Rhodium(i)-catalyzed C6-selective C-H alkenylation and polyenylation of 2-pyridones with alkenyl and conjugated polyenyl carboxylic acids

Article abstract of DOI:10.1039/c9sc03672e

A versatile Rh(i)-catalyzed C6-selective decarbonylative C-H alkenylation of 2-pyridones with readily available, and inexpensive alkenyl carboxylic acids has been developed. This directed dehydrogenative cross-coupling reaction affords 6-alkenylated 2-pyridones that would otherwise be difficult to access using conventional C-H functionalization protocols. The reaction occurs with high efficiency and is tolerant of a broad range of functional groups. A wide scope of alkenyl carboxylic acids, including challenging conjugated polyene carboxylic acids, are amenable to this transformation and no addition of external oxidant is required. Mechanistic studies revealed that (1) Boc₂O acts as the activator for the in situ transformation of the carboxylic acids into anhydrides before oxidative addition by the Rh catalyst, (2) a decarbonylation step is involved in the catalytic cycle, and (3) the C-H bond cleavage is likely the turnover-limiting step.

Full text of DOI:10.1039/c9sc03672e

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DOI: 10.1039/C9SC03672E
ARTICLE
Rhodium(I)-Catalyzed C6-Selective C–H Alkenylation and
polyenylation of 2-Pyridones with Alkenyl and conjugated
polyenyl Carboxylic Acids
Received 00th January 20xx,
Accepted 00th January 20xx
Haoqiang Zhao,a,c Xin Xu,a Zhenli Luo,a Lei Caoa, Bohan Li,a Huanrong Li,a Lijin Xu,a,b* Qinghua Fan,b,*
and Patrick J. Walshc,*
DOI: 10.1039/x0xx00000x
A versatile Rh(I)-catalyzed C6-selective decarbonylative C–H alkenylation of 2-pyridones with readily available, and
inexpensive alkenyl carboxylic acids has been developed. This directed dehydrogenative cross–coupling reaction affords 6-
alkenylated 2-pyridones that would otherwise be difficult to access using conventional C–H functionalization protocols. The
reaction occurs with high efficiency and is tolerant of a broad range of functional groups. A wide scope of alkenyl carboxylic
acids, including challenging conjugated polyene carboxylic acids, are amenable to this transformation, No addition of
external oxidant is required. Mechanistic studies revealed that 1) Boc2O acts as the activator for the in situ transformation
of the carboxylic acids into anhydrides before oxidative addition by the Rh catalyst, 2) a decarbonylation step is involved in
the catalytic cycle, and 3) the C–H bond cleavage is likely the turnover-limiting step.
Several approaches to the functionalization of 2-pyridones
have employed transition metals. Early studies focused on
transition-metal catalyzed cross-coupling of functionalized 2-
Introduction
The 2-pyridone motif is found in numerous naturally occurring
molecules and synthetic organic compounds that possess a
broad spectrum of bioactivities.1 For example, A58365A,
isolated from the fermentation broth of a soil bacteriumis,
serves as an angiotensin-converting enzyme inhibitor;1f
fredericamycin A, isolated from streptomyces griseus, is a
potent antitumor antibiotic;1g ciclopirox is a widely used
pyridones.4 More recent efforts to elaborate the 2-pyridone
motif have been devoted to their direct catalytic C–H
functionalization.2b,c In this context, rapid progress in site-
selective C–H functionalization at C3, C5 and C6 positions of 2-
pyridones has been advanced.5-8 Notably, Miura and co-workers
found that the use of easily attachable and detachable 2-pyridyl
directing groups at the nitrogen of the 2-pyridones could
effectively facilitate the copper-mediated C6-selective
dehydrogenative heteroarylation with 1,3-azoles.7b Following
this seminal work, transition-metal catalyzed directed
alkynylation,6d arylation,7h,j,o alkylation,7d,n,w,x borylation,7g,m
thiolation,7i annulation,7e,f,p,r allylation,7l,q and amidation7t-v of 1-
(2-pyridyl)-2-pyridones at the C6 positions have been
successfully accomplished. In general, installation of vinyl
groups has proven considerably more challenging than aryl or
alkyl substituents, and this holds true for the vinylation of 2-
pyridones at the C-6 position. Nakao and co-workers reported
an impressive C6-alkenylation of 2-pyridones via C–H
hydroarylation of N-alkylated 2-pyriodnes with alkynes at the C6
position under Ni/Al cooperative catalysis, albeit with limited
substrate scope and low functional group tolerance (Scheme
1a).8a Very recently, the group of Hirano and Miura reported
Rh(III)-catalyzed (10 mol%) C6-selective alkenylation of 1-(2-
pyridyl)-2-pyridones with acrylates and styrenes (Scheme 1b).8b
synthetic antifungal agent;1h and milrinone is
a
phosphodiesterase 3 inhibitor used to treat heart failure (Fig.
