Synthesis and reactions of 5-aryl-2-thiophenecarbaldehydes

Article abstract of DOI:10.1007/s10593-008-0135-0

The reaction of 2-thiophenecarbaldehyde with arene diazonium chlorides in the presence of CuCl₂ catalyst gave 5-aryl-2-thiophenecarbaldehydes. Use of 4-nitrobenzene diazonium chloride in the reaction also gave the isomeric 3-(4-nitrophenyl)-2-t

Full text of DOI:10.1007/s10593-008-0135-0

Chemistry of Heterocyclic Compounds, Vol. 44, No. 8, 2008
SYNTHESIS AND REACTIONS
OF 5-ARYL-2-THIOPHENECARB-
ALDEHYDES*
M. D. Obushak, V. S. Matiychuk, and R. Z. Lytvyn
The reaction of 2-thiophenecarbaldehyde with arene diazonium chlorides in the presence of CuCl2
catalyst gave 5-aryl-2-thiophenecarbaldehydes. Use of 4-nitrobenzene diazonium chloride in the
reaction also gave the isomeric 3-(4-nitrophenyl)-2-thiophenecarbaldehyde. Condensation products of
the 5-aryl-2-thiophenecarbaldehydes with cyanoacetic acid esters, cyanoacetamide, and with barbituric
and dimethylbarbituric acids were prepared.
Keywords: 5-aryl-2-thiophenecarbaldehydes, 2-thiophenecarbaldehyde, arylation, Meerwein reaction.
The copper-catalyzed reaction of arene diazonium salts with unsaturated compounds (the Meerwein
reaction) is a convenient method for the preparation of polyfunctional compounds [2-4]. Heteroaromatic
compounds occupy a special place amongst unsaturated substrates which have been used in this reaction.
Several furan derivatives (particularly furfural) have been well studied in arylation reactions with diazonium
salts since they proved to be most reactive [4-7]. The arylfuran compounds obtained have found use as reagents
for introducing 2-arylfuran fragments in the synthesis of practically useful substances (e.g. see [8, 9]).
5-Aryl-2-thiophenecarbaldehydes have also found widespread use as reagents [10-13]. They are usually
prepared by formylation of arylthiophenes [10] or by palladium-catalyzed arylation of 2-thiophenecarbaldehyde
by various reagents [11-15]. It should be noted that the reactions are not always selective in the latter case [16].
As seen in literature data [17-19], under Meerwein reaction conditions 2-thiophenecarbaldehyde is
arylated in low yields. At the same time this method is preparatively most attractive since it does not involve
hard to obtain starting compounds and catalysts.
_
+
N2Cl
O
CuCl2
O
R
+
R
S
S
1
2a–f
3a–f
2, 3 a R = 4-NO2, b R = 3-NO2, c R = 4-Cl, d R = 2,4-Cl2, e R = 2,5-Cl2, f R = SCHF2
_______
* Communication 16 in the series "Synthesis of heterocycles based on the products of arylation of unsaturated
compounds". For Communication 15 see [1].
__________________________________________________________________________________________
Ivano Franko Lviv National University, Lviv 79005, Ukraine; e-mail: obushak@in.lviv.ua. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1166-1171, August, 2008. Original article submitted
December 11, 2007.
936
0009-3122/08/4408-0936©2008 Springer Science+Business Media, Inc.

