Copper-Promoted Intramolecular Aminotrifluoromethylation of Alkenes with Langlois Reagent as the Trifluoromethyl Source

Article abstract of DOI:10.1055/s-0036-1588400

A novel approach for copper-promoted intramolecular aminotrifluoromethylation of alkenes using inexpensive CF₃SO₂Na as the trifluoromethyl source is described. The feature of this method is the concurrent construction of a five-membered ring and a C-CF₃ bond in the simple copper salt/TBHP system. A gram-scale reaction was tested with a slight decrease in the yield. This protocol provides an operationally simple, step-economical and synthetically useful access to a variety of trifluoromethyl indolines, pyrrolidines and lactams.

Full text of DOI:10.1055/s-0036-1588400

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
H.-Y. Zhang et al.
Letter
Synlett
Copper-Promoted Intramolecular Aminotrifluoromethylation of
Alkenes with Langlois Reagent as the Trifluoromethyl Source
CF3
Hong-Yu Zhang
Cu(TFA)2 • xH2O, CF3SO2Na
Wenge Huo
N
NH
PG
TBHP, MeCN, 65 °C
Chao Ge
PG
PG = protecting group
Jiquan Zhao
Yuecheng Zhang*
18 examples
30–76% yield
1. inexpensive CF3 source; gram-scale reaction
2. various substrates: indoline, pyrrolidine and lactam
School of Chemical Engineering and Technology, Hebei
University of Technology, 8 Guangrong Road, Tianjin
300130, P. R. of China
13820681390@163.com
Received: 13.10.2016
Accepted after revision: 31.12.2016
Published online: 06.02.2017
spired by these pioneering works, we attempted to explore
the possibility that there may be a comparably low-cost and
benchtop stable trifluoromethylation agents in aminotri-
fluoromethylation.
DOI: 10.1055/s-0036-1588400; Art ID: st-2016-w0686-l
Abstract A novel approach for copper-promoted intramolecular ami-
notrifluoromethylation of alkenes using inexpensive CF3SO2Na as the
trifluoromethyl source is described. The feature of this method is the
concurrent construction of a five-membered ring and a C–CF3 bond in
the simple copper salt/TBHP system. A gram-scale reaction was tested
with a slight decrease in the yield. This protocol provides an operation-
ally simple, step-economical and synthetically useful access to a variety
of trifluoromethyl indolines, pyrrolidines and lactams.
Sodium trifluoromethanesulfinate (Langlois reagent) is
an alternative CF3 source as it is inexpensive and easy to
handle.12 Since the pioneering studies by the Langlois group
on trifluoromethylation of aromatic compounds under oxi-
dative conditions,12a relatively few methods for the incorpo-
ration of CF3 into organic compounds have been developed,
which employ Langlois reagent as a trifluoromethylation
agent.13 Despite these significant progresses, there has been
no report on the direct aminotrifluoromethylation of unac-
tivated alkenes with Langlois reagent as the CF3 source.
Herein, we describe an operationally simple and one-pot
protocol of converting alkenes to various CF3-containing
heterocycles using inexpensive CF3SO2Na in the simple cop-
per salt/TBHP system. In contrast with previous works,9,11
this vicinal CF3-involving difunctionalization (Scheme 1)
expands the substrate scope and functional-tolerance to af-
ford various products such as CF3-containing indolines, pyr-
rolidines, and five-membered lactams.
