Copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes: Convenient synthesis of CF3-containing alkyl nitriles

Article abstract of DOI:10.1016/j.jfluchem.2014.04.004

A copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes has been developed, in which the less reactive Togni reagent 2 was used as a CF₃ source and TMSCN was employed as a cyano source. Both activated and unactivated alkenes were suitable for this transformation to give CF₃-containing organonitriles under mild conditions.

Full text of DOI:10.1016/j.jfluchem.2014.04.004

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Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Copper-catalyzed intermolecular cyanotrifluoromethylation of
alkenes: Convenient synthesis of CF3-containing alkyl nitriles
*
Zhaoli Liang, Fei Wang, Pinhong Chen, Guosheng Liu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A copper-catalyzed intermolecular cyanotrifluoromethylation of alkenes has been developed, in which
the less reactive Togni reagent 2 was used as a CF3 source and TMSCN was employed as a cyano source.
Both activated and unactivated alkenes were suitable for this transformation to give CF3-containing
organonitriles under mild conditions.
Received 28 January 2014
Received in revised form 26 March 2014
Accepted 7 April 2014
Available online xxx
ß 2014 Elsevier B.V. All rights reserved.
Keywords:
Copper-catalyzed
Trifluoromethylation
Alkene
Organonitrile
1. Introduction
Recently, a notable development of allylic trifluoromethylation
of alkenes was reported independently by Buchwald, Liu, Wang
Organonitriles have been widely recognized as important
organic compounds and applied in organic synthesis as valuable
intermediates and building blocks due to their versatile chemical
property and bioactivities [1]. Elegant methodologies have been
reported for the conversion of organonitrile to diverse organic
compounds, such as organocarboxylic acid, which have extensively
been applied in pharmaceuticals and agricultural chemicals [2].
Representative organonitriles and related carboxylic acid exhib-
ited some bioactivity, such as enzyme inhibitor, anti HIV and hNK2
receptor [3] (Fig. 1). Therefore, many efforts have been paid to
introduce nitrile group into organic molecules. On the other hand,
trifluoromethyl group is prevalent in pharmaceuticals and
agrochemicals due to its unique properties [4]. We speculated
that, if both CF3 and nitrile groups can be simultaneously
introduced into organic compounds, efficient synthesis of trifluor-
omethylated organonitriles and related derivatives might be
expected, which will shed a light to introduce CF3 into original
leading compounds or drugs to adjust their bioactivity. Herein we
report a copper-catalyzed intermolecular cyanotrifluoromethyla-
tion of alkenes to construct CF3-containing organonitriles under
very mild conditions [5].
and Sodeoka groups [6]. Since then, the trifluoromethylation of
alkenes has been disclosed to allowing the effective formation of
Csp3–CF3 bond [7]. Among them, three-component coupling
trifluoromethylation reactions have received more and more
attention [7c–g,k]. In 2012, our group reported the first difunctio-
nalization of alkenes involving trifluoromethylation using
a
palladium catalyst [8]. As a continuation of our interest in
difunctionalization of alkenes [9], our group recently discovered
a copper-catalyzed intermolecular trifluoromethylazidation of
alkenes [10], in which
a carbon radical or carbon cation
intermediate was proposed to be trapped by an azide reagent.
Inspired by this result, we envisioned that this carbon radical or
carbon cation intermediate might also be trapped by a cyano
reagent to introduce both CF3 and CN groups into the alkenes
(Scheme 1). If so, a variety CF3-containing organonitriles and their
derivatives could be expected to achieve through a very efficient
´
approach. Very recently, Szabo and Liang also independently
reported copper-mediated or -catalyzed cyanotrifluoromethyla-
tion of alkenes with the same strategy using more reactive ester
type Togni reagent [5].
2. Results and discussion
In our previous study, trimethylsilyl azide (TMSN3) plays an
*
Corresponding author. Tel.: +86 21 54925346; fax: +86 21 64166128.
E-mail address: gliu@mail.sioc.ac.cn (G. Liu).
important role to activate less active Togni reagent (2) to generate
http://dx.doi.org/10.1016/j.jfluchem.2014.04.004
0022-1139/ß 2014 Elsevier B.V. All rights reserved.
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Fig. 1. Representative bioactive trifluoromethylated nitriles and derivative.
CF3 radical in the presence of copper catalyst. Thus, the initial study
was focused on the reaction of styrene (1a) with Togni reagent (2)
in the presence of copper catalysts, and trimethylsilyl cyanide
(TMSCN) was employed as a cyano source. As shown in Table 1, the
reaction of 1a did afford the desired cyanotrifluoromethylation
product 3a in the presence of 5 mol% Cu(CH3CN)4PF6 in DMSO at
room temperature (Table 1, entry 1). Solvent screening implied
that DMSO was the best solvent for this reaction. Then different
copper salts were applied into the reaction which showed that all
listed copper salts could catalyze this reaction (entries 2–8). Firstly,
copper catalysts, such as CuTc and (CuOTf)2ÁC6H6, were tested to
give only moderate yield (entries 2 and 3). Secondly, when
copper(II) catalyst was used, the yield was not improved (entry 4).
