Fluoride ion-catalyzed conjugate addition for easy synthesis of 3-sulfanylpropionic acid from thiol and α,β-unsaturated carboxylic acid

Article abstract of DOI:10.1016/j.tet.2007.11.064

3-Sulfanylpropionic acids are obtained in excellent yields by proceeding through a simple, mild, and efficient procedure utilizing tetrabutylammonium fluoride (TBAF) as catalyst.

Full text of DOI:10.1016/j.tet.2007.11.064

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1955e1961
www.elsevier.com/locate/tet
Fluoride ion-catalyzed conjugate addition for easy synthesis
of 3-sulfanylpropionic acid from thiol and a,b-unsaturated
carboxylic acid
*
Shijay Gao, Chi Tseng, Cheng Hsuan Tsai, Ching-Fa Yao
Department of Chemistry, National Taiwan Normal University, 88, Section 4, Tingchow Road, Taipei 116, Taiwan, ROC
Received 29 September 2007; received in revised form 16 November 2007; accepted 20 November 2007
Available online 22 November 2007
Abstract
3-Sulfanylpropionic acids are obtained in excellent yields by proceeding through a simple, mild, and efficient procedure utilizing tetrabutyl-
ammonium fluoride (TBAF) as catalyst.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
from lower yields.5 To avoid the interference from carboxylic
acid functional group, these reactions were carried out under
conventional condition, which involves a three-step process
such as protection, conjugate addition, and deprotection.6 The
alternative approach to prepare the b-substituted propionic acids
is by hydrolyzing the corresponding b-substituted propionitriles,
which are generated from a,b-unsaturated nitriles.7 Our previ-
ous study found the use of molecular iodine (I2) as a catalyst
for conjugate addition of thiols to a,b-unsaturated ketones.8
The catalytic system could been also successfully applied to
a variety of a,b-unsaturated carboxylic acids as well as thiols
to synthesizevarious 3-sulfanylpropionic acids, however, the re-
action of acrylic acid with thiol afforded the desired products ac-
companied by a small amount of iodo adducts.9 In this context,
exploring efficient reagent as catalyst and the development of
simple and mild procedures for the preparation of b-substituted
propionic acids from free a,b-unsaturated carboxylic acids are
still an interesting topic for organic chemists.
The conjugate addition is one of the efficient methods in
organic synthesis for the formation of carbonecarbon, carbone
sulfur, and carbonenitrogen bonds.1 Among various nucleo-
philic additions, the conjugate addition of thiols to various
unsaturated systems to form a carbonesulfur bond is of much
importance, as it comprises a key reaction in the biosynthesis
and the synthesis of several biologically active compounds.2 A
number of methods have been reported in the literature, regard-
ing the conjugate addition of thiols to unsaturated carbonylcom-
pounds such as a,b-unsaturated aldehyde, ketone, ester, and
nitrile.3 Comparatively, the conjugate addition of thiols to a,b-
unsaturated carboxylic acids is more difficult, due to low reac-
tivity of carboxylic acid, and the functional group itself involves
or even destroys such reaction. In the literature, the treatment of
free a,b-unsaturated carboxylic acids with organometallic
reagents such as magnesium, lithium, and copper afforded the
desired products in lower yields or even afforded 1,2-addition
products and other side products.4 In 2000, Avery et al. reported
that the same reaction with primary carbon radicals also suffers
Over the past years, tetrabutylammonium fluoride (TBAF)
in organic synthesis has been widely used for most fluoride-as-
sisted reactions,10 deprotection of silyl groups,11 desilyation,12
and fluorination.13 TBAF has been widely recognized as a
convenient, organic-soluble source of naked fluoride ion. It
has also been widely used for a variety of base-catalyzed reac-
tions such as alkylation, elimination, Michael addition, and
* Corresponding author. Tel.: þ886 2 29309092; fax: þ886 2 29324249.
E-mail address: cheyaocf@scc.ntnu.edu.tw (C.-F. Yao).
0040-4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.11.064

1956
S. Gao et al. / Tetrahedron 64 (2008) 1955e1961
aldol condensation.14 The potential ability of the fluoride ion
to act as a base might be predicated by considering the
strength of the HeF bond. Most ionic fluorides are easy to pre-
pare and use, and are stable over long periods of time. The
fluoride ions are hygroscopic, but they do not react with water
and may therefore be recovered from aqueous solution by
conventional techniques. The reactions are usually carried
out below 100 ꢀC due to the low thermal stability of TBAF.