Key words Langlois reagent, aminotrifluoromethylation, azahetero-
cycles, copper-promoted, alkenes
Azaheterocycles, such as indoline and pyrrolidine, have
been recognized as important building blocks in a large
number of pharmaceuticals and biologically active mole-
cules.1 Among these molecules, trifluoromethyl-containing
azaheterocycles have many unique advantages in binding
selectivity, metabolic stability and lipophilicity.2 Therefore,
the introduction of CF3 into azaheterocyclic structures has
attracted much attention.3 Over the past several years,
some trifluoromethylation methodologies of unactivated
alkenes via direct difunctionalization strategy have been
successfully established,4 including carbotrifluoromethyl-
ation,5 oxytrifluoromethylation,6 and aminotrifluorometh-
ylation.7 The groups of Sodeoka,8 Liu9 and Wang10 have in-
dependently demonstrated the intramolecular aminotrifluo-
romethylation of terminal alkenes with Togni’s reagent as
the CF3 source. These methods represent the most direct
and atom-economical approaches to trifluoromethyl aziri-
dines, pyrrolidines, indolines and lactams. After that, the
group of Liu has further reported elegant copper-catalyzed
oxidative aminotrifluoromethylation using nucleophilic
Ruppert–Prakash reagent with broad substrate scope.11 In-
previous work:
Nu
[M]
Nu
CF3
CF3
CF3 or
Nu = C, O, N
Cu(I)
Togni's reagent or
Liu's work:
CF3
Ruppert–Prakash reagent
N
NH
PG
Cu(II)
PG
Langlois reagent
PG = protecting group
this work:
1. inexpensive CF3 source; gram-scale reaction
2. various substrates: indoline, pyrrolidine and lactam
Scheme 1 CF3-involving difunctionalization
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
H.-Y. Zhang et al.
Letter
Synlett
Recently, we have reported a convenient protocol for the
synthesis of various phosphorated indolines via copper-cat-
alyzed aminophosphorus difunctionalization.14 Encouraged
by this result, we chose N-Ts-2-allylaniline (1a) as the mod-
el substrate to screen the optimal conditions of aminotri-
fluoromethylation. The reaction was attempted with vari-
ous copper catalysts (10% mol) in different solvents at dif-
ferent temperatures, but only a trace of the desired product
was obtained. Delightfully, when the loading of copper cat-
alysts was increased to 1 equivalent, the desired product
(2a) was isolated in 56% yield in the presence of
Cu(TFA)2·xH2O (Table 1, entry 3). Other Cu(II) salts, such as
Cu(OAc)2 and Cu(acac)2 could prompt the reaction, but they
were not as efficient as Cu(TFA)2·xH2O (Table 1, entries 1–
5). However, Cu(I) salts were ineffective in this reaction (Ta-
ble 1, entries 6 and 7). Investigation of different solvents
showed that MeCN was more suitable than ClCH2CH2Cl and
toluene (Table 1, entries 8 and 9). A survey of different oxi-
dants showed that other peroxides, such as K2S2O8,
(NH4)2S2O8 and cumyl hydroperoxide, could also prompt
the reaction but the most appropriate oxidant was TBHP
(Table 1, entries 10–12). Subsequently, we screened the re-
action temperatures and observed that the yield increased
to 60% at 65 °C (Table 1, entries 13–15). After optimization
of the ratios of oxidant to sodium trifluoromethanesulfi-
nate, we were pleased to obtain product 2a in 73% yield (Ta-
ble 1, entries 16). Finally, we attempted to reduce the
amount of Cu(TFA)2·xH2O to 20 mol %, but the yield obvi-
ously decreased to 16% (Table 1, entries 17). We tried diver-
sified methods to reduce the loading of catalyst as follows:
1) we employed different ligands (2,2′-bipyridine, 1,10-
phenanthroline, terpyridyl ligand); 2) solution of TBHP or
CF3SO2Na was added dropwise with a syringe pump; 3) we
examined various metal catalysts like Mn, Fe, Co and Ni cat-
alysts. Unfortunately, there was no further increase of the
desired product. As our overall experimental results
demonstrated, the optimal reaction conditions involve the
use of 1 equivalent of Cu(TFA)2·xH2O, 2 equivalents of
CF3SO2Na and 3 equivalents of TBHP in 1.5 mL of MeCN for
0.2 mmol 1a at 65 °C under an argon atmosphere.
