Hydrogen peroxide-promoted metal free oxidative amidation of 2-oxoaldehydes: A facile access to unsymmetrical oxamides

Article abstract of DOI:10.1016/j.tet.2015.07.012

A novel and green H₂O₂-promoted oxidative amidation of 2-oxoaldehydes with amines to synthesize unsymmetrical oxamides has been developed. The reactions proceeded smoothly at room temperature under metal-free conditions and generated the corresponding products in good yields. This methodology has a broad substrate scope and opens up an interesting and attractive avenue for the synthesis of unsymmetrical oxamide derivatives.

Full text of DOI:10.1016/j.tet.2015.07.012

Tetrahedron 71 (2015) 6928e6934
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Hydrogen peroxide-promoted metal free oxidative amidation of
2-oxoaldehydes: a facile access to unsymmetrical oxamides
*
*
Zhen Zhan, Xu Cheng, Xiaojun Ma, Jie Li, Li Hai , Yong Wu
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University,
Chengdu, 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and green H2O2-promoted oxidative amidation of 2-oxoaldehydes with amines to synthesize
unsymmetrical oxamides has been developed. The reactions proceeded smoothly at room temperature
under metal-free conditions and generated the corresponding products in good yields. This methodology
has a broad substrate scope and opens up an interesting and attractive avenue for the synthesis of
unsymmetrical oxamide derivatives.
Received 23 May 2015
Received in revised form 1 July 2015
Accepted 4 July 2015
Available online 9 July 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Hydrogen peroxide
Oxidative amidation
Metal-free
Unsymmetrical oxamides
1. Introduction
expensive reagents, poor atom-efficiency and limited substrate
scope. Therefore, a more mild, convenient and efficient method
Amides, as an important structural backbone of various natural
products, pharmaceuticals and polymers, have attracted consider-
able interest because of their important biologically active prop-
erties.1 A recent survey on drug discovery shown that more than
50% of known drugs contain an amide functional group.2 As an
important and unique member of amides, oxamides also represents
a key framework of many bioactive compounds.3 They have been
developed as acetylcholine esterase inhibitors,4 C5a inhibitors,5
nitric oxide synthase inhibitors,6 anti-HIV agents,7 antiepileptic
drugs8 and HIV integrase inhibitors9 (Fig. 1).
for the synthesis of unsymmetrical oxamides is still in high
demand.
As far as we know, there has been no report on the synthesis of
unsymmetrical oxamides via oxidative amidation yet. Our work is
focused on the green oxidative amidation of 2-oxoaldehydes uti-
lizing clean and inexpensive oxidants. Hydrogen peroxide is a very
attractive candidate because of its wide application in laboratory
and industrial synthesis. In this study, we report a new method for
synthesizing unsymmetrical oxamides from 2-oxoaldehydes and
amines by using hydrogen peroxide as a reactant (Scheme 1).
A number of synthetic methods for oxamides have been
established in the past decades.10 However, only a few examples
of the synthetic methods for unsymmetrical oxamides have been
reported. Traditionally, unsymmetrical oxamides are synthesized
from the condensation of corresponding carboxylic acids with
amines, which needs either activating agents or conversion into
more reactive derivatives (Scheme 1a).11 In recent years, several
innovative approaches have been developed, which include the
direct amidation of isocyanates,12
a
-keto benzotriazole13 or tri-
chloropyruvamides14 with amines (Scheme 1bed). Nevertheless,
these methods have several drawbacks, such as harsh conditions,
* Corresponding authors. Tel.: þ86 028 85503235; fax: þ86 028 85506666;
e-mail addresses: smile@scu.edu.cn (L. Hai), wyong@scu.edu.cn (Y. Wu).
Fig. 1. Biologically active molecules containing an oxamide moiety.
http://dx.doi.org/10.1016/j.tet.2015.07.012
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

Z. Zhan et al. / Tetrahedron 71 (2015) 6928e6934
6929
CrO3 and OsO4 had only 13e33% yields of 3aa (Table 1, entries 4e9).
Among various solvents examined, EtOH turned out to be the best
choice, while others such as CH2Cl2, CH3COOC2H5, CH3CN, THF,
DMSO, dioxane and PEG-400 were less effective (Table 1, entries
10e16). The yield decreased to 11% when EtOH was replaced with
water (Table 1, entry 17). And addition of cosolvent such as Tween
80 or Bu4NI did not improve the yield (Table 1, entries 18e19).
Further investigation indicates that temperature is important for
this transformation. An excellent yield has been obtained when the
reaction carries out at 25 ꢀC (Table 1, entry 1). However, when the
temperature increases to 40 ꢀC, the yield of the desired product
drops to 56% (Table 1, entry 20). And no product formation was
observed when the reaction was conducted at 0 ꢀC (Table 1, entry
21). For the optimization of the amount of H2O2 used in the model
reaction, less than 3 equiv of H2O2 led to the incompletion of the
reaction (Table 1, entries 22e23). Meanwhile, up to 4 equiv of H2O2
did not increase the yield if 3aa significantly (Table 1, entry 24).
With respect to the molar proportion of the reactants, a 3:1 M ratio
of aldehyde and amine was found to be adequate, as neither bigger
nor smaller proportion shows better yields (Table 1, entries 25e27).
