Alkenylation of thiophenes at the 2-position with magnesium alkylidene carbenoids

Article abstract of DOI:10.1016/j.tetlet.2007.07.074

Treatment of magnesium alkylidene carbenoids, generated from 1-chlorovinyl p-tolyl sulfoxides with isopropylmagnesium chloride at -78 °C in toluene, with 2-lithiothiophenes gave 2-alkenylated thiophenes in good to high yields. The intermediate of this rea

Full text of DOI:10.1016/j.tetlet.2007.07.074

Tetrahedron Letters 48 (2007) 6453–6457
Alkenylation of thiophenes at the 2-position with magnesium
alkylidene carbenoids
Tsuyoshi Satoh,* Natsuki Mori and Kazumi Obuchi
Department of Chemistry, Faculty of Science, Tokyo University of Science, Ichigaya-funagawara-machi 12,
Shinjuku-ku, Tokyo 162-0826, Japan
Received 19 June 2007; revised 11 July 2007; accepted 13 July 2007
Available online 21 July 2007
Abstract—Treatment of magnesium alkylidene carbenoids, generated from 1-chlorovinyl p-tolyl sulfoxides with isopropylmagne-
sium chloride at À78 °C in toluene, with 2-lithiothiophenes gave 2-alkenylated thiophenes in good to high yields. The intermediate
of this reaction was found to be an alkenylmagnesium, which could be trapped with iodoalkanes and ethyl chloroformate. This pro-
cedure offers a novel and efficient one-pot synthesis of thiophenes having a disubstituted or a trisubstituted olefin at the 2-position
from thiophenes in good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
Thiophenes are obviously one of the most important
heterocyclic aromatic compounds in organic and syn-
thetic organic chemistry. Thiophene moiety is frequently
found in pharmaceuticals.1 Furthermore, thiophenes are
becoming very important compounds in material sci-
ence, especially in the science of conducting polymer.
Polythiophenes are receiving considerable attention
these days.2
We previously reported a new method for alkenylation
of arylamines at the ortho-position9 and N-alkenylation
of nitrogen-containing heterocycles10 utilizing the reac-
tion of magnesium alkylidene carbenoids with N-lithio
arylamines and N-lithio nitrogen-containing hetero-
cycles, respectively, as a key reaction. As the magnesium
alkylidene carbenoids are expected to have much ability
for alkenylation of many compounds having proper
nucleophilicity, we have been continuing to investigate
the reaction of magnesium alkylidene carbenoid with
some C-lithio heteroaromatic compounds. As a result,
2-lithiothiophenes are found to be reactive with the
magnesium alkylidene carbenoids to give 2-alkenylthio-
phenes in good yields as shown in Scheme 1.
Thiophenes are known to be relatively highly reactive
aromatic compounds and Friedel–Crafts-type reactions
(alkylations and acylations) are usually conducted with
weak Lewis or Bronsted acid. In contrast to the alkyl-
ations and acylations, alkenylations of thiophenes are
quite limited and some examples are reported as follows.
Heck-type reaction of 2-iodothiophene with olefins.3
Carbosilylation of 2-iodothiophenes with allenes.4 Negi-
shi cross-coupling of arylzinc chloride of thiophenes
with vinyl tellurides.5 Addition of thiophenes to alkynes
catalyzed by a dinuclear palladium complex.6 Addition
of thiophenes to alkynes catalyzed by tetrarhodium
dodecacarbonyl.7 Palladium-catalyzed alkenylation of
thiophene with olefins.8
O
R1
R2
R1
R2
R1
R2
i
-PrMgCl
Cl
Cl
TolSCH2Cl
O
-78 °C
in three steps
MgCl
STol
O
3
1
2
S
Li
R1
R2
R1
R2
R3
Electrophile
MgCl
E
S
S
-78 ~ -10 °C
R3
R3
Keywords: Magnesium alkylidene carbenoid; Sulfoxide–magnesium
exchange reaction; Alkenylation; Thiophene; 2-Alkenylthiophene.
