Direct access to 3-substituted 1,4-oxathiepino[5,6-b]pyridine-5-one through one-pot substitution cyclization reaction of 2-mercapto-3-nicotinic acid with α-bromo ketones

Article abstract of DOI:10.1016/j.tetlet.2013.11.030

A direct, one-pot synthesis route to [1,4]oxathiepino[5,6-b]pyridin-5-one derivatives was optimized by reacting different α-bromo ketones with 2-mercaptonicotinic acid. The advantages of this method include high efficiency, regioselective, and multistep conversion in a single-pot protocol. These types of pyridine annulated[1,4]oxathiepin-5-one derivatives are described here for the first time and seem to be interesting candidates for screening purpose. The presented protocol is suitable for using rare chemicals for synthesis of such derivatives.

Full text of DOI:10.1016/j.tetlet.2013.11.030

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Direct access to 3-substituted 1,4-oxathiepino[5,6-b]pyridine-5-one
through one-pot substitution cyclization reaction of
2-mercapto-3-nicotinic acid with
a-bromo ketones
a
b
Sukhdeep Singh a, , Andreas Schober , G. Alexander Gross
⇑
a Department of Nanobiosystem Technology, Institute of Micro- and Nanotechnologies MacroNanoÒ, Institute of Chemistry and Biotechnology, Ilmenau University of Technology,
Prof.-Schmidt-Str. 26/Heliosbau, 98693 Ilmenau, Germany
b Department of Physical Chemistry and Microreaction Technology, Institute of Chemistry and Biotechnology, Ilmenau University of Technology, Gustav-Kirchhoffstr. 7, 98693 Ilmenau,
Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct, one-pot synthesis route to [1,4]oxathiepino[5,6-b]pyridin-5-one derivatives was optimized by
Received 7 October 2013
Revised 4 November 2013
Accepted 8 November 2013
Available online xxxx
reacting different
a-bromo ketones with 2-mercaptonicotinic acid. The advantages of this method
include high efficiency, regioselective, and multistep conversion in a single-pot protocol. These types
of pyridine annulated[1,4]oxathiepin-5-one derivatives are described here for the first time and seem
to be interesting candidates for screening purpose. The presented protocol is suitable for using rare chem-
icals for synthesis of such derivatives.
Keywords:
One-pot reaction
Cyclization
Ó 2013 Elsevier Ltd. All rights reserved.
Multistep reaction
Oxathiepinone
Introduction
methods that can deliver diversification around these scaffolds. Re-
cently, a few methods appeared in the literature that depicts the
Due to increasing demands for new bioactive molecules for
pharmaceutical or agrochemical research, it is of high importance
to develop new synthetic routes to drug like molecules which are
not yet present in screening libraries.1,2 Especially heterocyclic
structures that have played a vital role in the lead discovery of bio-
active molecules of various pharmaceutical interests are important
candidates.1,3 The chemical methods to make drug-like molecules
become more valuable when they can facilitate the synthesis of a
diverse range of derivatives from simple starting material to
provide combinatorial libraries that can be then adapted for
automated processing in modern pharmaceutical industry.4 Here
one-pot or serial reagent addition strategies are of advantage
because those protocols can be easily and efficiently adapted to
synthesis robots omitting demanding separation steps.
The [1,4]-oxathiepin-5-one derivatives of type 2 represent a
rare scaffold that was not described in the literature until yet. Un-
like structurally analogous thiazepinones, for example, diltiazem, 1
that show a wide range of biological activity, the biological activity
of oxathiepinones of type 2 has not been described in the litera-
ture. The probable reason could be the lack of efficient synthetic
synthesis of oxathiepinone derivatives.5–8 However, these methods
are either requiring long reaction time or should be done in a mul-
tistep manner.
For the synthesis of 1,4-oxathiepino[5,6-b]pyridine-5-one 2, in
this study we used simple starting material 2-mercapto-3-
nicotinic acid that possesses thiol and carboxylic acid functional
group ortho to each other. Due to the possibility to derive reac-
tion/substitution in various directions the chemistry of this mole-
cule becomes very interesting. It holds a significant importance
due to its structural resemblance with 1,4-benzoxathiepinone 3.
A typical synthesis of 3 includes the use of relatively sensitive
epoxides and the reaction time required for such derivatives is
large.6 Moreover the selectivity due to ring opening of the epoxide
derivatives leads to a mixture of products that make the process
inefficient for rapid production of combinatorial libraries.7
In this Letter, we designed a facile and straightforward method
for the synthesis of analogs of 2. The most direct method appears
to be the reaction of 2-mercapto-3-nicotinic acid with a-bromo ke-
tones and subsequent dehydration that could lead to the bicyclic
heterocycle 1,4-oxathiepino[5,6-b]pyridine-5-one 2 (Scheme 1).
