Cu(II)-promoted oxidative C-N bond cleavage of N-benzoylamino acids to primary aryl amides

Article abstract of DOI:10.24820/ark.5550190.p009.726

A novel protocol for CuCl2-promoted oxidative C-N bond cleavage of N-benzoyl amino acids was developed. It is the first example of using accessible amino acid as an ammonia synthetic equivalent for the synthesis of primary aryl amides via CuCl2-promoted oxidative C-N bond cleavage reaction. The present protocol shows excellent functional group tolerance and provides an alternative method for the synthetic of primary aryl amides in 84-96% yields.

Full text of DOI:10.24820/ark.5550190.p009.726

General Papers
ARKIVOC 2016 (vi) 52-62
Cu(Ⅱ)-promoted oxidative C-N bond cleavage of N-benzoylamino
acids to primary aryl amides
Liandi Zhou, Wei Liu,Yongli Zhao, and Junmin Chen*
College of Chemistry & Chemical Engineering and Key Laboratory of Functional Small Organic
Molecules, Ministry of Education, Jiangxi Normal University, Nanchang, Jiangxi 330022, China;
E-mail: jxnuchenjm@163.com
DOI: https://doi.org/10.24820/ark.5550190.p009.726
Abstract
A novel protocol for CuCl2-promoted oxidative C-N bond cleavage of N-benzoyl amino acids was
developed. It is the first example of using accessible amino acid as an ammonia synthetic
equivalent for the synthesis of primary aryl amides via CuCl2-promoted oxidative C-N bond
cleavage reaction. The present protocol shows excellent functional group tolerance and provides
an alternative method for the synthetic of primary aryl amides in 84-96% yields.
Keywords: C-N bond cleavage, amino acid, aryl amide
Introduction
Amide bond forming reactions are among the most important and widely studied transformations
in organic chemistry,1 because they are widely present in detergents, lubricants, biologically active
molecules, agrochemicals, pharmaceuticals and polymers.2 Amide is the most important functional
group necessary to maintain biological systems,3 as well as the importance intermediates in organic
syntheses.4 Therefore, various approaches to the construction of the amide have been developed.
The traditional methods for the synthesis of primary amides rely on the treatment of acyl halides,
acid anhydrides, esters or acids with ammonia.5 However, the use of ammonia can often be
hampered by handling issues, importantly, since ammonia can react with carboxylic acids, esters
and other functional groups, these methods are sometimes not suitable for selective amide
generation. Other methods for amide synthesis include the Beckmann rearrangement6,7 and the
Schmidt reaction.8 However, both of them involve hazardous reagents and produce stoichiometric
quantities of noxious by-products. Recently, metal complexes have been used to access amides
through the dehydrogenative reaction between amines and alcohols or aldehydes.9,10 Furthermore,
the hydration of nitriles11 and the rearrangement of aldoximes12,13 can also provide alternative
synthetic routes to amides. Very recently, Sekar and coworkers developed an efficient process for
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ARKIVOC 2016 (vi) 52-62
the direct synthesis of amides from methylarenes and amines using an iron catalyst.14 In this new
catalytic reaction, the methyl group of the methylarene is oxidized to the corresponding aldehyde
through non-directed C(sp3)-H oxidation followed by its oxidative amidation with N-chloroamine,
yielding the carboxylic amide. However, these above-mentioned methods suffer several
drawbacks, such as low functional group tolerance, undesired hydrolysis of the amides into
carboxylic acids. Therefore, development of a general, practical and efficient method for the
construction of primary aryl amides is still a challenge, and such a method is highly desirable.
The C−N bond is one of the most abundant chemical bonds and widely exists in many organic
molecules and biomacromolecules. The formation and transformation of C−N bond are among the
central topics in organic chemistry, organometallic chemistry, and biochemistry.15 The C–N bond
is strong in organic molecules, thus, the transformations via C–N bond cleavage are usually
difficult.16 Recently, transition-metal-catalyzed decarboxylative coupling reactions have generated
much interest because of its efficiency, selectivity, as well as convenience (Scheme 1),17 Very
recently, decarbonylation/dehydration reactions also have been studied and constitute a useful tool
in synthesis of olefins18 Despite the significant advances in decarbonylation reactions, questions
19-22
concerning decarbonylation/dehydration of amino acids was less explored.
