An efficient method for aryl nitro reduction and cleavage of azo compounds using iron powder/calcium chloride

Article abstract of DOI:10.1055/s-0030-1259067

A novel, efficient Fe/CaCl₂ system is revealed for the reduction of nitroarenes and reductive cleavage of azo compounds by catalytic transfer hydrogenation (CTH). The selective reduction of nitro compounds in the presence of sensitive functional groups including halides, carbonyl, hydroxyl, aldehyde, methyl, methoxy, acetyl, nitrile, and ester substituents with an excellent yields is reported. The simple experimental procedure and easy purification make the protocol advantageous

Full text of DOI:10.1055/s-0030-1259067

LETTER
3019
An Efficient Method for Aryl Nitro Reduction and Cleavage of Azo
Compounds Using Iron Powder/Calcium Chloride
An
Efficient
M
.
ethod for
A
C
ryl
N
itro Reducti
h
on and Cleav
a
a
ge of
A
zo
n
C
ompounddrappa, K. Vinaya, T. Ramakrishnappa, K. S. Rangappa*
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
Fax +91(821)2412191; E-mail: rangappaks@chemistry.uni-mysore.ac.in; E-mail: rangappaks@gmail.com
Received 27 May 2010
60 °C and progress of the reaction was monitored by TLC.
After completion of the reaction (20–30 min), workup led
to isolation of the corresponding arylamine in 77–91%
yield. Experiments in the absence of either calcium chlo-
Abstract: A novel, efficient Fe/CaCl2 system is revealed for the re-
duction of nitroarenes and reductive cleavage of azo compounds by
catalytic transfer hydrogenation (CTH). The selective reduction of
nitro compounds in the presence of sensitive functional groups in-
cluding halides, carbonyl, hydroxyl, aldehyde, methyl, methoxy, ride or iron powder did not yield the reduced compound.
acetyl, nitrile, and ester substituents with an excellent yields is re-
The reductions of different substituted nitroarenes to the
ported. The simple experimental procedure and easy purification
make the protocol advantageous.
corresponding arylamines in high yields indicate the gen-
erality of this system as tabulated in Table 1 and Table 2.
Substituents such as Cl, Br, OMe, OH, CN, COMe, etc.
are not affected under the reaction conditions.
Key words: azo compounds, amines, iron powder, reduction,
hydrogen transfer, catalysis
Fe, CaCl2
NO2
NH2
Arylamines are widely used as important intermediates in
the synthesis of chemicals such as dyes, antioxidants, con-
ducting polymers, photographic, pharmaceutical, and
agricultural chemicals. Arylamines can be readily synthe-
sized from aryl nitro compounds by reduction. The most
general methods involve activated metal catalysis 1,2 and
transition-metal-catalyzed hydrogenation,3,4 although the
latter often employs harsh reaction conditions affecting
other reduction-sensitive functionalities such as halides,
ketones, aldehydes, esters, and nitriles in addition to the
nitro substituent.5–7
EtOH–H2O
R
R
R = F, Cl, Br, OMe, COMe, Me, CONH2, CHO, CN, OH
Scheme 1 Reduction of aryl nitro compounds
NH2
X
1
+
Fe, CaCl2
N
EtOH
N
Y
NH2
X
The selective reduction of aryl nitro compounds using
iron powder and dilute acid8,9 or tin(II) chloride10 have
been reported as efficient methods for the synthesis of
arylamines in good yields. However, notable disadvantag-
es to these methods include high reaction temperatures,
relatively long reaction times, and the incompatibility of
acid-sensitive functional groups. The use of milder condi-
tions, for example, acetic acid as solvent, has been report-
ed, but high temperatures and longer reaction times are
still required11,12 and metals such as indium, tellurium,
and samarium are needed. Other reagents reported for this
reaction include sodium borohydride,13 ruthenium carbo-
nyl,14 hydrazine hydrate,15 ionic liquids,16 and Raney
nickel.17 Most of the above systems lack chemoselectivity
and often yield a mixture of products.
Y
2
X or Y = H, –OH, OMe, Me
Scheme 2 Reduction of azo compounds
Entries 5 and 6 (Table 1) demonstrate the tolerance for the
ketone functionality which, under catalytic hydrogenation
conditions, could be reduced to the corresponding alcohol
or methylene products.18 The tolerance of ketone func-
tionalities to iron-catalyzed nitro reduction is well prece-
dented in the literature.1,19 Our yields of 77% and 85%
for p-aminoacetophenone and m-aminoacetophenone,
respectively, whilst lower that those reported in the
literature (92%1 and 80%20 for para- and meta-aminoace-
tophenone, respectively), but the latter reactions were car-
ried out under high pressure at a temperature of 210 °C for
two hours with water as solvent. Therefore, the Fe/CaCl2-
catalyzed reduction conditions carried out at 60 °C for 30
minutes are advantageous as they are significantly milder
and easier to perform.
As an alternative to these systems we report herein
(Scheme 1, Scheme 2) the use of iron powder in the pres-
ence of calcium chloride in ethanol and water. In a typical
experiment, the nitroarene or azobenzene, iron powder,
and calcium chloride were stirred in ethanol and water at
Aryl halides are known to be susceptible to dehalogena-
tion under harsh reduction conditions, in particular cata-
lytic hydrogenation.5–7 Entries 3, 4, and 7–14 (Table 1)
SYNLETT 2010, No. 20, pp 3019–3022
Advanced online publication: 24.11.2010
DOI: 10.1055/s-0030-1259067; Art ID: D13110ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

