Silver(I)-Catalyzed N-Trifluoroethylation of Anilines and O-Trifluoroethylation of Amides with 2,2,2-Trifluorodiazoethane

Article abstract of DOI:10.1002/anie.201507219

A straightforward N-trifluoroethylation of anilines has been developed based on silver-catalyzed N￡H insertions with 2,2,2-trifluorodiazoethane (CF₃CHN₂). Mechanistically, the reaction is proposed to involve migratory insertion of a silver carbene as the key step. In contrast, when amides are employed as the substrates under similar reaction conditions, O-trifluoroethylation occurs to afford trifluoroethyl imidates.

Full text of DOI:10.1002/anie.201507219

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Chemie
International Edition: DOI: 10.1002/anie.201507219
German Edition: DOI: 10.1002/ange.201507219
Carbenes
Silver(I)-Catalyzed N-Trifluoroethylation of Anilines and
O-Trifluoroethylation of Amides with 2,2,2-Trifluorodiazoethane
Haiqing Luo, Guojiao Wu, Yan Zhang, and Jianbo Wang*
Abstract: A straightforward N-trifluoroethylation of anilines
À
has been developed based on silver-catalyzed N H insertions
with 2,2,2-trifluorodiazoethane (CF3CHN2). Mechanistically,
the reaction is proposed to involve migratory insertion of
a silver carbene as the key step. In contrast, when amides are
employed as the substrates under similar reaction conditions,
O-trifluoroethylation occurs to afford trifluoroethyl imidates.
B
ecause of their importance in various fields, fluorine-
containing organic compounds have attracted significant
attention over the decades and enormous effort has been
devoted to their synthesis.[1] In this context, the methods for
trifluoromethylation have been extensively investigated,[2]
while the related 2,2,2-trifluoroethylation still lags behind.[3]
In contrast, aniline moieties are commonly found in pharma-
ceuticals, agrochemicals, and pigments.[4] The introduction of
a 2,2,2-trifluoroethyl group on the amino group of aniline is
important because the anilines bearing electron-withdrawing
substituents are expected to resist the oxidative degradation,
a vital issue in medicinal chemistry as well as in agrochem-
istry. Consequently, N-trifluoroethylated aniline or amide
moieties have been found in some drugs and drug candi-
dates.[5] However, the methods for N-trifluoroethylation of
anilines are less well developed, and significantly limits the
exploration of N-trifluoroethylated anilines in the pharma-
ceutical and agrochemical industries.
Scheme 1. Strategies to access N-trifluoroethylated anilines.
Although progress has been made in N-trifluoroethylation
of anilines, in view of the importance of such types of fluorine-
containing molecules and the limitation of the reported
methods, it is still highly desirable to develop alternative and
straightforward approaches.
Recently, 2,2,2-trifluorodiazoethane (CF3CHN2) has
emerged as an attractive CF3-containing synthon in various
reactions such as cyclopropanation,[11] cyclopropenation,[12]
1,3-dipolar cycloaddition,[13] a-trifluoromethylation of orga-
noborons,[14,3e] and trifluoroethylation of terminal alkynes,[15]
and other reactions.[16] Those transformations represent some
unique and efficient methods for the synthesis of fluorine-
The early efforts for N-trifluoroethylation of anilines were
focused on the nucleophilic substitution of aniline with
trifluoroethyl chloride at elevated temperatures (up to
2508C).[6] In 1986, Umemoto and co-workers reported
a method to achieve N-trifluoroethylation by using a hyper-
valent-iodine–CH2CF3 reagent.[7] The recently reported meth-
ods include SNAr reactions[8] and reductive amination reac-
tions using trifluoroacetaldehyde (Scheme 1a,b).[9] Very
recently, Hartwig and co-workers reported a palladium-
catalyzed arylation of trifluoroethylamine with aryl bromides
and aryl chlorides, thus providing an efficient approach to N-
trifluoroethylated aniline derivatives (Scheme 1c).[10]
À
containing molecules. Notably, N H insertions, which are
typical in metal carbene reactions,[17] have not been explored
with CF3CHN2 as the carbene precursor. In view of the
importance of N-trifluoroethylated anilines and also as
a continuation of our interest in metal carbene chemistry,
we report herein the silver(I)-catalyzed N-trifluoroethylation
of anilines and O-trifluoroethylation of amides (Scheme 1d).
