Harnessing in Situ Radical Oxygenation: Copper-Catalyzed Interrupted Azirine-Alkyne Ring-Expansion Reaction for the Synthesis of Pyrrolones

Article abstract of DOI:10.1021/acs.orglett.1c01162

Here we report a novel interrupted azirine-alkyne ring-expansion reaction with molecular oxygen for the direct synthesis of highly functionalized pyrrolones enabled by copper catalysis. Mechanistic investigations indicate that the present three-component reaction proceeds via two copper-catalyzed sequential reactions, an azirine-ring-opening alkynylation and an amine-directed radical oxygenation, leading to the formation of interesting pyrrolone structures under mild conditions.

Full text of DOI:10.1021/acs.orglett.1c01162

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Letter
Harnessing In Situ Radical Oxygenation: Copper-Catalyzed
Interrupted Azirine−Alkyne Ring-Expansion Reaction for the
Synthesis of Pyrrolones
Chandragiri Sujatha, Madhu Nallagangula, and Kayambu Namitharan*
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ABSTRACT: Here we report a novel interrupted azirine−alkyne
ring-expansion reaction with molecular oxygen for the direct
synthesis of highly functionalized pyrrolones enabled by copper
catalysis. Mechanistic investigations indicate that the present three-
component reaction proceeds via two copper-catalyzed sequential
reactions, an azirine-ring-opening alkynylation and an amine-
directed radical oxygenation, leading to the formation of interesting
pyrrolone structures under mild conditions.
atural and synthetic pyrrolones have attracted wide-
Nspread attention in medicinal chemistry because of their
broad spectrum of biological activities, including anticancer,
antibacterial, antiviral, and anti-inflammatory therapeutic
properties.1 Their promising bioactivities and possible
synthetic elaborations2 make pyrrolone structures particularly
important targets to inspire and develop new synthetic
methodologies.3 Recently, radical functionalization has proved
to be a powerful approach for the efficient construction of
challenging molecular fragments.4,5 In particular, in oxygen-
ation reactions it can directly introduce carbonyl functional
groups under milder conditions, and thus, more challenging
products can be effectively synthesized.6,7 Significantly, when
alkynes are subjected to oxygenation conditions, synthetically
valuable 1,2-diketones are obtained as products. Consequently,
numerous synthetic efforts have been made in this area by
employing both transition metal catalysts and photocatalysts.8
On the other hand, azirine ring-expansion reactions
represent a straightforward but challenging strategy to discover
new transformations for the synthesis of nitrogen-containing
heterocyclic structures.9,10 Although significant progress has
been made in this area, when alkynes are involved, this
methodology results mostly in the formation of pyrrole
structures (Figure 1a).11 The processes giving other N-
heterocycles have been less explored to date.12 In this regard,
we recently developed a copper-catalyzed ring-expansion
reaction of azirines and alkynes for the synthesis of pyridines
(Figure 1b).12a Mechanistically, it was proposed that this
process operated via two sequential copper-catalyzed reactions.
The reaction would begin with ring-opening alkynylation of
the azirine to give the corresponding skipped yne−imine
intermediate. This would generate an yne−enamine inter-
Figure 1. Azirine−alkyne ring-expansion reactions.
mediate by tautomerization. These in situ-generated inter-
mediates/tautomers could then undergo another copper-
catalyzed self-cyclization reaction to yield the final pyridine
Received: April 6, 2021
Published: May 19, 2021
https://doi.org/10.1021/acs.orglett.1c01162
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4219−4223
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product. In this reaction, triethylamine plays a crucial role as a
ligand in accelerating the initial copper-catalyzed ring-opening
reaction to produce these key intermediates in higher
concentrations, enabling the facile second self-cyclization
reaction to produce pyridines. We were intrigued by these in
situ-generated skipped yne−imine and yne−enamine inter-
mediates in this reaction and speculated that if the second self-
cyclization reaction between these two tautomers could be
interrupted, it might be possible to trap these intermediates
with a suitable third component and thereby develop an
unprecedented interrupted azirine−alkyne ring-expansion
strategy for the synthesis of useful N-heterocycles other than
pyrroles.
