Synthesis of 4h-thieno[3,2-c]chromenes by intramolecular arylation of 4-aryloxy-methyl-5-iodothiophene-2-carbaldehydes

Article abstract of DOI:10.1007/s10593-012-1102-3

The iodination of 4-chloromethylthiophene-2-carbaldehyde by N-iodosuccinimide under solvent-free conditions gives 4-chloromethyl-5- iodothiophene-2-carbaldehyde, which is used to obtain 4-aryloxy-methyl-5- iodothiophene-2-carbaldehydes. The palladium-cata

Full text of DOI:10.1007/s10593-012-1102-3

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
SYNTHESIS OF 4H-THIENO[3,2-c]CHROMENES BY
INTRAMOLECULAR ARYLATION OF 4-ARYLOXY-
METHYL-5-IODOTHIOPHENE-2-CARBALDEHYDES
A. S. Fisyuk1*, Yu. P. Bogza1, L. V. Belyaeva1, and V. B. Belyaev1
The iodination of 4-chloromethylthiophene-2-carbaldehyde by N-iodosuccinimide under solvent-free
conditions gives 4-chloromethyl-5-iodothiophene-2-carbaldehyde, which is used to obtain 4-aryloxy-
methyl-5-iodothiophene-2-carbaldehydes. The palladium-catalyzed intramolecular cyclization of
4-aryloxymethyl-5-iodothiophene-2-carbaldehydes yields 4H-thieno[3,2-c]chromene-2-carbaldehydes.
Keywords: 4-aryloxymethyl-5-iodothiophene-2-carbaldehydes, 4-chloromethyl-5-iodothiophene-2-carb-
aldehyde, 4H-thieno[3,2-c]chromene-2-carbaldehydes, intramolecular cyclization, palladium catalysis.
Derivatives of 4H-thieno[3,2-c]chromene are of interest due to their physiological activity. Some of
these compounds act as antipyretic, anti-inflammatory, analgesic [1-2], and mucoregulatory drugs [3-5], while
others possess diuretic [6] and antiparkinson action [7].
Methods involving the fusion of a thiophene ring to benzopyrans [7-12], the concurrent formation of
both rings [13-16], or formation of a pyran ring [17-19] are used to construct condensed systems consisting of
benzopyran and thiophene rings. A single example of a pyran ring C–C bond formation by means of the
Ullmann reaction [19] is among the methods involving formation of a pyran ring. Despite the good yields of the
desired products, the use of butyllithium, toxic reagents, and low temperatures reduce the value of this method
for preparative purposes.
The palladium-catalyzed intramolecular arylation of π-electron-rich hetarenes and aryl halides is an
efficient alternative synthesis for condensed structures [20-23], which is tolerant to functional groups and
proceeds under mild conditions.
In previous work [21], we showed that 4-[(2-iodoaryloxy)methyl]thiophene-2-carbaldehydes under
conditions of the Heck reaction are capable of forming a pyran ring to give the 4H-thieno[3,2-c]chromene
system. 2-Formyl-4H-thieno[3,2-c]chromene derivatives hold special interest since these compounds can be
readily transformed into other functional derivatives, including compounds with known biological activity [2, 4,
5]. At the same time, our method for the synthesis of 2-substituted 4H-thieno[3,2-c]chromenes [21] is limited by
the availability of the starting o-iodophenols.
_______
*To whom correspondence should be addressed, e-mail: fisyuk@omsu.ru.
1F. M. Dostoevskii Omsk State University, 55a Mira Ave., 644077 Omsk, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1160-1166, July, 2012. Original
article submitted October 7, 2011.
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0009-3122/12/4807-1078©2012 Springer Science+Business Media New York

