Visible-light-induced triple catalysis for a ring-opening cyanation of cyclopropyl ketones

Article abstract of DOI:10.1039/d0cc05167e

An unprecedented triple catalytic, general ring-opening cyanation reaction of cyclopropyl ketones for the construction of γ-cyanoketones is described. The key is to merge photoredox catalysis with Lewis acid catalysis and copper catalysis to enable the selective cleavage of the carbon-carbon bonds and the selective coupling of the generated radical and cyanide anion.

Full text of DOI:10.1039/d0cc05167e

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Visible-light-induced triple catalysis for a ring-opening cyanation
of cyclopropyl ketones
Received 00th January 20xx,
Accepted 00th January 20xx
Jing Liu,a Xiao-Peng Liu,a Hong Wu,a Yi Wei,a Fu-Dong Lu,a Kai-Rui Guo,a Ying Cheng,*a and Wen-
Jing Xiao*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
An unprecedented triple catalytic, general ring-opening cyanation and aliphatic alcohols6b by employing photoredox, HAT and
reaction of cyclopropyl ketones to construct γ-cyanoketones is transition metal (Pd, Ni) catalysis. Recently, Xu developed a
described. The key is to merge photoredox catalysis with Lewis dehydrogenative silylation of alkenes by combining
acid catalysis and copper catalysis to enable the selective cleavage photoredox, HAT and cobalt catalysis.7 Though these
of carbon-carbon bond and the selective coupling of the impressive achievements, it’s still highly desirable to exploit
generated radical and cyanide anion.
new multiple catalysis systems for accomplishing significant
chemical transformations.
Multienzymatic catalysis is a powerful tool to promote a plenty
of biological transformations in nature and also, it inspires
synthetic chemists to develop potent multiple catalysis
systems for chemical reactions in laboratory.1 In this context,
artificial multiple catalysis, also namely tandem catalysis and
synergistic catalysis, with precise catalyst compatibility and
reaction selectivity has been developed. However, multiple
catalysis with three catalysts for radical reactions is still in its
infancy.2 Lei and co-workers developed triple metal-catalyzed
radical oxidative alkynylation of terminal alkynes.3 In addition
to this triple metallic catalysis system, photoredox catalysis as
an efficient approach to generate radicals under mild
conditions has been introduced to triple catalyst system. In
2016, MacMillan reported an arylation of sp3 C-H bonds of
amines and cyclic ethers by the combination of photoredox,
hydrogen-atom transfer (HAT) and nickel catalysis.4a Soon after,
they extended the arylation to aldehydes4b and alcohols4c by
employing this triple catalyst system. Moreover, they disclosed
a direct and enantioselective α-alkylation of aldehydes with
olefins catalyzed by photoredox, HAT and organocatalysis.4d
Luo and Wu realized an asymmetric cross-dehydrogenative
coupling of tertiary amines with ketones enabled by synergistic
photoredox, cobalt and organocatalysis.5 Kanai achieved
Cyclopropanes with exceptional reactivity are useful
building blocks in chemical synthesis due to their ring strain.8
The ring-opening reaction has been developed to transform
cyclopropanes into an open-chain system. To our knowledge,
the use of synergistic three catalysts system in ring-opening
reaction of cyclopropanes is unknown. Encouraged by our
recent work on synergistic metal- and photocatalysis,9 we
present herein the first ring-opening cyanation of cyclopropyl
ketones through the combination of three different catalysts
(Scheme 1b). This protocol provides a novel and general
approach to synthetically valuable γ-cyanoketones10 from
readily available feedstocks under mild and green conditions.
Notably, since the mechanism is distinct from traditional
transition metal catalysis,11 i.e., Ni-catalyzed ring-opening
borylations of cyclopropyl ketones11d that proceed with a
a) Previous work: ring-opening borylation
R
O
O
O
R'
[Ni(II)]
R'
Ni
+
[B]-[B]
1
2
3
R
R
[B]
40-70 °C
[B]-[B]: bis(pinacolato)diboron
R'
3
oxidative addition
b) This work: ring-opening cyanation
Synergistic Triple Catalysis
LA
O
O
R'
2
R'
+
1
2
TMS-CN
PC Cu
R
R
CN
3
radical generation
radical coupling
aCCNU-uOttawa Joint Research Centre, Key Laboratory of Pesticide & Chemical
Biology, Ministry of Education; College of Chemistry, Central China Normal
University, 152 Luoyu Road, Wuhan, Hubei 430079, China. E-mail:
ycheng@mail.ccnu.edu.cn; wxiao@mail.ccnu.edu.cn. J.L. and X.P.L. contributed
equally to this work.
mild & green conditions: room temperature, visible light, redox-neutral
value-added transformation: easily available chemicals, significant products
Scheme 1 Strategies for the catalytic cleavage of C-C bonds and the
ring-opening functionalization of cyclopropyl ketones. PC:
cState Key Laboratory of Applied Organic Chemistry, College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
photocatalyst.
