A new procedure for the synthesis of 2-[(4-dodecyloxyphenyl)sulfonyl]butanoic acid

Article abstract of DOI:10.1515/chempap-2015-0125

A new, practical and cost-effective route for scalable synthesis of 2-[(4-dodecyloxyphenyl)sulfonyl] butanoic acid, a key intermediate of a new cyan dye-forming coupler containing a sulfone group, was developed by adopting phenol as the starting material. The synthesis was accomplished in five steps with etherification, chlorosulfonation, reduction, nucleophilic reaction by C-S coupling and hydrolyzation. An important objective of the new synthetic route was the synthesis of 2-[4-(dodecyloxyphenyl)sulfonyl]butanoate. Overall yield obtained at optimized conditions increased to 66 %. The synthetic strategy was proven to be a process enabling rapid delivery of the target product with high purity.

Full text of DOI:10.1515/chempap-2015-0125

Chemical Papers 69 (9) 1237–1243 (2015)
DOI: 10.1515/chempap-2015-0125
ORIGINAL PAPER
A new procedure for the synthesis
of 2-[(4-dodecyloxyphenyl)sulfonyl]butanoic acid
a
a
b
b
a
aYun-Long Shi, Ling Wang, Chao Qian, Ming Tao, Zu-Tai Liao, Xin-Zhi Chen*
aKey Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering,
Zhejiang University, 310027 Hangzhou, China
bJiangxi Renming Pharmaceutical Chemicals Ltd., 332700 Jiujiang, China
Received 11 January 2015; Revised 17 March 2015; Accepted 19 March 2015
A new, practical and cost-effective route for scalable synthesis of 2-[(4-dodecyloxyphenyl)sulfonyl]
butanoic acid, a key intermediate of a new cyan dye-forming coupler containing a sulfone group,
was developed by adopting phenol as the starting material. The synthesis was accomplished in
five steps with etherification, chlorosulfonation, reduction, nucleophilic reaction by C–S coupling
and hydrolyzation. An important objective of the new synthetic route was the synthesis of 2-[4-
(dodecyloxyphenyl)sulfonyl]butanoate. Overall yield obtained at optimized conditions increased to
66 %. The synthetic strategy was proven to be a process enabling rapid delivery of the target
product with high purity.
c
ꢀ 2015 Institute of Chemistry, Slovak Academy of Sciences
Keywords: cyan dye-forming coupler, 2-[(4-dodecyloxyphenyl)sulfonyl]butanoic acid, phenol, C–S
coupling.
Introduction
large-scale preparation of II because of the high ig-
nitability and instability of hydrogen peroxide as the
oxidant and lower overall yield of the final product.
Thus, a reinvestigation of possible synthesis routes
providing II was necessary to accelerate the scale-up
development and quick delivery of the product with
high purity.
Considering the drawbacks of the previous method,
an inexpensive and efficient process for the key in-
termediate II was attempted (Fig. 3). The new pro-
cedure substituting phenol for 4-mercaptophenol is
more economical and superior to those presented in
literature (Han et al., 2011). To accomplish high-
quality synthesis of II, some published procedures
(Murár et al., 2013) were applied to the synthe-
sis of II to reduce the safety issues and to im-
prove the overall yield of the method. Etherification
of phenol and 1-bromododecane was first studied.
2-[4-(Dodecyloxyphenyl)sulfonyl]butanoate (VI ) was
introduced as an intermediate by way of chlorosul-
fonation, reduction and a nucleophilic reaction. Sub-
Cyan dye-forming coupler I (Fig. 1), a typical class
of dye-forming couplers for silver halide photosensitive
materials in terms of improved color reproducibility
and image dye stability, has been extensively used in
color photographic film and paper products (Begley et
al., 2001). 2-[(4-Dodecyloxyphenyl)sulfonyl]butanoic
acid (II) (Fig. 1) is the key building block of I. Com-
pound II has been successfully substituted for other
intermediates because of its better stability.
An important method (Fig. 2) for the prepara-
tion of II (Han et al., 2011) involved the reaction of
4-mercaptophenol and 2-bromobutyric methyl ester.
