Rhodium-catalyzed C3-selective alkenylation of substituted thiophene-2-carboxylic acids and related compounds

Article abstract of DOI:10.1021/jo4011969

The regioselective C3-alkenylation of thiophene-2-carboxylic acids can be achieved effectively via rhodium/silver-catalyzed oxidative coupling with alkenes, unaccompanied by decarboxylation. A wide range of substrates including brominated thiophenecarboxy

Full text of DOI:10.1021/jo4011969

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Article
Rhodium-Catalyzed C3-Selective Alkenylation of Substituted
Thiophene-2-Carboxylic Acids and Related Compounds
Tomonori Iitsuka, Petra Schaal, Koji Hirano, Tetsuya Satoh, Carsten Bolm, and Masahiro Miura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo4011969 • Publication Date (Web): 26 Jun 2013
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Rhodium-Catalyzed C3-Selective Alkenylation of
Substituted Thiophene-2-Carboxylic Acids and Related
Compounds
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Tomonori Iitsuka,† Petra Schaal,§ Koji Hirano,† Tetsuya Satoh, *,†,‡ Carsten Bolm,§ and Masahiro
Miura*,†
†Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871,
Japan
‡JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan
§Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52056 Aachen, Germany
satoh@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required)
Abstract: The regioselective C3-alkenylation of thiophene-2-carboxylic acids can be achieved
effectively via rhodium/silver-catalyzed oxidative coupling with alkenes, unaccompanied by
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decarboxylation. A wide range of substrates including brominated thiophenecarboxylic acids and furan-
2-carboxylic acids can be employed together with styrenes as well as acrylates. The present catalyst
system is also applicable to ortho-alkenylation of benzoic acids.
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Introduction
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Alkenylthiophene and –furan structures can be seen in various organic functional materials and
bioactive compounds.1 As an atom- and step-economical tool for constructing such frameworks, the
transition-metal-catalyzed direct alkenylation of thiophenes and furans via C–H bond cleavage have
gained considerable attention. This type of reaction is known to usually take place at the electron-rich
C2-position on the heterocycles predominantly.2 Among the most powerful methods for direct
functionalization of non-activated C–H bonds is a chelation-assisted version with the aid of directing
groups.3 Although the methodology has been well-developed, its application to thiophene and furan
derivatives, especially to their C3-selective alkenylation has been less explored and only few examples
utilizing amide groups as directing groups have been reported.4,5 One of more promising directing
groups is a carboxyl function, which is readily removable and substitutable through decarboxylation and
decarboxylative coupling, respectively,6 after the chelation-assisted alkenylation. Recently, we reported
the palladium-,7 rhodium-,8 and ruthenium-catalyzed9 C3-alkenylation of thiophene-2-carboxylic acids
(Scheme 1). While the palladium-catalyzed version gave a mixture of C2-
Scheme 1. Catalytic C3-Alkenylation of Thiophene- and Furan-2-Carboxylic Acids
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and C3-alkenylated products, the use of a rhodium catalyst allowed exclusive C3-alkenylation. These
reactions proceeded accompanied by decarboxylation. In contrast, simple C3-alkenylation retaining the
carboxyl group was realized under ruthenium catalysis. The third version is synthetically meaningful
because the remained carboxyl group can be utilized for further transformations. However, the substrate
scope for the ruthenium catalysis is narrow: only some thiophene-2-carboxylic acids and acrylates
undergo the reaction smoothly. During further investigation, we succeeded in finding that the C3-
alkenylation of variously substituted thiophene-2-carboxylic acids proceeds efficiently with retaining
their carboxyl function in the presence of a rhodium/silver catalyst system. The present catalysis was
found to be applicable to the reactions of a wider range of substrates including substituted thiophene-
and furan-2-carboxylic acids, 2-substituted benzoic acids, and 1-naphthoic acid. Moreover, various
styrenes could be employed as alkenyl sources. The results obtained with respect to these reactions are
described herein.
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Results and Discussion
In an initial attempt, thiophene-2-carboxylic acid (1a) (0.5 mmol) was treated with butyl acrylate (2a)
(1 mmol) in the presence of [Cp*RhCl2]2 (0.005 mmol), AgSbF6 (0.02 mmol), and AgOAc (1 mmol) in
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dioxane (3 mL) at 120 C for 5 h. As a result, the C3-alkenylated product was formed, which was then
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esterified for quantification to produce 3a in a moderate yield (entry 1 in Table 1). Even at 120 C,
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decarboxylation was not observed at all under the Rh/Ag catalysis. The reaction was terminated with
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remaining unconsumed substrates. At 100 C, the yield of 3a was significantly improved (entry 2).
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Under similar conditions, however, the reaction did not proceed at all in the presence of Cu(OAc)2•H2O
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in place of AgOAc (entry 3). At 80 C, the reaction proceeded smoothly to produce 3a quantitatively
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(entry 4). In the absence of AgSbF6, the reaction was sluggish at 80 C (entry 5). In the presence of
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[Cp*RhCl2]2/AgSbF6 as catalyst at 80 C, 1a efficiently reacted with various acrylates 2b-e as well as
acrylonitrile (2f) to selectively produce the corresponding C3-alkenylated products 3b-f in 71-87% yield
(entries 6-10).
