A convenient synthesis of 2,3,4,5-functionalised thieno[2,3-b]thiophenes

Article abstract of DOI:10.1055/s-2003-38080

A two steps simple synthesis of 2,3,4,5-functionalised thieno[2,3-b]thiophenes 2-6 from ketene dimethylthioacetals is described.

Full text of DOI:10.1055/s-2003-38080

PAPER
735
A Convenient Synthesis of 2,3,4,5-Functionalised Thieno[2,3-b]thiophenes
F
unctionalisedThi
e
eno[2,3-
b
]t
o
hiophenes ffroy Sommen, Alain Comel, Gilbert Kirsch*
Laboratoire d’Ingénierie Moléculaire et Biochimie Pharmacologique, Faculté des Sciences, Ile du Saulcy, 57045 Metz Cedex, France
E-mail: kirsch@sciences.univ-metz.fr
Received 5 December 2002; revised 18 January 2003
Abstract: A two steps simple synthesis of 2,3,4,5-functionalised
thieno[2,3-b]thiophenes 2–6 from ketene dimethylthioacetals is de-
scribed.
Key words: bicyclic compounds, chemoselectivity, cyclisation,
heterocycles, thiols
Scheme 2
Substituted thieno[2,3-b]thiophenes and the methods of
their preparation are known since the 50s. One of the most
Other methylene active thiols can be used but they are not
commercially available and their preparation reduces sig-
nificantly the applications of the method, even if the
yields observed for each step were good to excellent with
ethyl thioglycolate.
recent synthetic pathways for their preparation is based on
the cyclisation of ketene dithioacetals, obtained from car-
bon disulfide, in basic media.1a–e The ketene dithioacetal
dipotassium salt intermediates are reacted generally with
the same methylene active halide or in combination with
methyl iodide in order to obtain 5-methylsulfanylth-
iophenes.1c,e The use of two different halides should lead
to a mixture of symmetrical and unsymmetrical
thieno[2,3-b]thiophenes barely separable and is not re-
ported in the literature.
We have described2 recently the formation of thiophenes
from ketene phenylaminomethylthioacetals using ethyl
thioglycolate in a basic medium (K2CO3/EtOH). The abil-
ity of thioglycolate to replace a methylsulfanyl group of
ketene dimethylthioacetals has been investigated and we
have selectively prepared 5-methylsulfanylthiophenes in
excellent yields (Scheme 1, Table 1).
Finally, we chose to use Na2S and a halide in order to pre-
pare 5-methylsulfanylthiophenes bearing a group other
than the ethoxycarbonyl group obtained with the use of
ethyl thioglycolate (see Scheme 1). This strategy allowed
us to avoid the tedious synthesis and use of other thiols for
the formation of thiophenes 1. This reaction is generally
well known and used for the preparation of thiophenes5
but was not described for such compounds. Various ex-
pected thiophenes have been successfully isolated in mod-
erate to good yields. The decrease in yield can be in
particular attributed to the formation of symmetrical sul-
fide. At this stage, two different ways can lead to unsym-
metrical thieno[2,3-b]thiophenes. The first one consists in
reacting the thiophenes 1, obtained from a ketene dimeth-
ylthioacetal and the appropriate halide in the presence of
sodium sulfide, with ethyl thioglycolate and potassium
carbonate as the condensation promoter. The second one
is almost the same, ethyl thioglycolate and the system ha-
lide/sodium sulfide being exchanged in the two steps of
this synthetic path (see Schemes 1 and 3). These two dif-
ferent ways have been investigated (see Table 2) but we
preferred the second one for practical reasons.
According
to
our
recent
work
on
5-
methylsulfanylpyrroles3 (see Scheme 2), we decided to
remove the remaining methylsulfanyl group with a second
equivalent of ethyl thioglycolate under previous condi-
tions, although this way leads only to symmetrical
thieno[2,3-b]thiophenes that can be prepared following a
much easier one-pot procedure.4
Scheme 1
Synthesis 2003, No. 5, Print: 01 04 2003.
