1,2-Benzoxathiin-4(3H)-one 2,2-dioxide-new enol nucleophile in three-component interaction with benzaldehydes and active methylene nitriles

Article abstract of DOI:10.1039/C8RA06801A

The reactivity of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide was studied in multicomponent type reactions for the first time, namely, in a three-component interaction with active methylene nitriles and aromatic aldehydes in order to construct condensed 2-amino-4H-pyran derivatives. The reaction outcome strongly depended on the nature of an active methylene nitrile and an arenecarbaldehyde. Application of malononitrile resulted in novel 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile 5,5-dioxides in most cases, whereas the utilization of ethyl cyanoacetate resulted in a complex mixture of products. In the last case, three different products were isolated depending on the arenecarbaldehyde used, namely ethyl 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carboxylate 5,5-dioxides, ethyl 2-cyano-3-arylacrylates, and salts of 3,3′-(arylmethylene)bis(4-hydroxybenzo[e][1,2]oxathiine 2,2-dioxides). Attempts to obtain separately ethyl 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carboxylate 5,5-dioxides enabled us to propose reaction pathways leading to these products. The salts were obtained for the first time. The preparative method for the synthesis of triethylammonium salts of 3,3′-(arylmethylene)bis(4-hydroxybenzo[e][1,2]oxathiine 2,2-dioxides) was proposed by the direct interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with arenecarbaldehydes. The application of ammonium acetate as a catalyst allowed us to synthesize 7-aryl-7,14-dihydrobenzo[5,6][1,2]oxathiino[4,3-b]benzo[5,6][1,2]oxathiino[3,4-e]pyridine 6,6,8,8-tetraoxides containing a novel heterocyclic system. These facts, combined with our past investigations, allowed us to assert that the reactivity of enol nucleophiles that include the COCH₂SO₂X fragment has not been reported previously.

Full text of DOI:10.1039/C8RA06801A

RSC Advances
View Article Online
View Journal | View Issue
PAPER
1,2-Benzoxathiin-4(3H)-one 2,2-dioxide – new
enol nucleophile in three-component interaction
with benzaldehydes and active methylene nitriles†
Cite this: RSC Adv., 2018, 8, 37295
a
a
a
Galyna V. Grygoriv,
Lucjusz Zaprutko,
Dmitry A. Lega,
Valentin P. Chernykh,
Anna Pawełczyk
b
b
b
*
Andrzej K. Gzella,
a
*
and Leonid A. Shemchuk
The reactivity of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide was studied in multicomponent type reactions for
the first time, namely, in a three-component interaction with active methylene nitriles and aromatic
aldehydes in order to construct condensed 2-amino-4H-pyran derivatives. The reaction outcome
strongly depended on the nature of an active methylene nitrile and an arenecarbaldehyde. Application of
malononitrile resulted in novel 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile 5,5-
dioxides in most cases, whereas the utilization of ethyl cyanoacetate resulted in a complex mixture of
products. In the last case, three different products were isolated depending on the arenecarbaldehyde
used, namely ethyl 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-carboxylate 5,5-dioxides, ethyl
2-cyano-3-arylacrylates, and salts of 3,30-(arylmethylene)bis(4-hydroxybenzo[e][1,2]oxathiine 2,2-
dioxides). Attempts to obtain separately ethyl 2-amino-4-aryl-4H-pyrano[3,2-c][1,2]benzoxathiine-3-
carboxylate 5,5-dioxides enabled us to propose reaction pathways leading to these products. The salts
were obtained for the first time. The preparative method for the synthesis of triethylammonium salts of
3,30-(arylmethylene)bis(4-hydroxybenzo[e][1,2]oxathiine 2,2-dioxides) was proposed by the direct
interaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide with arenecarbaldehydes. The application of
ammonium acetate as a catalyst allowed us to synthesize 7-aryl-7,14-dihydrobenzo[5,6][1,2]oxathiino
[4,3-b]benzo[5,6][1,2]oxathiino[3,4-e]pyridine 6,6,8,8-tetraoxides containing a novel heterocyclic system.
These facts, combined with our past investigations, allowed us to assert that the reactivity of enol
nucleophiles that include the COCH2SO2X fragment has not been reported previously.
Received 13th August 2018
Accepted 15th October 2018
DOI: 10.1039/c8ra06801a
rsc.li/rsc-advances
¨
transformations and are mainly disclosed in the works of Lowe
1. Introduction
et al.1 and also some other researchers.2 However, all of them are
based on multi-stage processes, which reduce their attractiveness
in terms of creating combinatorial libraries of new compounds.3
This could be related to the fact that the multicomponent
processes are oen associated with ambiguous reaction mecha-
nisms, selectivity issues or unexpected outcomes.4 However, such
reactions still remain the main provider of novel core-structures.5
At the beginning of the 20th century the concept of isosterism
became relevant in medicinal chemistry and remains
To date, synthetic organic chemistry does a great deal of work
and it is difficult to nd a relatively simple organic compound
which is poorly studied in respect of its chemical and/or bio-
logical properties. Nevertheless, 1,2-benzoxathiin-4(3H)-one 2,2-
dioxide (1) turned out to be one of these ‘dark places’ in
medicinal chemistry (Fig. 1).
