Direct Amidation of Carboxylic Acids with Nitroarenes

Article abstract of DOI:10.1021/acs.joc.9b02068

N-Aryl amides are an important class of compounds in pharmaceutical and agrochemical chemistry. Rapid and low-cost synthesis of N-aryl amides remains in high demand. Herein, we disclose an operationally simple process to access N-aryl amides directly from readily available nitroarenes and carboxylic acids as coupling substrates. This method involves the in situ activation of carboxylic acids to acyloxyphosphonium salt for one-pot amidation, without the need for isolation of the corresponding synthetic intermediates. Furthermore, the ease of preparation and workup allow the quick and efficient synthesis of a wide range of N-aryl amides, including several amide-based druglike and agrochemical molecules.

Full text of DOI:10.1021/acs.joc.9b02068

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Article
Direct Amidation of Carboxylic Acids with Nitroarenes
Shao-Peng Wang, Chi Wai Cheung, and Jun-An Ma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02068 • Publication Date (Web): 08 Oct 2019
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Direct Amidation of Carboxylic Acids with Nitroarenes
Shao-Peng Wang, Chi Wai Cheung,* and Jun-An Ma*
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Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic
Sciences, and Tianjin Collaborative Innovation Center of Chemical Science &
Engineering, Tianjin University, Tianjin 300072; and Joint School of NUS & TJU,
International Campus of Tianjin University, Fuzhou 350207, P. R. of China
*
E-mail: zhiwei.zhang@tju.edu.cn,
O
O
FG
PPh / I
FG
3
2
+
O N
2
R
OH
R
N
H
then Mn powder
TMSCl, KI
R = alkyl, (hetero)aryl, alkenyl
5
1 examples
Readily available reaction substrates & reagents
Diverse aryl amide synthesis & high functional group compatibility
Elaborations/preparations of amide herbicides and druglike molecules
ABSTRACT: N-aryl amides are an important class of compounds in pharmaceutical
and agrochemical chemistry. Rapid and low-cost synthesis of N-aryl amides remains in
high demand. Herein, we disclose an operationally simple process to access N-aryl
amides directly from readily available nitroarenes and carboxylic acids as coupling
substrates. This method involves the in-situ activation of carboxylic acids to
acyloxyphosphonium salt for one-pot amidation, without the need for isolation of the
corresponding synthetic intermediates. Furthermore, the ease of preparation and
workup allows the quick and efficient synthesis of a wide range of N-aryl amides,
including several amide-based druglike and agrochemical molecules
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INTRODUCTION
N-Aryl amides1-3 are ubiquitous structural motifs in many pharmaceuticals,4,5
6
agrochemicals, and functional material molecules. Generally, N-aryl amides are
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constructed via the coupling reactions of anilines with carboxylic acids in the presence
of stoichiometric activating reagents, such as acid chlorides, acid anhydrides,
7
carbodiimides, and boron compounds (Scheme 1a). However, these activating reagents
are usually unstable, toxic, or expensive (Scheme 1a, top). In addition, the pre-
activation process could lead to side reactions. On the other hand, anilines are usually
prepared beforehand via the tedious metal- and acid-mediated reduction of nitroarenes
8
(Scheme 1a, bottom). Such reduction processes would be incompatible with
nitroarenes containing reducible or sensitive functional groups. To overcome these
problems, recent research on the amide synthesis has paid more attention to the
transition metal-promoted direct chemical transformation of readily available
nitroarenes.9-14 For instance, the groups of Beller, Driver, and Wu described the Pd-
9
10
11
catalyzed aminocarbonylation of olefins or arenes with nitroarenes for the synthesis
1
2
13
various amides, whereas Hu and Zeng reported the Ni-catalyzed, Cr-catalyzed, or
Mn-mediated reductive amidation of nitroarenes with carboxylic acid esters, Boc-
protected secondary amides, or tertiary amides (Scheme 1b). In the latter protocols, Zn,
Mn, and Mg metals were used as reductants to reduce nitroarenes to more reactive
nitrogen-containing intermediates (e.g. nitrosoarenes, N-aryl hydroxylamines,
azoarenes, and azoxyarenes) for subsequent amidation. These studies have opened an
interesting and attractive research area for the development of alternative amidation
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methods using nitroarenes as nitrogen sources.15
Scheme 1. Synthesis of N-aryl amides from carboxylic acid derivatives and
nitroarenes.
1
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(a) Traditional methods: amidation of carboxylic acids with anilines
acyl chlorides
O
O
coupling reagents
isolation
acid anhydrides
activated esters
boron species
R
OH
R
X
R = alkyl, aryl or in-situ
base
O
FG
R
N
FG
FG
[
H]
H
O N
2
H N
2
isolation
requires prior transformations to reaction intermediates
requires toxic / unstable / expensive coupling reagents
reducible or sensitive functional groups may be incompatible
(b) Amidation of carboxylic acid derivatives with nitroarenes (Hu and Zeng)
O
FG
R1
O
O2N
O
≥
1 step
R
R
O
FG
O
R
OH
Ni catalyst, Zn/Mn metal R
or Cr catalyst, Mg metal
or Mn metal
N
isolation
R2
H
1
2
R, R , R = alkyl, aryl
R = alkyl, aryl, Boc
N
R3
3
usually requires prior conversions of carboxylic acids to esters / amides
(c) Direct amidation of carboxylic acids with nitroarenes (this work)
FG
O
O N
2
O
FG
R
OH
R
N
H
PPh / I , then Mn metal
3
2
R = alkyl, alkenyl, aryl
FG
O
XN
PPh , I
3
2
I
PPh3
in situ
R
O
X = O, NAr,N(O)R...
in situ
operationally simple one-pot process
bench-stable and inexpensive substrates
broad scope and wide functional group tolerance
applicable in medicinal and agrochemical chemistry
It is striking, however, that direct transformation of carboxylic acids and nitroarenes
into N-aryl amides still remains a formidable challenge and such a potentially useful
process is hitherto elusive. Robins and co-workers16a once reported the utility of
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triphenylphosphine (PPh ) and iodine (I ) to activate the amide linkages of
3
2
hypoxanthine nucleosides for further transformations, while Lakshman et al. described
the application of PPh /I to convert carboxylic acid into reactive acyloxyphosphonium
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iodide.16b Encouraged by these important precedents, we envisioned that direct
amidation could be achieved by activating carboxylic acids to acyloxyphosphonium
salts in situ using compatible additives, followed by the one-pot amidation with
nitroarenes (Scheme 1c). Herein we report the successful implementation of this
combination strategy and outline a more general and efficient approach to various N-
aryl amide derivatives, including several amide-based druglike and agrochemical
molecules.
RESULTS AND DISCUSSION
The amidation of hydrocinnamic acid (1a) with 1-chloro-4-nitrobenzene (2a) was
used as the test reaction (Table 1). 1a (1.2 equiv) was reacted with PPh (1.5 equiv) and
3
I2 (1.5 equiv) in N-methyl-2-pyrrolidinone solvent (NMP) at room temperature in 30
min to form acyloxyphosphonium iodide in situ.16b Inspired by Hu’s Mn-mediated
amidation protocol,12d,12e we then added Mn powder (3 equiv) and
chlorotrimethylsilane (TMSCl, 3 equiv) in combination with 2a (1 equiv) and
o
potassium iodide additive (KI, 2 equiv) to proceed the reaction at 105 C for 14 h.