Art Id.1437-210X,E;2003,0,05,0735,0741,ftx,en;Z15402SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

736
G. Sommen et al.
PAPER
Scheme 3
Table 1 Synthesis of Thiophenes 1
Entry
Compound
Yield (%)
95a or 60b
Entry
Compound
Yield (%)
43a,c
Ac
Me
NC
1a
1i
OH
CO2Et
Me
CO2Et
NH2
MeS
Ac
S
MeS
NC
S
1b
1c
1d
1e
1f
17b
68b
43b
37b
65a
50b
43a,c
1j
95a
17b
15b
75a
80b
96b
64a
CHO
Me
CO2Et
NH2
MeS
Ac
S
S
S
S
MeS
NC
S
S
S
S
S
S
S
1k
1l
Bz
Me
CHO
NH2
MeS
Ac
MeS
NC
Ac
Me
Bz
Ph
MeS
Ac
MeS
Bz
1m
1n
1o
1p
CN
CH3
CO2Et
Ph
MeS
MeS
Bz
EtO2C
CO2Et
CH3
Ac
Ph
MeS
MeS
Bz
S
S
S
1g
1h
EtO2C
Ac
NH2
CN
OH
MeS
MeS
EtO2C
EtO2C
CO2Et
CO2Et
MeS
MeS
a Obtained with ethyl thioglycolate.
b Obtained with Na2S/appropriate halide.
c Separated by acid and base treatment.
We have noticed that the yields obtained with ethyl compound 2c has been obtained in similar overall yields
thioglycolate are generally significantly higher than with using thioglycolate in the first step (2c from 1a) or in the
Na2S and we systematically used thioglycolate, for practi- second one (2c from 1e). Nevertheless, we demonstrated
cal reasons, in one of the two steps needed for the prepa- that thieno[2,3-b]thiophenes could be obtained in two dif-
ration of the thieno[2,3-b]thiophenes. We did not ferent manners using our strategy.
investigate whether or not the thioglycolate has to be used
in the first or second step of our synthetic method but
pared from ethyl acetoacetate (unsymmetrical starting
Finally, we focused on compounds 3d and 4d both pre-
Synthesis 2003, No. 5, 735–741 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Functionalised Thieno[2,3-b]thiophenes
737
Table 2 Synthesis of Thieno[2,3-b]thiophenes 2–6 from Thiophenes 1
Entry
Starting Compound
Reagents
Product
Yield (%)
Ac
2a
ethyl thioglycolate or
Na2S/ethyl bromoacetate
73
47
Me
Me
Me
EtO2C
OHC
CO2Et
CO2Et
CO2Et
MeS
Ac
S
S
S
2b
2c
2c
2d
2e
3d
Na2S/chloroacetaldehyde
Na2S/bromoacetophenone
ethyl thioglycolate
61
55
96
85
69
85
Me
Me
Me
CO2Et
Me
MeS
Ac
S
S
S
S
S
S
S
S
Me
Me
Bz
Bz
Ac
NC
CO2Et
CO2Et
Me
MeS
Ac
S
S
Me
Me
CO2Et
CO2Et
CO2Et
Bz
Me
MeS
Ac
S
S
Na2S/chloroacetone
Me
Me
CO2Et
Me
MeS
Ac
S
S
Na2S/chloroacetonitrile
Na2S/chloroacetone
Me
Me
CO2Et
CH3
MeS
S
S
EtO2C
HO
CH3
Ac
CO2Et
CO2Et
CH3
MeS
S
S
4d
5e
6d
6e
ethyl thioglycolate
93
81
86
85
EtO2C
HO
CH3
EtO2C
H2N
Ac
CO2Et
CO2Et
CO2Et
Ac
NH2
MeS
NC
S
S
S
S
S
S
Na2S/chloroacetonitrile
Na2S/chloroacetone
Na2S/chloroacetonitrile
NH2
NC
CO2Et
Ph
MeS
Bz
S
S
S
S
Ph
Ph
Ph
Ac
CO2Et
Ph
MeS
Bz
S
Ph
NC
CO2Et
MeS
S
Ketene Dithioacetals; General Procedure
material). In this particular case, we clearly demonstrated
that the order of the sequence Na2S/chloroacetone/ethyl
thioglycolate allowed to fully control the substituents in
the 2 and 5 position of the resulting thieno[2,3-
b]thiophenes. Our synthetic way appeared to be regiospe-
cific which greatly simplified the purification process.
A 250 mL three-necked round-bottom flask equipped with magnet-
ic stirrer, condenser and septum was charged with a solution of 1,3-
diketone (100 mmol) in DMF (100 mL). Dried K2CO3 (13.8 g, 100
mmol) was added and the mixture was stirred for 2 h at r.t. CS2 (18.0
mL, 300 mmol) was added and the mixture was stirred for 2 h at r.t.
