Pd(II)-catalyzed annulation reactions of epoxides with benzamides to synthesize isoquinolones

Article abstract of DOI:10.1021/acs.orglett.0c04097

Epoxides as alkylating reagents are unprecedentedly applied in Pd(II)-catalyzed C?H alkylation and oxidative annulation of substituted benzamides to synthesize isoquinolones rather than isochromans, which is accomplished through alerting the previously reported reaction mechanism by the addition of oxidant and TEA. Under these conditions, various isoquinolones have been prepared with yields up to 92%. In addition, this methodology has been successfully employed in the total syntheses of rupreschstyril, siamine, and cassiarin A in an expedient fashion.

Full text of DOI:10.1021/acs.orglett.0c04097

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Letter
Pd(II)-Catalyzed Annulation Reactions of Epoxides with Benzamides
to Synthesize Isoquinolones
Huihong Wang,§ Fei Cao,§ Weiwei Gao, Xiaodong Wang, Yuhang Yang, Tao Shi,* and Zhen Wang*
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ABSTRACT: Epoxides as alkylating reagents are unprecedentedly
applied in Pd(II)-catalyzed C−H alkylation and oxidative annulation of
substituted benzamides to synthesize isoquinolones rather than
isochromans, which is accomplished through alerting the previously
reported reaction mechanism by the addition of oxidant and TEA.
Under these conditions, various isoquinolones have been prepared with
yields up to 92%. In addition, this methodology has been successfully
employed in the total syntheses of rupreschstyril, siamine, and cassiarin
A in an expedient fashion.
soquinolone is a widely existing class of skeletons usually
Scheme 1. Coupling Partners for the Syntheses of
Isoquinolones
I
possessing unique bioactivities.1 Various methods for its
synthesis have gradually been reported.2 Among them,
employing alkynes as coupling partners3 and requiring
transition metal catalysts4−9 are the main features. Recently,
various intrinsically unique coupling partners have been
developed. In 2014, Glorius and co-workers employed α-
MsO/TsO/Cl ketones as alkylating reagents accomplishing the
syntheses of isoquinolones.10 In 2017, Huang and co-workers
developed β-keto esters as coupling partners to react with N-
alkoxybenzamides via a cascade DCC/annulation reaction,
resulting in isoquinolone derivatives.11 Meanwhile, novel diazo
compounds12 and sulfoxonium ylides13 as coupling/cyclization
partners to synthesize N-methoxyisoquinolones have been
gradually reported. More recently, Kou’s group14 reported Rh
(III)-catalyzed oxidative coupling of N-methoxybenzamides
with silyl enol ethers to render the N-methoxy-3-hydroxy
dihydroisoquinolones in good yields (Scheme 1). These
methodologies, however, suffer from some drawbacks, mainly
the coupling partners are highly active, are difficult to prepare
and store, and require prefunctionalization. Because of these
challenges, development of more effective methods to prepare
isoquinolones is still in demand.
As versatile coupling/cyclization partners, oxiranes have
shown robustness in heterocycle synthesis involving C−H
activation.15 In 2015, Kanai’s16 and Yu’s17 groups respectively
revealed the application of epoxides as the coupling partners
for the first time in Pd-catalyzed C−H alkylation reactions,
which provided a labor-saving alternative to construct
isochromans.
Received: December 11, 2020
Published: January 19, 2021
Recently, our group employed oxiranes to construct the
isochroman core of natural product berkelic acid.18a Together
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© 2021 American Chemical Society
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with our work, some other follow-up reports further revealed
the robustness of this alkylation reagents by synthesizing useful
phenethyl-substituted alcohols with high atom economy.18b,g
However, to our knowledge, syntheses of isoquinolones using
oxiranes as coupling partners has not been reported. The
challenge is the Pd-alkoxide, which is generated from ring
opening of epoxide, prefers to attack the carbonyl group of the
amide group, leading to lactonization to generate isochro-
mans,17,18a rather than conducted β-hydrogen elimination to
form the ketone carbonyl followed byintramolecular lactamiza-
tion/dehydration to afford isoquinolones. We proposed that
the existence of appropriate base may promote the β-H
elimination of Pd-alkoxide to afford isoquinolones (see the
mechanism section). In order to identify the above-mentioned
proposal and in continuation of our interest in heterocycle
building,19 we herein reveal an example of Pd(II)-catalyzed
cascade reaction of N-alkoxylbenzamides with oxiranes
derivatives for the synthesis of isoquinolones.
