Direct conversion of indoles to 3,3-difluoro-2-oxindoles via electrophilic fluorination

Article abstract of DOI:10.1021/ol302666d

3,3-Difluoro-2-oxindoles can be obtained directly from indoles in moderate yields via electrophilic fluorination using N-fluorobenzenesulfonimide as a mild fluorinating reagent. The presence of tert-butyl hydroperoxide during the reaction, together with additional heating after quenching the reaction with triethylamine, is beneficial to the formation of the desired product.

Full text of DOI:10.1021/ol302666d

ORGANIC
LETTERS
2012
Vol. 14, No. 22
5676–5679
Direct Conversion of Indoles
to 3,3-Difluoro-2-oxindoles via
Electrophilic Fluorination
Yee Hwee Lim,* Qunxiang Ong, Hung A. Duong,* Tuan Minh Nguyen, and
Charles W. Johannes
Organic Chemistry, Institute of Chemical and Engineering Sciences (ICES),
Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way,
The Helios Block, #03-08, Singapore 138667
lim_yee_hwee@ices.a-star.edu.sg; duong_hung@ices.a-star.edu.sg
Received September 27, 2012
ABSTRACT
3,3-Difluoro-2-oxindoles can be obtained directly from indoles in moderate yields via electrophilic fluorination using N-fluorobenzenesulfonimide
as a mild fluorinating reagent. The presence of tert-butyl hydroperoxide during the reaction, together with additional heating after quenching the
reaction with triethylamine, is beneficial to the formation of the desired product.
The introduction of fluorine(s) into organic molecules
typically changes their physiochemical properties signifi-
cantly due to the strong electronegativity and the relatively
small size of the fluorine atom. Fluorine and fluoroalkyls
are known to increase the metabolic stability, lipophilicity,
bioavailability, membrane permeability, and binding affi-
nity of bioactive molecules.1 It is estimated that 30À40%
of agrochemicals and 20% of pharmaceuticals contain
fluorine.1a,b The radioisotope 18F (t1/2 = 109.7 min) is
used in Positron Emission Tomography (PET) to provide
real time visualization and quantitative measurements
of metabolic, biochemical, and physiological function
in vivo.2 Moreover, perfluorinated compounds have found
a wide range of applications in materials.3
Significant advances have been made by various re-
search groups in the area of nucleophilic, electrophilic,
and radical fluorination, difluoromethylation, and tri-
fluoromethylation over the past few decades.1c,4 A num-
ber of novel fluorination methods have been reported
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(3) Hunng, M. H.; Farnham, W. B.; Feiring, A. E.; Rozen, S.
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(5) For recent examples on monofluorination, see: (a) Fiers, P. S.;
Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 10795. (b) Casitas, A.;
Canta, M.; Sola, M.; Costas, M.; Ribas, X. J. Am. Chem. Soc. 2011, 133,
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19386. (c) Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2010, 132,
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J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661. (f) Wang, X.;
Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520. (g) Furuya, T.;
Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed. 2008, 47, 5993. (h) Hull,
K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134.
(6) For recent examples on difluoromethylation and trifluoromethy-
lation, see: (a) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter,
R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S.
J. Am. Chem. Soc. 2012, 134, 1494. (b) Fier, P. S.; Hartwig., J. F. J. Am.
Chem. Soc. 2012, 134, 5524. (c) Chu, L.; Qing, F. L. J. Am. Chem. Soc.
2012, 134, 1298. (d) Liu, T.; Shao, X.; Wu, Y.; Shen, Q. Angew. Chem.,
Int. Ed. 2012, 51, 540. (e) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012,
134, 9034. (f) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.;
Su, S.; Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 14411. (g) Nagib, D. A.; MacMillan, D. W. Nature 2011, 480,
224.
(4) For some excellent reviews, see: (a) Studer, A. Angew. Chem., Int.
Ed. 2012, 51, 8950. (b) Besset, T.; Schneider, C.; Cahard, D. Angew.
Chem., Int. Ed. 2012, 51, 5048. (c) Wu, X.-F.; Neumann, H.; Beller, M.
Chem.;Asian J. 2012, 7, 1744. (d) Furuya, T.; Kamlet, A. S.; Ritter, T.
Nature 2011, 473, 470. (e) Tomashenko, O. A.; Grushin, V. V. Chem.
Rev. 2011, 111, 4475. (f) Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, V.-D.;
Roy, S. Tetrahedron 2011, 67, 2161. (g) Ni, C.; Hu, J. Synlett 2011, 770.
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r
10.1021/ol302666d
Published on Web 10/26/2012
2012 American Chemical Society

