A new three-step domino Knoevenagel-hetero-Diels-Alder oxidation reaction

Article abstract of DOI:10.1016/j.tetlet.2011.02.081

A new catalyst-free domino Knoevenagel-hetero-Diels-Alder oxidation reaction is reported. 6H-Chromeno[4′,3′:4,5]thiopyrano[2,3-d][1,3] thiazol-4-ium-2-olates are formed in good yields via reaction of 2-(2-propynyloxy)benzaldehydes with 4-thioxo-1,3-thiazolidin-2-one.

Full text of DOI:10.1016/j.tetlet.2011.02.081

Tetrahedron Letters 52 (2011) 2324–2326
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A new three-step domino Knoevenagel–hetero-Diels–Alder oxidation reaction
⇑
Andriy O. Bryhas, Yuri I. Horak, Yuri V. Ostapiuk, Mykola D. Obushak , Vasyl S. Matiychuk
Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla i Mefodiya St. 6, Lviv 79005, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
A
new catalyst-free domino Knoevenagel–hetero-Diels–Alder oxidation reaction is reported. 6H-
Chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]thiazol-4-ium-2-olates are formed in good yields via reaction
of 2-(2-propynyloxy)benzaldehydes with 4-thioxo-1,3-thiazolidin-2-one.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 7 December 2010
Revised 3 February 2011
Accepted 18 February 2011
Keywords:
Domino reactions
Domino Knoevenagel–hetero-Diels–Alder
reaction
4-Thioxo-1,3-thiazolidin-2-one
2-(2-Propynyloxy)benzaldehyde
Organic reactions are traditionally viewed as linear and step-
wise processes in which isolation and purification of key interme-
diates often lead to reduced yields. Domino reactions, on the other
hand, allow access to a myriad of complex molecules with high
stereocontrol in an efficient, atom-economical manner. Tietze
et al. reported the domino Knoevenagel–hetero-Diels–Alder reac-
tion of aromatic and aliphatic aldehydes which contain an alkene
moiety with various active methylene carbonyl compounds1–3
(Scheme 1).
hyde and barbituric acids. Arylidene derivatives of barbituric acid
in the presence of catalysts such as CuI undergo cyclisation to form
tetracyclic compounds.5 In the case of 1-methyl-1,3-dihydro-2H-
indole-2-thione the reaction proceeded without a catalyst.6
Recently, we reported7 the new domino Knoevenagel–hetero-
Diels–Alder reaction of unsaturated aromatic and aliphatic alde-
hydes with isorhodanine (4-thioxo-1,3-thiazolidin-2-one) (Scheme
2). The reaction is controlled by the interaction of the HOMO of the
diene and the LUMO of the dienophile (normal electron demand),
For a long time, the use of an alkyne moiety in domino Knoeve-
nagel–hetero-Diels–Alder reactions was limited, because of
the lower reactivity of unactivated alkynes compared to the corre-
sponding alkenes. The examples given in the literature are
restricted to the reaction of 2-(2-propynyloxy)benzaldehydes with
2-(1,3-benzothiazol-2-yl)acetonitrile and barbituric acids.4,5
In the case of 2-(1,3-benzothiazol-2-yl)acetonitrile, only the
Knoevenagel reaction takes place and the product of the subse-
quent Diels–Alder reaction was not observed. However, the use
of Lewis acids provides new opportunities for the domino Knoeve-
nagel–hetero-Diels–Alder reactions of 2-(2-propynyloxy)benzalde-
R
X
S
O
S
O
NH
+
O
S
NH
O
O
S
X
R
Scheme 2.
O
O
O
CHO
+
- H2O
Scheme 1.
⇑
Corresponding author. Tel.: +380 322728062; fax: +380 322616048.
E-mail address: obushak@in.lviv.ua (M.D. Obushak).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.081

