Synthesis of trisubstituted isoxazoles via in situ trapping strategy from α-nitro carbonyl compounds and methyl ketones or terminal aryl alkenes

Article abstract of DOI:10.1016/j.tet.2012.05.055

A highly efficient domino method for the synthesis of trisubstituted isoxazoles has been established from α-nitro carbonyl compounds and methyl ketones or terminal aryl alkenes. Simple and readily available starting materials, mild reaction conditions and very simple operation are significant advantages of the reaction.

Full text of DOI:10.1016/j.tet.2012.05.055

Tetrahedron 68 (2012) 6257e6262
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of trisubstituted isoxazoles via in situ trapping strategy from
carbonyl compounds and methyl ketones or terminal aryl alkenes
a
-nitro
*
Yan Yang, Meng Gao, Cong Deng, Dong-Xue Zhang, Liu-Ming Wu, Wen-Ming Shu, An-Xin Wu
Key Laboratory of Pesticide and Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan 430079, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient domino method for the synthesis of trisubstituted isoxazoles has been established from
Received 12 March 2012
Received in revised form 9 May 2012
Accepted 15 May 2012
a
-nitro carbonyl compounds and methyl ketones or terminal aryl alkenes. Simple and readily available
starting materials, mild reaction conditions and very simple operation are significant advantages of the
reaction.
Available online 24 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Isoxazoles
Domino reaction
a
-Nitro carbonyl compounds
Methyl ketones
Terminal aryl alkenes
1. Introduction
In our previous studies,2 methyl ketones or terminal aryl al-
kenes could be in situ transformed to
iodinationeKornblum oxidation reaction. Correspondingly, we
suppose that -nitro carbonyl compounds with acidic methylenes
could in situ trap the unstable -ketoaldehyde intermediates via
Knoevenagel-type condensation to generate 2-nitro-1,4-enediones,
which may further react with -nitro carbonyl compounds to
a-ketoaldehydes via domino
The in situ trapping of unstable intermediates via domino re-
actions has provided enormous opportunities for the efficient
synthesis of complex products from simple substrates.1 Recently,
we have successfully developed several novel domino reactions for
a
a
the synthesis of 1,4-enediones via in situ trapping of unstable
a
-
a
ketoaldehyde intermediates.2 To further expand this strategy for
the synthesis of pharmacologically interesting heterocycles, we
report herein a new and efficient domino method for the synthesis
of trisubstituted isoxazoles.
regioselectively afford trisubstituted isoxazoles due to the activat-
ing and leaving ability of nitro group (Scheme 1).11d
Isoxazoles have long been attractive targets for synthetic
chemists due to their well known biological activities, such as an-
tibacterial,3 antiviral,3 anticancer,4 and antithrombotic activity.5 In
addition, they also serve as versatile building blocks in organic
synthesis6 and materials science.7 Consequently, a variety of
methods have been developed for their synthesis, such as con-
densation of hydroxylamine with 1,3-dicarbonyl compounds,8 cy-
clization of propargylic oximes,9 rearrangement of subsituted
oxetanes,10 reaction of nitroacetates with dipolarophiles,11 1,3-
dipolar cycloaddition of nitrile oxides with alkynes,12 and multi-
component reactions.13 However, many of these methods suffer
from narrow substrate scopes and modest regioselectivities. Thus,
a general and regioselective method is still highly needed for
chemists to construct isoxazoles from simple and readily available
starting materials.
Scheme 1. Proposed reaction pathway.
2. Results and discussion
To verify our hypothesis, the initial study started with the re-
action between acetophenone 1a and ethyl nitroacetate 3a. Fortu-
nately, treatment of 1a with 3a in the presence of 1.0 equiv of CuO
and 1.0 equiv of I2 in DMSO at 70 ꢀC furnished the desired isoxazole
4aa in 72% yield (Table 1, Entry 1), which was unambiguously
confirmed by X-ray diffraction (Fig. 1).14 Much to our satisfaction,
by increasing the CuO and I2 loading to 2.0 equiv, isoxazole 4aa was
* Corresponding author. E-mail address: chwuax@mail.ccnu.edu.cn (A.-X. Wu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.055

6258
Y. Yang et al. / Tetrahedron 68 (2012) 6257e6262
Table 2
obtained in 85% yield after 16 h (Table 1, entry 4). However, further
increase the temperature led to lower yields, possibly due to the
Scope of methyl ketonesa
overoxidation of a-ketoaldehyde intermediates at high tempera-
ture.2 On the other hand, other bases employed under this condi-
tion failed to give the desired products (Table 1, entries 7e10).
Table 1
Optimization of the reaction conditionsa
Entry
1
4
Yield (%)b
1
2
3
4
5
6
7
8
1a (C6H4)
1b (4-MeC6H4)
1c (4-MeOC6H4)
1d (4-NO2C6H4)
1e (1-Naphthyl)
1f (2-Naphthyl)
1g (4-ClC6H4)
1h (4-BrC6H4)
1i (4-FC6H4)
1j (2-Thienyl)
1k (2-Furyl)
1l (2-Benzofuryl)
1m ((E)-PheCH]CHe)
1n ((E)-4-MeOC6H5eCH]CHe)
1o ((E)-4-NO2C6H5eCH]CHe)
1p ((E, E)-C6H5e(CH]CH)2e)
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
4ja
4ka
4la
4ma
4na
4oa
4pa
85
83
78
55
79
82
74
77
71
67
62
65
69
61
54
57
Entry
Base (equiv)
I2 (equiv)
t (h)
Temp (ꢀC)
Yield (%)b
1
2
3
4
5
6
7
8
9
CuO (1.0)
CuO (2.0)
CuO (1.0)
CuO (2.0)
CuO (2.0)
CuO (2.0)
K2CO3 (2.0)
Et3N (2.0)
DABCO (2.0)
DBU (2.0)
1.0
1.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
24
24
24
16
16
16
24
24
24
24
70
70
70
70
80
90
70
70
70
70
72
74
70
85
62
51
dc
dc
dc
dc
9
10
11
12
13
14
15
16
a
Reaction conditions: 1 (1.0 mmol), 3a (2.0 mmol), CuO (2.0 mmol), and I2
10
(2.0 mmol) in DMSO (5 mL) for 16 h at 70 ꢀC under an atmosphere of argon.
