Palladium-Catalyzed Formal (3 + 2) Cycloaddition Reactions of 2-Nitro-1,3-enynes with Vinylaziridines, -epoxides, and -cyclopropanes

Article abstract of DOI:10.1021/acs.orglett.1c01364

A two-step Pd-catalyzed (3 + 2) cycloaddition/HNO2 elimination reaction sequence has been developed to give novel cyclic 1,3-dien-5-yne systems from Pd-stabilized zwitterionic 1,3-dipoles and 2-nitro-1,3-enyne substrates. The process is highly atom-efficient and tolerates the reaction of 2-vinyloxirane, 1-tosyl-2-vinylaziridine, and diethyl 2-vinylcyclopropane-1,1-dicarboxylate derived 1,3-dipoles with a variety of 2-nitro-1,3-enyne substrates. The stereochemistry of the intermediate (3 + 2) cycloadducts was determined by single crystal X-ray analysis. Furthermore, a selective kinetic elimination of the cycloadduct with an antiperiplanar relationship between the NO2 group and the participating hydrogen was demonstrated, allowing for efficient isolation of a single diastereoisomer of the cycloadduct.

Full text of DOI:10.1021/acs.orglett.1c01364

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Letter
Palladium-Catalyzed Formal (3 + 2) Cycloaddition Reactions of
2‑Nitro-1,3-enynes with Vinylaziridines, -epoxides, and
-cyclopropanes
Melanie A. Drew, Andrew J. Tague, Christopher Richardson, Stephen G. Pyne,*
and Christopher J. T. Hyland*
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ABSTRACT: A two-step Pd-catalyzed (3 + 2) cycloaddition/HNO2 elimination reaction sequence has been developed to give
novel cyclic 1,3-dien-5-yne systems from Pd-stabilized zwitterionic 1,3-dipoles and 2-nitro-1,3-enyne substrates. The process is
highly atom-efficient and tolerates the reaction of 2-vinyloxirane, 1-tosyl-2-vinylaziridine, and diethyl 2-vinylcyclopropane-1,1-
dicarboxylate derived 1,3-dipoles with a variety of 2-nitro-1,3-enyne substrates. The stereochemistry of the intermediate (3 + 2)
cycloadducts was determined by single crystal X-ray analysis. Furthermore, a selective kinetic elimination of the cycloadduct with an
antiperiplanar relationship between the NO2 group and the participating hydrogen was demonstrated, allowing for efficient isolation
of a single diastereoisomer of the cycloadduct.
coworkers subsequently developed an enantioselective (3 +
2) cycloaddition of vinylcyclopropanes with nitroalkenes.22
Despite the high enantioselectivity observed, several substrates
again displayed low diastereoselectivity. The cycloaddition of
2-vinyl-2-methyloxirane to nitroalkenes has provided heavily
substituted tetrahydrofurans with high dr but only moderate
enantiomeric excess (ee).5 It was also found that the methyl
substituent on the epoxide was essential for a diastereoselective
reaction. To the best of our knowledge, however, there have
been no reports of vinylaziridines undergoing (3 + 2)
cycloaddition reactions with nitroalkenes.
he use of palladium-stabilized zwitterionic dipoles in (3 +
T2) cycloaddition reactions constitutes a potent method-
ology for the construction of five-membered ring systems.1
The three-membered dipole precursors vinylaziridines, vinyl-
epoxides, and vinylcyclopropanes have proven to be very
versatile reactants that undergo stepwise formal cycloaddition
to activated alkenes,2−7 activated indoles,8−17 benzofurans,17
isocyanates,18 carbodiimides,19 or aldehydes20 to give the
corresponding cycloadducts. Despite recent activity using
nitro-indoles and nitro-benzofurans in cycloadditions with
Pd-stabilized zwitterionic dipoles A derived from these three-
membered precursors, simple nitroalkenes 2 have yet to be
fully explored (Scheme 1a). This is despite the ready
availability of these systems and their ability to undergo
reductions to amines (4).
