Enantioselective Radical Carbocyanation of 1,3-Dienes via Photocatalytic Generation of Allylcopper Complexes

Article abstract of DOI:10.1021/jacs.1c01260

1,3-Dienes are readily available feedstocks that are widely used in the laboratory and industry. However, the potential of converting 1,3-dienes into value-Added products, especially chiral products, has not yet been fully exploited. By synergetic photoredox/copper catalysis, we achieve the first visible-light-induced, enantioselective carbocyanation of 1,3-dienes by using carboxylic acid derivatives and trimethylsilyl cyanide. Under mild and neutral conditions, a diverse range of chiral allyl cyanides are produced in generally good efficiency and with high enantioselectivity from bench-stable and user-safe chemicals. Moreover, preliminary results also confirm that this success can be expanded to 1,3-enynes and the four-component carbonylative carbocyanation of 1,3-dienes and 1,3-enynes.

Full text of DOI:10.1021/jacs.1c01260

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Enantioselective Radical Carbocyanation of 1,3-Dienes via
Photocatalytic Generation of Allylcopper Complexes
Fu-Dong Lu,§ Liang-Qiu Lu,§ Gui-Feng He, Jun-Chuan Bai, and Wen-Jing Xiao*
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ABSTRACT: 1,3-Dienes are readily available feedstocks that are widely used in the laboratory and industry. However, the potential
of converting 1,3-dienes into value-added products, especially chiral products, has not yet been fully exploited. By synergetic
photoredox/copper catalysis, we achieve the first visible-light-induced, enantioselective carbocyanation of 1,3-dienes by using
carboxylic acid derivatives and trimethylsilyl cyanide. Under mild and neutral conditions, a diverse range of chiral allyl cyanides are
produced in generally good efficiency and with high enantioselectivity from bench-stable and user-safe chemicals. Moreover,
preliminary results also confirm that this success can be expanded to 1,3-enynes and the four-component carbonylative
carbocyanation of 1,3-dienes and 1,3-enynes.
left).4−20 Even more exciting, excited-state chemistry21−23 has
he development of efficient methods to convert readily
Tavailable chemicals into value-added products is a been recently applied to achieve new transformations of 1,3-
dienes that are unapproachable or difficult via traditional
ground-state chemistry (Figure 1a, bottom right).24−28 For
example, in 2020, Glorius24 and Shi25 independently reported
radical dialkylations of 1,3-dienes for synthesizing homoallylic
alcohols by merging photoredox catalysis with Cr or Ti
catalysis. Furthermore, Gevorgyan26 and Glorius27 successively
disclosed a blue-light-induced, Pd-catalyzed radical carbofunc-
tionalization of 1,3-dienes for preparing functionalized alkenes.
More recently, Zhu developed a facile 1,2-aminoisothiocyana-
tion of 1,3-dienes through single photocatalysis.28 Despite
these impressive advances, the potential of difunctionalization
of 1,3-dienes via excited-state chemistry has not yet been fully
exploited. The search for novel photocatalytic reactions of 1,3-
dienes continues, with the goal of increasing the diversity of
functional groups and general asymmetric processes.29
fundamental task in modern synthetic chemistry. In this
context, selective difunctionalization of 1,3-dienes has attracted
increasing interest from industrial and academic commun-
ities.1−3 In particular, a variety of catalytic asymmetric
difunctionalizations of 1,3-dienes have been well accomplished
by using chiral organometallic catalysts (Figure 1a, bottom
Nitrile synthesis has received continuous attention due to
the synthetic versatility of cyano groups and their ubiquity in
pharmaceuticals and materials science.30−32 For this synthesis,
approaches toward chiral allyl cyanides have been explored
primarily through Ni-catalyzed asymmetric hydrocyanations of
unsaturated systems.20,33−39 Recently, the Liu group elegantly
reported a series of Cu-catalyzed asymmetric radical
cyanations40−44 and site-selective and enantioselective allylic
C−H cyanation of alkenes with the use of N-fluoroalkyl-
sulfonamide reagents.45 Inspired by the Liu cyanations as well
as our research interests on asymmetric organic photochemical
synthesis,46−50 we envisioned that a combination of photo-
Received: February 2, 2021
Published: March 11, 2021
Figure 1. Design plan for the asymmetric radical carbocyanation of
1,3-dienes by synergetic photoredox and copper catalysis. El,
electrophile; Nu, nucleophile; pin, pinacolato; NHP, N-hydroxyph-
thalimide; TMSCN, trimethylsilyl cyanide.
