A high-efficient method for the amidation of carboxylic acids promoted by triphenylphosphine oxide and oxalyl chloride

Article abstract of DOI:10.1002/hc.21364

A effective amidation reaction of carboxylic acids with various amines promoted by triphenylphosphine oxide and oxalyl chloride under mild and neutral conditions has been developed. The feature of this procedure was the using and recycling of triphenylphosphine oxide at room temperature in 0.5?h. Furthermore a plausible mechanism also be deduced with the help of ³¹P NMR spectroscopy.

Full text of DOI:10.1002/hc.21364

Received: 10 October 2016
DOI: 10.1002/hc.21364
Revised: 12 December 2016
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R E S E A R C H A R T I C L E
A high-efficient method for the amidation of carboxylic acids
promoted by triphenylphosphine oxide and oxalyl chloride
Lixue Jiang
Jing Yu
Fanfan Niu
Derundong Zhang
Xiaoling Sun
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School of Chemical and Environmental
Engineering, Shanghai Institute of
Technology, Shanghai, China
Abstract
A effective amidation reaction of carboxylic acids with various amines promoted by
triphenylphosphine oxide and oxalyl chloride under mild and neutral conditions has
been developed. The feature of this procedure was the using and recycling of triph-
enylphosphine oxide at room temperature in 0.5 h. Furthermore a plausible mecha-
nism also be deduced with the help of 31P NMR spectroscopy.
Correspondence
Xiaoling Sun, School of Chemical and
Environmental Engineering, Shanghai
Institute of Technology, Shanghai, China.
Email: xiaolingsun1@msn.com
Funding information
the Shanghai Alliance Program, Grant/
Award Number: LM 201666; the Shanghai
Students’ Science and Technology
Innovation Activities Key Projects,
Grant/Award Number: SH 2016001; the
Capacity-building Projects in Shanghai
Local Universities, Grant/Award Number:
15120503700
compounds such as PPh3,[9–16] T3P,[17] POCl3,[18] P(OEt)3,[19]
1
INTRODUCTION
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[20]
P(OMe)3
have also been reported, in which the reaction
mediated by PPh3 and halogen has received increasing re-
In nature, amides are fundamental building blocks in syn-
thetic organic chemistry, natural products, pharmaceuticals,
and agrochemicals; amides also have a wide range of applica-
tions in spices, dyes, plastics, textiles, and other industries. In
this regard, the formation of amide bond has been extensively
investigated. Amides are traditionally prepared from carbox-
ylic acids and amines; generally, carboxylic acids should be
preactivated by converting into reactive acid chlorides, an-
hydrides, active esters, or carboxylates before reacting with
amines.[1–6]
search attention. Up to now, halogen sources such as CCl4,[9]
CCl3CN,[10] I2,[11,20] NBS,[12] Br2,[13] BrCCl3[14] and CBr4
[15]
have all been explored. These reactions confirmed that halo-
phosphonium salts (Scheme 1, 1) as the intermediates could
be rapidly generated from PPh3 and halide, and this reagent
was effective to amidation (Scheme 1). However, the con-
comitant generation of stoichiometric compound triphenyl-
phosphine oxide (TPPO) by-products severely affects atom
efficiency and large-scale applicability of these reactions.
To overcome these drawbacks, Mecinovi′c[21] reported an
organocatalytic amide bond formation reaction mediated by
Ph3P/CCl4; in this reaction, TPPO is reduced into Ph3P in
situ (Scheme 2). Such in situ reduction of phosphorus oxides
Phosphonium, phosphinic salts, phosphonic acid deriva-
tives and organophosphorus esters as efficient coupling re-
agents can promote the formation of amides.[7,8] Thus far,
Contract grant sponsor: Shanghai Alliance Program.
Contract grant number: LM 201666.
Contract grant sponsor: Shanghai Students’ Science and Technology
Innovation Activities Key Projects
Contract grant number: SH 2016001.
Contract grant sponsor: Capacity-building Projects in Shanghai Local
Universities
O
Ph
RCOOH
+
R2
C
halide
P
Ph3PX
+
Ph3P=O
R
N
Ph
Ph
R1NHR2
R1
1
(1 eq)
SCHEME 1 PPh3 with halide as coupling reagents for the
Contract grant number: 15120503700.
amidation of carboxylic acids[9–16]
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Heteroatom Chemistry 2017; 00: e21364;
wileyonlinelibrary.com/journal/hc
© 2017 Wiley Periodicals, Inc.