Despite the presence of the synthetically attractive COCH2SO2
moiety in its structure, the chemistry of the 1,2-benzoxathiin-
4(3H)-one 2,2-dioxide core is scarcely investigated. There are only
a
few reports dedicated to the study of its chemical
aNational University of Pharmacy, Pushkinska Str. 53, Kharkiv, 61001, Ukraine.
E-mail: orgchem@nuph.edu.ua
bPoznan University of Medical Sciences, Pharmaceutical Faculty, Organic Chemistry
Department, 6 Grunwaldzka Str, 60-780 Poznan, Poland
† Electronic supplementary information (ESI) available: Full spectroscopic data
(1H and 13C NMR, IR, MS) for compounds 4, 6, 7 and 9 as well as X-ray
crystallographic data for compounds 4b and 6a. CCDC 1585657 and 1585656.
For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8ra06801a
Fig. 1 The main peculiarities of the 1,2-benzoxathiin-4(3H)-one 2,2-
dioxide (1) core.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 37295–37302 | 37295

View Article Online
RSC Advances
Paper
Fig. 2 Isosteric relations of the 1,2-benzoxathiin-4(3H)-one 2,2-dioxide (1) core with 4-hydroxycoumarin (A) and 1H-2,1-benzothiazin-4(3H)-
one 2,2-dioxide (B) derivatives.
a powerful tool for the purposeful searching of new bioactive aromatic aldehydes in order to construct condensed 2-amino-
substances.6 In this regard, the 1,2-benzoxathiin-4(3H)-one 2,2- 4H-pyrans.
dioxide core can be considered as an isostere for two groups of
heterocycles. The rst of them comprises such a famous phar-
macophore as the 4-hydroxycoumarin core A (Fig. 2). Its deriv-
2. Results and discussion
atives have become well-known drugs and among others are
used as anticoagulants by means of vitamin K inhibiting.7 The
second group includes 1H-2,1-benzothiazin-4(3H)-one 2,2-
dioxide B derivatives, which have recently shown a high effec-
tiveness in the treatment of pain and inammation and are
much stronger NSAIDs compared to the famous drugs
Piroxicam® and Meloxicam®.8 In this way 1,2-benzoxathiin-
4(3H)-one 2,2-dioxide (1) conceals inside itself a great potential
for drug creation.
Previously, we explored 1H-2,1-benzothiazin-4(3H)-one 2,2-
dioxide (B) as a synthetic analog of 1,3-dicarbonyls in the
multicomponent synthesis of fused 2-amino-4H-pyrans E based
on the three-component interaction of the former with wide
range of aldehydes C and active methylene nitriles D (Scheme
1).9,10 This allowed us to isolate two product types – 2-amino-4H-
pyrans E and/or salts F, depending on the starting reagents used
and conditions applied in the reaction.
As for 2-amino-4H-pyrans, they have previously appeared to
be a promising chemical class to search among for substances
displaying valuable kinds of bioactivity such as anticancer,11
antibacterial,12,13 anti-rheumatic14 and others.
Thereby, as a logical continuation of our research, in this
paper we, for the rst time, have uncovered the chemical
behavior of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide (1) in
multicomponent type reactions, particularly in the three-
component interaction with active methylene nitriles and
1,2-Benzoxathiin-4(3H)-one 2,2-dioxide (1) was synthesized by
a modied two-stage procedure described in the work15 using
methyl salicylate as the starting compound (see Experimental
section).
Literature data reveal the application of various reaction
conditions and catalysts in the three-component interaction of
enol nucleophiles with active methylene nitriles and carbonyl
compounds easily leading in most cases to 2-amino-4H-pyrans
irrespective of the reactant nature.16 Previously found features
gave us an opportunity to predict a non-conventional reactivity
of SO2-containing enol nucleophiles in such types of inter-
actions.9,10b Because of this, rst of all we studied the model
reaction of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide (1) with
malononitrile (3) as an active methylene nitrile and benzalde-
hyde (2a) as a representative of aromatic aldehydes to nd
acceptable reaction conditions resulting in the target
condensed 2-amino-4-phenyl-4H-pyran-3-carbonitrile 4a (Table
1). Initially, the task was set to nd the most suitable catalyst for
the reaction using common reaction conditions according to
the literature data,16,17 specically the interaction of equimolar
quantities of the reagents in ethanol. Results for this step are
given in Table 1. As can be seen from the table, without any
catalyst the reaction resulted in the formation of fused
compound 4a with only 4% yield. Thereby, the range of basic
and acidic catalysts was tested in order to increase the reaction
yield. According to the obtained data, triethylamine turned out
Scheme 1 Previously published results regarding 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide (B).
