α-Carbonylimine to α-Carbonylamide: An efficient oxidative amidation approach

Article abstract of DOI:10.1002/ejoc.201500251

Abstract Our interest in generating amide bonds by employing the activated C=N system has led to the development of an efficient oxidative amidation reaction between 2-oxoaldehyde and weak nucleophilic amines (anilines, benzamides and sulfonamides). Mechanistic studies support the involvement of α-carbonylimine (-CO-C=N-) based compounds or intermediates as a central feature of the reaction, in which an adjacent CO moiety enhances the electrophilicity of the C=N system, which favors attack of the oxidant (TBHP or SeO₂), thereby resulting in the generation of the desired products in good yields. The direct oxidative coupling of 2-oxoaldehydes and weak nucleophilic amines has been accomplished through either MgSO₄-TBHP-pyridine/CuBr, or SeO₂·pyridine promoted methods. In the current study, SeO₂·pyridine emerged as a versatile reagent with which to promote initial α-carbonylimine formation between 2-oxoaldehyde and weak nucleophilic amine, and subsequent oxidation to the corresponding α-carbonylamide. The reported methodology constitutes one of the few reports of the synthesis of α-ketoamides from anilines, perhaps the second report for the generation of α-ketoimides, and the first report of the generation of 2-oxoamides with sulfonamides.

Full text of DOI:10.1002/ejoc.201500251

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
FULL PAPER
DOI: 10.1002/ejoc.201500251
α-Carbonylimine to α-Carbonylamide: An Efficient Oxidative Amidation
Approach
Anil K. Padala,[a,b] Nagaraju Mupparapu,[a,b] Deepika Singh,[c] Ram A. Vishwakarma,[a,b]
and Qazi Naveed Ahmed*[a,b]
Keywords: Synthetic methods / Oxidation / Amines / Amides / Sulfonamides
Our interest in generating amide bonds by employing the
activated C=N system has led to the development of an ef-
ficient oxidative amidation reaction between 2-oxoaldehyde
and weak nucleophilic amines (anilines, benzamides and
sulfonamides). Mechanistic studies support the involvement
of α-carbonylimine (–CO–C=N–) based compounds or inter-
mediates as a central feature of the reaction, in which an
adjacent CO moiety enhances the electrophilicity of the C=N
system, which favors attack of the oxidant (TBHP or SeO2),
thereby resulting in the generation of the desired products
dehydes and weak nucleophilic amines has been ac-
complished through either MgSO4–TBHP–pyridine/CuBr, or
SeO2·pyridine promoted methods. In the current study,
SeO2·pyridine emerged as a versatile reagent with which to
promote initial α-carbonylimine formation between 2-oxoal-
dehyde and weak nucleophilic amine, and subsequent oxid-
ation to the corresponding α-carbonylamide. The reported
methodology constitutes one of the few reports of the synthe-
sis of α-ketoamides from anilines, perhaps the second report
for the generation of α-ketoimides, and the first report of the
in good yields. The direct oxidative coupling of 2-oxoal- generation of 2-oxoamides with sulfonamides.
cess of reactions with secondary amines, we presume that
the α-carbonyl moiety further activates the iminium ion
Introduction
electrophilicity and facilitates nucleophilic attack. Herein,
In the past few years, a number of novel routes for the
the C1-oxygen atom of the α-ketoamide was derived from
generation of valuable α-ketoamides have been estab-
DMSO, which acted as nucleophile/solvent. In this context,
lished.[1,2] Our group has contributed towards the genera-
we initiated a program to test imines with different nucleo-
tion of α-ketoamides through the use of the iminium ion as
philic oxidants to generate new chemistry and perhaps es-
a reactive intermediate.[1c] The potential of our method lies
tablish a general oxidative coupling protocol that over-
in the direct amidation procedure between 2-oxoaldehydes
comes the limitation towards the use of weak nucleophilic
and secondary amines via the iminium intermediate under
amines.
mild reaction conditions. Although this highly challenging
process was achieved by using dimethyl sulfoxide (DMSO)
promoted oxidative amidation reaction, it failed to produce
Beyond the synthesis of α-ketoamides with anilines, the
group of Wu recently reported the generation of α-keto-
imides through I2-catalyzed oxidative cross-coupling reac-
the desired products with anilines (Scheme 1). This limita-
tion between acetophenones/2-oxoaldehydes and benzamid-
tion was attributed to 1) weak nucleophilicity of anilines,
ine hydrochlorides.[3] Although these reactions generated
2) low reactivity of the imine compared with the iminium
valuable compounds in high yields, they failed to generate
ion under neutral conditions, and/or 3) failure of the reac-
the desired results with benzamides. Moreover, there are
tion to produce the imine in DMSO. However, for the suc-
very few reports of the direct utilization of the acyl C–H
moiety of aldehydes under oxidative conditions with weak
nucleophilic amines.[4] In view of this, a method is required
[a] Medicinal Chemistry Division, Indian Institute of Integrative that facilitates reaction with a complete set of weak nucleo-
Medicine (IIIM),
philic amines. In our current work, we have successfully ac-
180001, Canal Road, Jammu, Jammu & Kashmir, India
complished TBHP·pyridine, TBHP-CuBr, MgSO4–TBHP–
pyridine, and SeO2·pyridine promoted oxidative amidation
methods to achieve novel transformations of α-carb-
onylimines into α-carbonylamides. The reaction conditions
works well with both α-carbonylimine (CI) as substrate
(Scheme 1 a) and with CI generated in situ (Scheme 1 b and
c).
E-mail: naqazi@iiim.ac.in
http://www.iiim.res.in
[b] Academy of Scientific and Innovative Research (AcSIR),
110001, Anusandhan Bhawan, 2-Rafi Marg, New Delhi, India
[c] Quality Control and Quality Assurance, Indian Institute of In-
tegrative Medicine (IIIM),
180001, Canal Road, Jammu, Jammu & Kashmir, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500251.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Q. N. Ahmed et al.
FULL PAPER
Scheme 1. Oxidative amidation reactions between 2-oxoaldehydes and weak nucleophilic amines.
Results and Discussion
Table 1. Optimization studies for the synthesis of α-carbonylamides
from α-carbonylimines.
We started our investigation with imine 1a as a model
substrate for testing against oxidants with nucleophilic pro-
pensity (Table 1, entries 4 and 8–10). It was observed that
the desired product 2a was obtained in 40 and 20% yields
when 1a was treated with TBHP and SeO2, respectively, at
100 °C in acetonitrile (MeCN). Reactions with other oxi-
dants either failed or produced the required product in
trace amounts (entries 9 and 8). To improve the yield, we
initiated a program to test the reaction of 1a with TBHP in
the presence of different concentrations of pyridine (en-
tries 5–7). Upon optimization, the combination of 1a
(0.5 mmol) and TBHP (1.25 mmol) with pyridine (1 mmol)
in MeCN at 100 °C was found to be the best reaction condi-
tions for this transformation; these conditions furnished the
desired product 2a in 92% yield (entry 7). Although
TBHP·pyridine furnished the desired product in good
yields, we were keen to see whether the use of TBHP-metal
salts could provide a milder option. To this end, a test reac-
tion was performed between 1a (0.5 mmol) and TBHP
(1.25 mmol) in the presence of 20 mol-% copper salts (en-
tries 11–17); it was found that the best results were obtained
when CuBr was used as catalyst (90% yield, entry 13). Fur-
ther optimization of the reaction was performed with dif-
ferent amounts of CuBr, wherein the reaction with 10 mol%
CuBr gave yields that were comparable with those achieved
with TBHP·pyridine (entry 12). Furthermore, performing
the reaction between 1a (0.5 mmol) and SeO2 (0.5 mmol)
with pyridine (1 mmol) in MeCN at 100 °C produced 2a in
95% yield (entry 18).