DOI: 10.1002/hc.21364

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reducing agent
TPPO (1 equiv)/(COCl)2 (1.3 equiv) (Table 1, entry 1 and
2) as coupling reagent in toluene at 110°C. TLC analysis
indicated that the reactants were consumed at 0.5 h; a 95%
and 94.5% isolated yields of 4a were obtained, respectively.
The present study further optimized the reaction conditions
through gradually reducing the reaction temperature. Finally,
the desired product 4a exhibited 94% yield even at room
temperature (Table 1, entry 3). Many solvents (THF, CHCl3,
CH2Cl2, 1, 2-dichloroethane, and MeCN) (Table 1, entry 4-8
run1) are effective and the isolated yields of 4a more than
85% in all cases. However, the yield will decrease to 85%
if the ratio of carboxylic acid to amine is 1:1 at room tem-
perature (Table 1, entry 9). Further modification involving
decreasing the loading of TPPO to 50% and 75% had a det-
rimental effect on the yield (Table 1, entry 10 and 11). And
at the end of these reactions, recovery rate of TPPO up to
91%. In addition, after the reaction (Table 1, entry 8 run1)
completed, we added a certain amount of water-absorbing
agent and reactants once again apart from TPPO to reactor.
The yield of 4a can be achieved to 89% after 0.5 h. Hence, a
efficient and convenient method to synthesis of amides be ex-
ploited, in which TPPO can be reused and recycled (Table 1,
entry 8 run2).
O
PPh3 (cat.)
l
CC 4
+
R2
C
+
Ph3P=O
RCO2H
+
R1NHR2
R
N
R1
SCHEME 2 Ph3P/CCl4-promoted amidation of carboxylic acids
followed by in situ reduction[21]
re-use
O
Ph3P=O
(COCl)2
R2
C
RCOOH+ R1NHR2
+ Ph3P=O
R
N
R1
SCHEME 3 TPPO/(COCl)2 applied to the amidation reaction by
use and recycling of TPPO
has been exployed in several catalytic reaction, as the pio-
neer work of catalytic Wittig reaction by O’Brien and co-
workers[22–25], and van Delft et al. developed the first catalytic
Appel and Staudinger reaction[26,27]. This technique is effec-
tive, but its operating cost is high because of the harsh re-
agents and conditions required to regenerate phosphines and
the complexity of the reaction system. Although most studies
focused on the reduction of TPPO to TPP[28–30], we deter-
mining that the practical application of this waste product is
more meaningful and important. Inspired by the conception
of clean chemical reactions and promoted by the application
of TPPO in previous studies[31–55], we hypothesize amidation
reaction can be carried out at more easily and more conve-
niently condition with TPPO and (COCl)2, that bypass the
difficult TPPO reduction with a stoichiometric reductant and
improve the atom efficiency of these reactions by recycle and
re-use of TPPO (Scheme 3).
Montalbetti[3] reported that preparation of acyl chlorides
can be rapid from their corresponding acids and (COCl)2,
moreover acyl chlorides are one of the easiest methods used
to activate acid. Acyl chloride formation are often catalyzed
by DMF, and an additional base is usually required when
amines coupled with acyl chloride[56]. So a control reaction
was established in the presence of 1.3 equiv. of (COCl)2 and
without TPPO; only 25% of 4a were obtained from 2a and
3a even after 20 h at room temperature (Table 1, entry 12).
Moreover, the 1 equiv. of TPPO and absence of (COCl)2 were
tested; only traces of 4a were produced (Table 1, entry 13).
With this protocol, we explored the scope of the car-
boxylic acid substrates promoted by TPPO; the results
are summarized in Table 2. Moderate to excellent yields
were obtained for most cases. Firstly, a diverse set of para-
substituted benzoic acids (Table 2, entry 1-5) reacted with
3a to afford the corresponding amides that exhibit good to
excellent isolated yields (more than 70%) but did not show
an obvious electronic effect. With regard to the substitution
pattern, higher yields were obtained when using chlorine
(Table 2, entry 5) and nitro groups (Table 2, entry 3) in com-
parison with methyl (Table 2, entry 4) and methoxy (Table 2,
entry 2). Furthermore, 1-naphthoic and phenylacetic acids
also proceeded smoothly, affording the corresponding prod-
ucts with good yields (Table 2, entry 6-7). Only heterocyclic
substituted carboxylic acid-picolinic acids showed compara-
tively low conversion (65%) efficiency for the reaction with
benzylamine (Table 2, entry 8). Reactions in the absence of
TPPO afforded lower isolated yields than that with TPPO.
