A. Nakhi et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4418–4427
4427
12. (a) Puterová, Z.; Andicsová, A.; Moncol, J.; Rabong, C.; Végh, D. Tetrahedron Lett
2009, 50, 4670; (b) Perrior, T. R.; Tapolczay, D. J.; Whittle. A. J. US Patent No.
5077297, 31 Dec 1991.
was purified by column chromatography on silica gel using 9:1 hexane/ethyl
acetate to afford the compound 6a; yield: 60% (0.135 g); brown liquid; 1H NMR
(400 MHz, CDCl3) d: 0.96 (t, J = 6.9 Hz, 3H), 1.41–1.49 (m, 2H), 1.61–1.66 (m,
2H), 1.83–1.89 (m, 4H), 2.49 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H), 3.0 (t,
J = 6.1 Hz, 2H), 7.41–7.45 (m, 3H), 8.17–8.19 (m, 2H); 13C NMR (100 MHz,
CDCl3) d: 14.0, 19.0, 21.3, 21.9, 22.6, 24.7, 29.6, 31.4, 73.5, 96.2, 98.2, 125.0,
127.8 (2C), 129.3 (2C), 131.2, 131.9, 141.3, 141.7, 144.0, 147.1, 150.9; IR (KBr)
vmax (cmꢀ1): 2928, 2224, 1732, 1548, 1066, 690. MS (ESI) m/z: 363.3 [M+H]. (d)
Preparation of 7-aryl substituted-6-phenyl-4H-thieno[3,2-c]pyaran-4-one
derivatives 7; typical procedure for the synthesis of 7a: To a solution of
compound 5a (0.2 g, 0.49 mmol) in dry DMF (3 mL) was added 5 mol%
Pd(OAc)2 (0.001 g, 0.0049 mmol) and K2CO3 (0.13 g, 0.98 mmol) were added
under a nitrogen atmosphere and the mixture was stirred for 10 min. To this
was added, 4-hydroxy phenyl boronic acid (0.1 g, 0.73 mmol) and the mixture
was allowed to stir at 80 °C for 3 h. After completion of the reaction, the
mixture was cooled to room temperature, filtered through celite bed and the
filtrate was concentrated under vacuum. The crude mass was diluted with
dichloromethane (20 mL) and water (10 mL) and the mixture was extracted
with dichloromethane (3 ꢁ 30 mL). The organic layers were collected,
combined, washed with saturated aq NaCl (2 ꢁ 25 mL), dried over anhydrous
Na2SO4, filtered and concentrated under vacuum. The crude compound was
purified by column chromatography on silica gel using 7.5:2.5 hexane/ethyl
acetate to afford the compound 7a; yield: 52% (0.09 g); light brown semi solid;
1H NMR (400 MHz, CDCl3) d: 1.89–1.91 (m, 4H), 2.07–2.09 (m, 4H), 5.97–5.99
(m, 2H), 6.29–6.31 (m, 2H), 6.48–6.49 (m, 5H), 8.91 (s, 1H). 13C NMR (100 MHz,
CDCl3) d: 21.9, 22.7, 25.1, 25.3, 115.9, 116.1 (2C), 121.4, 125.3, 127.8 (2C), 128.8
(2C), 130.7 (2C), 132.4, 134.9, 137.3, 149.8, 150.2, 153.4, 157.4, 158.2; IR (KBr)
vmax (cmꢀ1): 3403, 2924, 1732, 754, 688. MS (ESI) m/z: 375.4 [M+H]. (e)
Preparation of 7-alkenyl substituted-6-phenyl-4H-thieno[3,2-c]pyaran-4-
one derivatives 8; typical procedure for the synthesis of 8a: The reaction
vessel was charged with compound 5a (0.2 g, 0.49 mmol), ethyl acrylate
(0.1 mL, 0.98 mmol), K2CO3 (0.13 g, 0.98 mmol), and the 5 mol% Pd(OAc)2
(0.001 g, 0.0049 mmol) in DMF (2 mL). The reaction mixture was stirred at
