Crotonic, cynnamic, and propiolic acids motifs in the synthesis of thiopyrano[2,3-d][1,3]thiazoles via hetero-Diels-Alder reaction and related tandem processes

Article abstract of DOI:10.1016/j.tet.2013.11.083

Various novel thiopyrano[2,3-d][1,3]thiazol-2-one-6-carboxylic acids derivatives were synthesized in 54-86% yields via hetero-Diels-Alder reactions and related acylation-based tandem processes of 5-arylidene-4-thioxo-2- thiazolidinones with crotonic, prop

Full text of DOI:10.1016/j.tet.2013.11.083

Accepted Manuscript
Crotonic, cynnamic and propiolic acids motifs in the synthesis of thiopyrano[2,3-d]
[1,3]thiazoles via hetero-Diels-Alder reaction and related tandem processes
Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Andriy Bryhas, Vasyl
Matiychuk, Andrzej Gzella, Roman Lesyk
PII:
S0040-4020(13)01804-8
10.1016/j.tet.2013.11.083
TET 25060
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 June 2013
Revised Date: 11 November 2013
Accepted Date: 25 November 2013
Please cite this article as: Zelisko N, Atamanyuk D, Vasylenko O, Bryhas A, Matiychuk V, Gzella A,
Lesyk R, Crotonic, cynnamic and propiolic acids motifs in the synthesis of thiopyrano[2,3-d][1,3]thiazoles
via hetero-Diels-Alder reaction and related tandem processes, Tetrahedron (2013), doi: 10.1016/
j.tet.2013.11.083.
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Crotonic, cynnamic and propiolic acids motifs in the
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Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Andriy Bryhas, Vasyl Matiychuk, Andrzej Gzella,
Roman Lesyk
H
S
H
N
N
Ar
H
S
S
O
H
O
H
N
O
H
N
N
S
S
H3C
O
S
S
H
O
O
H
O
O
S
O
O
HO
S
S
HOOC
HO
R1
H
9
R1
O
7
8
4

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Crotonic, cynnamic and propiolic acids motifs in the synthesis of thiopyrano[2,3-
d][1,3]thiazoles via hetero-Diels-Alder reaction and related tandem processes
Nataliya Zeliskoa , Dmytro Atamanyuka, f , Olexandr Vasylenkob , Andriy Bryhasc , Vasyl Matiychukc ,
Andrzej Gzellad, e , Roman Lesyka, *
aDepartment of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv, 79010, Ukraine
bInstitute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Murmanska 1, Kyiv, 02094, Ukraine
cDepartment of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla and Mefodiya 6, Lviv 79005, Ukraine
dDepartment of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, Poznan, 60780, Poland
eFaculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun’, A. Jurasza 2, Bydgoszcz, 85089, Poland
fPresent address: Mutabilis, 102 Avenue Gaston Roussel, Romainville, 93230, France
*corresponding author: dr_r_lesyk@org.lviv.net (Roman Lesyk), tel. +38 0322 75-59-66, fax. +38 0322 75-77-34
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Various novel thiopyrano[2,3-d][1,3]thiazol-2-one-6-carboxylic acids derivatives were
synthesized in 54–86% yields via hetero-Diels–Alder reactions and related acylation-based
tandem processes of 5-arylidene-4-thioxo-2-thiazolidinones with crotonic, propiolic and
cynnamic acids derivatives. Stereo- and regioselectivity of cycloaddition were investigated.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
4-thioxo-2-thiazolidinones
thiopyrano[2,3-d][1,3]thiazoles
hetero-Diels-Alder reaction
tandem reactions
without Michael accepting functionalities.4 Thiopyrano[2,3-
1. Introduction
d][1,3]thiazoles are usually synthesized via hetero-Diels-Alder
The antiinflammatory, antitumor, antimicrobial, antidiabetic
and antibacterial activities of 4-thiazolidinones and related
reaction
of
5-arylidene-2,4-dithioxothiazolidines
(5-
arylidenethiorhodanines)
or
5-arylidene-4-thioxo-2-
heterocyclic systems have been extensively explored.1
A
thiazolidinones (5-arylideneisorhodanines), which contain С=С5-
С4=S group in their structure and behave as active heterodienes.
Maleic acids and its derivatives (maleic anhydride and
maleimides), acrylic acid and its derivatives, acrylonitrile, β-
nitrostyrene, norbornene, 5-norbonene-2,3-dicarboxylic acid
derivatives etc. have been studied in such heterodiene
condensation as dienophiles.4,5 The reaction is presumably
controlled by the interaction of the HOMO of the diene and the
LUMO of the dienophile (normal electron demand), and we
assume that it can be activated by lowering the energy of the
dienophile-LUMO by the introduction of electron withdrawing
substituents. The cycloadditions are also highly regioselective
and form products according to Frontier Orbital Theory. Despite
сonsiderable number of the described biologically active 4-
thiazolidinone-based derivatives are 5-arylidenederivatives,
which contain the exocyclic double bond. The presence and
pattern of C5-substitution is crucial for pharmacological effect of
4-thiazolidinone derivatives.2 On the other hand, arylidene
fragment conjugation to the carbonyl group at position 4 of the
thiazolidine moiety makes the compounds electrophilic and
potentially reactive due to possible conjugate addition of the
nucleophilic protein residues to the exocyclic double bond. This
property characterizes 5-arylidene-4-thiazolidinones as frequent
hitters (promiscuous inhibitors) or pan assay interference
compounds (PAINS) that are useless in the modern drug
discovery process because of their insufficient selectivity.3 In the
attempts to solve this problem, the hypothesis of fixation of
numerous
literature
data
concerning
thiopyrano[2,3-
d][1,3]thiazoles synthesis, stereochemistry of the hetero-Diels-
highly
active
5-arylidene-4-thiazolidinone
in
fused
Alder reactions with 5-arylidenethio(iso)rhodanines was not
expolored.4a,6,7
Aiming
valorization
of
thiopyranothiazole system was confirmed and allowed the
activity vector to be conserved, while opening new possibilities
of derivatives optimization (Fig. 1). Thus, thiopyrano[2,3-
d][1,3]thiazoles could be of special interest as cyclic isosteric
mimics of synthetic precursors 5-arylidene-4-thiazolidinones
sufficiently
thiopyrano[2,3-d][1,3]thiazoles with carboxylic functionality as
pharmacologically attractive scaffolds [4+2]-cyclocondensation
reactions studies were performed based on crotonic, propiolic and
cynnamic acids representative derivatives.

ACCEPTED MANUSCRIPT
2
Tetrahedron
O
S
S
R
R
N
N
R
Ar
Ar
N
Ar
S
S
thionation
hetero-Diels-Alder
reaction
S
X
X
X
7-Arylthiopyrano[2,3-d]thiazoles
5-Arylidene-4-thiazolidinones
H
H
N
S
H
O
S
O
N
O
O
S
O
S
F
F
N
NH
S
S
NH
O
H
Anticancer
activity
S
F
O
Cl
O
Cl
S
S
Cl
N+
MeO
O
Anticancer activity
CH3
O
O
OMe
Antimicrobial activity
H
N
O
Antitrypanosomal
activity
Cl
O
N
N
S
S
OH
O
MeO
Antimycobacterial
activity
Antiinflammatory activity
Figure 1. Background for studies of thiopyrano[2,3-d][1,3]thiazoles analogs.
chromeno[4’,3’:4,5]thiopyrano[2,3-d]thia-zole-2,6-dione
4
(Scheme 2). Similar processes were previously described5a,5c
for acrylic acid and ester.
2. Results and discussions
2.1. Synthesis of new thiopyrano[2,3-d][1,3]thiazoles based on
crotonic acid and their derivatives as dienophiles
The 1H NMR spectra of the crude product of the reaction
revealed the presence of two diastereoisomeric products rel-
5R,5aR,11bS (4*) and rel-5S,5aR,11bS (4**). In contrast to the
analogous cycloaddition reaction of 2a, the configuration of the
dienophilic moiety was not retained in this case. The ratio of
cycloadducts 4* and 4** depends on the temperature and
dienophile used in the tandem rection. The reaction at room
temperature leads to a 4:1 ratio (crotonic acid and its anhydride),
while refluxing - to 1:1 (crotonic acid) or 2:3 ratio (4-
chlorophenylamide). Recrystallization of the crude product 4
from metanol allows diastereoselectively pure rel-5R,5aR,11bS
isomers (4*) to be isolated.
The reactivity of the sulfur atom at position 4 in 5-
arylideneisorhodanines 2a-h8 (Scheme 1) allows them to be used
as highly active heterodiene components. The hetero-Diels-Alder
reaction of 2a with crotonic acid or its amides proved to be regio-
and stereoselective leading to thiopyrano[2,3-d][1,3]thiazole-6-
carboxylic acids derivatives 3a-f (Scheme 1) as exclusively
racemic mixtures of rel-(5R,6R,7S)-annulated adducts (J5,6
10.6-10.8 Hz, J6,7 = 3.6-4.7 Hz).
=
The reactions between 2b and crotonic acid, either its
anhydride or 4-chlorophenylamide followed tandem hetero-
Diels-Alder and acylation processes, affording tetracyclic
fused
5-methyl-3,5a,6,11b-tetrahydro-2Н,5H-
CHO
S
S
2e R = 2-OH-5-NO2 2i R = 4-COOMe
R
2a R = 4-MeO
2b R = 2-OH
2j R = 3-PhO
2k R = 4-t-Bu
2l R = 4-CF3
NH
2f R = 4-Me
NH
2c R = 2-OH-5-Br 2g R = 3,4-(OMe)2
S
AcONa, AcOH
Ref. 8
2d R = 2-OH-3,5-Br
S
2 2h R = 2,6-Cl2
O
O
2
1
R
CH3
S
H
S
O
H
3a R = OH, 64%
H
CH3-CH=CH-COR
NH
N
3b R = 4-Cl-C6H4NH, 56%
3c R = 4-Me-C6H4NH, 77%
3d R = 4-MeO-C6H4NH, 67%
3e R = 2-CF3-C6H4NH, 71%
3f R = PhCONHNH, 78%
R
H
S
O
AcOH, reflux, 2h
56-78%
S
O
2a
3
MeO
MeO
Scheme 1. Synthesis of starting 5-arylidene-4-thioxo-2-thiazolidinones 2a-h and rel-(5R,6R,7S)-7-(4-methoxyphenyl)-5-methyl-
2-oxo-3,5,6,7-tetrahydro-2Н-thiopyrano-[2,3-d]thiazole-6-carboxylic acid derivatives 3a-f.

