Catalytic Asymmetric Electrochemical α-Arylation of Cyclic β-Ketocarbonyls with Anodic Benzyne Intermediates

Article abstract of DOI:10.1002/anie.202006016

Asymmetric catalysis with benzyne remains elusive because of the highly fleeting and nonpolar nature of benzyne intermediates. Reported herein is an electrochemical approach for the oxidative generation of benzynes (cyclohexyne) and its successful merging with chiral primary aminocatalysis, formulating the first catalytic asymmetric enamine–benzyne (cyclohexyne) coupling reaction. Cobalt acetate was identified to stabilize the in situ generated arynes and facilitate its coupling with an enamine. This catalytic enamine-benzyne protocol provides a concise method for the construction of diverse α-aryl (α-cyclohexenyl) quaternary carbon stereogenic centers with good stereoselectivities.

Full text of DOI:10.1002/anie.202006016

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Accepted Article
Title: Catalytic AsymmetricElectrochemicalα-Arylation of Cyclic β-
Ketocarbonyls with Anodic Benzyne Intermediates
Authors: Longji Li, Yao Li, N Fu, L Zhang, and Sanzhong Luo
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Catalytic Asymmetric Electrochemical α-Arylation of Cyclic β-
Ketocarbonyls with Anodic Benzyne Intermediates
Longji Li,[b,+] Yao Li,[a,+] Niankai Fu,[b] Long Zhang[a] and Sanzhong Luo[a, b]*
Dedicated to Professor Youqi Tang on the occasion of his 100th Birthday
Abstract: Asymmetric catalysis with benzyne remains elusive due
to the highly fleeting and non-polar nature of benzyne
intermediates. We reported herein an electrochemical approach
for the oxidative generation of benzynes and cyclohexyne and its
successful merging with chiral primary aminocatalysis, formulating
the first catalytic asymmetric enamine-benzyne (cyclohexyne)
coupling reaction. Cobalt acetate was identified to stabilize the in-
situ generated arynes and facilitate its coupling with enamine. This
catalytic enamine-benzyne protocol provides a concise method for
the construction of diverse α-aryl or cyclohexenyl quaternary
carbon stereogenic centers with good stereoselectivities.
Scheme 1. Reactive Intermediates in asymmetric electrochemical catalysis
The first asymmetric electrochemical catalysis was
[1]
reported in 1966,
almost the same time when modern
As a highly fleeting intermediate, benzyne is seldom
utilized in stereogenic reactions as the quench of this neutral
and highly reactive species occur spontaneously, in most
cases exceeding any noticeable external control. In addition,
the benzyne trapping is always accompanied by undesired
bond formation and fragmentation, adding more complexity in
stereocontrolling.[11] Hence, enantioselective reactions with
benzynes are extremely rare, to achieve asymmetric catalysis
with a benzyne intermediate remains elusive and has not been
reported so far. Recently, Garg and Houk reported an
enantioseletive coupling of preformed chiral enamine and
benzynes (Scheme 2, I).[12] Building on this pioneering study,
we tried to develop a catalytic enamine arylation of β-
ketoesters with benzynes on the basis of our chiral primary
amine catalyst.[13] It should be noted a general catalytic
asymmetric arylation of β-ketoesters has not been achieved.
