Systematic study of the reactivity of (E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate towards different classes of nucleophiles

Article abstract of DOI:10.1016/j.jfluchem.2015.10.006

A systematic study of the reactivity of (E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate towards different classes of nucleophiles (alcohols, amines, thiols and malonates) was performed. A single set of reaction conditions (with small variations) allowed the isolation of the substitution product in moderate to good yields for all the nucleophiles tested with the exception of benzyl alcohol and indole.

Full text of DOI:10.1016/j.jfluchem.2015.10.006

Accepted Manuscript
Title: Systematic Study of the Reactivity of
(E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate
Towards Different Classes of Nucleophiles
Author: Elsa Forcellini R e´ my Hemelaere Justine Desroches
Jean-Fran c¸ ois Paquin
PII:
S0022-1139(15)00299-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.10.006
FLUOR 8675
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
20-7-2015
5-10-2015
6-10-2015
Please cite this article as: E. Forcellini, R. Hemelaere, J. Desroches, J.-F.
Paquin, Systematic Study of the Reactivity of (E)-4,4,4-trifluorobut-2-en-1-yl 4-
methylbenzenesulfonate Towards Different Classes of Nucleophiles, Journal of
Fluorine Chemistry (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.10.006
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*Graphical Abstract - Pictogram
GRAPHICAL ABSTRACT - PICTOGRAM
Page 1 of 25

*Highlights (for review)
HIGHLIGHTS



The reactivity of (E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate towards
different nucleophiles was performed.
Phenol, amines, thiols, and malonates all provide the substitution product in moderate to
excellent yields.
Benzyl alcohol and indole provide low yield of the desired product.
Page 2 of 25

*Manuscript
Click here to view linked References
Systematic Study of the Reactivity of (E)-4,4,4-trifluorobut-2-
en-1-yl 4-methylbenzenesulfonate Towards Different Classes of
Nucleophiles
Elsa Forcellini, Rémy Hemelaere, Justine Desroches and Jean-François Paquin*
PROTEO, CCVC, Département de chimie, Université Laval,
Québec, QC, Canada G1V 0A6
*
Corresponding author. Tel.: +1 418 656-2131 ext. 11430; fax: +1 418 656-7916
E-Mail address: jean-francois.paquin@chm.ulaval.ca (J.-F. Paquin)
ABSTRACT: A systematic study of the reactivity of (E)-4,4,4-trifluorobut-2-en-1-yl 4-
methylbenzenesulfonate towards different classes of nucleophiles (alcohols, amines,
thiols and malonates) was performed. A single set of reaction conditions (with small
variations) allowed the isolation of the substitution product in moderate to good yields for
all the nucleophiles tested with the exception of benzyl alcohol and indole.
KEYWORDS: trifluoromethyl group, allylic tosylate, substitution reaction, nucleophile,
allylic substitution
1
Page 3 of 25

1
.
Introduction
A number of aromatic compounds used in medicinal chemistry [1], agrochemistry [2] or
in material sciences [3] bear a (E)-((4,4,4-trifluorobut-2-en-1-yl)oxy chain. Until
recently, these products could only be synthesized through a substitution reaction
between a phenol derivative and a suitable electrophilic partner, 1-3 (Figure 1) [1,2,3].
This approach is simple and good yields can be generally obtained for various phenols
even though the allylic mesylate 2 or the allylic chloride 3 have some volatility and
stability issues. Also, the use of other nucleophiles has not been really investigated [4,5].
Figure 1. Traditional approach to molecules containing the 4,4,4-trifluorobut-2-ene chain
attached to a phenolic oxygen.
We have recently explored an alternative strategy using a Tsuji-Trost reaction catalyzed
by nanoparticles starting from either 4,4,4-trifluorobut-2-en-1-yl acetate (4) or
ethyl(4,4,4-trifluorobut-2-en-1-yl)-carbonate (5) (Scheme 1) [6]. These conditions could
be used to attach a 4,4,4-trifluorobut-2-ene chain not only to phenols, but also to
secondary amines and malonates for the first time. However, isomerization of the product
(up to 20%) was observed in the case of the phenol, and a primary amine and thiols could
2
Page 4 of 25

