K. A. MacGregor, A. McCluskey / Tetrahedron Letters 52 (2011) 767–769
769
Table 3
2. Odell, L. R.; Chau, N.; Robinson, P. J.; McCluskey, A. ChemMedChem 2009, 4,
1182–1188.
3. Hill, T. A.; McGeachie, A. B.; Gordon, C. P.; Odell, L. R.; Chau, N.; Robinson, P. J.;
McCluskey, A. J. Med. Chem. 2010, 53, 4094–4102.
4. Odell, L. R.; Howan, D.; Gordon, C. P.; Robertson, M. J.; Chau, N.; Mariana, A.;
Whiting, A. E.; Abagyan, R.; Daniel, J. A.; Gorgani, N. N.; Robinson, P. J.;
McCluskey, A. J. Med. Chem. 2010, 53, 5267–5280.
Isolated yields of N-substituted-1,8-naphthalimides from the reaction of 1,8-naph-
thalic anhydride with various amines in [BMIM][NO3] at 140 °Ca
R
N
O
O
5. Hart, M. E.; Chamberlin, A. R.; Walkom, C.; Sakoff, J. A.; McCluskey, A. Bioorg.
Med. Chem. Lett. 2004, 14, 1969–1973.
6. Hill, T. A.; Stewart, S. G.; Sauer, B.; Gilbert, J.; Ackland, S. P.; Sakoff, J. A.;
McCluskey, A. Bioorg. Med. Chem. Lett. 2007, 17, 3392–3397.
7. Hill, T. A.; Stewart, S. G.; Gordon, C. P.; Ackland, S. P.; Gilbert, J.; Sauer, B.;
Sakoff, J. A.; McCluskey, A. ChemMedChem 2008, 3, 1878–1892.
8. Thaqi, A.; Scott, J. L.; Glibert, J.; Sakoff, J. A.; McCluskey, A. Eur. J. Med. Chem.
2010, 45, 1717–1723.
9. Bardajee, G. R.; Li, A. Y.; Haley, J. C.; Winnik, M. A. Dyes Pigments 2008, 79, 24–
32.
Entry
R
Time
Yield (%)
1
2
20 min
20 min
90
76
10. Stewart, W. W. Cell 1978, 14, 741–759.
11. Chang, S.-C.; Archer, B. J.; Utecht, R. E.; Lewis, D. E.; Judy, M. M.; Matthews, J. L.
Bioorg. Med. Chem. Lett. 1993, 3, 555–556.
12. Ingrassia, L.; Lefranc, F.; Kiss, R.; Mikatovic, T. Curr. Med. Chem. 2009, 16, 1192–
1213.
3
4
20 min
20 min
92
89
O
N
13. Hariprakasha, H. K.; Kosakowska-Cholody, T.; Meyer, C.; Cholody, W. M.;
Stinson, S. F.; Tarasova, N. I.; Michejda, C. J. J. Med. Chem. 2007, 50, 5557–5560.
14. Cholody, W. M.; Kosakowska-Cholody, T.; Hollingshead, M. G.; Hariprakasha,
H. K.; Michejda, C. J. J. Med. Chem. 2005, 48, 4474–4481.
15. Van Quaquebeke, E.; Mahieu, T.; Dumont, P.; Dewelle, J.; Ribaucour, F.; Simon,
G.; Sauvage, S.; Gaussin, J.-F.; Tuti, J.; El Yazidi, M.; Van Vynckt, F.; Mijatovic, T.;
Lefranc, F.; Darro, F.; Kiss, R. J. Med. Chem. 2007, 50, 4122–4134.
16. Braña, M.; Gradillas, A.; Gómez, A.; Acero, N.; Llinares, F.; Muñoz-Mingarro, D.;
Abradelo, C.; Rey-Stolle, F.; Yuste, M.; Campos, J.; Gallo, M. Á.; Espinosa, A. J.
Med. Chem. 2004, 47, 2236–2242.
17. Triboni, E. R.; Filho, P. B.; Berlinck, R. G. D. S.; Politi, M. J. Synth. Commun. 2004,
34, 1989–1999.
18. Gordon, C. M.; McCluskey, A. Chem. Commun. 1999, 1431–1432.
19. Judeh, Z. M. A.; Ching, C. B.; Bu, J.; McCluskey, A. Tetrahedron Lett. 2002, 43,
5089–5091.
20. Gordon, C. P.; Byrne, N.; McCluskey, A. Green Chem. 2010, 12, 1000–1006.
21. Synthesis of 1-butyl-3-methylimidazolium bromide, [BMIM][Br]: To a clean, dry
round-bottomed flask were added 1-methylimidazole (29.4 mL, 0.37 mol) and
1-bromobutane (44.1 mL, 0.41 mol). The reaction mixture was stirred at 70 °C
for 24 h. During this time, an emulsion formed, followed by the formation of
the colourless ionic liquid. The crude ionic liquid was washed with Et2O
(3 Â 30 mL) to remove excess 1-bromobutane, then dried in vacuo (50 °C,
40 mbar) for ꢀ2 h. On cooling to room temperature, the colourless, viscous
ionic liquid crystallised to form a white solid. Yield: 74.1 g (92%); 1H NMR
(DMSO-d6) d 0.86 (3H, t, J = 7.2 Hz), 1.23 (2H, m), 1.74 (2H, m), 3.86 (3H, s), 4.19
(2H, t, J = 7.2 Hz), 7.78 (1H, t, J = 1.8 Hz), 7.86 (1H, t, J = 1.8 Hz), 9.36 (1H, t,
J = 1.8 Hz); 13C NMR (DMSO-d6) d 13.4, 18.9, 31.5, 35.9, 48.6, 122.4, 123.7,
136.7 ppm.
