Copper-Promoted Conversion of Aromatic Amines into Trifluoromethylated Arenes: One-Pot Sandmeyer Trifluoromethylation

Article abstract of DOI:10.1002/cjoc.201700311

A simple copper-promoted one-pot Sandmeyer trifluoromethylation of aromatic amines with Langlois’ reagent has been demonstrated. The reaction is performed in mild reaction conditions under an air atmosphere with good substrate scope and functional group compatibility. It provides an alternative and straightforward synthetic approach to access a variety of trifluoromethylated arenes.

Full text of DOI:10.1002/cjoc.201700311

FULL PAPER
DOI: 10.1002/cjoc.201700311
Copper-Promoted Conversion of Aromatic Amines into
Trifluoromethylated Arenes: One-Pot Sandmeyer
Trifluoromethylation
Jianquan Hong,a Guifu Wang,a Lianguang Huo,a Changge Zheng*,a,b
a Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material
Engineering, Jiangnan University, Wuxi, Jiangsu 214122, China
b College of Chemistry Engineering, Xinjiang Agricultural University, Urumqi,
Xinjiang Uygur Autonomous Region 830052, China
A simple copper-promoted one-pot Sandmeyer trifluoromethylation of aromatic amines with Langlois’ reagent
has been demonstrated. The reaction is performed in mild reaction conditions under an air atmosphere with good
substrate scope and functional group compatibility. It provides an alternative and straightforward synthetic approach
to access a variety of trifluoromethylated arenes.
Keywords copper, sandmeyer trifluoromethylation, aromatic amine, langlois’ reagent, trifluoromethylated arene
Introduction
Organofluorine compounds are biologically im-
portant due to their ubiquity in many top-selling phar-
maceuticals, agrochemicals and functional materials.[1]
Among the commonly familiar fluoroalkyl groups, the
trifluoromethyl (CF3) group has occupied a significant
segment, because CF3 group could enhance the meta-
bolic stability, lipophilicity and bioavailability of the
parent molecules.[2] However, CF3-containing com-
pounds are absent in nature, which accounts for the vital
importance of developing efficient methods to introduce
CF3 group into parent structures.[1-3] The traditional
methods for incorporation of CF3 group into aromatic
backbones are Swarts-type reactions. However, this re-
action requires chlorine-fluorine exchange in the pres-
ence of HF under harsh conditions and has a relatively
narrow substrate scope (Figure 1a).[4] Such process is
not appropriate for late-stage incorporation of a CF3
group into an aromatic structure. To solve the problem,
methods for direct trifluoromethylation of aromatic
compounds have been developed. A commonly applied
approach is transition-metal-promoted or transi-
tion-metal-catalyzed trifluoromethylation of aryl halides
with CF3 reagents (Figure 1b),[5] most of which involve
an MCF3 intermediate that is generated in situ or
preisolated. Meanwhile, closely related methods for
conversion of boron group into a CF3 group have also
been disclosed (Figure 1c).[6] This transformation is
Figure 1 Methods for aryl trifluoromethylation.
usually accomplished by cross-coupling of aryl anion
with electrophilic CF3 sources ( CF＋ ) or oxidative
3
Chan-Lam-type coupling of aryl anion with nucleophilic
CF3 reagents ( CF－ ). Moreover, a distinct approach to
3
incorporate the CF3 group is the radical trifluoromethyl-
ation of an aromatic C－H bond via transition-metal-
catalyzed/promoted or transition-metal-free procedure
(Figure 1d).[7] Although significant advances in
aromatic trifluoromethylation have been made, for fur-
*
E-mail: cgzheng@jiangnan.edu.cn; Tel.: 0086-13382889189; Fax: 0086-0510-85917763
Received May 3, 2017; accepted June 25, 2017; published online XXXX, 2017.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201700311 or from the author.
Chin. J. Chem. 2017, XX, 1—7
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Hong et al.
FULL PAPER
Experimental
ther improvement of the flexibility and selectivity of the
trifluoromethylation process, it remains important to
explore the conversion of other functional groups into
CF3 group.
