Hydrothiolation and intramolecular cyclization sequence for the synthesis of 1,3-oxathiine frameworks

Article abstract of DOI:10.1055/s-0032-1316563

1,3-Oxathiine frameworks can be prepared via the sequential addition and intramolecular cyclization of thiosalicylic acid onto alkynes. A substituent on the alkyne and the presence of a palladium catalyst can allow product regioselectivity control. This strategy is applicable to the synthesis of heterocycles comprising sulfur and oxygen atoms, namely 3,1-benzoxathiines, without any unwanted byproduct. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316563

PAPER
▌2607
pHapyerdrothiolation and Intramolecular Cyclization Sequence for the Synthesis of
1,3-Oxathiine Frameworks
1,3-Oxathiine Frameworks
Yuta Nishina,* Junya Miyata
Research Core for Interdisciplinary Sciences, Okayama University, Tsushima, Kita-ku, Okayama 700-8530, Japan
Fax +81(86)2518718; E-mail: nisina-y@cc.okayama-u.ac.jp
Received: 17.04.2012; Accepted after revision: 25.05.2012
(cis, trans, and geminal) via hydroheterofunctionaliza-
Abstract: 1,3-Oxathiine frameworks can be prepared via the se-
tion. On the other hand, cross-coupling reactions that em-
quential addition and intramolecular cyclization of thiosalicylic
ploy a leaving group bearing substrate usually proceed to
give one exclusive regioisomer. Thus, predominantly,
acid onto alkynes. A substituent on the alkyne and the presence of a
palladium catalyst can allow product regioselectivity control. This
strategy is applicable to the synthesis of heterocycles comprising coupling or substitution protocols have been adopted to
sulfur and oxygen atoms, namely 3,1-benzoxathiines, without any
unwanted byproduct.
generate the desired cyclic product (Scheme 1).
We have focused on the regioselective addition of a thiol
Key words: heterocycles, hydrothiolation, palladium, sequential
to an alkyne (hydrothiolation)4 and intramolecular cycli-
reaction, alkynes, 3,1-benzoxathiines
zation via the addition of a carboxylic acid to the resulting
alkene (hydrooxycarbonylation).5 Although these reac-
tions have each been previously investigated indepen-
Heterocycles containing two different heteroatoms are
dently, there has been no report of a sequential one-pot
widely observed in natural and biologically active com-
protocol.6
pounds. Though there have been many methods for their
Initially, we investigated different catalysts and reaction
conditions for the model reaction of thiosalicylic acid (1a)
with dodec-1-yne (2a) (Table 1). A wide variety of transi-
tion metals promoted the hydrothiolation/intramolecular
cyclization sequence. However, most of them led to mix-
tures of uncharacterized products, including regioisomers
of 3a.7 Of these catalysts, palladium(II) acetate and
bis(benzonitrile)dichloropalladium selectively produced
the 1,3-oxathiine derivative 3a.8–10
preparation, the annulation of two different molecules has
been particularly effective in terms of molecular diversity.
Sequential addition–cyclizations are a typical approach,
but they often require one or more leaving groups.1 How-
ever, the introduction of two heteroatoms via sequential
hydroheterofunctionalizations on an alkyne would be
atom-economical. Hydroheterofunctionalizations both
with and without catalysts have been developed to date,
but two types of hydroheterofunctionalization occurring
in one pot is rare.2 The regioselectivity of the initial hydro-
heterofunctionalization presents another challenge.3
Asymmetric alkynes can lead to three types of alkenes
The scope of the reaction, with respect to the alkyne 2 was
also examined (Table 2). Alkynes with alkyl or aryl sub-
stituents gave the corresponding 1,3-oxathiine derivatives
our strategy
R
XH
+
XH
Y
X
Y
YH
R
high selectivity
R
common strategy
XH
Y
L
L
R
R
XH
YH
X
Y
– HL
R
XH
Y
R
– HL
L = leaving group
L
R
Scheme 1 Synthesis of heterocyclic compounds
SYNTHESIS 2012, 44, 2607–2613
Advanced online publication: 03.07.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316563; Art ID: SS-2012-F0280-OP
© Georg Thieme Verlag Stuttgart · New York

2608
Y. Nishina, J. Miyata
PAPER
Table 2 Survey of Unactivated Alkynesa
Table 1 Examination of Catalysts for the Formation of 3aa
O
O
O
O
O
catalyst
Pd(OAc)2 (5 mol%)
toluene, 120 °C, 1 h
O
(5 mol%)
OH
OH
R
+
n-C10H21
2a
+
2
toluene
150 °C, 24 h
S
SH
1a (1.2 equiv)
S
R
SH
1a (1.5 equiv)
n-C10H21
3
3a
Entry
Alkyne
R
Product
3a
Yieldb (%)
Entry
Catalyst
Yieldb (%)
1
2a
n-C10H21
72 (86)
83 (99)
1
2
3c
4
5
6
7
8
9
HAuCl4
2.0
7.2
9.1
24
2c
IrCl3·n H2O
RuCl3·n H2O
H2PtCl4
3
4
5
6
7
8c
2b
2c
2d
2e
2f
(CH2)2Ph
CH2OBn
Ph
3b
3c
3d
3e
3f
42 (56)
40 (44)
72 (83)
65 (73)
20 (25)
59 (78)
RhCl3·n H2O
NiCl2
27
4-MeC6H4
4-MeOC6H4
4-F3CC6H4
3-pyridyl
47
PdCl2
51
2g
2h
3g
3h
PdCl2(PPh3)2
Pd(dba)2
60
9
9 (9)
39 (39)
10c
82
11
2i
2-furyl
3i
56 (68)
64 (77)
10
PdCl2(PhCN)2
Pd(OAc)2
Pd(OAc)2
97
12d
11
96
a Reaction conditions: Pd(OAc)2 (5 mol%), 1a (0.24 mmol), 2 (0.20
mmol), toluene (1 mL), argon atmosphere.
b Isolated yield. NMR yield is given in parenthesis. Due to hydrolysis
of the product during column chromatography, the isolated yield was
lower than the NMR yield.
