Acylation of 3-acyl-2-methylbenzo[b]thiophene

Article abstract of DOI:10.1007/s10593-011-0737-9

The effect of the nature of the catalysts, reagents, and solvents on the acylation of 3-acyl-2-methyl-benzo[b]thiophene was studied. The structure of the products was supported by the two-dimensional ¹H and ¹³C NMR spectra (2D, HMBC)

Full text of DOI:10.1007/s10593-011-0737-9

Chemistry of Heterocyclic Compounds, Vol. 47, No. 2, May, 2011 (Russian Original Vol. 47, No. 2, February, 2011)
ACYLATION OF 3-ACYL-2-METHYLBENZO[b]THIOPHENE
1
1
1
1
V. N. Yarovenko , L. V. Khristoforova , L. I. Belen'kii , A. S. Shashkov ,
1
1
T. K. Baryshnikova , and M. M. Krayushkin *
The effect of the nature of the catalysts, reagents, and solvents on the acylation of 3-acyl-2-methyl-
1
benzo[b]thiophene was studied. The structure of the products was supported by the two-dimensional H
1
3
and C NMR spectra (2D, HMBC).
Keywords: 3-acyl-2-methylbenzo[b]thiophene, diketeones, 2-methylbenzo[b]thiophene, X-ray diffraction
structural analysis, electrophilic substitution.
Benzothiophene derivatives are commonly used in the synthesis of photochromic compounds [1-4] and
biologically active derivatives [5-7]. Thus, there is considerable current interest in developing convenient
methods for the functionalization of benzothiophenes. In light of the electron-donor nature of this system, it is
conveniently modified using aromatic electrophilic substitution. However, such reactions can be complicated by
the formation of isomers.
In the present work, we attempted to prepare 3-acyl-2-methylbenzo[b]thiophenes and their derivatives
substituted in the benzene ring as starting compounds for the synthesis of compounds with photochromic
properties.
An attractive method for the functionalization of 3-acyl-2-methylbenzo[b]thiophenes is the introduction
of acyl substituents, which can subsequently be converted into various functional groups, including heterocyclic
fragments. In the present work, we studied the acylation of 3-acyl-2-methylbenzo[b]thiophenes 1a [8] and 1b,
which were obtained in good yields by the reaction of 2-methylbenzo[b]thiophene (2) [9] with acetyl chloride
and chloroacetyl chloride in methylene chloride in the presence of AlCl3.
O
X
Me
XCH COCl
2
Me
S
S
AlCl3
2
1a,b
1
a X = H, b X = Cl
_
*
______
To whom correspondence should be addressed, e-mail: mkray@mail.ioc.ac.ru.
1
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Pr., Moscow
1
19991, Russia.
_
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 211-218, February, 2011. Original
article submitted January 24, 2011.
1
66 0009-3122/11/4702-0166©2011 Springer Science+Business Media, Inc.

