Enantioselective Radical Ring-Opening Cyanation of Oxime Esters by Dual Photoredox and Copper Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b03970

Catalytic enantioselective chemical reactions involving highly reactive radical species remain largely unexplored. We report herein for the first time a novel enantioselective radical ring-opening cyanation of redox-active oxime esters by dual photoreodox

Full text of DOI:10.1021/acs.orglett.9b03970

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Radical Ring-Opening Cyanation of Oxime Esters
by Dual Photoredox and Copper Catalysis
Jun Chen,†,§ Peng-Zi Wang,†,§ Bin Lu,† Dong Liang,† Xiao-Ye Yu,† Wen-Jing Xiao,*,†,‡
and Jia-Rong Chen*,†
†CCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide & Chemical Biology Ministry of Education, College of
Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan, Hubei 430079, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: Catalytic enantioselective chemical reactions
involving highly reactive radical species remain largely
unexplored. We report herein for the first time a novel
enantioselective radical ring-opening cyanation of redox-active
oxime esters by dual photoreodox and copper catalysis. This
mild protocol shows good functional group tolerance and
broad substrate scope, producing a wide range of optically
active alkyl dinitriles with high yields and excellent
enantioselectivities, which are difficult to access traditionally.
adical chemistry has been established as a potentially
ities, when using a Cu(I)/(S,S)-tBuBox or Cu(I)/chiral
Rpowerful synthetic platform for the construction of organic phosphoric acid dual-catalytic system. These methods enabled
synthesis of diverse enantioenriched oxygen and nitrogen
heterocycles under mild conditions.
molecules because of a unique profile of reactivity mode and
selectivity that is complementary to the traditional ionic
chemistry.1,2 Despite significant advances in this area, the
control of enantioselectivity remains a formidable challenge and
has been largely unsolved for many classes of radical trans-
formations. Among numerous efforts in subverting this
challenge, transition-metal-catalyzed radical cross-coupling
(RCC) in the presence of chiral ligands represents a
conceptually new strategy. In a typical catalytic cycle (Scheme
1A), the in situ-formed chiral metal complexes are explored as
radical traps to intercept open-shell carbon-centered radicals to
form high-valent metal complexes and thus control the following
reductive elimination in an enantioselective manner.3
Recently, Fu and Ito independently extended the RCC
strategy to Ni(II)- and Cu(I)-catalyzed asymmetric borylation
of racemic electrophilic benzyl chlorides.11 Despite being
powerful, in the majority of alkene-based RCC reactions, the
spectrum of radical classes is usually restricted to these small
functional organic radical precursors, such as Togni reagent,
NFSI, TMSN3, and O-acylhydroxlamines. Therefore, it is highly
desirable to explore other new radical precursors to generate
diversely functionalized benzylic radicals and their analogues,
which would provide access to more structurally complex and
useful molecules.
We and others have recently described a variety of
photoredox- or metal-catalyzed ring-opening/functionalization
reactions of these redox-active substrates.12,13 To date, progress
in this field has been limited to non-enantioselective trapping of
the key cyanoalkyl radicals (Scheme 1B). Expanding the profile
of trapping reagents to include chiral metal-complexed
nucleophiles such as L*Cu(II)Nu would probably enable
enantioselective RCC reaction of cyanoalkyl radicals. For
example, with use of TMSCN as a nucleophilic coupling
partner, the achievement of this reaction would provide a
practical approach to valuable chiral alkyl dinitriles,14 which are
difficult to access traditionally (Scheme 1C). Herein, we report
the development of a novel enantioselective ring-opening radical
cyanation of oxime esters for the first time by merging
photoredox and asymmetric copper catalysis.15
Inspired by the works of Fu on the nickel- and copper-
catalyzed enantioselective RCC reactions with various aliphatic
electrophiles as alkyl radical precursors,4 Liu et al. developed a
novel Cu(I)/Box-catalyzed radical relay strategy for generation
of various benzylic radicals through hydrogen atom abstraction
of C(sp3)−H bonds, photocatalyic decarboxylation, or radical
addition to styrenes.5 These radical species then intermolecu-
larly combine with the catalytically formed Cu(II) nucleophile
to form highly reactive chiral Cu(III) complexes, followed by
reductive elimination to form new carbon−carbon bonds with
excellent enantioselectivity. Depending on the properties of the
nucleophiles, a range of asymmetric functionalizations at the
benzylic positions could be achieved, including cyanation,6
arylation,7 and alkynylation.8 Meanwhile, the groups of
Buchwald9 and Liu10 independently disclosed that a range of
alkenes bearing pendant nucleophilic groups (e.g., carboxylic
acid, alcohol, oxime, urea) could undergo radical addition/
intramolecular cross-coupling with excellent enantioselectiv-
Received: November 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03970
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Background of the Methodology Development
Table 1. Condition Optimization
a
b
1a (0.1 mmol) and TMSCN (0.3 mmol) were used. Yields were
c
determined by GC analysis, with isolated yield in parentheses. The ee
values were determined by HPLC on a chiral stationary phase. With
2.0 mL of DMA. 0.5 mol % of fac-Ir(ppy)3, 1 mol % of
Cu(CH3CN)4PF6, and 1.2 mol % of L1. 2.5 mol % of Ph-PTZ, 1
d
We began our investigation by examination of the reaction of
less-strained 2-phenylcyclopenta-1-one-derived oxime ester 1a
with TMSCN as the cyanide source using photocatalyst fac-
Ir(ppy)3 and Cu(CH3CN)4PF6 combined with a series of chiral
bisoxazoline ligands in DMF under irradiation of 7 W blue LEDs
at room temperature (Table 1).16 To our delight, the
combination of Cu(CH3CN)4PF6 (10 mol %) and Box-type
ligand L1 (12 mol %) furnished the desired product 2a in 43%
yield with 89% ee (entry 1). A brief further screen of ligands
revealed that chiral ligands have an important role in the reaction
efficiency and enantioselectivity. Though bisoxazoline ligands
L2−L5 led to somewhat improved efficiency, inferior
enantioselectivity was obtained (5−61% ee, entries 2−5).
