Mendeleev Commun., 2002, 12(1), 19–20
A novel transformation of 2-acetylthiophene and its halogen derivatives under
Vilsmeier reaction conditions
Valerii Z. Shirinian,* Leonid I. Belen’kii and Mikhail M. Krayushkin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 137 6939; e-mail: shir@ioc.ac.ru
10.1070/MC2002v012n01ABEH001529
Under conditions of the Vilsmeier reaction either β-chloro-β-(2-thienyl)acrylic aldehydes or N,N-dimethyl-2-thiophenecarboxamides
can be synthesised from 2-acetylthiophenes depending on the reaction temperature and time.
The Vilsmeier reaction is a general procedure for introducing
R2
an aldehyde group into activated aromatic rings.1–3 This method
has been widely used for the synthesis of various aldehyde
60–100 °C
Cl
R1
derivatives of benzene, thiophene, furan, pyrrole etc., via a
complex derived from DMF and POCl3, SOCl2 or COCl2. The
Vilsmeier complex is also used as a halogenating and dehydrating
agent.4–6 In particular, the dehydration of N-monosubstituted
formamides by DMF–POCl3 is a simple procedure for the syn-
thesis of isonitriles.4 Specific transformations under the action of
Vilsmeier’s reagent are known, e.g., the synthesis of previously
unknown amidomercaptals from the 2-thienyl sulfides or alkane-
thiols.5,6 Interesting synthetic possibilities are offered by the
joint action of Vilsmeier’s reagent and hydride reductants.7
In addition to the electrophilic formylation of aromatic com-
pounds, Vilsmeier’s reagent has been also widely used in reac-
tions with carbonyl compounds.8 Arnold and Zemlicka9,10 found
that the reaction of Vilsmeier’s reagent with ketones containing
methyl or methylene groups adjacent to the carbonyl group
affords substituted β-chloroacrylaldehydes. The reaction can be
used for the preparation of β-chloroacrylaldehydes from ketones
including aryl alkyl ketones.8 The reaction proceeds on the
addition of a ketone to Vilsmeier’s reagent at 5–10 °C followed
by heating the reaction mixture at 60 to 100 °C up to the
complete transformation into β-chloroacrylaldehyde.
S
O
R2
2a–c
DMF/POCl3
R1
S
R2
O
> 120 °C
1a–c
N
R1
S
O
–
3a c
1–3: a R1 = R2 = H
b R1 = H, R2 = Br
1c, 2c R1 = R2 = Br
3c R1 = Cl, R2 = Br
Scheme 1
of β-chloroacrylaldehydes from acetylthiophenes and Vilsmeier’s
reagent at 60–100 °C was described.8,17,18 In particular, 3-chloro-
3-(2-thienyl)propenal was obtained in 11% yield by treatment
of 2-acetylthiophene with Vilsmeier’s reagent at 60 °C.17 The
formation of both 3-chloro-3-(2-thienyl)propenal and N,N-di-
methylthiophene-2-carboxamide in the ratio ~1:1 on the heating
of 2-acetylthiophene with Vilsmeier’s reagent for 1 h instead of
3 h§ may indirectly indicate that β-chloroacrylaldehydes are inter-
However, we found that 2-acetylthiophenes 1a–c heated
with Vilsmeier’s reagent above 120 °C afforded N,N-dimethyl-
thiophene-2-carboxamides 3a–c rather than expected β-chloro-
acrylaldehydes 2a–c (Scheme 1).†
‡
N,N-Dimethylthiophene-2-carboxamide 3a: yield 41%, mp 44–45 °C
The structures of amides 3a–c were found from spectroscopic
data and the results of elemental analyses,‡ in the case of 3a the
characteristics were compared with published data. The structure
of amide 3b was found by spectrometric techniques, elemental
analysis and through its independent synthesis from known
4-bromothiophene-2-carboxylic acid.15 As to the replacement
of bromine by a chlorine atom on the interaction of 2-acetyl-
4,5-dibromothiophene 1c with Vilsmeier’s reagent, the preparation
of 5-chlorothiophene-2-carbaldehyde by the reaction of 2-bromo-
thiophene with N-methylformanilide and POCl3 at 100 °C should
be mentioned.16 Note that there is a weak parent peak (m/z 313)
of N,N-dimethyl-4,5-dibromothiophene-2-carboxamide in the
mass spectrum of unpurified amide 3c.
(from light petroleum, lit.,12 mp 44–45 °C). 1H NMR [200 MHz,
(CD3)2CO] d: 3.18 (br. s, 6H, Me2N), 7.09 (dd, 1H, 4-H), 7.43 (dd, 1H,
3-H), 7.62 (dd, 1H, 5-H); J45 4.8 Hz, J34 3.7 Hz, J35 1.1 Hz (cf. ref. 13).