General information
All reagents were obtained commercially and used
without further purification. Column chromatography
was carried out on silica gel (200－300 mesh). 1H NMR
spectra were recorded on 400 MHz in CDCl3 or DMSO.
19F spectra were recorded on 376 MHz in CDCl3 or
DMSO. 13C NMR spectra were recorded on 101 MHz in
CDCl3 or DMSO. Chemical shifts (δ) were recorded
with tetramethylsilane (TMS) as the internal reference
standard. Multiplicities are given as: s (singlet), d (dou-
blet), t (triplet), dd (doublet of doublets), dq (doublet of
quartets), q (quartet) or m (multiplet).
Aromatic amines are inexpensive and readily availa-
ble substrates. It is well known that the aromatic amino
group can be easily converted into various functional
groups such as hydroxyl, halogen, cyano, borate, and
azido groups.[8] This transformation usually goes
through two reaction steps. The first one is the diazoti-
zation of aromatic amines with nitrous acid or alkyl
nitrite, generating the aryl diazonium salts which are
important intermediates in organic synthesis. The se-
cond step is the conversion of diazonium group into
target functional groups. Since the first discovery by
Griess in 1858,[9] aryl diazonium salts have been exten-
sively studied and widely used for the preparation of
functionalized arenes.[8,10] The conversion of anilines
into aryl halides or pseudohalides, known as the
Sandmeyer reaction,[11] is the most prominent method
for functional group transformation. This classic trans-
formation is not only routinely practiced in research
laboratories but also widely applied in chemical industry.
The conversion of anilines into trifluoromethylated
arenes, recently called the Sandmeyer trifluoromethyla-
tion, has been witnessed as an efficient strategy for in-
corporation of CF3 into an aromatic ring.[12] Examples
are one pot trifluoromethylations of aromatic amines
General procedure for the synthesis of the products
Aromatic amine (0.5 mmol) and aq. HCl (28% in
water, 1.0 mmol) were placed in a round-bottom flask
equipped with a stirring bar at 0 ℃. A minute later,
NaNO2 (0.55 mmol) was added to the reaction flask and
continued to react for 20 min. To this solution were
added NaHCO3 (0.4 mmol), NaSO2CF3 (1.5 mmol),
CuCl (0.3 mmol), TBHP (2.5 mmol) and CH3CN (5 mL)
in turn. The reaction mixture was stirred at ambient
temperature for 20 h. Then the resulting mixture was
filtered through a short pad of celite and rinsed with
diethyl ether (15 mL). The filtrate was washed with wa-
ter (3×10 mL) and brine (10 mL). The organic layer
was dried over Na2SO4, filtered and concentrated under
vacuum (low temperature). The residue was further pu-
rified by flash chromatography (silica gel, petroleum
ether/ethyl acetate gradient) to give the pure products.
+
with CF3 reagent (Umemoto's reagent) disclosed by
Fu’s group (Figure 1e),[12a] and with CF－ species
3
(Ruppert’s reagent (CF3SiMe3) and CHF3) developed by
Wang et al.,[12b,12f] Goossen et al.[12e,12g] and Grushin’s
group[12d] (Figure 1f). Another slightly cumbersome ap-
proach to access trifluoromethylated arenes is trifluo-
romethylation of arenediazonium tetrafluoroborates
preisolated from reaction of anilines and t-BuONO/
HBF4. Examples of this methodolog are developed by
Goossen et al.[12c] and Qing’s group.[12h] Although the
Sandmeyer trifluoromethylations have been reported
independently by the aforementioned groups, method to
access trifluoromethylated arenes by one pot manner in
combination with the empolyment of •CF3 species
hasn’t been revealed yet.
Herein, we want to report the copper-promoted tri-
fluoromethylation of aromatic amines, which can pro-
ceed via the reaction of active •CF3 species with aryl
diazonium salts generated in situ from the reaction of
aniline derivatives and NaNO2/HCl. To establish this
protocol, we pay attention to search for a practical po-
tential source of •CF3. Several documents have shown
that the incorporation of NaSO2CF3 (Langlois’ reagent)
and TBHP (t-BuOOH) can generate trifluoromethyl
radical at room temperature under ambient air and
moisture.[7c,13] We reason that trifluoromethylation of
anilines could achieve selectively in the presence of Cu
salt, NaSO2CF3 and TBHP (Figure 1g).
