Nickel-Catalyzed Reductive Electrophilic Ring Opening of Cycloketone Oxime Esters with Aroyl Chlorides

Article abstract of DOI:10.1021/acscatal.8b03930

By merging cross-electrophile coupling and C-C bond cleavage, we developed a Ni-catalyzed electrophilic ring opening of cycloketone oxime esters with aromatic acid chlorides in assistance of Mn as reductant. Notably, complete regioselectivity can be achieved in this C-C bond cleavage reaction, providing an efficient access to a variety of cyanoketones under cyanide-free conditions. A radical reaction pathway was proposed on the basis of the results of the mechanistic probing experiments.

Full text of DOI:10.1021/acscatal.8b03930

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Letter
Nickel-Catalyzed Reductive Electrophilic Ring Opening
of Cycloketone Oxime Esters with Aroyl Chlorides
Decai Ding, and Chuan Wang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b03930 • Publication Date (Web): 31 Oct 2018
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Nickel-Catalyzed Reductive Electrophilic Ring Opening of
Cycloketone Oxime Esters with Aroyl Chlorides
Decai Ding and Chuan Wang† *
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† Department of Chemistry, University of Science and Technology of China, Center for Excellence in Molecular Synthesis,
Hefei National Laboratory for Physical Science at the Microscale, 96 Jinzhai Road, Hefei, Anhui 20237 (P. R. China)
Supporting Information Placeholder
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ABSTRACT: By merging cross-electrophile coupling and C-C
bond cleavage we developed a Ni-catalyzed electrophilic ring
opening of cycloketone oxime esters with aromatic acid chlorides
in assistance of Mn as reductant. Notably, complete regioselectivity
can be achieved in this C-C bond cleavage reaction providing an
efficient access to a variety of cyanoketones under cyanide-free
conditions. A radical reaction pathway was proposed based on the
results of the mechanistic probing experiments.
Scheme 1. Redox-neutral (A, B) and reductive strategy (C) to
utilize cycloketone oxime esters in organic synthesis.
For optimization of the reaction conditions of this electrophilic ring
opening reaction, we used cyclobutanone O-acetyl oxime (1a) and
benzoyl chloride (2a) as standard substrates (Table 1). Initially, we
tested a series of ligands using NiCl2•glyme as catalyst and Mn as
reductant in DMF at room temperature. In the cases of bis(pyridine)
and tris(pyridine) ligands only traces of the desired product 3a was
formed (Entries 1-4). In contrast, the reactions using
phenanthroline-based ligands provided the nitrile 3a in moderate
yields (Entries 5 and 6). The main side-reaction was transacylation
of benzoyl chloride (2a) with the solvent DMF providing N,N-
dimethylbenzamide as the by-product. Replacing Mn by Zn as
reducing agent resulted in a lower yield (Entry 7). Next, a brief
solvent-screening was undertaken and no improved result was
obtained (Entries 8-10). Furthermore, the influence of the Ni-salts
was also explored (Entries 11-14) and the best result was achieved
in the case of Ni(acac)2 (Entry 13). Increasing the amount of
benzoyl chloride (2a) from 2 equiv to 3 equiv gave rise to a better
yield (Entry 15). Performing the reaction in a lower concentration
also benefited the efficiency of the studied reaction (Entry 16).
Moreover, the temperature turned out to have a crucial effect on the
outcome of this reaction (Entries 17 and 18). Through lowering the
reaction temperature and extending the reaction time, the reaction
yields could be significantly improved, providing the best result at
−55︒C (Entry 18).