And the copper powder was also used to catalyze this reaction,
albeit in low yield (entry 5). Finally, copper complexes with
bidentate nitrogen ligand L1–L3 were used, and the yield was
improved significantly to 93% in the presence of 10 mol% (L3)CuBr
(entries 6–8). The yield was decreased to 85% with lowered
catalyst loading (5%) (entry 9). The combination of CuBr and
ligand L3 to generate the copper complex in situ was not as
effective as the prepared complex (entry 10). Control experiment
showed that no reaction took place in the absence of a copper
catalyst (entry 11).
yield without loss of halides. In additional, the reaction of cyclic
styrene 1k afforded a desired product 3k in 73% yield with
excellent diastereoselectivity (>20:1).
Intrigued by the results of styrenes, we extended the substrate
scope to aliphatic substituted alkenes. To our delight, the reaction of
alkyl substituted alkenes proceeded smoothly to give desired
products. Forinstance, simplealkene1lcould betransformed to 3lin
74% yield. Importantly, the reaction of enamine substrate 1m
proceededwelltogive3mingoodyield, whichcould betransformed
to 2-amino-4,4,4-trifluorobutanenitrile as an important building
block after deprotection. The reaction of 1n–p with an imide group
afforded 3n–p in good yields. A free proton of N-allylaniline 1q did
Table 1
Optimization of reaction condition.a
.
With the optimized reaction conditions in hand, the substrate
scope was investigated and the results are summarized in Table 2.
Styrenes 1a–1j bearing various substituents on the aromatic ring,
including electron-donating and electron-withdrawing groups,
were compatible with this reaction condition to give 3a–j in good
to excellent yields. Among them, substrates 1c–1d, 1g–1h bearing
halides gave the corresponding products 3c–d, 3g–h in 84–98%
Entry
Catalyst (mol%)
Yield (%)b
1
2
Cu(CH3CN)4PF6 (5)
CuTc (5)
76
50
61
56
27
76
80
93
85
87
0
3
(CuOTf)2ÁC6H6 (5)
CuBr2 (10)
4
5
Cu powder (5)
(L1)CuBr (10)
(L2)CuBr (10)
(L3)CuBr (10)
(L3)CuBr (5)
(L3)CuBr (10)
-
6
7
8
9
10c
11d
a
Reaction conditions: 1a (0.1 mmol), Cu catalyst (10 mol%), TMSCN (0.2 mmol),
Togni reagent 2 (0.15 mmol) in DMSO (0.5 mL) at room temperature in 0.5 h.
b
NMR yield, determined by 19F NMR spectroscopy using N,N-dimethyltrifluor-
oacetamide (DMA-CF3) as an internal standard.
c
CuBr and L3 were added separately.
d
Scheme 1. Copper-catalyzed intermolecular difunctionalization of alkenes.
Without copper catalyst.
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3
Table 2
Copper-catalyzed cyanotrifluoromethylation of alkenes.a,b
a
Reaction conditions: 1 (0.2 mmol), (L3)CuBr (10 mol%), TMSCN (0.4 mmol), Togni reagent 2 (0.3 mmol) in DMSO (1.0 mL) at room temperature in 0.5 h.
b
Isolated yield.
c
d.r. > 20:1.
d
CH3CN was used as solvent instead of DMSO.
e
d.r. = 1:1.
not affect the reaction to give product 3q, rather than trifluor-
omethylated aziridine product [7k], albeit in 47% yield. Functional
groups in the alkene substrates, such as amide, ester, aldehyde and
ketone, were tolerated under the reaction condition to give 3r–u in
good yields. Forthe electron-deficientalkene, the reaction could also
smoothly proceed to give product 3v in moderate yield (53%).
To shed light on this transformation, some preliminary
mechanism studies were conducted. When 1.5 equiv of TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy) was added into the reac-
tion system, the desired product 3o was partly inhibited to give
in 24% yield and TEMPO–CF3 adduct was observed by 19F NMR
(Eq. (1)). Furthermore, when vinyl cyclopropane 4, a faster
radical clock, was conducted under the standard reaction
conditions, the ring-opening product 5 was obtained as a single
product in 71% yield (Eq. (2)). Based on those observations, a
mechanistic pathway was proposed that Togni reagent (2) was
activated by TMS group and Cu(I) to give CF3 radical, followed by
the reaction with alkene to give a carbon radical or carbon cation
intermediate which was trapped by TMSCN to yield the final
product.
(1)
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(2)
3. Conclusion
4.3.1. 4,4,4-Trifluoro-2-phenylbutanenitrile (3a)
General procedure A: Pale yellow liquid; 34.6 mg, 87%; 1H NMR
(400 MHz, CDCl3): 7.43–7.36 (m, 5H), 4.10 (dd, J = 9.6, 5.2 Hz, 1H),
2.90–2.77 (m, 1H), 2.66–2.54 (m, 1H); 13C NMR (100 MHz, CDCl3):
133.4, 129.5, 128.9, 127.1, 124.6 (q, J = 276.3 Hz), 118.5, 39.7 (q,
In this report, we have developed a copper-catalyzed intermo-
lecular cyanotrifluoromethylation of alkenes, in which the less
reactive Togni reagent 2 was used as a CF3 source and TMSCN was
employed as a cyano source under mild reaction conditions. Both
activated and unactivated alkenes were suitable for this transfor-
mation with good functional groups tolerance. This reaction
afforded a convenient way to trifluoromethylated nitriles for
medicinal chemistry. Further application of this reaction is in
progress.
d
d
J = 29.7 Hz), 31.2 (q, J = 3.4 Hz); 19F NMR (376 MHz, CDCl3):
d
À65.1
(t, J = 9.4 Hz); HRMS (EI), calcd. for C10H8F3N 199.0609 [M]+; found
199.0610.