ACCEPTED MANUSCRIPT
3
O
CH3
H
O
H3C
OH
S
H
AcOH, 2 h, r.t. (75%) or reflux (77%)
O
NH
A
H
B -
S
H
CH3
H
C+
S
O
O
NH
H
H
N
O
4*
S
H3C
N
O
O
S
S
O
H
O
O
+
H C
S
O
H3C
O
CH3
S
H
H
O
3
AcOH, 2 h, r.t., 80%
R
S
B
H
H
O
O
NH
2b
HO
H
S
H3C
O
O
4**
N
H
Cl
ratio of stereoisomers 4* and 4**
method A 4:1 (r.t.) or 1:1* (reflux)
method B 4:1 (r.t.)
AcOH, 2 h, reflux, 67%
C
method C 2:3 (reflux)
Scheme 2. Synthesis of 5-methyl-3,5a,6,11b-tetrahydro-2Н,5H-chromeno[4’,3’:4,5]thiopyrano[2,3-d]thiazole-2,6-dione 4 and its
possible epimerization mechanism.
In our opinion, the reaction pathway may proceed via
formation of [4+2]-cycloaddition intermediates, which
immediately undergo the ring closure by acylation of the o-
substituted phenolic group. The loss of stereochemical integrity
in the cycloaddition reaction could have been explained by the
two-step mechanism with a zwitterion or a biradical formed as
intermediate, as analogous transformations were observed for 1-
aza-1,3-butadiene by Tietze et al.9 Since the same result could
have been expected, but wasn’t observed in the case of reaction
of 2a with crotonic acid derivatives (Scheme 1), the latter
mechanism should be probably excluded. One of the possible
hypotheses would be concurring non-stereoselective sulphur
nucleophile conjugate addition into the ‘dienophile’ fragment.
We also don’t exclude possible epimerization mechanism by a
retro-Michael addition reaction of tetracyclic products 4 followed
by Michael addition cyclization (Scheme 2), which is known to
be non-stereoselective for this type of Michael acceptor.10 In the
compound 4* (Fig. 2) ‘trans’ configuration H-C-C-S is fixed and
make elimination easily possible and a conformational change
must precede the mentioned elimination, in contrast to acyclic
compouds (Fig. 2b, сompoud 5). Our conclusions were supported
by X-ray analysis. After recrystallization of 4 from DMF the 4*
hydrate was obtained (Fig. 2a).
assay of the latter transformation failed. The X-ray analysis of 5
showed that only one enantiomer (6R, 7R and 8S) formed the
crystal (Fig. 2b). (see supplementary information for more
details).
CH3
CH3
H
H
O
S
S
H3COOC
MeOH
H
H
NH
H
O
NH
H
HO
S
S
O
O
4*
5
Scheme 3. Lactone ring cleavage yielding
recrystallization of 4* with methanol.
5 during
2.2. Cynnamic acids motif in the synthesis of new
thiopyrano[2,3-d][1,3]thiazoles
To enlarge the synthetic scope of such cycloadditions we
studied the reaction of 5-arylideneisorhodanines with cynnamic
acids, whose derivatives are poorly studied in diene syntheses
apart from a common targeting of biphenyl derivatives via Diels-
Alder adducts.11 The reactions of 2a, 2g, 2f, 2h and cynnamic
acids proved to be regio- and diastereoselective yielding
respectively the singe diastereoisomers of rel-(5R,6S,7S)-5,7-
diaryl-2-oxo-3,5,6,7-tetrahydro-2Н-thiopyrano[2,3-d]thiazole-6-
carboxylic acids 6 (as racemic mixtures) in good yields (Scheme
4). The trans-configuration of the protons at positions 5, 6 and 7
of 6 differ from those in compouds 3, where protons at positions
6 and 7 are cis. The endo addition rule can be applied to explain
this fact. According to this rule the most stable transition state
arises from the orientation in which there is 'maximum
accumulation of double bonds'12. In case of formation of 3 double
bond of carbonyl group involves in secondary orbital interaction
while in case of 6 π-system of aromatic ring.
a)
4*
b)
5
Figure 2. X-ray crystal structures (ORTEP plot) of 4* and 5;
in 4* the water molecule is split into two alternative positions
with the site occupancy factor of 50%.
In contrast to compounds 2a, 2g, 2f, 2h the reaction of 5-
arylideneisorhodanines with ortho-phenolic group at arylidene
moiety 2b-e and cynnamic acid proceeds via a tandem hetero-
Diels-Alder-acylation process (Scheme 5). Moreover, based on
During crystalogenesis of 4 from methanol for X-ray studies
methyl ester of 7-(2-hydroxyphenyl)-5-methyl-2-oxo-3,5,6,7-
tetrahydro-2Н-thiopyrano[2,3-d]thiazole-6-carboxylic acid (5)
(Scheme 3) was also isolated (Scheme 4), however, preparative
1
the H NMR spectra of final products 7, these cascade reactions
were diastereoselective with only single rel-(5S,5aR,11bS)-
annulated diastereisomers being formed (equatorial-pseudoaxial

ACCEPTED MANUSCRIPT
4
Tetrahedron
interactions of protons 5, 5a and 11b established from the
after primary acylation specific orientation of cycloaddition is
possible. It is important to note that structurally similar rel-
(5S,5aR,11bS)-5-aryl-3,5a,6,11b-tetrahydro-2Н,5H-
coupling constants being within 3.8-5.2 Hz according to Karplus
equation)13. It is well known that hydrogen bonding plays a key
role in many Diels-Alder reactions, both in orienting the substrate
molecules and lowering energy barriers of reactions14. In the case
of the cascade processes towards 7, presumably due to
intermolecular OH--O=C hydrogen bonding, the orientation of
cinnamic acid in transition state could be opposite than in the
case of formation of 6 and favour the cis orientation of the
protons at positions 6 and 7. Here one can also speculate on
possible concurrent acylation and cycloaddition reactions, where
chromeno[4',3':4,5]thiopyrano[2,3-d]thiazole-2,6-diones
were
obtained by us previously in domino-Knoevenagel-hetero-Diels-
Alder reaction of isorhodanine and 2-formylphenyl-(E) 3-phenyl-
2-propenoates7 which support the above hypothesis.
Stereoselectivity of product 7 formation is coherent indeed
with analogical crotonic acid derivatives adducts 4, however
epimerization of the position 5 (in multiple diastereoisomers) was
not observed in this case.
R1
R1
H
S
S
R1
N
COOH
H
O
NH
O
H
S
H
O
S
H
AcOH
H
S
N
2 h, reflux
62-86%
H
HO
R
R
HOOC
H
O
S
2a R = 4-MeO
2g R = 4-Me
R
2f R = 3,4-(MeO)2
6
2h R = 2,6-Cl2
6a R = 4-MeO, R1 = 3,4-(MeO)2, 70%
6b R = R1 = 4-MeO, 75%
6c R = 4-Me, R1 = 3,4-(MeO)2, 69%
6d R = 4-Me, R1 = 4-MeO, 62%
6e R = R1 = 3,4-(MeO)2, 72%
6f R = 3,4-(MeO)2, R1 = H, 86%
6g R = 2,6-Cl2, R1 = 4-OMe, 70%
Scheme 4. Synthesis of rel-(5R,6S,7S)-5,7-diaryl-2-oxo-3,5,6,7-tetrahydro-2Н-thiopyrano[2,3-d]thiazole-6-carboxylic acids 6a-
g.
COOH
R1
R1
H
O
H
N
O
N
S
H
R1
H
H
N
S
R1
S
S
S
S
H
O
H
H
O
O
N
O
AcOH
2 h, reflux
54-84%.
H
R
S
HO
H
O
S
2
HO
O
H
HO
R
H
7
HO
R
OH
R
7a R = H, R1 = 3,4-(MeO)2, 83%
7b R =H, R1 = 4-MeO, 84%
7c R = 10-NO2, R1 = 4-MeO, 54%
2b R = H
2c R = 5-Br
2d R = 3,5-Br2
7d R = R1 = H, 63%
7e R = 8,10-Br2, R1 = 2-Cl, 68%
2e R = 5-NO2
7f R = 10-NO2, R1 = H, 80%
7g R = 8,10-Br2, R1 = 4-F, 71%
Scheme 5. Synthesis of rel-(5S,5aR,11bS)-5-aryl-3,5a,6,11b-tetrahydro-2Н,5H-chromeno[4',3':4,5]thiopyrano[2,3-d]thiazole-
2,6-diones 7a-g
.
The structure of 7f was confirmed by X-ray analysis (Fig. 3).
Compound 7f is built of a conjugated tetracyclic moiety, i.e.
3,5,5a,6,11b-tetrahydro-2H,5H-chromeno[4’,3’:4,5]thiopyrano-
[2,3-d]thiazol-2,6-dione, and has a geometry close to that of the
tetracyclic system in compound 4*.
2.3. Propiolic acid and its ethyl ester as dienophiles in the
hetero-Diels-Alder reactions with 5-arylideneisorhodanines.
The reaction of 5-arylideneisorhodanines 2 with propiolic acid
or its ethyl ester, after usual work-up, provided 2-oxo-3,7-
dihydro-2H-thiopyrano[2,3-d]thiazole-6-carboxylic acids or
corresponding esters 8 (Scheme 6), regioselectivity towards 6-
carboxysubstituted derivatives confirmed by 1H NMR (5H-
Figure 3. X-ray crystal structures (ORTEP plot) of 7f.
proton singlet at δ 7.54-7.99).

ACCEPTED MANUSCRIPT
5
S
S
ROOC
R1
COOR
R1
NH
O
NH
O
S
AcOH, 2 h, reflux
54-68%
8a R = H, R1 = 4-MeO, 61%
8b R = H, R1 = 4-COOMe, 54%
8c R = H, R1 = 3-PhO, 55%
8d R = H, R1 = 4-t-Bu, 62%
8e R = H, R1 = 4-CF3, 55%
8f R = Et, R1 = 4-MeO, 57%
8g R = Et, R1 = 4-COOMe, 68%
S
8
2a R1 = 4-OMe
2i R1 = 4-COOMe
2j R1 = 3-PhO
2k R1 = 4-t-Bu
2l R1 = 4-CF3
Scheme 6. Synthesis of 2-oxo-3,7-dihydro-2H-thiopyrano[2,3-d]thiazole-6-carboxylic acid derrivatives 8a-g.
(a)
COOR
S
H
N
(a)
S
S
H
N
ROOC
HO
HO
COOR
R1
O
O
NH
O
S
S
O
S
AcOH,
reflux, 2 h,
54-60%
R1
O
AcOH,
reflux, 2 h
8h R = R1 = H, 58%
8i R = H, R1 = Br, 60%
8j R = Et, R1 = H, 54%
R1
8
R1
2b R1 = H
2d R1 = Br
R1
R1
H
S
S
N
O
S
N
S
S
H
O
O
(b)
O
O
(b)
Br2
H
N
O
N
Br2
S
HOOC
HO
HOOC
HO
O
S
S
O
AcOH, 2 h,
reflux, 94%
method A
H
AcOH, 2h,
reflux, 58%
10
9
8h
method B
Scheme 7. Synthesis of 2-oxo-7-(2-hydrohyphenyl)-3,7-dihydro-2H-thiopyrano[2,3-d]thiazole-6-carboxylic acid derivatives 8h-j and
2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-d][1,3]thiazole-2,6-dione 9.
One should note that propiolic acid and its ethyl ester formed
with 5-(ortho-hydroxybenzylidene)-substituted isorhodanines
only 6-carboxysubstituted [4+2]-cycloaddition adducts. Unlike
with double bond bearing monocarboxylic acids (acrylic,
crotonic and cynnamic) and their derivatives, tandem acylation-
hetero-Diels-Alder process with tetracyclic fused derivatives
formation was not observed (Scheme 7, confirmed by mass
arylidene moiety and crotonic or cynnamic acids derivatives
undergone diastereoselective tandem acylation-hetero-Diels-
Alder
reaction
providing
2Н,5H-
chromeno[4’,3’:4,5]thiopyrano[2,3-d]thiazoles formation.
1
4. Experimental
spectra and the phenol OH proton at ~ 10.00 ppm in its H NMR
spectrum). Compounds 8h-j were formed with a double bond at
position 5-6 which makes core bicycle planar and create
unfavorable space configuration for spontaneous phenolic group
acylation. This conclusion was confirmed by dehydrogenation of
compound 8h with bromine in acetic acid, which provided
tetracyclic fused 2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-
d][1,3]thiazole-2,6-dione 9 (method A). The reaction proceeds
via formation of dehydrogenated intermediate with favorable
space planar configuration of aryl and thiopyran moieties, which
immediately undergoes the ring closure by acylation of ortho-
4.1. Chemistry
All starting materials were purchased from commercial
sources and used without purification. Melting points are
uncorrected and were measured in open capillary tubes on Buchi
B-545 melting point apparatus. IR spectra were recorded with
FT/IR-410 Spectrophotometer (Jasco Corp., Japan) and OMNIC-
510 spectrometer using potassium bromide pellets (frequencies
are expressed in cm-1). The H-NMR spectra were recorded on
1
Varian Gemini 400 MHz and 13C NMR spectra on Varian Gemini
100Hz in DMSO-d6 using tetramethylsilane (TMS) as an internal
standard (chemical shift values are reported in ppm units,
coupling constants (J) are in Hz). Abbreviations are as follows: s
- singlet; d - doublet; dd – double doublet; t - triplet; m -
multiplet; br – broad. The elemental analyses (C, H, N)
performed at the Perkin-Elmer 2400 CHN analyzer and were
within ±0.4% of the theoretical values. LC-MS spectra were
obtained on Finnigan MAT INCOS-50. Purity of compound
indicated in HPLC purity identified by diode array detection. The
mass spectra (ESI-MS) of the compounds showed (M-H) peaks,
in agreement with their molecular weight.
substituted phenolic group. The compound
9 was also
synthesised via alternative approach (method B) starting from
3,5a,6,11b-tetrahydro-2H,5H-chromeno[4',3':4,5]thiopyrano[2,3-
d]thiazole-2,6-dione 105a via dehydrogenation by bromine in
acetic acid (Scheme 7). Equatorial-axial interactions of the
protons of 10 at positions 5a and 11b and rel-(5aR,11bS)-
annulated product were established from the coupling constant
(6.0 Hz).
3. Conclusion
To summarize, we have developed an efficient, regio- and
diastereoselective methods for the preparation of a series
thiopyrano[2,3-d][1,3]thiazole-6-carboxylic acids derivatives
using hetero-Diels-Alder reaction of 5-arylideneisorhodanines as
heterodienes and monocarboxylic acids derivatives with double
and triple bonds as dienophile components. It was established
that 5-arylideneisorhodanines with ortho-phenolic group at
The starting compounds: 2,4-thiazolidinedione15 and 4-thioxo-
2-thiazolidinone8 were obtained according to the methods
described previously. 5-Arylidene-4-thioxo-2-thiazolidinones
were prepared by treating 4-thioxo-2-thiazolidinone with the
o
corresponding aldehydes in glacial acetic acid (100 C, 20 min)
according to published procedures8.

