D. J. Michaelis, T. A. Dineen / Tetrahedron Letters 50 (2009) 1920–1923
1923
Tetrahedron Lett. 1998, 39, 9389–9392; (d) Achmatowicz, M.; Chan, J.; Wheeler,
P.; Liu, L.; Faul, M. M. Tetrahedron Lett. 2007, 48, 4825–4829.
In conclusion, we have demonstrated that mono-substituted
aziridines undergo efficient ring opening with stabilized ortho-bro-
mo phenyl metal reagents. Although N-tosyl aziridines could be
opened with lithium organocuprates in good yields, the use of
phenyllithium reagents in conjunction with boron trifluoride as a
Lewis acid in toluene as solvent provided a more general method.
With this method N-tosyl, N-Boc, and N-Cbz-activated aziridines
undergo ring opening to give the desired ortho-bromo phenethyl-
amine products. Further, we have demonstrated that the
ortho-bromo phenethylamine products undergo efficient transi-
tion-metal-catalyzed cyclization to form chiral, non-racemic
2-substituted indolines. Further studies with stabilized ortho-bro-
mo phenyllithium reagents and additional applications of ortho-
bromo phenethylamines will be reported in due course.
9. Three examples of aziridine ring opening with ortho-fluoro substituted aryl
magnesium halide reagents are described in: Zhu, G.-D.; Ghandi, V. B.; Gong, J.;
Thomas, S.; Woods, K. W.; Song, X.; Li, T.; Diebold, R. B.; Luo, Y.; Liu, X.; Guan,
R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.; Olson, A.; Marsh, K. C.; Stoll, V. C.;
Mamo, M.; Polakowski, J.; Campbell, T. J.; Martin, R. L.; Gintant, G. A.; Penning,
T. D.; Li, Q.; Rosenberg, S. H.; Giranda, V. L. J. Med. Chem. 2007, 50, 2990–3003.
However, these examples all involved bis-fluorinated arenes and experimental
details are not provided.
10. (a) Gilman, H.; Gorsich, R. D. J. Am. Chem. Soc. 1956, 78, 2217–2222; (b) Prabhu,
U. D. G.; Eapen, K. C.; Tamborski, C. J. Org. Chem. 1984, 49, 2792–2795; For a
detailed examination of the decomposition of 2-chloro-6-fluorophenyllithium
into benzynes, see: (c) Riggs, J. C.; Ramirez, A.; Cremeens, M. E.; Bashore, C. G.;
Candler, J.; Wirtz, M. C.; Coe, J. W.; Collum, D. B. J. Am. Chem. Soc. 2008, 130,
3406–3412.
11. (a) Iwao, M. J. Org. Chem. 1990, 55, 3622–3627; (b) Castagnetti, E.; Schlosser, M.
Eur. J. Org. Chem. 2001, 691–695; (c) Leroux, F.; Schlosser, M. Angew. Chem., Int.
Ed. 2002, 41, 4272–4274; (d) Gohier, F.; Mortier, J. J. Org. Chem. 2003, 68, 2030–
2033; (e) Schlosser, M.; Cottet, F.; Heiss, C.; Lefebvre, O.; Marull, M.; Masson, E.;
Scopelliti, R. Eur. J. Org. Chem. 2006, 729–734.
Acknowledgment
12. Lulin´ ski, S.; Seratowski, J. J. Org. Chem. 2003, 68, 5384–5387.
13. (a) Boymond, L.; Rottländer, M.; Cahiez, G.; Knochel, P. Angew. Chem., Int. Ed.
1998, 37, 1701–1703; (b) Krasovsky, A.; Knochel, P. Angew. Chem., Int. Ed. 2004,
43, 3333–3336.
The authors would like to thank the Amgen Graduate Internship
Program for funding this research.
14. (a) Ebert, G. W.; Pfennig, D. R.; Suchan, S. D.; Donovan, T. A., Jr.; Aouad, E.;
Tehrani, S. S.; Gunnersen, J. N.; Dong, L. J. Org. Chem. 1995, 60, 2361–2364; (b)
Takahashi, H.; Hossain, K. M.; Nishihara, Y.; Shibata, T.; Takagi, K. J. Org. Chem.
2006, 71, 671–675.
References and notes
15. For an example of a reaction between a 2,6-dibromophenyllithium species and
an epoxide using toluene as solvent, see: Okano, K.; Tokuyama, H.; Fukuyama,
T. J. Am. Chem. Soc. 2006, 128, 7136–7137.
16. Aryl iodides were generated via deprotonation of the corresponding 1,3-
dihalobenzenes with LDA and quenching of the aryllithium intermediate with
iodine. For the syntheses of 1-bromo-3-chloro-2-iodobenzene and 1-bromo-3-
fluoro-2-iodobenzene, the aryllithium intermediate was treated with zinc
chloride prior to the iodine quench, according to the procedure of: Menzel, K.;
Fisher, E. L.; DiMichele, L.; Frantz, D. E.; Nelson, T. D.; Kress, M. H. J. Org. Chem.
2006, 71, 2188–2191.
1. (a) Cignarella, G.; Sanna, P. J. Med. Chem. 1981, 24, 1003–1006; (b) Hlasta, D. J.;
Luttinger, D.; Perrone, M. H.; Silbernagel, M. J.; Ward, S. J.; Haubrich, D. R. J.