3020
S. Chandrappa et al.
LETTER
demonstrate the selective reduction of the aryl nitro sub- duction reporting a yield of 64%.21 Finally, entries 3 and
stituent over the aryl halide, with good to excellent yields 4 indicate the tolerance of both nitrile and ester function-
obtained in all reactions. Entry 10 demonstrates the toler- alities. In both cases the reaction was complete in just 20
ance of a chlorine substituent on a pyrimidine ring with a minutes as confirmed by TLC analysis and provided the
yield of 85%, with previously reported iron-catalyzed re- corresponding arylamines in 90% and 88%, respectively.
Table 1 Reduction of Aryl Nitro Compounds into Arylamines by Fe/CaCl2 in a Mixture of EtOH–Water at Reflux Conditions with Reduction-
Sensitive Functional Groups (Scheme 1)
Entry Substrate
Product
Time (min) Yield (%)
O2N
O
CHO
H2N
O
CHO
1
30
20
88
85
O
O
CONH2
CONH2
H
N
H
N
N
O
N
O
CONH2
CONH2
N
N
2
COOBn
COOBn
NO2
NH2
CN
CN
3
30
28
90
88
NO2
NH2
Cl
Cl
O
O
NH2
F
NO2
F
4
MeO
MeO
NO2
NH2
5
6
30
30
92
80
O
O
O
NH2
NO2
O
OH
OH
NO2
Br
Br
NH2
Br
7
25
77
OMe
OMe
OMe
OMe
Br
NO2
NH2
8
9
30
30
80
86
OMe
Br
OMe
Br
NO2
NH2
Synlett 2010, No. 20, 3019–3022 © Thieme Stuttgart · New York

LETTER
An Efficient Method for Aryl Nitro Reduction and Cleavage of Azo Compound
3021
Table 1 Reduction of Aryl Nitro Compounds into Arylamines by Fe/CaCl2 in a Mixture of EtOH–Water at Reflux Conditions with Reduction-
Sensitive Functional Groups (Scheme 1) (continued)
Entry Substrate
Product
Time (min) Yield (%)
N
N
N
N
10
30
25
85
88
Cl
Cl
Cl
Cl
NO2
NH2
Cl
Cl
NH2
NO2
11
12
13
Cl
F
Cl
F
NH2
NO2
30
25
86
91
NO2
NH2
Cl
Cl
CN
CN
Cl
NH2
NO2
Cl
14
25
87
Br
Br
From the earlier reported methods, the reduction of ni- In summary, an effective and efficient method for the re-
troarenes to arylamines SnCl2·2H2O22 in ethanol–water duction of aryl nitro compounds and cleavage of azo-
requires 5–10 equivalents of tin(II) chloride for the com- arenes to their corresponding arylamines under mild
pletion of the reaction. The reduction of azoarenes to aryl- reaction conditions has been reported. Although, in some
amines by Al/NH4Br(5.0 equiv), Al/N2H4·H2O (3–5.0 instances, marginally higher yields are reported using al-
equiv)23,24 in methanol at 65 °C takes about 1.8–2.5 hours ternative procedures, use of iron powder and calcium
for completion with satisfactory yields. But in our meth- chloride in aqueous ethanol provides a much simpler pro-
od, the reduction of nitroarenes to arylamines with iron cedure. The short reaction times at relatively low temper-
powder (3.0 equiv) and calcium chloride (1.0 equiv) in a ature make this an attractive and advantageous method for
solvent mixture of ethanol and water goes to completion reduction of aryl nitro compounds and reductive cleavage
within 25–30 minutes at 60 °C with good yields as shown of azoarenes in organic synthesis.
in Table 2.
Table 2 Reductive Cleavage of Azoarenes into Arylamines by Fe/CaCl2 in EtOH at Reflux Conditions (Scheme 2)
Entry
Substrate
Producta
Time (min)
Yield (%)
Mp/bp (°C)
X
Y
X
Y
1
2
–
–
–
–
–
–
1
2
3
4
5
6
H
H
H
H
30
26
30
30
25
25
86
76
80
92
90
87
181b
174b
242b
200b
204b
72
2-HO
4-MeO
4-Me
3-Me
3,4-Cl
2-HO
4-MeO
4-Me
3-Me
3,4-Cl
2-HO
2-HO
4-MeO
4-Me
3-Me
3,4-Cl
4-MeO
4-Me
3-Me
3,4-Cl
a Characterized by 1H NMR, IR spectral analysis.
b Boiling point.
Synlett 2010, No. 20, 3019–3022 © Thieme Stuttgart · New York

