Nucleophilic trifluoromethylation of electron-deficient arenes

Article abstract of DOI:10.1039/c7cc05415g

A novel trifluoromethylation of arenes is presented, which proceeds under mild reaction conditions and has the potential for late-stage functionalisation of pharmaceuticals and agrochemicals. The new reaction allows for the regioselective conversion of nitroarenes into 1,2-trifluoromethylated nitroarenes, via a C-H activation pathway. Furthermore, a substitution of nitroarenes to trifluoromethyl arenes is also presented.

Full text of DOI:10.1039/c7cc05415g

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DOI: 10.1039/C7CC05415G
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Nucleophilic Trifluoromethylation of Electron-Deficient Arenes
Jack A. Pike and James W. Walton*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
a.
preparation:
Industrially-used trifluoromethylation
A
novel trifluoromethylation of arenes is presented, which
proceeds under mild reaction conditions and has the potential for
late-stage functionalisation of pharmaceuticals and
agrochemicals. The new reaction allows for the regioselective
conversion of nitroarenes into 1,2-trifluoromethylated
CCl3
HF
CF3
aromatic
trifluoromethylation
Nucleophilic
using
reagent:
b.
Ruppert-Prakash
NO2
CF3
nitroarenes, via a C‒H activation pathway. Furthermore, a
substitution of nitroarenes to trifluoromethyl arenes is also
presented.
CF3SiMe3
TASF
F
F
F
F
F
F
F
F
SiMe3F
THF, RT
F
F
The installation of trifluoromethyl moieties into organic
compounds is an intense area of research, particularly
regarding applications in pharmaceuticals, agrochemicals and
materials.1–12 Currently around 25% of all known
pharmaceuticals and 30% of all applied agrochemicals contain
at least one fluorine or trifluoromethyl substituent.13 The
industrial preparation of trifluoromethylated arenes relies
upon treatment of trichloromethyl arenes with HF (Scheme
1a). This method is inefficient and requires specialised
reactors, capable of handling HF. Alternative methods of direct
trifluoromethylation have been reported and proceed by one
of three mechanisms: nucleophilic,14 electrophilic15 and direct
free radical trifluoromethylation.16 Electrophilic and direct free
radical trifluoromethylation are often limited by a lack of
control over regiochemistry. Previous work from Bardin et al.
described how electron deficient perfluoronated nitrobenzene
undergoes trifluoromethylation with the Ruppert-Prakash
reagent, Me3SiCF3,17 via a nucleophilic aromatic substitution
(SNAr) mechanism (Scheme 1b).14 However, the need for
highly-activated pentafluoro-substituted arenes, which is not a
common pharmacophore, limits the general applicability of
this process.
c.
work:
This
i.
,
[CpRu(NCMe)3]PF6
80 °C
1,2-DCE,
NO2
CF3
NO2
CF3
H
ii. CF3TMS, KF, DMF, 0 °C
υ
iii. h MeCN, RT
,
H
or
MeCN, RT
DDQ,
1
Scheme
[CpRu]+.18 The π-complexation of an arene to a transition
metal increases its reactivity towards nucleophilic attack,19–23
resulting in efficient SNAr. Following the success of this
reaction, we hypothesised that the electron-withdrawing
effect of π-complexation could allow for trifluoromethylation
of arenes with nucleophilic CF3. This would overcome the
limitations of current nucleophilic trifluoromethylations, which
require highly electron-deficient perfluorinated arene
substrates (e.g. C6F5NO2).14 Herein, we report the successful
reaction of the nucleophilic Me3SiCF3 reagent towards [(η6-
arene)RuCp]+ π-complexes, producing a single regioisomer of
trifluoromethylated products (Scheme 1c). Importantly, we
also show the ability to recover the activating transition metal
complex, [CpRu(NCMe)3]+, by photolysis. Overall this process
allows for the late-stage trifluoromethylation of electron-
deficient arenes and could have significant impact upon the
pharmaceutical and agrochemicals industry.
