Development and Mechanistic Studies of the Iridium-Catalyzed C?H Alkenylation of Enamides with Vinyl Acetates: A Versatile Approach for Ketone Functionalization

Article abstract of DOI:10.1002/anie.202107331

Ketone functionalization is a cornerstone of organic synthesis. Herein, we describe the development of an intermolecular C?H alkenylation of enamides with the feedstock chemical vinyl acetate to access diverse functionalized ketones. Enamides derived from various cyclic and acyclic ketones reacted efficiently, and a number of sensitive functional groups were tolerated. In this iridium-catalyzed transformation, two structurally and electronically similar alkenes—enamide and vinyl acetate—underwent selective cross-coupling through C?H activation. No reaction partner was used in large excess. The reaction is also pH- and redox-neutral with HOAc as the only stoichiometric by-product. Detailed experimental and computational studies revealed a reaction mechanism involving 1,2-Ir-C migratory insertion followed by syn-β-acetoxy elimination, which is different from that of previous vinyl acetate mediated C?H activation reactions. Finally, the alkenylation product can serve as a versatile intermediate to deliver a variety of structurally modified ketones.

Full text of DOI:10.1002/anie.202107331

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Development and Mechanistic Studies of the Iridium-catalyzed
C−H Alkenylation of Enamides with Vinyl Acetates: A Versatile
Approach for Ketone Functionalization
Authors: Bo Zhou, Xiaotian Qi, Peng Liu, and Guangbin Dong
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202107331
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10.1002/anie.202107331
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RESEARCH ARTICLE
Development and Mechanistic Studies of the Iridium-catalyzed
C−H Alkenylation of Enamides with Vinyl Acetates: A Versatile
Approach for Ketone Functionalization
Bo Zhou,[a] Xiaotian Qi,*[b] Peng Liu,*[c] and Guangbin Dong*[a]
[a]
[b]
[c]
Dr. B. Zhou, Prof. Dr. G. Dong
Department of Chemistry, University of Chicago, Chicago, IL 60637 (USA)
E-mail: gbdong@uchicago.edu
Prof. Dr. X. Qi
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072 (China)
E-mail: qi7xiaotian@whu.edu.cn
Prof. Dr. P. Liu
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260 (USA)
E-mail: pengliu@pitt.edu
Supporting information for this article is given via a link at the end of the document.
Abstract: Ketone functionalization has been
a
cornerstone in
functionalized ketone products. Compared to regular alkenes,
vinyl acetate has not been commonly used in C−H activation
reactions.[6] Since the seminal work of Kakiuchi,[6a,b] only a
handful examples have been reported on vinyl acetate-mediated
C−H functionalization of arenes catalyzed by Ru,[6a,b] Rh[6c,e,f,g]
and Co.[6d,h] In particular, their use as a coupling partner for
alkene-based substrates has not been described yet. One
potential concern of using alkene substrates, such as enamides,
is that they have similar structural and electronic properties as
vinyl acetate. Hence, it is uncertain if such a selective C−H cross
coupling can be achieved between these two alkenyl substrates.
In this article, we report the development of an Ir-catalyzed C−H
alkenylation of enamides derived from various ketones with vinyl
acetates (Scheme 1B), which offers a versatile entry to access
diverse functionalization of ketones. In this transformation, vinyl
acetate serves as a convenient vinylation reagent with HOAc
formed as the only stoichiometric byproduct.[6c] Detailed
organic synthesis. Herein, we describe the development of an
intermolecular C−H alkenylation of enamides with feedstock
chemical vinyl acetate to access diverse functionalized ketones.
Enamides derived from various cyclic and acyclic ketones react
efficiently and a number of sensitive functional groups are tolerated.
In this Ir-catalyzed transformation two structurally and electronically
similar alkenes—enamide and vinyl acetate—are selectively cross-
coupled through C−H activation. The reaction does not need any
partner used in large excess. In addition, it is pH- and redox-neutral
with HOAc as the only stoichiometric byproduct. Detailed
experimental and computational studies of the reaction mechanism
reveal a pathway involving a 1,2-Ir−C migratory insertion followed by
a syn-β-acetoxyl elimination, which is different from the prior vinyl
acetate-mediated C−H activation reactions. Finally, the alkenylation
product can serve as a versatile intermediate to deliver a variety of
structurally modified ketones.
mechanistic studies disclose
a pathway involving 1,2-Ir-C
migratory insertion, followed by β-acetoxyl elimination; this
represents a different mechanistic feature from the prior vinyl
acetate-mediated C−H activation reactions.
