A novel method for the one-pot conversion of carboxylic acids to N,N-dimethylamides

Article abstract of DOI:10.1007/s13738-012-0112-5

A simple, efficient, and new method has been developed for the preparation of N,N-dimethylamides from carboxylic acids. As described below, treatment of a variety of aromatic carboxylic acids with N,N-dimethylsulfamoyl imidazole or N,N-dimethylsulfamoyl chloride in the presence of a mixture of methanesulfonic acid/phosphorus pentoxide (2:1, v/w) proceeded effectively to afford the corresponding N,N-dimethylamides inmoderate to good yields. Thismethod is easy, rapid, and good yielding for the synthesis of N,N-dimethylamides from carboxylic acids. Iranian Chemical Society 2012.

Full text of DOI:10.1007/s13738-012-0112-5

J IRAN CHEM SOC (2012) 9:951–955
DOI 10.1007/s13738-012-0112-5
ORIGINAL PAPER
A novel method for the one-pot conversion of carboxylic acids
to N,N-dimethylamides
•
Babak Kaboudin Hamideh Haghighat
Received: 12 March 2012 / Accepted: 16 May 2012 / Published online: 5 June 2012
Ó Iranian Chemical Society 2012
Abstract A simple, efficient, and new method has been
developed for the preparation of N,N-dimethylamides from
carboxylicacids. Asdescribed below, treatment ofa variety of
aromatic carboxylic acids with N,N-dimethylsulfamoyl
imidazole or N,N-dimethylsulfamoyl chloride in the presence
of a mixture of methanesulfonic acid/phosphorus pentoxide
(2:1, v/w) proceeded effectively to afford the corresponding
N,N-dimethylamides in moderate to good yields. This method
is easy, rapid, and good yielding for the synthesis of
N,N-dimethylamides from carboxylic acids.
chloride is known as the Vilsmeier complex, which is a
good reagent for the chlorination of carboxylic acids [9].
Thionyl chloride, as a traditional chlorinating reagent in the
Vilsmeier complex, is corrosive in moist air. An alternative
and efficient method for the synthesis of N,N-dimethyla-
mides is to use carboxylic acids and dimethyl amine in the
presence of coupling reagents [10]. Tetrakis dimethylami-
nosilane in an anhydrous solvent at high temperature has
been used for the preparation of N,N-dimethylamides from
carboxylic acids [11]. Recently, Kumagai et al. reported a
new and efficient procedure by one-pot tandem chlorina-
tion and amidation reaction of carboxylic acid in DMF in
the presence of thionyl chloride at 150 °C for 5 h. In this
method, chlorination and amidation of carboxylic acid
subsequently occurred in a one-pot manner [12]. Recently,
Keywords N,N-Dimethylamide Á Carboxylic acids Á
Imidazole Á Methanesulfonic acid Á One-pot
Introduction
a novel process has been reported for preparing
N,N-dimethylacetamide (DMAC) by continuously reacting
methyl acetate (MeOAc) with dimethylamine (DMA) in
the presence of a basic catalyst [13]. Although a variety of
synthetic methods have been reported for the synthesis of
N,N-dimethylamides, a simple method that uses simple
starting materials is still lacking.
N,N-Dimethylamides are valuable intermediates in organic
synthesis [1, 2]. The synthesis of N,N-dimethylamides is an
important objective in organic synthesis, since they have
found use in the preparation of biologically active mole-
cules, and also as a versatile intermediate in organic syn-
thesis [3–7]. The most typical and industrial method for the
easy preparation of N,N-dimethylbenzamide is the heating
of commercially available benzoyl chloride at 150 °C in
DMF for a long time [8]. The acid chlorides for this
method are prepared from the corresponding carboxylic
acids using chlorination reagents such as thionyl chloride.
A mixture of N,N-dimethylformamide (DMF) and thionyl
N,N-dimethylsulfamoyl imidazole, prepared by the
reaction of N,N-dimethylsulfamoyl chloride with imidazole
[14], is a very applicable, protective imidazole precursor
[15–19]. To the best of our knowledge, there is no report in
the literature of the use of N,N-dimethylsulfamoyl imid-
azole in organic transformations. In continuation of our
interest in developing novel methodologies for organic
transformations [20–33], herein we report an efficient,
practical, and moderate to good-yielding method for the
one-pot synthesis of N,N-dimethylamides from carbox-
ylic acids using N,N-dimethylsulfamoyl imidazole or
N,N-dimethylsulfamoyl chloride in the presence of a mixture
of methanesulfonic acid/phosphorus pentoxide (2:1, v/w).