Subsequent oxidation, etherification and hydrolization
provided II in a 57.4 % yield. However, the critical fac-
tor which has prevented this strategy from becoming
the preferential synthesis route was the high cost of
4-mercaptophenol (III), and the development of the
process was limited by non-availability of the starting
materials. Furthermore, this method is impractical for
*Corresponding author, e-mail: xzchen@zju.edu.cn
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Y. L. Shi et al./Chemical Papers 69 (9) 1237–1243 (2015)
Fig. 1. Structure of cyan dye-forming coupler (I) and 2-[(4-dodecyloxyphenyl)sulfonyl]butanoic acid (II).
Fig. 2. Previous method for the synthesis of II (Han et al., 2011).
Fig. 3. Summary route to the key intermediate II.
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Y. L. Shi et al./Chemical Papers 69 (9) 1237–1243 (2015)
Table 1. Spectral data of the corresponding compounds
1239
Compound
Spectral data
VIII
1H NMR (400 MHz, CDCl3), δ: 7.26–7.13 (m, 2H), 6.91–6.74 (m, 3H), 3.87 (t, J = 6.6 Hz, 2H), 1.70 (dt, J =
13.5 Hz, J = 6.7 Hz, 2H), 1.37 (dd, J = 13.7 Hz, J = 6.3 Hz, 2H), 1.19 (s, 16H), 0.81 (t, J = 6.5 Hz, 3H)
13C NMR (100 MHz, CDCl3), δ: 158.13, 128.36, 119.41, 113.49, 66.87, 30.91, 28.65, 28.63, 28.59, 28.57, 28.40, 28.34,
28.30, 25.06, 21.68, 13.10
IX
VI
1H NMR (400 MHz, CDCl3), δ: 7.88 (d, J = 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 3.98 (t, J = 6.5 Hz, 2H),
1.83–1.66 (m, 2H), 1.38 (dd, J = 13.8 Hz, J = 6.3 Hz, 2H), 1.19 (s, 16H), 0.81 (t, J = 6.5 Hz, 3H)
13C NMR (100 MHz, CDCl3), δ: 163.53, 134.78, 128.52, 114.07, 67.94, 30.90, 28.62, 28.61, 28.55, 28.50, 28.32, 28.27,
27.88, 24.87, 21.67, 13.10
1H NMR (400 MHz, CDCl3), δ: 7.69 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 3.95 (t, J = 6.5 Hz, 2H), 3.78
(dd, J = 11.2 Hz, J = 3.9 Hz, 1H), 3.64 (s, 3H), 1.99 (dqd, J = 15.0 Hz, J = 7.5 Hz, J = 4.0 Hz, 1H), 1.85 (ddd, J
= 13.5 Hz, J = 11.3 Hz, J = 7.2 Hz, 1H), 1.79–1.65 (m, 2H), 1.47–1.34 (m, 2H), 1.20 (s, 16H), 0.88 (t, J = 7.4 Hz,
3H), 0.81 (t, J = 6.7 Hz, 3H)
13C NMR (100 MHz, CDCl3), δ: 165.66, 162.84, 130.52, 127.05, 113.60, 71.47, 67.60, 51.83, 30.90, 28.63, 28.61,
28.56, 28.52, 28.32, 27.98, 24.93, 21.67, 19.86, 13.09, 10.42
II
1H NMR (400 MHz, CDCl3), δ: 7.73 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 6.74 (s, 1H), 3.95 (t, J = 6.5 Hz,
2H), 3.80 (dd, J = 11.1 Hz, J = 3.9 Hz, 1H), 2.08–1.93 (m, 1H), 1.92–1.79 (m, 1H), 1.80–1.66 (m, 2H), 1.48–1.33
(m, 2H), 1.19 (s, 15H), 0.94 (t, J = 7.4 Hz, 3H), 0.81 (t, J = 6.6 Hz, 3H)
13C NMR (100 MHz, CDCl3), δ: 169.12, 163.01, 130.58, 126.70, 113.77, 71.36, 67.66, 30.90, 28.64, 28.61, 28.57,
28.53, 28.33, 27.98, 24.93, 21.67, 19.87, 13.10, 10.38
sequently, VI was directly converted to II via a modi-
fied hydrolization process. In this paper, this route was
subjected to further studies and an optimized process
with the yield of 65.8 % is described.
