Photoredox generation of the trifluoromethyl radical from borate complexes: Via single electron reduction

Article abstract of DOI:10.1039/c8cc00245b

A method for the generation of the CF₃ radical from CF₃-substituted borate complexes bearing a pyridine-N-oxide ligand is described. Cleavage of the C-B bond occurs via single electron reduction by a Cu(i) photocatalyst activated by visible light.

Full text of DOI:10.1039/c8cc00245b

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Photoredox Generation of the Trifluoromethyl Radical from Borate
Complexes via Single Electron Reduction
Vladimir O. Smirnov,a Anton S. Maslov,a,b Vladimir A. Kokorekin,a,c Alexander A. Korlyukov,d,e
Alexander D. Dilman*,a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Oxidative quenching
+ e
Concept:
A
method for the generation of the CF3 radical from CF3-
F
F
B
substituted borate complexes bearing pyridine-N-oxide ligand is
described. Cleavage of the C-B bond occurs via single electron
reduction by a Cu(I) photocatalyst activated by visible light.
+ e
R
R
X
+ X
F3C
O
N
PC+1
PC*
Reductive quenching
– e
F
Organofluorine compounds play important role in medicinal
chemistry and related fields.1 Among wide variety of
F
F3C
B
R
M
R
M
+
O
N
approaches for the synthesis of fluorinated molecules,2
methodology of radical fluoroalkylation has witnessed
a
a
PC–1
PC*
renaissance in recent years.3 Despite significant advances in
this area, the development of shelf-stable, robust and readily
available reagents capable of generating fluorinated radicals
under mild conditions still would be desirable.
This work:
+ e
F
F
B
F3C
N
+
+
R
M
R
O
Scheme 1. Oxidation/Reduction Interplay.
Photoredox catalysis with visible light has emerged as a
powerful concept in organic chemistry.4 Mild temperature
regime and no need for strongly basic or acidic reagents makes
photocatalytic reactions applicable for highly functionalized
substrates. In these transformations, free radicals are
generated as a result of single electron transfer between the
light activated catalyst and a substrate (Scheme 1, left part).
Compounds with carbon-heteroatom or heteroatom-
heteroatom bonds typically serve as oxidants towards
photoexcited catalyst (oxidative quenching). For example,
perfluoroalkyl iodides are excellent substrates for this mode of
reactivity.5,6 On the other hand, organometallic reagents, in
which the electron density of carbon-element bond is shifted
from element to carbon, are supposed to be oxidized by the
catalyst (reductive quenching). The latter pathway has been
utilized for reactions of organyl trifluoroborates7 and
siliconates.8 Herein we describe a novel approach for the
generation of radicals by single electron reduction of
intrinsically nucleophilic organoborate complexes (Scheme 1,
bottom of the left part). To override the inherent bond
polarity, a redox active ligand attached to the boron atom is
involved.
The N-O bond as a reducible radical-forming motif has
been actively used in photoredox chemistry.9 We were
particularly inspired by the work of Stephenson on the
application of pyridine-N-oxide in combination with
trifluoroacetic acid anhydride.10 Furthermore, N-oxypyridinium
cations were shown to behave as good acceptors of electrons,
and the mechanism of the N-O bond fission was studied in
detail.11 Indeed, this homolytic cleavage of the N-O bond is
very fast and even barrierless in some cases.11b
Several trifluoromethyl borate salts have been described12
and used as equivalents of the trifluoromethyl carbanion.13
However, their oxidation to generate the CF3-radical is
problematic.14 We proposed that
a complex of a CF3-
substituted borane with pyridine-N-oxide can undergo a single
electron reduction by an excited photocatalyst (Scheme 1,
right). Subsequent cleavage of weak N-O bond accompanied
by restoration of the pyridine aromaticity and formation of
boryl-stabilized oxy-anionic species provide driving force for
the generation of the CF3-radical.