12c
91
a Reaction conditions: catalyst (5 mol%), 1a (0.30 mmol), 2a (0.20
mmol), toluene (1 mL), argon atmosphere.
b The yield was determined by GC using n-dodecane as an internal
standard.
c 150 °C, 3 h.
d 80 °C.
c 120 °C, 1 h.
Table 3 Survey of Activated Alkynesa
3a–g (entries 1–8). Since an alkyne with an electron-
donating aryl group 2f is susceptible to oligomerization,
3f was only obtained in low yield (entry 7). Although the
pyridyl-substituted alkyne 2h required high temperatures
to form the corresponding 1,3-oxathiine 3h (entries 9 and
10), the furyl-substituted alkyne 2i gave the correspond-
ing product 3i under mild conditions (entry 12). However,
internal alkynes, dodec-6-yne, and diphenylacetylene, did
not give the desired products.
O
O
no catalyst
toluene
O
OH
+
R
R
2
S
4
SH
1a (1.2 equiv)
Entry
Alkyne
R
Temp
(°C)
Time Product Yield
(h)
(%)
1
2
3
4
2j
CO2Et
CO2Ph
Ac
135
135
120
120
7
4
1
1
4j
86
97
84
98
When activated alkynes are employed, a similar reaction
occurs, even in the absence of a catalyst. It was recently
reported that a thiol can add to such alkynes selectively
via a Michael-type reaction,11,12 but a further cyclization
step has not been explored. More recently, the ruthenium-
catalyzed alkenylation of a C–H bond, and successive in-
tramolecular Michael addition has been reported,13 but
metal-free reaction conditions were not examined. Al-
kynes with a β-carbonyl group 2j–l provided their 1,3-ox-
athiine derivatives 4j–l, but with different
regioselectivities to that observed for the formation of 3
(Table 3). The ester moiety slowed down the intramolec-
ular cyclization, therefore, higher temperatures and longer
reaction times were necessary (entries 1 and 2).14 Despite
the result obtained for 3-ethynylpyridine (2h) (Table 2,
entry 9), 2-ethynylpyridine (2m) gave the corresponding
2k
2l
4k
4l
2m
2-pyridyl
4m
a Reaction conditions: 1a (0.24 mmol), 2 (0.20 mmol), toluene (1 mL),
argon atmosphere.
1,3-oxathiine 4m with no methyl group at the 2-position
(entry 4).15
Pent-4-ynyl propiolate (2n) was subjected to reaction un-
der catalyst-free conditions with 1a at 150 °C for six
hours, followed by addition of catalytic palladium(II) ace-
tate and an additional amount of 1a with heating at 120 °C
Synthesis 2012, 44, 2607–2613
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,3-Oxathiine Frameworks
2609
O
O
O
O
O
CO2H
1) toluene, 150 °C, 6 h
S
S
O
+
O
2) 1a (1.2 equiv)
Pd(OAc)2 (5 mol%)
toluene, 120 °C, 1 h
SH
1a (1.2 equiv)
2n
O
4n
46% isolated yield
(74% yield determined by NMR)
Equation 1
CO2H
S
CF3
CO2H
Pd(OAc)2 (5 mol%)
toluene, 100 °C, 1 h
+
+ 3g 13%
SH
1a (1.5 equiv)
2g
CF3
5b 53%
Equation 2
for one hour. This successfully generated the bis-1,3-ox-
athiine derivative 4n (Equation 1).16
We then monitored the profile of the reaction with thiosal-
icylic acid (1a) and dodec-1-yne (2a) in the presence of a
catalytic amount of palladium(II) acetate. To slow down
the reaction rate for a finer analysis, the reaction tempera-
ture was lowered to 80 °C; 1a, 3a, and intermediate 5a
were measured using 1H NMR after 0.5, 1, 2, 3, 6, 9, and
18 hours. The intramolecular cyclization is slower than
hydrothiolation, since after 0.5 hours, more 5a (33%) is
observed than 3a (11%) (Figure 1).
The proposed mechanism is further supported by the fol-
lowing investigations. The reaction of thiosalicylic acid
(1a) and 1-(trifluoromethyl)-4-vinylbenzene (2g),17 in the
presence of palladium(II) acetate provided the corre-
sponding vinyl sulfide 5b in 53% yield, along with 1,3-
oxathiine 3g in 13% yield (Equation 2).
We went on to investigate further the mechanism of the
intramolecular hydrooxycarbonylation of the vinyl sulfide
5b (Table 4). The reaction did not occur at 120 °C in the
absence and presence of palladium(II) acetate, suggesting
that the palladium catalyst does not promote the cycliza-
tion (entries 1 and 2). A catalytic amount of thiosalicylic
acid (1a) enhanced the reaction conversion (entry 3). To
determine the active moiety of 1a for the cyclization, the
addition of a catalytic amount of thiophenol and benzoic
acid was investigated, as a result, the thiol group was
found to be necessary (entries 4 and 5). The reaction was
also promoted by the radical initiator, 2,2′-azobisisobutyr-
onitrile (entry 6), and inhibited by the radical inhibitor,
galvinoxyl free radical (entry 7). These results suggest a
radical-mediated initiation. The same behavior was ob-
served for the intramolecular cyclization of a vinyl sulfide
bearing an electron-withdrawing group 5c;18 a catalytic
Figure 1 Reaction profile. Reaction conditions: Pd(OAc)2 (5.0
mol%), 1a (1.0 mmol), 2a (1.0 mmol), benzene-d6 (3 mL),
CHCl2CHCl2 (1.0 mmol, internal standard), argon atmosphere, 80 °C.
