4294
B. C. Das et al. / Tetrahedron Letters 52 (2011) 4292–4294
159.5. (b) General procedure for the synthesis of compound 3.To a flame-dried
10 mL round bottom flask was added Bromide (137.0 mg, 0.3 mmol,
Grants from the NSF (DBI9601607 and DBI0331934), the NIH
(RR017998) and the HHMI Research Resources for Biomedical
Sciences.
2
1.0 equiv), B2Pin2 (167.6 mg, 0.66 mmol, 0.22 equiv), AcOK (147.2 mg,
1.5 mmol, 5.0 equiv) was added 3.0 mL of anhydrous DMSO under nitrogen.
The resulting mixture was stirred at 80 °C for 12 h under nitrogen. Then the
reaction mixture was diluted with water (10 mL), extracted by ethyl acetate
(3 ꢀ 10 mL). The combined organic layer was dried over Na2SO4, filtered and
concentrated in vacuo. The resulting residue was subjected to a flash silica gel
chromatography (Hexanes: EtOAc: 60:40) and then recrystallized from
methanol to give a white crystal product 3 in 65% yield. A white solid. Mp
155–157 °C. 1H NMR (CDCl3, 300 MHz, TMS) d 1.41 (s, 12H, 4CH3), 3.79 (s, 3H,
CH3), 5.42 (s, 2H, CH2), 6.87 (d, J = 8.4 Hz, 2H, Ar), 7.52 (d, J = 8.4 Hz, 2H, Ar),
7.61 (d, J = 8.1 Hz, 2H, Ar), 7.72–7.78 (m, 3H, Ar), 7.99 (d, J = 8.1 Hz, 2H, Ar),
8.52–8.55 (m, 1H, Ar); 13C NMR (CDCl3, 75 MHz, TMS) d 25.3, 55.0, 55.6, 84.4,
114.2, 126.9, 127.7, 128.8, 129.2, 129.5, 129.6, 130.7, 131.7, 133.1, 135.3, 138.3,
147.2, 159.3, 159.6; 11B NMR (CDCl3, 300 MHz, TMS) d 30.9; HRMS (EI) calcd
for C28H30BN2O4 [M+H]+ requires 469.2299, found 469.2300.
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
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4. Huh, C. G.; Factor, V. M.; Thorgeirsson, S. S., et al Proc. Natl. Acad. Sci. 2004, 101,
4477–4482.
5. Ohashi, K.; Marion, P. L.; Nakai, H.; Meuse, L.; Cullen, J. M.; Bordier, B. B.;
Schwall, R.; Greenberg, H. B.; Glenn, J. S.; Kay, M. A. Nat. Med. 2000, 6, 327–331.
6. Ueki, T.; Kaneda, Y.; Tsutsui, H., et al Nat. Med. 1999, 5, 226–230.
7. Balkovetz, D. F.; Lipschutz, J. H. Int. Rev. Cytol. 1999, 186, 225–260.
8. Holmes, O.; Pillozzi, S.; Deakin, J.; Carafoli, F.; Kemp, L.; Butler, P. J.; Lyon, M.;
Gherardi, E. J. Mol. Biol. 2007, 367, 395–408.
9. (a) Mey, M.; Hatzelmann, A.; Van der Laan, V.; Sterk, G.; Thibaut, U.;
Timmerman, H. J. Med. Chem. 2001, 44, 2511–2522; (b) Bold, G.; Altmann, K.;
Frei, J.; Lang, M.; Manley, P.; Traxler, P.; Wietfeld, B.; Brüggen, J.; Buchdunger,
E.; Cozens, R.; Ferrari, S.; Furet, P.; Hofmann, F.; Martiny-Baron, G.; Mestan, J.;
Rösel, J.; Sills, M.; Stover, D.; Acemoglu, F.; Boss, E.; Emmenegger, R.; Lässer, L.;
Masso, E.; Roth, R.; Schlachter, C.; Vetterli, W.; Wyss, D.; Wood, J. J. Med. Chem.
2000, 43, 2310–2323; (c) Menear, K.; Adcock, C.; Boulter, R.; Cockcroft, X.-L.;
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H.; Kerrigan, K.; Knights, C.; Lau, A.; Loh, V., Jr.; Matthews, I.; Moore, S.;
O’Connor, M. J.; Smith, G. C. M.; Martin, N. M. M. J. Med. Chem. 2008, 51, 6581–
6591.
