Singlet oxygen mediated one pot synthesis of N-pyridinylamides via oxidative amidation of aryl alkyl ketones

Article abstract of DOI:10.1016/j.tet.2019.130536

An environmental friendly, efficient protocol has been realized for the synthesis of N-pyridinylamides via copper catalyzed oxidative amidation of aryl alkyl ketones with 2-aminopyridines. This one pot protocol involves chemo selective cleavage of C (O)–C bond in the presence of singlet oxygen. The reaction conditions are simple, tolerates wide range of substrates and the products were formed in good to excellent yields. This method offers a moderate improvement over the earlier successful attempts in generating N-pyridinylamides.

Full text of DOI:10.1016/j.tet.2019.130536

Journal Pre-proof
Singlet oxygen mediated one pot synthesis of N-pyridinylamides via oxidative
amidation of aryl alkyl ketones
Firdoos Ahmad Sofi, Rohit Sharma, S.N. Kavyasree, Sumi Aisha Salim, Pravin J.
Wanjari, Prasad V. Bharatam
PII:
S0040-4020(19)30869-5
https://doi.org/10.1016/j.tet.2019.130536
TET 130536
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 May 2019
Revised Date: 11 August 2019
Accepted Date: 18 August 2019
Please cite this article as: Sofi FA, Sharma R, Kavyasree SN, Salim SA, Wanjari PJ, Bharatam PV,
Singlet oxygen mediated one pot synthesis of N-pyridinylamides via oxidative amidation of aryl alkyl
ketones, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.130536.
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Singlet Oxygen Mediated One Pot Synthesis
of N-pyridinylamides via Oxidative
Amidation of Aryl Alkyl Ketones
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Firdoos Ahmad Sofi, Rohit Sharma, Kavyasree S.N, Sumi Aisha Salim, Pravin J. Wanjari and Prasad V.
Bharatam*

1
Tetrahedron
journal homepage: www.elsevier.com
Singlet Oxygen Mediated One Pot Synthesis of N-pyridinylamides via Oxidative
Amidation of Aryl Alkyl Ketones
Firdoos Ahmad Sofi,a Rohit Sharma,a,b Kavyasree S.N,a Sumi Aisha Salim,a Pravin J. Wanjari a and Prasad
V. Bharatama*
a
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research. S.A.S Nagar (Mohali)-160 062, Punjab, India
b Presently at Dr. Y.S. Parmar University of Horticulture and Forestry, Nauni, Solan – 173 230, Himachal Pradesh, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An environmental friendly, efficient protocol has been realized for the synthesis of N-
pyridinylamides via copper catalyzed oxidative amidation of aryl alkyl ketones with 2-
aminopyridines. This one pot protocol involves chemo selective cleavage of C (O)-C bond in the
presence of singlet oxygen. The reaction conditions are simple, tolerates wide range of
substrates and the products were formed in good to excellent yields. This method offers a
moderate improvement over the earlier successful attempts in generating N-pyridinylamides.
Available online
Keywords:
Amide Bond
One-pot
2009 Elsevier Ltd. All rights reserved
.
Oxidative amidation
Oxygen
SDOSS
are also known to produce N-pyridinylamides.9 Cerium nitrate
catalyzed reaction between nitro olefins and 2-aminopyridines
was also known to produce title compounds.10 (water was used as
a co-solvent).
1. Introduction
Water mediated synthesis of organic building blocks is a
topic of current interest.1 Several organic frameworks are
being generated using water as a reaction medium. Such
methods have tremendous advantages in terms of green
chemistry efforts.2 This approach is being adopted in the
manufacture of drugs, pharmaceuticals and industrial
chemicals,3 because such procedures help in reducing the
use of volatile organic solvents. However, the poor
solubility of most organic compounds in water reduces the
scope on water mediated organic synthesis and this has
brought to light the use of surfactants in aqueous organic
reactions.4
Aqueous oxidizing agents like TBHP and H2O2 were also
employed to generate N-pyridinylamides in an attempt to develop
metal free methods.11 Only one method is reported till now, in
which water was used as reaction medium for the preparation of
N-pyridinylamides (oxidative amidation using Cu(II)). In this
approach, use of micellar systems was found to be a requirement
to improve the yields. An attempt was made to generate N-
pyridinylamides in water medium using simpler reagents and
reaction conditions, the results are presented below (Figure 2).
The salient features of this transformation are (i) water as a
greener solvent (ii) shorter reaction time, (iii) good to excellent
yields, (iv) wide substrate scope and (v) use of oxygen gas
bubbling to facilitate oxidation.
