Synthesis of Novel Benzothiophene Derivatives via Cyclization Reactions
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ynthesis of Novel Benzothiophene Derivatives via Cyclization Reactions A. K. Hamaa, M. A. S. Algsoa, E. Kavaka, and A. Kivraka,* a
Department of Chemistry, Van Yüzüncü Yil University, Van, 65080 Turkey *e-mail: [email protected]
Received January 31, 2020; revised February 12, 2020; accepted February 18, 2020
Abstract—The Sonogashira cross coupling reaction of 2-bromo-5-(4-methoxyphenyl)thiophene and 1-ethynyl2-(methylsulfanyl)benzene gave 2-(4-methoxyphenyl)-5-{[2-(methylsulfanyl)phenyl]ethynyl}thiophene which was subjected to electrophilic cyclization by the action of iodine to obtain 3-iodo-2-[5-(4-methoxyphenyl)thiophen-2-yl]-1-benzothiophene. Stille and Sonogashira coupling reactions of the latter afforded a series of new 3-substituted 2-[5-(4-methoxyphenyl)thiophen-2-yl]-1-benzothiophene derivatives of potential pharmacological interest. Keywords: benzothiophenes; heteroaromatic compounds, cyclization reactions, coupling reactions
DOI: 10.1134/S1070428020070222 Heterocycles constitute one of the largest classes of organic compounds and are of huge biological and industrial importance. Heterocyclic compounds have been used in the development of biologically active compounds, as well as to understand living processes and improve the quality of life [1–5]. Thiophene structure can be found in certain natural products and is incorporated in many pharmacologically active compounds [6–9]. Thiophene derivatives have been used as antidepressants, neuroleptics, antidiabetics, antihypertensives, antispasmodics, analgesics, and antimetabolics [9–12]. Additionally, thiophene ring is present in many important compounds used for the preparation of liquid crystals, light-emitting diodes, and photovoltaic materials [13–19]. Benzothiophenes have also been used in medicinal chemistry, and they
have attracted great interest in industry, as well as in academic research [15, 20]. Benzothiophene derivatives exhibit a wide range of pharmacological activities [12] (Fig. 1). Numerous synthetic routes have been reported for the preparation of benzothiophene derivatives. Recently, electrophilic cyclization reactions of alkynes with halogen, sulfur, and selenium electrophiles have been shown to be a very powerful tool for the design of a variety of interesting carbo- and heterocyclic structures [8, 21–24]. Electrophilic cyclization reactions are generally very efficient and clean, and they proceed under very mild conditions and tolerate nearly all functional groups. Iodine-containing products can be further converted to a broad range of functionalized derivatives via palladium-catalyzed reactions [25].
N
N
Cl
N
HO
O O
O N
Cl
NH2
O
OH
S
S
N
CH3
S OH HO
Cl
S Raloxifene
Sertaconazole
Zileuton
Fig. 1. Benzothiophene-based commercially available drugs.
1272
Benocyclidine
1273
SYNTHESIS OF NOVEL BENZOTHIOPHENE DERIVATIVES Scheme 1. Br
I
MeO
S MeO
S MeO
1
2
3
SiMe3
CH
I
SMe
SMe
5
SMe
6
7 I
3
+
S
7
S MeS
MeO
MeO
8
9
In this study, we describe a new methodology for the formation of novel benz
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