One-pot protocol to synthesize N-(β-nitro)amides by tandem Henry/Ritter reaction

Article abstract of DOI:10.1039/c5ra01536g

A novel, efficient and atom economical one pot protocol for the synthesis of N-(β-nitro)amides has been described by combining the Henry reaction with the Ritter reaction. The designed products could be obtained from easily available aldehydes, nitroalkan

Full text of DOI:10.1039/c5ra01536g

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One-pot protocol to synthesize N-(b-nitro)amides
by tandem Henry/Ritter reaction†
Cite this: RSC Adv., 2015, 5, 24044
Wensi Ai,b Ronghua Shi,b Liyan Zhu,a Dehong Jiang,b Xiaobo Ma,a Jilan Yuana
ab
*
and Zhouyu Wang
A novel, efficient and atom economical one pot protocol for the synthesis of N-(b-nitro)amides has been
described by combining the Henry reaction with the Ritter reaction. The designed products could be
obtained from easily available aldehydes, nitroalkanes and nitriles with 60–83% overall yields under mild
reaction conditions. In addition, the product can easily be transformed into diamine or protective amine
derivatives.
Received 26th January 2015
Accepted 24th February 2015
DOI: 10.1039/c5ra01536g
www.rsc.org/advances
been developed greatly both in the catalyst system and the
substrate scope. Variously amides, such as unsymmetrical
Introduction
di- and trisubstituted ureas, 3-substituted-3-aminooxindoles,
4-acylam-inotetrahydroindazoles, N-(4-iodo-1,3-diarylbutyl)
acetamides, have been synthesized with this reaction. In prin-
ciple, Ritter reaction could be an efficient method to synthesize
N-(b-nitro)amides by reacting the corresponding b-nitro alco-
hols or nitro alkenes with nitriles. However, to the best of
knowledge, the synthesis of N-(b-nitro)amides by Ritter reaction
has been rarely explored. Only one example was reported by
Bach,21 which use 2-nitro-1-phenylpropan-1-ol 1 to react with
benzonitrile under the catalysis of triuoromethanesulfonic
acid to get the N-(b-nitro)amides 3 with good yield and
moderate diastereoselectivity (Scheme 1). Up to now, a general
preparation of N-(b-nitro)amides by Ritter reaction is still
underdeveloped.
N-(b-nitro)amides are important organic intermediates that
have been widely used in the synthesis of natural products,
drugs and agrochemicals since the nitro group can be easily
converted to other useful functional groups such as amine,
carboxylic acid, or oxime.1,2 Thus, studies for the development
of efficient methods to synthesize N-(b-nitro)amides have
attracted considerable attention both from organic chemists
and medicinal chemists. The rst method to synthesize
N-(b-nitro)amides was reported by Jelena and co-workers in
1952,3,4 which use nitro methane or ethyl nitro acetate to
substitution of the amide group of bisamides to form the
designed products. From then on, a variety of synthetic
methods have been reported to synthesize N-(b-nitro)amides
such as aza-Michael additions of amides to nitro alkenes,5–8 aza-
Henry reaction of nitro protected imines9–11 and nitro-
acetamidation12–14 of styrene (Fig. 1). However, most of the
present methods for synthesize N-(b-nitroalkyl)amides are not
atom economical and suffer from limited substrates. Therefore,
the development of an efficient and atom economical method
for the synthesis of N-(b-nitro)amides with sufficient diversity is
still highly desirable and of signicant value.
Ritter reaction is a classical acid-catalyzed reaction between
a carbocation precursor, such as a substituted olen or
alcohol, and nitriles to generate amides.15–38 This is an atom
economical reaction. It has versatile applications for the
synthesis of active pharmaceutical intermediates and hetero-
cycles, particularly for the preparation of bulky amides, which
can be precursors of hindered amines. In recent years, it has
aDepartment of Chemistry, Xihua University, Chengdu, 610039, China. E-mail:
zhouyuwang@mail.xhu.edu.cn; zhouyuwang77@gmail.com; Fax: +86-28-87723006
bDepartment of Pharmaceutics Engineering, Xihua University, Chengdu, 610039,
China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c5ra01536g
Fig. 1 Selected methods to synthesize N-(b-nitro)amides.
