Synthesis of heterocycles on the basis of arylation products of unsaturated compounds. 19. Arylation of 2-acetylthio- phene and the synthesis of 2-(5-aryl-2-thien- yl)-4-quinolinecarboxylic acids

Article abstract of DOI:10.1007/s10593-010-0468-3

The reaction of 2-acetylthiophene with acetylthiophene with arenediazonium chlorides in the presence of cupric chloride as catalyst gives 2-acetyl-5-arylthiophenes. These products react with 5-chloro- and 5-bromoisatins to give 6-chloro- and 6-bromo-subst

Full text of DOI:10.1007/s10593-010-0468-3

Chemistry of Heterocyclic Compounds, Vol. 46, No. 1, 2010
SYNTHESIS OF HETEROCYCLES ON THE BASIS
OF ARYLATION PRODUCTS OF UNSATURATED
COMPOUNDS. 19.* ARYLATION OF 2-ACETYLTHIO-
PHENE AND THE SYNTHESIS OF 2-(5-ARYL-2-THIEN-
YL)-4-QUINOLINECARBOXYLIC ACIDS
V. S. Matiychuk1, N. D. Obushak1**, R. Z. Lytvyn1, and Yu. I. Horak1
The reaction of 2-acetylthiophene with acetylthiophene with arenediazonium chlorides in the presence
of cupric chloride as catalyst gives 2-acetyl-5-arylthiophenes. These products react with 5-chloro- and
5-bromoisatins to give 6-chloro- and 6-bromo-substituted 2-(5-aryl-2-thienyl)-4-quinolinecarboxylic
acids.
Keywords: 2-acetyl-5-arylthiophenes, 2-acetylthiophene, 4-quinolinecarboxylic acid derivatives,
arylation, Meerwein reaction, Pfitzinger reaction.
Some heteroaromatic compounds are arylated by arenediazonium compounds under conditions of the
Meerwein reaction [2-5]. Furan derivatives (especially furfural) have been studied extensively in this reaction
since they have proved to be the most reactive [5-8]. Various workers [9-12] have described the arylation of
2-thiophenecarbaldehyde by arenediazonium salts. Shridhar et al. [13] have demonstrated the use of
2-acetylthiophene in this reaction. 2-Acetyl-5-arylthiophenes have usually been obtained by other methods,
namely, by acylation of 2-arylthiophenes [14] or by the palladium-catalyzed arylation of 2-acetylthiophene
using various reagents [15-18]. We should note that, in the latter case, the reactions do not always proceed
_
+
O
N2Cl
CuCl2
O
S
R
+
R
S
Me
H2O–Me2CO
Me
1
2a–j
3a–j
a R = 4-Me, b R = 4-F, c R = 2-Cl, d R = 4-Cl, e R = 4-Br, f R = 3-NO2, g R = 4-NO2,
h R = 3-CF3, i R = 2,5-Сl2, j R = 2-Cl-5-CF3
_______
* For Communication 18 see [1].
** To whom correspondence should be addressed, e-mail: obushak@in.lviv.ua.
1 Ivan Franko Lviv National University, 79005 Lviv, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 61-66, January, 2010. Original
article submitted January 22, 2009.
50
0009-3122/10/4601-0050©2010 Springer Science+Business Media, Inc.

selectively [19]. On the other hand, the preparative synthesis of 2-acetyl-5-arylthiophenes using the Meerwein
reaction is attractive since it does not require the use of not readily available starting compounds and catalysts.
With this in mind, we have carried out a detailed study of the arylation of 2-acetylthiophene 1 by
arenediazonium chlorides 2a-j. This reaction proceeds in the presence of cupric chloride as catalyst at room
temperature to give 5-aryl-2-acetylthiophenes 3a-j (Tables 1 and 2).
The yields of acetylthiophenes 3 are usually in the range 30-55%, which indicates that acetylthiophene
is somewhat less reactive than acetylfuran in this reaction [20]. Moderate yields of 30-40% are characteristic for
the Meerwein reaction [2, 5]. However, the starting reagents for the preparation of acetylthiophenes 3 in this
case are readily available aromatic amines and 2-acetylthiophene.