The only catalytic version with high enantioselectivity was
reported by Ma in the coupling of 2-methylacetoacetate with 2-
iodotrifluoroacetanilides (Scheme 2, I).[14]
asymmetric catalysis was born.[2] However, the development
in this field has long been overshadowed by the tremendous
successes of its thermal counterparts as well as the recent
breakthroughs in photochemical reactions.[3] The main
challenges may at least come from the preconceptions that
stereocontrol may be disfavored in a highly ionic media that is
essential in electrochemical reactions. In addition, electrode
interfacial e/mass transfer, distinctive from the typical solution
phase asymmetric catalysis, is usually obscure in asymmetric
electrochemical catalysis, which may hinder its rational
development.[4] Echoing the pursuit of sustainable
transformations, there recently appears a renaissance of
asymmetric electrochemical catalysis by merging asymmetric
catalysis and electrochemical process (Scheme 1).[5] Anodic
oxidation could be employed to in-situ generate stabilized
electrophilic species such as imine or iminium ion
intermediates in asymmetric aminocatalytic process by the
groups of Jørgensen[6] and Luo[7], respectively. Recently, the
groups of Meggers[8], Guo[9] and Lin[10] have also developed
asymmetric catalysis with anodically generated free radical
species. Despite of these advances, the potentials of
asymmetric electrochemical catalysis remains largely
unexplored. Herein, we report an anodic generation of
benzyne or cyclohexyne intermediates and its participation in
an asymmetric arylation reaction by chiral primary amine
catalysis.
We initially examined the coupling of a cyclic ketoester 2a
with the typical Kobayashi benzyne precursor (2-
(Trimethylsilyl)phenyl triflate) in the presence of our chiral
primary amine catalyst. Though the reaction gave a promising
80% ee, further efforts in improving the productivity were in
vain and the yield never exceeded 10% (Scheme 2, II). In this
context, we pursued different benzyne precursors and 1-
aminobenzotriazole, first developed by Campbell and Rees,
appeared as a promising alternative requiring an oxidative
condition for benzyne generation.[15] The common applied
protocol utilized Pb(OAc)4 as the oxidant, which is toxic and
undesirable in terms of reaction-economy and sustainability
and also causes issues on compatibility.[16] We then explore
an electrochemical approach to address these issues, and
such an electrochemical aryne generation, to the best of our
knowledge, was unknown.
[a]
[b]
Dr. Y. Li, Prof. Dr. L. Zhang, Prof. Dr. S. Luo
Center of Basic Molecular Science (CBMS), Department of
Chemistry, Tsinghua University, Beijing 100084, China
E-mail: luosz@tsinghua.edu.cn
L. Li, Prof. Dr. N. Fu, Prof. Dr. S. Luo
Key Laboratory of Molecular Recognition and Function, Institute
of Chemistry, Chinese Academy of Sciences, Beijing 100190,
China; University of Chinese Academy of Sciences, Beijing
100049, China
These authors contributed equally to this work.
Supporting information for this article is given via a link at the
end of the document.
[+]
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other cobalt salts showed no improvement on yields (Table 1,
entries 10-12). Mechansitically, the role of cobalt acetate may
lie in its capability in binding the triple bond, resulting in the
stabilization of benzyne intermediate to ensure a high
propensity for enamine trapping (vida infro for detailed
discussions). During optimization, it was verified that the use
of MeCN as media was important for reaction efficiency as the
use of either DCM (Table 1, entry 14) or MeOH (Table 1, entry
15) resulted in lower yields. Other anode material such as
graphite (Table 1, entry 16) were found to be less efficient
Table 1. Screening and optimization[a]
ee
Variation from standard
conditions
Yield [%][b]
Entry
[%][d]
Scheme 2. Asymmetric electrochemical arylation of cyclic β-ketocarbonyls
71(67[c]
36
)
94
78
63
74
67
90
82
84
---
None
1
2
We commenced the studies on catalytic asymmetric
arylation by using 1-aminobenzotriazole (1a) with ethyl 2-
oxocyclohexanecarboxylate (2a) as model substrates.
Oxidative compatibility of the primary amine catalyst and
enamine intermediate was the primary concern. By cyclic
voltammetry (CV) analysis, it was found that 1-
aminobenzotriazole 1a (Eox = 0.84 V) was much easier to be
oxidized than the primary amine catalyst (e.g. 3a, Eox = 1.54 V)
and the corresponding enamine intermediate (Eox = 1.15 V).
