Facile synthesis of 2-substituted benzo[b]thiophen-3-ols in water

Article abstract of DOI:10.1080/00397911.2011.633203

A facile synthesis of 2-substituted benzo[b]thiophen-3-ols in a simple reaction system is reported with water as the only media. Density functional theory (DFT) investigations suggest two pathways comparable in energetics: A neutral pathway with concerted

Full text of DOI:10.1080/00397911.2011.633203

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Facile Synthesis of 2-Substituted
Benzo[b]thiophen-3-ols in Water
Ben Pan a , Peng Ren a , Haibin Song a & Zhihong Wang a
a State Key Laboratory and Institute of Elemento-organic Chemistry,
Nankai University, Tianjin, China
Accepted author version posted online: 14 Mar 2012.Version of
record first published: 05 Mar 2013.
To cite this article: Ben Pan , Peng Ren , Haibin Song & Zhihong Wang (2013): Facile Synthesis of 2-
Substituted Benzo[b]thiophen-3-ols in Water, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 43:10, 1337-1344
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Synthetic Communications1, 43: 1337–1344, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.633203
FACILE SYNTHESIS OF 2-SUBSTITUTED
BENZO[b]THIOPHEN-3-OLS IN WATER
Ben Pan, Peng Ren, Haibin Song, and Zhihong Wang
State Key Laboratory and Institute of Elemento-organic Chemistry,
Nankai University, Tianjin, China
GRAPHICAL ABSTRACT
Abstract A facile synthesis of 2-substituted benzo[b]thiophen-3-ols in a simple reaction
system is reported with water as the only media. Density functional theory (DFT) investi-
gations suggest two pathways comparable in energetics: A neutral pathway with concerted
C-C bond formation and hydrogen transfer and an anionic pathway with anion attack to the
carbonyl group. Studies indicate that water plays crucial mechanistic roles in both cases.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Benzo[b]thiophen-3-ol; DFT; mechanism; water-catalyzed
INTRODUCTION
Benzothiophenes are considered as important tools in synthetic medicinal
chemistry and form the core structure in drugs such as raloxifene.[1–3] Benzo[b]-
thiophene derivatives also exhibit a wide spectrum of biological activities, such as
antibacterial and antifungal activity,[4] anabolic activity,[5] anxiolytic activity,[6]
and anticancer activity,[7] and have potential as enzyme inhibitors[8] and selective
estrogen receptor modulators.[9]
Conjugated 2-substituents are important in the exhibition of biological
activities of benzo[b]thiophenes,[4,5,10] and thus functionalization on this position
Received September 7, 2011.
Address correspondence to Zhihong Wang, State Key Laboratory and Institute of Elemento-
organic Chemistry, Nankai University, Tianjin 300071, China. E-mail: zhihongwang@nankai.edu.cn
1337

1338
B. PAN ET AL.
has attracted much attention, either from open-chain starting materials[11–15] or
by functionalizing the benzothiophene framework.[16,17] For a benzo[b]thiophene
carrying acyl function in the 2-position, when the 3-position is occupied by a
hydroxy group, the resulting hydroxy ketone may also act as an important inter-
mediate in the formation of other biological active heterocyclic compounds such
as benzothieno[3,2-b]-pyranones.[18,19] Thus the 3-hydroxybenzo[b] thiophenes also
become interesting targets for chemists.[20,21]
In our investigation of the coordination capability of 2-(pyridin-2-ylmethylsul-
fanyl)benzoic acid, we were deeply attracted by the serendipitous observation that
2-pyridin-2-yl-benzo[b]thiophen-3-ol was formed in good yield in the sole media of
water. To gain deeper understanding of the scope and the plausible mechanism of
this interesting conversion, we extended the reaction to a series of starting materials
containing 2-oxo-2-arylethylthio or pyridinylmethylsulfanyl groups.
RESULTS AND DISCUSSION
A series of 2-[(2-oxo-2-phenylethyl)thio]-benzoic acids 1a–1f were synthesized
from corresponding a-bromoacetophenone derivatives and 2-mercapto-benzoic
acid.[22] 2-Pyridinylsulfanyl-benzoic acids 1g and 1h were obtained in a similar way
from 2-mercapto-benzoic acid and chloromethylpyridine HCl.
When S-substituted 2-mercapto-benzoic acids 1 were heated to a temperature
above 100 ꢀC in water as the sole media, 2-substituted benzo[b]thiophen-3-ols 2 were
formed as exclusive products. Zinc powder was able to accelerate the reaction,
though it was not indispensable for the formation of 2-substituted benzo[b]thiophen-
3-ols as the only products.
Reaction conditions were examined to understand the influencing factors and
optimized for the formation of 2a as listed in Table 1. At a temperature of 130 ꢀC, 2a
was obtained quantatively after 12 h in the presence of zinc powder while a pretty
high isolated yield of 84% was still achieved without zinc in the reaction system.
When the temperature decreased, the reaction took place at a lower rate while the
recovery of unreacted starting material proved that 2a was still the only product.
This decrease in reaction speed could be offset by the presence of zinc powder, which
was proved by the formation of 2a in a yield of 81% when the reaction system
was refluxed for 12 h. Because refluxing in water could be considered with a facile
Table 1. Condition optimization for the formation of 2a
Temperature (ꢀC)
130a
Presence of Zn
Isolated yield (%)
Y
N
Y
N
Y
N
Y
99
84
94
45
95
37
81
110a
100a
100b
aAll the reactions were carried out in a hydrothermal bomb for 12 h.
bThe reaction was refluxed for 12 h.

