Vinylogous Elimination/C-H Functionalization/Allylation Cascade Reaction of Allenoate Adducts: Synthesis of Ring-Fused Dihydropyridinones

Article abstract of DOI:10.1021/acs.orglett.0c02956

A palladium-catalyzed cascade reaction of β′-allenoate adducts with aryl/heteroaryl carboxamides through a vinylogous elimination/C-H functionalization/intramolecular allylation reaction sequence has been developed with high Z stereoselectivity. Various ring-fused dihydropyridinones bearing an α,β-unsaturated ester substituent are obtained. It is the first example of application of the allenoate adducts to C-H functionalization annulations as practical precursors of hard-to-get functionalized electron-deficient 1,3-butadienes. Using air as the terminal oxidant also shows a great advantage in environmental friendliness.

Full text of DOI:10.1021/acs.orglett.0c02956

pubs.acs.org/OrgLett
Letter
Vinylogous Elimination/C−H Functionalization/Allylation Cascade
Reaction of Allenoate Adducts: Synthesis of Ring-Fused
Dihydropyridinones
Manman Sun, Weida Chen, Haijian Wu, Xiangyu Xia, Jianguo Yang, Lei Wang, Guodong Shen,
and Zhiming Wang*
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ABSTRACT: A palladium-catalyzed cascade reaction of β′-allenoate adducts with aryl/heteroaryl carboxamides through a
vinylogous elimination/C−H functionalization/intramolecular allylation reaction sequence has been developed with high Z
stereoselectivity. Various ring-fused dihydropyridinones bearing an α,β-unsaturated ester substituent are obtained. It is the first
example of application of the allenoate adducts to C−H functionalization annulations as practical precursors of hard-to-get
functionalized electron-deficient 1,3-butadienes. Using air as the terminal oxidant also shows a great advantage in environmental
friendliness.
Scheme 1. Reactions of Allyl Esters
hosphine catalysis of allenoates is well established as a
Ppowerful tool for the construction of carbon−carbon bond
and carbon−heteroatom bond.1 Among them, the nucleophilic
addition reactions, which are easy in operation and of low cost
for the preparation of functionalized alkenes, have been
extensively explored.1a,e,2 However, the studies on the
applications of allenoate adducts are rather limited.3 In 2011,
the Kwon group reported a phosphine-catalyzed β′-umpolung
additions of nucleophiles to α-disubstituted allenes.2j These β′-
allenoate adducts are structurally similar to Morita−Baylis−
Hillman adducts.4 Indeed, in the presence of palladium
catalyst, the allyl esters could derive η3-allylpalladium
intermediates smoothly, followed by nucleophilic substitutions
(Scheme 1a).5 Excitingly, in 2018, our group found that the β′-
adducts of ethyl 2-benzylbuta-2,3-dienoate and phenol could
undergo vinylogous elimination under base conditions.3c,d The
obtained 1,3-butadienes then performed Heck coupling/
allylation domino reaction to synthesize 2-substituted 2,3-
dihydrobenzofurans and indolines (Scheme 1b). Significantly,
1,3-butadienes are frequently found in natural products and
biologically active molecules6 and also act as important
synthetic targets for diverse molecules.7 Although numerous
methods have been developed for the synthesis of linear dienes
and electron-rich branched dienes,8 such as Wittig reaction,
ene−yne metathesis,8a Heck reaction,8b C−H vinylation,8c
isomerization of allenes,8d and vinylogous elimination,8e,f the
synthesis of electron-deficient substituted branched dienes9
especially the 1-aryl-1,3-butadiene-2-carboxylates10 remains a
challenge. Our method described in Scheme 1b provides an
Received: September 4, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02956
© XXXX American Chemical Society
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A

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Letter
ideal and practical precursor of the hard-to-get 1-aryl-1,3-
butadiene-2-carboxylates (two steps, about 80% overall
yields3c,d vs two steps, 10−28% overall yields10a). However,
the leaving groups of I and OPh reduced the atomic utilization.
