Enantioselective Copper-Catalyzed Radical Ring-Opening Cyanation of Cyclopropanols and Cyclopropanone Acetals

Article abstract of DOI:10.1002/adsc.202000202

A novel approach for enantioselective cyanation of cyclopropanols and their derivatives through copper-catalyzed radical relay processes has been developed. Various cyclopropanols and cyclopropanone acetals are compatible to the catalytic conditions, providing β-carbonyl nitriles with excellent enantioselectivity. These products can be readily converted to chiral γ-amino acids derivatives and drugs such as (R)-baclofen. Preliminary mechanistic studies have supported a ring-opening process for cyclopropanoxy radicals followed by copper-catalyzed enantioselective cyanation of benzylic radicals to form the C?CN bonds in an enantioselective manner. (Figure presented.).

Full text of DOI:10.1002/adsc.202000202

Title: Enantioselective Copper-Catalyzed Radical Ring-Opening
Cyanation of Cyclopropanols and Cyclopropanone Acetals
Authors: Guosheng Liu, Lianqian Wu, Pinhong Chen, and Yin-Long
Guo
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Enantioselective Copper-Catalyzed Radical Ring-Opening Cyanation of
Cyclopropanols and Cyclopropanone Acetals
Lianqian Wu, Lei Wang, Pinghong Chen, Yin-Long Guo,* and Guosheng Liu*
coupling of α-halonitriles with organozinc reagents.[6] Despite these
Abstract:
A
novel approach for enantioselective cyanation of
progresses, exploration of efficient approaches to access the chiral β-
carbonyl nitriles is still in strong demand.
cyclopropanols and their derivatives through copper-catalyzed radical
relay processes has been developed. Various cyclopropanols and
cyclopropanone acetals are compatible to the catalytic conditions,
providing β-carbonyl nitriles with excellent enantioselectivity. These
products can be readily converted to chiral γ-amino acids derivatives and
drugs such as (R)-baclofen. Preliminary mechanistic studies have
supported a ring-opening process for cyclopropanoxy radicals followed by
copper-catalyzed enantioselective cyanation of benzylic radicals to form
the C−CN bonds in an enantioselective manner.
In the last several decades, transition metal-catalyzed ring-opening
of cyclopropanols have been extensively studied. The -carbon
elimination of an alkyloxide metal complex int-I (M = Rh, Cu, Pd, Co,
Ni) involved in these reactions usually occurs preferentially at the less
substituted carbon centers, resulting in the formation of the -
functionalized carbonyl products through reductive elimination from
int-II (Scheme 1a, top). Based on this mechanistic hypothesis, a
variety of methods for the synthesis of -functionalized carbonyl
compounds
have
been
developed.[7]
Alternatively,
the
cyclopropanoxide complex int-I (M = Ag, Mn, etc) could undergo
homolytic cleavage of the M–O bond to generate the cyclopropoxy
radical int-III, which subsequently gives the carbon-centered radical
int-IV through a radical ring-opening process at the more substituted
carbon centers, thus leading to different β-functionalized carbonyl
products (Scheme 1a, bottom).[8] For instance, Zhu and coworkers
reported a series of Ag- and Mn-catalyzed ring-opening processes of
cyclopropanols and cyclobutanols in conjunction with fluorination,
azidation and alkynylation reactions.[8c-8f] Furthermore, Chiba and
coworkers reported the sequential Mn-catalyzed ring opening of
cyclopropanols and cycloaddition of vinylazides for the synthesis
of heterocycles.[8g-8h] However, owing to the highly reactive carbon-
centered radical, it is extremely difficult to achieve the stereoselective
control of radical speices int-IV. Thus far, asymmetric radical ring
opening of cyclopropanols has not been reported.
Optically pure organonitriles are found in many bioactive natural
products and therapeutics.[1] In addition, organonitriles are an
important class of synthons that are essential precursors to highly
valuable amines, carboxylic acids and their derivatives.[2] Among them,
enantiomerically enriched β-carbonyl nitriles are particularly
prominent targets, because they can be transformed into γ-lactams and
γ-amino acids, which are widely used as anti-depressant agents and
selective agonists of GABA (γ-aminobutyric acids) receptors (Figure
1).[3]
Figure 1. Representative compounds containing or derived from chiral
carbonyl nitriles
A variety of methods have been established for asymmetric
synthesis of β-carbonyl nitriles, including lewis acid-catalyzed
conjugate hydrocyanation of α,β-unsaturated compounds,[4] enzyme
catalyzed bioreduction of cyanoacrylates,[5] and nickel-catalyzed cross-
[*]
L. Wu, L, Wang, Dr. P. Chen, Prof. Dr. Y.-L. Guo, Prof. Dr. G. Liu
State Key Laboratory of Organometallic Chemistry, Center for
Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese
Academy of Sciences
345 Lingling Road, Shanghai, 200032 (China)
E-mail: gliu@mail.sioc.ac.cn, ylguo@mail.sioc.ac.cn
Homepage: http://guoshengliu.sioc.ac.cn/
Scheme 1. Transition metal-catalyzed ring opening of cyclopropanols.
