Pd/C-catalyzed reductive mono-N-alkylation of nitrophenol derivatives in one-pot way

Article abstract of DOI:10.1002/cjoc.201090029

A range of different nitrophenol derivatives were converted in one-pot to the corresponding secondary alkyl aminophenols in good to excellent yields by using ketones as alkyl source and hydrogen over 10 wt% Pd/C as reducing agent. In all examples, except for one, the secondary amine was the sole alkylation product isolated. When aldehydes were used as alkyl source, the corresponding tertiary amine as a sole alkylation product was isolated.

Full text of DOI:10.1002/cjoc.201090029

Communication
Pd/C-catalyzed Reductive Mono-N-alkylation of Nitrophenol
Derivatives in One-pot Way
JIN, Zhonghao(金中豪)
LI, Dao(李到)
WANG, Xingyi*(王幸宜)
LU, Guanzhong*(卢冠忠)
Laboratory for Advanced Materials, Research Institute of Industrial Catalysis, East China University of Science
and Technology, Shanghai 200237, China
A range of different nitrophenol derivatives were converted in one-pot to the corresponding secondary alkyl
aminophenols in good to excellent yields by using ketones as alkyl source and hydrogen over 10 wt% Pd/C as re-
ducing agent. In all examples, except for one, the secondary amine was the sole alkylation product isolated. When
aldehydes were used as alkyl source, the corresponding tertiary amine as a sole alkylation product was isolated.
Keywords one-pot, reductive mono-N-alkylation, nitrophenol, secondary alkyl aminophenol, Pd/C
Introduction
little attention has been paid to the synthesis of
mono-N-alkylated aminophenols. Herein, we report an
efficient, feasible reductive mono-N-alkylation of ni-
trophenol derivatives with ketones under hydrogen at-
mosphere over 10 wt% Pd/C.
N-Alkyl-aminophenol derivatives with unique bio-
logical properties are essential precursors to a variety of
biologically or pharmacologically active compounds.1
Traditional base-promoted direct N-alkylation of
aminophenols with halo-alkanes is undesirable because
of toxic and corrosive halo-containing chemicals related
to environmental concerns.2 Pd-catalyzed N-alkylation
of aminophenol derivatives by allyl acetate and allyl
alcohol gives a mixture of corresponding secondary and
tertiary aminophenols, which is troublesome to handle.3
Additionally, an inert atmosphere is prerequisite to
avoid some irreversible decomposition of aminophenols
which are usually air-sensitive. Therefore, direct con-
version of nitrophenols to mono-N-alkylated amino-
phenols in a one-pot way would become an important
alternative due to environmental and economical con-
cerns.
Catalytic reductive mono-N-alkylation of amine de-
rivatives in the presence of different carbonyl com-
pounds is one of the most attractive methods for the
synthesis of secondary amine derivatives. There have
been a few reports describing the one-pot reductive
mono-N-alkylation of aromatic nitro compounds. Byun
et al. reported a one-pot method of direct nitro-
reduction of nitroarene derivatives over Pd/C via reduc-
tive mono-N-alkylation using aldehydes and ammonium
formate as in situ hydrogen donor.4 Similarly, reductive
mono-N-alkylation of nitro-arenes with aldehydes can
be carried out in the presence of hydrogen over Pd/C
catalyst.5 Nitrobenzene derivatives can react with
α-ketoester to form the N-alkylated aniline.6 However,
Results and discussion
At first, we chose acetone as alkylating reagent to
investigate the efficiency of the reductive
mono-N-alkylation of nitrophenol in a 1∶1∶1 (V/V/V)
acetone/2-propanol/water mixture at 70 ℃ and 2.0
MPa hydrogen pressure on 10 wt% Pd/C (Table 1).
2-Nitrophenol, 3-nitrophenol, 4-nitrophenol and
2,4-dinitrophenol could be converted to the corre-
sponding mono-N-alkylated products in excellent yields
(Table 1, Entries 1—4). All examples only gave the
secondary amine as the sole isolable amine from these
reactions, although the amount of acetone was much
larger than the equivalent amount of substrate.