Small portions of the reaction mixture were taken at designated time
points for NMR analysis.
amount of 1a and thiophenol also accelerated the forma-
tion of 4j (Equation 3).19
In an attempt to broaden the scope of our strategy, other
hydroheterofunctionalizations were examined (Equation
4). Under similar reaction conditions, as shown in Table
1, 2-(hydroxymethyl)thiophenol (1b) underwent sequen-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2607–2613

2610
Y. Nishina, J. Miyata
PAPER
thiolations of the unactivated alkynes 2a–i with a
palladium catalyst, and of activated alkynes 2j–m without
a catalyst, led to the selective synthesis of 1,3-oxathiines
3 and 4. This strategy was applicable to the synthesis of
heterocycles containing sulfur and oxygen atoms.
O
CO2H
O
CO2Et
toluene, 150 °C, 12 h
CO2Et
S
S
4j
5c
additive: 1a (25 mol%)
PhSH (25 mol%)
none
95%
97%
34%
All reactions were carried out in dry solvent under an argon atmo-
sphere. Toluene was purchased from Wako Pure Chemical Indus-
tries, dried with molecular sieves 4A, and degassed before use.
Pd(OAc)2 was purchased from Wako Pure Chemical Industries. 1H
(400 MHz) and 13C (100 MHz) NMR spectra were recorded using a
Jeol JNM-LA400 spectrometer relative to solvent peaks [CHCl3: δ
= 7.26 (1H), δ = 77.00 (13C)]. IR (ATR) spectra were measured with
a Jasco ATR PRO450-S with Ge. HRMS were measured by Jeol
JMS-700 or Jeol JMS-T100LP AccuTOF LC-Plus (ESI) spectrom-
eters with a Jeol MS-5414DART attachment.
Equation 3
Table 4 Reaction Conditions for Intramolecular Cyclizationa
O
CO2H
O
S
2-Substituted 2-Methyl-3,1-benzoxathiine-4H-ones 3; General
Procedure
toluene, 120 °C, 3 h
S
Thiosalicylic acid (1a, 0.240 mmol), alkyne 2 (0.200 mmol), and
Pd(OAc)2 (0.01 mmol) were added to toluene (1 mL) under an ar-
gon atmosphere. The mixture was stirred at the temperature and for
the time indicated in Table 2. The mixture was concentrated in vac-
uo, and the residue was purified by column chromatography to give
1,3-oxathiin 3.
CF3
CF3
5b
3g
Entry
Catalyst
Yield (%)
When unreacted 1a was observed after the reaction, the mixture was
washed with aq K2CO3, and purified by column chromatography.
1
2
3
4
5
6
7
none
0
0
Pd(OAc)2 (5 mol%)
1a (25 mol%)
2-Decyl-2-methyl-4H-3,1-benzoxathiin-4-one (3a)
Colorless oil; yield: 53.2 mg (0.166 mmol, 83%).
IR: 2923, 2852, 1723, 1441, 1282, 1108, 1031, 742 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.20–8.16 (m, 1 H), 7.48–7.44 (m,
1 H), 7.29–7.25 (m, 2 H), 2.04–1.98 (m, 2 H), 1.77 (s, 3 H), 1.60–
1.48 (m, 2 H), 1.24 (s, 14 H), 0.87 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.5, 136.8, 133.8, 132.0, 127.9,
126.1, 123.6, 89.5, 41.2, 31.8, 29.5, 29.4, 29.4, 29.3, 29.2, 26.9,
24.4, 22.6, 14.1.
67
59
7
PhSH (25 mol%)
PhCO2H (25 mol%)
AIBN (25 mol%)
53
3
galvinoxyl free radical
(25 mol%) + PhSH (25 mol%)
HRMS (ESI): m/z [M + H]+ calcd for C19H29O2S: 321.18883; found:
321.18849.
a Reaction conditions: 5b (0.05 mmol), toluene (0.3 mL), argon atmo-
sphere, 120 °C, 3 h. The yields were determined by 1H NMR using
CHCl2CHCl2 as an internal standard.
2-Methyl-2-phenethyl-4H-3,1-benzoxathiin-4-one (3b)
Pale yellow oil; yield: 23.9 mg (0.084 mmol, 42%).
IR: 3062, 3027, 1716, 1441, 1284, 1113, 1031, 740, 698 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.21–8.16 (m, 1 H), 7.53–7.46 (m,
1 H), 7.33–7.27 (m, 3 H), 7.25–7.12 (m, 4 H), 2.94–2.86 (m, 2 H),
2.38–2.30 (m, 2 H), 1.86 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.3, 140.5, 136.5, 134.0, 132.1,
128.5, 128.3, 128.0, 126.3, 126.2, 123.5, 88.9, 43.0, 30.8, 27.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H17O2S: 285.09493; found:
285.09330.
tial hydrothiolation/hydroalkoxylation with alkyne 2a in
the presence of palladium(II) acetate, to give 1,3-oxathi-
ine 6 in 81% yield. When performed at 120 °C, the yield
of 6 was low (30%) and the hydrothiolation product was
observed in 50% yield. This indicates that the intramolec-
ular hydroalkoxylation is slower than not only the hydro-
thiolation, but also the intramolecular addition of
carboxylic acid to the alkene.
