A facile, one-pot procedure for forming diarylimines from nitroarenes and benzaldehydes

Article abstract of DOI:10.1055/s-2007-986668

An intermolecular reductive Schiff base formation from nitroarenes and benzaldehydes to yield diarylimines is carried out in the presence of iron powder and dilute acid. This process is tolerant of an array of functional groups and often proceeds quantitatively with no need for purification. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-986668

2602
LETTER
A Facile, One-Pot Procedure for Forming Diarylimines from Nitroarenes and
Benzaldehydes
O
ne-Pot Procedure
n
for
F
orming
d
D
iarylimine
r
s
ew L. Korich, Thomas S. Hughes*
University of Vermont, Chemistry Department, Cook Physical Science Building, 82 University Place, Burlington, VT 05405, USA
Fax +1(802)6568705; E-mail: Thomas.S.Hughes@uvm.edu
Received 30 April 2007
nitroarenes.8 Tandem nitroarene reduction and intra-
Abstract: An intermolecular reductive Schiff base formation from
molecular Schiff base condensation to give heteroarenes
nitroarenes and benzaldehydes to yield diarylimines is carried out in
the presence of iron powder and dilute acid. This process is tolerant
has been reported using iron in aqueous media.9 Sur-
prisingly, the breadth of this methodology in an inter-
molecular application has not been previously reported.
Herein we wish to report our findings of a tandem iron
reduction of nitroarenes and subsequent condensation of
arylaldehydes under mild reaction conditions.
of an array of functional groups and often proceeds quantitatively
with no need for purification.
Key words: condensation, imine, Schiff bases, iron, green chemis-
try
Several diarylimines were synthesized from the corre-
sponding nitroarene and arylaldehyde in the presence of
metallic iron and acid in good to excellent yields
(Table 1). The reaction was carried out by stirring an
equimolar mixture of both substrates with iron powder
and acid in a 2:1 (v/v) EtOH–H2O solution at 65 °C for 1.5
hours. Simple gravity filtration, extraction with CH2Cl2,
and concentration in vacuo gave the desired products
without any further purification. The yields of 75–95%
were less than quantitative, perhaps because an equilib-
rium occurs under the reaction conditions between the
product Schiff base and the aniline and arylaldehyde. The
structure of each imine synthesized was confirmed by
comparison of its spectroscopic data to literature values.10
The electron demand of the substituents has no effect of
the efficiency of the reaction; reactions involving elec-
tron-withdrawing or electron-donating aryl substituents
on either component proceed in good yields (entries 4–9,
Table 1).
Functionalized diarylimines are of current interest due to
their versatility in medicinal chemistry and materials
science. They are key precursors to the indazole,1 benzox-
azole,2 and N,N-diarylformamide3 scaffolds and are used
as models for mesogenic compounds.4 Furthermore, mac-
rocycles and dendrimers that incorporate the Schiff base
moiety in their backbones have received a great deal of
attention for their potential use in organometallic nano-
materials.5
Traditional formation of Schiff bases from nitroarene
starting materials requires a two-step process in which the
nitroarene is first reduced to the aniline, then isolated, and
subsequently condensed with the desired carbonyl. Re-
cently, catalytic Schiff base formation from nitroarenes
and carbonyls has been reported.6 However, these proto-
6a
cols require transition-metal catalysts such as Rh6(CO)16
or NH4VO3,6b and must be carried out with elevated
pressures of carbon monoxide in stainless-steel reactors at
high temperatures making them less than ideal for labora-
tory-scale synthetic chemistry.
Schiff base condensation was selective for the aldehyde
even in the presence of a ketone (entry 5, Table 1). Reduc-
tion of 4-nitroacetophenone in the presence of one equiv-
alent of aldehyde yielded 50% of the desired product
(determined by 1H NMR). When 20 equivalents of
benzaldehyde were used, however, the desired product
was recovered in 90% isolated yield. In a competition
A large number of other reducing agents for nitroarenes
are reported in the literature,7 of which hydrogenation is
arguably the most common method employed. This
method is not suitable for a single-pot reaction to convert
a nitroarene into an arylimine; when a 1:1 mixture of
nitrobenzene and benzaldehyde was hydrogenated7a using
of 10% Pd/C, the expected aniline and benzyl alcohol
were isolated. Similarly, a reduction using Zn in EtOH7b
yielded a mixture of unreacted starting material, aniline,
benzyl alcohol, and various undetermined side products.
In both cases, Schiff base formation did not occur, owing
to the reduction of both the nitroarene and the aldehyde.
O
NO2
+
Fe, HCl
N
N
EtOH–H2O
1 equiv
+
1 equiv
O
Iron is abundant, inexpensive, environmentally benign,
and has been shown to be an effective reducing agent for
82%
0%
1 equiv
SYNLETT 2007, No. 16, pp 2602–2604
Advanced online publication: 12.09.2007
DOI: 10.1055/s-2007-986668; Art ID: S02607ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.1
0
.2
0
0
7
Scheme 1 Reduction of nitrobenzene in the presence of aceto-
phenone and benzaldehyde (yields determined by H NMR). Initial
concentrations of each arene were 0.03 M.
1

