Microwave-assisted heteropolyanion-based ionic liquid promoted sustainable protocol to N-heteroaryl amides via N-directing dual catalyzed oxidative amidation of aldehydes

Article abstract of DOI:10.1039/C6RA20961K

A sustainable procedure for the synthesis of N-heteroaryl amides directly from oxidative amidation of aldehydes catalyzed by heteropolyanion-based ionic liquids under microwave-promoted conditions has been reported. The transformation has proven to tolerate a wide range of aldehydes and amino heterocycles with different functional groups. Moderate to excellent yields, solvent-free media, operational simplicity and reusability of catalysts are the main highlights. Furthermore, the proposed N-directing dual-catalysis mechanistic pathway was briefly investigated in this report.

Full text of DOI:10.1039/C6RA20961K

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ARTICLE
Microwave-assisted heteropolyanion-based ionic liquids
promoted sustainable protocol to N-heteroaryl amides via N-
directing dual catalyzed oxidative amidation of aldehydes
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Renzhong Fu, Yang Yang,* Weihua Jin, Hui Gu, Xiaojun Zeng, Wen Chai, Yunsheng Ma, Quan
Wang, Jun Yi* and Rongxin Yuan
www.rsc.org/
A sustainable procedure for the synthesis of N-heteroaryl amides directly from oxidative amidation of aldehydes catalyzed
by heteropolyanion-based ionic liquids under microwave-promoted conditions has been reported. The transformation has
proven to tolerate a wide range of aldehydes and amino heterocycles with different functional groups. Moderate to
excellent yields, solvent-free media, operational simplicity and reusability of catalysts are the main highlights.
Furthermore, the proposed N-directing dual-catalysis mechanistic pathway was briefly investigated in this report.
acylation of amino heterocycles with activated carboxylic acid
1
derivatives using suitable coupling reagents. Although novel
2
Introduction
1
3-18
coupling reagents
and improved chemical processing
Amide functionalities have attracted a great deal of attention
in current chemical and industrial research not only owing to
19
techniques were subsequently developed, these methods
-2 have several innate drawbacks due to the weak nucleophilicity
of amino heterocycles, such as harsh reaction conditions, toxic
reagents, poor atom-efficiency, excess amount of by-products.
To circumvent these limitations, several innovative strategies
have been explored to improve N-heteroaryl amide derivatives
1
their remarkable biological and pharmacological activities,
but also because they are versatile building blocks for the
3
-6
synthesis of various useful molecules. To our knowledge,
7
more than 50% of known drugs contain amide units. Among
amides, N-heteroaryl amides as an important class of
2
0-22
8
-11 synthesis, including amidation of heteroaryl halides,
2
pharmacophores are widely found in bioactive compounds.
3-24
aminocarbonylation of aryl halides,
trapping of ketenes
Recently, pyridyl benzamide derivative
8
inhibitors for the Trypanosoma brucei; tubulin polymerization
1
was reported as
2
5
with amino heterocycles, decomposition of N-heteroaryl-N’-
2
6
27-35
9
benzoylthioureas
and oxidative amidation methods.
inhibitor
were selective inhibitors of the protein methyltransferase;
compound was allosteric glutaminase inhibitors based on N-
2 showed tumor growth inhibition; thiazolyl amides
1
0
Among them, direct oxidative amidation of aldehydes with
amino heterocycles is of great interest in synthetic organic
chemistry due to atom economy and easily available
substrates. To date, several metal catalyst systems have been
3
4
heteroaryl amide scaffold (Fig. 1).
Conventionally, N-heteroaryl amides are synthesized by
reported to promote this oxidative amidation of aldehydes to
31-33
O
O
N
Br
i
O Pr
achieved N-heteroaryl amides, such as CuI/air
3
and
4
H
N
N
H
Rh(III)/Ag CO .
2
Just recently, Yadav et al. presented
3
N
2 2
Cu(OTf) /I as an effective catalyst for the oxidative amidation
O
N
reaction from the view point of green chemistry introducing
3
5
C
2
H
4
OMe
aqueous micellar reaction systems.
However, these
1
2
methodologies suffer from some common demerits that
greatly restricted large scale industrial applications, such as
requirement for toxic metal reagents and oxidants, narrow
substrate scope, difficulties in separation and recycling of the
catalysts. Therefore, there is an urgent need to develop more
efficient and sustainable catalytic processes to a wide range of
N-heteroaryl amides.
O
H
N
NHR
H
N
N
N
S
S
Bn
4
N
H
Bn
S
N
N
N
O
O
3
4
Fig. 1 Examples for N-heteroaryl amides with biological and pharmacological
activities.
Over the last few decades, the development of more
sustainable chemical and industrial processes was attractive
due to global concern for environmental protection. So far,
ionic liquids (ILs) as efficient and ecofriendly solvents and/or
catalysts in organic reactions provide both economical and
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3
6-37
ecological benefits.
Recently, a series of heteropolyanion-
1
-Methyl-3-(3-
X = PW12O
40
based ILs (HPAILs) have emerged as new species of hybrid
materials, which were prepared by combining Keggin
heteropolyanions with ‘task-specific’ IL (TSIL) cations
sulfopropyl)imidazolium
phosphotungstate
([MIMPS] PW O )
3
12 40
3
8-40
containing special functional groups.
In view of the
1
-Methyl-3-(3-
advantages of heteropolyanions and TSIL cations, HPAILs
generally have high melting points, thermal stability and
chemical stability due to the large volume and high valence of
heteropolyanions and hydrogen bonding networks existing in
the compounds. In addition, protocols containing HPAILs are
X = PMo12O
40
sulfopropyl)imidazolium
phosphomolybdate
3 40
([MIMPS] PMo12O )
1
-(3-Sulfopropyl)pyridinium
phosphotungstate
([PyPS] PW O )
4
1-46
X = PW12O
40
an attractive alternative for traditional acid-catalyzed
4
or
7-53
oxidative
organic transformations because of their
3
12 40
operational simplicity, no toxicity, easy isolation and
reusability.
1
-(3-Sulfopropyl)pyridinium
phosphomolybdate
[PyPS]
X = PMo12O
40
On the other hand, a large number of publications have
clearly shown that many types of chemical transformations
can be carried out successfully under microwave (MW)
(
3 40
PMo12O )
Triethyl-(3-
5
4
X = PW12O
40
conditions during the last years. Most importantly, MW
processing frequently leads to the significant rate
enhancements, yield and selectivity improvements, very
simplified ease of manipulation and work-up, less
environmental polluting processes as well as solvent-free
organic transformations matching with the goal of green
sulfopropyl)aminium
phosphotungstate
([TEAPS] PW O )
3
12 40
Triethyl-(3-
X = PMo12O
40
sulfopropyl)aminium
phosphomolybdate
5
5-56
chemistry.
Our group has previously reported HPAILs
([TEAPS]
3
PMo12
40
O )
catalyzed amidation via condensation using carboxylic acid
5
7-59
Fig. 2 N-substituted imidazole, pyridine and triethylamine based HPAILs.
derivatives and amines (Scheme 1(a)).
Whereafter, HPAILs
are introduced into catalyzed oxidative amidation by us, while
only aliphatic amines were well tolerated in the reactions with Table 1 Optimization of the reaction conditions for oxidative amidation of
a
benzaldehyde with 2-aminopyridine
limited substrate scope and practical application (Scheme
6
(b)). As a part of our research to pursue novel, efficient and
0
1
5
7-64
green methods for organic transformations,
herein we
wish to report the MW-assisted HPAILs catalyzed oxidative
amidation of aldehydes with amino heterocycles to N-
heteroaryl amides via N-directing dual catalysis process
Entry Catalyst [mol %]
Oxidant
Time
Yield
b
(Scheme 1(c)).
