Synthesis of 3,5-disubstituted 4-aminoisoxazoles by cyclization of O-(β-oxoalkyl)-substituted α-hydroxyimino nitriles

Article abstract of DOI:10.1007/s11172-005-0379-0

4-Amino-5-benzoyl(acetyl)isoxazole-3-carboxamides were prepared by cyclization of α-hydroxyimino nitriles O-alkylated with bromoacetophenones (bromoacetone). The purity of the target 4-aminoisoxazoles can be substantially increased by treating O-alkylated

Full text of DOI:10.1007/s11172-005-0379-0

Russian Chemical Bulletin, International Edition, Vol. 54, No. 5, pp. 1189—1196, May, 2005
1189
Synthesis of 3,5ꢀdisubstituted 4ꢀaminoisoxazoles by cyclization of
Oꢀ(βꢀoxoalkyl)ꢀsubstituted αꢀhydroxyimino nitriles
ꢀ
V. P. Kislyi, E. B. Danilova, and V. V. Semenov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: vs@zelinsky.ru
4ꢀAminoꢀ5ꢀbenzoyl(acetyl)isoxazoleꢀ3ꢀcarboxamides were prepared by cyclization of
αꢀhydroxyimino nitriles Oꢀalkylated with bromoacetophenones (bromoacetone). The purity of
the target 4ꢀaminoisoxazoles can be substantially increased by treating Oꢀalkylated oximes with
LiClO4 before cyclization.
Key words: 2ꢀ(2ꢀarylꢀ2ꢀoxoethoxyimino)cyanoacetamides, 4ꢀaminoꢀ5ꢀbenzoylisoxazoleꢀ
3ꢀcarboxamides.
Scheme 1
Procedures for the preparation of 4ꢀaminoisoxazoles
are much less developed than methods for the synthesis of
3ꢀaminoꢀ and 5ꢀaminoisoxazoles.1,2 However, 4ꢀaminoꢀ
isoxazoles bearing an ester, amide, or acyl group at posiꢀ
tion 3 or 5 of the ring can be used to prepare difficultly
accessible fused systems, such as isoxazolopyrimidines,
isoxazolopyridines, etc.1,3,4 Derivatives of these fused sysꢀ
tems, as well as 4ꢀaminoisoxazoles by themselves, can
exhibit biological activity.5—7 Hence, the development of
new efficient methods for the synthesis of these comꢀ
pounds is of considerable importance. Earlier, funcꢀ
tionalized 4ꢀaminoisoxazoles 1 have been synthesized by
the Hofmann reaction3,8 and cyclization of Oꢀacylated
nitroacetophenone oximes9,10 followed by reduction of
the resulting nitroisoxazoles.9—11 However, these proceꢀ
dures involve many steps and give products in low total
yields, which complicates their use in the synthesis of
bicyclic systems. More recently, a new procedure has been
developed3 for the synthesis of 4ꢀaminoisoxazoles 1 by
cyclization of Oꢀalkylated αꢀhydroxyimino nitriles 2 with
a large (30ꢀfold or larger) excess of LiOH. This method
has been used in subsequent studies.4,12
The aim of the present study was to examine the possiꢀ
bilities of this cyclization for preparing 4ꢀaminoisoxazoleꢀ
3ꢀcarboxamides bearing a functional substituent at posiꢀ
tion 5. We used various bases in cyclization of Oꢀ(βꢀoxoꢀ
alkyl)ꢀαꢀhydroxyimino nitriles 2 (Scheme 1).
The reactions with the use of aliphatic amines (triꢀ
ethylamine, benzylamine, or piperidine) as bases (by analꢀ
ogy with the reactions described in the study3) produced
aminoisoxazoles 1 in low yields. It should be noted that
isolation of the products was substantially complicated
(only preparative chromatography was used), because the
reaction mixtures contained large amounts of impurities.
