Novel and efficient method for esterification, amidation between carboxylic acids and equimolar amounts of alcohols, and amines utilizing Me2NSO2Cl and N,N-dimethylamines; Its application to the synthesis of coumaperine, a natural chemopreventive dieneamide

Article abstract of DOI:10.1016/S0040-4020(03)00734-8

Various carboxylic esters or amides were prepared in good to excellent yield between carboxylic acids and equimolar amounts of alcohols or amines under very mild conditions (0-45°C; within 3 h) using dimethylsulfamoyl chloride (Me₂NSO₂Cl; 1) combined with N,N-dimethylamines (Me₂NR: 2a; R=Me, 2b; R=Bu). The choice of the sulfamoyl chloride and the amine is crucial for the reaction; that is, sterically uncrowded amines accelerated the present esterification and amidation. This agent had some advantages over methanesulfonyl chloride (3)/amines as for the atom-economy, avoidance of side reactions, and had very high chemoselectivity toward the carboxyl group vs the hydroxyl group; the experiment was performed by the addition of 1 to the mixture of carboxylic acids and alcohols. Application of this method to the synthesis of coumaperine, a chemopreventive natural product, was performed using the present amidation as a key step.

Full text of DOI:10.1016/S0040-4020(03)00734-8

Tetrahedron 59 (2003) 5337–5345
Novel and efficient method for esterification, amidation between
carboxylic acids and equimolar amounts of alcohols, and
amines utilizing Me2NSO2Cl and N,N-dimethylamines;
its application to the synthesis of coumaperine,
a natural chemopreventive dieneamide
Kazunori Wakasugi,a Atsushi Nakamura,a Akira Iida,a Yoshinori Nishii,a Nobuji Nakatani,b
Shoji Fukushimac and Yoo Tanabea
,
*
aDepartment of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan
bLaboratory of Chemistry, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-0022, Japan
cFirst Department of Pathology, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-0022, Japan
Received 23 April 2003; revised 3 May 2003; accepted 6 May 2003
Abstract—Various carboxylic esters or amides were prepared in good to excellent yield between carboxylic acids and equimolar amounts of
alcohols or amines under very mild conditions (0–458C; within 3 h) using dimethylsulfamoyl chloride (Me2NSO2Cl; 1) combined with N,N-
dimethylamines (Me2NR: 2a; R¼Me, 2b; R¼Bu). The choice of the sulfamoyl chloride and the amine is crucial for the reaction; that is,
sterically uncrowded amines accelerated the present esterification and amidation. This agent had some advantages over methanesulfonyl
chloride (3)/amines as for the atom-economy, avoidance of side reactions, and had very high chemoselectivity toward the carboxyl group vs
the hydroxyl group; the experiment was performed by the addition of 1 to the mixture of carboxylic acids and alcohols. Application of this
method to the synthesis of coumaperine, a chemopreventive natural product, was performed using the present amidation as a key step. q 2003
Elsevier Science Ltd. All rights reserved.
1. Introduction
for simpler, more convenient, inexpensive, and atom-
economical agents. The mixed anhydride method using
different counter acids is recognized as a rational process.
The method using counter sulfonyl mixed anhydrides with
carboxylic acids is a promising candidate due to its
simplicity, availability, and economy.
From the standpoint of elaborated complex natural product
synthesis and process chemistry, mild and effective
esterification or amidation between equimolar amounts of
carboxylic acids and alcohols or amines is one of the most
frequently used unit reactions due to its broad utility.1
Several efficient methods have been exploited for the
esterification and/or amidation using specific dehydrating
reagents under mild liquid-phase conditions; 1,3-dicyclo-
hexylcarbodiimide (DCC),2 halopyridinium salts,3 2,4,6-
trichlorobenzoyl chloride,4 (Im)2CO (N,N-carbonyldiimida-
zole),5 bis(2-oxo-3-oxazoilodinyl)phosphinic chloride
(BOP-Cl),6 di-2-pyridyl carbonate (DPC),7 di-2-pyridyl
thiocarbonate (DPTC),8 2-methyl-6-nitrobenzoic anhydride
(MNBA)9 and other condensation agents.10
Consistent with our interests in green chemical esterifica-
tions,11 sulfonylations,12 and silylations,13 we have reported
some methods for smooth sulfonylations of alcohols using
sulfonyl chlorides promoted by the sterically unhindered
amines such as Me3N and Me2N(CH2)nNMe2, wherein
these amines significantly activate sulfonyl chlorides with
formation of the reactive sulfonylammonium chloride
intermediates. We describe the full details14 of a novel
efficient condensation agent for esterification and amida-
tion, dimethylsulfamoyl chloride (Me2NSO2Cl; 1) together
with sterically unhindered N,N-dimethylamines (Me2NR:
2a; R¼Me, 2b; R¼Bu) (Scheme 1), and its application to
the synthesis of coumaperine, a naturally occurring
bioactive compound, using the present amidation method
as a key step.
