Enantioconvergent photoredox radical-radical coupling catalyzed by a chiral-at-rhodium complex

Article abstract of DOI:10.1007/s11426-019-9584-x

Racemic α-chloro imidazol-2-yl-ketones undergo an enantioconvergent photoactivated C–C bond formation with N-aryl glycines catalyzed by a single bis-cyclometalated chiral-at-rhodium catalyst in yields of up to 80% and up to 98% enantiomeric excess (ee). C

Full text of DOI:10.1007/s11426-019-9584-x

SCIENCE CHINA
Chemistry
•
ARTICLES•
https://doi.org/10.1007/s11426-019-9584-x
SPECIAL TOPIC: Organic Free Radical Chemistry
Enantioconvergent photoredox radical-radical coupling catalyzed
by a chiral-at-rhodium complex
†
†
*
Zijun Zhou , Xin Nie , Klaus Harms, Radostan Riedel, Lilu Zhang & Eric Meggers
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany
Received June 30, 2019; accepted August 12, 2019; published online September 26, 2019
Racemic α-chloro imidazol-2-yl-ketones undergo an enantioconvergent photoactivated C–C bond formation with N-aryl gly-
cines catalyzed by a single bis-cyclometalated chiral-at-rhodium catalyst in yields of up to 80% and up to 98% enantiomeric
excess (ee). Control experiments support a mechanism which is initiated by a single electron transfer from N-aryl glycinate to the
photochemically excited rhodium-bound α-chloro imidazol-2-yl-ketone, followed by chloride fragmentation of the α-chlor-
oketone, decarboxylation of the glycinate, and a subsequent highly stereocontrolled radical-radical coupling. This work
showcases the ability of the chiral rhodium catalyst to serve a dual function as chiral Lewis acid and at the same time as the
photoredox active species upon substrate binding.
photoredox catalysis, asymmetric catalysis, visible light, enantioconvergent, radical recombination, chiral-at-metal,
rhodium
Citation:
Zhou Z, Nie X, Harms K, Riedel R, Zhang L, Meggers E. Enantioconvergent photoredox radical-radical coupling catalyzed by a chiral-at-rhodium
complex. Sci China Chem, 2019, 62, https://doi.org/10.1007/s11426-019-9584-x
1
Introduction
Our laboratory contributed to the area of asymmetric
photoredox catalysis with the development of reactive bis-
cyclometalated iridium and rhodium catalysts [4,5]. Our
standard catalysts contain two cis-coordinated cyclometa-
lating 5-(tert-butyl)-2-phenylbenzothiazoles or the analo-
gous benzoxazole ligands which set up a stereogenic metal
center with overall helical chirality and a visible-light-ab-
sorbing chromophore, while two additional exchange-labile
acetonitrile ligands create the site for catalysis (Figure 1(a))
[6,7]. Interestingly, in all of our reported examples on
asymmetric photoredox catalysis, the in situ assembled cat-
alyst-substrate complexes, and not the initial catalysts
themselves, serve as the light-absorbing photoactive species
which then trigger the redox chemistry, and allow for a large
variety of mechanistically distinct asymmetric photoredox
processes catalyzed by single chiral catalysts [4].
The combination of visible light photochemistry and asym-
metric catalysis is attractive from the perspective of sus-
tainability and at the same time provides untapped
opportunities to develop mechanistically unique reaction
schemes [1]. Photoinduced single electron transfer (SET) is a
powerful and mild method to use visible light for activating
chemical transformations by generating radical ions and ra-
dicals as reactive intermediates [2,3]. However, achieving
high enantioselectivities in catalytic asymmetric photoredox
reactions poses significant challenges, firstly due to diffi-
culties in controlling the asymmetric induction with the in-
volved reactive intermediates, and secondly due to
undesirable background reactions without the involvement
of the chiral catalyst.
In our first report back in 2014, we developed an iridium-
catalyzed visible-light-induced enantioselective α-alkylation
of 2-acyl imidazoles with electron-deficient benzyl bromides
†
*
These authors contributed equally to this work.
Corresponding author (email: meggers@chemie.uni-marburg.de)
©
Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019
chem.scichina.com link.springer.com

