Regioselective conversion of alkynes to 4-substituted and 3,4-disubstituted isoxazoles using titanium-catalyzed multicomponent coupling reactions

Article abstract of DOI:10.1016/j.tet.2011.11.043

Conditions have been developed for the regioselective synthesis of 4-substituted isoxazoles from terminal alkynes and 3,4-disubstituted isoxazoles from internal alkynes. The methodology involves a one-pot titanium-catalyzed multicomponent coupling reactio

Full text of DOI:10.1016/j.tet.2011.11.043

Tetrahedron 68 (2012) 807e812
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective conversion of alkynes to 4-substituted and 3,4-disubstituted
isoxazoles using titanium-catalyzed multicomponent coupling reactions
*
Amila A. Dissanayake, Aaron L. Odom
Michigan State University, Department of Chemistry, East Lansing, MI 48824, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 August 2011
Received in revised form 12 November 2011
Accepted 15 November 2011
Available online 19 November 2011
Conditions have been developed for the regioselective synthesis of 4-substituted isoxazoles from ter-
minal alkynes and 3,4-disubstituted isoxazoles from internal alkynes. The methodology involves a one-
pot titanium-catalyzed multicomponent coupling reaction followed by simple hydroxylamine hydro-
chloride addition.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Isoxazoles
Multicomponent coupling
Titanium
Alkyne
1. Introduction
2. Results and discussion
Isoxazoles are heterocyclic frameworks of some importance in
a large variety of applications including pharmaceuticals, herbi-
cides, and pesticides.1 Pharmaceutical examples, which are quite
varied, include Leflunomide (arthritis),2 Cloxacillin (antibiotic),3
and NVP-AUY922 (anticancer).4 Isoxazoles can also be converted
to other compounds of potential utility in organic chemistry, e.g., Z-
The titanium catalysts for these reactions use pyrrolyl-based
ancillary ligands prepared in a single step (Scheme 1). A double
Mannich reaction between methylamine hydrochloride, formal-
dehyde (formalin), and pyrrole generates N,N-di(methyl-a-pyr-
rolyl)-N-methylamine (H2dpma).14 The other ancillary commonly
employed, 5,5-dimethyldipyrrolylmethane (H2dpm), is prepared
from acid-catalyzed condensation of pyrrole and acetone.15
b
-siloxyacrylonitriles.5
In previous research, we have investigated the use of a titanium-
Addition of the NH-pyrrole compounds H2dpm and H2dpma to
commercially available Ti(NMe2)4 generates the catalysts in high
yield (Scheme 1). For this work, two different catalysts were
employed. For most of the reactions, the milder catalyst with the
tridentate ancillary, Ti(dpma)(NMe2)2 (2),16 was found to be optimal.
In a few cases, more reactive Ti(dpm)(NMe2)2 (1)17 gave higher con-
versions, especially with more sterically hindered (internal) alkynes.
In Scheme 2 is the proposed mechanism for the 3CC,18,6 which
has been dubbed alkyne iminoamination because the overall
transformation involves addition of an iminyl group and amine
across the CeC triple bond.19 The proposed pathway involves the
addition of the primary amine to the titanium precatalyst forming
an imido with liberation of dimethylamine. Titanium imido com-
plexes can undergo [2þ2]-cycloaddition with alkynes to produce
azatitanacyclobutenes. The CeC bond in metallacycles of this type
are known to 1,1-insert isonitriles to give the five-membered
metallacycle. Protolysis of the TieC and TieN bonds in the metal-
lacycle with primary amine liberates the iminoamination product
from the metal and regenerates the titanium imido species.20
catalyzed 3-component coupling (3CC) reaction6 for the synthesis
of unsymmetrical 1,3-diimine tautomers.7e9 The reaction involves
readily-prepared titanium catalysts that couple an alkyne, iso-
nitrile, and primary amine; in these processes, new CeC and CeN
bonds are formed in a single catalytic step.
One-pot procedures are being developed that utilize these
titanium-catalyzed 3CC reactions in conjunction with addition of
other reagents to generate a variety of different heterocyclic
frameworks, such as pyrimidines,10 quinolines,11 and pyrazoles.12
Here, we describe the use of these catalyzed 3CC reactions in
conjunction with hydroxylamine addition to produce isoxazoles.
Conditions for the regioselective cyclization have been developed
that allow formation and ready isolation of 4-substituted and 3,4-
disubstituted isoxazoles.13
* Corresponding author. Tel.: þ1 517 355 9715x171; fax: þ1 517 353 1793; e-mail
address: odom@chemistry.msu.edu (A.L. Odom).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.043

808
A.A. Dissanayake, A.L. Odom / Tetrahedron 68 (2012) 807e812
H
N
R1 NH2
+
H
N
R4HN
N
O
10 mol% TFA
50%
20
10 mol% 1 or 2
R1
R2
R3
NH
H2dpm
toluene, 100 °C
24 h
+
N
R2
R3
R4
C
ether
Ti(NMe2)4 RT, 3 h
91%
NH2OH•HCl
solvent
NMe2
N
N
Ti NMe2
N
NMe2
NMe2
R2
N
R3
Ti
N
N
Me
Ti(NMe2)2(dpma) (2)
Ti(NMe2)2(dpm) (1)
O
Scheme 3. General scheme for the synthesis of isoxazoles.
ether
substituted isoxazoles. A listing of the 4-substituted isoxazoles
prepared during this study is shown in Table 1.
