A four-step domino Knoevenagel-hetero-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2013.07.161

A new, catalyst-free, domino Knoevenagel-hetero-Diels-Alder elimination oxidation reaction is reported. 5-Aryl-2H,6H-chromeno[4′,3′:4,5] thiopyrano[2,3-d][1,3]thiazol-2-ones are formed in moderate to good yields via reaction of 2-(3-aryl-3-chloro-2-propenyloxy)benzaldehydes with 4-thioxo-1,3-thiazolidin-2-one.

Full text of DOI:10.1016/j.tetlet.2013.07.161

Accepted Manuscript
A four-step domino Knoevenagel–hetero-Diels–Alder reaction
Andriy O. Bryhas, Vasyl S. Matiychuk, Tadeusz Lis, Vasyl Kinzhybalo, Victor
V. Smalius, Mykola D. Obushak
PII:
S0040-4039(13)01353-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.161
TETL 43373
Reference:
To appear in:
Tetrahedron Letters
Please cite this article as: Bryhas, A.O., Matiychuk, V.S., Lis, T., Kinzhybalo, V., Smalius, V.V., Obushak, M.D.,
A four-step domino Knoevenagel–hetero-Diels–Alder reaction, Tetrahedron Letters (2013), doi: http://dx.doi.org/
10.1016/j.tetlet.2013.07.161
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A four-step domino Knoevenagel–hetero-Diels–Alder reaction
Andriy O. Bryhasa, Vasyl S. Matiychuka, Tadeusz Lisb, Vasyl Kinzhybaloc,
Victor V. Smaliusd, Mykola D. Obushaka*
a Department of Organic Chemistry, Ivan Franko National University of Lviv,
Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine
b Faculty of Chemistry, University of Wrocław, F. Joliot-Curie 14, 50-383
Wrocław, Poland
c Institute of Low Temperature and Structure Research, Okólna 2, 50-422
Wrocław, Poland
d Faculty of Natural Sciences, Bohdan Khmelnytsky National University of
Cherkasy, Shevchenko Blvd. 81, Cherkasy 18031, Ukraine
* Corresponding author.Tel.: +380 322600396; fax: +380 322616048. E-mail
address: obushak@in.lviv.ua (M.D. Obushak).
Abstract
A new, catalyst-free, domino Knoevenagel–hetero-Diels–Alder elimination
oxidation reaction is reported. 5-Aryl-2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-
d][1,3]thiazol-2-ones are formed in moderate to good yields via reaction of 2-(3-
aryl-3-chloro-2-propenyloxy)benzaldehydes with 4-thioxo-1,3-thiazolidin-2-one.
Keywords:
Domino reactions
Domino Knoevenagel–hetero-Diels–Alder reaction
4-Thioxo-1,3-thiazolidin-2-one
Thiazolidinone derivatives
2-Allyloxybenzaldehyde
Due to the importance of ecological considerations in modern chemistry,
domino reactions have become more and more popular. This type of reaction

allows complex structures to be obtained with high efficiency and stereoselectivity.
At the same time, the amount of waste produced is decreased significantly.
Domino reactions have been studied in detail by Tietze. The domino
Knoevenagel–hetero-Diels–Alder reactions of aromatic and aliphatic aldehydes
which contain an alkene moiety with different 1,3-dicarbonyl compounds have
been reported previously.1–3
Earlier we reported4 the domino Knoevenagel–hetero-Diels–Alder reactions
of unsaturated aldehydes 1 with 4-thioxo-1,3-thiazolidin-2-one (2) (Scheme 1).
The reaction is controlled by the interaction of the HOMO of the diene and the
LUMO of the dienophile (normal electron demand), so the presence of electron-
donating groups for activating the alkene moiety is not necessary, as is the case in
reactions with Meldrum’s acid or isoxazolones.5,6
R2
R2
S
R1
N
S
R1
N
O
+
O
X
O
S
O
X
S
O
2
X = CH2, C=O
3
1
Scheme 1.
As non-activated alkynes display lower reactivity in Diels-Alder reactions
than the corresponding alkenes, there are quite a few examples in the literature of
reactions with triple bonds, but which are mainly restricted to the reaction of 2-(2-
propynyloxy)benzaldehydes with 2-(1,3-benzothiazol-2-yl)acetonitrile, barbituric
acids, 4-hydroxycoumarin and indolin-2-thiones.7–9 For this reason, we previously
investigated10 the reactions between 4-thioxo-1,3-thiazolidin-2-one (2) and 2-(2-
propynyloxy)benzaldehydes. It was discovered that the classical cyclodiene
product of the domino Knoevenagel–hetero-Diels–Alder reaction underwent
oxidation under the reaction conditions.
To expand our investigation we decided to test salicylaldehyde with a β-
chloroallyl substituent under the same reaction conditions. As the carbonyl

