A continuous-flow synthesis of primary amides from hydrolysis of nitriles using hydrogen peroxide as oxidant

Article abstract of DOI:10.1016/j.tet.2018.02.017

A continuous-flow synthesis of primary amides from hydrolysis of nitriles using hydrogen peroxide as oxidant has been developed. Using this procedure, a variety of nitriles could be smoothly transformed into the desired primary amides in good to excellent yields. The mild reaction conditions and the flowing reaction system greatly improved the safety and make the reaction easy to scale up.

Full text of DOI:10.1016/j.tet.2018.02.017

Accepted Manuscript
A continuous-flow synthesis of primary amides from hydrolysis of nitriles using
hydrogen peroxide as oxidant
Wei Zhan, Ling Ji, Ze-mei Ge, Xin Wang, Run-tao Li
PII:
S0040-4020(18)30142-X
10.1016/j.tet.2018.02.017
TET 29288
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 December 2017
Revised Date: 4 February 2018
Accepted Date: 6 February 2018
Please cite this article as: Zhan W, Ji L, Ge Z-m, Wang X, Li R-t, A continuous-flow synthesis of primary
amides from hydrolysis of nitriles using hydrogen peroxide as oxidant, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.02.017.
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ACCEPTED MANUSCRIPT
A Continuous-flow Synthesis of Primary Amides from
Hydrolysis of Nitriles Using Hydrogen Peroxide as
Oxidant
Wei Zhan, Ling Ji, Ze-mei Ge, Xin Wang*, Run-tao Li*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Science, Peking University
Abstract:
A continuous-flow synthesis of primary amides from hydrolysis of nitriles using hydrogen peroxide as
oxidant has been developed. Using this procedure, a variety of nitriles could be smoothly transformed into the
desired primary amides in good to excellent yields. The mild reaction conditions and the flowing reaction system
greatly improved the safety and make the reaction easy to scale up.
primary amides can be mainly divided into four
1
.Introduction:
Amide, a very common class of organic
2
kinds: 1) hydrolysis of the corresponding nitriles;
2
) amidation of acids or acid chlorides with
compounds, has widely applied in organic
chemistry, pharmaceuticals, material science and so
on. Primary amide is an important kind of amides,
among which, many are biological active
3
ammonia; 3) oxidative amidation of corresponding
4
aldehydes or aldoximes; 4) oxidation of primary
5
amines or alcohols. Among them, hydrolysis of
nitriles has become one of the most widely used
1
compounds and even drugs (Scheme 1). Thus, the
6
methods in both academia and industry. Yet, the
development of efficient procedures for the
formation of primary amide has received
considerable attentions and many methods have
conventional methods usually require strong acid
2a-c
or base as catalyst which may cause
8
over-hydrolysis of primary amides and are not
2-7
been reported.
suitable for sensitive substrates along with a large
amount of salts after neutralization of the catalysts.
In order to overcome these shortcomings, different
kinds of metal catalysts, i.e. Ru, Pd, Ni, Au, have
2d-j
been used. However, the cost of expensive
metal-complex, the separation of products and
drastic condition are needed to be addressed.
Therefore, oxidative hydrolysis of nitriles using
hydrogen peroxide to produce primary amides was
7
expanded. To improve its effectivity, some efforts
have been made such as adding surfactant or using
As shown in scheme 2, the synthesis of
1

ACCEPTED MANUSCRIPT
sodium peroxide, sodium perborate or urea
we envisioned to synthesize primary amide from
9
peroxide instead of hydrogen peroxide. Although
hydrolysis of nitriles using hydrogen peroxide as
oxidant in flow mode in order to improve the safety
and make it easy to scale-up.
oxidative hydrolysis of nitriles using hydrogen
peroxide is well reported in the literature, its
application, especially on a larger scale, is still
limited due to the exothermic and explosive
problem in high concentration and weak reactivity
in low concentration.