ACCEPTED MANUSCRIPT
6
Tetrahedron
4.2. General procedure of Diels-Alder and tandem reactions
132.0, 132.3, 155.9, 159.0, 168.00, 171.4. IR (KBr): 3344, 3200,
affording 3a-f, 4, 5a-f, 6a-g, 7a-j.
3150-3100 (br), 3050-3000 (br), 2840, 1696, 1660, 1600, 1528,
1512, 1400, 1312, 1252, 1176, 1096, 1024, 896, 828, 720, 696, 564,
504 cm-1. LC-MS: m/z 444 (100.0%, (M+Н)+). Calcd. for
C22H22N2O4S2: C, 59.71; H, 5.01; N, 6.33; Found: C, 59.90; H, 5.10;
N, 6.40%.
A mixture of 10 mmol of the appropriate 5-arylidene-4-
thioxo-2-thiazolidinone and 11 mmol of the appropriate
dienophile was kept at room temperature or refluxed (mentioned
at the schemes appropriately r.t. or reflux) for 2 h with a catalytic
amount of hydroquinone (2–3 mg) to prevent of polymerization
processes in 10 mL of glacial acetic acid, then left overnight at
room temperature. The precipitated crystals were filtered off,
washed with ethanol, and recrystallized from appropriate solvent.
4.2.5.
N6-(2-Trifluoromethylphenyl)-rel-
(5R,6R,7S)-7-(4-methoxyphenyl)-5-methyl-2-oxo-
3,5,6,7-tetrahydro-2Н-thiopyrano[2,3-d]thiazole-6-
carboxamide (3e). Yield 71%, isolated as white powder, mp
224-226 °C (MeOH). 1H NMR (400 MHz, DMSO-d6): 1.27 (d, 3Н, J
= 6.0 Hz, СН3), 3.27 (dd, 1Н, J = 10.8, 4.0 Hz, 6-H), 3.66-3.69 (m,
1Н, 5-H), 3.74 (s, 3Н, ОСН3), 4.28 (d, 1Н, J = 4.0 Hz, 7-H), 6.88 (d,
2H, J = 8.0 Hz, arom.), 7.07 (d, 2H, J = 8.0 Hz, arom.), 7.40 (d, 1H,
J = 7.9 Hz, arom.), 7.42 (t, 1H, J = 7.5 Hz, arom.), 7.69 (t, 1H, J =
7.5 Hz, arom.), 7.76 (d, 1H, J = 7.7 Hz, arom.), 9.93 (s, 1Н, NH),
11.49 (br.s, 1Н, NH). 13C NMR (100 MHz, DMSO-d6): 19.1, 33.7,
42.3, 52.6, 55.5, 105.8, 114.0, 120.3, 123.8 (d, J = 226.6 Hz), 125.2
(d, J = 4.2 Hz), 126.8, 126.8, 127.2, 130.2, 132.0, 133.5, 135.2,
159.00, 169.6, 171.3. IR (KBr): 3250, 3200-3180 (br), 2864, 1688,
1672, 1600, 1508, 1316, 1252, 1172, 1116, 964, 900, 768, 712, 664,
564 cm-1. LC-MS: m/z 482 (100.0%, (M+Н)+). Calcd. for
C22H19F3N2O3S2: C, 54.99; H, 3.99; N, 5.83; Found: C, 55.10; H,
4.10; N, 5.90%.
4.2.1.
rel-(5R,6R,7S)-7-(4-Methoxyphenyl)-5-
methyl-2-oxo-3,5,6,7-tetrahydro-2Н-thiopyrano
[2,3-d] thiazole-6-carboxylic acid (3a). Yield 64%,
isolated as white powder, mp 212-214 °C (MeCN). 1H NMR (400
MHz, DMSO-d6): 1.29 (d, 3H, J = 6.4 Hz, CH3), 2.98 (dd, 1Н, J =
10.6, 4.8 Hz, 6-H), 3.52-3.55 (m, 1Н, 5-H), 3.71 (s, 3Н, ОСН3), 4.17
(d, 1Н, J = 4.8 Hz, 7-H), 6.85 (d, 2H, J = 8.4 Hz, arom.), 7.03 (d, 2H,
J = 8.4 Hz, arom.), 11.41 (s, 1Н, NH), 12.68 (br.s, 1Н, COOH). 13C
NMR (100 MHz, DMSO-d6): 19.5, 33.4, 41.5, 52.5, 55.5, 105.4,
114.1, 120.3, 130.2, 131.9, 159.1, 171.3, 171.8. IR (KBr): 3300,
3150-3050 (br), 2856, 1696, 1648, 1632, 1608, 1512, 1460, 1336,
1328, 1280, 1248, 1180, 1028, 896, 840, 776, 700, 608, 560 cm-1.
LC-MS: m/z 339 (100.0%, (M+Н)+). Calcd. for C15H15NO4S2: C,
53.40; H, 4.48; N, 4.15; Found: C, 53.20; H, 4.50; N, 4.20%.
4.2.6. Benzoic acid N6-[rel-(5R,6R,7S)-7-(4-
methoxyphenyl)-5-methyl-2-oxo-3,5,6,7-tetrahydro-
2Н-thiopyrano[2,3-d] thiazole-6-carbonyl] -
4.2.2. N6-(4-Chlorophenyl)-rel-(5R,6R,7S)-7-(4-
methoxyphenyl)-5-methyl-2-oxo-3,5,6,7-tetrahydro-
2Н-thiopyrano[2,3-d]thiazole-6-carboxamide (3b).
hydrazide (3f). Yield 78%, isolated as white powder, mp 192-
1
Yield 56%, isolated as white powder, mp 236-238 °C (MeCN). H
1
194 °C (i-PrOH). H NMR (400 MHz, DMSO-d6): 1.28 (d, 3Н, J =
NMR (400 MHz, DMSO-d6): 1.27 (d, 3Н, J = 6.4 Hz, СН3), 3.10
(dd, 1Н, J = 10.7, 4.6 Hz, 6-H), 3.62-3.64 (m, 1Н, 5-H), 3.70 (s, 3Н,
ОСН3), 4.25 (d, 1Н, J = 4.6 Hz, 7-H), 6.79 (d, 2H, J = 8.4 Hz,
arom.), 6.91 (d, 2H, J = 8.4 Hz, arom.), 7.36 (d, 2H, J = 8.7 Hz,
arom.), 7.47 (d, 2H, J = 8.7 Hz, arom.), 10.33 (s, 1Н, NH), 11.44 (s,
1Н, NH). 13C NMR (100 MHz, DMSO-d6): 19.3, 33.5, 42.6, 53.4,
55.5, 105.4, 114.0, 120.5, 121.4, 127.5, 129.2, 130.2, 131.8, 138.1,
159.0, 168.6, 171.3. LC-MS: m/z 448/450 (100.0%, (M+Н)+). Calcd.
for C21H19ClN2O3S2: C, 56.43; H, 4.28; N, 6.27; Found: C, 56.30; H,
4.40; N, 6.20%.
6.0 Hz, СН3), 3.05 (dd, 1Н, J = 10.8, 4.0 Hz, 6-H), 3.57-3.60 (m, 1Н,
5-H), 3.72 (s, 3Н, ОСН3), 4.18 (d, 1Н, J = 4.0 Hz, 7-H), 6.80 (d, 2H,
J = 8.4 Hz, arom.), 7.14 (d, 2H, J = 8.4 Hz, arom.), 7.52 (t, 1H, J =
7.4 Hz, arom.), 7.60 (t, 2H, J = 7.1 Hz, arom.), 7.91 (d, 2H, J = 7.5
Hz, arom.), 10.26 (s, 1Н, NH), 10.42 (s, 1Н, NH), 11.49 (s, 1Н, NH).
13C NMR (100 MHz, DMSO-d6): 19.2, 33.6, 42.5, 50.9, 55.4, 105.5,
113.7, 120.4, 128.0, 128.9, 130.7, 131.6, 132.4, 132.9, 158.8, 166.1,
169.5, 171.4. LC-MS: m/z 457 (100.0%, (M+Н)+). Calcd. for
C22H21N3O4S2: C, 58.00; H, 4.65; N, 9.22; Found: C, 57.90; H, 4.80;
N, 9.30%.
4.2.3. N6-(4-Methylphenyl)-rel-(5R,6R,7S)-7-(4-
methoxyphenyl)-5-methyl-2-oxo-3,5,6,7-tetrahydro-
2Н-thiopyrano[2,3-d]thiazole-6-carboxamide (3c).
4.2.7.
rel-(5R,5aR,11bS)-5-Methyl-3,5a,6,11b-
tetrahydro-2Н,5H-chromeno[4’,3’:4,5]thiopyrano-
[2,3-d] thiazole-2,6-dione (4*). Yields: method A - 77%
(reflux) and 75% (stirring, r.t.), method B - 80% (stirring, r.t.),
method C - 67% (reflux), isolated as white powder, mp 218-220 °C
1
Yield 77%, isolated as white powder, mp 218-220 °C (MeCN). H
NMR (400 MHz, DMSO-d6): 1.26 (d, 3Н, J = 6.3 Hz, СН3), 2.24 (s,
3H, СН3-C6H4), 3.07 (dd, 1Н, J = 10.7, 4.5 Hz, 6-H), 3.61-3.64 (m,
1Н, 5-H), 3.70 (s, 3Н, ОСН3), 4.22 (d, 1Н, J = 4.5 Hz, 7-H), 6.78 (d,
2H, J = 8.3 Hz, arom.), 6.91 (d, 2H, J = 8.3 Hz, arom.), 7.09 (d, 2H,
J = 8.0 Hz, arom.), 7.33 (d, 2H, J = 8.0 Hz, arom.), 10.10 (s, 1Н,
NH), 11.44 (s, 1Н, NH). 13C NMR (100 MHz, DMSO-d6): 18.8,
20.4, 33.1, 42.09, 52.7, 54.9, 105.0, 113.4, 119.4, 120.0, 129.1,
129.7, 131.4, 132.4, 136.1, 158.5, 167.7, 170.9. LC-MS: m/z 428
(100.0%, (M+Н)+). Calcd. for C22H22N2O3S2: C, 61.95; H, 5.20; N,
6.57; Found: C, 62.00; H, 5.40; N, 6.40%.
1
(MeOH). H NMR (400 MHz, DMSO-d6): 1.50 (d, 3Н, J = 7.2 Hz,
СН3), 3.74 (dd, 1Н, J = 6.1, 3.6 Hz, 5a-H), 3.94-3.96 (m, 1Н, 5-Н),
4.32 (d, 1Н, J = 6.1 Hz, 11b-H), 7.13 (d , 1H, J = 8.0 Hz, arom.),
7.23-7.25 (m, 1H, arom.), 7.38 (m, 1H, arom.), 7.46 (d, 1H, J = 7.4
Hz, arom.), 11.38 (s, 1Н, NH). 13C NMR (100 MHz, DMSO-d6):
21.5, 30.6, 35.2, 42.1, 101.9, 117.2, 120.0, 124.2, 125.4, 129.1,
130.1, 150.3, 166.9, 170.8. IR (KBr): 3450, 3400, 3250-3200 (br),
2848, 1752, 1662, 1624, 1588, 1552, 1504, 1488, 1360, 1224, 1104,
964, 800, 760, 536, 492 cm-1. LC-MS: m/z 307 (94.0%, (M+Н)+).
Calcd. for C14H11NO3S2: C, 55.07; H, 3.63; N, 4.59; Found: C,
55.20; H, 3.50; N, 4.40%.
4.2.4.
N6-(4-Methoxylphenyl)-rel-(5R,6R,7S)-7-
(4-methoxyphenyl)-5-methyl-2-oxo-3,5,6,7-
tetrahydro-2Н-thiopyrano[2,3-d] thiazole-6-
rel-(5S,5aR,11bS)-5-Methyl-3,5a,6,11b-
tetrahydro-2Н,5H-chromeno[4’,3’:4,5]thiopyrano-
[2,3-d] thiazole-2,6-dione (4**, not isolated). 1H
NMR (400 MHz, DMSO-d6): 1.60 (d, 3Н, J = 7.2 Hz, СН3), 3.81
(dd, 1Н, J = 5.8, 1.9 Hz, 5a-H), 3.95 (m, 1Н, 5-Н), 4.38 (d, 1Н, J =
5.9 Hz, 11b-H), 7.13 (d, 1H, J = 8.0 Hz, arom.), 7.24 (m, 1H, arom.),
7.38 (m, 1H, arom.), 7.46 (d, 1H, J = 7.4 Hz, arom.), 11.40 (s, 1Н,
NH).
carboxamide (3d). Yield 67%, isolated as white powder, mp
210-212 °C (MeCN). 1H NMR (400 MHz, DMSO-d6): 1.29 (d, 3Н, J
= 6.0 Hz, СН3), 3.10 (dd, 1Н, J = 10.4, 3.6 Hz, 6-H), 3.69-3.71 (m,
1Н, 5-H), 3.73 (s, 6Н, 2*ОСН3), 4.24 (d, 1Н, J = 3.6 Hz, 7-H), 6.81
(d, 2H, J = 8.0 Hz, arom.), 6.95 (d, 2H, J = 8.0 Hz, arom.), 6.89 (d,
2H, J = 8.4 Hz, arom.), 7.38 (4Н, d, 2H, J = 8.4 Hz, arom.), 10.08 (s,
1Н, NH), 11.47 (s, 1Н, NH). 13C NMR (100 MHz, DMSO-d6): 19.4,
33.7, 42.6, 53.2, 55.5, 55.7, 105.6, 113.9, 114.4, 120.5, 121.5, 130.2,