However, to execute this multistep reaction in one pot remains a
challenge. To the best of our knowledge, this method for convert-
ing 2-mercaptonicotinic acid to 1,4-oxathiepino[5,6-b]pyridine-
5-one is described for the first time.
⇑
Corresponding author. Fax: +49 3677 69 3379.
E-mail address: sukhdeep.singh@tu-ilmenau.de (S. Singh).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.030
Please cite this article in press as: Singh, S.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.11.030

2
S. Singh et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
O
Variation of reaction conditions for the synthesis of 3-phenyl-[1,4]oxathiepino
[5,6-b]pyridine-5-one 2a
O
O
O
OH
O
OH
OH
N
SH
O
Yielda (%) 6a
Yielda (%) 2a
Ar
Entry
Solvent
Base
Ar
4
Ar
N
S
N
S
N
S
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17b
18c
Methanol
Ethanol
DMF
Et3N
Et3N
Et3N
Et3N
55
45
85
87
85
74
87
90
78
65
89
87
35
40
55
62
82
—
Minor
—
—
Minor
8
Minor
Minor
6
OH
O
6
Br
6
2
Ar
5
DMSO
Scheme 1. Strategy for the synthesis of 1,4-oxathiepino[5,6-b]pyridine-5-one 2.
Methanol
Ethanol
DMF
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Pyridine
Pyridine
Pyridine
Pyridine
K2CO3
K2CO3
DMSO
Results and discussion
Methanol
Ethanol
DMF
5
Minor
10
Minor
—
—
—
—
Minor
90
It has been previously reported by us that the S-alkylation of
DMSO
thioamides can be very well executed using either inorganic base
9,10
Methanol
Ethanol
DMF
DMSO
DMSO
like K2CO3
or mild organic bases like Et3N.11,12 Under certain
circumstances alkyl analog of
a-bromo ketone results in thiazole
derivatives,11 while aromatic analogs lead to sulfide contraction
products.9 Unfortunately, the sulfide contraction reaction suffers
from relatively poor yields at low temperatures. Here, flow chem-
istry has played a vital role for overcoming this drawback. Even at
intensified process conditions the reaction can be very well con-
trolled by adjusting the flow rates (Fig. 1), temperatures, and pres-
sure in a facile manner.12
DMSO
a
b
c
Isolated yield after 30 min shaking at 80 °C.
The reaction time is 48 h.
2 equiva of phenacyl bromide was used.
For optimizing the reaction conditions for selective S-alkylation
of 2-mercaptonicotinic acid 4 we have chosen phenacyl bromide
5a as a model reactant. Initially we examined various solvent
systems and bases at 80 °C for 30 min to find the best reaction con-
ditions for S-alkylation (Table 1). Due to the poor solubility of
2-mercaptonicotinic acid in DCM, chloroform, DCE, dioxane, THF,
toluene, diethylether, and hexane these solvents were not optimal
for testing the optimization. In all of the optimization reactions
equimolar amounts of phenacyl bromide were used in order to
avoid further alkylation at carboxylic and nitrogen of pyridine that
could lead to a mixture of products. The reaction performance un-
der different conditions was investigated by LC–MS analysis. It was
observed that the expected sequence of S-alkylation and subse-
quent lactonization did not proceed under investigated conditions.
Instead of getting desired cyclic 2a we obtained the intermediate
6a (Scheme 1) as a major product in all the cases. However, it
was found that in case of DMSO as solvent and K2CO3 as base
(Table 1, entry 8), the S-alkylated intermediate 6a was formed in
quantitative yields. DMF, methanol, and ethanol and their combi-
nation with bases like Et3N, K2CO3, Na2CO3, and pyridine have also
furnished this intermediate 6a in moderate to low yields (Table 1).
The desired product 2a was observed only in trace amounts in
some cases. In a comparison between DMSO and DMF as the reac-
tion solvent, DMSO produced the reaction product in considerably
short reaction time than DMF. Therefore, we opted for the DMSO as
reaction solvent for further experiments.
ranging from 30 min to 48 h (Table 1, entry 17) and tuned the reac-
tion temperature from 60 to 120 °C but in no case the desired cycli-
zation was observed. The prolonged reaction time like 48 h at 80 °C
rather resulted in partial decomposition of the intermediate. We
have also attempted to activate the intramolecular cyclocondensa-
tion reaction under thermal intensified flow conditions at 240 °C
and 2.5 min residence time. But even this did not serve the pur-
pose. Finally, we found the solutions by converting corresponding
carboxylic acid to its analogous ester 7a (Scheme 2). This was sim-
ply achieved by using 2 equiv of phenacyl bromide (5a) inside of
1 equiv under similar conditions as described in Table 1 entry 18.
