Construction of Isoxazolidines through Formal [3+2] Cycloaddition Reactions of in situ Generated Nitrosocarbonyls with Donor–Acceptor Cyclopropanes: Synthesis of α-Amino γ-Butyrolactones

Article abstract of DOI:10.1002/ejoc.201600582

A straightforward approach for the synthesis of isoxazolidines through MgI₂-catalyzed [3+2] cycloaddition reactions of donor–acceptor cyclopropanes with in situ generated nitrosocarbonyls from hydroxycarbamates is described. This method facilit

Full text of DOI:10.1002/ejoc.201600582

DOI: 10.1002/ejoc.201600582
Full Paper
Isoxazolidine Synthesis
Construction of Isoxazolidines through Formal [3+2]
Cycloaddition Reactions of in situ Generated Nitrosocarbonyls
with Donor–Acceptor Cyclopropanes: Synthesis of α-Amino
γ-Butyrolactones
Rohit Kumar Varshnaya[a] and Prabal Banerjee*[a]
Abstract: A straightforward approach for the synthesis of method facilitates one-pot synthesis of α-amino-γ-butyro-
isoxazolidines through MgI2-catalyzed [3+2] cycloaddition reac-
tions of donor–acceptor cyclopropanes with in situ generated
nitrosocarbonyls from hydroxycarbamates is described. This
lactone by deprotection, reductive cleavage of N–O bond, and
successive lactonization.
Introduction
ity and used as versatile building blocks in organic synthesis.[5]
In the presence of Lewis acids DACs undergo retro-aldol rear-
rangement reactions to form 1,3-zwitterionic species. These
species have been used for the syntheses of five-, six- and
seven- membered heterocycles through [3+n] cycloaddition re-
actions.[6] Nitrosocarbonyls are highly reactive 2π components
that have been used in the construction of biologically active
molecules. As a result of their high reactivity and short lifetimes,
nitrosocarbonyls are generated in situ through the oxidation of
hydroxycarbamate in the presence of various oxidizing agents.
A literature survey revealed that the use of nitrosocarbonyl
compounds as dipolarophiles in [3+2] cycloaddition reactions
has not been well-documented to date.[7]
Over the years, heterocyclic chemistry has developed, to a large
extent, to synthesize biologically interesting compounds.
Among such heterocycles, isoxazolidines are important motifs
that show potential applications as useful building blocks in
natural products synthesis.[1] Isoxazolidine derivatives possess
various types of biological activities, such as antiviral, anti-in-
flammatory, herbicidal, and nucleoside.[2] This scaffold consti-
tutes the cyclic core structure of nucleoside analogue aza-dide-
oxyfluorouracil (ADF), which is highly potent and induces re-
markable levels of apoptosis of lymphoid and monocytoid
cells.[3] Isoxazolidines are useful precursors for the synthesis of
α-amino γ-butyrolactones, which are important constituents of
natural products and drugs that display diverse biological activ-
ities (Figure 1). These amino lactones constitute the cyclic core
structure present in pesticides and angiotensin converting
enzyme (ACE) inhibitors, which cause the relaxation of blood
vessels to lower blood pressure.[4]
Johnson and co-workers reported Lewis acid catalyzed [3+2]
cycloaddition reactions of DACs with aldehydes for the synthe-
sis of functionalized tetrahydrofurans.[8] In a series of reports,
Wang, Kerr and other groups demonstrated that various 2π
components react with DACs to form a range of heterocycles
and carbocycles.[9] Our group also explored the annulation re-
action of cyclopropane with strained rings (epoxides, aziridines)
in the presence of Lewis acids, such as MgI2.[10] Otsuji and co-
workers investigated [3+2] cycloaddition reactions between cy-
clopropanes and nitrosonium salt to afford isoxazolidines.[11]
Recently, Studer and co-workers in their seminal work, reported
the stereospecific [3+2] cycloaddition reaction of DACs and to
synthesize isoxazolidines (Scheme 1).[12] The difficulty in func-
tionalization of N-aryl derivatives make this protocol less gen-
Figure 1. Biologically active compounds that contain isoxazolidine and amino
lactone moieties.
In general, donor–acceptor cyclopropanes (DACs) are inher- eral towards other applications. A labile group on nitrogen
ent 1,3-dipolar species, which show a higher degree of reactiv- atom of isoxazolidine moiety would be beneficial; therefore we
report MgI2-catalyzed annulation reactions between DACs and
[a] Department of Chemistry, Indian Institute of Technology Ropar,
nitrosocarbonyls to construct isoxazolidine skeletons. Further-
more, this protocol gives one-step access to valuable α-amino-
γ-butyrolactones by reductive cleavage of a N–O bond, depro-
tection of N-protecting groups, and subsequent lactonization
Nangal Road, Rupnagar, Punjab 140001, India
E-mail: prabal@iitrpr.ac.in
http://www.iitrpr.ac.in/chemistry/praba
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600582.
of an isoxazolidine derivative in a single step.
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BF3·OEt2, GaCl3, and AlCl3 (40 mol-%) rapid decomposition of
DACs occurred (Table 1, Entries 11–13).
The influence of solvent on product yields was then evalu-
ated. When the reaction was carried out in CH2Cl2, a 72 % yield
of the product was obtained. Other solvents, such as
ClCH2CH2Cl, and tetrahydrofuran (THF) provided moderate
yields, and CCl4 and toluene gave trace amounts of 3a (Table 2).
With CH3CN no product was detected. Therefore, the best opti-
mized conditions for these cycloaddition reactions are MgI2
(40 mol-%) in CH2Cl2 at room temperature.
With the optimized reaction conditions the scope to the re-
action was studied (Table 1, Entry 3). Various DACs were tested
with benzyl hydroxycarbamate as a reaction partner. In the be-
ginning, activated DACs that had electron-donating substitu-
ents on the phenyl ring were used. For example, 3,4-dimethoxy-
phenyl DAC 1a gave 72 % yield of 3a (Table 3). Further in-
creases in the number of electron-donating substituents on the
phenyl ring of DACs did not improve the yields of correspond-
ing products 3c and 3m (Table 3). Interestingly, with 2,4,6-tri-
methylphenyl-substituted DAC, the desired product was not
formed. The yield of the reaction was decreased when p-tolyl
phenyl-substituted DAC 1e was used. Simple phenyl-substi-
tuted and 2-naphthyl-substituted DACs did not lead to the for-
mation of desired product. If DAC 1f, which bears benzyl ester
groups, was used slightly lower yields relative to ethyl ester 3f
were obtained. A heterocyclic incorporated DAC subjected to
above transformation yielded desired product 3g. The title
transformation with methyl hydroxycarbamate and 4-methoxy-
phenyl DAC 1d led to formation of desired product 3h in 68 %
yield (Table 3).
Scheme 1. Annulations of cyclopropane with nitrosocarbonyl compounds.
