Enantioselective Synthesis of Isoxazoline N-Oxides via Pd-Catalyzed Asymmetric Allylic Cycloaddition of Nitro-Containing Allylic Carbonates

Article abstract of DOI:10.1021/acs.orglett.9b03443

A useful method for the enantioselective preparation of isoxazoline N-oxides via Pd-catalyzed asymmetric allylic cycloaddition of nitro-containing allylic carbonates has been developed. By using palladium complex in situ generated from Pd₂(dba)₃·CHCl₃ and phosphoramidite L2 as a catalyst under mild conditions, the transformation afforded vinylated isoxazoline N-oxides in high yields with acceptably high enantioselectivities.

Full text of DOI:10.1021/acs.orglett.9b03443

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Enantioselective Synthesis of Isoxazoline N‑Oxides via Pd-Catalyzed
Asymmetric Allylic Cycloaddition of Nitro-Containing Allylic
Carbonates
Can Zhao,† Babar Hussain Shah,† Ijaz Khan,† Yuhe Kan,*,‡ and Yong Jian Zhang*,†
†School of Chemistry and Chemical Engineering, and Shanghai Key Laboratory of Electrical Insulation and Thermal Aging,
Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, PR China
‡Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials, School of Chemistry and Chemical Engineering, Huaiyin
Normal University, Huaian 223300, PR China
S
* Supporting Information
ABSTRACT: A useful method for the enantioselective
preparation of isoxazoline N-oxides via Pd-catalyzed asym-
metric allylic cycloaddition of nitro-containing allylic carbo-
nates has been developed. By using palladium complex in situ
generated from Pd2(dba)3·CHCl3 and phosphoramidite L2 as
a catalyst under mild conditions, the transformation afforded
vinylated isoxazoline N-oxides in high yields with acceptably high enantioselectivities.
Scheme 1. Synthetic Strategy for Pd-Catalyzed Asymmetric
Allylic Cycloaddition of Nitro-Containing Allylic
Carbonates
soxazoline N-oxides are versatile synthetic building blocks
for the synthesis of useful organic intermediates, biologically
I
active compounds, and natural products.1 In this context,
various synthetic approaches to this particular framework have
been reported.2 However, the catalytic asymmetric methods
for the enantioselective preparation of isoxazoline N-oxides
have been largely underdeveloped. Only a few examples have
been reported based on organocatalytic asymmetric conjugated
addition of carbon-nucleophiles with a leaving group to
nitroalkene derivatives followed by nucleophilic cyclization.3
Although this protocol could provide functionalized isoxazo-
line N-oxides with high enantioselectivities, the development
of new catalytic asymmetric approaches to this skeleton from
available precursors is highly desired.
Pd-catalyzed asymmetric allylic substitution is an important
method for the formation of carbon−carbon and carbon−
heteroatom bonds.4 Nitroalkanes as useful carbon-nucleophiles
have extensively been applied to the Pd-catalyzed allylic
substitution to produce versatile homoallylic nitro-com-
pounds.5 However, nitroalkanes as O-nucleophiles in this
transformation remain elusive. There has been only one
example reported by Trost in 1992 for Pd-catalyzed allylic
alkylation of cis-1,4-diacetoxycyclopent-2-ene with lithium
[(phenylsufonyl)methylene]nitronate through sequential C-
and O-nucleophilic attacks to afford isoxazoline N-oxide
(Scheme 1a).6 Most recently, we7 and others8 have developed
Pd-catalyzed asymmetric decarboxylative cycloaddition of
vinylethylene carbonates (VECs) with various unsaturated
electrophiles to construct functionalized heterocycles with high
efficiencies. Kleij and co-workers reported Pd-catalyzed allylic
substitution of VECs with various nucleophiles to produce
linear products with high E/Z-selective control.9 On the basis
of our continuous efforts to develop efficient methods for the
enantioselective construction of valuable heterocycles via Pd-
catalyzed allylic cycloaddition, we envisioned that nitro-
containing allylic carbonate 1a would be a useful substrate
for the intramolecular allylic cycloaddition to provide isoxazo-
line N-oxide 2a (Scheme 1b). We hypothesis that the nitro-
containing allylic carbonate 1a could react with palladium
complex to afford π-allylpalladium intermediate A. The α-
proton of nitro-group could be deprotonated by tert-butoxide
Received: September 29, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03443
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Letter
a
acting as a base to produce zwitterionic π-allylpalladium
intermediate B and its resonant form of nitronate intermediate
C. We reasoned that if the oxygen-anion of intermediate C
attacks as a nucleophile, the subsequent cycloaddition could be
feasible to form favored five-membered isoxazoline N-oxide 2a.