As part of our incessant research efforts with a,b-unsaturated
system chemistry,15 we now report a new, simple, and efficient
catalyst, TBAF, for the synthesis of 3-sulfanylpropionic acid
from thiols and a,b-unsaturated carboxylic acids.
screening other fluoride sources under the same conditions;
it was found that the fluoride ion of TBAF is the most reactive
than other fluoride sources (entries 6e11, Table 1). It is espe-
cially useful when other inorganic bases or fluoride sources
face solubility problems in organic solvents. Although the de-
sired products were obtained in good yield in the cases of the
alkali metal, KF, and CsF, the reactions needed longer periods
of time to be completed and the reactions could not be carried
out in solventless condition. Moreover, the effect of solvents
on the conjugate addition was also studied in the alkali metal
fluorides. In the case of KF, the desired products were obtained
in 85% in DMF, 12% in CH3CN, 9% in MeOH, and 3% in
THF, respectively. Similarly, the yields of the reaction in the
presence of CsF were 91% in DMF, 64% in CH3CN, 15% in
MeOH, and 7% in THF, respectively. In the cases of the alkali
metal fluorides, the product yields obtained in DMF are higher
than in any other solvents due to the higher solvating ability of
DMF, which makes the fluoride ions more naked. No reactions
could occur in the presence of H2SiF6, NH4F, and HFepyri-
dine either in solventless or even in solvent conditions, be-
cause these prefer to afford acidic HF molecular, not basic
Fꢁ ion (entries 9e11, Table 1). On the basis of the optimiza-
tion of the reaction conditions, the scope of this TBAF-
catalyzed conjugate addition of various thiols with various
a,b-unsaturated carboxylic acids was explored. Not only
aromatic a,b-unsaturated carboxylic acids, but also aliphatic
a,b-unsaturated carboxylic acids in the reactions with thiophe-
nol afforded 3-sulfanylpropionic acids in excellent yield
(Table 2). The 3-sulfanylpropionic acids thus formed (92e
99% yield) can be obtained in pure form by passing the crude
through a short plug of silica. The b-bulky substituted acids
took longer reaction times as compared to the other a,b-unsat-
urated acids. This may be due to steric hindrance of bulky sub-
stitution at b-position (compare entries 1e9, 11, 12 vs 10, 13,
14, Table 2). In order to extend the scope of the conjugate ad-
dition of thiols, thiophenol was replaced with various thiols
(Table 3). For thiols, both aromatic thiols and aliphatic thiols
could react with acrylic acid to give the corresponding prod-
ucts in 94e99% isolated yields. Similarly, the rate of the reac-
tion of acrylic acid with aromatic thiol is faster than with
aliphatic thiol, because the election-rich aromatic thiols are
more active than aliphatic thiols (compare entries 1e9 vs
10e13, Table 3). The electronic effect of substituent group
on aromatic thiol is not obvious as a result of the high activity
of aromatic thiols. The reaction of aromatic thiols with elec-
tron-donating group or electron-withdrawing group can com-
plete in the same period of time (entries 1, 3, 7, 8, and 9,
Table 3). However, the reaction of aliphatic thiols with elec-
tron-withdrawing group is faster than that of the normal ali-
phatic thiols; this phenomena may attribute to the difference
in acidity between the thiols (compare entries 11, 14 vs 10,
12, 13, Table 3). The steric effect of thiols also affects the
rate of thiol conjugated to acrylic acid (compare entries 1 vs
2, 3 vs 4, 10 vs 12, 13, Table 3). The scope of the conjugate
addition has been demonstrated by using a wide range of a,b-
unsaturated carboxylic acids as well as thiols in which the
phenyl group was substituted with different groups.
2. Results and discussion
Preliminary efforts were mainly focused on the evaluation
of different additives; the yields of 3-sulfanylpropionic acid
obtained by reacting trans-cinnamic acid with thiophenol
under various conditions are shown in Table 1. First, it was
clearly suggested that TBAF certainly catalyzed the conjugate
addition of thiophenol to trans-cinnamic acid (compare entries
1 and 2, Table 1). It is noteworthy to observe that correspond-
ing product was obtained in excellent yield, but no decarboxy-
lation16 or desulfurization17 product was observed. The
reactions carried out by using different ammonium halides
such as bromide, chloride, and iodide showed that the fluoride
ion was more active than other halides (entries 3e5, Table 1).