Hence, developing a more atom-economic approach for
expanding the application of β′-allenoate adducts as precursors
of hard-to-get functionalized electron-deficient 1,3-butadienes
for the construction of other heterocyclic compounds is
rewarding.
pared from ethyl 2-benzylbuta-2,3-dienoate and acetic acid,2j
instead of (Z)-ethyl 2-(phenoxy(phenyl)methyl)but-2-enoate,
which was used in previous report,3d as the model substrate to
optimize the reaction conditions with N-((4-nitrophenyl)-
sulfonyl)benzofuran-2-carboxamide (3a). The β′-allenoate
adduct 1a could afford 1,3-diene intermediate 2 smoothly
with NaHCO3 in DMF.3c,d We initially optimized the C−H
functionalization/allylation reaction conditions of 2 with 3a
and obtained the satisfactory reaction conditions of Pd(TFA)2
as the catalyst and Cu(OAc)2/air as the co-oxidant in p-xylene
at 120 °C for 24 h (see the Supporting Information). Then we
optimized the cascade reaction conditions based on the above-
mentioned conditions (Table 1). The inorganic bases of
In recent decades, direct C−H functionalization has received
great attention and has been identified as an increasingly viable
tool in organic synthesis by improving atomic utilization
efficiencies, shortening prefunctionalization steps of substrate,
and providing overwhelming opportunities for structural
modification.11 Among the various C−H functionalization
reactions, transition-metal catalyzed directed C(sp2)−H
functionalization of amides is an appealing area,12 for the
CONHR group is a weakly coordinating directing group,
which not only has superior reactivity and simplicity in
installation and removal but also is a precursor to the C−N
bond to construct cyclic nitrogen-containing compounds. The
Booker-Milburn group,13a,b Gong and Han group,13c Cramer
group,13d and our group13e,f have reported the [4 + 2]
heteroannulation of amides and 1,3-dienes. However, the
reaction scope was relatively limited to linear or single-
substituted branched 1,3-dienes. The 1,2-double substituted
branched 1,3-dienes were rarely explored, because the highly
stereochemical control of the carbon−carbon double bond in
products was still a challenge.14 Inspired by the highly
stereoselective palladium-catalyzed cascade reaction of β′-
allenoate adducts as the precursors of 1,2-double substituted
electron-deficient 1,3-butadienes,3c,d herein, we describe the
highly Z-stereoselective palladium-catalyzed vinylogous elimi-
nation/C−H functionalization/allylation cascade reaction of
β′-allenoate adducts with N-sulfonyl amides (Scheme 1c).
Because of the mild conditions and the high transformation
efficiency of β′-allenoate adducts to 1,3-butadienes, this
approach provides a significant synthetic advantage in
constructing heteroaromatic or aromatic ring-fused dihydro-
pyridinones, which are ubiquitous in bioactive natural products
and pharmaceuticals, as well as versatile synthetic precursors
for other important molecules (Figure 1).15 In addition to
these, the use of air as the terminal oxidant also provides an
advantage regarding environmental friendliness.
a
Table 1. Optimization of the Cascade Reaction Conditions
(i)
base (equiv)
(ii)
yield of 2
yield of 4aa
b
c
entry
(%)
ligand
(%)
1
2
3
4
5
6
7
8
NaHCO3 (1.0)
NaOAc (1.0)
Et3N (1.0)
25
20
0
90
0
−
−
−
−
−
−
−
−
−
−
−
0
0
−
0
−
−
0
0
42
83
72
93
90
86
90
85
d
DBU (1.0)
e
DABCO (1.0)
Pyridine (1.0)
0
f
DBN (1.0)
83
86
76
74
51
−
−
−
−
−
DBU (0.5)
DBU (0.2)
DBU (0.1)
DBU (0.05)
DBU (0.1)
DBU (0.1)
DBU (0.1)
DBU (0.1)
DBU (0.1)
9
10
11
12
13
14
Ac-Gly-OH
H-Gly-OH
N,N-dimethylglycine
Boc-Leu-OH
L-proline
g
15
16
g
a
Reaction conditions: (i) 1a (0.4 mmol) and base (equiv of 1a) in p-
xylene (2 mL) at 90 °C for 12 h under air, and then (ii) 3a (0.2
mmol), Pd(TFA)2 (0.02 mmol), ligand (0.04 mmol) and Cu(OAc)2
(0.04 mmol) were added and reacted at 120 °C for 24 h under air.
