3-Trifluoromethylated Coumarins and Carbostyrils by Radical Trifluoromethylation of ortho-Functionalized Cinnamic Esters

Article abstract of DOI:10.1002/ejoc.201601181

A method for the trifluoromethylation of ortho-hydroxycinnamic esters was developed to achieve the regioselective synthesis of 3-trifluoromethylated coumarins. The reaction was performed by using the Togni reagent as the CF₃source under mild conditions and showed good functional- group tolerance. The scope of this copper-mediated method was further expanded to the synthesis of 3-trifluoromethylated carbostyrils starting from ortho-aminocinnamic derivatives. Interestingly, a sequential one-pot synthesis of 3-trifluoromethylated coumarins starting from salicylaldehydes was further developed. The mechanism of this cascade reaction was explored, and a radical pathway was found to be consistent with the obtained results.

Full text of DOI:10.1002/ejoc.201601181

A Journal of
Accepted Article
Title: 3-Trifluoromethylated Coumarins and Carbostyrils via Radical Trifluorome-
thylation of ortho-Functionalized Cinnamic Esters
Authors: Slim CHAABOUNI; Florent SIMONET; Alison FRANCOIS; Souhir ABID;
Chantal GALAUP; Stefan CHASSAING
This manuscript has been accepted after peer review and the authors have elected
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Object Identifier (DOI) given below. The VoR will be published online in Early View as
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blished to ensure accuracy of information. The authors are responsible for the content
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601181
Link to VoR: http://dx.doi.org/10.1002/ejoc.201601181
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European Journal of Organic Chemistry
10.1002/ejoc.201601181
FULL PAPER
3-Trifluoromethylated Coumarins and Carbostyrils via Radical
Trifluoromethylation of ortho-Functionalized Cinnamic Esters
Slim Chaabouni,[a,b,c] Florent Simonet,[a] Alison François,[a] Souhir Abid,[b] Chantal Galaup,[c] and Stefan
Chassaing*[a]
Abstract:
A
method for the trifluoromethylation of ortho-
1a). First, the group of Piasecka-Maciejewska succeeded in the
synthesis of 3-trifluoromethylcoumarins via the fluorination of 3-
carboxylated coumarins using sulfur tetrafluoride as fluorine
source.[8] Much more recently, several groups elaborated
efficient methods for the direct trifluoromethylation of already
existing coumarin scaffolds, using Langlois or Togni (1) reagents
as CF3 sources and under transition metal-mediated or metal-
free conditions.[9] To date, only two examples utilizing non-
coumarin scaffolds as starting materials have been reported
(Scheme 1b).[10] The group of Augustine[10a] achieved the one-
pot synthesis of a methoxylated 3-trifluoromethylcoumarin via a
propylphosphonic anhydride-mediated Perkin condensation,
hydroxycinnamic esters was developed to achieve the regioselective
synthesis of 3-trifluoromethylated coumarins. The reaction proceeds
with Togni reagent as the CF3 source under mild conditions and with
good functional group tolerance. The scope of this copper-mediated
method was further expanded to the synthesis of 3-
trifluoromethylated carbostyrils starting from ortho-aminocinnamic
derivatives. Interestingly, a sequential one-pot synthesis of 3-
trifluoromethylated coumarins starting from salicylaldehydes was
further developed. The mechanism of this cascade reaction was
explored and a radical pathway was found consistent with the
obtained results.
while Ding[10b] described
a
copper-catalyzed cascade
construction method starting from acyclic arylpropiolates as
substrates and using Togni reagent 1 as CF3 source.
Introduction
Previous works
Methods to incorporate fluorine into organic molecules have
emerged as valuable and highly demanded synthetic tools in the
last decade, with relevance from agricultural and pharmaceutical
chemistries to materials science.[1,2] Indeed, it is commonly
accepted that the anchoring of a fluorine-containing group onto
useful organic scaffolds often leads to an improvement of its
chemical, physical and biological profiles.[3] To date, the
trifluoromethyl (CF3) group has appeared as the archetypal and
most sought-after fluorine-containing group, as revealed by the
huge and ever-increasing number of trifluoromethylated
compounds as well as trifluoromethylating methods/reagents
reported in the literature.[2a,4]
(a) from coumarin scaffolds
Piasecka-Maciejewska
R2
CO2H
R1
SF4
R2
4
O
O
CF3
3
R1
Ref. 9
R2
O
O
Langlois reagent with Mn(III),
Cu(I)/TBHP or PIFA
or Togni reagent 1 with Cu(I)
R1
O
O
In particular, some efforts have been made to incorporate
the CF3 group into the coumarin scaffold, a heterocyclic scaffold
encountered in numerous natural and synthetic products of
relevance in life[5] and materials[6] sciences. However,
regioisomeric 3- and 4-trifluoromethylated coumarins have so far
not received the same level of attention, especially regarding
their synthesis. While synthetic methods towards 4-
trifluoromethylated coumarins are highly documented in the
literature,[7] less examples focused on the regiocontrolled
synthesis of their 3-trifluoromethylated isomers, most of those
examples employing coumarin scaffolds as substrates (Scheme
(b) from non-coumarin scaffolds
CF3
Augustine
CF3
CO2H
3
O
propylphosphonic
anhydride
O
O
OH
OMe
OMe
Ding
Ar
Togni reagent 1
R2
Cu(II)
4
R
CF3
3
R1
O
O
O
O
[a]
ITAV, Université de Toulouse, CNRS, UPS
1 place Pierre Potier, 31106 Toulouse Cedex 1 (France)
E-mail: stefan.chassaing@itav.fr
Togni reagent 1
Cu(I)
O
This work
with
http://www.itav.fr/index.php/fr/
R2
[b]
[c]
Laboratoire de Chimie Appliquée : HGP
Université de Sfax, Faculté des Sciences
Sfax, 3000 (Tunisie)
Laboratoire de Synthèse et Physicochimie de Molécules d'Intérêt
Biologique (SPCMIB)
O
NaSO2CF3
Langlois reagent
CO2R3
I
R1
1
CF3
OH
Togni reagent
CNRS-UMR5068, Université Paul Sabatier-Toulouse III
118 Route de Narbonne, 31062 Toulouse Cedex 9 (France)
http://spcmib.univ-tlse3.fr/
Scheme 1. Synthesis of 3-trifluoromethylated coumarins.
