Peculiarities of 2-amino-3-R-4-aryl-4H-pyranes multicomponent synthesis derived from 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide

Article abstract of DOI:10.1039/c5ra24566d

The new 2-amino-3-R-4-aryl-6-ethyl-4,6-dihydropyrano[3,2-c][2,1]benzothiazine 5,5-dioxides were synthesized via three-component interaction of 1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide with arylcarbaldehydes and active methylene nitriles. Depending on the

Full text of DOI:10.1039/c5ra24566d

View Article Online
View Journal
RSC Advances
This article can be cited before page numbers have been issued, to do this please use: D. Lega, N. Yu.
Gorobets, V. Chernykh, S. Shishkina and L. Shemchuk, RSC Adv., 2016, DOI: 10.1039/C5RA24566D.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. This Accepted Manuscript will be replaced by the edited,
formatted and paginated article as soon as this is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/advances

Page 1 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
PECULIARITIES OF 2ꢀAMINOꢀ3ꢀRꢀ4ꢀARYLꢀ4HꢀPYRANES MULTICOMPONENT
SYNTHESIS DERIVED FROM 1Hꢀ2,1ꢀBENZOTHIAZINꢀ4(3H)ꢀONE 2,2ꢀDIOXIDE
Dmitry A. Lega,a Nikolay Yu. Gorobets,b Valentine P. Chernykh,a Svetlana V. Shishkina,b
∗
Leonid A. Shemchuka
Abstract
–
The new 2ꢀaminoꢀ3ꢀRꢀ4ꢀarylꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]
benzothiazine 5,5ꢀdioxides were synthesized via threeꢀcomponent interaction of 1Hꢀ2,1ꢀ
benzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide with arylcarbaldehydes and active methylene nitriles.
Depending on the nature of an active methylene nitrile and an arylcarbaldehyde this interaction
can lead either to the target 2ꢀaminoꢀ4Hꢀpyrans or to the stable triethylammonium salts of
bis(1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxides) (bisꢀadducts). The later is a completely new
product of such interaction. The structure of the bisꢀadduct was confirmed by the single crystal
Xꢀray diffraction. Actually, the formation of stable triethylammonium salts (as the process
competitive with the 2ꢀaminoꢀ4Hꢀpyrans formation) appeared to be reversible and their
interaction with active methylene nitriles led to the formation of 2ꢀaminoꢀ4Hꢀpyrans. The
extended and adjusted mechanism of threeꢀcomponent interaction, that includes the bisꢀadducts
formation stage, was proposed. Taking into account the peculiarities of the mechanism of studied
reaction, we were capable of controlling the reaction selectivity.
Keywords: 1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone, 4Hꢀpyran, triethylammonium salt,
benzaldehydes, active methylene nitriles, multicomponent reaction, mechanism,
competing reaction, equilibrium.
1. Introduction
Multicomponent reactions (MCRs) are an extremely effective tool for the rapid
generation of smallꢀmolecule libraries by creation of structural complexity in a single step from
three or more reactants, providing greater efficiency and an atom economy as compared with
stepwise synthesis. 1 , 2 Therefore, there is a continuous growth of interest in the MCRs
investigations, especially for their possible application in combinatorial and medicinal science.
In part, the pharmaceutical industry has fueled this resurgence because of the growing need to
assemble libraries of structurally complex substances for evaluation as lead compounds for drug
discovery and development.3 However, the multicomponent processes are often associated with
ambiguous reaction mechanisms and selectivity issues or unexpected outcome4 making the
design of novel MCRs as well as an extension of the scope of known MCRs to be an intriguing
but challenging task.
a.National University of Pharmacy, Pushkinska Str. 53, Kharkiv, 61001, Ukraine
b.SSI ‘Institute for Single Crystals’ of NAS of Ukraine, Lenin Ave. 60, Kharkiv, 61001, Ukraine
Electronic Supplementary Information (ESI) is available: Full spectroscopic data (1H and 13C NMR, IR, MS) for
compounds 5, 7 and 8 and Xꢀray crystallographic data for compounds 7b and 8b are included in the SI file

RSC Advances
Page 2 of 25
View Article Online
DOI: 10.1039/C5RA24566D
5
In our previous paper we described a threeꢀcomponent interaction of 1Hꢀ2,1ꢀ
benzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide with active methylene nitriles and isatines. This interaction
led to the formation of the corresponding fused 2ꢀaminoꢀ4Hꢀpyrans spirocondensed with 2ꢀ
oxindol ring. This article was the first, dedicated to the multicomponent interactions of such
benzothiazinones.
1Hꢀ2,1ꢀBenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide represents the active methylene CHꢀacid. Its
structure is an analogue of a cyclic active methylene 1,3ꢀdicarbonyl compounds. This makes it a
very convenient and promising synthon, which opens great opportunities for building of a new
heterocyclic systems based on СН2ꢀСО fragment in its molecule. One of the most prospective
routes to achieve this goal is using of MCRs. Unlike its carbonyl analogue, 1Hꢀ2,1ꢀbenzothiazinꢀ
4(3H)ꢀone 2,2ꢀdioxide exists entirely in the 4ꢀoxoform. Simultaneously, the carbonyl group of
the given heterocycle is distinguished by a high propensity for enolization in the course of
introducing an alkyl or an acyl groups into position 3.6,7
Furthermore, 1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide derivatives have recently
gained an additional value due to their reported biological activities such as potent antibacterial
effect, 8 lipoxygenase inhibition and, so, their potential for treat heart diseases treatment. 9
Moreover, 1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide core is bioisosteric to the 2,3ꢀdihydroꢀ
4Hꢀ1,2ꢀbenzothiazinꢀ4ꢀone 1,1ꢀdioxide (Figure 1). The last one is a core of wellꢀknown
analgesic and antiꢀinflammatory agents (Piroxicam®, Droxicam® and Meloxicam® and its
heteroanologues – Tenoxicam® and Lornoxicam®). Interestingly, isosteric benzothiazineꢀ3ꢀ
carboxamides (Figure 2(B), d) have been shown to posses much higher analgesic activity than
Piroxicam® and Meloxicam® (Figure 2(B), a, b).10,11,12
Figure 1. Common scaffold of applied analgesics (left side) and 1Hꢀ2,1ꢀbenzothiazinꢀ
4(3H)ꢀone 2,2ꢀdioxides possessing higher analgesic activity (right side).
Multicomponent interactions of enolꢀnucleophiles (1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀ
dioxide is one of them) with carbonyl compounds and active methylene nitriles are attracting
synthetic community for a long time. The reason – is the formation of various products
depending on the reaction conditions and the structure of starting compounds. In the most cases,
such interaction is the direct route for the 2ꢀaminoꢀ4Hꢀpyran core construction. The main
advantage of this methodology is the reduction of synthetic steps, which is of paramount
importance for the preparation of intermediate unsaturated nitriles which are, in many cases,

Page 3 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
toxic and lachrymatory.13,14,15 To date, a lot of approaches were applied for threeꢀcomponent
synthesis of 2ꢀaminoꢀ4Hꢀpyrans. Traditionally, the interactions of 1,3ꢀdicarbonyl compounds
with active methylene nitriles and benzaldehydes are easily carried out on heating in ethanol
with basic catalysts, such as triethylamine,16,17 piperidine,18 morpholine,15 which resulted into
formation of 2ꢀaminoꢀ4Hꢀpyrans in good to excellent yields.
In their turn, condensed 4Hꢀpyranes are ones of the most wellꢀknown natural and
synthetic heterocyclic compounds. They attract considerable attention since they possess an
extensive range of biological effects. Several naturally occurring pyranꢀannulated heterocyclic
compounds display antiꢀinflammatory,19 antiꢀHIV activity,20 cytotoxic activity against leukemia
cells,21 antileishmania activity,22 and slight activity against hepatitis B virus.23
24
Synthetically available 4Hꢀpyranes are also used as pigments
and photoactive
materials.25 Furthermore, some derivatives of 4Hꢀpyranes (for example cromakalim) can serve as
a typical ATPꢀsensitive potassium channel openers or possess potent relaxant activity on blood
vessels, cardiac muscle, and other smooth muscles. Thus, they may find an application in the
treatment of variety of diseases such as hypertension, asthma, ischemia, and urinary
incontinence.26,27 Moreover, several representatives of this class of compounds are known to be
cognitive enhancers used to treat neurodegenerative disorders, including Alzheimer’s,
Huntington’s, and Parkinson’s diseases and schizophrenia.28,29 In previous studies, 2ꢀaminoꢀ3ꢀ
cyanoꢀ4Hꢀpyran derivatives, which are closely related to the title compounds, were found to
possess anticancer,30 antibacterial,31,32 and antiꢀrheumatic33 effects; selected representatives of
them are given in Figure 2(A).
A
anticancer30
antibacterial31 antiꢀrheumatic33
NH2
Cl
O
N
O
OH
O
N
R
OH
O
N
O
N
O
S
N
N
N
Ar
H
H
SO2
N
N
SO2
Me
S
Me
N
O
O
O
Me
B
Me
O
target
compounds
Piroxicam®
Meloxicam®
Droxicam®
analgesic activity11
(a)
(b)
(c)
(d)
(e)
Figure 2. Examples of synthetically available bioactive 2ꢀaminoꢀ3ꢀcyanoꢀ4Hꢀpyranes (A),
benzothiazine (B) and the target compounds (e).