2-[(Benzyloxy)methyl]-2-methyl-4H-3,1-benzoxathiin-4-one
(3c)
Pale yellow oil; yield: 24.1 mg (0.080 mmol, 40%).
IR: 3063, 2925, 1724, 1590, 1442, 1286, 1090, 743, 698 cm–1.
In conclusion, we have developed an atom-economical
protocol for the synthesis of heterocycles via two sequen-
tial hydroheterofunctionalizations. Regioselective hydro-
Pd(OAc)2 (5 mol%)
toluene, 150 °C, 3 h
OH
O
+
n-C10H21
2a
SH
S
n-C10H21
1b (1.0 equiv)
6 81%
Equation 4
Synthesis 2012, 44, 2607–2613
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,3-Oxathiine Frameworks
2611
1H NMR (400 MHz, CDCl3): δ = 8.12–8.09 (m, 1 H), 7.46–7.41 (m,
1 H), 7.33–7.19 (m, 7 H), 4.56 (s, 2 H), 3.78–3.68 (m, 2 H), 1.81 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 162.8, 137.2, 136.4, 133.9, 132.0,
128.4, 127.8, 127.6, 127.6, 126.2, 123.4, 87.7, 74.6, 73.6, 25.1.
IR: 3064, 2980, 2929, 1718, 1587, 1441, 1284, 1226, 1084, 1021,
957, 815, 740, 714, 683 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.93 (s, 1 H), 8.56 (d, J = 4.0 Hz,
1 H), 8.20–8.00 (m, 2 H), 7.46–7.41 (m, 1 H), 7.35 (dd, J = 4.8, 5.2
Hz, 1 H), 7.31–7.18 (m, 2 H), 2.11 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H17O3S: 301.08825; found:
13C NMR (100 MHz, CDCl3): δ = 163.1, 148.7, 146.1, 138.8, 135.6,
301.08984.
134.5, 134.2, 132.3, 127.7, 127.1, 124.0, 123.6, 88.3, 31.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H12NO2S: 258.05887;
found 258.05913.
2-Methyl-2-phenyl-4H-3,1-benzoxathiin-4-one (3d)
Pale yellow solid; yield: 36.9 mg (0.144 mmol, 72%); mp 68.5–69.3
°C.
IR: 3060, 1720, 1590, 1441, 1279, 1027, 741, 698 cm–1.
2-(Furan-2-yl)-2-methyl-4H-3,1-benzoxathiin-4-one (3i)
Yellow oil; yield: 31.5 mg (0.128 mmol, 64%).
1H NMR (400 MHz, CDCl3): δ = 8.08–8.05 (m, 1 H), 7.65–7.61 (m,
2 H), 7.42–7.37 (m, 1 H), 7.32–7.24 (m, 4 H), 7.24–7.16 (m, 1 H),
2.07 (s, 3 H).
IR: 3064, 2925, 2825, 1714, 1588, 1441, 1283, 1014, 741, 687 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.15–8.10 (m, 1 H), 7.48–7.41 (m,
1 H), 7.32–7.29 (m, 1 H), 7.28–7.22 (m, 2 H), 6.35–6.32 (m, 1 H),
6.23–6.20 (m, 1 H), 2.13 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.9, 142.3, 136.6, 133.8, 132.0,
128.5, 128.4, 127.4, 126.5, 125.6, 124.4, 90.3, 31.3.
HRMS (ESI): m/z [M + H]+ calcd for C15H13O2S: 257.06363; found:
13C NMR (100 MHz, CDCl3): δ = 163.2, 152.3, 143.0, 136.2, 133.9,
132.0, 127.3, 126.5, 123.5, 110.4, 109.1, 84.4, 28.0.
257.0619.
HRMS (ESI): m/z [M + H]+ calcd for C13H11O3S: 247.04289; found:
247.04298.
2-Methyl-2-(p-tolyl)-4H-3,1-benzoxathiin-4-one (3e)
Pale yellow oil; yield: 35.1 mg (0.130 mmol, 65%).
2-Decyl-2-methyl-4H-3,1-benzoxathiin (6)
IR: 3029, 2925, 1721, 1592, 1441, 1279, 1112, 1084, 1030, 818,
741, 686 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.08–8.04 (m, 1 H), 7.50 (d, J =
8.2 Hz, 2 H), 7.42–7.36 (m, 1 H), 7.27–7.22 (m, 1 H), 7.21–7.09 (m,
1 H), 7.09 (d, J = 8.2 Hz, 2 H), 2.28 (s, 3 H), 2.05 (s, 3 H).
2-(Hydroxymethyl)thiophenol (1b, 0.200 mmol), alkyne 2a (0.200
mmol), and Pd(OAc)2 (0.01 mmol) were added to toluene (1 mL)
under an argon atmosphere. The mixture was stirred at 150 °C for 3
h. The mixture was concentrated in vacuo, and the residue was pu-
rified by column chromatography to give benzoxathiine 6.
Pale yellow oil; yield: 49.7 mg (0.162 mmol, 81%).
13C NMR (100 MHz, CDCl3): δ = 164.0, 139.4, 138.4, 136.8, 133.7,
IR: 2923, 2852, 1593, 1571, 1465, 1440, 1371, 1211, 1084, 742
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.18–7.10 (m, 2 H), 7.10–7.00 (m,
2 H), 4.83 (d, J = 2.8 Hz, 2 H), 1.96–1.80 (m, 2 H), 1.63 (s, 3 H),
1.54–1.43 (m, 2 H), 1.31–1.15 (m, 14 H), 0.88 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 132.6, 130.8, 128.0, 127.3, 125.5,
124.4, 85.3, 64.1, 42.4, 31.9, 29.8, 29.6, 29.6, 29.5, 29.3, 26.9, 23.9,
22.7, 14.1.