ACCEPTED MANUSCRIPT
7
4.2.8. rel-(5R,6S,7S)-5-(3,4-Dimethoxyphenyl)-7-
Calcd. for C21H19NO4S2: C, 61.00; H, 4.63; N, 3.39; Found: C,
(4-methoxyphenyl)-2-oxo-3,5,6,7-tetrahydro-2Н-
thiopyrano[2,3-d] thiazole-6-carboxylic acid (6a).
Yield 70%, isolated as white powder, mp 188-190 °C (MeCN). H
61.20; H, 4.50; N, 3.30%.
4.2.12.
rel-(5R,6S,7S)-5,7-Di(3,4-
1
dimethoxyphenyl)-2-oxo-3,5,6,7-tetrahydro-2Н-
thiopyrano[2,3-d] thiazole-6-carboxylic acid (6e).
Yield 72%, isolated as white powder, mp 220-222 °C (EtOH). 1H
NMR (400 MHz, DMSO-d6): 3.27 (t, 1Н, J = 10.4 Hz, 6-H), 3.78 (s,
6H, 2*ОСН3), 3.80 (s, 6Н, 2*ОСН3), 4.08 (d, 1Н, J = 10.4 Нz, 7-Н),
4.60 (d, 1Н, J = 10.4 Hz, 5-Н), 6.73-6.76 (m, 2H, arom.), 6.80 (s,
1H, arom.), 6.82 (d, 1Н, J = 7.8 Нz, arom.), 6.94 (d, 1Н, J = 7.8 Нz,
arom.), 6.96 (s, 1H, arom.), 11.15 (s, 1Н, NH), 11.98 (br.s, 1Н,
COOH). 13C NMR (100 MHz, DMSO-d6): 46.0, 48.4, 55.7, 55.9,
56.0, 56.2, 108.3, 112.1, 112.4, 112.9, 120.5, 121.3, 121.7, 129.2,
133.0, 148.9, 149.0, 149.2, 149.5, 171.3, 172.7. IR (KBr): 3380-3356
(br), 3176, 3064, 2976, 2904, 2860-2830 (br), 1656, 1632, 1552,
1504, 1496, 1432, 1416, 1388, 1262, 1160, 1140, 1016, 824, 704,
656 cm-1. LC-MS: m/z 490 (98.5%, (M+Н)+). Calcd. For
C23H23NO7S2: C, 56.43; H, 4.74; N, 2.86; Found: C, 56.60; H, 4.60;
N, 2.90%.
NMR (400 MHz, DMSO-d6): 3.42 (t, 1Н, J = 10.6 Hz, 6-H), 3.75 (s,
9Н, 3*ОСН3), 4.14 (d, 1Н, J = 10.6 Hz, 7-Н), 4.77 (d, 1Н, J = 10.6
Hz, 5-Н), 6.90 (d, 2H, J = 8.4 Hz, arom.), 7.19 (d, 2H, J = 8.4 Hz,
arom.), 6.92 (d, 1H, J = 8.0 Hz, arom.), 7.01 (d, 1H, J = 8.0 Hz,
arom.), 7.09 (s, 1H, arom.), 11.39 (s, 1Н, NH), 12.10 (br.s, 1Н,
COOH). 13C NMR (100 MHz, DMSO-d6): 45.6, 48.4, 55.5, 55.9,
56.0, 56.1, 108.4, 112.1, 112.8, 114.4, 120.5, 121.7, 130.0, 132.6,
133.4, 149.0, 149.5, 159.2, 171.2, 172.6. IR (KBr): 3480-3450 (br),
3400-3380 (br), 3280, 3184, 3152, 3136, 3064, 3040, 3008, 2856-
2848 (br), 1696, 1648, 1584, 1516, 1456, 1264, 1176, 1024, 840,
696, 568 cm-1. LC-MS: m/z 460 (93.5%, (M+Н)+). Calcd. for
C22H21NO6S2: C, 57.50; H, 4.61; N, 3.05; Found: C, 57.30; H, 4.50;
N, 3.20%.
4.2.9. rel-(5R,6S,7S)-5,7-Di(4-methoxyphenyl)-2-
oxo-3,5,6,7-tetrahydro-2Н-thiopyrano[2,3-
d] thiazole-6-carboxylic acid (6b). Yield 75%, isolated as
white powder, mp 220-222 °C (EtOH). 1H NMR (400 MHz, DMSO-
d6): 3.25 (t, 1Н, J = 10.4 Hz, 6-H), 3.77 (s, 6Н, 2*ОСН3), 4.10 (d,
1Н, J = 10.4 Hz, 7-Н), 4.62 (d, 1Н, J = 10.4 Hz, 5-Н), 6.84 (d, 2H, J
= 8.0 Hz, arom.), 7.34 (d, 2H, J = 8.0 Hz, arom.), 6.85 (d, 2H, J = 8.4
Hz, arom.), 7.15 (d, 2H, J = 8.4 Hz, arom.), 11.13 (br.s, 1Н, NH),
11.98 (br.s, 1Н, COOH). 13C NMR (100 MHz, DMSO-d6): 45.5,
48.0, 55.5, 55.6, 56.1, 108.5, 114.4, 120.5, 128.8, 130.0, 130.5,
132.6, 159.2, 159.8, 171.2, 172.6. IR (KBr): 3100, 3050, 3000-2950
(br), 2912, 2864, 1728, 1680, 1644, 1608, 1568, 1512, 1296, 1252,
1180, 1136, 1032, 964, 832, 664, 560, 544 cm-1. LC-MS: m/z 430
(91.6%, (M+Н)+). Calcd. for C21H19NO5S2: C, 58.73; H, 4.46; N,
3.26; Found: C, 58.60; H, 4.50; N, 3.40%.
4.2.13.
rel-(5R,6S,7S)-5-Phenyl-7-(3,4-
dimethoxyphenyl)-2-oxo-3,5,6,7-tetrahydro-2Н-
thiopyrano[2,3-d] thiazole-6-carboxylic acid (6f).
Yield 86%, isolated as white powder, mp 230-232 °C (MeCN). H
1
NMR (400 MHz, DMSO-d6): 3.31 (t, 1Н, J = 10.4 Hz, 6-H), 3.78 (s,
3H, ОСН3), 3.80 (s, 3Н, ОСН3), 4.10 (d, 1Н, J = 10.4 Hz, 7-Н), 4.66
(d, 1Н, J = 10.4 Hz, 5-Н), 6.74 (s, 1H, arom.), 6.75 (d, 1Н, J = 8.0
Hz, arom.), 6.80 (d, 1Н, J = 8.0 Hz, arom.), 7.20-7.40 (m, 3H,
arom.), 7.43 (d, 2Н, J = 7.0 Hz, arom.), 11.17 (s, 1Н, NH), 12.01
(br.s, 1Н, COOH). 13C NMR (100 MHz, DMSO-d6): 45.9, 48.5,
55.9, 56.0, 56.1, 108.4, 112.1, 112.4, 112.8, 120.5, 128.9, 130.5,
132.0, 132.6, 139.8, 149.1, 149.4, 171.3, 172.8. IR (KBr): 3424-3404
(br), 3080-3040 (br), 3000-2940 (br), 2850-2800 (br), 1720, 1672,
1632, 1588, 1536, 1504, 1400, 1264, 1232, 1152, 952, 836, 664, 560
cm-1. LC-MS: m/z 430 (98.0%, (M+Н)+). Calcd. for C21H19NO5S2: C,
58.73; H, 4.46; N, 3.26; Found: C, 58.60; H, 4.50; N, 3.40%.
4.2.10. rel-(5R,6S,7S)-5-(3,4-Dimethoxyphenyl)-
7-(4-methylphenyl)-2-oxo-3,5,6,7-tetrahydro-2Н-
thiopyrano[2,3-d] thiazole-6-carboxylic acid (6c).
Yield 69%, isolated as white powder, mp 198-200 °C (EtOH). 1H
NMR (400 MHz, DMSO-d6): 1.81 (s, 3H, CH3), 3.08 (t, 1Н, J = 10.4
Hz, 6-H), 3.75 (s, 3H, ОСН3), 3.77 (s, 3Н, ОСН3), 4.13 (d, 1Н, J =
10.4 Hz, 7-Н), 4.57 (d, 1Н, J = 10.4 Hz, 5-Н), 6.75 (d, 1H, J = 8.2
Hz, arom.), 6.92 (d, 1H, J = 8.2 Hz, arom.), 6.98 (s, 1Н, arom.), 7.03
(d, 2H, J = 7.6 Hz, arom.), 7.12 (d, 2H, J = 7.6 Hz, arom.), 11.40 (s,
1Н, NH), 12.10 (br.s, 1Н, COOH). 13C NMR (100 MHz, DMSO-d6):
21.2, 46.5, 49.6, 56.0, 58.0, 109.2, 111.9, 113.0, 121.5, 121.7, 128.8,
129.2, 130.8, 136.4, 139.6, 148.7, 148.9, 171.8, 173.0. IR (KBr):
3420-3400 (br), 3380-3320 (br), 3016-3320 (br), 2880-2860 (br),
1668, 1664, 1592, 1520, 1456, 1264, 1136, 1020, 976, 824, 700, 624,
568, 492 cm-1. LC-MS: m/z 445 (98.4%, (M+Н)+). Calcd. for
C22H21NO5S2: C, 59.58; H, 4.77; N, 3.16; Found: C, 58.60; H, 4.50;
N, 3.30%.
4.2.14.
rel-(5R,6S,7S)-5-(4-Methoxyphenyl)-7-
(2,4-dichlorophenyl)-2-oxo-3,5,6,7-tetrahydro-2Н-
thiopyrano[2,3-d] thiazole-6-carboxylic acid (6g).
Yield 70%, isolated as white powder, mp 242-244 °C (MeCN). H
1
NMR (400 MHz, DMSO-d6): 3.76 (s, 3Н, ОСН3), 3.99 (t, 1Н, J =
10.6 Hz, 6-H), 4.89 (d, 1Н, J = 10.6 Hz, 7-Н), 5.20 (d, 1Н, J = 10.6
Hz, 5-Н), 6.95 (d, 2H, J = 7.3 Hz, arom.), 7.36-7.44 (m, 3H, arom.),
7.50 (d, 2H, J = 7.2 Hz, arom.), 11.46 (s, 1Н, NH), 12.42 (br.s, 1Н,
COOH). 13C NMR (100 MHz, DMSO-d6): 41.8, 47.8, 50.1, 55.7,
104.7, 114.6, 121.4, 128.7, 129.4, 130.2, 131.1, 131.2, 134.6, 135.5,
135.9, 159.9, 170.7, 172.1. IR (KBr): 3420-3400 (br), 3080-3040
(br), 3008, 2856, 1680, 1652, 1608, 1584, 1508, 1460, 1424, 1416,
1392, 1296, 1256, 1216, 1176, 1096, 1064, 964, 928, 900, 824, 772,
656, 592, 552 cm-1. LC-MS: m/z 468/470 (95.0%, (M+Н)+). Calcd.
for C20H15Cl2NO4S2: C, 51.29; H, 3.23; N, 2.99; Found: C, 51.40; H,
3.40; N, 3.00%.
4.2.11. rel-(5R,6S,7S)-5-(4-Methoxyphenyl)-7-(4-
methylphenyl)-2-oxo-3,5,6,7-tetrahydro-2Н-
thiopyrano[2,3-d] thiazole-6-carboxylic acid (6d).
Yield 62%, isolated as white powder, mp 225-227 °C (EtOH). 1H
NMR (400 MHz, DMSO-d6): 2.33 (s, 3H, CH3), 3.25 (t, 1Н, J = 10.4
Hz, 6-H), 3.77 (s, 3Н, ОСН3), 4.10 (d, 1Н, J = 10.4 Hz, 7-Н), 4.61
(d, 1Н, J = 10.4 Hz, 5-Н), 6.84 (d, 2H, J = 8.4 Hz, arom.), 7.33 (d,
2H, J = 8.4 Hz, arom.), 7.08-7.14 (m, 4Н, arom.), 11.12 (s, 1Н, NH),
11.96 (br.s, 1Н, COOH). 13C NMR (100 MHz, DMSO-d6): 21.2,
45.9, 47.9, 55.6, 56.0, 108.3, 114.4, 120.6, 128.7, 128.8, 129.7,
130.5, 137.5, 137.8, 159.8, 171.2, 172.5. IR (KBr): 3384-3360 (br),
3168-3136 (br), 3080-3040 (br), 3000-2952 (br), 2860-2816 (br),
1700, 1668, 1636, 1552, 1524, 1480, 1472, 1396, 1324, 1256, 1176,
1032, 824, 688, 544, 508 cm-1 LC-MS: m/z 414 (100.0%, (M+Н)+).
4.2.15.
rel-(5S,5aR,11bS)-5-(3,4-
Dimethoxyphenyl)-3,5a,6,11b-tetrahydro-2Н,5H-
chromeno[4',3':4,5] thiopyrano[2,3-d]thiazole-2,6-
dione (7a). Yield 83%, isolated as white powder, mp 232-234 °C
1
(MeCN). H NMR (400 MHz, DMSO-d6): 3.74 (s, 3Н, ОСН3), 3.77
(s, 3Н, ОСН3), 3.81 (d, 1Н, J = 5.2 Hz, 11b-Н), 4.03 (t, 1Н, J = 4.0
Hz, 5a-H), 5.06 (d, 1Н, J = 4.0 Hz, 5-Н), 6.95 (d, 1H, J = 8.4 Hz,
arom.), 7.00 (d, 1H, J = 8.4 Hz, arom.), 7.06 (s, 1Н, arom.), 7.16 (d,
1H, J = 8.4 Hz, arom.), 7.20 (t, 1H, J = 7.4 Hz, arom.), 7.38-7.44 (m,
2H, arom.), 11.62 (s, 1Н, NH). 13C NMR (100 MHz, DMSO-d6):
31.4, 42.6, 44.8, 55.8, 55.9, 102.3, 113.5, 114.6, 117.2, 123.6, 123.8,
124.4, 125.5, 129.0, 129.46, 132.5, 148.6, 149.0, 150.3, 166.7, 171.2.
IR (KBr): 3452-3440 (br), 3280-3252 (br), 3112, 3056, 3000, 2976,

