One-pot synthesis of 4-alkoxybenzo[c]thiophenes

Article abstract of DOI:10.1081/SCC-120030696

The reaction of N-bromosuccinimide with 4,5,6,7-tetrahydrobenzo[c]thiophen-4-ones in the presence of 2,2′-azo-bis-isobutyronitrile followed by heating under reflux with different alcohols produces 4-alkoxybenzo[c]thiophenes in good yield.

Full text of DOI:10.1081/SCC-120030696

This article was downloaded by: [Moskow State Univ Bibliote]
On: 09 February 2014, At: 10:51
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
One‐Pot Synthesis of 4‐Alkoxybenzo[c]thiophenes
Tahmineh Akbarzadeh a & Abbas Shafiee a
a Department of Chemistry and Pharmaceutical Sciences Research Center, Faculty of
Pharmacy , Tehran University of Medical Sciences , Tehran, Iran
Published online: 21 Aug 2006.
To cite this article: Tahmineh Akbarzadeh & Abbas Shafiee (2004) One‐Pot Synthesis of 4‐Alkoxybenzo[c]thiophenes,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:8,
1455-1462, DOI: 10.1081/SCC-120030696
To link to this article: http://dx.doi.org/10.1081/SCC-120030696
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of
the Content. Any opinions and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied
upon and should be independently verified with primary sources of information. Taylor and Francis shall
not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other
liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 8, pp. 1455–1462, 2004
One-Pot Synthesis of
4-Alkoxybenzo[c]thiophenes
*
Tahmineh Akbarzadeh and Abbas Shafiee
Department of Chemistry and Pharmaceutical Sciences Research Center,
Faculty of Pharmacy, Tehran University of Medical Sciences,
Tehran, Iran
ABSTRACT
The reaction of N-bromosuccinimide with 4,5,6,7-tetrahydro-
benzo[c]thiophen-4-ones in the presence of 2,20-azo-bis-isobutyronitrile
followed by heating under reflux with different alcohols produces
4-alkoxybenzo[c]thiophenes in good yield.
Key Words: One-pot synthesis; 4-Alkoxybenzo[c]thiophenes; N-bromo-
succinimide; a,b-Unsaturated cyclic ketone.
*
Correspondence: Abbas Shafiee, Department of Chemistry and Pharmaceutical
Sciences Research Center, Faculty of Pharmacy, Tehran University of Medical
Sciences, Tehran, Iran; E-mail: ashaifee@ams.ac.ir.
1455
DOI: 10.1081/SCC-120030696
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
1456
Akbarzadeh and Shafiee
INTRODUCTION
Useful procedures for the synthesis of aryl alkyl ethers via aromatization
of a,b-unsaturated cyclic ketones involve: dehydrogenation of 2-cyclohexen-
1-one parts in polycylic compounds over palladium black in refluxing
ethanol followed by methylation of the corresponding phenol with dimethyl
sulfate,[1] oxidative aromatization of 2-cyclohexen-1-one with VO(OR)Cl2
or VO(OEt)Cl2-AgOTf in alcohols,[2] or with iodine-cerium (IV) ammonium
nitrate in alcohols,[3] reaction of tetralone with isopropenyl acetate in the pre-
sence of PTSA followed by dehydrogenation with DDQ[4] and dehydrohalo-
genation of 2-bromo-1-tetralone derivatives followed by methylation of the
corresponding naphthol with dimethyl sulfate in the presence of potassium
carbonate.[5] To our knowledge no aryl alkyl ether has been so far synthesized
from 4-halo-a,b-unsaturated cyclic ketones. Here, we report a facile one-pot
synthesis of 4-alkoxybenzo[c]thiophene employing these intermediates.
Reaction of compound 1 with N-bromosuccinimide (NBS) and catalytic
amount of 2,20-azo-bis-isobutyronitrile (AIBN),[6] followed by refluxing
in different alcohols leads to the corresponding 4-alkoxybenzo[c]thiophene
derivatives 2 in good yield (Sch. 1). Several examples illustrating this method
are summarized in Table 1.
The structure of the intermediate was established as 7-bromo-4-
oxo-4,5,6,7-tetrahydrobenzo[c]thiophene 3. To confirm the structure of 3,
1
a-bromoketone 4 was prepared according to the literature.[7] The H NMR
of the two compounds were different. For instance compound 4 gave a triplet
at 4.64 ppm for BrCH-5, while in compound 3 BrCH-7 appeared as a triplet at
6.20 ppm. Heating of a-bromoketone 4 with different alcohols did not give the
desired compounds 2a–g and in all cases the starting material 4 was recovered
unchanged. However heating of compound 3 with different alcohols gave the
corresponding aryl alkyl ethers 2a–g (Sch. 2).
Scheme 1.