Based on the
previous work, we reasoned that the C-N bond cleavage of N-benzoyl amino acids 1 can also be
realized via oxidative decarbonylation/dehydration reaction, followed by hydrolysis to afford the
corresponding primary amides 2 (Scheme 2). Herein, we describe the first example of the use of
amino acids as an ammonia synthetic equivalent for the synthesis of primary aryl amides via
Cu(Ⅱ)-promoted oxidative C-N bond cleavage of N-benzoyl amino acids.
R
2
R
2
cat.Pd
R
1
R
1
OH
R
R
2
1
R
3
or
H
H
O
Scheme 1. Transition metal catalyzed decarbonylation/dehydration reactions.
O
O
R
2
R
1
OH
Cu
?
NH
2
N
H
Ar
Ar
O
O
R
2
2
1
N
R
1
Ar
via
Scheme 2. Cu(Ⅱ)-promoted oxidative C-N bond cleavage of N-benzoylamino acids.
Results and Discussion
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In our initial study, 1a containing a 2-aminoisobutyric acid was chosen as a model substrate and
selected results from our screening experiments are summarized (Table 1). Only trace amount of
product 2a was detected by using 1 equivalent of CuO as oxidant in DMSO at 120 °C for 11 h
(Table 1, entry 1).
Table 1. Examination of reaction conditions
O
O
R
1
R
2
OH
oxidant
solvent
NH
2
N
H
O
o
120 C, 11h
2a
1a-c
1a R = Me; R = Me
1
2
1b R = Me; R = H
1
2
1c R = H; R = H
1
2
Entrya
1
Cu
Solvent Yield of 2a/%b
CuO
CuSO4
DMSO
DMSO
trace
12
2
3
Cu(OAc)2 DMSO
17
4
5
6
7
8
9
10
11
12
15
16 c
17d
18e
CuCl2
AgOAc
MnO2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
DMSO
DMSO
DMSO
DMF
DMA
Xylene
TFA
tBuOH
AcOH
Dioxane
DMSO
DMSO
DMSO
96
32
74
56
86
trace
trace
trace
trace
trace
56
93
trace
a
Reaction conditions: benzoyl amino acid (0.5 mmol), oxidant (0.5 mmol), solvent (0.5 mL), at
o
b
c
o
d
e
120 C for 11 h. Isolated yield. Reaction at 100 C. 1b was used substrate. 1c was used
substrate.
Then, other copper precursors were tested, only 12% and 17% yields of 2a were obtained with
CuSO4 and Cu(OAc)2 as oxidants, respectively (Table 1, entries 2,3). Surprisingly, the yield was
dramatically improved to 96% by using CuCl2 as oxidant, (Table 1, entry 4). In addition, we found
that 34 % yield of 2a was obtained by using AgOAc as oxidant (Table 1, entry 5). To our delight,
we found that MnO2 can afford the desired product 2a in good yield (Table 1, entry 6). To further
optimize the reaction, an extensive screening of various solvents was conducted by using CuCl2
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ARKIVOC 2016 (vi) 52-62
as the oxidant; we found that DMF as solvent gave a 56% yield (Table 1, entry 7). Notably, DMA
showed similar reactivity compared to that of DMSO and 86% yield was obtained (Table 1, entry
4 vs 8). However, we found that nonpolar solvents and protic solvents were ineffective in the
present protocol (Table 1, entries 9-15). Then, the effect of variation of reaction temperature was
o
studied; when the reaction temperature was decreased to 100 C, only 56% yield of 2a was
obtained (Table 1, entry 16). Finally, the substrates employing other amino acids were tested, for
example, 1b containing 2-amino-propionic acid showed almost the same reaction efficiency
compared to that of 1a (Table 1, entry 17). Interestingly, substrate 1c containing an aminoacetic
acid, only less than 5% yield of 2a was detected (Table 1, entry 18). Therefore, by a systematic
variation of the reaction parameters, the optimtimal reaction conditions were found to be: CuCl2
(1 equiv) as oxidant in DMSO at 120 °C for 11 h (Table 1, entry 4).
With the optimized conditions in hand, we investigated the scope of substrates (Table 2).