A. O. Bryhas et al. / Tetrahedron Letters 52 (2011) 2324–2326
2325
S
S
N
S
O
NaOAc, AcOH
reflux, 4 h
NH
O
O
+
S
O
O
2
3
1
S+
S+
S
O
O
O
O
NH
N
N
S
S
S
O
O
O
4
5a
Scheme 3.
so it does not require an electron-donating group for activating the
alkene moiety, as is the case with Meldrum’s acid or
isoxazolones.8,9
In view of this, we proposed that 4-thioxo-1,3-thiazolidin-2-
one (2) would react with 2-(2-propynyloxy)benzaldehyde (1) un-
der mild conditions without using any catalyst for activating the
propynyl moiety. The reaction was found to proceed smoothly in
acetic acid under refluxing conditions in the presence of sodium
acetate (Scheme 3).10
Neutral ammonium salts such as ethylenediammonium diace-
tate (EDDA), piperidinium acetate and ammonium acetate could
also be used as a base. However, the classical product of the dom-
ino Knoevenagel–hetero-Diels–Alder reaction 4 was not isolated.
Instead, it underwent oxidation to give 6H-chromeno[40,30:4,5]-
thiopyrano[2,3-d][1,3]thiazol-4-ium-2-olate 5a.11 The driving
force for the reaction is aromatization of the thiopyran ring and
the possibility of delocalization of the negative charge.
Table 1
6H-Chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]thiazol-4-ium-2-olates 5a–f
Next, to clarify the scope of this reaction, we used various prop-
argyl derivatives. As summarized in Table 1, they were similarly
effective in this reaction giving the corresponding products 5b–f.12
The yield of product 5f was significantly lower (26%) which was
probably due to steric hindrance in the Diels–Alder transition state.
N-Substituted 4-thioxo-1,3-thiazolidin-2-one (6) was also
investigated in reactions with 2-(2-propynyloxy)benzaldehydes
1a, d. Only the domino Knoevenagel–hetero-Diels–Alder reaction
was observed (Scheme 4).13,14 Oxidation of 3-(3-methylphenyl)-
3,11b-dihydro-2H,6H-chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]-
thiazol-2-ones 7a, b with formation of thiopyranium salts did not
occur under these conditions because the nitrogen atom in the thi-
azole ring is substituted.
Entry
Alkyne
Product
Yield (%)
S+
O
O
N
1
58
S
O
O
5a
1a
S+
Me
O
O
O
Me
N
2
3
4
53
57
77
S
O
5b
1b
S+
The structures of compounds 7a, b were supported by the pres-
ence of 13C NMR signals due to the carbonyl carbon atoms with
chemical shifts of ca. 168 ppm, which differ from those of the car-
bon atoms of C–Oꢀ groups with chemical shifts at ca. 177 ppm in
products 5.
Me
O
O
N
S
O
1c
O
5c
Me
O
In summary, we have developed a novel and efficient method
S+
for the construction of 6H-chromeno[40,30:4,5]thiopyrano[2,
O
3-d][1,3]thiazol-4-ium-2-olates using
a domino Knoevenagel–
N
hetero-Diels–Alder oxidation approach based on 2-(2-propynyl-
oxy)benzaldehydes (1) and 4-thioxo-1,3-thiazolidin-2-one (2).
The starting unsaturated aldehydes 1a–f were prepared via alkyl-
ation of commercially available salicylaldehydes with 2-propynyl
bromide.
Cl
Br
S
O
O
1d
5d
Cl
S+
O
O
N
5
6
65
26
Ar
S
S
S
N
O
1e
O
5e
Ar
Br
S
O
N
S+
1a,d
+
O
S
O
O
O
N
6
7a,b
R
S
O
Ar = 3-MeC6H4
Scheme 4.
O
R = H (a), Cl (b)
1f
5f