RSC Advances
Page 4 of 25
View Article Online
DOI: 10.1039/C5RA24566D
In continuation of our previous researches, the reaction of 1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀ
one 2,2ꢀdioxide with an active methylene nitriles and arylcarbaldehydes to synthesize
corresponding 4ꢀarylꢀ4Hꢀpyran derivatives fused with 1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀ
dioxide (Figure 2(B), e) was investigated. It acquires additional value, because of, currently, 2,3ꢀ
dihydroꢀ4Hꢀthiochromenꢀ4ꢀone is an example of sixꢀmembered sulfur containing heterocycles,
based on which, 2ꢀaminoꢀ4Hꢀpyranes were obtained.15,34
2. Results and discussion
The first step of our researches was to find out the most suitable catalyst for threeꢀ
component interaction of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide with malononitrile
and benzaldehyde. As representatives, we applied thriethanolamine (used in our previous work5),
triethylamine (as an inexpensive and widely used organic base) and urea (as an environmentally
benign organoꢀcatalyst and since it allows to apply relatively mild reaction conditions13) as
catalysts and ethanol or aqueous ethanol as solvents. However, the use of urea as a catalyst
showed the low efficiency. The reactions with malononitrile resulted into the corresponding 2ꢀ
aminoꢀ3ꢀcyanoꢀ4ꢀphenylꢀ4Hꢀpyran in 30ꢀ45% yields appeared to be unsatisfactory. In this regard,
thriethanolamine and triethylamine demonstrated much higher efficiency, since their applying in
MCR allowed us to obtain condensed 2ꢀaminoꢀ4ꢀphenylꢀ4Hꢀpyran in high yields. Triethylamine
was used as more convenient in use catalyst in our further experiments.
In general, the MCR between 1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1,
malononitrile (2) and benzaldehydes 3aꢀg was carried out in refluxing ethanol during 1 hour in
the presence of equimolar quantities of triethylamine and it resulted in the formation of the
expected 2ꢀaminoꢀ4Hꢀpyran derivatives 5aꢀg isolated in high yields (Table 1, Method A). The
products precipitated from the reaction mixture were recrystallized from ethanol. For 4ꢀ
nitrobenzaldehyde (3b), the reaction temperature and time were decreased up to 50 °C for 40
min to avoid formation of undesirable side products. Though one could expect the reactivity
decreases for 4ꢀdimethylaminobenzaldehyde (3f) due to its strong electron donating substituent
effect35, or for bulky 9ꢀantraldehyde (3g), the high yields were also obtained in these cases. The
application of the stepwise approach towards 2ꢀaminoꢀ4Hꢀpyranes 5aꢀg (Table 1, Method B)
resulted in the lower yields compared to those, obtained by the MCRs. The gathered results
confirm the preferred applicability of the multicomponent format for synthesis of 5aꢀg and serve
as evidence that the formation of 2ꢀaminoꢀ4Hꢀpyran heterocycle in the course of MCR most
likely proceeds via intermediate arylidenes 4.
Table 1. Yields for the compounds 5aꢀg synthesized by two methodsa

Page 5 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
Yields, %b
Compound
Ar
Method A
Method B
C6H5
82
95
85
84
89
81
93
55
71
66
58
81
63
91
5a
5b
5c
5d
5e
5f
4ꢀNO2ꢀC6H4
2ꢀMeOꢀC6H4
4ꢀMeOꢀC6H4
4ꢀClꢀC6H4
4ꢀMe2NꢀC6H4
9ꢀAnthracenyl
5g
a Reagents and conditions: (i) EtOH, Et3N (1.0 equiv), reflux for 1 h (for 5b heating at
50 °C for 40 min in both methods).
b Isolated yield.
The simple performance of the reaction given above, encouraged us to introduce other
active methylene nitriles into this MCR. Ethyl cyanoacetate (6), benzylcyanide (12) and Nꢀ(pꢀ
tolyl)cyanoacetamide (13) were chosen as representative building blocks to investigate the scope
and limitations of this MCR.
However, for ethyl cyanoacetate (6) reacted under similar conditions during 4 hours, a
significant decrease in the process efficiency and selectivity (Scheme 1) was observed. The only
exception was the starting 4ꢀnitrobenzaldehyde (3b) for which a pure target 2ꢀaminoꢀ4Hꢀpyran
7b was isolated in 51% yield. For aldehydes 3f,g the reaction stopped on the formation of
arylidenes 9f,g. In spite of our attempts to prolong the reaction time or to use a higher boiling
point solvent (DMF), we failed to obtain the expected products 7f,g.
When unsubstituted benzaldehyde (3а) and 4ꢀchlorobenzaldehyde (3е) were used, it
allowed us to obtain a new result of such threeꢀcomponent interactions, namely to get the stable
triethylammonium salts 8a and 8e in yields 35% and 17% respectively. These salts are uncolored
crystalline compounds which can be recrystallized unchanged from ethanol. The possibility of
the formation of such salts is caused by the raised CHꢀacidic properties of methyne group (as the
result of electron withdrawing influence of SO2ꢀgroup) which leads to ease of enolization.

RSC Advances
Page 6 of 25
View Article Online
DOI: 10.1039/C5RA24566D
Moreover, the intramolecular hydrogen bond formation increases the stability of
triethylammonium enolates (details of the salt structures are given in Xꢀray diffraction
experimental part). We found only one example of such threeꢀcomponent reaction wherein
similar (but nonꢀsymmetrical) salts were formed. These salts contained 4ꢀhydroxycoumarin core
in which an increase of acidic properties is also observed as the result of 2ꢀcarbonyl group
influence.36
In the case of benzaldehydes 3c,d, bisꢀadducts 8c,d were also formed as admixture (12ꢀ
1
15% according to H NMR) to the target 4Hꢀpyrans 7c,d. Pure products 7c,d were obtained by
recrystallization of crude products from ethanol with yields 50 and 39%, correspondingly.
NH2
CN
CO2Et
Ar
OH Ar
O Et3NH
O
N
CO2Et
O
N
Ar
CN
6
+
i
and/or
or
SO2 O2S
EtO2C
Ar
SO2
Me
N
N
SO2
Me
O
H
Me
Me
9f,g
1
8a,c-e
3a-g
7b-d
Ar
CN
1, i
EtO2C
9a
Scheme 1. Reagents and conditions: (i) EtOH (iꢀPrOH), Et3N (1.0 equiv), reflux for 4 h (for 3b –
50 °C for 2 h)
Taking into account the received information, we set the problem – to work out an
efficient method for the synthesis of 3ꢀethoxycarbonylꢀ4Hꢀpyrans 7, which could avoid the
formation of undesired bisꢀadducts 8. However, since the bisꢀadducts 8 have been obtained for
the first time in such threeꢀcomponent interactions, we also encouraged to study some aspects of
their reactivity, and the role of the bisꢀadducts 8 in the reaction.
Based on the structure of bisꢀadducts 8, it can be assumed that ethyl cyanoacetate (6) is
not involved in threeꢀcomponent interaction and, consequently, in the formation of bisꢀadducts 8.
Therefore, initially we synthesized arylidene 9 which is an intermediate in the synthesis of 2ꢀ
aminoꢀ4Hꢀpyrans. 37 , 38 This arylidene was reacted with 1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀ
dioxide 1 then. We supposed, that applying such conditions, we will be able to avoid the
formation of bisꢀadduct 8.
To our surprise, even this stepwise format resulted in the formation of unwanted bisꢀ
adduct 8 (usage of arylidene 9a led to 8a with yield of 43%).

Page 7 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
To rationalize this result one has to assume that initially formed Michael adduct 10 can be
further transformed by two ways (Scheme 2). The first way – is the desired heterocyclization,
that represents a cascade of protonꢀtransfer processes: enolization of the keto group followed by
chainꢀtoꢀring tautomeric transformation (heteroꢀThorpeꢀZiegler reaction, namely intramolecular
nucleophilic addition of OH to CN group) and finally enamineꢀimine tautomerism to form
product 7.15 The second one – is a retroꢀMichael reaction with elimination of ethyl cyanoacetate
(6) and formation of enone 11, which reacts with the second molecule of benzothiazinone 1
forming bisꢀadduct 8.
Scheme 2. Presumable mechanism for the formation of compounds 7 and 8
Enones 11 and arylidenes, similar to them, are the precursors for the synthesis of 2ꢀ
aminoꢀ4Hꢀpyrans while reacting with active methylene nitriles.39,40 Arylidenes 11 formed from
initial benzothiazinone 1 were described in only one publication41 and obtained under acidic
catalysis. Our attempt to obtain arylidenes 11 by interaction of benzothiazinone 1 with
benzaldehydes 3a,c (molar ratio 1:1) under basic conditions (EtOH, 1.0 of equiv Et3N, rt) led to
isolation of bisꢀadducts 8a,c in low yields and of poor purity. At the same time, when this
reaction was carried out under similar conditions in molar ratio 2:1 for compounds 1 and 3a,c we
isolated pure compounds 8a,c in yields 93% and 87% correspondingly. This approach can be
proposed as preparative for synthesis of salts 8. The fact, that interaction 1 with 3 leads to the
formation of bisꢀadducts 8 serves as evidence that the second way of threeꢀcomponent
interaction is also possible. It involves a primary formation of enones 11 (by interaction of 1+3
avoiding the formation of adduct 10). Apparently, the part of reagents reacts by this way.
Thereby, we can conclude that the arylidenes 11 are highly reactive intermediates and
behave as Michael acceptors in the reaction media. Depending on the nature of the substituent in
the benzaldehyde residue, these arylidenes can interact either with benzothiazinone 1 (to form

RSC Advances
Page 8 of 25
View Article Online
DOI: 10.1039/C5RA24566D
the symmetrical bisꢀadduct isolated as triethylammonium salt 8) or with ethyl cyanoacetate (6)
(to form desired 4Hꢀpyrans 7).
Since, most probably, all the stages in the mechanism (Scheme 2) are reversible15,42
(except 11 → 8, that required additional investigations) we attempted to take control over the
selectivity of this threeꢀcomponent reaction (Scheme 1) by using the excess of ethyl cyanoacetate
(6) in our further experiments to shift the reaction equilibrium towards the formation of 4Hꢀ
pyran derivatives 7.
As noted previously, bisꢀadduct 8a was the single isolated product when benzaldehyde 3a
was used in threeꢀcomponent interaction (Scheme 1). Using 3.0 equiv of 6 in the reaction with 1
and 3a in ethanol in the presence of triethylamine in oneꢀpot under reflux during 4 h led to
isolation of the desired 4Hꢀpyran derivative 7a. Though the final product was not contaminated
with bisꢀderivative 8a the yields appeared to be moderate (Table 2). Higher amounts of 6 did not
affect the yield significantly. These unsatisfactory results compelled us to search for better
reaction conditions; we tried to carry out this reaction by varying of the bases applied. In the
presence of 1.0 equiv of 4ꢀdimethylaminopyridine (DMAP) the yield of 7a was increased up to
70%. If lower amounts of DMAP (or Et3N) were used under abovementioned conditions, the
reaction was not complete (not shown in the Table 2). The use of DMAP in the case of 4ꢀ
nitrobenzaldehyde (3b) led to the increase of the yield of 7b up to 68%. For the aldehyde 3c, the
pure product 7c was formed in high yield using 2.0 equiv of 6 (Table 2). The satisfactory yield of
7d was obtained using iꢀPrOH instead of EtOH. However, for aldehydes 3c,d the use of 1.0
equiv of DMAP instead of Et3N decreased the reaction efficiency. To avoid the formation of side
product 8e and to obtain pure derivative 7e it was necessary to use 7.0 equiv of 6. In this case,
the use of DMAP significantly increased the yield of 7e in comparison with Et3N.
Thus, the reaction outcome is strongly dependent on the nature of the substituent in the
starting benzaldehyde and the conditions applied. In the case of ethyl cyanoacetate (6) it was
necessary to vary the reaction conditions to reach acceptable yield levels.
Table 2. Optimization steps in threeꢀcomponent reactions with ethyl cyanoacetatea
(Scheme 1)
Yields, %c
7
Conditions of
threeꢀcomponent reaction
Molar ratio of
Aldehyde
Equivalents of 6
products 7 and 8b
8d
35
–
1.0
3.0
5.0
1.0
3.0
1.0
3.0
3.0
1.0
0:1
1:0
1:0
1:0.58
1:0
1:0.67
1:0
–
EtOH, Et3N,
reflux for 4 h
24
25
14
24
25
22
70
51
–
16
–
34
–
iꢀPrOH, Et3N, boiling for 4 h
3a
3b
EtOH, morpholine,
reflux for 4 h
EtOH, DMAP, reflux for 4 h
EtOH, Et3N, 50 °C, 2 h
1:0
1:0
–
–

