Iron-catalyzed selective reduction of nitro compounds to amines

Article abstract of DOI:10.1016/j.tetlet.2010.01.067

An efficient reduction of the nitro group with a catalytic amount of Fe(acac)₃ and TMDS in THF at 60 °C affording the corresponding amine is described.

Full text of DOI:10.1016/j.tetlet.2010.01.067

Tetrahedron Letters 51 (2010) 1939–1941
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Iron-catalyzed selective reduction of nitro compounds to amines
Leyla Pehlivan a, Estelle Métay a, Stéphane Laval a, Wissam Dayoub a, Patrice Demonchaux b,
Gérard Mignani c, Marc Lemaire a,
*
a Laboratoire de Catalyse, Synthèse et Environnement, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), CNRS, UMR5246, Université Lyon 1, 43 Boulevard
du 11 Novembre 1918, Bât CPE, 69622 Villeurbanne, France
b Minakem SAS, 145 Chemin des Lilas, 59310 Beuvry la Foret, France
c Rhodia, Lyon Research Center, 85 Avenue des Frères Perret, BP 62, 69192 Saint-Fons Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient reduction of the nitro group with a catalytic amount of Fe(acac)3 and TMDS in THF at 60 °C
affording the corresponding amine is described.
Received 15 December 2009
Revised 18 January 2010
Accepted 20 January 2010
Available online 6 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Reduction
Nitro
Amines
1,1,3,3-Tetramethyldisiloxane
Iron catalyst
Amines can be prepared by the reduction of the nitro precursor
by hydrogenation, electron-transfer, electrochemical, and hydride-
transfer conditions.1 The reduction of nitro functions to amines by
iron was first described in 1854 by Bechamp.2 Despite the effi-
ciency of this reaction, the low cost and toxicity of iron, this tech-
nology presents two major drawbacks. The first one concerns the
utilization of more than a stoichiometric amount of iron powder
and the second one is the acidic medium which is not compatible
with many organic functions. Other metals have been used includ-
ing cobalt,3 zinc,4 tin,5 and molybdenum.6
Over the last decade, silanes or siloxanes have been associated
with metals in order to perform nitro compound reductions under
milder conditions. However metals used in these cases are very
expensive Pd,7 Pt,8 Rh,9 or Re.10 In the literature, only few articles
relate the reduction of organic functionality in the presence of
environmentally benign iron. Aldehydes11 and ketones12 can be re-
duced to alcohols or alkanes13 with silanes or siloxanes. Iron com-
plexes allowed the hydrogenation of double or triple bonds.14
Recently, Nagashima15 reported the reduction of amides to amines.
He pointed out the high reactivity for the nitro group in the pres-
ence of an amide by the use of a catalytic system involving iron
carbonyl and TMDS in toluene at 100 °C. The drawback associated
with the methodology is the release of carbon monoxide and the
high temperature leading to excess pressure in the reaction vessel.
This work prompted us to report our preliminary results that ben-
efit of lower temperature and environmentally benign
conditions.
a
In our laboratory, we previously described the reduction of
phosphine oxides to phosphines16 and more recently the reduction
of the cyano group to amine17 in the presence of Ti(OiPr)4 and
TMDS (1,1,3,3-tetramethyldisiloxane). In order to eliminate the
risk of generating pyrophoric gases from silanes,18 only siloxanes
(PMHS and TMDS) were used. In this Letter, we described the
reduction of the nitro group to amine with a catalytic quantity of
Fe(acac)3 and 4 equiv of TMDS in THF at 60 °C (Scheme 1).
We started our investigation by testing different sources of iron,
using PMHS as the reducing agent (Table 1).
The formation of the desired product was observed with
Fe(OAc)2, Fe(acac)3, and Fe(acac)2 (Table 1, entries 1, 3, 4, 5, 6).
However, when catalytic quantities of iron were used only Fe(a-
cac)3 and Fe(acac)2 displayed interesting results (Table 1, entries
5 and 6). No conversion was observed with other iron sources.
NO2
R
NH2
TMDS (4 equiv.)
Fe(acac)3 (10 mol%)
THF, 60°C
R
62-99%
* Corresponding author. Tel.: +33 472 314 07; fax: +33 472 314 08.
E-mail address: marc.lemaire@univ-lyon1.fr (M. Lemaire).
Scheme 1. Reduction of the nitro function to amine.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.067

