Cascade fluorofunctionalisation of 2,3-unsubstituted indoles by means of electrophilic fluorination

Article abstract of DOI:10.1039/c3cc46564k

Cascade fluorofunctionalisation of 2,3-unsubstituted indoles featuring the formation of C-C, C-F and C-O bonds via electrophilic fluorination using N-fluorobenzenesulfonimide is described. The use of an O-nucleophile tethered to the nitrogen of indoles en

Full text of DOI:10.1039/c3cc46564k

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Cascade fluorofunctionalisation of 2,3-unsubstituted
indoles by means of electrophilic fluorination†
Cite this: Chem. Commun., 2013,
49, 10602
Tuan Minh Nguyen,* Hung A. Duong,* Jean-Alexandre Richard,
Charles William Johannes, Fu Pincheng, Danson Kwong Jia Ye and
Eileen Lau Shuying
Received 28th August 2013,
Accepted 24th September 2013
DOI: 10.1039/c3cc46564k
www.rsc.org/chemcomm
Cascade fluorofunctionalisation of 2,3-unsubstituted indoles fea- as the fluorinating agent (Scheme 1a).4a A possible key inter-
turing the formation of C–C, C–F and C–O bonds via electrophilic mediate of this process was proposed to be a hemiaminal
fluorination using N-fluorobenzenesulfonimide is described. The (Scheme 1, V, Nu1 = OH), which subsequently undergoes HF
use of an O-nucleophile tethered to the nitrogen of indoles enables elimination and electrophilic fluorination to give oxindole II.
the synthesis of polycyclic fluorinated indoline derivatives from We envisioned that if V could, however, be generated with a
simple precursors in 40–63% yields.
nucleophile (Nu1 a OH), interception of the incipient iminium IX
with a second nucleophile (Nu2) may lead to a highly function-
The long-standing interests in fluorochemicals that are present alized fluorinated indoline III (Scheme 1a). Moreover, complex
in a wide range of applications in our daily lives,1 for example, polycyclic fluorinated scaffolds could potentially be generated if
pharmaceuticals, agrochemicals and materials, give impetus to a fluorocyclisation step is incorporated into the process by
the development of new methods to efficiently install fluorine(s) employing a nucleophile, for example a hydroxyl group, tethered
or fluorine-containing functional groups in organic molecules.2,3 to the nitrogen of indole (Scheme 1b). Overall, this strategy
In this context, electrophilic fluorination of indoles and indoline- entails a vicinal tetrafunctionalisation of indoles that installs
2-ones or oxindoles has attracted the attention of a number of four new bonds, featuring C–C, C–F and C–O bonds.
groups over the years,4 since indole and indoline are amongst
privileged structural motifs found in various drugs and natural
products,5a as well as in materials.5b,c Electrophilic fluorocycli-
sation, a powerful method to synthesise fluorinated hetero- and
carbocycles from alkenes,6 can offer a convenient access to
fluorinated indolines from indoles as demonstrated by several
groups.7 The common feature of this process is the concomi-
tant formation of two types of bonds (i.e. C–F and C–O, or C–F
and C–N). To the best of our knowledge, however, formation of
three different types of bonds in a cascade fashion through
fluorocyclisation reactions has not been documented to date.
As one could envision, such a process can offer new opportu-
nities to assemble highly complex structures in an efficient
manner. We herein demonstrate the feasibility of a domino
C–C/C–F/C–O bond forming sequence to rapidly access poly-
cyclic difluorinated indoline derivatives.
We recently reported the conversion of indoles into 3,3-
difluoro-2-oxindole II using N-fluorobenzenesulfonimide (NFSI)
Institute of Chemical and Engineering Sciences (ICES), Agency for Science,
Technology and Research (A*STAR), 8, Biomedical Grove, Neuros, #07-01,
Singapore 138665, Singapore. E-mail: nguyen_minh@ices.a-star.edu.sg,
duong_hung@ices.a-star.edu.sg; Fax: +6564642102
† Electronic supplementary information (ESI) available: Full experimental procedures,
compound characterisation and copies of NMR spectra. See DOI: 10.1039/c3cc46564k
Scheme 1 Electrophilic fluorofunctionalisation of indoles.
c
10602 Chem. Commun., 2013, 49, 10602--10604
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Table 2 Substrate scope of the cascade fluorofunctionalisation
To test our hypothesis, we subjected indole 1a possessing a
hydroxyl group as the pendant nucleophile to electrophilic fluori-
nation conditions, using NFSI in a 1 : 1 mixture of MeCN–MeOH at
25 1C (Table 1, entry 1). To our delight, compound 2a was isolated
in 35% yield (38% as determined by 19F NMR) as the major
product, demonstrating the viability of a cascade fluorofunction-
alisation. The minor product 4a was also observed by 19F NMR in
8% yield. Screening of reaction temperatures and concentra-
tions showed that the reaction was optimal at 0.05 M of 1a and
at ꢀ20 1C (entries 1–6). We next studied the influence of
solvents on the reaction (entries 7–13). The use of a co-solvent
system of MeOH with either MeCN, CH2Cl2 or PhMe was
critical to the formation of 2a.8 Interestingly, oxazolidine 3a
was selectively obtained in 40% yield when the reaction was
performed in a mixture of PhMe–MeCN (4: 1) at 100 1C (entry 13).
