A new domino-Knoevenagel-hetero-Diels-Alder reaction

Article abstract of DOI:10.1016/j.tetlet.2008.05.062

Various novel 3,5a,6,11b-tetrahydro-2H,5H-chromeno[4′,3′:4,5]thiopyrano[2, 3-d][1,3]thiazol-2-ones were synthesized in 60-80% yields via domino-Knoevenagel-hetero-Diels-Alder reactions of 4-thioxo-1,3-thiazolidin-2-one with 3,7-dimethyl-6-octenal, 2-allyl

Full text of DOI:10.1016/j.tetlet.2008.05.062

Tetrahedron Letters 49 (2008) 4648–4651
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Tetrahedron Letters
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A new domino-Knoevenagel–hetero-Diels–Alder reaction
c
Vasyl S. Matiychuk a, Roman B. Lesyk b, Mykola D. Obushak a, , Andrzej Gzella ,
*
Dmytro V. Atamanyuk b, Yuri V. Ostapiuk a, Anna P. Kryshchyshyn b
a Department of Organic Chemistry, Ivan Franko National University of Lviv, Kyryla and Mefodiya 6, Lviv 79005, Ukraine
b Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine
c Department of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan´, Poland
a r t i c l e i n f o
a b s t r a c t
Various novel 3,5a,6,11b-tetrahydro-2H,5H-chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]thiazol-2-ones were
synthesized in 60–80% yields via domino-Knoevenagel–hetero-Diels–Alder reactions of 4-thioxo-1,3-
thiazolidin-2-one with 3,7-dimethyl-6-octenal, 2-allyloxybenzaldehydes and 2-formylphenyl (E)-3-
aryl-2-propenoates with base catalysis. The possibility of stereo- and regioselective cycloaddition was
investigated.
Article history:
Received 7 March 2008
Revised 5 May 2008
Accepted 13 May 2008
Available online 16 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The creation of molecular complexity and diversity from simple
substrates, while combining economic with environmental aspects
constitutes a great challenge in modern organic chemistry. In this
regard, the development of new domino reaction methodologies is
very important.1–3 This type of reaction minimizes waste, since the
amount of solvents, reagents, adsorbents, and energy is dramati-
cally decreased, compared to stepwise reactions. Often, these dom-
ino reactions are accompanied by dramatic increases in molecular
complexity and impressive selectivity. Many of the reaction prod-
ucts have drug-like structures and might therefore exhibit interest-
ing biological activities.
oxo-1,3-thiazolidin-2-one 1, which has been described previously
as an excellent reagent for the synthesis of 3,5,6,7-tetra-
hydro-2H-thiopyrano[2,3-d][1,3]thiazol-2-ones via ylidene deriva-
tives11–13 (Scheme 2). Pharmaceutical interest in the abovemen-
tioned compounds appeared after approval of thiazolidinediones
as a separate group of antihyperglycaemics. In addition, several
compounds with antitumor and antioxidant activities among their
fused analogs have been discovered.14–16
The reaction is controlled by the interaction of the HOMO of the
diene and the LUMO of the dienophile (normal electron demand),
and 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.
Tietze et al. reported the domino-Knoevenagel–hetero-Diels–
Alder reaction of unsaturated aromatic and aliphatic aldehydes
with different 1,3-dicarbonyl compounds1–3 (Scheme 1).
Acetylacetone, acetoacetate, 1,3-cyclohexanediones,4 indanedi-
ones, Meldrum’s acid,5 and heterocyclic compounds such as barbi-
turic acids, pyrazolones, isooxazolones, and 1,2,3,4-tetrahydro-2,
4-pyridinedione,6 1,2,6-thiadiazinanedioxide-3,5-dione,7 oxothio-
lane,8 and 1-phenyl-3-indolinone9 can be employed in this type
R'
R'
S
S
N
N
O
+
EWG
O
of reaction. The reaction of heterocyclic and sugar-derived d,e-
S
S
EWG
unsaturated aldehydes has also been demonstrated.10
R
R
In this Letter, we report a new domino-Knoevenagel–hetero-
Diels–Alder reaction. As the methylene component we used 4-thi-
Scheme 2.
