Synthesis of 4-sulfanylcoumarins using thiourea and alkyl halides as the sulfanylation agent in polyethylene glycol-water

Article abstract of DOI:10.1055/s-0032-1318139

A novel and efficient route for the synthesis of 4-sulfanylcoumarins is disclosed. The direct sulfanylation of 4-tosyloxycoumarins with thiourea and various alkyl halides in polyethylene glycol 200-water (PEG 200-H₂O), at room temperature under an air atmosphere, affords the corresponding 4-sulfanylcoumarins in moderate to excellent yields. This transformation shows good substrate scope and takes place in a green solvent. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318139

PAPER
▌759
paper
Synthesis of 4-Sulfanylcoumarins Using Thiourea and Alkyl Halides as the
Sulfanylation Agent in Polyethylene Glycol–Water
Synthesis of 4-Sulfanylcoumarins
Zhenlan Yin,a Yu Wang,b Qin Yang,b Ying Wang,b Jingshi Xu,a Zhihong Deng,a Yiyuan Peng*a,b
a
Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry, Jiangxi Normal University, Nanchang, Jiangxi 330022,
P. R. of China
b
Key Laboratory of Small Functional Organic Molecule, Ministry of Education and College of Life Science, Jiangxi Normal University,
Nanchang, Jiangxi 330022, P. R. of China
Fax +86(791)88120396; E-mail: yypeng@jxnu.edu.cn; E-mail: yiyuanpeng@yahoo.com
Received: 18.12.2012; Accepted after revision: 08.01.2013
Abstract: A novel and efficient route for the synthesis of 4-sul-
fanylcoumarins is disclosed. The direct sulfanylation of 4-tosyloxy-
OH
O
S
coumarins with thiourea and various alkyl halides in polyethylene
glycol 200–water (PEG 200–H2O), at room temperature under an
air atmosphere, affords the corresponding 4-sulfanylcoumarins in
moderate to excellent yields. This transformation shows good sub-
strate scope and takes place in a green solvent.
SH
TsCl, base
H2O, r.t.
+
O
O
O
Scheme 1 Metal-free synthesis of 4-sulfanylcoumarins
Key words: 4-sulfanylcoumarins, 4-tosyloxycoumarins, thiourea,
alkyl halides, polyethylene glycol 200
Initially, optimization studies were carried out using
4-tosyloxycoumarin (1a) (prepared from the reaction of
4-hydroxycoumarin and TsCl in the presence of trimeth-
ylamine), thiourea (2) and benzyl bromide (3a), as model
substrates (Table 1). When the reaction was performed in
polyethylene glycol 200–water (PEG 200–H2O) in the
presence of trimethylamine, we observed formation of the
desired product 4a in 57% yield (Table 1, entry 1). Further
screening of bases (including inorganic and organic bas-
es) revealed that potassium carbonate (3 mmol with re-
spect to 4-tosyloxycoumarin) was the best choice. Under
these conditions, the desired 4-sulfanylcoumarin 4a was
isolated in 92% yield (Table 1, entry 3). It is also notewor-
thy that this reaction could be carried out under an air at-
mosphere without any reduction in the yield. Next,
screening of the solvent revealed that the presence of a
small amount of water was important, and that the opti-
mum ratio of polyethylene glycol/water was 10:1.
Coumarins are distributed widely in plant species and
many of them show interesting biological properties.1 The
prominence of coumarins in natural products and biologi-
cally active molecules has prompted considerable efforts
toward their synthesis.2 4-Sulfanylcoumarins have shown
promising activity against the hepatitis C virus (HCV),
and their synthesis has attracted significant attention.3
They have been synthesized either for biological evalua-
tion, or as key intermediates for the generation of complex
molecules. However, their syntheses usually suffer from
the requirement for multiple synthetic steps, harsh reac-
tion conditions, and poor substituent tolerance.4 Thus, it is
highly desirable to develop general and efficient methods
for the synthesis of 4-sulfanylcoumarins, in particular, via
green processes.
Our group has previously developed a novel, metal-free
synthesis of 4-sulfanylcoumarins from 4-hydroxycouma-
rins and thiols5 (Scheme 1). However, the use of unpleas-
ant mercaptans not only results in serious environmental
problems, but also limits the potential for expansion of the
reaction scope. The reported odorless protocols for the
formation of thioethers,6–10 and the use of thiourea and al-
kyl halides11–13 as reagents for the formation of thioethers,
encouraged us to apply these methods for the synthesis of
4-sulfanylcoumarins.