2326
A. O. Bryhas et al. / Tetrahedron Letters 52 (2011) 2324–2326
J = 7.6 Hz, 1H, C6H4), 7.31 (t, J = 6.8 Hz, 1H, C6H4), 7.57 (t, J = 6.8 Hz, 1H, C6H4),
Acknowledgement
8.06 (d, J = 7.2 Hz, 1H, C6H4), 8.36 (s, 1H, CH); 13C NMR (100 MHz, DMSO-d6):
d = 69.2, 118.9, 121.5, 123.8, 124.9, 127.1, 128.9, 129.3, 134.8, 134.9, 159.2,
176.8, 177.4; MS (m/z): 274 (M++1). Anal. Calcd for C13H7NO2S2: C, 57.13; H,
2.58; N, 5.12. Found: C, 56.85; H, 2.64; N, 4.99.
The authors are grateful to the Ministry of Education and Science
of Ukraine for financial support of this project (0109U002073).
12. 6H-Benzo[5’,6’]chromeno[4’,3’:4,5]thiopyrano[2,3-d][1,3]thiazol-4-ium-2-olate
(5f): Yield 26%, mp 301 °C with decomposition; 1H NMR (400 MHz, DMSO-d6):
d = 4.84 (d, J = 12.0 Hz, 1H, CH2), 5.50 (d, J = 12.0 Hz, 1H, CH2), 7.39 (d,
J = 8.8 Hz, 1H, C10H6), 7.57 (t, J = 7.6 Hz, 1H, C10H6), 7.61–7.70 (m, 2H, C10H6),
References and notes
8.04 (d, J = 8.0 Hz, 1H, C10H6), 8.19 (d, J = 8.8 Hz, 1H, C10H6), 8.46 (s, 1H, CH); 13
C
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.
NMR (100 MHz, DMSO-d6): d = 70.3, 116.5, 118.4, 126.2, 126.3, 127.6, 127.8,
127.9, 129.7, 130.7, 131.5, 132.3, 134.4, 136.2, 161.4, 176.9, 177.6; MS (m/z):
324 (M++1). Anal. Calcd for C17H9NO2S2: C, 63.14; H, 2.81; N, 4.33. Found: C,
62.93; H, 2.96; N; 4.24.
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. 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.
13. 3-(3-Methylphenyl)-3,11b-dihydro-2H,6H-chromeno[40,30:4,5]thiopyrano[2,3-d]
[1,3]thiazol-2-ones (7a): Yield 66%, mp 272 °C; 1H NMR (400 MHz, DMSO-d6):
d = 2.32 and 2.41 (s+s, 3H); 4.08 and 4.17 (s+s, 1H); 4.43 and 4.55 (d+d,
J = 14.7 Hz, 1H); 4.72 and 4.76 (d+d, J = 14.7 Hz, 1H); 6.90 and 6.95 (d+d, J = 7.8,
8.2 Hz, 1H); 7.04–7.08 (m, 1H); 7.16–7.20 (m, 2H); 7.26–7.46 (m, 4H); 7.57–
7.60 (m, 1H); 13C NMR (100 MHz, DMSO-d6): d = 21.2, 21.3; 42.5, 43.8; 68.0,
68.5; 104.6, 104.8; 117.1, 117.2; 120.6, 121.0; 121.1, 121.7; 122.5; 123.2;
123.9; 124.4, 124.5; 124.9, 125.0; 125.5; 128.2, 128.3; 129.6, 129.7; 130.38,
130.41; 130.5, 130.6; 134.5, 134.7; 139.4, 139.6; 154.9, 155.0; 168.8, 168.9; MS
(m/z): 366 (M++1). Anal. Calcd for C20H15NO2S2: C, 65.73; H, 4.14; N, 3.83.
Found: C, 65.56; H, 4.29; N, 3.88.
5. Khoshkholgh, M. J.; Balalaie, S.; Gleiter, R.; Rominger, F. Tetrahedron 2008, 64,
10924–10929.
6. Majumdar, K. C.; Taher, A.; Ponra, S. Tetrahedron Lett. 2010, 51, 147–150.
7. 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.
8. Tietze, L. F.; Stegelmeier, H.; Harms, K.; Brumby, T. Angew. Chem., Int. Ed. Engl.
1982, 21, 863.
14. 10-Chloro-3-(3-methylphenyl)-3,11b-dihydro-2H,6H-chromeno[40,30:4,5]thiopyrano
[2,3-d][1,3]thiazol-2-ones (7b): Yield 69%, mp 252 °C; 1H NMR (400 MHz,
DMSO-d6): d = 2.32 and 2.40 (s+s, 3H); 4.14 and 4.23 (s+s, 1H); 4.42 and 4.52
(d+d, J = 14.7 Hz, 1H); 4.71 and 4.78 (d+d, J = 14.7 Hz, 1H); 6.93 and 6.99 (d+d,
J = 8.6 Hz, 1H); 7.16–7.21 (m, 2H); 7.32–7.48 (m, 4H); 7.53 (br s, 1H); 13C NMR
(100 MHz, DMSO-d6): d = 21.3; 42.2, 43.6; 68.1, 68.5; 104.2, 104.5; 118.9,
121.6; 122.2, 122.6; 123.1, 123.2; 123.86; 123.9, 124.0; 124.7, 124.9; 125.9,
126.0; 128.1, 128.2; 129.6, 129.7; 130.0, 130.1; 130.4, 130.6; 134.4, 134.6;
139.5, 139.7; 153.7, 153.8; 168.5, 168.6; MS (m/z): 400 (M++1). Anal. Calcd for
9. Tietze, L. F.; Brumby, T.; Pretor, M.; Remberg, G. J. Org. Chem. 1988, 53, 810.
10. Typical procedure for the domino Knoevenagel–hetero-Diels–Alder oxidation
reaction: ice-cold AcOH (20 ml) was added to
a mixture of 4-thioxo-1,3-
thiazolidine-2-one (2) (0.82 g, 6.2 mmol), 2-(2-propynyloxy)benzaldehyde
(1a) (1 g, 6.2 mmol) and NaOAc (0.08 g, 1 mmol). The mixture was heated at
reflux for 4 h. The precipitate formed after cooling was filtered, washed with
H2O and purified by recrystallization from EtOH/DMF to give yellow crystals of
6H-chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]thiazol-4-ium-2-olate (5a).
11. 6H-Chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]thiazol-4-ium-2-olate (5a): Yield
58%, mp 267 °C; 1H NMR (400 MHz, DMSO-d6): d = 5.10 (s, 2H, CH2), 7.18 (d,
C
20H14ClNO2S2: C, 60.07; H, 3.53; N, 3.50. Found: C, 59.81; H, 3.29; N, 3.62.