Palladium-Catalyzed Direct C-H Trifluoroethylation of Aromatic Amides

Article abstract of DOI:10.1021/acs.orglett.7b01859

A simple and direct C-H trifluoroethylation of aromatic amides has been developed. The protocol is applicable to a variety of aromatic amides, including ones derived from amino acids. The developed method can be used for further modifications of peptides. Preliminary mechanistic studies have been done by isolating the reaction intermediate.

Full text of DOI:10.1021/acs.orglett.7b01859

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Direct C−H Trifluoroethylation of Aromatic
Amides
Manikantha Maraswami,‡ Sreekumar Pankajakshan,‡ Gang Chen,*,‡ and Teck-Peng Loh*,†,‡,§
†Institute of Advanced Synthesis, College of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for
Advanced Materials, Nanjing Tech University, Nanjing, Jiangsu 210009, P. R. China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371
§Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei 230026, China
S
* Supporting Information
ABSTRACT: A simple and direct C−H trifluoroethylation of
aromatic amides has been developed. The protocol is applicable
to a variety of aromatic amides, including ones derived from
amino acids. The developed method can be used for further
modifications of peptides. Preliminary mechanistic studies have
been done by isolating the reaction intermediate.
luorous functionalization of organic molecules is of vital
importance in synthetic manipulations in drug discovery,
method for the trifluoroethylation of benzamides using a
mesityl(2,2,2-trifluoroethyl)iodonium salt as the coupling
partner.
F
agrochemicals, and material science thanks to the profound
changes in the physiochemical and pharmacokinetic properties
of the substrates invoked by the installation of bioisosteric
fluorine/perfluoro groups.1 While substantial progress has
already been achieved in C−C bond-forming trifluoromethy-
lations,2 the corresponding homologous trifluoroethylations3
are understandably more challenging for a number of reasons,
such as the poor propensity of alkyl electrophiles to engage in
the classical transition-metal-catalyzed pathways3a (possibly
because of the tendency of the organometallic species to decay
via β-fluoride elimination),3f drastic reaction conditions,3d,h and
the need to prefunctionalize the substrates in many cases.3a−g
The advent of C−H functionalization methods has improved
the efficiency, selectivity, and environmental appeal of cross-
coupling reactions, as this chemistry obviates the need for
oxidized substrates by effecting intramolecular ligand-directed
carbometalations on C−H bonds.4 Hypervalent iodonium
reagents, on the other hand, are proving to be extremely
useful reagents in organic synthesis because of their enhanced
electrophilicity, longer shelf life, and nontoxicity.5 Though
directed C−H functionalization exploiting the reactivity of a
variety of iodonium salts has advanced the efficient
construction of many different types of C(sp2)−C(sp2)
scaffolds,6 mild, direct-trifluoroethylation is still highly under-
At the outset, optimization of the reaction began with N-
methylbenzamide (1a) as the model substrate. Palladium(II)
acetate was employed as the catalyst, and dichloroethane
(DCE) was the solvent of choice (Table 1, entries 1−10; see
the Supporting Information (SI) for more details). It was
pleasing to observe that the reaction conditions enabled
directed o-trifluoroethylation of the amide substrate at room
temperature, although the conversion was marginal (Table 1,
entry 1). Acid additives are known to enhance the catalytic
efficiency of palladium salts, so the reaction was repeated in the
presence of stoichiometric trifluoroacetic acid (TFA). Gratify-
ingly, complete conversion was obtained (24 h), and the
trifluoroethylated product (3) was isolated in a near-perfect
yield of 96% (Table 1, entry 2). Other additives were also
tested, but none of them were found to be as effective as TFA
(Table 1, entries 3−5 and SI). Other palladium salts, including
Pd(TFA)2, were found to be less ideal (Table 1, entries 6 and
7), and metals other than palladium were totally ineffective in
effecting this reaction (see the SI). The facat the control
experiment in the absence of the metal catalyst did not produce
any product (Table 1, entry 8) established the absolute
requirement of the palladium catalyst and also ruled out the
possible involvement of a protic/Lewis acid-mediated pathway.