An alternative method for the preparation of 4H-thieno[3,2-c]chromene-2-carbaldehydes based on the
intramolecular arylation of precursors 5, containing an iodine atom not in the benzene ring, but rather in the
thiophene ring, to date has not been carried out yet. 4-Chloromethyl-5-iodothiophene-2-carbaldehyde (3) may
be a starting compound for the preparation of precursors 5.
We have developed a convenient synthesis of 4-chloromethyl-5-iodothiophene-2-carbaldehyde (3) by
the iodination of 4-chloromethylthiophene-2-carbaldehyde (2), which is prepared by a reported method
involving the action of paraformaldehyde in the presence of excess aluminum chloride on commercially
available thiophene-2-carbaldehyde (1) [24].
Cl
Cl
NIS, H+
(CH2O)n, AlCl3
CHCl3
I
S
S
S
O
O
O
3
2
1
The iodination of carbaldehyde 2 was carried out using N-iodosuccinimide (NIS) in the presence of
sulfuric, methanesulfonic, polyphosphoric (PPA), or p-toluenesulfonic acid under solvent-free conditions.
Carbaldehyde 2 and NIS were taken in molar ratios 1.0:1.5, 1.0:1.8, and 1.0:2.0. The yields of iodocarbaldehyde
3 ranged from 20 to 80%. The best yields (70-80%) were achieved using PPA and p-toluene-sulfonic acid with
carbaldehyde 2 and NIS in 1.0:1.5 molar ratio.
4
O
Pd(OAc)2
O
K2CO3
KI
3
OH
6
PPh3, K2CO3
2
3 +
I
C16H33NMe3Br
DMF
DMF
7
S
S
R
R
O
O
9
5a–k
8
4a–k
R
6a–k
4–6 a R = Н, b R = 2(6)-Me, c R = 4(8)-Me, d R = 3(7)-Me, e R = 2(6)-MeO, f R = 4(8)-MeO,
g R = 3(7)-MeO, h R = 4(8)-HexO, i R = 2(6)-Cl, j R = 3(7)-Cl, k R = 4(8)-Cl
(the position of the substituent in product 6 is given in parentheses)
4-Aryloxymethyl-5-iodothiophene-2-carbaldehydes 5a-k were obtained by the reaction of
iodocarbaldehyde 3 with phenols 4a-k in dry DMF in the presence of potassium carbonate at room temperature
over 48 h. The yields of iodocarbaldehydes 5a-k were 60-87% (Table 1).
The cyclization of iodocarbaldehydes 5a-k was carried out by the action of palladium diacetate in the
presence of triphenylphosphine and potassium carbonate in DMF at 110-120°C for 5-6 h. A quaternary
ammonium salt, namely, hexadecyltrimethylammonium bromide was used to increase the rate of this reaction.
The reaction course was monitored by thin-layer chromatography. 4H-Thieno[3,2-c]chromene-2-carbaldehydes
6a-k were obtained in 44-85% yields (Table 1). The structures of all the products were supported by elemental
1
analysis (Table 1), mass spectrometry, H and 13C NMR spectroscopy, and IR spectroscopy (Table 2). The
spectral parameters for chromenecarbaldehydes 6b,d-j are in accord with the literature data for products 6a,c,k
previously prepared by a different method [21].
Thus, we have found a synthesis method for previously unreported 4-chloromethyl-5-iodothiophene-
2-carbaldehyde by the means of iodination of the available 4-chloromethylthiophene-2-carbaldehyde using
N-iodosuccinimide under solvent-free conditions. An efficient synthesis method was developed for 2-substituted
4H-thieno[3,2-c]chromenes using the intramolecular palladium-catalyzed cyclization of 4-aryl-oxymethyl-
5-iodothiophene-2-carbaldehydes.
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TABLE 1. Physicochemical Characteristics of Compounds 5a-k and 6a-k
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Mp, °С (EtOH)
Yield, %
C
H
5a
5b
5c
5d
5e
5f
C12H9IO2S
41.78
41.88
43.51
43.59
43.48
43.59
43.53
43.59
41.66
41.73
41.60
41.73
41.62
41.73
48.73
48.66
37.94
38.07
37.97
38.07
38.01
38.07
66.58
66.65
67.75
67.80
67.68
67.80
67.72
67.80
63.22
63.40
2.60
2.64
3.14
3.10
3.03
3.10
3.05
3.10
2.92
2.96
2.89
2.96
3.01
2.96
4.80
4.76
2.08
2.13
2.10
2.13
2.16
2.13
3.69
3.73
4.42
4.38
4.32
4.38
4.35
4.38
4.02
4.09
85-86
65
66
67
70
78
64
60
73
76
87
72
85
61
62
55
65
82
54
83
74
44
75
C13H11IO2S
C13H11IO2S
C13H11IO2S
C13H11IO3S
C13H11IO3S
C13H11IO3S
C18H21IO3S
C12H8ClIO2S
C12H8ClIO2S
C12H8ClIO2S
C12H8O2S
110-111
101-103
Oil
68-69
78-79
5g
5h
5i
51-52
65-66
114-115
5j
55-57
5k
6a
6b
6c
6d
6e
6f
98-100
114-115 (113 (EtOH) [21])
C13H10O2S
C13H10O2S
C13H10O2S
C13H10O3S
C13H10O3S
C13H10O3S
C18H20O3S
C12H7ClO2S
C12H7ClO2S
C12H7ClO2S
132-134
136-138 (136 (EtOH) [21])
135-137
134-136
63.31
63.40
63.28
63.40
68.58
68.33
57.38
57.49
57.32
57.49
57.58
57.49
4.05
4.09
4.12
4.09
6.43
6.37
2.75
2.81
2.74
2.81
2.83
2.81
104-105
6g
6h
6i
Oil
70-71
187-189
6j
191-193
6k
191-193 (192 (EtOH) [21])
EXPERIMENTAL
The IR spectra were recorded on an Infralum FT-801 spectrometer in KBr pellets. The 1H and 13C NMR
spectra were recorded on a Bruker DRX 400 spectrometer (400 and 100 MHz, respectively), in CDCl3 with
TMS as internal standard. The mass spectra were recorded on an Agilent 6890N mass spectrometer. The
ionizing electron energy was 70 eV, and the injector temperature was 230-250°C. The elemental analysis was
carried out on a Carlo Erba 1106 CHN analyzer. The melting points were determined on a Kofler bench. The
reaction course and purity of the products were checked by thin-layer chromatography on Sorbfil UV-254 plates
with chloroform as the eluent. The plates were visualized with iodine vapor or UV light.
1080

