An efficient and practical method for highly chemoselective hydrogenation of nitrobenzylamines to aminobenzylamine hydrochlorides

Article abstract of DOI:10.1002/adsc.200600521

Aqueous hydrochloric acid proved to be a very reliable modulator for adjusting the reactivity of palladium on carbon. Thus an efficient and practical method for the highly chemoselective hydrogenation of N,N- dialkylnitrobenzylamines to amino-N,N-dialkylbenzylamine hydrochlorides was established. The method features convenient performance, easy work-up and high efficiency

Full text of DOI:10.1002/adsc.200600521

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DOI: 10.1002/adsc.200600521
An Efficient and Practical Method for Highly Chemoselective
Hydrogenation of Nitrobenzylamines to Aminobenzylamine
Hydrochlorides
Chuanjie Cheng,a Xinyan Wang,a Lixin Xing,a Bo Liu,a Rui Zhu,a and Yuefei Hua,*
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, Peopleꢀs Republic of China
Phone: (+86)-10-6279-5380; fax: (+86)-10-6277-1149; e-mail: yfh@mail.tsinghua.edu.cn
Received: October 11, 2006; Revised: March 15, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Aqueous hydrochloric acid proved to be a The method features convenient performance, easy
very reliable modulator for adjusting the reactivity work-upand high efficiency.
of palladium on carbon. Thus an efficient and practi-
cal method for the highly chemoselective hydrogena-
tion of N,N-dialkylnitrobenzylamines to amino-N,N- Keywords: amines; chemoselectivity; hydrogenation;
dialkylbenzylamine hydrochlorides was established. palladium; reduction
Introduction
methyl-2H-pyran-4-amine (2c) was recognized as both
a key pharmacophore and an intermediate for the
Palladium-catalyzed chemoselective hydrogenations synthesis of TAK-779. As shown in Scheme 1, com-
have played an important role in modern organic syn- pound 2c was prepared smoothly by a chemoselective
thesis, such as the well-known Rosenmund reduction reduction of N-[(4-nitrophenyl)methyl]tetrahydro-N-
and Lindlar reduction. Palladium on carbon (Pd-C) is methyl-2H-pyran-4-amine (1c) with a stoichiometric
a commercially available catalyst featured by a low amount of SnCl2 in aqueous HCl and was then con-
price and easy regeneration. Pd-C-catalyzed hydroge- verted into 2c·2HCl for easy purification. Unfortu-
nations have been widely employed in numerous or- nately, the Pd-C- or Raney-Ni-catalyzed hydrogena-
ganic transformations with high efficiency in both aca- tion of 1c was non-selective and led to hydrogeno-
demic and industrial laboratories. Prominent among lyzed products 3 and 4c.[3a,b]
them are the catalytic hydrogenation of aromatic
nitro groups[1] and the catalytic hydrogenolysis of
N,N-dialkylbenzylamines.[2] Since these two transfor-
mations occur under very similar conditions (room
temperature and atmospheric hydrogen pressure), low
chemoselectivity was observed between them.[3] In
fact, no general and practical protocol by catalytic hy-
drogenation exists for this purpose to date, even
though many efforts have been made to developche-
moselective Pd-C-catalyzed hydrogenations.[4]
In past decades, amino-N,N-dialkylbenzylamines
(2) have been gaining increasing importance in medic-
inal chemistry and organic chemistry.[3,5,6] The most
convenient preparations of them are the chemoselec-
tive reduction of the corresponding N,N-dialkylnitro-
benzylamines (1). For example, TAK-779 was report-
ed as the first small-molecule, non-peptide CCR5 an-
tagonist with highly potent and selective anti-HIV-1
Scheme 1. Conditions: i) SnCl2, aqueous HCl, 20–408C, 1 h;
ii) aqueous HCl, i-PrOH; iii) Pd-C or Raney-Ni, H2, room
activity.[7] N-[(4-Aminophenyl)methyl]tetrahydro-N- temperature.
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Table 1. Effect of the size of substituents on the chemoselec-
tivity.