(h)/min
(%)
c
c
1
–
TBHP
TBHP
TBHP
TBHP
(12)
0
c
c
2
3
[PyPS]
[PyPS]
[PyPS]
[PyPS]
[PyPS]
[PyPS]
[PyPS]
[PyPS]
3
3
3
3
3
3
3
3
PW12
PW12
PW12
PW12
PW12
PW12
PW12
PW12
O40 [3]
O40 [3]
O40 [3]
O40 [3]
O40 [3]
O40 [3]
O40 [3]
O40 [2]
(12)
31
d
d
Results and Discussion
(12) , 50 54 , 61
e
e
4
(12) , 50
78 , 82
Based on our previous investigations in HPAIL catalyzed
5
5
H
2
O
2
50
50
<5
<5
<5
<5
83
86
77
78
81
71
40
36
7-60
organic reactions,
N-substituted imidazole, pyridine and
6
Oxone
triethylamine based HPAILs were chosen as potential catalysts
for this oxidative amidation (Fig. 2).
7
m-CPBA 50
8
9
NaOCl
TBHP
50
50
50
50
50
50
50
50
50
(
a) Previous work
R3
10
[PyPS]
3
PW12
PW12
PMo12
O
40 [1]
TBHP
O
H
N
HPAILs
1
1
1
1
2
3
[PyPS]
[PyPS]
3
O40 [0.5]
TBHP
R1
X
R2
Solvent-Free
O
40 [1]
40 [1]
TBHP
3
O
R2
4
5
6
X = OH, NR R , OR
[MIMPS]
[MIMPS]
[TEAPS]
[TEAPS]
3
PW12
PMo12
O
TBHP
N
(
b) Previous work
R1
R3
14
15
3
O
40 [1] TBHP
HPAILs
Oxidant
O
R3
H
3
PW12 40 [1]
O
TBHP
N
1
6
3
PMo12O40 [1] TBHP
R1
H
R2
Solvent-Free
2
3
R , R = aliphatic or H
a
Reaction conditions: benzaldehyde 5a (2 mmol), 2-aminopyridine 6a (2.4 mmol), HPAIL
(
c) This work
catalyst and TBHP (1.5 equiv., 70% aqueous solution) under MW (700 W) and solvent-free
O
HPAILs
Oxidant
conditions at 70
o
C in a sealed glass pressure tube.
b
Isolated yields based on benzaldehyde
O
Ar
N
Ar
N
H
c
d
R1
5a. Reaction was conducted under room temperature. Reaction was conducted under
N
N
R1
H
o
e
MW, Solvent-Free
conventional heating at 50 C. Reaction was conducted under conventional heating at 70
R2
R2
o
C.
Scheme 1 HPAIL catalyzed amidation reactions developed by our group
2
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Initially, our studies were commenced using commercially Table
2
HPAIL catalyzed oxidative amidation of aldehydes with amino
a
heterocycles
available benzaldehyde 5a and 2-aminopyridine 6a as the
model substrates to optimize the reaction conditions (Table 1).
Firstly, as a control experiment, tert-butyl hydroperoxide
(TBHP) was used as the oxidant in the absence of any catalyst
and additional solvent at room temperature. The complete
lack of reactivity was observed even after stirring for 12 h
b
Product: time (min)/yield (%)
(
Table 1, entry 1), whereas addition of 3 mol% amount of
O
[
3
PyPS] PW12O40 to the reaction mixture resulted in the desired
N
N
N-pyridinamide 7a in 31% yield (Table 1, entry 2). The results
revealed that oxidative amidation to N-heteroaryl amides
could be promoted by HPAILs. In order to improve the yield,
some adjustments to the reaction conditions were made. To
our delight, it was shown that the rate and yield of the
reaction both increased dramatically when the reaction
H
7
a: 50/86
7b: 50/91
7c: 50/90
7f: 50/80
7
e: 50/83
o
mixture was conventionally heated at 50 C (Table 1, entry 3,
o
4% yield) or 70 C (Table 1, entry 4, 78% yield). In addition,
7d: 50/88
5
more efficient results were observed when MW-assisted
heating was introduced (Table 1, entries 3–4). Then reactions
were performed using other common oxidants including H
2
O
2
,
7g: 50/81
7j: 50/70
7i: 50/75
7
7
h: 50/78
k:60/65
Oxone, NaOCl, and m-CPBA, but in all cases only 0–5% amide
product formation was observed (Table 1, entries 5–8). To our
surprise, decreasing the catalyst loading to 2 mol% and 1 mol%
led to the formation of the amide product in little higher
yields, while much less amount (0.5 mol%) was not beneficial
to the product (Table 1, entry 9–11). Afterwards the catalytic
activities of other related catalysts prepared earlier were
screened (Table 1, entry 12–16). PyPS species were found to
be more efficient than MIMPS and TEAPS species, while the
7
l: 60/75
7
7
m: 60/74
p: 50/89
7n: 60/62
7q: 50/83
7o: 50/84
results demonstrated that PW12
more active than PMo12 40 heteropolyanions. Finally, the
optimized condition for this oxidative amidation was shown
using 1 mol% of [PyPS] 40 under MW and solvent-free
O40 heteropolyanions was
O
O
N
N
H
N
7r: 60/78
3
PW12O
conditions at 70 °C affording N-(pyridin-2-yl)benzamide in 86%
yield (Table 1, entry 10).
With the optimal conditions in hand, the scope and
generality of this oxidative amidation were explored using
various aldehydes and amino heterocycles. Initially, a set of
aldehydes, including aromatic and aliphatic aldehydes, were
employed in the reaction with moderate to good yields (Table
7
s: 60/78
v: 60/67
7t: 60/81
7w: 60/63
9a: 50/90
7u: 60/72
7x: 50/76
7
2). The results shown that the reaction could tolerate a variety
of substituents (Me, OMe, F, Cl, Br, CO Me, CF , CN and NO )
2
2
3
on the aryl aldehyde moiety, which are very important
functional units in pharmaceutical chemistry. In general,
8
1
a: 50/88
10a: 50/86
13a: 60/66
16a: 60/72
bearing electron-donating substitutions (Table 2, 7a
the aryl nucleus showed relatively higher reactivity than those
of the electron-withdrawing (Table 2, 7f 7n) counterparts.
While sterically hindered substituents such as MeO (Table 2,
) and Br (Table 2, 7j) at the ortho-position of aryl aldehydes
–7e) on
–
1a: 50/84
12a: 60/79
7e
gave the lower yield than para position and meta position
substituted substrates. Following the aryl aldehydes, various
heterocyclic aldehydes were well tolerated and furnished the
corresponding products in moderate to good yields, including
14a: 60/41
15a: 60/78
18a: 60/74
pyridinecarboxaldehyde,
furfural
and
thiophenecarboxaldehyde (Table 2, 7o
–
7t). Subsequently, in
1
7a: 60/70
the cases of aliphatic aldehydes, the lower yields (Table 2, 7u
–
7w
) when compared to aromatic aldehydes may be due to the
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a
3
Reaction conditions: aldehyde (2 mmol), amino heterocycle (2.4 mmol), [PyPS] PW12O40 (1
9
8
8
7
7
0
5
0
5
0
mol %) and TBHP (1.5 equiv., 70% aqueous solution) under MW (700 W) and solvent-free
86
o
b
conditions at 70 C in a sealed glass pressure tube. Isolated yields based on aldehyde.
