Intramolecular electrophilic hydroarylation via Claisen rearrangement: synthesis of chromenes, heterothiochromenes and heterodihydrothiochromenes

Article abstract of DOI:10.1016/j.tet.2006.06.079

We have designed and synthesized several basic and novel fused ring heterocycles by intramolecular hydroarylation with an efficiency and scope to develop intermediates of potential value. This method demonstrated consistent performance with arene-ene and arene-yne substrates of diverse structural features, including propargyl ethers, allyl thioethers, and propargyl thioethers resulting in 6-endo products.

Full text of DOI:10.1016/j.tet.2006.06.079

Tetrahedron 62 (2006) 9280–9288
Intramolecular electrophilic hydroarylation via
Claisen rearrangement: synthesis of chromenes,
heterothiochromenes and heterodihydrothiochromenes
*
Rajesh S. Kenny, Uday C. Mashelkar, Deepak M. Rane
and Dinesh K. Bezawada
Organic Research Laboratory, Patkar–Varde College of Science, Goregaon (W), Mumbai 400062, India
Received 8 February 2006; revised 4 June 2006; accepted 22 June 2006
Available online 4 August 2006
Abstract—We have designed and synthesized several basic and novel fused ring heterocycles by intramolecular hydroarylation with an ef-
ficiency and scope to develop intermediates of potential value. This method demonstrated consistent performance with arene–ene and arene–
yne substrates of diverse structural features, including propargyl ethers, allyl thioethers, and propargyl thioethers resulting in 6-endo products.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
chromene and thiochromene as modulators of the estrogen
3
,4
receptors. The addition of an aromatic ring to alkenes
or alkynes to form C–C bonds via C–H functionalization
provides efficient and atom-economic synthetic methods.
This C–C bond formation forms the basis for the synthesis
of a large number of heterocycles. These seemingly sim-
ple points lead to consequences of significant importance
in both the strategy and design of simple organic mole-
cules. Intramolecular hydroarylation, a formal addition of
arene C–H bonds across multiple bonds, provides a direct
route to valuable organic compounds such as annulated
arenes, heterocycles, and carbocycles. In contrast to the
Heck reaction, a hydroarylation approach eliminates the
requirement of a halogen (or triflate) substituent, which
is also a feature of other routes. These alternative routes
Chromene and thiochromene analogs of the HIV-1 pro-
tease inhibitor, Ritonavir, have been prepared and are
under clinical trials (Fig. 1). Some of the patents report
1
,2
N
S
Ph
H
N
H
N
S
OH
Ph
O
O
N
N
H
N
O
O
A
O
Ph
H
N
OH
O
N
H
5
O
O
include arene metallation–Heck type addition, multiple
bond activation–electrophilic substitution, and metal-
O
Ph
B
6
7,8a,b
catalyzed Claisen rearrangement.
The compatibility
S
Ph
H
N
of Pt(IV)Cl and Ru(III)Cl on the cyclization of alkyne
4 3
substrates, specifically propargyl–aryl ethers and alkene–
aryl ethers, by multiple bond activation–electrophilic sub-
OH
O
N
H
9a,b
S
stitution have been studied.
rearrangement carried out under harsh conditions is also
Cyclization via Claisen
Ph
C
9
a
described (Scheme 1). The thermal rearrangement of
phenol D at 240 C resulted into E and F in a 7:3 ratio.
Figure 1. A is the HIV-1 protease inhibitor Ritonavir, B and C are chromene
and thiochromene analogs of Ritonavir.
ꢀ
In contrast, substrate D in the presence of 2 mol % of
PtCl in dioxane at ambient temperature afforded E in
4
5
9% yield, whereas isomer F was not detected in the
Keywords: Hydroarylation; Claisen rearrangement; Pyran; Thiopyran;
Dihydrothiopyran; Chromene.
crude reaction mixture. Many more studies with regard
to the development of catalysts for the hydroarylation
reaction of alkynes and olefins have been reported.
*
Corresponding author. Tel.: +91 22 28721875; fax: +91 22 28744755;
e-mail: ucmashelkar@yahoo.com
1
0–19
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.079

R. S. Kenny et al. / Tetrahedron 62 (2006) 9280–9288
9281
OH
O
O
5
0%
240 °C
70: 30
a
IIIb
IIIb'
OH
OH
OH
OH
Figure 2.
+
O
O
O
ꢀ
at 220 C and underwent rearrangement to give the fused
ring pyran derivatives IIIa–f. It is possible that one of the
propargyl ethers (e.g., 1-phenyl-3-(2-propynyloxy)benzene
IIb) could upon cyclization give rise to either chromene
D
b
E
F
OH
PtCl4
59%
E
PtCl4
0
IIIb and/or IIIb (Fig. 2), however, under our reaction con-
ditions only formation of chromene IIIb was ever observed.
-H+
H+
+
O
With the establishment of an exciting lead, we were
prepared to determine the efficacy of synthesizing thio-
pyran and dihydrothiopyran derivatives by following the
route depicted in Schemes 3 and 4. Thiophenes IVa–f
ꢀ
4
Scheme 1. Conditions: (a) 240 C, diethyleneglycol; (b) 2 mol % PtCl ,
dioxane, rt.
ꢀ
2
. Results and discussion
were reacted with n-butyllithium and sulfur at ꢁ70 C to
give the thiolate salts, which were then reacted in situ
with propargyl bromide and a-(bromomethyl)-acrylic
Initially we became interested in the possibility of making
simple moieties, which could be the basic framework for
various active ingredients of unexplored physiological and
pharmaceutical interest. For the synthesis of the desired
molecules, various phenols were reacted with propargyl bro-
mides in the presence of base to synthesize propargyl–aryl
ethers. The heteroaromatic compounds were first treated
with n-butyllithium and sulfur to give the thiolate salt
formed in situ, these were then reacted with propargyl and
alkenyl bromides to give propargyl and alkenyl thioethers.
Propargyl ethers underwent cyclization to give the desired
products when heated in N,N-diethylaniline as solvent and
base, whereas the alkenyl thioethers underwent cyclization
by heating in N,N-dimethylformamide. For the cyclization
of propargyl thioethers either N,N-diethylaniline or N,N-di-
methylformamide is used. The yields obtained are much
higher following our method of synthesis than those reported
when the cyclizations were carried out using transition metal
2
1
acid to give 2-propynylsulfanyl thiophenes Va–e and
2-acryloylsulfanyl thiophenes VIIa–e, respectively. The
conversion of the intermediates to the final thiopyrans
VIa–e and dihydrothiopyrans VIIIa–e was achieved by
ꢀ
heating at 145 C in DMF for 45 min. 5,6-Dihydro-4H-
thieno[2,3-b]thiopyran-5-carboxylic acid VIIIa has been
reported as a starting material for the synthesis of presyn-
aptic dopamine receptors.
2
0
R2
R1
R2
R2
1
) n-BuLi / S, -70 °C
DMF
2) Br
R1
R1
S
S
S
S
Va-e
S
VIa-e
IVa-e
IVa, Va, VIa:- R = R2 = H.
1
IVb, Vb, VIb:- R1 = Me, R2 = H.
1
2
1
2
IVc, Vc, VIc:- R = Et, R = H. IVd, Vd, VId:- R = n-Pr, R = H.
1
2
IVe, Ve, VIe:- R -R = Benzo.
9a,b
salts. In our first attempt we have synthesized some fused
ring heterocycles from various phenol derivatives as depicted
in Scheme 2. The hydroxyl derivatives Ia–f were reacted
with propargyl bromide in the presence of potassium carbon-
ate to give the propargyl–aryl ethers IIa–f. The resulting
intermediates IIa–f were then heated in N,N-diethylaniline
Scheme 3.
After successfully synthesizing the thiophene fused ring
thiopyran and dihydrothiopyran we diverted our research
interest to the synthesis of dibenzofuran and dibenzothio-
phene derivatives as depicted in Scheme 5. Dibenzofuran
and dibenzothiophene were reacted with n-butyllithium
2
2
resulting in mono-lithium salts, which were then treated
with sulfur at lower temperatures to give the S-lithium
salts. These were then reacted with bromides at the same
temperature to give the intermediate thioethers Xa,b and
XIIa,b. The intermediate thioethers were then heated in
N,N-diethylaniline or N,N-dimethylformamide to give the
cyclized products XIa,b and XIIIa,b as depicted in
Scheme 5.
