Efficient access to 3-alkyl-trifluoromethylbenzenes using Kumada's coupling reaction

Article abstract of DOI:10.1016/j.tetlet.2006.03.076

3-Alkyl-trifluoromethylbenzenes are obtained in good yields by Kumada's coupling reaction between methyl or ethyl magnesium halide and 3-bromo-trifluoromethylbenzene derivatives in the presence of Ni-Xantphos catalyst.

Full text of DOI:10.1016/j.tetlet.2006.03.076

Tetrahedron Letters 47 (2006) 3375–3378
Efficient access to 3-alkyl-trifluoromethylbenzenes using
Kumada’s coupling reaction
Nicolas Roques and Laurent Saint-Jalmes*
`
Rhodia Recherches et Technologies, Centre de Recherche de Lyon, 85 Avenue des Freres Perret, 69192 Saint-Fons Cedex, France
Received 31 January 2006; revised 10 March 2006; accepted 14 March 2006
Available online 31 March 2006
Abstract—3-Alkyl-trifluoromethylbenzenes are obtained in good yields by Kumada’s coupling reaction between methyl or ethyl
magnesium halide and 3-bromo-trifluoromethylbenzene derivatives in the presence of Ni-Xantphos catalyst.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
enough selective on xylene derivatives2a–c to obtain,
after fluorination, 1 or 2.
Trifluoromethyl aromatic derivatives form the most
important family of fluorinated intermediates used in
agrochemical, pharmaceutical and performances mar-
kets1 such as liquids crystals. Pharmaceutical and agro-
chemical companies are more and more interested in
trifluoromethylbenzene derivatives bearing a carbon
functionalized function in addition to the CF3 moiety,
such as 3-methyl-trifluoromethylbenzene, 3-trifluoro-
methylbenzylalcohol and 3-trifluoromethylacetophe-
none. Thus, we decided to look for a safe and efficient
access to central building-blocks such as 3-methyl-tri-
fluoromethylbenzene 1, 3-ethyl-trifluoromethylbenzene
Other routes to alkyl-trifluoromethyltoluenes are
described in the literature: they can be synthesized by
radical trifluoromethylation3 of toluenes but the low
selectivity of this reaction induces difficult purification
of the different isomers due to their close boiling points4.
Electrophilic trifluoromethylation of toluene is more
selective but requires reagents which are limited for
scale-up: CCl4–HF5 co-produces large amounts of flu-
orochloromethane derivatives that have to be treated as
CFC in accordance with the Montreal Protocol.6a,b
Nucleophilic trifluoromethylation of bromotoluenes is
possible with CF3À sources like trifluoroacetic acid salts7
or Ruppert’s reagent CF3SiMe3,8 but a stoichiometric
amount of cuprous salt must be used to obtain satisfac-
tory yields and treatment of copper wastes is necessary.
Beech’s reaction9 is an interesting route to transform tri-
fluoromethylanilines into the corresponding benzaldehy-
des or acetophenones but this route involves formation of
an aqueous diazonium salt of the starting aniline that is
not very productive and leads to big amounts of aqueous
wastes. Alkylation of Grignard derivatives of halo-triflu-
oromethylbenzenes seems to be an efficient access to 1, 2
or 3, but the formation of these Grignard reagents are
known to be dangerous10 and our experience on different
aromatic Grignard reagents bearing CF3 groups confirms
this safety issue. Recent work11 describes the synthesis of
trifluoromethylbenzene Grignard reagents using a halo-
gen–magnesium exchange reaction which leads to safer
conditions. Even if thermal analyses described in this
article11 show great differences between conditions where
the magnesium salt of bromo-trifluoromethylbenzene is
2
and 2-chloro-5-methyl-trifluoromethylbenzene
3
(Fig. 1).
Industrial syntheses of trifluoromethylbenzenes consist
in radical chlorination of the corresponding toluene
derivatives followed by chlorine–fluorine exchange in
anhydrous HF.1 This chemical route is very efficient
and is used at multi-tons scale, but chlorination is not
CF3
CF3
CF3
Cl
CH3
CH3
CH3
1
2
3
Figure 1. 3-Alkyl-trifluoromethylbenzene targets.
*
Corresponding author. Tel.: +33 472736648; e-mail: laurent.saint-
jalmes@eu.rhodia.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.076