1, 2
X
R
1, 2
X
R
a
b
c
d
e
f
EtOOC
CONH2
CONHPh
CONHPh
(4ꢀFC6H4)NHCO
MeNHCO
CONHCH2Ph
4ꢀBrC6H4
4ꢀBrC6H4
4ꢀBrC6H4 1j
Ph
Ph
Ph
Ph
h
i
CONHPh Me
Ph
4ꢀBrC6H4
4ꢀBrC6H4
OEt
COOH
Ph
2j
2k
2l
Ph
NHPh
PhNHCO NH2
g
3
X
3
X
a
b
c
d
EtOOC
CONH2
CONHPh
(4ꢀFC6H4)NHCO
e
f
g
MeNHCO
CONHCH2Ph
Ph
The use of stronger bases, such as LiOH, KOH, or EtONa,
in cyclization proved to be more efficient. The best results
were obtained with the use of LiOH. It should be noted
that cyclization in aqueous alcohol is most convenient
from the preparative viewpoint, because the reaction prodꢀ
uct can be separated by simple filtration. However, the
reactions even with the use of LiOH afforded 4ꢀaminoꢀ
isoxazoles 1, which were substantially contaminated (in
the presence of an aryl substituent in the amide fragment
(2c—e), the percentage of the impurity was as high
as 20%). We had to purify the product by fractional crysꢀ
tallization. Since the use of LiOH had a positive effect on
the yields of 4ꢀaminoisoxazoles, we expected that succesꢀ
sive treatment of Oꢀalkylated oximes with a lithium salt
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1159—1165, May, 2005.
1066ꢀ5285/05/5405ꢀ1189 © 2005 Springer Science+Business Media, Inc.

1190
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
Kislyi et al.
Table 1. Yields, melting points, and elemental analysis data for compounds 2a—l and 4a,b
Comꢀ
pound
R
X
Yield
(%)
M.p./°C
(solvent)
Rf*
Found
Calculated
Molecular
formula
(%)
C
H
N
2a
2b
2c
2d
COOEt
CONH2
4ꢀBrC6H4
4ꢀBrC6H4
4ꢀBrC6H4
Ph
54
78
82
85
74
61
82
59
71
89
82
85
45
67
118—122
(EtOH)
199—202
(DMF)
194—197
(EtOH)
161—163
(EtOH)
142—144
(MeOH)
162—164
(PriOH)
107—109
(EtOH)
132—134
(DMF—H2O)
108—110
(PhCH3)
57—60
(PhCH3)
117—119
(PriOH)
212—215
(DMF)
0.81
0.10
0.54
0.51
0.49
0.25
0.42
0.28
0.46
0.80
0.62
0.24
45.9
46.0
42.7
42.6
52.4
52.8
66.9
66.4
62.6
62.8
58.7
58.8
67.7
67.3
58.5
58.8
56.3
56.0
62.0
62.1
69.2
68.8
53.9
53.7
3.40
3.25
2.85
2.60
3.40
3.11
4.20
4.23
3.70
3.69
4.50
4.49
4.80
4.67
4.70
4.49
3.10
3.20
4.90
5.17
4.80
4.67
4.05
4.1
9.0
8.3
C13H11BrN2O4
C11H8BrN3O3
C17H12BrN3O3
C17H13N3O3
C17H12FN3O3
C12H11N3O3
C18H15N3O3
C12H11N3O3
C16H11BrN2O2
C12H12N2O3
C16H13N3O2
C11H10N4O3
C10H10N2O4
C16H15N3O3
13.9
13.9
10.7
10.9
13.3
13.7
12.4
12.9
16.8
17.1
12.9
13.1
16.7
17.1
8.0
CONHPh
CONHPh
2e CONHꢀ4ꢀFC6H4
Ph
2f
CONHMe
Ph
2g
2h
2i
CONHBn
Ph
CONHPh
Me
Ph
4ꢀBrC6H4
OEt
8.2
2j
Ph
12.4
12.1
14.7
15.1
22.4
22.8
12.1
12.6
13.7
14.1
2k
2l
Ph
NHPh
NH2
CONHPh
4a
4b
—
—
COOH
CONHPh
182—184
(H2O)
90—92
0.34—0.8 54.5
54.1
0.67
4.30
4.50
64.50 5.50
64.65 5.05
(BuOAc)
* The following systems were used: benzene (for 2i); benzene—EtOAc, 10 : 1 (for 2a—h,j,k); benzene—EtOAc, 1 : 1
(for 2l, 4b); EtOAc—EtOH, 5 : 1 (for 4a).
