Regio- and diastereoselective cu-mediated trifluoromethylation of functionalized alkenes

Article abstract of DOI:10.1021/jo402385g

α- and β-substituted N,N-diethylacrylamides undergo copper-mediated direct β-trifluoromethylation. The amide moiety acts as a directing group for the regio- and the stereo-controlled introduction of the trifluoromethyl group. The reaction is carried out u

Full text of DOI:10.1021/jo402385g

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Note
A Regio- and Diastereoselective Cu-Mediated
Trifluoromethylation of Functionalized Alkenes
tatiana besset, Dominique Cahard, and Xavier Pannecoucke
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 27 Nov 2013
Downloaded from http://pubs.acs.org on November 29, 2013
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A Regio- and Diastereoselective Cu-Mediated
Trifluoromethylation of Functionalized Alkenes
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Tatiana Besset,* Dominique Cahard* and Xavier Pannecoucke
UMR 6014 CNRS COBRA, Normandie Université, 1 rue Tesnière, 76821 Mont-Saint-Aignan, France
tatiana.besset@insa-rouen.fr; dominique.cahard@univ-rouen.fr
Abstract
O
O
R1
R2
R1
Copper salt
NR2
NR2
+
H
R2 CF3
TFA, N-methylformamide
S
Z-isomers
OTf–
CF3
11-69%
10 examples
α- and β-substituted N,N-diethylacrylamides undergo copper-mediated direct β-
trifluoromethylation. The amide moiety acts as a directing group for the regio- and the
stereocontrolled introduction of the trifluoromethyl group. The reaction is carried out under
acidic conditions in the presence of Umemoto’s reagent. This method does not require
prefunctionalized substrates and delivers excellent stereoselectivity.
The construction of trifluoromethylated molecules keeps vibrant the community of
organofluorine chemists by continuously attracting researchers in quest of new synthetic
approaches and novel applications for these compounds.1–4 In this context, the trifluoromethyl
alkene motif is particularly sought after, for instance as amide bond isostere for enhancing
metabolic resistance of peptides.5,6 Because of its significant importance, the design of
innovative accesses to build up valuable trifluoromethylated olefins has attracted growing
interest.7–11 Of the current methods, several cross-coupling reactions were revealed to be
efficient although prefunctionalization of alkenes with halogen,12–21 sulfonates,22 tin,23 or
boron substituents24–29 was generally required. α,β-Unsaturated carboxylic acids were also
employed as substrates submitted to functional group interconversion30 or decarboxylative
trifluoromethylation.31,32 The major advantage of these methods consists of their
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regiospecificity. Nevertheless, the stereochemical information (diastereomeric ratio) is
sometimes lost and the prerequisite for functionalized substrates mitigate the development
potential of these reactions. In contrast, methods that do not require a prefunctionalization of
the alkene are less frequent albeit more atom economical. In 2012, Cho and co-workers
described the trifluoromethylation of alkenes with CF3I by visible light photoredox catalysis
(Scheme 1, Eq. (1)).33 When studying the oxytrifluoromethylation of styrene derivatives,
Sodeoka and co-workers noticed that addition of p-TsOH to the cationic copper-catalyzed
reaction led to the thermodynamically favored E-isomer of β-trifluoromethylstyrene
derivatives (Scheme 1, Eq. (2)).34 Loh and Feng examined the copper-catalyzed olefinic
trifluoromethylation of enamides leading to E-isomers of the trifluoromethylated enamides
(Scheme 1, Eq. (3)).35 These three approaches relied on addition-elimination type mechanisms
affording exclusively E-isomers of the products. Surprisingly, the direct C-H bond
trifluoromethylation of electron-deficient alkenes giving access to highly substituted olefins
has not been explored and still remains an important challenge.
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Our laboratory is interested in the design of new fluorinated alkenes as peptido- and
glycomimetics36–38 that include the development of original methodologies such as palladium-
and copper-catalyzed fluoroalkenylation reactions37 and copper-catalyzed β-
difluoroacetylation of dihydropyrans.38 In this context, we are investigating new synthetic
approaches for the straightforward de novo construction of trifluoromethylated electron-
deficient alkenes. By analogy with the strategy reported by Yu and co-workers39 in the Pd(II)-
catalyzed ortho-trifluoromethylation of aromatic derivatives using secondary amides as
directing group (DG), we anticipated that a similar approach might be astutely employed for
the trifluoromethylation of electron-deficient alkenes, hypothetically leading to synthetically
challenging Z-trifluoromethylated functionalized alkenes. Herein, we report our results on the
copper-mediated direct β-trifluoromethylation of α- and β-substituted N,N-diethylacrylamides
in the presence of Umemoto’s reagent.40
Scheme 1. Examples of trifluoromethylation reactions
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Previous work
R
R
[Ru]
E-isomers
+
CF3I
(1)
(2)
CF3
photocatalysis
CF3
7
8
9
Ar
I
Ar
[Cu]
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O
E-isomers
+
p-TsOH
CF3
O
CF3
I
R
NHAc
R
NHAc
[Cu]
O
(3)
+
E-isomers
F3C
O
This work
O
O
R1
R1
NR2
NR2
R2 CF3
[Cu]
+
S
+
OTf–
R2
H
Z-isomers
CF3
+ highly stereoselective
+ !- and "-substituted olefins
Our investigation started with the study of the trifluoromethylation of phenyl acrylamide
1aa (Table 1). We were pleased to notice that in presence of CuI, Umemoto’s reagent 2,
trifluoroacetic acid (TFA), N-methylformamide, at 120 °C in DMF under air, the desired
product 3aa was obtained in 17% NMR yield (Table 1, entry 1). Interestingly, 3aa was
obtained as a single Z-isomer as ascertained by NMR experiments (NOE, see supporting
information), clearly indicating the key role of the tertiary amide as DG in this coupling
process. Other solvents were then tested (entries 2-5) leading either to no product formation in
chlorobenzene and 1,4-dioxane or to enhanced yield in toluene. Importantly, it turned out that
the best reactivity was observed when the reaction was carried out in dichloroethane affording
3aa in 70% yield (entry 5). To further study the reaction conditions, different copper sources
were tested (entries 5-8) demonstrating that both copper I and copper II species were efficient
in the direct trifluoromethylation reaction yielding 3aa in the same range of yields (61-
70%).41,42 Therefore, we decided to pursue our optimization with the bench stable CuI salt.