For this reason we have carried out a more detailed study of the arylation of 2-thiophenecarbaldehyde 1
by the arene diazonium chlorides 2a-f. The reaction takes place in the presence of CuCl2 catalyst at room
temperature to give the 5-aryl-2-thiophenecarbaldehydes 3a-f (Tables 1 and 2).
The reaction was performed in an aqueous–organic medium. Acetone, acetonitrile, DMF, and DMSO
were used as the organic solvent. Compounds 3a-f were obtained with the highest yields (greater than in [17-
19]) using DMSO. It should be stressed that the Meerwein reaction is associated with moderate yields (30-40%)
[4]. The aldehyde 1 reacts most vigorously with 4-nitrobenzene diazonium chloride. However, in this case, it
was found that an isomeric 3-(4-nitrophenyl)-2-thiophenecarbaldehyde (4) is formed together with compound 3a
(overall yield 77%). In the 1H NMR spectrum of compound 4 (Table 2) the thiophene ring protons appear as two
doublets, one of which is shifted to low field.
C6H4NO2-4
O
S
4
As already mentioned, the 5-aryl-2-thiophenecarbaldehydes 3a-f are promising reagents for organic
synthesis. We have studied their reaction with several active methylene compounds. It was found that they
readily condense with the cyanoacetic acid esters 5a-d, cyanoacetamide (5e), and with barbituric (6) and
dimethylbarbituric acids 7 to give compounds 8-10 (Table 1).
O
NC
NC
R1
R1
5a–e
S
O
R
8a–e
O
H
O
N
O
NH
Cl
NH
N
O
O
H
S
6
O
3
9
Cl
Me
O
O
N
O
Me
O
N
N
Me
N
Me
O
S
O
7
10
O2N
8 a R = 4-Cl, R1 = OMe, b R = 2,4-Cl2, R1 = OMe, c R = 2,4-Cl2, R1 = OEt,
d R = 2,4-Cl2, R1 = OBu, e R = 4-Cl, R1 = NH2
Compounds 8a-e can exist as Z- and E-isomers. In addition the thiophene ring and the exocyclic double
bond can take an s-cis- or s-trans configuration as discussed for similar furan series compounds in the studies
[6, 20, 21].
H
H
O
R
NC
R
CN
S
S
R1
R1
O
H
H
E-isomer
Z-isomer
937

TABLE 1. Characteristics of the Compounds 3a,d-f, 4, 8a-e, 9, 10
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
—
Yield %
C
H
N
S
3a,4
mixture
C11H7NO3S
56.32
56.64
2.96
3.03
6.12
6.01
13.59
13.75
50 (3a),
27 (4)
51.28
51.38
51.43
51.38
53.43
53.32
59.60
59.31
53.13
53.27
54.38
54.56
56.64
56.85
58.17
58.23
2.26
2.35
2.14
2.35
2.75
2.98
3.10
3.32
2.54
2.68
3.01