Table 2. CuCl2-promoted oxidative C-N bond cleavage of N-benzoylamino acids
O
O
Me
Me
OH
CuCl (1.0 equiv)
2
NH2
N
H
Ar
Ar
DMSO
120 oC, 11h
O
2
1
Entrya
Ar
Product Yield/%b
1
2
3
4
5
6
7
8
9
Ph 1a
2a
2b
2c
2d
2e
2f
2g
2h
2i
96
91
93
92
91
95
86
88
84
p-MeC6H4 1d
P-MeOC6H4 1e
p-ClC6H4 1f
p-FC6H4 1g
p-CF3C6H4 1h
m-MeC6H4 1i
o-ClC6H4 1j
2-naphthalene 1k
10
11
2- thiophene 1l
2j
89
trace
O
S
Me
Me
OH
O
2k
N
H
O
1m
a Reaction conditions: benzoyl amino acid 1 (0.5 mmol), CuCl2 (0.5 mmol), DMSO (0.5 mL), at
120 oC for 11 h. b Isolated yield.
We found that substrates 1 containing either electron-donating or electron-withdrawing group
smoothly reacted to afford the corresponding products 2 in 84-96% yields. For example, the
substrates 1d-h containing a substituent group at the para position such as p-Me, p-MeO, p-Cl, p-
F, and p-CF3 gave the corresponding aryl primary amides in excellent yield (Table 2, entries 2-6).
As for different substitution patterns in the arene ring, meta- and ortho- substituted substrates1i-j
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ARKIVOC 2016 (vi) 52-62
all worked well in this reaction to afford the desired products 2g-2h. For example, substrates 1i
bearing a meta-substituent such as m-Me gave an 86% isolated yield (Table 2, entry 7); substrate
1j bearing ortho-substituent such as o-Cl afforded the corresponding products in 88% isolated yield
(Table 2, entry 8). Substrate derived from 2-Naphthalene such as 1k was suitable, giving the
corresponding product 2i in 84% yield (Table 2, entry 9). Notably, a substrate 1l, bearing a
thiophenyl ring underwent reaction smoothly to afford the desired product 1j in 89% yield (Table
2, entry 10). Unfortunately, the present protocol does not appear to be applicable to the similar
arylsulfonyl amino acid 1m, only a trace amount of the primary sulfonamides product 2k was
obtained (Table 2, entry 11).
On the basis of these results and previous reports, a plausible reaction mechanism is proposed
(Scheme 4). Initially, interaction of CuCl2 and benzoylamino acid 1a afford organocopper species
A, The oxidative decarboxylation of A gives the radical intermediate B and simultaneously
generates CO2. Subsequently, B is further oxidized to afford the iminium intermediate C, which
affords the imine D after deprotonation. Finally, the imine D is hydrolyzed to afford the primary
arylamide 2a and acetone.
O
Me
Me
O
Me
Me
O
Me
Me
OH
O
-CO
+
Cu(II)
2
N
H
N
H
Cu
Cu(I)
N
H
+
-H
O
O
B
A
1a
Cu(II)
Me
Me
O
O
O
Me
+H O
2
NH
N
H
2
N
Me
+
-H
O
2b
C
D
Scheme 4. A plausible reaction mechanism.
Conclusions
In conclusion, a novel Cu(Ⅱ)-promoted oxidative C-N bond cleavage of N-benzoylamino acids
has been developed. Readily available benzoylamino acids with broad substrate scope were fully
compatible by employing CuCl2 as the oxidant. The present protocol shows excellent functional
group tolerance and provides an efficient method for the synthesis of aryl amides in excellent
yields. Further applications to the synthesis of biologically important molecules are in progress.
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Experimental Section
General. All reagents were obtained from commercial sources and used without further
purification. The reactions were carried out in air; all products were purified by column
chromatography on silica gel (200–300 mesh) using petroleum ether (60-90oC) and ethyl acetate
as eluate. Compounds described in the literature were characterized by HRMS and NMR. The 1H
and 13C NMR spectra were recorded on a Bruker AC-400 (400 MHz) spectrometer with TMS as
an internal standard. High-resolution mass spectral (HRMS) data were recorded on Bruker APEX
IV Fourier transform ion cyclotron resonance mass spectrometer using electrospray ionization
(ESI). Melting points were determined on an XT-4 electrothermal micro-melting-point apparatus.
