Novel microwave-assisted one-pot synthesis of isoxazoles by a three-component coupling-cycloaddition sequence

Article abstract of DOI:10.1055/s-2007-1000856

The consecutive Sonogashira coupling of acid chlorides with terminal alkynes, followed by 1,3-dipolar cycloaddition under dielectric heating of in situ generated nitrile oxides from hydroximinoyl chlorides furnishes isoxazoles in moderate to good yields i

Full text of DOI:10.1055/s-2007-1000856

PAPER
293
Novel Microwave-Assisted One-Pot Synthesis of Isoxazoles by a
Three-Component Coupling–Cycloaddition Sequence
T
hree-Componen
e
t
C
oupling
n
-Cycloadditio
j
n
Isox
a
azole Synth
m
esis in Willy,a Frank Rominger,b Thomas J. J. Müller*a
a
Institut für Organische Chemie und Makromolekulare Chemie, Lehrstuhl für Organische Chemie, Heinrich-Heine-Universität Düssel-
dorf, Universitätsstraße 1, 40225 Düsseldorf, Germany
Fax +49(211)8114324; E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69210 Heidelberg, Germany
b
Received 28 August 2007; revised 26 October 2007
the resulting alkynones are highly reactive and readily re-
act with all kinds of 1,3-dipoles, even in a one-pot fash-
ion.17 The 1,3-dipolar cycloaddition of aromatic nitrile
oxides, a class of propargyl-type 1,3 dipoles is, in general,
a suitable route to isoxazoles.14 Since aromatic nitrile ox-
ides are usually unstable compounds, it is necessary for
them to be prepared in situ by dehydrochlorination of the
corresponding hydroximinoyl chlorides with a suitable
base. If triethylamine is the base, this step should be fully
compatible with a preceding alkynone formation.
Abstract: The consecutive Sonogashira coupling of acid chlorides
with terminal alkynes, followed by 1,3-dipolar cycloaddition under
dielectric heating of in situ generated nitrile oxides from hydroxim-
inoyl chlorides furnishes isoxazoles in moderate to good yields in
the sense of a one-pot three-component reaction.
Key words: alkynes, cross-couplings, cycloaddition, isoxazole,
microwave reaction
The biological activity of many substituted isoxazoles1 is
an important theme in medicinal chemistry. Isoxazoles are
potent, selective agonists of human cloned dopamine D4
receptors2 and exhibit GABAA antagonist,3 analgesic,4
anti-inflammatory,4 ulcerogenic,4 COX-2 inhibitory,5 an-
tinociceptive,6 and anticancer7 activity. Therefore, many
synthetic approaches have been made to access the isox-
azole core,8 including reactions of hydroxylamine with
1,3-dicarbonyl compounds,9 a,b-unsaturated carbonyl
compounds,10 and a,b-unsaturated nitriles.11 The reaction
of an oxime-derived dianion and an ester12 or amide13 also
provides isoxazoles. In addition, [3+2] cycloadditions be-
tween alkynes and nitrile oxides have been reported.14 Al-
though these strategies are highly convergent, often strong
bases or strong mineral acids are required, or prolonged
heating to high temperatures is necessary. Other short-
comings are poor regioselectivities. Therefore, as part of
our program on the design and development of new multi-
component synthesis of heterocycles initiated by Sono-
gashira coupling,15,16 we have now focused on coupling–
cycloaddition sequences as an entry to heterocycle se-
quences.17 Here, we wish to report a concise, consecutive,
three-component synthesis of 3,4,5-substituted isoxazoles
with a flexible substitution pattern, applying dielectric
heating (microwave irradiation) in the concluding pericy-
clic step.
Therefore, after reacting acid chlorides 1 with terminal
alkynes 2 under modified Sonogashira conditions for one
hour at room temperature to furnish the expected
alkynones 3, subsequently, hydroximinoyl chlorides 4
and triethylamine are added. After heating for 30 minutes
under dielectric heating, the isoxazoles 5 were obtained in
moderate to excellent yields, often as crystalline solids
(Scheme 1, Table 1–3).
O
[2% PdCl2(PPh3)2, 4% CuI]
Et3N (1 equiv), THF, 1 h, r.t.
+
R2
R1
Cl
1
2
HO
N
O
4
O
R1
R2
5 (12–78%)
R3
R3
Cl
R1
N
R2
Et3N (1.10 equiv)
30 min, MW, 90 °C
O
3
Scheme 1 One-pot, three-component synthesis of isoxazoles
Initial attempts at performing the concluding cycloaddi-
tion step under conductive heating proved to be time-con-
suming (2–4 days) and were often inefficient;
conventional heating for 12 hours (85 °C, oil bath) of the
alkynone formed from 1c and 2b with 4a, gave rise to for-
mation of isoxazole 5c only in 49%. One major drawback
of the extended reaction times was that a side reaction of
the in situ generated nitrile oxides gave rise to the forma-
tion of furoxan oxides 620 (Scheme 2). Furoxane 6a, for
instance, was formed under conductive heating conditions
in 32% yield, whereas dielectric heating diminished the
amount of this side product to 14% (with respect to hy-
droximinoyl chloride 4a).
The Sonogashira coupling of acid chlorides with terminal
alkynes allows straightforward access to alkynones.18 Re-
cently, we reported that only one equivalent of triethyl-
amine as the hydrochloric acid scavenging base proved to
be most favorable for the successful coupling of even sen-
sitive alkynes such as trimethylsilyl acetylene.19 In turn,
SYNTHESIS 2008, No. 2, pp 0293–0303
x
x
.
x
x
.2
0
0
7
Advanced online publication: 18.12.2007
DOI: 10.1055/s-2007-1000856; Art ID: T14107SS
© Georg Thieme Verlag Stuttgart · New York

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Table 1 Coupling–Cycloaddition Synthesis of Isoxazoles 5; Variation of Acid Chlorides
Entry
Acid chloride 1
Alkyne 2
Hydroximinoyl chloride 4
R3 = 4-MeOC6H4 (4a)
Isoxazole 5 (yield, %)
OMe
O
1
1a: R1 = 2-thienyl
2a: R2 = Me3Si
S
N
Me3Si
O
5a (77)
OMe
O
O2N
2
3
4
5
6
7
1b: R1 = 4-O2NC6H4
1c: R1 = 4-MeOC6H4
1d: R1 = 4-ClC6H4
1e: R1 = 4-F3CC6H4
1f: R1 = 2-styryl
2b: R2 = n-butyl
4a
4a
4a
4a
4a
4a
N
nBu
O
5b (56)
OMe
O
MeO
2b
2b
2a
2a
2a
N
nBu
O
5c (64)
OMe
O
Cl
N
nBu
O
5d (59)
OMe
O
F3C
N
Me3Si
O
5e (56)
OMe
O
N
Me3Si
O
5f (12)
OMe
O
tBu
1g: R1 = t-Bu
N
Me3Si
O
5g (56)
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Three-Component Coupling–Cycloaddition Isoxazole Synthesis
295
Table 1 Coupling–Cycloaddition Synthesis of Isoxazoles 5; Variation of Acid Chlorides (continued)
Entry
Acid chloride 1
Alkyne 2
Hydroximinoyl chloride 4
Isoxazole 5 (yield, %)
OMe
O
8
1h: R1 = cyclopropyl
2a
4a
N
Me3Si
O
5h (54)
OMe
O
9
1i: R1 = cyclohexen-1-yl
2a
4a
N
Me3Si
O
5i (39)
O
O
R3
R3
N
N
base
O
O
+
4
4
R3
N
N
R3
6
Scheme 2 Dimerization of nitrile oxides to furoxan oxides 6
In addition to spectroscopic and analytical characteriza-
tion, the structure of 3,4-bis(4-methoxyphenyl)-1,2,5-
oxadiazole-2-oxide (6a) was corroborated by an X-ray
crystal structure analysis (Figure 1).21
Hence, the synthesis was optimized by heating the reac-
tion mixture under microwave irradiation. Thus, reaction
times were reduced from three days to 30 minutes, while
simultaneously increasing the yields, in some cases quite
dramatically, and significantly reducing the amount of
byproduct formation.