Amide bond formation reactions were also reported in water
medium, which showed distinct advantage in terms of low
generation of organic waste, high reaction yields, ease of
recyclability.5 However, for the synthesis of N-pyridinylamides
such methods are rarely being used. Kaliappan and co-workers
reported a biomimetic route for the generation of N-heterocyclic
amides.6 This reaction involves the formation of an imine, imine-
enamine tautomerism,7 copper mediated dioxetane generation
and the formation of phenyl glyoxal as initial steps.
Subsequently, the reaction follows a biomimetic path which is
similar to the luciferin-luciferage path.6 Huang and co-workers
reported a dehydrogenative reaction between aldehydes and 2-
aminopyridines to yield N-pyridinylamides using a Cu(I)
catalyzed pathway.8 The p-xylene mediated reaction between aryl
acetic acids and 2-aminopyridine as well as the m-xylene
mediated reaction between 1,2-diketones and 2-aminopyridines
Figure 2. Copper (I) Chloride catalyzed synthesis of N-
pyridinylamides via oxidative amidation reaction.

2
Tetrahedron Letters
O
O
CuI (0.03 mmol),
DMF, 80 C, 24 h
H
Ar
Ar
ref. 8
2. Results and discussions
CuCl2 (20 mol%)
Our initial attempt was to synthesize N-pyridinylamides from
2-aminopyridine (1a) and acetophenone (2a), with the aim to
generate acyl group from the acetophenones. After getting
insights from the literature (Figure 1) for the synthesis of N-
pyridinylamides, a model reaction of 2-aminopyridine and
acetophenone in the presence of CuCl at room temperature for 12
h using MeCN as a solvent was tried, the desired product 3a was
formed in 35% yield (Table 1, entry 12). When the same model
reaction was refluxed at 80 , an improvement in yield up to
50% was observed (Table 1, entry 14). Based on these results,
various copper salts were screened and CuCl in 10 mol% was
found to be the most efficient catalyst for such transformation.
Rhodium catalyst (Table 1, entry 3) as well as ruthenium catalyst
(Table 1, entry 4) were found to be ineffective. When CuCl2 was
used as the catalyst (Table 1, entry 7), the desired product was
obtained in only 20% yield. Various solvents were screened and
toluene was found to provide better yields of the desired product
in 69% (Table 1, entry 16).
O2, NMP:t- BuOH
(1:2, 3mL),
80 °C, 24 h
ref. 6
ref. 12
ref. 11b
Cu(OTf)2 (5 mol%),
I2 (50 mol%)
O
O
H
Ar
Ar
H2O, SDS (5 mol%),
RT, 15-35 min
H2O2 (3 equiv.)
H2O, 80 C, 4 h
H
O
N
NH2
N
N
Ar
H
Ce(NO3)3. 6 H2O (10 mol%)
O2N
ref. 10
Ar
H2O/dioxane, 100 C,
16 h
Cu(OAc)2 (1 equiv.)
ref. 9a
H2OOHC
O
Ar
p-xylene, 120 C,
16 h, air
TBAI (20 mol%)
TfOH (20 mol%)
ref. 11a
ref. 9b
Ar
TBHP (6 equiv)
H2O, 80 °C, 5-6 h
O
CuCl2 (20 mol%), O2
t-BuOH: m-xylene (1:2)
Ar
Ar
O
pivalic acid (0.1
equiv.) 80-85 C,
48 h
Figure 1. Various reported methods for the generation of N-
pyridinylamides.
Table 1. Solvent and catalyst optimization studies.a
Entry Catalyst
(mol %)
Temp. Time Surfactant Solvent % Yield
(
)
(h)
1
Cu-Mn B (5)
rt
12
-
-
-
-
-
-
-
-
-
-
-
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
n.r
n.r
2
Cu-Mn B (5)
rt
12
12
12
12
12
12
12
12
12
12
3
[RhCl(CO)2]2 (5) rt
[Ru(p-cp)Cl2]2 (5) rt
n.r
4
n.r
5
CuBr (5)
rt
rt
rt
rt
rt
rt
rt
trace
15
6
CuCl2 (5)
CuCl2 (10)
Cu(OTf)2 (10)
CuI (5)
7
20
8
25
9
10
10
11
CuCl (5)
trace
Iso-
propanol
CH3CN
CuCl (5)
20
12
13
14
15
16
17
18
19
20b
21
22c
23d
rt
12
12
12
12
12
12
12
12
12
12
12
3
-
-
-
-
-
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (5)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
CuCl (10)
35
trace
50
rt
DCE
80
80
80
rt
CH3CN
Toluene
Toluene
Water
Water
Water
Water
58
69
trace
26
80
rt
-
SDOSS
SDOSS
72
rt
73
rt
Tween 80 Water
60
80
80
SDOSS
SDOSS
Water
Water
82
Figure 3. Substrate scope with aryl methyl ketones and 2-aminopyridine.
