Citraconic acid and its anhydride-based hetero-Diels–Alder reactions in the synthesis of new thiopyrano[2,3-d][1,3]thiazole derivatives

Article abstract of DOI:10.1080/00397911.2020.1867868

Novel rel-(5R,5aR,11bS)-5-methyl-2,6-dioxo-3,5a,6,11b-tetrahydro-2H,5H-chromeno[4?,3?:4,5]thiopyrano[2,3-d][1,3]thiazole-5-carboxylic acids were synthesized in 63–72% yields via tandem acylation-hetero-Diels–Alder reaction of 5-(2-hydroxybenzylidene)-4-th

Full text of DOI:10.1080/00397911.2020.1867868

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Citraconic acid and its anhydride-based hetero-
Diels–Alder reactions in the synthesis of new
thiopyrano[2,3-d][1,3]thiazole derivatives
Nataliya Zelisko, Olexandr Karpenko, Volodymyr Muzychenko, Andrzej
Gzella & Roman Lesyk
To cite this article: Nataliya Zelisko, Olexandr Karpenko, Volodymyr Muzychenko, Andrzej Gzella
& Roman Lesyk (2021) Citraconic acid and its anhydride-based hetero-Diels–Alder reactions in
the synthesis of new thiopyrano[2,3-d][1,3]thiazole derivatives, Synthetic Communications, 51:6,
964-970, DOI: 10.1080/00397911.2020.1867868
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2021, VOL. 51, NO. 6, 964–970
https://doi.org/10.1080/00397911.2020.1867868
Citraconic acid and its anhydride-based hetero-Diels–Alder
reactions in the synthesis of new thiopyrano[2,3-d][1,3]
thiazole derivatives
Nataliya Zeliskoa, Olexandr Karpenkob, Volodymyr Muzychenkoa, Andrzej Gzellac,
and Roman Lesyka,d
aDepartment of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National
b
c
Medical University, Lviv, Ukraine; Enamine Ltd., Kyiv, Ukraine; Department of Organic Chemistry,
d
Poznan University of Medical Sciences, Poznan, Poland; Department of Public Health, Dietetics and
Lifestyle Disorders, Faculty of Medicine, University of Information Technology and Management in
Rzeszow, Rzeszow, Poland
ABSTRACT
ARTICLE HISTORY
Received 13 August 2020
Novel rel-(5R,5aR,11bS)-5-methyl-2,6-dioxo-3,5a,6,11b-tetrahydro-2H,
5H-chromeno[4΄,3΄:4,5]thiopyrano[2,3-d][1,3]thiazole-5-carboxylic acids
were synthesized in 63–72% yields via tandem acylation-hetero-
Diels–Alder reaction of 5-(2-hydroxybenzylidene)-4-thioxo-2-thiazoli-
dinones with citraconic acid and its anhydride. The regio- and
stereochemistry of the process was confirmed by NMR spectral data
and a single-crystal X-ray diffraction analysis.
KEYWORDS
Hetero-Diels–Alder reaction;
tandem reactions:
thiopyrano[2,3-d][1,3]thia-
zoles; 4-thioxo-2-
thiazolidinones
GRAPHICAL ABSTRACT
H C
O
O
COOH
S
3
O
O
H C
COOH
COOH
3
NH
O
S
S
or
H C
S
O
3
HO
O
NH
O
R
COOH
CH3
S
O
R
NH
S
O
R
Introduction
The Diels–Alder reaction is the most powerful synthetic method for unsaturated six-
membered rings.[1–4] It takes place under mild conditions with high regio- and stereo-
selectivity usually providing a rapid increase in skeletal complexity. Substantial gains in
insight and methodology have been accomplished with a body of creative and conceptu-
ally new applications in organic synthesis concerning Diels–Alder reactions.[5–7]
.
CONTACT Roman Lesyk
roman.lesyk@gmail.com
Department of Pharmaceutical, Organic and Bioorganic
Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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965
A variant is the hetero-Diels–Alder reaction, in which either the diene or the dienophile
contains a heteroatom, most often nitrogen or oxygen. This alternative constitutes a
powerful synthesis of six-membered ring heterocycles. Thus, the use of dienes contain-
ing a sulfur atom opens synthetic pathways to various thiopyran derivatives.[8,9]
Involvement of the hetero-Diels–Alder reaction in domino or tandem processes makes
this approach one of the most powerful methods for the synthesis of polycyc-
lic compounds.
This method has also been applied to the preparation of biologically active com-
pounds. Thus, hetero-Diels–Alder reactions have been used as an excellent synthetic
instrument for obtaining thiopyrano[2,3-d][1,3]thiazole derivatives combining thiazolidi-
none and thiopyrano fragments in the fixed skeleton.[10] Thiopyrano[2,3-d][1,3]thiazoles
have become a promising area of research because of their diverse biological
activities, such as anticancer,[11] antitrypanosomal,[12] antimycobacterial, antibacterial
and antifungal,[13–17] and antiviral[18]
.
Results and discussions
Previously, it was described the synthesis of the above-mentioned heterocyclic
system via domino-Knoevenagel-hetero-Diels–Alder reactions of isorhodanine with
some dienophile-containing aldehydes (3,7-dimethyl-6-octenal, 2-allyloxybenzaldehydes
and 2-formylphenyl (E)-3-aryl-2-propenoates).[19] Recently, we reported a formation of
some new thiopyrano[2,3-d]thiazole derivatives and we also described a diastereoselec-
tive tandem acylation-hetero-Diels–Alder reaction of 5-arylidene-4-thioxo-2-thiazolidi-
nones (5-arylideneisorhodanines) with ortho-phenolic group at arylidene moiety and
a,b-unsaturated mono- and dicarboxylic acids derivatives providing 2H,5H-chrome-
no[40,30:4,5]thiopyrano[2,3-d]thiazoles formation.[12,20–22]
As a continuation of our work, we evaluated the reaction between 5-(ortho-
hydroxybenzylidene)-substituted isorhodanines and citraconic acid or its anhydride as
dienophiles. The reaction proceeded smoothly in acetic acid at reflux with a catalytic
amount of hydroquinone to prevent of polymerization processes. We found that in
such conditions there is a regio- and diastereoselective tandem acylation-hetero-
Diels–Alder reaction affording the pure rel-(5R,5aR,11bS)-5-methyl-2,6-dioxo-
3,5a,6,11b-tetrahydro-2,5H-chromeno[40,30:4,5]thiopyrano[2,3-d]thiazoles
2a–f
in
good yields (Scheme 1). We came to a conclusion about the position of methyl
group at the C5 of the core heterocyclic system. It was deduced from two doublets
within 3.92–4.48 ppm which corresponding two protons at positions 5a and 11 b
with the coupling constants J ¼ 4.9 ꢀ 6.1 Hz. The last ones prove the cis-configuration
of those protons. The starting 5-(2-hydroxybenzylidene)-4-thioxo-2-thiazolidinones
2a–f were synthesized via Knoevenagel condensation of 4-thioxo-2-thiazolidinone
with the appropriate o-hydroxybenzaldehyde using acetic acid medium in the pres-
ence of sodium acetate.[11,12]
The reactions with citraconic acid and citraconic anhydride as dienophiles were both
effective giving the products 2a–f, but method B was slightly less productive (yield
varies between 63 and 69%), in the same time yield in method A equals 69–72%.