ACCEPTED MANUSCRIPT
8
Tetrahedron
2928, 2864, 1764, 1752, 1704, 1688, 1636, 1592, 1576, 1552,
for C19H12BrNO3S2: C, 51.13; H, 2.71; N, 3.14; Found: C, 51.20; H,
1512, 1504, 1456, 1416, 1264, 1140, 1024, 884, 852, 760, 664, 560
cm-1. LC-MS: m/z 428 (98.6%, (M+Н)+). Calcd. for C21H17NO5S2:
C, 59.00; H, 4.01; N, 3.28; Found: C, 58.90; H, 4.10; N, 3.40%.
2.70; N, 3.10%.
4.2.20.
rel-(5S,5aR,11bS)-5-Phenyl-10-nitro-
3,5a,6,11b-tetrahydro-2Н,5H-chromeno[4',3':4,5]-
thiopyrano[2,3-d] thiazole-2,6-dione (7f). Yield 80%,
isolated as white powder, mp 225-227 °C (EtOH). 1H NMR (400
MHz, DMSO-d6): 3.84 (t, 1Н, J = 4.0 Hz, 5a-H), 3.89 (d, 1Н, J = 4.0
Hz, 11b-Н), 5.07 (d, 1Н, J = 4.0 Hz, 5-Н), 7.20-7.45 (m, 6H, arom.),
8.27 (d, 1H, J = 8.4 Hz, arom.), 8.48 (s, 1Н, arom.), 11.75 (s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): 30.9, 42.9, 43.1, 101.2,
118.7, 121.6, 125.0, 125.7, 126.0, 128.4, 128.6, 129.3, 139.2, 144.3,
154.9, 165.5, 170.6. IR (KBr): 3400, 3300, 3052, 2856, 1776, 1676,
1632, 1588, 1504, 1488, 1460, 1432, 1348, 1312, 1248, 1120, 984,
964, 924, 832, 744, 696, 544 cm-1. LC-MS: m/z 413 (95.9%,
(M+Н)+). Calcd. for C19H12N2O5S2: C, 55.33; H, 2.93; N, 6.79;
Found: C, 55.20; H, 2.80; N, 6.90%.
4.2.16. rel-(5S,5aR,11bS)-5-(4-Methoxyphenyl)-
3,5a,6,11b-tetrahydro-2Н,5H-chromeno[4',3':4,5]-
thiopyrano[2,3-d] thiazole-2,6-dione (7b). Yield 84%,
isolated as white powder, mp 236-238 °C (MeCN). 1H NMR (400
MHz, DMSO-d6): 3.68 (t, 1Н, J = 4.6 Hz, 5a-H), 3.78 (m, 4Н, 11b-
Н, ОСН3), 4.94 (br.s, 1Н, 5-Н), 6.88 (d, 2H, J = 8.2 Hz, arom.), 7.06
(d, 1H, J = 8.0 Hz, arom.), 7.14 (t, 1H, J = 7.4 Hz, arom.), 7.06 (d,
1H, J = 8.0 Hz, arom.), 7.26 (t, 1H, J = 7.4 Hz, arom.), 7.30-7.38 (m,
4H, arom.), 11.43 (s, 1Н, NH). 13C NMR (100 MHz, DMSO-d6):
31.2, 42.6, 43.8, 55.7, 102.2, 114.6, 117.2, 120.9, 124.1, 125.4,
129.0, 129.5, 130.2, 131.4, 150.3, 159.4, 166.5, 170.8. IR (KBr):
3504, 3352, 3272, 3120, 3064, 2992, 2968, 2848, 1752, 1684, 1600,
1576, 1512, 1256, 1176, 1160, 1124, 1088, 1040, 928, 824, 768, 672,
648, 624, 596, 560, 488 cm-1. LC-MS: m/z 398 (100.0%, (M+Н)+).
Calcd. for C20H15NO4S2: C, 60.44; H, 3.80; N, 3.52; Found: C,
60.20; H, 4.00; N, 3.60%.
4.2.21.
rel-(5S,5aR,11bS)-5-(2-Chlorophenyl)-
8,10-dibromo-3,5a,6,11b-tetrahydro-2Н,5H-
chromeno[4',3':4,5] thiopyrano[2,3-d]thiazole-2,6-
dione (7g). Yield 71%, isolated as white powder, mp 235-227 °C
(EtOH). 1H NMR (400 MHz, DMSO-d6): 3.70 (t, 1Н, J = 3.8 Hz, 5a-
H), 3.90 (d, 1Н, J = 3.8 Hz, 11b-Н), 5.40 (d, 1Н, J = 3.8 Hz, 5-Н),
7.36 (t, 1H, J = 8.0 Hz, arom.), 7.40-7.44 (m, 2H, arom.), 7.49 (d,
1H, J = 8.0 Hz, arom.), 7.58 (d, 1H, J = 8.0 Hz, arom.), 7.72 (d, 1H,
J = 8.0 Hz, arom.), 11.50 (s, 1H, NH). 13C NMR (100 MHz, DMSO-
d6): 30.8, 43.1, 43.2, 101.8, 116.8, 119.5, 121.0, 126.5, 127.0, 127.7,
128.2, 128.5, 129.1, 131.7, 132.9, 138.7, 145.7, 165.9, 170.5. IR
(KBr): 3400, 3300, 3200-3184 (br), 3050-3000 (br), 2848, 1704,
1688, 1592, 1576, 1488, 1360, 1248, 1224, 1084, 1008, 952, 768,
720, 632, 560, 528, 504 cm-1. LC-MS: m/z 558/560 (98.0%,
(M+Н)+). Calcd. for C19H10Br2ClNO3S2: C, 40.78; H, 1.80; N, 2.50;
Found: C, 40.60; H, 2.00; N, 2.60%.
4.2.17. rel-(5S,5aR,11bS)-5-(4-Methoxyphenyl)-
10-nitro-3,5a,6,11b-tetrahydro-2Н,5H-chromeno-
[4',3':4,5]thiopyrano[2,3-d]thiazole-2,6-dione (7c).
Yield 54%, isolated as white powder, mp 238-240 °C (EtOH). 1H
NMR (400 MHz, DMSO-d6): 3.79 (s, 3Н, ОСН3), 3.85 (t, 1Н, J =
4.8 Hz, 5a-H), 4.08 (d, 1Н, J = 4.8 Hz, 11b-Н), 4.96 (d, 1Н, J = 3.9
Hz, 5-Н), 6.90 (d, 2H, J = 8.1 Hz, arom.), 7.31 (d, 2H, J = 8.1 Hz,
arom.), 7.32 (d, 1H, J = 8.1 Hz, arom.), 8.24 (d, 1H, J = 8.1 Hz,
arom.), 8.29 (s, 1H, arom.), 11.53 (s, 1Н, NH). 13C NMR (100 MHz,
DMSO-d6): 31.1, 42.4, 43.4, 55.7, 100.9, 114.6, 118.7, 121.7, 125.0,
125.9, 129.6, 130.8, 130.8, 144.3, 154.9, 159.5, 165.5, 170.6. IR
(KBr): 3424, 3232, 3200-3192 (br), 3152, 3104, 3048, 3000-2976
(br), 2920, 2816, 2752-2744 (br), 2712, 1772, 1752, 1728, 1676,
1588, 1542, 1512, 1460, 1344, 1248, 1136, 1088, 1032, 1004, 988,
824, 744, 680, 584, 568, 500, 488 cm-1. LC-MS: m/z 444 (94.9%,
(M+Н)+). Calcd. for C20H14N2O6S2: C, 54.29; H, 3.19; N, 6.33;
Found: C, 54.20; H, 3.00; N, 6.50%.
4.2.22. 7-(4-Methoxyphenyl)-2-oxo-3,7-dihydro-
2Н-thiopyrano[2,3-d] thiazole-6-carboxylic
acid
(8a). Yield 61%, isolated as pale yellow powder, mp 221-223 °C
(AcOH). 1H NMR (400 MHz, DMSO-d6): 3.70 (s, 3H, СН3), 4.93 (s,
1Н, 7-Н), 6.85 (d, 2Н, J = 8.6 Hz, arom.), 7.13 (d, 2Н, J = 8.6 Hz,
arom.), 7.77 (s, 1H, 5-H), 11.65 (br.s, 1Н, NH). 13C NMR (100 MHz,
DMSO-d6): 39.6, 55.6, 109.4, 114.5, 115.0, 125.1, 128.9, 129.0,
136.0, 158.9, 165.5, 171.2. IR (KBr): 3184, 3144, 3064-2968 (br),
2928, 2848, 1680, 1616, 1608, 1584, 1508, 1416, 1256, 1176, 1032,
840, 792, 696, 608, 576, 544, 512 cm-1. LC-MS: m/z 322 (100.0%,
(M+Н)+). Calcd. for C14H11NO4S2: C, 52.32; H, 3.45; N, 4.36;
Found: C, 52.20; H, 3.50; N, 4.30%.
4.2.18.
rel-(5S,5aR,11bS)-5-Phenyl-3,5a,6,11b-
tetrahydro-2Н,5H-chromeno[4',3':4,5] thiopyrano-
[2,3-d] thiazole-2,6-dione (7d). Yield 63%, isolated as
white powder, mp 221-222 °C (EtOH). 1H NMR (400 MHz, DMSO-
d6): 3.74 (t, 1Н, J = 3.8 Hz, 5a-H), 3.89 (d, 1Н, J = 3.8 Hz, 11b-Н),
5.09 (d, 1Н, J = 3.8 Hz, 5-Н), 7.11 (d, 1H, J = 8.2 Hz, arom.), 7.16
(t, 2H, J = 8.2 Hz, arom.), 7.30 (d, 2H, J = 8.2 Hz, arom.), 7.31-7.44
(m, 4Н, arom.), 11.54 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):
30.9, 43.1, 43.2, 101.5, 116.8, 119.6, 121.2, 126.8, 128.5, 129.0,
131.3, 132.8, 139.5, 150.3, 159.3, 165.5, 170.7. LC-MS: m/z 368
(96.0%, (M+Н)+). Calcd. for C19H13NO3S2: C, 62.11; H, 3.57; N,
3.81; Found: C, 62.20; H, 3.70; N, 3.70%.
4.2.23. 7-(4-Methoxycarbonylphenyl)-2-oxo-3,7-
dihydro-2Н-thiopyrano[2,3-d] thiazole-6-carboxylic
acid (8b). Yield 54%, isolated as white powder, mp 222-224 °C
(MeOH). 1H NMR (400 MHz, DMSO-d6): 3.81 (s, 3Н, СН3), 5.11 (s,
1H, 7-Н), 7.38 (d, 2Н, J = 8.0 Hz, arom.), 7.88 (s, 1H, 5-H), 7.90 (d,
2Н, J = 8.0 Hz, arom.), 11.76 (br.s, 1Н, NH). 13C NMR (100 MHz,
DMSO-d6): 39.7, 55.6, 109.4, 114.5, 115.0, 125.1, 128.9, 129.0,
136.0, 158.9, 165.5, 171.2. LC-MS: m/z 350 (96.0%, (M+Н)+).
Calcd. for C15H11NO5S2: C, 51.57; H, 3.17; N, 4.01; Found: C,
51.40; H, 3.20; N, 4.10%.
4.2.19.
rel-(5S,5aR,11bS)-5-Phenyl-10-bromo-
3,5a,6,11b-tetrahydro-2Н,5H-
chromeno[4',3':4,5]thiopyrano[2,3-d]thiazole-2,6-
dione (7e). Yield 68%, isolated as white powder, mp 221-223 °C
(EtOH). 1H NMR (400 MHz, DMSO-d6): 3.84 (t, 1Н, J = 4.0 Hz, 5a-
H), 3.89 (d, 1Н, J = 4.0 Hz, 11b-Н), 5.07 (d, 1Н, J = 4.0 Hz, 5-Н),
7.09 (d, 1H, J = 8.6 Hz, arom.), 7.30-7.45 (m, 5H, arom.), 7.51 (d,
1H, J = 8.0 Hz, arom.), 7.55 (s, 1H, arom.), 11.75 (s, 1H, NH). 13C
NMR (100 MHz, DMSO-d6): 30.9, 43.1, 43.2, 101.64, 116.9, 119.5,
121.2, 126.6, 128.3, 128.5, 129.3, 131.6, 132.9, 139.5, 149.7, 166.1,
170.6. IR (KBr): 3400-3380 (br), 3300-3280 (br), 3024, 2960, 2896-
2880 (br), 2848, 1768, 1720, 1712, 1680, 1632, 1588, 1568, 1536,
1520, 1496, 1464, 1424, 1388, 1344, 1268, 1192, 948, 912, 888, 856,
816, 736, 492 cm-1. LC-MS: m/z 446/448 (98.0%, (M+Н)+). Calcd.
4.2.24. 7-(3-Phenoxyphenyl)-2-oxo-3,7-dihydro-
2Н-thiopyrano[2,3-d] thiazole-6-carboxylic
acid
(8c). Yield 55%, isolated as white powder, mp 216-218 °C
(MeCN). 1H NMR (400 MHz, DMSO-d6): 5.01 (s, 1H, 7-Н), 6.81 (d,
1Н, J = 7.9 Hz, arom.), 6.90 (s, 1Н, arom.), 6.96-7.00 (m, 3Н,
arom.), 7.14 (t, 1Н, J = 7.9 Hz, arom.), 7.31 (t, 1Н, J = 7.9 Hz,
arom.), 7.38 (t, 2Н, J = 7.9 Hz, arom.), 7.82 (s, 1H, 5-H), 11.72 (br.s,
1Н, NH). 13C NMR (100 MHz, DMSO-d6): 40.3, 108.7, 115.5,
117.4, 117.9, 119.2, 122.6, 124.1, 124.5, 130.0, 130.5, 130.8, 145.9,

