A new and direct trifluoromethoxylation of aliphatic substrates with 2,4-dinitro(trifluoromethoxy)benzene

Article abstract of DOI:10.1002/adsc.201000488

The reaction of tetrabutylammonium triphenyldifluorosilicate with 2,4-dinitro(trifluoromethoxy)benzene, in acetonitrile and under microwave irradiation, generates a trifluoromethoxide anion which is able to substitute activated bromides (benzyl bromide, cinnamyl bromide), as well as, to some extent, alkyl iodides. Aliphatic trifluoromethyl ethers are thus formed. This is the first example of the nucleophilic displacement of the trifluoromethoxy group from an activated aromatic ring.

Full text of DOI:10.1002/adsc.201000488

FULL PAPERS
DOI: 10.1002/adsc.201000488
A New and Direct Trifluoromethoxylation of Aliphatic Substrates
with 2,4-Dinitro(trifluoromethoxy)benzene
Olivier Marrec,a Thierry Billard,a,* Jean-Pierre Vors,b Sergii Pazenok,c
and Bernard R. Langloisa,*
a
Universitꢀ de Lyon, Universitꢀ Lyon 1, CNRS ICBMS (UMR CNRS 5246) – Equipe SURCOOF, 43 Bd du 11 novembre
1918, Bat Raulin, 69622 Villeurbanne, France
Fax : (+33)-4-7243-1323; e-mail: bernard.langlois@univ-lyon1.fr or billard@univ-lyon1.fr
Bayer CropScience AG, Centre de Recherche de La Dargoire, 14-20 rue Pierre Baizet, 69009 Lyon, France
Bayer CropScience AG, Product Technology, Process Research, Building 6550, Alfred-Nobel-Str. 50, 40789 Monheim am
b
c
Rhein, Germany
Received: June 23, 2010; Published online: September 22, 2010
Dedicated to the memory of Prof. Lev M. Yagupolskii
Abstract: The reaction of tetrabutylammonium tri- ethers are thus formed. This is the first example of
phenyldifluorosilicate with 2,4-dinitro(trifluorometh- the nucleophilic displacement of the trifluoro-
A
ACHTUNGTRENmNUNG ethoxy group from an activated aromatic ring.
a
AHCTUNGTRENNUNG
Introduction
been named “super-halogen”[12] or “pseudo-halo-
gen”.[13] On the other hand, OCF3 is one of the most
Because of the intrinsic properties of the fluorine hydrophobic substituents, just after SCF3, as indicated
atom (small size, high electronegativity, formation of by its Hansch–Leo parameter [PR (SCF3)=+1.44, PR
À
strong C F bonds, etc.), the introduction of fluorinat-
ed moieties on organic skeletons induces dramatic
changes in their electronic, steric and hydrophobic pa-
rameters. Consequently, their pharmacodynamic and
pharmacokinetic properties are deeply modified.[1,2]
This is the reason why fluorine chemistry is now so
popular in the life sciences.
Among the fluorinated moieties currently used, the
trifluoromethoxy group (OCF3) is becoming more
and more prominent.[3,4] For example, in addition to
trifluoromethoxy-substituted liquid crystals[5] and
dyes,[6] several trifluoromethoxylated pesticides and
pharmaceuticals are now present on the market
(Figure 1).[5,7,8]
This growing interest for trifluoromethyl ethers is
related to the very peculiar characteristics of the
CF3O group. On one hand, this substituent looks like
chlorine[9] in the sense that it is electron-withdrawing
by induction (c=3.7,[10] sI =+0.51 to +0.60[11]), but
more than chlorine (sI =+0.47[11a]), and electron-do-
nating by resonance (sR =À0.13 to À0.18[11]), but less
than chlorine (sR =À0.25[11a]). For this reason, it has Figure 1. Some bioactive trifluoromethoxylated products.
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Olivier Marrec et al.
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Scheme 1. Usual accesses to trifluoromethyl ethers.
