Synthesis of polycyclic and 4,5-diacylthiophene-2-carboxylates via intramolecular Friedel-Crafts alkylations and unusual autooxidative fragmentation of the derivatives obtained from the samarium diiodide-promoted coupling reactions of thiophene-2-carboxylate with carbonyl compounds

Article abstract of DOI:10.1016/j.tet.2006.11.080

Our present study provides an expedient method for the synthesis of novel polycyclic and multi-substituted thiophene derivatives. A series of 4,5-di(hydroxyalkyl)-4,5-dihydrothiophene-2-carboxylates (e.g., 4a-c and 10) were prepared by the SmI₂-promoted three-component coupling reactions of thiophene-2-carboxylate with aromatic aldehydes and 4-methoxyacetophenone. Diol 4a was oxidized by DDQ or pyridinium dichromate to give 5-acyl-4-hydroxyalkyl-4,5-dihydrothiophene-2-carboxylate 6a, which was subjected to dehydration to give either alkene 7 with terminal C{double bond, long}C double bond or alkene 15a having conjugation with the ester group, depending on the reaction conditions using different quantities of p-toluenesulfonic acid. Alkene 7 underwent an intramolecular Friedel-Crafts alkylation to give a tetralone-fused thiophene-2-carboxylate 9. By the similar procedure, a carbazole-fused thiophene 14 was also prepared. Alkenes 15a-c underwent autooxidative fragmentation to give 4,5-diacylthiophene-2-carboxylates 5a-c that were elaborated to pyridazine-fused thiophenes.

Full text of DOI:10.1016/j.tet.2006.11.080

Tetrahedron 63 (2007) 1421–1428
Synthesis of polycyclic and 4,5-diacylthiophene-2-carboxylates
via intramolecular Friedel–Crafts alkylations and unusual
autooxidative fragmentation of the derivatives obtained from
the samarium diiodide-promoted coupling reactions of
thiophene-2-carboxylate with carbonyl compounds
*
Shyh-Ming Yang and Jim-Min Fang
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
Received 11 September 2006; revised 27 November 2006; accepted 28 November 2006
Available online 15 December 2006
Abstract—Our present study provides an expedient method for the synthesis of novel polycyclic and multi-substituted thiophene derivatives.
A series of 4,5-di(hydroxyalkyl)-4,5-dihydrothiophene-2-carboxylates (e.g., 4a–c and 10) were prepared by the SmI2-promoted three-com-
ponent coupling reactions of thiophene-2-carboxylate with aromatic aldehydes and 4-methoxyacetophenone. Diol 4a was oxidized by DDQ
or pyridinium dichromate to give 5-acyl-4-hydroxyalkyl-4,5-dihydrothiophene-2-carboxylate 6a, which was subjected to dehydration to give
either alkene 7 with terminal C]C double bond or alkene 15a having conjugation with the ester group, depending on the reaction conditions
using different quantities of p-toluenesulfonic acid. Alkene 7 underwent an intramolecular Friedel–Crafts alkylation to give a tetralone-fused
thiophene-2-carboxylate 9. By the similar procedure, a carbazole-fused thiophene 14 was also prepared. Alkenes 15a–c underwent auto-
oxidative fragmentation to give 4,5-diacylthiophene-2-carboxylates 5a–c that were elaborated to pyridazine-fused thiophenes.
Ó 2006 Elsevier Ltd. All rights reserved.
R2
Ar2
1. Introduction
H
O
O
2 SmI2
R2
THF, HMPA
+
HO
HO
Ar1
+
OMe
Ar1
R1
S
Ar2
Thiophenes and their polycyclic derivatives exhibit remark-
able electrochemical,1a,b optical,1c physical,1d and biologi-
cal1e,f properties that render their extensive applications in
material and pharmaceutical sciences. Though thiophene
derivatives have been prepared by various methods,2 elabo-
ration of the existing thiophene skeleton with multiple sub-
stituents at the desired positions is still a challenging task. To
our knowledge, there are only a few reports on the derivati-
zation of thiophene-2-carboxylates.3 For example, methyl
thiophene-2-carboxylate reacts with paraformaldehyde in
the presence of ZnCl2 to give a mixture of 4-chloromethyl-,
5-chloromethyl-, and 4,5-bis(chloromethyl)thiophene-2-
carboxylate.3a Metalation of thiophene-2-carboxylate and
the subsequent electrophilic substitution usually occur at
either C-3 or C-5 position;3b however, introduction of sub-
stituents at the C-4 position is still difficult.
OMe
S
O
1
2
3
H
R1
O
4
ð1Þ
In an approach to elaborate thiophene derivatives at C-4 and
C-5 positions, we have utilized SmI2 as the promoter to carry
out the tandem double electrophilic reactions of thiophene-
2-carboxylate 1 with carbonyl compounds (e.g., 2 and 3)
to obtain the three-component coupling products of 4,5-di-
(hydroxyalkyl)-4,5-dihydrothiophenes 4 in one-pot opera-
tion (Eq. 1).4 The three-component coupling products
prepared as such have been elaborated to the photochromic
compounds of 4,5-dialkenylthiophenes4c and the sulfur-
containing polyaromatic compounds4d that are applicable
to material and biological researches. In order to understand
the scope and limitation of this method, we extended this
study to synthesize the previously elusive compounds of
4,5-diacylthiophene-2-carboxylates (Fig. 1), and serendipi-
tously observed an unusual acid-catalyzed autooxidative
fragmentation reaction during this course of study.
Keywords: Samarium diiodide; Coupling reaction; Autooxidation; Frag-
mentation; Thiophene; Thieno[2,3-d]pyridazine.
