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.
1. Introduction
Thiophenes and their polycyclic derivatives exhibit remark-able electrochemical,1a,boptical,1cphysical,1dand
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.3For example, methyl
thiophene-2-carboxylate reacts with paraformaldehyde in the presence of ZnCl2to 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;3bhowever, introduction of
sub-stituents at the C-4 position is still difficult.
Ar1 R1 O + Ar2 R2 O + THF, HMPA 2 SmI2 1 2 3 4 S O OMe S O OMe HO Ar1 R1 R2 Ar2 HO H H ð1Þ In an approach to elaborate thiophene derivatives at C-4 and C-5 positions, we have utilized SmI2as 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:[email protected]
0040–4020/$ - see front matterÓ 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2006.11.080
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 6aby 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.
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,5we 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).
Diols 5a–c and 10 likely have the 4,5-trans configuration that can be established by an attack of the second electro-phile on the less hindered face of the dienolate intermediate A(Scheme 1).4The1H 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 12having 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)2as 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-constrictor5,6were also prepared by the similar procedures.
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 by the 1H 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.
S O OMe O Me R2 O R1 5a R1 = R2 = MeO R1 = H, R2 = MeO 5b 5c R1 = H, R2 = Me
Figure 1. Example of 4,5-diacylthiophene-2-carboxylates that are not reported previously. S O OMe H H OMe O S O OMe H H OMe OH HO Me H 4 S O OMe OMe O 7
Pd(OAc)2, K2CO3, MeCN cat. p-TsOH, CH2Cl2
S O OMe O Me OMe 8 9 R2 R1 MeO MeO MeO MeO MeO MeO cat. p-TsOH PhH; 94% for 6a DDQ, PhH 25 °C, 14 h; 25 °C, 2 h; 97% 25 °C, 15 h; 91% 89% S O OMe H H OMe O HO Me 4 R2 R1 + THF, HMPA 2 SmI2 Samarium dienolate A 1 S O OMe MeO MeO H O 2a 3a S OSmL2 OMe H OH H 4 MeO MeO OMe O Me 6a R1 = R2 = MeO R1 = H, R2 = MeO 6b 6c R1 = H, R2 = Me 4a R1 = R2 = MeO R1 = H, R2 = MeO 4b 4c R1 = H, R2 = Me
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 (25C, 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 and13C 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
17aand 17c in quantitative yields. Thieno[2,3-d]pyridazine derivatives have been shown to exhibit anti-inflammatory activity,7aand were used as a short-term hypnotic to treat
in-somnia.7bWe 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
cat. p-TsOH PhH 10 S O OMe H H OMe O N Me S O OMe H H OMe OH HO N Me Me H S O OMe OMe O N Me 12 Pd(OAc)2, K2CO3, MeCN cat. p-TsOH CH2Cl2 S O OMe N Me O Me OMe 13 14 95% 25 °C, 2 h; 98% 25 °C, 12 h; 93% 25 °C, 4 h; DDQ, PhH 88% 11 S O OMe H H OMe O HO N Me Me
Scheme 2. Synthesis of a carbazole-fused thiophene.
Excess p-TsOH CHCl3, 25 °C, 2.5 h, O2 (open system) S O OMe H OMe O Me R2 0.5 equiv p-TsOH, PhH N2, reflux, 1 h S O OMe H H OMe O HO Me 4 R2 6a S O OMe O Me R2 O R1 = R2 = MeO R1 = H, R2 = MeO 6b OMe HO + 16 R1 R1 R1 6c R1 = H, R2 = Me 15a R1 = R2 = MeO R1 = H, R2 = MeO 15b 15c R1 = H, R2 = Me 5a R1 = R2 = MeO R1 = H, R2 = MeO 5b 5c R1 = H, R2 = Me i) N2H4, EtOH, 25 °C, 10 min ii) Me2CO S O NH 17a R1 = R2 = MeO 17c R1 = H, R2 = Me N N Me R1 R2 N Me Me 5 5
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-MeOC
6H4)
and ketone 5a, by analogy to the well-known fragmentation reaction of cumyl hydroperoxide to phenol and acetone.8
3. Conclusion
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 12with 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),
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
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 100C 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).
Melting points were recorded using a Yanagimoto micro-melting point apparatus and were uncorrected. Chemical
D S O OMe Ar1 O Me O OH E + S O OMe Ar1 O Me 5a O S O OMe Ar1 O Me O OH+ + 2 F S O OMe Ar1 O Me O G hydrolysis S O OMe Ar1 OH Me O2 p-TsOH S O OMe Ar2 Ar2 Ar2 Ar2 Ar2 Ar2 Ar2 Ar2 Ar 2 H H Ar1 O HO Me 6a S O OMe H H Ar1 O H2O + Me S O OMe H H Ar O H3C + 4 B C S O OMe H H Ar1 O 4 7 − H+ S O OMe H Ar1 O 15a Me Isomerization − H+ tautomerization H+ − H2O rearrangement Ar2 OH
shifts of 1H and 13C NMR spectra are reported relative 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.
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 0C for 45 min, and then at room temperature (25C) for another 45 min. A solution of 4-methoxyacetophenone (180 mg, 1.2 mmol) in THF (2 mL) was added at 0C, and the mixture was stirred at 0–25C 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 the1H NMR analysis.
Without further purification, 4a (354 mg, 0.78 mmol) in benz-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 6a: oil; TLC (EtOAc/hexane, 1:1) Rf¼0.30; IR
(neat) 3502, 1709, 1665, 1265, 749 cm1; 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 (CDCl 3, 75 MHz) d 192.5, 161.8, 158.4, 153.6, 149.0, 137.6, 134.6, 133.1, 127.9, 126.0 (2), 123.1, 113.5 (2), 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+).
