Asymmetric Deoxygenative Cyanation of Benzyl Alcohols Enabled by Synergistic Photoredox and Copper Catalysis?

Article abstract of DOI:10.1002/cjoc.202000309

Summary of main observation and conclusion. An enantioselective deoxygenative cyanation of benzyl alcohols was accomplished for the first time through the synergistic photoredox and copper catalysis. This reaction features the use of organic photosensitizer and low-cost 3d metal catalyst, simple and safe operations, and extremely mild conditions. A variety of chiral benzyl nitriles were produced in generally good yields and high level of enantiocontrols from readily available feedstocks (22 examples, up to 93% yield and 92% ee).

Full text of DOI:10.1002/cjoc.202000309

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Asymmetric Deoxygenative Cyanation of Benzyl Alcohols Enabled by
Synergistic Photoredox and Copper Catalysis
Authors: Hong-Wei Chen, Fu-Dong Lu, Ying Cheng,* Yue Jia, Liang-Qiu Lu* and
Wen-Jing Xiao
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000309.
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Chinese Journal
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deoxygenative cyanation, synergistic catalysis, visible light, chiral nitrile
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CJC
中
国 化 学 - An International Journal
Asymmetric Deoxygenative Cyanation of Benzyl Alcohols Enabled by
Synergistic Photoredox and Copper Catalysis
Hong-Wei Chen,#,a Fu-Dong Lu,#,a Ying Cheng,*,a Yue Jia,a Liang-Qiu Lu*,a and Wen-Jing Xiaoa,b
aCCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China
Normal University, 152 Luoyu Road, Wuhan 430079, China
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, 345 Lingling Road, Shanghai 200032, China
#These two authors contribute equally to this work.
Cite this paper: Chin. J. Chem. 2020, 38, XXX—XXX. DOI: 10.1002/cjoc.202000XXX
Summary of main observation and conclusion An enantioselective deoxygenative cyanation of benzyl alcohols was accomplished for the first time
through the synergistic photoredox and copper catalysis. This reaction features the use of organic photosensitizer and low-cost 3d metal catalyst, simple
and safe operations, and extremely mild conditions. A variety of chiral benzyl nitriles were produced in generally good yields and high level of
enantiocontrols from readily available feedstocks (20 examples, up to 93% yield and 92% ee).
photoredox catalysis with asymmetric copper catalysis[11]] could
be utilized to realize enantioselective deoxygenative cyanation of
Background and Originality Content
Synthesis of organic nitriles has attracted much attention from
benzyl alcohols, affording optically active benzyl nitriles from
synthetic community, since nitrile functional group is a highly
readily available feedstocks under mild conditions (Scheme 1c).
valuable synthetic handle in organic synthesis[1] and a popular
moiety in pharmaceutical and agricultural chemicals.[2] In
particular, benzyl nitriles are often found in commercial
pharmaceuticals. For examples, Anastrozole[3] is an aromatase
inhibitor which exhibits antineoplastic activity, and Verapamil[4] is
used as an antiarrhythmic agent and is also employed in the
treatment of angina. In this context, the development of highly
efficient protocols for preparing benzyl nitriles has been
significantly developed.[5] Among them, the deoxygenative
cyanation of readily available benzyl alcohols has been regards as
one of the most efficient approaches to achieve benzyl nitriles. As
early as 1967, Mitsunobu reaction was proved to be useful in the
transformation of benzyl alcohols to benzyl nitriles.[6] Recently,
Lewis-acid-catalyzed substitutions of benzyl alcohols and their
methyl ether derivatives were successfully developed for the
synthesis of benzyl nitriles (Scheme 1a).[7] For example, in 2008,
Ding and coworkers reported a direct cyanation of α-aryl alcohols
with trimethylsilyl cyanide (TMSCN) in the presence of indium
halide catalysts.[7] Later, other Lewis acids, such as B(C6F5)3,[7]
Scheme 1 Cyanation of benzylic alcohols and derivatives
A possible mechanism of the designed reaction was outlined
in Scheme 2. Irradiation of the ground state photocatalyst PC with
visible light would generate the excited state of photocatalyst PC*.
