Synthesis of bicyclic isoxazoles and isoxazolines via intramolecular nitrile oxide cycloaddition

Article abstract of DOI:10.3390/molecules200610910

An efficient and straight forward procedure for the syntheses of bicyclic isoxazole/isoxazoline derivatives from the corresponding dimethyl-2-(2-nitro-1-aryl/alkyl)-2-(prop-2-yn-1yl)malonates or dimethyl 2-allyl-2-(2-nitro-1-aryl/alkyl ethyl)malonate is d

Full text of DOI:10.3390/molecules200610910

Molecules 2015, 20, 10910-10927; doi:10.3390/molecules200610910
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis of Bicyclic Isoxazoles and Isoxazolines via
Intramolecular Nitrile Oxide Cycloaddition
Wen-Chang Chen, Veerababurao Kavala, Yu-Hsuan Shih, Yu-Hsuan Wang, Chun-Wei Kuo,
Tang-Hao Yang, Chia-Yu Huang, Hao-Hsiang Chiu and Ching-Fa Yao *
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Ting-Chow Road,
Taipei 116, Taiwan; E-Mails: wcchen@taigenbiotech.com (W.-C.C.); kavalaveeru@gmail.com (V.K.);
coshih@gmail.com (Y.-H.S.); baby11710@hotmail.com (Y.-H.W.);
cwkuo.water@gmail.com (C.-W.K.); a129084303xx@gmail.com (T.-H.Y.);
tlotras@gmail.com (C.-Y.H.); a210627@hotmail.com (H.-H.C.)
* Author to whom correspondence should be addressed; E-Mail: cheyaocf@ntnu.edu.tw or
cheyaocf@yahoo.com.tw; Tel.: +886-2-29309092.
Academic Editor: Derek J. McPhee
Received: 30 April 2015 / Accepted: 4 June 2015 / Published: 12 June 2015
Abstract: An efficient and straight forward procedure for the syntheses of bicyclic
isoxazole/isoxazoline derivatives from the corresponding dimethyl-2-(2-nitro-1-aryl/alkyl)-
2-(prop-2-yn-1yl)malonates or dimethyl 2-allyl-2-(2-nitro-1-aryl/alkyl ethyl)malonate is
described. High yields and simple operations are important features of this methodology.
Keywords: bicyclic isoxazole/isoxazolines; cycloaddition; nitrile oxide; nitroalkane;
Yamaguchi reagent
1. Introduction
Isoxazole and isoxazoline derivatives are important scaffolds found in many naturally occurring
and biologically active compounds [1–5]. They are considered to be important precursors for the
synthesis of β-hydroxyketones or β-aminoalcohols, α,β-unsaturated ketones, and many other valuable
compounds [6–10]. Isoxazole or isoxazoline motifs fused with carbocycles or heterocycles are known
to possess a variety of bioactivities and are also useful surrogates for the generation of various other
bioactive compounds [11–15].

Molecules 2015, 20
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Isoxazole and isoxazoline derivatives are typically synthesized through in situ formation of a nitrile
oxide followed by an intramolecular dipolar cycloaddition [16–19]. The most common methods for
generating nitrile oxides are the dehydrohalogenation of hydroximoyl chlorides [20–24], the oxidation of
aldoximes [25–32], and the dehydration of nitroalkanes [33–36]. Although a wide variety of procedures
are available for the synthesis of diverse isoxazole and isoxazoline derivatives, few of them address
the preparation of carbocyclic fused isoxazole/isoxazoline derivatives [37–42]. The dehydration of the
nitroalkanes followed by intramolecular dipolar cycloaddition is the most popular method for the
construction of carbocycle fused isoxazole/isoxazoline derivatives. The literature procedures for the
generation of carbocycle fused isoxazole/isoxazoline from various nitroalkane derivatives [43–47]involve
the use of phenyl isocyanate and triethylamine, treatment of the nitronate with di-tert-butyl dicarbonate in
the presence of catalytic amounts of dimethylaminopyridine (DMAP), the use of chlorformates in the
presence trimethylamine and trimethylsilyl chloride (TMSCl) in the presence of trimethylamine. We
also reported on a different procedure for the construction of bicyclicisoxazole/isoxazoline derivatives
by using trichlorotriazine (TCT), chloroformate and phenyl isocyante as dehydrating agents. Although
a few methods for the synthesis of carbocycle fused isoxazole/isoxazoline derivatives are efficient, some
of the available methods suffer from drawbacks such as low yields and selectivity and long reaction
times. Hence, a simple and straightforward method for generating such derivatives in high yields and
in better selectivity would be highly desirable. It is well known that the Yamaguchi reagent (2,4,6-
trichlorobenzoyl chloride) is a dehydrating agent used in the construction of macrolides and highly
functionalized esters [48–50]. However, to our knowledge this reagent has not been utilized for the
dehydration of nitroalkanes. Herein, we wish to report on the synthesis of bicyclicisoxazole/isoxazoline
derivatives from the corresponding dimethyl 2-propargyl-2-(2-nitro-1-aryl/alkylethyl)malonate/dimethyl
2-allyl-2-(2-nitro-1-aryl/alkyl ethyl)malonates using the Yamaguchi reagent as a dehydrating agent.
2. Results and Discussion
We first synthesized the starting materials, including the dimethyl 2-propargyl-2-(2-nitro-1-
aryl/alkylethyl)malonates 1a–15a or dimethyl 2-allyl-2-(2-nitro-1-aryl/alkyl ethyl)malonates 1c–6c
from the corresponding nitroalkenes and propargylmalonate/allylmalonate derivatives in the presence of
potassium tertiary butoxide (t-BuOK) and lithium bis(trimethylsilyl)amide (LHMDS) [34,43]. We then
initiated our studies of the reaction by using dimethyl-2-(2-nitro-1-phenylethyl)-2-(prop-2-yn-1yl)malonate
(1a) as the substrate.
To start the reaction, 1a was treated with potassium tert-butoxide (2.5 equiv.) and the Yamaguchi
reagent (2,4,6-trichlorobenzoyl chloride) in dichloromethane at −78 °C. The corresponding bicyclic
isoxazole product was produced in 65% yield after 24 h. Encouraged by this initial result, we next focused
our attention on optimizing the reaction conditions for the formation the bicyclic isoxazole product. To
find a superior base for this transformation the reaction, various bases, including trimethylamine (Et3N),
1,8-diazabicycloundec-7-ene (DBU), and dimethylaminopyridine (DMAP) were screened. Among them,
DBU was found to be the most suitable one. As the Yamaguchi reagent functions as a dehydrating agent
in this reaction, we were curious to examine whether other benzoyl chlorides could be used for this
purpose. To check this, we reacted 1a with various benzoyl chlorides including unsubstituted, 2-chloro-,
and 3,4-dichlorobenzoyl chlorides in the presence of DBU. All of these reactions resulted in the