MeI (12.5 mL, 200 mmol) was then added and the mixture was
stirred for 4 h before being poured onto H2O (400 mL). The precip-
itated crude product was purified by filtration followed by crystalli-
sation from EtOH. When the product was an oil, the organic phase
was extracted with Et2O (3 × 100 mL). The combined organic ex-
tracts were washed with H2O (2 × 100 mL), dried (MgSO4), and
concentrated in vacuo.
In summary, we have described the first general and selec-
tive access to 2,3,4,5 functionalised thieno[2,3-
b]thiophenes using a two steps strategy based on the reac-
tivity of ketene dithioacetals towards thiols or equivalents
(Na2S/halides).
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738
G. Sommen et al.
PAPER
Thiophenes 1; General Procedures
13C NMR (62.5 MHz, CDCl3): δ = 16.3 (CH3), 18.4 (CH3), 30.2
(CH2), 31.3 (CH2), 134.6 (C), 139.1 (C), 144.3 (C), 155.1 (C), 189.9
(CO), 195.6 (CO).
Method A, Using Ethyl Thioglycolate: A 100 mL three-necked
round-bottom flask equipped with magnetic stirrer, condenser and
septum was charged with a solution of ethyl thioglycolate (1.1 mL,
10 mmol) in EtOH (30 mL). A dithioacetal (10 mmol) and dried
K2CO3 (1.38 g, 10 mmol) was added in one portion. The mixture
was stirred under reflux for 6 h and then the reaction was quenched
with H2O (100 mL). The precipitated crude product was purified by
filtration followed by crystallisation in EtOH.
Anal. Calcd for C10H12O2S2: C, 52.60; H, 5.30. Found: C, 52.55; H,
5.28.
4-Acetyl-3-methyl-5-methylsulfanylthiophene-2-carbonitrile
(1e)
Mp 114 °C.
Method B, Using Na2S: A 100 mL three-necked round-bottom flask
equipped with magnetic stirrer, condenser and septum was charged
with a solution of Na2S (2.40 g, 10 mmol) in DMF (30 mL). This
mixture was heated to 50 °C until dissolution and then an appropri-
ate dithioacetal (10 mmol) was added. After stirring for 1 h at 50 °C
the alkylating agent (10 mmol) was added and stirred for 0.5 h.
Dried K2CO3 (1.38 g, 10 mmol) was added and the mixture was
stirred for 6 h at 50 °C. The reaction was quenched with H2O (100
mL) and the crude product precipitated was purified by filtration
followed by crystallisation from EtOH.
IR (KBr): 2206, 1637 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.43 (s, 3 H), 2.47 (s, 3 H), 2.56
(s, 3 H).
13C NMR (62.5 MHz, CDCl3): δ = 14.4 (CH3), 17.1 (CH3), 30.5
(CH3), 113.1 (CN), 122.2 (C), 123.4 (C), 142.7 (C), 149.4 (C),
192.7 (CO).
Anal. Calcd for C9H9NOS2: C, 51,16; H, 4,29; N, 6,63. Found: C,
51.18; H, 4.26; N, 6.63.
Diethyl 3-Methyl-5-methylsulfanylthiophene-2,4-dicarboxy-
late (1f)
Mp 89 °C.
IR (KBr): 1682, 1630 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.34 (t, 3 H, J = 7.1 Hz), 2.58 (s,
3 H), 2.82 (s, 3 H), 4.28 (q, 2 H, J = 7.1 Hz).
13C NMR (62.5 MHz, CDCl3): δ = 14.3 (CH3), 15.4 (CH3), 17.9
(CH3), 60.7 (CH2), 60.8 (CH2), 123.8 (C), 127.1 (C), 148.5 (C),
157.9 (C), 161.7 (CO2), 163.6 (CO2).
Ethyl 4-Acetyl-3-methyl-5-methylsulfanylthiophene-2-carbox-
ylate (1a)
Mp 79 °C.
IR (KBr): 1701, 1706 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.36 (t, 3 H, J = 7.2 Hz), 2.55 (s,
3 H), 2.57 (s, 3 H), 2.73 (s, 3 H), 4.31 (q, 2 H, J = 7.2 Hz).
13C NMR (62.5 MHz, CDCl3): δ = 13.6 (CH3), 14.7 (CH3), 17.6
(CH3), 30.3 (CH3), 60.2 (CH2), 123.3 (C), 136.3 (C), 139.9 (C),
145.3 (C), 156.3 (C), 160.6 (CO2), 193.2 (CO).