compound for the first step we chose 2-[3-(4-bromophenyl)-3-chloro-2-
propenyloxy]benzaldehyde (4a), the chlorine atom of which would undergo
elimination to afford the same cyclodiene compound as mentioned before. As in
the case of aldehydes containing an alkyne moiety, the reaction proceeded
smoothly in refluxing acetic acid in the presence of sodium acetate (Scheme 2).11
No catalyst was used for activation of the alkene moiety.
Br
Br
O
S
H
O
O
N
NaOAc
+
Cl
O AcOH
S
Cl
S
S
N
H
2
4a
O
5
Br
Cl
Br
Br
O
O
S
7
O
S
[O]
S
S
-HCl
S
NH
NH
S
N
O
O
O
6
8a
Scheme 2.
The first step of the reaction sequence involved the Knoevenagel
condensation to form the heterodiene C=C–C=S system. Then, without changing
the conditions, intermediate 5 underwent the hetero-Diels–Alder cyclization to
give intermediate 6. An investigation of the NMR and mass spectra showed that
the product of the domino Knoevenagel–hetero-Diels-Alder reaction 6 eliminated
HCl as expected. The cyclodiene ring formed after elimination of HCl underwent
oxidation to give 5-(4-bromophenyl)-2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-
d][1,3]thiazol-2-one (8a).12 However, analysis of the bond lengths taken from X-
ray data led us to conclude that product 8a does not exist as an alternative betaine
structure.10 A conjugated π-electron system was formed as shown in Scheme 2.

In further studies, we used different 2-[(3-chloro-3-phenylprop-2-en-1-
yl)oxy]benzaldehydes in reactions with 4-thioxo-1,3-thiazolidin-2-one (2) under
the same conditions. The reactions were similarly effective giving the products 8b–
e (Table 1).12,13
Table 1
Entry
1
Alkene
Product
Yield
(%)
56
Br
O
Br
O
Cl
S
S
O
N
8a
4a
O
Br
O
Br
2
3
4
5
65
60
45
39
O
Br
Cl
Cl
Br
Cl
S
Br
S
O
N
8b
4b
O
Br
O
O
O
Br
O
Cl
S
S
S
Cl
S
O
N
4c
8c
O
O
Br
Br
Cl
Cl
S
O
N
8d
4d
O
O
Br
Br
Cl
Br
S
O
N
8e
4e
O
Single crystal X-ray structure determination was carried out on compound
8a (Figure 1).14 The crystal structure consists of three independent molecules with
very similar geometry. The O2-C13-C5-C4-C19-C14 ring adopts an intermediate
conformation between that of a half-chair and a screw-boat with the following

Cremer and Pople puckering parameters: Q = 0.422(3), 0.487(3) and 0.471(3) Å,
= 68.5(4), 71.6(4) and 70.3(4)°, = 37.9(4), 25.6(4) and 34.5(4)° for the three
independent molecules, respectively. Consequently, the molecules were not planar,
the dihedral angles between the planes of the phenyl (C14-C19) ring and
condensed thiopyrano-thiazolone ring were 18.0, 27.6 and 26.5° for the three
independent molecules, respectively. The geometrical parameters of the condensed
thiopyrano-thiazolone ring were different to those of previously studied related
compounds 915 and 104 (Figure 2) due to the presence of additional double bonds
in the studied compound.
S
N
S
S
N
S
O
O
H
H
H R
9
R = 4-FC6H4
10
Figure 2.
C15A
C16A
C17A
O2A
C14A
C9A
C13A
Br1A
C8A
C10A
C11A
C5A
C6A
C7A
C19A
C18A
C4A
C3A
C12A
S2A
S1A
C2A
N1A
C1A
O1A
Figure 1. The view of one of the three independent molecules of 8a along with the
numbering scheme. Thermal ellipsoids are shown at the 50% probability level.16
In summary, we have developed an efficient method for the construction of
5-aryl-2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-d][1,3]thiazol-2-ones using
a

