Ni-Catalyzed 1,2-Acyl Migration Reactions Triggered by C-C Bond Activation of Ketones

Article abstract of DOI:10.1021/acscatal.9b04112

A Ni-catalyzed 1,2-acyl migration triggered by C-C bond cleavage was developed. The process of 1,2-acyl migration followed by olefin isomerization provides a convenient access to α,β-unsaturated ketones, which are well-known building blocks in organic syn

Full text of DOI:10.1021/acscatal.9b04112

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Letter
Ni-Catalyzed 1,2-Acyl Migration Reactions
Triggered by C–C Bond Activation of Ketones
Cheng Jiang, Hong Lu, Wenhua Xu, Jianing Wu, Tian-Yang Yu, Peng-Fei Xu, and Hao Wei
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b04112 • Publication Date (Web): 06 Nov 2019
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ACS Catalysis
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Ni-Catalyzed 1,2-Acyl Migration Reactions Triggered by C–C Bond
Activation of Ketones
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Cheng Jiang,†§ Hong Lu,†§ Wen-Hua Xu,† Jianing Wu,† Tian-Yang Yu,† Peng-Fei Xu,‡ Hao Wei*†
†Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of
Chemistry & Materials Science, Northwest University, Xi’an 710069, China
‡State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, China
ABSTRACT: A Ni-catalyzed 1,2-acyl migration triggered by C–C bond cleavage was developed. The process of 1,2-acyl migration
followed by olefin isomerization provides a convenient access to α,β-unsaturated ketones, which are well-known building blocks in
organic synthesis. Experimental and computational studies show that the selective β-hydride elimination and Ni-hydride re-insertion
play an essential role in this reaction.
KEYWORDS: Ni catalysis, C−C bond cleavage, 1,2-acyl migration, olefin isomerization, unsaturated ketones
Skeletal rearrangements involving 1,2-carbon-to-carbon
migrations are fundamental, yet powerful, methods for the
structural reorganization of organic molecules.1 In general, 1,2-
migrations only take place at carbon cations,2 radicals,3 or
carbenes.4 They can also readily occur on an electrophilic
functional group, such as aldehydes,5 imines,6 or epoxides
(Figure 1A).7 However, the direct 1,2-migration of carbon-
based groups to an inactivated carbon atom remains a challenge.
The whole catalytic process would convert β,γ-unsaturated
ketones to more stable alkene isomers, accounting for the
overall thermodynamic benefits of this transformation.
A.
Previous carbon-based group 1,2-migration from vicinal carbon to carbon
1,2-group migration
= carbon cation, radical, carbene, aldehyde, imine, or epoxide
Transition-metal-catalyzed
transformations
involving
B.
Intramolecular acyl migration by CC bond activation
selective C−C bond activation/cleavage have recently received
widespread attention in the synthetic community.8 An
intriguing question is whether 1,2-migration can be directly
triggered by C−C bond cleavage. Great progress has been made
in the development of intramolecular acyl migration of
inactivated alkenes involving cleavage and formation of C−C
bonds. The development of these reactions is limited by the
requirement for substrates to contain either a strained cyclic
ketone9,10 or a directing group11 (Figure 1B). Compared with
these examples, one key concern for our desired 1,2-migration
is the reversibility of the C–C activation step. Simple unstrained
ketones generally lack sufficient thermodynamic driving forces
to favor the oxidative addition of the C–C bond; instead, the
reductive elimination is often preferred.12 Olefin isomerizations
are atom-economical and synthetically useful transformations,
that are thermodynamically driven to produce more stable
alkene isomers.13 We hoped that such a problem could be solved
by combining an unfavorable C–C activation reaction with a
double bond isomerization to enable an overall
thermodynamically favorable transformation. As depicted in
Figure 1C, the C–C bond adjacent to ketones can be cleaved
with transition metals (e.g. Ni(0)).14 We hoped that subsequent
β-hydride elimination with the resulting acylnickel-(II)
intermediate would lead to a Ni(II)-hydride intermediate, which
could undergo hydride re-insertion followed by reductive
elimination/isomerization to furnish the desired migration
products. These are well-known building blocks used in the
chemical industry15 and common structural motifs found in
natural products and pharmaceutically important molecules.16
O
acyl migration
O
Strained systems
Directing groups
N
O
O
N
R
O
N
R
NH2
+
O
N
R'
R
R'
Permanent
directing group
Temporary
directing group
C. This Work
: 1,2-acyl migration triggered by CC bond cleavage
R2
O
R2
R2
olefin
O
R1
migration
R1
R3
R3
Ni
R1
R4
R3
R4
R4
O
R2
migration to an inactivated olefin
non-directing group
O
R1 Ni
H
R4
R3
Figure 1. Inspiration for Ni-catalyzed 1,2-acyl migration.