The scope of this reaction was investigated by applying
the optimized conditions [K2CO3, PEG 200–H2O (10:1),
r.t., air] and the results are summarized in Table 2. In all
but one case, the 4-tosyloxycoumarin 1 reacted with thio-
urea (2) and the aliphatic halide 3 leading to the corre-
sponding products 4 in moderate to excellent yields. For
example, primary alkyl halides, including benzyl chlo-
ride, alkyl bromides and methyl iodide, underwent the sul-
fanylation reaction with thiourea and 4-tosyloxycoumarin
to give the desired products 4a–c in high yields (Table 2,
entries 1–4). The reaction with the long-chain alkyl ha-
lide, 1-bromotetradecane, was less efficient affording a
low 49% yield (Table 2, entry 5). Secondary halides such
as bromocyclopentane (3f) and 2-iodobutane (3g) gave
the corresponding products 4e and 4f in good yields (Ta-
ble 2, entries 6 and 7). However, reaction of the tertiary al-
kyl halide 3h resulted in only a trace amount of the
SYNTHESIS 2013, 45, 0759–0766
Advanced online publication: 05.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318139; Art ID: SS-2012-H0979-OP
© Georg Thieme Verlag Stuttgart · New York

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Z. Yin et al.
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Table 1 Optimization of the Reaction Conditions for the Synthesis of 4-Sulfanylcoumarin 4a
S
OTs
O
S
solvent
Br
+
+
H2N
NH2
base, r.t., 24 h
O
O
O
1a
2
3a
4a
Entry
Solvent
Base
Yield (%)a
1
2
3
4
5
6
7
8
PEG 200–H2O
PEG 200–H2O
PEG 200–H2O
PEG 200–H2O
PEG 200–H2O
1,4-dioxane
Et3N
57
60
92
40
55
37
50
58
NaOH
K2CO3
DBU
NaHCO3
K2CO3
K2CO3
K2CO3
1,4-dioxane–H2O
SDS–H2Ob
a Yield of isolated product based on 4-tosyloxycoumarin.
b SDS = sodium dodecyl sulfate.
expected product being detected (Table 2, entry 8). Other The reactions of other primary and secondary alkyl ha-
4-tosyloxycoumarin derivatives were also examined, and lides with these 4-tosyloxycoumarins also gave the de-
it transpired that the different substituents on the coumarin sired products in good to excellent yields (Table 2, entries
ring did not affect the reaction markedly. For example, 6- 10–12, 14–16 and 18–20). A very good yield of 93% was
methyl-, 6-chloro-, and 6-fluoro-4-tosyloxycoumarins re- obtained when 3-phenyl-4-tosyloxycoumarin was reacted
acted with benzyl bromide to give the corresponding with thiourea and benzyl bromide (Table 2, entry 21).
products in 92–97% yields (Table 2, entries 9, 13 and 17).
