Ligand-free-palladium-catalyzed direct 4-arylation of isoxazoles using aryl bromides

Article abstract of DOI:10.1002/ejoc.200900309

4-rylisoxazoles can be easily prepared by a palladium-catalysed C-H bond activation/arylation of 3,5-disubstituted isoxazoles using aryl or heteroaryl bromides. Good yields were generally obtained by using 0.1-0.5 mol-% of the airstable PdCl₂ c

Full text of DOI:10.1002/ejoc.200900309

FULL PAPER
DOI: 10.1002/ejoc.200900309
Ligand-Free-Palladium-Catalyzed Direct 4-Arylation of Isoxazoles Using Aryl
Bromides
Yacoub Fall,[a] Céline Reynaud,[a] Henri Doucet,*[b] and Maurice Santelli*[a]
Keywords: Atom-economy / Homogeneous catalysis / C–H activation / Heteroaryl halides / Isoxazole / Palladium
4-Arylisoxazoles can be easily prepared by a palladium-cata- methyl or nitrile on the aryl bromide is tolerated. This reac-
lysed C–H bond activation/arylation of 3,5-disubstituted
isoxazoles using aryl or heteroaryl bromides. Good yields
were generally obtained by using 0.1–0.5 mol-% of the air-
stable PdCl2 complex as the catalyst. A range of functional
groups such as acetyl, formyl, ester, fluoro, nitro, trifluoro-
tion is environmentally attractive, as the major waste is KBr/
AcOH instead of the metallic salts arising from classical
cross-coupling procedures.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
3- or 4-arylisoxazoles such as Valdecoxib, Parecoxib or
Oxacillin and its derivatives are useful compounds due to
their specific biological properties (Scheme 1).
Scheme 2.
The arylation of several heteroaromatics by C–H bond
activation using aryl halides has been reported in recent
years. For such couplings, no preparation of an organome-
tallic derivative is required.[4–6] Moreover, this reaction pro-
vides only HX associated with a base as a by-product and,
therefore, is very interesting both in terms of atom economy
and relatively inert wastes. However, even though this pro-
cedure has been widely applied for the synthesis of arylthio-
phenes, arylfurans, aryloxazoles or arylthiazoles, relatively
Scheme 1.
Palladium-catalysed Suzuki or Stille cross-coupling reac- few results have been reported with isoxazole derivatives. In
tions between aryl halides and organometallic derivatives the presence of 3,5-disubstituted isoxazoles, this procedure
of isoxazole and also between 3- or 4-haloisoxazoles and should provide an economic and environmentally attractive
arylmetal derivatives are some of the most important meth- procedure for the preparation of a variety of 4-arylisox-
ods for the synthesis of such compounds.[1–3] However, azoles. However, to date, only a few examples of 4-arylation
these reactions require the preliminary preparation of an of such heteroaromatics have been reported.[7–9] In 1982,
organometallic derivative and provide an organometallic the intramolecular cyclisation of a 3-substituted isoxazole
salt (MX) as a by-product (Scheme 2).
was described by the group of Nakamura.[7] By employing
10 mol-% of Pd(OAc)2/PPh3 as a catalyst, the desired com-
pound was formed in 45% yield. 5-Subtituted isoxazoles
have also been cyclised to give tricyclic compounds in 9–
60% yield.[8] The bimolecular 4-arylation of isoxazoles was
also found to be possible, though it required higher tem-
peratures and longer reaction times. With iodobenzene or
4-iodotoluene in the presence of 3,5-disubstituted isox-
azoles, the 4-arylated isoxazoles were obtained in 30–48%
yields.[7] These reactions were performed by using 10 or
[a] Laboratoire de Synthèse Organique associé au CNRS, Faculté
des Sciences de Saint Jérôme,
Avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France
E-mail: m.santelli@univ-cezanne.fr
[b] Institut Sciences Chimiques de Rennes, UMR 6226 CNRS –
Université de Rennes, “Catalyse et Organometalliques”,
Campus de Beaulieu, 35042 Rennes, France
Fax: +33-2-23236939
E-mail: henri.doucet@univ-rennes1.fr
Eur. J. Org. Chem. 2009, 4041–4050
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Y. Fall, C. Reynaud, H. Doucet, M. Santelli
FULL PAPER
5mol-% of Pd/C or Pd(OAc)2 as a catalyst, respectively. Re- Table 1. Palladium-catalysed cross-coupling with 3,5-dimethylisox-
azole and 4-bromobenzonitrile (Scheme 3).[a]
cently, the scope of this reaction was extended to an aryl
chloride, 1-chloronaphthalene.[9] For this reaction, in order
Entry
[Pd]
Substrate/
catalyst
Solvent
Base
Conversions
(%)
to facilitate the oxidative addition of 1-chloronaphthalene
to palladium, 5 mol-% of Pd(OAc)2 was associated with
10 mol-% of the bulky and electron-rich ligand, bis(1-ada-
mantyl)butylphosphane, to form the catalyst. The expected
(3,5-dimethyl-4-naphthalen-1-yl)isoxazole was obtained in
76% yield.
Since only a few syntheses of 4-arylisoxazoles by palla-
dium-catalysed C–H bond activation of isoxazole deriva-
tives followed by arylation have been described, the scope
of the reaction needs to be largely extended to a wider vari-
ety of aryl halides. Moreover, higher yields for the coupling
of such compounds have to be obtained in using lower cata-
lyst loadings, in order to obtain economically viable pro-
cedures. Herein, we wish to report on the reaction of a set
of electronically and sterically diverse aryl bromides using
3,5-disubstituted isoxazoles at low catalyst loadings with li-
gand-free palladium catalysts.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Pd(OAc)2
½[PdCl(C3H5)]2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
½[PdCl(C3H5)]2
½Pd2(dba)3
PdCl2
PdCl2/2P(Ad)2nBu
Pd(OAc)2
½[PdCl(C3H5)]2
½Pd2(dba)3
PdCl2
200
200
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
xylene
AcOK
AcOK
AcOK
K2CO3
Cs2CO3
AcONa
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
AcOK
100
98
96
10
25
70
15
52
92
95
96
100 (90)
28
53
72
71
60
15[b]
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
1000
2000
2000
2000
2000
100
DMF
NMP
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
PdCl2
[a] Conditions: 4-bromobenzonitrile (1 equiv.), 3,5-dimethylisox-
azole (1.5 equiv.), base (2 equiv.), 20 h, 130 °C; GC and NMR con-
version of 4-bromobenzonitrile; yield in parentheses is isolated. [b]
Reaction temperature: 100 °C.
