Facile consecutive three-component synthesis of 3,5-disubstituted isoxazoles

Article abstract of DOI:10.1007/s10593-017-2069-x

[Figure not available: see fulltext.] 3,5-Di(hetero)aryl-substituted isoxazoles can be rapidly synthesized in a one-pot fashion by a consecutive three-component alkynylation–cyclization sequence starting from (hetero)aroyl chloride, alkynes, and sodium azide/acetic acid under copper-free palladium catalysis as exemplified by 9 different products.

Full text of DOI:10.1007/s10593-017-2069-x

DOI 10.1007/s10593-017-2069-x
Chemistry of Heterocyclic Compounds 2017, 53(4), 422–429
Facile consecutive three-component synthesis
of 3,5-disubstituted isoxazoles
1
1
Christina Görgen , Thomas J. J. Müller *
1
Institut für Organische Chemie und Makromolekulare Chemie,
Heinrich-Heine-Universität Düsseldorf,
Universitätsstrasse 1, Düsseldorf D-40225, Germany;
e-mail: ThomasJJ.Mueller@hhu.de
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted December 23, 2016
Accepted January 23, 2017
2
017, 53(4), 422–429
3
,5-Di(hetero)aryl-substituted isoxazoles can be rapidly synthesized in a one-pot fashion by a consecutive three-component alkynylation–
cyclization sequence starting from (hetero)aroyl chloride, alkynes, and sodium azide/acetic acid under copper-free palladium catalysis as
exemplified by 9 different products.
Keywords: alkynes, isoxazoles, azidation, copper-free alkynylation, cyclization, multicomponent reactions.
8
Isoxazole is a constitutional isomer of oxazole and
despite the general importance of isoxazoles in various
which are used as pharmaceuticals, e.g., the antibiotic
sulfamethoxazole, the nonsteroidal anti-inflammatory drug
1–3
9
applications that have been reviewed its core structure is
relatively seldom found in nature. Ibotenate, an α-amino
acid, and its biogenic amine, muscimol (Fig. 1), naturally
occur in Amanita muscaria, the fly agaric, and the latter
represents the principal psychoactive constituent of this
mushroom. As a conformationally fixed analog of γ-amino-
butyric acid (GABA) muscimol acts as an agonist for
isoxicam, and immunosuppressive drug leflunomide. An
API containing a 3,5-diaryl-substituted isoxazole moiety as
a side chain of echinocandin-derived cyclic lipopeptide is the
®
antifungal drug micafungin (Mycamine ) against Candida-
and Aspergillus-caused dermatomycosis. In fact, the anti-
mycotic effect and toxicity are determined by the 3,5-diaryl-
isoxazole motif.1
0–12
As a consequence of the relevance of
GABA
A
receptors, displaying powerful neurotoxicity
biologically active isoxazoles and their application in orga-
4–7
13,14
ranging from sedative-hypnotic to hallucinogenic effects.
nic synthesis and natural product synthesis
the develop-
Despite its rare occurrence in natural products isoxazole
motif is found in many biologically active compounds,
ment of isoxazole syntheses has remained unabatedly
important and numerous approaches evolved.1
–3,15,16
Figure 1. Naturally occurring isoxazoles (ibotenate and muscimol) and isoxazole derivatives as pharmaceuticals (sulfamethoxazole,
isoxicam, leflunomide, micafungin).
0
009-3122/17/53(04)-0422©2017 Springer Science+Business Media New York
422

Chemistry of Heterocyclic Compounds 2017, 53(4), 422–429
In the past decade, we have conceptualized consecutive
3
Scheme 1. Cyclization of alkynone 1, NaN , and AcOH
to give isoxazole 2a
multicomponent syntheses of heterocycles based upon the
catalytic formation of alkynones as central intermediates.1
In particular, modified conditions of the Sonogashira
alkynylation employing only one stoichiometrically
7–20
necessary equivalent of NEt
access to alkynones under mild reaction conditions.
3
enabled a straightforward
21,22
For
accessing isoxazoles, we also employed alkynones, how-
ever, not as Michael acceptors but as dipolarophiles, in
coupling – 1,3-dipolar cycloaddition sequences to give 4-acyl-
isoxazoles with a broad substitution pattern in a one-pot
fashion.2
Table 1. Isoxazole 2a cyclization reaction
conditions optimization
3,24
Entry
Solvent
Reaction time, h
Yield*, %
One-pot transformations of alkynones into isoxazoles
upon cyclocondensation with hydroxylamine as a binucleo-
1
DCM
DCM
6–10
Not isolated**
philic component have already been exemplified by two
2***
6–10
Not isolated**
different routes.2
5,26
However, we reasoned that the
3
4
THF
4
4
4
72
69
69
Michael addition of azide anions under acidic conditions
1,4-Dioxane
1,4-Dioxane
might lead to β-azidoalkenones, intermediates known to
5
***
undergo cyclization to isoxazoles upon nitrogen extru-
sion.2
7,28
β-Azidoalkenoates were found to preferentially
* Isolated yield after chromatography on silica gel.
* Incomplete conversion (as monitored by TLC).