Molecules 2015, 20
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production of the desired product in moderate to good yields. However, the yield of the desired product
was higher when the Yamaguchi reagent was used as the dehydrating agent. Although the yield of the
product was satisfactory, the reaction time was longer when a base (2.5 equiv.) and a dehydrating agent
(3 equiv.) was used.
On the other hand, we observed that the efficiency of the nitroalkane to nitrile oxide dehydration
reaction was enhanced in the presence a catalytic amount of Lewis acid [43] and conducting the reaction
in the presence of a Lewis acid produced the corresponding product in a very short time. Hence, we
tested various Lewis acid catalysts, including SnCl4, ZnCl2 and ZrCl4. Among the Lewis acids tested,
ZrCl4 was found to the best choice. Further, to determine the optimum amount of base required for this
reaction, we carried out the reaction using 2 equiv., 1.5 equiv., and 1.0 equiv. of DBU. The reaction was
the most efficient when more than 1.5 equivalent of base was used. Moreover, the reaction resulted
in excellent yields and the reaction time was shorter when a base (1.5 equiv.) and 1.5 equiv. of the
Yamaguchi reagent was used. To determine the effect of temperature, we conducted the reactions at
0 °C and at room temperature. The reaction furnished the desired bicyclic isoxazole derivative in
moderate yield when it was conducted at 0 °C, whereas a poor yield of the bicyclic isoxazole was
obtained when the reaction was carried out at room temperature. Thus, the optimum reaction conditions
for the formation of the bicyclic isoxazole were determined to be the use of 1.5 equiv. DBU, 1.5 equiv.
of the Yamaguchi reagent and 10 mol % ZrCl4 as the catalyst in DCM at −78 °C. These optimization
studies are summarized in Table 1.
Table 1. Optimization studies.
Lewis Temp.
Time
(h)
24
24
24
24
48
35
24
3
Entry
Base (equiv.)
Dehydrating Agent (equiv.)
Yield a, b
Acid
—
(°C)
‒78
‒78
‒78
‒78
‒78
‒78
‒78
‒78
‒78
‒78
‒78
‒78
‒78
0
1
2
Kt-BuO
TEA
(2.5) 2,4,6-Trichlorobenzoyl chloride
(2.5) 2,4,6-Trichlorobenzoyl chloride
(2.5) 2,4,6-Trichlorobenzoyl chloride
(2.5) 2,4,6-Trichlorobenzoyl chloride
(3)
(3)
(3)
(3)
(3)
(3)
(3)
65
50
67
73
62
65
65
82
87
60
90
95
85
40
20
—
3
DMAP
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
—
4
—
5
(2.5)
(2.5)
(2.5)
Benzoyl chloride
—
6
2-Chlorobenzoyl; chloride
3,4-Dichlorobenzoyl chloride
—
7
—
8
(2.5) 2,4,6-Trichlorobenzoyl chloride (1.5) ZnCl2
(2.5) 2,4,6-Trichlorobenzoyl chloride (1.5) ZnCl4
(2.5) 2,4,6-Trichlorobenzoyl chloride (1.5) SnCl4
(2.0) 2,4,6-Trichlorobenzoyl chloride (1.5) ZnCl4
(1.5) 2,4,6-Trichlorobenzoyl chloride (1.5) ZnCl4
(1.0) 2,4,6-Trichlorobenzoyl chloride (1.5) ZnCl4
(1.5) 2,4,6-Trichlorobenzoyl chloride (1.5) ZnCl4
(1.5) 2,4,6-Trichlorobenzoyl chloride (1.5) ZnCl4
a NMR yields. b Reactions carried out in 0.5 mmol scale.
9
4
10
11
12
13
14
15
5
4
4
7
2
25
2

Molecules 2015, 20
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After determining the optimum conditions for the formation of bicyclic isoxazoles, we then
utilized these conditions for investigating the scope and limitations of the methodology with various
dimethyl-2-(2-nitro-1-aryl/alkyl)-2-(prop-2-yn-1yl)malonates derived from the corresponding
nitroalkenes and dimethylproparylmalonate (Table 2).
Table 2. Synthesis of bicyclic isoxazole derivatives.
Entry
Substrate
Product
Time (h)
Yield% a,b
1
4
95
1a
1b
2a
2
3
2
3
86
89
2b
2c
1c
1d
1e
4
5
3
5
92
90
2d
2e
6
5
87
2f
1f

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Table 2. Cont.
Entry
Substrate
Product
Time (h)
Yield% a,b
7
3
84
1g
1h
2g
2h
8
9
3
3
86
84
1i
1j
2i
2j
10
11
15
7
79
92
2k
1k
12
13
12
80
87
1l
2l
NO2
MeO2C
5
MeO2C
1m
2m
a Isolated yields. b Reactions performed in 0.5 mmol scale.
Under the optimized conditions, the substrate containing an unsubstituted phenyl group (compound 1a)
gave the corresponding bicyclic isoxazole derivative in excellent yield. The reactions of substrates
possessing an electron withdrawing group such as a bromo group (compound 1b) and substrates containing
an electron donating group such as methyl (compound 1c) and methoxy (compound 1d) groups at the ortho
position of the phenyl group reacted smoothly to yield the corresponding bicyclic isoxazole derivatives in
excellent yields. On the other hand, substrates containing an electron withdrawing group at the para
position of the phenyl group such as 1e and 1f, provided the corresponding bicycloisoxazole derivatives