2
.Results/Discussion:
Firstly, benzonitrile was chosen as a model
reaction substance. Considering the clogging of
materials is the key issue to concern in a flow
reaction, we first screened different volume
alcohols as solvents in batch mode to make sure
that there weren’t any insoluble ingredients
throughout the whole reaction process. As shown in
table 1, when using 15 mL EtOH as solvent (Table
1
, entry 4) the reaction showed higher conversation
and no solid precipitation. Later, simple
a
flow-platform was established as below,
benzonitrile and DMSO were taken up in EtOH
and pumped in inlet A, NaOH (aq) was taken up in
EtOH and pumped in inlet B, and 30% H O (aq)
In the past decade, micro-reactor technology
has emerged as a powerful tool for solving
synthetic problems in the field of pharmaceutical
and fine chemical researches due to its
2
2
was pumped in inlet C. The reaction stream was
pressurized by a 10 bar back pressure regulator
(BPR) and the outflow collected in saturated
environmental friendliness, efficiency and safety.
aqueous NaHSO and EtOH. After being filtered,
3
10a-g
The latest issue of Bioorganic & Medicinal
the outflow was analyzed by HPLC to determine
conversion (Scheme 3).
Chemistry has a special issue reported the organic
10h
synthesis in flow for medicinal chemistry. The
hydrogen peroxide as oxidant has been successfully
applied in several reactions in continuous flow
11
mode. For example, Gavriilidis et al. used
hydrogen peroxide as an oxidant to facilitate
epoxidation of 1-pentene in a microchannel coated
12a
with titanium silicalite-1 zeolite; Wiles and
Watts et al. investigated the oxidation of
1
-methylcyclohexene catalyzed by Candida
antarctica lipase B (Novozyms 435) with H O in a
2
2
continuous flow packed-bed reactor in full
conversion at 70°C with a residence time of 2.6
12b
min. By using a packed-bed microreactor loaded
with a new catalyst [PO4{WO(O2)2}4] @PIILP,
Doherty and Hardacre et al. successfully obtained
high yield of sulfoxide (92%) in methanol within 4
min of residence time and sulfone (96%) in
12c
acetonitrile in a 15 min residence time. Therefore,
2

ACCEPTED MANUSCRIPT
Table 1. reaction under batch mode.
entry
solvent
ambient
EtOH
Volume(mL)
conversion(%)
Additive
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
None
result
1
2
3
4
5
6
7
-
100
100
92
68
37
56
0
Much solid precipitation
Much solid precipitation
Few solid precipitation
No solid precipitation
No solid precipitation
No solid precipitation
No solid precipitation
5
EtOH
10
15
20
12
15
EtOH
EtOH
MeOH
EtOH
Reaction conditions: 10 mmol benzonitrile and 10 mmol DMSO was added into solvent under ice bath. After temperature went
down to 0°C, 0.5 mL 1M NaOH and 1.2 mL 30% H was added, the mixture was reacted for 5 min and quenched by saturated
aqueous NaHSO
2
O
2
3
.
In micro-reactors, temperature and residence
time are parameters need to be optimized (Table 2).
It can be seen that when the temperature rose from
100% (Table 2, entries 1-3). Reducing the amount
of DMSO 1.0 eq to 0.5 eq would lead to a sharp
drop in conversion (Table 2, entry 8) whereas
0
°C to 35 °C in a residence time of 50s (Table 2,
reducing H O to 1.8 eq or 1.2 eq would get a
2 2
entry 1, entries 4-6), the conversion of benzonitrile
would be increased from 84% to 98% and there
was no obvious conversion difference between 25
satisfied conversion with a prolonged residence
time (Table 2, entry 9, 10, 11). Therefore, the
reaction temperature of 25 °C , t =150s and a ratio
R1
°
C and 35 °C. If the tR1 lengthened from 50s to
50s, the conversion would be raised from 84% to
of A:B:C=1:0.0375:1.2 would be the preferable
conditions (Table 2, entry 11).