Table 1. Reaction of Thiophene-2-Carboxylic Acid (1a) with Alkenes 2a
a
Reaction conditions: (1) 1a (0.5 mmol), 2 (1 mmol), [Cp*RhCl2]2 (0.005 mmol), AgSbF6 (0.02
mmol), AgOAc (1 mmol), dioxane (3 mL) under N2 at 80 C for 8 h; (2) with the addition of MeI (3
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mmol), K2CO3 (1.5 mmol), and DMF (3 mL) at rt for 3 h. b At 120 oC for 5 h. c GC yield. d At 100 oC
for 5 h. e Cu(OAc)2•H2O (1 mmol) was employed as oxidant in place of AgOAc. f Without AgSbF6.
Next, we examined reactions using styrenes as alkenyl sources, which could not be utilized under
ruthenium catalysis (Scheme 1).9 Under the conditions employed for entry 2 in Table 1, 1a coupled with
styrene (2g) to form a C3-styrylated product 3g in a low yield (entry 1 in Table 2). In this case, the
reaction proceeded more smoothly at 120 oC to improve the product yield to 56% (entry 2). Increasing
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the amount of [Cp*RhCl2]2 to 0.01 mmol led to further enhancement of the yield (entry 3). Finally, 3g
was obtained in 74% yield, when the reaction was conducted using 4 equiv of 2g (entry 4). Under the
optimized reaction conditions, 1a reacted with a number of 4-substitued styrenes 2h-l and 2-
vinylnaphthalene (2m) in fair to good yields (entries 5-10).
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Table 2. Reaction of Thiophene-2-Carboxylic Acid (1a) with Styrenes 2a
a Reaction conditions: (1) 1a (0.5 mmol), 2 (2 mmol), [Cp*RhCl2]2 (0.01 mmol), AgSbF6 (0.02 mmol),
AgOAc (2 mmol), dioxane (3 mL) under N2 at 120 C for 8 h; (2) with the addition of MeI (3 mmol),
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K2CO3 (1.5 mmol), and DMF (3 mL) at rt for 3 h. With [Cp*RhCl2]2 (0.005 mmol). With 2g (1
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mmol). d At 80 oC. GC yield.
A series of 4- and/or 5-substituted thiophene-2-carboxylic acids 1b-f also underwent C3-alkenylation
upon treatment with 2a (Table 3). It should be noted that each of the C–Br bond in 1d-f was tolerated.
The retained bromine atom, as well as a carboxyl function, are utilizable for further transformation (vide
infra). In contrast, the ruthenium-catalyzed reaction of 1d gave a mixture of 3p and a debrominated
product in a moderate yield. Similar debromination was also observed in the palladium-catalyzed
alkenylation of 2-bromothiophene.2a,9
Table 3. Reaction of Thiophene-2-Carboxylic Acids 1 with Butyl Acrylate (2a)a
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Reaction conditions: (1) 1 (0.5 mmol), 2a (1 mmol), [Cp*RhCl2]2 (0.005 mmol), AgSbF6 (0.02
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mmol), AgOAc (1 mmol), dioxane (3 mL) under N2 at 80 C for 8 h; (2) with the addition of MeI (3
mmol), K2CO3 (1.5 mmol), and DMF (3 mL) at rt for 3 h.
A possible mechanism for the C3-alkenylation of 1a with 2 is illustrated in Scheme 2, in which
neutral ligands are omitted. Coordination of the carboxyl oxygen of 1a to a Cp*Rh(III)X2 species gives
a rhodium(III) carboxylate A. Subsequent cyclorhodation to form a rhodacycle B, alkene insertion, and
β-hydrogen elimination take place to produce the corresponding C3-alkenylated product. After
liberation of 3, the resulting Cp*Rh(I) species may be oxidized in the presence of AgOAc to regenerate
Cp*Rh(III)X2. To conduct the reaction efficiently under relatively mild conditions, the addition of
AgSbF6 as a cocatalyst was essential. Therefore, a cationic rhodium species may be generated in situ
and catalyze the reaction.
Scheme 2. Possible Mechanism for the Reaction of 1a with 2
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Under the conditions using [Cp*RhCl2]2/AgSbF6 and AgOAc as catalyst and oxidant, respectively, 2-
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acetylthiophene also underwent C3-alkenylation via acetyl-directed C–H bond cleavage10 (Scheme 3).
Thus, (E)-butyl 3-(2-acetylthiophene-3-yl)acrylate (4) was obtained in 78% yield. However, the
corresponding aldehyde and ester were found to be inefficient substrates.