2
Zhou et al. Sci China Chem
Figure 1 Previous work and this study on asymmetric photoredox α-alkylation using a single chiral-at-metal catalyst (color online).
and phenacyl bromides in excellent yields and with very high
enantioselectivities [8], and we subsequently expanded this
reaction type to α-trichloromethylations, α-trifluoromethyl-
ations, and α-perfluoroalkylations [9]. Key intermediate in
these photoinduced enantioselective α-alkylations is an in-
termediate iridium enolate complex, which is generated by
coordination of the 2-acyl imidazole or 2-acylpyridine to the
iridium center in a bidentate fashion, followed by deproto-
nation (Figure 1(b)). This iridium enolate serves as the
photoinduced initiator of a chain process and at the same
time as an intermediate in the catalytic cycle which reacts
with electron-deficient radicals in a stereocontrolled fashion.
In this work, we now present a new and mechanistically
different strategy to functionalize 2-acyl imidazoles in α-
position using asymmetric photoredox catalysis, namely
employing a single chiral rhodium complex to catalyze an
enantioconvergent photoredox radical-radical coupling
2 Experimental
Representative asymmetric catalysis: a pre-dried 10 mL
Schlenk tube (using a heating gun) was charged with catalyst
Λ-RhS (6.5 mg, 5 mol%), sodium bicarbonate (37.8 mg,
0.45 mmol), 4 Å molecular sieves (50 mg/mmol), 2-acyl
imidazole 1b (0.15 mmol, 1.0 equiv.) and N-phenyl glycine
(2a) (0.6 mmol, 4.0 equiv.) under an atmosphere of nitrogen.
Subsequently, 1,2-dimethoxyethane (1.5 mL) was added via
a syringe under nitrogen atmosphere. The resulting solution
was degassed via a freeze-pump-thaw for three cycles. After
that, the Schlenk tube was sealed and positioned in a cold
room (the reaction temperature was dertermined as 5–7 °C
approximately 2.5 cm from a 3 W blue light emitting diode
(LED) lamp). After 65 h stirring under nitrogen atmosphere,
the reaction solution was directly transferred to a column and
purified by a flash chromatography on a silica gel (n-hexane/
EtOAc=10:1 to 3:1) to afford the analytically pure product
3a as a pale yellow solid (25.0 mg, 72% yield) and with 95%
enantiomeric excess (ee) as determined by high performance
liquid chromatography (HPLC) analysis (column: Daicel
Chiralpak OD–H column 250×4.6 mm; absorption: λ=
(Figure 1(c)). In contrast to our previous work on the pho-
toredox α-functionalization of 2-acyl imidazoles (and 2-
acylpyridines) with highly electron-deficient alkyl groups
[10], here electron-rich α-aminoalkyl groups are in-
corporated in a stereocontrolled manner.