Then, it would reduce the redox-active benzyl ester 1, which can
[7]
[7]
Zn(OTf)2
and FeCl3 , were also used to catalyze this
transformation. In addition to these Lewis acid catalytic processes,
transition-metal-catalyzed coupling reactions of benzyl pivalate
esters was proven feasible for the synthesis of benzyl nitriles by
Rousseaux with Ni(II) salts as the catalyst and Zn(CN)2 as the
cyanide source (Scheme 1b).[8] Despite these important advances,
to our knowledge, there is no catalytic asymmetric conversion of
benzyl alcohols to significant chiral benzyl nitriles.
In recent years, attributed to the pioneering work of Liu and
coworkers, Cu-catalyzed asymmetric radical couplings have been
established an elegant approach to chiral benzyl nitriles.[9] A series
of enantioselective benzylic radical cyanation reactions, including
direct cyanation of benzylic/remote C-H bonds[9], decarboxylative
cyanation of N-hydroxy-phthalimide esters[9], difunctionalization
of alkenes[9] and ring-opening cyanation of cyclopropanols and
cyclopropanone acetals,[9] have been significantly exploited.
Along these lines and based on our research focus on visible light
photocatalysis,[10] we wondered whether the combination of
be
easily
prepared
from
benzyl
alcohol
and
3,5-bis(trifluoromethyl)benzoyl chloride, through a single electron
transfer (SET) event.[12],[13] Hydrolysis of benzyl C-O bond would
occur to produce the benzylic radical A and a carboxylic anion.
Following, cyanide anion (CN-) released from TMSCN (2) by
reacting with carboxylic anion would coordinate with chiral Cu(I)
catalyst to form L*Cu(I)(CN) (C). Oxidation of this Cu(I) species by
the oxidized state of photocatalyst PC+ would give L*Cu(II)(CN)2
(D), accompanying with regeneration of the ground-state
photocatalyst PC. Meanwhile, benzylic radical A would be trapped
by the L*Cu(II)(CN) species to give the Cu(III) intermediate E or E’.
Finally, a reductive elimination process would proceed to yield
the desired chiral benzyl nitrile 3 and the chiral Cu(I) catalyst
would be regenerated.
*E-mail: luliangqiu@mail.ccnu.edu.cn; ycheng@mail.ccnu.edu.cn
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10.1002/cjoc.202000309
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Scheme 2 A proposed mechanism for the designed cyanation
Table 1 Optimization of the reaction conditionsa
Entry Photocatalyst Cu source Chiral ligand Yield (%)b Ee (%)c
1
2
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuI
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
L8
20
10
19
23
26
3
64
56
49
59
21
33
77
88
88
90
89
89
85
91
92
ND
3
4
5
6
7
16
28
98
66
21
97
98
98
94
NR
8
9d
Results and Discussion
10d,e
11d,e
12d,e
13d,e
14d,e
15d,e,f
16d,e,f,g
To test this hypothesis, ester substrate 1a and commercially
available cyanating agent TMSCN (2) were chosen as starting
materials. Using fac-Ir(ppy)3 as the photocatalyst and the
combination of CuBr and chiral bisoxazoline ligand L1 as the chiral
catalyst, the desired chiral product 3a was afforded in 20% yield
and 64% ee after irradiating with 2 × 3 W blue LEDs in DMF for 10
hours at room temperature (rt) (Table 1, entry 1). In order to
improve the result, other chiral ligands were investigated (Table 1,
entries 2-8). Among them, the reaction with chiral ligand L8 which
has a cyclopropane unit showed the best catalysis efficiency and
enantioselectivity (Table 1, entry 8: 28% yield and 88% ee).
