Synergistic Pd(0)/Rh(II) Dual Catalytic [6 + 3] Dipolar Cycloaddition for the Synthesis of Monocyclic Nine-Membered N,O-Heterocycles and Their Alder-ene Rearrangement to Fused Bicyclic Compounds

Article abstract of DOI:10.1021/acs.orglett.1c01135

The catalytic construction of a monocyclic medium-sized N,O-heterocyclic ring represents a formidable challenge in organic synthesis. Herein we report the synergistic palladium(0)/rhodium(II) dual catalytic cycloaddition of vinylpropylene carbonates with N-sulfonyl-1,2,3-triazoles to afford monocyclic nine-membered N,O-heterocycles. The catalytically generated 1,6-dipole-equivalent zwitterionic π-allyl palladium(II) complex and the 1,3-dipole-equivalent α-imino rhodium(II) carbenoid intermediate react with each other in a formal [6 + 3] dipolar cycloaddition to furnish nine-membered oxazonines, which can be transformed into cis-fused [4.3.0] bicyclic compounds via a transannular Alder-ene rearrangement. The tandem one-pot cycloaddition/Alder-ene rearrangement sequence is also possible.

Full text of DOI:10.1021/acs.orglett.1c01135

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Letter
Synergistic Pd(0)/Rh(II) Dual Catalytic [6 + 3] Dipolar Cycloaddition
for the Synthesis of Monocyclic Nine-Membered N,O-Heterocycles
and Their Alder-ene Rearrangement to Fused Bicyclic Compounds
Kyu Ree Lee,† Subin Ahn,† and Sang-gi Lee*
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ABSTRACT: The catalytic construction of a monocyclic medium-
sized N,O-heterocyclic ring represents a formidable challenge in
organic synthesis. Herein we report the synergistic palladium(0)/
rhodium(II) dual catalytic cycloaddition of vinylpropylene carbo-
nates with N-sulfonyl-1,2,3-triazoles to afford monocyclic nine-
membered N,O-heterocycles. The catalytically generated 1,6-dipole-
equivalent zwitterionic π-allyl palladium(II) complex and the 1,3-
dipole-equivalent α-imino rhodium(II) carbenoid intermediate
react with each other in a formal [6 + 3] dipolar cycloaddition to furnish nine-membered oxazonines, which can be transformed
into cis-fused [4.3.0] bicyclic compounds via a transannular Alder-ene rearrangement. The tandem one-pot cycloaddition/Alder-ene
rearrangement sequence is also possible.
with dipolarophiles such as cyclic azadienes to afford
edium-sized heterocyclic moieties are commonly found
1
Min many natural products and bioactive compounds. benzofuran-fused nine-membered N,O-heterocycles (eq 1,
Scheme 1A).6a,b
However, due to their limited synthetic accessibility,2 only a
few particular eight- and nine-membered N,O-heterocyclic
molecules have been studied for therapeutic applications
(Figure 1).3 Hence, the development of an effective method
for the synthesis of medium-sized N,O-heterocycles is highly
desired.
Shibata and co-workers, meanwhile, have developed the
Pd(0)-catalyzed double decarboxylative annulation between
VECs and benzocarbamates to afford nine-membered N,O-
heterocyclic products (eq 2, Scheme 1A).6d−h However, most
of these reactions are limited to the production of aromatic
ring-fused heterocyclic products. Due to the limited availability
of dipolarophiles, the dipolar cycloaddition of zwitterionic π-
allyl Pd(II)-intermediates to construct monocyclic medium-
sized N,O-heterocycles have rarely been reported.7
We recently demonstrated for the first time the redox-
compatibility between Pd(0) and Rh(II) catalysts, which can
be utilized as a lynchpin to develop a synergistic Pd(0)/Rh(II)
dual catalytic coupling between allylic substrates and N-
sulfonyl-1,2,3-triazoles.8 During our ongoing studies on dual-
transition-metal catalysis,9 we envisioned that the monocyclic
medium-sized N,O-heterocyclic moieties could be accessed by
synergistic Pd(0)/Rh(II) dual catalysis. Herein we report a
novel Pd(0)/Rh(II) dual catalytic strategy to enable [6 + 3]
cycloadditions between vinylpropylene carbonates (VPCs) 110
and N-sulfonyl-1,2,3-triazoles 211 to furnish the monocyclic
1,4-oxazonines 3. As depicted in Scheme 1B, the catalytically
Figure 1. Examples of bioactive medium-sized N,O-heterocycles.
