Direct Transformation of Alkylarenes into N-(Pyridine-2-yl)amides by C(sp3)–C(sp3) Bond Cleavage

Article abstract of DOI:10.1002/ejoc.202001137

C(sp³)–H bond functionalization and C(sp³)–C(sp³) bond cleavage are very challenging transformations in chemistry. Herein, we report a mild and green methodology for the construction of N-(pyridine-2-yl)amides via tandem C(sp³)–H activation/C–C bond cleavage of alkylarenes. Various N-heterocyclic amides were directly synthesized from alkylarenes in water in moderate to good yields.

Full text of DOI:10.1002/ejoc.202001137

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Direct transformation of alkylarenes into N-(pyridine-2-yl)amides
via C(sp3)-C(sp3) bond cleavage
Authors: Haipin Zhou, Yanpeng Liu, Haidong Xia, Jinyi Xu, Tingfang
Wang, and Shengtao Xu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001137
Link to VoR: https://doi.org/10.1002/ejoc.202001137
01/2020

10.1002/ejoc.202001137
European Journal of Organic Chemistry
FULL PAPER
Direct transformation of alkylarenes into N-(pyridine-2-yl)amides
via C(sp3)-C(sp3) bond cleavage
Haipin Zhou,[a] Yanpeng Liu,[b] Haidong Xia,[b] Jinyi Xu,[b] Tingfang Wang*[c] and Shengtao Xu*[a,b]
Abstract: C(sp3)-H bond functionalization and C(sp3)-C(sp3) bond
cleavage are very challenging transformations in chemistry. Herein,
we report a mild and green methodology for the construction of N-
(pyridine-2-yl)amides via tandem C(sp3)-H activation/C-C bond
cleavage of alkylarenes. Various N-heterocyclic amides were directly
synthesized from alkylarenes in water in moderate to good yields.
Since Ishihara reported the synthesis of carboxamides by
LDA-catalyzed Haller-Bauer and Cannizzaro reactions,[7]
the construction of primary[8] or N-heterocyclic[9] amides via
direct C(O)-Me(or Alkyl) bond cleavage (Scheme 1, d) has
achieved considerable progress. Recently, we reported the
construction of N-(pyridine-2-yl)amides from ketones via
selective oxidative cleavage of C(O)-C(alkyl) bond.[10] Not
long ago, Shimokawa reported the direct transformation of
ethylarenes into primary aromatic amides with N-
[11]
Introduction
bromosuccinimide and I2/aqueous NH3
(Scheme 1, e),
and the corresponding primary aromatic amides were
synthesized in good yields via a one pot two steps reaction.
Amide bonds not only play a crucial role in proteins but are
also ubiquitous in pharmacologically active compounds and
materials (such as nylon, hydrogels, and artificial silks).
Indeed, amide bonds are found in 2/3rds of the drug
candidates reported in a 2006 survey.[1] The widespread
occurrence of amides in organic compounds makes the
construction of amide bonds one of the most important
topics in organic chemistry. Conventionally, amide bonds
are formed by the reaction of carboxylic acid surrogates
and amines or carboxylic acids and amine surrogates.
These existing methods are remarkably general but have
also reached their inherent limits, and concerns about their
waste generation and great expense are attracting
increasing attention. Therefore, researchers are eager to
find new methodologies for the construction of amides from
other substrates that were previously considered to be
impossible.[2]
In recent years, non-classical approaches to amide bond
construction have been developed. Aldehydes[3] and
alcohols[4] have been proven to be efficient substrates for
the construction of amides in the last twenty years (Scheme
1, a). Amidation by direct C-C bond cleavage is another
strategy under development and has attracted considerable
attention. C=C and C≡C bonds are relatively active, and the
synthesis of amides by C=C[5] or C≡C[6] bond cleavage has
been reported (Scheme 1, b or c). C-C single bond is
usually considered to be very stable, but its wide existence
in organic compounds makes the synthesis of amides via
C-C single bond cleavage attractive to organic chemists.
Scheme 1. Non-classical approaches to the construction of amides.
C(sp3)-H and C(sp3)-C(sp3) bonds are two of the most
common bonds in organics because of their inertness. Although
chemists have devoted considerable effort to selective C(sp3)-H
bond activation/functionalization[12] and C(sp3)-C(sp3) bond
cleavage,[13] the research is still fundamental and remains full of
challenges, thus, new methodologies are still urgently needed.