not be used as the desired product was observed in low yield along with multiple side-
products.
Scheme 1. Regioselective Tsuji−Trost reaction catalyzed by palladium nanoparticles.
Considering, on one hand, the simplicity of the S 2 approach, the known practical
N
setbacks of 2 and 3, and the fact that only phenols has been used as nucleophile, and on
the other hand, the limitations observed in our recently developed Tsuji-Trost reaction,
we decided to reinvestigate the use of the S 2 reaction with various nucleophiles,
N
including those who did not behave well in the Tsuji-Trost reaction, using allylic tosylate
1
(Scheme 2). We therefore report herein a systematic study of the reactivity of (E)-4,4,4-
trifluorobut-2-en-1-yl 4-methylbenzenesulfonate (1) towards different classes of
nucleophiles (alcohols, amines, thiols and malonates). A single set of reaction conditions
(with small variations) allowed the isolation of the substitution product in moderate to
good yields for all the nucleophiles tested with the exception of benzyl alcohol and
indole. For those nucleophiles, the desired products were observed in low yields,
suggesting that further optimization may eventually allow their preparation in
synthetically useful yields.
3
Page 5 of 25

Scheme 2. Reactions under study.
2
.
Results and discussion
The electrophilic partner, (E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate (1)
3b,4], was prepared from ethyl (E)-4,4,4-trifluorocrotonate (6) in two steps. First,
reduction using LiAlH in the presence of AlCl provided the crude (E)-4,4,4-
[
4
3
trifluorobut-2-en-1-ol (7) [7], which was used without further purification. Installation of
the tosylate under standard conditions provided the desired product in 78% for the two
steps.
Scheme 3. Synthesis of (E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate (1).
We started by investigating the use of phenol, the only nucleophile previous used
successfully in this reaction [1,2,3]. We choose 4-phenylphenol as a representative
4
Page 6 of 25

nucleophile for this class of nucleophile as the product is less volatile than with the
unsubstituted phenol and the results are shown in Table 1. Under our initial conditions
(entry 1), a conversion of 75% was observed. Analysis of the crude mixture by NMR
revealed that the desired product 8, was the major one (47% yield by NMR).
Interestingly, no isomerisation product (i.e., 9) was observed. This was a significant side-
reaction in the palladium-catalyzed transformation [6]. In this case, isomerisation of the
starting allylic tosylate was observed instead (10; 11% by NMR). The fact that using a
larger amount of the base increased its formation (entry 2) suggested that this was a base-
mediated process. Changing the solvent from THF to DMF (entry 3) or CH CN (entry 4)
3
provided full conversion. As the NMR yield was significantly better with CH CN (54%
3
vs 33%), this solvent was chosen for further optimization. Either augmenting the amount
of phenol (1.1 equiv instead of 1.0 equiv) or conducting the reaction at higher
concentration (0.25 M instead of 0.1 M) provided better yields (entries 5-6). Combining
those two factors provide the best NMR yield (75%) under those conditions (entry 7). At
this point, we wondered if the use of NaH, a pyrophoric base, was necessary and thus
explored the used of K CO , a safer alternative. Under the optimized conditions (entry 8)
2
3
but just changing the base, a low conversion of 43% was observed. However, the crude
reaction mixture showed a very clean reaction with only 1% of 10 present. Heating the
reaction at 60 °C, provided a full conversion with only trace amounts (ca. 3%) of the
isomerized product (9) and isomerized starting tosylate (10) (entry 9). The desired
product, 8, could be isolated in 90% yield. Those conditions would represent the basis of
the investigation with the other nucleophiles.
5
Page 7 of 25