ORDER
REPRINTS
One-Pot Synthesis of 4-Alkoxybenzo[c]thiophenes
1457
Table 1. Conversion of a,b-unsaturated cyclic ketone to aryl alkyl
ether.
Time (hr)
step 1/step 2
Yield
(%)
Entry
R
2a
2b
2c
2d
2e
2f
Me
Et
1/6
1/8
1/7
1/12
1/8
1/9
1/10
6/12
6/10
0.5/12
0.5/12
0.5/12
0.5/12
0.5/12
0.5/12
0.5/12
96
97
83
71
75
78
76
48
45
82
75
74
62
55
56
52
n-Pr
iso-Pr
n-Bu
iso-Bu
iso-Pent
Me
2g
2h
2i
8aa
8b
8c
8d
8e
8f
Et
Me
Et
n-Pr
iso-Pr
n-Bu
n-Pent
n-Hex
8g
aThe structures of compounds 8a–g were established by spectral data
and exhibited physical data in accordance with the literature.[8–10]
A plausible way of formation of compounds 2 from 3 is shown in
Sch. 3. It proceeds by nucleophilic attack of the hydroxyl group of alcohol
on the carbonyl group of 3 to give hemiacetal 5 followed by elimination of
water to give 6 which subsequently undergoes the elimination of hydrogen
bromide to afford compound 2.
In order to assess the generality of the process, the reaction was studied
with 3,4-dihydronaphthalen-1(2H)-one 7 (Sch. 4). The reaction of compound
7 with NBS and AIBN followed by refluxing of the intermediate 9 with differ-
ent alcohols gave the expected 1-alkoxynaphthalenes (8a–g) in good yield.
In conclusion, we believe that this procedure presents a useful and
convenient alternative to the existing methods for aromatization of a,b-
unsaturated cyclic ketones to the corresponding aryl alkyl ethers.
EXPERIMENTAL
Melting points were taken on a Kofler hot stage apparatus and are uncor-
rected. The 1H NMR were obtained using Bruker FT-80 or Varian 400 unity

ORDER
REPRINTS
1458
Akbarzadeh and Shafiee
Scheme 2.
plus spectrometers and chemical shifts (d) are in ppm relative to internal
tetramethylsilane. Mass spectra were obtained using a Finnigan TSQ 70
mass spectrophotometer at 70 eV. Elemental microanalyses were within
+0.4% of theoretical values for C, H, and N.
General Procedure for the Synthesis of Compounds
2a–i and 8a–g
NBS (0.49 g, 2.77 mmol) and AIBN (10 mg) were added in one portion to
a refluxing solution of compound 1 or 7 (2.52 mmol) in carbon tetrachloride
(10 mL). When the reaction was complete (tlc control) the reaction mixture
was cooled to room temperature. The excess amount of suitable alcohol
(30 mL) was added and the mixture was refluxed for a time given in the
Table 1. The solvent was removed under reduced pressure and the residue
Scheme 3.

