Synthesis of 5-Hydroxy-4-methoxy-α-methyl-(1,2-benzobutane sultone) from eugenol and eugenil acetate

Article abstract of DOI:10.14233/ajchem.2018.21398

The purpose of this study was to develop an efficient synthesis route to pharmacologically interesting sultone derivatives from readily accessed natural products. Synthetic approach of 5-hydroxy-4-methoxy-α-methyl-(1,2-benzobutane sultone) via eugenol (1) produced only in moderate yield (64 %). On the other hand synthetic approach via eugenil acetate (2) gave 5-hydroxy-4-methoxy-α-methyl-(1,2-benzobutane sultone) in high yield (96 %). Eugenol approach involved only one step reaction due to direct reaction of eugenol with chlorosulfonic acid but in eugenil acetate approach involved two-step reactions due to its preparation of eugenol before reaction with chlorosulfonic acid. Eugenil acetate was prepared smoothly in good yield by esterification of phenolic group of eugenol with acetic anhydride in the presence of sodium bicarbonate. A variety of bicarbonate catalysts such as NaHCO3, Na2CO3 and K2CO3 were investigated in O-acetylation of eugenol to afford eugenil acetate (84 %), (72 %) and (88 %), respectively. Structures of all the products have been established by spectral and GC-MS analysis data.

Full text of DOI:10.14233/ajchem.2018.21398

Asian Journal of Chemistry; Vol. 30, No. 11 (2018), 2411-2414
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21398
Synthesis of 5-Hydroxy-4-methoxy-α-methyl-(1,2-benzobutane sultone)
from Eugenol and Eugenil Acetate
*
I.M. SUDARMA , L. SUPIANI, A. SYAFITRI, W.K. HIDAYATI, H. OLTANTIA and M.G. DARMAYANTI
Department of Chemistry, Faculty of Mathematic and Natural Sciences, University of Mataram, Kota Mataram 83115, Indonesia
*Corresponding author: Fax: +62 370 648508; Tel: +62 370 646506; E-mail: sud_arma@yahoo.co.id
Received: 23 April 2018; Accepted: 2 August 2018; Published online: 27 September 2018;
AJC-19085
The purpose of this study was to develop an efficient synthesis route to pharmacologically interesting sultone derivatives from readily
accessed natural products. Synthetic approach of 5-hydroxy-4-methoxy-α-methyl-(1,2-benzobutane sultone) via eugenol (1) produced
only in moderate yield (64 %). On the other hand synthetic approach via eugenil acetate (2) gave 5-hydroxy-4-methoxy-α-methyl-(1,2-
benzobutane sultone) in high yield (96 %). Eugenol approach involved only one step reaction due to direct reaction of eugenol with
chlorosulfonic acid but in eugenil acetate approach involved two-step reactions due to its preparation of eugenol before reaction with
chlorosulfonic acid. Eugenil acetate was prepared smoothly in good yield by esterification of phenolic group of eugenol with acetic
anhydride in the presence of sodium bicarbonate.A variety of bicarbonate catalysts such as NaHCO
3
, Na
2
CO
3
and K
2
CO were investigated
3
in O-acetylation of eugenol to afford eugenil acetate (84 %), (72 %) and (88 %), respectively. Structures of all the products have been
established by spectral and GC-MS analysis data.
Keywords: Comparison reaction, Eugenol, Eugenil acetate, Cyclic sulfonic ester, Sultone, Markovnikov.
strategies utilized to mask hydroxyl functionalities during
multistep synthetic procedures. In addition, O-acetylation
procedures are widely employed for the protection and
purification of various natural and synthetic products. Solvent-
free O-acetylation of alcohols, phenols and thiols using cata-
lytic amounts of sodium acetate trihydrate gave good yields
[5]. A variety of primary alcohols and phenols were reacted
with acetic anhydride at room temperature in the presence
of sodium bicarbonate to produce corresponding esters and
eugenol was reacted with acetic anhydride at room temperature
in the presence of sodium bicarbonate to produce correspon-
ding esters in good to excellent yields [6]. A series of eco-
friendly solid acid catalysts including: Preyssler, Wells-Dowsen
and Keggin HPAs have been used as catalysts for acetylation
of alcohols, phenols and salicylic acid with acetic anhydride
INTRODUCTION
Eugenol (4-allyl-2-methoxyphenol) (1), a constituent of
clove, has been used as a fine chemical for further chemical
transformation [1-4]. Eugenol (1) has three reactive functional
groups namely: alcohol as a phenol, phenyl and alkene as an
allyl. These reactive functional groups can compete each other
and will disturb further reaction such as on reaction of eugenol
with chlorosulfonic acid to form sultone derivative.
In continuation of our work to increase the yield of sultone
derivative (3), which previously prepared directly from eugenol,
synthesis of this compound via Markovnikov addition of
chlrosulfonic acid to eugenil acetate (2) was reported. This
synthesis involved two steps reaction: firstly direct protection
of phenolic group of eugenol by acetic anhydride to form eugenil
acetate and secondly Markovnikov addition of chlorosulfonic
acid to eugenil acetate.
[7]. Acylation of eugenol with Ac O/Py/DMAP in dichloro-
2
methane at room temperature gave eugenil acetate in high yield
(98 %) [8].
Eugenil acetate (4-allyl-2-methoxyphenyl acetate) has
an asymmetrically substituted alkenes which can undergoes
Markovnikov addition by strong acid such as chlorosulfonic
Phenols are potentially reactive towards electrophilic
aromatic substitution. This is because the hydroxy group, -OH,
is a strongly activating, ortho- or para- directing substituent.
Protection of phenols is one of the most common synthetic
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(

