Silver-catalysed trifluoromethylation of arenes at room temperature

Article abstract of DOI:10.1039/c3cc41829d

A variety of heteroarenes and electron rich arenes can be trifluoromethylated at room temperature with TMSCF₃, catalytic silver and PhI(OAc)₂.

Full text of DOI:10.1039/c3cc41829d

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Silver-catalysed trifluoromethylation of arenes at room
temperature†
Sangwon Seo,a John B. Taylorb and Michael F. Greaney*a
Cite this: Chem. Commun., 2013,
49, 6385
Received 11th March 2013,
Accepted 16th May 2013
DOI: 10.1039/c3cc41829d
www.rsc.org/chemcomm
A variety of heteroarenes and electron rich arenes can be trifluoro-
We started with a screen of reaction conditions based around
methylated at room temperature with TMSCF3, catalytic silver and TMSCF3 as the trifluoromethylating agent.9 The groups of
¨
PhI(OAc)2.
Sanford, Brase and Wang have recently demonstrated the compat-
ibility of this reagent with stoichiometric silver salts,4g,k,5c encoura-
ging us that it could form the basis of a catalytic system. Using
1,4-dimethoxybenzene (1a) as the substrate, we conducted an
initial solvent screen using combinations of AgF, TMSCF3 and
PhI(OAc)2 (Table 1). We worked at room temperature under air
throughout, with the aim of developing a mild reaction with as
broad a functional group tolerance as possible. The reaction
proved sensitive to solvent choice with initially only MeCN from
a selection of common organic solvents producing any reaction
(entries 1 and 2). DMSO proved more effective still, affording the
trifluoromethylated compound 2a in 51% conversion (entry 3).
Fluoride was not a requirement, with Ag2CO3 being similarly
effective at promoting reaction (entry 4). Alternative oxidants did
not improve on PhI(OAc)2 (entries 5 and 6), and the use of a
The trifluoromethyl group is valued for its ability to modulate
the properties of diverse materials such as pharmaceuticals,
agrochemicals and polymers. Aryl CF3 groups are electron-
withdrawing, hydrophobic and generally very stable, all proper-
ties that can be harnessed in the design of biologically active
molecules and functional materials. Synthetic methods for aryl
and heteroaryl trifluoromethylation are thus critical to the
discovery and production of new molecules of high value to
society.1 Recent developments in metal-mediated trifluoro-
methylation have produced significant advances in this area,2
with common functional groups such as aryl boronic acids and
halides undergoing efficient trifluoromethylation under palladium
and copper catalysis.3 Metal-catalysed trifluoromethylation of
unactivated C–H positions, by contrast, is significantly less
developed and has great potential for accelerating medicinal
and agrochemical syntheses. Despite some recent ground-
breaking developments in this area,4 there is still great demand
for the development of catalytic C–H trifluoromethylation
methods that function under mild and simple conditions.
We were interested in developing a catalytic trifluoromethyla-
tion based on silver; in contrast to its Group 11 neighbour copper
there have been few reports on silver-mediated trifluoromethyla-
tion4g,k,5 and none that we are aware of using silver catalysis. The
redox catalysis of silver, comprising one electron steps between 0,
+1, +2 and +3 oxidation states, has been scarcely exploited in
synthesis relative to other late TMs6,7 and could offer productive
catalytic pathways for trifluoromethylation. We have recently devel-
oped silver-catalysed decarboxylative C–H cross-coupling under
oxidative radical conditions,8 and were keen to see if a similar
approach was viable for C–H trifluoromethylation.
Table 1 Ag-catalysed trifluoromethylation: reaction optimisation
Entrya
Catalyst (equiv.)