Decreasing the reaction temperature from 120 to 80 °C (entry 9) had a drastic effect since
only 7% of 3aa was detected, indicating that a threshold temperature was required for the
transformation to occur. Moreover, control experiments revealed that exclusion of any of the
reaction components, including copper salt, TFA,43 and N-methylformamide, afforded no or
little amount of the trifluoromethylated product (entries 10-12). Indeed, we found that TFA
was a key additive for the success of the olefinic trifluoromethylation as well as N-
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methylformamide that most likely acted as a ligand for copper.44 We also evaluated Togni’s
acid reagent as an alternative source of electrophilic CF3 donor but a much lower yield was
obtained compared to the use of Umemoto’s reagent (entry 13). Furthermore, to minimize the
amount of copper salt in the reaction, 10 mol % of copper iodide was used providing a yield
lower by 12% compared to the reaction run under stoichiometric conditions. While these
results nicely demonstrated the suitability of copper-catalyzed reaction conditions, we decided
to pursue our experiments under stoichiometric amounts of copper.
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Table 1. Optimization of reaction conditionsa
[Cu], TFA,
O
O
N-methylformamide,
NEt2
NEt2
S
solvent, 120 °C, 16h, air
CF3
OTf–
CF3
3aa
H
1aa
2
entry copper source solvent
NMR yield (%)b
1
CuI
DMF
PhCl
17
0
2
CuI
3
CuI
1,4-dioxane traces
4
CuI
toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
39
70
68
61
66
7
5
CuI
CuBr
Cu(OAc)
Cu(OAc)2
CuI
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7
8
9c
10
11d
12e
13f
-
0
CuI
19
10
37
CuI
CuI
aCopper source (1.1 equiv), 1aa (0.1 mmol), Umemoto’s reagent 2 (1.5 equiv), TFA (10 equiv), N-
b
methylformamide (15 equiv), [1aa] = 0.03 mol.L-1, 120 °C, 16 h, air. Yields determined by 19F NMR of the
c
crude reaction mixture using trifluoroacetophenone as internal standard. Reaction was carried out at 80 °C.
e
f
dWithout TFA. Wihout N-methylformamide. Togni’s acid reagent was used instead of Umemoto’s reagent.
DCE = 1,2-dichloroethane, DMF = N,N-dimethylformamide.
Encouraged by these promising results, the impact of the DG on the reactivity was studied
(Figure 1). For this purpose, five substrates bearing a chelating group commonly used in C–H
functionalization reactions were examined. The diethyl tertiary amide DG performed better
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than other typical DGs such as diisopropylamide 1ab (67 versus 30% yield) or morpholine
amide 1ac (57% of 3ac). Noteworthy, the synthetically versatile morpholine amide offers
great opportunities for further synthetic transformations, hence illustrating an additional
advantage of this methodology. In contrast, privileged secondary amide DGs such as the
pentafluoroarylamide moiety in 1ad or the bidentate amide prepared from 8-aminoquinoline
in 1ae gave no or little amount of 3ad and 3ae, respectively. These results suggested that in
our case, the acidity of the NH group is not crucial for the reactivity.39
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Figure 1. Screening of various directing groupsa
F
F
F
F
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
N
NiPr2
N
N
H
CF3
NEt2
H
N
O
F
CF3
CF3
CF3
CF3
3aa, 67%
3ab, 30%
3ac, 57 %
3ad, 0%
3ae,b 24%
aReactions were carried out on a 0.3 mmol scale; 1 (0.3 mmol), 2 (1.5 equiv), CuI (1.1 equiv), TFA (10 equiv),
b
N-methylformamide (15 equiv), DCE (9 mL), air, 120 °C, 16 h. Isolated yields. 3ae was isolated as an
inseparable mixture with 1ae in a 1/0.65 ratio (3ae/1ae).