Entry Oxidant
[mmol]
Base [mM] or metal
[mol-%]
Solvent
Temp. Time Yield
[°C] [h]
[%][a]
1
TBHP (0.5)
–
–
–
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
toulene
THF
80
4
4
4
4
4
4
2
4
4
4
4
1
1
4
4
4
4
1
4
4
4
4
4
4
20
30
40
40
60
80
92
0
2
3
4
TBHP (0.5)
TBHP (1)
TBHP (1)
100
100
120
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
5
TBHP (1.25) pyridine (0.5)
TBHP (1.25) pyridine (0.75)
TBHP (1.25) pyridine (1)
MnO2 (0.5)
IBX (0.5)
SeO2 (0.5)
TBHP (1.25) CuCl (20)
TBHP (1.25) CuBr (10)
TBHP (1.25) CuBr (20)
TBHP (1.25) CuCN (20)
TBHP (1.25) CuCl2 (20)
TBHP (1.25) CuBr2 (20)
TBHP (1.25) CuI (20)
SeO2 (0.5)
SeO2 (0.5)
SeO2 (0.5)
SeO2 (0.5)
SeO2 (0.5)
SeO2 (0.5)
SeO2 (0.5)
6
7[b]
8
–
–
–
9
0
10
11
12[c]
13
14
15
16
17
18[d]
19
20
21
22
23
24
20
50
90
90
40
0
0
40
95
0
0
0
0
0
0
pyridine (1)
pyridine (1)
pyridine (1)
pyridine (1)
pyridine (1)
pyridine (1)
pyridine (1)
MeOH
DMF
DMSO
1,4-dioxane 100
[a] Isolated yield. [b] Reaction conditions: α-carbonylimine
(0.5 mmol), TBHP (1.25 mmol), pyridine (1 mmol), MeCN (3 mL).
[c] α-Carbonylimine (0.5 mmol), TBHP (1.25 mmol), CuBr
(10 mol%), MeCN (3 mL). [d] α-Carbonylimine (0.5 mmol), SeO2
(0.5 mmol), pyridine (1 mmol), MeCN (3 mL).
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Efficient Oxidative Amidation Approach
With the optimized conditions in hand, reactions with a ence of a range of pyridine concentrations (entries 8–11).[5]
range of substituted imines were investigated. To our satis- It was observed that reaction with 2 equiv. pyridine pro-
faction, the results indicated that, irrespective of the nature duced the desired product 2a in good yields (94%; entry 11)
of the substitution being used, the reactions afforded the at 100 °C. The same reaction was subsequently examined in
desired products in good yields (90–95%; Table 3, en- the presence of different bases to establish the role of pyr-
tries 2a–d). Although this transformation is unique, we idine. The results clearly revealed the dual function of pyr-
wished to establish this method as a novel oxidative amid- idine. One role is perhaps as base and the second role is
ation protocol between 2-oxoaldehyde and sets of weak nu- related to its tendency to enhance the nucleophilicity of
cleophilic amines that have thus far presented a particular SeO2 through the formation of a pyridine-SeO2 complex.[5]
challenge. To this end, a reaction was initially planned be- Looking in detail at the unprecedented results obtained be-
tween aniline 4a and phenylglyoxal (3a) in MeCN at 100 °C tween aniline 4a and phenylglyoxal 3a, we were keen to test
with a range of oxidants (Table 2, entries 1–4). Initial the reaction of phenylglyoxal 3a against benzamide 5a and
screening results revealed that the desired product was ob- phenylsulfonamide 6a (entries 18 and 19). Surprisingly, we
tained in 20% yield with SeO2 (entry 4). Other oxidants in- found that this method gave good yields of the desired
cluding TBHP failed to produce 2a (entries 1–4). However, products in each case.
when the reaction between 3a and 4a was carried out in
With these results in hand, sets of reactions between 2-
the presence of 5 equiv. MgSO4, the use of TBHP·pyridine oxoaldehydes 3 and weak nucleophilic amines 4–6 were car-
(1.25:0.5) afforded the desired product with aniline in good ried out (as per optimization procedures), to overview the
yield (40%; entry 5). Further optimization established that generality and substrate scope of these reactions. For this
the best result in this case was achieved when 0.5 mmol 3a purpose, in each category, we conducted the reaction with
was treated with 0.5 mmol 4a in the presence of 2.5 mmol electron-rich and electron-deficient substrates. In one set of
MgSO4 (80%; entry 7). However, when the same method experiments, the reaction was performed between 2-oxo-
was applied to benzamides and sulfonamides, the desired aldehydes 3 and anilines 4 (Table 3, entries 2a–l). In each
product was not produced.
case, we observed complete conversion of reactants into
We then focused on the use of SeO2 to improve the yields product 2, irrespective of the nature of the substrate being
and establish a general protocol for amidation. Based re- used. Another set of reactions was performed between 3
ported precedents, we tested the model reaction in the pres- and benzamides 5. These reactions also proved to be excit-
Table 2. Optimization studies for coupling of 2-oxoaldehydes and weak nucleophilic amines.
Entry
Oxidant additive [mmol]
Base [mmol]
Time [h]
Yield [%][a]
1
2
3
4
TBHP (0.5)
MnO2 (0.5)
IBX (0.5)
SeO2 (0.5)
TBHP (1.25) + MgSO4 (2.5)
TBHP (1.25) + MgSO4 (2.5)
TBHP (1.25) + MgSO4 (2.5)
SeO2 (0.5)
SeO2 (0.5)
SeO2 (0.5)
SeO2 (0.5)
SeO2 (0.25)
SeO2 (0.25)
SeO2 (0.25)
SeO2 (0.25)
SeO2 (0.25)
SeO2 (0.25)
SeO2 (0.25)
–
–
–
–
4
4
4
4
4
4
4
1
1
1
1
4
4
4
4
4
4
4
2
0
0
0
20
40
60
80
25
50
80
94
50
60
0
0
0
0
90
80
5
pyridine (0.5)
pyridine (0.75)
pyridine (1)
pyridine (0.25)
pyridine (0.5)
pyridine (0.75)
pyridine (1)
pyridine (1)
TEA (1)
NaOH (1)
KOH (1)
Na2CO3 (1)
K2CO3 (1)
pyridine (1)
pyridine (1)
6
7[b]
8
9
10
11[c]
12
13
14
15
16
17
18[d]
19[e]
SeO2 (0.25)
[a] Isolated yield. [b] Reaction conditions: phenylglyoxal (0.5 mmol), aniline (0.5 mmol), TBHP (1.25 mmol), MgSO4 (2.5 mmol), pyridine
(1 mmol). [c] Reaction conditions: phenylglyoxal (0.5 mmol), aniline (0.5 mmol), SeO2 (0.5 mmol), pyridine (1 mmol). [d] Reaction condi-
tions: phenylglyoxal (0.5 mmol), benzamide (0.5 mmol), SeO2 (0.5 mmol), pyridine (1 mmol). [e] Reaction conditions: phenylglyoxal
(0.5 mmol), phenylsulfonamide (0.5 mmol), SeO2 (0.5 mmol), pyridine (1 mmol).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Q. N. Ahmed et al.
FULL PAPER
Table 3. Oxidative amidation reactions of 2-oxoaldehyde with weak nucleophilic amines.[a]
[a] Reaction conditions (a): 1 (0.5 mmol) TBHP (1.25 mmol), CuBr (10 mol-%) or pyridine (1 mmol), MeCN (3 mL), 2 h, 100 °C. Reaction
conditions (b): 3 (0.5 mmol), 4 (0.5 mmol), MgSO4 (2.5 mmol), TBHP (1.25 mmol), pyridine (1 mmol), MeCN (3 mL), 3 h, 100 °C.