1).1i 2-Pyridones are also valued as building blocks, because they
can be converted to pyridines, piperidines, quinolizidines and
indolizidines.1j As a result of their widespread utility, the
construction of 2-pyridones has been a vibrant research area in
the synthetic community, and numerous methods for their
synthesis are available.2,3
Fig. 1 Biologically active 2(1H)-pyridone molecules.
Recently, the use of readily available and inexpensive α,β
-
unsaturated carboxylic acids in transition metal catalyzed
decarboxylative and decarbonylative alkenylation reactions has
gained attention.9-11 We envisioned that 6-alkenylated 2-
pyridones might be accessible from 1-(2-pyridyl)-2-pyridones
and α,β-unsaturated acids under transition metal catalysis. In
connection with our ongoing interests in direct alkenylation of
C–H bonds,12 herein we report a Rh(I)-catalyzed C6-selective C–
H alkenylation of 2-pyridones using alkenyl carboxylic acids as
a. Department of Chemistry, Renmin University of China, Beijing 100872, China. E-
mail: 20050062@ruc.edu.cn
b. Beijing National Laboratory for Molecular Sciences and and Institute of Chemistry,
Chinese Academy of Sciences, Beijing, 100190, China. E-mail: fanqh@iccas.ac.cn
c. Roy and Diana Vagelos Laboratories, Penn/Merck Laboratory for High-
Throughput Experimentation, Department of Chemistry, University of
Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323,
United States E-mail: pwalsh@sas.upenn.edu
† Electronic supplementary information (ESI) available. CCDC 1874166. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/x0xx00000x
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the vinyl source (Scheme 1c). This protocol features a simple cymene)Cl2]2, [Cp*IrCl2]2 and Pd(OAc)2 were also ViniewefAfreticclteiOvenlinine
DOI: 10.1039/C9SC03672E
and easy-to-handle catalytic system, high efficiency, very broad this transformation (Table 1, entries 14–16).
substrate scope and high functional group tolerance.
(a) Previous work: direct alkenylation of 2-pyridones with alkynes
R
R
Ni(COD)2
P(i-Pr)3/AlMe3
R1
R2
R2
+
O
N
H
O
N
toluene
R1
alkyl
alkyl
(b) Previous work: Rh(III)-catalyzed alkenylation of 2-pyridones with acrylates and styrenes
R
R
[Cp*RhCl2]2 (5 mol%)
AgSbF6 (20 mol%)
Scheme 2. Unsuccessful catalytic direct alkenylations of 1-(2-pyridyl)-2-pyridone (1a).
R'
O
N
H
O
N
R'
+
Cu(OAc)2 (1 equiv)
N
N
We next screened different electrophiles to activate the
unsaturated acid. Poor conversion was obtained with
(MeOCO)2O (22%), Tf2O (NR), (CF3CO)2O (NR), or PivCl (39%) as
the acid activators (Table 1, entries 17–20). In contrast, Piv2O
was effective and gave 3aa in 92% yield (Table 1, entry 21).
Considering the price and compatibility, however, more
economical and milder Boc2O was preferred.
(c) This work: Rh(I)-catalyzed decarbonylative alkenylation of 2-pyridones
R
R
R2
R2 R3
HO2C
[Rh(CO)2Cl]2
R3
O
N
H
O
N
+
R1
Boc2O, 1,4-dioxane
-CO, -CO2, -tBuOH
R1
N
N
Readily available alkene source
Good to excellent yields
Further optimization involving decreasing the reaction
temperature or the catalyst loading led to dramatically lowered
yields (Table 1, entries 22 and 23). Notably, the reaction did not
proceed in the absence of either a rhodium catalyst or acid
activator (Table, entries 24 and 25). Finally, the effect of the N-
directing group in this reaction was examined. No reaction
occurred when free 2-pyridone or 2-pyridone substrates
bearing other substituents on the nitrogen, such as Me, Bn, Ph,
or 3-pyridyl. The 2-pyrimidyl resulted in only 31% yield (Table 1,
entry 26). These results clearly indicated that the judicious
choice of the N-directing group is critical for catalysis in this
transformation.
