NBS/DBU-Promoted One-Pot Three-Component Cycloaddition of Malonic Acid Derivatives, Nitrosoarenes, and Alkenes: Synthesis of Isoxazolidines

Article abstract of DOI:10.1021/acs.joc.0c02567

A general DBU-mediated one-pot three-component cycloaddition reaction of easily accessible malonic acid derivatives, nitrosoarenes, and alkenes has been successfully established with the aid of NBS to provide direct access to highly functionalized isoxazolidine derivatives with generally good to excellent yields, broad functional group tolerance, and excellent regio- and diastereo-selectivities under mild conditions. The mechanism study shows that the NBS-mediated formation of bromomalonic acid derivatives from malonic acid derivatives and DBU-promoted synthesis of nitrone intermediates via the reaction of bromomalonic acid derivatives with nitrosoarenes are key steps.

Full text of DOI:10.1021/acs.joc.0c02567

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Article
NBS/DBU-Promoted One-Pot Three-Component Cycloaddition of
Malonic Acid Derivatives, Nitrosoarenes, and Alkenes: Synthesis of
Isoxazolidines
Xing Li,* Leijie Zheng, Xiaolei Gong, Honghong Chang, Wenchao Gao, and Wenlong Wei
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ABSTRACT: A general DBU-mediated one-pot three-component cyclo-
addition reaction of easily accessible malonic acid derivatives, nitrosoarenes,
and alkenes has been successfully established with the aid of NBS to provide
direct access to highly functionalized isoxazolidine derivatives with generally
good to excellent yields, broad functional group tolerance, and excellent
regio- and diastereo-selectivities under mild conditions. The mechanism
study shows that the NBS-mediated formation of bromomalonic acid
derivatives from malonic acid derivatives and DBU-promoted synthesis of
nitrone intermediates via the reaction of bromomalonic acid derivatives with
nitrosoarenes are key steps.
developed ruthenium porphyrin- and [IPrAuCl]/AgNTf2-
catalyzed one-pot strategies of diazo compounds, nitro-
soarenes, and olefins to synthesize various isoxazolidines,
respectively (Scheme 1C1).10 Nevertheless, these two methods
rely on the use of diazo compounds, which are unstable and
high cost. Although Zhong, Molander, and Tan groups and our
group independently realized the transition-metal-free three-
component approaches of these three types of compounds,
diazo compounds were still adopted as starting materials
(Scheme 1C2).11 Hence, the development of an environ-
mentally friendly three-component cycloaddition that utilizes
cheap and readily available starting materials for the synthesis
of highly functionalized isoxazolidines is of high interest.
Notably, malonic acid derivatives are very abundant, cheap,
stable, and readily accessible reagents, and they have been
widely utilized in various bond-forming reactions.12 To the
best of our knowledge, however, reports on their application as
one of the key reactants for the preparation of isoxazolidines
have never been observed. Herein, we will report a NBS/DBU-
promoted one-pot three-component method for the synthesis
of various isoxazolidines containing two esters or cyano groups
INTRODUCTION
■
Multicomponent cycloadditions have proven to be powerful
and efficient methods to access diverse polyfunctionalized
heterocycles from simple starting materials in a single step.1
Despite impressive advances in this research area, environ-
mentally benign multicomponent cycloadditions that utilize
very cheap and readily available starting materials for the
preparation of target products bearing multifunctional groups
remain challenging.
Because isoxazolidine motif holds a prominent position in
medicinal,2 synthetic,3 and pharmaceutical4 chemistry, various
methods have been extensively reported for the synthesis of
this skeleton.5,6 Among these different approaches, the [3+2]
cycloaddition of nitrones with alkenes is one of the most
classical strategies.7 However, they usually require the use of
expensive reagents and multistep procedures involving the
preparation and isolation of nitrones. Therefore, the develop-
ment of more efficient and practical multicomponent
approaches is highly desirable. In this context, the groups of
́
Bhattacharya, Zhong, and Cordova independently demon-
strated that aryl hydroxylamines could be used as substrates to
participate in metal-free three-component reactions with
aldehydes, olefins for access to diverse isoxazolidines (Scheme
1A).8 Unfortunately, they suffer from the use of expensive,
unstable, and poorly accessible aryl hydroxylamines. Recently,
three-component processes of functionalized olefins, alkenes,
and nitrosoarenes have been well documented to construct this
scaffold by Liu, Huang, and their co-workers, respectively
(Scheme 1B).9 However, these reactions are limited to
moderate yields. Additionally, Che, Liu, and their co-workers
Received: October 28, 2020
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© XXXX American Chemical Society
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A

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a
Scheme 1. Three-Component Strategies to Construct
Isoxazolidines
Table 1. Optimization of Reaction Conditions
b
entry promoter (equiv)
solvent (mL)
NXS (equiv) yield (%)
1
2
3
4
5
6
7
8
NaH (1)
DCE (1)
DCE (1)
DCE (1)
DCE (1)
DCE (1)
DCE (1)
DCE (1)
DCE (1)
DCE (1)
CH3CN (1)
THF (1)
MePh (1)
CH3NO2 (1)
dioxane (1)
CHCl3 (1)
CH2Cl2 (1)
DCE (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1)
NCS (1)
NIS (1)
NBS (1)
NBS (1)
NBS (1)
NBS (1.3)
52
NaOH (1)
Na2CO3 (1)
NaOAc (1)
KOH (1)
LiOH (1)
DBU (1)
DABCO (1)
DIPEA (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1.4)
trace
trace
trace
trace
61
74
c
N.D.
N.D.
60
9
10
11
12
13
14
15
16
17
18
19
20
21
22
38
N.D.
N.D.
47
71
54
57
59
81
79
70
88
d
DCE (1)
DCE (0.5)
DCE (0.8)
DCE (1.2)
DCE (0.5)
e
through the reaction of malonic acid derivatives, nitrosoarenes,
and olefins (Scheme 1D).
94
ef
,
99
a
Unless noted, all reactions were performed with nitrosobenzene 1a
RESULTS AND DISCUSSION
■
(21.6 mg, 0.2 mmol), diethyl malonate 2a (30.7 uL, 0.2 mmol), and
styrene 3a (23.1 uL, 0.2 mmol) under specified reaction conditions at
At the outset of our studies, the three-component reaction of
nitrosobenzene 1a, diethyl malonate 2a, and styrene 3a was
selected as the model reaction to evaluate a range of
promoters. When the reaction was performed in the presence
of NaH and NBS in DCE under an air atmosphere at 50 °C for
12 h, the isolated yield of the isoxazolidine 4a was 52% (Table
1, entry 1). Some other bases such as NaOH, Na2CO3,
NaOAc, KOH, LiOH, and DBU have also been screened as
promoters. However, only trace amount of desired product 4a
was observed when NaOH, Na2CO3, NaOAc, and KOH were
adopted (Table 1, entries 2−5). Gratifyingly, the yields of
product 4a could be increased to 61 and 74% using LiOH and
DBU as promoters, respectively (Table 1, entries 6 and 7).
DABCO and DIPEA were then employed to further improve
the yield (Table 1, entries 8 and 9). Unfortunately, no product
4a was detected. Subsequently, a number of solvents were
examined. CH3CN, THF, MePh, CH3NO2, and dioxane failed
to increase the yield (Table 1, entries 10−14 vs 7). Other
halogenated alkane solvents such as CHCl3 and CH2Cl2 also
gave reduced yields (Table 1, entries 15 and 16 vs 7).
Additionally, when NCS and NIS were used instead of NBS,
inferior results were observed (Table 1, entries 17 and 18 vs 7).
The examination of solvent dosage indicated that 0.5 mL of
DCE was the most suitable for this transformation (Table 1,
entry 19 vs 7, 20, and 21). An 88% yield was achieved when
the amount of NBS and DBU was increased to 1.3 and 1.4
equiv, respectively (Table 1, entry 22 vs 19). At last, adjusting
substrate ratios (1a/2a/3a = 1.3:1.3:1) further improved the
b
c
d
50 °C for 12 h. Isolated yield of 4a. N.D. = not detected. 35 °C
e
f
was used. 1a/2a/3a = 1.3:1.3:1. The reaction time was 24 h.
yield to 94%, and up to 99% yield was obtained when the
reaction time was 24 h (Table 1, entry 22).
With the optimized reaction conditions in hand, we then
explored the substrate scope of different olefins 3 with
nitrosobenzene 1a and diethyl malonate 2a, and the results
are summarized in Scheme 2. First, all screened monosub-
stituted alkenes including aromatic and aliphatic ones could
afford the desired products 4a−4v in good to excellent yields.
In terms of monosubstituted aromatic alkenes, when the
substituent R5 on the phenyl ring of styrene was varied,
regardless of the positions and electronic nature, good to
excellent yields were achieved (4a−4j), which indicated that
the electronic properties of substituents did not affect the
reaction yields significantly, and the steric hindrance effect had
a little influence on the transformation. Moreover, good to
high yields were obtained when styrene was changed to
heteroarylenes (4k and 4l) or naphthenes (4m and 4n). It was
noteworthy that various aliphatic terminal alkenes bearing
different functional groups could be converted successfully into
the desired products (4o−4v) with high yields. Second, diverse
sterically hindered 1,1-disubstituted olefins were investigated
and the corresponding products 4w−4aa were obtained in
excellent yields. Third, a series of 1,2-disubstituted alkenes
were examined. Not only symmetrical but also asymmetrical
B
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a b
,
a b
,
Scheme 2. Scope of Different Types of Olefins
Scheme 3. Application of This Methodology
a
Unless noted, all reactions were carried out with nitrosobenzene 1a
(0.26 mmol, 1.3 equiv), diethyl malonate 2a (0.26 mmol, 1.3 equiv),
3 (0.2 mmol), NBS (0.26 mmol, 1.3 equiv), and DBU (0.28 mmol,
a
Unless noted, all reactions were carried out with nitrosobenzene 1a
(0.26 mmol, 1.3 equiv), diethyl malonate 2a (0.26 mmol, 1.3 equiv),
olefin 3 (0.2 mmol), NBS (0.26 mmol, 1.3 equiv), and DBU (0.28
b
1.4 equiv) in 0.5 mL of DCE at 50 °C. Isolated yields of 4.
b
mmol, 1.4 equiv) in 0.5 mL of DCE at 50 °C. Isolated yields of 4.
furnish the product 4am in 80% yield. Ethyl 3-(1H-
benzo[d][1,2,3]triazol-1-yl)acrylate was also compatible with
the conditions, delivering the product 4an in 90% yield. When
ethyl 3-(1H-indol-1-yl)acrylate was subjected to this trans-
formation, a 71% yield was provided (4ao). The above-
mentioned trans-olefins also gave the 4,5-trans isoxazolidine
products 4aj−4ao. Among them, the relative configuration of
product 4ao was confirmed by the analysis of NOESY (see the
Supporting Information). The ethyl 3-(2,4-dioxo-3,4-dihydro-
pyrimidin-1(2H)-yl)acrylates with various substituents were
well tolerated, offering the corresponding products 4ap−4at in
good yields. Moreover, the vinyl pyrimidine derived from 4-
aminopyrimidin-2(1H)-one also gave the desired product 4au
in 77% yield.
Subsequently, we investigated the scope of various nitro-
soarenes 1 and malonic esters 2, and the results are listed in
Scheme 4. First, all examined nitrosoarenes could afford the
corresponding products 4ba−4bi in good to excellent yields.
The electronic effect of substituents on the phenyl ring of the
nitrosobenzene had some influence on the reaction yields. The
nitrosobenzenes with electron-donating substituents on the
phenyl ring exhibited higher yields than those with electron-
withdrawing substituents (4ba−4bc vs 4be−4bh), and the
stronger electron-withdrawing group (NO2) showed relatively
lower reactivity and yield (4bh vs 4bg). Disubstituted
nitrosobenzenes were well tolerated, giving the products 4bd
and 4bi in good yields. Next, the investigation of malonic ester
olefins worked very well, affording the single diastereomeric
products 4ab−4ae in 80−96% yields. If a cis-alkene (dimethyl
maleate) was used, the 4,5-cis isoxazolidine product 4ab was
provided. The 4,5-trans isoxazolidine products were observed
(4ac−4ae) when trans-alkenes such as dimethyl fumarate, (E)-
chalcone, and ethyl cinnamate were utilized, respectively.11b11c
The stereochemistry was further confirmed by the analysis of
NOESY (see the Supporting Information).