1
Table 2: different combination of flowrate, temperature and residence time
Conversion (HPLC
entry
Mole Ratio A:B:C
T(°C)
t
R1 (s)
relative area%)
1
2
3
4
5
7
1:0.05:2.5
1:0.05:2.5
1:0.05:2.5
1:0.05:2.5
1:0.05:2.5
1:0.05:2.5
1:0.05:2.5
1:0.05:2.5
1:0.05:1.8
1:0.05:1.2
1:0.0375:1.2
0
50
100
150
50
84
99
0
0
100
85
15
25
25
25
35
25
25
25
50
97
150
150
50
100
17
a
8
6
9
98
100
100
150
93
1
0
1
88
1
99
3

ACCEPTED MANUSCRIPT
Reaction condition: solution A:0.6 mmol benzonitrile and 0.6 mmol DMSO solved in 3 mL EtOH solution B: 50 ꢀl 1M NaOH
(aq) solved in 1 mL EtOH. solution C: 1 mL 30% H
2 2
O solved in 7 mL EtOH. outlet liquid is poured into 0.3 mL EtOH and 50 ꢀl
saturated aqueous NaHSO . After being filtered, the clear liquid was analyzed by HPLC a: 0.5 eq DMSO was used.
3
With the optimized reaction conditions in
hand, we then turned our attention to the substrate
scope of this approach. As shown in table 3, all
tested substrates, including aromatic nitriles,
heteroaromatic nitriles and aliphatic nitriles
produced the expected primary amides in good to
excellent yields. For substituted benzonitriles,
different functional groups, whether halogen,
methyl, methoxyl, amino, nitro and ester group
Even high steric hindrance diphenyl-acetonitrile
and pivalonitrile afforded the desired product in 75 %
and 62% yield respectively under 480s retention
time (Table 3, entries 20, entries 21). It is worth
noting that we have successfully applied this
approach in the synthesis of
4-(4-methyl-piperazin-1-yl-methyl)- benzamide, a
key intermediate for the synthesis of Imatinib,
which is one of important kinase inhibitors as
anticancer agent in clinic (Table 3, entry 22). Also
alpha-chiral substrate was successfully transformed
into corresponding amide with a slightly change of
chirality (Table 3, entry 23).
(
Table 3, entries 2-9), or at different position (Table
, entries 8 -13), were all tolerated, achieving the
3
yields of 80-99 %. For the low reactive
benzonitriles bearing strong electron withdrawing
group (Table 3, entries 9 -11), satisfied yields were
obtained by extending the retention time. More
importantly, the heteroaromatic nitriles containing
pyridine, piperazine and thiophene were also
high-yielding (Table 3, entries 14 -16, 92 – 97 %).
Furthermore, this approach was also expanded to
the aliphatic nitriles, such as phenylacetonitrile,
In order to further explore the scope of the
reaction, we carried out the hydrolysis of nitriles in
the presence of unstable oximes and acetals. It's a
pleasure to find out that the reaction was tolerant of
free oxime and acetal under optimized reaction
conditions (Scheme 4).
3
-phenyl acrylonitrile and 3-acetoxyl butyronitrile.
a
Table 3：Substrate scope under optimized condition.
d
d
Entry
Nitriles
t
R1
Yieldꢀ%ꢁ Entry
Nitriles
t
R1
Yield ꢀ%ꢁ
1
2
3
4
150s
150s
150s
150s
99
92
96
99
13
14
15
16
150s
150s
150s
150s
90
95
92
97
4

ACCEPTED MANUSCRIPT
5
6
7
8
9
150s
150s
150s
150s
80
90
88
96
83
98
17
18
19
20
21
22
150s
150s
150s
94
97
93
75
62
81
c
480s
480s
b
c
480s
480s
CN
N
b
N
1
0
150S
O
O
b
c
1
1
480s
94
92
23
480s
56
CN
1
2
150s
a: Reaction condition: solution A:0.6 mmol benzonitrile and 0.6 mmol DMSO solved in 3 mL EtOH.; solution B: 50 ꢀl 1M
NaOH (aq) solved in 1 mL EtOH.; solution C: 1 mL 30% H solved in 7 mL EtOH. T=25℃ . 1 eq H . The whole system was
maintained on 25℃ . The flow system was equilibrated for 30 minutes, then the product stream was quenched and collected in a
glass vessel with saturated aqueous NaHSO in it for 2h. b: Reaction condition: solution A:0.6 mmol benzonitrile and 0.6 mmol
DMSO solved in 3 mL EtOH.; solution B: 50 ꢀl 1M NaOH (aq) solved in 1 mL EtOH; solution C: 1 mL 30% H solved in 7
mL ethanol, T=55℃ . 2 eq H was used. c: Reaction condition: solution A:0.6 mmol benzonitrile and 0.6 mmol DMSO solved
in 3 mL EtOH.; solution B: 50 ꢀl 1M NaOH (aq) solved in 1 mL EtOH; solution C: 1 mL 30% H solved in 7 mL ethanol,
T=55℃ . 4 eq H was used. d: HPLC yield.