In view of green chemistry, there still remains a strong need
Keywords: esterification; amidation; sulfamoyl chloride; tertiary amine;
coumaperine.
*
Corresponding author. Tel.: þ81-795-65-8394; fax: þ81-795-65-9077;
e-mail: tanabe@kwansei.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00734-8

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K. Wakasugi et al. / Tetrahedron 59 (2003) 5337–5345
Scheme 1.
2. Results and discussion
Although this reaction necessitated somewhat excess
amounts of the condensation reagents, application of the
conditions in Table 1 resulted in successful esterifications in
good to high yields (Table 2).
We focused on the mixed anhydride formation between
carboxylic acids and sulfonyl chlorides, because some
sulfonyl chlorides are more inexpensive and atom-economic
than acid chlorides such as 2,4,6-trichlorobenzoyl chloride.4
Thus, use of commercially available sulfonyl chlorides and
tertiary amines was initially examined.
The method using MsCl (3), however, was not chemose-
lective, that is, not applicable to the case of co-existence of
acids and alcohols; methanesulfonate 10 was produced as a
major by-product as exemplified in Eq. 1 of Scheme 2.
Moreover, in the case of amidation using 3-phenylpropanoic
acid with 1-phenethylamine produced not only the desired
amide 11 but also sulfonamide 12, which was apparently
derived from the sulfene-dimerization,15 even following the
standard procedure shown in Tables 1 and 2 (Eq. 2).
Methanesulfonyl chloride (MsCl; 3) is the most obvious
candidate, and a study using 3 together with Et3N has been
reported.10g As shown in Table 1, reexamination of this
method in our hands revealed that the high yields previously
reported were not reproducible; excess amounts of 3
(2.0 equiv.) and Et3N (4.0 equiv.) were required for
esterification (reported account; 1 equiv. of 3 and 2 equiv.
of Et3N at 2108C in THF solvent). Thus, we assumed that
the first step of the mixed-anhydride formation does not
proceed smoothly, i.e. considerable concomitant loss of 3
occurs due to undesirable side sulfene-dimerization.15 The
addition of Me3N·HCl to more basic Et3N for in situ
generation of Me3N (2a; bp 2.98C) and the use of 1.0 equiv.
of N,N-dimethylaminopyridine (DMAP) significantly
improved the yield, wherein 2a enhanced the reactivity of
3 and DMAP accelerated the acylation step.
To overcome these problems, we planned the use of
Me2NSO2Cl (1) instead of MsCl (3), because 1 lacks a-
hydrogens, which cause the undesirable sulfene-dimeriza-
tion. The initial trial of esterification of 3-phenylpropanoic
acid with an equimolar amount of 1-octanol resulted in 34%
yield using Et3N (3.0 equiv.) in MeCN at 0–58C—room
temperature (Table 3). The use of Me3N·HCl (2a·HCl) also
affected the present esterification, and the yield markedly
increased up to 86%. The addition of DMAP (0.1 and
1.0 equiv.) enhanced the second acylation step up to 93 and
Table 1. Esterification between 3-phenylpropanoic acid and equimolar amounts of 1-octanol using MsCl (3)/amines
MsCl
(3)
(equiv.)
Et3N
(equiv.)
Me3N·HCl
(2a·HCl)
(equiv.)
Solvent
Yield
(%)
1.2
1.2
1.2
1.2
1.2
2.0
2.0
2.0
3.6
3.6
3.6
3.6
3.6
4.5
4.5
4.5
None
None
None
1.2
3.6
4.5
Toluene
THF
Trace
Trace
20
48
60
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
4.5
4.5
83* a
92* b
a
DMAP (0.1 equiv.) was used in the second step.
DMAP (1.0 equiv.) was used in the second step.
b

K. Wakasugi et al. / Tetrahedron 59 (2003) 5337–5345
5339
Table 2. Esterification between carboxylic acids and equimolar amounts of alcohols using MsCl (3)/amines
R1CO2H
R2OH
Product
Yield (%)
92 (80)* a
93
4
5
6
91
7
8
89
94
9
93
a
Without DMAP.