*** In the absence of NEt .
29
*
form 3-alkoxycarbonyl-3H-azirines upon photolysis or
thermolysis,30 and only in the presence of α-ester
3
substitution in β-azidoalkenoates 5-ethoxyisoxazoles are
formed.31 Indeed, the transformation of alkynones and
hydrazoic acid within 2–6 days to furnish 3,5-disubstituted
isoxazoles was reported by Türck and Behringer already in
Scheme 2. Attempted concatenation of alkynylation
and cyclization under modified Sonogashira conditions
1
965.32 However, hydrazoic acid cannot be considered to
be a safe reactant in this context and, furthermore, the
implementation of hydrazoic acid surrogates, such as
TMSN
3
/AcOH or NaN
3
/AcOH, never has been probed in
catalytic alkynone
the context of concatenating
a
formation, azidation, and cyclization to isoxazoles in a one-
pot fashion. Therefore, we report the development of a
three-component coupling–azidation–cyclization sequence
to furnish isoxazoles in a consecutive one-pot reaction.
First screening reactions indicated that alkynones react
with TMSN
than by simple Michael addition furnishing the proposed
azidoalkenone intermediates. Also with NaN /AcOH the
3
/AcOH rather by formation of the isoxazole
Essentially the same result was obtained upon employing
TMSN as an azide source furnishing enaminone 5a in
3
3
42% yield. Independently, starting from alkynone 1 in the
presence of catalytic amounts of Pd and Cu catalysts
furnished enaminone 5a in 47% yield. However,
performing the same reaction only in the presence of the Pd
catalyst, i.e., a Cu-free variation, gave rise to the formation
of isoxazole 2a in 77% yield.
isoxazole was the only obtained reaction product. Neither
increasing reaction temperature under conductive nor
dielectric heating affected the yield of formation of
isoxazoles. Therefore, we first performed an optimization
study for the cyclization step starting from alkynone 1,
NaN
3
, and AcOH as reactants by variation of the solvent
For excluding a Cu-catalyzed ring opening–reduction of
isoxazole 2a after its formation, we reacted isoxazole 2a in
system and reaction times to furnish isoxazole 2a
(
Scheme1, Table 1).
the presence of both catalysts, NaN
3
, AcOH, and catalytic
DCM as a solvent was not effective in comparison to THF
amounts of NEt in THF. Indeed isoxazole 2a remained
3
or 1,4-dioxane. Interestingly, after 4 h, a complete conver-
unchanged and no formation of enaminone 5a was
observed.
sion of alkynone 1 was detected, regardless if a catalytic
amount of NEt
3
was present or not (Table 1, entries 4 and 5).
Although azides have been shown to remain untouched
Based upon this quick optimization of the cyclization
under Sonogashira conditions in the presence of NEt for
3
3
3
the concatenation with the modified Sonogashira
short reaction times in THF at room temperature it was
demonstrated that Cu-mediated Ullmann type arylations of
conditions2
1,22
to give isoxazole 2a was attempted by
generation of alkynone 1 from p-methoxybenzoyl chloride
aryl bromide with NaN
3
furnished the corresponding
34
(
3a) and 1-hexyne (4a) in the presence of catalytic amounts
anilines as products at elevated temperatures in DMSO.
of Pd and Cu catalysts. Indeed the reaction product was not
A closer inspection revealed that Cu(I) complexes were
necessary to promote the azidation–reduction.35 Several
related Cu-catalyzed coupling–reduction sequences gave
the expected isoxazole 2a but enaminone 5a was isolated in
59% yield (Scheme 2).
4
23

Chemistry of Heterocyclic Compounds 2017, 53(4), 422–429
Scheme 3. Mechanistic rationale for the Cu(I)-catalyzed azidation–reduction of alkynones
rise to similar results,36–38 however, the reduction agent was
never unambiguously identified. Further studies employing
this simultaneously liberates the enaminone product 5a and
reconstitutes the catalytically active Cu(I) species by
coordination of an azide anion.
TMSN as a nitrogen source indicated that the presence of
3
protic solvents such as 2-aminoethanol was responsible for
Therefore, we decided to opt for a Cu-free alkynylative
coupling of the acid chloride. Recently, we were able to
3
9
the successful reduction. This was additionally supported
by Ullmann azidation–reduction of aryl bromides with
disclose straightforward Cu-free alkynylation based on
Beller's cataCXium® ABn ligand system,4
1–44
which was
NaN
3
using Cu powder in the presence of 2-amino-
40
ethanol. Detailed FTIR studies furthermore indicated the
generation and consumption of Cu(I)N as a relevant
successfully implemented in various consecutive multi-
component heterocycle syntheses.4
5–48
Since aliphatic
3
species in the reduction scenario, whereas the presence of
aryl azide only affected the reduction process to a minor
extent.
alkynes, such as 1-hexyne (4a) only sluggishly undergo the
Cu-free alkynylation (alkynone 1 was formed in DCM in
16% and 1,4-dioxane in 40% yield), we decided to slightly
alter the test system using phenylacetylene (4b) as an
alkyne component (Scheme 4). As already observed for
attempted coupling–cyclization sequences with 1-hexyne
(4a) in 1,4-dioxane or DCM as solvents, the incomplete
alkynylation caused considerable formation of the
corresponding acyl azide. In 1,4-dioxane as a solvent, acyl
azide 6 was the only isolable compound. However,
changing the solvent to DCM gave an isolated yield of
71% of isoxazole 2b. The subtle influence of the solvent
was additionally underlined by employing 2-chlorobenzoyl
Therefore, we reasoned that the unexpected occurrence
of enaminone 5a can be rationalized as follows (Scheme 3).