Finally, as observed in this study, the optimized reaction conditions
tends to be: 2-oxoaldehyde (3.0 mmol), amine (1.0 mmol) and 30%
H2O2 (3.0 mmol) in EtOH under standard atmosphere at 25 ꢀC.
With optimized conditions in hand, a series of oxidative
amidations of pyrrolidine 2a with various 2-oxoaldehydes was
thus carried out. The results are summarized in Fig. 2. A host of
oxanilic acids bearing either the electron-donating groups such
as methyl and methoxy, or electron-withdrawing groups such as
chloro and bromo, were well tolerated during the course of the
reaction providing the desired oxamides 3baeha in moderate to
good yields. Besides, synthetically useful naphthyl and benzyl are
tolerated in this transformation, giving 3jaeka in good to mod-
erate yields. Notably, in addition to the aromatic systems, an
aliphatic oxamide 3la could also be obtained in an excellent
yield.
Scheme 1. Typical pathways for the synthesis of unsymmetrical oxamides.
2. Results and discussion
At the beginning of our investigation, the optimization of re-
action conditions was focused on a variety of reaction parameters
by using a model reaction of 2-oxo-N-phenylacetamide (1a) with
pyrrolidine (2a). As shown in Table 1, all the peroxides could pro-
mote this reaction to give the corresponding products with mod-
erate to high yields (Table 1, entries 1e3), while IBX, DMP, DIB, SeO2,
Table 1
Optimization studies for the synthesis of unsymmetrical oxamidesa
To further define the scope of this transformation, a wide range
of 2-oxoaldehydes and amines were reacted under the optimized
reaction conditions (Fig. 3). Good to excellent yields of tertiary
oxamides were obtained in most cases (3abead, bceeb and
hcejb). However, primary amines remained difficult substrates,
giving secondary amides in only moderate yields (3bb, hb and lb).
Interestingly, chiral oxamide could be synthesized from the corre-
sponding chiral amine in moderate yield without detectable race-
mization when compared with the HPLC chromatograms of the
racemic compounds (3ec). Furthermore, a variety of functional
groups such as ether, ester, and halogen are well tolerated for this
reaction.
A serious of control experiments has also been performed to
explore the mechanism of this transformation (Scheme 2). When
1,1-diphenylethylene (a radical scavenger) was added to the re-
action mixture, the oxidative amidation process was suppressed
dramatically, which suggested that the oxidative amidation step
may involve a radical pathway (Scheme 2a). When the reaction was
conducted in the darkness, only 29% yield of 3aa was obtained,
which implies that the sunlight is likely to play an important role in
the reaction process (Scheme 2b).
Entry 1a:2a Oxidant (equiv) Solvent
Additive
T (ꢀC) Yieldb (%)
1
2
3
4
5
6
7
8
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
2:1
3:1
5:1
H2O2 (3.0)
TBHP (3.0)
BPO (3.0)
IBX (3.0)
DMP (3.0)
DIB (3.0)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
CH3COOC2H5
CH3CN
THF
DMSO
dioxane
PEG-400
H2O
H2O
H2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
81
68
61
33
27
26
19
11
13
73
71
65
67
40
50
37
11
12
14
56
0
SeO2 (3.0)
CrO3 (3.0)
OsO4 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (1.0)
H2O2 (2.0)
H2O2 (4.0)
H2O2 (3.0)
H2O2 (3.0)
H2O2 (3.0)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Tween 80 25
Bu4NI
25
40
0
In Scheme 3, a plausible mechanism for the oxidative amidation
reaction has been proposed. Initially, hydrogen peroxide can be
transformed into hydroxyl radical under the triggering effect of
sunlight (Scheme 3a). Then, the hydroxyl radical traps the H of 1a to
produce the acyl radical 4a. Meanwhile, the aminyl radical 5a is
generated efficiently from 2a with the assistance of the hydroxyl
radical. Finally, the acyl radical 4a and aminyl radical 5a combine to
result in the desired amide 3aa.
/
/
/
/
/
/
/
/
25
25
25
25
25
25
54
65
82
84
91
90
a
Reaction condition: 1a (1 mmol), 2a (1 mmol) and oxidant (3 mmol) in 2 mL
The products prepared by this procedure are valuable pre-
cursors for the synthesis of heterocycles. For example, 3ac could
solvent at corresponding temperature, air, 3 h.
b
Isolated yield.

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Z. Zhan et al. / Tetrahedron 71 (2015) 6928e6934
Fig. 2. Substrate scope of aldehydes in direct oxidative amidation with pyrrolidine using aqueous hydrogen peroxide as the oxidant. Reaction conditions: aldehyde (1, 3.0 mmol),
pyrrolidine (2, 1.0 mmol), and 3.0 equiv of H2O2 (30% aqueous) in EtOH at room temperature for 2 h.
Fig. 3. H2O2 initiated amidation of various aldehydes with amines. Reaction conditions: 3.0 equiv of aldehyde, 1.0 equiv of amine, and 3.0 equiv of 30% H2O2 (aqueous) in EtOH at
room temperature for 2 h.
readily be reacted with phosphorus oxychloride to afford the in-
teresting isatin 6 in good yield (Scheme 4).
amidation of aldehydes. With amides mediated by hydrogen per-
oxide, this approach gives good yields of the product. The utiliza-
tion of cheap aqueous hydrogen peroxide as the oxidant also
provides a clean synthetic route with water being the sole
byproduct. In view of the wide functional group tolerance and the
mild reaction conditions, this protocol can be quite useful and
potential widely adapted in synthetic chemistry.