37296 | RSC Adv., 2018, 8, 37295–37302
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
Table 1 Optimization of the reaction conditions and synthesis and yields of annulated 2-amino-4H-pyran-3-carbonitriles 4
Entry
ArCHO
Ar
Catalysta
Time (h)
Yield of 4b, %
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
No cat.
L-Lysine
AcONH4
Et3N
DBU
TsOH
Et3N
Et3N
Et3N (1 equiv.)
Et3N
Et3N
Et3N
1
1
1
1
1
1
1c
3
1
1
1
1
1
1
1
1
1
4
60
68
89
23
Not isol.
75
64
83
77
85
96
88
79
66
87
81
9
Ph
10
11
12
13
14
15
16
17
2-MeO–C6H4
4-MeO–C6H4
4-HO-3-MeO–C6H4
3,4,5-TriMeO–C6H2
2-EtO2CCH2O–C6H4
2-NCCH2O–C6H4
4-Cl-C6H4
4-O2N–C6H4
Et3N
Et3N
Et3N
Et3N
2g
2h
2i
Et3N
a
b
A catalyst was used in the amount of 0.1 equiv. unless otherwise specied. Isolated yields. c Reaction was carried out at room temperature.
to be the most acceptable catalyst for the tested reaction (Table Knoevenagel products (b-aryl-a-cyanoacrylonitriles) with almost
1, entry 4). It should also be noted that the usage of the much quantitative yields despite our efforts to vary the reaction
stronger base 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) led to conditions (reux for 20 h, application of a range of basic
a signicant decrease of the 2-amino-4H-pyran 4a yield. catalysts). This result can be explained not only by means of
Applying more than 0.1 equiv. of triethylamine as well as a signicant decrease of the double bond reactivity of the
prolongation of the reaction time and carrying out of the reac- Knoevenagel products in the course of the Michael addition
tion under room temperature did not result in improving the reaction to benzoxathiinone 1, but also by a reduced nucleo-
reaction efficiency. Despite the previously reported successful philicity of 3-C in O-containing benzoxathiinone 1 compared
application of acidic catalysts in the synthesis of 2-amino-4H- with its N-containing analog – benzothiazinone B.9
pyrans,18,19 we failed in our efforts to obtain the target 2-amino-
4H-pyran 4a when p-toluenesulfonic acid was applied.
The next step of the current research was the utilization of
ethyl cyanoacetate (5) instead of malononitrile (3) in order to
According to the data given above, the reux of equimolar investigate the scope of the studied reaction (Scheme 2).
quantities of the reactants in ethanol for 1 h in the presence Applying unsubstituted benzaldehyde (2a) as a representative in
of 0.1 equiv. of triethylamine was chosen as the general the three-component interaction made it possible to get a new
condition for further investigations. In this regard, a range of interesting result in the chemistry of 1,2-benzoxathiin-4(3H)-
substituted aromatic aldehydes was employed at the next one 2,2-dioxide (1). Thus, the use of equimolar amounts of the
step and a series of 2-amino-4-aryl-4H-pyrano[3,2-c][1,2] reagents under reux for 4 h (Et3N, 1 equiv.) led to the isolation
benzoxathiine-3-carbonitrile 5,5-dioxides 4b–i was obtained of triethylammonium salt 6a in 17% yield, which can be easily
in high yields (Table 1). All the condensed derivatives 4 were detected in its 1H NMR spectrum by the presence of an OH
isolated as white or slightly colored crystalline precipitates signal as the most downeld peak at about 17 ppm.
that can be recrystallized from a mixture EtOH-DMF (5 : 1,
v/v).
Similar salts were isolated for the rst time under investi-
gations of the three-component condensation involving N-ethyl-
As it turned out, the application of 1,2-benzoxathiin-4(3H)- 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide, ethyl cyanoacetate
one 2,2-dioxide (1) as an enol nucleophile in the studied reac- and benzaldehydes.9 This allowed us to assert that such
tion had some limitations. Thus, the usage of benzaldehydes chemical behavior is the general property of cyclic SO2-con-
containing a strong electron donating substituent (4-dimethy- taining enol nucleophiles of the type XSO2CH2CO. Because of
laminobenzaldehyde), or a bulky aromatic residue (9-antralde- the low yield of 6a and still being surprised by its isolation, we
hyde) resulted in the isolation of only the corresponding additionally analyzed the residue obtained by removing the
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 37295–37302 | 37297

View Article Online
RSC Advances
Paper
Scheme 2 Three-component reaction involving ethyl cyanoacetate (5).