LA:
Lewis
acid.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
dehydrogenation of N-heterocycles, tetrahydronaphthalenes6a
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J. Name., 2013, 00, 1-3 | 1
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sterically sensitive oxidative addition (Scheme 1a),11d-11e this purple LEDs. γ-Cyanoketone product 3a was obtained in 80%
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DOI: 10.1039/D0CC05167E
ring-opening cyanation shows different regio-selectivity due to NMR yield without cyanoalcohol and ketyl dimerization side
the unique, photoredox-enabled single-electron transfer (SET) products (Table S1, entry 1). Subsequently, a set of control
process.
experiments was performed to examine the role of each
The details of the design are shown in Scheme 2. First, the catalyst. Not surprisingly, in the absence of Ph-PTZ, La(OTf)3,
excited-stated photocatalyst (PC*) would reduce the LA- Cu catalyst, or light, no product was observed (Table S1, entry
activated substrate (LA-1) via a SET process, and generated 2). Replacement with other Cu catalyst precursors (Table S1,
ketyl radical anion I would deliver homoallylic radical II via a entry 3), ligands (Table S1, entries 4 and 5) or LA catalysts
reversible ring-opening process. Next, the oxidized (Table S1, entries 7 and 8) in this photoreaction resulted in
photocatalyst (PC·+) would be reduced to its ground state (PC) lower reaction yields. A slightly increased yield was obtained
by the Cu(I) complex, LCu(I)(CN)2. At the same time, the by increasing the loading of ligand L1 to 10 mol% (Table S1,
generated Cu(II) complex, LCu(II)(CN)2, is expected to capture entry 6: 85% yield). In addition, metal-photocatalysts were also
radical II to form Cu(III) intermediate III. Reductive elimination tested. The reaction with Ru(bpy)3Cl2·6H2O provided a much
from this transient species would turn over the Cu catalysis lower yield (Table S1, entry 9: 6% yield ) and the reaction with
cycle and deliver enol intermediate IV. Finally, silyl enol ether fac-Ir(ppy)3 provided a comparable yield (Table S1, entry 10:
V, which can be hydrolyzed to product 3, would be obtained 77% yield).
from IV by the reaction with TMSCN, simultaneously enclosing
To prove the generality of this triple catalyst system, we
the LA catalysis cycle and regenerating LCu(I)(CN)2. For this started to evaluate the substrate scope of the ring-opening
synergistic triple catalysis, the organo-photocatalyst 10- cyanations. As shown in Scheme 3, variation of the electronic
phenyl-10H-phenothiazine (Ph-PTZ) would be highly suitable properties on the aryl ring of cyclopropyl ketones 1 did not
due to its capacity to harvest visible light and the strong obviously affect the reaction efficiency. Both electron-donating
reductive potential of its excited state (Ph-PTZ*).12 The (Me, MeS, Ph) and electron-withdrawing (F, Cl, Br, CF3) groups
oxidation of LCu(I)(CN)2 by Ph-PTZ·+ and the proposed radical were well tolerant, and provided corresponding products 3b-
cyanation involving the Cu(I) complex were believed to be 3h in 68-82% yields. A derivative of drug molecule probenecid
feasible according to our previous study9d and Cu-catalyzed was a suitable substrate for this catalyst system to give new
radical coupling reactions,13 especially the Liu cyanation.14 drug derivative 3i in 69% yield. Furthermore, the effects of the
Although this blueprint seems efficient in principle, the LA- position and number of substituent were also studied, and a
catalyzed addition of TMSCN to the carbonyls15a or the ketyl series of γ-cyanoketone products 3j-3p were delivered in 59-
dimerization15b might occur competitively.