In the presence of azide anions, Cu(I) forms a Cu(I)N
3
complex, which loses nitrogen to give a reactive copper
nitride. This complex reacts with alkynone 1, azide ions,
and a proton to formally give a Cu(II) nitrene diazido
complex. Via Cu-mediated decomposition, the two
electrons, formally required for a reduction of a nitrene to
an amine, are generated by nitrogen formation in the
presence of protons. Upon intramolecular electron transfer
Scheme 4. Consecutive three-component Cu-free alkynylation–cyclization synthesis
of isoxazoles 2b (in DCM) and 2c (in 1,4-dioxane and DCM)
4
24

Chemistry of Heterocyclic Compounds 2017, 53(4), 422–429
chloride (3b) and phenylacetylene (4b) as coupling
partners, furnishing comparable yields of isoxazole 2c,
both in 1,4-dioxane and DCM (Scheme 4). The one-pot
process is clearly superior to the stepwise process in DCM,
where the isolated corresponding alkynone (92% yield)
was separately transformed into isoxazole 2c in 63% yield,
giving a combined yield of only 59%.
Scheme 5. Consecutive three-component alkynylation–
cyclization synthesis of isoxazoles 2 and mechanistic rationale
Due to the better operational handling we finally
decided to employ in the most cases 1,4-dioxane as a
solvent in the one-pot sequence. The overall sequence for
the consecutive three-component synthesis of 3,5-disub-
stituted isoxazoles 2 from acid chlorides 3, alkynes 4, and
NaN /AcOH proceeds in moderate to good yields and the
3
tested substrate scope are summarized in Scheme 5 and
Table 2. Mechanistically this novel one-pot sequence can
be rationalized by a Pd-catalyzed alkynylation furnishing
an alkynone, which undergoes an (E)-selective Michael
addition to give an β-azido enone. As shown (Table 1)
already at room temperature the concerted electrocyclization–
nitrogen extrusion directly furnishes isoxazole 2.
Table 2. One-pot alkynylation–cyclization synthesis of isoxazoles 2
Exemplarily, the three carbon resonances of the isoxazole
core of compound 2b (numbering according to the syste-
Isoxazole
Entry
1**
***
3***,*4
Acid chloride
Alkyne
(
yield, %)*
1
13
matic nomenclature of isoxazole) were assigned by H– C
1
2
1
13
3a R = p-MeOC
6
6
4
H
4
4
4a R = n-Bu
2a (10)
HSQC and H– C HMBC spectra. The HSQC spectrum
1
2
2
3a R = p-MeOC
H
4b R = Ph
2b (71)
2c (72)
2d (32)
2e (51)
2f (29)
2g (42)
2h (12)
allows assigning carbon nucleus C-4 at 96.2 ppm via its
1
1
2
J
CH coupling of proton (C-4)-H. The cross peaks of the
CH coupling of (C-4)-H in the HMBC spectra support the
3b R = o-ClC
6
H
4b R = Ph
2
J
*5
1
2
4
5
6
7
8
3c R = 2-thienyl
4b R = Ph
assignment of nuclei C-3 and C-5. In addition nucleus C-5
*5
1
2
3b R = o-ClC
6
H
4
4c R = o-FC
6
H
4
3
at 170.5 ppm displays a JCH coupling with the protons of
1
2
3a R = p-MeOC
6
H
4
4d R = p-MeO
2
CC
6
H
4
the p-anisyl substituent. Therefore, the signal at 63.0 ppm
was assigned to nucleus C-3. All isoxazoles 2, depending
on their substitution pattern display carbon resonces for
nucleus C-3 at 158.5–164.8 ppm, for nucleus C-4 at 93.2–
1
2
3d R = cyclopropyl
4b R = Ph
1
2
3b R = o-ClC H
6
4
4e R = ferrocenyl
*
Isolated yield after chromatography on silica gel.
1
29.3 ppm, and for nucleus C-5 at 165.5–175.4 ppm. For
** The reaction time of the coupling step was 20 h.
*
*
** DCM was used as a solvent.
compound 2e additionally, the C,F-coupling constants were
employed for the assignment of the carbon resonances.
The ESI mass spectra show, besides the molecular
4
The reaction time of the coupling step was 2 h.
After column chromatography the product was recrystallized from EtOAc.
5
*
1
2
peaks, typical cleavages of the substituents R and R from
1
+
Scheme 6. Consecutive three-component activation–alkynylation–
cyclization synthesis of isoxazole 2i
the isoxazole core as well as the [R CO] fragments arising
from a cycloreversion of the isoxazole core of the
molecule's radical cation. The IR spectra of isoxazoles 2
4
9
display good agreement with the literature typical C=N
–1
(1580–1531 cm ) and C=C stretching vibrations (1443–
1
–1
414 cm ) of the isoxazole core.
As a result of this short study on the scope it becomes
apparent that aryl-substituted isoxazoles are generally
formed in higher yield (Table 2, entries 2–6) than aliphatic
(
entries 1, 7) or ferrocenyl derivatives (entry 8). The
relevance of the methodology is underlined by compound
2
f, which affects as a side chain of the antifungal drug
In conclusion, we have established a consecutive three-
component alkynylation–cyclization synthesis of 3,5-di-
substituted isoxazoles starting from the Cu-free catalytic
coupling of acid chlorides (or by in situ activation of a
sodium carboxylate) and terminal alkynes followed by
®
micafungin (Mycamine ) its biological activity.