Dipolar cycloaddition reactions are considered key synthetic
strategies to access cyclic molecules.4 In recent years, the
zwitterionic alkoxy π-allyl Pd(II)-intermediate I, which was
generated from vinylethylene carbonates (VECs),5 was utilized
as a five-atom dipole synthon to construct heterocyclic
skeletons.6 For example, Zhao and co-workers reported the
[5 + 4] dipolar cycloaddition reaction of Pd(II)-intermediate I
Received: April 2, 2021
Published: April 29, 2021
https://doi.org/10.1021/acs.orglett.1c01135
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3735−3740
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unprecedented transannular Alder-ene rearrangement12 to
afford the cis-fused [4.3.0] bicyclic compound 4.
Scheme 1. Catalytic Construction of Nine-Membered
Oxazonines
To demonstrate the feasibility of the dual catalytic
cycloaddition reaction, the VPC 1a and the N-tosylated
triazole 2a were chosen as the model substrates (Table 1; for
details on the optimization, see Table S1 in the Supporting
Information).13 We first explored the monocatalytic cyclo-
addition reaction between 1a and 2a using the Pd or Rh
catalyst alone, which as expected was found to be entirely
unreactive (entries 1 and 2, Table 1). To our delight, the [6 +
3] dipolar cycloaddition proceeded under PdCp(allyl)-L1/
Rh2esp2 dual catalytic conditions to afford the cycloadduct 3aa
in a modest yield (entry 3, Table 1). The reaction efficiency
was comparable when the rhodium catalyst was changed to
Rh2(OPiv)4 (entry 4, Table 1). Surprisingly, the reaction was
completely inhibited when Pd2dba3 was used as the palladium
catalyst (entry 5, Table 1). On the other hand, the reaction
efficacy was retained when the ligand L1 was replaced with L2
(compare entries 4 and 6, respectively, Table 1). The yield for
3aa increased further to 49% when PdCp(allyl)-L2/Rh2esp2
dual catalytic conditions were used (entry 7, Table 1), whereas
the reaction did not proceed at all when the sterically less
demanding ligand L3 was employed for the Pd catalyst (entry
8, Table 1). Careful monitoring of the reaction progress
suggested that the rate of the rhodium catalytic cycle was likely
faster than that of the palladium. Thus, simply exchanging the
equivalence of 1a and 2a (i.e., 1.5:1 to 1:1.5) dramatically
increased the yield of product of 3aa to 80% (entry 9, Table 1).
However, the reaction efficiency was decreased when the
amounts of the Pd and Rh catalysts were further increased,
resulting in 3aa in a 61% yield (entry 10, Table 1). The yield of
generated 1,6- and 1,3-dipole-equivalent intermediates, namely
the zwitterionic alkoxy π-allyl Pd(II) complex II and the α-
imino Rh(II) carbenoid III, respectively, undergo a [6 + 3]
dipolar cycloaddition to result in nine-membered N,O-
heterocyclic dienes 3, which could then further undergo an
a
Table 1. Optimization for the Synthesis of 1,4-Oxazonine 3aa
b
entry
1a (equiv)
2a (equiv)
[Pd] (mol %)
ligand (mol %)
L1 (10)
[Rh] (mol %)
3aa (%)
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
PdCp(allyl) (5.0)
NR
NR
21
23
ND
25
49
ND
80
61
70
Rh2esp2 (3.0)
Rh2esp2 (3.0)
Rh2(OPiv)4 (3.0)
Rh2(OPiv)4 (3.0)
Rh2(OPiv)4 (3.0)
Rh2esp2 (3.0)
Rh2esp2 (3.0)
Rh2esp2 (2.5)
Rh2esp2 (3.0)
Rh2esp2 (2.5)
Rh2esp2 (2.5)
Rh2esp2 (2.5)
Rh2esp2 (2.5)
PdCp(allyl) (5.0)
PdCp(allyl) (5.0)
Pd2dba3 (2.5)
L1 (10)
L1 (10)
L1 (10)
L2 (10)
L2 (10)
L3 (10)
L2 (10)
L2 (12)
L2 (8.0)
xantphos (5.5)
PPh3 (10)
dppf (5.5)
PdCp(allyl) (5.0)
PdCp(allyl) (5.0)
PdCp(allyl) (5.0)
PdCp(allyl) (5.0)
PdCp(allyl) (6.0)
PdCp(allyl) (4.0)
PdCp(allyl) (5.0)
PdCp(allyl) (5.0)
PdCp(allyl) (5.0)
9
10
11
12
13
14
ND
NR
NR
a
Reaction conditions are as follows: 0.2 mmol scale in toluene (1 mL, 0.2 M) at 60 °C. ND, product 3aa was not detected; NR, no reaction was
b
occurred and the starting materials were recovered. Isolated yield, Rh2esp2 = bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedipropionic acid)].