In our research project on the chemical biology, a
series of amino-N,N-dialkylbenzylamines (2) deriva-
tives was chosen as synthetic targets. The literature
shows that the most reliable methods for the chemo-
selective transformation of 1 to 2, in practice, are
those using reducing metals in acidic media, such as
Fe, Sn or SnCl2 in aqueous HCl.[3,6] But, these meth-
ods are unavoidably associated with tedious work-ups
and release of a large amount of hazardous wastes to
the environment. Therefore, there is a great need to
find a chemoselective catalytic hydrogenation method
as an alternative. We report herein a novel method to
accomplish this goal, which is characterized by adding
a suitable amount of aqueous HCl to the conventional
Pd-C-catalyzed system in MeOH. The method fea-
tures convenient performance, easy work-up and high
efficiency.
1, 2, 4
R
R1
2·2HCl [%] 3·HCl [%] 4·HCl [%]
a
b
c
Me Me
Et Et
Me 4-THP 19
i-Pr i-Pr
97
85
3
3
15
81
100
15
81
100
d
0
Results and Discussion
amine (Table 1). When 1c was employed as a sub-
It is well known that: (1) the hydrogenation ability of strate, the undesired hydrogenolyzed products were
the Pd-C catalyst is enhanced by a catalytic amount obtained in 81% yields.
of HCl, but retarded with an excess amount of HCl
Control experiments proved that the undesired hy-
(over 1 equivalent) due to the unproductive occupa- drogenolyzed products were produced totally in the
tion of Pd-C catalytic sites by HCl molecules.[8] (2) first 5 min of the hydrogenation. During that period,
The Pd-C-catalyzed hydrogenation of nitrobenzene in just a small amount of HCl was released from the
the presence of CHCl3 produced aniline hydrochlo- dechlorohydrogenation of CHCl3. Thus, HCl actually
ride in excellent yields, in which the hydrochloride enhanced rather than weakened the catalytic ability
came from the Pd-C-catalyzed hydrodechlorination of of the Pd-C catalyst.
CHCl3.[9] These results strongly imply that the Pd-C-
Many attempts have been made to avoid the hydro-
catalyzed hydrogenation of N,N-dialkylnitrobenzyla- genolysis occurring at the beginning of the hydroge-
mines (1) in the presence of CHCl3 could be a possi- nation. By using compound 1c as a model substrate,
ble method to chemoselectively obtain amino-N,N-di- we observed that the addition of anhydrous HCl
alkylbenzylamines (2·2HCl), because the catalytic made the catalyst lose its reactivity completely, while
ability of the Pd-C catalyst will be certainly retarded HOAc and TFA accelerated the hydrogenolysis of 1c
by the HCl produced from the dehydrochlorination of significantly. Luckily, when a few drops of concentrat-
CHCl3.
ed aqueous HCl were added to the hydrogenation
As was expected, when N,N-dimethyl-4-nitroben- system, the chemoselectivity for the conversion of 1c
zylamine (1a) was hydrogenated with Pd-C catalyst to 2c·2HCl was significantly improved to 78%. When
under 1 atmosphere hydrogen pressure at room tem- CHCl3 was replaced completely by the same amount
perature for 2 h in the presence of CHCl3 (2 mL), the of concentrated aqueous HCl (2 mL), the hydrogena-
desired 4-amino-N,N-dimethylbenzylamine dihydro- tion finished within 12 min and gave 2c·2HCl as the
chloride (2a·2HCl) was obtained as white crystals in single product in almost quantitative yield
97% yield. Only a 3% yield of hydrogenolyzed prod- (Scheme 2).
ucts 3·HCl and 4a·HCl were detected. Unfortunately,
We found that water is essential to control the cata-
the chemoselectivity of this method sharply decreased lytic ability of Pd-C catalyst when HCl was used as an
with increasing size of the substituents on the benzyl- inhibitor. For example, when anhydrous HCl (2.5
Scheme 2.