Results and Discussion
Under these conditions, the target product 1 formed in
almost quantitative yield (Table 1, Entries 1 and 2). We then
studied this reaction using various bases and solvents in the
presence of only 0.1 mol-% Pd(OAc)2 or ½[PdCl(C3H5)]2
(Table 1, Entries 3–10). The conversion was still almost
quantitative by using AcOK as the base, whereas K2CO3 or
Cs2CO3 gave much lower yields (Table 1, Entries 3–5 and
10). We obtained a conversion of 70% in the presence of
NaOAc (Table 1, Entry 6). When we employed xylene or
DMF as the solvent instead of DMAc, we observed conver-
sions of 15% and 52% (Table 1, Entries 7 and 8). On the
other hand, we found NMP gave a high conversion of 4-
bromobenzonitrile, and we obtained 1 in very good yield
(Table 1, Entry 9). We also examined the influence of the
palladium source. Pd(OAc)2, Pd2(dba)3 or [PdCl(C3H5)]2
gave 1 in high yields, and very clean reactions were observed
(Table 1, Entries 3, 10 and 11). However, we obtained the
most selective reaction using PdCl2 (Table 1, Entry 12).
With this catalyst, we detected no trace of side products
and isolated 1 in 90% yield. We note that the addition of
0.2 mol-% of P(Ad)2nBu to the reaction mixture led to a
lower yield of 1 (Table 1, Entry 13). With this electron-de-
ficient aryl bromide, the oxidative addition to palladium is
not the rate-limiting step of the catalytic cycle; therefore,
the presence of an electron-rich phosphane ligand is useless.
We then studied the reaction using a substrate/catalyst ratio
of 2000 with Pd(OAc)2, ½Pd2(dba)3, ½[PdCl(C3H5)]2 and
PdCl2 as catalyst precursors (Table 1, Entries 14–17). We
observed relatively similar conversions with these four cata-
lysts (53–72%), but again, we observed the most selective
reaction using PdCl2 as the catalyst. Finally, we found a
lower reaction temperature of 100 °C instead of 130 °C gave
1 in only 15% conversion (Table 1, Entry 18). At this tem-
perature, we recovered most of the aryl bromide unreacted.
We have recently reported that ligand-free Pd(OAc)2 or
[PdCl(C3H5)]2 are very powerful catalyst for the direct aryl-
ation of furans, thiophenes, thiazoles or pyrroles.[5g–5i,10]
With these heteroaromatics, several reactions can be per-
formed with as little as 0.5–0.001 mol-% of catalyst. At an
elevated temperature, when ligand-free Pd(OAc)2 is em-
ployed as a catalyst precursor, soluble palladium(0) colloids
or nanoparticles are formed. These nanoparticles seem to
produce monomeric or dimeric anionic palladium com-
plexes that are very active catalysts. For this ligand-free pro-
cedure, low catalyst loadings have to be employed (less than
0.5 mol-%). Under relatively high palladium concentrations
(Ͼ1 mol-%), so-called palladium black forms more rapidly.
This palladium black is generally inactive for such catalyzed
reactions. Consequently, the conversions of aryl bromides
and the yields of coupling products are not increased by a
higher catalyst loading.
First, we examined the reactivity of 3,5-dimethylis-
oxazole in the palladium-catalysed coupling reaction with
4-bromobenzonitrile by using 0.5 mol-% of Pd(OAc)2 or
½[PdCl(C3H5)]2 as catalyst precursors, DMAc as the sol-
vent and AcOK as the base at 130 °C in the absence of
ligand (Scheme 3, Table 1).
Scheme 3.
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Ligand-Free-Palladium-Catalyzed Direct 4-Arylation of Isoxazoles
We then investigated the scope and limitations of this Table 2. Palladium-catalysed direct coupling of para-substituted
aryl halides with 3,5-dimethylisoxazole (Scheme 4).[a]
reaction using other aryl bromides and also aryl chlorides
(Scheme 4, Tables 2, 3 and 4). First, we studied the reac-
tivity of para-substituted aryl bromides (Scheme 4 and
Table 2). We performed these reactions using DMAc,
AcOK, 130 °C and 0.2 mol-% of PdCl2 as reaction condi-
tions. In the presence of electron-deficient aryl bromides
such as 4-bromoacetophenone, 4-bromobenzophenone, 4-
bromobenzaldehyde, 4-bromonitrobenzene and 1-bromo-4-
(trifluoromethyl)benzene, we obtained the products 2–7 in
84–93% yield (Table 2, Entries 2, 4, 6, 7, 11 and 12).
Scheme 4.
A slightly activated aryl bromide, 1-bromo-4-fluoroben-
zene gave the expected product 8 in a high yield of 90%
(Table 2, Entry 13). Deactivated aryl bromides, 4-bromotol-
uene, 1-bromo-4-tert-butylbenzene and 4-bromoanisole
gave 9–11 in 87, 55 and 58% yields, respectively, by using
0.5 mol-% of catalyst (Table 2, Entries 14–16). With these
substrates, we obtained lower yields using 0.2 mol-% of cat-
alyst. Using the strongly deactivated aryl bromide, 4-
bromo-N,N-dimethylaniline, in the presence of 0.5 mol-%
of catalyst, we obtained 12 in only 44% yield (Table 2, En-
try 17). As expected, we found the aryl chlorides, 4-chloro-
acetophenone, 4-chlorobenzophenone and 4-chlorobenzal-
dehyde gave products 2, 3 and 5, respectively, in very low
yields using this catalyst (Table 2, Entries 3, 5 and 8). For
this reaction, the oxidative addition of aryl chlorides to pal-
ladium appears to be the rate-limiting step of the catalytic
cycle. Therefore, for such challenging substrates, the use of
palladium associated with electron-rich and congested
phosphane ligands should be preferred.[9] With 1 mol-% of
PdCl2 and 2 mol-% of P(Ad)2nBu as the catalyst, the reac-
tion of 4-chlorobenzaldehyde with 3,5-dimethylisoxazole
gave 5 in 58% yield (Table 2, Entry 10).
We next examined the reactivity of meta-substituted aryl
bromides with 3,5-dimethylisoxazole (Table 3). As expected,
the electron-deficient aryl bromides, 3-bromoacetophenone,
3-bromonitrobenzene and 1-bromo-3,5-bis(trifluorometh-
yl)benzene could be brought to reaction by using 0.2 mol-
% of catalyst as with the para-substituted aryl bromides
(Table 3, Entries 1–3).
ortho-Substituents on the aryl bromides generally have a
more important effect on the reactions rates and yields of
most palladium-catalysed reactions due to their steric and/
or coordination properties. However, we also obtained good
yields of coupling product 17 or 18 in the presence of 2-
bromobenzonitrile or 1-bromonaphthalene and 3,5-dimeth-
ylisoxazole (Table 3, Entries 5 and 6).
We then examined the reactivity of a few heteroaryl bro-
mides (Table 4). The unique characteristics of palladium
[a] Conditions: PdCl2 (0.002 equiv.), aryl halide (1 equiv.), 3,5-di-
methylisoxazole (1.5 equiv.), AcOK (2 equiv.), DMAc, 20 h,
130 °C; isolated yields. [b] 0.001 equiv. of PdCl2 was employed. [c]
0.005 equiv. of PdCl2 was employed. [d] PdCl2 (0.001 equiv.) and
P(Ad)2nBu (0.002 equiv.) were employed. [e] PdCl2 (0.01 equiv.)
chemistry involving heterocycles stem from the inherently and P(Ad)2nBu (0.02 equiv.) were employed.