Table 1. Selected optimization results for the synthesis of 8 from 1 using 4-
phenylphenol.
Entry Base
Phenol
x equiv)
Solvent
Conversion
Ratio
Yield
a
a
a
(
(%)
(8/9/10)
89:0:11
79:0:21
80:7:13
89:3:8
(%)
1
2
3
4
5
6
7
8
9
NaH
NaH
NaH
NaH
NaH
NaH
NaH
1.0
1.0
1.0
1.0
1.1
1.0
1.1
1.1
THF
THF
DMF
75
47
43
33
54
69
69
75
43
b
84
100
100
100
100
96
CH CN
3
CH CN
95:trace:5
92:1:7
3
c
CH CN
3
c
CH CN
96:4:trace
99:0:1
3
c
K CO
2
CH CN
56
3
3
c,d,e
f
K CO 1.1
2
CH CN
100
97:3:3
(90)
3
3
a
19
Determined by F NMR analysis of the crude mixture using 2-fluoro-4-nitrotoluene as
an internal standard.
b
1
.5 equiv of NaH was used.
c
The concentration was 0.25 M.
The temperature was 60 °C.
d
6
Page 8 of 25

e
f
Optimized system highlighted in bold.
Isolated yield after purification by flash chromatography.
We then investigated the use of an aliphatic alcohol, and benzyl alcohol was chosen as a
representative nucleophile for this class. Under the optimized conditions (Table 1, entry
9
), a moderate conversion of 58% was obtained. Analysis of the crude mixture by NMR
spectroscopy revealed the presence of the desired product 11 [8] in trace amounts (ca.
%). The isomerized tosylate 10 (Z/E = 87:13) was the major product (32%). Finally, 7%
of the product corresponding to the attack of the alcohol at the CF carbon was observed
1
3
1
2. Formation of a similar product has been previously observed with indole [5] and we
proposed that 12 is produced through a similar pathway (Scheme 5).
Scheme 4. Initial result using benzyl alcohol as the nucleophile.
Scheme 5. Proposed pathway for the formation of 12.
7
Page 9 of 25

Despite numerous attempts to further optimize the reaction (solvent, reaction
temperature, concentration, base, additives, order of addition, etc.), the "best" conditions
only provided 19% by NMR of the desired product, 11, with a similar amount of the
isomerized product 10 (Scheme 6). Clearly, this particular transformation will require
further investigation.
Scheme 6. Promising result obtained for the reaction of 1 with benzyl alcohol.
Thiols have never been used as nucleophile in substitution reactions with reagent 1-3, and
they did not behave well in our Tsuji-Trost reaction where they provided only trace
amounts (up to 6%) of the desired products (13) along with the isomerized product (14)
and various non-identified fluorinated side-products (7-15%) (Scheme 7) [6].
Scheme 7. Results of the thiols in the Tsuji-Trost reaction of carbonate 5 [6].
8
Page 10 of 25

Under slightly modified conditions using either an aliphatic thiol, 1-dodecanethiol, or an
aromatic thiol, thiophenol, the desired products (15 and 16) were obtained in 87 and 60%
yield respectively. While isomerization of the product was not observed for the aliphatic
thiol, only a limited amount (ca. 2%) was seen with the aromatic one.
Scheme 8. Thiols: reaction of tosylate 1 with 1-dodecanethiol and thiophenol.
We next investigated the use of amines. As shown in Scheme 9, using a primary aliphatic
amine, benzylamine, or a secondary aliphatic amine, N-methylbenzylamine, provided
excellent yields of the desired products (18 and 19). In the case of the primary aliphatic
amine, the use of 4.0 equivalents of benzylamine provided better conversions. Notably,
9
Page 11 of 25

the use of a primary amine was not possible with the Tsuji-Trost system as a complex
mixture was obtained [6].
Scheme 9. Aliphatic Amines: reaction of tosylate 1 with benzyl amine and N-
methylbenzylamine.
We next looked at the use of aromatic amines. Using either a primary aromatic amine,
aniline, or a secondary aromatic amine, N-methylaniline, the desired products (20 and 21)
were isolated in good yields (Scheme 10).
10
Page 12 of 25