The result accords with the literature revealed that quaternary
ammonium halides are known to give rise to an order of nucleo-
philicity for the halide ions, which parallels their electronega-
tivities, i.e., fluoride>chloride>bromide>iodide. We tried to
explore an effective system for the conjugate addition by
Table 1
Conjugate addition of thiophenol to cinnamic acid in the presence of various
derivativesa
SH
additive
solvent
CO2H
+
S
CO2H
1
2
3a
Entry Additive (equiv)
Solvent Temp (ꢀC) Time (h) 3ab (%) 1b (%)
1
d
Neat
Neat
Neat
Neat
Neat
DMF
DMF
DMF
Neat
Neat
50
50
50
50
50
50
50
50
50
50
50
24
24
24
24
24
24
24
24
24
24
24
0
>99
15
10
Tr
85
91
39
0
>99
0
2
TBAF (0.2)
TBACl (0.2)
TBABr (0.2)
TBAI (0.2)
KF (0.2)
3
85
90
4
5
>99
15
6c
7c
8c
9
CsF (0.2)
CaF2 (0.2)
H2SiF6 (0.2)
NH4F (0.2)
2
61
>99
>99
>99
10
11
a
0
HFepyridine (0.2) Neat
0
Condition: the reaction was performed by using 1 equiv (2 mmol) of cin-
namic acid and 1.5 equiv (3 mmol) of thiophenol in the presence of 20 mol %
of additive at 50 ꢀC.
b
NMR yield.
Reaction was carried out in 1 mL of solvent.
c

S. Gao et al. / Tetrahedron 64 (2008) 1955e1961
1957
Table 2
Fluoride ion-catalyzed conjugate addition of thiophenol to various unsaturated acidsa
R2
R2
TBAF20mol%
neat, 50 °C
R
R
R1
+
PhSH
CO2H
CO2H
R1
SPh
3
1
2
Entry
1
Product
Time (h)/yieldb (%)
24/98
Entry
Product
Time (h)/yieldb (%)
36/94
O
3h
3a
8
9
CO2H
CO2H
SPh
SPh
O
O
S
3b
2c
44/95
24/98
15/98
36/92
2/97
3i
CO2H
CO2H
SPh
SPh
MeO
CO2H
3j
3c
3
10
11
CO2H
CO2H
SPh
SPh
SPh
MeO
MeO
CO2H
CO2H
3d
4
24/96
3k
PhS
OMe
MeO
MeO
PhS
3l
3e
5
6
12/97
22/99
12
13
18/98
1/94
SPh
CO2H
SPh
F
3f
3m
PhS
PhS
CO2H
CO2H
CO2H
SPh
O2N
3n
3g
7
22/96
14
1/99
CO2H
SPh
a
Condition: the reaction was performed by using 1 equiv (2 mmol) of unsaturated acid and 1.5 equiv (3 mmol) of thiophenol in the presence of 20 mol % of
TBAF at 50 ꢀC in solventless condition.
b
Isolated yield.
Reaction was carried out in 1 mL of THF.
c
3. Conclusion
visualized with UV light. Flash column chromatography,
following the method of still, was carried out with E. Merck
silica gel 60 (Kieselgel 60, 230e400 mesh) using the indicated
In conclusion, we have developed a novel procedure for the
synthesis of 3-sulfanylpropionic acid, which is often encoun-
tered in molecules of biologically active compounds. The
procedures described here are simple, mild, and efficient.
The use of TBAF as a base has the advantages of being eco-
nomically viable and more efficient for the conjugate addition.
The reaction system can be successfully applied to a variety of
a,b-unsaturated acids as well as thiols to synthesize a wide
variety of sulfur containing carboxylic acids in excellent yields.
1
eluents. H nuclear magnetic resonance (NMR) spectra were
recorded routinely with a Bruker Avance 400 (400 MHz) spec-
trometer. The 1H NMR data are described as following: chemi-
cal shifts (d, given in parts per million with tetramethylsilane
(0.00 ppm) as internal reference), multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, br¼broad, m¼multiplet), cou-
pling constants (J, given in Hertz), with integration. 13C NMR
spectra were obtained with a Bruker Avance 400 (100 MHz)
spectrometer using CDCl3 (77.23 ppm) as internal reference.
