Z. Zhang et al. / Tetrahedron Letters 52 (2011) 2667–2669
2669
Ghosh, S. K. Tetrahedron Lett. 2000, 41, 759–762; (c) Sarkar, T. K.; Basak, S.;
Slanina, Z.; Chow, T. J. J. Org. Chem. 2003, 68, 4206–4214.
10. (a) Padwa, A.; Pearson, W. H. (Eds.), Synthetic Applications of 1, 3-Dipolar
Cycloaddition Chemistry Towards Heterocycles and Natural Products; Wiley: New
York, 2003; (b) Zhai, H.; Liu, P.; Luo, S.; Fang, F.; Zhao, M. Org. Lett. 2002, 4,
4385–4386.
11. (a) The route in Scheme 2 depicts the reagents and conditions we used for the
synthesis of 1 in the initial discovery phase without publication. This route
turned out to be essentially the same as the later published route by Yang et al.
(Ref. 11b) with only slight differences in reagents and conditions. Our detailed
procedures are now provided in the Supplementary data along with the
original characterization data for references; (b) Yang, X.; Luo, S.; Liu, F.; Fang,
P.; Lu, Y.; He, M.; Zhai, H. Tetrahedron 2006, 62, 2240–2246.
12. Furukawa, N.; Shibutani, T.; Fujihara, H. Tetrahedron Lett. 1989, 30, 7091–7094.
13. (a) Xu, R.; Dwoskin, L. P.; Grinevich, V.; Sumithran, S. P.; Crooks, P. A. Drug Dev.
Res. 2002, 55, 173–186; (b) Papke, R. L.; Zheng, G.; Horenstein, N. A.; Dwoskin,
L. P.; Crooks, P. A. Bioorg. Med. Chem. Lett. 2005, 15, 3874–3880.
In conclusion, expeditious syntheses of cis-1-methyl-
2,3,3a,4,5,9b-hexahydro-1H-pyrrolo-[3,2-h]iso-quinoline (1) and
cis-1-methyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo-[2,3-f]quinoline
(3) have been established utilizing intramolecular azomethine
ylide-alkene [3+2] cycloaddition. For the synthesis of 1 and 3, this
route is considerably more efficient than the previously reported
routes, and provides a viable route for large scale production of
such molecules, which is important for subsequent preclinical
development as therapeutic agents. Details of the synthesis and
characterization data for compounds 1, 3, 17, 18, 20 and 21 are
provided in the references and notes.16–17
Acknowledgments
14. Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev. 2006, 106, 4484–4517.
15. Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann, T. N.;
Christensen, B. G. J.Med. Chem. 1987, 30, 871–880.
This work was supported by a grant from the National Institutes
of Health (U19DA017548, 2002-2007). We thank the University of
Kentucky Mass Spectrometry Facility for providing high resolution
mass spectral data for the compounds in this study.