4.3.2. 2-(4-(Tert-butyl)phenyl)-4,4,4-trifluorobutanenitrile (3b)
General procedure A: Pale yellow solid; 46 mg, 90%; 1H NMR
(400 MHz, CDCl3):
4.08 (dd, J = 9.6, 4.8 Hz, 1H), 2.89–2.75 (m, 1H), 2.65–2.50 (m, 1H),
1.33 (s, 9H); 13C NMR (100 MHz, CDCl3):
152.2, 130.4, 126.8, 126.5,
124.7 (q, J = 275.9 Hz), 118.6, 39.7 (q, J = 29 Hz), 34.6, 31.1, 30.7 (q,
d 7.45 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H),
4. Experimental
d
4.1. General
J = 3.0 Hz); 19F NMR (376 MHz, CDCl3):
d
À65.2 (t, J = 9.7 Hz); HRMS
All reactions were carried out in an oven-dried glass tube with
rubber stopper caps under nitrogen atmosphere. All commercially
available compounds obtained from Aldrich, Alfa Aesar, Adamas are
used as received. NMR spectra were recorded on Varian Inova 400
and Aglient 400 (400 MHz for 1H; 376 MHz for 19F; 100 MHz for 13C)
(EI), calcd. for C14H16F3N 255.1235 [M]+, found 255.1233.
4.3.3. 2-(4-Chlorophenyl)-4,4,4-trifluorobutanenitrile (3c)
General procedure A: Pale yellow liquid; 39.2 mg, 84%; 1H NMR
(400 MHz, CDCl3):
4.09 (dd, J = 8.8, 5.2 Hz, 1H), 2.90–2.75 (m, 1H), 2.64–2.52 (m, 1H);
13C NMR (100 MHz, CDCl3):
135.2, 131.8, 129.8, 128.6, 124.4 (q,
J = 276.3 Hz), 118.1, 39.5 (q, J = 29.4 Hz), 30.7 (q, J = 3.0 Hz); 19F
NMR (376 MHz, CDCl3):
À64.9 (t, J = 9.4 Hz); HRMS (EI), calcd. for
10H7ClF3N 233.0219 [M]+, found 233.0217.
d 7.40 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H),
spectrometer. The chemical shifts (d) are given in ppm relative to
CDCl3 (7.26 ppm for 1H) and CDCl3 (77.0 ppm for 13C). Flash column
chromatography was performed on silica gel (particle size 300–400
mesh, purchased from Canada) and eluted with petroleum ether/
ethyl acetate. Dimethyl sulfoxide (DMSO) was distillated under
reduced pressure over CaH2 before using. Acetonitrile (CH3CN) was
dried by refluxing over CaH2 and distillated before using.
d
d
C
4.3.4. 2-(4-Bromophenyl)-4,4,4-trifluorobutanenitrile (3d)
General procedure A: Pale yellow liquid; 54.5 mg, 98%; 1H NMR
4.2. Typical procedure for copper complex [11]
(400 MHz, CDCl3):
4.08 (dd, J = 8.8, 5.2 Hz, 1H), 2.87–2.78 (m, 1H), 2.62–2.56 (m, 1H);
13C NMR (100 MHz, CDCl3):
132.7, 132.4, 128.9, 124.4 (q,
J = 276.2 Hz), 123.2, 118.0, 39.4 (q, J = 29.4 Hz), 30.8 (q, J = 3.4 Hz);
d 7.56 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H),
A mixture of CuBr (0.57 g, 4 mmol) and 2,9-dimethyl-1,10-
phenanthroline (L3) (0.72 g, 2 mmol) in CH3CN (30 ml) was stirred
overnight under nitrogen atmosphere at room temperature. The
copper complex was obtained as a brick-red solid in 90% yield.
d
19F NMR (376 MHz, CDCl3):
d
À64.9 (t, J = 9.4 Hz); HRMS (EI), calcd.
for C10H7BrF3N 276.9714 [M]+, found 276.9716.
4.3. Typical procedure for cyanotrifluoromethylation of alkenes
4.3.5. Methyl 4-(1-cyano-3,3,3-trifluoropropyl)benzoate (3e)
General procedure A: Pale yellow liquid; 38.1 mg, 74%; 1H NMR
General procedure A: To a dried glass tube, Togni reagent 2
(99 mg, 0.3 mmol, 1.5 equiv), (L3)CuBr (10 mg, 0.02 mmol,
0.1 equiv) and DMSO (1.0 mL) were added under N2 atmosphere,
(400 MHz, CDCl3):
4.17 (dd, J = 8.8, 5.2 Hz, 1H), 3.93 (s, 3H), 2.95–2.77 (m, 1H), 2.70–
2.55 (m, 1H); 13C NMR (100 MHz, CDCl3):
166.1, 138.0, 131.0,
130.8, 127.4, 124.5 (q, J = 276.3 Hz), 117.9, 52.4, 39.4 (q, J = 30 Hz),
d 8.09 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H),
d
followed by substrate 1 (0.2 mmol, 1.0 equiv) and TMSCN (54
mL,
0.4 mmol, 2.0 equiv). After the reaction mixture was stirred at
room temperature for 0.5 h, dichloromethane was added and the
mixture was filtered through a short pad of celite. The filtrate was
washed with water (15 mL Â 3) and dried over anhydride Na2SO4.