We recently showed the catalytic SNAr of unactivated aryl
chlorides (i.e. those without electron withdrawing
substituents), mediated by transient η6-coordination to
To determine firstly whether trifluoromethylation is
feasible, the sandwich complex [(η6-nitrobenzene)RuCp]PF6 (
1)
was synthesised. Synthesis was achieved through heating
[CpRu(NCMe)3]PF6 and the corresponding arene at reflux in
1,2-dichloroethane to give the η6-bound arene complex in high
yield (93%, Figure 1). Confirmation of successful complexation
to the metal was provided by heteronuclear NMR
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK.
E-mail: james.walton@durham.ac.uk
† Footnotes relating to the title and/or authors should appear here.
Electronic
Supplementary
Information
(ESI)
available:
See
DOI: 10.1039/x0xx00000x
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Journal Name
PF6
View Article Online
Table 1 Trifluoromethylation of complex 1 with Me3SiCF3. Conditions:
DOI: 10.1039/C7CC05415G
starting complex (0.2 mmol), Me3SiCF3 (1.1 equiv.), fluoride salt (1.1
equiv.). Conversions determined by 1H-NMR, using an internal standard.
N
O2
NO2
NCMe)
CF3
[CpRu(
3]PF6
Ru
Me
fluoride
3SiCF3
NO2
CF3
CH2ClCH2Cl
80 °C, 16 h
salt
NO2
Ru
Ru
Ru
1
PF6
PF6
DMF
Figure 1. Synthesis and molecular structure of complex 1; thermal
ellipsoids are drawn at 50% probability level.
2
3
1
T
(°C)
25
Time Conv. Product Ratio
spectroscopy, mass spectrometry and elemental analysis. In
addition, it was possible to obtain single crystals of a suitable
Entry Fluoride Source
(h)
(%)
(2:3)
1
2
3
4
TBAF
KF
8
0
–
quality for X-ray diffraction studies for compound
a concentrated acetone solution with diethyl ether (Figure 1,
CCDC 1546706). Complex displays the expected pseudo-
1 by layering
25
0
8
8
8
28
64
19
50:50
50:50
50:50
KF
1
KF
40
linear geometry about the Ru centre. The Ru-C6(plane)
distance (1.711 Å) and Ru-C5(plane) distance (1.819 Å) are in
agreement with structures of other similar sandwich
complexes.24 For crystal and structural refinement data, see
Table S1.
carried
out
with
a
sample
of
[(η6-α,α,α-
trifluorotoluene)RuCp]PF6 prepared by reaction between
trifluoromethylbenzene and [(MeCN)3CpRu]PF6.
The second species obtained from the crude reaction
mixture was the Meisenheimer complex [Ru(η5-1-nitro-2-
trifluoromethylcyclohexadienyl)(η5-cyclopentadienyl)] (
species is formed by the nucleophilic addition of “CF3 ” to the
carbon ortho to the aryl nitro group. Similar nucleophilic
addition reactions have been observed for related η6-arene
transition metal complexes.21,25–27 Heteronuclear NMR and IR
spectroscopy data were used to assign the Meisenheimer
intermediate and confirmed the intact nitro group in the
complex. Based on the 1H-NMR coupling constants, the
product of the exo-addition of CF3 moiety is exclusively
observed. This is likely due to the steric bulk of the ruthenium
In an attempt to achieve aryl trifluoromethylation, complex
1
was treated with Me3SiCF3 under similar conditions to those
3
). This
used previously for the substitution of pentafluoro-
nitrobenzene14 (Table 1). In order to activate Me3SiCF3 as a
nucleophilic source of CF3, a stoichiometric amount of F– is
required. Initial investigations using tetrabutylammonium
fluoride (TBAF) as the source of F– and anhydrous DMF as
solvent resulted in low reaction conversions. When anhydrous
KF was employed as the fluoride salt, however, the
trifluoromethylation proceeded smoothly. Monitoring the
reaction in situ by mass spectrometry showed complete
–
1
consumption of starting material after 12 hours. H- and 19F-
–
metal centre and Cp ring restricting the endo attack of “CF3 ”.
NMR spectroscopy of the reaction mixture prior to purification
showed a mixture of two compounds. The two species were
isolated by column chromatography on silica and fully
characterised. One of these species was confirmed to be the
complex [(η6-α,α,α-trifluorotoluene)RuCp]PF6 (
2), the product
of nitro substitution by CF3, via an SNAr mechanism. To validate
the formation of this complex, spectral comparison was
Figure 2 shows the shift assignment for the protons within the
6 membered ring. It is evident from the significant lower
chemical shifts of the peaks that the aromaticity has been
broken, and the introduction of fluorine brings about
increased complexity in splitting patterns. It is also worth
considering that the sample of this complex collected would be
a racemic mixture of two enantiomeric complexes, where the
3
Figure 2. 1H-NMR spectrum of Meisenheimer complex 3. (CO(CD3)2, 298 K, 400 MHz)
.
