Synthesis of Isoxazole- And Oxazole-4-carboxylic Acids Derivatives by Controlled Isoxazole-Azirine-Isoxazole/Oxazole Isomerization

Article abstract of DOI:10.1021/acs.joc.9b02536

The first synthesis of isoxazole-4-carboxylic acid derivatives by domino isoxazole-isoxazole isomerization is reported. Fe(II)-catalyzed isomerization of 4-acyl-5-methoxy-/5-aminoisoxazoles (dioxane, 105 °C) leads to the formation of isoxazole-4-carboxylic esters and amides in good yields. 4-Formyl-5-methoxyisoxazoles give methyl oxazole-4-carboxylates under the same reaction conditions. Fe(II)-catalyzed isomerization of 4-acyl-5-methoxyisoxazoles under milder conditions (MeCN, 50 °C) allows the preparation of transient 2-acyl-2-(methoxycarbonyl)-2H-azirines. The azirines isomerize quantitatively either into isoxazoles under catalytic conditions (dioxane, 105 °C) or into oxazoles under noncatalytic thermolysis (o-dichlorobenzene, 170 °C). The mechanism of the isomerization and dependence of the reaction routes on substituents at starting isoxazole core and reaction conditions are discussed on the basis of DFT calculations.

Full text of DOI:10.1021/acs.joc.9b02536

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Article
Synthesis of Isoxazole- and Oxazole-4-carboxylic Acids Derivatives
by Controlled Isoxazole-Azirine-Isoxazole/Oxazole Isomerization
Anna V. Serebryannikova, Ekaterina E. Galenko, Mikhail Sergeevich Novikov, and Alexander F. Khlebnikov
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02536 • Publication Date (Web): 28 Oct 2019
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Synthesis of Isoxazole- and Oxazole-4-carboxylic Acids Derivatives by
Controlled Isoxazole-Azirine-Isoxazole/Oxazole Isomerization
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Anna V. Serebryannikova, Ekaterina E. Galenko, Mikhail S. Novikov, Alexander F. Khlebnikov*
Saint Petersburg State University, Institute of Chemistry, 7/9 Universitetskaya nab.,
St. Petersburg 199034, Russia
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*E-mail: a.khlebnikov@spbu.ru.
Abstract:
The first synthesis of isoxazole-4-carboxylic acid derivatives by domino isoxazole-isoxazole
isomerization is reported. Fe(II)-catalyzed isomerization of 4-acyl-5-methoxy-/5-aminoisoxazoles
(dioxane, 105 °C) leads to the formation of isoxazole-4-carboxylic esters and amides in good yields.
4-Formyl-5-methoxyisoxazoles give methyl oxazole-4-carboxylates under the same reaction
conditions. Fe(II)-catalyzed isomerization of 4-acyl-5-methoxyisoxazoles under milder conditions
(MeCN, 50 °C) allows the preparation of transient 2-acyl-2-(methoxycarbonyl)-2H-azirines. The
azirines isomerize quantitatively either into isoxazoles under catalytic conditions (dioxane, 105 °C)
or into oxazoles under noncatalytic thermolysis (o-dichlorobenzene, 170 °C). The mechanism of the
isomerization and dependence of the reaction routes on substituents at starting isoxazole core and
reaction conditions are discussed on the basis of DFT calculations.
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Introduction
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Compounds containing the isoxazole ring exhibit activity against a wide spectrum of biological
targets1-4 and also serve as versatile synthetic precursors.5 Derivatives of isoxazole-4-carboxylic acid
in particular show immune suppressive and anti-inflammatory regulation of autoimmune
lymphocytes (leflunomide),6,7 anti-inflammatory properties,8 immunomodulatory activities,9
antibacterial activities (Flucloxacillin, Dicloxacillin, Oxacillin, Cloxacillin),7 anti-proliferative
activity.10 Isoxazole-4-carboxylic acid derivatives previously were prepared by cycloaddition of
nitrile oxides and alkynes,11 by reaction of nitrile oxides with β-keto esters12 and an enamino
carbonyl compound,13,14 These methods, however, often include the use of strong bases or strong
acids, and expensive catalysts. In addition, cycloaddition often proceeds non-regioselectively,
producing a mixture of regioisomers. Thus, there still remains a great need to find operationally
simple, high-yielding methodologies for the selective preparation of isoxazole-4-carboxylic acid
derivatives from inexpensive and easily available starting materials. Although ring-to-ring
intramolecular isomerization is a 100% atom economical reaction,15 the use of this type of process
for the preparation of isoxazole derivatives is, to the best of our knowledge, unknown.5, 16 Earlier we
found conditions for catalytic isomerization of isoxazoles, bearing unsaturated substituents at the 4
position, into the corresponding heterocycles,17 such as pyrroles,18 indoles19 and pyrazoles.20 It was
found that the isomerization of isoxazole I into heterocycle III proceeds via the transient formation
of the corresponding azirine II (Scheme 1).17-20
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Scheme 1. Isomerization of Isoxazoles, Bearing Unsaturated Substituents at the 4 Position
R2
X
O
O
N
X
R2
R1
R1
Z
R2
R1
N
Z
N
III
X
O
Z
II
I
R2
O
R2N/RO
R2
O
R1
R2N/RO
R2
O
R1
R1
N
N
R2N/RO
O
O
N
O
2
3
1
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We hypothesized that 4-acyl-5-alkoxy/aminoisoxazoles 1 (I, Z = O) could be isomerized into
isoxazole-4-carboxylic acids derivatives 3 (III, Z = O) under certain conditions (Scheme 1). Since
metal-catalyzed isomerization IIIIII is a thermodynamically controlled process the
transformation of I into III could be implemented only if III is thermodynamically more stable than
I. In order to choose 4-acylisoxazoles 1 which could be involved in the isomerization of 1→3 we
performed preliminary DFT calculations (Table 1, for details of the calculations see Supporting
information).
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Table 1. Relative Gibbs Free Energies of Isoxazoles 1, 3 and Azirines 2 Computed at the DFT
B3LYP/6-31+G(d,p) Level.a
R2
R1
R1
O
R1
O
entry compounds
X
R1
R2
3
X
2
O
4
1-3
N
X
1
N
N
O
R2
O
5
2
X
3
R2
O
1
1
2
3
4
5
6
7
8
a
b
c
MeO
MeO
MeO
MeO
MeO
Ph
Ph
Ph
H
0.0
-7.3
-7.0
-8.3
-4.6
-10.0
-0.4
0.1
-14.1
-15.8
-14.8
-15.5
-15.1
-8.5
Me 0.0
Ph
0.0
0.0
0.0
0.0
0.0
0.0
d
e
Me Ph
tBu Ph
f
Me2N Ph
MeHN Ph
H
H
H
f'
f"
-4.6
H2N
Ph
0.7
-4.7
a In kcal/mol, 298 K, PCM model for MeCN.
According to the calculations, the isomerization of 5-methoxy-substituted isoxazoles 1a-e into
azirines 2a-e is a thermodynamically favorable process which is characterized by G values from -
4.6 to -10.0 kcal/mol (Table 1, entries 1-5). 5-Unsubstituted and 5-methyl/phenylisoxazoles 3a-e are
more stable than 5-methoxyisoxazoles 1a-e (G = -14.1  -15.5 kcal/mol) that makes the
isomerization 1a-e3a-e thermodynamically favorable as a whole. Replacing the MeO group with
amino groups (Me2N, MeHN or H2N,) at the C5 (isoxazoles 1f-1f”) smooths out the difference in
thermodynamic stability between the starting isoxazoles and transient azirines (G = 0.7 - -0.4
kcal/mol), but further isomerization into isoxazoles 3f-3f” remains thermodynamically feasible.
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Inspired by these promising predictions we decided to explore in detail the isomerization of 5-
heteroatom-substituted 4-acylisoxazoles as a novel atom economical method for the preparation of
isoxazole-4-carboxylic acid derivatives.
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Results and discussion
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To start with, the available 1-(3-(4-bromophenyl)-5-methoxyisoxazol-4-yl)propan-1-one 1g was
reacted with Fe(II) chloride as a catalyst using the reaction conditions which were successfully used
for the isomerization 5-alkoxyisoxazoles I, bearing a C=C or C=N containing substituent in the 4
position, into the corresponding 2H-azirines II or heterocycle III.16-20
Table 2. Test Experiments on the Isomerization of Isoxazole 1g
R1
Et R1
O
O
R1
R1
Et
Catalyst
MeO
Et
MeO
O
NH2
N
O
O
Conditions
N
O
1g
N
MeO
O
Et
O
MeO
2g
4g
3g
R1 = 4-BrC6H4
entry catalyst
solvent
MeCN
MeCN
THF
t (°C) time (h)
product (yield, %)a
2g (90%)
1
2
3
4
5
FeCl2·4H2O (20 mol %)
FeCl2·4H2O (20 mol %)
Mo(CO)6·(100 mol %)
Mo(CO)6·(60 mol %)
FeCl2·4H2O (20 mol %)
20
82
66
66
105
24
5
2g+4g (70%)
4g (85%)
3
THF
2
4g (65%)
1,4-dioxane
3
3g (75%)
a Isolated yields.
17
As predicted,16,
the reaction of 5-methoxyisoxazole 1g with FeCl2·4H2O (20 mol %) in
acetonitrile at rt led to azirine 2g in good yield, whereas refluxing an acetonitrile solution of
isoxazole 1g in the presence of FeCl2·4H2O yielded a mixture of azirine 2g and enamine 4g, the
product of reductive cleavage of the isoxazole C-N bond (Table 2, entry 2). The reaction of
isoxazole 1g with molybdenum hexacarbonyl, a known promoter of reductive cleavage of the
isoxazole ring,21 gave enamine 4g exclusively (Table 2, entries 3 and 4). Therefore some other
solvents were tested to find optimal reaction conditions for the isomerization of 1→3. Eventually the
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target isoxazole 3g was obtained by heating a dioxane solution of isoxazole 1g in the presence of
FeCl2·4H2O catalyst (Table 2, entry 5).