4.1.2. 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 in the presence of molecular sieves (4 A˚ , 2 g). The mixture was subjected to silica gel column chromatography by
eluting with EtOAc/hexane (3:7) to give ketone 6b (232 mg) in 54% overall yield.
Compound 6b: oil; TLC (EtOAc/hexane, 3:7) Rf¼0.17; IR
(neat) 3492, 1708, 666, 1252 cm1; 1H NMR (CDCl 3, 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 (2), 127.9, 126.1 (2), 114.0 (2), 113.7 (2), 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+).
4.1.3. 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.
Compound 6c: oil; TLC (EtOAc/hexane, 3:7) Rf¼0.23; IR
(neat) 3494, 1711, 1671, 1249 cm1; 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 (CDCl 3, 50 MHz) d 193.4, 161.9, 158.6, 144.6, 137.6, 134.5, 133.4, 132.4, 129.4 (2), 128.7 (2), 126.1 (2), 113.6 (2), 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+). 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, 1599, 1262, 748 cm1; 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 (CDCl 3, 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 (2), 123.0, 114.0 (2), 113.2,
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+).
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)
Rf¼0.35; IR (neat) 1718, 1637, 1594, 1511, 1268 cm1; 1H NMR (CDCl 3, 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 (2), 124.4, 115.3, 113.4 (2), 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 C
24H22O6S:
438.1137, found: m/z 438.1140 (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) Rf¼0.23; IR (neat) 1719, 645, 1279 cm1; 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 (CDCl 3, 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 (2), 123.9, 114.0 (2), 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+).
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, 1661, 1613, 1251, 753 cm1;1H NMR (CDCl 3, 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), 3.74 (3H, s), 3.67 (3H, s), 2.40 (1H, br s, OH), 1.54 (3H, s); 13C NMR (CDCl 3, 75 MHz) d 187.6, 162.0, 158.6, 140.6, 137.6, 134.3, 133.8, 133.1, 126.4, 126.1 (2), 125.6, 123.1, 120.9, 113.7 (2), 112.1, 110.3, 75.9, 61.0, 55.1, 52.3, 52.0, 32.1, 27.7; FABMS m/z 452.1 (M+H 2O+H);
HRMS calcd for C25H25NO5S: 451.1453, found: m/z
451.1463 (M+).
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, 1511, 1250 cm1; 1H NMR (CDCl 3, 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 (CDCl 3, 75 MHz) d 187.3, 162.1, 159.4, 145.6, 140.5, 136.1, 133.4, 132.8, 131.5, 127.5 (2), 126.3, 125.6, 122.9, 120.9, 113.9 (2), 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+).
4.1.9. 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, 1510, 1247 cm1; 1H NMR (CDCl 3, 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, CDCl 3) 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 (2), 126.2, 125.7, 123.0, 120.7, 115.1, 114.9, 113.3 (2), 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+).
4.1.10. 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 CH2Cl2solution at room temperature for
2 h afforded the acid-catalyzed cyclization product 14 (49 mg, 98%) as colorless solid, mp 113–114C. TLC (EtOAc/hexane, 1:9) Rf¼0.13; IR (KBr) 1716, 1637, 1510, 1247 cm1; 1H 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 (CDCl 3, 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 (2), 126.5, 123.2, 122.2, 120.4, 114.1 (2), 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
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.
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 mixture was then subjected to silica gel column chro-matography by eluting with EtOAc/hexane (1:4) to give al-kene 15a (204 mg, 79% yield) as a solid; mp l56–158C; TLC (EtOAc/hexane, 1:4) Rf¼0.14; IR (KBr) 1701, 1669, 1245, 751 cm1; 1H NMR (CDCl 3, 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 (2), 128.0, 122.8, 113.7 (2), 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 C 24H24O6S:
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%).
Compound 5a: solid; mp 125–127C; TLC (EtOAc/hexane, 1:4) Rf¼0.07; IR (KBr) 1716, 1678, 1650, 1267, 754 cm1; 1H NMR (CDCl 3, 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 C
l7H16O6S: C, 58.61; H,
4.63. Found: C, 58.72; H, 4.56.
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 CHCl3for 2 h under an atmosphere
of air to give 5b (113 mg) in 85% overall yield.
Compound 5b: oil; TLC (EtOAc/hexane, 1:4) Rf¼0.09; IR
(neat) 1713, 1678, 1649, 1253 cm1; 1H NMR (CDCl 3, 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, 164.3, 161.4, 150.2, 141.2, 134.2, 132.9, 131.9 (2), 129.4, 114.0 (2), 55.5, 52.6, 28.8; MS m/z (rel intensity) 318 (54, M+), 135 (100); HRMS calcd for C l6H14O5S: 318.0562, found: m/z 318.0564 (M+). 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 209–211C; TLC (MeOH/CH2Cl2, 1:19) Rf¼0.13; IR (KBr) 3423, 1642, 1415, 1232 cm1;1H NMR (CDCl 3, 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 (2), 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. 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 CHCl3for 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 262–264C; TLC (MeOH/CH2Cl2, 1:19) Rf¼0.17; IR (KBr) 3447, 1648, 1390, 1259 cm1; 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 (CDCl 3/ 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 (2), 129.2, 127.9 (2), 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.
Acknowledgements
We thank the National Science Council for financial support.
Supplementary data
Supplementary data associated with this article can be found in the online version, atdoi:10.1016/j.tet.2006.11.080.
References and notes
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