Since the repeated acylation of 3-acyl-2-methylbenzo[b]thiophenes 1a and 1b may lead to the formation
of benzene ring regioisomers, we studied the effect of the nature of the catalysts, reagents, and solvents on the
regiospecificity of this reaction. We should note that the acylation of acyl derivatives 2-methylbenzo-
[b]thiophene (2) had not been studied previously.
There is a report in the patent literature concerning the bromination of 2-aminoacylbenzo[b]thiophene at
C-6 of the benzene ring [11].
The reaction of benzothiophene 1a with acetyl chloride in various solvents including dichloroethane,
methylene chloride, and nitrobenzene in the presence of two equivalents of AlCl leads to a mixture of 6- (3a)
3
and 4-acetyl derivatives (3b). The reaction does not proceed with other catalysts such as SnCl , TiCl , and
4
4
ZnCl2.
Me
O
O
O
Me
Me
AcCl
1
a
Me
Me
+
Me
2
equiv. AlCl3
S
S
O
3
a
3b
The structure of the products was established by analyzing one- and two-dimensional NMR spectra
Table 1). The splitting of the benzene ring proton signals indicated that the acyl substituent in isomer 3a is at C-
(
5
or C-6, while this substituent in isomer 3b is at C-4' or C-6'. Localization of the substituent at C-6 in 3a and at
C-4' in 3b follows from analysis of the correlation peaks in the HMBC spectrum due to coupling of the protons
and carbon atoms separated by three bonds.
H
b"
H
X
O
4
4
H
O
5'
H
9
10
O
X
10'
9
'
b'
4
H
4a'
X
H
4a
H
H
3
H
4'
3'
X
H
5
H
H
2
8
2
'
8
'
6
H
b"
6
7a S
H
H
6
b'
1
6'
7
H
7a' S
7
'
H H
1
'
O
H
H
X = H, Cl
Thus, the proton H-4 has correlation peaks with three quaternary carbon atoms separated from it by three
bonds and, consequently, the acetyl substituent is found specifically at C-6 and not at C-5. Similarly, the proton
H-6' in isomer 3b has correlation peaks due to coupling through three bonds with two quaternary carbon atoms,
which is possible if the acyl substituent is at C-4' but not at C-7'. The other correlations in the HMBC spectrum are
in complete accord with the proposed structures for these two isomers. Table 1 also gives the chemical shifts in the
1
13
H and C NMR spectra of the isomers and correlations in the HMBC spectra confirming the structure of 5a-7a
and 5b-7b.
The ratio of these isomers depends on the reaction time and the ratio of the AlCl catalyst and the
3
acylation reagent. The reaction gives 90% compound 3a and 10% compound 3b in the presence of two or three
equivalents of AlCl and the acyl halide in dichloroethane. In order to increase the yield of the minor isomer 3,
3
we varied the ratio of the catalyst and acylation reagent and the reaction time. The yield of isomer 3b is raised to
4
0% by using a sixfold excess of AlCl and threefold excess of acetyl chloride.
3
1
67

1
13
TABLE 1. Chemical Shifts in the H and C NMR Spectra of Isomers
a-7a and 3b-7b and Correlations in the HMBC Spectra Confirming the
Structure of these Compounds
3
1
3
1
Correlation peaks
in the НМВС
spectrum
С/ Н, δ, ppm
Atom
number
3
а and 3b
5a and 5b
6a and 6b
7a and 7b
С(2)
153.07
153.13
133.00
131.52
141.84
140.27
125.08/
159.01
159.68
135.18
133.97
144.36
142.43
159.31
158.91
135.12
135.09
144.05
144.21
158.31
158.98
136.98
137.05
142.99
143.05
С(2')
С(3)
С(3')
С(4a)
С(4a')
С(4)
125.01/
8.59 d
124.43/
8.68 d
125.44/
8.68 d
H-4/C(6),
C(7a), C(3)
8
.25 d
С(4')
129.88
197.55
26.20/
130.12
199.25
130.91
193.43
135.46
193.38
C(4b')
C(4b'')
27.24/
2.68 s
46.48/
4.80 s
46.41/
4.84 s
H-4b''/C(4')
2
.75 s
125.25/
.99 d
123.80/
.99 d
С(5)
С(5')
126.51/
7.97 d
126.98/
8.06 d
127.31/
8.26 d
H-5/C(4a),
C(7), С(6b')
7
125.23/
7.97
125.89/
8.06 d
125.90/
8.26 d
H-5'/C(4b'),
C(7'), C(3')
7
С(6)
133.88
197.28
26.69/
134.53
199.01
133.44
192.65
133.17
193.38
C(6b')
C(6b'')
27.52/
2.68 s
46.28/
4.83 s
46.41/
4.81 s
H-6b''/C(6)
2
.68 s
127.20/
.54 t
122.36/
.37 br. s
129.36/
.58 d
С(6')
С(7)
С(7')
126.97/
7.50 t
126.14/
7.43 t
126.31/
7.53 t
H-6'/C(4'), C(7a')
7
121.45/
8.42 br. s
121.51/
8.86 br. s
123.31/
8.83 br. s
H-7/C(6b'),
C(4a), C(5)
8
128.98/
8.84 d
129.01/
7.73 d
128.79/
7.69 d
H-7'/C(4a'), C(5')
8
С(7a)
С(7a')
С(8)
137.21
135.67
16.89
140.01
140.18
19.08/
138.56
137.05
140.41
143.05
16.01/
2.84 s
16.83/
2.87 s
H-8/C(2), C(3)
H-8'/C(2'), C(3')
2
.84 s
19.24/
.78 s
С(8')
17.39
17.31/
2.84 s
17.34/
2.93 s
2
С(9)
195.85
195.34
31.99
190.01
189.46
46.73/
190.21
189.14
197.46
198.24
С(9')
С(10)
45.54/
4.98 s
27.34/
2.46 s
H-10/C(3)
H-10'/C(3')
4
.80 s
46.24/
.82 s
C(10')
31.90
45.43/
5.02 s
28.51/
2.56 s
4
It is interesting to note that maintenance of a mixture of the two isomers in ethanol for several days leads
to the formation of naphthothiophene 4, which, probably is formed by cyclization of diketone 3b. This is further
evidence for the formation of isomer 3b.
O
Me
O
Me
3
b
Me
S
4
1
68