Beyond the issues on stereocontrol, another challenge is the
selective capture of the benzyne by the catalytic enamine
intermediate in preference to other reactive species such as
aminocatalyst itself and uncontrolled enol species. Bearing
these issues in mind, we first screened different
aminocatalysts focusing our efforts exclusively in a simple
electrochemical system consisting Co(OAc)2·4H2O (20 mol%)
as the additive and the platinum plates as the electrodes in an
undivided cell. Gratifyingly, in the catalysis with our chiral
primary amine catalyst 3a/TfOH, the desired α-arylation
product was obtained in 71% yield and 94% ee under the
optimized conditions (Table 1, entry 1).
3b
27
3c
3
14
3d
4
26
3e
5
41
6
3f
37
7
3g
3h
47
8
N. D
40
9
No 3
89
90
Zn(OAc)2·2H2O
Ni(OAc)2·4H2O
10
11
35
Other cobalt salts, e.g.
CoCl2, CpCo(CO)2,
Cp2Co
trace-23
---
12
28
25
88
92
---
89
93
92
No additive
CH2Cl2
13
14
15
16
17
18
Critical to the successful coupling were the identification of
primary amine catalyts 3a as well as the use of
Co(OAc)2·4H2O as an additive. Other L-tert Leucine derived
primary amine catalysts 3b~3c and L-phenylalanine derived
3d~3g showed inferior results in terms of both yield and
enantioselectivity (Table 1, entries 2-8) for the model reaction.
When the reaction was conducted in the absence of amine
catalyst (3a/TfOH), no desired product was detected (Table 1,
entry 9), indicating the essential role of aminocatalysis in
facilitating the desired benzyne trapping. Among different
metal additive screened, Co(OAc)2·4H2O was found to
significantly improve the productivity, and the reaction gave
only 28% yield with 88% ee in its absence (Table 1, entry 13).
Other metals such as Zn(OAc)2·2H2O or Ni(OAc)2·4H2O or
trace
30
CH3OH
C (+) |Pt (-)
3 mA
57
41
1 mA
[a] General conditions: 1a (0.20 mmol), 2a (0.10 mmol), 3 (20 mol%) in a
0.1 M nBu4NBF4 solvent mixture (3.0 mL) at room temperature. [b]
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Determined by GC-MS analysis with an internal standard. [c] Isolated by
flash chromatography. [d] Determined by HPLC.
Scheme 3. Substrate scopes. Reaction conditions: [a] 1 (0.20 mmol), 2a (0.10 mmol), 3a (20 mol%), nBu4NBF4 (0.1 M), MeCN (3.0 mL), constant current = 2
mA, reaction time 4−5 h (see SI). [b] 1a (0.80 mmol), 2a (0.40 mmol), 3a (20 mol%) in a 0.1 M nBu4NBF4 solvent mixture (12.0 mL) at room temperature was
electrolyzed at constant current of 8 mA. [c] With 3f as the amine catalyst and m-NO2PhCOOH (50 mol %) as an additive. [d] With 3f as the amine catalyst
and m-NO2PhCOOH (20 mol %) as an additive. Note: Grey dot denotes triazole carbons; the number indicates the position of substituents in the parent N-
aminobenzotriazole (entries 21, 22 and 24-26).
than platinum. Further optimization showed a current of 2 mA was
optimal, increasing the current to 3 mA or decreasing to 1 mA all
led to reduction of productivity (Table 1, entries 17 and 18).
benzyne (or aryne) (Scheme 3, entry 24). Both regio-isomers
were obtained with high enantioselectivity. Similar effect was also
observed when replacing methyl group with methoxyl and t-butyl
group (Scheme 3, entries 25 and 26). In the latter case, the
bulkiness of t-butyl moiety enhanced the bias toward para-isomer
4ga. The present electrochemical reaction could also be
conducted on a 0.4 mmol scale, affording 53% yield and 92% ee
(Scheme 3, entry 1).