Synthesis of N-benzoylamino acids 1: typical procedure.23 Amino acid (100 mmol) was
dissolved in 10% sodium hydroxide solution (100 mL), and then benzoyl chloride or aryl
sulfonly chloride (100 mmol) was added in portions to this solution, stirred vigorously after each
addition. Crushed ice (100 g) was added to the solution and then concentrated HCl was added
dropwise until the mixture was acidified (pH 2-3). The resulting compounds 1a-1m were
obtained as a white or yellow crystalline solid.
2-Benzoylamino-2-methyl-propionic acid24 (1a). White solid, mp 199-201oC (lit.24 199 °C). 1H
NMR (d-DMSO, 400 MHz): δ 1.45 (s, 6H), 7.52-7.44 (m, 2H), 7.54 (d, J 8.0 Hz, 1H), 7.85 (d, J
8.0 Hz, 2H), 8.47 (s, 1H).
2-Benzoylamino-propionic acid25 (1b). White solid, mp 119-121 °C (lit.25 119 °C). 1H NMR (d-
DMSO, 400 MHz): δ 1.13 (d, J 8.0 Hz, 3H), 3.73 (t, J 8.0 Hz, 1H), 7.37 (d, J 8.0 HZ, 2H), 7.67
(d, J 8.0 Hz, 2H), 8.05 (d, J 8.0 HZ, 1H).
Benzoylamino-acetic acid26 (1c). White solid, mp 191-193 °C (lit.26 191 °C). 1H NMR (d-DMSO,
400 MHz): δ 3.54 (d, J 4.0 Hz, 2H), 7.37 (d, J 8.0 Hz, 2H), 7.67 (d, J 8.0 Hz, 2H), 7.94 (s, 1H).
°
1
2-Methyl-2-(4-methyl-benzoylamino)-propionic acid (1d). White solid, mp 217-219 C. H
NMR (d-DMSO, 400 MHz): δ 1.44 (s, 6H), 2.35 (s, 3H), 7.26 (d, J 8.0 Hz, 2H), 7.77 (d, J 8.0 Hz,
2H), 8.38 (s, 1H). 13C NMR (d-DMSO, 100 MHz): δ 20.9, 25.0, 55.3, 127.4, 128.6, 131.5, 140.9,
166.7, 175.5. HRMS (Q-TOF): calcd. For C12H16NO3 [M+H]+ 222.1130; found 222.1134.
°
2-(4-Methoxy-benzoylamino)-2-methyl-propionic acid (1e). White solid, mp 234-236 C. 1H
NMR (d-DMSO, 400 MHz): δ 1.24 (s, 3H), 3.82 (d, J 4.0 Hz, 2H), 7.06 (d, J 8.0 Hz, 2H), 7.72 (d,
J 8.0 Hz, 2H), 7.79 (s, 1H). 13C NMR (d-DMSO, 100 MHz): δ 26.40, 55.07, 58.73, 124.71, 128.19,
149.62, 149.67, 175.19. HRMS (Q-TOF): calcd. For C12H16NO4 [M+H]+ 238.1079; found
238.1076.
°
1
2-(4-Chloro-benzoylamino)-2-methyl-propionic acid (1f): Yellow solid, mp 218-219 C. H
NMR (d-DMSO, 400 MHz): δ 1.46 (s, 3H), 7.53 (d, J 8.0 Hz, 2H), 7.87 (d, J 8.0 Hz, 2H), 8.50 (s,
13
1H). C NMR (d-DMSO, 100 MHz): δ 24.9, 55.7, 128.2, 129.3, 133.22, 135.9, 164.7, 175.5.
HRMS (Q-TOF): calcd. For C11H13ClNO3 [M+H]+ 242.0584; found 242.0581.