4-(Trifluoromethyl)biphenyl (3a)[14]
Colorless
1
solid, 0.090 g, 81%. H NMR (400 MHz, CDCl3) δ:
7.75 (d, J＝8.4 Hz, 4H), 7.64 (d, J＝7.7 Hz, 2H), 7.52 (t,
J＝7.6 Hz, 2H), 7.48－7.42 (m, 1H); 19F NMR (376
MHz, CDCl3) δ: 62.38 (s, 3F); 13C NMR (101 MHz,
CDCl3) δ: 144.77 (s), 139.79 (s), 129.38 (q, J＝32.5 Hz),
128.21 (s), 127.44 (s), 127.30 (s), 125.73 (q, J＝3.8 Hz),
124.3 (q, J＝272.0 Hz).
4-Chlorobenzotrifluoride (3b)[14] Colorless liquid,
55% (Yield determined by 19F NMR spectroscopy using
1,3,5-trifluorobenzene as an internal standard). 1H NMR
(400 MHz, CDCl3) δ: 7.59 (d, J＝8.4 Hz, 2H), 7.47 (d,
J＝8.5 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ: 62.84
(s, 3F); 13C NMR (101 MHz, CDCl3) δ: 138.1 (s), 129.0
(s), 129.1 (q, J＝32.5 Hz), 126.6 (q, J＝3.8 Hz), 123.8
(q, J＝272.0 Hz).
4-Bromobenzotrifluoride (3c)[15] Colorless liquid,
61% (Yield determined by 19F NMR spectroscopy using
1,3,5-trifluorobenzene as an internal standard). 1H NMR
(400 MHz, CDCl3) δ: 7.68－7.60 (m, 2H), 7.51 (d, J＝
8.4 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ: 63.00 (s,
3F); 13C NMR (101 MHz, CDCl3) δ: 132.0 (s), 129.6 (q,
J＝32.5 Hz), 126.8 (m), 126.4 (m), 123.9 (q, J＝272.0
Hz).
4-Trifluoromethyltoluene (3d)[14] Colorless liquid,
75% (Yield determined by 19F NMR spectroscopy using
2
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Conversion of Aromatic Amines into Trifluoromethylated Arenes
1,3,5-trifluorobenzene as an internal standard). 1H NMR
(400 MHz, CDCl3) δ: 7.58 (d, J＝8.0 Hz, 2H), 7.33 (d,
J＝8.0 Hz, 2H), 2.47 (s, 3H); 19F NMR (376 MHz,
CDCl3) δ: 62.38 (s, 3F); 13C NMR (101 MHz, CDCl3)
δ: 142.1 (s), 129.3 (s), 127.9 (q, J＝32.5 Hz), 125.1 (q,
J＝3.8 Hz), 124.5 (q, J＝272.0 Hz).
132.20 (s), 129.0 (s), 128.8 (s), 128.0 (s), 127.9 (s),
127.7 (q, J＝32.5 Hz), 127.1 (s), 125.6 (q, J＝4.6 Hz),
124.4 (q, J＝272.0 Hz), 121.4 (q, J＝3.8 Hz).
6-(Trifluoromethyl)quinolone (3m)[12c]
White
1
solid, 0.050 g, 46%. H NMR (400 MHz, CDCl3) δ:
8.91 (s, 1H), 8.06 (d, J＝8.5 Hz, 2H), 7.79 (s, 1H), 7.66
(s, 1H), 7.43 (s, 1H); 19F NMR (376 MHz, CDCl3) δ:
62.32 (s).