b
The intermediate 2 was not isolated, and the yields were determined
c
d
by HPLC. Isolated yield. DBU = 1,8-diazabicyclo[5.4.0]undec-7-
ene. DABCO = 1,4-diazabicyclo[2.2.2]octane. DBN = 1,5-diaza-
bicyclo[4.3.0]non-5-ene. 4aa with 0% ee.
e
f
g
To improve the atomic utilization efficiencies of the
vinylogous elimination reaction, we selected the (Z)-ethyl 2-
(acetoxy(phenyl)methyl)but-2-enoate (1a) which was pre-
NaHCO3 and NaOAc gave a small amount of 2 in p-xylene,
and no product 4aa was obtained after reactants for the second
step were added (entries 1 and 2). It may be due to the low
solubility of the inorganic base in p-xylene. Among a series of
organic bases, DBU and DBN gave the intermediates 2 in
excellent and good yields. Unfortunately, also no product 4aa
was obtained after reactants for the second step were added
(entries 3−7). Excitingly, the catalytic amount of DBU could
also conduct the vinylogous elimination process successfully
(entries 8−11).16 Product 4aa was obtained in optimal 83%
yield with Z stereoselectivity when the amount of DBU was 0.1
equiv of 1a (entry 10). The result that the excess base is not
beneficial for 4aa formation suggests that the C−H activation
process might go through an elelectrophilic palladation
pathway.17 However, about 15% of reactant 3a remained
unreacted. Considering that the weak and reversible bidentate
Figure 1. Examples of bioactive ring-fused dihydropyridinones and
derivatives.
B
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coordination of the amino acid ligand could activate the
palladium complex, and drastically accelerate the C(sp2)−H
activation process, we added a catalytic amount of Ac-Gly-OH
to the reaction.18 To our delight, the reactant 3a was fully
converted, and the yield of 4aa increased to 93% (entry 12).
Omitting the acetyl protecting group or changing the
protecting group to methyl decreased the yield (entries 13
and 14). Boc-Leu-OH and L-proline also did not give a higher
yield than Ac-Gly-OH (entries 15 and 16). Eventually, we
obtained the optimal cascade reaction conditions as shown in
entry 12.
4ah and 4ai slightly, probably due to the lower electron cloud
density of C−H bond at the 2-position than the 3-position.
Excitingly, furan-, thiophene-, and 1-methyl-pyrrole-2-carbox-
amides were all effective substrates, affording products 4aj−4al
in 85−89% yields. 1-Methyl-pyrazole-2-carboxamide was less
reactive, giving the product 4am in 26% yield. We suspect that
the electron-deficient property of the pyrazole ring affected the
reactivity greatly.
Then we turned our attention to the scope of the β′-
allenoate adducts (Scheme 2). Electron-rich or -deficient
substituents at the 4-, 3-, or 2-position of the phenyl ring were
well tolerated. Products 4ba−4ia were formed in good to
excellent yields. The β′-allenoate adduct with the 2-naphthyl
group at the allylic position also participated in the reaction,
affording the corresponding product 4ja in 63% yield. The
variations of electron-withdrawing groups showed that the β′-
allenoate adduct with a methoxylcarbonyl group performed
excellently with the desired product 4ka in 96% yield and with
a benzoxylcarbonyl group performed moderately with the
product 4la in 47% yield. Interestingly, a cyano substituted β′-
allenoate adduct analogue could also undergo the cascade
reaction, albeit with a low yield of 4ma.