* Corresponding author. Tel.: +8862 3366 1663; fax: +8862 2363 7812;
e-mail: jmfang@ntu.edu.tw
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.080

1422
S.-M. Yang, J.-M. Fang / Tetrahedron 63 (2007) 1421–1428
Diols 5a–c and 10 likely have the 4,5-trans configuration
O
Me
that can be established by an attack of the second electro-
phile on the less hindered face of the dienolate intermediate
A (Scheme 1).4 The 1H NMR analysis indicated that diol 10
existed as a mixture of two diastereomers (65:35) differing at
the carbinyl centers. Oxidation of diol 10 (as a diastereo-
meric mixture) with DDQ at room temperature afforded a
single product of ketone 11. This oxidation reaction was
also realized by using pyridinium dichromate (PDC) as the
oxidizing agent. No dehydrogenation to aromatic thiophene
derivatives occurred on treatment with DDQ or PDC under
such mild reaction conditions. Under an atmosphere of nitro-
gen, alcohol 11 was treated with a catalytic amount of p-
TsOH in refluxing benzene to give the dehydration product
12 having a terminal C]C double bond, instead of giving
the conjugated isomer. The oxidative aromatization of dihy-
drothiophene 12 to alkenylthiophene 13 is realized by using
Pd(OAc)2 as the oxidizing agent. The intramolecular Frie-
del–Crafts alkylation of 13 is then carried out by the cata-
lysis of p-TsOH to give the tetracyclic carbazolothiophene
14. Some carbazole-fused thiophene analogues of 14 exhib-
iting potent antagonistic activity against the endothelin vaso-
constrictor5,6 were also prepared by the similar procedures.
R2
R1
OMe
S
O
O
5a R1 = R2 = MeO
5b R1 = H, R2 = MeO
5c R1 = H, R2 = Me
Figure 1. Example of 4,5-diacylthiophene-2-carboxylates that are not
reported previously.
2. Results and discussion
The coupling reaction of thiophene-2-carboxylate with
3,4-dimethoxybenzaldehyde proceeded smoothly by the
promotion of SmI2 (Scheme 1). The intermediate samarium
dienolate (A) was trapped by 4-methoxyacetophenone to
give diol 4a in one-pot operation. The intermediate diol 4a,
without further purification, was readily converted to ketone
6a by oxidation with DDQ. Ketone 6a was then subjected to
an acid-catalyzed dehydration, an oxidative aromatization,
and an acid-catalyzed cyclization to afford the desired tetra-
lone-fused thiophene 9 via the intermediacy of alkene 7 and
thiophene 8.
Interestingly, we observed that the treatment of 6a with
an increased amount of p-TsOH (w0.5 equiv) in refluxing
benzene under an inert atmosphere afforded a 79% yield of
the conjugated compound 15a (Scheme 3), differing from
isomer 7 obtained from the acid-catalyzed dehydration
(Scheme 1). The (E)-configuration in 15a was determined
The three-component coupling products 4b and 4c were sim-
ilarly prepared, and then oxidized by DDQ to give the ketone
compounds 6b and 6c. In a recent communication,5 we also
reported a similar SmI2-promoted coupling reaction of thio-
phene-2-carboxylate with 1-methylindole-2-carbaldehyde
and 4-methoxyacetophenone to afford diol 10 (Scheme 2).
1
by the H NMR analysis, which showed a 12.3% nuclear
Overhauser enhancement of H-5 (at d 5.86) upon irradiation
of the methyl group at d 1.90.
O
OMe
3a
MeO
4
MeO
Me
OMe
2 SmI2
H
OMe
S
H
+
MeO
S
MeO
THF, HMPA
O
H
1
O
OH
OSmL2
2a
Samarium dienolate A
OMe
OMe
OMe
Me
HO
Me
HO
H
4
H
H
for 6a
DDQ, PhH
R2
R1
R2
R1
MeO
MeO
4
cat. p-TsOH
PhH; 94%
25 °C, 14 h;
89%
H
OMe
OMe
OMe
S
S
S
H
H
H
O
O
O
OH
O
O
4a R1 = R2 = MeO
4b R1 = H, R2 = MeO
4c R1 = H, R2 = Me
6a R1 = R2 = MeO
7
6b R1 = H, R2 = MeO
6c R1 = H, R2 = Me
OMe
OMe
Me
cat. p-TsOH, CH2Cl2
Pd(OAc)2, K2CO3, MeCN
25 °C, 15 h; 91%
MeO
MeO
MeO
MeO
25 °C, 2 h; 97%
OMe
S
OMe
S
O
O
O
O
8
9
Scheme 1. Synthesis of a tetralone-fused thiophene.

S.-M. Yang, J.-M. Fang / Tetrahedron 63 (2007) 1421–1428
1423
OMe
OMe
OMe
Me
HO
Me
cat. p-TsOH
HO
H
H
H
DDQ, PhH
PhH
95%
25 °C, 4 h;
88%
H
OMe
OMe
OMe
S
S
S
N
Me
N
N
Me
H
H
H
O
O
O
OH
10
Me
O
O
11
12
OMe
OMe
cat. p-TsOH
Me
Pd(OAc)2, K2CO3, MeCN
25 °C, 12 h; 93%
CH2Cl2
25 °C, 2 h; 98%
OMe
OMe
S
N
S
N
Me
O
Me
O
O
O
13
14
Scheme 2. Synthesis of a carbazole-fused thiophene.
OMe
OMe
Excess p-TsOH
CHCl3, 25 °C, 2.5 h,
2 (open system)
Me
HO
0.5 equiv p-TsOH, PhH
Me
H
4
O
N2, reflux, 1 h
R2
R1
R2
R1
5
5
OMe
OMe
S
S
H
H
O
O
O
O
6a R1 = R2 = MeO
15a R1 = R2 = MeO
6b R1 = H, R2 = MeO
6c R1 = H, R2 = Me
15b R1 = H, R2 = MeO
15c
R
1 = H, R2 = Me
Me
Me
Me
O
OMe
N
N
N
Me
R2
NH
i) N2H4, EtOH, 25 °C, 10 min
ii) Me2CO
S
+
OMe
O
R1
S
HO
O
O
R1
16
5a
R
1 = R2 = MeO
R2
5b R1 = H, R2 = MeO
17a R1 = R2 = MeO
17c R1 = H, R2 = Me
5c
R
1 = H, R2 = Me
Scheme 3. Formation of 4,5-diacylthiophenes via oxidative fragmentation.
In a serendipitous way, we also found an unusual autooxida-
tion of 15a, giving two oxidative cleavage products 16 and
5a in quantitative yields (Scheme 3). The autooxidation
occurred when a CHCl3 solution of 15a was stirred with
stoichiometric amount of p-TsOH in air (25 ꢀC, 2.5 h).