Molecules 2015, 20
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2e and 2f, respectively, in excellent yields. In addition, substrates possessing electron donating groups
(OMe and Me) and an electron neutral group (SMe) at the para position of the phenyl group reacted with
equal ease to provide the desired products 2g, 2h and 2i in good yields. Further, substrates containing
thiophene (compound 1j), and methyleneoxy groups (compound 1k) reacted smoothly and provided the
corresponding bicyclicisoxazole derivatives 2j and 2k, respectively, in good to excellent yields. Substrates
containing a naphthalene moiety (compound 2l) and an alkyl group (compound 2m) also produced the
corresponding products in high yields under the present reaction conditions.
To extend the scope of this reaction, we examined the reactions of dimethyl 2-(2-nitro-1-phenylethyl)-
2-(3-phenylprop-2-yn-1-yl)malonate (1n) and tetramethyl 2,2′-(1,4-phenylenebis(2-nitroethane-1,1-
diyl))bis(2-(prop-2-yn-1-yl)malonate) (1o). To our delight, both reactions provided the corresponding
bicyclic isoxazole derivatives (2n and 2o) in good yields (Scheme 1).
Scheme 1. Synthesis of bicyclic isoxazole derivatives.
We also investigated the reactions of 2-allyl-2-(2-nitro-1-aryl/alkyl ethyl)malonate derivatives under
the present reaction conditions and the results are listed in Table 3. As shown in Table 3, the reactions
of substrates containing both electron withdrawing as well as electron donating groups exhibited a
similar reactivity under the reaction conditions. However, when substrates containing thienyl and
naphthyl moieties were used a slightly longer reaction time was needed to produce good yield of the
corresponding bicyclic isoxazoline derivatives (Table 3).
It is important to note that the reactions of all 2-allyl-2-(2-nitro-1-aryl/alkylethyl)malonate derivatives
resulted in the production of mixture of diastereomers and among the diastereomers, the cis isomer was
the major component and the trans isomer was the minor one. The NMR signal for the methine proton
at the bridgehead carbon in the trans isomer appears at 4.62 ppm, compared to 3.82 ppm for the cis
isomer, which permits trans and cis isomers to be identified. The diastereoslectivity (cis:trans) ranged
from 5.6:1 to 3.6:1. The diasteroslectivity for this reaction slightly better than in our previous report [43].
These results were consistent with the our previous results as well as other literature reports [43,51,52].

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Table 3. Synthesis of bicyclic isoxazoline derivatives.
Entry
Substrate
Product
Time (h) Yield% a,b cis:trans c
1
3
4
88
83
5.3:1
4.6:1
4a
3a
Cl
N
O
MeO2C
2
3
MeO2C
4b
3b
3c
3d
5
81
3.6:1
4c
4
5
5
85
78
5.4:1
4.8:1
4d
4e
NO2
S
MeO2C
12
MeO2C
3e
NO2
6
7
84
5.6:1
MeO2C
MeO2C
4f
3f
a Isolated yields. b Reactions performed in 0.5 mmol scale. c cis:trans isomers were determined from 1H-NMR.
Based on our experience with nitroalkanes and the literature reports related to the Yamaguchi
reagent, the formation of bicyclic isoxazole/isoxazolines from dimethyl 2-propargyl-2-(2-nitro-1-
aryl/alkylethyl)malonates or dimethyl 2-allyl-2-(2-nitro-1-aryl/alkylethyl)malonates with a base and the
Yamaguchi reagent in the presence of an acidic catalyst could be explained by two mechanistic pathways
shown in Scheme 2. The reaction of the nitroalkane in the presence a base could result in the production

Molecules 2015, 20
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of a nitronate ion, which could be further converted into a benzoylnitronate [A] by reaction with the
Yamaguchi reagent and zirconium chloride. This benzoylnitronate [A] could then be converted into the
corresponding nitrile oxide [B] intermediate in the presence of zirconium chloride, which would further
undergo intramolecular nitrile oxide cycloaddition (INOC) to afford the desired carbocycle fused
isoxazole/isoxazoline (Scheme 2, Route B). Another possibility is that the benzoylnitronate might act as
a 1,3-dipole [53] to undergo INOC to obtain intermediate [C], which upon losing trichlorobenzoic acid,
would produce the desired bicyclic compound (Scheme 2, Route A).
Scheme 2. Plausible mechanistic pathways.
3. Experimental Section
3.1. General Information
All chemicals were purchased from various commercial sources and used directly without further
purification. Analytical thin-layer chromatography was performed using E. Merck (New York, NY,
USA) silica gel 60F glass plates and E. Merck silica gel 60 (230–400 mesh) was used in flash
chromatography separations. MS were measured by a JMS-HX110 spectrometer (JEOL, Hsinchu,
1
Japan). HRMS spectra were recorded using ESI-TOF or EI+ mode or FAB+. H- (400 MHz) and
13C-NMR (100 MHz) spectra were recorded with an Advance EX 400 MHz spectrometer (Bruker, San
Francisco, CA, USA). Chemical shifts are reported in parts per million (δ) using TMS as an internal
standard and coupling constant were expressed in hertz. IR spectra were performed on a 100 series
FT-IR instrument (Perkin Elmer, Waltham, MA, USA). Melting points were recorded using an capillary
melting point apparatus (Electrothermal, Staffordshire, UK) and are uncorrected. All substrates were
prepared using literature procedures.