A basic additive such as NaHCO3 or K2HPO4 was found to inhibit
the reaction (entry 14), while the addition of an acid such as
CF3COOH or CH3COOH led to a reduction in yield of 2a to 40%
(entry 15). Varying the amount of NFSI (entries 16 and 17) or
switching to another fluorinating reagent such as Selectfluor
(entry 18) was detrimental to the reaction outcome.
A range of indoles could undergo the cascade fluorofunctionali-
sation under our optimised conditions (Table 2). Notably, the three
Table 1 Optimisation of the cascade fluorofunctionalisation
a
Reaction was performed in a 1 : 1 mixture of MeCN–EtOH at ꢀ40 1C
b
c
for 40 h. Reaction was performed at ꢀ20 1C for 48 h. Reaction was
d
performed at ꢀ20 1C for 70 h. Reaction was performed at ꢀ20 1C for 96 h.
Yieldb (%)
Entrya
Solvents (ratio)
T (1C)
2a
3a
4a
best solvent systems from our optimization were tested for each
substrate (entries 3, 11 and 12) and MeCN–MeOH (1 : 1) was
found to give better yields of the desired products in most
cases. Indoles incorporating a pendant secondary or tertiary
hydroxyl group underwent the reaction to give products 2b and
2c in 58% and 63% yields, respectively. Formation of tetrahydro-
1,3-oxazine 2d, however, was less favored as it was only obtained
in 43% yield. Indoles possessing electron-donating, halogen or
phenyl substituents on the benzenoid ring could be converted to
the desired products in 40–52% yields (2e–2l). Notably, rapid
polymerisation was observed with 4-methoxyindole 1g under the
standard conditions. Performing the reaction in EtOH instead of
MeOH at ꢀ40 1C allowed for the isolation of 2g in 51% yield.
Indoles with diminished nucleophilicity such as 1i, 1j and 1k
required longer reaction times to convert. In accord with this
trend, highly deactivated indoles possessing strongly electron-
1
MeCN–MeOH (1 : 1)
MeCN–MeOH (1 : 1)
MeCN–MeOH (1 : 1)
MeCN–MeOH (1 : 1)
MeCN–MeOH (1 : 1)
MeCN–MeOH (1 : 1)
MeCN
MeOH
CH2Cl2
PhMe
CH2Cl2–MeOH (1 : 1)
PhMe–MeOH (1 : 1)
PhMe–MeCN (4 : 1)
MeCN–MeOH (1 : 1)
MeCN–MeOH (1 : 1)
MeCN–MeOH (1 : 1)
MeCN–MeOH (1 : 1)
MeCN–MeOH (1 : 1)
25
70
38 (35)c
9
60 (54)
6
26
16
43
18
28
42
60
65
Trace
0
40
40
26
0
Trace
4
0
0
0
0
0
0
Trace
Trace
0
0
42 (40)
0
0
8
8
3
2d
3
ꢀ20
ꢀ40
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
100
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
4
Trace
Trace
Trace
0
3
—
—
0
0
0
0
0
5e
6 f
7
8
9
10
11
12
13d,g
14h
15i
16 j
17k
18l
Trace
Trace
0
Trace
Trace
0
a
Conditions: indole (1 equiv.), N-fluorobenzenesulfonimide (NFSI,
3 equiv.), solvent (0.05 M), 20 h. Yield determined by 19F NMR using withdrawing groups such as nitrile (1m), ester (1n) or nitro (1o)
b
c
1,3-bis(trifluoromethyl)benzene as the internal standard. Isolated
failed to give the desired products. Interestingly, di- or tri-
d
e
yield. Reaction was completed in 1 h. Reaction was performed at
f
substituted indoles 1h and 1l afforded 2h and 2l in 44% and
0.01 M concentration. Reaction was performed at 0.25 M concen-
g
tration. Difluorooxindole was also formed with an estimated yield of 50% yields, respectively.
h
16%. NaHCO3 (2 equiv.) or K2HPO4 (equiv.) was used as an additive.
We further examined the scope of difluorocyclisation (Table 1,
entry 13) at high temperatures to prepare a range of oxazolidines
i
j
CH3COOH (2 equiv.) or CF3COOH (2 equiv.) was used as an additive.
5 equiv. of NFSI was used. 2 equiv. of NFSI was used. Selectfluor
k
l
was used instead of NFSI.
and tetrahydro-1,3-oxazines 3 (Table 3). Indoles possessing a
c
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Table 3 Difluorocyclisation of indoles 1 at high temperatures
on the benzenoid ring, the fluorocyclisation can produce
oxazolidines and tetrahydro-1,3-oxazines 3 in 40–60% yields.