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N. Roques, L. Saint-Jalmes / Tetrahedron Letters 47 (2006) 3375–3378
directly formed and others where the Grignard of bromo-
trifluoromethylbenzene is obtained via transmetalation
with i-PrMgCl, we preferred to look for other chemical
routes which minimize this potential safety problem.
We confirmed this difference of reactivity between chlo-
ride and bromide trifluoromethylbenzene derivatives
applying Kumada’s conditions on 2,5-dichloro-trifluo-
romethylbenzene and 2-chloro-5-bromo-trifluorometh-
ylbenzene (Table 2).
We chose to study the access to 1, 2, 3 using Kumada’s
reaction:12 coupling of methyl or ethyl magnesium salts
with 3-chloro or 3-bromo-trifluoromethylbenzene in the
presence of a Ni0 catalyst with phosphines (Fig. 2).
Conversion of 2,5-dichloro-trifluoromethylbenzene (en-
try 1) is very low confirming the weak reactivity of
chloro-trifluoromethylbenzenes in our conditions, even
if Kumada’s coupling reaction is described on this
substrate with another Ni–phosphine ligand in the liter-
ature.11 Kumada’s conditions applied on 2-chloro-5-
bromo-trifluoromethylbenzene (entry 2) mainly lead to
2-chloro-5-methyl-trifluoromethylbenzene, with very
low amounts of 2,5-dimethyl-trifluoromethylbenzene.
Literature13 indicates that dppe (1,2-bis(diphenylphos-
phinoethane)) is an efficient ligand of NiCl2 in Kuma-
da’s coupling reaction, with in situ reduction of NiII:
our first trials were conducted using NiCl2–dppe in
THF (Table 1).
3-Chloro and 3-bromo-trifluoromethylbenzene lead to
different behaviours in Kumada’s coupling reaction with
NiCl2–dppe.
Considering these first results, we planned to optimize
Kumada’s coupling reaction between 2-chloro-5-
bromo-trifluoromethylbenzene and MeMgCl in THF
with the goal to reduce the amounts of biaryls by-
products.
Reaction between 3-bromo-trifluoromethylbenzene and
methyl magnesium chloride (entry 1) leads to total con-
version of the starting materials and formation of 3-
methyltrifluoromethylbenzene 1 in a fair yield (65%),
accompanied by a small amount of reduced product (tri-
fluoromethylbenzene) and large amounts of biaryls
(mainly isomers of bis(trifluoromethyl)biphenyl). Reac-
tion between 3-bromo-trifluoromethylbenzene and ethyl
magnesium bromide (entry 2) leads to 3-ethyltrifluoro-
methylbenzene 2 in 76% yield, with low level of biaryls
but high level of trifluoromethylbenzene.
Variations of parameters, such as the nature of solvent
(methyl-terbutylether, isopropyl ether, toluene instead
of THF), increase of temperature (50 ꢁC instead of
20 ꢁC), the nature of the metal catalyst (Pd instead of
Ni), do not improve the selectivity of the alkylation
reaction. Thus, a study of the influence of the nickel
ligand was performed. Two types of easily available
phosphines were tested: mono and bidentates. Table 3
summarizes the tested phosphines and the results of cou-
pling between 2-chloro-5-bromo-trifluoromethylbenzene
and MeMgCl in THF at 20–25 ꢁC in the presence of
0.5 mol % of catalyst.
On 3-chloro-trifluoromethylbenzene, the coupling reac-
tion with MeMgCl (entry 3) is less efficient and leads
to low conversion and to 1 in low yield (18%). In the
presence of ethyl magnesium chloride, reduction of 3-
chloro-trifluoromethylbenzene into trifluoromethylbenz-
ene is prevailing (entry 4).
All the results of Table 3 can be compared to the perfor-
mances obtained with dppe as a ligand (entry 7). Meth-
ylation of 2-chloro-5-bromo-trifluoromethylbenzene
with MeMgCl occurs even without Nickel ligand (entry
1) but gives higher amounts of biaryls than in the pres-
ence of ddpe. Electron rich monodentate phosphines
(entries 3–5) lead to similar results to dppe. Triphenyl
phosphine (entry 2) leads to lower performance.
CF3
CF3
NiCl2dppe
+
RMgCl
+
MgClX
R
X
The length of the carbon chain between the two phos-
phorus atoms of bidentate phosphines seems to have
an influence:
R = Me, Et
X = Cl, Br
Figure 2. Kumada’s coupling principle.
Table 1. Kumada’s coupling between MeMgCl, EtMgCl and 3-chloro or 3-bromo-trifluoromethylbenzene with NiCl2–dppea
Entry
CF3Ar–X, RMgCl
CF3Ar–X Conversionb (%)
CF3Ar–R Yieldb (%)
CF3Ar–H Yieldb (%)
Biaryls Yieldc (%)
1
2
3
4
X = Br, R = Me
X = Br, R = Et
X = Cl, R = Me
X = Cl, R = Et
>98
>98
30
65
76
18
19
5
16
2
17
5
3
91
60
3
a NiCl2dppe (from Aldrich, 190 mg, 0.36 mmol; 0.5% equiv) was suspended in THF (tetrahydrofuran, 62 g) at 20 ꢁC. 3-bromo-trifluoromethyl-
benzene (16.4 g, 72.8 mmol) was added at once. Maintaining the reaction mixture between 20 and 25 ꢁC (the coupling reaction is exothermic),
methylmagnesium chloride in THF (23 wt %, 33.9 g, 104.3 mmol, 1.44 mol equiv) was slowly added in 2 h. The reaction mixture was mixed for 1 h.
Quenching with aqueous hydrochloric acid (2 mol/l, 45 g) and extraction with isopropyl ether (50 g) afforded the organic phase that was analysed
by GC with internal standard.
b GC assays.
c NMR and GC assays: mainly yields of isomers of bis-(trifluoromethyl)biphenyl.