After the removal of solvent, the residue was purified by column
chromatography on silica gel with a gradient eluent of petroleum
ether and ethyl acetate to afford the product.
General procedure B: To a dried glass tube, Togni reagent 2
(99 mg, 0.3 mmol, 1.5 equiv), (L3)CuBr (10 mg, 0.02 mmol,
0.1 equiv) and CH3CN (1.0 mL) were added under N2 atmosphere,
31.2(q, J = 3.1 Hz);19FNMR(376 MHz, CDCl3):
d
À64.9(t, J = 9.4 Hz);
HRMS (EI), calcd. for C12H10F3NO2 257.0664 [M]+, found 257.0668.
4.3.6. 2-(4-Acetylphenyl)-4,4,4-trifluorobutanenitrile (3f)
General procedure A: Pale yellow liquid; 36.1 mg, 75%; 1H NMR
(400 MHz, CDCl3):
4.18 (dd, J = 9.2, 5.2 Hz, 1H), 2.93–2.78 (m, 1H), 2.69–2.56 (m, 1H),
2.62 (s, 3H); 13C NMR (100 MHz, CDCl3):
197.0, 138.1, 137.5,
129.5, 127.6, 124.4 (q, J = 276.3 Hz), 117.9, 39.3 (q, J = 29.6 Hz),
31.1 (q, J = 3.1 Hz), 26.6; 19F NMR (376 MHz, CDCl3):
d 8.01 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H),
d
d
À64.9 (t,
followed by substrate 1 (0.2 mmol, 1.0 equiv) and TMSCN (54
m
L,
J = 9.8 Hz); HRMS (ESI), m/z: calcd. for C12H11F3NO 242.0793
0.4 mmol, 2.0 equiv). After the reaction mixture was stirred at
room temperature for 0.5 h, the mixture was concentrated under
vacuum. The residue was purified by column chromatography on
silica gel with a gradient eluent of petroleum ether and ethyl
acetate to afford the product.
[M+H]+, found 242.0793.
4.3.7. 2-(3-Bromophenyl)-4,4,4-trifluorobutanenitrile (3g)
General procedure A: Pale yellow liquid; 51.7 mg, 93%; 1H NMR
(400 MHz, CDCl3): d 7.56–7.50 (m, 2H), 7.35–7.28 (m, 2H), 4.07 (dd,
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5
J = 9.6, 5.6 Hz, 1H), 2.90–2.76 (m, 1H), 2.66–2.53 (m, 1H); 13C NMR
(100 MHz, CDCl3): 135.4, 132.3, 131.1, 130.3, 125.9, 124.4 (q,
J = 276.4 Hz), 123.4, 117.9, 39.8 (q, J = 31.1 Hz), 30.8 (q, J = 3.1 Hz);
4.3.14. 2-((1,3-Dioxoisoindolin-2-yl)methyl)-4,4,4-
d
trifluorobutanenitrile (3n)
General procedure B: Orange solid; 41.7 mg, 74%; 1H NMR
19F NMR (376 MHz, CDCl3):
d
À62.5 (t, J = 9.8 Hz); HRMS (EI), calcd.
(400 MHz, CDCl3):
4.05 (m, 1H), 3.94–3.89 (m, 1H), 3.51–3.42 (m, 1H), 2.70–2.55 (m,
1H), 2.55–2.40 (m, 1H); 13C NMR (100 MHz, CDCl3):
167.5, 134.6,
131.3, 124.7 (q, J = 276.3 Hz), 123.8, 117.2, 38.4, 34.3 (q,
J = 30.4 Hz), 25.4 (q, J = 3.0 Hz); 19F NMR (376 MHz, CDCl3):
d 7.92–7.86 (m, 2H), 7.81–7.74 (m, 2H), 4.15–
for C10H7BrF3N 276.9714 [M]+, found 276.9710.
d
4.3.8. 2-(2-Bromophenyl)-4,4,4-trifluorobutanenitrile (3 h)
General procedure A: Pale yellow liquid; 46.7 mg, 84%; 1H NMR
d
(400 MHz,CDCl3):
(t, J = 7.4 Hz, 1H), 4.63–4.58 (dd, J = 10.0, 4.0 Hz, 1H), 2.80–2.58 (m,
2H); 13C NMR (100 MHz, CDCl3):
133.8, 132.7, 130.7, 129.1, 128.7,
124.5 (q, J = 276.3 Hz), 122.6, 117.9, 37.9 (q, J = 29.6 Hz), 31.3 (q,
d
7.63(d,J = 7.6 Hz,2H),7.43(t,J = 7.2 Hz,1H),7.27
À64.8 (t, J = 10.2 Hz); HRMS (ESI), m/z: calcd. for C13H13F3N3O2
300.0954 [M+NH4]+, found 300.0958.
d
4.3.15. 2-(2-(1,3-Dioxoisoindolin-2-yl)ethyl)-4,4,4-
trifluorobutanenitrile (3o)
J = 3.1 Hz); 19F NMR (376 MHz, CDCl3):
d
À65.1 (t, J = 9.4 Hz); HRMS
(EI), calcd. for C10H7BrF3N 276.9714 [M]+, found 276.9712.