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20 ꢀC (entries 1–5, Table 1). To the best of our knowledge, there
is no report about DABCO was used as a promoter in Henry
reaction. Highest yield could be obtained when set up the
reaction in acetonitrile under otherwise identical conditions,
which clearly shown that the polar solvent system was helpful to
get better yield for the reaction (entries 5–8, Table 1). The yield
would drop to 71% from 83% when the reaction temperature
was increased to 40 ꢀC, and 90% yield could be obtained when
the reaction temperature was decreased to 0 ꢀC. Decreasing the
Scheme 1 Bach reported N-(b-nitro)amides by Ritter reaction.
ꢀ
It is obvious that the alcohol 1 could be synthesized by the
Henry reaction between benzylaldehyde and nitro ethane.39–44
Thus, we are wondering whether the N-(b-nitro)amide product 3
could be synthesized by reacting acetonitrile directly with the in
situ formed alcohol 1 that prepared by the nucleophilic addition
of nitro ethane to benzylaldehyde under the catalysis of base.
Herein, we wish to report a novel and efficient protocol to
synthesize N-(b-nitro)amides by tandem Henry/Ritter reaction,
which has a versatile substrates scope and an environment-
friendly reaction conditions.
reaction temperature to ꢁ20 C could not clearly improve the
yield (entries 8–11, Table 1). Thus, 0 ꢀC was used in the
following experiments. Next, we found 95% yield could be
achieved when 0.5 equivalent of DABCO was added into the
reaction. Further decreasing the loading of DABCO or reaction
time resulted poor yield (entries 13–16, Table 1). The same yield
was obtained when the reaction time was prolonged to 48 hours
(entry 17, Table 1).
With the optimized reaction conditions for Henry reaction in
hand, we started to test whether Ritter reaction would happen
by directly adding Lewis acid or Brønst acid to the reaction
mixture. At the beginning, three equivalents of pure tri-
uoromethanesulfonicacid (TfOH) were added to the reaction
mixture of Henry reaction, and no designed Ritter reaction
product was detected no matter the reaction temperature was
kept at 0 ꢀC or increased to 80 ꢀC for 24 hours (entries 1 and 2,
Table 2). Fortunately, we found moderate yield could be
obtained when 1 mL of acetonitrile was replaced with equal
volume of other solvents such as toluene, chloroform and
dichloromethane (entries 3–5, Table 2). Lewis acid such as
Bi(OTf)3, BF3$Et2O and FeCl3 were not efficient catalyst for the
current reaction system, and no more than 10% yield could be
obtained when these acids were used in the reaction (entries 15–
18, Table 2). Dichloromethane (DCM) was found to be the best
solvent for the reaction since highest yield could be obtained
albeit at low reaction temperature. Next, we found 82% yield
could be achieved when 0.5 mL acetonitrile and 1.5 mL DCM
were used as the solvent for the reaction. It seems that the ratio
of the two solvents was important to get high yield since adding
more DCM or acetonitrile into the reaction would cause a lower
Results and discussion
Initially, benzylaldehyde and nitro methane were chosen as the
standard substrates to optimize the reaction conditions of
Henry reaction. It was found that 1,4-diazabicyclo[2.2.2]octane
(DABCO) was a proper base for the Henry reaction, and 67%
yield could be obtained when one equivalent of DABCO was
added into the dichloromethane solution of the substrates at
Table 1 Optimization of reaction conditions of Henry reactiona
Entry Base (eq.)
Temp. (ꢀC) Sol.
Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
TEA (1)
DEA (1)
t-BuOK (1)
EtONa (1)
20
20
20
20
20
20
20
20
40
0
DCM
24
24
24
24
24
24
25
20
44
20
67
65
10
83
71
90
91
95
45
30
50
70
95
87
90
ꢀ
DCM
DCM
DCM
DCM
CHCl3
yield (entries 6–9, Table 2). 40 C was the best temperature for
the reaction, lowering the temperature would cause a clearly
decline of the yield. Three equivalents of TfOH were enough for
the reaction. We didn't found obviously impact on the yield
when more TfOH was added.
