Enantioselective, catalytic trichloromethylation through visible-light-activated photoredox catalysis with a chiral iridium complex

Article abstract of DOI:10.1021/jacs.5b06010

An enantioselective, catalytic trichloromethylation of 2-acyl imidazoles and 2-acylpyridines is reported. Several products are formed with enantiomeric excess of ≥99%. In this system, a chiral iridium complex serves a dual function, as a catalytically active chiral Lewis acid and simultaneously as a precursor for an in situ assembled visible-light-triggered photoredox catalyst.

Full text of DOI:10.1021/jacs.5b06010

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Enantioselective, Catalytic Trichloromethylation through Visi-
ble-Light-Activated Photoredox Catalysis with a Chiral Iridium
Complex
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Haohua Huo,† Chuanyong Wang,† Klaus Harms,† and Eric Meggers*,†,‡
†
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse, 35043 Marburg, Germany
‡ College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, People’s Republic of China
ABSTRACT: An enantioselective, catalytic trichlorometh-
ylation of 2-acyl imidazoles and 2-acyl pyridines is report-
ed. Several products are formed with enantiomeric excess
of ≥99%. In this system, a chiral iridium complex serves a
dual function, as a catalytically active chiral Lewis acid
and simultaneously as a precursor for an in situ assembled
visible-light-triggered photoredox catalyst.
Visible light constitutes an environmentally friendly
and sustainable source of energy for activating chemical
transformations, whereas asymmetric catalysis holds
Figure 1. Chiral iridium complexes for merging visible-light-
activated photoredox catalysis with Lewis acid catalysis.
promise as one of the most economical strategies for the
ited.9,10 Notably, Zakarian and co-workers developed an
synthesis of non-racemic compounds. Interfacing asym-
metric catalysis with visible light activation is therefore an
area of high current interest.1 Photosensitization provides
the opportunity to induce single electron transfer (SET)
processes under very mild conditions, thereby producing
intermediate radical ions and radicals with useful reactivi-
ties.2-4 However, at the same time, the high reactivities of
such intermediates pose a significant challenge for inter-
facing them with asymmetric catalysis, indicated by the
still limited number of mechanistically distinct visible-
light-driven catalytic asymmetric reaction schemes.5
We recently introduced a simple chiral-at-metal iridi-
um complex (Λ-IrS, Figure 1) as an effective asymmetric
photoredox catalyst for the visible-light-induced enanti-
oselective α-alkylation of 2-acyl imidazoles with electron
deficient benzyl bromides and phenacyl bromides.6 De-
spite its novelty, one can criticize that α-alkylations of
carbonyl compounds with primary organobromides may
be well executed under SN2 conditions without the abso-
lute need for involving redox chemistry.7 Going beyond
our previous proof-of-principle demonstration, we were
therefore seeking an application in which redox catalysis
is highly advantageous or even required. As a result, we
here wish to report the first method for an enantioselec-
tive, catalytic trichloromethylation through visible light
activated photoredox catalysis.
elegant diastereoselective Ru-catalyzed redox-mediated
radical addition to titanium enolates.10
We started our study by investigating the enantioselec-
tive α-trichloromethylation of 2-acyl imidazoles. Encour-
agingly, when we reacted 2-acyl imidazole 1a with BrCCl3
in the presence of iridium catalyst Λ-IrS and the base
Na2HPO4 under visible light irradiation, we obtained the
trichloromethylated product 2a in 69% yield and with
94% ee (Table 1, entry 1). Using NaHCO3 provided 2a even
in 77% yield and with outstanding 99.7% ee (entry 2). In
the absence of any base, the yield and enantiomeric ex-
cess deteriorated (entry 3). More importantly, in the pres-
ence of air no trichloromethylation was observed, but
instead a different product was obtained, namely the α-
brominated 2-acyl imidazole 3 (entry 4). Compound 3 was
also the only observed product in the dark (entry 5), while
conversely under visible light irradiation no traces of 3
were generated (entry 2). Obviously, in this system, light