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Scheme 3. Reaction of 2-Substituted Thiophenes with 2a
Further derivatization of C3-alkenylated thiophenes was then examined. Treatment of 3p with boronic
acid 5 under Suzuki-Miyaura coupling conditions11 gave 3-alkenyl-5-arylthiophene-2-carboxylic acid
derivative 6 (Scheme 4). This kind of push-pull molecule has attracted much attention due to their
optical, electronic, and biological properties.12 Meanwhile, a thienopyridazinone framework can be seen
in a range of bioactive compounds.13 The fused heterocyclic structure could be readily constructed in a
few steps from (E)-3-(3-butoxy-3-oxoprop-1-en-1-yl)thiophene-2-carboxylic acid (3a’) (Scheme 5).14
Scheme 4. Transformation of C3-Alkenylated Thiophene 3p
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Scheme 5. Transformation of C3-Alkenylated Thiophene 3a’
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Besides thienyl substrates 1, furan-2-carboxylic acid (9a) also underwent C3-alkenylation under
standard conditions (entry 2 in Table 1) to afford the desired product 10a, albeit with a low yield (entry
1 in Table 4). The use of Ag2CO3 (0.5 mmol) in place of AgOAc slightly improved the yield of 10a
(entry 2). Among solvents examined (entries 3-7), diglyme was found to be the solvent of choice (entry
3). At 120 oC in diglyme, the yield of 10a was enhanced up to 78% (entry 8). Under similar conditions,
benzofuran-2-carboxylic acid (9b) also reacted with 2a smoothly to give the C3-alkenylated product
10b in 83% yield (entry 10).
Table 4. Reaction of Furan- and Benzofuran-2-Carboxylic Acids 9 with Butyl Acrylate (2a)a
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a Reaction conditions: (1) 9 (0.5 mmol), 2 (1 mmol), [Cp*RhCl2]2 (0.005 mmol), AgSbF6 (0.02 mmol)
under N2 for 8 h; (2) with the addition of MeI (3 mmol), K2CO3 (1.5 mmol), and DMF (3 mL) at rt for 3
h. b The value in parentheses indicates GC yield.
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We next applied the present Rh/Ag catalyst system to the alkenylation of benzoic acids. Under
somewhat modified conditions in t-AmOH at 60 oC, ortho-alkenylated product 11a was obtained in 76%
yield from 2-bromobenzoic acid, unaccompanied by debromination nor nucleophilic cyclization
(Scheme 6). It should be noted that nucleophilically cyclized products were formed under previously
reported conditions at an elevated temperature.15 2-Methyl- and 2-methoxybenzoic acids also underwent
ortho-alkenylation under appropriate conditions to afford 11b and 11c, respectively. The alkenylation of
1-naphthoic acid took place selectively at the 2-position to give 12 in 62% yield.
Scheme 6. Reaction of ortho-Substituted Benzoic Acids and 1-Naphthoic Acids with 2a
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a In dioxane. b At 80 oC for 8 h.
Conclusions
We have demonstrated that the C3-alkenylation of thiophene- and furan-2-carboxylic acids as well as
2-acetylthiophene with acrylates and styrenes can be performed efficiently in the presence of a
rhodium/silver catalyst system and a silver salt oxidant. Several 2-substituted benzoic acids and 1-
naphthoic acid also undergo regioselective alkenylation. A bromine substituent and a carboxyl
directing-group in substrates are retainable during the reaction. These functions can be utilized for
further transformation.
Experimental Section
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General. H and C NMR spectra were recorded at 400 and 100 MHz for CDCl3 solutions. HRMS
data were obtained by EI using a double focusing mass spectrometer, unless noted. GC analysis was
carried out using a silicon OV-17 column (i. d. 2.6 mm x 1.5 m). GC-MS analysis was carried out using
a CBP-1 capillary column (i. d. 0.25 mm x 25 m). The structures of all products listed below were
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unambiguously determined by H and C NMR with the aid of NOE, COSY, HMQC, and HMBC
experiments.
All starting materials and reagents were commercially available.
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General Procedure for the Reaction of Thiophene-2-Carboxylic Acids with Alkenes. To a 20 mL
two-necked flask with a reflux condenser, a balloon, and a rubber cup were added thiophene-2-
carboxylic acid 1 (0.5 mmol), alkene 2 (1 mmol), [(Cp*RhCl2)2] (0.005 mmol, 3 mg), AgSbF6 (0.02
mmol, 6.8 mg), AgOAc (1 mmol, 167 mg), 1-methylnaphthalene (ca. 50 mg) as internal standard, and
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dioxane (3 mL). Then, the resulting mixture was stirred under nitrogen at 80 C for 8 h. After cooling,
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iodomethane (3 mmol, 423 mg), K2CO3 (1.5 mmol, 207 mg), and DMF (3 mL) were added and the
resulting mixture was stirred under air at room temperature for 3 h. GC and GC-MS analyses of the
mixtures confirmed formation of 3. Then, the reaction mixture was extracted with ethyl acetate (100
mL). The organic layer was washed by water (100 mL, three times), and dried over Na2SO4. After
evaporation of the solvent under vacuum, product 3 was isolated by column chromatography on silica
gel using hexane-ethyl acetate (10:1, v/v) as eluant.
Procedure for the Reaction of 3p with 5. To a 20 mL two-necked flask with a reflux condenser, a
balloon, and a rubber cup were added 3p (0.25 mmol, 87 mg), 5 (0.38 mmol, 109 mg), Pd(OAc)2 (4.5
μmol, 1.0 mg), K3PO4 (0.5 mmol, 106 mg), 1-methylnaphthalne (ca. 50 mg) as internal standard, and i-
PrOH/H2O (1.35 mL/0.65 mL). The resulting mixture was stirred under air at 80 oC for 6 h (Scheme 4).