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Highly Chemoselective Hydrogenation of Nitrobenzylamines
FULL PAPERS
equivalents) was used in the Scheme 2, no hydrogena- and 6. The excellent chemoselectivity was obtained
tion occurred in 30 min. However, the hydrogenation even with 20 wt% of Pd-C catalyst, while a satisfacto-
finished within 15 min to give 2c·2HCl in 99% yield ry hydrogenation speed was maintained by using 5
after 1.0 mL of H2O was added. Thus, we supposed wt% Pd-C catalyst.
that the occupation of Pd-C catalytic sites by HCl in
As shown in Table 3, a wide range of concentra-
the presence of H2O may be a reversible process. tions of aqueous HCl can be used in the reaction.
Therefore, the catalytic ability of Pd-C catalyst with However, a dilute solution of aqueous HCl made the
aqueous HCl is partially weakened to enable reduc- formation of the hydrochloride salt difficult because
tion of the aromatic nitro group, while the N,N-di- more water was brought into the reaction system (en-
alkylbenzylamine stays intact under these conditions.
Further experiments proved that at least 2.5 equiva-
lents of aqueous HCl were required to guarantee the
chemoselectivity (entry 3 in Table 2). Two equivalents
of aqueous HCl are necessary for the formation of
the product 2c·2HCl and 0.5 equivalents of aqueous
HCl are enough to maintain the reactivity of Pd-C
catalyst. The chemoselectivity is so good that the the-
oretical amount of hydrogen was absorbed exactly
even with prolonged reaction time. More than 2.5
equivalents of aqueous HCl proved to have no nega-
tive effect (entry 4). However, less than 2.0 equiva-
lents of aqueous HCl not only led to a cloudy end-
point of the hydrogenation (entry 1), but also dramat-
ically affected the chemoselectivity with extended re-
action time (entry 2). Clearly, these problems must
have occurred at the end of the hydrogenation be-
cause two equivalents of aqueous HCl were complete-
tries 2 and 3).
Table 3. Effect of concentration of aqueous HCl on the chemo-
selective hydrogenation of 1c.[a]
Entry Concentration Volume Time 2c·2HCl 3·HCl 4c·HCl
of aqueous
HCl [%]
[mL]
[min] [%][b]
[%][b] [%][b]
1
2
3
37
18.5
9.25
0.63
1.25
2.50
12
10
10
99
98
98
0
0
0
0
0
0
[a]
2.5 mmol of 1c and 10% Pd-C (10 wt%) were used in
MeOH at room temperature and 1 atmosphere pressure of
H2.
[b]
Isolated yields are given.
To generalize this highly chemoselective protocol,
ly captured as product 2c·2HCl was formed. Thus, the different N,N-dialkylnitrobenzylamines (1a–l) were
Pd-C catalyst was re-activated to lead to hydrogenoly- tested. As shown in Table 4, they all gave the corre-
sis of the products. The effects of the amount of Pd-C sponding amine hydrochlorides (2a–l·nHCl) as single
catalyst on the hydrogenation are shown in entries 5 products in excellent yields. The hydrogenation of
substrates with acyclic amines (1a–f) normally was
completed within a few minutes, while those with
cyclic amines (1g–i) took a little longer. Substrates
1g–i were reported to be converted into 2g–i in 43%,
75% and 1.9% yields, respectively, in conventional
Pd-C catalyzed hydrogenations.[3c] However, they
were obtained as 2g–i·2HCl using our protocol in
97%, 95% and 96% isolated yields, respectively. This
method is so efficient that the bulky N,N-dicyclohex-
ylbenzylamine (1f) also gave 2f·2HCl in excellent
chemoselectivity and yield. When 1k was employed as
the substrate and 3.5 equivalents of aqueous HCl
were used, the corresponding trihydrochloride
2k·3HCl (Figure 1) was obtained smoothly. It is note-
worthy that 2l·4HCl (Figure 1), which could be an at-
tractive dendrimeric core molecule, was obtained
from 1l in excellent yield under extremely convenient
conditions.