slightly lower yield of 46% (entries 5 and 6). Other Pd salts
like PdCl2 or Pd(TFA)2 decreased the yields to 47% and 38%,
respectively (entries 7 and 8). Further screening of oxidants
revealed that AgOAc could afford a small improvement yield
(59% entry 9) but the CuCl2 reduced the yield drastically
(entry 11); in addition, other oxidants like benzoquinone were
not effective in this case (entry 12). To our delight, in the
presence of TEA, the yield of 3aa increased to 64%, while the
yield of the byproduct isochroman 4a was low (entry 13).
When 20 mol % of TEA was added, a further improved yield of
3aa (82%) was realized (entry 14). This result indicated that
TEA may act as ligand that plays a crucial role in stabilizing the
Pd catalyst and promoting reoxidation of Pd(0) by O2.20
After determining the optimal reaction conditions, we
studied reactivities of other N-methoxybenzamide derivatives
(Scheme 2). To our delight, dimethoxy or trimethoxy
a
Scheme 2. Substrates Scope of N-Methoxybenzamides
The initial experiment was performed with N-2,4-trimethox-
ybenzamide 1aa and epoxide 2a using Pd(OAc)2 as the
catalyst and KOAc as the additive (Table 1, entry 1). Indeed,
a
Table 1. Optimization of Reaction Conditions
Yield (%)
Entry
Catalyst system
Solvents
Additives
3aa
4a
1
2
3
4
5
Pd(OAc)2/KOAc
Pd(OAc)2/KOAc
Pd(OAc)2/KOAc
Pd(OAc)2/KOAc
Pd(OAc)2/
CF3CO2K
Toluene
1,4-dioxane
HFIP
o-Xylene
HFIP
23%
12%
34%
30%
55%
13%
<5%
42%
21%
23%
6
Pd(OAc)2/
CF3CO2Na
HFIP
46%
17%
7
8
PdCl2/CF3CO2K
Pd(TFA)2/
CF3CO2K
HFIP
HFIP
47%
38%
14%
18%
9
Pd(OAc)2/
CF3CO2K
Pd(OAc)2/
CF3CO2K
Pd(OAc)2/
CF3CO2K
Pd(OAc)2/
CF3CO2K
Pd(OAc)2/
CF3CO2K
Pd(OAc)2/
CF3CO2K
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
AgOAc
59%
52%
<5%
22%
64%
82%
20%
22%
45%
14%
20%
11%
a
b
Isolated yields. Non-hydrogens atoms are shown as 30% ellipsoids.
c
Yields of corresponding isochromans.
10
11
12
13
14
Ag2O
CuCl2
BQ
substituted substrates all reacted well, affording isoquinolones
(3aa−3af) in 61%−87% yields. Not surprisingly, N-methox-
ybenzamides bearing trimethoxy groups gave corresponding
products with better yields than the dimethoxy substituted
substrates. Particularly, substrate 1ae with an electron-with-
drawing methyl ester behaved well in this reaction, affording
product 3ae in a slightly lower yield of 80% compared with the
methoxy-substituted substrate 1ad. The MOM protected
substrate 1af gave the corresponding product smoothly;
however, it was difficult to purify, which prompted us to
deprotect MOM in the process of post-treatment, giving the
product 3af in a good yield of 78% in two steps. Subsequently,
electron-donating groups (methyl, methoxy, and tert-butyl)
substituted N-methoxybenzamides gave the desired products
in 47−61% yields. In general, non/methyl substituents gave
inferior yields compared with the methoxy substituents and the
ortho-methoxy group gave a lower yield compared to the
methoxy group in the meta/para-position. Unexpectedly, the
presence of a meta-Cl substituent retarded the reactions
TEA
20 mol %
TEA
a
1aa (0.1 mmol), 2a (0.2 mmol), Pd salts (10 mol %), additives (1.0
equiv), solvent (0.3 mL), 100 °C, 24 h, air, isolated yields. BQ =
benzoquinone.
