Iron porphyrin-catalyzedN-trifluoroethylation of anilines with 2,2,2-trifluoroethylamine hydrochloride in aqueous solution

Article abstract of DOI:10.1039/d1ra03379d

An iron porphyrin-catalyzedN-trifluoroethylation of anilines has been developed with 2,2,2-trifluoroethylamine hydrochloride as the fluorine source. This one-pot N-H insertion reaction is conductedviacascade diazotization/N-trifluoroethylation reactions.

Full text of DOI:10.1039/d1ra03379d

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Iron porphyrin-catalyzed N-trifluoroethylation of
anilines with 2,2,2-trifluoroethylamine
hydrochloride in aqueous solution†
Cite this: RSC Adv., 2021, 11, 20322
*
*
and Cancheng Guo
Shuang Ren, Guiming Xu, Yongjia Guo, Qiang Liu
An iron porphyrin-catalyzed N-trifluoroethylation of anilines has been developed with 2,2,2-
trifluoroethylamine hydrochloride as the fluorine source. This one-pot N–H insertion reaction is
conducted via cascade diazotization/N-trifluoroethylation reactions. The developed transformation can
afford a wide range of N-trifluoroethylated anilines in good yields using readily available primary amines
and secondary anilines as starting materials.
Received 4th May 2021
Accepted 27th May 2021
DOI: 10.1039/d1ra03379d
rsc.li/rsc-advances
amines as substrates. Moreover, the available N–H insertion
with triuorodiazoethane as carbene precursor needs handle
Introduction
diazo compounds. The development of new strategies to access
N-triuroethylated amines from readily available primary and
secondary anilines in one pot still remains highly desired.
The N–H insertions, which are typical in metal-carbene reac-
tions, have been extensively explored with metalloporphyrins as
catalysts. For example, metalloporphyrin have been used in N–H
insertion with ethyl diazoacetate as carbene precursor (Scheme
1c).18 However, except for our patent,19 metalloporphyrin-based
N–H insertion with triuoroethylamine hydrochloride as the car-
bene precursor have not been explored to date. In view of the
importance of N-triuoroethylated anilines and also as part of our
ongoing interest in metalloporphyrin-based biomimetic catal-
ysis,20–24 herein, we report one-pot method for iron-porphyrin
catalyzed N-triuoroethylation of amines with triuoroethyl-
amine hydrochloride as the uorine source in aqueous solution, as
described in Scheme 1d.
The existence of uorine in organic molecules usually provides
favorable properties for these molecules; therefore, the devel-
opment of new synthetic methods for the introduction of uo-
rine and uorous functional groups is an emerging eld in
synthetic organic chemistry.1–3 N-triuoroethylated amines are
widely used as platform chemicals in the elds of synthetic
organic, medicinal and agrochemistry.4–6 To obtain N-tri-
uoroethylated amines, two approaches have been used: (1)
using aryl halides via the reaction with 2,2,2-triuoroethyl-
amine8–10 and (2) using amines through the reaction with tri-
uoroethylated reagents such as triuoroethyl chloride,11
hypervalent-iodine–CH2CF3 reagents,12 triuoroacetic acid13
and uoroalcohols.7 Triuorodiazoethane (CF3CHN2) synthe-
sized from triuoroethylamine hydrochloride was widely used
as an attractive CF3-containing synthon, largely owing to the
pioneering work in 1943 from Gilman and Jones.14 Since then,
triuorodiazoethane have been expanded for the synthesis of
various uorinated compounds including N-triuoroethylated
amines.15 The rst work on N-triuoroethylation of anilines
using CF3CHN2 as uoroethylated agent was reported by Wang
and co-workers,16 in which Ag(I) complex catalyzed anilines N–H
insertion, yielded triuoroethyl-substituted primary amines
(Scheme 1a). In another attempt, Gouverneur and co-workers
reported further extension of the insertion reactions of
CF3CHN2 into heteroatom-H bonds including N–H bond cata-
lyzed by Cu(I) catalyst (Scheme 1b).17 Despite signicant prog-
ress in this eld, the current methodologies could not afford
triuroethyl-substituted tertiary amines with secondary
Advanced Catalytic Engineering Research Center of the Ministry of Education, College
of Chemistry and Chemical Engineering, Hunan University, Changsha, 410082, P.R.
China. E-mail: fqiangliu@hotmail.com; ccguo@hnu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d1ra03379d
Scheme 1 Transition-metal catalyzed N–H insertion of anilines.