Reaction conditions: The magnetically stirred mixture of 1a (1.2 equiv), 2a (1
eqiv) was treated with CuCl (10 mol%) in the presence of SDOSS (5 mol%)
in water at 80 under O2 bubbling condition for 3 h (yields of the isolated
products).
86
24
80
80
80
3
SLS
Water
Water
Water
CuCl (10)
CuCl (10)
-
75
20
n.r
25e
26f
12
12
-
SDOSS
aReagents and conditions: 2-aminopyridine 1a (1.2 equiv.), acetophenone 2a
(1 equiv.) was treated with CuCl (10 mol%), SDOSS (5 mol%) in water (2
mL) at 80
(oil bath) under O2 bubbling for 3 h, b With 20 mol% SDOSS,
cThe reaction was performed under oxygen atmosphere using a ballon filled
with oxygen, dOptimized reaction conditions, without O2 ballon; without
CuCl; n.r = No reaction. All the reactions were performed under oxygen
atmosphere using a ballon filled with oxygen unless otherwise specified (d,
e).
e
f

But, when toluene was replaced with water as greener reaction
medium and in the presence of sodium dioctyl sulfosuccinate
(SDOSS), the reaction provided better yield 72% (Table 1, entry
19). Then various surfactants were screened for improvement of
yield, but SDOSS was found to be most effective (Table 1, entry
Many control experiments were carried out to probe the
mechanism of the reaction. The non-radical pathway of the
reaction was established by performing the reaction of 1a and 2a
in the presence of TEMPO (2 equiv) used as the radical
scavenger15 with the formation of desired product 3a (Figure 5,
entry 1). Next, when the reaction of 1a with 2a was tried under
the optimized reaction condition, but in the presence of DABCO
as singlet oxygen quencher16 (Figure 5, entry 2) the desired
product was not formed, suggesting that the participation of the
singlet oxygen species during the transformation is essential.
When the reaction was tried under nitrogen atmosphere, product
was not formed thereby suggesting the role of molecular oxygen
as the sole oxidant in the reaction (Figure 5, entry 3). Formation
of the desired product was not observed in the absence of CuCl,
thereby suggesting the crucial role of catalyst in the reaction
(Figure 5, entry 4). Similarly, when the reaction was carried out
in the absence of SDOSS, 3a was obtained in 30% yield (Figure
5, entry 5). The surfactant helps in the improvement of yield by
two processes – i) the formation of aqueous micellar system
thereby allowing the reactants to approach each other and, ii) the
surfactant helps in increasing the oxygen content in the aqueous
micellar system by having maximum capacity of oxygen
reuptake.13
23). This may be attributed due to the reduction of interfacial
14
tension and formation of aqueous micellar system.12,
The
greater efficiency of SDOSS can be accounted for the capability
of maximum oxygen uptake compared to other surfactants.13
Increase in the concentration of SDOSS from 5 mol% to 20
mol%, did not produce improved yields (Table 1, entry 20).
Next, oxygen gas bubbling into the reaction mixture was
considered – for a period of 1h, 2h and 3h, improvement of
yields was noticed in the order 52%, 67% and 86% respectively.
Thus, passing oxygen gas into the reaction mixture (O2
bubbling), instead of performing the reaction under oxygen
atmosphere using a balloon filled with oxygen, provided added
advantage in terms of reducing the reaction time from 12 h to 3
h. These results led to the following optimized reaction
conditions: 1a (1.2 equiv), 2a (1 equiv), CuCl (10 mol%),
SDOSS (5 mol%) in water (2 ml) at 80 under oxygen bubbling
(1 atm.) for 3 h.
Having the optimized reaction conditions in hand, substrate
scope of reaction was explored for various substituted aryl
methyl ketones, reaction works well with all substituted aryl
methyl ketones bearing electron withdrawing (Figure 3, entry,
3b, 3c, 3d, 3g, 3i, 3j, 3k, 3l and 3p) as well as electron donating
groups (Figure 3, entry, 3e, 3f and 3m). Yields in case of ketones
with electron withdrawing groups are slightly higher than in case
of ketones with electron donating groups. Ketones bearing
substituents in meta position (Figure 3, entry 3c, 3i and 3j) gave
slightly lower yield in comparison to ketones with substituents at
para position (Figure 3, entry 3k and 3l). Also, disubstituted aryl
methyl ketones (Figure 3, entry 3b, 3g and 3n) as well as
trisubstituted aryl methyl ketones (Figure 3, entry 3d) work well,
giving corresponding products in good yield.
The scope of the reaction was further established by using
various aryl alkyl ketones (Figure 4). To our pleasant surprise,
the corresponding products were formed in moderate yields.
