Divergent synthesis of fully substituted isoxazoles and spiro-fused pyrazolin-5-ones from cyclopropyl oximes

Article abstract of DOI:10.1016/j.tet.2011.05.136

Efficient and divergent synthesis of fully substituted isoxazoles and spiro-fused pyrazolin-5-ones is developed from cyclopropyl oximes based on selection of reaction conditions. Under Appel conditions (PPh ₃/CBr₄), substituted isoxa

Full text of DOI:10.1016/j.tet.2011.05.136

Tetrahedron 67 (2011) 6347e6351
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Divergent synthesis of fully substituted isoxazoles and spiro-fused
pyrazolin-5-ones from cyclopropyl oximes
,
a
a,b,
Xiaolan Fu a, Peng Huang b, Guangyuan Zhou b , Yinqiao Hu , Dewen Dong
*
*
a Department of Chemistry, Northeast Normal University, Changchun 130024, PR China
b Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 April 2011
Received in revised form 24 May 2011
Accepted 31 May 2011
Available online 14 June 2011
Efficient and divergent synthesis of fully substituted isoxazoles and spiro-fused pyrazolin-5-ones is
developed from cyclopropyl oximes based on selection of reaction conditions. Under Appel conditions
(PPh3/CBr4), substituted isoxazoles were synthesized from cyclopropyl oximes via a ring-opening and
intramolecular cyclization process, whereas by treatment of cyclopropyl oximes with p-toluenesulfonyl
chloride in the presence of potassium hydroxide, spiro-fused pyrazolin-5-ones were obtained via tandem
ketoxime tosylation and intramolecular cyclization.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Ar
Ar
O
N
O
N
N
O
N
N
R1
R1
Five-membered nitrogen-containing heterocycles have received
intensiveresearchinterestsduetotheirbiologicalactivities,andfound
a wide range of applications in pharmaceutical and agrochemistry.1
Among them, the isoxazole and pyrazolin-5-one motifs make up the
core structures of numerous natural products and biologically active
synthetic compounds.2,3 General methods for their synthesis involve
the intermolecular annulation of appropriately substituted 1,3-
dicarbonyl compounds and their equivalents with hydroxylamine4
or hydrazines.5 Nevertheless, to match the increasing scientific and
practical demand for isoxazoles and pyrazolin-5-ones, novel and ef-
ficient synthetic approach for the construction of these heterocyclic
skeletons, especially those with wide applicability to achieve more
elaborate and flexible substitution patterns, is still desirable.
On the other hand, cyclopropanes are extremely versatile syn-
thetic intermediates for their ready accessibility and good reactivity
originating from their inherent ring strain, which can lead to a va-
riety of ring-opening or ring-expanding reactions under the in-
fluence of a wide range of chemicals, such as electrophiles,
nucleophiles, and radicals.6,7 During the course of our studies on
NHAr
CH2CH2Cl
Cl
CH2CH2Cl
R1
PIFA/TFA
Path C
POCl3/CH2Cl2 Path A
POCl3/DMF Path B
R1 = Me, Ph
R2 = NHAr
HO
R1
N
O
R2
1
TsCl/KOH
Path E
PPh3/CBr4
R1 = Me, Ph
R1 = Me,
2 = NHAr
Path D
R
2 = NHAr, OEt
R
Ar
N
N
O
N
R1
R2
O
2
3
CH2CH2Br
Scheme 1. Reactions of 1-carbamoyl,1-oximyl cyclopropanes.
the synthesis of carbo- and heterocycles from
b-oxo amide de-
rivatives,8 we achieved one-pot synthesis of 2,3-dihydrofurans and
pyridine-2(1H)-ones from 1-carbamoyl cyclopropanes.9 Our recent
researches have demonstrated the synthetic potential of 1-
carbamoyl,1-oximyl cyclopropanes 1 in the construction of iso-
xazoles (Scheme 1, path A),10 1H-pyrazoles (Scheme 1, path B),10
and spiro-fused pyrazolin-5-one N-oxides (Scheme 1, path C).11
In connection with these studies and our continuing interest in
the further synthetic potential of cyclopropyl oximes 1, we exam-
ined their reactivity toward varied dehydration agents. As a result,
we developed an efficient and divergent synthesis of isoxazoles 2
(Scheme 1, path D) and spiro-fused pyrazolin-5-ones 3 (Scheme 1,
path E) under very mild conditions. Herein, we wish to report our
experimental results and present proposed mechanisms involved
in the ring-opening and/or cyclization reactions.
* Corresponding authors. Tel.: þ86 431 85262190; fax: þ86 431 85098635 (D.D.);
tel./fax: þ86 431 85262204 (G.Z.); e-mail addresses: gyzhou@ciac.jl.cn (G. Zhou),
dongdw663@nenu.edu.cn (D. Dong).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.136

6348
X. Fu et al. / Tetrahedron 67 (2011) 6347e6351
2. Results and discussion
proceeded smoothly to afford the corresponding isoxazoles 2 in
good to excellent yields (Table 1, entries 2e7). As shown in Table 1,
the ring-opening and cyclization reaction proved to be suitable for
cyclopropyl oximes 1beg bearing varied arylamide groups. The
versatility of this isoxazole synthesis was further evaluated by
performing reaction of cyclopropyl ester 1h with PPh3/CBr4 (Table
1, entry 8). In this case, the corresponding substituted isoxazole
2h was obtained in good yield, albeit with prolonged reaction time.
