A photoredox catalyzed iminyl radical-triggered C-C bond cleavage/addition/Kornblum oxidation cascade of oxime esters and styrenes: synthesis of ketonitriles

Article abstract of DOI:10.1039/C8CC07072E

A photoredox-catalyzed iminyl radical-triggered C-C bond cleavage/addition/Kornblum oxidation cascade of cycloketone oxime esters and styrenes in DMSO is described. This three-component, one-pot procedure features mild conditions, a broad substrate scope, and high functional group tolerance, providing an efficient approach to access diversely functionalized ketonitriles.

Full text of DOI:10.1039/C8CC07072E

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A photoredox catalyzed iminyl radical-triggered
C–C bond cleavage/addition/Kornblum oxidation
cascade of oxime esters and styrenes: synthesis of
ketonitriles†
Cite this: Chem. Commun., 2018,
54, 12262
Received 31st August 2018,
Accepted 8th October 2018
Bin-Qing He,a Xiao-Ye Yu,a Peng-Zi Wang,a Jia-Rong Chen *a and
Wen-Jing Xiao
DOI: 10.1039/c8cc07072e
ab
rsc.li/chemcomm
A photoredox-catalyzed iminyl radical-triggered C–C bond cleavage/ materials.7 The radical species associated with these processes
addition/Kornblum oxidation cascade of cycloketone oxime esters offer great opportunities in light of retrosynthetic bond dis-
and styrenes in DMSO is described. This three-component, one-pot connection and reaction selectivity. For instance, Shimizu first
procedure features mild conditions, a broad substrate scope, and disclosed Cu(II)-promoted photooxidative cleavage of trisubsti-
high functional group tolerance, providing an efficient approach to tuted cyclic olefins for the facile synthesis of 1,6-ketonitriles using
access diversely functionalized ketonitriles.
NaN3 as the nitrogen source (Scheme 1a).8a Shortly after, Nair
reported that cerium(IV) ammonium nitrate (CAN) could also
Ketonitriles are a versatile class of synthetic building blocks efficiently facilitate this reaction.8b A novel catalytic variant of this
because of the wide utility of both carbonyl1 and nitrile groups transformation was proved to be feasible by the group of Jiao
themselves.2 Moreover, cyanoalkyl moieties are widely found in a through TEMPO-catalyzed aerobic oxygenation and nitrogenation
multitude of natural products and pharmaceuticals.3 It has also of olefins, using TMSN3 as a nitrogen source.9 On the other hand,
been well documented by Streuff that 1,5- and 1,6-ketonitriles Narasaka reported that the addition of b-carbonyl radicals,
serve as viable substrates for titanium(III)-catalyzed intra- generated from various cyclopropanol derivatives by Mn(III)-
molecular asymmetric reductive coupling for the synthesis mediated oxidation, to acrylonitrile in the presence of stoichio-
of various cyclic a-hydroxyketones.4 As a result, developing metric tributylhydridotin provided an alternative approach for
methods for the synthesis of structurally diverse ketonitriles the synthesis of 1,6-ketonitriles (Scheme 1b).10 Along this avenue,
continues to be of great importance. Under thermal reaction
conditions, ketonitriles with different lengths of carbon chain
could be synthesized from the corresponding b-ketoesters and
nitrile precursors through a lengthy multistep route,4 or via SN2
reactions of chlorides with KCN,5 or by coupling of cyano-
containing alkylzinc chloride reagents with benzoyl chloride.6
Despite being powerful, some disadvantages inherent in these
classic methods such as tedious manipulation, use of toxic
nucleophiles or stoichiometric metal agents make developing
more mild and efficient methods for their synthesis highly
significant.
In sharp contrast, the strategy of radical reactions has also
been established as a potentially enabling tool for the construc-
tion of ketonitriles from various readily accessible starting
a CCNU-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: chenjiarong@mail.ccnu.edu.cn, wxiao@mail.ccnu.edu.cn
b Hubei Key Laboratory of Processing and Application of Catalytic Materials,
Huanggang Normal University, Huanggang, Hubei 438000, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Radical strategies for the synthesis of ketonitriles.
c8cc07072e
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Table 1 Condition optimizationa
Table 2 Scope of O-acyl oximesa,b
Entry
Photocatalyst
Base
Yieldbc (%)
47
1
2
3
4
5
6
7
8
fac-[Ir(ppy)3]
Ir(2,4-diFppy)3
[Ru(bpy)3]Cl2Á6H2O
Eosin Y
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
—
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaHCO3
K2CO3
Li2CO3
—
c
—
c
—
c
—
49
68
27
75
67
9d
10e
11f
—
—
—
c
—
c
fac-[Ir(ppy)3]
—
a
1a (0.20 mmol), 2a (0.30 mmol), photocatalyst (2 mol%), and base
(2.0 equiv.) in DMSO (2.0 mL) at room temperature under the irradia-
b
c
d
tion of 7 W blue LEDs for 10 h. Isolated yield. No reaction. Using
e
f
1.0 mL of DMSO (conc. = 0.20 M). Without photocatalyst. Without
visible light irradiation.