(OCF3)=+1.04, PR (CF3)=+0.88, PR (OCH3)=
Obviously, the best synthesis of trifluoromethyl
À0.02].[14] Thus, such a hydrophobic substituent dra- ethers would be the direct introduction of the whole
matically increases the bioavailability of the products OCF3 moiety. It was first done by radical condensa-
bearing it. It must be also noticed that the very pecu- tion of olefins and trifluoromethyl hypofluorite,[22]
liar conformation of (trifluoromethoxy)arenes (in which is highly hazardous and toxic. Then, numerous
which the OCF3 moiety is orthogonal to the ring attempts to carry out nucleophilic trifluoromethoxyla-
plane) could contribute to the original bioactivities of tion with trifluoromethoxide salts failed since, gener-
trifluoromethoxylated aromatic compounds (for a dis- ally, the CF3OÀ anion collapses into fluoride and fluo-
cussion, see[15]).
rophosgene, even at low temperature (Scheme 2).
Several teams tried to draw this equilibrium to-
Until now, mainly aryl trifluoromethyl ethers have
been described. Their different preparations have wards CF3OÀ and demonstrated that if fluorides are
been recently reviewed.[6,15] The best-established ones associated with rather bulky cations [CsF,[23,24]
can be divided into four methods that are, chlorine/ (Me2N)3S+ Me3SiF2À[25]], the resulting trifluorometh-
fluorine exchange on trichlorinated precursors,[16] oxide could be stable enough, in solution, to react
action of sulfur tetrafluoride on fluoroformates (Shep- with reactive electrophiles such as benzyl bromide[24]
pardꢂs method),[17] Hiyamaꢂs oxidative fluorodesulfuri- or primary triflates and bromides.[26] Nevertheless, the
zation[18] and electrophilic trifluoromethylation of hy- development of this reaction was limited by the high
droxy functions[19,20] (Scheme 1).
toxicity of gaseous fluorophosgene.
L. M. Yagupolskii et al. pioneered the chlorination/
Recently, Kolomeitsev et al. have described a more
fluorination technique,[16] applied to ArOCCl3 precur- convenient generation of trifluoromethoxide salts,
sors,[16,21] in the late 1950s. It is now currently em- from trifluoromethyl triflate (TFMT) and bulky fluo-
ployed on an industrial scale but is only applicable to rides, and its application to the trifluoromethoxylation
aromatic compounds. Deoxyfluorination of fluorofor- of aliphatic triflates.[27] We also studied this trifluoro-
mates[17] is greatly limited by the high toxicity of SF4. methoxylating system and extended its synthetic
Oxidative fluorodesulfurization[18] can be applied to scope to the substitutive trifluoromethoxylation of nu-
phenols, primary and even secondary alcohols, but merous aliphatic bromides and iodides[15] (Scheme 3).
this method is not compatible with numerous func-
TFMT is a volatile liquid (bp=198C), far less toxic
tional groups. Electrophilic trifluoromethylation of al- than fluorophosgene but expensive, since it is pre-
cohols and phenols has been first reported by Ume- pared from triflic anhydride,[28,29] and is only available
moto et al.,[19] using poorly stable O-trifluoromethyl- on the bench scale. Thus, we turned our interest to
dibenzofuranium salts, then by Togni et al. who devel- possibly more convenient precursors, especially (tri-
oped easily accessible trifluoromethyl-containing fluoromethoxy)benzenes bearing mesomeric electron-
iodineACHTUNGTRENNUNG
(III) reagents.[20] When these reagents are ap- withdrawing substituents, which are, for most of them,
plied to phenols, C-trifluoromethylation competes
with O-trifluoromethylation but, in the presence of
substoichiometric amounts of zinc triflimide, they
allow the O-trifluoromethylation of aliphatic alcohols
to proceed.[20e]
Scheme 2. Decomposition of the trifluoromethoxide anion.
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A New and Direct Trifluoromethoxylation of Aliphatic Substrates
Scheme 5. Putative displacement of CF3OÀ from an elec-
tron-poor aryl trifluoromethyl ether.
trile. 19F NMR indicated that, after three hours at
room temperature, up to 22% of 2,4-dinitrofluoroben-
zene 2 was formed and that after two more hours at
reflux, 1 was completely converted into 2. Conse-
quently, the hypothesis summarized in Scheme 5 was
Scheme 3. Generation and use of trifluoromethoxide from
TFMT.
available on the industrial scale. We anticipated that, proven to be true. This was the first example of a nu-
when attacked by an auxiliary nucleophile associated cleophilic displacement of the OCF3 group from an
to a bulky counterion, these electron-poor compounds aromatic ring.
could expel, through an aromatic nucleophilic substi-
tution, a trifluoromethoxide anion.