Molecules 2015, 20
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3.2. General Procedure for the Preparation of 1a–1o
Potassium tert-butoxide (3 mmol) was added to a solution of dimethyl propargylmalonate (2.4 mmol)
in anhydrous THF (15 mL) at room temperature under nitrogen atmosphere. The reaction mixture was
then cooled to −78 °C and a solution of the nitroalkene (2 mmol) in anhydrous THF (5 mL) was added
dropwise over a period of five minutes. The reaction mixture was then stirred at −78 °C until the reaction
was complete, which was monitored by TLC. A saturated aqueous NH4Cl was then added and the
resulting mixture extracted with ethyl acetate (3 × 10 mL). The combined organic phases were dried over
MgSO4 and the solvent removed in vacuo. The residue was purified by flash column chromatography over
silica (ethyl acetate and hexane).
Dimethyl 2-(1-(2-bromophenyl)-2-nitroethyl)-2-(prop-2-yn-1-yl)malonate (1b): Colorless solid; Yield:
1
67% (5 h); m.p. 100–101 °C; H-NMR (CDCl3) δ 7.60 (d, J = 8.0 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H),
7.20–7.14 (m, 2H), 5.22 (d, J = 8.0 Hz, 1H), 5.16–5.03 (m, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 2.76 (m, 2H),
2.15 (s, 1H); 13C-NMR (CDCl3) δ 169.2, 169.1, 134.8, 134.2, 130.1, 128.4, 128.2, 127.3, 78.8,
79
78.0, 72.8, 60.8, 53.6, 53.3, 44.8, 23.8; HRMS (EI) m/z calc. for C16H16NO6 Br (M+) 397.0161,
found 397.0156.
Dimethyl 2-(2-nitro-1-(o-tolyl)ethyl)-2-(prop-2-yn-1-yl)malonate (1c): Colorless solid; Yield: 75%
1
(4 h); m.p. 98–99 °C. H-NMR (CDCl3) δ 7.17–7.12 (m, 3H), 6.92–6.90 (m, 1H), 5.32 (dd, J = 6.7,
3.1 Hz, 1H), 4.96 (dd, J = 11.6 Hz, 6.6 Hz, 1H), 4.81 (dd, J = 5.6 Hz,, 2.9 Hz, 1H), 3.83 (s, 3H), 3.78 (s,
3H), 2.85 (dd, J = 8.7 Hz, 2.8 Hz, 1H), 2.51 (s, 3H), 2.41 (dd, J = 8.7 Hz, 2.6 Hz, 1H), 2.15 (t, J = 2.7 Hz,
1H); 13C-NMR (CDCl3) δ 169.5, 169.4, 139.2, 133.7, 131.7, 128.5, 126.6, 126.4, 79.2, 79.0, 73.2, 60.8,
53.4, 53.3, 40.8, 23.7, 20.1; HRMS (EI) m/z calc. for C17H19NO6 (M+) 372.1059, found 372.1069.
Dimethyl 2-(2-nitro-1-(2-methoxyphenyl)ethyl)-2-(prop-2-yn-1-yl)malonate (1d): Colorless solid;
1
Yield: 72% (4 h); m.p. 141–142 °C. H-NMR (CDCl3) δ 7.26–7.22 (m, 2H), 6.88–6.81 (m, 2H), 5.17
(d, J = 5.8 Hz, 2H), 4.65 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.71 (s, 3H), 2.80 (d, J = 17.1 Hz, 1H), 2.30
(d, J = 16.3 Hz, 1H), 2.11 (s, 1H); 13C-NMR (CDCl3) δ 169.5, 169.1, 157.6, 133.0, 130.0, 122.3, 120.9,
111.2, 78.6, 76.4, 72.6, 59.0, 55.3, 53.2, 52.7, 44.0, 24.3.
Dimethyl 2-(1-(4-fluorophenyl)-2-nitroethyl)-2-(prop-2-yn-1-yl)malonate (1e): Colorless solid; Yield:
84% (3 h); m.p. 89–90 °C. 1H-NMR (CDCl3) δ 7.18 (dd, J = 8.4, 5.3 Hz, 2H), 7.00 (t, J = 8.5 Hz, 2H),
5.28 (dd, J = 13.6, 3.0 Hz, 1H), 4.96 (dd, J = 13.5, 11.6 Hz, 1H), 4.50 (dd, J = 11.7, 2.9 Hz, 1H), 3.80
(s, 3H), 3.78 (s, 3H), 2.79 (dd, J =17.5 Hz, 2.5 Hz, 1H), 2.37 (dd, J =17.5 Hz, 2.5 Hz, 1H), 2.23
(t, J = 2.3 Hz, 1H); 13C-NMR (CDCl3) δ 169.1, 169.0, 164.0 (d, JC-F = 245.0), 130.7 (d, JC-F = 8.0), 130.6
(d, JC-F = 4.0), 116.3 (d, JC-F = 21.0), 78.0, 76.9, 73.8, 59.7, 53.6, 53.4, 44.9, 24.1; HRMS (EI) m/z calc.
for C16H16NO6F (M+) 337.0963, found 337.0969.
Dimethyl 2-(1-(4-chlorophenyl)-2-nitroethyl)-2-(prop-2-yn-1-yl)malonate (1f): Colorless solid; Yield:
98% (5 h); m.p. 123–124 °C; 1H-NMR (CDCl3) δ 7.30 (d, J = 8.3 Hz, 2H), 7.15 (d, J = 8.3 Hz, 2H), 5.30
(dd, J = 13.8, 2.9 Hz, 1H), 4.97 (dd, J = 13.8, 11.7 Hz, 1H), 4.51 (dd, J = 11.7, 2.9 Hz, 1H), 3.81 (s, 3H),
3.79 (s, 3H), 2.81 (dd, J =17.5 Hz, 2.2 Hz, 1H), 2.37 (dd, J =17.5 Hz, 2.2 Hz, 1H), 2.25 (s, 1H);