In the case of 2-chloro-4,6-dinitroresorcinol, dechlo-
rination was also observed (Table 1, Entry 5). It pro-
vided an interesting one-pot procedure to synthesize
4,6-bis(isopropylamino)resorcinol with a high yield of
91% through a domino sequence including reduction of
nitro groups, hydrodechlorination, and the following
reductive N-alkylation of 4,6-diaminoresorcinol, and the
starting material 2-chloro-4,6-dinitroresorcinol is
readily available on a large scale at low cost from
1
1,2,3-trichlorobenzene (Table 1, Entry 5).8 By H NMR
(D2O) analysis of the product, it was found that the
N-alkylation was the single product with no traces of
aminophenol compounds. Because halogen on aromatic
*
E-mail: wangxy@ecust.edu.cn; gzhlu@ecust.edu.cn; Tel./Fax: 0086-021-64253372
Received June 10, 2009; revised July 29, 2009; accepted September 8, 2009.
Project supported by the National Basic Research Program of China (Nos. 20977029 and 2010CB732300) and the Commission of Science and
Technology of Shanghai Municipality (No. 0852nm00900nm).
16
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Chin. J. Chem. 2010, 28, 16— 20

Pd/C-catalyzed Reductive Mono-N-alkylation of Nitrophenol Derivatives
ring can determine the selectivity of nitration, this
three-step reaction in one-pot is significant for synthesis
of some special mono-N-alkylated aminophenols from
facile halo-aromatics raw materials.
hydes as alkylating reagent (Table 2, Entries 4, 5), the
N,N-dialkylated products were isolated. These different
results between ketone and aldehyde probably stem
from the different imine intermediates as outlined in
Scheme 1. In the ketone case, the iminium ion interme-
diate A would be not formed presumably because of the
hindrance of secondary alkyl group. However, it would
be suitable for the aldehyde to form the iminium ion
intermediate B, which can be further transformed into
the N,N-dialkylated product.
With other various alkylating reagents, the reductive
N-alkylation of 2-nitrophenol was also operated under
the same reaction conditions (Table 2). In the presence
of different ketones, the corresponding mono-N-alkyl-
ated compounds as the sole product were obtained in
high yields (Table 2, Entries 1—3). In the case of alde-
Table 1 Reductive N-alkylation of nitrophenol derivatives with acetonea
Entry
Substrate
Time/min
Product
Yieldc/%
97
1
90
2
150
96
3
150
90
96
90
91
4b
5b
90
a All reactions were carried out with 0.10 mol for 1a—3a and 0.05 mol for 4a—5a of nitrophenol derivatives in 240 mL of 1∶1∶1
b
(V/V/V) acetone/2-propanol/water mixture at 70 ℃ and 2.0 MPa hydrogen pressure on 2.0 g 10 wt% Pd/C for different time. 20 mL
acetic acid was added into the reaction mass. c Isolated yields.
Scheme 1 Presumed reaction mechanism of the synthesis of 2-(isopropylamino)phenol and 2-(dipropylamino)phenol
Chin. J. Chem. 2010, 28, 16— 20
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17

Jin et al.
Communication
Table 2 Results of catalytic reductive N-alkylation of 1a with various alkylating reagentsa
Entry
1
Alkylating reagent
Time/min
Product
Yieldc/%
90
97
92
87
85
94
28
2
3
90
90
4
90
5
90
6b
600
a All reactions were carried out with 0.10 mol of 1a in 240 mL of 1∶1∶1 (V/V/V) alkylating reagent/2-propanol/water mixture at 70 ℃
and 2.0 MPa hydrogen pressure using 2.0 g of 10 wt% Pd/C for 90 min. b The reaction was carried out with 0.10 mol of 1a and 0.12 mol
of pyruvic acid in 240 mL of 4∶1 (V/V) 2-propanol/water mixture at 30 ℃ and 1.0 MPa hydrogen pressure using 2.0 g of 10 wt% Pd/C
for 600 min. c Isolated yields.