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J. Am. Chem. Soc. 2021, 143, 4168−4173
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redox catalysis and Cu catalysis would allow radical
carbocyanation of 1,3-dienes with carboxylic acid derived
NHP esters and TMSCN (Figure 1b). This promising plan
was designed to assemble a crucial allylcopper complex from
1,3-dienes, chiral Cu(II) complexes and photochemically
generated alkyl radicals, finally affording significant chiral
allyl nitrile products. Obviously, performing the reaction under
mild and neutral conditions can avoid the racemization of
sensitive chiral allyl cyanides.
only a trace amount of product (Table 1, entry 4). In addition,
variation in chiral ligands (L2−L4) did not lead to any
improvement on the results (Table 1, entries 5−7), while
increasing the equivalents of substrates 1a and 3 resulted in a
slightly enhanced yield (Table 1, entry 8, 54% yield and 91%
ee). We then identified the optimal photocatalysts (Table 1,
entries 9−11). When perylene (PC4) was used as the
photocatalyst and white LEDs were used as the light source,
similar reaction efficiency and enantiocontrol were afforded
(Table 1, entry 11), and increasing the reactant concentration
obviously improved the reaction efficiency (Table 1, entry 12:
71% yield and 92% ee). Control experiments confirmed that
photocatalysts, Cu catalysts, and light are all indispensable for
this multicomponent reaction.51
With this idea in mind, we first examined the multi-
component carbocyanation reaction between 1,3-dinene 1a,
NHP ester 2a, and TMSCN (3) (Table 1). Delightedly, we
a
Table 1. Condition Optimization
Having established the optimal reaction conditions, we
started to examine the generality of this methodology. As
highlighted in Table 2, a variety of bench-stable NHP esters
derived from readily available cyclic and linear alkylcarboxylic
acids were effective in this reaction, producing the correspond-
ing chiral allyl cyanide products in 66−73% yields and 89−
96% ee (Table 2, 4aa−4af). Many NHP esters with abundant
functional groups, such as alkenyl, alkynyl and chloride groups,
are also amenable to this synergetic catalysis system (4ag−
4ai). Next, we probed the scope of 1,3-diene components. As
illustrated in Table 2, regardless of the electronic properties
and substitution pattern of the benzene ring in 1,3-dienes,
chiral allyl cyanides were afforded in moderate to good yields
with high enantioselectivity (4bd−4hd, 50−67% yields and
92−97% ee). Moreover, thiophenyl- and furanyl-substituted
1,3-dienes 1i and 1j were converted to products 4id and 4jd in
70% yield with 94% ee and 73% yield with 95% ee,
respectively. Pyridinyl-substituted 1,3-diene 1k can also be
successfully converted to the desired product in moderate yield
and enantioselectivity (4kd, 45% yield and 70% ee). In
addition to monosubstituted 1,3-dienes, polysubstituted 1,3-
dienes were also investigated under the standard conditions.
For example, when an additional methyl or bromo substituent
was introduced at the β-position of the phenyl group, the
corresponding chiral allyl cyanides were obtained in moderate
yields with excellent enantioselectivities (4ld, 70% yield and
97% ee; 4md, 42% yield and 97% ee). We also found that the
1,1-disubstituted diene 1n and 1,4-disubstituted internal diene
1o were effective substrates, affording corresponding products
in promising results (4nd: 60% yield and 74% ee; 4od: 36%
yield, 79% ee, 96% ee, and 2.8:1 d.r.).52 However, internal
acyclic diene 1p failed to proceed with the carbocyanation at
the current stage. It is worth noting that nonactivated diene 1q
can be applied to this reaction, affording the desired product
4qd in 33% yield and 7% ee, which indicates that the aryl
group may be important to stabilize the generated allyl radical
and induce the enantioselectivity. Finally, the NHP ester
derived from commercially available drug dehydrocholin could
also be converted to the corresponding allyl cyanide in
moderate yield and good selectivity (4aj, 41% yield, >19:1
d.r.), which also proves the good functional group tolerance of
this strategy.
a
Conditions: 1,3-diene 1a (0.4 mmol), NHP ester 2a (0.2 mmol),
TMSCN 3 (0.3 mmol), Cu source (5 mol %), chiral ligand (6 mol
%), and PC (5 mol %) in anhydrous DCE (2 mL) at 29 °C for 24 h
under the irradiation of 2 × 3 W purple LEDs (light intensity = 37.4
b
mw/cm2). NMR yield determined using 1,3,5-trimethoxybenzene as
c
d
an internal standard. Determined by chiral HPLC analysis. Using
1,3-diene 1a (0.6 mmol) and TMSCN 3 (0.6 mmol). Using 2 × 3 W
white LEDs, 36 h. Using DCE (0.5 mL), isolated yield in
e
f
parentheses. ND: not determined.
found that the E-allyl cyanide product 4aa was formed in 40%
yield and 90% ee after irradiation with purple LEDs for 24 h in
the presence of organic photocatalyst PC1, Cu(MeCN)4BF4,
and chiral bisoxazoline ligand L1 (Table 1, entry 1). Notably,
To highlight the synthetic utility of the methodology, we
performed asymmetric radical carbocyanation on a gram scale.