B. Kaboudin (&) Á H. Haghighat
Department of Chemistry, Institute for Advanced
Studies in Basic Sciences (IASBS), Gava Zang,
45137-66731 Zanjan, Iran
e-mail: kaboudin@iasbs.ac.ir
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J IRAN CHEM SOC (2012) 9:951–955
N,N-Dimethyl-4-chlorobenzamide (2b)
Experimental
Chemicals and apparatus
White solid; mp 56–58 °C [Lit. mp 56–57 °C] [12, 13] 1H
NMR (CDCl3, 400 MHz): 2.98 (s, 3H), 3.11 (s, 3H),
7.30–7.38 (m, 4H). 13C NMR (CDCl3, 100 MHz): 35.4,
39.5, 128.6, 131.2, 134.6, 135.5, 170.5.
All chemicals were commercial products and distilled or
recrystallized before use. NMR spectra were taken with a
400-MHz Brucker Avance instrument with the chemical
shifts reported as d ppm and couplings expressed in Hertz.
N,N-Dimethyl-4-methylbenzamide (2c)
Colorless viscous oil [34]; 1H NMR (CDCl3, 400 MHz): 2.17
(s, 3H), 2.77 (s, 3H), 2.89 (s, 3H), 7.00 (d, 2H, J = 8.0 Hz),
7.13(d, 2H, J = 8.0 Hz). 13C NMR (CDCl3, 100 MHz): 21.1,
35.1, 39.4, 127.0, 128.7, 133.2, 139.3, 171.4.
Procedure for the preparation
of N,N-dimethylsulfamoyl imidazole
This compound was obtained according to the method
reported in the literature [14]. To a solution of 0.14 mol of
imidazole (9.54 g) in 50 mL of CHCl3, triethyl amine
(18 mL, 0.13 mol) and N,N-dimethylsulfamoyl chloride
(13 mL) were added. The reaction mixture was stirred
overnight at RT. After stirring, the reaction mixture was
washed with H2O (50 mL). The organic layer was then
concentrated to a small volume under vacuum, diluted with
normal hexane, and shaken vigorously by hand. A white
precipitate was at once formed and recovered by filtration
with 92 % yield. White solid; mp: 47–49 °C [Lit. mp
48–51 °C] [14]; 1H-NMR (CDCl3, 400 MHz): 2.87 (s,
6H), 7.16 (s, 1H), 7.28 (s, 1H), 7.92 (s, 1H), 13C-NMR
(CDCl3, 100 MHz): 38.5, 117.9, 131.5, 138.
N,N-Dimethyl-4-nitrobenzamide (2d)
Yellow solid [34], mp 88–90 °C 1H NMR (CDCl3,
400 MHz): 2.97 (s, 3H), 3.15 (s, 3H), 7.60 (d, 2H,
J = 8.8 Hz), 8.28 (d, 2H, J = 8.4 Hz). 13C NMR (CDCl3,
100 MHz): 35.3, 39.3, 123.8, 128.2, 142.4, 148.2, 169.2.
N,N-Dimethyl-3-methylbenzamide (2e)
1
Colorless viscous oil [34]; H NMR ((CDCl3, 400 MHz):
2.25 (s, 3H), 2.85 (s, 3H), 2.98 (s, 3H), 7.06–7.17 (m, 4H).
13C NMR (CDCl3, 100 MHz): 21.2, 35.1, 39.4, 123.8,
127.5, 128.0, 130.1, 136.2, 138.0, 171.6.
General procedure for the conversion of carboxylic
acids to N,N-dimethylamides (2) using
N,N-dimethylsulfamoyl imidazole
N,N-Dimethyl-3-fluorobenzamide (2f)
Yellow viscous oil [34]; 1H NMR (CDCl3, 400 MHz): 2.82
(s, 3H), 2.94 (s, 3H), 6.92–7.26 (m, 4H). 13C NMR (CDCl3,
100 MHz): 35.1, 39.2, 38.1, 114.0, 114.2, 116.2, 116.4,
122.7, 130.1, 138.3, 162.2 (d, JFC = 250 Hz), 169.9.
or N,N-dimethylsulfamoyl chloride
Carboxylic acid (5 mmol) was added to a stirred mixture of
methanesulfonic acid (5 mL) and phosphorus pentoxide
(2.5 g) at 70 °C. N,N-Dimethylsulfamoyl imidazole or
N,N-dimethylsulfamoyl chloride (6 mmol) was added to
the reaction mixture and the mixture was stirred for 8–12 h
at 90 °C. The resultant solution was cooled to room tem-
perature and quenched with ice water (30 ml). The reaction
mixture was extracted with ethyl acetate (2 9 50 ml). The
combined organic layer was washed with NaOH (30 mL,
5 %), dried over anhydrous Na2SO4 and filtered. The fil-
trate was concentrated in vacuo to obtain the pure product
without more purification with 47–73 % yields. All prod-
ucts gave satisfactory spectral data in accordance with the
assigned structures and literature reports.