Given our and others’ previous success using nickel to
promote C(=O)–C bond cleavage of unstrained ketones.14
Subsequently, nickel catalysis could also facilitate our desired
1,2-acyl migration reactions. To validate this hypothesis,
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readily accessible β,γ-unsaturated ketone 1a was used as the
Table 2. Scope of Aryl Ketones in 1,2-Acyl Migrationa,b
1
2
3
4
5
6
7
8
model substrate. This substrate could be constructed in two
steps from commercially available 1-bromo-3-methylbut-2-ene
and benzaldehyde: allylation of aldehydes followed by
oxidation delivered 1a.17 After judicious optimization of all
reaction parameters, the desired α,β-unsaturated ketone 2a was
afforded in 76% yield using Ni(cod)2/SIPr as the metal/ligand
combination and dioxane as the solvent (Table 1, entry 1). A set
of control experiments was then conducted to understand the
role of each reactant. As expected, the efficiency was found to
be strongly dependent on the nature of the ligand (entries 2−7).
Compared with the SIPr ligand, other NHC ligands also
promoted this reaction albeit in lower yields (entries 2−5) with
decomposition of the starting material. Use of exogenous
phosphine or nitrogen-based ligands was detrimental to the
reaction and 1a remained intact (entries 6 and 7). Dioxane as
the solvent proved to be superior to toluene or xylene (entries 8
and 9). An attempt to bring down the reaction temperature
resulted in incomplete conversion (78%) and moderate yield
(46%; entry 10). Furthermore, rigorous control experiments in
the absence of either Ni(cod)2 or SIPr·HCl revealed that these
reaction components were crucial for the C−C cleavage to occur
(entries 11 and 12). Decreasing the amount of Ni(cod)2 resulted
in diminished yields (entry 13), leading to decomposition of 1a.
Ni(cod)2 (10 mol%)
SIPrHCl (20 mol%)
Cs2CO3 (30 mol%)
Me
O
R
Me
R
dioxane, 150 oC, 24 h
O
Me
Me Me
2
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Cl
O
Me
2c
O
Me
O
Me
2a
2b
, 76%
, 79%
, 72%
9
F
10
11
12
13
14
15
16
17
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Me
Me
Me
Me
Me
Me
2d
O
Me
Me
O
Me
O
2f
, 66%
2e
, 76%
, 68%
CN
O
Me
Me
Me
Me
O
Me
2g
O
Me
O
2h
, 50%
, 81%
NMe
O
Me
Me
Me
O
=
Me
O
2i
X-ray of
Me
2i
, 74%
OH
Et
OMe
Me
Me
Table 1. Optimization of the Reaction Conditionsa
Me
Me
Me
O
Me
O
Me
O
1. Zn, THF/H2O
Ni(cod)2 (10 mol%)
SIPrHCl (20 mol%)
2l
, 76%
2j
2k
, 63%
, 83%
Me
Me
O
O
Me
Ph
Cs2CO3 (30 mol%)
dioxane, 150 oC, 24 h
Ph
Me
Br
i-Pr
t-Bu
Me
Ph
Me
Me
Me
Ph
H
Me Me
1a
Me
2a
O
2. PCC, DCM
Me
Me
Me
Me
"standard" conditions
Me
2o
O
Me
O
Me
O
c
Change from standard
conditions
Conversion Yield
2n
, 80%
, 86% (69%)
2m
, 75%
Entry
(%)b
100
100
100
90
(%)c
76
Me
Me
S
Me
O
1
2
none
Me
Me
Me
2p
O
Me
O
Me
2q
O
, 72%
IPr·HCl instead of SIPr·HCl
IPrMe·HCl instead of SIPr·HCl
IMes·HCl instead of SIPr·HCl
ICy·HCl instead of SIPr·HCl
dppe instead of SIPr·HCl
1,10-phen instead of SIPr·HCl
toluene instead of dioxane
xylene instead of dioxane
at 120 oC
66
, 80%
2r
, 67%
3
46
Me
4
31
Me
O
Me
O
5
92
trace
n.r.