After cooling, the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was
washed by water (100 mL, three times), and dried over Na2SO4. After evaporation of the solvent under
vacuum, product 6 (76 mg, 60%) was isolated by column chromatography on silica gel using hexane-
ethyl acetate (10:1, v/v) as eluant and preparative GPC using chloroform as eluant.
Procedure for Preparation of 7. To a 20 mL two-necked flask were added 3a’ (0.3 mmol, 77 mg),
SOCl2 (0.5 mL), and toluene (1.5 mL). Then, the resulting mixture was stirred at room temperature over
night. After azeotropic distillation under vaccum with toluene, NHPhNHAc (0.36 mmol, 54 mg),
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pyridine (0.72 mmol, 57 mg), and dry DCM (3 mL) were added at 0 C and the resulting mixture was
stirred at room temperature over night. The reaction mixture was washed with water (20 mL) and
extracted with ethyl acetate (20 mL, three times). The organic layer was dried over Na2SO4/Al2O3. After
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evaporation of the solvent under vacuum, product 7 (51 mg, 43%) was isolated by column
chromatography on silica gel using hexane-ethyl acetate (1:2, v/v) as eluant.
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Procedure for Preparation of 8. To a 20 mL two-necked flask were added 7 (0.06 mmol, 23 mg),
DBU (0.072 mmol, 11 mg), and DMSO (0.5 mL). Then, the resulting mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with water (3 mL) and ethyl acetate (5 mL). The
aqueous layer was extracted with ethyl acetate (5 mL, three times). The combined organic layer was
washed with brine (10 mL) and then dried over Na2SO4. After evaporation of the solvent under vacuum,
product 8 (21 mg, 90%) was isolated by column chromatography on silica gel using hexane-ethyl
acetate (2:1, v/v) as eluant.
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(E)-Methyl 3-(3-Butoxy-3-oxoprop-1-en-1-yl)thiophene-2-carboxylate (3a):9 oil, 113 mg (84%);
1H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H), 1.40-1.49 (m, 2H), 1.66-1.74 (m, 2H), 3.92 (s,
3H), 4.22 (t, J = 6.6 Hz, 2H), 6.38 (d, J = 16.5 Hz, 1H), 7.36 (d, J = 5.0 Hz, 1H), 7.48 (d, J = 5.0 Hz,
1H), 8.51 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7, 19.1, 30.6, 52.2, 64.5, 122.0, 126.6,
130.8, 131.1, 136.4, 141.7, 162.2, 166.7; HRMS m/z Calcd for C13H16O4S (M+) 268.0769, found
268.0771.
(E)-Methyl 3-(3-Ethoxy-3-oxoprop-1-en-1-yl)thiophene-2-carboxylate (3b):9 mp 65-67 oC
(colorless microcrystals), 104 mg (87%); 1H NMR (400 MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H), 3.92 (s,
3H), 4.28 (q, J = 7.2 Hz, 2H), 6.38 (d, J = 16.0 Hz, 1H), 7.35 (d, J = 5.5 Hz, 1H), 7.47 (d, J = 5.5 Hz,
13
1H), 8.51 (d, J = 16.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 14.3, 52.3, 60.6, 122.1, 126.6, 130.8,
131.1, 136.4, 141.8, 162.2, 166.6; HRMS m/z Calcd for C11H12O4S (M+) 240.0456, found 240.0455.
(E)-Methyl 3-[3-(Cyclohexyloxy)-3-oxoprop-1-en-1-yl]thiophene-2-carboxylate (3c):9 mp 75-76 oC
1
(colorless microcrystals), 116 mg (79%); H NMR (400 MHz, CDCl3) δ 1.25-1.56 (m, 6H), 1.76-1.83
(m, 2H), 1.90-1.94 (m, 2H), 3.92 (s, 3H), 4.90 (m, 1H), 6.37 (d, J = 16.0 Hz, 1H), 7.35 (d, J = 5.5 Hz,
1H), 7.47 (d, J = 5.5 Hz, 1H), 8.50 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 23.7, 25.4, 31.6,
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52.2, 72.8, 122.7, 126.6, 130.7, 131.0, 136.2, 141.8, 162.2, 166.1; HRMS m/z Calcd for C15H18O4S (M+)
294.0926, found 294.0927.
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(E)-Methyl 3-(3-Isobutoxy-3-oxoprop-1-en-1-yl)thiophene-2-carboxylate (3d):9 oil, 108 mg (81%);
1H NMR (400 MHz, CDCl3) δ 1.00 (d, J = 6.9 Hz, 6H), 1.98-2.08 (m, 1H), 3.92 (s, 3H), 4.01 (d, J = 6.9
Hz, 2H), 6.39 (d, J = 16.5 Hz, 1H), 7.36 (d, J = 5.5 Hz, 1H), 7.48 (d, J = 6.0 Hz, 1H), 8.52 (d, J = 16.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 19.1, 27.8, 52.3, 70.7, 122.0, 126.6, 130.8, 131.2, 136.4, 141.7,
162.2, 166.7; HRMS m/z Calcd for C13H16O4S (M+) 268.0769, found 268.0772.