The chemistry of the TPPO/(COCl)2 combination origi-
nally reported in 1977 by Fukui[33]. Then this reaction ex-
ploited by Denton and co-workers in Apple reaction and other
reactions under Apple condition, and Gilheany also used it to
the research of phosphine oxides reductions.[34–44]. however
applied it into the amide reaction rarely mentioned[37,45,46]
,
and high temperatures, complicated procedure and long reac-
tion time are required. Hence, in the present study, we further
exploited the application of TPPO and (COCl)2 and used it to
promote high-efficiently the amidation of carboxylic acids.
2
RESULT AND DISCUSSION
Basing on previous reports[21], we explored reaction condi-
tions with the model reaction between 2a (1 equiv) and 3a
(1.3 equiv) and used TPPO (2 equiv)/(COCl)2 (2 equiv) or
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TABLE 1 Optimization of
triphenylphosphine Oxide promoted
amidation reaction.a
1 eq.
O
1.3eq
O
Ph3PO
+
H
Ph
NH2
Ph
N
H
Ph
Ph
O
(COCl)2
2a
3a
4a
Ph3PO/(COCl)2
(equiv)
Entry
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
2/2
PhMe
PhMe
PhMe
THF
CHCl3
CH2Cl2
C2H4Cl2
MeCN
110
110
25
25
25
25
25
25
95
94.5
94
91
90
88
89
94 run1
89 run2
85
50
86
25
Trace
1/1.3
1/1.3
1/1.3
1/1.3
1/1.3
1/1.3
1/1.3
9c
9
10
11d
12d
1/1.3
MeCN
MeCN
MeCN
MeCN
MeCN
25
25
25
25
25
0.5/1.3
0.75/1.3
0/1.3
1/0
aReaction was carried out with 2a (5 mmol, 1 equiv), 3a (1.3 equiv), solvent (5 mL) at the indicated temperature
for 0.5 h.
bIsolated yield.
c2a (1 equiv) and 3a (1 equiv).
dTime to over 20 h.
This result shows that TPPO facilitated the amide bond for-
mation by generating halophosphonium salts with (COCl)2.
Both aliphatic amines (Table 2, entry 12, 13, 14, 17, 18)
and aromatic amines (Table 2, entry 9, 10, 11, 15, 16) re-
acted with benzoic acid to generate products in good to ex-
cellent yields. Aliphatic amines (cyclohexylamine) can react
with various benzoic acids to produce more than 70% iso-
lated yields (Table 2, entry 12, 17, 18). In addition, aniline
and 4-methoxy aniline that lower nucleophilic characteristics
when compared with aliphatic amines reacted with 2a under
the optimal conditions in 94% and 72% conversion (Table 2,
entry 9, 10). Moreover, the desired amide was obtained when
benzoic acid reacted with secondary amines, including N-
methyl aniline and diethylamine, with 75% and 68% isolated
yields, which demonstrating that the conditions of the present
study are also applicable to the synthesis of tertiary amides
(Table 2, entry 11, 14). Whereas in the control experiments,
only a small amount of amides was formed under the absence
of TPPO even if after 20 h.
previously[9,11,16,19,58,59], a plausible mechanism is deduced as
shown in Scheme 4. Firstly, the solution of TPPO in MeCN
showed a strong singlet at 29.26 ppm (Figure 1, I). Solid
dissolved after addition of oxalyl chloride and a new signal
appearance at 65.26 ppm (Figure 1, II), indicating the for-
mation of chlorotriphenylphosphonium 1 (Godfrey et al.[60]
,
δp=65.5 ppm). After adding benzoic acid 2a for about 5 min,
a new resonance was produced at δ=44.39 ppm (Figure 1,
III). In the end, the addition of 3a resulted in upfield shift
of the resonance (δ=33.14 ppm) (Figure 1, IV). Through the
post-processing, a sharp singlet at 29.26 ppm (Figure 1, I)
appeared again.
3
CONCLUSIONS
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In summary, we successfully developed the triphenylphos-
phine oxide-promoted amidation under mild and neutral con-
ditions, which can be also applied to industry. The reaction
is easy to operate and effective for inactivated aromatic car-
boxylic acids and primary or secondary amines. And we be-
lieve that TPPO can be multiple used through added reactants
one more time to reaction system. Significantly, TPPO was
recyclable and only CO and CO2 wasted in the end of reac-
tion. And a plausible mechanism be derived by tracked the
In order to elucidate the role of TPPO and (COCl)2 and
understand the reaction intermediates, 31P NMR spectros-
copy was used to detect the reaction process (Scheme 4).
