Synthesis of heterocycles from the products of anionic arylation of unsaturated compounds. 7*. Products of haloarylation of acrylic acid and its esters in the synthesis of benzo[b]thiophene derivatives

Article abstract of DOI:10.1023/A:1026190103546

3-Chloro-2-chlorocarbonylbenzo[b]thiophenes were obtained on oxidation of Meerwein reaction products, viz. 3-aryl-2-halopropionic acids and their esters, with thionyl chloride in the presence of N-benzyl-N-methylmorpholinium chloride. Disubstituted thioureas were synthesized by the reaction of these compounds with ammonium thiocyanate and aromatic amines, and were cyclized by interaction with iodoacetic acid with the formation of 4-thiazolidinone derivatives. The same cyclization in the presence of aromatic aldehydes leads to the formation of the corresponding 5-arylidene-substituted 4-thiazolidinones.

Full text of DOI:10.1023/A:1026190103546

Chemistry of Heterocyclic Compounds, Vol. 39, No. 7, 2003
SYNTHESIS OF HETEROCYCLES FROM
THE PRODUCTS OF ANIONIC ARYLATION OF
UNSATURATED COMPOUNDS. 7*. PRODUCTS OF
HALOARYLATION OF ACRYLIC ACID AND ITS ESTERS
b
IN THE SYNTHESIS OF BENZO[ ]THIOPHENE DERIVATIVES
N. D. Obushak, V. S. Matiichuk, and R. L. Martyak
3-Chloro-2-chlorocarbonylbenzo[b]thiophenes were obtained on oxidation of Meerwein reaction
products, viz. 3-aryl-2-halopropionic acids and their esters, with thionyl chloride in the presence of
N-benzyl-N-methylmorpholinium chloride. Disubstituted thioureas were synthesized by the reaction of
these compounds with ammonium thiocyanate and aromatic amines, and were cyclized by interaction
with iodoacetic acid with the formation of 4-thiazolidinone derivatives. The same cyclization in the
presence of aromatic aldehydes leads to the formation of the corresponding 5-arylidene-substituted
4-thiazolidinones.
Keywords: 3-aryl-2-halopropionic acids, benzo[b]thiophene, thiazolidinones, oxidation with thionyl
chloride, Meerwein reaction.
One of the most convenient methods of synthesizing benzo[b]thiophenes is the oxidation of cinnamic
acid and its derivatives [2-7] or 3-arylpropionic acids [2,6-9] with thionyl chloride. The synthetic possibilities of
this method depend mainly on the availability of the initial acids. Cinnamic acids substituted in the aromatic
ring or their esters may be obtained by the Meerwein reaction [10,11].
In the present work, continuing investigations on the products of interaction of unsaturated compounds
with arenediazonium salts [1,12-15], the possibility of synthesizing benzo[b]thiophene derivatives using the
products of haloarylation of acrylic acid has been studied.
We have established that the products of bromoarylation of acrylic acids 1a-e react with thionyl chloride
in the presence of pyridine with the formation of substituted 3-chloro-2-chlorocarbonylbenzo[b]thiophenes 2a-e
(method A).
Acids 1a-e were obtained by the interaction of arenediazonium bromides with acrylic acid catalyzed by
copper salts [16,17]. 3-Aryl-2-chloropropionic acids, obtained by the chloroarylation of acrylic acid, interact
with thionyl chloride analogously.
Products of the haloarylation of acrylic acid esters 3, 4 are more accessible from a preparative point of
view [10,14,18].
_______
* For Part 6 see [1].
__________________________________________________________________________________________
Lvov Ivan Franko National University, Lvov 79602, Ukraine; e-mail: kivan@txnet.com. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1019-1026, July, 2003. Original article submitted
May 18, 2000.
878
0009-3122/03/3907-0878$25.00©2003 Plenum Publishing Corporation