Molecules 2015, 20
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13C-NMR (CDCl3) δ 168.9, 168.8, 134.8, 133.2, 130.2, 129.3, 77.9, 77.5, 73.9, 59.5, 53.6, 53.4, 44.9,
35
24.1; HRMS (EI) m/z calc. for C16H16NO6 Cl (M+) 353.0666, found 353.0661.
Dimethyl 2-(1-(4-methoxyphenyl)-2-nitroethyl)-2-(prop-2-yn-1-yl)malonate (1g): Colorless solid; Yield:
81% (2 h); m.p. 111–112 °C; 1H-NMR (CDCl3) δ 7.11 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.27
(dd, J = 13.5, 2.9 Hz, 1H), 4.98 (dd, J = 13.5, 11.4 Hz, 1H), 4.46 (dd, J = 11.4, 2.9 Hz, 1H), 3.81 (s, 3H),
3.79 (s, 3H), 3.77 (s, 3H), 2.79 (dd, J =17.4 Hz, 2.2 Hz, 1H), 2.42 (dd, J =17.4 Hz, 2.2 Hz, 1H), 2.22
(s, 1H); 13C-NMR (CDCl3) δ 169.2, 169.1, 159.9, 130.0, 126.4, 114.5, 78.3, 77.9, 73.5, 59.9, 55.4, 53.4,
53.3, 45.0, 24.1; HRMS (EI) m/z calc. for C17H19NO7 (M+) 349.1162, found 349.1156.
Dimethyl 2-(2-nitro-1-(p-tolyl)ethyl)-2-(prop-2-yn-1-yl)malonate (1h): Colorless solid; Yield: 92%
(2 h); m.p. 91–92 °C; 1H-NMR (CDCl3) δ 7.15 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.0 Hz, 2H), 5.28 (dd,
J = 13.6, 3.0 Hz, 1H), 5.00 (dd, J = 13.6, 11.6 Hz, 1H), 4.47 (dd, J = 11.6, 2.9 Hz, 1H), 3.81 (s, 3H),
3.78 (s, 3H), 2.78 (dd, J =17.4 Hz, 2.4 Hz, 1H), 2.41 (dd, J =17.4 Hz, 2.4 Hz, 1H), 2.30 (s, 3H), 2.23
(s, 1H); 13C-NMR (CDCl3) δ 169.2, 169.1, 138.7, 131.5, 129.8, 128.6, 78.3, 77.8, 73.5, 59.7, 53.4, 53.3,
45.2, 24.1, 21.2; HRMS (EI) m/z calc. for C17H19NO6 (M+) 333.1212, found 333.1207.
Dimethyl 2-(2-nitro-1-(4-methylthiophenyl)ethyl)-2-(prop-2-yn-1-yl)malonate (1i): Yellow oil; Yield:
1
88% (2 h); H-NMR (CDCl3) δ 7.16 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 5.26 (dd, J = 13.7,
3.1 Hz, 1H), 4.97 (dd, J = 13.7, 11.4 Hz, 1H), 4.46 (dd, J = 11.4, 3.1 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H),
2.78 (dd, J =17.4 Hz, 2.6 Hz, 1H), 2.43 (s, 3H), 2.39 (dd, J =17.4, 2.4 Hz, 1H), 2.22 (t, J =2.6 Hz, 1H);
13C-NMR (CDCl3) δ 169.1, 169.0, 139.6, 131.1, 129.2, 126.6, 78.2, 77.7, 73.6, 59.7, 53.4, 53.3, 45.1,
24.1, 15.4; HRMS (EI) m/z calc. for C17H19NO6S (M+) 365.0933, found 365.0928.
Dimethyl 2-(2-nitro-1-(thiophen-2-yl)ethyl)-2-(prop-2-yn-1-yl)malonate (1j): Colorless solid; Yield:
90% (2.5 h); m.p. 101–102 °C; 1H-NMR (CDCl3) δ 7.25 (d, J = 5.0 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H),
6.95 (dd, J = 5.0, 3.6 Hz, 1H), 5.26 (dd, J = 13.4, 2.6 Hz, 1H), 4.97 (dd, J = 13.4, 11.1 Hz, 1H), .4.86 (d,
J = 11.1 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 2.89 (dd, J = 17.5, 2.7 Hz, 1H), 2.61 (dd, J = 17.4, 2.7 Hz,
1H); 2.23 (t, J = 2.7 Hz, 1H); 13C-NMR (CDCl3) δ 168.8, 168.7, 136.8, 128.6, 127.2, 126.3, 79.1, 78.0,
73.6, 60.1, 53.6, 53.5, 41.8, 24.1; HRMS (EI) m/z calc. for C14H15NO6S (M+) 325.0620, found 325.0615.
Dimethyl 2-(1-benzo[d][1,3]dioxol-5yl)-2-nitroethyl)-2-(prop-2-yn-1-yl)malonate (1k): Colorless solid;
Yield: 95% (4 h); m.p. 169–170 °C. 1H-NMR (CDCl3) δ 6.73 (d, J = 8.4 Hz, 1H), 6.67–6.65 (m, 2H),
5.95 (s, 2H), 5.24 (dd, J = 13.6, 3.1 Hz, 1H), 4.94 (dd, J = 13.6, 11.4 Hz, 1H), 4.42 (dd, J = 11.1, 3.1Hz,
1H), 3.81 (s, 3H), 3.78 (s, 3H), 2.81 (dd, J = 17.4, 2.6 Hz, 1H), 2.46 (dd, J = 17.4, 2.6 Hz, 1H); 2.17 (t,
13
J = 2.6 Hz, 1H); C-NMR (CDCl3) δ 169.1, 169.0, 148.2, 148.1, 128.1, 122.6, 109.0, 108.8, 101.5,
78.2, 77.9, 73.6, 59.9, 53.5, 53.4, 45.4, 25.2; HRMS (EI) m/z calc. for C17H17NO8 (M+) 363.0954,
found 363.0949.
Dimethyl 2-(1-(naphthalen-1-yl)-2-nitroethyl)-2-(prop-2-yn-1-yl)malonate (1l): Colorless solid; Yield:
77% (2 h); m.p. 145–146 °C; 1H-NMR (CDCl3) δ 8.45 (d, J = 8.6 Hz, 1H), 7.80 (t, J = 9.4 Hz, 2H), 7.54
(t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 5.56–5.48
(m, 2H), 5.22 (dd, J = 13.5, 10.9 Hz, 1H), 3.80 (s, 3H), 3.63 (s, 3H), 2.78 (dd, J = 17.5, 2.6 Hz, 1H),

Molecules 2015, 20
10920
2.36 (dd, J = 17.5, 2.6 Hz, 1H); 2.21 (t, J = 2.6 Hz, 1H); 13C-NMR (CDCl3) δ 169.4, 169.2, 134.1, 132.8,
131.9, 129.5, 128.8, 126.7, 126.3, 125.0, 124.8, 123.8, 79.1, 78.7, 73.3, 60.9, 53.4, 53.3, 39.2, 23.6;
HRMS (EI) m/z calc. for C20H19NO6 (M+) 369.1212, found 369.1207.
Dimethyl 2-(4-methyl-1-nitropentan-2yl-)-2-(prop-2-yn-1-yl)malonate (1m): Pale yellow oil; Yield:
82% (3 h); 1H-NMR (CDCl3) δ 4.98 (dd, J = 14.5, 3.9 Hz, 1H), .4.30 (dd, J = 14.5, 5.7 Hz, 1H), 3.75 (s,
3H), 3.74 (s, 3H), 3.36–3.31 (m, 1H), 2.93 (dd, J = 17.6, 2.7 Hz, 1H), 2.84 (dd, J = 17.6, 2.6 Hz, 1H);
2.11 (t, J = 2.7 Hz, 1H), 1.58–1.51 (m, 1H), 1.31–1.18 (m, 2H), 0.93 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.4 Hz,
13
3H); C-NMR (CDCl3) δ 169.7, 169.4, 78.5, 78.3, 72.9, 60.0, 53.2, 53.1, 39.7, 37.9, 25.7, 23.9, 23.3,
21.4;. HRMS (EI) m/z calc. for C14H21NO6 (M+) 300.1448, found 300.1444.
Dimethyl 2-(2-nitro-1-phenylethyl)-2-(3-phenylprop-2-yn-1-yl)malonate (1n): Pale yellow oil; Yield:
1
98% (3 h); H-NMR (CDCl3) δ 7.46–7.45 (m, 2H), 7.35–7.31 (m, 6H), 7.24–7.23 (m, 2H), 5.35 (dd,
J = 13.7, 3.0 Hz, 1H), 5.06 (dd, J = 13.7, 11.3 Hz, 1H), 4.61 (dd, , J = 11.2, 3.0 Hz, 1H) 3.84 (s, 3H),
13
3.80 (s, 3H), 3.02 (d, J = 17.5 Hz, 1H), 2.63 (d, J = 17.5 Hz, 1H); C-NMR (CDCl3) δ 169.2, 169.1,
134.8, 131.7, 129.0, 128.8, 128.7, 128.5, 128.4, 122.8, 85.5, 83.5, 77.0, 60.1, 53.3, 53.2, 45.7, 24.9;.
HRMS (EI) m/z calc. for C22H21NO6 (M+) 395.1369, found 395.1366.
Tetramethyl 2,2'-(1,4-phenylenebis(2-nitroethane-1,1-diyl))bis(2-(prop-2-yn-1-yl)malonate) (1o):
1
Colorless solid; Yield: 60% (2 h); m.p. 180–182 °C; H-NMR (CDCl3) δ 7.18 (s, 4H), 5.29 (dd,
J = 13.9, 3.0 Hz, 2H), 5.00 (ddd, J = 13.9, 11.1, 3.1 Hz, 2H), 4.48 (d, J = 9.9 Hz, 2H), 3.76 (s, 6H), 3.75
(s, 6H), 2.78 (dd, J = 17.4, 2.4 Hz, 2H), 2.34 (dt, J = 17.4, 3.5 Hz, 2H); 2.20 (s, 2H); 13C-NMR (CDCl3)
δ 169.2, 169.1, 169.0, 135.7, 135.6, 129.5, 78.2, 78.1, 73.8, 73.7, 59.9, 53.5, 53.4, 45.4, 24.2, 24.1;
HRMS (ESI) m/z calc. for C26H28N2O12 (M) + 560.1642, found 560.1642.
3.3. General Procedure for the Synthesis of 3a–3f
LHMDS (1.5 mmol) was added to a solution of dimethyl propargylmalonate (1.2 mmol) in anhydrous
THF (5 mL) at 0 °C under a nitrogen atmosphere, followed by stirring for 1 h. A solution of nitroalkene
(1 mmol) in anhydrous THF (5 mL) was then added drop wise over a period of five minutes at 0 °C. The
reaction mixture was then stirred at the same temperature until the reaction was complete, which was
monitored by TLC. After the completion of the reaction, a saturated aqueous NH4Cl was added and
the resulting mixture extracted with ethyl acetate (3 × 10 mL). The combined organic phases were
dried over MgSO4 and the solvent removed in vacuo. The residue was purified by flash column
chromatography over silica (ethyl acetate and hexane).
Dimethyl 2-allyl-2-(1-(4-chlorophenyl)-2-nitroethyl)malonate (3b): Colorless solid; Yield: 98% (2.5 h);
m.p. 98–99 °C; 1H-NMR (CDCl3) δ 7.29 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 5.75–5.65 (m,
1H), 5.15–4.91 (m, 4H), 4.18 (dd, J = 11.1, 3.1 Hz, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 2.58 (dd, J =14.5 Hz,
6.4 Hz, 1H), 2.27 (dd, J =14.5 Hz, 8.1 Hz, 1H); 13C-NMR (CDCl3) δ 170.0, 169.9, 134.7, 133.6, 131.7,
35
130.4, 129.2, 120.2, 78.2, 60.7, 53.0, 52.9, 46.3, 38.5; HRMS (EI) m/z calc. for C16H18NO6 Cl (M+)
355.0823, found 355.0817.

