Angewandte
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Chemie
Table 1: Selected optimization experiments.[a]
the necessity of the visible light and photoredox catalysts
(entries 6 and 7). Notably, the reaction proceeded under an
air atmosphere or in the presence of water without loss of
reactivity (entries 8 and 9).
With the optimized conditions (Table 1, entry 4) in hand,
we turned our attention to explore the generality of the
transformation. To our delight, a wide range of mono-, di-,
and tri-substituted (hetero)arenes reacted well to afford the
À
desired C H trifluoromethoxylation products (Table 2).
Functional groups such as halides (F, Cl, Br, 2a–2g, 2s–2t,
2v–2ab, 2ae–2ag, and 2ai–2aj), carboxylic acids (2g–2h,
2ab, and 2aj), ketones (2i and 2ae), esters (2j–2k, 2u, 2ac,
2ae–2ah), aldehyde (2aa), urea (2ai), substrates with weak
benzylic hydrogen atoms (BDE ꢀ 88 kcalmolÀ1, 2m, 2v–2w,
2ad, 2ah,and 2aa),[9] nitrile (2o, 2z, and 2ad), nitro (2ah),
sulfonyl (2q and 2ai), phosphine oxide (2r), and CF3 (2 f)
groups are all tolerated. In contrast to the previously reported
photoactive reagent,[3m] redox-active reagent 1 could be used
to functionalize electron-rich arenes such as toluene (2m) and
tert-butyl benzene (2n), affording the desired products in
synthetically useful yields. Notably, heteroarenes such as
pyridine, pyrimidine, and thiophene (2s–2ad), found in
thousands of medicinally important structures, could also be
used in this reaction. Although ten equivalents of arenes were
used, we could recover 7.9–9.2 equivalents of aromatic
substrates at the end of the reaction, which is critical for
valuable arenes. The synthetic utility of this process is further
highlighted by its amenability to a late-stage trifluoromethox-
ylation of biorelevant molecules using arenes as a limiting
reactant. For example, trans-androsterone, diacetonefructose,
l-menthol (analgesics and decongestants), and Metronida-
zole (antibiotic) derivatives reacted to afford the desired
OCF3-analogs (3ae–3ah) in modest yields based on the
recovery of starting materials. Other marketed drugs such as
Chlorpropamide (anti-diabetic drug, 2ai) and Baclofen
(muscle relaxant, 2aj) were viable substrates as well.
[a] 10 equivalents of 2a was used. [b] Yields were determined by 19F-NMR
using PhCF3 as an internal standard. [c] 1 equivalent of 2a was used.
[d] Without light. [e] Under air atmosphere. [f] With 100 equivalents of
H2O.
radical.[5] Thus, a series of 1-OCF3-benzotriazole reagents
were synthesized.
Photoredox catalysis has recently emerged as a powerful
tool in organic synthesis.[6] We hypothesised that an appro-
priate combination of photoredox catalysts and 1-OCF3-
benzotriazole reagents would allow the catalytic formation of
the OCF3 radical through a sequential SET process. An initial
attempt to subject compound A (1 equiv) to a mixture of
1,3,5-trichlorobenzene (2a, 10 equiv) and Ru(bpy)3(PF6)2
(1 mol%) in MeCN (0.200m) under irradiation with 10 W
blue LED light (lmax = 447 nm) failed to produce the desired
product 3a (Table 1, entry 1). Presumably, this is due to the
highly negative reduction potential of A (Ep = À1.97 V vs.
saturated calomel electrode (SCE); Supporting Information,
Figure S12). Even if the corresponding radical anion can be
accessed, DFT calculations show that the mesolytic cleavage
The regioselectivity of the reaction resembles other
radical-mediated aromatic substitution processes and is
guided by the electronics of the substituent except in the
case of a bulky substituent, for example, substrate 2o, for
which the OCF3 radical adds preferably to the position distal
from the tert-Bu group. Additionally, if an aromatic substrate
has multiple reaction sites, the OCF3 radical will add to these
sites to form regioisomers. Isolation of these regioisomers
allows rapid biological-activity assays of OCF3-analogs and
accelerates the discovery of new drugs.[10]
À
of the N OCF3 bond would favour the formation of the N-
centered benzotriazole radical rather than that of the OCF3
radical because of the electron withdrawing group (e.g., CF3)
on the O atom (Figure S6).[3m,7] We reasoned that cationic N
À
OCF3 reagents would be better electron acceptors and the
resulting reduced neutral radicals would fragment to form the
OCF3 radical selectively (Scheme 2a, see below). Indeed,
using methylated cationic reagent B instead of A under
otherwise identical conditions gave 3a in 60% yield along
with 33% of byproducts B’ (entry 2).[8] Deactivation of the
benzotriazole ring with an addition of a nitro-group (reagent
1) suppressed the formation of B’ and increased the product
yield to 70% (entry 3). Using a solvent mixture of MeCN and
CH2Cl2 (1:1 v/v) further improved the yield to 84% (entry 4)
and no N-arylated side product was observed. The reaction
also worked with one equivalent of trichlorobenzene albeit in
a lower yield and accompanied by 15% of bis-trifluorome-
thoxylated product (entry 5). Control experiments confirmed
Our unique ability to catalytically and selectively generate
the OCF3 radical at ambient conditions allows studying its
property and reactivity in organic solvents. Intermolecular
competition experiments demonstrated that the electrophilic
OCF3 radical reacts favourably with an electron-rich arene
(Supporting Information, Figure S8). Deuterium kinetic iso-
tope effect (KIE) studies showed no KIE (Figure S9), which
rules out the possibility of H-atom abstraction/deprotonation
as the rate-determining step. Determination of the quantum
yield and quenching constant through Stern–Volmer quench-
2+
ing studies proved to be challenging because the Ru(bpy)3
sensitiser and reagent 1 both absorb in the visible light region
(Figures S3 and S4). Nevertheless, light on/off experiments
2
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Angew. Chem. Int. Ed. 2018, 57, 1 – 6
These are not the final page numbers!
Zheng, Weijia