With the optimized conditions in hand, we then explored the
the scopes of substrates for this asymmetric electrochemical
catalysis. Different ester moieties in the cyclohexane β-ketoesters
including methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopentyl
and benzyl ester groups were tolerated to give the desired
arylation adduct in good yields (up to 69%) with high
enantioselectivity (93~96% ee) (Scheme 3, entries 2-7). Prochiral
4-substituted cyclohexanone could also be applied to furnish the
expected desymmetric arylation adducts (Scheme 3, entries 15
and 16). Though the diastereoselectivity was low in these cases,
both diasteroisomers were obtained with high enantioselectivity,
indicating the arylation step is under strict catalytic control. The
reaction worked well with cyclopentanone and in these cases
chiral primary amine catalyst 3f was found to give better
enantioselectivity (Scheme 3, entries 8-14). A free ketoamide
could also be accommodated to afford α-arylated adduct 4ar (33%
yield, 84% ee, entry 17). Acyclic β-ketoesters have also been
attempted with unfortunately no desired adducts being
observed.[17]
We next challenged the current catalysis with non-aromatic,
strained cyclic alkynes. For this end, a triazole precursor for
cyclohexyne was synthesized[18] and tested in the reaction.
Delightfully, the reaction worked smoothly to give cyclohexene
products in good stereoselectivities (Scheme 3, entries 27-28).
To probe the in-stiu generated benzyne or cyclohexyne, we
have added typical quenching reactant to the catalytic reactions.
When two equivalents of tetraphenylcyclopentadienone was
added, the corresponding quenching adducts (4ar and 4hr) were
obtained in 52% and 41% yield, respectively (Scheme 4, a), and
only trace amount of enamine coupling products were detected.
These results verified the electrochemical generation of reactive
benzyne or cyclohexyne intermediates.
Experiments were conducted to reveal the role of the cobalt
salts. By CV analysis, no obvious reaction current was observed
with cobalt acetate in the current asymmetric electrochemical
catalysis (Scheme S7, SI). The redox potential of Co(OAc)2·4H2O
was determined to be Eox = 0.83 V, which is comparable to that of
1-aminobenzotriazole 1a (Eox = 0.84 V). These observations
suggest that cobalt acetate is unlikely a redox mediator for anodic
generation of benzyne. The effect of cobalt acetate could be
further verified in benzyne quenching with other reagents such as
furan, cyclopentadienone and diphenyl diselenide. In the absence
Subsequently, the effect of substituents on different position
of 1-aminobenzotriazole was investigated. Symmetric dimethyl
substituted benzyne such as ortho-dimethyl- (Scheme 3, entries
18-20) or meta-dimethyl- substituted (entry 23) ones gave the
expected arylated adducts in good yields and high
enantioselectivities. In the latter, a single regioisomer 4da was
isolated. For mono-substituted benzyne, the ortho-methyl
substitution led to regioselectively single adducts with high
enantioselectivity (Scheme 3, entries 21-22). On the other hand,
two regioisomers were observed for meta-methyl substituted
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of cobalt acetate, only trace quenching adducts were detected
under anodic conditions (Scheme 4, b) and the triazole precursor
1a was completely consumed with unidentified brown tar
deposited on anode. In contrast, the addition of cobalt acetate
significantly facilitates the expected benzyne quenching with
much less anode deposition. Provided the known catalytic
capability of cobalt in activating and transforming alkynes[19] we
proposed that the cobalt may bind with the triple bond of benzyne,
hence stabilize this transient species and enhance its propensity
in coupling with the enamine intermediate. Our density functional
theory (DFT) calculation indicated that coordination with cobalt
acetate could stabilizing benzyne by 18.6 kcal/mol (Figure 1 and
Figure S8 for details).[19] In comparison, nickel acetate shows only
5.5 kcal/mol stabilization while zinc acetate is destabilizing by 1.1
kcal/mol. Considering that cobalt acetate only showed marginal
effect on enantioselectivity (Table 1, entry 1 vs 13, 94% ee vs 88%
ee), the effect of complexation on the stereocontrol in enamine
trapping should be minor, if not neglectable. In this instance, the
benzyne-Co complex may be regarded as reservoir of free
benzyne for enamine trapping under anodic conditions.
