Ultrasonically activated reduction of substituted nitrobenzenes to corresponding N-arylhydroxylamines

Article abstract of DOI:10.1016/j.tetlet.2005.06.126

Arylhydroxylamines can be obtained by reduction of the corresponding nitroaromatic compounds. We report here an efficient preparation of arylhydroxylamines by a controlled reduction of nitro compounds using zinc metal and ammonium chloride under ultrasonic activation in very short reaction times.

Full text of DOI:10.1016/j.tetlet.2005.06.126

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5913–5917
Ultrasonically activated reduction of substituted nitrobenzenes
to corresponding N-arylhydroxylamines
*
´
`
Stephane Ung, Annie Falguieres, Alain Guy and Clotilde Ferroud
Laboratoire de Chimie Organique UMR CNRS 7084, Case 303, Conservatoire National des Arts et Me´tiers, 2,
rue Conte´, F-75003 Paris, France
Received 10 May 2005; revised 17 June 2005; accepted 22 June 2005
Available online 11 July 2005
Abstract—Arylhydroxylamines can be obtained by reduction of the corresponding nitroaromatic compounds. We report here an
efficient preparation of arylhydroxylamines by a controlled reduction of nitro compounds using zinc metal and ammonium chloride
under ultrasonic activation in very short reaction times.
Ó 2005 Elsevier Ltd. All rights reserved.
OMe
Nitroaromatics are major industrial products and well-
OAc
OMe
HO
OH
HO
known precursors of other valuable organic products.
Indeed, the reduction of nitro compounds leads to
various versatile classes of products such as amines,
hydroxylamines, hydrazines, nitroso-, azo-, or azoxy
compounds. The main difficulty is to control the selec-
tive access of only one of these products.
N
H
N
NH
Ar
3
(-)-anisomycine
O GP
CN
GP O
O GP
GP O
O GP
GP O
As part of an ongoing program involving a photoin-
duced single electron transfer (SET) reaction1 to synthe-
size an antitumor substance, the (ꢀ)-anisomycin,2 we
were interested in the preparation of N-substituted aryl-
hydrazines 3 as starting material via an umpolung strat-
egy (Scheme 1).
N
NH
Ar
N
N
H
NH
Ar
+
NO2
NHOH
HN O POPh2
R
R
R
1
2
Arylhydrazines 3 could be obtained by condensation of
3,4-disubstituted pyrrolidines with an O-activated deriv-
ative of the N-arylhydroxylamine 2 activated with
diphenylphosphinyl chloride. This hydroxylamine 2
could result from the corresponding nitroaromatic
compound 1 on condition that the reduction step is well
controlled. It thus appeared that the conversion of nitro-
compound to the corresponding arylhydroxylamine is
the key step of our convergent planned synthetic route
to (ꢀ)-anisomycin (Scheme 1).
Scheme 1.
As arylhydroxylamines are an important class of com-
pounds frequently used as key intermediates in the syn-
thesis of numerous fine chemicals,3–5 we thus decided to
study such a transformation. Several methods have been
developed for the preparation of arylhydroxylamines;
the more conventional one involves the reduction of
nitroaromatic compounds to the corresponding N-
hydroxylamines. Widely used is a reduction process
involving a metal-mediated hydrogen transfer.6 The pro-
cedure typically involves the use of a catalytic amount of
an heavy metal (palladium, rhodium, iridium, or Raney
nickel) together with hazardous reagents (metallic sele-
nium or tellurium with sodium borohydride or bismuth
Keywords: Substituted nitrobenzenes; Reduction by zinc metal; Ultra-
sonication; Arylhydroxylamines; SET reactions.