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
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Similarly, some attention has also been given to the
incorporation of a CF3 group into the lactam-based equivalent of
the coumarin scaffold, namely the carbostyril scaffold[11]. As in
the case of coumarins, 4-trifluoromethylated carbostyrils have
received huge attention regarding their synthesis as well as their
biological and imaging properties,[12] while examples of their 3-
trifluoromethylated regioisomers are very scarce in the
literature.[13] Of note the so-reported methods towards 3-
trifluoromethylated carbostyrils utilize a cyclic scaffold (ie the
carbostyril scaffold) as substrates, again as with coumarins.
Herein we set out an alternative and complementary
cascade approach for the construction of 3-trifluoromethylated
coumarins and carbostyrils via the direct trifluoromethylation of
easy-to-prepare acyclic scaffolds, namely ortho-hydroxy- and
ortho-amino-cinnamic esters, and using Togni reagent 1 as CF3
source.
desired product 3a with a promising yield of 56 %.[18] Of note, a
control experiment revealed that the reaction could be promoted
without any CuI salts, but with a considerably lower efficiency in
terms of conversion and yield (Table 1, entry 13 vs 1).
Table 1. Screening of reaction conditions for the trifluoromethylation of E-
ethyl 3-(2-hydroxy-4-methoxyphenyl)acrylate 2a with Togni reagent 1.[a]
Entry
Solvent
Initiator
T (°C)
Yield of 3a
[%][b]
1
DMF
CH3CN
CH2Cl2
EtOH
DMF
CuI
CuI
80
80
80
80
60
100
80
80
80
80
80
80
80
75 (70[c]
55
)
Results and Discussion
2
To evaluate the potential of our trifluoromethylation approach
depicted in the bottom of Scheme 1, initial investigations were
conducted on ortho-hydroxylated ethyl cinnamate 2a as model
substrate and Togni reagent 1 as CF3 source[14] (Table 1).
Readily available 2a[15] was first submitted to standard
trifluoromethylation conditions, i.e. reaction at 80 °C in the
presence of 10 mol % CuI as initiator and with DMF as solvent.
Gratifyingly, the desired 3-trifluoromethylated coumarin 3a was
formed in good yield under these conditions, using 1.5 equiv. of
1 either in a pure synthetic form or in its commercial stabilized
form (Table 1, entry 1).[16] Various solvents were then examined
but without any improvement in efficiency (Table 1, entries 1-4).
DMF proved to be the best solvent, being more effective than
dichloromethane and acetonitrile (Table 1, entries 2 and 3 vs 1).
In a protic solvent such as ethanol, the reaction was also
effective but at a much slower rate than in DMF (Table 1, entry 4
vs 1). In this reaction, the temperature was shown to be crucial
as a significant decrease in conversion and yield was observed
when lowering the temperature to 60 °C (Table 1, entry 5 vs 1).
Similarly, increasing the temperature to 100 °C had a deleterious
effect on the reaction progress, probably due to the unstable
feature of 1 upon heating (Table 1, entry 6). Regarding the 1/2a
ratio, the initial 1.5:1 ratio appeared optimal, as lowering the
ratio to 1.3:1 led to a reduced yield while increasing to 2:1
provided similar results (Table 1, entries 7 and 8 vs 1).
3
CuI
67
4
CuI
29[d]
39[d]
5
CuI
[d,e]
6
DMF
CuI
-
7[f]
8[g]
9
DMF
CuI
55
72
DMF
CuI
DMF
CuBr
CuCl
Cu2O
CuI-USY
None
70
10
11
12
13
DMF
68
DMF
48
DMF
56[d]
29[d]
DMF
[a] Reactions run in the dark on a 0.25 mmol scale with 2a (1.0 equiv with a
0.25 M concentration) and freshly prepared 1 (1.5 equiv), unless otherwise
stated. [b] Yields of isolated pure product. [c] Reaction run with commercial
form of Togni reagent 1. [d] Incomplete conversion. [e] Complex mixture of
products. [f] Reactions run with 1.3 equiv of 1. [g] Reactions run with 2.0
equiv of 1.
Following these results, we screened various CuI salts as
initiators/catalysts. We were pleased to find that the
trifluoromethylated scaffold 3a was formed in moderate to good
yields in the presence of all investigated salts (Table 1, entries 1
and 9-11). CuI halides, i.e. CuI, CuBr and CuCl, provided quite
similar and good results (68-75 % yield), when the use of
cuprous oxide only led to a moderate yield of 48 %. Due to our
interest in metalated zeolites and their applications as
heterogeneous catalysts in organic synthesis,[17] we further
evaluated the potential of CuI-USY in this trifluoromethylation
process (Table 1, entry 12). Interestingly enough, the zeolite-
based CuI-USY material proved functional, furnishing the
With these reaction conditions in hands, we next explored
the scope and limitations of this trifluoromethylation process
(Table 2). For this purpose, diverse ortho-substituted cinnamic
derivatives were thus prepared and submitted to the optimal
conditions described in entry 1 of Table 1.