TABLE 1. Characteristics of Products 3a-j and 5a-n
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield %
C
H
N
3a
3b
3c
3d
3e
3f
C13H12OS
71.87
72.19
65.31
65.44
60.46
60.89
60.74
60.89
51.04
51.26
58.21
58.29
58.18
58.29
57.89
57.77
52.91
53.15
51.37
51.24
66.22
66.40
59.17
59.44
62.37
62.59
55.98
56.09
59.84
60.01
53.84
54.01
59.88
60.01
53.98
54.01
58.00
58.14
52.63
52.74
55.04
55.26
49.94
50.13
53.78
53.86
49.02
49.19
5.43
5.59
4.03
4.12
3.76
3.83
3.72
3.83
3.19
3.23
3.54
3.67
3.49
3.67
3.28
3.36
3.05
2.97
2.49
2.65
3.54
3.71
3.12
3.33
2.75
2.89
2.45
2.59
2.71
2.77
2.42
2.49
2.59
2.77
2.37
2.49
2.43
2.56
2.30
2.32
2.41
2.32
1.78
2.10
1.98
2.15
1.80
1.97
115-116
97-98
20
41
47
30
33
40
55
29
44
49
74
55
82
79
83
71
78
74
76
69
77
69
83
67
C12H9FOS
C12H9СlOS
67-68
C12H9СlOS
114-115
140-142
148-149
153-154
87-88
C12H9BrOS
C12H9NO3S
5.51
5.66
5.83
5.66
3g
3h
3i
C12H9NO3S
C13H9F3OS
C12H8Cl2OS
112-113
74-75
3j
C13H8СlF3OS
C21H14ClNO2S
C21H14BrNO2S
C20H11СlFNO2S
C20H11BrFNO2S
C20H11Сl2NO2S
C20H11BrСlNO2S
C20H11Сl2NO2S
C20H11BrСlNO2S
C21H11СlF3NO2S
C21H11BrF3NO2S
C20H10Cl3NO2S
C20H10BrCl2NO2S
C21H10Сl2F3NO2S
C21H10BrClF3NO2S
5a
5b
5c
5d
5e
5f
3.53
3.69
3.16
3.30
3.49
3.65
3.14
3.27
3.38
3.50
3.06
3.15
3.33
3.50
3.02
3.15
3.07
3.23
2.86
2.93
3.01
3.22
3.10
2.92
3.05
2.99
2.59
2.73
268-269
283-284
284-285
294-295
258-259
272-273
283-284
292-293
253-254
287-288
245-246
253-254
290-291
> 300
5g
5h
5i
5j
5k
5l
5m
5n
51

TABLE 2. 1H NMR Spectra of 3a-j and 5a-n
Com-
Chemical shifts, δ, ppm, (J, Hz)*
pound
1
2
3a
2.39 (3H, s, СH3); 2.55 (3H, s, СH3); 7.24 (2Н, d, J = 8.0, С6H4);
7.29 (1Н, d, J = 4.0, thiophene);7.52 (2Н, d, J = 8.0, С6H4);
7.66 (1Н, d, J = 4.0, thiophene)
3b
3c
3d
3e
3f
2.53 (3H, s, СH3); 7.11 (2Н, t, J = 8.4, С6H4); 7.26 (1Н, d, J = 4.2, thiophene);
7.57 (2Н, dd, J = 8.4 and J = 5.2, С6H4); 7.66 (1Н, d, J = 4.2, thiophene)
2.54 (3Н, s, СH3); 7.43 (1Н, t, J = 7.8, С6H4); 7.45-7.55 (2Н, m, thiophene + С6H4);
7.74 (1Н, d, J = 7.8, С6H4); 7.79 (1Н, d, J = 4.0, thiophene); 7.94 (1Н, d, J = 7.8, С6H4)
2.53 (3H, s, СH3); 7.45 (2Н, d, J = 8.4, С6H4); 7.54 (1Н, d, J = 4.0, thiophene);
7.72 (2Н, d, J = 8.4, С6H4); 7.83 (1Н, d, J = 8.4, thiophene)
2.52 (3H, s, СH3); 7.41 (2Н, d, J = 8.4, С6H4); 7.57-7.64 (3Н, m, thiophene + С6H4);
7.87 (1Н, d, J = 4.4, thiophene)
2.56 (3Н, s, СH3); 7.44 (1Н, d, J = 4.0, thiophene); 7.62 (1Н, t, J = 7.8, С6H4);
