Direct carboxylation of thiophenes and benzothiophenes with the aid of EtAlCl2

Full text of DOI:10.1246/bcsj.20110335

Short Articles
Bull. Chem. Soc. Jpn. Vol. 85, No. 3, 369-371 (2012)
Table 1. Carboxylation of 2-Methylthiophenea)
369
CO2 (3 MPa)
Lewis acid (1 mol equiv)
Direct Carboxylation of Thiophenes
and Benzothiophenes with
the Aid of EtAlCl2
CO2H
S
S
solvent
r.t. ~ 100 °C, 3 h
1
Temp
/°C
Yieldb)
/%
Entry
Lewis acid
Solvent
Koji Nemoto,* Satoru Onozawa, Megumi Konno,
Naoya Morohashi, and Tetsutaro Hattori*
1
2
3
4
5
6
7
8
9
MeAlCl2
EtAlCl2
MeAlCl2
EtAlCl2
MeAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
EtAlCl2
toluene
toluene
toluene
toluene
toluene
toluene
benzene
chlorobenzene
®
r.t.
r.t.
40
7
7
51
54
51
79
62
69
55
Department of Biomolecular Engineering, Graduate School
of Engineering, Tohoku University, 6-6-11 Aramaki-Aoba,
Aoba-ku, Sendai, Miyagi 980-8579
40
100
100
100
100
100
Received November 1, 2011
E-mail: hattori@orgsynth.che.tohoku.ac.jp
a) Reaction conditions: Substrate (1.00 mmol), CO2 (initial
pressure, 3.0 MPa), Lewis acid (1.00 mmol), solvent (3.0 mL).
Lewis acid was used as a hexane solution and, therefore,
hexane was included in the reaction mixture. b) Isolated yield.
Thiophenes and benzothiophenes bearing alkyl or
aryl substituents at the 2- or 3-positions are successfully
carboxylated with CO2 with aid of EtAlCl2 to give the
corresponding 2- or 3-carboxylic acids in up to 90% yield.
Table 2. Carboxylation of 2-Substituted Thiophenesa)
CO2 (3 MPa)
EtAlCl2 (1 mol equiv)
Thiophenecarboxylic acids are among the most attractive
synthetic targets with interesting biological activities.1 Thus far,
ring-closing syntheses have been most frequently employed to
construct the structures.2 However, the methods require multi-
step reaction sequences and/or prefunctionalization of starting
materials. Therefore, an easier to perform and more straight-
forward method is desired. Besides the recent progress in CO2
fixation via the transition-metal-catalyzed cleavage of aromatic
C-H bonds,3 it has been known that arenes and haloarenes can
be directly carboxylated with CO2 with the aid of strong Lewis
acids, such as AlCl3 and AlBr3.4 Recently, we have succeeded
in extending the substrate applicability of the Lewis acid-
mediated carboxylation toward indoles and pyrroles, using a
weaker Lewis acid, Me2AlCl.5 Herein, as an extension of our
efforts in this line, we report the carboxylation of thiophenes
and benzothiophenes.
First, the carboxylation of 2-methylthiophene was tested
with varying aluminum-based Lewis acids (1.0 mol equiv)
under CO2 pressure (3.0 MPa) at room temperature in toluene.
The reaction proceeded regioselectively at the 5-position with
the aid of MeAlCl2 and EtAlCl2, giving 5-methylthiophene-2-
carboxylic acid (1)6 though in poor yields (Table 1, Entries 1
and 2). The regioselectivity agreed with that generally observed
for the electrophilic aromatic substitution (SEAr) reactions of
thiophene. The use of stronger Lewis acids, AlCl3 and AlBr3,
as well as weaker ones, Me2AlCl and Et3Al, gave no acid in
detectable amounts; the substrate was consumed presumably
due to decomposition and/or polymerization with the aid of
the Lewis acids. The reaction temperature affected the acid
yield but its magnitude was different depending on the Lewis
acid employed; in the case of EtAlCl2, the yield was gradually
improved as increasing the temperature to reach 79% at 100 °C
(Entries 4 and 6), whereas in the case of MeAlCl2, the yield
reached a plateau (51%) at 40 °C (Entries 3 and 5). The
R
R
CO2H
S
S
toluene
100 °C, 3 h
Entry
R
H
Pentyl
Product
Yieldb)/%
1
2
3
4
27
3
48
5
69
7
30
81
85
88
74
90
75
41
10
12
Ph
1-Naphthyl
2-Thienyl
4-Fluorophenyl
4-Chlorophenyl
Cl
5c)
6
7
810
911
1012
1113
8d)
9d)
Br
OMe
10
a) Reaction conditions are the same as those employed in
Entry 6 in Table 1 unless otherwise noted. b) Isolated yield.