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
AgF (1)
AgF (1)
AgF (1)
Ag2CO3 (0.5)
AgF (1)
AgF (1)
AgF (1)
AgF (0.25)
AgF (0.25)
AgF (0.25)
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(TFA)2
K2S2O8
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
Solventc
MeCN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
26
51
48
5
20
35
7d
8e
9e,f
10e,h
55
55 (58g)
60
a
1,4-Dimethoxybenzene 1a (0.3 mmol), TMSCF3 (1.2 mmol), oxidant
(0.6 mmol), FÀ source or base, solvent (1.0 mL), room temperature,
a School of Chemistry, University of Manchester, Oxford Rd, Manchester, M13 9PL,
UK. E-mail: michael.greaney@manchester.ac.uk
b Syngenta, Jealott’s Hill International Research Centre, Bracknell, RG42 6EY, UK
† Electronic supplementary information (ESI) available: Synthesis and character-
isation data for all new compounds. See DOI: 10.1039/c3cc41829d
20 h. Yields determined by 19F NMR using 4-fluoroanisole as the
b
c
internal standard. THF, 1,4-dioxane, MeOH, (CF3)2CHOH, DCE, DCM.
d
e
Under N2. Slow addition of AgF to the stirring mixture of 1a, TMSCF3
f
g
and PhI(OAc)2 in DMSO.
2 equiv. of TMSCF3. Isolated yield.
h
TESCF3 (2 equiv.) instead of TMSCF3.
c
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Table 2 Ag-catalysed trifluoromethylation: substrate scopea,b
nitrogen atmosphere led to a reduction in yield (entry 7). Crucially,
sub-stoichiometric amounts of silver salts proved equally effec-
tive (entries 8–10), indicating that a catalytic reaction was
feasible. We settled on conditions of AgF (25 mol%) with
TMSCF3 (2 equiv.) and PhI(OAc)2 (2 equiv.), at room temperature
(entry 9) to take forward. The use of the more stable (and
expensive) TESCF3 reagent gave only marginal improvement
(entry 10), so we continued with the cheaper TMSCF3 reagent.
Substrate scope investigations established that the procedure
was effective for a variety of electron rich arenes with broad
substrate scope tolerance (Table 2). For unsymmetrical sub-
strates isomeric mixtures were generally observed, with regio-
selectivities consistent with radical SArH addition (vide infra).
Importantly, the reaction was compatible with halogen groups,
illustrating an orthogonal reactivity to conventional C–X trifluoro-
methylations whereby neighbouring C–H bonds undergo pre-
ferential reaction. The useful building blocks 2f, 2g, 2h and 2i
were prepared in this fashion. Electron-withdrawing groups such
as aldehyde (2j), ketone (2k) and ester (2l) were likewise tolerated
without problem. Importantly, dialkylanilines could be trifluoro-
methylated, a key class of building block that has rarely featured
in C–H trifluoromethylation reports.4i,10 A slight preference for
ortho over para selectivity was observed for simple dimethyl-
amine (2m), with bromo substitution also tolerated (2n) along
with N-acylation (2o). We were pleased to observe that the
reaction was also effective for un-activated arenes (2p, 2q and
2r), although these substrates did require an excess of the arene
and the reaction temperature raised to 70 1C.
The reaction could be extended to heteroarenes with N–Me
pyrroles in particular being excellent substrates (2s, 2t). Electron-
withdrawing groups on the heteroarene nucleus were well-
tolerated (2t), but on nitrogen less so (N–Boc, 2u). Furans (2v),
thiophenes (2w, 2x) and indoles (2y) were all productive, indicat-
ing that the method is viable for the major classes of p-excessive
heterocycle. p-Deficient heteroarenes, by contrast, were not gen-
erally effective in the reaction but could be efficiently captured by
masking the azine nucleus with electron-donating groups (2aa).