However, when 1a was subjected to another Appel agent PPh3/CCl4
under the otherwise identical conditions, no reaction was observed
as indicated by TLC. Upon treatment of 1a with 1.5 equiv of PPh3
and 1.0 equiv of CCl4 under reflux for 10 h in acetonitrile, the re-
action proceeded and furnished a product, which was characterized
as 4-(2-chloroethyl)-3-methyl-N-phenyl isoxazol-5-amine 2a0 on
the basis of its spectral and analytical data (85% yield, Scheme 2).
Indeed, isoxazole 2a0 was synthesized in our previous work by the
reaction of 1a with POCl3 in dichloromethane.10 Therefore, we
provided an alternative approach for the synthesis of substituted
isoxazole of type 2.
On the basis of the obtained results together with the related
reports,12fꢀi a plausible mechanism for the synthesis of substituted
isoxazoles 2 is presented in Scheme 3. The conversion involves the
interaction of PPh3 with CBr4 to form the intermediate A, which
reacts with cyclopropyl oxime 1 to produce an oxyphosphonium
intermediate C. Bromide anion attacks the intermediate C0 and
triggers a ring-opening reaction and subsequent intramolecular
cyclization to afford isoxazole 2 bearing a bromoethyl substituent,
with elimination of triphenylphosphine oxide (Ph3PO).
2.1. Synthesis of fully substituted isoxazoles
Appel agents (PPh3/CX4, X¼Cl, Br) have been extensively used in
dehydration, halogenation, and PeN linking reactions.12 Their ef-
ficient utilization in organic synthesis relies on their extremely
mild reaction conditions required, easy handling, reactivity similar
to aggressive, and readily hydrolyzed acid chlorides, such as PCl5,
POCl3, and thionyl chloride. Recently, Shi and co-workers in-
vestigated the reactions of varied cyclopropyl amides with PPh3/
CX4 and synthesized substituted benzoxazoles, pyrrolidin-2-ones,
and oxadiazoles.13
In the present work, the reaction of 1-[1-(hydroxyimino)ethyl]-
N-phenylcyclopropanecarboxamide 1a with PPh3 (2.0 equiv) and
CBr4 (1.0 equiv) was first attempted in acetonitrile at room tem-
perature. As indicated by TLC, the substrate 1a was consumed
within 20 min. The reaction proceeded smoothly and furnished one
product after workup and purification by column chromatography.
From the spectral and analytical data, the product was character-
ized as 4-(2-bromoethyl)-3-methyl-N-phenyl isoxazol-5-amine 2a
(89% yield, Scheme 2).
HO
N O
PPh3 /CX4
CH3CN
N
O
2a: X = Br
2a': X = Cl
NHPh
CH2CH2X
NHPh
1a
Scheme 2. The reaction of 1a with PPh3/CX4.
The reaction conditions, including reaction temperature, sol-
vent, and the ratio of 1a to PPh3 and CBr4, were then investigated. A
series of experiments revealed that 1.0 equiv of PPh3 and CBr4 were
sufficient for the synthesis of 2a and acetonitrile was the best sol-
vent among those tested, and the optimal results were obtained
when the reaction of 1a was performed with PPh3 (1.1 equiv) and
CBr4 (1.0 equiv) in acetonitrile at room temperature for 30 min,
whereby the yield of 2a reached 90% (Table 1, entry 1). It should be
mentioned that when treatment of 1a with PBr3 in dichloro-
methane followed our previous reported procedure,10 isoxazole 2a
could be obtained but in lower yield (<45%) along with some in-
separable byproducts.
Br3C
+
B
N
O
Br
C
Br
R1
R2
+
Br
Br
Ph3P
CH2CH2Br
2
Br
O
PPh3
A
-HBr
1
-Ph3PO
O
Ph3P
Ph3P
O
N
O
N
R2
R1
-Br
R2
R1
C
C'
Table 1
a
Scheme 3. Plausible mechanism of the reaction of cyclopropyl oximes 1 with PPh3/
The reactions of cyclopropyl oximes 1 with PPh3/CBr4
CBr4.
H
N
O
O
N
O
R2
PPh Br
3/C
R1
4
2.2. Synthesis of spiro-fused pyrazolin-5-ones
R1
R2
H N, rt
C 3C
H
C
H Br
2C
2
In the next study, we examined the reaction behavior of cyclo-
propyl oximes 1 toward another dehydration and halogenation
agent, p-toluenesulfonyl chloride (TsCl).14,15 The reaction of 1a with
TsCl (1.1 equiv) was then performed in acetonitrile in the presence
of potassium hydroxide (2.0 equiv). As monitored by TLC, the
substrate 1a was consumed within 2.0 h. After workup and puri-
fication by column chromatography, the reaction furnished a white
solid, which was characterized as 7-methyl-5-phenyl-5,6-
diazaspiro[2.4]hept-6-en-4-one 3a rather than an isoxazole on
the basis of its spectral and analytical data (Scheme 4).16
1
2
Entry
1
R1
R2
Time (min)
2
Yieldb (%)
1
2
3
4
5
6
7
8
1a
Me
Me
Me
Me
Me
Me
Me
Ph
PhNH
2-MeC6H4NH
30
40
50
40
35
50
50
300
2a
2b
2c
2d
2e
2f
90
93
91
94
90
87
93
75
1b
1c
1d
1e
1f
2-MeOC6H4NH
4-MeC6H4NH
4-MeOC6H4NH
4-ClC6H4NH
2,4-Me2C6H3NH
EtO
1g
1h
2g
2h
a
Reagents and conditions: 1 (1.0 mmol), PPh3 (1.1 mmol), CBr4 (1.0 mmol),
CH3CN (5.0 mL), rt.