Key Words: Ring Opening • Cross-electrophile • C-C bond cleavage •
Ni-catalysis • Cyanoesters
Ring opening reactions of small strained molecules is one of the
most important transformations in organic synthesis and in the last
decades tremendous progresses have been achieved in the field of
nucleophilic ring opening reactions.1 In contrast, ring opening of
the electrophilic small ring substrates with another electrophile are
much less developed, although this type of reactions could provide
diverse compounds inaccessible through the classic nucleophilic
pathway. The challenge of developing new electrophilic ring
opening reactions lies in finding an appropriate way to overturn the
intrinsic nature of the precursors. Therefore, only limited number
of successful examples, especially in the catalytic version, have
been reported up to date and most of them focus on epoxides and
aziridines.2,3 On the other side, great advancements have been
achieved in the field of Ni-catalyzed cross-electrophile coupling in
the recent years.4,5 However, most of these reactions involve
carbon-halide- or carbon-oxygen-cleavage, while the reductive
cross-coupling through a C-C bond activation is very rare.6
Recently, the C-C bond cleavage of cylcoketone oxime esters
proved to be a useful method to approach alkyl nitriles under
cyanide-free conditions.7-9 To the best of our knowledge all the
reported reactions involving cycloketone oxime esters proceed in
redox-neutral pathway including direct couplings9a-i (Scheme 1A)
and difunctionalizations of alkenes9j,k (Scheme 1B). Herein, we
report a Ni-catalyzed electrophilic ring opening reaction of
cycloketone oxime esters with aroyl chlorides under reductive
conditions providing an efficient cyanide-free synthesis of diverse
cyanoketones (Scheme 1C).
Table 1. Optimization of the reaction conditions for the Ni-
catalzyed ring opening reactiona
Ni-salt (10 mol%)
ligand (10 mol%)
AcO
N
O
O
+
NC
Cl
Ph
Ph
Mn (3 equiv)
solvent, 1 h
(2 equiv)
1a
2a
3a
R
R
L1
L2
L3
R= H,
tBu,
OMe,
N
N
N
N
N
N
N
L4
Ph
Ph
Ph
Ph
Redox-Neutral Strategy (Previous Work)
R2X
R1O
NC
NC
R2
(A)
N
N
n
n
N
Me
Me
L5
L6
R2
R2H
R2
(B)
(C)
R2
n
Ligand
Yield
T (︒C)
Entry
Metal-salt
Solvent
[%]b
traces
traces
traces
traces
22
ReductiveStrategy (This Work)
L1
L2
L3
L4
L5
L6
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
1
2
3
4
5
6
NiCl2•glyme
NiCl2•glyme
NiCl2•glyme
NiCl2•glyme
NiCl2•glyme
NiCl2•glyme
DMF
DMF
DMF
DMF
DMF
DMF
R1O
Ni-Catalysis
N
O
Mn as Reductant
Ar
+
NC
n
Cl
Ar
O
n
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NiCl2•glyme
NiCl2•glyme
NiCl2•glyme
NiCl2•glyme
NiCl2
Ni(COD)
Ni(acac)2
NiCl2(PCy3)2
Ni(acac)2
Ni(acac)2
23
12
25
traces
39
43
51
28
57
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
L6
DMF
MeCN
THF
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
-30
-55
employed as substrates, the products 3n-s were afforded in
moderate to high yields. In the case of unsymmetrical cyclic oxime
esters the challenge lies in the selective C−C bond cleavage. To our
delight, our Ni-catalyzed ring opening reactions all occurred
selectively at the more-substituted carbon-centre furnishing the
products 3t-af in complete regioselectivities and good to high
yields. Moreover, the favoured C−C bond cleavage at the benzylic
position was observed in the cases of 3ag-ai. For the bi- and
tricyclic oxime esters precursors with cis-configuration the
reactions proceeded with a conversion of the stereochemistry of the
new formed stereocenter (3z-af). When dihydroindenone or
dihydronaphthalenone O-acetyl oximes were used as the substrates,
C-C cleavage at the benzylic position could be achieved at higher
temperature in comparison to their four-membered ring analogues.
In this case the products 3ah and 3ai were obtained in the enol-
form instead of the keto-form.