General procedure B: Pale yellow liquid; 45.6 mg, 77%; 1H NMR
(400 MHz, CDCl3):
3.84 (m, 2H), 2.99–2.93 (m, 1H), 2.65–2.56 (m, 1H), 2.56–2.42 (m,
1H), 2.17–2.01 (m, 2H); 13C NMR (100 MHz, CDCl3):
168.1, 134.2,
131.7, 124.8 (q, J = 276.3 Hz), 123.4, 118.8, 35.8 (q, J = 29.9 Hz),
d 7.86–7.81 (m, 2H), 7.75–7.70 (m, 2H), 3.93–
4.3.9. 2-(3,4-Dimethylphenyl)-4,4,4-trifluorobutanenitrile (3i)
General procedure A: Pale yellow liquid; 41.8 mg, 92%; 1H NMR
d
(400 MHz, CDCl3):
d 7.18 (d, J = 7.6 Hz, 1H), 7.13 (s, 1H), 7.08 (d,
J = 8.0 Hz, 1H), 4.03 (dd, J = 10, 5.2 Hz, 1H), 2.87–2.74 (m, 1H),
2.63–2.51 (m, 1H), 2.29 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz,
34.8, 30.6, 23.3 (q, J = 3.0 Hz); 19F NMR (376 MHz, CDCl3):
d
À64.6
(t, J = 10.2 Hz); HRMS (EI), calcd. for C14H11F3N2O2 296.0773 [M]+,
CDCl3):
d
138.0, 137.6, 130.8, 130.6, 128.2, 124.6 (q, J = 276.3 Hz),
found 296.0778.
124.4, 118.8, 39.8 (q, J = 28.8 Hz), 30.8 (q, J = 3.0 Hz), 19.7, 19.4; 19
F
NMR (376 MHz, CDCl3):
d
À62.1 (t, J = 10.2 Hz); HRMS (EI), calcd.
4.3.16. 5-(1,3-Dioxoisoindolin-2-yl)-2-(2,2,2-
trifluoroethyl)pentanenitrile (3p)
for C12H12F3N 227.0922 [M]+, found 227.0919.
General procedure B: Pale yellow liquid; 45.6 mg, 77%; 1H NMR
4.3.10. 4,4,4-Trifluoro-2-(naphthalen-2-yl)butanenitrile (3j)
(400 MHz, CDCl3): d 7.84 (dd, J = 5.6, 3.2 Hz, 2H), 7.72 (dd, J = 5.6,
3.2 Hz, 2H), 3.75 (t, J = 6.8 Hz, 2H), 3.04–2.94 (m, 1H), 2.59–2.44
General procedure A: Pale yellow liquid; 184 mg, 74%; 1H NMR
(400 MHz, CDCl3):
7.53 (m, 2H), 7.42 (d, J = 8 Hz, 1H), 4.27 (dd, J = 9.6, 5.2 Hz, 1H), 2.99–
2.84 (m, 1H), 2.76–2.63 (m, 1H); 13C NMR (100 MHz, CDCl3):
133.2,
d
7.91 (d, J = 8 Hz, 1H), 7.89–7.83 (m, 3H), 7.59–
(m, 1H), 2.39–2.26 (m, 1H), 2.04–1.91 (m, 1H), 1.91–1.81 (m, 1H),
1.81–1.68 (m, 2H); 13C NMR (100 MHz, CDCl3):
d 168.3, 134.1,
d
131.8, 124.9 (q, J = 275.5 Hz), 123.3, 119.2, 36.5, 36.3 (q,
J = 29.7 Hz), 29.2, 26.0, 25.0 (q, J = 2.6 Hz); 19F NMR (376 MHz,
133.0, 130.5, 129.7, 127.9, 127.8, 127.1, 127.0, 126.6, 124.6 (q,
J = 276.7 Hz), 124.0, 118.6, 39.6 (q, J = 29.6 Hz), 31.3 (q, J = 3.0 Hz);
CDCl3):
d
À64.9 (t, J = 10.2 Hz); HRMS (EI), calcd. for C15H13F3N2O2
19F NMR (376 MHz, CDCl3):
d
À65.0 (t, J = 9.4 Hz); HRMS (EI), calcd.
310.0929 [M]+, found 310.0926.
for C14H10F3N 249.0765 [M]+, found 249.0768.
4.3.17. 4,4,4-Trifluoro-2-((phenylamino)methyl)butanenitrile (3q)
General procedure B: Green liquid; 21.6 mg, 47%; 1H NMR
4.3.11. 2-(Trifluoromethyl)-2,3-dihydro-1H-indene-1-carbonitrile
(3k)
(400 MHz, CDCl3):
d 7.32 (t, J = 8.4 Hz, 2H), 6.81 (t, J = 7.2 Hz, 1H),
General procedure A: Pale yellow liquid; 30.8 mg, 74%,
6.63 (d, J = 8.4 Hz, 2H), 4.07 (t, J = 6.0 Hz, 1H), 3.54 (t, J = 6.8 Hz, 2H),
3.25–2.18 (m, 1H), 2.63–2.40 (m, 2H); 13C NMR (100 MHz, CDCl3):
dr > 20:1; 1H NMR (400 MHz, CDCl3):
d
7.48–7.43 (m, 1H),
7.38–7.32 (m, 2H), 7.31–7.25 (m, 1H), 4.35 (d, J = 9.2 Hz, 1H),
3.55–3.40 (m, 1H), 3.36–3.30 (m, 1H), 3.21–3.14 (m, 1H); 13C NMR
d
145.8, 129.7, 125.1 (q, J = 274.4 Hz), 119.1, 118.7, 113.0, 45.1, 33.9
(q, J = 30.1 Hz), 26.1 (q, J = 2.6 Hz); 19F NMR (376 MHz, CDCl3):
d
(100 MHz, CDCl3):
d
139.2, 134.9, 129.4, 128.3, 126.2 (q,
À64.6 (t, J = 10.2 Hz); HRMS (ESI), m/z: calcd. for C11H12F3N2
J = 275.5 Hz), 125.0, 124.4, 118.8, 48.2 (q, J = 28.7 Hz), 35.4 (q,
229.0947 [M+H]+, found 229.0941.