1
solvent under reduced pressure using a H NMR method. The isolated when a 4-fold excess of 5 was used. This may serve as
obtained data evidenced the formation of the desired ethyl 2- evidence of an equilibrium established between the products 6a
amino-4-phenyl-4H-pyran-2-carboxylate 7a along with the salt and 7a in the course of the reaction performed. When a 5-fold or
6a and ethyl a-cyano-b-phenylacrylate 8a in an approximately more excess of 5 was introduced to the reaction, no solid was
molar ratio 1 : 0.6 : 0.45. The application of other benzalde- isolated from the mixture.
hydes gave us the following results: 2-methoxybenzaldehyde
(2b), reacted under the above-mentioned conditions, gave the 2.2. Variation of catalysts
target 2-amino-4H-pyran 7b in 27% yield, while the application
of 4-nitrobenzaldehyde (2i) resulted in the isolation of arylidene
8i.
It could be assumed that the product mixture, containing 6,
7 and 8, was formed in the course of the three-component
reaction involving ethyl cyanoacetate 5. In this regard, the
isolation of various compositions of the products, depending on
Literature data reveal that a wide range of basic catalysts can be
applied in similar interactions that result in high yields of 2-
amino-4H-pyrans irrespective of the nature of the 1,3-dicarbonyl
and nitrile components.21 However, it was shown that, in certain
instances, the catalyst is a crucial factor directing the reaction
towards unexpected outcomes.16 We selected 4-dimethylami-
nopyridine (DMAP), DBU and ammonium acetate as the tested
the benzaldehyde applied, is related to a different solubility of
catalysts. The rst was chosen since in the case of the N-
an individual product in ethanol.
containing analog of 1, DMAP appeared to be an effective
To achieve the goal of the current research we tested several
catalyst in the synthesis of some 3-ethoxycarbonyl derivatives of
routes, namely the utilization of ethyl cyanoacetate 5 excess,
2-amino-4H-pyrans9 and DBU was selected because of its high
applying different heating modes, variation of catalysts and also
basicity. However, reux for 4 h of the alcohol solution of
a two-component approach20 (8 + 1) towards 2-amino-4H-pyrans
benzoxathiinone 1 with benzaldehyde (2a) and 3 equiv. of 5
(Scheme 2) under the catalysis of DMAP (1 equiv.) led to the
7.
isolation of 4-dimethylaminopyridinium salt 6aP in 37% yield.
2.1. Excess of ethyl cyanoacetate 5
A similar result was also obtained when DBU was used as
a catalyst in the reaction and salt 6aD was isolated with 43%
yield. In the case of ammonium acetate utilization (1 equiv.,
The formation of triethylammonium salts 6 and ethyl 2-amino-
4H-pyran-3-carboxylates
7 was considered by us as two
1
AcOH, reux for 4 h), analysis of the reaction mixture by a H
competitive processes (Scheme 2). Previously, the application of
ethyl cyanoacetate excess allowed us to shi the equilibrium,
established in the reaction mixture, towards the formation of
the target ethyl 2-amino-4H-pyran-3-carboxylates.9,10b According
to this, it was logical to use an excess of 5 in the studied reac-
tion. Thus, the utilization of 2 equiv. of 5 (1 equiv. of Et3N, reux
NMR method showed the presence of the starting benzox-
athiinone 1 together with ethyl 2-amino-4H-pyran-3-carboxylate
7a and arylidene 8a.
2.3. Two-component approach
for 4 h) also led to the isolation of salt 6a in 24% yield. Applying According to the above-mentioned, variation of the reaction
of 3 equiv. of 5 under the previous reaction conditions allowed conditions did not provide us with the desired outcome.
us to isolate the mixture of the initial 1,2-benzoxathiin-4(3H)- Because of this, we focused our attention on the two-component
one 2,2-dioxide (1), arylidene 8a and target 2-amino-4H-pyran-3- format of ethyl 2-amino-4H-pyran-3-carboxylates 7 synthesis
carboxylate 7a in an approximate molar ratio of 1 : 1 : 1 based on the reaction of the Knoevenagel products 8 with
1
according to H NMR spectroscopy. It might have seemed like benzoxathiinone 1 (Scheme 2). One could assume that such an
the reaction did not complete during the heating time. In this approach would allow us to avoid the formation of salts 6 (as the
regard, the above-mentioned interaction was carried out for result of a possible direct interaction of 1 + 2) and additionally
10 h in similar conditions, but the mixture of equimolar would help to clarify some aspects of the reaction mechanism.
amounts of 2-amino-4H-pyran-3-carboxylate 7a and triethy- However, even such a stepwise format under the catalysis of
lammonium salt 6a was isolated. The same mixture was also Et3N (1 equiv., reux for 4 h) led to the isolation of
37298 | RSC Adv., 2018, 8, 37295–37302
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
Scheme 3 Formation of 7-phenyl-7,14-dihydrobenzo[5,6][1,2]oxathiino[4,3-b]benzo[5,6][1,2]oxathiino[3,4-e]pyridine 6,6,8,8-tetraoxide 9a.
