Amidation reaction of carboxylic acid with formamide derivative using SO3?pyridine

Article abstract of DOI:10.1246/cl.171216

The amidation reaction of carboxylic acid derivatives was developed using sulfur trioxide pyridine complex (SO₃?py) as a commercially available and easily handled oxidant. This method could be applied to the reaction of various aromatic and aliphatic carboxylic acids, including optically active ones, with formamide derivatives to afford the corresponding amides in good to high yields.

Full text of DOI:10.1246/cl.171216

CL-171216
Received: December 27, 2017 | Accepted: January 22, 2018 | Web Released: March 30, 2018
Amidation Reaction of Carboxylic Acid with Formamide Derivative Using SO3¢pyridine
Shota Kawano, Kodai Saito, and Tohru Yamada*
Department of Chemistry, Keio University, Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
E-mail: yamada@chem.keio.ac.jp
The amidation reaction of carboxylic acid derivatives was
Transition metal-catalyzed approach
developed using sulfur trioxide pyridine complex (SO3¢py) as a
O
O
cat. [Cu]
Oxidant
O
commercially available and easily handled oxidant. This method
could be applied to the reaction of various aromatic and aliphatic
carboxylic acids, including optically active ones, with form-
amide derivatives to afford the corresponding amides in good to
high yields.
R2
R2
N
R3
H
R1
N
R3
R1 OH
Metal-free amide synthesis by sulfur-containing reagent
Sulfinyl-amine mediated activation of carboxylic acid
(by Mukaiyama et al.)
Keywords: Amidation
| Sulfur oxide | Metal-free synthesis
R2
H
O
N
R2
Amides widely exist in various natural products, useful
pharmaceuticals, as well as in important synthetic building
blocks. Due to their importance and broad applications, a variety
of methodologies for their synthesis have been developed.1
However, traditional synthetic routes to amides usually require
multiple steps, and toxic or expensive reagents. For these reasons,
considerable effort has been made for developing efficient and
economically friendly methods, which are still highly desirable.
A carboxylic acid is one of the most ideal substrates of
amide synthesis. Recently, the Cu-catalyzed amidation reaction
using carboxylic acid derivatives with formamide derivatives
was reported by several research groups (Scheme 1).2 As
a seminal work, Reddy’s group reported the Cu-catalyzed
amidation reaction of various carboxylic acids with N,N-dialkyl
formamide derivatives using tert-butyl hydroperoxide (TBHP)
as a re-oxidant.2a After this report, although the Cu-catalyzed
oxidative coupling was frequently used,2b-2d the development
of other methods was not fully achieved.2e In particular, there
is concern over metal contamination for the transition metal
catalyzed methodologies. Thus, the development of alternative
approaches toward amides is highly desirable, and in this
context, transition-metal-free protocols appear particularly more
attractive.
A carboxylic acid could be generally activated either by
transformation into more reactive derivatives or by the use of
condensation reagent under transition-metal-free conditions.3
Among several works for the metal-free synthesis of amides
using a carboxylic acid as the starting material, the use of a
sulfur-containing reagent that mediated the in situ activation
of carboxylic acids is one of the representative approaches
(Scheme 1). Mukaiyama et al. reported sulfinyl amine mediated
amidation reaction of carboxylic acids with secondary amines.4
However, the generality of this method was not fully inves-
tigated, and it was needed to prepare the sulfinyl amine.
Although Olah’s group also reported SO2ClF-mediated method,5
and Kumagai and Kawase more recently developed SOCl2-
mediated conversion of carboxylic acid to amides,6 these sulfur
oxide derivatives are toxic and moisture sensitive. Among sulfur
oxide derivatives,7 sulfur trioxide pyridine complex (SO3¢py) is
a solid substance and could be easily available from commercial
sources and handled on the bench. Although the formation of an
acylated sulfuric acid as an intermediate in the reaction with an
O
S
R1
O
NR2
O
R2N
NR2
R2
S
R1
N
R1 OH
O
O
R2
SO2
HNR2
Sulfuryl chloride fluoride mediated synthesis of amide
(by Olah et al.)
R2
H
N
O
O
S
SO2ClF R1
O
O
R2
R2
F
R1
N
R2
R1 OH
O
O
SO2, HF
Thionyl chloride mediated synthesis of amide
(by Kumagai and Kawase et al.)
O
O
O
O
SOCl2
R1
N
N
H
Cl
Cl
N
H
R1 OH
R1 Cl
This study
Transition-metal free amidation from carboxylic acid with
formamide derivative
O
O
O
SO3•py
R2
R2
N
H
R1
N
R1 OH
R3
R3
Scheme 1. Related studies for the synthesis of an amide from a
carboxylic acid and this study.
aliphatic carboxylic acid with SO3 is known, the application of
this intermediate to convert to an amide has not been reported.8
We now wish to report SO3¢py mediated amide synthesis using
carboxylic acid as the starting material. A wide substrate scope
was confirmed for the synthesis of aromatic, aliphatic, and
optically active amides.
We initially selected 4-(trifluoromethyl)benzoic acid 1a as
the model substrate and treated it with (NH4)2S2O8 in DMF.9 At
first, we examined the effect of the reaction temperature. When
this reaction was carried out at 120 °C, no reaction was observed
(Table 1, Entry 1). When this reaction was done at 140 °C, the
corresponding amide 2a was obtained in 42% and 1a was
recovered in 56% yield (Entry 2). Although a higher temperature
was employed for this reaction to improve the conversion of
584 | Chem. Lett. 2018, 47, 584–586 | doi:10.1246/cl.171216
© 2018 The Chemical Society of Japan