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
14d
15e
16e,f
17e,f,g
18e,f,h
67
9
Ni(acac)2
Ni(acac)2
73
84 (82i)
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a Unless otherwise specified, reactions were performed on a 0.2 mmol scale
of cyclobutanone O-acetyl oxime (1a) with 2 equiv benzoyl chloride (2a),
10 mol% nickel-salt, 10 mol% ligand and 3 equiv Mn as reductant in 1 mL
solvent at room temperature. b Yields determined by 1H-NMR spectroscopy
using mesitylene as an internal standard. c Zn was used as reductant instead
of Mn. d No additional ligand was used. e 3 Equiv benzoyl chloride (2a) was
f
g
h
To demonstrate the utility of this method, some derivatizations
based on the conversion of the cyano moiety were conducted
(Scheme 2). The hydrolysis of 3z under basic conditions furnished
a cyclic carboxylic acid 4 in a good yield, while a ZnCl2-mediated
alcoholysis of 3z provided a butyl ester 5 with high efficiency
(Scheme 2A). Furthermore, a ring opening product 3f was
successfully converted into an α-amino cyclopentanone 6 via a
two-step synthesis consisting of the imine formation and the
followed Ti-catalyzed reductive cyclization (Scheme 2B).10
used. Reaction was performed in 2 mL DMF. Reaction time: 8 h.
Reaction time: 24 h. i Yield of the isolated product.
After establishing the best reaction conditions, we started to
evaluate the substrate spectrum of this Ni-catalyzed reductive ring
opening reaction (Table 2). First, we reacted O-acetyl oxime (1a)
with diverse aromatic acid chlorides 2a-m bearing electron-
donating or withdrawing groups on different positions. To our
delight, all the reactions proceeded smoothly, furnishing the
corresponding nitriles 3a-m in moderate to good yields. Notably,
the 5 mmol scale synthesis of 3d provided a similar yield (entry 4).
One limitation of this method was observed in the reactions
employing aliphatic acid chlorides, which failed to deliver the
desired products. In this case, only decomposition of the oxime
esters was observed.
A series of control experiments were carried out to explore the
mechanism of this Ni-catalyzed ring opening reaction (Scheme 3).
First, we performed a stoichiometric reaction between Ni(COD)2
and the aroyl chloride 2d (Scheme 3A).11 Upon completion the α-
phenyl cyclobutanone O-acyl oxime (1i) was added to the reaction
mixture both with and without the reductant Mn. In either case the
ring opening product 3u was not formed. This result implies that
this Ni-catalyzed reaction is likely not initiated through the
interaction between a Ni(0)-species and the aroyl chlorides. Next,
the oxime ester 1i was subjected to a stoichiometric reaction to
Ni(COD)2 (Scheme 3B). In this case a complete consumption of 1i
was observed after 30 min at room temperature. The subsequent
addition of aroyl chloride 2d to the reaction mixture in the absence
of Mn did not lead to the formation of the γ-cyanoketone 3u. In
contrast, the desired product 3u was obtained in a 55 % yield in the
presence of Mn, indicating that Mn is required in a step of an-
intermediate-reduction instead of serving as a terminal reductant.
