Enantioselective Remote C(sp3)-H Cyanation via Dual Photoredox and Copper Catalysis

Article abstract of DOI:10.1021/acs.orglett.0c02008

The remote C(sp3)-H cyanation of carboxamides has been described by merging photoredox and copper catalysis in a site-selective and enantiocontrolled manner. The protocol is the integration of photoinduced and nitrogen-centered radical-mediated intermolecular hydrogen atom transfer with chiral copper-complex-catalyzed radical cyanation. This strategy gives enantio-enriched cyanated amides in high yields.

Full text of DOI:10.1021/acs.orglett.0c02008

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Letter
Enantioselective Remote C(sp3)−H Cyanation via Dual Photoredox
and Copper Catalysis
Hui Chen, Weiwei Jin, and Shouyun Yu*
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ABSTRACT: The remote C(sp3)−H cyanation of carboxamides
has been described by merging photoredox and copper catalysis in
a site-selective and enantiocontrolled manner. The protocol is the
integration of photoinduced and nitrogen-centered radical-
mediated intermolecular hydrogen atom transfer with chiral
copper-complex-catalyzed radical cyanation. This strategy gives
enantio-enriched cyanated amides in high yields.
isible-light photoredox catalysis can generate radicals or
radical ions, which are otherwise difficult to access, under
achieved using this strategy. It has emerged as a distinct
approach to unlock unique synthetic planning in modern
organic synthesis. Despite these advances, enantioselective
HLF-type remote C(sp3)−H functionalization is still syntheti-
cally challenging and remains mainly unexplored. Recently, Liu
et al. reported an oxygen-centered radical-mediated enantio-
selective remote C(sp3)−H cyanation by dual photoredox and
copper catalysis.14 More recently, Nagib15 and Wang16
independently realized a copper-catalyzed enantioselective
remote C(sp3)−H cyanation of N-fluorosulfonamides, which
represents a highly enantioselective HLF-type reaction (Figure
1a). Inspired by the pioneering works of Liu on copper-
catalyzed enantioselective radical cyanation17 and other
V
mild and synthetically useful conditions.1 Its application has
therefore been rapidly booming in organic synthesis during the
past several decades,2 and the enantioselective version of this
catalytic mode has gained more and more attention.3 Visible-
light photoredox catalysis combined with enantioselective
transition-metal catalysis leads to the development of novel
enantioselective transformations.4 Dual photoredox and
copper catalysis has emerged as a powerful synergistic catalytic
system for incorporating functional groups into molecules.5
Because of the persistent radical effect,6 copper can efficiently
trap and thus stabilize reactive radical species generated under
photoredox catalytic conditions.5a In this dual-catalytic system,
the single electron transfer is mediated by the photocatalyst,
and the enantioselectivity is introduced by the copper with a
chiral ligand.5a,b Although considerable advances in this dual
catalysis have been made in the past few years, generalizing and
expanding the scope of enantioselective reactions still need to
be further investigated.
̈
The Hofmann−Loffler−Freytag (HLF) reaction has con-
stituted a significant breakthrough in the remote functionaliza-
tion of inherently inert C(sp3)−H bonds since it emerged in
the late 19th century.7 This reaction converts acyclic amines
into cyclic amines through an intermolecular hydrogen atom
transfer (HAT) process under ultraviolet photolysis or thermal
conditions in a strong acidic medium. The requirement of
harsh conditions has limited its applications in organic
synthesis. The synergism of visible-light photoredox catalysis
with intramolecular HAT lead to the renaissance of the HAT-
mediated remote functionalization of C(sp3)−H bonds.8
These nitrogen-centered-radical (NCR)-triggered radical trans-
location processes provide an appealing strategy for the
selective and controllable remote functionalization of C-
(sp3)−H bonds.9 The direct formation of new carbon−carbon
(C−C) bonds10 and carbon−heteroatom (C−O,11 C−N,12
and C−X13) bonds from remote C(sp3)−H bonds can be
Figure 1. Enantioselective remote C(sp3)−H cyanation of (sulfon)-
amides.
Received: June 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02008
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
asymmetric remote C(sp3)−H functionalizations18 as well as
our recent investigation on this topic,19 we would like to
provide our solution to the enantioselective remote C(sp3)−H
cyanation of carboxamides using dual photoredox and copper
catalysis (Figure 1b).