Anal. Calcd for C12H16O4S2: C, 49.98; H, 5.59; N, 4.62. Found: C,
50.02; H, 5.63; N, 4.58.
Anal. Calcd for C11H14O3S2: C, 51.14; H, 5.46. Found: C, 51.21; H,
5.36.
Ethyl 2-Acetyl-3-Methyl-5-methylsulfanylthiophene-4-carbox-
ylate (1g)
Mp 87 °C.
IR (KBr): 1725, 1698 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1,39 (t, 3 H, J = 7.2 Hz), 2.50 (s,
3 H), 2.58 (s, 3 H), 2.72 (s, 3 H), 4,36 (q, 2 H, J = 7.2 Hz).
13C NMR (62.5 MHz, CDCl3): δ = 14.2 (CH3), 16.0 (CH3), 18.0
(CH3), 60.9 (CH2), 127.8 (C), 134.5 (C), 146.7 (C), 158.3 (C), 163.6
(CO2), 189.8 (CO).
4-Acetyl-3-methyl-5-methylsulfanylthiophene-2-carbaldehyde
(1b)
Mp 100 °C.
IR (KBr): 1659, 1633 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.56 (s, 3 H), 2.60 (s, 3 H), 2.72
(s, 3 H), 9.96 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): δ = 14.9 (CH3), 18.7 (CH3), 31.2
(CH3), 123.2 (C), 134.3 (C), 135.5 (C), 136.8 (C), 147.2 (C), 180.6
(CHO), 193.9 (CO).
Anal. Calcd for C11H14O3S2: C, 51.14; H, 5.46. Found: C, 51.23; H,
5.40.
Anal. Calcd for C9H10O2S2: C, 50.44; H, 4.70. Found: C, 50.46; H,
4.68.
Diethyl 3-Amino-5-methylsulfanylthiophene-2,4-dicarboxylate
(1h)
Mp 103 °C.
IR (KBr): 3502, 3353, 1685, 1663 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.33 (t, 3 H, J = 7.2 Hz), 1.40 (t,
3 H, J = 7.2 Hz), 2.55 (s, 3 H), 4.26 (q, 2 H, J = 7.2 Hz), 4.36 (q, 2
H, J = 7.2 Hz), 6.84 (s, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 14.5 (CH3), 14.8 (CH3), 17.0
(CH3), 59.8 (CH2), 60.7 (CH2), 114.0 (C), 155.4 (C), 155.5 (C),
160.4 (C), 163.3 (CO2), 163.4 (CO2).
1-(5-Benzoyl-4-methyl-2-methylsulfanylthiophen-3-yl)ethan-
one (1c)
Mp 104 °C.
IR (KBr): 1611, 1636 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.53 (s, 3 H), 2.55 (s, 3 H), 2.57
(s, 3 H), 7.38–7.88 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): δ = 17.2 (CH3), 18.7 (CH3), 31.3
(CH3), 128.0 (2 CH), 128.4 (CH), 128.5 (C), 128.9 (C), 132.4 (2
CH), 133.8 (C), 139.5 (C), 144.6 (C), 188.7 (CO), 195.2 (CO).
Anal. Calcd for C15H14O2S2: C, 62.04; H, 4.86. Found: C, 62.19; H,
4.69.
Anal. Calcd for C11H14O3S2: C, 45.66; H, 5.22; N, 4.84. Found: C,
45.56; H, 5.20; N, 4.70.
1-(4-Acetyl-3-methyl-5-methylsulfanylthiophen-2-yl)ethanone
(1d)
Mp 80 °C.
IR (KBr): 1649, 1648 cm–1.
Ethyl 4-Cyano-3-hydroxy-5-methylsulfanylthiophene-2-car-
boxylate (1i)
Mp 110 °C.
IR (KBr): 3292, 2222, 1664 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.50 (s, 3 H), 2.54 (s, 3 H), 2.60
(s, 3 H), 2.69 (s, 3 H).
Synthesis 2003, No. 5, 735–741 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Functionalised Thieno[2,3-b]thiophenes
739
1H NMR (250 MHz, CDCl3): δ = 1.30 (t, 3 H, J = 7.2 Hz), 2.74 (s,
3 H), 4.34 (q, 2 H, J = 7.2 Hz), 9.86 (s, 1 H).
1H NMR (250 MHz, CDCl3): δ = 1.93 (s, 3 H), 2.59 (s, 3 H), 7.19–
7.60 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): δ = 14.3 (CH3), 17.4 (SCH3), 61.7
(CH2), 100.0 (C), 102.0 (C), 111.3 (CN), 159.3 (C), 163.7 (CO2),
164.3 (C).