Molecules 2015, 20
10921
Dimethyl 2-allyl-2-(2-nitro-1-(p-tolyl)ethyl)malonate (3c): Colorless solid; Yield: 97% (4 h); m.p.
88–89 °C; 1H-NMR (CDCl3) δ 7.10 (d, J = 7.9 Hz, 2H), 6.98 (d, J = 7.9 Hz, 2H), 5.78–5.68 (m, 1H),
5.14–4.93(m, 4H), 4.16 (dd, J = 10.8, 3.4 Hz, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 2.56 (dd, J = 14.4, 6.5 Hz, 1H),
2.30 (s, 3H) 2.29–2.25 (m, 1H); 13C-NMR (CDCl3) δ170.4, 170.2, 138.6, 132.1, 131.8, 129.7,
128.8, 120.0, 78.6, 61.1, 53.0 52.9, 46.7, 38.7, 21.2; HRMS (EI) m/z calc. for C17H21NO6 (M+) 335.1369,
found 335.1363.
Dimethyl 2-allyl-2-(1-(4-methoxyphenyl)-2-nitroethyl)malonate (3d): Yellow oil; Yield: 80% (7 h);
1H-NMR (CDCl3) δ 7.02 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.76–5.67 (m, 1H), 5.15–4.92 (m,
4H), 4.14 (dd, J = 11.0, 3.4 Hz, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.74 (s, 3H), 2.57 (dd, J =14.4, 8.0 Hz,
13
1H), 2.29 (dd, J =14.4, 8.0 Hz, 1H); C-NMR (CDCl3) δ 170.4, 170.2, 159.9, 132.1, 130.1, 126.7,
120.0, 114.4, 78.6, 61.2, 55.4, 53.0, 52.9, 46.4, 38.7; HRMS (EI) m/z calc. for C17H21NO7 (M+) 351.1318,
found 349.1313.
Dimethyl 2-allyl-2-(2-nitro-1-(thiophen-2-yl)ethyl)malonate (3e): Yellow oil; Yield: 95% (4 h);
1H-NMR (CDCl3) δ 7.24 (d, J = 5.0 Hz, 1H), 6.93–6.90 (m, 1H), 6.89 (d, J = 5.0 Hz, 1H), 5.79–5.72 (m,
1H), 5.17–4.92 (m, 4H), 4.52 (dd, J = 10.5, 3.1 Hz, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 2.69 (dd, J = 14.5,
13
6.5 Hz, 1H), 2.43 (dd, J = 14.5, 8.1 Hz, 1H); C-NMR (CDCl3) δ 169.8, 169.7, 137.1, 131.8, 128.4,
127.0, 126.1, 120.2, 79.6, 61.2, 53.0, 42.7, 38.6; HRMS (EI) m/z calc. for C14H17NO6S (M+) 327.0777,
found 327.0771.
Dimethyl 2-allyl-2-(1-(naphthalen-1-yl)-2-nitroethyl)malonate (3f): Yellow oil; Yield 98% (3.5 h);
1H-NMR (CDCl3) δ 8.31 (d, J = 8.6 Hz, 1H), 7.82 (dd, J = 13.7, 8.2 Hz, 1H), 7.59 (td, J = 7.4, 0.8 Hz,
1H), 7.50 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 5.75–5.65 (m, 1H), 5.35
(t, J = 7.0 Hz, 1H), 5.16 (d, J = 7.1 Hz, 2H), 5.00 (d, J = 10.1 Hz, 1H), 4.90 (d, J = 17.0 Hz, 1H), 3.85
(s, 3H), 3.73 (s, 3H), 2.38 (dd, J = 14.2, 6.6 Hz, 1H), 2.23 (dd, J = 14.2, 7.9 Hz, 1H); 13C-NMR (CDCl3)
δ 170.6, 170.4, 134.2, 133.1, 132.7, 132.2, 129.4, 129.1, 127.0, 126.3, 125.2, 124.6, 123.5, 119.6, 79.4,
62.8, 52.9, 40.6, 39.1; HRMS (EI) m/z calc. for C20H21NO6 (M+) 371.1369, found 371.1363.
3.4. General Procedure for the Preparation of 2a–2o and 4a–4f
A mixture of allyl or propargyl dimethyl malonate (1 mmol) and DBU (1.5 equiv.) in anhydrous
dichloromethane (3 mL) was stirred at −78 °C for 20 min under nitrogen. To this mixture, the Yamaguchi
reagent (1.5 equiv.) and ZrCl4 (10 mol %) were added. The reaction mixture was then stirred at the same
temperature for 10 min. then stopped the cooler and continued until the reaction was complete,
as indicated by TLC. After the completion of the reaction, the reaction mixture was washed with water,
and extracted with CH2Cl2, washed the organic layer with brine solution. The organic layers were collected,
combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The
residue was then purified by column chromatography using EtOAc-hexane to give the desired product.
2a, 2j, 2k, 4a–4f are known compounds [43].
Dimethyl-6-(2-bromophenyl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2b): Brown solid;
m.p. 127–129 °C; 1H-NMR (CDCl3) δ 8.10 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.16 (t, J = 7.4 Hz,1H),

