Communication
doi.org/10.1002/chem.202101324
Chemistry—A European Journal
evidence for iron coordination and direct activation of a CÀ F
bond. This method was applied and optimized for medicinally
relevant ArCF3 substrates (Figure 1c).
We explored a variety of halophilic Lewis acidic transition
metal complexes in the presence of BBr3 and trifluoromethyl
(m-fluoro)benzene 1a. In the absence of a catalyst, the known
background reaction provides compound 2a at 7% conversion
(Table 1, entry 1).[6d] While silver(I), copper(I), iron(0) and iron(II)
showed no improvements on CÀ F exchange efficiencies (en-
tries 2–5), iron(III) and gallium(III) compounds accelerated the
halex process (entries 6–10), generating tribrominated product
4a at 83–91%. Interestingly, the identity of the halide on the
iron(III) center did not affect the reaction significantly.
Figure 2. Transformations of ArCF2X (X=Br, Cl) reported in the literature.[12]
Ensuing investigations were performed with iron(III)fluoride.
Solvent selection proved important (Table 1, entries 11–13),
possibly due to the varying solubility of the iron(III)fluoride
reagent. However, it should be noted that the iron complex
showed a distinct increase in solubility upon boryl halide
addition (see Figure S5, S15 in Supporting Information). Nitro-
methane coordination with BBr3 was also observed in the 11B
NMR spectrum, and this interaction is suspected to mitigate
reactivity.
Different boryl halides were also competent in the halex
reaction (entries 14–16), although these reactions were slow
relative to those with BBr3. When employing BCl3, higher
catalyst loadings enabled a high total CÀ F conversion and
generation of the trichloromethyl arene as the sole product
(entry 16). Tribromomethyl arene 4a could also be obtained as
a single product, using excess BBr3 and an extended reaction
time (entry 17).
Trihalomethyl arenes can be used in a number of synthetic
applications, including conversion to carboxylic acids/esters,
alkynes and alkenes, and to generate heterocycles.[11,6b] Accord-
ingly, we envision this operationally-simple method to be quite
useful, given the prevalence of trifluoromethyl groups in high-
profile compounds.
Table 1. Screening Investigations.
However, there remained potential to optimize a single
halogen-exchange, generating compound 2a. In addition to
unique intrinsic properties, such as increased capacity for
halogen bonding, ArCF2X compounds are common intermedi-
ates for redox and cross-coupling reactions that generate a
range of high value difluoro derivatives (ArCF2R, Figure 2).[12,13]
Optimizing a single halogen exchange on a trifluoromethyl
center is a challenge, as the CÀ F bond strength decreases with
each fluorine removal.[14] Encouragingly, lowering of the reac-
tion temperature increased conversion to ArCF2Br (2a) relative
to ArCBr3 (4a) (entry 18). This observation indicated that
appropriate reaction tuning could provide synthetically viable
amounts of ArCF2Br.
The kinetic complexity of the mono-halex reaction led us to
use the statistical method Design of Experiments (DOE) for
optimization. DOE uses regression analysis to generate a
mathematical model of a reaction outcome as a function of
defined reaction parameters (variables).[15] The model devel-
oped is tailored to the reaction space defined by the chosen
parameters. The relative importance of each parameter, as well
as interaction effects between parameters is determined by
analysis of variance (ANOVA).
We first performed a 5-variable fractional factorial DOE to
evaluate main linear effects, followed by a response surface
design, a more predictive model that accounts for non-linear
effects. Evaluation of data normalcy, R2 fit, R2predicted (a leave-one-
out cross-validation test for over-fitting), and analysis of error
°
Reactions performed at 1.0 mmol scale, 0.2 M molarity, 20 C, and 5 h.
Conversions determined by 19F NMR (relative to 4-fluorotoluene internal
standard). 3a was trace in all entries (<3% conversion). cat=catechol. nd.
=not detected. tr.=trace. [a] CÀ Ftotal refers to the molar fraction of CÀ F
bonds converted to CÀ X bonds. [b] 3 equiv. R2BBr used. [c] Chlorinated
products formed (ArCCl3 instead of 4a). Conditions: DCM/NO2Me (4:1),
°
0.6 equiv. FeCl3, 4 equiv. BCl3, 30 C, 16 h. [d] Conditions: 10 mol% FeF3,
°
1.5 equiv. BBr3, 14 h. [e] Performed at À 10 C.
Chem. Eur. J. 2021, 27, 1–6
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