With L1 identified as the best chiral ligand, we further evaluated
a series of commonly used Cu(I) and Cu(II) salts and found that
Cu(CH3CN)4PF6 is still the best one of choice in terms of yields
(entries 6−8). With Cu(CH3CN)4PF6/L1 as the best chiral
catalyst, we examined a series of solvents and confirmed that
DMA afforded 2a in 90% ee though with somewhat lower yield
(entry 9). An extensive screening of catalyst loading
demonstrated that use of only 0.5 mol % of fac-Ir(ppy)3
together with 1 mol % of Cu(CH3CN)4PF6 and 1.2 mol % of
L1 resulted in a significant increase of yield, leading to 2a in 73%
yield with 91% ee (entry 10). Notably, the use of commercially
available organic photocatalyst 10-phenylphenothiazine (Ph-
PTZ)17 (2.5 mol %) further increased the reaction efficiency,
furnishing 2a in 92% yield with 91% ee (entry 11). A series of
control experimental results confirmed that each component is
essential for the target reaction.16
e
f
mol % of Cu(CH3CN)4PF6, and 1.2 mol % of L1 under irradiation of
2 × 3 W purple LEDs for 1 h.
aryl-substituted cyclopentanones were well-tolerated (Scheme
2A). Aside from 1a, substrates 1b−j with various either electron-
t
donating (e.g., OMe, Bu, TMS, Ph) or electron-withdrawing
(e.g., F, Cl, Br, CO2Me, SO2Me) groups at the para-position of
the aromatic ring all proved to be suitable candidates, and the
corresponding products 2b−j were obtained with excellent
yields (90−99%) and enantiomeric excess (81−94% ee). Halide
groups (2f−h) remained intact after the reaction, thereby
providing an easy handle for additional synthetic elaborations.
The reaction of 1k and 1l with synthetically useful amide and
Bpin functionalities at the para-position of the phenyl ring also
worked well to give 2k and 2l in satisfactory yields with excellent
ee values. As shown in the cases of 2m−p, variation of the
substitution pattern and steric hindrance of the phenyl ring has
no deleterious effect on the reaction efficiency and enantiose-
lectivity. In addition, substrates 1q−t containing extended
aromatic systems (e.g., 2-naphthyl), heterocycle-fused rings, or
pyridine all underwent the enantioselective ring-opening
cyanation efficiently, affording products 2q−t with 82−93%
yields and 81−92% ee.
The current catalytic system could also be successfully
extended to 2-aryl-substituted cyclobutanone-derived oxime
esters 3 (Scheme 2B). Oxime esters 3a and 3b−e with methyl or
halides (F, Br, I) at the para-position of the aromatic ring reacted
well with TMSCN. The desired alkyl dinitriles 4a−e were
isolated in high yields with 90−94% ee. Furthermore, as shown
With the optimal reaction conditions established, we then
examined the substrate scope of oxime esters (Scheme 2). A
wide range of oxime esters that can be easily prepared from 2-
B
DOI: 10.1021/acs.orglett.9b03970
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b c
, ,
Scheme 2. Scope of the Cycloketone Oxime Esters
To gain some insight into the working proposal, we first
performed a control experiment with 1q and TMSCN (Scheme
3a). Upon addition of stoichiometric TEMPO (4.0 equiv),
Scheme 3. Mechanistic Studies
a
1 or 3 (0.2 mmol), TMSCN (0.6 mmol), and DMA (4.0 mL) were
b
c
used. Isolated yields. The ee values were determined by HPLC on a
chiral stationary phase.
complete suppression of the formation of the desired product 2q
was observed, and the corresponding TEMPO-trapping product
7 was isolated in 77% yield. Moreover, the ring-opening product
9 was obtained in the reaction of radical clock substrate 8
(Scheme 3b), which should result from a radical cross-coupling
of radical intermediate 8-B with TMSCN. These results suggest
the involvement of cyanoalkyl radical 1q-B and a benzylic radical
such as 8-A.