O
O
O
CHO
+
- H2O
Scheme 1.
* Corresponding author. Tel.: +380 322728062.
E-mail address: obushak@in.lviv.ua (M. D. Obushak).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.062

V. S. Matiychuk et al. / Tetrahedron Letters 49 (2008) 4648–4651
4649
S
CHO
H
2
S
H
S
H
N
N
H
N
O
O
S
S
O
a
S
H
1
3
79%
CHO
b
O
4
H
H
S
S
S
N
H
N
N
H
O
O
H
O
O
S
S
O
+
S
O
H
H
5b
5a
13%*
0%
65%*
80%
*in refluxing AcOH
Scheme 3. Reactions of 4-thioxo-1,3-thiazolidine-2-one 1 with citronellal 2 and 2-allyloxybenzaldehyde 4. Reagents and conditions: (a) 1 (1.0 equiv), EDDA (0.15 equiv), 2
(1.3 equiv), MeCN, rt, 24 h; (b) 5a + 5b: 1 (1.0 equiv), 4 (1.0 equiv), NEt3 (1.0 equiv), AcOH, reflux, 2 h, 5b:1 (1 equiv), 4 (1.0 equiv), NEt3 (1.0 equiv), AcOH, room temperature,
12 h.17,18
The first substrate we examined was 3,7-dimethyloct-6-enal
(citronellal) 2 (Scheme 3). Condensation of aldehyde 2 with 4-thi-
oxo-1,3-thiazolidin-2-one 1 in the presence of a catalytic amount
of ethylenediamine diacetate (EDDA) in acetonitrile or acetic acid
at room temperature afforded the corresponding Knoevenagel
adduct intermediate which cyclized via an intramolecular hetero-
Diels–Alder reaction to give the tetracyclic product 3 with excel-
lent selectivity.17 The ene reaction was not observed.
between the least-squares planes of the central ring of the tricyclic
skeleton and the outer five- and six-membered rings were
6.79(7)° and 17.07(7)°. The angle between the outer rings was
21.88(7)°. The C4–C13 bond, 1.337(2) Å, being part of the five-
and six-membered heterocyclic rings, is a double bond. In the
five-membered thiazolone ring, the C2–N3 bond distance,
1.345(2) Å, is somewhat larger than a normal Csp2–N bond
[1.331(2) Å] for c
-lactams.21
Single crystal X-ray structure determination corroborated the
structure of compound 3 (Fig. 1).19 The hydrogen atoms at the ste-
reogenic C7 and C12 centers have a trans axial–axial orientation.
The torsion angle H7–C7–C12–H12 of ꢀ176° reveals an antiperi-
planar conformation for atoms H7 and H12. In the solid state, the
heterocyclic six-membered ring adopts a half-chair conformation
{Cremer and Pople20 puckering parameters: Q = 0.565(2) Å,
h = 129.3(2)°, / = 94.9(2)°}, whereas the carbocyclic ring adopts a
chair conformation {Cremer and Pople puckering parameters:
Q = 0.578(2) Å, h = 2.4(2)°, / = 319(5)°}. The dihedral angles
In the same way, thiazolidinone 1 was condensed with 2-allyl-
oxybenzaldehyde 4 in acetic acid to give tetracyclic hetero-Diels–
Alder cycloadduct 5. In boiling acetic acid the cycloaddition was
not diastereoselective. According to the 1H NMR of the crude mix-
ture, the ratio of trans/cis annulated cycloadducts was 5:1. At room
temperature, we isolated pure (5aRS,11bSR)-3,5a,6,11b-tetra-
hydro-2H,5H-chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]thiazol-2-
one 5b in 80% yield. The configuration of 5b was deduced from the
coupling constant between the 5a and 11b protons (Scheme 3).
Other examples of this reaction using aldehydes 6, 8a,b and
10a,b possessing an allyl moiety as the dienophile are shown in
Scheme 4. Only one diastereoisomer was formed in these reactions.
