Key words heterocycles - benzo[
b ]thiophene - nucleophilic aromatic substitution - thiol - cyclization
Benzo[b ]thiophene derivatives represent a major class of compounds displaying a wide range
of biological activities, acting as selective estrogen modulators,[
1
] antagonists for a vascular 5-HT1B receptor,[
2
] partial agonists at the benzodiazepine receptor,[
3
] and ligands for α1 and 5HT1A receptors.[
4
] The development of new methods for the synthesis of sulfur-containing heterocycles
is important in medicinal chemistry. Among these structures, benzothienopyridines
were recently reported to be highly efficient inhibitors of Eg5 kinesin and also cell-cycle
specific inducers of apoptosis in cancer cells.[
5
] Focusing on innovative methodologies to provide efficient access to the benzo[b ]thiophene nucleus is consistent with the widespread presence of this skeleton in
synthetic molecules.
In the laboratory, the functionalization of the benzo[b ]thiophene skeleton has already been described at the C-2 position (through pallado-catalyzed
direct arylation)[
6
] and the C-3 position (either by SN Ar or Friedel–Crafts acylation).[
7
] More recently, a new thematic direction was investigated to target molecules of
major therapeutic interest, such as alkaline phosphatase inhibitors[
8
] or a Raloxifene synthetic intermediate.[
9
]
As a natural extension to our research projects, we investigated the direct access
to 2-acetylbenzo[b ]thiophenes 1 and 2-acetyl-3-aminobenzo[b ]thiophenes 2 (Figure [1 ]). Several methods have already been reported for the synthesis of 2-acetylbenzo[b ]thiophene 1 , starting from 2-chlorobenzaldehyde,[
10
] 2-nitrobenzaldehyde,[
11
] 2-mercaptobenzaldehyde,[
12
] 2-mercaptobenzoic acid,[
13
] dihalobenzene derivatives[
14
] and thiophenol.[
15
] However, very little attention has been paid to 2-acetyl-3-aminobenzo[b ]thiophene 2 that, according to the literature, is prepared in four steps from o -(benzylthio)benzoic acid, with an overall yield of 60%.[
16
]
Figure 1 Structure of 2-acetylbenzo[b ]thiophenes 1 and 2-acetyl-3-aminobenzo[b ]thiophenes 2
In all of these reported methods, hazardous reagents and/or solvents are widely used,
and the synthetic strategies require multistep reaction sequence. This encouraged
us to consider a direct water-mediated reaction for the synthesis of highly functionalized
benzo[b ]thiophenes.
In this Letter we present a new efficient methodology for the synthesis of substituted
2-acetylbenzo[b ]thiophenes from simple aromatic and heteroaromatic halides. The strategy developed
in the laboratory to access a library of compounds 1 and 2 is based on a one-step sequence between 2-mercaptoacetone and the corresponding aryl
halides. An initial attempt involved commercially available 2-chlorobenzaldehyde (1
equiv) reacting with 2-mercaptoacetone (1 equiv), in the presence of potassium carbonate
(2 equiv), in water at 90 °C. After only two hours of reaction, the desired benzo[b ]thiophene (1a ) was isolated, in a high yield of 84%, by simple filtration (Scheme [1 ]).[
17
] 2-Mercaptoacetone was also easily prepared, following the procedure described by
Meakins.[
18
] Sodium hydrosulfide in water reacted with 2-chloropropanone, cooled to 0 °C for
one hour, producing a 70% yield of 2-mercaptoacetone.
Scheme 1 One-step procedure to 2-acetylbenzo[b ]thiophene (1a )
The first stage of the procedure is the nucleophilic aromatic substitution of the
chlorine atom, promoted by an electron-withdrawing substituent in the ortho position. Next, an aldol-type cyclization is followed by dehydration and a complete
rearomatization of the system (Scheme [2 ]).
Scheme 2 Suggested mechanism
A series of substituted aryl halides underwent reactions with 2-mercaptoacetone, followed
by cyclization into the corresponding benzo[b ]thiophenes using this procedure (Table [1 ]).[
19
] In general, the reactions were efficient and gave excellent yields (more than 80%).
Commercially available, but expensive, 2-acetylbenzo[b ]thiophene (1a ) was obtained with a good isolated yield of 84%. This sequence has the advantage
of a high yield and purity and also avoids the use of BuLi, usually used for C-2 acylation
or hygroscopic AlCl3 in the Friedel–Crafts acylation of benzo[b ]thiophene.[
20
] Substitutions, with a chlorine atom or a nitro moiety, gave an excellent yield of
the cyclized adducts, respectively, in C-4 and C-5 positions. In the case of 1-chloro-2-naphthaldehyde,
the compound 1d was almost obtained quantitatively whereas, in the case of 6-chloropiperonal, production
was more limited with a moderate yield of 35% for the derivative 1e . Electronic factors strongly influence the scope of the reaction with a significant
decrease in the electrophilicity of the aldehyde resulting in lower yields (1e , Table [1 ]). The lack of reactivity explains the recovery of the starting material.
The reaction was extended successfully to 2-chloro-3-pyridinecarboxaldehyde, resulting
in an almost quantitative yield of thieno[2,3-b ]pyridine 1f .
Table 1 Extension of the Scope of the Reaction to 2-Acetylbenzo[b ]thiophenes 1
Product
Isolated yield (%)
1a
84
1b
88
1c
86
1d
99
1e
35
1f
86
Replacing the 2-chlorobenzaldehyde with 2-chlorobenzonitrile resulted in a similar
mechanistic pathway producing 2-acetyl-3-aminobenzo[b ]thiophene (2a , Scheme [3 ]).[
17
]
Scheme 3 Synthesis of 2-acetyl-3-aminobenzo[b ]thiophene (2a )
Using a similar approach, substituted chlorobenzonitriles were introduced into the
same experimental procedures, producing 2-acetyl-3-aminobenzo[b ]thiophenes 2a –f (Table [2 ]).[
21
] This provides a significant improvement in access to this family of compounds, which
are rarely reported in the literature, and the one-step procedure described in this
communication represents a significant breakthrough compared with other multistep
methods that have been developed. When no substituent was introduced in the phenyl
core, there was a 91% yield of compound 2a . Chlorine, nitro, or methyl substituents do not affect the scope of the reaction,
with excellent yields obtained for 2b , 2c , and 2e , respectively. Again, the success of the condensation step was dependent on electronic
factors, as shown in Table [1 ]. Benzonitriles, substituted by electron-donating groups (2d ) condensed in poor yields, lower than 15%. The replacement of the phenyl core by
pyridine (with a lower electronic density) resulted in a yield of 96% for compound
2f .
Table 2 Extension of the Scope of the Reaction to 2-Acetyl-3-amino-benzo[b ]thiophenes 2
Product
Isolated yield (%)
2a
91
2b
82
2c
90
2d
15
2e
99
2f
96
In summary, a compound library of 12 highly substituted benzo[b ]thiophenes is described in this paper. The reaction is compatible with a wide range
of aromatic compounds based on a single step of condensation between 2-mercaptoacetone
and either halobenzaldehydes or benzonitriles. Some interesting parameters have been
highlighted, such as the water-mediated reaction conditions, short reaction times,
and an easy purification process as the final products were usually isolated by simple
filtration from the reaction mixture. Furthermore, the advantage of the procedure
presented here is the similar synthetic approach used for the families of both compounds
1 and 2 .
