Synthesis of 5-substituted 4-aminoalkylpyrazol-3-ones (isoxazol-3-ones) from 3-acyllactams

Article abstract of DOI:10.1007/s11172-005-0240-5

Structurally various 3-acyllactams act as 1,3-bielectrophiles in heterocyclization reactions with a variety of hydrazines and hydroxylamines to give aminoalkylpyrazolones and -isoxazol-ones in high yields.

Full text of DOI:10.1007/s11172-005-0240-5

220
Russian Chemical Bulletin, International Edition, Vol. 54, No. 1, pp. 220—225, January, 2005
Synthesis of 5ꢀsubstituted 4ꢀaminoalkylpyrazolꢀ3ꢀones (isoxazolꢀ3ꢀones)
from 3ꢀacyllactams
V. G. Nenajdenko,ꢀ E. P. Zakurdaev, A. M. Gololobov, and E. S. Balenkova
Department of Chemistry, M. V. Lomonosov Moscow State University,
Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (095) 932 8846. Eꢀmail: nen@acylium.chem.msu.ru
Structurally various 3ꢀacyllactams act as 1,3ꢀbielectrophiles in heterocyclization reactions
with a variety of hydrazines and hydroxylamines to give aminoalkylpyrazolones and ꢀisoxazolꢀ
ones in high yields.
Key words: 3ꢀacyllactams, pyrazolꢀ3ꢀones, isoxazolꢀ3ꢀones, hydrazines, hydroxylamine,
heterocyclization.
Reactions of 1,3ꢀdicarbonyl compounds with 1,2ꢀ,
unsymmetrical C,N,S,Oꢀbinucleophiles have been studꢀ
ied inadequately.
1,3ꢀ, and 1,4ꢀbinucleophiles represent a versatile approach
to the syntheses of important nitrogenꢀcontaining heteroꢀ
cycles such as pyrazoles, isoxazoles, pyrimidines, etc.1
3ꢀAcyllactams contain a 1,3ꢀdicarbonyl fragment with
the acyl and amide CO groups strongly differing in reacꢀ
tivity. This opens up a promising route to chemoꢀ and
regioselective heterocyclization with unsymmetrical biꢀ
nucleophiles. Acyllactams are mainly synthesized by
Cꢀacylation of Nꢀprotected lactams with acid anhydrides,
acid chlorides,2 acid fluorides,3 esters,4 carboxylic acids,5
chloroformates,6 diketene,7 and pyrrolidinꢀ2ꢀone.8
A survey of the literature data revealed that reactions
of 3ꢀacyllactams as bielectrophiles with symmetrical and
Single examples of pyrazole formation from 3ꢀacylꢀ
lactams and hydrazines were reported for the synthesis of
trifluoromethylpyrazoles.9 The reaction products were
mixtures of fused or aminoalkyl derivatives of pyrazoles,
depending on the hydrazine structure and the cyclization
conditions (Scheme 1).
There is only one documented synthesis of isoxazoles
by the reaction of 3ꢀacyllactam with hydroxylamine, which
was used to obtain analogs of a new fungicidal antibiotic.10
For investigation of the properties of Nꢀprotected
3ꢀacyllactams in reactions with binucleophiles and of the
effects of the nature of the acyl and protective groups and
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 215—220, January, 2005.
1066ꢀ5285/05/5401ꢀ0220 © 2005 Springer Science+Business Media, Inc.