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(E)-Methyl 3-[3-(tert-Butoxy)-3-oxoprop-1-en-1-yl]thiophene-2-carboxylate (3e):9 oil, 102 mg
(76%); 1H NMR (400 MHz, CDCl3) δ 1.54 (s, 9H), 3.91 (s, 3H), 6.31 (d, J = 16.0 Hz, 1H), 7.34 (d, J =
13
5.5 Hz, 1H), 7.46 (d, J = 5.0 Hz, 1H), 8.41 (d, J = 16.5 Hz, 1H); C NMR (100 MHz, CDCl3) δ 28.1,
52.3, 80.7, 124.0, 126.7, 130.7, 130.9, 135.6, 142.0, 162.3, 166.0; HRMS m/z Calcd for C13H16O4S (M+)
268.0769, found 268.0767.
(E)-Methyl 3-(2-Cyanovinyl)thiophene-2-carboxylate (3f):9 mp 125-126 oC (colorless
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microcrystals), 68 mg (71%); H NMR (400 MHz, CDCl3) δ 3.92 (s, 3H), 5.86 (d, J = 16.9 Hz, 1H),
13
7.31 (d, J = 5.0 Hz, 1H), 7.51 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 17.0 Hz, 1H); C NMR (100 MHz,
CDCl3) δ 52.5, 99.7, 117.8, 125.5, 131.3, 131.5, 140.4, 142.6, 161.9; HRMS m/z Calcd for C9H7NO2S
(M+) 193.0197, found 193.0198.
o
(E)-Methyl 3-styrylthiophene-2-carboxylate (3g):16 mp 83-84 C (colorless microcrystals), 90.4 mg
(74%); 1H NMR (400 MHz, CDCl3) δ 3.91 (s, 3H), 7.12 (d, J = 16.5 Hz, 1H), 7.26-7.30 (m, 1H), 7.35-
13
7.38 (m, 2H), 7.44-7.47 (m, 2H), 7.56-7.58 (m, 2H), 8.14 (d, J = 16.5 Hz, 1H); C NMR (100 MHz,
CDCl3) δ 51.9, 121.9, 126.1, 126.3, 126.9, 128.2, 128.7, 130.5, 132.9, 136.9, 145.6,163.0; HRMS m/z
Calcd for C14H12O2S (M+) 244.0558, found 244.0559.
(E)-Methyl 3-(4-Methylstyryl)thiophene-2-carboxylate (3h): mp 116-117 oC (colorless
microcrystals), 98 mg (76%); 1H NMR (400 MHz, CDCl3) δ 2.36 (s, 3H), 3.90 (s, 3H), 7.09 (d, J = 16.5
13
Hz, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.42-7.47 (m, 4H), 8.09 (d, J = 16.5 Hz, 1H); C NMR (100 MHz,
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CDCl3) δ 21.3, 51.9, 121.0, 125.9, 126.0, 126.9, 129.4, 130.4, 132.9, 134.2, 138.3, 145.9, 163.1; HRMS
m/z Calcd for C15H14O2S (M+) 258.0715, found 258.0715.
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(E)-Methyl 3-[4-(tert-Butyl)styryl]thiophene-2-carboxylate (3i): oil, 122 mg (84%); H NMR (400
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MHz, CDCl3) δ 1.33 (s, 9H), 3.90 (s, 3H), 7.10 (d, J = 16.5 Hz, 1H), 7.37-7.44 (m, 4H), 7.50 (d, J = 8.2
Hz, 2H), 8.09 (d, J = 16.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 31.2, 34.7, 51.9, 121.2, 125.6, 125.9,
126.0, 126.7, 130.4, 132.8, 134.2, 145.8, 151.5, 163.0; HRMS m/z Calcd for C18H20O2S (M+) 300.1184,
found 300.1181.
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(E)-Methyl 3-(4-Methoxystyryl)thiophene-2-carboxylate (3j): mp 126-127 C (colorless needle
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crystals), 83 mg (60%); H NMR (400 MHz, CDCl3) δ 3.82 (s, 3H), 3.89 (s, 3H), 6.89 (d, J = 8.7 Hz,
13
2H), 7.06 (d, J = 16.5 Hz, 1H), 7.40-7.43 (m, 2H), 7.48-7.52 (m, 2H), 8.01 (d, J = 16.5 Hz, 1H); C
NMR (100 MHz, CDCl3) δ 51.9, 55.3, 114.1, 119.9, 125.4, 125.9, 128.2, 129.7, 130.4, 132.5, 146.0,
159.8, 163.1; HRMS m/z Calcd for C15H14O3S (M+) 274.0664, found 274.0665.
