Fluoroform: An efficient precursor for the trifluoromethylation of aldehydes

Article abstract of DOI:10.1016/S0040-4020(99)00951-5

Fluoroform is shown to be an efficient trifluoromethylating agent when deprotonated using standard reagents in DMF. The important role of DMF as a solvent but also as a reactant was demonstrated.

Full text of DOI:10.1016/S0040-4020(99)00951-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 275–283
Fluoroform: an Efficient Precursor for the Trifluoromethylation
of Aldehydes
a
b
a,
c
*
ˆ
´
Benoıt Folleas, Ilan Marek, Jean-F. Normant and Laurent Saint-Jalmes
a
´ ´
´
Laboratoire de Chimie des Organoelements, Universite P. et M. Curie, 4 Place Jussieu 75252, Paris, Cedex 05, France
bTechnion—Israel Institute of Technology, Department of Chemistry, Technion City, 32000 Haifa, Israel
c
`
Rhodia Organique Fine, 85 avenue des freres Perret BP 62, 69192 Saint-Fons, Cedex, France
Received 28 June 1999; accepted 21 October 1999
Abstract—Fluoroform is shown to be an efficient trifluoromethylating agent when deprotonated using standard reagents in DMF. The
important role of DMF as a solvent but also as a reactant was demonstrated. ᭧ 1999 Elsevier Science Ltd. All rights reserved.
Introduction
Iodotrifluoromethane CF3I 2 is the most common trifluoro-
methylating agent.8,9 Most trifluoromethylmetals are avail-
able under mild conditions from 2 by formal insertion of a
metal into the carbon–iodine bond.8,9 On the other hand,
bromotrifluoromethane 3 has a lower reactivity than that
of 2, although it can insert many metals under harsher condi-
tions.8,9 CF2Br2 4, introduced by Burton10 can be used to
synthesise cadmium and zinc complexes in an efficient
manner. It has also been used for the direct trifluoromethyl-
ation of aromatic halides in the presence of copper.11 Many
other substrates are also effective trifluoromethylating
agents and have mainly been used for the formation of
copper complexes. In the presence of an aromatic halide
and copper(I) salts, 5 leads to the corresponding a,a,a-
trifluorotoluene.12 Compounds 6a,13 714 and 815 are also
reliable CF3Cu precursors and commercially available
whereas 6b,13c,16 6c,16 9,17 1018 and 1119 require a multi-
step synthesis. Finally, the formation of the trifluoromethyl-
ated organocopper compound CF3Cu was postulated from
trifluoromethylsilane20 CF3SiMe3 by a transmetallation
step21 although the organocopper intermediate was not
isolated. However, all these trifluoromethyl precursors
present several drawbacks such as the cost (2, 6a, 7, 8),
imminent prohibition for ecological reasons (2, 3 and 4),
difficult synthesis (6c, 6b, 9, 10, 11) and waste of fluorinated
materials (9 and 11). It is important to underline that among
all the previous trifluoromethyl sources, CF3SiMe3 displays
the most efficient reactivity towards numerous function-
alities.20,22 In the field of fluorine chemistry, it is still a
challenge to find a new approach (safe and with the preser-
vation of the ecological environment) for the introduction of
a trifluoromethyl group on organic molecules via a trifluoro-
methyl metal, and we were thus interested in using fluoro-
form23 as a source of the trifluoromethyl group. This gas is a
side-product of the industrial synthesis of CHF2Cl, a key
intermediate in the multiple-step synthesis of Teflon᭨ and
The trifluoromethyl group is a highly important substituent
in organic chemistry. Its powerful electron-withdrawing
ability and small size lead to significant changes in the
chemistry of substituted compounds when compared with
non-fluorinated analogues. Effects reported include stabili-
sation of small rings,1 as well as changes in both regio-
selectivity2 and reactivity.3 Many performance chemicals
benefit from the presence of a CF3 group. The high lipo-
philicity of the group gives active pharmaceutical and
agrochemical compounds with improved transport charac-
teristics in vivo and facilitates lower dosage rates. Substi-
tuted polymers that show enhanced stability, resistance to
chemicals, and flame retardance have been made from
trifluoromethylated precursors.4 The light and wash fastness
of dyes can be improved by the presence of CF3.5
Classical methods for the synthesis of trifluoromethylated
aromatics come from the beginning of this century. Indeed,
Swarts discovered that antimony trifluoride could be used to
convert benzotrichloride into benzotrifluoride.6 Later, it was
found that hydrogen fluoride could also fluorinate benzo-
trichloride to yield the trifluoride.7 These methods are still
used today, but have a number of disadvantages relating to
the harsh conditions they impose and their toxicity. These
facts have led to the development of milder alternative8
reagents and particularly the synthesis of trifluoromethyl
metals.9 In Scheme 1 the different approaches to these
trifluoromethyl organometallic complexes
summarised.
1
are
Keywords: fluoroform; trifluoromethylation.
* Corresponding author. Tel.: ϩ33-44-27-55-72; fax: ϩ33-1-44-27-51-50;
e-mail: normant@ccr.jussieu.fr
0040–4020/00/$ - see front matter ᭧ 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)00951-5

´
276
B. Folleas et al. / Tetrahedron 56 (2000) 275–283
Scheme 2.