n.r.
52
Me
O
Me
2s
, 63%
O
Me Me
1t
6
<5
Me
2t
, 75%
7
<5
Me
Me
Me
Me
8
58
Ph
Me
2u
O
Me
O
9
62
35
, 18%
2v,
n.r.
10
11
12
78
46
aStandard conditions: 1a (0.2 mmol), Ni(cod)2 (10 mol%),
without Ni(cod)2
<5
n.r
SIPr·HCl (20 mol%), Cs2CO3 (30 mol%) and dioxane (2.0 mL)
b
c
without SIPr·HCl
<5
n.r
at 150 °C in sealed tube. Isolated yields. The reaction was
performed on a 1.0 g scale.
5 mol% Ni(cod)2 and 10 mol%
SIPr·HCl
13
100
44
yields (50–86%) of isomerization products were obtained with
aryl ketones bearing a variety of substituents (2a–2t). The
reaction proceeded smoothly in the presence of aryl halides (2e
and 2f), thus leaving ample opportunities for further
functionalization via conventional cross-coupling reactions.
Notably, cyano (2g) and ester (2h and 2i) functional groups on
the aromatic rings were also tolerated, and the structure of α,β-
unsaturated ketone 2i was unambiguously confirmed by X-ray
crystallography. Surprisingly, an unprotected phenol was well
tolerated (2k) under the reaction conditions. The bulky
substituent on the phenyl (2m, 2n and 2o) and naphthyl (2p) did
not hinder the reaction. Various heteroaryls including furan
(2q), thiophene (2r) and dihydrobenzofuran (2s) could also be
Me
Me
N
N
R
N
N
R
N
N
R
R
R
R
IPrMe (R = 2,6-iPr2C6H3)
SIPr (R = 2,6-iPr2C6H3)
IMes (R = 2,4,6-Me3C6H2)
ICy (R = Cyclohexyl)
IPr (R = 2,6-iPr2C6H3)
aStandard conditions: 1a (0.2 mmol), Ni(cod)2 (10 mol%),
SIPr·HCl (20 mol%), Cs2CO3 (30 mol%) and dioxane (2.0 mL)
at 150 °C in sealed tube. bConversions were determined based on
recycled starting material after isolation. cIsolated yields
With the optimized conditions established, we then explored
the substrate scope of this reaction (Table 2). Good to high
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readily incorporated. Interestingly, another olefin isomerization
was observed when using an aromatic motif bearing an ortho-
allyl substituent (2t). Alkyl ketones 1u and 1v were also
investigated, but only a low yield was obtained for product 2u.
Moreover, the migration reaction can be performed on gram
scale, providing desired product 2o in 69% yield.
The usefulness of our synthetic method is illustrated in
Scheme 1. In the presence of BrØnsted acid, the products could
be readily transformed to multisubstituted indane derivatives in
high yields (78–92%). These scaffolds are widely found in
natural products and drug candidates possessing intriguing
bioactivities,19 highlighting the synthetic potential of the
present method.