Reaction conditions (c): 3 (0.5 mmol), 4 or 5 or 6 (0.5 mmol), SeO2 (0.5 mmol), pyridine (1 mmol), MeCN (3 mL), 1–4 h, 100 °C. *
Methods (a) and (b) produced the desired product in comparable yields.
ing, because they generated excellent yields of the desired clearly support our prediction that the α-carbonyl group
products 7 in all cases (entries 7a–i). To validate the sub- further activates iminium ion electrophilicity and facilitates
strate scope of our method between 2-oxoaldehydes 3 and attack of oxidants and thereby leads to generation of the
sulfonamides 6, we conducted a further set of reactions amide bond. To support our conclusion, LC-ESI-MS ex-
(Table 3, entries 8a–f). In each case, we could isolate the periments were used to analyze the reaction between 3b and
desired product in good yield (70–94%). These results dem- 4a after different time intervals; see experiment (c), page 3
onstrate clearly the generality of the method towards sulf- in the Supporting Information. As depicted in Table 3, it is
onamides.
clear that the reaction is only feasible through α-carb-
To shed light on the possible mechanism for the direct onylimine under heating conditions. Given that the reaction
coupling between 2-oxoaldehyde and weak nucleophilic works well with α-carbonylimine (CI) as substrate, we can
amine, a number of control experiments were conducted confidently predict a mechanism that involves generation of
(Figure 1). In experiment (a), we established that no reac- CI as intermediate during the course of the reaction. Based
tion took place under the optimized conditions when benz- on these elements, we propose a mechanism that can be
aldehyde was treated with aniline. Similarly, when imine summarized under two headings: 1) where TBHP acts as
substrate 11 was treated with SeO2·pyridine complex as per oxidant and 2) where SeO2 acts as the oxidizing source
the optimized procedure, all starting materials were reco- (Figure 2). The TBHP-promoted oxidative coupling mecha-
vered unchanged [experiment (b)]. These two observations nism can be subcategorized further into two parts: a pyr-
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Efficient Oxidative Amidation Approach
attacks the C=N system of CI leading to 12. Finally, the
latter produces the desired product through elimination of
tert-butanol. In contrast to the anionic mechanism, the cop-
per-catalyzed reaction proceeds through a free-radical
mechanism.[6] As expected, copper(I) is oxidized to cop-
per(II) by TBHP, generating a tert-butyloxy radical. Cop-
per(II) and the tert-butyloxy radical, on reacting with
TBHP, generate CuIIBr(OOtBu) and the tert-butylperoxy
radical, respectively. The tert-butyloxy radical along with
CuIIBr(OOtBu) attack the C=N system of CI, thereby gen-
erating 13, which ultimately generates the desired product
through tert-butanol elimination.
SeO2 in the SeO2-promoted reaction has dual role. Its
preliminary role involves generation of α-carbonylimine,
which is then oxidized to α-carbonylamide. Initially amine
4 reacts with 2-oxoaldehyde 3 in the presence of SeO2 to
form an intermediate 14, which ultimately generates α-carb-
onylimine 1 through loss of selenous acid. As previously
reported,[5] pyridine enhances the nucleophilicity of SeO2
through formation of a pyridine-SeO2 complex (Py2SeO2),
which, in our case, led to the formation of the desired prod-
uct in good yields by oxidizing the C=N system of CI. The
work with SeO2·pyridine was further extended by promot-
ing the direct oxidative coupling of amines with aryl methyl
ketones 16. For this, a set of test reactions were performed
Figure 1. Mechanistic scenario.
idine-promoted ionic mechanism (Figure 2b) and a copper- in one pot with aryl methyl ketones 16 as source of 2-oxo-
catalyzed free-radical mechanism (Figure 2a). In the former aldehyde. In these reactions, SeO2 primarily promoted the
mechanism, we presume that, after abstracting a proton oxidation to the aryl methyl ketones, followed by formation
from TBHP, pyridine genarates a tert-butyloxy anion that of α-carbonylimines and finally its further oxidation to the
Figure 2. Control experiments.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Q. N. Ahmed et al.
FULL PAPER
HRMS spectra were recorded with Agilent 1100 LC-Q-TOF and
HRMS-6540-UHD instruments. IR spectra were recorded with a
Perkin–Elmer IR spectrophotometer.
respective products. In all the reactions tested, we observed
comparable yields of the desired product (Table 4).
Table 4. Oxidative coupling reaction between aryl methyl ketones
with weak nucleophilic amines.[a]
General Procedure for the Conversion of α-Carbonylimine into α-
Carbonylamide. Method (a):
A mixture of α-carbonylimine 1
(0.5 mmol), TBHP (1.25 mmol), and either pyridine (1.0 mmol) or
CuBr (10 mol-%) in acetonitrile (3 mL) was stirred at 100 °C for
2 h.
Method (c): A mixture of α-carbonylimine 1 (0.5 mmol), selenium
dioxide (0.5 mmol) and pyridine (1 mmol) in acetonitrile (3 mL)
was stirred at 100 °C for 1 h. After completion of the reaction, the
crude mixture was cooled to room temperature, filtered, and puri-
fied by column chromatography [silica gel (100–200#); ethyl acet-
ate/hexane, 0.1:10]. The desired product 2 (90–95% yield) was ob-
tained as a yellow solid.
General Procedure for the Synthesis of α-Carbonylamides, α-Carb-
onylimides, and α-Carbonylsulfonamides from Arylglyoxals and
Weak Nucleophilic Amines. Method (b): A mixture of arylglyoxal
3 (0.5 mmol), arylamine 4 (0.5 mmol), MgSO4 (2.5 mmol), TBHP
(1.25 mmol), and pyridine (1 mmol) in acetonitrile (3 mL) was
stirred at 100 °C for 3 h.
Method (c): A mixture of arylglyoxal monohydrate (0.5 mmol),
arylamine or arylamide or arylsulfonamide (0.5 mmol), selenium
dioxide (0.5 mmol), and pyridine (1 mmol) in acetonitrile (3 mL)
was stirred at 100 °C for 1–4 h. After completion of the reaction,
the crude mixture was cooled to room temperature, filtered, and
purified by column chromatography [silica gel (100–200#); ethyl
acetate/hexane].
[a] Reaction conditions: 16 (0.5 mmol), 4 or 5 or 6 (0.5 mmol),
SeO2 (1.0 mmol), pyridine (1.0 mmol), MeCN (3 mL), 4–7 h,
100 °C.
General Procedure for the Synthesis of α-Carbonylamides, α-Carb-
onylimides, and α-Carbonylsulfonamides from Aryl Methyl Ketones
and Weak Nucleophilic Amines: A mixture of SeO2 (0.5 mmol),
acetonitrile (3 mL) and a catalytic amount of H2O was heated until
a clear solution was formed. Aryl methyl ketone (0.5 mmol) was
added and heating was continued for 3 h. Arylamine or arylamide
Conclusions
We have applied the concept of 2-oxoimine-promoted re-
actions to establish a general oxidative amidation method
between 2-oxoaldehydes and weak nucleophilic amines
(anilines, benzamides and sulfonamides). Notably, this pre-
liminary work demonstrates the first example of oxidative
amidation reactions of benzamides and sulfonamides with
2-oxoaldehyde. A major part of this work highlights the po-
tential of SeO2·pyridine to promote α-carbonylimine forma-
tion with weak nucleophilic amines, that later undergo oxid-
ation to α-carbonylamide. Further applications of this rea-
gent in terms of a direct coupling protocol between aceto-
phenones and weak nucleophilic amines was revealed.
or arylsulfonamide (0.5 mmol) and
a SeO2·pyridine cocktail
(0.5:1 mmol) were added, and the mixture was heated to 100 °C.
Upon completion of the reaction, the crude mixture was cooled to
room temperature, filtered, and purified by column chromatog-
raphy [silica gel (100–200#); ethyl acetate/hexane].
2-Oxo-N,2-diphenylacetamide (2a):[1d] Yield 106 mg (94%); yellow
1
solid. H NMR (400 MHz, CDCl3): δ = 8.96 (br. s, 1 H), 8.42 (d,
J = 8.0 Hz, 2 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.66 (t, J = 7.5 Hz, 1
H), 7.51 (t, J = 7.6 Hz, 2 H), 7.40 (t, J = 7.6 Hz, 2 H), 7.20 (t, J =
7.3 Hz, 1 H) ppm. IR (CHCl ): ν = 3360, 2919, 1667, 1596 cm–1.
˜
3
LC-MS (ESI): m/z calcd. for C14H10NO2 [M – H]– 224.0; found
224.0. HRMS (TOF): m/z calcd. for C14H10NO2 [M – H]–
224.0712; found 224.0715.
N-(4-Fluorophenyl)-2-oxo-2-phenylacetamide (2b):[1d] Yield 112 mg
(92%); yellow solid. H NMR (400 MHz, CDCl3): δ = 8.95 (br. s,
1
Experimental Section
1 H), 8.44–8.39 (m, 2 H), 7.70–7.64 (m, 3 H), 7.54–7.49 (m, 2 H),
7.12–7.06 (t, J = 8.0 Hz, 2 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 187.30, 159.95 (d, J = 245.1 Hz), 158.79, 134.80, 133.05, 132.7,
131.53, 128.66, 121.71 (d, J = 8.0 Hz), 116.05 (d, J = 22.7 Hz) ppm.