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Having carried out the desired isomerization on isoxazole 1g guided by the data of table 1, a series
of isoxazoles 1c, d, g-u were synthesized for subsequent experiments (Scheme 2) by known
methods. 4-Acyl-5-methoxyisoxazoles 1c, d, g-p were prepared according to slightly modified
published procedures by acylation of the 3-substituted isoxazol-5(4H)-ones 5 followed by
methylation of the resulting 4-acyl-5-hydroxyisoxazoles 6 with diazomethane.20 4-Formyl-5-
methoxy-isoxazoles 1q-u were prepared by the substitution of chlorine in 5-chloro-4-
formylisoxazoles 7 using MeONa or the corresponding amine.18
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Scheme 2. Synthesis of Isoxazoles 1
(R2CO)2O
or R2COCl
OH
OMe
O
O
O
CH2N2
R2
R2
O
N
O
N
O
N
5
DMAP
R1
R1
R1
6
1c, d, g-p
, R1 = R2 = Ph; , R1 = Me, R2 = Ph; , R1 = 4-BrC6H4, R2 = Et;
c
d
g
, R1 = Ph, R2 = n-C13H27; , R1 = 2-thienyl, R2 = Et;
h
i
, R1 = t-Bu, R2 = 4-MeC6H4; , R1 = 1-Ad, R2 = 4-MeC6H4;
, R1 = Ph, R2 = 4-MeC6H4; , R1 = 4-FC6H4, R2 = 4-MeC6H4;
j
k
l
m
, R1 = 4-BrC6H4, R2 = 4-MeC6H4; , R1 = 2-thienyl, R2 = 4-MeC6H4;
, R1 = 2-thienyl, R2 = 4-IC6H4
n
p
o
Cl
NR'2
O
OMe
O
O
R'2NH
MeONa
O
N
O
N
1q-s
H
H
O
N
1t, u
H
R1
R1
R1
7
1
'
, R = 4-NO2C6H4, R = Bn; , R1 = 4-BrC6H4, R'-R' = (CH2)4;
q
r
1
'
, R = 4-BrC6H4, R-R' = (CH2)2O(CH2)2; , R1 = 4-FC6H4;
s
t
, R1 = 4-BrC6H4
u
Isoxazoles 1 were then heated in dioxane in the presence of FeCl2·4H2O, and the isomerization
products, isoxazoles 3c, d, g-s, were isolated both from 4-alkanoyl/aroylisoxazoles 1c, d, g-s and 4-
formylisoxazoles 1q-s in moderate to excellent yield (Table 3). The reaction tolerates alkyl, aryl and
2-thienyl substituents in the 3 position (R1) and aliphatic and aromatic acyl substituents in the 4
position (R2CO) of isoxazole 1.
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Table 3. Synthesis of Isoxazoles 3c, d, g-s by Catalytic Isomerization of Isoxazole 1c, d, g-sa
4
5
6
7
R2
R1
R1
O
FeCl2·4H2O (20 mol %)
1,4-dioxane, 105 o
MeO
O
N
O
N
O
C
R2
3c, d, g-s
MeO
1c, d, g-s
8
Br
9
O
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O
O
MeO
O
MeO
N
N
MeO
O
MeO
O
N
N
O
( )12
O
3d
3g
3h
66% (1 h)
O
75% (2 h)
83% (5 h)
3c
89% (3 h)
O
O
S
MeO
MeO
O
MeO
N
N
N
O
MeO
O
O
N
O
b
b
b
3j
3i
93% (4 h)
43% (5 h)
3k
3l
40% (6 h)
82% (3 h)
F
Br
S
O
S
O
O
O
MeO
MeO
MeO
MeO
N
N
N
O
N
O
O
O
I
3m
3n
3p
84% (2 h)
73% (2 h)
79% (4 h)
Br
3o
61% (3 h)
Br
NO2
O
H
O
O
N
N
N
N
O
N
O
N
O
O
H
H
3q
3r
60% (3 h)
3s
91% (3 h)
88% (3 h)
a Isolated yields. b Reaction at 120 °C.
Unexpectedly, formyl-substituted isoxazoles 1t and u gave, upon heating in dioxane in the presence
of FeCl2·4H2O, oxazoles 8t and u instead of the expected isoxazoles 3t and u (Scheme 3). The
structure of oxazole 8t was confirmed by X-ray analysis (see Supporting Information). Previously,
the isomerization of isoxazoles to oxazoles via azirine and nitrile ylide intermediates was observed
under photolysis22 or high-pressure pulsed pyrolysis.23
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Scheme 3. Synthesis of Oxazoles 3t and u by Catalytic Isomerization of Isoxazoles 1t and u
4
R1
O
H
5
6
7
FeCl2·4H2O (20 mol %)
N
R1
MeO
O
N
O
1t, u
1,4-dioxane, 105 oC, 3-5 h
O
8t, u
H
MeO
8
9
O
O
H
R1
H
O
N
R1
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N
MeO
MeO
O
, R = 4-FC6H4, 63%; , R1 = 4-BrC6H4, 57%
1
t
u
It was found that the isomerization of isoxazole 1g under mild catalytic conditions (MeCN, 50 C)
stops at the stage of the formation of azirine 2g, which was isolated in 90% yield (table 2, entry 1).
Azirines 2c, d and m were also prepared, using similar reaction conditions from isoxazoles 1c, d and
m. Azirines 2c, d, g and m proved to be stable in dioxane at 105 °C for 24 h, but isomerized into
isoxazole 2c, d, g and m in 1-2 h in dioxane at 105 °C in the presence of FeCl2·4H2O (Scheme 4).
Scheme 4. Preparation and Transformations of Azirines 2 under Catalytic Conditions
O
R1
R2
R1
MeO
R2
2c, d, g, m
FeCl2·4H2O (20 mol %)
O
N
N
O
MeCN, 50 o
C
O
MeO
1c, d, g, m
, R1 = Ph, R2 = Ph, 64%;
c
, R1 = Me, R2 = Ph, 97%;
d
, R1 = 4-BrC6H4, R2 = Et, 90%;
g
, R1 = 4-FC6H4, R2 = 4-MeC6H4, 87%
m
FeCl2·4H2O (20 mol %)
1,4-dioxane, 105 oC, 1-2 h
2c, d, g,m
2c, d, g,m
3c, d, g, m
~100%
Without catalyst
3c, d, g, m
1,4-dioxane, 105 oC, 24 h
Recently, for Fe(II)-catalyzed intermolecular cycloaddition of 2H-azirines with enamides was
proposed free-radical mechanism, involving homolytic cleavage of the C-N bond of 2H-azirine.
This proposition was based on high yield formation of adduct of TEMPO with ring opened azirine
intermediate.24 In order to obtain additional information on the mechanistic aspects of the isoxazole-
isoxazole isomerization, the reaction of isoxazole 1d was performed in the presence of 0.2 equiv of
FeCl2·4H2O and 1.5 equiv of TEMPO. After 1 h, about half of the staring isoxazole was isomerized,
but the reaction stopped due to the entire catalyst was oxidize by TEMPO and precipitate as iron
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oxides. The reaction was completed after addition of further 0.2 equiv of FeCl2·4H2O for 1.5 h,
leading to isoxazole 3d in 70% isolated yield. Any other products were not detected in the reaction
mixture. Therefore, in the isoxazole-izoxazole isomerization Fe(II)-catalyst acts as a Lewis acid.25
The catalytic isoxazole-isoxazole isomerization of 1 into 3 is most likely mechanistically related to
the catalytic isomerization of 4-vinyl-substituted isoxazoles into pyrroles, which according to the
DFT calculations involved a single-state quintet reactivity of the Fe(II)-complexes of 4-(2-R-
vinyl)isoxazoles, 2-(2-R-vinyl)-2H-azirines and Fe(II)-nitrene complexes.18 The plausible
mechanism includes the following steps (Scheme 5): (a) the formation of isoxazole Fe-complex A,
(b) isoxazole ring opening across the N-O bond to form the Fe-nitrene complex B having
inappropriate configuration for 1,5-cyclization on the R2C=O carbonyl group; (c) recyclization of
Fe-nitrene complex B into Fe-azirine complex C; (d) low energy conformational transformations in
C followed by azirine ring opening leading to Fe-nitrene complex D with a configuration favorable
for 1,5-cyclization to occur; (e) 1,5-cyclization giving complex E; (f) liberation of the catalyst to
give isoxazole 3.
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Scheme 5. Plausible Reaction Mechanism for the Isomerization of Isoxazoles 1
R1
N
R1
R1
R2 = H
N
N
O
O
O
O
O
R2
O
H
X
2
8
X
X
X
R2
9
FeLn
(d)
R1
(c)
O
N
R1
O
O
O
O
LnFe
(b)
N
X
R2
N
X
LnFe
C
R1
O
R2
D
R2
(e)
X
B
R1
FeLn
O
FeLn
(f)
(a)
N
R1
R2
LnFe
N
O
O
R2
R1
O
N
O
X
E
R1
O
X
A
X
N
O
R2
O
R2
1
3
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Unlike previously studied 4-vinylisoxazoles,18 the isomerization of isoxazoles 1c, d, g-s proceeds
through the intermediate formation of azirines 2 bearing two strong electron-withdrawing
substituents at the 2 position. The presence of two such substituents in the azirine can facilitate the
azirine C-C bond cleavage with the formation of the stabilized nitrile ylide 9, the 1,5-cyclization of
which will lead to oxazoles 8. The formation of oxazoles 8t and u instead of isoxazoles 3t and u
could, therefore, be explained by the lower barrier to the formation of the corresponding nitrile
ylides 9 from isoxazoles 3t and u than from isoxazoles 1c, d, g-s. To check this hypothesis the
calculation of model azirines 2, nitrile ylides 9 and the transition states (TS) for their
transformations were performed at the DFT B3LYP/6-31+G(d,p) level (PCM model for 1,4-
dioxane) (Table 4, for details of the calculations see Supporting information).
9
10
11
12
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17
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19
20
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51
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Table 4. Relative Gibbs Free Energies of Azirines 2, Nitrile Ylides 9, Oxazoles 8 and TS for
Their Transformations Computed at the DFT B3LYP/6-31+G(d,p) Level.
R1
R1
R1
TS2-9
TS9-8
N
N
X
O
N
O
O
O
O
R2
R2
O
X
2
8
X
R2
9
R1
O
R1
O
O
entry compounds
X
R1
R2
X
X
2, 8, 9
TS2-9
TS9-8
N
X
O
N
R1
N
R2
R2
2
R2
9
O
O
8
1
2
3
4
5
a
f
MeO
Ph
Ph
H
0.0
0.0
0.0
0.0
0.0
24.8 -9.5
29.9 -3.9
29.8 -4.1
27.6 -7.1
29.8 -3.9
-5.1
-35.9
-36.7
-37.3
-37.2
-35.0
Me2N
H
-1.5
-2.3
-3.6
0.3
w
y
c
(CH2)4N Ph
H
MeO
Ph
Et
MeO
Ph
Ph
a In kcal/mol, 298 K, PCM model for 1,4-dioxane.