To further the synthetic scope of this cycloaddition we studied
the reaction of thiazolidinone 1 with 2-formyl-R3-phenyl (E)-3-
phenyl-2-propenoates 12a,b at 80 °C in the presence of triethyl-
amine. The reaction, after usual work-up, gave the corresponding
(5aRS,11bSR)-5-aryl-3,5a,6,11b-tetrahydro-2H,5H-chromeno[40,30:
4,5]thiopyrano[2,3-d]thiazole-2,6-diones 13a,b in excellent
yields.23 The configuration of the protons at positions 5a and 11b
of 7, 9a, 11a, and 13 was deduced from the coupling constants,
compounds 7, 9a, and 11a were trans, whereas 13a, b were cis.
The stereochemistry of the final products of the Diels–Alder reac-
tion depends on the endo- or exo-orientation of the dienophile in
the transition state. In the case of compounds with an allyl moiety
we observed exo transition states. In cinnamyl derivatives 13a,b,
due to secondary orbital interactions, endo transition states
occurred.
The required starting unsaturated aldehydes (Scheme 4) were
prepared through alkylation (6;8a,b;10a,b) of commercially avail-
able salicylaldehyde with 3-chlorocyclohexene, allyl or methallyl
chloride and acylation (12a,b) of salicylaldehyde with 4-chlorocin-
namoyl chloride.
Figure 1. X-ray crystal structure (ORTEP plot) of 3.

4650
V. S. Matiychuk et al. / Tetrahedron Letters 49 (2008) 4648–4651
H
S
H
N
N
S
R1
H
O
O
O
R1
CHO
S
S
CHO
O
H
H
O
O
7
60%
8a,b
6
a
a
S
Cl
H
9a R1=H 72%
CHO
R3
N
9b R1=Me 75%
O
H3C
CHO
O
O
O
S
1
12a,b
R2
10a,b
Cl
H
S
a
N
b
H
N
S
H3C
O
O
H
O
S
O
S
H
13a R3=H 73%
13b R3=Cl 77%
11a R2=H 71%
11b R2=Br 69%
H
O
R2
R3
Scheme 4. Reactions of 4-thioxo-1,3-thiazolidine-2-one 1 with unsaturated aldehydes. Reagents and conditions: (a) 1 (1.0 equiv), appropriate aldehyde (1.0 equiv), NEt3
(1.0 equiv), AcOH, room temperature 12 h.22,23 (b) 1 (1.0 equiv), appropriate aldehyde (1.0 equiv), NEt3 (1.0 equiv), AcOH, 80 °C, 2 h.
Preliminary antitumor activity studies were performed24 for
triethyamine (10 mmol). The progress of the reaction was monitored by TLC.
The solid product that formed was collected by filtration and recrystallized
from dioxane.
compound 9a according to the NCI (USA) standard protocol.25–27
In summary, we have successfully developed novel, efficient
and stereoselective methods for the synthesis of 3,5a,6,11b-tetra-
hydro-2H,5H-chromeno[40,30:4,5]thiopyrano[2,3-d]thiazol-2-ones
derivatives via a domino-Knoevenagel–hetero-Diels–Alder appr-
oach based on 4-thioxo-1,3-thiazolidine-2-one.
