A novel and efficient synthesis of 3-fluorooxindoles from indoles mediated by selectfluor

Article abstract of DOI:10.1021/ol991400y

(equation presented) Treatment of several 3-substituted indoles, including derivatives of tryptophan and serotonin, with commercially available Selectfluor in acetonitrile/ water furnished 3-substiuted 3-fluorooxindoles in good to high yields. Since 3-fluorooxindoles obtained are sterically similar to both oxindoles and 3-hydroxyoxindoles, they should be useful as probes for investigating the enzymatic mechanism of indole biosynthesis and metabolism.

Full text of DOI:10.1021/ol991400y

ORGANIC
LETTERS
2
000
Vol. 2, No. 5
39-642
A Novel and Efficient Synthesis of
-Fluorooxindoles from Indoles Mediated
6
3
by Selectfluor
Yoshio Takeuchi,* Takanao Tarui, and Norio Shibata
Faculty of Pharmaceutical Sciences, Toyama Medical & Pharmaceutical UniVersity,
Sugitani 2630, Toyama, 930-0194 Japan
takeuchi@ms.toyama-mpu.ac.jp
Received December 24, 1999
ABSTRACT
Treatment of several 3-substituted indoles, including derivatives of tryptophan and serotonin, with commercially available Selectfluor in acetonitrile/
water furnished 3-substiuted 3-fluorooxindoles in good to high yields. Since 3-fluorooxindoles obtained are sterically similar to both oxindoles
and 3-hydroxyoxindoles, they should be useful as probes for investigating the enzymatic mechanism of indole biosynthesis and metabolism.
Oxindole derivatives have received much attention as
synthetic intermediates for preparation of biologically active
identified as metabolites of biologically active indoles.
Oxindole derivatives structurally similar to these metabolites,
or similar to intermediates in their formation, are attractive
targets in the design of inhibitors of metabolic enzymes and
thus of the metabolic pathways of the corresponding in-
1
molecules and as useful probes for the study of enzymatic
2
mechanisms involved in indole metabolism and biosynthesis.
A variety of oxindoles and 3-hydoroxyoxindoles have been
3
,4
5a
doles. For example, oxindolyl-L-alanine (1a) and diox-
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1
0.1021/ol991400y CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/09/2000