The calculations show that the rate-controlling stage for the transformation of azirines 2 into
oxazoles 8 is the formation of nitrile ylide 9. Methyl 2-formyl-2H-azirine-2-carboxylate has the
lowest barrier for the azirine C-C bond cleavage into the nitrile ylide (Table 4, entry 1). Replacing
the formyl group with more bulky propanoyl or benzoyl group leads to a significant increase in the
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barrier (table 4, entries 4 and 5). The barrier also increases when the methoxycarbonyl group is
replaced with more bulky and less electron withdrawing aminocarbonyl groups (table 4, entries 2
and 3). Thus, the formation of oxazoles 8t and u from methyl 2-formyl-2H-azirine-2-carboxylates 1t
and u caused the low barriers for the transformation of azirines 2t and u to nitrile ylides 9t and u,
which is most likely lower than the barrier for the catalytic transformation of azirines to isoxazoles
(Scheme 5, Table 4). Replacing the formyl group with alkanoyl or aroyl groups or replacing of the
methoxycarbonyl group with (R2amino)carbonyl groups in azirine 2 redirects the reaction in the
catalytic route by increasing the barrier for the formation of the nitrile ylide.
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Azirines 2c, d, g and m do not transform in dioxane at 105 °C in the absence of the catalyst neither
to isoxazoles 3c, d, g and m (as it is catalytic reaction), nor oxazoles 8c, d, g and m due to the too
high barrier (Table 4, entries 2-5). The conclusions from the calculations prompted us to perform
some additional experiments to check whether azirines, which gave isoxazoles under catalytic
conditions in dioxane at 105 °C, will give oxazoles without catalyst and at higher temperature. In
complete accordance with the calculations oxazoles 8c, d, g and m were obtained quantitatively by
heating azirines 2c, d, g and m at 170 °C in o-dichlorobenzene, conditions which allow the
overcoming of this barrier (Table 5). Note that the isomerization of 2-acyl-2H-azirines to oxazoles is
usually occurs under photolysis26, 27 and very rarely under heating27 or metal catalysis.28
Table 5. Synthesis of Oxazoles 8c, d, g, m by Thermolysis of Azirines 2c, d, g, m a
O
O
R1
170 o
C
N
O
MeO
R2
MeO
R1
N
o-dichlorobenzene
R2
O
8c, d, g, m
, 100%
2c, d, g, m
O
O
MeO
MeO
N
N
O
8d
O
8c
O
O
MeO
Br
N
N
MeO
O
8m
O
8g
F
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a Isolated yields.
3
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5
Conclusion
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7
8
9
Fe(II)-catalyzed domino isomerization of 4-acyl-5-methoxy/5-amino-isoxazoles in dioxane at 105
°C leads to the formation of isoxazole-4-carboxylic acid derivatives, whereas 4-formyl-5-
methoxyisoxazoles give methyl oxazole-4-carboxylates under the same reaction conditions. Both
isomerizations proceed via the formation of 2-acyl-2-(methoxycarbonyl)-2H-azirines, which can be
isolated in high yields from the reaction of 4-acyl-5-methoxyisoxazoles, carried out under milder
conditions (MeCN, 50 °C). At higher temperatures (105 °C) the azirines transform into isoxazole-4-
carboxylates under catalytic conditions, while in the absence of the Fe(II) catalyst at 170 °C they
quantitatively isomerize into the oxazole derivatives. DFT calculations were used to elucidate a
mechanism of the isomerization and explain the influence of substituents at the starting isoxazole
core and reaction conditions on the outcome of the isomerization. It was found that 2-formyl-2-
(methoxycarbonyl)-substituted azirines, resulting from 4-formyl-5-methoxyisoxazoles, have the
barrier for the azirine C-C bond cleavage low enough for the azirine ring opening into the nitrile
ylide to occur. The latter undergoes rapid 1,5-cyclization into the oxazole derivative. The azirine C-
C bond cleavage in 2-alkanoyl/aroyl-2-(methoxycarbonyl)- and 2-formyl-2-((R2amino)carbonyl))-
substituted azirines leads to the more sterically congested nitrile ylides and this is the reason for the
much higher barriers for their formation compared to the catalytic C-N bond cleavage leading to the
isoxazole-4-carboxylates. However these high barriers are overcome at 170 °C under noncatalytic
conditions and oxazoles are formed.
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EXPERIMENTAL SECTION
General Information and Methods. Melting points were determined on a melting point
apparatus. 1H (400 MHz) and 13C (100 MHz) spectra were recorded on NMR spectrometer in CDCl3
or DMSO-d6. Chemical shifts (δ) are reported in parts per million downfield from tetramethylsilane
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(TMS δ =0.00). H NMR spectra were calibrated according to the residual peak of CDCl3 (7.26
4
5
6
7
8
9
ppm) and DMSO-d6 (2.50 ppm). For all new compounds, C{1H} and C DEPT-135 spectra were
recorded and calibrated according to the peak of CDCl3 (77.00 ppm) and DMSO-d6 (39.51 ppm).
Electrospray ionization (ESI) mass spectra were recorded on mass spectrometer, HRMS-ESI-QTOF,
electrospray ionization. Single crystal X-ray data were collected by means of diffractometer.
Cristallographic data for the structure 8t (CCDC 1953943) have been deposited with the Cambridge
Crystallographic Data Centre. Thin-layer chromatography (TLC) was conducted on aluminium
sheets with 0.2 mm silica gel with fluorescent indicator.
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Starting isoxazolones were commercially available or prepared by the well-studied reaction of
hydroxylamine with β-keto esters.29 Compounds 6 were prepared according to the published
procedure.20 Physical and spectral data of (5-hydroxy-3-phenylisoxazol-4-yl)(phenyl)methanone
(6c), (5-hydroxy-3-methylisoxazol-4-yl)(phenyl)-methanone (6d), and 1-(5-hydroxy-3-(thiophen-2-
yl)isoxazol-4-yl)propan-1-one (6i), were in agreement with previously reported values.20
1-(3-(4-Bromophenyl)-5-hydroxyisoxazol-4-yl)propan-1-one (6g). Compound 6g was
prepared following the published procedure20 from 3-(4-bromophenyl)isoxazolon-5(4H)-one 5c
(1.00 g, 4.2 mmol), propionic anhydride 10a (680 mg, 5.3 mmol) and DMAP (1.15 g, 9.5 mmol) in
benzene (45 mL) in 622 mg (60% yield) as a colorless solid: mp 78-80 °C (chloroform). 1H NMR
(DMSO-d6, 400 MHz): δ 1.02 (t, J = 7.5 Hz, 3H), 2.78 (q, J = 7.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H),
7.62 (d, J = 8.5 Hz, 2H). C{1H} NMR (DMSO-d6, 100 MHz): δ 9.8 (CH3), 29.6 (CH2), 92.1 (C),
13
122.8 (C), 130.0 (C), 130.7 (CH), 130.9 (CH), 161.3 (C), 173.3 (C), 191.0 (C). ESI/HRMS (m/z):
calcd for C12H9BrNO3 [M ˗ H]-, 293.9771; found, 293.9750.
-
1-(5-Hydroxy-3-phenylisoxazol-4-yl)tetradecan-1-one (6h). Compound 6h was prepared
following the published procedure20 from 3-phenylisoxazol-5(4H)-one 5a (750 mg, 4.66 mmol),
tetradecanoyl chloride 10b (1.94 g, 7.9 mmol) and DMAP (1.28 g, 10.49 mmol) in benzene (45 mL)
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in 1.28 g (74% yield) as a colorless solid: mp 43-45 °C (water).1H NMR (DMSO-d6, 400 MHz): δ
0.85 (t, J = 6.7 Hz, 3H), 1.22-1.23 (m, 20H), 1.38-1.48 (m, 2H), 2.58-2.60 (m, 2H), 7.27-7.33 (m,
5
6
7
13
3H), 7.47-7.50 (m, 2H). C{1H} NMR (DMSO-d6, 100 MHz): δ 13.9 (CH3), 22.1 (CH2), 24.9
8
9
(CH2), 28.7 (CH2), 29.01 (CH2), 29.03 (CH2), 29.06 (CH2), 29.06 (CH2), 29.07 (CH2), 29.08 (CH2),
29.2 (CH2), 31.3 (CH2), 38.5 (CH2), 89.9 (C), 127.1 (CH), 127.8 (CH), 128.8 (CH), 133.6 (C), 162.9
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+
(C), 176.0 (C), 191.7 (C). ESI/HRMS (m/z): calcd for C23H34NO3 [M + H]+, 372.2533; found,
372.2524.
(3-(tert-Butyl)-5-hydroxyisoxazol-4-yl)(p-tolyl)methanone (6j). Compound 6j was
prepared following the published procedure20 from 3-(tert-butyl)isoxazol-5 (4H)-one 5e (1.00 g, 7.1
mmol), 4-methylbenzoyl chloride 10c (1.37 g, 8.87 mmol) and DMAP (1.95 g, 15.95 mmol) in
1
benzene (45 mL) in 1.40 g (78% yield) as a yellowish solid: mp 174-178 °C (water). H NMR
(DMSO-d6, 400 MHz): δ 1.33 (s, 9H), 2.35 (s, 3H), 7.23 (d, J = 7.9 Hz, 2H), 7.54 (d, J = 7.9 Hz,
2H). C{1H} NMR (DMSO-d6, 100 MHz): δ 21.1 (CH3), 27.6 (CH3), 33.8 (C), 93.0 (C), 128.5
13
(CH), 129.1 (CH), 135.9 (C), 142.1 (C), 171.0 (C), 171.3 (C), 188.5 (C). ESI/HRMS (m/z): calcd for
+
C15H17NNaO3 [M + Na]+, 282.1101; found, 282.1097.
(3-(Adamantan-1-yl)-5-hydroxyisoxazol-4-yl)(p-tolyl)methanone (6k). Compound 6k
was prepared following the published procedure20 from 3-(adamantan-1-yl)isoxazol-5(4H)-one 5f
(256 mg, 1.2 mmol), 4-methylbenzoyl chloride 10c (226 mg, 1.5 mmol) and DMAP (322 mg, 2.6
1
mmol) in benzene (20 mL) in 133 mg (34% yield) as a colorless solid: mp 98-103 °C (water). H
NMR (DMSO-d6, 400 MHz): δ 1.67-1.72 (m, 6H), 1.96-2.00(m, 3H), 2.01-2.04 (m, 6H), 2.34-2.36
(m, 3H), 7.24 (d, J = 7.7 Hz, 2H), 7.54 (d, J = 7.7 Hz, 2H). 13C{1H} NMR (DMSO-d6, 100 MHz): δ
21.1 (CH3), 27.5 (CH3), 35.9 (CH2), 36.0 (C), 38.4 (CH2), 93.0 (C), 128.6 (CH), 129.1 (CH), 136.1
(C), 142.2 (C), 170.8 (C), 171.1 (C), 189.1 (C). ESI/HRMS (m/z): calcd for C21H24NO3 [M + H]+,
+
338.1751; found, 338.1741.
