Direct one-pot reductive N-alkylation of nitroarenes by using alcohols with supported gold catalysts

Article abstract of DOI:10.1002/chem.201100393

Gold standard support! The direct reductive mono- or di-N-alkylation of aromatic nitro compounds with alcohols, using a hydrogen-borrowing strategy, was efficiently promoted by a ligand-free titania-supported gold catalyst system (see scheme). A variety of nitroarenes were selectively converted into the corresponding secondary or tertiary amines in good to excellent yields without any co-catalysts, such as bases and stabilizing ligands. Copyright

Full text of DOI:10.1002/chem.201100393

DOI: 10.1002/chem.201100393
Direct One-Pot Reductive N-Alkylation of Nitroarenes by using Alcohols
with Supported Gold Catalysts
Chun-Hong Tang, Lin He, Yong-Mei Liu, Yong Cao,* He-Yong He, and
Kang-Nian Fan[a]
À
The formation of C N bonds is one of the most important
transformations in chemistry because nitrogen-containing
compounds, particularly amines and their derivatives, are
versatile building blocks for various organic molecules and
essential precursors to a variety of biologically active com-
drogen source for nitro reduction and as the alkylating re-
agent based on the catalytic hydrogen transfer. Although
excess alcohol is required to ensure the completion of the
reaction[9] (see the Supporting Information for possible reac-
tion stoichiometries), the operational simplicity of such
transformations may have practical advantages for a concise
synthesis of N-substituted amines in a more straightforward
manner. Compared to the great progress being made in the
amination of amines with alcohols,[10] there are scarcely
available reports dealing with the direct amination of nitro-
arenes with alcohols. To date, only three Ru-based homoge-
neous systems have been reported.[11] However, these homo-
geneous catalysts are problematic in terms of the recovery/
recycling of the catalyst and the necessity of special handling
of metal complexes. From a sustainable point of view, a
more efficient reaction with a ligand-free heterogeneous cat-
alyst is highly desired.
Over the last five years, we have been interested in the
unique catalytic properties of supported gold nanoparticles
(NPs) and involved in their application to sustainable organ-
ic synthesis.[9e,12] Recently, we have shown that very small
Au NPs (approx. 1.8 nm) deposited on TiO2 (Au/TiO2-VS;
VS=very small) acts as an efficient heterogeneous catalyst
for the clean and atom-efficient mono-N-alkylation of a
range of amines with alcohols in excellent yields under hy-
drogen-borrowing conditions.[12a] In view of the prominent
efficiency of the gold system for the amination of amines
with alcohols, we envisioned that the Au-mediated hydro-
gen-borrowing strategy could afford a green and efficient
protocol for the direct amination of nitroarenes with alco-
hols under mild conditions. Herein, we report for the first
time that the simple Au/TiO2-VS system can catalyze the se-
lective secondary or tertiary amine formation from the
direct condensation of nitroarenes and alcohols. Notably,
the reaction can proceed effectively under ligand- and base-
free conditions without any external hydrogen resources. To
the best of our knowledge, this study also forms the first
report of a one-pot selective preparation of imines from ni-
troarenes and alcohols by using a heterogeneous gold-medi-
ated “catalytic hydrogen-transfer” procedure.
pounds.[1] Although several methods are known for the syn-
[2]
À
thesis of C N bonds, preparation under mild and waste-
free conditions using simple, inexpensive, and readily avail-
able feedstock is still a challenging goal. The transition-
metal-catalyzed coupling of amines with alcohols by using a
hydrogen-borrowing strategy[3] (also known as a hydrogen-
autotransfer process) has proven to be an atom-economical
and environmentally attractive method for the construction
À
of C N bonds, especially for secondary amine preparation.
Although many efficient catalysts for such transformations
have been reported,[3e–f,4] the development of easily recover-
able and recyclable heterogeneous catalysts that can solve
the problem of the homogeneous systems has attracted spe-
cial attention. To the best of our knowledge, few heteroge-
neous catalyst systems[5] have been reported that enable effi-
cient and selective N-alkylation of amines with alcohols
under simple, mild, and environmentally benign conditions.
Nitroarenes are cheap and readily available organic com-
pounds and the reduction of nitro compounds is a key step
in the preparation of many pharmaceutical agents and fine
chemicals.[6] Despite numerous established procedures for
the reduction of nitro compounds,[7] the development of cat-
alytic methodologies that afford high chemo- and regioselec-
tivity under mild reaction conditions is still a challenging
problem.[8] As for the synthesis of secondary amines, the
direct use of commercially available and inexpensive nitro-
arenes and alcohols as starting materials is highly attractive,
especially when a single catalyst system could be employed.
