Silver-Mediated N-Trifluoromethylation of Amides and Peptides

Article abstract of DOI:10.1002/cjoc.202000132

We report herein the direct N-trifluoromethylation of N-H amides. Promoted by AgOTf and 2-fluoropyridine, the reaction of a variety of amides with Selectfluor, TMSCF₃ and CsF proceeds smoothly at room temperature leading to the corresponding N-trifluoromethylated products in satisfactory yields. The protocol is also applicable to amino acid derivatives, resulting in efficient and chemoselective N-trifluoromethylation of di- and tri-peptides with retention of configuration. A mechanism involving reductive elimination of Ag(III) intermediates to form N—CF₃ bonds is proposed.

Full text of DOI:10.1002/cjoc.202000132

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Accepted Article
Title: Silver-Mediated N-Trifluoromethylation of Amides and Peptides
Authors: Zhenzhen Zhang, Jiayan He, Lin Zhu, Haiwen Xiao, Yewen Fang,* and
Chaozhong Li*
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Keyword 1, Keyword 2, Keyword 3, Keyword 4, Keyword 5, Keyword 6
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Silver-Mediated N-Trifluoromethylation of Amides and Peptides
Zhenzhen Zhang, Jiayan He, Lin Zhu, Haiwen Xiao, Yewen Fang,* and Chaozhong Li*, a, b
a
a
a
a
, b
a
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032
b
School of Materials and Chemical Engineering, Ningbo University of Technology, 201 Fenghua Road, Ningbo 315211
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
We report herein the direct N-trifluoromethylation of N-H amides. Promoted by AgOTf and 2-fluoropyridine, the reaction of a variety of amides with
Selectfluor, TMSCF and CsF proceeds smoothly at room temperature leading to the corresponding N-trifluoromethylated products in satisfactory yields.
3
The protocol is also applicable to amino acid derivatives, resulting in efficient and chemoselective N-trifluoromethylation of di- and tri-peptides with
retention of configuration. A mechanism involving reductive elimination of Ag(III) intermediates to form N–CF bonds is proposed.
3
Trifluoromethyl groups exhibit a profound effect in properties
such as lipophilicity, permeability and metabolic stability, and
thus serve as important structural motifs in pharmaceuticals,
agrochemicals and materials. Trifluoromethylation of organic
molecules has therefore received considerable attention in the
isothiocyanates, bis(trichloromethyl) carbonate and AgF to
generate N-trifluoromethylcarbamoyl fluorides, which then
engaged in the reaction with Grignard reagents to provide N-
[
9]
trifluoromethylated amides.
These indirect syntheses are not
suitable for late-stage modification of amides. Direct N-
trifluoromethylation of N-H amides should be highly desirable
given the low cost and easy availability of amides. However, there
have been no reports to date of methods in his aspect. The few
available procedures of electrophilic or radical N-
[
1]
past decades. However, the research in this field mainly focuses
[1]
on C–CF
3
bond formations. As a comparison, construction of N–
CF bonds remains challenging. N-Trifluoromethyl amines are
3
typically prepared indirectly by reaction of dithiocarbamates,
thiocarbamoyl fluorides, formamides or related compounds with
[4, 5]
trifluoromethylation mentioned above
amides either. Also note that N-CF amides are unlikely to be
prepared from secondary N-CF amines due to the instability and
are not applicable to
fluorinating reagents such as SF
4
, dialkylaminosulfur trifluorides
3
[2, 3]
or AgF.
These approaches suffer from either harsh reaction
3
conditions, the use of toxic reagents or poor functional group
compatibility. Meanwhile, methods for direct introduction of CF
groups onto nitrogen atoms are rare and limited to electrophilic
fast HF extrusion of the later. Herein we report the silver-
mediated, direct N-trifluoromethylation of N-H amides and
peptides (Scheme 1).
3
[4]
[5]
or radical N-trifluoromethylation of pyridines, azoles, imines or
sulfoximines. The underdevelopment of N–CF chemistry may
also be attributed to the low stability of N-CF amines that are
3
3
Scheme 1 Synthesis of N-(trifluoromethyl)amides
prone to fluorine elimination because of the n(N)→σ*(C–F)
electron donation. Aromatic and/or electron-withdrawing
substitutions are generally required to make the amines isolable.
O
O
R1
MgBr
O
BrF3
2
R
R2
R2
R1
N
R1
N
F
N
3
However to our surprise, N-CF -substituted amides that are far
Ref. 8
Ref. 9
CF3
CF3
more stable than N-CF amines are far less explored. Yet, among
3
EtS
S
indirect
indirect
the known N-(trifluoromethyl)amides, some exhibit important
biological activities such as high anti-fungal or anti-HIV
this work
direct
Ag(I),
Selectfluor
TMSCF CsF, RT
,
3
(
)
[6]
properties, or serve as useful electrolyte additives for
[
7]
batteries. Of the few relevant synthetic reports, Rozen and
O
coworkers described the synthesis of N-(trifluoromethyl)amides
R2
R1
N
[
8]
3
by fluorination of N-acyldithiocarbamates with BrF (Scheme 1).
