Cascade Reactions Assisted by Microwave Irradiation: Ultrafast Construction of 2-Quinolinone-Fused γ-Lactones fromN-(o-Ethynylaryl)acrylamides and Formamide

Article abstract of DOI:10.1021/acs.orglett.1c01606

An ultrafast (10 s) methodology to construct novel highly functionalized 2-quinolinones fromN-(o-ethynylaryl)acrylamides (1,7-enynes) is described for the first time. Microwave irradiation enabled the ultrafast synthesis of 2-quinolinone-fused γ-lactones from Fenton’s reagents in formamide. After six key consecutive reactions, including a diastereoselective step, 2-quinolinone-fused γ-lactones were obtained in good overall yield (up to 46%; 10 s).

Full text of DOI:10.1021/acs.orglett.1c01606

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Letter
Cascade Reactions Assisted by Microwave Irradiation: Ultrafast
Construction of 2‑Quinolinone-Fused γ‑Lactones from
N‑(o‑Ethynylaryl)acrylamides and Formamide
Bruce A. L. Sacchelli, Bianca C. Rocha, and Leandro H. Andrade*
Cite This: Org. Lett. 2021, 23, 5071−5075
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ABSTRACT: An ultrafast (10 s) methodology to construct novel
highly functionalized 2-quinolinones from N-(o-ethynylaryl)-
acrylamides (1,7-enynes) is described for the first time. Microwave
irradiation enabled the ultrafast synthesis of 2-quinolinone-fused γ-
lactones from Fenton’s reagents in formamide. After six key
consecutive reactions, including a diastereoselective step, 2-
quinolinone-fused γ-lactones were obtained in good overall yield
(up to 46%; 10 s).
he construction of heterocycles is an important field in
Torganic chemistry, especially in the production of new
pharmaceutically relevant compounds.1 In this context, N-
heterocycles stand out, because of their vast presence in natural
and bioactive compounds.2 Among several classes of N-
heterocycles, the 3,4-dihydro-2-quinolinone is an important
scaffold that is present in a variety of pharmacologically active
compounds, such as FDA-approved drugs: cilostazol (vaso-
dilator), carteolol (glaucoma treatment) and aripiprazole
(schizophrenia and bipolar disorder treatments) (Figure 1).3
reagents (H2O2, FeSO4, and H2SO4).6 With this in mind, we
hypothesized that combining the reactivity of carbamoyl
radicals and 1,7-enynes might be result in a powerful approach
to the synthesis of novel heterocycles.
In this scenario, we disclose herein the previously unknown,
microwave-assisted ultrafast synthesis of 2-quinolinone-fused γ-
lactones enabled by a cascade reaction between 1,7-enynes and
hydroxyl and carbamoyl radicals, which were generated from
Fenton’s reagents in formamide. Surprisingly, after only 10 s, a
novel class of quinolinones was diastereoselectively obtained
(Scheme 1).
Formamide revealed itself as the key compound to achieve
the synthesis of highly functionalized 2-quinolinone-fused γ-
lactones. Our hypothesis was that two new C−C and three C−
O bonds were formed after six key reactions, as follows:
generation of hydroxyl and carbamoyl radicals and quinolinone
formation, hydroxylation, epoxidation, and lactone formation
via epoxide ring opening.
To the best of our knowledge, this is the first report using
1,7-enynes as starting materials for complex heterocycles in a
10 s process. Microwave irradiation is an important technology
that has gained great attention in organic synthesis.7a−d
Currently, several chemical reactions can be performed under
microwave irradiation, revealing excellent results for the
Figure 1. Examples of 3,4-dihydro-2-quinolinone rings.