With our optimized conditions in hands, the scope of the reaction was then studied using
various N,N-diethylacrylamides. Our methodology was applied to introduce the CF3 group
onto acrylamides featuring different substitution patterns: α- or β-substituted and α,β-
disubstituted olefins. The desired trifluoromethylated products 3 were isolated as single Z
diastereoisomers in up to 69% yield (Scheme 2). Firstly, the functionalization of various α-
aryl substituted acrylamides 3aa-3ea was examined. We were delighted to find out that the
trifluoromethylation demonstrated good functional group tolerance. Indeed, electron-donating
substituents such as methoxy (1ba) and tert-butyl (1ca) groups or electron-withdrawing
chlorine atom (1da) on the aryl moiety allowed the formation of products 3 in good yields,
electron-enriched aryls having a beneficial effect on the reactivity. Notably a chloride atom on
aryl group was tolerated, allowing further functionalization through other cross-coupling
reactions. The stereocontrolled trifluoromethylation of these substrates is challenging owing
to the presence of two competing C–H positions on the terminal olefin. Not only a
monotrifluoromethylation reaction occurred but, most importantly, a single Z isomer was
formed without detection of the E isomer at any stage of the process. Interestingly, acrylamide
1fa bearing a n-butyl chain at the α-position also gave the desired product 3fa, albeit in a
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lower yield compared to α-aryl derivatives. This was due to the concomitant formation of the
trifluoromethylated allylic product resulting from the isomerization of the double bond. To
further evaluate the scope of the reaction, the direct trifluoromethylation of the sterically more
congested α,β-disubstituted acrylamide 1ga from (2E)-2,3-diphenylacrylic acid led to the
formation of the desired tetrasubstituted alkene 3ga in only 11% yield probably due to the
overall steric hindrance. Nevertheless this example showcased the potential of our method to
access fully decorated alkenes. Finally, the E-configured β-phenyl substrate 1ha was a
suitable substrate leading to the trisubtituted alkene 3ha in 35% yield. Noteworthy, products
3ga and 3ha, although obtained in moderate yields, are quite exceptional because of their tri-
and tetrasubstituted patterns and their obtention as single geometrical isomers by direct C-H
functionalization.
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Scheme 2. Scope of the trifluoromethylation reactiona
CuI (1.1 equiv), TFA ,
N-methylformamide,
2 (1.5 equiv)
O
O
R1
R2
R1
R2
NEt2
NEt2
DCE, 120 °C, 16h, air
H
1
CF3
3
MeO
O
O
O
NEt2
NEt2
NEt2
CF3
3aa, 67%
CF3
3ba, 69%
CF3
3ca, 66%
Cl
Et
O
O
O
NEt2
CF3
NEt2
CF3
3ea, 34 %
NEt2
CF3
3fa,b 19%
3da, 54%
O
O
NEt2
NEt2
CF3
CF3
3ga, 11%
3ha, 35%
aReactions were carried out on a 0.3 mmol scale; 1 (0.3 mmol), 2 (1.5 equiv), CuI (1.1 equiv), TFA (10 equiv),
b
N-methylformamide (15 equiv), DCE (9 mL), air, 120 °C, 16 h. Isolated yields. Note that a separate fraction
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containing 24% of trifluoromethylated allylic product was isolated as an inseparable mixture with unreacted
1fa.
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In summary, we have developed a new method leading to the regioselective
trifluoromethylation of α- or β-substituted and α,β-disubstituted acrylamides in yields
ranging from 11–69%. This reaction turned out to be valuable for the direct construction of
Csp2-CF3 bond with a total control of the stereoselectivity toward the otherwise difficult-to-
access Z diastereoisomers. This method was not limited to terminal alkenes but was also
applied to sterically more hindered, substituted alkenes offering a straightforward approach
for the synthesis of valuable fluorinated building blocks.
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Experimental section
General information. The trifluoromethylation reactions were carried out in dried reaction
vessels with Teflon screw caps under air. Reaction temperatures are reported as the
temperature of the bath surrounding the vessel. DCE and toluene were distilled over CaH2
prior to use. Anhydrous DMF, 1,4-dioxane were purchased and used as received. NMR
spectra were recorded on a 300 MHz spectrometer. Chemical shifts (δ) are quoted in ppm
relative to TMS (1H) and CFCl3 (19F). Coupling constants (J) are quoted in Hz. The following
abbreviations were used to show the multiplicities: s: singlet, d: doublet, t: triplet, q:
quadruplet, dd: doublet of doublet, m: multiplet. The residual solvent signals were used as
references (CDCl3: δH = 7.26 ppm, δC = 77.00 ppm). High-resolution mass spectrometry was
carried out on an electrospray ionization mass spectrometer with a micro-TOF analyzer. The
wave numbers (ν) of recorded IR-signals (ATR) are quoted in cm-1. Note that due to the high
volatility of the products 3, evaporation was achieved under a pressure above 60 mbar without
heating.
N,N-diethylacrylamides 1ba, 1ca, 1da, 1ea were prepared from the corresponding esters45
after saponification, formation of acid chloride, and condensation with diethylamine,
successively.46 Note that intermediate acids and acid chlorides were not isolated and were
directly engaged in the next step without any purification. N,N-diethylacrylamides 1aa and
1ga were obtained by reaction of the commercially available corresponding acids with oxalyl
chloride followed by condensation with diethylamine.46 Other N,N-substituted acrylamides
1ab, 1ac, 1ad, 1ae were obtained in a similar way from 2-phenylacrylic acid with the aid of
diisopropylamine, morpholine, 2,3,4,5,6-pentafluoroaniline, 8-aminoquinoline, respectively.