Scheme 4 The study of the mutual transformation (EtOH, Et3N, reflux for 4h) of the compounds 4, 6 and 7.
Fig. 3 1H NMR spectra of 7a (DMSO-d6, r.t., analyzed by MestReNova v12.0.2) measured: I – immediately after dissolving; II – in 24 h after
dissolving; III – in 48 h after dissolving.
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 37295–37302 | 37299

View Article Online
RSC Advances
Paper
Scheme 5 Preparative methods for the synthesis of ammonium salts 6 and 1,4-dihydropyridines 9.
triethylammonium salt 6a in 78% yield. The application of DBU may be differences in the reactivity of the double bond in the
instead of Et3N in the two-component format led to the corre- resultant Knoevenagel condensation products. Taking into
sponding salt 6a (yield – 33%) even at room temperature. These account the obtained results, we may conclude that the forma-
facts suggest that the reaction proceeds through the formation tion of ammonium salts 6 dominates over the formation of ethyl
of the highly reactive arylidene G formed by Michael cleavage of 2-amino-4H-pyran-3-carboxylates 7 and even the application of
the initially generated adduct H (Scheme 2). Intermediate G ethyl cyanoacetate (5) excess, as well as that the use of a two-
subsequently adds benzoxathiinone 1 in the presence of a base component format of the synthesis did not allow us to manage
giving salt 6. Apparently, the transformation of salt 6 into ethyl the selectivity of the reaction. One could assume that the gener-
2-amino-4H-pyran-3-carboxylate 7 is also possible by means of ation of stable ammonium salts continuously pushes the reac-
the reverse reactions.
tion equilibrium towards their formation. Because of this we
The use of ammonium acetate provided us with another decided to check the possibility that salts 6 could be converted
new derivative of 1,2-benzoxathiine 2,2-dioxide and a novel into pyrans 7 (Scheme 4). This research we carried out together
product for such types of interactions – 7-phenyl-7,14-dihy- with the study of the transformation 6 / 4, since the utilization
drobenzo[5,6][1,2]oxathiino[4,3-b]benzo[5,6][1,2]oxathiino
of malononitrile (3) unambiguously led to 2-amino-4H-pyran-3-
[3,4-e]pyridine 6,6,8,8-tetraoxide (9a) when a mixture of 1 and carbonitriles 4. The reverse transformations 7 / 6 and 4 / 6
8a was reuxed in AcOH for 1 h in the presence of 1 equiv. of were also investigated. It was found that the interaction of salt 6a
ammonium acetate (Scheme 3). Apparently, the initially with malononitrile (3) or ethyl cyanoacetate (5) resulted in the
formed ammonium salt under the reaction conditions loses 2 isolation of a mixture of the starting salt and appropriate pyran
molecules of water and cyclizes into 1,4-dihydropyridine 9a.
4a or 7a. At the same time, only the 3-ethoxycarbonyl derivative
The interactions, presented in Scheme 2, resulted into salts 6 7b was able to be converted into salt 6b when reacted with 1; in
and/or 2-amino-4H-pyrans 7. Thus, there is a clear distinction the case of the 3-cyano derivative 4b reaction with 1, only the
between the reactivity of malononitrile and ethyl cyanoacetate in starting materials were recovered. These results explain the facts
the three-component reactions. It is possible that these differ- that the 2-amino-4H-pyran-3-carbonitriles 4 are formed as single
ences are associated with the different pKa values of the CH2 products in the three-component interaction when malononitrile
moiety of the two compounds; one other possible reason for this (3) was used (Table 1), whereas the application of ethyl
Fig. 4 Molecular structure (ORTEP plot) of 4b (deposition no. CCDC 1585657) and 6a (deposition no. CCDC 1585656) showing the atomic
labeling scheme. Non-H atoms are drawn as 30% probability displacement ellipsoids and H atoms are drawn as spheres of an arbitrary size.
37300 | RSC Adv., 2018, 8, 37295–37302
This journal is © The Royal Society of Chemistry 2018

View Article Online
Paper
RSC Advances
cyanoacetate (5) resulted in the isolation of the product mixture diethyl ether (700 mL), methanesulfonyl chloride (42.35 mL,
(Scheme 2). 0.55 mol) was added dropwise. The temperature was slowly
In respect of the interconversions established, the formation of raised to 15–20 ꢀC and the resulting mixture was stirred for 24 h.
relatively unstable salts in the course of the reaction might shi Aer the completion of this time, water (500 mL) was added to
the equilibrium towards 2-amino-4H-pyrans 7. To check this the suspension and the organic layer was separated. The ethe-
hypothesis, we introduced into the two-component reaction such real solution was successively washed with a 1 M solution of
a base as sodium acetate. Its application in the reaction of 1 with sodium bicarbonate (100 mL) and water (200 mL), dried over
8a allowed us to isolate pure target ethyl 2-amino-4-phenyl-4H- Na2SO4 and concentrated in vacuo. The residue obtained was
pyran-3-carboxylate 7a in 24% yield. A very unexpected result was methyl 2-((methylsulfonyl)oxy)benzoate as a light-yellow solid
1
ꢀ
occasionally gathered by us during the measurement of the H (mp 35–37 C) which was used in the next step without addi-
NMR spectra of 7a. This essential fact referred to the stability of tional purication.