7.67 (1Н, d, J = 4.0, thiophene); 7.96 (1Н, d, J = 7.8, С6H4); 8.17 (1Н, d, J = 7.8, С6H4);
8.40 (1Н, s, С6H4)
3g
2.56 (3Н, s, СH3); 7.78 (1Н, d, J = 3.8, Н-4 thiophene);
7.91 (1Н, d, J = 3.8, Н-3 thiophene); 7.99 (2Н, d, J = 8.8, С6H4);
8.26 (2Н, d, J = 8.8, С6H4)
3h
3i
2.54 (3Н, s, СH3); 7.60-7.82 (4Н, m, thiophene + С6H4); 7.84 (1Н, d, J = 4.2, thiophene);
8.05 (1Н, d, J = 2.0, С6H4)
2.52 (3H, s, СH3); 7.47 (1Н, d, J = 8.4, С6H3); 7.56 (1Н, d, J = 4.0, thiophene);
7.74 (1Н, dd, J = 8.4 and J = 2.0, С6H3); 7.97 (1Н, d, J = 4.0, thiophene);
8.08 (1Н, d, J = 2.0, С6H3)
3j
2.53 (3Н, s, СH3); 7.48 (1Н, d, J = 4.4, thiophene); 7.65-7.79 (3Н, m, thiophene + С6H3);
8.03 (1Н, d, J = 2.0, С6H3)
5a
2.38 (3H, s, CH3); 7.23 (2H, d, J = 8.0, С6H3); 7.49 (1Н, d, J = 3.9, Н-4 thiophene);
7.61 (2Н, d, J = 8.0, С6H4); 7.70 (1Н, dd, J = 2.4 and J = 8.8, Н-7 quinoline);
7.96-8.04 (2Н, m, Н-3 thiophene + Н-8 quinoline); 8.47 (1Н, s, Н-3 quinoline);
8.84 (1Н, d, J = 2.4, Н-5 quinoline)
5b
5c
5d
5e
2.38 (3H, s, CH3); 7.24 (2H, d, J = 8.0, С6H3); 7.47 (1Н, d, J = 4.0, Н-4 thiophene);
7.61 (2Н, d, J = 8.0, С6H4); 7.84 (1Н, dd, J = 2.0 and J = 8.8, Н-7 quinoline);
7.93 (1Н, d, J = 8.8, Н-8 quinoline); 7.96 (1Н, d, J = 4.0, Н-3 thiophene);
8.43 (1Н, s, Н-3 quinoline); 8.95 (1Н, d, J = 2.0, Н-5 quinoline)
7.13 (2Н, t, J = 8.8, С6H4); 7.39 (1Н, d, J = 3.9, Н-4 thiophene);
7.66 (1Н, dd, J = 2.0 and J = 8.8, Н-7 quinoline); 7.69-7.73 (2Н, m, С6H4);
7.87 (1Н, d, J = 3.9, Н-3 thiophene); 7.99 (1Н, d, J = 8.8, Н-8 quinoline);
8.43 (1Н, s, Н-3 quinoline); 8.84 (1Н, s, Н-5 quinoline)
7.13 (2Н, t, J = 7.8, Н-3,5 С6H4); 7.38 (1Н, d, J = 3.9, Н-4 thiophene);
7.68-7.73 (2Н, m, Н-2,6 С6Н4); 7.78 (1Н, d, J = 8.8, Н-7 quinoline);
7.86 (1Н, d, J = 3.9, Н-3 thiophene); 7.92 (1Н, d, J = 8.8, Н-8 quinoline);
8.41 (1Н, s, Н-3 quinoline); 9.00 (1Н, s, Н-5 quinoline)
7.34-7.40 (2Н, m, С6H4); 7.48 (1Н, d, J = 4.0, Н-4 thiophene);
7.54 (1Н, dd, J =1.2 and J = 7.6, С6H4); 7.69 (1Н, dd, J =1.6 and J = 7.6, С6H4);
7.72 (1Н, dd, J = 2.4 and J = 9.2, Н-7 quinoline); 7.98 (1Н, d, J = 4.0, Н-3 thiophene);
8.03 (1Н, d, J = 9.2, Н-8 quinoline); 8.47 (1Н, s, Н-3 quinoline);
8.81 (1Н, d, J = 2.4, Н-5 quinoline)
5f
7.36-7.40 (2Н, m, С6H4); 7.47 (1Н, d, J = 4.0, Н-4 thiophene);
7.54 (1Н, dd, J = 1.2 and J = 7.6, С6H4); 7.69 (1Н, dd, J = 1.2 and J = 7.6, С6H4);