Bicyclic isoxazolidines, isoxazolidinyl purines, isoxazolidinyl
imidazoles, isoxazolidinyl triazoles, isoxazolidinyl indoles, and
isoxazolidinyl pyrimidines represent attractive and privileged
structures, which have displayed significant antivirus or
anticancer activities. To make this methodology more
appealing, the three-component reactions of cyclic olefins,
vinyl purines, vinyl imidazole, vinyl triazole, vinyl indole, and
vinyl pyrimidine with nitrosobenzene 1a and diethyl malonate
2a were also examined, respectively (Scheme 3). To our
delight, the corresponding single diastereomeric products 4af−
4ao could be smoothly obtained, revealing that the newly
developed three-component method was broadly applicable. In
the case of various cycloolefins, 80−93% yields were obtained
(4af−4ai). Notably, vinyl purines bearing different functional
groups were efficiently applied in this transformation, affording
the corresponding products 4aj−4al in 85−94% yields. It was
found that vinyl imidazole could be reacted smoothly to
C
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Scheme 4. Scope of Various Nitrosoarenes 1 and Substrates
2
Scheme 6. Control Experiments
a b
,
a
Unless noted, all reactions were carried out with 1 (0.26 mmol, 1.3
equiv), 2 (0.26 mmol, 1.3 equiv), 3a (0.2 mmol), NBS (0.26 mmol,
1.3 equiv), and DBU (0.28 mmol, 1.4 equiv) in 0.5 mL of DCE at 50
b
°C. Isolated yields of 4.
2 revealed that the steric hindrance of ester groups did not
obviously affect this transformation, and all examined
substrates provided excellent yields (4bj−4bl). When
malononitrile was used as a substrate, the reaction produced
the product 4bm with a satisfactory result, too.
To demonstrate the practicability of this newly developed
methodology, the gram-scale (10 mmol scale) reaction was
also performed. Treatment of 1.40 g of nitrosobenzene 1a, 2.00
mL of diethyl malonate 2a and 1.16 mL of styrene 3a gave 3.51
g of cycloadduct 4a with 95% yield (see Scheme 5).
reaction and both began with the formation of diethyl
bromomalonate E. The first one continued to proceed with
subsequent reaction of diethyl bromomalonate E with
nitrosobenzene 1a to form intermediate 5a, which then
reacted with styrene 3a to afford the final product 4a via the
[3+2] cycloaddition (Scheme 6, route 1). The second one was
followed by the next reaction of diethyl bromomalonate E with
styrene 3a to give diethyl 2-phenylcyclopropane-1,1-dicarbox-
ylate 6, which then reacted with nitrosobenzene 1a to produce
the final product 4a via the [3+2] cycloaddition (Scheme 6,
route 2). It was noteworthy that the formation of nitrone
intermediate 5a was indeed observed and determined using
1HNMR and HRMS (see the Supporting Information) when
the reaction of nitrosobenzene 1a with diethyl bromomalonate
E was performed. Furthermore, nitrone 5a was found to be
able to smoothly react with styrene 3a to produce the final
product 4a in 99% yield. In sharp contrast, styrene 3a failed to
react with diethyl bromomalonate E to provide the imagined
cyclopropane intermediate 6 under the same conditions.13
Moreover, no product 4a was observed when intermediate 6
was treated with nitrosobenzene 1a.6a These results strongly
imply that this reaction should proceed through the proposed
reaction pathway route 1.
Scheme 5. Gram-Scale Reaction
To explore the function of NBS and mechanism details of
this transformation, we first tracked the model reaction using
TLC in the reaction process and detected small amount of
diethyl bromomalonate that should be formed via the reaction
of diethyl malonate 2a with NBS. As imagined, the 86% yield
of diethyl bromomalonate E was obtained when diethyl
malonate 2a was treated with NBS (Scheme 6, eq 1), which
suggested the involvement of diethyl bromomalonate as an
intermediate. Furthermore, no final product 4a was detected
when the model reaction was carried out in the absence of
NBS (Scheme 6, eq 2), which demonstrated that the existence
of NBS is crucial to trigger the reaction. Subsequently, other
several control experiments were designed. As listed in Scheme
6, two possible reaction pathways were proposed for this
To gain insights into the exact role of DBU, two other
control experiments were next performed (Scheme 7). The
reaction of nitrosobenzene 1a with diethyl bromomalonate E
failed to proceed to give the desired nitrone intermediate 5a in
D
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Scheme 7. Control Experiments
EXPERIMENTAL SECTION
■
General Information. 1H NMR data were acquired at 300 K on a
Bruker Advance 600 or 400 MHz spectrometer. The chemical shifts
are reported in ppm downfield to the CDCl3 resonance (δ = 7.27).
Spectra are reported as follows: chemical shift (δ ppm), multiplicity (s
= singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constants (Hz), integration, and assignment. 13C NMR data were
acquired at 300 K on a Bruker Advance 150 or 100 MHz
spectrometer using CDCl3 as a solvent with complete proton
decoupling. The chemical shifts are reported in ppm downfield to
the central CDCl3 resonance (δ = 77.0). Structural assignments were
also made with additional information from H-H NOESY experi-
ments. High-resolution mass spectra were performed on a micrO-
TOF-Q II instrument with an ESI source. Melting points were
measured with a RD-II melting point apparatus and are uncorrected.
Unless otherwise noted, all reagents and solvents obtained from
commercial sources were used without further purification.
Deuterated solvents were purchased from Sigma-Aldrich. Refinement
of the mixed system through column chromatography was performed
on silica gel (200−300mesh) with petroleum ether (solvent A)/ethyl
acetate (solvent B) gradients as elution. In addition, all yields were
referred to isolated yields (average of two runs) of compounds unless
otherwise specified. The known compounds were partly characterized
the absence of DBU (Scheme 7, eq 1). However, nitrone 5a
could smoothly react with styrene 3a to produce the final
product 4a in 99% yield without the use of DBU (Scheme 7,
eq 2). These two results demonstrated that the role of DBU is
to capture the hydrogen proton of diethyl bromomalonate E to
promote the formation of intermediate 5a, and it probably did
not play any role in the cycloaddition process.
On the basis of above-mentioned results and corresponding
literature,7,11 we proposed the following reaction mechanism
(Scheme 8). Initially, NBS could smoothly convert diethyl
malonate 2a into diethyl bromomalonate E. Under the action
of DBU, subsequently, E undergoes the deprotonation to form
intermediate F that then attacks the nitrosoarene 1 to generate
intermediate G, which could be transformed to nitrone
intermediate H via the removal of bromine anion. At last,
the target product 4 is provided through the [3+2]
cycloaddition of olefin 3 with nitrone intermediate H.
1
by melting points (for solid samples), H NMR, and compared to
authentic samples or the literature data.
General Procedure for Cycloadditon of Malonic Acid
Derivatives, Nitrosoarenes, and Alkenes. To a tube equipped
with a magnetic stir bar were added nitrosoarene 1 (0.26 mmol, 1.3
equiv), NBS (47.2 mg, 0.26 mmol, 1.3 equiv), DBU (42.7 μL, 0.28
mmol, 1.4 equiv), alkene 3 (0.2 mmol), malonic acid derivative 2
(0.26 mmol, 1.3 equiv), and DCE (0.5 mL) in turn. The reaction
system was then heated to 50 °C (oil bath) and stirred until alkene 3
was completely consumed as determined by TLC. At last, the reaction
mixture was purified by silica gel column chromatography to afford
the desired pure cycloaddtion product 4.
10 Mmol Scale Preparation of 4a. To a round-bottom flask
equipped with a magnetic stir bar were added nitrosobenzene 1a
(1.433 g, 13 mmol, 1.3 equiv), NBS (2.361 g, 13 mmol, 1.3 equiv),
DBU (2.14 mL, 14 mmol, 1.4 equiv), diethyl malonate 2a (2.00 mL,
13 mmol, 1.3 equiv), styrene 3a (1.16 mL, 10 mmol), and DCE (25
mL) in turn. The reaction system was then heated to 50 °C (oil bath)
and stirred until styrene 3a was completely consumed as determined
by TLC. At last, the reaction mixture was concentrated in vacuum and
purified by silica gel column chromatography to afford the desired
pure cycloaddtion product 4a (3.51 g, 95% yield).
CONCLUSIONS
■
In summary, we have established a general metal-free one-pot
three-component method for highly diastereoselective con-
struction of highly functionalized isoxazolidine derivatives via
the cycloaddition of readily accessible malonic acid derivatives,
nitrosoarenes, and alkenes as starting materials. In this reaction
system, NBS acts as a bromine reagent to prepare
bromomalonic acid derivatives from malonic acid derivatives,
and DBU serves as a promoter to trigger and accelerate the
formation of nitrone intermediates through the reaction of
bromomalonic acid derivatives with nitrosoarenes. The
operationally simple and practical protocol features good to
excellent yields, a broad substrate scope, cheap system, and
good functional group tolerance.
Characterization Data for Intermediate 5a. N-(1,3-Diethoxy-
1,3-dioxopropan-2-ylidene)aniline Oxide 5a. Yellow oil; Rf = 0.3
1
(PE/EtOAc = 8:1, v/v). H NMR (CDCl3, 400 MHz) δ 7.51−7.40
(m, 5H), 4.42 (q, 2H, J = 14.0, 6.8 Hz), 4.10 (q, 2H, J = 14.4, 7.2
Hz), 1.39 (t, 3H, J = 7.2 Hz), 1.12 (t, 3H, J = 6.8 Hz) ppm; 13C{1H}
NMR (CDCl3, 100 MHz) δ 160.3, 158.7, 147.1, 133.2, 130.9, 129.0,
Scheme 8. Proposed Reaction Mechanism
E
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123.0, 62.6, 62.3, 13.9, 13.6 ppm. HRMS (ESI) m/z [M + H]+ Calcd
for C13H16NO5 266.1023, found 266.1023.
62.1, 62.0, 46.7, 13.7, 13.5 ppm. HRMS (ESI) m/z [M + H]+ Calcd
for C21H23FNO5 388.1555, found 388.1550.
Diethyl 5-(3-Fluorophenyl)-2-phenylisoxazolidine-3,3-dicarboxy-
late (4g). Yellow solid (94% yield, 72.8 mg); mp 54−55 °C; TLC, Rf
= 0.3 (PE/EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.52
(dd, 2H, J = 8.8, 5.2 Hz), 7.37 (d, 2H, J = 7.6 Hz), 7.25 (t, 2H, J = 8.4
Hz), 7.08 (t, 2H, J = 8.8 Hz), 7.02 (d, 1H, J = 7.2 Hz), 5.30 (dd, 1H, J
= 9.6, 6.4 Hz), 4.17 (q, 2H, J = 7.2 Hz), 4.06−3.98 (m, 1H), 3.96−
3.88 (m, 1H), 3.20 (dd, 1H, J = 12.8, 6.4 Hz), 3.09 (dd, 1H, J = 12.8,
9.2 Hz), 1.19 (t, 3H, J = 7.2 Hz), 1.01 (t, 3H, J = 7.2 Hz) ppm;
13C{1H} NMR (CDCl3, 100 MHz) δ 168.4, 167.8, 164.1, 161.6,
Characterization Data for Cycloaddition Products 4. Diethyl
2,5-Diphenylisoxazolidine-3,3-dicarboxylate (4a).6a Yellow oil
1
(99% yield, 73.1 mg); TLC, Rf = 0.3 (PE/EtOAc = 20:1, v/v); H
NMR (CDCl3, 400 MHz) δ 7.54 (d, 2H, J = 6.8 Hz), 7.42−7.39 (m,
2H), 7.38−7.37 (m, 2H), 7.36−7.32 (m, 1H), 7.25 (t, 2H, J = 8.8
Hz), 7.03 (t, 1H, J = 7.6 Hz), 5.32 (dd, 1H, J = 9.6, 6.4 Hz), 4.17 (q,
2H, J = 7.2 Hz), 4.06−3.98 (m, 1H), 3.87−3.97 (m, 1H), 3.22 (dd,
1H, J = 12.8, 6.0 Hz), 3.12 (dd, 1H, J = 12.8, 9.2 Hz), 1.19 (t, 3H, J =
7.2 Hz), 1.02 (t, 3H, J = 7.2 Hz) ppm.
147.1, 133.2, 133.2, 129.0, 128.9, 128.2, 124.0, 118.3, 115.6, 115.4,
78.2, 78.2, 62.2, 62.1, 47.8, 13.8, 13.6 ppm. HRMS (ESI) m/z [M +
H]+ Calcd for C21H23FNO5 388.1555, found 388.1550.
Diethyl 2-Phenyl-5-(o-tolyl)isoxazolidine-3,3-dicarboxylate (4b).
Yellow oil (93% yield, 71.3 mg); TLC, Rf = 0.3 (PE/EtOAc = 20:1, v/
1
v); H NMR (CDCl3, 400 MHz) δ 7.70 (dd, 1H, J = 7.6, 1.2 Hz),
Diethyl 5-(4-Fluorophenyl)-2-phenylisoxazolidine-3,3-dicarboxy-
7.38 (dd, 2H, J = 8.8, 1.2 Hz), 7.26 (d, 2H, J = 7.2 Hz), 7.24 (t, 1H, J
= 1.6 Hz), 7.21 (dd, 1H, J = 7.6, 1.6 Hz), 7.16 (t, 1H, J = 7.2 Hz),
7.03 (t, 1H, J = 7.2 Hz), 5.54 (dd, 1H, J = 9.6, 6.0 Hz), 4.17 (qd, 2H,
J = 7.2, 1.6 Hz), 4.06−3.98 (m, 1H), 3.89−3.97 (m, 1H), 3.23 (dd,
1H, J = 12.8, 6.0 Hz), 3.01 (dd, 1H, J = 12.8, 9.6 Hz), 2.39 (s, 3H),
1.96 (t, 3H, J = 7.2 Hz), 1.01 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 168.6, 167.9, 147.3, 135.6, 135.5, 130.4, 128.3,
128.1, 126.4, 125.9, 123.8, 118.1, 78.8, 75.8, 62.7, 62.0, 46.8, 19.3,
13.9, 13.7 ppm. HRMS (ESI) m/z [M + H]+ Calcd for C22H26NO5
384.1805, found 384.1800.