At the outset, a CF3CHN2 solution in toluene was
prepared from commercially available CF3CH2NH2·HCl,
according to the method reported by Carreira and co-
workers.[12] Subsequently, we investigated the N-trifluoro-
ethylation of ethyl 4-aminobenzoate (1a) with the stock
toluene solution of CF3CHN2 at 508C and 1,2-dichloroethane
(DCE) as the solvent. A series of metal catalysts, including
CuI, FeCl2, FeCl3, [{Cp*RhCl2}2], [Rh2(OAc)4], [{Cp*IrCl2}2],
and various silver(I) salts were examined (Table 1, entries 1–
8). FeCl2, AgBF4, AgPF6, and AgSbF6 were found to be
effective, thus affording the desired product 2a in moderate to
good yields. Among these salts, AgSbF6 turned out to be the
best catalyst for the reaction (entry 5). The effect of solvent
was then investigated (entries 9–14), and toluene, CH2Cl2,
[*] Dr. H. Luo, G. Wu, Y. Zhang, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry, Peking University
Beijing 100871 (China)
E-mail: wangjb@pku.edu.cn
Dr. H. Luo
Department of Chemistry & Chemical Engineering, Gannan Normal
University, Ganzhou 341000 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507219.
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Table 1: Optimization of reaction conditions for the N-trifluoroethylation
of 1a with CF3CHN2.[a]
Entry
Catalyst
[mol%]
Solvent
T
[8C]
Yield
[%][b]
1
2
3
4
5
6
7
8
cat. (x)[c]
[Rh2(OAc)4] (2)
FeCl3 (5)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
CH2Cl2
CHCl3
MeCN
acetone
MeOH
DCE
50
50
50
50
50
50
50
50
50
50
50
50
50
50
35
40
60
0
5
trace
46
93
78
67
trace
18
46
48
0
0
0
0
88
65
FeCl2 (5)
AgSbF6 (5)
AgBF4 (5)
AgPF6 (5)
AgOTf (5)
AgSbF6 (5)
AgSbF6 (5)
AgSbF6 (5)
AgSbF6 (5)
AgSbF6 (5)
AgSbF6 (5)
AgSbF6 (5)
AgSbF6 (5)
AgSbF6 (5)
9
10
11
12
13
14
15
16
17
DCE
DCE
[a] Unless otherwise noted, the reaction conditions are as follows: 1a
(0.3 mmol), CF3CHN2 solution in toluene (0.45 mmol), DCE (3.5 mL).
[b] The yield was determined by 19F NMR spectroscopy by using PhCF3 as
the internal standard. [c] cat. (x)=CuI (5), [{Cp*RhCl2}2] (2), [{Cp*IrCl2}2]
(2), AgNO3 (5), AgOAc (5), AgSO3Me (5), AgF (5), Ag2O (5).
Cp*=C5Me5, DCE=1,2-dichloroethane.
and CHCl3 were found to be suitable for the reaction.
However, no desired product could be detected by using polar
solvents, such as MeCN, acetone, and MeOH. Furthermore,
the reaction temperatures (entries 15–17) were examined and
the results revealed that the reaction carried out at 508C
offered the optimal results. It was noted that no desired
product could be observed when the reaction temperature
was reduced to 358C (entry 15).
With the optimized reaction conditions in hand,[18] we
then proceeded to expand the scope with respect to the
substrates with a series of functionalized aniline derivatives.
As summarized in Scheme 2, in general moderate to excellent
yields were obtained under the optimized reaction conditions.