In this valuable one-pot multistep transformation, the alco-
hol may conceivably serve two possible functions: as the hy-
[a] C.-H. Tang, L. He, Dr. Y.-M. Liu, Prof. Dr. Y. Cao,
Prof. Dr. H.-Y. He, Prof. K.-N. Fan
Shanghai Key Laboratory of Molecular Catalysis
and Innovative Materials
Department of Chemistry, Fudan University
Shanghai 200433 (P.R. China)
Fax : (+86)21-65643774
Based on our previous results in heterogeneous Au-cata-
lyzed amine/alcohol coupling chemistry,[12a] the optimization
study was initiated with the direct amination of nitroben-
zene (1a) with eight equivalents of benzyl alcohol (2a) in
the presence of Au/TiO2-VS (0.5 mol% of Au, see the Sup-
E-mail: yongcao@fudan.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100393.
7172
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Chem. Eur. J. 2011, 17, 7172 – 7177

COMMUNICATION
porting Information) for 14 h at 1208C under argon atmos-
phere. The results showed that the corresponding secondary
tigated. Of the various solvents screened for this reaction,
toluene was shown to be the solvent of choice (Table S1, en-
tries 1–4). In toluene, the reaction rate increased as the tem-
perature was raised from 80 to 1208C (Table S1, entries 4–
6). Studies on the effect of the molar ratio of 2a to 1a re-
vealed that the reaction of 1a with eight equivalents of 2a
gave the best results (see the Supporting Information, Table
S1, entries 4, and 7–11). The use of three equivalents of 2a
led to incomplete conversion of 1a, and only a trace amount
of the desired secondary amine could be obtained (see the
Supporting Information, Table S1, entry 7). Upon increasing
the 2a/1a ratio from three to eight, the reaction proceeded
to completion along with a significant increase in the yield
of the product 3a (see the Supporting Information, Table
S1, entries 4, 7, and 9). This result suggests that the composi-
tion of the reaction medium was critical for the desired reac-
tion pathway. However, lower yields were observed when 10
or 15 equivalents of 2a were employed (see the Supporting
Information, Table S1, entries 10 and 11). It is noted that
under optimized conditions, the use of five equivalents of 2a
can afford the selective formation of N-benzylideneaniline
(3a’) with a high yield well above 95% (see the Supporting
Information, Table S1, entry 8). As imines are highly versa-
tile synthetic intermediates for dyes, fragrances, pharmaceut-
icals, fungicides, and agricultural chemicals,[13] the reaction
chemistry described here may also provide new possibility
to develop versatile heterogeneous catalysts for the tandem
synthesis of imines through a direct conversion of nitroar-
enes with alcohols.
With suitable reaction conditions established, the scope of
the Au/TiO2-VS catalyzed reductive mono-N-alkylation with
respect to nitrobenzene derivatives and alcohols was ex-
plored. As revealed in Table 2, various structurally diverse
nitroarenes, regardless of the presence of electron-withdraw-
ing or donating functional groups, could be mono-alkylated
with 2a to give the corresponding secondary amines in ex-
cellent yields. Relative to the direct coupling of substituted
anilines and benzyl alcohol over Au/TiO2-VS, the substitu-
ent at different positions on the nitroarenes affected the re-
action rate significantly. For example, a much longer reac-
tion time is required for reaction completion when para-me-
À
amine, N-phenylbenzylamine (3a) was the main C N cross-
coupling product (Table 1). The initial rate of formation of
3a was also measured under conditions in which conversion
was below 30% (result not shown). As observed with other
Table 1. Direct synthesis of secondary amine from nitrobenzene and
benzyl alcohol using various catalysts.[a]
Entry
Catalyst
Conversion [%][d]
Selectivity [%][d]
3a
3a’
1a’
1[b]
2[c]
3[d]
4[d]
5[d]
6[d]
7
8
9
10
11
Au/TiO2-VS
Au/TiO2-VS
Au/TiO2
Au/Al2O3
Au/ZnO
Au/Fe2O3
Au/CeO2
Au/ZrO2
Pd/TiO2
100
100
100
100
100
100
100
100
100
100
trace
>99
96
70
20
13
22
20
54
43
18
–
–
4
–
–
17
49
62
38
56
26
40
76
–
13
31
25
40
34
20
17
6
Ru/TiO2
TiO2
–
[a] Reaction conditions: nitrobenzene (1 mmol), benzyl alcohol
(8 mmol), toluene (1 mL), and catalyst (metal: 0.5 mol%) at 1208C for
14 h under argon (Ar) atmosphere. [b] Trace amount of tertiary amine
was detected (below 1% yield). [c] Fifth run. [d] Au/TiO2 and Au/Fe2O3
provided by World Gold Council (WGC). Au/Al2O3 and Au/ZnO provid-
ed by Mintek. [e] Selectivity based on nitrobenzene conversion, deter-
mined by GC using n-dodecane as the internal standard. Meanwhile, the
benzyl alcohol that was present in eightfold excess also gives appreciable
amounts of dehydrogenative byproducts including benzaldehyde and
benzyl benzoate.