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N,N-diethylacrylamide 1ha was obtained similarly from the commercially available
corresponding acid chloride and diethylamine.46 N,N-diethylacrylamide 1fa was obtained by
means of Kobayashi’s method for the acid synthesis47 followed by acid chloride formation
and condensation with diethylamine.46 N,N-diethylacrylamides 1aa,48 1ab,49 1ac,50 and 1fa48
are known compounds. Ester 4e is a new compound whereas 4b [CAS 39729-00-5], 4c [CAS
1264520-71-9], 4d [CAS 101492-44-8] are described in Barluenga and Valdés paper (see
ester structures in the supporting information).45
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Characterisation of acrylamides 1. N-(perfluorophenyl)-2-phenylacrylamide (1ad). The
product was isolated as a white solid (0.935 g, 60% from the 2-phenylacrylic acid (5 mmol))
using petroleum ether (PE)/EtOAc (90/10) as eluent. Rf (PE/ EtOAc = 90/10): 0.31. mp 98–
100 °C. 1H NMR (300.13 MHz, CDCl3): δ 7.47–7.32 (m, 5H), 7.26 (s, 1H), 6.20 (s, 1H), 5.76
(s, 1H). 13C NMR (75.5 MHz, CDCl3): δ 165.9, 144.6, 143.0, 141.4, 139.3, 135.8, 129.0,
128.9, 128.0, 124.5, 111.6. ATR-FTIR (cm-1): 2977, 2860, 1620, 1458, 1438, 1215, 1108,
916. HRMS (ESI+): m/z calc. 314.0599 [(C15H8F5NO)H]+, measured 314.0605.
2-phenyl-N-(quinolin-8-yl)acrylamide (1ae). The product was isolated as a yellow oil (0.605
g, 44% from 2-phenylacrylic acid (5 mmol)) using PE/EtOAc (90/10) as eluent. Rf
(PE/EtOAc = 90/10): 0.2. 1H NMR (300.13 MHz, CDCl3): δ 10.09 (s, 1H), 8.75 (dd, J = 7.5,
1.5 Hz, 1H), 8.40 (dd, J = 4.2, 1.6 Hz, 1H), 7.84 (dd, J = 8.4, 1.5 Hz, 1H), 7.44–7.18 (m, 7H),
13
7.12 (dd, J = 8.4, 4.2 Hz, 1H), 6.14 (s, 1H), 5.63 (s, 1H). C NMR (75.5 MHz, CDCl3): δ
165.5, 148.0, 145.6, 138.3, 136.4, 135.9, 134.1, 128.4, 128.4, 128.1, 127.5, 127.0, 121.9,
121.7, 121.3, 116.3. ATR-FTIR (cm-1): 2976, 2937, 1633, 1444, 1289, 1270, 1114, 765.
HRMS (ESI+): m/z calc. 275.1179 [(C18H14N2O)H]+, measured 275.1190.
N,N-diethyl-2-(4-methoxyphenyl)acrylamide (1ba). The product was isolated as a yellow oil
(0.105 g, 10% from the ester 4b) using PE/EtOAc (80/20) as eluent. Rf (PE/EtOAc = 80/20):
1
0.12. H NMR (300.13 MHz, CDCl3): δ 7.28 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H),
5.49 (s, 1H), 5.11 (s, 1H), 3.70 (s, 3H), 3.41 (q, J = 7.2 Hz, 2H), 3.14 (q, J = 7.2 Hz, 2H), 1.13
13
(t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H). C NMR (75.5 MHz, CDCl3): δ 170.2, 159.6,
144.5, 127.9, 126.6, 113.8, 110.5, 55.0, 42.5, 38.4, 13.8, 12.5. ATR-FTIR (cm-1): 2973, 2937,
1629, 1605, 1510, 1435, 1245, 1180, 1028, 836. HRMS (ESI+): m/z calc. 234.1489
[(C14H19NO2)H]+, measured 234.1489.
2-(4-tert-butylphenyl)-N,N-diethylacrylamide (1ca). The product was isolated as a yellow oil
(0.328 g, 29% from the ester 4c) using PE/EtOAc (from 90/10 to 80/20) as eluent. Rf (PE/
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EtOAc = 80/20): 0.24. H NMR (300.13 MHz, CDCl3): δ 7.41–7.31 (broad s, 4H), 5.66 (s,
5
6
7
8
1H), 5.26 (s, 1H), 3.51 (q, J = 7.2 Hz, 2H), 3.24 (q, J = 6.9 Hz, 2H), 1.31 (s, 9H), 1.23 (t, J =
13
6.9 Hz, 3H), 1.02 (t, J = 7.2 Hz, 3H). C NMR (75.5 MHz, CDCl3): δ 170.4, 151.6, 145.0,
132.7, 125.6, 125.2, 112.0, 42.8, 38.7, 34.6, 31.2, 14.0, 12.8. ATR-FTIR (cm-1): 2963, 1632,
1433, 1249, 841. HRMS (ESI+): m/z calc. 260.2014 [(C17H25NO)H]+, measured 260.2009.
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2-(4-chlorophenyl)-N,N-diethylacrylamide (1da). The product was isolated as a white powder
(0.364 g, 36% from the ester 4d) using PE/EtOAc (from 80/20 to 70/30) as eluent. Rf (PE/
EtOAc = 70/30): 0.28. mp 58 °C. 1H NMR (300.13 MHz, CDCl3): δ 7.37 (d, J = 8.3 Hz, 2H),
7.31 (d, J = 8.3 Hz, 2H), 5.68 (s, 1H), 5.33 (s, 1H), 3.49 (q, J = 6.9 Hz, 2H), 3.21 (q, J = 7.2
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Hz, 2H), 1.21 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 6.9 Hz, 3H). C NMR (75.5 MHz, CDCl3): δ
169.7, 144.3, 134.4, 134.2, 128.9, 126.9, 113.4, 42.7, 38.8, 14.0, 12.7. ATR-FTIR (cm-1):
2982, 2937, 1612, 1435, 1094, 912, 854. HRMS (ESI+): m/z calc. 238.0993
[(C13H16ClNO)H]+, measured 238.0995.