Figure 1 ORTEP plot of furoxan oxide 6a
Table 2 Coupling–Cycloaddition Synthesis of Isoxazoles 5; Variation of Alkynes
Entry
Acid chloride 1
Alkyne 2
Hydroximinoyl chloride 4
Isoxazole 5 (yield, %)
OMe
O
1
1a
2b
4a
S
N
nBu
O
5j (60)
OMe
O
2
1a
2c: R2 = n-decyl
4a
S
N
ndecyl
O
5k (42)
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Table 2 Coupling–Cycloaddition Synthesis of Isoxazoles 5; Variation of Alkynes (continued)
Entry
Acid chloride 1
Alkyne 2
Hydroximinoyl chloride 4
Isoxazole 5 (yield, %)
OMe
O
S
3
1a
2d: R2 = 4-MeO2CC6H4
4a
N
O
MeO
O
5l (72)
OMe
O
S
4
1a
2e: R2 = 4-(1-pyrrolidinyl)C6H4
4a
N
O
N
5m (48)
OMe
O
2f: R2 = 4-O2NC6H4
2g: R2 = 4-MeOC6H4
2h: R2 = 4-ClC6H4
4a
4a
4a
S
5
6
7
1a
1a
1a
N
O
O2N
5n (66)
OMe
O
S
N
O
MeO
5o (78)
OMe
O
S
N
O
O
Cl
5p (70)
OMe
S
8
1a
2i: R2 = 3,4-(MeO)2C6H4
4a
N
O
MeO
OMe
5q (44)
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Three-Component Coupling–Cycloaddition Isoxazole Synthesis
297
Table 2 Coupling–Cycloaddition Synthesis of Isoxazoles 5; Variation of Alkynes (continued)
Entry
Acid chloride 1
Alkyne 2
Hydroximinoyl chloride 4
Isoxazole 5 (yield, %)
OMe
O
S
9
1a
2j: R2 = 3-(10-methyl)phenothiazinyl 4a
S
N
O
N
Me
5r (55)
The structures of the isoxazoles 5 were unambiguously as-
signed by 1H and 13C NMR spectroscopy and, in addition,
by X-ray crystal structure analysis of the isoxazole 5w
(Figure 2).21
In accordance with theory for kinetically controlled 1,3-
dipolar cycloadditions,20 in each case only one of the two
possible regioisomers, i.e. isomer 5, was formed. Not
even traces of the regioisomers 7 could be detected. Sub-
stitution patterns were determined by NOESY NMR ex-
periments and supported by an X-ray crystal structure
analysis (Figure 3).
O
O
R1
4
R1
R2
R3
2
O
3
1
N
R2
N
O
R3
5
7
Figure 3 Possible regioisomers 5 and 6 of the isoxazoles
Figure 2 ORTEP plot of isoxazole 5w
Table 3 Coupling–Cycloaddition Synthesis of Isoxazoles 5; Variation of Hydroximinoyl Chlorides
Entry
Acid chloride 1
Alkyne 2
Hydroximinoyl chloride 4
Isoxazole 5 (yield, %)
OMe
O
1
1a
2k: R2 = CH2OTHP
4a
S
THPO
N
O
5s (54)
NO2
O
O2N
2
1b
2b
R3 = 4-O2NC6H4 (4b)
N
nBu
O
5t (67)
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Table 3 Coupling–Cycloaddition Synthesis of Isoxazoles 5; Variation of Hydroximinoyl Chlorides (continued)
Entry
Acid chloride 1
Alkyne 2
Hydroximinoyl chloride 4
R3 = 4-MeC6H4 (4c)
Isoxazole 5 (yield, %)
Me
O
3
1a
2b
S
N
nBu
O
5u (60)
OMe
O
OMe
4
1a
2b
R3 = 3,4-(MeO)2C6H4 (4d)
S
N
nBu
O
5v (57)
O
5
6
1a
1c
2b
R3 = 10-anthranyl (4e)
S
N
nBu
O
5w (68)
O
MeO
S
2l: R2 = n-propyl
R3 = 2-thienyl (4f)
N
nPr
O
5x (66)
As a consequence of 3,4,5-substitution, no peculiar reso- steps of the sequence. Aliphatic alkynes can be employed
nances of the isoxazole core were found in the proton as well as ethynylbenzenes with electron-donating or
NMR spectra. However, the carbon signals of the isox- electron-withdrawing substituents (Table 2; 2d–i). Even
azole, as well as the carbonyl nuclei, could be readily as- heterocyclic alkynes, such as the phenothiazine bearing
signed by 2D NMR spectroscopy and incremental alkyne 2j, can be used as starting materials. Silylated
calculations. Carbon atoms C-1 appeared in the carbon alkynes also undergo the coupling procedure, indeed, tri-
NMR spectra at about d = 175 ppm. The quaternary C-2 methylsilyl acetylene (1a) proved to be very favorable
resonances could be found at higher field (around d = 115 (Table 2, entries 1–10). With respect to the 1,3-dipolar ni-
ppm) as a consequence of the polarization caused by the trile oxide, electron-rich, polycyclic, electron-deficient
electron-withdrawing effect of the carbonyl group. Final- and heterocyclic substituents are all tolerated and react
ly, the imine-type nuclei emerged at about d = 161 ppm. readily with the alkynones 3 (Table 3, entries 2–6).
The signals around d = 185 ppm could be unambiguously
In conclusion, we have established a straightforward, one-
assigned to the nuclei of the carbonyl groups. According
pot, three-component synthesis of 3,4,5-substituted isox-
to the X-ray structure analysis, the aroyl moiety is distort-
azoles in the sense of a consecutive coupling-cycloaddi-
ed from coplanarity with respect to the isoxazole ring by
tion sequence starting with room temperature coupling
126°.
and subsequent dielectric heating for completion of the
The scope of this one-pot coupling–cycloaddition isox- cycloaddition. Preparation of starting materials is very
azole synthesis is fairly broad and can be performed under general and can be applied to a broad variety of substrates.
mild conditions and with excellent chemo- and regiose- Studies addressing this novel synthesis in order to en-
lectivity. As a consequence of using acid chlorides as the hance molecular diversity in material and pharmaceutical-
halide coupling partner, amines and hydroxy groups need ly interesting targets are currently underway.