Results and Discussion
We started the present investigation with DAC 1a (1 equiv.) and
benzyl hydroxycarbamate 2a (2 equiv.) to afford isoxazolidine
3a (Table 1). We examined a variety of Lewis acids and found
that MgI2 was the most effective catalyst for the reaction be-
tween 1a and 2a to give 3a. When MgI2 (20 mol-%) was used
the yield of the reaction was 40 % and further improved to
72 % when the catalyst loading was increased up to 40 mol-%
(Table 1, Entry 3). At 60 mol-% MgI2 loading, the decomposition
of DACs was observed, which led to a complex mixture. An
increase in temperature to 40 °C with MgI2 (40 mol-%) led to a
lower yield. At low temperatures, even in the presence of MgI2
(40 mol-%), no product was formed (Table 1, Entry 6). The use
of MgBr2 gave 3a in only 35 % yield. Other Lewis acids, such
as Cu(OTf)2, InCl3, Sc(OTf)3, and Yb(OTf)3, did not lead to the
formation of isoxazolidine (Table 1, Entries 8–10 and 14). With
We next explored the generality of the reaction by using tert-
butyl hydroxycarbamate with various DACs. Vinyl- and cinn-
amyl-substituted cyclopropane gave moderate yields of the
Table 1. Optimization study between 1a and 2a.[a]
Entry
Lewis acid
LA
[mol-%]
Temp.
[°C]
Solvent
Yield
[%][b]
1
2
3
4
5
6
7
8
MgI2
MgI2
MgI2
MgI2
MgI2
MgI2
MgBr2
Cu(OTf)2
InCl3
Sc(OTf)3
GaCl3
AlCl3
10
20
40
60
40
40
40
40
40
40
40
40
40
40
25
25
25
25
40
0
25
25
25
25
25
25
25
25
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
30
40
72
c.m.[d]
45
n.r.[c]
35
n.r.[c]
n.r.[c]
n.r.[c]
c.m.[d]
c.m.[d]
c.m.[d]
n.r.[c]
9
10
11
12
13
14
BF3·OEt2
Yb(OTf)3
[a] The reaction was carried out in inert atmosphere; 1a (0.34 mmol, 1 equiv.), 2a (0.68 mmol, 2 equiv.), Lewis acid (0.13 mmol, 0.4 equiv.), MnO2 (3.4 mmol,
5 equiv. with respect to 2a), and CH2Cl2. [b] Isolated yield after flash column chromatography. [c] n.r.: no reaction. [d] c.m.: complex mixture.
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Table 2. Effect of solvent.[a]
Entry
MgI2
[mol-%]
Solvent
t
[h]
Yield
[%][b]
1
2
3
4
5
6
40
40
40
40
40
40
CH2Cl2
ClCH2CH2Cl
CCl4
THF
CH3CN
toluene
6
8
12
12
12
12
72
35
10
40
n.r.[c]
10
[a] Reaction was carried out in inert atmosphere 1a (0.34 mmol, 1 equiv.), 2a (0.68 mmol, 2 equiv.), MgI2 (0.13 mmol, 0.4 equiv.), MnO2 (3.4 mmol, 5 equiv.
with respect to 2a), and solvent. [b] Isolated yield after flash column chromatography. [c] n.r.: no reaction.
Table 3. Scope of the methodology.[a]
[a] Reaction was carried out in inert atmosphere 1a (0.34 mmol, 1 equiv.), 2a (0.68 mmol, 2 equiv.), MgI2 (0.13 mmol, 0.4 equiv.), MnO2 (3.4 mmol, 5 equiv.
with respect to 2a), and CH2Cl2. [b] Isolated yield after flash column chromatography.
product. These moderate yields could be a result of the pres- ring, which may undergo rearrangement in the case of cinn-
ence of an additional double bond conjugated with the phenyl amyl-substituted cyclopropanes.
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Next, various electron-enriched DACs were tested with tert-
butyl hydroxycarbamate to obtain desired products 3k–3l
(Table 3) for which slightly lower yields relative to 3a and 3b
were observed. This situation may result from the lower stability
of the in situ generated tert-butyl nitrosocarbonyl molecule.
With electron-withdrawing group (p-nitro) DAC 1j was used the
yield of desired product 3n decreased.
Figure 2. X-ray crystal structure of 4b.
On the basis of previous reports and our observations, a
plausible mechanism for this transformation is depicted in
Scheme 2. Initially, MgI2 interacts with DAC 1 to undergo inter-
molecular nucleophilic ring opening to form open-chain com-
plex A. Complex A then reacts with nitrosocarbonyl compound
B, generated in situ from hydroxycarbamate 2 in the presence
of oxidizing agent MnO2 to construct six-membered transition
state C, which readily converts to intermediate D. The oxygen
atom of intermediate D undergoes C–O bond formation
(Scheme 4).[15] This one-step process gives access to the molec-
ular entity that can be further utilized for the synthesis of varie-
ties of biological active compounds.
1
through an intramolecular SN pathway to give isoxazolidine
molecule 3.
Scheme 4. Deprotection of Boc group.
Conclusions
In conclusion, we have developed an efficient protocol for the
synthesis of functionalized isoxazolidines through [3+2] cyclo-
addition reactions of DACs with in situ generated nitroso-
carbonyl compounds in the presence of Lewis acid. We have
also reported the efficient synthesis of α-amino-γ-butyro-
lactone from synthesized isoxazolidine by reductive cleavage of
the N–O bond, deprotection of the N-protecting group, and
subsequent lactonization in a single step.
Scheme 2. Plausible mechanism.
Experimental Section
Two analogs of synthesized isoxazolidine were used as build-
ing blocks for further synthetic applications. Cleavage of N–O
bond and deprotection of cbz group were achieved with H2 and
Pd/C to provide the corresponding 1,3-amino alcohols, which
spontaneously undergo lactonization with esters to afford α-
amino-γ-butyrolactones 4a and 4b (Scheme 3) in excellent
yields.[13] The structure of 4b was confirmed by NMR spectro-
scopy and single-crystal X-ray data (Figure 2, see also the Sup-
porting Information).[14]
General Procedure: All reactions were carried out under inert at-
mosphere with oven-dried glassware. All solvents and reagents
were obtained from commercial sources and were purified by using
standard procedures prior to use. Powdered molecular sieves (4 Å)
were dried at 200 °C under vacuum prior to use. Developed chro-
matograms were analyzed by means of UV lamp (254 nm), or p-
anisaldehyde solution. Products were purified by flash chromatogra-
phy with silica gel (mesh size 230–400). The 1H and 13C NMR spectra
were recorded in CDCl3. The description of the signals includes the
following: s = singlet, d = doublet, dd = doublet of doublet, t =
triplet, dt = doublet of triplet, q = quartet, quint = quintuplet, br. =
broad and m = multiplet.
General Procedure for Synthesis of Cyclopropane 1,1-Diester
Derivatives:[16]
Sodium hydride (2.5 equiv.) was filled into a three-necked round-
bottom flask and washed 3–4 times with hexane under N2 atmos-
phere. After washing, 100 mL of dimethyl sulfoxide (DMSO) was
added. The solution of trimethylsulfoxonium iodide (2.5 equiv.) in
DMSO (10 mL) was added to the flask at 0 °C. After 10 min, diethyl
Scheme 3. Synthesis of amino lactone.