Gratifyingly, the reaction underwent smoothly to afford the desired N-aryl amide
product 3a in 70% yield (entry 1). The use of bromotrimethylsilane (TMSBr) or
iodotrimethylsilane (TMSI) in place of TMSCl also furnished the desired product in the
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yields of 56% and 62%, respectively (entries 2 and 3). Changing the reaction
temperature resulted in relatively lower yields of 3a (entries 4 and 5). Exploration of
other solvents and phosphine / phosphite additives revealed that NMP and PPh were
3
1
1
1
1
1
1
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0
found to be the best choice for this direct amidation process (entries 6‒9). The loadings
of the additives were next examined, and good yields of amide were obtained when two
equivalents of TMSCl or two equivalents of Mn powder was used (entries 10 and 11).
Excess phosphine has been used as both deoxygenating reagent and reductant in
17
Cadogan reaction to reduce nitroaromatics for subsequent ring cyclizations. Indeed,
the amidation still proceeded in the presence of PPh (4 equiv) even without Mn and
3
TMSCl as reductant and deoxygenating reagent, respectively, delivering the amide in
54% yield (entry 12).
Table 1. Optimizations of direct amidation of carboxylic acids with nitroarenes.
Standard conditions:
Cl
O
O N
2
Cl (2a, 1 equiv)
O
Ph
Ph
OH
N
H
2
2
PPh (1.5 equiv), I (1.5 equiv), NMP, rt, 30 min,
3
2
1a
then Mn (3 equiv), TMSCl (3 equiv), KI (2 equiv)
3a
(1.2 equiv)
o
1
05 C, 14 h
Entry
Variations from standard conditionsa
No variation
Yield (%)b
1
2
3
4
5
70
56
62
52
54
TMSBr instead of TMSCl
TMSI instead of TMSCl
o
o
80 C instead of 105 C
o
o
120 C instead of 105 C
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1
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2
2
2
2
2
2
2
2
3
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3
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3
3
3
3
3
3
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DMF instead of NMP
DMA instead of NMP
P(OEt) instead of PPh
23
43
15
31
57
66
54
3
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0
1
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4
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9
0
P(Cy) instead of PPh
3
3
1
0
TMSCl (2 equiv) instead of (3 equiv)
Mn (2 equiv) instead of (3 equiv)
11
PPh (4 equiv) instead of (1.5 equiv), and
3
1
2
without Mn and TMSCl
a
Optimization was conducted based on the following reaction conditions: 1a (0.6 mmol), PPh
mmol), I (0.75 mmol), and NMP (1.5 mL) were stirred at room temperature (rt) for 30 min; then 2a (0.5
mmol), Mn (1.5 mmol), TMSCl (1.5 mmol), KI (1 mmol), and NMP (1 mL) were added and stirred at
3
(0.75
2
o
b
1
05 C for 14 h. Isolated yield.
We employed the optimized conditions (Table 1, entry 1) to study the scope of this
direct amidation transformation of carboxylic acids with nitroarenes (Figure 1). A wide
range of primary, secondary, and tertiary alkyl carboxylic acids were suitable substrates
to deliver the desired products 3a‒3g in 49‒85% yields. In addition, electron-neutral,
electron-rich, and electron-deficient aryl-substituted carboxylic acids as well as
naphthoic acids reacted smoothly to give the corresponding amides 3h‒3p in moderate
to good yields. This protocol also allowed the coupling of nitroarenes with heteroaryl
carboxylic acids, such as furan (1q and 1r), thiophene (1s), and benzothiophene-
carboxylic acids (1t). Moreover, acrylic acid derivatives, including cinnamic acid (1u),
p-methylcinnamic acid (1v), and 2-hexenoic acid (1w), were tolerated. The gram-scale
synthesis was also allowed by using 7 mmol of nitroarene, affording the amide product
3
v in 74% yield. Furthermore, this sequential one-pot amidation could be simplified to
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a single-step process by reacting all substrates and additives simultaneously. Under this
single-fraction protocol, 3a, 3e, and 3r could be synthesized in moderate to good yields
(42-64%).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
3
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3
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O
O
O2N
Cl (2a, 1 equiv)
Ar
R
OH
R = alkyl, aryl, alkenyl
a-1w
(1.2 equiv)
R
O
N
H
PPh3 (1.5 equiv), I2 (1.5 equiv), NMP, rt, 30 min,
then Mn (3 equiv), TMSCl (3 equiv), KI (2 equiv)
105 oC, 14 h
1
Ar =
Cl
O
O
O
O
O
Ar
Ar
Ar
Ar
Ar
N
N
H
Ar
Ph
N
N
N
tBu
H
N
H
H
H
O
H
3
a, 70% (64%)a
3b, 73%
3c, 85%
3e, 66% (60%)a
3d, 49%
3f, 49%
O
O
O
Me
O
O
O
Ar
Ar Me
Ar
Ar
Ar
Ar
N
N
N
N
N
H
N
H
H
H
H
H
tBu
MeO
3g, 67%
3h, 60%
3i, 57%
3j, 56%
3k, 53%
3l, 53%
O
O
O
O
O
N
O
Ar
Ar
Ar
Ar
Ar
Ar
N
N
N
H
N
H
N
H
H
H
H
O
O
Br
Cl
F3C
3r, 95% (42%)a
3m, 62%
3n, 42%
3o, 50%
3p, 56%
3q, 74%
O
O
O
O
O
Ar
Ar
Ar
N
N
Ar
N
N
H
Ar
H
Ph
N
H
Me
H
S
S
H
Me
3s, 59%
3t, 90%
3u, 76%
3v, 68% (7 mmol: 74%)
3w, 59%
Figure 1. Scope of carboxylic acids in direct amidation with nitroarene. Reaction
conditions: 1a-1w (0.6 mmol), PPh (0.75 mmol), I (0.75 mmol), and NMP (1.5 mL)
3
2
were stirred at room temperature for 30 min; then 2a (0.5 mmol), Mn (1.5 mmol),
o
TMSCl (1.5 mmol), KI (1 mmol), and NMP (1 mL) were added and stirred at 105 C
a
for 14 h. The reaction was performed by reacting all substrates and additives in a single
step.
An array of nitroarenes were suitable substrates for reductive amidation with
carboxylic acids as well (Figure 2). Electron-neutral and electron-rich nitroarenes were
tolerated, giving the corresponding amides 4a‒4h in generally good yields. In this
context, sterically bulky 2,4-dimethyl-1-nitrobenzene (2g’) also reacted smoothly. On
the other hand, the amidation of an even more sterically congested 2,6-dimethyl-1-
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nitrobenzene was not efficient, giving the amide in less than 20% yield. Electron-
deficient nitroarenes could also proceed smoothly to afford the amidation products
4
i‒4o in good to high yields. Furthermore, nitroheteroarenes containing benzodioxole
0
1
2
3
4
5
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7
8
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0
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(2p’), benzothiazole (2q’), N-benzyl indole (2r’), and quinoline moieties (2s’) were
compatible in this protocol. This protocol tolerated a wide range of functional groups
in the nitroarene substrates, including dialkylamino (2b’), thioether (2d’), chloro (2i’),
fluoro (2j’), bromo (2k’), trifluoromethyl (4l’, 4m’), cyano (2n’), and sulfonamide
groups (2o’).