Broad substrate scope
High functional group tolerance
Scheme 1. Catalytic direct C–H alkenylation of 2-pyridones at the C6 position.
Results and discussion
Recent studies have revealed that catalytic systems based on
Rh(III), Ru(II) and Pd(II) complexes perform well in directed
alkenylation of relatively inert (hetero)arene and alkene C–H
bonds.13 Inspired by these reports, we first attempted the
alkenylation of the model substrate 1-(2-pyridyl)-2-pyridone
(
1a) with styrene using Rh(III), Ru(II) and Pd(II) complexes (ESI,
Table 1 Optimization of the reaction conditions.[a]
Table S1). Unfortunately, various catalytic systems, including
those that have been shown to efficiently catalyze direct
alkenylation of structurally similar 2-phenylpyrimidines, 1-
(pyrimidin-2-yl)-1H-indoles and 2-(1H-pyrrol-1-yl)pyrimidines,14
did not furnish the desired products (Scheme 2a). Liu and co-
workers recently described Rh(III)-catalyzed site-selective C–H
alkylation and arylation of 1-(2-pyridyl)-2-pyridones at the C6
position with potassium trifluoroborates.7h Expanding the
substrate scope of this reaction to include potassium vinyl
trifluoroborates, however, was unsuccessful in our hands using
a similar Rh(III) catalyst (Scheme 2b and ESI, Table S2). Likewise,
Ru(II)-catalyzed alkenylation of 1a with styrylboronic acids did
not afford the desired alkenylation product (Scheme 2c and SI,
Table S2).7o
Entry
1
2
3
4
5
6
7
8
Catalyst
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(COD)Cl]2
[RhCl(PPh3)3]
[Rh(COD)2BF4]
[Cp*RhCl2]2
[Ru(p-cymene)2Cl2]
[Cp*IrCl2]2
Activator
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
Boc2O
(MeOCO)2O
Tf2O
Solvent
1,4-dioxane
toluene
PhCl
p-xylene
THF
CH3CN
DCE
DMF
DME
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
Yield (%)[b]
93
15
11
15
NR
NR
10
NR
NR
<5
NR
NR
NR
NR
NR
NR
22
NR
NR
39
We then turned our attention to the coupling reaction of
vinyl carboxylic acids with 2-pyridones. We were pleased to
discover that the reaction of 1a and trans-cinnamic acid (2a) in
the presence of [Rh(CO)2Cl]2 (1.0 mol%) and Boc2O (1.5 equiv)
9
10
11
12
13
14
15
16
17
18
19
20
at 130 °C in 1,4-dioxane, provided the desired product 3aa in
92% yield after 6 h (Table 1, entry 1). A solvent screen revealed
that 1,4-dioxane outperformed other frequently employed
solvents, such as toluene, PhCl, p-xylene, THF, CH3CN, DCE, DMF
and DME (Table 1, entries 2–9). Changing the rhodium source
to [Rh(COD)Cl]2, [RhCl(PPh3)3], [Rh(COD)2BF4], or [Cp*RhCl2]2,
did not lead to any improvement in the yield of 3aa (Table 1,
entries 10–13). Other transition metal complexes such as [Ru(p-
Pd(OAc)2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
(CF3CO)2O
PivCl
2 | J. Name., 2012, 00, 1-3
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yield. [c]2a (0.44 mmol) was employed.
21
22[c]
23[d]
24
25
26[e]
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[[Rh(CO)2Cl]2
none
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
Piv2O
Boc2O
Boc2O
Boc2O
none
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
92
55
43
NR
NR
31
View Article Online
DOI: 10.1039/C9SC03672E
Subsequently, we explored the reactivity of various
cinnamic acids with 1a. As shown in Table 3, a wide range of
cinnamic acids (2b
efficiently participated in the alkenylation with 1a to exclusively
furnish the desired C6-alkenlayed 2-pyriodne products (3ab
–2p) with mono-substituted aromatic rings
Boc2O
–
[a]Reaction Conditions: 1a (0.2 mmol), 2a (0.22 mmol), catalyst (1.0 mol%),
activator (1.5 equiv), solvent (2.0 mL), 130
C, 6 h, in air. [b]Isolated yield.