Periodic LC–MS analysis of the reaction revealed that the formation
of the dialkylated product was achieved within 15 min. Afterward,
the cyclization reaction took place and the dialkylated intermedi-
ate 7a has been converted to the cyclic derivative within the fol-
lowing 30 min and furnished the desired 2a.13 Additionally, no
side product due to alkylation of the pyridine N or thiazole forma-
tion has been observed in the LC–MS analysis. Moreover, after
acidic workup and extraction with DCM the desired product 2a
gets directly precipitated in acetone. This makes the method sim-
pler because additional chromatographic procedures can be
avoided.
In an independent experiment we have isolated the dialkylated
product 7a from the reaction mixture and the pure product was
subject to cyclization in DMSO without any base. To our surprise
The optimized reaction conditions for the synthesis of S-
alkylated intermediate 6a (Table 1, entry 8) of course led to clean
and high yielding product but the desired cyclization was only in
trace amounts. For achieving the cyclization, which is the second
step of the sequence, we have screened different reaction times
O
O
OH
OH
DMSO, 80
o
C, K2CO3, 1 eq. 5a
O
N
S
N
SH
6a
Ph
a
5
.
4
q
e
1
O
O
Ph
O
O
O
S
N
O
S
R
EtBr (1 eq.)
O
N
S
O
N
N
2
Ph
7a
O
O
O
O
S
O
OEt
O
Ph
N
S
7b
N
S
O
1,
Diltiazem
2a
3
Ph
Figure 1. Example structures containing analog of 1,4-oxathiepinone scaffold.
Scheme 2. Influence of ester substitution on conversion of 6a–2a.
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S. Singh et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
this does not lead to required product 2a. However upon addition
of catalytic amount of K2CO3 the required cyclization took place
within 5 min. To investigate the role of the ester moiety for the
cyclization reaction (Scheme 2) the ethyl ester 7b was prepared.
as the nucleophile in an intramolecular substitution reaction and
by removing the ester fragment provides desired cyclic lactone 2a.
To explore the scope of this reaction protocol various new
derivatives were prepared by altering the substituents of the
In this case 1 equiv of
a-bromo ketone was introduced under same
a-bromo ketones. Initially, we have tested the influence of electron
set of conditions to receive S-alkylated intermediate 6a. After com-
plete consumption of starting material 4, 1 equiv of ethyl bromide
was added to the reaction mixture to form ethyl ester 7b. Interest-
ingly, ethyl ester derivative 7b was obtained but no further cyclo-
condensation to derivative 2a was observed after 2 h of heating at
80 °C. However, after a prolonged heating of 24 h a partial conver-
sion to cyclic derivative 2a was observed. This experiment has con-
cluded that the esterification with bromo ketones 5a results in the
phenylethyl-2-one group which can act as a good leaving group
during intramolecular cyclocondensation (Scheme 2).
donating substituents like methoxy on the reaction performance.
Use of p-methoxyphenyl-1-bromo-2-ethanone 5b yields the
desired product 2b in 78%. A 2,5-dimethoxyphenyl-1-bromo-2-
ethanone 5c furnishes required product 2c in 84% yield. Electron
donating substituents seem to have no influence on the reaction
performance and furnishe the desired products in quantitative
yields. On the other hand strongly electron withdrawing substitu-
ents like NO2 and CN were tested for their performance and yielded
desired products 2d and 2e in 92% and 94% isolated yields. Moni-
toring the reaction kinetics by LC–MS analysis has shown that
the desired product was formed in relatively short reaction time
as compared to the reaction where the unsubstituted phenyl deriv-
The observed reactions revealed the sequential alkylation of the
sulfur and the carboxylic acid groups by the
a-bromo ketone and
the subsequent cyclization. Therefore the S-bound z-enolate acts
ative of a-bromo ketone was used. However, halogen substitutions
Table 2
1,4-Oxathiepino[5,6-b]pyridine-5-one derivatives
Entry
a
a
-Bromo ketone 5
Product 2
Isolated yield (%)
90
O
O
PhCOCH2Br
N
N
N
S
O
O
O
b
c
4-OMeC6H3COCH2Br
78
84
OMe
S
O
OMe
2,5-(OMe)2C6H3COCH2Br
S
MeO
O
NO2
O
O
O
O
O
O
d
e
f
3-NO2C6H4COCH2Br
4-CNC6H4CH2Br
92
94
88
90
87
N
N
N
N
N
N
S
O
CN
S
O
4-BrC6H4COCH2Br
4-ClC6H4COCH2Br
Br
Cl
S
O
g
h
S
O
b-C10H7COCH2Br
S
O
O
O
O
i
j
76
85
Br
S
O
O
O
4-PhC6H4COCH2Br
Ph
N
S
O
k
76
O
N
N
O
O
N
Br
S
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4
S. Singh et al. / Tetrahedron Letters xxx (2013) xxx–xxx
method to save expensive building blocks has been introduced
too. The capability of a straightforward method was proven by
the preparation of 11 different derivatives of 1,4-oxathiepino[5,6-
b]pyridine-5-one.