110 °C for 4 h. After completion of the reaction, the mixture was cooled to
room temperature, diluted with EtOAc (20 mL), and washed with 1 N aq HCl
and water. The organic phase was collected, dried over anhydrous Na2SO4,
filtered and concentrated. The residue was purified by column
chromatography on silica gel using 8:2 hexane/ethyl acetate to afford the
compound 8a; yield: 63% (0.11 g); colorless semi solid; 1H NMR (400 MHz,
CDCl3) d: 1.36 (t, J = 6.3 Hz, 3H), 2.58–2.61 (m, 4H), 3.04–3.06 (m, 2H), 3.21–
3.24 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 6.65 (d, J = 16.5 Hz, 1H), 7.53–7.55 (m, 3H),
7.76–7.78 (m, 2H) 7.82 (d, J = 16.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) d: 14.2,
23.7, 27.3, 33.1, 38.7, 60.7, 121.0, 125.5, 128.4, 128.7, 129.9, 130.6, 130.1, 130.8,
131.4, 132.4, 133.2, 134.4, 138.5, 139.1, 166.6, 172.7; IR (KBr) vmax (cmꢀ1):
2971, 1738, 1536, 872; MS (ESI) m/z: 381.7 [M+H]. (f) Synthesis of 9: To a
solution of compound 5c (0.2 g, 0.47 mmol) in 1,4-dioxane (2 mL) was added
Pd(OAc)2 (0.001 g, 0.0047 mmol), PPh3 (0.006 g, 0.023 mmol), and MnO2
(0.008 g, 0.094 mmol). The mixture was heated to reflux at 110 °C for 12 h.
After completion of the reaction, the mixture was cooled to room temperature,
and extracted with EtOAc (2 ꢁ 15 mL). The organic layers were collected,
combined, washed with water (15 mL), dried over anhydrous Na2SO4, filtered
and concentrated under low vacuum. The residue was then purified by column
chromatography on silica gel using 8:2 hexane/ethyl acetate to afford the
compound 9; yield: 58% (0.04 g); brown semi solid; 1H NMR (400 MHz, CDCl3)
d: 1.65–1.76 (m, 4H), 1.87–1.96 (m, 2H), 2.82–2.91 (m, 2H), 3.33–3.35 (m, 2H),
7.04 (s, 1H), 7.35–7.49 (m, 3H), 7.80–7.87 (m, 2H); 13C NMR (100 MHz, CDCl3)
d: 27.0, 27.6, 27.7, 29.9, 32.4, 98.2, 122.4, 125.0, 128.8 (2C), 129.7 (2C), 131.8,
140.4, 140.6, 147.1, 153.9, 158.6; IR (KBr) vmax (cmꢀ1): 3016, 2931, 1680, 1743,
852; MS (ESI) m/z: 297.1[M + H].
13. Pal, M. Synlett 2009, 2896.
14. (a) Yadav, J. S.; Reddy, B. V. S.; Hashim, S. R. J. Chem. Soc., Perkin Trans. 1 2000,
3025; (b) Yadav, J. S.; Reddy, B. V. S.; Premalatha, K.; Swamy, T. Tetrahedron
Lett. 2005, 46, 2687; (c) Yadav, J. S.; Reddy, B. V. S.; Rao, C. V.; Chand, P. K.;
Prasad, A. R. Synlett 2001, 1638; (d) Bandyopadhyay, D.; Mukherjee, S.; Banik,
B. K. Molecules 2010, 15, 2520.
15. For a review, see: Mphahlele, M. J. Molecules 2009, 14, 5308.
16. (a) Mulakayala, N.; Murthy, P. V. N. S.; Rambabu, D.; Aeluri, M.; Adepu, R.;
Krishna, G. R. C.; Reddy, M.; Prasad, K. R. S.; Chaitanya, M.; Kumar, C. S.; Rao, M.
V. B.; Pal, M. Bioorg. Med. Chem. Lett. 2012, 22, 2186; (b) Reddy, R.; Reddy, T. R.;
Joseph, S. C.; Reddy, K. S.; Reddy, L. S.; Kumar, P. M.; Pal, M. RSC Advances 2012,
2, 3387.