Related to nitroalkenes, 2-nitro-1,3-enyne substrates 5 are a
valuable class of electron-deficient unsaturated reactants that
have proven to be excellent Michael acceptors.23−34 To date,
Received: April 21, 2021
Published: June 3, 2021
Stoltz and coworkers reported the use of a Pd-catalyzed (3 +
2) cycloaddition between a β-nitrostyrene and a vinyl-
cyclopropane to construct the cyclopentane ring of Melodinus
alkaloids.21 While inconsequential to the target, the key
reaction proceeded to give an inseparable mixture of the
cycloadducts in low diastereomeric ratio (dr). Liu and
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© 2021 American Chemical Society
Org. Lett. 2021, 23, 4635−4639
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Scheme 1. (a) Known Pd-Catalyzed Cycloadditions to
Nitroalkenes and (b) This Work on Pd-Catalyzed
Cycloadditions to 2-Nitro-1,3-enyne Substrates Followed by
HNO2 Elimination
Scheme 2. Overview of (3 + 2) Cycloaddition−Elimination
Sequence between Vinylaziridine 1a and Nitroenyne 5a
a
Cycloadduct 6a′ had a purity of ∼93% (33% yield) due to dba ligand
contamination. The dba ligand was removed by reduction with
NaBH4 followed by chromatography; therefore, the yield is reported
over two steps.
they have not been shown to undergo (3 + 2) cycloaddition
reactions with Pd-stabilized zwitterionic dipoles. It was
speculated that they could act as partners in Pd-catalyzed (3
+ 2) cycloadditions with vinylaziridines, vinylepoxides, and
vinylcyclopropanes, given that these processes proceed via an
initial Michael-type attack by a Pd-stabilized zwitterionic
dipole. One benefit of this approach is that the resulting
cycloadduct 6 should be very amenable to elimination of
HNO2 to form conjugated diene-yne 7 by virtue of the
additional alkyne substituent vs the nitroalkene cycloadducts 3
(Scheme 1). Interestingly, while HNO2 eliminations have been
explored by ourselves and others in azomethine ylide
cycloadditions to nitroaromatics,35−38 this approach has not
been used with the cycloadducts derived from Pd-catalyzed (3
+ 2) cycloadditions with vinylaziridines, -epoxides, or -cyclo-
propanes. In the current case, such an approach negates the
issue of diastereoselectivity, which is problematic for some (3 +
2) cycloaddition reactions to nitroalkenes and provides routes
to synthetically valuable 1,3-dien-5-yne systems.39−41 Despite
their synthetic potential for the preparation of privileged
heterocyclic moieties for medicinal chemistry applications
(e.g., isoindolines/isoindoles42 and isobenzofurans), the syn-
thesis of the requisite 1,3-dien-5-yne precursors is not trivial.
Herein, we report the two-step Pd-catalyzed (3 + 2)
cycloaddition/HNO2 elimination reaction sequence to give
novel cyclic 1,3-dien-5-yne systems from Pd-stabilized
zwitterionic 1,3-dipoles and 2-nitro-1,3-enyne substrates. The
process is highly atom-efficient and tolerates the reactions of 2-
vinyloxirane, 1-tosyl-2-vinylaziridine, and diethyl 2-vinylcyclo-
propane-1,1-dicarboxylate. Furthermore, a selective E2 elimi-
nation of one diastereoisomer of the vinylaziridine-derived
cycloadduct was demonstrated.
by running the cycloaddition reaction, followed by addition of
the sterically hindered amine base DBU and heating to give the
1,3-dien-5-yne 7a in an excellent two-step yield of 80%
(Scheme 2).
Replacing the DBU with K2CO3 in this one-pot process
allowed for a selective elimination of cycloadduct 6a′ to
provide diastereomerically pure 6a and the elimination product
7a. Presumably, 6a′ underwent more rapid E2 elimination of
HNO2 in the presence of K2CO3 due to the favorable
antiperiplanar relationship of the relevant hydrogen and nitro
groups. With the optimized set of conditions in hand, efforts
were directed toward investigating the versatility of the one-pot
cycloaddition/HNO2 elimination reaction (Table 1). Pleas-
ingly, when reacted with 1-tosyl-2-vinylaziridine 1a (Method
A), nitroenynes with either an electron-rich or electron-poor
aryl group at R1 successfully underwent reaction to give the
corresponding products 7b and 7c in 68% and 83% yields,
respectively. The presence of an aromatic thien-2-yl group in
the R1 position and an aliphatic hexyl chain in the R2 position
also gave the desired 1,3-dien-5-yne 7d in moderate yield. A
TBS group in the R2 position gave the corresponding 1,3-dien-
5-yne 7e in good yield; however, use of the 2-nitro-1,3-enyne
substrate 5f with a terminal alkyne (R2 = H) in the reaction
failed to produce the corresponding 1,3-dien-5-yne (7f).