8
2
side reactions such as aldol condensation and oxidation to the
corresponding carboxylic acids. Moreover, it was worth
mentioning that N-(pyridin-2-yl)formamide was furnished via
this oxidative amidation methodology in 76% yield, which
normally showed poor yields in other reports.
7
3
7
76
7
5
With regard to the reactivities of amino heterocycles, 2-
aminopyridines analogues containing H, CH , Cl and NH
3
2
1
2
4
5
substitutions exhibited moderate to good reactivity. It was
shown that electron-donating substituents (Table 2, 8a 11a
Number of Cycles
–
)
on the pyridine ring were beneficial for the transformation,
whereas electron-withdrawing substituents decreased the
Fig. 3 Reusability studies of the catalyst for the catalyzed oxidative amidation.
yield (Table 2, 12a
–
13a, NH group shows electron-withdraw in
2
O
(
eqn. 1)
the acid catalyzed reaction conditions), while introducing steric
hindrance in pyridine ring had no obvious effect on the
PyPSCl (3 mol %)
Ph
N
H
N
TBHP
MW, 70 oC, solvent-free
O
7a yield = 25 %
outcome (Table 2, 8a
–
11a). Moreover, secondary amino
H
O
N
N
Ph
H
H PW12O (1 mol %)
pyridine (N-heptyl-2-aminopyridine) showed low reactivities in
this catalyzed oxidative amidation (Table 2, 14a). To our
delight, the methodology also worked well with
aminopyrazine, aminopyrimidine and aminobenzothiazole
H
3
40
(eqn. 2)
5a
6a
TBHP
Ph
N
H
N
o
MW, 70
C, solvent-free
7a
yield = 38 %
O
O
R [PyPS]
3
PW12O
40 (1 mol %)
R
(eqn. 3)
(Table 2, 15a–18a). which further demonstrated the generality
H
N
TBHP
Ph
N
H
Ph
H
H
MW, 70 oC, solvent-free
R = H, 4-chloro, 4-methyl,
of the present approach.
5
a
6
yield < 5 %
Since reusability is one of the advantages for HPAILs
catalyzed process, the potential recycling of HPAILs was
investigated with the reaction of benzaldehyde 5a and 2-
aminopyrine 6a under the optimized reaction conditions. After
completion of the first reaction,the aqueous reaction mixture
was concentrated under reduced pressure and then ethyl
acetate was added. Upon vigorous stirring, the catalyst can be
easily retrieved from the reaction mixture via simple
centrifugation or filtration, washed with ethyl acetate to
remove traces of the previous reaction mixture and then dried.
The recovered catalyst was used for further runs for the same
reaction. As was evident from Fig. 3, the reaction was repeated
4
-nitro, 3-nitro, 2-nitro
O
Y
X
[PyPS] PW12O40 (1 mol %)
O
Y
X
3
(eqn. 4)
H
TBHP
Ph
N
H
Ph
H
N
H
MW, 70 oC, solvent-free
5a
6
19a, X = N, Y = CH, yield = 55%;
20a, X = CH, Y = N, yield < 5%
O
O
[
PyPS] PW12O (1 mol %)
3 40
H
(eqn. 5)
N
TBHP
Ph
N
H
Ph
H
H
X
MW, 70 oC, solvent-free
X
5a
6
Y
Y
2
2
1a, X = N, Y = CH, yield = 51%;
2a, X = CH, Y = N, yield < 5%
Scheme 2 Control experiments for the mechanism study.
for up to five consecutive runs with a little loss of catalytic coordination of the PyPS cation and the PW O anion
efficiency.
1
2 40
(Scheme 2, eqn. 1 and eqn. 2). Secondly, several anilines
Furthermore, some control experiments were performed in (aniline, 4-chloroaniline, 4-methylaniline, 4-nitroaniline, 3-
order to investigate the reaction mechanism (Scheme 2). nitroaniline and 2-nitroaniline) were checked under optimized
3
Firstly, when PyPSCl or pure H PW12O40 was used as a catalyst reaction conditions, but no desired products were formed
under standard conditions, the relatively low yields implied the (Scheme 2, eqn. 3). The results revealed that the heteroatom
on the aromatic nucleus should be absolutely necessary for the
oxidative amidation. In addition, in the cases of amino
heterocycles with heteroatoms several bonds length distance
from the reaction centre, 3-aminopyridine (Scheme 2, eqn. 4,
1
9a) and 8-aminoquinoline (Scheme 2, eqn. 5, 21a) gave
moderate yields, while both 4-aminopyridine (Scheme 2, eqn.
20a) and 8-aminoisoquinoline (Scheme 2, eqn. 5, 22a) as
4,
substrates resulted in very low yields, indicating that the
nearness of heteroatoms on the aromatic nucleus with the
reactive centre benefited the amidation.
On the basis of the above analyses and our previous
6
0
report, a N-directing dual-catalysis mechanistic pathway is
proposed for understanding the catalytic performance of
HPAILs in Fig 4. Initially, the activation of carbonyl of aldehyde
4
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1
and N–H bond in amine are achieved via coordination with the instrument. H NMR spectra were recorded at 300 MHz or 400
aminium cation and sulfonic group in the HPAIL cation MHz and are reported in parts per million (ppm) on the δ scale
1
3
respectively. Subsequently, the addition of the amine to the relative to tetramethylsilane (TMS) as an internal standard.
C
carbonyl carbon atom give the dipolar adduct. After proton-
t-BuOOH
NMR spectra were recorded at 75 MHz or 100 MHz and are
reported in parts per million (ppm) on the δ scale relative to
CDCl3 (δ 77.16) and DMSO-d6 (δ 39.52). Multiplicities are
indicated as the following : s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; dd, doubled doublet; td, tripled doublet;
br, broad. Coupling constants (J values) where noted are
quoted in hertz. Mass spectra were obtained using Agilent
t-BuOH
N
N
SO3H 3
OH
Ar
O
H-O-H
O
R1
N
O
O
O
R1
H
R2
W
W
Ar
N
H
Ar
N
H
hemiaminal
intermediate
N
R1
N
R2
R2
-
-
O
O
O
+
N
O2S
O
H
+
O
W
N
N
O
O2
S
O
W
H
3
H
N
H
O
H
3
O
Ar
-
+
H
-
Ar
-
N
H
O
N
N
1260-6120 (ESI) instrument. MW-promoted heating was
+
N
Ar
R1
H
N
N
Ar
R1
H
R2
R1
R2
R1
R2
H
R2
obtained using MAS-II instrument manufactured by Shanghai
Sineo Microwave Chemistry Technology Co., Ltd. The melting
point was uncorrected.
O
=
PW12O403-
W
Fig. 4 Plausible N-directing dual-catalysis mechanistic pathway to N-heteroaryl
amide.
Typical Procedure for the Synthesis of N-heteroaryl Amides by
HPAILs catalyzed oxidative amidation.
exchange and desorption, a hemiaminal intermediate is
formed with a regenerated HPAIL cation catalyst. Meanwhile,
the oxidant reacts with the W sites in the HPAIL anion
framework, leading to the generation of the peroxo-W
complex that is supposed to be the active site which makes the
hemiaminal oxidation. Upon the oxidation is directed and
promoted by the coordination of heteroatoms on the aromatic
nucleus to the W sites, the final amide product is obtained
resuming the original state of W=O by ring opening, proton-
exchange, subsequent dehydration and desorption of the
adducted peroxo-W species.
[
3
PyPS] PW12O40 (0.07 g, 0.02 mmol) and TBHP (0.39 g, 1.5
equiv., 70% aqueous solution) were added to a mixture of
aldehyde (2 mmol) and amino heterocycle (2.4 mmol) in a 15
mL a glass pressure tube. After the pressure tube was closed,
o
the reaction mixture was stirred at 70 C under MW (700 W).