Deprotection of tert-butoxycarbonyl (Boc) group from 3k
was achieved by using trifluoroacetic acid (TFA) in CH2Cl2 at
0 °C to give N-deprotected isoxazolidine 4k in excellent yield 2-benzylidenemalonate (1 equiv.) in DMSO (10 mL) was added to
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the stirred solution and the reaction mixture was allowed to stir for
Dimethyl 2-Vinylcyclopropane-1,1-dicarboxylate (1h):[16g] To a
2 h at room temperature. Upon completion of the reaction (moni- stirred solution of sodium methoxide, prepared from sodium
tored by TLC), the reaction mixture was quenched with cold water.
The organic solution was extracted with diethyl ether (3 times) and
dried with anhydrous Na2SO4. The solution was concentrated under
reduced pressure. The crude mixture was further purified by silica
gel column chromatography.
(1.15 g, 50 mmol) and methanol (20 mL), was added dimethyl malo-
nate (5.89 mL, 51.5 mmol) followed by a solution of (E)-1,4 dibromo-
butene (5.35 g, 25 mmol) in methanol (20 mL). The reaction mixture
was heated to reflux for 2.5 h and then cooled to ambient tempera-
ture. The white precipitate was filtered (if present) and the filtrate
reduced in vacuo to leave an oily residue, which was partitioned
between diethyl ether (30 mL) and distilled water (30 mL). The di-
ethyl ether layer was further washed with distilled water (2 ×
30 mL), before being dried with MgSO4, filtered and concentrated
in vacuo to afford a pale yellow oil, which was purified by flash
silica chromatography (petroleum ether/diethyl ether, 5:1 v/v) to
Diethyl 2-(3,4-Dimethoxyphenyl)cyclopropane-1,1-dicarboxyl-
ate (1a):[16d] Diethyl 2-(3,4-dimethoxybenzylidene)malonate (0.5 g,
1.17 mmol), NaH (0.1 g, 4.06 mmol), trimethylsulfoxonium iodide
(0.9 g, 4.06 mmol), dry DMSO (10 mL), and reaction time = 6 h gave
1
1a (0.37 g, 72 %) as a colorless oil. H NMR: δ = 6.76 (m, 3 H), 4.23
(q, J = 7.12 Hz, 2 H), 3.89 (q, J = 7.12 Hz, 2 H), 3.86 (s, 3 H), 3.84 (s,
3 H), 3.18 (m, 1 H), 2.13 (m, 1 H), 1.68 (m, 1 H), 1.3 (t, J = 7.12 Hz, 3
H), 0.93 (t, J = 7.12 Hz, 3 H) ppm.
1
yield the title compound as a colorless oil (6.71 g, 90 %). H NMR:
δ = 5.41 (m, 1 H), 5.27 (d, 1 H), 5.13 (d, 1 H), 3.74 (s, 6 H), 2.57–2.59
(m, 1 H), 1.72 (dd, 1 H), 1.58 (dd, 1 H) ppm.
Diethyl
2-(Benzodioxol-5-yl)cyclopropane-1,1-dicarboxylate
(E)-Diethyl 2-Styrylcyclopropane-1,1-dicarboxylate (1i):[16f] (E)-
Diethyl 2-(3-phenylallylidene)malonate (0.5 g, 2.04 mmol), NaH
(0.08 g, 2.20 mmol), trimethylsulfoxonium iodide (0.8 g, 2.24 mmol),
dry DMF (5 mL), and reaction time = 15 min at 0 °C gave 1i (0.43 g,
81 %) as a colorless oil. 1H NMR: δ = 7.29 (m, 5 H): δ = 6.63 (d, 1
H), 5.81 (dd, 1 H), 4.28–4.12 (m, 4 H), 2.73 (q, 1 H), 1.81 (dd, 1 H),
1.65 (dd, 1 H), 1.28 (t, 3 H), 1.22 (t, 3 H) ppm.
(1b):[16d] Diethyl 2-(benzo[d][1,3]dioxol-5-ylmethylene)malonate
(0.5 g, 1.62 mmol), NaH (0.1 g, 4.06 mmol), trimethylsulfoxonium
iodide (0.9 g, 4.06 mmol), dry DMSO (10 mL), and reaction time =
1
6 h gave 1b (0.39 g, 76 %) as a colorless oil. H NMR: δ = 6.67 (m,
3 H), 5.9 (s, 2 H), 4.19 (q, 2 H), 3.89 (q, 2 H), 3.12 (t, 1 H), 2.08 (dd, 1
H), 1.63 (dd, 1 H), 1.27 (t, 3 H), 0.95 (t, 3 H) ppm.
Diethyl 2-(2,4,6-Trimethoxyphenyl)cyclopropane-1,1-dicarbox-
ylate (1c):[16d] Diethyl 2-(2,4,6-trimethoxybenzylidene)malonate
(0.5 g, 1.47 mmol), NaH (0.09 g, 3.67 mmol), trimethylsulfoxonium
iodide (0.8 g, 3.67 mmol), dry DMSO (9 mL), and reaction time =
7 h gave 1c (0.34 g, 65 %) as a colorless oil. H NMR: δ = 6.04 (s, 2
H), 4.22 (q, 2 H), 3.84 (q, 2 H), 3.76 (s, 3 H), 3.74 (s, 6 H), 2.82 (t, 1
Diethyl 2-(3,4,5-Trimethoxyphenyl)cyclopropane-1,1-dicarbox-
ylate (1j):[16d] Diethyl 2-(3,4,5-trimethoxybenzylidene)malonate
(0.5 g, 1.47 mmol), NaH (0.09 g, 3.67 mmol), trimethylsulfoxonium
iodide (0.8 g, 3.67 mmol), dry DMSO (9 mL), and reaction time =
5 h gave 1j (0.36 g, 70 %) as a colorless oil. H NMR: δ = 6.42 (s, 2
H), 4.24 (q, 2 H), 3.91 (q, 2 H), 3.83 (s, 6 H), 3.79 (s, 3 H), 3.17 (t, 1
1
1
H), 2.37 (dd, 1 H), 1.77 (dd, 1 H), 1.28 (t, 3 H), 0.95 (t, 3 H) ppm.
H), 2.11 (dd, 1 H), 1.68 (dd, 1 H), 1.30 (t, 3 H), 0.91 (t, 3 H) ppm.