induces a complete switch in the product formation and
the
reaction
mechanism:
Whereas
the
α-
trichloromethylation (2a) can be rationalized with photo-
redox chemistry, the α-bromination (3) in the absence of
light must rely on closed-shell SN2 enolate chemistry with
BrCCl3 serving as an electrophilic brominating reagent.11
Apparently, the reductive activation of BrCCl3 is required
for the observed α-trichloromethylation. In this respect it
is worth noting that the closely related iridium complex
Λ-IrO provides inferior results (entry 6), in line with our
Trichloromethyl groups are present in natural products
and contribute to their pharmacological properties.8
However, methods for the stereoselective implementation
of CCl3 groups as part of stereogenic carbons are lim-
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recent experimental observation that this catalyst is more
lyst (intermediate I), followed by base-promoted depro-
tonation to an electron-rich iridium enolate (intermediate
suitable for catalyzing oxidative chemistry.12
1
2
3
4
Table 1. Initial experiments for the catalytic enantiose-
lective α-trichloromethylation activated by visible lighta
5
6
7
8
9
hνb
entry catalyst
additive
2a (%)c 3 (%)c ee (%)d
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yes Na2HPO4
yes NaHCO3
yes none
69e
77
18
0
0
94
99.7
87
0
Λ-IrS
2
0f
Λ-IrS
3
4
5
0
Λ-IrS
Λ-IrS
Λ-IrS
Λ-IrO
yes NaHCO3, air
no NaHCO3
yes NaHCO3
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0
0
0
6
a
13
93
Reaction conditions: 1a and BrCCl3 (6 equiv) with catalyst
(2 mol%) in MeOH/THF 4:1 at room temperature for 17-29 h,
optional with base (1.1 equiv) and under light. Light source
20 W compact fluorescence lamp (CFL). Isolated yields.
Enantioselectivities of 2a determined by HPLC on chiral sta-
b
c
d
e
tionary phase. HCl elimination product was isolated in a
yield of 11%. f See Supporting Information for NMR experi-
ments which confirm that no detectable amounts of com-
pound 3 are formed.
Next, we evaluated the scope of the visible light activat-
ed enantioselective trichloromethylation. Figure 2 shows
the Λ-IrS-catalyzed α-trichloromethylation of twelve 2-
acyl imidazoles, with the products (62-96% yield) featur-
ing different substituents at the stereogenic carbon, such
as phenyl groups with electron donating or electron ac-
cepting groups (2a-f), a naphthyl (2g) and thiophenyl
(2h) moiety, an ether (2i), and aliphatic groups (2j-l). It is
worth noting that ten of these products are formed with
an enantiomeric excess of 99% or higher. For product 2c,
absolute no traces of the minor enantiomer can be de-
tected (≥99.9% ee), demonstrating the high degree of
stereocontrol that can be reached in this catalytic reac-
tion.
Finally, we were wondering if we can replace the imid-
azole moiety with another coordinating group and we
selected 2-acyl pyridines due to the prevalence of pyri-
dines and piperidines in bioactive compounds (Figure 3).13
Revealingly, with acetonitrile as a cosolvent and at a
higher catalyst loading of 4 mol% for most examples to
compensate for overall slower reaction rates, 2-acyl pyri-
dines 4 were converted to their α-trichloromethylated
products 5 in satisfactory to high yields (65-91%) and with
high enantioselectivities (90-99.6% ee).
a
Figure 2. Substrate scope with 2-acyl imidazoles. Higher
catalyst loading to increase yield and enantioselectivity.
O
O
1 BrCCl3 (6 eq), 2,6-lutidine (1.1 eq)
R
N
R1
N
CCl3
-IrS (2-4 mol%)
CFL (20 W)
R2
R2
4
5
MeOH/MeCN 1:1
22-53 h at 40 °C
O
O
O
N
Me
N
Ph
N
Me
CCl3
CCl3
CCl3
Me
5a, 24 h, 4 mol%
5b, 36 h, 4 mol%
5c, 45 h, 4 mol%
65% yield, 93% ee
83% yield, 99.6% ee
67% yield, 95% ee
O
O
O
N
Me
N
Me
N
Me
CCl3
CCl3
CCl3
Ph
Cl
Br
5d, 53 h, 4 mol%
5e, 24 h, 4 mol%
5f, 22 h, 2 mol%
68% yield, 92% ee
71% yield, 94% ee
81% yield, 95% ee
O
O
O
N
Me
N
Ph
N
Me
CCl3
A plausible mechanism is shown in Figure 4, which can
be classified as an electron-transfer-catalyzed nucleo-
philic substitution via SRN1.3,4,14 Accordingly, the catalytic
cycle is initiated by bidentate coordinating of the 2-acyl
imidazole or 2-acyl pyridine substrate to the iridium cata-
CCl3
CCl3
Br
nPr
5g, 48 h, 4 mol%
5h, 44 h, 4 mol%
5i, 48 h, 4 mol%
72% yield, 90% ee
91% yield, 96% ee
67% yield, 94% ee
Figure 3. Substrate scope with 2-acyl pyridines.