In TS-R, the dihedral angle of the catalyst skeleton (relative to
the planar enamine) as highlighted in green is -62.0°, slightly
deviated from that of the starting enamine intermediate (-66.0°).
In comparison, the disfavored TS-S has a dihedral angle of -84.5°,
a large conformation distortion in order to minimize the steric
effect for benzyne attacking. The preference of enamine Re-facial
benzyne attack can also be accounted by considering the
concerted C-C formation and H-transfer with either enamine N-H
or protonated tertiary amine N-H, which is clearly favored in the
Re-facial sphere.[22]
Figure 1. Calculated geometries and binding free energies of benzyne and
acetate complex at B3LYP-D3BJ/Def2-TZVPP-SMD//B3LYP/6-31g(d)+SDD(M)
(M = Co, Ni, Zn) level. Energies are given in kcal/mol. Interatomic distances are
denoted in Å.
Figure 2. Calculated transition state structures for addition of benzyne and
chiral enamine at B3LYP-D3BJ/Def2-TZVPP-SMD//B3LYP/6-31g(d) level.
Energies are given in kcal/mol. Interatomic distances are denoted in Å.
Noncritical hydrogen atoms are omitted for clarity.
Scheme 4. Benzyne or cyclohexyne-capture experiments.
In summary, we have developed an electrochemical method
for the generation of benzyne and cyclohexyne. Catalytic
asymmetric α-arylation or cyclohexenylation of cyclic β-
ketocarbonyls with benzyne or cyclohexyne was realized by
merging the anodic benzyne generation and chiral primary amine
catalysis. The use of cobalt acetate as an additive was found to
stabilize the benzyne intermediate and hence facilitate its
coupling with chiral enamine intermediate. The enamine-aryne
coupling could be applied to cyclic β-ketocarbonyls, such as five
or six-membered ring β-keto esters and five-membered ring β-
ketoamide, allowing the rapid construction of diverse optically
active α-aryl or cyclohexenyl derivatives with good
stereoselectivities.
DFT calculations were performed to elucidate the origins of
enantioselectivity of α-arylation.[20] The calculated energies
difference between TS-R and TS-S, 1.9 kcal/mol, is in good
accordance with the experimental value of 2.1 kcal/mol (94% ee)
favoring R-selectivity. The distortion/interaction model [21] could be
invoked to explain the origin of the energy difference between TS-
R and TS-S. Energy decomposition analysis showed that the
disfavored TS-S has higher distortion energy in enamine
(ΔEdist(enamines)
=
9.1 kcal/mol) than that in TS-R
(ΔEdist(enamines) = 6.1 kcal/mol). In both transition states, an
intramolecular H-bonding between the enamine N-H and carbonyl
was noted to restrict the conformational flexibility and distortion
mainly came from the catalyst part (Figure 2).
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Acknowledgements
We thank the Natural Science Foundation of China
(21861132003, 21672217and 21521002) and Tsinghua
University Initiative Scientific Research Program for financial
support. S.L. is supported by the National Program of Top-notch
Young Professionals.
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Keywords: chiral primary amine • electrochemical catalysis•
asymmetric arylation • benzyne • enamine
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10.1002/anie.202006016
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Longji Li,[b] Yao Li,[a] NianKai Fu,[b] Long
Zhang[a] and Sanzhong Luo[a,b]*
Page No. – Page No.
Catalytic Asymmetric Electrochemical
α-Arylation of Cyclic β-Ketocarbonyls
with Anodic Benzyne Intermediates
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