to be protected prior to the reaction. The use of the acid
chlorides 1 is predominantly limited to (hetero)aromatic
All reactions involving water-sensitive compounds were carried out
compounds and derivatives without b-hydrogens. With a
few exceptions, cyclopropyl (Table 1, entry 8) or cyclo-
hex-1-enyl substituents (entry 9) are tolerated in both
in flame-dried Schlenk glassware under nitrogen atmosphere unless
stated otherwise. Reagents and catalysts were purchased as reagent
grade and used without further purification. Solvents were dried and
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Three-Component Coupling–Cycloaddition Isoxazole Synthesis
299
distilled according to standard procedures.22 Aldoximes and the cor-
responding hydroximinoyl chlorides 4 were synthesized according
to literature procedures.23 Flash column chromatography: silica gel
60, mesh 230–400, Merck, Darmstadt. TLC: silica gel plates (60
F254 Merck, Darmstadt). 1H-, 13C-, DEPT-, NOESY-, COSY-, HM-
QC- and HMBC spectra were recorded with Bruker ARX 250,
Bruker DRX 300 or Bruker DRX 500 spectrometers using CDCl3
as solvent unless stated otherwise. The assignments of quaternary
C, CH, CH2 and CH3 were made on the basis of DEPT spectra. Mass
spectra were recorded with JEOL JMS-700 and Finnigan TSQ 700
spectrometers. The melting points (uncorrected) were measured
with Stuart Scientific Melting Point Apparatus SMP3. Elemental
analyses were carried out in the microanalytical laboratory of the
Organisch-Chemisches Institut, Universität Heidelberg. Dielectric
heating was performed in a SmithCreator (Personal Chemistry AB,
Uppsala, Sweden) and a Discover™ (CEM GmbH, Kamp-Lintfort,
Germany; Table 3, entries 2 and 6) single-mode microwave cavity,
producing continuous irradiation at 2450 MHz.
MS (EI, 70 eV): m/z (%) = 380 (100) [M]+, 351 (31), 296 (25), 202
(10), 174 (27), 150 (68), 104 (15), 28 (16).
Anal. Calcd for C21H20N2O5: C, 66.31; H, 5.30; N, 7.76. Found:
C, 66.36; H, 5.29; N, 7.33.
[5-n-Butyl-3-(4-methoxyphenyl)isoxazol-4-yl](4-methoxyphe-
nyl)methanone (5c)
Yellow resin.
1H NMR (500 MHz, CDCl3): d = 0.87 (t, 3J = 7.3 Hz, 3 H), 1.33 (m,
3
2 H), 1.69 (q, 3J = 7.5 Hz, 2 H), 2.79 (t, J = 7.5 Hz, 2 H), 3.75 (s,
3 H), 3.81 (s, 3 H), 6.79 (d, 3J = 8.9 Hz, 2 H), 6.82 (d, 3J = 8.9 Hz,
2 H), 7.44 (d, 3J = 8.9 Hz, 2 H), 7.73 (d, 3J = 8.9 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 13.6 (CH3), 22.2 (CH2), 26.3
(CH2), 29.6 (CH2), 55.2 (CH3), 55.5 (CH3), 113.8 (CH), 114.0 (CH),
114.5 (2 × CH), 115.1 (Cq), 120.7 (Cq), 129.8 (2 × CH), 130.4 (Cq),
132.0 (2 × CH), 160.7 (Cq), 161.0 (Cq), 164.0 (Cq), 175.1 (Cq),
189.0 (Cq).
MS (EI, 70 eV): m/z (%) = 366 (21) [M + H]+, 365 (77) [M]+, 364
(30) [M – H]+, 336 (19), 322 (35), 238 (59), 228 (20), 223 (23), 136
(18), 135 (100), 107 (14), 77 (16).
One-Pot, Three-Component Synthesis of Isoxazoles 5; General
Procedure
In a 10 mL microwave tube, PdCl2(PPh3)2 (15 mg, 0.02 mmol) and
CuI (8 mg, 0.04 mmol) were dissolved in degassed THF (5 mL). To
this orange solution, acid chloride 1 (1.00 mmol), alkyne 2
(1.00 mmol) and Et3N (1.05 mmol) were added. The reaction mix-
ture was stirred at r.t. for 1 h then aryl hydroximinoyl chloride 4
(1.00 mmol) and Et3N (1.1 mmol) were added to the suspension and
the reaction mixture was heated for 30 min at 90 °C under micro-
wave conditions (sealed reaction vessel, ramp time 2 min, tempera-
ture measured by infra-red sensor, 1.9 bar). After cooling to r.t., the
solvent was removed under reduced pressure and the crude products
were purified by silica gel flash column chromatography (hexane–
EtOAc, 50:1) to afford the analytically pure products.
HRMS: m/z calcd for C22H23NO4: 365.1627; found: 365.1635.
[5-n-Butyl-3-(4-methoxyphenyl)isoxazol-4-yl](4-chlorophe-
nyl)methanone (5d)
Colorless crystals; mp 83 °C.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, 3J = 7.3 Hz, 3 H), 1.35 (m,
3
2 H), 1.72 (q, 3J = 7.7 Hz, 2 H), 2.84 (t, J = 7.4 Hz, 2 H), 3.76 (s,
3 H), 6.78 (d, 3J = 8.8 Hz, 2 H), 7.28 (d, 3J = 8.6 Hz, 2 H), 7.36 (d,
3J = 8.8 Hz, 2 H), 7.63 (d, 3J = 8.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.6 (CH3), 22.3 (CH2), 26.5
(CH2), 29.6 (CH2), 55.3 (CH3), 114.0 (2 × CH), 114.7 (Cq), 120.3
(Cq), 128.8 (2 × CH), 129.9 (2 × CH), 130.9 (2 × CH), 135.7 (Cq),
139.9 (Cq), 160.8 (Cq), 161.0 (Cq), 176.6 (Cq), 189.1 (Cq).
[3-(4-Methoxyphenyl)-5-(trimethylsilyl)isoxazol-4-yl](thio-
phen-2-yl)methanone (5a)
MS (EI, 70 eV): m/z (%) = 372 (6) [37Cl: M + H]+, 371 (29) [37Cl:
M]+, 370 (27) [35Cl: M + H]+, 369 (83) [35Cl: M]+, 368 (24) [35Cl:
M – H]+, 340 (27), 326 (11), 285 (17), 174 (19), 149 (13), 141 (43),
139 (100), 113 (10), 111 (28).
HRMS: m/z calcd for C21H2037ClNO3: 371.1097; found: 371.1127.
HRMS: m/z calcd for C21H2035ClNO3: 369.1127; found: 369.1142.
Light-red crystals; mp 101 °C.
1H NMR (300 MHz, CDCl3): d = 0.32 (s, 9 H), 3.76 (s, 3 H), 6.83
3
3
(d, J = 8.8 Hz, 2 H), 6.96 (dd, J = 4.9, 3.8 Hz, 1 H), 7.30 (dd,
3J = 3.8 Hz, 4J = 1.2 Hz, 1 H), 7.51 (d, 3J = 8.8 Hz, 2 H), 7.65 (dd,
3J = 4.9 Hz, 4J = 1.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = –2.1 (3 × CH3), 55.1 (CH3), 114.1
(2 × CH), 120.4 (Cq), 127.2 (Cq), 128.2 (CH), 129.7 (2 × CH), 135.5
(CH), 135.6 (CH), 144.8 (Cq), 158.8 (Cq), 160.7 (Cq), 179.8 (Cq),
183.3 (Cq).
[3-(4-Methoxyphenyl)-5-(trimethylsilyl)isoxazol-4-yl][4-(tri-
fluoromethyl)phenyl)methanone (5e)
MS (EI, 70 eV): m/z (%) = 357 (92) [M]+, 314 (89), 240 (17), 208
(15), 141 (20), 133 (35), 111 (49), 90 (13), 73 (26), 32 (27), 28 (100)
[CO]+.
Light-red crystals; mp 108 °C.