R3
R3
R3
R2
R1
R2
R2
R1
Br
N,N-diethyl aniline
K CO / DMF
R1
2
3
OH
O
O
Ia-f
IIa-f
IIIa-f
Ia, IIa, IIIa:- R1 = Ph, R2 = R3 = H
2
1
3
Ib, IIb, IIIb:- R = Ph, R = R = H
3
1
2
Ic, IIc, IIIc:- R = Ph, R = R = H
3
1
2
Id, IId, IIId:- R = 4-BrPh, R = R = H
3
. Conclusions
1
2
R3 = H
Ie, IIe, IIIe:- R -R
=
O
We have synthesized a large number of novel heterocyclic
systems by means of Claisen rearrangement methodology.
The systems developed can give access to a large number
of compounds for biological testing.
1
2
R3 = H
If, IIf, IIIf :- R -R
=
S
Scheme 2.

9282
R. S. Kenny et al. / Tetrahedron 62 (2006) 9280–9288
O
O
R2
R1
OH
OH
R2
R2
1
) n-BuLi / S, -70 °C
DMF
S
2) Br
R1
S
R1
S
OH
S
S
O
IVa-d&f
VIIa-e
VIIIa-e
IVa, VIIa, VIIIa:- R = R2 = H.
1
IVb, VIIb, VIIIb:- R1 = Me, R2 = H.
1
2
1
2
IVc, VIIc, VIIIc:- R = Et, R = H. IVd, VIId, VIIId:- R = n-Pr, R = H.
1
2
IVf, VIIe, VIIIe:- R = CN, R = H.
Scheme 4.
N,N-diethyl
aniline
1) n-BuLi / S
2
)Br
X
S
X
S
X = O, S.
XIa-b
X = O, S.
Xa-b
X
OH
X = O, S.
IXa-b
OH
O
1) n-BuLi / S
DMF
O
2)
Br
S
X
X
S
OH
O
X = O, S.
XIIa-b
X = O, S.
XIIIa-b
Scheme 5.
4
. Experimental
4.2.2. 1-Phenyl-3-(2-propynyloxy)benzene IIb. Com-
pound IIb was prepared from 3-phenylphenol Ib (0.51 g,
3.0 mmol) in an analogous manner to that for the preparation
of IIa as a colorless oil (0.625 g, 100%); [Found: C, 86.33;
H, 5.90. C H O requires: C, 86.51; H, 5.81]; IR (neat):
4
.1. General
The 2-, 3- and 4-phenylphenols Ia–c and 4-bromo-4-
hydroxy biphenyl Id required for the synthesis were
purchased. 4-Hydroxydibenzofuran Ie and 4-hydroxydi-
benzothiophene If were synthesized according to the method
reported in the literature.
for the synthesis were purchased. Melting points are uncor-
1
5 12
3303, 3015, 1597, 1573, 1478, 1422, 1295, 1215, 1197,
and 1035 cm . H NMR (CDCl ): d 2.54 (t, J 2.4 Hz,
ꢁ
1 1
3
1H), 4.75 (d, J 2.4 Hz, 2H), 6.95 (dd, J 3.2 Hz, 1H), 7.20–
7.24 (m, 2H), 7.32–7.46 (m, 4H), 7.52–7.59 (m, 2H).
2
2a–c
Thiophenes IVa–f required
rected, measured on a B €u chi apparatus. Infrared spectra were
recorded on a FTIR Perkin–Elmer spectrometer. H NMR
spectra were recorded using a 300 MHz Varien (Mercury
Vx) SWBB Multinuclear Probe with tetramethylsilane
(TMS) as the internal standard. Mass spectra were recorded
on a MDS Sciex API 3000 LCMS.
4.2.3. 1-Phenyl-4-(2-propynyloxy)benzene IIc. Com-
pound IIc was prepared from 4-phenylphenol Ic (0.51 g,
3.0 mmol) in an analogous manner to that for the preparation
1
ꢀ
of IIa as a white solid (0.59 g, 95%), mp¼75–78 C;
[Found: C, 86.42; H, 5.69. C H O requires: C, 86.51; H,
1
5 12
5.81]; IR (KBr): 3275, 3303, 1603, 1584, 1519, 1486,
ꢁ
287, 1237, 1118, and 1027 cm . H NMR (DMSO-d ):
6
1 1
1
4.2. General method for the synthesis of 2-propynyloxy
aryl derivatives IIa–f. Procedure A
d 3.59 (t, J 2.4 Hz, 1H), 4.83 (d, J 2.4 Hz, 2H), 7.04–7.08
(m, 2H), 7.29(t, J 2.4 Hz, 1H), 7.41 (d, J 7.2 Hz, 2H), 7.41
(d, J 8.4 Hz, 4H).
4.2.1. 1-Phenyl-2-(2-propynyloxy)benzene IIa. Propargyl
bromide (0.40 g, 3.33 mmol) was added to a mixture of
4.2.4. 1-(4-Bromophenyl)-4-(2-propynyloxy)benzene IId.
Compound IId was prepared from 4-(4-bromophenyl)phe-
nol Id (0.75 g, 3.0 mmol) in an analogous manner to that
for the preparation of IIa as a white solid (0.82 g, 97%),
2
3
-phenylphenol (0.51 g, 3.0 mmol) and K CO (0.48 g,
2 3
.5 mmol) in dry DMF (10 mL) and stirred at room tem-
perature for 2 h under a nitrogen atmosphere. DMF was then
removed under reduced pressure and the residue dissolved in
ꢀ
mp¼93–95 C; [Found: C, 62.65; H, 3.99; Br, 27.62.
5
0 mL of ethyl acetate. The organic layer was washed with
C H BrO requires: C, 62.74; H, 3.86; Br, 27.83]; IR
1
5 11
water (2ꢂ25 mL), dried over sodium sulfate and concen-
trated under reduced pressure to give pure 1-phenyl-2-(2-
propynyloxy)benzene IIa (0.625 g, 100%) as a gummy oil;
(KBr): 3282, 2915, 1602, 1580, 1518, 1480, 1376, 1283,
ꢁ
1
1
1240, 1076, 1027, 817, and 805 cm
.
(CDCl ): d 2.55 (t, J 2.4 Hz, 1H), 4.75 (d, J 2.4 Hz, 2H),
H NMR
3
[
5
1
Found: C, 86.30; H, 5.93. C H O requires: C, 86.51; H,
1
7.06 (d, J 7.8 Hz, 2H), 7.42 (d, J 7.8 Hz, 2H), 7.50–7.58
(m, 4H).
5 12
.81]; IR (neat): 3289, 3061, 1503, 1480, 1434, 1266,
210, 1123, 1023, and 1009 cm
ꢁ
1
1
. H NMR (CDCl3):
d 2.54 (t, J 2.4 Hz, 1H), 4.66 (d, J 2.4 Hz, 2H), 7.04–7.14
m, 2H), 7.28–7.42 (m, 5H), 7.50–7.54 (m, 2H).
4.2.5. 4-(2-Propynyloxy)dibenzo[b,d]furan IIe. Com-
pound IIe was prepared from 4-hydroxydibenzo[b,d]furan
(

R. S. Kenny et al. / Tetrahedron 62 (2006) 9280–9288
9283
IIe (0.55 g, 3.0 mmol) in an analogous manner to that for the
preparation of IIa, and the crude semisolid obtained was pu-
rified by column chromatography (stationary phase: silica
gel 60–120, mobile phase: 10% ethyl acetate in hexane) as
J 7.5, 7.5 Hz, 1H), 7.33–7.45 (m, 5H). MS (EI) m/z 207.2
(M ).
ꢁ
1
4.3.3. 6-Phenyl-2H-chromene IIIc. Compound IIIc was
prepared from 1-phenyl-4-(2-propynyloxy)benzene IIc
(0.370 g, 1.78 mmol) in an analogous manner to that for
the preparation of IIIa, and the crude product obtained
was purified by column chromatography (stationary phase:
silica gel 60–120, mobile phase: 15% chloroform in hexane)
ꢀ
a white solid (0.62 g, 93%), mp¼32–34 C; [Found: C,
8
1.30; H, 4.66. C H O requires: C, 81.07; H, 4.54]; IR
15 10 2
(
and 932 cm . H NMR (CDCl ): d 2.63 (t, J 2.4, 2.4 Hz,
KBr): 3293, 2923, 1583, 1451, 1310, 1191, 1092, 1022,
ꢁ
1 1
3
1H), 5.05 (d, J 2.4 Hz, 2H), 7.20 (d, J 7.2 Hz, 1H), 7.33 (t,
J 7.8, 7.8 Hz, 1H), 7.40 (t, J 6.9, 6.9 Hz, 1H), 7.52 (t, J 6.9,
ꢀ
as a white solid (0.20 g, 55%); mp¼78–80 C; [Found: C,
6
1
.9 Hz, 1H), 7.66 (dd, J 1.0, 1.0 Hz, 1H), 7.70 (d, J 7.2,
H), 8.00 (dd, J 1.0, 1.0 Hz, 1H).