A literature survey revealed that 1,7-enynes are used as
starting materials to produce 2-quinolinones, through reactions
with different radical species.4 Despite these advances using
radical reactions, no study of reactivity toward carbamoyl
radicals has been conducted. We recently established a
research program focused on exploring the synthetic potential
of the simplest carbamoyl radical (•CONH2), for the synthesis
of highly functionalized compounds.5 Carbamoyl radical can
be generated from formamide in the presence of Fenton’s
Received: May 11, 2021
Published: June 21, 2021
https://doi.org/10.1021/acs.orglett.1c01606
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5071−5075
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Letter
solubility in formamide, FeSO4. In addition, the Fenton
reaction is not efficient in the absence of acid, especially in the
presence of formamide as a solvent.
Scheme 1. Ultrafast Construction of Novel Heterocycles
from 1,7-Enynes
a
Aiming to improve the solubility of 1a in formamide, we
performed the reactions at 80 °C for 4 and 8 h. The first
experiment showed only traces of a compound, which was
unexpectedly characterized as the 2-quinolinon-fused γ-lactone
2a (Table 1, entry 1). This compound would result from an
initial carbamoyl radical conjugate addition, followed by a
second radical addition across the triple bond and radical
hydroxylation. The resulting double bond would then be
epoxidized and a 5-exotet ring opening and hydrolysis would
yield the final observed product (for more details, see the
reaction mechanism). It is noteworthy that, after the
comprehension of the reaction mechanism for production of
2-quinolinon-fused γ-lactone 2a, we focused on the simplest
carbamoyl radical (•CONH2) generated from formamide. In
this case, NH3 can be released as a coproduct (a gas of low
molecular weight).
Motivated by the possibility of producing a novel highly
functionalized 2-quinolinone, we pursued further reaction
optimization. We tried to generate continuous hydroxyl
radicals by adding a solution of hydrogen peroxide with a
flow apparatus (Table 1, entry 2). The results provided enough
material to isolate and fully characterize 2a by NMR. The best
result was found when higher amounts of reactants (4 equiv of
H2O2, 2 equiv of H2SO4, and 1 mol % of FeSO4) were added
every hour, yielding the product 2a (39%; Table 1, entry 3).
This result indicated that excess of hydrogen peroxide is
important to increase the yield of compound 2a. However, a
longer reaction time did not increase the yield (Table 1, entry
5). It is noteworthy that the highest expected yield for the
diastereoselective formation of 2-quinolinone-fused γ-lactone
2a is 50%.
a
Fenton’s reagent (H2O2, FeSO4, and H2SO4) in formamide; 10 s
under microwave irradiation.
synthesis of organic compounds. It can also be considered a
green technology since it improves yield and productivity,
reduces reaction time, and consequently reduces energy
consumption.7e,f
This study was initiated by performing the reactions while
heating in an oil bath (Table 1). 1,7-Enyne 1a was selected as a
Table 1. Reaction of the N-(o-ethynylaryl)acrylamide 1a
with Fenton’s Reagents in Formamide
a
However, while pursuing an optimized protocol, we decided
to put all the chemicals in a round-bottom flask and expose
them to a domestic microwave oven. Surprisingly, product 2a
was obtained in 17% yield after 10 s (Figure 2).
Fenton’s Reagents
entry H2O2 (equiv) H2SO4 (equiv) FeSO4 (mol %) t (h) yield (%)
1
2
3
4
5
2
10
16
32
16
1
1
8
16
8
1
1
4
8
4
4
4
4
8
8
trace
14
39
24
34
b
c
c
d
a
Reaction conditions: N-(o-ethynylaryl)acrylamide 1a (100 mM),
Figure 2. Exploratory experiment conducted in a domestic microwave
oven.
formamide (5 mL), 80 °C and magnetic stirrer. The yields were
obtained after removal of formamide by distillation and purification of
b
crude material by chromatographic column. A solution of H2O2 in
The fact that 1,7-enyne 1a was not fully consumed using a
domestic microwave oven (87% conversion by GC-MS
analysis, see the Supporting Information) motivated us to
apply a monomodal microwave reactor (see Table 2).