Introduction
Preparation and derivatization of ketones, one of the basic and
prevalent functional groups, have been a cornerstone in organic
synthesis.[1] In particular, C−C bond forming reactions with
readily available feedstock chemicals, such as alkenes or
alkynes,
represent
attractive
methods
for
ketone
functionalization.[2,3] Compared to conventional organohalide-
based reactions, the coupling with alkene and alkyne feedstocks
hold significant economic advantages and avoid forming
halogen-containing byproducts.[4] Towards this goal, our
laboratory has been engaged in systematic development of
enamine
or
enamide-based
approaches
for
ketone
functionalization through catalytic C−H coupling with alkenes
and alkynes (Scheme 1A).[5] For example, the coupling with
olefins can provide either linear or branched C−H alkylation
products by tuning the bite-angles of the ligands.[5f,h]
Beyond simple olefins, vinyl acetate, with an annual global
production of about 7 million metric tons, has been one of the
key industry feedstock chemicals. We were fascinated by the
question of whether vinyl acetate can be employed as the
coupling partner in the enamide-based ketone functionalization
strategy, which, if successful, should provide more
Scheme 1. Enamine/enamide-mediated ketone functionalization.
1
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RESEARCH ARTICLE
Results and Discussion
PPh2
PPh2
PPh2
PPh2
Ph2P
PPh2
Ph2P
PPh2
Reaction discovery and optimization. To explore the
proposed C−H alkenylation with vinyl acetate (2a),
cyclopentanone-derived enamide 1a was employed as the
model substrate (Table 1). After careful evaluation of various
reaction parameters, the desired C−H vinylation product 3a was
ultimately obtained in 91% yield, with Ir(COD)2BArF[7]/dppbz as
catalyst, 1,4-dioxane as solvent at 150 oC under N2 (entry 1).
Notably, only 1.5 equivalent of vinyl acetate was needed as the
coupling partner, which is in sharp contrast to the regular
alkene-mediated C−H coupling reactions[8-10] with enamides.[5f–h]
The enhanced efficiency is likely due to the higher binding
affinity of vinyl acetate. Control experiments showed that, almost
no conversion of substrate 1a in the absence of the iridium
catalyst (entry 2), and replacing Ir with the corresponding
Rh(COD)2BArF only led to decomposition of the substrate (entry
3), suggesting the essential role of Ir in this reaction. The
phosphine ligand also proved to be critical, as without the
bidentate ligand no desired product was formed with most 1a
decomposed (entry 4). A survey of the ligand effect (entry 5)
indicates that dppbz was a superb ligand for this transformation.
Among other bidentate phosphine ligands examined, dppe and
dppp gave relatively higher yield (29% and 33%, respectively),
while the rest exhibited much lower reactivity or selectivity. It
appears that the combination of high rigidity and a suitable bite-
angle, as seen in dppbz, was important for this alkenylation
dppm
dppe
dppp
33%; 49% conv.
dppb
10%; 78% conv.
29%; 85% conv.
3%; 79% conv.
O
PPh2
O
O
O
PPh2
PPh2
PPh2
PPh2
PPh2
Fe
PPh2
O
PPh2
O
dppf
DIOP
BINAP
20%; 71% conv.
SEGPHOS
< 1%; 86% conv.
2%; 37% conv.
< 1%; 48% conv.
[a] The reaction was performed with 1a (0.1 mmol), 2a (0.15 mmol), catalyst
(0.01 mmol), L (0.01 mmol), in solvent (1 mL) under a N2 atmosphere at
corresponding temperature for 24 h. [b] Determined by 1H NMR using 1,1,2,2-
tetrachloroethane
bis(trifluoromethyl)phenyl)borate; COD
cyclopentyl methyl ether; THF = tetrahydrofuran.
as
internal
standard.