Scheme 2
and a base would facilitate the reaction. We chose perꢀ
chlorate as the lithium salt, because lithium perchlorate,
unlike other lithium salts, is readily soluble in organic
solvents. Actually, aminoisoxazole 1d was isolated in anaꢀ
lytically pure form by simple filtration of the reaction
mixture, which was prepared by the addition of an acetoꢀ
nitrile solution of Oꢀalkylated oxime 2d and an equimolar
amount of LiClO4 (the solution was allowed to stand for
14 h) to an aqueous LiOH solution.
This procedure has been successfully used to syntheꢀ
size a series of 4ꢀaminoisoxazoles bearing the benzoyl,
bromobenzoyl, or acetonyl group at position 5 of the
isoxazole ring (Tables 1 and 2).
The factors responsible for the efficiency of lithium
salts remain unclear. It is known13 that oximes can exist
as isomeric Z and E forms, whose interconversion is cataꢀ
lyzed, in particular, by traces of acids. Evidently, only the
(E) form of Oꢀalkylated oxime containing closelyꢀspaced
reaction centers can undergo cyclization to give aminoꢀ
isoxazole (Scheme 2).
In our opinion, compounds 2 (in the absence of lithium
salts) exist predominantly in the (Z ) form, which is able

Synthesis of 4ꢀaminoisoxazoleꢀ3ꢀcarboxamides
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
1191
Table 2. Yields, melting points, and elemental analysis data for compounds 1a—j
Comꢀ
pound
R
X
Yield
(%)
M.p./°C
(solvent)
Rf*
Found
Calculated
Molecular
formula
(%)
C
H
N
1a
1b
1c
1d
1e
1f
COOEt
CONH2
4ꢀBrC6H4
4ꢀBrC6H4
4ꢀBrC6H4
Ph
18
53
55
42
38
61
68
41
72
40
150—152
(PhCH3)
228—230
(DMF)
0.84
0.25
45.9
46.0
43.0
42.6
52.7
52.8
66.1
66.4
62.5
62.8
58.5
58.8
67.8
67.3
58.7
58.8
56.1
56.0
42.3
42.4
3.30
3.25
2.80
2.60
3.00
3.11
4.10
4.23
3.90
3.69
4.10
4.49
4.20
4.67
4.90
4.49
2.90
3.20
2.60
2.25
8.7
8.3
C13H11BrN2O4
C11H8BrN3O3
C17H12BrN3O3
C17H13N3O3
C17H12FN3O3
C12H11N3O3
C18H15N3O3
C12H11N3O3
C16H11BrN2O2
C11H7BrN2O4
13.7
13.6
10.4
10.9
13.2
13.7
12.5
12.9
16.5
17.1
13.8
13.1
16.9
17.1
7.9
CONHPh
CONHPh
CONHꢀ4ꢀFC6H4
CONHMe
CONHBn
CONHPh
Ph
235—238
(EtOH)
175—177
(EtOH)
196—198
(EtOH)
175—178
(EtOH)
167—170
(EtOH)
179—182
(EtOH)
185—187
(PhCH3)
200—205
(H2O)
0.80
0.76
Ph
0.76
Ph
0.50
1g
1h
1i
Ph
0.67
Me
0.67
4ꢀBrC6H4
4ꢀBrC6H4
0.65
8.2
8.2
9.0
1j
COOH
0.05—0.3
* The following systems were used: benzene (for 1i); benzene—EtOAc, 10 : 1 (for 1a—h); EtOAc—EtOH, 5 : 1 (for 1j).
to form an intramolecular hydrogen bond. The most probꢀ
able mechanism of the influence of the lithium cation
involves isomerization of the (Z ) form of oximes 2 to give
the (E) form necessary for cyꢀ
clization. Apparently, the forꢀ
mation of a chelated complex of
the (E) form of oxime with the
lithium cation is the driving
force for this transformation.
imino nitriles 3 are smoothly alkylated with chloroacetic
acid derivatives. However, we failed to synthesize the corꢀ
responding 4ꢀaminoisoxazoles from compounds 2j—l.
OꢀAlkylated nitriles 2j—l are absolutely inert to triꢀ
ethylamine. Under the conditions found in the present
study (LiOH, LiClO4 in aqueous acetonitrile), the nitrile
group in compounds 2j and 2k is hydrolyzed to the amide
group giving rise to compounds 4a and 4b, respectively.
