Isorhodanine and Thiorhodanine
Motifs in the Synthesis of Fused Thiopyrano[2,3-d][1,3]thiazoles

Danylo Kaminskyy; Olexandr Vasylenko; Dmytro Atamanyuk; Andrzej Gzella; Roman Lesyk

doi:10.1055/s-0030-1260765

LETTER

Isorhodanine and Thiorhodanine Motifs in the Synthesis of Fused Thiopyrano[2,3-d][1,3]thiazoles

Danylo Kaminskyy^a, Olexandr Vasylenko^b, Dmytro Atamanyuk^a, Andrzej Gzella^c, Roman Lesyk*^a
^a Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine
Fax: +380(322)757734; e-Mail: dr_r_lesyk@org.lviv.net;
^b Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of Ukraine, Murmanska 1, Kyiv 02094, Ukraine
^c Department of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznań, Poland

Abstract

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Abstract

Utilization of 4-thioxo-2-(thi)oxothiazolidines in the synthesis of new fused thiopyrano[2,3-d][1,3]thiazole derivatives under Knoevenagel and hetero-Diels-Alder reaction conditions has been studied.

Key words

iso(thio)rhodanine - condensation - Diels-Alder reaction - heterocycles - antitumor agents

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References

References and Notes

1 Lesyk RB. Zimenkovsky BS. Curr. Org. Chem. 2004, 1547

2 Lesyk R. Zimenkovsky B. Atamanyuk D. Jensen F. Kiec-Kononowicz K. Gzella A. Bioorg. Med. Chem. 2006, 5230

3 Lesyk R. Vladzimirska O. Holota S. Zaprutko L. Gzella A. Eur. J. Med. Chem. 2007, 641

4 Kaminskyy D. Zimenkovsky B. Lesyk R. Eur. J. Med. Chem. 2009, 3627

5 Matiychuk VS. Lesyk RB. Obushak MD. Gzella A. Atamanyuk DV. Ostapiuk YV. Kryshchyshyn AP. Tetrahedron Lett. 2008, 4648

6a Ohishi Y. Mukai T. Nagahara M. Yajima M. Kajikawa N. Miyahara K. Takano T. Chem. Pharm. Bull. 1990, 1911

6b Ohishi Y. Mukai T. Nagahara M. Yajima M. Kajikawa N. Chem. Pharm. Bull. 1992, 907

7 Borisova MA. Ginak AI. Sochilin YeG. Zh. Prikl. Khim. (in Russian) 1970, 1886 ; Chem. Abstr. 1970, 520550

8

Preparation of 5-alkylidene-4-thioxo-2-thiazolidinone (1) and 8,8-R^¹,R^²-5,8-dihydro-2H-[1,3]thiazolo[5′,4′:5,6]thio-pyrano[2,3-d][1,3]thiazol-2,6 (3H)-dithione (3). To a solution of 4-thioxo-2-thiazolidinone or 2,4-dithioxo-thiazolidine (5 mmol) in the appropriate ketone (20 mL),
2-3 drops of ethanolamine were added. The reaction mixture was stirred at room temperature for 1 h, then diluted with H₂O and 2-3 drops of AcOH were added. The solid product was filtered off, washed with H₂O, EtOH, and Et₂O, and recrystallized with ethanol or toluene for 1 or with mixtures of DMF-EtOH or DMF-AcOH (1:2) for 3

9

Spectral and analytical data for compounds 1 and 3 are as follows. 5-Isopropylidene-4-thioxo-2-thiazolidinone (1a): Yield: 90%; mp 152-154 ˚C (EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.67 (s, 3 H, CH₃), 2.17 (s, 3 H, CH₃), 11.85 (s, 1 H, NH). 5-Cyclohexylidene-4-thioxo-2-thiazolidinone (1b): Yield: 76%; mp 120-122 ˚C (EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.65 (m, 8 H), 2.30 (m, 2 H, cyclohexylidene), 10.90 (s, 1 H, NH). 5-Cyclopentylidene-4-thioxo-2-thiazolidinone (1c): Yield: 74%; mp 174-176 ˚C (toluene). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.78 (quint., J = 6.8 Hz, 2 H), 1.89 (quint., J = 6.8 Hz, 2 H), 2.41 (t, J = 6.4 Hz, 2 H), 3.03 (t, J = 6.4 Hz, 2 H, cyclopentylidene), 13.24 (s, 1 H, NH). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 192.83, 170.46, 166.64, 123.88, 39.71, 37.56, 27.69, 25.71. LC-MS: m/z (%) = 200.1 (100) [M⁺ + 1]. 8,8-Dimethyl-5,8-dihydro-2H-[1,3]thiazolo[5′,4′:5,6]thiopyrano[2,3-d][1,3]thiazol-2,6 (3H)-dithione (3a): Yield: 52%; mp 190-192 ˚C (DMF-AcOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.54 (s, 6 H, 2 × CH₃), 13.53 (s, 2 H, NH). LC-MS: m/z (%) = 305.2 (100) [M⁺ + 1]. Spiro[cyclopentane-1,8′-(5,8-dihydro-2H-[1,3]thiazolo[5′,4′:5,6]thiopyrano[2,3-d][1,3]thiazol)]-2,6 (3H)-dithione (3c): Yield: 24%; mp 155-157 ˚C (DMF-EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.55-2.03 (m), 2.10-2.45 (m, 8 H, cyclopentyl), 13.67 (s, 2 H, 2 × NH). LC-MS: m/z (%) = 331.1 (100)[M⁺ + 1]

