Organocatalytic Enantioselective Protonation for Photoreduction of Activated Ketones and Ketimines Induced by Visible Light

Article abstract of DOI:10.1002/anie.201707899

The first catalytic asymmetric photoreduction of 1,2-diketones and α-keto ketimines under visible light irradiation is reported. A transition-metal-free synergistic catalysis platform harnessing dicyanopyrazine-derived chromophore (DPZ) as the photoredox catalyst and a non-covalent chiral organocatalyst is effective for these transformations. With the flexible use of a chiral Br?nsted acid or base in H⁺ transfer interchange to control the elusive enantioselective protonation, a variety of chiral α-hydroxy ketones and α-amino ketones were obtained with high yields and enantioselectivities.

Full text of DOI:10.1002/anie.201707899

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Accepted Article
Title: Organocatalytic Enantioselective Protonation for Photoreduction
of Activated Ketones and Ketimines Induced by Visible Light
Authors: Lu Lin, Xiangbin Bai, Xinyi Ye, Xiaowei Zhao, Choon-Hong
Tan, and Zhiyong Jiang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707899
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10.1002/anie.201707899
Angewandte Chemie International Edition
COMMUNICATION
Organocatalytic Enantioselective Protonation for Photoreduction
of Activated Ketones and Ketimines Induced by Visible Light
Lu Lin,[a] Xiangbin Bai,[a] Xinyi Ye,[b] Xiaowei Zhao,[a] Choon-Hong Tan,[b] and Zhiyong Jiang*[a]
strong basicity. Accordingly, we hypothesized that a chiral
Brønsted acid (BA*−H) or Brønsted base (BB*), which can
abstract an H+ from R3N+• to form +BB*−H, would perform H+
transfer interchange, providing a practical opportunity to achieve
stereocontrol for enantioselective protonation (Scheme 1B). In
conjunction with our research interest in asymmetric hydrogen-
bonding catalysis for enantioselective protonation[9] and
photoredox catalysis,[10] we were thus fascinated by the possibility
of achieving the asymmetric photoredox reduction of 1,2-diketones
through a dual catalysis platform[8,10b,11-13] using an extrinsic H-
bonding organocatalyst. Significant challenges in this task include
the existence of a racemic background process occurring directly
via the intrinsic redox catalytic cycle, which decreases the
enantioselectivity; the difficulty of the enantioselective
manipulation of the small H atom to generate the stereocenter,
which has not yet been developed for asymmetric photoredox
catalysis; and the possible racemization of the C−O stereocenter in
basic meida,[4c,5] compromising the enantiomeric excess of the
products.
Abstract: The first catalytic asymmetric photoreduction of 1,2-
diketones and α-keto ketimines under visible light irradiation is
reported.
A transition-metal-free synergistic catalysis platform
harnessing dicyanopyrazine-derived chromophore (DPZ) as the
photoredox catalyst and a non-covalent chiral organocatalyst is
effective for these transformations. With the flexible use of a chiral
Brønsted acid or base in H+ transfer interchange to control the
elusive enantioselective protonation, a variety of chiral α-hydroxy
ketones and α-amino ketones were obtained with high yields and
enantioselectivities.
Catalytic chemical transformation induced by visible light often
provides an economical and sustainable approach to construct
significant molecules.[1] For example, the [Ru(bpy)3]Cl2−catalyzed
photoredox reduction of diverse ketones has been developed to
facilitate the synthesis of valuable secondary alcohols, and
commercially available and even inexpensive tertiary amines have
been used as the terminal reductant.[2] Such a single-electron-
transfer (SET) platform with stereocontrol[3] would be attractive for
preparing chiral secondary alcohols. However, no enantioselective
example has been reported to date. Given the lack of concise
absolute stereocontrol in the asymmetric direct reduction of 1,2-
diketones
organocatalysis,[5] a visible-light-driven photocatalysis manifold
should provide potential alternative for biologically and
synthetically important optically enriched α-hydroxy ketones,[6]
via
either
transition-metal
catalysis[4]
or
a
and its development thus becomes
challenging task.