a
Reaction conditions: 1a (1.0 mmol), 3a (2.0 mmol) in 5 mL of DMSO under an
b
Isolated yields.
atmosphere of argon.
b
Isolated yields.
No desired product was obtained.
c
Table 3
Scope of terminal aryl alkenesa
Entry
2
4
Yield (%)b
1
2
3
4
5
6
7
2a (C6H5)
4aa
4ba
4ca
4fa
4ga
4ha
4ia
78
76
71
62
67
66
62
2b (4-MeC6H4)
2c (4-MeOC6H4)
2d (2-naphthyl)
2e (4-ClC6H4)
2f (4-BrC6H4)
2g (4-FC6H4)
Fig. 1. X-ray structure of compound 4aa.
a
Reaction was performed with terminal aryl alkene 2 (1.0 mmol), IBX (1.2 mmol),
and I2 (2.0 mmol) in DMSO (5 mL) at room temperature for 0.5 h, then 3a (2.0 mmol)
and CuO (2.0 mmol) were added, and the mixture was stirred at 70 ꢀC for 12 h.
With the optimized result in hand, we first explored the scope
of methyl ketones for this reaction (Table 2). Pleasingly, electron
neutral (H, CH3), electron-donating (OCH3) and sterically hin-
dered (1-naphthyl, 2-naphthyl) methyl ketones all reacted effi-
ciently to give the desired isoxazoles in good to excellent excellent
yields (78e85%; entries 1e3 and 5e6). However, when strong
electron-withdrawing group (eNO2) was attached to the phenyl
ring of methyl ketone, the yield dropped substantially (55%; entry
4). To our delight, good yields were also obtained for halogenated
(eCl, eBr, eF) methyl ketones (71e77%; entries 7e9). Much to our
satisfaction, furanyl, benzofuranyl, and thienyl methyl ketones
could also give the corresponding isoxazoles in moderate yields
b
Isolated yield.
Using acetophenone, structural variations in the
ketones were then examined (Table 4). Although a moderate yield
was obtained for aliphatic -nitroketone (44%, entry 1), good
yields (75e85%; entries 2e7) were obtained for aryl -nitro-
ketones with electroneneutral (eH, eMe), electron-rich (eOMe),
electron-deficient (eNO2) and halogen substituents (eCl, eBr, eF).
Fortunately, the structure of 4ab was also confirmed by X-ray
diffraction (Fig. 2).14
Based on these results, a possible reaction mechanism is shown
as follows (Scheme 2) using acetophenone 1a, styrene 2a, and ethyl
nitroacetate 3a as an example: acetophenone 1a or styrene 2a
could be in situ transformed to phenylglyoxal B via domino iodi-
nationeKornblum oxidation reaction, which could further undergo
Knoevenagel-type condensation with ethyl nitroacetate 3a to
generate 2-nitro-1,4-enedione intermediate C. Further Michael
addition of 3a to intermediate C afforded intermediate D, which
could undergo intramolecular nucleophilic O-alkylation to give
isoxazoline N-oxide intermediate E. Isomerization of intermediate
E led to N-hydroxy intermediate F, which was finally converted into
isoxazole 4aa by elimination of a molecule of water.
a-nitromethyl
a
a
(62e67%; entries 10e12). It’s noteworthy that
a,b-unsaturated
methyl ketones with various substituents could also give the
corresponding isoxazoles in moderate to good yields (54e69%;
entries 13e16).
According to our previous studies,2d,e the substrates were next
extended to terminal aryl alkenes, which could also be in situ trans-
formed to a-ketoaldehydes (Table 3). Fortunately, electron neutral (H,
CH3), electron-donating (OCH3), sterically hindered (2-naphthyl), and
halogenated (eCl, eBr, eF) terminal aryl alkenes were all compatible
under this condition, and generally moderate to good yields were
obtained (62e78%).

Y. Yang et al. / Tetrahedron 68 (2012) 6257e6262
6259
literature method.15 Reactions were carried out under an argon
atmosphere unless indicated otherwise. Solvents were dried
according to published methods and distilled before use. IR spectra
were recorded on an infrared spectrometer as KBr pellets with
Table 4
Scope of a
-nitroketonesa
absorption in cmꢁ1 1H spectra were recorded in CDCl3 on 400/
.
600 MHz NMR spectrometers. Data are reported as follows:
chemical shift, multiplicity (s¼singlet, d¼doublet, t¼triplet,
m¼multiplet), coupling constants (Hz) and integration. 13C spectra
were recorded in CDCl3 on 100/150 MHz spectrometers and reso-
Entry
3 (R2)
4
Yield (%)b
1
2
3
4
5
6
7
3b (i-Pr)
3c (Ph)
4ab
4ac
4ad
4ae
4af
44
85
83
79
81
79
75
nances (d) are given in parts per million relative to the center line of
3d (4-MeC6H4)
3e (4-MeOC6H4)
3f (4-NO2C6H4)
3g (4-ClC6H4)
3h (4-BrC6H4)
a triplet at 77.0 ppm of chloroform-d. HRMS were obtained on a FT-
ICR MS equipped with an electrospray source. Column chroma-
tography was performed on silica gel (200e300 mesh).