10

Preparation of 8,8-R^¹,R^²-5,8-dihydro-2H-[1,3]thiazolo-[5′,4′:5,6]thiopyrano[2,3-d][1,3]thiazol-2,6 (3H)-diones (2). To a solution of 4-thioxo-2-thiazolidinone (5 mmol) and the appropriate ketone (6 mmol) in EtOH (20 mL), a catalytic amount of ethanolamine was added. The reaction mixture was heated at reflux for 15 min. After cooling the reaction mixture to room temperature, the product was filtered off, washed with EtOH, and Et₂O, and recrystallized (DMF-EtOH, 1:2)

11

Spectral and analytical data for compounds 2 are as follows. 8,8-Dimethyl-5,8-dihydro-2H-[1,3]thiazolo[5′,4′:5,6]-thiopyrano[2,3-d][1,3]thiazol-2,6 (3H)-dione (2a). Yield: 45%; mp 210-212 ˚C (DMF-EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.46 (s, 6 H, 2 × CH₃), 11.53 (s, 2 H, NH). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.14, 112.40, 112.33, 36.24, 31.59. LC-MS: m/z (%) = 273.0(100) [M⁺ + 1]. Spiro[cyclohexane-1,8′-(5,8-dihydro-2H-[1,3]thiazolo-[5′,4′:5,6]-thiopyrano[2,3-d][1,3]thiazol-2,6(3H)-dione (2b): Yield: 45%; mp 235-237 ˚C (DMF-EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.47 (br s, 2 H), 1.64 (br s, 4 H), 1.82 (t, J = 5.2 Hz, 4 H, cyclohexyl), 11.79 (s, 2 H, NH). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.49, 114.67, 112.84, 39.66, 38.63, 24.84, 23.30. LC-MS: m/z (%) = 313.1 (100) [M⁺ + 1]

12 Kumar A. Singh P. Saxena A. De A. Chandra R. Mozumbar S. Catal. Commun. 2008, 17

13

Crystallographic data for 2a: Empirical formula: C₉H₈N₂O₂S₃; formula weight: 272.35; yellow, block; crystal system: orthorhombic; space group: Pbca (#61); a = 10.0548 (17), b = 13.7198 (17), c = 16.3093 (18) Å; V = 2249.9 (5) Å^³; Z = 8; D _calc = 1.608 g/cm^³; F(000) = 1120; diffractometer: Kuma KM-4; residuals: R[F ^² > 2σ(F ^²)], wR(F ^²): 0.048, 0.1347.
Crystallographic data for 2b: Empirical formula: C₁₂H₁₂N₂O₂S₃; formula weight: 312.42: colorless, lath; crystal system: orthorhombic; space group: Pbca (#61); a = 15.5909 (19), b = 10.2253 (9), c = 16.4741 (17) Å; V = 2626.3 (5) Å^³; Z = 8; D _calc = 1.580 g/cm^³; F(000) = 1296; diffractometer: Kuma KM-4; residuals:
R[F ^² > 2σ(F ^²)], wR(F ^²): 0.040, 0.1329.
The supplementary crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC), 12 Union ROAD, Cambridge CB2 1EZ (UK), Tel.: (+44) 1223/336-408, Fax: (+44) 1223/336-033, E-mail: deposit@ccdc.cam.ac.uk, World Wide Web: http://www.ccdc.cam.ac.uk (CCDC for 2a: 780127, for 2b: 780128)

14 Etter MC. MacDonald JC. Bernstein J. Acta Crystallogr., Sect. B: Struct. Sci. 1990, 46: 256

15 Bernstein J. Davis RE. Shimoni L. Chang N.-L. Angew. Chem., Int. Ed. Engl. 1995, 1555

16

General experimental procedure for the hetero-Diels-Alder reaction yielding fused derivatives of thiopyrano[2,3-d]-[1,3]thiazol-2-ones (4-6). A mixture of the appropriate
5-alkylidene-4-thioxo-2-thiazolidinone (10 mmol) and the appropriate dienophile {1-(4-bromophenyl)pyrrole-2,5-dione, (3,5-dioxo-4-azatricyclo[5.2.1.0^²,6]dec-8-en-4-yl)acetic acid or norbornene} (12 mmol) was heated at reflux for 1 h with a catalytic amount of hydroquinone (2-3 mg) in glacial AcOH (10 mL), then left overnight at r.t. The precipitated crystals were filtered off, washed with EtOH, and recrystallized from the appropriate solvent

