Mendeleev
Communications
Mendeleev Commun., 2008, 18, 169–170
Synthesis of 4H-thieno[3,2-c][1]benzopyran-2-carboxaldehydes
Andrey L. Katsiel, Anna N. Sharipova and Alexander S. Fisyuk*
Department of Chemistry, Omsk State University, 644077 Omsk, Russian Federation.
Fax: +7 3812 64 2410; e-mail: fis@orgchem.univer.omsk.su
DOI: 10.1016/j.mencom.2008.05.020
The title compounds were synthesised by the palladium-catalysed intramolecular cyclization of 4-(2-iodoaryloxymethyl)-
thiophene-2-carboxaldehydes.
4H-Thieno[3,2-c][1]benzopyrans are of interest due to their
Cl
anti-inflammatory and antiparkinsonian activities.1 However,
well-known synthetic methods often imply multi-step and
laborious syntheses.1,2 Surprisingly, intramolecular arylation,
which was used for the synthesis of benzopyran derivatives,3
was not employed for the preparation of 4H-thieno[3,2-c]-
chromenes. Here, we describe a new approach to the above
compounds based on such an intramolecular interaction of
4-(2-iodoaryloxymethyl)thiophene-2-carboxaldehydes.
OH
I
i
+
CHO
R
S
2a–c
1
O
CHO
R
O
ii
S
CHO
S
We developed a method for the preparation of 4-aryloxy-
I
R
methyl substituted thiophene-2-carboxaldehydes 3a–c from 4-chloro-
3a–c
4a–c
methylthiophene-2-carbaldehyde 1, which can be prepared by
the chloromethylation of commercial thiophene-2-carboxaldehyde.4
Interactions of 1 with corresponding iodophenols 2a–c give
compounds 3a–c. The reaction was performed in DMF with an
excess of potassium carbonate. The yields of 4-substituted
thiophene-2-carboxaldehydes 3a–c were 47–83% (Scheme 1).†
a R = H
b R = Cl
c R = Me
Scheme 1 Reagents and conditions: i, K2CO3, DMF, room temperature;
ii, N2, K2CO3, PPh3, Pd(OAc)2, hexadecyltrimethylammonium bromide,
MeCN, 80 °C, 5 h.
†
For subsequent chromene ring formation, we used the Heck
reaction. Intermolecular thiophene arylation5 was used for the
intramolecular cyclization of 4-(2-iodoaryloxymethyl)thiophene-
2-carboxaldehydes 3a–c (Scheme 1). The cyclization was
performed using a Pd catalyst in the presence of triphenyl-
phosphine and an inorganic base (K2CO3). Hexadecyltrimethyl-
ammonium bromide was used to accelerate this reaction.
4H-Thieno[3,2-c][1]benzopyran-2-carboxaldehydes 4a–c were pre-
pared in 20–69% yields.‡ In accordance with published data,6
the addition of water and the nature of a quaternary ammonium
salt influence the yield of the Heck reaction product. However,
such an influence was not observed in our case.
IR spectra were recorded on an Infralum FT-801 instrument in KBr
tablets. The 1H and 13C NMR spectra were recorded on a Brucker ARX-300
spectrometer in CDCl3 with TMS as an internal standard. The 13C NMR
spectra were measured with complete 1H decoupling.
General procedure for the synthesis of 4-substituted thiophene-
2-carboxaldehydes 3a–c. A mixture of 4-chloromethylthiophene-2-carbox-
aldehyde 1 (1.6 g, 10 mmol), 2-iodophenol 2a (2.2 g, 10 mmol), K2CO3
(1.4 g, 10 mmol), DMF (5 ml) and a catalytic amount of KI was stirred
at room temperature for four days. Then, the reaction mixture was
poured into ice-cold water (100 ml) and a crystalline precipitate of 3a
was formed, which was collected by filtration, washed with water, dried
and recrystallised from ethanol.
4-(2-Iodophenoxymethyl)thiophene-2-carboxaldehyde 3a: yield 1.62 g
(47%), mp 78 °C (EtOH). 1H NMR, d: 5.14 (s, 2H, CH2), 6.74–6.79
(m, 1H, Harom.), 6.84–6.87 (m, 1H, Harom.), 7.28–7.34 (m, 1H, Harom.),
7.79–7.86 (m, 3H, Harom.), 9.93 (d, 1H, CHO, 4J 1.16 Hz). 13C NMR, d:
66.42 (CH2), 86.81 (CAr–I), 131.98 (CTh-5), 135.17 (CTh-3), 182.93 (CHO).
