An efficient difluorohydroxylation of indoles using selectfluor as a fluorinating reagent

Article abstract of DOI:10.1021/ol201896p

An efficient difluorohydroxylation of substituted indoles leading to 3,3-difluoroindolin-2-ols with good yields by using Selectfluor as the electrophilic fluorinating reagent has been developed. In this methodology, the indole rings were difluorinated hig

Full text of DOI:10.1021/ol201896p

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4498–4501
An Efficient Difluorohydroxylation of Indoles
Using Selectfluor as a Fluorinating Reagent
Riyuan Lin,† Shengtao Ding,† Zhuangzhi Shi,† and Ning Jiao*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Road 38, Beijing 100191, China,
and State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
jiaoning@bjmu.edu.cn
Received June 14, 2011
ABSTRACT
An efficient difluorohydroxylation of substituted indoles leading to 3,3-difluoroindolin-2-ols with good yields by using Selectfluor as the
electrophilic fluorinating reagent has been developed. In this methodology, the indole rings were difluorinated highly regioselectively at the C3
carbon site. This protocol is practically convenient, easily handled under mild conditions, and provides an efficient way to produce the unique
difluorinated indolin-2-ol structure. When alcohols were used as the nucleophiles instead of H2O, the corresponding products were obtained in
moderate yields. Based on the experimental observations, a plausible mechanism is proposed.
The indole unit is an ubiquitous skeleton of pharmaceu-
ticals and bioactive natural products.1 The modification of
the indole structure has attracted great interest from organic
chemists.2 On the other hand, fluorinated compounds3 often
possess unique biological and physiochemical properties4
and play an important role in pharmaceuticals,5,6 agro-
chemicals,7 and materials.8 The strong electronegativity of
fluorine and relatively small steric size of the fluorine atom
uniquely affects the properties of organic molecules.3 For
example, introducing fluorine atoms into pharmaceutical
molecules can make them more bioavailable and metaboli-
cally stable and can increase the strength of a compound’s
interactions with a target protein.3À5
† Peking University.
‡ Chinese Academy of Sciences.
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We have recently been interested in the design and modifi-
cation of indoles.9 Our literature search revealed that al-
though several methods for the synthesis of monofluorinated
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r
10.1021/ol201896p
Published on Web 08/09/2011
2011 American Chemical Society

