Synthesis of 2-(Trifluoromethyl)indoles via Domino Trifluoromethylation/Cyclization of 2-Alkynylanilines

Article abstract of DOI:10.1021/acs.orglett.8b00509

A new method for the synthesis of 2-(trifluoromethyl)indoles using easily accessible 2-alkynylanilines and a well-established fluoroform-derived CuCF₃ reagent is described. This method utilizes a domino trifluoromethylation/cyclization strategy

Full text of DOI:10.1021/acs.orglett.8b00509

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 2‑(Trifluoromethyl)indoles via Domino
Trifluoromethylation/Cyclization of 2‑Alkynylanilines
Yibin Ye, Kelvin Pak Shing Cheung, Lisi He, and Gavin Chit Tsui*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR
S
* Supporting Information
ABSTRACT: A new method for the synthesis of 2-(triflu-
oromethyl)indoles using easily accessible 2-alkynylanilines and
a well-established fluoroform-derived CuCF3 reagent is described.
This method utilizes a domino trifluoromethylation/cyclization
strategy to construct the indole cores with no ambiguity of
the CF3 position. The intriguing 3-formyl-2-(trifluoromethyl)-
indoles can also be synthesized by this protocol, which are
useful intermediates for the preparation of trifluoromethylated
drug analogues. The ultimate CF3 source is the inexpensive
industrial byproduct fluoroform.
he indole motif is one of the most prevalent and priv-
ileged heterocycles in natural products and drug mole-
approach has surprisingly not been reported, despite the fact
that the synthesis of functionalized indoles via cyclization of
2-alkynylanilines is well-documented.2
T
cules.1,2 The increasing interest in fluorinated indole derivatives
toward drug discovery led to the recent development of
methods accessing trifluoromethylated indoles, an important
class of trifluoromethylated heterocycles.3 Reports on Fischer
indole synthesis4a,b as well as other cyclization methods4c−k
using CF3-containing building blocks are known, though the
synthetic sequences were usually tedious due to the preparation
of trifluoromethylated precursors. The majority of current
methods are based on trifluoromethylation of existing indole
cores.5,6 Transition-metal-catalyzed cross-coupling of indoles
containing boron,5a−g halide,5h−j and silicon5k functional groups
have been successfully developed without the need of fluorinated
building blocks. However, the reliance of prefunctionalized
indoles bearing activating groups at specific positions was incon-
venient and equally demanding. More direct C−H trifluor-
omethylation of indoles using transition-metal-catalyzed,6a−f
photoredox catalysis,6g−i and radical6j−m methods has over-
come this disadvantage. At the same time, the control of regio-
selectivity (2-CF3 vs 3-CF3) was generally difficult with sub-
strates not containing a blocking group, therefore limiting the
reaction scope.6n−q In the context of our interest in developing
novel trifluoromethylation methods for synthesizing trifluor-
omethylated heterocycles,7 we herein describe the preparation
of 2-(trifluoromethyl)indoles via a domino trifluoromethyla-
tion/cyclization strategy.
To test the hypothesis and optimize the reaction conditions
(Table 1), the CuCF3 reagent was first prepared according to
a
Table 1. Optimization Studies
conc
(M)
temp
(°C)
yield of 3a
or 4a (%)
yield of
5a (%)
yield of
6a (%)
b
b
b
entry
R
1
2
3
H
0.06
0.06
0.13
0.13
0.13
0.13
0.13
0.06
0.06
0.06
0.06
23
23
23
23
50
80
80
80
80
50
23
0
0
0
0
7
6
0
0
2
0
0
Ts
77
c
Ts
Ts
81/82
0
d
4
20
57
47
0
0
5
6
7
8
Ts
0
Ts
trace
c
Ms
Ms
Ms
Ms
Ms
70
c
0
80
d
9
18
8
0
trace
0
We have previously reported an efficient trifluoromethylation
method of terminal alkynes using Grushin’s fluoroform-derived
CuCF3 and TMEDA (tetramethylethylenediamine).7a This
reaction can potentially be applied to the synthesis of 2-(triflu-
oromethyl)indoles from readily accessible 2-alknylanilines
(eq 1). In a domino fashion,8 the strategy relies on the tri-
fluoromethylation of terminal alkyne, followed by 5-endo-dig
cyclization, initiated by the ortho nitrogen nucleophilic attack to
the triple bond, to construct the indole core. Such a convenient
c
10
57/58
c
c
11
28/28
53/51
a
General conditions: 2-alkynylaniline (0.1−0.2 mmol), fluoroform-
b
derived CuCF3 (3.0 equiv), TMEDA (3.0 equiv). Determined by 19
NMR analysis using benzotrifluoride as the internal standard. Isolated
yield. Without TMEDA.