This experiment was repeated, except that benzyl
bromide 3a, chosen as an electrophilic model, was
added at the beginning: 19F NMR indicated that, after
four days at room temperature, only benzyl fluoride
was formed (20%) and no trace of benzyl trifluoro-
methyl ether 4a was detected. It was suspected that
Results and Discussion
Aryl trifluoromethyl ethers are usually thermally and this surprising result could be due to the strong inter-
chemically stable, except under harsh acidic condi- action between silver and bromine. Consequently,
tions, which cause the hydrolysis of the trifluorometh- silver fluoride was successfully replaced by tetrabutyl-
yl group and the formation of the corresponding phe-
ACHTUNGTRENaNGNU mmonium triphenyldifluorosilicate (TBAT): under
nols, or in the presence of aluminium trichloride the previous conditions, benzyl trifluoromethyl ether
which leads to their rapid transformation into aryl tri- 4a was obtained in a 34% yield (by 19F NMR) after
chloromethyl ethers.[21] Except for that, no cleavage four days at room temperature (Scheme 6).
À
of the CAr OCF3 bond had been reported until Iijima
This interesting result was optimized through a
À
and Amii described the reduction of Ar OCF3 by parametric study. The influences of the reactant ratio
sodium[30] (Scheme 4).
Thus, it appeared that the cleavage of a CAr OCF3 in Table 1.
bond is thermodynamically possible. Moreover, owing
and of temperature were firstly examined, as shown
À
It appeared, from Table 1, firstly that the fluoride
to the inductive electron-withdrawing power of the source could not be used in a catalytic amount (that
OCF3 substituent (sI =+0.51 to +0.60),[11] we thought means that BrÀ was not able to displace CF3OÀ from
that this moiety could be a good leaving-group and 1) (entry 2) and, secondly, that one of the components
could be displaced from an electron-poor (trifluoro- must be used in excess, the excess of 1 being the most
methoxy)benzene (Scheme 5).
crucial parameter (entries 5 to 8). The reaction was
In order to verify this assumption, 2,4-dinitro(tri- rather sluggish at room temperature but its kinetics
fluoromethoxy)benzene 1 appeared to be the best
candidate among the commercially available reagents.
Thus, by analogy with our previous work on TFMT,[15]
1 was exposed to silver fluoride (1 equiv.) in acetoni-
Scheme 4. Reduction of aryl trifluoromethyl ethers with
sodium.
Scheme 6. First trifluoromethoxylation of benzyl bromide
from 1 and TBAT.
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Olivier Marrec et al.
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Table 1. Influence of the reactant ratio and of temperature.
Table 2. Influence of the solvent.
Entry 1
TBAT
3a
T
Yield of 4a
Entry
Solvent
Yield of 4a[a]
[equiv.] [equiv.]
[equiv.] [8C] (time)[a]
1
2
3
4
5
6
7
8
acetonitrile
benzonitrile
THF
60%
50%
49%
42%
6%
0.5%
no reaction
no reaction
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
2.0
2.0
2.0
2.0
1.0
0.1
1.0
2.0
2.0
1.0
1.0
1.0
0.9
0.9
1.8
0.9
0.9
0.9
0.9
0.9
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
34% (4 d)
1.3% (4 d)
41% (4 d)
40% (4 d)
55% (4 d)
60% (4 d)
60% (20 h)
DMF
[b,c]
BMIM PF6
DMSO[c]
nitromethane
HFIP[d]
100 0% (16 h)[b]
[a]
Crude yield, after 4 days at room temperature, from
19F NMR with PhCF3 as internal standard.
BMIM PF6 =1-butyl-3-methylimidazolium hexafluoro-
phosphate.
1 was significantly converted into 2.
HFIP=hexafluoroisopropyl alcohol.
[a]
Crude Yield from 19F NMR with PhCF3 as internal stan-
dard.
Formation of 2 (100%) and benzyl fluoride (48%).