86.69; H, 5.65. C H O requires: C, 86.51; H, 5.81]; IR
5 12
1
(KBr): 3050, 2832, 1480, 1452, 1231, 1184, 1135, 1047,
ꢁ
016, 891, and 836 cm . H NMR (CDCl ): d 4.85 (dd,
3
1 1
1
4
.2.6. 4-(2-Propynyloxy)dibenzo[b,d]thiophene IIf. Com-
J 1.8, 1.8 Hz, 2H), 5.80 (dt, J 3.5, 2.4 Hz, 1H), 6.46 (d,
J 9.6 Hz, 1H), 6.82 (d, J 8.4 Hz, 1H), 7.17 (d, J 8.0 Hz,
1H), 7.24–7.28 (m, 2H), 7.39 (t, J 7.4, 7.4 Hz, 2H), 7.50
pound IIf was prepared from 4-hydroxydibenzo[b,d]thio-
phene IIf (0.60 g, 3.0 mmol) in an analogous manner to
that for the preparation of IIa, and the crude semisolid
obtained was purified by column chromatography (station-
ary phase: silica gel 60–120, mobile phase: 10% ethyl
ꢁ
1
(d, J 8.0 Hz, 2H). MS (EI) m/z 207.4 (M ).
4.3.4. 6-(4-Bromophenyl)-2H-chromene IIId. Compound
IIId was prepared from 1-(4-bromophenyl)-4-(2-propynyl-
oxy)benzene IId (0.43 g, 1.5 mmol) in an analogous manner
to that for the preparation of IIIa, and the crude product
obtained was purified by column chromatography (station-
ary phase: silica gel 60–120, mobile phase: 5% chloroform
in hexane) as a white solid (0.27 g, 63%); mp¼107–
acetate in hexane) as a white solid (0.60 g, 84%), mp¼
ꢀ
109–110 C; [Found: C, 75.79; H, 4.11; S, 13.58.
C H OS requires: C, 75.60; H, 4.23; S, 13.45]; IR
1
5 10
(
1
KBr): 3305, 1568, 1445, 1321, 1271, 1233, 1107, 1061,
H NMR (CDCl ): d 2.55 (t,
3
ꢁ
1
1
010, and 927 cm
.
J 2.4 Hz, 1H), 4.91 (d, J 2.4 Hz, 2H), 7.05 (d, J 7.5 Hz,
H), 7.38–7.46 (m, 3H), 7.85 (dd, J 0.9, 0.9 Hz, 1H), 7.86
d, J 7.5 Hz, 1H), 8.10 (d, J 7.5 Hz, 1H).
ꢀ
1
(
110 C; [Found: C, 62.83; H, 3.69; Br, 27.70. C H BrO re-
1
5 11
quires: C, 62.74; H, 3.86; Br, 27.83]; IR (KBr): 3282, 2915,
1602, 1518, 1480, 1376, 1283, 1240, 1196, and 1076 cm .
ꢁ
1
1
4.3. General method for the synthesis of chromene
derivatives IIIa–f. Procedure B
H NMR (CDCl ): d 4.87 (dd, J 1.8, 1.8 Hz, 2H), 5.82 (dt, J
3
3.6, 2.4 Hz, 1H), 6.49 (d, J 9.0 Hz, 1H), 6.80 (d, J 8.0 Hz,
1H), 7.25–7.28 (m, 2H), 7.35–7.41 (m, 2H), 7.48–7.55 (d,
J 8.0 Hz, 2H). MS (EI) m/z 287.0 (M ).
+
4.3.1. 8-Phenyl-2H-chromene IIIa. 1-Phenyl-2-(2-propy-
nyloxy)benzene IIa (0.370 g, 1.78 mmol) was taken up in
N,N-diethylaniline (20 mL) and stirred at a temperature of
ꢀ
4.3.5. 2H-Benzo[4,5]furo[3,2-h]chromene IIIe. Com-
pound IIIe was prepared from 4-(2-propynyloxy)di-
benzo[b,d]furan IIe (0.45 g, 2.0 mmol) in an analogous
manner to that for the preparation of IIIa, and the crude prod-
uct obtained was purified by column chromatography (sta-
tionary phase: silica gel 60–120, mobile phase: 2% ethyl
acetate in hexane) as a pale yellow solid (0.29 g, 65%);
2
30–240 C for 18 h under a nitrogen atmosphere. It was
then cooled to room temperature and diluted with ethyl ace-
tate (50 mL), washed three times with 50 mL of 2 N aq HCl,
and then two times with 25 mL of brine. The organic layer
was dried over sodium sulfate and concentrated under
reduced pressure to give crude IIIa. The crude compound
was purified by column chromatography (stationary phase:
silica gel 60–120, mobile phase: 15% chloroform in hexane)
to give 8-phenyl-2H-chromene IIIa (0.10 g, 27%) as a white
gummy semisolid; [Found: C, 86.41; H, 5.70. C H O
ꢀ
mp¼68–70 C; [Found: C, 80.90; H, 4.38. C H O
15 10 2
requires: C, 81.07; H, 4.54]; IR (KBr): 2921, 1497, 1427,
1306, 1228, 1191, 1665, 1012, and 930 cm . H NMR
ꢁ
1 1
(CDCl ): d 5.03 (dd, J 2.1, 2.1 Hz, 2H), 5.82 (dt, J 3.2,
3
15
12
requires: C, 86.51; H, 5.81]; IR (neat): 2918, 1461, 1429,
1212, 1110, 1070, and 1035 cm . H NMR (CDCl3):
d 4.80 (dd, J 2.1, 2.1 Hz, 2H), 5.82 (dt, J 3.6, 2.4 Hz, 1H),
2.0 Hz, 1H), 6.56 (d, J 9.0 Hz, 1H), 6.95 (d, J 7.8 Hz, 1H),
7.31 (t, J 5.9, 5.9 Hz, 1H), 7.43–7.46 (m, 2H), 7.56 (d, J
7.8 Hz, 1H), 7.87 (d, J 7.8 Hz, 1H). MS (EI) m/z 223.3 (M ).
ꢁ
1
1
+
1
6
2
7
.48 (d, J 9.5 Hz, 1H), 6.90–6.98 (m, 2H), 7.17 (dd, J 2.4,
.4 Hz, 1H), 7.29 (d, J 7.4 Hz, 1H), 7.38–7.43 (m, 2H),
.53 (d, J 8.0 Hz, 2H). MS (EI) m/z 207.2 (M ).
4.3.6. 2H-Benzo[4,5]thieno[3,2-h]chromene IIIf. Com-
pound IIIf was prepared from 4-(2-propynyloxy)di-
benzo[b,d]thiophene IIf (0.475 g, 2.0 mmol) in an analogous
manner to that for the preparation of IIIa, and the crude
product obtained was purified by column chromatography
(stationary phase: silica gel 60–120, mobile phase: 2% ethyl
acetate in hexane) as a white solid (0.33 g, 70%); mp¼88–
ꢁ
1
4
.3.2. 7-Phenyl-2H-chromene IIIb. Compound IIIb was
prepared from 1-phenyl-3-(2-propynyloxy)benzene IIb
0.370 g, 1.78 mmol) in an analogous manner to that for
(
the preparation of IIIa, and the crude product obtained
was purified by column chromatography (stationary phase:
silica gel 60–120, mobile phase: 5% chloroform in hexane)
as a gummy oil (0.11 g, 30%); [Found: C, 86.66; H,
5
2
1
2
6
ꢀ
90 C; [Found: C, 75.42; H, 4.05; S, 13.29. C H OS
1
5 10
requires: C, 75.60; H, 4.23; S, 13.45]; IR (KBr): 2923, 1553,
1483, 1406, 1249, 1202, 1131, 1063, 1016, and 813 cm .
ꢁ
1
1
.99. C H O requires: C, 86.51; H, 5.81]; IR (neat):
1
H NMR (CDCl ): d 5.30 (dd, J 2.1, 2.1 Hz, 2H), 5.78 (dt,
3
5
12
189, 1596, 1463, 1435, 1237, 1200, 1116, and
018 cm . H NMR (CDCl ): d 4.79 (dd, J 2.1, 2.1 Hz,
J 3.6, 2.3 Hz, 1H), 6.52 (d, J 9.2 Hz, 1H), 7.05 (d, J 7.8 Hz,
1H), 7.37–7.42 (m, 2H), 7.64 (d, J 7.8 Hz, 1H), 7.82
(d, J 8.0 Hz, 1H), 8.05 (d, J 8.0 Hz, 1H). MS (EI) m/z 238.9
ꢁ
1 1
3
H), 5.77 (dt, J 3.0, 2.2 Hz, 1H), 6.43 (d, J 9.5 Hz, 1H),
.83 (d, J 8.1 Hz, 1H), 6.89 (d, J 8.0 Hz, 1H), 7.16 (t,
+
1
(M ).