2
412 Sudarma et al.
Asian J. Chem.
acid (H-O-SO
2
Cl), which states that when a strong acid is added
Sudarma et al. [1]. To stirred solution of eugenil acetate (2)
(500 mg, 2.43 mmol) in dichloromethane (25 mL) was added
chlorosulfonic acid (2.5 mL) drop by drop. The solution was
stirred at room temperature for 30 min then refluxed for 15 min.
The solution was evaporated and water (15 mL) then added,
basified to pH 8 with 1 M sodium hydroxide, then extracted
with dichloromethane. The organic phase was dried and evapo-
rated to dryness to give an amorphous brown solid (96 %).
to an asymmetrically substituted alkene, the major product
results from the addition of hydrogen atom to double-bonded
carbon that is attached to more hydrogen atoms [9]. Further-
more, a sultone derivative (3) was formed from this addition.
Sultones are heterocyclic compounds and are internal esters
of the corresponding hydroxy sulfonic acids [10]. Sultones are
reactive intermediates having commercial applications in
detergents, polymers, antistatics and other industrial applica-
tions [11].
+.
Compound (3), GC-MS: M 244, cal for C10
H
12SO Major
5
fragments: 200, 183, 165, 151, 136 (base peak). IR (film),
-1
In the present work, an effort for design and synthesis of
biologically active sultone derivative from eugenol and eugenil
acetate will be discussed.
νmax, cm ): 3232 (O-H), 3084 (C=CH-Ar), 2936, 2829, 1399,
1
1327, 1260 (C-O), 1127 (C-O), 1066, 999, 912, 764. H NMR
(400.1 MHz, CDCl ): δ 1.62 (3H, d, J 6.6 Hz, -CH ); 2.16
1H, s, OH); 2.85 – 2.31 (2H, m,-CH -); 3.93 (3H, s, -OCH );
3
3
(
5
2
3
13
EXPERIMENTAL
.20 (1H, m, -CH-); 6.60 (1H, s, ArH); 7.33 (1H, s, ArH). C
): δ 21.3 (-CH ); 35.6 (-CH ); 56.4
-CH-); 110.1 (ArCH); 110.6 (ArCH); 126.8 (ArC); 127.2
ArC); 145.4 (ArC); 150.1 (ArC).
NMR (400.1 MHz, CDCl
(
(
3
3
2
The material used included: clove, dichloromethane,
hexane, methanol, acetonitrile, acetate anhydride, ethanol,
sodium hydroxide pellet, hydrochloric acid, sodium hydrogen
carbonate anhydrous, ethyl acetate, sodium carbonate anhy-
drous, chlorosulfonic acid, analytical thin layer chromato-
graphy, silica gel chromatography.
RESULTS AND DISCUSSION
Eugenol (1) was extracted and isolated from clove oil in
General procedure: Dried clove buds were ground into
fine particles (powder) for extraction. Clove powder (150 g)
were percolated with dichloromethane (1 L) and stored away
from light for 2 × 24 h. The result then filtered and the filtrate
was evaporated with rotary evaporator to obtain the brownish
clove oil (32 g; 21 %).
good yield (83.7 %). The presence of –OH group as a phenol
in eugenol (1) is potentially decreased the yield of sultone
because this functional group is very reactive towards electro-
philic aromatic substitution, oxidation, etc. To increase the
yield of sultone, presumably the –OH group of eugenol (1)
has to be protected. Protection of hydroxyl is one common
synthetic strategies utilized to mask hydroxyl functionalities
during further step synthetic procedures. Esterification is one
way to protect the –OH of eugenol. A varies of catalyst were
employed to increase the yield of esterification of eugenol by