[b]
[b]
[c]
[d]
were dramatically enhanced by heating at 508C
(entry 7). Higher temperatures were deleterious to into 2 but essentially reacted with 3a to give benzyl
the yield of the desired product: no benzyl trifluoro- fluoride. Tetramethylammonium fluoride completely
methyl ether 4a was detected at 1008C, although 1 converted 1 into 2, but without formation of 4a,
was totally transformed into 2, and benzyl fluoride whereas triphenylphosphine and hexamethylphos-
was significantly formed (entry 8). That means that, at phoric triamide (HMPT) induced the degradation of
1008C, the trifluoromethoxy group of 1 was complete- the starting material. Finally, no reaction occurred
ly displaced by the fluoride anion but that the gener- with tetra-n-butylammonium chloride or diethylami-
ated trifluoromethoxide anion was not stable enough nosulfur trifluoride (DAST).
to react with benzyl bromide. Indeed, it probably col-
lapsed into fluorophosgene and FÀ and the latter sub-
stituted benzyl bromide 3a to deliver benzyl fluoride.
In conclusion from Table 1, the best result was ob-
It must be noted that, when 2,4-dinitro(trifluoro-
methoxy)benzene 1 was replaced by 4-nitro(trifluoro-
methoxy)benzene 5 (2.0 equiv.), no benzyl trifluoro-
methyl ether was formed from benzyl bromide 3a (0.9
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
tained at 508C, within 20 h, with the reactant ratio equiv.) and TBAT (1 equiv.), even after 4 days at
1:TBAT:3=2.0:1.0:0.9. 508C or at reflux. Benzyl fluoride was only obtained
The influence of the solvent (aprotic, protic or and 5, which is probably not activated enough, was re-
ionic) was also studied (Table 2). It appeared that ace- covered unchanged.
tonitrile (yield: 60%, entry 1) was the most efficient,
Finally, other halogenated substrates 3b–e were re-
followed by benzonitrile (yield: 50%, entry 2), THF acted with 1 and TBAT (Scheme 7). The results were
(yield: 49%, entry 3) and DMF (yield: 42%, entry 4). rather disappointing since, except for the reactive cin-
Surprisingly, DMSO delivered a very poor yield namyl bromide 3b which provided 4b in a medium
(yield: 0.5%, entry 6) and no reaction occurred in ni- yield (45%). a-Bromoacetophenone 3c, a-iodoaceto-
tromethane (entry 7) or hexafluoroisopropyl alcohol phenone 3d and citronellyl iodide 3e (chosen as a
(entry 8). Maybe these three solvents are too acidic model alkyl iodide) delivered poor yields (respec-
and protonate the generated CF3OÀ anion to give tri- tively 10%, 8% and 6%).
fluoromethanol which is known to decompose into
In order to improve the scope and the kinetics of
HF and fluorophosgene above À278C. The yield was this reaction, the reaction was carried out under mi-
also poor in an ionic liquid such as 1-butyl-3-methyl- crowave irradiation. The influence of such an irradia-
ACHTUNGTRENNUNGimidazolium hexafluorophosphate (BMIM PF6) tion was first examined with benzyl bromide 3a as
(yield: 6%, entry 5), though 2 was significantly substrate and the influence of the reactant ratio was
formed. Maybe BMIM PF6 is a too dissociating sol- also revisited under these conditions (Table 3).
vent and favors the decomposition of the CF3OÀ
anion.
It appeared that this activation was extremely effi-
cient since, after 2 h only at 508C, 4a was already ob-
Then, the nature of the fluoride source was exam- tained in a 24% yield (Table 3 - entry 2, to be com-
ined under the conditions depicted in Table 1 and pared to Table 1, entry 7). As the kinetics were dra-
Table 2. Except TBAT, which delivered 4a in a 60% matically accelerated, it was possible to carry out the
yield, only tris(dimethylamino)sulfonium trimethyldi- reaction at 1008C without extensive decomposition of
fluorosilicate (TASF) provided a significant amount the CF3OÀ intermediate. At this temperature, 4a was
of benzyl trifluoromethyl ether 4a (yield: 29%). As produced in a 50% after 30 min (Table 3, entry 4) but,
already mentioned, silver fluoride partly converted 1 as observed in the absence of microwave irradiation
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A New and Direct Trifluoromethoxylation of Aliphatic Substrates
bromoacetophenone 3c was not stable enough to
resist to such harsh conditions and did not delivered
any 4c.