9284
R. S. Kenny et al. / Tetrahedron 62 (2006) 9280–9288
4
.4. General method for the synthesis of 2-(2-propynyl-
60–120, mobile phase: 10% chloroform in hexane) as a vis-
cous oil (3.87 g, 83%); [Found: C, 61.38; H, 6.03; S, 32.45.
C H S requires: C, 61.18; H, 6.16; S, 32.66]; IR (neat):
sulfanyl)thiophene and benzothiophene derivatives
Va–f. Procedure C
1
0 12 2
ꢁ1
1
3
NMR (CDCl ): d 0.97 (t, J 7.2, 7.2 Hz, 3H), 1.68 (sextet,
294, 2960, 1455, 1437, 1226, 977, and 801 cm . H
4.4.1. 2-(2-Propynylsulfanyl)thiophene Va. A solution of
n-butyllithium (13.34 cm of 15% in n-hexane, 31.25
3
3
J 2.3 Hz, 2H), 2.18 (t, J 2.4, 2.4 Hz, 1H), 2.74 (t, J 7.8,
7.8 Hz, 2H), 3.43 (d, J 2.9 Hz, 2H), 6.66 (d, J 3.6 Hz, 1H),
7.07 (d, J 3.6 Hz, 1H).
mmol) was added to a solution of thiophene IVa (2.0 g,
2
1
gen atmosphere. Granular sulfur (0.76 g, 23.8 mmol) was
added in one portion and then the reaction mixturewas stirred
ꢀ
3.8 mmol) in dry THF (20 mL) at ꢁ70 C for a period of
ꢀ
0 min and stirred at ꢁ70 to ꢁ60 C for 30 min under a nitro-
4.4.5. 2-(2-Propynylsulfanyl)benzo[b]thiophene Ve. Com-
pound Ve was prepared from benzo[b]thiophene IVe (3.2 g,
23.8 mmol) in an analogous manner to that for the prepara-
tion of Va, and the crude product obtained was purified by
column chromatography (stationary phase: silica gel 60–
120, mobile phase: 10% chloroform in hexane) as a viscous
oil (3.88 g, 80%); [Found: C, 64.46; H, 3.87; S, 31.15.
C H S requires: C, 64.67; H, 3.95; S, 31.39]; IR (neat):
ꢀ
at ꢁ70 to ꢁ60 C for another 30 min. A cold solution of
propargyl bromide (3.11 g, 26.2 mmol) dissolved in dry
THF (10 mL) was added so as to maintain the temperature
ꢀ
between ꢁ70 and ꢁ60 C. After the addition was complete
ꢀ
the temperature was gradually raised to ꢁ30 C over a period
of 1 h. Reaction was quenched with 2 N cold dilute HCl
solution. The mixture was extracted with ethyl acetate
1
1 8 2
ꢁ
1
3306, 2923, 1423, 1215, 1156, 1081, 972, and 831 cm
H NMR (CDCl ): d 2.30 (t, J 3.0, 3.0 Hz, 1H), 3.60 (d, J
.
1
(
2ꢂ100 mL) and the combined organic layers were washed
with water (2ꢂ100 mL), saturated sodium bicarbonate
100 mL) followed by brine solution (100 mL) and dried
3
2.4 Hz, 2H), 7.30–7.35 (m, 2H), 7.45 (s, 1H), 7.70–7.76
(m, 2H).
(
over sodium sulfate. This organic layer was concentrated
to give the crude product, which was purified by column
chromatography (stationary phase: silica gel 60–120, mobile
phase: 10% ethyl acetate in hexane)to give2-(2-propynylsul-
fanyl)thiophene Va (1.8 g, 49%) as a viscous oil; [Found: C,
4.5. General method for the synthesis of 6H-thieno[1,3-
b]thiopyran and 2H-benzo[4,5]thieno[2,3-b]thiopyran
derivatives VIa–e. Procedure D
5
S, 41.57]; IR (neat): 3292, 2919, 1594, 1438, 1226, 1213,
4.73; H, 4.03; S, 41.79. C H S requires: C, 54.51; H, 3.92;
4.5.1. 6H-Thieno[1,3-b]thiopyran VIa. 2-(2-Propynylsul-
fanyl)thiophene Va (0.2 g, 1.29 mmol) was taken up in dry
N,N-dimethylformamide (5 mL) and stirred at 150 C for
7
6 2
ꢁ
1
1
ꢀ
9
2
1
53, and 798 cm . H NMR (CDCl ): d 2.28 (t, J 2.4,
3
.4 Hz, 1H), 3.46 (d, J 2.4 Hz, 2H), 7.00 (dd, J 1.8, 1.8 Hz,
H), 7.25 (dd, J 0.9, 0.9 Hz, 1H), 7.49 (dd, J 0.9, 0.9 Hz, 1H).
30 min under a nitrogen atmosphere. Then N,N-dimethyl-
formamide was evaporated under reduced pressure and the
residue was dissolved in ethyl acetate (50 mL). The ethyl
acetate layer was washed with water (2ꢂ25 mL), followed
by brine (25 mL). The organic layer was dried over sodium
sulfate and concentrated to give the crude compound as an
oil. This crude compound was purified by column chromato-
graphy (stationary phase: silica gel 60–120, mobile phase:
10% ethyl acetate in hexane) to give 6H-thieno[1,3-b]thio-
pyran VIa (140 mg, 70%) as a viscous oil; [Found: C,
54.39; H, 3.78; S, 41.75. C H S requires: C, 54.51; H,
4
.4.2. 2-Methyl-5-(2-propynylsulfanyl)thiophene Vb.
Compound Vb was prepared from 2-methylthiophene IVb
2.35 g, 23.8 mmol) in an analogous manner to that for the
preparation of Va, and the crude product obtained was puri-
(
fied by column chromatography (stationary phase: silica gel
6
0–120, mobile phase: 10% chloroform in hexane) as a vis-
cous oil (2.1 g, 53%); [Found: C, 57.33; H, 4.62; S, 38.33.
C H S requires: C, 57.10; H, 4.79; S, 38.11]; IR (neat):
8
8
2
7 6 2
ꢁ
1 1
3309, 3018, 1439, 1215, 1161, 1068, and 953 cm . H
NMR (CDCl ): d 2.27 (t, J 2.4, 2.4 Hz, 1H), 2.45 (s, 3H),
3.92; S, 41.57]; IR (neat): 3037, 2878, 1613, 1406, 1207,
1042, and 874 cm . H NMR (CDCl ): d 3.48 (dd, J 1.5,
ꢁ
1 1
3
3
3
4
.41 (d, J 3.0 Hz, 2H), 6.64 (d, J 4.2 Hz, 1H), 7.05 (d, J
.2 Hz, 1H).
1.5 Hz, 2H), 5.71 (dt, J 3.6, 2.4 Hz, 1H), 6.50 (d, J 7.4 Hz,
1H), 6.85 (d, J 5.4 Hz, 1H), 7.00 (d, J 5.4 Hz, 1H). MS
ꢁ
1
(EI) m/z 153.3 (M ).
4
.4.3. 2-Ethyl-5-(2-propynylsulfanyl)thiophene Vc. Com-
pound Vc was prepared from 2-ethylthiophene IVc (2.67 g,
3.8 mmol) in an analogous manner to that for the prepara-
tion of Va, and the crude product obtained was purified by
4.5.2. 2-Methyl-6H-thieno[1,3-b]thiopyran VIb. Com-
pound VIb was prepared from 2-methyl-5-(2-propynylsulfa-
nyl)thiophene Vb (0.34 g, 2.0 mmol) in an analogous
manner to that for the preparation of VIa, and the crude
product obtained was purified by column chromatography
(stationary phase: silica gel 60–120, mobile phase: 10%
chloroform in hexane) as a viscous oil (0.235 g, 70%);
[Found: C, 56.88; H, 4.65; S, 37.85. C H S requires: C,
2
column chromatography (stationary phase: silica gel 60–
1
20, mobile phase: 10% chloroform in hexane) as a viscous
oil (2.3 g, 54%); [Found: C, 59.15; H, 5.64; S, 35.42.