4
5
*
Corresponding author. Tel.: +81 3 5228 8272; fax: +81 3 5261
4631; e-mail: tsatoh@rs.kagu.tus.ac.jp
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.074

6454
T. Satoh et al. / Tetrahedron Letters 48 (2007) 6453–6457
Table 2. Reaction of magnesium alkylidene carbenoid 7 with several 2-
lithiothiophenes to afford 2-alkenylthiophenes 8
Thus, 1-chlorovinyl p-tolyl sulfoxides 2 were synthesized
from ketones 1 and chloromethyl p-tolyl sulfoxide in
three steps in high overall yields.11 Vinyl sulfoxide 2
was treated with i-PrMgCl in toluene at À78 °C to give
magnesium alkylidene carbenoid 3 instantaneously. To
this magnesium carbenoid a solution of 2-lithiothio-
phene in THF was added at À78 °C and the temperature
of the reaction mixture was slowly allowed to warm to
À10 °C to give 2-alkenylated thiophene 5 (E = H) in
good to high yield via alkenylmagnesium intermediate
4. The alkenylmagnesium intermediate 4 was found to
be reactive with several electrophiles to afford thio-
phenes having a fully substituted olefin at 2-position 5
(E = alkyl group, ethoxycarbonyl group, etc.) in good
overall yield from 2. Details of these results are reported
hereinafter.
Entry 2-Lithiothiophenes Product/8
Yield
(%)
S
H
H
H
H
O
O
Li
1
2
67a
77
S
S
S
S
8b
8c
O
O
S
S
S
Li
Li
Li
CH3
OCH3
Cl
CH3
OCH3
Cl
O
O
3
4
80
80
8d
O
O
At first, in order to remove a trace of moisture in the
reaction mixture, t-BuMgCl (0.13 equiv) was added to
a solution of 1-chlorovinyl p-tolyl sulfoxide 611 in dry
THF at À78 °C. i-PrMgCl (2.8 equiv) was added to
the reaction mixture to afford instantaneously magne-
sium alkylidene carbenoid 7. To this solution of the
carbenoid was added 2-lithiothiophene, derived from
thiophene (3 equiv) and n-BuLi (3.3 equiv) in THF,
and the reaction mixture was slowly allowed to warm
to À10 °C (Table 1, entry 1). Fortunately, the desired
reaction took place to afford 2-alkenylthiophene 8a in
60% yield.
8e
a 2-Lithiobenzothiophene was generated from benzothiophene with t-
BuLi.
described in entry 3 as the optimized conditions and
used them throughout this study.
Next, generality of this reaction was investigated using
several 2-lithiothiophenes and magnesium alkylidene
carbenoid 7, and the results are summarized in Table
2. Benzothiophene gave the desired 2-alkenylthiophene
8b; however, the yield slightly diminished (entry 1).
Thiophenes having an electron-donating group, and
also having an electron-withdrawing group gave good
yields of the desired 2-alkenylthiophenes 8c–e (entries
2–4). From these results generality of this reaction was
verified.
Because we recognized that this is quite interesting and
novel reaction, improvement of the yield of 8a was
investigated and the results are summarized in Table 1.
Generation of 7 in toluene worked well; however, as
thiophene did not dissolve in toluene, this reaction could
not be carried out in toluene (entry 2). Next, magnesium
alkylidene carbenoid 7 was generated in toluene and to
this was added 2-lithiothiophene (generated in a mixture
of toluene–THF 3:1) (entry 3). This reaction gave 78%
yield of the desired 8a.12 As a result, the reaction was
conducted in a mixture of toluene and THF in a ratio
of 9:1. We further investigated this reaction with adding
an additive (ether-type solvent) expecting for better
yields; however, no improvement of the yield was
achieved (entries 4–6). So we decided the conditions
Based on our previous studies,13 the intermediate of this
reaction was thought to be alkenylmagnesium 9 (Table
3). To ascertain that the intermediate was the alkenyl-
magnesium, the reaction between magnesium alkylidene
carbenoid 7 and 2-lithiothiophene was quenched with
CH3OD. This reaction afforded deuteriated 2-alkenyl-
thiophene 10 (E = D) in 78% yield with 97% deuterium
incorporation (Table 3, entry 1). From this result, the
Table 1. Reacton of magnesium alkylidene carbenoid 7, derived from 6 with i-PrMgCl, with 2-lithiothiophene to afford 2-alkenylthiophene 8a
S
Li
1)
2)
t
i
- BuMgCl (0.13 eq)
- PrMgCl (2.8 eq)
Cl
O
O
H
Cl
O
O
(3 eq)
S
solvent, -78 °C
-78 ~ -10 °C
additive (10 eq)
S(O)Tol
MgCl
8a
6
7
Entry
Solvent
Additive
8a Yield (%)
1
2
3
4
5
6
THF
Toluene
Toluene/THFb
Toluene/THFb
Toluene/THFb
Toluene/THFb
None
None
None
Et2O
CPME
DME
60
—
78
47
37
27
a
a Thiophene did not dissolve in toluene and the desired reaction could not be conducted.
b The ratio of toluene and THF is 9:1. See the text.