Diethyl 2-Phenyl-5-(m-tolyl)isoxazolidine-3,3-dicarboxylate (4c).
Yellow oil (96% yield, 73.6 mg); TLC, Rf = 0.3 (PE/EtOAc = 20:1, v/
v); 1H NMR (CDCl3, 600 MHz) δ 7.38 (t, 3H, J = 9.0 Hz), 7.34 (d,
1H, J = 7.6 Hz), 7.29 (t, 1H, J = 7.6 Hz), 7.26 (t, 2H, J = 9.0 Hz),
7.17 (d, 1H, J = 7.6 Hz), 7.04 (t, 1H, J = 7.2 Hz), 5.31 (dd, 1H, J =
9.6, 6.0 Hz), 4.18 (q, 2H, J = 6.6 Hz), 4.07−4.02 (m, 1H), 3.98−3.93
(m, 1H), 3.21 (dd, 1H, J = 12.6, 6.0 Hz), 3.14 (dd, 1H, J = 13.2, 10.2
Hz), 2.39 (s, 3H), 1.20 (t, 3H, J = 7.2 Hz), 1.04 (t, 3H, J = 7.2 Hz)
ppm; 13C{1H} NMR (CDCl3, 150 MHz) δ 168.5, 167.9, 147.2, 138.2,
137.0, 129.3, 128.4, 128.1, 127.6, 124.0, 123.6, 117.9, 78.9, 78.7, 62.1,
62.0, 47.9, 21.4, 13.7, 13.6 ppm; HRMS (ESI) m/z [M + H]+ Calcd
for C22H26NO5 384.1805, found 384.1800.
Diethyl 2-Phenyl-5-(p-tolyl)isoxazolidine-3,3-dicarboxylate (4d).
Yellow oil (98% yield, 75.1 mg); TLC, Rf = 0.3 (PE/EtOAc = 20:1, v/
v); 1H NMR (CDCl3, 400 MHz) δ 7.43 (d, 2H, J = 7.2 Hz), 7.36 (d,
2H, J = 8.4 Hz), 7.24 (t, 2H, J = 8.0 Hz), 7.19 (d, 2H, J = 7.6 Hz),
7.02 (t, 1H, J = 7.2 Hz), 5.29 (dd, 1H, J = 9.6, 6.4 Hz), 4.17 (q, 2H, J
= 7.2 Hz), 4.06−3.98 (m, 1H), 3.96−3.90 (m, 1H), 3.23−3.12 (m,
2H), 2.36 (s, 3H), 1.19 (t, 3H, J = 7.2 Hz), 1.01 (t, 3H, J = 7.2 Hz)
ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.6, 167.9, 147.3, 138.5,
134.1, 129.3, 128.2, 127.1, 123.7, 118.1, 78.9, 78.8, 62.2, 62.0, 47.9,
21.2, 13.8, 13.6 ppm; HRMS (ESI) m/z [M + H]+ Calcd for
C22H26NO5 384.1805, found 384.1800.
late (4h). White solid (97% yield, 75.1 mg); mp 55−56 °C; TLC, Rf =
1
0.3 (PE/EtOAc = 20:1, v/v); H NMR (CDCl3, 400 MHz) δ 7.29
(dd, 2H, J = 8.8, 2.0 Hz), 7.25 (dd, 1H, J = 7.6, 2.0 Hz), 7.23−7.15
(m, 4H), 6.96 (t, 2H, J = 7.2 Hz), 5.23 (dd, 1H, J = 9.2, 6.8 Hz), 4.06
(q, 2H, J = 6.8 Hz), 3.98−3.90 (m, 1H), 3.89−3.81 (m, 1H), 3.15
(dd, 1H, J = 12.8, 6.4 Hz), 2.99 (dd, 1H, J = 12.8, 9.2 Hz), 1.08 (t,
3H, J = 7.2 Hz), 0.93 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 167.7, 161.7, 147.0, 130.2, 130.1, 128.3, 124.0,
122.5, 122.5, 118.3, 78.6, 78.0, 62.2, 62.1, 47.7, 13.8, 13.6 ppm.
HRMS (ESI) m/z [M + H]+ Calcd for C21H23FNO5 388.1555, found
388.1550.
Diethyl 5-(2-Chlorophenyl)-2-phenylisoxazolidine-3,3-dicarbox-
ylate (4i). Yellow oil (92% yield, 74.2 mg); TLC, Rf = 0.3 (PE/EtOAc
1
= 20:1, v/v); H NMR (CDCl3, 400 MHz) δ 7.79 (dd, 1H, J = 8.4,
1.6 Hz), 7.40 (dd, 2H, J = 8.4, 0.8 Hz), 7.35 (dd, 1H, J = 8.0, 1.2 Hz),
7.33−7.22 (m, 4H), 7.06 (d, 1H, J = 7.2 Hz), 5.74 (t, 1H, J = 7.6 Hz),
4.09 (q, 2H, J = 7.2 Hz), 4.07−4.02 (m, 1H), 4.01−3.94 (m, 1H),
3.46 (dd, 1H, J = 12.8, 6.8 Hz), 2.91 (dd, 1H, J = 12.8, 8.0 Hz), 1.12
(t, 3H, J = 7.2 Hz), 1.04 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 167.9, 167.8, 147.1, 136.7, 131.9, 129.3, 129.1,
128.3, 127.2, 127.1, 124.0, 118.3, 78.5, 75.2, 62.1, 62.0, 46.7, 13.7,
13.7 ppm. HRMS (ESI) m/z [M + H]+ Calcd for C21H23ClNO5
404.1259, found 404.1266.
Diethyl 5-(4-Chlorophenyl)-2-phenylisoxazolidine-3,3-dicarbox-
ylate (4j). Yellow solid (98% yield, 79.0 mg); mp 70−74 °C; TLC, Rf
= 0.3 (PE/EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.39
(d, 2H, J = 8.4 Hz), 7.28 (d, 2H, J = 6.4 Hz), 7.26 (d, 2H, J = 6.4 Hz),
7.15 (t, 2H, J = 8.4 Hz), 6.94 (t, 1H, J = 7.2 Hz), 5.21 (dd, 1H, J =
8.8, 6.4 Hz), 4.07 (q, 2H, J = 7.2 Hz), 3.96−3.90 (m, 1H), 3.88−3.80
(m, 1H), 3.13 (dd, 1H, J = 12.8, 6.8 Hz), 2.99 (dd, 1H, J = 12.8, 9.2
Hz), 1.08 (t, 3H, J = 7.2 Hz), 0.92 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
NMR (CDCl3, 100 MHz) δ 168.3, 167.8, 147.0, 136.1, 134.3, 128.8,
128.4, 124.2, 118.3, 78.6, 78.0, 62.2, 62.1, 47.8, 13.8, 13.6 ppm.
HRMS (ESI) m/z [M + H]+ Calcd for C21H23ClNO5 404.1259,
found 404.1266.
Diethyl 2-Phenyl-5-(pyridin-2-yl)isoxazolidine-3,3-dicarboxylate
(4k). Yellow oil (89% yield, 65.9 mg); TLC, Rf = 0.3 (PE/EtOAc =
20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 8.55 (d, 1H, J = 4.4 Hz),
7.73−7.67 (m, 2H), 7.39 (d, 2H, J = 7.6 Hz), 7.27 (t, 2H, J = 8.8 Hz),
7.23−7.20 (m, 1H), 7.05 (t, 1H, J = 7.2 Hz), 5.51 (t, 1H, J = 7.2 Hz),
4.13−3.99 (m, 4H), 3.46 (dd, 1H, J = 12.8, 7.2 Hz), 3.28 (dd, 1H, J =
13.2, 7.2 Hz), 1.06 (td, 6H, J = 7.2, 1.6 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 168.0, 167.8, 158.5, 148.9, 147.0, 136.8, 128.2,
123.9, 122.9, 120.7, 118.2, 78.7, 78.2, 62.1, 62.0, 46.0, 13.7, 13.6 ppm.
HRMS (ESI) m/z [M + H]+ Calcd for C20H23N2O5 371.1601, found
371.1593.
Diethyl 2-Phenyl-5-(pyridin-4-yl)isoxazolidine-3,3-dicarboxylate
(4l). Yellow oil (92% yield, 68.1 mg); TLC, Rf = 0.3 (PE/EtOAc =
20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 8.54 (d, 2H, J = 5.6 Hz),
7.35 (d, 2H, J = 6.0 Hz), 7.30 (t, 2H, J = 8.0 Hz), 7.20 (t, 2H, J = 8.4
Hz), 7.00 (d, 1H, J = 7.2 Hz), 5.27 (t, 1H, J = 7.6 Hz), 4.12−4.02 (m,
2H), 4.00−3.94 (m, 1H), 3.92−3.83 (m, 1H), 3.24 (dd, 1H, J = 12.8,
6.8 Hz), 2.95 (dd, 1H, J = 12.8, 8.4 Hz), 1.05 (t, 3H, J = 7.2 Hz), 0.95
(t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 167.8,
167.5, 150.1, 147.3, 146.7, 128.3, 124.3, 121.2, 118.5, 78.3, 76.8, 62.2,
Diethyl 5-(2,6-Dimethylphenyl)-2-phenylisoxazolidine-3,3-dicar-
boxylate (4e). Yellow oil (90% yield, 71.5 mg); TLC, Rf = 0.3 (PE/
1
EtOAc = 20:1, v/v); H NMR (CDCl3, 400 MHz) δ 7.51 (s, 1H),
7.38 (d, 2H, J = 8.8 Hz), 7.26 (t, 2H, J = 8.4 Hz), 7.04 (d, 2H, J = 3.6
Hz), 7.01 (d, 1H, J = 7.2 Hz), 5.53 (dd, 1H, J = 10.0, 6.0 Hz), 4.22−
4.14 (m, 2H), 4.08−4.02 (m, 1H), 3.98−3.92 (m, 1H), 3.21 (dd, 1H,
J = 12.4, 5.6 Hz), 3.00 (dd, 1H, J = 12.4, 10.0 Hz), 2.34 (s, 6H), 1.83
(t, 3H, J = 7.2 Hz), 1.05 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 168.6, 168.0, 147.5, 135.9, 135.2, 135.2, 132.4,
130.4, 128.9, 128.3, 126.3, 123.7, 117.9, 78.9, 76.0, 62.2, 62.0, 46.9,
21.1, 18.8, 13.8, 13.7 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C23H28NO5 398.1962, found 398.1954.
Diethyl 5-(2-Fluorophenyl)-2-phenylisoxazolidine-3,3-dicarboxy-
late (4f). Yellow oil (91% yield, 70.5 mg); TLC, Rf = 0.3 (PE/EtOAc
= 20:1, v/v); 1H NMR (CDCl3, 600 MHz) δ 7.71 (td, 1H, J = 7.2, 1.2
Hz), 7.38 (d, 2H, J = 7.6 Hz), 7.30−7.29 (m, 1H), 7.27 (t, 2H, J = 7.6
Hz), 7.19 (t, 1H, J = 7.6 Hz), 7.07−7.04 (m, 2H), 5.65 (dd, 1H, J =
8.4, 6.6 Hz), 4.12 (q, 2H, J = 7.2 Hz), 4.08−4.01 (m, 1H), 3.98−3.93
(m, 1H), 3.33 (dd, 1H, J = 13.2, 6.6 Hz), 3.07 (dd, 1H, J = 13.2, 9.0
Hz), 1.34 (t, 3H, J = 7.2 Hz), 1.03 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
NMR (CDCl3, 150 MHz) δ 168.0, 167.8, 147.0, 129.6, 129.6, 128.2,
127.5, 127.5, 124.3, 124.3, 123.9, 118.1, 115.2, 115.1, 78.4, 72.3, 72.3,
F
https://dx.doi.org/10.1021/acs.joc.0c02567
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
62.1, 47.2, 13.7, 13.6 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C20H23N2O5 371.1601, found 371.1593.
2.34 (s, 1H), 1.92−2.08 (m, 2H), 1.13 (t, 3H, J = 7.2 Hz), 1.04 (t,
3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.4,
168.1, 147.1, 128.2, 123.8, 118.1, 78.2, 75.2, 62.1, 62.0, 59.8, 45.5,
35.2, 13.7, 13.6 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C17H24NO6 338.1598, found 338.1594.