84% yields. In addition, substrates bearing functionalized aryl
groups (i.e., allyl and propargyl) and heteroaryl motif (i.e.,
O
LA
IV
OTMS
O
O
O
R'
H+
R'
CN
O
R'
R
R'
CN
Ph-PTZ (5 mol%), La(OTf)3 (5 mol%)
R
R
Ar1
Ar1
1
3
R
+
TMS-CN
1
3
Ph
CN
Ph
Cu(MeCN)4BF4/L1 (5 mol%/ 10 mol%)
product 3
V
1
DMF, 24 h, rt, 2*3 W purple LEDs
CN
CN-
1
2
3
PC
LA-1
LCu(I)(CN)2
TMS CN
R
O
S
LCu(I)CN
+
1
IV
O
Photoredox
Catalysis
O
3c, R = SMe, 68% yield
3d, R = Ph, 82% yield
O
Cu Catalysis
Ph
N(n-Pr)2
LA
O
III
3e, R = F,
70% yield
CN
3a, R = H, 80% yield
Ph
3f, R = Cl, 81% yield
3g, R = Br, 69% yield
3h, R = CF3, 74% yield
PC*
[Cu(III)]
CN
R
LCu(II)(CN)2
LA Catalysis
PC
1
3b, R = Me, 79% yield
R'
3i, 69% yield
LA
LCu(II)(CN)2
R
LA
O
O
O
LA
O
LA
LA
O
O
O
R'
Ph
R
Ph
OMe
R'
Ph
R
R
R
CN
CN
CN
LA-1
R'
II
R'
I
II
3j, R = F,
3k, R = OMe, 59% yield
70% yield
3l, 64% yield
3m, 70% yield
OMe
carbon-carbon bond cleavage
carbon-carbon bond formation
Cl
Cl
O
O
O
O
Scheme 2 Proposed ring-opening cyanation of cyclopropyl ketones.
[Cu(III)] Cu(III)L(CN)2. TMSCN: trimethylsilanecarbonitrile.
O
=
Ph
Ph
Ph
OMe
CN
CN
CN
3n, 73% yield
3o, 65% yield
3p, 84% yield
To realize the above reaction, we commenced this study
with phenyl(2-phenylcyclopropyl)-methanone (1a) as the
model substrate and TMSCN (2) as the cyanide source (please
see Table S1-5 for the details of condition optimization in
Supporting Information). Based on our experience and a
simple evaluation of the reaction parameters, the ring-opening
cyanation of cyclopropyl ketones was successfully achieved
using 5 mol% Ph-PTZ as the photocatalyst and 5 mol% La(OTf)3
as the LA catalyst, together with 5 mol% Cu(MeCN)4BF4 and 5
mol% nitrogen-containing ligand L1, under the irradiation of
O
O
O
X
O
O
Ph
Ph
Ph
CN
CN
CN
3q, 73% yield
3r, 77% yield
3s, X = O, 65% yield
3t, X = S, 76% yield
Scheme 3 Variation of the aryl substituents in the cyclopropyl ketones.
Reaction conditions: as indicated in entry 6 in Table S1; isolated yield
based on 1.
2 | J. Name., 2012, 00, 1-3
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furan and thiophene) were effective in this transformation, This procedure represents an important complement to the
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producing γ-cyanoketone products 3q-3t in 65-77% yields.
current limitation that aryl or heteroaryl DkeOtI:o1n0e.1s03a9r/eDn0CecCe0s5s1a67rEy
Given the synthetic versatility of alkenes and alkynes, we for the photochemical reductions.18
further examined the cyclopropyl ketones having these
Table 1 Variation of the acyl group in the cyclopropyl ketonesa
functional groups under the optimal conditions. As illustrated
in Scheme 4, a variety of alkenyl groups with an alkyl (5a) or
aryl substituent (5b), or having two alkyl substituents (5c) were
proven to be compatible, affording the different γ-
cyanoketones in 57-70% yields. The reaction of cyclopropyl
ketones with an alkyl alkyne (4d), aryl alkyne (4e) and TMS-
substituted alkyne (4f) also proceeded well and afforded the
desired products in 66-80% yields.16 Moreover, this protocol
can be successfully extended to substrates with ester
functional groups. For example, when two esters were
introduced to the substrate, the reaction can proceed
smoothly and produce highly functionalized product 5g in a
good yield. When vinylcyclopropane substrate 4h was
subjected to the triple catalyst system, the reaction occurred
and afforded the cyanation product 5h with an unexpected
terminal selectivity. At current stage, alkyl-substituted
substrates were ineffective under the optimal conditions might
due to the low ring opening rate.17
O
O
Ph-PTZ (5 mol%), La(OTf)3 (5 mol%)
Ph
Ph
1
3
1
3
R
R
TMS-CN
2
+
Cu(MeCN)4BF4/L1 (5 mol%/5 mol%)
DMF, 24 h, rt, 2*3 W purple LEDs
CN
7
6
Entry
Substrate 6
Product 7
Yield (%)b
1
2
3
4
5
6
7
8
9
6a: R = 4-F-C6H4
7a
7b
7c
7d
7e
7f
90
79
88
85
89
72
89
75
89
6b: R = 4-Cl-C6H4
6c: R = 4-Me-C6H4
6d: R = 4-OMe-C6H4
6e: R = 2-OMe-C6H4
6f: R = 3-Br-C6H4
6g: R = 3,4-MeO-C6H3
6h: R = 2-Naphthyl
6i: R = N-methylimidazole
7g
7h
7i
a Standard conditions as indicated in entry 6 of Table S1. b Isolated yield.