(E)-Methyl 3-(4-Chlorostyryl)thiophene-2-carboxylate (3k): m.p. 117-118 oC (pale yellow
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microcrystals), 118 mg (85%); H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 7.04 (d, J = 16.5 Hz, 1H),
13
7.30-7.34 (m, 2H), 7.42-7.50 (m, 4H), 8.11 (d, J = 16.5 Hz, 1H); C NMR (100 MHz, CDCl3) δ 52.0,
122.5, 125.9, 126.5, 128.1, 128.9, 130.6, 131.5, 133.8, 135.5, 145.2, 163.0; HRMS m/z Calcd for
C14H11ClO2S (M+) 278.0168, found 278.0165.
o
(E)-Methyl 3-[4-(Trifluoromethyl)styryl]thiophene-2-carboxylate (3l): mp 88-90 C (pale yellow
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microcrystals), 112 mg (74%); H NMR (600 MHz, CDCl3) δ 3.91 (s, 3H), 7.09 (d, J = 16.4 Hz, 1H),
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7.44-7.46 (m, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 8.20 (d, J = 16.4 Hz, 1H); C
NMR (150 MHz, CDCl3) δ 52.0, 124.13 (q, J = 271.7 Hz), 124.2, 125.6 (q, J = 3.8 Hz), 125.9, 126.9,
127.2, 129.7 (q, J = 32.2 Hz), 130.6, 131.1, 140.4, 144.8, 162.8; HRMS m/z Calcd for C15H11F3O2S (M+)
312.0432, found 312.0428.
o
(E)-Methyl 3-[2-(Naphthalen-2-yl)vinyl]thiophene-2-carboxylate (3m): mp 131-132 C (pale
yellow needle crystal), 119 mg (82%); 1H NMR (400 MHz, CDCl3) δ 3.91 (s, 3H), 7.26 (d, J = 16.5 Hz,
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1H), 7.43-7.49 (m, 4H), 7.78-7.83 (m, 4H), 7.87 (s, 1H), 8.26 (d, J = 16.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 52.0, 122.2, 123.7, 126.0, 126.18, 126,22, 126.4, 127.4, 127.7, 128.1, 128.4, 130.5, 133.1,
133.4, 133.6, 134.5, 145.7, 163.1; HRMS m/z Calcd for C18H14O2S (M+) 294.0715, found 294.0716.
(E)-Methyl 3-(3-Butoxy-3-oxoprop-1-en-1-yl)-5-methylthiophene-2-carboxylate (3n): oil, 118 mg
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(84%); H NMR (400 MHz, CDCl3) δ 0.96 (t, J = 7.6 Hz, 3H), 1.39-1.48 (m, 2H), 1.66-1.73 (m, 2H),
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2.49 (s, 3H), 3.88 (s, 3H), 4.21 (t, J = 6.9 Hz, 2H), 6.31 (d, J = 16.5 Hz, 1H), 7.03 (s, 1H), 8.45 (d, J =
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16.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.7, 15.6, 19.1, 30.7, 52.1, 64.5, 121.8, 125.0, 129.0,
136.6, 142.0, 145.8, 162.2, 166.8; HRMS m/z Calcd for C14H18O4S (M+) 282.0926, found 282.0924.
(E)-Methyl 3-(3-Butoxy-3-oxoprop-1-en-1-yl)-5-chlorothiophene-2-carboxylate (3o): mp 45-46 oC
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(pale yellow microcrystals), 120 mg (80%); H NMR (400 MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 3H),
1.39-1.48 (m, 2H), 1.66-1.73 (m, 2H), 3.90 (s, 3H), 4.21 (t, J = 6.6 Hz, 2H), 6.30 (d, J = 16.0 Hz, 1H),
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7.18 (s, 1H), 8.40 (d, J = 16.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.7, 19.1, 30.6, 52.4, 64.6,
123.0, 125.7, 129.3, 135.4, 136.4, 141.5, 161.2, 166.4; HRMS m/z Calcd for C13H15ClO4S (M+)
302.0380, found 302.0383.
(E)-Methyl 5-Bromo-3-(3-butoxy-3-oxoprop-1-en-1-yl)thiophene-2-carboxylate (3p):9 mp 34-36
1
oC (colorless microcrystals), 158 mg (91%); H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H),
1.39-1.48 (m, 2H), 1.66-1.73 (m, 2H), 3.90 (s, 3H), 4.21 (t, J = 6.9 Hz, 2H), 6.31 (d, J = 16.5 Hz, 1H),
13
7.32 (s, 1H), 8.40 (d, J = 16.5 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.6, 19.1, 30.6, 52.4, 64.6,
119.5, 122.9, 129.4, 132.0, 135.1, 142.2, 161.0, 166.3; HRMS m/z Calcd for C13H15BrO4S (M+)
345.9874, found 345.9873.
(E)-Methyl 4-Bromo-3-(3-butoxy-3-oxoprop-1-en-1-yl)thiophene-2-carboxylate (3q): mp 43-45 oC
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(colorless microcrystals), 162 mg (93%); H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H), 1.40-
1.49 (m, 2H), 1.67-1.74 (m, 2H), 3.91 (s, 3H), 4.23 (t, J = 6.6 Hz, 2H), 6.80 (d, J = 16.5 Hz, 1H), 7.52 (s,
1H), 8.18 (d, J = 16.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7, 19.1, 30.6, 52.6, 64.6, 112.3, 124.9,
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129.4, 131.2, 135.2, 139.4, 161.2, 166.5; HRMS m/z Calcd for C13H15BrO4S (M+) 345.9874, found
345.9872.