1
2
3
4
5
6
7
8
Table 3. Substrate Scopea,b
Me
Me
R3
O
Me
Ph
Ni(cod)2 (10 mol%)
SIPrHCl (20 mol%)
Cs2CO3 (30 mol%)
dioxane, 150 oC, 24 h
Me
Ph
olefin
migration
R3
O
R2
R1
Ph
Me
O
2a
O
2a'
9
Ph
R1
O
R2
Me
Me
Ni(II)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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45
46
47
48
49
50
51
52
53
54
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57
58
59
60
3
4
Me
Ph
Me
Ph
O
L
Ni(II)
L
Me
Me
Me
Me
Me
III-B
Ni(0)
Et
Ph Ph
Ph n-Hex
Ph Ph
Ph
III-A
Et
O
Me
O
Me
O
Me
O
c
1a
c
c
4a
, 65%
Path B
4b
4c
4d
Path A
, 82% (1:2)
, 82% (2:3)
, 52% (2:3)
O
H
Me
Me
Me
Me
L
3
Ph
Ph
Ph
Ph
•
Ph
Ni(II)
O
2
L
O
O
O
O
O
Ph
Ni(II)
L
Me
Me
H
II-B
Me
Ph
Ni(II)
4e
4f
4g
4h
, 88%
C2 : C3 = 1:5
(separable)
, 87%
C2 : C3 = 3:1
(separable)
, 89%
, 91%
C2 : C3 = 1:2
(separable)
II-A
Hb
H2C Ha
Me
I
OAc
Me
Me
n
Me
O
Scheme 2. Possible Mechanism
Me
H
H
Ph
Me
Ph
H
Me
O
Me
Two different pathways to achieve the desired products are
proposed in Scheme 2. The initial oxidative addition of one of
the C–C bonds to the nickel(0) species would lead to the
formation of aroyl nickel(II) intermediate I, which undergoes
β-hydride elimination of Ha to generate Ni(II)–hydride
intermediate II-A (Path A). Subsequent Ni-hydride insertion
can occur on the less-hindered olefin, which provides a Ni-π-
allylic intermediate III-A. As reductive elimination tends to
favor branched products,20 we reasoned that III-A would yield
allylic ketone 2a′, which would finally isomerize into the α,β-
unsaturated ketone 2a.21 In path B, β-hydride elimination of Hb
would provide Ni(II)–hydride intermediate II-B. Re-insertion
of the terminal allene into Ni(II)–hydride yields III-B, which
would undergo reductive elimination to yield product 2a.
H
4k
, n = 5, 58%
n = 7, 55%
d
O
Ph
4l
,
4i
4j
, 75%
, 85%
aStandard conditions: 3 (0.2 mmol), Ni(cod)2 (10 mol%),
SIPr·HCl (20 mol%), Cs2CO3 (30 mol%) and dioxane (2.0 mL)
at 150 °C in sealed tube. bIsolated yields. cZ/E ratios of products
determined by 1H NMR of crude reaction mixtures are reported
in parentheses. dThe ratio was determined to be 1:1 by 1H NMR.
Next, the substituents at different positions of substrates were
investigated (Table 3). High reactivity was achieved for
substrates bearing various substituents at the α-position, as in
the cases of 4a–4d, with aryl and a range of alkyl groups all
successfully tolerated in this reaction. Notably, cyclic
substituents could also be installed at the α-position, 5-, 6-, 7-
and 8-membered ring substrates all underwent this
transformation smoothly (4e–4h), and two olefin isomers were
observed except in the case of the 6-membered ring substrate
(4e, 4g, 4h versus 4f).18 It is likely possible that tetrasubstituted
enones bearing a ring compounds 4e–4h are highly congested,
in which a allylic A1,3 strain forces the π-system to not be in
conjugation. Furthermore, we applied this protocol to indene
(4i) and stanolone (4j) derivatives, and the reactions also
proceeded smoothly to give good yields. Finally, the substrates
with 1,2-disubstituted alkenes were also accommodated,
furnishing the conjugate ketones with moderate yields (4k and
4l).