gold-catalyzed processes,[9e,12a–e] both the nature of the sup-
port and the particle size have a strong influence on the ac-
tivity of the Au catalysts (Table 1, entries 1–8). Among the
various supported gold catalysts tested, Au/TiO2-VS gave
the best results, with the highest yield of 3a and the highest
reaction rate (Table 1, entries 1–8). Of yet further interest is
that this catalyst can be reused at least five times and still
maintains a complete conversion of 1a to give 3a in yields
of up to 96% (Table 1, entry 2). No formation of 3a was ob-
served in the presence of Au-free TiO2 (Table 1, entry 11).
Under the conditions described in Table 1, Pd or Ru NPs
supported on TiO2 were not effective (Table 1, entries 9 and
10), illustrating that gold is far superior to other noble
metals for the direct reductive mono-N-alkylation of 1a
with 2a.
thoxynitrobenzene was used as
a substrate (Table 2,
entry 3). The reaction tolerates the presence of halogens
(Table 2, entries 4–7 and 9); however, a lower yield was ob-
tained when the substituent was changed from fluoride to
bromide, partially due to the poor solubility of substrate[11a]
(Table 2, entries 4–6). In the transformations of chloroni-
troarenes, the lower reaction rate of o-chloronitrobenzene
relative to meta and para analogues indicated a steric effect
(Table 2, entries 5, 7, and 9). Notably, reducible functional
groups such as alkene and ketone, as well as ester moieties,
remained intact during the reductive mono-N-alkylation
process (Table 2, entries 10–12), demonstrating the high ver-
satility of the present methodology for secondary amine syn-
thesis.
Subsequently, the reaction conditions were optimized with
the Au/TiO2-VS catalyst through variation of the solvents,
temperature, and the 2a/1a ratio (see Table S1 in the Sup-
porting Information). First, the nature of solvents was inves-
Furthermore, the reaction also proceeds successfully with
other structurally and electronically diverse alcohols
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Y. Cao et al.
Table 2. Catalytic reaction of nitroarenes with benzyl alcohols.[a]
Table 3. Catalytic reaction of nitrobenzene with various alcohols.[a]
R1
Product
t
Yield
[%][b]
Entry
R2
Product
t
Yield
[%][e]
Entry
[h]
[h]
1
C6H5CH2
21
35
91
1
H
14
28
33
32
32
36
33
25
27
24
35
>99
95 (92)
96
2[c]
C6H
N
87 (85)
2
p-Me
p-MeO
p-F
3
3
4
5
6
7
8
9
p-MeC6H4
p-MeOC6H4
p-BrC6H4
p-ClC6H4
18
20
36
33
27
48
48
97 (95)
93
4
95
5
p-Cl
93 (90)
86
88
6
p-Br
85 (83)
90
7
o-Cl
89 (84)
98
p-FC6H4
8
m-Me
m-Cl
o-MeC6H4
o-MeOC6H4
80
9
92 (90)
83
73
10
11
p-MeCO
p-MeCO2
10
o-ClC6H4
n-C7H15
48
48
66
11[b]
68 (62)
76
12
p-CH2 =CH
28
94 (91)
12[b,d]
C6H12O
48
72
[a] Reaction conditions: nitroarenes (1 mmol), benzyl alcohol (8 mmol),
toluene (1 mL), catalyst (Au/TiO2-VS, metal: 0.5 mol%), 1208C, under
argon atmosphere. [b] Yields based on nitroarenes, determined by GC
using n-dodecane as the internal standard. Numbers in parenthesis refer
to yields of isolated products.