We showed that diacylated derivatives 3a and 3b can also be obtained in one step in the reaction of
-methylbenzo[b]thiophene (2) with two equivalents of acetic anhydride in the presence of AlCl3.
The same approach may be used to prepare various symmetrical and asymmetrical diketones 5-7.
2
X
Y
Y
O
O
O
1
a,b
+
Me
Me
O
X
S
S
5b–7b
5
a–7a
5a,b X = H, Y = Cl; 6a,b X = Y = Cl; 7a,b X = Cl, Y = H
The structure of 4-acetyl-2,3-dimethylnaphtho[1,8-b,c]thiophen-5-one (4) was unequivocally established
by X-ray diffraction structural analysis (see Fig. 1 and Table 2).
Fig. 1. General view of naphthothiophenone 4 showing the thermal ellipsoids of the atoms (p = 50%).
EXPERIMENTAL
1
The H NMR spectra were taken on a Bruker Avance 600 spectrometer at 600 MHz in CDCl . The
3
residual protons of the solvent ( 7.25 ppm) served as the internal standard. The mass spectra were taken on a
Kratos mass spectrometer with direct sample inlet into the ion source. The ionization energy was 70 eV and the
control voltage was 1.75 kV. The melting points were determined on a Boetius heating block and not corrected.
Commercially available reagents obtained from Acros were used in this work.
1
69