18. Spectral and analytical data for new compounds 3 and 5b are as follows.
(5aRS,8R,9aRS)-5,5,8-trimethyl-3,5,5a,6,7,8,9,9a-octahydro-2H-[2]benzothio-
pyrano[3,4-d][1,3]thiazol-2-one 3: Yield 79%, mp 189–190 °C (EtOH); 1H NMR
(400 MHz, DMSO-d6): 0.87 (d, J = 6.8 Hz, 3H, CH3CH), 0.90–1.05 (m, 3H), 1.25 (s,
3H, CH3), 1.28 (s, 3H, CH3), 1.42–1.51 (m, 1H), 1.55 (t, J = 12.0 Hz, 1H), 1.73 (d,
J = 12.0 Hz, 1H), 1.83 (m, 2H), 2.24 (t, J = 8.0 Hz, 1H), 11.12 (s, 1H, NH); 13C NMR
(100 MHz, DMSO-d6): 22.6, 23.8, 26.1, 27.9, 32.2, 35.0, 36.8, 42.8, 47.6, 50.6,
107.7, 119.1, 171.7; EI-MS (m/z): 269 (M+). Anal. Calcd for C13H19NOS2: C,
57.95; H, 7.11; N, 5.20. Found: C, 58.03; H, 7.27; N, 5.08. (5aRS,11bRS)-
3,5a,6,11b-Tetrahydro-2H,5H-chromeno[40,30:4,5]thiopyrano[2,3-d][1,3]thia-
zol-2-one 5b: Yield 80%, mp 230–231 °C (dioxane); 1H NMR (400 MHz,
DMSO-d6): 2.22–2.36 (m, 1H, 5a-H), 3.00–3.08 (m, 1H, 5-H), 3.15 (dd, 1H,
J = 3.6, 12.0 Hz, 5-H), 3.82–4.00 (m, 1H, 6-H), 3.97 (d, 1H, J = 10.5 Hz, 11b-H),
4.39 (dd, 1H, J = 3.6, 10.3 Hz, 6-H), 6.85 (d, 1H, J = 7.6 Hz, 8-H), 6.95 (t, 1H,
J = 7.8 Hz, 10-H), 7.17 (t, 1H, J = 7.6 Hz, 9-H), 7.43 (d, 1H, J = 7.8 Hz, 11-H), 11.50
(s, 1H, NH); 13C NMR (100 MHz, DMSO-d6): 27.9, 30.2, 38.7, 69.2, 105.6, 117.4,
121.2,121.6, 123.4, 127.7, 129.2, 153.7, 170.9. EI-MS (m/z): 277 (100%, M+).
Anal. Calcd for C13H11NO2S2: C, 56.30; H, 4.00; N, 5.05. Found: C, 56.45; H, 4.15;
N, 5.00.
Acknowledgments
We thank Dr. V. L. Narayanan from the Drug Synthesis and
Chemistry Branch, National Cancer Institute, Bethesda, MD, USA,
for in vitro evaluation of anticancer activity.
References and notes
1. Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic Synthesis;
Wiley-VCH, 2006.
2. Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
3. Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967–1983.
4. Bogdanowicz-Szwed, K.; Palasz, A. Monatsh. Chem. 1999, 130, 795–807.
5. Tietze, L. F. J. Heterocycl. Chem. 1990, 27, 47–69.
19. Crystallographic data for 3: Empirical formula: C13H19NOS2, formula weight:
269.41, crystal color, habit: colorless, block, crystal system: monoclinic, space
group: P21/n (#14), a = 9.3084(4), b = 12.9824(4), c = 12.1118(4) Å, b =
104.462(4)°, V = 1417.28(9) Å3, Z = 4, Dcalc = 1.263 g/cm3, F(000) = 576, diffra-
ctometer: Kuma-KM-4-CCD, residuals: R[F2 > 2 (F2)], wR(F2): 0.032, 0.096.
r
Crystallographic data for the structure have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 655431. 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).
6. Snider, B. B.; Lu, Q. J. Org. Chem. 1996, 61, 2839–2844.
7. Haake, M.; Holz, H. Phosphorus, Sulfur, Silicon Relat. Elem. 1999, 153, 407–408.
8. Tietze, L. F.; Pfeiffer, T.; Schuffenhauer, A. Eur. J. Org. Chem. 1998, 12, 2733–
2741.
9. Davion, Y.; Joseph, B.; Merour, J. Y. Synlett 1998, 1051–1052.
10. Sabitha, G.; Reddy, E. V.; Fatima, N.; Yadav, J. S.; Krishna, K. V. S. R.; Kunwar, A.
C. Synthesis 2004, 1150–1154.
11. Kassab, N. A. E. L.; Allah, S. O. A.; Messeha, N. A. J. Prakt. Chem. 1974, 316, 209–
214.
12. Ead, H. A.; Abdallah, S. O.; Kassab, N. A.; Metwalli, N. H.; Saleh, Y. E. Arch. Pharm.
1987, 320, 1227–1232.
13. Metwally, N. H. J. Sulfur Chem. 2007, 28, 275–284.
14. Lesyk, R.; Zimenkovsky, B.; Atamanyuk, D.; Jensen, F.; Kiec-Kononowicz, K.;
Gzella, A. Bioorg. Med. Chem. 2006, 14, 5230–5240.