General: All chemicals were obtained from Sigma–Aldrich and
used as received. 1H and 13C NMR spectra were recorded with
Bruker-Avance DPX FT-NMR 500 and 400 MHz instruments.
Chemical data for protons are reported in parts per million (ppm)
downfield from tetramethylsilane and are referenced to the residual
proton in the NMR solvents (CDCl3: 7.26 ppm). 13C NMR spectra
(CDCl3: 77.0 ppm) were recorded at 125 or 100 MHz: chemical
data for carbon atoms are reported in parts per million (ppm, δ
scale) downfield from tetramethylsilane and are referenced to the
carbon resonance of the solvent. Mass spectra of compounds were
recorded with VARIAN GC–MS-MS instrument, ESI-MS and
IR (CHCl ): ν = 3440, 3337, 1671, 1545, 1509 cm–1. LC-MS (ESI):
˜
3
m/z calcd. for C14H9FNO2 [M – H]– 242.0; found 241.9. HRMS
(TOF): m/z calcd. for C14H11FNO2 [M + H]+ 244.0774; found
244.0774.
N-(2-Fluorophenyl)-2-oxo-2-phenylacetamide (2c): Yield 110.5 mg
1
(91%); yellow solid. H NMR (400 MHz, CDCl3): δ = 9.21 (br. s,
1 H), 8.47–8.38 (m, 3 H), 7.66 (t, J = 7.4 Hz, 1 H), 7.51 (t, J =
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Efficient Oxidative Amidation Approach
7.8 Hz, 2 H), 7.17 (tt, J = 5.8, 3.6 Hz, 3 H) ppm. 13C NMR 2-(2-Chlorophenyl)-2-oxo-N-phenylacetamide (2i):[7] Yield 122.0 mg
1
(101 MHz, CDCl3): δ = 186.67, 158.94, 152.95 (d, J = 245.5 Hz), (94%); yellow solid. H NMR (400 MHz, CDCl3): δ = 8.84 (br. s,
134.70, 132.98, 131.46, 128.61, 125.54 (d, J = 7.6 Hz), 125.28 (d, J 1 H), 7.76–7.65 (m, 3 H), 7.51–7.43 (m, 2 H), 7.41–7.33 (m, 3 H),
= 10.3 Hz), 124.68 (d, J = 3.8 Hz), 121.43, 115.19 (d, J =
7.18 (t, J = 7.4 Hz, 1 H) ppm. 13C NMR (126 MHz, CDCl3): δ =
19.0 Hz) ppm. IR (CHCl ): ν = 3385, 1671, 1620, 1595, 1528 cm–1. 190.20, 157.94, 136.49, 133.64, 133.27, 133.19, 131.32, 130.51,
˜
3
LC-MS (ESI): m/z calcd. for C14H9FNO2 [M – H]– 242.0; found
242.0. HRMS (TOF): m/z calcd. for C14H11FNO2 [M + H]+
244.0774; found 244.0774.
129.29, 126.63, 125.47, 119.89 ppm. IR (CHCl ): ν = 3900, 3735,
˜
3
3364, 2922, 1682, 1599, 1536, 1495 cm–1. LC-MS (ESI): m/z calcd.
for C14H11ClNO2 [M + H]+ 260.0; found 260.1.
2-(4-Bromophenyl)-N-(4-chlorophenyl)-2-oxoacetamide (2j): Yield
158.0 mg (94%); yellow solid. 1H NMR (400 MHz, CDCl3): δ =
9.00 (br. s, 1 H), 8.34 (d, J = 8.4 Hz, 2 H), 7.68 (dd, J = 8.2, 5.6 Hz,
4 H), 7.39 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 185.97, 158.42, 135.04, 133.00, 132.06, 131.64, 130.70, 130.58,
2-(3-Nitrophenyl)-2-oxo-N-(p-tolyl)acetamide (2d): Yield 130.5 mg
(92%); yellow solid. 1H NMR (400 MHz, CDCl3): δ = 9.28 (s, 1
H), 8.91 (br. s, 1 H), 8.83–8.78 (m, 1 H), 8.50 (ddd, J = 8.2, 2.3,
1.1 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 2 H),
7.22 (d, J = 8.2 Hz, 2 H), 2.37 (s, 3 H) ppm. 13C NMR (126 MHz,
CDCl3): δ = 185.44, 157.68, 148.27, 137.04, 135.62, 134.36, 133.65,
129.37, 121.16 ppm. IR (CHCl ): ν = 3848, 3744, 3441, 3328, 2918,
˜
3
2850, 1674, 1587, 1535, 1491 cm–1. LC-MS (ESI): m/z calcd. for
C14H8BrClNO2 [M – H]– 335.9; found 337.9. HRMS (TOF): m/z
calcd. for C14H8BrClNO2 [M – H]– 335.9427; found 335.9419.
129.86, 129.79, 128.56, 126.40, 120.01, 21.02 ppm. IR (CHCl ): ν
˜
3
= 3572, 3563, 3458, 2075, 1658, 1650, 1643, 1633 cm–1. LC-MS
(ESI): m/z calcd. for C15H11N2O4 [M – H]– 283.0; found 283.0.
HRMS: m/z calcd. for C15H13N2O4 [M + H]+ 285.0875; found
285.0856.
Ethyl 4-[2-(4-methoxyphenyl)-2-oxoacetamido]benzoate (2k): Yield
149.0 mg (92%); yellow solid. 1H NMR (400 MHz, CDCl3): δ =
9.20 (br. s, 1 H), 8.50 (d, J = 7.6 Hz, 2 H), 8.08 (d, J = 7.5 Hz, 2
H), 7.78 (d, J = 7.6 Hz, 2 H), 6.99 (d, J = 7.7 Hz, 2 H), 4.38 (q, J
= 7.1 Hz, 2 H), 3.91 (s, 3 H), 1.40 (t, J = 7.1 Hz, 3 H) ppm. IR
N-(4-Methoxyphenyl)-2-(3-nitrophenyl)-2-oxoacetamide (2e): Yield
139.5 mg (93%); yellow solid. 1H NMR (400 MHz, CDCl3): δ =
9.29 (s, 1 H), 8.89 (br. s, 1 H), 8.81 (d, J = 7.8 Hz, 1 H), 8.50 (dd,
J = 8.2, 1.0 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.63 (t, J = 8.7 Hz,
2 H), 6.95 (d, J = 8.7 Hz, 2 H), 3.84 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 185.51, 157.56, 157.39, 148.26, 137.03,
134.41, 129.79, 129.32, 128.55, 126.39, 121.63, 114.49, 55.53 ppm.
(CHCl ): ν = 3744, 3340, 2985, 2923, 2849, 2586, 2043, 1925, 1720,
˜
3
1691, 1642, 1602, 1587, 1531, 1512, 1271, 1161, 1026 cm–1. LC-MS
(ESI): m/z calcd. for C14H8BrClNO2 [M – H]– 326.1; found 326.1.
2-(4-Bromophenyl)-N-(4-methoxyphenyl)-2-oxoacetamide (2l): Yield
155.0 mg (93%); yellow solid. 1H NMR (400 MHz, CDCl3): δ =
8.81 (br. s, 1 H), 8.25 (d, J = 8.4 Hz, 2 H), 7.55 (dd, J = 16.1,
8.6 Hz, 4 H), 6.85 (d, J = 8.8 Hz, 2 H), 3.75 (s, 3 H) ppm. 13C
NMR (126 MHz, CDCl3): δ = 186.51, 158.31, 157.16, 132.98,
IR (CHCl ): ν = 3834, 3746, 3669, 3646, 3355, 2919, 2850, 2060,
˜
3
1673, 1650, 1512 cm–1. LC-MS (ESI): m/z calcd. for C15H11N2O5
[M – H]– 299.0; found 298.9. HRMS: m/z calcd. for C15H13N2O5
[M + H]+ 301.0824; found 301.0834.