Nevertheless, if the carbanion of intermediate B works as a
nucleophile, vinylcyclopropane or cyclopentene would be
provided. Herein, we report a palladium-catalyzed asymmetric
cycloaddition of nitro-containing allylic carbonates, a useful
method that provides isoxazoline N-oxides with complete
chemo- and regioselectivities and good to high enantioselec-
tivities.
Table 1. Condition Optimizations
The nitro-containing allylic carbonates were synthesized by
allylic substitution of VECs with arylated nitromethanes using
Pd(PPh3)4 as a catalyst as a modified Kleij process,9e and
followed by Boc-formation (Scheme 2, see Supporting
Information for details).
b
c
entry
ligand
solvent
THF
THF
THF
THF
THF
THF
THF
THF
toluene
dioxane
CH2Cl2
ClCH2CH2Cl
C6H5Cl
yield (%)
ee (%)
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L6
26
53
48
21
11
21
10
11
26
70
85
95
89
85
74
46
80
78
9
15
−84
−28
−3
85
89
50
Scheme 2. Synthesis of Nitro-Containing Allylic Carbonates
(R)-BINAP
Trost ligand
9
L2
L2
L2
L2
L2
L2
L2
10
11
12
13
14
15
On the basis of our previous studies,7 we chose nitro-
containing allylic carbonate 1a (a mixture with E:Z = 3.5:1) as
a standard substrate to examine the cycloaddition reaction with
Pd-catalyst bearing different phosphoramidite ligands in THF
(Table 1). To our delight, the reactions using phosphor-
amidites derived from binol10 gave the desired isoxazoline N-
oxide 2a as the only product (entries 1−3), albeit the yields
were moderate. The cyclopropane or cyclopentene were not
observed in the reaction mixture; only the starting material was
recovered. The reaction with ligand L2 showed the best results
to give product 2a in 53% yield with 80% of enantiomeric
excess (ee) (entry 2). The enantioselectivity could be
improved by using Zhou’s spiro-type phosphoramidite L6;11
however, poor catalytic activity was observed (entry 6). Lower
efficiencies were observed while the reaction with BINAP
(entry 7) or Trost ligand (entry 8). With phosphoramidite L2
in hand, the reaction in the different solvents was examined
(entries 9−15, for details, see Supporting Information). We
found that the reaction was very sensitive for the reaction
media. When the reactions were carried out in 1,4-dioxane, the
yield and enantioselectivity could be improved (entries 10).
The yields were significantly improved when the reaction was
performed in the chloride solvents (entries 11−13). The
reaction in the chlorobenzene showed best results to afford
isoxazoline N-oxide 2a in 89% yield with 89% ee (entry 13).
The reactions in methanol or acetonitrile also proceeded
smoothly, but poor enantioselectivities were observed (entry
14 and 15).
54
89
31
33
MeOH
CH3CN
a
Reaction conditions: Pd2(dba)3·CHCl3 (2.5 mol %), ligand (10 mol
b
%), 1a (0.1 mmol), solvent (1.0 mL), 40 °C, 15 h. Isolated yields.
c
Determined by HPLC using a Chiralcel AS-H column. THF =
tetrahydrofuran; DME = 1,2-dimethoxyethane; MTBE = methyl tert-
butyl ether.
isoxazoline N-oxide 2p could also be obtained in 78% yield
with 86% ee. Significantly, the reaction of 1-phenylvinyl-
substituted allylic carbonate also performed well to furnish the
desired isoxazoline N-oxide 2q in 90% yield with 92% ee.
However, lower yield and enantioselectivity were observed for
the reaction of 1-cyclohexenyl allylic carbonate 1r. The
reaction conditions were less effective for the reaction of the
allylic substrates bearing R1- or R2-substituents. Although the
reactions proceeded smoothly to give corresponding isoxazo-
line N-oxides 2v−2w in good to high yields, poor to moderate
enantioselectivities were observed.
The reaction of alkylated nitro-containing allylic carbonate
1x could not proceed (Scheme 4, eq 1), and the starting
material was recovered almost quantitatively. This result
implied that a certain degree of acidity of the α-proton of
nitro-group is necessary for this transformation. The one-pot
sequential reaction of allylic substitution and allylic cyclo-
addition of allylic bicarbonate 3 with nitromethylbenzene was
also investigated (Scheme 4, eq 2). However, under the
identical conditions as described in Table 1, the reaction gave a
complex mixture including bis-alkylated product 4, allylic
carbonate 1a, trace amount of cyclized product 2a, starting
material 3, and some others.