TABLE 2. Major Bond Lengths (l) in Naphthothiophenone 4
Bond
S(1)–C(9)
l, Å
Bond
l, Å
1.722(2)
1.725(3)
1.370(3)
1.422(4)
1.442(4)
1.353(3)
1.494(4)
1.455(4)
C(5)–C(15)
C(6)–C(7)
1.506(4)
1.466(4)
1.383(4)
1.388(3)
1.387(4)
1.380(4)
1.370(4)
1.384(4)
S(1)–C(2)
C(2)–C(3)
C(3)–C(8)
C(3)–C(4)
C(4)–C(5)
C(4)–C(14)
C(5)–C(6)
C(7)–C(12)
C(7)–C(8)
C(8)–C(9)
C(9)–C(10)
C(10)–C(11)
C(11)–C(12)
3
-Chloroacetyl=2-methylbenzo[b]thiophene (1b). Chloroacetyl chloride (0.31 g, 27.1 mmol) was
added to a solution of 2-methylbenzo[b]thiophene [9] (0.5 g, 3.38 mmol) in dry dichloroethane at from -5 to
°C. The reaction mixture was stirred for 30 min and then AlCl (1.3 g, 9.75 mmol) was added in portions. The
0
3
reaction was carried out over 5 h at room temperature. The mixture was then poured into 10% hydrochloric acid
and extracted with methylene chloride. The organic layer was washed with three 150-ml water portions, dried
over magnesium sulfate, and filtered. The solvent was distilled off. The oily precipitate formed was triturated
1
with ethanol, filtered, and washed with ice ethanol to give thiophene 1b in 73% yield; mp 128°C (ethanol). H
NMR spectrum, , ppm (J, Hz): 2.75 (3H, s, 2-CH ); 4.45 (2H, s, CH ); 7.26 (2H, m, H-5, H-6); 7.77 (1H, d,
3
2
+
+
J =7.9, H-7); 8.44 (1H, d, J = 8.4, H-4). Mass spectrum, m/z (I , %): 224 [M] (100), 189 [M-Cl] (88), 148
rel
+
+
+
[
M-ClCH CO] (24), 134 [M-CHCH CO-Me] (45). Found: m/z 224.7034 [M] . C H ClOS. Calculated:
2 2 11 9
M 224.7065.
Isomers 3,6-Diacetyl-2-methylbenzo[b]thiophene (3a) and 3,4-Diacetyl-2-methylbenzo[b]thio-
phene (3b). Acetyl chloride (0.52 g, 6.5 mmol) was added to a solution of 1-(2-methylbenzo[b]thiophen-
3
-yl)ethanol (1a) (0.5 g, 2.63 mmol) in dry dichloroethane at from -5 to 0°C and stirred for 30 min. Then, AlCl3
(
1.05 g, 7.9 mmol) was added in portions. The reaction was carried out over 3 h at room temperature. The
temperature was then raised to 60°C and stirred for an additional 6-7 h. The mixture was poured into 10%
hydrochloric acid and extracted with methylene chloride. The organic solution was washed with three 150-ml
water portions, dried over magnesium sulfate, and filtered. The solvent was distilled off. The oily precipitate
formed was triturated with ethanol, filtered, and washed with ice ethanol. The precipitate was subjected to
chromatography on a silica gel column using 3:2 petroleum ether–ethyl acetate as eluent. The isomers were
1
obtained in 83% yield (0.49 g) as a mixture. The 3a/3b isomer ratio was determined using H NMR
1
spectroscopy (60:40). H NMR spectrum, , ppm (J, Hz): isomer 3a) 2.68 (3H, s, 3-C(O)CH ); 2.75 (3H, s,
3
6
-C(O)CH ); 2.83 (3H, s, 2-CH ); 7.99 (1H, d, J = 8.1, H-5); 8.26 (1H, d, J = 8.65, H-4); 8.37 (1H, br. s, H-7);
3 3
isomer 3b) 2.67 (3H, s, 3'-C(O)CH ); 2.75 (3H, s, 4'-C(O)CH ); 2.84 (3H, s, 2'-CH ); 7.54 (1H, t, J = 7.8, H-6');
3
3
3
+
+
7
(
.99 (1H, d, J = 8.1, H-5'); 8.58 (1H, d, J = 8.2, H-7'). Mass spectrum, m/z (I , %): 232 [M] (35), 217 [M–Me]
rel
100), 189 [M-MeCO] (14), 174 [M-Me–MeCO] (37), 146 [M-MeCO-MeCO] (32). Found, %: C 67.20;
+
+
+
H 5.18; S 13.82. C H O S. Calculated, %: C 67.22; H 5.21; S 13.80.
1
3
12
2
4
-Acetyl-2,3-dimethylnaphtho[1,8-b,c]thiophen-5-one (4). The 60:40 mixture of isomers 3a,b (0.1 g)
was dissolved in 5 ml ethanol upon heating and maintained for two weeks. The precipitate formed was washed
+
with hexane. Found: m/z 256.3184 [M] . C H O S. Calculated: M 256.3195. X-ray diffraction structural
1
5
12
2
analysis.
Isomers 6-Acetyl-3-chloroacetyl-2-methylbenzo[b]thiophene (5a) and 4-Acetyl-3-chloroacetyl-2-
methylbenzo[b]thiophene (5b) were obtained in 63% yield as a mixture from thiophene 1b analogously to
1
1
compound 3. The 5a/5b isomer ratio was determined by H NMR spectroscopy (70:30). H NMR spectrum, ,
ppm (J, Hz): isomer 5a) 2.68 (3H, s, 3-C(O)CH ); 2.84 (3H, s, 2-CH ); 4.80 (2H, s, CH ); 7.97 (1H, d, J = 8.2,
3
3
2
H-5); 8.42 (1H, br. s, H-7); 8.59 (1H, d, J = 8.4, H-4); isomer 5b) 2.68 (3H, s, 3'-C(O)CH ); 2.78 (3H, s, 2'-
3
1
70