Page 9 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
EtOH, DMAP, 50 °C, 2 h
1.0
1.0
2.0
3.0
2.0
3.0
1.0
3.0
3.0
1.0
3.0
5.0
7.0
7.0
1:0
1:0.16
1:0
68
50
84
78
62
20
39
55
62
–
–
16
–
–
–
–
10
–
–
17
14
4
–
–
EtOH, Et3N, reflux for 4 h
3c
1:0
EtOH, DMAP, reflux for 4 h
EtOH, Et3N, reflux for 4 h
1:0e
1:0
1:0.13
1:0
iꢀPrOH, Et3N, reflux for 4 h
3d
EtOH, DMAP, reflux for 4 h
1:0e
0:1
1:0.36
1:0.07
1:0
19
29
33
63
EtOH, Et3N, reflux for 4 h
3e
EtOH, DMAP, reflux for 4 h
1:0
a
The reaction was carried out using 1 mmol of 1 and 3 in 5 mL of solvent (EtOH or iꢀPrOH).
b
1
Confirmed by H NMR spectra of isolated precipitate without purification as intensity ratio of proton in 4th
position of 4Hꢀpyran ring and methyne moiety proton of bisꢀderivative.
c
The yields of each component 7 and 8 in the isolated product.
d Yields of compound 8 were calculated based on 2.0 eq. of compound 1.
e The admixture of appropriate arylidenes was observed in an amount of 15ꢀ17 mol% as was confirmed by 1H NMR
spectra of isolated precipitates without purification as intensity ratio of proton in 4th position of 4Hꢀpyran ring and
CH moiety proton of arylidenes
As it was mentioned above, the mechanism of this reaction (Scheme 2) suggests the
formation of the key intermediate 11 that can be transformed into both 4Hꢀpyran derivatives 7
and bisꢀadducts 8. Though this intermediate was neither isolated, nor identified in the reaction
mixtures, its formation was additionally confirmed by studying of mutual transformations of
products 5, 7 and 8. Among all the stages of the mechanism, the possibility of reverse
transformation of 8 → 11 was unknown. To determine the possibility of the retroꢀreactions 8 →
7 and 8 → 5, the interactions of bisꢀadducts 8 with ethyl cyanoacetate (6) and malononitrile (2)
were studied. Since the products 8 were isolated for the first time, these experiments allowed us
to demonstrate some aspects of their reactivity.
Bisꢀadducts 8a,c were used to study the transformation of 8 → 7. The reactions were
carried out by the treatment of 8 with 1.0 equiv of both ethyl cyanoacetate (6) and triethylamine
in refluxing ethanol for 6h. In the case of 8a (Ar = C6H5) only the starting material was
recovered after the heating, whereas when compound 8c (Ar = 2ꢀMeOꢀC6H4) was used, the final
mixture contained the initial bisꢀadduct 8c, 3ꢀethoxycarbonylꢀ4Hꢀpyran 7c and benzothiazinone
1 in molar ratio 1:2:2 (in accordance with 1H NMR spectrum).
To study the transformation of 8 → 5, the bisꢀadducts 8a,c were used. The reactions of
8a,c with 1.0 equiv of 2 under the standard reaction conditions resulted in the formation of pure
compounds 5a,c isolated in yields 53% and 61% respectively.
Thus, it was experimentally confirmed that the bisꢀadducts 8 can be transformed into 4Hꢀ
pyrans 5 and 7 under reaction conditions. This fact clearly indicates the reversibility of the stage
11 ⇄ 8 and consequently all the stages of proposed mechanism (Scheme 2) are reversible.

RSC Advances
Page 10 of 25
View Article Online
DOI: 10.1039/C5RA24566D
We have also studied the possibility of reverse transformations of 7 → 8 and 5 → 8.
While there is no data about the transformation of such adducts, similar to compounds 8, into 2ꢀ
aminoꢀ4Hꢀpyranes, we found only two suitable references about reverse transformations (similar
to 5 or 7 into 8)43,44 which were carried out in AcOH/AcONH4 or under heating in DMF.
Transformation of 7 → 8 was achieved in the case of 7a. It performed by treatment of 7a with
1.0 equiv of both benzothiazinone 1 and triethylamine in refluxing ethanol for 6h. As a result,
pure bisꢀadduct 8a was isolated in yield 47%. However, such transformation did not proceed in
the case of pyran 7c. The reverse transformation of 5a,c into bisꢀadducts 8a,c was not achieved
under similar conditions (Scheme 3).
Given the fact that 3ꢀethoxycarbonylꢀ4Hꢀpyran 7a transformed into bisꢀadduct 8a and 3ꢀ
cyanoꢀ4Hꢀpyran 5a did not undergo this transformation we suggested that malononitrile derived
products, 3ꢀcyanoꢀ4Hꢀpyrans 5, are more stable compared with products, derived from ethyl
cyanoacetate, 3ꢀethoxycarbonylꢀ4Hꢀpyrans 7. To confirm this assumption a model reactions 7 →
5 were finally carried out using 7a,c (Scheme 3). Thus, heating of 7a,c at 60 °C for 1 h with 1.0
equiv of malononitrile (2) in ethanol in the presence of equimolar quantity of triethylamine
allowed formation of 5a,c isolated in yield 58% and 67% correspondingly. An example of this
type of transformation was previously reported.45 In opposite, the reverse interactions of 5a,c
with ethyl cyanoacetate (6) under the same conditions resulted in the recovery of the starting
products 5a,c.
6
, i
NH2
NH2
CO2Et
Ar
CN
Ar
O
N
OH Ar
O Et3NH
O
N
2, i
SO2
Me
SO2 O2S
SO2
Me
N
N
2
, ii
Me
8a,c
Me
5a,c
7a,c
1
, i
Scheme 3. Reagents and conditions: (i) EtOH, Et3N, reflux, 4ꢀ6h; (ii) EtOH, Et3N, 50ꢀ60°C, 1h
Therefore, when ethyl cyanoacetate (6) is used in threeꢀcomponent interaction (Scheme
1) we can conclude that in addition to the reaction conditions, the outcome of the studied MCR is
controlled by the relative stability of the products 7 and 8 that is, in its turn, dictated by the
substituent nature in the benzaldehyde fragment.
According to our research plan, we also used other active methylene nitriles, such as
benzyl cyanide (12) and Nꢀ(pꢀtolyl)cyanoacetamide (13), in this threeꢀcomponent interaction

Page 11 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
(Scheme 4). But contrary to our expectations, only bisꢀadducts 8a,b in both cases were isolated
in 53% and 44% yields correspondingly. In accordance with the previously established
regularities, we used fivefold excess of benzyl cyanide (12) to obtain the target 4Hꢀpyran
derivative, but the bisꢀadduct 8b was again the sole product of this transformation.
Scheme 4. Reagents and conditions: (i) EtOH, Et3N, r.t., 4 h; (ii) EtOH, Et3N, reflux for 4 h
The IR spectra of all the obtained compounds 5, 7, 8 contain two absorption bands of
sulfonyl group at 1329ꢀ1296 and 1174ꢀ1102 cmꢀ1 regions. The valence oscillations of amino
group in compounds 5 and 7 can be observed as two bands at 3456ꢀ3285 cmꢀ1. The IR spectra of
5aꢀg are characterized by the highly intense narrow band of the cyano group which can be found
at 2202ꢀ2187 cmꢀ1. The frequency of the highly intense band of ester carbonyl function in
position 3 of pyran ring is considerably lowered and this band appears in IR spectra of
compounds 7 at 1690ꢀ1687 cmꢀ1. This is due to the conjugation with a C=C bond of the pyran
ring, additionally to the formation of an intramolecular hydrogen bond with the NH2 group.15
The IR spectra of compounds 8 have a series of characteristic absorption bands of the OHꢀgroup
(broadened band at 3456ꢀ3396 cmꢀ1), N+–Hꢀgroup of triethylammonium cation (2499ꢀ2470 cmꢀ1)
and bridging CHꢀgroup (high intensity band at 3108ꢀ2973 cmꢀ1).
The narrow highꢀintensity singlet of the 4th position of 4Hꢀpyran ring can be observed at
1
4.48ꢀ4.95 ppm in H NMR spectra of compounds 5aꢀf dissolved in DMSOꢀd6. The same proton
in compound 5g is at 6.54 ppm, which can be explained by unshielding effect of the bulky
aromatic anthracene core. The singlet of the 4th position of 4Hꢀpyran ring for 7aꢀe can be found
in the same region, as for compounds 5, 4.78ꢀ4.99 ppm. The signal of protons of 2ꢀamino group
for pyrans 5aꢀg is situated in the range of 7.21ꢀ7.50 ppm as well as for 7aꢀe the singlet of
1
the 2ꢀamino group is observed at 7.72ꢀ7.94 ppm. The H NMR spectra of adducts 8a,b,e are
characterized by the presence of singlet of benzothiazine OHꢀgroup at 17.10ꢀ17.25 ppm and
bridging CHꢀgroup at 5.69ꢀ5.78 ppm. The signals of triethylammonium NHꢀgroup are not found
in the spectra probably due to the fast deuteroexchange. The 13C NMR spectra of the synthesized
compounds reveal the following general features.15 The signal of the Cꢀ2 carbon atom of the
pyran ring for compounds 5, 7 is found at 158ꢀ159 ppm. The peak of the Cꢀ3 carbon atom of the