13C NMR (62.5 MHz, CDCl3): δ = 19.1 (CH3), 28.9 (CH3), 127.1
(CH), 128.2 (2 CH), 128.5 (2 CH), 129.5 (2 CH), 129.8 (2 CH),
133.1 (CH), 134.4 (C), 137.2 (C), 140.0 (C), 140.1 (C), 146.0 (C),
150.3 (C), 191.1 (CO), 192.5 (CO).
Anal. Calcd for C9H9NO3S2: C, 44.43; H, 3.73; N, 5.76. Found: C,
44.26; H, 3.78; N, 5.66.
Anal. Calcd for C20H16O2S2: C, 68.15; H, 4.58. Found: C, 68.06; H,
4.44.
Ethyl 3-Amino-4-cyano-5-methylsulfanylthiophene-2-carboxy-
late (1j)
4-Benzoyl-5-methylsulfanyl-3-phenylthiophene-2-carboni-
Mp 147 °C.
trile(1o)
Mp 89 °C.
IR (KBr): 2204, 1651 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.58 (s, 3 H), 7.19–7.60 (m, 10 H).
IR (KBr): 3445, 3339, 2220, 1672 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.34 (t, 3 H, J = 7.2 Hz), 2.64 (s,
3 H), 4.30 (q, 2 H, J = 7.2 Hz), 5.76 (s, 2 H).
13C NMR (62.5 MHz, CDCl3): δ = 14.4 (CH3), 16.8 (CH3), 60.2
(CH2), 112.7 (CN), 148.7 (C), 154.2 (C), 159.5 (C), 162.1 (C),
163.6 (CO2).
13C NMR (62.5 MHz, CDCl3): δ = 19.4 (CH3), 113.5 (CN), 127.0
(CH), 127.6 (C), 128.3 (2 CH), 128.4 (2 CH), 128.5 (C), 128.7 (2
CH), 129.1 (CH), 129.4 (2 CH), 132.1 (C), 133.3 (C), 136.5 (C),
152.1 (C), 191.4 (CO).
Anal. Calcd for C9H10N2O2S2: C, 44.61; H, 4.16; N, 11.56. Found:
C, 44.65; H, 4.13; N, 11.57.
Anal. Calcd for C19H13NO2S2: C, 68,03; H, 3,91; N, 4,18. Found: C,
68.13; H, 3.71; N, 4.10.
4-Amino-5-formyl-2-methylsulfanylthiophene-3-carbonitrile
(1k)
Diethyl 3-Hydroxy-5-methylsulfanylthiophene-2,4-dicarboxy-
Mp 173 °C.
late (1p)
Mp 96 °C.
IR (KBr): 1688, 1659 cm–1.
IR (KBr): 2208, 1609 cm–1.
1H NMR (250 MHz, CDCl3): δ = 2.71 (s, 3 H), 7.47 (s, 2 H), 9.66
(s,1 H).
1H NMR (250 MHz, CDCl3): δ = 1.15 (t, 3 H, J = 7.1 Hz), 1.25 (t,
3 H, J = 7.1 Hz), 2.45 (s,3 H), 4.02 (q, 2 H, J = 7.1 Hz), 4.14 (q, 2
H, J = 7.1 Hz).
13C NMR (62.5 MHz, CDCl3): δ = 13.9 (CH3), 14.0 (CH3), 16.5
(CH3), 60.5 (CH2), 61.3 (CH2), 102.2 (C), 114.3 (C), 154.6 (C),
162.0 (C), 163.3 (CO2), 167.0 (CO2).
13C NMR (62.5 MHz, CDCl3): δ = 16.9 (CH3), 97.5 (C), 110.8 (C),
110.9 (CN), 142.5 (C), 155.2 (C),165.1 (CHO).
Anal. Calcd for C7H6N2OS2: C, 42.40; H, 3.05; N, 14.13. Found: C,
42.38; H, 3.06; N, 14.21.
4-Amino-5-benzoyl-2-methylsulfanylthiophene-3-carbonitrile
(1l)
Anal. Calcd for C11H14O5S2: C, 45.50; H, 4.86. Found: C, 45.46; H,
4.76.
Mp 209 °C.
Thieno[2,3-b]thiophenes 2–6; General Procedure
IR (KBr): 2200, 1603 cm–1.