Compounds 2j,k did not react with EtONa at room temꢀ
perature, whereas heating led to deep resinification giving
rise to unidentified compounds (Scheme 3). Presumably,
However, the available exꢀ
perimental data are insufficient
to support this hypothesis. It is
known14 that the signal for the carbon atom of the nitrile
group located in the trans position with respect to the
N—O bond is observed at lower field than the signal for
the CN group of the cis isomer, although the difference is
small (0.2—0.3 ppm).15 Since both the 1H and 13C NMR
spectra of compounds 2 show one set of signals and conꢀ
tain no signals of the minor isomer, it is impossible to
determine the configuration of the only isomer from the
13C NMR spectrum. The determination of the structure
of the complex of Oꢀalkylated oxime with lithium is an
even more complex problem, because the corresponding
data are lacking in the literature.
Scheme 3
Since the syntheses of 4ꢀaminoꢀ3ꢀphenylisoxazoleꢀ5ꢀ
carboxylic acid and its derivatives described earlier9,10
involve many steps, we attempted to prepare these comꢀ
pounds according to Scheme 1. Sodium salts of hydroxyꢀ
R = OEt (2j), NHPh (2k)

1192
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
Kislyi et al.
Scheme 4
R = 4ꢀBrC6H4
compounds 2j—l do not undergo cyclization due to the
fact that the methylene group in amides has much lower
acidity compared to this group in ketones, with the result
that the nucleophilic attack of the base on the nitrile
group of compounds 2 is the main reaction pathway.
We examined the possibility of synthesizing 4ꢀaminoꢀ
5ꢀ(4ꢀbromobenzoyl)isoxazoleꢀ3ꢀcarboxamides from ester
1a or acid 1j (Scheme 4). However, this procedure proved
to be inefficient. Under the standard conditions (LiOH),
cyclization affords (after acidification to pH 1) only amino
acid 1j, the yield being low (5%). We succeeded in preꢀ
paring amino ester 1a, although in moderate yield (18%),
by the reaction of ester 2a with sodium ethoxide in anꢀ
hydrous ethanol. Alkaline saponification of amino ester
1a affords amino acid 1j also in moderate yield (40%).
Low yields of amino ester 1a produced by alkaline saꢀ
ponification are, apparently, attributed to the fact that the
isoxazole ring can be opened under the action of bases.16,17
The reactions of ester 1a with amines (ammonia or
benzylamine) produced the corresponding amides 1b,c,
although the reactions were accompanied by noticeable
resinification, whereas the reactions of anilines with ester
1a did not afford anilides. Earlier, it has been found that
4ꢀaminoꢀ3ꢀphenylisoxazoleꢀ5ꢀcarboxamides can be synꢀ
thesized only by the reaction of the Nꢀhydroxysuccinimide
derivative of the acid with amines18 (the reaction of
isoxazolooxazine, which was prepared by the reaction of
phosgen, with amines produces exclusively 4ꢀureidoꢀ
isoxazoleꢀ5ꢀcarboxylic acid derivatives rather than
amides18).
known19 that alkylation of oximes generally affords mixꢀ
tures of Nꢀ and Oꢀalkylation products, the presence of
electronꢀwithdrawing substituents in the oxime molecule
suppressing Nꢀalkylation.20 We isolated the only alkylaꢀ
tion product in high yield from the reaction mixture preꢀ
pared by alkylation of oximes 3, and this product did not
show isomerism (1H and 13C NMR spectroscopic data).
The structures of compounds 2 as Oꢀalkylation products
can be confirmed based on spectral correlations.14 Neverꢀ
theless, the structure of the alkylation product is unamꢀ
biguously supported by the fact that it is easily transꢀ
formed into 4ꢀaminoisoxazole (provided that the strucꢀ
tures of compounds 1 were reliably established). Since
4ꢀaminoisoxazoles 1 are completely substituted isoxazoles
(contain no protons at the carbon atoms of the isoxazole
ring), their structures cannot be proved by 1H NMR specꢀ
troscopy. Hence, we measured the 13C NMR spectra of
these compounds. In particular, a comparison of the
chemical shifts in the 13C NMR spectra of compounds
1c—f and the use of the APT technique allowed us to
assign all signals for the carbon atoms in the phenyl rings
and, consequently, assign the signals for the carbon atꢀ
oms of the isoxazole ring: C(5) (δ 146.5—149.9), C(3)
(δ 147.6—148.2), and C(4) (δ 134.99—136.0). The posiꢀ
tions of the signals for the carbon atoms of the isoxazole
ring are in satisfactory agreement with the signals for
4ꢀaminoꢀ3ꢀphenylisoxazoleꢀ5ꢀcarboxamide 5 described
earlier18,21 (see Table 5).