4-Trifluoromethylanisole (3e)[14] Colorless liquid,
67% (Yield determined by 19F NMR spectroscopy using
1,3,5-trifluorobenzene as an internal standard). 1H NMR
(400 MHz, CDCl3) δ: 7.60 (d, J＝8.8 Hz, 2H), 7.00 (d,
J＝8.7 Hz, 2H), 3.87 (s, 3H); 19F NMR (376 MHz,
CDCl3) δ: 61.56 (s, 3F); 13C NMR (101 MHz, CDCl3)
δ: 162.1 (s), 126.8 (q, J＝3.8 Hz), 124.6 (q, J＝272.0
Hz), 122.8 (q, J＝32.5 Hz), 113.9 (s), 55.1 (s).
4-(Trifluoromethyl)benzoic acid (3n)[12d] White
1
solid, 0.067 g, 70%. H NMR (400 MHz, DMSO-d6) δ:
13.47 (s, 1H), 8.13 (d, J＝8.1 Hz, 2H), 7.89－7.82 (m,
2H); 19F NMR (376 MHz, DMSO-d6) δ: 61.72 (s, 3F);
13C NMR (101 MHz, DMSO-d6) δ: 166.6 (s), 135.0 (s),
133.0 (q, J＝32.5 Hz), 130.5 (s), 126.0 (s), 124.2 (q, J＝
272.0 Hz).
4-(Trifluoromethyl)benzonitrile (3f)[15]
White
1
solid, 0.039 g, 46%. H NMR (400 MHz, CDCl3) δ:
7.83 (d, J＝8.2 Hz, 2H), 7.78 (d, J＝8.3 Hz, 2H); 19F
NMR (376 MHz, CDCl3) δ: 63.55 (s, 3F); 13C NMR
(101 MHz, CDCl3) δ: 134.5 (q, J＝32.5 Hz), 132.7 (s),
126.2 (q, J＝3.8 Hz), 123.1 (q, J＝272.0 Hz), 117.4 (s),
116.1 (s).
3-(Trifluoromethyl)benzoic acid (3o)[12d] White
1
solid, 0.054 g, 57%. H NMR (400 MHz, CDCl3) δ:
12.22 (br s, 1H), 8.60－8.23 (m, 2H), 7.91 (d, J＝7.8
Hz, 1H), 7.67 (t, J＝7.8 Hz, 1H); 19F NMR (376 MHz,
CDCl3) δ: 62.91 (s, 3F); 13C NMR (101 MHz, CDCl3)
δ: 171.1 (s), 133.4 (s), 131.3 (q, J＝32.5 Hz), 130.4 (q,
J＝3.6 Hz), 130.1 (s), 129.2 (s), 127.2 (q, J＝3.8 Hz),
123.6 (q, J＝272.0 Hz).
1-Nitro-4-(trifluoromethyl)benzene
(3g)[14]
White solid, 0.030 g, 32%. 1H NMR (400 MHz, CDCl3)
δ: 8.37 (d, J＝8.7 Hz, 2H), 7.86 (d, J＝8.8 Hz, 2H); 19F
NMR (376 MHz, CDCl3) δ: 63.31 (s, 3F); 13C NMR
(100 MHz, CDCl3) δ: 150.0 (s), 136.0 (q, J＝32.5 Hz),
126.7 (q, J＝3.8 Hz), 124.0 (s), 127.3 (q, J＝272.0 Hz).
2-(Trifluoromethyl)benzoic acid (3p)[10d] White
1
solid, 0.061 g, 64%. H NMR (400 MHz, CDCl3) δ:
10.86 (br s, 1H), 8.02 (br s, 1H), 7.83 (br s, 1H), 7.70
(br s, 2H); 19F NMR (376 MHz, CDCl3) δ: 59.32 (s,
3F); 13C NMR (101 MHz, CDCl3) δ: 172.1 (s), 132.2 (s),
131.8 (s), 131.2 (s), 129.6 (q, J＝1.8 Hz), 129.5 (q, J＝
32.5 Hz), 127.0 (q, J＝5.6 Hz), 123.2 (q, J＝272.0 Hz).
1-(4-(Trifluoromethyl)phenyl)ethanone
(3h)[14]
1
Colorless solid, 0.069 g; 73%. H NMR (400 MHz,
CDCl3) δ: 8.00 (d, J＝7.9 Hz, 2H), 7.66 (d, J＝8.1 Hz,
2H), 2.66－2.58 (m, 3H); 19F NMR (376 MHz, CDCl3)
δ: 63.18 (s, 3F); 13C NMR (101 MHz, CDCl3) δ: 196.8
(s), 139.6 (s), 134.2 (q, J＝32.5 Hz), 128.5 (s), 125.5 (q,
J＝3.8 Hz), 123.5 (q, J＝272.0 Hz), 26.5 (s).