A wide range of solvents were also screened: while dichloro-
methane (DCM) was almost on par with DCE (Table 1, entry
9), coordinating solvents such as MeOH (Table 1, entry 10),
́
developed. Novak’s group recently reported palladium-
catalyzed trifluoroethylations of anilides and ureas employing
hypervalent iodonium reagents as the perfluoroalkyl source,
representing the only reports pertaining to this chemistry to
date.3m,n As a continuation of our own interest in directing-
group-assisted C−H bond functionalizations and perfluoroal-
kylations,7 we herein disclose an efficient palladium-catalyzed
Received: June 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01859
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Organic Letters
Letter
though the tert-butyl group understandably induced steric
inhibition (Scheme 1, entries 3a-c). Substituents meta to the
directing group imposed no significant electronic bias, and
substrates bearing methyl or functionally manipulable groups
like methoxy, chloro, and trifluoromethyl all reacted efficiently
to provide the corresponding products in good yields (Scheme
1, entries 3d−g). Para-substituted amides were also tested, and
both electron-donating and electron-depleting groups were
well-tolerated (Scheme 1, entries 3h−n). Highly substituted
benzene rings are generally averse to further cross-coupling, but
the current protocol allowed for the easy synthesis of
tetrasubstituted trifluoroethyl benzamides in high yields
(Scheme 1, entries 3o−q). Both 1- and 2-napthamides reacted
with the same ease, and the heterocyclic substrate 1t could also
be trifluoroethylated, albeit with a low yield (Scheme 1, entry
3t).
Table 1. Key Optimization Results for the
Trifluoroethylation of Benzamide 1a
a
b
entry
catalyst
solvent
additive
yield (%)
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(dba)3
−
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM
MeOH
DCE
−
25
96
92
91
15
80
45
0
TFA
HBF4
BF3·OEt
AcOH
TFA
TFA
TFA
TFA
TFA
TFA
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
93
0
In order to broaden the substrate scope and identify whether
the substituents on the amide nitrogen atom have any crucial
bearing on the reaction profile, a variety of differently N-
substituted handles were tested under the standard conditions
(Scheme 2, entries 5a−m). The screening showed that the
10
11
67
a
Unless otherwise specified, the reaction conditions were as follows: a
mixture of 1a (0.1 mmol), solvent (0.5 mL), Pd(OAc)2 (10 mol %),
and additive (1 equiv) was stirred for 24 h at rt. See the SI for
b
detailed optimization.
Scheme 2. Scope of N-Substituents on the Amide
DMF, DMSO, and MeCN totally inhibited the reaction (see
the SI). The catalyst loading could be reduced to 7.5 mol % at
the expense of the isolated yield (Table 1, entry 11).
Having established the right set of conditions, we proceeded
to explore the robustness of the protocol with respect to the
ring substituents of the substrate. It was found that a range of
substituents could be accommodated without any serious
compromise in the reaction efficiency (Scheme 1, entries 3a−
t). Ortho substituents like methyl and chloro were tolerated,
Scheme 1. Exploration of the Substrate Scope of Aromatic
Amides
electronic nature of the N-substituent did not exert any crucial
influence, and a variety of substrates featuring alkyl/cycloalkyl,
benzyl (no competing trifluoroethylation was observed on the
phenyl ring on the handle), and amino acid residues were all
tolerated with no striking disparity. That being the case, it was
interesting to observe that increasing the steric bulk on the
heteroatom substituent had a positive influence on the reaction
efficiency (Scheme 2, entries 5f and 5j). Importantly, the
preservation of enantiopurity without loss was detected during
the coupling reaction (Scheme 2, entries 5j−l).Another vital
observation was the total lack of reactivity of an N,N-
disubstituted substrate (Scheme 2, entry 5e), hinting at the
B
DOI: 10.1021/acs.orglett.7b01859
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
indispensability of the N−H bond for the reaction to occur
(vide infra).