p-Dodecyloxybenzenesulfonyl chloride (IX)
Chlorosulfonic acid (26.64 g, 0.23 mol) was added
dropwise to a stirred mixture of NaCl (3 g, 0.05 mol)
and VIII (20.00 g, 0.076 mol) in CH2Cl2 (120 mL)
at 15◦C. The mixture was kept at this temperature
for 3 h; then, the mixture was slowly poured into
an ice-water mixture (300 g). The organic layer was
partitioned and the water layer was extracted with
CH2Cl2 (50 mL). The combined organic phase was
washed with a saline solution, dried over Na2SO4 and
condensed under reduced pressure. The product (IX)
was purified by recrystallization from ethanol. Yield:
24.18 g (87.9 %). Melting point: 35.0–37.0◦C.
Experimental
The reactants were supplied by Jiangxi Renming
Pharmaceutical Chemicals (China) and all solvents
were purchased from Sinopharm Chemical Reagent
(China). TLC analyses were performed on a glass plate
(30 mm × 100 mm). GC analyses were performed on
a GC Agilent 1790F series. HPLC analyses were done
on an HPLC Agilent 1100 series. Melting points were
determined using a melting point apparatus (INESA,
WRS-2). 1H NMR and 13C NMR spectrums were
recorded in CDCl3 on a NMR spectrometer (Bruker,
AV 400) using 400 MHz and 100 MHz. Spectral data
of prepared compounds are in Table 1. and in supple-
mentary data.
2-[4-(Dodecyloxyphenyl)sulfonyl]butanoate
(VI)
Sodium sulfite (12.61 g, 0.1 mol) and sodium bicar-
bonate (8.40 g, 0.105 mol) were added to 100 mL of
water and 10 mL of tetrahydrofuran and then stirred.
When the salts dissolved completely, IX (18.05 g, 0.05
mol) was added and the temperature of 15◦C was
maintained for 12 h, while stirring. Upon the reac-
tion completion, the precipitated solid was obtained
by filtration and the filter cake was directly added to
a stirred mixture of 2-bromobutyric acid methyl es-
ter (9.05 g, 0.05 mol) and methanol (200 mL), which
was then heated to 60◦C. The progress of the re-
action was monitored by GC up to complete disap-
pearance of 2-bromobutyric acid methyl ester. The
resulting mixture was then cooled to room temper-
ature and the first precipitated solid was removed
by filtration. VI was further crystallized from the fil-
trate. Yield: 18.27 g (85.6 %). Melting point: 47.9–
48.9◦C.
(Dodecyloxy)benzene (VIII)
Phenol (18.95 g, 0.2 mol), K2CO3 (55.66 g, 0.4
mol) and butan-2-one (80 g) were heated to reflux un-
der stirring for 0.5 h. Then, 1-bromododecane (50.18 g,
0.2 mol) was added dropwise to the solution. A Dean–
Stark apparatus was used to remove water from the
reaction by azeotropic distillation. After a further 4 h,
butan-2-one was distilled and then the reaction mix-
ture was slowly cooled to 25◦C, followed by dilution
with water (100 mL) and extraction with ethyl ac-
etate (2 × 75 mL). The organic extracts were dried
over Na2SO4, filtered, and concentrated under reduced
pressure. The result was a white solid (VIII ). Yield:
48.67 g (92.1 %). Melting point: 24.7–25.6◦C.
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Y. L. Shi et al./Chemical Papers 69 (9) 1237–1243 (2015)
2-[(4-dodecyloxyphenyl)sulfonyl]butanoic acid
Table 2. Screening of solvents for the synthesis of VIIIa
(II)
Solvent
Temperature/◦C Time/h Yieldb/%
To a solution of NaOH (3.2 g, 0.08 mol) dissolved in
80 mL of water 2-[[4-(dodecyloxyphenyl]sulfonyl]buta-
noate (VI) (17.1 g, 0.04 mol) was added. The mixture
was stirred at 75◦C for 2 h. The reaction mixture was
then cooled to room temperature acidified with 1 M
HCl (80 mL) to precipitate a solid mass (II), which
was purified by filtration. Yield: 15.71 g (95.0 %).