Mass spectra were obtained on a JOEL SX-102A spectrometer
at an ionization potential of 70 eVand reported as mass/charge
(m/z) with percent relative abundance. High-resolution mass
spectra (HRMS) were acquired with a FINNIGAN MAT-
95XL spectrometer. Solvents for extraction and chromatogra-
phy were of reagent grade. All reagents such as a series of
4. Experimental
4.1. General
All analytical thin layer chromatographies were performed
with E. Merck silica gel 60F254 aluminum sheets and were

1958
S. Gao et al. / Tetrahedron 64 (2008) 1955e1961
Table 3
Fluoride ion-catalyzed conjugate addition of acrylic acids with various thiolsa
TBAF 20 mol%
RS
+
RSH
CO2H
CO2H
neat, 50 °C
1
2
4
Entry
1
Product
Time (h)/yieldb (%)
0.5/98
Entry
Product
Time (h)/yieldb (%)
0.5/99
F
F
S
F
F
S
F
4h
4a
8
MeO
F3C
S
4i
S
4b
2
3
1/96
9
0.5/97
18/95
OMe
S
CF3
S
0.5/96
10
4c
4j
S
F3C(F2C)7H2CH2CS
4
2.5/94
11
10/96
4d
4k
S
S
S
5c
6
0.5/98
4/94
12d
13d
45/97
45/98
4e
4l
4f
4m
S
S
O
7c
0.5/95
14
1/99
4g
4n
S
O
O2N
a
Condition: the reaction was performed by using 1 equiv (2 mmol) of acrylic acid and 1.5 equiv (3 mmol) of thiols in the presence of 20 mol % of TBAF at
50 ꢀC in solventless condition.
b
Isolated yield.
Reaction was carried out in 1 mL of THF.
c
d
The reaction was performed by using 1 equiv (2 mmol) of unsaturated acid and 2 equiv (4 mmol) of thiol in the presence of 50 mol % of TBAF at 50 ꢀC in
solventless condition.
substituted a,b-unsaturated carboxylic acids and thiols were
commercially available from Acros and Aldrich Chemical Co.
and were used directly without further purification.
4.2.2. 3-Benzo[1,3]dioxol-5-yl-3-phenylsulfanyl-propionic
acid (3b)
White solid with the melting point of 122e123 ꢀC; 1H
NMR (400 MHz, CDCl3) d 7.31 (d, J¼2.6 Hz, 2H), 7.27e
7.22 (m, 3H), 6.80 (s, 1H), 6.66 (s, 2H), 5.93 (s, 2H), 4.54
(t, J¼7.7 Hz, 1H), 2.97e2.83 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 176.17, 148.00, 147.25, 134.17, 133.72, 133.53,
129.14, 128.14, 121.30, 108.27, 108.18, 101.33, 48.87,
41.04; HRMS (EI) m/z calcd for C16H14O4S (Mþ) 302.0613,
found 302.0618.
4.2. Procedures and analytical data
To a mixture of trans-cinnamic acid (301 mg, 2 mmol)
and thiophenol (341 mg, 3 mmol), TBAF$3H2O (127 mg,
0.4 mmol) was added and the mixture was stirred at 50 ꢀC
in solventless condition for 24 h. After completion of reac-
tion (monitored by NMR), the crude product was purified by
flash column chromatography using silica gel (eluent: ethyl
acetateehexane; 1:5) to obtain 3-sulfanylpropionic acid (3a)
(506 mg, 98% yield).
4.2.3. 3-(4-Methoxy-phenyl)-3-phenylsulfanyl-propionic
acid (3c)
White solid with the melting point of 105e107 ꢀC; 1H
4.2.1. 3-Phenyl-3-phenylsulfanyl-propionic acid (3a)
NMR (400 MHz, CDCl3)
d
7.30 (d, J¼3.3 Hz, 2H),
1
White solid with the melting point of 85e86 ꢀC; H NMR
7.26e7.20 (m, 3H), 7.16 (d, J¼8.8 Hz, 2H), 6.79 (d,
J¼8.8 Hz, 2H), 4.58 (t, J¼7.7 Hz, 1H), 3.76 (s, 3H), 2.99e
2.86 (m, 2H); 13C NMR (100 MHz, CDCl3) d 176.68,
159.18, 133.78, 133.60, 132.31, 129.09, 128.94, 128.06,
114.11, 55.44, 48.29, 40.94; HRMS (EI) m/z calcd for
C16H16O3S (Mþ) 288.0820, found 288.0819.
(400 MHz, CDCl3) d 7.30e7.18 (m, 10H), 4.59 (t, J¼7.4 Hz,
1H), 3.00e2.89 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 177.1, 140.3, 133.7, 133.5, 129.1, 128.7, 128.1, 127.84,
127.80, 48.8, 40.8; HRMS (EI) m/z calcd for C15H14O2S
(Mþ) 258.0715, found 258.0707.