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a
3aa could not be improved further by varying Pd/Rh ratio
(entry 11, Table 1). The reactions with other types of
phosphine ligands, such as bidentate Xantphos, monodentate
PPh3, and ferrocene-type dppf, were not successful (entries
12−14, respectively, Table 1). Finally, we also explored the
dipolar cycloaddition reaction of 2-phenyl-2-vinyl oxetane 1a′,
which generated the same zwitterionic π-allyl Pd(II) complex
from VPC 1a with triazole 2a to result in 1,4-oxazonine 3aa in
a moderate yield of 61%. In addition, 4-phenylpyran and
seven-membered azepine were also formed as minor products.
It was reported that the Lewis acid-promoted ring expansion of
1a′ could afford 4-phenylpyran,14 while the ring fragmentation
of 1a′ to 1,3-diene15 followed by a [4 + 3] cycloaddition with
α-imino Rh(II) carbenoid afforded azepine16 (for details, see
Table S2 in the Supporting Information).
Table 2. Synthesis of Oxazonines 3
With the optimal reaction conditions in hand (entry 9, Table
1), we next explored the generality of this dual catalytic
reaction for synthesis of 1,4-oxazonines 3 (Table 2). The
cycloaddition reaction of various VPCs with the triazole 2a
were first explored. It was found that VPCs with electron-
donating groups, such as CH3 (1b and 1c) and CH3O groups
(1d), a phenyl group (1e), and electron-withdrawing halides
(1f-1i) and CF3 groups (1j) on the phenyl ring were all
tolerated to furnish the corresponding cycloadducts 3ba−3ja
in moderate to good yields (53%−81%). Although the yield
was not excellent, the Pd(0)/Rh(II) dual catalytic cyclo-
addition of sterically demanding 4-cyclohexyl-substituted VPC
1k could also undergo the desired transformation to yield the
corresponding cycloadduct 3ka. We next investigated the
reaction scope with respect to the triazole coupling partner.
The cycloaddition of VPC 1a with triazoles bearing an
electron-donating methyl group at the para- (2b) and meta-
positions (2c) afforded the corresponding oxazonines 3ab and
3ac in good yields, while sterically demanding ortho-tolyl-
substituted triazoles could not participate in the reaction.
The reactions of VPC 1a with triazole 2d−2i, which had
halogenated phenyl moieties, also proceeded to furnish
cycloadducts 3ad−3ai, respectively, in moderate to good
yields. Although the yield was low, the triazole 2j with an
electron-withdrawing para-trifluoromethylphenyl moiety also
smoothly reacted with 1a to afford the corresponding
cycloadduct 3aj, the structure of which was determined
unambiguously by X-ray analysis.17 Moreover, naphthyl- (2k)
and benzodioxole-substituted triazoles (2l) were also success-
fully incorporated into the cycloadducts 3ak and 3al,
respectively, in moderate yields. The heteroaromatic thio-
phenyl-substituted product 3am was also obtained, albeit in a
low yield. However, the reaction of the cyclohexenyl-
substituted triazole 2n was not effective, and the corresponding
adduct 3an was formed in a very low yield. Moreover, it was
found that the alkyl-substituted triazole 2o was unsuited for
participation in this transformation to form 3ao. The reaction
was successful when the sulfonyl moiety was changed from a
tosyl group to a benzenesulfonyl group (3ap). Different
substituents could easily be installed on the 1,4-oxazonine
products through the combination of the appropriate VPC and
triazole, which is exemplified by syntheses of 3hf and 3ek.
