Visible-Light-Activated Enantioselective Perfluoroalkylation with a Chiral Iridium Photoredox Catalyst

Article abstract of DOI:10.1055/s-0035-1561284

A visible-light-activated enantioselective radical perfluoroalkylation of 2-acyl imidazoles with perfluoroalkyl iodides (CF₃I, C₃F₇I, C₄F₉I, C₆F₁₃I, C₈F₁₇I

Full text of DOI:10.1055/s-0035-1561284

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Visible-Light-Activated Enantioselective Perfluoroalkylation with
a Chiral Iridium Photoredox Catalyst
Haohua Huoa
Xiaoqiang Huanga
Xiaodong Shena
Klaus Harmsa
Eric Meggers*a,b
a Fachbereich Chemie, Philipps-Universität Marburg,
Hans-Meerwein-Straße 4, 35043 Marburg, Germany
b College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005, P. R. of China
meggers@chemie.uni-marburg.de
Received: 31.10.2015
Accepted: 18.11.2015
Published online: 23.12.2015
DOI: 10.1055/s-0035-1561284; Art ID: st-2015-r0855-c
cept to develop a photoactivated enantioselective perfluo-
roalkylation9–11 of 2-acyl imidazoles. The photoredox
chemistry through intermediate perfluoroalkyl radicals oc-
curs at ambient temperature and requires visible light. High
enantioselectivities with up to >99.5% ee are observed.
We initiated our study by investigating the enantiose-
lective perfluoroalkylation of 2-acyl imidazoles by using
the previously established dual-function chiral Lewis ac-
id/photoredox catalyst Λ-Ir1 (Table 1).5,7 When 2-acyl imid-
azole 1a′ reacted with C4F9I (6 equiv) in the presence of
NaHCO3 (1.5 equiv) and 4 mol% Λ-Ir1, the desired α-perfluo-
roalkylation product 2a′ was produced in a disappointing
yield of 24% and with unsatisfactory enantioselectivity of
92% ee (entry 1). Increasing the steric congestion of the 2-
acyl imidazole by replacing the N-Ph substituent (1a′) with
N-(2-MePh) (1a) improved the enantioselectivity but the
yield remained low (29%; entry 2).
However, we found that replacing Λ-Ir1 with the related
catalyst Λ-Ir2 afforded the perfluoroalkylation product 2b
with satisfactory yield (78%) and excellent enantioselectivi-
ty ee (99%; Table 1, entry 3). The catalyst loading of Λ-Ir2
could even be reduced to 2 mol% without affecting the per-
formance (entry 4). Control experiments conducted either
in the absence of the catalyst or in the dark confirmed that
this reaction requires the combined presence of the iridium
catalyst and light, otherwise no traces of product were ob-
served (entries 5 and 6). Furthermore, the presence of air
completely suppresses the perfluoroalkylation (entry 7),
thus supporting the conclusion that this process constitutes
a photoredox process that proceeds via intermediate per-
fluoroalkyl radicals.
Abstract A visible-light-activated enantioselective radical perfluoroal-
kylation of 2-acyl imidazoles with perfluoroalkyl iodides (CF3I, C3F7I,
C4F9I, C6F13I, C8F17I and C10F21I) and perfluorobenzyl iodide at the α-po-
sition of the carbonyl group is reported. Enantioselectivities with up to
>99.5% ee are achieved. The process uses a dual-function chiral Lewis
acid/photoredox catalyst at loadings of 2–4 mol% and constitutes a re-
dox-neutral, electron-catalyzed reaction that proceeds via intermediate
perfluoroalkyl radicals.