131.95, 130.39, 129.62, 121.55, 114.40, 55.52 ppm. IR (CHCl ): ν
˜
3
2-(3-Nitrophenyl)-2-oxo-N-[4-(trifluoromethoxy)phenyl]acetamide
(2f): Yield 159.0 mg (90%); yellow solid. 1H NMR (400 MHz,
CDCl3): δ = 9.29 (s, 1 H), 9.02 (br. s, 1 H), 8.80 (d, J = 7.8 Hz, 1
H), 8.54–8.48 (m, 1 H), 7.79–7.73 (m, 3 H), 7.28 (d, J = 8.7 Hz, 2
H) ppm. 13C NMR (126 MHz, CDCl3): δ = 184.99, 157.78, 148.26,
146.29, 137.03, 134.80, 134.05, 129.93, 128.80, 126.43, 122.06,
= 3349, 3241, 3138, 3086, 2920, 2850, 1657, 1582, 1512, 1033 cm–1.
LC-MS (ESI) m/z calcd. for C15H11BrNO3 [M – H]– 331.9; found
332.0. HRMS (TOF): m/z calcd. for C15H11BrNO3 [M – H]–
331.9922; found 331.9927.
2-(4-Bromophenyl)-2-oxo-N-phenylacetamide (2m):[8] Yield 127 mg
1
121.30 ppm. IR (CHCl ): ν = 3851, 3441, 3339, 3116, 3084, 2954,
˜
3
(84%); yellow solid. H NMR (400 MHz, CDCl3): δ = 8.88 (br. s,
2923, 2853, 2079, 1685, 1531, 1260 cm–1. LC-MS (ESI): m/z calcd.
for C15H8F3N2O5 [M – H]– 353.0; found 353.0. HRMS: m/z calcd.
for C15H10F3N2O5 [M + H]+ 355.0542; found 355.0547.
1 H), 8.25 (d, J = 8.4 Hz, 2 H), 7.60 (dd, J = 12.6, 8.4 Hz, 4 H),
7.33 (t, J = 7.7 Hz, 2 H), 7.13 (t, J = 7.4 Hz, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 186.33, 158.53, 136.47, 132.98, 131.99,
131.84, 130.48, 129.28, 125.47, 119.98 ppm. IR (CHCl ): ν = 3850,
˜
(2g):[1l]
Yield
3
2-(4-Methoxyphenyl)-2-oxo-N-phenylacetamide
3646, 3442, 3333, 2918, 2850, 1682, 1659, 1580, 1537, 1496 cm–1.
LC-MS (ESI): m/z calcd. for C14H11BrNO2 [M + H]+ 303.9; found
304.0. HRMS (TOF): m/z calcd. for C14H9BrNO2 [M – H]–
301.9817; found 302.0571.
120.0 mg (94%); yellow solid. 1H NMR (400 MHz, CDCl3): δ =
9.01 (br. s, 1 H), 8.50 (d, J = 9.0 Hz, 2 H), 7.69 (d, J = 7.6 Hz, 2
H), 7.39 (t, J = 7.9 Hz, 2 H), 7.19 (t, J = 7.4 Hz, 1 H), 6.97 (d, J
= 9.0 Hz, 2 H), 3.90 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3):
δ = 185.24, 164.95, 159.52, 136.79, 134.30, 129.22, 126.11, 125.19,
2-Oxo-N-phenyl-2-(m-tolyl)acetamide (2n): Yield 101.5.0 mg (85%);
yellow solid. 1H NMR (400 MHz, CDCl3): δ = 8.94 (br. s, 1 H),
8.22 (d, J = 6.9 Hz, 2 H), 7.70 (d, J = 8.0 Hz, 2 H), 7.47 (d, J =
7.3 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 3 H), 7.20 (t, J = 7.3 Hz, 1 H),
2.44 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 187.66,
159.03, 138.43, 136.68, 135.55, 133.06, 131.84, 129.26, 128.75,
119.92, 113.96, 55.63 ppm. IR (CHCl ): ν = 3440, 3354, 2922, 2454,
˜
3
2078, 1689, 1601, 1642 cm–1. LC-MS (ESI): m/z calcd. for
C15H12NO3 [M + H]+ 254.0; found 253.9. HRMS: m/z calcd. for
C15H14NO3 [M + H]+ 256.0974; found 256.0974.
N-(3,4-Dimethylphenyl)-2-(3-nitrophenyl)-2-oxoacetamide
(2h):
128.51, 125.32, 119.95, 21.40 ppm. IR (CHCl ): ν = 3443, 3341,
˜
3
1
Yield 134.0 mg (90%); yellow solid. H NMR (400 MHz, CDCl3):
δ = 9.28 (s, 1 H), 8.87 (br. s, 1 H), 8.81 (d, J = 7.8 Hz, 1 H), 8.53–
8.46 (m, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.50 (s, 1 H), 7.43 (dd, J
= 8.1, 1.9 Hz, 1 H), 7.17 (d, J = 8.1 Hz, 1 H), 2.30 (s, 3 H), 2.27
(s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 185.48, 157.65,
148.23, 137.76, 137.06, 134.38, 134.35, 133.89, 130.30, 129.78,
3056, 2918, 2850, 1686, 1660, 1593, 1535, 1498, 1443 cm–1. LC-MS
(ESI): m/z calcd. for C15H12NO2 [M – H]– 238.1; found 237.9.
HRMS (TOF): m/z calcd. for C15H12NO2 [M – H]– 238.0868; found
238.0861.
N-(3-Fluorophenyl)-2-oxo-2-(m-tolyl)acetamide (2o): Yield 110.5 mg
1
128.54, 126.38, 121.21, 117.49, 19.97, 19.37 ppm. IR (CHCl ): ν = (86%); yellow solid. H NMR (500 MHz, CDCl3): δ = 9.07 (br. s,
˜
3
3643, 3351, 3073, 2919, 2851, 1677, 1526 cm–1. LC-MS (ESI) m/z 1 H), 8.25–8.19 (m, 2 H), 7.71 (dd, J = 11.1, 1.5 Hz, 1 H), 7.49 (d,
calcd. for C16H13N2O4 [M – H]– 297.0; found 296.9. HRMS (TOF): J = 7.5 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.35 (dd, J = 5.5, 4.4 Hz,
m/z calcd. for C16H15N2O4 [M + H]+ 299.1032; found 299.1038.
2 H), 6.96–6.89 (m, 1 H), 2.45 (s, 3 H) ppm. 13C NMR (126 MHz,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Q. N. Ahmed et al.
FULL PAPER
CDCl3): δ = 185.52, 161.32 (d, J = 245.6 Hz), 157.31, 136.80, (CHCl ): ν = 3786, 3284, 2922, 2852, 1717, 1681, 1466, 1243,
˜
3
136.45 (d, J = 10.8 Hz), 134.00, 131.16, 130.13, 128.67 (d, J = 1156 cm–1. LC-MS (ESI): m/z calcd. for C17H14NO3 [M – H]–
9.3 Hz), 127.08, 126.85, 113.65 (d, J = 3.0 Hz),110.37 (d, J =
280.1; found 280.1. HRMS (TOF): m/z calcd. for C17H14NO3 [M –
21.4 Hz), 105.74 (d, J = 26.5 Hz), 19.67 ppm. LC-MS (ESI): m/z H]– 280.0974; found 280.0979.
calcd. for C15H12NO2 [M – H]– 256.1; found 256.3.
N-[2-Oxo-2-(p-tolyl)acetyl]benzamide (7g):[3a] Yield 120.0 mg
N-(2-Oxo-2-phenylacetyl)benzamide (7a):[3a] Yield 114.0 mg (90%);
white solid. 1H NMR (400 MHz, CDCl3): δ = 10.02 (br. s, 1 H),
8.12 (d, J = 7.5 Hz, 2 H), 7.94 (d, J = 8.0 Hz, 2 H), 7.64 (dd, J =
11.6, 7.4 Hz, 2 H), 7.52 (dd, J = 16.3, 8.1 Hz, 4 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 186.63, 165.35, 134.72, 134.02, 132.36,
(90%); white solid. H NMR (400 MHz, CDCl3): δ = 9.88 (br. s, 1
1
H), 7.98 (d, J = 7.7 Hz, 2 H), 7.85 (d, J = 7.6 Hz, 2 H), 7.56 (t, J
= 7.4 Hz, 1 H), 7.44 (t, J = 7.6 Hz, 2 H), 7.26 (d, J = 7.9 Hz, 2 H),
2.37 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 186.21,
165.26, 146.18, 133.98, 131.16, 130.42, 129.83, 129.75, 129.15,
130.98, 130.13, 129.14, 128.95, 128.15 ppm. IR (CHCl ): ν = 3285,
128.13, 22.00 ppm. IR (CHCl ): ν = 3851, 3744, 3387, 2920, 2851,
˜
3
˜
3
2921, 2851, 1719, 1687, 1467, 1451, 1212 cm–1. LC-MS (ESI) m/z 1717, 1681, 1606, 1465, 1248, 1176 cm–1. LC-MS (ESI): m/z calcd.
calcd. for C15H10NO3 [M – H]– 252.1; found 252.0. HRMS (TOF):
for C16H12NO3 [M – H]– 266.1; found 266.0. HRMS (TOF): m/z
m/z calcd. for C15H10NO3 [M – H]– 252.0661; found 252.0665.
calcd. for C16H12NO3 [M – H]– 266.0817; found 266.0813.
