Direct fluoroalkylation of indoles with fluoroalkyl halides mediated by copper

Article abstract of DOI:10.1002/ejoc.201402526

An efficient and mild copper-mediated reaction for the direct perfluoroalkylation and difluoromethylation of indoles with perfluoroalkyl halides and ICF₂COOEt to produce 2-substituted indoles was developed. Both free indole derivatives and N-su

Full text of DOI:10.1002/ejoc.201402526

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402526
Direct Fluoroalkylation of Indoles with Fluoroalkyl Halides Mediated by
Copper
Ru-Yi He,[a] Hui-Ting Zeng,[a] and Jing-Mei Huang*[a]
Keywords: Copper / Halides / Fluorine / Fluoroalkylation / Nitrogen heterocycles
An efficient and mild copper-mediated reaction for the direct
perfluoroalkylation and difluoromethylation of indoles with
perfluoroalkyl halides and ICF2COOEt to produce 2-substi-
tuted indoles was developed. Both free indole derivatives
and N-substituted indole derivatives could be used in this
process to obtain the desired products in moderate to good
yields.
a limited number of examples of a simple indole were
studied.[9–11] Médebielle developed an electrochemical ap-
proach for the synthesis of perfluoroalkylated purine and
indole analogues of plant-growth regulators, but only ind-
ole-3-acetic acid (ester) was studied.[12] Currently, no gene-
ral method with full scope for the perfluoroalkylation of
indoles has been reported. Thus, the development of
straightforward and effective methods for the facile intro-
duction of a perfluoroalkyl group to indoles is highly desir-
able. In connection with our interests in the construction of
substituted indoles,[13] herein we report the first method for
the Cu-mediated direct C–H perfluoroalkylation and di-
fluoromethylation of indoles with perfluoroalkyl halides
and ICF2COOEt under mild conditions.
Introduction
Exploitation of efficient methods to construct C–Rf (Rf
= trifluoromethyl and perfluoroalkyl group) bonds has at-
tracted much attention owing to the special biological and
physical properties of fluorine-containing organic com-
pounds.[1] Compared to methods for the incorporation of
the trifluoromethyl group into organic molecules,[2,3] meth-
ods for perfluoroalkylation reactions, particularly on aryl
or heteroaryl rings, are less developed,[4] despite the fact
that the properties of perfluoroalkyl compounds (C Ն 2), in
certain cases, are superior to those of CF3 derivatives.[5,1b]
Indoles are ubiquitous motifs present in both physiologi-
cally active natural products and important pharmaceuti-
cals, and the synthesis of this important structure has at-
tracted extensive attention from chemists for many years.
However, methods for the perfluoroalkylation of indoles are
quite rare.[6] One type of transformation relies on the indi-
rect synthesis of the indole ring through cyclization by
multistep reactions.[7] For the direct synthesis, several meth-
ods have been reported. Yoshida’s group reported the per-
fluoroalkylation of nitrogen-containing heteroaromatic
compounds by using bis(perfluoroalkyanoyl) peroxides.[8]
Kamigata reported a method for the synthesis of fluoro-
alkyl-containing aromatic heterocyclic compounds from
F(CF2)nSO2Cl catalyzed by RuCl2(PPh3)3.[9] Later, an ap-
proach relying on the employment of a reaction system of
perfluoroalkyl iodides/H2O2/Fe2+ in DMSO that worked on
pyrroles and some derivatives was reported.[10] Chen and
Huang reported the perfluoroalkylation of aromatic and
heteroaromatic compounds with perfluoroalkyl chlorides in
the presence of sodium dithionite.[11] In these reports, only
Results and Discussion
Initially, we selected 3-methylindole (1a) as a model sub-
strate and n-C4F9I as a perfluoroalkylation reagent to opti-
mize the reaction conditions (Table 1). Inspired by previous
work on copper-catalyzed or -mediated functionalization of
arenes, we chose copper as a catalyst. Treatment of a mix-
ture of 1a (1.0 equiv.) and n-C4F9I (1.4 equiv.) with CuI
(0.5 equiv.) and 2,2Ј-bipyridine (bipy, 0.2 equiv.) in N,N-di-
methyformamide (DMF) at 80 °C in air for 24 h resulted in
desired product 3a in 36% yield (Table 1, entry 1). Encour-
aged by this result, different copper sources were further
examined. Reactions performed with the use of Cu powder
and Cu2O provided higher yields than those reactions pro-
moted by CuBr, CuCl, CuCl2, and Cu(OAc)2·H2O (Table 1,
entries 2–7). If 1.5 equiv. of Cu powder was used, the yield
of 3a dramatically increased to 79% (Table 1, entry 8), and
it was found that Cu2O was the most efficient catalyst: 3a
was delivered in 80% yield if 0.5 equiv. of Cu2O was em-
ployed (Table 1, entry 9). Other solvents and ligands were
also screened, but the yield of 3a was not as good as that
obtained if DMF and bipy were applied (Table 1, en-
[a] School of Chemistry and Chemical Engineering, South China
University of Technology,
Guangzhou, Guangdong 510640, China
E-mail: chehjm@scut.edu.cn
http://www.scut.edu.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402526.