Indeed, in light of the thermal instability of the trifluoro-
Scheme 1.
methyl metal with MˆLi, Mg and Na described above, it
was difficult to understand the good results obtained by
Shono31 with these very ionic organometallics. So, we
decided to investigate in detail the metallation of fluoroform
with the Group IA organometallics.
we thought it would be challenging to deprotonate it and to
build trifluoromethylated organometallic complexes.
However, fluoroform is the weakest acid of all the halo-
forms24 (pKa CF3Hˆ28, pKa CCl3Hˆ15.5, pKa
CBr3Hˆ13.7) and in a series of investigations of the
mechanism of hydrolysis of mixed halomethanes,25 Hine
and co-workers have found that the basic hydrolysis of
CF3H is too slow to be measured26 and indeed fluoroform
does not undergo any deuterium exchange after 21–47 days
in labelled, alkaline aqueous dioxane.27 On the other hand,
the trifluoromethyllithium (generated by the halogen–
lithium exchange of iodotrifluoromethane) can not be
trapped even at low temperature and decomposes to yield
tetrafluoroethylene9 (the same trend is observed for the
trifluoromethyl magnesium halide28 and trifluoromethyl
sodium29). Then, from this overview, only the trifluoro-
methyl metals with MˆCu, Zn, Si, Cd, Sn, Hg and Pb are
stable8,9 (covalent organometallic) and can be used for
organic transformations.
Results and Discussion33
As expected, treatment of fluoroform with lithiated bases at
low temperature led only to a violent exothermic reaction
and then to the degradation of the starting material. If the
reaction was performed in the presence of electrophiles (as
benzaldehyde or zinc salt in Barbier conditions), 19F NMR
examination of the crude reaction mixture revealed an
outstanding number of fluorinated products characteristic
of the degradation of the carbenoids. However, addition of
1 equiv. of CF3H to tertBuOK in DMF in the presence of
benzaldehyde (Barbier conditions) at Ϫ40ЊC led, in agree-
ment with Shono,31 to a mixture of the corresponding
trifluoromethyl carbinol 13 in 40% yield with 30% of
benzoic acid, 22% of benzyl alcohol34 and 8% of remaining
benzaldehyde as described in Equation 1.
Our first attempts to generate trifluoromethyl metal with
MˆCu and Zn from fluoroform were based on the metalla-
tion concept with basic organocopper and organozinc deri-
vatives in order to directly obtain the trifluoromethyl copper
or zinc derivatives. However, whatever the organometallic
used ((nBu)2CuLi, (nBu)2CuCNLi2, (nBu)3CuCNLi3,30 tert-
Bu2CuCNLi2, Et2Zn, (nBu)3ZnLi, AllylZnBr,…) in differ-
ent conditions (heating, sonication, in pressurised flask) or
different solvents (Et2O, THF, HMPA) no trace of the corre-
sponding trifluoromethyl organometallic was detected by
19F NMR. However, we were very intrigued by the recent
results of Shono31 who reported that the trifluoromethyl
anion could be formed at Ϫ10ЊC in 5 h by treatment of
trifluoromethane with some common bases as NaH or tert-
BuOK in DMF, in the presence of benzaldehyde as electro-
phile, to give the corresponding carbinol in, respectively, 28
and 40% yield. Even better, the use of the electrogenerated
anion of pyrrolidine31 as a base led to a remarkable increase
in the yield of the carbinol (75–80%) as described in
Scheme 2 (path A). In a similar manner, Troupel et al.32
showed more recently that the phenylide anion produced
by electroreduction of a large excess of iodobenzene was
able to deprotonate fluoroform in the presence of a series of
aldehydes to afford the corresponding trifluoromethylated
carbinols (Scheme 2, path B).
More importantly, when the benzaldehyde was added after
the formation of the trifluoromethyl metal species (Grignard
conditions), the yield in the corresponding alcohol 13
remained unchanged (Equation 2), which meant that there
was no degradation of the supposed organometallic species
12 at Ϫ40ЊC.
When the same reaction was performed at room temperature
instead of Ϫ40ЊC, only the starting material was recovered.
Equation 1.
Equation 2.

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B. Folleas et al. / Tetrahedron 56 (2000) 275–283
277
Equation 3.
Equation 4.
It is important to note that the presence of potassium is
compulsory since the addition of one equivalent of lithium
bromide (known to convert the potassium organometallic
into the organolithium at very low temperature35) gave no
trace of trifluoromethyl carbinol 13, but intensive degrada-
tion. However, although the formation of a trifluoromethyl
metal in these conditions was a very promising method for
the trifluoromethylation of benzaldehyde in moderate yield,
two points needed to be clarified: what was the exact
mechanism of this reaction and how could we avoid the
presence of one equivalent of tertBuOH in this transforma-
tion. Indeed, in order to increase the reactivity of the
trifluoromethyl metal 12 it would be absolutely necessary
to carry out some transmetallations as described in
Equation 3 and then we were afraid that, once formed, the
new organometallic derivative would suffer from the
presence of the tertiary alcohol.
using a,a,a-trifluorotoluene as an internal standard). This
intermediate was stable at this temperature for a very long
period of time (after 14 h, 38% of this intermediate was still
present in the reaction mixture) but when the reaction was
warmed up to room temperature, a rapid degradation of 14
was noticed. This result could be explained by the following
mechanism: deprotonation of fluoroform by potassium
dimsylate afforded the trifluoromethyl anion which was
trapped in situ by the carbonyl moiety of DMF37 to form
the gem-aminoalcoholate 14 (Ϫ78.8 ppm by 19F NMR versus
CFCl3, Scheme 3 step A). This intermediate is a masked and
stable form of the trifluoromethyl anion at Ϫ20ЊC, therefore
avoiding the degradation of the carbenoid CF3K.