FG
O
2
O N
(
2a'-2s'
, 1 equiv)
O
FG
OH
R
N
PPh3 (1.5 equiv), I2 (1.5 equiv), NMP, rt, 30 min,
then Mn (3 equiv), TMSCl (3 equiv), KI (2 equiv)
H
Me
1v
05 oC, 14 h
1
R = Me
(1.2 equiv)
NMe2
OMe
SPh
Me
O
O
O
O
O
R
O
N
R
N
H
R
N
H
R
N
R
N
H
H
H
4
a, 68%
4b, 78%
4c, 66%
4d, 86%
4e, 54%
Me
tBu
F
Me
O
O
O
O
R
N
R
N
Cl
R
N
H
R
R
N
OMe
R
N
H
H
H
Me
4g, 52%
H
4f, 68%
4h, 58%
4i, 71%
4j, 65%
O
Br
CF3
Me
CN
NEt2
O
O
O
O
S
O
O
N
R
N
CF3
R
N
H
R
N
H
H
H
R
N
H
4k, 79%
4l, 88%
4m, 64%
4n, 72%
4
o, 55%
Me
Bn
N
O
O
N
S
N
O
O
O
O
O
N
R
N
H
R
N
H
R
N
H
H
Me
Me Me
4p, 64%
4q, 64%
4s, 37%a
4r, 47%
Figure 2. Scope of nitroarenes in direct amidation with carboxylic acid. Reaction
conditions: 1v (0.6 mmol), PPh (0.75 mmol), I (0.75 mmol), and NMP (1.5 mL) were
3
2
stirred at room temperature for 30 min; then 2a’-2s’ (0.5 mmol), Mn (1.5 mmol),
o
TMSCl (1.5 mmol), KI (1 mmol), and NMP (1 mL) were added and stirred at 105 C
a
for 14 h. Gemfibrozil was used instead of 1v.
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To illustrate its utility, the present amidation method was applied for the modification
of agrochemical and pharmaceutical molecules bearing the carboxylic acid moieties
(Figure 3). MCPA, an herbicide, could be transformed to the amide derivative 5a in
1
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1
1
1
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2
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2
2
2
2
2
2
2
2
3
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3
3
3
3
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3
4
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5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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9
0
1
2
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0
1
2
3
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0
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0
61% yield under this protocol. Moreover, the drug-based carboxylic acids, such as
Naproxen, Ibuprofen, Probenecid, Gemfibrozil, dehydrocholic acid, and Bezafibrate,
could all undergo this amidation reaction to afford the corresponding drug derivatives
1
8
5
b‒5g. Furthermore, the fungicide Mepronil 5h was prepared in 83% yield using
stable and inexpensive o-toluic acid as well as readily available 1-isopropyl-3-
nitrobenzene under the current protocol. Likewise, the benzoxazole-bearing
1
9
20
antibacterial agent 5i and the inhibitor of human 11β-HSD1 5j could also be
synthesized directly from the corresponding carboxylic acids and nitroheteroarenes. In
contrast to the traditional methods for synthesis of these bioactive compounds,18-20 the
current transformation could be conducted without the need for isolation or purification
of any synthetic intermediates.
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O
PPh3 (1.5 equiv), I2 (1.5 equiv), NMP, rt, 30 min,
then Mn (3 equiv), TMSCl (3 equiv), KI (2 equiv)
O
+
O2N Ar
(1 equiv)
Ar
R
OH
R
N
(
1.2 equiv)
05 oC, 14 h
H
1
(
a) Elaboration of agrochemical and drug-based carboxylic acids
(Ar = 4-ClC6H4)
Me
Me
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
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9
0
1
2
3
4
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0
1
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1
2
3
4
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0
O
MeO
Ar
O
N
O
Ar
O
O
H
N
Ar
O
N
Ar
S
O
H
N
2
Pr N
H
Cl
Me
Me
H
Me
from MCPA
from Naproxen
from Ibuprofen
from Probenecid
5
a, 61%
5b, 70%
5c, 87%
5d, 68%
Me
O
O
O
O
Me
O
Me
O
Me
O
N
Me Me
Ar
Ar
H
NH
Ar
Me
N
H
N
H
2
H
Me Me
H
H
Cl
O
from Gemfibrozil
from Dehydrocholic acid
from Bezafibrate
5g, 41%
5e, 76%
5f, 41%
(b) Synthesis of herbicides and potent drugs
S
N
O
O
Me
Me
Me
O
Cl
O
N
Ph
N
O
H
H
N
Ph
N
H
Me
Mepronil
5h, 83%
Cl
Inhibitor of human 11β-HSD1
j, 53%
Antibacterial agent
5i, 36%
5
Figure 3. Synthetic utility of the direction amidation in agrochemical and medicinal
chemistry.
During the amidation process, nitroarenes could be converted to nitrosoarenes, N-
aryl hydroxylamines, azoarenes, azoxyarenes, 1,2-diaryl hydrazines, and anilines under
the reductive conditions.12,14b,21 To probe the roles of these nitrogen-containing species
as intermediates in this amidation transformation, the reactions of these species with
carboxylic acid under the conditions relevant to the amidation were monitored (Figure
4
a). While 4-methylcinnamic acid 1v reacted with nitrobenzene to give N-phenyl 4-
methylcinnamate 4a in 68% yield (Figure 2), the condensation of nitrosobenzene 6a or
N-phenyl hydroxylamine 6b with 1v under otherwise identical conditions proceeded to
afford 4a in 36% and 39% isolated yields, respectively. Thus, nitrosobenzene and N-
phenyl hydroxylamine are most likely the active intermediates for this amidation
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reaction. The diminishment of yields with N-containing intermediates could be
attributed to the difference in effective concentration of substrates or additives
compared with the parent reaction. TMSCl is essential in the amidation with
nitrosobenzene or N-phenyl hydroxylamine, as only low yields of the amide product
were formed (6‒16%) when TMSCl was omitted. On the other hand, azobenzene 6c
only reacted with 4-methylcinnamic acid to give the amide in 14% yield, while
azoxybenzene 6d, 1,2-diphenyl hydrazine 6e, and aniline 6f reacted to give a trace of
amides, suggesting that they are unlikely the intermediates for amidation.
1
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0
(a) Reactivity of nitrogen-containing intermediates in amidation
Ph NX (6a-6f, 1 equiv)
PPh3 (1.5 equiv), I2 (1.5 equiv), NMP, rt, 30 min,
O
O
Ph
p-Tol
OH
p-Tol
N
then Mn (3 equiv), TMSCl (3 equiv), KI (2 equiv)
05 oC, 14 h
H
(
1v, 1.2 equiv)
4
a
1
nitrogen-containing
intermediate (Ph-NX)
nitrogen-containing
intermediate (Ph-NX)
yield of 4a
yield of 4a
Ph
1/2
O
36%
(6d)
(6e)
(6f)
Ph NO
(
6a)
<5%
N
N
(
16% without TMSCl)
Ph
Ph
/2 HN NH
Ph
Ph NHOH (6b)
39%
<
5%
1
(6% without TMSCl)
14%
Ph
1/2
N
N
(
6c
)
Ph NH2
<5%
Ph
(b) Effect of KI on amidation
Cl
O
Cl
NO2 (2a, 1 equiv)
O
p-Tol
OH
(1)
p-Tol
N
PPh3 (1.5 equiv), I2 (1.5 equiv), NMP,
rt, 30 min,
H
(
1v, 1.2 equiv)
3v
then Mn (3 equiv), TMSCl (3 equiv),
1
05 oC, 14 h
i) KI (0 equiv)
ii) KI (2 equiv)
(
55%
68%
(
Cl
Cl
NO2
(
2a, 1 equiv)
O
O
(2)
Ph
Cl
Ph
N
Mn (3 equiv), TMSCl (3 equiv),
NMP,105 oC, 14 h
H
(
1.2 equiv)
3h
5%
53%
Reaction with PhCO H: 60%)
(i) KI (2 equiv)
5
(ii) KI (0 equiv)
(
2
Figure 4. Mechanistic study on the direct amidation of carboxylic acids with
nitroarenes.
