Arylidene Pyruvic Acids Motif in the Synthesis of New 2H,5H-Chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazoles via Tandem Hetero-Diels-Alder-Hemiacetal Reaction

Article abstract of DOI:10.1080/00397911.2015.1076004

We have developed a tandem hetero-Diels-Alder-hemiacetal reaction using arylidene pyruvic acids with 5-(ortho-hydroxybenzylidene)-substituted 4-thioxo-2-thiazolidinones, leading to 6-hydroxy-2-oxo-5-phenyl-3,5a,6,11b-tetrahydro-2H,5H-chromeno[4′,3′:4,5]thiopyrano[2,3-d][1,3]thiazole-6-carboxylic acids. The stereochemistry of cycloaddition was confirmed by NMR spectra and a single-crystal x-ray diffraction analysis.

Full text of DOI:10.1080/00397911.2015.1076004

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Arylidene Pyruvic Acids Motif in the Synthesis of New
2H,5H-Chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazoles
via Tandem hetero-Diels–Alder-Hemiacetal Reaction
Andrii Lozynskyia, Borys Zimenkovskya, Andrzej K. Gzellab & Roman Lesyka
a Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv
National Medical University, Lviv, Ukraine
b Department of Organic Chemistry, Poznan University of Medical Sciences, Poznań, Poland
Accepted author version posted online: 03 Aug 2015.
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To cite this article: Andrii Lozynskyi, Borys Zimenkovsky, Andrzej K. Gzella & Roman Lesyk (2015): Arylidene Pyruvic
Acids Motif in the Synthesis of New 2H,5H-Chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazoles via Tandem hetero-Diels–Alder-
Hemiacetal Reaction, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
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Arylidene pyruvic acids motif in the synthesis of new 2H,5H-
chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazoles via tandem hetero-Diels–Alder-
hemiacetal reaction
Andrii Lozynskyi1, Borys Zimenkovsky1, Andrzej K. Gzella2, Roman Lesyk1
1Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky
Lviv National Medical University, Lviv, Ukraine, 2Department of Organic Chemistry,
Poznan University of Medical Sciences, Poznań, Poland
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky
Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine;
E-mails: dr_r_lesyk@org.lviv.net, roman.lesyk@gmail.com
Abstract
We have developed a tandem hetero-Diels–Alder-hemiacetal reaction using arylidene
pyruvic acids with 5-(ortho-hydroxybenzylidene)-substituted 4-thioxo-2-thiazolidinones,
leading to 6-hydroxy-2-oxo-5-phenyl-3,5a,6,11b-tetrahydro-2H,5H-
chromeno[4’,3’:4,5]thiopyrano[2,3-d][1,3]thiazole-6-carboxylic acids. The
stereochemistry of cycloaddition was confirmed by NMR spectra and a single crystal X-
ray diffraction analysis.
KEYWORDS: 5-ylidene-4-thioxo-2-thiazolidinones, thiopyrano[2,3-d][1,3]thiazoles,
hetero-Diels-Alder reaction, tandem reactions
1

INTRODUCTION
The construction of multiple carbon-carbon bonds in a single chemical step represents a
particularly efficient approach to the synthesis of complex molecular structures. In
support of this view, the hetero-Diels-Alder reaction had particularly evolved as an
efficient route to wide range of polycyclic compounds.[1-7] The thiopyrano[2,3-d]thiazoles
constructed on this principle formed a central skeleton of many compounds which are
known for their anticancer, antimicrobial, antiinflammatory, and antitrypanosomal
activity.[8-16] A particular interest in the synthesis of these heterocyclic systems includes
the study of hetero-Diels–Alder reactions and related tandem processes. Earlier we
reported the diastereoselective tandem acylation-hetero-Diels-Alder reaction of 5-
arylidene-4-thioxo-2-thiazolidinones (5-arylideneisorhodanines) with ortho-phenolic
group at arylidene moiety and α,β-unsaturated carboxylic acids derivatives providing
2H,5H-chromeno[4’,3’:4,5]thiopyrano[2,3-d]thiazoles formation.[15,17] As a consequence,
we decided to investigate the reaction between 5-(ortho-hydroxybenzylidene)-substituted
isorhodanines and arylidene pyruvic acids (APAs) as dienophiles. The classical regio-
and diastereoselective hetero-Diels–Alder reaction between 5-arylideneisorhodanines
(without ortho-phenolic group at arylidene moiety) and APAs providing novel rel-
(5R,6S,7S)-2-oxo-5,7-diaryl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl-oxo-
acetic acids has been already reported in our research before. Furthermore, previously
synthesized compounds could be employed as templates for search of biologically active
compounds.[18] Hence, the aim of the presented Letter was the synthesis of new 2H,5H-
chromeno[4’,3’:4,5]thiopyrano[2,3-d]thiazoles via a novel hetero-Diels-Alder-hemiacetal
reaction.
2