Experimental
Therefore, since hydroxyiminoacetonitriles 3 are
readily accessible, whereas acid 1j or its esters are syntheꢀ
sized in low yields, it is more convenient to synthesize
amines 1 from oximes 3.
The structures of the resulting compounds were conꢀ
firmed by 1H and 13C NMR spectroscopy, mass specꢀ
trometry, and elemental analysis (Tables 1—5). It is
1
The H NMR spectra were recorded on a Bruker DRXꢀ500
instrument operating at 500.13 MHz in DMSOꢀd6. The
13C NMR spectra were measured on a Bruker AMꢀ300 instruꢀ
ment operating at 75.47 MHz in DMSOꢀd6. The IR spectra
were recorded on a Specord Mꢀ80 instrument in KBr pellets.
The mass spectra were obtained on a FinniganꢀMAT instrument

Synthesis of 4ꢀaminoisoxazoleꢀ3ꢀcarboxamides
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
1193
Table 3. 1H NMR spectroscopic data for compounds 2a—l and 4a,b
Comꢀ
pound
X
R
δ (J/Hz)
X
OCH2
R
(s, 2 H)
3
2a
2b
2c
COOEt
CONH2
CONHPh
4ꢀBrC6H4
4ꢀBrC6H4
4ꢀBrC6H4
1.30 (t, 3 H, OCH2Me, J = 7.1);
6.05
5.80
5.95
7.80 (d, 2 H, H(3), H(5), 3J = 8.2);
7.90 (d, 2 H, H(2), H(6), 3J = 8.2)
7.70 (d, 2 H, H(3), H(5), 3J = 8.3);
7.92 (d, 2 H, H(2), H(6), 3J = 8.2)
7.80 (d, 2 H, H(3), H(5), 3J = 8.3);
7.92 (d, 2 H, H(2), H(6), 3J = 8.2)
3
4.35 (q, 2 H, OCH2Me, J = 7.1);
7.55, 7.80 (both s, 1 H each, CONH2)
7.18 (t, 1 H, H(4), 3J = 7.5);
3
7.35 (t, 2 H, H(3), H(5), J = 7.5);
7.65 (d, 2 H, H(2), H(6), 3J = 7.4);
10.40 (br.s, 1 H, NHCO)
2d
2e
CONHPh
Ph
Ph
7.15 (t, 1 H, H(4), 3J = 7.2);
6.00
6.00
7.60 (2 H, H(3), H(5), 3J = 7.5);
7.70 (t, 1 H, H(4), 3J = 7.5);
8.00 (d, 2 H, H(2), H(6), 3J = 7.3)
3
7.35 (t, 2 H, H(3), H(5), J = 7.6);
7.65 (d, 2 H, H(2), H(6), 3J = 7.4);
10.40 (br.s, 1 H, NHCO)
CONHꢀ4ꢀFC6H4
7.20 (t, 2 H, H(3), H(5),
7.58 (t, 2 H, H(3), H(5), 3J = 7.5);
7.70 (t, 1 H, H(4), 3J = 7.3);
8.00 (d, 2 H, H(2), H(6), 3J = 7.5)
3JH,F = 3JH,H = 9.0); 7.65 (dd, 2 H,
H(2), H(6), 3JH,H = 9.0, 4JH,F = 5.1);
10.50 (br.s, 1 H, NHCO)
2f
CONHMe
CONHBn
CONHPh
Ph
Ph
2.70 (d, 3 H, Me, J = 4.7);
8.60 (br.s, 1 H, NHCO)
5.95
5.90
5.21
7.61 (t, 2 H, H(3), H(5), 3J = 7.7);
7.74 (t, 1 H, H(4), 3J = 7.25);
8.00 (d, 2 H, H(2), H(6), 3J = 7.1)
7.58 (t, 2 H, H(3), H(5), 3J = 7.5);
7.68 (t, 1 H, H(4), 3J = 7.4);