Ph
b
HO
Isolated yield.
N
N
N
O
TsCl/KOH
CH3CN, rt
O
NHPh
Having established the optimal conditions for the isoxazole
synthesis, we intended to determine its scope with respect to the
amide motif. Thus, a series of cyclopropyl oximes 1beg were sub-
jected to PPh3/CBr4 under the identical conditions, all the reactions
3a
1a
Scheme 4. The reaction of 1a with TsCl/KOH in CH3CN.

X. Fu et al. / Tetrahedron 67 (2011) 6347e6351
6349
The reaction conditions, including solvent, base, and the feed ratio
of 1a/TsCl/base were evaluated. After extensive experiments, the
best results were obtained when the reaction between 1a and TsCl
(1.0 equiv) was conducted in dichloromethane in the presence of
potassium hydroxide (2.0 equiv) at room temperature for 40 min,
whereby the yield of 3a reached 92% (Table 2, entry 1).
It was interesting to note that TsCl, being a dehydration and
halogenation agent, showed different reaction behavior from Appel
reagent, PPh3/CX4. On the basis of the obtained results together
with the related reports, a plausible mechanism for the synthesis of
spiro-fused pyrazolin-5-ones 3 is depicted in Scheme 6. It was as-
sumed that the transformation commenced from the tosylation of
cyclopropyl oxime 1, followed by an intramolecular cyclization of
the intermediate D to afford spiro-fused pyrazolin-5-one 3 with the
elimination of p-toluenesulfonic acid.
Table 2
a
The reaction of cyclopropyl oximes 1 with TsCl/KOH in CH2Cl2
Ar
H
O
N
N
N
O
TsCl K
H
/ O
Ar
O
TsO
HO
N
N
N
O
N
NHAr
O
H l , r t
C 2C 2
O
NHAr
TsCl/KOH
NHAr
3
1
D
3
1
Entry
1
Ar
Ph
Time (min)
3
3a17
3b
Yieldb (%)
Scheme 6. Plausible mechanism of the reaction of cyclopropyl oximes 1 with TsCl/
KOH in CH2Cl2.
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
40
60
75
50
60
80
90
92
90
88
93
91
85
91
2-MeC6H4
2-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-ClC6H4
3c
3d17a
3e
3. Conclusions
3f17a
3g
1g
2,4-Me2C6H3
In summary, an efficient and divergent synthesis of fully
substituted isoxazoles 2 andspiro-fused pyrazolin-5-ones 3 hasbeen
developed from readily available 1-carbamoyl,1-cyclopropyl oximes
1. Under Appel conditions (PPh3/CBr4), oximes 1 were converted into
isoxazoles 2 via a ring-opening and intramolecular cyclization pro-
cess. Treatment of oximes 1 with p-toluenesulfonyl chloride in the
presence of potassium hydroxide, spiro-fused pyrazolin-5-ones 3
were obtained via tandem ketoxime tosylation and intramolecular
cyclization, which could be expanded to the synthesis of general
pyrazolin-5-ones with more elaborate and flexible substitution
patterns. The protocol is associated with readily available substrates,
mildconditions, highyields, simpleexecution, andeasycontrolof the
reaction orientation by reaction conditions selection.
a
Reagents and conditions: 1 (1.0 mmol), KOH (2.0 mmol), TsCl (1.0 mmol), CH2Cl2
(10 mL), rt.
b
Isolated yield.
Under the optimal conditions as for 3a (Table 2, entry 1), a range
of reactions of cyclopropyl oximes 1beg with TsCl (1.0 equiv) were
carried out in the presence of potassium hydroxide (2.0 equiv) in
CH2Cl2 at room temperature. As summarized in Table 2, the effi-
ciency and synthetic interest of the cyclization reaction were
demonstrated with respect to cyclopropyl oximes 1beg bearing
varied electron-withdrawing and electron-donating arylamide
groups to afford the corresponding spiro-fused pyrazolin-5-ones
3beg. The structure of 3e was further confirmed by single-crystal
X-ray diffraction analysis (Fig. 1). Thus, we provided an efficient
and facile synthesis of spiro-fused pyrazolin-5-ones.
4. Experimental
4.1. General information
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
purified by column chromatography over silica gel. 1H NMR and 13
C
NMR spectra were recorded at 500 MHz and 125 MHz, respectively,
with TMS as internal standard at 25 ꢁC. IR spectra (KBr) were recor-
ded on FTIR-spectrophotometer in the range of 400e4000 cmꢀ1
.
Elemental analyses were carried out on a PerkineElmer PE-2400
analyzer.
Fig. 1. The ORTEP drawing of 3e.
With the aim to exploring the utility of the pyrazolin-5-one
synthesis protocol, we prepared acyclic oxime, 2,2-diethyl-3-
(hydroxyimino)-N-phenylbutanamide 4a, and subjected it to the
identical conditions as for 3a in Table 2 (entry 1). To our de-
lighted, substituted pyrazolin-5-one 5a was obtained in 82% yield
(Scheme 5),18 which suggested that the spiro-fused pyrazolin-5-
one synthesis could be expanded to the synthesis of more gen-
eral pyrazolin-5-ones with more elaborate and flexible sub-
stitution patterns.