In order to assess this mechanistic hypothesis, the inter-
mediate 14 was hydrolysed at Ϫ25ЊC, without adding any
electrophile. As expected, fluoral was identified by 19F
NMR (Ϫ84 ppm versus CFCl3) (Bouveault reaction38).
Moreover, by treatment of this latter (or its hydrate form)
with benzoic anhydride, we obtained the corresponding
diacylate, namely 1,1,1-trifluoro-2,2-di(phenylcarbonyl-
oxy)ethane 15 as described in Scheme 4.
So, for these reasons we first decided to investigate an alter-
native route for the formation of the trifluoromethyl anion
12 and then our choice was turned to the use of potassium
hydride36 as a base. According to the same experimental
conditions as described in Equation 1 but with potassium
hydride instead of tertBuOK, only 1% of the carbinol 13
was isolated. One possible explanation for this frustrating
result is that KH was totally insoluble in these experimental
conditions, and then it could not react with fluoroform. In
order to solve this problem, we then investigated the use of
the metallated dimethylsulfoxide (dimsyl-K) as a base by
treatment of DMSO with KH as described in Equation 4.
This gem-aminoalcoholate had already been observed by
39
´
Perichon et al. during electroreduction experiments of
bromotrifluoromethane in DMF to form trifluoromethylzinc
bromide and also by Lang et al.40 during the formation of
fluoral by reduction of iodotrifluoromethane by zinc metal
in DMF.
According to these new experimental conditions, the
isolated yield of 13 was 65%. If we performed an analogous
reaction with NaH instead of KH, 13 was obtained in 10%
yield only. Once we had found suitable experimental condi-
tions for the synthesis of 13, we still had to investigate the
mechanism of this new trifluoromethylation reaction.
Mechanism of the trifluoromethylation
In order to determine the mechanism of this reaction, we
studied the evolution of our reaction by 19F NMR.
When dimsyl-K was mixed with CF3H in DMF at Ϫ20ЊC, a
new doublet appeared after less than 30 minutes (Ϫ78 ppm
versus CFCl3, Jˆ7.6 Hz) in an extent of 40% (determined
Scheme 3.

´
B. Folleas et al. / Tetrahedron 56 (2000) 275–283
278
Scheme 4.
Then the DMF solvent played the role of an in situ electro-
phile to give the trifluoromethylated alcoholate 14 and this
latter reacted as a nucleophile with a stronger electrophile
(i.e. the aldehyde) to give the corresponding carbinol
(Scheme 3, step B). The second step of this reaction is the
equivalent of the haloform reaction41 with the unknown
amino-alcoholate as intermediate. Moreover, it was shown
from an NMR study that the reaction between the amino-
alcoholate 14 and benzaldehyde is a fast and quantitative
reaction (i.e. 10 mmol of 1442 reacted with an excess of
benzaldehyde between Ϫ20ЊC and room temperature to
give 9.7 mmol of carbinol 13;42 see Scheme 3, step B).
Equation 3 but using THF instead of DMF as a solvent,
no trace of the carbinol 13 was detected.
This simple reaction was generalised to various other
aldehydes as described in Table 1.
The yields of trifluoromethylated carbinols were slightly
dependent on the substitution on the aromatic ring: the
presence of electron-donating substituents in para position
improved yields (entries 2–4) while their presence in meta
position had the opposite effect (compare entry 4 and entries
5–7). This methodology was also applied to 2-furfural
(entry 9) and cyclohexanecarboxaldehyde as an aliphatic
aldehyde. When primary aliphatic aldehydes were
involved, the major reaction to take place was aldolisation–
crotonisation.
In order to have some valuable information on the impor-
tance of the DMF, trifluoromethylation of benzaldehyde
was attempted using the dimethylacetal of DMF as a
solvent; here, the carbonyl of DMF is masked.
From this study, we have proved that it is possible to depro-
tonate fluoroform at Ϫ20ЊC using standard reagents and to
trifluoromethylate several aldehydes with the trifluoro-
methyl anion so obtained. The key step of this reaction
seems to be the nucleophilic addition of the trifluoromethyl
anion onto the carbonyl moiety of DMF to form the inter-
mediate trifluoromethylated amino alcoholate 14, a masked
form of the trifluoromethyl anion. In the second step,
namely the reaction with a stronger electrophile, the
trifluoromethyl moiety is transferred to the carbonyl via a
In this instance, addition of fluoroform at low temperature
resulted in a violent exothermic reaction and the reaction
mixture immediately became black. This exothermic colour
change is often characteristic of carbenoid degradation.