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(5-Hydroxy-3-phenylisoxazol-4-yl)(p-tolyl)methanone (6l). Compound 6l was prepared
4
5
6
7
8
9
following the published procedure20 from 3-phenylisoxazol-5(4H)-one 5a (3.00 g, 18.6 mmol), 4-
methylbenzoyl chloride 10c (3.6 g, 23.3 mmol) and DMAP (5.1 g, 41.9 mmol) in benzene (115 mL)
in 3.94 g (75% yield) as a yellowish solid: mp 138-140 °C (water). 1H NMR (DMSO-d6, 400 MHz):
δ 2.33 (s, 3H), 7.17 (d, J = 7.9 Hz, 2H), 7.36-7.43 (m, 3H), 7.46-7.58 (m, 2H), 7.56 (d, J = 7.9 Hz,
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13
2H). C{1H} NMR (DMSO-d6, 100 MHz): δ 21.1 (CH3), 92.6 (C), 128.1 (CH), 128.3 (CH), 128.4
(CH), 129.3 (CH), 129.4 (C), 129.8 (CH), 135.2 (C), 141.7 (C), 163.5 (C), 171.5 (C), 186.2 (C).
+
ESI/HRMS (m/z): calcd for C17H13NNaO3 [M + Na]+, 302.0788; found, 302.0798.
(3-(4-Fluorophenyl)-5-hydroxyisoxazol-4-yl)(p-tolyl)methanone (6m). Compound 6m
was prepared following the published procedure20 from 3-(4-fluorophenyl)isoxazol-5 (4H)-one 5g
(1.00 g, 5.6 mmol), 4-methylbenzoyl chloride 10c (1.08 g, 7.0 mmol) and DMAP (1.54 g, 12.6
1
mmol) in benzene (45 mL) in 1.02 g (61% yield) as a colorless solid: mp 160-164 °C (water). H
13
NMR (DMSO-d6, 400 MHz): δ 2.33 (s, 3H), 7.15-7.22 (m, 4H), 7.52-7.56 (m, 4H). C{1H} NMR
(DMSO-d6, 100 MHz): δ 21.1 (CH3), 92.7 (C), 115.1 (d, J = 21.6 Hz, CH), 126.0 (d, J = 2.8 Hz, C),
128.3 (CH), 129.3 (CH), 130.8 (d, J = 8.8 Hz, CH), 135.0 (C), 141.8 (C), 162.3 (C), 162.9 (d, J =
+
247.2 Hz, C), 171.7 (C), 186.0 (C). ESI/HRMS (m/z): calcd for C17H12FNNaO3 [M + Na]+,
320.0693; found, 320.0687.
(3-(4-Bromophenyl)-5-hydroxyisoxazol-4-yl)(p-tolyl)methanone (6n). Compound 6n was
prepared following the published procedure20 from 3-(4-bromophenyl)isoxazolon-5(4H)-one 5c
(1.00 g, 4.2 mmol), 4-methylbenzoyl chloride 10c (800 mg, 5.2 mmol) and DMAP (1.15 g, 9.5
1
mmol) in toluene (45 mL) in 400 mg (26% yield) as a yellowish solid: mp 122-124 °C (water). H
NMR (DMSO-d6, 400 MHz): δ = 2.23 (s, 3H), 7.04 (d, J = 7.9 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H),
13
7.59 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 10.3 (br.s, 1H). C{1H} NMR (DMSO-d6, 100
MHz): δ 20.4 (CH3), 82.4 (C), 118.5 (CH), 122.2 (C), 129.1 (CH), 130.4 (CH), 130.5 (C), 130.8
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(C), 131.1 (CH), 137.5 (C), 161.5 (C), 161.6 (C), 175.7 (C). ESI/HRMS (m/z): calcd. for
4
5
-
C17H11BrNO3 [M ˗ H]-, 355.9928; found, 355.9918.
6
7
8
(5-Hydroxy-3-(thiophen-2-yl)isoxazol-4-yl)(p-tolyl)methanone (6o). Compound 6o was
9
prepared following the published procedure20 from 3-(thiophen-2-yl)isoxazol-5(4H)-one 5d (700
mg, 4.2 mmol), 4-methylbenzoyl chloride 10c (800 mg, 5.3 mmol) and DMAP (1.15 g, 9.5 mmol) in
benzene (45 mL) in 594 mg (49% yield) as a yellow solid: mp 77-79 °C (water). 1H NMR (DMSO-
d6, 400 MHz): δ 2.34 (s, 3H), 7.11 (dd, J = 5.1, 3.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.57 (d, J =
8.0 Hz, 2H), 7.64 (dd, J = 5.1, 1.3 Hz, 1H), 7.80 (dd, J = 3.6, 1.3 Hz, 1H). 13C{1H} NMR (DMSO-
d6, 100 MHz): δ 21.1 (CH3), 91.3 (C), 127.3 (CH), 128.2 (CH), 128.6 (CH), 129.2 (CH), 129.9
(CH), 136.08 (C), 136.13 (C), 141.3 (C), 157.6 (C), 172.8 (C), 186.9 (C). ESI/HRMS (m/z): calcd
for C15H12NO3S+ [M + H]+, 286.0532; found, 286.0540.
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(5-Hydroxy-3-(thiophen-2-yl)isoxazol-4-yl)(4-iodophenyl)methanone (6p). Compound
6p was prepared following the published procedure20 from 3-(thiophen-2-yl)isoxazol-5(4H)-one 5d
(530 mg, 3.2 mmol), 4-iodobenzoyl chloride 10d (1.35 g, 4.5 mmol) and DMAP (1.0 g, 8.2 mmol)
in benzene (45 mL) in 762 mg (60% yield) as a yellowish solid: mp 96-99 °C (water).1H NMR
(DMSO-d6, 400 MHz): δ 7.04 (dd, J = 5.1 Hz, J = 3.6 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.47 (dd, J
13
= 5.1 Hz, 1.2 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.98 (dd, J = 3.6 Hz, J = 1.2 Hz, 1H). C{1H}
NMR (DMSO-d6, 100 MHz): δ 88.7 (C), 96.5 (C),126.3 (CH), 126.8 (CH), 129.0 (CH), 130.7 (CH),
134.2 (C), 135.9 (CH), 140.8 (C), 157.7 (C), 175.0 (C), 186.4 (C). ESI/HRMS (m/z): calcd for
C14H8INNaO3S+ [M + Na]+, 419.9162; found, 419.9161.
Compounds 7 were prepared according to the published procedure.18 Physical and spectral data of 3-
(4-nitrophenyl)isoxazol-5(4H)- one (7a), and 3-(4-bromophenyl)isoxazol-5(4H)- one (7b), were in
agreement with previously reported values.18
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5-Chloro-3-(4-fluorophenyl)isoxazole-4-carbaldehyde (7c). Compound 7c was prepared
4
5
6
7
8
9
following the published procedure18 from N,N-dimethylformamide (3.0 mL, 39 mmol), phosphorus
oxychloride (6 mL, 65 mmol) and 3-(4-fluorophenyl)isoxazol-5(4H)- one 5g (659 mg, 3.7 mmol) in
325 mg (40% yield) as a colorless solid: mp 51−53 °C (water). 1H NMR (CDCl3, 400 MHz): δ 7.18-
7.22 (m, 2H), 7.82-7.86 (m, 2H), 9.96 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz): δ 113.3 (C), 116.0
(d, J = 22.1 Hz, CH), 122.5 (d, J = 3.5 Hz, C), 131.3 (d, J = 8.6 Hz, CH), 162.1 (C), 163.3 (C),
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60
+
164.5 (d, J = 252.4 Hz, C), 181.6 (CH). ESI/HRMS (m/z): calcd for C10H5AgClFNO2 [M + Ag]+,
331.9038; found, 331.9041.
4-Acyl-5-methoxy-3-substituted isoxazoles 1c, d, g-p were prepared according to the published
procedure.20 Physical and spectral data of (5-methoxy-3-phenylisoxazol-4-yl)(phenyl)methanone
(1c), (5-methoxy-3-methylisoxazol-4-y)(phenyl)methanone (1d), and 1-(5-methoxy-3-(thiophen-2-
yl)isoxazol-4-yl)propan-1-one (1i) were in agreement with previously reported values.20
1-(3-(4-Bromophenyl)-5-methoxyisoxazol-4-yl)propan-1-one (1g). Compound 1g was
prepared following the published procedure20 from 1-(3-(4-bromophenyl)-5-hydroxyisoxazol-4-
yl)propan-1-one 6g (509 mg, 1.72 mmol) and NMU (531 mg, 5.16 mmol) in THF (5 mL) and ether
(20 mL) in 313 mg (59% yield) as a colorless solid: mp 102-106 °C (light petroleum/ethyl acetate).
1H NMR (CDCl3, 400 MHz): δ 1.10 (t, J = 7.3 Hz, 3H), 2.74 (q, J = 7.3 Hz, 2H), 4.33 (s, 3H), 7.49-
13
7.52 (m, 2H), 7.55-7.58 (m, 2H). C{1H} NMR (CDCl3, 100 MHz): δ 7.5 (CH3), 34.9 (CH2), 58.8
(CH3), 95.7 (C), 124.6 (C), 127.7 (C), 130.9 (CH), 131.3 (CH), 164.4 (C), 173.1 (C), 193.0 (C).
+
ESI/HRMS (m/z): calcd for C13H12BrNNaO3 [M + Na]+, 331.9893; found, 331.9883.
1-(5-Methoxy-3-phenylisoxazol-4-yl)tetradecan-1-one (1h). Compound 1h was prepared
following the published procedure20 from 1-(5-hydroxy-3-phenylisoxazol-4-yl)tetradecan-1-one 6h
(200 mg, 0.81 mmol) and NMU (209 mg, 2.03 mmol) in THF (5 mL) and ether (20 mL) in 209 mg
(67% yield) as a colorless solid: mp 45-47 °C (pentane). 1H NMR (CDCl3, 400 MHz): δ 0.88 (t, J =
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6.8 Hz, 3H), 1.22-127 (m, 20H), 1.57-1.61 (m, 2H), 2.64-2.68 (m, 2H), 4.32 (s, 3H), 7.39-7.47 (m,
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3H), 7.58-7.60 (m, 2H). C{1H} NMR (CDCl3, 100 MHz): δ 14.1 (CH3), 22.7 (CH2), 23.8 (CH2),
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29.25 (CH2), 29.32 (CH2), 29.44 (CH2), 29.46 (CH2), 29.61 (CH2), 29.62 (CH2), 29.63 (CH2), 29.65
(CH2), 31.9 (CH2), 41.7 (CH2), 58.7 (CH3), 96.1 (C), 128.1 (CH), 128.8 (C), 129.2 (CH), 130.0
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(CH), 165.3 (C), 172.9 (C), 192.9 (C). ESI/HRMS (m/z): calcd for C24H35NNaO3 [M + Na]+,
408.2509; found, 408.2515.