4.2. Synthesis of fully substituted isoxazoles
4.2.1. Typical procedure for the preparation of 2 (with 2a as an ex-
ample). To a well-stirred solution of PPh3 (1.1 mmol) and CBr4
(1.0 mmol) in acetonitrile (5.0 mL), was added 1a (1.0 mmol) in one
portion. The reaction mixture was stirred at room temperature for
30 min. After 1a was consumed (monitored by TLC), the resulting
mixture was poured into water (25 mL) and extracted with CH2Cl2
(3ꢂ20 mL). The combined organic phase was washed with water
(3ꢂ20 mL), dried over MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by flash column chromatography
(silica gel, petroleum ether/ethyl acetate¼10:1) to give 2a as
a white solid (0.25 g, 90%).
Ph
O
HO
N
O
N
N
TsCl/KOH
CH2Cl2, rt
NHPh
4.2.2. Physical data of compounds 2.
4.2.2.1. 4-(2-Bromoethyl)-3-methyl-N-phenylisoxazol-5-amine
4a
5a
(2a). White solid: mp 136e138 ꢁC; 1H NMR (500 MHz, CDCl3)
Scheme 5. The reaction of oxime 4a with TsCl/KOH in CH2Cl2.
d¼2.23 (s, 3H), 2.86 (t, J¼7.0, 2H), 3.43 (t, J¼7.0, 2H), 6.42 (s, 1H),

6350
X. Fu et al. / Tetrahedron 67 (2011) 6347e6351
7.02 (t, J¼7.5, 1H), 7.12 (d, J¼8.0, 2H), 7.29e7.32 (m, 2H); 13C NMR
7.40e7.44 (m, 3H), 7.90e7.92 (dd, J1¼8.0, J2¼1.5, 2H); 13C NMR
(125 MHz, CDCl3)
d
¼10.6, 25.8, 32.4, 95.0, 117.2, 122.3, 129.4, 139.7,
(125 MHz, CDCl3)
d
¼15.1, 28.8, 30.9, 70.6, 115.4, 125.4, 127.6, 128.7,
160.6, 162.5; IR (KBr) 3296, 3206, 3110, 3041, 2966, 2925, 1648,
1589, 1530, 1480, 1304, 1225, 1173, 751, 706 cmꢀ1; Anal. Calcd for
C12H13BrN2O: C, 51.26; H, 4.66; N, 9.96. Found: C, 51.34; H, 4.69; N,
9.94.
129.7, 152.6, 154.9; Anal. Calcd for C13H14BrNO2: C, 52.72; H, 4.76; N,
4.73. Found: C, 52.55; H, 4.77; N, 4.68.
4.3. Synthesis of spiro-fused pyrazolin-5-ones
4.2.2.2. 4-(2-Bromoethyl)-3-methyl-N-o-tolylisoxazol-5-amine
4.3.1. Typical procedure for the preparation of 3 (with 3a as an ex-
ample). To a 50 mL round-bottomed flask was added CH2Cl2
(10 mL), 1a (1.0 mmol) and KOH (2.0 mmol). The mixture was
stirred at room temperature for 10 min, to which was then added
tosyl chloride (1.0 mmol). The reaction mixture was stirred at room
temperature for 30 min. After 1a was consumed (monitored by
TLC), the resulting mixture was poured into water (25 mL) and
extracted with CH2Cl2 (3ꢂ20 mL). The combined organic phase was
washed with water (3ꢂ20 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
column chromatography (silica gel, petroleum ether/ethyl
acetate¼8:1) to give 3a as a white solid (0.18 g, 92%).
(2b). White solid: mp 83e84 ꢁC; 1H NMR (500 MHz, CDCl3)
d¼2.22
(s, 3H), 2.29 (s, 3H), 2.83 (t, J¼6.5, 2H), 3.42 (t, J¼6.5, 2H), 6.25 (s,
1H), 6.96e6.99 (m, 1H), 7.16e7.19 (m, 2H), 7.22 (d, J¼8.0, 1H); 13C
NMR (125 MHz, CDCl3)
126.3, 127.1, 130.8, 138.0, 160.7, 163.0; Anal. Calcd for C13H15BrN2O:
C, 52.90; H, 5.12; N, 9.49. Found: C, 53.01; H, 5.14; N, 9.45.
d
¼10.6, 17.8, 25.9, 33.0, 95.3, 117.9, 122.9,
4.2.2.3. 4-(2-Bromoethyl)-N-(2-methoxyphenyl)-3-methyl
xazol-5-amine (2c). White solid: mp 85e86 ꢁC; 1H NMR (500 MHz,
CDCl3)
¼2.22 (d, J¼1.0, 3H), 2.88 (t, J¼6.5, 2H), 3.45 (t, J¼6.5, 2H),
iso-
d
3.91 (d, J¼1.5, 3H), 6.87e6.89 (m, 1H), 6.92e6.96 (m, 2H), 7.00 (s,
1H), 7.53 (dd, J1¼6.5, J2¼2.0,1H); 13C NMR (125 MHz, CDCl3)
¼10.6,
d
25.9, 32.3, 55.8, 94.4, 110.2, 115.6, 121.3, 121.7, 129.3, 147.1, 160.3,
162.6; IR (KBr) 3388, 3073, 3018, 2967, 2931, 1649, 1598, 1528, 1462,
1244, 1114, 1027, 744 cmꢀ1; Anal. Calcd for C13H15BrN2O2: C, 50.18;
H, 4.86; N, 9.00. Found: C, 50.27; H, 4.91; N, 8.96.