O
_
+
Br
N2
CuBr
OH
OH
+
R1
Br
O
1a–e
SOCl2
F
O
Cl
OH
SOCl2
R1
R1
Cl
B
S
6a–e
KOH
2a–e
O
O
Cl
OR
R1
R1
Hal
3a,c,e; 4a–d
OR
_
S
O
5a–e
+
CuBr (or CuCl2)
N2 Hal
OR
+
R1
O
1, 3, 4, 6 a R1 = H, b R1 = 2-Cl, c R1 = 4-Me, d R1 = 4-Cl, e R1 = 4-NO2; 3 Hal = Cl, R = Me;
4 Hal = Br, R = Et; 2, 5 a R1 = H, b R1 = 4-Cl, c R1 = 6-Me, d R1 = 6-Cl, e R1 = 6-NO2
We attempted to obtain benzo[b]thiophene derivatives by the oxidation of esters 3, 4 with thionyl
chloride. However compounds 5a-e were formed in low yield or were not isolated at all. It is possible to obtain
acid chlorides 2a-e from esters 3, 4 through cinnamic acids 6a-e (method B). Dehydrohalogenation and
saponification of esters 3, 4 takes place smoothly and in high yield on treatment with alkali.
3-Chloro-2-chlorocarbonylnaphtho[2,1-b]thiophene 8 was obtained from acid 7 by an analogous scheme
(method A). A modified Meerwein reaction (method B) proved to be more efficient in this case using the new
arylating reagent, 1-naphthalenediazonium tetrachlorocuprate(II) 9, proposed in [19]. This enabled the yield of
2-chloro-3-(1-naphthyl)propionic acid methyl ester 10 to be increased from 42 to 69%.
The use of equimolar amounts of triethylbenzylammonium chloride in place of pyridine in oxidations
with thionyl chloride increases the yield of acid chlorides 2 [5]. We used N-benzyl-N-methylmorpholinium
chloride in these reactions.
_
+
Cl
N2
O
COOMe, CuCl2
Cl
O
OMe
Cl
F
SOCl2
Cl
10
S
KOH
8
+
O
N2
_
COOMe
B
2
CuCl4
OH
2
7
9
879

We used acid chlorides 2a,c-e for the synthesis of more complex heterocyclic systems. The interaction
of these compounds with ammonium thiocyanate gave substituted 3-chloro-2-isothiocyanatocarbonylbenzo-
[b]thiophenes 11a,c-e, which were reacted without isolation with aromatic amines. N,N'-disubstituted thioureas
12a-h (Table 1) were synthesized in this way. The latter react with iodoacetic acid in the presence of sodium
acetate with closure of the 4-thiazolidinone ring (compounds 13a-d, Table 1).
Cl
R1
4-R2C6H4NH2
NH4SCN
N=C=S
Cl
S
2a–c,e
O
S
11a–c,e
H
H
N
R1
N
O
S
12a–h
R2
Cl
O
O
R1
AcONa
N
S
I
12a,b,e–f
+
S
OH
N
O
R2
13a–d
12 a–d R1 = H; a R2 = H, b R2 = Me; c R2 = Cl; d R2 = COOH; e R1 = 6-Me, R2 = H;
f R1 = 6-Me, R2 = Me; g R1 = 4-Cl, R2 = H; h R1 = 6-NO2, R2 = H; 13 a R1 = R2 = H;
b R1 = H, R2 = Me; c R1 = 6-Me, R2 = H; d R1 = 6-Me, R2 = Me
It was shown using the examples of thioureas 12a-e that cyclization with simultaneous condensation at
the methylene group of the thiazolidinone ring was possible. On interacting these compounds with iodoacetic
acid and benzaldehyde or 3-nitrobenzaldehyde the 5-arylidene-substituted 4-thiazolidinones 14a-c were formed
(Table 1).
O
O
H
AcONa
I
12a,c
+
+
OH
R3
R3
S
Cl
O
N
S
N
O
R2
14a–c
14 a R2 = H, R3 = NO2; b R2 = Cl, R3 = H; c R2 = Cl, R3 = NO2
880