7.97 (d, 2 H, H(2), H(6), 3J = 7.6)
2.17 (s, 3 H, Me)
2g
2h
4.37 (d, 2 H, CH2Ph, J = 6.4);
7.20—7.35 (m, 5 H, Ph);
9.10 (br.s, 1 H, NHCO)
Me
7.18 (t, 1 H, H(4), 3J = 7.5);
3
7.38 (t, 2 H, H(3), H(5), J = 7.7);
7.80 (d, 2 H, H(2), H(6), 3J = 7.6);
10.50 (br.s, 1 H, NHCO);
10.90 (br.s)
2i
Ph
Ph
Ph
4ꢀBrC6H4
OEt
7.50—7.60 (m, 3 H, H(3), H(4), H(5));
7.80 (d, 2 H, H(2), H(6), 3J = 7.3)
7.50—7.60 (m, 3 H, H(3), H(4), H(5));
7.75 (d, 2 H, H(2),H(6), 3J = 7.5)
7.50—7.60 (m, 3 H, H(3), H(4),
H(5)); 7.78 (d, 2 H, H(2), H(6),
3J = 7.4)
5.70
5.10
5.05
7.72 (d, 2 H, H(3), H(5), 3J = 8.3);
8.15 (d, 2 H, H(2), H(6), 3J = 8.1)
1.22 (t, 3 H, OCH2Me, 3J = 7.1);
4.20 (q, 2 H, OCH2Me, 3J = 7.1)
7.09 (t, 1 H, H(4), 3J = 7.2); 7.31
(t, 2 H, H(3), H(5), 3J = 7.6); 7.60
(d, 2 H, H(2), H(6), 3J = 7.2);
10.10 (br.s, 1 H, NHCO)
2j
2k
NHPh
2l
CONHPh
NH2
7.18 (t, 1 H, H(4), 3J = 7.5);
7.38 (t, 2 H, H(3), H(5), J = 7.6);
4.90
7.40, 7.50 (both s, 1 H each, CONH2)
3
7.68 (d, 2 H, H(2), H(6), 3J = 7.5);
10.40 (br.s, 1 H, NHCO)
7.45—7.55 (m, 5 H, Ph)
7.45—7.50 (m, 3 H, H(3), H(4),
H(5)); 7.75 (d, 2 H, H(2), H(6),
3J = 7.2)
4a
4b
—
—
OH
NHPh
4.60
4.80
7.70, 8.30 (both s, 1 H each, CONH2)
7.09 (t, 1 H, H(4), 3J = 7.2);
7.31 (t, 2 H, H(3), H(5), 3J = 7.5);
7.60 (d, 2 H, H(2), H(6), 3J = 7.4);
8.05, 8.30 (both s, 1 H each, CONH2);
9.60 (br.s, 1 H, CONH)

1194
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Kislyi et al.
1
Table 4. H NMR spectroscopic data for compounds 1a—j
Comꢀ
pound
X
R
δ (J/Hz)
X
NH2
R
(br.s, 2 H)
3
1a
1b
1c
COOEt
CONH2
CONHPh
4ꢀBrC6H4
4ꢀBrC6H4
4ꢀBrC6H4
1.45 (t, 3 H, OCH2Me, J = 7.1);
4.50 (q, 2 H, OCH2Me, 3J = 7.1)
7.95, 8.25 (both s, 1 H each, CONH2)
6.30
6.40
6.52
7.75 (d, 2 H, H(3), H(5), J = 8.2);
3
8.07 (d, 2 H, H(2), H(6), J = 8.2)
3
7.82 (d, 2 H, H(3), H(5), J = 8.3);
3
8.00 (d, 2 H, H(2), H(6), J = 8.3)
3
7.20 (t, 1 H, H(4), 3J = 7.6);
7.87 (d, 2 H, H(3), H(5), J = 8.4);
3
3
7.40 (t, 2 H, H(3), H(5), J = 7.6);
8.05 (d, 2 H, H(2), H(6), J = 8.4)
7.80 (d, 2 H, H(2), H(6), 3J = 7.4);
10.90 (br.s, 1 H, NHCO)
3
1d
1e
CONHPh
Ph
Ph
7.18 (t, 1 H, H(4), 3J = 7.2);
6.40
6.45
7.62 (t, 2 H, H(3), H(5), J = 7.5);
3
3
7.38 (t, 2 H, H(3), H(5), J = 7.6);
7.70 (t, 1 H, H(4), J = 7.4);