The first reaction condition, which was evaluated in a
monomodal microwave reactor, showed only trace amounts of
product 2a (80 °C, 10 s; see Table 2, entry 1). However,
conducting the reaction under microwave irradiation at 80 °C
for 40 s and adding the same amount of Fenton’s reagents
every 10 s gave the desired product 2a in 35% yield (Table 2,
entry 2). This result was similar to that of the best reaction
under conventional heating (4 h, Table 1, entry 2). Increasing
the reaction time and amount of reagents decreased the
formamide (2.5 mL) was added under continuous flow conditions
(10.4 μL/min) onto a solution of substrate 1a (0.5 mmol),
c
formamide (2.5 mL), H2SO4, and FeSO4. Fenton’s reagents were
d
added proportionally every hour. The full amount of Fenton’s
reagents was added up to 4 h.
model substrate to evaluate its reactivity toward formamide
and Fenton’s reagents (H2O2, FeSO4, and H2SO4). In the
Fenton process,6 iron(II) is the most employed catalyst for
hydroxyl radical generation from H2O2. Few other metals (i.e.,
copper and chromium) can be used to replace iron in systems
known as Fenton-like reactions;8 however, we decided to
consider the most efficient and inexpensive catalyst with good
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Table 2. Reaction of N-(o-Ethynylaryl)acrylamide 1a with
Fenton’s Reagents in Formamide under Microwave
a
Irradiation
Figure 3. Key NOESY interaction of compounds 2.
Fenton’s Reagents
H2O2
H2SO4
(equiv)
FeSO4
T
t
yield
entry
1
(equiv)
(mol %)
(°C)
(s)
(%)
4
16
24
4
8
16
4
16
8
4
2
8
12
2
4
8
2
8
4
2
1
4
6
1
2
4
1
4
2
1
80
80
80
100
100
100
130
130
130
130
10
40
60
10
10
40
10
10
20
10
trace
35
21
27
15
28
36
13
28
43
b
2
3
b
4
5
6
b
7
8
b
9
c
10
a
Reaction conditions: N-(o-ethynylaryl)acrylamide 1a (100 mM),
formamide (4 mL), t-BuOH (1 mL) and Fenton’s reagents (H2O2,
H2SO4 and FeSO4) in a microwave tube (10 mL). The yields were
obtained after the removal of formamide by distillation and
purification of the crude material by column chromatography.
b
c
Fenton’s reagents were added proportionally every 10 s. The
reaction mixture was added directly to a chromatographic column
without formamide distillation.
product yield (Table 2, entry 3). Since we were convinced that
a longer reaction time (>40 s) and higher amount of Fenton’s
reagents would not improve the yield of the desired product
2a, we decided to evaluate the effect of the reaction
temperature. At 100 °C for 10 s (Table 2, entries 4−6), the
results were similar to those of previous experiments at 80 °C
(Table 2, entry 4). However, when the reaction was performed
at 130 °C for 10 s, a high yield for the product 2a was
obtained, even using the smallest amount of Fenton’s reagents
(Table 2, entry 7). Once again, the increase in Fenton’s
reagents and reaction time did not give better results (Table 2,
entries 8 and 9). In addition, the reaction workup (Table 2,
entry 7) was improved by avoiding the formamide distillation
step. In this case, the crude reactional mixture was added
directly to the chromatographic column for product
purification (43% isolated yield, Table 2, entry 10).
NOESY-NMR experiments for compound 2a and several
others (see the Supporting Information) have been performed
to confirm the syn-stereochemistry assignment (Figure 3). The
key NOESY interaction was observed between the hydrogens
of the aromatic ring (H-2,6 of the benzoyl group) and the
methyl hydrogen (position 3a).
In addition, the syn-stereochemistry of products 2 was
essential to propose a reaction mechanism in which the lactone
formation would result from a precursor with proper
stereochemistry.
Figure 4. Substrate scope (isolated yield in parentheses).