Methyl
4-(trifluoromethyl)benzoate
(3q)[12d]
1
Colorless liquid, 0.069 g, 68%. H NMR (400 MHz,
CDCl3) δ: 8.06 (d, J＝7.1 Hz, 2H), 7.62 (d, J＝7.1 Hz,
2H), 3.89 (ddd, J＝6.8, 5.3, 3.6 Hz, 3H); 19F NMR (376
MHz, CDCl3) δ: 63.55 (s, 3F); 13C NMR (101 MHz,
CDCl3) δ: 165.5 (s), 134.2 (q, J＝32.5 Hz), 133.3 (s),
129.8 (s), 125.2 (q, J＝3.8 Hz), 123.6 (q, J＝272.0 Hz),
52.1 (s).
3-Trifluoromethylpyridine (3i)[15] Colorless liq-
uid, 19% (Yield determined by 19F NMR spectroscopy
using 1,3,5-trifluorobenzene as an internal standard). 1H
NMR (400 MHz, CDCl3) δ: 8.88－8.65 (m, 2H), 7.90－
7.79 (m, 1H), 7.39－7.30 (m, 1H); 19F NMR (376 MHz,
CDCl3) δ: 63.03 (s, 3F); 13C NMR (101 MHz, CDCl3)
δ: 152.8 (s), 146.5 (q, J＝3.8 Hz), 132.9 (m), 126.6 (q,
J＝32.5 Hz), 123.3 (q, J＝272.0 Hz), 123.2 (s).
Ethyl 4-(trifluoromethyl)benzoate (3r)[15] Light
yellow liquid, 0.067 g, 61%. 1H NMR (400 MHz,
CDCl3) δ: 8.22－8.11 (m, 2H), 7.67 (t, J＝5.4 Hz, 2H),
4.45－4.37 (m, 2H), 1.44－1.37 (m, 3H); 19F NMR
(376 MHz, CDCl3) δ: 63.33 (s, 3F); 13C NMR (101
MHz, CDCl3) δ: 165.2 (s), 134.3 (q, J＝32.5 Hz), 133.7
(s), 129.8 (s), 125.2 (m), 123.6 (q, J＝272.0 Hz), 61.41
(s), 14.03 (s).
Trifluoromethylbenzene (3j)[14] Colorless liquid,
83% (Yield determined by 19F NMR spectroscopy using
1,3,5-trifluorobenzene as an internal standard). 1H NMR
(400 MHz, CDCl3) δ: 7.76 (d, J＝7.7 Hz, 2H), 7.64 (t,
J＝7.4 Hz, 1H), 7.57 (t, J＝7.5 Hz, 2H); 19F NMR (376
MHz, CDCl3) δ: 62.91 (s, 3F); 13C NMR (101 MHz,
CDCl3) δ: 131.7 (s), 130.8 (q, J＝32.5 Hz), 128.7 (s),
125.1 (q, J＝3.8 Hz), 124.4 (q, J＝272.0 Hz).
1-Ethynyl-4-(trifluoromethyl)benzene
(3s)[12d]
1
Colorless liquid, 0.030 g, 36%. H NMR (400 MHz,
CDCl3) δ: 7.61 (s, 4H), 3.22 (s, 1H); 19F NMR (376
MHz, CDCl3) δ: 63.01 (s, 3F); 13C NMR (101 MHz,
CDCl3) δ: 132.4 (s), 130.8 (q, J＝32.5 Hz), 125.2 (q,
J＝3.8 Hz), 124.5 (q, J＝272.0 Hz), 82.2 (s), 79.6 (s).