The progress of the reaction was monitored by TLC. On
completion, the aqueous reaction mixture was concentrated
under reduced pressure, the remaining mixture was diluted
with ethyl acetate (20 mL) with vigorous stirring for 30 min.
The insoluble catalyst was recovered by filtration or
centrifugation. After washing with ethyl acetate to remove
traces of the previous reaction mixture and then drying, the
recovered catalyst could be used for further runs for the same
reaction. The filtrate was evaporated and the residue was
Conclusions
In conclusion, all the above results demonstrate that an
efficient and sustainable protocol for the synthesis of N-
heteroaryl amides using HPAIL as catalyst and TBHP as an
oxidant under MW-assisted and solvent-free conditions was
achieved. Compared to previously known oxidative amidation
catalysts, operational simplicity, solvent-free media, reusable
directly
purified
by
recrystallization
or
column
chromatography to give amide product.
Characterization data of N-heteroaryl amides
N-(pyridin-2-yl)benzamide (7a). White solid. Mp: 88.1-90.7 °C;
1
3
H NMR (400 MHz, CDCl ) δ 9.26 (brs, 1H), 8.42 (d, J = 8.4 Hz,
catalysts and the compatibility with various functional groups 1H), 8.15 (dd, J = 7.6, 0.8 Hz, 1H), 7.95-7.93 (m, 2H), 7.75 (td, J
are the advantages of this procedure. The proposed N- = 8.0, 1.6 Hz, 1H), 7.57-7.54 (m, 1H), 7.49-7.45 (m, 2H), 7.03
1
3
directing dual-catalysis process was briefly investigated. This (ddd, J = 7.2, 5.0, 0.4 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ
report complements previous oxidative amidation strategy. On 166.1, 151.8, 147.8, 138.6, 134.4, 132.3, 128.8, 127.4, 119.9,
+
the basis of the findings of this report, the expansion of this 114.5; HRMS Calcd for C12
chemistry to other organic transformations is currently 199.0864.
11 2
H N O (M + H ): 199.0866; Found:
underway in our laboratory.
4-Methyl-N-(pyridin-2-yl)benzamide (7b). White solid. Mp:
1
1
15.5-117.7 °C; H NMR (400 MHz, CDCl
d, J = 8.4 Hz, 1H), 8.23 (dd, J = 4.8, 0.4 Hz, 1H), 7.86 (d, J = 8.0
Hz, 2H), 7.75 (td, J = 8.0, 2.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H),
3
) δ 9.13 (brs, 1H), 8.42
(
Experimental section
1
3
7
.05 (dd, J = 6.8, 5.2 Hz, 1H), 2.42 (s, 3H); C NMR (100 MHz,
General methods
CDCl ) δ 166.0, 151.9, 147.7, 142.9, 138.7, 131.5, 129.5, 127.5,
3
Reagent grade solvents were used for extraction,
recrystallization and flash chromatography. All other
commercial reagents were used as received without additional
purification. The progress of reactions were checked by
analytical thin-layer chromatography (TLC, silica gel 60 F-254
plates). The plates were visualized first with UV illumination
followed by iodine or phosphomolybdic acid hydrate. Column
chromatography was performed using silica gel (200-300
mesh). NMR spectra were obtained using BRUKER AVANCE III
+
1
2
19.8, 114.5, 21.6; HRMS Calcd for C13
13.1022; Found: 213.1025.
13 2
H N O (M + H ):
4
-Methoxy-N-(pyridin-2-yl)benzamide (7c). White solid. Mp:
1
1
3
31.5-133.3 °C; H NMR (400 MHz, CDCl ) δ 9.10 (brs, 1H), 8.40
(
d, J = 8.4 Hz, 1H), 8.19 (brs, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.74
(
t, J = 8.0 Hz, 1H), 7.04-7.01 (m, 1H), 6.97 (d, J = 8.4 Hz, 2H),
13
.86 (s, 3H); C NMR (100 MHz, CDCl ) δ 165.4, 162.8, 152.9,
3
3
1
47.7, 138.5, 129.3, 126.5, 119.7, 114.3, 114.0, 55.5; HRMS
+
(M + H ): 229.0972; Found: 229.0970.
Calcd for C13
H
13
N
2
O
2
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DOI: 10.1039/C6RA20961K
ARTICLE
Journal Name
3
-Methoxy-N-(pyridin-2-yl)benzamide (7d). White solid. Mp: Hz, 2H), 8.00 (d, J = 8.0 Hz, 2H), 7.79 (t, J = 7.6 Hz, 1H), 7.11 (t, J
1
13
5
2.6-64.1 °C; H NMR (400 MHz, CDCl
d, J = 8.4 Hz, 1H), 8.24-8.21 (m, 1H), 7.80-7.75 (m, 1H), 8.52- 165.0, 151.4, 148.0, 138.8, 138.2, 133.5, 130.2, 127.4, 120.4,
.50 (m, 2H), 7.40-7.35 (m, 1H), 7.11-7.05 (m, 2H), 3.87 (s, 3H); 114.4, 52.6; HRMS Calcd for C14 (M + H+): 257.0921;
3 3
) δ 9.25 (brs, 1H), 8.42 = 6.0 Hz, 1H), 3.97 (s, 3H); C NMR (100 MHz, CDCl ) δ 166.3,
(
7
13 2 3
H N O
1
3
C NMR (100 MHz, CDCl
3
) δ 166.0, 160.0, 151.8, 147.6, 138.8, Found: 257.0924.
4-Cyano-N-(pyridin-2-yl)benzamide (7l). White solid. Mp:
1
35.8, 129.9, 120.0, 119.4, 118.8, 114.6, 112.5, 55.6; HRMS
+
(M + H ): 229.0972; Found: 229.0973.
1
Calcd for C13
H
13
N
2
O
2
3
151.5-153.1 °C; H NMR (400 MHz, CDCl ) δ 9.05 (brs, 1H), 8.37
2
-Methoxy-N-(pyridin-2-yl)benzamide (7e). White solid. Mp: (d, J = 8.4 Hz, 1H), 8.22-8.20 (m, 1H), 8.05-8.03 (m, 2H), 7.82-
13
1
0.5-73.1 °C; H NMR (400 MHz, CDCl
7
3
) δ 10.36 (brs, 1H), 8.44 7.77 (m, 3H), 7.11 (ddd, J = 7.2, 4.8, 0.8 Hz, 1H); C NMR (100
) δ 164.1, 151.2, 148.0, 138.9, 138.3, 132.8, 128.1,
(
d, J = 8.4 Hz, 1H), 8.32 (ddd, J = 5.2, 2.0, 0.8 Hz, 1H), 8.27 (dd, J MHz, CDCl
3
+
=
7
10 3
8.0, 2.0 Hz, 1H), 7.75-7.71 (m, 1H), 7.53-7.49 (m, 1H), 7.15- 120.6, 117.9, 115.9, 114.6; HRMS Calcd for C13H N O (M + H ):
1
3
.11 (m, 1H), 7.06-7.03 (m, 2H), 4.07 (s, 3H); C NMR (100 224.0818; Found: 224.0820.
) δ 163.7, 157.6, 152.1, 148.0, 138.4, 133.8, 132.6, N-(pyridin-2-yl)-4-(trifluoromethyl)benzamide (7m). White
21.6, 121.4, 119.7, 114.9, 111.6, 56.3; HRMS Calcd for solid. Mp: 138.8-140.1 °C; H NMR (400 MHz, CDCl
MHz, CDCl
3
1
1
C
3
) δ 9.19
(brs, 1H), 8.39 (d, J = 8.0 Hz, 1H), 8.17 (ddd, J = 5.0, 1.6, 0.8 Hz,
-Fluoro-N-(pyridin-2-yl)benzamide (7f). Yellow solid. Mp: 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.80-7.74 (m, 3H), 7.07 (ddd, J =
+
13 13 2 2
H N O (M + H ): 229.0972; Found: 229.0974.