966
N. ZELISKO ET AL.
H C
O
COOH
S
3
H3C
COOH
COOH
O
NH
method A
or
S
S
H
O
O
N
R
O
2a. R = H, 70% (A), 65% (B)
2b. R = 8,10-Br2, 72% (A), 63% (B)
2c. R = 10-Br, 71% (A), 68% (B)
2d. R = 10-Cl, 69% (A), 69% (B)
2e. R = 8-OCH3, 71% (A), 67% (B)
O
S
O
H3C
method B
HO
R
2f. R = 9-OH, 72% (A), 69% (B)
1a. R = H
1b. R =3,5-Br2
1c. R =5-Br
1d. R =5-Cl
1e. R =3-OCH3
O
COOH
S
CH3
O
NH
1f. R =4-OH
S
O
R
Scheme 1. Synthesis of rel-(5R,5aR,11bS)-5-methyl-2,6-dioxo-3,5a,6,11b-tetrahydro-2,5H-chrome-
no[40,30:4,5]thiopyrano[2,3-d]thiazoles 2a–f. Reagents and conditions: 2a–f (1.0 equiv), appropriate
dienophile (1.1 equiv), hydroquinone (cat.), AcOH, reflux, 3 h. Yields: method A – 69–72%, method B
– 63–69%.
Scheme 2. Plausible mechanism of tandem reaction of citraconic acid and 5-(ortho-hydroxybenzyli-
dene)-isorhodanines.
The regioselectivity of the reaction is due to the electron-donating properties of the
methyl group, which leads to a redistribution of the electron density of the double bond
of citraconic acid and its anhydride. The diastereoselectivity of the studied tandem reac-
tion of citraconic acid and 5-(ortho-hydroxybenzylidene)-isorhodanines with the forma-
tion of rel-5R,5aR,11bS diastereomers is explained by endo transition state at the stage
of the [4 þ 2]-cycloaddition. The [4 þ 2] adduct formed undergoes intramolecular lacto-
nization with the formation of a tetracyclic derivative. Citraconic anhydride reacts simi-
larly (Scheme 2).
The structure of 2a was confirmed by X-ray analysis (Figure 1). X-ray analysis
revealed that the investigated compound 2a crystallized in the form of an acetonitrile
solvate. The molar ratio of the solute and the solvent molecules in the crystal is 1:1.
The molecules of the compound 2a have a rigid tetracyclic system of 2,6-diox-
o-3,5a,6,11b-tetrahydro-2H,5H-chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]thiazole
folded internal six-membered dihydrothiopyran and dihydropyran rings (Figure 1).
The first one has distorted half-chair form [Cremer Pople puckering
with
a
&