four-step, domino Knoevenagel–hetero-Diels-Alder elimination oxidation
approach using 2-[(3-chloro-3-phenylprop-2-en-1-yl)oxy]benzaldehydes and 4-
thioxo-1,3-thiazolidine-2-one (2). The starting unsaturated aldehydes 4a–e were
prepared via alkylation of commercially available salicylaldehydes with the
corresponding β-chloroallyl chlorides.
Acknowledgement
The authors are grateful to the State fund for fundamental research of
Ukraine for financial support (Projects F41.3/008 and F54.3/004).
References and notes
1. Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 105, 137; Tietze, L. F.,
Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, 2006. pp. 160–185.
2. Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
3. Tietze, L. F. J. Heterocycl. Chem. 1990, 27, 47; Tietze, L. F. In Selectivity–A
Goal for Synthetic Efficiency; Bartmann, W., Trost, B. M., Eds.; Verlag-
Chemie: Weinheim, 1984; p. 299.
4. Matiychuk, V. S.; Lesyk, R. B.; Obushak, M. D.; Gzella, A.; Atamanyuk, D.
V.; Ostapiuk, Y. V.; Kryshchyshyn, A. P. Tetrahedron Lett. 2008, 49, 4648–
4651.
5. Tietze, L. F.; Stegelmeier, H.; Harms, K.; Brumby, T. Angew. Chem., Int. Ed.
Engl. 1982, 21, 863–864.
6. Tietze, L. F.; Brumby, T.; Pretor, M.; Remberg, G. J. Org. Chem. 1988, 53,
810–820.
7. Sakamoto, M.; Nozaka, A.; Shimamoto, M.; Ozaki, H.; Suzuki, Y.; Yoshioka,
S.; Nagano, M.; Okamura, K.; Date, T.; Tamura, O. J. Chem. Soc., Perkin
Trans. 1 1995, 1759–1770.

8. Khoshkholgh, M. J.; Balalaie, S.; Gleiter, R.; Rominger, F. Tetrahedron 2008,
64, 10924–10929 ; Khoshkholgh, M. J.; Balalaie, S.; Bijanzadeh, H. R.;
Rominger, F.; Gross, J. H. Tetrahedron Lett. 2008, 49, 6965–6968.
9. Majumdar, K. C.; Taher, A.; Nandi, R. K. Tetrahedron 2012, 68, 5693–5718;
Khoshkholgh, M. J.; Lotfi, M.; Balalaie, S.; Rominger, F. Tetrahedron 2009,
65, 4228–4234; Kiamehr, M.; Moghaddam, F. M. Tetrahedron Lett. 2009, 50,
6723–6727.
10.Bryhas, А. О.; Horak, Y. I.; Ostapiuk, Y. V.; Obushak, M. D.; Matiychuk V. S.
Tetrahedron Lett. 2011, 52, 2324–2326.
11.Typical procedure for the domino-Knoevenagel-hetero-Diels-Alder elimination
oxidation reaction: ice-cold AcOH (20 ml) was added to a mixture of 4-thioxo-
1,3-thiazolidin-2-one (2) (0.3 g, 2.2 mmol), 2-{[3-(4-bromophenyl)-3-
chloroprop-2-en-1-yl]oxy}benzaldehyde (4a) (0.8 g, 2.2 mmol) and NaOAc
(0.04 g, 0.5 mmol). The mixture was heated at reflux for 5 h. The precipitate
formed after cooling was filtered, washed with H2O and purified by
recrystallization from EtOH/DMF to give light-brown crystals of 5-(4-
bromophenyl)-2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-d][1,3]thiazol-2-one
(8a).
12.5-(4-Bromophenyl)-2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-d][1,3]thiazol-
2-one (8a): Yield 56%, mp 297–298 oC; 1Н NMR (400 MHz, CF3COOH): δ =
4.98 (s, 2H, CH2), 7.17 (d, J = 8.3 Hz, 1H, C6H4), 7.35 (t, J = 7.3 Hz, 1H,
C6H4), 7.57–7.60 (m, 3H, C6H4), 7.83 (d, J = 8.3 Hz, 2H, C6H4), 8.13 (d, J =
13
7.8 Hz, 1H, C6H4); C NMR (100 MHz, CF3COOH): δ = 66.2, 119.3, 120.4,
124.8, 125.4, 128.5, 128.9, 129.4, 130.7 (2C), 132.7, 133.8 (2C), 139.3, 147.5,
79
81
150.9, 159.7, 160.8, 174.7; MS (m/z): 428 (M++1, Br), 430 (M++1, Br).
Anal. Calcd for C19H10BrNO2S2: C, 53.28; H, 2.35; N, 3.27. Found: C, 53.45;
H, 2.41; N, 3.16.
13.10-Bromo-5-(4-bromophenyl)-2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-
o
1
d][1,3]thiazol-2-one (8b): Yield 65%, mp 288–289 C; Н NMR (400 MHz,
CF3COOH): δ = 5.01 (s, 2H, CH2), 7.16 (d, J = 8.8 Hz, 1H, C6H3), 7.57 (d, J =