Zhou et al. Sci China Chem
3
2
54 nm; mobile phase: n-hexane/isopropanol=70:30; flow
alyst Λ-IrS [8,14] (5 mol%) under optimized reaction con-
ditions such as stoichiometric amounts of the base NaHCO3,
additional molecular sieves, and 5–7 °C reaction tempera-
ture, we could isolate the expected C–C coupling product 3a,
albeit in a low yield of only 14% (Table 1, entry 1). Due to
our recent success using bis-cyclometalated rhodium instead
of iridium complexes for catalytic asymmetric photo-
chemistry [4b], we next tested Λ-RhS [14,15] under the
same reaction conditions. To our delight, the desired C–C
bond formation product was isolated in 51% yield and 95%
ee (Table 1, entry 2). However, we were not able to further
improve the yield of this reaction and observed that the
bromide substrate 1a slowly decomposed under blue LEDs
irradiation, which could explain the reduced yield (see
Supporting Information online for details). We therefore
replaced the bromide substituent (1a) with a more photo-
stable chloride (1b). Although this is counterintuitive since
the chloride is a weaker leaving group, we found that it is
more stable under the reaction conditions (see Supporting
Information online for details). Indeed, when we reacted the
α-chlorinated 2-acyl imidazole 1b with N-phenyl glycine
(2a) under the standard conditions with Λ-RhS as the cata-
lyst, the C–C coupling product 3a was formed in 72% yield
with 95% ee (entry 3). A deviation from the standard con-
ditions resulted in inferior results (entries 4–11). For ex-
ample, replacing low intensity (3 W) with stronger blue
LEDs (24 W) provided both lower yield and lower en-
antioselectivity (entry 4). Increasing the reaction temperature
rate: 1.0 mL/min; column temperature: 25 °C; retention
times: t (major)=6.4 min, t (minor)=8.0 min). [α] =−41.4°
22
r
r
D
(c 1.0, CH Cl ).
2
2
1
H NMR (300 MHz, CDCl ) δ 7.47–7.41 (m, 5H), 7.34 (t,
3
J=7.5 Hz, 2H), 7.30–7.27 (m, 1H), 7.24 (d, J=0.9 Hz, 1H),
7
1
.20–7.17 (m, 2H), 7.16–7.13 (m, 2H), 7.12 (d, J=0.9 Hz,
H), 6.69 (t, J=7.5 Hz, 1H), 6.60 (d, J=7.5 Hz, 2H), 5.49 (dd,
J=6.6, 2.1Hz, 1H), 3.91 (dd, J=8.4, 4.5 Hz, 1H), 3.49 (q, J=
13
6
1
1
.6 Hz, 1H). C NMR (75 MHz, CDCl ) δ 189.8, 147.7,
3
42.9, 138.3, 137.0, 130.0, 129.3, 129.0, 128.9, 128.8, 127.5,
27.3, 125.7, 117.5, 113.0, 53.0, 46.5, 29.7. HRMS (ESI, m/
+
z) calcd. for C H N O [M+H] : 368.1757, found:
24
22
3
3
68.1754.
3
Results and discussion
Jiang and co-workers [11–13] recently reported an en-
antioconvergent alkylation of α-bromoketones with N-aryl
amino acids via catalytic asymmetric photoredox radical
coupling enabled by dual catalysis using a chiral phosphoric
acid in combination with a dicyanopyrazine photosensitizer.
Inspired by this work, we were envisioning to achieve an
analogous coupling by instead using a single bis-cyclome-
talated iridium or rhodium catalyst. Indeed, when we reacted
α-brominated 2-acyl imidazole 1a with N-phenyl glycine
(2a) under blue light irradiation and employing iridum cat-
a)
Table 1 Initial experiments and catalyst optimization
b)
c)
d)
Entry
Substrate
1a
Catalyst
Λ-IrS
Conditions
Standard
Standard
Standard
Yield (%)
ee (%)
e)
1
2
3
4
5
6
7
8
9
14
51
72
64
52
67
45
57
n.d.
95
95
91
94
94
90
91
–
1a
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
Λ-RhS
No cat.
Λ-RhS
Λ-RhS
1b
1b
24 W blue LED
r.t. instead of 5–7 °C
2,6-Lutidine as base
No base
1b
1b
1b
1b
No 4 Å MS
f)
1b
Standard
0
f)
1
0
1
1b
No light
0
–
g)
1
1b
Under air
0
–
a) Standard conditions: 1a or 1b (0.15 mmol), 2a (0.6 mmol), Λ-RhS (0.0075 mmol) and NaHCO (0.45 mmol) in 1,2-dimethoxyethane (1.5 mL) were
3
stirred at 5–7 °C under N for 65 h with blue LEDs (3 W) irradiation; b) deviations from standard reaction conditions are shown; c) yield of isolated product;
2
d) ee values were determined by HPLC analysis on chiral stationary phase; e) not determined; f) no reaction was detected; g) 1b was consumed and 3a was
not detected.