Compound 16 was identified as 4-methoxyphenol, and the
structure of 5a was determined to be methyl 4-acetyl-
5-(3,4-dimethoxybenzoyl)thiophene-2-carboxylate by IR,
MS, 1H and 13C NMR spectral analyses. By the similar pro-
cedures, compounds 6b and 6c were, respectively, treated
with p-TsOH to give the alkene intermediates 15b and
15c, which underwent autooxidative cleavages in situ to
the corresponding 4,5-diacylthiophene-2-carboxylates 5b
and 5c, along with the counterpart of 4-methoxyphenol 16.
The diacylthiophenes 5a–c are equipped with the function
of 1,4-diketone, which is useful in the construction of vari-
ous heterocycles.7 For example, 5a and 5c were, respec-
tively, treated with hydrazine, followed by condensation
with acetone, to give thieno[2,3-d]pyridazine derivatives
17a and 17c in quantitative yields. Thieno[2,3-d]pyridazine
derivatives have been shown to exhibit anti-inflammatory
activity,7a and were used as a short-term hypnotic to treat in-
somnia.7b We also attempted to carry out a straightforward
synthesis of 5a–c by the SmI2-promoted double electrophilic
reactions of methyl thiophene-2-carboxylate with aromatic
aldehyde Ar1CHO (or benzoyl chloride) and acetaldehyde
(or acetyl chloride). However, all the reactions resulted in
complicated mixtures.
Though the real reaction pathways for the dichotomous for-
mation of alkenes 7 and 15a from the alcohol 6a were not
rigorously determined, we speculated that the dehydration
might proceed with E1 mechanism through a stabilized ter-
tiary carbocationic intermediate C (Scheme 4). The subse-
quent removal of a proton from the less hindered methyl
group would give alkene 7, whereas removal of the internal
proton at C-4 would furnish the conjugated compound 15a.
Alkene 7 having an isolated C]C double bond was partially

1424
S.-M. Yang, J.-M. Fang / Tetrahedron 63 (2007) 1421–1428
Ar2
H
Ar2
H
Ar2
H
Me
+
Me
HO
H3C
Ar
H2O
p-TsOH
+
4
Ar1
Ar1
OMe
OMe
OMe
S
S
S
H
H
H
O
O
O
O
O
O
6a
C
B
− H+
− H+
Ar2
H
Ar2
Me
Ar1
Isomerization
4
Ar1
OMe
OMe
S
S
H
H
O
O
O
O
15a
7
tautomerization
Ar2
Ar2
Me
O2
Me
Ar1
O
OH
Ar1
OMe
OMe
S
S
O
O
O
OH
D
E
H+
Ar2 OH
Ar2
Ar2
+
+
O
O
+
Me
Ar1
Me
Ar1
O
OH2
hydrolysis
OMe
rearrangement
− H2O
Me
Ar1
OMe
OMe
S
S
S
O
O
O
O
O
O
G
5a
F
Scheme 4. Putative mechanism for conversion of 6a to 5a via dehydration and autooxidative fragmentation.
converted to the conjugated alkene 15a on treatment with
p-TsOH in refluxing benzene under an atmosphere of
nitrogen. We also proposed a possible mechanism for the
conversion of 15a–c to diacylthiophenes 5a–c via the frag-
mentation reaction of a hydroperoxide intermediate. For ex-
ample, a facilitated enolization of 15a could be effected by
a strong acid, p-TsOH (in stoichiometric amount). Upon ex-
posure to air, the dienol intermediate D would react with
dioxygen to give a hydroperoxide intermediate E. The sub-
sequent rearrangement of the hydroperoxide intermediate
E would afford 4-methoxyphenol (16, Ar2¼4-MeOC6H4)
and ketone 5a, by analogy to the well-known fragmentation
reaction of cumyl hydroperoxide to phenol and acetone.8
alcohols 6a–c were converted to the dehydration products
15a–c, which underwent an unusual autooxidative fragmen-
tation reaction in air to give very high yields of 4,5-diacyl-
thiophene-2-carboxylates. Our present study thus provides
an expedient method for the synthesis of novel polycyclic
and multi-substituted thiophene compounds. Thiophene
derivatives 5a–c bearing the moiety of 1,4-diketone are ready
for further elaboration to numerous heterocyclic compounds,
e.g., condensation with hydrazine to form thieno[2,3-d]-
pyridazine derivatives 17a and 17c as demonstrated in this
study.
4. Experimental
4.1. General
3. Conclusion
All reactions requiring anhydrous conditions were con-
ducted in flame-dried apparatus under an atmosphere of
nitrogen. Syringes and needles for the transfer of reagents
were dried at 100 ꢀC and allowed to cool in a desiccator
over P2O5 before use. Ethers were distilled from sodium
benzophenone ketyl; chlorinated hydrocarbons from CaH2.
Reactions were monitored by thin-layer chromatography
using pre-coated aluminum plates with a 0.25 mm layer of
silica gel containing a fluorescent indicator (Merck Art.
5544). Column chromatography was carried out on Kiesel-
gel 60 (40–63 mm).
We have extended the scope of the previously discovered
SmI2-promoted tandem double electrophilic reactions of
thiophene-2-carboxylate with aromatic aldehydes and ke-
tones. The three-component coupling products, e.g., 4a and
10, were readily oxidized to the corresponding ketones,
e.g., 6a and 11, using DDQ or PDC as the oxidizing agents.
In one approach, dehydration of 6a and 11 was carried out
by using catalytic amount of p-TsOH to give alkenes 7 and
12 with terminal C]C double bonds. The alkenes 7 and 12
were subjected to oxidative aromatization and intramolecu-
lar Friedel–Crafts alkylation to afford tetralone- and carb-
azole-fused thiophene-2-carboxylate 9 and 14. In another
approach using increased amounts of p-TsOH (w0.5 equiv),
Melting points were recorded using a Yanagimoto micro-
melting point apparatus and were uncorrected. Chemical

S.-M. Yang, J.-M. Fang / Tetrahedron 63 (2007) 1421–1428
1425
1
shifts of H and 13C NMR spectra are reported relative
eluting with EtOAc/hexane (3:7) to give ketone 6b
(232 mg) in 54% overall yield.
to CHCl3 [dH 7.24, dC (central line of t) 77.0]. Coupling
constants (J) are given in hertz. Distortionless enhancement
polarization transfer (DEPT) spectra were taken to deter-
mine the types of carbon signals.