Moreover, at the end of the reaction, no trace of the expected
trifluoromethylated carbinol could be detected.
If the trifluoromethylation reaction was performed in
exactly the same experimental conditions as described in
Table 1. Trifluoromethylation of aldehydes

´
B. Folleas et al. / Tetrahedron 56 (2000) 275–283
279
Equation 5.
process equivalent to the haloform reaction41 to give, in
moderate to good yields, the corresponding alcohols.
never exceeded 15%, either after 4 days at room tempera-
ture or after 1 h at 60ЊC. In the same way, when 17 was
warmed in the presence of 4-iodoanisole 20, the expected
a,a,a-trifluorotoluene 21 was observed with a low yield
(Ͻ10%, 19F NMR using a,a,a-trifluorotoluene as an inter-
nal standard).
Numerous attempts to incorporate the trifluoromethyl group
directly into a substrate via in situ generation and coupling
of CF3M with aryl iodides were published in the litera-
ture.8,9,43 Having in our hands the intermediate 14, it was
interesting to study the transmetallation reaction with zinc
or copper salt in order to prepare the corresponding CF3ZnX
and CF3Cu.
The influence of the nature of the copper(I) salt in the forma-
tion of 17 and its transformation in 18, 19 was investigated.
As shown in Table 2, the presence of solvating agents such
as Me2S, TMEDA, HMPT or PBu3 (entries 2–5) supposed
to stabilise organometallic species did not improve the yield
of 17, nor that of the expected trifluoromethylcopper,
CF3Cu. In the case of CuCN.2LiBr (entry 6), the modest
yield was explained by the presence of THF which could
have destabilised 17 once formed. In the following work,
CuI was the only copper(I) salt used. It is important to note
that in any of the following experiments (Tables 3 and 4),
When ZnBr2 was added to 14 at Ϫ30ЊC and the reaction
mixture was warmed up to room temperature, a new tetra-
hedral intermediate 16 was identified by 19F NMR (as a
doublet at Ϫ76.5 ppm versus CFCl3, Jˆ7.5 Hz). By acidic
hydrolysis, this latter afforded fluoral (Ϫ84 ppm versus
CFCl3). Moreover, 16 had an extraordinary thermal stability
and it could stand at room temperature for hours, or be
heated at 60ЊC for 5 h without degradation. We assume
that 16 arose from a transmetallation reaction of 14 with
zinc salts (see Equation 5). Its high stability could be
attributed to the strength of the oxygen–zinc bond.44
However, despite all our trials, the conversion of 16 into
the trifluoromethylzinc halide failed and 16 proved to be
unreactive with classical electrophiles.
Table 3. Replacement of DMSO by an aprotic solvent for the preparation
of dimsyl-K
Entrya
Dimsyl-Kb
Solvent
17(%)c
CF3Cu(%)c,d
Total(%)e
1
2
3
4
1
1
1
2
Et2O
Toluene
THF
15
12
30
70
–
10
–
15
22
30
90
THF
20
In a comparable manner the addition of copper iodide to a
mixture of 14 at Ϫ30ЊC provided a new tetrahedral inter-
mediate 17 (Ϫ76.5 ppm versus CFCl3, Jˆ7.5 Hz) hydro-
lysed to fluoral (19F NMR). Once more, 17 proved to be
much more stable than its analogue 14, probably due to
the strength of the oxygen–copper bond which is much
higher than that of the oxygen–potassium one. 17 also
proved to be less stable than 16: its evolution at room
temperature partially afforded the expected trifluoromethyl
metal complex (CF3Cu) which was observed by 19F NMR as
its two forms (18, Ϫ25 ppm and 19, Ϫ30 ppm versus
CFCl3) in agreement with Burton’s results.45,46 Unfortu-
nately, the total yield of trifluoromethylcopper species
a Dimsyl-K was prepared in 10 ml of solvent at room temperature by
addition of 1 eq. of DMSO on potassium hydride.
b Number of equivalents vs CF3H.
c Yields of fluorinated species was determined by 19F NMR with a,a,a-
trifluorotoluene as an internal standard.
d CF3Cu unders its two forms: 18, 19.
e Total yield in trifluoromethylated metallic species 17, 18 and 19.
Table 4. Influence of the presence of Lewis bases
Entrya
tb
L.B.c
17 (%)
CF3Cud (%)
Totale (%)
1
2
3
4
5
6
7
8
9
0
14
0
14
0
14
0
None
Pyr
66
20
65
Trace
91
27
88
29
27
14
38
20
trace
–
31
4
47
47
80
58
85
Trace
91
58
92
76
74
Table 2. Influence of the nature of Cu(I) on the formation of 17
Entrya
Cu(I)
17(%)b
CF3Cu (%)b,c
TDA-1
DMEU
1
2
3
4
5
6
CuI
46
40
3
38
–
–
3
6
–
–
–
CuBr.Me2S
CuI.TMEDAd
CuI.HMPTd
CuI.PBu3
CuCN.2LiBr
14
19
d
a CF3H/KH/DMSO/CuI: 20/40/40/20 mmol in 20 ml of DMF. Yields of
fluorinated species were determined by 19F NMR with a,a,a-trifluoro-
toluene as an internal standard.