2-SUBSTITUTED BENZO[b]THIOPHEN-3-OLS
1339
Scheme 1. Formation of 2-substituted benzo[b]thiophen-3-ols.
condition for a reaction, it was adopted in the following experiments to gain the tar-
get 2-substituted benzo[b]thiophen-3-ols.
Sulfanyl benzoic acids 1 can be converted smoothly into 2-substituted
benzo[b]thiophen-3-ols 2 (Scheme 1) in moderate to good yields under these con-
ditions, as shown in Table 2. Products are obtained in satisfactory purity after a sim-
ple workup of washing with water several times. Taking into account the simplicity
of the reaction system, this is not unexpected.
In solution, products exist in enol form as benzo[b]thiophen-3-ols, which can
be deduced from the appearance of the hydroxy group at above 13 ppm in 1H
NMR. The highlighted low-field chemical shift values also suggest the existence of
intramolecular hydrogen bonding between the hydroxy proton and the carbonyl
oxygen or pyridine nitrogen. The explaination is verified with corroborative evidence
that in 2h the signal of the hydroxy proton shifts to about 11 ppm, owing to the loss
of this intramolecular hydrogen bonding when the nitrogen atom occupies the
para-position.
Though no keto tautomer is detected in solution, it is observed in solid state by
x-ray crystallography. The crystal structure of 2h in Fig. 1. indicates the existence of
Table 2. Formation of 2-substituted benzo[b]thiophen-3-ols 2a
Starting material
Ar=Ar0
Isolated yield (%)
Product
1a
1b
1c
1d
1e
1f
Ph
p-BrPh
81
96
79
88
77
79
69
71
2a
2b
2c
2d
2e
2f
p-OMePh
p-NO2Ph
naphthyl
thiophenyl
2-pyridinyl
4-pyridinyl
1g
1h
2g
2h
aAll the reactions were carried out by refluxing for 12 h in the presence of zinc powder.

1340
B. PAN ET AL.
Figure 1. Crystal structure of 2h.
both keto and enol isomers in the crystal packing. An interesting outcome of this
tautomerization to keto isomer is the transfer of methine proton to the pyridine
nitrogen to form a quinoid structure, as shown in Scheme 2, in all probability due
to the fairly strong basicity of the nitrogen atom. Another feature of the crystal
structure is the formation of 1-D linkage by strong intermolecular hydrogen bond-
˚
˚
ings. The distances of 1.52(3) A for O(1)-H(1). . .O(2) and 1.63(3) A for N(2)-
H(2). . .N(1) point out the strong interaction between the two moieties.
Besides serving as a proper solvent in certain organic reactions, water may also
play important roles from the reaction mechanistic angles, especially when proton
transfer might be involved in the reaction pathways.[23–25] To look into the mech-
anism of the reaction and the effect of water in this facile conversion to 2-substituted
benzo[b]thiophen-3-ols, density functional theory (DFT) studies were carried out in
B3LYP[26–30] calculations.
A net result of the conversion is the loss of water, which means a methylene
hydrogen in the starting material must be transferred to the carboxylate oxygen in
a certain step of the reaction. Two possible ways are shown in Fig. 2 as pathways
A and B. This concerned hydrogen is directly transferred from methylene to oxygen
via a four-membered transition state in pathway A. The crucial C-C bond forms in a
concerted way at the same time as the hydrogen transfers. The energy barrier of
Scheme 2. Intramolecular hydrogen bonding and tautomerism in 2h.

2-SUBSTITUTED BENZO[b]THIOPHEN-3-OLS
1341
Figure 2. Energy profiles of neutral concerted pathways (B3LYP=6-31Gꢁꢁ). Blue: ketone pathway
(pathway A). Violet: enol pathway (pathway B). Black: enol pathway with water assistance (pathway C).
(Figure is provided in color online.)
this process is suggested to be extremely high with a value of 65.4 kcal=mol. In the
alternative pathway B, the hydrogen transfer happens after the enolization of
ketone. The hydrogen transfer step itself has a six-membered transition state with
an energy requirement of 39.0 kcal=mol. However, the barrier for enolization is
61.1 kcal=mol, which is too high to agree with the reaction conditions and implies
the existence of certain types of catalysis. Taking into consideration the fact that
reaction can happen at a certain rate without the presence of any other reagent
but water, this catalysis should be directly related to water molecule. Thus the influ-
ence of water is examined as in pathway C, in which the proton transfer is facilitated
by the coordination of a water molecule to the enol and the formation of the hydro-
gen bond to the carbonyl oxygen. As expected, the presence of water in the transition
states changes the energy requirement dramatically, decreasing the barrier of hydro-
gen transfer by 16.1 kcal=mol. A more striking energy decrease is gained for the eno-
lization, by a value of 35.1 kcal=mol. The resulting energy barrier for this step, still as
the rate-determining step, is 26.0 kcal=mol and is in agreement with the reaction
conditions.
In our studies on other influencing factors of the reaction, we noticed that reac-
tion is also accelerated when zinc is replaced by zinc oxide. This observation implies