J = 2.9 Hz), 31.8 (q, J = 2.2 Hz); 19F NMR (376 MHz, CDCl3):
d
À68.5
(d, J = 7.9 Hz); HRMS (EI), calcd. for C11H8F3N 211.0609 [M]+, found
4.3.18. 10-Cyano-N,N-diethyl-12,12,12-trifluorododecanamide (3r)
General procedure A: Pale yellow solid; 49.5 mg, 74%; 1H NMR
211.0605.
(400 MHz, CDCl3):
d 3.34 (q, J = 7.2 Hz, 2H), 3.28 (q, J = 7.2 Hz, 2H),
4.3.12. 4,4,4-Trifluoro-2-phenethylbutanenitrile (3l)
2.87–2.80 (m, 1H), 2.59–2.42 (m, 1H), 2.35–2.30 (m, 1H), 2.26 (t,
J = 7.6 Hz, 2H), 1.70–1.40 (m, 6H), 1.40–1.20 (m, 8H), 1.15 (t,
J = 7.2 Hz, 3H), 1.08 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
General procedure A: Pale yellow liquid; 33.6 mg, 74%; 1H NMR
(400 MHz, CDCl3):
d
7.33 (t, J = 6.8 Hz, 2H), 7.26 (d, J = 6.0 Hz, 1H),
7.20 (t, J = 6.8 Hz, 2H), 3.00–2.90 (m, 1H), 2.90–2.70 (m, 2H), 2.60–
172.0, 125.0 (q, J = 275.9 Hz), 119.6, 41.8, 39.9, 36.2 (q, J = 29.4 Hz),
32.9, 31.9, 29.2, 29.1, 28.9, 28.6, 26.5, 25.3 (q, J = 3.3 Hz), 25.2, 14.2,
2.45 (m, 1H), 2.45–2.35 (m, 1H), 2.10–1.90 (m, 2H); 13C NMR
(100 MHz,CDCl3):
119.4, 36.3 (q, J = 29.6 Hz), 33.6, 32.7, 24.9 (q, J = 2.7 Hz); 19F NMR
(376 MHz, CDCl3):
À64.8(t, J = 10.2 Hz); HRMS (ESI), m/z: calcd. for
12H13F3N 228.0995 [M+H]+, found 228.0991.
d
139.0,128.8,128.3,126.7,125.0(q,J = 276.3 Hz),
12.9; 19F NMR (376 MHz, CDCl3):
d
À65.0 (t, J = 10.2 Hz); HRMS
(ESI), m/z: calcd. for C17H30F3N2O 335.2305 [M+H]+, found
d
335.2295.
C
4.3.19. Benzyl 3-cyano-5,5,5-trifluoropentanoate (3s)
4.3.13. 2-(1,3-Dioxoisoindolin-2-yl)-4,4,4-trifluorobutanenitrile
(3m)
General procedure A: Pale yellow liquid; 39.9 mg, 70%; 1H NMR
(400 MHz, CDCl3):
d 7.41–7.32 (m, 5H), 5.15 (d, J = 2.4 Hz, 2H),
General procedure B: Pale yellow solid; 46.6 mg, 87%; 1H NMR
3.10–3.00 (m, 1H), 2.70–2.60 (m, 2H), 2.60–2.45 (m, 1H), 2.45–
2.30 (m, 1H), 2.15–2.00 (m, 1H), 2.00–1.90 (m, 1H); 13C NMR
(400 MHz, CDCl3):
3.2 Hz, 2H), 5.54 (dd, J = 8.4, 5.2 Hz, 1H), 3.33–3.17 (m, 1H), 3.06–
2.94 (m, 1H); 13C NMR (100 MHz, CDCl3):
165.5, 135.1, 131.0,
124.3, 124.0 (q, J = 276.3 Hz), 114.0, 35.0 (q, J = 30.0 Hz), 33.9 (q,
J = 3.8 Hz); 19F NMR (376 MHz, CDCl3):
À65.1 (t, J = 10.0 Hz);
HRMS (EI), calcd. for C12H7F3N2O2 268.0460 [M]+, found 268.0456.
d 7.94 (dd, J = 5.2, 3.2 Hz, 2H), 7.82 (dd, J = 5.2,
(100 MHz, CDCl3):
d 171.4, 135.3, 128.6, 128.3, 124.9 (q,
d
J = 275.9 Hz), 118.9, 66.8, 36.3 (q, J = 29.6 Hz), 30.9, 27.1, 24.8
(q, J = 2.7 Hz); 19F NMR (376 MHz, CDCl3):
d
À64.8 (t, J = 10.2 Hz);
d
HRMS (EI), calcd. for C14H14F3NO2 285.0977 [M]+, found
285.0980.