ORDER
REPRINTS
One-Pot Synthesis of 4-Alkoxybenzo[c]thiophenes
1459
Scheme 4.
was purified by flash chromatography (petroleum ether–chloroform 2 : 1) to
give following compounds:
Ethyl-4-methoxy-3-methylthiobenzo[c]thiophene-1-carboxylate
(2a). Yield 96%, m.p. 119–1208C. 1H NMR (CDCl3) d 7.90 (d, J ¼ 8.6 Hz,
1H, aromatic), 7.19 (dd, J ¼ 8.6, 7. 2 Hz, 1H, aromatic), 6.28 (d, J ¼ 7.2 Hz,
1H, aromatic), 4.39 (q, 2H, CH2), 3.93 (s, 3H, OCH3), 2.68 (s, 3H, SCH3), 1.41
(t, 3H, CH3). MS m/z: 282 (Mþ, 100), 254 (28), 238 (18), 210 (15), 16 (10).
Elemental analysis for C13H14O3S2 calcd.: C, 55.30; H, 5.00; S, 22.71; found:
C, 55.44; H, 5.12; S, 22.43.
Ethyl-4-ethoxy-3-methylthiobenzo[c]thiophene-1-carboxylate
1
(2b). Yield 97%, m.p. 93–948C. H NMR (CDCl3) d 7.87 (d, J ¼ 8.9 Hz,
1H, aromatic), 7.17 (dd, J ¼ 8.9, 7.5 Hz, 1H, aromatic), 6.25 (d, J ¼ 7.5 Hz,
1H, aromatic), 4.38 (q, 2H, CO2CH2), 4.14 (q, 2H, OCH2), 2.67 (s, 3H,
SCH3), 1.54 (t, 3H, CH3), 1.40 (t, 3H, CH3). MS m/z: 296 (Mþ, 100), 268
(38), 253 (43), 238 (60), 225 (40), 195 (42), 150 (43), 120 (20). Elemental
analysis for C14H16O3S2 calcd.: C, 56.73; H, 5.44; S, 21.63; found: C,
56.69; H, 5.09; S, 21.38.
Ethyl-4-propoxy-3-methylthiobenzo[c]thiophene-1-carboxylate
(2c). Yield 83%, m.p. 87–888C. 1H NMR (CDCl3) d 7.91 (d, J ¼ 8.8 Hz, 1H,
aromatic), 7.17 (dd, J ¼ 8.8, 7.4 Hz, 1H, aromatic), 6.26 (d, J ¼ 7.4 Hz, 1H,
aromatic), 4.38 (q, 2H, CO2CH2), 4.01 (t, 2H, O–CH2), 1.78 (m, 2H, CH2),
1.03 (t, 3H, CH3), 1.40 (t, 3H, CH3). MS m/z: 310 (Mþ, 48), 282 (58), 267
(80), 253 (70), 225 (38), 195 (100), 150 (68), 121 (25). Elemental analysis
for C15H18O3S2 calcd.: C, 58.04; H, 5.84; S, 20.66; found: C, 58.12; H,
5.88; S, 20.98.
Ethyl-4-isopropoxy-3-methylthiobenzo[c]thiophene-1-carboxylate
(2d). Yield 71%, m.p. 79–808C. 1H NMR (CDCl3) d 7.93 (d, J ¼ 8.8 Hz, 1H,