F
c
d
Received: February 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00509
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the literature procedures9 from copper(I) chloride, potassium
tert-butoxide, and fluoroform in DMF, stabilized with triethyl-
amine trihydrofluoride (Et3N·3HF). Under previously devel-
oped conditions, 2-ethynylaniline did not provide any indole
products (entry 1); only alkyne trifluoromethylation took place
(80% yield) without subsequent cyclization.7a A drastic change
in reactivity was observed when the N-tosyl derivative 1a was
employed, which provided the desired 2-(trifluoromethyl)-
indole product 3a in 77% yield (entry 2). Increasing the con-
centration further improved the yield to 81% (entry 3). The
addition of TMEDA was important for the reaction (entry 4).
Higher temperatures led to decreased yields with small amounts
of desulfonylated product 5a (entries 5 and 6). To our surprise,
when the N-mesyl substrate 2a was used at 80 °C, the 3-formyl
2-CF3 N-H indole product 6a was obtained exclusively (entry 7).
In this case, a lower concentration increased the yield (entry 8).
The addition of TMEDA (entry 9) and higher temperature
(entries 10 and 11) were crucial for the formation of 6a,
although at 50 °C the desulfonylated product 5a was isolated in
reasonable yield as the major product (entry 10). Overall, three
conditions were found to obtain three distinct 2-(trifluoromethyl)-
indole products 3a, 5a, and 6a from the common substrate
2-alkynylanilines (entries 3, 10, and 8, respectively). Other
N-protecting groups were also screened at both 23 and 80 °C
(see the Supporting Information for full details). It was found
that substrates containing electron-deficient groups, such as
−NHAc, −NHBz, and −NHCbz, were more prone to cyclization
to give products similar to 3a/4a (albeit in much poorer yields,
3−27%) than electron-rich groups such as −NHBn (only alkynyl-
CF3 product obtained). None of these substrates afforded
products 5a and 6a. We also found that the use of secondary
amines such as 1a/2a was important for the reaction. For example,
using substrates containing −NTsMe and −NMsMe did not give
any 3a and 6a, respectively, under standard conditions (cf. entries
3 and 8). Instead, only alkynyl-CF3 products were detected.
The scope of 2-(trifluoromethyl)indoles 3 was subsequently
investigated (Scheme 1). Indoles 3a−j were prepared from 1 at
nitrile (3f), and ester (3j), were obtained in lower yields, com-
pared to those with electron-donating groups (3b,g), which was
mainly due to the formation of desulfonylated side products.
In particular, the nitrile-containing N-H indole product 3f was
isolated as the major product from the reaction.
On the other hand, the 3-formyl-2-(trifluoromethyl)indoles
6a−m were prepared from 2 at 80 °C in good yields tolerating
halogens (6d−f,k-l), nitrile (6g), ketone (6h), and ester (6m)
(Scheme 2). The lower yield of 6c was due to the partial
a
Scheme 2. Scope of 3-Formyl-2-(trifluoromethyl)indoles 6
a
General conditions: 2 (0.2 mmol, 0.06 M in DMF), fluoroform-
derived CuCF3 (3.0 equiv), TMEDA (3.0 equiv), isolated yields.
b
c
1 mmol scale The N-(4-nitrobenzyl) derivative of 6a.
a
Scheme 1. Scope of 2-(Trifluoromethyl)indoles 3
decomposition of the substrate 2c during the reaction. In all
cases, the relatively sensitive formyl group remained intact under
the reaction conditions. The structure of 6a was confirmed by
X-ray crystallography through its derivative 6a′. The C-2 CF3
group and the C-3 formyl group were unambiguously confirmed.
The formyl functionality of the indole product 6 was versa-
tile for further transformations. To demonstrate its utility,
compound 6b was employed to synthesize the trifluoromethy-
lated analogue of melatonin (Scheme 3), a hormone involved in
circadian entrainment and numerous physiological processes.10a
In two simple operations, condensation with nitromethane,
followed by reduction and N-acetylation,10b the corresponding
2-CF3 analogue of melatonin 8 was prepared successfully. Such
a compound could find useful applications in the structure−
activity relationship (SAR) studies.