3. Conclusion
In this study, we have successfully demonstrated a new, efficient
and metal-free synthesis of unsymmetrical oxamides via oxidative

Z. Zhan et al. / Tetrahedron 71 (2015) 6928e6934
6931
crude residue was purified by flash chromatography on silica (pe-
troleum ether/ethyl acetate) to afford pure unsymmetrical oxa-
mides 3.
4.2.1. 2-Oxo-N-phenyl-2-(pyrrolidin-1-yl)acetamide
(3aa). Pale
9.48
yellow solid, mp 126e132 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
(s, 1H), 7.62 (d, J¼7.6 Hz, 2H), 7.36 (t, J¼7.6 Hz, 2H), 7.16 (t,
J¼7.6 Hz, 1H), 4.09 (t, J¼6.8 Hz, 2H), 3.62 (t, J¼6.8 Hz, 2H),
2.04e1.97 (m, 2H), 1.92e1.86 (m, 2H); 13C NMR (CDCl3, 150 MHz):
d
159.0, 158.1, 136.9, 128.9, 124.7, 119.7, 48.8, 48.2, 26.8, 23.3. ESI
Scheme 2. Control experiments for the reaction mechanism.
HRMS: calcd for C12H14N2O2þNaþ 241.0947, found 241.0948. El-
emental Analysis: C, 66.04; H, 6.47; N, 12.84, found C, 66.17; H,
6.41; N, 12.78.
4.2.2. 2-Oxo-N-phenyl-2-(piperidin-1-yl)acetamide (3ab). Yellow
solid, mp 152e154 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.12 (s, 1H), 7.60
(d, J¼8.0 Hz, 2H), 7.36 (t, J¼7.6 Hz, 2H), 7.16 (t, J¼7.2 Hz, 1H),
4.15e4.05 (m, 2H), 3.66e3.64 (m, 2H), 1.75e1.60 (m, 6H); 13C NMR
(CDCl3, 150 MHz): d 160.6, 159.0, 136.9, 129.1, 125.0, 119.8, 47.7, 44.9,
26.8, 25.8, 24.4. ESI HRMS: calcd for C13H16N2O2þNaþ 255.1104,
found 255.1104. Elemental Analysis: C, 67.22; H, 6.94; N, 12.06,
found C, 67.31; H, 7.01; N, 11.88.
4.2.3. 2-Morpholino-2-oxo-N-phenylacetamide (3ac). Pale yellow
Scheme 3. A proposed mechanism accounting for the formation of 3aa.
solid, mp 84e86 ꢀC; 1H NMR (CDCl3, 600 MHz):
d 9.29 (s, 1H), 7.60
(d, J¼8.4 Hz, 2H), 7.36 (t, J¼7.6 Hz, 2H), 7.17 (t, J¼7.6 Hz, 1H),
4.31e4.29 (m, 2H), 3.78e3.75 (m, 4H), 3.73e3.72 (m, 2H); 13C NMR
(CDCl3, 150 MHz): d 160.5, 158.1, 136.7, 129.0, 125.1, 119.9, 66.9, 66.5,
47.2, 43.9. ESI HRMS: calcd for C12H14N2O3þNaþ 257.0897, found
257.0899. Elemental Analysis: C, 61.53; H, 6.02; N, 11.96, found C,
61.60; H, 6.10; N, 11.80.
Scheme 4. Synthesis of isatin 6 from 3ac.
4.2.4. 2-(4-Methylpiperidin-1-yl)-2-oxo-N-phenylacetamide
(3ad). Off-white solid, mp 118e120 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
9.14 (s, 1H), 7.60 (d, J¼7.8 Hz, 2H), 7.36 (t, J¼7.8 Hz, 2H), 7.16 (t, 1H,
4. Experimental section
4.1. General information
J¼7.8 Hz), 5.09e5.06 (m, 1H), 4.56e4.54 (m, 1H), 3.16e3.11 (m, 1H),
2.79e2.74 (m, 1H), 1.79e1.75 (m, 2H), 1.72e1.66 (m, 1H), 1.32e1.18
(m, 2H), 0.979 (d, J¼6.6 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d 160.7,
159.1, 136.9, 129.0, 124.9, 119.8, 46.9, 44.2, 34.9, 33.8, 31.0, 21.5. ESI
HRMS: calcd for C14H18N2O2þNaþ 269.1260, found 269.1266. Ele-
mental Analysis: C, 68.27; H, 7.37; N, 11.37, found C, 68.35; H, 7.32;
N, 11.32.
All the direct oxidative reactions of aldehydes with amines were
carried out under an air atmosphere. 1H and 13C NMR spectra were
measured on a Bruker Avance 400 or 600 MHz NMR spectrometer
with CDCl3 or DMSO-d6 as solvent and recorded in ppm relative to
an internal tetramethylsilane standard. Thin layer chromatography
(TLC) characterization was performed with precoated silica gel
GF254 (0.2 mm), while column chromatography characterization
was performed with silica gel (100e200 mesh). Melting points
were measured with YRT-3 melting point apparatus (Shantou Keyi
Instrument & Equipment Co., Ltd., Shantou, China). High resolution
mass spectroscopy data of the product were collected on a Waters
Micromass GCT or a Bruker Apex IV FTMS instrument. The synthesis
method of 2-Oxoaldehyde derivatives 1ae1l were according to the
reported procedure.15 General chemicals were purchased from
commercial suppliers and used without further purification.