The nature of the alkyl substituent R1 of the ester moiety was
first examined. Shifting R1 from ethyl to methyl or t-butyl enabled
the trifluoromethylation reaction but with lower efficiency,
especially in the case of the sterically demanding t-butyl group
(Table 2, entries 2 and 3 vs 1). Hence the ethyl group was fixed
as R1 substituent for the ensuing studies. Several ethyl ortho-
hydroxycinnamates 2b-i bearing various aryl substitution
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European Journal of Organic Chemistry
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patterns were then evaluated as possible substrates (Table 2,
entries 4-11). While exposure of 2b-i to the trifluoromethylation
conditions provided all desired products 3b-i, the obtained
results revealed several manifest effects of the substitution
pattern on the reaction. Regarding electronic effects, it is clear
that the more electron-donating the R2 group, the more effective
was the reaction, as shown by the increasing reaction efficiency
seen from simple cinnamate 2b through the model 2a to the
N,N-diethylamino analogue 2c (Table 2, entry 4 vs 1 vs 5). This
trend was further confirmed when the aryl moiety was equipped
with electron-withdrawing groups, such as bromine or nitro
groups (Table 2, entries 6-8). Regioisomeric bromine-
substituted cinnamates 2d and 2e proved suitable substrates for
the transformation, but only modest yields were obtained under
standard conditions due to incomplete conversion. To
circumvent this issue, a slight modification - i.e. extension of
reaction time to 24 h with addition of CuI (10 mol %) and 1 (0.5
equiv) after 7 h - has been applied to the procedure, thus
furnishing the expected coumarins 3d,e with increased yields.
Applying these modified reaction conditions to nitro-substituted
and naphtyl derivatives (respectively 2f and 2g) also gave the
expected products 3f and 3g in appropriate yields (Table 2,
entries 8 and 9). Moreover, hydroxy-substituted cinnamates 2h
and 2i were subjected to standard conditions to afford phenolic
compounds 3h and 3i (Table 2, entries 10 and 11). Interestingly,
the highly substituted cinnamate 2i was converted to the novel
benzofurane 4 as byproduct, in addition to the expected product
3i.
5
6
7
8
9
10
Table 2. Scope of the trifluoromethylation reaction.[a]
11
Product(s) and yield [%][b]
12
13
14
Entry
1
Precursor
2
3
4
[a] Reactions run in the dark on a 0.25 mmol scale with 2a-i/5a-c (1.0 equiv
with a 0.25 M concentration) and freshly prepared 1 (1.5 equiv), unless
otherwise stated. [b] Yields of isolated pure product. [c] Incomplete
conversion. [d] Reaction time extended to 24 h, with addition of CuI (10
mol %) and 1 (0.5 equiv) after 7 h to complete the reaction.
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European Journal of Organic Chemistry
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To further expand the scope, ortho-aminocinnamic
derivatives 5a-c were prepared[19] and were successfully
engaged in the trifluoromethylation process, as shown by the
effective formation of 3-trifluromethylated carbostyrils 6a-c
(Table 2, entries 12-14). In sharp contrast with the previous
hydroxylated series, the more electron-donating the R2 group,
the less effective was here the trifluoromethylation.
without 1
CO2Et
CuI (10 mol %)
(a)
MeO
MeO
OH
2a
MeO
O
O
DMF, 80 °C
7
< 10 % after 7 h heating
1 (1.5 equiv)
CF3
CuI (10 mol %)
(b)
Considering mechanistic aspects, the reaction clearly
involves a cascade of successive events, mainly including an
intermolecular trifluoromethylation event together with the
formation of the heterocyclic pyrone ring via a lactonization
event. In order to determine in what order these key events
would occur, two first control experiments were carried out
(Scheme 2, equations (a) and (b)). While the thermal conversion
of cinnamate 2a to coumarin 7 proved unsubstantial in the
absence of Togni reagent 1 (Scheme 2, equation (a)), coumarin
MeO
O
DMF, 80 °C
O
O
O
3a
ca. 20 % after 7 h and still
incomplete conversion after 24 h
7
1 (1.5 equiv)
CuI (10 mol %)
CO2Et
CF3
(c)
K2CO3 (2.0 equiv)
MeO
OH
MeO
O
O
DMF, 80 °C
3a
2a
7
appeared as
a poor substrate under the optimized
< 10 % after 7 h reaction
trifluoromethylation conditions (Scheme 2, equation (b)). Taken
together, these results revealed that the lactonization event does
not take place prior to the trifluoromethylation event. To further
gain insight into the reaction mechanism, inhibition experiments
were conducted on the model reaction between 1 and 2a, using
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 2,6-di-tert-
butyl-p-cresol (BHT) as radical scavengers. In both cases, the
formation of 3a was seriously inhibited[20] and the TEMPO-CF3
adduct was detected in the crude mixture of the TEMPO-based
control experiment, thus supporting the involvement of radical
species (including the CF3 radical) in this cascade reaction.