TABLE 1. Characteristics of Compounds 12-14
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
Т., °С*
Yield, %
C
H
N
C16H11ClN2OS2
C17H13ClN2OS2
C16H10Cl2N2OS2
C17H11ClN2O3S2
C17H13ClN2OS2
C18H15ClN2OS2
C16H10Cl2N2OS2
C16H10ClN3O3S2
C18H11ClN2O2S2
C19H13ClN2O2S2
C19H13ClN2O2S2
C20H15ClN2O2S2
C25H14ClN3O4S2
C25H14Cl2N2O2S2
C25H13Cl2N3O4S2
55.23
55.40
3.18
3.20
7.95
8.08
156-157
158.5-159
180-181.5
218-220
162-163
177-178
175-176
178-179
240-241
230-232
223
85
74
80
75
65
83
84
56
85
63
40
38
41
50
53
12a
12b
12c
12d
12e
12f
56.69
3.65
7.58
56.58
3.63
7.76
50.23
50.40
2.57
2.64
7.23
7.35
52.16
2.75
7.14
52.24
2.84
7.17
56.40
56.58
3.52
3.63
7.69
7.76
57.38
3.95
7.53
57.67
4.03
7.47
50.51
50.40
2.60
2.64
7.33
7.35
12g
12h
13a
13b
13c
13d
14a
14b
14c
48.93
2.48
10.61
49.04
2.57
10.72
55.71
55.88
2.82
2.87
7.14
7.24
57.07
3.20
6.82
56.92
3.27
6.99
56.85
56.92
3.30
3.27
6.86
6.99
57.63
3.62
6.52
219-220
297-298
>300
57.89
3.64
6.75
57.48
57.75
2.70
2.71
8.02
8.08
58.83
2.69
5.44
58.94
2.77
5.50
54.22
54.16
2.28
2.36
7.40
7.58
290-291
_______
* Mp are given for compounds 12a-h, decomposition points are given for
compounds 13, 14.
3-Aryl-2-bromo(chloro)propionic acids and their esters may be used in addition to cinnamic and
hydrocinnamic acid derivatives for the synthesis of substituted 3-chloro-2-chlorocarbonylbenzo[b]thiophene.
The starting materials are readily obtained by the haloarylation of acrylic acids or acrylates. Combination of the
haloarylation reaction with subsequent oxidation of the obtained products with thionyl chloride enables
derivatives of benzo[b]thiophene to be obtained with various substituents in the benzene ring.
EXPERIMENTAL
1
The H NMR spectra were taken on a Varian VXR-300 (300 MHz) instrument in DMSO-d6, internal
standard was HMDS. The mass spectra were taken on a Finnigan MAT INKOS-50 chromato-mass spectrometer,
ionization energy was 70 eV.
Acids 1a-e were obtained by procedures close to those described in [16,17], their constants coincided
with the data of [16,17,20].
Procedures for the synthesis of esters 3, 4 are described in [15]. The constants of compounds 3, 4a,c
agreed with the data of [10,11,14,15].
881

TABLE 2. 1H NMR Spectra of the Compounds Synthesized
Chemical shifts, δ, ppm*
Com-
R2
NHC=S
(1H, s)
NHC=O
(1H, s)
CH2 (2H, s)
Benzo[b]thiophene fragment
R2C6H4, R3C6H4
pound
R1 (3H, s)
(3H, s)
or CH= (1H, s)
4-Н
5-Н
6-Н
7-Н
7.97 (1Н, m)
7.65 (2Н, m)
8.17 (1Н, m)
7.29 (1Н, t); 7.44 (2Н, t);
7.71 (2Н, d)
11.28
12.06
12a
7.97 (1Н, m)
7.98 (1Н, m)
7.85 (1Н, d)
7.65 (2Н, m)
7.66 (2Н, m)
7.46 (1Н, d)
8.18 (1Н, m)
8.18 (1Н, m)
7.95 (1Н, s)
8.17 (1Н, d)
7.23 (2Н, d); 7.58 (2Н, d)
7.49 (2Н, d); 7.73 (2Н, d)
7.23 (2Н, d); 7.57 (2Н, d)
7.29 (1Н, t); 7.44 (2Н, t);
7.70 (2Н, d)
7.44 (2Н, d)
7.30 (2Н, d);
7.38 (2Н, d)
7.30 (2Н, d);
7.38 (2Н, d)
3-O2NC6H4: 7.91 (2Н, m);
8.34 (1Н, d); 8.57 (1Н, s)
7.78 (2Н, d, С6Н5)
3-O2NC6H4; 8.35 (1Н, d),
8.61 (1Н, s)
2.33
2.32
11.25
11.40
11.08
11.68
12.00
12.02
11.99
12.04
12b
12c
12f
12g
2.50
2.42
7.60 (2Н, m)
7.90 (1Н, d)
7.91 (1Н, d)
7.56 (5Н, m)*2
7.57 (2Н, m)
8.01 (1Н, d)
8.02 (1Н, d)
4.22
4.20
13a
13b
2.42
2.42
7.77 (1Н, d)
8.01 (1Н, d)
7.34 (1Н)
7.78 (1Н, s)
8.16 (1Н, d)
4.19
8.12
13d
14a
7.50-7.65 (7Н, m)*2
7.93 (1Н, d)
7.50-7.67 (9Н, m)*2
7.96 (1Н, d)
8.19 (1Н, d)
8.03
8.15
14b
14c
7.87-8.00 (3Н, m)*2
7.50-7.67 (6H, m)*2
_______
* In the case of narrow multiplets the centers are indicated.
*2 Partial overlap of signals of the benzene ring protons.