4.2.5. 2-Oxo-2-(pyrrolidin-1-yl)-N-(p-tolyl) acetamide (3ba). White
solid, mp 162e163 ꢀC; 1H NMR (CDCl3, 600 MHz):
d 9.40 (s,1H), 7.50
(d, J¼8.4 Hz, 2H), 7.16 (d, J¼7.8 Hz, 2H), 4.09 (t, J¼6.8 Hz, 2H), 3.61 (t,
J¼6.8 Hz, 2H), 2.33 (s, 3H), 2.01e1.98 (m, 2H), 1.91e1.88 (m, 2H); 13
C
NMR (CDCl3, 150 MHz):
d 160.0, 158.0, 134.9, 133.9, 129.5, 119.8,
48.7, 48.1, 26.6, 23.3, 20.8. ESI HRMS: calcd for C13H16N2O2þNaþ
255.1104, found 255.1108. Elemental Analysis: C, 67.22; H, 6.94; N,
12.06, found C, 67.30; H, 6.89; N, 12.01.
4.2.6. N1-Isopropyl-N2-(p-tolyl)oxalamide (3bb). Off-white solid,
mp 192e196 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.23 (s, 1H), 7.51 (d,
J¼8.0 Hz, 2H), 7.40 (s, 1H), 7.18 (d, J¼8.0 Hz, 2H), 4.13e4.08 (m, 1H),
4.2. General reaction procedure for the direct oxidative re-
actions of aldehydes with amines
2.34 (s, 3H), 1.25 (d, J¼6.4 Hz, 6H); 13C NMR (CDCl3, 150 MHz):
d
159.1, 157.5, 134.9, 133.9, 129.6, 119.8, 42.2, 22.3, 20.9. ESI HRMS:
calcd for C12H16N2O2þNaþ 243.1104, found 243.1106. Elemental
2-Oxoaldehydes (3.0 mmol), amines (1.0 mmol), and 2 mL of
ethanol were added to a reaction tube under air, and H2O2
(3.0 mmol, 30% aqueous solution) was dropped in over three
minutes. The solution was then stirred at room temperature until
the starting material was completely consumed (monitored by
TLC). The mixture was diluted with water and extracted with ethyl
acetate (20 mL ꢁ 3). The organic layer was dried over anhydrous
sodium sulfate and the solvent was evaporated to dryness. The
Analysis: C, 65.43; H, 7.32; N,12.72, found C, 65.52; H, 7.39; N,12.54.
4.2.7. 2-Morpholino-2-oxo-N-(p-tolyl)acetamide (3bc). Pale yellow
solid, mp 94e98 ꢀC; 1H NMR (CDCl3, 600 MHz):
d 9.15 (s, 1H), 7.47
(d, J¼8.4 Hz, 2H), 7.17 (d, J¼8.4 Hz, 2H), 4.33 (t, J¼4.8 Hz, 2H),
3.79e3.75 (m, 4H), 3.73 (t, J¼4.8 Hz, 2H), 2.34 (s, 3H); 13C NMR
(CDCl3,150 MHz): d 160.2,158.0,135.0,134.0,129.6,119.8, 67.2, 66.8,
47.3, 44.0, 20.9. ESI HRMS: calcd for C13H16N2O3þNaþ 271.1053,

6932
Z. Zhan et al. / Tetrahedron 71 (2015) 6928e6934
found 271.1058. Elemental Analysis: C, 62.89; H, 6.50; N, 11.28,
found C, 62.96; H, 6.58; N, 11.12.
C
12H13ClN2O2þNaþ 275.0558, found 275.0560. Elemental Analysis:
C, 57.04; H, 5.19; N, 11.09, found C, 57.13; H, 5.17; N, 11.06.
4.2.8. N-(4-Methoxyphenyl)-2-oxo-2-(pyrrolidin-1-yl)acetamide
4.2.15. N-(4-Chlorophenyl)-2-oxo-2-(piperidin-1-yl)acetamide
(3ca). White solid, mp 136e140 ꢀC; 1H NMR (CDCl3, 600 MHz):
(3eb). Pale yellow solid, mp 122e125 ꢀC; 1H NMR (CDCl3,
d
9.41 (s, 1H), 7.54 (d, J¼9.6 Hz, 2H), 6.89 (d, J¼8.4 Hz, 2H), 4.08 (t,
J¼7.2 Hz, 2H), 3.80 (s, 3H), 3.61 (t, J¼7.2 Hz, 2H), 2.01e1.97 (m, 2H),
1.90e1.87 (m, 2H); 13C NMR (CDCl3, 150 MHz):
159.1, 157.8, 156.4,
400 MHz):
d
9.22 (s, 1H), 7.56 (d, J¼8.8 Hz, 2H), 7.31 (d, J¼8.8 Hz,
2H), 4.10e4.08 (m, 2H), 3.66e3.63 (m, 2H) 1.71e1.68 (m, 6H); 13C
d
NMR (CDCl3, 150 MHz): d 160.7, 159.2, 135.6, 129.9, 129.0, 121.1, 47.7,
130.1, 121.2, 113.8, 55.2, 48.6, 48.0, 26.6, 23.2. ESI HRMS: calcd for
C
62.89; H, 6.50; N, 11.28, found C, 63.02; H, 6.44; N, 11.20.