17

Spectral and analytical data for compounds (4-6) are as follows. 6-(4-Bromophenyl)-8,8-dimethyl-3,4a,7a,8-tetrahydropyrrolo[3′,4′:5,6]thiopyrano[2,3-d]thiazol-2,5,7-trione (4a): Yield 85%; mp >240 ˚C (DMF-EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.39 (s, 3 H, CH₃), 1.49 (s, 3 H, CH₃), 3.50 (d, J = 8.7 Hz, 1 , 7a-H), 4.93 (d, J = 8.7 Hz, 1 , 4a-H), 7.19 (d, J = 8.7 Hz, 2 H, ArH), 7.68 (d, J = 8.7 Hz, 2 H, ArH), 11.55 (s, 1 H, NH, major isomer). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 174.53, 172.92, 170.92, 132.91, 131.53, 122.52, 117.48, 116.12, 52.87, 43.57, 36.31, 26.93, 23.94 major isomer. LC-MS: m/z (%) = 426.0 (91.59) [M⁺ + 1]. Spiro[cyclohexane-1,8′-(6-(4-bromophenyl)-3,4a,7a,8-tetrahydropyrrolo[3′,4′:5,6]thiopyrano[2,3-d]thiazol)]-2,5,7-trione (4b): Yield: 74%; mp 236-238 ˚C (EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.52-1.80 (m, 6 H), 2.03 (m, 3 H), 2.27 (m, 1 H, cyclohexyl), 4.14 (d, J = 8.4 Hz, 1 , 7a-H), 4.67 (d, J = 8.4 Hz, 1 , 4a-H), 7.13 (d, J = 8.8 Hz, 2 , ArH), 7.67 (d, J = 8.8 Hz, 2 , ArH), 11.50 (s, 1 H, NH, major isomer). Spiro[cyclopentane-1,8′-(6-(4-bromophenyl)-3,4a,7a,8-tetrahydropyrrolo[3′,4′:5,6]thiopyrano[2,3-d]thiazol)]-2,5,7-trione (4c): Yield: 70%; mp 227-229 ˚C (DMF-EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.48-1.62 (m, 1 H), 1.64-1.82 (m, 4 H), 1.87-1.96 (m, 1 H), 2.06-2.17 (m, 3 H, cyclopentyl fragment), 3.85 (d, J = 8.5 Hz, 1 , 7a-H), 4.78 (d, J = 8.5 Hz, 1 , 4a-H), 7.06 (d, J = 8.5 Hz, 2 H, ArH), 7.69 (d, J = 8.5 Hz, 2 H, ArH), 11.62 (s, 1 H, NH, major isomer). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 174.44, 174.37, 170.45, 132.61, 131.42, 129.07, 122.08, 118.44, 117.35, 53.68, 47.44, 44.65, 37.24, 36.84, 24.02, 23.42 major isomer. LC-MS: m/z (%) = 452.0 (90.64) [M⁺ + 1].
2-[9,9-Dimethyl-6,13,15-trioxo-3,7-dithia-5,14-diazapenta-cyclo[9.5.1.0^²,¹0.0^4,8.0^¹²,¹6]heptadec-4 (8)-en-14-yl]acetic acid (5a): Yield: 69%; mp >240 ˚C (EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.14 (s, 3 H, CH₃), 1.17 (s, 3 H, CH₃), 1.50 (d, J = 10.5 Hz, 1 H), 1.75 (d, J = 10.5 Hz, 1 H), 2.17 (d, J = 2.4 Hz, 1 H), 2.72 (dd, J = 4.7, 14.9 Hz, 2 H,), 3.23 (m, 1 H), 3.27-3.33 (m, 1 H), 3.38 (d, J = 8.2 Hz, 1 H, norbornane), 4.00 (d, J = 18.2 Hz, 1 H, NCH₂C), 4.08 (d,
J = 18.2 Hz, 1 H, NCH₂C), 11.43 (s, 1 H, NH). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 177.03, 176.76, 170.79, 169.20, 119.98, 116.91, 52.29, 49.48, 48.26, 47.98, 46.70, 41.87, 39.88, 36.01, 28.43, 25.99. LC-MS: m/z (%) = 395.21 (100) [M⁺ + 1]. 2-{Spiro[cyclohexane-1,9′-(6,13,15-trioxo-3,7-dithia-5,14-diazapentacyclo[9.5.1.0^²,¹0.0^4,8.0^¹²,¹6]heptadec-4 (8)-en-14-yl)]}acetic acid (5b): Yield: 71%; mp >240 ˚C (EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.27-1.35 (m, 2 H), 1.38-1.67 (m, 8 H), 1.83-1.89 (m, 2 H), 2.77 (dd, J = 4.0, 14.6 Hz, 2 H), 3.19 (m, 3 H), 3.35 (d, J = 8.4 Hz, 1 H, norbornane and cyclohexyl), 3.99 (d, J = 17.3 Hz, 1 H, NC ₂C), 4.11 (d, J = 17.3 Hz, 1H, NCH₂C), 11.31 (s, 1 H, NH), 13.21 (br. s, 1 H, COOH). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 177.39, 177.04, 171.37, 169.51, 120.79, 51.03, 50.79, 49.74, 48.58, 46.27, 39.95, 39.50, 38.82, 26.01, 22.42, 22.27. LC-MS: m/z (%) = 435.2 (100) [M⁺ + 1]. 9,9-Dimethyl-3,7-dithia-5-azatetracyclo[9.2.1.0^²,¹0.0^4,8]-tetradecen-4 (8)-one-6 (6a): Yield: 63%; mp 125-127 ˚C (MeCN). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 1.21 (s, 6 , 2 × CH₃), 1.03 (d, J = 9.9 Hz, 1 H), 1.38 (m, 2 H), 1.46-49 (m, 3 H), 1.87 (d, J = 8.2 Hz, 1 H), 2.22 (m, 2 H), 3.37 (d, J = 8.2 Hz, 1 H, norbornane fragment), 11.34 (s, 1 H, NH). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.90, 120.65, 116.47, 58.06, 45.36, 38.94, 36.03, 35.02, 31.36, 28.75, 28.17, 24.70. LC-MS: m/z (%) = 268.0 (98.18) [M⁺ + 1]. Spiro[cyclohexane-1,9′-(3,7-dithia-5-azatetracyclo-[9.2.1.0^²,¹0.0^4,8]tetradecen-4 (8)]one-6 (6b): Yield: 52%; mp 195-197 ˚C (EtOH). ^¹H NMR (400 MHz, DMSO-d ₆): δ = 0.93 (d, J = 9.7 Hz, 1 H), 1.17 (m, 3 H), 1.32 (m, 3 H), 1.45-1.55 (m, 7 H), 1.79 (m, 1 H), 1.91 (m, 1 H), 2.17 (m, 2 H), 2.25 (d, J = 3.6 Hz, 1 H), 3.29 (d, J = 8.2 Hz, 1 H, norbornane and cyclohexyl), 11.35 (s, 1 H, NH). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 171.23, 121.79, 50.48, 48.21, 37.17, 35.69, 34.57, 31.82, 27.95, 25.87, 22.53.
LC-MS: m/z (%) = 308.1 (100) [M⁺ + 1]