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The reaction works well with cyclic alkenes and styrenes
leading to the expected products arising from the radical
addition at the double bond in good yields. However,
unactivated aliphatic terminal alkenes such as N-
allylphthalimide were unreactive. The process tolerates
various functional groups such as ester, silyl ether,
tetrahydropyranyl ether, azide, N-Boc-protected amine, and a
reactive benzyl chloride moiety. An unprotected hydroxy
group does not intervene since methanol is used as solvent
(see product 3q). Besides the CF3-group, other perfluorinated
groups can be transferred in excellent yields (Scheme 3).
Scheme 2. Synthesis of boryl complexes 1.
Complexes 1a-d were prepared from the trifluoroborate
salt, which in turn can be accessed either from the silicon
reagent12 or from a bulk industrial product, trifluoromethane15
(Scheme 2). These complexes are air-stable crystalline
compounds, which can be stored at room temperature for
weeks or in the refrigerator for months without noticeable
decomposition.16 Because of low migratory aptitude of the
CF3-group,17 the oxidative 1,2-B-O shift does not take place in
these complexes.
The developed method can be applied for the synthesis of
α-CF3-susbtituted ketones using complex 1d as a source of the
trifluoromethyl group (Scheme 4). Thus, ketones were first
silylated, and then unpurified triethylsilyl enol ethers were
trifluoromethylated under standard photocatalysis conditions.
The ability of complexes
1 to undergo single electron
Though precious ruthenium and iridium catalysts dominate
in photoredox area,4 we focused on less costly copper-based
photocatalysts.18,19 1,1-Diphenylethylene (2a) was selected as
reduction was evaluated by cyclic voltammetry (CV)20 (Scheme
4). Indeed, these complexes are reduced readily, with the
potential of –1.22 V (vs SCE) for unsubstituted complex 1a, and
–1.01 V for 1d (Figure 1). The value of reduction potential of
1d suggests that it is reduced much more readily compared to
CF3I (–1.52 V)21 and is similar to Togni iodanes.22 It should also
be pointed out that the previously reported CF3-borate salts
could not be utilized for the generation of the CF3-radical,14
and under conditions of the CV measurements they were
redox inactive23 (Figure 1, right).
a model substrate and its reaction with complexes
1 in MeOH
was evaluated (Table 1). Reactions were performed with 1
mol% of catalyst using blue light (450 nm) for 1 h. With
unsubstituted complex 1a only traces of product 3a were
detected, whereas reagent 1d originating from nicotinic acid
was notably more reactive affording the product in 83% yield
(entries 1-5).
Table 1. Reaction of 1,1-diphenylethylene 2a.
The redox potential for the excited copper complex
+
[Cu(dap)2 */Cu(dap)22+] of –1.43 V18b provides an opportunity
for a facile reduction of complex 1d with the driving force of
0.42 V! To verify the intermediacy of the CF3-radical, the
stoichiometric reaction of complex 1d with Cu(dap)2PF6 in the
presence of TEMPO was carried out, and the compound arising
from the trapping of the CF3-radical (TEMPOCF3, 6) was formed
in 79% yield. Moreover, the reaction of 1d with N-methacryl-
oyl-N-methylaniline also afforded a cyclized product arising
from the trapping of the CF3-radical (see Supp. Inf. for details).
#
1
2
3
4
5
6
7d
8
9
1
Cat.
Cu(dap)2PF6
Cu(dap)2PF6
Cu(dap)2PF6
Cu(dap)2PF6
Cu(dap)2PF6
Cu(dipp)2PF6
Cu(xanthphos)(dmp)PF6
Cu(dmp)2PF6
Cu(dap)2PF6
Cu(dap)2PF6
–
Basea
Y. of 3a, %b
1a
1b
1c
1d
1e
1d
1d
1d
1d
–
1c
< 1
70
83
13
55
38
< 1
95
–
–
–
–
Scheme 3. Transfer of perfluoroalkyl groups.