Finally, we also probed the activation–coupling approach,
particularly developed for accessing alkynones starting
from delicate N-heterocyclic sodium carboxylates for in situ
50
generation of acid chlorides, starting from sodium nicotinate,
activated by reaction with 1.0 equiv of oxalyl chloride,
followed by alkynylation with phenylacetylene (4b) and
cyclization to furnish 3-phenyl-5-(3-pyridyl)isoxazole (2i)
in 51% yield after workup and purification (Scheme 6).
cyclization with NaN /AcOH in a one-pot fashion. This
3
room temperature process is particularly efficient for the
regioselective synthesis of 3,5-di(hetero)aryl-substituted
isoxazoles. Due to their electronical similarity to 3,5-di-
(hetero)aryl-substituted pyrazoles the elucidation of their
4
25

Chemistry of Heterocyclic Compounds 2017, 53(4), 422–429
electronic structure and photophysical properties, as well as
Optimization of the cyclization of alkynone 1 and
the extension of the alkynone-based methodology to
persubstituted isoxazoles, additional studies are currently
underway.
NaN . Alkynone 1 (136 mg, 0.50 mmol) and the
3
corresponding solvent (0.5 ml) were placed under nitrogen
into a screw-cap Schlenk tube with magnetic stir bar (for
experimental details, see Table 1). Then NaN (162 mg,
3
Experimental
2
.50 mmol), AcOH (0.14 ml, 2.50 mmol), and dry NEt
3
IR spectra were obtained on a Shimadzu IRAffinity-1
(8.9 μl, 0.10 mmol) were added, and the reaction mixture
was stirred at the temperature and for the time indicated
(monitored by TLC). Then the solvents were removed
under reduced pressure. The crude product was adsorbed
(
ATR) spectrometer. The intensity of the signals is
abbreviated as following: s (strong), m (medium), w
1
13
1
13
(
weak). H, C, and 135-DEPT NMR, H– C HSQC and
HMBC spectra were recorded on a Bruker AVIII-300 spectro-
meter (300 and 75 MHz, respectively) in CDCl . The
resonances of CDCl were locked as internal standards
®
on Celite and purified by flash chromatography on silica
3
gel (petroleum ether – EtOAc) to give analytically pure
3
isoxazole 2a with the corresponding yield (Table 1), mp
1
13
(
H δ 7.26 ppm, C δ 77.0 ppm). The type of carbon
40°C. R 0.11 (petroleum ether – EtOAc, 30:1). IR spectrum,
f
–1
nucleus was determined on the basis of 135-DEPT NMR
spectra. Mass spectra were measured on a Finnigan MAT
ν, cm : 3121 (w), 3013 (w), 2957 (w), 2936 (w), 2874 (w),
1898 (w), 1614 (m), 1591 (w), 1568 (w), 1512 (m), 1464
(w), 1431 (m), 1416 (w), 1381 (w), 1306 (w), 1287 (w),
1256 (m), 1177 (m), 1113 (w), 1092 (w), 1049 (w), 1022
(s), 945 (w), 899 (w), 835 (s), 799 (s), 768 (w), 745 (w),
8
200 spectrometer (EI, 70 eV). Melting points (uncor-
rected) were measured on a Büchi Melting Point B-540
apparatus. Elemental analyses were carried out on Perkin
Elmer Series II Analyzer 2400 in the Microanalytical
laboratory of the Institut für Pharmazeutische und Medi-
zinische Chemie at the Heinrich-Heine-Universität,
Düsseldorf. All products were purified by column
chromatography on silica gel 60 M (0.04–0.063 mm) from
Machery Nagel GmbH & Co KG using flash technique
under a pressure of 2 bar. The crude mixtures were
absorbed on Celite® 545 (0.02–0.10 mm) from Merck
KGaA Darmstadt before chromatographic purification. The
reaction progress was observed qualitatively by using TLC
Silica gel 60 F254 aluminum sheets. The spots were
detected with UV light at 254 nm.
1
725 (w), 683 (w), 652 (w). H NMR spectrum, δ, ppm
(J, Hz): 0.95 (3H, t, J = 7.3); 1.32–1.52 (2H, m); 1.58–1.80
(2H, m); 2.69 (2H, t, J = 7.7); 3.85 (3H, s); 6.25 (1H, s);
13
6.90–7.04 (2H, m); 7.62–7.78 (2H, m). C NMR spectrum,
δ, ppm: 13.9 (CH
3
); 22.4 (CH
2
); 25.9 (CH
2
); 30.6 (CH );
2
55.5 (CH ); 97.9 (CH); 114.4 (CH); 120.7 (C); 127.4 (CH);
3
161.0 (C); 164.8 (C); 169.6 (C). Mass spectrum, m/z (Irel, %):
+
+
231 [M] (19), 230 (14), 202 [M–C
2
]
H
5
] (8), 190 (13), 189
+
+
[M–C
[C
3
O
H
2
8
]
(100), 174 [M–C
4
H
9
(7), 161 (18), 135
+
+
8
H
7
] (64), 111 (11), 107 [C
7
H
7
O] (10), 97 (17), 95
(11), 85 (23), 83 (16), 81 (11), 77 (16), 71 (28), 69 (18),
57 (38), 55 (21), 43 (27), 41 (18). Found, %: C 72.55;
PdCl
a,b were commercially available and used as supplied. Di-
1-adamantyl)benzylphosphonium bromide (cataCXium®
2
, acid chlorides 3, sodium nicotinate, and alkynes
H 7.21; N 6.22. C14
H 7.41; N 6.06.