Compound 6b: oil; TLC (EtOAc/hexane, 3:7) Rf¼0.17; IR
(neat) 3492, 1708, 666, 1252 cmꢁ1 1H NMR (CDCl3,
;
200 MHz) d 7.86 (2H, d, J¼8.9 Hz), 7.37 (2H, d, J¼8.8 Hz),
6.90 (2H, d, J¼8.9 Hz), 6.84 (2H, d, J¼8.8 Hz), 6.28 (1H, d,
J¼3.1 Hz), 5.34 (1H, d, J¼7.0 Hz), 4.66 (1H, dd, J¼7.0,
3.1 Hz), 3.82 (3H, s), 3.75 (3H, s), 3.64 (3H, s), 2.90 (1H,
br s), 1.46 (3H, s); 13C NMR (CDCl3, 50 MHz) d 192.5,
163.9, 161.9, 158.6, 137.7, 134.6, 133.4, 131.0 (2ꢂ), 127.9,
126.1 (2ꢂ), 114.0 (2ꢂ), 113.7 (2ꢂ), 75.9, 61.1, 55.4, 55.1,
52.3, 50.4, 28.0; MS m/z (rel intensity) 428 (1, M+), 151
(100); HRMS calcd for C23H24O6S: 428.1294, found: m/z
428.1298 (M+).
4.1.1. Methyl 5-(3,4-dimethoxybenzoyl)-4-[1-hydroxy-1-
(4-methoxyphenyl)ethyl]-4,5-dihydrothiophene-2-car-
boxylate (6a). Under an atmosphere of argon, a deep blue
SmI2 solution (0.1 M) was prepared by the treatment of
Sm (661 mg, 4.4 mmol) with 1,2-diiodoethane (1.01 g,
3.6 mmol) in HMPA (2.8 mL, 16 mmol) and anhydrous
THF (20 mL) for 1.5 h at room temperature. To the SmI2
solution (cooled in an ice bath) was added a THF solution
(3 mL) of methyl thiophene-2-carboxylate (142 mg, 1 mmol)
and 3,4-dimethoxybenzaldehyde (167 mg, 1.0 mmol). The
reaction mixture was stirred at 0 ꢀC for 45 min, and then at
room temperature (25 ꢀC) for another 45 min. A solution
of 4-methoxyacetophenone (180 mg, 1.2 mmol) in THF
(2 mL) was added at 0 ꢀC, and the mixture was stirred at
0–25 ꢀC for additional 10 h. The reaction was quenched
by the addition of saturated aqueous NH4Cl solution
(0.1 mL). The mixture was passed through a short silica
gel column by eluting with EtOAc/hexane (1:1). The filtrate
was concentrated, and chromatographed on a silica gel col-
umn by eluting with EtOAc/hexane (3:7) to give the desired
coupling product 4a (354 mg) containing two isomers
(45:55) as shown by the 1H NMR analysis.
4.1.3. Methyl 4-[1-hydroxy-1-(4-methoxyphenyl)ethyl]-
5-(4-methylbenzoyl)-4,5-dihydrothiophene-2-carboxyl-
ate (6c). According to the procedure similar to that for 6a,
the SmI2-promoted three-component coupling reaction of
methyl thiophene-2-carboxylate (142 mg, 1 mmol) with 4-
methylbenzaldehyde (0.12 mL, 1.0 mmol) and 4-methoxy-
acetophenone (180 mg, 1.2 mmol) afforded 4c (307 mg).
Without further purification, a solution of 4c (307 mg,
0.75 mmol) in CH2Cl2 (10 mL) was treated with pyridinium
dichromate (420 mg, 1.12 mmol) at room temperature for
˚
1 h in the presence of molecular sieves (4 A, 1.5 g). The
mixture was subjected to silica gel column chromatography
by eluting with EtOAc/hexane (1:4) to give ketone 6c
(226 mg) in 54% overall yield.
Withoutfurtherpurification,4a(354 mg, 0.78 mmol)inbenz-
ene (10 mL) was stirred with DDQ (216 mg, 0.94 mmol) at
room temperature for 4 h. The reaction mixture was con-
centrated under reduced pressure, and chromatographed on
a silica gel column by elution with EtOAc/hexane (1:2) to
afford the corresponding ketone 6a (317 mg) in 69% overall
yield.
Compound 6c: oil; TLC (EtOAc/hexane, 3:7) Rf¼0.23; IR
(neat) 3494, 1711, 1671, 1249 cmꢁ1 1H NMR (CDCl3,
;
200 MHz) d 7.78 (2H, d, J¼8.2 Hz), 7.38 (2H, dd, J¼8.9,
2.0 Hz), 7.24 (2H, d, J¼8.2 Hz), 6.86 (2H, dd, J¼8.9,
2.0 Hz), 6.29 (1H, d, J¼3.1 Hz), 5.34 (1H, d, J¼6.8 Hz),
4.67 (1H, dd, J¼6.8, 3.1 Hz), 3.78 (3H, s), 3.67 (3H, s), 2.39
(3H, s), 2.14 (1H, br s), 1.48 (3H, s); 13C NMR (CDCl3,
50 MHz) d 193.4, 161.9, 158.6, 144.6, 137.6, 134.5, 133.4,
132.4, 129.4 (2ꢂ), 128.7 (2ꢂ), 126.1 (2ꢂ), 113.6 (2ꢂ),
75.9, 61.0, 55.1, 52.3, 50.6, 27.9, 21.6; MS m/z (rel intensity)
412 (7, M+), 151 (100); HRMS calcd for C23H24O5S:
412.1344, found: m/z 412.1340 (M+).