c) EtAlCl2 (2.0 mol equiv) was employed. d) Chlorobenzene
was used as a solvent.
replacement of the solvent with benzene and chlorobenzene
(Entries 7 and 8), as well as conducting the reaction without the
addition of a solvent (Entry 9), exhibited no beneficial effect.
Next, thiophenes and benzothiophenes bearing various
substituents, as well as unsubstituted ones, were subjected to
the carboxylation under the optimized conditions to evaluate
the scope and limitation of this reaction. Thiophenes bearing
alkyl or aryl substituents at the 2-positions gave the corre-
sponding 2-carboxylic acids in good yields, regardless of the
bulkiness of the substituents (Table 2, Entries 2-5). Halogen
atoms attached to the 4-position on the benzene ring of 2-
phenylthiophene did not bring about apparent electronic effects
on the product yield (Entries 6 and 7). On the other hand,
the direct introduction of a chlorine atom on the thiophene
ring significantly lowered the reactivity of the substrate, giving
Published on the web March 3, 2012; doi:10.1246/bcsj.20110335

370
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
© 2012 The Chemical Society of Japan
Table 4. Carboxylation of Benzothiophenesa)
Table 3. Carboxylation of 3-Substituted Thiophenesa)
CO2 (3 MPa)
EtAlCl2
(1 mol equiv)
CO2 (3 MPa)
EtAlCl2
(1 mol equiv)
CO2H
R
R
R
3
R
4
R
or
R
CO2H
+
toluene
100 °C, 3 h
S
S
S
HO2C
CO2H
toluene
100 °C, 3 h
S
S
S
Product
(Substituent)
1920 (3-CO2H)
2021 (2-Me, 3-CO2H)
2122 (2-Ph, 3-CO2H)
2223 (3-Me, 2-CO2H)
2324 (3-Ph, 2-CO2H)
23 (3-Ph, 2-CO2H)
Yieldb)/%
Yieldb)/%
Product
3-R 4-R
Entry
R
Entry
R
(3-R:4-R ratio)c)
1
2
3
4
5
6c)
H
37
88
84
81
18
64
1
2
3
4d)
5d)
Me
Pentyl
Ph
Cl
Br
1214
1314
86 (41:2)
78 (12:1)
88
34
19
2-Me
2-Ph
3-Me
3-Ph
3-Ph
14
15
®
1615
1716
1817
®
®
a) Reaction conditions are the same as those employed in
Entry 6 in Table 1 unless otherwise noted. b) Yield of isomer
mixture or single isomer. c) Determined by H NMR analysis.
a) Reaction conditions are the same as those employed in
Entry 6 in Table 1. b) Isolated yield. c) EtAlCl2 (3.0 mol
equiv) was employed.
1
d) Chlorobenzene was used as a solvent.
5-chlorothiophene-2-carboxylic acid in 41% yield. This caused
the simultaneous formation of toluic acid by the competitive
carboxylation of the solvent. The competition could be avoided
by using less reactive chlorobenzene as a solvent (Entry 8).
Bromothiophene underwent debromination under the reaction
conditions, giving thiophene-2-carboxylic acid as a by-product
(6%) (Entry 9); a similar observation has been made in the
carboxylation of bromobenzene.4b The electron-donating me-
thoxy group did not promote the carboxylation (Entry 10),
which could be attributed to the coordination of the methoxy
oxygen to the aluminum center. The employment of 2.0 mol
equiv of EtAlCl2, however, did not improve the product
yield (5%). Methyl 2-thienyl ketone, as well as thiophene-
2-carbaldehyde, gave no desired acid. Thiophenes bearing
substituents at the 3-positions exhibited similar reactivities to
those of 2-substituted regioisomers (Table 3). The observed
regioselectivity agreed with the ortho/para-directing nature of
the substituents, besides with the higher reactivity of the 2-
position of the thiophene ring relative to the 3-position.18 It is
known that benzothiophene undergoes SEAr reactions at both
the 2- and 3-positions but has a preference for the 3-position
to some extent. The present carboxylation took place at the
3-positions19 for unsubstituted and 2-substituted benzothio-
phenes and at the 2-positions for 3-substituted benzothiophenes
(Table 4). Benzothiophene bearing a phenyl moiety at the
3-position resisted the carboxylation, giving carboxylic acid
23 in 18% yield with the recovery of the substrate (42%)
(Entry 5). The yield could be improved by increasing the molar
equivalent of EtAlCl2 (Entry 6).