BArF
=
tetrakis(3,5-
=
1,5-cyclooctadiene; CPME
=
Substrate scope. With the optimized reaction conditions in
hand, the scope of cyclic ketone-derived substrates was first
investigated (Table 2). In general, enamides with different ring
sizes, e.g., from five- to eight-membered rings, can all react to
give the desired C−H vinylation products. Comparing to our prior
work on the C−H alkylation with regular alkenes,[5f–h] the use of
vinyl acetate gave a much broader substrate scope. Besides
simple cyclopentanone-derived emamide (3a), the one bearing
3,3-dimethyl substituents exclusively underwent the C−H
vinylation at the less sterically hindered position in good yield
(3b). In addition, 1-indanone-based substrate also worked. The
six-membered enamides used to be problematic substrates due
to the ease of aromatization under the Ir-catalyzed reaction
conditions.[5f–h] However, with vinyl acetate as the coupling
partner and the use of dppbz ligand, the desired C−H
functionalization outcompeted the dehydrogenation side-reaction.
This reaction not only gave good yields, but also exhibited
excellent functional group compatibility. For example, benzyl
ether (3h), ester (3i), amide (3j), thioether (3k), iodide (3m),
bromide (3n), trifluoromethyl (3p), nitrile (3q), nitro (3r), ketone
(3s), pinacolboronate (3t) and naphthalene (3u) were all
tolerated. The terminal alkene moiety from the eugenol-derived
substrate underwent complete isomerization to the conjugated
product (3v), which is consistent with the involvement of metal-
hydride species in the reaction (vide infra). Gratifyingly, estrone-
derived (3w) and cholestan-3-one-based (3x) substrates also
successfully produced the corresponding vinylation products,
showing the potential utility for late-stage modification of
complex molecules (vide infra). Moreover, geminal-disubstituted
six-membered enamides, e.g., 4,4-dimethyl (3y), 4,4-diphenyl
(3z) and 3,3-dimethyl (3aa), all worked smoothly. The α-
tetralone-derived substrate gave the desired product in 73%
yield without touching the aromatic ortho C−H bond.[11] Finally,
good to excellent yields have been obtained with
cycloheptanone- and benzocycloheptenone-derived substrates
(3ad, 3ae); promising preliminary success has also been
achieved with the more challenging eight-membered-ring
enamide (3af).
reaction. The reaction can also take place at
a lower
temperature albeit in lower yield (entry 6). Finally, 1,4-dioxane
proved to be better solvent than less polar toluene or other
ethers, such as THF and CPME (entries 7-9).
Table 1. Selected optimization for the C−H alkenylation.[a]
Entry
Variation from the ‘standard’ condition
Yield of
3a (%)[b]
Conv. (%)[b]
1
2
3
4
5
6
7
8
9
none
91
> 99
w/o [Ir(COD)2]BArF
< 1
< 5
< 1
94
[Rh(COD)2]BArF as catalyst
w/o dppbz
< 1
92
other L instead of dppbz
130 °C instead of 150 °C
toluene instead of 1,4-dioxane
THF instead of 1,4-dioxane
CPME instead of 1,4-dioxane
see below
see below
51
17
63
6
94
55
75
89
2
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10.1002/anie.202107331
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RESEARCH ARTICLE
Table 2. Scope of cyclic ketone-derived enamides.[a]
[a] Unless otherwise noted, reactions were run on a 0.2 mmol scale in a 8 mL vial under the standard conditions; All yields are isolated yields. [b] E/Z ratio was
determined by 1H NMR analysis of the reaction crude. [c] 48 h.
Compared to cyclic substrates, enamides derived from
linear ketones proved to be much less reactive, which is likely
due to slower C−H oxidative addition and migratory insertion into
vinyl acetate (see Supporting Information, Figure S5). For
example, under the standard condition developed in Table 1,
enamide 4a only gave 47% conversion and 28% yield of the
C−H vinylation product (5a) (Table 3, entry 1). As the ligand
plays a critical role in this transformation, the ligand effect was
then investigated using linear enamide 4a as the substrate.