indole derivatives have been reported,10 only a few methods
are available for access to difluorinated indole deriva-
tives.11À13 In 1977, Hesse and co-workers reported the 2,3-
difluoroindolines from indole derivatives in moderate yields
by using the toxic gas CF3OF in Freon at À78 °C.11a
Recently, Fuchigami and co-workers11b reported the difluor-
ination of indole derivatives by using an electrolysis techni-
que with Et4NFÀ4HF as the fluorine sources, providing 2,
3-difluoroindolines in moderate yields. Middleton’s group11c
reported one case of 3,3-difluorooxindole from isatin by
using the nucleophilic fluorinating reagent DAST (Figure 1),
which was thermally unstable (it would fume in air and
reacted explosively on contact with water).11d Shreeve’s
group11e developed an analogue, bis(methoxyethyl)amino-
sulfur trifluoride (Deoxofluor) (Figure 1), with enhanced
thermal stability, to achieve higher yields of 3,3-difluoroox-
indoles from isatins by using an excess (3.0 equiv) of fluor-
inating reagent. Very recently, Umemoto et al.11f developed a
new fluorinating agent, 4-tert-butyl-2,6-dimethylphenylsul-
fur trifluoride (Fluolead) (Figure 1), which had high thermal
stability and unusual resistance to aqueous hydrolysis which
could also produce the 3,3-difluorooxindoles from electro-
philic isatins.
Figure 1. Fluorinating reagents.
Herein, we describe an efficient difluorohydroxylation
of readily available indoles to afford 3,3-difluoroindolin-
2-ols using an electrophilic fluorinating reagent. The sig-
nificance of the present method is twofold: (1) The electro-
philicfluorinating reagent Selectfluor14 (Figure 1), which is
safe, nontoxic, and easy to handle, was used as the
fluorinating reagent. (2) By using electrophilic fluorinating
reagent, the readily available indoles, which are natively
nucleophliles, could be directly fluorinated and a novel
difluorohydroxylated indoline structure was produced.
(10) For some examples, see: (a) Labroo, R. B.; Labroo, V. M.; King,
M. M.; Cohen, L. A. J. Org. Chem. 1991, 56, 3637. (b) Hou, Y.;
Higashiya, S.; Fuchigami, T. J. Org. Chem. 1997, 62, 8773. (c) Hayakawaa,
Y.; Singha, M.; Shibatab, N.; Takeuchib, Y.; Kirk, K. L. J. Fluorine Chem.
1999, 97, 161. (d) Takeuchi, Y.; Tarui, T.; Shibata, N. Org. Lett. 2000, 2,
639. (e) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc.
2001, 123, 7001. (f) Shibata, N.; Tarui, T.; Doi, Y.; Kirk, K. L. Angew.
Chem., Int. Ed. 2001, 40, 23. (g) Baudoux, J.; Salit, A.-F.; Cahard, D.;
Plaquevent, J.-C. Tetrahedron Lett. 2002, 43, 6573. (h) Jacquesy, J.-C.;
Berrier, C.; Jouannetaud, M.-P.; Zunino, F.; Fahy, J.; Duflos, A.; Ribet, J.-
P. J. Fluorine Chem. 2002, 114, 139. (i) Shibata, N.; Ishimaru, T.; Suzuki, E.;
Kirk, K. L. J. Org. Chem. 2003, 68, 2494. (j) Zoute, L.; Audouard, C.;
Plaquevent, J.-C.; Cahard, D. Org. Biomol. Chem. 2003, 1, 1833. (k)
Hamashima, Y.; Suzuki, T.; Takano, H.; Shimura, Y.; Sodeoka, M. J.
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Ed. 2005, 44, 4204. (m) Ishimaru, T.; Shibata, N.; Horikawa, T.; Yasuda,
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4157. (n) Fujiwara, T.; Yin, B.; Jin, M.; Kirk, K. L.; Takeuchi, Y. J. Fluorine
Chem. 2008, 129, 829. (o) Baumann, M.; Baxendale, I. R.; Martin, L. J.;
Ley, S. V. Tetrahedron 2009, 65, 6611. (p) Fujiwara, T.; Seki, T.; Miura, M.;
Takeuchi, Y. Heterocycles 2009, 79, 427. (q) Seki, T.; Fujiwara, T.;
Takeuchi, Y. J. Fluorine Chem. 2011, 132, 181.
Figure 2. X-ray structure of 2a.
First, the reaction of 1-methyl-2-phenylindole (1a) was
investigated using the commercially available Selectfluor
as the electrophilic fluorinating reagent, which was widely
used for the fluorination of organic molecules.14 Interest-
ingly, 3,3-difluoro-1-methyl-2-phenylindolin-2-ol (2a) was
accidentally obtained instead of the anticipated C3 mono-
fluorinated indole. The structure of 2a was further con-
firmed by single-crystal X-ray analysis (Figure 2).
Subsequently, various parameters were screened to im-
prove the reaction efficiency (Table 1). The results indicate
that the choice of solvent, the amount of H2O, and the tem-
perature were important for optimizing the yield of 2a. The
reaction yield increased to 57% when MeCN was used as the
solvent (entry 2, Table 1). Considering that the hydroxyl
group in 2a was originated from H2O in air (entries 1À2), 1.0
equiv of H2O was added to the reaction system, which im-
proved the yield a little (entry 3). 2a was obtained in 81%
yield when the reaction was carried out at a lower tempera-
ture (0 °C, entry 6). The best result was obtained (85% yield)
when the reaction was performed under air at 0 °C with
(11) (a) Barton, D. H. R.; Hesse, R. H.; Jackman, G. P.; Pechet,
M. M. J. Chem. Soc., Perkin Trans. 1 1977, 2604. (b) Yin, B.; Wang, L.;
Inagi, S.; Fuchigami, T. Tetrahedron 2010, 66, 6820. (c) Middleton,
W. J.; Bingham, E. M. J. Org. Chem. 1980, 45, 2883. (d) Cochran, J.
Chem. Eng. News 1979, March 19, 4. (e) Singh, R. P.; Majumder, U.;
Shreeve, J. M. J. Org. Chem. 2001, 66, 6263. (f) Umemoto, T.; Singh,
R. P.; Xu, Y.; Saito, N. J. Am. Chem. Soc. 2010, 132, 18199.
(12) For other examples of using DAST for difluorination of isatins,
see: (a) Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Luo, Y.; Liu, X.; Shi, Y.;
Guan, R.; Magnone, S. R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.;
Shoemaker, A.; Oleksijew, A.; Jarvis, K.; Park, C.; Jong, R. D.; Oltersdorf,
T.; Li, Q.; Rosenberg, S. H.; Giranda, V. L. Bioorg. Med. Chem. Lett. 2006,
16, 3424. (b) McAllister, L. A.; McCormick, R. A.; James, K. M.; Brand, S.;
Willetts, N.; Procter, D. J. Chem.;Eur. J. 2007, 13, 1032. (c) Podichetty,
€
A. K.; Faust, A.; Kopka, K.; Wagner, S.; Schober, O.; Schafers, M.; Haufe,
G. Bioorg. Med. Chem. 2009, 17, 2680. (d) Baumann, M.; Baxendale, I. R.;
Martin, L. J.; Ley, S. V. Tetrahedron 2009, 65, 6611. (e) 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.
(13) For an example of producing 3,3-difluorooxindoles by a transi-
tion metal catalytic method, see: Zhu, J.; Zhang, W.; Zhang, L.; Liu, J.;
Zheng, J.; Hu, J. J. Org. Chem. 2010, 75, 5505.
(14) For reviews, see: (a) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res.
ꢀ
S. P.; Wong, C.-H. Angew. Chem., Int. Ed. 2005, 44, 192.
2004, 37, 31. (b) Nyffeler, P. T.; Duron, S. G.; Burkart, M. D.; Vincent,
Org. Lett., Vol. 13, No. 17, 2011
4499