97%, respectively. (Note: After finishing this work, we have
recently found that DMAP was replaced by more inexpen-
sive and less toxic 1-methylimidazole for the acylation
step. See Table 3 and Experimental Section 3.5.) The only
amine used, N,N-dimethylbutylamine (BuNMe2, 2b) in the
place of Et3N and 2a·HCl, also promoted esterification at
40–45 8C (92%). Results of the screening of other amines
with DMAP (0.1 equiv.) under identical conditions were as
follows; DABCO16 (82%), TMEDA (63%), DBU (42%),
and PhCH2NMe2 (31%). MeCN was a better solvent than
toluene or THF.
Based on these results, esterifications between several
carboxylic acids and alcohols were successfully performed
(Table 4). The esters of primary and secondary alcohols
were prepared in good to excellent yields under the two
unified conditions. Several functionalities on alcohols such
as a double and a triple bond, a halogen, and an ester were
tolerated. Higher yields were generally obtained compared
with those reported using the halopyridinium salts method.3a
This reaction is so mild that E-crotonic acid, a base-sensitive
substrate (leading to easy isomerization) underwent esterifica-
tion and maintained good stereochemistry. Unfortunately,
Scheme 2.

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K. Wakasugi et al. / Tetrahedron 59 (2003) 5337–5345
Table 3. Esterification between 3-phenylpropanoic acid and equimolar amounts of 1-octanol using Me2NSO2Cl (1)/amines
Me2NSO2Cl
(equiv.)
Et3N
(equiv.)
Me3N·HCl
(equiv.)
DMAP
(equiv.)
Yield
(%)
2.0
2.0
2.0
2.0
1.5
2.0
2.0
2.0
2.0
3.0
3.0
3.0
3.0
2.5
3.0
–
–
–
34
86
93
97
88
92
31
79
92* b
2.0
2.0
2.0
1.5
2.0
–
0.1
1.0
1.0
1.0* a
–
3.0 (BnNMe2)
3.0 (BuNMe2)
3.0 (BuNMe2)
–
–
0.1
0.1
a
Use of 1-methylimidazole instead of DMAP.
Reaction temperature; 45–508C.
b
sterically crowded substrates such as pivalic acid and t-butyl
alcohol did not produce high yields. The yields were 40%
between pivalic acid and 1-octanol and only trace amounts
between 3-phenylpropanoic acid and t-butyl alcohols.
experiment could be performed with the addition of 1 into
the mixture of carboxylic acids and alcohols. This
chemoselectivity is rarely observed using other sulfonyl
chloride reagents. Thus, the experimental procedure is
simple and convenient, and would ensures the lactonization
reaction of v-hydroxyl carboxylic acids.
The salient features are as follows: (i) Me2NSO2Cl (1) and
the amines used are relatively inexpensive and commer-
cially available, structurally simple, and atom-economical,
and 1 is slightly less hygroscopic among sulfonyl chlorides.
(ii) The N,N-dimethyl structure in 2a and 2b is crucial,
except for the case of DABCO,16 because our previous
studies of green chemical sulfonylations suggest that such
less-hindered amines significantly activate the sulfonyl
chlorides during the first mixed-anhydride formation.12
(iii) This agent had very high chemoselectivity toward the
carboxyl group vs the hydroxyl group, namely, the
This protocol could also be extended to an amidation
reaction between carboxylic acids and equimolar amounts
of primary or secondary amines (Table 5). The present
reaction proceeded with good to excellent yield in every
case examined. It should be noted that no substantial
isomerization occurred when using E-crotonic acid.
Finally, we describe an application to natural product
synthesis. Coumaperine (34) is a dieneamide isolated from
Scheme 3.

K. Wakasugi et al. / Tetrahedron 59 (2003) 5337–5345
5341
Table 4. Esterification between various carboxylic acids and equimolar amounts of alcohols using Me2NSO2Cl (1)/amines (2a or 2b)
R1CO2H
R2OH
Method* a
Product
Yield (%)
A
B
93
92
4
A
B
95
92
5
A
B
91
93
6
A
B
90
94
13
A
B
86 (69)* b
86
14
15
A
B
80 (61)* b
80
PhOH
A
B
91
90
16
17
A
B
90
88
A
B
95* c
94* c
7
8
A
B
96* c
94* c
9
A
B
93
92
A
B
90* c
94* c
18
19
PhCO2H
A
B
92
92
A
B
91* c
92* c
20
21
A
B
73* d
71* e
a
A: use of Me3N·HCl (29·Hcl)/Et3N, 0–58C, 3 h. B: use of BuNMe2 (2b), 40–458C, 1 h.
Parantheses indicate the reported data using 2-chloro-1-methylpyridinium iodide.
b
c
d
e
DMAP (1.0 equiv.) was used.
E/Z¼10:1.
E/Z¼7:1.