Furthermore, we conducted the reaction under the standard
reactions with TEMPO as a radical scavenger (Scheme 3C). In this
case the reaction was completely inhibited suggesting the existence
of a key radical intermediate in this studied reaction. However, we
did not obtain any radical trapping product. In addition, a radical
clock experiment reaction employing the cyclobutanone oxime
ester 1q incorporating a bishomoallyl group was carried out under
the optimum reaction conditions providing a cyclic product with a
moderately good diastereomeric ratio (Scheme 3D). This result
supports the possible generation of an iminyl radical, which results
in the formation of a C-centered radical via the ring opening
reaction and the following cyclization reaction.9c,9g,12
Table 2. Evaluation of the substrate scope the Ni-catalyzed reaction
through variation of the structure of acid chloridesa
Ni(acac)2 (10 mol%)
AcO
O
N
L6
(10 mol%)
O
+
NC
Ar
Cl
Ar
2a m
Mn (3 equiv)
DMF, 55 °C, 24 h
1a
3a m
-
-
Entry
1
2
3
4
5
6
7
8
Ar
Ph (3a)
Yield [%]b
83
93
75
4-MeC6H4 (3b)
4-tBuC6H4 (3c)
3,5-(Me)2C6H3 (3d)
3-MeOC6H4 (3e)
4-MeOC6H4 (3f)
3,5-(MeO)2C6H3 (3g)
4-F3COC6H4 (3h)
4-FC6H4 (3i)
93 (88c)
84
76
77
79
46
57
64
52
87
9
10
11
12
13
3-ClC6H4 (3j)
4-ClC6H4 (3k)
4-BrC6H4 (3l)
2-Naphthyl (3m)
a Unless otherwise specified, reactions were performed on a 0.2 mmol scale
of cyclobutanone O-acetyl oxime (1a) with 3 equiv aroyl chloride 2, 10 mol%
Ni(acac)2, 10 mol% ligand L6 and 3 equiv Mn as reductant in 2 mL DMF
at −55 ︒ C for 24 h. b Yields of the isolated products. b Reaction was
performed on a 5 mmol scale.
Based on the experimental results aforementioned we proposed the
following plausible mechanism for this Ni-catalyzed reaction
(Scheme 4). Initially, under the reductive reaction conditions a
Ni(I)-species I is generated, which interacts with cycloketone
oxime esters 1, to afford a cage II consisting of an iminyl racial and
a Ni(II) complex. The instant ring opening of the resultant iminyl
radical gives a C-centered radical, which recombines rapidly with
the Ni(II) complex. In the next step, the generated Ni(III)
intermediate III is reduced by Mn providing a Ni(I) species IV,
Subsequently, we continued to explore the scope of this Ni-
catalyzed reaction by varying the structure of the cycloketone
oxime esters (Table 3). A panel of representative oxime esters were
reacted with different aroyl chlorides under the optimum reaction
conditions. When symmetrical cycloketone O-acetyl oximes were
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which undergoes subsequently an oxidative addition with aroyl
chlorides 2. Finally, reductive elimination on the Ni(III) complex
V furnished the cyanoketones 3 as products and regenerates the
Ni(I) species I for the next catalytic cycle.
3
4
5
Table 3. Evaluation of the substrate scope the Ni-catalyzed reductive ring opening reaction through variation of the structure of the
cycloketone O-acetyl oximes.13,a,b
6
7
8
9
AcO
Ni(acac)2 (10 mol%)
N
R2 R2
O
O
L6
(10 mol%)
+
NC
R1
Ar
Cl
Ar
n
Mn (3 equiv)
DMF, 55 °C, 24 h
n
R1
R2 R3
n= 1-3.