H
Very recently, the Schoenebeck group introduced the reaction of
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First author et al.
a
As a start, we selected N-methylbenzamide (1a) as the model
substrate to explore the N-trifluoromethylation. After an
The reaction was carried out at 0.20 mmol scale in DCM (3.0 mL)–PhCl
b
(1.0 mL) solution. Isolated yield based on 1a.
extensive search of reaction conditions (see Tables S1–S7 in the
Supporting Information for details), we were pleased to find that
the reaction of 1a, AgOTf (1.1 equiv), 2-fluoropyridine (1.1 equiv),
Selectfluor (1-chloromethyl-4-fluorodiazoniabicyclo[2,2,2]octane
With the optimized conditions in hand (entry 1, Table 1), we
set out to examine the scope of the method. As shown in Scheme
2, a number of N-methylbenzamides with either electron-
withdrawing or electron-donating substituents on the aromatic
ring all underwent N-trifluoromethylation, providing the expected
products 2b–2o in satisfactory yields. Benzamides with different
N-alkyl-substitutions also participated in the reaction to afford
the corresponding products 2p–2s. The protocol was also
applicable to a variety of N-alkylalkanamides, as exemplified by
the synthesis of 2t–2x. N-Arylamides could also be used as
[10]
[11]
bis(tetrafluoroborate)) (4 equiv), Ruppert–Prakash reagent
TMSCF , 5 equiv) and CsF (5 equiv) in dichloromethane –
(
3
chlorobenzene (3:1) solution at room temperature furnished the
expected N-trifluoromethylation product 2a in 74% isolated yield
(
entry 1, Table 1). Lowering the amount of Selectfluor to two
equivalents led to a lower yield of 2a, while no 2a could be
observed without Selectfluor (entries 2 and 3, Table 1). Switching
the oxidant Selectfluor to N-fluorobis(benzenesulfonyl)imide
(
1
bipyridine) or (bpy)Cu(CF )
3 3
(
3
substrates to give N-CF amides such as 2y, albeit in a low
[12]
efficiency. The presence of a range of functional group was
tolerated by the process. For example, ethers, ketones, esters,
nitriles and aryl halides (F, Cl, Br) all proved to be compatible with
the reaction. The broad substrate scope enabled late-stage
modification of complex molecules, as evidenced by the efficient
synthesis of 2z1–2z3. Nevertheless, the method had its limitation
in that N-tert-butyl-substituted amides or lactams failed to
produce the corresponding products (such as 2z4 and 2z5) under
the optimized conditions, and the reason remained unclear.
However, a brief survey on N-nucleophiles other than amides
revealed that N-trifluoromethylation of phosphonamides and
sulfonamides (to give 2z6 and 2z7) could also be achieved under
the same conditions as above without further optimization. These
results further expanded the substrate scope of the reaction.
NFSI) resulted in a sharp drop in product yield (entry 4, Table
). Changing the CF source to (bpy)Zn(CF (bpy = 2,2’-
yielded no desired product
entries 5 and 6, Table 1). The silver salt AgOTf proved to be
3
3 2
)
[13]
[14]
essential for the transformation, as evidenced by control
experiments (entries 7 and 8, Table 1). As a comparison, the use
of Cu(OTf)
2
in place of AgOTf failed to give any product 2a (entry
9
, Table 1). In addition, a suitable ligand was also required for the
reaction (entry 10, Table 1), and 2-fluoropyridine turned out to be
superior over other ligands screened (see Table S2 in SI). Finally,
3
reducing the loading of TMSCF or CsF decreased the yield of 2a
(
see Table S7 in SI).