5
b
indolyl-L-alanine (1b), which are structurally similar to the
proposed intermediate in tryptophan metabolism, were found
to be potent competitive inhibitors of both tryptophan
substitution of the hydroxy group of 3-hydroxyoxindoles 4
by fluoride anion employing DAST seems to be a practical
12
method for the preparation of 2 only if the starting materials
4 are readily available. Successful electrochemical mono-
5
synthase and tryptophanase. As a part of our research
program involving the design and synthesis of fluorine-
containing biologically active compounds, we were inter-
fluorination of 3-phenylthiooxindoles 5a has been achieved
using Et NF to give 3-fluoro-3-phenylthiooxindoles 5b.
4
6
13
ested in the structure of 3-fluorooxindoles 2. Fluorine most
closely resembles the size of hydrogen than does any other
substituent, and replacement of hydrogen by fluorine is often
regarded as an isosteric substitution.7 However, recent
evidence indicates that fluorine and oxygen, not fluorine and
hydrogen, are very nearly isosteric.8 Further, possible
participation of fluorine as a hydrogen bond acceptor suggests
that the replacement of hydroxyl group by fluorine would
result in production of useful analogues of their parent
This procedure, however, is clearly limited due to the
presence of a 3-phenylthio moiety (Figure 2).
9
molecules. Thus, 3-fluorooxindoles 2 are potential mimics
both of the corresponding oxindoles and 3-hydoroxyindoles
that are often found as metabolites of indoles. In this paper,
we wish to report a direct and efficient synthesis of
Figure 2.
3
-fluorooxindoles 2 from indoles using commercially avail-
able Selectfluor, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-
2.2.2]octane bis(tetrafluoroborate) (Figure 1).
We first investigated reaction conditions using skatole (6a).
We found that the choice of solvent and the amount of
reagent are important for optimizing the yields. Use of 2
[
14
equiv of Selectfluor in acetonitrile gave a complex mixture,
whereas reaction in acetonitrile/water (4/1) produced a 45%
of 3-fluoro-3-methyloxindole (2a) together with a small
amount of 3-methyloxindole (7a) as a side product. Addition
of trifluoroethanol instead of water lowered the yield to 29%.
The best result (71% yield) was obtained when the reaction
was performed in a 1/1 mixture of acetonitrile/water system
1
5
with 3 equiv of Selectfluor. Another good solvent system
was found to be a 4/1 mixture of acetonitrile/methanol, which
produced 2a in 57%. Lower yields of 2a were obtained when
Figure 1.
1
equiv or more than 3 equiv of Selectfluor was employed
for this reaction (Table 1).
To demonstrate the generality of this Selectfluor-mediated
fluorination, the procedure was extended to other indoles
Although several methods for the synthesis of 3-bromoox-
10
indoles have been reported, only a few methods are
available for the synthesis of 2.1
1-13
Treatment of isatin with
6
6
b-k including the derivatives of tryptophan 6i,j, tryptamine
h, and serotonin 6k (Table 2). In all cases, the conversions
DAST furnishes 3,3-difluorooxindole (3).11 Nucleophilic
(6) (a) Takeuchi, Y.; Shiragami, T.; Kimura, K.; Suzuki, E.; Shibata, N.
Org. Lett. 1999, 1, 1571-1573. (b) Takeuchi, Y.; Kamezaki, M.; Kirihara,
K.; Haufe, G.; Laue, K. W.; Shibata, N. Chem. Pharm. Bull. 1998, 46,
Table 1. Reaction of Skatole (6a) with Selectfluora
1
062-1064. (c) Haufe, G.; Laue, K. W.; Triller, M. U.; Takeuchi, Y.;
Shibata, N. Tetrahedron 1998, 54, 5929-5938. (d) Hayakawa, Y.; Singh,
M.; Shibata, N.; Takeuchi, Y.; Kirk, K. L. J. Fluorine Chem. 1999, 97,
1
61-164. (e) Yokoyama, H.; Hyodo, R.; Nakada, A.; Yamaguchi, S.; Hirai,
Y.; Kometani, T.; Goto, M.; Shibata, N.; Takeuchi, Y. Tetrahedron Lett.
998, 39, 7741-7744.
7) (a) Biomedical Aspects of Fluorine Chemistry; Filler, R., Kobayashi,
1
(
Y., Eds.; Kodansha/Elsevier Biomedical Press: Tokyo, Amsterdam-New
York-Oxford, 1982. (b) Biomedical Frontiers of Fluorine Chemistry;
Ojima, I., McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium Series
6
39; American Chemical Society: Washington, DC, 1996. (c) Fusso &
Yakugaku; Kobayashi, Y., Kumadaki, I., Taguchi, T., Eds.; Hirokawa
Publishing Co.: Tokyo, 1992.
(8) Smart, B. E. In Organofluorine Chemistry: Principles and Com-
mercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum
Press: New York, 1994; Chapter 3, pp 57-88.
(
9) For example Davis, F. A.; Reddy, R. E. Tetrahedron: Asymmetry
1
994, 5, 955-960.
(10) For example: (a) Lawson, W. B.; Patchornik, A.; Witkop, B. J.
Am. Chem. Soc. 1960, 82, 5918-5923. (b) Hinman, R. L.; Bauman, C. P.
J. Org. Chem. 1964, 29, 1206-1215. (c) Kornet, M. J.; Thio, P. A.; Malone,
N.; Lubawy, W. C. J. Pharm. Sci. 1975, 64, 639-642. (d) Hino, T.;
Tonozuka, M.; Ishii, Y.; Nakagawa, M. Chem. Pharm. Bull. 1977, 25, 354-
a
Experimental conditions: Selectfluor was added to a solution of 6a,
and the mixture was stirred at rt overnight. *Small to medium amount of
3-methyloxindole (7a) was isolated as a side product in all cases.
3
58. (e) Szab o´ -Pusztay, K.; Szab o´ , L. Synthesis 1979, 276-277.
640
Org. Lett., Vol. 2, No. 5, 2000