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Figure 4. Putative mechanism for the visible light activated
II). The subsequent addition of a reductively generated
1
2
3
4
5
6
7
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asymmetric catalysis. SET = single electron transfer, PS =
photosensitizer in form of enolate intermediate II.
electrophilic trichloromethyl radical to the nucleophilic
double bond provides an iridium-coordinated ketyl radi-
cal (intermediate III), which is oxidized to an iridium-
coordinated product (intermediate IV), followed by prod-
uct release. In the case of the stronger coordinating 2-acyl
pyridines,15 the replacement of coordinated product with
new substrate (IV→I) is probably mediated by an initial
coordination of one or two acetonitriles, thus explaining
the requirement for acetonitrile as a cosolvent.
9
enolate complex II
cationic complex I
rac-IrS
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5
I0 / I
4
9
3
2
1
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The described catalytic cycle intertwines with a photo-
redox cycle that generates a trichloromethyl radical upon
SET from the photoactivated photosensitizer to BrCCl3
and subsequent release of bromide. A determined quan-
tum yield of 5 indicates that the trichloromethy radical is
also formed by direct electron transfer from the strongly
reducing ketyl radical intermediate III to BrCCl3, thereby
leading to a chain propagation. The formation of transient
trichloromethyl radicals could be verified by trapping
with an electron-rich alkene (see Supporting Infor-
mation). Importantly, previous mechanistic experiments6
and a Stern-Volmer plot shown in Figure 5 strongly sug-
gest that it is the neutral intermediate iridium enolate
complex (II) which serves as the active photosensitizer, as
its photoexcited state is quenched by BrCCl3 significantly
faster compared to the cationic complexes I and rac-IrS.
Furthermore, the single-electron-oxidized complex II
(corresponding to PS+ in Figure 4) was trapped efficiently
by TEMPO (see Supporting Information). Thus, chiral
iridium enolate II is a key intermediate which provides
the crucial asymmetric induction in the reaction with
trichloromethyl radicals, in analogy to Zakarian’s radical
addition to metal enolates,10 and simultaneously serves as
the visible-light-activated photosensitizer for triggering
electron transfer catalysis. It is also worth noting that
enolate II is a common intermediate of both the light and
dark reaction cycle, and the observed light-induced
switch in product formation (Table 1) can be explained
with an outcompetition of the electrophilic bromination
by the fast radical addition step.16
0
1
2
3
4
5
BrCCl3 (mM)
Figure 5. Luminescence quenching experiments. I0 and I =
luminescence intensities in the absence and presence of the
indicated concentrations of BrCCl3, respectively. N-Methyl
instead of N-phenyl imidazole derivatives were used for I and
II due to higher stability of the enolate complex.
In conclusion, we here reported the first example of an
enantioselective, catalytic trichloromethylation. Excellent
enantioselectivities are observed with multiple reactions
reaching 99% ee and even higher. The method is based on
a chiral iridium complex which serves a dual function, as
a catalytically active chiral Lewis acid and simultaneously
as a precursor for an in situ assembled visible-light-
triggered photoredox catalyst. The development of relat-
ed enantioselective perfluoroalkylations is underway in
our laboratory.
ASSOCIATED CONTENT
Supporting Information. Experimental details and chiral
HPLC traces. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
meggers@chemie.uni-marburg.de
Notes
The authors declare no competing financial interest.
[Ir]
O
baseH+
-
N
R
CCl3
Br
ACKNOWLEDGMENT
II
base
We gratefully acknowledge funding from the German Re-
search Foundation (ME 1805/11-1) and the Philipps-
Universität Marburg. H.H. thanks the China Scholarship
Council for a stipend.
[Ir]+
N
[Ir]
O
O
N
R
R
asymmetric
catalysis
-IrS
BrCCl3
BrCCl3
CCl3
I
III
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