*
Corresponding author. Tel.: +33 (0)140272402; fax: +33
(0)142710534; e-mail: ferroud@cnam.fr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.126

5914
S. Ung et al. / Tetrahedron Letters 46 (2005) 5913–5917
chloride with potassium borohydride).7 Recently, Cui
and co-workers have reported the reduction of nitroaro-
matic compounds to the corresponding hydroxylamines
using bakerÕs yeast or plant cells which represents the
first example for preparation of arylhydroxylamines
using a biological process.8 The quantitative reduction
of nitroarenes bearing electron-withdrawing groups
has shown good selectivity (hydroxylamine vs amine:
ratios >90:10); however the major drawback of this
biological process is the large quantity of biocatalyst
required (2.5–5.0 g per 100 mg of substrate).
reactions and, in many cases, improve product yields
and sometimes can replace phase-transfer catalyst.
As depicted in Scheme 2,12 a literature survey reveals
that reduction of nitroaromatic compounds proceeds
by SET mechanisms to form amines through intermedi-
ate stages involving hydroxylamines and nitroso com-
pounds. N-Hydroxylamines are often reduced further
to the corresponding amines. Moreover, amines and
hydroxylamines generated in situ can react together
and lead to the formation of azoxy- or azo-compounds.
The reduction of the nitroaromatic compounds is also
possible using zinc metal together with ammonium chlo-
ride in an aqueous suspension. First described by
Kamm,9 this procedure is frequently used but yields
are not often mentioned due to the high reactivity of
the resulting N-arylhydroxylamines that are generally
engaged in the next step without isolation or further
purification steps. The best results are obtained when
the reaction occurs at 65–70 °C.
We thus herein, report an effective conversion of nitro-
aromatic compounds to the corresponding N-arylhydr-
oxylamines using 2 equiv of zinc dust (as proposed in
Scheme 2) and ammonium chloride under ultrasonic
activation. The easy experimental protocol together with
the safety of the reagents implied encouraged us to
choose this latter reductive method to prepare the target
hydoxylamine 2.
We decided to use the 4-hydroxyamino-benzoic acid
ethylester 1a as a model substrate in order to find opti-
mal conditions. The conversion to the corresponding N-
hydroxylamine 2a was found to best proceed by using
2.1 M equiv of zinc in a 9:1 ethanol–water solvent mix-
ture and in the presence of ammonium chloride (Scheme
3). In these conditions, we observed a dramatic effect of
the ultrasonic activation, as the total conversion occurs
within few minutes at room temperature (zinc dust was
added by portions within a few minutes and the ultra-
sounds irradiation was halted 3–5 min after addition
of the powder). Moreover, the crude N-hydroxylamine
In order to improve this reduction procedure in terms of
selectivity, generality and reaction time, we were inter-
ested in studying the effect of ultrasounds on the reac-
tion. Indeed, the advantageous use of ultrasound
irradiation technique for activating various reactions
proceeding via electron transfer mechanism or radical
route is well documented in the literature.10 Solid–liquid
heterogeneous reactions under ultrasound irradiation
undergo pulverization of solid particles and simulta-
neous activation of surface.11 As well as being energy
efficient, ultrasounds can also enhance the rate of the
2 éq. zinc
1 éq. zinc
O
1 éq. zinc
e-, H+
H
N
e-, H+
e-, H+
-H2O
e-, H+
OH
N
+
Ar
NO2
1b
N
Ar
Ar
NO
3b
Ar
Ar
OH
OH
2b
e-, H+
-H2O
O
N
OH
O
e-, H+
-H2O
N+
N
Ar
N
Ar
Ar
Ar
5b
H
e-, H+
N
Ar
OH
e-, H+
.
N
N
Ar
Ar
e-, H+
-H2O
NH2
4b
Ar
O
H
N
e-, H+
-H2O
N
N
N
Ar
Ar
Ar
Ar
Ar
6b
e-, H+
Ar =
H
N
.
CF3
N
Ar
e-, H+
H
H
N
2e-, 2H+
N
7b
Ar
Ar
3 éq. zinc
Scheme 2.