2-(4-Fluoro-benzoylamino)-2-methyl-propionic acid (1g): Yellow solid, mp 214-216 C. H
NMR (d-DMSO, 400 MHz): δ 1.46 (s, 3H), 7.28 (t, J 8.0 Hz, 2H), 7.92 (t, J 8.0 Hz, 2H), 8.42 (s,
°
1
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1H). 13C NMR (d-DMSO, 100 MHz): δ 24.9, 55.5, 114.8, 115.1, 130.0, 130.1, 130.8, 162.6, 164.8,
175.4. HRMS (Q-TOF): calcd. For C11H13FNO3 [M+H]+ 226.0879; found 226.0876.
2-Methyl-2-(4-trifluoromethyl-benzoylamino)-propionic acid (1h): White solid, mp 226-228
°C. 1H NMR (d-DMSO, 400 MHz): δ 1.48 (s, 3H), 7.84 (d, J 8.0 Hz, 2H), 8.05 (d, J 8.0 Hz, 2H),
8.68 (s, 1H). 13C NMR (d-DMSO, 100 MHz): δ 25.4, 56.2, 123.1, 125.6, 125.6, 128.9, 131.5,
131.2, 131.8, 132.1, 138.6, 165.3, 175.8. HRMS (Q-TOF): calcd. For C12H13F3NO3 [M+H]+
276.0847; found 278.0849.
°
1
2-Methyl-2-(3-methyl-benzoylamino)-propionic acid (1i): White solid, mp 200-202 C. H
NMR (d-DMSO, 400 MHz): δ 1.45 (s, 6H), 2.36 (s, 3H), 7. 32 (s, 2H), 7.66-7.61 (m, 2H), 8.35 (s,
1H). 13C NMR (d-DMSO, 100 MHz): δ 20.9, 24.9, 55.4, 124.6, 127.9, 127.9, 131.6, 134.4, 137.3,
165.9, 175.5. HRMS (Q-TOF): calcd. For C12H13NO3 [M+H]+ 222.1130; found 222.1136.
°
1
2-(2-Chloro-benzoylamino)-2-methyl-propionic acid (1j): White solid, mp 195-197 C. H
NMR (d-DMSO, 400 MHz): δ 1.44 (s, 6H), 7.48-7.39 (m, 4H), 8.56 (s, 1H). 13C NMR (d-DMSO,
100 MHz): δ 24.8, 55.5, 126.9, 128.9, 129.5, 130.0, 130.6, 136.7, 165.5, 175.2. HRMS (Q-TOF):
calcd. For C10H13N2O6S [M+H]+ 242.0584; found 242.0587.
2-Methyl-2-[(naphthalene-2-carbonyl)-amino]-propionic acid (1k): White solid; mp 196-198
1
°C. H NMR (d-DMSO, 400 MHz): δ 1.53 (s, 6H), 7.63-7.57 (m, 2H), 7.93-7.91 (m, 1H), 8.02-
13
7.96 (m, 2H), 8.04 (d, J 8.0 Hz, 1H), 8.46 (s, 1H), 8.61 (s, 1H). C NMR (d-DMSO, 100 MHz):
δ 24.9, 55.8, 124.3, 126.6, 127.4, 127.5, 127.7, 128.6, 132.1, 165.7, 170.9, 175.9. HRMS (Q-TOF):
calcd. For C15H16NO3 [M+H]+ 258.1130; found 258.1134.
2-Methyl-2-[(thiophene-2-carbonyl)-amino]-propionic acid (1l): White solid, mp 224-226 C.
°
1H NMR (d-DMSO, 400 MHz): δ 1.45 (s, 6H), 7.13 (t, J 4.0 Hz, 1H), 7.73 (d, J 4.0 Hz, 1H), 7.81
(d, J 8.0 Hz, 1H), 8.40 (s, 1H). 13C NMR (d-DMSO, 100 MHz): δ 24.9, 55.8, 127.7, 128.4, 130.50,
140.1, 160.5, 175.7. HRMS (Q-TOF): calcd. For C9H12NO3S [M+H]+ 214.0538; found 214.0535.
2-Benzenesulfonylamino-2-methyl-propionic acid27 (1m): White solid, mp 145-147 °C (lit. 145-
146 °C). 1H NMR (d-DMSO, 400 MHz): δ 1.23 (s, 6H), 7.56 (dd, J 8.0 Hz, J 12.0 Hz, 2H), 7.80
(d, J 4.0 Hz, 2H), 7.97 (s, 1H).
General procedure for CuCl2-promoted oxidative C-N bond cleavage of N-benzoyl amino
acids for primary aryl amides 2. A mixture of benzoyl amino acid 1 (0.5 mmol), CuCl2 (85 mg,
0.5 mmol), and DMSO (0.5 mL) was placed in a 25 mL flask under air. The tube was heated at
120 ℃ for 11 h. The reaction mixture was cooled, diluted with ethyl acetate (10 mL), filtered
through Celite, and concentrated in vacuo. The residue was purified by silica gel column
chromatography with ethyl acetate/ petroleum ether (ethyl acetate/ petroleum ether = 1:3) to afford
the desired product 2.