RSC Advances
Page 12 of 25
View Article Online
DOI: 10.1039/C5RA24566D
pyran ring for compounds 5 is observed at 55ꢀ58 ppm as well as for compounds 7 at 58ꢀ59 ppm.
The Cꢀ4 carbon of compounds 5aꢀg and 7aꢀe gives signal at 31ꢀ37 ppm. The signal at 118ꢀ119
ppm was assigned to the nitrile carbon in the pyran ring for compounds 5 and the signal at 166ꢀ
167 ppm was assigned to the carbonyl carbon of the ester group for compounds 7. The 13C NMR
spectra of compounds 8 are characterized by the presence of bridged carbon peak at 35ꢀ36 ppm.
Molecular ion peaks are observed in mass spectra of 2ꢀaminoꢀ4Hꢀpyranes 5 and 7. The
mass spectra of bisꢀadducts 8 are characterized by the presence of the heaviest fragment of ion
peak ([Mꢀ326]+) corresponding to enones 11 (Scheme 5).
Scheme 5. Characteristic mass fragmentation of compounds 8
The structures of compounds 7b and 8b have been additionally confirmed by single
crystal Xꢀray diffraction study (Fig. 3). The compound 7b exists as methanol monosolvate in the
crystal phase (more detailed information about molecular and crystal structure see in
Supplementary Information). The 8b compound corresponds to the triethylammonium salt with
organic anion. The hydrogen atom at the N1s is located from the electron density difference
maps. Only one peak corresponding to the hydrogen atom is observed between O1 and O4 atoms
from the experimental data and it is located nearer to the O4 atom. The O1ꢀC7 and O4ꢀC11 bond
lengths are comparable (1.309(4) Å and 1.314(4) Å, respectively) and slightly shorter than the
mean value46 for the Csp2ꢀOH bond (1.333 Å). The O4ꢀH…O1 strong chargeꢀassisted hydrogen
bond (H…O 1.54 Å, OꢀH…O 177°) is formed. Summary, only one tautomer of organic anion
with negative charge at the O1 atom may exist in the crystal phase.

Page 13 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
7b
8b
Figure 3. Molecular structure of the compounds 7b and 8b according to the Xꢀray diffraction
study.
3. Conclusion
In this paper the threeꢀcomponent interaction of 1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀ
dioxide with benzaldehydes and active methylene nitriles which led to condensed 2ꢀaminoꢀ4ꢀ
arylꢀ4Hꢀpyrans was studied. The direction of the threeꢀcomponent reaction is controlled by the
nature of active methylene nitrile and the nature of the substituent in the arylcarbaldehyde: the
formation of either 2ꢀaminoꢀ4Hꢀpyrans or bisꢀadducts (or their mixture) was observed. New
products of such interactions – triethylammonium salts of bis(1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone
2,2ꢀdioxide) – were obtained for the first time. The structure of these salts was proved by the
single crystal Xꢀray diffraction study as well as their purity by the other instrumental methods.
The ability of the bisꢀadducts to be transformed into 2ꢀaminoꢀ4Hꢀpyrans was experimentally
confirmed. Based on the known mechanism of the 2ꢀaminoꢀ4Hꢀpyrans formation and on the
accomplished conversions 7 → 8 and 8 → 7 we proposed the mechanism of the studied MCR
which includes the bisꢀadduct formation stage (Scheme 6). According to the proposed
mechanism, arylidenes 11 are formed in threeꢀcomponent reaction as highly reactive
intermediates. These intermediates are the key products for the formation of bisꢀadducts 8
(Scheme 6). The reversibility of all stages of the mechanism allowed us to synthesize
purposefully the target 2ꢀaminoꢀ4Hꢀpyrans.
Scheme 6. The general scheme of mutual transformations of compounds 7 and 8

RSC Advances
Page 14 of 25
View Article Online
DOI: 10.1039/C5RA24566D
The oneꢀway conversions of 7,8 → 5 (Scheme 3) demonstrated the highest stability of 2ꢀ
aminoꢀ3ꢀcyanoꢀ4Hꢀpyrans 5 caused, probably, by the effective pushꢀpull interaction between the
strong electron donating 2ꢀamino group and the strong electron withdrawing 3ꢀcyano group in
the product 5.
The found regularities of threeꢀcomponent interaction can be more general. Currently,
there is no information regarding obtaining of such bisꢀadducts in similar threeꢀcomponent
condensations. Although compounds such as triethylammonium salts of bis(1Hꢀ2,1ꢀ
benzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide) have not been previously reported in the literature as the
possible products of synthesis of 2ꢀaminoꢀ4Hꢀpyrans, the potential of their formation should be
considered in similar interactions as impurities or as main products.
4. Experimental section
4.1. General
Starting aldehydes and active methylene nitriles were obtained from commercial sources
and used without further purification. Starting 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀ
dioxide was obtained according to the previously described procedure.5 Arylidenes 4aꢀg and 9a
were prepared via Knoevenagel condensation of the corresponding benzaldehydes 3aꢀg and
active methylene nitriles 2 or 6 in the presence of a base as was reported.47 Dry DMF was
prepared in accordance with standard method. Melting points were determined on a Gallenkamp
1
melting point apparatus, Model MFBꢀ595 in open capillary tubes. H NMR spectra were
recorded on Varian Mercury VX 200 instrument or Bruker AMX 500 spectrometer (for 8c) using
DMSOꢀd6 as solvent and TMS as an internal standard. 13C NMR experiments were performed
using Bruker AMX 500 spectrometer or Varian Mercury MRꢀ400 (for 7e and 8a). IR spectra
were taken on a Perkin–Elmer 298 spectrophotometer in KBr pellets. Elemental analyses were
carried out using Carlo Erba CHNSꢀO EA 1108 analyzer. Mass spectra were taken on a Varian
1200L DIP (EI, 70 eV).
4.2. Xꢀray diffraction experimental part.
The crystals of 7b (C22H21N3O7S · СН3ОН) are monoclinic. At 100 K a = 21.5619(7), b =
11.3694(4), c = 18.9777(7) Å, β = 93.367(3)°, V = 4642.4(3) Å3, Mr = 500.77, Z = 1, space
group C2/c, dcalc= 1.433 g/cm3, ꢀ(MoKα) = 0.194 mmꢀ1, F(000) = 2096. Intensities of 24414
reflections (6761 independent, Rint = 0.029) were measured on the «Xcaliburꢀ3» diffractometer
(graphite monochromated MoKα radiation, CCD detector, ωꢀscaning, 2Θmax = 60°).
ꢀ
The crystals of 8b (С6Н15NH+ · C27H24N3O8S2 ) are orthorhombic. At 293 K a = 13.1522(7),
b = 23.496(2), c = 11.0242(5) Å, V = 3406.8(3) Å3, Mr = 684.81, Z = 4, space group Pna21,
dcalc= 1.335 g/cm3, ꢀ(MoKα) = 0.212 mmꢀ1, F(000) = 1448. Intensities of 33893 reflections

Page 15 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
(9887 independent, Rint = 0.053) were measured on the«Xcaliburꢀ3» diffractometer (graphite
monochromated MoKα radiation, CCD detector, ωꢀscaning, 2Θmax = 60°).
The structures were solved by direct method using SHELXTL package48. Position of the
hydrogen atoms were located from electron density difference maps and refined by “riding”
model with Uiso = nUeq of the carrier atom (n = 1.5 for methyl and hydroxyl groups and for water
molecule and n = 1.2 for other hydrogen atoms). Fullꢀmatrix leastꢀsquares refinement of the
structures against F2 in anisotropic approximation for nonꢀhydrogen atoms using 6714 (7b), 9840
(8b) reflections was converged to: wR2 = 0.131 (R1 = 0.048 for 5324 reflections with F>4σ(F), S
= 1.046) for structure 7b and wR2 = 0.189 (R1 = 0.067 for 4692 reflections with F>4σ(F), S =
0.918) for structure 8b. The final atomic coordinates, and crystallographic data for molecules 7b
and 8b have been deposited to with the Cambridge Crystallographic Data Centre, 12 Union Road,
CB2 1EZ, UK (fax: +44ꢀ1223ꢀ336033; eꢀmail: deposit@ccdc.cam.ac.uk) and are available on
request quoting the deposition numbers CCDC 1405511 for 7b and CCDC 1405512 for 8b).
4.3. General procedure for the synthesis of 2ꢀaminoꢀ4ꢀarylꢀ3ꢀcyanoꢀ6ꢀethylꢀ4,6ꢀ
dihydropyrano[3,2ꢀc][2,1]benzothiazine 5,5ꢀdioxides (5aꢀg)
Method A. Threeꢀcomponent oneꢀpot procedure. To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ
4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g, 0.001 mol), malononitrile 2 (0.066g, 0.001 mol) and
appropriate benzaldehyde 3aꢀg (0.001 mol) in ethanol (5ꢀ10 mL), triethylamine (0.14 mL, 0.001
mol) was added. The mixture was refluxed during 1 h (in case of 3b the mixture was heated at
50 °C for 40 min). A precipitate usually formed in a few minutes after the beginning of heating.
The mixture was cooled to the room temperature; the resulting precipitates of 5aꢀg were filtered
off, washed with ethanol then dried on air and recrystallized from ethanol.
Method B. Synthesis using arylidenes 4a-g. To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀ
one 2,2ꢀdioxide 1 (0.225 g, 0.001 mol) and arylidenes 4a–g (0.001 mol) in ethanol (5ꢀ10 mL),
triethylamine (0.14 mL, 0.001 mol) was added. The resulted mixture was refluxed for 1 h (in
case of 4b mixture was heated at 50 °C for 40 min). During boiling precipitates of 5aꢀe was
gradually formed. The resulting reaction mixtures were treated as mentioned in method A.
The yields for the synthesized compounds 5a–g are presented in Table 1.
Method
dihydropyrano[3,2ꢀc][2,1]benzothiazine 5,5ꢀdioxides 7a,c. To a solution of 2ꢀaminoꢀ3ꢀ
ethoxycarbonylꢀ4ꢀRꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]benzothiazine 5,5ꢀdioxides 7a,c
С
(for 5a,c). Synthesis using 2ꢀaminoꢀ3ꢀethoxycarbonylꢀ4ꢀRꢀ6ꢀethylꢀ4,6ꢀ
(0.001 mol) and malononitrile 2 (0.066g, 0.001 mol) in ethanol (10 mL), triethylamine (0.14 mL,
0.001 mol) was added. The mixture was heated at 60 °C for 1 h and the resulting solution was
cooled to the room temperature. After precipitate of 5a,c was formed it was filtered off, washed