1-(Trifluoromethyl)-4-vinylbenzene (3t)[12b] Vol-
atile compound, 0.005g, 6%. 19F NMR (376 MHz,
CDCl3) δ: 62.06 (s, 3F). EI-MS (m/z): 172 (M＋).
3-Bromobenzotrifluoride (3v)[12h] Colorless oil,
1,4-Bis(trifluoromethyl)benzene (3k)[16]
Color-
less liquid, 0.040 g, 37%. 1H NMR (400 MHz, CDCl3) δ:
8.17 (s, 4H); 19F NMR (376 MHz, CDCl3) δ: 63.00 (s).
2-(Trifluoromethyl)naphthalene (3l)[17]
White
1
solid, 0.058 g, 59%. H NMR (400 MHz, CDCl3) δ:
8.19 (s, 1H), 8.06－7.90 (m, 3H), 7.77－7.57 (m, 3H);
19F NMR (376 MHz, CDCl3) δ: 62.24 (s, 3F); 13C
NMR (101 MHz, CDCl3) δ: 134.6 (q, J＝0.9 Hz),
1
0.024 g, 22%. H NMR (400 MHz, CDCl3) δ: 7.65 (s,
1H), 7.58－7.52 (m, 2H), 7.45 (t, J＝7.9 Hz, 1H); 19F
Chin. J. Chem. 2017, XX, 1—7
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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3

Hong et al.
FULL PAPER
NMR (376 MHz, CDCl3) δ: 62.98 (s, 3F); 13C NMR
(100 MHz, CDCl3) δ: 134.9 (s), 132.3 (q, J＝32.5 Hz),
132.0 (s), 130.2 (s), 125.6 (q, J＝3.8 Hz), 123.4 (q, J＝
3.8 Hz), 123.3 (q, J＝272.0 Hz).
sented in Table 1, the conversion worked in a range of
solvents such as toluene, DMSO, DMF and CH3CN,
and afforded the desired product in 19%－69% isolated
yields based on the aromatic amine (Table 1, Entries
1－5). Significantly, employment of CH3CN as reaction
solvent gave a best yield for this transformation. In fur-
ther screening the effect of different promoters, CuCl
was proved to be more efficient comparing with other
copper salts such as CuBr, Cu(OTf)2, CuCl2, CuBr2,
CuO, and Cu(OAc)2 (Table 1, Entries 6－11). Examin-
ing the effect of inorganic base led to arriving at much
improved condition in which 3a was obtained in 79%
yield when the reaction was carried out using NaHCO3
as additive (Table 1, Entry 14). After screening of Na-
SO2CF3, TBHP and NaHCO3 loading, the best outcome
was found when 4-biphenylamine reacted with 3 equiv.
of NaSO2CF3, 5 equiv. of TBHP, and 0.8 equiv. of Na-
HCO3 using CuCl as a promoter in CH3CN (Table 1,
Entry 23). It is worth mentioning that no desired product
was observed in the absence of copper salts (Table 1,
Entry 24). Some important features of this protocol
should be demonstrated here. Firstly, the reaction was
performed under an air atmosphere without any purifi-
cation of the commercial solvents and reagents. Moreo-
ver, the transformation was conducted under mild reac-
tion conditions and gave 4-(trifluoromethyl)-1,1'-biphe-
nyl in good yield.
3-Trifluoromethyltoluene (3w)[12c] Colorless liq-
1
uid, 0.059 g, 74%. H NMR (400 MHz, CDCl3) δ:
7.48－7.37 (m, 4H), 2.44 (s, 3H); 19F NMR (376 MHz,
CDCl3) δ: 62.64 (s, 3F); 13C NMR (100 MHz, CDCl3)
δ: 138.7 (s), 132.4 (s), 130.5 (q, J＝32.5 Hz), 128.6 (s),
125.7 (q, J＝3.8 Hz), 124.4 (q, J＝272.0 Hz), 122.3 (q,
J＝3.8 Hz), 21.3 (s).