Ti(NMe2)4
NH
RT, 1 h
97%
H
N
H
Table 1
N
N
+ 2 HCHO
+ MeNH3Cl
Examples of 4-aryl isoxazoles prepareda
Me
2
EtOH/H2O
55 °C
88%
H2dpma
Entry
Alkyne
Catalyst
Product
Isolated yield (%)
35b
Scheme 1. Synthesis of catalysts 1 and 2.
a
2
[Ti](NMe2)2
precatalyst
H2NR1 – 2 HNMe2
R4HN
N
b
c
2
2
55b
R1
R1
N
R2
R3
[Ti]
51b
H2NR1
R2
R3
R1
N
R2
R3
[Ti]
N
d
e
2
2
48b
R1
R2
R3
R4
N
C
[Ti]
N
R4
R3
R4HN
N
57b
titanium
catalyst
R1
H2NR1
C
N
R4
R2
R2
R3
Scheme 2. Proposed catalytic cycle for alkyne iminoamination and the overall trans-
formation (bottom).
f
1
50c
The choice of amine is flexible, but good results were obtained
when using cyclohexylamine with catalyst 2 and aniline with cat-
alyst 1.
The general strategy for the one-pot synthesis of isoxazoles used
here is shown in Scheme 3. The 3CC reaction is commonly done at
100 ꢀC in toluene. The products of iminoamination can be converted
to isoxazoles by addition of H2NOH$HCl and a more polar solvent.
The one-pot synthesis of 4-substituted isoxazoles was readily
accomplished using the procedure in Scheme 3 where R2¼H. The
added solvent for the cyclization step involving hydroxylamine
hydrochloride was ethanol in this case.
The reaction, for reasons currently unknown, was limited to
vinyl-, heterocycle-, and aryl-substituted terminal alkynes. With
alkyl-containing terminal alkynes, e.g., 1-hexyne, the 3-CC reaction
works well; however, the addition of hydroxylamine under any
conditions we investigated did not result in formation of the alkyl-
g
2
2
48b
60b
h
a
Reaction conditions: cyclohexylamine or aniline (1 mmol), tert-butylisonitrile
(1.5 mmol), alkyne (1 mmol), 1 or 2 (0.1 mmol), 2 mL toluene, 24 h, 100 ꢀC. Then,
H2NOH$HCl (1.2 mmol) in 2 mL absolute ethanol was added, and the solution was
stirred for 16 h at room temperature.
b
Catalyst 2 and cyclohexylamine were used.
Catalyst 1 and aniline were used.
c

A.A. Dissanayake, A.L. Odom / Tetrahedron 68 (2012) 807e812
809
The multicomponent coupling reaction is quite sensitive to the
size of the alkynes. As a consequence, terminal alkynes react more
readily, and the less reactive catalyst 1 can be employed.21
For these terminal alkynes, the regioselectivity of the 3-
component coupling product is extremely good. The regiose-
lectivity for the [2þ2]-cycloaddition between the alkyne and tita-
nium imido (Scheme 2) that goes onto product22 favors having the
aromatic group adjacent to titanium in the metallacyclobutene
intermediate, which may be due to stabilization of the partial
negative charge on the carbon connected to titanium by the aro-
matic group. The result is a single observed isomer from the mul-
ticomponent coupling reaction. From the observed isomer, the
addition of hydroxylamine can only result in a single regioisomer
for monosubstituted aromatic alkynes.
a mixture of two regioisomers. However, the reaction with catalyst
1 did provide single observed regioisomer.
For internal alkynes, the iminoamination reaction typically gives
a single product for the substrates investigated; however, regiose-
lectivity of the hydroxylamine cyclization reaction often gave mix-
tures using the conditions described above for terminal alkynes.
We explored changing the amine (R1) substituent as a method of
controlling the 3,4- to 4,5-isomer ratio of isoxazole products ob-
tained. Using 1-phenylpropyne as the test system, we investigated
the effect of aniline substituents on the isomer ratio. The results of
those studies are shown in Table 2. Ethanol was used as the solvent
here as before, and the reactions were heated slightly as the cy-
clizations were somewhat slower than with terminal alkynes.
While most substitutions on the aniline ring had little conse-
quence on the isomer ratios and there is no clear electronic effect,
one of the aniline derivatives did significantly improve the regio-
selectivity, 3,5-dichloroaniline (Table 2, entry e).