15. Lesyk, R. B.; Zimenkovsky, B. S. Curr. Org. Chem. 2004, 8, 1547–1577.
16. Zimenkovsky, B. S.; Lukyanchuk, V. D.; Atamanyuk, D. V.; Renzyak, S. Ya.;
Lesyk, R. B. Farm. Zh. (in Ukrainian) 2007, 78–88; Chem. Abstr. 2007, 836917.
17. Preparation of (5aRS,8R,9aRS)-5,5,8-trimethyl-3,5,5a,6,7,8,9,9a-octahydro-2H-
[2]benzothiopyrano[3,4-d][1,3]thiazol-2-one (3). To a suspension of 10 mmol
of 4-thioxo-2-thiazolidinone 1 in 10 ml of anhydrous acetonitrile, 13 mmol of
20. Cremer, D.; Pople, J. A. J. Am. Chem. Soc. 1975, 97, 1354–1358.
21. Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpen, A. G.; Taylor, R. J.
Chem. Soc., Perkin Trans. 2 1987, S1–S19.
22. Typical procedure: A solution of appropriate unsaturated aldehyde (12 mmol),
triethylamine (10 mmol) and 4-thioxo-2-thiazolidinone
1 (10 mmol) was
stirred at room temperature in acetic acid (20 ml) for 12 h. The progress of
the reaction was monitored by TLC. The solid product that formed was
collected by filtration and recrystallized from ethanol.
23. Spectral and analytical data for new compounds: (7bRS,12bRS)-
3,4a,5,6,7,7a,7b,12b-octahydro-2H-xantheno[90,10:4,5,6]thiopyrano[2,3-d][1,
3]thiazol-2-one 7: Yield 60%, mp 205–207 °C (EtOH); 1H NMR (200 MHz,
DMSO-d6): 1.35–1.80 (m, 6H, CH2), 2.31–2.41 (m, 1H, 7b-H), 3.50–3.65 (m, 1H,
4a-H), 4.09 (d, 1H, J = 11.2 Hz, 12b-H), 4.40–4.52 (m, 1H, 7a-H), 6.81 (d, 1H,
J = 8.0 Hz, Ar), 6.90 (t, 1H, J = 7.4 Hz, Ar), 7.12–7.19 (m, 1H, Ar), 7.41 (d, 1H,
J = 7.7 Hz, Ar), 11.46 (s, 1H, NH). 13C NMR (95 MHz, DMSO-d6): d 22.5, 26.1,
28.5, 29.4, 39.7, 40.9, 74.7, 104.3, 117.2, 120.1, 122.2, 126.9, 128.3, 152.5,
170.4. EI-MS (m/z): 317 (M+). Anal. Calcd for C16H15NO2S2: C, 60.54; H, 4.76; N,
4.41. Found: C, 60.29; H, 4.65; N, 4.30. (5aRS,13cRS)-3,5a,6,13c-Tetrahydro-
2H,5H-naphtho[100,200:50,60]pyrano[40,30:4,5]thiopyrano[2,3-d]thiazol-2-one 9a:
Yield 72%, mp >260 °C (AcOH); 1H NMR (200 MHz, DMSO-d6): 2.77–2.87 (m,
1H, 5a-H), 3.25–3.33 (m, 1H, 5-H), 3.70 (dd, 1H, J = 2.6, 12.8 Hz, 5-H), 4.25 (t,
1H, J = 10.9 Hz, 6-H), 4.38 (dd, 1H, J = 2.9, 11.1 Hz, 6-H), 4.64 (d, 1H, J = 4.0 Hz,
13c-H), 7.05 (d, 1H J = 8.8 Hz, Ar), 7.34–7.41 (m, 1H, Ar), 7.49–7.57 (m, 1H, Ar),
citronellal
2 was added. Next, 5 mmol of EDDA in 10 ml of anhydrous
acetonitrile was added under stirring. After 48 h, the reaction mixture was
refluxed for 5 min and then cooled. The obtained precipitate was filtered off,
washed with hexane and recrystallized from ethanol. Preparation of
(5aRS,11bRS)-3,5a,6,11b-tetrahydro-2H,5H-chromeno[40,30:4,5]thiopyrano[2,
3-d][1,3]thiazol-2-one (5b). A solution of 2-allyloxybenzaldehyde 4 (10 mmol)
and thiazolidinone 1 (10 mmol) in acetic acid or acetonitrile (20 ml) was
stirred at room temperature in the presence of
a catalytic amount of

V. S. Matiychuk et al. / Tetrahedron Letters 49 (2008) 4648–4651
4651
7.74–7.87 (m, 2H, Ar), 7.97 (d, 1H, Ar), 11.29 (s, 1H, NH). 13C NMR (95 MHz,
DMSO-d6): d 27.3, 28.1, 29.5, 64.5, 105.8, 114.9, 117.5, 118.8, 122.3, 123.5,
126.5, 128.5, 128.6, 129.3, 132.1, 151.0, 170.3. EI-MS (m/z): 327 (M+).