S. Gao et al. / Tetrahedron 64 (2008) 1955e1961
1959
4.2.4. 3-(3,4-Dimethoxyphenyl)-3-phenylsulfanyl-propanoic
acid (3d)
125.15, 44.39, 41.78; HRMS (EI) m/z calcd for C13H12O2S2
(Mþ) 264.0279, found 264.0273.
White solid with the melting point of 117e118 ꢀC; 1H
NMR (400 MHz, CDCl3) d 7.32e7.27 (m, 2H), 7.27e7.20
(m, 3H), 4.57 (t, J¼7.6 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H),
3.00e2.85 (m, 2H); 13C NMR (100 MHz, CDCl3) d 176.82,
148.94, 148.59, 133.76, 133.58, 132.75, 129.05, 128.11,
119.87, 111.13, 111.02, 55.97, 48.66, 40.86; HRMS (EI) m/z
calcd for C17H18O4S (Mþ) 318.0926, found 318.0925.
4.2.10. 3-Phenylsulfanyl-butanoic acid (3j)
1
Brown oil; H NMR (400 MHz, CDCl3) d 7.45e7.42 (m,
2H), 7.38e7.24 (m, 3H), 3.64e3.55 (m, 1H), 2.68 (dd,
J¼16.0, 5.9 Hz, 1H), 5.47 (dd, J¼16.0, 8.4 Hz, 1H), 1.35 (d,
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 178.0,
133.7, 133.2, 129.2, 127.8, 41.8, 39.3, 21.0; HRMS (EI) m/z
calcd for C10H12O2S (Mþ) 196.0558, found 196.0562.
4.2.5. 3-(Phenylthio)-3-(3,4,5-trimethoxyphenyl)-propanoic
acid (3e)
4.2.11. 3-Methyl-3-phenysulfanyl-butanoic acid (3k)
Colorless oil; 1H NMR (400 MHz, CDCl3) d 7.58e7.55 (m,
2H), 7.39e7.34 (m, 3H), 2.56 (s, 2H), 1.41 (s, 6H); 13C NMR
(100 MHz, CDCl3) d 177.3, 137.8, 131.3, 129.3, 128.8, 46.8,
46.5, 28.6; HRMS (EI) m/z calcd for C11H14O2S (Mþ)
210.0715, found 210.0716.
White solid with the melting point of 120e121 ꢀC; 1H
NMR (400 MHz, CDCl3) d 7.34e7.29 (m, 2H), 7.28e7.23
(m, 3H), 6.41 (s, 2H), 4.54 (t, J¼7.7 Hz, 1H), 3.81 (s, 3H),
3.69 (s, 6H), 3.02e2.88 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 176.44, 153.25, 137.58, 135.92, 134.01, 13.41,
129.11, 128.30, 104.86, 61.01, 56.26, 49.27, 40.77; HRMS
(EI) m/z calcd for C18H20O5S (Mþ) 348.1031, found 348.1033.
4.2.12. 3,3-Bis(phenylsulfanyl)-propanoic acid (3l)
1
White solid with the melting point of 53e54 ꢀC; H NMR
4.2.6. 3-(4-Fluorophenyl)-3-phenylsulfanyl-propanoic acid
(3f)
(400 MHz, CDCl3) d 7.52e7.47 (m, 4H), 7.36e7.29 (m, 6H),
4.77 (t, J¼7.3 Hz, 1H), 2.85 (d, J¼7.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 175.40, 133.77, 133.05, 129.31, 128.64,
53.21, 41.05; HRMS (EI) m/z calcd for C15H14O2S2 (Mþ)
290.0435, found 290.0439.
Colorless oil; 1H NMR (400 MHz, CDCl3) d 7.31e7.21 (m,
5H), 7.21e7.15 (m, 2H), 6.94 (t, J¼8.6 Hz, 2H), 4.57 (t,
J¼7.6 Hz, 1H), 3.01e2.85 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 176.42, 162.29 (d, J¼245.0 Hz), 136.18 (d,
J¼3.0 Hz), 133.88, 133.20, 129.46 (d, J¼8 Hz), 129.17,
128.36, 115.61 (d, J¼21 Hz), 48.23, 40.80; HRMS (EI) m/z
calcd for C15H13FO2S (Mþ) 276.0620, found 276.0627.
4.2.13. 2-Methyl-3-phenylsulfanyl-propanoic acid (3m)
Colorless oil; 1H NMR (400 MHz, CDCl3) d 7.39e7.37 (m,
2H), 7.31e7.29 (m, 2H), 7.22e7.18 (m, 1H), 3.29 (dd, J¼13.4,
7.0 Hz, 1H), 2.93 (dd, J¼13.4, 7.0 Hz, 1H), 2.75e2.67 (m, 1H),
1.31 (d, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 181.1,
135.7, 130.5, 129.3, 126.9, 39.8, 37.4, 16.8; HRMS (EI) m/z
calcd for C10H12O2S (Mþ) 196.0558, found 196.0568.