T. Satoh et al. / Tetrahedron Letters 48 (2007) 6453–6457
6455
Table 3. Reaction of the alkenylmagnesium intermediate 9 with
electrophiles to give thiophene having a fully substituted olefin 10
Table 4. Reaction of magnesium alkylidene carbenoid 7 with 2-
lithiothiophenes followed by iodomethane in the presence of 5 mol %
of Cu(I) iodide to give thiophenes having a fully substituted olefin at
the 2-position 11
S
Li
MgCl
S
Cl
O
O
O
O
i-PrMgCl
(3 eq)
6
Entry 2-Lithiothiophenes
Product 11
Toluene-THF (9:1)
MgCl
Yield
(%)
-78 ~ -10 °C
7
9
Electrophile
cat. CuI
E
S
O
O
S
CH3
S
O
O
Li
-10 °C ~ r.t., then
r.t. 1 h
1
58
75
10
11a
11b
11c
11d
Entry Electrophile
(equiv)
CuI
E
Yield of
10 (%)
CH3
O
O
(mol %)
S
S
S
Li
Li
Li
CH3
OCH3
Cl
S
CH3
OCH3
Cl
2
3
4
1
2
CH3OD (excess)
None
5
D
CH3
78a
72
69b
CH3I (3)
3
4
5
6
7
8
9
10
11
CH3CH2I (10)
5
CH2CH3
CH3
S
O
O
CH2@CHCH2I (3)
(CH3)2CHI (10)
PhCH2Br (3)
I2 (10)
ClCOOC2H5 (10)
PhCHO (10)
5
CH2CH@CH2 67
c
70
77
5
CH(CH3)2
—
72
71
70
—
—
—
5
CH2Ph
None
None
None
None
None
I
CH3
S
O
O
COOC2H5
CH(Ph)OH
C(CH3)2OH
COPh
c
c
d
(CH3)2CO (10)
PhCOCl (10)
a Deuterium content 97%.
b The reaction mixture was stirred for 3 h at room temperature.
c Compound 8a was obtained as a main product.
d A complex mixture was obtained.
for a synthesis of thiophenes having a fully substituted
olefin would be achieved. At first, iodomethane
(10 equiv) was added to the reaction mixture. This reac-
tion gave the methylated product 10 (E = CH3); how-
ever, the yield was not acceptable (54%). After some
investigations, fortunately, Cu(I) iodide was found to
be effective catalyst in this reaction. Thus, after genera-
tion of intermediate 9, Cu(I) iodide (5 mol %) followed
by iodomethane (3 equiv) were added to the reaction
intermediate of this reaction was confirmed to be alken-
ylmagnesium 9.
It was thought that if this alkenylmagnesium intermedi-
ate 9 could be trapped with electrophiles, a new method
Table 5. Synthesis of 2-alkenylthiophenes 12 from 1-chlorovinyl p-tolyl sulfoxides 2 with 2-lithiothiophene
S
Li
1)
2)
t
i
- BuMgCl (0.13 eq)
- PrMgCl (2.8 eq)
R1
R2
Cl
R1
R2
H
(3 eq)
S
Toluene, -78 °C
Toluene, THF
-78 ~ -10 °C
S(O)Tol
2
12
Entry
1-Chlorovinyl p-tolyl sulfoxide
2-Alkenylthiophene 12
E/Z
Yield (%)
63
Cl
H
15
15
1
—
S
S(O)Tol
2a
12a
H
Cl
S
2
3
—
72
60
S(O)Tol
2b
12b
H
Cl
S
S
34/66
Ph
12c (
Ph
Ph
S(O)Tol
2c (
E)
Z)
Ph
H
Cl
4
81/19
73
S(O)Tol
2d (Z)
12d (E)

6456
T. Satoh et al. / Tetrahedron Letters 48 (2007) 6453–6457
6. Tsukada, N.; Murata, K.; Inoue, Y. Tetrahedron Lett.
2005, 46, 7515.
7. Hong, P.; Cho, B.-Re.; Yamazaki, H. Chem. Lett. 1980,
507.