H
17NO . Calculated, %: C 72.70;
2
4
(
(Z)-3-Amino-1-(4-methoxyphenyl)hept-2-en-1-one (5a),
ABn·HBr) was prepared recording to literature pro-
cedure.51 Alkynes 4c–e were synthesized by the Sono-
gashira coupling from the corresponding iodides with
consecutive coupling–azide addition conditions. PdCl
2 3 2
(PPh )
(14 mg, 20 mmol) and CuI (8 mg, 40 mmol) were placed
under nitrogen into a screw-cap Schlenk tube with
magnetic stir bar. Then dry THF (2.5 ml), p-methoxy-
benzoyl chloride (3a) (176 mg, 1.0 mmol), 1-hexyne (4a)
(
trimethylsilyl)acetylene followed by subsequent disily-
lation with K CO /MeOH according to literature pro-
1-(4-Methoxyphenyl)hept-2-yn-1-one (1) was
prepared according to our published procedure by modified
2
3
cedures.5
2-54
(0.12 ml, 1.0 mmol), and NEt
successively added, and the reaction mixture was stirred at
room temperature for 1 h (monitored by TLC). Then NaN
(656 mg, 10.0 mmol), AcOH (0.56 ml, 10.0 mmol), and
(0.14 ml, 1.0 mmol) were
3
2
1,22
Sonogashira conditions.
3
Qualitative test on the presence of azide ions. At the
end of the reaction sequence, i.e., after completion of the
cyclization (monitored by TLC), the reaction mixtures were
NEt (17.8 ml, 0.1 mmol) were added, and the reaction
3
mixture was stirred at room temperature for 4 h (monitored
by TLC). Then the solvents were removed under reduced
qualitatively checked for the presence of azide (iodine–
azide reaction).5
5–57
This qualitative test is founded on the
pressure. The crude product was adsorbed on Celite and
®
following two redox reactions:
purified by flash chromatography on silica gel (petroleum
–
(
(
1) S2– + I
2
→ S + 2 I
ether – EtOAc, 5:1 to 3:1). Yield 138 mg (59%), colorless
–
2–
2) S + 2 N
3
→ S + 3 N
2
↑
solid, mp 52°C. R 0.13 (petroleum ether – EtOAc, 3:1).
f
–1
The presence of azide ions in the reaction mixture
causes gas evolution, while the decoloration of the iodine
solution is independent of the presence of azide ions.
IR spectrum, ν,cm : 3285 (w), 3142 (w), 3001 (w), 2959
(w), 2932 (w), 2874 (w), 2859 (w), 2835 (w), 1587 (s),
1566 (m), 1526 (s), 1503 (s), 1454 (w), 1439 (w), 1420
(m), 1406 (w), 1377 (w), 1314 (m), 1302 (m), 1285 (m),
1252 (s), 1217 (m), 1204 (w), 1169 (s), 1103 (m), 1063
(w), 1030 (m), 1005 (w), 968 (w), 862 (w), 845 (m), 773
A spatula tip with ground Na
2
S·H O was placed on a
2
watch glass and a droplet of the reaction mixture was added.
Then a few drops of 2 M ethanolic iodine solution were added.
Evolution of gas bubbles and a decoloration of the iodine
solution were detected. Therefore, not all azide was com-
pletely consumed at the end of the terminal cyclization step.
1
(s), 731 (m), 662 (m), 633 (m), 610 (m). H NMR
spectrum, δ, ppm (J, Hz): 0.94 (3H, t, J = 7.3); 1.31–1.48
(2H, m); 1.51–1.68 (2H, m); 2.18–2.30 (2H, m); 3.84 (3H,
4
26

Chemistry of Heterocyclic Compounds 2017, 53(4), 422–429
s); 5.25 (1H, br. s); 5.71 (1H, s); 6.86–6.96 (2H, m); 7.82–
1420 (w), 1398 (m), 1269 (w), 1213 (w), 1130 (w), 1078
1
3
7
1
.92 (2H, m); 10.20 (1H, br). C NMR spectrum, δ, ppm:
3.9 (CH ); 22.4 (CH ); 30.3 (CH ); 36.8 (CH ); 55.4
); 91.2 (CH); 113.5 (CH); 129.1 (CH); 133.1 (C);
(w), 1032 (m), 949 (m), 916 (w), 810 (w), 758 (s), 733 (m),
1
3
2
2
2
725 (w), 683 (s), 646 (w). H NMR spectrum, δ, ppm: 7.26
(
CH
3
(1H, s); 7.33–7.44 (2H, m); 7.45–7.57 (4H, m); 7.84–7.94
(2H, m); 7.96–8.05 (1H, m). 13C NMR spectrum, δ, ppm:
102.6 (CH); 126.4 (C); 127.0 (CH); 127.4 (CH); 129.1
(CH); 129.2 (Cquat); 129.5 (CH); 130.2 (CH); 131.0 (CH);
131.8 (C); 163.1 (C); 166.7 (C). Mass spectrum, m/z
1
61.9 (C); 166.8 (C); 188.8 (C). Mass spectrum, m/z (Irel, %):
+
+
2
33 [M] (12), 232 (12), 204 [M–C
2
H
5
]
(16), 191
+
+
[
M–C
3
H
6
] (21), 136 (10), 135 [C
8
H
7
O
2
] (100), 96 (12),
8
5 (11), 77 (11), 57 (13), 43 (16). Found, %: C 72.02;
3
7
+
37
+
H 7.91; N 6.24. C14
H 8.21; N 6.00.
H
19NO
2
. Calculated, %: C 72.07;
(Irel, %): 257 [( Cl)–M] (16), 256 (10), 255 [( Cl)–M]
+
(45), 254 (10), 212 (11), 202 (20), 144 [M–C
6
H
4
Cl] (26),
4
H ] (11), 75 (10).