this compound is considered to be a carbonation of an
arylmetal species. In order to gain insight into the reaction
mechanism, the carboxylation of 2-methylthiophene was
carried out in the presence of 1.0 mol equiv of Ph3SiCl at
room temperature for 3 h or under the standard conditions in the
presence of 1.0 mol equiv of i-Pr3SiCl. However, no promotion
effect was observed for the silyl halides in both cases, giving
5-methylthiophene-2-carboxylic acid in 5% and 67% yields,
respectively. In addition, although the possibility of metalation
was tested by treating 2-methylthiophene with 1.0 mol equiv of
EtAlCl2 in toluene at 100 °C for 3 h, followed by quenching
the resulting mixture with D2O, deuterated 2-methylthiophene
could not be obtained; instead, severe decomposition of the
substrate was observed. Therefore, the reaction mechanism
is not clear at present for the carboxylation of the sulfur-
containing heteroaromatics.
In conclusion, we have shown that thiophenes and benzo-
thiophenes bearing alkyl or aryl substituents at the 2- or 3-
positions are successfully carboxylated with the aid of 1.0 mol
equiv EtAlCl2 under CO2 pressure at 100 °C.
Experimental
General. Melting points were taken using a micro melting
1
point apparatus and are uncorrected. H and 13C NMR spectra
were measured using tetramethylsilane as an internal standard
and CDCl3 as a solvent unless otherwise noted. J values are
given in Hz. Silica gel (63-200 mm) was used for TLC.
Benzene and toluene were distilled from sodium diphenyl ketyl
before use. Chlorobenzene was distilled from calcium hydride
and stored under nitrogen.
The Lewis acid-mediated carboxylation of arenes is believed
to be an electrophilic fixation of CO2, in which a Lewis acid-
activated CO2 molecule electrophilically attacks an aromatic
nucleus, according to the SEAr mechanism.4b We have recently
reported that the reaction is promoted by the addition of
R3SiCl.4d This was attributed to the formation of a silyl
haloformate-like active species with the aid of AlBr3. On the
other hand, 1-methylindole was found to be metalated at the
3-position with Me2AlCl, presumably via the electrophilic
metalation mechanism,25 under similar reaction conditions to
those for the carboxylation and, therefore, the carboxylation of
Typical Procedure for the Carboxylation of 2-Methyl-
thiophene (Table 1, Entry 6).
In a 50 cm3 autoclave
equipped with a glass inner tube and a magnetic stirring bar
were charged 2-methylthiophene (98.1 mg, 1.00 mmol), toluene
(3.0 mL), and EtAlCl2 (1.0 M solution in hexane; 1.0 mL) under
nitrogen and the apparatus was purged with CO2 by repeated
pressurization and subsequent expansion, the final pressure
being adjusted to 3.0 MPa. After stirring the mixture at 100 °C
for 3 h, the reactor was depressurized and the mixture was
quenched with 2 M HCl and extracted with chloroform. The

K. Nemoto et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 3 (2012)
371
organic layer was extracted with 0.5 M Na2CO3 and the ex-
tract was acidified with concd. HCl to liberate the free acid,
which was extracted with chloroform. The extract was dried
over MgSO4 and evaporated to leave a residue, which was
purified by TLC with ethyl acetate-hexane (1:1) as a developer
to give 5-methylthiophene-2-carboxylic acid (1) as crystals
(112 mg, 79%), mp 134-135 °C (lit.6 137-138 °C); IR (ATR):
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1
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Following are the characterization data of some products
obtained by similar procedures. For the other products, NMR
spectra and/or melting points were essentially identical to those
reported in the literature.7-17,20-24
4
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5-Pentylthiophene-2-carboxylic Acid (3): Mp 72-74 °C;
¹1
IR (ATR): 2930, 1673, 1541, 1464, 1288 cm
;
1H NMR
(400 MHz): ¤ 0.91 (3H, t, J = 7.0 Hz), 1.31-1.39 (4H, m),
1.66-1.74 (2H, m), 2.85 (2H, t, J = 7.6 Hz), 6.83 (1H, d,
J = 3.8 Hz), 7.73 (1H, d, J = 3.8 Hz); 13C NMR (100 MHz):
¤ 14.1, 22.5, 30.7, 31.2, 31.3, 125.7, 129.9, 135.5, 156.2,
168.0. Anal. Calcd for C10H14O2S: C, 60.57; H, 7.12%. Found:
C, 60.86; H, 7.12%.