Eur. J. Org. Chem. 2009, 4041–4050
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Y. Fall, C. Reynaud, H. Doucet, M. Santelli
FULL PAPER
Table 3. Palladium-catalysed direct coupling of meta- and ortho- different structural and electronic properties of heterocycles
substituted aryl bromides with 3,5-dimethylisoxazole (Scheme 4).[a]
in comparison to the corresponding carbocyclic aryl com-
pounds. Pyridines and pyrimidines are π-electron-deficient
heterocycles. Therefore, their reactivity is quite similar to
electron-deficient aryl bromides. As expected, using 3-bro-
mopyridine, 3-bromoquinoline, 4-bromoisoquinoline or 5-
bromopyrimidine, we obtained the coupling products 19–
22 in very high yield with only 0.2 mol-% of catalyst.
The reaction was not limited to the use of 3,5-dimethyl-
isoxazole. We also found 3-methyl-5-phenylisoxazole to be
a suitable reactant for this reaction (Scheme 5 and Table 5).
We coupled a variety of aryl bromides with this substrate
to give the desired products 23–35. First, we studied the
reactivity of para-substituted aryl bromides. Again, we ob-
tained higher yields using electron-deficient aryl bromides.
In the presence of 4-bromobenzaldehyde, 4-bromoace-
tophenone, 4-bromobenzonitrile and 4-bromonitrobenzene
we obtained the products 23–26 in 85–90% yields using
only 0.2 mol-% of catalyst (Table 5, Entries 1–4).
Scheme 5.
On the other hand, using 4-bromoanisole, we had to em-
ploy 0.5 mol-% of catalyst in order to obtain a good yield
of 77% of 28 (Table 5, Entry 6). Electron-deficient meta-
and ortho-substituted aryl bromides also gave the coupling
products 29, 30, 32 and 33 in very high yield with 0.2 mol-
% of catalyst (Table 5, Entries 7, 8, 10 and 11). We also
tested the coupling with the three heteroaryl bromides. 3-
Bromopyridine, 3-bromopyridine and 4-bromoisoquinoline
gave the expected 4-arylated isoxazoles 34–36 in very good
yields (Table 5, Entries 12–14).
[a] Conditions: PdCl2 (0.002 equiv.), aryl bromide (1 equiv.), 3,5-
dimethylisoxazole (1.5 equiv.), AcOK (2 equiv.), DMAc, 20 h,
130 °C; isolated yields. [b] 0.005 equiv. of PdCl2 was employed.
Table 4. Palladium-catalysed direct coupling of heteroaryl bromides
with 3,5-dimethylisoxazole (Scheme 4).[a]
Finally, we examined the reactivity of functionalised
isoxazoles. The presence of an ester function in position 3
led to an important change in the reactivity. Using 0.5 or
2 mol-% of PdCl2, AcOK, and DMAc, 80 or 130 °C as the
reaction temperature and 4-bromoacetophenone as the re-
action partner, we detected no arylation product 37. On the
other hand, in the presence of 2 mol-% of [Pd(C3H5)Cl]2 as
a catalyst precursor at 80 °C, we obtained product 37 in
27% yield (Scheme 6). During the course of this reaction,
we also observed the formation of a very important amount
of 4,4Ј-diacetylbiphenyl. We found methyl 5-methylisox-
azole-4-carboxylate to be even less reactive. With this reac-
tant, we did not detect the formation of 38 using various
reaction conditions (Scheme 7).
In order to confirm this important change in reactivity
in the presence of a functional group on isoxazoles, we also
studied the 4-arylation of 3-formyl-5-methylisoxazole with
4-bromobenzonitrile (Scheme 8). With this reactant, 26%
of product 39 formed when we used [PdCl(C3H5)]2 as the
catalyst at 60 °C. During the course of this reaction, we
[a] Conditions: PdCl2 (0.002 equiv.), aryl bromide (1 equiv.), 3,5-
dimethylisoxazole (1.5 equiv.), AcOK (2 equiv.), DMAc, 20 h,
130 °C; isolated yields.
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Ligand-Free-Palladium-Catalyzed Direct 4-Arylation of Isoxazoles
Table 5. Palladium-catalysed direct coupling with 3-methyl-5-phen-
ylisoxazole (Scheme 5).[a]
Scheme 6.
Scheme 7.
observed the formation of a very important amount of bi-
phenyl-4,4Ј-dicarbonitrile. This oxazole derivative appeared
to be quite unstable under the reaction conditions at more
elevated temperatures (80–130 °C). At these temperatures,
we did not recover the starting isoxazole material at the
end of the reaction, and several unidentified compounds
formed.
Scheme 8.
Conclusions
A wide variety of 4-arylisoxazole derivatives can be pre-
pared easily and in good yields by the direct 4-arylation of
3,5-disubstituted isoxazole derivatives. This reaction can be
performed by using as little as 0.1–0.5 mol-% of a ligand-
free palladium catalyst. Therefore, this low catalyst loading
procedure is economically attractive. Moreover, there is no
need to eliminate phosphane derivatives at the end of the
reaction. At such low catalyst concentrations, palladium-
stabilizing agents like ammonium salts are useless, thus re-
ducing the amount of wastes. Both 3,5-dimethyl- and 3-
methyl-5-phenylisoxazole can be employed as coupling
partners. On the other hand, we found isoxazoles substi-
tuted by electron-withdrawing substituents to be less reac-
tive. We generally obtained better results using electron-de-
ficient aryl bromides. However, it should be noted that a
wide range of groups such as acetyl, formyl, ester, nitro,
trifluoromethyl, fluoro, amino and nitrile on the aryl bro-
[a] Conditions: PdCl2 (0.002 equiv.), aryl bromide (1 equiv.), 3-
methyl-5-phenylisoxazole (1.5 equiv.), AcOK (2 equiv.), DMAc,
20 h, 130 °C; isolated yields. [b] 0.005 equiv. of PdCl2 was em-
ployed.
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Y. Fall, C. Reynaud, H. Doucet, M. Santelli
FULL PAPER
195.9, 165.7, 158.2, 137.3, 136.4, 134.7, 132.4, 130.4, 129.9, 128.7,
128.2, 115.8, 11.6, 10.8 ppm. C18H15NO2 (277.32): calcd. C 77.96,
H 5.45; found C 77.99, H 5.58.
mide were tolerated. This procedure is very simple, uses
commercially available substrates and catalyst, and the air
stability of the catalyst also makes this procedure very con-
venient. We note that an important number of the products Methyl 4-(3,5-dimethylisoxazol-4-yl)benzoate (4): The reaction of
methyl 4-bromobenzoate (0.215 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 4 in 93% (0.215 g) isolated yield.