16. Procedure for the preparation of 17 and 20. For 17: compound 16 (4.2 g,
24.4 mmol) was dissolved in anhydrous THF (100 mL) and LDA (2 M, 15 mL,
30 mmol) was added at À78 °C over 5 min. The mixture was stirred at À78 °C
for an additional 45 min, a solution of allyl bromide (2.0 mL, 30 mmol) in THF
(10 mL) was added drop-wise over 15 min. After stirring at À78 °C for another
2 h, aqueous NaHCO3 was added to quench the reaction and the mixture was
warmed up to RT. Most of the solvent was removed in vacuo and the resulting
residue was partitioned into ethyl acetate (50 mL) and brine (50 mL). The
aqueous layer was further extracted with ethyl acetate (3 Â 50 mL) and the
combined organic layers were dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by chromatography (SiO2,
hexane:ethyl acetate, 10:1) to afford 17 (4.8 g, 92% yield) as a pale yellow
oil. 1H NMR (300 MHz, CDCl3), d 8.62 (s, 1 H), 8.38 (d, J = 8.8 Hz, 1H), 7.18 (d,
J = 8.8 Hz, 1H), 5.76–5.84 (m, 1H), 4.96–5.02 (m, 2H), 2.80 (t, J = 7.2 Hz, 2H),
2.38–2.40 (m, 2H). 13C NMR (75 MHz, CDCl3), 151.9, 150.0, 148.2, 136.7, 125.4,
123.3, 116.2, 35.1, 33.0. HRMS m/e 210.9993, 212.0860 (calcd for C9H10BrN,
210.9997; C9H1081BrN, 212.0864). Following the same procedure, compound
20 was prepared form 3-bromo-2-picoline (19) in 88% yield as a pale yellow
oil. 1H NMR (300 MHz, CDCl3), d 8.47 (dd, J = 4.8, 1.5 Hz, 1H), 7.82 (dd, J = 8.4,
1.5 Hz, 1H), 7.00 (dd, J = 8.4, 4.8 Hz, 1H), 5.85–5.99 (m, 1H), 4.96–5.11 (m, 2H),
3.06 (t, J = 8.4 Hz, 2H), 2.46–2.54 (m, 2H). 13C NMR (75 MHz, CDCl3), d 159.8,
147.8, 140.4, 137.7, 122.7, 121.6, 115.4, 37.2, 32.7. HRMS m/e 210.9993 (calcd
for C9H10NBr, 210.9997).
17. Procedure for the preparation of 18 and 21. For 18: n-BuLi (2 M in hexane, 7 mL,
14 mmol), was added drop-wise to a solution of 17 (2.56 g. 12.1 mmol) in
anhydrous THF (30 mL) under N2 at À78 °C over 10 min. After stirring an
additional 20 min at À78 °C, anhydrous methyl formate (1.5 mL, 25 mmol) was
added over 10 min and the mixture stirred at À78 °C for 1 h. The reaction was
quenched with saturated aqueous NaHCO3 and warmed up to rt. The reaction
mixture was concentrated under reduced pressure and the resulting residue
was partitioned into ethyl acetate (50 mL) and water (50 mL). The aqueous
layer was further extracted with ethyl acetate (3 Â 20 mL). The combined
organic layers were washed with brine, dried over MgSO4, and concentrated in
vacuo, the residue was purified by chromatography (SiO2, hexane/ethyl
acetate, 5:1) to give 18 (1.70 g, 87%) as a pale yellow oil. 1H NMR (300 MHz,
CDCl3), d 10.26 (s, 1H), 8.94 (s, 1H), 8.65 (d, J = 4.8 Hz, 1H), 7.22 (d, J = 4.8 Hz,
1H). 5.76–5.87 (m, 1H), 4.98–5.04 (m, 2H). 3.14 (t, J = 5.7 Hz, 2H), 2.34–2.40 (m,
2H). 13C NMR (75 MHz, CDCl3), d 191.6, 154.5, 153.6, 153.0, 136.7, 125.8, 116.3,
34.7, 32.0. HRMS m/e 161.0843 (calcd for C10H11NO, 161.0841). Following the
same procedure, compound 21 was prepared from 20 in 87% yield as brownish
oil. 1H NMR (300 MHz, CDCl3), d 10.25 (s, 1H), 8.72 (dd, J = 4.5, 1.5 Hz, 1H), 8.12
(dd, J = 7.5, 1.8 Hz, 1H) 7.32 (dd, J = 7.8, 4.8 Hz, 1H), 5.81–5.94 (m, 1H), 4.96–
5.07 (m, 2H), 2.98 (t, J = 7.8 Hz, 2H), 2.46–2.55 (m, 2H). 13C NMR (75 MHz,
CDCl3), d 191.1, 163.51, 153.6, 138.1, 137.2, 129.5, 122.0, 116.0, 34.5, 34.4.
HRMS m/e 161.0842 (calcd for C10H11NO, 161.0841).