N,N-diethyl-2-(2-ethylphenyl)acrylamide (1ea). The product was isolated as a yellow oil
(0.376 g, 38% from the ester 4e) using PE/EtOAc (70/30) as eluent. Rf (PE/ EtOAc = 70/30):
0.66. 1H NMR (300.13 MHz, CDCl3): δ 7.37–7.11 (m, 4H), 5.72 (s, 1H), 5.46 (s, 1H), 3.42 (q,
J = 6.6 Hz, 2H), 3.23 (q, J = 6.9 Hz, 2H), 2.72 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H),
1.17 (t, J = 6.9 Hz, 3H), 0.80 (t, J = 6.6 Hz, 3H). 13C NMR (75.5 MHz, CDCl3): δ 170.5,
146.6, 141.8, 137.3, 129.2, 128.8, 128.2, 126.0, 120.9, 42.6, 39.5, 25.8, 15.3, 13.3, 12.5.
ATR-FTIR (cm-1): 2970, 2934, 1629, 1427, 1379, 1218, 1082, 752. HRMS (ESI+): m/z calc.
232.1696 [(C15H21NO)H]+, measured 232.1701.
(E)-N,N-diethyl-2,3-diphenylacrylamide (1ga). The product was isolated as a white solid
(1.52 g, 54% from α-phenylcinnamic acid (10 mmol)) using PE/EtOAc (70/30) as eluent. Rf
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(PE/ EtOAc = 70/30): 0.6. mp 92–94 °C. H NMR (300.13 MHz, CDCl3): δ 7.42–7.06 (m,
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10H), 6.70 (s, 1H), 3.55–3.26 (m, 4H), 1.32–0.79 (m, 6H). C NMR (75.5 MHz, CDCl3): δ
170.7, 138.2, 135.2, 129.1, 128.8, 128.8, 128.6, 128.4, 127.9, 127.7, 127.3, 42.7, 38.9, 13.5,
12.5. ATR-FTIR (cm-1): 2996, 1604, 1444, 1429, 1268, 1139, 693. HRMS (ESI+): m/z calc.
280.1696 [(C19H21NO)H]+, measured 280.1694.
N,N-diethylcinnamamide (1ha). The product was isolated as a colorless oil (0.93 g, 76%
from cinnamoyl chloride (6 mmol)) using PE/EtOAc (70/30) as eluent. Rf (PE/EtOAc =
70/30): 0.31. 1H NMR (300.13 MHz, CDCl3): δ 7.71 (d, J = 15.4 Hz, 1H), 7.58–7.28 (m, 5H),
6.82 (d, J = 15.4 Hz, 1H), 3.58–3.41 (m, 4H), 1.34–1.11 (m, 6H). 13C NMR (75.5 MHz,
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CDCl3): δ 165.6, 142.2, 135.4, 129.3, 128.6, 127.6, 117.7, 42.2, 41.0, 15.0, 13.1. ATR-FTIR
(cm-1): 3059, 2968, 2932, 1654, 1588, 1431, 1147, 984, 767, 689. HRMS (ESI+): m/z calc.
204.1388 [(C13H17NO)H]+, measured 204.1384.
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Synthesis of ethyl 2-(2-ethylphenyl)acrylate (4e). The product was prepared according to
the method described by Barluenga et al.45 and was isolated as a yellow oil (0.966 g, 86%)
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using petroleum ether (PE)/EtOAc (8/1) as eluent. Rf (PE/ EtOAc = 8/1): 0.46. H NMR
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(300.13 MHz, CDCl3): δ 7.45-7.14 (m, 4H), 6.59 (s, 1H), 5.76 (s, 1H), 4.30 (q, J = 7.2 Hz,
2H), 2.64 (q, 3J = 7.5 Hz, 2H), 1.33 (t, 3J = 7.2 Hz, 3H), 1.26 (t, J = 7.5 Hz, 3H). 13C NMR
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(75.5 MHz, CDCl3): δ 166.5, 141.7, 136.5, 129.4, 128.0, 127.7, 125.3, 60.7, 26.0, 14.7, 13.9.
ATR-FTIR (cm-1): 2969, 2935, 1716, 1304, 1201, 1183, 1083, 1025, 757. HRMS (ESI+): m/z
calc. 205.1229 [(C13H16O2)H]+, measured 205.1223.
General procedure for the optimization reaction. Unless otherwise specified, CuI (0.11
mmol, 1.1 equiv), Umemoto’s reagent (1.5 equiv) and 3 mL DCE were united under air a
Schlenk flask (10 mL). Acrylamide derivatives (0.1 mmol scale), TFA (10 equiv), N-
methylformamide (15 equiv) was then added, the reactor closed and exposed to 120 °C for 16
h. The reactor was then cooled to r.t. and 0.4 g of K2CO3 was added. The conversion was then
controlled by 19F NMR of the crude mixture, and 19F NMR yield were determined using
trifluoroacetophenone as internal standard. Note that when a catalytic amount of CuI was
tested, a similar procedure was followed, and CuI (0.01 mmol, 10 mol %) was used instead of
CuI (0.11 mmol, 1.1 equiv).