1
ethyl 2-amino-4H-pyran-3-carboxylates 7 (Fig. 3). H NMR spectra
A solution of methyl 2-((methylsulfonyl)oxy)benzoate (46.0 g,
of 7a recorded at 24 h and 48 h showed the presence of a high 0.2 mol) in dry DMF (100 mL) was added dropwise to
percentage of the initial benzoxathiinone 1 and ethyl a-cyano-b- a suspension of NaH (8.8 g of 60%ꢀsuspension in mineral oil,
phenylacrylate (8a) increasing over time. Apparently, DMSO 0.22 mol) in dry DMF (70 mL) at 0 C. Aer completion of the
induces the retro-Michael cleavage of 7a, most probably as a result hydrogen evolution, the mixture was additionally stirred for
of its weak basic properties.22
1.5 h at 0 C and to the resulted suspension diluted HCl was
ꢀ
Additionally, preparative two-component approaches were added to achieve pH 1. The precipitate of 1,2-benzoxathiin-
worked out for the synthesis of salts 6 and 1,4-dihydropyridines 4(3H)-one 2,2-dioxide (1) was collected by ltration, dried in air
9. These routes are based on the interaction of benzoxathiinone and recrystallized from ethanol. The total yield of 1 was 64%.
ꢀ
1 with benzaldehydes 2 in different reaction conditions
(Scheme 5).
White crystalline powder; mp 87–89 C (from EtOH) (lit. 2a
89–91 ꢀC); anal. calcd for C18H12N2O4S: C, 48.48; H, 3.05; S,
1
Structural features of the synthesized 2-amino-4-aryl-4H- 16.18. Found, %: C 48.61; H 3.11; S, 16.04; H NMR (400 MHz,
pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile
5,5-dioxides DMSO-d6)23: d (ppm) 8.00 (d, J ¼ 7.19 Hz, 1H, Ar), 7.85 (t, J ¼
and triethylammonium 3-((4-hydroxy-2,2-dioxidobenzo[e][1,2] 7.05 Hz, 1H, Ar), 7.42–7.56 (m, 2H, Ar), 5.34 (br. s., 2H, CH2).
oxathiin-3-yl)(aryl)methyl)benzo[e][1,2]oxathiin-4-olate
2,2-
dioxides were conrmed by X-ray crystallographic analysis of 4.2. General procedure for the synthesis of 2-amino-4-aryl-4H-
example compounds 4b and 6a (Fig. 4).
pyrano[3,2-c][1,2]benzoxathiine-3-carbonitrile 5,5-dioxides (4a–i)
To a solution of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide (1)
(0.198 g, 0.001 mol), the appropriate aromatic aldehyde 2a–i
(0.001 mol) and malononitrile (3) (0.066 g, 0.001 mol) in ethanol
(10 mL), triethylamine (0.014 mL, 0.0001 mol) was added. The
mixture was reuxed for 1 h and cooled to room temperature.
The resulting precipitates of 4a–i were ltered off, washed with
ethanol, dried in air and recrystallized from the mixture EtOH–
DMF (5 : 1, v/v).
3. Conclusion
The three-component interaction of 1,2-benzoxathiin-4(3H)-one
2,2-dioxide (1) with benzaldehydes and active methylene nitriles
is a complicated process. Its outcome was controlled by the
nitrile nature. In the case of malononitrile (3), the products
formed were solely 2-amino-4H-pyran-3-carbonitriles 4. When
ethyl cyanoacetate (5) was used under basic catalysis, the reac-
tion led to the product mixture as a result of a number of
equilibrium processes existing between the starting
compounds, ethyl 3-aryl-2-cyanoacrylates 8, ethyl 2-amino-4-
aryl-4H-pyran-3-carboxylates 7 and triethylammonium salts 6.
In this instance, the composition of the isolated mixture
strongly depended on the reaction conditions applied and
relative solubility of the components. The low stability estab-
lished for ethyl 2-amino-4-aryl-4H-pyran-3-carboxylates 7 and
the difficulties of obtaining them motivated us to search for
a new effective route towards these condensed derivatives, for
reasons including their pharmacological attractiveness. The
study of the three-component interaction involving ethyl cya-
noacetate (5) allowed us to isolate for the rst time the ammo-
nium salts 6 and 1,4-dihydropyridines 9.