4.3.2. Physical data of compounds 3.
4.3.2.1. 7-Methyl-5-phenyl-5,6-diazaspiro[2.4]hept-6-en-4-one
(3a). White solid: mp 71e72 ꢁC; 1H NMR (500 MHz, CDCl3)
d
¼1.66e1.68 (m, 2H), 1.77e1.79 (m, 2H), 1.98 (s, 3H), 7.17 (t, J¼7.5,
1H), 7.39e7,42 (m, 2H), 7.92e7.94 (m, 2H); 13C NMR (125 MHz,
CDCl3)
4.2.2.4. 4-(2-Bromoethyl)-3-methyl-N-p-tolylisoxazol-5-amine
d
¼12.5, 18.7, 33.7, 118.6, 124.7, 128.7, 138.6, 159.8, 172.4; IR
(2d). White solid: mp 141e143 ꢁC; 1H NMR (500 MHz, CDCl3)
(KBr) 3389, 3009, 2953, 2917, 1964, 1707, 1592, 1502, 1456, 1362,
1176, 984, 758, 715, 690 cmꢀ1; Anal. Calcd for C12H12N2O: C, 71.98;
H, 6.04; N, 13.99. Found: C, 71.83; H, 6.10; N, 14.07.
d
¼2.21 (s, 3H), 2.30 (s, 3H), 2.83 (t, J¼7.0, 2H), 3.40 (t, J¼7.0, 2H),
6.44 (s, 1H), 7.03e7.04 (m, 2H), 7.10 (d, J¼8.5, 2H); 13C NMR
(125 MHz, CDCl3)
d
¼10.5, 20.6, 25.8, 32.3, 94.0, 117.7, 129.9, 132.1,
137.0, 160.6, 162.9; IR (KBr) 3285, 3204, 3091, 3033, 2991, 2943,
4.3.2.2. 7-Methyl-5-o-tolyl-5,6-diazaspiro[2.4]hept-6-en-4-one
1643, 1589, 1519, 1480, 1236, 816 cmꢀ1
;
Anal. Calcd for
(3b). White solid: mp 54e55 ꢁC; 1H NMR (500 MHz, CDCl3)
C13H15BrN2O: C, 52.90; H, 5.12; N, 9.49. Found: C, 52.78; H, 5.13; N,
9.55.
d
¼1.65e1.67 (m, 2H), 1.75e1.77 (m, 2H), 1.93 (s, 3H), 2.28 (s, 3H),
7.24e7.28 (m, 3H), 7.32e7.33 (m, 1H); 13C NMR (125 MHz, CDCl3)
d
¼12.6, 18.4, 18.5, 32.5, 126.5, 126.6, 128.2, 131.0, 135.1, 136.3, 159.6,
4.2.2.5. 4-(2-Bromoethyl)-N-(4-methoxyphenyl)-3-methyl
xazol-5-amine (2e). White solid: mp128e129 ꢁC; 1H NMR
(500 MHz, CDCl3)
¼2.20 (s, 3H), 2.80 (t, J¼7.0, 2H), 3.37 (t, J¼7.0,
2H), 3.80 (s, 3H), 6.34 (s, 1H), 6.86 (d, J¼9.0, 2H), 7.10 (d, J¼9.0, 2H);
13C NMR (125 MHz, CDCl3)
120.4, 132.4, 155.7, 160.7, 163.3; IR (KBr) 3294, 3209, 3101, 2969,
2833, 1643, 1592, 1511, 1491, 1247, 1035, 824 cmꢀ1; Anal. Calcd for
C13H15BrN2O2: C, 50.18; H, 4.86; N, 9.00. Found: C, 50.30; H, 4.82; N,
8.93.
iso-
172.9; Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found:
C, 72.96; H, 6.54; N, 13.12.
d
4.3.2.3. 5-(2-Methoxyphenyl)-7-methyl-5,6-diazaspiro[2.4]hept-
d
¼10.6, 25.8, 32.4, 55.6, 92.7, 114.6,
6-en-4-one (3c). White solid: mp 138e139 ꢁC; 1H NMR (500 MHz,
CDCl3)
3H), 7.00e7.02 (m, 2H), 7.34e7.36 (m, 2H); 13C NMR (125 MHz,
CDCl3)
d
¼1.67 (t, J¼4.0, 2H), 1.78 (t, J¼4.0, 2H), 1.96 (s, 3H), 3.85 (s,
d
¼12.5, 18.4, 32.3, 55.8, 112.2, 120.6, 126.0, 128.4, 129.6,
154.9, 159.3, 173.3; IR (KBr) 3388, 3090, 3076, 2969, 2920, 2841,
1909, 1706, 1596, 1503, 1468, 1381, 1278, 1244, 1176, 1122, 1107, 757,
742 cmꢀ1; Anal. Calcd for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17.
Found: C, 67.94; H, 6.17; N, 12.12.