During our investigations, we observed that the cyclo-
addition reaction of 4-methyl-substituted VPCs 1l with triazole
2a afforded the five-membered tetrahydrofuran 5la in a 58%
yield after the in situ reduction of the imine group (Scheme
2).18
a
Reaction conditions are as follows: 1 (0.2 mmol) and 2 (0.3 mmol)
were reacted in toluene (1 mL, 0.2 M) at 60 °C until all VPCs were
b
consumed. The yield presented is the isolated yield. Used 0.4 mmol
2. The X-ray structure of 3aj shows a 50% thermal ellipsoid
probability.
c
This result indicated that the zwitterionic π-allyl Pd(II)
intermediate II acts as a four-atom dipole synthon, effecting a
[4 + 1] dipolar cycloaddition. We suggest that the selectivity
between the [6 + 3] and [4 + 1] modes of the dipolar
cycloaddition may be largely determined by the steric property
of the substituent R1. Thus, by using sterically less demanding
unsubstituted VPCs 1m (R1 = H, R3 = Ph) and 1n (R1 = H, R3
= nPr) in the Pd(0)/Rh(II) dual catalytic reaction, a [4 + 1]
dipolar cycloaddition was affected to furnish the corresponding
five-membered tetrahydrofurans 5ma in a 51% and 5na in a
76% yields. Interestingly, these reactions proceeded with
similar dr values (1:0.6). The structure and relative stereo-
chemistry of 5ma could be unambiguously determined by X-
ray crystallographic analysis.17
The transannular transformations of cyclic molecules
represent a powerful method to access complex polycyclic
compounds, rapidly enhancing the molecular diversity and
complexity.19 In the present work, the transannular Alder-ene
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On the basis of all these results, the plausible reaction
pathways for the synergistic Rh(II)/Pd(0) dual catalytic
cycloaddition of vinyl carbonates 1 and triazole 2 are depicted
in Scheme 4. First, the Pd(0) and Rh(II) catalysts selectively
Scheme 2. [4 + 1] Dipolar Cycloaddition for
Tetrahydrofurans 5
a
Scheme 4. Plausible Reaction Pathways for the Formation
of 3, 4, and 5
a
Reaction conditions are as follows: 1 (0.2 mmol) and 2a (0.3 mmol)
were reacted in toluene (1 mL, 0.2 M) at 60 °C for 1−2 h, then the
toluene was evaporated. To the mixture was added a solution of
NaBH3CN (0.24 mmol) in THF (4.0 mL, 0.05 M), and the reaction
mixture was stirred for additional 30 min. The yield presented is the
1
isolated yield, and the diastereomeric ratio was determined by H
NMR analysis. The X-ray structure of 5ma shows a 50% thermal
ellipsoid probability.
rearrangement of the nine-membered 1,4-oxazonine products
3 was investigated to afford the fused-bicyclic hexahydropyr-
anopyrroles 4 (Scheme 3). Thus, the isolated 1,4-oxazonine
Scheme 3. Tandem One-Pot Synthesis of
Hexahydropyranopyrroles 4 via an Alder-ene
Rearrangement
activate 1 and 2 to generate intermediates I and II,
respectively. The oxygen anion of intermediate I could
undergo a nucleophilic addition to the electrophilic carbenoid
carbon of intermediate II to generate the Pd/Rh-bimetalated
intermediate III. The following intramolecular cyclization
pathways (path a and path b) are dependent on the R1 and R
groups of the substituents. When R1 is an aryl group and R is
H, the cyclization occurs at the sterically less-hindered terminal
carbon to form nine-membered oxazonine 3. However,
tetrahydrofuran 5 was formed when R1 was a Me group and
R was H or when R1 was H and R was aryl and alkyl groups.