Diethyl 5-(Naphthalen-1-yl)-2-phenylisoxazolidine-3,3-dicar-
boxylate (4m). Yellow oil (84% yield, 70.4 mg); TLC, Rf = 0.3
1
(PE/EtOAc = 20:1, v/v); H NMR (CDCl3, 600 MHz) δ 8.12 (d,
1H, J = 8.4 Hz), 7.90 (t, 2H, J = 7.2 Hz), 7.85 (d, 1H, J = 7.6 Hz),
7.58−7.51 (m, 3H), 7.46 (dd, 2H, J = 8.4, 0.6 Hz), 7.31 (t, 2H, J = 7.2
Hz), 7.08 (t, 1H, J = 7.6 Hz), 6.11 (dd, 1H, J = 9.0, 6.0 Hz), 4.22 (q,
2H, J = 7.2 Hz), 4.08−4.02 (m, 1H), 4.02−3.96 (m, 1H), 3.52 (dd,
1H, J = 13.2, 6.6 Hz), 3.20 (dd, 1H, J = 12.6, 9.0 Hz), 1.22 (t, 3H, J =
7.2 Hz), 1.05 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 150
MHz) δ 168.4, 167.9, 147.3, 133.6, 133.3, 130.6, 128.6, 128.3, 126.3,
125.6, 125.5, 123.4, 123.1, 118.0, 78.7, 76.0, 62.2, 62.0, 47.0, 13.8,
13.6 ppm. HRMS (ESI) m/z [M + H]+ Calcd for C25H26NO5
420.1805, found 420.1803.
Diethyl 5-(3-Hydroxypropyl)-2-phenylisoxazolidine-3,3-dicar-
boxylate (4s). Yellow oil (92% yield, 64.6 mg); TLC, Rf = 0.3
(PE/EtOAc = 5:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.26 (t, 3H, J
= 8.0 Hz), 7.21 (d, 1H, J = 8.0 Hz), 7.01 (t, 1H, J = 6.8 Hz), 4.39−
4.33 (m, 1H), 4.09 (q, 2H, J = 7.2 Hz), 4.07−4.01 (m, 1H), 4.00−
3.92 (m, 1H), 3.69 (s, 2H), 2.95 (dd, 1H, J = 12.4, 5.6 Hz), 2.69 (dd,
1H, J = 12.4, 5.2 Hz), 2.02 (s, 1H), 1.90−1.68 (m, 4H), 1.14 (t, 3H, J
= 7.2 Hz), 1.04 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100
MHz) δ 168.5, 168.1, 147.3, 123.2, 117.8, 78.3, 62.3, 62.1, 62.0, 45.8,
29.3, 29.0, 13.7, 13.6 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C18H26NO6 352.1755, found 352.1749.
Diethyl 5-(Bromomethyl)-2-phenylisoxazolidine-3,3-dicarboxy-
late (4t). Yellow oil (83% yield, 64.0 mg); TLC, Rf = 0.3 (PE/
EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.30 (d, 2H, J =
8.8 Hz), 7.24 (t, 2H, J = 8.4 Hz), 7.05 (t, 1H, J = 7.2 Hz), 4.65−4.55
(m, 1H), 4.17−4.09 (m, 2H), 4.08−4.03 (m, 1H), 4.01−3.94 (m,
1H), 3.70−3.62 (m, 1H), 3.51 (dd, 1H, J = 10.0, 7.2 Hz), 3.21−3.14
(m, 1H), 2.88−2.83 (m, 1H), 1.12 (td, 3H, J = 7.2, 1.2 Hz), 1.03 (td,
3H, J = 7.2, 2.0 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.0,
167.8, 158.5, 148.9, 147.0, 136.8, 128.2, 123.9, 122.9, 120.7, 118.2,
78.7, 75.8, 62.1, 62.0, 44.3, 31.9, 13.7, 13.6 ppm. HRMS (ESI) m/z
[M + H]+ Calcd for C16H21BrNO5 386.0598, found 386.0588.
Diethyl 5-((Methylthio)methyl)-2-phenylisoxazolidine-3,3-dicar-
boxylate (4u). Yellow oil (91% yield, 64.3 mg); TLC, Rf = 0.3 (PE/
EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.28 (d, 2H, J =
8.8 Hz), 7.23 (t, 2H, J = 8.0 Hz), 7.02 (t, 1H, J = 6.8 Hz), 4.59−4.52
(m, 1H), 4.13−3.97 (m, 4H), 3.07 (dd, 1H, J = 12.8, 6.4 Hz), 2.83−
2.94 (m, 2H), 2.75 (dd, 1H, J = 14.0, 6.4 Hz), 2.22 (s, 3H), 1.06 (q,
6H, J = 6.4 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.0,
168.0, 147.0, 128.2, 123.8, 118.2, 78.1, 76.9, 62.9, 62.0, 45.0, 36.2,
16.5, 13.7 ppm. HRMS (ESI) m/z [M + H]+ Calcd for C17H24NO5S
354.1370, found 354.1375.
3,3-Diethyl 5-Methyl-2-phenylisoxazolidine-3,3,5-tricarboxylate
(4v). Yellow oil (96% yield, 67.4 mg); TLC, Rf = 0.3 (PE/EtOAc =
20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.29 (d, 2H, J = 7.6 Hz),
7.17 (t, 2H, J = 8.4 Hz), 6.99 (t, 1H, J = 7.2 Hz), 4.79 (dd, 1H, J =
8.4, 5.6 Hz), 4.15−4.07 (m, 2H), 3.97−3.87 (m, 1H), 3.84−3.76 (m,
1H), 3.72 (s, 3H), 3.28−3.17 (m, 2H), 1.11 (t, 3H, J = 7.2 Hz), 0.88
(t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 169.4,
166.5, 166.0, 145.3, 127.1, 123.6, 118.2, 75.8, 73.2, 61.1, 61.0, 51.6,
41.2, 12.8, 12.5 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C17H22NO7 352.1391, found 352.1395.
3-Ethyl 4,5-Dimethyl-2-phenylisoxazolidine-3,4,5-tricarboxylate
(4w). Yellow oil (93% yield, 82.8 mg); TLC, Rf = 0.3 (PE/EtOAc =
20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.40 (d, 4H, J = 7.6 Hz),
7.25 (d, 2H, J = 8.0 Hz), 7.22 (t, 4H, J = 7.6 Hz), 7.16 (d, 2H, J = 8.0
Hz), 7.12 (d, 2H, J = 6.8 Hz), 6.90 (t, 1H, J = 7.2 Hz), 3.87−3.77 (m,
4H), 3.71 (s, 2H), 0.86 (t, 6H, J = 7.2 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 168.3, 147.1, 142.0, 128.3, 127.6, 126.4, 122.8,
116.9, 85.9, 78.9, 62.1, 51.6, 13.7 ppm. HRMS (ESI) m/z [M + H]+
Calcd for C27H28NO5 446.1962, found 446.1960.
Diethyl 5-(Naphthalen-2-yl)-2-phenylisoxazolidine-3,3-dicar-
boxylate (4n). Yellow oil (92% yield, 77.1 mg); TLC, Rf = 0.3
1
(PE/EtOAc = 20:1, v/v); H NMR (CDCl3, 400 MHz) δ 7.85 (s,
1H), 7.77 (d, 1H, J = 8.4 Hz), 7.77−7.72 (m, 2H), 7.59 (dd, 1H, J =
8.4, 1.6 Hz), 7.39−7.37 (m, 2H), 7.32 (d, 2H, J = 7.6 Hz), 7.17 (t,
2H, J = 8.8 Hz), 6.95 (t, 1H, J = 7.2 Hz), 5.41 (dd, 1H, J = 9.6, 6.4
Hz), 4.08 (q, 2H, J = 7.2 Hz), 3.98−3.90 (m, 1H), 3.89−3.81 (m,
1H), 3.25−3.12 (m, 2H), 1.09 (t, 3H, J = 7.2 Hz), 0.92 (t, 3H, J = 7.2
Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.5, 168.0, 147.3,
134.8, 134.4, 133.4, 133.2, 128.6, 128.3, 128.1, 127.7, 126.4, 126.3,
124.4, 123.9, 118.2, 79.1, 78.9, 62.3, 62.1, 48.0, 13.9, 13.7 ppm.
HRMS (ESI) m/z [M + H]+ Calcd for C25H26NO5 420.1805, found
420.1803.
Diethyl 5-Hexadecyl-2-phenylisoxazolidine-3,3-dicarboxylate
(4o). White solid (96% yield, 99.3 mg); mp 79−80 °C; TLC, Rf =
0.3 (PE/EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.19 (d,
2H, J = 8.4 Hz), 7.12 (t, 2H, J = 8.4 Hz), 6.89 (t, 1H, J = 7.2 Hz),
4.02 (q, 2H, J = 6.8 Hz), 4.00−3.92 (m, 1H), 3.91−3.83 (m, 1H),
2.85 (dd, 1H, J = 12.4, 5.6 Hz), 2.60 (dd, 1H, J = 12.4, 9.2 Hz), 1.77−
1.69 (m, 1H), 1.61−1.53 (m, 1H), 1.48−1.39 (m, 1H), 1.25−1.18
(m, 28H), 1.07 (t, 3H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.2 Hz), 0.80 (t,
3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.6,
168.2, 147.5, 128.1, 123.3, 117.7, 78.4, 77.3, 62.0, 61.8, 45.9, 32.5,
31.9, 29.7, 29.5, 29.5, 29.3, 26.2, 22.6, 14.1, 13.7, 13.6 ppm. HRMS
(ESI) m/z [M + H]+ Calcd for C31H52NO5 518.3840, found
518.3836.
Diethyl 5-Butyl-2-phenylisoxazolidine-3,3-6-dicarboxylate (4p).
Yellow oil (97% yield, 67.7 mg); TLC, Rf = 0.3 (PE/EtOAc = 20:1, v/
v); 1H NMR (CDCl3, 400 MHz) δ 7.19 (d, 2H, J = 8.8 Hz), 7.15 (t,
2H, J = 8.8 Hz), 6.92 (t, 1H, J = 7.2 Hz), 4.03 (q, 2H, J = 7.2 Hz),
4.02−3.94 (m, 1H), 3.92−3.84 (m, 1H), 2.86 (dd, 1H, J = 12.4, 5.6
Hz), 2.60 (dd, 1H, J = 12.8, 9.2 Hz), 1.79−1.70 (m, 1H), 1.63−1.55
(m, 1H), 1.42−1.39 (m, 1H), 1.38−1.29 (m, 4H), 1.08 (t, 3H, J = 7.2
Hz), 0.97 (t, 3H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
NMR (CDCl3, 100 MHz) δ 168.7, 168.2, 147.5, 128.1, 123.3, 117.7,
78.4, 77.4, 62.0, 61.9, 45.9, 32.2, 28.3, 22.6, 13.9, 13.7, 13.6 ppm.
HRMS (ESI) m/z [M + H]+ Calcd for C19H28NO5 350.1962, found
350.1967.
Diethyl 5-(Hydroxymethyl)-2-phenylisoxazolidine-3,3-dicarboxy-
late (4q). Yellow oil (90% yield, 58.2 mg); TLC, Rf = 0.3 (PE/EtOAc
= 5:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.33 (d, 2H, J = 8.0 Hz),
7.25 (t, 2H, J = 8.4 Hz), 7.06 (t, 1H, J = 7.6 Hz), 4.56−4.51 (m, 1H),
4.16−4.06 (m, 2H), 4.06−3.93 (m, 2H), 3.92−3.87 (m, 1H), 3.79−
3.73 (m, 1H), 3.03 (dd, 1H, J = 12.8, 7.2 Hz), 2.87 (dd, 1H, J = 12.8,
6.4 Hz), 2.63 (t, 1H, J = 6.0 Hz), 1.12 (t, 3H, J = 7.2 Hz), 1.02 (t, 3H,
J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.2, 167.5,
146.7, 128.2, 124.4, 119.0, 78.0, 77.1, 63.1, 62.1, 62.0, 40.8, 13.7, 13.6
ppm. HRMS (ESI) m/z [M + H]+ Calcd for C16H22NO6 324.1442,
found 324.1450.
3,3-Diethyl 5-Methyl-5-methyl-2-phenylisoxazolidine-3,3,5-tri-
carboxylate (4x). Yellow oil (94% yield, 68.6 mg); TLC, Rf = 0.3
1
(PE/EtOAc = 20:1, v/v); H NMR (CDCl3, 400 MHz) δ 7.35 (d,
2H, J = 8.0 Hz), 7.23 (t, 2H, J = 7.6 Hz), 7.05 (t, 1H, J = 7.2 Hz),
4.24 (q, 2H, J = 7.2 Hz), 3.94−3.82 (m, 1H), 3.76 (s, 3H), 3.75−3.68
(m, 1H), 3.50 (d, 1H, J = 13.2 Hz), 3.00 (d, 1H, J = 13.2 Hz), 1.68 (s,
3H), 1.27 (t, 3H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
NMR (CDCl3, 100 MHz) δ 173.6, 168.2, 167.0, 146.1, 128.0, 124.4,
119.2, 80.9, 78.0, 61.9, 61.8, 52.8, 47.9, 21.3, 13.9, 13.0 ppm. HRMS
(ESI) m/z [M + H]+ Calcd for C18H24NO7 366.1547, found
366.1557.