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(E)-Methyl 4,5-Dibromo-3-(3-butoxy-3-oxoprop-1-en-1-yl)thiophene-2-carboxylate (3r): mp 76-
78 oC (colorless needle crystals), 190 mg (89%); 1H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H),
1.42-1.49 (m, 2H), 1.67-1.74 (m, 2H), 3.90 (s, 3H), 4.23 (t, J = 6.9 Hz, 2H), 6.76 (d, J = 16.5 Hz, 1H),
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8.13 (d, J = 16.5 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.7, 19.2, 30.7, 52.8, 64.8, 116.6, 119.6,
125.6, 131.2, 135.2, 140.1, 160.6, 166.3; HRMS m/z Calcd for C13H14Br2O4S (M+) 423.8980, found
423.8980.
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(E)-Butyl 3-(2-Acetylthiophen-3-yl)acrylate (4): mp 50-51 C (colorless needle crystals), 98 mg
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(78%); H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H), 1.40-1.50 (m, 2H), 1.66-1.73 (m, 2H),
2.59 (s, 3H), 4.22 (t, J = 6.6 Hz, 2H), 6.38 (d, J = 16.5 Hz, 1H), 7.38 (d, J = 5.0 Hz, 1H), 7.48 (d, J = 5.0
13
Hz, 1H), 8.46 (d, J = 16.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.7, 19.1, 30.0, 30.6, 64.6, 122.7,
127.6, 130.1, 137.2, 139.1, 140.8, 166.7, 190.8; HRMS m/z Calcd for C13H16O3S (M+) 252.0820, found
252.0821.
(E)-Methyl
3-(3-Butoxy-3-oxoprop-1-en-1yl)-5-(4-(diphenylamino)phenyl)thiophene-2-
carboxylate (6): oil, 76 mg (60%); 1H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.6Hz, 3H), 1.40-1.49 (m,
2H), 1.67-1.74 (m, 2H), 3.91 (s, 3H), 4.22 (t, J = 6.6 Hz, 2H), 6.41 (d, J = 16.5 Hz, 1H), 7.04-7.14 (m,
8H), 7.25-7.31 (m, 4H), 7.41 (s, 1H), 7.44-7.48 (m, 2H), 8.49 (d, J = 16.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 13.7, 19.2, 30.7, 52.2, 64.5, 120.9, 122.1, 122.6, 123.7, 125.0, 125.9, 126.9, 128.6, 129.4,
136.7, 142.6, 147.0, 148.9, 149.1, 162.3, 166.8; HRMS m/z Calcd for C31H29NO4S (M+) 511.1817, found
511.1814.
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(E)-Butyl 3-(2-(2-Acetyl-1-phenylhydrazinecarbonyl)thiophen-3-yl)acrylate (7): mp 113-115 C
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(colorless microcrystals), 51 mg (43%); H NMR (400 MHz, CDCl3) δ 0.94 (t, J = 7.4Hz, 3H), 1.38-
1.45 (m, 2H), 1.62-1.69 (m, 2H), 2.02 (s, 3H), 4.16 (t, J = 6.7 Hz, 2H), 6.17 (d, J = 15.2 Hz, 1H), 7.12
13
(d, J = 5.2 Hz, 1H), 7.16-7.29 (m, 6H), 8.06 (d, J = 16.0 Hz, 1H), 8.97 (s, 1H); C NMR (100 MHz,
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CDCl3) δ 13.7, 19.1, 20.7, 30.6, 64.5, 120.4, 125.2, 126.2, 127.6, 128.8, 129.0, 134.3, 136.7, 139.5,
141.7, 163.2, 166.9, 169.6; HRMS m/z Calcd for C20H22N2O4S (M+) 386.1300, found 386.1301.
Butyl 2-(5-Acetyl-7-oxo-6-phenyl-4,5,6,7-tetrahydrothieno[2,3-d]pyridazin-4-yl)acetate (8): mp
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102-103 C (colorless microcrystals), 21 mg (90%); H NMR (400 MHz, CDCl3) δ 0.91 (t, J = 7.3Hz,
3H), 1.28-1.37 (m, 2H), 1.54-1.61 (m, 2H), 1.98 (s, 3H), 2.69 (dd, J = 7.1 Hz, 16.0 Hz, 1H), 2.90 (dd, J
= 7.5 Hz, 16.5 Hz, 1H), 4.11 (t, J = 6.6 Hz, 2H), 6.55 (t, J = 7.1 Hz, 1H), 7.07 (d, J = 5.0 Hz, 1H), 7.20
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(t, J = 7.34 Hz, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.62 (d, J = 5.0 Hz, 1H), 7.83 (d, J = 7.8 Hz, 2H); C
NMR (100 MHz, CDCl3) δ 13.6, 19.0, 21.9, 30.5, 37.5, 49.5, 65.1, 118.9, 125.2, 125.4, 129.3, 130.6,
134.1, 141.3, 149.4, 158.9, 169.5, 175.3; HRMS m/z Calcd for C20H22N2O4S (M+) 386.1300, found
386.1298.
(E)-Methyl 3-(3-Butoxy-3-oxoprop-1-en-1-yl)furan-2-carboxylate (10a): mp 32-33 oC (pale yellow
microcrystals), 77 mg (63%); 1H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H), 1.39-1.49 (m, 2H),
1.66-1.73 (m, 2H), 3.97 (s, 3H), 4.22 (t, J = 6.6 Hz, 2H), 6.34 (d, J = 16.0 Hz, 1H), 6.73 (d, J = 1.38 Hz,
13
1H), 7.53 (d, J = 1.83 Hz, 1H), 8.19 (d, J = 16.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.7, 19.2,
30.7, 52.2, 64.6, 109.7, 122.8, 128.6, 133.8, 142.0, 145.8, 159.1, 166.4; HRMS m/z Calcd for C13H16O5
(M+) 252.0998, found 252.0999.