N,N-Dimethyl-3-chlorobenzamide (2g)
1
Yellow viscous oil [4]; H NMR (CDCl3, 400 MHz): 2.95
(s, 3H), 3.08 (s, 3H), 7.60–7.38 (m, 4H). 13C NMR (CDCl3,
100 MHz): 35.3, 39.5, 125.1, 127.2, 129.6, 129.8, 134.3,
137.9, 170.0.
N,N-Dimethyl-2-formylbenzamide (2h)
1
Yellow viscous oil [5]; H NMR (CDCl3, 400 MHz): 2.80
(s, 3H), 3.17 (s, 3H), 7.36–7.93 (m, 4H), 10.04 (s, 1H). 13
C
NMR (CDCl3, 100 MHz): 35.0, 38.6, 127.1, 129.3, 130.6,
132.5, 134.3, 138.6, 169.5, 190.8.
N,N-Dimethylbenzamide (2a)
N,N-Dimethyl-2,3-dimethylbenzamide (2i)
1
Colorless viscous oil [34]; H NMR (CDCl3, 400 MHz):
2.79 (s, 3H), 2.92 (s, 3H), 7.22 (s, 5H). 13C NMR (CDCl3,
1
Yellow viscous oil [6]; H NMR (CDCl3, 400 MHz): 2.13
100 MHz): 35.2, 39.5, 126.9, 128.2, 129.5, 135.7, 171.6.
(s, 3H), 2.23 (s, 3H), 2.78 (s, 3H), 3.09 (s, 3H), 6.95–7.29
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J IRAN CHEM SOC (2012) 9:951–955
953
(m, 3H). 13C NMR (CDCl3, 100 MHz): 16.0, 20.0, 34.5,
38.4, 123.3, 125.8, 130.0, 132.2, 137.4, 137.6, 172.1.
methanesulfonic acid (Entry 6). The reaction failed to give
2a using methanesulfonic acid at 90 °C for 24 h. Surpris-
ingly, as shown in Table 1, the conversion of benzoic acid
to N,N-dimethylbenzamide was generally completed in a
mixture of methanesulfonic acid and phosphorus pentoxide
at 90 °C after 8 h in the presence of N,N-dimethylsulfa-
moyl imidazole (Entry 8). The reaction failed to give 2a
using a mixture of methanesulfonic acid and phosphorus
pentoxide at 110 °C in the presence of dimethyl formamide
as an amine source, without the presence of N,N-dim-
ethylsulfamoyl imidazole (Entry 9).
N,N-Dimethyl-2-naphthylcarbamide (2j)
Colorless viscous oil [12, 13]; 1H NMR (CDCl3,
400 MHz): 3.06 (s, 3H), 3.24 (s, 3H), 7.53–7.94 (m, 7H).
13C NMR (CDCl3, 100 MHz): 35.4, 39.7, 124.4, 126.6,
126.8, 127.0, 127.8, 128.2, 128.4, 132.6, 133.6, 133.6,
171.6.
To study the scope and limitations of the reaction, var-
ious carboxylic acids were subjected to the treatment with
N,N-dimethylsulfamoyl imidazole in a mixture of me-
thanesulfonic acid and phosphorus pentoxide at 90 °C
(Table 2). As shown in Scheme 2 and Table 2, the reaction
of a mixture of aromatic carboxylic acids with N,N-dim-
ethylsulfamoyl imidazole in a mixture of methanesulfonic
acid and phosphorus pentoxide at 90 °C afforded the cor-
responding amides in good yields (2a–2i). 2-Naphthyl-
carboxylicacid, asa polynuclear aromaticacid, alsoreactedto
give N,N-dimethyl-2-naphthylcarbamide in 68 % isolated
yield (2j). The reaction of aliphatic carboxylic acids using
N,N-dimethylsulfamoyl imidazole in a mixture of methane-
sulfonic acid and phosphoruspentoxide at90 °C failed to give
the corresponding amide (Entries 11 and 12). The reactions
were clean and no tar formation was observed.