3022
S. Chandrappa et al.
LETTER
General Procedure for the Reduction of Nitroarenes
the reaction mixture was filtered to remove the iron residue, which
was washed with EtOAc (2 × 25 mL). The organic extracts were
washed with H2O (3 × 50 mL), brine (2 × 25 mL), and dried over
Na2SO4, the organic phase was evaporated and the residue directly
loaded onto a small plug of silica gel column and eluted using PE–
EtOAc (20% EtOAc in hexane).
To a suspension of nitro compound (0.01 mol) in a mixture of EtOH
(10 mL) and H2O (0.5 mL), iron powder (0.03 mol), and CaCl2
(0.01 mol) were added. The resulting suspension was stirred at
60 °C for 30 min. Progress of the reaction was monitored by TLC.
After completion, the reaction mixture was filtered to remove the
iron residues, which were washed with EtOAc (2 × 20 mL). The or-
ganic extracts were washed with H2O (3 × 10 mL), brine (2 × 10
mL), and dried over Na2SO4, the organic phase was evaporated, and
the residue directly loaded onto a silica column and eluted using
PE–EtOAc (20% EtOAc in hexane).
Acknowledgment
The authors are grateful to UGC, Govt. of India for financial sup-
port to K.S.R. under the projects vide no. F. 31-143/2005(SR) Pro-
grammes.
Benzyl-2-[3-amino-5-formyl)phenyl]-5-carbamoylbenzoate
1
Pale yellow solid; mp 135–137 °C. H NMR (400 MHz, DMSO-
d6): d = 10.10 (s, 1 H), 8.48 (d, J = 8.1 Hz, 2 H), 8.30 (d, J = 7.6 Hz,
1 H), 1.13 (m, 1 H), 8.0 (m, 1 H), 7.45 (dd, J = 7.4, 6.5 Hz, 1 H),
7.26 (m, 3 H), 7.08 (m, 2 H), 5.11 (s, 2 H), 4.85 (br s, 2 H). 13C NMR
(100.6 MHz, DMSO-d6): d = 190.1, 156.7, 146.3, 136.1, 134.2,
130.3, 129.2, 129.1, 128.7, 128.6, 127.5, 126.9, 126.4, 126.1, 125.4,
125.2, 124.8, 124.2, 124.1, 54.1. IR (KBr): nmax = 3392, 3052, 2950,
2228, 1740, 1674, 1645, 1325, 1268, 876 cm–1.
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Yellow solid; mp 123–125 °C. 1H NMR (400 MHz, DMSO-d6): d =
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Off-white solid; mp 86–89 °C (lit. 87–91 °C). 1H NMR (400 MHz,
DMSO-d6): d = 7.66 (dd, J = 8.1, 7.5 Hz, 2 H), 7.56 (d, J = 7.6, 7.3
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General Procedure for the Reductive Cleavage of Azoarenes
Using Iron and Calcium Chloride
To a suspension of the azo compound (0.01 mol) in a mixture of
EtOH (12 mL), iron powder (0.04 mol) and CaCl2 (0.012 mol) were
added. The resulting suspension was stirred at 60 °C for 30 min.
Progress of the reaction was monitored by TLC. After completion,
Synlett 2010, No. 20, 3019–3022 © Thieme Stuttgart · New York