1H NMR (300 MHz, CDCl3): d = 0.35 (s, 9 H), 3.73 (s, 3 H), 6.74
(d, 3J = 8.4 Hz, 2 H), 7.30 (d, 3J = 8.4 Hz, 2 H), 7.54 (d, 3J = 8.6 Hz,
2 H), 7.76 (d, 3J = 8.6 Hz, 2 H).
HRMS: m/z calcd for C18H19NO3SSi: 357.0855; found: 357.0846.
13C NMR (75 MHz, CDCl3): d = –2.0 (3 × CH3), 55.2 (CH3), 114.1
Anal. Calcd for C18H19NO3SSi: C, 60.47; H, 5.26; N, 3.92. Found:
C, 60.21; H, 5.60; N, 3.80.
1
(2 × CH), 120.1 (Cq), 123.3 (q, JC–F = 272.8 Hz, Cq), 125.4 (q,
3JC–F = 3.8 Hz, CH), 127.0 (Cq), 129.9 (2 × CH), 130.0 (CH), 134.5
2
5
(q, JC–F = 32.7 Hz, Cq), 140.1 (q, JC–F = 1.2 Hz, Cq), 159.5 (Cq),
[5-n-Butyl-3-(4-methoxyphenyl)isoxazol-4-yl](4-nitrophe-
nyl)methanone (5b)
Light-yellow crystals; mp 98 °C.
160.8 (Cq), 182.5 (Cq), 190.4 (Cq).
MS (EI, 70 eV): m/z (%) = 420 (30) [M + H]+, 419 (58) [M]+, 377
1H NMR (300 MHz, CDCl3): d = 0.92 (t, 3J = 7.3 Hz, 3 H), 1.40 (m,
2 H), 1.77 (q, 3J = 7.6 Hz, 2 H), 2.93 (t, 3J = 7.4 Hz, 2 H), 3.74 (s,
3 H), 6.73 (d, 3J = 8.9 Hz, 2 H), 7.28 (d, 3J = 8.9 Hz, 2 H), 7.77 (d,
3J = 8.9 Hz, 2 H), 8.10 (d, 3J = 8.9 Hz, 2 H).
(30), 376 (100), 302 (39), 270 (32), 173 (26), 145 (18), 73 (29).
Anal. Calcd for C21H20F3NO3Si: C, 60.13; H, 4.81; N, 3.34. Found:
C, 59.81; H, 4.76; N, 3.37.
13C NMR (75 MHz, CDCl3): d = 13.6 (CH3), 22.3 (CH2), 26.6
(CH2), 29.6 (CH2), 55.3 (CH3), 114.1 (2 × CH), 114.5 (Cq), 119.9
(Cq), 123.5 (2 × CH), 130.0 (2 × CH), 130.3 (2 × CH), 142.1 (Cq),
150.1 (Cq), 160.9 (Cq), 161.1 (Cq), 178.3 (Cq).
(E)-1-[3-(4-Methoxyphenyl)-5-(trimethylsilyl)isoxazol-4-yl]-3-
phenylprop-2-en-1-one (5f)
Colorless crystals; mp 124 °C.
1H NMR (300 MHz, CDCl3): d = 0.44 (s, 9 H), 3.83 (s, 3 H), 6.71
3
3
(dd, J = 15.9, 0.6 Hz, 1 H), 6.97 (d, J = 8.3 Hz, 2 H), 7.22–7.31
(m, 5 H), 7.50–7.58 (m, 3 H).
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13C NMR (75 MHz, CDCl3): d = –2.2 (3 × CH3), 55.4 (CH3), 114.3
(2 × CH), 120.8 (Cq), 125.7 (CH), 128.4 (CH), 128.9 (2 × CH),
129.2 (Cq), 130.6 (CH), 130.7 (CH), 134.3 (Cq), 144.4 (CH), 159.6
(Cq), 161.0 (Cq), 183.5 (Cq), 187.2 (Cq).
MS (EI, 70 eV): m/z (%) = 341 (91) [M]+, 312 (11), 257 (26), 242
(18), 228 (28), 174 (14), 149 (22), 111 (100).
HRMS: m/z calcd for C19H19NO3S: 341.1086; found: 341.1088.
MS (EI, 70 eV): m/z (%) = 378 (20) [M + H]+, 377 (65) [M]+, 362
(22), 248 (14), 335 (25), 334 (100), 162 (10), 151 (13), 133 (10),
131 (12), 86 (16), 84 (24), 77 (16), 73 (26).
[5-n-Decyl-3-(4-methoxyphenyl)isoxazol-4-yl](thiophen-2-
yl)methanone (5k)
Colorless crystals; mp 109 °C.
3
HRMS: m/z calcd for C22H23NO5Si: 377.1447; found: 377.1440.
1H NMR (300 MHz, CDCl3): d = 0.85 (t, J = 6.6 Hz, 3 H), 1.16–
1.37 (m, 14 H), 1.66–1.79 (m, 2 H), 2.84 (t, 3J = 7.5 Hz, 2 H), 3.75
(s, 3 H), 6.81 (d, 3J = 8.4 Hz, 2 H), 6.93 (dd, 3J = 4.9, 3.8 Hz, 1 H),
7.23 (dd, 3J = 4.9, 1.2 Hz, 1 H), 7.48 (d, 3J = 8.4 Hz, 2 H), 7.62 (dd,
3J = 3.8, 1.2 Hz, 1 H).
1-[3-(4-Methoxyphenyl)-5-(trimethylsilyl)isoxazol-4-yl]-2,2-
dimethylpropan-1-one (5g)
Colorless crystals; mp 136 °C.
1H NMR (300 MHz, CDCl3): d = 0.34 (s, 9 H), 0.96 (s, 9 H), 3.83
13C NMR (75 MHz, CDCl3): d = 14.0 (CH3), 22.6 (CH2), 26.5
(CH2), 27.5 (CH2), 29.0 (CH2), 29.0 (CH2), 29.2 (CH2), 29.3 (CH2),
29.4 (CH2), 31.8 (CH2), 55.1 (CH3), 114.0 (2 × CH), 115.0 (Cq),
120.5 (Cq), 128.1 (CH), 129.7 (2 × CH), 135.0 (CH), 135.1 (CH),
144.1 (Cq), 160.4 (Cq), 160.7 (Cq), 175.2 (Cq), 182.0 (Cq).
MS (EI, 70 eV): m/z (%) = 426 (29) [M + H]+, 425 (100) [M]+, 424
(11), 312 (22), 257 (13), 111 (32).
(s, 3 H), 6.94 (d, 3J = 8.9 Hz, 2 H), 7.44 (d, 3J = 8.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = –1.5 (3 × CH3), 27.3 (CH3), 45.4
(Cq), 55.3 (CH3), 114.3 (2 × CH), 122.0 (Cq), 128.1 (Cq), 129.7
(2 × CH), 158.3 (Cq), 160.9 (Cq), 175.8 (Cq), 209.4 (Cq).
MS (EI, 70 eV): m/z (%) = 331 (15) [M]+, 275 (12), 274 (61), 247
(13), 246 (69), 101 (11), 73 (100).
HRMS: m/z calcd for C25H31NO3S: 425.2025; found: 425.2004.
HRMS: m/z calcd for C18H25NO3Si: 331.1604; found: 331.1601.
Anal. Calcd for C25H31NO3S: C, 70.55; H, 7.34; N, 3.29. Found:
C, 70.23; H, 7.44; N, 3.32.
Cyclopropyl[3-(4-methoxyphenyl)-5-(trimethylsilyl)isoxazol-4-
yl)methanone (5h)
Colorless crystals; mp 137 °C.