C H S requires: C, 59.30; H, 5.53; S, 35.18]; IR (neat):
9
10 2
ꢁ
1
3
293, 2968, 1456, 1439, 1226, 1073, 981, and 805 cm .
H NMR (CDCl ): d 1.28 (t, J 7.2, 7.2 Hz, 3H), 2.28 (t, J
8
8 2
1
57.10; H, 4.79; S, 38.11]; IR (neat): 2918, 1436, 1378,
3
ꢁ1
1
2.4, 2.4 Hz, 1H), 2.82 (q, J 7.5, 6.8, 7.5 Hz, 2H), 3.43 (d,
J 3.0 Hz, 2H), 6.68 (d, J 4.0 Hz, 1H), 7.08 (d, J 4.0 Hz, 1H).
1196, 1120, 1062, and 962 cm
d 2.41 (s, 3H), 3.45 (dd, J 1.5, 1.5 Hz, 2H), 5.66 (dt, J 3.4,
.4 Hz, 1H), 6.40 (d, J 7.4 Hz, 1H), 6.53 (s, 1H). MS (EI)
.
H NMR (CDCl3):
2
ꢁ1
4
.4.4. 2-Propyl-5-(2-propynylsulfanyl)thiophene Vd.
Compound Vd was prepared from 2-propylthiophene IVd
3.0 g, 23.8 mmol) in an analogous manner to that for the
m/z 167.0 (M ).
(
4.5.3. 2-Ethyl-6H-thieno[1,3-b]thiopyran VIc. Compound
VIc was prepared from 2-ethyl-5-(2-propynylsulfanyl)thio-
phene Vc (0.36 g, 2.0 mmol) in an analogous manner to
preparation of Va, and the crude product obtained was puri-
fied by column chromatography (stationary phase: silica gel

R. S. Kenny et al. / Tetrahedron 62 (2006) 9280–9288
9285
that for the preparation of VIa, and the crude product ob-
tained was purified by column chromatography (stationary
phase: silica gel 60–120, mobile phase: 10% chloroform in
hexane) as a viscous oil (0.27 g, 75%); [Found: C, 59.06;
H, 5.45; S, 35.01. C H S requires: C, 59.30; H, 5.53; S,
HCl solution till pH was acidic. The mixture was extracted
with ethyl acetate (2ꢂ100 mL) and the combined organic
layers were washed with water (2ꢂ50 mL) and dried over
sodium sulfate. This organic layer was concentrated to give
the crude product, which was purified by column chromato-
graphy (stationary phase: silica gel 60–120, mobile phase:
2% methanol in chloroform) as a white solid (3.42 g,
9
10 2
3
8
2
2
6
5.18]; IR (neat): 2969, 1450, 1414, 1215, 1185, 1065, and
36 cm . H NMR (CDCl ): d 1.34 (t, J 7.5, 7.5 Hz, 3H),
ꢁ
1 1
3
ꢀ
.28 (q, J 7.5, 6.5, 7.5 Hz, 2H), 3.53 (dd, J 1.5, 1.5 Hz,
H), 5.74 (dt, J 3.6, 2.2 Hz, 1H), 6.48 (d, J 7.4 Hz, 1H),
.63 (s, 1H). MS (EI) m/z 181.3 (M ).
72%); mp¼84–86 C; [Found: C, 47.76; H, 4.18; S, 32.27.
C H O S requires: C, 47.98; H, 4.03; S, 32.02]; IR (neat):
8 2 2
8
ꢁ
1
ꢁ1
1
3031, 2629, 1685, 1622, 1443, 1402, and 1231 cm . H
NMR (DMSO-d ): d 3.59 (s, 2H), 5.88 (s, 1H), 6.24 (s,
6
4
.5.4. 2-Propyl-6H-thieno[1,3-b]thiopyran VId. Com-
1H), 6.95 (t, J 4.5, 4.5 Hz, 1H), 7.08 (d, J 4.2 Hz, 1H),
7.34 (d, J 5.1 Hz, 1H).
pound VId was prepared from 2-propyl-5-(2-propynylsulfa-
nyl)thiophene Vd (0.39 g, 2.0 mmol) in an analogous
manner to that for the preparation of VIa, and the crude
product obtained was purified by column chromatography
4.6.2. 2-(5-Methyl-2-thienyl sulfanylmethyl)acrylic acid
VIIb. Compound VIIb was prepared from 2-methylthio-
phene IVb (2.35 g, 23.8 mmol) in an analogous manner to
that for the preparation of VIIa, and the crude product ob-
tained was purified by column chromatography (stationary
phase: silica gel 60–120, mobile phase: 2% methanol in
chloroform) as a white solid (3.56 g, 70%); mp¼157–
(
stationary phase: silica gel 60–120, mobile phase: 10%
chloroform in hexane) as a viscous oil (0.3 g, 75%); [Found:
C, 61.36; H, 6.25; S, 32.90. C H S requires: C, 61.18;
H, 6.16; S, 32.66]; IR (neat): 2917, 1441, 1314, 1212,
1
7
7
1
0 12 2
ꢁ
1 1
131, 964, and 912 cm . H NMR (CDCl ): d 0.96 (t, J
3
ꢀ
.2, 7.2 Hz, 3H), 1.65 (sextet, J 3.0 Hz, 2H), 2.68 (t, J 7.8,
.8 Hz, 2H), 3.46 (dd, J 1.4, 1.4 Hz, 2H), 5.67 (dt,
160 C; [Found: C, 50.23; H, 4.55; S, 29.70. C H O S
9
10
2
2
requires: C, 50.44; H, 4.70; S, 29.92]; IR (KBr): 2632,
ꢁ
1
1
J 3.6, 2.4 Hz, 1H), 6.41 (d, J 8.0 Hz, 1H), 6.54 (s, 1H).
MS (EI) m/z 195.1 (M ).
1687, 1622, 1445, 1408, and 1232 cm
.
H NMR
(DMSO-d ): d 2.44 (s, 3H), 3.54 (s, 2H), 5.38 (s, 1H), 6.24
ꢁ
1
6
(s, 1H), 6.60 (d, J 4.8 Hz, 1H), 6.87 (d, J 4.2 Hz, 1H).
4
.5.5. 2H-Benzo[4,5]thieno[2,3-b]thiopyran VIe. Com-
pound VIe was prepared from 2-(2-propynylsulfanyl)-
benzo[b]thiophene Ve (0.41 g, 2.0 mmol) in an analogous
manner to that for the preparation of VIa, and the crude
product obtained was purified by column chromatography
4.6.3. 2-(5-Ethyl-2-thienyl sulfanylmethyl)acrylic acid
VIIc. Compound VIIc was prepared from 2-ethylthiophene
IVc (2.67 g, 23.8 mmol) in an analogous manner to that for
the preparation of VIIa, and the crude product obtained was
purified by column chromatography (stationary phase: silica
gel 60–120, mobile phase: 2% methanol in chloroform) as
(
stationary phase: silica gel 60–120, mobile phase: 10%
chloroform in hexane) as a white solid (0.3 g, 75%); mp¼
ꢀ
ꢀ
88–90 C; [Found: C, 64.49; H, 4.08; S, 31.55. C H S
requires: C, 64.67; H, 3.95; S, 31.39]; IR (KBr): 2880,
a white solid (3.8 g, 70%); mp¼67–68 C; [Found: C,
1
1
8
2
52.84; H, 5.45; S, 28.27. C H O S requires: C, 52.60;
1
0 12 2 2
ꢁ
1 1
1457, 1420, 1312, 1247, 1133, 1092, and 1014 cm . H
NMR (CDCl ): d 3.58 (dd, J 1.8, 1.8 Hz, 2H), 5.81 (dt, J
H, 5.30; S, 28.09]; IR (KBr): 2965, 2629, 1691, 1622,
1440, 1323, 1218, and 926 cm . H NMR (DMSO-d ):
ꢁ
1 1
3
6
3
6
1
.6, 2.5 Hz, 1H), 6.75 (d, J 8.0 Hz, 1H), 7.24 (t, J 6.6,
.6 Hz, 1H), 7.32 (t, J 6.6, 6.6 Hz, 1H), 7.69 (d, J 7.8 Hz,
H), 7.79 (d, J 7.8 Hz, 1H), MS (EI) m/z 203.3 (M ).
d 1.28 (t, J 7.5, 7.5 Hz, 3H), 2.80 (q, J 7.5, 6.6, 7.5 Hz,
2H), 3.55 (s, 2H), 5.39 (s, 1H), 6.24 (s, 1H), 6.63 (d, J
3.6 Hz, 1H), 6.90 (d, J 3.6 Hz, 1H).
ꢁ
1
4.6. General method for the synthesis of 2-(2-thienyl
sulfanylmethyl)acrylic acid derivatives VIIa–e
4.6.4. 2-(5-Propyl-2-thienyl sulfanylmethyl)acrylic acid
VIId. Compound VIId was prepared from 2-propylthio-
phene IVd (3.0 g, 23.8 mmol) in an analogous manner to
that for the preparation of VIIa, and the crude product ob-
tained was purified by column chromatography (stationary
phase: silica gel 60–120, mobile phase: 2% methanol in
The 2-(2-thienyl sulfanylmethyl)acrylic acid derivatives
VIIa–e were synthesized following the general procedure
C from thiophenes IVa–d and IVf, a-(bromomethyl)acrylic,
acid and sulfur in the presence of n-butyllithium as base.