Finally, we examined the direct Selectfluor fluorination
at the C-3 position of the oxindoles 7 in order to gain
mechanistic information. Treatment of oxindoles 7 with 1
equiv of Selectfluor in acetonitrile/water (1/1) system
furnished 2, although the yields were much lower than those
observed in the fluorination of indoles (Table 3).
Table 2. Preparation of 3-Fluorooxindoles 2 from Indoles 6a
Table 3. Fluorination of Oxindoles 7a
a
Experimental conditions: Selectfluor (3 equiv) was added to a solution
a
Experimental conditions: Selectfluor (1 equiv) was added to a solution
of 7 in MeCN/H2O (1/1), and a mixture was stirred at rt overnight. (a)
Isolated yield after silica gel column chlomatography.
of 6 in MeCN/H2O (1/1), and the mixture was stirred at rt overnight. pNB:
p- nitrobenzoyl. (a) Corresponding oxindoles 7 were isolated as side products
in all cases. (b) Isolated yield after silica gel column chlomatography. (c)
Mixture of diastereoisomers (46% de). (d) Mixture of diastereoisomers (5%
de).
On the basis of the above results and on information from
10a,b
the literature,
we propose the reaction mechanism outlined
to 3-fluorooxindoles 2 proceeded in good to high yields. It
is of interest to note that, with N-Ac-Trp-OMe (6i) as a
substrate, the corresponding fluorooxindole 2i was obtained
with 46% de, whereas no diastereoselectivity was observed
in the case of N-pNB-Trp-OMe (6j). A typical experimental
procedure is as follows. Selectfluor (3.0 equiv) was added
to a stirred solution of indoles 6 (0.2s0.4 mmol) in
actonitrile/water (1/1, 2 mL) at room temperature. After
overnight stirring, the reaction mixture was diluted with ethyl
acetate (50 mL), washed with water (10 mL), 4% HCl (10
mL), a saturated solution of sodium bicarbonate (10 mL),
in Scheme 1. According to this proposal, reaction of 6 with
Selectfluor yields the unstable 3-fluoroindolenine A, which
undergoes loss of HF by addition of water. A subsequent
1
,5-prototopic shift gives the enol B. Finally, fluorination
Scheme 1. Proposed Reaction Mechanism from 6 to 2
2 4
and brine (10 mL), and dried over Na SO . The solvent was
removed under reduced pressure to give a residue that was
purified by column chromatography on silica gel eluting with
ethyl acetate/hexane to furnish 2 in a pure state. Identification
1
19
of the products was achieved by H and F NMR, IR, mass
1
9
spectrometry, and elemental analysis. The characteristic F
NMR (254 MHz, CDCL ) peaks appear around at δ-155
ppm for all fluorooxindoles 2.16
3
(
11) (a) Middleton, W. J.; Bingham, E. M. J. Org. Chem. 1980, 45,
883-2887. (b) Torres, J. C.; Garden, S. J.; Pinto, A. C.; da Silva, F. S.
Q.; Boechat, N. Tetrahedron 1999, 55, 1881-1892.
12) Labroo, R. B.; Labroo, V. M.; King, M. M.; Cohen, L. A. J. Org.
Chem. 1991, 56, 3637-3642.
13) Hou, Y.; Higashiya, S.; Fuchigami, T. J. Org. Chem. 1997, 62,
773-8776.
14) (a) Banks, R. E. J. Fluorine Chem. 1998, 87, 1-17. (b) Lal, G. S.;
Pez, G. P.; Syvret, R. G. Chem. ReV. 1996, 96, 1737-1755.
15) Since Selectfluor seems to decompose slowly in water, 3 equiv of
2
(
(
8
(
(
reagent (not 2 equiv) was used when the reaction was performed in aqueous
media just in case.
1
9
(
16) F NMR (254 MHz, CDCL3) δ: 2a -153.7 ppm (q, J ) 22.2
Hz); 2b, -159.6 ppm (br dd J ) 12.9 Hz, 14.8 Hz); 2c, -153.6 ppm (t, J
10.2 Hz); 2d, -156.7 ppm (t, J ) 14.8 Hz); 2e, -155.3 ppm (t, J )
3.9 Hz); 2f, -157.8 ppm (t, J ) 15.7 Hz); 2g, -156.7 ppm (t, J ) 14.8
Hz); 2h, -154.8 ppm (t, J ) 13.9 Hz); 2i, -152.4 ppm (t, J ) 17.8 Hz),
)
1
-
152.6 ppm (t, J ) 13.4 Hz); 2j, -154.1 ppm (t, J ) 16.6 Hz), -155.0
ppm (br d J ) 16.5 Hz); 2k, -156.8 ppm (t, J ) 15.7 Hz).
Org. Lett., Vol. 2, No. 5, 2000
641

of B with additional Selectfluor yields 2. Formation of the
oxindole 7 as a side product could be explained by tau-
tomerization of the enol B catalyzed by solvent water. The
lower yield of 2 from 7 may be due to the difficulty of the
tautomerization from keto-form 7 to enol-form B under the
we did not detect C nor D in the reaction mixture. Trapping
the proposed initial adducts is now in progress.
In summary, we have developed a novel and efficient
synthesis of 3-fluorooxindoles. Although there are two
reports of the reaction of indoles with fluorinating reagents,
17,18
1
0a,b
including Selectfluor, in the literature,
these reactions do
reaction conditions (Scheme 1). Another pathway
con-
not furnish any 3-fluorooxindoles. To our knowledge, this
transformation represents the first reported example of direct
synthesis of 3-fluorooxindoles 2 from indoles.
siderable from 6 to 2 via 2-fluoroindole C and 2,3-
difluoroindolenine D especially in nonaqueous media such
as in methanol/acetonitrile cannot be ruled out as well, though
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Science, Sports and Culture of Japan. N.S. wishes
to thank the Nissan Science Foundation for support. Y.T.
thanks the Asahi Glass Foundation.
(
17) (a) Barton, D. H. R.; Hesse, R. H.; Jackman, G. P.; Pechet, M. M.
J. Chem. Soc., Perkin Trans. 1 1977, 2604-2608. (b) Hodson, H. F.; Madge,
D. J.; Slawin, A. N. Z.; Widdowson, D. A.; Williams, D. J. Tetrahedron
1
994, 50, 1899-1906.
18) It is of particular interest to note that 3-fluorooxindoles 2 are solely
(
produced in our system, while 3-fluoro-2-methoxyindoline is the product
in the reaction of N-tosylindole with Selectfluor. See ref 17b.
OL991400Y
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Org. Lett., Vol. 2, No. 5, 2000