A.
Deuterium-labeling Experiments
(93%)
CH2D
(94%)
CH2D
a
a
a
O
(25%)
HD2C
Ph
Ar
Ph
"standard" conditions
b
+
Ph
H
b
b
Ar
O
(26%)
(99%)
HD2C
O
D3C Ar
4b-D-E 26%
4b-D-Z 55%
3b-D
Ar = C6D5
(99%)
D
D
a
CHD2(99%)
O
a
b Me
Ph
"standard" conditions
Ph
b Me Mec
H
c Me
O
1a-D
2a-D
75%
B.
3m
as substrate
Compound
O
Me
O
R
"standard" conditions
Ph
Ph
Me
CH3SO3H
Ph
H
Me
Me
Me
50 oC, overnight
Ph Ph
3m
R
Ph
O
Me
5a
4m
Me
O
, 90%
5o
2a
2o
R = H
R = Ph
5o
X-ray of
not detected by GC-MS
, 92%
Scheme 3. Probing the Mechanism
O
Me
O
CH3SO3H
50 oC, 5 h
O
Me
Me
Me
To further probe the mechanism of this transformation,
deuterium-labeling studies were carried out with ketones 3b-D
and 1a-D (Scheme 3). For the reaction of 3b-D, one of the
deuteriums on the methyl group was transferred to carbon a in
the product structure.22 This observation provided strong
Me
O
Me
5q
2q
, 78%
Scheme 1. Synthetic Utilities of the 1,2-Acyl Migration
Reaction
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-H Elimination
Oxidative Addition
Ni-Hydride Insertion
Reductive Elimination
Product Release
Path B
1
2
3
4
5
6
7
N
N
Ar
Ar
O
N
N
Ar
Ar
O
H
Ni
H
Ni
N
N
N
H
N
Ar
Ar
O
Ar
Ar
O
H
Me
Ni
Me
Ni
Me
Me
Me
Me
TS3-B
Me
INT2'-B
Me
TS2-B
INT2-B
39.7
39.0
37.2
36.0
TS3-B
INT2'-B
TS2-B
INT2-B
N
N
8
9
28.6
Ar
Ar
O
N
N
Ar
25.4
N
N
Ar
Ar
Ar
O
TS2-A
24.2
Ni
TS3-A
Ni
Me
Ni
Me
INT2-A
O
Me
Me
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Me
Me
N
N
N
N
N
N
Ar
O
TS4-A
13.6
Ar
Ar
O
Ar
Ar
O
N
N
Ar
Ar
Ar
H
INT3-B
H
TS1
H
TS4-A
Ni
Ni
Ni
Ni
H2
C
11.7
O
10.0
TS1
Me
TS4-B
7.5
Me
Me
Me
6.0
INT2-A
Me
INT4-A
TS2-A
Me
INT1'
TS3-A
INT3-B
Me
Ph
N
N
0.6
Ar
Ar
O
0.0
1a
-1.1
INT1
Me
O
Ni
2a'
-3.0
2a'
INT4-A
-6.6
O
-5.0
Me
INT1'
-6.5
2a
Me
N
N
N
N
-6.8
INT0
Ar
Ar
O
Ar
Ar
O
N
N
INT4-B
Ar
Ar
O
INT3-A
Me Me
Ni
Ni
N
N
Me
Me
Ar
Ar
Ni
N
N
Ar
1a
Ar
Me
Me
Ph
Me
INT3-A
Ni
Me
Me
Me
INT1
Ni
O
O
Me
TS4-B
Me
2a
O
Me
Me
INT4-B
Me Me
INT0
Product
Release
Olefin
Migration
Oxidative Addition
-H Elimination
Ni-Hydride Insertion
Reductive Elimination
Path A
Figure 2. DFT-calculated reaction energy profile of Ni-catalyzed 1,2-acyl migration reaction. See ESI for computational details.