1H NMR (300 MHz, CDCl3): δ = 8.10 (d, J = 8.2 Hz, 2 H, Ar),
7.34 (d, J = 8.2 Hz, 2 H, Ar), 3.94 (s, 3 H, CO2Me), 2.43 (s, 3 H,
Me), 2.29 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ =
167.0, 166.1, 158.7, 135.7, 130.4, 129.5, 129.2, 116.3, 52.6, 12.0,
11.2 ppm. C13H13NO3 (231.25): calcd. C 67.52, H 5.67; found C
67.60, H 5.57.
prepared by this method have never been described so far,
indicating that this procedure provides a convenient access
to compounds which cannot be prepared very easily by
more classical cross-coupling methods. Finally, due to envi-
ronmental considerations, the advantage of such an atom-
economical and inert-waste procedure (formation of acetic
acid and potassium bromide) should become increasingly
important for industrial processes.
4-(3,5-Dimethylisoxazol-4-yl)benzaldehyde (5):[12] The reaction of 4-
bromobenzaldehyde (0.187 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 5 in 90% (0.181 g) isolated yield.
1H NMR (300 MHz, CDCl3): δ = 10.01 (s, 1 H, CHO), 7.92 (d, J
= 8.2 Hz, 2 H, Ar), 7.41 (d, J = 8.2 Hz, 2 H, Ar), 2.41 (s, 3 H,
Me), 2.27 (s, 3 H, Me) ppm.
3,5-Dimethyl-4-(4-nitrophenyl)isoxazole (6):[13] The reaction of 1-
bromo-4-nitrobenzene (0.202 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 6 in 85% (0.185 g) isolated yield.
1H NMR (300 MHz, CDCl3): δ = 8.29 (d, J = 8.2 Hz, 2 H, Ar),
7.43 (d, J = 8.2 Hz, 2 H, Ar), 2.44 (s, 3 H, Me), 2.29 (s, 3 H, Me)
ppm.
Experimental Section
General Remarks: All reactions were run under argon in Schlenk
tubes by using vacuum lines. DMAc (analytical grade) was not dis-
tilled before use. Potassium acetate (99%) was used. Commercially
available aryl halides and isoxazole derivatives were used without
purification. 1H and 13C NMR spectra were recorded with a Bruker
300 MHz spectrometer in CDCl3 solutions. Chemical shifts are re-
1
ported in ppm relative to CDCl3 (δ = 7.25 ppm for H NMR and
δ = 77.0 ppm for 13C NMR). Flash chromatography was performed
on silica gel (230–400 mesh).
General Procedure for Coupling Reactions: In a typical experiment,
the heteroaryl bromide (1 mmol), isoxazole derivative (1.5 mmol),
AcOK (0.196 g, 2 mmol) and PdCl2 (0.0004 g, 0.002 mmol) were
dissolved in DMAc (5 mL) under argon. The reaction mixture was
stirred at 130 °C for 20 h. The product was then extracted three
times with CH2Cl2. The combined organic layers were dried with
MgSO4, and the solvent was removed in vacuo. The crude product
was purified by silica gel column chromatography.
3,5-Dimethyl-4-[4-(trifluoromethyl)phenyl]isoxazole (7): The reac-
tion of 1-bromo-4-(trifluoromethyl)benzene (0.225 g, 1 mmol), 3,5-
dimethylisoxazole (0.144 g, 1.5 mmol) and AcOK (0.196 g,
2 mmol) at 130 °C in dry DMAc (5 mL) in the presence of PdCl2
(0.0004 g, 0.002 mmol) afforded the corresponding product 7 in
92% (0.222 g) isolated yield. 1H NMR (300 MHz, CDCl3): δ = 7.69
(d, J = 8.2 Hz, 2 H, Ar), 7.37 (d, J = 8.2 Hz, 2 H, Ar), 2.41 (s, 3
H, Me), 2.27 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ =
165.8, 158.3, 134.3, 129.6 (q, J = 32.7 Hz), 129.3, 125.8, 124.1 (q,
J = 271.9 Hz), 115.6, 11.5, 10.7 ppm. C12H10F3NO (241.21): calcd.
C 59.75, H 4.18; found C 59.70, H 4.13.
4-(3,5-Dimethylisoxazol-4-yl)benzonitrile (1):[11] The reaction of 4-
bromobenzonitrile (0.182 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 1 in 90% (0.178 g) isolated yield.
1H NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 8.2 Hz, 2 H, Ar),
7.36 (d, J = 8.2 Hz, 2 H, Ar), 2.41 (s, 3 H, Me), 2.26 (s, 3 H, Me)
ppm.
4-(4-Fluorophenyl)-3,5-dimethylisoxazole (8): The reaction of 1-
bromo-4-fluorobenzene (0.175 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 8 in 90% (0.172 g) isolated yield.
1H NMR (300 MHz, CDCl3): δ = 7.23 (dd, J = 8.7 and 5.5 Hz, 2
H, Ar), 7.37 (t, J = 8.7 Hz, 2 H, Ar), 2.39 (s, 3 H, Me), 2.26 (s, 3
H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 247.2, 158.5, 130.7
(d, J = 8.1 Hz), 126.3 (d, J = 3.4 Hz), 115.8 (d, J = 21.7 Hz), 115.7,
11.4, 10.6 ppm. C11H10FNO (191.20): calcd. C 69.10, H 5.27; found
C 69.19, H 5.34.
4-(3,5-Dimethylisoxazol-4-yl)acetophenone (2): The reaction of 4-
bromoacetophenone (0.199 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 2 in 84% (0.181 g) isolated yield.
1H NMR (300 MHz, CDCl3): δ = 7.99 (d, J = 8.2 Hz, 2 H, Ar),
7.34 (d, J = 8.2 Hz, 2 H, Ar), 2.60 (s, 3 H, COMe), 2.40 (s, 3 H,
Me), 2.25 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ =
197.3, 165.7, 158.2, 135.9, 135.3, 128.9, 128.7, 115.7, 26.5, 11.6,
10.7 ppm. C13H13NO2 (215.25): calcd. C 72.54, H 6.09; found C
72.41, H 6.07.
3,5-Dimethyl-4-p-tolylisoxazole (9):[14] The reaction of 4-bromotol-
uene (0.171 g, 1 mmol), 3,5-dimethylisoxazole (0.144 g, 1.5 mmol)
and AcOK (0.196 g, 2 mmol) at 130 °C in dry DMAc (5 mL) in
the presence of PdCl2 (0.0009 g, 0.005 mmol) afforded the corre-
sponding product 9 in 87% (0.163 g) isolated yield. 1H NMR
(300 MHz, CDCl3): δ = 7.33 (d, J = 8.2 Hz, 2 H, Ar), 7.23 (d, J =
8.2 Hz, 2 H, Ar), 2.48 (s, 6 H, Me), 2.35 (s, 3 H, Me) ppm.
4-(3,5-Dimethylisoxazol-4-yl)benzophenone (3): The reaction of 4-
bromobenzophenone (0.261 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 3 in 88% (0.244 g) isolated yield.