Table 1 Optimization of reaction conditions
"
standard conditions":
equiv)
O
O
AgOTf (1.1
Selectfluor (4 equiv)
conditions
Me
Me
Ph
N
Ph
2a
N
2
-fluoropyridine (1.1 equiv)
H
CF3
TMSCF (5 equiv), CsF (5 equiv)
1a
3
DCM/PhCl (3:1), RT, 24 h
Entrya
Conditions
None
Yield (%) b
1
2
3
4
5
6
7
8
9
74
58
0
Less Selectfluor (2 equiv) used
Without Selectfluor
NFSI in place of Selectfluor
14
0
(bpy)Zn(CF
3
)
2
in place of TMSCF
3
/CsF
(bpy)Cu(CF
3
)
3
in place of TMSCF
3
/CsF
0
Less AgOTf (0.5 equiv) used
Without AgOTf
25
0
Cu(OTf)
2
in place of AgOTf
0
1
0
Without 2-fluoropyridine
< 5
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
Scheme 2 N-Trifluoromethylation of amides[a]
3
phenylalaninate proceeded nicely providing the N-CF amide 3c in
an excellent yield with retention of configuration. Moreover,
when glycosyl N-acylphenylalaninate as a diastereomeric mixture
2
2c
b
= p
62%
2h
2i
= p-OBn), 53%
= p-OMe), 70%
= m-Me), 60%
(
R
-F),
(R
(R
O
= p-Cl), 61%
= p-Br), 70%
(R
(
37:63) was subjected to the optimized conditions, the
2d
Me
(R
2j (R
N
2e
=
p-CN), 63%
2k
2l
2m
=
m
-Br), 66%
= o-OMe), 41%
corresponding product 3d was obtained in the same
(R
(R
(R
R
-
CF3
2f (R = p CF ), 76%
diastereomeric ratio, thus confirming that the N-
3
2g
= p-Me), 72%
= p-CO2
78%
(R
(R
Me),
trifluoromethylation had no influence on the stereochemistry.
Interestingly, N-Boc-protected N’-cyclohexyl-valinamide engaged
in the trifluoromethylation leading to the exclusive formation of
O
O
O
Me
Me
O
N
N
N
N’-CF amides 3e while the NHBoc moiety remained intact. The
3
CF3
CF3
O
CF
2p, 52%
inertness of carbamates in the reaction was further demonstrated
by the failure of naphthalene-1-yl methylcarbamate towards N-
trifluoromethylation under the above optimized conditions. This
unique chemoselectivity paved the road for selective N-
trifluoromethylation of peptides. For example, the reaction of
dipeptide Boc-Phe-Gly-OEt afforded the trifluoromethylated
3
2n, 56%
2o, 69%
O
O
O
N
N
N
CF3
CF3
CF3
2s, 66%
F
2
q, 58%
2r, 63%
product 3f in 63% yield. Analogously, Boc-Phg-Phe-NMe was
2
transformed into Boc-Phg-N-CF
3
-Phe-NMe
2
(3g) highly efficiently.
O
N
O
O
O
t
In a similar fashion, N-Cbz-protected Ala-Gly-O Bu was converted
Me
Ph
2v, 59%
OCF3
t
Ph
Ph
2u, 57%
N
N
to Cbz-Ala-N-CF -Gly-O Bu (3h). The strategy could be further
3
CF3
CF3
CF3
applied to the N-trifluoromethylation of tripeptides. As an
example, N-CF tripeptide 3i was readily achieved from Boc-Gly-
3
Ile-Glu-OBn in a high efficiency. Thus the method offers a
convenient route to late-stage modification of polypeptides.
2
t, 54%
MeO
O
O
Me
N
N
N
CF3
2w, 65%
CF3
2x
, 47%
CF3 2y
, 34%
Scheme 3 N-Trifluoromethylation of α-amino acid derivatives[a]
O
O
CF3
N
O
CF3
N
O
CF
N
3
O
O
O
O
O
Me
R
N
O
H
H
OEt
OMe
O
N
O
H
Me
CF3
CF3
O
O
O
Cl
N
Ph
Ph
O
H
3a
=
85%
(R
Ph),
2
z, 54%
O
-
3d, 75%[b]
3b
= n C H
60%
3c, 94%
(
R
5
11),
2z1, 40%
acid derivative)
(
dehydrocholic
Ph
Ph CF3
N
O
O
O
Boc
O
N
CF3
O
O
O
N
HN
O
N
HN
Boc
N
Me
Ph
N
HN
OEt
N
O
CF3
CF
e, 66%
3
Boc
O
Ph
CF
3
CF3
O
3
3f, 63%
3g, 87%
2
z3, 66%
2
z2, 56%
derivative)
2z4, 0%
(isoxepac
(
mexiletine derivative)
O
Me CF3
N
O
O
O
OBn
CF3
O
O
O O
BnO
N
O
N
S
Me
PhO
Me
P
N
OPh
H
BocHN
3i, 72%
N
N
Ph
N
O
O
CF3
CF3
CF3
3h, 40%
2z5, 0%
2z6, 19%
2z7, 16%
a
See Scheme 2. b d.r. = = 37:63 for both 3d and its precursor.
a
Reaction conditions: 1 (0.20 mmol), AgOTf (0.22 mmol), 2-fluoropyridine
0.22 mmol), Selectfluor (0.80 mmol), TMSCF (1.00 mmol), CsF (1.00
(
3
mmol), DCM (3.0 mL), PhCl (1.0 mL), rt, 24 h. Isolated yield based on 1.