RESULTS AND DISCUSSION
Combination of highly reactive sulfur atom at the 4th position and methylidene group in
position 5 in 5-arylideneisorhodanines allows them to be used as highly active
heterodiene components in hetero-Diels-Alder reactions.[19] Thus, the starting 5-(2-
hydroxybenzylidene)-4-thioxo-2-thiazolidinones 1a-b were synthesized via Knoevenagel
condensation (ethanol medium in the presence of ethylendiaminediacetate).[18] The APAs
were synthesized by the reaction of the corresponding aromatic aldehyde with a pyruvic
acid in aqueous methanol solution.[20] The reactions between 5-(2-hydroxybenzylidene)-
4-thioxo-2-thiazolidinones 1a-b and arylidene pyruvic acids 2a-c followed by the tandem
hetero-Diels-Alder and hemiacetal formation processes, affording tetracyclic fused 6-
hydroxy-2-oxo-5-phenyl-3,5a,6,11b-tetrahydro-2H,5H-
chromeno[4’,3’:4,5]thiopyrano[2,3-d][1,3]thiazole-6-carboxylic acids 3a-d/3a-d
(Scheme 1).
Moreover, the stereochemical features of final products were predicted by the 1H NMR
spectra. In particular, we have observed that the use of APAs in the hetero-Diels-Alder
reaction with 5-(2-hydroxybenzylidene)-4-thioxo-2-thiazolidinones 1a-b proved to be
regio- and moderate stereoselective yielding the mixture of rel-(5S,5aR,11bR) and rel-
(5R,5aS,11bR)-annulated diastereisomers. This reaction leads to a 2:1 diastereomeric
ratio of cycloadducts 3a-d and 3a-d. Considering this fact, the reaction can occur through
endo or exo transition states, leading in each case to a distinct stereochemical relationship
between the protons at the C-5, C-5a, and C-11b positions of the adducts. In this case, the
addition is predominantly exo was caused by the steric properties of arylidene pyruvic
3

acids as dienophiles in the hetero-Diels-Alder reaction. This statement is based on
equatorial-pseudoaxial interactions of protons 5, 5a and 11b and established from the
coupling constants value of the endo-isomer within the range of 6.0-6.4 Hz and exo-
isomer within 4.0 Hz. In addition, the structure of adducts 3a/3a was established by X-
ray crystallography (Fig. 1).
Thus, the X-ray analysis of 3a/3a showed that two isomers of 6-hydroxy-2-oxo-5-phenyl-
3,5a,6,11b-tetrahydro-2H,5H-chromeno[4’,3’:4,5]thiopyrano[2,3-d][1,3]thiazole-6-
carboxylic acid are presented in the crystal with the site occupancy factor of 0.942 (3a)
and 0.058 (3a). In molecule 3a dihydrothiopyrane and dihydropyrane rings are cis while
in molecule 3a trans-fused. The torsion angles H7–C7–C16–H16 and H7’–C7’–C16’–
H16’ amount to 55° and -149°, respectively. Moreover, an inversion of configuration at
C6 is observed (Fig. 1).
EXPERIMENTAL
All starting materials were purchased from commercial sourses and used without
purification. Melting points are uncorrected and were measured in open capillary tubes
on a Buchi B-545 melting-point apparatus. The 1H NMR spectra were recorded on a
Varian Gemini 400-MHz instrument and 13C NMR spectra on Varian Mercury-400 100-
MHz instrument in dimethylsulfoxide (DMSO-d6) with tetramethylsilane (TMS) as an
internal standard [chemical shift values are reported in parts per million (ppm) units,
coupling constants (J) are in hertz]. The elemental analyses (C, H, N) performed on the
Perkin-Elmer 2400 CHN analyzer were within ±0.4% of the theoretical values. Mass
spectra were obtained on the Varian 1200L instrument.
4