2-Bromo-3-(2-chlorophenyl)propionic Acid Ethyl Ester (4b) was obtained in 48% yield;
1
bp 140-142°C (2 mm Hg), mp 41-43°C (ethanol). H NMR spectrum, δ, ppm: 1.22 (3H, t, CH3); 4.18 (2H, dq,
OCH2); 3.35 (1H, dd, CH2); 3.52 (1H, dd, CH2); 4.61 (1H, t, CH); 7.25-7.43 (4H, m, C6H4). Found, %:
Cl + Br 39.45. C11H12BrClO2. Calculated, %: Cl + Br 39.56.
2-Bromo-3-(4-chlorophenyl)propionic Acid Ethyl Ester (4d) was synthesized in 60% yield;
bp 142-143°C (2 mm Hg), nD20 1.5391. Found, %: Cl + Br 39.50. C11H12BrClO2. Calculated, %: Cl + Br 39.56.
3-(2-Chlorophenyl)acrylic Acid (6b). Sodium hydroxide (13 g) was dissolved with heating in ethanol
(70 ml), ester 4b (16 g, 55 mmol) was added, and the mixture boiled for 2.5 h. The reaction mixture was poured
into hot water (200 ml). Acid 6b was isolated by acidification with HCl.
Compounds 6a,c-e were obtained analogously. The constants of acids 6a-e corresponded with the data
of [21].
3-Chloro-2-chlorocarbonyl-R1-benzo[b]thiophenes (2a-e). A. A mixture of acid 1a-e (7.5 mmol),
N-benzyl-N-methylmorpholinium chloride (1.7 g, 7.5 mmol), and SOCl2 (2 ml) was heated to 140°C and further
SOCl2 (3 ml) poured in at this temperature. The mixture was heated for 2.5 h, and the product extracted with
boiling heptane. Yields (%) were 2a 58, 2b 30, 2c 55, 2d 52, and 2e 32.
B. Acid 6a-e (140 mmol), N-benzyl-N-methylmorpholinium chloride (20.4 g, 90 mmol), and SOCl2
(15 ml) were heated to 140°C. Then SOCl2 (35 ml) was added to the reaction mixture dropwise so that the
temperature did not exceed 135-140°C. Heating was continued for a further 3 h, and acid chlorides 2a-e
extracted with boiling heptane. Yields (%) were 2a 76, 2b 55, 2c 64, 2d 62, and 2e 58.
The melting points and spectral characteristics of compounds 2a-e corresponded with those given in
studies [2-5].
2-Chloro-3-(1-naphthyl)propionic Acid Methyl Ester (10). A. A solution of 1-naphthalenediazonium
chloride, obtained by the diazotization of 1-naphthylamine (14.3 g, 100 mmol), was added dropwise with
stirring to a mixture of methyl acrylate (9 ml, 100 mmol), CuCl2·2H2O (4 g), and acetone (100 ml). The reaction
mixture was heated gently until evolution of nitrogen started. The reaction proceeded at room temperature until
the end of gas evolution. Water (100 ml) was poured in, the mixture extracted with ether, and the extract dried
over MgSO4. The solvent was evaporated, and 1-chloronaphthalene and ester 10 [19] were obtained by
distillation in vacuum, yield 42%; bp 167-169°C (2 mm Hg), mp 48-49°C (ethanol).
B. Methyl acrylate (9 ml, 100 mmol), HCl (2 ml), acetone (100 ml), and water (100 ml) were mixed and
at 30°C naphthalenediazonium tetrachlorocuprate(II) 9 (5.16 g, 10 mmol), obtained by the procedure of [19],
was added with stirring. After the beginning of nitrogen evolution the temperature of the mixture was brought to
20-22°C, and further diazonium salt 9 (20.63 g, 40 mmol) was added in portions during 1 h. Treatment of the
reaction mixture and isolation of the products was carried out analogously to method A. The yield of compound
10 was 69%.
3-(1-Naphthyl)acrylic Acid (7). Compound 10 (15.6 g, 63 mmol) was added to a hot solution of KOH
(14 g) in ethanol (80 ml). The reaction mixture was boiled for 3 h, then poured into 10% HCl (300 ml). The
precipitate was filtered off, and recrystallized from ethanol. Yield 12 g (96%); mp 210-211°C (mp 211-212°C
[21]).
3-Chloro-2-chlorocarbonylnaphtho[2,1-b]thiophene (8). A mixture of acid 7 (12.9 g, 65 mmol),
N-benzyl-N-methylmorpholinium chloride (14.8 g), and thionyl chloride (13 ml) was heated to 140°C and
thionyl chloride (25 ml) was added dropwise at this temperature. Reaction was conducted for a further 2 h at
140°C. Compound 8 was extracted with boiling heptane. Yield 8.4 g (46%); mp 147-148°C (mp 147-149°C
[22]).
1-(3-Chlorobenzo[b]thien-2-ylcarbonyl)-3-phenylthiourea (12a). Acid chloride 2a (2.31 g,
10 mmol), dissolved in the minimum amount of anhydrous acetone, was added to a solution of ammonium
thiocyanate (0.91 g, 12 mmol) in acetone (15 ml). The reaction mixture was heated, aniline (0.93 g, 10 mmol)
was added, and the mixture boiled for 2-3 min. After cooling, the mixture was poured into water, the solid was
filtered off, and recrystallized from DMF.
883