4ag
4ah
4.2. General procedure for the preparation of isoxazoles 4
a
Reaction conditions: 1a (1.0 mmol), 3 (2.0 mmol), CuO (2.0 mmol), and I2
from methyl ketones 1 and
a
-nitro carbonyl compounds 3
(2.0 mmol) in DMSO (5 mL) for 16 h at 70 ꢀC under an atmosphere of argon.
b
Isolated yields.
Methyl ketone 1 (1.0 mmol),
a
-nitro carbonyl compound 3
(2.0 mmol), CuO (2.0 mmol), and iodine (2.0 mmol) were placed in
an oven-dried and argon filled Schlenk tube. After addition of an-
hydrous DMSO (5 mL), the mixture was stirred at 70 ꢀC for 16 h.
After the reaction completed (monitored by TLC), the reaction
mixture was cooled to room temperature, then filtered through
a layer of silica gel and eluted with EtOAc. The filtrate was diluted
with water and treated with Na2S2O3 (5% w/w, aq) until the color
turned to pale yellow. The mixture was then extracted with addi-
tional EtOAc (2ꢂ30 mL), the combined organic layers were washed
with brine and dried over Na2SO4. After evaporation, the crude
product was purified by column chromatography on silica gel (el-
uent: petroleum ether/EtOAc) to afford the pure product 4.
4.3. General procedure for the preparation of isoxazoles 4
from a-nitro carbonyl compounds 3 and terminal
aryl alkenes 2
Fig. 2. X-ray structure of compound 4ab (all hydrogen atoms are omitted for clarity).
To an oven-dried and argon filled Schlenk tube was added IBX
(1.2 mmol) and anhydrous DMSO (5 mL), followed by terminal aryl
alkene 2 (1.0 mmol) and iodine (2.0 mmol). The reaction mixture
was stirred at room temperature for 0.5 h, then ethyl nitroacetate
3a (2.0 mmol) and CuO (2.0 mmol) were added, the mixture was
stirred at 70 ꢀC for 12 h. After the reaction completed (monitored by
TLC), the reaction mixture was cooled to room temperature, then
filtered through a layer of silica gel and eluted with EtOAc. The
filtrate was diluted with water and treated with Na2S2O3 (5% w/w,
aq) until the color turned to pale yellow. The mixture was then
extracted with additional EtOAc (2ꢂ30 mL), the combined organic
layers were washed with NaOH (5% w/w, aq) and brine successively.
After drying over Na2SO4 and evaporation, the crude product was
purified by column chromatography on silica gel (eluent: petro-
leum ether/EtOAc) to afford the product 4.
Scheme 2. Proposed reaction mechanism.
3. Conclusion
4.4. Spectroscopic data
In conclusion, we have developed an efficient route for the syn-
thesis of isoxazoles from easily available a-nitroketones and methyl
ketones or terminal aryl alkenes. This method not only represents an
interesting domino process but also provides a practical access to
trisubstituted isoxazoles with potential applications in the drug
discovery.
4.4.1. Diethyl 4-benzoylisoxazole-3,5-dicarboxylate (4aa). White
solid; mp 109e110 ꢀC; 1H NMR (CDCl3, 600 MHz):
d (ppm) 7.83 (d,
J¼7.2 Hz, 2H), 7.64 (t, J¼7.2 Hz, 1H), 7.50 (t, J¼7.2 Hz, 2H), 4.33e4.25
(m, 4H), 1.20 (t, J¼7.2 Hz, 3H), 1.12 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
150 MHz):
d (ppm) 186.2, 158.5, 157.9, 155.1, 155.0, 136.1, 134.3,
129.2, 128.8, 123.4, 63.0, 62.9, 13.6, 13.4; IR (KBr): 1746, 1682, 1277,
1239, 1029, 849 cmꢁ1; HRMS (ESI): m/z [MþNa]þ calcd for
C16H15NNaO6: 340.0791; found: 340.0788.
4. Experimental section
4.1. General methods
4.4.2. Diethyl 4-(4-methylbenzoyl)isoxazole-3,5-dicarboxylate
(4ba). White solid; mp 82e83 ꢀC; 1H NMR (CDCl3, 600 MHz):
All commercially available reagents were used without further
d
(ppm) 7.71 (d, J¼7.8 Hz, 2H), 7.29 (d, J¼7.8 Hz, 2H), 4.33e4.26 (m,
purification.
a-Nitroketones 3be3h were prepared according to the
4H), 2.44 (s, 3H), 1.21 (t, J¼7.2 Hz, 3H), 1.14 (t, J¼7.2 Hz, 3H); 13C

6260
Y. Yang et al. / Tetrahedron 68 (2012) 6257e6262
NMR (CDCl3, 100 MHz):
d
(ppm) 185.8, 158.3, 157.8, 155.1, 154.9,
132.7, 132.0, 131.9, 123.2, 116.3, 116.1, 63.1, 63.0, 13.7, 13.6; 13C NMR
19
145.5, 133.6, 129.5, 129.3, 123.5, 62.9, 62.8, 21.8, 13.6, 13.5; IR (KBr):
1749, 1680, 1602, 1309, 1275, 1226, 1181, 1024, 915, 837 cmꢁ1; HRMS
(ESI): m/z [MþH]þ calcd for C17H18NO6: 332.1129; found: 332.1127.