2
O
2
2 2
O
3
2
O
2
2
O
2
2
O
2
2
O
2
3
.Conclusion:
In summary, we have realized the first
hydrolysis of nitriles to primary amides using H O2
2
as oxidant in a continuous-flow microreactor. The
advantages of this method include broad substrate
scope, high yields, rapid reaction, simplicity and
convenience. Most importantly, this procedure
greatly improved the safety and is easy to scale-up.
5

ACCEPTED MANUSCRIPT
Thus, this approach will be very useful in the
preparation of various primary amides.
4
. Experimental section:
4
.1. General
1
13
HNMR spectra
C-NMR spectra were
Figure 2: Syringe pumps 1 to 5
1
recorded on Bruker NMR spectrometer ( H 400
13
MHz,
C 100 MHz). HPLC analysis was
performed on Agilent 1260 (DAD:254nm; column:
agilent zorbax eclipse ZORBAX SB-C18 (4.6×150
mm, I.D. 5 µm); mobile phase: MeCN-water, 30%
MeCN within 20 min, flow rate 1.0 mL/min).
Selective hydrolysis of nitriles was performed in a
Labtrix® S1 system (Chemtrix BV, NL). This
commercially available microreactor system can be
fitted with different glass chip reactors, of which in
this project a 15 ꢀL microreactor chip (Chemtrix
Figure 3: Heating/cooling unit and micro reactor
holder
3
224 reactor, 4 inlets and 1 outlets) was employed.
This reactor chip employs staggered oriented ridge
SOR-2) static micromixers to assure fast mixing.
Reaction temperatures are controlled via
Figure 4: microreactor 3224 ꢀ4 inlets and 1 outlets
with staggered oriented ridge static micromixersꢁ
(
a
MTTC1410 temperature controller (Melcor
Thermal Solutions, temperature range –20 to
1
95°C), while the reactor pressure was maintained
at 20 bar backpressure via a preset back pressure
regulator (Upchurch Scientific). Reactant solutions
are injected into the reactor via 1 mL gastight
syringes (SGE). Flowrates vary between 0.1 and 40
4.2. General procedure for the Selective hydrolysis
of nitriles in continuous flow
0.6 mmol benzonitrile and 0.6 mmol DMSO
were solved in 3 mL EtOH and pumped into inlet A,
50 mL 1M NaOH (aq) solved in 1 mL EtOH and
pumped into inlet B, 30% H O (aq) was solved in
ꢀ
L/min, and are controlled via syringe pumps 1 to
5
.
2
2
7
mL ethanol and pumped into inlet C (flow rate A:
B: C=1.54 ꢀl/min:0.46 ꢀl/min:0.3 ꢀl/min for a 400s
residence time). The whole system was maintained
on 25℃ . The flow system was equilibrated for 30
minutes, then the product stream was quenched and
collected in a glass vessel with saturated aqueous
NaHSO in it for 2h. After being filtered, 5.0µL of
3
this solution was injected to the HPLC-instrument
for analysis. The conversion of the reaction was
determined by relative area percentage of nitriles
and corresponding amides. Conversion= Area
Figure 1. Photographs of Labtrix® S1 continuous
flow system.
(benzamide)/
[Area
(benzamide)+
Area
(benzonitrile)].
6

ACCEPTED MANUSCRIPT
4
.3 General procedure for the Selective hydrolysis
J = 6.9 Hz, 1H), 6.30 (d, J = 39.0 Hz, 1H). 13C
of nitriles in batch
NMR (101 MHz, CDCl ) δ 170.06, 133.52, 132.09,
3
1
mmol benzonitrile and 1 mmol DMSO was
128.71, 127.47.