a highly desirable but
As described by Willner et al. (Scheme 1a),[2c] the reduction of
red
red
benzil [E (1) = −1.169 V vs SCE and E (2) = −1.251 V vs SCE
1/2
1/2
in CH3CN] with the indispensable [Ru(bpy)3]Cl2 photoredox
catalyst and Et3N reductant should involve two successive SET
processes: the first reduction by Ru(bpy)+ (E1II//2I = −1.33 V vs SCE
in CH3CN) affords a ketyl intermediate, which can subsequently be
reduced by the [Et2NCHCH3]• radical to generate a carbanion
species. The final step to form benzoin is protonation. Therefore,
the introduction of a suitable enantiofacial control pattern to
manipulate the delivery of H+ to the carbanion intermediate is
crucial for the asymmetric variant.[7] In 2013, Knowles and co-
workers[8] reported highly enantioselective photoredox catalysis for
an asymmetric intramolecular aza-pinacol cyclization through the
reductive coupling of ketones and hydrazones. This elegant work
revealed the feasibility of hydrogen-bonding interaction between a
Brønsted acid catalyst and the ketyl intermediate because of its
Scheme 1. Precedent and plan objectives
Our initial investigation was focused on the asymmetric
photoredox reduction of benzil (1a) as a model reaction (Table 1).
To provide a rare but highly desirable transition-metal-free dual
catalysis system,[10b,12c] we first tested the viability of our
developed dicyanopyrazine-derived chromophore (DPZ)[10] as the
photoredox catalyst instead of [Ru(bpy)3]Cl2 based on their
comparable electrochemical properties (entry 1).[14] The reaction
worked smoothly with 0.5 mol% of DPZ and 1.0 equiv of Et3N in
CH2Cl2 solvent at 25 °C and under irradiation with a 3 W blue
LED, affording benzoin (2a) in 90% yield within 6 hours. Chiral
Brønsted bases such as L-amino acid-based urea−tertiary amine
[a]
[b]
[†]
L. Lin,[†] X. Bai,[†] X. Zhao, Prof. Dr. Z. Jiang
Key Laboratory of Natural Medicine and Immuno-Engineering of
Henan Province, Henan University
Jinming Campus, Kaifeng, Henan, 475004, P. R. China
E-mail: chmjzy@henu.edu.cn
X. Ye, Prof. Dr. C.-H. Tan
Division of Chemistry and Biological Chemistry
Nanyang Technological University
(C1)[9]
and
Takemoto’s
1,2-cyclohexanediamine-based
21 Nanyang Link, 637371, Singapore
urea−tertiary amine (C2),[15] which are well known in asymmetric
ground-state reactions, were then evaluated (entries 2−3).
However, almost no enantiocontrol effect was observed. Inspired
by the successful stereocontrol of anion radical species with a
L.L. and X.B. contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707899
Angewandte Chemie International Edition
COMMUNICATION
chiral ionic Brønsted acid reported by Ooi,[12l-m] we examined our
previously developed guanidinium salt C3[16] for the
enantioselective phospho-Mannich reaction (entry 4). To our
delight, 2a was obtained in 95% yield with a promising 20% ee.
Next, iPr2EtN was tested, yielding 2a with 30% ee (entry 5). The
evaluation of a variety of solvents identified chlorobenzene (PhCl)
as the optimal medium (entry 7), while the use of
tetrahydroisoquinolines (THIQ) with a 2-naphthyl N-substituent
ee when 10 mol% of NaBArF was used (entry 13). No
improvement in enantioselectivity was found after increasing the
amount of NaBArF to 20 mol% (footnote g). Other feasible and
commonly used photocatalysts, such as [Ru(bpy)3]Cl2, Rose
Bengal and Eosin Y, were also tested, but no improvement in
enantioselectivity was obtained, although the same reactivity was
achieved.[17] In the absence of C3, 2a still formed (85% yield) as
an achiral mixture, demonstrating the remarkable existence of a
racemic background transformation under the reaction conditions
(entry 14). Interestingly, 2a could be obtained with similar yield
and enantioselectivity without DPZ, and 3 was identified as the
byproduct in 94% yield (entry 15).
(THIQ-2) as the reductant resulted in
a good level of
enantioselectivity but a slightly longer reaction time (70% ee, 12 h,
entry 9).[17] Further lowering the temperature to 0 °C increased the
enantioselectivity to 77% ee (entry 10). It is worth mentioning that
tetrahydrobiisoquinoline 3, which has significant applications in
medicinal chemistry,[18] was obtained as the byproduct in a
quantitative yield.