S. Ung et al. / Tetrahedron Letters 46 (2005) 5913–5917
5915
solvent / water
9 / 1
that spontaneously were transformed in a mixture of
over-reduced products. We have also observed a sponta-
neous conversion of 4-chlorophenyl-N-hydroxylamine
2f (R = p-Cl) (obtained in 65% yield with 95% purity)
to the corresponding azo derivative 7f and 4-chloroani-
line 5f when zinc dust was not rapidly filtered. In such
conditions, only 20% of 4-chlorophenyl-N-hydroxyl-
amine 2f had been recovered in less than 1 h.
NHOH
NO2
Zn, NH4Cl
r.t., ))))
R
R
1
2
Scheme 3.
2a was isolated in high yield (90%) with an NMR esti-
mated degree of purity superior to 95% (Table 1, entry
1).
In the case of compound 1b, we observed an interesting
conjugated effect of the quantity of zinc dust, the nature
of the medium and the time of ultrasonication on the
course of the reaction. We have thus established four
experimental protocols that selectively lead to one of
the four reduction products, N-arylhydroxylamine 2b,
amine 5b, azo 7b, or hydrazine 8b (Table 2).
In order to avoid some difficulties in solubilizing other
substrates, we then changed ethanol to acetone. Such a
change improved the system as the crude hydroxylamine
2a was obtained in a quantitative yield without any loss
of purity (>95%). Various other substituted nitrobenz-
enes were then converted to N-arylhydroxylamines using
this procedure (Table 1, entries 2–5). In all cases, the
yields were good to excellent and the purity of the crude
products always superior to 95%. Over-reduction to the
corresponding anilines 5 was prevented by simple filtra-
tion of the zinc dust. However, long-term storage of the
hydroxylamines is not advised since they are known to
deteriorate over rather short periods of time.
Moreover, from 3,30-trifluoromethylhydrazobenzene 8b
in HCl 3 N under ultrasonic conditions, we observed,
after the cleavage of the hydrazo bond, the radical cou-
pling with acetone providing m-trifluoromethyl-N-iso-
propylaniline 9 (Scheme 4).
As shown in Table 2, the results we have obtained by
reduction with zinc under ultrasonication are consistent
with mechanisms by SET proposed in the literature12
(Scheme 2).
Very good results were obtained with nitroaromatics
bearing electron-withdrawing substituents. The reac-
tions proceeded in about 5 min in almost quantitative
yields. It is noteworthy that 4-hydroxyamino-benzoic
acid ethylester 2a and m-trifluoromethylphenyl-N-
hydroxylamine 2b were found to be stable under storage
at room temperature.
In summary, we reported here a study on the ultrasonic
activation which can be a fast and powerful tool in selec-
tive nitroaromatics reduction reactions to corresponding
N-arylhydroxylamines, avoiding the formation of over-
reduced products. Because of its simplicity, high selec-
tivity, short reaction times and high yields, this method
can be used as a valid alternative to other reduction
processes.
The electron-donating substituted nitroaromatics such
as p-methyl or p-methoxy were found to react as well
in these conditions but led to unstable hydroxylamines
Table 1.
Entry
Substrate 1
Solvent
Time (min)
Product 2
Yielda (%)
Purityb (%)
O
O
Ethanol
Acetone
5
5
90
100
>95
>95
NO2
NHOH
1
O
O
2a
1a
NO2
NHOH
2
3
4
5
Acetone
Acetone
Acetone
Acetone
5
5
5
5
95
95
75
85
>95
100
>95
100
2b
CF3
Cl
1b
CF3
Cl
NO2
NHOH
1c
2c
Cl
Cl
NO2
NHOH
2d
O2N
O2N
O2N
O2N
1d
NO2
NHOH
2e
1e
a Crude products.
b Estimated by NMR analysis.13

5916
S. Ung et al. / Tetrahedron Letters 46 (2005) 5913–5917
Table 2.