ꢀ
chloroform) as a white solid (3.45 g, 60%); mp¼61–62 C;
[Found: C, 54.32; H, 5.68; S, 26.34. C H O S requires:
C, 54.51; H, 5.82; S, 26.46]; IR (KBr): 2958, 2629, 1693,
11 14 2 2
2
0
4
solution of n-butyllithium (13.34 cm of 15% in n-hexane,
.6.1. 2-(2-Thienyl sulfanylmethyl)acrylic acid VIIa.
A
3
ꢁ1
1
1622, 1441, 1325, and 1230 cm . H NMR (DMSO-d ):
6
3
1.25 mmol) was added to a solution of thiophene IVa
ꢀ
d 0.97 (t, J 7.5, 7.5 Hz, 3H), 1.68 (sextet, J 2.9 Hz, 2H),
2.74 (t, J 7.2, 7.2 Hz, 2H), 3.56 (s, 2H), 5.38 (s, 1H), 6.24
(s, 1H), 6.64 (d, J 2.7 Hz, 1H), 6.91 (d, J 3.6 Hz, 1H).
(
2.0 g, 23.8 mmol) in dry THF (20 mL) at ꢁ78 C for a
ꢀ
period of 10 min and stirred at ꢁ78 C for 30 min under a
nitrogen atmosphere. Granular sulfur (0.762 g, 23.8 mmol)
was added in one portion and then the reaction mixture
4.6.5. 2-(5-Cyano-2-thienyl sulfanylmethyl)acrylic acid
VIIe. Compound VIIe was prepared from 2-cyanothiophene
IVf (2.6 g, 23.8 mmol) in an analogous manner to that for the
preparation of VIIa, and the crude product obtained was pu-
rified by column chromatography (stationary phase: silica
gel 60–120, mobile phase: 2% methanol in chloroform) as
ꢀ
was stirred at ꢁ78 C for another 30 min. A cold solution
of a-(bromomethyl)acrylic acid (4.32 g, 26.2 mmol) dis-
solved in a solution of sodium hydroxide (2.2 g, 55 mmol)
in water (20 mL) is then added slowly while maintaining
ꢀ
the temperature at ꢁ78 C. After the addition is complete
ꢀ
of 1 h. Then the reaction was quenched with 2 N cold dilute
ꢀ
the temperature is gradually raised to ꢁ30 C over a period
a white solid (2.73 g, 51%); mp¼94–96 C; [Found: C,
47.76; H, 3.27; N, 6.02; S, 28.65. C H NO S requires: C,
7
9
2 2

9286
R. S. Kenny et al. / Tetrahedron 62 (2006) 9280–9288
ꢀ
[Found: C, 54.27; H, 5.97; S, 26.20. C H O S requires:
4
2
7.98; H, 3.13; N, 6.22; S, 28.46]; IR (KBr): 2880, 2522,
222,1687, 1622, 1440, 1417, 1311, and 1215 cm . H
chloroform) as a white solid (0.83 g, 86%); mp¼96–98 C;
ꢁ
1 1
1
1 14 2 2
NMR (DMSO-d ): d 3.70 (s, 2H), 5.56 (s, 1H), 6.32 (s,
6
C, 54.51; H, 5.82; S, 26.46]; IR (KBr): 2876, 1705, 1413,
ꢁ
1269, 1205, and 1022 cm . H NMR (DMSO-d ): d 0.95
6
1 1
1
H), 7.04 (d, J 3.9 Hz, 1H), 7.24 (d, J 4.2 Hz, 1H).
(t, J 7.5, 7.5 Hz, 3H), 1.62 (sextet, J 3.0 Hz, 2H), 2.65 (t, J
7.5, 7.5 Hz, 2H), 2.86–3.02 (m, 2H), 3.05–3.23 (m, 3H),
6.43 (s, 1H). MS (EI) m/z 241.1 (M ).
4.7. General method for the synthesis of 5,6-dihydro-4H-
thieno[2,3-b]thiopyran-5-carboxylic acid derivatives
VIIIa–e
ꢁ
1
4
.7.5. 2-Cyano-5,6-dihydro-4H-thieno[2,3-b]thiopyran-
5,6-Dihydro-4H-thieno[2,3-b]thiopyran-5-carboxylic acids
VIIIa–e were synthesized following the general procedure
5-carboxylic acid VIIIe. Compound VIIId was prepared
from 2-(5-cyano-2-thienyl sulfanylmethyl)acrylic acid
VIIe (0.97 g, 4.0 mmol) in an analogous manner to that
for the preparation of VIa, and the crude product obtained
was purified by column chromatography (stationary phase:
silica gel 60–120, mobile phase: 3% methanol in chloro-
D by heating 2-(2-thienyl sulfanylmethyl)acrylic acids
ꢀ
VIIa–e in N,N-dimethylformamide at 135 C for 45 min.
4.7.1. 5,6-Dihydro-4H-thieno[2,3-b]thiopyran-5-car-
boxylic acid VIIIa. Compound VIIIa was prepared from
2
0
ꢀ
form) as a white solid (0.85 g, 88%); mp¼169–171 C;
2-(2-thienyl sulfanylmethyl)acrylic acid VIIIa (0.80 g,
4.0 mmol) in an analogous manner to that for the preparation
[Found: C, 48.10; H, 3.00; N, 6.45; S, 28.27. C H NO S
2
9
7
2
requires: C, 47.98; H, 3.13; N, 6.22; S, 28.46]; IR (KBr):
2919, 2213, 1695, 1409, 1279, and 1211 cm . H NMR
ꢁ1 1
of VIa, and the crude product obtained was purified by col-
umn chromatography (stationary phase: silica gel 60–120,
(DMSO-d ): d 2.90–3.10 (m, 2H), 3.17–3.36 (m, 3H), 7.28
6
ꢁ
1
mobile phase: 3% methanol in chloroform) as a white solid
(
(s, 1H). MS (EI) m/z 224.0 (M ).
ꢀ
S, 31.80. C H O S requires: C, 47.98; H, 4.03; S, 32.02]; IR
0.73 g, 91%); mp¼130–132 C; [Found: C, 48.17; H, 4.15;
4.8. Synthesis of propynyl and acryloyl thioethers of
dibenzo[b,d]furan and dibenzo[b,d]thiophene Xa,b,
XIIa,b
8
8 2 2
ꢁ
1 1
(
(
7
KBr): 2892, 2601, 1699, 1336, and 1213 cm . H NMR
DMSO-d ): d 2.90–3.29 (m, 5H), 6.76 (d, J 4.9 Hz, 1H),
6
ꢁ1
.03 (d, J 5.1 Hz, 1H). MS (EI) m/z 199.0 (M ).
4.8.1. 4-(2-Propynylsulfanyl)dibenzo[b,d]furan Xa. A
solution of n-butyllithium (4.2 mL of 15% in n-hexane,
4
5
.7.2. 2-Methyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-
-carboxylic acid VIIIb. Compound VIIIb was prepared
9.84 mmol) was added to a stirred solution of dibenzofuran
(1.5 g, 8.93 mmol) in dry THF (15 mL) at ꢁ40 C over a
ꢀ
from 2-(5-methyl-2-thienyl sulfanylmethyl)acrylic acid
VIIb (0.85 g, 4.0 mmol) in an analogous manner to that
for the preparation of VIa, and the crude product obtained
was purified by column chromatography (stationary phase:
silica gel 60–120, mobile phase: 3% methanol in chloro-
period of 10 min then stirred at room temperature for 2 h
under a nitrogen atmosphere. Reaction was cooled to
ꢀ
ꢁ40 C, sulfur (0.286 g, 8.93 mmol) was added and stirring
ꢀ
maintained at ꢁ40 to ꢁ30 C for 30 min. Then propargyl
ꢀ
form) as a white solid (0.77 g, 90%); mp¼126–128 C;
bromide (1.07 g, 8.99 mmol) was added at the same temper-
ature. The temperature of the reaction was raised to room
temperature and stirred for another 30 min. The reaction
mixture was slowly quenched with water and extracted
with ethyl acetate (2ꢂ50 mL). The combined organic layer
was washed with water (50 mL) and finally with brine
[
Found: C, 50.65; H, 4.89; S, 30.13. C H O S requires:
9 10 2 2
C, 50.44; H, 4.70; S, 29.92]; IR (KBr): 2889, 2611, 1695,
1
ꢁ
330, 1225, and 1109 cm . H NMR (DMSO-d ): d 2.37
6
1 1
(
1
s, 3H), 2.80–3.03 (m, 2H), 3.13–3.25 (m, 3H), 6.41 (s,
H). MS (EI) m/z 213.0 (M ).