4.2.2.6. 4-(2-Bromoethyl)-N-(4-chlorophenyl)-3-methylisoxazol-
5-amine (2f). White solid: mp 113e115 ꢁC; 1H NMR (500 MHz,
CDCl3)
d
¼2.22 (s, 3H), 2.87 (t, J¼6.0, 2H), 3.44 (t, J¼6.0, 2H), 6.64 (s,
1H), 7.07 (d, J¼8.0, 2H), 7.24 (d, J¼8.0, 2H); 13C NMR (125 MHz,
4.3.2.4. 7-Methyl-5-p-tolyl-5,6-diazaspiro[2.4]hept-6-en-4-one
CDCl3)
d
¼10.5, 25.7, 32.5, 95.3, 118.3, 127.2, 129.3, 138.4, 160.6,
(3d). White solid: mp 102e103 ꢁC; 1H NMR (500 MHz, CDCl3)
162.1; IR (KBr) 3287, 3218, 3099, 3028, 2989, 1642, 1517, 1484, 1466,
1401, 1303, 1230, 820, 798 cm-1; Anal. Calcd for C12H12BrClN2O: C,
45.67; H, 3.83; N, 8.88. Found: C, 45.52; H, 3.79; N, 8.97.
d
¼1.63e1.66 (m, 2H), 1.74e1.77 (m, 2H), 1.97 (s, 3H), 2.34 (s, 3H),
7.20 (d, J¼8.5, 2H), 7.79 (d, J¼8.5, 2H); 13C NMR (125 MHz, CDCl3)
d¼12.6, 18.7, 20.9, 33.7, 118.7, 129.3, 134.3, 136.3, 159.7, 172.3; IR
(KBr) 2992, 2918, 2861, 1918, 1697, 1612, 1516, 1445, 1362, 1170, 983,
852 cmꢀ1; Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59; N, 13.07.
Found: C, 72.75; H, 6.67; N, 13.16.
4.2.2.7. 4-(2-Bromoethyl)-N-(2,4-dimethylphenyl)-3-methyl iso-
xazol-5-amine (2g). White solid: mp 114e115 ꢁC; 1H NMR
(500 MHz, CDCl3)
d
¼2.20 (s, 3H), 2.25 (s, 3H), 2.29 (s, 3H), 2.78 (t,
J¼6.5, 2H), 3.37 (t, J¼6.5, 2H), 6.13 (s, 1H), 6.98 (d, J¼8.0, 1H), 7.00 (s,
4.3.2.5. 5-(4-Methoxyphenyl)-7-methyl-5,6-diazaspiro[2.4]hept-
1H), 7.12 (d, J¼8.0,1H); 13C NMR (125 MHz, CDCl3)
d¼10.6,17.8, 20.7,
6-en-4-one (3e). White solid: mp 71e72 ꢁC; 1H NMR (500 MHz,
25.9, 32.9, 93.9, 119.3, 127.5, 131.5, 133.1, 135.1, 160.8, 163.4; Anal.
Calcd for C14H17BrN2O: C, 54.38; H, 5.54; N, 9.06. Found: C, 54.48; H,
5.59; N, 8.98.
CDCl3)
3H), 6.92e6.94 (m, 2H), 7.79e7.81 (m, 2H); 13C NMR (125 MHz,
CDCl3)
d
¼1.66 (t, J¼4.0, 2H), 1.75 (t, J¼4.0, 2H), 1.96 (s, 3H), 3.81 (s,
d
¼12.4, 18.6, 33.5, 55.3, 113.8, 120.4, 132.0, 156.6, 159.6,
172.0; IR (KBr) 3107, 3018, 2960, 2930, 2837, 1895, 1689, 1601, 1578,
1508, 1445, 1360, 1294, 1248, 1166, 1031, 989, 835 cmꢀ1; Anal. Calcd
for C13H14N2O2: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.93; H, 6.08;
N, 12.23. Crystal data: C13H14N2O2.
4.2.2.8. 4-(2-Bromoethyl)-5-ethoxy-3-phenylisoxazole
(2h). Colorless liquid; 1H NMR (500 MHz, CDCl3)
3H), 3.04 (t, J¼7.0, 2H), 3.65 (t, J¼7.0, 2H), 4.30 (q, J¼7.0, 2H),
d
¼1.44 (t, J¼7.0,

X. Fu et al. / Tetrahedron 67 (2011) 6347e6351
6351
ꢀ
Frigerio, F.; De Amici, M.; Dorsch, S.; Klotz, K.-N.; De Micheli, C. Bioorg. Med. Chem.
2007, 15, 2533e2543.
Colorless crystal, M¼230.11, Orthorhombic, Pbca, a¼8.4987(7) A,
¼90.00ꢁ,
b
¼90.00ꢁ,
g
¼90.00ꢁ,
ꢀ
ꢀ
b¼12.3021(10) A, c¼22.5908(17) A,
a
3. (a) Castagnolo, D.; Manetti, F.; Radi, M.; Bechi, B.; Pagano, M.; De Logu, A.;
Meleddu, R.; Saddi, M.; Botta, M. Bioorg. Med. Chem. 2009, 17, 5716e5721; (b)
Kimata, A.; Nakagawa, H.; Ohyama, R.; Fukuuchi, T.; Ohta, S.; Suzuki, T.;
Miyata, N. J. Med. Chem. 2007, 50, 5053e5056; (c) Chande, M. S.; Barve, P. A.;
Suryanarayan, V. J. Heterocycl. Chem. 2007, 44, 49e53; (d) Shelke, S. N.; Dalvi,
N. R.; Kale, S. B.; More, M. S.; Gill, C. H.; Karale, B. K. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 2007, 46, 1174e1178; (e) Sogawa, Y.; Shimizu-
gawa, A.; Ohyama, T.; Maeda, H.; Hirahara, K. J. Pharmacol. Sci. 2009, 111,
317e321.
3
ꢀ
V¼2361.9(3) A , Z¼8, T¼293(2), F000¼1024, R1¼0.0638,
wR2¼0.1278. CCDC deposition number: 781729. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/retrie-
ving.html (or from the Cambridge Crystallographic Data Center, 12
Union Road, Cambridge CB21EZ, UK; fax: (þ44) 1223 336 033; or
deposit@ccdc.cam.ac.uk).