These results points to the chemoselective cleavage of C(CO)-
C(alkyl) bond for synthesis of the title compounds.
Figure 5. Control experiments.
Based on the control experiments and previous literature re-
ports,17-19 the plausible mechanism for the generation of the title
compound has been proposed (Scheme 1). Initially condensation
reaction of methyl ketone and 2-aminopyridine leads to the
generation of imine intermediate I. This intermediate I undergoes
tautomerism (1,3-H shift), leading to the formation of reversible
enamine II7 A Cu-peroxy radical (reactive oxygen species) gets
generated by the oxidation of Cu(I) in the presence of molecular
.-
oxygen with the formation of superoxide radical (O2 ) and
Cu(II). Subsequently, superoxide radical (O2 ) delivers electron
.-
Figure 4. Substrate scope with aryl alkyl ketones and 2-aminopyridine.
Reaction conditions: The magnetically stirred mixture of 6 (1 equiv), 1a (1.2
eqiv) was treated with CuCl (10 mol%) in the presence of SDOSS (5 mol%)
in water at 80o C under O2 bubbling condition for 3 h (yields of the isolated
products).
to the Cu(II) leading to generation of Cu(I) and singlet oxygen
species (1O2). Singlet oxygen species immediately reacts with the
enamine leading to formation of aminodioxetane intermediate
III. Oxidative C-C bond cleavage of dioxetane intermediate
leads to the generation of the desired product 3a and
formaldehyde.

4
Tetrahedron
CuI + O2
were recorded at 100 MHz: chemical data for carbons
are reported in parts per million (ppm, δ scale)
downfield from tetramethylsilane and are referenced to
the carbon resonance of the solvent (CDCl3, 77.16 ppm;
CD3OD, 49.0; DMSO-d6 39.51 ppm). ESI-MS spectra
were recorded on Agilent 1100 LC-Q-TOF. IR spectra
were recorded on Perkin-Elmer IR spectrophotometer.
Melting points were recorded on digital melting point
apparatus.
2a
N
NH
CuII
Cl
O
O.
N
N
N
NH
CuII
4.2. Typical procedure for the synthesis of N-(pyridin-2-
yl)benzamide (3a)
N
NH2
N
Ar
Cl
O
1a
I
1O2
O
HN
Ar
III
O
The magnetically stirred mixture of the 2-amino pyridine 1a
(112.9 mg, 1.2 mmol), acetophenone 2a (120.2 mg, 1 mmol,
O
H
1equiv),
CuCl
(10
mol%,
9.9
mg),
sodium
H2O
H
O
HN
N
dioctylsulphosuccinate (SDOSS, 5 mol%, 22.2 mg) in water (2
mL) was heated at 80 C while oxygen gas was bubbled into the
Simultanious
C-C bond and
O-O bond
Ar
2a
o
Ar
mixture for 3 h. After completion of the reaction (TLC), the
mixture was cooled to room temperature and diluted with EtOAc
(10 mL), filtered by ordinary filter paper to recover the catalyst.
The organic layer was washed with brine and dried over
anhydrous Na2SO4. The filtrate was concentrated under rotary
vacuum evaporation, and the residue was charged on to
chromatography (100-200 mesh silica gel) column and eluted
with EtOAc-hexane to afford pure 3a ( 170.4 mg, 86%). All the
remaining reactions were performed following this general
procedure. The spectral data of the synthesized compounds are
provided below.
II
cleavage
O
H
H
O
Ar
N
N
H
3a
Scheme 1. Plausible mechanism for the generation of title
compounds.
When 2-aminopyridine was replaced with aniline and
subjected to reaction with optimised conditions, the formation of
an amide was not observed (Figure 5, entry 6). These results
suggest that ring nitrogen in 2-aminopyridine is playing a crucial
supportive role in terms of coordination with copper catalyst and
thereby assisting in the delivery of singlet oxygen to the enamine
intermediate (II) as propped in the plausible reaction mechanism.