ꢁ1
(50 mL). The organic layer was dried over sodium sulfate
4
.7.3. 2-Ethyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-5-
and concentrated under reduced pressure to give crude prod-
uct, which was purified by column chromatography (station-
ary phase: silica gel 60–120, mobile phase: 30% chloroform
carboxylic acid VIIIc. Compound VIIIc was prepared
from 2-(5-ethyl-2-thienyl sulfanylmethyl)acrylic acid VIIc
ꢀ
(
0.91 g, 4.0 mmol) in an analogous manner to that for
in hexane) to give a white solid (0.51 g, 24%); mp 45–46 C;
[Found: C, 75.38; H, 4.15; S, 13.67. C H OS requires: C,
the preparation of VIa, and the crude product obtained
was purified by column chromatography (stationary phase:
silica gel 60–120, mobile phase: 3% methanol in chloro-
1
5 10
75.60; H, 4.23; S, 13.45]; IR (KBr): 3275, 2955, 1432, 1375,
and 1030 cm . H NMR (CDCl ): d 2.17 (t, J 2.7, 2.7 Hz,
ꢁ
1 1
3
ꢀ
form) as a white solid (0.77 g, 85%); mp¼141–143 C;
1H), 3.81 (d, J 2.4 Hz, 2H), 7.30–7.38 (m, 2H), 7.46 (t, J
6.6, 6.6 Hz, 1H), 7.58–7.64 (m, 2H), 7.85–7.95 (m, 2H).
[
C, 52.60; H, 5.30; S, 28.09]; IR (KBr): 2971, 1698, 1418,
Found: C, 52.33; H, 5.05; S, 28.32. C H O S requires:
1
0 12 2 2
ꢁ
1 1
1
287, 1209, and 1022 cm . H NMR (DMSO-d ): d 1.25
6
4.8.2. 4-(2-Propynylsulfanyl)dibenzo[b,d]thiophene Xb.
Compound Xb was prepared from dibenzothiophene
(1.64 g, 8.93 mmol) in an analogous manner to that for the
preparation of Xa, and the crude product obtained was puri-
fied by column chromatography (stationary phase: silica gel
60–120, mobile phase: 5% ethyl acetate in hexane) as a pale
(
2
(
t, J 7.5, 7.5 Hz, 3H), 2.72 (q, J 7.1, 6.2, 7.1 Hz, 2H),
.79–3.02 (m, 2H), 3.07–3.25 (m, 3H), 6.44 (s, 1H). MS
EI) m/z 227.1 (M ).
ꢁ1
4
5
.7.4. 2-Propyl-5,6-dihydro-4H-thieno[2,3-b]thiopyran-
-carboxylic acid VIIId. Compound VIIId was prepared
ꢀ
yellow solid (0.68 g, 30%); mp¼64–65 C; [Found: C,
from 2-(5-propyl-2-thienyl sulfanylmethyl)acrylic acid
VIId (0.97 g, 4.0 mmol) in an analogous manner to that
for the preparation of VIa, and the crude product obtained
was purified by column chromatography (stationary phase:
silica gel 60–120, mobile phase: 3% methanol in
70.69; H, 3.91; S, 25.39. C H S requires: C, 70.83; H,
1
5 10 2
3.96; S, 25.21]; IR (KBr): 3283, 2946, 1438, 1384, and
1034 cm . H NMR (CDCl ): d 2.21 (t, J 2.4, 2.4 Hz,
ꢁ
1 1
3
1H), 3.73 (d, J 3.0 Hz, 2H), 7.44–7.50 (m, 3H), 7.46 (d, J
7.6 Hz, 1H), 7.87–7.90 (m, 1H), 8.10–8.15 (m, 2H).

R. S. Kenny et al. / Tetrahedron 62 (2006) 9280–9288
9287
4
.8.3. 2-Dibenzo[b,d]furan-4-ylsulfanylmethylacrylic
crude product obtained was purified by column chromato-
graphy (stationary phase: silica gel 60–120, mobile phase:
15% chloroform in hexane) as a gummy oil (1.0 g, 70%);
[Found: C, 70.93; H, 3.84; S, 25.38. C H S requires: C,
acid XIIa. A solution of n-butyllithium (4.2 mL of 15% in
n-hexane, 9.84 mmol) was added to a stirred solution of
dibenzofuran (1.5 g, 8.93 mmol) in dry THF (15 mL) at
1
5 10 2
ꢀ
ꢁ
40 C over a period of 10 min and stirred at room temper-
ature for 2 h under a nitrogen atmosphere. Reaction was
70.83; H, 3.96; S, 25.21]; IR (neat): 3033, 1446, 1366,
1115, 1038, and 832 cm . H NMR (CDCl ): d 3.62 (dd,
ꢁ
1 1
3
ꢀ
cooled to ꢁ40 C, sulfur (0.286 g, 8.93 mmol) was added
J 1.5, 1.5 Hz, 2H), 6.01 (q, J 5.5, 4.0, 5.5 Hz, 1H), 6.66
(dt, J 3.5, 2.6 Hz, 1H), 7.18 (d, J 7.8 Hz, 1H), 7.43–7.46
(m, 2H), 7.85–7.89 (m, 2H), 9.10 (d, J 8.8 Hz, 1H). MS
ꢀ
Then a solution of a-(bromomethyl)acrylic acid (0.73 g,
and stirring maintained at ꢁ40 to ꢁ30 C for 30 min.
ꢁ
1
4
.47 mmol) in THF (5 mL) and NaOH (0.35 g, 8.95 mmol)
(EI) m/z 253.2 (M ).
in water (5 mL) was added simultaneously over 10 min at
the same temperature. The temperature was raised to room
temperature and stirred for 30 min. Water (50 mL) was
added to the reaction mixture and extracted with ethyl ace-
tate (50 mL). The aqueous layer was acidified with 2 N aq
HCl solution, extracted with chloroform (3ꢂ50 mL). The
combined organic layer was washed with brine (50 mL),
dried over sodium sulfate and concentrated to give crude
product, which was purified by column chromatography
4.8.7. 3,4-Dihydro-2H-benzo[b]thiochromeno[7,8-d]-
furan-3-carboxylic acid XIIIa. Compound XIIIa is
synthesized following the procedure D by heating 2-di-
benzo[b,d]furan-4-ylsulfanylmethylacrylic acid XIIa (1.1 g,
ꢀ
4.0 mmol) in N,N-dimethylformamide at 150 C for 5 h
under a nitrogen atmosphere. The crude product obtained
was purified by column chromatography (stationary phase:
silica gel 60–120, mobile phase: 2% methanol in chloroform)
ꢀ
(
stationary phase: silica gel 60–120, mobile phase: 3%
methanol in chloroform) to give a white solid (0.46 g,
as a white solid (0.72 g, 65%); mp¼253–254 C; [Found: C,
67.75; H, 4.13; S, 11.40. C H O S requires: C, 67.59;
1
6 12 3
ꢀ
1.06. C H O S requires: C, 67.59; H, 4.25; S, 11.28];
1
8%); mp¼149–150 C; [Found: C, 67.48; H, 4.41; S,
H, 4.25; S, 11.28]; IR (KBr): 2885, 2603, 1694, 1409,
1192, 1152, and 938 cm . H NMR (DMSO-d ): d 3.28–
ꢁ
1 1
1
IR (KBr): 2914, 2522, 1698, 1621, 1437, and 1218 cm
1
6
12
3
6
ꢁ1
.