Molecules 2015, 20
10922
7.08 (td, J = 7.7, 1.3 Hz, 1H),6.73 (d, J = 7.6 Hz, 1H), 5.97 (s, 1H), 3.88 (d, J = 17.2 Hz, 1H), 3.80 (s,
13
3H), 3.29 (s, 3H), 3.25 (d, J = 17.2 Hz, 1H); C-NMR (CDCl3) δ 172.8, 170.9, 168.2, 150.8, 137.1,
133.2, 129.8, 129.5, 127.8, 125.5, 121.3, 72.6, 53.7, 52.5, 46.9, 29.9; HRMS (EI) m/z calc. for C16H1479Br
NO5 (M+) 379.0055, found 379.0050.
Dimethyl-6-(o-tolyl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2c): White solid; m.p. 117–118 °C;
1H-NMR (CDCl3) δ 8.08 (s, 1H), 7.16–7.08 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H), 6.97 (d, J = 7.4 Hz, 1H),
5.63 (s, 1H), 3.63 (d, J = 17.4, 1.5 Hz, 1H), 3.79 (s, 3H), 3.25 (d, J = 17.4, 1.4Hz, 1H), 3.19 (s, 3H), 2.49
(s, 3H); 13C-NMR (CDCl3) δ 173.5, 171.5, 168.5, 150.5, 137.1, 135.8, 130.6, 128.3, 127.9, 126.3,
121.4, 72.9, 53.6, 52.4, 44.0, 29.8, 20.2. HRMS (EI) m/z calc. for C17H17NO5Na (M+ + Na) 338.1005,
found 338.1015.
Dimethyl-6-(2-methoxyphenyl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2d): Pale yellow oil;
1H-NMR (CDCl3) δ 8.02 (s, 1H), 7.21 (td, J = 7.8, 1.5 Hz, 1H), 6.97 (d, J = 6.8 Hz, 1H), 6.86–6.81 (m,
2H), 5.63 (s, 1H), 3.88 (dd, J = 16.7, 1.2 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.22 (s, 3H), 3.16 (d,
13
J = 16.7 Hz, 1H); C-NMR (CDCl3) δ 172.9, 171.6, 168.7, 157.4, 149.8, 130.5, 129.4, 125.8, 121.6,
120.7, 111.1, 72.3, 55.6, 53.5, 52.4, 43.5, 30.4; HRMS (EI) m/z calc. for C17H17NO6 (M+) 331.1056,
found 331.1064.
Dimethyl-6-(4-fluorophenyl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2e): Pale yellow oil;
1H-NMR (CDCl3) δ 8.10 (s, 1H), 7.21 (dd, J = 8.0, 3.9 Hz, 1H), 6.97 (t, J =8.4 Hz, 3H), 5.31 (s, 1H),
13
3.80 (s, 3H), 3.67 (d, J = 16.4 Hz, 1H), 3.24 (s, 3H), 3.11 (d, J = 16.8 Hz, 1H); C-NMR (CDCl3) δ
171.8, 171.0, 168.9, 162.6 (d, J = 245 Hz), 150.6, 131.8 (d, J = 3 Hz), 130.5 (d, J = 8 Hz), 121.6,
115.5 (d, J = 21 Hz), 72.9, 53.5, 48.0, 29.7; HRMS (EI) m/z calc. for C16H14FNO5 (M+) 319. 0856,
found 319.0851.
Dimethyl-6-(4-chlorophenyl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2f): Pale yellow solid;
m.p. 124–125 °C; 1H-NMR (CDCl3) δ 8.11 (s, 1H), 7.26 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H),
5.30 (s, 1H), 3.81 (s, 3H), 3.68 (d, J = 16.6 Hz, 1H), 3.25 (s, 3H), 3.13 (d, J = 16.6 Hz, 1H); 13C-NMR
(CDCl3) δ 171.5, 170.9, 168.8, 150.6, 134.6, 134.2, 130.5, 128.7, 121.4, 72.9, 53.6, 52.7, 48.1, 29.7;
HRMS (EI) m/z calc. for C16H1435ClNO5 (M+) 335. 056, found 335.0555.
Dimethyl-6-(4-methoxyphenyl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2g): White solid;
m.p. 111–110 °C; 1H-NMR (CDCl3) δ 8.06 (s, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 8.64 Hz, 2H),
5.24 (s, 1H), 3.77 (s, 3H), 3.74 (s, 3H), 3.66 (d, J = 16.5 Hz, 1H), 3.23 (s, 3H), 3.10 (d, J = 16.5 Hz, 1H);
13C-NMR (CDCl3) δ 172.2, 171.1, 168.9, 159.4, 150.3, 130.1, 128.0, 121.2, 113.9, 72.8, 55.3, 53.4, 52.5,
48.0, 29.5; HRMS (EI) m/z calc. for C17H17NO6 (M+) 331.1056, found 331.1050.
Dimethyl-6-(p-tolyl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2h): White solid; m.p.
102–103 °C; 1H-NMR (CDCl3) δ 8.00 (s, 1H), 7.01 (d, J = 8.2 Hz, 2H), 6.98 (d, J = 8.2 Hz, 2H), 5.19
(s, 1H), 3.72 (s, 3H), 3.63 (d, J = 16.6 Hz, 1H), 3.17 (s, 3H), 3.06 (d, J = 16.6 Hz, 1H), 2.22 (s, 3H);
13C-NMR (CDCl3) δ 171.9, 170.9, 168.5, 150.1, 137.6, 132.8, 128.9, 128.6, 121.1, 72.7, 53.2, 52.3, 48.1,
29.4, 21.0; HRMS (EI) m/z calc. for C17H17NO5 (M+) 315.1107, found 315.1101.