acetate anhydride. Eugenol was reacted with acetic anhydride
at room temperature in the presence of bicarbonate catalyst to
produce corresponding esters or eugenil acetate (2) in moderate
to good yield (Table-1).
Isolation of eugenol (1): Clove oil (21 g) were dissolved in
dichloromethane (65.7 mL). The mixture was added with NaOH
(
5.36 g), which had been dissolved with H O (39 mL). Mixture
2
was stirred with magnetic stirrer for 60 min in room temperature.
Two layers were formed where the aqueous phase in the top
layer was separated from the organic phase in the bottom layer.
The aqueous phase that contains eugenol salt was acidified with
concentrated HCl to pH 3. The organic layer was then separated
from the aqueous layer with separation funnel. The remaining
aqueous layer then extracted with dichloromethane (15 mL, 3x).
The crude eugenol then filtered with dichloromethane:n-hexane
TABLE-1
ACETYLATION OF EUGENOL (1)
TO BE EUGENIL ACETATE (2)
(
1:1) through dilica gel mixture and evaporated with rotary
evaporator to afford yellowish oil (18.3 g, 83.7 %). The oil was
analyzed by TLC. TLC analyses showed eugenol sample R 0.72
and eugenol standard R 0.72 (eluent: CH Cl ).
Yield of
compd. 2 (%)
No.
Catalyst and its condition
f
1
2
3
4
NaHCO /(CH CO) O, ethyl acetate, r.t., 24 h
84
72
88
88
3
3
2
f
2
2
NaHCO /(CH CO) O, acetonitrile, r.t., 24 h
3
3
2
Synthesis of eugenil acetate (2): This reaction was con-
ducted by adopting method from Lugemwa et al. [6].A mixture
of eugenol (1 g, 6.10 mmol), acetate anhydride (3 g, 30 mmol),
Na CO /(CH CO) O, ethyl acetate, r.t., 24 h
2
3
3
2
K CO /(CH CO) O, ethyl acetate, r.t., 24 h
2
3
3
2
2
K CO
3
(1 g, 12 mmol), ethyl acetate (75 mL) was stirred at
It has been reported that eugenol (1) reacted with chloro-
room temperature for the 24 h. The progress of the reaction
was monitored by TLC. After completion of the reaction, the
mixture was filtered and the filtrate was evaporated by rotary
evaporator. The residue was added dichloromethane (25 mL)
and water (10 mL) and the phases separated. The organic layer
sulfonic acid to form sultone derivative (3) in moderate yield
(64 %) [1]. After protection of the –OH group of eugenol (1)
to be eugenil acetate (2) and further reaction with chlorosul-
fonic acid, presumably will afford sultone derivative (2c), but
this hypothesis was not correct. These reaction gave the same
product as reaction of eugenol (1) with chlorosulfonic acid
(Scheme-I).
In the first stage, the chemical basis for Markovnikov’s
rule is the transformation of the most stable carbocation during
the addition process (Scheme-II) [1,9]. The addition of the
was dried (Na
.34 mmol, 87.5 %). The syrup was analyzed by TLC and
GC-MS. TLC analyses showed eugenil acetate sample R 0.78
2
CO ) and concentrated to afford syrup (1.1 g,
3
5
f
+.
(
2
eluent: CH Cl
2
). GC-MS: M 206, cal for C12
14
H O3, major
fragments : 164 (base peak), 149, 131, 121, 103, 91, 77.
Synthesis of cyclic sulfonic ester or sultone derivative
hydrogen from H-OSO Cl to one carbon atom in the double
2
(
3): This reaction was conducted by adopting method from
bond of allyl group of eugenil acetate (2) creates a positive