Piper nigrum L. (white pepper), and is present at a
rich carboxylic acid 32, which was recrystallized from 2-
propanol to give pure a,b-E, g,d-E acid 32.
concentration of approximately 6 ppm in dry fruit.17 There
was notable antioxidative activity of 34 against linoleic
acid oxidation.17b A recent study indicates that 34 has
significant chemopreventive activity in rats carcinogen-
esis.18 These informations prompted us to synthesize
coumaperine (34) using the present amidation as a key
step (Scheme 3).
The present essentially neutral amidation of 32 with
piperidine proceeded successfully in 90% yield (compared
to 76% with small amounts of polymer by the method using
2-chloro-1-methylpyridinium iodide under standard con-
ditions3a). Finally, the deprotection of MOM with conc. HCl
gave coumaperine (34) (purity; 99.8% by HPLC analysis) in
52% overall yield.
Methoxymethyl (MOM) protection of 4-hydroxybenzalde-
hyde (29) followed by the Wadsworth–Horner–Emmons
reaction using methyl 4-phosphono-2-butenoate (30)
afforded the a,b-E, g,d-E rich diene ester 31 in a one-pot
procedure. Hydrolysis of methyl ester 31 gave a,b-E, g,d-E
In conclusion, practical esterification and amidation were
achieved using the combined reagents, Me2NSO2Cl (1) and
Me2NR (2a; R¼Me, 2b; R¼Bu). This method has the

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K. Wakasugi et al. / Tetrahedron 59 (2003) 5337–5345
Table 5. Amidation between various carboxylic acids and equimolar amounts of primary or secondary amines using Me2NSO2Cl (1)/amines (2a or 2b)
R1CO2H
R2R3NH
Method* a
Product
Yield (%)
A
B
95
96
22
23
24
A
B
96
97
tBuNH2
A
B
92
93
92
92
A
B
25
26
A
B
90
94
PhCO2H
A
B
88* b,c
92* b,c
tBuNH2
27
28
A
B
90* c
93* c
a
A: use of Me3N·HCl (2a·HCl)/Et3N, 0–58C, 3 h. B: use of BuNMe2 (2b), 40–458C, 1 h.
DMAP (1.0 equiv.) was used.
E only.
b
c
advantages of being the mild conditions (0–458C; within
compounds: 1-octyl 3-phenylpropanoate (4);11d 2-octyl 3-
phenylpropanoate (7);19 1-octyl cyclohexanecarboxylate
(9);20 2-phenylethyl 3-phenylpropanoate (13);21 benzyl 3-
phenylpropanoate (14);22 phenyl 3-phenylpropanoate
(15);23 1-octyl benzoate (19);24 2-octyl benzoate (20);25
N-[(S)-1-phenylethyl]-3-phenylpropionamide (22);26 N-
(1,1-dimethylethyl)-3-phenylpropionamide (23);27 N-(3-
phenylpropionoyl)piperidine (24);28 N-(cyclohexanecarbo-
nyl)piperidine (25);29 N-(benzoyl)piperidine (26);30 N-(2E-
butenoyl)piperidine (28).31
3 h), chemoselective, operationally simple, reagent econ-
omical, and has good reactivity. These characteristics rival
those reported for related condensation agents.
3. Experimental
3.1. General
Melting points were determined on a hot-stage microscope
apparatus (Yanagimoto) and are uncorrected. NMR spectra
were recorded on a JEOL ALPHA 400 or DELTA 300
spectrometer, operating at 400 or 300 MHz for 1H NMR and
100 MHz for 13C NMR. Chemical shifts (d ppm) in CDCl3
were reported downfield from TMS (¼0) for 1H NMR. For
13C NMR, chemical shifts were reported in the scale relative
to CDCl3 (77.00 ppm) as an internal reference. IR Spectra
were recorded on a JASCO FT/IR-8000 spectrophotometer.
Optical rotations were measured on a JASCO DIP-370 (D
589 nm).
3.2. General procedure of esterification using MeSO2Cl
(3), Et3N, and Me3N·HCl (2a·HCl)
Me3N·HCl (2a·HCl; 4.50 mmol) was added to a stirred
solution of a carboxylic acid (1.00 mmol) and Et3N
(4.50 mmol) in MeCN (1.0 ml) at 0–58C under an Ar
atmosphere, and the mixture was stirred for 10 min. MsCl
(3; 2.00 mmol) in MeCN (1.0 ml) was added to the mixture
at 215–2108C, and the mixture was stirred at that
temperature for 30 min. An alcohol (1.00 mmol) and
DMAP (1.00 mmol) in MeCN (1.0 ml) was successively
added to the mixture at 215–2108C. Then the mixture was
stirred at that temperature for 1 h and at 20–258C for 1 h.
