A Novel method for the synthesis of 2-trifluoromethylindoles from N -(o -Haloaryl)alkynylimines

Article abstract of DOI:10.1055/s-0029-1219904

Treatment of various types of N-(o-haloaryl)-alkynylimines in the presence of Pd(PPh₃)₂Cl₂ gave 2-trifluoromethylindoles in high yields. This approach provides a novel and facile access to the biologically important fluorine-containing indole derivatives.

Full text of DOI:10.1055/s-0029-1219904

1418
LETTER
A Novel Method for the Synthesis of 2-Trifluoromethylindoles from
N-(o-Haloaryl)alkynylimines
S
ynthesis of 2-T
i
rifluor
x
omethylindo
i
le
s
from
a
N
-(
o
-Halo
n
aryl)alkynylimine
C
s
hen,a,b Jiangtao Zhu,a Haibo Xie,a Shan Li,a Yongming Wu,*a Yuefa Gong*b
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86(21)54925192; E-mail: ymwu@mail.sioc.ac.cn
School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P. R. of China
E-mail: gongyf@mail.hust.edu.cn
b
Received 3 March 2010
rivatives are still in need. Herein, we wish to describe a
novel and facile synthesis of 2-trifluoromethylindole de-
rivatives by palladium-catalyzed cyclization reaction of
N-(o-haloaryl)alkynylimines.
Abstract: Treatment of various types of N-(o-haloaryl)-alky-
nylimines in the presence of Pd(PPh3)2Cl2 gave 2-trifluoromethylin-
doles in high yields. This approach provides a novel and facile
access to the biologically important fluorine-containing indole de-
rivatives.
Table 1 Optimization of Reaction Conditionsa
Key words: indoles, trifluoromethyl, palladium, alkynylimine, het-
erocycles
O
Ph
Pd(PPh3)2Cl2 (10 mol%)
I
K3PO4 (2 equiv), H2O (1 equiv)
CF3
DME (2 mL), 60° C, 0.5 h
The indole scaffold is a prominent and privileged structur-
al motif found in numerous natural products and various
synthetic compounds.1 It is well known that the properties
of a bioactive molecule can often be modulated by adding
fluorine atoms since this leads to changes in solubility, li-
pophilicity, metabolic stability, conformation, hydrogen-
bonding ability, or chemical reactivity.2 Biologically ac-
tive 2-trifluoromethylindole compounds have previously
been reported. For example, 2-trifluoromethylated indoles
are of significant pharmacological interest for their use as
potent chemokine receptor 5 (CCR5) antagonists,3 gener-
al anesthesia inducers,4 tyrosine kinase inhibitors,5 and
antitumor compounds.6
N
H
N
F3C
Ph
Entry Catalyst
Base
Solvent Time Yield
(h)
(%)b
1
2
Pd(OAc)2/Ph3P
PdCl2/Ph3P
K3PO4
K3PO4
DME
DME
DME
DME
DME
DME
DME
0.5 87
15
25
3
Pd2(dba)3⋅CHCl3/Ph3P K3PO4
0.5 94
4
Pd(PPh3)2Cl2/Ph3P
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
K3PO4
K3PO4
K2CO3
KOAc
0.5 96 (80)
0.5 95
5
In view of the importance of fluorine-containing indole
compounds, considerable effort has been placed in devel-
oping an efficient method for the synthesis of trifluorom-
ethylated indole derivatives. Classical methods include
direct fluoroalkylation of indoles with perfluoroalkanoyl
peroxides or perfluoroalkyl halides,7 titanium-catalyzed
carbonyl coupling of 2-acyltrifluoroacetanilides,8 photo-
chemical intramolecular cyclizations of trifluoroacetim-
idoyl iodide or trifluoroacetimidoyl telluride,9
thermolysis of 2-(N-trifluoroacetylamino)benzylphos-
phonium salts, and intramolecular cyclization of N-triflu-
oroacetyl-p-benzoquinone.10,11 Recently, Pd-catalyzed
annulation of fluorine-comprising internal alkynes with 2-
iodoanilines,12 Grignard cyclization reaction of fluorinat-
ed N-arylimidoyl chlorides, and Cu-catalyzed coupling of
2-halotrifluoroacetanilides with b-keto esters were also
reported.13,14 However, most of them suffered from either
poor yields or the limitation of starting materials. New
methods for synthesizing fluorine-containing indole de-
6
1
1
1
1
1
1
4
2
1
85
19
15
68
72
21
68
47c
66d
7
8
Na2CO3 DME
9
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMSO
MeCN
dioxane
H2O
10
11
12
13
14
DME
DME
a Reactions were carried out on a 0.2 mmol scale in DME (2 mL)
under nitrogen with H2O (1.0 equiv), catalyst (10 mol%), and base
(2 equiv) unless otherwise stated.
b Reported yields were based on 1a determined by 19F NMR. Values