132.0, 129.1, 127.4, 126.4, 125.5, 124.4, 90.3, 31.4, 21.0.
HRMS (ESI): m/z [M + H]+ calcd for C16H15O2S: 271.07928; found:
271.07979.
2-(4-Methoxyphenyl)-2-methyl-4H-3,1-benzoxathiin-4-one (3f)
Pale yellow solid; yield: 11.4 mg (0.040 mmol, 20%); mp 80.5–81.3
°C.
IR: 2932, 2836, 1718, 1607, 1509, 1252, 1179, 1029, 832, 742, 686,
583 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.08–8.04 (m, 1 H), 7.56–7.47 (m,
2 H), 7.42–7.36 (m, 1 H), 7.28–7.16 (m, 2 H), 6.82–6.76 (m, 2 H),
3.76 (s, 3 H), 2.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.0, 159.5, 136.8, 134.2, 133.7,
132.0, 127.4, 127.0, 126.4, 124.4, 113.7, 90.2, 55.2, 31.3.
HRMS (FAB): m/z [M + H]+ calcd for C19H31OS: 306.2017; found:
306.2006.
2-Substituted 3,1-Benzoxathiin-4H-ones 4; General Procedure
Thiosalicylic acid (1a, 0.240 mmol) and alkyne 2 (0.200 mmol)
were added to toluene (1 mL) under an argon atmosphere. The mix-
ture was stirred following the conditions shown in Table 3. The
mixture was concentrated in vacuo, and the residue was purified by
column chromatography to give 1,3-oxathiines 4.
HRMS (ESI): m/z [M + H]+ calcd for C16H15O3S: 287.07419; found:
287.07882.
2-Methyl-2-[4-(trifluoromethyl)phenyl]-4H-3,1-benzoxathiin-
Ethyl 4-Oxo-4H-3,1-benzoxathiin-2-ylacetate (4j)
Pale yellow solid; yield: 43.4 mg (0.172 mmol, 86%); mp 54.9–55.9
°C.
IR: 2985, 2941, 1730, 1587, 1443, 1270, 1102, 1010, 740, 680 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.18–8.15 (m, 1 H), 7.52–7.46 (m,
1 H), 7.37–7.30 (m, 2 H), 6.00 (t, J = 6.6 Hz, 1 H), 4.22 (q, J = 7.2
Hz, 2 H), 3.18 (dd, J = 7.2, 7.6 Hz, 1 H), 2.96 (dd, J = 5.6, 5.6 Hz,
1 H), 1.29 (t, J = 7.2 Hz, 3 H).
4-one (3g)
Pale yellow solid; yield: 38.3 mg (0.118 mmol, 59%); mp 59.0–59.9
°C.
IR: 3072, 2935, 1723, 1325, 1278, 1115, 1075, 745, 674 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.08–8.03 (m, 1 H), 7.75 (d, J =
8.2 Hz, 2 H), 7.55 (d, J = 8.2 Hz, 2 H), 7.44–7.38 (m, 1 H), 7.27–
7.18 (m, 2 H), 2.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 163.3, 146.4, 136.0, 134.0, 132.1,
130.7 (q, J = 32.7 Hz), 127.5, 126.8, 126.0, 125.6, 125.5, 124.1,
123.7 (q, J = 270.9 Hz), 89.5, 31.2.
HRMS (ESI): m/z [M + H]+ calcd for C16H12F3O2S: 325.05101;
found: 325.05493.
13C NMR (100 MHz, CDCl3): δ = 167.9, 163.3, 137.5, 133.7, 132.6,
127.6, 126.9, 123.9, 78.3, 61.5, 39.4, 14.0;
HRMS (ESI): m/z [M + H]+ calcd for C12H13O4S: 253.05345; found:
253.05157.
Phenyl 4-Oxo-4H-3,1-benzoxathiin-2-ylacetate (4k)
Pale yellow solid; yield: 58.3 mg (0.194 mmol, 97%); mp 83.8–84.1
°C.
2-Methyl-2-(pyridin-3-yl)-4H-3,1-benzoxathiin-4-one (3h)
Pale yellow solid; yield: 20.0 mg (0.078 mmol, 39%); mp 81.5–82.6
°C.
IR: 3065, 2929, 1722, 1589, 1378, 1333, 1113, 1019, 838, 741, 693
cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2607–2613

2612
Y. Nishina, J. Miyata
PAPER
1H NMR (400 MHz, CDCl3): δ = 8.12 (d, J = 7.6 Hz, 1 H), 7.44 (t,
J = 7.6 Hz, 1 H), 7.42–7.25 (m, 4 H), 7.21–7.16 (m, 1 H), 7.07 (d,
J = 8.4 Hz, 2 H), 6.04 (t, J = 6.6 Hz, 1 H), 3.37 (dd, J = 7.2, 7.2 Hz,
1 H), 3.16 (dd, J = 5.2, 5.6 Hz, 1 H).
was concentrated under reduce pressure. The residue was purified
by column chromatography (silica gel) to give 4n′ as a pale yellow
oil; yield: 48.2 mg (0.166 mmol, 83%).
IR: 3291, 2961, 1725, 1589, 1441, 1332, 1276, 1216, 1166, 1110,
1016, 743, 641 cm–1.