1342
B. PAN ET AL.
Figure 3. Anionic pathway with water assistance.
the possibility of involvement of an alkaline species, and thus an anionic mechanism
as shown in Fig. 3 is also studied in comparison with the neutral pathway.
Keeping in mind the dramatic influence of water on the neutral pathway, it is
reasonable to believe that water also plays significant roles in the anionic mechanism.
This presumption is proved by the calculational results that show that without the
stabilization of a water molecule, the energy of the anion intermediate is too high
to connect two transition states. On the other hand, when a water molecule is intro-
duced into the mechanism, the anion attack to the carbonyl carbon acts as the
rate-determining step after a equilibrium proton transfer from the methylene to
the carboxylate and the energy requirement of the whole reaction is proposed to
be 25.1 kcal=mol, which is comparable to the energy barrier of the neutral pathway,
as shown in Fig. 4. The comparability of the energy barrier of these two pathways
indicates that both mechanisms play a part in the reaction process while in both cases
water acts as a crucial participator.
In summary, we report here a facile synthesis of 2-substituted benzo[b]-
thiophen-3-ols in a simple reaction system with water as the only media. Mechanistic
studies in DFT calculations suggest two pathways comparable in energetics: a neu-
tral pathway with concerted C-C bond formation and hydrogen transfer, and an
anionic pathway with the anion attack to the carbonyl group as the rate-determining
step. Water plays crucial mechanistic roles in both cases.
Figure 4. Energy profiles. Black: neutral pathway via enol from starting material (B3LYP=6-31Gꢁꢁ).
Gray: anionic pathway with water assistance (B3LYP=6-31þþGꢁꢁ). (Figure is provided in color online.)

2-SUBSTITUTED BENZO[b]THIOPHEN-3-OLS
1343
EXPERIMENTAL
Infrared (IR) spectra were obtained from a Nicolet 380 spectrometer as KBr
discs. Multinuclear NMR spectra were recorded with a Bruker 400 spectrometer
using CDCl3 as solvent unless otherwise noted, and the chemical shifts were reported
in parts per million (ppm) with respect to reference standards (internal SiMe4 for 1H
NMR and 13C NMR spectra). Electrospray ionization–mass spectra (ESI-MS) were
recorded with a Thermofinnigan Trace DSQ spectrometer. Melting points were mea-
sured with an X-4 digital micro-melting-point apparatus and were uncorrected.
Preparation of Starting Materials
2-[(2-Oxo-2-phenylethyl)thio]-benzoic acids 1a–1f were synthesized from
corresponding a-bromoacetophenone derivatives and 2-mercapto-benzoic acid. a-
Bromoacetophenone derivative (15 mmol) and 15 mmol of 2-mercapto-benzoic acid
were mixed with 30 mmol of KOH in 90 mL of ethanol. The reaction mixture was
stirred under reflux under an Ar atmosphere for 2 h and poured into a mixture of
10% HCl in ice water. The resulting solids were recrystallized from ethanol to gain
pure acids.
2-Pyridinylsulfanyl-benzoic acids 1g and 1h were obtained in a similar way
from 2-mercapto-benzoic acid and chloromethylpyridine HCl. 2-Mercapto-benzoic
acid (0.1 mol) and 0.1 mol of chloromethylpyridine HCl were added to a mixture
of 70 mL of ethanol, 14 mL of water, and 18.5 g of KOH. The reaction mixture
was stirred at room temperature for 2 h before 100 mL of water was poured into
the system and extracted with three times with 100 mL of ether. The aqueous layer
was acidified with 2 M HCl to a pH value of 4 to allow the product to precipitate.
The resulting solids were filtered off, washed with water, and recrystallized from
methanol to gain pure acids of 1g as white solids and 1h as pink crystals.
Synthesis of 2-Substituted Benzo[b]thiophen-3-ols
2-[(2-Oxo-2-phenylethyl)thio]-benzoic acid or 2-pyridinylsulfanyl-benzoic acid
(0.5 mmol) was mixed with 0.25 mmol of zinc powder in 10 mL of water and stirred
under reflux for 12 h. The resulting product was cooled to room temperature and
washed with water several times to obtain pure 2-substituted benzo[b]thiophen-3-ol 2.
Further experimental details can be found online in the Supplementary
Material.
ACKNOWLEDGMENTS
This work was funded by National Natural Science Foundation of China (No.
20802036) and partly by grants from the Specialized Research Fund for the Doctoral
Program of Higher Education of China (20070055043) and the Foundation of the
Ministry of Education of China for Returned Scholars.
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