DABCO (1)
DABCO (1)
DABCO (1)
DABCO (1)
DABCO (1)
DABCO (1)
DABCO (1)
DABCO (0.5)
DABCO (0.2)
DABCO (0.1)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
Toluene 24
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
PhCN
BnCN
24
24
24
24
24
24
24
6
12
48
24
24
With the optimized reaction conditions in hand, the
substrate scope of the reaction was explored. Various aldehydes
and nitriles were used and a series of N-(b-nitro)amides were
synthesized through this protocol. We found the structure of
nitrile was important for the reaction. As shown in Table 3,
moderate to good yields could be obtained when acetonitrile,
benzonitrile and phenylacetonitrile were used in the reaction,
but no product could be isolated when acrylonitrile was used
under otherwise identical conditions. All the tested aromatic
aldehydes were good substrates for the reaction. Nevertheless,
aliphatic aldehydes were not good substrate for the reaction,
and no designed product could be isolated when they were
used. The yield of the reaction was barely impacted by the
9
10
11
12
13
14
15
16
17
18
19
ꢁ20
0
0
0
0
0
0
0
0
a
1.0 mmol of benzaldehyde and 4.0 mmol of nitromethane were used
b
for each reaction. Isolated yield. DABCO ¼ 1,4-diazabicyclo[2.2.2]
octane.
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Table 2 Optimization of reaction conditions of Ritter reactiona
Entry
MeCN (mL)
Sol. (mL)
Temp. (ꢀC)
Acid (eq.)
Yieldb (%)
1
2
3
4
5
6
7
8
2.0
2.0
1.0
1.0
1.0
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
—
—
0
80
100
60
40
40
40
40
40
40
20
0
40
40
40
40
40
40
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (3.0)
TfOH (2.0)
TfOH (4.0)
Bi(OTf)3 (3.0)
DNBSA (3.0)
BF3$Et2O (3.0)
FeCl3 (3.0)
ND
ND
34
25
35
82
78
50
20
55
60
35
47
80
<5
<5
<5
<5
Toluene (1.0)
CHCl3 (1.0)
DCM (1.0)
DCM (1.5)
DCM (2.0)
DCM (4.0)
DCM (6.0)
DCM (1.0)
DCM (1.5)
DCM (1.5)
DCM (1.5)
DCM (1.5)
DCM (1.5)
DCM (1.5)
DCM (1.5)
DCM (1.5)
9
10
11
12
13
14
15
16
17
18
a
1.0 mmol of benzaldehyde and 4.0 mmol of nitromethane were used for each reaction. b Isolated yield. DNBSA ¼ 2,4-dinitrobenzene sulfonic acid.
electron donating or withdrawn groups on the phenyl ring of
the aromatic aldehydes. The stereohindrance of the aldehyde
would not decline the activity signicantly. As shown in 3r–w,
62–71% yield could be obtained also when 2-bromobenzalde-
hyde and 2-naphthaldehyde were used in the reaction. Nitro-
ethane was still a proper substrate for the reaction, and more
than 70% yield and 69% dr value could be obtained. Hetero-
aromatic aldehyde such as thiophene-2-carbaldehyde could be
used as good substrate for the current reaction system, and 80%
of 3aa was obtained.
Table 3 Synthesis of various N-(b-nitro)amides via Henry/Ritter
reactiona
To illustrate the synthetic utility of the present method, the
conversion of N-(2-nitro-1-phenylethyl) benzamide 3b into 1,2-
diamine 7 and double protective derivatives 8 were conducted
by known methods, respectively (Scheme 2). The corresponding
products 7 and 8 were obtained in good yields.
a
1.0 mmol of benzaldehyde and 4.0 mmol of nitromethane were used
for each reaction, isolated yield.
Scheme 2 Conversion of N-(2-nitro-1-phenylethyl) benzamide 3b
into 1,2-diamine 7 and double protective derivatives 8.