Various attempts to synthesize an alkylnitroenyne (i.e., R1 =
alkyl) substrate from the corresponding bromonitroalkene for
further reaction scope investigation proved unsuccessful. As far
as we know, no examples of any such alkylnitroenynes exist in
the literature. Furthermore, Ganesh and Namboothiri43
reported substrate decomposition when attempting to
synthesize a similar alkylnitroenyne (R1 = isobutyl).
Our starting investigations involved the reaction of 1-tosyl-2-
vinylaziridine 1a (1.0 equiv) with the NO2-activated enyne 5a
under slightly modified conditions from those previously
described by Hyland and coworkers (see Supporting
Information).8 These Pd-catalyzed conditions gave the 3-
nitropyrrolidine (3 + 2) cycloadducts as a 1:1 mixture of two
diastereomers (6a/6a′) (Scheme 2). Pleasingly, the two
diastereoisomers could be separated by chromatography, and
the relative stereochemistry was determined unambiguously by
X-ray crystallography (Supporting Information). Furthermore,
a one-pot cycloaddition−elimination reaction could be realized
The Pd-catalyzed (3 + 2) cycloaddition/HNO2 elimination
reaction sequence was also successfully performed with
vinylepoxide 1b. Method B (Table 1) was used for these
reactions as the epoxide was highly volatile, and utilizing the
nitroenyne as the limiting reagent allowed for facile reaction
monitoring. As with the vinylaziridine substrate 1a, reactions
with the vinylepoxide 1b tolerated a phenyl ring or an electron-
donating 2-MeO-phenyl ring in the R1 position, giving the
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Table 1. Reactions of Nitroenynes with 1-Tosyl-2-
vinylaziridine (1a) and 2-Vinyloxirane (1b) Using Method
A or B
Scheme 3. Reactions of Nitroenynes with Diethyl 2-
Vinylcyclopropane-1,1-dicarboxylate (1c)
a
Reaction was performed sequentially in one pot, yield is reported
b
over two steps. The (3 + 2) cycloaddition intermediate 6/6′ was
isolated by silica gel chromatography to remove unreacted nitroenyne,
catalyst and dba ligand prior to NaH-promoted HNO2 elimination;
therefore, the yield is reported directly from the purified cycloadduct
c
(6/6′). Unreacted starting material was recovered as a single
d
diastereomer (6m) in 36% yield. Reaction was heated for 6 h.
Further product (7n), isomerized product 8, and unreacted starting
material (single diastereomer, 6n) were also recovered as a mixture
(∼1:2:2 ratio, respectively, 40%).
a
The (3 + 2) cycloaddition intermediate 6/6′ was isolated to remove
Scheme 4. Chemical Transformations of Cycloadducts
b
dba ligand; therefore, the yield is reported for two steps. 1,3-Dien-5-
yne 7i had a purity of ∼89% (87% yield) due to dba ligand
contamination. The dba ligand was removed by reduction with
NaBH4; therefore, the yield is reported for two steps.
corresponding 1,3-dien-5-ynes 7g and 7i in 74% and 52%
yields, respectively. A larger 1 mmol scale reaction to produce
7g was also carried out and gave the product in comparable
yield (76%). However, having a para-chloro group on the aryl
ring in the R1 position resulted in a low yield of 1,3-dien-5-yne
7h due to incomplete cycloaddition. Reaction of the vinyl
epoxide 1b with a nitroenyne bearing a thien-2-yl ring in the R1
position and a hexyl chain in the R2 position gave 7j in 68%
yield. The nitroenyne containing a TBS group in the R2
position of the triple bond (5e) reacted smoothly with the
vinyl epoxide to give compound 7k (77%). However, reaction
of vinylepoxide 1b with the terminal nitroenyne 5f (R2 = H)
did not produce any desired product, paralleling the result for
the vinylaziridine substrate 1a.
While the cycloaddition reaction between the activated
vinylcyclopropane substrate 1c and nitroenynes 5 proceeded
efficiently, the DBU-promoted elimination was substantially
slower for the less reactive diastereoisomer 6 (requiring days to
effect complete elimination). Furthermore, the DBU-promoted
HNO2 elimination conditions resulted in base-catalyzed
isomerization of the intended 1,3-dien-5-yne product (7) to
the conjugated exocyclic alkene (e.g., compound 8). Therefore,
the base-promoted HNO2 elimination reaction conditions
were reoptimized for these carbocyclic analogues. The
intermediate (3 + 2) cycloadducts were purified by silica gel
column chromatography prior to NaH (1.2 equiv) promoted
HNO2 elimination in DMF at 75 °C for 3 h; this methodology
gave compounds 7m and 7n in 55% and 28% yields,
respectively (Scheme 3).