The N-trifluoroethylation has shown excellent tolerance to
both electron-withdrawing and electron-donating groups as
aromatic substituents, including ester (2a), nitro (2b, 2n, 2t),
trifluoromethyl (2c), alkane (2p, 2q, 2r, 2t), aryl (2r),
methoxy (2u), and azo (2v) groups. The diminished yield in
the case of 2u may be attributed to deactivation by the
methoxy substituent, presumably caused by the coordination
of the lone pair of the methoxy group with the silver cation.
Notably, the reaction tolerates halogen substituents on the
aromatic rings, including fluoro (2d, 2m, 2n, 2w–y), chloro
(2e, 2g, 2k), bromo (2 f, 2l), and iodo (2h–m) groups.
Essentially no steric effect was observed as shown by the
reactions with para-, ortho-, and meta-iodo anilines as the
substrates (2h–j). In addition, the reaction with poly-fluo-
roanilines also afforded the desired product in good yields. In
Scheme 2. Silver(I)-catalyzed N-trifluoroethylation of aniline derivatives
with CF3CHN2. Unless otherwise noted, the reaction conditions are as
follows 1a (0.3 mmol), CF3CHN2 solution in toluene (0.45 mmol), DCE
(3.0 mL). All the yields refer to those of the isolated products unless
otherwise noted. [a] Yield determined by 19F NMR spectroscopy. Ther-
mal ellipsoids shown at 30% probability.
the case of 2y the yield of the isolated product was diminished
and attributed to the volatility of the products. The reaction
showed 72% yield as determined by 19F NMR spectroscopy.
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The structure of 2g was unambiguously confirmed by the X-
ray crystallographic analysis.[19]
Furthermore, we applied the same protocol to the syn-
thesis of N-trifluoroethylated amide derivatives. To our
reaction mechanism (see below). Then CF3CHN2 in toluene
was added and the mixture was stirred at 508C for 30 minutes.
The color of the mixture turned from yellow to grey, and was
accompanied by the extrusion of N2 from the solution. A
standard work up afforded 2a in 90% yield upon isolation.
Next, intramolecular competition experiments were car-
ried out between 1a and 1r [Eq. (1)]. The mixture was stirred
under the standard reaction conditions and the reaction was
terminated after 10 minutes. Inspection of the crude reaction
mixture by 19F NMR spectroscopy showed that the ratio of 2a
to 2r was approximately 1:61, thus clearly indicating that the
reaction with the aniline bearing an electron-donating
substituent is favored over that bearing an electron-with-
drawing substituent.
À
surprise, the expected N H insertion products were not
observed, and instead, O-trifluoroethylation occurred to
afford trifluoroethyl imidates. As summarized in Scheme 3,
Finally, we attempted the trapping of the possible Ag/
carbene intermediate through cyclopropanation. Thus, in the
presence of catalytic amount of 1a and AgSbF6, styrene (5)
was subjected to the reaction with CF3CHN2 under the
standard reaction conditions. The anticipated cyclopropana-
tion product 6 was not observed, but the N-trifluoroethylation
product 2a formed in 65% yield based on the amount of
added 1a [Eq. (2)]. In the absence of 1a, the same trapping
reaction also did not show the formation of 6.
Scheme 3. Silver(I)-catalyzed O-trifluoroethylation of amides with
CF3CHN2. Unless otherwise noted, the reaction conditions are as
follows: 3a–i (0.3 mmol), CF3CHN2 solution in toluene (0.60 mmol),
DCE (3.5 mL). All the yields refer to the isolated products. Thermal
ellipsoids shown at 30% probability.