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Table 2 Substrate scope of primary anilinesa
Results and discussion
We initiated our studies with o-methyl aniline (1a) as the model
substrate to screen the optimal reaction conditions and the
results are summarized in Table 1. Among the investigated
transition-metal catalysts, an iron–porphyrin complex tetra-
phenylporphyrinatoiron(III) chloride [Fe(TPP)Cl] performed well
under the conditions show as note in Table 1, 2-methyl-N-(2,2,2-
triuoroethyl) aniline was afforded as product in 78% yield
(Table 1, entry 1). The use of metalloporphyrin catalysts
(MnTPPCl, CuTPPCl and CoTPP) as well as Vitamin B12 (VB12)
gave trace of products (Table 1, entries 2–5). Iron salts such as
FeCl3, FeCl2 were examed and had almost no catalytic activity
(Table 1, entries 6 and 7). Two common metal salts used in N-
triuoroethylation reactions AgSbF6 and Cu[(CH3CN)4]PF6
afforded very poor yields (Table 1, entries 8 and 9). These results
exhibit the importance of the iron porphyrin for the reaction.
Next, it was found that the aqueous solvent plays a key role in
the reaction and that H2O : CH2Cl2 ¼ 1 : 1 stood out as the best
one among the solvents examined (Table 1, entries 1, 10 and
11). In addition, a careful survey of acids revealed that organic
acid was better than inorganic acid as catalyst in diazotization
reaction, and acetic acid was the best one (Table 1, entries 12–
14). It is worth note that the desired reaction could also
occurred without any acids (Table 1, entry 15), owing to the
participation in diazotization reaction of hydrochloric acid of
triuoroethylated reagents.
a
Reaction conditions: 1 (0.3 mmol, 1.0 equiv.), triuoroethylamine
hydrochloride (0.6 mmol, 2 equiv.), FeTPPCl (0.9 mol%), NaNO2
(0.6 mmol, 2 equiv.), CH3COOH (0.6 mmol, 2 equiv.), H2O : CH2Cl2
1 : 1 (4 mL), air atmosphere, r. t., 12 h.
¼
triuoroethylation reactions in moderate to high yields of 45–
93%. Compared with anilines with electron-decient groups on
para position of the phenyl ring, anilines with electron-rich
groups favored the N–H insertions (2a–2k), unlike the reaction
reported by Wang's group.16 This might because that the car-
bene complex generated in situ become more prone to attack by
the electron-rich amines. Addition two electron-rich substitu-
ents on phenyl ring could enhance the yields of products
evidently (2h–2k), while no reaction was observed with anilines
containing strong electron-withdrawing groups such as –NO2 or
Encouraged by above results, we investigated the scope of
the reaction (Table 2). A series of anilines bearing electron-rich
(2a–2k) and electron-decient (2m–2s) groups performed the N-
Table 1 Optimization of reaction conditionsa
Temperature
Entry
Catalyst
Solvent
Acid
[ꢀC]
Yield [%]
1
2
3
4
5
6
7
8
FeTPPCl
MnTPPCl
CuTPPCl
CoTPPCl
VB12
FeCl3
FeCl2
AgSbF6
Cu[(CH3CN)4]PF6
FeTPPCl
FeTPPCl
FeTPPCl
FeTPPCl
FeTPPCl
FeTPPCl
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : toluene ¼ 1 : 1
H2O : CH2ClCH2Cl ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
H2O : CH2Cl2 ¼ 1 : 1
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
HCOOH
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
r.t
78
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
50
67
70
58
60
9
10
11
12
13
14
15
HCl
H2SO4
62
a
Reaction conditions: 1a (0.3 mmol, 1.0 equiv.), triuoroethylamine hydrochloride (0.6 mmol, 2 equiv.), catalyst (0.9 mol%), NaNO2 (0.6 mmol, 2
equiv.), Acid (0.6 mmol, 2 equiv.), solvent (4 mL), air atmosphere, r. t., 12 h.
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–CN. Interestingly, the position of substituents on the benzene
ring had a slight effect on the reaction because o-, m- and p-
substituted anilines gave similar yields of the desired products
(2a–2c, 2d–2f, 2m–2o). Unfortunately, when we explored the 2-
tert-butyl aniline as substrate, this reaction did not occur. It
suggested that the steric hindrance effects could play an
important part in the reactions.
Scheme 2 FeTPP (NO)-catalyzed N–H insertion of o-methyl aniline.
literature.27,28 This result proves that FeTPP (NO) was indeed
synthesized.
Aer that, we tried to utilize FeTPP (NO) instead of FeTPPCl
to catalyze the N-triuoroethylation of o-methyl aniline, shown
in Scheme 2. 83% yield of 2-methyl-N-(2,2,2-triuoroethyl)
aniline was obtained. This result suggests the formation of
FeTPP (NO) in this reaction.
