Me2NSO2Cl and N,N-dimethylamines; a novel and efficient agent for esterification, amidation between carboxylic acids, and equimolar amounts of alcohols and amines

Article abstract of DOI:10.1016/S0040-4039(01)01444-7

Various carboxylic esters or amides were prepared in good to excellent yields between carboxylic acids and equimolar amounts of alcohols or amines under very mild conditions using dimethylsulfamoyl chloride (Me₂NSO₂Cl) combined with N,N-dimethylamines. The choice of the sulfamoyl chloride and the amine is crucial for the reactions.

Full text of DOI:10.1016/S0040-4039(01)01444-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7427–7430
Me2NSO2Cl and N,N-dimethylamines; a novel and efficient
agent for esterification, amidation between carboxylic acids, and
equimolar amounts of alcohols and amines
Kazunori Wakasugi, Atsushi Nakamura and Yoo Tanabe*
School of Science, Kwansei Gakuin University, 1-1-155 Uegahara, Nishinomiya, Hyogo 662-8501, Japan
Received 2 July 2001; revised 1 August 2001; accepted 3 August 2001
Abstract—Various carboxylic esters or amides were prepared in good to excellent yields between carboxylic acids and equimolar
amounts of alcohols or amines under very mild conditions using dimethylsulfamoyl chloride (Me2NSO2Cl) combined with
N,N-dimethylamines. The choice of the sulfamoyl chloride and the amine is crucial for the reactions. © 2001 Elsevier Science Ltd.
All rights reserved.
Mild and effective esterification or amidation of car-
boxylic acids with alcohols or amines has been exten-
sively examined due to their wide utility in organic,
bioorganic, and related fine-chemical syntheses.1 There
are many methods for esterification and/or amidation
using specific dehydrating reagents under mild liquid-
phase conditions; DCC,2 halopyridinium salts,3 2,4,6-
trichlorobenzoyl chloride,4 N,N-carbonyldiimidazaole,5
BOP-Cl,6 DPC,7 DPTC,8 and several other condensa-
tion agents.9
cially available sulfonyl chlorides and tertiary amines.
Methanesulfonyl chloride (MeSO2Cl) is the most obvi-
ous candidate, and indeed a study using MeSO2Cl
together with Et3N has been reported,9g this method,
however, has two serious problems. Reexamination in
our hands revealed that high yields reported were not
reproducible; over 4 equiv. of each MeSO2Cl and Et3N
were required to complete the esterification (reported
account; 1 equiv. of MeSO2Cl and 2 equiv. of Et3N).
We assume that the first step for a mixed-anhydride
formation does not proceed smoothly, i.e. concomitant
loss of Me2SO2Cl considerably occurs due to the unde-
sirable side sulfene-dimerization.11 Moreover, there was
an unavoidable critical side reaction of mesylation of
alcohols.
From the recent standpoint of a green chemical require-
ment, there still exists the request of a simpler, more
convenient, inexpensive, and less toxic agent, particu-
larly between carboxylic acids and equimolar amounts
of alcohols or amines. Consistent with our interest in
green chemical esterification,10 we introduce here a
novel efficient condensation agent, dimethylsulfamoyl
chloride (Me2NSO2Cl; 1) together with N,N-dimethy-
lamines (Me2NR: 2a; R=Me 2b; R=Bu) (Scheme 1).
To overcome the problem, we planned the use of
Me2NSO2Cl (1) instead of MeSO2Cl, because 1 lacks
a-hydrogens, which causes the undesirable sulfene-
dimerization. The initial trial of esterification of 3-
phenylpropanoic acid with an equimolar amount of
1-octanol resulted in 34% yield using 1 (2.0 equiv.)
First, we focused our attention on the use of commer-
R1CO2SO2NMe2
R1CO2H (1.0 eq.)
Me2NSO2Cl (1) (2.0 eq.)
+
R2OH
cat. DMAP (0.1 eq.)
R1CO2R2
+
R2OH (1.0 eq.)
Me2NR (2) (3.0 eq.)
+
Me2NRH+.Cl-
Scheme 1.
Keywords: esterification; amidation; sulfamoyl chloride; tertiary amine; chemoselective.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01444-7

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K. Wakasugi et al. / Tetrahedron Letters 42 (2001) 7427–7430
combined with Et3N (3.0 equiv.) in MeCN at 0–5°C.
To activate 1, Me3N·HCl (3.0 equiv.) was added for in
situ generation of Me3N (2a; bp 2.9°C). Thus, the yield
markedly increased up to 86%.12 DMAP (0.1 equiv.)
should be added in order to enhance the second
acylation step (up to 93%, Table 1, entry 1). The only
amine used during the first step, N,N-dimethylbutyl-
amine (BuNMe2, 2b) also promoted the esterification at
45–50°C (92%).
esters of primary and secondary alcohols were prepared
in good to excellent yields under the two unified condi-
tions. Several functionalities on alcohols such as a
double and a triple bond, a halogen, and an ester were
tolerated (entries 2, 3, 7, and 8). Higher yields were
generally obtained compared with the report using
halopyridinium salts method.3a Unfortunately, steri-
cally crowded substrates such as pivalic acid and t-
butyl alcohol did not produce high yields.14 E-Crotonic
acid, a base sensitive substrate (leading to easy isomer-
ization) underwent this esterification with keeping good
stereochemistry.
Based on these results, esterifications between several
carboxylic acids and alcohols were performed.13 The
Table 1. Esterification between carboxylic acids and equimolar amounts of alcohols
R1CO2H
Entry
Methoda)
R2OH
Yield / %
93
92
A
B
CO2H
1
OH
OH
Ph
A
B
95
92
2
A
B
91
93
OH
3
4
A
B
90
94
OH
OH
Ph
Ph
A
B
A
B
A
B
86
86
80
80
91
90
5
6
7
PhOH
Cl
OH
OH
A
B
90
88
8
9
EtO2C
95b)
94b)
A
B
OH
96b,c)
94b,c)
A
B
10
OH
CO2H
A
B
93
92
90b)
94b)
11
12
OH
A
B
OH
A
B
92
92
91b)
92b)
CO2H
OH
13
14
A
B
OH
A
B
73 (E : Z = 10 : 1)
71 (E : Z = 7 : 1)
CO2H
15
OH
a
A: Use of Me3N·HCl (2a·HCl)/Et3N, 0–5°C, 3 h, MeCN solvent. B: Use of BuNMe2 (2b), 40–45°C, 1 h, MeCN solvent.
b DMAP (1.0 equiv.) was used.
c [h]2D3 −59.5 (c 1.47, CHCl3).