RSC Advances
Page 16 of 25
View Article Online
DOI: 10.1039/C5RA24566D
with ethanol, dried on air and recrystallized from ethanol. Yields of 5a,c were 58% and 67%
correspondingly.
Method D (for 5a,c). Synthesis using 3ꢀ[(4ꢀhydroxyꢀ1ꢀethylꢀ2,2ꢀdioxidoꢀ1Hꢀ2,1ꢀbenzothiazinꢀ3ꢀ
yl)(aryl)methyl]ꢀ1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ5ꢀolat 2,2ꢀdioxides 8a,c. To a solution of 3ꢀ[(4ꢀ
hydroxyꢀ1ꢀethylꢀ2,2ꢀdioxidoꢀ1Hꢀ2,1ꢀbenzothiazinꢀ3ꢀyl)(aryl)methyl]ꢀ1ꢀethylꢀ1Hꢀ2,1ꢀ
benzothiazinꢀ5ꢀolat 2,2ꢀdioxides 8a,c and malononitrile 2 (0.066g, 0.001 mol) in ethanol (10
mL), triethylamine (0.14 mL, 0.001 mol) was added. The mixture was refluxed during 4 h,
cooled to 0 °C and kept at this temperature overnight. The resulting precipitate of 5a,c was
filtered off, washed with cold ethanol, dried on air and recrystallized from ethanol. Yields of 5a,c
were 53% and 61% respectively.
4.3.1. 2ꢀAminoꢀ3ꢀcyanoꢀ4ꢀphenylꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]benzothiazine 5,5ꢀ
dioxide (5a)
White needles; mp > 250 °C (from EtOH); Anal. Calcd for C20H17N3O3S: C, 63.31; H, 4.52; N,
11.07; S, 8.45. Found: C, 63.30; H, 4.39; N, 10.82; S, 8.23; IR (KBr): νmax/cmꢀ1 3456, 3364,
3187, 3062, 2984, 2943, 2187, 1678, 1636, 1596, 1453, 1407, 1344, 1300, 1267, 1172, 702 cmꢀ1;
1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 7.95 (d, J = 7.94 Hz, 1H), 7.72 – 7.50 (m, 2H), 7.48 ꢀ
13
7.13 (m, 8H), 4.65 (s, 1H), 3.89 (q, J = 6.61 Hz, 2H), 1.02 (t, J = 6.87 Hz, 3H); C NMR (125
MHz, DMSOꢀd6): δ (ppm) 158.9, 146.3, 142.6, 137.8, 132.4, 128.6, 127.8, 127.6, 124.6, 123.8,
119.3, 119.0, 117.3, 114.4, 58.2, 42.5, 37.5, 13.8; MS (EI) m/z: 379 [M]+.
4.3.2. 2ꢀAminoꢀ3ꢀcyanoꢀ4ꢀ(4ꢀnitrophenyl)ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]
benzothiazine 5,5ꢀdioxide (5b)
Light yellow needles; mp 242ꢀ243 °C (decomp.) (from EtOH); Anal. Calcd for C20H16N4O5S: C,
56.60; H, 3.80; N, 13.20; S, 7.55. Found: C, 57.03; H, 3.53; N, 12.83; S, 7.43; IR (KBr):
νmax/cmꢀ1 3430, 3325, 3252, 3214, 3080, 2975, 2931, 2851, 2202, 1683, 1598, 1515, 1455, 1415,
1346, 1325, 1267, 1170, 1147, 1122 cmꢀ1; 1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 8.20 (d, J =
8.85 Hz, 2H), 7.96 (d, J = 7.63 Hz, 1H), 7.73 ꢀ 7.34 (m, 7H), 4.95 (s, 1H), 3.89 (q, J = 7.02 Hz,
2H), 1.04 (t, J = 6.87 Hz, 3H); 13C NMR (125 MHz, DMSOꢀd6): δ (ppm) 158.9, 150.0, 147.0,
146.8, 137.8, 132.7, 129.4, 124.7, 123.9, 123.8, 119.3, 118.7, 117.0, 113.1, 57.0, 42.5, 37.0,
13.9; MS (EI) m/z: 424 [M]+.
4.3.3. 2ꢀAminoꢀ3ꢀcyanoꢀ4ꢀ(2ꢀmethoxyphenyl)ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]
benzothiazine 5,5ꢀdioxide (5c)
White needles; mp 193ꢀ195 °C (decomp.) (from EtOH); Anal. Calcd for C21H19N3O4S: C, 61.60;
H, 4.68; N, 10.26; S, 7.83. Found: C, 62.04; H, 4.32; N, 10.06; S, 7.41; IR (KBr): νmax/cmꢀ1 3381,
3316, 3212, 3064, 2981, 2939, 2842, 2195, 1671, 1599, 1454, 1352, 1324, 1251, 1168, 1145,
1118, 749 cmꢀ1; 1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 7.94 (d, J = 7.63 Hz, 1H), 7.70 – 7.49

Page 17 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
(m, 2H), 7.39 (t, J = 7.33 Hz, 1H), 7.29 – 7.16 (m, 3H), 7.10 (d, J = 7.63 Hz, 1H), 6.98 (d, J =
8.24 Hz, 1H), 6.87 (t, J = 7.52 Hz, 1H), 4.89 (s, 1H), 3.88 (q, J = 6.92 Hz, 2H), 3.70 (s, 3H), 1.01
(t, J = 7.02 Hz, 3H); 13C NMR (125 MHz, DMSOꢀd6): δ (ppm) 159.5, 157.1, 146.7, 137.7, 132.2,
130.0, 129.2, 129.0, 124.3, 123.7, 120.6, 119.4, 119.2, 117.4, 113.6, 111.9, 57.0, 55.9, 42.4, 32.4,
13.7; MS (EI) m/z: 409 [M]+.
4.3.4. 2ꢀAminoꢀ3ꢀcyanoꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]
benzothiazine 5,5ꢀdioxide (5d)
White needles; mp 236ꢀ238 °C (decomp.) (from EtOH); Anal. Calcd for C21H19N3O4S: C, 61.60;
H, 4.68; N, 10.26; S, 7.83. Found: C, 61.91; H, 4.35; N, 9.83; S, 7.67; IR (KBr): νmax/cmꢀ1 3412,
3322, 3252, 3213, 3070, 2957, 2930, 2836, 2202, 1678, 1598, 1512, 1407, 1329, 1246, 1164,
1146, 1117, 1027, 835 cmꢀ1; 1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 7.93 (d, J = 7.94 Hz, 1H),
7.72 – 7.49 (m, 2H), 7.39 (t, J = 7.48 Hz, 1H), 7.29 (s, 2H), 7.17 (d, J = 8.55 Hz, 2H), 6.87 (d, J
= 8.55 Hz, 2H), 4.60 (s, 1H), 3.89 (q, J = 6.82 Hz, 2H), 3.71 (s, 3H), 1.04 (t, J = 6.87 Hz, 3H);
13C NMR (125 MHz, DMSOꢀd6): δ (ppm) 158.7, 158.7, 145.9, 137.7, 134.6, 132.3, 129.0, 124.5,
123.7, 119.3, 119.1, 117.3, 114.7, 114.0, 58.4, 55.1, 42.4, 36.8, 13.8; MS (EI) m/z: 409 [M]+.
4.3.5. 2ꢀAminoꢀ3ꢀcyanoꢀ4ꢀ(4ꢀchlorophenyl)ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]
benzothiazine 5,5ꢀdioxide (5e)
White plates; mp 234ꢀ236 °C (decomp.) (from EtOH); Anal. Calcd for C20H16ClN3O3S: C,
58.04; H, 3.90; N, 10.15; S, 7.75. Found: C, 58.21; H, 3.57; N, 10.08; S, 7.59; IR (KBr): νmax/cmꢀ
1
3381, 3316, 3254, 3189, 2969, 2935, 2191, 1671, 1643, 1596, 1489, 1416, 1354, 1315, 1253,
1167, 1143, 1119, 1075, 753 cmꢀ1; 1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 7.94 (d, J = 7.94 Hz,
1H), 7.73 – 7.50 (m, 2H), 7.48 – 7.23 (m, 7H), 4.72 (s, 1H), 3.89 (q, J = 6.71 Hz, 2H), 1.04 (t, J
= 7.02 Hz, 3H); 13C NMR (125 MHz, DMSOꢀd6): δ (ppm) 158.8, 146.3, 141.7, 137.7, 132.5,
132.2, 129.8, 128.6, 124.6, 123.8, 119.3, 118.9, 117.2, 113.9, 57.7, 42.5, 36.8, 13.9; MS (EI)
m/z: 413 [M]+.
4.3.6. 2ꢀAminoꢀ3ꢀcyanoꢀ4ꢀ(4ꢀ(N,Nꢀdimethylamino)phenyl))ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀ
c][2,1] benzothiazine 5,5ꢀdioxide (5f)
Brown plates; mp 147ꢀ150 °C (decomp.) (from EtOH); Anal. Calcd for C22H22N4O3S: C, 62.54;
H, 5.25; N, 13.26; S, 7.59. Found: C, 62.38; H, 5.02; N, 13.15; S, 7.34; IR (KBr): νmax/cmꢀ1 3325,
3255, 3212, 2922, 2197, 1682, 1598, 1522, 1486, 1452, 1399, 1344, 1325, 1260, 1174, 1147,
1116, 759 cmꢀ1; 1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 7.92 (d, J = 6.71 Hz, 1H), 7.71 – 7.48
(m, 2H), 7.38 (t, J = 7.54 Hz, 1H), 7.21 (s, 2H), 7.03 (d, J = 8.55 Hz, 2H), 6.64 (d, J = 8.55 Hz,
2H), 4.48 (s, 1H), 3.89 (q, J = 6.82 Hz, 2H), 2.85 (s, 6H), 1.04 (t, J = 6.94 Hz, 3H); 13C NMR
(125 MHz, DMSOꢀd6): δ (ppm) 158.6, 149.8, 145.6, 137.7, 132.2, 130.0, 128.4, 124.5, 123.7,
119.3, 117.4, 115.1, 112.3, 58.8, 42.4, 40.1, 36.8, 13.9; MS (EI) m/z: 422 [M]+.