1
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2
3n ai
-
Symmetrical Cycloketone O-Acetal Oximes
Boc
N
2
R = H, R3= Bn 85 %
R2 R3
O
Boc
O
3n
AcO
N
O
2
R = H, R3= Ph 69 %
NC
N
Me
NC
Me
3o
3p
3q
NC
Me
2
3
R = Me, R = Ph 65 %
2
3
R = Ph, R = Ph 53 %
R2 R3
3rc
3s
, 58 %
, 83 %
Me
Me
Me
Unsymmetrical Cycloketone O-Acetal Oximes
3t
Me
1
R = Bn, Ar= 3,5-(Me)2C6H3 82 %
AcO
1
O
3u
3v
R = Ph, Ar= 3,5-(Me)2C6H3 89 %
AcO
N
N
1
NC
R = Allyl, Ar= 3,5-(Me)2C6H3 85 %
Me
H
Ar
O
R1
1
3w
3x
3y
R = Allyl, Ar= Ph
89 %
64 %
R1
1
R = Allyl, Ar= 4-MeC6H4
3z
, 65 %
dr> 20:1d
H
1
R = Allyl, Ar= 4-CF3OC6H4 76 %
NC
AcO
H
N
Ar
AcO
O
Ar
N
H
O
H
Ar= 3,5-(Me)2C6H3 84 %, dr> 20:1d
Ar= 4-CF3OC6H4 71 %, dr> 20:1d
3aa
3ab
3ac
NC
Ar= 3,5-(Me)2C6H3 84 %, dr> 20:1d
Ar= 4-ClC6H4
73 %, dr> 20:1d
H
NC
3ad
3ae
3af
Ar= 3-MeOC6H3
Ar= 2-Naphthyl
73 %, dr> 20:1d
94 %, dr> 20:1d
Me
AcO
Me
Me
AcO
N
NC
N
3ahe
3aie
3ag
, 88 %
n= 1, 84 %
n= 2, 93 %
NC
n
n
OH
Me
O
a Unless otherwise specified, reactions were performed on a 0.2 mmol scale of cycloketones O-acetyl oximes 1 with 3 equiv aroyl chloride 2, 10 mol%
Ni(acac)2, 10 mol% ligand L6 and 3 equiv Mn as reductant in 2 mL DMF at −55︒C for 24 h. b Yields of the isolated products. c Reaction was performed at
room temperature for 3 h. d Determined by 1H-NMR-spectroscopy. e Reaction was performed at −30︒C.
Ar
Scheme 2. Derivatizations of the Ni-catalyzed ring opening
O
1) NaOH (0.1 M)
products.
100 °C, 24 h
2) conc. HCl
A)
HO2C
In summary, a Ni-catalyzed electrophilic reductive ring opening of
cycloketone oxime esters with aromatic acid chlorides has been
accomplished through merging C-C bond cleavage and cross-
electrophile coupling. This new method demonstrates a broad
substrate scope with respect to both coupling partners. Remarkably,
this reaction proceeds with complete regioselectivity for the key C-
C cleavage step allowing the synthesis of diverse cyanoketones
under cyanide-free conditions. The preliminary mechanistic studies
indicate that this Ni-catalyzed reaction might proceed in a radical
pathway initiated through the interaction between oxime esters and
a Ni(I) species with intermediate-reduction in the following steps.
Ar
O
4
, 68 %
O
ZnCl2 (1 equiv)
n-BuOH, 120 °C, 20 h
Ar
NC
3z
Ar= 3,5-(Me)2C6H3
n-BuO2C
5
, 77 %
B)
1) BnNH2 (1.2 equiv), MS 4 A
toluene, reflux, 24 h
O
O
NH2
Ar
NC
Ar
2) TiCp2Cl2 (10 mol%)
3f
Zn (2 equiv), Et3N•HCl (2 equiv),
TMSCl (3 equiv), THF, 40 C, 24 h
Ar= 4-MeOC6H4
6
, 61 %
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AcO
N
Notes
Ph
3
4
5
6
7
8
9
The authors declare no competing financial interest.
A)
2d
(1 equiv)
ArCOCl (
)
1i
Ni(COD)2
(1 equiv)
Ph
(1 equiv)
ACKNOWLEDGMENT
Ar
L6
X
NC
rt, 30 min
DMF, r.t., 30 min
Mn (0 or 3 equiv)
3u
O
This work is supported by “1000-Youth Talents Plan” starting up
funding, National Natural Science Foundation of China (Grant No.
21772183), the Fundamental Research Funds for the Central
Universities (WK2060190086), as well as by the University of
Science and Technology of China.