isoquinolone 3aa as well as isochroman 4a was generated
respectively in 23% and 13% yields. Subsequently, we
investigated the infulence of solvent (entries 1−4), and
HFIP was proven to be the optimal one that produced 3aa
in 34% yield (entry 3). Significantly, changing KOAc to
potassium trifluoroacetate (CF3CO2K) displayed some extent
of selectivity toward isoquinolone, increasing the yield of 3aa
to 55%, but sodium trifluoroacetate (CF3CO2Na) gave a
864
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Letter
a
greatly, providing product 3an in trace amount. The apparent
electron effect of a substituent in the 3-position was also
observed in substrate 1ao, in which isoquinolones 3ao was
obtained in 22% yield. Moreover, 4-methoxy-2-methylbenza-
mide 1ap, 2,4-dimethylbenzamide 1aq, and 2-naphthamide 1ar
were compatible in this transformation, and moderate yields of
corresponding products 3ap, 3aq, and 3ar were obtained.
Beyond the N-methoxy group, a variety of N-protecting
groups were investigated and electronic and steric effects were
observed (Scheme 3). For example, substrate 1ba containing
Scheme 4. Substrates Scope of Epoxides
a
Scheme 3. Substrates Scope of N-Protecting Groups
a
b
Isolated yields. Yields of corresponding isochromans.
extensive pharmacological activities, leading to 3cn in 58%
yield.
The practicability of this protocol was also demonstrated by
the total syntheses of rupreschstyril,21 siamine,22 and cassiarin
A;23 which, however, were previously synthesized in slightly
lower overall yields and many steps. Removal of the methoxy
group and subsequent deprotection of the MOM group in
isoquinolin-1-one 3af′ provided rupreschstyril in 83% yield.
Similarly, siamine (2), another alkaloid of Cassia siamea, was
obtained in 76% yield from isoquinolin-1-one 3ca. As for
cassiarins A (3), treatment of 3ca with sodium hydride at 120
°C removed the methoxy group, followed by treatment with N-
phenyl-bis(trifluoromethanesulfonimide) providing triflate 4 in
73% yield in one pot, which subsequently coupled with the in
situ generated propyne to provide alkyne 5 in 87% yield. Then,
demethylation of 5 with BBr3 and spontaneous 6-endo-dig
cyclization gave cassiarin A (3) in a total of 4 steps and 37%
overall yield from 1aa (Scheme 5).
a
b
Isolated yields. Corresponding isochromans were not observed.
an N-ethoxy group afforded a better yield compared with the
N-methoxy substituent by increasing the nucleophilicity of the
nitrogen atom. The reaction of linear N-butoxy substrate 1bd
offered the desired isoquinolone in 81% yield, while substrate
1bb bearing an isopropoxy gave 3bb in 56% yield and tert-
butoxy substituted substrate did not provide the desired
product. It is pleasing that the reaction of N-isobutoxy
substituted substrate 1bc afforded 3bc in 92% yield, and this
N-protecting group was also employed in 4-methoxy/methyl
benzamides 1bf and 1bg, and synthetically useful yields were
obtained. When the N-protecting group was benzyloxy,
isoquinolone 3bh was obtained in 47% yield; however, N-
phenoxy substrate 1bi did not offer the desired product.
Finally, the scope of epoxides was extensively tested
(Scheme 4). Alkylation with simple propylene oxide and
other 2-alkyloxiranes gave N-methoxyisoquinolones 3ca−3cc
in 80−85% isolated yields. Actually, phenyl and protected
hydroxyl groups (3 cd−3ch, 3cm) gave inferior yields (61−
75%) compared with 2-alkyloxiranes, presumably due to the
additional coordinating oxygen atom or π-electrons of the
phenyl of oxiranes might inhibit the β-hydrogen elimination
process for coordinating to the palladium catalyst. Surprisingly,
2-ylmethanol oxirane was also tolerant in this reaction,
affording 3ci in 46% yield. Further exploration demonstrated
that α-ester and vinyl moieties (1cj, 1ck) were not compatible
with this protocol. Besides, isoindoline-1,3-dione worked well
in this transformation, and a moderate yield of corresponding
product 3cl was obtained.