H10ClNO. Calcu-
37
+
35
+
3
,5-Disubstituted isoxazoles 2 (General method, sequential
7
141 [C H
4
( Cl)O] (33), 140 (8), 139 [C
7
H
( Cl)O]
+
three-component conditions). PdCl
and (1-Ad)
2
(3.5 mg, 0.02 mmol)
PBn·HBr (18.9 mg, 0.04 mmol) were placed
(100), 127 (13), 111 (28), 90 (10), 77 [C
6
5
2
Found, %: C 70.57; H 4.06; N 5.54. C15
lated, %: C 70.46; H 3.94; N 5.48.
under an atmosphere of argon into a screw-cap Schlenk
tube with magnetic stir bar. Then dry 1,4-dioxane (2.0 ml),
3-Phenyl-5-(thiophen-2-yl)isoxazole (2d). Purified by
acid chloride 3 (2.00 mmol), alkyne 4 (2.00 mmol), and dry NEt
3
flash chromatography on silica gel (petroleum ether –
(
0.30 ml, 2.20 mmol) were successively added. The reaction
mixture was then stirred at room temperature for 19 h to
complete conversion (monitored by TLC). NaN (656 mg,
0.00 mmol) and glacial AcOH (0.56 ml, 10.00 mmol)
EtOAc, 50:1, R 0.09), recrystallization from EtOAc. Yield
f
143 mg (32%), colorless solid, mp 95°C. IR spectrum,
–1
3
ν, cm : 3115 (w), 3400 (w), 3082 (w), 1601 (w), 1580 (w),
1466 (w), 1443 (w), 1414 (w), 1400 (m), 1360 (w), 1261
(w), 1202 (w), 1184 (w), 1159 (w), 1053 (w), 1022 (w),
949 (w), 907 (w), 849 (m), 833 (w), 810 (w), 764 (s), 708
1
were then added to this reaction mixture. The mixture was
stirred at room temperature for 4 h (monitored by TLC).
CAUTION! Upon releasing nitrogen during the reaction
pressure was built up in the reaction vessel. The reaction
mixture was transferred to a round-bottom flask and the
solvents were carefully removed in vacuo. The crude product
was adsorbed on Celite® and purified by flash
chromatography on silica gel (petroleum ether – EtOAc) to
give the analytically pure isoxazoles 2.
1
(m), 685 (s), 658 (w). H NMR spectrum, δ, ppm (J, Hz):
6.69 (1H, s); 7.13 (1H, dd, J = 3.7, J = 5.0); 7.41–7.52 (4H,
m); 7.55 (1H, dd, J = 1.1, J = 3.7); 7.79–7.89 (2H, m).
13
C NMR spectrum, δ, ppm: 97.4 (CH); 127.0 (CH); 127.2
(CH); 128.1 (CH); 128.2 (CH); 129.0 (CH); 129.0; 129.4
(C); 130.2 (CH); 163.1 (C); 165.5 (C). Mass spectrum, m/z
+
+
(Irel, %): 227 [M] (31), 199 (10), 111 [M–C
8
H
6
N] (50), 44
3
-Butyl-5-(4-methoxyphenyl)isoxazole (2a). Purified
by flash chromatography on silica gel (petroleum ether –
EtOAc, 30:1, R 0.11). Yield 47 mg (10%), light-yellow
(15), 43 (13), 40 (100). Found, %: C 68.93; H 4.04; N 6.11;
S 13.86. C13
H NOS. Calculated, %: C 68.70; H 3.99;
9
f
N 6.16; S 14.11.
solid, mp 40°C. The spectroscopic data was fully consistent
with the analytical data of the previously prepared
compound 2a.
5-(2-Chlorophenyl)-3-(2-fluorophenyl)isoxazole (2e).
Purified by flash chromatography on silica gel (petroleum
ether – EtOAc, 50:1, R 0.13), recrystallization from EtOAc.
f
5
-(4-Methoxyphenyl)-3-phenylisoxazole (2b). Purified
by flash chromatography on silica gel (petroleum ether –
EtOAc, 15:1, R 0.16). Yield 358 mg (71%), colorless
solid, mp 126°C. IR spectrum, ν, cm : 3117 (w), 3003 (w),
967 (w), 2936 (w), 2901 (w), 2839 (w), 1612 (m), 1599
w), 1578 (w), 1518 (w), 1501 (w), 1464 (m), 1441 (w),
418 (w), 1400 (m), 1317 (w), 1306 (w), 1248 (m), 1177
Yield 140 mg (51%), colorless solid, mp 68°C.
–1
IR spectrum, ν, cm : 3204 (w), 3103 (w), 3059 (w), 3028
(w), 2920 (w), 2851 (w), 1620 (w), 1589 (w), 1564 (w),
1514 (w), 1464 (m), 1443 (m), 1422 (w), 1400 (m), 1273
(w), 1258 (w), 1219 (m), 1157 (w), 1107 (w), 1090 (w),
1076 (w), 1034 (m), 955 (m), 856 (w), 816 (w), 806 (m),
f
–
1
2
(
1
1
752 (s), 731 (s), 719 (m), 681 (w), 665 (m). H NMR
spectrum, δ, ppm: 7.15–7.32 (2H, m); 7.33–7.50 (4H, m);
(
m), 1119 (w), 1072 (w), 1032 (m), 949 (m), 926 (m), 841
m), 822 (m), 800 (m), 768 (s), 689 (s), 662 (w), 611 (w).