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Aer purication by ash chromatography with neutral
alumina (dichloromethane/methyl alcohol ¼ 10/1), the product
7 was obtained (82% yield).
Conclusions
In conclusion, a novel, efficient and atom economical one pot
protocol for the synthesis of N-(b-nitro)amides has been
described by combining the Henry reaction with Ritter reaction.
The DABCO was rstly found to be an efficient promoter in the
Henry reaction. The designed N-(b-nitro)amides could be easily
obtained with 60–83% over all yields by directly adding TfOH to
the solution of Henry reaction under mild reaction conditions.
The electron rich and decient aromatic and heteroaromatic
aldehydes were tolerable in the current system, and high yield
could be obtained for all the tested aromatic aldehydes. The
protocol provided a simple and environment-friendly alterna-
tive to prepare N-(b-nitro)amides from easily available alde-
hydes, nitroalkane and nitriles. Furthermore, the product can
be transformed into diamine or protective amine derivatives.
The procedures for the synthesis of 8
To a well-stirred mixture of N-(2-nitro-1-phenylethyl) benzamide
(130.1 mg, 0.5 mmol) and nickel chloride hexahydrate (119 mg,
0.5 mmol) in absolute ethyl alcohol (5 mL) at 0 ꢀC, sodium
borohydrideꢀ (90 mg, 5 mmol) was added. The mixture was
stirred at 0 C for 2 hours and then quenched with saturated
aqueous NH4Cl. The mixture was diluted with dichloro-
methane. The organic layer was separated and aqueous layer
was extracted with CH2Cl2 (10 mL ꢂ 3). The combined extracts
were washed with water, dried over magnesium sulfate and
concentrated under vacuum to afford crude amine intermediate
4. The crude amine 4 and were dissolved in H2O/1,4-dioxane
(1 : 2 mL). The (Boc)2O (130.8 mg, 0.6 mmol) was added. Then
sodium hydroxide was introduced slowly which made the pH
exceed 12. The mixture was stirred at room temperature for 2
hours and then extracted with EtOAc (10 mL ꢂ 3). The
combined organic extracts were dried over MgSO4. The solvent
was removed under reduced pressure. Aer purication by ash
chromatography (petroleum ether/ethyl acetate ¼ 5/1), the
product 8 were obtained (72% yield).
Experimental section
General procedures for the synthesis of 2-nitro-1-phenyl-
ethanol
The mixture of benzaldehyde (1.0 mmol), nitromethane (4.0
mmol) and base were stirred in the solvent at designed
temperature for designed time. Then the solvent was removed
under reduced pressure and the residue was puried by silica-
gel column chromatography (petroleum ether/ethyl acetate ¼
10/1) to give the corresponding 2-nitro-1-phenylethanol.
Acknowledgements
General procedures for the synthesis of N-(b-nitroalkyl)
amides
We are grateful for the nancial supports from the National
Natural Science Foundation of China (21102115), the Chun-
huiProject (Z2012020), the Great Cultivate Project from the
Education Department of SichuanProvince (14CZ0014), the
Undergraduate Scientic and Technological Innovation Project,
and the Innovation Foundation of Graduate Student of Xihua
University.
The 2-nitro-1-arylethanol (1.0 mmol), nitrile (4 mmol), and 1,4-
diazabicyclo[2.2.2]octane (DABCO, 0.5 mmol) were dissolved in
nitrile (0.5 mL). The reaction mixture was stirred at 0 ꢀC for 24
hours. Then the triuoromethanesulfonic acid (3 mmol) was
ꢀ
added and the mixture was stirred at 40 C for 24 hours. The
reaction was then quenched by the addition of sodium bicar-
bonate at room temperature. The solvent was removed under
reduced pressure and the residue was puried by silicagel
column chromatography (petroleum ether/ethyl acetate ¼ 10/1)
to give the corresponding N-(b-nitroalkyl)amides.
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To a well-stirred mixture of N-(2-nitro-1-phenylethyl) benzamide
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