Diethyl 2-(4-Nitro)cyclopropane-1,1-dicarboxylate (1k):[16f] Di-
ethyl 2-(4-nitrobenzylidene)malonate (0.5 g, 1.70 mmol), NaH
(0.10 g, 4.26 mmol), trimethylsulfoxonium iodide (0.90 g,
4.26 mmol), dry DMSO (12 mL), and reaction time = 4 h gave 1g
(0.39 g, 76 %) as a white solid. H NMR: δ = 8.15 (d, 2 H), 7.37 (d, 2
H), 4.29 (q, 2 H), 3.87 (q, 2 H), 3.22 (t, 1 H), 2.19 (dd, 1 H), 1.79 (dd,
1 H), 1.30 (t, 3 H), 0.92 (t, 3 H) ppm.
Diethyl
2-(4-Methoxyphenyl)cyclopropane-1,1-dicarboxylate
(1d):[16d] Diethyl 2-(4-methoxybenzylidene)malonate (0.5 g,
1.80 mmol), NaH (0.1 g, 4.50 mmol), trimethylsulfoxonium iodide
(1.0 g, 4.50 mmol), dry DMSO (11 mL), and reaction time = 5 h gave
1
1
1d (0.39 g, 74 %) as a colorless oil. H NMR: δ = 7.13 (d, 2 H), 6.79
(d, 2 H), 4.22 (q, 2 H), 3.85 (q, 2 H), 3.76 (s, 3 H), 3.16 (t, 1 H), 2.12
(dd, 1 H), 1.67 (dd, 1 H), 1.28 (t, 3 H), 0.91 (t, 3 H) ppm.
Diethyl 2-p-Tolylcyclopropane-1,1-dicarboxylate (1e):[16d] Di-
ethyl 2-benzylidenemalonate (0.5 g, 2.01 mmol), NaH (0.12 g,
5.02 mmol), trimethylsulfoxonium iodide (1.1 g, 5.02 mmol), dry
DMSO (12 mL), and reaction time = 4 h gave 1e (0.35 g, yield: 67 %)
as a colorless oil. 1H NMR: δ = 7.19–7.31 (m, 5 H), 4.12 (q, J = 7.12 Hz,
2 H), 3.81 (q, J = 7.12 Hz, 2 H), 3.11–3.20 (m, 1 H), 2.16–2.19 (m, 1
H), 1.66–1.73 (m, 1 H), 1.27 (t, J = 7.12 Hz, 3 H), 0.84 (t, J = 7.12 Hz,
3 H) ppm.
General Procedure for the Synthesis of Hydroxycarbamate: Hy-
droxycarbamate was prepared in accordance with the literature.[17]
Benzyl Hydroxycarbamate (2a):[17a] Yield 83.6 %, m.p. 62–64 °C
(ref. 65–70). 1H NMR: δ = 7.36 (s, 5 H), 7.21 (s, 1 H), 6.70 (s, 1 H),
5.19 (s, 2 H) ppm.
tert-Butyl Hydroxycarbamate (2b):[17b] 1H NMR: δ = 1.48 (s, 9
H) ppm.
Methyl Hydroxycarbamate (2c):[17c] 1H NMR: δ = 3.77 (s, 3 H) ppm.
Dibenzyl 2-(3,4-Dimethoxyphenyl)cyclopropane-1,1-dicarbox-
ylate (1f):[16d] Dibenzyl 2-(3,4-dimethoxybenzylidene)malonate
(0.5 g, 1.15 mmol), NaH (0.06 g, 2.89 mmol), trimethylsulfoxonium
iodide (0.61 g, 2.89 mmol), dry DMSO (11 mL), and reaction time =
3 h gave 1f (0.39 g, 76 %) as a white solid. 1H NMR: δ = 7.35 (m, 15
H), 6.88 (dd, 1 H), 6.83 (d, 1 H), 6.74 (s, 1 H), 4.65 (s, 2 H), 3.86 (s, 6
H), 3.11 (dd, 1 H), 2.79 (dd, 1 H) ppm.
General Procedure for the Cycloaddition Reaction of Donor–
Acceptor Cyclopropanes with Nitrosocarbonyl Compounds: To a
stirred solution of donor–acceptor cyclopropane (1 equiv.) with
MgI2 (0.4 equiv.) and MnO2 (5 equiv., with respect to hydroxycar-
bamate) dissolved in CH2Cl2 under a nitrogen atmosphere, was
added a solution of hydroxycarbamate (2 equiv.) dissolved in CH2Cl2
dropwise through a syringe over the period of 15 min under a
nitrogen atmosphere. The reaction was stirred at room temperature
until the consumption of starting material (as monitored by TLC).
Reaction mixture was filtered through a thin pad of Celite and the
filtrate was concentrated by means of a rotary evaporator. The resi-
due was purified by flash column chromatography with silica gel
(ethyl acetate/hexane).
Diethyl 2-(Furan-2-yl)cyclopropane-1,1-dicarboxylate (1g):[16d]
Diethyl 2-(furan-2-ylmethylene)malonate (0.5 g, 2.09 mmol), NaH
(0.12 g, 5.22 mmol), trimethylsulfoxonium iodide (1.18 g,
5.22 mmol), dry DMSO (12 mL), and reaction time = 5 h gave 1g
(0.36 g, 69 %) as a colorless oil. 1H NMR (400 MHz): δ = 7.27–7.29
(m, 1 H), 6.27–6.28 (m, 1 H), 6.11–6.12 (m, 1 H), 4.24 (q, J = 7.12 Hz,
2 H), 4.02 (q, J = 7.12 Hz, 2 H), 3.06–3.10 (m, 1 H), 2.04–2.07 (m, 1
H), 1.73–1.76 (m, 1 H), 1.28 (t, J = 7.12 Hz, 3 H), 1.07 (t, J = 7.12 Hz,
3 H) ppm.
2-Benzyl 3,3-Diethyl 5-(3,4-Dimethoxyphenyl)isoxazolidine-
2,3,3-tricarboxylate (3a): Reaction time:
6 h, 1a (0.100 g,
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0.31 mmol), and 2a (0.103 g, 0.62 mmol) gave a viscous liquid
(0.108 g, 72 %). Rf 0.66 (EtOAc/hexane, 4:10 v/v). 1H NMR (400 MHz):
δ = 7.30 (m, 5 H), 6.91 (s, 1 H), 6.86 (dd, J = 1.68, 6.39 Hz, 1 H), 6.78
(d, J = 8.20 Hz, 1 H), 5.40 (dd, J = 5.78, 2.69 Hz, 1 H), 5.15 (s, 2 H),
2.32 (s, 3 H), 1.22 (t, J = 7.21 Hz, 3 H), 1.17 (t, J = 7.33 Hz, 3 H) ppm.
13C NMR (100 MHz): δ = 167.3, 166.0, 157.6, 137.6, 137.1, 129.5,
128.5, 128.3, 126.1, 87.0, 68.3, 62.7, 44.5, 21.2, 14.0, 13.9 ppm. IR
(neat): ν = 2924, 1735, 1454, 1384, 1257, 1063, 855, 812, 745,
˜
4.22 (m, 2 H), 4.09–3.99 (m, 2 H), 3.82 (s, 6 H), 3.42 (dd, J = 8.42, 697 cm–1. HRMS (ESI, quadrupole): m/z calcd. for C24H27NO7Na [M
4.73 Hz, 1 H), 2.66 (dd, J = 5.74, 7.53 Hz, 1 H), 1.20 (t, J = 7.37 Hz,
3 H), 1.16 (t, J = 7.26 Hz, 3 H) ppm. 13C NMR (100 MHz): δ = 167.1,
165.8, 157.4, 149.2, 148.5, 135.4, 132.5, 128.4, 128.3, 128.2, 118.4,
+ Na]+ 464.1685; found 464.1647.