Among varies of bidentate phosphine ligands tested, dppp
showed the best conversion and yield (entry 5). Other ligands
with either small bite-angles, such as dppm and dppe (entries 3
and 4), or larger bite angles, such as DIOP, dppb, dppf, BINAP
and SEGPHOS (entry 2 and entries 6-9), gave much lower
reactivity. Finally, after extending the reaction time to 48 h, the
desired C−H vinylation product 5a can be obtained in 58% yield
(entry 10). It is noteworthy that product 5a exhibits complete Z
geometry, which is consistent with a directed C−H activation
pathway (vide infra).
Table 3. Selected optimization for acyclic enamides.[a]
3
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10.1002/anie.202107331
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located, which is opposite from the pathway of the Rh-catalyzed
C−H vinylation with vinyl acetate.[6e] In addition, increasing the
loading of 2b to 2.2 equiv boosted the yield from 20% to 24%,
while the use of 2b with a higher Z/E ratio showed a more
Entry
Ligand
dppbz
DIOP
Yield of 5a (%)[c]
Conv. (%)[c]
1
28
< 1
8
47
10
14
11
60
25
< 5
20
9
2
obvious improvement. These results suggested that the
Z
isomer of 2b is responsible for the desired coupling and the E
isomer does not significantly inhibit the reaction.
3
dppm
dppe
4
7
5
dppp
43
20
< 1
15
< 1
58
6
dppb
Based on the observed regioselectivity, at least two
possible reaction pathways are possible to explain the formation
of the alkenylation products (Figure 1). Path a involves a
directed oxidative addition of the low-valent Ir(I) into the alkenyl
C−H bond, followed by Ir−H migratory insertion into vinyl acetate,
where the hydride is added on the carbon containing the OAc
substituent.[12] The subsequent β-acetoxy elimination generates
an Ir-olefin complex, which undergoes vinyl migratory insertion
and β-hydrogen elimination to give the alkenylation product. This
pathway is analogous to the one previously proposed by
Kakiuchi and co-workers in the Ru-catalyzed vinylation
reactions.[6a,b] Alternatively, as illustrated in path b, after C−H
activation, the Ir−C migratory insertion takes place instead;[5f−h,13]
the resulting alkyl-Ir intermediate then undergoes β-acetoxy
elimination to give the product.
7
dppf
8
BINAP
SEGPHOS
dppp
9
10[d]
> 95
[a] The reaction was performed with 4a (0.1 mmol), 2a (0.15 mmol),
[Ir(COD)2]BArF (0.01 mmol), L (0.01 mmol), in 1,4-dioxane (1 mL) under a N2
atmosphere at corresponding temperature for 24 h. [b] Z/E > 20/1 in all cases.
[c] Determined by 1H NMR using 1,1,2,2-tetrachloroethane as internal
standard. [d] reaction time 48 h.
The scope of acyclic substrates was then explored (Table 4).
Enamides derived from various acetophenones can all be
converted to the desired vinylation products 5a−e in moderate
yields. Of note, no C−H vinylation at arene ortho positions was
observed in all these cases, revealing the higher preference of
the α-enamide C−H bond. Besides aryl-substituted substrates,
enamides derived from simple ketones, such as acetone and 2-
pentanone, also worked smoothly (5f, g).
path a: Ir-H
migratory
insertion
β-OAc
elimination
migratory
insertion
O
OAc
R
O
O
N
N
N
[Ir]
OAc
OAc
[Ir]
[Ir]
H
H
3
1
2
R
R
H
H
H
Table 4. Scope of acyclic ketone derivatives.[a]
β-H
elimination
[Ir]
O
1a
N
H
2a/b
[Ir]
OAc
R
β-OAc elimination
O
H
O
N
N
[Ir]
path b: Ir-C
migratory
insertion
-HOAc
3
R
1
R
2
4
OAc
3a
Figure 1. Proposed reaction pathways.
To gain some insights into the reaction mechanism, several
deuterium-labelling experiments were conducted. First, when
deuterated enamide 1a-D reacted with vinyl acetate 2b under
the standard conditions except for 72 h, no incorporation of
deuterium was observed on either the recovered vinyl acetate
2b or the alkenyl moiety in the product (3ag-D) (Scheme 2A).