(3-(tert-Butyl)-5-methoxyisoxazol-4-yl)(p-tolyl)methanone (1j). Compound 1j was
prepared following the published procedure20 from (3-(tert-butyl)-5-hydroxyisoxazol-4-yl)(p-
tolyl)methanone 6j (900 mg, 3.47 mmol) and NMU (900 mg, 8.69 mmol) in THF (10 mL) and ether
(40 mL) in 640 mg (67% yield) as a colorless solid: mp 93-95 °C (light petroleum/ethyl acetate). 1H
NMR (CDCl3, 400 MHz): δ 1.40 (s, 9H), 2.42 (s, 3H), 3.98 (s, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.66
(d, J = 8.0 Hz, 2H). C{1H} NMR (CDCl3, 100 MHz): δ 21.7 (CH3), 28.4 (CH3), 34.2 (C), 58.1
13
(CH3), 94.3 (C), 129.0 (CH), 129.4 (CH), 136.0 (C), 143.7 (C), 171.6 (C), 173.4 (C), 189.0 (C).
+
ESI/HRMS (m/z): calcd for C16H19NNaO3 [M + Na]+, 296.1257; found, 296.1258.
(3-(Adamantan-1-yl)-5-methoxyisoxazol-4-yl)(p-tolyl)methanone (1k). Compound 1k
was prepared following the published procedure20 from (3-adamantan-1-yl)-5-hydroxyisoxazol-4-
yl)(p-tolyl)methanone 6k (120 mg, 0.36 mmol) and NMU (90 mg, 0.9 mmol) in THF (5 mL) and
ether (15 mL) in 43 mg (34% yield) as a colorless solid: mp 135-139 °C (light petroleum/ethyl
1
acetate). H NMR (CDCl3, 400 MHz): δ 1.75-1.77 (m, 6H), 2.01-2.03 (m, 3H), 2.10-2.12 (m, 6H),
2.42 (s, 3H), 3.97 (s, 3H), 7.24 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H). 13C{1H} NMR (CDCl3,
100 MHz): δ 21.7 (CH3), 28.2 (CH3), 36.53 (C), 36.55 (CH2), 39.6 (CH2), 58.0 (CH3), 94.2 (C),
129.0 (CH), 129.4 (CH), 136.1 (C), 143.8 (C), 171.5 (C), 173.2 (C), 189.3 (C). ESI/HRMS (m/z):
+
calcd for C22H25NNaO3 [M + Na]+, 374.1727; found, 374.1720.
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(5-Methoxy-3-phenylisoxazol-4-yl)(p-tolyl)methanone (1l). Compound 1l was prepared
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following the published procedure20 from (5-hydroxy-3-phenylisoxazol-4-yl)(p-tolyl)methanone 6l
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(2.0 g, 7.0 mmol) and NMU (1.80 g, 17.5 mmol) in THF (20 mL) and ether (90 mL) in 1.54 g (75%
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yield) as a colorless solid: mp 96-101 °C (light petroleum/ethyl acetate). H NMR (CDCl3, 400
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MHz): δ 2.38 (s, 3H), 4.17 (s, 3H), 7.16 (d, J = 7.9 Hz, 2H), 7.30-7.40 (m, 3H), 7.51-7.54 (m, 2H),
13
7.65 (d, J = 7.9 Hz, 2H). C{1H} NMR (CDCl3, 100 MHz): δ 21.6 (CH3), 58.5 (CH3), 94.8 (C),
128.3 (CH), 128.6 (C), 128.6 (CH), 128.9 (CH), 129.5 (CH), 129.9 (CH), 135.2 (C), 143.8 (C),
+
165.3 (C), 171.9 (C), 187.3 (C). ESI/HRMS (m/z): calcd for C18H15NNaO3 [M + Na]+, 316.0944;
found, 316.0936.
(3-(4-Fluorophenyl)-5-methoxyisoxazol-4-yl)(p-tolyl)methanone (1m). Compound 1m
was prepared following the published procedure20 from (3-(4-fluorophenyl)-5-hydroxyisoxazol-4-
yl)(p-tolyl)methanone 6m (900 mg, 3.03 mmol) and NMU (780 mg, 7.58 mmol) in THF (12 mL)
and ether (55 mL) in 623 mg (66% yield) as a colorless solid: mp 133-137 °C (light petroleum/ethyl
1
acetate). H NMR (CDCl3, 400 MHz): δ 2.39 (s, 3H), 4.17 (s, 3H), 7.01-7.05 (m, 2H), 7.18 (d, J =
8.0 Hz, 2H), 7.53-7.57 (m, 2H), 7.65 (d, J = 8.0 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 21.6
(CH3), 58.6 (CH3), 94.7 (C), 115.5 (d, J = 22.2 Hz, CH), 124.7 (d, J = 3.1 Hz, C), 129.0 (CH), 129.5
(CH), 130.6 (d, J = 8.5 Hz, CH), 135.1 (C), 144.0 (C), 163.8 (d, J = 250.4, C), 164.4 (C), 172.0 (C),
+
187.3 (C). ESI/HRMS (m/z): calcd for C18H14FNNaO3 [M + Na]+, 334.0850; found, 334.0850.
(3-(4-Bromophenyl)-5-methoxyisoxazol-4-yl)(p-tolyl)methanone (1n). Compound 1n
was prepared following the published procedure20 from (3-(4-bromophenyl)-5-hydroxyisoxazol-4-
yl)(p-tolyl)methanone 6n (400 mg, 1.1 mmol) and NMU (300 mg, 2.8 mmol) in THF (5 mL) and
ether (20 mL) in 241 mg (58% yield) as a colorless solid: mp 123-126 °C (light petroleum/ethyl
1
acetate). H NMR (CDCl3, 400 MHz): δ 2.40 (s, 3H), 4.17 (s, 3H), 7.19 (d, J = 8.0 Hz, 2H), 7.40-
13
7.7.51 (m, 4H), 7.65 (d, J = 8.0 Hz, 2H). C{1H} NMR (CDCl3, 100 MHz): δ 21.7 (CH3), 58.6
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(CH3), 94.7 (C), 124.6 (C), 127.5 (C), 129.0 (CH), 129.5 (CH), 130.1 (CH), 131.6 (CH), 135.1 (C),
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+
144.1 (C), 164.4 (C), 172.0 (C), 187.2 (C). ESI/HRMS (m/z): calcd for C18H14BrNNaO3 [M + Na]+,
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394.0049; found, 394.0036.
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(5-Methoxy-3-(thiophen-2-yl)isoxazol-4-yl)(p-tolyl)methanone (1o). Compound 1o was
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prepared following the published procedure20 from (5-hydroxy-3-(thiophen-2-yl)isoxazol-4-yl)(p-
tolyl)methanone 6o (315 mg, 1.1 mmol) and NMU (270 mg, 2.6 mmol) in THF (9 mL) and ether
(20 mL) in 153 mg (48% yield) as a yellow solid: mp 126-130 °C (pentane). 1H NMR (CDCl3, 400
MHz): δ 2.41 (s, 3H), 4.12 (s, 3H), 7.03 (dd, J = 5.1, 3.8 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.40 (dd,
J = 5.1, 1.1 Hz, 1H), 7.63 (dd, J = 3.8, 1.1 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H). 13C{1H} NMR (CDCl3,
100 MHz): δ 21.7 (CH3), 58.6 (CH3), 94.4 (C), 127.4 (CH), 127.5 (C), 128.3 (CH), 129.0 (CH),
129.5 (CH), 130.5 (CH), 135.2 (C), 144.0 (C), 159.4 (C), 171.9 (C), 187.3 (C). ESI/HRMS (m/z):
calcd for C16H13NNaO3S+ [M + Na]+, 322.0508; found, 322.0503.
(4-Iodophenyl)(5-methoxy-3-(thiophen-2-yl)isoxazol-4-yl)methanone (1p). Compound
1p was prepared following the published procedure20 from (5-hydroxy-3-(thiophen-2-yl)isoxazol-4-
yl)(4-iodophenyl)methanone 6p (250 mg, 0.63 mmol) and NMU (200 mg, 1.9 mmol) in THF (5 mL)
and ether (20 mL) in 170 mg (65% yield) as a yellowish solid: mp 155-159 °C (pentane). 1H NMR
(CDCl3, 400 MHz): δ 4.14 (s, 3H), 7.06 (dd, J = 5.0 Hz, J = 3.9 Hz), 7.40-7.44 (m, 1 H), 7.48 (d, J =
8.4 Hz, 2H), 7.65-7.69 (m, 1H), 7.79 (d, J = 8.4 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 58.7
(CH3), 94.2 (C), 100.8 (C), 127.5 (CH), 128.6 (CH), 128.7 (C), 130.6 (CH), 130.7 (CH), 137.2 (C),
137.6 (CH), 159.4 (C), 172.2 (C), 186.7 (C). ESI/HRMS (m/z): calcd for C15H10AgINO3S+ [M +
Ag]+, 517.8472; found, 517.8473.
5-Aminoisoxazole-4-carbaldegydes 1q-s were prepared from 5-chloroizoxazoles 7 and the
appropriate amine according to the published procedure.18 Physical and spectral data of 5-
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(dibenzylamino)-3-(4-nitrophenyl)isoxazole-4-carbaldehyde (1q), and 3-(4-bromophenyl)-5-
(pyrrolidin-1-yl)isoxazole-4-carbaldehyde (1r) were in agreement with previously reported values.18
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3-(4-Bromophenyl)-5-morpholinoisoxazole-4-carbaldehyde (1s). Compound 1s was
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prepared following the published procedure18 from morpholine (300 mg, 3.5 mmol), potassium
carbonate (350 mg, 2.6 mmol) and 5-chloroisoxazole-4-carbaldehyde 7b (500 mg, 1.7 mmol) in
DMF (2 mL) in 542 mg (95% yield) as a yellowish solid: mp 155-157 °C (water). 1H NMR (CDCl3,
400 MHz): δ 3.84-3.86 (m, 4H), 3.97-3.99 (m, 4H), 7.45 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz,
2H), 9.32 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz): δ 48.4 (CH2), 66.4 (CH2), 97.1 (C), 125.0 (C),
126.6 (C), 130.6 (CH), 132.2 (CH), 165.4 (C), 168.3 (C), 181.4 (CH). ESI/HRMS (m/z): calcd for
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C14H14BrN2O3 [M + H]+, 337.0182; found, 337.0180.