Here, we report the direct transformation of alkylarenes to N-
(pyridine-2-yl)amides
via
tandem
C(sp3)-H
bond
activation/oxidative cyclization/C-C bond cleavage (Scheme 1, f),
where the N-(pyridine-2-yl)amides are formed via catalysis by
TBAI in one step in water.
[a]
[b]
[c]
Dr. H. Zhou, Prof. Dr. S. Xu,
College of Materials & Chemical Engineering, Chuzhou University
1 West Huifeng Road, Chouzhou, 239000, Anhui, China.
E-mail: cpuxst@cpu.edu.cn
Y. Liu, Dr. H. Xia, Prof. Dr. J Xu
Results and Discussion
State Key Laboratory of Natural Medicines and Department of
Medicinal Chemistry, China Pharmaceutical University
24 Tong Jia Xiang, Nanjing 210009, China.
Prof. Dr. T. Wang
School of Medicine, Shanghai University, 99 Shangda Road,
Shanghai, 200444, China.
wangtf66@shu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
Originally, ethylbenzene (1a) and 2-aminopyridine (2a) were
treated in a reaction system containing a catalytic amount of I2
and excess TBHP in toluene at 80 °C, and to our delight, N-
(pyridin-2-yl)benzamide (3) was obtained in 22% yield (Table 1,
entry 1). Subsequent screening of solvents showed that H2O
1
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10.1002/ejoc.202001137
European Journal of Organic Chemistry
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was a substantially better solvent, giving a yield of 34% (Table 1,
entry 6). Then, the yield increased slightly to 38% when TBAI
was used as the catalyst (Table 1, entry 10). After that, we
screened peroxides, and the results showed that DTBP, K2S2O8
and O2 (balloon) were not effective oxidants (Table 1, entries 11-
13). These results indicated that TBHP was crucial for this
reaction. Since we had not yet achieved a synthetically useful
yield, acid additives were introduced into the reaction system to
improve the yield. To our delight, an enhancement was
observed when 0.2 equivalents of a protic acid were used (Table
1, entries 14-16), but the addition of more acid did not further
increase the yield (Table 1, entry 18). Finally, with the increase
of temperature from 80 to 100 °C, N-(pyridine-2-yl)benzamide
(3) was isolated in a moderate yield of 61% (Table 1, entry 20).
could be transformed into the corresponding amides in moderate
yields. The six-membered heterocycle 2-ethylpyridine gave the
amide product in low yield (20), and 4-ethylbiphenyl also
exhibited acceptable yield (21). Finally, substituted 2-
aminopyridines were examined, and all substrates were suitable
for the reaction except 6-substituted 2-aminopyridine, which had
a low yield of 3% (22-26).
Table 1. Optimization of the reaction conditions.[a]
Catalyst Oxidant Additives Temp Yield[b]
Entry Solvent
(20 mol%) (8 equiv) (20 mol%) (°C) (%)
1
2
3
4
5
6
7
8
Toluene I2
DMSO I2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
K2S2O8
O2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
-
-
-
-
-
-
-
-
-
-
-
-
-
80
80
80
80
80
80
80
80
80
80
80
80
80
22
17
5
17
25
34
32
3
34
38
trace
-
DMF
DCE
I2
I2
CH3CN I2
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
I2
KI
CuI
NIS
9
10
11
12
13[c]
14
15
16
17
18[d]
19
20
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
-
CH3COOH 80
CF3COOH 80
43
42
56
13
56
49
TfOH
FeCl3
TfOH
TfOH
TfOH
80
80
80
60
100 61
[a] Reaction conditions: 1a (0.6 mmol), 2a (1.2 mmol), catalyst (0.12 mmol),
additive (0.12 mmol), oxidant (4.8 mmol), solvent (2 mL), 6 h.
[b] Isolated yields.
[c] O2 (1 atm; balloon)
[d] 1.2 equivalent of TfOH was used.
With the optimized reaction conditions in hand, the scope of
suitable alkylarenes was explored (Scheme 2). First,
alkylbenzenes with substituents in the para position were
examined to determine whether electron-donating substituents
(4, 6) or electron-withdrawing substituents (5, 7-9) could be
applied to this reaction. Then, different long chains-substituted
alkylbenzenes were treated under the standard conditions.