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KI is essential in promoting the efficiency of amidation. When KI was omitted, 4-
methylcinnamic acid 1v reacted with 1-chloro-4-nitrobenzene 2a to form the amide 3v
in 55% yield [Figure 4b, eq (1), (i)]. When KI was added, the yield of 3v could be
promoted to 68% yield [Figure 4b, eq (1), (ii)]. The results suggested that the in-situ
formed acyloxyphosphonium iodide itself is sufficiently reactive for amidation, while
the additional iodide probably aids in partially converting acyloxyphosphonium iodide
to more reactive acyl iodide to further promote the amidation process. Moreover,
benzoyl iodide, which was formed via the in-situ substitution of benzoyl chloride with
KI, and benzoyl chloride itself underwent amidation smoothly under the otherwise
identical conditions to give the amide 3h in 55% and 53% yields, respectively [Figure
0
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0
4
b, eq (2), (i) and (ii)]. The results implied that both acyl iodide and acyl chloride are
the viable reaction intermediate in this amidation protocol.
Based on the above results and the analogous reaction mechanisms,12d,12e we
proposed the mechanism of the reductive amidation of carboxylic acids with nitroarenes.
1
6b
Carboxylic acid is activated by PPh and I to form acyloxyphosphonium iodide and
3
2
hydrogen iodide, which is then neutralized by the basic NMP solvent [Figure 5, (i)].
Acyloxyphosphonium iodide can partially react with KI16b and TMSCl to form acyl
iodide and acyl chloride, respectively, and both of them are also interconvertible
[Figure 5, (i)]. TMSCl can also react with KI to form a more reactive TMSI [Figure 5,
(ii)]. Meanwhile, nitroarene is reduced by Mn in the presence of TMSCl or TMSI to
form nitrosoarene and N-aryl hydroxylamine as the most probable nitrogen-containing
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intermediates [Figure 5, (iii)]. TMSCl and TMSI likely react as deoxygenating
1
2
reagents to promote the reduction of nitroarene to nitrosoarene. Nitrosoarene is then
further reduced to form N-aryl hydroxylamine, and hydrogen iodide (NMP-H+I-)
1
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generated from the activation of carboxylic acid likely behaves as the proton source to
facilitate this process. Finally, nitrosoarene presumably reacts with
acyloxyphosphonium iodide, acyl iodide, and acyl chloride in the presence of Mn and
2
2
TMSCl/TMSI to form a N-(trimethylsilyl)oxy amide species A, presumably via the
oxidative addition of acyloxyphosphonium iodide and acyl halides to Mn to form acyl-
Mn species23 [Figure 5, (iv)]. N-Aryl hydroxylamine also presumably reacts with
acyloxyphosphonium iodide and acyl halides to form N-hydroxy amide species B24
[Figure 5, (iv)]. Both species A and B further undergo reduction to form amide anion
C. During the workup process with aqueous acid solution, the amide anion C is
protonated to furnish N-aryl amide. The detailed mechanism of this amidation
transformation, especially the bond activation processes mediated by the Mn metal, will
be subjected to a further dedicated study.
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(
i) Activation of carboxylic acid
O
KI
-P(O)Ph
3
R
I
O
PPh , I2
O
3
KI
I
PPh3
-KCl
NMP
[NMP-H] I
TMSCl
[Ph P-OTMS] I
R
OH
R
O
+
-
-
-
-
O
3
0
1
2
3
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9
0
1
2
3
4
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9
0
1
2
3
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9
0
1
2
3
4
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9
0
1
2
3
4
5
6
7
8
9
0
R
Cl
(ii) Conversion of TMSCl to TMSI
TMSCl + KI
TMSI + KCl
(iii) Reduction of nitroarene to nitrogen-containing intermediates
O
Mn
Ar
TMSX -X-
O
N
Ar NO + Ar NHOH
TMSX (X = Cl, I)
O
-
Mn2+, -X-
Mn, [NMP-H]+
Mn
Ar
N
Ar N O
Ar NHOH
-
2+
Mn2+, -NMP
O TMS -TMSO , -Mn
-
(iv) Reaction of acyloxyphosphonium iodide & acyl halides with nitrogen-containing intermediates
O
Ar NO
Mn
Ar
O
R
R
N
Mn2+, -TMSO-
Mn, TMSX (X = Cl, I)
-
O
-
-
2+
A OTMS
O
-
X' , -X , -Mn
+
R
X'
H O
3
Ar
Ar
R
N
R
N
workup
X' = O-PPh3
X' = I, Cl
O
H
C
Ar NHOH
Mn, TMSX
Ar
N
-
X' , -H+
-
Mn2+, TMSOH
-
OH
B
Figure 5. Proposed mechanism of direct amidation of carboxylic acids with nitroarenes.
In conclusion, we have developed a one-pot and streamlined method for direct
amidation of carboxylic acids with nitroarenes. Bench-stable and readily available
substrates could be employed to afford a wide variety of N-aryl amides. A rapid
derivatization of agrochemical and drug molecules bearing the carboxylic acid moieties,
as well as the expedient synthesis of amide-based agrochemical and druglike molecules,
are also demonstrated. This operationally simple protocol also provides a complement
to the existing approaches in amide synthesis and would find widespread use in various
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industry settings.
EXPERIMENTAL SECTION
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
1
2
3
4
5
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8
9
0
General information.
Nuclear Magnetic Resonance (NMR) spectra were recorded on a Bruker Avance III
1
HD 400 MHz instruments at ambient temperature. All H NMR spectra were measured
in part per million (ppm, δ) relative to the signal of tetramethylsilane (TMS, 0.00 ppm),
the signal of deuterated chloroform (CDCl , 7.26 ppm), or the signal of residual
3
2
5
1
dimethyl sulfoxide in dimethyl-d sulfoxide (DMSO-d , 2.50 ppm). Data for H NMR
6
6
were reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet,
1
3
q = quartet, m = multiplet), coupling constant, and integration. All C NMR spectra
were reported in ppm relative to CDCl (77.16 ppm) or DMSO-d (39.52 ppm) and
3
6
1
25
were obtained with complete H decoupling. High-resolution mass spectrometry
(HRMS) images were obtained on a microTOF-QII or Waters Micromass GCT Premier
Instrument.