We initially anticipated that the retro-Aza−Claisen rearrange-
ment of 5 could afford oxazonine 3, but the rearrangement did
not occur with prolonged heating of 5. Finally, the nine-
membered oxazonines 3 could be transformed into the
corresponding cis-fused bicyclic compound 4 through the
transannular Alder-ene rearrangement.
a
In conclusion, we have established a novel synergistic
Pd(0)/Rh(II) dual catalytic [6 + 3] dipolar cycloaddition
reaction between vinylpropylene carbonates (VPCs) 1 and N-
sulfonyl-1,2,3-triazoles 2 to yield monocyclic nine-membered
1,4-oxazonines 3. The catalytically generated intermediates, an
alkoxy π-allyl Pd(II) complex and an α-imino Rh(II)
carbenoid, undergo [6 + 3] dipolar cycloaddition. We also
demonstrate the transannular Alder-ene rearrangement of the
1,4-oxazonines 3 to furnish cis-fused bicyclic hexahydropyr-
anopyrroles 4. Further studies and the development of
synergistic dual catalytic reactions are currently underway in
our laboratory.
a
Reaction conditions are as follows: 1 (0.2 mmol) and 2a (0.3 mmol)
were reacted in toluene (1 mL, 0.2 M) at 60 °C. After the reaction
was complete, the reaction mixture was heated at either 120 or 150
°C. The yield presented is the isolated yield. After the formation of
3, a catalytic amount of pyridinium p-toluenesulfonate (PPTS) (5.0
mol %) was added to the reaction mixture and heated at 120 °C. The
X-ray structure of 4aa shows a 50% thermal ellipsoid probability.
b
3aa was induced to undergo a thermal rearrangement reaction,
furnishing the cis-fused [4.3.0] bicyclic compound 4aa in a
quantitative yield. The structure of 4aa was confirmed by X-ray
analysis.17 In addition, the reaction could also be conducted in
a tandem one-pot manner to afford 4aa in a 70% overall yield,
starting from VPC 1a and triazole 2a. Various cis-fused bicyclic
hexahydropyranopyrrole derivatives 4 could be synthesized
through the tandem one-pot reaction of different VPCs 1 with
triazoles 2. It was also found that the addition of catalytic
amounts of PPTS could often accelerate the Alder-ene
rearrangement;20 thus, products 4ca, 4fa, and 4ha were
synthesized from the reactions at 120 °C.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01135.
Experimental procedures and detailed characterization
and spectroscopic data for all new compounds, including
1
copies of H, 19F, and 13C NMR spectra (PDF)
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Accession Codes
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CCDC 2042302 and 2053876−2053877 contain the supple-
mentary 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 Cambridge Crystallographic Data Centre, 12
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AUTHOR INFORMATION
Corresponding Author
■
Sang-gi Lee − Department of Chemistry and Nanoscience,
Ewha Womans University, 03760 Seoul, Korea;
orcid.org/0000-0003-2565-5233; Email: sanggi@
ewha.ac.kr
(4) (a) Cycloaddition Reactions in Organic Synthesis; Kobayashi, S.,
Jørgensen, K. A., Eds.; Wiley, 2001. (b) Lautens, M.; Klute, W.; Tam,
W. Transition Metal-Mediated Cycloaddition Reactions. Chem. Rev.
1996, 96, 49−92.
Authors
Kyu Ree Lee − Department of Chemistry and Nanoscience,
Ewha Womans University, 03760 Seoul, Korea
Subin Ahn − Department of Chemistry and Nanoscience,
Ewha Womans University, 03760 Seoul, Korea
(5) For selected reviews, see: (a) Allen, B. D. W.; Lakeland, C. P.;
Harrity, J. P. A. Utilizing Palladium-Stabilized Zwitterions for the
Construction of N-Heterocycles. Chem. - Eur. J. 2017, 23, 13830−
̀
Complete contact information is available at:
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̀
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Author Contributions
†K.R.L. and S.A. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was made possible by the support of the National
Research Foundation (NRF-2019R1A2B5B02069449). We
thank Dr. Y. Kim and Dr. U. B. Kim at Ewha Womans
University for X-ray analysis and the critical reading of this
manuscript.
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