Unexpectedly, the corresponding amide products were also
obtained by selective C(sp3)-C(sp3) bond cleavage (3, 5, 6). In
addition, meta- or ortho-substituted derivatives were also
explored, and the results showed that the yield decreased
slightly for the meta-substituted derivatives (10-12), whereas the
yields of the ortho-substituent derivatives decreased
dramatically to 34%-49% (13-15). Additionally, polycyclic
alkylarenes (16, 17) and five-membered heterocycles (18, 19)
Scheme 2. Amidation of alkylbenzenes by C(sp3)-C(sp3) bond cleavage.
[a] (Unless otherwise stated, R1 = -CH3)
[b] Isolated yields.
To elucidate the mechanism of this reaction, several control
experiments were conducted. TEMPO, a well-known radical
trapping reagent, was added into the standard reaction system,
which caused a decline of the yield of N-(pyridin-2-yl)benzamide
(3) to 14%, and a new product 27, whose structure was
confirmed later, was detected in a yield of 3% (Scheme 3, entry
1). Using 27 as the starting material, product 3 was obtained
smoothly under the standard conditions (Scheme 3, entry 2),
indicating that the reaction might proceed through a radical
2
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10.1002/ejoc.202001137
European Journal of Organic Chemistry
FULL PAPER
process and that 27 might be a key intermediate. Next, amide 3
was synthesized in a yield of 76% from acetophenone under the
standard conditions (Scheme 3, entry 3), and -
iodoacetophenone could also be successfully transformed into 3
under oxidation by TBHP (Scheme 3, entry 4). Finally, no 3 or
imine 28 could detected when replacing TBAI with TBAB
(Scheme 3, entry 5).
Scheme 4. Proposed mechanism.
Experimental Section
General Information. All chemicals were of chemical pure
grade quality and used without further purification, all organic
solvents were analytical pure grade quality, water was ordinary
domestic water and used without further purification, tert-butyl
hydroperoxide (TBHP) was 70% aqueous solution purchased
from Sinopharm Chemical Reagent Co.,Ltd. Reactions were
monitored by TLC (Merck silica gel 60 F254), column
chromatography was performed on silica gel 200~300 mesh. All
1H NMR (300 MHz), 13C{1H} NMR (75 MHz) spectra were
recorded on a Bruker Avance 300 spectrometer in CDCl3 with
tetramethylsilane as an internal standard and reported in parts
per million (ppm, δ). High-resolution mass spectrums (HRMS)
were measured on Finnigan MAT 95 spectrometer (Finnigan,
Germany).
Scheme 3. Control experiments.
Based on the above investigation, a plausible mechanism was
proposed (Scheme 4). First, (1-iodoethyl)benzene is formed
from ethylbenzene and subsequently transformed into 1-
phenylethanol.
1-Phenylethanol
is
then
oxidized
to
acetophenone by TBHP, and subsequent reaction of
acetophenone with iodine forms α-iodoacetophenone, which
reacts with A to produce the imine B.[14] B is subsequently
transferred to the key intermediate, 27.[15] The addition of two
hydroxyl radicals to the double bond of 27 affords diol C. Then, a
four-membered peroxide ring D is formed by the abstraction of
hydrogens from the diol by two iodine radicals. The strained
four-membered ring is unstable, and the C-C bond is cleaved to
form aldehyde E.[16] Finally, tert-butyl formate is released from E,
leading to the formation of amide F,[17] which undergoes
isomerization to afford the desired amide 3.
General Procedure for the Synthesis of N-heterocyclic
Amides from Alkylbenzene. To a solution of alkylbenzene (0.6
mmol), 2-aminopyridine (1.2 mmol) and tetrabutylazanium iodide
(TBAI) (0.12 mmol) in water in sealed tube, was added triflic acid
(TfOH) (0.12 mmol) and tert-butyl hydroperoxide (TBHP) (4.8
mmol). The solution was heated at 100 oC for 5-6 h and
monitored by thin layer chromatography. The reaction mixture
was cooled to room temperature and added saturated sodium
thiosulfate, then the inorganic layer was extracted and separated
with dichloromethane for 3 times. The combined organic layer
was dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The residue was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate as
the eluent, typically 100:5-100:10).