Anal. Calcd for C17H13NO2S2: C, 62.36; H, 4.00; N, 4.28. Found: C, 62.50; H,
4.10; N, 4.40. (5aRS,13cRS)-3,5a,6,13c-Tetrahydro-5a-methyl-2H,5H-naphtho-
[100,200:50,60]pyrano[40,30:4,5]thiopyrano[2,3-d]thiazol-2-one 9b: Yield 75%, mp
>250 °C (AcOH); 1H NMR (400 MHz, DMSO-d6): 1.21 (s, 3H, CH3), 2.94 (d, 1H,
J = 13.8 Hz, SCH2), 3.51 (d, 1H, J = 13.8 Hz, SCH2), 3.91 (d, 1H, J = 10.5 Hz, OCH2),
4.56 (d, 1H, J = 10.5 Hz, OCH2), 4.14 (s, 1H, 13c-H), 6.97–7.91 (6H, C10H6), 10.93
(s, 1H, NH). 13C NMR (95 MHz, DMSO-d6): d 24.2, 29.5, 33.8, 36.1, 68.7, 107.8,
115.0, 117.9, 119.2, 122.8, 124.3, 127.1, 129.3, 129.6, 129.9, 133.1, 150.7, 171.2.
EI-MS (m/z): 341 (M+). Anal. Calcd for C18H15NO2S2: C, 63.32; H, 4.43; N, 4.10.
Found: C, 63.07; H, 4.50; N, 4.14. (5aRS,11bRS)-3,5a,6,11b-Tetrahydro-5a-
methyl-2H,5H-[1]benzopyrano[40,30:4,5]thiopyrano[2,3-d][1,3]thiazol-2-one
11a: Yield 71%, mp 294–295 °C (dioxane); 1H NMR (400 MHz, DMSO-d6): 0.87
(s, 3H, CH3), 2.85 (d, 1H, J = 11.7 Hz, 5-H), 3.08 (d, 1H, J = 11.7 Hz, 5-H), 3.89 (d,
1H, J = 9.8 Hz, 6-H), 4.09 (s, 1H, 11b), 4.12 (d, 1H, J = 9.8 Hz, 6-H), 6.86 (d, 1H
J = 7.8 Hz, 8-H), 6.95 (t, 1H J = 7.8 Hz, 10-H), 7.18 (t, 1H J = 7.8 Hz, 9-H), 7.43 (d,
1H, J = 7.8 Hz, 11-H), 11.55 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d 16.3,
33.1, 35.0, 41.4, 74.1, 104.6, 117.6, 121.4, 121.7, 121.8, 128.1, 129.0, 154.5,
170.9. EI-MS (m/z): 291 (M+). Anal. Calcd for C14H13NO2S2: C, 57.71; H, 4.50;
N, 4.81. Found: C, 57.47; H, 4.34; N, 4.92. (5aRS,11bRS)-10-Bromo-3,5a,6,
11b-tetrahydro-5a-methyl-2H,5H-[1]benzopyrano[40,30:4,5]thiopyrano[2,3-
d]thiazol-2-one 11b: Yield 69%, mp 229–231 °C (AcOH); 1H NMR (200 MHz,
DMSO-d6): 0.85 (s, 3H, CH3), 2.85 (d, 1H, J = 11.9 Hz, 5-H), 3.08 (d, 1H,
J = 11.9 Hz, 5-H), 3.90 (d, 1H, J = 10.4 Hz, 6-H), 4.12 (s, 1H, 11b-H), 4.14 (d, 1H,
J = 10.4 Hz, 6-H), 6.84 (d, 1H, J = 8.6 Hz, Ar), 7.34 (d, 1H, J = 8.6 Hz, Ar), 7.55 (s,
1H, Ar), 11.61 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): d 15.9, 32.4, 34.2,
40.8, 73.8, 102.9, 111.7, 119.0, 121.5, 123.8, 129.7, 130.9, 153.1. 169.8. EI-MS
(m/z): 369 (M+, 79Br), 371 (M+, 81Br). Anal. Calcd for C14H12BrNO2S2: C, 45.41; H,