24
a CF3H, KH and Cu(I) were involved in equimolar quantities in a 2/1
mixture of DMF/DMSO (v/v).
b Time at room temperature in hours.
b Yields of fluorinated species was determined by 19F NMR with
a,a,a-trifluorotoluene as an internal standard.
c Lewis bases added at Ϫ20ЊC before warming up. 5 ml of pyr. and
TDA-1 and 10 ml of DMEU were involved.
c CF3Cu under its two forms: 18, 19.
d CF3Cu in its two forms: 18, 19.
d CuI added as a suspension in 10 ml of the Lewis base.
e Total yield in trifluoromethylated metallic species 17, 18 and 19.

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B. Folleas et al. / Tetrahedron 56 (2000) 275–283
280
Scheme 5.
among the two copper species 18 and 19, 18 has always
appeared first, which is in total agreement with Burton’s
observations.45
toluene as an internal standard). On the other hand, when 20
was heated directly in the presence of 17 in the same
solvents system, 22 was obtained in a 20% yield. Finally,
when the same experiment was attempted in a 1/1 DMF/
DMEU mixture, 21 was formed in a 40% yield (see
Scheme 5).
Although potassium dimsylate had proved to be very useful
for the deprotonation of fluoroform and the subsequent
formation of the gem-aminoalcoholate 14, we investigated
the role of DMSO in the formation of 17, 18, 19 and 21. For
this purpose, dimsyl-K was formed from equimolar amounts
of potassium hydride and DMSO47 in an aprotic solvent.
Diethyl ether, THF and toluene were tested (see Table 3).
When one equivalent of dimsyl-K (versus fluoroform) was
involved, yields were poor (entries 1–3). On the other hand,
17, 18 and 19 were much less stable than in the presence of
DMSO (their total disappearance took some hours at room
temperature and some minutes at 60ЊC) which made them
unreliable for subsequent coupling reactions.
From this study, we have demonstrated that 17, arising from
a transmetallation reaction of 14 in the presence of copper
iodide, afforded the trifluoromethylated copper complex
CF3Cu. Even if the mechanism of this transformation
is not precisely known, we assume that 17 could both
rearrange (Scheme 6, path a) or transfer a trifluoromethyl
moiety on copper iodide (Scheme 6, path b). Moreover,
these two pathways could account for the two forms of
CF3Cu observed by 19F NMR, namely 18 and 19.
Thus, when heated in the presence of 17, 4-iodoanisole
afforded its trifluoromethylated analogue in a 40% yield,
probably via in situ formation of a trifluoromethylcopper
species and Ullmann coupling reaction. Despite the modest
observed yields, an aromatic halide was for the first time to
our knowledge trifluoromethylated starting from fluoroform
as a trifluoromethyl source.
In the presence of two equivalents of dimsyl-K prepared in
THF (entry 4), yields increased dramatically (17, 70% and
18, 20%). Unfortunately, 17 and 18 suffered from the same
lack of stability. It was possible to stabilise these two
trifluoromethylated complexes at room temperature by
adding HMPT to the reaction mixture, but at 60ЊC, the
stabilising effect seemed to disappear: after 0.5 h, none of
17, 18 or 19 was present.
These reactions seem to be solvent-sensitive and the reac-
tion, as well as the role of solvents in the formation of 17,
18, 19 and then 20, are still under investigation in our
laboratory.
Aprotic cosolvents were therefore suppressed and dimsyl-K
was prepared by addition of 1.1 equiv. of DMSO on potas-
sium hydride at room temperature (see Table 4). In the
absence of any Lewis base, 17 was obtained in 66% yield
along with 18 (entry 1). After 14 h at room temperature, the
total yield in trifluoromethylated species was still 58%
(entry 2). The presence of TDA-148 (tris(2-(2-methoxy-
ethoxy)ethyl)amine) or pyridine, expected to stabilise 18
and 19 once formed was quite disappointing: after 14
hours, 17, 18 and 19 had almost disappeared in the latter
case (entry 4) while in the former, their total yield was the
same as in the absence of any chelating agent (entry 6). On
the other hand, when DMEU49 was involved as a cosolvent,
17 and 18 were formed in a 92% total yield and were still
present in a 74% yield after 19 h, with a 47% yield in the
expected trifluoromethylcopper species (18 and 19) (entry
9). Thus, the destabilising effect of THF, diethyl ether or
toluene quoted in Table 3 had been overridden by the use of
DMEU.
Conclusion
We have demonstrated the efficiency of fluoroform in
trifluoromethylating reactions. Its deprotonation by potas-
sium dimsylate in the presence of DMF afforded the gem-
aminoalcoholate 14, a stable form of the trifluoromethyl
anion. This latter exhibited an interesting reactivity. In the
presence of an aldehyde, it transferred its trifluoromethyl
moiety, affording the corresponding carbinol. On the other
hand, in the presence of copper iodide, it was trans-
metallated to 17. In the presence of a stabilising agent like
DMEU, 17 was transformed to trifluoromethylcopper
CF3Cu. And finally, when heated in the presence of an
aromatic compound and DMEU, it afforded the correspond-
ing a,a,a-trifluorotoluene. These first results are more than
Given these results, we then investigated the reactivity of
the obtained CF3Cu (18 and 19) on aromatic halides. When
4-iodoanisole 20 was introduced in a solution of 18 and 19
in a mixture of DMF/DMEU (formed as described in
Table 4, entry 8) and heated at 60ЊC for 10 h, the expected
4-trifluoromethylated anisole 21 was formed in a 15% yield
(versus 20, determined by 19F NMR using a,a,a-trifluoro-
Scheme 6.