Conclusion
In summary, we have developed a mild and green methodology
for the construction of N-(pyridine-2-yl)amides from alkylarenes
and 2-aminopyridine in one step. Various alkylarenes were
directly transformed into the corresponding N-(pyridine-2-
yl)amides via tandem C(sp3)-H bond activation/oxidative
cyclization/C-C bond cleavage. Mechanistic investigations
showed that cyclization was a key step of C-C bond cleavage.
Direct amidation via C(sp3)-C(sp3) bond cleavage has been
rarely reported, and this is the first work to report the synthesis
of N-heterocyclic amides via C(sp3)-C(sp3) bond cleavage of
alkylarenes.
N-(Pyridin-2-yl)benzamide (3). White solid; 73 mg, 61% yield;
m.p. 84-87 oC; 1H NMR (300 MHz, Chloroform-d): δ 8.93 (s, 1H),
8.40 (d, J = 8.4 Hz, 1H), 8.20 (d, J = 3.2 Hz, 1H), 7.93 (d, J = 6.9
Hz, 2H), 7.78-7.72 (m, 1H), 7.59-7.54 (m, 1H), 7.51-7.49 (m, 2H),
7.06-7.02 (m, 1H); 13C{1H} NMR (75 MHz, Chloroform-d): δ
166.4, 151.9, 147.5, 138.3, 134.5, 131.9, 128.5, 127.4, 119.6,
114.5; HRMS (ESI-TOF) m/z: calcd for C12H11N2O [M+H]+
199.0866, found 199.0864.
3
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10.1002/ejoc.202001137
European Journal of Organic Chemistry
FULL PAPER
4-Methyl-N-(pyridin-2-yl)benzamide (4). Yellow solid; 90 mg,
130.8, 130.4, 125.9, 123.1, 120.3, 114.6; HRMS (ESI-TOF) m/z:
calcd for C12H10BrN2O [M+H]+ 276.9971, found 276.9966.
3-Methoxy-N-(pyridin-2-yl)benzamide (12). White semisolid;
73 mg, 53% yield; H NMR (300 MHz, Chloroform-d): δ 9.53 (s,
1H), 8.42-8.39 (m, 1H), 8.07-8.04 (m, 1H), 7.74-7.69 (m, 1H),
o
1
71% yield; m.p. 107-108 C; H NMR (300 MHz, Chloroform-d):
δ 8.79 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8.16-8.14 (m, 1H), 7.75
(d, J = 8.2 Hz, 2H), 7.70-7.64 (m, 1H), 7.21 (d, J = 7.9 Hz, 2H),
6.99-6.94 (m, 1H), 2.35 (s, 3H); 13C{1H} NMR (75 MHz,
1
Chloroform-d): δ 165.9, 151.8, 148.0, 143.0, 138.6, 131.5, 129.6, 7.48-7.44 (m, 2H), 7.35-7.29 (m, 1H), 7.08-7.04 (m, 1H), 7.01-
127.4, 119.90, 114.3, 21.6; HRMS (ESI-TOF) m/z: calcd for
C13H13N2O [M+H]+ 213.1022, found 213.1024.
6.96 (m, 1H), 3.80 (s, 3H); 13C{1H} NMR (75 MHz, Chloroform-d):
δ 166.1, 159.9, 151.9, 147.8, 138.5, 135.9, 129.7, 119.8, 119.3,
118.5, 114.5, 112.5, 55.4; HRMS (ESI-TOF) m/z: calcd for
C13H12N2O2 [M+H]+ 251.0792, found 251.0794.
4-Bromo-N-(pyridin-2-yl)benzamide (5). White solid; 105 mg,
o
1
63% yield; m.p. 132-134 C; H NMR (300 MHz, Chloroform-d):
δ 8.71 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.27-8.25 (m, 1H), 7.81-
7.74 (m, 3H), 7.66-7.62 (m, 2H), 7.10-7.06 (m, 1H); 13C{1H} NMR
(75 MHz, Chloroform-d): δ 164.9, 151.5, 148.1, 138.7, 133.3,
132.3, 128.9, 127.3, 120.3, 114.4; HRMS (ESI-TOF) m/z: calcd
for C12H10BrN2O [M+H]+ 276.9971, found 276.9974.