Scheme 10. Aromatic amines: reaction of tosylate 1 with aniline and N-methylaniline.
We also investigated the use of indole as its reaction with 1 has been reported to provide,
unexpectedly, 4-fluoro-4-(indol-1-yl)buta-1,3-dien-1-yl methanesulfonate (22) along with
the isomerized starting material, 10. (Scheme 11) [4,5]. We repeated the reaction under
similar conditions (NaH (1.0 equiv), indole (1.1 equiv), CH CN, 0 °C to rt) and observe a
3
comparable result (100% conversion, 22 (20%; (Z,Z)/(Z,E) = 75:25), 10 (80%, Z/E =
8
8:12)).
11
Page 13 of 25

Scheme 11. Reported reaction of 1 with indole by Marques and coworkers. [4]
Marques and coworkers, through DFT calculations and experimentations, have shown
that various factors, including the base counter-ion and the solvent could influence the
reaction outcome (although the desired S 2 product was never observed). In our case,
N
running the reaction in CH CN using K CO as the base, a conversion of 64% was
3
2
3
observed (Scheme 12). Interestingly, NMR analysis of the crude mixture showed the
presence of the desired product, 23, albeit in low yield (4%). Nonetheless, this result
indicates that the desired pathway (i.e., formation of 23) is possible, even though further
optimization will be required to obtain 23 in a useful yield.
Scheme 12. Reaction of 1 with indole under different conditions.
12
Page 14 of 25

Finally, the use of malonate as the nucleophile was investigated. Specifically, dibenzyl
malonate was chosen as the benzyl ester facilitated the purification (since the product is
significantly less volatile than the corresponding methyl or ethyl ester). The results are
shown in Table 2. Under the standard conditions using 2 equivalent of dibenzyl malonate
(R = H), an excellent conversion of 93% was obtained (entry 1). NMR analysis of the
crude mixture revealed a mixture of mono (24a) and dialkylated (25) products in a 71:29
ratio. The yield of the product 24a was estimated at 49% by NMR. Increasing the number
of equivalent of the malonate to 4 provided full conversion in 48 h. A better ratio in favor
of 24a was obtained (83:17) and the desired product could be isolated in 72% yield. This
product could not be obtained under the Tsuji-Trost reaction as 25 was the major product
[
6]. The reaction with dibenzyl methylmalonate proved to be slower and only 70%
conversion was obtained after 96 h with 1.1 equivalent of the nucleophile. It this case, the
product 24b could be isolated in 57% yield (entry 3). Using 3.3 equivalent of dibenzyl
methyl malonate only slightly improve the conversion. Nonetheless, the desired product
could be isolated in 76% yield (entry 4). A slightly lower isolated yield (56%) for the
same product was obtained using the Tsuji-Trost reaction using acetate 4 albeit in a
shorter reaction time (24 h) [6].
13
Page 15 of 25

Table 2. Reaction of 1 with dibenzyl malonate and dibenzyl methylmalonate.
a
Entry
Malonate
x equiv)
Time
(h)
20
Conversion Ratio
Yield
b
b
c
(
(%)
93
(24/25)
(%)
b
1
2
3
24a (2.0)
24a (4.0)
24b (1.1)
24b (3.3)
71:29
83:17
NA
(49)
48
100
70
72
57
76
96
4
96
82
NA
a
For entries 1-3, 1.0 equiv of K CO was used while 3 equiv was utilized for entry 4.
2
3
b
19
Determined by F NMR analysis of the crude mixture using 2-fluoro-4-nitrotoluene as
an internal standard. NA = not applicable.
c
Isolated yield after purification by flash chromatography.
3
.
Conclusion
In conclusion, we have reported a systematic study on the reactivity of (E)-4,4,4-
trifluorobut-2-en-1-yl 4-methylbenzenesulfonate towards different classes of nucleophiles
(alcohols, thiols, amines, and malonates). A single set of reaction conditions (with only
small variations) allowed the isolation of the substitution product in moderate to good
14
Page 16 of 25