Unless otherwise noted, all chemicals were used as received without further
purifications. 1-Methyl-2-pyrrolidinone (NMP, 99% purity) were dried with 4Å
molecular sieve beads prior to use. Manganese powder (Mn), triphenylphosphine
(PPh ), and potassium iodide (KI) were in 99.9%, 98%, and 99% purities. Respectively,
3
o
chlorotrimethylsilane (TMSCl, 98% purity) was stored in the refrigerator (4 C) prior
to use. Nitroarenes, including N,N-diethyl-4-nitrobenzene-sulfonamide,26 (4-
nitrophenyl)(phenyl)sulfane,27
1-benzyl-5-nitro-1H-indole,28
1-isopropoxy-3-
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nitrobenzene, and 2-methyl-5-nitrobenzo[d]thiazole, were prepared according to the
literature procedures.
Flash column chromatography was performed using silica gel (200-300 mesh). The
eluents used for column chromatography were presented as ratios of solvent volumes.
Yields reported in the publication are isolated yields unless otherwise noted. All new
amide products were characterized by H and 13C NMR spectroscopies and high-
resolution mass spectrometry (HRMS). All known amide products were characterized
0
1
2
3
4
5
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7
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9
0
1
2
3
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9
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
13
by H and C NMR spectroscopies and the spectra were compared with the reported
data.
General Procedure for the Amide Synthesis via Sequential One-pot Manganese-
Mediated Direct Amidation of Carboxylic Acids with Nitroarenes (General
Procedure A). An oven-dried 20 mL Schlenk tube equipped with a Teflon-coated
magnetic stir bar was sequentially charged with carboxylic acid (1.2 equiv, 0.60 mmol),
triphenylphosphine (PPh , 1.5 equiv, 0.75 mmol, 196.7 mg), iodine (I , 1.5 equiv, 0.75
3
2
mmol, 190 mg), and 1-methyl-2-pyrrolidinone solvent (NMP, 1.5 mL). The tube was
capped with an airtight rubber septum, and the tube was degassed in vacuo and then
backfilled with argon gas for three times. A plastic balloon filled with argon gas was
added on the side arm opening of the Schlenk tube, and the resulting mixture was stirred
at room temperature for 30 min under the positive argon pressure. At this point,
nitroarene (1.0 equiv, 0.50 mmol), manganese powder (Mn, 3.0 equiv, 1.5 mmol, 82
mg), potassium iodide (KI, 2.0 equiv, 166 mg), and chlorotrimethylsilane (TMSCl, 3.0
equiv, 1.5 mmol, 191 μL) followed by NMP solvent (~1.0 mL, to wash away the
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chemicals attached on the inner wall) were then quickly transferred into the reaction
mixture under a positive balloon argon pressure. The resulting mixture was stirred at
o
1
05 C in a preheated oil bath for 14 h. After the reaction, the reaction mixture was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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9
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9
0
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2
3
4
5
6
7
8
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2
3
4
5
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8
9
0
1
2
3
4
5
6
7
8
9
0
cooled down to room temperature. The reaction mixture was quenched with water (~10
mL) and the aqueous phase was extracted three times with ethyl acetate (EtOAc, ~3×20
mL). The combined organic fraction was further acidified with HCl solution (~1 M
(
aq), ~20 mL), neutralized with saturated NaHCO solution (~30 mL), washed with
3
saturated NaCl solution, dried with anhydrous Na SO , and then concentrated in vacuo
2
4
with the aid of a rotary evaporator. The residue was purified by flash column
chromatography using a solvent mixture (petroleum ether, EtOAc) as an eluent to give
the purified amide product.
General Procedure for the Amide Synthesis via Single-step Manganese-Mediated
Direct Amidation of Carboxylic Acids with Nitroarenes (General Procedure B).
An oven-dried 20 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar
was charged with carboxylic acid (1.2 equiv, 0.60 mmol), triphenylphosphine (PPh3,
1
.5 equiv, 0.75 mmol, 197 mg), iodine (I , 1.5 equiv, 0.75 mmol, 190 mg), nitroarene
2
(1.0 equiv, 0.50 mmol), manganese powder (Mn, 3.0 equiv, 1.5 mmol, 82 mg), and
potassium iodide (KI, 2.0 equiv, 1.0 mmol, 166 mg). The tube was capped with an
airtight rubber septum, and the tube was degassed in vacuo and then backfilled with
argon gas for three times. 1-Methyl-2-pyrrolidinone solvent (2.5 mL) followed by
chlorotrimethylsilane (TMSCl, 3.0 equiv, 1.5 mmol, 191 μL) were then quickly
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transferred into the reaction mixture under a positive balloon argon pressure. After the
addition, a plastic balloon filled with argon gas was added on the side arm opening of
o
the Schlenk tube. The resulting mixture was stirred at 105 C in a preheated oil bath for
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14 h. After the reaction, the reaction mixture was cooled down to room temperature.
The reaction mixture was quenched with water (~10 mL) and the aqueous phase was
extracted three times with ethyl acetate (EtOAc, ~3×20 mL). The combined organic
fraction was further acidified with HCl solution (~1 M (aq), ~20 mL), neutralized with
saturated NaHCO solution (~30 mL), washed with saturated NaCl solution, dried with
3
anhydrous Na SO , and then concentrated in vacuo with the aid of a rotary evaporator.
2
4
The residue was purified by flash column chromatography using a solvent mixture
(petroleum ether, EtOAc) as an eluent to give the purified amide product.
N-(4-chlorophenyl)-3-phenylpropanamide (3a).31
(i) One-pot, Two-step Reaction: Following the general procedure A, the title
compound was prepared using hydrocinnamic acid (1.2 equiv, 0.60 mmol, 90.1 mg)
and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
ether/EtOAc (9:1) as an eluent to give the title compound as an off-white amorphous
1
solid (90 mg, 70%). H NMR (400 MHz, CDCl ): δ 7.37 (d, J = 8.3 Hz, 2H), 7.33-7.27
3
(m, 2H), 7.23 (t, J = 8.2 Hz, 5H), 7.16 (s, 1H), 3.04 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.5
1
3
1
Hz, 2H). C{ H} NMR (101 MHz, CDCl ): δ 170.5, 140.5, 136.3, 129.3, 129.0, 128.7,
3
128.4, 126.5, 121.2, 39.4, 31.5.
(ii) Single-step Reaction: Following the general procedure B, the title compound
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was isolated in 64% yield (84 mg).
N-(4-chlorophenyl)undec-10-enamide (3b). Following the general procedure A, the
title compound was prepared using undec-10-enoic acid (1.2 equiv, 0.60 mmol, 110.6
mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
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ether/EtOAc (16:1) as an eluent to give the title compound as a white amorphous solid
1
(
106.7 mg, 73%). H NMR (400 MHz, CDCl ): δ 7.52-7.42 (m, 3H), 7.26 (d, J = 7.7
3
Hz, 2H), 5.81 (dq, J = 12.0, 7.0 Hz, 1H), 4.98 (d, J = 27.4 Hz, 1H), 4.94 (d, J = 20.5
Hz, 1H), 2.34 (t, J = 7.4 Hz, 2H), 2.03 (q, J = 6.7 Hz, 2H), 1.77-1.63 (m, 2H), 1.44-
1
3
1
1
.24 (m, 10H). C{ H} NMR (101 MHz, CDCl ): δ 171.6, 139.2, 136.5, 129.1, 129.0,
3
121.1, 114.2, 37.8, 33.8, 29.3, 29.3, 29.1, 28.9, 25.6. (14 carbon signals were observed
out of expected 15 carbon signals). HRMS (electrospray ionization (ESI)): m/z Calc.