The overall yield was not over 50%, since a diastereose-
lective formation of 2-quinolinone-fused γ-lactones was
observed. Aromatic rings containing fluorine at the para-
position to nitrogen (2l, 2m, 2n) led to a decrease in the yield.
Otherwise, the presence of fluorine on the aromatic ring of the
benzoyl group (2d, 2k) did not show any special influence.
Having the optimized conditions, we focused our attention
on the reaction scope (see Figure 4).
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The large benzoyl group bonded to nitrogen resulted in a
smaller yield (2o).
Scheme 2 shows the proposed mechanism for the synthesis
of 2-quinolinone-fused γ-lactones 2a−2o from 1,7-enynes 1a−
In conclusion, cascade reactions assisted by microwaves
enabled the ultrafast diastereoselective synthesis of novel 2-
quinolinone-fused γ-lactones from 1,7-enynes in only 10 s. The
role of Fenton’s reagents (H2O2, FeSO4, and H2SO4) in the
formamide was essential to achieve such a highly function-
alized heterocycle. In addition, the use of formamide as a
solvent under microwave irradiation allowed the ultrafast
generation of hydroxyl and carbamoyl radicals and, con-
sequently, 2-quinolinone formation, hydroxylation, epoxida-
tion, and finally, diastereoselective lactone formation via
epoxide ring opening. Despite the high complexity of this
process involving several reactions in 10 s, we can expect
further synthetic application for Fenton’s reagents in
formamide under microwave-assisted reactions.
Scheme 2. Proposed Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01606.
A description of experimental procedures, character-
ization of the new compounds and photographs of the
reaction and MW equipment (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Leandro H. Andrade − Instituto de Química, Universidade de
̃ ̃
Sao Paulo, Sao Paulo, Brasil; orcid.org/0000-0001-
5975-4980; Email: leandroh@iq.usp.br
Authors
Bruce A. L. Sacchelli − Instituto de Química, Universidade de
Sao Paulo, Sao Paulo, Brasil
Bianca C. Rocha − Instituto de Química, Universidade de Sao
Paulo, Sao Paulo, Brasil
̃
̃
̃
̃
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01606
1o. The first step is the generation of hydroxyl radicals via
Fenton’s reaction.6 H2O2 and Fe(II) in acidic media promote
the formation of hydroxyl radicals, water, and Fe(III). Fe(II)
can be regenerated from the reaction between Fe(II) and
H2O2.6b,9 Then, the carbamoyl radical is generated from
formamide by the action of hydroxyl radical.5a Next, the
carbamoyl radical attacks the carbon−carbon double bond of
the acrylic amide moiety and subsequently undergoes
cyclization with the carbon−carbon triple bond, generating
vinyl radical II. The recombination reaction of hydroxyl and
vinyl radicals II yields enol III.10
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Prof. Erick Leite Bastos (USP) and Prof. Ana Maria
da Costa Ferreira (USP) for their loan of a monomode-
microwave equipment. We also appreciate CNPq (Grant No.
312751/2018-4), FAPESP (Grant Nos. 2019/24784-7, 2019/
10762-1, and 2017/02854-8), and CAPES (Grant No.
88882.328246/2019-01) for the financial support.
Intermediate III (enol) can be converted to racemic epoxide
IV through an epoxidation reaction. Other authors have
demonstrated that peroxides in the presence of iron can
oxidize C−C double bound conjugated to aromatic rings into
epoxides.11 The pathway for the construction of lactone is via a
selective epoxide opening reaction through SN2-type mecha-
nism.12 This step explains the maximum yield (50%) for this
process. Once intermediate IV is formed with the proper
stereochemistry (anti), a 5-exo-tet cyclization can occur,13 in
which a nucleophilic attack of the amide group occurs from the
backside of the epoxide via an SN2-type mechanism,12 giving
intermediate V (geminal diol). After simple hydrolysis and
dehydration of V, product 2 is formed with the loss of
ammonia.
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