Conclusions
We have demonstrated for the first time that the tri-
fluoromethoxy moiety of 2,4-dinitro(trifluorometh-
AHCTUNGTRENNUNG
Scheme 7. Trifluoromethoxylation of halogenated substrates
(crude yields from 19F NMR with PhCF3 as internal stan-
dard).
Table 3. Influence of the microwave irradiation.
Entry 1:TBAT:3a [equiv.] T [8C] Time
Yield of 4a[a]
Experimental Section
1
2
3
4
5
6
7
8
9
2:1:0.9
2:1:0.9
2:1:0.9
2:1:0.9
2:1:0.9
2:2:0.9
4:1:0.9
4:2:0.9
6:2:0.9
50
50
30 min 10%
2 h 24%
10 min 39%
30 min 50%
THF was distilled over sodium/benzophenone prior to use.
Dichloromethane was dried over molecular sieves. Other re-
agents were used as purchased. 2,6-Dimethyl-8-iodo-oct-2-
ene (citronellyl iodide) was prepared according to ref.[31]
100
100
100
100
100
100
100
1 h
32%
20 min 46%
20 min 48%
20 min 70%
25 min 65%
Typical Procedure at Room Temperature
To TBAT (540 mg, 1 mmol) were added, under nitrogen, an-
hydrous acetonitrile (2 mL) followed, successively, by 2,4-di-
nitro(trifluoromethoxy)benzene (155 mL, 2 mmol) and the
electrophile (0.9 mmol). Then, the reaction vessel was
closed and the mixture was stirred at room temperature for
4 days. Crude yields were determined by 19F NMR after ad-
dition of benzotrifluoride (30 mL, 0.23 mmol) as internal
standard.
[a]
Crude yield from 19F NMR with PhCF3 as internal stan-
dard.
(Table 1, entry 8), prolonged heating was deleterious
to the yield: after 1 h at 1008C, the yield of 4a drop-
ped down to 32% (Table 3, entry 5). However, an in-
crease of the reagent ratios successfully counterbal-
anced the decrease of yield due to the high tempera-
ture: with 1:TBAT:3a=4:2:0.9, 4a was obtained in a
70% yield within 20 min.
Typical Procedure under Microwave Irradiation
To TBAT (540 mg, 1 mmol) were added, under nitrogen, an-
hydrous acetonitrile (2 mL) followed, successively, by 2,4-di-
nitro(trifluoromethoxy)benzene (310 mL, 4 mmol) and the
electrophile (0.9 mmol). Then, the reaction vial was sealed
and introduced in a Biotage InitiatorTM Eight apparatus
where the reaction mixture was heated at 1008C under mi-
crowave irradiation (initial power P=30 W, this power
being monitored by temperature). After depressurization,
crude yields were determined by 19F NMR after addition of
benzotrifluoride (30 mL, 0.23 mmol) as internal standard.
Benzyl trifluoromethyl ether (4a): Colorless oil; yield:
Similar conditions (microwave irradiation, 1008C,
20 min, 1:TBAT:3a=4:2:1) were successfully applied
to the substitutive trifluoromethoxylation of cinnamyl
bromide 3b and citronellyl iodide 3e: 4b and 4e were
obtained in 60% and 48% yields, respectively (vs.
45% and 6% without MW irradiation, cf. Scheme 7).
It must be emphasized that this procedure significant-
ly broadened the scope of the reaction since it al-
lowed the trifluoromethoxylation of a non-activated
76%. 1H NMR: d=7.40–7.35 (m, 5H), 4.99 (s, 2H);
1
13C NMR: d=134.0, 129.1, 128.7, 127.5, 121.8 (q, JC,F
=
alkyl iodide such as citronellyl iodide. However, a- 255.4 Hz), 69.2 (q, JC,F =3.5 Hz); 19F NMR: d=À60.78 (s);
3
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Olivier Marrec et al.
FULL PAPERS
anal. calcd. for C8H7F3O: C 54.55, H 4.01; found: C 54.34, H
3.90.