5-Methoxyisoxazole-4-carbaldegydes 1t, u were prepared from 5-chloroizoxazoles 7 and sodium
methoxide according to the published procedure.18 Physical and spectral data of 3-(4-bromophenyl)-
5-methoxyisoxazole-4-carbaldehyde (1u) were in agreement with previously reported values.18
3-(4-Fluorophenyl)-5-methoxyisoxazole-4-carbaldehyde (1t). Compound 1t was prepared
following the published procedure18 from compound 7c (300 mg, 1.3 mmol) in absolute methanol
(10 mL) and sodium methoxide, prepared from sodium (109 mg, 4.7 mmol) and absolute methanol
1
(5 mL) in 218 mg (74% yield) as a colorless solid, mp 111-112 °C (water/methanol). H NMR
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(CDCl3, 400 MHz): δ 4.34 (s, 3H), 7.15-7.19 (m, 2H), 7.84-7.87 (m, 2H), 9.74 (s, 1H). C{1H}
NMR (CDCl3, 100 MHz): δ 58.9 (CH3), 96.0 (C), 115.8 (d, J = 21.9 Hz, CH), 123.6 (d, J = 3.1 Hz,
C), 131.1 (d, J = 8.6 Hz, CH), 162.9 (C), 164.3 (d, J = 251.3 Hz, C), 175.8 (C), 181.1 (CH).
+
ESI/HRMS (m/z): calcd for C11H8FNNaO3 [M + Na]+, 244.0380; found, 244.0378.
General procedure A for the preparation of 2H-azirinecarboxylates (2). A mixture
of isoxazoles 1 (1 mmol) and FeCl2·4H2O (20 mol %) in dry acetonitrile (5 mL) was stirred at 50 °C
until the completion of the reaction (~24 h, monitoring by TLC). The solvent was evaporated in
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petroleum/ethyl acetate, 10:1) to give, after evaporation of the solvents, pure compound 2.
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Methyl 2-benzoyl-3-phenyl-2H-azirine-2-carboxylate (2c). Compound 2c was prepared
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following general procedure A from (5-methoxy-3-phenylisoxazol-4-yl)(phenyl)methanone 1c (100
mg, 0.36 mmol) and FeCl2·4H2O (18 mg, 89 μmol) in acetonitrile (10 mL) for 24 h at 50 °C in 64
mg (64% yield) as a colorless solid: mp 66-69 °C (light petroleum/ethyl acetate). 1H NMR (CDCl3,
400 MHz): δ 3.73 (s, 3H), 7.49-7.53 (m, 2H), 7.58-7.69 (m, 4H), 8.01-8.03 (m, 2H), 8.14-8.16 (m,
2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 43.1 (C), 52.9 (CH3), 121.0 (C), 128.6 (CH), 129.3 (CH),
129.4 (CH), 131.0 (CH), 133.7 (CH), 134.4 (CH), 135.2 (C), 157.9 (C), 169.9 (C), 193.9 (C).
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ESI/HRMS (m/z): calcd for C17H13NNaO3 [M + Na]+, 302.0788; found, 302.0788.
Methyl 2-benzoyl-3-methyl-2H-azirine-2-carboxylate (2d). Compound 2d was prepared
following general procedure A from (5-methoxy-3-methylisoxazol-4-y)(phenyl)methanone 1d (103
mg, 0.47 mmol) and FeCl2·4H2O (23.5 mg, 0.12 mmol) in acetonitrile (10 mL) for 24 h at 50 °C in
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100 mg (97% yield) as a yellowish oil. H NMR (CDCl3, 400 MHz): δ 2.65 (s, 3H), 3.69 (s, 3H),
7.46-7.50 (m, 2H), 7.57-7.62 (m, 1H), 7.99-8.01 (m, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 11.9
(CH3), 41.6 (C), 52.7 (CH3), 128.6 (CH), 128.9 (CH), 133.6 (CH), 135.7 (C), 158.4 (C), 169.9 (C),
+
194.4 (C). ESI/HRMS (m/z): calcd for C12H11NNaO3 [M + Na]+, 240.0631; found, 240.0635.
Methyl 3-(4-bromophenyl)-2-propionyl-2H-azirine-2-carboxylate (2g). Compound 2g
was prepared following general procedure A from 1-(3-(4-bromophenyl)-5-methoxyisoxazol-4-
yl)propan-1-one 1g (100 mg, 0.32 mmol) and FeCl2·4H2O (12.5 mg, 63 μmol) in acetonitrile (10
mL) for 24 h at 50 °C in 90 mg (90% yield) as a colorless solid: mp 83-89 °C (light petroleum/ethyl
1
acetate). H NMR (CDCl3, 400 MHz): δ 1.08 (t, J = 7.2 Hz, 3H), 2.63-2.85 (m, 2H), 3.75 (s, 3H),
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7.72-7.76 (m, 4H). C{1H} NMR (CDCl3, 100 MHz): δ 7.5 (CH3), 34.0 (CH2), 44.5 (C), 52.8
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(CH3), 119.4 (C), 129.8 (C), 132.1 (CH), 133.1 (CH), 154.8 (C), 168.5 (C), 203.9 (C). ESI/HRMS
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+
(m/z): calcd for C13H12BrNNaO3 [M + Na]+, 331.9893; found, 331.9891.
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Methyl
3-(4-fluorophenyl)-2-(4-methylbenzoyl)-2H-azirine-2-carboxylate
(2m).
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Compound 2m was prepared following general procedure A from (3-(4-fluorophenyl)-5-
methoxyisoxazol-4-yl)(p-tolyl)methanone 1m (201 mg, 64 mmol) and FeCl2·4H2O (26 mg, 0.13
mmol) in acetonitrile (10 mL) for 24 h at 50°C in 175 mg (87% yield) as a colorless solid: mp 81-
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85 °C (light petroleum/ethyl acetate). H NMR (CDCl3, 400 MHz): δ 2.43 (s, 3H), 3.73 (s, 3H),
13
7.28-7.32 (m, 4H), 8.03-8.06 (m, 4H). C{1H} NMR (CDCl3, 100 MHz): δ 21.8 (CH3), 43.0 (C).
53.0 (CH3), 117.0 (d, J = 22.7 Hz, CH), 117.5 (d, J = 3.0 Hz, C), 129.4 (CH), 129.5 (CH), 132.4 (C),
133.6 (d, J = 9.8 Hz, CH), 144.9 (C), 157.4 (C), 166.3 (d, J = 257.9 Hz, C), 169.9 (C), 193.3 (C).
+
ESI/HRMS (m/z): calcd for C18H15FNO3 [M + H]+, 312.1030; found, 312.1031.
Methyl
2-(amino(4-bromophenyl)methylene)-3-oxopentanoate
(4g).
1-(3-(4-
Bromophenyl)-5-methoxyisoxazol-4-yl)propan-1-one 1g (30 mg, 97 µmol) and Mo(CO)6 (15 mg,
58 µmol) in MeCN (5 mL) with few drops of water was refluxed for 2 h at 85 °C. The solvent was
evaporated in vacuo, the residue was dissolved in DCM and purified by column chromatography
(light petroleum/ethyl acetate, 5:1) to give, after evaporation of the solvents, pure compound 4g in
19.5 mg (65% yield) as a yellowish oil. 1H NMR (CDCl3, 400 MHz): δ 1.12 (t, J = 7.3 Hz, 3H), 2.71
(q, J = 7.3 Hz, 2H), 3.34 (s, 3H), 5.35 (br s, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.5 Hz, 2H),
10.91 (br s, 1H). 13C{1H} NMR (CDCl3, 100 MHz): δ 9.0 (CH3), 34.1 (CH2), 51.2 (CH3), 103.9 (C),
124.4 (C), 128.2 (CH), 131.9 (CH), 137.1 (C), 164.7 (C), 169.9 (C), 200.2 (C). ESI/HRMS (m/z):
+
calcd for C13H14BrNNaO3 [M + Na]+, 334.0049; found, 334.0041.
General procedure B for the transformation of isoxazoles 1 into isoxazole-4-
carboxylates 3 and oxazole-4-carboxylates 8. A mixture of 4-acyl-5-methoxy-3-
substituted isoxazole 1 (1 mmol) and FeCl2·4H2O (20 mol %) in dry dioxane (5 mL) was stirred in a
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glass tube with a screw cap at 105-120 °C (bath temperature) until the completion of the reaction
(monitored by TLC). The solvent was evaporated in vacuo, the residue was dissolved in DCM and
purified by column chromatography (light petroleum/ethyl acetate, 7:1) to give, after evaporation of
the solvents, pure product.
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Methyl 3,5-diphenylisoxazole-4-carboxylate (3c). Compound 3c was prepared following
general procedure B from (5-methoxy-3-phenylisoxazol-4-yl)(phenyl)methanone 1c (75 mg, 0.27
mmol) and FeCl2·4H2O (11 mg, 55 μmol) in dioxane (5 mL) for 3 h at 105 °C in 67 mg (89% yield)
as a yellow solid: mp 92-94 °C (light petroleum/ethyl acetate), lit.30 mp 94-96 °C (hexane/ethyl
1
acetate) H NMR (CDCl3, 400 MHz): δ 3.72 (s, 3H), 7.44-7.61 (m, 6H), 7.62-7.71 (m, 2H), 7.89-
13
7.98 (m, 2H). C{1H} NMR (CDCl3, 100 MHz): δ 52.0 (CH3), 108.0 (C), 126.8 (C), 128.3 (CH),
128.50 (C), 128.55 (CH), 128.64 (CH), 128.9 (CH), 129.9 (CH), 131.3 (CH), 162.8 (C), 163.0 (C),
+
172.4 (C). ESI/HRMS (m/z): calcd for C17H13NNaO3 [M + Na]+, 302.0788; found, 302.0785.
Spectral data are in agreement with previously reported values.30
Methyl 3-methyl-5-phenylisoxazole-4-carboxylate (3d). Compound 3d was prepared
following general procedure B from (5-methoxy-3-methylisoxazol-4-y)(phenyl)methanone 1d (93
mg, 0.428 mmol) and FeCl2·4H2O (16 mg, 80 μmol) in dioxane (5 mL) for 1 h at 105 °C in 61 mg
(66% yield) as a yellowish oil. 1H NMR (CDCl3, 400 MHz): δ 2.51 (s, 3H), 3.84 (s, 3H), 7.44-7.56
(m, 3H), 7.87-7.90 (m, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 12.2 (CH3), 51.7 (CH3), 108.0 (C),
127.0 (C), 128.3 (CH), 129.1 (CH), 131.2 (CH), 160.7 (C), 162.6 (C), 173.1 (C). ESI/HRMS (m/z):
+
calcd for C12H11NNaO3 [M + Na]+, 240.0631; found, 240.0629.