13C NMR (100 MHz, CDCl3): δ = 166.5, 163.1, 150.2, 137.3, 133.8,
132.7, 129.5, 127.7, 127.0, 126.2, 123.9, 121.3, 78.1, 39.5.
HRMS (ESI): m/z [M + H]+ calcd for C16H13O4S: 301.05345; found:
301.05271.
1H NMR (400 MHz, CDCl3): δ = 8.18–8.15 (m, 1 H), 7.55–7.43 (m,
1 H), 7.37–7.32 (m, 2 H), 6.00 (dd, J = 5.6, 5.6 Hz, 1 H), 4.28 (t, J =
6.4 Hz, 2 H), 3.19 (dd, J = 7.2, 7.6 Hz, 1 H), 2.98 (dd, J = 5.6, 5.6
Hz, 1 H), 2.38–2.22 (m, 2 H), 1.97 (t, J = 2.6 Hz, 1 H), 1.94–1.84
(m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 167.8, 163.2, 137.4, 133.7, 132.6,
127.6, 126.9, 123.9, 82.7, 78.1, 69.1, 63.9, 39.3, 27.2, 15.0.
2-(2-Oxopropyl)-4H-3,1-benzoxathiin-4-one (4l)
Pale yellow oil; yield: 37.3 mg (0.168 mmol, 84%).
IR: 3064, 2923, 1705, 1588, 1442, 1291, 1116, 1028, 741, 683 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.19–8.16 (m, 1 H), 7.53–7.46 (m,
1 H), 7.37–7.29 (m, 2 H), 6.07 (dd, J = 5.2, 4.8 Hz, 1 H), 3.35 (dd,
J = 7.2, 7.2 Hz, 1 H), 3.02 (dd, J = 4.8, 5.2 Hz, 1 H), 2.29 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H15O4S: 291.06910; found:
291.06954.
13C NMR (100 MHz, CDCl3): δ = 202.2, 163.5, 137.7, 133.6, 132.6,
127.6, 126.8, 123.9, 77.6, 47.1, 30.7.
HRMS (ESI): m/z [M + H]+ calcd for C11H11O3S: 223.04289; found:
223.04122.
2-({1-[4-(Trifluoromethyl)phenyl]vinyl}sulfanyl)benzoic Acid
(5b)
Thiosalicylic acid (1a, 3.00 mmol), 1-(trifluoromethyl)-4-vinylben-
zene (2g, 2.00 mmol), and Pd(OAc)2 (0.1 mmol) were added to tol-
uene (10 mL) under an argon atmosphere. The mixture was stirred
at 100 °C for 1 h. Then, the mixture was concentrated under reduce
pressure. The residue was purified by column chromatography (sil-
ica gel) to give 5b and 3g in 53% and 13% yields, respectively.
2-(Pyridin-2-ylmethyl)-4H-3,1-benzoxathiin-4-one (4m)
Pale yellow solid; yield: 50.4 mg (0.196 mmol, 98%); mp 52.5–53.8
°C.
Benzoic Acid 5b
Pale yellow solid; yield: 344 mg (1.06 mmol, 53%); mp 73.2–74.9
°C.
IR: 3062, 2925, 1719, 1588, 14391, 1279, 1110, 1029, 741, 683
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, J = 4.8 Hz, 1 H), 7.58–
7.55 (m, 1 H), 7.13–7.06 (m, 1 H), 6.90–6.83 (m, 1 H), 6.76–6.69
(m, 3 H), 6.66–6.60 (m, 1 H), 5.52 (t, J = 6.6 Hz, 1 H), 3.05 (dd, J =
6.8, 7.2 Hz, 1 H), 2.88 (dd, J = 6.4, 6.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 163.9, 154.7, 149.5, 138.3, 136.8,
133.5, 132.5, 127.6, 126.6, 124.4, 124.1, 122.5, 82.0, 42.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H12NO2S: 258.05887;
found: 258.05886.
IR: 2960, 1678, 1408, 1323, 1260, 1167, 1114, 1064, 846, 742, 693
cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 8.0 Hz, 1 H), 7.99 (d,
J = 8.1 Hz, 2 H), 7.74 (d, J = 8.1 Hz, 2 H), 7.47 (t, J = 7.6 Hz, 1 H),
7.38–7.31 (m, 2 H), 6.38 (s, 1 H), 6.29 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 171.7, 141.8, 140.6, 140.6, 133.1,
132.3, 130.3 (t, J = 32.8 Hz), 128.7, 127.3, 126.4, 126.3, 125.5 (d,
J = 3.6 Hz), 125.0, 123.9 (q, J = 270.9 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C16H12O2S: 325.05101; found:
325.05137.
3-(2-Methyl-4-oxo-4H-3,1-benzoxathiin-2-yl)propyl 4-Oxo-4H-
3,1-benzoxathiin-2-ylacetate (4n); One-Pot Synthesis
Thiosalicylic acid (1a, 0.240 mmol) and pent-4-ynyl propiolate (2n,
0.200 mmol) were added to toluene (1 mL) under an argon atmo-
sphere. The mixture was stirred at 150 °C for 6 h and then Pd(OAc)2
(0.01 mmol) and thiosalicylic acid (1a, 0.240 mmol) were added.
The mixture was heated at 120 °C for 3 h, and concentrated under
reduced pressure. The residue was added CHCl2CHCl2 (0.200
mmol) as an internal standard for NMR analysis. The crude NMR
yield was determined by comparison with integration values of the
protons of CHCl2CHCl2 (δ = 5.93, 2 H) and the methyl moiety of 4n
(δ = 1.81, 3 H). The crude mixture was purified by column chroma-
tography (silica gel) to give 4n as a pale yellow oil; yield: 40.9 mg
(0.092 mmol, 46%).