Table 2 The Scope of the Reaction of 4-Tosyloxycoumarins with Thiourea and Alkyl Halides under the Optimized Conditions
R2
S
OTs
S
R1
O
Y
R1
O
Y
K2CO3
+
R2X
+
H2N
NH2
PEG 200–H2O
O
O
1
2
3
4
Entry
1
Coumarina
R2X
Product
Yield (%)b
S
Br
Cl
1a
92
O
O
3a
3b
4a
4a
2
3
1a
1a
86
82
S
PrBr
3c
O
O
4b
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Synthesis of 4-Sulfanylcoumarins
761
Table 2 The Scope of the Reaction of 4-Tosyloxycoumarins with Thiourea and Alkyl Halides under the Optimized Conditions (continued)
R2
S
OTs
S
R1
O
Y
R1
O
Y
K2CO3
+
R2X
+
H2N
NH2
PEG 200–H2O
O
O
1
2
3
4
Entry
4
Coumarina
R2X
Product
Yield (%)b
S
MeI
3d
1a
86
O
S
O
4c
C14H29-n
n-C14H29Br
3e
5
6
1a
1a
49
84
O
O
4d
S
Br
3f
O
O
4e
S
s-BuI
3g
7
1a
67
O
O
4f
t-BuBr
3h
8
9
1a
1b
–
trace
97
S
3a
3c
O
S
O
O
4g
4h
10
11
1b
1b
94
86
O
S
3g
O
O
4i
© Georg Thieme Verlag Stuttgart · New York
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Table 2 The Scope of the Reaction of 4-Tosyloxycoumarins with Thiourea and Alkyl Halides under the Optimized Conditions (continued)
R2
S
OTs
S
R1
O
Y
R1
O
Y
K2CO3
+
R2X
+
H2N
NH2
PEG 200–H2O
O
O
1
2
3
4
Entry
Coumarina
R2X
Product
Yield (%)b
S
12
1b
3f
77
O
O
4j
S
Cl
13
14
1c
1c
3a
3c
97
86
O
S
O
O
4k
Cl
O
4l
S
Cl
15
16
1c
1c
3g
84
83
O
O
4m
S
Cl
3f
O
O
4n
S
F
17
18
1d
1d
3a
3c
92
74
O
S
O
4o
F
O
O
4p
S
F
19
1d
3g
83
O
O
4q
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Synthesis of 4-Sulfanylcoumarins
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Table 2 The Scope of the Reaction of 4-Tosyloxycoumarins with Thiourea and Alkyl Halides under the Optimized Conditions (continued)
R2
S
OTs
S
R1
O
Y
R1
O
Y
K2CO3
+
R2X
+
H2N
NH2
PEG 200–H2O
O
O
1
2
3
4
Entry
Coumarina
R2X
Product
Yield (%)b
S
F
20
1d
3f
64
O
O
4r
S
21
1e
3a
93
O
O
4s
a 1a: Y = H, R1 = H; 1b: Y = Me, R1 = H; 1c: Y = Cl, R1 = H; 1d: Y = F, R1 = H; 1e: Y = H, R1 = Me.
b Yield of isolated product based on the 4-tosyloxycoumarin.
We have proposed a general pathway for the reaction as In conclusion, we have described an efficient and novel
presented in Scheme 2. We reasoned that the sulfur anion, route for the synthesis of 4-sulfanylcoumarins via direct
formed in situ from the reaction between thiourea and the sulfanylation of 4-tosyloxycoumarins with thiourea and
alkyl halide, is a key intermediate, which attacks the 4-to- alkyl halides. This transformation was performed in poly-
syloxycoumarin to afford the 4-sulfanylcoumarin prod- ethylene glycol 200–water at room temperature without
uct.
the exclusion of air. The efficiency of this method, com-
bined with the operational simplicity should make it at-
tractive for the preparation of compound libraries.
H2O CO2
•
K2CO3
HN
KX
H2N
XH2N
H2N
S
R
S
S
R
R
X
+
H2N
H2N
OH
urea
OTs
O
NH2
NH
S
R
S R
+
S R
H2N
H2N
O
O
OH
TsO
SR
TsO
SR
O
O
O
O
Scheme 2 A proposed reaction mechanism
© Georg Thieme Verlag Stuttgart · New York
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13C NMR (100 MHz, CDCl3): δ = 14.1, 22.7, 27.7, 28.9, 29.1, 29.3,
29.4, 29.5, 29.6, 30.9, 31.9, 106.8, 117.2, 118.3, 123.8, 123.9,
132.0, 152.2, 156.7, 159.3.
HRMS (ESI): m/z [M + Na]+ calcd for C23H34O2SNa: 397.2177;
found: 397.2139.
Unless otherwise stated, all commercial reagents were used as re-
ceived. All solvents were dried and distilled according to standard
procedures. Flash column chromatography was performed using
Qingdao Haiyang silica gel (60 Å pore size, 32–63 μm, standard
grade). Analytical thin-layer chromatography was performed using
Qingdao Haiyang glass plates, pre-coated with silica gel (0.25 mm,
230–400 mesh) impregnated with a fluorescent indicator (254 nm);
the plates were visualized by exposure to UV light. Petroleum ether
(PE) refers to the fraction boiling in the 60–90 °C range. Organic so-
lutions were concentrated by rotary evaporation at ~20 Torr and at
25–35 °C. Melting points were recorded using a Taike X-6 appara-
tus. IR spectra were obtained using a Perkin-Elmer FTIR 683 spec-
4-Cyclopentylsulfanylcoumarin (4e)
Yield: 41.3 mg (84%); yellow solid; mp 130–132 °C.