Methyl 4-[3-(4-Methoxyphenyl)-4-(thiophene-2-carbonyl)isox-
azol-5-yl]benzoate (5l)
Colorless crystals; mp 147 °C.
1H NMR (300 MHz, CDCl3): d= 0.38 (s, 9 H), 0.80 (m, 2 H), 1.18
(s, 2 H), 1.82 (m, 1 H), 3.85 (s, 3 H), 6.98 (d, 3J = 8.7 Hz, 2 H), 7.56
(d, 3J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = –2.2 (3 × CH3), 13.1 (2 × CH2),
21.5 (CH), 55.3 (CH3), 114.1 (2 × CH), 120.9 (Cq), 130.1 (Cq),
130.6 (2 × CH), 159.8 (Cq), 161.0 (Cq), 182.7 (Cq), 197.7 (Cq).
1H NMR (300 MHz, CDCl3): d = 3.78 (s, 3 H), 3.90 (s, 3 H), 6.85–
6.94 (s, 3 H), 7.36 (dd, 3J = 3.9, 1.0 Hz, 1 H), 7.58–7.66 (m, 3 H),
7.81 (d, 3J = 8.5 Hz, 2 H), 8.05 (d, 3J = 8.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 52.3 (CH3), 55.2 (CH3), 114.3
(2 × CH), 115.1 (Cq), 120.1 (Cq), 127.2 (2 × CH), 128.5 (CH), 129.5
(2 × CH), 130.0 (2 × CH), 130.4 (Cq), 131.9 (Cq), 135.7 (CH), 136.3
(CH), 144.0 (Cq), 161.1 (Cq), 161.4 (Cq), 166.0 (Cq), 167.2 (Cq),
182.6 (Cq).
MS (EI, 70 eV): m/z (%) = 315 (35) [M]+, 300 (20), 273 (21), 272
(100), 198 (27), 99 (10), 73 (40).
HRMS: m/z calcd for C17H21NO3Si: 315.1291; found: 315.1293.
MS (EI, 70 eV): m/z (%) = 420 (15) [M + H]+, 419 (58) [M]+, 390
(12), 268 (15), 244 (13), 242 (13), 216 (47), 164 (10), 163 (100),
149 (12), 135 (30), 111 (85), 103 (14), 32 (14), 28 (56).
Cyclohexenyl[3-(4-methoxyphenyl)-5-(trimethylsilyl)isoxazol-
4-yl]methanone (5i)
Colorless crystals; mp 124 °C.
HRMS: m/z calcd for C23H17NO5S: 419.0827; found: 419.0816.
1H NMR (500 MHz, CDCl3): d = 0.31 (s, 9 H), 1.46–1.61 (m, 4 H),
1.97–2.02 (m, 2 H), 2.28–2.33 (m, 2 H), 3.80 (s, 3 H), 6.48–6.52
(m, 1 H), 6.89 (d, 3J = 8.8 Hz, 2 H), 7.43 (d, 3J = 8.8 Hz, 2 H).
Anal. Calcd for C23H17NO5S: C, 65.86; H, 4.09; N, 3.34. Found:
C, 65.65; H, 4.22; N, 3.29.
13C NMR (125 MHz, CDCl3): d = –2.0 (3 × CH3), 21.3 (CH2), 21.6
(CH2), 23.0 (CH2), 26.1 (CH2), 55.2 (CH3), 114.0 (2 × CH), 120.9
(Cq), 127.2 (Cq), 129.7 (2 × CH), 140.8 (Cq), 146.7 (CH), 159.3
(Cq), 160.5 (Cq), 178.6 (Cq), 192.8 (Cq).
MS (EI, 70 eV): m/z (%) = 356 (16) [M + H]+, 355 (54) [M]+, 340
(30), 313 (23), 312 (100), 238 (17), 206 (12), 139 (10), 121 (10), 73
(40), 32 (10).
{3-(4-Methoxyphenyl)-5-[4-(pyrrolidin-1-yl)phenyl]isoxazol-4-
yl}(thiophen-2-yl)methanone (5m)
Yellow crystals; mp 141 °C.
1H NMR (300 MHz, CDCl3): d = 1.96–2.01 (m, 4 H), 3.25–3.31 (m,
4 H), 3.78 (s, 3 H), 6.48 (d, 3J = 8.8 Hz, 2 H), 6.86 (d, 3J = 8.6 Hz,
2 H), 6.87–6.92 (m, 1 H), 7.36–7.41 (m, 1 H), 7.55–7.64 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 25.4 (2 × CH2), 47.4 (2 × CH2),
55.2 (CH3), 111.0 (Cq), 111.4 (2 × CH), 113.3 (Cq), 114.1 (2 × CH),
121.0 (Cq), 128.3 (CH), 128.8 (2 × CH), 129.5 (2 × CH), 135.34
(CH), 135.39 (CH), 144.7 (Cq), 149.2 (Cq), 160.7 (Cq), 161.2 (Cq),
169.8 (Cq), 183.7 (Cq).
HRMS: m/z calcd for C20H25NO3Si: 355.1604; found: 355.1617.
[5-n-Butyl-3-(4-methoxyphenyl)isoxazol-4-yl](thiophen-2-
yl)methanone (5j)
Yellow resin.
MS (EI, 70 eV): m/z (%) = 420 (15) [M + H]+, 419 (58) [M]+, 340
(94), 281 (44), 191 (16), 170 (15), 139 (36), 111 (100), 74 (16), 41
(24), 40 (29), 39 (47).
1H NMR (300 MHz, CDCl3): d = 0.89 (t, 3J = 7.4 Hz, 3 H), 1.36 (m,
2 H), 1.73 (q, 3J = 7.6 Hz, 2 H), 2.86 (t, 3J = 7.4 Hz, 2 H), 3.77 (s,
3
3
3 H), 6.83 (d, J = 8.9 Hz, 2 H), 6.96 (dd, J = 4.9, 3.9 Hz, 1 H),
7.31 (dd, 3J = 3.9 Hz, 4J = 1.1 Hz, 1 H), 7.49 (d, 3J = 8.9 Hz, 2 H),
7.64 (dd, 3J = 4.9 Hz, 4J = 1.1 Hz, 1 H).
Anal. Calcd for C25H22N2O3S: C, 69.75; H, 5.15; N, 6.51. Found:
C, 69.44; H, 5.29; N, 6.39.
13C NMR (75 MHz, CDCl3): d = 13.6 (CH3), 22.2 (CH2), 26.4
(CH2), 29.6 (CH2), 55.3 (CH3), 114.1 (2 × CH), 115.1 (Cq), 120.6
(Cq), 128.2 (CH), 129.8 (2 × CH), 135.1 (CH), 135.3 (CH), 144.2
(Cq), 160.5 (Cq), 160.8 (Cq), 175.3 (Cq), 182.1 (Cq).
[3-(4-Methoxyphenyl)-5-(4-nitrophenyl)isoxazol-4-yl](thio-
phen-2-yl)methanone (5n)
Colorless crystals; mp 139 °C.
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Three-Component Coupling–Cycloaddition Isoxazole Synthesis
301
1H NMR (300 MHz, CDCl3): d = 3.80 (s, 3 H), 6.89 (d, 3J = 8.9 Hz,
MS (EI, 70 eV): m/z (%) = 422 (33), 421 (100) [M]+, 420 (20), 357
(20), 356 (36), 163 (19), 135 (18), 133 (11), 121 (18).