Melting point: 81.3–82.6◦C.
N,N-Dimethylformamide
Cyclohexanone
Butan-2-one
Toluene
Tetrahydrofuran
Cyclohexane
80
80
80
80
80
80
4
4
4
4
4
4
87.3
83.3
92.1
78.5
75.4
80.4
a) All reactions were charged with phenol : 1-bromododecane :
K2CO3 = 1 : 1 : 2 (molar ratio); b) yields were determined by
GC with butanoic acid ethyl ester as the internal standard.
Results and discussion
Preparation of (dodecyloxy)benzene (VIII)
fonyl chlorides are available, including the Reed reac-
tion (Reed, 1933, 1934, 1938), chlorosulfonation with
chlorosulfonic acid (Alam et al., 2007), chlorination
of sulfonic acid (Greig et al., 2006), etc. Chlorosul-
fonic acid is an easy to use eco-friendly reagent effi-
ciently converting reactants to the corresponding sul-
fonyl chlorides. In our improved process, sodium chlo-
ride was an additional reagent reacting with the re-
dundant sulfuric acid providing sodium hydrogen sul-
fate and HCl; experimental data showed that it can
accelerate the reaction process (Table 3). In addition,
the molar ratio of VIII and chlorosulfonic acid played
an important role in the yields. However, an increase
in the chlorosulfonic acid concentration does not cor-
respond to the increase in the reaction yield. In lit-
erature (Feng et al., 2011), the yield of IX was lower
than 80 %. Decreasing the amount of chlorosulfonic
acid seemed to be favorable (Table 3) as under the
same conditions, the participation of sodium chloride
resulted in an increased yield of IX (Table 3, entries
2, 4, 6).
In order to find a convenient method for the syn-
thesis of (dodecyloxy)benzene (VIII), the method re-
ported by Haap (2006) was applied with some modi-
fications. In this method, phenol is used as the raw
material reacting with an equivalent amount of 1-
bromododecane in N, N-dimethylformamide under
moderate temperature. In preliminary experiments,
the high hydroscopicity of the solvent resulted in a
byproduct which was formed by hydrolyzation of 1-
bromododecane. Thus, the conversion of phenol at a
high rate could not be achieved and a low yield was ob-
tained. Considering this issue, a series of solvents were
screened in order to find an optimal solvent. The re-
sults showed that no conventional solvent provides the
desired product VIII except for butanone (Table 2).
Compared with other solvents, butanone has the ad-
vantage of forming a low boiling point azeotrope. Wa-
ter was eliminated from the process by a Dean–Stark
apparatus. At the end of the reaction, the solvent,
butanone, was evaporated under reduced pressure for
recycling and VIII was collected by extraction with
ethyl acetate. The salts were filtered on a Buchner
funnel under vacuum and the filtered liquor was dis-
tilled under vacuum to provide the desired product as
a white solid.
Preparation of 2-[4-(dodecyloxyphenyl)
sulfonyl]butanoate (VI)
Sulfinates were prepared by two approaches: reduc-
tion with zinc or sodium sulfite (Field & Clark, 1963).
The first approach reported by Frank C. Whitmore
and Hamilton (1922) involves the application of metal
zinc. However, the catalyst resulted in a large amount
of metal residue causing serious negative environmen-
tal problems. Therefore, the second approach, where
Preparation of p-dodecyloxybenzenesulfonyl
chloride (IX)
A variety of methods for the preparation of sul-
Table 3. Different equivalents of acids and NaCl screening for the preparation of IXa
Entry
Molar ratio of VIII : ClSO3H
Mass of NaCl/g
Time/h
Yield/%
1
2
3
4
5
6
1 : 2
1 : 2
1 : 3
1 : 3
1 : 4
1 : 4
–
3
–
3
–
3
4
3
4
3
4
3
75.3
81.1
79.7
87.9
75.4
82.0
a) Solvent used in all reactions was CH2Cl2 and the reaction temperature was 15◦C.