Starting material
Zinc (equiv)
2.1
Solvent
Timea,b
5 min
Product
CF3
Yieldc (%)
95
Purityd (%)
94.8
NHOH
2b
NO2
Acetone/H2O
1b
CF3
CF3
NH2
5b
NO2
3.3
2.1
1.2
EtOH/HCl 3 N
Acetone/H2O
Acetone/H2O
10 min
3 days
<5 min
100
96.2
99.4
97.6
1b
CF3
N
N
NO2
20–30
92
1b
CF3
CF3
CF3
CF3
CF3
CF3
7b
N
H
N
H
N
N
CF3
CF3
7b
8b
N
H
N
H
N
10
Acetone/HCl 3 N
30 min
55
100
H
CF3
8b
CF3
9
a All reactions were realized under ultrasonic activation.
b Reactions were monitored by analytical HPLC at 280 nm wavelength (ODS C18 column; acetonitrile–water 70:30; 1.4 mL/min flow rate).
c Crude yield.
d Estimated by HPLC.
4. (a) Balaban, A. T.; Garrett, R. E.; Leskoand, M. J.; Seitz,
W. A. Org. Prep. Proced. Int. 1998, 30, 439; (b) Naisbitt,
D. J.; OÕNeill, P. M.; Pirmohamed, M.; Park, B. K.
Bioorg. Med. Chem. 1996, 6, 1511; (c) Smith, D. G.;
Gribble, A. D.; Haigh, D.; Ife, R. J.; Lavery, P.; Skett, P.;
Slingsby, B. P.; Ward, F. W.; West, A. Bioorg. Med.
Chem. 1999, 9, 3137; (d) Mcgill, A. D.; Zhang, W.;
Wittbrodt, J.; Wang, J.; Schlegel, H. B.; Wang, P. G.
Bioorg. Med. Chem. 2000, 10, 405; (e) Yadav, J. S.; Reddy,
B. V. S.; Sreedhar, P. S. Adv. Synth. Catal. 2003, 345, 564.
5. (a) Cobb, C. L. M.; Connors, T. A.; Elson, L. A.; Khan,
A. H.; Mitchley, B. V. C.; Ross, W. J. C.; Whisson, M. E.
Biochem. Pharmacol. 1969, 18, 1519; (b) Knox, R. J.;
Friedlos, F.; Jarman, M.; Roberts, J. Biochem. Pharmacol.
1988, 37, 4661; (c) Anlezark, G. M.; Melton, R. G.;
Sherwood, R. F.; Wilson, W. R.; Denny, W. A.; Palmer,
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Pharmacol. 1995, 50, 609; (d) Johansson, E.; Parkinson,
G. N.; Denny, W. A.; Neidle, S. J. Med. Chem. 2003, 46,
4009.
OH
O
H
+
OH
H
e-, H+
e-, H+
Zn, HCl
H+
-H2O
.
.
H
H
N
R
R
N
H
R
H
8b
.
N
H
2
2
9
R =
Scheme 4.
CF3
As the reactions occur in less than 5 min at room tem-
perature, this method is appropriate to highly function-
alized nitrocompounds. Moreover, as zinc is inexpensive
and non toxic, the use of this metal enhances the syn-
thetic convenience and fulfills the demand for an envi-
ronmentally friendly process.
6. (a) Entwistle, I. D.; Jackson, A. E.; Johnstone, R. A. W.;
Telford, R. P. J. Chem. Soc., Perkin Trans. 1 1977, 443;
(b) Entwistle, I. D.; Gilkerson, T.; Johnstone, R. A. W.;
Telford, R. P. Tetrahedron 1978, 34, 213; (c) Ayyangar, N.
R.; Brahme, K. C.; Kalkote, R. U.; Srinivasan, K. Y.
Synthesis 1984, 938; (d) Cordero, F. M.; Barile, I.;
De Sarlo, F.; Brandi, A. Tetrahedron Lett. 1999, 40,
6657.
References and notes
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Chem. Soc., Chem. Commun. 1986, 1655; (b) Uchida, S.;
Yanada, K.; Yamaguchi, H.; Meguri, H. Chem. Lett.