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Figure 1. X-ray crystal structure (ORTEP plot) of compound 2a.
Figure 2. The hydrogen bonding (a,b) in the crystal lattice of 2a. H atoms not involved in hydrogen
bonds have been omitted for clarity.
parameters[23]: Q ¼ 0.5221(12) Å, q ¼ 130.63(14)ꢁ, u ¼ 84.51(16)ꢁ], and the other one a
screw-boat conformation [Cremer & Pople puckering parameters: Q ¼ 0.4351(13) Å,
q ¼ 64.67(17)ꢁ, u ¼ 147.68(19)ꢁ]. Dihydrothiopyran and dihydropyran rings are fused in
a cis-decalin pattern and the dihedral angle between their least squares planes is
78.86(3)ꢁ. The H atoms at C7 and C16 stereogenic centers occupy an equatorial and

968
N. ZELISKO ET AL.
ꢁ
Table 1. Hydrogen-bond geometry (Å, ) for 2a.
D–HꢃꢃꢃA
D–H (Å)
HꢃꢃꢃA (Å)
DꢃꢃꢃA (Å)
D–HꢃꢃꢃA (ꢁ)
N3–H3ꢃꢃꢃN24
0.84 (2)
0.91 (2)
0.98
0.98
ii
2.13 (2)
1.71 (2)
2.58
2.9395 (17)
2.6133 (12)
3.4688 (15)
3.219 (2)
161.7 (19)
170.5 (19)
150
O21–H21ꢃꢃꢃO18i
C22–H22BꢃꢃꢃO20ii
C26–H26CꢃꢃꢃO18iii
Symmetry codes: x, 1.5ꢂy, ꢂ0.5þz; 1þx,y,z; ꢂx, 1ꢂy, 1ꢂz.
2.58
123
i
iii
axial position, respectively, with respect to the dihydrothiopyran ring. The H atoms in
the pair H(-C7) and H(-C16) adopt a synclinal conformation (-sc). The torsion angle
H7–C7–C16–H16 found is ꢂ51ꢁ. The carboxylic group present at C6 position
(Figure 1) is only slightly tilted from the least squares plane of the dihydrothiopyran
ring. The dihedral angle is 10.88(17)ꢁ. The spatial arrangement of the mentioned group
is also defined by the torsion angle S5–C6–C19–O20 of ꢂ20.76(15)ꢁ which reveals that
S5–C6 and C19–O20 bonds are synperiplanar. The C4–C17 bond length of 1.3438 (18)
Å confirms the presence of a double bond between these atoms.
In the crystal lattice, the molecules are connected by the hydrogen bonds
O21–H21ꢃꢃꢃO18i in chains growing along the c axis (Figure 2a; Table 1). Neighboring
chains related by translation along the a axis are linked through non-classical
C22–H22BꢃꢃꢃO20ii hydrogen bonds into layers parallel to the ac plane (Figure 2b).
Solvent (acetonitrile) molecules present in the crystal connect the neighboring layers via
N3–H3ꢃꢃꢃN24 and C26–H26CꢃꢃꢃO18iii [(iii) -x,1-y,1-z] hydrogen bonds into a three-
dimensional hydrogen-bond network (Figure 2a and b; Table 1).
Conclusions
To summarize, we have reported an efficient regio- and diastereoselective method for
the preparation of novel rel-(5 R,5aR,11bS)-5-methyl-2,6-dioxo-3,5a,6,11b-tetrahydro-
2H,5H-chromeno[4΄,3΄:4,5]thiopyrano[2,3-d][1,3]thiazole-5-carboxylic acids via tandem
acylation-hetero-Diels–Alder reaction of 5-arylideneisorhodanines with ortho-phenolic
group at arylidene moiety and citraconic acid or citraconic anhydride.
Experimental
All starting materials were purchased from commercial sources and used without purifi-
cation. Melting points are uncorrected and were measured in open capillary tubes on
1
Buchi B-545 melting point apparatus. The H NMR spectra were recorded on Varian
Gemini 400 MHz and 13C NMR spectra on Varian Gemini 100 Hz 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) were 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 þ H]þ peaks, in
agreement with their molecular weight.