3
7.80 (d, 2 H, H(2), H(6), 3J = 7.4);
10.80 (br.s, 1 H, NHCO)
8.10 (d, 2 H, H(2), H(6), J = 7.2)
3
CONHꢀ4ꢀFC6H4
7.27 (t, 2 H, H(3), H(5),
7.65 (t, 2 H, H(3), H(5), J = 7.5);
3JH,F = 3JH,H = 8.7); 7.80 (dd, 2 H,
H(2), H(6), 3JH,H = 9.0, 4JH,F = 5.1);
11.00 (br.s, 1 H, NHCO)
7.70 (t, 1 H, H(4), J = 7.1);
3
3
8.10 (d, 2 H, H(2), H(6), J = 7.2)
3
1f
CONHMe
CONHBn
CONHPh
Ph
Ph
2.80 (d, 3 H, Me, J = 4.6);
8.90 (br.s, 1 H, NHCO)
6.40
6.35
6.10
7.60 (t, 2 H, H(3), H(5), J = 7.8);
7.70 (t, 1 H, H(4), 3J = 7.8);
3
8.07 (d, 2 H, H(2), H(6), J = 7.8)
3
1g
1h
4.50 (d, 2 H, CH2, J = 6.3);
7.25—7.35 (m, 5 H, Ph);
9.50 (br.s, 1 H, NHCO)
7.14 (t, 1 H, H(4), 3J = 7.5);
7.62 (t, 2 H, H(3), H(5), J = 7.5);
3
7.68 (t, 1 H, H(4), J = 7.3);
3
8.08 (d, 2 H, H(2), H(6), J = 7.7)
Me
2.47 (s, 3 H, Me)
3
7.38 (t, 2 H, H(3), H(5), J = 7.8);
7.80 (d, 2 H, H(2), H(6), 3J = 7.5);
10.90 (br.s, 1 H, NHCO)
7.50—7.60 (m, 3 H, H(3), H(4), H(5));
7.80 (d, 2 H, H(2), H(6), 3J = 7.2)
—
1i
1j
Ph
4ꢀBrC6H4
4ꢀBrC6H4
6.25
6.25
7.72 (d, 2 H, H(3), H(5), 3J = 8.2);
3
8.15 (d, 2 H, H(2), H(6), J = 8.3)
3
COOH
7.72 (d, 2 H, H(3), H(5), J = 8.5);
3
8.05 (2 H, H(2), H(6), J = 8.4)
(EI, 70 eV). Sodium salts of αꢀhydroxyimino nitriles were preꢀ
pared according to a procedure described earlier.12
compound 2d was isolated in a yield of 6.7 g, m.p. 161—163 °C.
1
The H and 13C NMR spectroscopic data are given in Tables 3
Alkylation of sodium salts of oxyimino derivatives 3 with bromo
ketones (synthesis of 2a—i, general procedure). A mixture of the
sodium salt of oxime 3a—f (5 mmol), the corresponding bromo
ketone (6 mmol), and a solvent (DMF for 2b—e,h, EtOH for
2a,f,g,i; 5—10 mL) was stirred at room temperature for 8 h.
Then water (5—10 mL) was added to the solution in DMF.
After a time, the product was filtered off (when the reaction was
carried out in EtOH, the product was filtered without dilution
with water), washed on a filter with a small amount of diethyl
ether, and dried in vacuo.
and 5, respectively. IR, ν/cm–1: 3472, 3392, 3352 (NH); 1688
(C=O); 1648, 1600, 1540 (CONH). MS, m/z (Irel (%)): 307 [M]+
(20); 173 [M – PhCOCH2O]+ (16); 146 [173 – CN]+ (14); 119
[PhCOCH2]+ (55); 105 [PhCO]+ (100); 91 (42); 77 (69).