Extension of the current strategy to incorporate other nucleo-
philes, and studies on the photochromic properties of these
fluoroindoline derivatives as potential molecular switches5b,c
are now underway in our laboratory.
Financial support for this work was provided by ICES,
A*STAR, Singapore. We thank Ms Doris Tan (ICES) for high
resolution mass spectrometric (HRMS) assistance, and the
Experimental Therapeutic Center (ETC, A*STAR) for generous
use of their NMR facilities for 19F NMR analysis. We also
thank Dr Paul Huleatt and Dr Brendan Burkett (ICES) for their
support.
a
Reaction was performed at 100 1C for 18 h.
Notes and references
1 (a) P. Kirsch, Modern Fluoroorganic Chemistry: Synthesis, Reactivity
and Applications, Wiley-VCH, Weinheim, 2004; (b) D. O’Hagan,
Chem. Soc. Rev., 2008, 37, 308; (c) S. Purser, P. R. Moore,
S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008, 37, 320.
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Catal., 2013, 335, 617; (b) T. Liang, C. N. Neumann and T. Ritter,
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D. Cahard, Angew. Chem., Int. Ed., 2012, 51, 5048; (d) C.-P. Zhang,
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41, 4536; (e) T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011,
473, 470.
3 For recent examples, see: (a) P. S. Fier, J. Luo and J. F. Hartwig, J. Am.
Chem. Soc., 2013, 135, 2552; (b) Y. Ye and M. Sanford, J. Am. Chem.
Soc., 2013, 135, 4648; (c) A. Casitas, M. Canta, M. Sola, M. Costas and
X. Ribas, J. Am. Chem. Soc., 2011, 133, 19386; (d) S. Mizuta, S. Verhoog,
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4 For selected examples, see: (a) Y. H. Lim, Q. Ong, H. A. Duong,
T. M. Nguyen and C. W. Johannes, Org. Lett., 2012, 14, 5676;
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T. Toru and S. Kanemasa, Angew. Chem., Int. Ed., 2005, 44, 4204;
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Biol., 2010, 14, 347. For examples of indoline derivatives in applica-
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L. Ducasse, F. Castet, A. Plaquet and B. Champagne, Chem.–Eur. J.,
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6 For a recent review on fluorocyclisation, see: (a) S. C. Wilkinson,
R. Salmon and V. Gouverneur, Future Med. Chem., 2009, 1, 847. For
selected examples of fluorocyclisation, see: (b) J. R. Wolstenhulme,
J. Rosenqvist, O. Lozano, J. Ilupeju, N. Wurz, K. M. Engle, G. V.
Pidgeon, P. R. Moore, G. Sanford and V. Gouverneur, Angew. Chem.,
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8 Ethanol and i-propanol were also tried in this reaction and showed
that the reaction rate was dramatically decreased.
9 Oxindoles were also formed under these reaction conditions
in 15–20% yields as determined by 19F NMR. See ESI† for the
example 7i.
10 An alternative pathway leading to 6i from 1i via an intermediate
other than 5i is also possible. See ESI† for more details.
Scheme 2 Possible mechanism of the cascade fluorofunctionalisation of indoles 1.
strong electron-withdrawing group such as nitrile (1m), ester
(1n) or nitro (1o) afforded oxazolidines 3m–o in 49–60% yield.
Tetrahydro-1,3-oxazine 3d was also obtained in 41% yield.9
To probe whether 3 is an intermediate en route to 2
(Scheme 2, pathway A), we subjected 3i to the cascade fluoro-
functionalisation conditions (NFSI, MeCN–MeOH 1 : 1). How-
ever, no conversion of 3i was observed, suggesting that 3i did
not undergo the HF elimination process to afford 3i0. Interest-
ingly, we were able to isolate bisindole 6i in ca. 4% yield in
the reaction of 1i with 1.7 equiv. of NFSI under the cascade
fluorofunctionalisation conditions. Importantly, 6i was fully
converted to 2i upon treatment with NFSI. Overall, these obser-
vations favour a mechanism whereby the C–C bond formation
precedes the O-cyclisation step (Scheme 2, pathway B) via an
intermediate such as difluorinated indoline 5i.10 The failure of
electron-deficient indoles such as 1m–o to give 2 could be
explained by their inability to intercept an iminium inter-
mediate. At high temperatures, indoles 1 could rapidly undergo
fluorination with NFSI,4a rendering them unavailable towards
the C–C bond forming process (pathway B). Thus, difluorocyclisa-
tion products were obtained under these conditions (pathway A).
In conclusion, we have developed a new cascade tetrafunction-
alisation of 2,3-unsubstituted indoles via electrophilic fluoro-
cyclisation. A range of polycyclic fluorinated indolines can be
prepared in 40–63% yields by this process that simultaneously
generates four new bonds, featuring C–C, C–F and C–O bonds.
In cases of indoles bearing electron-withdrawing substituents
c
10604 Chem. Commun., 2013, 49, 10602--10604
This journal is The Royal Society of Chemistry 2013