1986, 1069; (c) Ren, P.; Pan, X.; Jin, Q.; Yao, Z. Synth.
Commun. 1997, 27, 3497.
8. (a) Li, F.; Cui, J.; Qian, X.; Zhang, R. Chem. Commun.
2004, 2338–2339; (b) Li, F.; Cui, J.; Qian, X.; Zhang, R.;
Xiao, Y. Chem. Commun. 2005, 1901.
3. (a) Toshiya, S.; Masatomo, N.; Shigekazu, K. J. Org.
Chem. 1990, 55, 4221; (b) Srivastava, R. S.; Nicholas, K.
M. J. Am. Chem. Soc. 1997, 119, 3302; (c) Ming, H. C.;
Chu, L. T. New J. Chem. 2000, 24, 859; (d) Lin, L. J.;
Sheng, H. J.; Yuan, Z. Z.; Kai, C. K.; Ming, C. C. Chem.
Eur. J. 2001, 11, 2306; (e) Hiroshi, T.; Ichi, T. J.; Suguru,
H.; Keisuke, T.; Yoshinori, O. Eur. J. Org. Chem. 2003,
3920; (f) Neri, G.; Rizzo, G.; Milone, C.; Spence, J. D.;
Raymond, A. E.; Norton, D. E. Tetrahedron Lett. 2003,
44, 849.
9. (a) Kamm, O.; Marvel, C. S. Org. Synth. Coll. 1941, I, 445;
(b) Brink, C. P.; Crumbliss, A. L. J. Org. Chem. 1982, 47,
1171; (c) Gassman, P. G.; Grandrud, J. E. J. Am. Chem.
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Soc. 1984, 106, 1498; (d) Bartra, M.; Romea, P.; Urpı, F.;

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5917
Vilarrasa, J. Tetrahedron 1990, 46, 587; (e) Bordwell, F.
G.; Liu, W. J. Am. Chem. Soc. 1996, 118, 8777; (f) Heaney,
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J.; Wang, J.; Schlegel, B.; Wang, P. G. Bioorg. Med. Chem.
2000, 8, 405.
4-Hydroxyamino-benzoic acid ethylester 2a: GC/MS: m/z
(%): 166 (100), 165 (27), 120 (27). IR (KBr plate): 3388,
3292, 2973, 1686 cmꢀ1 1H NMR (400 MHz, CDCl3): d
.
7.97 (d, 2H, J = 9.2 Hz, H-2), 6,98 (d, 2H, J = 9.2 Hz, H-
3), 6.98 (s, 1H, OH), 5.58 (s, 1H, NH), 4.34 (q, 2H,
J = 7.2 Hz), 1.39 (t, 3H, J = 7.2 Hz). 13C NMR
(100 MHz, CDCl3): d 166.7 (C@O), 153.9 (C-1), 130.9
(C-2), 123.4 (C-4), 112.9 (C-3), 60.7 (CH2), 14.3 (CH3).
N-(3-Trifluoromethylphenyl)-hydroxylamine 2b: GC/MS:
m/z (%): 177 (100) [M+], 160 (97), 158 (18), 145 (48), 120
10. Luche, J. L. Synthetic Organic Sonochemistry; Kluwer
Academic/Plenum: Hingham, 1998.
11. (a) Loupy, A.; Luche, J.-L. In Handbook of Phase Transfer
Catalysis; Sasson, Y., Neumann, R., Eds.; Chapman &
Hall: London, 1997, Chapter 11; (b) Shoh, A. In Ultra-
sound, its Chemical, Physical and Biological Effect; Suslick,
K., Ed.; VCH: Weinheim, 1989, p 107; (c) Moon, S.;
Duchin, L.; Cooney, J. Tetrahedron Lett. 1979, 3917; (d)
Davidson, R. S.; Patel, A. M.; Safdar, A.; Thornthwaitf,
D. Tetrahedron Lett. 1983, 5907.
(15), 76 (3). IR (KBr plate): 3224, 3084, 2853 cmꢀ1
.