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B. Folleas et al. / Tetrahedron 56 (2000) 275–283
281
promising and many aspects of this new reaction are still
under study in our laboratory.
Preparation of 2,2,2-trifluoroethanols 13
The solution of potassium dimsylate was prepared in a two-
necked flask (equipped with magnetic stirring and nitrogen
inlet) according to the above procedure from KH in mineral
oil (2 ml, 20 mmol) and DMSO (10 ml).
Experimental
General
It was added to a solution of fluoroform (440 ml, 20 mmol)
in DMF (20 ml) at Ϫ40ЊC. After 30 mins, a solution of
aldehyde (10 mmol) in DMF (5 ml) was added dropwise
and after 30 mins more the mixture was allowed to warm
to 0ЊC and quenched by 2N HCl (10 ml). It was poured into
Et2O (40 ml) and washed with 2N HCl (2×20 ml). Organic
layers were dried over MgSO4 and Et2O removed by evapora-
tion under reduced pressure. The obtained oil was purified by
column chromatography on silica gel.
1H, 13C and 19F NMR spectra were recorded on a Bru¨ker
ARX-400 at 400, 100 and 380 MHz respectively. For 19F
NMR, CFCl3 was taken as an internal reference. Micro-
analyses and mass spectroscopy were accomplished at
Paris VI University. Infrared (IR) spectra were recorded
on a Perkin–Elmer 1420 Spectrophotometer.
DMF, DMSO and DMEU were distilled from calcium
hydride under reduced pressure. Reactions were carried
out under inert atmosphere of nitrogen and fluoroform was
added through a gazometer. Merck plates (Silica gel 60
GF254, 0.25 mm) were used for thin layer chromatography
(TLC) and the crudes were purified by column chromato-
graphy on silica gel (Silica Gel Geduran Si 60, 43–60 mm)
The physical properties and analytical data for the trifluoro-
methylated carbinols are listed below.
2,2,2-Trifluoro-1-(4-dimethylaminophenyl)ethanol 13a.
1
IR (neat): 3460, 2820 cmϪ1; H NMR (CDCl3) d(ppm):
7.34 (d, 2H, Jˆ8.6 Hz), 6.74 (d, 2H, Jˆ8.6 Hz), 4.93 (dq,
1H, JHFˆ6.4 Hz et JHHˆ4.4 Hz), 3.00 (s, 6H), 2.38 (d, 1H,
Jˆ4.4 Hz); 13C NMR (CDCl3) d(ppm): 151.65, 128.79,
124.94 (q, JCFˆ282 Hz), 121.84, 112.52, 73.14 (q, JCFˆ
32 Hz), 40.76; 19F NMR (CDCl3) d(ppm): Ϫ78.82 (d,
JHFˆ6.4 Hz).; Anal. calculated for C10H12F3NO: C, 54.79;
H, 5.52. Found: C, 54.82 H, 5.47.
General preparation of a solution of potassium
dimsylate in DMSO
A flask equipped with a nitrogen inlet was charged with
potassium hydride in suspension in mineral oil. The mineral
oil was removed by washing with pentane (15 ml) and
DMSO was added. The obtained mixture was then stirred
for 1 h at room temperature.
1
2,2,2-Trifluoro-1-(3-phenyloxyphenyl)ethanol 13b39. H
NMR (CDCl3) d(ppm): 7.39 (m, 3H), 7.23 (m, 1H), 7.19
(m, 2H), 7.16 (m, 1H), 7.06 (m, 3H), 4.99 (q, 1H,
JHFˆ6.6 Hz), 2.95 (s, 1H); 13C NMR (CDCl3) d(ppm):
157.55, 156.68, 135.82, 129.99, 129.91, 123.98 (q,
JCFˆ290 Hz), 123.72, 122.07, 119.61, 119.11, 117.80,
72.45 (q, JCFˆ32 Hz); 19F NMR (CDCl3) d(ppm): Ϫ78.67
(d, JHFˆ6.6 Hz); Anal. calculated for C14H11F3O2: C, 62.69;
H, 4.13. Found: C, 62.70; H, 4.11.
Preparation of 1,1,1-trifluoro-2,2-di(phenylcarbonyl-
oxy)ethane 15
The solution of potassium dimsylate was prepared in a four-
necked flask (equipped with mechanical stirring, nitrogen
inlet and internal thermometer) according to the above
procedure from KH in mineral oil (1 ml, 10 mmol) and
DMSO (1.42 ml, 20 mmol).