10. (a) Zhao, S.-H.; Berger, J.; Clark, R. D.; Sethofer, S. G.; Krauss, N. E.; Brothers, J.
M.; Martin, R. S.; Misner, D. L.; Schwab, D.; Alexandrova, L. Bioorg. Med. Chem.
Lett. 2007, 17, 3504–3507; (b) Das, B. C.; Madhukumar, A. V.; Anguiano, J.;
Mani, S. Bioorg. Med. Chem. Lett. 2009, 19, 4204; (c) Ohno, M.; Tanaka, Y.;
Myyamoto, M.; Takeda, T.; Hoshi, K.; Yamada, N.; Ohtake, A. Bioorg. Med. Chem.
2006, 14, 2005–2021.
13. (a) Sylvain, D.; Jean-Pierre, G. Chem. Rev. 2008, 288–325; (b) Molander, G. A.;
Ellis, N. Acc. Chem. Res. 2007, 40, 275–286; (c) Liu, F.; Evans, T.; Das, B. C.
Tetrahedron Lett. 2008, 49, 1578.
14. (a) Oliveira1, R. A.; Savegnago, L.; Jesse, C. R.; Menezes1, P. H.; Molander, G. A.;
Nogueira, C. W. Basic Clin. Pharmacol. Toxicol. 2009, 104, 448–454; (b) Lecat-
Guillet, N.; Yves Ambroise, Y. Chem. Med. Chem. 2008, 3, 120–1209.
15. Ting, R.; Harwig, C.; auf dem Keller, U.; McCormick, S.; Austin, P.; Overall, C. M.;
Ruth, T. J.; Perrin, D. M. J. Am. Chem. Soc. 2008, 130, 12045–12055.
16. General procedure for the synthesis of compound 7. 6-Amino-m-cresol 5 (1.23 g,
10.0 mmol, 1.0 equiv), Bu4NHSO3 (1.7 g, 5.0 mmol, 0.5 equiv), K2CO3 (2.76 g,
20.0 mmol, 2.0 equiv) in 10 mL water were added into a 100 mL of RBF. DCM
(60 mL) was added and the resulting mixture was stirred for around 5 min.
2,40-dibromoacetophenone in 20 mL of DCM was added dropwise over a period
of 10 min. The reaction mixture was stirred at rt over night. After the reaction
was completed, water (30 mL) was added and the mixture was extracted by
DCM (3 ꢀ 25 mL). The combined organic layer was washed by
1 N HCl,
brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was
purified by a silica gel chromatography to give a yellow solid product 7 (1.5 g,
51%).
A yellow solid. Mp 141–143 °C. 1H NMR (CDCl3, 300 MHz, TMS) d 2.36 (s, 3H,
CH3), 5.02 (s, 2H, CH2), 6.75 (s, 1H, Ar), 6.85 (d, J = 7.8 Hz, 1H, Ar), 7.32 (d,
J = 7.8 Hz, 1H, Ar), 7.61 (d, J = 8.4 Hz, 2H, Ar), 7.79 (d, J = 8.4 Hz, 2H, Ar); 13C
NMR (CDCl3, 75 MHz, TMS) d 21.5, 62.6, 116.0, 123.2, 125.5, 127.5, 127.8,
131.4, 131.9, 134.4, 139.5, 146.0, 156.3.
Synthesis of 8: To a 10 mL round bottom flask charged with Bromide 7 (91.0 mg,
0.3 mmol, 1.0 equiv), B2Pin2 (167.6 mg, 0.66 mmol, 0.22 equiv), AcOK
(147.2 mg, 1.5 mmol, 5.0 equiv) and Pd(PPh3)2Cl2 (21.0 mg, 0.03 mmol,
0.1 equiv) was added 3.0 mL of anhydrous DMSO under nitrogen. The
resulting mixture was stirred at 80 °C for 12 h under nitrogen. Then the
reaction mixture was diluted with water, extracted with ethylacetate. The
combined organic layer was dried over Na2SO4, filtered and concentrated in
vacuo. The residue was subjected to a flash silica gel chromatography to give a
yellow solid product 8 (62 mg, 59%). A yellow solid. Mp 120–122 °C. 1H NMR
(CDCl3, 300 MHz) d 1.39 (s, 12H, 4CH3), 2.36 (s, 3H, CH3), 5.07 (s, 2H, CH2), 6.75
(s, 1H, Ar), 6.85 (dd, J1,2 = 7.8, 1.2 Hz, 1H, Ar), 7.34 (d, J = 7.8 Hz, 1H, Ar), 7.91 (s,
4H, Ar); 13C NMR (CDCl3, 75 MHz) d 21.5, 24.9, 62.9, 84.1, 116.0, 123.1, 125.4,
127.6, 131.6, 135.0, 137.8, 139.3, 146.1, 157.4; HRMS (EI) calcd for C21H25BNO3
[M+H]+ requires 350.1927, found 350.1933.