Compound 6a: oil; TLC (EtOAc/hexane, 1:1) Rf¼0.30; IR
(neat) 3502, 1709, 1665, 1265, 749 cmꢁ1
;
1H NMR
(CDCl3, 200 MHz) d 7.49 (1H, d, J¼l.9 Hz), 7.45 (1H, dd,
J¼8.4, 1.9 Hz), 7.37 (2H, d, J¼8.6 Hz), 6.85 (2H, d,
J¼8.6 Hz), 6.84 (1H, d, J¼8.4 Hz), 6.27 (1H, d, J¼3.0 Hz),
5.36 (1H, d, J¼7.2 Hz), 4.67 (1H, dd, J¼7.2, 3.0 Hz), 3.91
(3H, s), 3.90 (3H, s), 3.77 (3H, s), 3.65 (3H, s), 2.18 (1H,
br s, OH), 1.46 (3H, s); 13C NMR (CDCl3, 75 MHz)
d 192.5, 161.8, 158.4, 153.6, 149.0, 137.6, 134.6, 133.1,
127.9, 126.0 (2ꢂ), 123.1, 113.5 (2ꢂ), 110.6, 109.9, 75.6,
61.1, 55.9, 55.7, 54.9, 52.1, 50.l, 27.8; MS m/z (rel intensity)
440 (11, M+ꢁH2O), 165 (100); HRMS calcd for C24H26O7S:
458.1399, found: m/z 458.1400 (M+).
4.1.4. Methyl 5-(3,4-dimethoxybenzoyl)-4-[1-(4-methoxy-
phenyl)ethenyl]-4,5-dihydrothiophene-2-carboxylate (7).
Under an atmosphere of nitrogen, a mixture of alcohol
6a (25 mg, 0.054 mmol) and p-TsOH monohydrate (cata-
lytic amount, ca. 1 mg) in benzene (20 mL) was heated at re-
flux for 5 h, while the generated water was removed by
a Dean–Stark apparatus. The reaction mixture was concen-
trated under reduced pressure, and chromatographed on a sil-
ica gel column by eluting with EtOAc/hexane (1:9) to afford
the corresponding alkene 7 (23 mg, 94% yield) as an oil.
TLC (EtOAc/hexane, 3:7) Rf¼0.12; IR (neat) 1710, 1663,
4.1.2. Methyl 4-[1-hydroxy-1-(4-methoxyphenyl)ethyl]-
5-(4-methoxybenzoyl)-4,5-dihydrothiophene-2-carb-
oxylate (6b). According to the procedure similar to that for
6a, the SmI2-promoted three-component coupling reaction
of methyl thiophene-2-carboxylate (142 mg, 1 mmol), 4-
methoxybenzaldehyde (0.12 mL, 1.0 mmol), and 4-methoxy-
acetophenone (180 mg, 1.2 mmol) afforded 4b (323 mg).
Without further purification, a solution of 4b (323 mg,
0.75 mmol) in CH2Cl2 (15 mL) was treated with pyridinium
dichromate (376 mg, 1.0 mmol) at room temperature for 3 h
1599, 1262, 748 cmꢁ1 1H NMR (CDCl3, 200 MHz) d
;
7.46 (1H, d, J¼1.9 Hz), 7.32 (2H, d, J¼8.7 Hz), 7.28 (1H,
dd, J¼8.5, 1.9 Hz), 6.81 (2H, d, J¼8.7 Hz), 6.80 (1H, d,
J¼8.5 Hz), 6.66 (1H, d, J¼3.4 Hz), 5.44 (1H, s), 5.23 (1H,
dd, J¼4.3, 3.4 Hz), 5.15 (1H, s), 4.87 (1H, d, J¼4.3 Hz),
3.89 (6H, s), 3.75 (3H, s), 3.74 (3H, s); 13C NMR (CDCl3,
50 MHz) d 191.9, 162.1, 159.5, 153.7, 149.2, 145.5, 136.5,
133.0, 131.5, 127.8, 127.5 (2ꢂ), 123.0, 114.0 (2ꢂ), 113.2,
˚
in the presence of molecular sieves (4 A, 2 g). The mixture
was subjected to silica gel column chromatography by

1426
S.-M. Yang, J.-M. Fang / Tetrahedron 63 (2007) 1421–1428
110.9, 110.0, 56.1, 56.0, 55.2, 54.6, 52.4, 52.3; MS m/z (rel
intensity) 440 (58, M+), 165 (100); HRMS calcd for
C24H24O6S: 440.1294, found: m/z 440.1289 (M+).
3.74 (3H, s), 3.67 (3H, s), 2.40 (1H, br s, OH), 1.54 (3H,
s); 13C NMR (CDCl3, 75 MHz) d 187.6, 162.0, 158.6,
140.6, 137.6, 134.3, 133.8, 133.1, 126.4, 126.1 (2ꢂ), 125.6,
123.1, 120.9, 113.7 (2ꢂ), 112.1, 110.3, 75.9, 61.0, 55.1,
52.3, 52.0, 32.1, 27.7; FABMS m/z 452.1 (M+ꢁH2O+H);
HRMS calcd for C25H25NO5S: 451.1453, found: m/z
451.1463 (M+).
4.1.5. Methyl 5-(3,4-dimethoxybenzoyl)-4-[1-(4-methoxy-
phenyl)ethenyl]thiophene-2-carboxylate (8). A solution
of alkene 7 (150 mg, 0.34 mmol) in degassed anhydrous
acetonitrile (7 mL) was stirred with Pd(OAc)2 (153 mg,
0.68 mmol) and K2CO3 (142 mg, 1.02 mmol) at room tem-
perature for 12 h. The reaction mixture was concentrated un-
der reduced pressure, and chromatographed on a silica gel
column by eluting with EtOAc/hexane (1:9) to give com-
pound 8 (136 mg, 91% yield) as an oil. TLC (CH2Cl2)
4.1.8. Methyl 4-[1-(4-methoxyphenyl)ethenyl]-5-(1-
methylindole-2-carbonyl)-4,5-dihydrothiophene-2-car-
boxylate (12). By a procedure similar to that for 7, treatment
of 11 (95 mg, 0.21 mmol) with catalytic amount of p-TsOH
monohydrate (ca. 3 mg) in refluxing benzene for 5 h gave
the dehydration product 12 (87 mg, 95%) as an oil; TLC
(EtOAc/hexane, 3:7) Rf¼0.13; IR (neat) 1720, 1660, 1607,
Rf¼0.35; IR (neat) 1718, 1637, 1594, 1511, 1268 cmꢁ1
;
1H NMR (CDCl3, 300 MHz) d 7.74 (1H, s), 7.14 (1H, dd,
J¼8.2, 2.0 Hz), 6.93 (1H, d, J¼2.0 Hz), 6.85 (2H, dd, J¼
8.8, 2.0 Hz), 6.65 (1H, d, J¼8.2 Hz), 6.60 (2H, dd, J¼8.8,
2.0 Hz), 5.29 (1H, s), 5.20 (1H, s), 3.86 (3H, s), 3.84 (3H,
s), 3.71 (3H, s), 3.69 (3H, s); 13C NMR (CDCl3, 75 MHz)
d 188.1, 161.9, 159.1, 153.2, 148.5, 144.8, 143.6, 142.9,
135.4, 134.9, 132.9, 130.1, 127.9 (2ꢂ), 124.4, 115.3, 113.4
(2ꢂ), 110.4, 109.4, 55.9, 55.6, 55.0, 52.4; MS m/z (rel inten-
sity) 438 (31, M+), 55 (100); HRMS calcd for C24H22O6S:
438.1137, found: m/z 438.1140 (M+).