The only terminal alkyne not giving good regioselectivity with 2
as catalyst was 3-alkynylindole (Table 1, entry f), which gave
Further optimization was undertaken through examining sol-
vent effects on the isomer ratio. Those results are summarized in
Table 3. As shown, the use of THF with 3,5-dichloroaniline as the
amine substrate provided a single isomer, the 3,4-disubstituted
Table 2
Effect of R1 on the isomer ratio in the synthesis of 4-phenyl-3-methylisoxazole
NHBut
Amine
+
N
R1
Ph
But
Me
Ph
10 mol% 1
toluene, 100 °C
+
Table 3
Me
Solvent effects on the isomer ratio in the synthesis of 4-phenyl-3-methylisoxazole
N
C
Cl
(1) 10 mol% 1
ethanol, 45 °C
16 h
NH2
NH2OH•HCl
toluene, 100 °C, 48 h
Ph
H3C
CH3
Ph
(2) NH2OH•HCl
solvent, 45 °C, 16 h
Cl
+
+
+
N
Ph
Me
N
Ph
O
O
CH3
Ph
But
N C
+
N
H3C
N
O
O
Entry
Solvent
Isomer ratio
Entry
Amine
Isomer ratio
a
b
c
d
e
f
EtOH
EtOAc
DMF
THF
1,4-Dioxane
N,N-Dimethylacetamide
DMSO
1.0:8.0
1.0:5.2
1.0:4.6
1.0:>50
1.0:3.1
1.0:4.0
1.0:5.3
a
b
c
1.0:1.8
1.0:1.1
1.0:2.3
1.0:1.8
g
Table 4
The 3,4-disubstituted isoxazoles prepared during this studya
Entry
Alkyne
Catalyst
Product
Isolated yield (%)
35
d
a
1
e
1.0:8.0
b
1
1
25
30
f
1.0:1.5
1.0:1.1
g
c
h
i
1.0:1.5
1.0:1.4
a
Reaction conditions: 3,5-dichloroaniline (1 mmol), tert-butylisonitrile
(0.1 mmol), 2 mL toluene, 24 h, 100 ꢀC. Then,
(1.5 mmol), alkyne (1 mmol),
1
H2NOH$HCl (1.2 mmol) in 2 mL THF was added, and the solution was stirred for 16 h
at 45 ꢀC.

810
A.A. Dissanayake, A.L. Odom / Tetrahedron 68 (2012) 807e812
isoxazole, which was by far the best result of the seven solvents
investigated.
a second solvent (2 mL). The cyclization reactions were carried out
at either 25 ꢀC in ethanol (terminal alkynes) or 45 ꢀC in THF (in-
ternal alkynes) for 16 h. After completion, volatiles were removed
under reduced pressure, and the crude product was dissolved in
CH2Cl2 (20 mL) and washed with water (50 mL). The organic layer
was dried over Na2SO4 and concentrated on a rotary evaporator.
The crude product was purified by column chromatography as
described for the individual compounds below.
Products derived from a few internal alkynes were isolated
during the course of the study using the conditions found (Table 4).
The yields are w30% from the one-pot reaction, but the other iso-
mer is not an observable impurity. The products were readily iso-
lated in pure form by column chromatography.
3. Conclusions
4.2.1. 4-Phenylisoxazole (Table 1, entry a). The general procedure
was followed. The reaction vessel was loaded with tert-butylisoni-
trile (171 mL, 1.5 mmol), cyclohexylamine (95 mg, 1 mmol), phenyl-
The route described here compares favorably with other known
routes to this class of compounds. For example, the product in Table
4 (entry a), 3-methyl-4-phenylisoxazole was isolated in 35% yield
using the methodology described here in a two-step, one-pot
procedure from commercially available 1-phenylpropyne.
Thiscompoundhasbeenpreviouslydescribedintheliterature. Itis
available from a four step synthesis starting with 3-methyl-4-phenyl-
5(4H)-isoxazone, which doesn’t appear to be commercially available,
in 33% overall yield.23 The compound is also accessible using 1,3-
dipolar cycloaddition between 1-phenyl-1-trimethylsiloxyethylene
and acetonitrile oxide in 54% yield where the compound was iso-
lated by TLC.24,25
In summary, using a one-pot titanium-catalyzed multicompo-
nent coupling route, it is possible to readily access a large number of
4-substituted and 3,4-disubstituted isoxazoles in a regioselective
manner. The products are easily isolated in pure form after the one-
pot syntheses.
acetylene (102 mg, 1 mmol), and 2 (32.4 mg, 0.1 mmol) in toluene
(2 mL) and was heated for 24 h at 100 ꢀC. After completion of the
reaction, the pressure tube was cooled to room temperature. Then
the same pressure tube was charged with hydroxylamine hydro-
chloride (83 mg, 1.2 mmol) and absolute ethanol (2 mL). The re-
action was stirred at room temperature for 16 h. After completion of
the reaction, solvents were removed under reduced pressure, and
the crude product was dissolved in CH2Cl2 (20 mL) and washed with
water (50 mL). Purification was accomplished by column chroma-
tography on neutral alumina. The eluent was hexanes/ethyl acetate
9:1, which afforded the desired compound (51 mg, 35%) as a white
solid. Mp: 44e45 ꢀC (lit.27 mp: 44e46). 1H NMR (CDCl3, 500 MHz):
7.27e7.34 (1H, m, AreH), 7.39e7.42 (2H, m, AreH), 7.46e7.48 (2H,
m, AreH), 8.55 (1H, s, 3-CH isoxazole), 8.66 (1H, s, 5-CH isoxazole).
13C{1H} NMR (CDCl3, 125 MHz): 121.3, 126.3, 128.0, 128.4, 129.1,
147.9, 153.3. MS(EI): m/z 145 (Mþ). Elemental Analysis: found: %C,
74.85; %H, 4.52; %N, 9.71; expected: %C, 74.47; %H, 4.86; %N, 9.65.
4. Experimental section
4.1. General considerations
4.2.2. 4-(4-Bromophenyl)isoxazole (Table 1, entry b). The general
procedure was followed. The reaction was carried out with tert-
All manipulations of air sensitive compounds were carried out
in an MBraun dry box under a purified nitrogen atmosphere. Tol-
uene was purified by sparging with dry N2 and removing water by
running through activated alumina systems purchased from Solv-
Tek. 1H and 13C spectra were recorded on VXR-500 spectrometers.