(CDCl3, 150 MHz):
d
(ppm) 184.7, 166.4 (d, J ¼255.8 Hz), 158.5,
CeF
19
157.9, 155.1, 154.9, 132.7, 132.0, 131.9 (d, J ¼10.4 Hz), 123.2, 116.2
CeF
19
(d, J ¼22.7 Hz), 63.1, 63.0, 13.7, 13.6; IR (KBr): 1738, 1680, 1598,
CeF
1272, 1227, 1027, 916, 850 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
4.4.3. Diethyl 4-(4-methoxybenzoyl)isoxazole-3,5-dicarboxylate
C16H15FNO6: 336.0878; found: 336.0882.
(4ca). White solid; mp 86e88 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 7.79 (d, J¼8.4 Hz, 2H), 6.96 (d, J¼8.4 Hz, 2H), 4.34e4.27 (m,
4.4.10. Diethyl 4-(thiophene-2-carbonyl)isoxazole-3,5-dicarboxylate
4H), 3.89 (s, 3H),1.22 (t, J¼7.2 Hz, 3H),1.15 (t, J¼7.2 Hz, 3H); 13C NMR
(4ja). White solid; mp 78e79 ꢀC; 1H NMR (CDCl3, 600 MHz):
(CDCl3, 150 MHz):
d
(ppm) 184.6, 164.5, 158.3, 157.9, 155.2, 155.0,
d (ppm) 7.79e7.78 (m, 1H), 7.44e7.43 (m, 1H), 7.15e7.14 (m, 1H),
131.6, 129.4, 123.6, 114.1, 62.93, 62.87, 55.6, 13.7, 13.6; IR (KBr): 1750,
1669, 1600, 1262, 1226, 1179, 1026, 914, 845 cmꢁ1; HRMS (ESI): m/z
[MþNa]þ calcd for C17H17NNaO7: 370.0897; found: 370.0897.
4.37e4.30 (m, 4H), 1.25 (t, J¼7.2 Hz, 3H), 1.18 (t, J¼7.2 Hz, 3H); 13C
NMR (CDCl3,150 MHz): d (ppm) 177.9,158.7,157.8,155.1,154.7,143.4,
136.0, 134.9, 128.5, 123.0, 63.1, 63.0, 13.7, 13.6; IR (KBr): cmꢁ1; 1749,
1734, 1653, 1599, 1389, 1290, 1226, 1027, 846, 748; HRMS (ESI): m/z
[MþH]þ calcd for C14H14NO6S: 324.0536; found: 324.0540.
4.4.4. Diethyl 4-(4-nitrobenzoyl)isoxazole-3,5-dicarboxylate
(4da). White solid; mp 94e95 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
(ppm) 8.36 (d, J¼8.8 Hz, 2H), 8.04 (d, J¼8.8 Hz, 2H), 4.38e4.30 (m,
4.4.11. Diethyl 4-(furan-2-carbonyl)isoxazole-3,5-dicarboxylate
4H), 1.27 (t, J¼7.2 Hz, 3H), 1.21 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
(4ka). White solid mp 93e94 ꢀC; 1H NMR (CDCl3, 600 MHz):
100 MHz):
d
(ppm) 184.8, 158.9, 157.7, 154.9, 154.8, 150.8, 140.2,
d (ppm) 7.63 (s, 1H), 7.25 (s, 1H), 6.62 (s, 1H), 4.37e4.34 (m, 4H), 1.28
130.1, 124.0, 122.6, 63.4, 63.2, 13.8, 13.6; IR (KBr): 1759, 1733, 1691,
1529, 1269, 1227, 1027, 850 cmꢁ1; HRMS (ESI): m/z [MþNH4]þ calcd
for C16H18N3O8: 380.1088; found: 380.1094.
(t, J¼7.2 Hz, 3H), 1.23 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d
(ppm) 173.1, 159.1, 157.9, 155.2, 154.9, 152.3, 147.8, 122.1, 119.7,
113.1, 63.1, 63.0, 13.7, 13.6; IR (KBr): 1743, 1668, 1565, 1244,
1028 cmꢁ1
308.0765; found: 308.0763.
;
HRMS (ESI): m/z [MþH]þ calcd for C14H14NO7:
4.4.5. Diethyl 4-(1-naphthoyl)isoxazole-3,5-dicarboxylate (4ea). -
White solid; mp 94e96ꢀC;1HNMR(CDCl3, 600MHz):
d(ppm)9.18(d,
J¼7.8 Hz, 1H), 8.09 (d, J¼7.8 Hz, 1H), 7.93 (d, J¼7.8 Hz, 1H), 7.74e7.60
(m, 3H), 7.45 (t, J¼7.8 Hz, 1H), 4.26 (q, J¼7.2 Hz, 2H), 4.18 (q, J¼7.2 Hz,
2H), 1.11 (t, J¼7.2 Hz, 3H), 0.96 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
4.4.12. Diethyl 4-(benzofuran-2-carbonyl)isoxazole-3,5-
dicarboxylate (4la). White solid; mp 85e86 ꢀC; 1H NMR (CDCl3,
400 MHz):
d
(ppm) 7.73 (d, J¼8.0 Hz, 1H), 7.57e7.51 (m, 3H),
100 MHz):
d
(ppm) 187.4, 158.4, 157.9, 155.2, 155.0, 135.1, 133.8,133.0,
7.37e7.35 (m, 1H), 4.36e4.30 (m, 4H), 1.24 (t, J¼7.2 Hz, 3H), 1.18 (t,
132.5, 130.7, 129.1, 128.5, 126.9, 125.9, 124.9, 124.1, 62.8, 13.6, 13.4; IR
(KBr): 1678, 1659,1596,1579,1300,1243, 906 cmꢁ1; HRMS (ESI): m/z
[MþH]þ calcd for C20H18NO6: 368.1129; found: 368.1132.
