Organic Letters
Letter
a
the nascent carbon anion/radical species ultimately achieves
Table 1. Optimization of Reaction Conditions
7
1
,2-difunctionalization. Based on these achievements, we
posited whether it is possible to further expand the potential
applicability of this strategy, for example, enabling ring-opening
1
,3-fluorofunctionalization of gem-difluorocyclopropanes
(
F2CPs). In principle, the successful development of this
b
entry
fluoride
solvent
yield (%)
homologous reaction would build up a new dimension for the
expedient construction of structurally complicated CF3-
decorated frameworks that is not easily acquired by resorting
to previously known regimes. Although seemingly enticing, the
relative inertness of cyclopropane ring compared with alkene
π-system would pose a remarkable challenge, much less the
realization of exquisite site-selectivity, with respect to C−C
bond cleavage (Scheme 1b).
1
2
3
4
5
6
7
8
9
Py·9HF
AgF
KF
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
MeCN
DCE
16
NR
NR
NR
5
31
30
43
36
23
CsF
BF ·OEt
3 2
Et
3
Et
3
Et
3
N·3HF
N·3HF
N·3HF
The exploitation of avenues that enable regioselective ring-
Et N·3HF
PhCF3
opening functionalization of F CPs has aroused much interest
3
2
8
10
11
12
13
Et N·3HF
acetone
from synthetic chemists. Although diverse efficacious
3
c
Et N·3HF
DCE
DCE
DCE
89 (74)
strategies for the activation of cyclopropane ring have been
put forward, most of the reported protocols still fall short of
general applicability, such that specific neighboring activating
3
d
Et N·3HF
NR
3
e
Et N·3HF
3
NR
9
−11
a
groups are always required.
In this vein, the regioselective
Standard reaction conditions: 1a (0.1 mmol), 2a (0.3 mmol), PC-II
(2.0 mol %, 0.002 mmol), Et N·3HF (2.0 equiv, 0.2 mmol), dioxane
0.5 mL) under N atmosphere while irradiating with 8 W blue LEDs
for 12 h. Yield was determined by F NMR with PhOCF as the
internal standard. DCE (0.25 mL) and the reaction time was 48 h.
Isolated yield was given in parentheses. Without photocatalyst.
Without light irradiation.
functionalization of alkyl- or aryl-based F CPs, which are
3
2
(
devoid of extra activating elements, still proved to be
nontrivial. Notably, by capitalizing on tactics including
hypervalent iodine catalysis and bromine radical-engaged
homolytic-substitution, as well as C−C bond cleavage through
low-valent palladium insertion, elegant examples were reported
2
b
19
3
c
d
e
12−14
by the groups of Jacobsen, Kawasaki-Takasuka, and Fu.
Notwithstanding these notable progresses, the aforementioned
works mainly focus on monofunctionalization, despite the fact
that rapid construction of molecular complexity is more
favored for difunctionalization reactions. With our continuing
interest in fluorine chemistry, we would like to report our
recent progress in regioselective 1,3-carbofluorination of aryl
F2CPs (Scheme 1c). The notable features as well as the
underlying reasons, with regard to the present work are as
follows: (i) by resorting to photoredox catalysis, the aryl group
readily undergoes single-electron oxidation, with the in-situ-
generated aryl radical cation segment enabling a remote
whereas other metallic fluorides proved unsuitable for this
transformation (Table 1, entries 2−6). Further enhancement
of reaction efficiency was observed when substituting DCE for
dioxane as the reaction media, while no further yield increase
was gained with other reaction solvents (Table 1, entries 7−
10). Pleasingly, by further prolonging the reaction time to 48 h
along with increasing the reaction concentration, full
consumption of starting materials was observed and the
NMR yield of desired product could be increased to 89%
(Table 1, entry 11). Furthermore, control experiments clearly
indicated that both photocatalyst and light irradiation were
indispensable to the success of this reaction and no any
product was obtained with the omission of either (Table 1,
entries 12 and 13).
15
activation of the attached F CPs motif toward exogenous
2
1
6
fluoride attack; (ii) the positive charge in aryl moiety is
effectively delocalized to F CPs through hyperconjugation
2
effect, thus resulting in an enrichment of positive charge on
gem-difluorine substituted carbon atom, because of the p-
electron-donating ability of F atoms; (iii) beside the cation-
stabilization capacity of gem-difluorine substituents, which
secure a high regioselectivity concerning the fluoride attack,
extra thermodynamic gains could be anticipated by the
With the optimized reaction conditions in hand, the
exploration of substrate scope, with respect to aryl F CPs,
2
was subsequently pursued and the representative results are
compiled in Scheme 2. The para position of the aryl group
decorated with electron-donating alkoxyl or aryloxyl function-
alities were all tolerated and moderate to good yields could be
obtained with these substrates (3a−3c). Although there were
more recalcitrant toward SET oxidation, the less electron-rich
substrates bearing a phenyl or alkyl group were also amenable
to this reaction and delivered the desired products 3d in 54%
and 3e in 49% yield, respectively, when using Fukuzumi salt as
the catalyst. Notably, substrate 3f, which is decorated with
propargyl ether, also participated in this fluoroallylation
reaction readily, with the propargyl group remaining intact
throughout this transformation. In addition, heterocycle-
9a,b,17
formation of CF groups.
3
Before we started to validate our hypothesis, the redox
potential of 1-(2,2-difluorocyclopropyl)-4-methoxybenzene
(1a) was determined using cyclic voltammetry, which was
identified around +1.68 V (vs SCE in MeCN). Based on this
assessment, initial attempts of the reaction between 1a and
ethyl 2-((phenylsulfonyl)methyl)acrylate (2a) was performed
desired product 3a could be isolated in 16% yield, when using
containing aryl F CPs also turned out to be amenable, as
2
[
+
Ir(dF(CF )ppy) (5,5′-d(CF )bpy)](PF ) (PC-II, E
=
showcased by the example of 3g. With the activation of
methoxy group at the para-position, a set of additional
substituents differs in electronic property were accommodated
such as F, Cl, Br, Me, Ph, and OMe (3h−3l, 3n, 3o).
Interestingly, while 1a reacted efficiently, its ortho-OMe-
3
2
3
6
Red
1.69 V vs SCE in MeCN) as the catalyst and Py·9HF as
18
the fluorine source (Table 1, entry 1). Among the
nucleophilic fluoride tested, Et N·3HF was revealed to be
the best choice, which resulted in the generation of 3a in 31%,
3
B
Org. Lett. XXXX, XXX, XXX−XXX
Feng, Chao