LETTER
One-Pot Procedure for Forming Diarylimines
2603
experiment using nitrobenzene, benzaldehyde, and ace- would be less likely in a haloarylaldehyde, the arylalde-
tophenone only the condensation between benzaldehyde hyde should also be tolerant of halide substituents.
and nitrobenzene was observed (Scheme 1).
In order to better understand the role and significance of
It should be noted that esters and halides are stable under HCl in the reaction mixture, nitrobenzene and benzalde-
these mild conditions (entries 6 and 7, Table 1). The reac- hyde were subjected to standard reaction conditions using
tion of methyl-4-nitrobenzoate and benzaldehyde yielded a variety of acids (Table 2). Both nitric and acetic acids
the desired product with no indication of amide formation yielded the desired product, in 77% and 52%, respective-
or hydrolysis. When 1-iodo-4-nitrobenzene was used, the ly, while sulfuric acid gave a mixture of starting material
desired diarylimine was isolated in good yield. It has been and product in as little as 40% overall yield. Without acid,
previously noted that at higher temperatures aryl iodides only starting material was recovered, thus indicating that
undergo reductive elimination in the presence of iron to acid increases the reactivity of the iron. Increasing the
give aniline,8a but this is evidently not a competitive path- concentration of HCl did not increase the yield apprecia-
way at lower temperature in EtOH–H2O. Given the bly, but above 0.3 M the yield decreased slightly, perhaps
relative stabilities of aryl halides, it seems reasonable to as a result of hydrolysis of the product imine back to
assume that this protocol would be compatible with aryl arylamine and arylaldehyde.
bromides and chlorides. Since this competitive reduction
Table 1 Diaryliminea Formation from Nitroarenes and Aldehydes
Fe(0), HCl
N
Ar2
Ar1 NO2
+
Ar2 CHO
Ar1
EtOH–H2O
Entry
Ar1NO2
Ar2CHO
Product
Yield (%)b
88
NO2
CHO
N
1
2
3
4
5
6
7
8
CHO
CHO
NO2
Me
N
87
95
85
50c
81
75
87
Me
Me
Me
Me
NO2
N
Me
NO2
CHO
CHO
CHO
CHO
MeO
N
MeO
NO2
Ac
N
Ac
NO2
MeO2C
N
MeO2C
NO2
I
N
I
CHO
NO2
N
N
OMe
CF3
MeO
F3C
CHO
CHO
NO2
NO2
9
85
75
N
10
a Reaction conditions: ArNO2 (1 equiv, 0.03 M), ArCHO (1 equiv, 0.03 M), Fe(0) (10 equiv), HCl (6 equiv, 0.19 M), EtOH–H2O (2:1 v/v).
b Isolated yield.
c Determined via 1H NMR. If 20 equiv of ArCHO are used, the yield increases to 90%.
Synlett 2007, No. 16, 2602–2604 © Thieme Stuttgart · New York