4.3. Preparative procedure for the synthesis of
triethylammonium 3-((4-hydroxy-2,2-dioxidobenzo[e][1,2]
oxathiin-3-yl)(aryl)methyl)benzo[e][1,2]oxathiin-4-olate 2,2-
dioxides (6a–c,h)24
To a solution of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide (1)
(0.198 g, 0.001 mol) and the appropriate aromatic aldehyde 2a–
c,h (0.0005 mol) in propan-2-ol (10 mL), triethylamine (0.07 mL,
0.0005 mol) was added. The solution was stirred for 1 h under
reux. The obtained precipitates of 6a–c,h were ltered off,
washed with propan-2-ol, dried in air and recrystallized from
ethanol.
4.4. Synthesis of ethyl 2-amino-4-phenyl-4H-pyrano[3,2-c]
[1,2]benzoxathiine-3-carboxylate 5,5-dioxides (7)
4.4.1 Ethyl 2-amino-4-phenyl-4H-pyrano[3,2-c][1,2]benzoxathiine-
3-carboxylate 5,5-dioxide (7a). Solution of 1,2-benzoxathiin-4(3H)-
one 2,2-dioxide (1) (0.198 g, 0.001 mol), ethyl 2-cyano-3-
4. Experimental
4.1. Synthesis of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide (1)
ꢀ
To a cooled to 0 C vigorously stirred mixture of methyl salicy- phenylacrylate (8a) (0.201 g, 0.001 mol) and sodium acetate
late (64.50 mL, 0.5 mol), triethylamine (76.51 mL, 0.55 mol) and (0.2 g) in ethanol (10 mL) was reuxed for 24 h and cooled to
This journal is © The Royal Society of Chemistry 2018
RSC Adv., 2018, 8, 37295–37302 | 37301

View Article Online
RSC Advances
Paper
room temperature. The formed precipitate was ltered off,
washed successively with water and ethanol and dried in air.
4.4.2 Ethyl 2-amino-4-(20-methoxyphenyl)-4H-pyrano[3,2-c]
[1,2]benzoxathiine-3-carboxylate 5,5-dioxide (7b). A solution of
1,2-benzoxathiin-4(3H)-one 2,2-dioxide (1) (0.198 g, 0.001 mol),
2-methoxybenzaldehyde (2b) (0.136 g, 0.001 mol), ethyl cya-
noacetate (5) (0.113 g, 0.001 mol) and triethylamine (0.14 mL,
8 (a) I. V. Ukrainets, L. A. Petrushova, S. P. Dzyubenko and
G. Sim, Chem. Heterocycl. Compd., 2014, 50, 103–110; (b)
D. A. Lega, N. I. Filimonova, I. A. Zupanets, S. K. Shebeko,
V. P. Chernykh and L. A. Shemchuk, J. Org. Pharm. Chem.,
2016, 14, 3–11.
9 D. A. Lega, N. Y. Gorobets, V. P. Chernykh, S. V. Shishkina
and L. A. Shemchuk, RSC Adv., 2016, 6, 16087–16099.
0.001 mol) in ethanol (10 mL) was reuxed for 4 h and cooled to 10 (a) D. A. Lega, V. P. Chernykh, L. Zaprutko, A. K. Gzella and
room temperature. The formed precipitate of 7b was ltered off,
washed with cooled to 0 ꢀC ethanol and dried in air.
L. A. Shemchuk, Chem. Heterocycl. Compd., 2017, 53, 219–
229; (b) D. A. Lega, V. P. Chernykh and L. A. Shemchuk, J.
Org. Pharm. Chem., 2016, 14, 6–16.
4.5. Preparative procedure for the synthesis of 7-aryl-7,14-
dihydrobenzo[5,6][1,2]oxathiino[4,3-b]benzo[5,6][1,2]
oxathiino[3,4-e]pyridine 6,6,8,8-tetraoxides (9)
11 A.-G. E. Amr, A. M. Mohamed, S. F. Mohamed, N. A. Abdel-
Hafez and A. E.-F. G. Hammam, Bioorg. Med. Chem., 2006,
14, 5481–5488.
12 P. Paliwal, S. Jetti and S. Jain, Med. Chem. Res., 2013, 22,
2984–2990.
13 D. Kumar, V. B. Reddy, S. Sharad, U. Dube and S. Kapur, Eur.
J. Med. Chem., 2009, 44, 3805–3809.
14 C. W. Smith, J. M. Bailey, M. E. J. Billingham,
S. Chandrasekhar, C. P. Dell, A. K. Harvey, C. A. Hicks,
A. E. Kingston and G. N. Wishart, Bioorg. Med. Chem. Lett.,
1995, 5, 2783–2788.