The traditional method of synthesizing 3-methyl-
benzomorpholone, an effective blocking group of the
blocked photographic agent,9 is complicated and
multi-step. Methyl pyruvate must be used directly to
form the intermediate of 3-alkyl-2H-benzo-[1,4]-
oxazin-2-one,10 which then can be reduced to 3-methyl-
benzomorpholone. In our experiments, 3-methyl-ben-
zomorpholone was prepared by the reductive
N-alkylation and lactonization of 2-nitrophenol with
pyruvic acid in a one-pot way (Table 2, Entry 6), but the
yield was relatively low. 2-Aminophenol was detected
with a significant amount, indicating that the condensa-
tion between amino group of 2-aminophenol and the
carbonyl compound of pyruvic acid was extremely slow
under a relatively low reaction temperature.
N,N-Dialkylation was also observed with aldehyde as
alkylating reagent. Besides, this protocol has been ex-
perimented in the one-pot procedure of domino reaction
with hydrodechlorination and lactonization to synthe-
size 4,6-bis(isopropylamino)resorcinol and 3-methyl-
benzomorpholone innovatively.
Experimental
The catalyst was prepared by an impregnation-
deposition method and active carbon was used as sup-
port. The 2.4 g of 20 wt% aqueous PdCl2 solution was
added to a suspension of 28.0 g of the active carbon in
300 mL of deionized water and the mixture stirred at 80
℃ for 1.5 h. 80 mL of 37 wt% formaldehyde aqueous
solution whose pH value was controlled at 8.5 by so-
dium bicarbonate was added to reduce Pd. After filtra-
tion, the sample was washed with deionized water until
no chloride ions could be detected with AgNO3 solu-
In summary, we have established an efficient, feasi-
ble procedure for the conversion of nitrophenols to
N-alkyl secondary aminophenols with ketones using
hydrogen over 10 wt% Pd/C in a one-pot way.
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Pd/C-catalyzed Reductive Mono-N-alkylation of Nitrophenol Derivatives
tion, dried at 80 ℃ overnight to get 10 wt% Pd/C
catalyst. Other reagents and solvents were obtained
from commercial source and used without further puri-
fication. All NMR spectra were recorded on a BRUKER
AVANCE 500 (500 MHz) spectrometer, and chemical
shifts were expressed as δ values using tetramethylsi-
with AcOEt-petroleum (V/V, 1∶5) as eluent to afford
1
product 2b in 96% yield as pale yellow crystal. H
NMR (CDCl3, 500 MHz) δ: 6.99—6.93 (m, 1H), 6.16—
6.02 (m, 3H), 3.54—3.48 (m, 1H), 1.14 (d, J＝6.3 Hz,
6H); 13C NMR (CDCl3, 126 MHz) δ: 157.4, 149.6,
130.9, 107.3, 105.1, 101.1, 45.1, 23.6; HRMS (EI＋)
＋
1
•
lane (δ 0.00) as an internal standard for H NMR and
calcd for C9H13NO (M ) 151.0997, found 151.0998.
4-(Isopropylamino)phenol (3b) 200 mL of satu-
rated Na2CO3 aqueous solution was added to 3b hydro-
chloride salt to make the solution alkaline. The aqueous
layer was extracted with dichloromethane, and the crude
product was chromatographed on a column of silica gel
with AcOEt-petroleum (V/V, 1∶5) as eluent to afford
residual chloroform (δ 77.0) as an internal standard for
carbon (13C) NMR. HRMS data were obtained on a Mi-
cromass GCTTM spectrometer.