The starting compounds: 2,4-thiazolidinedione [21], 4-thioxo-2-thiazolidinone[19] were
obtained according to methods described previously. 5-Ylidene-4-thioxo-2-
thiazolidinones (1a-1b) were prepared by treating 4-thioxo-2-thiazolidinone with the
corresponding aldehydes and refluxed for 10 min in the ethanol medium in the presence
of catalytic amount of EDDA according to published procedures.
General Procedure Of Diels-Alder And Tandem Reactions Affording 3a-D/3a-D.
A mixture of appropriate 5-arylidene-4-thioxo-2-thiazolidinone 1a-b (5 mmol) and
arylidene pyruvic acid 2a-c (5.5 mmol) was refluxed for 1 h with a catalytic amount of
hydroquinone (2-3 mg) in 15 ml of glacial acetic acidand left overnight at room
temperature. The precipitated crystals were filtered off, washed with ethanol, and
recrystallized from appropriate solvent.
rel-(5S,5aR,11bR)- and rel-(5R,5aS,11bR)-6-Hydroxy-2-oxo-5-phenyl-3,5a,6,11b-
tetrahydro-2H,5H-chromeno[4’,3’:4,5]thiopyrano[2,3-d][1,3]thiazole-6-carboxylic
acid (3a/3a). Yield 80%, mp 218-220ºC (DMF:AcOH). 1H NMR (400 MHz, DMSO-d6):
δ 4.11 (d, 1H, J = 6.0 Hz, 11b-H, 3a), 4.34 (dd, 1H, J = 9.6, 11.5 Hz, 5a-H, 3a), 4.51 (d,
1H, J = 6.0 Hz, 5-H, 3a), 4.56 (d, 1H, J = 11.5 Hz, 5-H, 3a), 4.78 (d, 1H, J = 4.0 Hz, 11b-
H, 3a), 4.85 (dd, 1H, J = 4.0, 11.5 Hz, 5a-H, 3a), 6.87 (t, 1H, J = 7.4 Hz, arom.), 7.03 (d,
1H, J = 7.4 Hz, arom.),7.11 (t, 1H, J = 7.4 Hz, arom.), 7.22-7.30 (m, 5H, arom., OH),
7.39 (d, 2H, J = 7.0 Hz, arom.), 11.57 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δ
31.01, 45.52, 47.91, 96.62, 108.09, 120.01, 121.37, 126.62, 128.22, 128.55, 128.77,
5

129.23, 131.43, 137.15, 150.44, 160.37, 169.33, 170.37. Anal. Calcd for C20H15NO5S2:
C, 58.10; H, 3.66; N, 3.39. Found: C, 58.12; H, 3.65; N, 3.40. ESI-MS m/z 413 (M+H)+.
SUPPLEMENTAL MATERIAL
Structural characterization, spectral data for synthesized compounds 3b-d/3b-d, crystal
data and refinement details for 3a/3a for this article can be accessed on the publisher’s
website.
Crystallographic data (CCDC-1401842 for molecules 3a/3a) have been deposited at the
Cambridge Crystallographic Database Centre (www.ccde.cam.ac.uk).
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8

Scheme 1. Synthesis of rel-(5S, 5aR, 11bR) and rel-(5R, 5aS, 11bR)- 6-hydroxy-2-oxo-5-
phenyl-3,5a,6,11b-tetrahydro-2H,5H-chromeno[4’,3’:4,5]thiopyrano[2,3-d][1,3]thiazole-
6-carboxylic acids 3a-d/3a-d.
S
H
N
O
CH3COCOOH
MeOH, KOH
O
OH
2a Ar = C6H5
S
Ar CHO
Ar
O
CHO
2b Ar = thiophen-2-yl
2c Ar= 4-F-C6H5
2a-2c
EtOH,
EDDA
R
O
H
H
Ar
S
Ar
H
H
N
OH
S
S
O
H
Ar
H
O
H
N
N
2a-c
O
O
+
S
HOOC
HO
HO
HOOC
HO
O
S
O
S
H
R
H
R
AcOH, hydroquinone
R
1a-b
exo-adduct
endo-adduct
1a R = H
1b R = 5-Br
H
H
S
H
H
N
Ar
S
Ar
N
3a/3a* Ar = C6H5 , R = H
H
O
H
O
3b/3b* Ar = thiophen-2-yl, R = H
3c/3c* Ar = C6H5, R = 5-Br
HOOC
HO
HOOC
HO
S
S
H
H
3d/3d* Ar = 4-F-C6H5 , R = H
O
O
3a-d/3a-d*
R
R
9

Figure 1. The alternative molecules (3a/3a) (ORTEP plot) in the same monocrystal
(Figure is provided in color online).
molecule 3a
molecule 3a*
10