1H NMR (400 MHz, CDCl3): δ = 1.67–1.82 (m, 6 H), 2.26–2.29 (m,
2 H), 3.72–3.73 (m, 1 H), 6.22 (s, 1 H), 7.24–7.27 (m, 1 H), 7.32 (d,
J = 8.4 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.1, 33.2, 43.2, 107.7, 117.2,
118.3, 123.9, 124.0, 132.0, 152.2, 157.2, 159.4.
HRMS (ESI): m/z [M + Na]+ calcd for C14H14O2SNa: 269.0612;
found: 269.0586.
1
trometer. H and 13C NMR spectra were recorded in CDCl3 on a
Bruker DRX-400 spectrometer operating at 400 MHz and 100
MHz, respectively. Chemical shifts (δ) are recorded in parts per mil-
lion with tetramethylsilane as the internal standard. Coupling con-
stants (J) are quoted in Hz. High-resolution mass spectrometry
(HRMS) was performed using a Bruker micrOTOF II instrument.
4-sec-Butylsulfanylcoumarin (4f)
Yield: 31.4 mg (67%); yellow solid; mp 85–86 °C.
IR (KBr): 3442, 2919, 1714, 1594, 1341, 1233, 740, 703, 642 cm–1.
4-Sulfanylcoumarins; General Procedure
A mixture of haloalkane 3 (0.4 mmol), thiourea (2) (0.5 mmol) and
K2CO3 (0.6 mmol) in PEG 200 (3 mL) and H2O (0.3 mL) was stirred
magnetically at r.t. for several hours. Following completion of this
step as indicated by TLC, the 4-tosyloxycoumarin 1 (0.2 mmol) was
added and the mixture was stirred at r.t. for 24–48 h. After comple-
tion of the reaction as indicated by TLC, the mixture was extracted
with EtOAc (3 × 2 mL), and the combined organic layer washed
with H2O (3 mL) and dried over Na2SO4. Evaporation of the solvent
and purification of the residue by silica gel chromatography (PE–
EtOAc, 10:1–8:1) afforded the desired product 4. The structures of
the products were confirmed by 1H NMR and 13C NMR spectrosco-
py.
1H NMR (400 MHz, CDCl3): δ = 1.11 (t, J = 7.2 Hz, 3 H), 1.49 (d,
J = 6.4 Hz, 3 H), 1.73–1.89 (m, 2 H), 3.41–3.44 (m, 1 H), 6.19 (s, 1
H), 7.26–7.34 (m, 2 H), 7.55 (t, J = 7.8 Hz, 1 H), 7.78 (d, J = 8.0 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 11.3, 19.9, 29.0, 41.9, 107.3,
117.2, 118.4, 123.9, 124.0, 132.0, 152.3, 156.2, 159.4.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14O2S: 257.0612; found:
257.0592.
4-Benzylsulfanyl-6-methylcoumarin (4g)5
Yield: 54.7 mg (97%); white solid; mp 139–140 °C.
4-Benzylsulfanylcoumarin (4a)3a
Yield: 49.3 mg (92%); white solid; mp 176–178 °C.
1H NMR (400 MHz, CDCl3): δ = 2.73 (s, 3 H), 4.23 (s, 2 H), 6.19
(s, 1 H), 7.18 (d, J = 8.4 Hz, 1 H), 7.30–7.47 (m, 7 H).
1H NMR (400 MHz, CDCl3): δ = 4.26 (s, 2 H), 6.23 (s, 1 H), 7.25–
7.45 (m, 7 H), 7.53 (t, J = 7.2 Hz, 1 H), 7.73 (d, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 35.8, 106.9, 116.7, 117.5, 123.3,
13C NMR (100 MHz, CDCl3): δ = 20.9, 35.8, 107.3, 116.9, 117.6,
123.6, 128.2, 129.0, 129.1, 133.2, 133.8, 133.9, 150.3, 155.9, 159.4.
6-Methyl-4-propylsulfanylcoumarin (4h)
Yield: 44 mg (94%); white solid; mp 104–105 °C.