We next turned to the trifluoromethylation of more complex,
biologically active molecules – a major driver for the development
of new methods in this area. Introduction of the CF3 group at
unactivated C–H positions represents a very versatile approach to
fluorine incorporation for modulation of biological activity,4c,d,j
demanding mild reaction conditions that are tolerant of func-
tional groups and reasonable stoichiometries with respect to the
(often valuable) C–H substrate. Accordingly, we extended the
reaction to trifluoromethylate some more complex molecules in
the agrochemistry field, an area where the CF3 group is parti-
cularly prevalent. We could successfully incorporate the CF3 group
into the commercial herbicides pyriftalid11 and napropamide12
(Scheme 1). The functional group tolerance of the reaction was
illustrated by sulfide, lactone and a-hydroxyamide functionality all
being stable to the reaction conditions (Scheme 1, 3 and 4).
A radical mechanism is implicated for the trifluoromethylation
reaction,13 as radical quenching reactions using TEMPO and
galvinoxyl radical both shut down the reaction, with the TEMPO–
a
1 (0.3 mmol), TMSCF3 (0.6 mmol), PhI(OAc)2 (0.6 mmol), AgF
b
(0.075 mmol), DMSO (1.0 mL), room temperature, 20 h. Isolated
yields. For isomer mixtures, the minor regioisomeric position is labeled
with *. Yields determined by 19F NMR using 4-fluoroanisole as the
c
d
internal standard. Reaction conducted at 70 1C, 5–10 equiv. of arene.
Scheme 1 Agrochemical trifluoromethylation.
CF3 adduct being clearly observed in the crude 19F NMR. The displays a marked preference for electron rich substrates, as seen
electrophilic CF3 radical usually (but with some exceptions)4c,j here, underlining the likelihood of a radical pathway. A possible
c
6386 Chem. Commun., 2013, 49, 6385--6387
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the CF3 radical, followed by SArH addition, then a second one
electron oxidation and proton loss to give the product 2. Control
experiments to investigate the role of silver in the first step of the
proposed mechanism indicated that AgF alone was insufficiently
ꢀ
oxidizing to generate CF3 (mixing AgF with TMSCF3 in the
presence of TEMPO in DMSO at room temperature gave only trace
quantities of TEMPO–CF3). PhI(OAc)2 alone was moderately effec-
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PhI(OAc)2 and AgF highly effective (91% NMR yield).14 The back-
ground oxidizing activity of the hypervalent iodine reagent could be
quantified in the trifluoromethylation of 1,4-dimethoxybenzene 1a
in the absence of any silver salt, producing a low conversion to the
trifluoromethylated product 2a (26% NMR yield).
Alternative mechanisms were investigated by treating dimethoxy-
anisole 1a with in situ prepared AgCF35b in both MeCN and DMSO
as solvents. No reaction could be observed in each case, suggesting
organometallic AgCF3 intermediates are not participating under
our reaction conditions. A further control experiment with Togni’s
reagent4a in DMSO at room temperature gave no reaction, ruling
out simple SEAr attack on an electrophilic CF3 source. Finally, we
considered the possibility of initial arene oxidation by PhI(OAc)2,
followed by CF3 anion addition to a cationic arene intermediate.
Extensive work by Kita has demonstrated the C–H functionaliza-
tion of electron rich arenes using PhI(TFA)2 in the presence of
stoichiometric BF3ÁOEt2 and nucleophiles.15 It seems the present
conditions are not sufficiently oxidizing to enable an analogous
pathway, as a control reaction in the absence of TMSCF3 gave no
reaction, where some degree of homocoupling would be expected if
this mechanism was in operation.
In conclusion, we have developed a silver-catalysed trifluoro-
methylation system for electron rich aromatic and hetero-
aromatic substrates. The reaction works at room temperature
under air, does not require excessive stoichiometries of sub-
strate or reagent, and is operationally simple to carry out. The
application of this chemistry to new trifluoromethylation sub-
strates will be the subject of future work in our laboratory.
We thank Syngenta, the University of Manchester and the
EPSRC for funding (Leadership Fellowship to M.F.G.), and the
EPSRC mass spectrometry service at the University of Swansea.
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c
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Chem. Commun., 2013, 49, 6385--6387 6387