4
1
13
1
36.5-139.7 °C; H NMR (400 MHz, CDCl
3 3
) δ 9.28 (brs, 1H), 8.39 7.2, 4.8, 0.8 Hz, 1H); C NMR (100 MHz, CDCl ) δ 164.8, 151.5,
(
d, J = 8.4 Hz, 1H), 8.14 (dd, J = 4.8, 0.8 Hz, 1H), 7.98-7.94 (m, 148.0, 138.8, 137.8, 137.7, 127.9, 126.0, 126.0, 125.9, 125.9,
+
2
2
H), 7.75 (td, J = 7.8, 2.0 Hz, 1H), 7.18-7.12 (m, 2H), 7.03 (ddd, 120.4, 114.6; HRMS Calcd for C13H10FN O (M + H ): 267.0740;
1
3
J = 7.2, 4.8, 0.8 Hz, 1H); C NMR (100 MHz, CDCl
3
) δ 166.5, Found: 267.0743.
65.1, 164.0, 151.8, 147.8, 138.7, 130.7, 130.6, 130.0, 129.9, 4-Nitro-N-(pyridin-2-yl)benzamide (7n). White solid. Mp:
20.1, 116.1, 115.8, 114.6; HRMS Calcd for C12 O (M + 163.3-165.1 °C; H NMR (400 MHz, DMSO-d
8.43 (dd, J = 8.0, 0.8 Hz, 1H), 8.35-8.32 (m, 2H), 8.29-8.19 (m,
1
1
1
H10FN
2
6
) δ 11.21 (brs, 1H),
+
H ): 217.0772; Found: 217.0775.
-Chloro-N-(pyridin-2-yl)benzamide (7g). White solid. Mp: 3H), 7.93-7.86 (m, 1H), 7.22 (dd, J = 7.2, 4.8 Hz, 1H); C NMR
1
3
4
1
38.5-139.7 °C; H NMR (400 MHz, CDCl
1
3 6
) δ 9.85 (brs, 1H), 8.45 (100 MHz, DMSO-d ) δ 164.6, 151.8, 149.0, 148.1, 140.9,
(
d, J = 8.4 Hz, 1H), 8.23 (d, J = 4.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 138.3, 129.6, 123.4, 120.3, 114.8; HRMS Calcd for C12H N O
10 3 3
+
H), 7.81 (td, J = 8.0, 2.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.05 (M + H ): 244.0717; Found: 244.0719.
2
1
3
(d, J = 7.6 Hz, 1H), 7.11 (dd, J = 7.2, 5.2 Hz, 1H); C NMR (100
3
MHz, CDCl ) δ 165.3, 151.8, 146.9, 139.4, 131.4, 129.3, 129.1, 165.1 °C; H NMR (400 MHz, CDCl ) δ 9.74 (brs, 1H), 8.46 (d, J =
N-(pyridin-2-yl)-1-naphthamide (7o). White solid. Mp: 163.5-
1
3
+
1
28.8, 120.1, 115.2; HRMS Calcd for C12
33.0476; Found: 233.0478.
H10ClN
2
O (M + H ): 8.4 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.88
(dd, J = 7.6, 1.6 Hz, 1H), 7.75 (dd, J = 7.2, 1.2 Hz, 1H), 7.70 (td, J
2
4
-Bromo-N-(pyridin-2-yl)benzamide (7h). White solid. Mp: = 7.8, 1.6 Hz, 1H), 7.60-7.51 (m, 3H), 7.45 (dd, J = 8.4, 7.2 Hz,
1
13
1
36.3-138.1 °C; H NMR (400 MHz, CDCl
3
) δ 9.06 (brs, 1H), 8.37 1H), 6.85 (ddd, J = 7.6, 5.2, 1.2 Hz, 1H); C NMR (100 MHz,
) δ 168.2, 151.9, 147.7, 138.6, 134.1, 133.8, 131.3, 130.2,
m, 3H), 7.63-7.60 (m, 2H), 7.06 (ddd, J = 7.6, 5.2, 0.8 Hz, 1H); 128.5, 127.5, 126.7, 125.6, 125.3, 124.8, 119.9, 114.5; HRMS
(
d, J = 8.4 Hz, 1H), 8.19 (ddd, J = 5.2, 2.0, 0.8 Hz, 1H), 7.82-7.74 CDCl
3
(
1
3
+
C NMR (100 MHz, CDCl
3
) δ 165.1, 151.6, 147.9, 138.7, 133.3, Calcd for C16
13 2
H N O (M + H ): 249.1022; Found: 249.1025.
1
32.1, 129.0, 127.2, 120.2, 114.5; HRMS Calcd for C12H10BrN O
2
N-(pyridin-2-yl)-2-naphthamide (7p). White solid. Mp: 158.5-
1
160.8 °C; H NMR (400 MHz, CDCl ) δ 9.23 (brs, 1H), 8.48-8.46
3
+
M + H ): 276.9973; Found: 276.9971.
(
3
-Bromo-N-(pyridin-2-yl)benzamide (7i). White solid. Mp: (m, 2H), 8.24 (d, J = 3.6 Hz, 1H), 8.01-7.99 (m, 1H), 7.94-7.88
1
1
3
57.3-159.1 °C; H NMR (400 MHz, CDCl ) δ 9.19 (brs, 1H), 8.39 (m, 3H), 7.77 (td, J = 7.8, 1.2 Hz, 1H), 7.61-7.53 (m, 2H), 7.05
1
3
(
d, J = 8.4 Hz, 1H), 8.24 (dd, J = 4.8, 0.8 Hz, 1H), 8.12 (t, J = 1.6 (dd, J = 6.4, 5.6 Hz, 1H); C NMR (100 MHz, CDCl
Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.81-7.76 (m, 1H), 7.71-7.68 151.9, 147.9, 138.7, 135.2, 132.7, 131.5, 129.2, 128.9, 128.2,
m, 1H), 7.39-7.34 (m, 1H), 7.09 (ddd, J = 7.2, 5.2, 0.4 Hz, 1H); 128.1, 127.9, 127.1, 123.8, 120.0, 114.5; HRMS Calcd for
3
) δ 166.0,
(
1
3
+
C NMR (100 MHz, CDCl
3
) δ 164.6, 151.5, 147.7, 138.9, 136.3,
C
16
H
13
N
2
O (M + H ): 249.1022; Found: 249.1025.
1
35.3, 130.8, 130.4, 126.0, 123.1, 120.3, 114.7; HRMS Calcd for
+
O (M + H ): 276.9971; Found: 276.9973.