[c]Reaction temperature 120 C. [d][Rh(CO)2Cl]2 (0.5 mol%) was used. [e]1-
3ap) in good to excellent yields (77–92%). The alkenylation
proved to be insensitive to the nature of the substituents on the
aryl ring, with various electron-withdrawing (NO2, CO2Me and
CN) and donating substituents (alkyl, OMe and NMe2)
participating. Sensitive functional groups, including OH, B(OH)2,
and halogens, were all well tolerated. The structure of 3ap was
confirmed by single-crystal X-ray diffraction (CCDC 1874166).
°
°
(Pyrimidin-2-yl)pyridin-2(1H)-one was employed.
With the optimized conditions in hand, we investigated the
scope of 1-(2-pyridyl)-2-pyridones with 2a as the coupling
partner (Table 2). It was found that a series of C3- and C4-
substituted 1-(2-pyridyl)-2-pyridones
smooth alkenylation with 2a exclusively at the C6-position to
deliver the corresponding products (3ba 3la) in good to
(
1b
–
1l
)
underwent
Similarly, the more complex cinnamic acids (2q–2v), with
polysubstituted aromatic rings, displayed good reactivity,
affording the target products (3aq–3av) in 70–90% yields.
Notably, a vinyl group bearing a pentafluoro phenyl provided
the product (3au) in 70% yield. Heteroaryl groups are vital
substructures in medicinal chemistry.15 We, therefore,
examined the compatibility of heteroaryl cinnamic acids with
1a. Heteroaryl cinnamic acids bearing 3-pyridyl, 2-furanyl, and
–
excellent yields (77–91%) with high tolerance of functional
groups, including halides at the 3- or 4-positions. Notably, the
C5-substituted 2-pyridones (1m
Rh-catalyzed system to afford the C6-alkenylated products
3ma 3qa) in 67–83% yield, despite the increased steric
hindrance on C5. The 3,4-disubstituted 2-pyridones (1r and 1s
–1q) were compatible with our
(
–
)
2-thiofuranyl (2w
desired products (3aw
–
2y) reacted smoothly with 1a to give the
3ay) in 82–90% yields. Importantly, the
were also readily engaged under the current conditions to give
the corresponding products (3ra and 3sa) in 75 and 63% yields,
respectively. Substrates bearing electron donating or electron
withdrawing substituents on the pyridyl rings (1t
smoothly with 2a to generate the desired products (3ta
83–89% yields. Moreover, this reaction could be readily
extended to 4H-[1,2'-bipyridin]-4-one (1w) and 1-(pyridin-2-
yl)quinolin-4(1H)-one (1x), thus producing 3wa and 3xa in 88
and 91% yields, respectively. It is notable that only the
formation of the dialkenylated product was observed in the
–
estrone-derived cinnamic acid 2z proved to be equally effective
in this transformation, indicating the robustness of the current
catalytic system.
–
1v) coupled
3va) in
–
Table 3. Direct olefination of 1a with cinnamic acids[a,b]
case of 1w
.
Table 2. Catalytic alkenylation of various 2-pyridones with 2a[a,b]
[a]Reaction Conditions: 1a (0.2 mmol), 2a (0.22 mmol), [Rh(CO)2Cl]2 (1.0
mol%), Boc2O (1.5 equiv.), 1,4-dioxane (2.0 mL), 130 oC, 6 h, in air. [b]Isolated
yield.
To further demonstrate the potential of our catalytic
system, the reaction was extended to other substituted alkenyl
carboxylic acids, and the results are summarized in Table 4. It
was found that treatment of various β-alkylated acrylic acids
[a]Reaction Conditions: 1a (0.2 mmol), 2a (0.22 mmol), [Rh(CO)2Cl]2 (1.0
mol%), Boc2O (1.5 equiv.), 1,4-dioxane (2.0 mL), 130 oC, 6 h, in air. [b]Isolated
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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4a
Journal Name
(
–
4d) with 1a resulted in exclusive formation of C6- performed to deliver 3aa in 88% yield (SchemeVi3ewa)A.rtiFclue rOtnhliener
DOI: 10.1039/C9SC03672E
alkenylated 2-pyridone products (5aa–5ad) in 85–92% yields, transformations of the products were then explored. As
irrespective of the nature of the β-alkyl groups. In the case of depicted in Scheme 3b, hydrogenation of 3aa at room
acid 4e containing a sensitive Cl group, the reaction furnished temperature favored the reduction of the alkene moiety to
the desired product 5ae in 87% yield without dechlorination. generate the C6-alkylated 2-pyridone product
Notably, the simple acrylic acid (4f) was also reactive, giving rise Increasing the reaction temperature to 50 C, however, enabled
to the C6-vinylated 2-pyridone product 5af in 75% yield. formation of piperidin-2-one product (92% yield). The pyridine
6 in 84% yield.