MS (EI, 70 eV), m/z (%): 155 (46) [M]+, 111 (100) [M – NMe2]+.
N,N-Dimethyl-4-bromothiophene-2-carboxamide 3b: yield 39%, mp 98–
1
100 °C (from heptane). H NMR (200 MHz, CDCl3) d: 3.21 (br. s, 6H,
Me2N), 7.25 (s, 1H, 5-H), 7.38 (s, 1H, 3-H). 13C NMR (50 MHz, CDCl3)
d: 30.85 (Me), 109.12 (C–Br), 126.36 [C(3)], 131.12 [C(5)], 139.21
[C(2)], 162.80 (C=O). MS (EI, 70 eV), m/z (%): 235 (59) [M]+, 191 (99)
[M – NMe2]+. Found (%): C, 36.41; H, 3.83; Br, 33.78; S, 13.55; N, 6.24.
Calc. for C7H8BrNOS (%): C, 35.91; H, 3.44; Br, 34.13; S, 13.7; N, 5.98.
N,N-Dimethyl-4-bromo-5-chlorothiophene-2-carboxamide 3c: yield 47%,
mp 75–76 °C (from heptane). 1H NMR (200 MHz, CDCl3) d: 3.19 (br. s,
6H, Me2N), 7.13 (s, 1H, 3-H). 13C NMR (50 MHz, CDCl3) d: 34.74
(Me), 35.37 (Me), 98.92 (C–Cl), 107.48 (C–Br), 128.34 [C(3)], 133.96
[C(2)], 159.35 (C=O). MS (EI, 70 eV), m/z (%): 271 (11) [M]+, 269 (38)
[M]+, 267 (24) [M]+, 227 (24) [M – NMe2]+, 225 (78) [M – NMe2]+, 223
(64) [M – NMe2]+. Found (%): C, 31.32; H, 2.52; Br, 30.32; Cl, 13.46;
S, 12.17; N, 4.39. Calc. for C7H7BrClNOS (%): C, 31.22; H, 2.60; Br,
29.74; Cl, 13.19; S, 11.89; N, 5.24. Found (by the Schöniger14 method)
(%): S, 10.81. Calc. for C7H7BrClNOS (%): S, 11.89.
The mechanism of this novel transformation remains unclear.
The reaction likely involves many steps (Scheme 2) and in-
cludes the formation of intermediate 6, which is analogous to
key compounds yielding β-chloroacrylaldehydes.8 The formation
†
Preparation of N,N-dimethylthiophene-2-carboxamides 3a–c (general
procedure). Phosphorus oxychloride (2.5 ml, 4.1 g, 0.027 mol) was added
dropwise to DMF (8.5 ml, 8.2 g, 0.11 mol) cooled to 0–10 °C. The mix-
ture was kept for 15 min at this temperature, then for 15 min at 45–50 °C
and cooled again to 0–10 °C; a starting 2-acetylthiophene (0.024 mol)
was added. (2-Acetylthiophene was purchased from Aldrich, 2-acetyl-
4-bromothiophene 1b and 2-acetyl-4,5-dibromothiophene 1c were pre-
pared according to the published procedure.11) The reaction mixture was
gradually heated to 120–130 °C and kept at this temperature for 2.5–3 h.
After cooling, CH2Cl2 (50 ml) was added, and the organic layer was
washed successively with concentrated AcONa and NaHCO3 solutions
and finally with water. The residue after evaporation of the extract was
recrystallised from a suitable solvent.
§
On the interaction of 2-acetylthiophene 1a with Vilsmeier’s reagent at
100–120 °C for 1 h, the residue (2.06 g of a yellow oil) obtained after
evaporation of the solvent was chromatographed on silica gel (light
petroleum–EtOAc, 2.5:1, as an eluent) to give two substances. After
recrystallization from light petroleum the following compounds were
obtained: 3-chloro-3-(2-thienyl)propenal 2a, 0.75 g (yield 21%), mp 54–
1
55 °C (lit.,17 55–57 °C). H NMR (200 MHz, CDCl3) d: 6.55 (d, 1H,
C=CH, J 3.6 Hz), 7.08 (dd, 1H, 4-H, J45 4.8 Hz, J34 3.7 Hz), 7.51 (dd,
1H, 5-H, J35 1.2 Hz), 7.61 (m, 1H, 3-H), 10.08 (d, 1H, CH=O, J 6.05 Hz).
Amide 3a, 0.92 g (yield 25%), identical to the above substance mp and
1H NMR spectrum.
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