After establishing the optimized reaction conditions, we then
focused on investigating the generality and limitations of this
enantioselective remote C(sp3)−H cyanation. As shown in
Figure 2, O-acyl hydroxamides 1a−e with different alkyl groups
We commenced our investigation by selecting O-acyl
hydroxamide (1a) as a model substrate with TMSCN (Table
1). Reaction conditions screening disclosed that the reaction
a
Table 1. Reaction Conditions Optimization
b
c
entry
variation of reaction conditions
none
L2 instead of L1
L3 instead of L1
L4 instead of L1
Ru(bpy)3(PF6)2 instead of Ir(ppy)3
Eosin Y instead of Ir(ppy)3
CH2Cl2 instead of MTBE
CH3CN instead of MTBE
MeOH instead of MTBE
without light or Ir(ppy)3
air instead of N2
yield (%)
ee (%)
d
1
2
3
4
5
6
7
8
>99 (97)
96
83
9
78
52
42
0
0
0
86
>99
>99
0
0
6
94
93
86
9
10
11
12
13
without Cu(CH3CN)4BF4
without ligand
27
0
a
Reaction parameters: 1a (0.1 mmol), TMSCN (2.0 equiv),
photocatalyst (0.5 mol %), Cu(CH3CN)4BF4 (2.0 mol %), L (3.0
b
mol %), solvent (1.0 mL), rt, 40 W blue LEDs. GC yields with an
c
internal standard (tetradecane). Enantiomeric excess (ee) values were
d
based on HPLC analysis on a chiral stationary phase. Isolated yield
on a 0.2 mmol scale.
Figure 2. Substrate scope. Reaction parameters: 1 (0.2 mmol),
TMSCN (2.0 equiv), Ir(ppy)3 (0.5 mol %), Cu(CH3CN)4BF4 (2.0
mol %), L1 (3.0 mol %), MTBE (2.0 mL), rt, 40 W blue LEDs. Yields
are based on the isolated products. CH2Cl2 was used as the solvent
instead of MTBE.
was best conducted with Cu(CH3CN)4BF4 (2.0 mol %)/chiral
box-type ligand L1 (3.0 mol %) and photocatalyst Ir(ppy)3
(0.5 mol %) in MTBE irradiated by 40 W blue light-emitting
diodes (LEDs) at room temperature for 24 h. (For details, see
the Supporting Information.) The remote C(sp3)−H cyanated
amide 2 was obtained in >99% GC yield (97% isolated yield)
with 96% ee (entry 1). The reactivity and enantioselectivity
were significantly affected by chiral ligands. When box ligand
L2 was employed, lower reactivity and enantioselectivity were
obtained (78% GC yield, 83% ee, entry 2). Replacing chiral
box-type ligand L1 with other ligands, such as chiral pyrox-type
ligand L3 and (R,R)-Ph-BPE (L4), resulted in significantly
lower or no enantioselectivity (9% ee for L3 and 0% ee for L4,
respectively, entries 3 and 4). Several other photocatalysts
(Ru(bpy)3(PF6)2 and Eosin Y) were also examined, but no
desired product was observed, and most of starting material 1a
(>90%) was recovered (entries 5 and 6). Replacing MTBE
with other solvents (such as DCM, CH3CN, and MeOH)
showed inferior results (entries 7−9). Control experiments
showed that visible light, the photocatalyst, the copper catalyst,
the ligand, and the nitrogen atmosphere are all critical to the
success of the reaction (entries 10−13).
a
on the nitrogen atom could participate in this enantioselective
reaction very well and afford cyanated amides 2−6 in excellent
yields (94−99%) with excellent enantioselectivities (96% ee).
The substitutions of the nitrogen atom have almost no impact
on the reactivity and selectivity in these O-acyl hydroxamides.
The (S)-configuration of 2 was established by analyzing its X-
ray diffraction. O-acyl hydroxamides 1f−k with electron-rich
groups (OMe and Me) or electron-poor groups (Cl, F, and
CF3) on the benzene ring all proved to be suitable starting
materials, and the desired products 7−12 were provided in
good yields (64−97%) with excellent enantioselectivities (85−
98% ee). O-acyl hydroxamide with a naphthalene ring could go
through this transformation smoothly (76% yield and 90% ee
for 13). O-acyl hydroxamide bearing a pyridine ring could
tolerate this dual-catalytic system, but with significantly lower
enantioselectivity (85% yield and 69% ee for 14). Gratifyingly,
B
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Letter
O-acyl hydroxamides possessing two active sites for HAT were
examined, and only 1,5-HAT products 15 (90% yield and 96%
ee) and 16 (91% yield and 96% ee) were produced in excellent
yields with excellent enantioselectivities. γ-Aryl linear aliphatic
carboxamides were proven successful for this transformation,
and the corresponding products 17−23 were provided in 74−
98% yields with 64−83% ee. Enantio-enriched N-(4-cyano-4-
phenylbutyl)benzamide 24 could be provided in 86% yield
with 89% ee. Limited success was achieved on nonbenzylic
remote C(sp3)−H cyanation. Low enantioselectivities were
observed (17% ee for 25 and 12% ee for 26), albeit with good
yields (62% yield for 25 and 80% yield for 26).