in parentheses are of isolated yield.
c Pd(PPh3)2Cl2 (5 mol%) was used.
d K3PO4 (1 equiv) was used.
SYNLETT 2010, No. 9, pp 1418–1420
x
x.
x
x.
2
0
1
0
Advanced online publication: 20.04.2010
DOI: 10.1055/s-0029-1219904; Art ID: W03410ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Trifluoromethylindoles from N-(o-Haloaryl)alkynylimines
1419
2-Iodo-N-(1,1,1-trifluoro-4-phenylbut-3-yn-2-ylidene)- After optimization, the best reaction conditions were as-
aniline (1a) was chosen as a model substrate to screen the certained as 10 mol% Pd(PPh3)2Cl2, 1 equiv of H2O, and
optimal reaction conditions (Table 1). Initial experiments 2 equiv of K3PO4 in DME at 60 °C under nitrogen atmo-
were performed using H2O (1 equiv), K3PO4 (2 equiv), in sphere (Table 1, entry 5).
the presence of 10 mol% of Pd(OAc)2 and 20 mol% of
Next, the scope and limitations of this annulation reaction
Ph3P as the catalyst system in DME (dimethoxyethane) at
were examined. Table 2 summarizes the results of the re-
60 °C under nitrogen atmosphere. This reaction was com-
actions of a variety of N-(o-haloaryl)alkynylimines under
optimized reaction conditions. N-(o-Bromoaryl)alky-
nylimine could also give a good yield at 60 °C without
pleted after 0.5 hours, and the indole product was formed
in 87% yield (Table 1, entry 1). Next, different palladium
sources were screened, and preliminary results showed
loss of reactivity compared with chlorides (Table 2, en-
that the use of Pd(PPh3)2Cl2 gave excellent yield of the
tries 1 and 2). Then, the substituent effects were investi-
product even without an additional ligand (Table 1, en-
gated. When R1 was an electron-donating group, the
tries 2–5). Among the bases studied, K3PO4 provided the
product was isolated in good yield (Table 2, entries 3 and
best result (Table 1, entries 6–8). We then probed the sol-
4). Electron-withdrawing group such as F and CF3 gave
vent effect and found that DME was considerably superior
the products in lower yields with longer times (Table 2,
to DMSO, MeCN, dioxane, and H2O (Table 1, entries 9–
entries 5 and 6). Further modifying the alkyne moiety re-
12). The attempt to reduce loading of the catalyst and base
vealed that when R2 was an aromatic ring with an elec-
led to longer reaction times and lower yields (Table 1, en-
tron-donating group such as Me and MeO or a tert-butyl
group, the reaction was completed within 30 minutes in
tries 13 and 14).
good yield (Table 2, entries 7–9, 15), while electron-defi-
cient aryl group needed prolonged reaction time to give
products in lower yield (Table 2, entries 10–12).
Table 2 Synthesis of 2-Trifluoromethylindole Derivatives 2 from
N-(o-haloaryl)alkynyliminesa
O
R2
A possible mechanism of this transformation is proposed.
The first step is oxidative addition of Pd(0) with aryl ha-
lide, then carbo-palladation followed by reductive elimi-
nation of Pd(0) leading to 3-(1-iodo-1-phenyl)-
methyleneindole as an intermediate,9b which is hydro-
lyzed under the reaction conditions to provide the final
acylindole.
Pd(PPh3)2Cl2 (10 mol%)
K3PO4 (2 equiv), H2O (1 equiv)
X
N
R1
R1
CF3
DME (2 mL), 60 °C
N
H
F3C
R2
Entry
X
R1
R2
Time
(h)
Product Yield
(%)b
In conclusion, we have developed a novel and facile meth-
od for the synthesis of biologically important 2-trifluo-
romethyl-substituted indole derivatives from the easily
prepared N-(o-haloaryl)alkynylimines. Using this proto-
col, a wide variety of functionalized 2-trifluoromethylin-
doles can be synthesized in good yields under mild
conditions.
1
2
Br
Cl
I
H
Ph
Ph
Ph
0.5
5
2a
2a
2b
2c
2d
2e
2f
80
H
13
3
4-Me
0.5
0.5
1
82.5
78.4
75.7
52.5
82.5
85.4
80.7
70.3
59.4
70.3
73.8
84.7
85.7
4
I
5-MeO Ph
5
I
4-F
4-F3C
H
Ph
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
6
I
Ph
3
7
I
4-MeC6H4
4-MeOC6H4
3-MeOC6H4
4-ClC6H4
4-FC6H4
2-ClC6H4
2-naphthyl
2-thienyl
t-Bu
0.5
0.5
0.5
0.5
1
Acknowledgment
8
I
H
2g
2h
2i
This work was supported by the National Science Foundation of
China (Nos. 20772145).
9
I
H
10
11
12
13
14
15
I
H
References
I
H
2j
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