recently.5,6 Yet, these areas remain of immense interest to
the synthetic community.
Electrophilic fluorination of indoles can lead to diverse
fluorinated structures, depending on the substitution pat-
tern of the precursors. Fluorination of N-tosylindole in the
presence of either cesium fluoroxysulfate or Selectfluor in
an acetonitrile/methanol mixture (1:1) affords 3-fluoro-2-
methoxyindoline (Scheme 1a).12 Recently, indoles posses-
sing substituents at either C2 or C3 were shown to undergo
electrophilic fluorination with Selectflour to produce 3,3-
difluoroindolin-2-ols (Scheme 1b)13 or 3-fluorooxindoles
(Scheme 1c),14 respectively. Indoles with pendant hetero-
nucleophiles tethered at either C3 or N can give rise to
interesting heterocyclic structures under fluorocycliza-
tion conditions (Scheme 1d and 1e).14,15 Herein, we report
a one-step synthesis of 3,3-difluoro-2-oxindoles from
N-alkylindoles (where R1, R2 = H) via electrophilic
fluorination (Scheme 1f).
The initial investigation focused on the fluorination of
N-methylindole (1a) withvariouselectrophilic fluorinating
reagents such as Selectfluor and N-fluorobenzenesulfoni-
mide (NFSI). Under conditions similar to those previously
employed for electrophilic fluorination of indoles,12À15
only trace amounts of the desired product could be ob-
served by 19F NMR.16 Pleasantly, treating 1a with 3 equiv
of NFSI in a solvent mixture of toluene/acetonitrile (4:1)
at 70 °C for 1 h gave difluorooxindole 2a in 18% yield as
determined by 19F NMR (Table 1, entry 1). The addition
of tert-butyl hydroperoxide (TBHP) to the reaction mix-
ture proved highly beneficial as the yield of 2a improved to
32% (entry 2). Significant amounts of two other fluori-
nated species were observed in the crude mixture by 19F
NMR. We speculated that they could be the hemiaminal
intermediates17 (vide infra) that were not fully converted
to the desired difluorooxindole. Running the reaction at
a higher temperature (100 °C, 60 min) or for a longer
reaction time (70 °C, 120 min) only gave 2a in 21% and
36% yields, respectively (entries 3 and 4). A yield of 46%
could be obtained, however, if the reaction was first run
at 70 °C until the complete consumption of 1a, followed
by addition of excess triethylamine (Et3N) and further
heating at 100 °C for 1 h (entry 5). A clean conversion of
the hemiaminal intermediates to the desired product was
observed by 19F NMR in this case. Upon screening a range
of additives,16 we found that addition of K2HPO4 led to an
additional enhancement in yield to 55% (entry 6). While
running the fluorination at ambient temperature for
16 h resulted in a much lower yield (13%) of the product
(entry 7), a yield of 62% could be obtained at 90 °C after
20 min (entry 8). Finally, the optimized conditions involve
1.5 equiv of TBHP, 5 equiv of K2HPO4, and 3 equiv of
Isatin and derivatives have been shown to display
antimicrobial, anticancer, antiviral, and anti-inflamma-
tory activities.7 The replacement of the keto carbonyl in
isatins with the isosteric8 gem-difluoro moiety leads to 3,3-
difluoro-2-oxindole, a useful analogue for biological
studies.9,10 This class of compounds is often synthesized
by nucleophilic fluorination of isatins using thermally
unstable diethylaminosulfur trifluoride (DAST)9f or,
more recently, bis(methoxyethyl)aminosulfur trifluoride
(Deoxofluor)9d and 4-tert-butyl-2,6-dimethylphenyl-
sulfur trifluoride (Fluolead).9b Alternatively, copper-
mediated intramolecular cyclization of iododifluoroace-
tamides affords 3,3-difluoro-2-oxindoles in moderate
yields.11 Yet, to the best of our knowledge, there has been
no report on the direct conversion of broadly available
indoles to 3,3-difluoro-2-oxindoles. This is rather remark-
able considering the rich chemistry that indoles display.
Scheme 1. Electrophillic Fluorination of Indoles
(7) (a) Bhrigu, B.; Pathak, D.; Siddiqui, N.; Alam, M. S.; Ahsan, W.
Int. J. Pharm. Sci. Drug Res. 2010, 2, 229. (b) Vine, K. L.; Matesic, L.;
Locke, J. M.; Ranson, M.; Skropeta, D. Anti-Cancer Agents Med. Chem.
2009, 9, 397.
(8) For a discussion on isosteric groups, see: Meanwell, N. A. J. Med.
Chem. 2011, 54, 2529.
(9) For some other methods of preparation of 3,3-difluoro-2-
oxindoles, see: (a) Ohtsuka, Y.; Yamakawa, T. Tetrahedron 2011, 67,
2323. (b) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc.
2010, 132, 18199. (c) McAllister, L. A.; McCormick, R. A.; James,
K. M.; Brand, S.; Willetts, N.; Procter, D. J. Chem.;Eur. J. 2007, 13,
1032. (d) Singh, R. P.; Majumder, U.; Shreeve, J. M. J. Org. Chem. 2001,
66, 6263. (e) Torres, J. C.; Garden, S. J.; Pinto, A. C.; da Silva, F. S. Q.;
Boechat, N. Tetrahedron 1999, 55, 1881. (f) Middleton, W. J.; Bingham,
E. M. J. Org. Chem. 1980, 45, 2883.
(10) For some examples of 3,3-difluoro-2-oxindole analogues in
biological studies, see: (a) Zhou, N.; Polozov, A. M.; O’Connell, M.;
Burgeson, J.; Yu, P.; Zeller, W.; Zhang, J.; Onua, E.; Ramirez, J.;
Palsdottir, G. A.; Halldorsdottir, G. V.; Andresson, T.; Kiselyov, A. S.;
Gurney, M.; Singh, J. Bioorg. Med. Chem. Lett. 2010, 20, 2658.
(b) Podichetty, A. K.; Faust, A.; Kopka, K.; Wagner, S.; Schober, O.;
(11) Zhu, J.; Zhang, W.; Zhang, L.; Liu, J.; Zheng, J.; Hu, J. J. Org.
Chem. 2010, 75, 5505.
(12) Hodson, H. F.; Madge, D. J.; Slawin, A. N. Z.; Widdowson,
D. A.; Williams, D. J. Tetrahedron 1994, 50, 1899.
(13) Takeuchi, Y.; Tarui, T.; Shibata, N. Org. Lett. 2000, 2, 639.
(14) Lin, R.; Ding, S.; Shi, Z.; Jiao, N. Org. Lett. 2011, 13, 4498.
(15) Lozano, O.; Blessley, G.; Martinez Del Campo, T.; Thompson,
A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman, R.; Gouverneur,
V. Angew. Chem., Int. Ed. 2011, 50, 8105.
(16) For more details, see Supporting Information.
(17) One of the hemiaminal intermediates identified as V (Scheme 2)
was isolated as a mixture with oxindole IX for the case of 1a.
€
Schafers, M.; Haufe, G. Bioorg. Med. Chem. 2009, 17, 2680.
Org. Lett., Vol. 14, No. 22, 2012
5677