Tribenzyl 5-(3,4-Dimethoxyphenyl)isoxazolidine-2,3,3-tricarb-
oxylate (3f): Reaction time: 4 h, 1f (0.100 g, 0.22 mmol), and 2a
(0.074 g, 0.44 mmol) gave a white solid (0.087 g, 64 %), m.p. 67 °C.
111.0, 109.0, 86.8, 68.3, 62.6, 55.8, 44.3, 13.8 ppm. IR (neat): ν =
˜
3781, 3701, 2925, 2849, 2357, 2257, 1734, 1595, 1513, 1453, 1255,
1141, 1069, 1025, 911, 856, 809, 734 cm–1. HRMS (ESI, quadrupole):
m/z calcd. for C25H29NO9Na [M + Na]+ 510.1740; found 510.1732.
1
Rf 0.72 (EtOAc/hexane, 5:10, v/v). H NMR (400 MHz): δ = 7.32–7.27
(m, 10 H), 7.24–7.14 (m, 5 H), 6.88 (s, 1 H), 6.85 (dd, J = 2.39, 6.22 Hz,
1 H), 6.76 (d, J = 8.19 Hz, 1 H), 5.43 (dd, J = 5.28, 3.12 Hz, 1 H), 5.15–
5.07 (m, J = 3.54, 4.24 Hz, 4 H), 5.03 (d, J = 12.47 Hz, 1 H), 4.88 (d,
J = 12.14 Hz, 1 H), 3.85 (s, 3 H), 3.79 (s, 3 H), 3.45 (dd, J = 8.43,
4.81 Hz,1 H), 2.69 (dd, J = 5.47, 7.73 Hz, 1 H) ppm. 13C NMR
(100 MHz): δ = 167.0, 165.8, 157.6, 149.3, 148.6, 134.6, 132.5, 128.6,
128.4, 128.2, 118.5, 111.1, 109.0, 87.0, 68.2, 62.7, 56.0, 44.4 ppm. IR
2-Benzyl 3,3-Diethyl 5-(Benzo[d][1,3]dioxol-5-yl)isoxazolidine-
2,3,3-tricarboxylate (3b): Reaction time:
6 h, 1b (0.100 g,
0.32 mmol), and 2a (0.109 g, 0.65 mmol) gave a yellow solid
(0.105 g, 69 %), m.p. 71 °C. Rf 0.52 (EtOAc/hexane, 4:10, v/v). 1H NMR
(400 MHz): δ = 7.36–7.29 (m, 5 H), 6.88 (d, J = 1.87 Hz, 1 H), 6.81
(dd, J = 7.85 Hz, 1 H), 6.73 (d, J = 8.18 Hz, 1 H), 5.93 (s, 2 H), 5.37
(dd, J = 6.13, 2.68 Hz, 1 H), 5.17 (s, 2 H), 4.24 (m, 2 H), 4.12–4.01 (m,
2 H), 3.41 (dd, J = 8.74, 4.72 Hz, 1 H), 2.64 (dd, J = 7.40, 5.96 Hz, 1
H), 1.25 (t, J = 7.30 Hz, 3 H), 1.17 (t, J = 7.09 Hz, 3 H) ppm. 13C NMR
(100 MHz): δ = 167.2, 165.9, 157.4, 148.1, 147.2, 135.6, 134.0, 128.5,
128.3, 128.3, 119.7, 108.3, 106.7, 101.2, 86.9, 68.4, 62.7, 44.6,
(neat): ν = 3297, 2947, 1727, 1596, 1505, 1453, 1391, 1324, 1265,
˜
1119, 1065, 1024, 964, 859, 808, 738, 692 cm–1. HRMS (ESI, quadru-
pole): m/z calcd. for C35H33NO9Na [M + Na]+ 634.2053; found
634.2037.
2-Benzyl 3,3-Diethyl 5-(Furan-2-yl)isoxazolidine-2,3,3-tricarbox-
ylate (3g): Reaction time: 6 h, 1g (0.100 g, 0.39 mmol), and 2a
(0.132 g, 0.79 mmol) gave a viscous liquid (0.102 g, 62 %). Rf 0.74
(EtOAc/hexane, 4:10, v/v). 1H NMR (400 MHz): δ = 7.39–7.34 (m, 5
H), 7.32 (d, J = 2.10 Hz, 1 H), 6.31 (d, J = 1.47 Hz, 2 H), 5.57 (dd, J =
5.17, 3.37 Hz, 1 H), 5.19 (s, 2 H), 4.41–4.25 (m, 2 H), 4.11–3.97 (m, 2
H), 3.31 (dd, J = 8.65, 4.54 Hz, 1 H), 2.96 (dd, J = 5.38, 8.44 Hz, 1 H),
1.27 (t, J = 7.18 Hz, 3 H), 1.17 (t, J = 7.39 Hz, 3 H) ppm. 13C NMR
(100 MHz): δ = 167.2, 166.0, 157.6, 151.4, 142.7, 135.5, 128.6, 128.4,
13.9 ppm. IR (neat): ν = 3781, 3702, 3639, 2975, 2920, 2780, 2357,
˜
1813, 1733, 1596, 1489, 1445, 1385, 1246, 1037, 931, 858, 809,
740 cm–1. HRMS (ESI, quadrupole): m/z calcd. for C24H25NO9Na [M
+ Na]+ 494.1427; found 494.1416.
2-Benzyl 3,3-Diethyl 5-(2,4,6-Trimethoxyphenyl)isoxazolidine-
2,3,3-tricarboxylate (3c): Reaction time:
4 h, 1c (0.100 g,
0.28 mmol), and 2a (0.094 g, 0.56 mmol) gave a viscous liquid
(0.093 g, 64 %). Rf 0.55 (EtOAc/hexane, 4:10, v/v). 1H NMR (400 MHz):
δ = 7.35–7.28 (m, 5 H), 6.08 (s, 2 H), 5.97 (dd, J = 8.00 Hz,1 H), 5.10
(d, J = 5.12 Hz, 2 H), 4.31 (m, J = 7.19, 7.07 Hz, 2 H), 4.11–4.06 (m,
2 H), 3.78 (s, 3 H), 3.72 (s, 6 H), 3.14 (dd, J = 9.23, 3.23 Hz, 1 H), 2.94
(dd, J = 7.88, 4.52 Hz, 1 H), 1.31 (t, J = 7.04 Hz, 3 H), 1.19 (t, J =
7.25 Hz, 3 H) ppm. 13C NMR (100 MHz): δ = 168.0, 166.1, 161.2,
159.3, 136.1, 128.3, 128.2, 128.0, 108.0, 91.2, 87.3, 67.7, 62.4, 55.9,
110.6, 107.8, 68.6, 62.8, 57.0, 40.1, 14.0 ppm. IR (neat): ν = 2982,
˜
2962, 2923, 2873, 2852, 1737, 1608, 1501, 1453, 1390, 1370, 1297,
1258, 1215, 1187, 1138, 1065, 1011, 953, 931, 908, 884, 855, 812,
740, 698 cm–1. HRMS (ESI, quadrupole): m/z calcd. for C21H23NO8Na
[M + Na]+ 440.1321; found 440.1308.