Method A, Using Ethyl Thioglycolate: A 100 mL three-necked
round-bottom flask equipped with magnetic stirrer, condenser and
septum was charged with a solution of ethyl thioglycolate (1.1 mL,
10 mmol) in EtOH (30 mL). The appropriate 5-methylsulfanyl-
thiophene 1 (10 mmol) and dried K2CO3 (1.38 g, 10 mmol) was add-
ed in one portion. The mixture was stirred under reflux for 6 h and
then the reaction was quenched with H2O (100 mL). The precipitat-
ed crude product was purified by filtration followed by crystallisa-
tion from EtOH.
1H NMR (250 MHz, DMSO-d6): δ = 3.23 (s, 3 H), 7.45–7.61 (m, 5
H), 7.93 (s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 39.7 (CH3), 90.6 (C), 112.6
(CN), 123.8 (2 CH), 125.4 (2 CH), 127.4 (CH), 128.2 (C), 138.0
(C), 156.4 (C), 163.9 (C), 180.5 (CO).
Anal. Calcd for C13H10N2OS2: C, 56.91; H, 3.67; N, 10.21. Found:
C, 57.03; H, 3.74; N, 10.14.
Method B, Using Na2S: A 100 mL three-necked round-bottom flask
equipped with magnetic stirrer, condenser and septum was charged
with a solution of Na2S (2.40 g, 10 mmol) in DMF (30 mL). This
mixture was heated to 50 °C until dissolution, before adding the ap-
propriate thiophene 1 (10 mmol). After stirring for 1 h at 50 °C, the
alkylating agent (10 mmol) was added. The mixture was stirred for
0.5 h and then dried K2CO3 (1.38 g, 10 mmol) was added. The mix-
ture was stirred for 6 h at 50 °C and the reaction was quenched with
H2O (100 mL). The precipitated crude product was purified by fil-
tration followed by crystallisation from EtOH.
Ethyl 4-Benzoyl-5-methylsulfanyl-3-phenylthiophene-2-car-
boxylate (1m)
Mp 96 °C.
IR (KBr): 1712, 1637 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.16 (t, 3 H, J = 7.2 Hz), 2.59 (s,
3 H), 4.20 (q, 2 H, J = 7.2 Hz), 7.19–7.60 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): δ = 14.0 (CH3), 19.5 (CH3), 61.1
(CH2), 126.9 (CH), 127.4 (2 CH), 127.9 (CH), 128.1 (2 CH), 129.1
(CH), 129.4 (2 CH), 129.5 (CH), 133.0 (2 CH), 134.1 (C), 137.3
(C), 142.2 (C), 147.9 (C), 192.7 (CO2), 205.6 (CO).
Diethyl 3,4-Dimethylthieno[2,3-b]thiophene-2,5-dicarboxylate
Anal. Calcd for C21H18O3S2: C, 65.94; H, 4.74. Found: C, 65.79; H,
4.74.
(2a)
Mp 142 °C (Lit.4 mp 142 °C).
IR (KBr): 2987, 2941, 1703 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.38 (t, 6 H, J = 7.1 Hz), 2.86 (s,
6 H), 4.35 (q, 4 H, J = 7.1 Hz).
1-(4-Benzoyl-5-methylsulfanyl-3-phenylthiophen-2-yl)etha-
none (1n)
Mp 134 °C.
IR (KBr): 1659, 1639 cm–1.
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13C NMR (62.5 MHz, CDCl3): δ = 14.4 (2 CH3), 21.2 (2 CH3), 61.0
(2 CH2), 130.7 (2 C), 138.9 (C), 142.6 (2 C), 152.1 (C), 176.3 (2
CO2).
1H NMR (250 MHz, CDCl3): δ = 1.42 (t, 3 H, J = 7.2 Hz), 2.47 (s,
3 H), 2.74 (s, 3 H), 4.42 (q, 2 H, J = 7.2 Hz).
13C NMR (62.5 MHz, CDCl3): δ = 13.6 (CH3), 14.8 (CH3), 17.3
(CH3), 60.2 (CH2), 121.4 (C), 123.4 (C), 126.6 (C),148.0 (C), 149.5
(C), 161.0 (COH), 162.8 (CO2), 200.8 (CO).
Anal. Calcd for C14H16O4S2: C, 53.82; H, 5.16. Found: C, 53.98; H,
5.28.
Anal. Calcd for C12H12O4S2: C, 50,69; H, 4,25. Found: C, 50.56; H,
4.29.