As the Ph-PTZ and fac-Ir(ppy)3 demonstrated comparable
results, we then investigated the luminescence quenching of fac-
Ir(ppy)3 with excitation at 355 nm by 1a, CuCN/L1, and
TMSCN.16 The Stern−Volmer plot results revealed that 1a
could more significantly quench the excited state of the
photocatalyst than CuCN/L1 or TMSCN (Figure 1).
The excited-state photocatalyst *Ph-PTZ is reported to be a
very strong reductant (E1/2[Ph-PTZ•+/Ph-PTZ*] = −2.1 V vs
SCE in CH3CN).17 The redox potential of 1a was determined to
be −1.69 V vs SCE in DMA,16 suggesting that an SET event
between 1a and *Ph-PTZ was presumably engaged in the
reaction to enable SET reduction of 1a. On the other hand, the
oxidized state Ph-PTZ•+ is a strong oxidant (E1/2[Ph-PTZ•+/
Ph-PTZ] = 0.68 V vs SCE in CH3CN) capable of oxidizing
L1*Cu(I)CN to L1*Cu(II)CN (E1/2[Cu(II)/Cu(I)] = +0.36 V
vs SCE in CH3CN).6b We determined the quantum yield of the
reaction of 1a and TMSCN to be 0.509. A value below unity
suggests that the reaction should proceed by a sequential redox
process rather than a radical chain pathway. Finally, a study of
the impact of the ee of ligand L1 on the ee of the product 2a did
in the reactions of 3f and 3g, the change of the position of
substituent has no obvious effect on the reaction, with the
corresponding products 4f and 4g being obtained in quantitative
yields with 93 and 86% ee, respectively. Oxime ester 3h with a 2-
naphthyl group also proved to be suitable for the reaction, giving
rise to 4h with 92% ee.
Notably, the reaction of 1a and TMSCN performed on 10.0
mmol scale also worked well to furnish the product 2a in 95%
yield (90% ee) within 4 h, when using only 1.25 mol % of Ph-
PTZ, 0.5 mol % of Cu(CH3CN)PF6, and 0.6 mol % of ligand L1
(Scheme 2C). The photocatalyst Ph-PTZ could also be
recovered with 97% yield. Suitable crystals of compound 2e
were obtained, and a single-crystal analysis revealed the
configuration to be S.
Moreover, the model reaction of 1a and TMSCN carried out
on 1.0 mmol scale proceeded smoothly to give 2a with 85% yield
(184.1 mg) and 90% ee, when replacing Ph-PTZ with fac-
Ir(ppy)3 under only 2 h of sunlight exposure (eq 1). Preliminary
efforts have established that the current catalytic system could
also be applied to a three-component enantioselective ring-
opening cross-coupling of oxime esters. It was found that the
reaction of cyclobutanone oxime ester 3i, para-phenyl-
substituted styrene 5, and TMSCN worked well under the
standard conditions, giving alkyl dinitrile 6 in synthetically useful
yield with 91% ee (eq 2). Further optimization studies to
improve the yield of this reaction are ongoing.
C
DOI: 10.1021/acs.orglett.9b03970
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
In conclusion, we have developed a novel enantioselective
radical ring-opening cyanation of oxime esters by dual
photoredox and copper catalysis. This protocol demonstrates
broad substrate scope, producing various optically active alkyl
dinitriles with high yields and excellent enantioselectivities,
which are difficult to access traditionally. This work has also
established a platform to explore cyanoalkyl radicals derived
from cycloketone oxime esters in catalytic asymmetric radical
cross-coupling chemistry. Further expansion of this dual
catalytic system to other carbon- and heteroatom-based
nucleophiles is currently in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 1. Stern−Volmer plot for the emission quenching of excited
photocatalyst fac-Ir(ppy)3 in toluene by different quenchers.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03970.
not demonstrate an obvious nonlinear effect, suggesting that a
copper complex should contain one ligand L1.16
Finally, we proposed a dual photoredox and copper-catalyzed
pathway for the present enantioselective radical ring-opening
cross-coupling reaction (Scheme 4). The reaction begins with
Experimental procedures, full analysis data for new
compounds, and copies of NMR spectra (PDF)
Accession Codes
CCDC 1956493 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 4. Proposed Mechanism
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wxiao@mail.ccnu.edu.cn.
*E-mail: chenjiarong@mail.ccnu.edu.cn.
ORCID
Wen-Jing Xiao: 0000-0002-9318-6021
Jia-Rong Chen: 0000-0001-6054-2547
Author Contributions
§J.C. and P.-Z.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NNSFC (21971081, 21622201,
91856119, 21820102003, and 21772053) and the Program of
Introducing Talents of Discipline to Universities of China (111
Program, B17019) for support of this research.
SET reduction of redox-active oxime ester 1 or 3 by the
photoexcited Ph-PTZ*, followed by fragmentation to give
−
iminyl radical A and carboxylic anion (RCO2 ). Next, iminyl
radical A undergoes a selective β-C−C bond cleavage to
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