CH
3 2
); 4.82 (2H, s, CH ); 7.50 (1H, t, J = 7.9, H-6'); 7.97 (1H, d, J = 8.1, H-5'); 8.84 (1H, d, J = 8.15, H-7'). Mass
+
+
+
+
spectrum, m/z (I , %): 266 [M] (68), 231 [M-Cl] (88), 190 [M-ClCH CO] (46), 148 [M-ClCH CO-CH CO]
rel
2
2
2
(
44). Found, %: C 58.50; H 4.11; Cl 13.21; S 12.05. C H ClO S. Calculated, %: C 58.54; H 4.16; Cl 13.29;
13 11 2
S 12.02.
Isomers 3,6-Dimethyl(chloroacetyl)-2-methylbenzo[b]thiophene (6a) and 3,4-Di(chloroacetyl)-
-methylbenzo[b]thiophene (6b) were obtained as a mixture in 56% yield from thiophene 1b analogously to
2
1
1
compound 3. The 6a/6b isomer ratio was determined by H NMR spectroscopy (90:10). H NMR spectrum, ,
ppm (J, Hz): isomer 6a) 2.84 (3H, s, 2-CH ); 4.98 (2H, s, –C(O)CH Cl); 4.83 (2H, s, C(O)CH Cl); 8.06 (1H, d,
3
2
2
J = 8.3, H-5); 8.68 (1H, d, J = 8.55, H-4); 8.86 (1H, br. s, H-7); isomer 7a) 2.84 (3H, s, CH ); 5.02 (2H, s,
3
-
-C(O)CH Cl); 4.80 (2H, s, –C(O)CH Cl); 7.43 (1H, t, J = 7.9, H-6); 7.73 (1H, d, J = 8.1, H-7); 8.06 (1H, d,
2
2
+
+
+
J = 8.0, H-5). Mass spectrum, m/z (I , %): 302 [M] (65), 266 [M-Cl] (71), 230 [M-2Cl] (57), 148
[
rel
+
M-2ClCH CO] (43). Found, %: C 51.80; H 3.37; Cl 23.57; S 10.61. C H Cl O S. Calculated, % C 51.84;
2 13 10 2 2
H 3.35; Cl 23.54; S 10.65%.
Isomers 3-Acetyl-6-chloroacetyl-2-methylbenzo[b]thiophene (7a) and 3-Acetyl-4-chloroacetyl-2-
methylbenzo[b]thiophene (7b) were obtained in 59% yield as a mixture from thiophene 1a analogously to
1
1
compound 3. The 7a/7b isomer ratio was determined by H NMR spectroscopy (80:20). H NMR spectrum, ,
ppm (J, Hz): isomer 7a) 2.87 (3H, s, 2-CH ); 2.46 (3H, s, –C(O)CH ); 4.81 (2H, s, CH ); 8.68 (1H, d, J = 8.35,
3
3
2
H-4); 8.26 (1H, d, J = 8.1, H-5); 8.83 (1H, br. s, H-7); isomer 7b) 2.93 (3H, s, 2-CH ); 2.46 (3H, s, C(O)CH ); 4.84
3
3
(
2H, s, CH ); 7.69 (1H, t, J = 7.8, H-6'); 8.26 (1H, d, J = 8.1, H-7'); 8.69 (1H, d, J = 8.1, H-7'). Mass spectrum, m/z
2
+
+
+
+
(I , %): 266 [M] (68), 231 [M-Cl] (88), 190 [M-ClCH CO] (46), 148 [M-ClCH CO-CH CO] (44). Found, %:
rel
2
2
2
C 58.58; H 4.19; Cl 13.18; S 12.08. C H ClO S. Calculated, %: C 58.54; H 4.16; Cl 13.29; S 12.02.
1
3
11
2
X-ray Diffraction Analysis of Thiophenone 4. The unit cell parameters of orthorhombic crystals of
thiophenone 4 (C H O S, M 256.31) were determined at 100 K: a = 6.953(1), b = 10.665(2), c = 15.414(3) Å,
1
5
12
2
3
3
-1
V = 1143.1(4) Å , Z = 4 (Z' = 1), space group P2 2 2 , d =1.489 g/cm , (MoK) = 2.72 cm , F(000) = 928.
1
1
1
calc
The intensities of 5976 reflections were measured at 100 K on a SMART APEX II CCD diffractometer with

(MoK) = 0.71072 Å, -scanning, 2 < 56° and 2758 independent reflections (R = 0.0388) were used in the
int
subsequent refinement. The structure was solved by the direct method and refined anisotropically by the full
2
matrix method of least squares relative to F hkl. The positions of the hydrogen atoms were calculated from
geometric considerations and refined isotropically with fixed thermal parameters Uiso = 1.2C . The final
iso
reliability factors for the structural determination of 4: R1 = 0.0487 (calculated relative to Fhkl for 2230
2
reflections with I > 2(I), wR2 = 0.1310 (calculated relative to F hkl for all reflections, GOOF = 1.020. The
calculations were carried out using the SHELXTL 5.10 program package.
The authors thank K. A. Lysenko of the Institute of Organoelement Compounds of the Russian
Academy of Sciences for carrying out the X-ray diffraction study.
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