1
added into EtOH under ice bath. After temperature
went down to 0°C, 0.5 mL 1M NaOH and 1.2 mL
4-fluorobenzamide (2), white solid; H NMR (400
MHz, CDCl ) δ 7.91 – 7.79 (m, 2H), 7.20 – 7.04
3
1
3
3
5
0% H O was added, the mixture was reacted for
(m, 2H), 5.78 (t, J = 105.2 Hz, 1H). C NMR (101
2
2
min and quenched by saturated aqueous NaHSO3.
MHz, CDCl ) δ 168.16, 164.78, 129.82, 129.73,
3
The crude mixture was dissolved in ethyl acetate
and washed with brine. The combined organic
layers were dried over magnesium sulfate, filtered,
and concentrated under reduced pressure. The
resulting crude product was purified by flash
chromatography on silica gel with hexane and
AcOEt as eluent to afford the product amide.
115.69.
1
4-chlorobenzamide (3), white solid; H NMR (400
MHz, CDCl ) δ 7.76 (d, J = 8.5 Hz, 2H), 7.43 (d, J
3
13
= 8.4 Hz, 2H), 5.89 (d, J = 100.4 Hz, 1H).
C
NMR (101 MHz, CDCl ) δ 168.12, 138.36, 131.65,
3
128.92, 128.79.
1
4-bromobenzamide (4), white solid; H NMR (400
MHz, DMSO) δ 8.04 (s, 1H), 7.81 (d, J = 8.5 Hz,
13
4
.4 HPLC determination of the yield of product
2H), 7.67 (d, J = 8.5 Hz, 2H), 7.46 (s, 1H). C
(4-methoxybenzonitrile as an example)
NMR (101 MHz, DMSO) δ 167.36, 133.86, 131.70,
The yield was calculated by using benzamide
130.06, 125.47.
1
as an internal standard. Firstly, 0.6 mmol
-methoxybenzamide and 0.6 mmol benzamide
ethyl-4-carbamoylbenzoate (5), white solid; H
4
NMR (400 MHz, CDCl ) δ 8.13 (d, J = 8.4 Hz, 2H),
3
were dissolved in 4mL EtOH. 5.0µL of this
solution was injected to the HPLC-instrument for
7.88 (d, J = 8.4 Hz, 2H), 6.10 (d, J = 79.4 Hz, 2H),
4.41 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H).
1
3
analysis.
s-4-methoxybenzamide)/ Area (s-benzamide).
Then 0.6 mmol benzonitrile, 0.6 mmol DMSO and
.6mmol benzamide were solved in 3 mL EtOH
The
correction
factor
f=Area
C NMR (101 MHz, CDCl ) δ 168.50, 165.76,
3
(
137.04, 133.53, 129.86, 127.36, 61.47, 14.30.
1
4-methylbenzamide (6), white solid; H NMR (400
0
MHz, CDCl ) δ 7.71 (d, J = 8.1 Hz, 2H), 7.26 (s,
3
1
3
and pumped into inlet A. The rest procedures were
unvaried. Yield= Area (r-4-methoxybenzamide)/
2H), 5.88 (d, J = 132.6 Hz, 2H), 2.41 (s, 3H). C
NMR (101 MHz, CDCl ) δ 169.25, 142.55, 130.45,
3
[
f∗ Area (r-benzamide)] ∗ 100%.
129.29, 127.37, 21.49.
1
4
-(dimethylamino) benzamide (7), white solid; H
4
2
.5 HPLC determination of the ee of
-amino-2-oxo-1-phenylethyl benzoate
NMR (400 MHz, CDCl ) δ 7.71 (d, J = 9.0 Hz, 2H),
3
6.66 (d, J = 8.9 Hz, 2H), 5.79 (s, 2H), 3.03 (s, 6H).
1
3
The HPLC process was performed on Agilent
260 (DAD:254nm; column: Daical Chiralpak
C NMR (101 MHz, CDCl ) δ 169.41, 152.73,
3
1
129.03, 119.76, 110.93, 40.13.