The transformation of 2 to the formylated indoles 6 is
intriguing (cf. Scheme 2, vide supra) and, to the best of our
knowledge, is unprecedented. Control experiments showed that
aerobic conditions were crucial for the formylation process
(eq 2). Separately prepared 5a gave product 6a in good yield
(83%) under standard conditions, thus suggesting its inter-
mediacy (eq 3). By monitoring the reaction of 2a over time
using 19F NMR (Scheme 4), we were able to detect the various
intermediates toward product 6a, including the CF3-containing
alkyne I1 prior to cyclization, the N-mesyl indole 4a, the N-H
a
General conditions: 1 (0.2 mmol, 0.13 M in DMF), fluoroform-derived
b
CuCF3 (3.0 equiv), TMEDA (3.0 equiv), isolated yields. 1 mmol scale.
room temperature in moderate to good yields tolerating a
variety of functional groups. In general, compounds containing
electron-withdrawing groups, such as halogens (3c−e, h,i),
B
DOI: 10.1021/acs.orglett.8b00509
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the basis of the above studies and the known literature
examples, the following mechanism is proposed for the formation
of the 3-formyl-2-(trifluoromethyl)indole 6a from 2a (Scheme 5).
Scheme 3. Synthesis of the Trifluoromethylated Analogue of
Melatonin
Scheme 5. Proposed Mechanism for Domino
Trifluoromethylation/Cyclization/Desulfonylation/
Formylation of 2a
Scheme 4. 19F NMR Studies of the Conversion of 2a to 6a over
Time under Standard Conditions (NMR Solvent = Acetone-d6)
2-Alkynylaniline 2a undergoes facile trifluoromethylation at the
alkyne terminus to form intermediate I1, facilitated by Cu(II)CF3
and TMEDA under aerobic conditions.7a To investigate the
subsequent 5-endo-dig cyclization and desulfonylation for the
formation of 4a and 5a, respectively, I1 was separately prepared
and subjected to additives, such as Et3N·3HF, Et3N, KF, and
TMEDA, which were likely to be present in the fluoroform-
derived CuCF3 reagent9a,c and the reaction mixture (see the
Supporting Information). The results revealed that simple heat-
ing at 80 °C (or with Et3N·3HF, Et3N, and TMEDA) could
trigger the cyclization of I1 to 4a quantitatively, which might be
due to the strong activating (electron-withdrawing) effect by
the CF3 group at the alkyne terminus. In contrast, in the pre-
sence of a fluoride such as KF, the desulfonylated product 5a
was obtained exclusively. This observation is consistent with
the literature reports,11 thus suggesting that desulfonylation of
4a to 5a is caused by the fluoride used for stabilizing the CuCF3
reagent.9a
Copper(II)-catalyzed C-3 formylation of indoles using ter-
tiary amines and molecular oxygen at high temperature (120 °C)
is known.12a Under the oxidative conditions (aerobic), we
expected a copper(II) species to be present after the formation
of I1.7a,12b TMEDA presumably first undergoes one-electron
oxidation to the corresponding amine radical cation in the pres-
ence of copper and oxygen. Subsequent C−C bond cleavage
results in a highly reactive iminium ion.12c Attack of iminium by
indole 5a installs one carbon unit at the C-3 position leading to
intermediate I2.12d A second one-electron oxidation takes place
to give radical cation I3, followed by hydrogen atom abstraction
leading to iminium I4. Hydrolysis upon aqueous workup
eventually provides the 3-formyl-2-(trifluoromethyl)indole 6a,
where the one carbon unit is derived from TMEDA and oxygen
comes from water (see the SI for H218O-labeling experiments).
The dual role of TMEDA as both a ligand (in the alkyne
trifluoromethylation step) and reactant (one carbon donor in
the formylation sequence) is worth noting. Overall, a remark-
able domino trifluoromethylation−cyclization−desulfonylation−
formylation sequence is achieved.
indole 5a, and a transient intermediate I2. When the reaction
was stopped after 3 h, we were able to isolate and characterize
intermediate I2 (eq 4). To probe whether the solvent DMF
participated in the formylation step, the reaction was carried out in
DMF-d7 and showed no deuterium-incorporated product (eq 5).
In conclusion, we have developed a new synthetic method
for the preparation of 2-(trifluoromethyl)indoles from readily
available 2-alkynylanilines with no ambiguity of the CF3
position. An intriguing process for the synthesis of 3-formyl-
2-(trifluoromethyl)indoles was discovered that involved a
C
DOI: 10.1021/acs.orglett.8b00509
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00509.
Experimental procedures, characterization data and
NMR spectra (PDF)
Accession Codes
2011, 50, 1896. (j) Gonda, Z.; Kovac
́ ́ ́
s, S.; Weber, C.; Gati, T.;
Meszaros, A.; Kotschy, A.; Novak, Z. Org. Lett. 2014, 16, 4268.
́
́
́
CCDC 1571261 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
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■
Corresponding Author
*E-mail: gctsui@cuhk.edu.hk.
ORCID
Gavin Chit Tsui: 0000-0003-4824-8745
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Research Grants Council of
Hong Kong (CUHK 24301217) and the Chinese University of
Hong Kong (the Faculty Strategic Fund for Research from the
Faculty of Science and the Direct Grant for Research 4053199).
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