+
for C H NOCl [M+H] : 294.1625; Found: 294.1628.
1
7
25
N-(4-chlorophenyl)cyclopentanecarboxamide (3c). Following the general procedure
A, the title compound was prepared using cyclopentanecarboxylic acid (1.2 equiv, 0.60
mmol, 68.5 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using
petroleum ether/EtOAc (14:1) as an eluent to give the title compound as a white
1
amorphous solid (95.1 mg, 85%). H NMR (400 MHz, CDCl ): δ 7.48 (d, J = 8.3 Hz,
3
2
H), 7.34 (s, 1H), 7.26 (d, J = 7.9 Hz, 2H), 2.67 (p, J = 8.0 Hz, 1H), 1.99-1.84 (m, 4H),
1
3
1
1.82-1.72 (m, 2H), 1.67-1.55 (m, 2H). C{ H} NMR (101 MHz, CDCl ): δ 174.7,
3
1
36.7, 129.0, 121.0, 46.8, 30.6, 26.0. (7 carbon signals were observed out of expected
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8 carbon signals). HRMS (ESI): m/z Calc. for C H NOCl [M+H] : 224.0842; Found:
1
2
15
2
24.0842.
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N-(4-chlorophenyl)cyclohexanecarboxamide (3d).32 Following the general
procedure A, the title compound was prepared using cyclohexanecarboxylic acid (1.2
equiv, 0.60 mmol, 76.9 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8
mg) using petroleum ether/EtOAc (15:1) as an eluent to give the title compound as a
1
white amorphous solid (57.7 mg, 49%). H NMR (400 MHz, CDCl ): δ 7.48 (d, J = 8.4
3
Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.14 (s, 1H), 2.22 (t, J = 11.7 Hz, 1H), 1.95 (d, J =
1
2.5 Hz, 2H), 1.84 (d, J = 11.0 Hz, 2H), 1.72 (s, 1H), 1.53 (dd, J = 22.5, 10.6 Hz, 2H),
1
3
1
1.37-1.17 (m, 3H). C{ H} NMR (101 MHz, CDCl ): δ 174.3, 136.6, 129.0, 120.9,
3
4
6.6, 29.6, 25.6. (7 carbon signals were observed out of expected 9 carbon signals).
N-(4-chlorophenyl)tetrahydro-2H-pyran-4-carboxamide (3e).
i) One-pot, two-step Reaction: Following the general procedure A, the title
(
compound was prepared using tetrahydro-2H-pyran-4-carboxylic acid (1.2 equiv, 0.60
mmol, 78.1 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using
petroleum ether/EtOAc (2:1) as an eluent to give the title compound as a white
1
amorphous solid (78.9 mg, 66%). H NMR (400 MHz, CDCl ): δ 7.48 (d, J = 8.4 Hz,
3
2
H), 7.28 (d, J = 9.6 Hz, 2H), 4.07 (d, J = 11.4 Hz, 2H), 3.45 (t, J = 11.5 Hz, 2H), 2.50
1
3
1
(td, J = 11.2, 5.6 Hz, 1H), 2.00-1.77 (m, 4H). C{ H} NMR (101 MHz, CDCl ): δ
3
1
72.5, 136.3, 129.4, 129.1, 121.1, 67.1, 43.3, 29.2. HRMS (ESI): m/z Calc. for
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C H NO Cl [M+H] : 240.0791; Found: 240.0793.
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15
2
(
ii) Single-step Reaction: Following the general procedure B, the title compound
was isolated in 60% yield (73 mg).
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N-(4-chlorophenyl)pivalamide (3f). Following the general procedure A, the title
compound was prepared using pivalic acid (1.2 equiv, 0.60 mmol, 61.3 mg) and 1-
chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum ether/EtOAc
(
18:1) as an eluent to give the title compound as a white amorphous solid (51.8 mg,
1
49%). H NMR (400 MHz, CDCl ): δ 7.49 (d, J = 8.2 Hz, 2H), 7.32 (s, 1H), 7.28 (d, J
3
1
3
1
=
8.9 Hz, 2H), 1.31 (s, 9H). C{ H} NMR (101 MHz, CDCl ): δ 176.6, 136.6, 129.1,
3
129.0, 121.2, 39.7, 27.6.
N-(4-chlorophenyl)adamantane-1-carboxamide (3g).34 Following the general
procedure A, the title compound was prepared using adamantane-1-carboxylic acid (1.2
equiv, 0.60 mmol, 108.2 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8
mg) using petroleum ether/EtOAc (25:1) as an eluent to give the title compound as a
1
white amorphous solid (97.5 mg, 67%). H NMR (400 MHz, CDCl ): δ 7.49 (d, J = 8.3
3
13
1
Hz, 2H), 7.34-7.17 (m, 3H), 2.11 (s, 3H), 1.96 (s, 6H), 1.84-1.68 (m, 6H). C{ H}
NMR (101 MHz, CDCl ): δ 176.1, 136.6, 129.0, 128.9, 121.2, 41.5, 39.3, 38.6, 36.4,
3
2
8.1, 27.8.
3
5
N-(4-chlorophenyl)benzamide (3h). Following the general procedure A, the title
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compound was prepared using benzoic acid (1.2 equiv, 0.60 mmol, 73.3 mg) and 1-
chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum ether/EtOAc
(15:1) as an eluent to give the title compound as a white amorphous solid (68.9 mg,
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60%). H NMR (400 MHz, CDCl ): δ 7.86 (d, J = 7.5 Hz, 2H), 7.82 (s, 1H), 7.61 (d, J
3
=
8.5 Hz, 2H), 7.56 (d, J = 7.0 Hz, 1H), 7.50 (t, J = 7.4 Hz, 2H), 7.34 (d, J = 8.4 Hz,
1
3
1
2H). C{ H} NMR (101 MHz, CDCl ): δ 165.7, 136.5, 134.6, 132.1, 129.6, 129.2,
3
1
28.9, 127.0, 121.4.
3
6
N-(4-chlorophenyl)-4-methoxybenzamide (3i). Following the general procedure A,
the title compound was prepared using 4-methoxybenzoic acid (1.2 equiv, 0.60 mmol,
91.3 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
ether/EtOAc (8:1) as an eluent to give the title compound as a white amorphous solid
1
(
74.7 mg, 57%). H NMR (400 MHz, CDCl ): δ 7.83 (d, J = 8.5 Hz, 2H), 7.72 (s, 1H),
3
7.59 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 3.88 (s, 3H).
1
3
1
C{ H} NMR (101 MHz, CDCl ): δ 165.1, 162.6, 136.7, 129.3, 129.1, 128.9, 126.7,
3
121.3, 114.1, 55.5.
37
4
-(tert-butyl)-N-(4-chlorophenyl)benzamide (3j). Following the general procedure
A, the title compound was prepared using 4-(tert-butyl)benzoic acid (1.2 equiv, 0.60
mmol, 106.9 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using
petroleum ether/EtOAc (20:1) as an eluent to give the title compound as a white
1
amorphous solid (79.9 mg, 56%). H NMR (400 MHz, CDCl ): δ 7.86-7.75 (m, 3H),
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7.60 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 7.7 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 1.35 (s, 9H).
1
3
1
C{ H} NMR (101 MHz, CDCl ): δ 165.6, 155.7, 136.6, 131.7, 129.4, 129.1, 126.9,
3
1
25.8, 121.3, 35.0, 31.2.