ACCEPTED MANUSCRIPT
9
156.7, 157.3, 165.4, 171.1. IR (KBr): 3400, 3300, 2950, 2856, 1680,
1636, 1584, 1552, 1536, 1488, 1400, 1328, 1256, 1216, 1088, 964,
872, 808, 752, 672, 664, 560, 520, 488 cm-1. LC-MS: m/z 384
(95.5%, (M+Н)+). Calcd. for C19H13NO4S2: C, 59.52; H, 3.42; N,
3.65; Found: C, 59.40; H, 3.30; N, 3.70%.
Hz, arom.), 7.02 (t, 1Н, J = 7.5 Hz, arom.), 7.93 (s, 1H, 5-H), 9.77
(s, 1Н, ОН), 11.51 (br.s, 1Н, NH). 13C NMR (100 MHz, DMSO-d6):
33.6, 109.0, 114.3, 115.7, 119.9, 124.2, 127.8, 128.4, 130.1, 130.8,
154.0, 165.5, 171.5. IR (KBr): 3400-3360 (br), 3200-3150 (br),
3050-3000 (br), 2900-2800 (br), 1728, 1680, 1628, 1504, 1460,
1368, 1272, 1224, 1176, 872, 832, 800, 752, 712, 636, 600, 584, 560,
544, 520 cm-1. LC-MS: m/z 308 (98.0%, (M+Н)+). Calcd. for
C13H9NO4S2: C, 50.80; H, 2.95; N, 4.56; Found: C, 51.00; H, 3.00;
N, 4.40%.
4.2.25. 7-(4-tert-Butylphenyl)-2-oxo-3,7-dihydro-
2Н-thiopyrano[2,3-d]thiazole-6-carboxylic
acid
(8d). Yield 62%, isolated as white powder, mp 310-312 °C (EtOH).
1H NMR (400 MHz, DMSO-d6): 1.23 (s, 9Н, С(СН3)3), 4.95 (s, 1H,
7-Н), 7.13 (d, 2Н, J = 8.0 Hz, arom.), 7.32 (d, 2Н, J = 8.0 Hz,
arom.), 7.81 (s, 1H, 5-H), 11.69 (s, 1Н, NH). 13C NMR (100 MHz,
DMSO-d6): 31.6, 34.7, 39.6, 109.1, 115.2, 124.9, 126.0, 127.3,
129.5, 140.7, 150.0, 165.5, 171.1. IR (KBr): 3280, 3200-3180 (br),
3150, 2856, 2824, 1660, 1580, 1524, 1504, 1472, 1448, 1420, 1360,
1280, 1252, 1128, 1064, 988, 828, 688, 592, 516, 488 cm-1. LC-MS:
m/z 349 (95.8%, (M+Н)+). Calcd. for C17H17NO3S2: C, 58.77; H,
4.93; N, 4.03; Found: C, 58.90; H, 4.70; N, 3.90%.
4.2.30. 7-(2-Hydroxy-3,5-dibromophenyl)-2-oxo-
3,7-dihydro-2Н-thiopyrano[2,3-d] thiazole-6-
carboxylic acid (8i). Yield 60%, isolated as white powder, mp
306-308 °C (EtOH). 1H NMR (400 MHz, DMSO-d6): 5.40 (s, 1H, 7-
Н), 7.04 (s, 1Н, arom.), 7.60 (s, 1Н, arom.), 7.99 (s, 1H, 5-H), 10.20
(s, 1Н, ОН), 11.70 (br.s, 1Н, NH). 13C NMR (100 MHz, DMSO-d6):
33.8, 109.1, 115.3, 116.7, 124.3, 127.6, 129.3, 130.8, 132.5, 134.3,
154.1, 165.3, 171.3. IR (KBr): 3400-3300 (br), 3168, 3144, 3120,
3056, 2856, 1684, 1600, 1584, 1520, 1504, 1416, 1360, 1260, 1224,
1088, 1016, 932, 900, 836, 752, 728, 576, 536 cm-1. LC-MS: m/z
466/468 (97.4%, (M+Н)+). Calcd. for C13H7Br2NO4S2: C, 33.57; H,
1.52; N, 3.01; Found: C, 33.70; H, 1.80; N, 3.10%.
4.2.26.
7-(4-Trifluoromethylphenyl)-2-oxo-3,7-
dihydro-2Н-thiopyrano[2,3-d] thiazole-6-carboxylic
acid (8e). Yield 55%, isolated as white powder, mp 236-238 °C
(MeCN). 1H NMR (400 MHz, DMSO-d6): 5.16 (s, 1H, 7-Н), 7.47 (d,
2Н, J = 8.0 Hz, arom.), 7.70 (d, 2Н, J = 8.0 Hz, arom.), 7.91 (s, 1H,
5-H), 11.77 (s, 1Н, NH). 13C NMR (100 MHz, DMSO-d6): 40.3,
108.1, 115.9, 124.1, 126.2 (d, J = 242.0 Hz), 127.7 (d, J = 3.6 Hz),
128.6, 130.7, 148.3, 165.2, 171.0. IR (KBr): 3380, 3200, 3056, 3000,
2920, 2856, 1728, 1680, 1632, 1584, 1568, 1552, 1520, 1504, 1416,
1368, 1336, 1280, 1108, 1088, 964 cm-1. LC-MS: m/z 361 (96.2%,
(M+Н)+). Calcd. for C14H8F3NO3S2: C, 46.79; H, 2.24; N, 3.90;
Found: C, 46.90; H, 2.30; N, 3.70%.
4.2.31.
Ethyl
7-(2-hydroxyphenyl)-2-oxo-3,7-
dihydro-2Н-thiopyrano[2,3-d] thiazole-6-
carboxylate (8j). Yield 54%, isolated as white powder, mp 256-
258 °C (MeCN). H NMR (400 MHz, DMSO-d6): 1.09 (t, 3Н, J =
1
7.1 Hz, СН3СН2), 4.03 (qu, 2Н, J = 7.1 Hz, СН3СН2), 5.36 (s, 1H, 7-
Н), 6.74 (t, 1Н, J = 7.5 Hz, arom.), 6.81 (d, 1H, J = 7.5 Hz, arom.),
6.98 (d, 1H, J = 7.5 Hz, arom.), 7.04 (t, 1Н, J = 7.5 Hz, arom.), 7.96
(s, 1H, 5-H), 7.98 (s, 1Н, ОН), 11.56 (br.s, 1Н, NH). 13C NMR (100
MHz, DMSO-d6): 14.3, 33.6, 61.0, 108.9, 114.2, 115.6, 119.9, 123.4,
127.9, 128.5, 130.0, 131.4, 154.1, 164.0, 171.4. LC-MS: m/z 336
(96.0%, (M+Н)+). Calcd. for C15H13NO4S2: C, 53.72; H, 3.91; N,
4.18; Found: C, 53.50; H, 4.00; N, 4.10%.
4.2.27.
Ethyl
7-(4-methoxyphenyl)-2-oxo-3,7-
dihydro-2Н-thiopyrano[2,3-d] thiazole-6-
carboxylate (8f). Yield 57%, isolated as white powder, mp 178-
1
180 °C (MeCN). H NMR (400 MHz, DMSO-d6): 1.14 (t, 3Н, J =
6.8 Hz, СН3СН2), 3.72 (s, 3Н, ОСН3), 4.04 (qu, 2Н, J = 6.8 Hz,
СН3СН2), 4.98 (s, 1H, 7-Н), 6.88 (d, 2H, J = 8.6 Hz, arom.), 7.16 (d,
2Н, J = 8.6 Hz, arom.), 7.84 (s, 1H, 5-H), 11.71 (br.s, 1Н, NH). 13C
NMR (100 MHz, DMSO-d6): 14.4, 39.7, 55.5, 61.2, 109.4, 114.5,
114.9, 124.2, 128.9, 129.9, 135.9, 158.9, 164.0, 171.1. IR (KBr):
3400, 3296, 3088, 3024, 2952, 2856, 1696, 1676, 1584, 1512, 1472,
1368, 1344, 1304, 1256, 1232, 1176, 1068, 1032, 896, 864, 840, 808,
728, 680, 616, 572, 512, 488 cm-1. LC-MS: m/z 350 (96.0%,
(M+Н)+). Calcd. for C16H15NO4S2: C, 55.00; H, 4.33; N, 4.01;
Found: C, 55.20; H, 4.20; N, 3.90%.
4.2.32.
rel-(5aR,11bS)-3,5a,6,11b-Tetrahydro-
2Н,5H-chromeno[4’,3’:4,5] thiopyrano[2,3-
d]thiazole-2,6-dione (10). Yields 75%, isolated as white
powder, mp 264-266 °C (AcOH), lit. 265 °C.5a 1H NMR (400 MHz,
DMSO-d6): 3.44 (d, 2Н, J = 3.5 Hz, 5-H), 3.77 (m, 1Н, 5a-Н), 4.31
(d, 1Н, J = 6.0 Hz, 11b-H), 7.05 (d , 1H, J = 7.9 Hz, arom.), 7.18 (t,
1H, J = 7.9 Hz, arom.), 7.30-7.35 (m, 2H, arom.), 11.22 (s, 1Н, NH).
13C NMR (100 MHz, DMSO-d6): 26.6, 36.4, 42.2, 102.0, 117.3,
121.0, 124.8, 126.2, 129.4, 130.4, 150.6, 167.3, 170.9. LC-MS: m/z
292 (98.0%, (M+Н)+). Calcd. for C13H9NO3S2: C, 53.59; H, 3.11; N,
4.81; Found: C, 53.30; H, 3.20; N, 4.70%.
4.2.28.
Ethyl
7-(4-methoxycarbonylphenyl)-2-
oxo-3,7-dihydro-2Н-thiopyrano[2,3-d] thiazole-6-
carboxylate (8g). Yield 68%, isolated as white powder, mp
204-206 °C (PhH). 1H NMR (400 MHz, DMSO-d6): 1.11 (t, 3Н, J =
6.8 Hz, СН3СН2), 3.84 (s, 3Н, СООСН3), 4.05 (qu, J = 6.8 Hz, 2Н,
СН3СН2), 5.17 (s, 1H, 7-Н), 7.41 (d, 2H, J = 7.6 Hz, arom.), 7.92 (s,
4.2.33.
2H,6H-
Chromeno[4',3':4,5] thiopyrano[2,3-d]thiazole-2,6-
dione (9). To the solution of 10 mmol of 8j or 105a in 10 mL of
glacial acetic acid 20 mmol of bromine in 10 mL of glacial acetic
acid was added dropwise over 20 min. The obtained mixture was
refluxed for 2 h till the decolorization. The precipitated crystals were
filtered off, washed with ethanol, and recrystallized from DMF.
Yields 94% (method A), 58% (method B), isolated as yellow
powder, mp 330-332 °C (DMF). 1H NMR (400 MHz, DMSO-d6):
7.43 (d, 1H, J = 7.4 Hz, arom.), 7.55 (t, 1H, J = 7.4 Hz, arom.), 7.75
(t, 1H, J = 7.4 Hz, arom.), 8.36 (d, 1H, J = 7.4 Hz, arom.), 9.56 (s,
1H, 5-H). 13C NMR (100 MHz, DMSO-d6): 115.2, 118.8, 119.8,
126.2, 127.1, 128.4, 134.8, 135.1, 143.2, 153.0, 157.5, 176.8, 177.5.
IR (KBr): 3400, 3300, 3200, 3064, 3008, 1744, 1676, 1564, 1416,
1408, 1352, 1268, 1244, 1208, 1096, 976, 920, 844, 768, 744, 720,
688, 656, 624, 564, 528 cm-1. LC-MS: m/z 288 (96.6%, (M+Н)+).
Calcd. for C13H5NO3S2: C, 54.35; H, 1.75; N, 4.87; Found: C, 54.50;
H, 1.90; N, 4.70%.
1H, 5-H), 7.95 (d, 2Н, J = 7.6 Hz, arom.), 11.79 (br.s, 1Н, NH). 13
C
NMR (100 MHz, DMSO-d6): 14.4, 40.3, 52.6, 61.3, 108.2, 115.5,
123.3, 128.2, 129.2, 130.2, 131.3, 148.8, 163.7, 166.4, 171.0. IR
(KBr): 3544, 3520, 3456, 3248, 3208, 3136, 3064, 2984, 2952, 2864,
2800, 1720, 1656, 1616, 1584, 1568, 1540, 1500, 1416, 1392, 1368,
1336, 1292, 1256, 1232, 1116, 1016, 944, 900, 808, 744, 720, 592,
560 cm-1. LC-MS: m/z 378 (96.0%, (M+Н)+). Calcd. for
C17H15NO5S2: C, 54.10; H, 4.01; N, 3.71; Found: C, 54.20; H, 4.20;
N, 3.60%.
4.2.29. 7-(2-Hydroxyphenyl)-2-oxo-3,7-dihydro-
2Н-thiopyrano[2,3-d]thiazole-6-carboxylic
acid
(8h). Yield 58%, isolated as white powder, mp 250-252 °C (EtOH).
1H NMR (400 MHz, DMSO-d6): 5.31 (s, 1H, 7-Н), 6.73 (t, 1Н, J =
7.5 Hz, arom.), 6.78 (d, 1H, J = 7.5 Hz, arom.), 6.96 (d, 1H, J = 7.5