[a] Reaction conditions: nitrobenzene (1 mmol), alcohol (8 mmol), tolu-
ene (1 mL), and catalyst (Au/TiO2-VS, metal: 0.5 mol%) at 1208C, under
argon atmosphere. [b] Alcohol (10 mmol). [c] alcohol: 1-phenylethanol.
[d] Alcohol: cyclohexanol. [e] Yields based on nitroarenes, determined by
GC using n-dodecane as the internal standard. The numbers in parenthe-
sis refer to yields of isolated products.
(Table 3). Alcohols with halogens reacted smoothly with ni-
trobenzene to give the corresponding products in good
yields (Table 3, entries 5–7). Again, a bromide substituent
dramatically decreased the reaction rate, and a prolonged
reaction time of 36 h was needed for obtaining a high yield
of the desired product when p-bromobenzyl alcohol was
used as a substrate (Table 3, entry 5). The substituent at the
ortho position has a great impact on the reaction; a moder-
ate yield was obtained when o-chlorobenzyl alcohol, o-me-
thoxybenzyl alcohol, or o-methylbenzyl alcohol was used
(Table 3, entries 8–10). The Au/TiO2-VS catalyst also shows
promise for direct coupling of nitrobenzene with simple ali-
phatic alcohols under similar conditions (Table 3, entries 11–
12). The notoriously difficult secondary alcohols (Table 3,
entries 2 and 12) were successfully converted without any
additives, which has no precedent in the literature. It is
again noteworthy that the reaction of 2-phenethyl alcohol
with nitrobenzene can afford a highly valuable 2-phenyl-
ethanamine derivative (Table 3, entry 1), a common structur-
al feature found in many medicinal drugs such as Piriton[14]
and Tripelennamine.[15]
hols. Tertiary amines are important building blocks in organ-
ic synthesis and routinely served as synthons for pharma-
ceuticals, herbicides, agricultural chemicals, and functional-
ized materials.[16] The synthesis of tertiary amines is tradi-
tionally carried out with a number of non-catalytic or cata-
lytic procedures such as N-alkylation of amines with alkyl
halides or alcohols,[17] reductive amination of carbonyl com-
pounds,[18] or amination of alkyl halides,[19] mostly by multi-
step procedures. Despite their utility, clear drawbacks of
these methods are the use of expensive amines as starting
materials, low selectivity, tedious workup procedures and
concomitant formation of large amounts of wasteful salts.
Therefore, the development of a simple, efficient and waste-
free one-pot process is of high actual interest. We have per-
formed the straightforward one-pot reaction at 1508C using
various combinations of nitroarenes and alcohols (1:8 molar
ratio for all examples) with Au/TiO2-VS. The results pre-
sented in Table 4 show that it is possible to achieve high
conversion of nitroarenes with excellent selectivity to terti-
ary amines without the separation of aniline intermediates
through this one-pot di-N-alkylation procedure.
Given that the reductive mono-N-alkylation of nitroben-
zene proceeded smoothly, we have explored the applicability
of this protocol to tertiary amine formation through direct
amination of various nitrobenzene derivatives by using alco-
The reaction profiles for the Au/TiO2-VS-catalyzed terti-
ary amine formation by the direct reductive condensation of
1a with 2a (Figure 1)[20] showed that the initially formed 3a’
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Chem. Eur. J. 2011, 17, 7172 – 7177

Direct One-Pot Reductive N-Alkylation of Nitroarenes
COMMUNICATION
Table 4. Catalytic formation of tertiary amines from nitroarenes and al-
cohols.[a]
Entry
R1
R2
Product
Yield
[%][c]
1
2
3
4
H
C6H5
C6H5
C6H5
C6H5
98 (96)
94
p-Me
p-MeO
p-Cl
87
85 (83)
5
6
m-Me
C6H5
88
80
Figure 1. Reaction profile for tertiary amine synthesis from nitrobenzene
H
C6H5CH2
!
*
and benzyl alcohol. (&) Conversion of 1a; ( ) yield of 1a’; ( ) yield of
~
&
3a; ( ) yield of 3a’; ( ) yield of 3a’’. Reaction conditions: nitrobenzene
(1 mmol), benzyl alcohol (8 mmol), toluene (1 mL), and catalyst (Au/
TiO2-VS, metal: 0.5 mol%) at 1508C for 48 h under argon (Ar) atmos-
phere.