7.83 (1Н, dd, J = 2.0 and J = 9.2, Н-7 quinoline); 7.96 (1Н, d, J = 9.2, Н-8 quinoline);
7.99 (1Н, d, J = 4.0, Н-3 thiophene); 8.45 (1Н, s, Н-3 quinoline);
8.98 (1Н, d, J = 2.0, Н-5 quinoline)
5g
5h
7.37 (2Н, d, J = 8.4, С6H4); 7.45-7.52 (3Н, m, Н-4 thiophene + С6H4);
7.70 (1Н, dd, J = 1.6 and J = 9.2, Н-7 quinoline); 7.87 (1Н, d, J = 3.9, Н-3 thiophene);
8.02 (1Н, d, J = 9.2, Н-8 quinoline); 8.45 (1Н, s, Н-3 quinoline);
8.82 (1Н, d, J = 1.6, Н-5 quinoline)
7.36 (2Н, d, J = 8.8, С6H4); 7.47-7.53 (3Н, m, Н-4 thiophene + С6H4);
7.82 (1Н, dd, J = 8.8, Н-7 quinoline); 7.88 (1Н, d, J = 3.9, Н-3 thiophene);
7.94 (1Н, d, J = 8.8, Н-8 quinoline); 8.41 (1Н, s, Н-3 quinoline);
9.01 (1Н, s, Н-5 quinoline)
52

TABLE 2 (continued)
1
2
5i
7.54-7.63 (3Н, m, Н-4 thiophene + С6H4); 7.67 (1Н, d, J = 8.8, Н-7 quinoline);
7.89-7.96 (3Н, m, Н-3 thiophene + С6H4); 8.00 (1Н, d, J = 8.8, Н-8 quinoline);
8.43 (1Н, s, Н-3 quinoline); 8.85 (1Н, s, Н-5 quinoline)
5j
5k
7.53-7.62 (3Н, m, Н-4 thiophene + С6H4); 7.80 (1Н, d, J = 8.8, Н-7 quinoline);
7.89-7.99 (4Н, m, Н-3 thiophene + С6H4 + Н-8 quinoline); 8.43 (1Н, s, Н-3 quinoline);
8.99 (1Н, s, Н-5 quinoline)
7.31 (1Н, dd, J = 1.6 and J = 7.8, С6H3); 7.48-7.54 (2Н, m, Н-4 thiophene + С6H3);
7.71 (1Н, dd, J = 2.0 and J = 9.2, Н-7 quinoline); 7.91 (1Н, d, J = 3.9, Н-3 thiophene);
8.01-8.07 (2Н, m, С6H3 + Н-8 quinoline); 8.46 (1Н, s, Н-3 quinoline);
8.84 (1Н, d, J = 2.0, Н-5 quinoline)
5l
7.32 (1Н, dd, J = 1.2 and J = 7.8, С6H3); 7.48-7.53 (2Н, m, Н-4 thiophene + С6H3);
7.80 (1Н, d, J = 8.8, Н-7 quinoline); 7.91-7.97 (2Н, m, Н-3 thiophene + Н-8 quinoline);
8.04 (1Н, d, J = 1.2, С6H3); 8.42 (1Н, s, Н-3 quinoline); 9.02 (1Н, s, Н-5 quinoline)
5m
7.53 (1Н, d, J = 3.9, Н-4 thiophene); 7.61 (1Н, d, J = 8.8, Н-4 С6H3);
7.69 (1Н, dd, J =2.0 and J = 8.8, Н-7 quinoline); 7.73 (1Н, d, J = 8.8, Н-3 С6H3);
7.92 (1Н, s, Н-6 С6H3); 7.96 (1Н, d, J = 3.9, Н-3 thiophene);
8.05 (1Н, d, J = 8.8, Н-8 quinoline); 8.48 (1Н, s, Н-3 quinoline);
8.87 (1Н, s, Н-5 quinoline)
5n
7.53 (1Н, d, J = 3.9, Н-4 thiophene); 7.62 (1Н, d, J = 7.8, Н-4 С6H3);
7.74 (1Н, d, J = 7.8, Н-3 С6H3); 7.82 (1Н, d, J = 8.8, Н-7 quinoline);
7.92 (1Н, s, Н-6 С6H3); 7.95-8.02 (2Н, m, Н-3 thiophene + Н-8 quinoline);
8.47 (1Н, s, Н-3 quinoline); 9.04 (1Н, s, Н-5 quinoline)
_______
1
*The H NMR spectra were obtained in CDCl3 for 3a-c and 3f and in
DMSO-d6 for 3d, 3e, 3g-j, and 5a-n.