According to these experimental results and literature
precedents,[14] a plausible mechanism is proposed in the bottom
of Scheme 2. The reaction pathway starts with the generation of
the CF3 free radical via the well-established single-electron
transfer (SET) process involving 1 and CuI.[14] The so-formed
CF3 radical regioselectively adds to cinnamate 2a to give the
benzylic radical intermediate I, which subsequently undergoes a
second SET process to furnish carbocation intermediate II and
concomitantly recycle the active CuI species. Then,
deprotonation of intermediate II generates trifluoromethylated
cinnamate III as key intermediate, with the stable E-
configuration.[21] E-intermediate III ultimately leads to the desired
coumarin 3a via the previously suggested lactonization event.
Importantly, a control experiment performed in the presence of
potassium carbonate supported the facts that the final
lactonization step is under proton catalysis (Scheme 2, equation
(c)).
O
CF3
CO2Et
O
I
CO2Et
CF3
MeO
OH
MeO
OH
CF3
1
CuI
(E)-III
II
H
SET
SET
EtOH
CuII
CO2Et
CF3
CF3
CF3
MeO
OH
CO2Et
MeO
O
3a
I
O
MeO
OH
2a
Scheme 2. Control experiments and resulting proposed mechanism.
Lastly, we examined the feasibility of a sequential one-pot
version starting with salicylaldehydes, as commercially available
and cheap materials. As shown in Scheme 3, the one-pot two-
step sequence, made up of a Wittig reaction prior to the
trifluoromethylation of the cinnamate intermediate, proved to be
suitable and useful for the synthesis of 3-trifluoromethylated
coumarins 3a-e, giving rise to the desired products in moderate
to good yields without the need for isolation/purification of the
cinnamate intermediate. Noteworthy is that the one-pot version
is at least equally efficient as the standard two-step synthesis,
even more efficient in the cases of 3b,c (Scheme 3).
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European Journal of Organic Chemistry
10.1002/ejoc.201601181
FULL PAPER
for 1H and 29.8 ppm for 13C). Carbon multiplicities were determined by
DEPT135 experiments. – ElectroSpray Ionization (ESI), Desorption
Chemical Ionization (DCI) and Atmospheric-Pressure Chemical
Ionization (APCI) low/high-resolution mass spectra were obtained from
the 'Service Commun de Spectroscopie de Masse' of the Plateforme
Technique, Institut de Chimie de Toulouse.
General procedure for the synthesis of 3-trifluoromethylated
coumarins 3a-i and quinolin-2-ones 6a-c: In a 5 mL microwave reactor
under argon were successively added ortho-substituted cinnamic ester
2a-i[15]/5a-c[16] (0.25 mmol, 1 equiv.), copper(I) iodide (5 mg, 0.025 mmol,
10 mol%), dry DMF as solvent (1 mL) and TOGNI reagent 1 (121 mg,
0.38 mmol, 1.5 equiv.). After stirring in the dark at 80°C for 7 h, the
resulting mixture was diluted with 20 mL of diethyl ether and the resulting
organic phase was washed with aqueous 1M NaHCO3 (3 x 10 mL), brine
(2 x 10 mL), dried over MgSO4 and evaporated. Purification of the crude
Scheme 3. Sequential one-pot synthesisa of 3-trifluoromethylated coumarins
from salicylaldehydes. aOne-pot version run with : i) salicylaldehyde (1.0 equiv)
and ylide (1.05 equiv) for the Wittig step, and ii) 1 (2.0 equiv) and CuI (20
mol %) for the trifluoromethylation step. bOverall yields of isolated pure product
via the standard two-step synthesis.
by
column
chromatography,
eluting
with
an
appropriate
cyclohexane/EtOAc or cyclohexane/Et2O mixture, afforded the desired
trifluoromethylated product 3a-i/6a-c in pure form.
7-Methoxy-3-trifluoromethyl-2H-chromen-2-one 3a: Using the general
procedure and starting from ortho-hydroxylated cinnamic ester 2a,[15] the
expected coumarin 3a was isolated as a yellowish solid. – Yield: 75 %. –
Rf = 0.55 (7:3 PE/EtOAc). – M.p. 111-113°C. – FTIR-ATR (neat): 2990,
2860, 1740, 1610, 1125 cm-1. – 1H NMR (300 MHz, CDCl3, 25 °C):  =
8.07 (s, 1H), 7.49 (d, 3J = 8.8 Hz, 1H), 6.85 (dd, 3J = 8.8 Hz & 4J= 2.5 Hz,
1H), 6.85 (d, 4J = 2.5 Hz, 1H), 3.91 (s, 3H) ppm. – 13C NMR (75 MHz,
Conclusions
In summary, we presented here a novel approach for the
synthesis of 3-trifluoromethylcoumarins starting with readily
prepared ortho-hydroxycinnamic esters as substrates and Togni
reagent as CF3 source. The method offers a wide scope and
tolerates a variety of functional groups, including alkoxy, hydroxy,
amino, nitro, naphtyl and halide substituents. Under the so-
elaborated trifluoromethylation conditions, ortho-aminocinnamic
esters were also shown to be suitable substrates for the
synthesis of 3-trifluoromethylcarbosstyrils, another class of
relevant trifluoromethylated heteroarenes.
3
CDCl3, 25 °C):  = 165.0, 156.8, 156.4, 143.2 (q, JC-F = 4.5 Hz), 130.5,
1
2
121.7 (q, JC-F = 271 Hz), 113.9, 113.8 (q, JC-F = 33 Hz), 110.4, 100.7,
56.0 ppm. – 19F NMR (282 MHz, CDCl3, 25 °C):  = -65.65 ppm. – MS
(DCI, positive mode) m/z (rel intensity) 245 ([M+H]+, 15), 262 ([M+NH4]+,
100).