1081

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4-Chloromethyl-5-iodothiophene-2-carbaldehyde (3). 4-Chloromethylthiophene-2-carbaldehyde (0.300
g, 1.87 mmol) was added to finely ground N-iodosuccinimide (0.632 g, 2.80 mmol), and the mixture was
thoroughly ground. Then, one or two drops of PPA were added. The mixture was again ground and left for 48 h
in the dark. Then, water (20 ml) was added, and the mixture was extracted with CHCl3 (3×15 ml). The extract
was washed with saturated aqueous sodium sulfite, then water and dried over anhydrous magnesium sulfate.
The solvent was distilled off in vacuum, and the residue was recrystallized from hexane. Yield 0.407 g (76%);
mp 88-89°C. IR spectrum, ν, cm-1: 1650 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 4.54 (2H, s, CH2); 7.60 (1H,
s, H-3); 9.79 (1H, s, CHO). 13C NMR spectrum, δ, ppm: 41.8 (CH2); 91.0 (C-5); 135.8 (C-3); 143.6 (C-2); 148.7
(C-4); 181.13 (CHO). Mass spectrum, m/z (Irel, %): 285.9 [M-H]+ (42); 252.9 (5); 251.9 (8); 250.9 (100); 96.0
(12); 95.0 (10); 70.0 (7); 69.0 (11). Found, %: C 25.04; H 1.37. C6H4ClIOS. Calculated, %: C 25.15; H 1.41.
4-(Aryloxymethyl-5-iodothiophene-2-carbaldehydes 5a-k (General Method). A mixture of 4-chlo-
romethyl-5-iodothiophene-2-carbaldehyde (3) (0.287 g, 1.0 mmol), the corresponding phenol (1.1 mmol),
K2CO3 (0.138 g, 1.0 mmol), and potassium iodide (0.017 g, 0.1 mmol) in anhydrous DMF (1 ml) was stirred for
24-48 h until the starting compounds disappeared. The reaction mixture was poured into cold water (25-30 ml).
The crystalline products were filtered off, while the oily products were extracted with ether. The extract was
washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuum, and
the reaction product was recrystallized from ethanol.
4H-Thieno[3,2-c]chromenes 6a-k (General Method). A suspension of K2CO3 (0.502 g, 3.60 mmol)
and hexadecyltrimethylammonium bromide (0.531 g, 1.41 mmol) was prepared in anhydrous DMF (5 ml) and
stirred for 20 min under an inert atmosphere. Then, PPh3 (0.038 g, 0.15 mmol), compound 5a-k (1.40 mmol),
and Pd(OAc)2 (0.024 g, 0.10 mmol) were added consecutively. The reaction mixture was heated under an inert
atmosphere for 5-6 h at 110-120°C until the starting compound disappeared. After cooling, the mixture was
poured into water (30 ml) and extracted with ether (3×15 ml). The extract was filtered to remove solid particles.
The organic phase was washed with saturated aqueous sodium chloride (2×10 ml) and dried over anhydrous
magnesium sulfate. The solvent was distilled off in vacuum. The crude product was purified by flash
chromatography on silica gel (0.035-0.070 mm) with 1:1 chloroform–hexane as the eluent. The product was
recrystallized from ethanol. The physicochemical and spectral data for compounds 6a,c,k corresponded to the
literature values [21].
This work was carried out with the financial support of the Russian Foundation for Basic Research
(grant 12-03-98013-p_sibir'_a).
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