7.8 Hz, 2H, C6H4), 7.74 (d, J = 8.8 Hz, 1H, C6H3), 7.84 (d, J = 8.3 Hz, 2H,
13
C6H4), 8.21 (s, 1H, C6H3); C NMR (100 MHz, CF3COOH): δ = 66.2, 120.9,
121.7, 125.1, 125.8, 129.2, 129.3, 130.5, 130.6 (2C), 132.4, 133.9 (2C), 141.6,
79
79
145.8, 151.3, 157.7, 159.6, 170.0; MS (m/z): 506 (M++1, Br, Br), 508
(M++1, 79Br, 81Br), 510 (M++1, 81Br, 81Br). Anal. Calcd for C19H9Br2NO2S2: C,
44.99; H, 1.79; N, 2.76. Found: C, 44.71; H, 1.90; N, 2.62.
14.Crystallographic data for 8a: Empirical formula: C19H10BrNO2S2, formula
weight: 428.31 g/mol, orange blocks, crystal system: triclinic, space group: P-1
(#2), a = 13.312(4), b = 13.461(4), c = 14.363(4) Å, α = 73.91(3), β =
79.29(3), γ = 84.26(3)° , V = 2426.6(12) Å3, T = 100(2) K, Z = 6, Dcalc = 1.76
g/cm3, F(000) = 1284, diffractometer: Oxford Diffraction Xcalibur CCD,
residuals: R[F2 > 2σ(F2)], wR(F2): 0.0348, 0.0770.
Crystallographic data for the structure have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
863094. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 (0)1233 336033 or
e-mail deposit@ccdc.cam.ac.uk).
15.Lesyk, R., Zimenkovsky, B., Atamanyuk, D., Jensen, F., Kieć-Kononowicz, K.,
Gzella, A. Bioorg. Med. Chem., 2006, 15, 5230–5240.
16.Diamond – Crystal and Molecular Structure Visualization Crystal Impact – Dr.
H. Putz & Dr. K. Brandenburg GbR, Kreuzherrenstr. 102, 53227 Bonn,
Germany http://www.crystalimpact.com/diamond

Graphical abstract
A four-step domino Knoevenagel–hetero-Diels–Alder reaction
Andriy O. Bryhas, Vasyl S. Matiychuk, Tadeusz Lis,
Vasyl Kinzhybalo, Victor V. Smalius, Mykola D. Obushak
O
Ar
S
S
H
Ar
O
O
N
+
Cl
O
S
S
N
O

R2
R2
R1
S
N
S
S
R1
N
O
+
O
X
O
X
S
O
O
2
X = CH2, C=O
3
1
Scheme 1. Domino Knoevenagel–hetero-Diels–Alder reaction
Br
Br
O
S
H
O
O
N
NaOAc
+
Cl
O
S
Cl
S
S
N
H
2
4a
O
5
Br
Cl
Br
Br
O
O
O
S
[O]
S
S
-HCl
S
NH
S
NH
S
N
O
O
O
6
7
8a
Scheme
2.
Reaction
of
2-[3-(4-bromophenyl)-3-chloro-2-
propenyloxy]benzaldehyde 4a with 4-thioxo-1,3-thiazolidin-2-one 2

Table 1
5-Aryl-2H,6H-chromeno[4',3':4,5]thiopyrano[2,3-d][1,3]thiazol-2-ones 8a–e
Entry
1
Alkene
Product
Yield
(%)
56
Br
O
Br
O
Cl
S
S
O
N
8a
4a
O
Br
O
Br
2
3
4
5
65
60
45
39
O
Br
Cl
Cl
Br
Cl
S
Br
S
O
N
8b
4b
O
Br
O
O
O
Br
O
Cl
S
S
S
Cl
S
O
N
4c
8c
O
O
Br
Br
Cl
Cl
S
O
N
8d
4d
O
O
Br
Br
Cl
Br
S
O
N
8e
4e
O
S
N
S
S
N
O
O
H
S
H
H R
9
R = 4-FC6H4
10
Scheme 3. Condensed thiopyrano-thiazolones