AD-H (250×4.6mm, I.D.); mobile phase:
Isopropanol-n-hexane. Gradient elution method
was specified as follows: 80% n-hexane at 0-40
min, linear gradient from 80–10% n-hexane in
4-methoxybenzamide (8), white solid; 1H NMR
(400 MHz, DMSO) δ 7.84 (s, 3H), 7.25 – 7.09 (m,
1H), 6.97 (d, J = 8.2 Hz, 2H), 3.80 (s, 3H). 13C
NMR (101 MHz, DMSO) δ 167.91, 162.03, 129.79,
1
4
26.98, 113.83, 55.76.
-nitrobenzamide (9), yellow solid; H NMR (400
1
1
0minꢂkeep 10% n-hexane at 50-70min, flow rate
1
.0 mL/min).
MHz, DMSO) δ 8.33 (d, J = 8.7 Hz, 3H), 8.12 (d, J
13
=
8.7 Hz, 2H), 7.76 (s, 1H). C NMR (101 MHz,
Benzamide (1), white solid; 1H NMR (400 MHz,
DMSO) δ 166.64, 149.51, 140.44, 129.37, 123.92.
1
CDCl ) δ 7.84 (s, 1H), 7.57 – 7.50 (m, 1H), 7.46 (d,
2-nitrobenzamide (10), yellow solid; H NMR (400
3
7

ACCEPTED MANUSCRIPT
MHz, DMSO) δ 8.14 (s, 1H), 7.99 (d, J = 8.0 Hz,
CDCl ) δ 7.67 (d, J = 15.7 Hz, 1H), 7.53 (s, 2H),
3
1
H), 7.77 (t, J = 7.2 Hz, 1H), 7.72 – 7.60 (m, 3H).
C NMR (101 MHz, DMSO) δ 167.61, 147.70,
33.78, 133.04, 131.08, 129.30, 124.40.
7.39 (s, 3H), 6.49 (d, J = 15.7 Hz, 1H), 6.01 – 5.61
13
13
(m, 2H). C NMR (101 MHz, CDCl ) δ 167.88,
3
1
3
142.53, 134.49, 129.99, 128.87, 127.94, 119.50.
ethyl 3-amino-3-oxopropanoate (19), white
1
-nitrobenzamide (11), yellow solid; H NMR (400
1
MHz, DMSO) δ 8.72 (s, 1H), 8.50 – 8.23 (m, 3H),
solid; H NMR (400 MHz, Chloroform-d) δ 7.10 (s,
13
7
.79 (dd, J = 17.7, 9.7 Hz, 2H). C NMR (101
1H), 5.96 (s, 1H), 4.20 (qd, J = 7.1, 1.2 Hz, 2H),
13
MHz, DMSO) δ 166.14, 148.26, 136.23, 134.27,
3.31 (s, 2H), 1.29 (td, J = 7.1, 1.2 Hz, 3H).
C
1
2
30.53, 126.35, 122.68.
-methoxybenzamide (12), white solid; H NMR
NMR (101 MHz, CDCl ) δ 169.40, 167.67, 77.48,
3
1
77.16, 76.84, 61.79, 41.12, 14.16.
1
(
400 MHz, CDCl ) δ 8.22 (dd, J = 7.8, 1.6 Hz, 1H),
2,2-diphenylacetamide (20), white solid; H NMR
3
7
.73 (s, 1H), 7.55 – 7.40 (m, 1H), 7.09 (t, J = 7.6
(400 MHz, CDCl ) δ 7.37 – 7.31 (m, 4H), 7.27 (dd,
3
Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 5.81 (d, J =
J = 9.6, 4.9 Hz, 6H), 5.85 (d, J = 199.4 Hz, 2H),
13
13
1
42.3 Hz, 1H), 3.98 (s, 3H). C NMR (101 MHz,
4.96 (s, 1H). C NMR (101 MHz, CDCl ) δ 174.62,
3
CDCl ) δ 167.02, 157.80, 133.38, 132.58, 121.24,
139.17, 128.89, 128.86, 127.40, 58.75.
3
1
1
3
20.78, 111.34, 55.92.