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The starting compounds: 2,4-thiazolidinedione[24] and 4-thioxo-2-thiazolidinone[25] were
obtained according to the methods described previously. 5-(2-Hydroxybenzylidene)-4-thi-
oxo-2-thiazolidinones were prepared by treating 4-thioxo-2-thiazolidinone with the appro-
priate o-hydroxybenzaldehyde in glacial acetic acid (100ꢁC, 20min) in the presence of
sodium acetate according to published procedures.[11,12]
General procedure of tandem acylation-hetero-Diels–Alder reaction affording
2a-f
A mixture of 10 mmol of appropriate 5-(2-hydroxybenzylidene)-4-thioxo-2-thiazolidi-
none and 11 mmol of citraconic acid or citraconic anhydride was refluxed for 3 h with
catalytic amount of hydroquinone (2–3 mg) for preventing 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 acetonitrile. rel-
(5R,5aR,11bS)-5-Methyl-2,6-dioxo-3,5a,6,11b-tetrahydro-2H,5H-chromeno[4΄ ,3΄ :4,5]thio-
pyrano[2,3-d][1,3]thiazole-5-carboxylic acid (2a). Yields: method A ꢂ 70%, method B ꢂ
1
65%. White solid, mp 230–232 ꢁC (MeCN). H NMR (400 MHz, DMSO-d6): 1.72 (s,
3H, ‘3), 4.04 (d, 1H, J ¼ 6.1 Hz, 5a-H), 4.44 (d, 1H, J ¼ 6.1 Hz, 11b-), 7.14 (d, 1H,
J ¼ 8.1 Hz, arom.), 7.27 (t, 1H, J ¼ 7.4 Hz, arom.), 7.41 (t, 1H, J ¼ 7.7 Hz, arom.), 7.47 (d,
1H, J ¼ 7.3 Hz, arom.), 11.46 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): 26.5 (CH3),
33.1 (11b-C), 44.8 (5a-C), 53.9 (5-C), 101.9, 117.1, 121.1, 123.5, 125.5, 129.3, 130.2,
150.1 (3a-C), 166.1 (C¼O), 170.9 (C¼O), 173.3 (C¼O). LC-MS: m/z 350 (100.0%,
(M þ H)þ). Anal. Calcd for C15H11NO5S2: C, 51.57; H, 3.17; N, 4.01. Found: C, 51.63;
H, 3.22; N, 4.08%.
Crystallographic data and structural refinement parameters for compound 2a
Empirical formula C17H14N2O5S2, formula weight 390.42, crystal system monoclinic,
space group P21/c, a ¼ 5.79610(6), b ¼ 17.1840(2), c ¼ 16.79478(19) Å, b ¼ 94.0536(11)ꢁ,
V¼1668.58(3) Å3, Z¼4, Dcalc¼1.554 g/cm3. An pale-yellow lath crystal (acetonitrile)
(0.22 ꢄ 0.16 ꢄ 0.06 mm) was used to record 21088 (CuKa-radiation, hmax¼76.51ꢁ) inten-
sities on a Super Nova Dual Atlas diffractometer. The supplementary crystallographic
data of 1 have been deposited at the Cambridge Crystallography Data Center (CCDC)
as supplementary publication CCDC1998123. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax:
þ44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
1
Spectral and analytical data for compounds 2b–f, copies of the H and 13C NMR are
available in the supplementary material.
ORCID
Roman Lesyk
http://orcid.org/0000-0002-3322-0080

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N. ZELISKO ET AL.
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