3-Methoxy-N-(2-oxo-2-phenylacetyl)benzamide
(7b):[3a]
Yield
2-Methyl-N-[2-oxo-2-(p-tolyl)acetyl]benzamide (7h): Yield 121.0 mg
(86%); white solid. H NMR (400 MHz, CDCl3): δ = 9.44 (br. s, 1
H), 8.03 (d, J = 7.7 Hz, 2 H), 7.48 (d, J = 7.8 Hz, 1 H), 7.36 (t, J
= 7.4 Hz, 1 H), 7.23 (t, J = 9.6 Hz, 4 H), 2.42 (s, 3 H), 2.37 (s, 3
1
129.0 mg (91%); white solid. 1H NMR (400 MHz, CDCl3): δ =
10.12 (br. s, 1 H), 8.10 (d, J = 7.4 Hz, 2 H), 7.66 (t, J = 7.0 Hz, 1
H), 7.58–7.46 (m, 4 H), 7.39 (t, J = 7.9 Hz, 1 H), 7.16 (d, J =
8.2 Hz, 1 H), 3.79 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ H) ppm. 13C NMR (101 MHz, CDCl3): δ = 185.79, 167.32, 146.28,
= 186.75, 165.39, 160.12, 134.75, 132.31, 132.03, 130.16, 129.98,
138.32, 132.47, 132.08, 131.91, 130.79, 129.83, 129.65, 127.41,
129.02, 121.02, 120.13, 112.64, 55.54 ppm. IR (CHCl ): ν = 3278,
126.14, 21.96, 20.29 ppm. IR (CHCl ): ν = 3851, 3747, 3671, 3242,
˜
˜
3
3
2922, 2851, 1718, 1686, 1471, 1451, 1272, 1211 cm–1. LC-MS (ESI):
m/z calcd. for C16H12NO4 [M – H]– 282.1; found 282.1. HRMS
(TOF): m/z calcd. for C16H12NO4 [M – H]– 282.0766; found
282.0762.
2922, 2852, 1715, 1680, 1606, 1453, 1285, 1176 cm–1. LC-MS (ESI):
m/z calcd. for C17H14NO3 [M – H]– 280.1; found 280.1. HRMS
(TOF): m/z calcd. for C17H14NO3 [M – H]– 280.0974; found
280.0967.
N-[2-(4-Methoxyphenyl)-2-oxoacetyl]benzamide
(7c):[3a]
Yield
2-Nitro-N-[2-oxo-2-(p-tolyl)acetyl]benzamide (7i): Yield 131.0 mg
(84%); light-yellow solid. 1H NMR (400 MHz, CDCl3): δ = 9.83
130.0 mg (92%); white solid. 1H NMR (400 MHz, CDCl3): δ =
9.91 (br. s, 1 H), 8.26 (d, J = 8.9 Hz, 2 H), 7.99–7.85 (m, 2 H), (br. s, 1 H), 8.29 (d, J = 8.2 Hz, 1 H), 8.11 (d, J = 8.1 Hz, 2 H),
7.71–7.60 (m, 1 H), 7.52 (dd, J = 10.6, 4.8 Hz, 2 H), 7.06–6.95 (m, 7.79 (t, J = 7.4 Hz, 1 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.49 (d, J =
2 H), 3.91 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 184.51, 7.3 Hz, 1 H), 7.25 (d, J = 7.6 Hz, 2 H), 2.41 (s, 3 H) ppm. 13C
165.13, 165.00, 133.79, 133.31, 131.69, 129.12, 128.01, 125.30, NMR (126 MHz, CDCl3): δ = 184.21, 166.85, 146.91, 145.32,
114.35, 55.67 ppm. IR (CHCl ): ν = 3743, 3281, 2934, 2844, 1717, 134.59, 132.00, 131.46, 130.87, 129.58, 129.43, 127.89, 124.37,
˜
3
1681, 1599, 1463, 1451, 1265, 1218 cm–1. LC-MS (ESI): m/z calcd.
22.01 ppm. IR (CHCl ): ν = 3403, 3290, 2921, 2851, 1731, 1699,
˜
3
for C16H12NO4 [M – H]– 282.1; found 282.1. HRMS (TOF): m/z 1674, 1605, 1531, 1466, 1348 cm–1. LC-MS (ESI): m/z calcd. for
calcd. for C16H12NO4 [M – H]– 282.0766; found 282.0758.
C16H11N2O5 [M – H]– 311.1; found 311.1. HRMS (TOF): m/z
calcd. for C16H11N2O5 [M – H]– 311.0668; found 311.0672.
N-[2-(4-Methoxyphenyl)-2-oxoacetyl]-3-methylbenzamide
(7d):
Yield 133.5 mg (90%); white solid. 1H NMR (500 MHz, CDCl3): 3-Methoxy-N-[2-oxo-2-(m-tolyl)acetyl]benzamide
(7j):
Yield
δ = 10.00 (br. s, 1 H), 8.22 (s, 2 H), 7.77–7.67 (m, 2 H), 7.49–7.36
122.0 mg (82%); white solid. 1H NMR (400 MHz, CDCl3): δ =
(m, 2 H), 7.00 (d, J = 7.3 Hz, 2 H), 3.90 (s, 3 H), 2.42 (s, 3 H) ppm. 10.13 (br. s, 1 H), 7.94–7.84 (m, 2 H), 7.48 (dt, J = 7.5, 6.7 Hz, 3
13C NMR (126 MHz, CDCl3): δ = 184.68, 165.24, 165.07, 139.16,
134.64, 133.21, 131.54, 128.99, 128.70, 125.30, 125.07, 114.36,
H), 7.40 (dd, J = 16.1, 7.9 Hz, 2 H), 7.15 (dd, J = 8.2, 1.8 Hz, 1
H), 3.80 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3):
55.70, 21.37 ppm. IR (CHCl ): ν = 3744, 3292, 2921, 2850, 1716, δ = 187.32, 171.59, 166.26, 159.87, 138.84, 135.92, 133.74, 132.25,
˜
3
1680, 1599, 1464, 1266, 1216, 1165 cm–1. LC-MS (ESI): m/z calcd.
130.73, 129.81, 128.78, 127.76, 119.39, 118.92, 112.64, 55.50,
for C17H14NO4 [M – H]– 296.1; found 296.1. HRMS (TOF): m/z 21.29 ppm. LC-MS (ESI): m/z calcd. for C17H14NO4 [M – H]–
calcd. for C17H14NO4 [M – H]– 296.0923; found 296.0929.
296.1; found 296.1.
N-[2-Oxo-2-(m-tolyl)acetyl]benzamide (7e):[3b] Yield 123.0 mg
(92%); white solid. H NMR (400 MHz, CDCl3): δ = 9.79 (br. s, 1
2-Methyl-N-[2-(3-nitrophenyl)-2-oxoacetyl]benzamide (7k): Yield
125.0 mg (80%); light-yellow solid. H NMR (400 MHz, CDCl3):
1
1
H), 7.85 (d, J = 7.4 Hz, 4 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.43 (dd,
J = 17.4, 9.4 Hz, 3 H), 7.34 (t, J = 7.5 Hz, 1 H), 2.36 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 186.80, 165.24, 138.88, 135.60,
133.95, 132.36, 130.48, 129.13, 128.83, 128.11, 127.46, 21.30 ppm.