RSC Advances
Page 18 of 25
View Article Online
DOI: 10.1039/C5RA24566D
4.3.7. 2ꢀAminoꢀ3ꢀcyanoꢀ4ꢀ(9ꢀanthracenyl)ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]
benzothiazine 5,5ꢀdioxide (5g)
Brown prisms; mp > 250 °C (from EtOH); Anal. Calcd for C28H21N3O3S: C, 70.13; H, 4.41; N,
8.76; S, 6.69. Found: C, 70.12; H, 4.24; N, 8.33; S, 6.37; IR (KBr): νmax/cmꢀ1 3455, 3346, 2921,
1
2190, 1662, 1626, 1590, 1400, 1324, 1253, 1171, 1149, 1118, 1089, 727 cmꢀ1; H NMR (200
MHz, DMSOꢀd6): δ (ppm) 8.74 – 8.57 (m, 2H), 8.25 – 7.99 (m, 4H), 7.72 – 7.28 (m, 9H), 6.54 (s,
1H), 3.76 (q, J = 6.41 Hz, 2H), 0.92 (t, J = 6.71 Hz, 3H); 13C NMR (125 MHz, DMSOꢀd6): δ
(ppm) 158.2, 145.5, 137.7, 132.4, 131.6, 131.1, 131.0, 131.0, 129.94, 129.86, 129.2, 129.0, 126.7,
125.7, 125.1, 124.7, 124.4, 124.2, 123.9, 123.2, 119.4, 118.7, 117.3, 115.2, 58.0, 42.4, 31.0,
13.7; MS (EI) m/z: 479 [M]+.
4.4. Procedures for the synthesis of 2ꢀaminoꢀ4ꢀarylꢀ3ꢀethoxycarbonylꢀ6ꢀethylꢀ4,6ꢀ
dihydropyrano[3,2ꢀc][2,1]benzothiazine 5,5ꢀdioxides (7aꢀe)
Compounds 7aꢀe were obtained by interaction of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀ
dioxide 1, ethyl cyanoacetate 6 and benzaldehydes 3aꢀe in conditions submitted below. The
yields for the synthesized compounds 7a–e are presented in Table 2.
4.4.1. 2ꢀAminoꢀ3ꢀethoxycarbonylꢀ4ꢀphenylꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]
benzothiazine 5,5ꢀdioxide (7a)
To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g, 0.001 mol),
ethyl cyanoacetate 6 (0.33 mL, 0.003 mol) and benzaldehyde 3a (0.1 mL, 0.001 mol) in ethanol
(5 mL), DMAP (0.122 g, 0.001 mol) was added. The mixture was refluxed during 4 h, cooled to
0 °C. After precipitate of 7a was formed it was filtered off, washed with cold ethanol, dried on
air and recrystallized from ethanol.
White prisms; mp 168ꢀ171 °C (from EtOH); Anal. Calcd for C22H22N2O5S: C, 61.96; H, 5.20; N,
6.57; S, 7.52. Found: C, 62.14; H, 5.08; N, 6.49; S, 7.19; IR (KBr): νmax/cmꢀ1 3419, 3293, 3058,
2982, 2938, 2904, 1951, 1930, 1881, 1812, 1688, 1657, 1617, 1603, 1571, 1520, 1489, 1452,
1320, 1254, 1166, 1147, 1096, 1069, 757 cmꢀ1; 1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 8.04 (d,
J = 7.63, 1H), 7.80 (s, 2H), 7.71 – 7.49 (m, 2H), 7.39 (t, J = 7.54, 1H), 7.32 – 7.07 (m, 5H), 4.83
13
(s, 1H), 4.09 ꢀ 3.79 (m, 4H), 1.11 (t, J = 7.17 Hz, 3H), 0.97 (t, J = 7.23 Hz, 3H); C NMR (125
MHz, DMSOꢀd6): δ (ppm) 167.2, 159.5, 146.1, 144.4, 137.6, 132.1, 128.2, 127.8, 126.8, 124.5,
123.6, 119.2, 117.2, 116.9, 77.8, 59.2, 42.2, 35.8, 14.3, 13.7; MS (EI) m/z: 426 [M]+.
4.4.2. 2ꢀAminoꢀ3ꢀethoxycarbonylꢀ4ꢀ(4ꢀnitrophenyl)ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀc][2,1]
benzothiazine 5,5ꢀdioxide (7b)
To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g, 0.001 mol),
ethyl cyanoacetate 6 (0.11 mL, 0.001 mol) and 4ꢀnitrobenzaldehyde 3b (0.151 g, 0.001 mol) in
ethanol (5 mL), DMAP (0.122 g, 0.001 mol) was added. The reaction mixture was heated at

Page 19 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
50 °C for 2 h, cooled to the room temperature and allowed to stand overnight. The formed
crystalline precipitate of 7b was filtered off, washed with ethanol, dried on air and recrystallized
from ethanol.
Yellow prisms; mp 170ꢀ172 °C (from EtOH); Anal. Calcd for C22H21N3O7S: C, 56.04; H, 4.49;
N, 8.91; S, 6.80. Found: C, 56.23; H, 4.21; N, 8.60; S, 6.41; IR (KBr): νmax/cmꢀ1 3430, 3396,
3304, 3076, 2976, 2933, 2449, 1949, 1812, 1689, 1657, 1515, 1347, 1316, 1255, 1166, 1146,
1100, 758 cmꢀ1; 1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 8.18 ꢀ 8.02 (m, 3H), 7.94 (s, 2H), 7.72
– 7.34 (m, 5H), 4.97 (s, 1H), 4.06 ꢀ 3.79 (m, 4H), 1.10 (t, J = 7.02 Hz, 3H), 0.99 (t, J = 6.87 Hz,
3H); 13C NMR (125 MHz, DMSOꢀd6): δ (ppm) 166.9, 159.4, 152.0, 146.5, 146.4, 137.7, 132.5,
129.4, 124.7, 123.7, 123.5, 119.2, 117.0, 115.4, 76.3, 59.4, 42.3, 35.9, 14.2, 13.8; MS (EI) m/z:
471 [M]+.
4.4.3. 2ꢀAminoꢀ3ꢀethoxycarbonylꢀ4ꢀ(2ꢀmethoxyphenyl)ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀ
c][2,1]benzothiazine 5,5ꢀdioxide (7c)
To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g, 0.001 mol),
ethyl cyanoacetate 6 (0.22 mL, 0.002 mol) and 2ꢀmethoxybenzaldehyde 3c (0.136 g, 0.001 mol)
in ethanol (5 mL), triethylamine (0.14 mL, 0.001 mol) was added. The mixture was refluxed
during 4 h, cooled to the room temperature and allowed to stand overnight. The formed
crystalline precipitate of 7c was filtered off, washed with ethanol, dried on air and recrystallized
from ethanol.
Colorless prisms; mp 175ꢀ177 °C (from EtOH); Anal. Calcd for C23H24N2O6S: C, 60.51; H, 5.30;
N, 6.14; S, 7.02. Found: C, 60.88; H, 5.18; N, 6.35; S, 6.81; IR (KBr): νmax/cmꢀ1 3395, 3287,
3085, 3062, 2983, 2936, 2835, 1959, 1930, 1901, 1805, 1689, 1652, 1615, 1531, 1486, 1463,
1
1305, 1254, 1163, 1102, 1030, 753 cmꢀ1; H NMR (200 MHz, DMSOꢀd6): δ (ppm) 8.01 (d, J =
6.71 Hz, 1H), 7.72 (s, 2H), 7.67 – 7.32 (m, 3H), 7.12 (d, J = 7.32 Hz, 2H), 6.94 – 6.72 (m, 2H),
4.99 (s, 1H), 4.04 ꢀ 3.77 (m, 4H), 3.62 (s, 3H), 1.08 (t, J = 7.17 Hz, 3H), 0.93 (t, J = 6.97 Hz,
3H); 13C NMR (125 MHz, DMSOꢀd6): δ (ppm) 167.7, 160.0, 157.6, 146.0, 137.6, 131.8, 131.2,
130.7, 128.3, 124.2, 123.6, 119.9, 119.3, 117.7, 115.6, 111.6, 75.8, 58.9, 55.6, 42.3, 32.4, 14.2,
13.4; MS (EI) m/z: 456 [M]+.
4.4.4. 2ꢀAminoꢀ3ꢀethoxycarbonylꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀ
c][2,1]benzothiazine 5,5ꢀdioxide (7d)
To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g, 0.001 mol),
ethyl cyanoacetate 6 (0.33 mL, 0.003 mol) and 4ꢀmethoxybenzaldehyde 3d (0.12 mL, 0.001 mol)
in 2ꢀpropanol (5 mL), triethylamine (0.14 mL, 0.001 mol) was added. The mixture was refluxed
during 4 h, cooled to 0 °C and kept at this temperature overnight. The resulting precipitate of 7d
was filtered off, washed with cold ethanol, dried on air and recrystallized from ethanol.