Table 1 Selected Reaction Conditions Optimizationa
CF3
Cu salt, oxidant
CF3SO2Na
+
solvent, temp
N
NH
Ts
Ts
Entry Copper salts
Oxidants (equiv)
T (°C)
Yield (%)b
c
1
Cu(EN)2
TBHPd (2)
TBHP (2)
80
80
80
80
80
80
80
80
80
80
80
80
95
65
50
65
65
23
28
56
14
48
N. R.
N. R.
31
16
39
40
51
54
60
56
73
16
2
Cu(OAc)2
3
Cu(TFA)2·xH2O
Cu(OTf)2
TBHP (2)
4
TBHP (2)
5
Cu(acac)2
TBHP (2)
6
CuBF4·4MeCN
CuI
TBHP (2)
7
TBHP (2)
8e
9f
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
Cu(TFA)2·xH2O
TBHP (2)
TBHP (2)
10
K2S2O8 (2)
(NH4)2S2O8 (2)
cumyl hydroperoxide (2)
TBHP (2)
11
12
13
14
15
16
17g
TBHP (2)
TBHP (2)
TBHP (3)
TBHP (3)
a Reaction conditions: 1a (0.2 mmol), CF3SO2Na (0.4 mmol), copper salt (0.2
mmol), MeCN (1.5 mL), under argon.
b Yield of isolated product. N.R. = no reaction.
c Cu(EN)2 = Copper(II) 2-ethylhexanoate.
d TBHP = tert-Butyl hydroperoxide (70% solution in H2O).
e The reaction was carried out in toluene (1.5 mL).
f The reaction was carried out in ClCH2CH2Cl (1.5 mL).
g The reaction was carried out in the presence of Cu(TFA)2·xH2O (0.04
mmol).
thesize complex organic molecules because chlorine atom
was active to introduce other functional groups.16 However,
under the same conditions, Ac-protected 2-allylaniline
failed to provide the desired product.
We next evaluated the scope of different substituted Ts-
protected 2-allylaniline derivatives. A series of substituted
CF3-containing indolines (2f–m) with various functional
groups (X = Me, MeO, Cl, F) on different positions were ob-
tained in moderate to good yields. In general, electron-
withdrawing groups led to slightly better yields than elec-
tron-donating groups. Furthermore, an investigation of dif-
ferent N-protecting 4-pentenamine derivatives showed
that sulfonyl protecting groups were compatible under the
reaction condition (2n–o) giving the desired pyrrolidine
products in moderate yields, but Bn, Bz, Boc and Ac protect-
ing groups did not work at all. To our delight, when amides
1p and 1q with a MeO group were used as substrates, ami-
notrifluoromethylated lactams 2p and 2q were successfully
formed in 68% and 56% yields, respectively. Encouraged by
this result, we further tested 4-pentenoic acid derivative,
With the optimal reaction conditions in hand, the sub-
strate scope was investigated and the results are summa-
rized in Scheme 2.15 Initial studies were focused on the re-
action of substrates with various protecting groups on the
nitrogen atom (2b–e) and we found that sulfonyl group
protected substrates were compatible with this reaction, af-
fording the corresponding products in moderate yields.
However, 4-nitrophenylsulfonyl-protected 2-allylaniline
was converted into the desired product only in 30% yield as
a result of the electron-withdrawing effect. To our pleasure,
chloropropanesulfonyl group protected 2-allylaniline was
also suitable for this transformation, thus giving the prod-
uct 2e in 51% yield. Obviously, 2e could be applied to syn-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
H.-Y. Zhang et al.
Letter
Synlett
the trifluoromethyl source. Notably, this reaction is easy to
handle, can operate under mild conditions with good func-
tional group tolerance, and affords various CF3-containing
indoline, pyrrolidine, lactam and lactone.