On the basis of that halophosphonium salts intermediate 1
[57]
could be generated by the reaction of TPPO and (COCl)2
and intermediates acyl phosphonium 5 have been invoked

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TABLE 2 Scope of the amidation of 2 and 3.a
TABLE 2 (Continued)
O
O
O
H
O
H
Ph3P=O (COCl)2
Ph3P=O (COCl)2
R2
R2
+
+
+
TPPO
+
R
N
R
N
TPPO
N
N
R
R
OH2
R1
OH2
rt, 0.5h, CH3CN,
R2
rt, 0.5h, CH3CN,
R2
R1
R1
R1
2
2
3
4
3
4
Yieldb
(%)
Yieldc
(%)
Yieldb
(%)
Yieldc
Entry
Amides
Products
4s
Entry
Amides
Products
(%)
31d (25e)
19
90
15
O
O
1
4a
94
N
N
H
H
O2N
OCH3
O
aAddition: To solution of Ph3PO (1 equiv) in acetonitrile (3 mL) was added
(COCl)2 (1.3 equiv). After 10 min, 3 (1.3 equiv) in acetonitrile (2 mL) was added
to solution after 2 (5 mmol, 1 equiv) added 5 min later, for 0.5 h at room
temperature.
2
3
4
5
6
4b
91
41(36)
10
N
H
H
3CO
O
4c
4d
4e
4f
81
89
90
81
N
bIsolated yield.
H
O2
N
cThe reaction carried out without TPPO.
dYield was determined by HPLC analysis.
eIsolated yield.
O
36
N
H
H
3C
O
3
reaction with 31P NMR spectroscopy. Due to these issues, the
direct catalytic amidation of non-activated carboxylic acids
with TPPO has attracted our attention. Further investigations
to extend the application of TPPO are underway in our lab-
oratory. Furthermore, in view of this method is simple and
easy to operate, we anticipate our scheme can also be applied
to more useful transformation, eg, the esterification reaction.
N
H
Cl
O
Trace
N
H
O
7
8
4g
4h
74
65
Trace
16
N
H
O
N
H
N
4
EXPERIMENTAL
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O
9
4i
4j
94
72
2
1
N
H
Chemicals were obtained from commercial sources and were
used without further purification. The reaction was monitored
by thin-layer chromatography carried out on silica gel plates
(HSGF 254) and visualized under UV light (245 nm). Column
chromatography was performed on 200-300 mesh silica gel.
OCH3
10
O
N
H
O
11
12
4k
4l
75
86
Trace
16
N
CH3
1
The H NMR spectra were recorded on a Bruker Avance
500 MHz spectrometer using chloroform-d (CDCl3) (δ=7.28)
as the solvent and TMS as an internal standard. 13C NMR spec-
tra were recorded on 125 MHz spectrometer using chloroform-
d (CDCl3) (δ=77.1 ppm) or dimethylsulfoxide-d6 (DMSO-d)
as the solvent with the central peak at 40.0 and TMS as an inter-
nal standard. Chemical shifts were reported in parts per million
(ppm, δ) downfield from TMS. Data was manipulated directly
via a networked PC with appropriate software. Splitting pat-
terns are described as br=broad singlet, s=singlet, d=doublet,
doublet of doublet (dd), t=triplet, q=quartet, m=multiplet.
High-Resolution Mass Spectra (HRMS) were recorded on
a Bruker (Fällanden, Switzerland) SolariX 70 FT ICR-MS
spectrometer. HPLC analysis was performed on a Themo
Scientific Dionex Ultimate 3000 (Waltham, MA, USA) HPLC
system using C18, 5 μm, 120 Å (250×4.6 mm) column with
acetonitrile: water as the mobile phase. Melting points were
determined using Manon, MP120 Automatic melting point ap-
paratus at a heating rate of 1°C /min.
O
N
H
O
13
14
15
4m
4n
4o
80
68
97
3
N
H
O
17
35
N
O
N
H
OCH3
O
16
17
4p
4q
96
70
16
17
N
H
O
N
H
H3CO
O
18
4r
73
13
N
H
Cl

JIAN etIal
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O
(1.3 equiv, 6.5 mmol) in acetonitrile (3 mL) added dropwise.
The reaction was stirred at the same temperature for 0.5 h. The
mixture was diluted with 100 mL of EtOAc, washed with three
50 mL saturated sodium hydrogen carbonate and the separated
organic phase dried over anhydrous Na2SO4. Drying agent re-
moved by filtrated and the solvent were evaporated in vacuo.
Then the yield was then determined via purified by column
chromatography using ethyl acetate / hexane (2:1) as eluent to
give appropriate amide. All amide products presented in the ar-
ticle’s Table 2 are previously known and reported compounds.