15 C. F. Schwender and B. R. Sunday, US pat. US4116961A,
1978.
A
solution of 1,2-benzoxathiin-4(3H)-one 2,2-dioxide (1)
(0.396 g, 0.002 mol), the appropriate aromatic aldehyde 2a,c
(0.001 mol) and ammonium acetate (0.77 g, 0.01 mol) in AcOH
(10 mL) was reuxed for 1 h and cooled to room temperature.
The resulting precipitates of 9a,c were ltered off, washed
successively with AcOH and water and dried in air.
Conflicts of interest
There are no conicts to declare.
16 Y. M. Litvinov and A. M. Shestopalov, in Adv. Heterocycl.
Chem., ed. A. R. Katritzky, Academic Press, 2011, vol. 103,
pp. 175–260.
Acknowledgements
17 (a) K. Azizi and A. Heydari, RSC Adv., 2014, 4, 6508–6512; (b)
M.-J. Yao, Z. Guan and Y.-H. He, Synth. Commun., 2013, 43,
2073–2078; (c) J. Safaei-Ghomi, R. Teymuri, H. Shahbazi-
Alavi and A. Ziarati, Chin. Chem. Lett., 2013, 24, 921–925;
(d) G. H. Mahdavinia, M. Mirzazadeh and B. Notash,
Tetrahedron Lett., 2013, 54, 3487–3492.
The authors are thankful to Mr Eugene S. Gladkov (SSI “ISC”
NASU) for his support in obtaining the spectroscopic data for
the compounds presented in this paper.
Notes and references
18 L. Jalili-Baleh, N. Mohammadi, M. Khoobi, L. Ma'mani,
A. Foroumadi and A. Shaee, Helv. Chim. Acta, 2013, 96,
1601–1609.
¨
¨
1 For some examples, see: (a) W. Lowe and C. Muller-Menke,
¨
Arch. Pharm., 1985, 318, 954–956; (b) W. Lowe and
C. Muller-Menke, Arch. Pharm., 1988, 321, 755–756; (c)
¨
19 B. Maheshwar Rao, G. N. Reddy, T. V. Reddy, B. L. A. P. Devi,
R. B. N. Prasad, J. S. Yadav and B. V. S. Reddy, Tetrahedron
Lett., 2013, 54, 2466–2471.
20 A. Thakur, M. Tripathi, U. C. Rajesh and D. S. Rawat, RSC
Adv., 2013, 3, 18142–18148.
21 G. Brahmachari, in Green Synthetic Approaches for
Biologically Relevant Heterocycles, ed. G. Brahmachari,
Elsevier, Boston, 2015, pp. 185–208.
22 W. S. MacGregor, Ann. N. Y. Acad. Sci., 1967, 141, 3–12.
23 According to 1H NMR spectrum, 1,2-benzoxathiin-4(3H)-one
2,2-dioxide (1) in DMSO-d6 solution exists in two tautomeric
forms – 4-oxo form and 4-hydroxy (enol) form in aproximate
molar ratio 10 : 1.
¨
W. Lowe, P. Jeske and A. Kradepohl, J. Heterocycl. Chem.,
1988, 25, 699–701.
2 (a) V. R. Arava, U. B. R. Siripalli, V. Nadkarni and
R. Chinnapillai, Beilstein J. Org. Chem., 2007, 3, 20; (b)
C. Peixoto, P. Laurin, M. Klich, C. Dupuis-Hamelin,
P. Mauvais, P. Lassaigne, A. Bonnefoy and B. Musicki,
Tetrahedron Lett., 2000, 41, 1741–1745.
3 C. Hulme and V. Gore, Curr. Med. Chem., 2003, 10, 51–80.
4 (a) Y. V. Sedash, N. Y. Gorobets, V. A. Chebanov,
I. S. Konovalova, O. V. Shishkin and S. M. Desenko, RSC
Adv., 2012, 2, 6719–6728; (b) E. A. Muravyova,
S. M. Desenko, R. V. Rudenko, S. V. Shishkina,
O. V. Shishkin, Y. V. Sen'ko, E. V. Vashchenko and
V. A. Chebanov, Tetrahedron, 2011, 67, 9389–9400.
5 V. A. Chebanov and S. M. Desenko, Chem. Heterocycl.
Compd., 2012, 48, 566–583.
24 The same synthetic procedure was applied for the
preparation of 4-(dimethylamino)pyridin-1-ium 6aP and
3,4,5,6,7,8,9,10-octahydro-2H-pyrimido[1,2-a]azepin-5-ium
6aD salts using DMAP and DBU, respectively.
6 C. W. Thornber, Chem. Soc. Rev., 1979, 8, 563–580.
7 N. Au and A. E. Rettie, Drug Metab. Rev., 2008, 40, 355–375.
37302 | RSC Adv., 2018, 8, 37295–37302
This journal is © The Royal Society of Chemistry 2018