NFSI (entries 9À12). It should be noted that the presence
of TBHP at the beginning of the reaction was important.
Indeed, when TBHP and Et3N were added after 1a had
been fully consumed, further heating at 100 °C for 1 h only
resulted in a 23% yield of 2a (entry 13). No formation of 2a
was observed when Selectfluor was used instead of NFSI
(entry 14).
Table 2. Fluorination of Different N-Substituted Indolesa
temp
t
Table 1. Screening Results for Electrophilic Fluorination of
N-Methylindolea
entry
indole
R
(°C)
(min)b
% yieldc
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Me
90
90
90
90
90
90
90
90
90
20
20
20
20
20
20
45
70
30
50
46
32
47
43
60
56
57
64
CH2CH2OBn
iPr
Bu
s-Bu
Bn
1g
1h
1i
4-tBuC6H4CH2
2-O2NC6H4CH2
5-MeO-2-Br-
C6H4CH2
C6H5
TBHP
K2HPO4
(equiv)
temp
t
entry
(equiv)
(°C)
(min)b
% yieldc
1
À
3
À
À
À
À
À
5
70
70
100
70
70
70
25
90
90
90
90
90
90
90
60
60
60
120
60
60
960
20
20
20
20
20
20
20
18
32
21
36
46
55
13
62
55
55
51
63
23
0
10d
11d
1j
120
120
180
120
40
48
2
1k
4-MeOC6H4
3
3
a Conditions: Indole (1 equiv), NFSI (3 equiv), K2HPO4 (5 equiv),
PhMe/MeCN (4:1, 0.05 M) at the specified temperature and time; then
Et3N (18 equiv), 100 °C for 1 h. b Reaction was monitored by tlc until
all starting material was consumed. c Isolated yields. d K2HPO4 was not
used.
4
3
5d
3
6d
3
7d
3
5
8d
3
5
9d,e
10d,f
11d
12d
13d,g
14d,h
3
5
3
5
A variety of N-benzylindoles can be converted to the
corresponding 3,3-difluoro-2-oxindoles employing our
method (Table 3). A higher temperature (120 °C) was
necessary to achieve good conversions for substrates pos-
sessing an electron-withdrawing substituent (entries 1À5,
9, 10, and 12). Functional groups amenable to further
manipulations, such as bromide (entries 1, 10, and 12),
nitro (entry 3), ketone (entry 4), and nitrile (entry 9),
are all compatible with our conditions to give the corre-
sponding difluorooxindoles in moderate yields (45À60%).
It is noteworthy that carbonyl containing indole 3d can
also be difluorinated, demonstrating the complementar-
ity of our method to the existing nucleophilic conditions
(entry 4).9b,d,f For N-benzyl 5-nitroindole (3c), the reaction
proceeded with a reasonable conversion only when K2HPO4
was eliminated from the reaction to give 4c in 50% yield
(entry 3). For indoles with electron-donating groups, yields
of 42À54% were achieved at slightly lower temperatures
(70À90 °C) (entries 6À8).
3
3
1.5
1.5
1.5
5
5
5
a Conditions: Indole (1 equiv), NFSI (3 equiv), PhMe/MeCN
(4:1, 0.05 M). b Reaction was monitored by tlc until all starting material
was consumed. c Determined by 19F NMR with 2-fluoronitrobenzene as an
internal standard. d After the reaction, Et3N (18 equiv) was added, and the
reaction was heated further at 100 °C for 1 h. e 4 equiv of NFSI was used.
f 2 equiv of NFSI was used. g TBHP was added at the end of the reaction
instead, together with Et3N. h Selecfluor was used instead of NFSI.
Under the optimized conditions, N-methyl-3,3-difluoro-
2-oxindole(2a) wasisolatedin50% yield (Table2, entry 1).
Other N-substituted indoles were also tested. The bulkier
iPr group resulted in a lower yield (32%) compared to
other straight chain alkyl groups (entries 2À5). A slightly
higher yield was obtained with the benzyl protecting group
(60%, entry 6). Substituted benzyl groups with varied
electronic and steric requirements on the benzene ring
did not influence the reaction to any significant extent,
with the exception of requiring longer reaction times for
completion (entries 7À9). The reactions of N-aryl indoles
(1j and 1k) proceeded rather slowly under the standard
conditions. Running the reactions at 120 °C for a pro-
longed reaction time in the absence of K2HPO4 could help
to obtain 2j and 2k in 40% and 48% yields, respectively
(entries 10 and 11). Of note, free indoles or indoles posses-
sing electron-withdrawing N-protecting groups, such as
Boc, Ts, and Ac, only resulted in trace amounts of the
desired products under all the conditions tested.
The hydroxyl functional group is not tolerated under
the fluorination conditions. However, indole 3m can be
directly transformed to the oxindole 4m in 54% yield
(eq 1), where the boronic ester effectively serves as a
masked hydroxyl group for further manipulations.
Several mechanistic scenarios can be envisioned
for the electrophilic fluorination of indoles leading to
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Org. Lett., Vol. 14, No. 22, 2012