To show the synthetic utility of our method, a scale-up
experiment and transformation of the resultant chiral nitrile
were conducted (Figure 3). A gram-scale reaction of 1a (1.97
Figure 4. Mechanistic investigation. aGC yields with an internal
standard (tetradecane). Ar = p-CF3C6H4.
Figure 5. Proposed mechanism.
The Ir(IV) species oxidizes L*CuICN to L*CuII(CN)2 and
regenerate Ir(III) in the presence of TMSCN and a
carboxylate anion.18a,22 The side product ArCO2TMS can be
detected by GC-MS (Figure S4). The benzylic radical B, which
is generated from amidyl radical A by the 1,5-HAT,8 is trapped
by L*CuII(CN)2 to afford CuIII species C. Finally, reductive
elimination gives enantio-enriched product 2 and regenerates
the L*CuICN species.17,22b,23
In summary, we have developed an asymmetric remote
C(sp3)−H cyanation of carboxamides by the synergism of
photoredox and copper catalysis. O-acyl hydroxamides are
employed as benign internal oxidants and precursors of NCRs
in this dual-catalytic process. The protocol is enabled by the
integration of a photoinduced and amidyl-radical-mediated
intramolecular 1,5-HAT process with the chiral copper-
complex-catalyzed radical cyanation in a site-selective and
enantiocontrolled manner. This strategy gives structurally
diverse cyanated amides in decent yields with decent
enantioselectivities and good functional group tolerance.
Further discoveries of enantioselective remote C(sp3)−H
transformations enabled by this dual-catalytic strategy are
currently ongoing in our laboratory.
Figure 3. Gram-scale experiment and synthetic application.
g, 5.0 mmol) with TMSCN was conducted under the standard
conditions (Figure 3a). Satisfactorily, chiral nitrile 2 was
afforded in 98% yield (1.13 g) with 96% ee. Furthermore, the
enantio-enriched chiral nitrile 2 could be converted to Boc-
protected amine 27 by reduction and amide 28 by hydrolysis,
respectively, without a loss of optical purity (Figure 3b).
To gain some insights into the mechanism of this dual-
catalytic system, several control experiments were performed.
Upon the addition of radical inhibitors TEMPO and BHT into
the model reaction, the formation of 2 was inhibited (Figure
4a). Moreover, the radical-clock experiment with O-acyl
hydroxamide ( )-1z led to the ring-opening/cyanation
product (29) in 81% yield with 80% ee (Figure 4b). These
phenomena suggest the radical nature of this reaction.
Furthermore, the cyclic voltammogram studies revealed that
the reduction potential of 1a is −1.22 V vs Ag/Ag+ in MeCN
(Figure S2), thus indicating that 1a can be easily reduced by
IV/ III
the excited-state photocatalyst Ir(III)* (E1/2
*
= −1.73 V
vs SCE).20 A luminescence quenching experiment also showed
that the excited photocatalyst Ir(III)* is efficiently quenched
by the O-acyl hydroxamide 1a (Figure S3).
ASSOCIATED CONTENT
* Supporting Information
■
On the basis of these results and literature prece-
dents,14,17b,18a the proposed mechanism of this cooperative
photoredox and copper catalysis is depicted in Figure 5.
Initially, O-acyl hydroxamide 1a reductively quenches the
excited photocatalyst Ir(III)* to form an amidyl radical A,
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02008.
General methods, conditions optimization, procedures
for starting material preparation, analytic data and copies
19c,d,21
−
together with a carboxylate anion (ArCO2 ) and Ir(IV).
C
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(e) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis.
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Accession Codes
CCDC 2009244 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
Shouyun Yu − State Key Laboratory of Analytical Chemistry for
Life Science, Jiangsu Key Laboratory of Advanced Organic
Materials, Chemistry and Biomedicine Innovation Center
(ChemBIC), School of Chemistry and Chemical Engineering,
School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing 210023, China; orcid.org/0000-0003-
4292-4714; Email: yushouyun@nju.edu.cn
Authors
Hui Chen − State Key Laboratory of Analytical Chemistry for
Life Science, Jiangsu Key Laboratory of Advanced Organic
Materials, Chemistry and Biomedicine Innovation Center
(ChemBIC), School of Chemistry and Chemical Engineering,
School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing 210023, China
Weiwei Jin − State Key Laboratory of Analytical Chemistry for
Life Science, Jiangsu Key Laboratory of Advanced Organic
Materials, Chemistry and Biomedicine Innovation Center
(ChemBIC), School of Chemistry and Chemical Engineering,
School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing 210023, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(21971110 and 21732003) for the financial support.
■
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