Procedure for (Table 1 entry 8 run2): Firstly, TPPO (1.4 g,
5 mmol), CH3CN, (COCl)2 (0.55 mL, 1.3equiv, 6.5 mmol), ben-
zoic acid (1 equiv, 5 mmol), benzylamine (1.3 equiv, 6.5 mmol)
added to the reactor as the previous procedure. Reaction after
half an hour at room temperature, 2 g anhydrous Na2SO4 was
added. Then (COCl)2 (0.55 mL, 1.3 equiv, 6.5 mmol), benzoic
acid (1 equiv, 5 mmol), benzylamine (1.3 equiv, 6.5 mmol)
added one more time. The reaction was stirred at the same tem-
perature for 0.5 h. In the end, the yield was 1.88 g (89%).
R
O
N
R2
P
(COCl)2
Ph
Ph
R1
Ph
δ : 29.26
4
CO+CO2
O
l
C
l
C
P
O
Ph
R
C
l
C
P
Ph
Ph
Ph
Ph
NH
Ph
R1
R2
δ : 33.14
6
δ : 65.26
1
RCOOH
2
COR
O
l
C
H
C
l
P
Ph
Ph
Ph
R1NHR2
δ : 44.39
5
3
4.1.1
N-Benzylbenzamide (4a)
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SCHEME 4 Proposed mechanism of amidation mediated by
TPPO and (COCl)2
The product (0.96 g, 94% yield) was obtained as a white
solid. mp 103.4-104.4°C [Wangngae et al.[61] 104-105°C];
1H NMR (500 MHz, CDCl3): δ 7.82 (d, J = 7.5 Hz, 2H),
7.53 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.38 (t,
J = 9.9 Hz, 4H), 7.33 (dd, J = 8.5, 4.2 Hz, 1H), 6.42 (s, 1H),
4.68 (d, J = 5.6 Hz, 2H); 13C NMR (125 MHz, CDCl3):
δ 167.5, 138.2, 134.3, 131.5, 128.7, 128.5, 127.8, 127.5,
127.0, 44.0; HRMS (FT ICR-MS) m/z: [M+H]+ calcd for
C14H13NO 212.10699; found 212.10694.
4.1.2
N-Benzyl-4-methoxybenzamide (4b)
|
The product (1.11 g, 91% yield) was obtained as a white
solid; mp 127.3-128.7°C [Green et al.[62] 128-130°C]; H
1
NMR (500 MHz, CDCl3): δ 7.78 (d, J = 8.6 Hz, 2H), 7.43-
7.30 (m, 5H), 6.94 (d, J = 8.6 Hz, 2H), 6.33 (s, 1H), 4.66 (d,
J = 5.5 Hz, 2H), 3.87 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ 167.0, 162.2, 138.5, 128.8, 128.7, 127.8, 127.4, 126.6,
113.7, 55.4, 44.0; HRMS (FT ICR-MS) m/z: [M+H]+ calcd
for C15H15NO2 242.11756; found 242.11709.
FIGURE 1 31P NMR spectra for synthesis 4a. I: Ph3PO (1
equiv), MeCN (3 mL). II: after addition of oxalyl chloride (1.3 equiv)
to I. III: 2a (5 mmol, 1 equiv) added to II. IV: 3a (1.3 equiv) in MeCN
(2 mL) was added to solution of III
4.1.3
N-Benzyl-4-nitrobenzamide (4c)
|
The product (1.04 g, 81% yield) was obtained as a light yel-
low solid; mp 139.0-139.9°C [Bahrami et al.[63] 139-140°C];
1H NMR (500 MHz, CDCl3): δ 8.31 (d, J = 8.3 Hz, 2H), 7.98
(d, J = 8.4 Hz, 2H), 7.38 (dd, J = 20.0, 6.1 Hz, 5H), 6.47 (bs,
1H), 4.70 (d, J = 5.5 Hz, 2H); 13C NMR (125 MHz, CDCl3):
δ 165.4, 149.5, 139.9, 137.5, 128.9, 128.2, 127.9, 123.7, 44.4;
HRMS (FT ICR-MS) m/z: [M-H]+ calcd for C14H12N2O3
255.076419; found 255.07993.