Melting points were measured on a Mel-Temp II apparatus with
a mercury thermometer and are uncalibrated. Ti(NMe2)2(dpm) (1)
and Ti(NMe2)2(dpma) (2) were made following the literature pro-
cedures. Alkynes were purchased either from Aldrich or from GFS
chemicals and were distilled from CaO under dry nitrogen. Amines
were purchased from Aldrich, dried over KOH, and distilled under
dry nitrogen. tert-Butylisonitrile was made according to the liter-
ature procedure26 and purified by distillation under nitrogen. Hy-
droxylamine hydrochloride was purchased from Columbus
Chemical Industries, and neutral alumina was purchased Sigma-
eAldrich Co and used as received. EtOH, CH2Cl2, hexanes, and
EtOAc were purchased from Mallinckrodt chemicals and used as
received.
butylisonitrile (171 mL,1.5 mmol), cyclohexylamine (95 mg,1 mmol),
1-bromo-4-ethynylbenzene (181 mg, 1 mmol), and 2 (32.4 mg,
0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 ꢀC. After
completion of the reaction the pressure tube was cooled to room
temperature. Then the same pressure tube was charged with hy-
droxylamine hydrochloride (83 mg, 1.2 mmol) and absolute ethanol
(2 mL) and stirred at room temperature for 16 h. After completion of
the reaction, solvents were removed under reduced pressure, and
the crude product was dissolved in CH2Cl2 (20 mL) and washed with
water (50 mL). Purification was accomplished by column chroma-
tography on neutral alumina. The eluent was hexanes/ethyl acetate
9.5:0.5, which afforded the desired compound (123 mg, 55%) as
a yellow solid. Mp: 111e113 ꢀC (lit.28 mp: 113). 1H NMR (CDCl3,
500 MHz): 7.32e7.34 (2H, d, 11 Hz, AreH), 7.51e7.53 (2H, d, 11 Hz,
AreH), 8.51 (1H, s, 3-CH isoxazole), 8.65 (1H, s, 5-CH isoxazole). 13C
{1H} NMR (CDCl3, 125 MHz): 120.4, 121.9, 127.4, 127.9, 132.3, 147.7,
153.5. MS(EI): m/z 224 (Mþ). Elemental Analysis: found: %C, 47.93; %
H, 2.59; %N, 6.34; expected: %C, 48.25; %H, 2.70; %N, 6.25.
4.2. General procedure for isoxazole synthesis
4.2.3. 4-p-Tolylisoxazole (Table 1, entry c). The general procedure
was followed. The reaction was carried out with tert-butylisonitrile
In an N2 filled glove box, a 40 mL pressure tube, equipped with
a magnetic stir bar was loaded with amine (1 mmol), catalyst
(10e20 mol %), alkyne (1 mmol), isonitrile (1.5 mmol), and 2 mL of
dry toluene. While many different amines can be employed, the
two amines most commonly used were cyclohexylamine (with
catalyst 2) and aniline (with catalyst 1). For internal alkynes, the
more active catalyst, 1, was used with 3,5-dichloroaniline. The
pressure tube was sealed with a Teflon screw cap, taken out of the
dry box, and heated at the temperature listed for either 24 h (ter-
minal alkynes) or 48 h (internal alkynes) with stirring. After com-
pletion of the reaction (checked by GC-FID), the pressure tube was
cooled to room temperature. Then the same pressure tube was
charged with hydroxylamine hydrochloride (1.2 mmol) and
(171 mL, 1.5 mmol), cyclohexylamine (95 mg, 1 mmol), 1-ethynyl-4-
methylbenzene (116 mg, 1 mmol), and 2 (32.4 mg, 0.1 mmol) in
toluene (2 mL) and was heated for 24 h at 100 ꢀC. After completion
of the reaction the pressure tube was cooled to room temperature.
Then the same pressure tube was charged with hydroxylamine
hydrochloride (83 mg, 1.2 mmol) and absolute ethanol (2 mL) and
stirred at room temperature for 16 h. After completion of the re-
action, solvents were removed under reduced pressure, and the
crude product was dissolved in CH2Cl2 (20 mL) and washed with
water (50 mL). Purification was accomplished by column chroma-
tography on neutral alumina. The eluent was hexanes/ethyl acetate
9:1, which afforded the desired compound (81 mg, 51%) as a yellow
oil. 1H NMR (CDCl3, 500 MHz): 2.36 (3H, s, CH3), 7.20e7.22 (2H, d,

A.A. Dissanayake, A.L. Odom / Tetrahedron 68 (2012) 807e812
811
8 Hz, AreH), 7.34e7.36 (2H, d, 8 Hz, AreH), 8.52 (1H, s, 3-CH iso-
xazole), 8.62 (1H, s, 5-CH isoxazole). 13C{1H} NMR (CDCl3,
125 MHz): 21.2,121.3,125.5,126.3, 129.8,138.0,148.0,153.0. MS(EI):
m/z 159 (Mþ). Elemental Analysis: found: %C, 74.98; %H, 5.88; %N,
8.66; expected: %C, 75.45; %H, 5.70; %N, 8.80.