3,3-Diethyl 2-Methyl 5-(4-Methoxyphenyl)isoxazolidine-2,3,3-
tricarboxylate (3h): Reaction time: 6 h, 1d (0.100 g, 0.34 mmol),
and 2c (0.061 g, 0.68 mmol) gave a viscous liquid (0.084 g, 68 %).
Rf 0.76 (EtOAc/hexane, 4:10, v/v). 1H NMR (400 MHz): δ = 7.30 (d,
J = 8.22 Hz, 2 H), 6.87 (d, J = 8.22 Hz, 2 H), 5.38 (dd, J = 5.94, 2.23 Hz,
1 H), 4.26 (m, J = 7.13, 7.08, 7.13 Hz, 4 H), 3.79 (s, 3 H), 3.77 (s, 3 H),
3.39 (dd, J = 8.33, 4.52 Hz, 1 H), 2.72 (dd, J = 6.37, 6.97 Hz, 1 H),
1.31 (t, J = 7.30 Hz, 3 H), 1.25 (t, J = 7.24 Hz, 3 H) ppm. 13C NMR
(100 MHz): δ = 175.2, 165.7, 159.1, 158.0, 132.0, 127.4, 114.1, 62.7,
55.4, 54.0, 40.8, 14.0 ppm. IR (neat): ν = 3779, 3700, 2925, 2850,
˜
2359, 1732, 1599, 1456, 1383, 1263, 1199, 1124, 1070, 952, 812, 744,
699 cm–1 HRMS (ESI, quadrupole): m/z calcd. for C26H31NO10Na [M
+ Na]+ 540.1846; found 540.1846.
2-Benzyl 3,3-Diethyl 5-(4-Methoxyphenyl)isoxazolidine-2,3,3-
tricarboxylate (3d): Reaction time: 4 h, 1d (0.100 g, 0.34 mmol),
and 2a (0.114 g, 0.68 mmol) gave a viscous liquid (0.107 g, 69 %).
Rf 0.66 (EtOAc/hexane, 2:10, v/v). 1H NMR (400 MHz): δ = 7.32 (m, 5
H), 7.28 (d, J = 8.01 Hz, 2 H), 6.85 (d, J = 8.55 Hz, 2 H), 5.41 (dd, J =
6.31 Hz, 1 H), 5.17 (s, 2 H), 4.25–4.20 (m, J = 4.23, 4.0, 2.92 Hz, 2 H),
4.11–4.03 (m, 2 H), 3.78 (s, 3 H), 3.42 (dd, J = 8.47, 4.25 Hz, 1 H),
2.69 (dd, J = 7.47, 6.0 Hz, 1 H), 1.23 (t, J = 7.31 Hz, 3 H), 1.18 (t, J =
7.24 Hz, 3 H) ppm. 13C NMR (100 MHz): δ = 167.3, 165.9, 159.2,
157.5, 135.6, 132.1, 128.5, 128.3, 127.5, 114.1, 87.0, 68.3, 62.8, 62.5,
55.3, 44.5, 29.7, 14.0 ppm. IR (neat): ν = 2991, 1737, 1612, 1514,
˜
1442, 1301, 1249, 1178, 1064, 1045, 958, 829 cm–1. HRMS (ESI, quad-
rupole): m/z calcd. for C18H23NO8Na [M + Na]+ 404.1321; found
404.1309.
2-tert-Butyl 3,3-Dimethyl 5-Vinylisoxazolidine-2,3,3-tricarboxyl-
ate (3i): Reaction time: 8 h, 1h (0.100 g, 0.54 mmol), and 2b
(0.144 g, 1.08 mmol) viscous liquid (0.104 g, 61 %). Rf 0.66 (EtOAc/
hexane, 2:10, v/v). 1H NMR (400 MHz): δ = 5.77–5.73 (m, J = 7.08,
6.92, 3.30 Hz, 1 H), 5.34 (d, J = 17.4 Hz, 1 H), 5.24 (d, J = 10.4 Hz, 1
H), 4.64 (dd, J = 8.21, 6.80 Hz, 1 H), 3.76 (s, 6 H), 2.96 (dd, J = 6.52,
55.4, 44.5, 13.9 ppm. IR (neat): ν = 3781, 3701, 2977, 2931, 2846,
˜
2357, 1733, 1609, 1512, 1453, 1386, 1250, 1176, 1067, 832, 742,
698 cm–1. HRMS (ESI, quadrupole): m/z calcd. for C22H31NO9Na [M
+ Na]+ 480.1643; found 480.1639.
6.43 Hz, 1 H), 2.64 (dd, J = 9.01, 4.02 Hz, 1 H), 1.41 (s, 9 H) ppm. 13
C
NMR (100 MHz): δ = 168.2, 153.1, 133.0, 120.6, 83.0, 80.2, 53.6, 45.6,
2-Benzyl 3,3-Diethyl 5-(p-Tolyl)isoxazolidine-2,3,3-tricarboxyl-
ate (3e): Reaction time: 12 h, 1e (0.100 g, 0.36 mmol), and 2a
(0.120 g, 0.72 mmol) gave a viscous liquid (0.086 g, 54 %). Rf 0.50
(EtOAc/hexane, 4:10, v/v). 1H NMR (400 MHz): δ = 7.34–7.29 (m, 5
H), 7.26–7.24 (m, 2 H), 7.13 (d, J = 8.07 Hz, 2 H), 5.42 (dd, J = 5.97,
2.46 Hz, 1 H), 5.17 (s, 2 H), 4.23–4.21 (m, 2 H), 4.11–4.00 (m, 2 H),
3.43 (dd, J = 8.66, 4.68 Hz, 1 H), 2.68 (dd, J = 6.19, 6.73 Hz, 1 H),
28.2 ppm. IR (neat): ν = 3740, 3606, 3322, 2923, 2857, 1736, 1446,
˜
1367, 1257, 1161, 1115, 1025, 852, 790, 635 cm–1. HRMS (ESI, quad-
rupole): m/z calcd. for C20H26N2O9Na [M + Na]+ 338.1216; found
338.1208.