4.1
General procedure
|
Triphenylphosphine oxide (1.4 g, 5 mmol) and acetonitrile
(2.0 mL) was added in 50 mL mouth flask, oxalyl chloride
(0.55 mL, 6.5 mmol) was then added dropwise to the hetero-
geneous mixture. The resulting homogeneous, clear solution
was stirred at room temperature for 10 min, at which time the
appropriate acid (1 equiv, 5 mmol) added before the amine

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1.6 Hz, 1H), 7.42 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H), 7.40-
7.32 (m, 4H), 7.29 (t, J = 7.0 Hz, 1H), 4.69 (d, J = 6.1 Hz,
2H); 13C NMR (125 MHz, CDCl3): δ 164.2, 149.8, 148.1,
138.2, 137.3, 128.7, 127.8, 127.4, 122.3, 43.5; HRMS (FT
ICR-MS) m/z: [M+H]+ calcd for C13H12N2O 213.102239;
found 213.10176.
4.1.4
N-Benzyl-p-methylbenzamide (4d)
|
The product (1.01 g, 89% yield) was obtained as a white
solid; mp 133.3-134.1°C [Kim et al.[64] 133-134°C]; 1H
NMR (500 MHz, CDCl3): δ 7.71 (d, J = 8.0 Hz, 2H), 7.38
(d, J = 4.2 Hz, 4H), 7.33 (dd, J = 8.4, 4.1 Hz, 1H), 7.25 (d,
J = 7.8 Hz, 2H), 6.37 (s, 1H), 4.67 (d, J = 5.6 Hz, 2H), 2.42
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 167.4, 141.9, 138.4,
131.5, 129.2, 128.7, 127.8, 127.5, 127.0, 44.0, 21.4; HRMS
(FT ICR-MS) m/z: [M+H]+ calcd for C15H15NO 226.122641;
found 226.12224.
4.1.9
N-Phenylbenzamide (4i)
|
The product (0.93 g, 94% yield) was obtained as a yellow
1
solid; mp 161-162°C [Wangngae et al.[61] 162-163°C]; H
NMR (500 MHz, CDCl3): δ 7.90 (d, J = 7.4 Hz, 2H), 7.84
(s, 1H), 7.67 (d, J = 7.9 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H),
7.52 (t, J = 7.5 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.18 (t,
J = 7.4 Hz, 1H); 13C NMR (125 MHz, DMSO): δ 166.0,
139.6, 135.4, 132.0, 129.2, 129.0, 128.8, 128.1, 124.1, 120.8,
114.3, 40.5, 40.3, 40.1, 40.0, 39.8, 39.6, 39.5; HRMS (FT
ICR-MS) m/z: [M+H]+ calcd for C14H13NO 198.091340;
found 198.09106.
4.1.5
N-Benzyl-4-chlorobenzamide (4e)
|
The product (1.10 g, 90% yield) was obtained as a white
solid; mp 162.7-163.4°C [Green et al.[62] 161-163°C];
1H NMR (500 MHz, CDCl3): δ 7.75 (d, J = 8.4 Hz, 2H),
7.43 (d, J = 8.4 Hz, 2H), 7.41-7.30 (m, 5H), 6.37 (s, 1H),
4.66 (d, J = 5.6 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ
166.4, 137.9, 137.8, 132.7, 128.8, 128.4, 127.9, 127.7, 44.2;
HRMS (FT ICR-MS) m/z: [M+H]+ calcd for C14H12NOCl
246.068018; found 246.06766.
4.1.10
N-(4-methoxyphenyl)benzamide (4j)
|
The product (0.81 g, 72% yield) was obtained as a white
solid; mp 154.1-155.0°C [Duangkamol et al.[67] 153-154°C];
1H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 7.4 Hz, 2H), 7.75
(s, 1H), 7.56 (d, J = 7.3 Hz, 3H), 7.51 (t, J = 7.5 Hz, 2H),
6.94 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H); 13C NMR (125 MHz,
DMSO) δ 165.5, 156.0, 135.5, 132.7, 131.8, 128.8, 128.0,
122.4, 114.2, 55.6; HRMS (FT ICR-MS) m/z: [M+H]+ calcd
for C14H13NO 228.10191; found 228.10134.
4.1.6
N-Benzyl-1-naphthamide (4f)
|
The product (1.06 g, 81% yield) was obtained as a white
solid; mp 124.3-124.8°C [Kim et al.[64] 120-122°C]; 1H
NMR (500 MHz, CDCl3): δ 8.38 (d, J = 8.3 Hz, 1H), 7.92
(dd, J = 24.2, 8.1 Hz, 2H), 7.59 (m, J = 22.2, 18.5, 7.2 Hz,
3H), 7.52-7.31 (m, 6H), 6.30 (s, 1H), 4.77 (d, J = 5.6 Hz, 2H);
13C NMR (125 MHz, CDCl3): δ 169.4, 138.1, 134.2, 133.7,
130.7, 130.1, 128.8, 128.3, 127.8, 127.6, 127.1, 126.4, 125.4,
124.9, 124.6, 44.0; HRMS (FT ICR-MS) m/z: [M+H]+ calcd
for C18H15NO 262.12264; found 262.12232.
