2-(Trifluoromethyl)indoles via Pd(0)-Catalyzed C(sp3)-H Functionalization of Trifluoroacetimidoyl Chlorides

Article abstract of DOI:10.1021/acs.orglett.6b00795

Perfluoroalkylated indoles are valuable compounds in drug discovery. A Pd(0)-catalyzed C(sp³)-H functionalization enables access to 2-(trifluoromethyl)indoles from trifluoroacetimidoyl chlorides. These are stable compounds, easily obtained from

Full text of DOI:10.1021/acs.orglett.6b00795

Letter
pubs.acs.org/OrgLett
2‑(Trifluoromethyl)indoles via Pd(0)-Catalyzed C(sp3)−H
Functionalization of Trifluoroacetimidoyl Chlorides
Julia Pedroni and Nicolai Cramer*
́ ́
Laboratory of Asymmetric Catalysis and Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de
Lausanne, EPFL SB ISIC LCSA, BCH 4305, CH-1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: Perfluoroalkylated indoles are valuable compounds in
drug discovery. A Pd(0)-catalyzed C(sp3)−H functionalization enables
access to 2-(trifluoromethyl)indoles from trifluoroacetimidoyl chlorides.
These are stable compounds, easily obtained from anilines. The
cyclization operates with catalyst loadings as low as 1 mol % and
accommodates a variety of substituents.
pose important limitations, along with the frequent use of
luorinated molecules have found extensive applications as
Factive ingredients in pharmaceuticals and agrochemicals. In protective groups. Transition-metal-catalyzed C−H functional-
ization became an attractive strategy for the construction of
complex molecules often through complementary disconnec-
tions.10 For instance, C−C bond-forming processes initiated by
Pd(0)-catalyzed C(sp3)−H functionalizations have been a focus
of investigation over the past years. Whereas a wide range of
different C−H groups was investigated,11−14 the electrophilic
partner was mostly limited to aryl halides,12 vinyl halides,13 or
triflates.14 In stark contrast, the use of trifluoroacetimidoyl
chlorides remains almost completely underdeveloped in this
context.15 This functional group can be conveniently accessed
by simply exposing the parent amine to trifluoroacetic acid,
CCl4, and PPh3. Moreover, it is stable toward silica gel
chromatography.16
Herein we report a method for 2-(trifluoromethyl)indoles 2
via an Pd(0)-catalyzed C(sp3)−H functionalization of trifluor-
oacetimidoyl chlorides 1 derived from widely available o-
methylanilines (Scheme 1). After initial oxidative addition to 1,
the adjacent CH3 group is activated, enabling reductive
elimination and tautomerization to indole 2.
search of novel development candidates, the systematic
introduction of fluorine atoms and perfluoroalkyl groups in
scaffolds has become widespread, as such substitution affects
the metabolic stability, conformation, and dipole moment of a
given molecule, ultimately resulting in altered biological
activity.1 The indole scaffold is a prevalent motif in biologically
active natural and unnatural products.2 The increasing interest
in fluorinated derivatives3 led to the development of methods
to access 2-(trifluoromethyl)indoles.4 These are largely based
on the modification of an existing indole ring5−7 and require a
stoichiometric amount of an electrophilic trifluoromethylating
reagent such as Togni’s6 or Umemoto’s reagent7 (Scheme 1).
Reports on the Fischer indole synthesis using perfluoroalky-
lated substrates,8 as well as other cyclization strategies, are
known.9 However, in many cases, one requires either
prefunctionalized starting materials or regioselectivity issues
Scheme 1. Complementary Strategies for the Synthesis of 2-
(Trifluoromethyl)indoles
Initially, 2,6-dimethylaniline derivative 1a was selected as the
model substrate (Table 1). Exposure of 1a to catalytic amounts
of Pd(0) and PPh3 as the ligand provided the desired
trifluoromethyl-substituted indole, albeit in a moderate yield
of 24% (entry 1). The use of PCy3 led to a very smooth
reaction, giving 2a in 97% yield (entry 2). The catalyst loading
was lowered to 2.0 mol % of Pd(dba)2, and air-stable PCy3·
HBF4 could be employed with no impact on the reaction
performance (entry 3). Moreover, inexpensive KOAc could be
used without any loss of reactivity (entry 4). As second model
substrate, 2-methylaniline derivative 1b was selected to expand
the methodology to a broader substrate class. However, when
monosubstituted trifluoroacetimidoyl chloride 1b was sub-
mitted to previous reaction conditions, only traces of indole 2b
Received: March 18, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00795
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Optimisation of the 2-CF3-indole Formation
Scheme 2. 2-CF3-indoles Scope of the C(sp3)−H
a
Functionalization
b
b
entry
1
L
additive
2
(%)
3
(%)
1
2
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
PPh3
PCy3
PCy3
PCy3
PCy3
PCy3
PPh3
IPr
CsOAc
CsOAc
CsOAc
KOAc
24
97
90
96
<5
17
<5
<5
48
53
56
49
99
0
c