8. Maruyama, O.; Yoshidomi, M.; Fujiwara, Y.; Taniguchi,
H. Chem. Lett. 1979, 1229.
mixture at À10 °C and the reaction mixture was slowly
allowed to warm to room temperature. The stirring
was continued for 1 h at room temperature to give the
desired methylated product in 72% yield (entry 2).14
Iodoethane, allyl iodide, benzyl bromide worked well;
however, 2-iodopropane did not give the desired prod-
uct at all (entry 3–6). Iodine and ethyl chloroformate
gave iodinated and ethoxycarbonylated product, respec-
tively, in good yield (entries 7 and 8). Benzaldehyde and
acetone did not afford the expected adduct but the pro-
tonated product 8a (entries 9 and 10). Benzoyl chloride
only gave a complex mixture (entry 11).
9. (a) Satoh, T.; Ogino, Y.; Nakamura, M. Tetrahedron Lett.
2004, 45, 5785; (b) Satoh, T.; Ogino, Y.; Ando, K.
Tetrahedron 2005, 61, 10262.
10. (a) Satoh, T.; Sakurada, J.; Ogino, Y. Tetrahedron Lett.
2005, 46, 4855; (b) Sakurada, J.; Satoh, T. Tetrahedron
2007, 63, 3806.
11. (a) Satoh, T.; Kawashima, T.; Takahashi, S.; Sakai, K.
Tetrahedron 2003, 59, 9599; (b) Sugiyama, S.; Satoh, T.
Tetrahedron: Asymmetry 2005, 16, 665.
12. To a solution of 6 (98 mg; 0.3 mmol) in 6 mL of dry
toluene in a flame-dried flask at À78 °C under argon
atmosphere was added t-BuMgCl (1.0 M solution in THF,
0.04 mL; 0.04 mmol) dropwise with stirring. After 10 min,
i-PrMgCl (2.0 M solution in THF, 0.42 mL; 0.84 mmol)
was added dropwise to the reaction mixture to give
magnesium alkylidene carbenoid 7. In an another flask, n-
BuLi (1.65 M solution in hexane, 0.6 mL; 0.99 mmol) was
added dropwise to a solution of thiophene (0.072 mL;
0.9 mmol) in a mixture of 3 mL of dry toluene and 1 mL of
THF at À78 °C under argon atmosphere to give 2-
lithiothiophene. After 30 min, this solution was added to
a solution of carbenoid 7 through a cannula. Temperature
of the reaction mixture was gradually allowed to warm to
À10 °C. The reaction was quenched by satd aq NH4Cl and
the whole was extracted with CHCl3. The organic layer
was dried over MgSO4 and concentrated in vacuo. The
residue was purified by silica gel flash column chromatog-
raphy to give 8a (55 mg; 78%) as a colorless oil; IR (neat)
3104, 2949, 2881, 1648, 1432, 1120, 1082, 1034, 907, 761,
Table 4 shows the above-mentioned synthesis of thio-
phenes having a fully substituted olefin at the 2-position
by combination of three components, 1-chlorovinyl p-
tolyl sulfoxide 6, 2-lithiothiophenes, and iodomethane.
From the results shown in Table 4, it is recognized that
the method mentioned above is applicable to various
thiophenes. Comparing the yields shown in Table 4 with
those in Table 2, it is obvious that the methylation with
the alkenylmagnesium intermediates proceeded in high
yields.
Finally, the substrate scope of this reaction was investi-
gated using various 1-chlorovinyl p-tolyl sufoxides with
2-lithiothiophene and the results are shown in Table 5.
1-Chlorovinyl p-tolyl sulfoxides prepared from cyclo-
pentadecanone and cyclohexanone gave the desired
products 12a and 12b, respectively, in good yields
(entries 1 and 2). Low stereospecificity was observed in
the reaction with geometrical isomers 2c and 2d (entries
3 and 4). E-Vinyl sulfoxide 2c gave Z-olefin 12c as main
product. In contrast to this, Z-vinyl sulfoxide 2d mainly
gave E-olefin 12d.15
1
693 cmÀ1; H NMR d 1.76 (4H, dt, J = 6.5, 5.5 Hz), 2.42
(2H, t, J = 6.6 Hz), 2.70 (2H, t, J = 6.6 Hz), 3.99 (4H, s),
6.36 (1H, s), 6.89 (1H, d, J = 3.4 Hz), 6.97 (1H, dd,
J = 5.1, 3.5 Hz), 7.19 (1H, d, J = 5.1 Hz). MS m/z (%) 236
(M+, 100), 207 (40), 192 (9), 191 (13), 174 (17), 163 (10),
149 (12), 135 (30), 121 (14). Calcd for C13H16O2S: M,
236.0869. Found: m/z 236.0864.
In conclusion, we found that the reaction of magnesium
alkylidene carbenoids 2 with 2-lithiothiophenes gave
thiophenes having an olefin at the 2-position in good
yields. Intermediates of these reactions were found to
be alkenylmagnesiums and these were trapped with
several electrophiles to give thiophenes having fully
substituted olefins. The results described in this paper
contribute further development of the chemistry of mag-
nesium carbenoid and also new synthesis of 2-alkenyl-
ated thiophenes.