–
–
–
–
KHCO3
KHCO3
KHCO3
10e 1d
11 1d
–
a 2.7 equiv. b Isolated yield. c Determined by 19F NMR. d 400 LED was used. e In the dark.
Further increase in yield was achieved by addition of
potassium bicarbonate acting as a base (entry 9). The reaction
did not proceed in the dark or in the absence of the catalyst
(entries 10 and 11). Other evaluated copper complexes were
less effective (entries 6-8).
Scheme 4. Trifluoromethylation of ketones.
2 | J. Name., 2012, 00, 1-3
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Table 2. Methoxytrifluoromethylation of alkenes.a
F
F
B
Cu(dap)2PF6 (1%)
KHCO3
F3C
O
CF3
R3
R1
MeO
R1
R3
N
+
R2
MeOH, blue LED, rt,1 h
R2
3
2
MeO2C
1d
F3C
OMe
OMe
MeO
MeO
MeO
OMe
CF3
CF3
CF3
CF3
F3
C
b
3b, 84% (1.5:1)
3c, 79% (1:1)
3d, 62% (11:1)
3e, 65% (3.8:1)
3f
, 95%
3g, 91%
OMe
OMe
MeO
OMe
CF3
OMe
CF3
CF3
CF3
OH
CF3
MeO
Ph
3h, 78% (1:1)
3k, 59% (1.5:1)
3l, 94%
3i
3j, 76%
, 65% (4:1)
OMe
OMe
OMe
OMe
OMe
CF3
CF3
CF3
CF3
CF3
TBSO
THPO
AcO
HO
MeO
3m
3n
3o
3p
3q
, 87%
, 86%
, 95%
, 87%
, 85%
OMe
CF3
OMe
OMe
OMe
O
CF3
CF3
CF3
H
N
N
N3
Cl
Boc
O
3r
3s
, 84%
3t
3u
, 67%
, 91%
, 83%
a Isolated yield. Ratio of isomers is given in parenthesis. b Single diastereomer was formed.
F
F
photoinitiated chain process involving the electron transfer
from radical to complex 1d seems unlikely because: (a) Cu(II)
F
F
B
B
F3C
O
7
F3
C
O
F3C BX3
K
N
N
species is a stronger oxidant than 1d by as much as 1.66 V
[Cu(dap)22+/Cu(dap)2+ +0.65 V], and (b) the redox potentials of
X = F, OMe
1a
1d
MeO2
C
Ered < – 1.7 V
Eox > +1.7 V
Ered = – 1.22 V
Ered = – 1.01 V
F
F
N
F
F
B
B
Figure 1. Redox potentials (vs SCE) and a crystal structure of boron compounds.
+
F3
C
O
O
MeO2
C
N
Unfortunately, we have not been able to perform the Stern-
Volmer quenching studies for 1d and Cu(dap)2PF6, because of
the strong fluorescence of the borate complex16b and weak
fluorescence of the copper catalyst. Of special note is that
reactions involving 1d finish within 1 hour. The quantum yield
of the reaction of complex 1g with 1,1-diphenylethylene (see
Scheme 3) was determined to be 0.6224 that reflects high
efficiency of light utilization.
CF3
MeO2C
F
F
R
B
F3C
O
Cu(II)
N
CF3
R
MeO2C
*
Cu(I)
7
1d
CF3
R
Cu(I)
R
h
ν
The proposed mechanism is shown in Scheme 5. The light
activated Cu(I) catalyst serves as a reducing agent towards
complex 1d generating the CF3-radical, which adds at the
CF3
8
MeOH
H
OMe
double bond. Then, radical
7 is oxidized by Cu(II), and the
Scheme 5. Proposed mechanism.
carbocation 8 is trapped by MeOH. At the same time, the
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than 1d. In particular, for 1 h in methanol solution, only 5%
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converts to other unidentified species.
8
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