This result is in sharp contrast to the Ru-catalyzed C−H
vinylation reaction.[6b] The lack of deuterium incorporation in the
alkenyl moiety of the product can exclude path a where
deuteration at the C3 position is expected. The lack of deuterium
incorporation in the recycled 2b indicates that the Ir−H migratory
insertion into vinyl acetate either did not occur or occurred in a
reversible and stereo-retentive way (vide infra, Figure 4). On the
other hand, this observation is consistent with path b, as
through the Ir-C migratory insertion pathway the deuterium does
not add to the product (instead, it is eliminated with the OAc
group). In addition, erosion of deuterium incorporation at the α-
positions of recycled 1a and the product was observed, which
[a] Unless otherwise noted, reactions were run on a 0.2 mmol scale in a 8 mL
vial under the standard conditions; All yields are isolated yields. [b] Z/E ratio
was determined by 1H NMR analysis of the reaction crude.
Mechanistic study. To explore the reaction mechanism,
substituted vinyl acetate was first examined in this reaction to
elucidate the regioselectivity of the reaction [Eq. (1)]. When
benzyl-substituted vinyl acetate (2b) was employed as the
coupling partner, the desired alkenylation product (3ag) was
indeed formed and isolated under the standard condition.
Interesting, product 3ag was isolated as a single E isomer
despite that 2b was used as a mixture of E/Z isomers. The
position of the benzyl group in the product suggests that the
C−C bond was formed at the position where the OAc group was
4
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10.1002/anie.202107331
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RESEARCH ARTICLE
was likely due to D/H exchange with adventitious water or other
proton source in the reaction. Meanwhile, the kinetic isotope
C−H bond is not involved in the rate-determining step (RDS).
Finally, a control experiment was carried out using a 1:1 ratio of
effect (KIE) of the parallel reactions was measured (Scheme 2B), regular 2b and d5-allylbenzene (2c) as the coupling partners
and a small KIE value was obtained (kH/kD = 1.2). This result
(Scheme 2C). If an olefin-coordinated iridium intermediate is
suggests that oxidative addition of Ir(I) into the enamide alkenyl
generated as shown in Kakiuchi’s system,[6b] it would likely
undergo ligand exchange with the more abundant alkene 2c,
which is anticipated to result in deuterium incorporation into the
vinylation product (3ag). The lack of deuterium incorporation in
product 3ag can further exclude path a.
Scheme 2. Deuterium labelling studies.
A)
(0% D)
D
D
H
(95% D)
(50% D)
O
N
Bn
To obtain deeper understanding of the reaction mechanism,
density functional theory (DFT) calculations were performed.[13]
OAc
(0% D)
E/Z = 1/1
(50% D)
D
D
D
H
D
D
+
(95% D)
(99% D)
'standard'
conditions
All
energies
were
calculated
at
the
M06/6-
O
D
2b
, 53%
N
1a-D, 61%
Bn
+
OAc
311+G(d,p)−SDD/SMD(1,4-dioxane)//B3LYP-D3/6-31G(d)−SDD
level of theory. First, to investigate the proposed Ir−C migratory
insertion/β-acetoxy elimination pathway (path b), the Ir-
catalyzed C−H alkenylation of enamide 1a with vinyl acetate 2a
was computed (Figure 2). The oxidative addition of the C(sp2)−H
bond to Ir(I) (via 7-TS) has a low energy barrier with respect to
the reactant complex 6. The low barrier and the small
endergonicity to form Ir(III) hydride 8 are consistent with the
deuterium labelling experiment (vide supra, Scheme 2B) that
suggests oxidative addition with the enamide vinyl C−H bond is
reversible and is not the RDS. Subsequent Ir−C migratory
insertion via transition state 10-TS is irreversible. The β-acetoxy
elimination step, which delivers product 3a, prefers to occur
through a six-membered cyclic transition state 13-TS. The
corresponding four-membered cyclic transition state 13-TS’ has
a higher energy barrier. The anti-elimination via transition state
14-TS also requires a higher barrier than the syn-elimination
pathway. The optimized structure of 13-TS (Figure 3) shows a
nearly perpendicular geometry between the plane of the forming
alkenyl C=C bond and the OAc group, which allows good orbital
alignment in the syn-elimination. The catalytic cycle is closed by
the AcO−H reductive elimination (16-TS) and the enamide
coordination to the Ir(I) catalyst. In this catalytic cycle, the β-
acetoxy elimination via 13-TS is the RDS (ΔG‡ = 22.7 kcal/mol
with respect to 11).