13. (a) Satoh, T.; Takano, K.; Ota, H.; Someya, H.; Matsuda,
K.; Koyama, M. Tetrahedron 1998, 54, 5557; (b) Wata-
nabe, M.; Nakamura, M.; Satoh, T. Tetrahedron 2005, 61,
4409.
14. To a solution of 6 (98 mg; 0.3 mmol) in 6 mL of dry
toluene in a flame-dried flask at À78 °C under argon
atmosphere was added t-BuMgCl (1.0 M solution in THF,
0.04 mL; 0.04 mmol) dropwise with stirring. After 10 min,
i-PrMgCl (2.0 M solution in THF, 0.42 mL; 0.84 mmol)
was added dropwise to the reaction mixture to give
magnesium alkylidene carbenoid 7. In an another flask, n-
BuLi (1.65 M solution in hexane, 0.6 mL; 0.99 mmol) was
added dropwise to a solution of thiophene (0.072 mL;
0.9 mmol) in a mixture of 3 mL of dry toluene and 1 mL of
THF at À78 °C under argon atmosphere to give 2-
lithiothiophene. After 30 min, this solution was added to
a solution of carbenoid 7 through a cannula. Temperature
of the reaction mixture was gradually allowed to warm to
À10 °C. Copper iodide (2.9 mg; 0.015 mmol) was added to
the reaction mixture and was stirred for 10 min. Iodo-
methane (0.056 mL; 0.9 mmol) was added dropwise to the
reaction mixture. The reaction mixture was gradually
allowed to warm to room temperature, and then was
stirred for 1 h at room temperature. The reaction was
quenched by satd aq NH4Cl and the whole was extracted
with CHCl3. The organic layer was dried over MgSO4 and
concentrated in vacuo. The residue was purified by silica
References and notes
1. USP Dictionary of USAN and International Drug Names,
US Pharmacopeia: Rockville, Meryland, 2002.
2. (a) MacDiarmid, A. G. Angew. Chem., Int. Ed. 2001, 40,
2581; (b) Heeger, A. J. Angew. Chem., Int. Ed. 2001, 40,
2591; (c) Iyoda, M.; Nishinaga, T. In The Frontiers of
Sulfur Chemicals; Nakayama, J., Ed.; CMC Press: Tokyo,
2007.
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2005, 46, 6159.
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Nogueira, C. W. Tetrahedron Lett. 2004, 45, 4823.

T. Satoh et al. / Tetrahedron Letters 48 (2007) 6453–6457
6457
gel flash column chromatography to give 10 (E = CH3)
(53.9 mg; 72%) as colorless crystals; mp 54–54.5 °C
(AcOEt–hexane); IR (KBr) 2947, 2880, 1438, 1364, 1232,
(M+, 100), 235 (21), 221 (26), 205 (15), 191 (25), 173 (15),
163 (22), 149 (47), 135 (27), 121 (12), 99 (23). Calcd for
C14H18O2S: M, 250.1025. Found: m/z 250.1024. Anal.
Calcd for C14H18O2S: C, 67.13; H, 7.23; S, 12.78. Found:
C, 67.17; H, 7.25; S, 12.81.
1124, 1097, 1034, 900, 764, 693 cmÀ1 1H NMR d 1.64
;
(2H, t, J = 6.4 Hz), 1.76 (2H, t, J = 6.4 Hz), 2.04 (3H, s),
2.40 (2H, t, J = 6.8 Hz), 2.47 (2H, t, J = 6.8 Hz), 3.97 (4H,
s), 6.75 (1H, dd, J = 3.6, 1.3 Hz), 6.96 (1H, dd, J = 5.0,
3.4 Hz), 7.20 (1H, dd, J = 5.1, 1.1 Hz). MS m/z (%) 250
15. Structure of products 12c and 12d was determined with
their NOESY spectrum.