°
7
Likewise, the α-substituted acrylic acids 4g and 4h were directing group could be conveniently removed by treatment
competent substrates, delivering 5ag and 5ah both in 80% yield. with MeOTf and KOtBu to give the C6-alkenylated 2-pyridone
Furthermore, trisubstituted acrylic acids (4i
naturally occurring geranic acid (4k), shikimic acid (4m) and
perillic acid (4n), were good substrates, producing 5ai 5an in
–
4n), including the products in 68–73% yield (Scheme 3c).7h
–
63–91% yields. Potentially reactive groups, like OH and C=C,
were not detrimental to the overall yields. Remarkably, a variety
of conjugated polyene carboxylic acids were also efficient
coupling partners in this transformation. More substituted and
less sensitive conjugated dienyl carboxylic acids (4o–4s) formed
the desired products (5ao–5as) in 65–86% yields. The formation
of a mixture of Z/E isomers in the case of 5ar was due to the low
stereochemical purity of the starting trienoic acid 4r (4Z/4E ratio
1:1). Surprisingly, both the bioactive retinoic acid (4t) and its
derivative 4u containing a conjugated hexaene unit, formed the
corresponding products (5at and 5au) in 72% and 65% yields,
respectively. Application of 5-phenylpent-2-en-4-ynoic acid (4v
)
led to the formation of 5av in 67% yield, with the alkyne having
no obvious adverse effect on the reaction outcome.
Table 4. Direct olefination of 1a with substituted alkenyl carboxylic acids[a,b]
Scheme 3. Synthetic applications.
We next desired to probe the basic steps of the reaction
mechanism. Activation of the carboxylic acid was envisioned to
proceed via an anhydride derivative.16 To test this hypothesis, a
control experiment with cinnamic anhydride 11 and 1a
demonstrated that the coupling worked equally (91% yield) as
well as acid 2a with Boc2O (93% yield). Treatment of acid 2a with
an equimolar amount of Boc2O in 1,4-dioxane at 130 °C for 6 h
led to the predominant formation of cinnamic anhydride 11 in
85% yield. This observation supports the involvement of in situ
generation of the anhydride in the vinylation reaction.16 The
generation of CO gas during the reaction was confirmed by
analyzing the head gas of the reaction mixture with GC-TDC (ESI,
Fig. S1). Moreover, employing [Rh(COD)Cl]2 as the catalyst also
generated CO gas albeit with a longer reaction time (18 h) and
lower yield of 3aa (50%) (ESI, Fig. S2). These results rule out the
possibility that CO gas might derive from [Rh(CO)2Cl]2, thus
indicating the presence of a decarbonylation step in the
catalytic cycle. As shown in Scheme 4b, treatment of 1a with
D2O (5 equiv.) under the standard conditions for 1 h, in the
absence or presence of 2a resulted in approximately 38% and
27% deuteration at the C6-position, respectively, suggesting the
reversibility of the C–H activation step under these conditions.
To gain insight into the turnover-limiting step, we conducted
initial rate studies and a parallel kinetic isotope effect (KIE) on
[a]Reaction Conditions: 1a (0.2 mmol), 2a (0.22 mmol), [Rh(CO)2Cl]2 (1.0
mol%), Boc2O (1.5 equiv.), 1,4-dioxane (2.0 mL), 130 oC, 6 h, in air. [b]Isolated
yield. [C]Ratio of isomers (E/Z).
1a. The kinetic analyses highlighted a first-order (n=1.30±0.09)
dependence on the concentration of 1a for the reaction
(Scheme 4c and ESI). In separate reaction vessels, 1a and [D1]-
In order to explore the synthetic practicality of this
transformation, a gram scale reaction of 1a and 2a was
4 | J. Name., 2012, 00, 1-3
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1a were subjected to identical reaction conditions (ESI); it was exchange for the substrate follows, giving intermediate
C.