3-Trifluoromethyl-2H-chromen-2-one 3b: Using the general procedure
and starting from ortho-hydroxylated cinnamic ester 2b,[15] the expected
coumarin 3b was isolated as a yellowish solid. – Yield: 69 %. – Rf = 0.35
(8:2 PE/EtOAc). – M.p. 116-118°C. – FTIR-ATR (neat): 3065, 2913, 1730,
1125 cm-1. – 1H NMR (300 MHz, [D6]acetone, 25 °C):  = 8.61 (s,
Work is currently underway to expand the potential of ortho-
substituted cinnamic derivatives as valuable building blocks for
heterocyclic synthesis.
3
4
3
4
1H), 7.92 (dd, J = 7.7 Hz & J = 1.5 Hz, 1H), 7.80 (td, J = 7.7 Hz & J =
1.6 Hz, 1H), 7.47 (td, 3J = 7.6 Hz & 4J = 1.1 Hz, 1H), 7.45 (bd, 3J= 7.6 Hz,
1H) ppm. – 13C NMR (75 MHz, [D6]acetone, 25 °C):  = 156.3, 155.6,
3
1
145.3 (q, JC-F = 4.8 Hz), 135.4, 131.1, 126.0, 122.8 (q, JC-F = 270 Hz),
Experimental Section
118.1, 117.6 (q, JC-F = 29 Hz), 117.3 ppm. – 19F NMR (282 MHz,
2
[D6]acetone, 25 °C):  = -66.63 ppm. – MS (DCI, positive mode) m/z (rel
intensity) 214 ([M+H]+, 10), 232 ([M+NH4]+, 100).
General: All starting materials were commercial and were used as
received, unless otherwise stated. In particular, the Togni reagent 1 was
synthesized according to a recently reported two-step procedure[22]
whereas ortho-hydroxy- and ortho-amino-cinnamic esters, 2a-i and 5a-c
respectively, were easily prepared from commercially available starting
7-(N,N-Diethylamino)-3-trifluoromethyl-2H-chromen-2-one 3c: Using
the general procedure and starting from ortho-hydroxylated cinnamic
ester 2c,[15] the expected coumarin 3c was isolated as a yellowish solid.
– Yield: 83 %. – Rf = 0.55 (CH2Cl2). – M.p. 52-55°C. – FTIR-ATR (neat):
2980, 1735, 1605, 1520, 1230, 1130 cm-1. – 1H NMR (300 MHz,
materials.[15,19]
–
The reactions were monitored by thin-layer
chromatography carried out on silica plates (silica gel 60 F254, Merck)
using UV-light for visualization. Column chromatographies were
performed on silica gel 60 (0.040-0.063 mm, Merck) using mixtures of
3
[D6]acetone, 25 °C):  = 8.24 (s, 1H), 7.58 (d, J = 9.1 Hz, 1H), 6.81 (dd,
4
3J = 9.1 Hz & 4J = 2.5 Hz, 1H), 6.55 (d, J = 2.4 Hz, 1H) ppm. – 13C NMR
ethyl acetate (or diethyl ether) and cyclohexane as eluents.
–
3
(75 MHz, [D6]acetone, 25 °C):  = 158.7, 157.5, 153.8, 144.6 (q, JC-F
=
Evaporation of solvents were conducted under reduced pressure at
temperatures less than 30°C unless otherwise noted. – Melting points
(M.p.) were measured with a Stuart SMP30 apparatus in open capillary
tubes and are uncorrected. – IR spectra were obtained from the 'Service
Commun de Spectroscopie Infrarouge et Raman' of the Plateforme
Technique, Institut de Chimie de Toulouse. Values are reported in cm-1. –
1H, 19F & 13C NMR spectra were recorded on a Bruker Avance 300
spectrometer at 300 and 75 MHz, respectively. Chemical shifts  and
coupling constants J are given in ppm and Hz, respectively. Chemical
shifts  are reported relative to residual solvent as an internal standard
1
2
4.5 Hz), 132.1, 123.9 (q, JC-F = 271 Hz), 110.6, 108.7 (q, JC-F = 32 Hz),
106.9, 97.3, 45.4, 12.6 ppm. – 19F NMR (282 MHz, [D6]acetone, 25 °C): 
= -65.00 ppm. – MS (DCI, positive mode) m/z (rel intensity) 286 ([MH]+,
100). – HRMS (DCI, positive mode): m/z: calcd for C14F3H15NO2
286.1055, found 286.1057 M+H+.
7-Bromo-3-trifluoromethyl-2H-chromen-2-one 3d: Using the general
procedure[23] and starting from ortho-hydroxylated cinnamic ester 2d,[15]
the expected coumarin 3d was isolated as a white solid. – Yield: 77 %. –
Rf = 0.45 (8:2 PE/EtOAc). – M.p. 90-93°C. – FTIR-ATR (neat): 3440,
1
(CDCl3: 7.26 ppm for H and 77.0 ppm for 13C – [D6]acetone: 2.05 ppm
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European Journal of Organic Chemistry
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3065, 1750, 1600, 1140 cm-1. – 1H NMR (300 MHz, CDCl3, 25 °C):  =
8.12 (s, 1H), 7.57 (d, 4J = 1.6 Hz, 1H), 7.54-7.47 (m, 2H) ppm. – 13C NMR
(75 MHz, CDCl3, 25 °C):  = 155.1, 154.7, 142.6 (q, 3JC-F = 4.8 Hz), 130.3,
128.8, 121.2 (q, JC-F = 272 Hz), 120.3, 117.8 (q, JC-F = 33 Hz), 115.7
ppm. – 19F NMR (282 MHz, CDCl3, 25 °C):  = -66.20 ppm. – MS (DCI,
positive mode) m/z (rel intensity) 267 (55), 292 ([M(79Br)+H]+, 100), 294
([M(81Br)+H]+, 100). – HRMS (DCI, positive mode): m/z: calcd for
C10BrF3H5O2 292.9423, found 292.9425 M+H+.