Molecules 2015, 20
10923
Dimethyl-6-(4-(methylthio)phenyl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2i): Orange
solid; m.p. 114–116 °C; 1H-NMR (CDCl3) δ 8.09 (s, 1H), 7.16 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz,
2H), 5.27 (s, 1H), 3.79 (s, 3H), 3.69 (dd, J = 16.0, 1.0 Hz, 1H), 3.25 (s, 3H), 3.12 (dd, J = 16.0, 1.0 Hz,
13
1H), 2.44 (s, 3H); C-NMR (CDCl3) δ 171.9, 171.1, 168.8, 150.5, 138.7, 132.8, 129.5, 126.6, 121.3,
72.9, 53.5, 52.6, 48.3, 29.7, 15.9; HRMS (EI) m/z calc. for C17H17NO5S (M+) 347. 0827, found 347.0822.
Dimethyl-6-(thiophen-2-yl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2j): White solid; m.p.
129–130 °C; 1H-NMR (CDCl3) δ 8.08 (s, 1H), 7.23–7.21(m, 1H), 6.94–6.91 (m, 2H), 5.53(s, 1H), 3.81
(s, 3H), 3.68 (dd, J = 16.5, 1.2Hz, 1H), 3.41 (s, 3H), 3.14 (dd, J = 16.5, 1.2 Hz, 1H); 13C-NMR (CDCl3)
δ 171.5, 170.7, 168.5, 150.6, 137.4, 127.5, 126.8, 125.9, 120.6, 72.9, 53.5, 52.8, 44.1, 29.3; HRMS (EI)
m/z calc. for C14H13NO5S (M+) 307. 0514, found 307.0513.
Dimethyl-6-(benzo[d][1,3]dioxol-5-yl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2k): White
1
solid; m.p. 93–94 °C; H-NMR (CDCl3) δ 8.08 (s, 1H), 6.72–6.66 (m, 3H), 5.91–5.90 (m, 2H), 5.23
(s, 1H), 3.79 (s, 3H), 3.66 (d, J = 16.5 Hz, 1H), 3.33 (s, 3H), 3.11 (d, J = 16.5 Hz, 1H); 13C-NMR (CDCl3)
δ 171.9, 171.0, 168.7, 150.4, 147.7, 129.5, 122.5, 121.2, 109.4, 108.1, 101.2, 72.7, 53.4, 52.6, 48.3, 29.5;
HRMS (EI) m/z calc. for C17H15NO7 (M+) 345. 0849, found 345.0847.
Dimethyl-6-(naphthalen-1-yl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2l): White solid; m.p.
131–133 °C; 1H-NMR (CDCl3) δ 8.39 (d, J =5.4 Hz, 1H), 8.15 (s, 1H), 7.83 (d, J =8.1 Hz, 1H), 7.75 (d,
J=8.2 Hz, 1H), 7.58 (t, J =6.8 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 6.91 (s, 1H),
6.31 (s, 1H), 3.91 (d, J = 16.9 Hz, 1H), 3.83 (s, 3H), 3.31 (d, J = 16.9 Hz, 1H), 2.71 (s, 3H); 13C-NMR
(CDCl3) δ 173.3, 171.4, 168.2, 150.6, 133.9, 133.5, 131.9, 128.8, 128.7, 126.6, 126.3, 125.9,
125.3, 124.2, 121.6, 73.0, 53.7, 52.0, 43.2, 29.8; HRMS (EI) m/z calc. for C20H17NO5 (M+) 351.1106,
found 351.1101.
Dimethyl-6-isobutyl-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2m): White solid; m.p.
101–102 °C; 1H-NMR (CDCl3) δ 7.93 (s, 1H), 3.95 (dd, J = 11.7, 4.2 Hz, 1H), 3.76 (s, 3H), 3.75 (s, 3H),
3.46 (dd, J = 16.4, 1.5 Hz, 1H), 3.08 (dd, J =16.4, 1.5 Hz, 1H), 2.03–1.96 (m, 1H), 1.41 (td, J =12.9, 3.7 Hz,
1H), 1.33–1.26 (m, 1H), 1.04 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.5 Hz, 3H); 13C-NMR (CDCl3) δ 172.4,
171.2, 169.7, 149.5, 120.1, 70.4, 53.3, 52.9, 41.7, 38.0, 29.4, 25.8, 24.0, 21.2; HRMS (EI) m/z calc. for
C20H17NO5 (M+) 281.1263, found 281.1258.
Dimethyl-6-(2-bromophenyl)-4H-cyclopenta[c]isoxazole-5,5(6H)-dicarboxylate (2n): White solid; m.p.
1
209–211 °C; H-NMR (CDCl3) δ 7.76–7.74 (m, 2H), 7.51–7.41 (m, 3H), 7.31–7.22 (m, 5H), 5.35
(s, 1H), 3.94 (d, J = 16.7 Hz, 1H), 3.81 (s, 3H), 3.24 (d, J = 16.7 Hz, 1H), 3.22 (s, 3H); 13C-NMR (CDCl3)
δ 173.5, 171.2, 168.8, 161.3, 136.3, 130.1, 129.3, 129.2, 128.2, 127.8, 126.3, 116.9, 73.3, 53.6, 52.6,
49.0, 31.1; HRMS (EI) m/z calc. for C22H19NO5 (M+) 377.1263, found 377.1265.
4. Conclusions
In summary we report on a practical and efficient regioselective synthesis of bicyclic
isoxazole/isoxazoline derivatives via intramolecular nitrile oxide cycloaddition reactions using the
Yamaguchi reagent and DBU in the presence of ZrCl4. The process is straightforward, easy to perform

Molecules 2015, 20
10924
and does not involve the use of costly reagents or catalysts. A wide variety of carbocyclic fused isoxazole
and isoxazoline derivatives were synthesized in good to moderate yields.
Acknowledgments
Financial support by the Ministry of Science and Technology of the Republic of China (MOST
103-2113-M-003-008-MY3) National Taiwan Normal University (103-07-C) and the Instrumentation
Centre at National Taiwan Normal University is gratefully acknowledged. The authors are grateful to
Hsiu-Ni Huan, Mei-Ling Chen and Chiu-Hui He for providing mass, HRMS and NMR spectral data.
Author Contributions
Ching-Fa Yao, Wen-Chang Chen, Veerababurao Kavala, conceived and designed the experiments;
Wen-Chang Chen, Yu-Hsuan Shih, Yu-Hsuan Wang, Chun-Wei Kuo, Tang-Hao Yang and Chia-Yu Huang,
performed the experiments; Chia-Yu Huang, Hao-Hsiang Chiu analyzed the data; Veerababurao Kavala
and Ching-Fa Yao wrote the paper.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds 2a–2o and 4a–4f are available from the authors.
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