2-Methyl-N-(pyridin-2-yl)benzamide (13). White solid; 51 mg,
o
1
40% yield; m.p. 112-113 C; H NMR (300 MHz, Chloroform-d):
δ 9.54 (s, 1H), 8.39 (d, J = 8.2 Hz, 1H), 7.73 (t, J = 7.5 Hz, 1H),
7.64-7.62 (m, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.39-7.34 (m, 1H),
7.26-7.20 (m, 2H), 6.93-6.89 (m, 1H), 2.50 (s, 3H); 13C{1H} NMR
(75 MHz, Chloroform-d): δ 168.8, 151.9, 147.7, 138.6, 136.5,
136.3, 131.4, 130.6, 127.1, 126.1, 119.9, 114.4, 19.9; HRMS
(ESI-TOF) m/z: calcd for C13H13N2O [M+H]+ 213.1022, found
213.1025.
4-Methoxy-N-(pyridin-2-yl)benzamide (6). Yellow solid; 85 mg,
o
1
62% yield; m.p. 88-90 C; H NMR (300 MHz, Chloroform-d): δ
8.94 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.19 (d, J = 4.0 Hz, 1H),
7.89 (d, J = 8.7 Hz, 2H), 7.75-7.69 (m, 1H), 7.03-6.99 (m, 1H),
6.97-6.92 (m, 2H), 3.85 (s, 3H); 13C{1H} NMR (75 MHz,
2-Bromo-N-(pyridin-2-yl)benzamide (14). White solid; 56 mg,
o
1
Chloroform-d): δ 165.5, 162.9, 152.0, 147.9, 138.5, 129.3, 126.6, 34% yield; m.p. 160-162 C; H NMR (300 MHz, Chloroform-d):
119.8, 114.3, 114.1, 55.6; HRMS (ESI-TOF) m/z: calcd for
C13H13N2O2 [M+H]+ 229.0972, found 229.0969.
δ 9.32 (s, 1H), 8.39 (d, J = 8.4 Hz, 1H), 7.94-7.91(m, 1H), 7.75
(td, J = 8.8, 8.4, 1.9 Hz, 1H), 7.64-7.60 (m, 2H), 7.40 (td, J = 7.5,
1.4 Hz, 1H), 7.33 (td, J = 7.7, 1.9 Hz, 1H), 7.02-6.97 (m, 1H);
13C{1H} NMR (75 MHz, Chloroform-d): δ 166.2, 151.4, 147.8,
138.7, 137.8, 133.7, 131.9, 129.6, 127.8, 120.3, 119.6, 114.6;
HRMS (ESI-TOF) m/z: calcd for C12H10BrN2O [M+H]+ 276.9971,
found 276.9972.
4-Cyano-N-(pyridin-2-yl)benzamide (7). White solid; 108 mg,
o
1
81% yield; m.p. 198-200 C; H NMR (300 MHz, Chloroform-d):
δ 9.20 (s, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.18-8.16 (m, 1H), 8.03
(d, J = 8.1 Hz, 2H), 7.81-7.77 (m, 3H), 7.26-7.07 (m, 1H); 13C{1H}
NMR (75 MHz, Chloroform-d): δ 164.2, 151.3, 148.0, 138.9,
138.3, 132.7, 128.1, 120.6, 118.0, 115.9, 114.7; HRMS (ESI-
TOF) m/z: calcd for C13H10N3O [M+H]+ 224.0818, found
224.0815.