N-(pyridin-2-yl)nicotinamide (7q). White solid. Mp: 142.6-
1
144.1 °C; H NMR (400 MHz, CDCl ) δ 9.54 (brs, 1H), 9.19 (dd, J
3
C
12
H10BrN
2
2
-Bromo-N-(pyridin-2-yl)benzamide (7j). White solid. Mp: = 2.4, 0.8 Hz, 1H), 8.78 (dd, J = 4.8, 1.6 Hz, 1H), 8.38 (d, J = 8.4
1
46.5-148.1 °C; H NMR (400 MHz, CDCl
1
3
) δ 10.14 (brs, 1H), Hz, 1H), 8.24 (dt, J = 8.0, 2.0 Hz, 1H), 8.19 (ddd, J = 4.8, 1.6, 0.4
8
.39 (d, J = 8.4 Hz, 1H), 7.72 (td, J = 8.0, 1.6 Hz, 1H), 7.60-7.55 Hz, 1H), 7.79-7.75 (m, 1H), 7.42 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H),
1
3
m, 3H), 7.37 (td, J = 7.2, 1.2 Hz, 1H), 7.31 (td, J = 8.0, 1.6 Hz, 7.42 (ddd, J = 7.2, 4.8, 0.8 Hz, 1H); C NMR (100 MHz, CDCl
(
3
) δ
1
H), 6.89 (ddd, J = 7.2, 5.2, 0.8 Hz, 1H); C NMR (100 MHz, 164.4, 152.9, 151.5, 148.6, 147.9, 138.7, 135.4, 130.3, 123.6,
3
1
+
CDCl
27.7, 120.0, 119.7, 114.8; HRMS Calcd for C12
H+): 276.9971; Found: 276.9970.
Methyl 4-(pyridin-2-ylcarbamoyl)benzoate (7k). White soild. °C; H NMR (400 MHz, CDCl
3
) δ 166.6, 151.7, 147.4, 138.7, 138.1, 133.6, 131.6, 129.3, 120.4, 114.7; HRMS Calcd for C13
O (M + Found: 200.0814.
N-(pyridin-2-yl)picolinamide (7r). White solid. Mp: 142.5-145.1
13 2 2
H N O (M + H ): 200.0818;
1
H10BrN
2
1
3
) δ 10.56 (brs, 1H), 8.64-8.63 (m,
) δ 8.81 (brs, 1H), 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.38-8.36 (m, 1H), 8.29 (d, J = 7.6
.40 (d, J = 8.4 Hz, 1H), 8.30 (d, J = 4.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.91 (td, J = 7.6, 1.6 Hz, 1H), 7.76 (td, J = 7.6, 1.6 Hz,
1
Mp: 137.3-139.1 °C; H NMR (400 MHz, CDCl
3
8
6
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA20961K
ARTICLE
1
H), 7.51-7.48 (m, 1H), 7.10-7.06 (m, 1H); C NMR (100 MHz, 138.8, 134.5, 132.2, 128.8, 127.3, 119.5, 111.1, 24.0; HRMS
3
1
+
O (M + H ): 213.1022; Found: 213.1026.
CDCl
3
) δ 162.7, 151.3, 149.4, 148.4, 148.3, 138.4, 137.7, 126.8, Calcd for C13
+
H
13
N
2
122.5, 120.0, 114.0; HRMS Calcd for C11
10 3
H N O (M + H ):
N-(5-methylpyridin-2-yl)benzamide (9a). White solid. Mp:
1
200.0818; Found: 200.0816.
3
122.5-124.3 °C; H NMR (400 MHz, CDCl ) δ 8.58 (brs, 1H), 8.29
N-(pyridin-2-yl)furan-2-carboxamide (7s). White solid. Mp: (d, J = 8.8 Hz, 1H), 8.11 (d, J = 0.8 Hz, 1H), 7.94-7.91 (m, 2H),
1
13
1
8
1
34.5-135.7 °C; H NMR (400 MHz, CDCl
.34-8.31 (m, 2H), 7.74 (td, J = 7.8, 2.0 Hz, 1H), 7.53 (dd, J = (100 MHz, CDCl
.6, 0.8 Hz, 1H), 7.29-7.27 (m, 1H), 7.07 (ddd, J = 7.2, 4.8, 0.8 129.3, 128.8, 127.4, 113.9, 17.9; HRMS Calcd for C13
3
) δ 8.90 (brs, 1H), 7.59-7.55 (m, 2H), 7.52-7.48 (m, 2H), 2.32 (s, 3H); C NMR
) δ 166.0, 149.6, 147.9, 139.1, 134.7, 132.1,
O (M
3
13 2
H N
1
3
+
Hz, 1H), 6.56 (dd, J = 3.6, 1.6 Hz, 1H); C NMR (100 MHz, + H ): 213.1022; Found: 213.1023.
CDCl ) δ 156.3, 151.1, 148.1, 147.4, 144.8, 138.5, 120.0, 116.0, N-(4-methylpyridin-2-yl)benzamide (10a). White solid. Mp:
14.3, 112.7; HRMS Calcd for C10
Found: 189.0656.
N-(pyridin-2-yl)thiophene-2-carboxamide (7t). White solid. Mp: 7.53 (m, 1H), 7.49-7.45 (m, 2H), 6.85 (d, J = 4.8 Hz, 1H), 2.39 (s,
3
+
1
1
H
9
N
2
O (M + H ): 189.0659; 117.5-119.3 °C; H NMR (400 MHz, CDCl
3
) δ 9.21 (brs, 1H), 8.27
(brs, 1H), 7.80 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.57-
1
13
1
51.5-153.1 °C; H NMR (400 MHz, CDCl
3 3
) δ 9.10 (brs, 1H), 8.35 3H); C NMR (100 MHz, CDCl ) δ 166.1, 151.8, 150.2, 147.4,
(
d, J = 8.4 Hz, 1H), 8.26 (d, J = 5.2 Hz, 1H), 7.78-7.73 (m, 2H), 134.6, 132.2, 128.8, 127.4, 121.1, 115.0, 21.5; HRMS Calcd for
+
7
.58 (dd, J = 4.8, 1.2 Hz, 1H), 7.13 (dd, J = 4.8, 4.0 Hz, 1H), 7.07
C
13
H
13
N
2
O (M + H ): 213.1022; Found: 213.1024.
N-(3-methylpyridin-2-yl)benzamide (11a). White oil. H NMR
60.3, 151.5, 147.7, 139.1, 138.8, 131.8, 129.1, 128.1, 120.0, (400 MHz, CDCl ) δ 9.59 (brs, 1H), 8.22 (d, J = 4.0 Hz, 1H), 8.01-
OS (M + H ): 205.0430; Found: 7.99 (m, 2H), 7.65 (d, J = 7.6 Hz, 1H), 7.56-7.52 (m, 1H), 7.48-
1
3
1
3
(ddd, J = 7.2, 5.2, 0.8 Hz, 1H); C NMR (100 MHz, CDCl ) δ
1
1
2
3
+
14.6; HRMS Calcd for C10
05.0433.
9 2
H N
1
3
7.44 (m, 2H), 7.16 (dd, J = 7.6, 5.0 Hz, 1H), 2.34 (s, 3H);
) δ 171.3, 166.2, 150.0, 144.9, 140.7,
3
) δ 8.95 (brs, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.19 132.2, 129.9, 128.7, 128.0, 121.9, 18.6; HRMS Calcd for
C
1
3
-Phenyl-N-(pyridin-2-yl)propanamide (7u). White oil. H NMR NMR (100 MHz, CDCl
400 MHz, CDCl
d, J = 4.8 Hz, 1H), 7.72-7.68 (m, 1H), 7.29-7.25 (m, 2H), 7.20-
.18 (m, 3H), 7.01 (ddd, J = 7.2, 4.8, 0.4 Hz, 1H), 3.04 (t, J = 7.8
3
(
(
+
C
13
H
13
N
2
O (M + H ): 213.1022; Found: 213.1025.
7
N-(5-chloropyridin-2-yl)benzamide (12a). White solid. Mp:
1
3
1
Hz, 2H), 2.69 (t, J = 7.8 Hz, 2H); C NMR (100 MHz, CDCl
3
3
) δ 144.1-146.5 °C; H NMR (400 MHz, CDCl ) δ 9.93 (brs, 1H), 8.50
1
1
2
71.1, 151.7, 147.6, 140.6, 138.6, 128.7, 128.4, 126.4, 119.8, (d, J = 8.8 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.06-8.03 (m, 2H),
+
14.5, 39.3, 31.3; HRMS Calcd for C14
27.1179; Found: 227.1181.
