protocol for the
synthesis of imines via a facile one-pot nitro-reduction-direct
reductive imination sequence, which proceeds at room temper-
ature using cheap and easily accessible CO and H2O as the
hydrogen source. This protocol can be used to generate a diverse
range of substituted imines in good to excellent yields. The
operational simplicity and the mild reaction condition of our
new catalyst system is expected to contribute to its utilization
for the development of benign chemical processes and products.
This work was financially supported by the National Natu-
ral Science Foundation of China (20873026, 21073042), New
Century Excellent Talents in the University of China (NCET-
09-0305), the State Key Basic Research Program of PRC (2009
CB623506), andScience & TechnologyCommission of Shanghai
Municipality (08DZ2270500).
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Scheme 2 One-pot two-step aza Diels–Adler reaction.
The Au/TiO2-VS catalyst was stable and can be easily reused
in the reductive imination of nitrobenzene with benzaldehyde
to afford N-benzylidenebenzenamine (Table 2, entry 1). After
the first reaction, the catalyst was separated from the reaction
mixture by filtration, thoroughly washed with ethanol and water,
and then reused as catalyst for the next run under the same
conditions. As shown in Fig. 2, the yield of target imine remained
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Fig.
2
Recycling of the catalyst for the synthesis of N-
benzylidenebenzenamine from nitrobenzene and benzaldehyde. Reac-
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21 It was confirmed that there is only a weak relationship between the
imine yield and the pKa value of solvents (See Table S2†), indicating
that solvent basicity is not the key factor determining the catalytic
performance of the present reductive imination process.
22 The use of 5 atm H2 in place of CO did not initiate the reductive
imination reaction at all (Table 1, entry 13), owing to the inability of
gold to dissociate hydrogen under such mild conditions.
23 It was verified that the sole reduction of benzaldehyde did not proceed
under the same reaction conditions (see Supporting Information for
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