Synthesis of compound 9: compound 8 (0.052 mmol, 18 mg) was dissolved in
MeOH (1 mL). To the above solvent was added 4.5 M KF2H aqueous solution
drop wise (0.21 mmol, 47 lL). The reaction mixture was stirred at rt for 2 h,
then the solvent was removed in vacuo. Hot acetone was added and the solvent
was removed in vacuo again. The resulting white solid was washed with EA for
(3 ꢀ 25 mL) to obtain a pure solid product 9 (10 mg, 60%). A yellow solid. Mp
166–168 °C. 1H NMR (CDCl3, 300 MHz) d 2.31 (s, 3H, CH3), 5.10 (s, 2H, CH2),
6.73 (s, 1H, Ar), 6.82 (d, J = 8.1 Hz, 1H, Ar), 7.23 (d, J = 8.1 Hz, 1H, Ar), 7.63 (d,
J = 8.1 Hz, 2H, Ar), 7.80 (d, J = 8.1 Hz, 2H, Ar); 13C NMR (CDCl3, 75 MHz) d 20.8,
63.0, 116.1, 123.0, 124.9, 127.4, 132.2, 132.3, 132.6, 138.3, 146.9, 159.3.
11. (a) Groziak, M. P. In Progress in heterocyclic chemistry; Gribble, G. C., Gilchrist, T.
L., Eds.; Pergamon: Oxford, 2000; Vol. 12, pp 1–21; (b) Morin, C. Tetrahedron
1994, 50, 12521–12569; (c) Yang, W.; Gao, X.; Wang, B. Med. Res. Rev. 2003, 23,
346; (d) Matterson, D. S. Tetrahedron 1989, 45, 1859; (e) Tian, Z.-Q.; Brown, B.
B.; Mack, D. P.; Hutton, C. A.; Bartlett, P. A. J. Org. Chem. 1997, 62, 514; (f) Leung,
D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2003, 63, 1144; (g) Kabalka, G. W.;
Das, B. C.; Das, S. Tetrahedron Lett. 2001, 42, 7145–7146.
12. (a) General procedure for the synthesis of compound 2. Bromo phenyl
phthalazinone
4
(500.0 mg, 1.65 mmol, 1.0 equiv), K2CO3 (460.0 mg,
3.3 mmol, 2.0 equiv) and anhydrous DMF (25.0 mL) were added into
a
100 mL round bottom flask. To the above mixture was added 4-
methoxybenzyl chloride (517.8 mg, 3.3 mmol) dropwise and the reaction
mixture was stirred at room temperature for about 3 h. After the reaction
completed, the solid was filtered and mother liquid was poured into water, the
resulting mixture was extracted by ethylacetate, dried over Na2SO4, filtered
and concentrated in vacuo. The small amount of DMF remained was removed
by high vacuum and the residue was recrystallized from ethylacetate and
hexanes (95:5) to give a white solid 2 in 89% yield. A white solid. Mp 147–
148 °C. 1H NMR (CDCl3, 300 MHz, TMS) d 3.70 (s, 3H, CH3), 5.31 (s, 2H, CH2),
6.88 (d, J = 8.7 Hz, 2H, Ar), 7.33 (d, J = 8.7 Hz, 2H, Ar), 7.56 (d, J = 8.1 Hz, 2H, Ar),
7.67–7.70 (m, 1H, Ar), 7.76 (d, J = 8.1 Hz, 2H, Ar), 7.88–7.91 (m, 2H, Ar), 8.36–
8.39 (m, 1H, Ar); 13C NMR (CDCl3, 75 MHz, TMS) d 54.4, 55.9, 114.7, 123.6,
127.4, 128.4, 129.1, 130.0, 130.3, 132.4, 132.5, 133.0, 134.6, 134.8, 146.1, 158.8,