17. Barange, D. K.; Batchu, V. R.; Gorja, D.; Pattabiraman, V. R.; Tatini, L. K.; Babu, J.
M.; Pal, M. Tetrahedron 2007, 63, 1775.
18. For recent and leading examples, see: (a) Mancuso, R.; Mehta, S.; Gabriele, B.;
Salerno, G.; Jenks, W. S.; Larock, R. C. J. Org. Chem. 2010, 75, 897; (b) Verma, A.
K.; Aggarwal, T.; Rustagi, V.; Larock, R. C. Chem. Commun. 2010, 46, 4064; (c)
Mehta, S.; Larock, R. C. J. Org. Chem. 2010, 75, 1652; (d) Cho, C.-H.;
Neuenswander, B.; Larock, R. C. J. Comb. Chem. 2010, 12, 278.
19. (a) Crystal data of 5d: Molecular formula = C18H15IO2S, Formula
weight = 422.27, Monoclinic, P2(1)/c, a = 9.137 (2) Å, b = 23.917 (6) Å,
c = 7.2826 (19) Å, V = 1565.9 (7) Å3, T = 100 K, Z = 4, Dc = 1.791 Mg m–3
) = 0.71073 mm–1
13961 reflections were measured with 2748 unique
reflections (Rint= 0.0439), of which 2748 (I >2 (I)) were used for the structure
, l(Mo-
Ka
,
r
solution. Final R1 (w R2) = 0.0330 (0.0769), 200 parameters. The final Fourier
difference synthesis showed minimum and maximum peaks of ꢀ0.361 and
+1.584 e Åꢀ3 respectively. Goodness of fit = 1.060. Crystallographic data
(excluding structure factors) for 5d have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication number CCDC
867625. (b) Bondi, A. J. Phys. Chem. 1964, 68, 441.
20. (a) Preparation of alkynes 4; typical procedure for the synthesis of 4a: To a
solution of compound 3a (0.2 g, 0.59 mmol) in ethanol (3 mL) was added 10%
Pd/C (0.0006 g, 0.0059 mmol), PPh3 (0.006 g, 0.02 mmol), CuI (0.001 g,
0.0059 mmol) and Et3N (0.16 mL, 1.18 mmol) and the mixture was stirred for
15 min under nitrogen. Then, phenyl acetylene (0.1 mL, 0.89 mmol) was added
and the mixture was stirred at 60 °C for 2 h. After completion of the reaction,
the mixture was cooled to room temperature, filtered through celite bed and
the filtrate was concentrated under vacuum. The crude mass was diluted with
dichloromethane (20 mL) and water (10 mL) and the mixture was extracted
with dichloromethane (3 ꢁ 30 mL). The organic layers were collected,
combined, washed with saturated aq NaCl (2 ꢁ 25 mL), dried over anhydrous
Na2SO4, filtered and concentrated under vacuum. The crude compound was
purified by column chromatography on silica gel using 9:1 hexane/ethyl
acetate to afford the compound 4a; yield 72% (0.13 g); off white solid; mp:
88.5–89.5 °C; 1H NMR (400 MHz, CDCl3) d: 1.39 (t, J = 7.2 Hz, 3H), 1.78–1.84(m,
4H), 2.72 (t, J = 6.0 Hz, 2H), 2.83 (t, J = 6.0 Hz, 2H), 4.36 (q, J = 6.2 Hz, 2H), 7.28–
7.31 (m, 3H), 7.33–7.35 (m, 2H); 13C NMR (100 MHz, CDCl3) d: 14.1, 21.0, 22.3,
22.7, 26.1, 60.3, 82.8, 97.5, 107.3, 114.1, 114.3 (2C), 116.5, 128.3, 131.3, 136.2,
137.9, 150.4, 171.1. (b) Preparation of 7-iodo-4H-thieno[3, 2-c]pyran-4-one
derivatives 5; typical procedure for the synthesis of 5a:
A solution of
compound 4a (0.2 g, 0.64 mmol) and I2 (0.16 g, 0.64 mmol) in dichloromethane
