Ionic liquids as solvents of choice for electrophilic fluorination: Fluorination of indoles by F-TEDA-BF4

Article abstract of DOI:10.1016/S0040-4039(02)01417-X

Selectfluor was shown to be soluble in ionic liquid, thus allowing the 'green' electrophilic fluorination of indole compounds in high chemoselectivity and yields.

Full text of DOI:10.1016/S0040-4039(02)01417-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6573–6574
Ionic liquids as solvents of choice for electrophilic fluorination:
fluorination of indoles by F-TEDA-BF4
Je´roˆme Baudoux, Anne-Fre´de´rique Salit, Dominique Cahard and Jean-Christophe Plaquevent*
Laboratoire des Fonctions Azote´es et Oxyge´ne´es Complexes, IRCOF et UMR 6014, Faculte´ des Sciences, Universite´ de Rouen,
F-76821 Mont-Saint-Aignan, France
Received 22 May 2002; revised 12 July 2002; accepted 14 July 2002
Abstract—Selectfluor™ was shown to be soluble in ionic liquid, thus allowing the ‘green’ electrophilic fluorination of indole
compounds in high chemoselectivity and yields. © 2002 Elsevier Science Ltd. All rights reserved.
Fluorinated five and six-membered heterocycles are
targets of importance in the field of organofluorine
compounds.1 3-Fluorooxindoles are especially interest-
ing as synthetic intermediates and tools for elucidating
biological processes. In this context, a recent report
from Takeuchi’s group described the access to the target
compounds via a direct fluorination of several 3-substi-
tuted indoles by means of commercially available Selec-
tfluor™ in acetonitrile (Scheme 1).2 The method gave
fairly good results (yields 71% for fluorination of 1 and
in the 64–92% range for other 3-alkyl indoles), although
it led to the oxoindole 3 as a side product.
In connection with our studies on electrophilic enan-
tioselective fluorination,3 we now report the fluorina-
tion of 3-methyl indole 1 in various conditions
including the use of ionic liquids as solvents. Ionic
liquids present many advantages in the green chemistry
context,4 and we assumed that they could be powerful
solvents for electrophilic fluorination since Selectfluor™
is a charged compound. A recent report from Laali and
Borodkin regarding the electrophilic fluorination of
arenes in those solvents prompts us to disclose our
own results.5 Our main results are reported in
Table 1.
Me
F
Me
H
Me
Selectfluor (3eq)
+
O
O
Solvent
N
N
N
H
H
H
1
3
2
Scheme 1.
Table 1. Electrophilic fluorination in ionic liquids
Solvent
Cosolvent (1/1)
T (°C)
Time (h)
2 (%)
3 (%)
Acetonitrilea
Water
rt
Overnight
71
Side product
[bmim] [PF6]
[bmim] [BF4]
[bmim] [PF6]
[bmim] [BF4]
MeOH
MeOH
EtOH
EtOH
20
20
20
20
3
3
12
12
99
99
88
92
–
–
12
8
a Data taken from Ref. 2.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01417-X

6574
J. Baudoux et al. / Tetrahedron Letters 43 (2002) 6573–6574
Me
F
Me
Selectfluor (3eq)
R=Me, 96 %
R=Bn, 66%
O
CH3CN/2-propanol (1/1)
N
N
R
R
4
5
Scheme 2.
Me
Me
Ph
Selectfluor (3eq)
+
S
S
S
CH3CN / PhCH2SH (1/1)
1,4 benzoquinone
N
N
Ph
Ph
H
1
H
6, 92%
7
Scheme 3.
Interestingly, very high conversions were observed. The
reaction in ionic liquid minimizes the protonated oxoin-
dole 3, when using methanol or ethanol as cosolvent.
Thus, both chemoselectivity and yield appear to be
highly increased when using ionic liquid as solvent. This
study, as well as the recent results from Laali and
Borodkin,5 clearly demonstrates the unique properties
of this new class of ‘green’ solvents in the field of
electrophilic fluorination. We also realized a set of
experiments in which a nucleophilic reagent was added
in acetonitrile in order to test the role of this additive in
the fluorination process. When applied to N-alkylated
compounds 4, the use of 2-propanol led to high trans-
formation into the fluorinated targets 5, especially for
the N-methyl substrate (Scheme 2).
ify the electrophilic fluorination of indoles. Worth not-
ing are the results obtained in ionic liquids, in which
high yields and chemoselectivity were observed. An
interesting access to thio-substituted indoles was also
discovered.
References
1. For a recent review, see: Erian, A. W. J. Heterocyclic
Chem. 2001, 38, 793–808.
2. Takeuchi, Y.; Tarui, T.; Shibata, N. Org. Lett. 2000, 2,
639–642.
3. (a) Cahard, D.; Audouard, C.; Plaquevent, J. C.; Roques,
N. Org. Lett. 2000, 2, 3699–3701; (b) Cahard, D.;
Audouard, C.; Plaquevent, J. C.; Toupet, L.; Roques, N.
Tetrahedron Lett. 2001, 42, 1867–1869; (c) Mohar, B.;
Baudoux, J.; Plaquevent, J. C.; Cahard, D. Angew. Chem.,
Int. Ed. 2001, 40, 4214–4217.
4. For recent reviews, see: (a) Freemantle, M. Chem. Eng.
News September 3, 2001, 41–43; (b) Freemantle, M. Chem.
Eng. News January 1, 2001, 21–25; (c) Freemantle, M.
Chem. Eng. News May 15, 2000, 37–50; (d)Wasserscheid,
P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3373–3789;
(e) Welton, T. Chem. Rev. 1999, 99, 2071–2083; (f) Shel-
don, R. Chem. Commun. 2001, 2399–2407; (g) Zao, D.;
Wu, M.; Kou, Y.; Min, E. Catal. Today 2002, 157–189; (h)
Olivier-Bourbigou, H.; Magna, L. J. Mol. Catal. A: Chem.
2002, 419–437.
Substantially different results were observed in the pres-
ence of thiols (Scheme 3).
The reaction stopped at the intermediate 6 in good
yield, an observation which supports Takeuchi mecha-
nism,2 since 6 is not obtained in the absence of Select-
fluor. Indeed, the excess of thiol is oxidized into 7, thus
reducing Selectfluor and preventing the subsequent
fluorination of 6. When using only 2 equiv. of thiol, the
fluorinated oxoindole 2 is obtained (63%). This part of
our work gives an interesting methodology for the
access to the sulfur substituted indoles of type 6.6
5. Laali, K. K.; Borodkin, G. I. J. Chem. Soc., Perkin Trans.
Conclusion
2, 2002, 953–957.
6. For a recent interesting discussion, see: Hamel, P. J. Org.
Chem. 2002, 67, 2854–2858.
In this study, we have demonstrated that modifications
of experimental conditions can either improve or mod-