Water was added to the mixture, which was extracted with
ether. The organic phase was washed with water, brine,
Attention. It is important to dry up Me3N·HCl (2a·HCl)
under reduced pressure before use.
The following obtain esters and amides are known

K. Wakasugi et al. / Tetrahedron 59 (2003) 5337–5345
5343
dried (Na2SO4), and concentrated. The obtained crude
product was purified by silica-gel column chromatography
(hexane/ether¼40:1–10:1) to give the desired ester.
NMR (400 MHz, CDCl3) d 1.60 (3H, d, J¼7.1 Hz), 3.12
(3H, s), 3.55 (1H, d, J¼15.1 Hz), 4.16 (1H, d, J¼15.1 Hz),
4.62–4.72 (1H, m), 5.60 (1H, d, J¼8.1 Hz), 7.16–7.46 (5H,
m); 13C NMR (100 MHz, CDCl3) d 23.04, 42.18, 55.03,
68.90, 126.71, 128.53, 129.19, 140.52; IR (KBr) 3308,
2980, 1426, 1339, 1321, 1167, 1138 cm21. Anal. found: C,
43.21; H, 5.43; N, 4.92%. Calcd for C10H15NO4S2: C,
43.30; H, 5.45; N, 5.05%.
3.3. General procedure of esterification using
Me2NSO2Cl (1), Et3N, Me3N·HCl (2a·HCl), and cat.
DMAP kmethod Al
Me3N·HCl (2a·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 0–58C under an Ar atmosphere, and the
mixture was stirred for 10 min. Me2NSO2Cl (1; 2.00 mmol)
in MeCN (1.0 ml) was added to the mixture at 0–58C, and
the mixture was stirred at that temperature for 3 h. Water
was added to the mixture, which was extracted with ether.
The organic phase was washed with water, brine, dried
(Na2SO4), and concentrated. The obtained crude product
was purified by silica-gel column chromatography (hexane/
ether¼40:1–10:1) to gave the desired ester.
3.5.4. 6-Chlorohexyl 3-phenylpropanoate (16). Colorless
oil; 1H NMR (400 MHz, CDCl3) d 1.27–1.37 (2H, m),
1.29–1.39 (2H, m), 1.56–1.66 (2H, m), 1.71–1.81 (2H, m),
2.63 (2H, t, J¼7.6 Hz), 2.95 (2H, t, J¼7.6 Hz), 3.52 (2H, t,
J¼6.7 Hz), 4.06 (2H, t, J¼6.6 Hz), 7.17–7.31 (5H, m); 13C
NMR (100 MHz, CDCl3) d 25.22, 26.47, 28.44, 30.97,
32.41, 35.86, 44.89, 64.31, 126.22, 128.26, 128.45, 140.51,
172.93; IR (neat) 2938, 2863, 1734, 1454, 1258, 1163,
700 cm21. Anal. found: C, 66.8; H, 7.7%. Calcd for
C15H21ClO2: C, 67.03; H, 7.88%.
3.5.5. Ethyl 6-(3-phenylpropanoyloxy)hexanoate (17).
1
Colorless oil; H NMR (400 MHz, CDCl3) d 1.25 (3H, t,
3.4. General procedure of esterification using
Me2NSO2Cl (1), BuNMe2 (2b), and cat. DMAP kmethod Bl
J¼7.3 Hz), 1.29–1.39 (2H, m), 1.56–1.68 (4H, m), 2.28
(2H, t, J¼7.5 Hz), 2.62 (2H, t, J¼7.8 Hz), 2.95 (2H, t,
J¼7.8 Hz), 4.06 (2H, t, J¼6.6 Hz), 4.07–4.17 (2H, m),
7.16–7.32 (5H, m); 13C NMR (100 MHz, CDCl3) d 14.21,
24.53, 25.45, 28.28, 30.95, 34.13, 35.86, 60.21, 64.22,
126.20, 128.24, 128.44, 140.50, 172.90, 173.48; IR (neat)
2941, 2866, 1734, 1454, 1238, 1163 cm21. Anal. found: C,
69.9; H, 8.3%. Calcd for C17H24O4: C, 69.84; H, 8.27.
Me2NSO2Cl (1; 2.00 mmol) in MeCN (1.0 ml) was added to
a stirred solution of a carboxylic acid (1.00 mmol), an
alcohol (1.00 mmol), BuNMe2 (3.00 mmol), and DMAP
(0.10 mmol) in MeCN (1.0 ml) at 40–458C under an Ar
atmosphere, and the mixture was stirred at that temperature
for 1 h. A similar work up procedure as described above (the
method A) gave the desired ester.