Table 2: Scope of 1,2-diketones.[a]
Table 1: Screening and optimization.[a]
Entry
1
2
Yield [%][b]
92 (94)
68 (77)
85 (94)
83 (94)
72 (90)
77 (87)
78 (88)
73 (91)
99 (96)
99 (97)
86 (90)
85 (93)
88 (93)
99 (99)
60[d] (84)
67 (58)
Ee [%][c]
91 (92)
80 (80)
91 (90)
91 (92)
88 (90)
90 (89)
92 (85)
90 (85)
92 (92)
91 (89)
90 (81)
92 (83)
90 (90)
90 (68)
98[d] (64)
80 (80)
2a: Ar = R = C6H5
2
2b: Ar = R = 4-CF3C6H4
2c: Ar = R = 4-FC6H4
2d: Ar = R = 2-FC6H4
2e: Ar = R = 4-ClC6H4
2f: Ar = R = 4-BrC6H4
2g: Ar = R = 4-MeC6H4
2h: Ar = R = 3-MeC6H4
2i: Ar = R = 4-tBuC6H4
2j: Ar = R = 4-nBuC6H4
2k: Ar = R = 3,5-Me2C6H3
2l: Ar = R = 4-MeOC6H4
2m: Ar = R = 3-MeOC6H4
2n: Ar = R = 2-naphthyl
2o: Ar = R = 2-thienyl
2p: Ar = C6H5, R = Me
3
4
5
6
7
Entry
Cat.
none
C1
R3N
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
PhCl
T [°C]
25
25
25
25
25
25
25
25
25
0
Yield [%][b]
90
Ee [%][c]
−
8
9
1
Et3N
10
11
12
13
14
15
16[e]
2
Et3N
94
6
3
C2
Et3N
92
0
4
C3
Et3N
95
20
30
25
46
67
70
77
79
85
91[g]
−
5
C3
iPr2EtN
iPr2EtN
iPr2EtN
THIQ-1
THIQ-2
THIQ-2
THIQ-2
THIQ-2
THIQ-2
THIQ-2
THIQ-2
94
6
C3
92
7
C3
94
8
C3
PhCl
47
[a] Reaction conditions: 1 (0.10 mmol), DPZ (0.5 x 10-3 mmol), C3 (0.01
mmol), THIQ-2 (0.2 mmol) and NaBArF (0.01 mmol) in PhCl (3.0 mL) at 0 °C
under an argon atmosphere. The data in parentheses were obtained without
DPZ under standard conditions. [b] Yield of isolated product. [c] Enantiomeric
excess determined by HPLC on chiral stationary phase. [d] The data were
obtained after a single recrystallization. Initial data: 82% yield, 75% ee. [e] C1-
derived Brønsted base catalyst C4 (0.01 mmol) and N-ethyl-N-phenyl
benzylamine (0.2 mmol) was used and in m-bromo anisole (3.0 mL) at 0 °C.
9
C3
PhCl
44
10
C3
PhCl
45
11[d]
12[d,e]
13[d,f]
14[d,f]
15[d,f,h]
C3
PhCl
0
93
C3
PhCl
0
94
C3
PhCl
0
92
none
C3
PhCl
0
85
Although the similar results were achieved when without
photoredox catalyst, which features a more sustainable and
attractive approach,[19] the reasonable electrochemical properties of
DPZ for the transformation promoted us to identify the substrate
scope under two distinct reaction conditions and evaluate their
differences (Table 2). When in the presence of DPZ catalyst, all
reactions for symmetric 1,2-diketones were found to be complete
within 24 hours, providing optically active α-hydroxyl ketones 2a-
o in 60−99% yields with 80−98% ee (entries 1−15). Both electron-
deficient and electron-donating substituents at the para-, meta-,
and ortho-positions of the aromatic were well tolerated. For 1-
phenyl-1,2-propanedione as an representative of unsymmetrical
diketones, the reaction was messy and no desired product 2p was
observed. However, the modified reaction conditions, that are C1-
derived Brønsted base C4 as chiral catalyst and N-ethyl-N-phenyl
benzylamine as the reductant, could provide 2p in 67% yield with
specific regioselectivity and high enantioselectivity (80% ee, entry
PhCl
0
91
91
[a] Reaction conditions: 1a (0.02 mmol) and tertiary amine (0.02 mmol) in
solvent (0.2 mL) under an argon atmosphere. Entries 1−7, 6 h; entries 8−9, 12
h; entries 10−15, 16 h. [b] Yield of isolated product. [c] Enantiomeric excess
determined by HPLC on chiral stationary phase. [d] 0.04 mmol of THIQ-2 and
0.6 mL of PhCl were used. [e] 10 mol% of KPF6 was used as an additive. [f] 10
mol% of NaBArF was used as an additive. [g] When 20 mol% of NaBArF was
used, ee = 91%. [h] No DPZ was used.