K. Wakasugi et al. / Tetrahedron Letters 42 (2001) 7427–7430
7429
The salient features are as follows. (1) Me2NSO2Cl (1)
and the amines used are relatively cheap and commer-
cially available, structurally simple (atom-economic),
and 1 is less hygroscopic among sulfonyl chlorides. (2)
N,N-Dimethyl structure in 2a and 2b is crucial, except
for the case of DABCO, because our previous studies
of green chemical sulfonylations suggest that such less
hindered amines significantly activate the sulfonyl chlo-
rides during the first mixed-anhydride formation.15 (3)
This agent had very high chemoselectivity toward the
carboxyl group versus the hydroxyl group, namely, the
experiment could be performed with the addition of
both carboxylic acids and alcohols. This chemoselectiv-
ity was rarely observed using other sulfonyl chloride
reagents. Thus, the experimental procedure is simple
and convenient, and, moreover, would ensure the lac-
tonization reaction of v-hydroxyl carboxylic acids.
yields in every case examined. It should be noted that
no substantial isomerization occurs in the case using
E-crotonic acid (entries 6 and 7). Synthetic application
to the synthesis of a certain biologically active natural
product is now in progress.
In conclusion, useful esterification and amidation were
achieved using the combined reagents, Me2NSO2Cl (1)
and Me2NR (2a; R=Me 2b; R=Bu). This method has
merits of the operational simplicity, economy in use of
reagents and substrates, and reactivities, which rival
those reported for related condensation agents.
Acknowledgements
This research was partially supported by a Grant-in-
Aid for Scientific Research on Priority Areas (A)
‘Exploitation of Multi-Element Cyclic Molecules’ and
Basic Areas (C) from the Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan.
This protocol could be also extended to an amidation
reaction between carboxylic acids and equimolar
amounts of primary or secondary amines (Table 2).16
The present reaction proceeded with good to excellent
Table 2. Amidation between carboxylic acids and equimolar amounts of amines
R1CO2H (1.0 eq.)
Me2NSO2Cl (1) (2.0 eq.) / Me2NR (2) (3.0 eq.)
R1CONR2R3
+
R2R3NH (1.0 eq.)
cat. DMAP (0.1 eq.) / MeCN
Methoda)
R1CO2H
R2R3NH
Entry
Yield / %
95b)
96b)
A
B
CO2H
1
2
Ph
Ph
NH2
96
97
A
B
tBuNH2
A
B
92
93
3
N
H
CO2H
CO2H
92
92
A
B
4
5
6
7
N
H
90
94
A
B
N
H
88c) (E only)
92c) (E only)
tBuNH2
A
B
CO2H
90c) (E only)
93c) (E only)
A
B
N
H
a
A: Use of Me3N·HCl (2a·HCl)/Et3N, 0–5°C, 3 h, MeCN solvent. B: Use of BuNMe2 (2b), 40–45°C, 1 h, MeCN solvent.
b [h]2D4 −54.0 (c 1.01, CHCl3).
c DMAP (1.0 equiv.) was used.

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K. Wakasugi et al. / Tetrahedron Letters 42 (2001) 7427–7430
10. Wakasugi, K.; Misaki, T.; Yamada, K.; Tanabe, Y.
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under reduced pressure before use. General procedure of
method A: Me3N·HCl (2.00 mmol) was added to a stirred
solution of a carboxylic acid (1.00 mmol), an alcohol
(1.00 mmol), Et3N (3.00 mmol), and DMAP (0.10 mmol)
in MeCN (1.0 ml) at 0–5°C under an Ar atmosphere, and
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16. General procedure of method A: An amine (1.00 mmol),
Et3N (3.00 mmol), and DMAP (0.10 mmol) in MeCN
(1.0 ml) was added to a stirred solution of a carboxylic
acid (1.00 mmol), Me3N·HCl (2.00 mmol), and
Me2NSO2Cl (1; 2.00 mmol) in MeCN (1.0 ml) at 0–5°C
under an Ar atmosphere, and the mixture was stirred at
that temperature for 3 h. A similar work-up procedure as
described above gave the desired amide.
Method B: Amines (1.00 mmol), BuNMe2 (3.00 mmol)
and DMAP (0.10 mmol) in MeCN (1.0 ml) was added to
the stirred solution of a carboxylic acid (1.00 mmol) and
Me2NSO2Cl (1; 2.00 mmol) in MeCN (1.0 ml) at 45–50°C
under an Ar atmosphere, and the mixture was stirred at
that temperature for 3 h. A similar work-up procedure as
described above gave the desired amide.