On this basis and inspired by the alkyne oxygenation
reactions,8 we envisaged that an intermolecular oxygenation of
the alkyne unit of these tautomers and intramolecular
cyclization cascade strategy could facilitate the synthesis of
valued pyrrolone compounds (Figure 1c). Notably, this would
represent a first example of a ring-expansion reaction of
azirines with alkynes for the synthesis of pyrrolone structures.
However, in order to accomplish this goal, we would have to
solve the challenging chemoselectivity issue of achieving the
complete azirine−alkyne ring-opening reaction for the
generation of the skipped yne−imine and yne-enamine
intermediates while fully suppressing the self-cyclization
reaction between these intermediates. In this report, we
describe how we were able to address these challenges to
develop a new three-component interrupted ring-expansion
reaction of azirines with alkynes and molecular oxygen for the
synthesis of highly valued 3-pyrrolones enabled by copper
catalysis.
We started our study by investigating 3-phenyl-2H-azirine
and phenylacetylene (2a) as model substrates with molecular
oxygen as the third component and acetonitrile as the solvent
(Table S1 in the Supporting Information). When triethylamine
was tested under these modified oxidative conditions, in
addition to the alkyne homocoupling product, alkynylated
pyridine was isolated as the major product (Table S1, entry 1).
In contrast, when inorganic bases such as Na2CO3, K2CO3,
Cs2CO3, and NaOH were employed, as expected, the pyridine
product was completely suppressed, but the desired oxy-
genated product was not observed (Table S1, entries 2−5). In
all of these cases, the starting azirine was completely
consumed, and homocoupling products were isolated.
Reactions performed at a low temperature of 5 °C resulted
only in poor conversion of the azirine, and the desired product
was not observed (Table S1, entry 6). The same result was
observed when less base was used (Table S1, entry 7).
We next moved on to investigate the more hindered diaryl
azirine 1a under these modified oxidative conditions (Table 1).
When TEA was tested as the base, 1a underwent complete
conversion and delivered the desired oxygenated product, 3-
pyrrolone 3a, in 84% yield (Table 1, entry 1). Consistent with
our mechanistic hypothesis, the presence of an additional
aromatic ring makes the self-cyclization reactions between the
skipped yne−imine and yne−enamine intermediates very
difficult and allows for the second radical oxygenation step
to form the desired pyrrolone products. The structure of 3a
was determined by NMR spectroscopic analysis and X-ray
crystallography of its derivative 3s (Figure S1), which
confirmed that oxygen is incorporated into the product.
Lower yields were observed when DIPEA and DBU were used
instead of TEA (Table 1, entries 2 and 3). Especially with
Table 1. Ring Expansion Reaction of Diaryl-Substituted
Azirine
a
b
b
entry
base
solvent
ACN
ACN
yield of 3a (%) yield of 1,3-diyne (%)
1
2
3
4
5
6
7
8
TEA
DIPEA
DBU
TEA
TEA
TEA
TEA
TEA
TEA
84
45
7
10
53
45
12
55
58
6
15
60
38
31
15
18
4
ACN
toluene
1,4-dioxane
DCE
DCM
DMSO
ACN
c
9
12
a
Conditions: 1a (0.52 mmol), 2a (0.6 mmol), base (1.04 mmol), CuI
b
(0.05 mmol), ACN (3 mL), O2 atmosphere, 25 °C, 24 h. Isolated
yields. The reaction was performed under air.
c
DBU, the alkyne homocoupling product was predominant and
was obtained in 60% yield. A quick survey of solvents revealed
that ACN is best for this transformation (Table 1, entries 4−
8). When the reaction was performed under open air
atmosphere, product 3a was obtained in a lower yield of
58% (entry 9). Other copper(I) sources like CuOAc, CuBr,
and CuCl were also tested under the present reaction
conditions. Surprisingly, all of the above-mentioned copper(I)
salts failed to catalyze the reaction (Table S3, entries 1−3). To
check the role of the anion associated with copper, reactions
were performed with a stoichiometric amount of KI as an
additive, but no improvement was noticed (Table S3, entries
4−6). Also, when Cu(II) salts such as Cu(OAc)2 and CuCl2
were tested in place of CuI, no conversion of the azirine to the
desired product was observed (Table S3, entries 7 and 8).