yields for all the nucleophiles tested with the exception of benzyl alcohol and indole. For
those nucleophiles, the desired products were observed in low yields, suggesting that
further optimization may eventually allow their preparation in synthetically useful yields.
Overall, this approach complements nicely the Tsuji-Trost reaction catalyzed by
nanoparticules developed earlier by our group, and provide altogether convenient
approaches for the introduction of a 4,4,4-trifluorobut-2-ene chain into organic
molecules.
4
.
Experimental
4
.1. General information
Solvents were purified using a Vacuum Atmospheres Inc. Solvent Purification System.
All commercially available compounds were used as received. Thin-layer
chromatography (TLC) analysis of reaction mixtures was performed using Silicyle silica
gel 60 Å F254 TLC plates, and visualized under UV or by staining with potassium
permanganate. Flash column chromatography was carried out on Silicycle Silica Gel 60
1
13
19
Å, 230-400 mesh. H, C and F NMR spectra were recorded in CDCl at ambient
3
1
13
temperature using Agilent DD2 500 and Varian Inova 400 spectrometers. H and C
NMR chemical shifts are reported in ppm downfield of tetramethylsilane and are
respectively referenced to tetramethylsilane (δ = 0.00 ppm) and chloroform (δ = 77.16
1
9
ppm). For F NMR, CFCl is used as the external standard. High-resolution mass spectra
3
were obtained on a LC/MS–TOF Agilent 6210 using electrospray ionization (ESI).
15
Page 17 of 25

Infrared spectra were recorded using a Thermo Scientific Nicolet 380 FT-IR
spectrometer.
4
.2. Synthesis of the starting compound (E)-4,4,4-trifluorobut-2-en-1-yl 4-
methylbenzenesulfonate (1)
To a solution of LiAlH (1.35 g, 35.5 mmol, 1.5 equiv) in dry Et O (13.0 mL) under
4
2
argon atmosphere was added dropwise a solution of AlCl (2.22 g, 16.6 mmol, 0.7 equiv)
3
in dry Et O (6.5 mL). After 20 min of stirring at 0 °C, a solution of ethyl (E)-4,4,4-
2
trifluorocrotonate (4.00 g, 23.8 mmol, 1.0 equiv) in dry Et O was added dropwise. The
2
resulting mixture was allowed to stir at 0 °C for 2 hours. A saturated aqueous solution of
Na SO was then added (Caution: very exothermic reaction). The mixture was filtrated
2
4
and the solid was washed several times with Et O. The organic layers were combined and
2
washed with brine and dried over MgSO . Solvent was removed by thorough distillation
4
at atmospheric pressure to afford (E)-4,4,4-trifluorobut-2-en-1-ol (7) as a colorless oil
which was used without any further purification. To a solution of 7 (2.89 g, 22.9 mmol,
1
.0 equiv) in dry Et O (50 mL) were successively added triethylamine (3.2 mL, 22.9
2
mmol, 1 equiv), DMAP (280 mg, 2.29 mmol, 0.1 equiv) and TsCl (4.37 g, 22.9 mmol,
.0 equiv). The resulting mixture was allowed to stir at room temperature for 72 hours.
1
Water was then added to quench the reaction and the mixture was extracted with Et O.
2
The organic layers were combined and washed with 3 N aq. HCl then with a saturated
aqueous solution of NaHCO . Organic solvent were removed under reduced pressure.
3
The crude product was purified by column chromatography on silica gel using
16
Page 18 of 25