Diethyl 5-(2-Hydroxyethyl)-2-phenylisoxazolidine-3,3-dicarboxy-
late (4r). Yellow oil (95% yield, 64.1 mg); TLC, Rf = 0.3 (PE/EtOAc
= 5:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.28 (d, 2H, J = 7.6 Hz),
7.23 (t, 2H, J = 8.8 Hz), 7.02 (t, 1H, J = 7.2 Hz), 4.55−4.48 (m, 1H),
4.14−4.09 (m, 2H), 4.08−4.01 (m, 1H), 4.00−3.92 (m, 1H), 3.82 (s,
2H), 3.00 (dd, 1H, J = 12.8, 6.4 Hz), 2.77 (dd, 1H, J = 12.4, 8.8 Hz),
Diethyl 5-Methyl-2,5-diphenylisoxazolidine-3,3-dicarboxylate
(4y). Yellow oil (96% yield, 73.6 mg); TLC, Rf = 0.3 (PE/EtOAc =
20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.46 (d, 2H, J = 8.0 Hz),
G
https://dx.doi.org/10.1021/acs.joc.0c02567
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
7.30 (q, 4H, J = 8.0 Hz), 7.25 (t, 3H, J = 8.4 Hz), 6.99 (t, 1H, J = 7.2
Hz), 4.08−3.98 (m, 2H), 3.96−3.83 (m, 2H), 3.44 (d, 1H, J = 12.8
Hz), 3.14 (d, 1H, J = 12.4 Hz), 1.73 (s, 3H), 1.03 (t, 3H, J = 7.2 Hz),
0.95 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ
168.3, 168.2, 147.0, 144.1, 128.2, 128.1, 127.1, 125.0, 123.0, 117.4,
81.9, 78.7, 62.1, 61.8, 52.3, 27.1, 13.7, 13.6 ppm. HRMS (ESI) m/z
[M + H]+ Calcd for C22H26NO5 384.1805, found 384.1807.
129.1, 128.7, 128.2, 127.4, 124.9, 119.7, 81.8, 81.1, 63.1, 62.4, 62.1,
61.5, 14.0, 13.7, 13.4 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C24H28NO7 442.1860, found 442.1861.
Diethyl-4,6-dioxo-2-phenyltetrahydrofuro[3,4-d]isoxazole-
3,3(2H)-dicarboxylate (4af). Yellow oil (84% yield, 61.0 mg); TLC,
1
Rf = 0.3 (PE/EtOAc = 10:1, v/v); H NMR (CDCl3, 400 MHz) δ
7.42 (d, 2H, J = 8.4 Hz), 7.28 (t, 2H, J = 8.0 Hz), 7.13 (t, 1H, J = 6.8
Hz), 5.31 (d, 1H, J = 8.0 Hz), 4.61 (d, 1H, J = 7.6 Hz), 4.28−4.17 (m,
1H), 3.98−3.90 (m, 1H), 3.75−3.67 (m, 1H), 3.92−3.84 (m, 1H),
1.20 (t, 3H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 171.3, 166.0, 165.4, 145.7, 128.3, 125.9, 120.3,
80.4, 62.9, 62.7, 58.8, 13.5, 13.3 ppm. HRMS (ESI) m/z [M + H]+
Calcd for C17H18NO8 364.1027, found 364.1030.
Diethyl-4,6-dioxo-2,5-diphenyltetrahydro-2H-pyrrolo[3,4-d]-
isoxazole-3,3(3aH)-dicarboxylate (4ag). Yellow oil (80% yield, 70.1
mg); TLC, Rf = 0.3 (PE/EtOAc = 10:1, v/v); 1H NMR (CDCl3, 400
MHz) δ 7.50 (t, 2H, J = 7.6 Hz), 7.43 (d, 1H, J = 7.2 Hz), 7.41 (d,
2H, J = 8.0 Hz), 7.33 (d, 2H, J = 8.0 Hz), 7.30 (t, 2H, J = 7.6 Hz),
7.18 (t, 1H, J = 7.2 Hz), 5.19 (d, 1H, J = 7.6 Hz), 4.59 (d, 1H, J = 7.6
Hz), 4.32 (q, 2H, J = 6.8 Hz), 4.10−4.02 (m, 1H), 3.87−3.79 (m,
1H), 1.30 (t, 3H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
NMR (CDCl3, 100 MHz) δ 172.7, 172.0, 164.7, 164.6, 144.7, 131.2,
129.3, 129.1, 128.2, 126.5, 126.0, 120.6, 80.8, 74.5, 63.0, 62.3, 55.0,
13.8, 13.3 ppm. HRMS (ESI) m/z [M + H]+ Calcd for C23H23N2O7
439.1500, found 439.1500.
Diethyl 2-Phenyloctahydrocycloocta[d]isoxazole-3,3(2H)-dicar-
boxylate (4ah). Yellow oil (93% yield, 69.8 mg); TLC, Rf = 0.3
(PE/EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.21 (d, J =
8.4 Hz, 2H), 7.14 (t, J = 8.0 Hz, 2H), 6.95 (d, J = 7.2 Hz, 1H), 4.43
(t, J = 8.8 Hz, 1H), 4.18−4.01 (m, 1H), 4.05−3.99 (m, 1H), 3.96−
3.84 (m, 2H), 3.00 (t, J = 9.6 Hz, 1H), 1.90 (q, J = 12.4 Hz, 2H), 1.82
(d, J = 14.4 Hz, 1H), 1.75−1.64 (m, 2H), 1.61−1.49 (m, 3H), 1.37−
1.26 (m, 3H), 1.19−1.14 (m, 1H), 1.10 (t, J = 7.2 Hz, 3H), 0.94 (t, J
= 7.2 Hz, 3H) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.0,
166.1, 146.9, 128.0, 124.0, 119.3, 82.6, 80.9, 61.7, 61.1, 54.8, 29.8,
27.8, 27.4, 25.6, 25.5, 23.3, 13.8, 13.7 ppm. HRMS (ESI) m/z [M +
H]+ Calcd for C21H30NO5 376.2118, found 376.2131.
Diethyl 5-Formyl-5-methyl-2-phenylisoxazolidine-3,3-dicarboxy-
late (4z). Colorless oil (91% yield, 61.0 mg); TLC, Rf = 0.3 (PE/
1
EtOAc = 20:1, v/v); H NMR (CDCl3, 400 MHz) δ 9.70 (s, 1H),
7.40 (d, 2H, J = 8.0 Hz), 7.29 (t, 2H, J = 6.4 Hz), 7.13 (t, 1H, J = 7.2
Hz), 4.26 (qd, 2H, J = 7.2, 2.8 Hz), 3.94−3.85 (m, 1H), 3.75−3.67
(m, 1H), 3.17 (d, 1H, J = 13.2 Hz), 3.02 (d, 1H, J = 12.8 Hz), 1.51 (s,
3H), 1.29 (t, 3H, J = 7.2 Hz), 0.84 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
NMR (CDCl3, 100 MHz) δ 203.3, 168.0, 166.6, 145.8, 128.2, 125.0,
119.6, 83.9, 77.8, 62.1, 61.9, 45.8, 17.4, 13.9, 13.4 ppm. HRMS (ESI)
m/z [M + H]+ Calcd for C17H22NO6 336.1442, found 336.1447.
Triethyl 2,5-Diphenylisoxazolidine-3,3,5-tricarboxylate (4aa).
Yellow oil (90% yield, 79.4 mg); TLC, Rf = 0.3 (PE/EtOAc = 20:1,
1
v/v); H NMR (CDCl3, 600 MHz) δ 7.54 (d, 2H, J = 6.6 Hz), 7.45
(dd, 2H, J = 8.4, 1.2 Hz), 7.39 (t, 2H, J = 13.8 Hz), 7.35 (d, 1H, J =
7.2 Hz), 7.27 (t, 2H, J = 8.4 Hz), 7.08 (t, 1H, J = 7.2 Hz), 4.28 (q,
2H, J = 7.2 Hz), 4.27−4.23 (m, 1H), 4.19−4.14 (m, 1H), 3.96 (d,
1H, J = 7.2 Hz), 3.88−3.82 (m, 1H), 3.73−3.67 (m, 1H), 3.32 (d,
1H, J = 12.6 Hz), 1.29 (t, 3H, J = 7.2 Hz), 1.20 (t, 3H, J = 7.2 Hz),
0.84 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 150 MHz) δ
171.6, 168.1, 166.9, 146.1, 136.7, 128.4, 128.0, 125.3, 124.4, 119.4,
85.0, 77.9, 62.0, 61.9, 48.7, 13.9, 13.8, 13.3 ppm. HRMS (ESI) m/z
[M + H]+ Calcd for C24H28NO7 442.1860, found 442.1864.
3,3-Diethyl 4,5-Dimethyl-2-phenylisoxazolidine-3,3,4,5-tetracar-
boxylate (4ab). Yellow oil (90% yield, 73.6 mg), TLC, Rf = 0.3 (PE/
1
EtOAc = 5:1, v/v); H NMR (CDCl3, 400 MHz) δ 7.37 (d, 2H, J =
8.4 Hz), 7.18 (t, 2H, J = 8.0 Hz), 7.01 (t, 1H, J = 7.2 Hz), 5.16 (d,
1H, J = 7.6 Hz), 4.47 (d, 1H, J = 7.6 Hz), 4.10 (q, 2H, J = 7.2 Hz),
3.95−3.87 (m, 1H), 3.78−3.73 (m, 1H), 3.71 (s, 3H), 3.65 (s, 3H),
1.14 (t, 3H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 168.1, 168.0, 166.0, 165.7, 146.4, 128.2, 125.0,
119.5, 80.1, 76.7, 62.6, 62.3, 58.5, 52.6, 52.6, 13.7, 13.3 ppm. HRMS
(ESI) m/z [M + H]+ Calcd for C19H24NO9 410.1446, found
410.1434.
Diethyl 2-Phenyltetrahydrofuro[2,3-d]isoxazole-3,3(2H)-dicar-
boxylate (4ai). Colorless oil (92% yield, 61.7 mg); TLC, Rf = 0.3
1
(PE/EtOAc = 20:1, v/v); H NMR (CDCl3, 600 MHz) δ 7.42 (d,
2H, J = 7.6 Hz), 7.23 (t, 2H, J = 8.4 Hz), 7.09 (t, 1H, J = 7.2 Hz),
5.96 (d, 1H, J = 5.4 Hz), 4.36−4.31 (m, 1H), 4.29−4.21 (m, 2H),
3.98 (td, 1H, J = 7.6, 2.4 Hz), 3.90−3.86 (m, 2H), 3.67−3.62 (m,
1H), 2.14−2.06 (m, 1H), 1.94−1.90 (m, 1H), 1.28 (t, 3H, J = 7.2
Hz), 0.76 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 150
MHz) δ 166.6, 165.7, 146.1, 127.9, 125.3, 120.8, 104.2, 82.4, 69.0,
61.8, 61.4, 54.0, 28.9, 13.9, 13.2 ppm. HRMS (ESI) m/z [M + H]+
Calcd for C17H22NO6 336.1442, found 336.1438.
Triethyl 5-(6-Chloro-9H-purin-9-yl)-2-phenylisoxazolidine-3,3,4-
tricarboxylate (4aj). Yellow oil (86% yield, 86.5 mg); TLC, Rf = 0.3
(PE/EtOAc = 2:1, v/v); 1H NMR (CDCl3, 600 MHz) δ 8.78 (s, 1H),
8.76 (s, 1H), 7.26 (t, 2H, J = 6.6 Hz), 7.24−7.21 (m, 2H), 7.16 (d,
1H, J = 7.2 Hz), 7.13 (t, 1H, J = 7.2 Hz), 4.80 (d, 1H, J = 4.8 Hz),
4.40−4.32 (m, 2H), 4.00 (dd, 1H, J = 7.2, 3.6 Hz), 3.92 (dd, 1H, J =
7.2, 3.6 Hz), 3.75 (s, 3H), 1.27 (t, 3H, J = 7.2 Hz), 0.94 (t, 3H, J = 7.2
Hz) ppm; 13C{1H} NMR (CDCl3, 150 MHz) δ 166.8, 165.7, 164.2,
151.6, 151.1, 144.5, 143.8, 128.4, 125.8, 119.4, 81.4, 80.0, 63.2, 62.3,
62.2, 53.0, 13.8, 13.7, 13.3 ppm. HRMS (ESI) m/z [M + H]+ Calcd
for C22ClH23N5O7 504.1281, found 504.1288.