2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol 13c. 1H NMR
(CDCl3) d(ppm): 7.39 (d, 2H, Jˆ8.6 Hz), 6.94 (d, 2H,
Jˆ8.6 Hz), 4.92 (q, 1H, JHFˆ6.7 Hz), 3.82 (s, 3H), 3.42 (s,
3H); 13C NMR (CDCl3) d(ppm): 160.74, 129.22, 126.69,
124.90 (q, JCFˆ290 Hz), 114.40, 72.73 (q, JCFˆ32 Hz),
55.67; 19F NMR (CDCl3) d(ppm): Ϫ78.64 (d, JHFˆ6.7 Hz;
Anal. calculated for C9H9F3O2: C, 52.43; H, 4.40. Found: C,
52.42; H, 4.40.
It was frozen at Ϫ40ЊC and DMF (20 ml) and fluoroform
(440 ml, 20 mmol) were added. The mixture was stirred for
1 h at Ϫ25ЊC: during this period, the frozen potassium
dimsylate was slowly solubilised. Then, a mixture of
benzoic anhydride (2.26 g, 10 mmol) in DMF (5 ml) was
added and the reaction mixture allowed to reach room
temperature within 2 h before being quenched by a 2N
HCl aqueous solution (10 ml). The crude product was
poured in Et2O (40 ml) and washed with 2N HCl
(2×20 ml). Et2O was removed from organic layers by
evaporation under reduced pressure and replaced by pentane
(15 ml). Most of the benzoic acid present in the crude
product was then removed by precipitation at Ϫ20ЊC and
filtration. The filtrate was condensed and purified by column
chromatography on silica gel (cyclohexane/ethyl acetate:
4/1). The product was isolated as a colourless oil (0.58 g,
1
2,2,2-Trifluoro-1-(3,4-dimethoxyphenyl)ethanol 13d31. H
NMR (CDCl3) d(ppm): 7.03 (m, 2H), 6.90 (m, 1H), 5.0 (q,
1H, JHFˆ7.5 Hz), 3.93 (s, 3H), 3.92 (s, 3H), 2.54 (s, 1H); 13
C
NMR (CDCl3) d(ppm): 149.86, 149.02, 126.59, 124.80 (q,
JCFˆ290 Hz), 120.33, 110.86, 110.17, 72.55, 55.91; 19F
NMR (CDCl3) d(ppm): Ϫ78.86 (d, JHFˆ7.5 Hz); Anal.
calculated for C10H11F3O3: C, 50.85; H, 4.69. Found: C,
50.92; H, 4.65.
1
18%). IR (neat): 1750 cmϪ1; H NMR (CDCl3) d (ppm):
1
8.15 (m, 4H), 7.72 (q, 1H, JHFˆ3.6 Hz), 7.68 (m, 2H),
7.51 (m, 4H); 13C NMR (CDCl3) d (ppm): 163.31, 161.12
(q, JCFˆ291 Hz), 134.52, 130.51, 128.82, 127.66, 83.25 (q,
JCFˆ39 Hz); 19F NMR (CDCl3) d(ppm): Ϫ81.28 (d,
JHFˆ3.6 Hz); MS (i.e.): m/zˆ324 (Mϩ).
2,2,2-Trifluoro-1-(2,3-dimethoxyphenyl)ethanol 13e. H
NMR (CDCl3) d(ppm): 7.07 (t, 1H, Jˆ8 Hz), 7.00 (d, 1H,
Jˆ8 Hz), 6.92 (d, 1H, Jˆ8 Hz), 5.28 (dq, 1H, JHHˆ7.2 Hz,
JHFˆ7.2 Hz), 4.08 (d, 1H, Jˆ7.2 Hz), 3.89 (s, 3H), 3.86 (s,
3H); 13C NMR (CDCl3) d(ppm): 158.58, 152.49, 127.44,

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B. Folleas et al. / Tetrahedron 56 (2000) 275–283
282
124.72 (q, JCFˆ280 Hz), 124.34, 120.57, 113.46, 69.30 (q,
JCFˆ33 Hz), 61.25, 55.84; 19F NMR (CDCl3) d(ppm):
Ϫ78.46 (d, JHFˆ7.2 Hz); Anal. calculated for C10H11F3O3:
C, 50.85; H, 4.69. Found: C, 50.89; H, 4.65.
References
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2,2,2-Trifluoro-1-(3,4,5-trimethoxyphenyl)ethanol 13f. 1H
NMR (CDCl3) d(ppm): 6.54 (s, 2H), 4.80 (q, 1H,
JHFˆ6.6 Hz), 3.76 (s, 6H), 3.71 (s, 3H); 13C NMR (CDCl3)
d(ppm): 153.30, 138.37, 130.76, 124.66 (q, JCFˆ282 Hz),
104.87, 72.93 (q, JCFˆ32 Hz), 61.2, 56.34; 19F NMR
(CDCl3) d(ppm): Ϫ78.61 (d, JHFˆ6.6 Hz); Anal. calculated
for C11H13F3O4: C, 49.63; H, 4.92. Found: C, 49.52; H, 4.91.