44.7, 26.7, 25.7, 24.3. ESI HRMS: calcd for C13H15ClN2O2þNaþ
289.0714, found 289.0716. Elemental Analysis: C, 58.54; H, 5.67; N,
10.50, found C, 58.61; H, 5.75; N, 10.40.
13H16N2O3þNaþ 271.1053, found 271.1056. Elemental Analysis: C,
4.2.9. N-(4-Methoxyphenyl)-2-oxo-2-(piperidin-1-yl)acetamide
4.2.16. (S)-N1-(4-Chlorophenyl)-N2-(1-phenylethyl)
oxalamide
(3cb). White solid, mp 92e94 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 9.15
(3ec). Off-white solid, mp 181e184 ꢀC; 1H NMR (CDCl3, 600 MHz):
(s, 1H), 7.53 (d, J¼8.4 Hz, 2H), 6.88 (d, J¼8.8 Hz, 2H), 4.10e4.00 (m,
d
9.25 (s, 1H), 7.76 (s, 1H), 7.57 (d, J¼8.4 Hz, 2H), 7.37 (d, J¼8.4 Hz,
2H), 3.80 (s, 3H), 3.70e3.63 (m, 2H), 1.70e1.60 (m, 6H); 13C NMR
2H), 7.35e7.29 (m, 5H), 5.13e5.10 (m, 1H), 1.60 (d, J¼7.2 Hz, 3H); 13
C
(CDCl3, 150 MHz):
d
159.3, 157.9, 156.6, 130.0, 121.4, 114.0, 55.3, 47.7,
NMR (CDCl3, 150 MHz): d 159.3, 159.0, 143.9, 136.9, 128.8, 128.5,
128.4, 127.1, 126.5, 122.1, 49.0, 21.8. ESI HRMS: calcd for
C
44.8, 26.7, 25.6, 24.4. ESI HRMS: calcd for C14H18N2O3þNaþ
285.1210, found 285.1216. Elemental Analysis: C, 64.11; H, 6.92; N,
10.68, found C, 64.20; H, 6.99; N, 10.50.
16H15ClN2O2þNaþ 325.0714, found 325.0716. Elemental Analysis:
C, 63.48; H, 4.99; N, 9.25, found C, 63.61; H, 4.97; N, 9.18.
4.2.10. N-(4-Methoxyphenyl)-2-(4-methylpiperidin-1-yl)-2-
4.2.17. N-(4-Bromophenyl)-2-oxo-2-(pyrrolidin-1-yl)acetamide
oxoacetamide (3cc). Pale brown liquid; 1H NMR (CDCl3, 400 MHz):
(3fa). Pale brown solid, mp 192e194 ꢀC; 1H NMR (CDCl3,
d
9.04 (s, 1H), 7.52 (d, J¼8.8 Hz, 2H), 6.89 (d, J¼8.8 Hz, 2H), 5.10 (d,
600 MHz):
2H), 4.07 (t, J¼6.6 Hz, 2H), 3.61 (t, J¼6.6 Hz, 2H), 2.03e1.98 (m,
2H), 1.92e1.88 (m, 2H); 13C NMR (CDCl3, 150 MHz):
158.7, 158.1,
d
9.50 (s, 1H), 7.53 (d, J¼8.4 Hz, 2H), 7.47 (d, J¼8.4 Hz,
J¼12.8 Hz, 1H), 4.55 (d, J¼12.8 Hz, 1H), 3.81 (s, 3H), 3.13 (t,
J¼12.8 Hz, 1H), 2.76 (t, J¼12.8 Hz, 1H), 1.79e1.75 (m, 2H), 1.71e1.66
(m, 1H), 1.31e1.20 (m, 2H), 0.98 (d, J¼6.4 Hz, 3H); 13C NMR (CDCl3,
d
136.0, 132.0, 121.2, 117.5, 48.9, 48.4, 26.8, 23.4. ESI HRMS: calcd
150 MHz):
d
160.0, 158.1, 156.8, 129.9, 121.7, 114.1, 55.2, 46.8, 44.1,
for
C
12H13BrN2O2þNaþ 319.0053, found 319.0064. Elemental
34.6, 33.7, 30.9, 21.6. ESI HRMS: calcd for C15H20N2O3þNaþ
299.1366, found 299.1369. Elemental Analysis: C, 65.20; H, 7.30; N,
10.14, found C, 65.28; H, 7.25; N, 10.09.
Analysis: C, 48.50; H, 4.41; N, 9.43, found C, 48.59; H, 4.39; N,
9.40.