1H NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 8.2 Hz, 2 H, Ar),
7.80 (d, J = 8.2 Hz, 2 H, Ar), 7.58 (t, J = 7.9 Hz, 1 H, Ar), 7.47
(t, J = 7.9 Hz, 2 H, Ar), 7.36 (d, J = 8.2 Hz, 2 H, Ar), 2.43 (s, 3
4-(4-tert-Butylphenyl)-3,5-dimethylisoxazole (10):[13] The reaction of
H, Me), 2.29 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 1-bromo-4-tert-butylbenzene (0.213 g, 1 mmol), 3,5-dimethylisox-
4046
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 4041–4050

Ligand-Free-Palladium-Catalyzed Direct 4-Arylation of Isoxazoles
azole (0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in
dry DMAc (5 mL) in the presence of PdCl2 (0.0009 g, 0.005 mmol)
afforded the corresponding product 10 in 55% (0.126 g) isolated
yield. H NMR (300 MHz, CDCl3): δ = 7.54 (d, J = 8.2 Hz, 2 H,
Ar), 7.27 (d, J = 8.2 Hz, 2 H, Ar), 2.49 (s, 3 H, Me), 2.36 (s, 3 H,
Me), 1.44 (s, 9 H, tBu) ppm.
CDCl3): δ = 165.1, 158.7, 138.4, 130.3, 129.7, 128.6, 128.2, 126.1,
116.6, 21.4, 11.5, 10.8 ppm. C12H13NO (187.24): calcd. C 76.98, H
7.00; found C 76.89, H 6.88.
1
2-(3,5-Dimethylisoxazol-4-yl)benzonitrile (17): The reaction of 2-
bromobenzonitrile (0.182 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
4-(4-Methoxyphenyl)-3,5-dimethylisoxazole (11):[13] The reaction of DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
4-bromoanisole (0.187 g, 1 mmol), 3,5-dimethylisoxazole (0.144 g, forded the corresponding product 17 in 83% (0.165 g) isolated
1
1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry DMAc
(5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) afforded
the corresponding product 11 in 58% (0.118 g) isolated yield. 1H
NMR (300 MHz, CDCl3): δ = 7.17 (d, J = 8.2 Hz, 2 H, Ar), 7.96
(d, J = 8.2 Hz, 2 H, Ar), 3.84 (s, 3 H, OMe), 2.37 (s, 3 H, Me),
2.24 (s, 3 H, Me) ppm.
yield. H NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 8.3 Hz, 1 H,
Ar), 7.64 (t, J = 7.7 Hz, 1 H, Ar), 7.49 (t, J = 7.7 Hz, 1 H, Ar),
7.32 (d, J = 8.3 Hz, 1 H, Ar), 2.35 (s, 3 H, Me), 2.20 (s, 3 H, Me)
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.8, 158.4, 134.0, 133.4,
132.9, 131.1, 128.5, 117.6, 113.9, 113.5, 11.8, 10.4 ppm. C12H10N2O
(198.22): calcd. C 72.71, H 5.08; found C 72.79, H 5.09.
4-(3,5-Dimethylisoxazol-4-yl)-N,N-dimethylaniline (12):[15] The re-
action of 1-bromo-4-(dimethylamino)benzene (0.200 g, 1 mmol),
3,5-dimethylisoxazole (0.144 g, 1.5 mmol) and AcOK (0.196 g,
2 mmol) at 130 °C in dry DMAc (5 mL) in the presence of PdCl2
(0.0009 g, 0.005 mmol) afforded the corresponding product 12 in
44% (0.095 g) isolated yield. 1H NMR (300 MHz, CDCl3): δ = 7.11
3,5-Dimethyl-4-(naphthalen-1-yl)isoxazole (18):[9] The reaction of 1-
bromonaphthalene (0.207 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 18 in 91% (0.203 g) isolated
yield. 1H NMR (300 MHz, CDCl3): δ = 8.00–7.70 (m, 2 H, Ar),
(d, J = 8.2 Hz, 2 H, Ar), 6.77 (d, J = 8.2 Hz, 2 H, Ar), 2.98 (s, 6 7.60–7.45 (m, 4 H, Ar), 7.32 (dd, J = 6.9 and 1.1 Hz, 1 H, Ar),
H, NMe2), 2.37 (s, 3 H, Me), 2.25 (s, 3 H, Me) ppm. 2.26 (s, 3 H, Me), 2.09 (s, 3 H, Me) ppm.
3-(3,5-Dimethylisoxazol-4-yl)acetophenone (13): The reaction of 3- 3-(3,5-Dimethylisoxazol-4-yl)pyridine (19): The reaction of 3-bro-
bromoacetophenone (0.199 g, 1 mmol), 3,5-dimethylisoxazole mopyridine (0.158 g, 1 mmol), 3,5-dimethylisoxazole (0.144 g,
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry DMAc
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
(5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) afforded
the corresponding product 19 in 95% (0.166 g) isolated yield. 1H
NMR (300 MHz, CDCl3): δ = 8.58 (dd, J = 4.7 and 1.3 Hz, 1 H,
Ar), 8.50 (d, J = 1.7 Hz, 1 H, Ar), 7.57 (dt, J = 7.7 and 1.7 Hz, 1
forded the corresponding product 13 in 89% (0.192 g) isolated
1
yield. H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 8.2 Hz, 1 H,
Ar), 7.81 (s, 1 H, Ar), 7.52 (t, J = 7.7 Hz, 1 H, Ar), 7.43 (d, J =
8.2 Hz, 1 H, Ar), 2.60 (s, 3 H, COMe), 2.37 (s, 3 H, Me), 2.23 (s, H, Ar), 7.35 (dd, J = 7.7 and 4.7 Hz, 1 H, Ar), 2.39 (s, 3 H, Me),
3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 197.5, 165.5, 2.24 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.0,
158.3, 137.5, 133.4, 131.0, 129.0, 128.5, 127.4, 115.8, 26.6, 11.4,
10.6 ppm. C13H13NO2 (215.25): calcd. C 72.54, H 6.09; found C
72.68, H 6.17.
158.4, 149.8, 148.7, 136.2, 126.5, 123.5, 113.4, 11.5, 10.6 ppm.
C10H10N2O (174.20): calcd. C 68.95, H 5.79; found C 68.78, H
5.89.
3,5-Dimethyl-4-(3-nitrophenyl)isoxazole (14):[14] The reaction of 1-
3-(3,5-Dimethylisoxazol-4-yl)quinoline (20): The reaction of 3-bro-
bromo-3-nitrobenzene (0.202 g, 1 mmol), 3,5-dimethylisoxazole
moquinoline (0.208 g, 1 mmol), 3,5-dimethylisoxazole (0.144 g,
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry DMAc
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
(5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) afforded
the corresponding product 20 in 92% (0.206 g) isolated yield. 1H
NMR (300 MHz, CDCl3): δ = 8.78 (d, J = 2.3 Hz, 1 H, Ar), 8.08
(d, J = 8.5 Hz, 1 H, Ar), 7.98 (d, J = 2.3 Hz, 1 H, Ar), 7.80 (d, J
= 8.5 Hz, 1 H, Ar), 7.70 (t, J = 7.7 Hz, 1 H, Ar), 7.54 (t, J =
7.7 Hz, 1 H, Ar), 2.42 (s, 3 H, Me), 2.27 (s, 3 H, Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.1, 158.5, 150.5, 147.1, 135.4,
129.7, 129.2, 127.6, 127.5, 127.1, 123.6, 113.5, 11.5, 10.6 ppm.