Methyl-3-(trifluoromethyl)benzene (3x)[12c] Col-
orless liquid, 0.060 g, 68%. 1H NMR (400 MHz, CDCl3)
δ: 7.42 (t, J＝8.0 Hz, 1H), 7.25 (d, J＝7.7 Hz, 1H), 7.18
(s, 1H), 7.11 (d, J＝8.3 Hz, 1H), 3.87 (s, 3H); 19F NMR
(376 MHz, CDCl3) δ: 62.76 (s, 3F); 13C NMR (100
MHz, CDCl3) δ: 159.8 (s), 131.8 (q, J＝32.5 Hz), 129.9
(s), 124.1 (q, J＝272.0 Hz), 117.5 (s), 117.3 (q, J＝3.8
Hz), 110.7 (q, J＝3.8 Hz), 55.3 (s).
Results and Discussion
We initiated our study on the model reaction of Na-
SO2CF3 with biphenyl diazonium salt generated in situ
by treatment of 4-biphenylamine and NaNO2/HCl at
0 ℃. To our delight, the trifluoromethylated product 3a
was obtained in 33% yield when the reaction was car-
ried out in DMSO in the presence of CuCl and TBHP.
Inspired by this result, we further tested the effect of
different solvents, copper salts, and additives. As pre-
With optimized conditions established (Table 1, En-
try 23) for the Sandmeyer trifluoromethylation, we
subsequently investigated the scope of aromatic amine
Table 1 Optimization of reaction conditions for the trifluoromethylation of 1aa
Entry
1
Cu salt
CuCl
Base
Solvent
DMSO
T/℃
0－r.t.
Yield/%
33
Entry
13
Cu salt
Base
Solvent
T/℃
Yield/%
46
－
－
－
－
－
－
－
－
－
－
－
CuCl K2CO3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
2
CuCl
DMF
0－r.t.
0－r.t.
0－r.t.
0－40C
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
0－r.t.
46
69
19
54
14
39
47
25
31
33
61
14
15
CuCl NaHCO3
CuCl KHCO3
CuCl NaOH
79
3
CuCl
CH3CN
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
57
4
CuCl
16
27
5
CuCl
17
CuCl KOH
29
6
CuBr
18c
19d
20e
21f
22g
23h
24
CuCl NaHCO3
CuCl NaHCO3
CuCl NaHCO3
CuCl NaHCO3
CuCl NaHCO3
67
7
Cu(OTf)2
CuCl2
CuBr2
CuO
78
8
75
9
79
10
11
12
70
Cu(OAc)2
CuCl NaHCO3 CH3CN
none NaHCO3 CH3CN
81
CuCl
Na2CO3 CH3CN
0
a Conditions: preparation of the diazonium salt: 4-biphenylamine 1a (0.5 mmol), aq. HCl (28% in water, 1.0 mmol), NaNO2 (0.55 mmol),
solvent, 0 ℃ (ice salt bath), 20 min; Cu salt (0.6 mmol), base (0.6 mmol, 1.0 mL H2O), NaSO2CF3 (1.5 mmol), TBHP (2.5 mmol), sol-
vent, temp., 20 h under an air atmosphere. b Yields of isolated pure products. c 1.0 mmol NaSO2CF3 was used. d 2.0 mmol NaSO2CF3 was
used. e 2.0 mmol TBHP was added. f 3.0 mmol TBHP was added. g 0.3 mmol NaHCO3 was used. h 0.4 mmol NaHCO3 was used.