15 2
H N O (M + H ): 7.78 (dd, J = 8.8, 2.4 Hz, 1H), 7.61-7.57 (m, 1H), 7.54-7.48 (m,
1
3
3
2H); C NMR (100 MHz, CDCl ) δ 166.4, 150.4, 145.6, 139.0,
N-(pyridin-2-yl)heptanamide (7v). White solid. Mp: 68.5-70.1 133.7, 132.6, 130.2, 128.6, 127.9, 116.0; HRMS Calcd for
1
+
°
C; H NMR (400 MHz, CDCl
H), 7.73-7.69 (m, 1H), 7.04 (ddd, J = 7.2, 4.8, 0.8 Hz, 1H), 2.39
t, J = 7.2 Hz, 2H), 1.76-1.68 (m, 2H), 1.38-1.28 (m, 6H), 0.88 (t, 136.3-138.1 °C; H NMR (400 MHz, DMSO-d
3
) δ 8.79 (brs, 1H), 8.27-8.25 (m,
C
12
H10ClN
2
O (M + H ): 233.0476; Found: 233.0478.
2
N-(3-aminopyridin-2-yl)benzamide (13a). White solid. Mp:
1
(
6
) δ 13.49 (brs, 1H),
3
) δ 172.2, 151.8, 8.35 (brs, 1H), 8.25-8.34 (m, 2H), 8.01 (brs, 1H ), 7.59-7.51 (m,
1
3
J = 6.8 Hz, 3H); C NMR (100 MHz, CDCl
3
47.6, 138.7, 119.7, 114.4, 37.9, 31.6, 29.0, 25.5, 22.6, 14.1; 3H), 7.24 (dd, J = 8.0, 4.8 Hz, 1H); C NMR (100 MHz, DMSO-
1
1
+
O (M + H ): 207.1492; Found:
HRMS Calcd for C12
H
19
N
2
6
d ) δ 167.3, 143.8, 132.8, 130.5, 129.6, 129.2, 128.9, 128.5,
+
2
07.1494.
12 3
126.7, 118.1; HRMS Calcd for C12H N O (M + H ): 214.0975;
1
N-(pyridin-2-yl)isobutyramide (7w). White oil. H NMR (400 Found: 214.0977.
MHz, CDCl
3
) δ 9.17 (brs, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.24-8.22
N-heptyl-N-(pyridin-2-yl)benzamide (14a). The presence of two
(
m, 1H), 7.75-7.70 (m, 1H), 7.06-7.03 (m, 1H), 2.66-2.55 (m, rotamers (ratio 1:1) was observed in the NMR spectra. White
1
1
H), 1.25 (d, J = 7.2 Hz, 6H); C NMR (100 MHz, CDCl
3
1
3 3
) δ 176.3, oil. H NMR (400 MHz, CDCl ) δ 8.13-8.11 (m, 4H), 7.91 (d, J =
1
52.0, 147.1, 138.9, 119.6, 114.6, 36.5, 19.5; HRMS Calcd for 4.4 Hz, 1H), 7.84 (d, J = 4.4 Hz, 1H), 7.52-7.35 (m, 8H), 6.62 (dd,
+
O (M + H ): 165.1022; Found: 165.1024.
C
9
H
13
N
2
J = 15.2, 8.8 Hz, 2H), 6.54 (t, J = 6.4 Hz, 1H), 6.46 (t, J = 6.4 Hz,
N-(pyridin-2-yl)formamide (7x). The presence of two rotamers 1H), 6.85-6.77 (m, 2H), 3.41-3.31 (m, 2H), 1.68-1.22 (m, 20H),
1
13
(
ratio 1.2:1) was observed in the NMR spectra. Yellow solid. H 0.85-0.80 (m, 6H); C NMR (100 MHz, CDCl
NMR (300 MHz, CDCl ) δ 10.40 (brs, 1H), 10.21 (brs, 1H), 9.34 157.3, 142.9, 142.5, 140.3, 140.2, 134.3, 131.7, 129.8, 128.1,
d, J = 10.8 Hz, 1H), 8.32 (brs, 1H), 8.55 (s, 1H), 8.36-8.33 (m, 111.5, 111.1, 108.1, 107.8, 53.5, 43.0, 42.0, 32.2, 32.1, 31.9,
H), 8.28 (d, J = 8.4 Hz, 1H), 7.76 (td, J = 8.0, 1.8 Hz, 1H), 7.69 29.4, 28.9, 27.4, 26.5, 22.7, 22.6, 14.2, 14.1; HRMS Calcd for
3
) δ 165.2, 157.4,
3
(
1
+
(
td, J = 7.8, 1.8 Hz, 1H), 7.137-7.06 (m, 2H), 6.96 (d, J = 8.1 Hz,
C
19
H
25
N
2
O (M + H ): 297.1961; Found: 297.1963.
1
H); C NMR (75 MHz, CDCl
3
1
3
) δ 163.2, 159.7, 151.2, 151.1,
N-(pyrazin-2-yl)benzamide (15a). White solid. Mp: 161.3-163.1
1
) δ 9.75 (d, J = 1.2 Hz, 1H), 8.90
(brs, 1H), 8.38 (d, J = 2.4 Hz, 1H), 8.23-8.22 (m, 1H), 7.97-7.95
1
48.6, 147.5, 139.0, 138.8, 120.3, 119.9, 115.3, 110.6; HRMS °C; H NMR (400 MHz, CDCl
+
3
Calcd for C
6 7 2
H N O (M + H ): 123.0553; Found: 123.0556.
1
N-(6-methylpyridin-2-yl)benzamide (8a). White solid. Mp: (m, 2H), 7.63-7.59 (m, 1H), 7.54-7.50 (m, 2H); C NMR (100
3
1
26.5-127.7 °C; H NMR (400 MHz, CDCl
1
3 3
) δ 8.83 (brs, 1H), 8.20 MHz, CDCl ) δ 165.7, 148.4, 142.0, 140.4, 137.4, 133.4, 132.7,
+
d, J = 8.0 Hz, 1H), 7.93-7.90 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 129.0, 127.5; HRMS Calcd for C11H N O (M + H ): 200.0818;
(
10 3
7
.56-7.52 (m, 1H), 7.48-7.44 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), Found: 200.0819.
1
.40 (s, 3H); C NMR (100 MHz, CDCl
3
2
3
) δ 165.8, 157.0, 151.0,
N-(pyrimidin-2-yl)benzamide (16a). White solid. Mp: 157.3-
1
1
6
59.1 °C; H NMR (400 MHz, DMSO-d ) δ 10.99 (brs, 1H), 8.74
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ARTICLE
Journal Name
(
d, J = 4.8 Hz, 2H), 7.98 (d, J = 7.2 Hz, 2H), 7.63-7.59 (m, 1H),
6
7
8
H. Lundberg, F. Tinnis, N. Selander and H. Adolfsson, Chem.
Soc. Rev., 2014, 42, 2714-2742.
1
.54-7.50 (m, 2H), 7.26 (t, J = 4.8 Hz, 1H); C NMR (100 MHz,
3
7
S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54
451-3479.
,
DMSO-d
6
) δ 165.5, 163.6, 158.3, 134.2, 132.0, 128.3, 128.2,
3
+
1
17.3; HRMS Calcd for C11
00.0816.