in general the reactions occurred smoothly under similar
reaction conditions, thus affording products bearing
OCH2CF3 groups in good to excellent yields. The results
indicate that the reaction of the substrates bearing electron-
withdrawing groups on aromatic rings (4d–g) affords slightly
higher yields than those bearing electron-donating groups
(4b,c). The reaction with N-phenyl-substituted benzamide
afforded the product 4i in 98% yield. The structures of 4d
and 4i were unambiguously confirmed by the X-ray crystallo-
graphic analysis.[19]
To gain insight into the reaction mechanism, some control
experiments have been carried out. First, when a clear
solution of 1a in toluene was added dropwise to a clear
solution of AgSbF6 in toluene at room temperature, the
solution turned turbid and a white suspension quickly
precipitated.[20] This observation indicates the possible for-
mation of an AgI/aniline complex as shown in the proposed
Based on these experimental observations, a plausible
mechanism is proposed as shown in Scheme 4. The aniline
derivatives 1 firstly react with Ag+ to form the AgI/aniline
complex A. Then, the reaction of CF3CHN2 with A produces
the AgI/carbene intermediate B.[21,22] Migratory insertion of
the amine ligand to the carbenic carbon atom gives the
intermediate C, from which protonation affords the N-
trifluoroethylated product 2. For O-trifluoroethylation of
amides, a similar mechanism is proposed. In this case, the AgI/
imidate complex A’ is favored because of the relatively hard
basicity of the oxygen atom relative to the nitrogen atom.
Imidate ligand migration from the AgI/carbene intermediate
B’, followed by protonation affords the product 4.
Notably, for the N-trifluoroethylation of anilines, an
alternative mechanism cannot be ruled out, that is, the
À
direct insertion of a N H bond with Ag/carbene (or through
ylide formation and 1,2-H shift), as generally accepted for
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Scheme 4. Proposed reaction mechanism.
[17,20,22]
À
classic metal carbene N H insertions.
However, such
mechanism seems less likely in view of the control experiment
results as well as the O-trifluoroethylation in the case of
amide under the similar reaction conditions.
In summary, we have developed a silver-catalyzed N-
trifluoroethylation of anilines with CF3CHN2, which can be
generated from readily available CF3CH2NH2·HCl. Mecha-
À
nistically, this formal N H insertion reaction is proposed to
involve AgI/carbene formation and subsequent amine ligand
migratory insertion. With amides as the substrates, O-
trifluoroethylation products were obtained following a similar
reaction mechanism. Since the reaction conditions are mild
and the reaction tolerates various functional groups, this
novel tactic for trifluoroethylation may find useful applica-
tions in the drug discovery process in medicinal chemistry.[23]
[7] T. Umemoto, Y. Gotoh, J. Fluorine Chem. 1986, 31, 231.
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Experimental Section
General procedure for N-trifluoroethylation of aniline derivatives.
The aniline derivative (1a–y; 0.3 mmol) and AgSbF6 (0.015 mmol,
5.2 mg) were added to a Schlenk tube. 1,2-dichloroethane (3.0 mL)
and CF3CHN2 in toluene (about 0.85m, 0.45 mmol) were then added.
The resulting mixture was stirred at 508C for 0.5–5 h. Upon
completion of the reaction, the solvent was removed and the resulting
residue was purified by column chromatography on silica gel to afford
the N-trifluoroethylation products 2a–y.
[10] A. T. Brusoe, J. F. Hartwig, J. Am. Chem. Soc. 2015, 137, 8460.
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Acknowledgements
The project is supported by the National Basic Research
Program of China (973 Program, No. 2012CB821600) and
NSFC (Grant 21472004 and 21332002).
Keywords: amides · aniline · carbenes · diazo compounds ·
silver
À
[17] For selected examples of carbene N H insertions, see: a) S.
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[23] We have also attempted the O- and S-trifluoroethylation with
phenol and thiophenol under similar conditions. The corre-
sponding products could be identified by GC-MS. However, the
reactions were not efficient. Further optimization of the reaction
conditions is under way.
[18] We have also tried the N-trifluoroethylation reaction by in situ
generation of CF3CHN2, however, no desired product could be
obtained.
[19] CCDC 1414829, 1414830, and 1415161 contain the supplemen-
tary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[20] For details see the Supporting Information.
[21] For the examples of silver(I)-catalyzed reactions of diazo
compounds, see: a) H. V. R. Dias, R. G. Browning, S. A.
Polach, H. V. K. Diyabalanage, C. J. Lovely, J. Am. Chem. Soc.
Received: August 3, 2015
Revised: August 25, 2015
Published online: September 10, 2015
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