W. F. Bailey et al. / Tetrahedron Letters 44 (2003) 5303–5305
5305
122, 6787; (b) Gil, G. S.; Groth, U. M. J. Am. Chem. Soc.
2000, 122, 6789.
4. Barluenga, J.; Perez-Prieto, J.; Asensio, G. Tetrahedron
1990, 46, 2453.
5. Yoshida, Y.; Tanabe, Y. Synthesis 1997, 533.
6. On a molecular scale, deprotonation of 1 likely occurs
more rapidly than does the exchange. For a detailed
discussion of the relative rates of such processes in a
related system, see: Gallagher, D. J.; Beak, P. J. Am.
Chem. Soc. 1991, 113, 7984.
7. Experimental procedure: An approximately 0.1 M solu-
tion of N-allyl-2-bromoaniline, 1, (typically 2–3 mmol) in
anhydrous diethyl ether was cooled under argon to
−78°C, 3.3 molar equiv. of t-BuLi in heptane was added,
and the resulting solution was allowed to stir at
−78°C for 1 h prior to the addition of 3.3 molar equiv. of
TMEDA. The reaction flask was then equipped with an
argon-filled balloon, submerged in a +5°C bath, and
allowed to stir for 2 h at +5°C. The bright-yellow solu-
tion was then recooled to −78°C and 0.9 molar equiv. of
the first electrophile (E1) was added dropwise (typically as
a solution in Et2O) followed by dropwise addition of the
second electrophile (E2). The reaction mixture was
removed from the cooling bath and allowed to warm and
stir at room temperature for 1 h before being poured into
water. The organic layer was washed with water, dried
(MgSO4), concentrated by rotary evaporation, and the
residue was purified by flash chromatography on silica
gel.
8. With the exception of 1-methyl-3-ethylindoline (Table 1,
entry 2), all of the indolines prepared in this study are
known compounds whose physical and spectroscopic
properties were in accord with those reported in the
literature. Data for 1-methyl-3-ethylindoline (Table 1,
entry 2): colorless oil: 1H NMR l 1.00 (t, J=7.43 Hz,
3H), 1.49–1.60 (m, 1H), 1.80–1.91 (m, 1H), 2.74 (s, 3H),
2.93 (t, J=8.05 Hz, 1H), 3.05–3.15 (m, 1H), 3.46 (t,
J=8.47 Hz, 1H), 6.48 (d, J=7.75 Hz, 1H), 6.78 (t,
J=7.34 Hz, 1H), 7.08 (apparent q, J=7.62 Hz, 2H); 13C
NMR d 12.16, 26.94, 36.43, 42.67, 62.15, 107.48, 117.91,
123.71, 127.76, 134.32, 153.43; HRMS calcd for C11H15N
161.1204, found 161.1222.
Scheme 3.
Indeed, conducting the isomerization of 2 in the pres-
ence of 3 molar equivalents of dry (1S,2S)-(+)-N,O-
dimethylpseudoephedrine,10
a
ligand
that
is
considerably more conformationally flexible than is (−)-
sparteine,11 effected an asymmetric ring closure. Thus,
as illustrated in Scheme 3, (R)-(−)-1-allyl-3-methylindo-
line, of known absolute configuration,3 is produced in
62% isolated yield with e.r. of 84:16 when (R)-3 is
trapped by sequential addition of EtOH and allyl
bromide.12
In summary, the chemistry described above provides an
experimentally convenient one-pot route to differen-
tially 1,3-disubstituted indolines from readily available
N-allyl-2-bromoaniline. The ability to effect the cycliza-
tion of 2 to 3 in an asymmetric fashion using a deriva-
tive
of
commercially
available,
enantiopure
pseudoephedrine allows for the preparation of enan-
tiomerically enriched indolines.
Acknowledgements
This work was supported by a grant from the Process
Chemistry Division, H. Lundbeck A/S, Copenhagen,
Denmark We are grateful to Dr. James Schwindeman
of FMC, Lithium Division, for a generous gift of
t-BuLi in heptane.
9. (a) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.;
Ovaska, T. V.; Rossi, K.; Thiel, Y.; Wiberg, K. B. J. Am.
Chem. Soc. 1991, 113, 5720; (b) Ro¨lle, T.; Hoffmann, R.
W. J. Chem. Soc., Perkin Trans. 2 1995, 1953.
10. Coote, S. J.; Davies, S. G.; Goodfellow, C. L.; Sutton, K.
H.; Middlemiss, D.; Naylor, A. Tetrahedron: Asymmetry
1990, 1, 817.
References
11. Wiberg, K. B.; Bailey, W. F. J. Mol. Struct. 2000, 556, 2.
12. It might be noted that we have not attempted to optimize
the enantioselectivity of the cyclization by modification of
the pseudoephedrine-derived ligand.
1. Bailey, W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61, 2596.
2. Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1996, 61,
2594.
3. (a) Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000,