50% yield (Scheme 4a). A nitration reaction using conditions
reported by Maity and coworkers successfully produced
product (E)-11 in 81% yield (Scheme 4b).45 An X-ray crystal
structure of (E)-11 was obtained, which unambiguously
confirmed the structure (Supporting Information).
A cross-metathesis reaction was also successful between 1,3-
dien-5-yne 7a and allyltrimethylsilane, providing the desired
Chemical transformations were also performed with the 1,3-
dien-5-yne 7a, compounds 6n/6n′, and compound 8, as shown
in Scheme 4. Using a literature procedure reported by Werner
and Sigman,44 7a was reacted with the diazonium salt 9 under
Heck-type conditions to obtain the desired product (E)-10 in
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Authors
product 12 in 43% yield (Scheme 4c). The 1,3-dien-5-yne 8
was found to undergo an interesting base-promoted cyclo-
aromatization reaction when heated in a microwave reactor at
150 °C with DBU,46 presumably via the allene intermediate
14, to give the tricyclic benzothiophene compound 13 in 67%
yield (Scheme 4d). Compound 13 was also obtained directly
from the diastereoisomeric mixture of 6n/6n′ in 57% yield
under the same basic reaction conditions.
Melanie A. Drew − School of Chemistry and Molecular
Bioscience, Molecular Horizons Research Institute, University
of Wollongong, Wollongong 2522, Australia
Andrew J. Tague − School of Chemistry and Molecular
Bioscience, Molecular Horizons Research Institute, University
of Wollongong, Wollongong 2522, Australia; orcid.org/
0000-0003-0561-4629
In conclusion, a novel methodology for the synthesis of
heterocyclic and carbocyclic 1,3-dien-5-yne systems was
developed and investigated. Pd-catalyzed (3 + 2) cycloaddition
of vinylaziridine, -epoxide and -cyclopropane-derived 1,3-
dipoles with NO2-activated enynes allows for construction of
the target cyclic scaffold in excellent yields. This is the first use
of 2-nitro-1,3-enyne substrates as dipolarophiles for (3 + 2)
cycloaddition reactions with Pd-stabilized zwitterionic 1,3-
dipoles. The resulting cycloadducts undergo facile base-
promoted HNO2 elimination in a one-pot reaction to yield
complex cyclic 1,3-dien-5-ynes in a short synthetic sequence.
These products were shown to be amenable to further
synthetic modifications, as the pendant vinyl and alkyne
handles serve as easily manipulated functionalities. Further
investigation into cycloaddition reactions of 2-nitro-1,3-enyne
substrates, including stereoselective variants, is underway in
our laboratory.
Christopher Richardson − School of Chemistry and
Molecular Bioscience, Molecular Horizons Research Institute,
University of Wollongong, Wollongong 2522, Australia;
orcid.org/0000-0002-5804-6322
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01364
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors acknowledge ARC Discovery Grant
DP180101332 for funding of this research.
■
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sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01364.
General synthetic information (S2); preparation of
precursor materials (S3), synthesis and characterization
of all novel compounds (S8); postsynthetic chemical
1
transformations (S17); H and 13C NMR spectra of all
novel compounds (S20); X-ray crystallography struc-
tures and data tables for compounds 6a, 6a′, and 11
(S43) (PDF)
FAIR data, including the primary NMR FID files, for
compounds 5e, 5f, 6a, 6a′, 6m/6m′, 6n/6n′, 7a−e, 7g−
k, 7m, 7n, 8, and 9−13 (ZIP)
Accession Codes
CCDC 2073395−2073397 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
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.
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AUTHOR INFORMATION
■
Corresponding Authors
Christopher J. T. Hyland − School of Chemistry and
Molecular Bioscience, Molecular Horizons Research Institute,
University of Wollongong, Wollongong 2522, Australia;
orcid.org/0000-0002-9963-5924;
Email: Chris_Hyland@uow.edu.au
Stephen G. Pyne − School of Chemistry and Molecular
Bioscience, Molecular Horizons Research Institute, University
of Wollongong, Wollongong 2522, Australia; orcid.org/
0000-0003-0462-0277; Email: spyne@uow.edu.au
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