hexane/EtOAc (90/10) as the eluent to afford the desired product 1 as a colorless oil (5.2
-1
g, 82 %). IR (ATR, ZnSe)  (cm ) = 1363, 1311, 1190, 1175, 1120, 1095, 1052, 943,
1
8
2
13, 757, 696, 661; H NMR (500 MHz, CDCl )  = 7.80 (d, 2H, J = 8.4 Hz), 7.37 (d,
3
H, J = 8.4 Hz), 6.30 (dtq, 1H, J = 15.8, 4.4, 2.3 Hz), 5.89 (dqt, 1H, J = 15.8, 6.2, 1.9
1
3
Hz), 4.68-4.62 (m, 2H), 2.46 (s, 3H); C NMR (125 MHz, CDCl )  = 145.6, 132.6,
3
1
2
32.0 (q, J = 6.6 Hz), 130.2, 128.1, 122.4 (q, J = 269.6 Hz), 121.2 (q, J = 34.7 Hz), 66.8,
19
1.8; F NMR (470 MHz, CDCl )  = -64.9 (m, 3F); HRMS-ESI calcd for C H F O S
3
11 11
3
3
+
[
M+H] , 281.0454 found 281.0454.
4
.3. Typical procedure for the S 2 reaction
N
To a 2-5 mL microwave vial under inert atmosphere were successively charged, the
nucleophile (0.27 mmol, 1.1 equiv), K CO (0.25 mmol, 1.0 equiv) and dry CH CN (0.5
2
3
3
mL). The vial was then sealed with a cap and resulting mixture was heated for 10 min at
6
4
0 °C in a preheated oil bath before dropwise addition of (E)-4,4,4-trifluorobut-2-en-1-yl
-methylbenzenesulfonate (0.25 mmol, 1.0 equiv) diluted in dry CH CN (0.5 mL). The
3
resulting mixture was heated at 60 °C for 20 h. Water was then added to quench the
reaction, and the mixture was extracted three times with EtOAc or Et O. The organic
2
layers were combined and washed with brine, dried over MgSO and concentrated under
4
reduced pressure. The crude product was purified by flash chromatography on silica gel.
17
Page 19 of 25

4
.3.1 (E)-4-((4,4,4-trifluorobut-2-en-1-yl)oxy)-1,1'-biphenyl (8)
Following general procedure: (E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate
(70 mg, 0.25 mmol, 1.0 equiv), 4-phenylphenol (70 mg, 0.27 mmol, 1.1 equiv), K CO
2 3
(
35 mg, 0.25 mmol, 1.0 equiv) and CH CN (1.0 mL). The crude product was purified by
3
flash chromatography on silica gel using hexane/EtOAc (98/2) as the eluent to afford 8 as
a white solid (62 mg, 90%). Spectral data were in accordance with the literature [6].
4
.3.2 (E)-dodecyl(4,4,4-trifluorobut-2-en-1-yl)sulfane (15)
Following the general procedure using (E)-4,4,4-trifluorobut-2-en-1-yl 4-
methylbenzenesulfonate (70 mg, 0.25 mmol, 1.0 equiv), 1-dodecanethiol (101 mg, 0.50
mmol, 2.0 equiv), K CO (35 mg, 0.25 mmol, 1.0 equiv) and CH CN (1.0 mL), the
2
3
3
obtained crude product was purified by flash chromatography on silica gel using pentane
-
(100%) as the eluent to afford 15 as a colorless oil (68 mg, 87%). IR (ATR, ZnSe)  (cm
1
1
)
= 2923, 2853, 1327, 1272, 1184, 1116, 1048, 968; H NMR (500 MHz, CDCl )  =
3
6
2
=
.36 (dtq, 1H, J = 15.6, 4.6, 2.1 Hz), 5.71 (dqt, 1H, J = 15.6, 6.3, 1.4 Hz), 3.20-3.17 (m,
H), 2.45 (m, 2H), 1.58-1.52 (m, 2H), 1.40-1.33 (m, 2H), 1.26 (br s, 16H), 0.88 (t, 3H, J
1
3
7.0 Hz); C NMR (125 MHz, CDCl ):  = 136.6 (q, J = 6.4 Hz), 122.8 (q, J = 269.4
3
Hz), 120.0 (q, J = 33.7 Hz), 32.3, 32.1, 31.3, 29.80, 29.78, 29.74, 29.65, 29.5, 29.37,
1
9
2
9.35, 28.9, 22.8, 14.3; F NMR (470 MHz, CDCl ) = 63.9 (m, 3F); HRMS-ESI
3
+
calcd for C H F S [M+H] , 311.2015 found 311.2010.
1
6
29 3
18
Page 20 of 25