O
Br
OH
N
O
N
SH
O
5k
(1 eq.)
DMSO, 80°C
K2CO3,
4
Acknowledgments
O
This work has been supported by the German Federal Ministry
of Education and Research and the Thuringian Ministry of Culture
(FKZ03ZIK062, FKZ03ZIK465, OPTIMI I FKZ 16SV3701 OPTIMI II,
BMBF FKZ 16SV5473 and Nanozellkulturen, TMK/TMWAI FKZ
B714-09064) within the Initiative ‘Centre for Innovation Compe-
tence’, MacroNanoÒ, the AIF FKZ: KF2731201MDO, Carl Zeiss Stif-
tung 0563-2.8/399/1, WK Basis FKZ: 03WKCB010 and European
Commission under FP7 ICT FET OPEN (FKZ 296590). We thank
Katrin Risch and Dr. Eric Täuscher for measuring the NMR and IR
and CHNS data.
O
O
O
5a
Ph
HO
S
Br
N
O
N
O
N
O
N
S
6k
2k
Scheme 3. Synthesis of 2k.
like p-bromo 5f, and p-chloro 5g derivatives have shown similar
reactivity compared to unsubstituted or electron donating substit-
uents and furnished products in 88% and 90% yields, respectively.
Furthermore we made use of b-naphthyl 5h, benzofuran 5i, and
Supplementary data
p-phenyl 5j derivatives of
a-bromo ketones. All have furnished
the required products 2h, 2i, and 2j in 87%, 76%, and 85% yields,
respectively.
Supplementary data (experimental procedures, characteriza-
tion data and copies of 1H NMR and 13C NMR spectra for all new
compounds) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.11.030.
As discussed above the method is based on the use of two
equivalents of
a-bromo ketones that may become a disadvantage
when rare or expensive
We used the expensive
receive more complex derivatives of type 2k (Table
a
a
-bromo ketone derivatives are necessary.
-bromo ketone 5k (Table 2) as reactant to
and
2
References and notes
Scheme 3). In analogy to the observation from the reaction optimi-
zation the use of equivalent quantities of both reactants (4 and 5k)
did not furnish cyclization product at all. Only the mono substi-
tuted S-alkylated derivative was obtained. In order to overcome
this problem, we have introduced another equivalent of abun-
dantly available phenacyl bromide 5a to the reaction mixture to
make ester of carboxylic acid and subsequent cyclization
(Scheme 3). As expected this strategy has smoothly furnished the
required cyclic derivative 2k in 76% yields. By using this method
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2. Katritzky, A. R.; Ramsden, C. A.; Seriven, E. F. V.; Taylor, R. J. K. Comprehensive
Heterocyclic Chemistry III In ; Elsevier, 2008; vol. 15.,
3. Font, D.; Heras, M.; Villalgordo, J. M. J. Comb. Chem. 2003, 5, 311–321.
4. Gross, G. A.; Singh, S.; Schlingloff, G.; Schwienhorst, A.; Riester, D.; Wegener, D.;
Wurziger, H.; Schober, A. Eng. Life Sci. 2013, 13, 344–351.
5. Kim, B. S.; Kim, K. Tetrahedron Lett. 2001, 42, 4637–4640.
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atom economy, with respect to rare
a-bromo ketone derivatives,
has been significantly improved and the useful multistep single-
pot method has been introduced that is suitable for using rare
chemicals.
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Conclusions
13. Representative procedure: A 4-mL screw capped reaction vial was charged
successively with 2-mercaptonicotinic acid (100 mg, 0.65 mmol), phenacyl
bromide (256 mg, 1.30 mmol) and potassium carbonate (180 mg, 1.30 mmol)
in 2 ml DMSO. The solution was shaked at 80 °C for 1 h. Complete
disappearance of 2-mercaptonicotinic acid in LCMS confirms the completion
of reaction. Upon completion of the reaction, the mixture was quenched with
few drops of conc. HCl and 10 mL water. The mixture was extracted with DCM
(3 Â 10 mL), and the combined extract was dried with sodium sulfate and
concentrated. The solid product obtained after the evaporation of solvent was
further purified by filtration and washing with acetone. The combined yield of
the isolated product 2a was 90%.
In summary, we have described an unprecedented and efficient
method for the synthesis of 1,4-oxathiepino[5,6-b]pyridine-5-one
derivatives from 2-mercaptonicotinic acid. The reaction proceeds
as stepwise alkylation with
carboxylic acid and continues in a cyclization reaction. This one-
pot methodology permits the use of a wide variety of -bromo
ketones. For rare starting materials an alternative economical
a-bromo ketones, first on sulfur then
a
Please cite this article in press as: Singh, S.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.11.030