2-Methoxy-N-(pyridin-2-yl)benzamide (15). White solid; 67 mg,
o
1
49% yield; m.p. 56-60 C; H NMR (300 MHz, Chloroform-d): δ
10.37 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.29-8.23 (m, 2H), 7.69 (t,
J = 7.6 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H),
7.02-6.95 (m, 2H), 3.99 (s, 3H); 13C{1H} NMR (75 MHz,
Chloroform-d): δ 163.7, 157.7, 152.1, 148.1, 138.4, 133.8, 132.6,
Methyl 4-(pyridin-2-ylcarbamoyl)benzoate (8). White solid; 95
mg, 62% yield; m.p. 200-202 oC; 1H NMR (300 MHz,
Chloroform-d): δ 8.68 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.31-8.28
(m, 1H), 8.17 (d, J = 8.1 Hz, 2H), 7.99 (d, J = 8.1 Hz, 2H), 7.78 (t, 121.6, 121.5, 119.8, 114.9, 111.7, 56.4; HRMS (ESI-TOF) m/z:
J = 8.0 Hz, 1H), 7.10 (m, 1H), 3.96 (s, 3H); 13C{1H} NMR (75
MHz, Chloroform-d): δ 166.3, 165.0, 151.4, 148.1, 138.7, 138.2,
133.5, 130.2, 127.4, 120.4, 114.4, 52.6; HRMS (ESI-TOF) m/z:
calcd for C14H13N2O3 [M+H]+ 257.0921, found 257.0924.
calcd for C13H13N2O2 [M+H]+ 229.0972, found 229.0970.
N-(Pyridin-2-yl)-1-naphthamide (16). White solid; 75 mg, 50%
yield; m.p. 143-146 oC; 1H NMR (300 MHz, Chloroform-d): δ
9.33 (s, 1H), 8.48 (d, J = 8.4 Hz, 1H), 8.42-8.38 (m, 1H), 7.98 (d,
J = 8.3 Hz, 1H), 7.92-7.89 (m, 1H), 7.84-7.82 (m, 1H), 7.79-7.72
(m, 2H), 7.61-7.52 (m, 2H), 7.51-7.46 (m, 1H), 6.97-6.92 (m, 1H);
13C{1H} NMR (75 MHz, Chloroform-d): δ 168.2, 151.9, 147.8,
138.6, 134.0, 133.9, 131.4, 130.2, 128.6, 127.54, 126.7, 125.6,
125.3, 124.8, 119.9, 114.4; HRMS (ESI-TOF) m/z: calcd for
C16H13N2O [M+H]+ 249.1022, found 249.1018.
4-Nitro-N-(pyridin-2-yl)benzamide (9). White solid; 101 mg,
o
1
69% yield; m.p. 235-236 C; H NMR (300 MHz, DMSO-d6): δ
11.20 (s, 1H), 8.42-8.32 (m, 3H), 8.23-8.18 (m, 3H), 7.90-7.85
(m, 1H), 7.22-7.19 (m, 1H); 13C{1H} NMR (75 MHz, DMSO-d6): δ
164.6, 151.9, 149.3, 148.1, 139.9, 138.3, 129.6, 123.4, 120.3,
114.9; HRMS (ESI-TOF) m/z: calcd for C12H10N3O3 [M+H]+
244.0717, found 244.0718.
9,10-Dioxo-N-(pyridin-2-yl)-9,10-dihydroanthracene-2-
carboxamide (17). Yellow solid; 120 mg, 61% yield; m.p. 211-
3-Methyl-N-(pyridin-2-yl)benzamide (10). White solid; 65 mg,
o
1
o
1
51% yield; m.p. 77-81 C; H NMR (300 MHz, Chloroform-d): δ
9.02 (s, 1H), 8.41 (d, J = 8.3 Hz, 1H), 8.20-8.18 (m, 1H), 7.78-
7.74 (m, 3H), 7.37 (s, 2H), 7.06-7.02 (m, 1H), 2.40 (s, 3H);
13C{1H} NMR (75 MHz, Chloroform-d): δ 166.2, 151.8, 147.9,
138.8, 138.6, 134.4, 133.1, 128.8, 128.1, 124.4, 119.9, 114.3,
21.5; HRMS (ESI-TOF) m/z: calcd for C13H13N2O [M+H]+
213.1022, found 213.1021.
213 C; H NMR (300 MHz, Chloroform-d): δ 8.91 (s, 1H), 8.79
(s, 1H), 8.46-8.32 (m, 6H), 7.87-7.77 (m, 3H), 7.15-7.11 (m, 1H);
13C{1H} NMR (75 MHz, Chloroform-d): δ 182.5, 182.4, 164.0,
151.2, 148.2, 139.3, 138.8, 135.7, 134.7, 133.8, 133.5, 133.2,
128.3, 127.7, 127.6, 125.6, 120.7, 114.5; HRMS (ESI-TOF) m/z:
calcd for C20H13N2O3 [M+H]+ 329.0921, found 329.0924.