4
.3.3 (E)-dodecyl(4,4,4-trifluorobut-2-en-1-yl)sulfane (16)
Following general procedure using (E)-4,4,4-trifluorobut-2-en-1-yl
methylbenzenesulfonate (70 mg, 0.25 mmol, 1.0 equiv), thiophenol (51 µL, 0.50 mmol,
.0 equiv), K CO (35 mg, 0.25 mmol, 1.0 equiv) and CH CN (1.0 mL), the obtained
4-
2
2
3
3
crude product was purified by flash chromatography on silica gel using pentane (100%)
1
as the eluent to afford 16 as a colorless oil (33 mg, 60%). IR (ATR, ZnSe)  (cm ) =
1
1
7
5
1
3
326, 1273, 1182, 1110, 1050, 965, 736, 688, 664; H NMR (500 MHz, CDCl )  = 7.37-
3
.35 (m, 2H), 7.33-7.29 (m, 2H), 7.27-7.24 (m, 1H), 6.40 (dtq, 1H, J = 15.8, 4.8, 2.1 Hz),
1
3
.58 (dqt, 1H, J = 15.8, 6.4, 1.4 Hz), 3.57-3.53 (m, 2H); C NMR (125 MHz, CDCl )  =
3
35.5 (q, J = 6.5 Hz), 134.1, 113.4, 129.2, 127.9, 122.7 (q, J = 269.5 Hz), 120.7 (q, J =
1
9
3.8 Hz), 35.5; F NMR (470 MHz, CDCl ) = 64.2 (m, 3F); HRMS-ESI calcd for
3
+
C H F S [M+H] , 219.0450 found 219.0454.
10
9 3
4
.3.4 (E)-N-benzyl-4,4,4-trifluorobut-2-en-1-amine (18)
Following general procedure with 4.0 equiv of benzylamine using (E)-4,4,4-trifluorobut-
-en-1-yl 4-methylbenzenesulfonate (70 mg, 0.25 mmol, 1.0 equiv), benzylamine (0.11
mL, 1.0 mmol, 4.0 equiv), K CO (35 mg, 0.25 mmol, 1.0 equiv) and CH CN (1.0 mL),
2
2
3
3
the obtained crude product was purified by flash chromatography on silica gel using
hexane/EtOAc (80/20) as the eluent to afford 18 as a colorless oil (49 mg, 92%). Spectral
data were in accordance with the literature [6].
19
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4
.3.5 (E)-N-benzyl-4,4,4-trifluoro-N-methylbut-2-en-1-amine (19)
Following general procedure using (E)-4,4,4-trifluorobut-2-en-1-yl
methylbenzenesulfonate (70 mg, 0.25 mmol, 1.0 equiv), N-methylbenzylamine (33 mg,
.27 mmol, 1.1 equiv), K CO (35 mg, 0.25 mmol, 1.0 equiv) and CH CN (1.0 mL), the
4-
0
2
3
3
obtained crude product was purified by flash chromatography on silica gel using
pentane/Et O (90/10) as the eluent to afford 19 as a colorless oil (41 mg, 72%). Spectral
2
data were in accordance with the literature [6].
4
.3.6 (E)-N-(4,4,4-trifluorobut-2-en-1-yl)aniline (20)
Following general procedure with 4.0 equiv of aniline using (E)-4,4,4-trifluorobut-2-en-
1
4
-yl 4-methylbenzenesulfonate (70 mg, 0.25 mmol, 1.0 equiv), aniline (90 µL, 1.0 mmol,
.0 equiv), K CO (35 mg, 0.25 mmol, 1.0 equiv) and CH CN (1.0 mL), the obtained
2
3
3
crude product was purified by flash chromatography on silica gel using hexane/EtOAc
90/10) as the eluent to afford 20 as a colorless oil (43 mg, 85%). Spectral data were in
accordance with the literature [6].
(
4
.3.7 (E)-N-methyl-N-(4,4,4-trifluorobut-2-en-1-yl)aniline (21)
Following general procedure using (E)-4,4,4-trifluorobut-2-en-1-yl
4-
methylbenzenesulfonate (112 mg, 0.4 mmol, 1.0 equiv), N-methylaniline (48 µL, 0.44
mmol, 1.1 equiv), K CO (55 mg, 0.4 mmol, 1.0 equiv) and CH CN (1.6 mL), the
2
3
3
obtained crude product was purified by flash chromatography on silica gel using
20
Page 22 of 25