1511, 1250 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 7.59
;
(1H, d, J¼8.0 Hz), 7.36–7.32 (4H, m), 7.14–7.08 (1H, m),
6.97 (1H, s), 6.83 (2H, d, J¼8.7 Hz), 6.69 (1H, d,
J¼3.5 Hz), 5.47 (1H, s), 5.20 (1H, dd, J¼4.6, 3.5 Hz),
5.19 (1H, s), 4.98 (1H, d, J¼4.6 Hz), 4.06 (3H, s), 3.77
(3H, s), 3.74 (3H, s); 13C NMR (CDCl3, 75 MHz) d 187.3,
162.1, 159.4, 145.6, 140.5, 136.1, 133.4, 132.8, 131.5,
127.5 (2ꢂ), 126.3, 125.6, 122.9, 120.9, 113.9 (2ꢂ), 113.2,
111.5, 110.3, 56.2, 55.1, 52.4, 52.3, 32.1; MS m/z (rel inten-
sity) 433 (57, M+), 374 (13), 275 (100), 158 (88), 133 (32);
HRMS calcd for C25H23NO4S: 433.1348, found: m/z
433.1346 (M+).
4.1.6. Methyl 6,7-dimethoxy-4-(4-methoxyphenyl)-4-
methyl-9-oxo-4,9-dihydronaphtho[2,3-b]thiophene-2-
carboxylate (9). Compound 8 (55 mg, 0.125 mmol) and
catalytic amount of p-TsOH monohydrate in CH2Cl2 solu-
tion (15 mL) were stirred at room temperature for 2 h. The
reaction mixture was filtered, concentrated under reduced
pressure, and chromatographed on a silica gel column by
eluting with EtOAc/hexane (1:9) to give compound 9
(53 mg, 97% yield) as an oil; TLC (EtOAc/hexane, 3:7)
4.1.9. Methyl 4-[1-(4-methoxyphenyl)ethenyl]-5-
(1-methylindole-2-carbonyl)thiophene-2-carboxylate
(13). By a procedure similar to that for 8, alkene 12 (70 mg,
0.16 mmol) was treated with Pd(OAc)2 (70 mg, 0.31 mmol)
and K2CO3 (130 mg, 0.94 mmol) at room temperature
for 12 h to give compound 13 (65 mg, 93%) as an oil.
TLC (EtOAc/hexane, 1:9) Rf¼0.13; IR (neat) 1719, 1626,
Rf¼0.23; IR (neat) 1719, 645, 1279 cmꢁ1
;
1H NMR
(CDCl3, 200 MHz) d 7.73 (1H, s), 7.39 (1H, s), 7.07 (2H,
dd, J¼8.6, 2.1 Hz), 6.77 (2H, dd, J¼8.6, 2.1 Hz), 6.47
(1H, s), 3.95 (3H, s), 3.83 (3H, s), 3.74 (3H, s), 3.73 (3H,
s), 1.94 (3H, s); 13C NMR (CDCl3, 75 MHz) d 178.0, 162.2,
158.4, 157.3, 153.7, 148.3, 146.2, 139.3, 139.1, 136.2, 133.3,
128.1 (2ꢂ), 123.9, 114.0 (2ꢂ), 110.2, 107.3, 56.0, 55.9,
55.1, 52.5, 46.2, 30.4; MS m/z (rel intensity) 438 (75, M+),
423 (100); HRMS calcd for C24H22O6S: 438.1137, found:
m/z 438.1142 (M+).
1510, 1247 cmꢁ1 1H NMR (CDCl3, 300 MHz) d 7.83
;
(1H, s), 7.59 (1H, d, J¼8.0 Hz), 7.35 (1H, t, J¼8.0 Hz),
7.24 (1H, d, J¼8.0 Hz), 7.11 (1H, t, J¼8.0 Hz), 6.99 (1H,
s), 6.82 (2H, d, J¼8.5 Hz), 6.59 (2H, d, J¼8.5 Hz), 5.34
(1H, s), 5.33 (1H, s), 3.92 (3H, s), 3.70 (3H, s), 3.57 (3H,
s); 13C NMR (75 MHz, CDCl3) d 180.5, 162.2, 159.2,
145.6, 143.9, 143.5, 140.3, 135.7, 135.2, 135.0, 133.5,
128.0 (2ꢂ), 126.2, 125.7, 123.0, 120.7, 115.1, 114.9, 113.3
(2ꢂ), 110.1, 55.2, 52.5, 31.1; FABMS m/z 431 (M+);
HRMS calcd for C25H21NO4S: 431.1191, found: m/z
431.1183 (M+).