1940
L. Pehlivan et al. / Tetrahedron Letters 51 (2010) 1939–1941
Table 1
Moreover when reaction occurred, the formation of a gel was ob-
Reduction of 4-nitrobenzonitrile with different iron sources
served and may prevent complete conversion after 48 h. This is
the major drawback of PMHS. Thus, studies were carried out with
TMDS and different solvents were evaluated.
[Fe]/PMHS
O2N
CN
H2N
CN
Toluene, 90°C, 15 hours
Based on the known activated effect of fluorides,7b,19 some tests
were realized in the presence of fluoride sources CeF3, TBAF, and
KF. No significant improvement was observed. Because of the
low boiling point of TMDS (71 °C), tests were realized at lower
temperature in order to avoid the use of sealed tubes. At room tem-
perature, after 36 h the conversion was less than 5%, but at 60 °C in
24 h good results were obtained. When the experiments were per-
formed in toluene (Table 2, entry 2), DEC (Table 2, entry 6), or t-
BuOH (Table 2, entry 7) the reactions were slower. Without the sol-
vent, the reaction mixture was heterogeneous and conversion was
not complete after 36 h. A solvent screening indicated that the best
results were obtained in THF or MeTHF. MeTHF is more expensive
than THF but is environmentally more friendly. Fe(acac)2 and Fe(a-
cac)3 have shown similar reactivity but from an economical point
of view only cheaper FeIII was employed. Best conditions20 (Table
2, entry 4) were applied on different nitroarenes.
Entry
Iron Source Quantity (mol/mol) PMHS (SiH equiv)
Conv.a (%)
1
2
3
4
5
6
7
8
9
Fe(OAc)2
Fe(acac)3
1
0.1
1
2
4
2
4
4
4
2
2
2
44
—
90
85
55
51
—
0.2
0.1
0.1
1
Fe(acac)2
FeCl3
FeCl2
1
—
—
K3Fe(CN)6
1
Conversions were determined with 1H NMR.
a
Table 2
Conditions study
As depicted in Table 3, the reduction of aromatic nitro com-
pounds is selective and efficient except when the nitro compound
is para substituted by an aldehyde (Table 3, entry 3). In this partic-
ular case, the aldehyde, substituted by a withdrawing group, is
probably reduced first followed by the conversion of the nitro
group into amine. Moreover Beller11 previously reported that Fe(a-
cac)3 was not a good catalyst for the reduction of aldehyde to alco-
hol. Only 5% conversion of benzaldehyde to alcohol was detected.
When nitroarenes are substituted by other functionalities, carbox-
ylic acids (Table 3, entry 4), nitriles (Table 3, entry 2), or esters (Ta-
ble 3, entry 5), this method is selective, only nitro groups are
reduced to amines. The nitro arene substituted by an ester function
has shown, surprisingly, a low reactivity in comparison with the
nitrile derivative. In order to obtain complete conversion, the reac-
tion was performed in toluene at 90 °C (Table 3, entry 5). In the
Fe(acac)3
10 mol%
O2N
CN
H2N
CN
Entry
Solvent
Siloxane
T (°C)
C
Time
Conv. (%)
1
2
3
4
5
6
7
Toluene
THF
PMHS
TMDS
PMHS
TMDS
TMDS
TMDS
TMDS
90
60
70
60
60
60
60
0.5
1
0.5
1
1
0.6
0.6
17 h
48 h
17 h
24 h
24 h
24 h
4 d
55
>98
93
>98
>98
50
MeTHF
DECa
t-BuOH
>98
Conversions were determined with 1H NMR.
a
DEC: diethylcarbonate.
Table 3
Reduction of different nitro compounds to amines
Entry
Substrates
NO2
Amines
Conversion (%)
Time (h)
24
Isolated yield (%)
1
2
3
4
5
NH2.HCl
100
100
100
87
>99
92
NC
NO2
NO2
NO2
NO2
NC
NH2.HCl
NH2.HCl
24
OHC
HOOC
HOH2C
HOOC
MeOOC
24
80
24
62
NH2.HCl
NH2.HCl
100
48
95a
MeOOC
NO2
NH2.HCl
6
7
8
100
24
>99%
Br
NH2.HCl
Br
Br
44
85
24
48
nd
66
NO2
NO2
Br
NO2
100
24
98
NO2
NH2.HCl
Conditions: nitro compounds (2 mmol), Fe(acac)3 (0.2 mmol), TMDS (8 mmol), THF, 60 °C. Conversions were determined with 1H NMR. Isolated as hydrochlorides salts with
>99% purity.
a
Reaction was performed in toluene at 90 °C.