Table 2. Effect of amount of aqueous HCl on the chemose-
lective hydrogenation of 1c.[a]
Entry 10%
Pd-C
aq. HCl[b] Time[c] 2c·2
[mol equiv] [min] HCl
[%][d]
3·HCl 4c·HCl
[%][d] [%][d]
[wt%]
1
2
3
4
5
6
10
10
10
10
20
5
2.0
2.0
2.5
5.0
2.5
2.5
9
83
50
99
99
99
99
16
49
0
16
49
0
(+10)
9
(+60)
12
(+60)
12
(+60)
5
0
0
0
0
(+30)
15
0
0
To explore the chemoselectivity of this method
with other functional groups, the mixture of 1c with
chlorobenzene, bromobenzene or octadec-1-ene was
hydrogenated (Scheme 3). As a result, highly chemo-
selectivity between the aryl nitro groupand the chloro-
benzene was observed. The chlorobenzene was re-
covered in quantitative yield while 2c·2HCl was ob-
tained in 98% yield. Unfortunately, the method had
(+30)
[a]
Hydrogenation was performed in MeOH at room tem-
perature and 1 atmosphere pressure of H2.
37% aqueous HCl was used.
The number in parenthesis is the extended time after the
absorption of the theoretical amount of hydrogen.
Isolated yields are given and the ratios were determined
by 1H NMR.
[b]
[c]
[d]
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Table 4. Chemoselective hydrogenation of N,N-dialkylnitrobenzylamines (1a–j).
[a]
2.5 mmol of 1c and 10% Pd-C (10 wt%) were used in MeOH at room temperature and 1 atmosphere pressure of H2.
Isolated yields are given.[a] Isolated as 2c, see ref.[3a]
[b]
[b]
Isolated as 2g, 2h and 2i, see ref.[3c]
no chemoselectivity between an aryl nitro groupand
aryl bromobenzene or octadec-1-ene, which was hy-
drogenated completely to give the corresponding ben-
zene or octadecane.
Conclusions
We found that aqueous HCl is a very reliable modula-
tor for adjusting the reactivity of the Pd-C catalyst.
By addition of a suitable amount of aqueous HCl to a
routine Pd-C-catalyzed hydrogenation system, an effi-
cient and practical method for highly chemoselective
hydrogenation of N,N-dialkylnitrobenzylamines to
amino-N,N-dialkylbenzylamine hydrochlorides was
established. The method features convenient perfor-
mance, easy work-upand high efficiency. It is likely
that the replacement of the routine procedures (using
reducing metals in acidic media) by this method will
also significantly reduce the release of hazardous
Figure 1.
wastes to the environment.
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Highly Chemoselective Hydrogenation of Nitrobenzylamines
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Scheme 3.
4 h. Then it was cooled to room temperature and poured
into H2O (20 mL). The resulting mixture was extracted with
CH2Cl2 and the combined organic layers were dried over
Na2SO4. Removal of the solvents yielded a yellow solid,
which was recrystallized in EtOAc to give 1l as a light
yellow crystal; yield: 0.72 g (68%); mp170 8C (lit.[10]
Experimental Section
Typical Procedure for the Hydrogenation of N-[(4-
Nitrophenyl)methyl]tetrahydro-N-methyl-2H-pyran-4-
amine (1c)
1
1688C); H NMR (CDCl3): d=8.20 (d, J=8.6 Hz, 6H), 7.58
A mixture of 1c (626 mg, 2.5 mmol), 10% Pd-C (31.3 mg),
and aqueous HCl (37%, 800 mg, ca. 8 mmol) in MeOH
(30 mL) was stirred under H2 at ambient temperature and
atmospheric pressure until the absorption of hydrogen
ceased (15 min). After the catalyst was filtered off, the fil-
trate was evaporated and Et2O (20 mL) was added. The de-
sired product 2c·2HCl was collected by filtration as yellow-
ish crystals; yield: 726 mg (99%); mp177–179 8C (MeOH-
Et2O, lit.[3a] 177–1798C); IR: n=3429, 2951, 2858, 1611,
(d, J=8.6 Hz, 6H), 3.70 (s, 6H); 13C NMR (CDCl3): d=
147.4, 146.0, 129.2, 123.8, 57.7.