4.2.7. 3-(4-Nitrophenyl)-3-phenylsulfanyl-propanoic acid
(3g)
White solid with the melting point of 148e150 ꢀC; 1H NMR
(400 MHz, CDCl3) d 8.10 (d, J¼8.6 Hz, 2H), 7.34 (d,
J¼8.5 Hz, 2H), 7.25 (s, 5H), 4.63 (t, J¼7.7 Hz, 1H), 3.10e
2.90 (m, 2H); 13C NMR (100 MHz, CDCl3) d 175.75, 148.08,
147.42, 134.4, 132.04, 129.39, 128.97, 128.73, 123.94, 48.47,
39.99; HRMS (EI) m/z calcd for C15H13NO4S (Mþ)
303.0565, found 303.0570.
4.2.14. 3-Phenylsulfanyl-propanoic acid (3n)
1
White solid with the melting point of 58e60 ꢀC; H NMR
(400 MHz, CDCl3) d 7.40e7.36 (m, 2H), 7.32e7.28 (m, 2H),
7.24e7.20 (m, 1H), 3.16 (t, J¼7.2 Hz, 2H), 2.67 (t,
J¼7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 177.3, 135.1,
130.6, 129.3, 126.9, 34.3, 29.0; HRMS (EI) m/z calcd for
C9H10O2S (Mþ) 182.0402, found 182.0406.
4.2.8. 3-(Furan-2-yl)-3-phenylsulfanyl-propanoic acid (3h)
1
White solid with the melting point of 88e89 ꢀC; H NMR
(400 MHz, CDCl3) d 7.36 (d, J¼0.7 Hz, 1H), 7.33e7.23 (m,
6H), 6.24 (dd, J¼2.9, 1.8 Hz, 1H), 5.99 (d, J¼3.3 Hz, 1H),
4.65 (t, J¼7.7 Hz, 1H), 3.05e2.87 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 176.12, 152.74, 142.39, 134.65, 132.43,
129.08, 128.62, 110.52, 107.67, 42.24; HRMS (EI) m/z calcd
for C13H12O3S (Mþ) 248.0507, found 248.0501.
4.2.15. 3-(4-Methoxyphenylsulfanyl)-propanoic acid (4a)
1
White solid with the melting point of 82e83 ꢀC; H NMR
(400 MHz, CDCl3) d 7.38 (d, J¼8.6 Hz, 2H), 6.85 (d,
J¼8.6 Hz, 2H), 3.79 (s, 3H), 3.03 (t, J¼7.2 Hz, 2H), 2.60 (t,
J¼7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 178.32,
159.64, 134.55, 125.03, 114.90, 55.51, 34.55, 30.97; HRMS
(EI) m/z calcd for C10H12O3S (Mþ) 212.0507, found 212.0501.
4.2.9. 3-(Phenylsulfanyl)-3-(thiophen-2-yl)-propanoic acid
(3i)
1
White solid with the melting point of 68e69 ꢀC; H NMR
4.2.16. 3-(2-Methoxyphenylsulfanyl)-propanoic acid (4b)
1
(400 MHz, CDCl3) d 7.36e7.32 (m, 2H), 7.28e7.24 (m, 4H),
7.19 (dd, J¼4.9, 0.9 Hz, 1H), 6.84 (dd, J¼5.1, 3.7 Hz, 1H),
6.78 (d, J¼3.3 Hz, 1H), 4.89 (t, J¼7.5 Hz, 1H), 3.00 (d,
J¼7.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 175.88,
144.36, 134.01, 133.13, 129.17, 128.50, 126.73, 125.65,
White solid with the melting point of 92e93 ꢀC; H NMR
(400 MHz, CDCl3) d 7.34 (dd, J¼7.6, 0.6 Hz, 1H), 7.25 (t,
J¼8.0 Hz, 1H), 6.94 (t, J¼8.1 Hz, 1H), 6.88 (d, J¼8.2 Hz,
1H), 3.90 (s, 3H), 3.14 (t, J¼7.4 Hz, 2H), 2.67 (t, J¼7.4 Hz,
2H); 13C NMR (100 MHz, CDCl3) d 178.21, 158.32, 131.64,

1960
S. Gao et al. / Tetrahedron 64 (2008) 1955e1961
128.50, 122.83, 121.26, 110.98, 55.96, 34.36, 27.37; HRMS
(EI) m/z calcd for C10H12O3S (Mþ) 212.0507, found 212.0505.