Triethyl 5-(6-Methoxy-9H-purin-9-yl)-2-phenylisoxazolidine-
3,3,4-tricarboxylate (4ak). Yellow oil (94% yield, 96.5 mg); TLC,
Rf = 0.3 (PE/EtOAc = 2:1, v/v); 1H NMR (CDCl3, 600 MHz) δ 8.55
(s, 1H), 8.52 (s, 1H), 7.24 (d, 2H, J = 1.2 Hz), 7.23 (s, 2H), 7.09 (d,
2H, J = 4.8 Hz), 4.79 (d, 1H, J = 4.8 Hz), 4.34−4.28 (m, 2H), 4.21−
4.16 (m, 2H), 4.15 (s, 3H), 4.04−3.95 (m, 1H), 3.97−3.91 (m, 1H),
1.25 (t, 3H, J = 7.2 Hz), 1.20 (t, 3H, J = 7.2 Hz), 0.95 (t, 3H, J = 7.2
Hz) ppm; 13C{1H} NMR (CDCl3, 150 MHz) δ 166.4, 165.9, 164.3,
161.0, 152.5, 151.9, 144.9, 140.6, 128.3, 125.5, 121.1, 119.3, 81.2,
80.0, 63.0, 62.2, 62.1, 54.2, 13.7, 13.7, 13.4 ppm. HRMS (ESI) m/z
[M + H]+ Calcd for C24H28N5O8 514.1932, found 514.1930.
3,3-Diethyl-4,5-dimethyl-2-phenylisoxazolidine-3,3,4,5-tetracar-
boxylate (4ac). Yellow oil (95% yield, 77.7 mg); TLC, Rf = 0.3 (PE/
1
EtOAc = 5:1, v/v); H NMR (CDCl3, 400 MHz) δ 7.22 (t, 2H, J =
7.6 Hz), 7.18 (t, 2H, J = 7.6 Hz), 7.02 (t, 1H, J = 7.2 Hz), 5.08 (d,
1H, J = 6.4 Hz), 4.51 (d, 1H, J = 6.8 Hz), 4.17−4.09 (m, 1H), 4.06−
4.00 (m, 1H), 3.92 (q, 2H, J = 7.2 Hz), 3.76 (s, 3H), 3.69 (s, 3H),
1.07 (t, J = 7.2 Hz, 3H), 0.95 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 168.1, 167.4, 164.2, 144.7, 127.2, 124.0, 118.3,
78.9, 75.2, 61.7, 61.2, 57.6, 51.9, 51.7, 12.6, 12.5 ppm. HRMS (ESI)
m/z [M + H]+ Calcd for C19H24NO9 410.1446, found 410.1434.
Diethyl 4-Benzoyl-2,5-diphenylisoxazolidine-3,3-dicarboxylate
(4ad). White solid (96% yield, 90.9 mg); mp 144−145 °C; TLC,
1
Rf = 0.3 (PE/EtOAc = 20:1, v/v); H NMR (CDCl3, 400 MHz) δ
7.70 (d, 2H, J = 7.6 Hz), 7.49 (d, 2H, J = 7.6 Hz), 7.44 (dd, 2H, J =
7.2, 1.2 Hz), 7.41 (t, 1H, J = 7.6 Hz), 7.27 (t, 2H, J = 7.6 Hz), 7.22 (t,
4H, J = 7.2 Hz), 7.18 (d, 1H, J = 4.0 Hz), 7.05 (t, 1H, J = 7.2 Hz),
5.47 (s, 2H), 4.05−3.96 (m, 1H), 3.86−3.77 (m, 2H), 3.53−3.45 (m,
1H), 0.78 (t, 3H, J = 7.2 Hz), 0.70 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
NMR (CDCl3, 100 MHz) δ 196.4, 166.6, 166.5, 146.2, 137.1, 135.6,
133.7, 129.1, 128.8, 128.6, 128.6, 128.2, 127.4, 125.7, 121.0, 83.3,
82.5, 62.8, 62.3, 61.8, 13.3, 13.2 ppm. HRMS (ESI) m/z [M + H]+
Calcd for C28H28NO6 474.1911, found 474.1913.
Triethyl 2,5-Diphenylisoxazolidine-3,3,4-tricarboxylate (4ae).
Yellow oil (80% yield, 70.6 mg), TLC, Rf = 0.3 (PE/EtOAc = 20:1,
v/v); 1H NMR (CDCl3, 400 MHz) δ 7.57 (dd, 2H, J = 7.6, 1.2 Hz),
7.39 (dd, 5H, J = 18.0, 7.6 Hz), 7.27 (t, 2H, J = 8.4 Hz), 7.09 (t, 1H, J
= 7.6 Hz), 5.42 (d, 1H, J = 8.8 Hz), 4.38 (d, 1H, J = 9.2 Hz), 4.31−
4.23 (m, 1H), 4.17−4.09 (m, 3H), 4.04−3.96 (m, 1H), 3.83−3.75
(m, 1H), 1.19 (td, 6H, J = 7.2, 2.4 Hz), 0.95 (t, 3H, J = 7.2 Hz) ppm;
13C{1H} NMR (CDCl3, 100 MHz) δ 168.8, 166.4, 146.4, 136.0,
H
https://dx.doi.org/10.1021/acs.joc.0c02567
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Triethyl 2-Phenyl-5-(6-(piperidin-1-yl)-9H-purin-9-yl)-
NMR (CDCl3, 150 MHz) δ 167.2, 165.8, 160.9, 148.6, 147.9, 147.0,
145.0, 134.4, 128.4, 126.0, 123.0, 120.1, 116.5, 86.8, 81.8, 77.0, 62.6,
62.2, 46.1, 27.4, 20.2, 13.9, 13.4, 12.4 ppm. HRMS (ESI) m/z [M +
H]+ Calcd for C26H34N3O9 532.2290, found 532.2297.
isoxazolidine-3,3,4-tricar-boxylate (4al). White solid (85% yield,
1
96.3 mg); mp 93−94 °C; TLC, Rf = 0.3 (PE/EtOAc = 2:1, v/v); H
NMR (CDCl3, 600 MHz), δ 8.33 (d, 2H, J = 1.8 Hz), 7.24 (s, 2H),
7.23 (d, 2H, J = 2.4 Hz), 7.10−7.07 (m, 1H), 7.06 (d, 1H, J = 4.8
Hz), 4.77 (d, 1H, J = 4.8 Hz), 4.34−4.26 (m, 3H), 4.23−4.14 (m,
5H), 4.04−3.98 (m, 1H), 3.97−3.93 (m, 1H), 1.71−1.64 (m, 6H),
1.25 (t, 3H, J = 7.2 Hz), 1.21 (t, 3H, J = 7.2 Hz), 0.97 (t, 3H, J = 7.2
Hz) ppm; 13C{1H} NMR (CDCl3, 150 MHz) δ 166.5, 166.0, 164.4,
153.7, 152.8, 151.0, 145.1, 136.2, 128.2, 125.3, 119.3, 80.8, 80.0, 62.9,
62.0, 53.3, 46.3, 26.0, 24.7, 13.8, 13.7, 13.4 ppm. HRMS (ESI) m/z
[M + H]+ Calcd for C28H35N6O7 567.2562, found 567.2565.
Diethyl 5-(3-(tert-Butoxycarbonyl)-5-fluoro-2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl)-2-phenylisoxazolidine-3,3-dicarboxylate
(4ar). Yellow solid (86% yield, 89.6 mg); mp 90−91 °C; TLC, Rf =
0.3 (PE/EtOAc = 2:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 8.05 (d,
1H, J = 6.4 Hz), 7.39 (d, 2H, J = 8.0 Hz), 7.33 (t, 2H, J = 8.0 Hz),
7.21 (t, 1H, J = 7.2 Hz), 6.43 (d, 1H, J = 5.2 Hz), 4.38−4.24 (m, 2H),
3.98−3.90 (m, 1H), 3.83 (q, 1H, J = 7.2 Hz), 3.79−3. 71 (m, 1H),
2.88 (dd, 1H, J = 14.8, 2.8 Hz), 1.62 (s, 9H), 1.28 (t, 3H, J = 7.2 Hz),
0.85 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ
167.0, 165.6, 154.6, 154.3, 147.2, 146.4, 144.7, 141.2, 138.9, 128.5,
126.3, 124.1, 123.7, 120.2, 87.8, 82.4, 76.9, 62.7, 62.3, 46.3, 27.4, 13.9,
13.3 ppm. HRMS (ESI) m/z [M + H]+ Calcd for C24H29FN3O9
522.1882, found 522.1886.
Triethyl 5-(5-Chloro-1H-benzo[d]imidazol-1-yl)-2-phenylisoxa-
zolidine-3,3,4-tricarboxylate (4am). Yellow oil (80% yield, 82.4
1
mg); TLC, Rf = 0.3 (PE/EtOAc = 2:1, v/v); H NMR (CDCl3, 600
MHz) δ 8.30 (s, 1H), 7.97 (d, 1H, J = 8.4 Hz), 7.78 (d, 1H, J = 1.8
Hz), 7.30−7.26 (m, 3H), 7.18 (d, 2H, J = 7.6 Hz), 7.14 (t, 1H, J = 7.2
Hz), 6.72 (d, 1H, J = 6.0 Hz), 4.63 (d, 1H, J = 6.0 Hz), 4.32 (q, 2H, J
= 7.2 Hz), 4.21−4.13 (m, 2H), 4.09−4.04 (m, 1H), 4.01−3.96 (m,
1H), 1.29 (t, 3H, J = 7.2 Hz), 1.20 (t, 3H, J = 7.2 Hz), 0.95 (t, 3H, J =
7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 150 MHz) δ 166.5, 165.2,
164.7, 144.9, 144.8, 143.2, 130.4, 128.6, 128.5, 125.4, 124.1, 118.8,
112.4, 120.1, 83.9, 80.5, 63.2, 62.2, 62.1, 60.9, 13.7, 13.7, 13.3 ppm.
HRMS (ESI) m/z [M + H]+ Calcd for C25H27ClN3O7 516.1532,
found 516.1527.
Diethyl 5-(3-(tert-Butoxycarbonyl)-5-chloro-2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl)-2-phenylisoxazolidine-3,3-dicarboxylate
(4as). Yellow solid (88% yield, 94.5 mg); mp 105−106 °C; TLC, Rf =
1
0.3 (PE/EtOAc = 2:1, v/v); H NMR (CDCl3, 400 MHz) δ 8.14 (s,
1H), 7.40 (d, 2H, J = 8.0 Hz), 7.34 (t, 2H, J = 8.0 Hz), 7.22 (t, 1H, J
= 7.2 Hz), 6.42 (dd, 1H, J = 7.2, 2.4 Hz), 4.39−4.25 (m, 2H), 3.98−
3.90 (m, 1H), 3.84 (q, 1H, J = 7.2 Hz), 3.89−3.71 (m, 1H), 2.90 (dd,
1H, J = 14.4, 2.4 Hz), 1.62 (s, 9H), 1.29 (t, 3H, J = 7.2 Hz), 0.86 (t,
3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 167.0,
165.6, 156.6, 147.7, 146.6, 144.7, 136.3, 128.5, 126.3, 120.3, 109.0,
87.7, 82.8, 76.9, 62.8, 62.3, 46.5, 27.3, 13.9, 13.3 ppm. HRMS (ESI)
m/z [M + H]+ Calcd for C24H29ClN3O9 538.1587, found 538.1589.
Diethyl 5-(5-Bromo-3-(tert-butoxycarbonyl)-2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl)-2-phenylisoxazolidine-3,3-dicarboxylate
(4at). Yellow solid (87% yield, 101.1 mg); mp 105−106 °C; TLC, Rf
= 0.3 (PE/EtOAc = 2:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 8.24 (s,
1H), 7.40 (d, 2H, J = 8.0 Hz), 7.34 (t, 2H, J = 8.0 Hz), 7.21 (t, 1H, J
= 7.2 Hz), 6.41 (dd, 1H, J = 7.6, 2.8 Hz), 4.38−4.25 (m, 2H), 3.98−
3.90 (m, 1H), 3.83 (q, 1H, J = 7.2 Hz), 3.79−3.71 (m, 1H), 2.91 (dd,
1H, J = 14.4, 2.4 Hz), 1.61 (s, 9H), 1.29 (t, 3H, J = 7.2 Hz), 0.85 (t,
3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 167.0,
165.6, 156.6, 148.0, 146.7, 144.7, 138.9, 128.5, 126.3, 120.3, 96.5,
87.7, 82.8, 76.9, 62.8, 62.3, 46.5, 27.3, 13.9, 13.3 ppm. HRMS (ESI)
m/z [M + H]+ Calcd for C24H29BrN3O9 582.1082, found 582.1083.