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 175.0, 159.3,
157.8, 156.1, 155.1, 154.9, 151.9, 129.2, 126.7, 124.3, 123.6, 122.0, 115.6,
112.4, 63.1, 63.0, 13.6, 13.6; IR (KBr): 1756, 1740, 1672, 1552, 1244,
1024 cmꢁ1; HRMS (ESI): m/z [MþNa]þ calcd for C18H15NNaO7:
380.0741; found: 380.0739.
4.4.6. Diethyl 4-(2-naphthoyl)isoxazole-3,5-dicarboxylate (4fa). -
White solid; mp 102e103 ꢀC; 1H NMR (CDCl3, 600 MHz):
d (ppm)
8.17 (s, 1H), 8.03 (d, J¼8.4 Hz, 1H), 7.95 (d, J¼8.4 Hz, 1H), 7.91e7.89
(m, 2H), 7.64 (t, J¼7.2 Hz, 1H), 7.56 (t, J¼7.2 Hz, 1H), 4.31e4.23 (m,
4H), 1.17 (t, J¼7.2 Hz, 3H), 1.08 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
4.4.13. Diethyl 4-cinnamoylisoxazole-3,5-dicarboxylate (4ma).-
Yellow solid; mp 108e110 ꢀC; 1H NMR (CDCl3, 600 MHz):
d (ppm)
7.55 (d, J¼7.2 Hz, 2H), 7.44e7.40 (m, 3H), 7.34 (d, J¼16.2 Hz, 1H),
150 MHz):
d (ppm) 186.1, 158.6, 157.9, 155.2, 155.1, 136.1, 133.6,
7.05 (d, J¼16.2 Hz,1H), 4.43e4.38 (m, 4H), 1.35 (t, J¼7.2 Hz, 3H), 1.32
132.3, 132.23, 132.17, 129.7, 129.2, 128.9, 127.9, 127.1, 123.6, 63.0,
62.9, 13.6, 13.5; IR (KBr): 1756, 1678, 1223, 1189, 1026 cmꢁ1; HRMS
(ESI): m/z [MþH]þ calcd for C20H18NO6: 368.1129; found: 368.1124.
(t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 185.6, 158.3,
158.1, 155.3, 154.9, 147.4, 133.7, 131.4, 129.1, 128.7, 126.8, 123.6, 63.1,
63.0, 13.9, 13.8; IR (KBr): 1749, 1651, 1618, 1269, 1222, 1184,
1026 cmꢁ1
;
HRMS (ESI): m/z [MþH]þ calcd for C18H18NO6:
4.4.7. Diethyl 4-(4-chlorobenzoyl)isoxazole-3,5-dicarboxylate
334.1129; found: 334.1130.
(4ga). White solid; mp 81e82 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 7.77 (d, J¼8.4 Hz, 2H), 7.48 (d, J¼8.4 Hz, 2H), 4.34e4.29 (m,
4.4.14. (E)-Diethyl 4-(3-(4-methoxyphenyl)acryloyl)isoxazole-3,5-
4H), 1.24 (t, J¼7.2 Hz, 3H), 1.17 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
dicarboxylate (4na). Yellow solid; mp 143e144 ꢀC; 1H NMR (CDCl3,
150 MHz):
d
(ppm) 185.0, 158.6, 157.9, 155.1, 155.0, 141.0, 134.5,
600 MHz):
6.95e6.91 (m, 3H), 4.41e4.38 (m, 4H), 3.85 (s, 3H),1.37e1.30 (m, 6H);
13C NMR (CDCl3, 150 MHz):
(ppm) 185.4, 162.4, 158.3, 158.2, 155.4,
d
(ppm) 7.49 (d, J¼8.4 Hz, 2H), 7.27 (d, J¼16.0 Hz, 1H),
130.5, 129.3, 123.1, 63.2, 63.1, 13.7, 13.6; IR (KBr): 1751, 1689, 1595,
1311, 1271, 1181, 913 cmꢁ1; HRMS (ESI): m/z [MþNH4]þ calcd for
C16H19ClN2O6: 352.0582; found: 352.0579.
d
155.0, 147.2, 130.6, 126.3, 124.7, 123.9, 114.6, 63.1, 62.9, 55.5, 13.9; IR
(KBr): 1743, 1658, 1599, 1511, 1306, 1268, 1224, 1022 cmꢁ1; HRMS
(ESI): m/z [MþH]þ calcd for C19H20NO7: 374.1234; found: 374.1236.
4.4.8. Diethyl 4-(4-bromobenzoyl)isoxazole-3,5-dicarboxylate
(4ha). White solid; mp 110e111 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 7.69 (d, J¼8.4 Hz, 2H), 7.65 (d, J¼8.4 Hz, 2H), 4.35e4.28 (m,
4.4.15. (E)-Diethyl 4-(3-(4-nitrophenyl)acryloyl)isoxazole-3,5-
4H), 1.24 (t, J¼7.2 Hz, 3H), 1.17 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
dicarboxylate (4oa). Yellow solid; mp 148e150 ꢀC; 1H NMR
150 MHz):
d
(ppm) 185.3, 158.6, 157.8, 155.1, 154.9, 134.9, 132.2,
(CDCl3, 600 MHz):
2H), 7.42 (d, J¼16.2 Hz,1H), 7.15 (d, J¼16.2 Hz,1H), 4.45e4.41 (m, 4H),
1.39e1.34 (m, 6H); 13C NMR (CDCl3, 150 MHz):
(ppm) 184.9, 158.5,
d
(ppm) 8.27 (d, J¼8.4 Hz, 2H), 7.71 (d, J¼8.4 Hz,
130.6, 129.9, 123.1, 63.2, 63.1, 13.7, 13.6; IR (KBr): 1749, 1689, 1588,
1310, 1270, 1227, 1182, 912, 862 cmꢁ1; HRMS (ESI): m/z [MþH]þ
calcd for C16H15BrNO6: 396.0077; found: 396.0083.
d
158.0,155.2,154.8,148.9,143.4,139.8,129.9,129.2,124.2,123.5, 63.3,
63.2, 13.9, 13.8; IR (KBr): 1743, 1660, 1630, 1521, 1346, 1187,
1026 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for C18H17N2O8:
389.0979; found: 389.0975.