Thus, the optimal conditions were found to be the stirring of
1a with 2a (1.1 equiv), CuI (0.1 equiv), and TEA (2 equiv)
with an O2 balloon in ACN at room temperature (25 °C) for
24 h (Table 1, entry 1).
With the optimized conditions in hand, initially the scope of
the reaction was explored with a variety of 2,3-diaryl azirines
and the corresponding pyrrolone products 3a−g were isolated
in 56−85% yield (Figure 2). Azirines with phenyl rings
containing halogen substituents generally gave better yields
(3d−g, 80−83%). However, with the dimethyl-substituted
phenyl ring, a significant drop in yield was observed (3c, 56%).
Notably, when an azirine with a strong electron-donating
group, namely, 3-(4-methoxyphenyl)-2-phenyl-2H-azirine, was
employed with the optimized reaction conditions, the reaction
did not proceed, and more than 80% of the starting azirine was
recovered after the reaction (Scheme S7). These results
indicate that the electronics of the azirine aryl rings plays a
huge role in the reaction outcome. Next, aryl alkynes having
various substituents on the aromatic ring, including electron-
withdrawing and electron-donating functional groups, were
tested in this copper-catalyzed reaction cascade. The reaction
efficiency was not very sensitive to the electronic properties of
the substituents, and the corresponding 3-pyrrolones were
formed in good to high yields. Notably, substrates with a bulky
tert-butyl group or n-pentyl substituent were also well-tolerated
and afforded the corresponding products 3j and 3l in high
yields (84% and 82%, respectively). Aryl alkynes with fluorine
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Figure 2. Substrate Scope
substituents also reacted smoothly to give the desired
pyrrolone products (3n−p, 79−81%). Also, when a
thiophene-derived alkyne was used, the pyrrole product 3q
was isolated in 80% yield. Next, the scope of the reaction with
respect to aliphatic alkynes was also examined, and these
substrates were well-tolerated in the reactions, giving products
3r−x. It is worth mentioning that an ether-substituted aliphatic
alkyne was also found to work under our oxidative conditions
to produce the desired pyrrolone product 3r. In addition to
straight-chain aliphatic alkynes, our methodology was also
extended to comparatively sterically hindered cycloalkyl
alkynes. Three cycloalkyl alkynes (cyclopropyl-, cyclopentyl-,
and cyclohexylacetylene) were tested under our reaction
conditions and gave the corresponding cycloalkyl-substituted
3-pyrrolones 3v, 3w, and 3x in 60−69% isolated yield.
Furthermore, we also synthesized 3y, the bismethylated
derivative of 3a (Figure 2 and Scheme S6). To our delight,
this copper-catalyzed protocol can be scaled up to give a good
yield of pyrrolone 3a, as 1 g of 1a was smoothly converted to
1.35 g of 3a in 80% yield (Scheme S3). While the present
method has been shown to be effective for the synthesis of
pyrrolones from 2,3-diaryl azirines, it was also of interest to
study the reactivity of 2-methyl-3-phenyl-2H-azirine (Scheme
S8). Unfortunately, the reaction was very vigorous, and
multiple spots were overserved in the TLC. Attempts to
optimize the reaction and to isolate the spots were
unsuccessful.
Next, to confirm the structure of the regioisomer obtained in
our reactions, 2D NMR experiments were performed on
derivative 3c. The observation of NOE cross-peaks for the N−
H proton and methyl protons of the dimethylaryl ring (Figure
S2) confirmed that the obtained structure was regioisomer 3c
and that the azirine ring opening proceeds via the C−N single
bond (Figure 3). Furthermore, the observation of different
Figure 3. Structure identification.
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Figure 4. Proposed mechanism.
NMR signatures for products 3d and 3g confirmed that the
present copper-catalyzed cascade synthesis of pyrrolones is
strictly regioselective and that the proposed regioisomers are
formed.
which spontaneously undergoes cyclization and elimination of
copper and base to yield product 3.