J¼7.1 Hz, 2H), 2.75 (t, J¼7.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 177.26, 139.58 (q, J¼33.0 Hz), 128.72
(d, J¼3.0 Hz), 127.27, 123.20 (d, J¼271.2 Hz), 120.24e
120.17 (m), 119.13, 33.88, 28.27; HRMS (EI) m/z calcd for
C11H8F6O2S (Mþ) 318.0149, found 318.0148.
4.2.17. 3-(3,5-Dimethylphenylsulfanyl)-propanoic acid (4c)
1
White solid with the melting point of 93e94 ꢀC; H NMR
(400 MHz, CDCl3) d 6.99 (m, 2H), 6.85 (s, 1H), 3.13 (t,
J¼7.3 Hz, 2H), 2.67 (t, J¼7.3 Hz, 2H), 2.28 (s, 6H); 13C
NMR (100 MHz, CDCl3) d 178.13, 138.92, 134.56, 128.85,
128.16, 34.48, 28.92, 21.40; HRMS (CI) m/z calcd for
C11H14O2S (Mþ) 210.0715, found 210.0709.
4.2.24. 3-(Hexylsulfanyl)-propanoic acid (4j)
Colorless oil; 1H NMR (400 MHz, CDCl3) d 2.78 (t,
J¼7.1 Hz, 2H), 2.66 (t, J¼7.2 Hz, 2H), 2.54 (t, J¼7.3 Hz,
2H), 1.62e1.52 (m, 2H), 1.42e1.22 (m, 6H), 0.93e0.85 (m,
3H); 13C NMR (100 MHz, CDCl3) d 178.15, 34.92, 32.44,
31.62, 29.71, 28.74, 26.83, 22.74, 14.22; HRMS (EI) m/z calcd
for C9H18O2S (Mþ) 190.1028, found 190.1025.
4.2.18. 3-(2,6-Dimethylphenylsulfanyl)-propanoic acid (4d)
1
White solid with the melting point of 66e67 ꢀC; H NMR
(400 MHz, CDCl3) d 7.12 (s, 3H), 2.93 (t, J¼7.3 Hz, 2H), 2.57
(t, J¼7.5 Hz, 2H), 2.56 (s, 6H); 13C NMR (100 MHz, CDCl3)
d 178.21, 143.45, 132.51, 128.73, 128.43, 34.71, 29.80, 22.21;
HRMS (EI) m/z calcd for C11H14O2S (Mþ) 210.0715, found
210.0714.
4.2.25. 3-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-
Heptadecafluorodecylsulfanyl)-propanoic acid (4k)
1
White solid with the melting point of 85e87 ꢀC; H NMR
(400 MHz, CDCl3) d 2.84 (t, J¼7.1 Hz, 2H), 2.81e2.75 (m,
4.2.19. 3-(Naphthalen-2-ylsulfanyl)-propanoic acid (4e)
Pale yellow crystal with the melting point of 103e104 ꢀC;
1H NMR (400 MHz, CDCl3) d 7.79e7.72 (m, 4H), 7.47e7.40
(m, 3H), 3.22 (t, J¼7.3 Hz, 2H), 2.68 (t, J¼7.3 Hz, 2H); 13C
NMR (100 MHz, CDCl3) d 178.3, 133.9, 132.5, 132.3,
128.9, 128.7, 128.2, 127.9, 127.4, 126.8, 126.2, 34.4, 28.8;
HRMS (EI) m/z calcd for C13H12O2S (Mþ) 232.0558, found
232.0562.
2H), 2.69 (t, J¼7.1 Hz, 2H), 2.48e2.32 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d 177.64, 118.81, 118.00, 117.70,
117.37, 116.27, 115.94, 113.76, 111.53, 111.19, 110.79,
108.84, 108.52, 34.62, 32.27 (t, J¼22.0 Hz), 26.95, 23.09 (t,
J¼4.2 Hz); HRMS (EI) m/z calcd for C13H9F17O2S (Mþ)
552.0052, found 552.0051.
4.2.26. 3-(Isopropylsulfanyl)-propanoic acid (4l)
4.2.20. 3-(Benzylsulfanyl)-propanoic acid (4f)
Colorless oil; 1H NMR (400 MHz, CDCl3) d 3.00e2.90 (m,
1H), 2.81 (t, J¼7.4 Hz, 2H), 2.66 (t, J¼6.7 Hz, 2H), 1.28 (d,
J¼6.7 Hz, 6H); 13C NMR (100 MHz, CDCl3) d 177.48,
35.30, 34.92, 25.32, 23.52; HRMS (EI) m/z calcd for
C6H12O2S (Mþ) 148.0558, found 148.0525.