40 %. – Rf = 0.15 (3:7 PE/EtOAc). – M.p. 152-155°C. – FTIR-ATR (neat):
3340, 2925, 1735, 1635, 1230 cm-1. – 1H NMR (300 MHz, [D6]acetone,
25 °C):  = 8.51 (s, 1H), 8.16 (s, 1H) ppm. – 13C NMR (75 MHz,
1
2
3
[D6]acetone, 25 °C):  = 157.4, 155.8, 153.6, 144.3 (q, JC-F = 4.8 Hz),
1
2
133.3, 122.8 (q, JC-F = 271 Hz), 114.7 (q, JC-F = 34 Hz), 112.9, 107.9,
99.2 ppm. – 19F NMR (282 MHz, [D6]acetone, 25 °C):  = -66.20 ppm. –
MS (ESI, positive mode) m/z (rel intensity) 385 ([M(79Br2)+H]+, 50), 387
([M(79Br-81Br)+H]+, 100), 389 ([M(81Br2)+H]+, 50). – HRMS (ESI, positive
mode): m/z: calcd for C10Br2F3H2O3 384.8313, found 384.8323M+H+.
Benzofurane 4: Yield: 14 %. – Rf = 0.30 (3:7 PE/EtOAc). – FTIR-ATR
(neat): 3360, 1695, 1295, 1260, 1170 cm-1. – 1H NMR (300 MHz,
[D6]acetone, 25 °C):  = 8.01 (s, 1H), 7.66 (s, 1H), 4.40 (q, 3J = 7.2 Hz,
2H), 1.38 (t, 3J = 7.2 Hz, 3H) ppm. – 13C NMR (75 MHz, CDCl3, 25 °C): 
= 158.3, 153.1, 149.3, 146.5, 124.3, 121.6, 113.5, 107.1, 92.4, 61.7, 14.3
ppm. – MS (DCI, positive mode) m/z (rel intensity) 363 ([M(79Br2)+H]+,
50), 365 ([M(79Br-81Br)+H]+, 100), 367 ([M(81Br2)+H]+, 50). – HRMS (DCI,
positive mode): m/z: calcd for C11Br2H9O4 362.8868, found 362.8867
M+H+.
6-Bromo-3-trifluoromethyl-2H-chromen-2-one 3e: Using the general
procedure[23] and starting from ortho-hydroxylated cinnamic ester 2e,[15]
the expected coumarin 3e was isolated as a yellowish solid. – Yield:
69 %. – Rf = 0.75 (7:3 PE/EtOAc). – M.p. 116-119°C. – FTIR-ATR (neat):
3065, 1740, 1715, 1635 cm-1. – 1H NMR (300 MHz, CDCl3, 25 °C):  =
8.09 (s, 1H), 7.77-7.73 (m, 2H), 7.30-7.27 (m, 1H) ppm. – 13C NMR (75
3
MHz, CDCl3, 25 °C):  = 155.1, 153.4, 142.0 (q, JC-F = 4.3 Hz), 137.1,
1
2
131.6, 124.6 (q, JC-F = 271 Hz), 119.2, 118.7, 118.0 (q, JC-F = 30 Hz)
ppm. – 19F NMR (282 MHz, CDCl3, 25 °C):  = -66.90 ppm. – MS (DCI,
positive mode) m/z (rel intensity) 292 ([M(79Br)+H]+, 100), 294
([M(81Br)+H]+, 100).
7-Methoxy-3-trifluoromethylquinolin-2(1H)-one 6a: Using the general
procedure and starting from ortho-aminocinnamic ester 5a,[19] the
expected quinoline 6a was isolated as a white solid. – Yield: 34 %. – Rf =
0.20 (7:3 PE/EtOAc). – M.p. 196-199°C. – FTIR-ATR (neat): 3440, 2925,
1675, 1630, 1120 cm-1. – 1H NMR (300 MHz, [D6]acetone, 25 °C):  =
6-Nitro-3-trifluoromethyl-2H-chromen-2-one 3f: Using the general
procedure[23] and starting from ortho-hydroxylated cinnamic ester 2f,[15]
the expected coumarin 3f was isolated as a yellowish solid. – Yield: 49 %.
– Rf = 0.65 (8:2 PE/EtOAc). – M.p. 156-159°C. – FTIR-ATR (neat): 3080,
1745, 1620 cm-1. – 1H NMR (300 MHz, [D6]acetone, 25 °C):  = 8.88 (d,
4J = 2.8 Hz, 1H), 8.83 (s, 1H), 8.60 (dd, 3J = 9.1 Hz & 4J = 2.8 Hz, 1H),
4
10.94 (bs, 1H, NH), 8.33 (s, 1H), 7.77 (d, 3J = 8.8 Hz, 1H), 6.97 (d, J =
3
2.4 Hz, 1H), 6.91 (dd, J = 8.8 Hz & 4J = 2.4 Hz, 1H), 3.92 (s, 3H) ppm. –
13C NMR (75 MHz, [D6]acetone, 25 °C):  = 164.7, 158.7, 143.3, 141.0 (q,
1
2
3J = 5.2 Hz), 132.1, 120.5 (q, J = 265 Hz), 118.5 (q, J = 31 Hz), 112.9,
112.3, 98.6, 56.1 ppm. – 19F NMR (282 MHz, [D6]acetone, 25 °C):  = -
65.50 ppm. – MS (ESI, positive mode) m/z (rel intensity) 244 ([M+H]+, 60),
240 ([M+Na]+, 70). – HRMS (ESI, positive mode): m/z: calcd for
C11F3H9NO2 244.0585, found 244.0585 M+H+.