4.4.9. Diethyl 4-(4-fluorobenzoyl)isoxazole-3,5-dicarboxylate
(4ia). White solid; mp 67e69 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 7.88e7.85 (m, 2H), 7.18 (t, J¼8.4 Hz, 2H), 4.36e4.28 (m, 4H),
1.24 (t, J¼7.2 Hz, 3H), 1.16 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3,
4.4.16. Diethyl 4-((2E,4E)-5-phenylpenta-2,4-dienoyl)isoxazole-3,5-
150 MHz):
d
(ppm) 184.7, 167.3, 165.6, 158.5, 157.9, 155.1, 154.9,
dicarboxylate (4pa). Yellow oil; 1H NMR (CDCl3, 600 MHz):

Y. Yang et al. / Tetrahedron 68 (2012) 6257e6262
6261
d
(ppm) 7.48 (d, J¼7.2 Hz, 2H), 7.39e7.34 (m, 3H), 7.14e7.10 (m, 1H),
6.97e6.96 (m, 2H), 6.58 (d, J¼15.0 Hz, 1H), 4.44e4.39 (m, 4H),
1.38e1.34 (m, 6H); 13C NMR (CDCl3, 150 MHz):
(ppm) 185.5, 158.2,
1258, 1236, 1092, 904 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C24H14Cl2NO4: 450.0294; found: 450.0308.
d
158.1, 155.3, 154.9, 147.3, 143.4, 135.5, 129.9, 129.7, 128.9, 127.5,
126.0, 123.7, 63.1, 63.0, 13.9, 13.8; IR (KBr): 1749, 1651, 1618, 1314,
1269, 1222, 1184, 1025 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C20H20NO6: 370.1285; found: 370.1279.
4.4.23. (4-Benzoylisoxazole-3,5-diyl)bis((4-bromophenyl)meth-
anone) (4ah). White solid; mp 167e169 ꢀC; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 8.16 (d, J¼8.4 Hz, 2H), 8.01 (d, J¼8.4 Hz, 2H), 7.84
(d, J¼7.2 Hz, 2H), 7.69e7.68 (m, 4H), 7.60 (t, J¼7.2 Hz, 1H), 7.45 (t,
J¼7.2 Hz, 2H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 186.8, 182.4,
4.4.17. 1,10-(4-Benzoylisoxazole-3,5-diyl)bis(2-methylpropan-1-one)
179.0, 164.6, 160.4, 136.2, 134.2, 133.3, 133.0, 132.4, 132.2, 132.1,
132.0, 131.5, 130.6, 129.0, 128.8, 125.7; IR (KBr): 1725, 1683, 1658,
1304, 1256, 1236, 903, 881 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd for
C24H14Br2NO4: 539.9274; found: 539.9294.
(4ab). White solid; mp 107e108 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 7.77 (d, J¼7.8 Hz, 2H), 7.59 (t, J¼7.8 Hz, 1H), 7.45 (t,
J¼7.8 Hz, 2H), 3.58 (hept, J¼6.6 Hz, 1H), 3.41 (hept, J¼6.6 Hz,
1H), 1.24e1.22 (m, 12H); 13C NMR (CDCl3, 150 MHz):
(ppm)
d
196.5, 192.3, 187.0, 163.7, 159.5, 136.0, 134.1, 128.9, 128.8, 122.2,
38.4, 38.1, 18.0, 17.5; IR (KBr): 1707, 1675, 941, 906 cmꢁ1; HRMS
(ESI): m/z [MþNa]þ calcd for C18H19NNaO4: 336.1206; found:
336.1201.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant 20872042 and 21032001).
4.4.18. Isoxazole-3,4,5-triyltris(phenylmethanone)
(4ac). White
(ppm) 8.28 (d,
Supplementary data
solid; mp 138e139 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
J¼7.6 Hz, 2H), 8.13 (d, J¼7.6 Hz, 2H), 7.85 (d, J¼7.2 Hz, 2H),
The general experimental methods and the characterizing data
including 1H NMR, 13C NMR, IR, and HRMS for compound 4 are
available in Supplementary data. Supplementary data related to
this article can be found online at doi:10.1016/j.tet.2012.05.055.
7.71e7.52 (m, 7H), 7.44 (t, J¼7.6 Hz, 2H); 13C NMR (CDCl3,
150 MHz):
d (ppm) 187.1, 183.6, 180.2, 164.9, 160.6, 136.4, 134.85,
134.80, 134.7, 134.4, 134.0, 130.8, 130.2, 129.1, 128.9, 128.8, 125.4,
109.7; IR (KBr): 1726, 1675, 1658, 1597, 1581, 1257, 1233, 906,
684 cmꢁ1; HRMS (ESI): m/z [MþNa]þ calcd for C24H15NNaO4:
404.0893; found: 404.0885.