4.2.18. Methyl
dine-4-carboxylate (3fb). Brown liquid; 1H NMR (CDCl3, 600 MHz):
9.19 (s, 1H), 7.51e7.46 (m, 4H), 4.96e4.94 (m, 1H), 4.39e4.36 (m,
1-(2-((4-bromophenyl)amino)-2-oxoacetyl)piperi-
4.2.11. N-(4-Methoxyphenyl)-2-morpholino-2-oxoacetamide
(3cd). Yellow solid, mp 89e91 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
9.13
d
(s, 1H), 7.51 (d, J¼9.0 Hz, 2H), 6.90 (d, J¼9.6 Hz, 2H), 4.33 (t,
1H), 3.72 (s, 3H), 3.49e3.45 (m, 1H), 3.08e3.04 (m, 1H), 2.67e2.62
J¼4.8 Hz, 2H), 3.81 (s, 3H), 3.78 (t, J¼4.8 Hz, 2H), 3.76 (t, J¼4.8 Hz,
(m, 1H), 2.05e2.03 (m, 2H), 1.89e1.76 (m, 2H); 13C NMR (CDCl3,
2H), 3.73 (t, J¼4.8 Hz, 2H); 13C NMR (CDCl3,150 MHz):
d
160.3,157.9,
150 MHz): d 174.2, 158.6, 158.0, 136.1, 131.9, 121.4, 117.6, 51.7, 45.8,
156.9, 129.8, 121.5, 114.2, 67.2, 66.7, 55.4, 47.2, 43.9. ESI HRMS: calcd
for C13H16N2O4þNaþ 287.1002, found 287.1004. Elemental Analysis:
C, 59.08; H, 6.10; N, 10.60, found C, 59.17; H, 6.17; N, 10.42.
43.3, 40.5, 28.8, 27.8. ESI HRMS: calcd for C15H17BrN2O4þNaþ
391.0264, found 391.0266. Elemental Analysis: C, 48.80; H, 4.64; N,
7.59, found C, 48.87; H, 4.72; N, 7.49.
4.2.12. N-(3,5-Dimethoxyphenyl)-2-oxo-2-(pyrrolidin-1-yl)acet-
4.2.19. N-(3-Chlorophenyl)-2-oxo-2-(pyrrolidin-1-yl)acetamide
amide (3da). White solid, mp 126e130 ꢀC; 1H NMR (CDCl3,
(3ga). White solid, mp 133e135 ꢀC; 1H NMR (CDCl3, 600 MHz):
400 MHz):
(d, J¼6.8 Hz, 2H), 3.80 (s, 6H), 3.61 (t, J¼6.8 Hz, 2H), 2.02e1.97 (m,
2H), 1.92e1.87 (m, 2H); 13C NMR (CDCl3, 150 MHz):
161.1, 158.9,
d
9.43 (s,1H), 6.86e6.85 (m, 2H), 6.28e6.27 (m,1H), 4.08
d
9.55 (s, 1H), 7.43 (d, J¼8.4 Hz, 1H), 7.28 (d, J¼7.8 Hz, 2H), 7.13 (d,
J¼7.8 Hz, 1H), 4.07 (t, J¼7.2 Hz, 2H), 3.62 (t, J¼7.2 Hz, 2H), 2.03e1.99
(m, 2H), 1.92e1.88 (m, 2H); 13C NMR (CDCl3, 150 MHz):
158.6,
d
d
158.0, 138.6, 97.9, 97.4, 55.4, 49.0, 48.4, 26.9, 23.4. ESI HRMS: calcd
for C14H18N2O4þNaþ 301.1159, found 301.1162. Elemental Analysis:
C, 60.42; H, 6.52; N, 10.07, found C, 60.49; H, 6.60; N, 9.91.
158.1, 138.1, 134.7, 130.0, 124.9, 119.8, 117.8, 49.0, 48.5, 26.8, 23.3. ESI
HRMS: calcd for C12H13ClN2O2þNaþ 275.0558, found 275.0560.
Elemental Analysis: C, 57.04; H, 5.19; N, 11.09, found C, 57.11; H,
5.27; N, 10.99.
4.2.13. N-(3,5-Dimethoxyphenyl)-2-morpholino-2-oxoacetamide
(3db). White solid, mp 114e118 ꢀC; 1H NMR (CDCl3, 400 MHz):
4.2.20. N-(3,5-Dichlorophenyl)-2-oxo-2-(pyrrolidin-1-yl)acetamide
d
9.17 (s, 1H), 6.82e6.81 (m, 2H), 6.30e6.29 (m, 1H), 4.32 (t,
(3ha). Off-white solid, mp 188e192 ꢀC; 1H NMR (CDCl3, 400 MHz):
J¼4.8 Hz, 2H), 3.79 (s, 6H), 3.77e3.75 (m, 4H), 3.74e3.73 (m, 2H);
d
9.56 (s, 1H), 7.61e7.60 (m, 2H), 7.15e7.14 (m, 1H), 4.06 (t, J¼7.2 Hz,
13C NMR (CDCl3, 150 MHz):
d
161.0, 158.8, 157.9, 138.6, 98.0, 97.6,
2H), 3.62 (t, J¼7.2 Hz, 2H), 2.05e1.98 (m, 2H), 1.93e1.86 (m, 2H); 13
C
67.1, 66.7, 55.3, 47.3, 44.0. ESI HRMS: calcd for C14H18N2O5þNaþ
317.1108, found 317.1109. Elemental Analysis: C, 57.14; H, 6.16; N,
9.52, found C, 57.23; H, 6.23; N, 9.34.
NMR (CDCl3, 150 MHz): d 174.3, 159.8, 158.6, 138.8, 135.2, 124.6,
118.4, 48.7, 48.3, 26.6, 23.2. ESI HRMS: calcd for
C
12H12Cl2N2O2þNaþ 309.0168, found 309.0170. Elemental Analysis:
C, 50.20; H, 4.21; N, 9.76, found C, 50.33; H, 4.19; N, 9.69.