4.1.11
N-menthyl-N-phenylbenzamide (4k)
|
The product (0.79 g, 75% yield) was obtained as a light yel-
low oily liquid; H NMR (500 MHz, CDCl3): δ 7.27 (d,
1
J = 7.3 Hz, 2H), 7.15 (dd, J = 10.3, 5.0 Hz, 3H), 7.12-7.03
(m, 3H), 6.99 (d, J = 7.6 Hz, 2H), 3.44 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 170.6, 144.8, 135.9, 129.5, 129.1,
128.6, 127.7, 126.8, 126.4, 38.3; HRMS (FT ICR-MS) m/z:
[M+H]+ calcd for C14H13NO 212.10699; found 212.10648.
4.1.7
N-Benzyl-2-phenylacetamide (4g)
|
The product (0.84 g, 75% yield) was obtained as a white solid;
mp 120.9-121.4°C [Valeur and Bradley[65] 119-121°C]; H
1
NMR (500 MHz, CDCl3): δ 7.37 (t, J = 7.3 Hz, 2H), 7.34-
7.26 (m, 6H), 7.20 (d, J = 7.3 Hz, 2H), 5.78 (s, 1H), 4.43 (d,
J = 5.7 Hz, 2H), 3.65 (s, 2H); 13C NMR (125 MHz, CDCl3):
δ 170.9, 138.1, 134.8, 129.4, 129.0, 128.6, 127.5, 127.4,
127.4, 43.8, 43.6; HRMS (FT ICR-MS) m/z: [M+H]+ calcd
for C15H15NO 226.122641; found 226.12232.
4.1.12
N-Cyclohexyl Benzamide (4l)
|
The product (0.87 g, 86% yield) was obtained as a white
solid; mp 143.4-143.9°C [Wangngae et al.[61] 143-144°C]; 1H
NMR (500 MHz, CDCl3): δ 7.77 (d, J = 7.3 Hz, 2H), 7.51 (t,
J = 7.3 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 5.97 (s, 1H), 4.12-
3.89 (m, 1H), 2.06 (d, J = 9.4 Hz, 2H), 1.78 (d, J = 13.4 Hz,
2H), 1.68 (d, J = 12.9 Hz, 1H), 1.46 (dd, J = 25.0, 12.4 Hz,
2H), 1.34-1.24 (m, 3H); 13C NMR (125 MHz, CDCl3): δ
166.6, 135.1, 131.2, 128.4, 126.8, 48.7, 33.2, 25.5, 24.9;
HRMS (FT ICR-MS) m/z: [M+H]+ calcd for C13H17NO
204.138291; found 204.13761.
4.1.8
(4h)
N-Benzyl-2-pyridinecarboxamide
|
The product (0.69 g, 65% yield) was obtained as a light
yellow solid; mp 81.0-81.9°C [Lamar and Liebeskind[66]
1
81°C]; H NMR (500 MHz, CDCl3): δ 8.53 (d, J = 4.3 Hz,
1H), 8.44 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.85 (td, J = 7.7,

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|
(125 MHz, CDCl3): δ 166.1, 161.9, 128.6, 127.3, 113.6, 55.3,
48.6, 33.3, 25.6, 24.9; HRMS (FT ICR-MS) m/z: [M+H]+
calcd for C14H19NO2 234.148855; found 234.148994.
4.1.13
N-Isopropylbenzamide (4m)
|
The product (0.64 g, 80% yield) was obtained as a white
solid; mp 98.0-98.9°C [Liang et al.[68] 99-101°C]; H NMR
1
(500 MHz, CDCl3): δ 7.77 (d, J = 7.4 Hz, 1H), 7.50 (t,
J = 7.3 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 5.98 (s, 1H), 4.44-
4.18 (m, 1H), 1.28 (d, J = 6.6 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 166.8, 134.9, 131.2, 128.4, 126.9, 41.9, 22.7;
HRMS (FT ICR-MS) m/z: [M+H]+ calcd for C10H13NO
164.106990; found 164.106151.