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
1. (a) Taylor, P.; Talley, T. T.; Radic, Z.; Hansen, S. B.; Hibbs, R. E.; Shi, J. Biochem.
Pharmacol. 2007, 74, 1164–1171; (b) Soudijn, W.; van Wijngaarden, I.;
Ijzerman, A. P. Med. Res. Rev. 2007, 27, 417–433; (c) Bunnelle, W. H.; Dart, M.
J.; Schrimpf, M. R. Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2004, 4,
299–334; (d) Astles, P. C.; Baker, S. R.; Boot, J. R.; Broad, L. M.; Dell, C. P.;
Keenan, M. Curr. Drug Targets: CNS Neurol. Disorders 2002, 1, 337–348.
2. (a) Ullrich, T.; Krich, S.; Binder, D.; Mereiter, K.; Anderson, D. J.; Meyer, M. D.;
Pyerin, M. J. Med. Chem. 2002, 45, 4047–4054; (b) Ji, J.; Schrimpf, M. R.; Sippy, K.
B.; Bunnelle, W. H.; Li, T.; Anderson, D. J.; Faltynek, C.; Surowy, C. S.; Dyhring,
T.; Ahring, P. K.; Meyer, M. D. J. Med. Chem. 2007, 50, 5493–5508; (c) Bunnelle,
W. H.; Daanen, J. F.; Ryther, K. B.; Schrimpf, M. R.; Dart, M. J.; Gelain, A.; Meyer,
M. D.; Frost, J. M.; Anderson, D. J.; Buckley, M.; Curzon, P.; Cao, Y.; Puttfarcken,
P.; Searle, X.; Ji, J.; Putman, C. B.; Surowy, C.; Toma, L.; Barlocco, D. J. Med. Chem.
2007, 50, 3627–3644; (d) Lennox, J. R.; Turner, S. C.; Rapoport, H. J. Org. Chem.
2001, 66, 7078–7083.
3. Glassco, W.; Suchocki, J.; George, C.; Martin, B. R.; May, E. L. J. Med. Chem. 1993,
36, 3381–3385.
4. Elmore, D. E.; Dougherty, D. A. J. Org. Chem. 2000, 65, 742–747.
5. Damaj, M. I.; Glassco, W.; Marks, M. J.; Slobe, B.; James, J. R.; May, E. L.;
Rosecrans, J. A.; Collins, A. C.; Martin, B. R. J. Pharmacol. Exp. Ther. 1997, 282,
1425–1434.
6. Rao, T. S.; Sacaan, A. I.; Menzaghi, F. M.; Reid, R. T.; Adams, P. B.; Correa, L. D.;
Whelan, K. T.; Vernier, J.-M. Brain Res. 2004, 1003, 42–53.
7. (a) Cerny, E. H.; Cerny, T. Expert Opin. Invest. Drugs 2008, 17, 691–696; (b)
Meijer, M. M.; Matsushita, M.; Altobell, L. J.; Wirsching, P.; Janda, K. D. J. Am.
Chem. Soc. 2003, 125, 7164–7165.
8. (a) Chavdarian, C. G.; Seeman, J. I.; Wooten, J. B. J. Org. Chem. 1983, 48, 492–494;
(b) Glassco, W.; Suchocki, J.; George, C.; Martin, B. R.; May, E. L. J. Med. Chem.
1993, 36, 3381–3390; (c) Dickerson, T. J.; Lovell, T.; Meijler, M. M.; Noodleman,
L.; Janda, K. D. J. Org. Chem. 2004, 69, 6603–6609.
9. (a) Sarkar, T. K.; Basak, S.; Wainer, I.; Moaddel, R.; Yamaguchi, R.; Jozwiak, K.;
Chen, H. T.; Lin, C. C. J. Med. Chem. 2004, 47, 6691; (b) Sarkar, T. K.; Basak, S.;