Alkylation of sodium salts of oxyimino derivatives 3 with
chloroacetamides (synthesis of 2j—l, general procedure). The
corresponding chloroacetamide (8 mmol) and NaI•2H2O
(1.6 mmol) were added to a suspension of sodium salt 3
(12 mmol) in EtOH (10 mL) and the reaction mixture was
stirred at 60 °C for 3 h. The precipitate that formed was filtered
off, washed successively with water and EtOH, dried, and addiꢀ
tionally recrystallized from AcOH.
The yields and melting points of products 2a—i are listed in
1
Table 1. The H NMR spectroscopic data are given in Table 3.
2ꢀ(Benzoylmethoxyimino)cyanoꢀNꢀphenylacetamide (2d).
Amide 2d was prepared according to the general procedure from
the K salt of hydroxyiminocyanoꢀNꢀphenylacetamide (3d) (5.8 g)
in a yield of 8.4 g (85%). After recrystallization from EtOH,
The yields, melting points, and 1H NMR spectroscopic data
for compounds 2j—l are given in Table 1.
Synthesis of 4ꢀaminoisoxazoleꢀ3ꢀcarboxamides 1a—i (genꢀ
eral procedure).
A mixture of amide 2a—i (5 mmol),

Synthesis of 4ꢀaminoisoxazoleꢀ3ꢀcarboxamides
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 5, May, 2005
1195
Table 5. 13C NMR spectroscopic data for compounds 1c—f, 2d, and 5 18,21
*
Comꢀ
pound
δ (J/Hz)
C(1´) C(2´), C(3´),
C(1)
C(2)
C(3)
C(4)
C(5)
C(4´)
Other signals
C(6´) C(5´)
1c
1d
1e
–157.72 –179.0 –148.24 –135.65 –146.66 –138.36 +131.89 +130.72 –127.17
–157.29 –179.7 –147.8 –134.99 –146.5 –137.68 +132.6 +128.25 +128.4
–157.7 –180.25 –148.1 –136.01 –146.9 –138.12 +133.1 +128.79 +128.73
137.58 (C(1″)); +128.69 (C(3″),
C(5″)); +124.58 (C(4″)); +120.8
(C(2″), C(6″))
137.15 (C(1″)); +128.32 (C(3″),
C(5″)); +124.2 (C(4″)); +120.5
(C(2″), C(6″))
–158.7 (C(4″), 1JC,F = 241.4);
–133.95 (C(1″)); +122.7 (C(2″),
C(6″), 3JC,F = 8.1); +115.4 (C(3″),
C(5″), 2JC,F = 22.3)
1f
–159.56 –180.19 –147.7 –136.0 –146.7 –137.96 +132.99 +128.72 +128.72
+25.59 (MeNH)
2d
154.98 192.6
128.44 107.9
78.52 133.38 133.67 128.51 127.4
136.7 (C(1″)); 128.38 (C(3″),
C(5″)); 124.4 (C(4″)); 120.5
(C(2″), C(6″))
5
160.0
—
155.5
132.0
142.5
—
—
—
—
—
* The plus sign of the chemical shift indicates that the signal is not inverted in the APT (Attached Proton Test) experiment, and the
minus sign indicates that the signal is inverted.
LiClO4•3H2O (1 g), and acetonitrile (10—25 mL) was brought
to boiling (complete dissolution was observed) and allowed to
stand for ∼14 h. Then the resulting solution was added dropwise
to a solution of LiOH•H2O (0.2 g) in water (10—20 mL), and
the mixture was stirred for 2 h. The precipitate that formed was
filtered off, washed successively on a filter with 2% HCl and
water, and dried in vacuo. The yields and melting points of
products 1a—i are listed in Table 2. The 1H and 13C NMR
spectroscopic data are given in Tables 4 and 5, respectively.
4ꢀAminoꢀ5ꢀbenzoylisoxazoleꢀNꢀphenylꢀ3ꢀcarboxamide (1d).
A solution of compound 2d (3 g) and LiClO4 (2 g) in acetonitrile
(30 mL) was kept for ∼14 h and then concentrated. A suspension
of LiOH (0.3 g) in EtOH (20 mL) was added to the residue. The
mixture was stirred for 2 h. The residue was filtered off, washed
successively on a filter with 2% HCl and water, and dried
in vacuo. The 1H and 13C NMR spectroscopic data for comꢀ
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Received June 27, 2004;
in revised form December 24, 2004