8.49 (1H, s, 3-CH isoxazole), 8.65 (1H, s, 5-CH isoxazole). 13C{1H}
NMR (CDCl3, 125 MHz): 50.2, 100.2, 119.4, 120.5, 122.7, 125.9,
126.9, 127.9, 128.9, 136.8, 148.8, 152.1. MS(EI): m/z 274 (Mþ). Ele-
mental Analysis: found: %C, 78.64; %H, 5.22; %N, 10.32; expected:
%C, 78.81; %H, 5.14; %N, 10.21.
4.2.4. 4-(4-Methoxyphenyl)isoxazole (Table 1, entry d). The general
procedure was followed. The reaction was carried out with tert-
4.2.7. 4-(Isoxazol-4-yl)-N,N-diphenylaniline (Table 1, entry g). The
general procedure was followed. The reaction was carried out
butylisonitrile (171
m
L,1.5 mmol), cyclohexylamine (95 mg,1 mmol),
with tert-butylisonitrile (171
(95 mg, 1 mmol), 4-ethynyl-N,N-diphenylaniline
m
L, 1.5 mmol), cyclohexylamine
(269 mg,
1-ethynyl-4-methoxybenzene (132 mg, 1 mmol), and 2 (32.4 mg,
0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 ꢀC. After
completion of the reaction the tube was cooled to room temperature.
Then the same pressure tube was charged with hydroxylamine hy-
drochloride (83 mg, 1.2 mmol) and absolute ethanol (2 mL) and
stirred at room temperature for 16 h. After completion of the re-
action, solvents were removed under reduced pressure, and the
crude product was dissolved in CH2Cl2 (20 mL) and washed with
water (50 mL). Purification was accomplished by column chroma-
tography on neutral alumina. The eluent was hexanes/ethyl acetate
9:1, which afforded the desired compound (81 mg, 51%) as a yellow
solid. Mp: 40e42 ꢀC (lit.29 mp: 40). 1H NMR (CDCl3, 500 MHz): 3.82
(3H, s, CH3), 6.93e6.94 (2H, d, 8.5 Hz, AreH), 7.37e7.39 (2H, d, 8.5 Hz,
AreH), 8.49 (1H, s, 3-CH isoxazole), 8.57 (1H, s, 5-CH isoxazole). 13C
{1H} NMR (CDCl3, 125 MHz): 55.4, 114.6, 127.7, 128.4, 129.6, 148.0,
152.5, 159.5. MS(EI): m/z 175 (Mþ). Elemental Analysis: found: %C,
67.98; %H, 5.33; %N, 8.13; expected: %C, 68.56, %H, 5.18, %N, 8.00.
1 mmol), and 2 (32.4 mg, 0.1 mmol) in toluene (2 mL) and was
heated for 24 h at 100 ꢀC. After completion of the reaction the
pressure tube was cooled to room temperature. Then the same
pressure tube was charged with hydroxylamine hydrochloride
(83 mg, 1.2 mmol) and absolute ethanol (2 mL) and stirred at room
temperature for 16 h. After completion of the reaction, solvents
were removed under reduced pressure, and the crude product was
dissolved in CH2Cl2 (20 mL) and washed with water (50 mL). Pu-
rification was accomplished by column chromatography on neu-
tral alumina. The eluent was hexanes/ethyl acetate 9.5:0.5, which
afforded the desired compound (143 mg, 48%) as a white solid.
Mp: 144e146 ꢀC. 1H NMR (CDCl3, 500 MHz) 6.97e6.99 (2H, t, 7 Hz,
AreH), 7.02e7.05 (6H, m, AreH), 7.18e7.22 (4H, m, AreH),
7.25e7.27 (2H. d, 9 Hz, AreH) 8.44 (1H, s, 3-CH isoxazole), 8.54
(1H, s, 5-CH isoxazole). 13C{1H} NMR (CDCl3, 125 MHz): 121.1,
122.1, 123.3, 123.7, 124.6, 127.2, 129.4, 147.4, 147.8, 147.9, 152.7.
MS(EI): m/z 312 (Mþ). Elemental Analysis: found: %C, 80.82; %H,
5.24; %N, 8.82; expected: %C, 80.75; %H, 5.16; %N, 8.97.
4.2.5. 4-(4-(Benzyloxy)phenyl)isoxazole (Table 1, entry e). The gen-
eral procedure was followed. The reaction was carried out with tert-
butylisonitrile (171
m
L,1.5 mmol), cyclohexylamine (95 mg,1 mmol),
4.2.8. 4-(Cyclohex-1-enyl)isoxazole (Table 1, entry h). The general
procedure was followed. The reaction was carried out with tert-
1-(benzyloxy)-4-ethynylbenzene (208 mg, 1 mmol), and 2 (32.4 mg,
0.1 mmol) in toluene (2 mL) and was heated for 24 h at 100 ꢀC. After
completion of the reaction the pressure tube was cooled to room
temperature. Then the same tube was charged with hydroxylamine
hydrochloride (83 mg, 1.2 mmol) and absolute ethanol (2 mL) and
stirred at room temperature for 16 h. After completion of the re-
action, solvents were removed under reduced pressure, and the
crude product was dissolved in CH2Cl2 (20 mL) and washed with
water (50 mL). Purification was accomplished by column chroma-
tography on neutral alumina. The eluent was hexanes/ethyl acetate
9.5:0.5, which afforded the desired compound (143 mg, 57%) as
a light brown solid. Mp: 110e112 ꢀC.1H NMR (CDCl3, 500 MHz): 5.09
(2H, s, CH2), 7.00e7.01 (2H, d, 6.5 Hz, AreH), 7.32e7.34 (1H, d, 6.5 Hz,
AreH), 7.37e7.44 (6H, m, AreH) 8.45 (1H, s, 3-CH isoxazole), 8.57
(1H, s, 5-CH isoxazole). 13C{1H} NMR (CDCl3, 125 MHz): 70.1, 115.5,
121.0, 121.2, 127.4, 127.7, 128.1, 128.6, 136.6, 148.0, 152.6, 158.6.