O
5
6
7
8
9
20 min
20 min
3 h
95
96
NH2
Cl
93b
88
20 min
20 min
H2N
97
Cl
10
11
20 min
20 min
97
95
N
a
Reactions were carried out in a thick-walled sealed reaction vessel at 140 °C;
temperature measured at the baseplate of a 12-position Radleys’ carousel reaction
station.22
Synthesis of 1-butyl-3-methylimidazolium nitrate, [BMIM][NO3]: To a stirring
solution of 1-butyl-3-methylimidazolium bromide (65.7 g, 0.30 mol) in H2O
(100 mL) was added a solution of AgNO3 (51.0 g, 0.30 mol) in H2O (100 mL). A
pale yellow precipitate of AgBr instantly formed. The reaction mixture was
stirred for 2 h, then filtered twice to remove the AgBr by-product. The H2O was
removed in vacuo, resulting in the crude product, as a yellow viscous liquid.
This was dissolved in MeCN (20 mL) and the resulting solution was filtered.
The MeCN was evaporated, and the product dried in vacuo (50 °C, 40 mbar) for
ꢀ2 h to yield the pure ionic liquid as a pale yellow viscous liquid. Yield: 51.5 g
(85%); 1H NMR (DMSO-d6) d 0.86 (3H, t, J = 7.2 Hz), 1.23 (2H, m), 1.74 (2H, m),
3.84 (3H, s), 4.15 (2H, t, J = 7.2 Hz), 7.70 (1H, t, J = 1.8 Hz), 7.77 (1H, t,
J = 1.8 Hz), 9.17 (1H, t, J = 1.8 Hz); 13C NMR (DMSO-d6) d 13.5, 19.0, 31.6, 35.9,
48.8, 122.6, 123.9, 136.9 ppm.
10–15% conversion by 1H NMR spectroscopy after 20 min at 140 °C.
b
N-substituted-1,8-naphthalimides. This method is clearly applica-
ble to the synthesis of focused libraries, and hence the develop-
ment of new biologically active 1,8-naphthalimides. We will
report our efforts in this latter area in due course.
Acknowledgements
Typical Synthesis of N-(2-hydroxyethyl)-1,8-naphthalimide in
a VOC: 2-
The authors acknowledge the financial support of the Australian
Research Council and the National Health and Medical Research
Council (Australia). K.A.M. acknowledges the APA postgraduate
funding from the University of Newcastle.
Aminoethanol (350 L, 5.8 mmol) was added to a stirred suspension of 1,8-
l
naphthalic anhydride (1.005 g, 5.1 mmol) in EtOH (20 mL). The resulting
suspension was refluxed at 100 °C for 18 h, then cooled to room temperature.
The precipitated product was collected by filtration, washed with EtOH and
dried under vacuum. Where PhCH3 was used as the solvent, three drops of Et3N
were added to reaction mixture. Mp 174–176 °C; 1H NMR (DMSO-d6) d 3.61
(2H, m), 4.14 (2H, t, J = 6.6 Hz), 4.81 (1H, t, J = 6.0 Hz, OH), 7.85 (2H, dd, J = 7.5,
8.1 Hz), 8.44 (2H, dd, J = 0.9, 8.1 Hz), 8.47 (2H, dd, J = 0.9, 7.5 Hz); 13C NMR
(DMSO-d6) d 42.0, 58.0, 122.4, 127.4, 127.6, 130.8, 131.5, 134.4, 163.7 ppm.
Typical Synthesis of N-(2-hydroxyethyl)-1,8-naphthalimide in [BMIM][NO3]: 2-
Supplementary data
Supplementary data (spectral data for novel products and refer-
ences to various compounds) associated with this article can be
Aminoethanol (150 lL, 2.5 mmol) was added to a stirred suspension of 1,8-
naphthalic anhydride (0.459 g, 2.3 mmol) in [BMIM][NO3] (2.5 mL). The
resulting suspension was stirred at 140 °C for 15–20 min. After cooling to
100 °C, the reaction mixture was diluted with EtOH (5 mL) resulting in
precipitation of the product. The mixture was then cooled to room temperature
with stirring. The precipitated product was collected by filtration, washed with
EtOH and dried under vacuum. NMR data and mp as above.
References and notes
1. Hill, T. A.; Gordon, C. P.; McGeachie, A. B.; Venn-Brown, B.; Odell, L. R.; Chau, N.;
Quan, A.; Mariana, A.; Sakoff, J. A.; Chircop, M.; Robinson, P. J.; McCluskey, A. J.
Med. Chem. 2009, 52, 3762–3773.