Key words photoredox catalysis, asymmetric catalysis, visible light,
perfluoroalkylation, radical reaction, electron catalysis
Visible-light-driven asymmetric catalysis promises to
provide an economical and environmentally sustainable
strategy for the synthesis of nonracemic chiral molecules.1
Photoactivation permits single electron transfer (SET) steps
to be induced under very mild reaction conditions, thereby
generating intermediate radical ions and radicals with use-
ful reactivities, which expands the mechanistic toolbox for
developing novel synthetic transformations.2,3 However, the
often very high reactivities and concomitant short lifetimes
of these odd-electron intermediates comprise a significant
challenge for interfacing them with asymmetric catalysis.4
Recently, our laboratory reported several examples of
cooperative photoredox and asymmetric catalysis using a
single chiral iridium5–7 or rhodium8 complex, which serves
both as a photosensitizer to induce and catalyze redox
chemistry and, at the same time, as an asymmetric catalyst.
We developed a visible-light-activated enantioselective α-
alkylation of 2-acyl imidazoles with electron-deficient ben-
zyl bromides and phenacyl bromides,5 as well as an enantio-
selective, catalytic trichloromethylation of 2-acyl imidaz-
oles and 2-acylpyridines.7 Here, we further advance the
dual-function chiral Lewis acid/photoredox catalyst con-
The structure of catalyst Δ-Ir2 is shown in Figure 1. This
compound bears two cyclometalating 2-phenylbenzothia-
zole ligands in addition to two exchange-labile acetonitrile
groups; the chirality originates exclusively from metal cen-
trochirality and thereby creates a C2-symmetrical propeller-
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Table 1 Initial Experiments and Optimization of the Visible-Light-Induced Enantioselective Perfluoroalkylationa
Entry
Ar
Ph
Catalyst (mol%)b
Lightc
Yield (%)d
ee (%)e
1
2
3
4
5
6
7f
Λ-Ir1 (4.0)
Λ-Ir1 (4.0)
Λ-Ir2 (4.0)
Λ-Ir2 (2.0)
Λ-Ir2 (2.0)
none
yes
yes
yes
yes
no
24
29
78
79
0
92
2-MeC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
2-MeC6H4
98
99
99
n.d.
n.d.
n.d.
yes
yes
0
Λ-Ir2 (2.0)
0
a Reaction conditions: 1a or 1b (1 equiv), C4F9I (6 equiv), NaHCO3 (1.5 equiv), catalyst (0–4 mol%), MeOH–THF (4:1), r.t., 34–46 h.
b Catalyst loading (mol%) in parentheses.
c Light source: 21 W compact fluorescent lamp (CFL).
d Isolated yield.
e Determined by chiral HPLC analysis; n.d. = not determined.
f Under air atmosphere.
type coordination sphere.12,13 Compared with Ir1, Ir2 con-
tains two additional t-Bu groups at the phenyl moieties.
This modification raises the HOMO and renders Ir2 a better
electron donor in both the ground and excited state,14
which is apparently beneficial for the perfluoroalkylation
reported herein.
The scope of this reaction with respect to the 2-acyl im-
idazole substrate is shown in Scheme 1.15 Satisfactory yields
(59–90%) and excellent enantioselectivities (96–99% ee)
were achieved for the introduction of a C6F13 substituent
into the α-position of 2-acyl imidazoles, providing the
products 3a–h bearing aromatic (3a–d) or aliphatic (3e–g)
substituents in the α-position to the carbonyl group. Even
3h, bearing an aryl ether, was tolerated. We also investigat-
ed the scope of the reaction with respect to the perfluoroal-
kyl groups, synthesizing the perfluoroalkylated products
3i–n. As shown in Scheme 2, CF3, C3F7, C4F9, C6F13, and C10F21
substituents can be introduced in a highly enantioselective
fashion (3i–m). Furthermore, perfluorobenzylation (3n)
was achieved in 93% yield, providing virtually only a single
enantiomer (>99.5% ee), demonstrating the high asymmet-
ric induction that can be achieved in this asymmetric pho-
toredox catalysis.