3.15
3.84
3.98
2.91
3.14
12.33
12.47
12.52
12.47
23.66
23.72
10.39
10.56
9.40
9.48
8.89
9.10
8.40
8.43
11.01
11.10
3d
3e
3f
C11H6Cl2OS
112-113
103-104
57-58
42
31
36
40
45
55
59
70
35
30
C11H6Cl2OS
C12H8F2OS2
4.45
4.61
4.25
4.14
4.05
3.98
3.87
3.68
9.59
9.70
7.59
7.63
11.19
11.31
8a
8b
8c
8d
8e
9
C15H10ClNO2S
C15H9Cl2NO2S
C16H11Cl2NO2S
C18H15Cl2NO2S
C14H9ClN2OS
C15H8Cl2N2O3S
C17H13N3O5S
160-161
174-175
150-152
108-109
242-243
>300
48.87
49.06
54.87
54.98
2.06
2.20
3.76
3.53
8.61
8.73
8.69
8.63
10
319-320
1
As is evident from the H NMR spectra (Table 2), compounds 8a,c,e are formed as a mixture of Z- and
E-isomers but 8b,d have an E-configuration The alkoxycarbonyl or amide group (RCO) deshields the proton
situated in a cis-position to it more strongly than does the CN group.
TABLE 2. 1H NMR Spectra of Compounds 3, 4, 8-10
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1
2
3a
7.80-7.89 (2Н, m, thiophene); 9.95 (1Н, s, СНО)
4
7.42 (1Н, d, J = 4.5, Н-4 thiophene); 8.12 (1Н, d, J = 4.5, Н-5 thiophene);
9.84 (1Н, s, СНО)
3а+4
8.02-8.07 (2H, m, С6Н4); 8.27-8.35 (2H, m, С6Н4)
3d
7.47 (1Н, dd, J = 2.2 and J = 8.4, H-5 С6Н3); 7.56 (1H, d, J = 3.8, Н-4 thiophene);
7.65 (1Н, d, J = 2.2, Н-3 С6Н3); 7.69 (1H, d, J = 8.4, Н-6 С6Н3);
7.98 (1H, d, J = 3.8, Н-3 thiophene); 9.94 (1Н, s, СНО)
3e
3f
7.44 (1Н, d, J = 8.2, H-3 С6Н3); 7.49 (1H, d, J = 3.8, Н-4 thiophene);
7.63-7.67 (1Н, m, Н-4 С6Н3); 7.94 (1H, d, J = 3.8, Н-3 thiophene);
8.03 (1H, d, J = 2.0, Н-6 С6Н3); 9.96 (1Н, s, СНО)
7.44 (1Н, t, JHF = 56, СНF2); 7.53 (1Н, d, J = 3.8, Н-4 thiophene);
7.55 (2H, d, J = 8.0, С6Н4); 7.76 (2H, d, J = 8.0, С6Н4);
7.84 (1Н, d, J = 3.8, Н-3 thiophene); 9.95 (1Н, s, СНО)
8a
3.83 (1.5H, s, OCH3); 3.87 (1.5H, s, OCH3);
7.37-7.58 (3.5Н, m, С6Н4+Н-4 thiophene, Z-isomer);
7.69 (0.5Н, d, J = 4.8, Н-4 thiophene, E-isomer); 7.78 (1H, d, J = 8.8, C6H4);
8.00 (0.5H, d, J = 3.5, Н-3 thiophene, E-isomer);
8.18 (0.5Н, d, J = 4.8, Н-3 thiophene, Z-isomer); 8.19 (0.5Н, s, =СН, Z-isomer);
8.51 (0.5H, s, =CН, E-isomer)
8b
3.88 (3H, s, OCH3); 7.49 (1Н, dd, J = 1.8 and J = 8.0, H-5 C6H3);
7.61 (1H, d, J = 4.0, Н-4 thiophene); 7.66 (1Н, d, J = 1.8, Н-3 C6H3);
7.73 (1H, d, J = 8.0, Н-6 C6H3); 8.04 (1H, d, J = 4.0, Н-3 thiophene); 8.56 (1Н, s, СН)
938