RSC Advances
Page 20 of 25
View Article Online
DOI: 10.1039/C5RA24566D
Colorless prisms; mp 175ꢀ177 °C (from EtOH); Anal. Calcd for C23H24N2O6S: C, 60.51; H, 5.30;
N, 6.14; S, 7.02. Found: C, 60.85; H, 5.20; N, 6.09; S, 6.77; IR (KBr): νmax/cmꢀ1 3399, 3285,
3072, 2981, 2935, 2901, 2848, 1927, 1844, 1812, 1690, 1656, 1608, 1509, 1450, 1321, 1300,
1255, 1168, 1102, 1032, 756 cmꢀ1; 1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 8.03 (d, J = 7.94 Hz,
1H), 7.75 (s, 2H), 7.69 – 7.47 (m, 2H), 7.38 (t, J = 7.53 Hz, 1H), 7.10 (d, J = 8.55 Hz, 2H), 6.80
(d, J = 8.55 Hz, 2H), 4.78 (s, 1H), 4.08 ꢀ 3.81 (m, 4H), 3.67 (s, 3H), 1.13 (t, J = 7.02 Hz, 3H),
13
1.00 (t, J = 7.17 Hz, 3H); C NMR (125 MHz, DMSOꢀd6): δ (ppm) 167.3, 159.4, 158.1, 145.8,
137.6, 136.5, 132.1, 128.8, 124.5, 123.6, 119.1, 117.2, 117.1, 113.5, 77.9, 59.2, 55.0, 42.2, 35.0,
14.3, 13.8; MS (EI) m/z: 456 [M]+.
4.4.5. 2ꢀAminoꢀ3ꢀethoxycarbonylꢀ4ꢀ(4ꢀchlorophenyl)ꢀ6ꢀethylꢀ4,6ꢀdihydropyrano[3,2ꢀ
c][2,1]benzothiazine 5,5ꢀdioxide (7e)
To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g, 0.001 mol),
ethyl cyanoacetate 6 (0.77 mL, 0.007 mol) and 4ꢀchlorobenzaldehyde 3e (0.14 g, 0.001 mol) in
ethanol (5 mL), DMAP (0.122 g, 0.001 mol) was added. The mixture was refluxed during 4 h,
cooled to the room temperature and allowed to stand overnight. The formed precipitate of 7e was
filtered off, washed with cold ethanol, dried on air and recrystallized from ethanol.
White fineꢀcrystalline powder; mp 198ꢀ200 °C (from EtOH); Anal. Calcd for C22H21ClN2O5S: C,
57.33; H, 4.59; N, 6.08; S, 6.96. Found: C, 57.47; H, 4.33; N, 6.21; S, 6.55; IR (KBr): νmax/cmꢀ1
3432, 3328, 3112, 3047, 2982, 2924, 1687, 1601, 1485, 1458, 1332, 1319, 1253, 1167, 1146,
1118, 780 cmꢀ1; 1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 8.04 (d, J = 7.93 Hz, 1H), 7.85 (s, 2H),
7.71 – 7.50 (m, 2H), 7.46 – 7.16 (m, 5H), 4.83 (s, 1H), 4.07 ꢀ 3.80 (m, 4H), 1.11 (t, J = 7.17 Hz,
3H), 0.99 (t, J = 6.95 Hz, 3H); 13C NMR (100 MHz, DMSOꢀd6): δ (ppm) 167.5, 159.7, 146.5,
143.8, 138.0, 132.6, 131.7, 130.1, 128.5, 125.0, 124.0, 119.5, 117.5, 116.7, 77.5, 59.6, 42.6, 35.8,
14.6, 14.1; MS (EI) m/z: 460 [M]+.
4.5.
Isolation
of
3ꢀ[(4ꢀhydroxyꢀ1ꢀethylꢀ2,2ꢀdioxidoꢀ1Hꢀ2,1ꢀbenzothiazinꢀ3ꢀ
yl)(aryl)methyl]ꢀ1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ5ꢀolat 2,2ꢀdioxides (8aꢀc,e). These
products were obtained during our attempts to synthesize the products of threeꢀcomponent
interactions using the procedures described below.
4.5.1. 3ꢀ[(4ꢀHydroxyꢀ1ꢀethylꢀ2,2ꢀdioxidoꢀ1Hꢀ2,1ꢀbenzothiazinꢀ3ꢀyl)(phenyl)methyl]ꢀ
1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ5ꢀolat 2,2ꢀdioxide (8a)
Procedure A. To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g,
0.001 mol), ethyl cyanoacetate 6 (0.11 mL, 0.001 mol) and benzaldehyde 3a (0.1 mL, 0.001 mol)
in ethanol (5 mL), triethylamine (0.14 mL, 0.001 mol) was added. The mixture was refluxed
during 4 h, cooled to the room temperature and solvent was evaporated in vacuum. The oily
residue was mixed with 1 mL of iꢀPrOH. Under intensive mixing the precipitate of 8a was

Page 21 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
formed, which was filtered off, washed with cold ethanol, dried on air and recrystallized from
ethanol. Yield of 8a was 35%.
Procedure B. To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g,
0.001 mol) and ethyl 2ꢀcyanoꢀ3ꢀphenylacrylate 9a (0.201 g, 0.001 mol) in ethanol (5 mL),
triethylamine (0.14 mL, 0.001 mol) was added. The mixture was refluxed during 4 h, cooled to
0 °C and kept at this temperature. The precipitate of 8a was formed, washed with cold ethanol,
dried on air and recrystallized from ethanol. Yield of 8a was 43%.
Procedure C. Compound 8a was obtained using Nꢀ(pꢀtolyl)cyanoacetamide 13 instead ethyl
cyanoacetate 6 under conditions represented in Procedure A. Yield of 8a was 53%.
Procedure D. To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g,
0.001 mol) and 7a (0.426 g, 0.001 mol) in ethanol (5 mL), triethylamine (0.14 mL, 0.001 mol)
was added. The mixture was refluxed during 6 h. Next it was treated as described in Procedure B.
Yield of 8a was 47%.
Preparative procedure. To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1
(0.450 g, 0.002 mol), benzaldehyde 3a (0.1 mL, 0.001 mol) in ethanol (10 mL), triethylamine
(0.14 mL, 0.001 mol) was added. The solution was stirred at the room temperature. After about 1
h a white precipitate of 8a was formed, this was filtered off, washed with ethanol, dried on air
and recrystallized from ethanol. Yield of 8a was 93%.
White needles; mp 153ꢀ155 °C (from EtOH); Anal. Calcd for C33H41N3O6S2: C, 61.95; H, 6.46;
N, 6.57; S, 10.02. Found: C, 62.42; H, 6.12; N, 6.76; S, 9.63; IR (KBr): νmax/cmꢀ1 3431, 3087,
2987, 2934, 2882, 2814, 2498, 1613, 1542, 1479, 1310, 1263, 1170, 1141, 1045, 758, 575 cmꢀ1;
1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 17.25 (s, 1H), 7.86 (d, J = 7.63, 2H), 7.52 – 7.35 (m,
2H), 7.34 – 6.97 (m, 9H), 5.71 (s, 1H), 3.95 (q, J = 7.02 Hz, 4H), 3.04 (q, J = 7.32 Hz, 6H), 1.33
– 1.05 (m, 15H); 13C NMR (100 MHz, DMSOꢀd6): δ (ppm) 160.4, 141.8, 138.7, 130.5, 128.0,
127.7, 126.8, 125.7, 124.8, 122.1, 117.5, 110.6, 46.2, 41.3, 36.2, 14.5, 9.0; MS (EI) m/z: 313 [Mꢀ
326]+.
4.5.2. 3ꢀ[(4ꢀHydroxyꢀ1ꢀethylꢀ2,2ꢀdioxidoꢀ1Hꢀ2,1ꢀbenzothiazinꢀ3ꢀyl)
(4ꢀnitrophenyl)methyl]ꢀ1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ5ꢀolat 2,2ꢀdioxide (8b)
To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1 (0.225 g, 0.001 mol),
benzyl cyanide 12 (0.115 mL, 0.001 mol) and 4ꢀnitrobenzaldehyde 3b (0.151 g, 0.001 mol) in
ethanol (5 mL), triethylamine (0.14 mL, 0.001 mol) was added. The solution was mixed at room
temperature for 4 h and allowed to stand overnight. The formed yellow crystalline precipitate of
8b was filtered off, washed with ethanol, dried on air and recrystallized from ethanol. Yield of
8b was 44%.

RSC Advances
Page 22 of 25
View Article Online
DOI: 10.1039/C5RA24566D
Yellow prisms; mp 168ꢀ170 °C (from EtOH); Anal. Calcd for C33H40N4O8S2: C, 57.88; H, 5.89;
N, 8.18; S, 9.36. Found: C, 58.12; H, 5.94; N, 8.40; S, 9.14; IR (KBr): νmax/cmꢀ1 3396, 3108,
2985, 2935, 2496, 1606, 1514, 1480, 1347, 1308, 1254, 1163, 1143, 1109, 1047, 751, 567 cmꢀ1;
1H NMR (200 MHz, DMSOꢀd6): δ (ppm) 17.10 (s, 1H), 8.09 (d, J = 8.85, 2H), 7.86 (d, J = 6.41
Hz, 2H), 7.54 – 7.39 (m, 4H), 7.36 – 7.27 (m, 2H), 7.20 – 7.07 (m, 2H), 5.78 (s, 1H), 3.96 (q, J =
6.71 Hz, 4H), 3.05 (q, J = 7.32 Hz, 6H), 1.29 – 1.05 (m, 15H); 13C NMR (125 MHz, DMSOꢀd6):
δ (ppm) 160.4, 150.3, 145.7, 138.4, 130.5, 128.5, 126.5, 124.2, 123.1, 121.9, 117.4, 109.5, 45.9,
41.1, 36.3, 14.1, 8.7; MS (EI) m/z: 358 [Mꢀ326]+.
4.5.3. 3ꢀ[(4ꢀHydroxyꢀ1ꢀethylꢀ2,2ꢀdioxidoꢀ1Hꢀ2,1ꢀbenzothiazinꢀ3ꢀyl)
(2ꢀmethoxyphenyl)methyl]ꢀ1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ5ꢀolat 2,2ꢀdioxide (8c).
Preparative procedure. To a solution of 1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ4(3H)ꢀone 2,2ꢀdioxide 1
(0.450 g, 0.002 mol), 2ꢀmethoxybenzaldehyde 3c (0.136 g, 0.001 mol) in ethanol (10 mL),
triethylamine (0.14 mL, 0.001 mol) was added. The solution was stirred at the room temperature.
After about 1 h a white precipitate of 8c was formed, this was filtered off, washed with ethanol,
dried on air and recrystallized from ethanol. Yield of 8c was 87%.
Colorless prisms; mp 145ꢀ147 °C (from EtOH); Anal. Calcd for C34H43N3O7S2: C, 60.96; H,
6.47; N, 6.27; S, 9.57. Found: C, 61.31; H, 6.46; N, 6.24; S, 9.22; IR (KBr): νmax/cmꢀ1 3429,
2973, 2917, 2850, 2470, 1606, 1587, 1474, 1335, 1296, 1247, 1164, 1143, 1108, 1046, 744, 567
1
cmꢀ1; H NMR (500 MHz, DMSOꢀd6): δ (ppm) 16.84 (s, 1H), 7.99 – 7.84 (m, 2H), 7.52 – 7.35
(m, 3H), 7.33 – 7.00 (m, 5H), 6.84 – 6.70 (m, 2H), 5.89 (s, 1H), 4.06 – 3.81 (m, 4H), 3.62 (s, 3H),
3.11 – 2.90 (m, 6H), 1.39 – 0.96 (m, 15H); 13C NMR (125 MHz, DMSOꢀd6): δ (ppm) 160.0,
156.6, 138.9, 130.4, 129.9, 129.8, 126.8, 126.4, 124.9, 121.6, 119.0, 117.5, 110.6, 110.4, 55.2,
45.9, 41.8, 31.9, 14.3, 8.7.
4.5.4. 3ꢀ[(4ꢀHydroxyꢀ1ꢀethylꢀ2,2ꢀdioxidoꢀ1Hꢀ2,1ꢀbenzothiazinꢀ3ꢀyl)
(4ꢀchlorophenyl)methyl]ꢀ1ꢀethylꢀ1Hꢀ2,1ꢀbenzothiazinꢀ5ꢀolat 2,2ꢀdioxide (8e)
Compound 8e was obtained using 4ꢀchlorobenzaldehyde 3e, instead 3a, according to the
procedure described in section 4.5.1 (Route A). Yield of 8e was 17%.
Colorless prisms; mp 163ꢀ165 °C (from EtOH); Anal. Calcd for C33H40ClN3O6S2: C, 58.78; H,
5.98; N, 6.23; S, 9.51. Found: C, 58.91; H, 5.87; N, 6.41; S, 9.34; IR (KBr): νmax/cmꢀ1 3456,
3079, 2988, 2937, 2904, 2878, 2835, 2499, 1610, 1542, 1486, 1311, 1263, 1170, 1139, 1113,
1
1047, 757, 571 cmꢀ1; H NMR (200 MHz, DMSOꢀd6): δ (ppm) 17.19 (s, 1H), 7.86 (d, J = 7.94,
2H), 7.51 – 7.36 (m, 2H), 7.34 – 7.19 (m, 6H), 7.18 – 7.06 (m, 2H), 5.69 (s, 1H), 3.95 (q, J =
7.22 Hz, 4H), 3.03 (q, J = 7.32 Hz, 6H), 1.28 – 1.05 (m, 15H); 13C NMR (125 MHz, DMSOꢀd6):
δ (ppm) 160.1, 140.6, 138.4, 130.3, 130.0, 129.2, 127.6, 126.5, 124.3, 121.8, 117.2, 110.0, 45.9,
40.9, 35.5, 14.1, 8.7; MS (EI) m/z: 347 [Mꢀ326]+.

