N-Fluorocinchona Alkaloids
J. Am. Chem. Soc., Vol. 123, No. 29, 2001 7005
and C-OH moieties,16 3-fluorooxindoles 7 are potential mimics
of both the corresponding oxindoles and 3-hydoroxyoxindoles
that are often found as metabolites of indoles.17 Although several
methods are available for the preparation of racemic 7,18,19 as
yet no enantioselective synthesis of 7 has been reported.
Therefore, we examined oxindoles 8 as substrates for enantios-
lective fluorination using the alkaloid/Selectfluor combinations.
Fluorination of 8 using the best combinations described in the
previous section (DHQDA and DHQB) gave unsatisfactory
enantioselectivities in the formation of 3-benzyl-3-fluorooxin-
dole (7a) (37% ee, 7% ee, respectively, Table 9, entries 1 and
2). These fluorination reactions were performed at 0 °C since
lower temperatures led to incomplete reaction. In attempts to
improve on these results, we found that extensive variation of
the cinchona alkaloid derivatives failed to give any improvement
in enantioselection over that obtained with DHQDA. However,
good levels of enantioselection in the fluorination of 8a were
finally achieved using bis-cinchona alkaloids/Selectfluor com-
binations (entries 9-15). Thus, the (DHQ)2AQN/Selectfluor
combination and (DHQD)2PYR/Selectfluor combination in
MeCN afforded excellent yields of 7a with 78% ee and 72%
ee, respectively (entries 9 and 11).
It is noteworthy that use of equimolar amounts of Selectfluor
and bis-cinchona alkaloids gave the highest yield as well as
high stereoselectivity (entry 9; 100% yield, 78% ee). In contrast,
use of 2 molar equiv of Selectfluor to bis-cinchona alkaloid
(i.e. equivalent amounts of alkaloid base) resulted in an
unsatisfactory yield along with a slight decrease in stereose-
lectivity (entry 10; 50% yield, 64% ee). Qualitatively similar
results were obtained for the monomer alkaloid/Selectfluor
combinations used in the fluorination (entries 1, 4, 17, and 18).
For example, the combination with a molar DHQDA/Selectfluor
ratio of 2/1 gave better results (entry 17; 53% yield, 44% ee)
than that with a molar DHQDA/Selectfluor ratio of 1/1 (entry
1; 27% yield, 37% ee) with respect to both yield and selectivity.
Similarly, while fluorination using a 1/1 molar ratio of DHQDB/
Selectfluor gave a 46% yield with 38% ee, this was increased
to 77% yield and 55% ee when the fluorination was carried out
using a 2/1 molar ratio of DHQDB/Selectfluor (entries 4 and
18). These results suggest that the reaction is facilitated by the
additional equivalent of alkaloid (moiety) acting as a base to
remove a proton at the reactive center of 8a to form an anion.
Additionally we note that choice of solvent was important for
this reaction. For example, when 8a was treated with the
combination in MeOH, the product was obtained in lower
Table 9. Enantioselective Fluorination of Oxindole 8a: Variation
of Cinchona Alkaloid and Solvent
yield ee
major
entry
alkaloidh
solvent (%) (%)b isomerc,d
1
2
3
4
5
6
7
8
9
DHQDA
DHQBe
DHQD
MeCN
MeCN
MeCN
27
60
17
46
19
26
32
34
37
7
18
38
0
7
18
9
78
64
72
10
42
23
62
17
44
55
S
S
S
S
DHQD-4-chlorobenzoate MeCN
DHC
DHCD
DHCD-acetate
DHC-acetate
(DHQ)2AQN
MeCN
MeCN
MeCN
MeCN
S
S
F
F
F
F
S
S
F
S
F
S
S
MeCN 100
10 (DHQ)2AQNf
11 (DHQD)2PYR
12 (DHQD)2AQN
13 (DHQ)2PYR
14 (DHQ)2PHAL
15 (DHQD)2PHAL
16 (DHQD)2PHAL
17 DHQDAg
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
MeCN
50
91
88
94
74
99
81
53
77
18 DHQD-4-chlorobenzoateg MeCN
a The cinchona alkaloid/Selectfluor combination was prepared from
1.5 equiv of cinchona alkaloid and 1.5 equiv of Selectfluor in MeCN
or MeOH at room temperature for 1 h. b Ee values were determined
by HPLC analysis using a Chiralcel OB column. c S: slower isomer.