O
R'
O
Ph-PTZ (5 mol%), La(OTf)3 (5 mol%)
R
1
3
R
+
TMS-CN
2
1
3
Ph
Ph
Cu(MeCN)4BF4/L1 (5 mol%/ 10 mol%)
DMF, 24 h, rt, 2*3 W purple LEDs
CN
To further demonstrate the utility of this methodology, a
R'
4
5
gram-scale reaction of model substrate 1a was conducted
using the synergistic triple catalyst system. As highlighted in
Scheme 5b, 2.12 g of product 3a was obtained without erosion
of the reaction efficiency. Notably, 83% yield of the organo-
photocatalyst, Ph-PTZ, can be recovered. Additionally,
synthetic transformations of γ-cyanoketone 3a were carried
O
O
O
Ph
Ph
Ph
Ph
CN
CN
5b, 70% yield (E/Z = 3:1)
CN
5a, 57% yield (E/Z = 2.5:1)
5c, 63% yield
O
O
Ph
O
TMS
O
Ph
Ph
O
Ph
MeOTf, 4Å MS
a
Ph
CN
CN
CN
Bn
then BnMgBr
-78 oC, 30 min
O
5d, 80% yield
5e, 76% yield
5f, 66% yield
CN
8: 79% yield
Ph
N
O
O
CO2t-Bu
CO2t-Bu
O
N
CN
triple
catalysis
CN
Ph
Ph
7i
MeOTf, 4Å MS
Ph
Ph
MeO
then MeOH, DBU
0 oC, 30 min
CN
5g, 80% yield (3:1 dr)
Ph
O
Ph
O
CN
4h
5h, 85% yield (E/Z = 2:1)
9: 83% yield
b
Scheme 4 Introducing other substituents in the cyclopropyl ketones.
Reaction conditions: as indicated in entry 6 in Table S1; isolated yield
based on 4.
O
O
standard conditions
Ph
Ph
+
TMS-CN
Ph
Ph
recovered Ph-PTZ:
83% yield
CN
1a: 10 mmol
2: 30 mmol
3a: 2.12 g, 85% yield
Next, we investigated the substrate generality with respect
to the aryl ketone component (Table 1). The substitution
pattern and electronic properties of the aryl ring did not
obviously affect the reaction efficiency and a series of γ-
cyanoketones 7a-7g possessing F, Cl, Br, Me or MeO groups
were produced in 72-90% yields (Table 1, entries 1-7). 2-
Naphthyl-substituted substrate 6h also reacted well with
TMSCN to afford corresponding product 7h in 75% yield (Table
1, entry 8). Moreover, a cyclopropyl ketone bearing a
heteroaryl substituent, N-methyl imidazole, was well tolerated
and provided the desired product 7i in 89% yield (Table 1,
entry 9). Notably, sequential operations to this product,
namely a methylation followed by a nucleophilic substitution
by benzyl Grignard reagent or methanol, afforded alkyl-
substituted γ-cyanoketone 8 or γ-cyanoester 9 (Scheme 5a).
Ph
c
(1) Raney Ni, EtOH
H2 (25 atm), 24 h, rt
Ph
N
(2) TsCl, NEt3
DCM, 0 oC, 4 h
O
Ts
10a, 78% yield
>20:1 dr (over 2 steps)
Ph
Ph
CN
Ph
(1) H2O2, K2CO3
DMSO, 2 h, rt
3a
(2) BF3 Et2O
CHCl3, rt, 30 min
Ph
N
O
H
10b, 69% yield
over 2 steps
Scheme 5 Synthetic utility of methodology. a Synthesis of γ-cyano
ketone and ester. b Gram-scale experiment. c Aza-heterocycle
synthesis from 3a.
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54, 1625; (c) W. Ding, L.-Q. Lu, Q.-Q. Zhou, Y. WVeiei,wJA.-rtRic.leCOhnelinne,
W.-J. Xiao, J. Am. Chem. Soc., 2017, 1D3O9,I: 6103.;10(3d9)/DF.0-CDC. 0L5u1,6D7E.