N. Roques, L. Saint-Jalmes / Tetrahedron Letters 47 (2006) 3375–3378
3377
Table 2. Kumada’s coupling between 2,5-dichloro-trifluoromethylbenzene, 2-chloro-5-bromo-trifluoromethylbenzene and MeMgCl with NiCl2–
dppe in THF at 25 ꢁC
Entry
Starting compounds
CF3Ar–X Conversion
(%)
CF3Ar–Mea
Yieldc (%)
3
CF3Ar–H
Yieldc (%)
Biaryls
Yieldd (%)
1
2
2,5-Dichloro-trifluoromethylbenzene
2-Chloro-5-bromo-trifluoromethylbenzene
6
>98
3
63b
<1
5
<1
10
a Product: 2-chloro-5-methyl-trifluoromethylbenzene 3.
b 3% of 2,5-dimethyl-trifluoromethylbenzene is detected.
c GC assays.
d GC and NMR assays of isomers of biaryls:
CF3
CF3
CF3
H3C
Cl
Cl
CH3
CH3
Cl
CF3
CF3
CF3
Table 3. Influence of the Nickel phosphine ligand on coupling between 2-chloro-5-bromo-trifluoromethylbenzene and MeMgCl in THFa
Entry
Nickel ligand
Molar ratio
phosphine/Ni
CF3Ar–Br
Conversion (%)
CF3Ar–Me 3
Yielda (%)
CF3Ar(Me)2
Yieldb (%)
CF3Ar–H
Yieldb (%)
Biaryls
Yieldc (%)
1
2
3
4
5
6
7
8
9
No phosphine
Triphenylphosphine
Triethylphosphine
Tri-(o-tolyl)phosphine
Tri-(p-tolyl)phosphine
dppm
dppe
dppp
dppb
Binap
0
2
2
2
2
1
1
1
1
1
1
>98
90
>98
>98
>98
78
>98
>98
94
>98
>98
55
52
62
64
65
45
60
57
58
63
81
<2
<2
3
4
3
2
3
3
6
<2
6
4
3
2
5
5
5
6
18
9
10
10
7
7
10
8
7
7
3
10
11
<2
7
3
<2
Xantphos
a The procedure described below Table 1 was used for this screening of ligands.
b GC assays.
c GC and NMR assays of isomers of biaryls:
CF3
CF3
CF3
H3C
Cl
Cl
CH3
CH3
Cl
CF3
CF3
CF3
• dppm (bis-diphenylphosphinomethane) has a too
short carbon chain and leads to the lowest methyl-
ation rate (entry 6).
in 75% yield. 3-Methyl-trifluoromethylbenzene 1 is ob-
tained in 76% yield from 3-bromo-trifluoromethylbenz-
ene and MeMgCl in the presence of NiCl2/Xantphos.
• dppp (bis-diphenylphosphinopropane, entry 8) and
dppb (bis-diphenylphosphinobutane, entry 9) give
similar coupling results to dppe.
In any of these cases, purification of products is easy:
after quench of the reaction with aqueous hydrochloric
acid and extraction with isopropyl ether, fractional dis-
tillation leads to the trifluoromethyltoluene derivatives
with high purity (>98%), biaryls by-products remain in
the boiler.
Binap (entry 10) also leads to similar results to dppe.
The best result is obtained with Xantphos (4,5-bis(di-
phenylphosphino)-9,9-dimethylxanthene, entry 11): the
coupling product 2-chloro-5-methyl-trifluoromethyl-
benzene 3 is obtained in 81% yield, together with 7%
yield of 2,5-dimethyl-trifluoromethylbenzene and very
low amounts of reduction and biaryls by-products.
We scaled-up these Kumada’s coupling procedure from
25 ml to 2 l reactors.
On the safety issue, we report above that Grignard
derivatives of trifluoromethylbenzene are hazardous.
In Kumada’s coupling reaction, there is always a risk
of transmetalation between MeMgCl (or EtMgCl) and
halogenated aromatic substrates. This transmetalation
The same conditions with NiCl2/Xantphos (0.5% molar
equivalent) applied to 2-chloro-5-bromo-trifluorometh-
ylbenzene and EtMgCl also lead efficiently to the cou-
pling product (2-chloro-5-ethyl-trifluoromethylbenzene)