Given the results indicating that THIQ-2 can present only a
single hydrogen atom, its amount was increased from 1.0 to 2.0
equivalents, and product 2a was attained in 93% yield with 79% ee
at a lower concentration (Table 1, entry 11). To improve the
enantioselectivity, we then sought to change the anion species of
guanidinium salt C3 via an in situ generation strategy by directly
adding inorganic salts to the reaction system (entries 12−13).[17]
We were pleased that the enantioselectivity was enhanced to 91%
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10.1002/anie.201707899
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COMMUNICATION
16).[17] We next examined the reactions without DPZ catalyst, and
products 2a-p were obtained in 58−99% yields with 64−92% ee
(see data in parentheses). The corresponding yield of the latter is
mainly equal to or greater than that of the former, and the
enantioselectivity of some substrates is similar except for that of
1,2-diketones with an electron-donating group on the aromatic ring
(1g-h, 1k-l and 1n) or substituted by an electron-rich aromatic
heterocycle (1o). Given the roughly higher enantioselectivity, we
suggest that the cooperative catalysis platform would be a more
preferential choice for the transformations.
SET reduction of 1,2-diketones 1 with THIQ-2 through the
photochemically active electron donor-acceptor (EDA) complex
6,[17,19] yielding ketyl radical 7 and THIQ-2•+. Due to its strong
basicity, 7 will interact with the Brønsted acid C3 through non-
covalent bonds to generate the chiral ion pair 9,[22] with a BF4− ion
−
leaving from C3 to form THIQ-2•+•BF4 species 8 or THIQ-
2•HBF4 salt. The observation of the same enantioselectivity when
0.1 or 0.2 equiv of NaBArF was used (Table 1, entry 13 and
footnote g) provides robust evidence demonstrating the abstraction
of BF4− but not of BArF−. Considering the high yield of byproduct
3, the transformation of 9 to the carbanion complex 10 should
proceed through reduction by THIQ-2 but not THIQ-2•. Based on
the absolute configuration of C3,[17] preferable transition states are
Table 3: Scope of α-amino ketimines.[a]
proposed for complexes
9 and 10; after enantioselective
protonation from the Re-face of 10, products 2 were obtained with
the observed absolute configuration.[17] C3 would then be
regenerated from its conjugate base by the addition of H+,[12l-m]
indicating its substantial role in H+ transfer interchange. The homo-
coupling of the THIQ-2• radical produces 3.[23] The reduction with
the DPZ catalyst would involve a dual catalysis process, which is
similar to previously reported mechanisms[2] except for the
secondary reduction enabled by THIQ. Our Stern−Volmer
experiment demonstrated that THIQ-2, as a reductive quencher,
can be readily oxidized by DPZ*.[17,24] The type of EDA is
probably involved in the process. The lower enantioselectivity for
electron-rich substituted 1,2-diketones 1 without DPZ catalyst than
with probably occurs because the concurrently generated THIQ-2•+
and ketyl species 7 from EDA complex 6 would have similar
concentrations, and the higher electron density of 7 with electron-
rich substituents should result in stronger basicity and greater
difficulty in reduction than those with electron-deficit substituents,
increasing the chance to abstract H+ from THIQ-2•+ and diminish
the generation of chiral ion pair 9. In fact, the choice of tertiary
amine reductant is also crucial to the formation of 9 and ultimately
affects the enantioselective results (Table 1, entries 4−5 and 8−9).
We reason that THIQ-2• has lower reductive capability than
[(alkyl)2NCHCH3]• for the conjugation effect of the neighboring
aryl ring. With the concurrent generation of 3 through homo-
coupling[23] to decrease the concentration of THIQ-2•, the reduction
of ketyl radical was addressed by THIQ-2, thus requiring longer
reaction time than by [(alkyl)2NCHCH3]•. Combined by the weaker
basicity of THIQ-2 than those two tertiary amines, 9 would be
more easily formed with stronger stability when in the presence of
THIQ-2, providing higher enantioselectivity as observed.[25]
Entry
5
Yield [%][b]
Ee [%][c]
90
1
2
3
4
5
6
7
8
9
10
5a: Ar = R = C6H5
83
68
71
78
92
89
70
88
95
77
5b: Ar = R = 4-FC6H4
5c: Ar = R = 4-MeC6H4
5d: Ar = R = 4-nBuC6H4
5e: Ar = R = 4-iPrC6H4
5f: Ar = R = 3-MeC6H4
5g: Ar = R = 3,5-Me2C6H3
5h: Ar = R = 4-MeOC6H4
5i: Ar = R = 2-naphthyl
5j: Ar = C6H5, R = Et
90
90
85
86
90
89
90
86
64
[a] Reaction conditions: 1 (0.10 mmol), DPZ (0.001 mmol), C2 (0.01 mmol),
THIQ-2 (0.20 mmol) and 3 Å MS (50 mg) in 2-bromoanisole (2.0 mL) at 0 °C
under an argon atmosphere. [b] Yield of isolated product. [c] Enantiomeric
excess determined by HPLC on chiral stationary phase.