4. For the synthesis of isoxazoles, see: (a) Lautens, M.; Roy, A. Org. Lett. 2000, 2,
555e557; (b) Savant, M. M.; Pansuriya, A. M.; Bhuva, C. V.; Kapuriya, N.; Patel,
A. S.; Audichya, V. B.; Pipaliya, P. V.; Naliapara, Y. T. J. Comb. Chem. 2010, 12,
176e180; (c) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203e5205; (d) Barr, L.;
Lincoln, S. F.; Easton, C. J. Chem.dEur. J. 2006, 12, 8571e8580; (e) Grecian, S.;
Fokin, V. V. Angew. Chem., Int. Ed. 2008, 47, 8285e8287.
4.3.2.6. 5-(4-Chlorophenyl)-7-methyl-5,6-diazaspiro[2.4]hept-6-
en-4-one (3f). White solid: mp 121e122 ꢁC; 1H NMR (500 MHz,
CDCl3)
d
¼1.68 (t, J¼4.0, 2H),1.77 (t, J¼4.0, 2H),1.98 (s, 3H), 7.34e7.36
(m, 2H), 7.90e7.92 (m, 2H); 13C NMR (125 MHz, CDCl3)
d
¼12.6, 18.9,
5. For the synthesis of pyrazolin-5-ones, see: (a) Tietze, L. F.; Evers, H.; Hippe, T.;
33.8,119.6,128.8,129.6,137.3,160.1,172.4; IR (KBr) 3086, 3055, 2952,
2916, 2849,1908,1695,1606,1592,1492,1448,1358,1177,1133,1088,
981, 841, 816 cmꢀ1; Anal. Calcd for C12H11ClN2O: C, 61.41; H, 4.72; N,
11.94. Found: C, 61.28; H, 4.64; N, 11.88.
€
Steinmetz, A.; Topken, E. Eur. J. Org. Chem. 2001, 1631e1634; (b) Attanasi, O. A.;
Baccolini, G.; Boga, C.; De Crescentini, L.; Giorgi, G.; Mantellini, F.; Nicolini, S.
Eur. J. Org. Chem. 2008, 5965e5973; (c) Attanasi, O. A.; De Crescentini, L.; Fili-
ppone, P.; Foresti, E.; Mantellini, F. J. Org. Chem. 2000, 65, 2820e2823.
6. For reviews, see: (a) Danishefsky, S. Acc. Chem. Res. 1979, 12, 66e72; (b) Wong,
H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C. Chem. Rev. 1989, 89, 165e198; (c)
Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151e1196; (d) Sydnes, L. K.
Chem. Rev. 2003, 103, 1133e1150; (e) Reichelt, A.; Martin, S. F. Acc. Chem. Res.
2006, 39, 433e442.
7. For selected examples, see: (a) Korotkov, V. S.; Larionov, O. V.; Hofmeister, A.;
Magull, J.; De Merjere, A. J. Org. Chem. 2007, 72, 7504e7510; (b) Tanaka, M.;
Ubakata, M.; Matsuo, T.; Yasue, K.; Matsumoto, K.; Kajimoto, Y.; Ogo, T.; Inaba, T.
Org. Lett. 2007, 9, 3331e3334; (c) Morales, C. L.; Pagenkopf, B. L. Org. Lett. 2008,
10, 157e159; (d) Tsuritani, T.; Yamamoto, Y.; Kawasaki, M.; Mase, T. Org. Lett.
2009, 11, 1043e1045; (e) Hours, A. E.; Snyder, J. K. Organometallics 2008, 27,
410e417.
4.3.2.7. 5-(2,4-Dimethylphenyl)-7-methyl-5,6-diazaspiro[2.4]
hept-6-en-4-one (3g). White solid: mp 76e77 ꢁC; 1H NMR
(500 MHz, CDCl3)
d
¼1.65e1.67 (m, 2H), 1.76e1.78 (m, 2H), 1.95 (s,
3H), 2.23 (s, 3H), 2.33 (s, 3H), 7.05 (d, J¼8.0, 1H), 7.09 (s, 1H), 7.20 (d,
J¼8.0, 1H); 13C NMR (125 MHz, CDCl3)
¼12.6, 18.2, 18.4, 21.1, 32.5,
d
126.6, 127.2, 131.7, 133.8, 134.9, 138.1, 159.4, 173.0; Anal. Calcd for
C14H16N2O: C, 73.66; H, 7.06; N, 12.27. Found: C, 73.79; H, 7.09; N,
12.23.
8. (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem. Soc. 2005, 127,
4578e4579; (b) Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem. Commun. 2005,
3580e3582; (c) Xiang, D.; Yang, Y.; Zhang, R.; Liang, Y.; Pan, W.; Huang, J.;
Dong, D. J. Org. Chem. 2007, 72, 8593e8596; (d) Xiang, D.; Huang, P.; Wang, K.;
Zhou, G.; Liang, Y.; Dong, D. Chem. Commun. 2008, 6236e6238; (e) Xiang, D.;
Wang, K.; Liang, Y.; Zhou, G.; Dong, D. Org. Lett. 2008, 10, 345e348; (f) Zhang,
R.; Zhang, D.; Guo, Y.; Zhou, G.; Jiang, Z.; Dong, D. J. Org. Chem. 2008, 73,
9504e9507; (g) Wang, Y.; Xin, X.; Liang, Y.; Lin, Y.; Duan, H.; Dong, D. Adv.