ORDER
REPRINTS
1460
Akbarzadeh and Shafiee
aromatic), 7.17 (dd, J ¼ 8.8, 7.4 Hz, 1H, aromatic), 6.26 (d, J ¼ 7.4 Hz, 1H,
aromatic), 4.69 (m, 1H, O–CH), 4.38 (q, 2H, CO2CH2), 2.67 (s, 3H,
SCH3), 1.46 (d, 6H, 2 ꢀ CH3), 1.40 (t, 3H, CH3). MS m/z: 310 (Mþ, 65),
267 (70), 253 (60), 225 (75), 195 (100), 180 (41), 150 (60), 121 (20). Elemen-
tal analysis for C15H18O3S2 calcd.: C, 58.04; H, 5.84; S, 20.66; found: C,
58.28; H, 6.11; S, 20.38.
Ethyl-4-butoxy-3-methylthiobenzo[c]thiophene-1-carboxylate
(2e). Yield 75%, m.p. 96–978C 1H NMR (CDCl3) d 7.88 (d, J ¼ 8.8 Hz, 1H,
aromatic), 7.17 (dd, J ¼ 8.8, 7.3 Hz, 1H, aromatic), 6.25 (d, J ¼ 7.3 Hz, 1H),
4.39 (q, 2H, CO2CH2), 4.07 (t, 2H, OCH2), 2.66 (s, 3H, SCH3), 1.82 (m, 4H,
CH2CH2), 1.41 (t, 3H, CH3), 1.01 (t, 3H, CH3). MS m/z: 324 (Mþ, 80), 268
(100), 253 (42), 225 (40), 195 (55), 180 (22), 150 (38). Elemental analysis
for C16H20O3S2 calcd.: C, 59.23; H, 6.21; S, 19.76; found: C, 59.01; H,
6.53; S, 19.49.
Ethyl-4-isobutoxy-3-methylthiobenzo[c]thiophene-1-caboxylate
(2f). Yield 78%, m.p. 85–868C. 1H NMR (CDCl3) d 7.8 (d, J ¼ 8.8 Hz, 1H,
aromatic), 7.17 (dd, J ¼ 8.8, 7.3 Hz, 1H, aromatic), 6.26 (d, J ¼ 7.3 Hz, 1H,
aromatic), 4.39 (q, 2H, CO2CH2), 3.61 (d, 2H, OCH2), 1.92 (m, 1H, CH),
1.40 (t, 3H, CO2CH2CH3), 0.95 (d, 6H, 2 ꢀ CH3). MS m/z: 324 (Mþ, 78),
268 (50), 253 (42), 238 (100), 225 (62), 195 (75), 150 (25). Elemental analysis
for C16H20O3S2 calcd.: C, 59.23; H, 6.21; S, 19.76; found: C, 59.45; H, 6.02;
S, 19.99.
Ethyl-4-isopentoxy-3-methylthiobenzo[c]thiophene-1-carboxylate
(2g). Yield 76%, m.p. 70–718C. 1H NMR (CDCl3) d 7.88 (d, J ¼ 8.8 Hz, 1H,
aromatic), 7.18 (dd, J ¼ 8.8, 7.4 Hz, 1H, aromatic), 6.27 (d, J ¼ 7.4 Hz, 1H,
aromatic), 4.39 (q, 2H, CO2CH2), 4.10 (t, 2H, OCH2), 2.68 (s, 3H, SCH3),
1.84 (m, 2H, CH2), 1.41 (t, 3H, CH2CH3), 1.18 (m, 1H, CH), 0.99 (d, 6H,
2 ꢀ CH3). MS m/z: 338 (Mþ, 80), 268 (100), 253 (35), 238 (30), 195 (40),
181 (20). Elemental analysis for C17H22O3S2 calcd.: C, 60.33, H, 6.55; S,
18.94; found: C, 59.97; H, 6.39; S, 19.01.
Ethyl-4-methoxy-3-methanesulfonylbenzo[c]thiophene-1-carboxylate
(2h). Yield 48%, m.p.191–1938C. 1H NMR (CDCl3) d 8.11 (d, J ¼
8.8 Hz, 1H, aromatic), 7.33 (dd, J ¼ 8.8, 7.3 Hz, 1H, aromatic), 6.67
(d, J ¼ 7.3 Hz, 1H, aromatic), 4.45 (q, 2H, CO2CH2), 4.04 (s, 3H, OCH3),
3.55 (s, 3H, SO2CH3), 1.43 (t, 3H, CH3). MS m/z: 314 (Mþ, 42), 286 (30),
269 (28), 195 (100), 161 (90), 120 (50), 89 (18). Elemental analysis for
C13H14O5S2 calcd.: C, 49.67; H, 4.49; S, 20.40; found: C, 49.92; H, 4.58; S,
20.17.
Ethyl-4-ethoxy-3-methanesulfonylbenzo[c]thiophene-1-carboxylate
1
(2i). Yield 45%, m.p.165–1678C. H NMR (CDCl3) d 8.03 (m, 1H, aro-
matic), 7.22 (m, 1H, aromatic), 6.68 (m, 1H, aromatic), 4.36 (q, 2H,
CO2CH2), 4.26 (q, 2H, OCH2), 3.52 (s, 3H, SO2CH3), 1.52 (t, 3H, CH3),