5
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7
8
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5-(1-Naphthyl)thiophene-2-carboxylic Acid (5):
202-204 °C; IR (ATR): 2977, 1659, 1534, 1469, 1292 cm
Mp
9
E. Campaigne, R. L. White, Jr., J. Heterocycl. Chem. 1988,
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25, 367.
;
1H NMR (400 MHz): ¤ 7.30 (1H, d, J = 3.8 Hz), 7.51-7.57
(3H, m), 7.60-7.62 (1H, m), 7.92-7.95 (2H, m), 7.98 (1H, d,
J = 3.8 Hz), 8.17-8.20 (1H, m); 13C NMR (100 MHz, DMSO-
d6): ¤ 124.6, 125.5, 126.4, 127.2, 128.2, 128.5, 128.7, 129.3,
130.5, 130.6, 133.4, 133.5, 134.5, 147.5, 162.7. Anal. Calcd for
C15H10O2S: C, 70.84; H, 3.96%. Found: C, 70.67; H, 4.15%.
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5-(4-Fluorophenyl)thiophene-2-carboxylic Acid (7): Mp
¹1
246-248 °C; IR (ATR): 2873, 1657, 1537, 1448, 1310 cm
;
1H NMR (400 MHz, DMSO-d6): ¤ 7.31 (2H, dd, J = 8.4,
8.4 Hz), 7.56 (1H, d, J = 3.8 Hz), 7.72 (1H, d, J = 3.8 Hz),
7.80 (2H, dd, J = 8.4, 5.4 Hz), 13.17 (1H, br); 13C NMR
(100 MHz, DMSO-d6): ¤ 116.2 (d, J = 21.8 Hz), 124.7, 128.1
(d, J = 8.5 Hz), 129.5 (d, J = 3.1 Hz), 133.4, 134.4, 148.6,
162.4 (d, J = 245.3 Hz), 162.8. Anal. Calcd for C11H7FO2S:
C, 59.45; H, 3.17%. Found: C, 59.44; H, 3.33%.
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3-Pentylthiophene-2-carboxylic Acid (14): Mp 40-41 °C;
IR (ATR): 2865, 1676, 1527, 1455, 1278 cm
¹1
;
1H NMR
(400 MHz): ¤ 0.91 (3H, t, J = 7.0 Hz), 1.31-1.39 (4H, m),
1.60-1.68 (2H, m), 3.02 (2H, t, J = 7.8 Hz), 7.00 (1H, d,
J = 5.0 Hz), 7.50 (1H, d, J = 5.0 Hz); 13C NMR (100 MHz,
CDCl3): ¤ 14.1, 22.6, 29.8, 30.3, 31.8, 126.1, 131.1, 132.0,
153.4, 168.8. Anal. Calcd for C10H14O2S: C, 60.57; H, 7.12%.
Found: C, 60.80; H, 7.00%.
4-Pentylthiophene-2-carboxylic Acid (15): Mp 53-55 °C;
¹1
IR (ATR): 2871, 1683, 1549, 1452, 1276 cm
;
1H NMR
(400 MHz): ¤ 0.91 (3H, t, J = 7.0 Hz), 1.31-1.39 (4H, m),
1.60-1.68 (2H, m), 2.62 (2H, t, J = 7.7 Hz), 7.25 (1H, d,
J = 1.5 Hz), 7.73 (1H, d, J = 1.5 Hz); 13C NMR (100 MHz,
CDCl3): ¤ 14.1, 22.6, 29.8, 30.3, 31.5, 129.3, 132.6, 136.0,
144.6, 168.3. Anal. Calcd for C10H14O2S: C, 60.57; H, 7.12%.
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