SO3•py
(4 equiv)
Table 1. Examination of reaction conditions
O
O
O
O
R1
R1
O
Oxidant
H
N
R2
Ar
N
Alk
OH
160 oC
2 d
(X equiv)
Me
R2
1
N
R
OH
2
(0.1 mmol)
(0.5 mL)
DMF (0.5 mL)
temp.
F3C
F3C
2 d
O
O
(0.1 mmol)
O
2a: R = Me
3a: R = H
1a
Me
Me
Me
Ph
N
Ph
N
Ph
N
Me Me
2n
quant
Me
Me
X
Temp Yield of 2a Yield of 3a RSM
2m
97%
Entry Oxidant
2o
97%
/equiv /oC
/%a
/%a
/%a
1
2
3
4
5
6
7
8c
9
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
K2S2O8
H2SO4
SO3¢py
SO3¢py
none
2
2
2
4
4
4
4
4
®
120
140
160
160
160
160
160
160
160
No reaction
Me
Me
N
O
42
30
56
47
81
96b
95b
15
0
6
13
23
0
0
0
4
56
18
8
24
4
0
0
80
N
Me
Me PMP
Me
n-C8H17
N
O
O
2r
Me
Br
2p
86%
2q
93%
quantb
O
Me
N
Me
N
Ph
Me
Et
Me
Ph
N
O
O
Me
2s
Et
2t
2u
aNMR yields. bIsolated yields. c1,2-Dichlorobenzene (DCB)
was used as co-solvent (DCB:DMF = 3:2, 0.5 mL).
92%
90%
77%
O
O
O
N
Et
N
Ph
N
Ph
Table 2. Generality of amidation of aromatic carboxylic acids
O
Et
O
Br
2w
81%b
SO3•py
2v
95%
2x
78%b
O
O
O
(4 equiv)
160 o
2 d
R1
R1
H
N
R2
Ar
N
R2
Ar
OH
C
O
O
1
Bn
2
(0.1 mmol)
(0.5 mL)
Ph
N
n-C8H17
N
Me
R1
R2
2
Yielda
O
Entry
Ar
2z
quantc
2y
81%b
1
2
4-CF3C6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
4-PhC6H4
1-Naphthyl
2-IC6H4
2-MeC6H4
3-HOC6H4
4-CF3C6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
2a
96
quant
87
82
87
83
quant
97
63
74
2b
2c
2d
2e
2f
2g
2h
2i
3b
4b
5b
6b
7
Figure 1. Generality of amidation of conjugated and aliphatic
carboxylic acids. aIsolated yields. bDCB:formamides = 3:2
(0.5 mL) was used. cN-Benzyl-N-methylformamide (0.3 mL)
was used. PMP = 4-methoxyphenyl.
O
O
Cbz
N
Cbz
N
8
9b
10
SO3•py (4 equiv)
OH
N
DMF(0.5 mL)
160-150 oC, 3 d
2j
4
5
11
4-CF3C6H4
2k
84
79
O
N
(0.1 mmol, >99% ee)
12b,c
4-NO2C6H4
Me
Bn
2l
O
O
O
Cbz
HN
Cbz
Cbz
aIsolated yields. 1,2-Dichlorobenzene (DCB) was used as a
co-solvent (DCB:formamides = 3:2, 0.5 mL). 150 °C.
b
N
N
HN
N
N
c
5c
5a
5b
the starting material, the yield of 1a decreased, involving
the formation of the side-product 3a (Entry 3). The use of
4 equivalents of (NH4)2S2O8 resulted in the improvement of the
yield of 2a and the conversion of 1a, however, the production of
3a increased (Entry 4). Next, we investigated the effect of sulfur
oxides. Although the significant formation of 3a was observed
in the case of K2S2O8 (Entry 5), the use of H2SO4 and SO3¢py
dramatically improved the efficiency of this amidation reaction
to furnish 2a in 81% and 96% yields, respectively (Entries 6 and
7).10-12 As another available conditions, we discovered that 1,2-
dichlorobenzene could be used as a co-solvent for this reaction
and the amount of DMF could be reduced by approximately
half (Entry 8).13 We studied the thermally-induced background
reaction in the absence of the sulfur oxide, revealing that the
48%, 94% ee
(150 oC)
72%, >99% ee
28%, >99% ee
(150 oC)
(160 oC)
Figure 2. Amidation of amino acids.
reaction was highly accelerated by the addition of the sulfur
oxide (Entry 9). Finally, we concluded that Entries 7 and 8 were
the optimal conditions.
With the optimized reaction conditions in hand, the scope
of the aromatic carboxylic acid in SO3¢py mediated amidation
reaction was next examined using various formamide derivatives
(Table 2). The reaction of an aromatic carboxylic acid bearing
an electron-withdrawing group 1b smoothly provided 2b
quantitatively. Electron-donating group substituted aromatic
Chem. Lett. 2018, 47, 584–586 | doi:10.1246/cl.171216
© 2018 The Chemical Society of Japan | 585

