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effective, balancing the electronic effects of the resorcinol
with a p-CO2Me in catalyst 9 led to notably superior catalysis
(87% yield, vicinal:geminal 3:1). As the logical next step, C2-
symmetric resorcinol derivatives were investigated as sum-
marised in Figure 5.[23,24] Reactions were performed under
standard conditions with an amine:HF ratio of 1:7.5 in CHCl3
at ambient temperature. Initially, the effect of modifying the
substituent X was assessed using the methyl esters 10–13.
Counterintuitively, augmenting the steric footprint at site X
had a detrimental effect on selectivity. Catalyst 10 (X = Me)
proved to be most effective, generating compound 2a with
86:14 e.r. (> 95% conversion, 88% combined yield). Struc-
tural editing at site Y was not tolerated as exemplified by
catalysts 14–16. As a control series, the C1-symmetric catalysts
17–19 were examined (Figure 5, lower). Direct comparison of
17 with the most promising scaffold 10 confirmed the
importance of C2 symmetry (72:28 versus 86:14 e.r.). Interest-
ingly, substituting the methyl ester for benzyl (catalyst 18) did
not erode selectivity, although efficiency was decreased.
Moreover, the a-Bn catalyst (19) proved to be less efficient
than the C2-symmetric derivative 12. Having identified
catalyst 10 as the most promising scaffold to validate an
Figure 4. The effect of Brønsted acidity on catalysis.
This led to the identification of methods A, B and C,
reflecting amine:HF ratios of 1:4.5, 1:6 and 1:7.5 respectively
(Figures 3 and 4). Method A proved to be highly effective in
generating the electron rich products 2b–2d with high levels
of regioselectivity favouring formation of the desired vicinal
product (> 20:1, up to 86%). The presence of the CF3 group
clearly distinguish this substrate class from the parent
styrenes, which rearrange to generate the geminal product.[20]
Control reactions again confirmed the necessity for the
catalyst. The seemingly subtle change to Method B proved
to be optimal for substrates 2e–2k, enabling the
generation of alkyl derivatives (2e–2h, up to > 20:1,
vic:gem) as well as the electron deficient aniline
derivative 2i (74%, 15.5:1).
Comparable efficiency and selectivity were also
noted for the biphenyl system 2j and adduct 2k.
Augmenting the amine:HF ratio further to Method C
provided optimised conditions to access products
2a,l–2q. Whereas employing higher HF ratios/
Brønsted acidities under the conditions developed
by this laboratory tend to favour 1,1-difluorination,[20f]
electron-deficient a-CF3-styrenes proved to be nota-
bly more recalcitrant to rearrangement and the vicinal
products predominated throughout. Given the impor-
tance of aryl bromides in contemporary medicinal
chemistry, where the C(sp2)-Br provides a handle for
subsequent cross-coupling, the synthesis of 2l was
conducted on a 1 mmol scale. Despite the volatility of
the product, the vicinal product could be isolated in
43% yield. Products 2m, 2n and 2o behaved similarly
and were generated in a vicinal:geminal ratio of ca.
3:1. Given the prominence of aniline fragments
bearing isopropyl units in drug and agrochemical
discovery (See Figure 1), the phthalimide 2p was
generated cleanly in 61% yield. Finally, access to the
disubstituted aryl 2q was realised, this time with an
improvement in regioselectivity (5.0:1). Having es-
tablished conditions to enable the vicinal difluorina-
tion of a-CF3-styrenes via I(I)/(III) catalysis, attention
was focussed on a preliminary validation of an
enantioselective variant. Whilst catalyst p-iodoto-
Figure 5. Catalyst optimisation to enable preliminary validation of enantioselec-
tion. The conversion and combined yield (in parentheses) was determined by
19F NMR spectroscopy of the crude reaction mixture using a,a,a-trifluorotoluene
as internal standard. Enantioselectivity determined by chiral HPLC. Standard
reaction conditions: a-CF3-p-chlorostyrene 1a (0.2 mmol), catalyst (20 mol%),
Selectfluorꢃ (1.5 equiv), amine:HF 1:7.5 (0.5 mL), CHCl3 (0.5 mL), ambient
luene 5 is a highly competent catalyst, sites to
append stereodirecting groups are conspicuously
absent. The investigation was therefore repeated
with resorcinol derivatives 7–9 in which proximal
stereocentres might induce enantioinduction.
Whereas catalysts 7 and 8 proved to be moderately temperature, 24 h.
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Angew. Chem. Int. Ed. 2021, 60, 6430 –6434