4.1.18
4-Chloro-N-cyclohexylbenzamide (4r)
|
The product (0.86 g, 73% yield) was obtained as a white
solid; mp 187.7-188.5°C [Wangngae et al.[61] 186-187°C];
1H NMR (500 MHz, CDCl3): δ 7.71 (d, J = 8.3 Hz, 2H),
7.42 (d, J = 8.4 Hz, 2H), 5.94 (s, 1H), 4.07-3.89 (m, 1H),
2.05 (d, J = 9.8 Hz, 2H), 1.78 (d, J = 13.4 Hz, 2H), 1.67
(d, J = 24.1 Hz, 1H), 1.45 (dd, J = 25.0, 12.3 Hz, 2H), 1.25
(dd, J = 23.5, 10.9 Hz, 3H); 13C NMR (125 MHz, CDCl3):
δ 165.6, 137.4, 133.4, 128.7, 128.3, 48.8, 33.1, 25.5, 24.9;
HRMS (FT ICR-MS) m/z: [M+H]+ calcd for C13H16NOCl
238.099318; found 238.099117.
4.1.14
N, N-Diethylbenzamide (4n)
|
The product (0.60 g, 68% yield) was obtained as colourless
oil liquid; 1H NMR (500 MHz, CDCl3): δ 7.34 (s, 5H), 3.50
(s, 2H), 3.21 (s, 2H), 1.21 (s, 3H), 1.06 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 171.2, 137.1, 129.0, 128.3, 126.1, 43.2,
39.2, 14.1, 12.8; HRMS (FT ICR-MS) m/z: [M+H]+ calcd
for C14H13NO 178.122641; found 178.122048.
4.1.19
N-(4-methoxybenzyl)-4-
|
nitrobenzamide1 (4s)
The product (1.28 g, 90% yield) was obtained as a light yel-
low solid; mp 136.5-137.0°C; 1H NMR (500 MHz, CDCl3):
δ 8.29 (d, J = 8.6 Hz, 2H), 7.96 (d, J = 8.6 Hz, 2H), 7.34-
7.27 (m, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.47 (s, 1H), 4.61 (d,
J = 5.4 Hz, 2H), 3.83 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ 165.2, 159.4, 149.6, 140.0, 129.4, 128.1, 123.8, 114.3,
55.3, 44.0; HRMS (FT ICR-MS) m/z: [M+H]+ calcd for
C14H13NO 287.102633; found 287.101863.
4.1.15
N-(4-Methoxybenzyl)benzamide (4o)
|
The product (1.17 g, 97% yield) was obtained as a white solid;
mp 94.9-95.9°C [Kim et al.[64] 95-97°C]; 1H NMR (500 MHz,
CDCl3): δ 7.80 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.4 Hz, 1H),
7.42 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 6.89 (d,
J = 8.6 Hz, 2H), 6.58 (s, 1H), 4.58 (d, J = 5.6 Hz, 2H),
3.81 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 167.3, 159.1,
134.4, 131.5, 130.3, 129.2, 128.5, 126.9, 114.1, 55.3, 43.6;
HRMS (FT ICR-MS) m/z: [M+H]+ calcd for C15H15NO2
242.117555; found 242.11701.
ACKNOWLEDGEMENTS
The work was supported by the Shanghai Alliance Program
(No. LM 201666), the Shanghai Students’ Science and
Technology Innovation Activities Key Projects (SH 2016001)
and the Capacity-building Projects in Shanghai Local
Universities (No. 15120503700). The authors are grateful to
the Shanghai Institute of Technology for providing laboratory.
4.1.16
N-Phenethylbenzamide (4p)
|
The product (1.11 g, 98% yield) was obtained as a white
solid; mp 116.7-117.4°C [Boehner et al.[69] 113-116°C]; H
1
NMR (500 MHz, CDCl3): δ 7.71 (d, J = 7.3 Hz, 2H), 7.50 (t,
J = 7.3 Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.35 (t, J = 7.3 Hz,
2H), 7.27 (t, J = 7.0 Hz, 3H), 6.25 (s, 1H), 3.74 (q, J = 6.7 Hz,
2H), 2.96 (t, J = 6.8 Hz, 2H); 13C NMR (125 MHz, CDCl3):
δ 167.5, 138.9, 134.6, 131.4, 128.8, 128.7, 128.5, 126.8,
126.6, 41.1, 35.7; HRMS (FT ICR-MS) m/z: [M+H]+ calcd
for C15H15NO 226.12264; found 226.12199.
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Additional Supporting Information may be found online in
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How to cite this article: Jiang L, Yu J, Niu F, Zhang D,
and Sun X. A high-efficient method for the amidation of
carboxylic acids promoted by triphenylphosphine oxide
and oxalyl chloride. Heteroatom Chem.
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2017;00:e21364. doi:10.1002/hc.21364.