On the basis of the optimal conditions (Table 1, entry 13),
the reaction scope of present process was evaluated. As shown
in Scheme 3, a variety of aryl-substituted nitro-containing
allylic carbonates 1a−1m (Z:E = 1:2.4−8.8) bearing different
steric and electronic natures could be converted into the
corresponding isoxazoline N-oxides 2a−2m in high yields with
complete chemo- and regioselectivities and good to high
enantioselectivities. 1- and 2-naphthyl groups could also be
installed to afford 2n and 2o in high yield with good
enantioselectivities. A heteroaromatic, 3-benzothiophenyl
According to the proposed reaction mechanism as shown in
Scheme 1, the final cycloaddition should be the stereo-
chemistry-determining step. To acquire the stereochemical
outcome of the cycloaddition, density functional theory (DFT)
B
DOI: 10.1021/acs.orglett.9b03443
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Scheme 3. Pd-Catalyzed Asymmetric Allylic Cycloaddition
of Nitro-Containing Allylic Carbonates
Scheme 4. Pd-Catalyzed Allylic Cycloaddition of Allylic
Carbonate 1x and Intermolecular Cycloaddition of
Bicarbonate 3 with Nitromethylbenzene
a
Figure 1. Stereochemical outcome via geometric optimization of
plausible allylpalladium intermediates B.
group) showed much lower energies than that with anti allylic
group. The intermediate Bsyn‑a revealed lowest relative energy;
thus, the reaction afforded product 2a with (S)-configuration
as a major enantiomer, which matched with experimental
results, through inner-attack of cycloaddition.15
The synthetic utility of the allylic cycloaddition reaction was
realized by scale-up transformation and the elaboration of the
cyclized products (Scheme 5). The cycloaddition of 1a in 4
mmol scale with 1 mol % of Pd2(dba)3·CHCl3 and 4 mol % of
ligand L2 proceeded smoothly to afford isoxazoline N-oxide 2a
in 83% yield with 89% ee. Hydrogenation of 2a with Pd/C
could isolate hydroxy oxime 5 in 72% yield. When the reaction
time was extended to 14 h, the amino alcohol 6 could be
obtained in 89% yield, albeit with poor diastereoselectivity
observed. Reduction of isoxazoline N-oxide 2a with trimethyl
phosphite gave dihydroisoxazole 7 in high yield. The vinyl
group of dihydroisoxazole 7 could be oxidized to ester 8 in
61% yield. Reduction of compound 8 with NaBH4 gave 3-
phenyl-5-hydoxymethyldihydroisoxazole 9 in 89% yield. The
cyclic oxime of 8 could be selectively reduced with NaBH4 in
the presence of NiCl2 to afford 3-hydroxy-5-phenylpyrrolidi-
none 10 in 91% yield with a 1:1.2 diastereomeric ratio.3d
a
Reaction conditions: Pd2(dba)3·CHCl3 (2.5 mol %), (S,S,S)-L2 (10
mol %), 1a (0.2 mmol), C6H5Cl (2.0 mL), 40 °C, 15 h. The yields are
of isolated materials. The enantioselectivities were determined by
HPLC using a chiral stationary phase. The absolute configuration of
2v was confirmed by X-ray crystallography (see Supporting
Information). Those of the other products were assigned by analogy.
b
c
The reaction was carried out in DCE solvent. The reaction was
carried out in (R)-L1 and DCE solvent.
calculations were carried out using the three-parameter
exchange-correlation hybrid functional B3LYP12 with D3
dispersion correction13 for the geometry optimizations of the
conceivable four models14 of π-allylpalladium intermediates B
with ligand L2 (see Supporting Information for details). As
revealed in Figure 1, the intermediate B with syn allylic group
(syn position between nitronate group and C2-protone of allyl
C
DOI: 10.1021/acs.orglett.9b03443
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Scheme 5. Scale-up Transformation and the Elaboration of
Product 2a
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science Foundation
of China (21871179, 21572130) and Shanghai Jiao Tong
University. We thank the Instrumental Analysis Center of
Shanghai Jiao Tong University for HRMS analysis.
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enantioselective synthesis of isoxazoline N-oxides via Pd-
catalyzed allylic cycloaddition of nitro-containing allylic
carbonates. By using palladium complex in situ generated
from Pd2(dba)3·CHCl3 and phosphoramidite L2 as a catalyst
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isoxazoline N-oxides in high yields with acceptably high
enantioselectivities. The stereochemistry of the transformation
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03443.
Detailed experimental procedures; characterization data
of all of the new compounds; copies of HPLC
chromatography, 1H and 13C NMR spectra of the
products (PDF)
Accession Codes
CCDC 1947874 contains the supplementary crystallographic
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kyh@hytc.edu.cn.
*E-mail: yjian@sjtu.edu.cn.
ORCID
Yuhe Kan: 0000-0002-2082-6796
Yong Jian Zhang: 0000-0001-5808-1745
Notes
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The authors declare no competing financial interest.
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D
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E
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