2-tert-Butyl 3,3-Diethyl (E)-5-Styrylisoxazolidine-2,3,3-tricarb-
oxylate (3j): Reaction time: 8 h, 1i (0.100 g, 0.0.34 mmol), and 2b
Eur. J. Org. Chem. 0000, 0–0
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6
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(0.092 g, 0.69 mmol) gave a viscous liquid (0.087 g, 60 %). Rf 0.42 ν = 3780, 2979, 2355, 1737, 1602, 1523, 1457, 1344, 1258, 1162,
˜
(EtOAc/hexane, 2:10, v/v). H NMR (400 MHz): δ = 7.49–7.28 (m, J =
7.17, 6.95 Hz, 5 H), 6.62 (d, J = 15.71 Hz, 1 H), 6.14 (dd, J = 8.85,
7.04 Hz, 1 H), 5.01 (dd, J = 7.71, 4.71 Hz, 1 H), 4.30–4.24 (m, 4 H),
3.22 (dd, J = 7.77, 4.71 Hz, 1 H), 2.53 (dd, J = 8.15, 5.05 Hz, 1 H),
1.46 (s, 9 H), 1.31 (t, J = 6.89 Hz, 3 H), 1.25 (t, J = 7.34 Hz, 3 H) ppm.
13C NMR (100 MHz): δ = 168.9, 167.4, 156.8, 136.3, 132.0, 128.7,
127.9, 127.2, 126.6, 86.4, 82.7, 62.7, 61.7, 41.9, 31.6, 28.2, 14.0 ppm.
1073, 850, 746 cm–1. HRMS (ESI, quadrupole): m/z calcd. for
1
C20H26N2O9Na [M + Na]+ 461.1536; found 461.1536.
Ethyl 3-Amino-5-(3,4-dimethoxyphenyl)-2-oxotetrahydrofuran-
3-carboxylate (4a): A mixture of 3b (100 mg, 0.21 mmol) and 10 %
Pd/C (0.045 mg, 0.02 mmol) in EtOH (10 mL) was shaken in a
hydrogen atmosphere for 5 h. The catalyst was separated by filtra-
tion with Celite. The filtrate was concentrated in vacuo and the
residue was purified by flash column chromatography to give a
white solid (0.059 g, 94 %), m.p. 171 °C. Rf 0.95 (EtOAc/hexane, 8:10,
IR (neat): ν = 3739, 2973, 1734, 1596, 1455, 1366, 1254, 1155, 1086,
˜
1023, 908, 853, 796, 744, 697 cm–1. HRMS (ESI, quadrupole): m/z
calcd. for C22H29NO7Na [M + Na]+ 442.1842; found 442.1840.
1
v/v). H NMR (400 MHz): δ = 6.90 (dd, J = 2.16, 5.77, 2.26 Hz, 1 H),
2-tert-Butyl 3,3-Diethyl 5-(3,4-Dimethoxyphenyl)isoxazolidine-
6.87 (m, 2 H), 4.88 (t, J = 7.32 Hz, 1 H), 4.33 (q, J = 7.22, 7.32 Hz, 2
H), 3.90 (s, 3 H), 3.89 (s, 3 H), 2.65 (m, J = 6.80, 6.91, 6.91, 7.42 Hz,
2 H), 1.32 (t, J = 7.01 Hz, 3 H) ppm. 13C NMR (100 MHz): δ = 173.3,
171.5, 133.1, 118.6, 111.3, 108.9, 63.2, 56.1, 55.4, 43.1, 31.0,
2,3,3-tricarboxylate (3k): Reaction time:
6 h, 1a (0.100 g,
0.31 mmol), and 2b (0.082 g, 0.62 mmol) gave a viscous liquid
(0.087 g, 62 %). Rf 0.54 (EtOAc/hexane, 4:10, v/v). 1H NMR (400 MHz):
δ = 6.90 (s, 1 H), 6.81 (dd, J = 1.93, 6.46 Hz, 1 H), 6.73 (d, J = 8.40 Hz,
1 H), 5.31 (dd, J = 4.23, 3.51 Hz, 1 H), 4.24–4.15 (m, J = 17.42, 16.89,
12.60, 4.55 Hz, 4 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 3.38 (dd, J = 8.54,
4.66 Hz, 1 H), 2.54 (dd, J = 5.52, 7.89 Hz, 1 H), 1.38 (s, 9 H), 1.25 (t,
J = 7.39 Hz, 3 H), 1.15 (t, J = 7.25 Hz, 3 H) ppm. 13C NMR (100 MHz):
δ = 167.3, 166.4, 156.8, 149.2, 148.4, 133.2, 118.4, 111.0, 109.1, 86.6,
14.2 ppm. IR (neat): ν = 3336, 2960, 2324, 1707, 1701, 1517, 1442,
˜
1257, 1234, 1205, 1195, 1157, 1109, 1095, 1022, 854, 810 cm–1
.
HRMS (ESI, quadrupole): m/z calcd. for C15H19NO6Na [M + Na]+
332.1110; found 332.1106.
Ethyl
3-Amino-5-(Benzo[d][1,3]dioxol-5-yl)-2-oxotetrahydro-
h, 3b (0.100 g,
furan-3-carboxylate (4b): Reaction time:
5
82.7, 62.6, 55.9, 44.4, 28.1, 13.9 ppm. IR (neat): ν = 3740, 3606, 3323,
˜
0.28 mmol), and 10 % Pd/C (0.045 mg, 0.02 mmol) gave a white
solid (0.057 g, 92 %), m.p. 146 °C. Rf 0.92 (EtOAc/hexane, 7:10, v/v).
1H NMR (400 MHz): δ = 6.86 (s, 1 H), 6.79 (s, 2 H), 5.97 (s, 2 H), 4.85
(t, J = 7.37 Hz, 1 H), 4.32 (q, J = 7.37, 7.26 Hz, 2 H), 2.63 (dd, J =
7.15, 6.96 Hz, 1 H), 2.53 (dd, J = 7.48, 7.04 Hz, 1 H), 1.32 (t, J =
7.39 Hz, 3 H) ppm. 13C NMR (100 MHz): δ = 173.5, 171.5, 148.4,
147.8, 134.7, 119.9, 108.5, 106.3, 101.4, 63.2, 55.4, 42.9, 14.1 ppm. IR
2972, 2926, 2855, 1734, 1594, 1514, 1457, 1365, 1254, 1152, 1081,
1023, 853, 802, 764 cm–1. HRMS (ESI, quadrupole): m/z calcd. for
C22H31NO9Na [M + Na]+ 476.1897; found 476.1888.
2-tert-Butyl 3,3-Diethyl 5-(Benzo[d][1, 3]dioxol-5-yl)isoxazol-
idine-2,3,3-tricarboxylate (3l): Reaction time: 6 h, 1b (0.100 g,
0.32 mmol), and 2b (0.086 g, 0.65 mmol) gave a viscous liquid
(0.092 g, 65 %). Rf 0.77 (EtOAc/hexane, 4:10, v/v). 1H NMR (400 MHz):
δ = 6.88 (s, 1 H), 6.79 (dd, J = 6.30 Hz, 1 H), 6.71 (d, J = 7.98 Hz, 1
H), 5.91 (s, 2 H), 5.31 (dd, J = 5.6, 2.94 Hz, 1 H), 4.29–4.21 (m, 4 H),
3.40 (dd, J = 8.16, 4.65 Hz, 1 H), 2.56 (dd, J = 7.37, 5.78 Hz, 1 H),
1.42 (s, 9 H), 1.30 (t, J = 7.03 Hz, 3 H), 1.22 (t, J = 7.19 Hz, 3 H) ppm.