References and notes
1. For reviews on domino reactions, see: (a) Tietze, L. F.; Brasche, G.; Gericke, K.
4.4.19. (4-Benzoylisoxazole-3,5-diyl)bis(p-tolylmethanone)
Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006;
(4ad). White solid; mp 150e152 ꢀC; 1H NMR (CDCl3, 600 MHz):
ꢀ
(b) Zhu, J. P.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
2005; (c) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003,
551e564; (d) Padwa, A.; Bur, S. K. Tetrahedron 2007, 63, 5341e5378; (e) Shin-
doh, N.; Takemoto, Y.; Takasu, K. Chem.dEur. J. 2009, 15, 12168e12179.
2. (a) Yin, G. D.; Zhou, B. H.; Meng, X. G.; Wu, A. X.; Pan, Y. J. Org. Lett. 2006, 8,
2245e2248; (b) Yin, G. D.; Wang, Z. H.; Chen, A. H.; Gao, M.; Wu, A. X.; Pan, Y. J.
J. Org. Chem. 2008, 73, 3377e3383; (c) Gao, M.; Yin, G.; Wang, Z.; Wu, Y.; Guo,
C.; Pan, Y.; Wu, A. Tetrahedron 2009, 65, 6047e6049; (d) Gao, M.; Yang, Y.; Wu,
Y.-D.; Deng, C.; Shu, W.-M.; Zhang, D.-X.; Cao, L.-P.; She, N.-F.; Wu, A.-X. Org.
Lett. 2010, 12, 4026e4029; (e) Gao, M.; Yang, Y.; Wu, Y.-D.; Deng, C.; Cao, L.-P.;
Meng, X.-G.; Wu, A.-X. Org. Lett. 2010, 12, 1856e1859; (f) Yang, Y.; Gao, M.; Wu,
L.-M.; Deng, C.; Zhang, D.-X.; Gao, Y.; Zhu, Y.-P.; Wu, A.-X. Tetrahedron 2011, 67,
5142e5149.
3. (a) Lilienkampf, A.; Pieroni, M.; Wan, B.; Wang, Y.; Franzblau, S. G.; Kozi-
kowski, A. P. J. Med. Chem. 2010, 53, 678e688; (b) Lee, Y. S.; Kim, B. H. Bioorg.
Med. Chem. Lett. 2002, 12, 1395e1397; (c) Srivastava, S.; Bajpai, L. K.; Batra, S.;
Bhaduri, A. P.; Maikhuri, J. P.; Gupta, G.; Dhar, J. D. Bioorg. Med. Chem. 1999, 7,
2607e2613.
d
(ppm) 8.18 (d, J¼7.8 Hz, 2H), 8.04 (d, J¼7.8 Hz, 2H), 7.84 (d,
J¼7.2 Hz, 2H), 7.56 (t, J¼7.2 Hz, 1H), 7.42 (t, J¼7.8 Hz, 2H), 7.33e7.32
(m, 4H), 2.45 (s, 6H); 13C NMR (CDCl3, 150 MHz):
(ppm) 187.1,
d
183.1, 179.8, 165.2, 160.7, 146.2, 146.0, 136.5, 133.8, 132.3, 132.0,
130.8, 130.7, 130.3, 129.6, 129.5, 129.0, 128.7, 125.1, 21.9; IR (KBr):
1659, 1603, 1263, 1182, 904 cmꢁ1; HRMS (ESI): m/z [MþH]þ calcd
for C26H20NO4: 410.1387; found: 410.1396.
4.4.20. (4-Benzoylisoxazole-3,5-diyl)bis((4-methoxyphenyl)-meth-
anone) (4ae). White solid; mp 156e157 ꢀC; 1H NMR (CDCl3,
600 MHz):
d
(ppm) 8.16 (d, J¼7.8 Hz, 2H), 8.01 (d, J¼7.8 Hz, 2H),
7.84 (d, J¼7.8 Hz, 2H), 7.60 (t, J¼7.2 Hz, 1H), 7.43 (t, J¼7.2 Hz, 2H),
7.01e7.00 (m, 4H), 3.92 (s, 6H); 13C NMR (CDCl3, 150 MHz):
4. Li, W.-T.; Hwang, D.-R.; Chen, C.-P.; Shen, C.-W.; Huang, C.-L.; Chen, T.-W.; Lin,
C.-H.; Chang, Y.-L.; Chang, Y.-Y.; Lo, Y.-K.; Tseng, H.-Y.; Lin, C.-C.; Song, J.-S.;
Chen, H.-C.; Chen, S.-J.; Wu, S. H.; Chen, C.-T. J. Med. Chem. 2003, 46,
1706e1715.
d
(ppm) 187.4, 181.9, 178.5, 165.4, 165.0, 164.9, 160.9, 136.6, 133.8,
133.3, 132.8, 129.1, 128.7, 127.9, 127.5, 124.9, 114.3, 114.1, 55.64,
55.60; IR (KBr): 1682, 1656, 1594, 1325, 1258, 1169, 905 cmꢁ1
;
HRMS (ESI): m/z [MþNa]þ calcd for C26H19NNaO6: 464.1105;
5. Batra, S.; Roy, A. K.; Patra, A.; Bhaduri, A. P.; Surin, W. R.; Raghavan, S. A. V.;
Sharma, P.; Kapoor, K.; Dikshit, M. Bioorg. Med. Chem. 2004, 12, 2059e2077.
6. (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D. Synthesis 1987,
857e869; (b) Heasley, B. Angew. Chem., Int. Ed. 2011, 50, 8474e8477.