123.6, 127.7, 128.4, 128.9, 129.1, 131.6, 133.2, 151.7, 156.6, 158.7.
4-Propylsulfanylcoumarin (4b)5
Yield: 36.1 mg (82%); white solid; mp 83–85 °C.
IR (KBr): 3444, 3063, 1709, 1301, 1234, 1139, 1122, 699, 618 cm–
.
1
1H NMR (400 MHz, CDCl3): δ = 1.13 (t, J = 7.4 Hz, 3 H), 1.82–1.87
(m, 2 H), 3.00 (t, J = 7.2 Hz, 2 H), 6.14 (s, 1 H), 7.25–7.32 (m, 2 H),
7.53 (t, J = 7.2 Hz, 1 H), 7.74 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.5, 21.2, 32.7, 106.7, 117.1,
118.3, 123.8, 123.9, 132.0, 152.1, 156.6, 159.3.
1H NMR (400 MHz, CDCl3): δ = 1.12 (t, J = 7.2 Hz, 3 H), 1.82–1.87
(m, 2 H), 2.41 (s, 3 H), 2.99 (t, J = 7.2 Hz, 2 H), 6.12 (s, 1 H), 7.20
(d, J = 8.4 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.52 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.6, 20.9, 21.2, 32.7, 106.6,
116.9, 117.9, 123.6, 133.1, 133.8, 150.2, 156.5, 159.6.
HRMS (ESI): m/z [M + Na]+ calcd for C13H14O2SNa: 257.0612;
found: 257.0606.
4-Methylsulfanylcoumarin (4c)
Yield: 33 mg (86%); white solid; mp 119–121 °C.
IR (KBr): 3443, 1717, 1346, 1254, 708, 619 cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.54 (s, 3 H), 6.10 (s, 1 H), 7.26–
7.32 (m, 2 H), 7.52 (t, J = 7.2 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.8, 106.5, 117.1, 118.1, 123.7,
124.0, 132.1, 152.0, 157.2, 159.2.
4-sec-Butylsulfanyl-6-methylcoumarin (4i)
Yield: 42.7 mg (86%); yellow solid; mp 122–123 °C.
IR (KBr): 3414, 2954, 1702, 1348, 1222, 679, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.09 (t, J = 7.2 Hz, 3 H), 1.47 (d,
J = 6.8 Hz, 3 H), 1.72–1.88 (m, 2 H), 2.41 (s, 3 H), 3.38–3.43 (m, 1
H), 6.16 (s, 1 H), 7.19–7.35 (m, 2 H), 7.54 (s, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C10H8O2SNa: 215.0143;
found: 215.0164.
13C NMR (100 MHz, CDCl3): δ = 11.4, 19.9, 20.9, 29.0, 41.8, 107.1,
116.9, 118.1, 123.8, 133.1, 133.7, 150.3, 156.0, 159.7.
HRMS (ESI): m/z [M + Na]+ calcd for C14H16O2S: 271.0769; found:
271.0760.
4-Tetradecylsulfanylcoumarin (4d)
Yield: 36.7 mg (49%); white solid; mp 79–80 °C.
IR (KBr): 3443, 2921, 1716, 1341, 1272, 704, 619 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.6 Hz, 3 H), 1.26–1.82
(m, 24 H), 3.01 (t, J = 7.2 Hz, 2 H), 6.15 (s, 1 H), 7.25–7.33 (m, 2
H), 7.52 (t, J = 7.6 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H).
4-Cyclopentylsulfanyl-6-methylcoumarin (4j)
Yield: 40 mg (77%); white solid; mp 150–152 °C.
IR (KBr): 3415, 2959, 2918, 1697, 1350, 1267, 777, 617 cm–1.
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Synthesis of 4-Sulfanylcoumarins
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1H NMR (400 MHz, CDCl3): δ = 1.71–1.82 (m, 6 H), 2.26–2.29 (m,
2 H), 2.40 (s, 3 H), 3.71 (d, J = 4.4 Hz, 1 H), 6.20 (s, 1 H), 7.20 (d,
J = 8.4 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 1 H), 7.50 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.9, 25.0, 33.2, 43.1, 107.6,
116.9, 117.9, 123.7, 133.0, 133.7, 150.3, 157.0, 159.7.