δ = 9.51 (br. s, 1 H), 8.94 (s, 1 H), 8.52 (d, J = 6.9 Hz, 2 H), 7.76
(t, J = 8.0 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.47 (t, J = 7.4 Hz,
1 H), 7.33 (t, J = 7.7 Hz, 2 H), 2.49 (s, 3 H) ppm. LC-MS (ESI):
m/z calcd. for C16H11N2O5 [M – H]– 311.1; found 311.1.
IR (CHCl ): ν = 3292, 2921, 2851, 1718, 1682, 1465, 1242,
˜
3
2-Oxo-2-phenyl-N-(phenylsulfonyl)acetamide (8a): Yield 115.5 mg
(80%); white solid. H NMR (500 MHz, CDCl3): δ = 8.26 (d, J =
1157 cm–1. LC-MS (ESI): m/z calcd. for C16H12NO3 [M – H]–
266.1; found 266.1. HRMS (TOF): m/z calcd. for C16H12NO3 [M –
H]– 266.0817; found 266.0812.
1
7.5 Hz, 2 H), 8.16 (d, J = 7.5 Hz, 2 H), 7.74–7.61 (m, 2 H), 7.61–
7.53 (m, 2 H), 7.50–7.41 (m, 2 H) ppm. 13C NMR (126 MHz,
3-Methyl-N-[2-oxo-2-(m-tolyl)acetyl]benzamide (7f): Yield 125.0 mg CDCl3): δ = 183.98, 158.09, 137.89, 135.46, 134.50, 131.78, 131.47,
1
(89%); white solid. H NMR (400 MHz, CDCl3): δ = 10.16 (br. s,
129.18, 128.81, 128.60 ppm. IR (CHCl ): ν = 3443, 3241, 3096,
˜
3
1 H), 7.87–7.74 (m, 2 H), 7.71–7.63 (m, 2 H), 7.39–7.25 (m, 4 H),
3070, 2921, 2851, 1734, 1676, 1447, 1405, 1352, 1268, 1187, 1171,
2.32 (s, 3 H), 2.27 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ 544 cm–1. LC-MS (ESI): m/z calcd. for C14H10NO4S [M – H]–
= 187.14, 165.80, 139.10, 138.90, 135.49, 134.81, 132.42, 130.69,
288.0; found 288.0. HRMS (TOF): m/z calcd. for C14H10NO4S
130.19, 128.96, 128.84, 127.19, 125.33, 21.31, 21.25 ppm. IR [M – H]– 288.0331; found 288.0336.
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Efficient Oxidative Amidation Approach
2-Oxo-N-(phenylsulfonyl)-2-(m-tolyl)acetamide (8b): Yield 113.5 mg
(75%); white solid. 1H NMR (400 MHz, CDCl3): δ = 9.53 (s, 1 H),
8.08 (d, J = 7.7 Hz, 2 H), 7.99 (d, J = 6.7 Hz, 2 H), 7.61 (t, J =
7.4 Hz, 1 H), 7.51 (t, J = 7.6 Hz, 2 H), 7.39 (d, J = 7.5 Hz, 1 H),
7.27 (t, J = 7.8 Hz, 1 H), 2.31 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 184.12, 158.15, 138.73, 137.98, 136.31, 134.44, 131.77,
[1]
a) L. Liu, L. Du, D. Zhang-Negrerie, Y. Du, K. Zhao, Org.
Lett. 2014, 16, 5772; b) M. Zhou, Q. Song, Synthesis 2014, 46,
1853; c) N. Mupparapu, S. Khan, S. Battula, M. Kushwaha,
A. P. Gupta, Q. N. Ahmed, R. A. Vishwakarma, Org. Lett.
2014, 16, 1152; d) R. Deshidi, M. Kumar, S. Devari, B. A.
Shah, Chem. Commun. 2014, 50, 9533; e) Q. Zhao, T. Miao, X.
Zhang, W. Zhou, L. Wang, Org. Biomol. Chem. 2013, 11, 1867;
f) Z. Zhang, J. Su, Z. Zha, Z. Wang, Chem. Commun. 2013,
49, 8982; g) X. Zhang, W. Yang, L. Wang, Org. Biomol. Chem.
2013, 11, 3649; h) D. Li, M. Wang, J. Liu, Q. Zhao, L. Wang,
Chem. Commun. 2013, 49, 3640; i) X. Zhang, L. Wang, Green
Chem. 2012, 14, 2141; j) J. Zhang, Y. Wei, S. Lin, F. Liang, P.
Liu, Org. Biomol. Chem. 2012, 10, 9237; k) C. Zhang, X. Zong,
L. Zhang, N. Jiao, Org. Lett. 2012, 14, 3280; l) J. Shao, X.
Huang, S. Wang, B. Liu, B. Xu, Tetrahedron 2012, 68, 573; m)
W.-P. Mai, H.-H. Wang, Z.-C. Li, J.-W. Yuan, Y.-M. Xiao, L.-
R. Yang, P. Mao, L.-B. Qu, Chem. Commun. 2012, 48, 10117;
n) M. Lamani, K. R. Prabhu, Chem. Eur. J. 2012, 18, 14638;
o) C. Zhang, Z. Xu, L. Zhang, N. Jiao, Angew. Chem. Int. Ed.
2011, 50, 11088; p) Z. Zhang, Q. Zhang, Z. Ni, Q. Liu, Chem.
Commun. 2010, 46, 1269; q) G. G. Xu, F. A. Etzkorn, Org. Lett.
2010, 12, 696; r) J. L. Jesuraj, J. Sivaguru, Chem. Commun.
2010, 46, 4791; s) M. Bouma, G. r. Masson, J. Zhu, J. Org.
Chem. 2010, 75, 2748; t) C. Zhang, N. Jiao, J. Am. Chem. Soc.
2010, 132, 28; u) J. Liu, R. Zhang, S. Wang, W. Sun, C. Xia,
Org. Lett. 2009, 11, 1321.
a) S. Alvarez, R. Alvarez, H. Khanwalkar, P. Germain, G. R.
Lemaire, F. T. Rodríguez-Barrios, H. Gronemeyer, A. N. R.
de Lera, Bioorg. Med. Chem. 2009, 17, 4345; b) K. K. S. Sai,
P. M. Esteves, E. T. da Penha, D. A. Klumpp, J. Org. Chem.
2008, 73, 6506; c) E. R. Murphy, J. R. Martinelli, N. Zabor-
enko, S. L. Buchwald, K. F. Jensen, Angew. Chem. Int. Ed.
2007, 46, 1734; Angew. Chem. 2007, 119, 1764; d) Y.-H. Chen,
Y.-H. Zhang, H.-J. Zhang, D.-Z. Liu, M. Gu, J.-Y. Li, F. Wu,
X.-Z. Zhu, J. Li, F.-J. Nan, J. Med. Chem. 2006, 49, 1613; e)
A. Natarajan, K. Wang, V. Ramamurthy, J. R. Scheffer, B. Pat-
rick, Org. Lett. 2002, 4, 1443; f) M. M. Sheha, N. M. Mahfouz,
H. Y. Hassan, A. F. Youssef, T. Mimoto, Y. Kiso, Eur. J. Med.
Chem. 2000, 35, 887; g) G. M. Dubowchik, J. L. Ditta, J. J.
Herbst, S. Bollini, A. Vinitsky, Bioorg. Med. Chem. Lett. 2000,
10, 559; h) S. Chatterjee, D. Dunn, M. Tao, G. Wells, Z.-Q.
Gu, R. Bihovsky, M. A. Ator, R. Siman, J. P. Mallamo, Bioorg.
Med. Chem. Lett. 1999, 9, 2371; i) Z. Li, A.-C. Ortega-Vilain,
G. S. Patil, D.-L. Chu, J. E. Foreman, D. D. Eveleth, J. C. Pow-
ers, J. Med. Chem. 1996, 39, 4089.
131.74, 129.16, 128.73, 128.68, 128.57, 21.24 ppm. IR (CHCl ): ν
˜
3
= 3440, 3259, 2921, 2851, 1718, 1676, 1602, 1449, 1174, 544 cm–1.
LC-MS (ESI): m/z calcd. for C15H12NO4S [M – H]– 302.0; found
302.1. HRMS (TOF): m/z calcd. for C15H12NO4S [M – H]–
302.0487; found 302.0516.