N-(Pyridin-2-yl)thiophene-2-carboxamide (18). White soild; 66
mg, 54% yield; m.p. 117-120 oC; 1H NMR (300 MHz,
Chloroform-d): δ 8.97 (s, 1H), 8.32 (dt, J = 8.4, 1.1 Hz, 1H),
8.24-8.22 (m, 1H), 7.75-7.70 (m, 1H), 7.69-7.67 (m, 1H), 7.57-
3-Bromo-N-(pyridin-2-yl)benzamide (11). White solid; 95 mg,
o
1
57% yield; m.p. 110-112 C; H NMR (300 MHz, Chloroform-d):
δ 9.16 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.08-8.06 (m, 1H), 8.01-
7.99 (m, 1H), 7.77-7.73 (m, 1H), 7.71-7.64 (m, 1H), 7.61-7.57 (m, 7.55 (m, 1H), 7.11-7.08 (m, 1H), 7.06-7.02 (m, 1H); 13C{1H} NMR
1H), 7.28-7.23 (m, 1H), 6.99-6.95 (m, 1H); 13C{1H} NMR (75
(75 MHz, Chloroform-d): δ 160.2, 151.5, 147.9, 139.1, 138.6,
131.7, 129.1, 128.0, 120.0, 114.5; HRMS (ESI-TOF) m/z: calcd
for C10H9N2OS [M+H]+ 205.0430, found 205.0432.
MHz, Chloroform-d): δ 164.6, 151.6, 148.0, 138.7, 136.5, 135.2,
4
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10.1002/ejoc.202001137
European Journal of Organic Chemistry
FULL PAPER
N-(Pyridin-2-yl)thiophene-3-carboxamide (19). White solid; 69
mg, 56% yield; m.p. 103-105 oC; 1H NMR (300 MHz,
Chloroform-d): δ 9.01 (s, 1H), 8.37-8.33 (m, 1H), 8.20-8.17 (m,
1H), 8.06-8.03 (m, 1H), 7.75-7.69 (m, 1H), 7.56-7.53 (m, 1H),
7.38-7.35 (m, 1H), 7.04-7.00 (m, 1H); 13C{1H} NMR (75 MHz,
Chloroform-d): δ 161.2, 151.6, 147.9, 138.7, 137.4, 129.6, 127.1,
126.4, 120.0, 114.4; HRMS (ESI-TOF) m/z: calcd for C10H9N2OS
[M+H]+ 205.0430, found 205.0431.
N-(Pyridin-2-yl)picolinamide (20). White solid; 13 mg, 11%
yield; m.p. 117-119 oC; 1H NMR (300 MHz, Chloroform-d): δ
10.53 (s, 1H), 8.61-8.60 (m, 1H), 8.40 (d, J = 8.4 Hz, 1H), 8.36-
8.33 (m, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.88 (td, J = 7.7, 1.7 Hz,
1H), 7.76-7.70 (m, 1H), 7.48-7.44 (m, 1H), 7.07-7.03 (m, 1H);
13C{1H} NMR (75 MHz, Chloroform-d): δ 162.7, 151.2, 149.4,
148.3, 138.3, 137.6, 126.8, 122.5, 119.9, 114.0; HRMS (ESI-
TOF) m/z: calcd for C11H10N3O [M+H]+ 200.0818, found
200.0816.
3.86 (s, 3H); 13C{1H} NMR (75 MHz, Chloroform-d): δ 167.6,
166.5, 153.7, 148.4, 134.6, 132.1, 128.7, 127.5, 107.8, 99.0,
55.4; HRMS (ESI-TOF) m/z: calcd for C13H13N2O2 [M+H]+
229.0972, found 229.0972.
Acknowledgements
This work is supported by the National Natural Science
Foundation of China (No. 81973167, 81703348), "Double First-
Class" University project of China Pharmaceutical University (No.
CPU2018GY04,
CPU2018GY35),
Jiangsu
Post-doctoral
Research Funding Program (No. 2020Z135), Shanghai
Municipal Health and Family Planning Commission (No.
20184Y0033)，and the Natural Science key Project of Anhui
Education Department (No. KJ2019A0635).