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Y. L. Shi et al./Chemical Papers 69 (9) 1237–1243 (2015)
1241
Fig. 4. Mechanism of the synthesis of VI.
Table 4. Effects of bases on the yield (VI)a
cess is inhibited at lower temperatures. Thus, it is un-
reasonable to increase the temperature of the reduc-
tion reaction. The reaction time was determined by
the conversion of IX which was monitored by TLC.
Upon completion of the reduction, the mixture was
filtered and then the filter cake was directly added to
a stirred mixture of 2-bromobutyric acid methyl ester
and different solvents. As shown in Table 5, methanol
resulted in the best yield of this reaction compared
with other solvents. Using solvents like ethanol, iso-
propanol, dichloroethane and DMF, the yield and
purity of the products were lower. DMF is usually
the best solvent for nucleophilic reactions. Neverthe-
less, the use of DMF in this reaction gave an un-
expectedly low yield probably due to the hydroly-
sis of 2-bromobutyric acid methyl ester. Therefore, to
minimize the moisture content, water-carrying agents
were added to DMF (Table 5, entries 6, 7) to form
azeotropes with water so that it could be removed
from the reaction by azeotropic distillation. Similarly,
the Dean-Stark apparatus was used to remove water
produced in the reaction.
Entry
Base
Yield/%
1
2
3
4
5
–
70.3
74.8
77.1
80.2
85.6
NaOH
Na2CO3
Na2HPO4
NaHCO3
a) Reduction condition: mole ratio of IX : Na2SO3 : base of
1 : 2 : 2.1, reaction temperature of 15◦C, solvent = a mixture of
100 mL of water and 10 mL of tetrahydrofuran. Nucleophilic re-
action condition: mole ratio of IX : 2-bromobutyric acid methyl
ester of 1 : 1, reaction temperature of 60◦C, solvent = methanol.
sulfonic chloride is reduced by sodium sulfite (Krishna
& Singh, 1928) is investigated in this study. The as-
sertion that the alkali metal salts of sulfinic acids
give only sulfones on alkylation with alkyl halides has
been confirmed repeatedly (Wildeman & Van Leusen,
1979). In the present study, reduction was combined
with nucleophilic reaction so that the process of pu-
rification was greatly simplified. Based on the analysis
of Smiles and Bere (1941) and to our further study,
the possible mechanism of synthesis of VI presented
in Fig. 4. can be assumed. Alkalinity of the solution
played a major role in the formation of the intermedi-
ate. Under this hypothesis, reactions of IX and sodium
sulfite were carried out under diverse alkaline condi-
tions (Table 4).
To our delight, the decreasing temperature led to
direct VI crystallization in methanol. Moreover, the
solubility of sodium bromide in methanol was lower
than that of VI. After the reaction completion, the
reaction mixture was cooled to room temperature and
the precipitated sodium bromide was removed by fil-
tration. Then, the filtrate was cooled to lower temper-
ature and the product was obtained. Hence, methanol
was chosen as the best solvent for the reaction and
crystallization process. Under optimal condition, the
yield of VI was 85.6 % and the purity of VI reached
as high as 99.5 %. The chemical structure of VI was
Experimental data in Table 4 indicate that the in-
crease in the basicity of the base resulted in lower
yield of VI and that sodium bicarbonate as the re-
ductant (Table 4, entry 5) is more favorable than
other bases. Sulfonylchloride is easily hydrolyzed un-
der higher temperatures, but the hydrolyzation pro-
1
confirmed by H NMR and 13C NMR spectra and its
purity was determined by HPLC.