Methyl 3-(4-bromophenyl)-5-ethylisoxazole-4-carboxylate (3g). Compound 3g was
prepared following general procedure B from 1-(3-(4-bromophenyl)-5-methoxyisoxazol-4-
yl)propan-1-one 1g (20 mg, 0.064 mmol) and FeCl2·4H2O (2.5 mg, 13 μmol) in dioxane (2 mL) for
1
2 h at 105 °C in 15 mg (75% yield) as a yellowish oil. H NMR (CDCl3, 400 MHz): δ 1.38 (t, J =
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7.6 Hz, 3H), 3.15 (q, J = 7.6 Hz, 2H), 3.78 (s, 3H), 7.50 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz,
2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 11.4 (CH3), 21.3 (CH2), 51.7 (CH3), 107.2 (C), 124.3 (C),
127.5 (C), 130.9 (CH), 131.3 (CH), 161.7 (C), 162.2 (C), 180.6 (C). ESI/HRMS (m/z): calcd for
8
9
+
C13H13BrNO3 [M + H]+, 310.0073; found, 310.0070.
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Methyl 3-phenyl-5-tridecylisoxazole-4-carboxylate (3h). Compound 3h was prepared
following general procedure B from 1-(5-methoxy-3-phenylisoxazol-4-yl)tetradecan-1-one 1h (42
mg, 0.11 mmol) and FeCl2·4H2O (4.3 mg, 22 μmol) in dioxane (5 mL) for 5 h at 105 °C in 35 mg
1
(83% yield) as a yellowish oil. H NMR (CDCl3, 400 MHz): δ 0.88 (t, J = 6.8 Hz, 3H), 1.27-1.42
(m, 20H), 1.74-1.83 (m. 2H), 3.05-3.17 (m, 2H), 3.76 (s, 3H), 7.42-7.46 (m, 3H), 7.61-7.62 (m, 2H).
13C{1H} NMR (CDCl3, 100 MHz): δ 14.1 (CH3), 22.7 (CH2), 27.3 (CH2), 27.5 (CH2), 29.17 (CH2),
29.24 (CH2), 29.3 (CH2), 29.4 (CH2), 29.58 (CH2), 29.62 (CH2), 29.62 (CH2), 29.65 (CH2), 31.9
(CH2), 51.5 (CH3), 107.7 (C), 128.1 (CH), 128.6 (C), 129.3 (CH), 129.7 (CH), 162.46 (C), 162.47
+
(C), 179.6 (C). ESI/HRMS (m/z): calcd for C24H35NNaO3 [M + Na]+, 408.2509; found, 408.2515.
Methyl 5-ethyl-3-(thiophen-2-yl)isoxazole-4-carboxylate (3i). Compound 3i was prepared
following general procedure B from 1-(5-methoxy-3-(thiophen-2-yl)isoxazol-4-yl)propan-1-one 1i
(40 mg, 0.17 mmol) and FeCl2·4H2O (13 mg, 68 μmol) in dioxane (5 mL) for 5 h at 120 °C in 17
mg (43% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 1.36 (t, J = 7.6 Hz, 3H), 3.13 (q, J =
7.6 Hz, 2H), 3.88 (s, 3H), 7.13 (dd, J = 5.1 Hz, J = 3.7 Hz, 1H), 7.46 (dd, J = 5.1 Hz, J = 1.1 Hz,
13
1H), 7.86 (dd, J = 3.7 Hz, J = 1.1 Hz, 1H). C{1H} NMR (CDCl3, 100 MHz): δ 11.4 (CH3), 21.4
(CH2), 51.7 (CH3), 106.8 (C), 127.3 (CH), 128.3 (CH), 128.7 (C), 130.7 (CH), 156.7 (C), 162.3 (C),
180.7 (C). ESI/HRMS (m/z): calcd for C11H11NNaO3S+ [M + Na]+, 260.0352; found, 260.0348.
Methyl 3-(tert-butyl)-5-(p-tolyl)isoxazole-4-carboxylate (3j). Compound 3j was prepared
following general procedure B from (3-(tert-butyl)-5-methoxyisoxazol-4-yl)(p-tolyl)methanone 1j
(75 mg, 0.27 mmol) and FeCl2·4H2O (9.9 mg, 50 μmol) in dioxane (5 mL) for 4 h at 120 °C in 70
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mg (93% yield) as a yellowish oil. 1H NMR (CDCl3, 400 MHz): δ 1.45 (s, 9H), 2.41 (s, 3H), 3.80 (s,
4
5
13
3H), 7.26 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H). C{1H} NMR (CDCl3, 100 MHz): δ 21.5
6
7
(CH3), 28.7 (CH3), 33.4 (C), 52.1 (CH3), 107.6 (C), 124.5 (C), 127.9 (CH), 129.2 (CH), 141.1 (C),
8
9
+
164.4 (C), 169.5 (C), 171.5 (C). ESI/HRMS (m/z): calcd for C16H19KNO3 [M + K]+, 312.0997;
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found, 312.0999.
Methyl 3-(adamantan-1-yl)-5-(p-tolyl)isoxazole-4-carboxylate (3k). Compound 3k was
prepared following general procedure B from (3-adamantan-1-yl)-5-methoxyisoxazol-4-yl)(p-
tolyl)methanone 1k (30 mg, 0.09 mmol) and FeCl2·4H2O (3.4 mg, 17 μmol) in dioxane (5 mL) for 6
h at 120 °C in 12 mg (40% yield) as a colorless solid: mp 87-91 °C (light petroleum/ethyl acetate).
1H NMR (CDCl3, 400 MHz): δ 1.78-1.80 (m, 6H), 2.08-2.10 (m, 3H), 2.13-2.15 (m, 6H), 2.41 (s,
3H), 3.81 (s, 3H), 7.25 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H). C{1H} NMR (CDCl3, 100
13
MHz): δ 21.5 (CH), 28.3 (CH3), 35.8 (C), 36.6 (CH2), 40.0 (CH2), 52.2 (CH3), 107.6 (C), 124.6 (C),
127.8 (CH), 129.3 (CH), 141.1 (C), 164.8 (C), 169.3 (C), 171.2 (C). ESI/HRMS (m/z): calcd for
+
C22H26NO3 [M + H]+, 352.1907; found, 352.1918.
Methyl 3-phenyl-5-(p-tolyl)isoxazole-4-carboxylate (3l). Compound 3l was prepared
following general procedure B from (5-methoxy-3-phenylisoxazol-4-yl)(p-tolyl)methanone 1l (50
mg, 0.17 mmol) and FeCl2·4H2O (7.0 mg, 34 μmol) in dioxane (7 mL) for 3 h at 105 °C in 41 mg
(82% yield) as a colorless solid: mp 91-92 °C (light petroleum/ethyl acetate). 1H NMR (CDCl3, 400
MHz): δ 2.44 (s, 3H), 3.72 (s, 3H), 7.32 (d, J = 8 Hz, 2H), 7.46-7.50 (m, 3H), 7.62-7.69 (m, 2H),
7.82 (d, J = 8 Hz, 2H). C{1H} NMR (CDCl3, 100 MHz): δ 21.6 (CH3), 51.9 (CH3), 107.5 (C),
13
124.0 (C), 128.3 (CH), 128.6 (CH), 128.9 (CH), 129.3 (CH), 129.8 (CH), 141.8 (C), 162.95 (C),
162.97 (C), 172.7 (C). ESI/HRMS (m/z): calcd for C18H15NNaO3 [M + Na]+, 316.0944; found,
+
316.0934.
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Methyl 3-(4-fluorophenyl)-5-(p-tolyl)isoxazole-4-carboxylate (3m). Compound 3m was
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prepared following general procedure B from (3-(4-fluorophenyl)-5-methoxyisoxazol-4-yl)(p-
tolyl)methanone 1m (75 mg, 0.24 mmol) and FeCl2·4H2O (9.5 mg, 48 μmol) in dioxane (5 mL) for
2 h at 105 °C in 63 mg (84% yield) as a colorless solid: mp 106-108 °C (light petroleum/ethyl
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acetate). H NMR (CDCl3, 400 MHz): δ 2.45 (s, 3H), 3.72 (s, 3H), 7.12-7.21 (m, 2H), 7.32 (d, J =
8.0 Hz, 2H), 7.62-7.70 (m, 2H), 7.80 (d, J = 8.0 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz): δ 21.6
(CH3), 51.9 (CH3), 107.4 (C), 115.4 (d, J = 21.7 Hz, CH), 123.9 (C), 124.7 (d, J = 3.2 Hz, C), 128.6
(CH), 129.3 (CH), 130.9 (d, J = 8.5 Hz, CH), 141.9 (C), 162.2 (C), 162.8 (C), 163.8 (d, J = 249.7,
C), 173.0 (C). ESI/HRMS (m/z): calcd for C18H14FNNaO3 [M + Na]+, 334.0850; found, 334.0841.
+
Methyl 3-(4-bromophenyl)-5-(p-tolyl)isoxazole-4-carboxylate (3n). Compound 3n was
prepared following general procedure B from (3-(4-bromophenyl)-5-methoxyisoxazol-4-yl)(p-
tolyl)methanone 1n (60 mg, 0.16 mmol) and FeCl2·4H2O (6 mg, 32 μmol) in dioxane (5 mL) for 2 h
at 105 °C in 44 mg (73% yield) as a colorless solid: mp 128-132 °C (light petroleum/ethyl acetate).
1H NMR (CDCl3, 400 MHz): δ 2.45 (s, 3H), 3.73 (s, 3H), 7.32 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.5
Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H). C{1H} NMR (CDCl3, 100 MHz): δ
13
21.6 (CH3), 52.0 (CH3), 107.3 (C), 123.9 (C), 124.4 (C), 127.6 (C), 128.7 (CH), 129.3 (CH), 130.6
(CH), 131.5 (CH), 142.0 (C), 162.2 (C), 162.7 (CD), 173.2 (C). ESI/HRMS (m/z): calcd for
C18H14BrNNaO3 [M + Na]+, 394.0049; found, 394.0031.