3.0 equiv of H2O in MeCN (entry 8). It is possible that
water might help to dissolve NaHCO3 and Selectfluor
to react with organic compounds dissolved in MeCN
more efficiently. In some reported cases, the employ-
ment of an excess of Selectfluor was required to realize
optimal results.10d,q In this present methodology, 2.0
equiv (as the reaction needed) of Selectfluor were en-
ough to obtain the desired products in high yields. The other
solvent was not as good as MeCN (entries 11À13). The
Table 2. Difluorohydroxylation of 1 with Selectfluora
Table 1. Reaction of 1-Methyl-2-phenylindole (1a) with Select-
fluora
t
yield
(%)b
entry
base
additive
solvent
(°C)
1
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
-
À
À
DCE
90
25
25
25
0
31
57
59
56
74e
81
79
85e
67
56
trace
78
75
82
73
76
63
81
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Et2O
3
H2O (1 equiv)
H2O (5 equiv)
À
4
5
6
H2O (1 equiv)
H2O (2 equiv)
H2O (3 equiv)
H2O (3 equiv)
H2O (3 equiv)
H2O (3 equiv)
H2O (3 equiv)
H2O (3 equiv)
H2O (3 equiv)
H2O (3 equiv)
H2O (3 equiv)
H2O (3 equiv)
H2O (3 equiv)
0
7
0
8
0
9
0
10c
11
12
13d
14
15
16
17
18
NaHCO3
NaHCO3
NaHCO3
NaHCO3
Na2CO3
KHCO3
K2CO3
0
0
CH3NO2
acetone
MeCN
MeCN
MeCN
MeCN
MeCN
0
0
0
0
0
DABCO
NaHCO3
0
À20
a Reaction conditions: 1a (0.2 mmol), Selectfluor (2.0 equiv), base
(1.0 equiv), additive, and solvent (1 mL) for 0.5 h under air atmosphere.
b Isolated yields. c NFSI was used instead of Selectfluor. d The reaction
time was 4.5 h. e This experiment has been carried out for three trials.
a Reaction conditions: 1 (0.2 mmol), Selectfluor (2.0 equiv), NaH-
CO3 (1.0 equiv), H2O (3.0 equiv), and MeCN (1 mL) at 0 °C under air
atmosphere. b Isolated yields.
reation yield dropped to 67% in the absence of a base (entry
9). Other bases such as KHCO3, K2CO3, and DABCO gave
low efficiencies (entries 14À17). A lower yield of 2a was
obtained when another electrophilic fluorinating reagent
(NFSI) was used instead of Selectfluor (entry 10). This
transformation occurred well even at À20 °C (81%, entry
18, Table 1).
Under these optimized reaction conditions, the difluor-
ohydroxylation of different substituted indoles were
investigated (Table 2). Indoles with N-protecting
groups such as Me, Et, and Bn were well tolerated to
give the desired products 2 with excellent yields, re-
spectively (entries 1À3, Table 2). A variety of substi-
tuents were well-tolerated at the indoles, including a
halo-group (2d, 2e, 2l), an aryl group (2aÀ2i), a hetero-
aryl group (2j, 2k), and an ester group (2l). The sub-
stitution of the phenyl ring with an o-methoxyl group
even led to a higher yield than that with a p-methoxyl
group, showing the steric hindrance did not affect the
efficiency of the reaction (cf. entries 7 and 9, Table 2).
As expected the difluorinated indolenines instead of the
hydroxyl substituted indoline were obtained when the
unprotected indole derivatives were used as the sub-
strates (3aÀ3c). With a different substituted aryl group,
the difluorination products were isolated in good yields
(3aÀ3c).
The intermolecular reaction with different nucleophiles
such as PhCOOH, Ph(CH2)2COOH, p-toluidine, BnNH2,
and CH3CONH2 have been investigated. However, the
desired corresponding products were not obtained. Inter-
estingly, alcohols are well tolerated in this transformation
as shown in Figure 3. Furthermore, the intramolecular
reaction using 2-(2-phenyl-1H-indol-1-yl)ethanol as the
substrate was also investigated. The desired difluorinated
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Org. Lett., Vol. 13, No. 17, 2011