Eur. J. Org. Chem. 0000, 0–0
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R.-Y. He, H.-T. Zeng, J.-M. Huang
SHORT COMMUNICATION
tries 10–21). With regard to the effect of temperature on the the temperature (3b and 3j; see Table 2). The CF2H unit is
reaction, we discovered that if the temperature was de- of special interest in isoster-based drug design and has great
creased, the yield of the desired product dropped drastically potential value, but methods for the introduction of a di-
(Table 1, entries 22–24). If the reaction was conducted at fluoromethyl group into arenes or heteroarenes are lim-
a higher temperature (100 °C), the yield decreased slightly ited.[14] Under the present conditions, we were delighted to
(Table 1, entry 25). No product was detected in the absence find that coupling of indoles with commercial ICF2COOEt
of copper (Table 1, entry 26). Notably, the product was ob- afforded difluoromethylated products 4m–p in good yields.
tained in only 4% yield if no ligand was employed (Table 1, Thus, this reaction provides a new approach for the con-
entry 27).
struction of difluoromethylated compounds. 1-Methylind-
Under the optimized conditions, various indole deriva- ole (1q) was also subjected to the standard reaction condi-
tives were used to react with perfluoroalkyl halides. Cu tions (Table 2, entry 17), and the desired C2-perfluoroalk-
powder was chosen as a promoter for some substrates, and ylated product was isolated in 25% yield. The C3-perfluoro-
the results are summarized in Table 2. Both free indole de- alkylated product was obtained in 32% yield on the basis
1
rivatives (e.g., 1a–h, see Table 2) and N-substituted indole of H NMR spectroscopy. The structures of 3a, 3b, and 3g
derivatives (e.g., 1i–l, see Table 2) reacted with perfluoro- were confirmed by X-ray diffraction analysis (Table 2, en-
alkyl halides to give the desired products (e.g., 3a–l, see try 18).[15]
Table 2). Moreover, a wide range of functional groups was
Notably, to test whether this method could be used to
tolerated under the reaction conditions, including hydroxy, introduce a trifluoromethyl group into the indoles, the reac-
ester, amide, carboxylic acid, and acyl groups (see products tion of 1i (0.25 mmol, 1.0 equiv.) with a stock solution of
3c–h, 3l, and 4p). Perfluoroalkyl bromides also underwent CF3I (10.0 equiv.) in the presence of Cu powder (2.5 equiv.)
this transformation to produce good yields without raising was performed (Scheme 1). Delightedly, desired product 4i
Table 1. Optimization of the reaction conditions for the Cu-mediated coupling of 3-methyl-1H-indole with perfluoroalkyl iodides.[a]
Entry
[Cu]
Solvent
Ligand
T [°C]
Conv.[b] [%]
Yield[b,c] [%]
1
2
3
4
5
6
CuI
CuBr
CuCl
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMSO
NMP
CH3CN
CH3OH
dioxane
THF
toluene
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
bipy
phen[g]
tmeda[h]
eta[i]
PPh3
bipy
bipy
bipy
bipy
bipy
–
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
40
r.t.