3.5.6. 2-Octyl cyclohexanecarboxylate (18). Colorless oil;
1H NMR (400 MHz, CDCl3) d 0.88 (3H, t, J¼7.0 Hz), 1.18
(3H, d, J¼6.1 Hz), 1.21–1.36 (12H, m), 1.40–1.50 (2H, m),
1.55–1.65 (2H, m), 1.70–1.80 (2H, m), 1.84–1.94 (2H, m),
2.21–2.29 (1H, m), 4.81–4.89 (1H, m); 13C NMR
(100 MHz, CDCl3) d 14.04, 20.01, 22.56, 25.34, 25.44,
25.49, 25.81, 28.98, 29.10, 29.12, 31.74, 35.97, 43.48,
70.39, 175.78; IR (neat) 2932, 2857, 1730, 1453, 1377,
1248, 1173 cm21. Anal. found: C, 75.1; H, 11.6%. Calcd for
C15H28O2: C, 74.95; H, 11.74%.
3.5. Typical procedure of esterification of 3-
phenylpropanoic acid with 1-octanol using Me2NSO2Cl
(1), Et3N, Me3N·HCl (2a·HCl) and cat. 1-imidazole (in
the place of cat. DMAP)
In a similar manner as for the general procedure of kmethod
Al the reaction proceeded in 92% yield.
3.5.1. 9-Decene-1-yl 3-phenylpropaonate (5). Colorless
1
oil; H NMR (400 MHz, CDCl3) d 1.24–1.42 (10H, m),
1.54–1.64 (2H, m), 1.99–2.09 (2H, m), 2.62 (2H, t,
J¼7.8 Hz), 2.95 (2H, t, J¼7.8 Hz), 4.05 (2H, t,
J¼6.7 Hz), 4.89–5.05 (2H, m), 5.74–5.89 (1H, m), 7.16–
7.32 (5H, m); 13C NMR (100 MHz, CDCl3) d 25.86, 28.59,
28.80, 29.01, 29.17, 29.32, 31.00, 33.76, 35.93, 64.62,
114.15, 126.21, 128.27, 128.46, 139.14, 140.57, 172.99; IR
(neat)3028, 2928, 2855, 1736, 1456, 1161 cm21. Anal. found:
C, 79.2; H, 9.7%. Calcd for C19H28O2: C, 79.12; H, 9.78%.
3.5.7. 1-Octyl 2-butenoate (E/Z510:1) (21). Colorless oil;
1H NMR (400 MHz, CDCl3) d 0.80–0.96 (3H, m), 1.21–
1.41 (10H, m), 1.59–1.69 (2H, m), 1.80–1.96 (3H, m), 4.09
(2H£1/11, t, J¼6.8 Hz), 4.11 (2H£10/11, t, J¼6.8 Hz),
5.81–5.89 (1H, m), 6.92–7.00 (1H, m); 13C NMR
(100 MHz, CDCl3) d 14.05, 17.91, 22.62, 25.87, 25.95,
28.58, 28.69, 29.17, 29.22, 31.78, 39.21, 64.33, 64.87,
118.37, 122.85, 130.43, 144.30, 166.67; IR (neat) 2928,
2857, 1726, 1447, 1312, 1181, 1103 cm21. Anal. found: C,
72.5; H, 11.3%. Calcd for C12H22O2: C, 72.68; H, 11.18.
3.5.2. 2-Hexyn-1-yl 3-phenylpropaonate (6). Colorless
1
oil; H NMR (400 MHz, CDCl3) d 0.97 (3H, t, J¼7.3 Hz),
1.48–1.58 (2H, m), 2.14–2.24 (2H, m), 2.66 (2H, t,
J¼7.8 Hz), 2.96 (2H, t, J¼7.8 Hz), 4.67 (2H, s), 7.17–
7.31 (5H, m); 13C NMR (100 MHz, CDCl3) d 13.43, 20.72,
21.84, 30.81, 35.68, 52.85, 74.03, 87.56, 126.27, 128.29,
128.49, 140.35, 172.21; IR (neat) 2965, 2240, 1742, 1454,
1381, 1152, 1032 cm21. Anal. found: C, 78.1; H, 7.6%.
Calcd for C15H18O2: C, 78.23; H, 7.88.