The reaction has been tried with pyridine-2,3-diamine, 2-
4.2.1 N-(pyridin-2-yl) benzamide (3a) compound 3a was
prepared using typical experimental procedure shown in section
1
4.2. H NMR (CDCl3, 400 MHz) δ 8.89 (bs, 1H), 8.44 (d, J =
8Hz, 1H), 8.29 (d, J = 4Hz, 1H), 7.98-7.95 (m, 2H), 7.81-7.77
(m, 1H), 7.61-7.50 (m, 3H), 7.11-7.08 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 164.8, 150.6, 146.7, 137.6, 133.2, 131.2,
127.8, 126.2, 118.9, 113.3; IR (CH2Cl2) 3749.9, 3245.1, 3064.1,
2924.7, 2853.5, 1674.6, 1595.9, 1576.5, 1522.3, 1492.9, 1431.2,
1303.5, 1261.5, 1237.5, 1181.5, 1150.0, 1092.7, 1074.1, 1051.9,
1027. 7 cm-1 ; ESI-MS (LTQ) : [M+H]+ 199.10
aminopyridin-3-ol,
5-chloro-3-nitropyridin-2-amine,
2-
aminoisonicotinonitrile, benzo[d]thiazol-2-amine and thiazol-2-
amine. In each case the product formation wasn’t noticed. This
may be due to weak electron donating capability of ring nitrogen
to the metal centre as required in the complex (Scheme 1). (See
ESI, section 4)
4.2.2. 3,4-dichloro-N-(pyridin-2-yl)benzamide (3b) compound
3b was prepared using typical experimental procedure. White
3. Conclusions
o
1
powder; m.p 100-102 C; H NMR (CDCl3, 400 MHz) δ 8.69
(bs, 1H), 8.38 (d, J = 8Hz, 1H), 8.32-8.31 (m, 1H), 8.07(d, J =
4Hz, 1H), 7.82-7.76 (m, 2H), 7.61 (d, J = 8Hz, 1H), 7.15-7.11
(m, 1H); 13C NMR (CDCl3, 100 MHz) δ 163.5, 158.1.0, 142.4,
138.7, 136.9, 134.0, 133.4, 131.7, 130.9, 129.6, 126.2, 120.4,
114.3; IR (CH2Cl2) 3006.9, 1528.8, 1433.4, 1308.5, 1275.1,
1261.5 cm-1; ESI-MS (LTQ) : [M+H]+ 267.40
In summary, an efficient method for the synthesis of N-
pyridinylamides by copper (I)-catalyzed oxidative C–C bond
cleavage of aryl alkyl ketones using molecular oxygen as an
oxidant was developed. The reaction has wide substrate scope,
various functional groups are well tolerated and products are
formed in good to excellent yields.
4. Experimental
4.1 General
4.2.3. 3-bromo-N-(pyridin-2-yl) benzamide (3c) compound 3c
was prepared using typical experimental procedure. H NMR
1
(CDCl3, 400 MHz) δ 8.58 (bs, 1H), 8.39 (d, J = 8Hz, 1H), 8.34
(d, J = 4Hz, 1H), 8.11 (s, 1H), 7.88 (d, J = 8Hz, 1H), 7.82 (t, J
=8Hz, 1H), 7.74 (d, J = 8Hz, 1H), 7.43 (t, J = 8Hz, 1H), 7.14 (t, J
= 4Hz, 1H) ; 13C NMR (CDCl3, 100 MHz) δ 163.5, 150.6, 147.1,
137.6, 134.2, 129.1, 124.7, 122.3, 119.2, 113.2; IR (CH2Cl2)
3378.8, 1433.0, 1275.9, 1267.3, 1261.7 cm-1 ; ESI-MS (LTQ) :
[M+H]+ 279.04
All chemicals were obtained from Sigma-Aldrich
Company and used as received. 1H, 13C and DEPT
NMR spectra were recorded on Brucker-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 solvent (CDCl3, 7.26
ppm; CD3OD, 3.31 ppm; DMSO-d6 2.51 ppm). The
carbon nuclear magnetic resonance spectra (13C NMR)
4.2.4. 2,3,4-trichloro-N-(pyridin-2-yl)benzamide (3d) compound
3d was prepared using typical experimental procedure. Yellow

5
1
semisolid; H NMR (CDCl3, 400 MHz) δ 8.69 (bs, 1H), 8.37 (d, 4.2.10. 3-fluoro-N-(pyridin-2-yl) benzamide (3j) compound 3i
J = 8Hz, 1H), 8.24 (d, J = 4Hz, 1H), 7.83-7.79 (m, 1H), 7.55- was prepared using typical experimental procedure. Cream
7.51 (m, 2H), 7.14-7.11 (m, 1H) ; 13C NMR (CDCl3, 100 MHz) δ
163.9, 151.1, 147.4, 138.8, 136.3, 135.9, 133.0, 131.3, 128.7,
127.1, 120.4, 114.7; IR (CH2Cl2) 2961.4, 2921.5, 2850.3, 1686.9,
1574.9, 1537.5, 1463.5, 1435.5, 1363.6, 1309.6, 1261.7, 1179.1,