On the basis of the above-mentioned results and the litera-
ture,3,18,29 we proposed a similar reaction mechanism to that of
iron porphyrin-catalyzed N-triuoroethylation reaction (Scheme
3). Iron porphyrin reacts with sodium nitrite to produce Fe(III)
TPP (NO2), which can react with reducing substances to produce
ferrous nitrosyl complex Fe(II)TPP (NO) under weak acid
conditions. Fe(II)TPP (NO) is particularly susceptible to the
attack of triuoromethyl diazomethane formed by the reaction
of sodium nitrite and triuoroethylamine hydrochloride. The
ferrous nitrosyl intermediate then forms an iron-carbene
intermediate, which is sensitive to nucleophilic attack by an
aniline. Finally, N-triuoroethylated amine is generated and the
active catalyst is recycled.
The relative broad scope of this method encouraged further
studies on the N-triuoroethylation of secondary anilines,
which could not be applied in the works by Wang's and Gou-
verneur's groups.16,17 Firstly, we examined N-methylaniline as
the model of secondary amine substrate under the standard
condition. However, the yield of the desired product was only
30% (see the ESI, S2 entry 1†). When we increase the reaction
temperature and use the higher boiling point solvent (DCE), the
yield of desired products also increased (see the ESI, S2 entries
ꢀ
2–4†). The optimal temperature is 80 C. Next, several N-meth-
ylanilines were expanded and the results are shown in Table 3.
The N-triuoroethylation reactions have shown excellent toler-
ance to both electron-withdrawing and electron-donating
groups on the m- and p-position of phenyl rings (4b–4g) with
good yields of 70–75%. Similarly, this reaction seems to be
sensitive to steric effects, because no reaction was observed with
4-bromo-N-isopropylaniline and 2-methoxy-N-methylaniline as
substrates. Regrettably, with N-ethylaniline as substrates, the
yield of desired product reduced a lot, and even only trace of
product was detected with N-isopropyl-aniline as substrate.
With the substrate scopes in hand, we further explore the
catalytic mechanism of iron porphyrin-catalyzed N-tri-
uoroethylation reaction. According to Castro and Ford's
reports,25,26 iron(III) porphyrins could be easily converted to
a ferrous nitrosyl complex (FeTPP (NO)) in presence of nitrate
and acid. We wonder if this ferrous nitrosyl intermediate also
exists in our catalytic system, so we tried to synthesize and
characterized it with ESR, shown in Fig. 1 and 2 (see the ESI
S2†). Three g value of the ESR spectrum of FeTPP (NO) are
observed at 2.09, 2.05, and 2.0 under 77 k test, and g value of the
ESR spectrum of FeTPP (NO) are observed at 2.05 under room
temperature test, which are similar with that reported in the
Experimental
General procedure for N-triuoroethylation
To an oven-dried Schlenk tube was added 2,2,2-triuoroethyl-
amine hydrochloride (81.3 mg, 0.6 mmol), acetic acid (36.0 mg,
0.6 mmol), 2 mL H2O and 1 mL dichloromethane under an air
atmosphere at room temperature. NaNO2 (41.4 mg, 0.6 mmol)
was added into the Schlenk tube. The mixed solution was stir-
red at room temperature for half an hour. Aer that, o-methyl
aniline (32.2 mg, 0.3 mmol) and Fe(TPP)Cl (2 mg, 0.9% mol) was
added into the vigorously stirred aqueous solution at room
temperature. Aer 12 hours, the crude product was extracted
three times with ethyl acetate and puried by column chro-
matography on silica gel to afford the product in order to
analyze NMR.
Table 3 Substrate scope of secondary anilinesa
Ferrous nitrosyl complex (FeTPP(NO)) was synthesized
according to literature,28 and characterized by electron spin
resonance spectroscopy (ESR).
a
Reaction conditions: 3 (0.3 mmol, 1.0 equiv.), triuoroethylamine
hydrochloride (0.6 mmol, 2 equiv.), FeTPPCl (0.9 mol%), NaNO2
(0.6 mmol,
2
equiv.), CH3COOH (0.6 mmol,
2
equiv.),
H2O : CH2ClCH2Cl ¼ 1 : 1 (4 mL), air atmosphere, 80 ꢀC, 12 h.
Scheme
fluoroethylation in water.
3 Potential routes for iron porphyrin-catalyzed N-tri-
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Conclusions
In summary, we have developed
a method of N-tri-
uoroethylation of anilines in the presence of an iron(III)
porphyrin catalyst with 2,2,2-triuoroethylamine hydrochloride
as the uorine source. The reaction exhibits good substrate
scope (primary and secondary anilines) and functional group
compatibility. This new useful protocol (absent inert atmo-
sphere, aqueous solution) should nd use in the preparation of
N-triuoroethylated amines under these reaction conditions.
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Conflicts of interest
There are no conicts to declare.
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