(Z)-2-{[2-(Ethoxycarbonyl)vinyl]sulfanyl}benzoic Acid (5c)
Methyl thiosalicylate (4.00 mmol) and ethyl propiolate (2j, 4.00
mmol) were added to H2O (10 mL) under an argon atmosphere. The
mixture was stirred at 25 °C for 3 h. Then, the mixture was extracted
with EtOAc, concentrated in vacuo, and the residue was purified by
column chromatography to give the corresponding vinyl sulfide.
The product was hydrolyzed with aq KOH to give 5c as a pale yel-
low solid; yield: 434 mg (1.72 mmol, 43%); mp 111.5–112.1 °C.
IR: 3074, 2988, 2646, 1687, 1583, 1469, 1267c, 1227, 1187, 1030,
820, 748, 649 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 8.0 Hz, 1 H), 7.57–
7.43 (m, 2 H), 7.43–7.32 (m, 1 H), 7.29 (d, J = 10.4 Hz, 1 H), 6.00
(d, J = 10.4 Hz, 1 H), 4.27 (q, J = 7.2 Hz, 2 H), 1.33 (t, J = 7.2 Hz,
3 H).
13C NMR (100 MHz, CDCl3): δ = 171.0, 166.4, 148.1, 148.1, 139.4,
133.2, 131.6, 130.3, 127.4, 115.0, 60.5, 14.3.
HRMS (ESI): m/z [M + H]+ calcd for C12H13O4S: 253.05345; found:
IR: 3064, 2928, 1720, 1589, 1440, 1330, 1281, 1241, 1167, 1112,
1017, 914, 741, 685 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.17 (d, J = 6.8 Hz, 2 H), 7.56–
7.43 (m, 2 H), 7.40–7.32 (m, 2 H), 7.32–7.25 (m, 2 H), 6.05–5.92
(m, 1 H), 4.20 (t, J = 6.2 Hz, 2 H), 3.23–3.12 (m, 1 H), 2.96 (dd, J =
6.0, 5.2 Hz, 1 H), 2.18–2.05 (m, 2 H), 2.03–1.92 (m, 2 H), 1.81 (s,
3 H).
253.05335.
13C NMR (100 MHz, CDCl3): δ = 167.8, 163.2, 163.1, 137.4, 136.4,
134.0, 133.8, 132.6, 132.0, 128.0, 127.7, 126.9, 126.4, 123.9, 123.3,
88.7, 78.1, 64.7, 39.3, 37.6, 27.1, 23.8.
(E)-{[2-(Ethoxycarbonyl)vinyl]sulfanyl}benzoic Acid (5c′)
Methyl thiosalicylate (4.00 mmol) and ethyl propiolate (2j, 4.00
mmol) were added to toluene (10 mL) under an argon atmosphere.
The mixture was stirred at 150 °C for 3 h. Then, the mixture was ex-
tracted with EtOAc, concentrated in vacuo, and the residue was pu-
rified by column chromatography to give the corresponding vinyl
sulfides. The product was hydrolyzed with aq KOH to give a mix-
ture of 5c and 5c′. The mixture was separated by column chroma-
tography (silica gel).
HRMS (ESI): m/z [M + H]+ calcd for C22H21O6S2: 445.07795;
found: 445.07988.
Pent-4-ynyl 4-Oxo-4H-3,1-benzoxathiin-2-ylacetate (4n′)
Thiosalicylic acid (1a, 0.240 mmol) and pent-4-ynyl propiolate (2n,
0.200 mmol) were added to toluene (1 mL) under an argon atmo-
sphere. The mixture was stirred at 150 °C for 6 h. Then, the mixture
Synthesis 2012, 44, 2607–2613
© Georg Thieme Verlag Stuttgart · New York

PAPER
1,3-Oxathiine Frameworks
2613
(E)-Isomer 5c′
González, D. F.; Waser, J. Org. Lett. 2010, 12, 384. (c) Oe,
Y.; Ohta, T.; Ito, Y. Tetrahedron Lett. 2010, 51, 2806.
(d) Chaminade, X.; Coulombel, L.; Olivero, S.; Dunach, E.
Eur. J. Org. Chem. 2006, 3554. (e) Yang, C. G.; Reich, N.
W.; Shi, Z.; He, C. Org. Lett. 2005, 7, 4553.
Pale yellow solid; yield: 595 mg (2.36 mmol, 59%); mp 134.5–
135.3 °C.
IR: 3072, 2979, 2649, 1685, 1596, 1463, 1413, 1260, 1157, 1027,
920, 741, 692 cm–1.
(6) Recent works on sequential transformations: (a) Attanasi, O.
A.; De Crescentini, L.; Favi, G.; Nicolini, S.; Perrulli, F. R.;
Santeusanio, S. Org. Lett. 2011, 13, 353. (b) Hong, B. C.;
Dange, N. S.; Hsu, C. S.; Liao, J. H.; Lee, G. H. Org. Lett.
2011, 13, 1338. (c) Cao, J.; Yang, X.; Hua, X.; Deng, Y.;
Lai, G. Org. Lett. 2011, 13, 478. (d) Wu, J.; Becerril, J.;
Lian, Y.; Davies, H. M. L.; Porco, J. A.; Panek, J. S. Angew.
Chem. Int. Ed. 2011, 50, 5938. (e) Cao, J.; Huang, X. Org.
Lett. 2010, 12, 5048.