Results and discussion
Initially, treatment of benzoic acid (1a) with N,N-dim-
ethylsulfamoyl imidazole in a variety of condition was
chosen as a model reaction (Table 1; Scheme 1). In the
absence of any solvent, benzoic acid did not undergo the
conversion reaction with N,N-dimethylsulfamoyl imidazole
at 50 and 100 °C (Entries 1 and 2). The reaction failed if
solvents such as dichloromethane were used (Entry 3). Only
\5 % of product 2a was detected using acetonitrile or
toluene as solvent after 24 h at reflux (Entries 4 and 5). A
mixture of methanesulfonic acid and phosphorus pentoxide
has been reported as an efficient medium for organic
compounds [35]. Therefore we decided, for the first
attempt, to investigate the reaction of benzoic acid with
N,N-dimethylsulfamoyl imidazole in the presence of
The reaction of a mixture of methanesulfonic acid and
phosphorus pentoxide media is easy and clean (simple
washing with water). It is suggested that the intermediate 3
may be generated in situ by treatment of a carboxylic acid
with N,N-dimethylsulfamoyl imidazole in the presence of a
mixture of methanesulfonic acid and phosphorus pentoxide
(in situ generation of methanesulfonic anhydride via dehy-
dration of methanesulfonic acid in the presence of phosphorus
pentoxide) [36] followed by decomposition and SO3 removal
to produce N,N-dimethylamide (Scheme 2).
Table 1 Reaction of benzoic acid with N,N-dimethylsulfamoyl
imidazole under various condition
Entry Solvent
Temperature (°C) Time (h) Yielda (%)
1
2
3
4
5
6
7
8
9
a
–
50
24
24
24
24
24
24
12
8
–
–
100
–
CH2Cl2
CH3CN
Toluene
MeSO3H
MeSO3H/P2Ob5 70
MeSO3H/P2O5 90
MeSO3H/P2O5 110
Reflux
Reflux
Reflux
90
–
\5
\5
–
Interestingly, we found that N,N-dimethylsulfamoyl
chloride was also capable of converting carboxylic acids
to N,N-dimethylamides (2) in the presence of a mixture
of methanesulfonic acid and phosphorus pentoxide
(Scheme 3; Table 2). It is suggested that the intermediate 3
may be generated in situ by treatment of a carboxylic acid
with N,N-dimethylsulfamoyl chloride in the presence of a
mixture of methanesulfonic acid and phosphorus pentoxide
followed by decomposition and SO3 removal to produce
N,N-dimethylamide (Scheme 3).
45
73
c
24
–
Isolated yield
b
MeSO3H/P2O5 (2:1, v/w)
c
In the presence of DMF, without N,N-dimethylsulfamoyl imidazole
O
C
O
C
O
S
Me
Me
Me
Me
In summary, simple, mild reaction conditions, good
yields and relatively clean reactions with no tar formation
make this method an attractive and useful contribution to
present methodologies. An easily handled air-stable solid
reagent, N,N-dimethylsulfamoyl imidazole or N,N-dim-
ethylsulfamoyl chloride, was introducedas a novel reagent for
+
OH
N
N
N
N
O
2a
1a
Scheme 1 Reaction of benzoic acid with N,N-dimethylsulfamoyl
imidazole
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954
J IRAN CHEM SOC (2012) 9:951–955
Table 2 Conversion of carboxylic acids to N,N-dimethylamides using of N,N-dimethylsulfamoyl imidazole and N,N-dimethylsulfamoyl
chloride in the presence of a mixture of methanesulfonic acid/phosphorus pentoxide (2:1, v/w) at 90 °C
Entry
R
Time
Product
Yield %a
Yield (%)a using
N,N-dimethylsulfamoyl
chloride
1
C6H5-
8
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
73
68
59
47
52
52
61
58
47
68
–
68
65
54
45
55
47
56
55
55
65
–
2
p-ClC6H4–
3
p-MeC6H4–
p-NO2C6H4–
m-MeC6H4–
m-FC6H4–
12
8
4
5
12
8
6
7
m-ClC6H4–
o-OHCC6H4–
2,3-Me2C6H3–
b-Naphthyl
1-Adamantyl
C6H5-CH2CH2–
8
8
12
12
12
12
12
9
10
11
12
a
2j
–
–
–
–
Yields refer to the isolated pure products
Scheme 2 Conversion of
carboxylic acids to
N,N-dimethylamides
O
O
O
Me
O
O
S
Me
Me
Me
Me
-SO3
R
C
N
+
R
C
OH
N
S
N
R
C
O
N
N
Me
O
O
2
1
3
O
O
S
MeSO3H + P2O5
Me
S
O
Me
O
O
Scheme 3 Reaction
of carboxylic acids with N,N-
dimethylsulfamoyl chloride
O
C
O
O
C
O
S
O
C
Me
Me
Me
Me
-SO3
R
OH +
Cl
S
N
R
O
N
R
N
Me
Me
O
O
1
2
3
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8–12 h to give 47–73 % isolated yield of the product. The
same reaction, reported in the literature, gave 34–89 % yield
of the product by using a mixture of thionyl chloride and DMF
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