H NMR spectrum, δ, ppm (J, Hz): 3.85 (3H, s); 6.69 (1H,
13
(
7.50–7.58 (1H, m); 7.94–8.10 (2H, m). C NMR spectrum,
δ, ppm (J, Hz): 105.0 (d, JCF = 9, CH); 116.6 (d, JCF = 22,
CH); 117.3 (d, JCF = 12, C); 124.8 (d, JCF = 4, CH); 126.4
(C); 127.3 (CH); 129.3 (d, JCF = 3, CH); 129.6 (CH); 131.0
(CH); 131.1 (CH); 131.8 (d, JCF = 9, CH); 158.5 (d, JCF = 2,
C); 160.4 (d, JCF = 252, C); 166.7 (d, JCF = 2, C). Mass
+
1
s); 6.93–7.06 (2H, m); 7.39–7.54 (3H, m); 7.71–7.81 (2H,
1
3
m); 7.28–7.93 (2H, m). C NMR spectrum, δ, ppm: 55.5
(
CH
3
); 96.2 (CH); 114.5 (CH); 120.4 (C); 126.9 (CH);
1
1
27.5 (CH); 129.0 (CH); 129.4 (C); 130.0 (CH); 161.2 (C);
37
+
35
63.0 (C); 170.5 (C). Mass spectrum, m/z (Irel, %): 251
spectrum, m/z (Irel, %): 275 [( Cl)–M] (14), 273 [( Cl)–M]
+
+
+
+
+
[
M] (46), 135 [C
8
H
7
O
2
] (100), 77 [C
6
H
5
] (15), 40 (10).
(44); 238 [M–Cl] (10), 162 [M–C
6
H
4
Cl] (18),
3
7
+
35
+
Found, %: C 76.48; H 4.96; N 5.55. C16
lated, %: C 76.48; H 5.21; N 5.57.
H
13NO
2
. Calcu-
141 [C
7
H
4
ClO] (32), 139 [C
7
H ( Cl)O] (100), 113
4
3
7
+
35
+
[C
6
H
4
( Cl)] (7), 111 [C
6
H
4
( Cl)] (22). Found, %:
ClFNO. Calculated, %:
5
-(2-Chlorophenyl)-3-phenylisoxazole (2c). Purified
C 65.57; H 3.31; N 5.07. C15
C 65.83; H 3.31; N 5.12.
H
9
by flash chromatography on silica gel (petroleum ether –
EtOAc, 100:1 to 50:1, R 0.15 (petroleum ether – EtOAc,
0:1)). Yield 370 mg (72%), yellow solid, mp 60°C.
f
Methyl 4-[5-(4-methoxyphenyl)isoxazol-3-yl]benzoate
5
(2f). Purifed by flash chromatography on silica gel
–
1
IR spectrum, ν, cm : 3067 (w), 2920 (w), 2851 (w), 1601
w), 1576 (w), 1522 (w), 1479 (w), 1460 (m), 1447 (m),
(petroleum ether – EtOAc, 10:1 to 5:1, R 0.07 (petroleum
f
(
ether – EtOAc, 10:1)). Yield 178 mg (29%), light-yellow
4
27

Chemistry of Heterocyclic Compounds 2017, 53(4), 422–429
–
1
solid, mp 185°C. IR spectrum, ν, cm : 3115 (w), 3046 (w),
951 (w), 2922 (w), 2841 (w), 2154 (w), 1709 (m), 1653
w), 1601 (m), 1572 (w), 1504 (m), 1470 (w), 1452 (w),
3-Phenyl-5-(pyridin-3-yl)isoxazole (2i), three-component
activation–alkynylation–cyclization conditions. Sodium nico-
tinate (296 mg, 2.00 mmol) and dry 1,4-dioxane (2.0 ml)
were placed under an atmosphere of Ar into a screw-cap
Schlenk tube with magnetic stir bar. Then oxalyl chloride
(0.18 ml, 2.00 mmol) was added dropwise at room
temperature, and the reaction mixture was stirred at room
2
(
1
429 (m), 1389 (w), 1371 (w), 1304 (w), 1277 (s), 1254
(
(
6
s), 1175 (m), 1109 (s), 1018 (m), 962 (w), 949 (m), 918
w), 864 (m), 835 (m), 812 (s), 795 (w), 775 (s), 708 (s),
1
92 (w), 662 (w), 631 (w), 615 (m). H NMR spectrum,
δ, ppm (J, Hz): 3.88 (3H, s); 3.95 (3H, s); 6.75 (1H, s);
temperature for 4 h. Then PdCl
2
(3.5 mg, 0.02 mmol),
6
8
.96–7.06 (2H, m); 7.73–7.83 (2H, m); 7.89–7.99 (2H, m);
(1-Ad) PBn·HBr (18.9 mg, 0.04 mmol), phenylacetylene
2
1
3
.11–8.18 (2H, m). C NMR spectrum, δ, ppm: 52.5
(4b) (0.22 ml, 2.00 mmol), and dry NEt (0.30 ml,
3
(
CH
3
); 55.6 (CH
3
); 96.3 (CH); 114.6 (CH); 120.2 (C);
2.20 mmol) were successively added. The reaction mixture
was then stirred at room temperature for 19 h to complete
1
1
26.9 (CH); 127.6 (CH); 130.3 (CH); 131.4 (C); 133.6 (C);
61.4 (C); 162.2 (C); 166.7 (C); 171.0 (C). Mass spectrum,
conversion (monitored by TLC). NaN (656 mg, 10.00 mmol)
3
+
+
m/z (Irel, %): 309 [M] (46), 294 [M–CH
3
]
(5), 278
and glacial AcOH (0.56 ml, 10.00 mmol) were then added
to this reaction mixture. The mixture was stirred at room
temperature for 4 h (monitored by TLC). CAUTION! Upon
releasing nitrogen during the reaction, pressure was built
up in the reaction vessel. The reaction mixture was
transferred to a round-bottom flask and the solvents were
carefully removed in vacuo. The crude product was
+
[
[
(
(
M–OCH
3
]
(5), 149 (20), 139 (12), 136 (10), 135
+
+
C
8
H
7
O
2
] (100), 129 (26), 111 (17), 107 [C
7
H
7
O] (10), 97
+
13), 85 (17), 83 (15), 77 [C
6
H
5
] (13), 71 (26), 70 (11), 69
12), 57 (32), 55 (15), 43 (18), 41 (10). Found, %: C 69.71;
H 5.07; N 4.62. C18
H 4.89; N 4.53.