2-Acetyl-5-arylthiophenes are promising reagents for organic synthesis. We have studied the reaction of
ketones 3 with 5-chloroisatin 4a and 5-bromoisatin 4b under conditions of the Pfitzinger reaction [21, 22]. This
reaction of ketones with isatin is the most convenient method for the synthesis of cinchonic (4-quinoline-
carboxylic) acids. Many derivatives of cinchonic acid possess biological activity and several such compounds
are drugs [22, 23]. Acetylthiophenes 3a-d and 3h-j react with isatins 4a,b in ethanol at reflux in the presence of
KOH to give 2-(5-aryl-2-thienyl)-4-quinolinecarboxylic acids 5a-n in high yield.
Thus, we have shown that the arylation of 2-acetylthiophene by arenediazonium salts is a convenient
method for the synthesis 2-acetyl-5-arylthiophenes, which may be used for the preparation of synchonic acids
with arylthienyl fragments.
R1
O
Me
KOH, EtOH
R
+
S
N
H
O
O
4a, b
3a–d, h–j
O
OH
R1
R
S
N
5a–n
5 a R = 4-Me, R1 = Cl; b R = 4-Me, R1 = Br; c R = 4-F, R1 = Cl; d R = 4-F, R1 = Br;
e R = 2-Cl, R1 = Cl; f R = 2-Cl, R1 = Br; g R = 4-Cl, R1 = Cl; h R = 4-Cl, R1 = Br;
i R = 3-CF3, R1 = Cl; j R = 3-CF3, R1 = Br; k R = 2,5-Cl2, R1 = Cl; l R = 2,5-Cl2, R1 = Br;
m R = 2-Cl-5-CF3, R1 = Cl; n R = 2-Cl-5-CF3, R1 = Br
53

EXPERIMENTAL
The 1H NMR spectra of thiophenes 3a-c, 3f, and 5a-n were taken on a Varian Mercury 400 spectrometer
at 400 MHz, while the corresponding spectra of thiophenes 3d, 3e, and 3g-j were taken on a Bruker WM-250
spectrometer at 250 MHz using TMS as the internal standard.
2-Acetyl-5-arylthiophenes 3a-j. Aromatic amine (0.1 mol) was dissolved in 20% hydrochloric acid
(60 ml), heating when necessary. The solution was cooled to 0-5°C and a solution of NaNO2 (7 g) in water
(25 ml) was added dropwise with stirring. After completion of the reaction, the solution of arenediazonium
salt 2a-j was filtered and added dropwise to a mixture of 2-acetylthiophene 1 (12.6 g, 0.1 mol), CuCl2·2H2O
(1 g), and acetone (40 ml). The reaction was carried out at 15-25°C such that nitrogen was released at a
moderate rate. After nitrogen evolution ceased, 150 ml water was added to the reaction mixture. The precipitate
formed was filtered off and thiophenes 3c-g and 3i. If an oil is formed, as in the case of compounds 3a,b,h,j, it
was extracted with chloroform. After distilling off the solvent, the residue was distilled in vacuum and
recrystallized from ethanol.