General procedure for the trifluoromethylation reaction. Unless otherwise specified,
CuI (0.063 g, 0.33 mmol, 1.1 equiv), Umemoto’s reagent (0.180 g, 0.45 mmol, 1.5 equiv) and
9 mL DCE were united under air in a Schlenk flask (50 mL). Acrylamides (0.3 mmol), TFA
(10 equiv), N-methylformamide (15 equiv) were then added, the reactor closed and exposed to
120 °C for 16 h. The reactor was then cooled to r.t. and the products were directly purified by
SiO2 column chromatography with a K2CO3 layer on the top. Note that in case of solid
acrylamides, these are added in the Schlenk flask before the solvent.
(Z)-N,N-diethyl-4,4,4-trifluoro-2-phenylbut-2-enamide (3aa). The product was isolated as a
pale yellow oil (54.4 mg, 67%) using pentane/Et2O (from 100:0 to 0:100) as eluent. Rf
(pentane/Et2O = 90/10): 0.35. 1H NMR (300.13 MHz, CDCl3): δ 7.56–7.31 (m, 5H), 5.98 (q, J
= 7.9 Hz, 1H), 3.73–3.28 (m, 2H), 3.19–3.03 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2
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Hz, 3H). 19F NMR (282.4 Hz, CDCl3, CFCl3): δ –60.35 (d, J = 7.9 Hz). 13C NMR (75.5 MHz,
CDCl3): δ 165.8, 146.6 (q, J = 5.5 Hz), 133.6, 130.2, 129.1, 126.4, 122.7 (q, J = 270.3 Hz),
113.5 (q, J = 34.7 Hz), 42.5, 38.4, 13.0, 12.1. ATR-FTIR (cm-1): 2976, 2937, 1633, 1444,
1289, 1270, 1114, 765. HRMS (ESI+): m/z calc. 272.1257 [(C14H16F3NO)H]+, measured
272.1255.
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(Z)-4,4,4-trifluoro-N,N-diisopropyl-2-phenylbut-2-enamide (3ab). The product was isolated
as a pale yellow oil (26.7 mg, 30%) using pentane/Et2O (from 100:0 to 0:100) as eluent. Rf
(pentane/Et2O = 80/20): 0.56. 1H NMR (300.13 MHz, CDCl3): δ 7.56–7.34 (m, 5H), 5.89 (q, J
= 8.1 Hz, 1H), 3.74 (heptuplet, 1H), 3.39 (heptuplet, 1H), 1.56–1.48 (m, 6H), 1.14 (d, J = 6.6
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Hz, 3H), 0.70 (d, J = 6.6 Hz, 3H). F NMR (282.4 Hz, CDCl3, CFCl3): δ –59.49 (d, J = 8.1
Hz). 13C NMR (75.5 MHz, CDCl3): δ 165.3, 147.4 (q, J = 5.5 Hz), 133.8, 130.1, 129.0, 126.5,
122.8 (q, J = 270.7 Hz), 112.4 (q, J = 34.5 Hz), 50.8, 45.8, 20.0, 19.9, 19.7, 19.6. ATR-FTIR
(cm-1): 2972, 2933, 1637, 1444, 1315, 1273, 1128, 1044. HRMS (ESI+): m/z calc. 300.1570
[(C16H20F3NO)H]+, measured 300.1563.
(Z)-4,4,4-trifluoro-1-morpholino-2-phenylbut-2-en-1-one (3ac). The product was isolated as a
yellow oil (48.8 mg, 57%) using pentane/Et2O (from 100:0 to 0:100) as eluent, then the
product contaminated with residual traces of TFA was diluted in diethyl ether, washed with an
aqueous solution of NaHCO3 5%, dried over MgSO4, filtered and the solvents were carefully
removed under reduced pressure (60 mbar max, no heating). Rf (pentane/Et2O = 80/20): 0.09.
1H NMR (300.13 MHz, CDCl3): δ 7.55–7.35 (m, 5H), 6.06 (q, J = 7.9 Hz, 1H), 3.86–3.13 (m,
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8H). F NMR (282.4 Hz, CDCl3, CFCl3): δ –59.87 (d, J = 7.9 Hz). C NMR (75.5 MHz,
CDCl3): δ 165.1, 145.4 (q, J = 5.5 Hz), 132.8, 130.6, 129.3, 126.3, 122.4 (q, J = 270.9 Hz),
114.1 (q, J = 34.8 Hz), 66.4, 66.1, 46.6, 41.6. ATR-FTIR (cm-1): 2970, 2859, 1642, 1439,
1274, 1112, 1045. HRMS (ESI+): m/z calc. 286.1049 [(C14H14F3NO2)H]+, measured
286.1052.