a
our group11 and Selander12 independently developed a photo-
catalytic and Fe(II)-catalyzed iminyl-radical-mediated ring-opening
C–C bond cleavage/addition sequence of cyclobutanone O-acyl
oximes and silyl enol ethers (Scheme 1c).13 Mechanistically,
1 (0.30 mmol), 2a (0.45 mmol), and fac-[Ir(ppy)3] (2 mol%), in DMSO
(3.0 mL) at room temperature under irradiation of 7 W blue LEDs for
10 h. Isolated yield. 0.2 mmol scale.
b
c
both reactions are enabled by the generation of iminyl radicals catalyst fac-Ir(ppy)3 in hand, we then tested several inorganic
and their subsequent fragmentation to cyanoalkyl radicals.13 bases such as NaHCO3, K2CO3, and Li2CO3, leading to a
However, the advanced preparation of silyl enol ethers limited significant increase of yield (68%) when using K2CO3 as the
the practicability of these methods to some extent. Moreover, base (entry 6). Interestingly, without the use of a base, a 75%
drawing inspiration from the radical reaction profiles of cyclo- yield of 3aa could finally be obtained (entry 8). Under more
butanone oxime derivatives14,15 and visible light photocatalytic concentrated conditions, the reaction gave a somewhat lower
styrene difunctionalization,16 we became interested in the yield (entry 9, 67%). As expected, control experiments performed
development of a photoredox-catalyzed iminyl radical-triggered without a photocatalyst or visible light irradiation resulted in no
C–C bond cleavage/addition/Kornblum oxidation cascade of cyclo- formation of any desired product 3aa, suggesting the photoredox
ketone oxime derivatives and styrenes in DMSO (Scheme 1d).17 catalytic properties of the reaction (entries 10 and 11).
The achievement of this three-component reaction would provide
With the optimal reaction conditions in hand, we first inves-
a general and mild approach to synthesize various diversely tigated the substrate scope of the cyclobutanone-derived O-acyl
functionalized ketonitriles from simple starting materials.18 As oximes on a 0.3 mmol scale. As summarized in Table 2, the
revealed in Narasaka’s10 and our studies,14f small amounts of catalytic system exhibited a broad substrate scope and high
polymerized products and hydrogen-abstraction products of functional group tolerance. In addition to 1a, a representative
radical intermediates might also be encountered as the main array of symmetric O-acyl oximes 1b–1e with sterically different
challenges in the target reaction. To our knowledge, there is no ester groups and an ether moiety at the 3-position were all well
precedent of such a photochemical reaction.
tolerated to furnish the corresponding products 3ba–3ea in
Building on our studies on the photocatalytic iminyl radical 63–73% yield. Moreover, the reactions of O-acyl oximes 1f–1h
generation from cycloketone O-acyl oximes,11 we initially bearing an electron-neutral or electron-rich phenyl ring at the
examined the feasibility of the target three-component radical 3-position also proceeded smoothly, and the products 3fa–3ha
addition/Kornblum oxidation cascade using O-acyl oxime 1a were obtained in good yields (51–66%). The sterically more
and commercially available 2-vinylnaphthalene 2a as the model demanding substrates, such as disubstituted 1i and 1j, also
substrates in DMSO at room temperature (Table 1).19 In line reacted well with 2a to produce 3ia and 3ja in 57% and 67%
with our previous observation, the reaction also proved to be yields, respectively. Once again, substrates 1k and 1l with methyl
extremely sensitive to the photoredox catalysts. A brief screening and benzyl groups at the 2-position proved to be compatible for
of commonly used photocatalysts revealed that only in the the reaction, leading to 1,6-ketonitriles 3ka and 3la with 64% and
presence of fac-Ir(ppy)3, can the reaction occur under the irradia- 87% yields. Notably, this catalytic system could also accommodate
tion of 7 W blue LEDs with Na2CO3 as the base, giving the desired oxetan-3-one and 1-Cbz-3-azetidinone derived O-acyl oximes 1m
product 1,6-ketonitrile 3aa in 47% yield (entries 1 vs. 2–4). With and 1n, delivering products 3ma and 3na in satisfactory yields.
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Table 3 Scope of styrene derivativesa,b
Scheme 2 Examination of other cyclic ketone O-acyl oximes.
from 5e and DMSO probably due to the stability of the benzyl
radical intermediate. However, the seven-membered substrate 5f
is not suitable for the reaction.
a
1a (0.30 mmol), 2a (0.45 mmol), and fac-[Ir(ppy)3] (2 mol%), in DMSO
(3.0 mL) at room temperature under irradiation of 7 W blue LEDs for
b
c
d
10 h. Isolated yield. Performed on a 1.0 mmol scale. Run for 20 h.
e
Lawesson reagent (1.0 equiv.).