Am. Chem. Soc. 1963, 85, 709 and 3146; d) L. M. Yagu-
polskii, V. F. Bystrov, A. U. Stepanyants, Yu. A. Fialkov,
J. Gen. Chem. USSR 1964, 34, 3731–3738.
1-Phenyl-2-(trifluoromethoxy)ethanone
[a-(trifluoro-
methoxy)acetophenone] (4c): Yellow oil; yield: 69%.
1H NMR: d=7.91 (m, 2H), 7.65 (m, 1H), 7.52 (m, 2H), 5.18
(s, 2H); 13C NMR: d=190.2, 134.4, 133.8, 129.1, 127.9, 121.8
(q, 1JC,F =256.3 Hz), 68.4 (q, 3JC,F =2.9 Hz); 19F NMR: d=
À61.44 (s); anal. calcd. for C9H7F3O2: C 52.95, H 3.46;
found: C 53.12, H 3.15.
[12] W. A. Sheppard, J. Am. Chem. Soc. 1963, 85, 1314–
1318.
[13] A. Haas, Adv. Inorg. Chem. Radiochem. 1984, 28, 167–
202.
[14] a) C. Hansch, A. Leo, Substituent Constants for Corre-
lation Analysis in Chemistry and Biology, John Wiley &
Sons, New York, 1979; b) A. Leo, P. Y. C. Jow, C.
Silipo, C. Hansch, J. Med. Chem. 1975, 18, 865–868.
[15] O. Marrec, T. Billard, J.-P. Vors, S. Pazenok, B. R. Lan-
glois, J. Fluorine Chem. 2010, 131, 200–207.
[16] a) L. M. Yagupolskii, Dokl. Akad. Nauk USSR 1955,
105, 100–102; Chem. Abstr. 1955, 50, 11270b; b) L. M.
Yagupolskii, V. I. Troitskaya, J. Gen. Chem. USSR
1961, 31, 845–852; c) L. M. Yagupolskii, V. V. Orda, J.
Gen. Chem. USSR 1964, 34, 1994–1998; d) L. M. Yagu-
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(2E)-3-Phenylprop-2-en-1-yl trifluoromethyl ether (cin-
namyl trifluoromethyl ether) (4b): Colorless oil; yield: 47%.
3
1H NMR: d=7.45–7.29 (m, 5H), 6.72 (bd, 1H, JH,H
=
15.8 Hz), 6.29 (dt, 1H, 3JH,H =15.8 Hz, 3JH,H =6.4 Hz), 4.65
(dd, 2H, JH,H =6.4 Hz, JH,H =1.3 Hz); 13C NMR: d=135.8,
3
4
135.3, 128.8, 128.6, 126.9, 121.9 (q, 1JC,F =255.2 Hz), 121.5,
68.1 (q, JC,F =3.5 Hz); 19F NMR: d=À60.54 (s); anal. calcd.
3
for C10H9F3O: C 59.41, H 4.49; found: C 59.53, H 4.40.
2,6-Dimethyl-8-(trifluoromethoxy)oct-2-ene (citronellyl
trifluoromethyl ether) (4e): Colorless oil; yield: 58%.
1H NMR: d=5.09 (m, 1H), 4.00 (m, 2H), 1.98 (m, 2H),
1.63–1.12 (massif, 11H) ; 0.91 (d, 3H, 3JH,H =6.4 Hz);
13C NMR: d=131.7, 124.5, 121.9 (q, 1JC,F =253.6 Hz), 66.0
(q, 3JC,F =3.1 Hz), 37.0, 35.7, 29.1, 25.8, 25.5, 19.3, 17.7;
19F NMR: d=À61.13 (s); anal. calcd. for C11H19F3O: C
58.91, H 8.54; found: C 59.12, H 8.45.
[17] a) W. A. Sheppard, J. Org. Chem. 1964, 29, 1–11;
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Chem. 1978, 52, 547–559.
[18] a) M. Kuroboshi, K. Suzuki, T. Hiyama, Tetrahedron
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Shimizu, M. Kuroboshi, T. Hiyama, Chem. Commun.
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Acknowledgements
One of the authors (O.M.) gratefully acknowledges the Bayer
CropScience Co. and the “French National Agency for Re-
search and Technology”, for a grant for his PhD work.
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