Chiral product 4ad was facilely produced in 62% yield with
95% ee starting from 1,3-diene 1a, NHP ester 2d, and TMSCN
(Figure 2a). Furthermore, we converted allyl cyanide 4ad into
many other useful chiral compounds by simple operations
(Figure 2b). For example, treatment of 4ad under a H2
1
no Z-allyl cyanide was detected through H NMR analysis of
the reaction mixture. Screening of Cu sources indicated that
Cu(I) catalyst selection was crucial for this transformation. For
example, replacement of Cu(MeCN)4BF4 with CuOAc and
CuCN did not obviously affect the reaction efficiency and
selectivity (Table 1, entries 2 and 3), and Cu(OTf)2 afforded
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Table 2. Scope of the Radical Carbocyanation of 1,3-
a
Dienes
Figure 2. Utility of the reaction methodology. (i) Pd/C (5 mol %),
EtOH (40 mL), H2 balloon, rt, 16 h. (ii) NiCl2 (1.5 equiv),
NaBH4(12 equiv), Boc2O (3.0 equiv), MeOH (10 mL), 0 °C to rt, 6
h. (iii) H2SO4 (0.35 mL), MeOH (0.8 mL), 0 to 65 °C, overnight.
(iv) [Ir{dF(CF3) ppy}2(bpy)]PF6(2 mol %), DCM (1 mL), 2 × 3 W
blue LEDs, rt, 36 h. dF(CF3) ppy: 3,5-difluoro-2-[5-(trifluoromethyl)-
2-pyridyl]phenyl. dtbpy: 4,4′-di-tert-butyl-2,2′-dipyridyl.
which were used to produce allyl radicals via direct
photocatalytic C−O bond breaking,53 were subjected to
standard conditions (Figure 3a). Regardless of which allyl
a
All the reaction were performed in 0.2 mmol scale; isolated yields
b
and ee values were determined by chiral HPLC analysis. fac-Ir(ppy)3
(1 mol %) instead of perylene, 2 × 3 W blue LEDs, 24 h. Ph-PTZ (5
mol %) instead of perylene, DCE (2 mL), 2 × 3 W purple LEDs.
c
Figure 3. Mechanistic investigations.
atmosphere with Pd/C as the catalyst or reduction of 4ad with
NiCl2 and NaBH4 afforded chiral alkyl cyanide 5a and chiral
alkyl amine 5b in good yields and optimal purities, respectively.
Product 4ad can also be converted to chiral allyl ester 5c in
good yield under alcoholysis conditions. Moreover, we
achieved photocatalytic olefin isomerization of 4ad to afford
the difficult to obtain Z-conformation of the chiral allyl cyanide
5d in high yield and high enantiopurity.
ester was used, the same chiral allyl cyanides 7 were delivered
with similar yields and the same enantioselectivity. These
results indicated that (1) the isomerization of allylic radical
intermediates might occur faster than the capture of these
open-shelled species by chiral copper complexes and (2) the
regioselectivity might be controlled by steric repulsion during
the capture process (Ph vs CH2R). Second, when 2,2,6,6-
tetramethylpiperidinooxy (TEMPO) was added to the
carbocyanation of 1,3-diene 1a, the conversion of the starting
materials was remarkably reduced. We assume that (1)
Next, we conducted a series of experiments to shed light on
the mechanism. First, two different allyl esters 6a and 6b,
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TEMPO might add to Cu complex and shut down the reaction
in some extent and (2) the possible intermediates, alkyl
radicals and allyl radicals, were trapped by TEMPO as we
observed the corresponding adducts by GC-MS analysis of the
reaction mixture (Figure 3b). Third, when a radical clock
experiment with cyclopropyl-containing NHP ester 2k was
conducted under the standard conditions, only ring-opening
product 4ag and not 4ak was observed (Figure 3c). These two
experiments strongly suggested the generation of alkyl radicals
from NHP esters and allyl radicals via the radical addition of
alkyl radicals to 1,3-dienes.
Based on the above experimental evidence and existing
related literature, we proposed a possible synergetic catalysis
mechanism for this multicomponent transformation (Figure
4). With the model reaction as an example, initially, the
a
Figure 5. Extensions of reaction methodology. Ph-PTZ (5 mol %)
b
instead of perylene, 2 × 3 W purple LEDs. DCE (2 mL), 3 W blue
LEDs.
ments indicated that the four-component reactions with 1,3-
diene 1a or 1,3-enyne 8c occurred in an orderly manner,
affording chiral allyl ketocyanide 10 and chiral propargyl
ketocyanide 11 in moderate yields and high enantioselectivities
(Figure 5b, 10: 46% yield and 91% ee; 11: 48% yield and 88%
ee).