4.2.14. N-(4-Chlorophenyl)-2-oxo-2-(pyrrolidin-1-yl)acetamide
(3ea). White solid, mp 191e194 ꢀC; 1H NMR (CDCl3, 400 MHz):
4.2.21. N1-(3,5-Dichlorophenyl)-N2-isopropyloxalamide (3hb). Pale
d
9.51 (s, 1H), 7.58 (d, J¼8.4 Hz, 2H), 7.32 (d, J¼8.8 Hz, 2H), 4.07 (t,
J¼6.8 Hz, 2H), 3.61 (t, J¼6.8 Hz, 2H), 2.04e1.97 (m, 2H), 1.92e1.86
(m, 2H); 13C NMR (CDCl3, 150 MHz):
160.6, 159.2, 135.8, 129.8,
128.9, 121.0, 48.9, 48.3, 26.8, 23.3. ESI HRMS: calcd for
yellow solid, mp 164e166 ꢀC; 1H NMR (CDCl3, 600 MHz):
d 9.48 (s,
1H), 7.64e7.63 (m, 2H), 7.36 (s, 1H), 7.18e7.17 (m, 1H), 4.13e4.10 (m,
d
1H), 1.27 (d, J¼6.6 Hz, 6H); 13C NMR (CDCl3, 150 MHz):
d 159.8,
158.6, 138.7, 135.3, 124.9, 118.1, 42.1, 22.3. ESI HRMS: calcd for

Z. Zhan et al. / Tetrahedron 71 (2015) 6928e6934
6933
C11H12Cl2N2O2þNaþ 297.0168, found 297.0170. Elemental Analysis:
1.98e1.91 (m, 2H), 1.87e1.80 (m, 2H), 1.59e1.52 (m, 2H), 0.93 (t,
C, 48.02; H, 4.40; N, 10.18, found C, 48.09; H, 4.48; N, 10.08.
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d 160.4, 159.2, 48.4, 47.5,
40.7, 26.6, 23.2, 22.3, 11.1. ESI HRMS: calcd for C9H16N2O2þNaþ
207.1104, found 207.1105. Elemental Analysis: C, 58.67; H, 8.75; N,
15.21, found C, 58.75; H, 8.70; N, 15.16.
4.2.22. Methyl 1-(2-((3,5-dichlorophenyl)amino)-2-oxoacetyl)piper-
idine-4-carboxylate (3hc). Off-white solid, mp 122e126 ꢀC; 1H NMR
(CDCl3, 400 MHz):
d 9.24 (s, 1H), 7.57e7.56 (m, 2H), 7.16 (s, 1H),
4.96e4.92 (m, 1H), 4.38e4.34 (m, 1H), 3.72 (s, 3H), 3.51e3.45 (m,
1H), 3.10e3.03 (m, 1H), 2.67e2.61 (m, 1H), 2.06e2.03 (m, 2H),
4.2.29. N1-Isopropyl-N2-propyloxalamide (3lb). White solid, mp
153e156 ꢀC; 1H NMR (CDCl3, 600 MHz):
d 7.49 (s, 1H), 7.30 (s, 1H),
1.90e1.75 (m, 2H); 13C NMR (CDCl3, 150 MHz):
d
174.2, 159.9, 158.7,
4.08e4.02 (m, 1H), 3.28 (q, J¼6.6 Hz, 2H), 1.62e1.56 (m, 2H),
138.7, 135.3, 124.9, 118.2, 51.9, 45.8, 43.3, 40.4, 28.8, 27.7. ESI HRMS:
calcd for C15H16Cl2N2O4þNaþ 381.0379, found 381.0381. Elemental
Analysis: C, 50.16; H, 4.49; N, 7.80, found C, 50.25; H, 4.47; Cl, N,
7.77.
1.25e1.21 (m, 6H), 0.97e0.93 (m, 3H); 13C NMR (CDCl3, 150 MHz):
d
160.0, 159.0, 41.9, 41.3, 22.4, 22.2, 11.2. ESI HRMS: calcd for
C8H16N2O2þNaþ 195.1104, found 195.1105. Elemental Analysis: C,
55.79; H, 9.36; N, 16.27, found C, 55.86; H, 9.44; N, 16.11.
4.2.23. N-(4-Nitrophenyl)-2-oxo-2-(pyrrolidin-1-yl)acetamide
4.2.30. Methyl 1-(2-oxo-2-(propylamino)acetyl) piperidine-4-
(3ia). Off-white solid, mp 216e219 ꢀC; 1H NMR (CDCl3, 600 MHz):
carboxylate (3lc). Yellow liquid; 1H NMR (CDCl3, 600 MHz):
d 7.22
d
9.85 (s, 1H), 8.25 (d, J¼8.4 Hz, 2H), 7.82 (d, J¼8.4 Hz, 2H), 4.08 (t,
J¼7.2 Hz, 2H), 3.63 (t, J¼7.2 Hz, 2H), 2.04e2.01 (m, 2H), 1.94e1.90
(m, 2H); 13C NMR (CDCl3, 150 MHz):
158.3, 158.1, 144.0, 142.6,
(s, 1H), 4.82e4.79 (m, 1H), 4.35e4.32 (m, 1H), 3.70 (s, 3H),
3.38e3.33 (m, 1H), 3.26 (q, J¼6.6 Hz, 2H), 2.99e2.94 (m, 1H),
2.62e2.59 (m, 1H), 2.01e1.98 (m, 2H), 1.83e1.71 (m, 2H), 1.61e1.56
d
125.1, 119.3, 49.0, 48.5, 26.9, 23.4. ESI HRMS: calcd for
C
54.75; H, 4.98; N, 15.96, found C, 54.82; H, 5.06; N, 15.80.