4
Zhou et al. Sci China Chem
to room temperature reduced the yield of the reaction (entry
). NaHCO appears to be the optimal base for this reaction
formed a substrate scope (Figure 2). A bulky N-mesityl
group at the imidazole moiety of the 2-acyl imidazole sub-
strate was well tolerated and provided the aminoalkylation
product 3b in 71% yield with 93% ee. A strongly electron-
withdrawing CF3 group in para-position of the phenyl
moiety of the 2-acyl imidazole afforded the aminoalkylation
product 3c in 74% yield with higher enantioselectivity of
5
3
(see entry 6 for an example and the Supporting Information
online for further base optimizations), whereas omitting the
base altogether reduced the yield to 45% with a reduced 90%
ee (entry 7). Molecular sieves were confirmed as an additive
for improving yield and enantioselectivity of product for-
mation (entry 8). Finally, control experiments demonstrate
that the rhodium catalyst, visible light, and the avoidance of
air are all required for the formation of 3a (entries 9–11).
With optimized reaction conditions in hand, we next per-
97% ee. Replacing the CF group with a fluorine resulted in
3
an unexpected drop in yield (64% for 3d) and enantios-
electivity (89% ee), whereas chlorine (75% yield, 95% ee for
3e) and bromine (70% yield, 92% ee for 3f) provided sa-
Figure 2 Substrate scope. DME=1,2-dimethoxyethane (color online).

Zhou et al. Sci China Chem
5
tisfactory results. A methyl group was well-tolerated at the
para- and meta-position (products 3g and 3h, respectively),
but led to a deterioration in yields (62%) and enantiomeric
excess (76% ee) when introduced in the sterically hindering
ortho-position (product 3i). An electron-donating para-
methoxy group provided the aminoalkylation product 3j in a
modest yield of 65% but with satisfactory 93% ee. More
extended aromatic systems such as 4-biphenyl (product 3k)
and 1- and 2-naphthyl substituents (products 3l and 3m) were
also investigated with the 2-naphthyl moiety giving the best
results with 80% yield and 97% ee. As a limitation, without
an aromatic moiety in α-position of the 2-acyl imidazole
substrates, the desired radical-radical coupling product was
not formed (see Supporting Information online for details).
Finally, we varied the N-phenyl glycine substrate by in-
troducing electron-withdrawing substituents (F, Cl, Br) or an
electron-donating methoxy group into the para-position of
the phenyl moiety. While the halogen substituents provided
the aminoalkylation products 3n–3p with satisfactory results
cyclometalated iridium and rhodium catalysts [4]. The cat-
alytic cycle is initiated by the N,O-bidentate coordination of
the racemic 2-acyl imidazole substrate to the rhodium cata-
lyst under the release of the two labile acetonitrile ligands to
form the chelate I. Complex I constitutes the in situ as-
sembled relevant photoactive species and converts to its
photoexcited state (intermediate II) upon absorption of blue
light. This photoexcited rhodium/substrate complex II is a
strong oxidant [16] and facilitates a single electron transfer
(SET) from N-arylglycinate to the photoexcited complex II,
to provide an amine radical cation and a rhodium-
coordinated ketyl III. Ketyl III fragments under the release
of a chloride to form a catalyst-bound prochiral radical (IV).
At the same time, the glycinate amine radical cation releases
CO to provide an intermediate α-aminoalkyl radical [17,18]
2
which undergoes a stereocontrolled radical-radical coupling
[19,20] with the persistent catalyst-bound radical IV [21], to
provide the rhodium-coordinated C–C coupling product V
[22]. The persistent radical effect can explain why no un-
desirable homo-coupling was observed [21]. After product
release and coordination of new substrate, a new catalytic
cycle can be initiated (V→I).
This proposed mechanism is backed by a number of ex-
periments. First, visible light and rhodium catalyst are es-
sential for this reaction to proceed (Table 1, entries 9 and 10),
and no product is formed in the presence of air, which is
consistent with a radical pathway (Table 1, entry 11). A ra-
dical trapping experiment with (2,2,6,6-tetramethylpiper-
idin-1-yl)oxyl (TEMPO) (6 equiv.), which completely sup-
presses any product formation (Figure 4(a)), and electron
paramagnetic resonance (EPR) experiments (see Supporting
Information online) further support the involvement of free
(67%–78% yield, 88%–93% ee), the methoxy group af-
forded the C–C coupling product 3q only with 42% yield and
just 6% ee. N-methylated phenyl glycine was also tested as a
substrate which provided a very low yield of the desired
product (see Supporting Information online for details). To
summarize the substrate scope, different functional groups at
the phenyl moiety of 2-acyl imidazole substrates were well
tolerated with an exception of sterically demanding sub-
stituents. Substituents on the phenyl moiety of the N-phenyl
glycines should be electron-withdrawing instead of electron-
donating in order to achieve high enantioselectivity.
The proposed mechanism is shown in Figure 3 and based
on our extensive studies on the photochemistry of our bis-
Figure 3 Proposed mechanism of the rhodium-catalyzed enantioconvergent photoredox coupling (color online).