100
80
80
47
41
35
8
36
34
25
0
CuCl2
Cu(OAc)2·H2O
Cu powder
Cu2O
Cu powder
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
–
36
69
84
98
Ͼ99
94
96
94
92
81
31
61
32
67
90
50
8
24
61
68
79
80 (72)
74
76
77
70
63
21
57
14
53
72
47
0
7[d]
8[e]
9[f]
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
61
33
10
97
6
53
19
trace
70
0
Cu2O
14
4
[a] Reaction conditions: 1a (0.25 mmol, 1.0 equiv.), n-C4F9I (0.35 mmol, 1.4 equiv.), Cu catalyst (0.125 mmol, 0.5 equiv.), ligand
(0.05 mmol, 0.2 equiv.) in solvent (1.0 mL) for 24 h, unless otherwise noted. [b] Determined by analysis of the crude reaction mixture by
1H NMR spectroscopy with nitrobenzene as an internal standard; yields are based on starting material 1a. [c] In most cases, compounds
from further perfluoroalkylation of the benzene ring were observed as the major byproducts. [d] Cu2O (0.25 equiv.). [e] Cu powder
(1.5 equiv.). [f] Yield of isolated product is given in parentheses. [g] phen = 1,10-phenanthroline. [h] tmeda = N,N,NЈ,NЈ-tetramethylethane-
1,2-diamine. [i] eta = ethanolamine.
2
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Direct Fluoroalkylation of Indoles with Fluoroalkyl Halides
Table 2. Scope of Cu-mediated coupling of indoles with fluoroalkyl halides.[a]
[a] Reaction conditions: 1 (0.25 mmol, 1.0 equiv.), bipy (0.2 equiv.), 80 °C. Unless otherwise noted, the conversion of 1 was Ͼ95%.
[b] Yield of isolated product based on starting material 1. [c] Byproducts were not identified. [d] The starting material was recovered in
15% yield. [e] The starting material was recovered in 47% yield. [f] The starting material was recovered in 25% yield. [g] For details of
other regioisomers, see the Supporting Information. [h] The ORTEP view of 3a is drawn at the 30% probability level.
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R.-Y. He, H.-T. Zeng, J.-M. Huang
SHORT COMMUNICATION
was obtained in 83% yield based on conversion. This result
provides promising precedent for the viability of the Cu-
mediated trifluoromethylation of indoles with CF3I. The
optimization of this process is currently under investigation
in our laboratory. Furthermore, other aromatic heterocycles
as well as (electron-rich) benzene derivatives, such as benzo-
furan, quinoline, and anisole, were also examined under our
standard reaction conditions for perfluoroalkylation, but
we failed to detect the desired products.
Conclusions
In summary, we described a mild, efficient, and straight-
forward method for the Cu-mediated C–H perfluoroalk-
ylation and difluoromethylation of indoles with perfluoro-
alkyl halides and ICF2COOEt. The reaction tolerates a
broad substrate scope and a wide range of functional
groups. In addition, the reaction is not sensitive to air or
moisture, so it may hold great potential for medicinal chem-
ists for the synthesis of fluorinated bioactive compounds.
Further investigations of the mechanistic details and appli-
cations of this reaction are currently underway in our labo-
ratory.
Experimental Section
Scheme 1. Cu-mediated trifluoromethylation of indoles. The con-
version and yield were determined by H NMR spectroscopy.
Procedure for the Polyfluoroalkylation of Indoles by Using Cu2O as
a Catalyst: A 4.0 mL vial was charged with Cu2O (18.0 mg,
0.125 mmol, 0.5 equiv.), bipy (7.8 mg, 0.05 mmol, 0.2 equiv.), ind-
ole 1 (0.25 mmol, 1.0 equiv.), and DMF (1.0 mL). Polyfluoroalkyl
iodide 2 (typically 2.0 equiv. according to the amount of 1 added)
was then added. The vial was capped, and the mixture was stirred
at 80 °C. Upon completion of the reaction (typically 24 h), the mix-
ture was cooled to room temperature. Next, the mixture was
poured into cool water and then 25% (w/w) aqueous ammonia
(3.0 mL) and ethyl acetate (10.0 mL) were added. The organic layer
was separated, and the aqueous layer was extracted with ethyl acet-
ate (2 ϫ 15.0 mL). The combined organic layer was washed with
brine (10.0 mL), dried with anhydrous magnesium sulfate, filtered,
and concentrated in vacuo. The crude product was purified by col-
umn chromatography on silica gel.