HRMS (ESI): m/z [M + Na]+ calcd for C15H16O2SNa: 283.0769;
found: 283.0775.
HRMS (ESI): m/z [M + Na]+ calcd for C16H11FO2SNa: 309.0361;
found: 309.0346.
6-Fluoro-4-propylsulfanylcoumarin (4p)
Yield: 35.2 mg (74%); white solid; mp 110–111 °C.
IR (KBr): 3413, 3113, 2872, 1720, 1344, 1225, 712, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.13 (t, J = 7.6 Hz, 3 H), 1.83–1.90
(m, 2 H), 3.01 (t, J = 7.2 Hz, 2 H), 6.17 (s, 1 H), 7.25–7.31 (m, 2 H),
7.39–7.41 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.5, 21.1, 32.9, 107.5, 109.7 (d,
2JC–F = 25 Hz), 118.7 (d, 3JC–F = 8 Hz), 119.0 (d, 3JC–F = 9 Hz), 119.5
(d, 2JC–F = 24 Hz), 148.3, 155.6, 158.5 (d, 1JC–F = 242 Hz), 158.9.
4-Benzylsulfanyl-6-chlorocoumarin (4k)
Yield: 58.6 mg (97%); white solid; mp 135–136 °C.
IR (KBr): 3412, 2920, 1713, 1339, 1244, 740, 680, 614 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.25 (s, 2 H), 6.23 (s, 1 H), 7.22–
7.65 (m, 7 H), 7.66 (d, J = 2.4 Hz, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C12H11FO2SNa: 261.0361;
found: 261.0367.
13C NMR (100 MHz, CDCl3): δ = 35.9, 108.2, 118.6, 119.0, 123.4,
128.4, 129.0, 129.1, 129.6, 132.1, 133.4, 150.6, 154.9, 158.5.
HRMS (ESI): m/z [M + Na]+ calcd for C16H11ClO2SNa: 325.0094;
4-(sec-Butylsulfanyl)-6-fluorocoumarin (4q)
Yield: 41.8 mg (83%); white solid; mp 120–121 °C.
IR (KBr): 3417, 2969, 1711, 1345, 1221, 1134, 701, 612 cm–1.
found: 325.0066.
1H NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 7.2 Hz, 3 H), 1.48 (d,
J = 6.8 Hz, 3 H), 1.72–1.86 (m, 2 H), 3.42–3.44 (m, 1 H), 6.21 (s, 1
H), 7.25–7.32 (m, 2 H), 7.43 (dd, J = 2.8, 8.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 11.4, 19.8, 28.9, 42.2, 108.0,
109.9 (d, 2JC–F = 25 Hz), 118.7 (d, 3JC–F = 9 Hz), 119.2, 119.5 (d,
2JC–F = 25 Hz), 148.4, 155.3, 158.5 (d, 1JC–F = 242 Hz), 159.1.
6-Chloro-4-propylsulfanylcoumarin (4l)
Yield: 43.7 mg (86%); white solid; mp 102–103 °C.
IR (KBr): 3443, 2926, 1741, 1463, 1383, 1337, 1243, 701, 745, 614
cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.13 (t, J = 7.2 Hz, 3 H), 1.82–1.88
(m, 2 H), 3.01 (t, J = 7.2 Hz, 2 H), 6.16 (s, 1 H), 7.26 (d, J = 8.8 Hz,
1 H), 7.48 (dd, J = 8.8, 2.4 Hz, 1 H), 7.70 (d, J = 2.0 Hz, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C13H13FO2SNa: 275.0518;
found: 275.0522.
13C NMR (100 MHz, CDCl3): δ = 13.5, 21.1, 32.9, 107.5, 118.6,
119.3, 123.5, 129.6, 132.0, 150.6, 155.5, 158.7.
HRMS (ESI): m/z [M + Na]+ calcd for C12H11ClO2SNa: 277.0066;
4-Cyclopentylsulfanyl-6-fluorocoumarin (4r)
Yield: 33.8 mg (64%); yellow solid; mp 115–117 °C.
IR (KBr): 3445, 2960, 1707, 1343, 1225, 1135, 716, 625, 612 cm–1.
found: 277.0085.