C14H12N2O (224.26): calcd. C 74.98, H 5.39; found C 75.01, H
5.28.
forded the corresponding product 14 in 88% (0.192 g) isolated
1
yield. H NMR (300 MHz, CDCl3): δ = 8.20 (d, J = 8.2 Hz, 1 H,
Ar), 8.11 (s, 1 H, Ar), 7.64 (t, J = 7.7 Hz, 1 H, Ar), 7.59 (d, J =
8.2 Hz, 1 H, Ar), 2.43 (s, 3 H, Me), 2.28 (s, 3 H, Me) ppm.
4-[3,5-Bis(trifluoromethyl)phenyl]-3,5-dimethylisoxazole (15): The
reaction of 1-bromo-3,5-bis(trifluoromethyl)benzene (0.293 g,
1 mmol), 3,5-dimethylisoxazole (0.144 g, 1.5 mmol) and AcOK
(0.196 g, 2 mmol) at 130 °C in dry DMAc (5 mL) in the presence
of PdCl2 (0.0004 g, 0.002 mmol) afforded the corresponding prod-
uct 15 in 92% (0.285 g) isolated yield. 1H NMR (300 MHz,
CDCl3): δ = 7.90 (s, 1 H, Ar), 7.73 (s, 2 H, Ar), 2.47 (s, 3 H, Me),
2.31 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.4,
158.0, 132.9, 132.5 (q, J = 33.8 Hz), 129.0, 122.5 (q, J = 273.1 Hz),
121.4, 114.5, 11.6, 10.6 ppm. C13H9F6NO (309.21): calcd. C 50.50,
H 2.93; found C 50.61, H 3.07.
4-(3,5-Dimethylisoxazol-4-yl)isoquinoline (21): The reaction of 4-
bromoisoquinoline (0.208 g, 1 mmol), 3,5-dimethylisoxazole
(0.144 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 21 in 89% (0.200 g) isolated
1
yield. H NMR (300 MHz, CDCl3): δ = 9.28 (s, 1 H, Ar), 8.36 (s,
1 H, Ar), 8.06 (d, J = 8.5 Hz, 1 H, Ar), 7.71 (t, J = 7.8 Hz, 1 H,
Ar), 7.64 (t, J = 7.7 Hz, 1 H, Ar), 7.55 (d, J = 8.5 Hz, 1 H, Ar),
2.27 (s, 3 H, Me), 2.09 (s, 3 H, Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.0, 159.8, 153.0, 144.3, 134.8, 131.0, 128.4, 128.2,
127.6, 124.0, 121.3, 111.6, 11.4, 10.5 ppm. C14H12N2O (224.26):
calcd. C 74.98, H 5.39; found C 75.04, H 5.47.
3,5-Dimethyl-4-m-tolylisoxazole (16): The reaction of 3-bromotolu-
ene (0.171 g, 1 mmol), 3,5-dimethylisoxazole (0.144 g, 1.5 mmol)
and AcOK (0.196 g, 2 mmol) at 130 °C in dry DMAc (5 mL) in
the presence of PdCl2 (0.0009 g, 0.005 mmol) afforded the corre-
sponding product 16 in 89% (0.167 g) isolated yield. 1H NMR
(300 MHz, CDCl3): δ = 7.32 (t, J = 7.8 Hz, 1 H, Ar), 7.16 (d, J =
8.2 Hz, 1 H, Ar), 7.05 (s, 1 H, Ar), 7.04 (d, J = 8.2 Hz, 1 H, Ar),
5-(3,5-Dimethylisoxazol-4-yl)pyrimidine (22): The reaction of 5-bro-
2.39 (s, 6 H, Me), 2.26 (s, 3 H, Me) ppm. 13C NMR (75 MHz, mopyrimidine (0.159 g, 1 mmol), 3,5-dimethylisoxazole (0.144 g,
Eur. J. Org. Chem. 2009, 4041–4050
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4047

Y. Fall, C. Reynaud, H. Doucet, M. Santelli
FULL PAPER
1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry DMAc
(5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) afforded
the corresponding product 22 in 84% (0.147 g) isolated yield. 1H
NMR (300 MHz, CDCl3): δ = 9.18 (s, 1 H, Ar), 8.66 (s, 2 H, Ar),
4-(4-Methoxyphenyl)-3-methyl-5-phenylisoxazole (28): The reaction
of 4-bromoanisole (0.187 g, 1 mmol), 3-methyl-5-phenylisoxazole
(0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0009 g, 0.005 mmol) af-
2.43 (s, 3 H, Me), 2.27 (s, 3 H, Me) ppm. 13C NMR (75 MHz, forded the corresponding product 28 in 77% (0.204 g) isolated
CDCl3): δ = 166.8, 158.1, 157.6, 156.4, 125.1, 110.2, 11.5, 10.6 ppm.
C9H9N3O (175.19): calcd. C 61.70, H 5.18; found C 61.79, H 5.27.
yield. 1H NMR (300 MHz, CDCl3): δ = 7.65–7.50 (m, 2 H, Ar),
7.30–7.25 (m, 3 H, Ar), 7.20 (d, J = 8.2 Hz, 2 H, Ar), 6.97 (d, J =
8.2 Hz, 2 H, Ar), 3.86 (s, 3 H, OMe), 2.23 (s, 3 H, Me) ppm. 13C
NMR (75 MHz, CDCl3): δ = 164.0, 160.2, 159.4, 130.9, 129.5,
128.5, 128.0, 126.7, 122.6, 115.8, 114.5, 55.2, 10.5 ppm. C17H15NO2
(265.31): calcd. C 76.96, H 5.70; found C 76.97, H 5.57.
4-(3-Methyl-5-phenylisoxazol-4-yl)benzaldehyde (23): The reaction
of 4-bromobenzaldehyde (0.187 g, 1 mmol), 3-methyl-5-phenylisox-
azole (0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in
dry DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol)
afforded the corresponding product 23 in 90% (0.226 g) isolated
3-Methyl-4-(3-nitrophenyl)-5-phenylisoxazole (29): The reaction of
1-bromo-3-nitrobenzene (0.202 g, 1 mmol), 3-methyl-5-phenylisox-
azole (0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in
dry DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol)
afforded the corresponding product 29 in 90% (0.252 g) isolated
yield. 1H NMR (300 MHz, CDCl3): δ = 8.25 (m, 1 H, Ar), 8.16
(m, 1 H, Ar), 7.62 (d, J = 8.4 Hz, 2 H, Ar), 7.50–7.25 (m, 5 H,
Ar), 2.27 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.3,
159.4, 148.6, 135.9, 132.4, 130.2, 130.1, 128.8, 127.0, 126.8, 124.5,
123.0, 113.9, 10.5 ppm. C16H12N2O3 (280.28): calcd. C 68.56, H
4.32; found C 68.59, H 4.21.