18 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, 757

19 Boyd MR. Paull KD. Drug Dev. Res. 1995, 91

20 Monks A. Scudiero DA. Johnson GS. Paull KD. Sausville EA. Anti-Cancer Drug Des. 1997, 533

21

Compounds 2a, 3a, and 2b were evaluated with a 60 human tumor cell lines panel at concentrations of 10^-5 M and showed the following mean growth percent values: 2a - 101.51%, 3a - 108.41%, 2b - 105.07%. However, decreases in the growth percent values were detected following treatment of selected cell lines with compounds: MOLT-4 (leukemia) - 62.73% (compound 2a); IGROV1 (ovarian cancer) - 50.98% and UO-31 (renal cancer) - 49.34% (compound 2b). Compounds 4a, 5a, and 6a were passed on for evaluation in the full panel of 60 human tumor cell lines at 10-fold dilutions ranging from 10^-4 to 10^-8 M. Compounds were characterized by the following values of mean dose response parameters: lgGI₅₀ = -4.04, lgTGI = -4.01, lgLC₅₀ = -4.0 (compound 4a); lgGI₅₀ = -4.00, lgTGI =
-4.00, lgLC₅₀ = -4.00 (compound 5a); lgGI₅₀ = -4.66, lgTGI = -4.25, lgLC₅₀ = -4.04 (compound 6a). Compound 4a showed the highest antitumor cytotoxicity against leukemia cell lines: HL-60 (TB), (lgGI₅₀ = -4.62), MOLT-4; (lgGI₅₀ = -4.48) and SR (lgGI₅₀ = -5.13). Compound 6a sensitized melanoma UACC-62 cell line (lgGI₅₀ = -4.91)
as well as breast cancer MDA-MB-435 cell line (lgGI₅₀ =
-4.87) but did not show a selective influence on any whole cancer subtype cell line panel.