One-pot reductive monoalkylation of nitro aryls with hydrogen over Pd/C

Article abstract of DOI:10.1016/j.tetlet.2007.12.030

A range of different nitro aryls were converted in one-pot to the corresponding secondary alkyl amino aryls in good to excellent yields by using aldehydes as alkyl source and hydrogen over Pd/C (10%) as reducing agent. In all examples, but one, the second

Full text of DOI:10.1016/j.tetlet.2007.12.030

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Tetrahedron Letters 49 (2008) 1199–1202
One-pot reductive monoalkylation of nitro aryls with hydrogen
over Pd/C
Magne O. Sydnes a, Minoru Isobe a,b,
*
a Laboratory of Organic Chemistry, Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan
b Institute of Advanced Research, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan
Received 2 November 2007; revised 5 December 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
A range of different nitro aryls were converted in one-pot to the corresponding secondary alkyl amino aryls in good to excellent yields
by using aldehydes as alkyl source and hydrogen over Pd/C (10%) as reducing agent. In all examples, but one, the secondary amine was
the sole alkylation product isolated. When formaldehyde was used as the alkyl source, substantial amount of the corresponding tertiary
amine was isolated, however, by altering the reaction conditions slightly the corresponding secondary amine could be isolated in superb
yield.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: One-pot; Reductive monoalkylation; Nitro aryls; Secondary alkyl amino aryls; Pd/C
1. Introduction
give acetaldehyde)],4 carbonyls,5,6 or nitriles7–9 as the alkyl
source. Conversion of nitro aryls to the corresponding car-
bamates (Boc and CO2Et) using Sn/NH4Cl and Boc2O or
ClCO2Et in one-pot has also been reported.10 Herein we
report a simple one-pot procedure for the reductive mono-
alkylation of nitro aryls with aldehydes using hydrogen
over Pd/C (10%) as the reducing agent.11
The nitro group is a versatile moiety in organic synthe-
sis.1 Especially, aromatic nitro compounds are frequently
used in synthesis, mostly due to their ease of formation
and their subsequent efficient conversion to aromatic
amines.2 Primary aromatic amines in their place are vital
starting materials for further elaboration to secondary
amines, which for example, are important pharmacophores
in numerous biologically active compounds.3 However,
preparing secondary amines and obtaining them in good
yields with high selectivity still remain a challenge.3
There have been a few reports describing the one-pot
reductive monoalkylation of aromatic nitro compounds
using hydrogen and Raney nickel,4 decaboran,5,6 hydrogen
and Pd/C (10%),7 ammonium formate and Pd/C (5%)8 or
polymethylhydrosiloxane, and Pd(OH)2/C (20%)9 as the
reducing agent and ethanol [acetaldehyde is the actual alkyl
source (ethanol is oxidized under the reaction conditions to
2. Results and discussion
The work presented herein was prompted by an interest-
ing finding during the conversion of nitro aryl 1 to primary
amine 2, required as an intermediate for the synthesis of the
corresponding aryl azide.12 We observed that prolonged
reaction time (48 h) provided a significant amount (41%)
of secondary amine 3a (Scheme 1). Interestingly no trace
of the corresponding tertiary amine was formed under
these conditions.
The alkylation agent in the forgoing reaction is most
likely the corresponding aldehyde, viz. acetaldehyde, which
is formed in low quantity during the reaction by the
dehydrogenation of the solvent upon reaction with Pd.13
*
Corresponding author. Tel.: +81 52 789 4109; fax: +81 52 789 4111.
E-mail address: isobem@agr.nagoya-u.ac.jp (M. Isobe).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.030