1
yield. H NMR (300 MHz, CDCl3): δ = 10.05 (s, 1 H, CHO), 7.94
(d, J = 8.2 Hz, 2 H, Ar), 7.52–7.20 (m, 7 H, Ar), 2.27 (s, 3 H, Me)
ppm. 13C NMR (75 MHz, CDCl3): δ = 191.5, 165.1, 159.4, 137.1,
135.7, 130.4, 130.2, 130.1, 128.7, 127.3, 127.0, 115.0, 10.6 ppm.
C17H13NO2 (263.29): calcd. C 77.55, H 4.98; found C 77.60, H
4.87.
4-(3-Methyl-5-phenylisoxazol-4-yl)acetophenone (24): The reaction
of 4-bromoacetophenone (0.199 g, 1 mmol), 3-methyl-5-phenyl-
isoxazole (0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at
130 °C in dry DMAc (5 mL) in the presence of PdCl2 (0.0004 g,
0.002 mmol) afforded the corresponding product 24 in 85%
3-(3-Methyl-5-phenylisoxazol-4-yl)acetophenone (30): The reaction
of 3-bromoacetophenone (0.199 g, 1 mmol), 3-methyl-5-phenyl-
isoxazole (0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at
130 °C in dry DMAc (5 mL) in the presence of PdCl2 (0.0004 g,
0.002 mmol) afforded the corresponding product 30 in 80%
1
(0.236 g) isolated yield. H NMR (300 MHz, CDCl3): δ = 8.02 (d,
J = 8.3 Hz, 2 H, Ar), 7.55–7.20 (m, 7 H, Ar), 2.64 (s, 3 H, COMe),
2.26 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 197.5,
164.9, 159.6, 136.5, 135.7, 130.0, 129.9, 129.0, 128.7, 127.4, 127.0,
115.2, 26.6, 10.6 ppm. C18H15NO2 (277.32): calcd. C 77.96, H 5.45;
found C 77.99, H 5.37.
1
(0.222 g) isolated yield. H NMR (300 MHz, CDCl3): δ = 7.98 (dt,
J = 7.2 and 1.7 Hz, 1 H, Ar), 7.90–7.81 (m, 1 H, Ar), 7.60–7.45
(m, 4 H, Ar), 7.35–7.28 (m, 3 H, Ar), 2.57 (s, 3 H, COMe), 2.24
(s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 197.5, 164.8,
159.8, 138.0, 134.5, 131.4, 130.0, 129.7, 129.5, 128.8, 128.0, 127.6,
126.9, 115.3, 26.7, 10.6 ppm. C18H15NO2 (277.32): calcd. C 77.96,
H 5.45; found C 77.79, H 5.54.
4-(3-Methyl-5-phenylisoxazol-4-yl)benzonitrile (25): The reaction of
4-bromobenzonitrile (0.182 g, 1 mmol), 3-methyl-5-phenylisoxazole
(0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 25 in 88% (0.229 g) isolated
3-Methyl-5-phenyl-4-m-tolylisoxazole (31): The reaction of 3-bro-
motoluene (0.171 g, 1 mmol), 3-methyl-5-phenylisoxazole (0.239 g,
1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry DMAc
(5 mL) in the presence of PdCl2 (0.0009 g, 0.005 mmol) afforded
the corresponding product 31 in 84% (0.209 g) isolated yield. 1H
NMR (300 MHz, CDCl3): δ = 7.60–7.50 (m, 2 H, Ar), 7.40–7.00
(m, 7 H, Ar), 2.38 (s, 3 H, Me), 2.24 (s, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 164.1, 160.1, 138.7, 130.5, 130.4, 129.5,
128.9, 128.8, 128.5, 128.0, 126.9, 126.8, 116.2, 21.3, 10.5 ppm.
C17H15NO (249.31): calcd. C 81.90, H 6.06; found C 82.04, H 6.14.
1
yield. H NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 8.4 Hz, 2 H,
Ar), 7.50–7.20 (m, 7 H, Ar), 2.26 (s, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.2, 159.2, 135.6, 132.7, 130.4, 130.2,
128.8, 127.0, 126.9, 118.3, 114.5, 111.8, 10.6 ppm. C17H12N2O
(260.29): calcd. C 78.44, H 4.65; found C 78.50, H 4.79.
3-Methyl-4-(4-nitrophenyl)-5-phenylisoxazole (26): The reaction of
1-bromo-4-nitrobenzene (0.202 g, 1 mmol), 3-methyl-5-phenylisox-
azole (0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in
dry DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol)
afforded the corresponding product 26 in 90% (0.252 g) isolated
2-(3-Methyl-5-phenylisoxazol-4-yl)benzonitrile (32): The reaction of
2-bromobenzonitrile (0.182 g, 1 mmol), 3-methyl-5-phenylisoxazole
(0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 32 in 86% (0.224 g) isolated
yield. 1H NMR (300 MHz, CDCl3): δ = 7.80 (dd, J = 8.2 and
1.1 Hz, 1 H, Ar), 7.68 (td, J = 7.7 and 1.5 Hz, 1 H, Ar), 7.54 (td,
J = 7.7 and 1.5 Hz, 1 H, Ar), 7.45–7.25 (m, 6 H, Ar), 2.24 (s, 3 H,
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8, 159.6, 134.6,
133.6, 133.3, 131.6, 130.1, 128.9, 128.8, 127.2, 126.6, 117.1, 114.0,
112.7, 10.3 ppm. C17H12N2O (260.29): calcd. C 78.44, H 4.65;
found C 78.57, H 4.71.
1
yield. H NMR (300 MHz, CDCl3): δ = 8.28 (d, J = 8.2 Hz, 2 H,
Ar), 7.52–7.20 (m, 7 H, Ar), 2.28 (s, 3 H, Me) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.5, 159.2, 147.5, 137.7, 130.6, 130.3,
128.9, 127.1, 124.2, 114.2, 10.6 ppm. C16H12N2O3 (280.28): calcd.
C 68.56, H 4.32; found C 68.64, H 4.14.
4-(4-Fluorophenyl)-3-methyl-5-phenylisoxazole (27): The reaction of
1-bromo-4-fluorobenzene (0.175 g, 1 mmol), 3-methyl-5-phenyl-
isoxazole (0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at
130 °C in dry DMAc (5 mL) in the presence of PdCl2 (0.0004 g,
0.002 mmol) afforded the corresponding product 27 in 88%
(0.223 g) isolated yield. 1H NMR (300 MHz, CDCl3): δ = 7.60–
7.45 (m, 2 H, Ar), 7.40–7.20 (m, 5 H, Ar), 7.13 (t, J = 8.2 Hz, 2
H, Ar), 2.23 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ =
165.2, 162.1 (d, J = 247.2 Hz), 160.0, 131.6 (d, J = 8.1 Hz), 129.8,
128.7, 127.4, 126.9, 126.5 (d, J = 3.4 Hz), 116.2 (d, J = 21.7 Hz),
3-Methyl-4-(naphthalen-1-yl)-5-phenylisoxazole (33): The reaction
of 1-bromonaphthalene (0.207 g, 1 mmol), 3-methyl-5-phenylisox-
azole (0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in
dry DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol)
115.2, 10.5 ppm. C16H12FNO (253.27): calcd. C 75.88, H 4.78; afforded the corresponding product 33 in 90% (0.256 g) isolated
1
found C 75.62, H 4.80.
yield. H NMR (300 MHz, CDCl3): δ = 7.97 (d, J = 8.2 Hz, 2 H,
4048
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Eur. J. Org. Chem. 2009, 4041–4050

Ligand-Free-Palladium-Catalyzed Direct 4-Arylation of Isoxazoles
Ar), 7.75–7.30 (m, 7 H, Ar), 7.25–7.10 (m, 3 H, Ar), 2.09 (s, 3 H,
H, Ar), 2.51 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ =
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.8, 161.1, 133.9, 184.9, 169.4, 158.2, 132.2, 130.4, 118.4, 114.5, 112.2, 11.4 ppm.