Page 23 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
Acknowledgements
Authors are thankful to Mr. Maxim A. Nechayev (Enamine Ltd) and Ms. Maria A.
Vodolazhenko (SSI "ISC" NASU) for measurement of 13C NMR spectra. We also acknowledge
Mr. Aleksey L. Shemchuk and Mr. Pavel S. Arzumanov for their valuable remarks.
References
1 H. Bienaymé, C. Hulme, G. Oddon and P. Schmitt, Chem. Eur. J., 2000, 6, 3321ꢀ3329.
2 B. Jiang, S.ꢀJ. Tu, P. Kaur, W. Wever and G. Li, J. Am. Chem. Soc., 2009, 131, 11660ꢀ11661.
3 C. Hulme and V. Gore, Curr. Med. Chem., 2003, 10, 51ꢀ80.
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, 6719ꢀ6728; (b) V. A. Chebanov and S. M. Desenko, Chem. Heterocycl. Comp., 2012, 48, 566ꢀ583;
(c) V. A. Chebanov, V. E. Saraev, S. M. Desenko, V. N. Chernenko, S. V. Shishkina, O. V. Shishkin, K. M. Kobzar
and C. O. Kappe, Org. Lett., 2007, 9, 1691ꢀ1694; (d) N. Y. Gorobets, Y. V. Sedash, K. S. Ostras, O. V. Zaremba, S.
V. Shishkina, V. N. Baumer, O. V. Shishkin, S. M. Kovalenko, S. M. Desenko and E. V. Van der Eycken,
Tetrahedron Lett., 2010, 51, 2095ꢀ2098; (e) 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, 9389ꢀ9400.
5 L. A. Shemchuk, D. A. Lega, R. G. Redkin, V. P. Chernykh, O. V. Shishkin and S. V. Shishkina, Tetrahedron,
2014, 70, 8348ꢀ8353.
6 J. G. Lombardino and N. W. Treadway, Jr., Org. Prep. Proced. Int., 1971, 3, 33ꢀ36.
7 F. T. Coppo and M. M. Fawzi, J. Heterocycl. Chem., 1998, 35, 983ꢀ987.
8 M. Shafiq, M. ZiaꢀUrꢀRehman, I. U. Khan, M. N. Arshad and S. A. Khan, J. Chil. Chem. Soc., 2011, 56, 527ꢀ531.
9 Y. Misu and H. Togo, Org. Biomol. Chem., 2003, 1, 1342ꢀ1346.
10 I. V. Ukrainets, L. A. Petrushova and S. P. Dzyubenko, Chem. Heterocycl. Compd. (N. Y., NY, U. S.), 2013, 49,
1378ꢀ1383.
11 I. V. Ukrainets, L. A. Petrushova, S. P. Dzyubenko and Y. Liu, Chem. Heterocycl. Compd. (N. Y., NY, U. S.),
2014, 50, 564ꢀ572.
12 I. V. Ukrainets, L. A. Petrushova, S. P. Dzyubenko and G. Sim, Chem. Heterocycl. Compd. (N. Y., NY, U. S.),
2014, 50, 103ꢀ110.
13 G. Brahmachari and B. Banerjee, ACS Sustainable Chemistry & Engineering, 2013, 2, 411ꢀ422.
14 H. R. Shaterian, M. Arman and F. Rigi, J. Mol. Liq., 2011, 158, 145ꢀ150.
15 Y. M. Litvinov and A. M. Shestopalov, in Adv. Heterocycl. Chem., ed. A. R. Katritzky, Academic Press, 2011,
Volume 103, pp. 175ꢀ260.
16 R. Ghahremanzadeh, G. Hosseini, R. Akbarzadeh and A. Bazgir, J. Heterocycl. Chem., 2013, 50, 272ꢀ280.
17 A. A. Shestopalov, L. A. Rodinovskaya, A. M. Shestopalov and V. P. Litvinov, Russ. Chem. Bull., 2004, 53,
724ꢀ725.
18 D. Heber and E. V. Stoyanov, Synthesis, 2003, 2003, 0227ꢀ0232.
19 D.ꢀO. Moon, Y. H. Choi, N.ꢀD. Kim, Y.ꢀM. Park and G.ꢀY. Kim, International Immunopharmacology, 2007, 7,
506ꢀ514.
20 Z.ꢀQ. Xu, M. G. Hollingshead, S. Borgel, C. Elder, A. Khilevich and M. T. Flavin, Bioorg. Med. Chem. Lett.,
1999, 9, 133ꢀ138.
21 M. Makino and Y. Fujimoto, Phytochemistry, 1999, 50, 273ꢀ277.
22 S. Ray, H. K. Majumder, A. K. Chakravarty, S. Mukhopadhyay, R. R. Gil and G. A. Cordell, J. Nat. Prod., 1996,
59, 27ꢀ29.
23 Y.ꢀL. Lin, C.ꢀC. Shen, Y.ꢀJ. Huang and Y.ꢀY. Chang, J. Nat. Prod., 2005, 68, 381ꢀ384.
24 E. E. Schweizer and D. MeederꢀNycz, in Chem. Heterocycl. Comp., John Wiley & Sons, Inc., 2008, pp. 11ꢀ139.
25 D. Armesto, W. M. Horspool, N. Martin, A. Ramos and C. Seoane, J. Org. Chem., 1989, 54, 3069ꢀ3072.
26 B. Pirotte, J. Fontaine and P. Lebrun, Curr. Med. Chem., 1995, 2, 573.
27 K. S. Atwal, Curr. Med. Chem., 1996, 3, 227.
28 C. S. Konkoy, D. B. Fick, S. X. Cai, N. C. Lan, J. F. W. Keana, US Pat., 6 680 332 B1, 2004.
29 S. Kang, G. Cooper, S. F. Dunne, C.ꢀH. Luan, D. James Surmeier and R. B. Silverman, Bioorg. Med. Chem.,
2013, 21, 4365ꢀ4373.
30 A.ꢀG. E. Amr, A. M. Mohamed, S. F. Mohamed, N. A. AbdelꢀHafez and A. E.ꢀF. G. Hammam, Bioorg. Med.
Chem., 2006, 14, 5481ꢀ5488.
31 P. Paliwal, S. Jetti and S. Jain, Med. Chem. Res., 2013, 22, 2984ꢀ2990.
32 D. Kumar, V. B. Reddy, S. Sharad, U. Dube and S. Kapur, Eur. J. Med. Chem., 2009, 44, 3805ꢀ3809.

RSC Advances
Page 24 of 25
View Article Online
DOI: 10.1039/C5RA24566D
33 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, 2783ꢀ2788.
34 T. A. Nakib, V. Bezjak, S. Rashid, B. Fullam and M. J. Meegan, Eur. J. Med. Chem., 1991, 26, 221ꢀ230.
35 Y. A. Sharanin, L. Y. Sukharevskaya and V. V. Shelyakin, Russ. J. Org. Chem. (Engl. Transl.), 1998, 34, 552ꢀ
553.
36 M. P. Goncharenko and Y. A. Sharanin, Russ. J. Org. Chem. (Engl. Transl.), 1993, 29, 1218 ꢀ 1229.
37 Z. H. Khalil, A. A. AbdelꢀHafez, A. A. Geies and A. M. Kamal ElꢀDean, Bull. Chem. Soc. Jpn., 1991, 64, 668ꢀ
670.
38 L. Rodinovskaya, A. Shestopalov, A. Gromova and A. Shestopalov, Synthesis, 2006, 2006, 2357ꢀ2370.
39 N. Martín, A. MartínezꢀGrau, C. Seoane and J. Marco, Tetrahedron: Asymmetry, 1995, 6, 255ꢀ262.
40 A. M. Shestopalov and O. A. Naumov, Russ. Chem. Bull., 2003, 52, 961ꢀ968.
41 J. L. Hicks and W. H. Roark, Pat. WO 2004/014388 A1, 2004.
42 A. M. Shestopalov and Yu. M. Emel'yanova, in Selected methods for synthesis and modification of heterocycles
(Russ. Transl.), ed. V. G. Kartsev, IBS Press, 2003, Volume 2, pp. 534ꢀ563.
43 H. A. A. ElꢀNabi, Pharmazie, 1997, 52, 28 ꢀ 32.
44 R. A. Mekheimer, N. H. Mohamed and K. U. Sadek, Bull. Chem. Soc. Jpn., 1997, 70, 1625 ꢀ 1630.
45 M. R. H. Elmoghayer, M. A. E. Khalifa, M. K. A. Ibraheim and M. H. Elnagdi, Monatsh. Chem., 1982, 113, 53ꢀ
57.
46 Structure correlation; H.ꢀB. Burgi and J. D. Dunitz, Ed.; VCH. Weinheim, 1994; Vol. 2, pp 741ꢀ784.
47 R. G. Redkin, L. A. Shemchuk, V. P. Chernykh, O. V. Shishkin and S. V. Shishkina, Tetrahedron, 2007, 63,
11444ꢀ11450.
48 G. Sheldrick, Acta Crystallographica Section A, 2008, 64, 112ꢀ122.

Page 25 of 25
RSC Advances
View Article Online
DOI: 10.1039/C5RA24566D
219x149mm (300 x 300 DPI)