2-(4-Bromophenyl)-2-oxo-N-(phenylsulfonyl)acetamide (8c): Yield
135.5 mg (74%); white solid. 1H NMR (400 MHz, CDCl3): δ =
9.59 (s, 1 H), 8.21–8.10 (m, 4 H), 7.70 (t, J = 7.3 Hz, 1 H), 7.60
(dd, J = 15.1, 7.9 Hz, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ
= 182.96, 157.77, 137.82, 134.57, 132.83, 132.25, 131.50, 130.53,
129.20, 128.60 ppm. IR (CHCl ): ν = 3857, 3440, 3239, 2922, 2065,
˜
3
1732, 1682, 1643, 1633, 1585 cm–1. LC-MS (ESI): m/z calcd. for
C14H9BrNO4S [M – H]– 365.9; found 367.9. HRMS (TOF): m/z
calcd. for C14H9BrNO4S [M – H]– 365.9436; found 365.9440.
2-(4-Fluorophenyl)-2-oxo-N-(phenylsulfonyl)acetamide (8d): Yield
110.5 mg (72%); white solid. 1H NMR (400 MHz, CDCl3): δ =
8.36 (dd, J = 7.8, 5.9 Hz, 2 H), 8.15 (d, J = 7.8 Hz, 2 H), 7.69 (t,
J = 7.4 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 2 H), 7.14 (t, J = 8.4 Hz, 2
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 190.2, 181.1, 135.4,
134.8, 134.6, 130.0, 128.3, 127.4, 125.1, 124.9, 110.3, 37.6 ppm. IR
[2]
(CHCl ): ν = 3439, 3276, 2921, 2921, 2851, 1736, 1668, 1597, 1404,
˜
3
1270 cm–1. LC-MS (ESI): m/z calcd. for C14H9FNO4S [M – H]–
306.0; found 306.0. HRMS (TOF): m/z calcd. for C14H9FNO4S
[M – H]– 306.0236; found 306.0237.
2-(4-Fluorophenyl)-2-oxo-N-tosylacetamide (8e): Yield 122 mg
(76%); white solid. 1H NMR (400 MHz, CDCl3): δ = 8.42–8.32 (m,
2 H), 8.03 (d, J = 7.9 Hz, 2 H), 7.38 (d, J = 7.9 Hz, 2 H), 7.14 (t,
J = 8.4 Hz, 2 H), 2.45 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 182.17, 167.19 (d, J = 259.9 Hz), 157.92, 145.83, 134.85, 134.61
(d, J = 9.9 Hz), 129.79, 128.66, 116.20 (d, J = 22.0 Hz), 21.74 ppm.
IR (CHCl ): ν = 3435, 3245, 2921, 2851, 2346, 1733, 1674, 1596,
˜
3
1270, 1171 cm–1. LC-MS (ESI): m/z calcd. for C15H11FNO4S [M –
H]– 320.0; found 320.0. HRMS (TOF): m/z calcd. for
C15H11FNO4S [M + H]+ 322.0549; found 322.0572.
[3]
[4]
2-Oxo-2-(m-tolyl)-N-tosylacetamide (8f): Yield 111.0 mg (70%);
white solid. H NMR (400 MHz, CDCl3): δ = 8.03 (t, J = 7.5 Hz,
4 H), 7.45 (d, J = 7.4 Hz, 1 H), 7.35 (dd, J = 11.7, 8.0 Hz, 3 H),
2.44 (s, 3 H), 2.38 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ
= 184.27, 158.31, 145.72, 138.70, 136.28, 134.94, 131.79, 131.74,
a) X. Wu, Q. Gao, S. Liu, A. Wu, Org. Lett. 2014, 16, 2888;
b) H. P. Kalmode, K. S. Vadagaonkar, A. C. Chaskar, RSC
Adv. 2014, 4, 60316; c) Z. F. Al-Rashid, W. L. Johnson, R. P.
Hsung, Y. Wei, P.-Y. Yao, R. Liu, K. Zhao, J. Org. Chem. 2008,
73, 8780.
1
a) D. Leow, Org. Lett. 2014, 16, 5812; b) S. Yang, H. Yan, X.
Ren, X. Shi, J. Li, Y. Wang, G. Huang, Tetrahedron 2013, 69,
6431; c) M. Zhu, K.-i. Fujita, R. Yamaguchi, J. Org. Chem.
2012, 77, 9102; d) H. Yao, K. Yamamoto, Chem. Asian J. 2012,
7, 1542; e) B. Tan, N. Toda, C. F. Barbas, Angew. Chem. Int.
Ed. 2012, 51, 12538; f) X. Liu, K. F. Jensen, Green Chem. 2012,
14, 1471; g) J. Li, F. Xu, Y. Zhang, Q. Shen, J. Org. Chem.
2009, 74, 2575; h) K. R. Reddy, C. U. Maheswari, M. Venka-
teshwar, M. L. Kantam, Eur. J. Org. Chem. 2008, 3619; i) J.
Gao, G.-W. Wang, J. Org. Chem. 2008, 73, 2955; j) S. Seo, T. J.
Marks, Org. Lett. 2007, 9, 317; k) K. Ekoue-Kovi, C. Wolf,
Org. Lett. 2007, 9, 3429; l) W.-J. Yoo, C.-J. Li, J. Am. Chem.
Soc. 2006, 128, 13064; m) K. Nakagawa, H. Onoue, K. Min-
ami, Chem. Commun. 1966, 17.
129.79, 128.72, 128.68, 128.64, 21.77, 21.29 ppm. IR (CHCl ): ν =
˜
3
3444, 3241, 3096, 3070, 2921, 2851, 1734, 1676, 1447, 1405, 1352,
1268, 1187, 1171 cm–1. LC-MS (ESI): m/z calcd. for C16H14NO4S
[M – H]– 316.0; found 316.0. HRMS (TOF): m/z calcd. for
C16H14NO4S [M – H]– 316.0644; found 316.0648.
Acknowledgments
A. P. and N. M. gratefully acknowledge the Council of Scientific
and Industrial Research (CSIR) for the award of a senior research
fellowship and the Academey of Scientific and Innovative Research
(AcSIR) for Ph. D. registration. This work was generously
supported by the Council of Scientific and Innovative research
(CSIR) through network project grant number BSC0108 (IIIM/
1753/2015).
[5]
[6]
J. Touzin, K. Neplechova, Z. Zak, M. Cernik, Coll. Czech.
Chem. Commun. 2002, 67, 577.
a) E. Boess, C. Schmitz, M. Klussmann, J. Am. Chem. Soc.
2012, 134, 5317; b) M. S. Kharasch, A. Fono, J. Org. Chem.
1959, 24, 72; c) M. S. Kharasch, A. Fono, W. Nudenberg, B.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Q. N. Ahmed et al.
[7]
J. Dai, J.-L. Wu, Struct. Rep. Online 2011, 67, o3152.
FULL PAPER
Bischof, J. Org. Chem. 1952, 17, 207; d) S. A. Girard, T.
Knauber, C.-J. Li, Angew. Chem. Int. Ed. 2014, 53, 74; e) M. O.
Ratnikov, M. P. Doyle, J. Am. Chem. Soc. 2013, 135, 1549; f)
F. Minisci, F. Fontana, S. Araneo, F. Recupero, S. Banfi, S.
Quici, J. Am. Chem. Soc. 1995, 117, 226.
[8] M. J. Haddadin, H. T. Tannus, Heterocycles 1984, 22, 773.
Received: February 20, 2015
Published Online: ᭿
10
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O50251
/KAP1
Date: 20-04-15 16:05:19
Pages: 11
Efficient Oxidative Amidation Approach
Synthetic Methods
A. K. Padala, N. Mupparapu, D. Singh,
R. A. Vishwakarma,
Q. N. Ahmed* ................................. 1–11
α-Carbonylimine to α-Carbonylamide: An
Efficient Oxidative Amidation Approach
Keywords: Synthetic methods / Oxidation /
Amines / Amides / Sulfonamides
An efficient oxidative amidation reaction
between 2-oxoaldehyde and weak nucleo-
philic amines (anilines, benzamides, and
sulfonamides) is reported. Mechanistic
studies show that α-carbonylimine (–CO–
C=N–) based compounds are a central fea-
ture of the reaction. It was found that an
adjacent CO moiety enhances the electro-
philicity of the C=N system, which favors
attack of oxidant (TBHP or SeO2).
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11