1152.9, 1105.0, 1088.2, 1047.7, 1023.4 cm-1 ; ESI-MS (LTQ) :
[M+H]+ 301.15
o
1
powder; m.p 62-64 C; H NMR (CDCl3, 400 MHz) δ 8.90 (bs,
1H), 8.40 (d, J = 8Hz, 1H), 8.27-8.25 (m, 1H), 7.81-7.77 (m,
1H), 7.72-7.66 (m, 2H), 7.51-7.46 (m, 1H), 7.31-7.26 (m, 1H),
7.12-7.08 (m, 1H) ; 13C NMR (CDCl3, 100 MHz) δ 163.5 (1JCF
= 249 Hz) 160.6, 150.3, 146.9, 137.5, 129.5, 121.7, 119.2, 118.4,
113.9, 113.7, 113.3; IR (CH2Cl2) 3391.5, 3007.2, 1524.9, 1434.9,
1274.8, 1261.6, 1046.6 cm-1; ESI-MS (LTQ) : [M+H]+ 231.18
4.2.5. 4-methyl-N-(pyridin-2-yl) benzamide (3e) compound 3e
was prepared using typical experimental procedure. 1H NMR
(CDCl3, 400 MHz) δ 8.81 (bs, 1H), 8.43 (d, J = 8Hz, 1H), 8.29
(d, J = 4Hz, 1H), 7.87 (d, J = 8Hz, 2H), 7.80-7.75 (m, 1H), 7.32
(t, J = 8Hz, 2H), 7.10-7.06 (m, 1H), 2.45 (s, 3H) ; ; 13C NMR
(CDCl3, 100 MHz) δ 165.9, 151.6, 148.1, 142.7, 138.3, 131.5,
130.1, 127.1, 119.9, 114.4, 21.3; IR (CH2Cl2) 2959.6, 2925.1,
2854.8, 1682.6, 1673.9, 1578.8, 1537.0, 1524.8, 1520.2, 1504.7,
1455.6, 1434.7, 1303.2, 1261.9, 1110.5, 1091.7, 1020.1 cm-1 ;
ESI-MS (LTQ) : [M+H]+ 213.10
4.2.11. 4-chloro-N-(pyridin-2-yl) benzamide (3k) compound 3k
was prepared using typical experimental procedure. 1H NMR
(CDCl3, 400 MHz) δ 9.07 (bs, 1H), 8.41 (d, J = 8Hz, 1H), 8.22
(s, 1H), 7.91 (d, J = 8Hz, 2H), 7.80 (t, J = 8Hz, 1H), 7.48 (d, J =
8Hz, 2H), 7.10 (t, J = 8Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ
164.8, 160.6, 151.5, 147.8, 138.6, 132.7, 129.1, 128.8, 120.1,
114.4; IR (CH2Cl2) 3347.4, 2923.7, 2853.6, 1658.7, 1577.2,
1524.5, 1488.6, 1432.2, 1308.4, 1261.5, 1094 cm-1; ESI-MS
(LTQ) : [M+H]+ 233.34
4.2.12. 4-fluoro-N-(pyridin-2-yl) benzamide (3l) compound 3l
was prepared using typical experimental procedure. 1H NMR
(CDCl3, 400 MHz) δ 8.64 (bs, 1H), 8.43 (d, J = 8Hz, 1H), 8.32
(d, J = 4Hz, 1H), 7.89 (d, J = 8Hz, 2H), 7.80-7.76 (m, 1H), 7.37
(d, J = 8Hz, 2H), 7.10-7.07 (m, 1H) ; 13C NMR (CDCl3, 100
MHz) δ 165.6 (1JCF = 249 Hz), 160.6, 152.9, 151.7, 147.9,
138.5, 131.7, 127.3, 127.2, 119.8, 114.1; IR (CH2Cl2) 3369,
2924.1, 2851.5, 1676.9, 1600.7, 1578.5, 1530.2, 1503.9, 1461.7,
1433.3, 1274.8, 1261.5, 1230.7, 1158.4, 1093.1 cm-1; ESI-MS
(LTQ): [M+H]+ 217.23
4.2.6. 4-methoxy-N-(pyridin-2-yl) benzamide (3f) compound 3f
was prepared using typical experimental procedure. 1H NMR
(CDCl3, 400 MHz) δ 8.76 (bs, 1H), 8.42 (d, J = 8Hz, 1H), 8.30
(d, J = 4Hz, 1H), 7.95 (d, J = 12Hz, 2H), 7.79 (t, J= 12Hz, 1H),
7.09-7.06 (m, 1H), 7.01(d, J= 8Hz, 2H) 3.90 (s, 3H) 13C NMR
(CDCl3, 100 MHz) δ 165.2, 162.8, 151.6, 147.9, 138.6, 129.1,
126.4, 119.6, 114.2, 114.0, 55.6; IR (CH2Cl2) 2925.1, 1676.1,
1606.8, 1577.8, 1505.1, 1431.9, 1275.8, 1267.1, 1259.3, 1175.1,
1029.6 cm-1 ; ESI-MS (LTQ) : [M+H]+ 229.12
4.2.7. 2,4-dichloro-N-(pyridin-2-yl)benzamide (3g) compound 3g
was prepared using typical experimental procedure. 1H NMR
(CDCl3, 400 MHz) δ 9.03 (bs, 1H), 8.38 (d, J = 8Hz, 1H), 8.17
(d, J = 4Hz, 1H), 7.81-7.77 (m, 1H), 7.72 (d, J = 8Hz, 1H), 7.50
(d, J = 4Hz, 1H), 7.40-7.37 (m, 1H), 7.11-7.08 (m, 1H); 13C
NMR (CDCl3, 100 MHz) δ 164.0, 162.8, 151.0, 147.9, 138.7,
137.5, 133.3, 131.8, 131.2, 130.3, 127.9, 120.5, 114.3; IR
(CH2Cl2) 3182.9, 2925.3, 1688.6, 1579.4, 1532.6, 1471.6,
1435.6, 1375.2, 1281.7, 1239.0, 1150.1, 1096.7, 1050.4 cm-1;
ESI-MS (LTQ) : [M+H]+ 267.18
4.2.13.