Med. Chem. 1987, 30, 1555–1562; (c) Bermudez, J.; Dabbs, S.; Joiner, K. A.; King,
F. D. J. Med. Chem. 1990, 33, 1929–1932; (d)The Alkaloids: Chemistry and Biology;
Cordell, G. A., Ed.; Academic Press: San Diego, 1998; Vol. 50.
2. (a) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 8451–
8558; (b) Deboves, H. J. C.; Hunter, C.; Jackson, R. F. W. J. Chem. Soc., Perkin. Trans. 1
2002, 733–736; (c) Yu, Y.; Ostresh, J. M.; Houghten, R. A. Tetrahedron Lett. 2003,
44, 2569–2572; (d) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35–37.
3. (a) Minatti, A.; Buchwald, S. L. Org. Lett. 2008, 10, 2721–2724. and references
cited therein; (b) Aoki, K.; Peat, A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
3068–3073; (c) Thansandote, P.; Raemy, M.; Rudolph, A.; Lautens, M. Org. Lett.
2007, 5255–5258; (d) Li, K.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008,
47, 6452–6455.
4. (a) Gross, K. M. B.; Jun, Y. M.; Beak, P. J. Org. Chem. 1997, 62, 7679–7689; (b)
Viswanathan, R.; Mutnick, D.; Johnston, J. N. J. Am. Chem. Soc. 2003, 123, 7266–
7271; (c) Srinivasan, J. M.; Burks, H. E.; Smith, C. R.; Viswanathan, R.; Johnston,
J. N. Synthesis 2005, 2, 330–333; (d) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7,
4777–4779.
5. (a) Aggarwal, V. K.; Badine, M. D.; Moorthie, V. A. Aziridines and Epoxides in
Organic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
2006. pp 1–35; (b) Wessig, P.; Schwarz, J. Synlett 1997, 893–894.
6. For reviews, see: (a) McCoull, W.; Davis, F. A. Synthesis 2000, 10, 1347–1365;
(b) Hu, X. E. Tetrahedron 2004, 60, 2701–2743; (c) Pineschi, M. Eur. J. Org. Chem.
2006, 4979–4988.
17. Representative procedure: A 10-mL round-bottomed flask was charged with n-
BuLi (0.23 mL of
a 2.20 M solution in hexane, 0.51 mmol, 1.2 equiv) and
toluene (0.6 mL). The resulting solution was cooled to À78 °C, then a solution
of 1,3-dibromo-2-iodobenzene (232 mg, 0.64 mmol, 1.5 equiv) in toluene
(0.9 mL) was added dropwise via syringe. The mixture was stirred for 30 min
to give
a white slurry, and boron trifluoride-diethyl etherate (65
lL,
0.64 mmol, 1.5 equiv) and a solution of (R)-tert-butyl 2-benzylaziridine-1-
carboxylate (100 mg, 0.43 mmol) in toluene (0.7 mL) were added in sequence.
The resulting mixture was stirred at À78 °C for 2 h, then was quenched with
methanol (1 mL). After warming to room temperature, the reaction mixture
was diluted with brine (4 mL), and the aqueous mixture was extracted with
dichloromethane (3 Â 6 mL). The organic extracts were combined, and the
combined solution was dried over sodium sulfate, filtered, and evaporated.
The crude product was purified by chromatography on silica gel (eluting with
5–20% ethyl acetate in hexane) to give (S)-tert-butyl 1-(2,6-dibromophenyl)-
3-phenylpropan-2-ylcarbamate (180 mg, 87% yield) as a white solid. At room
temperature, this compound existed as a 3:1 mixture of rotamers in DMSO-d6
on the NMR timescale, and the two sets of peaks coalesced at ca. 60 °C. Data
for the major rotamer: 1H NMR (600 MHz, DMSO-d6, 23 °C) d ppm 7.58 (d,
J = 7.9 Hz, 2H), 7.15–7.28 (m, 6H), 7.04 (t, J = 8.1 Hz, 1H), 6.67 (d, J = 9.5 Hz,
1H), 4.06–4.16 (m, 1H), 3.15 (dd, J = 13.4, 9.5 Hz, 1H), 3.03 (dd, J = 13.4,
4.6 Hz, 1H), 2.91 (dd, J = 13.7, 9.5 Hz, 1H), 2.72 (dd, J = 13.6, 5.3 Hz, 1H), 1.17
(s, 9H).
7. (a) Hudlicky, T.; Tian, X.; Königsberger, K.; Rouden, J. J. Org. Chem. 1994, 59,
4037–4039; (b) Toshimitsu, A.; Abe, H.; Hirosawa, C.; Tamao, K. J. Chem. Soc.,
Perkin. Trans. 1 1994, 3465–3471; (c) Beresford, K. J. M.; Church, N. J.; Young, D.
W. Org. Biomol. Chem. 2006, 4, 2888–2897; (d) Tian, X.; Hudlicky, T.;
Königsberger, K. J. Am. Chem. Soc. 1995, 117, 3643–3644.
8. (a) Baldwin, J. E.; Farthing, C. N.; Russell, A. T.; Schofield, C. J.; Spivey, A. C.
Tetrahedron Lett. 1996, 37, 3761–3764; (b) Chakraborty, T. K.; Gangakhedkar, K.
K. Synth. Commun. 1996, 26, 2045–2056; (c) Travins, J. M.; Etzkorn, F. A.