D
D
72 h
E/Z = 1.2/1
2b
(1.5 equiv)
(99% D)
D
1a-D
(95% D)
(52% D)
O
H
D
N
3
(0% D)
Bn
D
D
No deuterium incorporation in recycled 2b.
4
No deuterium incorporation in the alkenyl moiety of 3d-D
(0% D)
H
3ag-D
, 22%
B)
'standard'
conditions
+
O
O
OAc
N
N
kH
1a
2a
3a
'standard'
conditions
D
D
D
D
(95% D)
(99% D)
+
O
O
OAc
N
N
kD
D
D
H/D
H/D
D
(99% D)
1a-D
2a
3a-D
kH/kD = 1.2
Oxidative addition of Ir(I) into the enamide vinyl C−H bond is not rate-determining.
C)
Ph
OAc
2b
H
(1.5 equiv)
H
'standard'
conditions
O
H
N
+
O
D
(0% D)
N
H
72 h
D
H
1a
D
D (95% D)
3ag, 16%
2c
D
(1.5 equiv)
An olefin-Ir intermediate is unlikely involved in the product formation.
Figure 2. Free energy profile of the Ir−C migratory insertion/syn-β-acetoxy elimination pathway of the Ir-catalyzed C−H alkenylation of enamide 1a with vinyl
acetate. Dppbz was used as the ligand.
5
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RESEARCH ARTICLE
than the Ir−C migratory insertion (via 10-TS). Furthermore, a
subsequent step in this pathway, the β-H elimination via
transition state 24-TS, requires an activation free energy of 24.2
kcal/mol, which is 1.5 kcal/mol higher than that of β-acetoxy
elimination transition states 13-TS. Therefore, the direct Ir−H
migratory insertion from intermediate 9 as shown in Figure 4 can
be ruled out.
In the alternative Ir−H migratory insertion pathway via 9b
(Figure 5), although the Ir−H migratory insertion via 17b-TS is
feasible because of the low activation free energy, the
subsequent β-acetoxy elimination via 27-TS requires a high
energy barrier (ΔG‡ = 28.9 kcal/mol with respect to 26). The
distortion of 27-TS evidenced by the non-planar six-membered
ring [θ(C-C-O-C) = 58.7°] is responsible for the high barrier that
disfavors this pathway. This distortion is caused by the sterically
congested iridium center in 27-TS. In contrast, the β-acetoxy
elimination transition state in the Ir−C migratory insertion
pathway (13-TS) is not distorted because of the less crowded
steric environment around the iridium center.
Although the low barrier to 17b-TS suggests the Ir−H
migratory insertion is reversible, scrambling of the enamide C−H
(H1) and the vinyl acetate C−H (H2) cannot take place. This is
because, after 26 is formed, the β-H2 elimination via 17c-TS has
a 2.9 kcal/mol higher energy barrier than the β-H1 elimination via
17b-TS, which indicates that the reversible Ir−H migratory
insertion is stereo-retentive due to the much faster rate to
eliminate the same β-H bond formed in the migratory insertion
than eliminating the other β-H originated from the vinyl acetate.
This observation is consistent with the lack of deuterium
incorporation in the recycled vinyl acetate or the installed alkenyl
moiety (vide supra, Scheme 2A). Besides, a third mechanism
that initiates from the C−O oxidative addition[17] of the vinyl
acetate to Ir(I) can also be ruled out due to the higher energy
barrier of the C(sp2)−O oxidative addition transition state (ΔG‡ =
32.0 kcal/mol, see Supporting Information, Figure S6). Taken
together, the computational results and the experimental
mechanistic studies both support the Ir−C migratory insertion
over the Ir−H migratory insertion mechanism.
Figure 3. Optimized structures of syn-β-acetoxy elimination transition states
13-TS and 13-TS’.