(Z)-4,4,4-trifluoro-2-phenyl-N-(quinolin-8-yl)but-2-enamide (3ae). The product was isolated
as a pale yellow oil (40.2 mg, 24% (3ae)) as an inseparable mixture with 1ae (1/0.65
(3ae/1ae) ratio) using pentane/Et2O (from 100:0 to 0:100) as eluent. Rf (pentane/Et2O =
80/20): 0.70. 1H NMR (300.13 MHz, CDCl3): δ 10.27 (broad s, 1H, 1ae), 10.09 (broad s, 1H,
3ae), 8.95–8.87 (m, 2H), 8.79–8.60 (m, 2H), 8.20–8.08 (m, 2H), 7.68–7.35 (m, 15H), 6.33 (d,
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J = 0.9 Hz, 1H, 1ae), 6.21 (q, J = 7.9 Hz, 1H, 3ae), 5.84 (d, J = 0.9 Hz, 1H, 1ae). F NMR
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(282.4 Hz, CDCl3, CFCl3): δ –58.82 (d, J = 7.9 Hz). C NMR (75.5 MHz, CDCl3): δ 165.8,
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164.1, 148.4, 148.2, 146.7 (q, J = 5.5 Hz), 145.8, 138.7, 138.3, 138.2, 137.9, 136.7, 136.3,
136.2, 134.4, 133.8, 133.7, 130.4, 129.2, 129.1, 128.7, 128.6, 128.3, 127.9, 127.8, 127.7,
127.3, 127.3, 126.9, 122.5, 122.4 (q, J = 271.1 Hz), 122.3, 121.9, 121.8, 121.5, 120.6, 117.0,
116.6, 115.7 (q, J = 35.0 Hz). ATR-FTIR (cm-1): 3074, 1666, 1377, 1154, 707. HRMS (ESI+):
m/z calc. 343.1053 [(C19H13F3N2O)H]+, measured 343.1049.
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(Z)-N,N-diethyl-4,4,4-trifluoro-2-(4-methoxyphenyl)but-2-enamide (3ba). The product was
isolated as a pale yellow oil (62.7 mg, 69%) pentane/Et2O (from 100:0 to 0:100) as eluent,
then the product contaminated with residual traces of TFA was diluted in diethyl ether,
washed with an aqueous solution of NaHCO3 5%, dried over MgSO4, filtered and the solvents
were carefully removed under reduced pressure (60 mbar max, no heating). Rf (pentane/Et2O
= 80/20): 0.08. 1H NMR (300.13 MHz, CDCl3): δ 7.43–7.36 (m, 2H), 6.94–6.84 (m, 2H), 5.88
(q, J = 8.1 Hz, 1H), 3.82 (s, 3H), 3.72-3.26 (m, 2H), 3.24–3.08 (m, 2H), 1.19 (t, J = 7.2 Hz,
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3H), 0.91 (t, J = 7.2 Hz, 3H). F NMR (282.4 Hz, CDCl3, CFCl3): δ –59.38 (d, J = 8.1 Hz).
13C NMR (75.5 MHz, CDCl3): δ 166.1, 161.2, 145.9 (q, J = 5.6 Hz), 127.9, 125.7, 122.8 (q, J
= 270.5 Hz), 114.4, 111.0 (q, J = 35.0 Hz), 55.3, 42.5, 38.3, 13.0, 12.0. ATR-FTIR (cm-1):
2977, 2942, 1634, 1513, 1461, 1244, 1109, 1030, 826. HRMS (ESI+): m/z calc. 302.1362
[(C15H18F3NO2)H]+, measured 302.1362.
(Z)-2-(4-tert-butylphenyl)-N,N-diethyl-4,4,4-trifluorobut-2-enamide (3ca). The product was
isolated as a pale yellow oil (64.5 mg, 66%) using pentane/Et2O (from 100:0 to 0:100) as
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eluent. Rf (pentane/Et2O = 80/20): 0.36. H NMR (300.13 MHz, CDCl3): δ 7.39 (s, 4H), 5.96
(q, J = 8.1 Hz, 1H), 3.74–3.28 (m, 2H), 3.24 (q, J = 7.2 Hz, 2H), 1.30 (s, 9H), 1.20 (t, J = 7.2
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Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H). F NMR (282.4 Hz, CDCl3, CFCl3): δ –59.60 (d, J = 8.1
Hz). 13C NMR (75.5 MHz, CDCl3): δ 165.9, 153.7, 146.3 (q, J = 5.5 Hz), 130.6, 126.1, 126.0,
122.8 (q, J = 270.6 Hz), 112.3 (q, J = 34.7 Hz), 42.5, 38.4, 34.7, 31.0, 13.0, 12.1. ATR-FTIR
(cm-1): 2967, 1636, 1461, 1291, 1269, 1107, 731. HRMS (ESI+): m/z calc. 328.1888
[(C18H24F3NO)H]+, measured 328.1893.
(Z)-2-(4-chlorophenyl)-N,N-diethyl-4,4,4-trifluorobut-2-enamide (3da). The product was
isolated as a yellow oil (49.3 mg, 54%) using pentane/Et2O (from 100:0 to 0:100) as eluent. Rf
(pentane/Et2O = 80/20): 0.20. 1H NMR (300.13 MHz, CDCl3): δ 7.48–7.33 (m, 4H), 5.96 (q, J
= 7.8 Hz, 1H), 3.78–3.25 (m, 2H), 3.24–3.08 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H), 0.90 (t, J = 7.2
Hz, 3H). 19F NMR (282.4 Hz, CDCl3, CFCl3): δ –59.99 (d, J = 7.8 Hz). 13C NMR (75.5 MHz,
CDCl3): δ 165.4, 145.5 (q, J = 5.4 Hz), 136.4, 132.1, 129.4, 127.7, 122.4 (q, J = 271.0 Hz),
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113.9 (q, J = 35.2 Hz), 42.5, 38.5, 13.1, 12.0. ATR-FTIR (cm-1): 2982, 2943, 1633, 1493,
1439, 1344, 1287, 1264, 1113, 1095, 821. HRMS (ESI+): m/z calc. 306.0867
[(C14H15ClF3NO)H]+, measured 306.0872.
