Palladium-Catalyzed C-H Trifluoroethoxylation of N-Sulfonylbenzamides

Article abstract of DOI:10.1021/acs.orglett.7b01103

The trifluoroethyl aryl ethers are important motifs in drug molecules. However, a report devoted specifically to the study of transition-metal-catalyzed C-H trifluoroethoxylation has not been reported to date. A protocol of Pd(II)-catalyzed o-C-H trifluor

Full text of DOI:10.1021/acs.orglett.7b01103

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed C−H Trifluoroethoxylation of
N‑Sulfonylbenzamides
Long Yang,† Shangda Li,† Lei Cai,† Yongzheng Ding,† Lei Fu,† Zhihua Cai,† Huafang Ji,*,†
and Gang Li*,†,‡
‡
†Key Laboratory of Coal to Ethylene Glycol and Its Related Technology and State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
S
* Supporting Information
ABSTRACT: The trifluoroethyl aryl ethers are important
motifs in drug molecules. However, a report devoted specifically
to the study of transition-metal-catalyzed C−H trifluoroethox-
ylation has not been reported to date. A protocol of Pd(II)-
catalyzed o-C−H trifluoroethoxylation of a broad range of
benzoic acid derivatives (i.e., N-sulfonylbenzamides) has been
developed. This method is also applied to the formal synthesis of the drug molecule flecainide, wherein the first m-C−H
trifluoroethoxylation is also exemplified.
he distinctly important role of fluorinated organic
Scheme 1. Methods of Introducing the Trifluoroethoxyl
T
compounds in material sciences, pharmaceuticals, and
Group
agrochemicals has induced numerous efforts to develop effective
methods for introducing fluorine and fluorinated groups into
organic molecules.1,2 The trifluoroethyl aryl ether motif is widely
found in many drugs with enhanced bioavailability resulting from
the metabolic stability and distinct physicochemical properties
such as a high electron-withdrawing effect and significant
lipophilicity of the trifluoroethoxyl (CF3CH2O) group (Figure
1).3 Consequently, the development of an efficient method of
formation by the reaction of phenols with TFE mediated by
PhenoFluor (Scheme 1c).7 However, all the present methods
require the use of prefunctionalized aryl groups with hydroxyl,
halides, or boryl substituents. Herein, we report a method of
direct trifluoroethoxylation of benzoic acid derivatives (i.e., N-
sulfonylbenzamides) via o-C−H activation. Moreover, the first
m-C−H trifluoroethoxylation of a benzoic acid derivative is also
exemplified in the formal synthesis of flecainide.
In the past decade, transition-metal-catalyzed direct C−H
bond functionalization has emerged as a powerful tool for step-
and atom-economical synthesis of complex organic molecules.8,9
In particular, formation of C−O bonds through directed C−H
bond activation has been extensively investigated since Sanford’s
pioneering work of palladium-catalyzed directed C−H alkox-
ylation and acetoxylation of arenes employing PhI(OAc)2 as the
terminal oxidant.10 As one of the valuable C−O formation
methods, C−H alkoxylation has also been developed rapidly with
C(sp2)−H as well as C(sp3)−H bonds.10−12 However, only a few
isolated instances of C−H trifluoroethoxylation have been
reported to date (Scheme 1d).10a,13 In this work, we focus on the
Figure 1. Representative drug molecules with the CF3CH2O group.
introducing the CF3CH2O group onto arenes is of considerable
interest.4−7 One conventional method is trifluoroethylation of
phenols with trifluoroethyl iodide or mesylate via SN2 reactions
(Scheme 1a).4 However, this method requires elevated temper-
atures and suffers from competing β-fluorine eliminations.4c
Another method is the trifluoroethoxylation of aromatic halides/
nitrobenzenes using 2,2,2-trifluoroethanol (TFE) under basic
conditions at high temperatures via direct aromatic nucleophilic
substitution, which is limited to activated arenes/heteroarenes
(Scheme 1b).5 Other valuable routes are transition-metal-
catalyzed/-mediated cross-coupling reactions of aryl halides or
aryl boronic acids with TFE (Scheme 1b).6 Recently, the Ritter
group reported an interesting method of aryl trifluoroethyl ether
Received: April 12, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
investigation of alkoxylation using electron-deficient TFE with
various N-sulfonylbenzamides.