5-(4-((Di-tert-butoxycarbonyl)amino)-2-oxopyrimidin-1(2H)-yl)-
2-phenylisoxazolidine-3,3-carboxylate (4au). White solid (77%
yield, 92.7 mg); mp 105−106 °C; TLC, Rf = 0.3 (PE/EtOAc =
Triethyl 5-(1H-Benzo[d][1,2,3]triazol-1-yl)-2-phenylisoxazoli-
dine-3,3,4-tricar-Boxylate (4an). Yellow solid (90% yield, 86.8
1
mg); mp 100−101 °C; TLC, Rf = 0.3 (PE/EtOAc = 2:1, v/v); H
NMR (CDCl3, 600 MHz) δ 8.06 (dd, 2H, J = 12.0, 8.4 Hz), 7.53 (t,
1H, J = 7.6 Hz), 7.39 (t, 1H, J = 7.2 Hz), 7.26−7.21 (m, 5H), 7.08 (t,
1H, J = 6.6 Hz), 5.47 (d, 1H, J = 5.4 Hz), 4.47−4.38 (m, 2H), 4.26−
4.16 (m, 2H), 4.08−4.02 (m, 1H), 3.99−3.94 (m, 1H), 1.36 (t, 3H, J
= 7.2 Hz), 1.24 (t, 3H, J = 7.2 Hz), 0.95 (t, 3H, J = 7.2 Hz) ppm;
13C{1H} NMR (CDCl3, 150 MHz) δ 166.5, 165.6, 164.8, 146.8,
145.1, 131.9, 128.3, 128.1, 125.0, 124.4, 120.1, 118.7, 110.8, 85.4,
80.4, 63.1, 62.2, 62.1, 59.6, 13.8, 13.8, 13.4 ppm. HRMS (ESI) m/z
[M + H]+ Calcd for C24H27N4O7 483.1874, found 483.1869.
Triethyl 5-(1H-Indol-1-yl)-2-phenylisoxazolidine-3,3,4-tricarbox-
ylate (4ao). Black oil (71% yield, 68.2 mg); TLC, Rf = 0.3 (PE/
1
EtOAc = 2:1, v/v); H NMR (CDCl3, 600 MHz) δ 7.76 (d, 1H, J =
7.6 Hz), 7.64 (s, 1H), 7.63 (d, 1H, J = 5.4 Hz), 7.29 (s, 2H), 7.28 (d,
2H, J = 4.2 Hz), 7.26 (d, 1H, J = 8.4 Hz), 7.17 (t, 1H, J = 7.2 Hz),
7.13−7.10 (m, 1H), 6.80 (d, 1H, J = 6.6 Hz), 6.64 (d, 1H, J = 3.6
Hz), 4.75 (d, 1H, J = 6.6 Hz), 4.29−4.23 (m, 1H), 4.21−4.10 (m,
5H), 1.20 (td, 6H, J = 7.2, 3.0 Hz), 1.07 (t, 3H, J = 7.2 Hz) ppm;
13C{1H} NMR (CDCl3, 150 MHz) δ 167.4, 165.9, 165.3, 145.5,
135.8, 129.1, 128.3, 125.4, 124.9, 122.4, 121.0, 120.5, 119.0, 110.2,
104.4, 84.2, 80.5, 62.8, 61.8, 60.7, 13.8, 13.6, 13.5 ppm. HRMS (ESI)
m/z [M + H]+ Calcd for C26H29N2O7 481.1969, found 481.1965.
Diethyl 5-(3-(tert-Butoxycarbonyl)-5-methyl-2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl)-2-phenylisoxazolidine-3,3-dicarboxylate
(4ap). Colorless oil (85% yield, 87.9 mg); TLC, Rf = 0.3 (PE/EtOAc
= 2:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.66 (d, 1H, J = 1.2 Hz),
7.31 (d, 2H, J = 8.4 Hz), 7.26−7.21 (m, 2H), 7.12−7.05 (m, 1H),
6.39 (d, 1H, J = 7.2 Hz), 4.26−4.16 (m, 2H), 3.91−3.83 (m, 1H),
3.74−3.67 (m, 2H), 2.80 (d, 1H, J = 7.2 Hz), 1.86 (s, 3H), 1.54 (s,
9H), 1.18 (t, 3H, J = 7.2 Hz), 0.79 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
NMR (CDCl3, 150 MHz) δ 166.1, 164.7, 160.2, 147.7, 146.8, 144.1,
133.9, 127.4, 124.9, 119.0, 109.8, 85.8, 80.9, 76.1, 61.6, 61.1, 45.2,
26.4, 12.8, 12.3, 11.7 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C25H32N3O9 518.2133, found 518.2138.
1
2:1, v/v); H NMR (CDCl3, 400 MHz) δ 8.11 (d, 1H, J = 8.0 Hz),
7.41 (d, 2H, J = 8.0 Hz), 7.32 (t, 2H, J = 8.0 Hz), 7.18 (t, 1H, J = 7.2
Hz), 7.07 (d, 1H, J = 8.0 Hz), 6.32 (dd, 1H, J = 6.8, 2.0 Hz), 4.31−
4.17 (m, 2H), 3.97−3.86 (m, 2H), 3.76−3.68 (m, 1H), 2.94 (dd, 1H,
J = 14.8, 2.4 Hz), 1.56 (s, 18H), 1.23 (t, 3H, J = 7.2 Hz), 0.84 (t, 3H,
J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 167.2, 165.9,
162.6, 154.5, 149.5, 145.1, 143.4, 128.4, 125.9, 120.0, 96.0, 84.9, 84.1,
76.8, 62.4, 62.1, 47.2, 27.6, 13.9, 13.4 ppm. HRMS (ESI) m/z [M +
H]+ Calcd for C29H39N4O10 603.2661, found 603.2656.
Diethyl 5-Phenyl-2-(o-tolyl)isoxazolidine-3,3-dicarboxylate
(4ba). Yellow oil (94% yield, 72.0 mg); TLC, Rf = 0.3 (PE/EtOAc
= 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.41 (d, 2H, J = 7.6 Hz),
7.37 (d, 1H, J = 8.0 Hz), 7.29 (t, 2H, J = 7.6 Hz), 7.23 (d, 1H, J = 6.8
Hz), 7.05 (t, 2H, J = 6.4 Hz), 7.00 (t, 1H, J = 7.2 Hz), 5.25 (dd, 1H, J
= 9.2, 6.4 Hz), 4.12−4.00 (m, 2H), 3.91−3.83 (m, 1H), 3.70−3.62
(m, 1H), 3.21−3.10 (m, 2H), 2.38 (s, 3H), 1.07 (t, 3H, J = 7.2 Hz),
0.90 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ
167.2, 166.2, 144.6, 136.4, 134.4, 129.4, 127.5, 125.8, 124.7, 123.0,
78.0, 77.9, 60.9, 60.9, 46.0, 17.6, 12.7, 12.4 ppm. HRMS (ESI) m/z
[M + H]+ Calcd for C22H26NO5 384.1805, found 384.1800.
Diethyl 5-(3-(tert-Butoxycarbonyl)-5-ethyl-2,4-dioxo-3,4-dihy-
dropyrimidin-1(2H)-yl)-2-phenylisoxazolidine-3,3-dicarboxylate
(4aq). Yellow solid (80% yield, 85.0 mg); mp 100−101 °C; TLC, Rf =
Diethyl 5-Phenyl-2-(m-tolyl)isoxazolidine-3,3-dicarboxylate
(4bb). Yellow oil (95% yield, 72.8 mg); TLC, Rf = 0.3 (PE/EtOAc
= 20:1, v/v); 1H NMR (CDCl3, 600 MHz) δ 7.55 (d, 2H, J = 7.2 Hz),
7.40 (t, 2H, J = 7.6 Hz), 7.35 (t, 1H, J = 7.6 Hz), 7.20 (s, 1H), 7.17
(d, 1H, J = 8.4 Hz), 7.14 (t, 1H, J = 8.4 Hz), 6.85 (d, 1H, J = 7.2 Hz),
5.33 (dd, 1H, J = 9.6, 6.0 Hz), 4.19 (qd, 2H, J = 7.2, 1.8 Hz), 4.07−
4.02 (m, 1H), 3.98−3.93 (m, 1H), 3.22 (dd, 1H, J = 12.6, 6.0 Hz),
1
0.3 (PE/EtOAc = 3:1, v/v); H NMR (CDCl3, 400 MHz) δ 7.76 (s,
1H), 7.38 (d, 2H, J = 8.4 Hz), 7.30 (t, 2H, J = 7.6 Hz), 7.17 (t, 1H, J
= 6.8 Hz), 6.49 (d, 1H, J = 3.2 Hz, 7.6 Hz), 4.35−4.21 (m, 2H),
3.97−3.89 (m, 1H), 3.83−3.17 (m, 2H), 2.87 (dd, 1H, J = 7.6, 3.2
Hz), 2.34 (q, 2H, J = 7.6 Hz), 1.60 (s, 9H), 1.24 (t, 3H, J = 7.2 Hz),
1.13 (, 3H t, J = 7.2 Hz), 0.85 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
I
https://dx.doi.org/10.1021/acs.joc.0c02567
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3.13 (dd, 1H, J = 12.6, 9.6 Hz), 2.31 (s, 3H), 1.20 (t, 3H, J = 7.2 Hz),
1.04 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 150 MHz) δ
168.9, 167.9, 147.1, 137.2, 128.5, 128.0, 127.0, 124.5, 118.5, 115.2,
78.8, 78.6, 62.1, 61.9, 47.9, 21.5, 13.7, 13.5 ppm. HRMS (ESI) m/z
[M + H]+ Calcd for C22H26NO5 384.1805, found 384.1800.
Diethyl 5-Phenyl-2-(p-tolyl)isoxazolidine-3,3-dicarboxylate
(4bc).6a Yellow oil (96% yield, 73.6 mg); TLC, Rf = 0.3 (PE/
EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.45 (d, 2H, J =
6.8 Hz), 7.30 (t, 2H, J = 7.2 Hz), 7.25 (d, 1H, J = 7.2 Hz), 7.20 (d,
2H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 5.22 (dd, 1H, J = 9.2, 6.4
Hz), 4.09 (q, 2H, J = 7.2 Hz), 3.96−3.88 (m, 1H), 3.86−3.78 (m,
1H), 3.15−3.04 (m, 2H), 2.20 (s, 3H), 1.11 (t, 3H, J = 7.2 Hz), 0.93
(t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.6,
167.9, 144.7, 137.6, 133.6, 128.7, 128.6, 128.5, 127.1, 118.8, 78.8,
78.8, 62.1, 61.9, 47.8, 20.8, 13.8, 13.6 ppm. HRMS (ESI) m/z [M +
H]+ Calcd for C22H26NO5 384.1805, found 384.1800.
Diethyl 2-(2,4-Dimethylphenyl)-5-phenylisoxazolidine-3,3-dicar-
boxylate (4bd). Yellow oil (81% yield, 64.3 mg); TLC, Rf = 0.3 (PE/
EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.40 (d, 2H, J =
7.2 Hz), 7.30−7.23 (m, 4H), 6.87 (s, 1H), 6.84 (d, 1H, J = 8.4 Hz),
5.25 (t, 1H, J = 8.0 Hz), 4.16−4.01 (m, 2H), 3.94−3.85 (m, 1H),
3.75−3.67 (m, 1H), 3.14 (d, 2H, J = 8.0 Hz), 2.35 (s, 3H), 2.18 (s,
3H), 1.08 (t, 3H, J = 7.2 Hz), 0.92 (t, 3H, J = 7.2 Hz) ppm; 13C{1H}
NMR (CDCl3, 100 MHz) δ 168.5, 167.4, 143.0, 137.7, 136.6, 135.4,
131.0, 128.5, 128.3, 126.8, 126.5, 124.1, 79.1, 78.8, 62.0, 61.9, 46.9,
20.9, 18.5, 13.8, 13.5 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C23H28NO5 398.1962, found 398.1954.
Diethyl 2-(2-Chlorophenyl)-5-phenylisoxazolidine-3,3-dicarbox-
ylate (4be). Yellow oil (86% yield, 69.3 mg); TLC, Rf = 0.3 (PE/
EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.52 (d, 1H, J =
8.4 Hz), 7.42 (d, 2H, J = 7.2 Hz), 7.30 (t, 2H, J = 7.6 Hz), 7.26 (t,
2H, J = 8.0 Hz), 7.13 (t, 1H, J = 7.6 Hz), 7.01 (t, 1H, J = 7.2 Hz),
5.33 (dd, 1H, J = 9.6, 6.0 Hz), 4.16−4.08 (m, 2H), 3.97−3.89 (m,
1H), 3.79−3.71 (m, 1H), 3.15 (dd, 1H, J = 12.8, 10.0 Hz), 3.08 (dd,
1H, J = 12.8, 6.0 Hz), 1.13 (t, 3H, J = 7.2 Hz), 0.96 (t, 3H, J = 7.2
Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.2, 167.0, 144.3,
136.8, 129.7, 128.6, 127.3, 126.9, 126.8, 124.9, 79.3, 78.3, 62.2, 62.1,
47.6, 13.8, 13.5 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C21H23ClNO5 404.1259, found 404.1266.