2 | ChemComm, 2012, 00, 1-3
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exo-addition occurs at the ortho carbon either side of the nitro
group.
Under the initial conditions described above, analysis of
the 1H- and 19F-NMR suggests an approximate 50:50 ratio
View Article Online
3DOI: 10.1039/C7CC05415G
a.
CF
CF3
PF6
υ
h
Ru
]PF6
[CpRu(NCMe)3
conversion
CD3CN
RT, 27 h
>
99%
CF3
between complexes
2 and 3. In an attempt to shift the ratio in
which the two complexes are produced and probe if any
thermodynamic or kinetic preference exists for either complex,
the reaction was repeated using similar conditions at a variety
of temperatures (Table 1, entries 2-4). While the product ratio
was unaffected by the change in reaction temperature, it was
found that lower temperatures increased the overall reaction
yield, suggesting decreased complex decomposition at lower
temperature.
CF3
b.
DDQ
NO2
NO2
MeCN
RT, 24 h
Ru
>
conversion
99%
2
Scheme
treated under the same trifluoromethylation conditions, no
reaction is observed, confirming the importance of the [CpRu]+
fragment, which is essential to facilitate both the SNAr reaction
and the ortho addition reaction.
Next, we investigated the potential to liberate the
functionalised arenes from their Ru complexes. Complex
2 was
dissolved in deuterated acetonitrile and subjected to
ultraviolet irradiation (Scheme 2a). Photolysis was monitored
by 1H-NMR and revealed 90% decomplexation of
trifluoromethylbenzene after 8 h irradiation (365 nm), along
with an equimolar quantity of [CpRu(NCCD3)3]+. This Ru species
is the MeCN-d3 analogue of the Ru complex used to synthesise
complex 1, highlighting the ability to fully recycle the activating
Ru complex. After 27 h, quantitative conversion had been
achieved (Figure 3).
To determine the versatility of our trifluoromethylation
method, a selection of alternative arenes was investigated
under the optimised reaction conditions (Table 2). Several Ru
complexes were synthesised, incorporating η6-bound
substituted arenes, including nitrotoluene, cyanobenzene,
benzoic
acid,
chlorotoluene,
fluorobenzene
and
trifluoromethylbenzene. Each new complex was subjected to
the trifluoromethylation conditions. Reaction of [(η6-4-
nitrotoluene)RuCp]PF6 gave a 1:1 mixture of substitution
product (5, R = Me) and Meisenheimer complex (6, R = CH3, X =
NO2) (Table 2, entry 1). The observation that the substitution
product is a single regioisomer provides confirmation of an
SNAr mechanism, in which initial attack of the CF3 moiety
occurs at the nitro-bound carbon. Reaction with the
cyanobenzene complex (Table 2, entry 2) gave exclusively the
Meisenheimer complex (6, R = H, X = CN). The absence of any
substitution product is consistent with the poorer leaving
group ability of the cyano group. This highlights the potential
Table 2 Trifluoromethylation of various Ru complexes, with Me3SiCF3.
Conditions: starting complex (0.2 mmol), Me3SiCF3 (1.1 equiv.), KF (1.1
equiv.). Conversions determined by 1H-NMR, using an internal standard.
aCarried out at 40 °C. bReaction with the fluorobenzene complex resulted
in slow hydrolysis and formation of the bound phenol complex.