N-(pyrimidin-4-yl)benzamide (17a). White solid. Mp: 157.3-
10 3
H N O (M + H ): 200.0818; Found:
L. Ferrins, M. Gazdik, R. Rahmani, S. Varghese, M. L. Sykes, A.
J. Jones, V. M. Avery, K. L. White, E. Ryan, S. A. Charman, M.
Kaiser, C. A. S. Bergström and J. B. Baell, J. Med. Chem., 2014,
57, 6393–6402.
H. E. Colley, M. Muthana, S. J. Danson, L. V. Jackson, M. L.
Brett, J. Harrison, S. F. Coole, D. P. Mason, L. R. Jennings, M.
Wong, V. Tulasi, D. Norman, P. M. Lockey, L. Williams, A. G.
Dossetter, E. J. Griffen and M. J. Thompson, J. Med. Chem.,
2
1
1
8
7
59.1 °C; H NMR (400 MHz, DMSO-d
6
) δ 10.59 (brs, 1H), 8.49-
9
.48 (m, 2H), 7.98 (d, J = 7.2 Hz, 2H), 7.80 (d, J = 5.2 Hz, 1H ),
1
3
.65-7.63 (m, 1H), 7.58-7.54 (m, 2H); C NMR (100 MHz,
) δ 166.5, 150.3, 145.9, 134.2, 132.1, 128.5, 127.8,
DMSO-d
6
+
2015, 58, 9309
0 C. Gao, B. J. Margolis, J. M. Strelow, L. R. Vidler and M. M.
Mader, ACS Med. Chem. Lett., 2016,
, 156−161.
−9333.
1
14.0; HRMS Calcd for C11
00.0816.
N-(benzo[d]thiazol-2-yl)benzamide (18a). White solid. Mp:
10 3
H N O (M + H ): 200.0818; Found:
1
1
2
7
1 S. C. Zimmermann, E. F. Wolf, A. Luu, A. G. Thomas, M.
Stathis, B. Poore, C. Nguyen, A. Le, C. Rojas, B. S. Slusher and
T. Tsukamoto, ACS Med. Chem. Lett., 2016, 7
, 520−524.
1
1
8
7
43.3-145.1 °C; H NMR (400 MHz, DMSO-d
6
) δ 12.32 (brs, 1H),
.06 (d, J = 7.6 Hz, 2H), 7.85-7.83 (m, 1H), 7.57-7.53 (m, 1H ),
1
3
.43-7.39 (m, 2H), 7.31-7.23 (m, 3H); C NMR (100 MHz, 12 S. Robert-Piessard, G. L. Baut, J. Courant, J. Brion, L. Sparfel,
S. Bouhayat, J. Petit, R. Sanchez, M. Juge, N. Grimaud and L.
6
DMSO-d ) δ 166.3, 160.4, 147.5, 133.2, 132.1, 131.7, 129.1,
Welin, Eur. J. Med. Chem., 1990, 25, 9-19.
3 J. M. Muñoz, J. Alcázar, A. Hoz, Á. Díaz-Ortiz and S. A. Diego,
Green Chem., 2012, 14, 1335–1341.
1
11 2
28.2, 126.3, 124.2, 121.5, 120.5; HRMS Calcd for C14H N OS
1
+
M + H ): 255.0587; Found: 255.0589.
(
N-(pyridin-3-yl)benzamide (19a). Yellow solid. Mp: 102.5- 14 R. M. Lanigan, P. Starkov and T. D. Sheppard, J. Org. Chem.,
1
1
1
7
1
1
C
05.3 °C; H NMR (400 MHz, CDCl
3
) δ 9.25 (brs, 1H), 8.68 (d, J =
2013, 78, 4512–4523.
5 L. Becerra-Figueroa, A. Ojeda-Porras and D. Gamba-Sánchez,
J. Org. Chem., 2014, 79, 4544−4552.
6 V. Karaluka, R. M. Lanigan, P. M. Murray, M. Badland and T.
D. Sheppard, Org. Biomol. Chem., 2015, 13, 10888–10894.
1
1
.6 Hz, 1H), 8.24 (d, J = 5.6 Hz, 2H), 7.87 (d, J = 7.2 Hz, 2H),
.52-7.48 (m, 1H), 7.41-7.39 (m, 2H), 7.23 (dd, J = 8.0, 5.2 Hz,
1
3
3
H); C NMR (100 MHz, CDCl ) δ 166.9, 145.1, 141.8, 135.4,
34.2, 132.2, 128.7, 128.2, 127.4, 123.8; HRMS Calcd for 17 M. Kumar, S. Bagchi and A. Sharma, New J. Chem., 2015, 39
,
+
O (M + H ): 199.0866; Found: 199.0868.
H
11
N
2
8329–8336.
8 S. Rasheed, D. N. Rao, A. S. Reddy, R. Shankar and P. Das, RSC
Adv., 2015, , 10567–10574.
9 J. L. Vrijdag, F. Delgado, N. Alonso, W. M. D. Borggraeve, N.
12
1
1
N-(quinolin-8-yl)benzamide (21a). White soild. Mp: 161.3-
1
5
1
63.1 °C; H NMR (400 MHz, CDCl
J = 7.6, 1.2 Hz, 1H), 8.83 (dd, J = 4.4, 1.6 Hz, 1H), 8.16 (dd, J =
.0, 1.6 Hz, 1H), 8.11-8.07 (m, 2H), 7.60-7.51 (m, 5H), 7.47-7.44
3
) δ 10.74 (brs, 1H), 8.95 (dd,
Pe´rez-Macias and J. Alca´zar, Chem. Commun., 2014, 50
15094-15097.
,
8
1
3
(
m, 1H); C NMR (100 MHz, CDCl
3
) δ 165.6, 148.4, 138.8, 20 Z. Yao and X. Wei, Chin. J. Chem., 2010, 28, 2260–2268.
2
2
2
1 S. M. Crawford, C. B. Lavery and M.Stradiotto, Chem. Eur. J.,
2013, 19, 16760–16771.
2 L. Nicolas, P.Angibaud, I. Stansfield, L. Meerpoel, S. Reymond
1
36.5, 135.2, 134.6, 132.0, 128.9, 128.1, 127.5, 127.4, 121.8,
+
13 2
121.7, 116.7; HRMS Calcd for C16H N O (M + H ): 249.1022;
Found: 249.1024
and J. Cossy, RSC Adv., 2013,
3 F. Karimi and B. Långström, Org. Biomol. Chem., 2003,
41-546.
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1
,
5
Acknowledgements
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Bhanage, Catalysis Today, 2012, 198, 148–153.
Financial Support from the National Natural Science
Foundation of China (Grant No. 21302013), Suzhou Science
and Technology Project (Grant No. SNG201620) and Natural
Science Foundation of Jiangsu Province (Grant No.
BK20161267 and BK20160405) are acknowledged.
2
5 C. Henry, D. Bolien, B. Ibanescu, S. Bloodworth, D. C.
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, 6212−6215.
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DOI: 10.1039/C6RA20961K
ARTICLE
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RSC Advances
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DOI: 10.1039/C6RA20961K
Graphical abstract
Microwave-assisted heteropolyanion-based ionic liquids promoted sustainable protocol to
N-heteroaryl amides via N-directing dual catalyzed oxidative amidation of aldehydes
Renzhong Fu, Yang Yang,* Weihua Jin, Hui Gu, Xiaojun Zeng, Wen Chai, Yunsheng Ma, Quan Wang, Jun
Yi* and Rongxin Yuan
A sustainable procedure for the synthesis of N-heteroaryl amides directly from oxidative amidation of aldehydes
catalyzed by heteropolyanion-based ionic liquids under microwave-promoted conditions has been reported. The
proposed N-directing dual-catalysis mechanistic pathway was briefly investigated.