MS(EI): m/z 251 (Mþ). Elemental Analysis: found: %C, 76.12; %H,
5.01; %N, 5.72; expected: %C, 76.48; %H, 5.21; %N, 5.57.
butylisonitrile (171
mL, 1.5 mmol), cyclohexylamine (95 mg,
1 mmol), 1-ethynylcyclohex-1-ene (106 mg, 1 mmol), and
2
(32.4 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at
100 ꢀC. After completion of the reaction the pressure tube was
cooled to room temperature. Then the same pressure tube was
charged with hydroxylamine hydrochloride (83 mg, 1.2 mmol) and
absolute ethanol (2 mL) and stirred at room temperature for 16 h.
After completion of the reaction, solvents were removed under
reduced pressure, and the crude product was dissolved in CH2Cl2
(20 mL) and washed with water (50 mL). Purification was accom-
plished by column chromatography on neutral alumina. The eluent
was hexanes/ethyl acetate 9.5:0.5, which afforded the desired
compound (143 mg, 57%) as a yellow oil. 1H NMR (CDCl3, 500 MHz):
1.60e1.64 (2H, m, CH2), 1.68e1.73 (2H, m, CH2), 2.12e2.15 (2H, m,
CH2), 2.20e2.23 (2H, m, CH2), 6.02e6.04 (1H, m, CH), 8.24 (1H, s, 3-
CH isoxazole), 8.33 (1H, s, 5-CH isoxazole). 13C{1H} NMR (CDCl3,
125 MHz): 22.0, 22.3, 25.2, 27.3, 122.9, 125.2, 125.3, 146.8, 151.4.
MS(EI): m/z 149 (Mþ). Elemental Analysis: found: %C, 72.33; %H,
7.29; %N, 9.24; expected: %C, 72.46; %H, 7.43; %N, 9.39.
4.2.6. 4-(1-Benzyl-1H-indol-3-yl)isoxazole (Table 1, entry f). The
general procedure was followed. The reaction was carried out
with tert-butylisonitrile (171
m
L, 1.5 mmol), aniline (93 mg,
4.2.9. 3-Methyl-4-phenylisoxazole (Table 4, entry a). The general
procedure was followed. The reaction was carried out with tert-
1 mmol), 1-benzyl-3-ethynyl-1H-indole (231 mg, 1 mmol) and 1
(30.8 mg, 0.1 mmol) in toluene (2 mL) and was heated for 24 h at
100 ꢀC. After completion of the reaction the pressure tube was
cooled to room temperature. Then the same pressure tube was
charged with hydroxylamine hydrochloride (83 mg, 1.2 mmol)
and absolute ethanol (2 mL) and stirred at room temperature for
16 h. After completion of the reaction, solvents were removed
under reduced pressure, and the crude product was dissolved in
CH2Cl2 (20 mL) and washed with water (50 mL). Purification was
accomplished by column chromatography on neutral alumina. The
eluent was hexanes/ethyl acetate 8:2, which afforded the desired
compound (137 mg, 50%) as a light brown solid. Mp: 128e130 ꢀC.
1H NMR (CDCl3, 500 MHz): 5.28 (2H, s, CH2) 7.08e7.10 (2H, d, 7 Hz,
AreH), 7.14e7.29 (8H, m, AreH), 7.63e7.65 (2H, d, 9.5 Hz, AreH)
butylisonitrile (171
mL, 1.5 mmol), 3,5-dichloroaniline (162 mg,
1 mmol), 1-phenylpropyne (116 mg, 1 mmol), and 1 (30.8 mg,
0.1 mmol) in toluene (2 mL) with heating for 48 h at 100 ꢀC. The
pressure tube was cooled to room temperature. The reaction tube
was charged with hydroxylamine hydrochloride (83 mg, 1.2 mmol)
and tetrahydrofuran (2 mL) then stirred at 45 ꢀC for 16 h. Solvents
were removed in vacuo, and the crude product was dissolved in
CH2Cl2 (20 mL) and washed with water (50 mL). Purification was
accomplished by column chromatography on neutral alumina. The
eluent was hexanes/ethyl acetate 9:1, which afforded the desired
compound (55 mg, 35%) as a yellow oil. 1H NMR (CDCl3, 500 MHz):
2.56 (3H, s, CH3), 7.32e7.34 (1H, d, AreH), 7.35e7.37 (2H, m, AreH),
7.40e7.44 (2H, m, AreH), 8.34 (1H, s, 5-CH isoxazole). 13C{1H} NMR

812
A.A. Dissanayake, A.L. Odom / Tetrahedron 68 (2012) 807e812
(CDCl3, 125 MHz): 31.0, 126.0, 126.7, 127.4, 127.9, 129.1, 130.1, 150.2.