In summary, we have developed a new copper-catalyzed
three-component relay alkynylation/oxygenation strategy to
deliver interesting 3-pyrrolone structures from azirines,
alkynes, and molecular oxygen. Overall, this report demon-
strates that by the use of sterically hindered diaryl azirines and
a Cu/TEA catalyst system, self-cyclization between the in situ-
generated skipped yne−imine and yne−enamine intermediates
can be completely suppressed, allowing them to be used for
further reactions. Investigations in this direction are currently
underway in our laboratory.
To gain more mechanistic insight, a series of control
experiments were performed, and the results are shown in
(Scheme S4). When the reaction was performed in the
presence of the radical quencher 2,2,6,6-tetramethylpiperidin-
1-oxyl (TEMPO), the desired product 3a was obtained in only
trace amounts, indicating a radical pathway for the reaction
(Scheme S4a). Notably, the reaction conducted with dry ACN
in the presence of molecular sieves proceeded with the same
efficiency, suggesting that residual water has no significant role
in the present reaction (Scheme S4b). On the other hand, no
reaction took place under an argon atmosphere (Scheme S4c).
Also, other oxygenation catalysts like potassium persulfate and
potassium peroxymonosulfate failed to produce the desired
products under argon atmosphere conditions (Scheme S4d).
These results suggest that the oxygen atoms in the products are
from molecular oxygen and not from trace amounts of water
present in the acetonitrile. Furthermore, to confirm the role of
the amine group of the yne−enamine intermediate in the
radical oxygenation, other simple alkynes such as phenyl-
acetylene and diphenylacetylene were subjected to the present
reaction conditions. However, oxygenated products were not
formed in these cases (Scheme S5). Therefore, the amine
group must have played a crucial role in the second alkyne
oxygenation by chelating the copper catalyst and directing
molecular oxygen to the nearby alkyne functionality.
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01162.
Experimental procedures and characterization of all new
1
products, including H and 13C NMR spectra (PDF)
Accession Codes
CCDC 2000575 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, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Based on the results obtained and literature precedents, a
plausible catalytic cycle for the present copper-catalyzed three-
component synthesis of 3-pyrrolones is illustrated in Figure 4.
Initially, alkynylcopper intermediate I is generated from the
alkyne in the presence of CuI and the base. The ring-opening
reaction of intermediate I with azirine 1 via the C−N single
bond gives the alkynylation product, yne−enamine copper
intermediate II. This intermediate can proceed through either
of two pathways to form a four-membered dioxetene
intermediate V. Path A includes the formation of copper-
containing six-membered alkene radical intermediate III′,
which would then react with molecular oxygen to generate
intermediate IV′ and then V; path B includes reaction of the
copper center with molecular oxygen, which is then transferred
to the alkyne part to generate V via copper proxy radical
intermediates III and IV. Finally, intermediate V undergoes a
ring-opening rearrangement to form diketone intermediate VI,
Kayambu Namitharan − Organic Synthesis and Catalysis
Laboratory, SRM Research Institute and Department of
Chemistry, SRMIST, Kattankulathur 603 203, Tamil Nadu,
India; Amity Institute of Click Chemistry Research and
Studies, Amity University, Noida 201 301, Uttar Pradesh,
India; orcid.org/0000-0002-4283-1895;
Email: knamitharan@amity.edu
Authors
Chandragiri Sujatha − Organic Synthesis and Catalysis
Laboratory, SRM Research Institute and Department of
Chemistry, SRMIST, Kattankulathur 603 203, Tamil Nadu,
India
Madhu Nallagangula − Organic Synthesis and Catalysis
Laboratory, SRM Research Institute and Department of
Chemistry, SRMIST, Kattankulathur 603 203, Tamil Nadu,
India
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge DST for financial support via the
DST-INSPIRE Faculty Scheme (DST/INSPIRE/04/2015/
001003) and the DST-SERB Research Scientist Scheme
(SB/SRS/2020-21/57/CS). C.S. thanks CSIR for the Senior
Research Fellowship [File Number 09/1045(0033) 2k19
EMR-I].The authors thank SRM Institute of Science and
Technology for providing NMR and laboratory facilities. We
also extend our thanks to Prof. Kesavan of IIISM, SRMIST, for
2D NMR studies.
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