132.1, 129.5, 128.8, 128.7, 128.6, 128.5, 128.0, 127.7, 126.7, 126.3,
126.2, 125.7, 125.0, 114.0, 10.3 ppm. C20H15NO (285.34): calcd. C
84.19, H 5.30; found C 84.40, H 5.15.
C12H8N2O2 (212.20): calcd. C 67.92, H 3.80; found C 67.87, H
3.69.
3-(3-Methyl-5-phenylisoxazol-4-yl)pyridine (34): The reaction of 3-
bromopyridine (0.158 g, 1 mmol), 3-methyl-5-phenylisoxazole
(0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 34 in 90% (0.213 g) isolated
yield. 1H NMR (300 MHz, CDCl3): δ = 8.60 (dd, J = 4.8 and
1.6 Hz, 1 H, Ar), 8.52 (d, J = 2.3 Hz, 1 H, Ar), 7.57 (dt, J = 8.0
and 2.0 Hz, 1 H, Ar), 7.50–7.20 (m, 6 H, Ar), 2.21 (s, 3 H, Me)
ppm. 13C NMR (75 MHz, CDCl3): δ = 165.2, 159.6, 150.3, 149.1,
137.0, 129.9, 128.7, 127.2, 126.7, 123.6, 112.5, 10.4 ppm.
C15H12N2O (236.27): calcd. C 76.25, H 5.12; found C 76.41, H
5.18.
Acknowledgments
We thank the Centre National de la Recherche Scientifique and
“Rennes Metropole” for providing financial support.
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3-(3-Methyl-5-phenylisoxazol-4-yl)quinoline (35): The reaction of 3-
bromoquinoline (0.208 g, 1 mmol), 3-methyl-5-phenylisoxazole
(0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in dry
DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol) af-
forded the corresponding product 35 in 91% (0.260 g) isolated
1
yield. H NMR (300 MHz, CDCl3): δ = 8.78 (d, J = 2.3 Hz, 1 H,
Ar), 8.15 (d, J = 8.5 Hz, 1 H, Ar), 8.08 (d, J = 2.3 Hz, 1 H, Ar),
7.81 (d, J = 8.5 Hz, 1 H, Ar), 7.75 (t, J = 7.5 Hz, 1 H, Ar), 7.57
(t, J = 7.5 Hz, 1 H, Ar), 7.50 (d, J = 7.5 Hz, 2 H, Ar), 7.33–7.20
(m, 3 H, Ar), 2.28 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3):
δ = 165.4, 159.9, 151.1, 147.3, 136.3, 130.0, 129.9, 129.3, 128.7,
127.7, 127.6, 127.2, 127.1, 126.7, 123.9, 112.6, 10.5 ppm.
C19H14N2O (286.33): calcd. C 79.70, H 4.93; found C 79.84, H
4.98.
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4-(3-Methyl-5-phenylisoxazol-4-yl)isoquinoline (36): The reaction of
4-bromoisoquinoline (0.208 g, 1 mmol), 3-methyl-5-phenylisox-
azole (0.239 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 130 °C in
dry DMAc (5 mL) in the presence of PdCl2 (0.0004 g, 0.002 mmol)
afforded the corresponding product 36 in 91% (0.260 g) isolated
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1
yield. H NMR (300 MHz, CDCl3): δ = 9.35 (s, 1 H, Ar), 8.47 (s,
1 H, Ar), 8.30–8.05 (m, 1 H, Ar), 7.75–7.50 (m, 3 H, Ar), 7.38 (d,
J = 7.5 Hz, 2 H, Ar), 7.30–7.10 (m, 3 H, Ar), 2.09 (s, 3 H, Me)
ppm. 13C NMR (75 MHz, CDCl3): δ = 165.8, 161.0, 153.2, 144.4,
134.7, 131.3, 129.8, 128.6, 128.4, 128.2, 127.8, 127.3, 126.3, 124.0,
121.9, 110.4, 10.3 ppm. C19H14N2O (286.33): calcd. C 79.70, H
4.93; found C 79.84, H 4.71.
Methyl 4-(4-Acetylphenyl)-5-methylisoxazole-3-carboxylate (37):
The reaction of 4-bromoacetophenone (0.199 g, 1 mmol), methyl
5-methylisoxazole-3-carboxylate (0.212 g, 1.5 mmol) and AcOK
(0.196 g, 2 mmol) at 80 °C in dry DMAc (5 mL) in the presence
of [PdCl(C3H5)]2 (0.007 g, 0.02 mmol) afforded the corresponding
product 37 in 27% (0.070 g) isolated yield. 1H NMR (300 MHz,
CDCl3): δ = 8.01 (d, J = 8.3 Hz, 2 H, Ar), 7.41 (d, J = 8.3 Hz, 2
H, Ar), 3.88 (s, 3 H, CO2Me), 2.62 (s, 3 H, COMe), 2.46 (s, 3 H,
Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 197.4, 168.7, 160.2,
153.4, 136.7, 133.6, 130.1, 128.3, 116.8, 52.7, 26.6, 11.5 ppm.
C14H13NO4 (259.26): calcd. C 64.86, H 5.05; found C 64.69, H
5.20.
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4-(3-Formyl-5-methylisoxazol-4-yl)benzonitrile (39): The reaction of
4-bromobenzonitrile (0.182 g, 1 mmol), 3-formyl-5-methylisoxazole
(0.167 g, 1.5 mmol) and AcOK (0.196 g, 2 mmol) at 60 °C in dry
DMAc (5 mL) in the presence of [PdCl(C3H5)]2 (0.007 g,
0.02 mmol) afforded the corresponding product 39 in 26%
(0.055 g) isolated yield. 1H NMR (300 MHz, CDCl3): δ = 10.18 (s,
1 H, CHO), 7.72 (d, J = 8.3 Hz, 2 H, Ar), 7.45 (d, J = 8.3 Hz, 2
Eur. J. Org. Chem. 2009, 4041–4050
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4049

Y. Fall, C. Reynaud, H. Doucet, M. Santelli
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4050
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Eur. J. Org. Chem. 2009, 4041–4050