3,5-bis(benzyloxy)-N-(pyridin-2-yl)benzamide
(3m)
compound 3m was prepared using typical experimental
procedure. Yellow semisolid; 1H NMR (CDCl3, 400 MHz) δ 9.10
(bs, 1H), 8.43 (d, J = 8Hz, 1H), 8.23-8.22 (m, 1H), 7.79-7.74 (m,
1H), 7.46-7.34 (m, 10H), 7.19 (d, J = 4Hz, 2H), 7.08-7.05 (m,
1H); 6.82 (t, J = 4Hz, 1H); 5.08 (s, 4H); 13C NMR (CDCl3, 100
MHz) δ 165.7, 160.1, 151.6, 147.9, 138.5, 136.5, 136.4, 128.7,
128.2, 127.6, 119.9, 114.3, 106.4, 106.1, 70.3; IR (CH2Cl2)
3007.1, 2872, 1678.5, 1593.6, 1520.3, 1433.6, 1275.1, 1261.6,
1158.7, 1054.7 cm-1; ESI-MS (LTQ) : [M+H]+ 411.41
4.2.8. 3-acetamido-N-(pyridin-2-yl) benzamide (3h) compound
4.2.14.
4-(benzyloxy)-N-(pyridin-2-yl)benzamide
(3n)
3g was prepared using typical experimental procedure. Brown
compound 3n was prepared using typical experimental
procedure. White semisolid; H NMR (CDCl3, 400 MHz) δ 8.55
1
1
semisolid; H NMR (CDCl3 + MeOD), 400 MHz) δ 9.22 (bs,
1H), 8.69 (s, 1H), 8.33 (d, J = 8Hz, 1H), 8.19 (s, 1H), 7.99 (s,
1H), 7.89 (d, J = 8Hz, 1H), 7.74 (t, J = 8Hz, 1H), 7.59 (d, J =
8Hz, 1H); 7.37 (t, J = 8Hz, 1H), 7.04 (t, J = 4Hz, 1H), 2.14 (s,
3H); 13C NMR (CDCl3 + MeOD), 100 MHz) δ 175.3, 169.2,
165.9, 158.4, 151.6, 138.9, 138.4, 134.8, 129.4, 123.7, 122.7,
119.9, 118.8, 114.5; 24.3; IR (CH2Cl2) 3304.9, 3007.2, 2922.0,
1670, 1592.8, 1526, 1486.7, 1433.4, 1372.3, 1274.6, 1261.8 cm-
1; ESI-MS (LTQ) : [M+H]+ 256.35
(bs, 1H), 8.41 (d, J = 8Hz, 1H), 8.32 (d, J = 4Hz, 1H), 7.93 (d, J
= 8Hz, 2H), 7.79 (t, J = 8Hz, 1H), 7.48-7.37 (m, 5H), 7.10 (d, J =
8Hz, 3H), 5.17 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ 165.0,
162.1, 151.7, 147.9, 138.4, 136.3, 129.1, 128.7, 128.1, 127.4,
126.7, 119.8, 115.0, 114.1, 69.9; IR (CH2Cl2) 3393.2, 2958.5,
2925.6, 2860.1, 1736.7, 1679.3, 1601.4, 1507, 1432.9, 1298,
1261.0, 1024.4 cm-1;
4.2.15. 4-cyclohexyl-N-(pyridin-2-yl)benzamide (3o) compound
3o was prepared using typical experimental procedure. cream
4.2.9. 3-chloro-N-(pyridin-2-yl) benzamide (3i) compound 3i was
prepared using typical experimental procedure. White powder;
m.p 95-97 oC; 1H NMR (CDCl3, 400 MHz) δ 8.64 (bs, 1H), 8.40
(d, J = 12Hz, 1H), 8.33 (d, J = 4Hz, 1H), 7.96 (s, 1H), 7.82 (t, J
= 8Hz, 2H), 7.58 (d, J = 8Hz, 1H), 7.49 (t, J = 8Hz, 1H), 7.14 (t,
J = 8Hz, 1H) ; 13C NMR (CDCl3, 100 MHz) δ 164.3, 151.3,
148.1, 138.5, 135.9, 135.3, 132.5, 130.3, 127.9, 125.1, 120.3,
114.1; IR (CH2Cl2) 3373.0, 3016.6, 2931.0, 2854, 1678.3,
1576.5, 1526, 1433.5, 1307.3, 1261.1, 1048.7 cm-1; ESI-MS