4
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© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2017, XX, 1—7

Conversion of Aromatic Amines into Trifluoromethylated Arenes
derivatives (Table 2). It was found that aromatic amines
bearing electron-withdrawing groups such as halogens,
cyano, nitro, acyl, trifluoromethyl, esters, and even car-
boxyl worked well under standard reaction conditions,
giving the corresponding trifluoromethylated products
(3b－3c, 3f－3h, 3k, 3n－3r and 3v) in modest to good
yields. Meanwhile, trifluoromethylation of aniline
derivatives containing electron-donating groups includ-
ing aryl, alkyl and alkoxy afforded the desired trifluo-
romethylated products (3a, 3d－3e, 3l and 3w－3x) in
59%－81% yields. In some previous reports, NaSO2CF3
in combination with TBHP was proven to be capable of
trifluoromethylating the aromatic or heteroaromatic C－
H bond under transition-metal-catalyzed/promoted or
transition-metal-free conditions.[7c,13a,13b] However,
under the present condition, all the C－H bonds were
inert to the trifluoromethylation process. The reaction
also tolerated well multiple bond such as C≡C triple
bond, giving the trifluoromethylated product 3s in mod-
est yields. In regard to 4-vinylaniline 1t, the trifluoro-
methylated products were very complicated (The for-
mation of compound 3t was confirmed by 19F NMR
nylbenzenediazonium. In the case of heteroaromatic
amines (including 3-aminopyridine 2i and 6-aminoqui-
noline 2m), the transformation was still efficient to
produce the corresponding trifluoromethylated products
in spite of a decrease in the reaction yield, presumably
attributed to the protonation of the nitrogen heteroatom
during the diazotization. For heteroaromatic amine such
as adenine 1u, the trifluoromethylation process was
completely shut down as a result of the strong protona-
tion of heterocyclic nitrogen atoms. All the products
were obtained in sufficiently pure form. Only for some
simple, low-boiling substrates, the yields of the products
were determined by 19F NMR spectroscopy using
1,3,5-trifluorobenzene as an internal standard.
To shed light on the mechanism of the reaction, the
following experiments were performed (Figure 2).
Firstly, 4 equiv. of radical scavenger TEMPO was in-
troduced to standard trifluoromethylation reaction (Fig-
ure 2a), no desired product 3j was detected in 19F NMR
spectroscopy. Meanwhile, a signal at δ 56.18 ascribing
to TEMPO-CF3 4 was observed.[12b] This result indi-
cates CF3 radical should be a key species for the tri-
fluoromethylation of aromatic amine. On the other hand,
the reaction of Langlois’ reagent, TBHP and CuCl in
addition of TEMPO was examined (Figure 2c). The
comparing with the previously reported data).[12b] This
＋
may be due to the competitive substitution of －N2
and radical addition to C＝C double bond in the vi-
Table 2 Substrate scope of copper-promoted trifluoromethylation of aromatic aminesa
CF3
CF3
CF3
N
3j, 83%c
3l, 59%b
3i, 19%c
CF3
O
O
3q, 68%b
a Conditions: preparation of the diazonium salts: aromatic amines (0.5 mmol), aq. HCl (28% in water, 1.0 mmol), NaNO2 (0.55 mmol),
CH3CN, 0 ℃ (ice salt bath), 20 min; CuCl (0.6 mmol), NaHCO3 (0.4 mmol, 1.0 mL H2O), NaSO2CF3 (1.5 mmol), TBHP (2.5 mmol)
and CH3CN, at room temperature, 20 h under an air atmosphere. b Yields of isolated pure products. c Yields determined by 19F NMR spec-
troscopy using 1,3,5-trifluorobenzene as an internal standard.
Chin. J. Chem. 2017, XX, 1—7
© 2017 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
5

Hong et al.
FULL PAPER
generation of TEMPO-CF3 4 was also confirmed by 19
F
tion of aromatic amines with Langlois’ reagent. The
reaction is operationally simple and proceeds well for a
range of different aromatic amine substrates with elec-
tron-donating groups as well as electron-withdrawing
groups in mild reaction conditions under an air atmos-
phere. Thus, this transformation is a valuable comple-
ment to the previously established Sandmeyer trifluoro-
methylation methods.
NMR. However, when treating Langlois’ reagent with
TBHP and TEMPO without addition of CuCl (Figure
2b), no reaction was observed. Thus, these experiments
imply the generation of CF3 radical when Langlois’ re-
agent is treated with TBHP in the presence of CuCl.
Acknowledgement
We acknowledge the financial support for this work
from the National Natural Science Foundation of China
(Nos. 21502070 and 21562041) and the Fundamental
Research Funds for the Central Universities (No.
JUSRP51626B).
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7