3
7.70 (d, J = 9.1 Hz, 1H) ppm. – 13C NMR (75 MHz, [D6]acetone, 25 °C):
 = 159.1, 155.4, 145.3, 142.0 (q, 3JC-F = 3.6 Hz), 129.6, 126.8, 122.4 (q,
2
1JC-F = 271 Hz), 119.4 (q, JC-F = 33 Hz), 118.9, 118.5 ppm. – 19F NMR
(282 MHz, [D6]acetone, 25 °C):  = -67.15 ppm. – MS (DCI, positive
mode) m/z (rel intensity) 256 ([M-H]-, 100).
3-Trifluoromethylquinolin-2(1H)-one 6b: Using the general procedure
and starting from ortho-aminocinnamic ester 5b,[19] the expected
quinoline 6b was isolated as a white solid. – Yield: 53 %. – Rf = 0.20 (8:2
PE/EtOAc). – M.p. 192-195°C. – FTIR-ATR (neat): 3340, 2755, 1720,
3-Trifluoromethyl-3H-benzo[f]chromen-3-one (3g): Using the general
procedure[23] and starting from ortho-hydroxylated cinnamic ester 2g,[15]
the expected coumarin 3g was isolated as a yellowish solid. – Yield:
61 %. – Rf = 0.35 (9:1 PE/EtOAc). – M.p. 156-160°C. – FTIR-ATR (neat):
3070, 1730, 1575 cm-1. – 1H NMR (300 MHz, CDCl3, 25 °C):  = 8.88 (s,
1
1625 cm-1. – H NMR (300 MHz, [D6]acetone, 25 °C):  = 11.14 (bs, 1H,
3
4
3
3
3
3
NH), 8.44 (s, 1H), 7.87 (dd, J = 8.0 Hz & J = 0.9 Hz, 1H), 7.69 (td, J =
1H), 8.24 (d, J = 8.3 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.95 (d, J = 8.1
7.5 Hz & 4J = 1.4 Hz, 1H), 7.48 (bd, 3J = 8.3 Hz, 1H), 7.31 (td, 3J = 8.0 Hz
4J = 1.0 Hz, 1H) ppm. – 13C NMR (75 MHz, [D6]acetone, 25 °C):  =
3
3
Hz, 1H), 7.77 (td, J = 8.3 Hz & 4J = 1.2 Hz, 1H), 7.64 (td, J = 8.1 Hz &
4J = 1.0 Hz, 1H), 7.49 (d, 3J = 9.0 Hz, 1H) ppm. – 13C NMR (75 MHz,
&
158.4, 141.3 (q, 3J = 5.6 Hz), 141.2, 133.7, 130.6, 123.7 (q, 1J = 272 Hz),
123.6, 121.9 (q, 2J = 30 Hz), 118.2, 116.1 ppm. – 19F NMR (282 MHz,
[D6]acetone, 25 °C):  = -66.10 ppm. – MS (DCI, positive mode) m/z (rel
intensity) 214 ([M+H]+, 100).
3
CDCl3, 25 °C):  = 156.0, 155.2, 138.8 (q, JC-F = 5.1 Hz), 136.0, 130.3,
129.4, 129.3, 129.2, 126.8, 121.6 (q, 1JC-F = 274 Hz), 121.1, 116.6, 116.2
(q, JC-F = 35 Hz), 111.2 ppm. – 19F NMR (282 MHz, CDCl3, 25 °C):  =
2
-66.20 ppm. – MS (DCI, positive mode) m/z (rel intensity) 265 ([M+H]+,
55).
3,7-Ditrifluoromethylquinolin-2(1H)-one 6c: Using the general
procedure (METHOD 1) and starting from ortho-aminocinnamic ester 5c,
the expected quinoline 6c was isolated as a white solid. – Yield: 63 %. –
Rf = 0.25 (9:1 PE/EtOAc). – M.p. 231-234°C. – FTIR-ATR (neat): 3305,
7-Hydroxy-3-trifluoromethyl-2H-chromen-2-one 3h: Using the general
procedure and starting from ortho-hydroxylated cinnamic ester 2h,[15] the
expected coumarin 3h was isolated as a yellowish solid. – Yield: 57 %. –
Rf = 0.25 (7:3 PE/EtOAc). – M.p. 166-170°C. – FTIR-ATR (neat): 3275,
3095, 1720, 1620 cm-1. – 1H NMR (300 MHz, [D6]acetone, 25 °C):  =
1
2920, 1685, 1575, 1325 cm-1. – H NMR (300 MHz, [D6]acetone, 25 °C):
 = 11.32 (bs, 1H, NH), 8.57 (s, 1H), 8.13 (d, 3J = 8.2 Hz, 1H), 7.81 (d, 4J
3
4
= 1.5 Hz, 1H), 7.60 (dd, J = 8.2 Hz & J = 1.2 Hz, 1H) ppm. – 13C NMR
(75 MHz, [D6]acetone, 25 °C):  = 158.1, 141.0, 140.7 (q, 3J = 5.2 Hz),
139.6, 134.1 (q, 2J = 33 Hz), 132.1, 124.6 (q, 1J = 272 Hz), 124.3 (q, 2J =
3
10.09 (s, 1H, OH), 8.47 (s, 1H), 7.77 (d, 3J = 8.6 Hz, 1H), 6.98 (dd, J =
4
4
8.5 Hz & J = 2.4 Hz, 1H), 6.85 (d, J = 2.4 Hz, 1H) ppm. – 13C NMR (75
3
MHz, [D6]acetone, 25 °C):  = 165.5, 158.9, 157.8, 146.2 (q, JC-F = 5.0
1
3
3
1
2
32 Hz), 123.3 (q, J = 272 Hz), 119.5 (q, J = 3.4 Hz), 113.2 (q, J = 4.2
Hz) ppm. – 19F NMR (282 MHz, [D6]acetone, 25 °C):  = -63.70, -66.56
ppm. – MS (ESI, positive mode) m/z (rel intensity) 214 (100), 282 ([M+H]+,
40). – HRMS (ESI, positive mode): m/z: calcd for C11F6H6NO 282.0356,
found 282.0354 M+H+.