Increasing the amount of TMSCN led to a further improvement of
yield (88%, Table 1, entry 9). Next, the solvent effect was
evaluated,[14] and the mixed solvent of DMF and p-xylene (2:3)
CuCl
fac-Ir(ppy)3 Cu(MeCN)4PF6
fac-Ir(ppy)3 Cu(MeCN)4BF4
Ph-PTZ
Cu(MeCN)4BF4
Control experiments
aReaction conditions: 1a (0.2 mmol), 2 (0.22 mmol), photocatalyst (2
mol %), Cu source (10 mol %), chiral ligand L (12 mol %), DMF (2 mL), 2 × 3
W blue LEDs, rt, 10 h. bDetermined by the 1H NMR of reaction mixtures
with 1,3,5-trimethoxybenzene as an internal standard. cDetermined by
chiral HPLC analysis. dUsing 2 (0.6 mmol). eUsing mixed solvent of DMF
and p-xylene (2:3, 2 mL). fUsing Ph-PTZ (2 mol%), Cu(MeCN)4BF4 (2.5
mol %) and L8 (3 mol %) at rt for 24 h under the irradiation of 2 × 3 W
purple LEDs. gNo Cu(MeCN)4BF4, no light or no photocatalyst. Ph-PTZ =
10-phenyl-10H-phenothiazine; DMF: N,N-dimethylformamide.
gave
a slightly increased enantioselectivity, albeit with a
diminished yield (Table 1, entry 10: 66% yield and 90% ee). Other
copper sources were screened (Table 1, entries 10-14), and
Cu(MeCN)4BF4 stood out the best one (Table 1, entry 14: 94%
yield and 91% ee). Notably, when metallic photocatalyst
fac-Ir(ppy)3 was replaced by organic photocatalyst Ph-PTZ, the
yield and enantioselectivity of 3a remain excellent even with a
reduced loading of chiral copper catalyst (Table 1, entry 15: 94%
yield and 92% ee). Control experiments indicated that copper
catalyst, photocatalyst or light irradiation are necessary for this
synergistic catalytic asymmetric cyanation of pre-activated benzyl
alcohols (Table 1, entry 16).
After established the optimal reaction conditions, we turned
our attention to determine the generality of methodology. As
shown in the Scheme 3, a wide range of benzyl esters that can be
easily prepared from simple alcohols can successfully participate
in this cyanation reaction. For examples, introducing a methoxy
group to the naphthalene ring did not obviously affect the
reaction efficiency and selectivity (3b: 93% yield and 90% ee).
Replacement of methyl group with other functional groups, such
as phenyl, benzyl, alkyne and ether, the reaction can still proceed
smoothly, providing corresponding chiral nitriles 3c-3f in 40-91%
yields and 67-92% ee. 1-Naphthyl-substituted esters 1g can also
participate in this transformation, chiral nitrile 3g was afforded in
a high yield with a good enantioselectivity (3g: 58% yield, 76% ee).
In addition to the naphthalene ring, substrates bearing the
benzene ring, regardless of the electronic properties and
substitution manners, can be converted to the corresponding
chiral benzyl nitriles in generally good yields with excellent
enantioselectivities (3h-3o, 32-91% yields and 70-90% ee).
Moreover, substrate containing a heteroaryl unit, pyridine, was
tolerated here, affording chiral product 3p in 82% yield and 63%
ee. The reduced yields and enantioselectivities might be the result
of unfavored interaction between the heteroatom on substrate
with Cu catalyst. The catalytical system works well in the reaction
of ethyl-, pentyl-, isopropyl-substituted and cyclic benzyl esters,
too (3q-3u: 55-92% yields and 73-87% ee). To demonstrate the
utility of methodology, ester 1v that was prepared from a
antimalarial drug, Lumefantrine,[15] was subjected to the standard
conditions. Cyanation product 3v we successfully afforded in a
good yield and ee value (67% yield and 71% ee), which represent
a possibility to find new drugs by modifying prescription drugs.
Furthermore, a gram-scale reaction was performed under the
syngestic catalysis conditions by using 8 mmol of substrate 1a and
24 mmol of TMSCN (2) in the presence of 2.5 mmol% of
Cu(MeCN)4BF4,
3 mmol% of L8 and 5 mmol% of Ph-PTZ.
Irradiating the reaction system with 2 x 3W purple LEDs for 36
2
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Running title
Chin. J. Chem.