6
Zhou et al. Sci China Chem
rhodium center results in a blocking of the prochiral Si-face
of the prochiral radical by one of the tert-butyl groups to
achieve a high asymmetric induction (Figure 4(b)).
In conclusion, we here reported a photochemical method to
introduce α-aminoalkyl groups in α-position of 2-acyl imi-
dazoles in a stereocontrolled fashion through an en-
antioconvergent replacement of a chloride substituent. The
photoredox reaction is catalyzed by a single chiral rhodium
catalyst which fulfills several crucial functions at the same
time [25]. The catalyst/substrate complex constitutes the
visible light absorbing photoactive species, the Lewis acidity
of the rhodium center facilitates the reduction of the chelated
substrate by SET, the rhodium complex stabilizes the co-
ordinated ketyl intermediate, and finally the stereogenic
rhodium center with the helical arrangement of the two cy-
clometalated ligands provides an excellent asymmetric in-
duction in the radical-radical recombination step. This
mechanism therefore complements our previous work on
iridium- and rhodium-catalyzed asymmetric photocatalysis.
Acknowledgements
This work was supported by the Deutsche For-
schungsgemeinschaft (ME 1805/17-1).
Conflict of interest The authors declare that they have no conflict of
interest.
Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
editing. The responsibility for scientific accuracy and content remains en-
tirely with the authors.
Figure 4 Mechanistic investigations. For standard reaction conditions see
Table 1. X-ray structure: CCDC 1936355 (color online).
1
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1
0
For another approach to incorporate α-aminoalkyl groups in α-position
of 2-acyl imidazoles, see: Wang C, Zheng Y, Huo H, Röse P, Zhang
L, Harms K, Hilt G, Meggers E. Chem Eur J, 2015, 21: 7355–7359
Li J, Kong M, Qiao B, Lee R, Zhao X, Jiang Z. Nat Commun, 2018, 9:
20 For computational investigations on the stereoselectivity of asym-
metric radical reactions with chiral-at-metal catalysts, see: (a)
Tutkowski B, Meggers E, Wiest O. J Am Chem Soc, 2017, 139: 8062–
8065; (b) Chen S, Huang X, Meggers E, Houk KN. J Am Chem Soc,
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21 For the persistent radical effect, see: (a) Studer A. Chem Eur J, 2001,
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10.1002/anie.201903726
11
2445
1
2
For related work from Jiang’s group regarding asymmetric photoredox
chemistry involving α-aminoalkyl radicals, see: (a) Yin Y, Dai Y, Jia
H, Li J, Bu L, Qiao B, Zhao X, Jiang Z. J Am Chem Soc, 2018, 140:
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Chai G, Qiao B, Zhao X, Jiang Z. Org Lett, 2018, 20: 6298–6301;
22 A related radical-radical coupling between a rhodium-coordinated α-
carbonyl radical and an α-aminoalkyl radical was proposed by us in a
mechanistically distinct dual redox catalysis system, see: (a) Ma J,
Harms K, Meggers E. Chem Commun, 2016, 52: 10183–10186; (b)
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(e) Cao K, Tan SM, Lee R, Yang S, Jia H, Zhao X, Qiao B, Jiang Z. J
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1
3
For asymmetric photoredox chemistry involving α-aminoalkyl radi-
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23 Huang X, Zhang Q, Lin J, Harms K, Meggers E. Nat Catal, 2019, 2:
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016, 22: 6519–6523; (b) Ma J, Lin J, Zhao L, Harms K, Marsch M,
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25 For a recent example using a single chiral copper complex for a
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(
(
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