3
3
2 H), 6.96 (dd, J = 4.7, 3.9 Hz, 1 H), 7.37 (dd, J = 3.9, 1.0 Hz,
3
3
1 H), 7.60 (d, J = 8.7 Hz, 2 H), 7.70 (dd, J = 4.9, 1.0 Hz, 1 H),
HRMS: m/z calcd for C23H19NO5S: 421.0984; found: 421.0985.
7.96 (d, 3J = 8.7 Hz, 2 H), 8.27 (d, 3J = 8.9 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 55.3 (CH3), 114.4 (2 × CH), 116.1
(Cq), 119.8 (Cq), 124.2 (2 × CH), 128.3 (2 × CH), 128.8 (CH),
129.6 (2 × CH), 132.2 (Cq), 136.0 (CH), 136.8 (CH), 143.8 (Cq),
148.8 (Cq), 161.3 (Cq), 161.6 (Cq), 165.9 (Cq), 182.3 (Cq).
MS (EI, 70 eV): m/z (%) = 408 (11), 407 (27), 406 (100) [M]+, 378
(15), 377 (13), 216 (11), 162 (14), 151 (15), 150 (11), 113 (11), 112
(10), 111 (100), 104 (10).
[3-(4-Methoxyphenyl)-5-(10-methyl-10H-phenothiazin-3-
yl)isoxazol-4-yl](thiophen-2-yl)methanone (5r)
Orange crystals; mp 172 °C.
1H NMR (300 MHz, CDCl3): d = 3.30 (s, 3 H), 3.76 (s, 3 H), 6.68–
6.77 (m, 2 H), 6.83–6.95 (m, 4 H), 7.05–7.17 (m, 2 H), 7.36 (dd,
3J = 3.8, 1.1 Hz, 1 H), 7.48–7.63 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 35.3 (CH3), 55.1 (CH3), 112.9
(Cq), 113.8 (CH), 114.1 (2 × CH), 114.3 (CH), 120.4 (Cq), 120.6
(Cq), 122.3 (Cq), 123.0 (CH), 123.9 (Cq), 125.5 (CH), 126.99 (CH),
127.07 (CH), 127.6 (CH), 128.4 (CH), 129.5 (2 × CH), 135.6 (CH),
135.9 (CH), 144.1 (Cq), 144.4 (Cq), 147.8 (Cq), 160.8 (Cq), 161.2
(CH), 167.8 (Cq), 182.9 (Cq).
MS (EI, 70 eV): m/z (%) = 497 (19), 496 (63) [M]+, 241 (17), 240
(100), 239 (15), 224 (13), 216 (28), 213 (22), 212 (73), 210 (13),
197 (25), 196 (19), 153 (11), 111 (11).
HRMS: m/z calcd for C21H14N2O5S: 406.0623; found: 406.0613.
Anal. Calcd for C21H14N2O5S: C, 62.06; H, 3.47; N, 6.89. Found:
C, 61.90; H, 3.59; N, 6.75.
[3,5-Bis(4-methoxyphenyl)isoxazol-4-yl](thiophen-2-yl)meth-
anone (5o)
Colorless crystals; mp 138 °C.
1H NMR (300 MHz, CDCl3): d = 3.78 (s, 3 H), 3.80 (s, 3 H), 6.84–
6.93 (m, 5 H), 7.36 (dd, 3J = 3.9, 1.2 Hz, 1 H), 7.60 (d, 3J = 8.9 Hz,
2 H), 7.61 (dd, 3J = 4.9, 1.1 Hz, 1 H), 7.71 (d, 3J = 9.0 Hz, 2 H).
HRMS: m/z calcd for C28H20N2O3S2: 496.0915; found: 496.0925.
{3-(4-Methoxyphenyl)-5-[(tetrahydro-2H-pyran-2-yloxy)meth-
yl]isoxazol-4-yl}(thiophen-2-yl)methanone (5s)
Colorless crystals; mp 133 °C.
13C NMR (75 MHz, CDCl3): d = 55.3 (CH3), 55.4 (CH3), 112.8
(Cq), 114.2 (2 × CH), 114.4 (2 × CH), 119.3 (Cq), 120.6 (Cq), 128.5
(CH), 129.1 (2 × CH), 129.6 (2 × CH), 135.7 (CH), 135.9 (CH),
144.4 (Cq), 160.9 (Cq), 161.3 (Cq), 161.6 (Cq), 168.7 (Cq), 183.2
(Cq).
MS (EI, 70 eV): m/z (%) = 391 (36) [M]+, 216 (15), 136 (11), 135
(100), 111 (21), 77 (12), 59 (11).
1H NMR (300 MHz, CDCl3): d = 1.40–1.71 (m, 6 H), 3.41–3.49 (m,
1 H), 3.41–3.49 (m, 1 H), 3.62–3.71 (m, 1 H), 3.76 (s, 3 H), 4.60–
4.68 (s, 2 H), 4.83 (d, 3J = 13.7 Hz, 1 H), 6.84 (d, 3J = 8.9 Hz, 2 H),
3
3
7.00 (dd, J = 4.9, 3.9 Hz, 1 H), 7.43 (dd, J = 3.8, 1.1 Hz, 1 H),
7.53 (d, 3J = 8.9 Hz, 2 H), 7.67 (dd, 3J = 4.9, 1.1 Hz, 1 H).
HRMS: m/z calcd for C22H17NO4S: 391.0878; found: 391.0871.
13C NMR (75 MHz, CDCl3): d = 18.5 (CH2), 25.1 (CH2), 29.8
(CH2), 55.2 (CH3), 59.1 (CH2), 61.6 (CH2), 98.4 (CH), 114.1
(2 × CH), 116.5 (Cq), 120.1 (Cq), 128.2 (CH), 129.6 (2 × CH), 135.3
(CH), 135.6 (CH), 144.3 (Cq), 160.4 (Cq), 160.9 (Cq), 169.7 (Cq),
181.3 (Cq).
MS (EI, 70 eV): m/z (%) = 400 (22) [M + H]+, 343 (12), 315 (13),
300 (12), 299 (59), 298 (97), 286 (16), 271 (10), 270 (19), 266 (21),
257 (14), 175 (10), 174 (45), 111 (71), 97 (30), 85 (32).
Anal. Calcd for C22H17NO4S: C, 67.50; H, 4.38; N, 3.58. Found:
C, 67.28; H, 4.44; N, 3.55.
[5-(4-Chlorophenyl)-3-(4-methoxyphenyl)isoxazol-4-yl](thio-
phen-2-yl)methanone (5p)
Colorless crystals; mp 126 °C.
1H NMR (300 MHz, CDCl3): d = 3.79 (s, 3 H), 6.88 (d, 3J = 8.9 Hz,
2 H), 6.93 (dd, 3J = 4.9, 3.8 Hz, 1 H), 7.34–7.40 (m, 3 H), 7.65 (dd,
HRMS: m/z calcd for C21H21NO5S: 399.1140; found: 399.1115.
3
3
3J = 4.9, 1.1 Hz, 1 H), 7.59 (d, J = 8.9 Hz, 2 H), 7.70 (d, J =
8.7 Hz, 2 H).
Anal. Calcd for C21H21NO5S: C, 63.14; H, 5.30; N, 3.51. Found:
C, 62.93; H, 5.45; N, 3.44.
13C NMR (75 MHz, CDCl3): d = 55.2 (CH3), 114.3 (2 × CH), 114.4
(Cq), 120.2 (Cq), 125.1 (Cq), 128.5 (CH), 128.6 (2 × CH), 129.3
(2 × CH), 129.5 (2 × CH), 135.8 (CH), 136.3 (CH), 137.1 (Cq),
144.0 (Cq), 161.0 (Cq), 161.4 (CH), 167.4 (Cq), 182.7 (Cq).