3.6. General procedure of amidation using Me2NSO2Cl
(1), Et3N, Me3N·HCl (2a·HCl), and cat. DMAP kmethod
Al
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
(2a·HCl; 2.00 mmol), and Me2NSO2Cl (1; 2.00 mmol) in
MeCN (1.0 ml) at 0–58C under an Ar atmosphere, and the
mixture was stirred at that temperature for 3 h. Water was
3.5.3. N-1-Phenylethyl(methylsulfonyl)methanesulfon-
amide (12). Colorless crystals; mp 120.0–121.08C; 1H

5344
K. Wakasugi et al. / Tetrahedron 59 (2003) 5337–5345
added to the mixture, which was extracted with EtOAc. The
organic phase was washed with water, brine, dried
(Na2SO4), and concentrated. The obtained crude product
was purified by silica-gel column chromatography (hexane/
EtOAc¼3:1–1:1) to give the desired amide.
water and brine, dried (Na2SO4) and concentrated to give 5-
(4-methoxymethoxyphenyl)-2E,4-butadienoic acid (1.37 g,
93%). Recrystallization from 2-propanol gave pure 2E,4E-
acid (32).
Colorless crystals; mp 149.5–151.08C; 1H NMR (400 MHz,
CDCl3) d 3.48 (3H, s), 5.20 (2H, s), 5.95 (1H, d J¼15.1 Hz),
6.79 (1H, dd, J¼10.7, 15.1 Hz), 6.90 (1H, d, J¼15.1 Hz),
7.02–7.04 (2H, m), 7.41–7.43 (2H, m), 7.53 (1H, dd,
J¼10.7, 15.1 Hz), 10.64 (1H, brs); 13C NMR (100 MHz,
CDCl3) d 56.09, 94.23, 116.48, 119.27, 124.31, 128.78,
129.72, 141.22, 147.29, 158.18, 173.57; IR (KBr) 2905,
2536, 1676, 1597, 1315, 1277, 1236, 1151, 1074, 1003,
920 cm21. Anal. found: C, 66.8; H, 6.0%. Calcd for
C13H14O4: C, 66.66; H, 6.02%.
3.7. General procedure of amidation using Me2NSO2Cl
(1), BuNMe2 (2b), and cat. DMAP kmethod Bl
An amine (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 40–458C under an Ar
atmosphere, and the mixture was stirred at that temperature
for 1 h. A similar work-up procedure as described above
(method A) gave the desired amide.
3.7.4. N-5-(4-Methoxymethoxyphenyl)-2E,4E-butadie-
noyl piperidine (33). Piperidine (85 mg, 1.00 mmol),
BuNMe2 (303 mg, 3.00 mmol), and DMAP (12 mg,
0.10 mmol) in MeCN (1.0 ml) was added to a stirred
solution of 5-(4-methoxymethoxyphenyl)-2E,4E-butadie-
noic acid (32; 234 mg, 1.00 mmol) and Me2NSO2Cl (1;
287 mg, 2.00 mmol) in MeCN (1.0 ml) at 40–458C under
an Ar atmosphere, and the mixture was stirred at that
temperature for 1 h. Water was added to the mixture, which
was extracted with EtOAc. The organic phase was washed
with water, brine, dried (Na2SO4), and concentrated. The
obtained crude product was purified by silica-gel column
chromatography (hexane/EtOAc¼3:2) to give N-5-(4-
3.7.1. N-(1,1-Dimethylethyl)-2E-butenamide (27). Color-
less crystals; mp 102.5–103.58C; 1H NMR (400 MHz,
CDCl3) d 1.38 (9H, s), 1.82 (3H, dd, J¼1.7, 6.8 Hz), 5.25
(1H, brs), 5.72 (1H, dq, J¼1.7, 15.1 Hz), 6.75 (1H, dq,
J¼6.8, 15.1 Hz); 13C NMR (100 MHz, CDCl3) d 17.47,
28.82, 51.09, 126.21, 138.72, 165.28; IR (neat) 3264, 1626,
1458, 1354, 1227, 980 cm21. Anal. found: C, 67.8; H, 10.6;
N, 9.88%. Calcd for C8H15NO: C, 68.04; H, 10.71; N, 9.92.
3.7.2. Methyl 5-(4-methoxymethoxyphenyl)-2E,4-buta-
dienoate (31). A mixture of chloromethyl methyl ether
(874 mg, 10.9 mmol) and 4-hydroxybenzaldehyde (29;
1.11 g, 9.05 mmol) in MeCN (10.0 ml) was added to a
stirred suspension of NaH (0.94 g, 23.5 mmol) in MeCN
(10.0 ml) at 0–58C under an Ar atmosphere and the mixture
was stirred the same temperature for 1 h. Methyl 4-
phosphono-2-butenoate (30; 2.14 g, 9.05 mmol) in MeCN
(10.0 ml) was added to that stirred suspension at 0–58C and
the mixture was stirred the same temperature for 1 h. Water
was added to the mixture, which was extracted with EtOAc.