General procedure for Table 1
The 10 wt% Pd/C (2.0 g, 1.89 mmol) was added to a
stirred solution of nitrophenol derivative (1a— 3a, 0.1
mol; 4a— 5a, 0.05 mol) and 240 mL of 1∶1∶1 (V/V/V)
acetone/2-propanol/water mixture in an autoclave (0.5 L)
with a mechanical stirrer. The resulting reaction mixture
was then subjected to three cycles of vacuum followed
by flush with hydrogen gas before being stirred vigor-
ously at 1300 r/min under a hydrogen pressure of 2.0
MPa and heated up to 70 ℃ at which the reaction was
carried out for different time. The catalyst was removed
from the reaction mixture by filtration and 10 mL of 36
wt% HCl aqueous solution was added into the filtration
liquor. Acetone, 2-propanol and water were removed
from the reaction mixture by a rotary evaporator, and
the remains were the desired N-alkyl secondary amino-
phenol (1b— 5b) hydrochloride salt.
1
product 3b in 96% yield as pale yellow crystal. H
NMR (CDCl3, 500 MHz) δ: 6.71—6.67 (m, 2H), 6.54—
6.51 (m, 2H), 3.56—3.50 (m, 1H), 1.18 (d, J＝6.3 Hz,
6H); 13C NMR (CDCl3, 126 MHz) δ: 147.5, 141.8,
116.2, 115.2＋, 45.4, 23.1; HRMS (EI ＋ ) calcd for
•
C9H13NO (M ) 151.0997, found 151.0997.
2,4-Bis(isopropylamino)phenol (4b) 20 mL of
acetic acid was added in the mixture. Compound 4b
hydrochloride salt was obtained in 90% yield as white
1
crystal. H NMR (D2O, 500 MHz) δ: 7.38—7.35 (m,
2H), 7.17—7.14 (m, 1H), 3.84—3.80 (m, 1H), 3.71—
3.67 (m, 1H), 1.27 (d,＋J＝6.5 Hz, 6H), 1.23 (d, J＝6.5
＋
•
Hz, 6H); HRMS (EI ) calcd for C12H20N2O (M )
208.1531, found 208.1532.
4,6-Bis(isopropylamino)resorcinol (5b) 20 mL of
acetic acid was added in the mixture. Compound 5b
hydrochloride salt was obtained in 91% yield as white
General procedure for Table 2
1
The 10 wt% Pd/C catalyst (2.0 g, 1.89 mmol) was
added to a stirred solution of 2-nitrophenol 1a (13.9 g,
0.1 mol), 240 mL of 1∶1∶1 (V/V/V) alkylating re-
agent/2-propanol/water mixture in an autoclave (0.5 L)
with a mechanical stirrer. The resulting reaction mixture
was then subjected to three cycles of vacuum followed
by flush with hydrogen gas before being stirred vigor-
ously at 1300 r/min under a hydrogen pressure of 1.0
MPa and heated up to 30 ℃, at which the reaction was
carried out for 10 h. The catalyst was removed by filtra-
tion and 10 mL of 36 wt% HCl aqueous solution was
added into the filtration liquor. Solvents were removed
from the reaction mixture by a rotary evaporator, and
the remains were the desired N-alkyl secondary amino-
phenol (1b— 1g) hydrochloride salt.
crystal. H NMR (D2O, 500 MHz) δ: 7.28 (s, 1H), 6.69
(s, 1H), 3.79—3.75 (m, 2H), 1.28 (d, J＝6.6 Hz, 12H);
13C NMR (D2O, 126 MHz) δ: 152.5, 120.9, 113.1, 104.6,
＋
＋
•
55.3, 18.1; HRMS (EI ) calcd for C12H20N2O2 (M )
224.1525, found 224.1527.
2-(sec-Butylamino)phenol (1c)
Compound 1c
hydrochloride salt was obtained in 92% yield as white
1
crystal. H NMR (D2O, 500 MHz) δ: 7.39—7.31 (m,
2H), 7.08—6.99 (m, 2H), 3.63—3.59 (m, 1H), 1.82—
1.78 (m, 1H), 1.62—1.58 (m, 1H), 1.27 (d, J＝6.6 Hz,
3H), 0.95 (t, J＝7.5 Hz, 3H); 13C NMR (D2O, 126 MHz)
δ: 151.5, 132.6, 126.1, 126.2, 122.2, 122.0, 118.4, 61.＋6,
＋
•
26.9, 16.5, 10.5; HRMS (EI ) calcd for C10H15NO (M )
165.1154, found 165.1155.