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Y. L. Shi et al./Chemical Papers 69 (9) 1237–1243 (2015)
Table 5. Screening of solvents for the synthesis of VIa
Entry
Solvent
Temperature/◦C
Yield/%
Purity/%b
1
2
3
4
5
6
7
Methanol
Ethanol
Isopropanol
60
60
60
60
60
60
60
85.6
75.7
72.1
70.1
65.7
85.8
82.3
99.5
99.0
98.9
97.3
95.0
96.2
95.6
Dichloroethane
DMF
DMF + toluene
DMF + cyclohexane
a) Reduction condition: mole ratio of IX : Na2SO3 : NaHCO3 of 1 : 2 : 2.1, reaction temperature of 15◦C, solvent = a mixture
of 100 mL of water and 10 mL of tetrahydrofuran. Nucleophilic reaction condition: mole ratio of IX : 2-bromobutyric acid methyl
ester of 1 : 1; b) Separations were performed using a reverse-phase C18 column. HPLC analysis conditions included the mobile
phase (acetonitrile : methanol = 60 : 40 (vol.) at 1.0 mL min−1), detection wavelength (254 nm) and retention time (15.3 min).
Preparation of 2-[(4-dodecyloxyphenyl)
sulfonyl]butanoic acid (II)
Aranapakam, V., Davis, J. M., Grosu, G. T., Baker, J., Elling-
boe, J., Zask, A., Levin, J. I., Sandanayaka, V. P., Du, M.
L., Skotnicki, J. S., DiJoseph, J. F., Sung, A., Sharr, M. A.,
Killar, L. M., Walter, T., Jin, G. X., Cowling, R., Tillett,
J., Zhao, W. U., McDevitt, J., & Xu, Z. B. (2003). Syn-
thesis and structure–activity relationship of N-substituted
4-arylsulfonylpiperidine-4-hydroxamic acids as novel, orally
active matrix metalloproteinase inhibitors for the treatment
of osteoarthritis. Journal of Medicinal Chemistry, 46, 2376–
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Begley, W. J., Russo, G. M., & Curt, D. T. (2001). U.S. Patent
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The hydrolysis reaction was used to convert an
ester into the corresponding carboxylic acid (Arana-
pakam et al., 2003). The reaction of VI was per-
formed in the presence of NaOH in water employ-
ing the modified method to get II as a solid mass.
Eventually, II was obtained by filtration after the re-
action mixture acidification with 1 M HCl. The yield
of the final hydrolysis product was 95 % and its pu-
rity was over 95.0 % after its recrystallization from
1,2-dichloroethane.
Conclusions
Greig, I. R., Idris, A. I., Ralston, S. H., & van’t Hof, R. J. (2006).
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as novel inhibitors of bone resorption. Journal of Medicinal
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pean Patent Office.
The key intermediate II was successfully prepared
using a new and efficient method. This synthetic se-
quence is more suitable for further optimization and
scale-up because it benefits from the use of inexpensive
starting materials, the synthesis of VI and acceptable
yields. This paper presents a significant improvement
with respect to the usual methods and the total yield
of up to 65.8 %.
Han, L., Zhang, X. Y., & Qi, Y. M. (2011). The synthe-
sis of
a new cyan dye-forming coupler containing sul-
fone group. Dyestuffs and Coloration, 48(2), 1–4. DOI:
Acknowledgements. The authors are grateful for the finan-
cial support from the Natural Science Foundation of China
(21376213, 21476194) and the Zhejiang Provincial Public
Technology Research of China (2014C31123).
10.3969/j.issn.1672-1179.2011.02.001.
Krishna, S.,
& Singh, H. (1928). Estimation of —SOOH
(sulfinic) group and Fe+++ . Journal of the American Chem-
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5-(ethylsulfonyl)-2-methoxyaniline: An important pharma-
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Supplementary data
Supplementary data (spectral data of prepared
compounds) associated with this article (A new proce-
dure for the synthesis of 2-[(4-dodecyloxyphenyl)sulfo-
nyl]butanoic acid) can be found in the online version
of this paper (DOI: 10.1515/chempap-2015-0125).
Reed, C. F. (1933). U.S. Patent No. 2,046,090. Washington,
D.C.: U.S. Patent and Trademark Office.
Reed, C. F. (1934). U.S. Patent No. 2,174,110. Washington,
D.C.: U.S. Patent and Trademark Office.
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Smiles, S., & Bere, C. M. (1941). p-Acetaminobenzenesulfinic
acid. Organic Syntheses, 5, 1. DOI: 10.15227/orgsyn.005.
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