MS (EI, 70 eV): m/z (%) = 397 (16) [37Cl: M]+, 396 (10) [M + H]+,
395 (47) [35Cl – M]+, 244 (14), 220 (11), 216 (36), 149 (10), 141
(23), 139 (70), 113 (13), 111 (100).
[5-n-Butyl-3-(4-nitrophenyl)isoxazol-4-yl](4-nitrophenyl)meth-
anone (5t)
Colorless crystals; mp 97 °C.
3
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 7.3 Hz, 3 H), 1.30–
1.43 (m, 2 H), 1.76 (q, 3J = 7.6 Hz, 2 H), 2.90 (t, 3J = 7.4 Hz, 2 H),
6.71 (d, 3J = 8.9 Hz, 2 H), 7.25 (d, 3J = 8.9 Hz, 2 H), 7.74 (d,
3J = 8.9 Hz, 2 H), 8.07 (d, 3J = 8.9 Hz, 2 H).
HRMS: m/z calcd for C21H14ClNO3S: 395.0383; found: 395.0395.
13C NMR (75 MHz, CDCl3): d = 14.1 (CH3), 22.3 (CH2), 27.8
(CH2), 30.1 (CH2), 114.0 (2 × CH), 114.8 (Cq), 119.3 (Cq), 123.4
(2 × CH), 130.0 (2 × CH), 130.2 (2 × CH), 142.4 (Cq), 150.3 (Cq),
160.8 (Cq), 161.1 (Cq), 178.5 (Cq).
MS (EI, 70 eV): m/z (%) = 395 (100) [M]+, 366 (27), 245 (19), 150
(68), 85 (12), 28 (11).
Anal. Calcd for C21H14ClNO3S: C, 67.50; H, 4.38; N, 3.58. Found:
C, 67.44; H, 4.59; N, 3.56.
[5-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)isoxazol-4-
yl](thiophen-2-yl)methanone (5q)
Colorless crystals; mp 151 °C.
1H NMR (300 MHz, CDCl3): d = 3.74 (s, 3 H), 3.78 (s, 3 H), 3.84
(s, 3 H), 6.80–6.90 (m, 4 H), 7.23 (d, 4J = 2.0 Hz, 1 H), 7.30–7.37
(m, 2 H), 7.55–7.61 (m, 3 H).
Anal. Calcd for C20H17N3O6: C, 60.76; H, 4.33; N, 10.63. Found:
C, 60.39; H, 4.47; N, 10.46.
13C NMR (75 MHz, CDCl3): d = 55.1 (CH3), 55.72 (CH3), 55.76
(CH3), 110.1 (CH), 111.0 (CH), 112.8 (Cq), 114.1 (2 × CH), 119.1
(Cq), 120.4 (Cq), 120.8 (CH), 128.4 (CH), 129.4 (2 × CH), 135.5
(CH), 135.8 (CH), 144.2 (Cq), 148.9 (Cq), 151.0 (Cq), 160.8 (CH),
161.2 (Cq), 168.4 (Cq), 183.1 (Cq).
(5-n-Butyl-3-p-tolylisoxazol-4-yl)(thiophen-2-yl)methanone
(5u)
Yellow resin.
3
1H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 7.4 Hz, 3 H), 1.29–
1.42 (m, 2 H), 1.66–1.79 (m, 2 H), 2.30 (s, 3 H), 2.86 (t,
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B. Willy et al.
PAPER
3J = 7.9 Hz, 2 H), 6.93 (dd, 3J = 4.9, 3.8 Hz, 1 H), 7.11 (d,
3J = 8.3 Hz, 2 H), 7.29 (dd, 3J = 3.8, 1.2 Hz, 1 H), 7.43 (d,
3J = 8.3 Hz, 2 H), 7.62 (dd, 3J = 4.9, 1.2 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.5 (CH3), 21.3 (CH3), 22.2
(CH2), 26.3 (CH2), 29.5 (CH2), 115.2 (Cq), 125.3 (Cq), 128.2
(2 × CH), 128.1 (CH), 129.3 (2 × CH), 135.0 (CH), 135.1 (CH),
139.9 (Cq), 144.1 (Cq), 160.8 (Cq), 175.3 (Cq), 182.0 (Cq).
Acknowledgment
Financial support of the Fonds der Chemischen Industrie and the
Dr.-Otto-Röhm Gedächtnisstiftung is gratefully acknowledged. We
also cordially thank Mario Altendorfer for experimental assistance,
CEM for a research cooperation, and BASF AG for the generous
donation of chemicals.
MS (EI, 70 eV): m/z (%) = 326 (21) [M + H]+, 325 (92) [M]+, 324
(21), 296 (22), 283 (15), 241 (10), 212 (21), 111 (100) [C4H3SCO]+.
References
HRMS: m/z calcd for C19H19NO2S: 325.1136; found: 325.1115.
(1) For a review, see: Carlsen, L.; Döpp, D.; Döpp, H.; Duus, F.;
Hartmann, H.; Lang-Fugmann, S.; Schulze, B.; Smalley, R.
K.; Wakefield, B. J. In Houben-Weyl, Methods in Organic
Chemistry, Vol. E8a; Schaumann, E., Ed.; Georg Thieme
Verlag: Stuttgart, Germany, 1992, 45–204.
[5-n-Butyl-3-(3,4-dimethoxyphenyl)isoxazol-4-yl](thiophen-2-
yl)methanone (5v)
Colorless crystals; mp 147 °C.
(2) Rowley, M.; Broughton, H. B.; Collins, I.; Baker, R.; Emms,
F.; Marwood, R.; Patel, S.; Ragan, C. I. J. Med. Chem. 1996,
39, 1943.
(3) Frolund, B.; Jorgensen, A. T.; Tagmose, L.; Stensbol, T. B.;
Vestergaard, H. T.; Engblom, C.; Kristiansen, U.; Sanchez,
C.; Krogsgaard-Larsen, P.; Liljefors, T. J. Med. Chem. 2002,
45, 2454.
(4) Daidone, G.; Raffa, D.; Maggio, B.; Plescia, F.; Cutuli, V.
M. C.; Mangano, N. G.; Caruso, A. Arch. Pharm. Pharm.
Med. Chem. 1999, 332, 50.
(5) (a) Talley, J. J. Prog. Med. Chem. 1999, 13, 201. (b)Talley,
J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C.
M.; Masferrer, J. L.; Perkins, W. E.; Rogers, R. S.; Shaffer,
A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K. J. Med.
Chem. 2000, 43, 775.
3
1H NMR (300 MHz, CDCl3): d = 0.84 (t, J = 7.3 Hz, 3 H), 1.26–
3
1.38 (m, 2 H), 1.63–1.74 (m, 2 H), 2.84 (t, J = 7.4 Hz, 2 H), 3.73
(s, 3 H), 3.80 (s, 3 H), 6.74 (d, 3J = 8.2 Hz, 1 H), 6.92 (dd, 3J = 4.9,
3
3.8 Hz, 1 H), 7.05–7.12 (s, 2 H), 7.27 (dd, J = 3.8, 1.1 Hz, 1 H),
7.61 (dd, 3J = 4.9, 1.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.4 (CH3), 22.1 (CH2), 26.2
(CH2), 29.5 (CH2), 55.7 (2 × CH3), 110.9 (CH), 111.0 (CH), 115.0
(Cq), 120.6 (Cq), 121.3 (CH), 128.2 (CH), 135.0 (CH), 135.1 (CH),
144.1 (Cq), 148.8 (Cq), 150.2 (Cq), 160.4 (Cq), 175.4 (Cq), 182.1
(Cq).