In summary, we have successfully achieved enantioselective
carbocyanation of 1,3-dienes with carboxylic acid derivatives
and TMSCN through synergetic photoredox/copper catalysis.
This unprecedented protocol produced a diverse range of
enantioenriched allyl cyanides in generally good yields and
with high enantioselectivities. Moreover, a possible mechanism
was proposed on the basis of control experiments and the
redox properties of substrates, photocatalysts, and Cu catalysts.
Importantly, the same strategy can be further applied to the
similar difunctionalization of 1,3-enynes and the asymmetric
four-component radical carbonylative carbocyanation of both
1,3-dienes and 1,3-enynes. We believe that this work provides a
new avenue for the catalytic asymmetric difunctionalization of
readily available 1,3-dienes and related feedstocks.
Figure 4. A proposed reaction mechanism.
photocatalyst perylene (PC4) approaches its excited state
PC4* under irradiation with visible light. This high-energy
species possesses a strong reducing capacity (E1/2[PC4•+/
PC4*] = −2.23 V vs SCE)54 and can reduce redox-active NHP
ester 2a (E1/2[2a/2a•+] = −1.15 V vs SCE) to radical I, which
is accompanied by the release of CO2, the NHP anion, and
oxidized photocatalyst PC4•+.55,56 Next, the resulting alkyl
radical adds to 1,3-diene 1a to generate allyl radical II.
Meanwhile, the chiral Cu(I) catalyst coordinates with the
cyanide anion, which was generated by the reaction between
TMSCN and the NHP anion, and then is oxidized by PC4•+
(E1/2[PC4•+/ PC4] = 0.61 V vs SCE) to generate L*Cu(II)-
(CN) and close the photocatalytic cycle.46 Allyl radical II is
captured by L*Cu(II)(CN) to form chiral allyl Cu(III) species
VI. Finally, product 4aa is delivered after reductive elimination
from Cu(III) intermediate VI, and the Cu(I) catalyst is
regenerated to close the copper catalytic cycle.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01260.
■
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Experimental procedures, and characterization data for
all the products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Following the successful asymmetric radical carbocyanations
of 1,3-dienes, we further probed the possibility of using 1,3-
enynes57−60 to access chiral propargylic cyanides. With aryl-
and heteroaryl-substituted 1,3-enynes 8a and 8b as examples,
the desired products were produced in good yields and high
enantioselectivities under the standard conditions (Figure 5a,
9a: 51% yield and 87% ee; 9b: 65% yield and 84% ee).
Moreover, we further expanded the success of this synergetic
catalysis system to the more challenging four-component
reaction radical carbonylative carbocyanation. Notably, CO
would coordinatively saturate the Cu center and/or compete
with cyanides and chiral ligands, thus making the chiral Cu
catalyst ineffective or making radical carbonylative carbocya-
nation unordered.61−64 To our delight, preliminary experi-
Wen-Jing Xiao − CCNU-uOttawa Joint Research Centre, Key
Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal
University, Wuhan 430079, China; State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China; orcid.org/0000-0002-9318-6021;
Email: wxiao@mail.ccnu.edu.cn
Authors
Fu-Dong Lu − CCNU-uOttawa Joint Research Centre, Key
Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal
University, Wuhan 430079, China
4171
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Liang-Qiu Lu − CCNU-uOttawa Joint Research Centre, Key
Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal
University, Wuhan 430079, China; State Key Laboratory for
Oxo Synthesis and Selective Oxidation, Lanzhou Institute of
Chemical Physics (LICP), Chinese Academy of Sciences,
Lanzhou 730000, People’s Republic of China; orcid.org/
0000-0003-2177-4729
Gui-Feng He − CCNU-uOttawa Joint Research Centre, Key
Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal
University, Wuhan 430079, China
Jun-Chuan Bai − CCNU-uOttawa Joint Research Centre, Key
Laboratory of Pesticide and Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal
University, Wuhan 430079, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01260
Author Contributions
§F.-D.L. and L.-Q.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21822103, 21820102003, 21822303, 21772052,
21772053, 21572074, and 21472057), the Program of
Introducing Talents of Discipline to Universities of China
(111 Program, B17019), the Natural Science Foundation of
Hubei Province (2017AHB047), and Hubei International
Scientific and Technological Cooperation Base of Pesticide
and Green Synthesis for support of this research. We thank
Professors Jia-Rong Chen and Ying Cheng in CCNU for
helpful discussions.
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