55 °C, 1 h
w/o Mn
2d
3u
ArCOCl (
(1 equiv)
)
Ni(COD)2
(1 equiv)
B)
X
1i
(1 equiv)
L6
10
11
12
13
14
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48
49
50
51
52
53
54
55
56
57
58
59
60
DMF, r.t.,
30 min
rt, 30 min
Mn (3 equiv)
55 °C, 1 h
3u
, 55 %
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AcO
C)
D)
N
Ph
L6
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Reaction:ꢀ Titanocene-Catalyzed Reductive Opening of Epoxides.
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Ouellet, S. G.; Raeppel, S. Amphoteric Character of 2-
Vinyloxiranes: Synthetic Equivalents of β , γ -Unsaturated
Aldehydes and a Vinylogous Enolate. Angew. Chem. Int. Ed. 2000,
39, 4079-4082. (d) Ohno, H.; Hamaguchi, H.; Tanaka, T.
Umpolung of Chiral 2-Ethynylaziridines:ꢀ Indium(I)-Mediated
Stereoselective Synthesis of Nonracemic 1,3-Amino Alcohols
Bearing Three Chiral Centers, Catalyzed by Palladium(0). Org.
Lett. 2000, 2, 2161-2163 (e) Araki, S.; Kameda, K.; Tanaka, J.;
Hirashita, T.; Yamamura, H.; Kawai, M. Umpolung of
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Allylation of Carbonyl Compounds. J. Org. Chem. 2001, 66, 7919-
7921. (f) Gansäuer, A.; Pierobon, M.; Bluhm, H. Stereoselective
Synthesis of Tri ‐ and Tetrasubstituted Olefins by Tandem
+
ArCOCl
Ar
X
NC
Ph
Mn (3 equiv)
3u
O
DMF, 55 °C, 24 h
TEMPO (1 equiv)
1i
2d
CN
Ni(acac)2 (10 mol%)
AcO
L6
(10 mol%)
N
+
O
ArCOCl
Ar
Mn (3 equiv)
DMF, 55 °C, 24 h
*
*
3
2d
1q
Ar= (Me)2C6H3
3aj
86 %, dr= 4:1
Scheme 3. Control experiments for investigation of the mechanism.
R3
AcO
N
Ar
NC
n
R3
R1 R2
O
n
3
R1 R2
Ni(I)LnCl
1
I
R3
O
N
Ni(II)ClOAc
R3
NC
Ni(III)
Cl
n
Ar
R1 R2
n
R1 R2
II
V
O
R3
Cl
Ar
R3
2
NC
Ni(III)ClOAc
n
NC
Ni(I)
R1 R2
n
R1 R2
IV
III
Mn
MnOAcCl
Scheme 4. Proposed mechanism of the Ni-catalyzed electrophilic
ring opening of cycloketone oxime esters.
ASSOCIATED CONTENT
Supporting Information
Representative experimental procedures and necessary
characterization data for all new compounds are provided. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
chuanw@ustc.edu.cn
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DiBenedetto, T. A.; Kim, S.; Ackerman, L. K. G.; Weix, D. J.
reported an example of cross-electrophile coupling involving C-C
bond cleavage: Decarboxylative Cross-Electrophile Coupling of
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Soc. 2016, 138, 5016-5019.
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Nitrogen-Radical Precursors in Visible-Light Photochemistry.
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(9) For selected examples on C-C bond cleavage reactions involving
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(13) The trans configuration of compound 3aa and the Z-configuration
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configuration of 3z, 3ab-af and 3ai was assigned by analogy
assuming a common reaction pathway..
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Graphical Abstract
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C-C Bond
Cleavage
Cross-Electrophile
Coupling
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AcO
n
R3
R1 R2
N
Ni-cat.
Mn as reductant
O
Ar
R3
+
NC
n
Cl
Ar
38 Examples
up to 94 %
O
R1 R2
A Ni-catalyzed electrophilic reductive ring opening of cycloketone oxime esters with aromatic acid chlorides has been accomplished through
merging C-C bond cleavage and cross-electrophile coupling.
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