support for the mechanism of path A. Next, 1a-D was subjected
to the migration reaction. Deuterium was completely retained at
carbon a and was not redistributed to any other position. We
further tested the reactivity of compound 3m, which does not
have hydrogen atoms at carbons b and c in the substrate
structure. Under the standard conditions, the reaction did not
proceed at all, and 3m remained intact. This result further
supports path A.
only offers an alternative way to synthesize α,β-unsaturated
ketones but also sets a precedent for C−C bond cleavage with
olefin isomerization. Mechanistic exploration via DFT
calculations has also been executed. Through the computational
study, a proposed catalytic mechanism has been carefully
evaluated. We believe this strategy of C−C bond cleavage can
be applied to other reactions, and development of new reactions
based on this strategy is currently in progress.
Preliminary DFT study was also conducted. The geometries
were optimized at the density functional B3LYP-D3/DZ level
of theory23-25 and the electronic energies were further improved
by single-point calculations at the M06L/TZ level.26 Solvation
effects in 1,4-dioxane were treated by the continum implicit
solvation model IEFPCM.27,28 Two possible mechanistic
pathways are shown in Figure 2. The catalytic cycle starts from
the coordination between the Ni(0) complex and substrate 1,
giving catalyst–substrate complex INT0. INT0 undergoes
oxidative addition via TS1, requiring an activation free energy
of 15.0 kcal mol−1. This step is endergonic by 5.6 kcal mol−1 and
generates INT1. Then η3-intermediate INT1 can rearrange into
the intermediate INT1’. Subsequently, β-hydride elimination of
Ha (path A) via TS2-A transforms INT1’ to INT2-A, requiring
an activation free energy of 21.1 kcal mol−1. The β-hydride
elimination is endergonic by 16.7 kcal mol−1. Ni-hydride
insertion converts INT2-A to INT3-A (via TS3-A), which
undergoes reductive elimination to give to INT4-A (via TS4-
A). An alternative pathway is β-hydride elimination (via TS2-
B) of Hb (path B), which is disfavored by more than 15.5 kcal
mol−1 compared to the β-hydride elimination of Ha. The
computed activation energy barrier for this step is 36.6 kcal
mol−1, which is higher than the total activation energy in path
A. Consequently, path B could be ruled out at this stage. Our
calculations also indicated that the rate-determining step of the
catalytic cycle is the β-hydride elimination step.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*haow@nwu.edu.cn
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interests.
SUPPORTING INFORMATION
The Supporting Information is available free of charge on the
ACS Publications website.
Crystallographic data for 2i (CIF)
Crystallographic data for 5o (CIF)
Experimental details; characterization data, and spectral (PDF)
ACKNOWLEDGMENT
We are grateful to financial support from the National Natural
Science Foundation of China (NSFC 21632003 and 21971205),
Scientific Research Program Funded by Shaanxi Provincial
Education Department (17JS129 and 2018JM2012) and the Key
Science and Technology Innovation Team of Shaanxi Province
In conclusion, a Ni-catalyzed 1,2-acyl migration process that
proceeds via C−C bond cleavage is described. This method not
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2014, 16, 5968–5971. (b) Andreou, D.; Kallitsakis, M. G.;
(2017KCT-37). We thank Prof. Zhi-Xiang Yu and Prof. Shaolin
Zhu for insightful discussions.
Loukopoulos, E.; Gabriel, C.; Kostakis, G. E.; Lykakis, Copper-
Promoted Regioselective Synthesis of Polysubstituted Pyrroles from
Aldehydes, Amines, and Nitroalkenes via 1,2-Phenyl/Alkyl Migration.
J. Org. Chem. 2018, 83, 2104–2113.
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33 examples (up to 91% yield)
1,2-acyl migration triggered by C-C bond cleavage
C-C cleavage driven by olefin isomerization
non-directing group
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