1200
M. O. Sydnes, M. Isobe / Tetrahedron Letters 49 (2008) 1199–1202
compound 1 to the corresponding secondary amine 3a
OMe
NO2
(98% isolated yield) in the course of 3 h (Table 1, entry 1)
EtO2C
1
(no trace of the tertiary amine could be detected by H
1
NMR).
Acetaldehyde is most likely formed from ethanol via a
similar mechanism to the one recently proposed by Sajiki
et al. to explain the formation of ketones (in some cases
in high yield) from secondary alcohols when treated with
hydrogen in D2O at elevated temperature over Pd/C
(Scheme 2).14
H2, Pd/C (10%),
EtOH, rt, 48 h
OMe
OMe
+
EtO2C
EtO2C
NH2
NHEt
2 47%
3a 41%
Based on our investigation post these initial results it
seems that in the case of ethanol the equilibrium is located
far to the left. However, due to the presence of the primary
amine, which removes the aldehyde from the reaction mix-
ture forming the corresponding imine, and eventually the
secondary amine after reduction, and the prolonged reaction
Scheme 1. Initial finding.
Indeed, when a control experiment was performed where
1.1 equiv of acetaldehyde was added to the reaction
mixture from the start, it resulted in quick conversion of
Table 1
Reductive monoalkylation of nitro aryls
Entry
1
Starting material
Aldehyde (equiv)
Time (h)
3
Product
Isolated yielda (%)
98
OMe
NHR
1a
CH3CHO (ca. 1.1)b
3a, R = Et
EtO2C
2
3
1a
1a
HCHO (1.0)c
CH3CH2CHO (1.6)
3
4
3b, R = Me
3c, R = n-Pr
61d
95
OMe
OMe
4
CH3CHO (ca. 1.7)b
6
99
EtO2C
NHEt
EtO2C
HO2C
NO2
1b
1c
3d
OMe
NO2
OMe
5
6
7
8
9
CH3CHO (ca. 1.6)b
CH3CHO (ca. 1.1)b
CH3CHO (ca. 1.6)b
CH3CH2CHO (1.6)
CH3CHO (ca. 1.1)b
CH3CH2CHO (1.6)
16
7
90
84
96
99
79
87
HO2C
NHEt
3e
F
F
EtO2C
OMe
NO2
EtO2C
NHEt
3f
1d
OMe
8
3g, R = Et
NO2
NHR
1e
1e
6.5
5
3h, R = n-Pr
MeO
MeO
3i, R = Et
NO2
NHR
1f
10
1f
6.5
3j, R = n-Pr
a
All compounds had characterization data consistent with the assigned structure.
Acetaldehyde is supplied as a ca. 2% solution in DMF.
Formaldehyde solution was used (37 wt % in water).
Ethyl-(3-dimethylamino-4-methoxyphenyl)acetate (4) (16%) and ethyl-(3-amino-4-methoxyphenyl)acetate (2)12 (17%) were also isolated.
b
c
d