To gain further insight into the N-trifluoromethylation, the
following mechanistic experiments were carried out. The reaction
of N-cyclopropylhexanamide (4) under the optimized conditions
afforded the N-trifluoromethylated product 5 in 61% yield while
no ring-opening products could be detected (eq 1). This radical
clock experiment pointed out that amidyl radicals were unlikely to
be involved in the N-trifluoromethylation. A careful examination
on the reactions of N-alkylamides leading to 2s and 2v showed
We then extended the method to the N-trifluoromethylation
of α-amino acid derivatives. Given the vital role of α-amino acids
and peptides in life sciences, their N-CF derivatives should be an
3
interesting target in biological and medicinal chemistry. As
illustrated in Scheme 3, ethyl N-Benzoylglycinate underwent
smooth N-trifluoromethylation furnishing the corresponding
product 3a in a high yield. The N-hexanoyl analog 3b could also be
produced similarly. The reaction of methyl N-acyl-L-
[13b]
that no remote aliphatic or benzylic C–H trifluoromethylation
Chin. J. Chem. 2019, 37, XXX－XXX
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Report
First author et al.
byproducts could be observed, also suggesting that amidyl
radicals capable of 1,5-H abstraction were not generated under
the experimental conditions. Furthermore, control experiments
revealed that, in the absence of an amide substrate, the reaction
[
(CF
3
)
4
Ag(III)]
TMSCF
/CsF
3
TMSCF /CsF
Selectfluor
3
AgOTf
Ag(I)
F
3
C
Ag(I)
F
C
3
Ag(III)
[15]
-
produced the complex [(CF
demonstrated by F NMR analysis. Subsequent addition of amide
3
)
4
Ag(III)] exclusively, as
2-fluoropyridne
F
A
19
O
1
a into the resulting solution yielded no product 2a, indicating
R2
-
O
that the stable [(CF
3
)
4
Ag(III)] complex was not the active species
reductive
elimination
O
R1
N
R2
R2
responsible for the N-trifluoromethylation. On the other hand, 9F
1
+
R1
1
N
R
N
NMR monitoring on the N-trifluoromethylation of 1a showed
CF3
F3C
Ag(III)
B
that, along with the increasing formation of product 2a, the
-
[
3
(CF )
4
Ag(III)] complex was also accumulated, implying that the
X
two processes were competing with each other (see SI for
details).
=
O)
O
N
(X
C,
C
F3C
Ag(III)
Figure 1 Proposed mechanism.
O
O
standard conditions
In conclusion, we have successfully developed the silver-
mediated N-trifluoromethylation of N-H amides, providing a
(1)
N
N
H
4
5, 61% CF3
straightforward access to N-CF amides. The unprecedented
3
protocol also enables the efficient and chemoselective N-
trifluoromethylation of polypeptides. As the procedure is
operationally simple and the conditions are mild, the method
should find application in the synthesis of important N-
trifluoromethylated molecules.
A plausible mechanism is then proposed as depicted in Figure
-
1
. Interaction of AgOTf with 2-fluoropyridine and CF
derived from TMSCF /CsF generates Ag(I)–CF
that is then oxidized by Selectfluor to give the Ag(III)–CF
3
anion
3
intermediate
[
16]
3
3
species
3
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
[
17, 18]
-
A.
In the meantime, deprotonation of an amide by CF
anion
gives the corresponding amidyl anion. Ligand exchange of A with
the amidyl anion produces the Ag(III)-complex B, which
undergoes reductive elimination to provide the N-
Acknowledgement
This project was supported by the National Natural Science
Foundation of China (Grants 21421002, 21532008, 21871285 and
-
2
1971253), by the Chinese Academy of Sciences (Grants
XDB20020000 and ZDBS-LY-SLH026) and by Zhejiang Provincial
Natural Science Foundation of China (Grant LY20B020008).
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© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
3
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www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
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Entry for the Table of Contents
Page No.
Silver-Mediated N-Trifluoromethylation of
Amides and Peptides
,
Selectfluor
Ag(I)
TMSCF , CsF, RT
O
O
3
R2
R2
R1
N
R1
N
H
CF3
direct N-trifluoromethylation
retention of
configuration
to
applicable peptides
chemoselective
Direct and chemoselective N-trifluoromethylation of amides and peptides was achieved under
mild conditions with retention of configuration.
Zhenzhen Zhang, Jiayan He, Lin Zhu, Haiwen
Xiao, Yewen Fang,* Chaozhong Li*
a
c
Department, Institution, Address 1
Department, Institution, Address 3
E-mail:
E-mail:
b
Department, Institution, Address 2
E-mail:
Chin. J. Chem. 2018, template
© 2018 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA,
Weinheim
This article is protected by copyright. All rights reserved.