13C NMR (100 MHz): δ = 167.3, 166.3, 156.6, 148.0, 147.0, 134.6,
119.6, 108.2, 106.7, 101.1, 86.7, 82.6, 62.5, 44.5, 28.0, 13.9 ppm. IR
(neat): ν = 3347, 2975, 2313, 1746, 1692, 1492, 1443, 1380, 1251,
˜
1200, 1119, 1035, 930, 868, 804, 680 cm–1. HRMS (ESI, quadrupole):
m/z calcd. for [M + Na]+ 316.0797; found 316.0757.
Diethyl 5-(3,4-Dimethoxyphenyl)isoxazolidine-3,3-dicarboxyl-
ate (4k): TFA (0.5 mL) was added slowly to a solution 3k (100 mg,
0.22 mmol) in CH2Cl2 (2 mL) at 0 °C. The reaction mixture was stirred
at this temperature for 1 h before the reaction was quenched slowly
with cold saturated aqueous NaHCO3 until a basic pH was achieved.
The product was extracted with CH2Cl2 (3 times). The combined
organic layers were dried with Na2SO4, concentrated in vacuo, and
purified by flash column chromatography to give a yellow viscous
liquid (0.068 g, 88 %). Rf 0.79 (EtOAc/hexane, 7:10, v/v). 1H NMR
(400 MHz): δ = 6.93–6.83 (m, 3 H), 5.99 (d, J = 13.80 Hz, 1 H), 4.51
(m, 1 H), 4.33–4.28 (m, J = 7.17, 6.81 Hz, 4 H), 3.88 (s, 6 H), 3.37 (dd,
J = 6.81, 6.26 Hz, 1 H), 2.62 (dd, J = 10.08, 3.07 Hz, 1 H), 1.31 (t, J =
6.99 Hz, 6 H) ppm. 13C NMR (100 MHz): δ = 170.1, 167.3, 148.7,
126.2, 119.4, 110.7, 110.4, 88.9, 64.9, 63.1, 56.1, 44.1, 14.3 ppm. IR
(neat): ν = 3781, 3701, 2972, 2992, 2860, 2358, 1733, 1597, 1488,
˜
1446, 1246, 1161, 931, 854, 803 cm–1. HRMS (ESI, quadrupole): m/z
calcd. for C21H27NO9Na [M + Na]+ 460.1584; found 460.1584.
2-tert-Butyl 3,3-Diethyl 5-(3,4,5-Trimethoxyphenyl)isoxazol-
idine-2,3,3-tricarboxylate (3m): Reaction time: 4 h, 1j (0.100 g,
0.28 mmol), and 2b (0.074 g, 0.56 mmol) gave a viscous liquid
(0.096 g, 66 %). Rf 0.55 (EtOAc/hexane, 4:10, v/v). 1H NMR (400 MHz):
δ = 6.59 (s, 2 H), 5.36 (dd, J = 5.29, 2.14 Hz, 1 H), 4.33–4.30 (m, J =
6.92 Hz, 2 H), 4.23–4.20 (m, J = 7.11 Hz, 2 H), 3.83 (s, 6 H), 3.79 (s,
3 H), 3.45 (dd, J = 8.56, 4.51 Hz, 1 H), 2.58 (dd, J = 7.91, 5.31 Hz, 1
H), 1.44 (s, 9 H), 1.31 (t, J = 7.20 Hz, 3 H), 1.29 (t, J = 7.14 Hz, 3
H) ppm. 13C NMR (100 MHz): δ = 167.3, 166.3, 156.6, 153.4, 136.5,
102.9, 86.6, 82.9, 62.9, 62.5, 60.8, 56.2, 44.4, 28.1, 14.0 ppm. IR (neat):
(neat): ν = 2977, 2842, 1735, 1597, 1597, 1515, 1457, 1373, 1252,
˜
1148, 1025, 856, 808, 760, 625 cm–1. HRMS (ESI, quadrupole): m/z
calcd. for [M + Na]+ 376.1372; found 376.1368.
ν = 3738, 3605, 3304, 2981, 2895, 2833, 2251, 1734, 1593, 1505,
˜
1459, 1362, 1246, 1122, 1008, 915, 848, 775, 732, 657 cm–1 HRMS
(ESI, quadrupole): m/z calcd. for C23H33NO10Na [M + Na]+ 506.2002;
found 506.1992.
Acknowledgments
R. K. V. thanks to the University Grants Commitee (UGC), New
Delhi for a research fellowship. P. B. acknowledges the Depart-
ment of Science and Technology (DST), New Delhi for financial
support. The authors are also thankful to Dr. C. M. Nagaraja,
Department of Chemistry, IIT Ropar for solving the single-crys-
tal X-ray structure mentioned in this paper.
2-tert-Butyl 3,3-Diethyl 5-(4-Nitrophenyl)isoxazolidine-2,3,3-tri-
carboxylate (3n): Reaction time: 12 h, 1k (0.100 g, 0.32 mmol), and
2b (0.086 g, 0.65 mmol) gave a viscous liquid (0.071 g, 50 %). Rf
1
0.77 (EtOAc/hexane, 4:10, v/v). H NMR (400 MHz): δ = 8.22 (d, J =
8.85 Hz, 2 H), 7.57 (d, J = 8.87 Hz, 2 H), 5.36 (dd, J = 7.62 Hz, 1 H),
4.32 (m, J = 3.87, 3.72, 3.48, 3.09 Hz, 2 H), 4.25 (m, J = 7.31, 7.06 Hz,
2 H), 3.34 (dd, J = 6.63, 6.24 Hz, 1 H), 2.90 (dd, J = 8.57, 4.35 Hz, 1
H), 1.50 (s, 9 H), 1.35 (t, J = 7.21 Hz, 3 H), 1.27 (t, J = 7.26 Hz, 3
H) ppm. 13C NMR (100 MHz): δ = 167.3, 152.9, 148.1, 144.4, 127.3,
124.0, 83.4, 79.0, 73.1, 63.1, 62.8, 47.6, 29.8, 28.2, 14.1 ppm. IR (neat):
Keywords: Synthetic methods · Nitrogen heterocycles ·
Cycloaddition · Lewis acids
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Received: May 12, 2016
Published Online: ■
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Full Paper
Isoxazolidine Synthesis
R. K. Varshnaya, P. Banerjee* .......... 1–9
Construction
of
Isoxazolidines
through Formal [3+2] Cycloaddition
Reactions of in situ Generated Ni-
trosocarbonyls with Donor–Ac-
ceptor Cyclopropanes: Synthesis of
α-Amino γ-Butyrolactones
MgI2-catalyzed [3+2] cycloaddition re- alized isoxazolidines. Furthermore,
actions of donor–acceptor cycloprop- isoxazolidines readily transformed into
anes with in situ generated nitroso- synthetically important α-amino-γ-
carbonyls from hydroxycarbamates is butyrolactones.
explored for the synthesis of function-
DOI: 10.1002/ejoc.201600582
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