1
White solid with the melting point of 82e83 ꢀC; H NMR
(400 MHz, CDCl3) d 7.31e7.23 (m, 5H), 3.73 (s, 2H),
2.69e2.65 (m, 2H), 2.59e2.56 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 138.1, 129.0, 128.8, 127.4, 36.5, 34.5,
26.1; HRMS (EI) m/z calcd for C10H12O2S (Mþ) 196.0558,
found 196.0555.
4.2.27. 3-(Cyclohexylsulfanyl)-propanoic acid (4m)
Colorless oil; 1H NMR (400 MHz, CDCl3) d 2.80 (t,
J¼7.4 Hz, 2H), 2.70e2.63 (m, 1H), 2.64 (t, J¼7.3 Hz, 2H),
2.00e1.92 (m, 2H), 1.81e1.75 (m, 2H), 1.63e1.59 (m, 1H),
1.37e1.21 (m, 5H); 13C NMR (100 MHz, CDCl3) d 178.5,
43.8, 35.3, 33.7, 26.2, 25.9, 24.8; HRMS (EI) m/z calcd for
C9H16O2S (Mþ) 188.0871, found 188.0869.
4.2.21. 3-(4-Nitrophenylsulfanyl)-propanoic acid (4g)
White solid with the melting point of 132e133 ꢀC; 1H
NMR (400 MHz, CDCl3) d 8.15 (d, J¼8.6 Hz, 2H), 7.37 (d,
J¼8.6 Hz, 2H), 3.30 (t, J¼7.2 Hz, 2H), 2.78 (t, J¼7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3) d 176.48, 146.08, 145.78,
127.16, 124.35, 33.58, 27.07; HRMS (EI) m/z calcd for
C9H9NO4S (Mþ) 227.0252, found 227.0246.
4.2.22. 3-(Perfluorophenylsulfanyl)-propanoic acid (4h)
White solid with the melting point of 111e112 ꢀC; 1H
NMR (400 MHz, CDCl3) d 3.12 (t, J¼7.0 Hz, 2H), 2.67 (t,
J¼7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 177.61,
149.20e149.06 (m), 146.80e146.50 (m), 143.60e142.90 (m),
140.90e139.90 (m), 139.50e139.00 (m), 136.90e136.50 (m),
108.80e108.20 (m), 34.99, 29.73; HRMS (EI) m/z calcd for
C9H5F5O2S (Mþ) 271.9930, found 271.9929.
4.2.28. 3-(2-Methoxy-2-oxoethylsulfanyl)-propanoic acid
(4n)
1
Colorless oil; H NMR (400 MHz, CDCl3) d 3.75 (s, 3H),
3.27 (s, 2H), 2.92 (t, J¼7.3 Hz, 2H), 2.71 (t, J¼7.3 Hz, 2H);
13C NMR (100 MHz, CDCl3) d 177.58, 171.00, 52.70, 34.27,
33.70, 27.42; HRMS (EI) m/z calcd for C6H10O4S (Mþ)
178.0300, found 178.0301.
4.2.23. 3-(3,5-Bis(trifluoromethyl)phenylsulfanyl)-
propanoic acid (4i)
Acknowledgements
1
White solid with the melting point of 59e60 ꢀC; H NMR
(400 MHz, CDCl3) d 7.74 (s, 2H), 7.69 (s, 1H), 3.28 (t,
Financial support of this work by the National Science
Council of the Republic of China is gratefully acknowledged.

S. Gao et al. / Tetrahedron 64 (2008) 1955e1961
7. Hurd, C. D.; Gershbein, L. L. J. Am. Chem. Soc. 1947, 69, 2328.
1961
Supplementary data
8. Chu, C.-M.; Gao, S.; Sastry, M. N. V.; Yao, C.-F. Tetrahedron Lett. 2005,
46, 4971.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2007.11.064.
9. Gao, S.; Tzeng, T.; Sastry, M. N. V.; Chu, C.-M.; Liu, J.-T.; Lin, C.; Yao,
C.-F. Tetrahedron Lett. 2006, 47, 1889.
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Fernandez-Rodriguez, M. A.; Garcia-Garcia, P.; Merino, I.; Aquilar, E.
J. Org. Chem. 2004, 69, 7352.
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