CF3
Cu(TFA)2 • xH2O (1 equiv)
CF3SO2Na
(2 equiv)
+
NH
N
TBHP (3 equiv), MeCN
65 °C
PG
PG
O
2a–r
1a–r
CF3
CF3
CF3
N
N
O
Acknowledgment
N
S
S
O
Ts
O
The authors are grateful for financial supports from the National Nat-
ural Science Foundation of China (no. 21276061), the Natural Science
Foundation of Hebei Province, China (no. B2013202158), the Research
Development Foundation for Introduced Talent, Hebei University of
Technology (no. 208031) and the Research Fund for the Doctoral Pro-
gram of Higher Education of China (no. 20121317110010).
2a 73%
2b 57%
2c 30%
NO2
CF3
CF3
CF3
N
N
O
N
S
Ms
O
Ts
2d 43%
2e 51%
2f 51%
2i 56%
Cl
Supporting Information
CF3
CF3
CF3
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588400.
N
N
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Ts
N
Ts
F
OMe
Ts
2g 66%
2h 79%
References and Notes
MeO
CF3
Cl
F
CF3
CF3
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N
N
N
Ts
2j 43%
2k 63%
Ph
Ts
2l 61%
Ts
CF3
Ph
Ts
Ph
N
Ms
Ph
N
N
Ts
CF3
2m 76%
2n 44%
2o 42%
CF3
O
O
OMe
O
O
N
N
OMe
Ph
Ph
Ph
Ph
2q 56%
CF3
CF3
CF3
2p 68%
2r 61%
Scheme 2 Substrates scope. Reagents and conditions: 1 (0.2 mmol),
CF3SO2Na (0.4 mmol), Cu(TFA)2·xH2O (0.2 mmol), TBHP (0.6 mmol),
MeCN (1.5 mL), 65 °C, under argon. Yields given are for isolated prod-
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and the corresponding oxytrifluoromethylation lactone 2r
was obtained with the current reaction condition in 61%
yield. Finally, we examined internal alkenes but the desired
products were not detected.
To demonstrate scalability of the protocol, a scaled-up
reaction with 1a (1.005 g) as substrate was carried out and
2a was obtained with a slight decrease in the yield (Scheme 3).
CF3
CF3SO2Na
(2 equiv)
Cu(TFA)2
•
xH2O (1 equiv)
+
NH
Ts
1a: 1.005 g
N
TBHP (3 equiv), MeCN
65 °C
Ts
2a: 0.869 g (70%)
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Scheme 3 Gram-scale reaction
In conclusion, we have developed a convenient copper-
promoted intramolecular CF3-involving difunctionalization
of alkenes using readily available, economical CF3SO2Na as
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
H.-Y. Zhang et al.
Letter
Synlett
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lar Aminotrifluoromethylation of Alkenes: To a Schlenk tube
were added 1a (0.2 mmol), CF3SO2Na (0.4 mmol), Cu(TFA)2·xH2O
(0.2 mmol) and charged with argon three times. Anhydrous
MeCN (1.5 mL) and TBHP (0.6 mmol) were added via a syringe
and the mixture was stirred at 60 °C under Ar. When the sub-
strate was consumed (monitored by TLC), the reaction mixture
was cooled to r.t. The solvent was removed by rotary evapora-
tion and the resulting residue was purified by column chroma-
tography on silica gel to afford the product 2a in 73% yield.
Characterization of Typical Products:
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2e: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.42–7.45 (m, 1
H), 7.22–7.25 (m, 2 H), 7.09–7.13 (m, 1 H), 4.59–4.66 (m, 1 H),
3.60–3.67 (m, 2 H), 3.50–3.56 (m, 1 H), 3.13–3.17 (m, 2 H),
3.04–3.09 (m, 1 H), 2.85–2.92 (m, 1 H), 2.41–2.55 (m, 1 H),
2.24–2.30 (m, 2 H). 13C NMR (101 MHz, CDCl3): δ = 140.32,
129.61, 128.48, 125.72, 124.96, 115.40, 125.36 (q, J = 256.1 Hz),
57.33 (d, J = 4.0 Hz), 46.82, 42.64, 40.78 (q, J = 27.3 Hz), 34.34,
26.18. 19F NMR (376 MHz, CDCl3): δ = –62.90 (s, 3 F). HRMS
(ESI): m/z [M + NH4]+ calcd for C13H19ClF3N2O2S: 359.0808;
found: 359.0802.