With the optimized reaction conditions in hand, we first
investigated the substrate scope of heteroaryl carboxamides
(Scheme 2). The benzofuran-2-carboxamides with either
Scheme 2. Scope of Heteroaryl Carboxamides and β′-
a
Allenoate Adducts
Subsequently, this cascade reaction was applied to aryl
carboxamides 5 with 1a (Scheme 3). Due to the relatively
lower reactivity, N-((4-nitrophenyl)sulfonyl)benzamide 5a
afforded product 6a in moderate yield under the optimized
reaction conditions. When the amount of 1a was raised, the
benzamide 5a could be fully converted, and 6a was obtained in
an excellent yield of 93%. Then we explored the scope of the
a
Scheme 3. Scope of Aryl Carboxamides
a
Reaction conditions: 1 (0.4 mmol), 3 (0.2 mmol), and DBU (0.04
mmol) in p-xylene (2 mL) at 90 °C for 12 h under air, and then
Pd(TFA)2 (0.02 mmol), Ac-Gly-OH (0.04 mmol) and Cu(OAc)2
(0.04 mmol) were added and reacted at 120 °C for 24 h under air.
electron-rich or -deficient substituents on the phenyl ring all
functioned well, achieving the desired products 4ab−4ad in
88−90% yields. Benzothiophene-2-carboxamides and 1-meth-
yl-indole-2-carboxamide also reacted smoothly under the
reaction conditions. Products 4ae−4ag were obtained in 78−
91% yields. X-ray crystallographic analysis of 4af (CCDC
2020218) unequivocally confirmed the Z stereoselectivity of
the carbon−carbon double bond. Switching the amide group
to the 3-position of the indole moiety decreased the yields of
a
Reaction conditions: 1a (0.6 mmol), 5 (0.2 mmol), and DBU (0.06
mmol) in p-xylene (2 mL) at 90 °C for 12 h under air, and then
Pd(TFA)2 (0.02 mmol), Ac-Gly-OH (0.04 mmol), and Cu(OAc)2
(0.04 mmol) were added and reacted at 120 °C for 24 h under air.
b
1a (0.4 mmol) was added.
C
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Letter
N-sulfonyl aryl carboxamides. Gratifyingly, this protocol was
compatible with a variety of electron-rich benzamides,
achieving the desired products 6b−6h in 73−94% yields.
With regard to meta-substituted benzamide which may
produce regionselective isomers, only one isomer 6f was
afforded, probably due to steric hinderance. The excellent
yields of 6g and 6h showed that the steric effects produced
from ortho-substitution on phenyl ring did not influence the
Pd-catalyzed ortho C−H functionalization. Furthermore, N-
((4-nitrophenyl)sulfonyl)-2-naphthamide 5l also worked well
under those optimized conditions to synthesize the single
product 6l in 72% yield. When electron-deficient benzamides
were subjected to the typical conditions, the yields of desired
products 6i−6k were reduced. Simultaneously, some E-
products 6i′−6k′ were obtained. X-ray crystallographic
analysis of 6k′ (CCDC 2020219) unequivocally confirmed
the E stereoselectivity of the carbon−carbon double bond.
These results demonstrate that the electronic properties of the
substituents on the phenyl ring of benzamides have some
significant effect on the reactivity and stereoselectivity of this
cascade reaction, implying that the C−H activation process
might go through an elelectrophilic palladation pathway.
Eventually, the protecting groups on the benzamides were
also explored. Tosyl, methylsulfonyl, and 4-(trifluoromethyl)-
phenyl)sulfonyl protected benzamides performed well in this
transformation, leading to the corresponding products 6m, 6n,
and 6o in 90%, 75%, and 75% yield, respectively. However,
when the sulfonyl group was replaced by the Ac, Ph, or OMe
group, no corresponding product was detected, showing that
the strong acidity of the N−H bond benefited this cascade
reaction.
Scheme 5. Mechanistic Studies
nucleophile to the π-allylpalladium moiety. The highly
stereochemical control of the carbon−carbon double bond in
product may be due to the steric clash between the nitrogen
nucleophile and phenyl group.5b,20,22
On the basis of the above-mentioned observations and
previous reports3c,d,23 we can propose the following plausible
catalytic cycle (Scheme 6). A Pd(II) species complexes with
Scheme 6. Proposed Plausible Mechanism
substrate 3 or 5. Deprotonation of the N−H bond and
electrophilic palladation of C−H bond generate the five-
membered palladacycle I. Migratory insertion of the 1,3-diene
2 which is obtained through the vinylogous elimination of β′-
allenoate adducts 1 leads to π-allylpalladium intermediates II
and III. The intermediate II tends to isomerize to the
intermediate III. The following nucleophilic attack of the
nitrogen nucleophile to the π-allylpalladium intermediate
affords the final product 4 or 6. The obtained Pd(0) species
can be oxidized to Pd(II) catalyst by Cu(OAc)2 and O2 to
participate in the next catalytic cycle.