3378
N. Roques, L. Saint-Jalmes / Tetrahedron Letters 47 (2006) 3375–3378
reaction on 3-bromo or 3-chloro trifluoromethylbenzene
can lead to hazardous conditions. A way to estimate the
level of transmetalation is to quantify the rate of
reduced product (which can come from hydrolysis of
the Grignard derivative of trifluoromethylbenzene
during work-up) and the level of biaryl compounds. In
our conditions using Xantphos as the Nickel ligand,
the level of these by-products is very low and thus we
think that transmetalation reaction is limited.
3-bromo-trifluoromethylbenzene or derivatives in the
presence of NiCl2/Xantphos (1/1; 0.5 mol %) at 20–
25 ꢁC affords the corresponding 3-methyl and 3-ethyltri-
fluoromethylbenzene in 81% and 75% yield, respectively.
These two compounds are versatile intermediates whose
derivatizations by bromination or oxidation of benzylic
positions are in progress.
References and notes
To explore the thermal behaviour and potential hazard
of this Kumada’s coupling reaction, we performed ther-
mal analysis:
1. Langlois, B. In Organofluorine Chemistry, Principles and
Commercial Applications; Banks, R. E., Smart, B. E.,
Tatlow, J. C., Eds.; Plenum Press: New York, London,
1994.
2. (a) Fey, P.; Van Laak, K.; Mittendorf, J., for Bayer, DE
4446337, 1994; (b) Chupp, J. P.; Grabiak, R. C.; Leschin-
ski, K. L.; Neumann, T. L. Synthesis 1986, 3, 224–226; (c)
Marhold, A.; Klauke, E. Synthesis 1982, 11, 951–952.
3. Tordeux, M.; Langlois, B.; Wakselman, C. J. Chem. Soc.,
Perkin Trans. 1 1990, 8, 2293–2299.
4. Boiling points of trifluoromethyltoluenes isomers (at atm.
pressure): ortho: 125–126 ꢁC, meta: 127–129 ꢁC, para: 129–
130 ꢁC.
5. Marhold, A.; Klauke, E., for Bayer, DE 2837499, 1980.
6. (a) McCulloch, A. J. Fluorine Chem. 2003, 123, 21–29; (b)
Powell, R. L. J. Fluorine Chem. 2002, 114, 237–250.
7. Carr, G. E.; Chambers, R. D.; Thomas, F.; Parker, D. G.
J. Chem. Soc., Perkin Trans. 1 1988, 4, 921–926.
8. Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91–
94.
• DSC analysis of a mixture of MeMgCl, 2-chloro-5-
bromo-trifluoromethylbenzene in the presence of
Ni–dppe (0.5 mol %) in THF shows an exothermy
which begins at 25 ꢁC and strongly increases above
70 ꢁC with a maximum at 100 ꢁC.
• Measurement of the enthalpy of this coupling reac-
tion in a Mettler Calorimeter (79 kcal/mol of 2-
chloro-5-bromo-trifluoromethylbenzene) shows that,
at 20–25 ꢁC, the exothermy begins as soon as the
MeMgCl solution is added and the coupling reaction
is instantaneous. That is the safety criteria of this cou-
pling reaction: it is necessary that the Grignard
reagent is consumed as soon as possible to avoid
any accumulation and risk of transmetalation. Even
if in our case we did not detect any safety issue, we
recommend in any coupling reaction of this type on
trifluoromethylbenzene derivatives, to analyze the
thermal behaviour of the medium by DSC and calo-
rimeter analysis.
9. Beech, W. F. J. Chem. Soc. 1954, 1297–1302.
10. Appleby, I. C. Chem. Indust. 1971, 120.
11. Leazer, J. L., Jr.; Cvetovich, R.; Tsay, F.-R.; Dolling, U.;
Vickery, T.; Bachert, D. J. Org. Chem. 2003, 68, 3695–
3698.
12. Kumada, M.; Tamao, K.; Sumitani, K. Org. Synth. 1978,
58, 127–133; Kumada, M. Pure Appl. Chem. 1980, 52,
669–679; Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi,
M.; Fujioka, A.; Kodama, S.; Nakajima, I.; Minato, A.;
Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958–1969.
13. Reddy, G. S.; Tam, W. Organometallics 1984, 3, 630–632.
2. Conclusion
Addition of methylmagnesium chloride or ethyl magne-
sium chloride in THF (1.5 mol equiv) to a solution of