2l: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.62–7.65 (m, 1
H), 7.53 (d, J = 8.3 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 6.92–6.97 (m,
1 H), 6.75–6.78 (m, 1 H), 4.42–4.48 (m, 1 H), 2.83–2.94 (m, 2 H),
2.70–2.75 (m, 1 H), 2.40–2.49 (m, 1 H), 2.38 (s, 3 H). 13C NMR
(101 MHz, CDCl3): δ = 160.55 (d, J = 245.1 Hz), 144.57, 136.79
(d, J = 2.1 Hz), 133.84, 132.95 (d, J = 8.8 Hz), 129.84, 127.17,
125.53 (q, 278.8 Hz), 118.57 (d, J = 8.8 Hz), 114.83 (d, J = 23.6
Hz), 112.42 (d, J = 24.3 Hz), 57.29 (q, J = 3.1 Hz), 40.46 (q, J = 27.0
Hz), 34.09, 21.54. 19F NMR (376 MHz, CDCl3): δ = –63.09 (s, 3 F),
–117.49 (s, 1 F). HRMS (ESI): m/z [M + NH4]+ calcd for
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C17H19F4N2O2S: 391.1103; found: 391.1098.
2o: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.19–7.39 (m,
10 H), 4.24 (d, J = 11.2 Hz, 1 H), 4.13–4.16 (m, 1 H), 3.98–4.05
(m, 1 H), 3.33–3.38 (m, 1 H), 3.01–3.15 (m, 1 H), 2.39–2.44 (m, 1
H), 2.22 (s, 3 H), 2.04–2.17 (m, 1 H). 13C NMR (101 MHz, CDCl3):
δ = 144.48, 143.81, 129.13, 128.85, 127.38, 126.99, 126.76,
126.40, 125.72 (q, J = 278.4 Hz), 59.29, 54.28, 53.37, 43.25, 40.45
(q, J = 26.26 Hz), 35.06. 19F NMR (376 MHz, CDCl3): δ = –63.43 (s,
3 F). HRMS (ESI): m/z [M + NH4]+ calcd for C19H24F3N2O2S:
401.1511; found: 401.1505.
2q: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.21–7.45 (m,
10 H), 4.46–4.53 (m, 1 H), 3.86 (s, 3 H), 3.07 (dd, J = 12.7, 4.6 Hz,
1 H), 2.76–2.90 (m, 1 H), 2.65–2.71 (m, 1 H), 2.37–2.51 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 158.96, 142.20, 141.21, 128.77,
128.13, 128.07, 127.62, 127.59, 127.13, 125.10 (q, J = 278.0 Hz),
73.87 (d, J = 3.0 Hz), 62.74, 57.41, 45.44, 38.84 (q, J = 28.3 Hz).
19F NMR (376 MHz, CDCl3): δ = –63.70 (s, 3 F). HRMS (ESI): m/z
[M + H]+ calcd for C19H19F3NO2: 350.1368; found: 350.1362.
2r: colorless oil. 1H NMR (400 MHz, CDCl3): δ = 7.24–7.40 (m, 10
H), 4.56–4.63 (m, 1 H), 3.19 (dd, J = 13.1, 3.2 Hz, 1 H), 2.65–2.78
(m, 2 H), 2.39–2.52 (m, 1 H). 13C NMR (101 MHz, CDCl3): δ =
176.01, 141.33, 138.94, 129.15, 128.56, 128.06, 127.58, 127.52,
127.21, 125.02 (q, J = 278.3 Hz), 70.47 (d, J = 3.0 Hz), 57.52,
43.44, 39.17 (q, J = 29.3 Hz). 19F NMR (376 MHz, CDCl3): δ = –63.76
(s, 3 F). HRMS (ESI): m/z [M + NH4]+ calcd for C18H19F3NO2:
338.1368; found: 338.1362.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D