As part of our ongoing programs focused on transition metal-
catalyzed asymmetric radical transformations (ARTs),[9] we have
demonstrated a Cu-catalyzed radical relay process for the asymmetric
Supporting information for this article is given via a link at the end of the
document.
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functionalizations of styrenes,[10]benzylic[11] and allylic C–H bond,[12]
in which the in situ generated benzylic radicals can be captured by
chiral Cu(II) intermediates to construct new chemical bonds with
excellent enantioselectivity. We reasoned that, if a L*Cu(I)/oxidant
system could be designed to trigger the oxidation of cyclopanols 1 to
int-III, the generated benzylic radical int-IV might be captured by
chiral Cu(II) cyanide to give enantiomerically enriched β-carbonyl
nitriles 2 (Scheme 1b).[13] Herein, we communicates our results as the
first asymmetric system for radical ring opening of cyclopropanols .
proceeded well, providing 2k in good yield and enantioselectivity.
Cyclopropanol bearing a naphthalene ring was also a viable substrate
Table 2. Scope of cyclopropanols.[a,b]
Table 1. Optimization of the reaction parameters[a,b,c]
On the basis of our mechanistic hypothesis, the initial study was
focused on the reaction of cyclopropanol 1a. First, a series of oxidants
were tested in the presence of [Cu(MeCN)4]PF6 and chiral ligand (1R,
2S)-L1 as the catalyst and trimethylsilyl cyanide (TMSCN) as the
t
cyanation reagent. As shown in Table 1, the reaction with PhCO3 Bu
and (tBuO)2 did not proceed with the substrate being quantitatively
recovered (entries 1-2). We were delighted to find that, hypervalent
iodine PhI(OAc)2 was effective to promote the reaction, and the desired
product 2a was obtained in 49% yield with 82% ee, along with a
byproduct benzalacetone (entry 3). Electrophilic fluorination reagents,
such as N-fluorobenzenesulfonimide (NFSI) or selectfluor, were also
suitable oxidants for this reaction, but gave poor enantioselectivities
(38 or 39% ee, entries 4-5). Encouragingly, when benzoyl peroxide
(BPO) was used as the oxidant, the reaction provided 2a in a nearly
quantitative yield with good enantioselectivity (82% ee, entry 6).
Evaluation of different copper catalysts indicated that enantiomeric
excess could be slightly improved to 85% ee by using CuBr•SMe2
(entry 7). Solvent screening revealed that the enantiomeric excess was
further improved to 91% ee in acetone (entry 8). The best result was
obtained in the presence of 5 mol% of CuTc (Tc = thiophene-2-
carboxylate) in acetone, in which case 2a was produced in 99% yield
with 91% ee (entry 9). The absolute configuration of the cyanation
product 2a was assigned as an R isomer based on the comparation of
specific rotation with the literature value (see SI).
for the reaction, giving 2l in 72% yield with 94 % ee. Finally, apart
from cyclopropanols with a methyl group at the C-1 position,
substrates with other aliphatic groups, such as ethyl and n-propyl, also
reacted smoothly and yielded the target compounds 2m-2r in good
yields (52-86%) with excellent enantioselectivities (90-93% ee).
Notably, various functional groups, such as halides, ether and
trifluoromethyl group, were tolerated under the reaction conditions.
The aforementioned results confirmed that it was possible to use
copper-catalyzed radical relay strategy for the asymmetric cyanation of
cyclopropanols via a radical ring-opening process, and -cyanoketones
with various structures could be obtained with good to excellent
enantioselectivities. We then turned our attention to investigating the
cyanation of cyclopropanone acetals for the efficient synthesis of
optically active β-cyanoesters.