TABLE 2 (continued)
1
2
8c
1.32 t and 1.36 t (3H, J = 6.8, CH3); 4.24-4.39 (2H, m, OCH2);
7.36-7.59 (2.4Н, m, С6Н3 + Н-4 thiophene, Z-isomer);
7.68 (0.6H, d, J = 3.5, Н-4 thiophene, E-isomer); 7.78 (2Н, d, J = 9.0, С6Н3);
7.99 (0.6H, d, J = 3.5, Н-3 thiophene, E-isomer);
8.17 (0.4H, d, J = 4.8, Н-3 thiophene, Z-isomer); 8.20 (0.4Н, s, =СН, Z-isomer);
8.49 (0.6Н, s,=СН, E-isomer)
8d
8e
0.98 (3H, t, J = 7.0, CH3); 1.40-1.51 (2H, m, СН2CH3); 1.65-1.76 (2H, m, СН2СН2СН2);
4.27 (2H, t, J = 6.5, ОCH2); 7.49 (1Н, d, J = 8.5, H-5 С6Н3);
7.60 (1H, d, J = 4.0, Н-4 thiophene); 7.67 (1Н, s, Н-3 С6Н3);
7.73 (1H, d, J = 8.5, Н-6 С6Н3); 8.04 (1H, d, J = 4.0, Н-3 thiophene); 8.52 (1Н, s, =СН)
7.32 (0.5H, d, J = 4.8, Н-4 thiophene, Z-isomer); 7.38-7.59 (4Н, m, С6Н4 + NH2);
7.63 (0.5Н, d, J = 3.8, Н-4 thiophene, E-isomer); 7.75 (2H, d, J = 7.8, C6H4);
7.81 (0.5H, d, J = 3.8, Н-3 thiophene, E-isomer);
8.03 (0.5Н, d, J = 4.8, Н-3 thiophene, Z-isomer); 8.11 (0.5Н, s, =СН, Z-isomer);
8.32 (0.5Н, s, CН, E-isomer)
9
7.48 (1Н, dd, J = 2.0 and J = 8.7, Н-5 С6Н3); 7.58 (1H, d, J = 3.8, Н-4 thiophene);
7.65 (1Н, d, J = 2.0, Н-3 С6Н3); 7.71 (1Н, d, J = 8.7, Н-6 С6Н3);
8.10 (1Н, d, J = 3.8, Н-3 thiophene); 8.52 (1Н, s, =СН); 11.22 (2Н, s, NH)
10
3.33 (3H, s, NCH3); 3.35 (3H, s, NCH3); 7.88 (1H, d, J = 3.8, Н-4 thiophene);
8.09 (2H, d, J = 8.0, C6H4); 8.13 (1Н, d, J = 3.8, Н-3 thiophene);
8.31 (2H, d, J = 8.0, C6H4); 8.62 (1H, s, =CH)
For the E-isomer such an effect corresponds to the shift to low field of the proton signal of the exocyclic
bond (CH=). For the Z-isomer the proton signal at position 3 of the thiophene ring is shifted to low field and this
is specifically caused by the s-cis configuration. According to the intensities of the corresponding signals the
ratio of E- to Z-isomers is: 8a,e ~50:50, 8c 60:40.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker WM-250 instrument (250 MHz) using DMSO-d6 using
HMDS (δ 0.05 ppm) as internal standard. Mass spectra were obtained on a Finnigan MAT INKOS-50 chromato-
mass spectrometer with ionization energy of 70 eV.
5-Arylthiophene-2-carbaldehydes 3a-f (General Method). A solution of NaNO2 (7 g) in water
(25 ml) was added dropwise with stirring to a solution of the aromatic amine (0.1 mol) in 20% HCl (60 ml)
cooled to 0-5ºC. The solution of arene diazonium salt 2a-f obtained was filtered and added dropwise with
stirring to a mixture of the aldehyde 1 (15 ml, 12.25 g, 0.11 mol), DMSO (40 ml), and CuCl2·2H2O (1.5 g,
8.7 mmol). The reaction was carried out at 15-25ºC in such a manner that the nitrogen was evolved at a
moderate rate. Water (150 ml) was added to the reaction mixture after nitrogen evolution had ceased. The
precipitate formed was recrystallized from a mixture of ethanol and DMF. The ratio of aldehydes 3a to 4 in the
1
precipitate formed after carrying out the reaction was about 2:1 according to H NMR. An analytically pure
sample of aldehyde mixture was recrystallized from a mixture of ethanol and DMF.
5-(3-Nitrophenyl)-2-thiophenecarbaldehyde (3b) was obtained in 28% yield; mp 144-145ºC ([22],
mp 147ºC) and 5-(4-chlorophenyl)-2-thiophenecarbaldehyde (3c) in 27% yield; mp 88-89ºC ([23], mp 89-90ºC).
The characteristics of the remaining aldehydes are given in Tables 1 and 2.
3-(5-Aryl-2-thienyl)-2-cyanopropenoate Esters 8a-d. The aldehyde 3 (50 mmol) and ethyl
cyanoacetate (50 mmol) were dissolved in ethanol (20 ml), several drops of pyridine were added, and the
product was refluxed for 0.5-1.5 h. The precipitate formed was filtered off, washed with ethanol, and
recrystallized from benzene. Compound 8e was prepared similarly from cyanoacetamide.
939

5-[5-(2,4-Dichlorophenyl)-2-thienylmethylene]hexahydropyrimidine-2,4,6-trione (9). The aldehyde
3d (2.58 g, 10 mmol) and barbituric acid 6 (1.28 g, 10 mmol) were dissolved in acetic acid (30 ml), several
drops of pyridine added, and the product was refluxed for 1 h. The precipitate formed was filtered off, washed
with ethanol, and recrystallized from ethanol.
1,3-Dimethyl-5-[5-(4-nitrophenyl)-2-thienylmethylene]hexahydropyrimidine-2,4,6-trione (10) was
prepared similarly by treating the aldehyde 3a with dimethylbarbituric acid 7. Mass spectrum, m/z (Irel, %): 371
(100), 257 (49), 171 (24), 139 (90).
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