Scheme 4. Isotopic Studies in the Trifluoroethylation of 1a
Having established the substrate generality of the process, we
next performed a set of experiments to understand the
mechanistic course of the palladium-catalyzed transformation.
Cyclopalladated species are viable intermediates in directed C−
H functionalizations, and the first attempt was to exper-
imentally validate the operation of such a species under our
reaction conditions. In this direction, isolation of a potential
palladacycle that could be generated upon treatment of the
amide substrate with stoichiometric amounts of palladium
acetate in TFA was envisaged.8 To our delight, dimeric
palladacycle 6 could be isolated from the N-adamantyl-
substituted amide 4j (Scheme 3, eq 1). X-ray-quality crystals
On the basis of the mechanistic data gathered, a plausible
mechanism is proposed (Scheme 5). The protic acid TFA
Scheme 5. Plausible Mechanism
Scheme 3. Isolation of the Palladacycle and Its
Trifluoroethylation
were generated, thereby establishing the structural integrity of 6
supposedly activates the palladium catalyst through ligand
exchange,3n,10 and the activated catalyst then undergoes C−H
insertion assisted by the directing group to form cyclometalated
intermediate A (the feasibility of A to exist in equilibrium with
the N-palladated species A′ is a realistic possibility considering
the indispensability of the N−H bond in the substrate).10c The
strongly oxidizing conditions served by the presence of the
hypervalent iodonium reagent could enable the conversion of
the putative intermediate A to oxidatively added Pd(IV) species
B.8b,10c,11 Reductive elimination from B furnishes the product
and closes the catalytic cycle through regeneration of the active
Pd(II) oxidation state.
beyond dispute (Figure 1).9 As expected, the organopalladium
In summary, a palladium-catalyzed method for the direct
trifluoroethylation of aromatic amides has been developed. The
substrate scope has been elaborated, and sound mechanistic
data have been collected. The report adds to the nascent field
of direct fluoroalkylations, and future efforts will be channelled
toward expanding the strategy to other structural platforms.
Figure 1. Crystal structure of the dimeric palladacycle.
species 6 collapsed upon exposure to the alkyl electrophile 2,
forming the trifluoroethylated product 5j in 80% isolated yield
(Scheme 3, eq 2). That this step worked in the absence of
added TFA specifies the latter’s role in the reaction mechanism.
These experiments amply support a direct C−H alkylation
pathway and the intermediacy of a cyclopalladated species.
Intramolecular isotopic studies were then conducted with an
equimolar mixture of 1a and [D5]-1a (Scheme 4). Trifluor-
oethylation favored cleavage of the C−H bond over the C−D
bond, and a kinetic isotopic effect (KIE) of 1.98 was calculated
from the 1H NMR spectra. The presence of a KIE indicates that
the breakage of the C−H bond could well be a kinetically
relevant step in the mechanistic profile. The recovered starting
material 1a did not show any significant H/D exchange, which
is an indicator of a largely irreversible cyclometalation.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01859.
■
S
Experimental procedures and spectral data for all new
compounds (1H NMR, 13C NMR, HRMS) (PDF)
Crystallographic data for 6 (CIF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: teckpeng@ntu.edu.sg.
*E-mail: rnachen@ntu.edu.sg.
C
DOI: 10.1021/acs.orglett.7b01859
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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(8) For palladacycles that were isolated during directed C−H
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deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number 1542567.
Teck-Peng Loh: 0000-0002-2936-337X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Nanjing Tech University, Nanyang
Technological University, the Singapore Ministry of Education
Academic Research Fund (Tier 1: MOE2015-T1-001-070
(RG5/15) and MOE2014-T1-001-102 (RG9/14) to T.P.L.
and MOE2015-T1-001-098 (RG42/15) to G.C.), and the
Singapore National Research Foundation (NRF2015NRF-
POC001-024) to T.P.L.) for generous financial support. We
also thank Dr. Rakesh Ganguly for X-ray analysis.
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