L. Pehlivan et al. / Tetrahedron Letters 51 (2010) 1939–1941
1941
3. Lee, H.-Y.; An, M. Bull. Korean Chem. Soc. 2004, 25, 1717–1719.
4. Khan, F. A.; Sudheer, C. Tetrahedron Lett. 2009, 50, 3394–3396.
5. (a) Zhou, Y.; Li, J.; Liu, H.; Zhao, L.; Jiang, H. Tetrahedron Lett. 2006, 47, 8511–
8514; (b) Gamble, A. B.; Garner, J.; Gordon, C. P.; O’Conner, S. M. J.; Keller, P. A.
Synth. Commun. 2007, 37, 2777–2786.
6. Iyer, S.; Kulkarni, G. M. Synth. Commun. 2004, 34, 721–725.
7. (a) Rahaim, R. J.; Maleczka, R. E. Org. Lett. 2005, 7, 5087–5090; (b) Rahaim, R. J.;
Maleczka, R. E. Synthesis 2006, 3316–3340.
8. Motoyama, Y.; Kamo, K.; Nagashima, H. Org. Lett. 2009, 11, 1345–1348.
9. Brinkman, H. R.; Miles, W. H.; Hilborn, M. D.; Smith, M. C. Synth. Commun. 1996,
26, 973–980.
10. Noronha, R. G.; Romao, C. C.; Fernandes, A. C. J. Org. Chem. 2009, 74, 6960–6964.
11. Shaikh, N. S.; Junge, K.; Beller, M. Org. Lett. 2007, 9, 5429–5432.
12. (a) Nishiyama, H.; Furuta, A. Chem. Commun. 2007, 760–762; (b) Tondreau, A.
M.; Lobkovsky, E.; Chirik, P. J. Org. Lett. 2008, 10, 2789–2792.
13. Dal Zotto, C.; Virieux, D.; Campagne, J.-M. Synlett 2009, 276–278.
14. Bart, S. C.; Lobkovsky, E.; Chirik, P. J. J. Am. Chem. Soc. 2004, 126, 13794–13807.
15. Sunada, Y.; Kawakami, H.; Imaoka, T.; Motoyama, Y.; Nagashima, H. Angew.
Chem., Int. Ed. 2009, 48, 9511–9514.
presence of a bromide substituent (Table 3, entries 6 and 7), no
dehalogenated product was observed. However, a difference in
reactivity between ortho- and meta- substituted nitroarene was
noticed. From the 1,4-dinitrobenzene (Table 3, entry 8) under this
condition only one nitro function was reduced. The reaction was
performed on 3 g (20.2 mmol) of p-nitrobenzonitrile. Same isolated
yield was obtained (Table 3, entry 2). Analytical data of the pre-
pared compound were compared to those of the literature.21
In conclusion, we have developed a mild, safe, and efficient
reduction procedure of the nitro function to amine. This method
can constitute an alternative to the Bechamp procedure which pre-
sented several drawbacks detailed above. Scope and limitations as
well as mechanistic investigations are currently underway in our
laboratory.
16. (a) Berthod, M.; Favre-Réguillon, A.; Mohamad, J.; Mignani, G.; Docherty, G.;
Lemaire, M. Synlett 2007, 1545–1548; (b) Petit, C.; Favre-Réguillon, A.; Albela,
B.; Bonneviot, L.; Mignani, G.; Lemaire, M. Organometallics 2009, 28, 6379–
6382; (c) Petit, C.; Favre-Réguillon, A.; Mignani, G.; Lemaire, M. Green Chem.
2010, 12, 326–330.
17. Laval, S.; Dayoub, W.; Favre-Reguillon, A.; Berthod, M.; Demonchaux, P.;
Mignani, G.; Lemaire, M. Tetrahedron Lett. 2009, 50, 7005–7007.
18. Berk, S. C.; Buchwald, S. L. J. Org. Chem. 1993, 58, 3221.
19. Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. Rev. 1993, 93, 1371–1448.
20. Typical procedure for the reduction of nitro compounds: In a solution of nitro
compound (2 mmol) in 0.6 mL of THF were added Fe(acac)3 (10 mmol %,
70 mg) and TMDS (4 equiv or 8 Si-H, 1.4 mL). After 24 h under heating the
reaction mixture was diluted with Et2O 5 mL, stirred for 5 min, and filtered
through a plug of Celite (top layer) and neutral alumina (bottom layer) in a
1 cm diameter column by flushing with EtOAc. The filtrate was concentrated,
diluted with a minimum of toluene, and mixed with 1 M HCl. The aqueous
layer was washed with toluene, and concentrated to afford the desired
product.
Acknowledgment
This work was supported by the Fond Unique Interministériel
‘REDSUP’.
References and notes
1. (a) Kabalka, G. W.; Verma, R. S.. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 8, pp 363–379; (b) Larock, R. C.
Comprehensive Organic Transformations: A Guide to Functional Group Preparation,
2nd ed.; Wiley-VCH: Weinheim, 1999. pp 821–828; (c) Schilling, S. L. Kirk-
Othmer Encyclopaedia of Chemical Technology, 4th ed.; John Wiley & Sons, Inc.,
1991, Vol. 2, pp 482–503.
2. (a) Béchamp, A. J. Ann. Chim. Phys. 1854, 42, 186; (b) Werner, J. Ind. Eng. Chem.
1948, 40, 1574–1583. 1949, 41, 1841–1846; (c) Courtin, A. Helv. Chim. Acta
1980, 62, 2280–2286; (d) Hamilton, C. S.; Morgan, J. F. Org. React. 1944, 2, 428–
431.
21. Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 1114–1116.