hexane/EtOAc (96/4) as the eluent to afford 21 as pale yellow oil (62 mg, 72%). Spectral
data were in accordance with the literature [6].
4
.3.8 (E)-dibenzyl 2-(4,4,4-trifluorobut-2-en-1-yl)malonate (24a)
Following general procedure with 4.0 equiv of dibenzylmalonate with a reaction time of
8 h using (E)-4,4,4-trifluorobut-2-en-1-yl 4-methylbenzenesulfonate (70 mg, 0.25
mmol, 1.0 equiv), dibenzylmalonate (280 mg, 1.0 mmol, 4.0 equiv), K CO (35 mg, 0.25
4
2
3
mmol, 1.0 equiv) and CH CN (1.0 mL), the obtained crude product was purified by flash
3
chromatography on silica gel using hexane/Et O (90/10) as the eluent to afford 24a as a
2
-1
colorless oil (69 mg, 70%). IR (ATR, ZnSe)  (cm ) = 1731, 1272, 1222, 1115, 969, 732,
1
6
1
3
1
3
3
95; H NMR (500 MHz, CDCl )  = 7.36-7.33 (m, 5H), 7.31-7.28 (m, 4H), 6.34 (dtq,
3
H, J = 15.8, 4.6, 2.1 Hz), 5.68 (dqt, 1H, J = 15.8, 6.3, 1.5 Hz), 5.17 (s, 2H), 5.16 (s, 2H),
13
.59 (t, 1H, J = 7.4 Hz), 2.80-2.76 (m, 2H); C NMR (125 MHz, CDCl )  = 168.0,
3
35.9 (q, J = 6.6 Hz), 135.1, 128.7, 128.6, 128.4, 122.6 (q, J = 269.5 Hz), 121.5 (q, J =
1
9
3.7 Hz), 67.6, 50.7 (q, J = 0.9 Hz), 30.54; F NMR (470 MHz, CDCl ): = 64.4 (m,
3
+
F); HRMS-ESI calcd for C H F O [M+H] , 393.1308 found 393.1310.
2
1
19
3
4
4
.3.9 (E)-dibenzyl 2-methyl-2-(4,4,4-trifluorobut-2-en-1-yl)malonate (24b)
Following general procedure with a reaction time of 96 h using (E)-4,4,4-trifluorobut-2-
en-1-yl 4-methylbenzenesulfonate (70 mg, 0.25 mmol, 1.0 equiv), dibenzyl 2-
methylmalonate (246 mg, 0.825 mmol, 3.3 equiv), K CO (104 mg, 0.750 mmol, 3.0
2
3
equiv) and CH CN (1.0 mL), the obtained crude product was purified by flash
3
21
Page 23 of 25

chromatography on silica gel using hexane/Et O (90/10) as the eluent to afford 24b as a
2
colorless oil (77 mg, 76 %). Spectral data were in accordance with the literature [6].
Acknowledgments
This work was supported by the Canada Research Chair Program, the Natural Sciences
and Engineering Research Council of Canada, The Fonds de recherche du Québec –
Nature et technologies, and the Université Laval.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at …
References
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22
Page 24 of 25

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[
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[
5] Using indole as a N-based nucleophile, regiochemistry issue (i.e., S 2 vs S 2’) has
N
N
been observed, see reference 4.
[
[
[
6] R. Hemelaere, J. Desroches, J.-F. Paquin, Org. Lett. 17 (2015) 1770–1773.
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Y. Qin, F.-L. Qing, J. Org. Chem. 68 (2003) 75447547;
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23
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