Hz), 133.7, 124.3 (q, JC-F = 270 Hz), 115.9, 114.0 (q, JC-F = 33 Hz),
111.9, 104.2 ppm. – 19F NMR (282 MHz, [D6]acetone, 25 °C):  = -66.00
ppm. – MS (APCI, positive mode) m/z (rel intensity) 211 (100), 231
([M+H]+, 80).
6,8-Dibromo-7-hydroxy-3-trifluoromethyl-2H-chromen-2-one
3i:
General procedure for the one-pot sequential synthesis of 3-
trifluoromethylated coumarins 3a-e from salicylaldehydes: In a
microwave reactor under argon were successively added
Using the general procedure and starting from ortho-hydroxylated
cinnamic ester 2i,[15] the expected coumarin 3i was isolated as a
yellowish solid, as well as the benzofurane 4 as by-product. – Yield:
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European Journal of Organic Chemistry
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FULL PAPER
(carbethoxymethylene)triphenylphosphorane
(1.05
equiv.),
the
[5]
For examples of biologically-relevant coumarins, see: a) S. Penta,
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salicylaldehyde (1.0 equiv.) and dry DMF as solvent (ca. 50 mL per g of
salicylaldehyde). After stirring 24 h at room temperature, the reaction was
monitored by TLC and proved complete. To the reaction mixture were
then added copper(I) iodide (20 mol%) and TOGNI reagent 1 (2.0 equiv.).
After stirring in the dark at 80°C for 7 h, the resulting mixture was diluted
with 20 mL of diethyl ether and the resulting organic phase was washed
with aqueous 1M NaHCO3 (3 x 10 mL), brine (2 x 10 mL), dried over
MgSO4 and evaporated. Purification of the crude by column
chromatography, eluting with an appropriate cyclohexane/EtOAc or
cyclohexane/Et2O mixture, afforded the desired trifluoromethylated
product 3a,c,d in pure form.
[6]
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Acknowledgements
This work was supported by the Agence Nationale de la
Recherche (ANR-13-JS07-0003-01 CiTrON-Fluo) and the CNRS.
Sl.C. thanks the Campus France agency and the Université de
Sfax for financial support.
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Keywords: Coumarins • Trifluoromethylation • Radical
Reactions • Fluorine • Carbostyrils
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[3]
[4]
Such improvement is mainly due to enhanced lipophilicity, metabolic
stability and bioavailability of fluorinated molecules.
Remarkably, nearly 15 % of the most recently approved drugs are
trifluoromethylated
compounds.
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[13] Two examples, including compound 6b of the present work, are
reported in Reference 8. For the other few examples, see: a) S. L.
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European Journal of Organic Chemistry
10.1002/ejoc.201601181
FULL PAPER
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references therein; b) L. Ling, K. Liu, X. Li, Y. Li, ACS Catal. 2015, 5,
2458-2468.
[15] For details on the facile one-step Wittig-type preparation of ortho-
hydroxycinnamic esters 2a-i from salicylaldehydes, see the Supporting
Information.
[16] We choose to continue this work with home-made Togni reagent
because 1 is easy to prepare in large scale.
[17] For selected applications of CuI-zeolites in organic synthesis, see: a) V.
Magné, T. Garnier, M. Danel, P. Pale, S. Chassaing, Org. Lett. 2015,
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[18] Further exploitation of this promising result will be reported elsewhere.
[19] For details on the two-step preparation of ortho-aminocinnamic esters
5a-c from ortho-nitrobenzaldehydes, see the Supporting Information.
[20] Only trace amount of 3a detected in TEMPO- and BHT-based inhibition
experiments.
[21] For similar works dealing with E-stereoselective trifluoromethylation of
C=C double-bonds, see Reference 9c and: a) A. Prieto, E. Jeamet, N.
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CuI (10 mol %) and 1 (0.5 equiv) after 7 h to complete the reaction.
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European Journal of Organic Chemistry
10.1002/ejoc.201601181
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Trifluoromethylation*
Slim Chaabouni, Florent Simonet, Alison
François, Souhir Abid, Chantal Galaup,
and Stefan Chassaing*
Page No. – Page No.
A method for the regioselective synthesis of 3-trifluoromethylated coumarins and
carbostyrils via the direct trifluoromethylation of appropriately substituted ortho-
functionalized esters is described. The reaction proceeds with Togni reagent as the
CF3 source under mild conditions and with good functional group tolerance.
3-Trifluoromethylated Coumarins and
Carbostyrils via Radical
Trifluoromethylation of ortho-
Functionalized Esters
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