MS(EI): m/z 159 (Mþ). Elemental Analysis: found: %C, 75.28; %H,
5.59; %N, 8.92; expected: %C, 75.45; %H, 5.70; %N, 8.80.
References and notes
€
1. (a) Grunanger, P.; Vita-Finzi, P. Isoxazoles In The Chemistry of Heterocyclic
Compounds; John Wiley: New York, NY, 1991; (b) Wakefield, B. J. Sci. Synth. 2001,
11, 229; (c) Zhou, Y.; Chen, Y.; Miao, W.; Qu, J. J. Heterocycl. Chem. 2010, 47, 1310.
2. For a recent review see Behrens, F.; Koehm, M.; Burkhardt, H. Curr. Opin.
Rheumatol. 2011, 23, 282.
3. For a recent study see Peter-Getzlaff, S.; Polsfuss, S.; Poledica, M.; Hombach, M.;
Giger, J.; Gottger, E. C.; Zbinden, R.; Bloemberg, G. V. J. Clin. Microbiol. 2011, 49,
2924.
4. Brough, Paul A.; Aherne, Wynne; Barril, Xavier; Borgognoni, Jenifer; Boxall,
Kathy; Cansfield, Julie E.; Cheung, Kwai-Ming J.; Collins, Ian; Davies, Nicholas
G. M.; Drysdale, Martin J.; Dymock, Brian; Eccles, Suzanne A.; Finch, Harry;
Fink, Alexandra; Hayes, Angela; Howes, Robert; Hubbard, Roderick E.; James,
Karen; Jordan, Allan M.; Lockie, Andrea; Martins, Vanessa; Massey, Andrew;
Matthews, Thomas P.; McDonald, Edward; Northfield, Christopher J.; Pearl,
Laurence H.; Prodromou, Chrisostomos; Ray, Stuart; Raynaud, Florence I.;
Roughley, Stephen D.; Sharp, Swee Y.; Surgenor, Allan; Walmsley, D. Lee; Webb,
Paul; Wood, Mike; Workman, Paul; Wright, Lisa J. Med. Chem. 2008, 51, 196.
5. Gonzales, B.; Gonzales, A. M.; Pulido, F. J. Synth. Commun. 1995, 25, 1005.
6. Cao, C.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2003, 125, 2880.
7. For a review on azadienes in synthesis see Jayakumar, S.; Ishar, M. P. S.; Ma-
hajan, M. P. Tetrahedron 2002, 58, 379.
8. Calvo, L. M.; Gonzalez-Nogal, A. M.; Gonzalez-Ortega, A.; Sanudo, M. C. Tetra-
hedron Lett. 2001, 42, 8981.
9. For reviews on the extensive work of Barluenga and co-workers on applications
of 1,3-diimines to organic synthesis see (a) Barluenga, J.; Tomas, M. Adv. Het-
erocycl. Chem. 1993, 57, 1; (b) Barluenga, J. Bull. Soc. Chim. Belg. 1988, 97, 545.
10. Majumder, S.; Odom, A. L. Tetrahedron 2010, 66, 3152.
11. Majumder, S.; Gipson, K. R.; Odom, A. L. Org. Lett. 2009, 11, 4720.
12. Majumder, S.; Gipson, K. R.; Staples, R. J.; Odom, A. L. Adv. Synth. Catal. 2009,
351, 2013.
4.2.10. 3,4-Diphenylisoxazole (Table 4, entry b). The general pro-
cedure was followed. The reaction was carried out with tert-buty-
lisonitrile (171 mL, 1.5 mmol), 3,5-dichloroaniline (162 mg, 1 mmol),
diphenylacetylene (178 mg, 1 mmol), and 1 (30.8 mg, 0.1 mmol) in
toluene (2 mL) with heating for 48 h at 100 ꢀC. The pressure tube
was cooled to room temperature. Then, the reaction tube was
charged with hydroxylamine hydrochloride (83 mg, 1.2 mmol) and
THF (2 mL) then stirred at 45 ꢀC for 16 h. Solvents were removed
under reduced pressure, and the crude product was dissolved in
CH2Cl2 (20 mL) and washed with water (50 mL). Purification was
accomplished by column chromatography on neutral alumina. The
eluent was hexanes/ethyl acetate 9:1, which afforded the desired
compound (55 mg, 25%) as a yellow solid. Mp: 90e92 ꢀC (lit.30 mp:
91 ꢀC). 1H NMR (CDCl3, 500 MHz): 7.35e7.40 (8H, m, AreH),
7.61e7.62 (1H, m, AreH), 7.62e7.64 (1H, m, AreH), 8.35 (1H, s, 5-CH
isoxazole). 13C{1H} NMR (CDCl3, 125 MHz): 116.2, 127.2, 127.6, 128.0,
128.3, 128.6, 128.7, 129.0, 130.0, 131.6, 151.9, 164.0. MS(EI): m/z 221
(Mþ). Elemental Analysis: found: %C, 81.29; %H, 5.13; %N, 6.42;
expected: %C, 81.43; %H, 5.01; %N, 6.33.