M. O. Sydnes, M. Isobe / Tetrahedron Letters 49 (2008) 1199–1202
1201
Pd
R
H
one-pot
1) H2,1.33 h
2) formaldehyde solution, 2.5 h
3) H2, 15 min
OH
O
O
Pd
R
H Pd H
R
OMe
oxidative
addition
β-hydride
1
EtO2C
Pd/C (10%), EtOH, rt
elimination
NHMe
3b 99%
Scheme 2. Mechanism proposed by Sajiki et al.14 for the formation of
ketones from secondary alcohols under an atmosphere of H2 in the
presence of Pd/C (10%).
Scheme 3. Optimized reaction conditions for the formation of compound
3b.
time results in the formation of the secondary amine in rea-
sonable yield after 48 h. It should be noted that primary
amine 2 is formed cleanly with no traces of compound 3a
being detected as evident by crude 1H NMR analysis, when
the reaction is conducted for 1 h under the same conditions
as given in Scheme 1 (the reaction is normally complete after
1 h) or when 10% water is added to the reaction mixture.
The fact that the secondary amine was formed in these
reactions without a trace of the corresponding tertiary
amine was intriguing and bears the potential to be a useful
method for the direct conversion of nitro aryls to second-
ary alkyl amino aryls. To test this theory we treated a range
of nitro aryls in ethanol in the presence of various alde-
hydes (1.0–1.7 equiv) under an atmosphere of hydrogen
gas (balloon) over Pd/C (10%) (3–5 mol %) (see Table
1).15 Under these conditions the corresponding secondary
amines could mostly be isolated in high yield and excellent
purity after a simple purification, which in many cases only
consisted of filtration through a pad of CeliteÒ (see Supple-
mentary data for details). For reactions that were proceed-
ing slowly an excess of the aldehyde was applied in order
for the reaction to go to completion. These conditions also
worked well for the conversion of the nitro aryl to the
corresponding secondary aryl ethyl amine, even in the case
when the nitro aryl possessed a free acid group (Table 1,
entry 5).
an atmosphere of hydrogen for 15 min (Scheme 3).16 Under
these conditions nitro aryl 1a could be converted to the sec-
ondary amine 3b in 99% yield.
In summary, we have developed a simple one-pot proce-
dure for the conversion of nitro aryls to the corresponding
secondary amines using aldehydes as alkyl source and
hydrogen over Pd/C as reducing agent.
Acknowledgements
The authors would like to acknowledge financial sup-
port from Grant-in-Aid for Specially Promoted Research
(16002007) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan, the Inoue
Foundation for Science (MOS, July 2006–June 2007) and
JSPS (MOS, July 2007–June 2009). We thank Dr. M. Kuse
for MS analysis.
Supplementary data
Supplementary data (isolation procedures for all com-
pounds and characterization data for all new compounds)
associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2007.12.030.
All examples, but one, only gave the secondary amine as
the sole isolable amine from these reactions, even when
close to two equivalents of the aldehyde was used. The
exception occurred when formaldehyde was used as the
alkylation agent. In this case the amount of formaldehyde
had to be restricted to one equivalent to diminish the
formation of the corresponding tertiary amine, viz. ethyl-
(3-dimethylamino-4-methoxyphenyl)acetate (4). By such
means the secondary amine 2b could be isolated in 61%
yield after purification by flash chromatography (Table 1,
entry 2), however, the yield of compound 2b could be fur-
ther improved by altering the reaction conditions slightly.
As alluded to, the yield of amine 3b could be dramati-
cally improved by slightly changing the reaction condi-
tions. The conditions implemented conducting the initial
reduction reaction with hydrogen over Pd/C (10%) without
formaldehyde present in the reaction mixture. Formalde-
hyde was then added once the primary amine was formed,
and the resulting reaction mixture was then stirred under
an atmosphere of air at room temperature until the imine
formation had reached completion. Finally, the resulting
imine was reduced by stirring the reaction mixture under
References and notes
1. Ono, N. The Nitro Group in Organic Synthesis; Wiley: New York,
2001.
2. Ono, N. In The Nitro Group in Organic Synthesis; Wiley: New York,
2001; pp 170–175.
3. Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57,
7785–7811.
4. Xiaojian, Z.; Zuwang, W.; Li, L.; Guijuan, W.; Jiaping, L. Dyes and
Pigments 1998, 36, 365–371.
5. Bae, J. W.; Cho, Y. J.; Lee, S. H.; Yoon, C.-O. M.; Yoon, C. M.
Chem. Commun. 2000, 1857–1858.
6. Yoon and co-workers later extended the chemistry described in Ref. 5
to the synthesis of tertiary aromatic amines containing two different
alkyl groups, see: Jung, Y. J.; Bae, J. W.; Park, E. S.; Chang, Y. M.;
Yoon, C. M. Tetrahedron 2003, 59, 10331–10338.
7. (a) Sajiki, H.; Ikawa, T.; Hirota, K. Org. Lett. 2004, 6, 4977–4980; (b)
Sajiki, H.; Ikawa, T.; Hirota, K. Org. Process Res. Dev. 2005, 9, 219–
220.
8. (a) Nacario, R.; Kotakonda, S.; Fouchard, D. M. D.; Tillekeratne, L.
M. V.; Hudson, R. A. Org. Lett. 2005, 7, 471–474; (b) Fouchard, D.
M. D.; Tillekeratne, L. M. V.; Hudson, R. A. Synthesis 2005, 17–18.
9. Reddy, C. R.; Vijeender, K.; Bhusan, P. B.; Madhavi, P. P.;
Chandrasekhar, S. Tetrahedron Lett. 2007, 48, 2765–2768.
10. Chandrasekhar, S.; Narsihmulu, Ch.; Jagadeshwar, V. Synlett 2002,
771–772.