4.1.7. Methyl 4-[1-hydroxy-1-(4-methoxyphenyl)ethyl]-
5-(1-methylindole-2-carbonyl)-4,5-dihydrothiophene-2-
carboxylate (11). According to the procedure similar to that
for 4a, the SmI2-promoted three-component coupling reac-
tion of methyl thiophene-2-carboxylate (142 mg, 1 mmol)
with N-methylindole-2-carboxaldehyde (159 mg, 1 mmol)
and 4-methoxyacetophenone (180 mg, 1.2 mmol) afforded
10 (349 mg) containing two isomers (65:35) as shown by
the 1H NMR analysis. Without further purification, 10
(349 mg, 0.77 mmol) was treated with DDQ (216 mg,
0.94 mmol) by a procedure similar to that for 6a to give ke-
tone 11 (306 mg) in 65% overall yield. Compound 11: oil;
TLC (EtOAc/hexane, 3:7) Rf¼0.23; IR (neat) 3502, 1717,
4.1.10. Methyl 4,9-dimethyl-4-(4-methoxyphenyl)-10-
oxo-4,10-dihydrocarbazolo[2,3-b]thiophene-2-carboxyl-
ate (14). By a procedure similar to that for 9, treatment of 13
(50 mg, 0.12 mmol) with a catalytic amount of p-TsOH
monohydrate in CH2Cl2 solution at room temperature for
2 h afforded the acid-catalyzed cyclization product 14
(49 mg, 98%) as colorless solid, mp 113–114 ꢀC. TLC
(EtOAc/hexane, 1:9) Rf¼0.13; IR (KBr) 1716, 1637, 1510,
1
1247 cmꢁ1; H NMR (CDCl3, 200 MHz) d 7.53 (1H, s),
7.38–7.30 (2H, m), 7.23–7.16 (3H, m), 6.97 (1H, m), 6.77
(2H, dd, J¼8.8, 2.1 Hz), 4.26 (3H, s), 3.85 (3H, s), 3.73
(3H, s), 2.08 (3H, s); 13C NMR (CDCl3, 75 MHz) d 173.7,
162.3, 158.4, 158.0, 141.8, 140.5, 138.4, 135.6, 134.9,
132.7, 128.8, 127.8 (2ꢂ), 126.5, 123.2, 122.2, 120.4, 114.1
(2ꢂ), 110.5, 55.1, 52.5, 44.4, 31.6, 28.1; FABMS m/z 431
(M+); HRMS calcd for C25H21NO4S: 431.1191, found: m/z
1
1661, 1613, 1251, 753 cmꢁ1; H NMR (CDCl3, 300 MHz)
d 7.66 (1H, d, J¼8.0 Hz), 7.41 (2H, d, J¼8.7 Hz), 7.38–
7.33 (2H, m), 7.20 (1H, s), 7.13 (1H, td, J¼8.0, 2.0 Hz),
6.86 (2H, d, J¼8.7 Hz), 6.34 (1H, d, J¼3.0 Hz), 5.42 (1H,
d, J¼7.2 Hz), 4.64 (1H, dd, J¼7.2, 3.0 Hz), 4.03 (3H, s),

S.-M. Yang, J.-M. Fang / Tetrahedron 63 (2007) 1421–1428
1427
431.1192 (M+). Anal. Calcd for C25H21NO4S: C, 69.59; H,
4.91; N, 3.25. Found: C, 69.42; H, 4.98; N, 3.14.
164.3, 161.4, 150.2, 141.2, 134.2, 132.9, 131.9 (2ꢂ),
129.4, 114.0 (2ꢂ), 55.5, 52.6, 28.8; MS m/z (rel intensity)
318 (54, M+), 135 (100); HRMS calcd for Cl6H14O5S:
318.0562, found: m/z 318.0564 (M+).
4.1.11. Methyl 5-(3,4-dimethoxybenzoyl)-4-[1-(4-meth-
oxyphenyl)ethylidene]-5H-thiophene-2-carboxylate
(15a). Under an atmosphere of nitrogen, a mixture of 6a
(263 mg, 0.59 mmol) and p-TsOH monohydrate (57 mg,
0.30 mmol) in benzene (20 mL) was heated at reflux for
1 h. The mixturewas thensubjected tosilica gelcolumn chro-
matography by eluting with EtOAc/hexane (1:4) to give al-
kene 15a (204 mg, 79% yield) as a solid; mp l56–158 ꢀC;
TLC (EtOAc/hexane, 1:4) Rf¼0.14; IR (KBr) 1701, 1669,
4.1.14. 6-(2,3-Diaza-4-methyl-1-oxo-3-penten-1-yl)-1-
methyl-4-(3,4-dimethoxyphenyl)thieno[2,3-d]pyridazine
(17a). A mixture of 5a (20 mg, 0.06 mmol) and excess
amount of hydrazine monohydrate (9 mg, 0.18 mmol) in
EtOH (15 mL) was stirred at room temperature for 10 min.
The mixture was concentrated, acetone was added (20 mL),
and concentrated again under reduced pressure. This proce-
dure was repeated twice to give the desired product 17a
(23 mg) in 99% yield. Solid; mp 209–211 ꢀC; TLC
(MeOH/CH2Cl2, 1:19) Rf¼0.13; IR (KBr) 3423, 1642,
1415, 1232 cmꢁ1; 1H NMR (CDCl3, 200 MHz) d 9.69 (1H,
br s), 8.53 (1H, s), 7.71 (1H, s), 7.69 (1H, d, J¼8.1 Hz), 7.00
(1H, d, J¼8.1 Hz), 3.59 (3H, s), 3.94 (3H, s), 2.99 (3H, s),
2.13 (3H, s), 2.03 (3H, s); 13C NMR (CDCl3, 75 MHz)
d 161.5, 154.3, 153.9, 152.3, 150.8, 149.3, 141.0, 139.8,
134.9, 129.8, 128.8, 121.1, 111.3, 110.9, 55.9 (2ꢂ), 25.1,
19.9, 16.2; MS m/z (rel intensity) 384 (70, M+), 285 (100);
HRMS calcd for C19H20N4O3S: 384.1256, found: m/z
384.1259 (M+). Anal. Calcd for C19H20N4O3S: C, 59.36;
H, 5.24; N, 14.57. Found: C, 59.46; H, 5.12; N, 14.62.