H NMR (DMSO-d ): d 4.00 (s, 2H), 5.45 (s, 1H), 6.00 (s,
3.74 (m, 5H), 7.21 (d, J 7.8 Hz, 1H), 7.39 (t, J 7.2, 7.2 Hz,
1H), 7.50 (t, J 7.2, 7.2 Hz, 1H), 7.76 (t, J 8.1, 8.1 Hz, 2H),
8.09 (d, J 7.5 Hz, 1H), 12.75 (hump, 1H). MS (EI) m/z
1
6
1
7
H), 7.38–7.60 (m, 4H), 7.78 (d, J 7.8 Hz, 1H), 8.05 (d, J
.8 Hz, 1H), 8.16 (d, J 7.8 Hz, 1H) 12.80 (hump, 1H).
ꢁ
1
283.1 (M ).
4
.8.4. 2-Dibenzo[b,d]thiophene-4-ylsulfanylmethyl-
4.8.8. 3,4-Dihydro-2H-benzo[4,5]thieno[3,2-h]thiochro-
mene-3-carboxylic acid XIIIb. Compound XIIIb was
prepared from 2-dibenzo[b,d]thiophene-4-ylsulfanylmethyl-
acrylic acid XIIb (1.2 g, 4.0 mmol) in an analogous manner
to that for the preparation of XIIIa, and the crude product
obtained was purified by column chromatography (station-
ary phase: silica gel 60–120, mobile phase: 2% methanol
in chloroform) as a white solid (0.888 g, 74%); mp¼254–
acrylic acid XIIb. Compound XIIb was prepared from
dibenzothiophene (1.0 g, 5.43 mmol) in an analogous man-
ner to that for the preparation of XIIa, and the crude product
obtained was purified by column chromatography (station-
ary phase: silica gel 60–120, mobile phase: 2% methanol
in chloroform) as a white solid (0.41 g, 25%); mp¼162–
ꢀ
requires: C, 63.97; H, 4.03; S, 21.35]; IR (KBr): 2916,
1
65 C; [Found: C, 63.72; H, 4.21; S, 21.45. C H O S
1
6
12
2
2
ꢀ
256 C; [Found: C, 64.17; H, 3.97; S, 21.56. C H O S
1
6
12
2
2
ꢁ
1 1
1696, 1438, 1309, and 1213 cm . H NMR (DMSO-d ):
d 3.94 (s, 2H), 5.48 (d, J 0.9 Hz, 1H), 5.94 (d, J 1.2 Hz,
requires: C, 63.97; H, 4.03; S, 21.35]; IR (KBr): 2888,
1697, 1406, 1271, and 1192 cm . H NMR (DMSO-d ):
6
ꢁ
1 1
6
1
8
H), 7.51–7.60 (m, 4H), 8.06 (d, J 7.5 Hz, 1H), 8.30 (d, J
.7 Hz, 1H), 8.35 (d, J 7.8 Hz, 1H), 12.80 (hump, 1H).
d 3.09–3.45 (m, 5H), 7.33 (d, J 8.4 Hz, 1H), 7.51 (m, 2H),
8.03 (d, J 7.8 Hz, 2H), 8.13 (d, J 7.8 Hz, 1H), 12.75
ꢁ
1
(hump, 1H). MS (EI) m/z 299.1 (M ).
4.8.5. 2H-Benzo[b]thiochromeno[7,8-d]furan XIa. Com-
pound XIa is synthesized following the procedure B by heat-
Acknowledgements
ing 4-(2-propynylsulfanyl)dibenzo[b,d]furan Xa (0.95 g,
ꢀ
4
.0 mmol) in N,N-diethylaniline at 220 C for 8 h under
One of the authors acknowledges Dr. B. Gopalan, Sr. Vice
President, Glenmark Pharmaceuticals Limited for technical
assistance.
nitrogen atmosphere. The crude product obtained was puri-
fied by column chromatography (stationary phase: silica gel
6
0–120, mobile phase: 15% chloroform in hexane) as a white
ꢀ
.13; S, 13.64. C H OS requires: C, 75.60; H, 4.23; S,
solid (0.52 g, 55%); mp¼95–97 C; [Found: C, 75.88; H,
4
1
1
2
1
7
References and notes
1
5 10
3.45]; IR (KBr): 2884, 1450, 1407, 1201, 1185, and
019 cm . H NMR (CDCl ): d 3.55 (dd, J 1.5, 1.5 Hz,
H), 5.97 (q, J 5.4, 4.2, 5.4 Hz, 1H), 6.65 (d, J 10.5 Hz,
H), 7.05 (d, J 7.8 Hz, 1H), 7.31 (t, J 6.6, 6.6 Hz, 1H),
.43 (t, J 7.3, 7.3 Hz, 1H), 7.68 (d, J 9.3 Hz, 1H), 7.71 (d,
ꢁ
1 1
1. Kaye, P. T.; Musa, M. A.; Nchinda, A. T.; Nocanda, X. W.
Synth. Commun. 2004, 34, 2575.
2. Kaye, P. T. S. Afr. J. Chem. 2004, 57, 545.
3. Kaltenbach, R. F.; Robinson, S. P.; Trainor, G. L. U.S. Patent
2005/0267183 A1, December 1, 2005.
4. Zhang, X.; Sui, Z. U.S. Patent 2006/0020018 A1, January 26,
3
J 7.8 Hz, 1H), 7.86 (d, J 8.1 Hz, 1H). MS (EI) m/z 237.3
).
ꢁ1
(
M
2
006.
4
.8.6. 2H-Benzo[b]thiochromeno[7,8-d]thiophene XIb.
5. (a) Kakiuchi, F.; Yamauchi, M.; Chatani, N.; Murai, S. Chem.
Lett. 1996, 25, 111; (b) Thalji, R. K.; Ahrendt, K. A.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123,
9692; (c) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries,
Compound XIb was prepared from 4-(2-propynylsulfanyl)-
dibenzo[b,d]thiophene Xb (0.95 g, 4.0 mmol) in an analo-
gous manner to that for the preparation of XIa, and the

9288
R. S. Kenny et al. / Tetrahedron 62 (2006) 9280–9288
A. H. M.; Kamer, P. C. J.; de Vries, J. G.; Leeuwen, P. W. N. M.
J. Am. Chem. Soc. 2002, 124, 1586; (d) Baran, P. S.; Corey, E. J.
J. Am. Chem. Soc. 2002, 124, 7904.
14. Trost, B. M.; Toste, F. D.; Greenman, K. J. Am. Chem. Soc.
2003, 125, 4518.
15. Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M.
J. Am. Chem. Soc. 2002, 124, 1586.
6
7
8
. Chatani, N.; Inoue, H.; Ikeda, T.; Murai, S. J. Org. Chem. 2000,
65, 4913.
. Koch-Pomeranz, U.; Hansen, H.-J.; Schmid, H. Helv. Chim.
Acta 1973, 56, 2981.
. (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1996, 118,
6305; (b) Larock, R. C.; Dotty, M. J.; Tian, Q.; Zenner, J. M.
J. Org. Chem. 1997, 62, 7536.
16. Song, C. E.; Jung, D.-U.; Choung, S. Y.; Roh, E. J.; Lee, S.-g.
Angew. Chem., Int. Ed. 2004, 43, 6183.
17. Reetz, M. T.; Sommer, K. Eur. J. Org. Chem. 2003, 18, 3485.
18. Matsumoto, T.; Taube, D. J.; Periana, R. A.; Taube, H.;
Yoshida, H. J. Am. Chem. Soc. 2000, 122, 7414.
19. Shi, Z.; He, C. J. Org. Chem. 2004, 69, 3669.
20. Hutchison, A. J.; Verona, N. J. U.S. Patent 4,816,474, March
28, 1989.
9
. (a) Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003, 59,
8859; (b) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2004,
6, 581.
1
1
1
1
0. Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara,
Y. Science 2000, 287, 1992.
1. Jia, C.; Lu, W.; Oyamada, J.; Kitamura, T.; Matsuda, K.; Irie,
M.; Fujiwara, Y. J. Am. Chem. Soc. 2000, 122, 7252.
2. Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34,
21. Ramarajan, K.; Ramalingam, K.; O’Donnell, D. J.; Berlin,
K. D. Org. Synth. VII 1990, 210.
22. (a) Gilmen, H.; Young, R. V. J. Am. Chem. Soc. 1935, 57, 1121;
(b) Nishioka, M.; Castle, R. N.; Lee, M. L. J. Heterocycl.
Chem. 1985, 22, 215; (c) Oliveira, M. M.; Moustrou, C.;
Carvalho, L. M.; Silva, J. A. C.; Samat, A.; Guglielmetti, R.;
Dubest, R.; Aubard, J.; Oliveira-Campos, A. M. F.
Tetrahedron 2002, 58, 1709.
633.
3. Viciu, M. S.; Stevens, E. D.; Petersen, J. L.; Nolan, S. P.
Organometallics 2004, 23, 3752.