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N-(4-chlorophenyl)-3-methylbenzamide (3k). Following the general procedure A,
the title compound was prepared using 3-methylbenzoic acid (1.2 equiv, 0.60 mmol,
8
1.7 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
ether/EtOAc (15:1) as an eluent to give the title compound as a white amorphous solid
1
(64.8 mg, 53%). H NMR (400 MHz, CDCl ): δ 7.81 (s, 1H), 7.68 (s, 1H), 7.66-7.56
3
1
3
1
(
m, 3H), 7.38 (d, J = 4.3 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 2.43 (s, 3H). C{ H} NMR
(101 MHz, CDCl ): δ 165.9, 138.8, 136.6, 134.6, 132.8, 129.5, 129.1, 128.7, 127.8,
3
1
24.0, 121.4, 21.4.
3
9
N-(4-chlorophenyl)-2-methylbenzamide (3l). Following the general procedure A,
the title compound was prepared using 2-methylbenzoic acid (1.2 equiv, 0.60 mmol,
81.7 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
ether/EtOAc (15:1) as an eluent to give the title compound as a white amorphous solid
1
(
64.7 mg, 53%). H NMR (400 MHz, CDCl ): δ 7.58 (d, J = 8.1 Hz, 2H), 7.48 (d, J =
3
1
3
1
7.1 Hz, 2H), 7.42-7.31 (m, 3H), 7.30-7.25 (m, 2H), 2.50 (s, 3H). C{ H} NMR (101
MHz, CDCl ): δ 168.1, 136.6, 136.0, 131.4, 130.5, 129.5, 129.1, 126.6, 126.0, 121.1,
3
19.9.
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4-bromo-N-(4-chlorophenyl)benzamide (3m). Following the general procedure A,
the title compound was prepared using 4-bromobenzoic acid (1.2 equiv, 0.60 mmol,
1
20.6 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using
0
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petroleum ether/EtOAc (18:1) as an eluent to give the title compound as a white
1
amorphous solid (95.5 mg, 62%). H NMR (400 MHz, CDCl ): δ 7.80-7.70 (m, 3H),
3
1
3
1
7.64 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.9 Hz, 2H). C{ H}
NMR (101 MHz, CDCl ): δ 164.7, 136.2, 133.4, 132.2, 129.9, 129.2, 128.6, 126.9,
3
1
21.5.
4
1
4
-chloro-N-(4-chlorophenyl)benzamide (3n). Following the general procedure A,
the title compound was prepared using 4-chlorobenzoic acid (1.2 equiv, 0.60 mmol,
4.0 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
9
ether/EtOAc (14:1) as an eluent to give the title compound as a white amorphous solid
1
(54.9 mg, 42%). H NMR (400 MHz, CDCl ): δ 7.80 (d, J = 7.8 Hz, 2H), 7.77 (s, 1H),
3
1
3
1
7
.59 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H). C{ H}
NMR (101 MHz, CDCl ): δ 164.6, 138.4, 136.2, 133.0, 129.8, 129.2, 129.2, 128.5,
3
1
21.5.
N-(4-chlorophenyl)-4-(trifluoromethyl)benzamide (3o). Following the general
procedure A, the title compound was prepared using 4-(trifluoromethyl)benzoic acid
(1.2 equiv, 0.60 mmol, 114.1 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol,
7
8.8 mg) using petroleum ether/EtOAc (18:1) as an eluent to give the title compound
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as a white amorphous solid (75.2 mg, 50%). H NMR (400 MHz, CDCl ): δ 7.98 (d, J
3
=
7.9 Hz, 2H), 7.82 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.36 (d,
13
1
J = 8.5 Hz, 2H). C{ H} NMR (101 MHz, CDCl ): δ 164.4, 137.9, 136.0, 133.8 (d,
3
1
1
1
1
1
1
1
1
1
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J = 32.9 Hz), 130.1, 129.3, 127.5, 126.0 (d, J = 3.75 Hz), 123.5 (d, J = 272.3
CF
CF
CF
+
Hz), 121.6. HRMS (ESI): m/z Calc. for C H ClF NO [M+H] : 300.0403; Found:
1
4
10
3
300.0410.
42
N-(4-chlorophenyl)-1-naphthamide (3p). Following the general procedure A, the
title compound was prepared using 1-naphthoic acid (1.2 equiv, 0.60 mmol, 103.3 mg)
and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
ether/EtOAc (14:1) as an eluent to give the title compound as a white amorphous solid
1
(
78.2 mg, 56%). H NMR (400 MHz, CDCl ): δ 8.33 (d, J = 8.0 Hz, 1H), 7.97 (d, J =
3
8
.2 Hz, 1H), 7.91 (d, J = 7.4 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 6.9 Hz, 1H), 7.64 (d, J
= 8.1 Hz, 2H), 7.57 (p, J = 7.1 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.1 Hz,
1
3
1
2
H). C{ H} NMR (101 MHz, CDCl ): δ 167.5, 136.6, 134.1, 133.8, 131.3, 130.0,
3
129.7, 129.2, 128.5, 127.5, 126.7, 125.2, 124.7, 121.2. (14 carbon signals were
observed out of expected 15 carbon signals).
N-(4-chlorophenyl)furan-2-carboxamide (3q). Following the general procedure A,
the title compound was prepared using furan-2-carboxylic acid (1.2 equiv, 0.60 mmol,
67.3 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
ether/EtOAc (9:1) as an eluent to give the title compound as a pale yellow amorphous
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solid (81.5 mg, 74%). H NMR (400 MHz, CDCl ): δ 8.07 (s, 1H), 7.61 (d, J = 8.3 Hz,
3
2
H), 7.53 (s, 1H), 7.33 (d, J = 8.3 Hz, 2H), 7.26 (d, J = 4.4 Hz, 2H), 6.59-6.56 (m, 1H).
13
1
C{ H} NMR (101 MHz, CDCl ): δ 156.0, 147.6, 144.3, 136.0, 129.5, 129.2, 121.1,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
115.6, 112.8. HRMS (ESI): m/z Calc. for C H NO Cl [M+H] : 222.0322; Found:
1
1
9
2
2
22.0325.
N-(4-chlorophenyl)furan-3-carboxamide (3r).
i) One-pot, Two-step Reaction: Following the general procedure A, the title
(
compound was prepared using furan-3-carboxylic acid (1.2 equiv, 0.60 mmol, 67.3 mg)
and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
ether/EtOAc (10:1) as an eluent to give the title compound as a white amorphous solid
1
(
104.9 mg, 95%). H NMR (400 MHz, CDCl ): δ 8.03 (s, 1H), 7.54 (d, J = 8.3 Hz, 2H),
3
13
1
7
.49 (s, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.71 (s, 1H). C{ H} NMR (101 MHz, CDCl ):
3
δ 160.6, 145.2, 144.2, 136.1, 129.6, 129.1, 122.8, 121.5, 108.2. HRMS (ESI): m/z Calc.
+
for C H NO Cl [M+H] : 222.0322; Found: 222.0325.
1
1
9
2
(ii) Single-step Reaction: Following the general procedure B, the title compound
was isolated in 42% yield (47 mg).