Benzamide28 (2a). (table 2, entry 1). White solid, yield 96%, 58 mg, mp 124-126 °C (lit.28 127
°C). 1H NMR (400 MHz, DMSO-d6 /TMS): δ 7.93 (s, 1H), 7.87 (d, J 8.0 Hz, 2H), 7.35 (s, 1H),
7.31 (d, J 8.0 Hz, 2H).
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4-Methylbenzamide28 (2b). (table 2, entry 2). White solid, yield 91%, 62 mg, mp 163-165 °C
(lit.28 163 °C). 1H NMR (400 MHz, DMSO-d6 /TMS): δ 7.97 (s, 1H), 7.83 (d, J 8.0 Hz, 2H), 7.35
(s, 1H), 7.31 (d, J 8.0 Hz, 2H), 2.40 (s, 3H).
4-Methoxylbenzamide28 (2c). (table 2, entry 3). White solid, yield 93%, 70 mg, mp 165-167 °C
(lit.28 166 °C). 1H NMR (400 MHz, DMSO-d6 /TMS): δ 7.75 (2 H, d = 8.0 Hz) 7.17 (s, 2H), 7.08
(2 H, d, J 8.0 Hz), 3.80 (s, 3H).
4-Chlorobenzamide29 (2d). (table 2, entry 3). White solid, yield 92%, 72 mg, mp 178-180 °C
(lit.29 180 °C). 1H NMR (400 MHz, DMSO-d6 /TMS): δ 8.08 (s, 1H), δ 7.89 (d, J 8.0 Hz, 2H),
7.54-7.52 (m, 3H).
4-Fluorobenzamide30 (2e). (table 2, entry 4). White solid, yield 91%, 63 mg, mp 124-126 °C
(lit.30 123 °C). 1H NMR (400 MHz, DMSO-d6 /TMS): δ 8.03 (s, 1H), 7.97-7.93 (m, 2H), 7.45 (s,
1H).7.31-7.26 (m, 2H).
4-Trifluoromethylbenzamide31 (2f). (table 2, entry 5). White solid, yield 95%, 90 mg, mp 183-
1
185 °C (lit.31 185-188 °C). H NMR (400 MHz, DMSO-d6 /TMS): δ 8.16 (s, 1H), 8.07 (d, J 8.0
Hz, 2H), 7.83 (d, J 8.0 Hz, 2H), 7.58 (s, 1H).
3-Methylbenzamide32 (2g). (table 2, entry 6) White solid, yield 86%, 58 mg, mp 93-95 °C (lit.32
93-94 °C).1H NMR (400 MHz, DMSO-d6 /TMS): δ 7.88 (s, 1H), 7.70-7.66 (m, 2H), 7.33 (m, 2H),
7.26 (s, 1H).
2-Chlorobenzamide33 (2h). (table 2, entry 7). White solid, yield 88%, 68 mg, mp 139-141 °C
(lit.33 141 °C). 1H NMR (400 MHz, DMSO-d6 /TMS): δ 7.90 (s, 1H), δ 7.61 (s, 1H), 7.50-7.36 (m,
4H).
Naphthalene-2-carboxylic acid amide34 (2i). (table 2, entry 8). White solid, yield 84%, 72 mg,
mp 194-196 °C (lit.34 195 °C). 1H NMR (400 MHz, DMSO-d6 /TMS): δ 8.48 (s, 1H), 7.97 (m,
5H), 7.60 (m, 2H), 7.42 (s, 1H).
Thiophene-2-carboxylic acid amide35 (2j). (table 2, entry 9). White solid, yield 96%, 32 mg,
mp 147-149 °C (lit.35 147°C). 1H NMR (400 MHz, DMSO /TMS): δ 7.92 (s, 1H), 7.73 (d, J 8.0
Hz, 2H), 7.33 (m, 1H), 7.13 (s, 1H).
Acknowledgements
We are grateful for the financial support of Science and Technology Planning Project of Jiangxi
Province, China (20142BAB203007).
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