With the optimized reaction conditions in hand, we next explored
the substrate scope of the reaction. As shown in Table 2,
cyclopropanols with both electron-rich and electron-deficient aryl
groups were compatible to the reaction conditions, furnishing a variety
of β-cyano ketones in good to excellent yields (up to 91% yield) with
excellent ee values (up to 95%). For instance, when substrates have an
ortho-substituent in the aryl ring, the reactions exhibited a better
enantioselectivities (91-95% ee) to give 2b-2d in moderate to good
yields (40-74%). When a substituent was introduced to the meta- or
para-position of the aryl ring, the reaction performed similarly as 1a to
give the corresponding cyanation products 2e-2j in 66-84% yields with
85-92% ee. Moreover, a substrate with 3,5-dichlorobenzene ring also
The acetal 3a was initially used for reaction optimization, and it
became clear that the previous reaction conditions needed to be slightly
modified as follows: (1) for a higher enantioselectivity, bis(oxazoline)
(1S, 2R)-L2 bearing geminal benzyl and methyl groups should be
employed; (2) NFSI should be used as the oxidant as it performed
better than BPO (For details, see SI). As shown in Table 3, a large
number of cyclopropanone acetals showed excellent reactivities to give
β-cyano propanoic esters 4a-4d in good yields (64-72%) with excellent
enantioselectivities (90-94% ee). In general, our protocol
accommodated a broad range of cyclopropanone acetals containing
electron-poor (4e-4f) or electron-rich aryl groups (4g-4k), delivering
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enantiomerically enriched esters with a high level of stereocontrol (87-
97% ee). The absolute configuration of 4d was determined to be S by
X-ray crystallography.[14]
give the product 7 in 30% yield (Scheme 3a). These observations
supported a radical ring-opening pathway for our reaction.
Table 3. Scope of cyclopropanone acetals.[a,b]
Scheme 3. Control experiments and mechanistic studies.
For the radical ring opening of cyclopropanols, previous studies by
Depuy and coworkers showed a significant kinetic isotope effect (KIE
= kH/kD ranged from 3.6 to 6.6) due to direct hydrogen atom
abstraction.[18] However, a small kinetic isotopic effect (KIE = 1.6) was
obtained by comparing the rates for the individual reactions of 1b and
1b-d1 (Scheme 3b), indicating that the direct hydrogen atom
abstraction process was less likely involved in our reaction.
Similar to our previous studies of asymmetric cyanation of
alkenes,[10a] a induction period was observed in the reaction of 1b,
which could be shortened by adding 1 mol % Bu4NCN and eliminated
with 2 mol % Bu4NCN. However, the reaction rate was significantly
decreased in both cases (Figure 2a), suggesting that the reaction could
be inhibited in the presence of excess cyanide. In addition, when the
catalytic reaction was monitored by in situ SAESI-MS spectroscopy,
signals at m/z 706 and 611 were detected (see SI), possibly which were
[(int-V) - CN] and [(int-V) - BzO] (for the structure of int-V, see
Scheme 4a). Taken together these observations, the complex int-V is
likely to be involved in the catalytic cycle, and the following O–H
bond cleavage from int-V partially contributes to the rate-determining
step.
To demonstrate the synthetic utility of this asymmetric cyanation
method, the gram-scale reactions of 3a and 3f were conducted. The
copper catalyst loading could be reduced to 1 mol %, and these
reactions proceeded smoothly to afford 4a and 4f in 58% yield (93%
ee) and 61% yield (91% ee), respectively (Table 3). In addition,
selective hydrogenation of 4a afforded the chiral γ-amino acids
derivatives 5 in 90% yield (92% ee).[15] Reductive cyclization of 4f
followed by hydrolysis of the 6 represented a short 3-step synthesis of
(R)-baclofen,[16] an inhibitory neurotransmitter as a GABA receptor
agonist (Scheme 2).
12
standard condition
external Bu NCN (1 mol %)
4
10
external Bu NCN (2 mol %)
4
8
6
4
2
0
0
5
10
15
20
25
Reaction Time (min)
Firure 2. a) Effect of cyanide on the reaction of 1b (2 mol% copper
catalyst) by adding Bu4NCN (0-2 mol %) externally (left); b)
Electronic effect of aryl acylperoxides (right).
Scheme 2. Synthetic applications.