Vol. 30, No. 11 (2018)
Synthesis of 5-Hydroxy-4-methoxy-α-methyl-(1,2-benzobutane sultone) 2413
HO
Isolation
ClSO H
3
Clove Oil
(
3), 64%
MeO
CH2
Eugenol (1)
(
CH CO) O/Na CO
3 2 2 3
Me
O
Me
O
O
O
O
O
O
S
O
HO
O
S
ClSO H
3
O
MeO
Me
MeO
CH2
MeO
Me
(
3
), 96 %
(2), 87.5%
(
2c)
Markovnikov Product
ClSO H
3
O
O
S
HO
O
MeO
(4)
Anti-Markovnikov Product
Scheme-I: Synthesis route of sultone derivative (3) from eugenol (1) and eugenil acetate (2)
O
O
O
O
CH COO
H
3
S
H
S
CH COO
H
-
O
3
Cl
H
O
Cl
H
'
+
MeO
2'
H
H
1
MeO
(
2)
H
H
2
(1a)
H
O
HCl +
O
O
O
O
O
S
HO
S
CH COO
S
CH COO
H
Cl
3
3
O
O
O
CH COCl
3
+
H
MeO
CH3
MeO
CH3
MeO
H
H
(
3)
(2c)
(
2b)
H
Scheme-II: Formation mechanism of sultone derivative (3) from eugenil acetate
charge on the other carbon, forming a carbocation intermediate
2a). The more substituted the carbocation the more stable it
is, due to induction and hyperconjugation effects [9]. The
On the basis of spectroscopic evidence and mechanistic
considerations, the structure of sultone derivative (3) was
proposed for Markovnikov product and excluded the Anti-
Markovnikov product (4) as proposed in Scheme-I.Additional
(
carbocation C2’ is more stable than carbocation C1’ and
-
1
OSO
2
Cl will attack the carbocation C2’ leads to the formation
methyl group as a doublet at δ 1.58 in H NMR spectrum gave
of intermediate (2b). However, the other less substituted C1’
or less stable carbocation C1’ will still be formed and will
appropriate information about cyclic sulfonic ester derivative
(3) compare to (4). This analysis was supported by C NMR
13
proceed to form the minor product with the opposite attachment
and DEPT, which gave 4 quaternary carbons, 3 methine carbons,
1 methylene carbon and 2 methyl carbons. Generally, the H
–
1
2
of OSO Cl but such intermediate is not detected from the GC-
MS and NMR analyses [1]. In the second stage of the reaction,
a base donates electrons to the hydrogen atom and generated
the losses of HCl to afford cyclic product (2c). Final stage,
cleavage of ester by HCl produced sultone derivative (3).
NMR spectrum supported the proposed structure (3).
Conclusion
Reaction of eugenol (1) with chlorosulfonic acid gave
cyclic sulfonic ester or sultone derivative (3) in moderate yield

2
414 Sudarma et al.
Asian J. Chem.
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ACKNOWLEDGEMENTS
The authors thank Indonesian Ministry of Research,
Technology and Higher Education (Kementerian Riset,
Teknologi, dan Pendidikan Tinggi) through “Hibah Kompetensi”
for financial support.
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