Please cite this article in press as: Z. Liang, et al., J. Fluorine Chem. (2014), http://dx.doi.org/10.1016/j.jfluchem.2014.04.004

G Model
FLUOR-8300; No. of Pages 6
6
Z. Liang et al. / Journal of Fluorine Chemistry xxx (2014) xxx–xxx
4.3.20. 11-Oxo-2-(2,2,2-trifluoroethyl)undecanenitrile (3t)
References
General procedure B: Pale yellow liquid; 42.7 mg, 81%; 1H NMR
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(400 MHz, CDCl3):
1H), 2.42 (t, J = 7.2 Hz, 2H), 2.36–2.26 (m, 1H), 1.74–1.52 (m, 5H),
1.40–1.26 (m, 9H); 13C NMR (100 MHz, CDCl3):
202.9, 125.1 (q,
J = 275.8 Hz), 119.7, 43.8, 36.3 (q, J = 29.8 Hz), 32.0, 29.1, 29.0, 28.9,
28.7, 26.6, 25.5 (q, J = 3.0 Hz), 21.9; 19F NMR (376 MHz, CDCl3):
d 9.75 (s, 1H), 2.87–2.80 (m, 1H), 2.60–2.46 (m,
d
[3] (a) R.A. Buhrmester, J.E. Ebinger, D.S. Seigler, Biochem. Syst. Ecol. 28 (2000)
689–695;
d
À65.0 (t, J = 9.4 Hz); HRMS (ESI), m/z: calcd. for C13H18F3NO
´
(b) A. Benjahad, K. Courte, J. Guillemont, D. Mabire, S. Coupa, A. Poncelet, I. Csoka,
261.1340 [MÀ2H]+, found 261.1337.
K. Andries, R. Pauwels, M.-P. de Be´thune, C. Monneret, E. Bisagni, C.H. Nguyen, D.S.
Grierson, J. Med. Chem. 47 (2004) 5501–5514;
(c) C. Bissantz, P. Jablonski, H. Knust, A. Koblet, A. Limberg, M. Nettekoven, H.
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(d) A. Bhardwaj, J. Kaur, S.K. Sharma, Z. Huang, F. Wuest, E.E. Knaus, Bioorg. Med.
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4.3.21. 4,4,4-Trifluoro-2-((2-oxocyclohexyl)methyl)butanenitrile
(3u)
General procedure B: Brown solid; 40.5 mg, 71%, dr = 1:1; 1H
[4] (a) T. Hiyama, Organofluorine Compounds: Chemistry and Applications, Spring-
er, Berlin, 2000;
NMR (400 MHz, CDCl3):
2.55–2.32 (m, 4H), 2.17–2.00 (m, 3H), 1.90–1.60 (m, 3H), 1.50–1.35
(m, 2H); 13C NMR (100 MHz, CDCl3):
212.0, 125.0 (q,
J = 277.9 Hz), 119.9, 48.0, 42.3, 37.0 (q, J = 29.7 Hz), 35.3, 33.0,
28.1, 25.2, 24.3 (q, J = 2.9 Hz); 19F NMR (376 MHz, CDCl3):
À64.6
(t, J = 9.8 Hz); 1H NMR (400 MHz, CDCl3):
3.00–2.90 (m, 1H),
2.62–2.10 (m, 9H), 1.80–1.60 (m, 3H), 1.43–2.30 (m, 1H); 13C NMR
(100 MHz, CDCl3): 210.9, 125.0 (q, J = 273.3 Hz), 119.3, 47.6, 42.0,
36.7 (q, J = 29.4 Hz), 33.2, 31.6, 27.7, 25.0, 22.9 (q, J = 3.1 Hz); 19F
d 3.32–3.23 (m, 1H), 2.71–2.61 (m, 1H),
(b) P. Jeschke, Chembiochem 5 (2004) 570–589;
(c) K. Mu¨ller, C. Faeh, F. Diederich, Science 317 (2007) 1881–1886;
(d) I. Ojima, Fluorine in Medical Chemistry and Chemical Biology, Wiley-Black-
well, Chichester, UK, 2009.
d
d
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´
Szabo and Liang; N.O. Ilchenko, P.G. Janson, K.J. Szabo, J. Org. Chem. 78 (2013)
d
11087–11091;
(b) Y.-T. He, L.-H. Li, Y.-F. Yang, Z.-Z. Zhou, H.-L. Hua, X.-Y. Liu, Y.-M. Liang, Org.
Lett. 16 (2014) 270–273.
d
[6] (a) A.T. Parsons, S.L. Buchwald, Angew. Chem. Int. Ed. 50 (2011) 9120–9123;
(b) J. Xu, Y. Fu, D. Luo, Y. Jiang, B. Xiao, Z. Liu, T. Gong, L. Liu, J. Am. Chem. Soc. 133
(2011) 15300–15303;
NMR (376 MHz, CDCl3):
d
À64.9 (t, J = 9.8 Hz); HRMS (ESI), m/z:
calcd. for C11H18F3N2O 251.1366 [M+NH4]+, found 251.1364.