N-(4-chlorophenyl)thiophene-2-carboxamide (3s). Following the general procedure
A, the title compound was prepared using thiophene-2-carboxylic acid (1.2 equiv, 0.60
mmol, 76.9 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using
petroleum ether/EtOAc (9:1) as an eluent to give the title compound as a pale yellow
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amorphous solid (70.2 mg, 59%). H NMR (400 MHz, CDCl ): δ 7.76 (s, 1H), 7.63 (d,
3
J = 2.6 Hz, 1H), 7.57 (m, J = 8.7 Hz, 3H), 7.32 (d, J = 8.4 Hz, 2H), 7.13 (t, J = 4.1 Hz,
13
1
1
H). C{ H} NMR (101 MHz, CDCl ): δ 159.9, 138.8, 136.2, 131.1, 129.7, 129.2,
3
1
1
1
1
1
1
1
1
1
1
2
2
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3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
128.6, 127.9, 121.4. HRMS (ESI): m/z Calc. for C H NOSCl [M+H] : 238.0093;
1
1
9
Found: 238.0092.
N-(4-chlorophenyl)benzo[b]thiophene-5-carboxamide (3t). Following the general
procedure A, the title compound was prepared using benzo[b]thiophene-5-carboxylic
acid (1.2 equiv, 0.60 mmol, 106.9 mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50
mmol, 78.8 mg) using petroleum ether/EtOAc (10:1) as an eluent to give the title
1
compound as a white amorphous solid (129.9 mg, 90%). H NMR (400 MHz, DMSO-
d6): δ 10.62 (s, 1H), 8.36 (s, 1H), 8.06 (d, J = 7.5 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H),
13
1
7
.81 (d, J = 8.5 Hz, 2H), 7.49 (m, 2H), 7.44 (d, J = 8.6 Hz, 2H). C{ H} NMR (101
MHz, DMSO-d ): δ 160.9, 141.0, 140.1, 139.5, 138.1, 129.2, 128.1, 127.1, 126.5, 125.9,
6
+
1
25.6, 123.4, 122.3. HRMS (ESI): m/z Calc. for C H NOSCl [M+H] : 288.0250;
1
5
11
Found: 288.0248.
43
N-(4-chlorophenyl)cinnamamide (3u). Following the general procedure A, the title
compound was prepared using cinnamic acid (1.2 equiv, 0.60 mmol, 88.9 mg) and 1-
chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum ether/EtOAc
(11:1) as an eluent to give the title compound as a white amorphous solid (97.4 mg,
1
7
6%). H NMR (400 MHz, CDCl ): δ 7.76 (d, J = 15.5 Hz, 1H), 7.58 (d, J = 7.7 Hz,
3
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2H), 7.51 (s, 2H), 7.47 (s, 1H), 7.38 (s, 3H), 7.31 (d, J = 7.9 Hz, 2H), 6.54 (d, J = 15.4
1
3
1
Hz, 1H). C{ H} NMR (101 MHz, CDCl ): δ 164.0, 142.9, 136.6, 134.5, 130.2, 129.1,
3
1
28.9, 128.0, 121.2, 120.4. (10 carbon signals were observed out of expected 11 carbon
0
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2
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signals).
(E)-N-(4-chlorophenyl)-3-(p-tolyl)acrylamide (3v).44
(i) 0.5 mmol Scale: Following the general procedure A, the title compound was
prepared using (E)-3-(p-tolyl)acrylic acid (1.2 equiv, 0.60 mmol, 97.3 mg) and 1-
chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum ether/EtOAc
(12:1) as an eluent to give the title compound as a pale yellow amorphous solid (92.5
1
mg, 68%). H NMR (400 MHz, CDCl ): δ 7.73 (d, J = 15.5 Hz, 1H), 7.58 (d, J = 8.0
3
Hz, 2H), 7.42 (d, J = 7.8 Hz, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H),
13
1
6
.49 (d, J = 15.4 Hz, 1H), 2.38 (s, 3H). C{ H} NMR (101 MHz, CDCl ): δ 164.2,
3
142.9, 140.6, 136.7, 131.7, 129.7, 129.3, 129.1, 128.0, 121.1, 119.3, 21.5.
ii) 7 mmol Scale: Following the general procedure A, the title compound was
(
prepared using (E)-3-(p-tolyl)acrylic acid (1.2 equiv, 8.4 mmol, 1362.4 mg) and 1-
chloro-4-nitrobenzene (1.0 equiv, 7.0 mmol, 1102.9 mg) using petroleum ether/EtOAc
(10:1) as an eluent to give the title compound as a pale yellow amorphous solid (1.41
g, 74%).
(E)-N-(4-chlorophenyl)hex-2-enamide (3w). Following the general procedure A, the
title compound was prepared using (E)-hex-2-enoic acid (1.2 equiv, 0.60 mmol, 68.5
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mg) and 1-chloro-4-nitrobenzene (1.0 equiv, 0.50 mmol, 78.8 mg) using petroleum
ether/EtOAc (18:1) as an eluent to give the title compound as a white amorphous solid
1
(
65.5 mg, 59%). H NMR (400 MHz, CDCl ): δ 7.52 (d, J = 7.8 Hz, 2H), 7.35 (s, 1H),
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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7.28 (d, J = 8.5 Hz, 2H), 7.04-6.93 (m, 1H), 5.91 (d, J = 15.1 Hz, 1H), 2.20 (q, J = 7.0
1
3
1
Hz, 2H), 1.56-1.44 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). C{ H} NMR (101 MHz, CDCl ):
3
δ 164.2, 147.0, 136.6, 129.2, 129.0, 123.7, 121.1, 34.2, 21.4, 13.7. HRMS (ESI): m/z
+
Calc. for C H NOCl [M+H] : 224.0842; Found: 224.0842.
1
2
15
(E)-N-phenyl-3-(p-tolyl)acrylamide (4a). Following the general procedure A, the title
compound was prepared using (E)-3-(p-tolyl)acrylic acid (1.2 equiv, 0.60 mmol, 97.3
mg) and nitrobenzene (1.0 equiv, 0.50 mmol, 61.6 mg) using petroleum ether/EtOAc
(9:1) as an eluent to give the title compound as a white amorphous solid (80.4 mg,
1
6
8%). H NMR (400 MHz, CDCl ): δ 7.73 (d, J = 15.5 Hz, 1H), 7.68-7.58 (m, 3H),
3
7.40 (d, J = 7.6 Hz, 2H), 7.34 (t, J = 7.5 Hz, 2H), 7.17 (d, J = 7.7 Hz, 2H), 7.14-7.07
1
3
1
(
m, 1H), 6.54 (d, J = 15.5 Hz, 1H), 2.37 (s, 3H). C{ H} NMR (101 MHz, CDCl ): δ
3
164.3, 142.4, 140.4, 138.1, 131.8, 129.6, 129.1, 128.0, 124.4, 120.0, 119.8, 21.5.
+
HRMS (ESI): m/z Calc. for C H NO [M+H] : 238.1232; Found: 238.1234.
1
6
16
(E)-N-(4-(dimethylamino)phenyl)-3-(p-tolyl)acrylamide (4b). Following the general
procedure A, the title compound was prepared using (E)-3-(p-tolyl)acrylic acid (1.2
equiv, 0.60 mmol, 97.3 mg) and N,N-dimethyl-4-nitroaniline (1.0 equiv, 0.50 mmol,
8
3.1 mg) using petroleum ether/EtOAc (6:1) as an eluent to give the title compound as
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