The proposed mechanism for the perfluoroalkylation
involves the intermediate iridium(III) enolate complex that
is highlighted in Scheme 3, which is expected to act as the
chiral reaction partner for the electron-deficient perfluoro-
alkyl radicals and, simultaneously, serves as the active pho-
tosensitizer (II + hν → II* → II+ + e–). Accordingly, coordina-
Figure 1 Crystal structure of Δ-Ir2. ORTEP drawing with 30% probabil-
ity thermal ellipsoids. The counterion is omitted.
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cle. The electron that is released upon oxidation of the ketyl
intermediate (III→IV + e–) either flows into the photoredox
cycle by regenerating the oxidized enolate photoredox sen-
sitizer (II+ + e– → II) or directly reduces a perfluoroalkyl ha-
lide substrate and thereby leads to a chain process. This
process can be classified as a redox-neutral, electron-trans-
fer-catalyzed (electron-catalyzed) reaction.17,18
In summary, we have reported a visible-light-activated,
highly enantioselective perfluoroalkylation of 2-acyl imid-
azoles with perfluoroalkyl iodides and perfluorobenzyl io-
dide. The process uses a dual-function chiral Lewis ac-
id/photoredox catalyst at loadings of 2–4 mol% and consti-
tutes a redox-neutral, electron-catalyzed reaction that
proceeds via intermediate perfluoroalkyl radicals. This
work demonstrates the generality of the dual-function chi-
ral Lewis acid/photoredox catalyst concept. From the per-
spective of the catalyst, it is intriguing that the metal center
is capable of serving multiple functions at the same time: it
constitutes the exclusive center of chirality (only achiral li-
Scheme 1 Substrate scope with respect to 2-acyl imidazoles
tion of 2-acyl imidazole substrate 1 into Λ-Ir2 under release
of the two acetonitrile ligands generates the substrate-co-
ordinated intermediate I, which, upon deprotonation, sub-
sequently converts into the key intermediate, namely eno-
late complex II. The electron-rich π-system of the enolate
double bond enables a rapid reaction with the electron-de-
ficient perfluoroalkyl radicals, which themselves are gener-
ated by a SET-reduction of the corresponding perfluoroalkyl
halides.16 The highly stereoselective radical addition gener-
ates an intermediate iridium-coordinated ketyl III, which is
strongly reducing and converts into iridium-coordinated
product IV upon oxidation. Release of the product and coor-
dination to a new substrate then leads to a new catalytic cy-
Scheme 2 Substrate scope with respect to perfluoroalkyl iodides and
perfluorobenzyl iodide
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Scheme 3 Plausible mechanism for the photoactivated asymmetric perfluoroalkylation of 2-acyl imidazoles. The proposed mechanism involves the
highlighted intermediate iridium(III) enolate complex, which likely serves as the active photosensitizer and the chiral reaction partner for the electron-
deficient radicals.
gands), the catalytically active Lewis acid center, and addi-
tionally functions as the key component of the photosensi-
tizer that is formed in situ.
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Acknowledgment
H.H. and X.H. contributed equally to this study. This work was sup-
ported by the German Research Foundation (ME 1805/11-1) and the
Philipps-Universität Marburg. H.H. thanks the China Scholarship
Council for a stipend.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561284.
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(15) General photolysis procedure: A dried 10 mL Schlenk tube was
charged with catalyst Λ-Ir2 or Δ-Ir2 (2 or 4 mol%), NaHCO3
(25.2 mg, 0.3 mmol, 1.1 equiv), and the corresponding 2-acyl
imidazole (0.2 mmol, 1.0 equiv). The tube was purged with
nitrogen and MeOH–THF (4:1, 0.5 mL) was added by using a
syringe, followed by the perfluoroalkyl iodide (6–10 equiv). The
reaction mixture was degassed in three freeze-pump-thaw
cycles, then the vial was sealed and positioned approximately 5
cm from a 21 W compact fluorescent lamp (CFL). The reaction
was stirred at room temperature for the indicated time (moni-
tored by TLC) under a nitrogen atmosphere.
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