7
8
H
H
p-MeC6H4
p-ClC6H4
92 (90)
81
9
H
H
o-MeC6H4
56
the similar sequential processes (see Figure S3 in Supporting
Information) in a cascade mode, that is, 1) the dehydrogena-
tion of an alcohol, 2) the formation of an imine (or an imini-
um cation), and 3) the reduction of the imine (or an imini-
um cation) intermediate.[4d,5d]
10[b]
C7H15
70 (67)
[a] Reaction conditions: nitroarenes (1 mmol), alcohol (8 mmol), toluene
(1 mL), and catalyst (Au/TiO2-VS, metal: 0.5 mol%) at 1508C for 48 h
under argon atmosphere. [b] Catalyst (Au/TiO2-VS, metal: 1.0 mol%).
[c] Yields based on nitroarenes, determined by GC using n-dodecane as
the internal standard. Numbers in parenthesis refer to the yields of the
isolated products.
In conclusion, we have reported here the noteworthy fea-
tures of an Au/TiO2-VS catalyst for the direct reductive
mono- or di-N-alkylation of a range of aromatic nitro com-
pounds with alcohols via a hydrogen-borrowing strategy.
This process has significant advantages when compared with
other N-alkylation methods, such as 1) cheap and readily
available reactants (nitroarenes and alcohols), 2) high cata-
lytic activity and selectivity, 3) no external molecular hydro-
gen or other stoichiometric reducing agents are necessary in
our catalytic system, and 4) the reaction takes place without
any stabilizing ligands and/or co-catalysts. We believe that
the reaction chemistry described here may enable the devel-
opment of new sustainable processes for clean and efficient
synthesis of secondary or tertiary amines from nitroarenes
with alcohols.
was converted to 3a with subsequent N-alkylation to pro-
duce 3a’’. In addition, aniline and N-benzylideneaniline
(3a’, below 10% yield) could be detected during the reac-
tion, albeit in only small amounts. Furthermore, it was con-
firmed in a separate experiment that the Au-catalyzed N-al-
kylation of 3a with 2a efficiently proceeded to afford the
corresponding tertiary amine 3a’ in quantitative yields
(based on starting amine, see the Supporting Informa-
tion).[21] Therefore, the present reductive N-alkylation would
proceed through the double (or single) N-alkylation reac-
tions, in which alcohols act as both reducing and alkylating
reagents. In the first N-alkylation, the dehydrogenation of
an alcohol into the corresponding carbonyl compound ini-
tially proceeds with the transitory formation of the gold-hy-
dride species.[9e,12a] Then, the carbonyl compound readily
reacts with anilines (produced through the reduction of 1a)
to form the corresponding imine. Finally, the hydrogen
transfer reaction from the hydride species to the imine pro-
ceeds to afford the corresponding secondary amine. The
second N-alkylation, if occurred,[21] would proceed through
Experimental Section
General procedure: Nitroarene, alcohol (8 equiv), metal catalyst
(0.5 mol% metal), toluene (1 mL) and n-dodecane (10 mL, as the internal
standard) were placed into a Teflon-lined autoclave (4 mL capacity). The
resulting mixture was vigorously stirred at the given temperature under
an argon atmosphere (1 atm) for the given reaction time. The product
was identified by GC-MS and the spectra obtained were compared with
the standard spectra. The conversion and product selectivity were deter-
mined by a GC-17A gas chromatograph equipped with a HP-Free Fatty
Chem. Eur. J. 2011, 17, 7172 – 7177
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Y. Cao et al.
Acid Analyses (HP-FFAP) column (30 mꢁ0.25 mm) and a flame ioniza-
tion detector (FID). For isolation, the combined organic layer was dried
over anhydrous Na2SO4, concentrated, and purified by silica gel column
chromatography.
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Keywords: alcohols · alkylation · gold · heterogeneous
catalysis · nitroarenes · one-pot reaction
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Chem. Eur. J. 2011, 17, 7172 – 7177

Direct One-Pot Reductive N-Alkylation of Nitroarenes
COMMUNICATION
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[20] For time-dependent conversion of benzyl alcohol as well as the evo-
lution of corresponding dehydrogenative byproducts including ben-
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formation.
[21] The N-alkylation of 3a with 2a to afford the corresponding tertiary
amine proceeds smoothly at 1508C. In contrast, the same reaction
practically does not occur at 1208C. See the Supporting Information
for details.
Received: February 4, 2011
Published online: May 17, 2011
Chem. Eur. J. 2011, 17, 7172 – 7177
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7177