7. (a) Li, Y.-T.; Chen, C.-L.; Hsu, Y.-Y.; Hsu, H.-C.; Chi, Y.; Chen, B.-S.; Liu, W.-H.; Lai,
C.-H.; Lin, T.-Y.; Chou, P.-T. Tetrahedron 2010, 66, 4223e4229; (b) Pu, S.; Li, H.;
Liu, G.; Liu, W.; Cui, S.; Fan, C. Tetrahedron 2011, 67, 1438e1447; (c) Lee, Y.-G.;
Koyama, Y.; Yonekawa, M.; Takata, T. Macromolecules 2009, 42, 7709e7717.
found: 464.1129.
4.4.21. (4-Benzoylisoxazole-3,5-diyl)bis((4-nitrophenyl)methanone)
(4af). White solid; mp 151e152 ꢀC; 1H NMR (CDCl3, 600 MHz):
d
(ppm) 8.49 (d, J¼7.8 Hz, 2H), 8.40e8.39 (m, 4H), 8.33 (d, J¼7.8 Hz,
2H), 7.86 (d, J¼7.8 Hz, 2H), 7.65 (t, J¼7.8 Hz, 1H), 7.50 (t, J¼7.8 Hz,
2H); 13C NMR (CDCl3, 150 MHz):
(ppm) 186.2, 181.9, 178.4, 163.9,
€
8. Bandiera, T.; Grunanger, P.; Albini, F. M. J. Heterocycl. Chem. 1992, 29,
1423e1428.
d
9. (a) Waldo, J. P.; Larock, R. C. Org. Lett. 2005, 7, 5203e5205; (b) Ueda, M.; Sato,
A.; Ikeda, Y.; Miyoshi, T.; Naito, T.; Miyata, O. Org. Lett. 2010, 12, 2594e2597.
10. Burkhard, J. A.; Tchitchanov, B. H.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50,
5379e5382.
11. (a) Trogu, E.; Vinattieri, C.; De Sarlo, F.; Machetti, F. Chem.dEur. J. 2012, 18,
2081e2093; (b) Yavari, I.; Moradi, L. Tetrahedron Lett. 2006, 47, 1627e1629; (c)
Yavari, I.; Piltan, M.; Moradi, L. Tetrahedron 2009, 65, 2067e2071; (d) Chen, K.-
P.; Chen, Y.-J.; Chuang, C.-P. Eur. J. Org. Chem. 2010, 5292e5300.
12. (a) Easton, C. J.; Hughes, C. M. M.; Savage, G. P.; Simpson, G. W. In Adv. Heter-
ocycl. Chem; Alan, R., Katritzky, F. R. S., Eds.; Academic: 1994; pp 261e327; (b)
Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, K. B.;
Fokin, V. V. J. Am. Chem. Soc. 2004, 127, 210e216; (c) Bhosale, S.; Kurhade, S.;
Prasad, U. V.; Palle, V. P.; Bhuniya, D. Tetrahedron Lett. 2009, 50, 3948e3951; (d)
Basel, Y.; Hassner, A. Synthesis 1997, 309e312; (e) Cecchi, L.; De Sarlo, F.;
Machetti, F. Eur. J. Org. Chem. 2006, 4852e4860; (f) Lee, C. C.; Fitzmaurice, R. J.;
Caddick, S. Org. Biomol. Chem. 2009, 7, 4349e4351; (g) Zhu, S.; Shi, S.; Gerritz,
160.1, 151.11, 151.06, 138.8, 138.6, 135.9, 134.6, 131.8, 131.2, 129.03,
128.99, 126.4, 124.1, 123.9; IR (KBr): 1676, 1600, 1527, 1351, 1253,
908, 887 cmꢁ1; HRMS (ESI): m/z [MþNa]þ calcd for C24H13N3NaO8:
494.0595; found: 494.0580.
4.4.22. (4-Benzoylisoxazole-3,5-diyl)bis((4-
anone) (4ag). White solid; mp 145e147 ꢀC; 1H NMR (CDCl3,
600 MHz):
(ppm) 8.24 (d, J¼8.4 Hz, 2H), 8.08 (d, J¼8.4 Hz, 2H),
chlorophenyl)meth-
d
7.84 (d, J¼7.2 Hz, 2H), 7.58 (t, J¼7.2 Hz, 1H), 7.51e7.49 (m, 4H), 7.44
(t, J¼7.2 Hz, 2H); 13C NMR (CDCl3, 150 MHz):
d (ppm) 186.8, 182.1,
178.7, 164.6, 160.4, 141.7, 141.6, 136.2, 134.1, 132.9, 132.6, 132.1, 131.5,
129.4, 129.2, 129.0, 128.8, 125.7; IR (KBr): 1727, 1680, 1661, 1587,

6262
Y. Yang et al. / Tetrahedron 68 (2012) 6257e6262
S. W. Tetrahedron Lett. 2011, 52, 4001e4004; (h) Denmark, S. E.; Kallemeyn, J. M.
J. Org. Chem. 2005, 70, 2839e2842.
13. (a) Mohamed Ahmed, M. S.; Kobayashi, K.; Mori, A. Org. Lett. 2005, 7,
4487e4489; (b) Adib, M.; Mahdavi, M.; Ansari, S.; Malihi, F.; Zhu, L.-G.; Bi-
janzadeh, H. R. Tetrahedron Lett. 2009, 50, 7246e7248.
14. CCDC 861459e861460 (4aa, 4ab) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data_request/cif.
15. Katritzky, A. R.; Abdel-Fattah, A. A. A.; Gromova, A. V.; Witek, R.; Steel, P. J. J. Org.
Chem. 2005, 70, 9211e9214.