Ethyl 5-Formyl-3,4-dimethylthieno[2,3-b]thiophene-2-carboxy-
late (2b)
Mp 133 °C.
IR (KBr): 1668, 1709 cm–1.
Ethyl 5-Acetyl-3-hydroxy-4-methylthieno[2,3-b]thiophene-2-
carboxylate (4d)
Mp 136 °C.
IR (KBr): 1725, 1671 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.39 (t, 3 H, J = 7.2 Hz), 2.84 (s,
3 H), 2.86 (s, 3 H), 4.34 (q, 2 H, J = 7.2 Hz), 10.11 (s, 1 H).
13C NMR (62.5 MHz, CDCl3): δ = 14.2 (CH3), 14.5 (CH3), 14.6
(CH3), 61.2 (CH2), 140.7 (C), 141.5 (C), 142.0 (C), 147.6 (C), 148.7
(C), 162.2 (CO2), 181.9 (CHO).
1H NMR (250 MHz, CDCl3): δ = 1.42 (t, 3 H, J = 7.2 Hz), 2.47 (s,
3 H), 2.74 (s, 3 H), 4.42 (q, 2 H, J = 7.2 Hz).
13C NMR (62.5 MHz, CDCl3): δ = 14.2 (CH3), 16.2 (CH3), 29.7
(CH3), 61.3 (CH2), 130.5 (C), 136.0 (C), 136.2 (C), 138.5 (C), 146.8
(C), 161.8 (COH), 163.6 (CO2), 190.3 (CO).
Anal. Calcd for C12H12O2S2: C, 53.71; H, 4.51. Found: C, 53.69; H,
4.45.
Anal. Calcd for C12H12O4S2: C, 50,69; H, 4,25. Found: C, 50.50; H,
4.26.
Ethyl 5-Benzoyl-3,4-dimethylthieno[2,3-b]thiophene-2-carbox-
ylate (2c)
Mp 181 °C.
IR (KBr): 1642, 1710 cm–1.
Ethyl 3,4-Diamino-5-cyanothieno[2,3-b]thiophene-2-carboxy-
late (5e)
Mp 219 °C.
IR (KBr): 2197, 1656 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.41 (t, 3 H, J = 7.2 Hz), 2.65 (s,
3 H), 2.89 (s, 3 H), 4.36 (q, 2 H, J = 7.2 Hz),7.45–7.88 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): δ = 14.2 (CH3), 14.3 (CH3), 15.7
(CH3), 61.0 (CH2), 128.3 (2 CHarom), 129.1 (2 CHarom), 132.4
(CHarom), 137.4 (C), 138.9 (C), 139.3 (C), 140.8 (C), 145.6 (C),
147.8 (C), 149.0 (C), 162.4 (CO2), 181.6 (CO).
1H NMR (250 MHz, DMSO-d6): δ = 1.27 (t, 3 H, J = 7.2 Hz), 4.23
(q, 2 H, J = 7.2 Hz), 6.90 (s, 2 H), 7.09 (s, 2 H).
13C NMR (62.5 MHz, DMSO-d6): δ = 14.6 (CH3), 59.9 (CH2), 115.9
(CN), 126.9 (C), 128.2 (C), 147.0 (C), 148.2 (C), 148.8 (C), 150.8
(C), 163.7 (CO2).
Anal. Calcd for C18H16O3S2: C, 62.76; H, 4.68. Found: C, 62.60; H,
4.60.
Anal. Calcd for C10H9N2O2S2: C, 44.61; H, 4.16; N, 11.56. Found:
C, 44.65; H, 4.13; N, 11.57.
5-Acetyl-3,4-dimethylthieno[2,3-b]thiophene-2-carboxylate
(2d)
Mp 154 °C.
IR (KBr): 1666, 1705 cm–1.
Ethyl 5-Acetyl-3,4-diphenylthieno[2,3-b]thiophene-2-carboxy-
late (6d)
Mp 92 °C.
1H NMR (250 MHz, CDCl3): δ = 1.38 (t, 3 H, J = 7.2 Hz), 2.55 (s,
3 H), 2.88 (s, 3 H), 2.94 (s, 3 H), 4.35 (q, 2 H, J = 7.2 Hz).
13C NMR (62.5 MHz, CDCl3): δ = 13.8 (CH3), 14.0 (CH3), 14.9
(CH3), 61.1 (CH2), 130.2 (C), 139.2 (C), 139.4 (C), 141.0 (C), 144.8
(C), 147.9 (C), 162.2 (CO), 191.3 (CO).