To showcase the practicality of the protocol, a gram-scale
reaction and two further transformation reactions were carried
out (Scheme 4). The cascade reaction of 3a on a 3 mmol scale
Scheme 4. Gram-Scale and Synthetic Transformations
In conclusion, we have developed a highly stereoselective
palladium-catalyzed cascade reaction through a vinylogous
elimination/C−H functionalization/allylation pathway of β′-
allenoate adducts and amides. It is the first example of
application of the allenoate adducts to C−H functionalization
annulations as practical precursors of hard-to-get function-
alized electron-deficient 1,3-butadienes. Various heteroaryl
carboxamides, aryl carboxamides, and allyl esters are explored
to construct bioactively important and medicinally important
ring-fused dihydropyridinones. Using air as the terminal
oxidant also shows a great advantage in environmental
friendliness.
with 1a performed smoothly, giving the desired product 4aa in
82% yield. Removing the N-protecting group by p-MePhSH
afforded amide 7 in 90% yield.19 Further treatment of 7 with
DIBAL-H selectively reduced the ester group to achieve
alcohol 8 in 87% yield.3c
During the cascade reactions, we found that the vinylogous
elimination of allenoate adducts produced the major Z-
butadienes and a small amount of E-butadienes. To gain
more insight into the mechanism of the cascade reaction, we
isolated the 1,3-butadienes Z-2 and E-2 and subjected them to
the standard C−H functionalization/allylation cascade reaction
system respectively (Scheme 5). Expectedly, both experiments
led to the same product 4aa with high Z stereoselectivity in
excellent yield. These observations suggest that the C−H
functionalization/allylation cascade reaction includes a syn−
anti isomerization of the π-allylpalladium intermediate
process,20 and the isomerization can be fast to give rise to
the same product21 after nucleophilic attack of the nitrogen
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02956.
Experimental details, NMR (1H, 13C) spectra for all new
compounds (PDF)
Accession Codes
CCDC 2020218−2020219 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
D
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Letter
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emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Zhiming Wang − Advanced Research Institute and Department
of Chemistry, Taizhou University, Taizhou 318000, P. R.
China; orcid.org/0000-0002-6583-3826;
Email: zhiming@tzc.edu.cn, wzmmol@hotmail.com
Authors
Manman Sun − Advanced Research Institute and Department of
Chemistry, Taizhou University, Taizhou 318000, P. R. China
Weida Chen − Advanced Research Institute and Department of
Chemistry, Taizhou University, Taizhou 318000, P. R. China
Haijian Wu − Advanced Research Institute and Department of
Chemistry, Taizhou University, Taizhou 318000, P. R. China
Xiangyu Xia − Advanced Research Institute and Department of
Chemistry, Taizhou University, Taizhou 318000, P. R. China
Jianguo Yang − Advanced Research Institute and Department of
Chemistry, Taizhou University, Taizhou 318000, P. R. China;
orcid.org/0000-0003-4268-7384
Lei Wang − Advanced Research Institute and Department of
Chemistry, Taizhou University, Taizhou 318000, P. R. China;
orcid.org/0000-0001-6580-7671
Guodong Shen − School of Chemistry and Chemical
Engineering, School of Pharmacy, Liaocheng University,
Liaocheng 252000, P. R. China; orcid.org/0000-0002-
0631-1913
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02956
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Natural Science Foundation of
Zhejiang Province (Nos. LQ20B020007, LY18B020002) and
the Leading Innovative and Entrepreneur Team Introduction
Program of Zhejiang (No. 2019R01005) is gratefully acknowl-
edged.
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