2,2,2-Trifluoro-1-(2-furyl)ethanol 13g39. 1H NMR
(CDCl3) d(ppm): 7.45 (m, 1H), 6.51 (m, 1H), 6.41 (m,
1H), 5.02 (q, 1H, JHFˆ6.4 Hz), 3.34 (s, 1H); 13C NMR
(CDCl3) d(ppm): 147.32, 143.70, 123.56 (q, JCFˆ280 Hz),
110.81, 110.18, 67.23 (q, JCFˆ34 Hz); 19F NMR (CDCl3)
d(ppm): Ϫ78.42 (d, JHFˆ6.4 Hz); Anal. calculated for
C6H5F3O2: C, 43.39; H, 3.03. Found: C, 43.35; H, 3.08.
2,2,2-Trifluoro-1-(cyclohexyl)ethanol 13h50. 1H NMR
(CDCl3) d(ppm): 3.64 (m, 1H), 2.74 (m, 1H), 1.82 (m,
1H), 1.77Ϫ1.58 (m,5H), 1.28Ϫ1.03 (m, 5H); 13C NMR
(CDCl3) d(ppm): 125.74 (q, JCFˆ284 Hz), 74.63 (q,
JCFˆ29.2 Hz),38.58, 29.60, 27.15, 26.37, 26.33, 26.07; 19F
NMR (CDCl3) d(ppm): Ϫ75.98 (d, JHFˆ7.5 Hz).
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Preparation of 4-trifluoromethylanisole 21
The solution of potassium dimsylate was prepared in a four-
necked flask (equipped with mechanical stirring, nitrogen
inlet and internal temperature) according to the above
procedure from KH in mineral oil (4 ml, 40 mmol) and
DMSO (3.12 ml, 44 mmol).
17. Long, Z. Y.; Duan, J. X.; Lin, Y. B.; Guo, C. Y.; Chen, Q. Y. J.
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It was frozen at Ϫ40ЊC and DMF (20 ml) and fluoroform
(440 ml, 20 mmol) were added. The mixture was stirred for
one hour at Ϫ25ЊC: during this period, the frozen potassium
dimsylate was slowly solubilised. Copper Iodide (3.81 g,
20 mmol) was added and the mixture was allowed to
warm up to room temperature. Then DMEU (20 ml) and
4-iodoanisole (2.34 g, 10 mmol) were added and the
mixture was warmed at 60ЊC for 10 h. After cooling to
room temperature, it was quenched with NH3/sat. NH4Cl
(2/1 v/v, 30 ml) and filtered through a celite pad. It was
then extracted by Et2O (2×30 ml). Combined organic layers
were dried over MgSO4 and concentrated under reduced
pressure. The product was purified by column
chromatography on silica gel (Pentane/Et2O: 9/1). 1H
NMR (CDCl3) d(ppm): 7.58 (d, 2H, Jˆ8.8 Hz), 6.98 (d,
2H, Jˆ8.8 Hz), 3.87 (s, 3H); 13C NMR (CDCl3) d(ppm):
160.97, 125.85, 123.45 (q, JCFˆ270 Hz), 121.78 (q,
JCFˆ32 Hz), 112.90, 54.37; 19F NMR (CDCl3) d(ppm):
Ϫ61.8; MS (i.e.): m/zˆ176 (Mϩ).
19. Umemoto, T.; Ando, A. Bull. Chem. Soc. Jpn. 1986, 59, 447.
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23. Generously provided by Rhone-Poulenc. This gas has a low
boiling point (Ϫ82ЊC) but is very soluble in polar solvents as DMF.
24. Reutov, O. A.; Butin, K. P.; Beletskaya, I. P. Usp. Khim. 1974,
43, 35.
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Acknowledgements
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The authors thank the RHONE-POULENC Company for a
grant to B.F.

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42. Determined by using a,a,a-trifluorotoluene as an internal
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30. Although we have no evidence of the formation of these
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´
32. Barhadi, R.; Troupel, M.; Perichon, J. Chem. Commun. 1998,
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33. Preliminary results of this work have already been published:
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Lett. 1998, 39, 2973, and more recently, a parallel study from
ˆ
Rhone-Poulenc Company has been disclosed concerning the potas-
sium trifluoromethylide: Russell, J.; Roques, N. Tetrahedron 1998,
54, 13771.
34. Formed probably by the Tishchenko reaction, followed by
saponification in the work-up; see Kamm, O.; Kamm, F. Org.
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46. Moreover, in the presence of I2, 18 and 19 afforded almost
36. After metallation, one equivalent of hydrogen is formed which
will not react with the trifluoromethyl metal.
37. The reaction of several organometallics with DMF as a
formylating agent is a well known reaction.
38. Olah, G.; Prakash, G. K. S.; Arvanaghi, M. Synthesis 1978,
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instantaneously Iodotrifluoromethane (19F NMR).
47. In above studies, dimsyl-K was formed in DMSO as a solvent.
48. (a) Soula, G. J. J. Org. Chem. 1985, 50, 3717. (b) Greiner, A.
Synthesis 1989, 312.
49. This environmentally friendly urea has a polarity comparable
to that of HMPT and can replace it in many cases. See: Sakurai, H.;
Kondo, F. J. Organomet. Chem. 1975, 92, C46.
50. Note added in proof: During our corrections, a recent publica-
tion (Mispelaere, C.; Roques, N. Tetrahedron Letters 1999, 40,
6411) showed that our postulated mechanism involving 14 as the
trifluoromethylating intermediate is indeed viable.