ACCEPTED MANUSCRIPT
10
Tetrahedron
5. (a) Kassab, N. A.; Abd-Allah, S. O.; Abd-El-Razik, F. M. Indian
4.3. Crystallographic data and structural refinement
J. Chem. 1976, 14B, 864; (b) Kassab, N. A.; Abd-Allah, S. O.;
Meseha, N. A. J. Prakt. Chem. 1974, 316, 209; (c) Metwally, N.
H. J. Sulf. Chem. 2007, 28, 275.
parameters for compounds 4* and 5
Intensity data for compounds 4*, 5 and 7f were collected on an
Agilent Xcalibur A diffractometer using a graphite monochromated
Mo Kα radiation source. Structures were solved by direct methods
using the program SHELXS-97,16 and refined against F2 for all data
using SHELXL-97.16 Data were treated using the CrysalisPro
program,17 and permitted to improve the final results. All non-
hydrogen atoms were refined anisotropically. Except for the
hydroxyl or amine H atoms which were refined freely the remaining
H atoms were positioned geometrically and were refined within the
riding model approximation, and Uiso(H) values were constrained to
be 1.2 (1.5 for methyl group) times Ueq of the appropriate carrier
atom. The methyl H atoms were refined as a rigid group which was
allowed to rotate. Crystals of 4* were non-merohedral twinned,
hence the lower accuracy of the final results.
6. Kowiel, M; Zelisko, N; Atamanyuk, D; Lesyk, R; Gzella, A. K.
Acta Cryst. 2012, E68, o2721.
7. Matiychuk, V. S.; Lesyk, R. B.; Obushak, M. D.; Gzella, A.;
Atamanyuk, D. V.; Ostapiuk, Yu. V.; Kryshchyshyn, A. P.
Tetrahedron Lett. 2008, 49, 275.
8. (a) Komaritsa, I. D.; Baranov, S. N.; Grishchuk, A. P. Khimiya
Geterotsiklicheskikh Soedinenii 1967, 4, 664; (b) Chem. Abstr.
1968, 68, 49495; (c) Grishchuk, A. P.; Komaritsa, I. D.; Baranov,
C. N. U.S.S.R. Patent SU 197594, 1967 (in Russian); (d) Chem.
Abstr. 1968, 68, 36112.
9. Tietze L. F.; Fennen J.; Geißler H.; Schulz G.; Anders E. Eur. J.
Org. Chem. 1995, 9, 1681.
10. Miyata O.; Ninomiya I.; Naito T.; Date T.; Okamura K.; Inagaki
S. J. Org. Chem. 1991, 56, 6556.
11. (a) Crane S. N.; Black W. C.; Palmer J. T.; Davis D. E.; Setti E.;
Robichaud J.; Paquet J.; Oballa R. M.; Bayly C. I.; McKay D. J.;
Somoza J. R.; Chauret N.; Seto C.; Scheigetz J.; Wesolowski G.;
Massé F.; Desmarais S.; Ouellet M. J. Med. Chem. 2006, 49,
1066; (b) Coppola G. M.; Damon R. E.; Shapiro M. J.; Gunderson
K. G.; Kolpak, M. X. Organic Preparations and Procedures
International 2000, 32, 75; (c) Saito, A.; Yanai, H.; Taguchi, T.
Tetrahedron 2004, 60, 12239; (d) Saito, A.; Ito, H.; Taguchi, T.
Org. Lett. 2002, 4, 4619; (e) Areces P.; Jimenez J. L.; Pozo M. C.;
Roman E.; Serrano J. A. Journal of the Chemical Society, Perkin
Translations 1 2011, 7, 754.
CCDC-906401 (4*), 906402 (5) and 941501 (7f) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk.
References and notes
12. Ishida, M.; Inagaki S. In Topics in Current Chemistry; Inagaki,
1. For reviews on the biological activity of 4-thiazolidinones see: (a)
Lesyk, R. B.; Zimenkovsky, B. S. Curr. Org. Chem. 2004, 8,
1547; (b) Verma, A.; Saraf, S. K. Eur. J. Med. Chem. 2008, 43,
897; (c) Tomasic, T.; Masic, L.P. Curr. Med. Chem. 2009, 16,
1596; (d) Lesyk, R. B.; Zimenkovsky, B. S.; Kaminskyy, D. V.;
Kryshchyshyn, A. P.; Havrylyuk, D. Ya.; Atamanyuk, D. V.;
Subtel’na, I. Yu.; Khyluk, D. V. Biopolym. Cell 2011, 27, 107.
2. For the recent advances in the medicinal chemistry of 5-arylidene-
4-thiazolidinones see: (a) Ottanà, R.; Maccari, R.; Barreca, M. L.;
Bruno, G.; Rotondo, A.; Rossi, A.; Chiricosta, G.; Di Paola R.;
Sautebin, L.; Cuzzocrea, S.; Vigorita M. G. Bioorg. Med. Chem.
2005, 13, 4243; (b) Havrylyuk, D.; Mosula, L.; Zimenkovsky, B.;
Vasylenko, O.; Gzella, A.; Lesyk R. Eur. J. Med. Chem. 2010, 45,
4243; (c) Sim, M. M.; Ng, S. B.; Buss, A. D.; Crasta, S. C.; Goh,
K. L.; Lee, S. K. Bioorg. Med. Chem. Lett. 2002, 12, 697; (d)
Cutshall, N. S.; O’Day, C.; Prezhdo, M. Bioorg. Med. Chem. Lett.
2005, 15, 3374; (e) Xia, Z.; Knaak, C.; Ma, J.; Beharry, Z. M.;
McInnes, C.; Wang, W.; Kraft, A. S.; Smith, C. D. J. Med. Chem.
2009, 52, 74; Vicini, P.; Geronikaki, A.; Incerti, M.; Zani, F.;
Dearden, J.; Hewitt, M. Bioorg. Med. Chem. 2008, 16, 3714; (f)
Kaminskyy, D.; Khyluk, D.; Vasylenko, O.; Zaprutko, L.; Lesyk,
R. Sci. Pharm. 2011, 79, 763; (g) Kaminskyy, D.; Zimenkovsky,
B.; Lesyk, R. Eur. J. Med. Chem. 2009, 44, 3627; (h) Havrylyuk,
D.; Kovach, N., Zimenkovsky, B.; Vasylenko, O., Lesyk, R. Arch.
Pharm. Chem. Life Sci. 2011, 344, 514; (i) Havrylyuk, D.;
Zimenkovsky, B.; Vasylenko, O.; Zaprutko, L.; Gzella, A.; Lesyk,
R. Eur. J. Med. Chem. 2009, 44, 1396; (j) Subtelna I., Atamanyuk
D., Szymańska E., Kieć-Kononowicz K., Zimenkovsky B.,
Vasylenko O., Gzella A., Lesyk R. Bioorg. Med. Chem. 2010, 18,
5089; (k) Havrylyuk, D.; Zimenkovsky, B.; Vasylenko, O.;
Gzella, A.; Lesyk, R. J. Med. Chem. 2012, 55, 8630.
S., Ed.; Springer, 2010; Vol.289, pp 183-218.
13. Minch M. J. Concepts in Magnetic Resonance 1994, 6, 41.
14. (a) Huang, Y; Rawal, V. H. J. Am. Chem. Soc. 2002, 124, 9662;
(b) Pégot, B.; Nguyen Van Buu, O.; Gori, D.; Vo-Thanh, G.
Beilstein Journal of Organic Chemistry 2006, 2(18),
doi:10.1186/1860-5397-2-18. (c) Kelly, T. R.; Meghani, P.;
Ekkundi, V. S. Tetrahedron Lett. 1990, 31, 3381. (d) Hine, J.;
Ahn, K.; Galluci, J. C.; Linden, S.-M. J. Am. Chem.
Soc. 1984, 106, 7980. (e) Braddock, D. C.; MacGilp, I. D.; Perry,
B. G. Synlett 2003, 8, 1121. (f) Etter, M. C.; Urbañczyk-
Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto, T. W. J. Am. Chem.
Soc. 1990, 112, 8415.
15. (a) Turkevych, N. M.; Vvedenskij, V. M.; Petlichnaya, L. P. Ukr.
Khim. Zh. (Russ. Ed.) 1961, 27, 680; (b) Chem. Abstr. 1962, 56,
73455.
16. Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112−122.
17. CrysAlis PRO, version 1.171.35.11; Agilent Technologies Ltd.
(Oxford Diffraction): Yarnton, U.K., 2011.
3. For reviews on the 4-thiazolidinones as pan assay interference
compounds see: (a) Tomasic, T.; Masic, L.P. Expert Opin. Drug.
Discov. 2012, 7(7), 549; (b) Baell, J. B. Future Med. Chem. 2010,
2(10), 1529; (c) Baell, J. B.; Holloway, G. A. J. Med. Chem. 2010,
53, 2719; (d) Mendgen, T.; Steuer, C.; Klein, C. D. J. Med. Chem.
2012, 55, 743.
4. For the recent advances in the medicinal chemistry of
thiopyrano[2,3-d][1,3]thiazoles see: (a) Lesyk, R.; Zimenkovsky,
B.; Atamanyuk, D.; Jensen, F.; Kiec-Kononowicz, K.; Gzella, A.
Bioorg. Med. Chem. 2006, 14, 5230; (b) Atamanyuk, D.;
Zimenkovsky, B.; Lesyk, R. J. Sulf. Chem. 2008, 29, 151; (c)
Kaminskyy, D.; Vasylenko, O.; Atamanyuk, D.; Gzella, A.; Lesyk
R. Synlett 2011, 10, 1385; (d) Kryshchyshyn, A.; Atamanyuk, D.;
Lesyk, R. Sci. Pharm. 2012, 80, 509; (e) Zelisko, N.; Atamanyuk,
D.; Vasylenko, O.; Grellier, P., Lesyk, R. Bioorg. Med. Chem.
Lett. 2012, 22, 7071; (f) Atamanyuk, D.; Zimenkovsky, B.;
Atamanyuk, V.; Nektegayev, I.; Lesyk, R. Sci. Pharm. 2013, 81,
423.