Scheme 1. Proposed Mechanism for the Transformation
Figure 3. Difluorination of 1a using alcohols as nucleophiles.
tricyclic tetrahydrooxazolo[3,2-a]indole was obtained in
68% isolated yield (eq 1).15
3-fluoroindolin-2-ol C. Dehydration of C gives the 3-fluor-
oindole 5, which then undergoes the same process to produce
the unstable 3,3-difluoroindoline cation D or 3,3-difluoroin-
dolenine cation E. Finally, the carbon cation of D or E is
attacked by H2O to produce 3,3-difluoroindolin-2-ol 2.
When the substitutional group R2 is an aryl group, which can
stabilize the carbon cation, the substrates would generally
achieve good yields as shown in Table 2. In contrast, when
the R2 was changed to an ester group, the carbon cation was
not stable enough and the yield dropped (2l, Table 2).
We also tried the methyl group; although we could obtain the
desired product, it was not stable enough at room tem-
perature and decomposed quickly. In the cases of unpro-
tected indole derivatives (R1 = H) as the substrates, the
direct deprotonation of intermediate D or E, or dehydration
of 2 leads to the formation of 3. When alcohols are used as
nucleophiles instead of H2O, the reactions proceed through a
similar mechanism.
In summary, we have developed an efficient method for
the synthesis of 3,3-difluoroindolin-2-ol. In this method, the
indole ring was difluorinated highly regioselectively at the C3
carbon site with equivalent (not excess) Selectfluor. Addi-
tionally, mild conditions and practical convenience would
make it a valuable synthetic tool in organic chemistry. When
alcohols were used as the nucleophiles instead of H2O, the
corresponding products were obtained in moderate yields.
The study of the bioactivity of these novel compounds is
ongoing in our laboratory.
During the process of optimizing the conditions, when
the reaction of 1a was stopped at 15 min in acetone as the
solvent, the desired difluorinated product 2a (21%) and
monofluorinated product 5a (45%) were obtained with
34% of 1a recovered (eq 2). Furthermore, 5a was then
resubjected to the standard reaction conditions (only using
1.0 equiv of Selectfluor), which produced 2a in 80% yield
(eq 3). These results indicate that the monofluorinated pro-
duct serves as an intermediate in the transformation.
On the basis of the above results and information from
the literature,10d,14b the mechanism of this transformation is
proposed (Scheme 1). Initially, reaction of 1 with Selectfluor
yields the unstable 3-fluoroindoline cation A or its resonance
3-fluoroindolenine cation B, and then the proton is extracted
by the base (NaHCO3 or DABCO from Selectfluor16)
quickly to give the 3-fluoroindole 5. Alternatively, the un-
stable 3-fluoroindoline cation A or its resonance 3-fluoroin-
dolenine cation B can also be attacked by H2O to furnish the
Acknowledgment. Financial support from Peking Uni-
versity, the National Science Foundation of China (2087-
2003), and the National Basic Research Program of China
(973 Program 2009CB825300) is greatly appreciated. We
also thank Guolin Wu in this group for reproducing the
results of 2g and 4a.
(15) During the revision of this manuscript, a similar intramolecular
result has been reported; see: Lozano, O.; Blessley, G.; del Campo, T. M.;
Thompson, A. L.; Giuffredi, G. T.; Bettati, M.; Walker, M.; Borman R.;
Gouverneur, V. Angew. Chem., Int. Ed. DOI: 10.1002/anie.201103151.
(16) Radwan-Olszewska, K.; Palacios, F.; Kafarski, P. J. Org. Chem.
2011, 76, 1170.
Supporting Information Available. Experimental proce-
dures, characterization data, and X-ray crystallographic
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
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