(m, 2H), 0.95 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d 174.3,
12H13N3O4þNaþ 286.0798, found 286.0802. Elemental Analysis: C,
159.8, 158.6, 51.9, 45.8, 43.2, 40.7, 40.4, 28.7, 27.7, 22.2, 11.1. ESI
HRMS: calcd for C12H20N2O4þNaþ 279.1315, found 279.1319. Ele-
mental Analysis: C, 56.24; H, 7.87; N, 10.93, found C, 56.33; H, 7.94;
N, 10.75.
4.2.24. 2-(4-Methylpiperidin-1-yl)-N-(4-nitrophenyl)-2-
oxoacetamide (3ib). Pale yellow solid, mp 242e244 ꢀC; 1H NMR
(CDCl3, 400 MHz):
d
9.62 (s, 1H), 8.25 (d, J¼8.8 Hz, 2H), 7.79 (d,
4.3. The experiment to synthesis of 6
J¼8.8 Hz, 2H), 5.07e5.03 (m, 1H), 4.56e4.53 (m, 1H), 3.20e3.13 (m,
1H), 2.83e2.76 (m, 1H), 1.82e1.78 (m, 2H), 1.76e1.71 (m, 1H),
1.35e1.17 (m, 2H), 0.99 (d, J¼6.8 Hz, 3H); 13C NMR (CDCl3,
A
mixture of 2-morpholino-2-oxo-N-phenylacetamide 3ac
(13 mg, 0.033 mmol), POCl3 (1.0 ml) was stirred at room temper-
ature for 5 min. Then, transfer the reaction liquid to 65 ꢀC and stir
overnight under argon. After disappearance of the reactant (mon-
itored by TLC), the reaction liquid was poured into 20 ml ice water,
extracted with ethyl acetate three times (3 ꢁ 25 mL). The organic
layer was washed with water and saturated brine, dried over an-
hydrous Na2SO4 and evaporation. The residue was purified by col-
umn chromatography on silica gel (eluent: petroleum ether/ethyl
acetate) to afford the product 6 as an orange solid (63% yield). Mp
150 MHz):
d 160.1, 159.5, 144.0, 142.8, 125.0, 119.5, 47.0, 44.3, 34.8,
33.8, 30.9, 21.5. ESI HRMS: calcd for C14H17N3O4þNaþ 314.1111,
found 314.1113. Elemental Analysis: C, 57.72; H, 5.88; N, 14.42,
found C, 57.81; H, 5.95; N, 14.24.
4.2.25. N-(Naphthalen-2-yl)-2-oxo-2-(pyrrolidin-1-yl)acetamide
(3ja). White solid, mp 169e170 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
9.64 (s, 1H), 8.36 (s, 1H), 7.84e7.79 (m, 3H), 7.54e7.41 (m, 3H), 4.14
(t, J¼6.8 Hz, 2H), 3.65 (t, J¼6.8 Hz, 2H), 2.05e2.00 (m, 2H),1.95e1.90
(m, 2H); 13C NMR (CDCl3, 150 MHz):
158.9, 158.2, 134.4, 133.7,
200e202 ꢀC (Lit16 202e203 ꢀC); 1H NMR (CDCl3, 400 MHz):
d 8.05
d
(s, 1H), 7.61e7.53 (m, 2H), 7.11 (t, J¼7.2 Hz, 1H), 6.90 (d, J¼8.0 Hz,
130.8, 128.8, 127.7, 127.5, 126.5, 125.2, 119.6, 116.6, 49.0, 48.4, 26.8,
23.3. ESI HRMS: calcd for
291.1105. Elemental Analysis: C, 71.62; H, 6.01; N, 10.44, found C,
71.75; H, 5.95; N, 10.36.
1H).
C
16H16N2O2þNaþ 291.1104, found
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (NSFC) (grant number 81373259).
4.2.26. 2-Morpholino-N-(naphthalen-2-yl)-2-oxoacetamide
(3jb). Pale brown solid, mp 112e116 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
9.40 (s, 1H), 8.32e8.31 (m, 1H), 7.85e7.80 (m, 3H), 7.52e7.44 (m,
3H), 4.38 (t, J¼4.8 Hz, 2H), 3.80 (t, J¼4.8 Hz, 2H), 3.79e3.76 (m, 4H);
13C NMR (CDCl3, 150 MHz):
158.8, 158.2, 134.5, 133.6, 130.7, 128.8,
References and notes
d
127.8, 127.5, 126.4, 125.3, 119.5, 116.5, 66.8, 66.3, 47.2, 43.9. ESI
HRMS: calcd for C16H16N2O3þNaþ 307.1053, found 307.1055. Ele-
mental Analysis: C, 67.59; H, 5.67; N, 9.85, found C, 67.67; H, 5.62;
N, 9.80.
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J¼6.8 Hz, 2H), 3.54 (t, J¼6.8 Hz, 2H), 3.24 (q, J¼6.8 Hz, 2H),
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d
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