2-(Cyclohexylamino)phenol (1d) Compound 1d
hydrochloride salt was obtained in 87% yield as white
2-(Isopropylamino)phenol (1b) Compound 1b
hydrochloride salt was obtained in 97% yield as white
1
crystal. H NMR (D2O, 500 MHz) δ: 7.40—7.29 (m,
1
crystal. H NMR (D2O, 500 MHz) δ: 7.32—7.23 (m,
2H), 7.09—7.00 (m, 2H), 3.51—3.47 (m, 1H), 2.01—
1.12 (m, 10H); 13C NMR (D2O, 126 MHz) δ: 151.5,
132.6, 126.＋1, 122.0, 118.4, 62.7, 30.3, 25.9, 25.4;
HRMS (EI ) calcd for C12H17NO (M＋ •) 191.1310,
found 191.1311.
2H), 7.01—6.92 (m, 2H), 3.75—3.71 (m, 1H), 1.25 (d,
J＝6.6 Hz, 6H); 13C NMR (D2O, 126 MHz) δ: 151.1,
132＋.2, 125.7, 121.7, 121.6, 118.0, 56.1, 19.2; HRMS
(EI ) calcd for C9H13NO (M ＋ •) 151.0997, found
151.0997.
2-(Dimethylamino)phenol (1e) 200 mL of satu-
rated Na2CO3 aqueous solution was added to 1e hydro-
chloride salt to make the solution alkaline. The aqueous
layer was extracted with dichloromethane, and the crude
product was chromatographed on a column of silica gel
with AcOEt-petroleum (V/V, 1∶200) as eluent to afford
3-(Isopropylamino)phenol (2b) 200 mL of satu-
rated Na2CO3 aqueous solution was added to 2b hydro-
chloride salt to make the solution alkaline. The aqueous
layer was extracted with dichloromethane, and the crude
product was chromatographed on a column of silica gel
Chin. J. Chem. 2010, 28, 16— 20
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19

Jin et al.
Communication
product 1e in 85% yield as pale yellow crystal. 1H NMR
(CDCl3, 500 MHz) δ: 7.17—7.14 (m, 1H), 7.07—7.03
(m, 1H), 6.95—6.92 (m, 1H), 6.87—6.82 (m, 1H), 2.64
(s, 6H); 13C NMR (CDCl3, 126 MHz) δ: 152.0, 141.2,
126.5, 121.2,＋120.6, 114.7, 45.7; HRMS (EI＋) calcd for
silica gel with AcOEt-petroleum (V/V, 1∶5) as eluent
to afford product 1g in 28% yield (Table 2, Entry 6). 1H
NMR (CDCl3, 400 MHz) δ: 9.10 (br, 1H), 7.12—6.96
(m, 4H), 3.92 (q, J＝7.2 Hz, 1H), 1.67 (d, J＝7.2 Hz,
3H).10c
•
C8H11NO (M ) 137.0841, found 137.0842.
2-(Diproylamino)phenol (1f) 200 mL of saturated
Na2CO3 aqueous solution was added to 1f hydrochloride
salt to make the solution alkaline. The aqueous layer
was extracted with dichloromethane, and the crude
product was chromatographed on a column of silica gel
with AcOEt-petroleum (V/V, 1∶200) as eluent to afford
product 1f in 94% yield as pale yellow crystal. 1H NMR
(CDCl3, 400 MHz) δ: 6.98—6.95 (m, 1H), 6.90—6.85
(m, 1H), 6.79—6.76 (m, 1H), 6.68—6.63 (m, 1H), 2.65
(t, J＝7.6 Hz, 4H), 1.21 (sex, J＝7.6 Hz, 4H), 0.69 (t,
J＝7.6 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ: 153.6,
137.1, 126.＋2, 122.8, 119.5, 113.3, 58.0, 20.7, 11.4;
HRMS (EI ) calcd for C12H19NO (M＋ •) 193.1467,
found 193.1468.
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