(3 mL) was placed in a round bottom flask and stirred for 5 min under a
nitrogen atmosphere. The mixture was then diluted with ether (25 mL) and
washed with aq Na2S2O3 (20 mL). The organic layer was collected, dried over
anhydrous Na2SO4, filtered and concentrated under vacuum. The crude
compound was purified by column chromatography on silica gel using 9:1
hexane/ethyl acetate to afford the compound 5a; yield: 80% (0.21 g); light
yellow solid; mp: 213.7–214.7 °C; 1H NMR (400 MHz, CDCl3) d: 1.81–1.93 (m,
4H), 2.82 (t, J = 5.6 Hz, 2H), 2.99 (t, J = 6.0 Hz, 2H), 7.44–7.45 (m, 3H), 7.73–7.75
(m, 2H); 13C NMR (100 MHz, CDCl3) d: 27.0, 27.6, 28.3, 29.9, 64.7, 121.1, 128.0
(2C), 129.7 (2C), 130.1, 133.6, 141.8, 142.0, 153.9, 154.4, 158.1; IR (KBr) vmax
(cmꢀ1): 2920, 1654, 1138, 786; MS (ESI) m/z: 409.0 [M+H]. (c) Preparation of
7-alkynyl substituted-6-phenyl-4H-thieno [3,2-c]pyaran-4-one derivatives
6; typical procedure for the synthesis of 6a: A mixture of compound 5a (0.2 g,
0.49 mmol), 10% Pd/C (0.0005 g, 0.0049 mmol), PPh3 (0.005 g, 0.02 mmol), CuI
(0.0009 g, 0.0049 mmol) and Et3N (0.1 mL, 0.98 mmol) in ethanol/methanol
(3.0 mL) was stirred for 15 min under nitrogen. Then, 1-hexyne (0.08 mL,
0.73 mmol) was added and the mixture was stirred at 80 °C for 4 h. After
completion, the reaction mixture was cooled to room temperature, filtered
through celite bed and the filtrate was concentrated under vacuum. The crude
mass was diluted with dichloromethane (20 mL) and water (10 mL) and the
mixture was extracted with dichloromethane (3 ꢁ 30 mL). The organic layers
were collected, combined, washed with saturated aq NaCl (2 ꢁ 25 mL), dried
over anhydrous Na2SO4 and concentrated under vacuum. The crude compound
21. MTT assay: Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide (MTT) assay. Cells (5 ꢁ 103 cells/well) were
seeded to 96-well culture plate and cultured with or without compounds at
10
0.01
200
l
M concentration (five different concentrations i.e., 10, 5, 1, 0.5, 0.1 and
M for dose response study) in duplicates for 24 h in a final volume of
L. After treatment, the medium was removed and 20 L of MTT (5 mg/mL
L of
l
l
l
in PBS) was added to the fresh medium. After 3 h incubation at 37 °C, 100
l
DMSO was added to each well and plates were agitated for 1 min. Absorbance
was read at 570 nm on a multi-well plate reader (Victor3, Perkin Emler).
Percent inhibition of proliferation was calculated as a fraction of control
(without compound).
22. (a) Michan, S.; Sinclair, D. Biochem. J. 2007, 404, 1; (b) Sauve, A. A.; Wolberger,
C.; Schramm, V. L.; Boeke, J. D. Annu. Rev. Biochem. 2006, 75, 435; (c) Saunders,
L. R.; Verdin, E. Oncogene 2007, 26, 5489; (d) Zhao, W.; Kruse, J. P.; Tang, Y.;
Jung, S. Y.; Qin, J.; Gu, W. Nature 2008, 451, 587.
23. Layek, M.; Kumar, Y. S.; Islam, A.; Karavarapu, R.; Sengupta, A.; Halder, D.;
Mukkanti, K.; Pal, M. Med. Chem. Commun. 2011, 2, 478.