1202
M. O. Sydnes, M. Isobe / Tetrahedron Letters 49 (2008) 1199–1202
11. Pd/C (10%) used during these experiments was a gift from Kawaken
Fine Chemicals.
12. Sydnes, M. O.; Doi, I.; Ohishi, A.; Kuse, M.; Isobe, M. Chem. Asian
J. 2008, doi:10.1002/asia.200700211.
41.3, 38.1, 14.8, 14.2; MS (EI+) m/z 237 (M+, 88%), 222 (100), 194
(14), 164 (28), 134 (29); HRMS (EI+) found: M+, 237.1347.
C
13H19NO3 requires M+, 237.1365; Anal. found: C, 65.91; H, 8.16;
N, 5.94. C13H19NO3 requires: C, 65.80; H, 8.07; N, 5.90.
13. Ethanol (99.5%) from Wako Pure Chemical Industries, Ltd was used
as solvent for these experiments. According to the analytical data
sheet provided by the company the ethanol contains <0.001% mass/
mass of aldehydes and ketones. This rules out the possibility that
acetaldehyde is present in the solvent as a contaminant in high
quantity from the start of the reaction.
16. Improved synthetic procedure for the synthesis of compound 3b: Pd/C
(10%) (2.9 mg, 2.73 lmol) was added to a stirred solution of nitro aryl
1a (22.7 mg, 0.0949 mmol) in ethanol (1.5 mL). The resulting reaction
mixture was then subjected to three cycles of vacuum followed by flush
with H2 before being stirred vigorously under an atmosphere of H2 for
1.33 h. The H2 atmosphere was then replaced with air and the reaction
mixture was stirred vigorously for 5 min before formaldehyde solution
(8.5 lL of a 37 wt % in water solution, 0.105 mmol) was added. The
resulting reaction mixture was stirred for 2.5 h at room temperature
before being subjected to three cycles of vacuum followed by flush with
H2 before being stirred vigorously under an atmosphere of H2 for
15 min. The crude reaction mixture was subjected to flash chromato-
graphy (silica, hexane/Et2O/Et3N 60:39.95:0.05 elution) and concen-
tration of the relevant fractions (Rf 0.4 in hexane/Et2O 60:40) gave the
desired compound 3b (21.0 mg, 99%) as a light yellow oil. IR mmax
14. Esaki, H.; Ohtaki, R.; Maegawa, T.; Monguchi, Y.; Sajiki, H. J. Org.
Chem. 2007, 72, 2143–2150.
15. General procedure for the reductive monoalkylation of nitro aryls as
exemplified for compound 3a: Pd/C (10%) (4.0 mg, 3.76 lmol) was
added to a stirred solution of nitro aryl 1a (18.3 mg, 0.0765 mmol)
and acetaldehyde (0.20 mL of a ca. 2% solution in DMF, ca.
0.0863 mmol) in ethanol (1.3 mL). The resulting reaction mixture was
then subjected to three cycles of vacuum followed by flush with H2
before being stirred vigorously under an atmosphere of H2 for 3 h.
The resulting reaction mixture was then filtered through a plug of
CeliteÒ and washed afterwards with ethanol. Concentration of the
filtrate gave the desired secondary amine 3a (17.7 mg, 98%) as a light
yellow oil. IR mmax 3411, 2923, 2856, 1730, 1599, 1521, 1439, 1103,
1
3428, 2925, 1732, 1603, 1524, 1262, 1225, 1168, 1029 cmÀ1; H NMR
(CDCl3, 400 MHz) d 6.69 (d, J = 8.0 Hz, 1H), 6.56 (dd, J = 2.0 and
8.0 Hz, 1H), 6.51 (d, J = 2.0 Hz, 1H), 4.22 (br s, 1H), 4.14 (q,
J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.52 (s, 2H), 2.85 (s, 3H), 1.25 (t,
J = 7.2 Hz, 3H); 13C NMR (CDCl3, 101 MHz) d 172.2, 146.0, 139.4,
127.0, 116.7, 110.2, 109.1, 60.6, 55.5, 41.3, 30.3, 14.2; MS (EI+) m/z
223 (M+, 100%), 208 (44), 150 (17), 135 (15); HRMS (EI+) found: M+,
223.1222 C12H17NO3 requires M+, 223.1208; Anal. found: C, 64.55; H,
7.51; N, 6.31. C12H17NO3 requires: C, 64.55; H, 7.67; N, 6.27.
935 cmÀ1 1H NMR (CDCl3, 600 MHz) d 6.68 (d, J = 7.8 Hz, 1H),
;
6.55 (dd, J = 1.8 and 8.1 Hz), 6.52 (d, J = 1.8 Hz, 1H), 4.14 (q,
J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.51 (s, 2H), 3.16 (q, J = 7.2 Hz, 2H),
1.28 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
151 MHz) d 172.2, 145.8, 138.3, 126.9, 116.7, 110.6, 109.2, 60.6, 55.4,