6-Chloro- and 6-Bromo-substituted 2-(5-aryl-2-thienyl)-4-quinolinecarboxylic acids 5a-n. Ethanol
(50 ml) and water (5 ml) were added to a mixture of 5-aryl-2-acetylthiophene 3 (4 mmol), 5-chloroisatin 4a or
5-bromoisatin 4b (4 mmol), and KOH (0.70 g, 12.5 mmol). The reaction mixture was heated at reflux for 6 h,
then poured into water (100 ml), and brought to pH 7 by adding glacial acetic acid. The residue was filtered off
and recrystallized from ethanol-DMF.
REFERENCES
1.
2.
3.
4.
R. L. Martyak, N. D. Obushak, and V. S. Matiichuk, Zh. Org. Khim., 45, 555 (2009).
A. V. Dombrovskii, Usp. Khim., 53, 1625 (1984).
K. H. Saunders and R. L. Allen, Aromatic Diazo Compounds, Edward Arnold, London (1985).
H. Zollinger, Diazo Chemistry. 1. Aromatic and Heteroaromatic Compounds, VCH, Weinheim,
Germany (1994), p. 243.
5.
6.
C. S. Rondestvedt, in: Organic Reactions, vol. 24, John Wiley, New York-London (1976), p. 225.
N. D. Obushak, A. I. Lesyuk, N. I. Ganushchak, G. M. Mel’nik, and Yu. P. Zavalii, Zh. Org. Khim., 22,
2331 (1986).
7.
8.
9.
N. D. Obushak, N. I. Ganushchak, A. I. Lesyuk, L. M. Dzikovskaya, and P. P. Kisilitsa, Zh. Org. Khim.,
26, 873 (1990).
A. F. Oleinik, T. I. Vozyakova, G. A. Modnikova, and K. Yu. Novitskii, Khim. Geterotsikl. Soedin., 441
(1972). [Chem. Heterocycl. Soedin., 8, 402 (1972)].
N. D. Obushak, V. S. Matiichuk, and R. Z. Lytvyn, Khim. Geterotsikl. Soedin., 1166 (2008). [Chem.
Heterocycl. Chem., 44, 936 (2008)].
10.
11.
12.
R. Frimm, L. Fišera, and J. Kovač, Collect. Czech. Chem. Commun., 38, 1809 (1973).
L. Racane, V. Tralić-Kulenovic, D. W. Boykin, and G. Karminski-Zamola, Molecules, 8, 342 (2003).
L. Racane, V. Tralić-Kulenović, G. Karminski-Zamola, and L. Fišer-Jakić, Monatsh. Chem., 126, 1375
(1995).
13.
D. R. Shridhar, C. V. Reddy Sastry, S. C. Chaturvedi, R. Gurumurthy, P. P. Singh, C. Seshagiri Rao,
and A. Y. Junnarkar, Indian J. Chem., 23B, 692 (1984).
14.
15.
S. Kotha, K. Chakraborty, and E. Brachmachary, Synlett, 1621 (1999).
K. M. Lawson Daku, R. F. Newton, S. P. Pearce, J. Vile, and J. M. J. Williams, Tetrahedron Lett., 44,
5095 (2003).
54

16.
K. Arentsen, S. Caddick, F. G. N. Cloke, A. P. Herring, and P. B. Hitchcock, Tetrahedron Lett., 45,
3511 (2004).
17.
18.
19.
20.
21.
I. R. Baxendale, C. M. Griffiths-Jones, S. V. Ley, and G. K. Tranmer, Chem. Eur. J., 12, 4407 (2006).
A. Battace, M. Lemhadri, T. Zair, H. Doucet, and M. Santelli, Adv. Synth. Cat., 349, 2507 (2007).
T. Itahara, J. Org. Chem., 50, 5272 (1985).
N. D. Obushak, Yu. I. Gorak, V. S. Matiichuk, and R. Z. Lytvyn, Zh. Org. Khim., 44, 1712 (2008).
M.-G. A. Shvekhgeimer, Khim. Geterotsikl. Soedin., 323 (2004). [Chem. Heterocycl. Comp., 40, 257
(2004)].
22.
23.
J. F. M. da Silva, S. J. Garden, and A. C. Pinto, J. Braz. Chem. Soc., 12, 273 (2001).
M. D. Mashkovskii, Drugs [in Russian], Novaya Volna, Moscow (2000).
55