Compounds 12b-h were obtained analogously (12d was crystallized from DMSO).
2-(3-Chlorobenzo[b]thien-2-ylcarbonylimino)-3-phenylthiazolidin-4-one (13a).
A
mixture of
thiourea 12a (1.9 g, 5.5 mmol), monoiodoacetic acid (1 g, 5.5 mmol), and anhydrous sodium acetate (0.9 g,
11 mmol), in glacial acetic acid (30 ml) was boiled for 4 h. The mixture was cooled, the solid separated, washed
with water, and with alcohol, and recrystallized from DMF.
Compounds 13b-d were obtained analogously.
2-(3-Chlorobenzo[b]thien-2-ylcarbonylimino)-5-(3-nitrobenzylidene)-3-phenylthiazolidin-4-one (14a).
A mixture of thiourea 12a (1.04 g, 3 mmol), monoiodoacetic acid (0.56 g, 3 mmol), 3-nitrobenzaldehyde
(0.45 g, 3 mmol), and anhydrous sodium acetate (0.5 g, 6 mmol) in glacial acetic acid (25 ml) was boiled for
3.5 h. The solid was filtered off, washed with water, and with alcohol, and recrystallized from DMF. Yield 0.6 g
(38%). Mass spectrum, m/z (I, %): 519 [M]+ (20), 386 (62), 352 (10), 236 (10), 195 (100), 167 (22), 123 (11),
77 (12).
Compounds 14b,c were obtained analogously.
Mass spectra, m/z (I, %): 14b, 508 [M]+ (8), 195 (100), 167 (30), 134 (75), 132 (22), 123 (23), 90 (15),
89 (15); 14c, 553 [M]+ (3), 195 (100), 179 (13), 167 (30), 132 (30), 123 (20), 89 (30).
The 1H NMR spectra of compounds 12-14 are given in Table 2.
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