MS (EI, 70 eV): m/z (%) = 372 (19) [M + H]+, 371 (100) [M]+, 287
(10), 162 (11), 111 (29).
HRMS: m/z calcd for C20H21NO4S: 371.1191; found: 371.1215.
(6) Giovannoni, M. P.; Vergelli, C.; Ghelardini, C.; Galeotti, N.;
Bartolini, A.; Kal Piaz, V. J. Med. Chem. 2003, 46, 1055.
(7) 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, 1706.
(8) For a recent review, see: Wakefield, B. J. In Science of
Synthesis: Houben–Weyl Methods of Molecular
Transformations, Vol. 11; Schaumann, E., Ed.; Georg
Thieme Verlag: Stuttgart, Germany, 2001, 229.
(9) Bandiera, T.; Grünanger, P.; Albini, F. M. J. Heterocycl.
Chem. 1992, 29, 1423.
[3-(Anthracen-9-yl)-5-n-butylisoxazol-4-yl](thiophen-2-
yl)methanone (5w)
Colorless crystals; mp 112 °C.
1H NMR (500 MHz, CDCl3): d = 1.00 (t, 3J = 7.4 Hz, 3 H), 1.51 (m,
2 H), 1.93 (q, 3J = 7.6 Hz, 2 H), 3.14 (t, 3J = 7.4 Hz, 2 H), 6.40 (dd,
3J = 4.9, 3.9 Hz, 1 H), 6.95 (dd, 3J = 3.9 Hz, 4J = 1.1 Hz, 1 H), 7.22
3
4
(dd, J = 4.9 Hz, J = 1.1 Hz, 1 H), 7.41–7.50 (m, 4 H), 7.89–7.97
(m, 4 H), 8.43 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 13.7 (CH3), 22.5 (CH2), 26.8
(CH2), 29.7 (CH2), 118.8 (Cq), 121.6 (Cq), 125.2 (CH), 125.3 (CH),
126.9 (CH), 129.3 (CH), 130.9 (Cq), 130.9 (Cq), 133.1 (CH), 134.1
(CH), 143.1 (Cq), 159.1 (Cq), 176.7 (Cq), 181.2 (Cq).
MS (EI, 70 eV): m/z (%) = 411 (100) [M]+, 327 (15), 219 (14), 194
(13), 111 (26), 32 (11), 28 (39).
(10) Cuadrado, P.; Gonzalez-Nogal, A. M.; Valero, R.
Tetrahedron 2002, 58, 4975.
(11) Vicentini, C. B.; Verones, A. C.; Poli, T.; Guarneri, M.;
Giori, P.; Ferretti, V. J. Heterocycl. Chem. 1990, 27, 1481.
(12) He, Y.; Lin, N.-H. Synthesis 1994, 989.
HRMS: m/z calcd for C26H21NO2S: 411.1293; found: 411.1303.
(13) (a) Barber, G. N.; Olofson, R. A. J. Org. Chem. 1978, 43,
3015. (b) Nitz, T. J.; Volkots, D. L.; Aldous, D. J.; Oglesby,
R. C. J. Org. Chem. 1994, 59, 5828.
(4-Methoxyphenyl)[5-n-propyl-3-(thiophen-2-yl)isoxazol-4-
yl]methanone (5x)
Colorless crystals; mp 152 °C.
(14) (a) Denmark, S. E.; Kallemeyn, J. M. J. Org. Chem. 2005,
70, 2839. (b) Jaeger, V.; Colinas, P. A. Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products, In Chemistry of
Heterocyclic Compounds, Vol. 59; Padwa, A.; Pearson, W.
H., Eds.; Wiley: Hoboken, 2002, 361.
(15) (a) Müller, T. J. J. In Targets in Heterocyclic Systems, Vol.
10; Attanasi, O. A.; Spinelli, D., Eds.; Società Chimica
Italiana: Rome, 2006, 54. (b) Müller, T. J. J. Chimica Oggi/
Chemistry Today 2007, 25, 70.
(16) For a recent review on multi-component synthesis of
heterocycles by transition-metal catalysis, see: D’Souza, D.
M.; Müller, T. J. J. Chem. Soc. Rev.; 2007, 36, 1095.
(17) Rotaru, A. V.; Druta, I. D.; Oeser, T.; Müller, T. J. J. Helv.
Chim. Acta 2005, 88, 1798.
1H NMR (300 MHz, CDCl3): d = 0.90 (t, 3J = 7.3 Hz, 3 H), 1.70 (s,
3
2 H), 2.68 (t, 3J = 7.4 Hz, 2 H), 3.88 (s, 3 H), 6.75 (d, J = 4.0 Hz,
1 H), 6.92 (d, 3J = 8.8 Hz, 2 H), 7.01 (d, 3J = 4.0 Hz, 1 H), 7.80 (d,
3J = 8.8 Hz, 2 H), 8.08–8.14 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 13.6 (CH3), 20.9 (CH2), 28.6
(CH2), 55.6 (CH3), 114.0 (Cq), 114.1 (2 × CH), 126.6 (CH), 127.8
(Cq), 128.9 (CH), 130.3 (Cq), 132.1 (2 × CH), 155.2 (Cq), 164.4
(Cq), 174.9 (Cq), 188.2 (Cq).
MS (EI, 70 eV): m/z (%) = 328 (11) [M + H]+, 327 (100) [M]+, 266
(10), 151 (11), 79 (29).
Anal. Calcd for C18H17NO3S: C, 66.03; H, 5.23; N, 4.28. Found:
C, 65.99; H, 5.54; N, 4.12.
Synthesis 2008, No. 2, 293–303 © Thieme Stuttgart · New York

PAPER
Three-Component Coupling–Cycloaddition Isoxazole Synthesis
303
(18) Toda, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1977,
777.
Cambridge Crystallographic Data Centre as supplementary
publication nos. CCDC-661680 (5w), and CCDC-661681
(6a). Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [Fax: +44(1223)336033; E–mail:
(19) (a) Karpov, A. S.; Müller, T. J. J. Org. Lett. 2003, 5, 3451.
(b) Karpov, A. S.; Müller, T. J. J. Synthesis 2003, 2815.
(c) Karpov, A. S.; Merkul, E.; Rominger, F.; Müller, T. J. J.
Angew. Chem. Int. Ed. 2005, 44, 6951. (d) Karpov, A. S.;
Merkul, E.; Rominger, F.; Müller, T. J. J. Eur. J. Org. Chem.
2006, 2991.
(20) For important reviews on 1,3-dipolar cycloadditions, see:
(a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
(b) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; John
Wiley & Sons: New York, 1984.
deposit@ccdc.cam.ac.uk].
(22) Becker, H. G. O.; Beckert, R.; Domschke, G.; Fanghänel, E.;
Habicher, W. D.; Metz, P.; Pavel, D.; Schwetlick, K.
Organikum; Wiley-VCH: Weinheim, New York,
Chichester, Brisbane, Singapore, Toronto, 2001, 21st ed.
(23) (a) Liu, K.-C..; Shelton, R. B.; Howe, R. K. J. Org. Chem.
1980, 45, 3916. (b) Shaw, K. N.F.; McMillan, A.;
Gudmundson, A. G.; Armstrong, M. D. J. Org. Chem. 1958,
23, 1171.
(21) Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Synthesis 2008, No. 2, 293–303 © Thieme Stuttgart · New York