c
c
,
,
,
d
d
d
3
4
5
6
7
8
9
e
KOAc
CsOAc
CsOAc
CsOAc
CsOAc
NaOAc
KOAc
34
50
25
16
10
11
S-IPr
S-IPr
S-IPr
S-IPr
S-IPr
10
11
12
13
14
f
KOAc, K2CO3 (2 equiv)
KOAc, K2CO3 (3.5 equiv)
CsOAc
<5
<1
14
g
h
e
a
Conditions A: 0.1 mmol of 1, 5.0 mol % of Pd(dba)2, 5.0 mol % of S-
IPr, 2.0 equiv of KOAc, 3.5 equiv of K2CO3, 0.1 M in toluene, 110 °C
for 12 h. Conditions B: 0.1 mmol of 1, 2.0 mol % of Pd(dba)2, 4.0 mol
% of PCy3·HBF4, 2.0 equiv of KOAc, 0.2 M in toluene, 110 °C for 12
a
Conditions: 0.1 mmol of 1, 5.0 mol % of Pd(dba)2, 10.0 mol % of L,
2.0 equiv of additive, 0.1 M in toluene, 110 °C for 12 h. Determined
by H NMR with an internal standard. 2.0 mol % of Pd(dba)2, 4.0
mol % of L. 0.2 M. Isolated yield. 0.5 equiv of KOAc. 5.0 mol % of
b
b
c
d
c
1
h; isolated yields. 0.5 mmol scale. 83% conversion. 53% conversion.
e
1H NMR yield.
d
e
f
g
h
L. No Pd(dba)2.
in almost quantitative yield. Besides trifluoromethyl, longer
fluorinated chains such as the C2F5 group (1o) provide the
corresponding indole in very good yield (87%, conditions A;
67%, conditions B). Moreover, the transformation accommo-
dates in addition to the methyl group activation as well
methylene groups. For instance, ethyl-substituted substrate 1p
provides selectively 2,3-disubstituted indole 2p. Conditions A,
using S-IPr as the ligand, were found to provide the better
reactivity.
were detected (entry 5). An increased catalyst loading of 5.0
mol % formed 2b in 17% yield along with 34% of side product
3b (entry 6). Among the tested ligands (entries 6−9), S-IPr
delivered the most promising result, giving 48% yield of the
desired indole 2b and just 16% of 3b (entry 9). Further
screening revealed that KOAc is superior (56% 2b, entry 11).
Moreover, the addition of K2CO3 almost completely sup-
pressed the formation of side product 3b (entry 12).
Adjustments of the amount and ratio of the two additives as
well as the Pd/ligand ratio to 1:1 furnished 2b in nearly
quantitative yield (entry 13). Surprised by the fact that the
amounts of formed imide 3b strongly depended on the
employed ligand, substrate 1b was exposed to reaction
conditions in the absence of the palladium catalyst. In this
case, imide 3b is observed in minor quantity (14%, entry 14),
suggesting a contribution of the Pd catalyst to its formation.
Next, the cyclization of a range of trifluoroacetimidoyl
chlorides was investigated (Scheme 2). For the C−H
functionalization of 6-substituted imidoyl chlorides, the
Pd(0)/S-IPr catalyst system (conditions A) showed often
superior performance compared to the Pd(0)/PCy3 system
(conditions B). Both conditions were well suited for the
synthesis of 7-alkylindoles 2a and 2c, and higher yields of
heteroatom-containing 2d,e were obtained using conditions A.
Moreover, trifluoroacetimidoyl chlorides 1f−l substituted in
meta-position to the N-atom underwent cyclization delivering
indoles decorated with functional groups such as methyl ester
(2h), CF3 (2g, 2k) and halogen atoms (2i, 2l) in good to
excellent yields. 2-Methyl-1-naphthyl derivative 1q reacted well
with the Pd(0)/S-IPr catalyst but provided a 5:1 mixture of 2q
and its C(sp2)−H functionalization product 2q′. In contrast,
the Pd(0)/PCy3 catalyst system gave exclusive rise to indole 2q
Further investigations were conducted with substrate 1m
toward the scalability of the process (Table 2). First, the
a
Table 2. Scale-up and Reduced Catalyst Loadings
b
b
entry
1m (mmol)
c (M)
conv (%)
2m (%)
1
2
3
4
2.0
2.0
2.0
10
0.50
0.40
0.25
0.25
46
84
30
70
c
100
100
85
c
77
a
Conditions: 1m, 1.0 mol % of Pd(dba)2, 1.1 mol % of S-IPr, 2.0 equiv
b
of KOAc, 3.2 equiv of K2CO3, toluene, 110 °C for 20 h. Determined
by H NMR with an internal standard. Isolated yield.
c
1
catalyst loading was lowered to 1.0 mol % while the
concentration was increased 5-fold (entry 1). Indole 2m was
obtained in 30% yield, and the reaction stalled at 46%
conversion. The concentration has a significant influence
(entries 1−3), and an optimum was found at 0.25 M, giving
2m in 85% isolated yield. These conditions proved to be
B
DOI: 10.1021/acs.orglett.6b00795
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
suitable for further scale up, and 2.5 g (10.0 mmol) of 1m
delivered 2m in 77% isolated yield (entry 4).
AUTHOR INFORMATION
Corresponding Author
■
On the basis of previous work,17 the following reaction
mechanism is likely (Scheme 3). Following the oxidative
*E-mail: nicolai.cramer@epfl.ch.
Notes
The authors declare no competing financial interest.
Scheme 3. Proposed Reaction Mechanism
ACKNOWLEDGMENTS
This work is supported by the Swiss National Science
Foundation (no. 155967).
■
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00795.
Experimental procedures and analytical and spectral data
for all new compounds (PDF)
C
DOI: 10.1021/acs.orglett.6b00795
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