(c) X. Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y. Zhang, J. Wang, J. Am. Chem. Soc. 133
(2011) 16410–16413;
(d) R. Shimizu, H. Egami, Y. Hamashima, M. Sodeoka, Angew. Chem. Int. Ed. 51
(2012) 4577–4580;
(e) L. Chu, F. Qing, Org. Lett. 14 (2012) 2106–2109.
4.3.22. 4,4,4-Trifluoro-2-(phenylsulfonyl)butanenitrile (3v)
General procedure B: Brown solid; 27.9 mg, 53%; 1H NMR
(400 MHz, CDCl3):
7.69 (t, J = 8.0 Hz, 2H), 4.15 (dd, J = 12.0, 2.8 Hz, 1H), 3.15–3.02 (m,
1H), 2.82–2.68 (m, 1H); 13C NMR (100 MHz, CDCl3):
136.1, 134.2,
129.9, 129.8, 124.1 (q, J = 276.3 Hz), 112.3, 51.1 (q, J = 3 Hz), 31.6
d 8.04 (d, J = 7.2 Hz, 2H), 7.83 (t, J = 7.2 Hz, 1H),
[7] (a) For recent reviews on trifluoromethylation of alkenes, see: A. Studer, Angew.
Chem. Int. Ed. 51 (2012) 8950–8958;
(b) P. Chen, G. Liu, Synthesis (2013) 2919–2939;
(c) For recent trifluoromethylation of alkenes, see: P.G. Janson, I. Ghoneim, N.O.
IIchenko, K.J. Szabo´, Org. Lett. 14 (2012) 2882–2885;
(d) Y. Li, A. Studer, Angew. Chem. Int. Ed. 51 (2012) 8221–8224;
(e) Y. Yasu, T. Koike, M. Akita, Angew. Chem. Int. Ed. 51 (2012) 9567–9571;
(f) R. Zhu, S.L. Buchwald, J. Am. Chem. Soc. 134 (2012) 12462–12465;
(g) C. Feng, T.-P. Loh, Chem. Sci. 3 (2012) 3458–3462;
(h) S. Mizuta, S. Verhoog, K.M. Engle, T. Khotavivattana, M. O’Duill, K. Wheel-
d
(q, J = 32.7 Hz); 19F NMR (376 MHz, CDCl3):
d
À64.4 (t, J = 10.2 Hz);
HRMS (ESI), m/z: calcd. for C10H9F3NO2S 264.0306 [M+H]+, found
264.0309.
´
house, G. Rassias, M. Medebielle, V. Gouverneur, J. Am. Chem. Soc. 135 (2013)
2505–2508;
4.3.23. (E)-7,7,7-Trifluoro-2,5-diphenylhept-4-enenitrile (5)
General procedure A: Pale yellow liquid; 44.8 mg, 71%; 1H NMR
(i) X. Wu, L. Chu, F. Qing, Angew. Chem. Int. Ed. 52 (2013) 2198–2202;
(j) H. Egami, R. Shimizu, S. Kawamura, M. Sodeoka, Angew. Chem. Int. Ed. 52
(2013) 4000–4003;
(k) H. Egami, S. Kawamura, A. Miyazaki, M. Sodeoka, Angew. Chem. Int. Ed. 52
(2013) 7841–7844;
(l) C. Feng, T.-P. Loh, Angew. Chem. Int. Ed. 52 (2013) 12414–12417;
(m) H. Egami, R. Shimizu, Y. Usui, M. Sodeoka, Chem. Commun. 49 (2013)
7346–7348;
(n) H. Egami, R. Shimizua, M. Sodeoka, J. Fluorine Chem. 152 (2013) 51–55;
(o) X. Liu, F. Xiong, X. Huang, L. Xu, P. Li, X. Wu, Angew. Chem. Int. Ed. 52 (2013)
6962–6966;
(400 MHz, CDCl3):
3.97 (t, J = 7.2 Hz, 1H), 3.25 (q, J = 10.4 Hz, 2H), 2.88 (m, 2H); 13C
NMR (100 MHz, CDCl3): 141.1, 134.7, 133.5 (q, J = 2.2 Hz), 129.2,
129.1, 128.4, 128.3, 127.8, 127.2, 126.4, 125.6 (q, J = 277.1 Hz),
120.1, 37.1, 35.1, 34.6 (q, J = 28.8 Hz); 19F NMR (376 MHz, CDCl3):
d 7.45–7.33 (m, 10H), 6.05 (t, J = 5.6 Hz, 1H),
d
d
À63.4 (t, J = 10.5 Hz); HRMS (EI), calcd. for C19H16F3N: 315.1235
[M]+, found 315.1240.
(p) Z.-M. Chen, W. Bai, S.-H. Wang, B.-M. Yang, Y.-Q. Tu, F.-M. Zhang, Angew.
Chem. Int. Ed. 52 (2013) 9781–9785.
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We are grateful for financial support from 973 program (no.
2011CB808700), NSFC (nos. 21225210, 20923005 and 21121062),
STCSM (11JC1415000), and the CAS/SAFEA International Partner-
ship Program for Creative Research Teams.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.jfluchem.2014.04.004.
Please cite this article in press as: Z. Liang, et al., J. Fluorine Chem. (2014), http://dx.doi.org/10.1016/j.jfluchem.2014.04.004