Enantiomerically pure α-amino ketones containing a chiral
secondary amine instead of a secondary alcohol at the α-position of
ketones are also highly important motifs in synthetic and medicinal
chemistry.[20] The asymmetric reduction of α-keto ketimines should
be a reliable method to directly access these chiral entities.
However, only one successful example has been described,[21] and
importantly, it suffers from a hydrogen source that is not
conveniently available and from undesired waste as a byproduct.
Hence, we were interested in attempting this transformation using
our reaction system. However, preliminary work revealed that the
current method efficiently promoted the reduction of α-keto
ketimines
in
high
yield
but
with
unsatisfactory
enantioselectivity.[17] After carefully investigating the reaction
conditions, we found that α-keto ketimine 4a with 2-bromo-4-
methoxy-phenyl as the N-protecting group could be reduced to the
corresponding α-amino ketone 5a in 83% yield with 90% ee by
using C2 as the chiral catalyst and a 3 Å molecular sieve (MS) as
an additive in 2-bromoanisole solvent at 0 °C (Table 3, entry 1). A
variety of α-amino ketones, featuring different electron properties
and substitution patterns at the aryl ring (5b-i) and alkyl as the
ketone substituent (5j), were also obtained in 63−95% yields with
64−90% ee values from α-keto ketimines 4b-i, indicating the broad
effectiveness of the reaction conditions. For these transformations,
a strong racemic background reaction without the chiral catalyst
C2 was likewise observed, but no reaction was detected in the
absence of the DPZ catalyst. Even more noteworthy is that the
valuable tetrahydrobiisoquinoline 3 was obtained rapidly.[17]
Figure 1. Plausible mechanism.
In conclusion, we have developed the first catalytic asymmetric
photoreduction of 1,2-diketones and α-keto ketimines. Synergistic
catalysis by combining the photoredox catalyst DPZ and a chiral
non-covalent organocatalyst is effective for these transformations.
Figure 1 shows two proposed mechanisms with and without the
DPZ catalyst for the asymmetric reduction of 1,2-diketones.
Without DPZ, the reaction is initiated by the visible-light-induced
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10.1002/anie.201707899
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COMMUNICATION
The advantage of flexibly selecting a chiral Brønsted acid or base
for proton shuttle enables two distinct reductions through highly
enantioselective protonation is that it affords the production of
diverse and valuable chiral α-hydroxy ketones and α-amino
ketones with high ee values. Given the first realization of
enantioselective protonation strategy in photoredox catalysis, we
anticipate that it will find prolific application in this powerful and
sustainable area for constructing diverse important and challenging
chiral molecules with tertiary carbon stereocenters.
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Acknowledgements
We acknowledge grants from NSFC (21672052) and Henan
province (14IRTSTHN006). We also appreciate Mr. Yangyang
Shen (ICIQ) and Dr. Zhan Lu (ZJU) for their helpful discussions.
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Keywords: Asymmetric Photoredox Catalysis • Organocatalysis
• Cooperative Catalysis • Photoreduction • Protonation
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[14] DPZ: Et(S* /S•−) = +0.91 V vs SCE in CH Cl , E = −1.45 V vs SCE in
red
1/2
2
2
CH2Cl2 for DPZ•−. Ru(bpy)32+: E = +0.77 V vs SCE in CH3CN.
*II/I
1/2
[15] Topics in Current Chemistry 291: Asymmetric Organocatalysis (Volume
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10.1002/anie.201707899
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
L. Lin, X. Bai, X. Ye, X. Zhao, C.-H. Tan,
Z. Jiang*
Page No. – Page No.
Organocatalytic Enantioselective
Protonation for Photoreduction of
Activated Ketones and Ketimines
Induced by Visible Light
Enantioselective protonation: The first catalytic asymmetric photoreduction of 1,2-diketones and α-keto
ketimines under visible light irradiation is developed. A transition-metal-free cooperative catalysis platform
harnessing dicyanopyrazine-derived chromophore (DPZ) as the photoredox catalyst and a non-covalent
chiral organocatalyst is effective for these transformations. With the flexible use of a chiral Brønsted acid or
base as proton shuttle to control enantioselective protonation, a variety of chiral α-hydroxy ketones and α-
amino ketones were obtained with high yields and enantioselectivities.
This article is protected by copyright. All rights reserved.