(E)-Methyl 3-(3-Butoxy-3-oxoprop-1-en-1-yl)benzofuran-2-carboxylate (10b):9 mp 63-65 C (pale
o
yellow microcrystals), 118 mg (78%); 1H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.3 Hz, 3H), 1.43-1.52
(m, 2H), 1.70-1.77 (m, 2H), 4.04 (s, 3H), 4.26 (t, J = 6.6 Hz, 2H), 6.77 (d, J = 16.5 Hz, 1H), 7.40 (m,
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1H), 7.52 (m, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 8.46 (d, J = 16.5 Hz, 1H); C
NMR (100 MHz, CDCl3) δ 13.7, 19.2, 30.7, 52.7, 64.7, 112.7, 122.4, 123.0, 123.5, 124.6, 125.1, 128.3,
134.2, 143.3, 154.8, 159.9, 166.5; HRMS m/z Calcd for C17H18O5 (M+) 302.1154, found 302.1151.
1
(E)-Methyl 2-Bromo-6-(3-butoxy-3-oxoprop-1-en-1-yl)benzoate (11a): oil, 131 mg (76%); H
NMR (400 MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 3H), 1.38-1.47 (m, 2H), 1.64-1.72 (m, 2H), 3.99 (s, 3H),
4.20 (t, J = 6.9 Hz, 2H), 6.40 (d, J = 15.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.56-7.60 (m, 3H); 13C NMR
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(100 MHz, CDCl3) δ 13.7, 19.1, 30.6, 52.9, 64.7, 120.0, 122.3, 125.2, 130.8, 133.7, 133.9, 136.0, 139.9,
166.0, 167.3; HRMS m/z Calcd for C15H17BrO4 (M+) 340.0310, found 340.0310.
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(E)-Methyl 2-(3-Butoxy-3-oxoprop-1-en-1-yl)-6-methylbenzoate (11b): oil, 95 mg (69%); 1H NMR
(400 MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 3H), 1.38-1.48 (m, 2H), 1.64-1.71 (m, 2H), 2.35 (s, 3H), 3.95
(s, 3H), 4.20 (t, J = 6.6 Hz, 2H), 6.37 (d, J = 15.6 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz,
1H), 7.47 (d, J = 7.3 Hz, 1H), 7.70 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7, 19.2, 19.7,
30.7, 52.3, 64.5, 120.8, 124.0, 129.7, 131.7, 132.3, 134.1, 135.9, 141.6, 166.6, 169.3; HRMS m/z Calcd
for C16H20O4 (M+) 276.1362, found 276.1363.
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(E)-Methyl 2-(3-Butoxy-3-oxoprop-1-en-1-yl)-6-methoxybenzoate (11c): oil, 118 mg (81%); H
NMR (400 MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 3H), 1.38-1.47 (m, 2H), 1.64-1.71 (m, 2H), 3.85 (s, 3H),
3.95 (s, 3H), 4.19 (t, J = 6.6 Hz, 2H), 6.40 (d, J = 15.6 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 7.8
Hz, 1H), 7.38 (t, J = 8.2 Hz, 1H), 7.62 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.7, 19.1,
30.7, 52.6, 56.1, 64.5, 112.2, 118.5, 121.4, 124.0, 130.8, 133.3, 140.8, 156.6, 166.4, 167.6; HRMS m/z
Calcd for C16H20O5 (M+) 292.1311, found 292.1313.
1
(E)-Methyl 2-(3-Butoxy-3-oxoprop-1-en-1-yl)-1-naphthoate (12): oil, 97 mg (62%); H NMR (400
MHz, CDCl3) δ 0.98 (t, J = 7.3 Hz, 3H), 1.41-1.50 (m, 2H), 1.65-1.74 (m, 2H), 4.09 (s, 3H), 4.23 (t, J =
6.6 Hz, 2H), 6.54 (d, J = 15.5 Hz, 1H), 7.52-7.58 (m, 2H), 7.70 (d, J = 9.2 Hz, 1H), 7.83-7.90 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 13.7, 19.2, 30.7, 52.7, 64.6, 121.3, 122.5, 125.6, 127.5, 127.7, 128.2,
129.7, 129.8, 130.3, 132.5, 133.7, 141.2, 166.5, 169.0; HRMS m/z Calcd for C19H20O4 (M+) 312.1362,
found 312.1363.
Acknowledgment. This work was supported by Grants-in-Aid from MEXT, JSPS, and JST, Japan,
the Deutsche Forschungsgemeinschaft through the International Research Training Group Seleca (IGRK
1628) and the Forschungscluster SusChemSys. SusChemSys is co-financed by the Regional
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Development Fund - investing in your future - of the European Union and the state of North Rhine -
Westphalia.
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Supporting Information Available: Copies of 1H- and 13C-NMR spectra of products. This material is
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