IR (KBr): 1712, 1637 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.18 (t, 3 H, J = 7.2 Hz), 2.60 (s,
3 H), 4.19 (q, 2 H, J = 7.2 Hz), 7.11–7.59 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): δ = 13.8 (CH3), 19.3 (CH3), 60.9
(CH2), 126.6 (CH), 127.1 (2 CH), 127.5 (CH), 128.0 (2 CH), 128.8
(CH), 129.2 (2 CH), 129.3 (2 CH), 133.9 (C), 137.0 (C), 137.1 (C),
140.4 (C), 147.7 (C), 147.8 (C), 160.8 (C), 192.4 (CO2), 200.9
(CO).
Anal. Calcd for C13H14O3S2: C, 55.29; H, 5.00. Found: C, 55.22; H,
4.99.
Ethyl 5-Cyano-3,4-dimethylthieno[2,3-b]thiophene-2-carboxy-
late (2e)
Mp 171 °C.
Anal. Calcd for C23H18O3S2: C, 67.95; H, 4.46. Found: C, 67.81; H,
4.42.
IR (KBr): 2206, 1716 cm–1.
Ethyl 5-Cyano-3,4-diphenylthieno[2,3-b]thiophene-2-carboxy-
late (6e)
Mp 180 °C.
1H NMR (250 MHz, DMSO-d6): δ = 1.31 (t, 3 H, J = 7.2 Hz), 2.64
(s, 3 H), 2.77 (s, 3 H), 4.31 (q, 2 H, J = 7.2 Hz).
13C NMR (62.5 MHz, DMSO-d6): δ = 13.8 (CH3), 14.3 (CH3), 15.2
(CH3), 61.2 (CH2), 114.3 (CN), 130.7 (C), 139.7 (C), 144.4 (C),
144.5 (C), 145.7 (C), 153.3 (C), 162.0 (CO2).
IR (KBr): 2213, 1719 cm–1.
1H NMR (250 MHz, CDCl3): δ = 1.16 (t, 3 H, J = 7.2 Hz), 4.19 (q,
2 H, J = 7.2 Hz), 6.91–7.04 (m, 10 H).
Anal. Calcd for C12H11NO2S2: C, 54.32; H, 4.18; N, 5.28. Found: C,
54.41; H, 4.40; N, 5.25.
13C NMR (62.5 MHz, CDCl3): δ = 13.7 (CH3), 61.3 (CH2), 109.1
(C), 113.7 (CN), 125.8 (2 C), 126.7 (2 C), 127.9 (C), 128.1 (C),
128.5 (C), 128.9 (2 C), 128.6 (2 C), 129.0 (C), 130.4 (C), 133.2 (C),
133.4 (C), 147.6 (C), 142.0 (C), 161.1 (CO2).
Ethyl 5-Acetyl-4-hydroxy-3-methylthieno[2,3-b]thiophene-2-
carboxylate (3d)
Mp 93 °C.
IR (KBr): 1717, 1688 cm–1.
Anal. Calcd for C22H15NO2S2: C, 67.84; H, 3.88; N, 3.60. Found: C,
67.80; H, 3.90; N, 3.61.
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Functionalised Thieno[2,3-b]thiophenes
741
(2) Sommen, G.; Comel, A.; Kirsch, G. Tetrahedron Lett. 2002,
43, 257.
References
(1) (a) Mashraqui, S. H.; Hariharasubrahmanian, H.; Kumar, S.
Synthesis 1999, 2030. (b) Mashraqui, S. H.;
(3) Sommen, G.; Comel, A.; Kirsch, G. Tetrahedron, submitted.
(4) Comel, A.; Kirsch, G. J. Heterocycl. Chem. 2001, 38, 1167.
(5) The Chemistry of Heterocyclic Compounds, Part 2, Vol. 44;
Gronowitz, S., Ed.; Wiley: New York, 1986, ; and references
cited therein.
Hariharasubrahmanian, H. Synth. Commun. 2000, 30, 1695.
(c) Augustin, M.; Rudorf, W. D.; Schmidt, U. Tetrahedron
1976, 32, 3055. (d) Dalgaard, L.; Jansen, L.; Lawesson, S.
O. Tetrahedron 1974, 30, 93. (e) Gompper, R.; Kutter, E.;
Töpfl, W. Liebigs Ann. Chem. 1962, 659, 90.
Synthesis 2003, No. 5, 735–741 ISSN 0039-7881 © Thieme Stuttgart · New York