Table 3. Scope of N-Benzyl Indolesa
Scheme 2. Proposed Pathways for Electrophilic Fluorination of
Indoles Leading to 3,3-Difluoro-2-oxindoles
Elimination of HF followed by another fluorination step
and tautomerization can lead to the oxindole IX (path b).
Direct oxidation of the hemiaminal V could also directly
produce the desired product (path c). Alternatively, VIII
can be formed via path d, involving trapping of II with
water followed by oxidation and fluorination. While the
exact role of TBHP remains unclear at this stage, it is
possible that TBHP could promote the oxidative steps in
path a and/or path d over other unproductive events.
In conclusion, we have developed a convenient method
for the synthesis of 3,3-difluoro-2-oxindoles directly from
indoles under electrophilic conditions. A wide range of
indoles incoporating different substituents and functional
groups can be fluorinated in reasonable yields. Studies into
extending this method for the synthesis of other fluori-
nated classes of compounds are ongoing and will be
reported in due course.
Acknowledgment. We thank the reviewers for helpful
suggestions, Ms. Doris Tan (ICES) for high resolution
mass spectrometric (HRMS) assistance, and Experimental
Therapeutic Center (ETC), A*STAR for generous use
of their NMR facilities for 19F NMR analysis. Financial
support for this work was provided by A*STAR, Singa-
pore and A*STAR Graduate Academy (AGA) (to Q.O.).
a Conditions:: Indole (1 equiv), NFSI (3 equiv), K2HPO4 (5 equiv),
PhMe/MeCN (4:1, 0.05 M) at the specified temperature and time; then
TEA (18 equiv), 100 °C for 1 h. b Reaction was monitored by tlc until all
starting material was consumed. c Isolated yields. d Reaction mixture
was heated for 1.5 h at 100 °C after addition of Et3N instead. e K2HPO4
was not used. f 1 equiv K2HPO4 was used. g Benzene was used instead of
toluene.
Supporting Information Available. Full experimental
procedures and compound characterization. This materi-
al is available free of charge via the Internet at http://
pubs.acs.org.
3,3-difluoro-2-oxindoles (Scheme 2). Electrophilic fluori-
nation at C3 of indole I followed by rearomatization leads
to the monofluorinated indole III (path a). A second
fluorination step then leads to iminium IV which can be
captured by water in the medium to give hemiaminal V.17
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 22, 2012
5679