1
To gain more insight into the reaction mechanism, sev-
eral control experiments were conducted (Table 3). We
found that if the radical inhibitor TEMPO (2,2,6,6-tet-
ramethylpiperidine-1-oxyl) was added to the reaction mix-
ture, the reaction was significantly inhibited and the desired
product was detected in only 6% yield. If diallyl ether
(1.4 equiv.) was added to the standard reaction system, de-
sired product 3a was obtained in 50% yield with recovery
of 1a in 37% yield. The cyclized product from diallyl ether
1
was also observed by GC–MS and H NMR spectroscopy.
At the currently stage, the formation of a perfluoroalkyl
radical through a single-electron transfer (SET) process is
tentatively proposed (Scheme 2).[16,17,4a]
Procedure for the Polyfluoroalkylation of Indoles by Using Cu Pow-
der as the Catalyst: A 4.0 mL vial was charged with Cu powder
(1.5 or 2.5 equiv.), bipy (7.8 mg, 0.05 mmol, 0.2 equiv.), indole 1
(0.25 mmol, 1.0 equiv.), and DMF (1.0 mL). Polyfluoroalkyl iodide
2 (typically 2.0 equiv. according to the amount of 1 added) was
then added. The vial was capped, and the mixture was stirred at
80 °C. Upon completion of the reaction (typically 48 h), the mix-
ture was cooled to room temperature. Next, the mixture was
poured into cool water and then 25% (w/w) aqueous ammonia
(3.0 mL) and ethyl acetate (10.0 mL) were added. The organic layer
was separated, and the aqueous layer was extracted with ethyl acet-
ate (2 ϫ 15.0 mL). The combined organic layer was washed with
brine (10.0 mL), dried with anhydrous magnesium sulfate, filtered,
and concentrated in vacuo. The crude product was purified by col-
umn chromatography on silica gel.
Table 3. Control experiments.
Supporting Information (see footnote on the first page of this arti-
cle): Control experiments, characterization data, NMR spectra for
all compounds, and crystallographic data for 3a, 3b, and 3g.
[a] All yields were determined by analysis of the crude reaction mix-
ture by 1H NMR spectroscopy with an internal standard; the yields
are based on staring material 1a. [b] The cyclized product 3-(iodo-
methyl)-4-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)tetrahydrofuran from
Acknowledgments
1
diallyl ether was observed by GC–MS and H NMR spectroscopy.
The authors are grateful to the National Natural Science Founda-
tion of China (NSFC) (grant numbers 21172080 and 21372089)
and the Changjiang Scholars and Innovation Team Project of the
Ministry of Education for financial support. J.-M. H. would like
to thank Prof. Loh Teck Peng for hosting her visit to Nanyang
Technological University. The authors would also like to thank Dr.
Ganguly (NTU) and Dr. Li (NTU) for their assistance with single-
crystal X-ray crystallographic analysis.
Scheme 2. Proposed mechanism.
4
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Direct Fluoroalkylation of Indoles with Fluoroalkyl Halides
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In contrast, much more methods have been reported for the
synthesis of trifluoromethyl indoles. For recent examples, see:
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O42526
/KAP1
Date: 10-06-14 12:55:15
Pages: 7
R.-Y. He, H.-T. Zeng, J.-M. Huang
SHORT COMMUNICATION
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif..
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more detail.
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Received: May 1, 2014
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42526
/KAP1
Date: 10-06-14 12:55:15
Pages: 7
Direct Fluoroalkylation of Indoles with Fluoroalkyl Halides
Fluoroalkylation
R.-Y. He, H.-T. Zeng,
J.-M. Huang* ................................... 1–7
Direct Fluoroalkylation of Indoles with
Fluoroalkyl Halides Mediated by Copper
An efficient method for the synthesis of
perfluoroalkylated and difluoromethylated
indole derivatives is described. The reaction
is mediated by copper under mild con-
ditions. Both free indoles and N-substi-
tuted indoles react with perfluoroalkyl hal-
ides and ICF2COOEt to afford the desired
products in moderate to good yields.
Keywords: Copper / Halides / Fluorine /
Fluoroalkylation / Nitrogen heterocycles
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