Based on above analysis and our previous studies, [10a] a plausible
mechanism for the enantioselective cyanation of cyclopropanols is
outlined in Scheme 4a. The reaction is initiated by a (L*)CuICN
species, which can be oxidized by BPO to give the copper(II) species
A. Cyclopropanol 1 then coordinates to the copper center of A, before
intramolecular deprotonation occurs with int-V to yield a key
intermediate int-I.[19] After homolytic cleavage of O–CuII bond of int-
I,[20] the generated cyclopopoxy radical int-III undergoes rapid ring-
opening to generate a distal benzylic radical int-IV. Meanwhile, the
active radical species BzO•, generated from initial SET process,[21] is
Recently, Dai and coworkers reported copper-catalyzed
trifluoromethylation and amination of cyclopropanols, in which -
carbon elimination of the cyclopropanoxide CuII complex int-I was
proposed to be responsible for the C–C bond cleavage.[17] In that
particular system, radical scavengers such as TEMPO exhibited a
negligible effect on the reaction. In contrast, our reaction was
completely inhibited by TEMPO (see SI) and the product yield
diminished significantly by the addition of 2,6-(tBu)2-4-MeC6H2OH
(BHT). In the latter case, the benzylic radical was captured by BHT to
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trapped by (L*)CuI(CN) to form another copper(II) complex A,[22]
which reacts with TMSCN to give (L*)CuII(CN)2 (B). Finally, the
benzylic radical int-IV is stereoselectively captured by B to yield the
desired product 2 with a high level of enantioselective control. [10a, 11]
Under this mechanistic scenario, owing to the strong binding of
cyanide, copper complex A can be converted to B quickly in the
presence of exogenous cyanide, but also exhibits slower coordination
and deprotonation to give the key intermediate int-I, resulting in a
decrease in overall reaction rate (Figure 2a).
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Scheme 4. Proposed mechanism.
Alternatively, complex int-V could undergo direct hydrogen atom
abstraction of int-V by BzO• to give the key cyclopropoxy radical int-
III (Scheme 4b). To differentiate these two possible pathways (a
versus b in Scheme 4), several substituted aryl acylperoxides were
employed to test the electronic effect of the oxidants, and a small
negative -value (-0.26) was observed from the Hammett plot,
suggesting that complex int-V with an electron-rich ArCO2 group
reacts more rapidly than that with an electron-poor ArCO2 group. We
prefer the pathway in Scheme 4a because the intramolecular
deprotonation of int-V O-H moiety by the inner base ArCO2 (Scheme
4a) should be entropic more favorable. It is also more consistent with
the observed small Hammett ρ-value and relatively small KIE value
(1.6).[23]
In conclusion, we have demonstrated that a copper-catalyzed
radical relay strategy can be successfully applied to enantioselective
ring-opening of cyclopropanols and cyclopropanone acetals. This has
led to a practical and streamlined approach to chiral β-carbonyl nitriles
that are key synthons in organic synthesis. The mechanistic details and
further applications based on this new process are ongoing efforts in
our laboratories.
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www.ccdc. cam.ac.uk/services/structure_deposit/cif.
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Acknowledgements
We are grateful for financial support from the National Nature Science
Foundation of China (Nos. 21532009, 21472217, 21790330 and
21728201), the Science and Technology Commission of Shanghai
Municipality (Nos. 17QA1405200 and 17JC1401200), and the
strategic Priority Research Program (No. XDB20000000) and the Key
Research Program of Frontier Science (QYZDJSSW-SLH055) of the
Chinese Academy of Sciences.
Keywords:
asymmetric radical reaction • radical ring-opening •
cyclopropanol • copper-catalyzed radical relay • -carbonyl nitriles
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acetone to form benzene. For details, see SI.
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[23] Small kinetic isotope effects (KIEs) and Hammett ρ-values have been observed in
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10.1002/adsc.202000202
Advanced Synthesis & Catalysis
Very Important Publication
COMMUNICATION
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COMMUNICATION
Novel
enantioselective
L. Wu, L, Wang, P.
Chen, Y.-L. Guo, H.
Guan,* G. Liu*
cyanation of cyclopropanols and
their derivatives has been
developed via copper-catalyzed
radical relay processes. Various
cyclopropanols and cyclopro-
panone acetals are employed to
provide β-carbonyl nitriles with
Page No. – Page
No.
excellent
enantioselectivity.
Title
Preliminary mechanistic studies
suggest that the reaction
involves radical ring-opening of
cyclopropanols followed by
Enantioselective
Copper-Catalyzed
Radical Ring-
Opining Cyanation
of Cyclopropanols
and Cycloproanone
Acetals
copper-catalyzed
enantio-
selective cyanation of benzylic
radicals.
This article is protected by copyright. All rights reserved.