~
ꢀ
4.2.11. 3-(3-(tert-Butyldimethylsilyloxy)propyl)-4-phenylisoxazole
13. For related chemistry on isoxazole synthesis from 1,3-diimines see Barluenga,
J.; Jardon, J.; Rubio, V.; Gotor, V. J. Org. Chem. 1983, 48, 1379 The conditions in
this paper for isoxazole formation, which involve heating pyridine solutions of
hydroxylamine with 1,3-diimines followed by an H2SO4 quench, where not
successful with the somewhat different 1,3-diimines available using the
titanium-catalyzed multicomponent coupling chemistry discussed here.
14. Li, Y.; Turnas, A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2002, 41, 6298.
15. Littler, B. J.; Miller, M. A.; Hung, C. H.; Wagner, R. W.; O’Shea, D. F.; Boyle, P. D.;
Lindsey, J. S. J. Org. Chem. 1999, 64, 1391.
16. Harris, S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001, 40, 1987.
17. Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Chem. Commun. 2003, 586.
18. Vujkovic, N.; Fillol, J. L.; Ward, B. D.; Wadepohl, H.; Mountford, P.; Gade, L. H.
Organometallics 2008, 27, 2518.
(Table 4, entry c). The general procedure was followed. The reaction
was carried out with tert-butylisonitrile (171
mL, 1.5 mmol), 3,5-
dichloroaniline (162 mg, 1 mmol), tert-butyldimethyl(5-
phenylpent-4-ynyloxy)silane (274 mg, 1 mmol), and 1 (30.8 mg,
0.1 mmol) in toluene (2 mL) with heating for 48 h at 100 ꢀC. The
pressure tube was cooled to room temperature. Then the same
pressure tube was charged with hydroxylamine hydrochloride
(83 mg, 1.2 mmol) and THF (2 mL) then stirred at 45 ꢀC for 16 h.
Solvents were removed in vacuo, and the crude product was dis-
solved in CH2Cl2 (20 mL) then washed with water (50 mL). Purifi-
cation was accomplished by column chromatography on neutral
alumina. The eluent was hexanes/ethyl acetate 19:1, which afforded
the desired compound (95 mg, 30%) as a yellow oil. 1H NMR (CDCl3,
500 MHz): 0.059 (6H, s, SieCH3), 0.85 (9H, s, SieCMe2CH3),
1.94e1.98 (2H, m, CH2CH2CH2OTBS), 2.99e3.02 (2H, m,
CH2CH2CH2OTBS), 3.64e3.66 (2H, m, CH2CH2CH2OTBS), 7.31e7.32
(1H, m, AreH), 7.32e7.42 (4H, m, AreH), 8.33 (1H, s, 5-CH isoxazole).
13C{1H} NMR (CDCl3, 125 MHz): 1.0, 22.4, 25.9, 30.6, 35.7, 61.7,127.4,
127.6,128.2,128.9,131.5,150.3,167.8. Elemental Analysis: found: %C,
67.94; %H, 8.42; %N, 4.52; expected: %C, 68.09; %H, 8.57; %N, 4.41.
19. Odom, A. L. Dalton Trans. 2005, 225.
20. For discussions of mechanism in related titanium-catalyzed multicomponent
couplings see Banerjee, S.; Odom, A. L. Organometallics 2006, 25, 3099.
21. One possible side reaction is the oligomerization of the alkyne, which has been
observed in some titanium catalysts, although not directly reported for 1 or 2.
We typically employ the milder dpma-based catalyst 2 for terminal alkynes Shi,
Y.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 3767.
22. The product ratio may not be directly related to the ratio of [2þ2]-
cycloaddition products due to a CurtineHammett equilibrium in the system.
See (a) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1993, 115,
2753 However see; (b) Tillack, A.; Khedkar, V.; Jiao, H.; Beller, M. Eur. J. Org.
Chem. 2005, 5001 For discussions of CurtineHammett kinetics see; (c) Follett,
A. D.; McNeill, K. J. Am. Chem. Soc. 2005, 127, 844; (d) Seeman, J. I. Chem. Rev.
1983, 83, 83.
23. Beccalli, E. M.; Marchesini, A.; Pilati, T. Synth. Commun. 1993, 23, 685.
24. (a) Hosomi, A.; Shoji, H.; Sakurai, H. Chem. Lett. 1985, 1049 Caution, nitrile
oxides are unstable and sometimes explosive. For a review see; (b) Belen’Kii, L.
I. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis: Novel Strategies in
Synthesis, 2nd ed.; John Wiley: 2008.
25. For an alternative synthesis involving reduction of the 5-chloroisoxazole see
Ponticelli, F.; Tedeschi, P. Synthesis 1985, 792.
Acknowledgements
The authors thank the National Science Foundation (CHE-
1012537) for financial support.
26. Gokel, G. W.; Widera, R. P.; Weber, W. P. Org. Synth. 1976, 55, 96.
27. Olofson, R. A.; Landesberg, J. M.; Berry, R. O.; Leaver, D.; Robertson, W. A. H.;
McKinnon, D. M. Tetrahedron 1966, 22, 2119.
Supplementary data
28. De Munno, A.; Bertini, V.; Lucchesini, F. J. Chem. Soc., Perkin Trans. 2 1977, 1121.
29. Bravo, P. Gazz. Chim. Ital. 1972, 102, 395.
30. Kohler, E. P.; Davis, A. R. J. Am. Chem. Soc. 1930, 52, 4520.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.11.043.