(1)
Then, we turned our attention to study the generality of this
protocol by reacting 1a with a diverse range of styrenes 2 under
the standard conditions (Table 3). Along with 2a, 2-vinyl-
naphthalene 2b with an electron-donating group (MeO) at the
benzene ring was a viable substrate for the reaction, affording a
62% yield of 3ab. Additionally, simple styrene 2c and a set of
(2)
To gain some insight into the mechanism, we carried out
styrene derivatives 2d–2i with electron-withdrawing (e.g., Br, Cl, several control experiments with substrates 1a and 2a. In the
t
and CO2Me) and electron-donating (e.g., Bu, MeO, and Ph) presence of 2.0 equiv. of TEMPO, complete inhibition of the
functional groups at the para-position of the benzene ring were target reaction was observed, and the radical trapping product
well tolerated to confer the products 3ac–3ai in 50–90% yield. It 7 was isolated in 66% yield (eqn (1)). This result implies the
was also found that the substitution pattern of the phenyl ring involvement of the cyanoalkyl radical and radical properties of
has no obvious effect on the reaction. For example, meta- the process. When DMSO was replaced with dibenzyl sulfoxide
(2j and 2k) and ortho-substituted styrenes (2l–2n) reacted and DMF was employed as the solvent in the model reaction of
smoothly with 1a to give the corresponding 1,6-ketonitriles 1a and 2a, product 3aa and dibenzyl sulfide 8 could be detected
3aj–3an in good yields. Remarkably, internal olefins, such as by HRMS analysis, though with low conversion (eqn (2)). This
b-methyl styrene derivatives 2o–2p, were also well tolerated in observation suggests that DMSO serves not only as the reaction
the reaction to give products 3ao and 3ap in 60% and 78% media but also as an oxidant in Kornblum oxidation.19
yields, respectively. Notably, the reaction of biologically impor-
On the basis of these results and the literature,14 we proposed
tant estron-derived styrene 3q also proceeded smoothly to give a plausible mechanism with the reaction of 1a and 2a as an
the product 3aq in 64% yield, showing great potential of this example (Scheme 3). First, under visible light irradiation, the
protocol in late-stage functionalization of complex compounds. ground state catalyst fac-[IrIII(ppy)3] is reversibly converted to its
Finally, the synthetic potential of the current reaction was excited state *fac-[IrIII(ppy)3]. A SET from *fac-[Ir(ppy)3] to O-acyl
demonstrated in the preparation of 3ag in good yield on a oxime 1a results in a reductive N–O bond cleavage of 1a to give
1.0 mmol scale of 1a. The treatment of 3ag with the Lawesson iminyl radical A and the oxidizing form fac-[IrIV(ppy)3]. Then,
reagent gave rise to the thiolation product 6-phenyl-6-thioxo- iminyl radical A undergoes ring-opening C–C bond fragmentation
hexanenitrile 4 in 67% yield.20
to form cyanoalkyl radical B, which could be intercepted by
To demonstrate the potential of this reaction, we applied the styrene 2a via a radical addition process to furnish the new benzyl
catalytic system to other iminyl radical precursors (Scheme 2). radical C. Subsequently, the radical C is oxidized to a carbon
Five-membered cyclic ketone-derived O-acyl oximes 5a–5c reacted cation intermediate D by fac-[IrIV(ppy)3] via another SET process
well with 2a to furnish the products 6aa–6ca with 39–74% yields. with the release of the ground state catalyst fac-[IrIII(ppy)3],
Six-membered cyclic camphor-derived O-acyl oxime 5d was also completing the photocatalytic cycle. At this stage, the carbon
compatible with the reaction to give 6da in 32% yield. In contrast, cation D undergoes DMSO-mediated Kornblum oxidation to
the reaction of 5e only afforded product 6e in 60% yield, resulting afford the final product ketonitrile 3aa.19,21
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Scheme 3 The proposed mechanism.
In summary, we have developed the first example of a
photoredox-catalyzed iminyl radical-triggered C–C bond cleavage/
addition/Kornblum oxidation cascade of cycloketone oxime esters
and styrenes in DMSO. This reaction features mild redox-neutral
conditions, a broad substrate scope, and high functional group
tolerance, providing a general and complementary approach to
synthesize ketonitrile building blocks.
We are grateful to the NNSF of China (No. 21622201, 21472058,
21472057 and 21772053), the Science and Technology Department
of Hubei Province (2016CFA050 and 2017AHB047), and the
Program of Introducing Talents of Discipline to Universities of
China (111 Program and B17019) for support of this research.
Conflicts of interest
There are no conflicts to declare.
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