1H NMR (400 MHz, CDCl3): δ = 1.72–1.86 (m, 6 H), 2.27–2.30 (m,
2 H), 3.70–3.73 (m, 1 H), 6.25 (s, 1 H), 7.22–7.32 (m, 2 H), 7.38
(dd, J = 2.8, 8.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.0, 33.1, 43.4, 108.4, 109.8 (d,
2JC–F = 26 Hz), 118.7 (d, 3JC–F = 9 Hz), 119.1 (d, 3JC–F = 9 Hz), 119.4
(d, 2JC–F = 25 Hz), 148.3, 156.2, 158.5 (d, 1JC–F = 243 Hz), 159.0.
4-(sec-Butylsulfanyl)-6-chlorocoumarin (4m)
Yield: 45 mg (84%); white solid; mp 109–111 °C.
IR (KBr): 3443, 3073, 1724, 1338, 1229, 741, 705, 612 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 7.2 Hz, 3 H), 1.48 (d,
J = 6.8 Hz, 3 H), 1.71–1.88 (m, 2 H), 3.40–3.45 (m, 1 H), 6.19 (s, 1
H), 7.26 (d, J = 9.2 Hz, 1 H), 7.46 (dd, J = 8.8, 2.4 Hz, 1 H), 7.73
(d, J = 2.0 Hz, 1 H).
HRMS (ESI): m/z [M + Na]+ calcd for C14H13FO2SNa: 287.0518;
found: 287.0506.
13C NMR (100 MHz, CDCl3): δ = 11.4, 19.8, 28.9, 42.2, 107.9,
118.6, 119.5, 123.7, 129.5, 131.9, 150.7, 155.1, 158.8.
HRMS (ESI): m/z [M + Na]+ calcd for C13H13ClO2SNa: 291.0222;
4-Benzylsulfanyl-3-phenylcoumarin (4s)
Yield: 64 mg (93%); white solid; mp 159–160 °C.
found: 291.0247.
IR (KBr): 3446, 3062, 1709, 1603, 1586, 1507, 1477, 1328, 1234,
704, 604 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.59 (s, 2 H), 6.90–7.42 (m, 13 H),
8.15 (d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 39.2, 116.9, 120.6, 124.4, 127.2,
127.7, 128.2, 128.6, 128.9, 130.4, 131.7, 131.8, 134.6, 136.1, 148.7,
152.1, 159.7.
6-Chloro-4-cyclopentylsulfanylcoumarin (4n)
Yield: 46.5 mg (83%); white solid; mp 139–140 °C.
IR (KBr): 3442, 2960, 2918, 1736, 1337, 1266, 704, 681, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 1.72–1.82 (m, 6 H), 2.26–2.29 (m,
2 H), 3.71–3.73 (m, 1 H), 6.23 (s, 1 H), 7.27 (t, J = 7.2 Hz, 1 H),
7.46 (dd, J = 8.4, 2.0 Hz, 1 H), 7.67 (d, J = 2.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 25.0, 33.1, 43.4, 108.4, 118.6,
119.4, 123.6, 129.5, 131.9, 150.6, 156.0, 158.8.
HRMS (ESI): m/z [M + Na]+ calcd for C14H13ClO2SNa: 303.0222;
Acknowledgment
We are grateful to the National Natural Science Foundation of Chi-
na (grants 20962010 and 21162012), Jiangxi Provincial Department
of Science and Technology (for the Jiangxi Key Laboratory of
Green Chemistry), and the Science Foundation of the Education
Department of Jiangxi province (grant no. GJJ10386) for financial
support.
found: 303.0257.
4-Benzylsulfanyl-6-fluorocoumarin (4o)
Yield: 52.6 mg (92%); yellow solid; mp 118–119 °C.
IR (KBr): 3442, 2958, 1708, 1348, 1225, 696, 613 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.27 (s, 2 H), 6.26 (s, 1 H), 7.26–
7.44 (m, 8 H).
Supporting Information for this article is available online at
13C NMR (100 MHz, CDCl3): δ = 35.9, 108.3, 109.7 (d, 2JC–F = 26
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Hz), 118.7, 118.8, 118.9, 119.6 (d, JC–F = 24 Hz), 128.4, 128.9,
129.1, 133.5, 148.4, 155.0, 158.6 (d, 1JC–F = 243 Hz), 158.8.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 759–766

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© Georg Thieme Verlag Stuttgart · New York