(LTQ) : [M+H]+ 231.18
1
semisolid; H NMR (CDCl3, 400 MHz) δ 8.94 (bs, 1H), 8.31 (d,
J = 8Hz, 1H), 8.13 (s, 1H), 7.90-7.86 (m, 2H), 7.70 (t, J = 8Hz,
1H), 7.10 (t, J = 8Hz, 2H), 7.00-6.97 (m, 1H), 1.18 (s, 11H); 13C
NMR (CDCl3, 100 MHz) δ 166.4, 164.8, 163.9, 151.6, 147.8,
138.6, 130.5, 129.8, 120.0, 116.0, 115.8, 114.3, 31.9, 29.9, 22.7,
14.1 IR (CH2Cl2) 3013.4, 2924.5, 2855.8, 1679.82, 1574, 1432.8,
1304.3, 1274.9, 1261.5, 1028.2 cm-1; ESI-MS (LTQ) : [M+H]+
281.41
4.2.16. 2-bromo-N-(pyridin-2-yl)benzamide (3p) compound 3p
was prepared using typical experimental procedure. Brown

6
Tetrahedron
semisolid; 1H NMR (CDCl3, 400 MHz) δ 8.31 (bs, 1H), 8.20 (t,
12. Patel, O. P. S; Anand, D; Maurya, R. K; Yadav, P. P; Green Chem. 2015,
17, 3728-3732.
J = 8Hz, 2H), 7.71 (d, J = 8Hz, 2H), 7.46 (t, J = 8Hz, 1H), 7.25-
7.19 (m, 2H), 6.86 (t, J = 8Hz, 1H); 13C NMR (CDCl3, 100 MHz)
δ 165.7, 151.8, 145.4, 132.9, 128.9, 128.5, 128.3, 127.9, 125.1,
124, 118, 113.1; IR (CH2Cl2) 2925.7, 2852, 1470.2, 1261.7,
1105, 1019.1 cm-1; ESI-MS (LTQ) : [M+H]+ 279.04
13 Parikh, N; Kumar, D; Roy, S. R; Chakraborti, A. K; Chem. Commun.
2011, 47, 1797-1799.
14 a) Kumar, D; Seth, K; Kommi, D. N; Bhagat, S; Chakraborti, A. K; RSC
Adv. 2013, 3, 15157-15168. b) Sorella, G. L; Strukul, G; Scarso, A;
Green Chem. 2015, 17, 644-683. c) Vaidya, G. N; Fiske, S; Verma, H;
Lokhande, S. K; Kumar, D; Green Chem. 2019, 21, 1448-1454.
15 a) Seth, K; Roy, S. R; Kumar, A. Chakraborti, A. K; Catal. Sci. Technol.
2016, 6, 2892-2896. b) Seth, K; Roy, S. R; Chakraborti, A. K; Chem.
Commun. 2016, 52, 922-925.
Acknowledgments
RS thanks DST-SERB, New Delhi for the award of Postdoctoral
research fellowship. PVB thanks CSIR, New Delhi for research
grant.
16 Ouannes, C; Wilson, T; J. Am. Chem. Soc. 1968, 90, 6527-6528.
17 Du, F. T; Ji, J. X; Chem. Sci. 2012, 3, 460-465.
18 Tang, C; J. Ning; Angew. Chem. 2014, 126, 1-6.
19 Mohammed, S; Vishwakarma, R. A; Bharate, S. B; J. Org. Chem. 2015,
80, 6915–6921.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
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Highlights
• A greener protocol for the synthesis of N-pyridinylamides, was
achieved with the cheap and easily available oxygen as an oxidant.
• Generation of singlet oxygen in the presence of copper (I) salt is the
key feature of this transformation.
• Method for the chemo selective cleavage of C(O)-C(alkyl) bond in
long chain alkyl aryl ketones.