1
1245, 751 cmꢁ1; H NMR (CDCl3, 300 MHz) d 7.57 (1H,
s), 7.56 (1H, d, J¼8.1 Hz), 7.21 (2H, d, J¼8.5 Hz), 7.04
(1H, s), 6.91 (1H, d, J¼8.1 Hz), 6.88 (2H, d, J¼8.5 Hz),
5.86 (1H, s), 3.95 (3H, s), 3.92 (3H, s), 3.81 (3H, s), 3.70
(3H, s), 1.90 (3H, s); 13C NMR (CDCl3, 75 MHz) d 190.3,
162.9, 159.2, 153.8, 149.3, 141.6, 138.3, 134.9, 134.4,
133.7, 129.2 (2ꢂ), 128.0, 122.8, 113.7 (2ꢂ), 110.9, 110.1,
56.1, 55.9, 55.3, 54.1, 52.3, 22.6; MS m/z (rel intensity)
440 (55, M+), 165 (100); HRMS calcd for C24H24O6S:
440.1293, found: m/z 440.1294 (M+). Anal. Calcd for
C24H24O6S: C, 65.44; H, 5.49. Found: C, 65.68; H, 5.42.
4.1.12. Methyl 4-acetyl-5-(3,4-dimethoxybenzoyl)thio-
phene-2-carboxylate (5a). A mixture of 15a (30 mg,
0.07 mmol) and stoichiometric amount of p-TsOH mono-
hydrate (19 mg, 0.1 mmol) in CHCl3 (10 mL) was placed in
a round-bottomed flask without capping. The mixture was
stirred in air for 2.5 h at room temperature, and then sub-
jected to a short silica gel column to remove p-TsOH. The
crude product eluted by EtOAc/hexane (1:1) was concen-
trated, and purified by chromatography by eluting with
EtOAc/hexane (1:4) to give 4-methoxyphenol (16, 8.1 mg,
95%) and diacylthiophene 5a (23 mg, 95%).
4.1.15. 6-(2,3-Diaza-4-methyl-1-oxo-3-penten-1-yl)-1-
methyl-4-(4-methylphenyl)thieno[2,3-d]pyridazine
(17c). By a procedure similar to that for 5b, compound 6c
(200 mg, 0.51 mmol) was first treated with 0.5 equiv of
p-TsOH in refluxing benzene under an atmosphere of nitro-
gen to give a crude product 15c. The crude product was sub-
sequently stirred with stoichiometric amount of p-TsOH in
CHCl3 for 2.5 h under an atmosphere of air to give a mixture
of 4-methoxyphenol and 5c, which were inseparable by sil-
ica gel column chromatography. By a procedure similar to
that for 17a, the mixture was treated with excess amounts
of hydrazine and acetone to afford a crude product, which
was purified on a silica gel column by eluting with MeOH/
CH2Cl2 (1:19) to give 17c (168 mg) in 97% overall yield.
Solid; mp 262–264 ꢀC; TLC (MeOH/CH2Cl2, 1:19)
Compound 5a: solid; mp 125–127 ꢀC; TLC (EtOAc/hexane,
1:4) Rf¼0.07; IR (KBr) 1716, 1678, 1650, 1267, 754 cmꢁ1
;
1H NMR (CDCl3, 200 MHz) d 8.03 (1H, s), 7.52 (1H, d,
J¼2.0 Hz), 7.21 (1H, dd, J¼8.4, 2.0 Hz), 6.78 (1H, d,
J¼8.4 Hz), 3.90 (6H, s), 3.89 (3H, s), 2.38 (3H, s); 13C
NMR (CDCl3, 50 MHz) d 192.3, 187.7, 161.4, 154.3, 150.0,
149.3, 141.4, 134.3, 132.8, 129.7, 125.4, 110.5, 109.9, 56.1,
56.0, 52.7, 28.8; MS m/z (rel intensity) 348 (100, M+);
HRMS calcd for Cl7H16O6S: 348.0667, found: m/z
348.0670 (M+). Anal. Calcd for Cl7H16O6S: C, 58.61; H,
4.63. Found: C, 58.72; H, 4.56.
Rf¼0.17; IR (KBr) 3447, 1648, 1390, 1259 cmꢁ1
;
1H
NMR (CDCl3/CD3OD¼4:1, 200 MHz) d 8.39 (1H, s), 7.80
(2H, J¼8.0 Hz), 7.23 (2H, d, J¼8.0 Hz), 2.83 (3H, s), 2.32
(3H, s), 1.98 (3H, s), 1.87 (3H, s); 13C NMR (CDCl3/
CD3OD¼3:1), 75 MHz) d 161.5, 154.8, 154.1, 152.7,
141.3, 140.4, 140.0, 132.9, 134.7, 129.4 (2ꢂ), 129.2, 127.9
(2ꢂ), 24.6, 21.0, 19.3, 16.3; MS m/z (rel intensity) 338
(42, M+), 239 (100); HRMS calcd for C18H18N4OS:
338.1202, found: m/z 338.1199 (M+). Anal. Calcd for
C18H18N4OS: C, 63.88; H, 5.36; N, 16.56. Found: C,
63.82; H, 5.40; N, 16.42.
4.1.13. Methyl 4-acetyl-5-(4-methoxybenzoyl)thiophene-
2-carboxylate (5b). By a procedure similar to that for 15a,
alcohol 6b (182 mg, 0.42 mmol) was first treated with
0.5 equiv of p-TsOH (40 mg, 0.21 mmol) in refluxing benz-
ene under an atmosphere of nitrogen to give a crude product
of alkene 15b (148 mg). Without further purification, the
crude product was stirred with excess amount of p-TsOH
(100 mg, 0.53 mmol) in CHCl3 for 2 h under an atmosphere
of air to give 5b (113 mg) in 85% overall yield.
Acknowledgements
We thank the National Science Council for financial support.
Compound 5b: oil; TLC (EtOAc/hexane, 1:4) Rf¼0.09; IR
(neat) 1713, 1678, 1649, 1253 cmꢁ1
;
1H NMR (CDCl3,
Supplementary data
200 MHz) d 8.03 (1H, s), 7.45 (2H, dd, J¼8.9, 2.0 Hz),
6.88 (2H, dd, J¼8.9, 2.0 Hz), 3.89 (3H, s), 3.82 (3H, s),
2.38 (3H, s); 13C NMR (CDCl3, 50 MHz) d 192.2, 187.7,
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.11.080.

1428
S.-M. Yang, J.-M. Fang / Tetrahedron 63 (2007) 1421–1428
S.-M.; Chen, C.-T.; Fang, J.-M. Org. Lett. 2002, 4, 1099; (d)
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