-methoxybenzamide (13), white solid; H NMR
Pivalamide(21)ꢀwhite solidꢀH NMR (400 MHz,
1
DMSO) δ 7.00 (s, 1H), 6.68 (s, 1H), 1.07 (s,
13
(
400 MHz, CDCl ) δ 7.41 (s, 1H), 7.39 – 7.30 (m,
9H). C NMR (101 MHz, DMSO) δ 180.22, 38.30,
3
2
H), 7.07 (dt, J = 7.2, 2.3 Hz, 1H), 6.07 (d, J = 43.5
27.93.4-((4-methylpiperazin-1-yl) methyl)
13
1
Hz, 2H), 3.86 (s, 3H). C NMR (101 MHz, CDCl )
benzamide (22), white solid; H NMR (400 MHz,
3
δ 169.34, 159.85, 134.78, 129.62, 119.16, 118.30,
CDCl ) δ 7.77 (dd, J = 8.1, 4.8 Hz, 1H), 7.40 (s,
3
112.56, 55.46
1H), 6.07 (s, 1H), 3.55 (d, J = 5.1 Hz, 1H), 2.73 –
1
13
Picolinamide (14), white solid; H NMR (400 MHz,
2.30 (m, 1H), 2.29 (d, J = 5.0 Hz, 1H). C NMR
CDCl ) δ 8.55 (d, J = 4.7 Hz, 1H), 8.19 (d, J = 7.8
(101 MHz, CDCl ) δ 169.45, 142.96, 132.24,
3
3
Hz, 1H), 7.89 (s, 1H), 7.82 (dd, J = 7.7, 1.5 Hz,
129.30, 127.46, 62.65, 55.23, 53.27, 46.16.
13
1
H), 7.50 – 7.36 (m, 1H), 6.42 (s, 1H). C NMR
(R)-2-amino-2-oxo-1-phenylethyl benzoate (23),
1
(
101 MHz, CDCl ) δ 167.09, 149.58, 148.31,
white solid, H NMR (400 MHz, DMSO) δ 8.08 (d,
3
1
37.30, 126.45, 122.41.
pyrazine-2-carboxamide (15), white solid; H NMR
400 MHz, CDCl ) δ 9.47 (s, 1H), 8.83 (d, J = 2.2
J = 7.2 Hz, 2H), 7.83 (s, 1H), 7.69 (t, J = 7.4 Hz,
1H), 7.65 – 7.52 (m, 4H), 7.41 (dt, J = 31.2, 13.0
1
13
(
Hz, 4H), 6.04 (s, 1H). C NMR (101 MHz, DMSO)
δ 170.16, 165.39, 136.44, 134.09, 129.97, 129.69,
129.22, 129.04, 128.94, 127.67, 76.10.
3
Hz, 1H), 8.61 (s, 1H), 7.69 (s, 1H), 5.89 (s, 1H).
13
C NMR (101 MHz, CDCl ) δ 165.30, 147.57,
3
1
44.61, 144.11, 142.76.
1
thiophene-2-carboxamide (16), white solid;
H
Acknowledgement
NMR (400 MHz, DMSO) δ 7.98 (s, 1H), 7.75 (d,
The authors thank the National Natural Science
Foundation of China (No. 81673287) for financial
support.
13
J = 5.7 Hz, 2H), 7.38 (s, 1H), 7.15 (s, 1H).
C
NMR (101 MHz, DMSO) δ 163.36, 140.73,
1
31.42, 129.13, 128.33.
-phenylacetamide (17), white solid; H NMR (400
1
2
References
MHz, DMSO-d ) δ 7.52 (s, 1H), 7.32 – 7.29 (m,
1.
(a) Arthur, G.; Curt, M. B.; Joel, F. L. The Amide
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4
H), 7.26 – 7.21 (m, 1H), 6.95 (s, 1H), 3.42 (s, 2H).
Linkage: Structural Significance in Chemistry, Biochemistry
and Materials Science, Wiley, New York, 2003; (b) Jacob, Z.
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1970; (c) Schneider, N.; Lowe, D. M.; Sayle, R. A.; Tarselli,
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C NMR (101 MHz, DMSO) δ 172.43, 136.52,
1
29.10, 128.19, 126.31, 42.34.
1
Cinnamamide (18), white solid; H NMR (400 MHz,
8

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