Tris-(4-aminobenzyl)amine Tetrahydrochloride
(2l·4HCl)
A
mixture of tris(4-nitrobenzyl)amine (1l, 634 mg,
1.5 mmol), 10% Pd-C (31.7 mg), and aqueous HCl (37%,
3.0 g) in MeOH (30 mL) was hydrogenated at ambient tem-
perature and atmospheric hydrogen pressure for 310 min.
After the catalyst was filtered off and MeOH was evaporat-
ed, the residue was dissolved in anhydrous ethanol (10 mL).
Removal of ethanol (as an azeotropic mixture with water)
yielded a light yellow solid, which was washed with anhy-
drous diethyl ether to give pure 2l·4HCl; yield: 680 mg
(95%); mp >2508C (MeOH); IR: n=3412, 2857, 1616,
1
1575 cmÀ1; H NMR (D2O): d=7.71 (d, J=8.6 Hz, 2H), 7.46
(d, J=8.6 Hz, 2H), 4.58 (d, J=13.1 Hz, 1H), 4.18 (d, J=
13.1 Hz, 1H), 4.01 (d, J=11.3 Hz, 2H), 3.48–3.64 (m, 1H),
3.38 (t, J=12.4 Hz, 2H), 2.64 (s, 3H), 2.06 (t, J=10.9 Hz,
2H), 1.77–1.94 (m, 2H); 13C NMR (D2O): d=133.4, 132.9,
131.1, 124.1, 66.2, 62.9, 55.8, 35.3, 28.0, 27.0; MS: m/z (%)=
221 (M+1, 2.4), 220 (M+, 18.0), 106 (100.0); anal. calcd. for
C13H22Cl2N2O: C 53.25, H 7.56, N 9.55; found: C 53.23, H
7.57, N 9.54.
1
1573 cmÀ1; H NMR (D2O): d=7.56 (d, J=8.6 Hz, 6H), 7.42
(d, J=8.6 Hz, 6H), 4.30 (s, 6H); 13C NMR (D2O): d=131.7,
131.6, 131.5, 123.8, 50.0; MS m/z (%): 227 (5.4), 122 (55.1),
121 (86.4), 107 (26.3), 106 (100.0), 94 (28.1); anal. calcd. for
C21H28Cl4N4: C 52.74, H 5.90, N 11.71; found: C 52.86, H,
5.89, N 11.80.
A similar procedure was used to convert the substrates
1a–j chemoselectively to 2a–j.
4-[(4-Methyl-1-piperazinyl)methyl]benzenamine
Trihydrochloride (2k·3HCl)
Supporting Information
Characterization data and 1H NMR and 13C NMR spectra
Using as similar procedure as that above and 3.5 equivalents
of aqueous HCl, compound 2k·3HCl; mp139–141 8C
(MeOH-Et2O). IR: n=3341, 2986, 2897, 1615 cmÀ1
;
for products 2a–l are given in the Supporting Information.
1H NMR (D2O): d=7.74 (d, J=6.5 Hz, 2H), 7.43 (d, J=
6.5 Hz, 2H), 4.46 (s, 2H), 3.50–3.70 (m, 8H), 2.91 (s, 3H);
13C NMR (D2O): d=140.2, 129.3, 123.1, 50.1, 42.8, 41.0; MS:
m/z (%)=206 (M+1, 9.9), 205 (M+, 79.0), 106 (100.0); anal.
calcd. for C11H22Cl3N3: C 45.80, H 7.05, N 13.35; found: C
45.91, H 7.04, N 13.57.
Acknowledgements
Tris-(4-nitrobenzyl)amine (1l)
This work was supported by the National Natural Science
Foundation of China (20025204, 20272023) and the Key Sub-
ject Foundation from Beijing Department of Education
(XK100030514).
A mixture of 4-nitrobenzyl bromide (1.62 g, 7.5 mmol) and
aqueous ammonia solution (25%, 5 mL) in anhydrous
MeOH (2.5 mL), was heated in a sealed tube at 1008C for
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