Scheme 3 Substrate scopea
Scheme 5 Mechanistic investigation
To gain insight into the mechanism of the reaction, several
mechanistic probe experiments were investigated. First, radical
clock experiment was carried out (Scheme 5a). When cyclopropyl
group was introduced into the ester substrate, the
ring-opening/cyanation product
4 and ring-opening/coupling
product 5 were detected by GC-MS. This result indicated the
generation of benzylic radical in the reaction. Second, the
quantum yield (Scheme 5b, 0.36) and the light/dark experiments
(Scheme 5c) suggested a possible nonchain radical process for this
deoxygenative cyanation reaction.
aPerformed under the optimal conditions in 0.2 mmol scales as indicated
in entry 15, Table 1; isolated yields.
Conclusions
Scheme 4 Gram-scale reaction
In summary, we have developed an enantioselective
deoxygenative cyanation reaction through the synergistic
photoredox/copper catalysis strategy. This method allows the
facile synthesis of chiral benzylic cyanides from readily available
benzyl alcohols and TMSCN with high reaction efficiency and
enantioselectivity under mild conditions. It was believed that, this
work added a new example to the few asymmetric deoxygenative
transformations via SET processes.
Experimental
General procedure for the asymmetric cyanation: in an
argon-filled glove box, a flame-dried 10 ml Schlenk tube equipped
with a magnetic stirrer bar was charged with Cu(MeCN)4BF4 (1.57
mg, 0.005 mmol), L8 (2.14 mg, 0.006 mmol) and DMF (0.125 mL).
The mixture was stirred at room temperature for 30 min and then,
the vial was closed and the Schlenk tube was removed from the
glove box. Ph-PTZ (1.10 mg, 0.004 mmol) and DMF (0.675 mL)
were added, followed by the addition of substrate 1a (0.2 mmol)
and p-xylene (1.2 mL). The resulting mixture was degassed via
hours afforded the chiral nitrile product 3a in 83% yield with 90%
ee (Scheme 4). Organic photocatalyst Ph-PTZ and activating
reagent 3,5-(ditrifluoromethyl) benzoic acid can be recovered in
good yields. These results proved the practicality of present
reaction methodology.
‘freeze-pump-thaw’ procedure for
3 times under argon
atmosphere and TMSCN (75 L, 0.6 mmol) was introduced. The
reaction mixture was stirred at a distance of ~1 cm from a 2 × 3 W
purple LEDs at rt for 24 h. Water (20 mL) was added and aqueous
Chin. J. Chem. 2020, 38, XXX－XXX
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3

First author et al.
Report
layer was extracted with ethyl acetate (3 × 50 mL). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated. The product 3 was obtained by flash column
chromatography on silica gel (petroleum ether/ethyl acetate =
20:1).
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Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2020xxxxx.
Acknowledgement
We are grateful to the National Science Foundation of China (No.
21901080, 21822103, 21820102003 and 91956201), the Program
of Introducing Talents of Discipline to Universities of China (111
Program, B17019), the Natural Science Foundation of Hubei
Province (2017AHB047) and the International Joint Research
Center for Intelligent Biosensing Technology and Health for
support of this research.
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Chin. J. Chem.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2020
Manuscript revised: XXXX, 2020
Manuscript accepted: XXXX, 2020
Accepted manuscript online: XXXX, 2020
Version of record online: XXXX, 2020
[12] Rackl, D.; Kais, V.; Kreitmeier, P.; Reiser, O. Visible Light
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[13] The redox potential of model substrate 1a was determined:
E1/2[1a/1a•−] = −1.82 V vs saturated calomel electrode (SCE) in CH3CN.
See details in the Supporting Information.
Chin. J. Chem. 2020, 38, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Entry for the Table of Contents
Page No.
Asymmetric Deoxygenative Cyanation of Benzyl
Alcohols Enabled by Synergistic Photoredox
and Copper Catalysis
An enantioselective deoxygenative cyanation of benzyl alcohols has been accomplished through
synergistic copper/photoredox catalysis. This reaction provides an efficient approach to a variety of
chiral benzyl nitriles in high yields and enantioselectivities under mild conditions.
Hong-Wei Chen,# Fu-Dong Lu,# Ying Cheng,* Yue
Jia, Liang-Qiu Lu* and Wen-Jing Xiao
Chin. J. Chem. 2020, 38, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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This article is protected by copyright. All rights reserved.