ORDER
REPRINTS
One-Pot Synthesis of 4-Alkoxybenzo[c]thiophenes
1461
1.44 (t, 3H, CH3). MS m/z: 328 (Mþ, 37), 299 (45), 269 (60), 195 (100), 161
(80), 132 (40). Elemental analysis for C14H16O5S2 calcd.: C, 51.20; H, 4.91; S,
19.53; found: C, 51.08; H, 4.59; S, 19.74.
Ethyl-7-bromo-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophene-
1-carboxylate (3). A solution of compound 1a (0.68 g, 2.52 mmol) in carbon
tetrachloride (10 mL) was heated to reflux and NBS (0.49 g, 2.77 mmol) and
AIBN (10 mg) were added in one portion to the refluxing solution. When the reac-
tion was complete (monitored by tlc), the reaction mixture was filtered, the solvent
was removed under reduced pressure and the residue was crystallized from carbon
tetrachloride and petroleum ether to give compound 3. Yield 0.69 g (78%). M.p.
1
170–1718C. H NMR (CDCl3)d 6.20 (t, 1H, BrCH-7), 4.36 (q, 2H, CH2), 3.02
(m, 2H, CH2), 2.61 (s, 3H, SCH3), 2.45 (m, 2H, CH2), 1.41 (t, 3H, CH3). MS
m/z: 350 (Mþ þ 2, 55), 348 (Mþ, 53), 269 (100), 241(55), 223 (20), 150 (10),
122 (18), 95 (10). Elemental analysis for C12H13BrO3S2 calcd.: C, 41.27; H,
3.75; S, 18.36; found: C, 40.92; H, 3.92; S, 18.12.
4-Bromo-3,4-dihydronaphthalen-1(2H)-one (9). This compound was
prepared similar to 3 as an oil in 70% yield. The compound was unstable
1
and decomposed on standing. H NMR (CDCl3) d 8.04 (dd, J ¼ 8.0, 1.6 Hz,
1H, aromatic), 7.56 (dt, J ¼ 8.0, 1.6 Hz, 1H, aromatic), 7.46 (m, 2H,
aromatic), 5.59 (t, 1H, BrCH-4), 3.17 (m, 1H, CH), 2.74 (m, 1H, CH), 2.58
(m, 2H, CH2). Ms m/z: 226 (Mþ þ 2, 45), 224 (Mþ, 46), 145 (100), 115
(80), 89 (20), 75 (25), 63 (40).
ACKNOWLEDGMENT
This work was partially supported by a grant from the Research Council
of Tehran University of Medical Sciences.
REFERENCES
1. Turner, R.B.; Meschino, J.A. Assignment of the sixth hydroxyl group and
a structural correlation with strophanthidin. J. Am. Chem. Soc. 1958, 80,
4862–4865.
2. Hirao, T.; Mori, M.; Ohshiro, Y. VO(OR)Cl2-induced oxidative
aromatization of a,b-unsaturated cyclohexenones. J. Org. Chem. 1990,
55, 358–360.
3. Horiuchi, C.A.; Fukunishi, H.K.; Yamaguchi, A.; Kiyomiya, H.; Kiji, Sh.
New oxidative aromatization of a,b-unsaturated cyclohexenones with
iodine cerium (IV) ammonium nitrate in alcohol. Chem. Lett. 1991,
1921–1924.

ORDER
REPRINTS
1462
Akbarzadeh and Shafiee
4. Mohan, H.R.; Rao, A.S. A convenient route for the synthesis of
plumbagin. Ind. J. Chem. 1997, 36B, 1044–1046.
5. Velusamy, T.P.; Krishna Rao, G.S. On the structure of 1,4-dimethyl-6-
methoxytetralin obtained from anisole via Fridel-crafts reaction with
alkyl acetone. Ind. J. Chem. 1981, 20B, 98–99.
6. Zhang, P.; Liu, R.; Cook, J.M. Regiospecific bromination of 3-methyl-
indoles with N-bromosuccinimide. Tetrahedron Lett. 1995, 36 (18),
3103–3106.
7. Prim, D.; Joseph, D.; Kirsch, G. New compounds from 6,7-dihydrobenzo
[c]thiophen-4(5H)-ones. Liebigs Annalen 1996, 239–245.
8. Dermer, V.H.; Dermer, O.C. The identification of naphthyl alkyl ethers as
picrates. J. Org. Chem. 1938, 3, 289–293.
9. Weast, R.C.; Astle, M.J.; Beyer, W.H. Physical constants of organic
compounds. In CRC Handbook of Chemistry and Physics, 69th Ed.;
CRC Press, Inc.: Florida, 1988–1989.
10. Gray, G.W.; Jones, B. The preparation of 4- and 5-n-alkoxy-1-naphthoic
and 6- and 7-n-alkoxy-2-naphthoic acids. J. Chem. Soc. 1954, 678–683.
Received in Poland May 10, 2003

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
Fair Use in the Classroom.
(AAP) website for guidelines on
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our
Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120030696