3.27; N, 3.78. Found: C, 45.15; H, 3.20; N, 3.90. (5aRS,11bSR)-3,5a,6,11b-
Tetrahydro-5-(4-chlorophenyl)-2H,6H-[1]benzopyrano[40,30:4,5]thiopyrano[2,
3-d][1,3]thiazol-2,6-dione 13a: Yield 73%, mp 240–242 °C (EtOH); 1H NMR
(400 MHz, DMSO-d6): 3.75 (d, 1H, J = 4.9 Hz, 11b-H), 4.00–4.02 (m, 1H, 5a-H),
5.14 (d, 1H, J = 3.2Hz, 5-H), 7.13–7.18 (m, 2H, Ar), 7.30–7.44 (m, 6H, Ar) 11.66
(s, 1H, NH). 13C NMR (95 MHz, DMSO-d6): d 31.2, 43.3, 43.6, 102.6, 117.4, 121.0,
124.2, 125.6, 128.5, 128.6, 129.2, 129.5, 130.4, 140.0, 150.5, 166.7, 170.9. MS
(m/z): 401 (M+). Anal. Calcd for C19H12ClNO3S2: C, 56.78; H, 3.01; N, 3.49.
Found: C, 56.87; H, 3.12; N, 3.32. (5aRS,11bSR)-10-Chloro-5-(4-chlorophenyl)-
3,5a,6,11b-tetrahydro-2H,6H-[1]benzopyrano[40,30:4,5]thiopyrano[2,3-d][1,3]-
thiazol-2,6-dione 13b: Yield 77%, mp 277–279 °C (EtOH); 1H NMR (400 MHz,
DMSO-d6): 3.78 (d, 1H, J = 5.9 Hz, 11b-H), 3.83–3.86 (m, 1H, 5a-H), 5.08 (d, 1H,
J = 3.9Hz, 5-H), 7.12 (d, 1H, J = 7.8 Hz Ar), 7.34–7.40 (m, 4H, Ar), 7.44 (d, 2H,
J = 7.8 Hz Ar), 11.53 (s, 1H, NH). MS (m/z): 435 (M+). Anal. Calcd for
C19H11Cl2NO3S2: C, 52.30; H, 2.54; N, 3.21. Found: C, 52.44; H, 2.65; N, 3.03.
24. Compound 9a was evaluated toward a three human tumor cell line panel and
showed the following growth percent values: at NCI-H460 cell line (Non-Small
Cell Lung Cancer)—3%, MCF7 (Breast Cancer)—25%, and SF-268 (CNS Cancer)—
31%. Therefore substance 9a which reduced the growth of the cell lines to 32%
or less was passed on for evaluation in the full panel of 60 human tumor cell
lines. Compound 9a showed the highest antitumor cytotoxicity against
leukemia cell lines MOLT-4 (LogGI50 = ꢀ4.08) and RPMI-8226 (LogGI50
=
ꢀ4.70), as well as the melanoma cell line SK-MEL-2 (LogGI50 = ꢀ4.27). These
preliminary results are promising and need further investigation of the
antitumor activity of reported and related compounds.
25. Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose,
C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A. J. Nat. Cancer Inst. 1991, 83,
757–766.
26. Boyd, M. R.; Paull, K. D. Drug Dev. Res. 1995, 34, 91–109.
27. Monks, A.; Scudiero, D. A.; Johnson, G. S.; Paull, K. D.; Sausville, E. A. Anticancer
Drug Des. 1997, 12, 533–541.