Synth. Catal. 2009, 351, 2217e2223.
4.3.2.8. 2,2-Diethyl-3-(hydroxyimino)-N-phenylbutanamide
(4a). White solid, mp: 135e136 ꢁC; 1H NMR (400 MHz, CDCl3)
d
¼0.81 (t, J¼7.6, 6H), 1.86e2.02 (m, 7H), 7.12 (t, J¼8.0, 1H), 7.31 (t,
J¼8.0, 2H), 7.50 (d, J¼8.0, 2H), 8.13 (s, 1H), 8.16 (s, 1H); 13C NMR
(100 MHz, CDCl3)
159.7, 171.4; Anal. Calcd for C14H20N2O2: C, 67.71; H, 8.12; N, 11.28.
Found: C, 67.55; H, 8.31; N, 11.36.
d
¼8.4, 11.5, 24.9, 58.1, 120.2, 124.4, 128.9, 137.6,
9. (a) Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.; Liu, Q. Org. Lett.
2007, 9, 2421e2423; (b) Zhang, R.; Liang, Y.; Zhou, G.; Wang, K.; Dong, D. J. Org.
Chem. 2008, 73, 8089e8092.
10. Wang, K.; Xiang, D.; Liu, J.; Pan, W.; Dong, D. Org. Lett. 2008, 10, 1691e1694.
11. Wang, K.; Fu, X.; Liu, J.; Liang, Y.; Dong, D. Org. Lett. 2009, 11, 1015e1018.
12. For review, see: (a) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801e811; (b)
For the use of Ph3P/CCl4, see: Das, B.; Kanth, B. S.; Reddy, K. R.; Satyalakshmi, G.;
Kumar, R. A. Chem. Lett. 2008, 37, 512e513; (c) Ori, M.; Toda, N.; Takami, K.;
Tago, K.; Kogen, H. Angew. Chem., Int. Ed. 2003, 42, 2540e2543; (d) Wang, Z.;
Wan, W.; Jiang, H.; Hao, J. J. Org. Chem. 2007, 72, 9364e9367; (e) Morwick, T.;
Hrapchak, M.; De Turi, M.; Campbell, S. Org. Lett. 2002, 4, 2665e2668; (f) For
the use of Ph3P/CBr4, see: Das, B.; Damodar, K.; Bhunia, N.; Shashikanth, B.
Tetrahedron Lett. 2009, 50, 2072e2074; (g) Gouin, S. G.; Kovensky, J. Tetrahedron
Lett. 2007, 48, 2875e2879; (h) Yadav, J. S.; Mishra, R. K. Tetrahedron Lett. 2002,
43, 5419e5422; (i) Nishida, Y.; Shingu, Y.; Dohi, H.; Kobayashi, K. Org. Lett. 2003,
5, 2377e2380.
4.3.2.9. 4,4-Diethyl-3-methyl-1-phenyl-1H-pyrazol-5(4H)-one
(5a). 1H NMR (600 MHz, CDCl3)
d
¼0.85 (t, J¼7.2, 6H), 1.70e1.74 (m,
2H), 1.89e1.92 (m, 2H), 1.99 (s, 3H), 7.10 (t, J¼7.2, 1H), 7.15 (d, J¼7.2,
2H), 7.32 (t, J¼7.2, 2H); 13C NMR (150 MHz, CDCl3)
¼8.8, 10.6, 29.6,
d
60.4, 122.6, 124.2, 128.6, 145.7, 163.7, 165.6; Anal. Calcd for
C14H18N2O: C, 73.01; H, 7.88; N, 12.16. Found: C, 73.31; H, 7.61; N,
12.34.
Acknowledgements
13. (a) Yang, Y.-H.; Shi, M. Tetrahedron 2006, 62, 2420e2427; (b) Yang, Y.-H.; Shi, M.
J. Org. Chem. 2005, 70, 8645e8648; (c) Yang, Y.-H.; Shi, M. Tetrahedron Lett.
2005, 46, 6285e6288.
14. For chlorination, see: (a) Brummond, K. M.; Gesenberg, K. D. Tetrahedron Lett.
1999, 40, 2231e2234; (b) Lai, G.; Tan, P.-Z.; Ghoshal, P. Synth. Commun. 2003,
33, 1727e1732; (c) Nair, R. P.; Kim, T. H.; Frost, B. J. Organometallics 2009, 28,
4681e4688.
Financial support of this research by the National Natural Sci-
ence Foundation of China (20872136 and 51073150) is greatly
acknowledged.
Supplementary data
15. For dehydration, see: (a) Khalafi-Nezhad, A.; Parhami, A.; Rad, M. N. S.; Zarea, A.
Tetrahedron Lett. 2005, 46, 6879e6882; (b) Kazemi, F.; Sharghi, H.; Nasseri, M.
A. Synthesis 2004, 205e207; (c) Pirrung, M. C.; Tumey, L. N. J. Comb. Chem. 2000,
2, 675e680; (d) Wakasugi, K.; Iida, A.; Misaki, T.; Nishii, Y.; Tanabe, Y. Adv.
Synth. Catal. 2003, 345, 1209e1214; (e) Katritzky, A. R.; Wang, M.; Wilkerson, C.
R.; Yang, H. J. Org. Chem. 2003, 68, 9105e9108; (f) Dale, T. J.; Sather, A. C., Jr.
Tetrahedron Lett. 2009, 50, 6173e6175.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.136.
References and notes
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€
€
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