Keywords: Construction of amides • C-C bond cleavage • Metal
free • N-heterocyclic amides • Water
N-(Pyridin-2-yl)-[1,1'-biphenyl]-4-carboxamide (21). White
o
1
solid; 78 mg, 47% yield; m.p. 154-156 C; H NMR (300 MHz,
Chloroform-d): δ 9.19 (s, 1H), 8.44 (d, J = 8.4 Hz, 1H), 8.20-8.18
(m, 1H), 8.03-7.99 (m, 2H), 7.78-7.73 (m, 1H), 7.71-7.68 (m, 2H),
7.64-7.61 (m, 2H), 7.50-7.45 (m, 2H), 7.43-7.37 (m, 1H), 7.06-
7.02 (m, 1H); 13C{1H} NMR (75 MHz, Chloroform-d): δ 165.8,
151.8, 148.0, 145.1, 139.8, 138.6, 133.0, 129.1, 128.3, 128.0,
127.5, 127.3, 120.0, 114.5; HRMS (ESI-TOF) m/z: calcd for
NaC18H14N2O [M+Na]+ 297.0998, found 297.1001.
N-(3-Methylpyridin-2-yl)benzamide (22). Yellow semisolid; 60
mg, 47% yield; 1H NMR (300 MHz, Chloroform-d): δ 9.24 (s, 1H),
8.19 (d, J = 4.8 Hz, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 7.6
Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 2H), 7.11
(dd, J = 7.6, 4.8 Hz, 1H), 2.31 (s, 3H); 13C{1H} NMR (75 MHz,
Chloroform-d): δ 166.3, 150.1, 145.5, 140.2, 134.2, 132.1, 129.5,
128.7, 127.8, 121.9, 18.5; HRMS (ESI-TOF) m/z: calcd for
C13H13N2O [M+H]+ 213.1022, found 213.1023.
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o
1
51% yield; m.p. 107-110 C; H NMR (300 MHz, Chloroform-d):
δ 8.94 (s, 1H), 8.25 (s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.93-7.90
(m, 2H), 7.59-7.53 (m, 1H), 7.50-7.45 (m, 2H), 6.87 (d, J = 5.0
Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR (75 MHz, Chloroform-d): δ
166.0, 151.7, 150.2, 147.5, 134.5, 132.3, 128.9, 127.4, 121.2,
114.9, 21.6; HRMS (ESI-TOF) m/z: calcd for C13H13N2O [M+H]+
213.1022, found 213.1020.
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N-(5-Methylpyridin-2-yl)benzamide (24). Yellow solid; 61 mg,
o
1
48% yield; m.p. 89-93 C; H NMR (300 MHz, Chloroform-d): δ
8.86 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 8.01 (s, 1H), 7.94-7.90 (m,
2H), 7.58-7.53 (m, 2H), 7.50-7.45 (m, 2H), 2.29 (s, 3H); 13C{1H}
NMR (75 MHz, Chloroform-d): δ 165.8, 149.6, 147.9, 139.1,
134.6, 132.2, 129.4, 128.9, 127.3, 113.8, 17.9; HRMS (ESI-TOF)
m/z: calcd for C13H13N2O [M+H]+ 213.1022, found 213.1021.
N-(6-Methylpyridin-2-yl)benzamide (25). Yellow solid; 4 mg,
3% yield; m.p. 107-110 oC; 1H NMR (300 MHz, Chloroform-d): δ
8.56 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H), 7.96-7.89 (m, 2H), 7.65 (t,
J = 7.9 Hz, 1H), 7.59-7.53 (m, 1H), 7.51-7.46 (m, 2H), 6.93 (d, J
= 7.5 Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (75 MHz, Chloroform-
d): δ 165.8, 157.1, 150.9, 138.9, 134.5, 132.3, 128.9, 127.3,
119.6, 111.1, 24.1; HRMS (ESI-TOF) m/z: calcd for C13H13N2O
[M+H]+ 213.1022, found 213.1020.
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Entry for the Table of Contents
Amides Synthesis
A mild and green methodology for the construction of N-(pyridine-2-yl)amides from alkylarenes and 2-aminopyridine in one step was
developed. Various alkylarenes were directly transformed into the corresponding N-(pyridine-2-yl)amides via tandem C(sp3)-H bond
activation/oxidative cyclization/C-C bond cleavage.
7
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