2604
A. L. Korich, T. S. Hughes
LETTER
Table 2 Effect of Acid Type and Concentration on Imine Formation
good to excellent yields with no purification required.
This process is facile, inexpensive, and environmentally
friendly.
Entry
Acid
Amount of acid
6 equiv, 0.19 M
10 equiv, 0.30 M
20 equiv, 0.60 M
0
Yield (%)
1
2
3
4
5
6
7
HCl
88
90
82
0
HCl
Typical Procedure
HCl (0.13 mL, 4.5 mmol) was added to a mixture of nitrobenzene
(0.073 mL, 0.72 mmol), benzaldehyde (0.074 mL, 0.72 mmol), and
iron powder (0.409 g, 7.32 mmol) in 24 mL of EtOH–H2O (2:1 v/v)
solution. The reaction was heated to 65 °C for 1.5 h before being
filtered while hot. The filtrate was extracted using CH2Cl2 (2 × 20
mL) after which the organic layers were combined, dried over
MgSO4, filtered, and concentrated in vacuo to yield 0.115 g (88%)
of the desired diphenylimine.
HCl
None
HNO3
H2SO4
MeCO2H
6 equiv, 0.19 M
6 equiv, 0.19 M
6 equiv, 0.19 M
77
40
52
Changing the amount of the iron species as well as its
oxidation state affected the efficiency of the reaction
(Table 3). One equivalent of iron in the reaction mixture
yielded only starting material. However, when greater
than six equivalents of iron were used, only the desired
Acknowledgment
We would like to thank the University of Vermont for financial sup-
port of this research.
product was observed. It should be noted that when more References
than 10 equivalents are used, the isolation of products is
laborious. Such reaction conditions require the reaction
mixture to be centrifuged prior to gravity filtration.
(1) Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994,
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Table 3 Schiff Base Formation between Nitrobenzene and Benz-
aldehyde Using Various Iron Species and Equivalents
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Entry
Iron species
Fe(0)
Equiv
10
6
Yield (%)
1
2
3
4
5
6
88
69
0
Fe(0)
Fe(0)
1
Fe(0)
20
10
10
78
0
(6) (a) Iqbal, A. F. J. Org. Chem. 1972, 37, 2791. (b) Macho,
V.; Králik, M.; Hudec, J.; Cingelova, J. J. Mol. Catal. A:
Chem. 2004, 209, 69.
FeCl2
FeCl3
0
(7) (a) Mendenhall, D.; Smith, P. A. S. Org. Synth., Coll. Vol. V
1979, 829. (b) Sundberg, R. J.; Pitts, W. J. J. Org. Chem.
1991, 56, 3048. (c) Doxsee, K. M.; Feigel, M.; Stewart, K.
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Soc. 1987, 109, 3098. (d) Saramh, P.; Barua, N.
Tetrahedron Lett. 1990, 31, 4065.
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Synth., Coll. Vol. V 1973, 346.
When Fe0 was replaced with either FeCl2 or FeCl3, no re-
action was observed. Since the reduction of nitroarenes to
the corresponding anilines is a six-electron process in to-
tal, under these reaction conditions it is not surprising that
FeCl3 yields only starting material. Ferrous chloride is not
a strong enough reducing agent to reduce nitrobenzene to
aniline in aqueous acid. The redox couple for Fe3+ to Fe2+
is +0.77 versus a SHE while Fe2+ to Fe0 is –0.447 versus
SHE, thus allowing for the reduction in the presence of
Fe0 and not Fe2+.11 No attempt was made to identify the
iron species at the conclusion of the reaction, and there
was no evidence that chelation of any iron species cata-
lyzed or inhibited the condensation of the aldehyde and
aniline, although we cannot rule out these possibilities.
(9) (a) Merlic, C. G.; Motamed, S.; Quinn, B. J. Chem. Soc.
1995, 60, 3365. (b) Stefancich, G.; Artico, M.; Massa, S.;
Corelli, F. Synthesis 1981, 321.
(10) For spectroscopic data on entries 1, 3, 4, 7–9, see ref. 3, for
entry 2, see: (a) Bolognese, A.; Diurno, A. V.; Mazzoni, O.;
Giordano, F. Tetrahedron 1997, 47, 1991. (b) For entry 5,
see: Tabei, K.; Saitou, E. Bull. Chem. Soc. Jpn. 1969, 42,
1440. (c) For entry 6, see: Marshall, R. L.; Muderawan, I.
W.; Young, D. J. J. Chem. Soc., Perkin Trans. 2 2000, 957.
(d) For entry 10, see: Afarinkia, K. J.; Rees, C. W.
Tetrahedron 1997, 46, 7175.
In conclusion, we have developed a facile one-pot method
for preparing diarylimines from nitroarenes and arylalde-
hydes. A tandem nitroarene reduction and in situ Schiff
base condensation yielded substituted diarylimines in
(11) Milazzo, G.; Caroli, S. Table of Standard Electrode
Potentials; John Wiley and Sons: New York, 1978.
Synlett 2007, No. 16, 2602–2604 © Thieme Stuttgart · New York