carboxylic acids were also applicable to give the corresponding
amides 2c and 2d in good yields under similar reaction
conditions. Substitution of a phenyl group and fused aromatic
ring, such as the 1-naphthyl structure, did not affect the
efficiency of this amidation. Substrates 2g and 2h bearing an
ortho-substituted aromatic ring also displayed high reactivities.
3-Hydroxybenzoic acid 1i could be directly transformed into 2i
without the protection of the hydroxy group. N,N-Diethylform-
amide, 4-formylmorpholine and N-benzyl-N-methylformamide
were also applicable for this reaction as an amidation reagent to
give the corresponding amides 2j-2l in good yields.
Next, we investigated the scope of the amidation reaction
using various conjugated and aliphatic carboxylic acids
(Figure 1). Cinnamic acid and its derivative were successfully
converted to the corresponding amides 2m and 2n in high yields.
Substrates 1o and 1p bearing simple alkyl groups, such as
phenethyl and n-octyl, were also applicable. Benzyl amide
derivatives containing various functional groups and the
substrate bearing a quaternary carbon center at the α-position
were tolerant to the conditions, furnishing 2q-2s in high yields.
These substrates could be applied to the amidation reactions
with other amidation reagents to give 2t-2z in good yields.
A further substrate scope was explored by using amino acid
derivatives (Figure 2). When N-Cbz-L-proline was employed for
this reaction, the corresponding amide 5a was obtained in good
yields without any loss of the enantiomeric excess.14,15 Although
N-CBz-L-valine and N-CBz-L-alanine were not efficiently con-
verted to amides, the ees of the starting materials were highly
retained under the optimized conditions.
Hobbs, H. Weingarten, J. Org. Chem. 1970, 35, 1542. c) T.
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T. Mukaiyama, H. Takei, H. Shimizu, Bull. Chem. Soc. Jpn.
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4
5
6
7
8
9
a) W. E. Truce, C. E. Olson, J. Am. Chem. Soc. 1953, 75,
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1980, 285.
Examination of amidation reaction using dialkyl amine as
amine source resulted in failure. Therefore, DMF was used
as dimethyl amine source.
In summary, we have established SO3¢py based conditions
for the amidation of aromatic and aliphatic carboxylic acid with
various formamide derivatives. Using this protocol, the corre-
sponding amides were obtained in good to high yields.
Elucidation of the detailed reaction mechanism and exploration
of further application of this method are currently underway in
our laboratory.
10 Although H2SO4 is one of the most ideal sulfur oxides and
we extensively examined the reaction conditions using
H2SO4, side products 3 (N-methyl amides) were significantly
observed in the reactions of aromatic carboxylic acids
bearing an electron-donating group such as 1c and 1d.
11 We also investigated on the effect of the addition of H2O
(10 equivalents) under the condition based on Entry 7 in
Table 1, in which the yield of 2a dramatically decreased.
12 According to previous reports,8 the reaction of sulfur
trioxide with a carboxylic acid proceeds to afford the
corresponding acylated sulfuric acid intermediate. The
intermediate would react with DMF under high temperature,
involving the release of carbon monoxide and sulfuric acid,
to furnish the amide.
13 It was found that DCB was the best for this reaction after co-
solvent screening. However, the effect of DCB is not clear.
14 When L-proline was employed for this reaction, no reaction
was observed. Therefore, we used N-protected amino acids
as the substrates.
15 After several examinations of the reaction temperature and
time using an amino acid derivative as a substrate, it turned
out that the yield tends to be improved by performing the
reaction at a slightly lower temperature (150 °C) and longer
reaction time (3 d) in some cases. The enantiomeric excess
did not change below 160 °C.
Supporting Information is available on http://dx.doi.org/
10.1246/cl.171216.
This communication is dedicated to Professor Teruaki
Mukaiyama in celebration of his 90th birthday.
References and Notes
1
For selected reviews of amide synthesis, see: a) E. Valeur,
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catalyzed amidation reaction of α-keto acids, see: e) X.
Zhang, W. Yang, L. Wang, Org. Biomol. Chem. 2013, 11,
3649.
2
3
Representative examples, see: a) J. C. Sheehan, G. P. Hess,
J. Am. Chem. Soc. 1955, 77, 1067. b) J. D. Wilson, C. F.
586 | Chem. Lett. 2018, 47, 584–586 | doi:10.1246/cl.171216
© 2018 The Chemical Society of Japan