F: faster isomer. d The configuration of 7a was not determined. e This
reaction was carried out with 3 equiv of cinchona alkaloid and 3 equiv
f
of Selectfluor. This reaction was carried out with 1.5 equiv of cinchona
alkaloid and 3.0 equiv of Selectfluor. g This reaction was carried out
with 3 equiv of cinchona alkaloid and 1.5 equiv of Selectfluor.
h DHQDA ) dihydroquinidine acetate, DHQB ) dihydroquinine
4-chlorobenzoate, DHC ) dihydrocinchonine, DHCD ) dihydrocin-
chonidine.
enantiopurity and with reversed facial selectivity (compare
entries 15 and 16) (Table 9).
On the basis of these results, the alternative Selectfluor
combinations derived from bis-cinchona alkaloids [(DHQ)2AQN/
Selectfluor and (DHQD)2PYR/Selectfluor] were chosen for the
fluorination of a series of 3-substituted oxindoles 8 in MeCN.
As summarized in Table 10, both combinations produced
optically active 3-substituted 3-fluorooxindoles 7 in modest to
good enantioselectivities (up to 82% ee). While there are several
reported methods for the preparation of racemic 7, to our
knowledge this is the first example of an enantioselective
synthesis of 7 (Table 10).
Structure of the Reactive Intermediate in the Enantiose-
lective Fluorination: N-Fluorocinchona Alkaloids. We based
our development of alkaloid/Selectfluor combinations as enan-
tioselective fluorinating reagents on the fundamental idea that
in situ “transfer fluorination”20 would generate the N-fluorocin-
chona alkaloid (Scheme 2). Our hope was that such a species
would be capable of transferring the fluorine to an enolate with
enantioselective bias. The successful realization of enantiose-
lective fluorination is suggestive of this mechanism but, in itself,
does not prove that N-fluorocinchona alkoloids are intermediates.
Therefore, we have examined this question in greater depth.
We report here the results of experiments that confirm that this
novel enantioselective fluorination reaction, in fact, is mediated
(16) Current evidence indicates that fluorine and oxygen, not fluorine
and hydrogen, are nearly isosteric. See: Smart, B. E. In Organofluorine
Chemistry: Principles and Commercial Applications; Banks, R. E., Smart,
B. E., Tatlow, J. C., Eds.; Plenum Press: New York, 1994; Chapter 3, pp
57-88.
(17) (a) Kato, Y.; Shimokawa, M.; Yokoyama, T.; Mohri, K. J.
Chromatogr. Biomed. Appl. 1993, 616, 67-71. (b) Itakura, K.; Uchida,
K.; Kawakishi, S. Chem. Res. Toxicol. 1994, 7, 185-190. (c) Oestin, A.;
Catala, C.; Chamarro, J.; Sandberg, G. J. Mass Spectrom. 1995, 30, 1007.
(d) Thorton, M. J.; Appleton, M. L.; Gonzalez, F. J.; Yost, G. S. J.
Pharmacol. Exp. Ther. 1996, 276, 21-29. (e) Carpenedo, R.; Carla, V.;
Moneti, G.; Chiarugi, A.; Moroni, F. Anal. Biochem. 1997, 244, 74-79.
(f) Hu, T.; Dryhurst, G. J. Electroanal. Chem. 1997, 432, 7-18. (g)
Anisimoviene, N. Biologija 1997, 34-39. (h) Yang, Z.; Wrona, M. Z.;
Dryhurst, G. J. Neurochem. 1997, 68, 1929-1941. (i) Mannaioni, G.;
Carpenedo, R.; Pugliese, A. M.; Corradetti, R.; Moroni, F. Br. J. Pharmacol.
1998, 125, 1751-1760. (j) Carpenedo, R.; Mannaioni, G.; Moroni, F. J.
Neurochem. 1998, 70, 1998-2003.
(18) (a) Middleton, W. J.; Bingham, E. M. J. Org. Chem. 1980, 45,
2883-2887. (b) Torres, J. C.; Garden, S. J.; Pinto, A. C.; da Silva, F. S.
Q.; Boechat, N. Tetrahedron 1999, 55, 1881-1892. (c) Labroo, R. B.;
Labroo, V. M.; King, M. M.; Cohen, L. A. J. Org. Chem. 1991, 56, 3637-
3642. (d) Hou, Y.; Higashiya, S.; Fuchigami, T. J. Org. Chem. 1997, 62,
8773-8776.
(20) Transfer fluorination was developed by Banks, see: Abdul-Ghani,
M.; Banks, R. E.; Besheesh, M. K.; Sharif, I.; Syvret, R. G. J. Fluorine
Chem. 1995, 73, 255-257.
(19) Takeuchi, Y.; Tarui, T.; Shibata, N. Org. Lett. 2000, 2, 639-642.