Found (%): C, 41.52; H, 2.72. Calc. for C12H9IO2S (%): C, 41.88; H, 2.64.
4-(2-Iodo-4-chlorophenoxymethyl)thiophene-2-carboxaldehyde 3b: yield
‡
General procedure for the synthesis of 4H-thieno[3,2-c][1]benzopyran-
2-carboxaldehydes 4a–c. A suspension of K2CO3 (502 mg, 3.6 mmol)
and hexadecyltrimethylammonium bromide (531 mg, 1.41 mmol) in MeCN
(5 ml) was stirred for 20 min in inert atmosphere. The flask was purged
with argon and PPh3 (38 mg, 0.15 mmol), 4-(2-iodophenoxymethyl)thio-
phene-2-carboxaldehyde 3a (500 mg, 1.4 mmol) and Pd(OAc)2 (24 mg,
0.1 mmol) were successively added. The resulting reaction mixture was
refluxed for 5 h maintaining inert atmosphere, then poured into water
(40 ml), extracted with diethyl ether (3×15 ml). The extracts were washed
with brine, dried over Na2SO4 and the solvents were removed in vacuo.
The residue was flash-chromatographed (aluminia/CH2Cl2–hexane, 1:1)
to give product 4a, which was additionally purified by recrystallization
from ethanol.
4H-Thieno[3,2-c][1]benzopyran-2-carboxaldehyde 4a: yield 191 mg
(63%), mp 113 °C (EtOH). 1H NMR, d: 5.27 (s, 2H, CH2), 6.94–7.41
(m, 4H, Harom.), 7.47 (s, 1H, H-3), 9.85 (s, 1H, CHO). 13C NMR, d:
65.62 (C-4), 117.14 (C-6), 122.4 (C-8), 124.12 (C-9), 131.3 (C-7), 132.89
(C-3), 182.30 (CHO). IR (n/cm–1): 1660 (C=O), 3058 (CAr–H). Found
(%): C, 66.21; H, 3.85. Calc. for C12H8O2S (%): C, 66.65; H, 3.73.
1
2.92 g (77%), mp 105 °C (EtOH). H NMR, d: 5.07 (s, 2H, CH2), 6.76
(d, 1H, Harom., 3J 8.79 Hz), 7.26 (dd, 1H, Harom., 3J 8.79 Hz, 4J 2.54 Hz),
7.75 (d, 1H, Harom.
,
4J 2.54 Hz), 7.81 (s, 1H, 5-H), 7.83 (d, 1H, 3-H,
4J 1.16 Hz), 9.91 (d, 1H, CHO, J 1.16 Hz). 13C NMR, d: 66.71 (CH2),
86.98 (CAr–I), 132.06 (CTh-5), 135.04 (CTh-3), 182.85 (CHO). Found
(%): C, 37.85; H, 2.29. Calc. for C12H8ClIO2S (%): C, 38.07; H, 2.13.
4-(2-Iodo-4-methylphenoxymethyl)thiophene-2-carboxaldehyde 3c. Yield
2.97 g (83%), mp 87 °C (EtOH). 1H NMR, d: 2.25 (s, 3H, Me), 5.07 (s,
2H, CH2), 6.73 (d, 1H, Harom., 3J 8.09 Hz), 7.08 (dd, 1H, Harom., 3J 8.32 Hz,
4J 1.62 Hz), 6.61 (d, 1H, Harom., 4J 1.85 Hz), 7.80 (s, 1H, 5-H), 7.83 (d,
1H, 3-H, 4J 1.16 Hz), 9.90 (d, 1H, CHO, 4J 1.16 Hz). 13C NMR, d: 19.97
(Me), 66.55 (CH2), 86.68 (CAr–I), 131.95 (CTh-5), 135.29 (CTh-3),
182.93 (CHO). Found (%): C, 43.22; H, 3.26. Calc. for C13H11IO2S (%):
C, 43.59; H, 3.10.
4
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© 2008 Mendeleev Communications. All rights reserved.
Katsiel, Andrey L.