Next, we considered the Ir−H migratory insertion/β-acetoxy
elimination pathway (path a). In the π-alkene Ir(III) hydride
complex 9, the hydride is cis to the vinyl acetate and trans to the
carbonyl of the enamide. From this complex, several Ir−H
migratory insertion pathways were computed, including the
direct insertion into the Ir−H bond in 9 (Figure 4) and the
isomerization of 9 to a less stable isomer 9b, in which the
hydride is trans to a phosphorus on the dppbz ligand (Figure
5).[14] Due to the stronger trans effect of phosphines, the
migratory insertion with 9b is expected to be more favorable
than the direct insertion with 9.[15] Indeed, the reaction with 9b
(via 17b-TS) only requires a very small barrier of 1.5 kcal/mol
with respect to 9b. On the other hand, after multiple attempts,
we cannot locate the geometry of the direct alkene insertion
transition state (17-TS) with 9 or the five-coordinated alkyl
iridium intermediate after the alkene insertion (18), presumably
due to their instability.[16] Constrained geometry optimization by
fixing the β-C−H bond distances suggests that 18 is 16.8
kcal/mol less stable than 9. Because the alkene insertion
transition state 17-TS is higher in energy than 18, this Ir−H
migratory insertion step will require a higher activation barrier
6
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Figure 4. Free energy profile of the Ir−H migratory insertion/β-acetoxy elimination pathway of the Ir-catalyzed C−H alkenylation of enamide 1a with vinyl acetate.
Dppbz was used as the ligand. [a] The structure of 18 was optimized by fixing the C−H1 and C−H2 bond distances
Figure 5. An alternative Ir−H migratory insertion/β-acetoxy elimination pathway from iridium hydride intermediate 9b. Dppbz was used as the ligand.
Synthetic applications. To show the synthetic utility of this
C−H alkenylation method, a series of transformations have been
developed for versatile ketone functionalization (Scheme 3).
Notably, a larger scale C−H vinylation reaction can be carried
out with cyclohexanone-derived enamide substrate 1y, which
of a more complex natural product (Scheme 4). Diverse
functionalized cholestan-3-one derivatives 28b–32b can be
conveniently prepared in a regio- and diastereoselective manner.
was prepared via
a one-pot procedure from commercially
available 4,4-dimethylcyclohexanone. From the conjugated
enamide 3y, diverse transformations have been achieved. For
example, direct hydrolysis of the enamide moiety produced α,β-
enone 28a with excellent yield and E/Z (> 20/1) selectivity.
Coupled with another Ir-catalyzed process[18] followed by
hydrolysis, the γ-Bpin-substituted ketone (31a) was isolated in
good yield. The conventional hydroboration-oxidation and then
hydrolysis delivered the γ-hydroxyl ketone (32a). Due to the
unique electron-rich conjugated diene moiety in product 3y, its
reactions with electrophiles have been explored. Interesting
transformations have been observed with ICl as the electrophile.
By changing the equivalency of ICl, vastly different products
were obtained. When 1.1 equiv ICl was added to a solution of 3y
in DCM at room temperature followed by water quench in the air,
1,2-diketone 29a with a diosphenol moiety was isolated in 52%
yield (see Supporting Information for the tentatively proposed
reaction pathway). However, when 2.5 equiv of ICl was used
instead, an allyl chloride (30a) was formed as the major product.
These transformations can be further adopted for derivatization
Scheme 3. Synthetic utility study to access diverse functionalized ketones.
7
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Scheme 4. Late-stage modification of the cholestan-3-one derivatives.
Conclusion
Keywords: enamide • C−H alkenylation • ketones • iridium
catalysis • mechanistic study
In summary, an iridium-catalyzed enamide C−H alkenylation
with feedstock chemical vinyl acetate has been developed,
[1]
[2]
M. B. Smith, J. March, March’s Advanced Organic Chemistry, 7th ed.,
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a
convenient entry to access diverse
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i.e., enamide and vinyl acetate, could have implications beyond
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We thank University of Chicago and NSF (CHE-1855556 G.D.
and CHE-1654122 P.L.) for financial support. B.Z.
acknowledges the International Postdoctoral Exchange
Fellowship Program 2019 from the Office of China Postdoctoral
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Entry for the Table of Contents
An Ir-catalyzed C−H alkenylation of enamides with vinyl acetates have been developed, which provides a versatile approach for
diverse ketone functionalization. The method exhibits a broad substrate scope and high chemoselectivity. It also features a reaction
pathway involving 1,2-Ir−C migratory insertion and syn-β-acetoxyl elimination.
10
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