To gain insights into the mechanism, coupling of 1al with 2a
in the absence of 4 Å molecular sieve and TEA has been
conducted. As a result, isochroman 3as, 3-hydroxy-3,4-
dihydroisoquinolin-1-one 3at, and isoquinolone 3al were
obtained in 24%, 13%, and 21% yields, respectively. Notably,
3at could fully convert to isoquinolone 3al in the presence of 4
Å molecular sieve at 100 °C in HFIP. When the reaction was
performed under an O2 or Ar atmosphere, 3al was obtained
respectively in 69% and 14% yields, indicating the critical role
of oxygen in this reaction. According to our preliminarily
mechanistic experiments and the literature precedent,24
a
plausible mechanism is proposed (Scheme 6). Cyclometalation
of benzamide with palladium(II) generates a palladacyclic
intermediate A,25 which reacted with epoxide via an SN2
nucleophilic ring-opening process generating Pd-alkoxide
species B.17 Intermediate B undergoes β-hydrogen elimination
to form the ketone carbonyl product D and Pd-hydride
species,20a,26 followed by the nucleophilic addition of nitrogen
Moreover, this methodology was successfully applied to the
late stage modification of estrone, a compound possessing
865
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been synthesized in high efficiency by this new methodology.
In addition, other novel transformations of epoxides are
ongoing in our laboratory.
Scheme 5. Late-Stage Modification and Synthetic
Applications
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04097.
Experimental procedures, spectroscopic data, and
crystallographic data for 3ae (CCDC 2042086) (PDF)
Accession Codes
CCDC 2042086 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Scheme 6. Control Experiments and Proposed Reaction
Mechanism
Zhen Wang − State Key Laboratory of Applied Organic
Chemistry and School of Pharmacy, Lanzhou University,
Lanzhou 730000, China; orcid.org/0000-0003-4134-
1779; Email: zhenw@lzu.edu.cn
Tao Shi − School of Pharmacy, Lanzhou University, Lanzhou
730000, China; Email: shit18@lzu.edu.cn
Authors
Huihong Wang − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Fei Cao − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Weiwei Gao − State Key Laboratory of Applied Organic
Chemistry, Lanzhou University, Lanzhou 730000, China
Xiaodong Wang − School of Pharmacy, Lanzhou University,
Lanzhou 730000, China
Yuhang Yang − School of Pharmacy, Lanzhou University,
Lanzhou 730000, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04097
Author Contributions
§H.W. and F.C. contributed equally.
Notes
to the carbonyl group in D giving intermediate E, which then
affords isoquinolone upon dehydration.13 The Pd-hydride
species is oxidized by O2 to Pd(II),20 which re-enters the
catalytic cycle. In contrast, protonation and lactonization of
species B would afford 3,4-dihydroisocoumarins as byproducts.
In conslusion, an example of palladium-catalyzed C−H
alkylation and cascade annulation unprecedentedly using the
easily prepared oxiranes as coupling partners to generate
isoquinolones rather than isochromans is presented. Notably,
the formation of isoquinolones or isochromans is controlled by
the reaction conditions; that is, compared to conditions giving
isochromans, the addition of potassium trifluoroacetate and
TEA could promote the dehydration of Pd-alkoxide, resulting
in the formation of isoquinolones rather than isochromans.
The reaction works efficiently in various substrates, and natural
products including supreschstyril, siamine, and cassiarin A have
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the Recruitment Program of
Global Experts (1000 Talents Plan), the Fundamental
Research Funds for the Central Universities (lzujbky-2019-
ct08), and Gansu Province Science Foundation for Distin-
guished Young Scholars (20JR5RA304).
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