Our study began with extensive directing group optimization,
which led to N-nosylbenzamide 1a as the best substrate and N-
tosylbenzamides11d,14 as comparable candidates (Table 1). After
significant reduction of the yield (entry 14).16 Notably, addition
of TFA proved to be crucial as only a trace of product was
produced without TFA, while changing the loading of TFA did
not further increase the yield (entries 15−17). Finally, control of
the reaction concentration seemed to be important (entries 18
and 19), since the yields were diminished at lower or higher
reaction concentration (see the Supporting Information for more
substrate and condition screenings).
Table 1. Optimization of Reaction Conditions
With the optimized standard conditions in hand, we examined
the scope of this ortho-selective C−H trifluoroethoxylation
protocol with N-nosylbenzamides or N-tosylbenzamides
(Scheme 2). To our delight, ortho substituents such as
b
entry
variation from the standard condition
yield (%)
c
1
none
70 (62)
a
Scheme 2. Substrate Scope of o-C−H Trifluoroethoxylation
2
under argon instead of air
Pd(TFA)2 instead of Pd(OAc)2
Pd(TFA)2 instead of Pd(OAc)2
PdCl2 instead of Pd(OAc)2
AgOAc (3 equiv) instead of PhI(OAc)2
K2S2O8 instead of PhI(OAc)2
NFSI instead of PhI(OAc)2
add 20 mol % of Ac-Gly-OH
add 60 mol % of Ac-Gly-OH
add 60 mol % of Ac-Ile-OH
at 50 °C
57
c
3
70 (60)
d
4
9
5
0
6
0
7
0
8
40
58
58
37
60
49
31
2
9
10
11
12
13
14
15
16
17
18
19
at 90 °C
add 10 equiv of HFIP
no TFA
10 equiv of TFA
48
64
50
52
30 equiv of TFA
1.85 mL of TFE (0.05 M)
0.35 mL of TFE (0.2 M)
a
All reactions were carried out on a 0.1 mmol scale in 1 mL of solvents
(solvents include TFA and TFE) for 24 h, TFA (0.15 mL, 20 equiv).
b
1
The yield was determined by H NMR using CH2Br2 as the internal
c
d
standard. Isolated yield in parentheses. No TFA added. TFA,
trifluoroacetic acid; TFE, 2,2,2-trifluoroethanol; Ns, 4-nitrobenzensul-
fonyl (nosyl); NFSI, N-fluorobenzenesulfonimide; Gly, glycine; Ile,
isoleucine; HFIP, hexafluoro-2-propanol.
the reaction conditions were extensively optimized, we were
delighted to find that the desired trifluoroethoxylated product 2a
was obtained in 62% isolated yield at room temperature; no
substrate or other product such as acetoxylated benzamide was
observed, which may imply that partial decomposition of
substrate might occur in this challenging C−H trifluoroethox-
ylation (entry 1). Running the reaction under argon atmosphere
instead of air did not promote the reaction (entry 2). Use of
Pd(TFA)2 as the catalyst was also feasible and gave similar
isolated product (entry 3), but this reaction was almost shutdown
without TFA (entry 4). However, PdCl2 was not an effective
alternative catalyst (entry 5). Other oxidants were also
investigated. Weak oxidant AgOAc was not a viable oxidant
(entry 6). Strong oxidant potassium persulfate (K2S2O8) did not
afford any product either (entry 7), although NFSI was capable
of generating 40% of desired product (entry 8). Monoprotected
amino acid ligands that might promote C−H oxidation in the
literature and our previous study were also tested.15,16b However,
no improved yield was observed using such ligands with different
loadings (entries 9−11). Surprisingly, inferior reaction perform-
ance was observed when the reaction temperature was increased
to 50 or 90 °C possibly due to more decomposition of the
substrate at higher temperature (entries 12 and 13). The addition
of potential promoter hexafluoro-2-propanol only led to a
a
Reaction conditions: 1 (0.1 mmol), Pd(OAc)2 (0.01 mmol),
PhI(OAc)2 (0.2 mmol), TFA (2.0 mmol, 0.15 mL), TFE (0.85
mL), 24 h, rt, under air. Isolated yields were reported. Isolated yield
in a 1.0 mmol scale. 50 °C. Ac-Gly-OH (60 mol %). TFA (15
equiv). TFA (5 equiv).