H
15NO . Calculated, %: C 69.89;
4
®
5
-Cyclopropyl-3-phenylisoxazole (2g). Purified by
adsorbed on Сelite and purified by flash chromatography
flash chromatography on silica gel (petroleum ether –
EtOAc, 100:1 to 50:1, R 0.15 (petroleum ether – EtOAc,
0:1)). Yield 155 mg (42%), yellow solid, mp 42°C.
on silica gel (petroleum ether – EtOAc, 3:1, R 0.08). Yield
f
f
225 mg (51%), yellow solid, mp 140–141°C. IR spectrum,
–1
5
ν, cm : 3109 (w), 3046 (w), 2955 (w), 2920 (w), 2851 (w),
1611 (m), 1574 (w), 1560 (w), 1483 (w), 1462 (w), 1443
(w), 1412 (m), 1395 (m), 1339 (w), 1273 (w), 1223 (w),
1188 (w), 1126 (w), 1094 (w), 1053 (w), 1020 (w), 1001
(w), 947 (m), 912 (m), 826 (w), 808 (m), 766 (s), 692 (s),
–
1
IR spectrum, ν, cm : 3111 (w), 3005 (w), 2955 (w), 2922
w), 2851 (w), 1595 (m), 1578 (m), 1510 (w), 1474 (m),
445 (w), 1416 (m), 1369 (m), 1339 (w), 1287 (w), 1238
w), 1196 (w), 1150 (w), 1096 (w), 1057 (w), 1028 (w),
(
1
(
1
9
(
(
84 (m), 953 (w), 918 (m), 887 (m), 816 (m), 793 (w), 773
667 (m), 617 (m). H NMR spectrum, δ, ppm (J, Hz): 6.93
1
s), 692 (s), 669 (m). H NMR spectrum, δ, ppm: 0.99–1.15
(1H, s); 7.39–7.55 (4H, m); 7.81–7.93 (2H, m); 8.09–8.18
4H, m); 1.99–2.15 (1H, m); 6.20 (1H, s); 7.36–7.49 (3H,
(1H, m); 8.69 (1H, dd, J = 1.7, J = 4.9); 9.08 (1H, s).
1
3
13
m); 7.71–7.81 (2H, m). C NMR spectrum, δ, ppm: 8.3
C NMR spectrum, δ, ppm:  98.6 (CH); 123.8 (C); 123.9
(CH); 8.5 (CH
1
2
); 97.0 (CH); 126.8 (CH); 128.9 (CH);
(CH); 126.9 (CH); 128.7 (C); 129.1 (CH); 130.4 (CH);
133.0 (CH); 147.1 (CH); 151.1 (CH); 163.2 (C); 167.7 (C).
29.5 (C); 129.9 (CH); 162.6 (C); 175.4 (C). Mass
+
+
spectrum, m/z (Irel, %): 186 (13), 185 [M] (92), 184 (32),
Mass spectrum, m/z (Irel, %): 223 (12), 222 [M] (79), 221
+
+
+
+
1
70 [M–CH
3
] (22), 156 [M–HNO] (28), 145 (10), 144
(100), 144 [M–C
(44), 78 (35), 77 [C
5
H
4
N] (38), 116 [M–C
6
6
H
4
NO] (11), 106
+
+
+
[
M–C
3
H
5
] (100), 117 (36), 116 [M–C
4
H
5
O] (33), 89 (15),
] (52), 69 (57), 51 (19), 41 (28), 40 (44),
9 (13). Found, %: C 77.91; H 6.07; N 7.30. C12
H
5
] (13), 51 (15), 40 (32). Found, %:
+
8
3
2 (17), 77 [C
6
H
5
C 75.72; H 4.75; N 12.30. C14
C 75.66; H 4.54; N 12.60.
H
10
N
2
O. Calculated, %:
H
11NO.
Calculated, %: C 77.81; H 5.99; N 7.56.
1
The Supplementary information file, containing H and
5
-(2-Chlorophenyl)-3-ferrocenylisoxazole (2h). Purified
by flash chromatography on silica gel (petroleum ether –
EtOAc, 25:1, R 0.15). Yield 84 mg (12%), red solid, mp
18°C. IR spectrum, ν, cm : 3136 (w), 2901 (w), 1601
w), 1582 (m), 1568 (w), 1530 (w), 1476 (w), 1435 (w),
425 (w), 1395 (w), 1362 (w), 1269 (w), 1223 (w), 1215
w), 1107 (w), 1078 (w), 1035 (m), 1022 (w), 1005 (w),
45 (m), 920 (w), 870 (m), 833 (w), 824 (m), 816 (m), 756
13
C NMR spectra of compounds 2a–i and 5a, is available from
the journal website at http://link.springer.com/journal/10593.
f
–
1
1
This work was supported by the Fonds der Chemischen
Industrie and Merck Serono, Darmstadt.
(
1
(
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