+
Methyl 3-(thiophen-2-yl)-5-(p-tolyl)isoxazole-4-carboxylate (3o). Compound 3o was
prepared following general procedure B from (5-methoxy-3-(thiophen-2-yl)isoxazol-4-yl)(p-
tolyl)methanone 1o (31 mg, 0.1 mmol) and FeCl2·4H2O (5 mg, 20 μmol) in dioxane (5 mL) for 3 h
at 105 °C in 19 mg (61% yield) as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ 2.44 (s, 3H), 3.83 (s,
3 H), 7.15 (dd, J = 5.1, 3.7 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 5.1, 1.2 Hz, 1H), 7.72 (d,
J = 8.0 Hz, 2H), 7.75 (dd, J = 3.7, 1.2 Hz, 1H). C{1H} NMR (CDCl3, 100 MHz): δ 21.6 (CH3),
13
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52.0 (CH3), 107.0 (C), 123.9 (C), 127.4 (CH), 128.4 (CH), 128.5 (CH), 128.7 (C), 129.3 (CH), 130.0
(CH), 141.9 (C), 157.0 (C), 162.8 (C), 173.1 (C). ESI/HRMS (m/z): calcd for C16H14NO3S+ [M +
H]+, 300.0689; found, 300.0673.
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Methyl 5-(4-iodophenyl)-3-(thiophen-2-yl)isoxazole-4-carboxylate (3p). Compound 3p
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was prepared following general procedure B from (4-iodophenyl)(5-methoxy-3-(thiophen-2-
yl)isoxazol-4-yl)methanone 1p (42 mg, 0.1 mmol) and FeCl2·4H2O (5 mg, 20 μmol) in dioxane (5
mL) for 4 h at 105 °C in 33 mg (79% yield) as a colorless solid: mp 84-87 °C (light petroleum/ethyl
1
acetate). H NMR (CDCl3, 400 MHz): δ 3.83 (s, 3H), 7.16 (dd, J = 5.1, 3.7 Hz, 1H), 7.50 (dd, J =
5.1, 1.1 Hz, 1H), 7.57 (d, J = 8.6 Hz. 2H), 7.74 (dd, J = 3.7, 1.1 Hz, 1H), 7.87 (d, J = 8.6 Hz. 2H).
13C{1H} NMR (CDCl3, 100 MHz): δ 52.2 (CH3), 98.4 (C), 107.8 (C), 126.2 (C), 127.5 (CH), 128.4
(C), 128.6 (CH), 130.1 (CH), 130.2 (CH), 137.9 (CH), 157.2 (C), 162.4 (C), 172.0 (C). ESI/HRMS
(m/z): calcd for C15H10AgINO3S+ [M + Ag]+, 517.8472; found, 517.8467.
N,N-Dibenzyl-3-(4-nitrophenyl)isoxazole-4-carboxamide (3q). Compound 3q was
prepared following general procedure B from 5-(dibenzylamino)-3-(4-nitrophenyl)isoxazole-4-
carbaldehyde 1q (41 mg, 0.1 mmol) and FeCl2·4H2O (4 mg, 20 μmol) in dioxane (5 mL) for 3 h at
1
105 °C in 36 mg (88% yield) as a yellowish solid: mp 86-90 °C (light petroleum/ethyl acetate). H
NMR (CDCl3, 400 MHz): δ 4.32 (br s, 2H), 4.72 (br s, 2H), 7.03-7.07 (m, 2H), 7.19-7.38 (m, 8H),
7.84 (d, J = 7.3 Hz, 2H), 8.17 (d, J = 7.3 Hz, 2H), 8.48 (s, 1H). 13C{1H} NMR (CDCl3, 100 MHz): δ
48.2 (CH2), 51.5 (CH2), 115.1 (C), 124.0 (CH), 126.4 (CH), 128.2 (CH), 129.0 (CH), 129.0 (CH),
129.2 (C), 133.8 (C), 148.8 (C), 157.3 (CH), 158.02 (C), 162.5 (C). ESI/HRMS (m/z): calcd for
+
C24H19N3NaO4 [M + Na]+, 436.1268; found, 436.1275.
(3-(4-Bromophenyl)isoxazol-4-yl)(pyrrolidin-1-yl)methanone (3r). Compound 3r was
prepared following general procedure B from 3-(4-bromophenyl)-5-(pyrrolidin-1-yl)isoxazole-4-
carbaldehyde 1r (30 mg, 0.093 mmol) and FeCl2·4H2O (3.7 mg, 19 μmol) in dioxane (5 mL) for 3 h
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at 105 °C in 18 mg (60% yield) as a colorless solid: mp 117-120 °C (light petroleum/ethyl acetate).
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1H NMR (CDCl3, 400 MHz): δ 1.77-1.84 (m, 2H), 1.87-1.93 (m, 2H), 3.14 (t, J = 6.7 Hz, 2H), 3.60
6
7
13
(t, J = 6.7 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 8.62 (s, 1H). C{1H} NMR
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9
(CDCl3, 100 MHz): δ 24.3 (CH2), 25.8 (CH2), 46.0 (CH2), 48.5 (CH2), 116.3 (C), 124.8 (C), 127.0
(C), 129.3 (CH), 132.2 (CH), 157.9 (CH), 158.4 (C), 160.6 (C). ESI/HRMS (m/z): calcd for
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+
C14H14BrN2O2 [M + H]+, 321.0233; found, 321.0234.
(3-(4-Bromophenyl)isoxazol-4-yl)(morpholino)methanone (3s). Compound 3s was
prepared following general procedure B from 3-(4-bromophenyl)-5-morpholinoisoxazole-4-
carbaldehyde 1s (35 mg, 0.1 mmol) and FeCl2·4H2O (4.1 mg, 20 μmol) in dioxane (5 mL) for 4 h at
105 °C in 32 mg (91% yield) as a colorless solid: mp 145-146 °C (light petroleum/ethyl acetate). 1H
NMR (CDCl3, 400 MHz): δ 3.15 (br s, 2H), 3.29 (br s, 2H), 3.66-3.77 (m, 4H), 7.57-7.63 (m, 4H),
13
8.62 (s, 1H). C{1H} NMR (CDCl3, 100 MHz): δ 47.9 (CH2), 66.3 (CH2), 114.5 (C), 125.2 (C),
126.6 (C), 129.3 (CH), 132.4 (CH), 158.38 (C), 158.42 (CH), 161.1 (C). ESI/HRMS (m/z): calcd for
C14H13BrN2NaO3 [M + Na]+, 359.0002; found, 359.0001.
+
Methyl 2-(4-fluorophenyl)oxazole-4-carboxylate (8t). Compound 8t was prepared
following general procedure B from 3-(4-fluorophenyl)-5-methoxyisoxazole-4-carbaldehyde 1t (70
mg, 0.32 mmol) and FeCl2·4H2O (14 mg, 70 μmol) in dioxane (6 mL) for 3 h at 105 °C in 44 mg
1
(63% yield) as a colorless solid: mp 107-110 °C (light petroleum/ethyl acetate). H NMR (CDCl3,
400 MHz): δ 3.95 (s, 3H), 7.14-7.18 (m, 2H), 8.09-8.13 (m, 2H), 8.27 (s, 1H). C{1H} NMR
13
(CDCl3, 100 MHz): δ 52.3 (CH3), 116.1 (d, J = 22.1 Hz, CH), 122.7 (d, J = 3.4 Hz, C), 129.1 (d, J =
8.9 Hz, CH), 134.5 (C), 143.8 (CH), 161.67 (C), 161.69 (C), 164.7 (d, J= 252.6 Hz, C). ESI/HRMS
(m/z): calcd for C11H9FNO3 [M + H]+, 222.0561; found, 222.0554.
+
Methyl 2-(4-bromophenyl)oxazole-4-carboxylate (8u). Compound 8u was prepared
following general procedure B from 3-(4-bromophenyl)-5-methoxyisoxazole-4-carbaldehyde 1u (30
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mg, 0.11 mmol) and FeCl2·4H2O (4.2 mg, 20 μmol) in dioxane (5 mL) for 3 h at 105 °C in 17 mg
(57% yield) as a colorless solid: mp 150-153 °C (light petroleum/ethyl acetate), lit.31 mp 154-156
°C. 1H NMR (CDCl3, 400 MHz): δ 3.96 (s, 3H), 7.62 (d, J = 8.6 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H),
8
9
13
8.29 (s, 1H). C{1H} NMR (CDCl3, 100 MHz): δ 52.3 (CH3), 125.3 (C), 125.9 (C), 128.3 (CH),
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132.2 (CH), 134.6 (C), 143.9 (CH), 161.6 (C), 161.7 (C). ESI/HRMS (m/z): calcd for
+
C11H8BrNNaO3 [M + Na]+, 303.9580; found, 303.9571. Spectral data are in agreement with
previously reported values.31
General procedure C for the preparation of oxazoles 8 from azirines 2. A solution
of 2H-azirinecarboxylate 2 (1 mmol) in o-dichlorobenzene was heated for 5 h at 170 °C. The solvent
was evaporated in vacuo. To remove traces of o-dichlorobenzene, the residue was dissolved in
ethanol and the solution was evaporated in vacuo to give pure compound 8.
Methyl 2,5-diphenyloxazole-4-carboxylate (8с). Compound 8с was prepared following
general procedure C from methyl 2-benzoyl-3-phenyl-2H-azirine-2-carboxylate 2с (10 mg, 36
μmol) in o-dichlorobenzene (2 mL) in 10 mg (100 % yield) as a colorless solid: mp 63-68 °C
1
(ethanol), lit.32 74-75 °C (diethyl ether/petroleum). H NMR (CDCl3, 400 MHz): δ 3.98 (s, 3H),
13
7.48-7.53 (m, 6H), 8.14-8.18 (m, 4H). C{1H} NMR (CDCl3, 100 MHz): δ 52.4 (CH3), 126.3 (C),
126.9 (CH), 127.0 (C), 128.0 (C), 128.5 (CH), 128.5 (CH), 128.8 (CH), 130.4 (CH), 131.1 (CH),
+
155.3 (C), 159.8 (C), 162.7 (C). ESI/HRMS (m/z): calcd for C17H13NNaO3 [M + Na]+, 302.0788;
found, 302.0788. Spectral data are in agreement with previously reported values.32
Methyl 2-methyl-5-phenyloxazole-4-carboxylate (8d). Compound 8d was prepared
following general procedure C from methyl 2-benzoyl-3-methyl-2H-azirine-2-carboxylate 2d (15
1
mg, 69 μmol) in o-dichlorobenzene (2 mL) in 15 mg (100 % yield) as a yellowish oil. H NMR
13
(CDCl3, 400 MHz): δ 2.55 (s, 3H), 3.93 (s, 3H), 7.43-7.50 (m, 3H), 8.05-8.07 (m, 2H). C{1H}
NMR (CDCl3, 100 MHz): δ 13.8 (CH3), 52.2 (CH3), 126.5 (C), 126.9 (C), 128.2 (CH), 128.4 (CH),
29
ACS Paragon Plus Environment