Liu, L. Zhu, L.-Q. Lu, Q. Yang, Q.-Q. Zhou, Y. Wei, Y. Lan, W.-J.
Xiao, J. Am. Chem. Soc., 2019, 141, 6167; (e) K. Zhang, L.-Q.
Lu, Y. Jia, Y. Wang, F.-D. Lu, F. Pan, W.-J. Xiao, Angew. Chem.
Int. Ed., 2019, 58, 13375.
out to generate a piperidine skeleton, which is an important
aza-heterocyclic moiety in alkaloids, pharmaceuticals and
agrochemicals.19 For example,
a
reductive cyclization
promoted by Raney Ni under a H2 atmosphere followed by
protection can afforded piperidine product 10a in 78% yield
(Scheme 5c, up); complete hydrolysis of the nitrile to the
10 M. S. Taylor, D. N. Zalatan, A. M. Lerchner, E. N. Jacobsen, J.
Am. Chem. Soc., 2005, 127, 1313, and references therein.
11 (a) G. Fumagalli, S. Stanton, J. F. Bower, Chem. Rev., 2017,
117, 9404; (b) L. Liu, J. Am. Chem. Soc., 2006, 128, 5348; (c) S.
Ogoshi, M. Nagata, H. Kurosawa, J. Am. Chem. Soc., 2006,
128, 5350; (d) Y. Sumida, H. Yorimitsu, K. Oshima, J. Org.
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12 Ph-PTZ can absorb purple light (ab. 390-420 nm) to reach its
exited state (E1/2[Ph-PTZ·+/Ph-PTZ*] = -1.97 V vs SCE); please
see: X.-C. Pan, C. Fang, M. Fantin, N. Malhotra, W. Y. So, L. A.
Peteanu, A. A. Isse, A. Gennaro, P. Liu, J. Am. Chem. Soc.,
2016, 138, 2411. The oxidative potential of cyclopropyl
ketone 6i in the presence of La (OTf)3 was determined to be -
1.10 V (vs -2.08 V in the absence of La(OTf)3). The quantum
yield of reaction was determined to be 0.055. Please see the
details in Supporting Information.
amide followed by
a
BF3-promoted intramolecular
condensation gave the dihydropyridin-2(1H)-one product 10b
in 69% yield (Scheme 5c, bottom).
In summary, a synergistic triple catalyst system has been
developed for the ring-opening cyanation of cyclopropyl
ketones. The combination of organo-photoredox catalysis with
Lewis acid catalysis and copper catalysis enables the selective
cleavage of carbon-carbon bonds and radical cyanation. This
protocol provided a series of γ-cyanoketones in good yields in
an eco-friendly and sustainable manner. The synthetic utility of
the methodology has been demonstrated through the
construction of significant piperidine moieties. It is anticipated
that synergistic triple catalysis strategy developed in this study
will have broad applications in the development of new
catalytic ring-opening transformations of strained systems.
We are grateful to the National Science Foundation of
China (No. 21901080, 91956201, 21820102003, and
21772053), 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 Centre for Intelligent Biosensing
Technology and Health for support of this research.
13 (a) F. Wang, P. Chen, G. Liu, Acc. Chem. Res., 2018, 51, 2036;
(b) A. Hossain, A. Bhattacharyya, O. Reiser, Science, 2019,
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16 The ee values of three representative products bearing
phenyl, alkenyl or alkynyl functional group were measured
(3a: 64% yield, 91:9 er; 5b: 70% yield, E/Z = 3:1, 88:12 er for
(E)-5b, 90:10 er for (Z)-5b; 5e: 76% yield, 88:12 er). Please
see the details in Supporting Information.
17 J. M. Tanko, J. P. Phillips, J. Am. Chem. Soc., 1999, 121, 6078.
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Notes and references
1
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DOI: 10.1039/D0CC05167E
Graphic abstract for
Visible-light-induced triple catalysis for a ring-opening cyanation of cyclopropyl ketones
Synergistic Triple Catalysis
O
O
R'
CN
1
2
R'
1
2
LA
PC Cu
R
R
radical generation
Ring-Opening Cyanation:
radical coupling
37 examples, up to 90% yield
A ring-opening cyanation of cyclopropyl ketones was developed via a synergistic triple
catalysis strategy, providing a wide range of γ-cyanoketones in good reaction efficiencies under
mild and eco-friendly conditions.