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(Z)-N,N-diethyl-2-(2-ethylphenyl)-4,4,4-trifluorobut-2-enamide (3ea). The product was
isolated as a pale yellow oil (30.2 mg, 34%) using pentane/Et2O (from 100:0 to 0:100) as
eluent. Rf (pentane/Et2O = 80/20): 0.42. 1H NMR (300.13 MHz, CDCl3): δ 7.39–7.28 (m, 3H),
7.24–7.13 (m, 1H), 5.68 (q, J = 7.9 Hz, 1H), 3.40 (q, J = 6.9 Hz, 2H), 3.23 (q, J = 6.9 Hz,
2H), 2.83 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H), 0.83 (t, J = 7.2
Hz, 3H). 19F NMR (282.4 Hz, CDCl3, CFCl3): δ –60.27 (d, J = 7.9 Hz). 13C NMR (75.5 MHz,
CDCl3): δ 166.0, 147.1 (q, J = 5.6 Hz), 141.9, 134.1, 129.8, 129.3, 128.5, 126.1, 122.2 (q, J =
271.4 Hz), 118.9 (q, J = 34.6 Hz), 42.1, 38.9, 25.5, 15.9, 13.1, 11.9. ATR-FTIR (cm-1): 2975,
2943, 1636, 1433, 1282, 1114, 762. HRMS (ESI+): m/z calc. 300.1570 [(C16H20F3NO)H]+,
measured 300.1568.
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(Z)-N,N-diethyl-2-(2,2,2-trifluoroethylidene)hexanamide (3fa). The product was isolated as a
pale yellow oil (14.1 mg, 19%) using pentane/Et2O (from 100:0 to 0:100) as eluent. Rf
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(pentane/Et2O = 80/20): 0.30. H NMR (300.13 MHz, CDCl3): δ 5.45 (qt, J = 7.9, 1.8 Hz,
1H), 3.70–3.16 (m, 4H), 3.41–2.20 (m, 2H), 1.60–1.30 (m, 4H), 1.15 (t, J = 7.2 Hz, 3H), 1.14
(t, J = 7.2 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H). 19F NMR (282.4 Hz, CDCl3, CFCl3): δ –60.56 (dt,
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J = 7.9, 2.3 Hz). C NMR (75.5 MHz, CDCl3): δ 167.6, 148.4 (q, J = 5.4 Hz), 122.4 (q, J =
270.8 Hz), 113.4 (q, J = 34.3 Hz), 42.0, 37.8, 34.6, 28.8, 22.2, 13.8, 13.5, 12.0. ATR-FTIR
(cm-1): 2946, 1665, 1375, 1148, 704. HRMS (ESI+): m/z calc. 252.1570 [(C12H20F3NO)H]+,
measured 252.1574.
(Z)-N,N-diethyl-4,4,4-trifluoro-2,3-diphenylbut-2-enamide (3ga). The product was isolated as
a yellow oil (11.2 mg, 11%) using pentane/Et2O (from 100:0 to 0:100) as eluent. Rf
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(pentane/Et2O = 80/20): 0.55. H NMR (300.13 MHz, CDCl3): δ 7.84 (d, J = 7.5 Hz, 1H),
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NMR (282.4 Hz, CDCl3, CFCl3): δ –60.00. C NMR (75.5 MHz, CDCl3): δ 168.6, 140.0,
136.6, 135.8, 134.6, 131.9, 130.4, 129.4, 128.9, 128.8, 128.6, 128.4, 128.1, 127.7, 126.2,
124.0 (q, J = 263.0 Hz), 42.4, 38.4, 13.5, 12.2. ATR-FTIR (cm-1): 2977, 1627, 1324, 1167,
1119. HRMS (ESI+): m/z calc. 348.1570 [(C20H20F3NO)H]+, measured 348.1569.
(Z)-N,N-diethyl-4,4,4-trifluoro-3-phenylbut-2-enamide (3ha). The product was isolated as a
pale yellow oil (28.3 mg, 35%) using pentane/Et2O (from 100:0 to 0:100) as eluent. Rf
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(pentane/Et2O = 80/20): 0.29. 1H NMR (300.13 MHz, CDCl3): δ 7.54–7.34 (m, 5H), 5.98 (q, J
= 7.9 Hz, 1H), 3.76–3.27 (m, 2H), 3.25–3.11 (m, 2H), 1.20 (t, J = 7.2 Hz, 2H), 0.90 (t, J = 7.2
Hz, 3H). 19F NMR (282.4 Hz, CDCl3, CFCl3): δ –59.83 (d, J = 7.9 Hz). 13C NMR (75.5 MHz,
CDCl3): δ 165.8, 146.6 (q, J = 5.6 Hz), 133.7, 130.3, 129.1, 126.4, 122.6 (q, J = 270.7 Hz),
113.5 (q, J = 34.9 Hz), 42.5, 38.4, 13.1, 12.1. ATR-FTIR (cm-1): 2980, 2939, 1634, 1443,
1289, 1270, 1113, 693. HRMS (ESI+): m/z calc. 272.1257 [(C14H16F3NO)H]+, measured
272.1259.
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Associated content
Supporting Information
1H, 13C, and 19F NMR spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
Author information
*E-mail: tatiana.besset@insa-rouen.fr; dominique.cahard@univ-rouen.fr
Notes
The authors declare no competing financial interest
Acknowledgments
We are grateful to Delphine Dru and Jonathan Cousin for the preparation of some reactants
required for this work. This work has been partially supported by Normandie Université,
CNRS, CRUNCH and LABEX SYNORG (ANR-11-LABX-0029).
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