ACCEPTED MANUSCRIPT
Supplementary information
Crotonic, cynnamic and propiolic acids motifs in the synthesis of
thiopyrano[2,3-d][1,3]thiazoles via hetero-Diels-Alder reaction and related
tandem processes
Nataliya Zelisko a, Dmytro Atamanyuk a,f, Olexandr Vasylenko b, Andriy
Bryhas c, Vasyl Matiychuk c, Andrzej Gzella d,e, Roman Lesyk a,*
a Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo
Halytsky Lviv National Medical University, Pekarska 69, Lviv, 79010, Ukraine
b Institute of Bioorganic Chemistry and Petrochemistry, National Academy of
Science of Ukraine, Murmanska 1, Kyiv, 02094, Ukraine
c Department of Organic Chemistry, Ivan Franko National University of Lviv,
Kyryla and Mefodiya 6, Lviv 79005, Ukraine
d Department of Organic Chemistry, Poznan University of Medical Sciences,
Grunwaldzka 6, Poznan, 60780, Poland
e Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz,
Nicolaus Copernicus University in Torun’, A. Jurasza 2, Bydgoszcz, 85089,
Poland
f Present address: Mutabilis, 102 Avenue Gaston Roussel, Romainville, 93230,
France
*corresponding author
dr_r_lesyk@org.lviv.net (Roman Lesyk)
tel. +38 0322 75-59-66
fax. +38 0322 75-77-34

ACCEPTED MANUSCRIPT
S1. Crystallographic data and structural refinement parameters for
compounds 4*, 5 and 7f
CCDC-906401, 906402 and 941501 contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk.

ACCEPTED MANUSCRIPT
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx
Summary of Data CCDC 906401 :
Authors: Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Andriy Bryhas,
Vasyl Matiychuk, Andrzej Gzella, Roman Lesyk
Journal: Tetrahedron (0016)
Compound: (5RS,5aRS,11bSR)-5-methyl-3,5a,6,11b-tetrahydro-2H,5H-
chromeno(4',3':4,5)-thiopyrano(2,3-d)thiazole-2,6-dione
Formula: C14 H13 N1 O4 S2
Unit cell parameters: a 8.0337(5), b 18.0784, c 9.5343(5), beta 91.301(5)
space group P21/c
----------------------------------------------------------------
Summary of Data CCDC 906402 :
Authors: Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Andriy Bryhas,
Vasyl Matiychuk, Andrzej Gzella, Roman Lesyk
Journal: Tetrahedron (0016)
Compound: (5R,6R,7S)-7-(1-hydroxyphenyl)-6-methoxycarbonyl-5-methyl-5H-
2,3,6,7-tetrahydrothiopyrano(2,3-d)(1,3)thiazol-2-one
Formula: C15 H15 N1 O4 S2
Unit cell parameters: a 10.1438(6), b 7.1373(3), c 11.1067(6), beta 111.573(6)
space group P21
---------------------------------------------------------------
Summary of Data CCDC 941501 :
Authors: Nataliya Zelisko, Dmytro Atamanyuk, Olexandr Vasylenko, Andriy Bryhas,
Vasyl Matiychuk, Andrzej Gzella, Roman Lesyk
Journal: Tetrahedron (0016)
Compound: (5SR,5aRS,11bSR)-5-Phenyl-10-nitro-3,5a,6,11b-tetrahydro-2Н,5H-
chromeno[4',3':4,5]thiopyrano[2,3-d]thiazole-2,6-dione
Formula: C19 H12 N2 O5 S2
Unit cell parameters: a 16.3939(18) b 6.2313(6) c 19.0560(13) beta 107.865(9)
space group P21/n
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

ACCEPTED MANUSCRIPT
4*
5
7f
Chemical formula
M (g mol–1)
C14H13NO4S2
323.37
C15H15NO4S2
337.40
C19H12N2O5S2
412.43
Crystal system
Space group
a (Å)
Monoclinic
P21/c
Monoclinic
P21
Monoclinic
P21/n
8.0337(5)
18.0784(8)
9.5343(5)
90.00
10.1438(6)
7.1373(3)
11.1067(6)
90.00
16.3939(18)
b (Å)
6.2313(6)
19.0560(13)
c (Å)
90.00
107.865(9)
90.00
α
β
γ
(°)
(°)
(°)
91.301(5)
90.00
111.573(6)
90.00
V (Å3)
1384.37(12)
4
747.79(6)
2
1852.8(3)
4
Z
calcd (g cm-3)
1.552
1.498
1.479
ρ
(mm–1)
0.400
0.373
0.322
µ
29.06
30.72
28.92
Θ
max (°)
Crystal size (mm)
(Å)
0.50 x 0.40 x 0.12
0.71073 (Mo Kα)
Ω scans
130(2)
0.40 x 0.25 x 0.04
0.71073 (Mo Kα)
Ω scans
130(2)
0.55 x 0.20 x 0.05
0.71073 (Mo Kα)
Ω scans
293(2)
λ
Scan mode
T (K)
Refl. measured
Refl. unique
Rint
10928
15334
17008
3335
4220
4429
0.0482
0.0275
0.0258
2737
4074
3284
Refl. with I >2σ(I)
Nb. parameters
210
209
257
0.0495
0.0253
0.0437
R [I > 2σ(I)]
wR (all data)
0.1238
0.0645
0.1041
S (all data)
1.121
1.032
1.013
Residual electron density (e Å-3)
-0.51/0.51
-0.19/0.27
-0.26/0.32

ACCEPTED MANUSCRIPT
The structure of 4* is constructed from the conjugated tetracyclic framework,
i.e. 3,5,5a,6,11b-tetrahydro-2H,5H-chromeno[4’,3’:4,5]thiopyrano[2,3-d]thiazol-2,6-dione, in
which the external five- and six-membered rings A and D are flat, whereas the internal B and
C rings are puckered (Fig. 2). Ring B is in a distorted half-chair conformation [Cremer &
Pople parameters: Q = 0.531(2) Å,
distorted skew-boat conformation [Cremer & Pople parameters : Q = 0.407(2) Å,
= 159.7(4)°]. Rings B and C are fused in a cis-decalin pattern and the dihedral angle
between their least squares planes is 79.67(6)°.
θ
= 133.3(2)°,
ϕ
= 99.0(3)°], whereas ring C is in a
θ
= 67.9(3)°,
ϕ
Compound 4* has three stereogenic centres, namely C6, C7, and C16 (Fig. 2).
However, the C6 hydrogen atom is in the different orientation than the hydrogens at C7 and
C16. In the enantiomer shown in Fig. 2, the former hydrogen is α oriented, while the latter
hydrogens are β oriented. The H(-C7) hydrogen atom is equatorial relative to the ring B,
whereas the H(-C6) and H(-C16) hydrogens are pseudoequatorial and pseudoaxial,
respectively, to this ring. The hydrogen atoms in the pairs H(-C6) and H(-C7) as well as H(-
C7) and H(-C16) adopt solely a synclinal conformation (-sc). The torsion angles H6–C6–C7–
H7 and H7–C7–C16–H16 are -59 and -46°, respectively. The C4–C17 bond length of
1.340(4) Å confirms the presence of a double bond between these atoms (Fig. 2).
The X-ray analysis of 5 showed that only one enantiomer formed the crystal (Fig. 2).
For the molecule 5 shown in Fig. 2, the tetrahedral C6, C7, and C8 atoms are chiral centres.
The absolute configuration of those atoms was established as 6R, 7R and 8S. In the X-Ray
structure of 5 both carbon atoms C11 of the methyl group and C16 of the phenyl ring are
synclinal (+sc) relative to the C12 carbon atom of the methoxycarbonyl group. The torsion
angles C11–C6–C7–C12 and C12–C7–C8–C16 are 55.39(14) and 57.81(13)°, respectively.
The C4=C9 and C2–N3 bond lengths in the thiazol-2-one moiety [1.3371(19) Å and
1.3572(18) Å, respectively] are similar to those for 4a. The six-membered dihydrothiopyrane
ring has an envelope conformation [Cremer & Pople parameters: Q = 0.5202(14) Å,
47.89(15)°, = 251.90(18)°].
θ =
ϕ
The flat methoxycarbonyl and phenyl groups are significantly tilted from the least-
squares plane of dihydrothiopyrane ring. The dihedral angle between the latter ring and the
methoxycarbonyl group is 64.97(7)°, and between this ring and the phenyl moiety is
89.64(4)°. The spatial relationship of the methoxycarbonyl and 2-hydroxyphenyl groups is
also determined by the torsion angles C8–C7–C12–O13 and C7–C8–C16–C17 of -89.77(15)

ACCEPTED MANUSCRIPT
and 89.99(14)° values. These values imply that the conformation of both C12=O13 carbonyl
group (methoxycarbonyl substituent) and C16–C17 (2-hydroxyphenyl substituent) relative to
the C7–C8 bond is intermediate between synclinal and anticlinal (-sc/-ac).
Analysing X-Ray structure of 7f, the resemblance concerns, inter alia, the conformation of
dihydropyran rings that are in halfchair forms, lactone rings that are in skew-boat forms, as
well as the spatial configuration of the above rings (cis) and stereogenic centres at C6, C7,
and C16 (see the comment concerning compound 4*).