1H
NMR (400 MHz, CDCl3): 7.37 (t, 1H, J5,6
d
ꢁ
J6,7 ꢁ 8.0 Hz), 7.25 (s, 1H), 7.21 (d, 1H, J = 7.7 Hz, H-
4), 7.11 (d, 1H, J = 8.2 Hz, H-6), 6.88 (s, 1H, OH), 5.49 (s,
1H, NH).
N-(3,5-Dichlorophenyl)-hydroxylamine 2c: GC/MS: m/z
(%): 178 (7) [M+], 161 (100), 145 (13), 125 (22), 90 (22), 75
(13). IR (KBr plate): 3430, 3280, 3087, 2863 cmꢀ1 1H
.
12. (a) Nunez-Vergara, L. J.; Bonta, M.; Navarrete-Encina, P.
A.; Squella, J. A. Electrochim. Acta 2001, 46, 4289; (b)
Maldotti, A.; Andreotti, L.; Molinari, A.; Tollari, S.;
Penoni, A.; Cenini, S. J. Photochem. Photobiol. A: Chem.
2000, 133, 129.
NMR (400 MHz, CDCl3): d 6.92 (s, 1H), 6.87 (s, 2H), 6.79
(s, 1H, OH), 5.23 (s, 1H, NH). 13C NMR (100 MHz,
CDCl3): d 151.6 (C-3), 135.4 (C-5), 121.9 (C-1), 112.6 (C-2).
N-(3-Nitrophenyl)-hydroxylamine 2d: IR (KBr plate):
1
3288, 3196, 3068 cmꢀ1. H NMR (400 MHz, DMSO-d6):
13. Typical procedure for substituted phenylhydroxylamines
preparation:To a suspension of nitrocompound 1 (3 mmol,
1 equiv) in acetone (40 mL) and saturated NH4Cl aqueous
solution (2 mL) was added distilled water (2–3 mL) until
the solution became clear. Zinc dust (2.1 equiv) was added
slowly by portions while sonicating (Transonic Elma
ultrasonic bath, 35 kHz) the reaction mixture at 15–
20 °C for few minutes (5–10 min). TLC monitoring of the
reaction was done till the completion of the reaction. The
crude mixture was concentrated under reduced pressure
and a temperature never exceeding 15 °C. The residue
obtained was dissolved in CH2Cl2 (20 mL) at 0 °C. The
organic phase was dried over magnesium sulfate, then
concentrated as above to provide the pure hydroxylamine
2 as a pale-yellow oil.
d 8.88 (s, 1H, OH), 8.77 (s, 1H, NH), 7.61 (s, 1H), 7.56 (d,
1H, J = 8.1 Hz, H-4), 7.42 (t, 1H, J6,7 = J5,6 = 8.1 Hz),
7.19 (d, 1H, J = 8.1 Hz, H-6). 13C NMR (100 MHz,
DMSO-d6): d 153.1 (C-3), 148.3 (C-4), 129.5 (C-2), 118.7
(C-1), 113.2 (C-6), 106.1 (C-5).
N-(4-nitrophenyl)-hydroxylamine 2e: IR (KBr plate): 3355,
3306, 3070, 3030 cmꢀ1. 1H NMR (400 MHz, DMSO-d6): d
9.64 (s, 1H, OH), 9.10 (s, 1H, NH), 8.07 (d, 2H, J = 9.4 Hz,
H-3), 6.80 (d, 2H, J = 9.4 Hz, H-2). 13C NMR (100 MHz,
DMSO-d6): d 156.6 (C-4), 137.5 (C-3), 125.5 (C-1), 109.8
(C-2).
N-(4-Chlorophenyl)-hydroxylamine
2f:
1H
NMR
(400 MHz, CDCl3): d 7.17 (d, 2H, J = 8.8 Hz, H-3), 7.16
(s, 1H, OH), 6.83 (d, 2H, J = 8.8 Hz, H-2), 6.76 (s, 1H,
NH).