View Article Online
observed that 1a was alkenylated to 3aa at a greater rate than Rather than a second oxidative addition, DwOeI:p1r0e.1f0e3r9a/Cc9oSnCc0e36rt7e2Ed
the corresponding deuterium-labelled substrate. The KIE value metalation deprotonation (CMD) by the carboxylate ligand via
determined from the average of five runs via the method of transition state
D to generate the acid and the cyclometallated
initial rates was 1.9 ± 0.1. This result implies that the C−H bond species with the key Rh–C bond. The liberated acid can react
cleavage is likely involved in the turnover-limiting step.
with the Boc2O to re-enter the cycle as the anhydride. E is
envisioned to undergo loss of coordinated CO and then
deinsertion of CO to afford the Rh–vinyl intermediate.
Reductive elimination regenerates Rh(I) with the bound product
G
, which undergoes exchange with the solvent to liberate the
product and close the catalytic cycle to form . At this point, the
A
exact ordering of the steps remains to be determined.
CO2H
R
1/2 [Rh(CO)2Cl]2
S
Boc2O
O
CO2, t-BuOH
O
N
R
S
O
N
R
O
R
Cl
S
3
Rh
OC
CO
R
CO
A
OC Rh Cl
Ox. Add.
O
O
N
R
O
Cl
N
Rh
O
C
O
OC
S
O
N
H
B
G
R
N
- S
R
Red. Elim.
1
R
O
R
Cl
OC
OC
Rh
N
O
OC
Cl
O
Rh
N
OC
N
N
O
O
CO loss/
Deinsertion
C
CMD
F
R
O
CO
R
OC
R
Cl
N
Rh
O
OC
N
Cl
OC
Rh
OC
O
O
O
H
N
E
CO2H
R
N
O
D
Scheme 5. Plausible Mechanism.
Conclusions
We have developed the first Rh(I)-catalyzed decarbonylative
alkenylation at C6 of 2-pyridones using readily available and
inexpensive alkenyl carboxylic acids. This C6 alkenylation of 2-
pyridones is applicable to the coupling of a wide range of
substituted acyclic acids and conjugated polyene carboxylic
acids. The reaction proceeds under oxidant-free conditions,
enabling facile access to C6-alkenylated 2-pyridones in high
yields with a broad functional group tolerance. Mechanistic
studies support the following steps: initial activation of the
carboxylic acid in the form of an anhydride, oxidative addition
of the activated acid, coordination of the substrate followed by
CMD to cleave the C–H bond. Dissociation of CO is followed by
decarbonylation of the acyl group to generate the Rh-bound
vinyl, and finally reductive elimination and liberation of product
closes the cycle. A turnover limiting C–H bond cleavage is likely
based on the observed KIE. Further investigation of the
Scheme 4. Mechanistic studies.
Based on the aforementioned results and literature
precedence,17 a plausible mechanism highlighting the key steps
is presented in Scheme 5. First, solvent (S) or the substrate
pyridine breaks up the dimer [Rh(CO)2Cl]2 to give the monomer
and enter the catalytic cycle. Meanwhile, the acid reacts with
Boc2O to generate the anhydride, which undergoes oxidative
addition to a Rh(I) species
A and leads to the formation of the
Rh(III) intermediate . In the event that S is solvent, ligand
B
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mechanism of this reaction and synthetic applications are
underway in our laboratory.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
H.Z. thanks the Program for China Scholarship Council
(201806360122), National Natural Science Foundation of China
(21372258) and the Beijing National Laboratory for Molecular
Sciences (BNLMS201845) for financial support. P.J.W. thanks
the US National Science Foundation (CHE- 1902509).
5
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Journal Name
View Article Online
DOI: 10.1039/C9SC03672E
TOC:
R
R
R2
[Rh(CO)2Cl]2
(cat.)
R2
HO2C
+
R3
O
N
R3
O
N
H
Boc2O
dioxane
R1
R1
N
N
Readily available alkene source
Good to excellent yields
Broad substrate scope
High functional group tolerance
A versatile Rh(I)-catalyzed C6-selective decarbonylative C–H
alkenylation of 2-pyridones with readily available alkenyl
carboxylic acids has been developed.
8 | J. Name., 2012, 00, 1-3
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