CF3
R
Me
3SiCF3
KF
R
X
R
CF3
X
Ru
Ru
Ru
We hypothesised that oxidation of the Meisenheimer
DMF
PF6
PF6
complex
aromatic complex. A range of oxidising agents showed no
reactivity with , including trityl chloride (Ph3CCl), trityl
3
would lead to a disubstitued η6-coordinated
8
0 °C
h,
5
6
4
3
Conversion
Product Ratio
(5:6)
Entry
R
X
tetrafluoroborate (Ph3CBF4) and pentachlorophosphate (PCl5),
while reaction with nitrosyl tetrafluoroborate (NOBF4) gave a
(%)
61
1
2
3
4
5
6
7
8
CH3
H
NO2
CN
Cl
50:50
26
12
10
0
0:100
0:100
0:100
‒
mixture of unassignable products. Treatment of
3 with 2,3-
CH3
H
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), however, led to
successful oxidation and decomplexation to give quantitative
CH3
CF3
CO2H
H
H
conversion
to
the
unbound
arene,
1-nitro-2-
H
0
‒
trifluoromethylbenzene (Scheme 2b). Overall this reaction is a
regioselective mild C‒H activation and trifluoromethylation of
nitrobenzene. Importantly, when unbound nitrobenzene is
H
22a
0b
0:100
‒
H
F
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for a selective C‒H activation and trifluoromethylation and
Journal Name
Fluoropolymers 1 Synthesis, Kluwer Academic Publishers, 2002.
View Article Online
DOI: 10.1039/C7CC05415G
also demonstrates the versatility of the mild activation 10 R. Berger, G. Resnati, P. Metrangolo, E. Weber and J. Hulliger,
protocol. Exclusive formation of the Meisenheimer
intermediate was also observed for 4-chlorotoluene- and 11 E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly and N. A.
toluene-bound complexes, albeit in low conversion (Table 2,
Meanwell, J. Med. Chem., 2015, 58, 8315–8359.
entries 3 and 4). The benzene complex reacted to give 22% 12 T. Liang, C. N. Neumann and T. Ritter, Angew. Chemie Int. Ed.,
conversion to the Meiesenheimer complex, but required
2013, 52, 8214–8264.
Chem. Soc. Rev., 2011, 40, 3496–3508.
heating at 40 °C to ensure solubility of the starting complex. 13 T. Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470–7.
No reaction was observed with the other arene complexes 14 V. V. Bardin, A. A. Kolomeitsev, G. G. Furin and Y. L. Yagupolskii,
tested, with the exception of the fluorobenzene complex,
which undergoes slow hydrolysis to the phenol complex.
In summary, we present the trifluoromethylation of nitro-
Izv. Akad. Nauk SSSR, Ser. Khim., 1990, 1693.
15 T. Umemoto and S. Ishihara, J. Am. Chem. Soc., 1993, 115,
2156–2164.
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coordination to [CpRu]+. Under the optimised reaction
32, 7525–7528.
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products. The substitution product, trifluoromethylbenzene, is 18 J. W. Walton and J. M. J. Williams, Chem. Commun., 2015, 51,
isolated by photolysis, with recovery of the [RuCp]+ activating
2786–2789.
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Meisenheimer intermediate with DDQ. The 20 L. A. Wilkinson, J. A. Pike and J. W. Walton, ACS Catal., in press.
trifluoromethylation proceeds under very mild conditions and 21 Y. K. Chung, H. S. Choi, D. A. Sweigart and N. G. Connelly, J. Am.
liberation of the unbound arene from the complex is high
yielding. To our knowledge, this method
Chem. Soc., 1982, 104, 4245–4247.
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the η6-binding to a Ru metal fragment is the first of its kind and
Chem. Commun., 2017, 53, 2146.
could be applied to the late-stage functionalisation of 24 A. I. Konovalov, E. O. Gorbacheva, F. M. Miloserdov and V. V.
pharmaceuticals and agrochemicals. Furthermore, the ability
Grushin, Chem. Commun., 2015, 51, 13527–13530.
to produce 1,2-substituted trifluoro-nitroarenes may lead to 25 E. P. Kündig, Pure Appl. Chem., 1985, 57, 1855–1864.
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26 N. G. Connelly and R. L. Kelly, J. Chem. Soc., Dalt. Trans., 1973,
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27 Y. K. Chung, P. G. Williard and D. A. Sweigart, Organometallics,
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Acknowledgment
We thank Durham University and the Engineering and Physical
Sciences Research Council (EPSRC, grant EP/N007441/1) for
funding and Dr. Dmitry S. Yufit for crystal structure
determination of complex 1.
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A new trifluoromethylation of arenes is presented, which proceeds via a Ru(II) π-arene
complex and is carried out under mild reaction conditions.