Diethyl 2-(3-Chlorophenyl)-5-phenylisoxazolidine-3,3-dicarbox-
ylate (4bf). Yellow oil (90% yield, 72.6 mg); TLC, Rf = 0.3 (PE/
EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.42 (d, 2H, J =
6.8 Hz), 7.33−7.24 (m, 4H), 7.13 (d, 1H, J = 8.4 Hz), 7.08 (t, 1H, J =
8.4 Hz), 6.89 (d, 1H, J = 7.6 Hz), 5.23 (dd, 1H, J = 9.6, 6.0 Hz), 4.11
(q, 2H, J = 7.2 Hz), 4.04−3.90 (m, 2H), 3.16 (dd, 1H, J = 12.8, 6.0
Hz), 3.01 (dd, 1H, J = 12.8, 9.6 Hz), 1.13 (t, 3H, J = 7.2 Hz), 0.99 (t,
3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.2,
167.7, 148.5, 136.8, 134.0, 129.3, 128.8, 128.7, 127.0, 123.2, 117.6,
115.6, 115.6, 79.1, 78.5, 62.2, 62.5, 62.3, 48.0, 13.8, 13.7 ppm. HRMS
(ESI) m/z [M + H]+ Calcd for C21H23ClNO5 404.1259, found
404.1266.
151.7, 141.6, 135.7, 129.1, 128.3, 126.8, 124.7, 114.4, 79.6, 63.0, 62.8,
48.4, 13.9, 13.9 ppm. HRMS (ESI) m/z [M + H]+ Calcd for
C21H23N2O7 415.1500, found 415.1505.
Diethyl 2-(3,5-Dichlorophenyl)-5-phenylisoxazolidine-3,3-dicar-
boxylate (4bi). Yellow oil (83% yield, 72.6 mg); TLC, Rf = 0.3 (PE/
EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.41 (d, 2H, J =
6.8 Hz), 7.35−7.27 (m, 3H), 7.14 (d, 2H, J = 6.0 Hz), 6.90 (s, 1H),
5.23 (dd, 1H, J = 9.6, 5.6 Hz), 4.25−4.16 (m, 2H), 4.12−4.00 (m,
2H), 3.19 (dd, 1H, J = 12.8, 5.6 Hz), 3.00 (dd, 1H, J = 12.8, 9.6 Hz),
1.18 (t, 3H, J = 7.2 Hz), 1.07 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR
(CDCl3, 100 MHz) δ 167.9, 167.5, 149.0, 136.3, 134.6, 128.9, 128.7,
126.9, 122.6, 115.2, 79.3, 78.3, 62.7, 62.5, 48.1, 13.8, 13.8 ppm.
HRMS (ESI) m/z [M + H]+ Calcd for C21H22Cl2NO5 438.0870,
found 438.0875.
Dimethyl 2,5-Diphenylisoxazolidine-3,3-dicarboxylate (4bj).6a
Yellow oil (98% yield, 67.1 mg); Rf = 0.3 (PE/EtOAc = 20:1, v/v);
1H NMR (CDCl3, 600 MHz) δ 7.54 (d, 2H, J = 7.2 Hz), 7.41 (t, 2H,
J = 7.6 Hz), 7.38−7.35 (m, 3H), 7.28 (t, 2H, J = 8.4 Hz), 7.05 (t, 1H,
J = 7.2 Hz), 5.34 (dd, 1H, J = 15.6, 6.0 Hz), 3.73 (s, 3H), 3.51 (s,
3H), 3.24 (dd, 1H, J = 12.6, 6.0 Hz), 3.14 (dd, 1H, J = 12.6, 9.6 Hz)
ppm.
Diisopropyl 2,5-Diphenylisoxazolidine-3,3-dicarboxylate (4bk).
Yellow oil (96% yield, 76.3 mg); Rf = 0.3 (PE/EtOAc = 20:1, v/v);
1H NMR (CDCl3, 400 MHz) δ 7.56 (d, 2H, J = 7.2 Hz), 7.41−7.32
(m, 5H), 7.26−7.22 (m, 2H), 7.04−7.00 (m, 1H), 5.35 (dd, 1H, J =
6.4, 2.8 Hz), 5.06 (t, 1H, J = 6.4 Hz), 4.88−4.82 (m, 1H), 3.22−3.11
(m, 2H), 1.19 (dd, 6H, J = 3.6, 2.8 Hz), 1.08 (d, 3H, J = 6.4 Hz), 0.94
(d, 3H, J = 6.4 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 168.1,
167.5, 147.2, 137.5, 128.6, 128.5, 128.2, 127.1, 123.7, 118.4, 78.7,
78.5, 70.0, 70.0, 48.2, 21.4, 21.4, 21.3, 21.1 ppm. HRMS (ESI) m/z
[M + H]+ Calcd for C23H28NO5 398.1962, found 398.1965.
Di-tert-butyl 2,5-Diphenylisoxazolidine-3,3-dicarboxylate (4bl).
Yellow oil (87% yield, 74.0 mg); Rf = 0.3 (PE/EtOAc = 20:1, v/v);
1H NMR (CDCl3, 400 MHz) δ 7.46 (d, 2H, J = 6.8 Hz), 7.37−7.24
(m, 5H), 7.19−7.15 (m, 2H), 6.95 (t, 1H, J = 7.6 Hz), 5.22 (dd, 1H, J
= 9.2, 6.8 Hz), 3.11−3.00 (m, 2H), 1.32 (s, 9H), 1.17 (s, 9H) ppm;
13C{1H} NMR (CDCl3, 100 MHz) δ 167.7, 166.9, 147.5, 137.8,
128.5, 128.4, 128.1, 127.1, 123.5, 118.6, 82.9, 82.7, 79.2, 78.2, 48.3,
27.7, 27.5 ppm. HRMS (ESI) m/z [M + H]+ Calcd for C25H32NO5
426.2275, found 426.2278.
2,5-Diphenylisoxazolidine-3,3-dicarbonitrile (4bm). Colorless oil
1
(80% yield, 44.0 mg); TLC, Rf = 0.3 (PE/EtOAc = 20:1, v/v); H
NMR (CDCl3, 400 MHz) δ 7.52−7.41 (m, 9H), 7.32 (t, 1H, J = 7.2
Hz), 5.41 (t, 1H, J = 8.0 Hz), 3.60 (dd, 1H, J = 13.2, 8.0 Hz), 3.19
(dd, 1H, J = 13.2, 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ
143.7, 136.0, 129.5, 129.4, 129.1, 127.5, 126.9, 119.8, 112.6, 112.3
ppm. HRMS (ESI) m/z [M + H]+ Calcd for C17H14N3O 276.1131,
found 276.1133.
ASSOCIATED CONTENT
■
Diethyl 2-(4-Chlorophenyl)-5-phenylisoxazolidine-3,3-dicarbox-
ylate (4bg). Yellow oil (91% yield, 73.4 mg); TLC, Rf = 0.3 (PE/
EtOAc = 20:1, v/v); 1H NMR (CDCl3, 400 MHz) δ 7.51 (d, 2H, J =
6.8 Hz), 7.39 (t, 2H, J = 7.6 Hz), 7.35 (d, 1H, J = 7.2 Hz), 7.31 (d,
2H, J = 8.8 Hz), 7.20 (d, 2H, J = 9.2 Hz), 5.30 (dd, 1H, J = 9.6, 6.4
Hz), 4.19 (q, 2H, J = 7.2 Hz), 4.09−3.93 (m, 2H), 3.22 (dd, 1H, J =
12.8, 6.0 Hz), 3.11 (dd, 1H, J = 12.8, 9.6 Hz), 1.21 (t, 3H, J = 7.2
Hz), 1.05 (t, 3H, J = 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100
MHz) δ 168.3, 167.6, 145.8, 137.0, 128.7, 128.7, 128.2, 127.0, 119.4,
79.0, 78.6, 62.4, 62.2, 47.8, 13.9, 13.7 ppm. HRMS (ESI) m/z [M +
H]+ Calcd for C21H23ClNO5 404.1259, found 404.1266.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02567.
1
H-H NOESY of 4ab, 4ac, 4ae, and 4ao; H NMR
1
spectra of 4a and 4bj; H- and 13C-NMR spectra for
nitrone intermediate 5a; and cycloaddition products
4b−4z, 4ab−4au, 4ba−4bi, and 4bk−4bm (PDF)
Diethyl 2-(4-Nitrophenyl)-5-phenylisoxazolidine-3,3-dicarboxy-
late (4bh).6a Colorless oil (70% yield, 58.0 mg); TLC, Rf = 0.3
AUTHOR INFORMATION
■
1
(PE/EtOAc = 20:1, v/v); H NMR (CDCl3, 400 MHz) δ 8.13 (d,
Corresponding Author
2H, J = 9.6 Hz), 7.48 (dd, 2H, J = 7.8, 1.6 Hz), 7.44−7.39 (m, 3H),
7.23 (d, 2H, J = 9.2 Hz), 5.35 (dd, 1H, J = 9.6, 5.6 Hz), 4.25 (q, 2H, J
= 7.2 Hz), 4.16 (q, 2H, J = 7.2 Hz), 3.35 (dd, 1H, J = 12.8, 5.6 Hz),
3.12 (dd, 1H, J = 12.8, 9.6 Hz), 1.25 (t, 3H, J = 7.2 Hz), 1.16 (t, 3H, J
= 7.2 Hz) ppm; 13C{1H} NMR (CDCl3, 100 MHz) δ 167.6, 167.4,
Xing Li − Department of Biomedical Engineering, Taiyuan
University of Technology, Taiyuan 030024, People’s Republic
of China; orcid.org/0000-0001-8096-4499;
Email: lixing@tyut.edu.cn
J
https://dx.doi.org/10.1021/acs.joc.0c02567
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Enantioselective Syntheses and Cytotoxicity of N, O-Nucleosides. J.
Med. Chem. 2003, 46, 3696.
Authors
Leijie Zheng − Department of Biomedical Engineering,
Taiyuan University of Technology, Taiyuan 030024,
People’s Republic of China
Xiaolei Gong − Department of Biomedical Engineering,
Taiyuan University of Technology, Taiyuan 030024,
People’s Republic of China
Honghong Chang − Department of Biomedical Engineering,
Taiyuan University of Technology, Taiyuan 030024,
People’s Republic of China
Wenchao Gao − Department of Biomedical Engineering,
Taiyuan University of Technology, Taiyuan 030024,
People’s Republic of China; orcid.org/0000-0002-1382-
6210
(5) Reviews on the preparation of the isoxazolidine ring: (a) Klier,
L.; Tur, F.; Poulsen, P. H.; Jørgensen, K. A. Asymmetric Cyclo-
addition Reactions Catalysed by Diarylprolinol Silyl Ethers. Chem.
Soc. Rev. 2017, 46, 1080. (b) Romeo, G.; Chiacchio, U.; Corsaro, A.;
Merino, P. Chemical Synthesis of Heterocyclic−Sugar Nucleoside
Analogues. Chem. Rev. 2010, 110, 3337. Selected recent examples for
cycloadditions of hydroxylamines with alkenes: (c) Kobayashi, Y.;
Taniguchi, Y.; Hayama, N.; Inokuma, T.; Takemoto, Y. A Powerful
Hydrogen-Bond-Donating Organocatalyst for the Enantioselective
Intramolecular Oxa-Michael Reaction of α,β-Unsaturated Amides and
Esters. Angew. Chem., Int. Ed. 2013, 52, 11114. (d) Gioia, C.; Fini, F.;
Mazzanti, A.; Bernardi, L.; Ricci, A. Organocatalytic Asymmetric
Formal [3+2] Cycloaddition with in Situ-Generated N-Carbamoyl
Nitrones. J. Am. Chem. Soc. 2009, 131, 9614. and references cited
therein. (e) LaLonde, R. L.; Wang, Z. J.; Mba, M.; Lackner, A. D.;
Dean Toste, F. Gold(I)-Catalyzed Enantioselective Synthesis of
Pyrazolidines, Isoxazolidines, and Tetrahydrooxazines. Angew. Chem.,
Int. Ed. 2010, 49, 598. Selected recent example for cycloadditions of
oxaziridines with olefins or arynes: (f) Partridge, K. M.; Guzei, I. A.;
Yoon, T. P. Carbonyl Imines from Oxaziridines: Generation and
Cycloaddition of N-O=C Dipoles. Angew. Chem., Int. Ed. 2010, 49,
930. Selected recent example for cycloadditions of O-silyloxime with
alkenes: (g) Morita, N.; Kono, R.; Fukui, K.; Miyazawa, A.; Masu, H.;
Azumaya, I.; Ban, S.; Hashimoto, Y.; Okamoto, I.; Tamura, O. BF3-
Mediated cis-Selective Cycloaddition of O-Silyloxime with Alkenes. J.
Org. Chem. 2015, 80, 4797.
Wenlong Wei − Department of Biomedical Engineering,
Taiyuan University of Technology, Taiyuan 030024,
People’s Republic of China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02567
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We appreciate gratefully the Natural Science Foundation of
Shanxi Province (no. 201601D011028) for financial support.
(6) Selected recent examples for other methods, see: (a) Chakra-
barty, S.; Chatterjee, I.; Wibbeling, B.; Daniliuc, C. G.; Studer, A.
Stereospecific Formal [3+2] Dipolar Cycloaddition of Cyclopropanes
with Nitrosoarenes: an Approach to Isoxazolidines. Angew. Chem., Int.
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