b
c
d
e
f
electron-donating methyl groups and electron-withdrawing
halides were tolerated, producing good yields of o-trifluoroe-
thoxylated products (2b−e). It should be noted that a higher
temperature of 50 °C was required for some substrates during
expantion of the substrate scope (2c, 2e, and 2g−s). Satisfactory
results were also obtained with meta-substituted substrates,
affording the desired products in moderate yields (2f−h).
Pleasingly, the reaction was also compatible with various para-
substituted compounds (2i−m). Notably, multiple disubstituted
substrates reacted smoothly to give desired products in moderate
to good yields (2n−s). Importantly, the chloro and bromo
substituents are tolerated in the reaction for several substrates,
enabling further elaboration of the trifluoroethoxylated products
at the respective halogenated sites.
B
DOI: 10.1021/acs.orglett.7b01103
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To showcase the utility of this new method, we executed a
formal synthesis of flecainide, that is used to prevent and treat
tachyarrhythmias (Scheme 3). The synthesis started with
with [Pd(O2CCF3)]+. Oxidation of palladacycle A with PhI-
(OAc)2 followed by subsequent ligand exchange of the resulting
complex B produces a Pd(IV) intermediate C. Finally,
palladacycle C undergoes reductive elimination to generate the
desired product 2 and [Pd(O2CCF3)]+. Alternatively, a Pd(II)/
Pd(III) catalytic cycle could not be excluded at the current
stage.21
Scheme 3. Formal Synthesis of Flecainide via C−H Activation
In conclusion, we have developed a protocol for Pd(II)-
catalyzed ortho-C−H trifluoroethoxylation of a broad range of N-
sulfonylbenzamides. Moreover, the first meta-C−H trifluoroe-
thoxylation was also proved to be viable in the formal synthesis of
flecainide. Given the importance of the trifluoroethoxyl group in
promoting bioavailability of organic molecules in medicinal
chemistry, we anticipate that this reaction would be of
considerable interest in drug discovery. Studies on site-selective
C−H trifluoroethoxylation of other classes of substrates are
underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01103.
Experimental procedures, characterization data, and NMR
spectra (PDF)
conversion of 2a to 2-(2,2,2-trifluoroethoxy)benzoic acid (3)
in two steps under mild conventional conditions.17 Then a meta-
directing group developed by us for meta-C−H functionalization
of benzoic acids was attached to acid 3 to afford intermediate
5.16b Much to our delight, substrate 5 underwent meta-C−H
oxygenation to give desired product 6 as well as acetoxylated
product 7 smoothly. Notably, to the best of our knowledge, this is
the first direct meta-C−H trifluoroethoxylation of an arene.16b,18
Finally, both 6 and 7 could be transformed to ester 8, a precursor
of flecainide, in high yields, thus providing an alternative
synthetic route for felcainide.19 It should be noted that our
method is potentially applicable for the synthesis of flecainide
derivatives with other substituents on the arene, which is difficult
to achieve in the reported methods but is important in medicinal
chemistry and drug discovery.19
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: jihuafang@fjirsm.ac.cn.
*E-mail: gangli@fjirsm.ac.cn.
ORCID
Gang Li: 0000-0001-5229-554X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from NSFC
(Grant No. 21402198), the Strategic Priority Research Program
of the Chinese Academy of Sciences (Grant No.
XDB20000000), the 100 Talents Program of Fujian Province,
and The National 1000 Youth Talents Program.
Based on the above results, a plausible catalytic cycle for this
ortho-trifluoroethoxylation reaction is proposed in Scheme 4.
First, a reactive cationic Pd(II) species is generated from
Pd(OAc)2 with TFA.20 Then the palladacyclic intermediate A is
generated from benzamide 1 via C−H bond activation catalyzed
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