1H NMR (400 MHz, CDCl3): δ = 8.14–8.11 (m, 1 H), 7.88 (d, J =
15.2 Hz, 1 H), 7.65–7.55 (m, 1 H), 7.53–7.47 (m, 1 H), 7.41–7.35
(m, 1 H), 6.16 (d, J = 15.2 Hz, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 1.31
(t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.8, 165.3, 144.3, 137.4, 133.6,
132.2, 130.2, 128.3, 126.9, 119.8, 60.6, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C12H13O4S: 253.05345; found:
253.05335.
(7) Conversion of 1a is more than 80%; we detected isomers of
3a and a dimer of 1a by GC-MS.
Acknowledgment
(8) In the Pd(OAc)2 catalyzed reaction, various solvents were
investigated; DMSO, 0%; EtOH, 9%, DMF, 27%; 1,4-
dioxane, 60%; 1,2-dichloroethane, 90%; hexane, 88%.
(9) Palladium-catalyzed selective hydrothiolation has been
reported; see ref. 4a.
Financial support for this study was provided by Special Coordina-
tion Funds for Promoting Science and Technology of MEXT.
(10) For reports on transformations with similar substrates, see:
(a) Volkov, A. N.; Volkova, K. A. Zh. Org. Khim. 1989, 25,
33. (b) Greengrass, C. W.; Hughman, J. A.; Parsons, P. J.
J. Chem. Soc., Chem. Commun. 1985, 889.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(11) Nickel-catalyzed reaction: Ananikov, V. P.; Malyshev, D.
A.; Beletskaya, I. P.; Aleksandrov, G. G.; Eremenko, I. L.
Adv. Synth. Catal. 2005, 347, 1993.
(12) Water-mediated reaction: Nair, V. A.; Randive, N. A.;
Kumar, V. Monatsh. Chem. 2010, 141, 1329.
(13) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153.
(14) When the reactions were stopped after 1 h, 4j and 4k were
obtained in 48% and 69% yields, respectively.
(15) Even in the presence of the palladium catalyst, a product
with a structure like 3 was not observed.
References
(1) Recent reports on the construction of heterocycles with two
different heteroatoms: (a) Hu, Z.; Ye, W.; Zou, H.; Yu, Y.
Synth. Commun. 2010, 40, 222. (b) Bhadra, S.; Adak, L.;
Samanta, S.; Islam, A. K. M. M.; Mukherjee, M.; Ranu, B.
C. J. Org. Chem. 2010, 75, 8533. (c) Guo, D. L.; Huang, H.;
Zhou, Y.; Xu, J.; Jiang, H.; Chen, K.; Liu, H. Green Chem.
2010, 12, 276. (d) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y.
Angew. Chem. Int. Ed. 2009, 48, 348. (e) Dahl, T.; Tornøe,
C. W.; Bang-Anderson, B.; Nielsen, P.; Jørgensen, M.
Angew. Chem. Int. Ed. 2008, 47, 1726. (f) Viña, D.; del
Olmo, E.; López-Pérez, J. L.; Feliciano, A. S. Org. Lett.
2007, 9, 525.
(16) We also obtained the intermediate. If the reaction is stopped
before the addition of the palladium catalyst, the activated
alkyne moiety is selectively functionalized to give 1,3-
oxathiine 4n′ in 83% yield (Figure 2).
(2) Double hydroamination of alkynol with platinum and gold
catalyst has been developed: (a) Patil, N. T.; Kavthe, R. D.;
Raut, V. S.; Shinde, V. S.; Sridhar, B. J. Org. Chem. 2010,
75, 1277. (b) Patil, N. T.; Lakshmi, P. G. V. V.; Singh, V.
Eur. J. Org. Chem. 2010, 4719.
(3) (a) Lee, A. V.; Schafer, L. L. Organometallics 2006, 25,
5249. (b) Tillack, A.; Khedkar, V.; Jiao, H.; Beller, M. Eur.
J. Org. Chem. 2005, 5001. (c) Tan, S. T.; Fan, W. Y. Eur. J.
Inorg. Chem. 2010, 4631. (d) Ohmiya, H.; Yorimitsu, H.;
Oshima, K. Angew. Chem. Int. Ed. 2005, 44, 2368.
(e) Takaki, K.; Takeda, M.; Koshoji, G.; Shishido, T.;
Takehira, K. Tetrahedron Lett. 2001, 42, 6357.
(4) (a) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am.
Chem. Soc. 1999, 121, 5108. (b) Kuniyasu, H.; Ogawa, A.;
Sato, K. I.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am. Chem.
Soc. 1992, 114, 5902. (c) Kondo, T.; Mitsudo, T. Chem. Rev.
2000, 100, 3205. (d) Weiss, C. J.; Wobser, S. D.; Marks, T.
J. Organometallics 2010, 29, 6308. (e) Weiss, C. J.; Marks,
T. J. J. Am. Chem. Soc. 2010, 132, 10533.
O
O
O
S
O
4n'
Figure 2
(17) We chose 2g to isolate a vinyl sulfide intermediate, since
intramolecular cyclization of 5b was slow. Other alkynes
also gave the corresponding vinyl sulfides, but with a low
yield.
(18) The trans-vinyl sulfides 5c′ (see Supporting Information)
were also transformed into 4j under the same reaction
conditions of Equation 2.
(19) In this case, AIBN did not work as an appropriate promoter;
4j was obtained in 52% yield and unknown mixture of
products was observed.
(5) (a) Utsunomiya, M.; Kawatsura, M.; Hartwig, J. F. Angew.
Chem. Int. Ed. 2003, 42, 5865. (b) Nicolai, S.; Erard, S.;
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2607–2613