The organic phase was washed with water, brine, dried
(Na2SO4), and concentrated. The obtained crude product
was purified by silica-gel column chromatography (hexane/
EtOAc¼7:1) to give the desired product 31 (2.28 g, 70%; 2-
(a,b)-E,4-(g,d)-E/2-(a,b)-E,4-(g,d)-Z¼.95:5).
methoxymethoxyphenyl)-2E,4E-butadienoyl
(33; 271 mg, 90%).
piperidine
1
Colorless crystals; mp 70.0–71.58C; H NMR (300 MHz,
CDCl3) d 1.53–1.72 (6H, m), 3.49 (3H, s), 3.49–3.59 (2H,
m), 3.60–3.70 (2H, m), 5.21 (2H, s), 6.47 (1H, d,
J¼14.7 Hz), 6.76–6.86 (2H, m), 6.97–7.07 (2H, m),
7.34–7.44 (2H, m), 7.40–7.50 (1H, m); 13C NMR
(75 MHz, CDCl3) d 24.57, 25.55, 26.66, 43.14, 46.83,
56.06, 94.04, 116.22, 119.72, 125.23, 128.19, 130.16,
138.02, 142.66, 157.37, 165.32; IR (KBr) 3450, 2934,
2855, 1638, 1588, 1510, 1449, 1242, 1010, 839 cm21. Anal.
found: C, 71.7; H, 7.6%. Calcd for C18H23NO3: C, 71.73; H,
7.69; N, 4.65%.
1
Colorless crystals; mp 52.0–54.08C; H NMR (400 MHz,
CDCl3) d 3.47 (3H, s), 3.76 (3H, s), 5.19 (2H, s), 5.95 (1H,
d, J¼15.4 Hz), 6.75 (1H, dd, J¼10.5, 15.4 Hz), 6.85 (1H, d,
J¼15.6 Hz), 7.01–7.03 (2H, m), 7.35–7.45 (2H, m), 7.43
(1H, dd, J¼10.5, 15.6 Hz); 13C NMR (75 MHz, CDCl3) d
51.28, 55.87, 94.09, 116.31, 119.67, 124.38, 128.45, 129.73,
139.96, 144.97, 157.88, 167.36; IR (KBr) 3383, 2951, 1714,
1626, 1599, 1510, 1437, 1246, 1153, 995, 847 cm21. Anal.
found: C, 67.55; H, 6.39%. Calcd for C14H16O4: C, 67.73;
H, 6.50%.
3.7.5. N-5-(4-hydroxyphenyl)-2E,4E-pentadienoyl piper-
idine (Coumaperine) (34) .17 Conc. HCl (0.89 g) was added
to a stirred solution of N-5-(4-Methoxymethoxyphenyl)-
2E,4E-butadienoyl piperidine (33; 532 mg, 1.77 mmol) in
THF–2-propanol (3.5 ml, v/v¼1) at 0–58C. The mixture
was stirred at room temperature for 15 h. Water was added
to the mixture, which was extracted with EtOAc. The
organic phase was washed with water, brine, dried
(Na2SO4), and concentrated. The obtained crude product
was purified by silica-gel column chromatography (hexane/
EtOAc¼2:3) to give coumaperine (34; 404 mg, 89%).
3.7.3. 5-(4-Methoxymethoxyphenyl)-2E,4E-butadienoic
acid (32). KOH (1.76 g, 31.4 mmol) in water (6.0 ml) was
added to a stirred solution of methyl 5-(4-methoxymethox-
yphenyl)-2E,4-butadienoate (31; 1.56 g, 6.29 mmol) in
MeOH (12 ml) at room temperature. The mixture was
stirred at 808C for 15 h. After cool down, the reaction
mixture was concentrated under reduced pressure. 6 M-HCl
aqueous solution was added to the mixture, which was
extracted with EtOAc. The organic phase was washed with
1
Colorless crystals (MeOH); mp 209.5–211.08C; H NMR
(300 MHz, Acetone-d6) d 1.38–1.69 (6H m), 3.55 (4H, s),
6.64 (1H, d, J¼14.4 Hz), 6.82–6.96 (4H, m), 7.28–7.42
(3H, m), 8.84 (1H, s, OH); IR (KBr) 3200, 1634, 1603,
1572, 1510, 1460, 1440, 1277, 1256, 1007, 841 cm21
.
HPLC analysis; 99.8% purity [SHIMADZU HPLC system
(SLC-10A, DGU-4A, LC-10AD, SIL-10A, CTO-10A, and

K. Wakasugi et al. / Tetrahedron 59 (2003) 5337–5345
5345
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solvent: hexane/2-propanol¼95:5] tR¼17.56 min.
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 on Basic Areas (C)
from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, Open Research Center Project, and
by the Cosmetology Foundation in Japan.
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