Synthesis of 4ꢀaminoalkylpyrazolꢀ3ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
221
the ring size on heterocyclization, previously we syntheꢀ
sized11 a wide range of 3ꢀacyllactams containing various
substituents (aromatic, heteroaromatic, aliphatic, steriꢀ
cally bulky, framework, and those with the vinyl and
diethoxymethyl protective groups).
The goal of the present work was to develop a versatile
approach to the syntheses of aminoalkylpyrazoles and
ꢀisoxazoles. During the course of the reaction, closure of
one heterocycle is accompanied by the opening of the
other. The presence of an aminoalkyl fragment in the
compounds obtained suggests their potential biological
activities.
tuted 4ꢀaminoalkylpyrazolꢀ3ꢀones in virtually quantitaꢀ
tive yields (Scheme 2). It turned out that heterocyclization
into pyrazoles is promoted by 5% solutions of acids
(H2SO4, HCl, HCO2H, and AcOH) in ethanol; in the
absence of an acid, the reaction is 2 to 3 times slower. The
reaction is of general character; the yield and the reaction
course do not depend on the nature of the acyl group and
the size of the acyllactam ring. In all cases, the Nꢀvinyl
and Nꢀdiethoxymethyl protective groups were completely
eliminated during the reaction. The developed method is
simple and can be easily scaled.
Analogously, Nꢀmethylated 3ꢀacyllactams react with
hydrazine and phenylhydrazine to give substituted
Nꢀmethylpyrazoles (Scheme 3).
The reactions of 3ꢀacyllactams with hydrazine and its
derivatives occur under mild conditions to give 5ꢀsubstiꢀ
Scheme 3
Scheme 2
Procedures for the reactions of 3ꢀacyllactams with
hydroxylamine leading to isoxazoles should be slightly
different, depending on the nature of the acyl group
(Scheme 4). For instance, the optimum reaction condiꢀ
tions for 3ꢀacyllactams containing 3ꢀ or 4ꢀpyridyl subꢀ
stituents are NH2OH•HCl (1 equiv.) in boiling ethanol.
In the reactions with other 3ꢀacyllactams, a mixture of
hydroxylamine (1 equiv.) and its hydrochloride (1 equiv.)
in aqueous ethanol was used.
1—15: n = 1, PG = CH2=CH;
16—18: n = 2, PG = CH(OEt)2
19—22: n = 3, PG = CH2=CH
In the case of the 2ꢀpyridyl or pyrazinyl substituents,
the heterocyclization conditions were not found: a comꢀ
plex mixture of products was obtained. Neither 3ꢀacylꢀ
lactams with a N—Me fragment gave isoxazoles because
the reaction stopped at the step of oxime formation.
Being 1,3ꢀbielectrophiles, 3ꢀacyllactams could react
with unsymmetrical binucleophiles along two pathways.
Nevertheless, the heterocyclization is regiospecific beꢀ
cause the acyl CO group is substantially more reactive
than the amide one and the βꢀN atom in phenylhydrazine
is more nucleophilic than the αꢀN atom due to the
–I effect of the benzene ring. This was additionally conꢀ
firmed by spectroscopic data: all the pyrazoles obtained
contain no isomeric products and their 1H and 13C NMR
spectra are similar. Irradiation of the orthoꢀprotons of the
phenyl group in compound 23 resulted in no NOE on the
rest of the molecule.
Product
R
R´
Method*
Yield (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
A
A
A
A
B
B
B
B
B
B
B
B
B
A
A
B
B
B
B
B
B
B
89
93
90
96
88
96
95
93
91
82
90
92
88
91
95
94
93
87
90
92
88
84
4ꢀMeOC6H4
4ꢀMeOC6H4
Ph
4ꢀBrC6H4
H
H
H
H
H
H
H
H
Ad
But
4ꢀFC6H4
4ꢀMeOC6H4
3ꢀMe2NC6H4
Bn
MeSCH2
Me
9
10
11
12
13
14
15
16
17
18
19
20
21
22
H
Ph
(C=O)NH2
(C=S)NH2
(C=NH)NH2
3ꢀClC6H4
Ph
3ꢀBrC6H4
4ꢀPy
4ꢀMe2NC6H4
4ꢀPy
H
H
H
H
H
H
H
Ph
4ꢀMeC6H4
cꢀHexyl
Thus, we developed a new general method for the
synthesis of 4ꢀaminoalkylpyrazolꢀ3ꢀones and ꢀisoxazolꢀ
3ꢀones. Various hydrazines and hydroxylamine react with
* A. 4% H2SO4, ∆; B. EtOH, ∆.

222
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
Nenajdenko et al.
Scheme 4
4ꢀ(2ꢀAminoethyl)ꢀ2,5ꢀdiphenylꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ
3ꢀone sulfate hydrate (1). Procedure A. Yield 89%, m.p.
158—160.5 °C (decomp.). Found (%): C, 51.85; H, 5.24.
C17H21N3O6S. Calculated (%): C, 51.64; H, 5.35. IR, ν/cm–1
:
2820—3020. 1H NMR (400 MHz, (CD3)2SO), δ: 2.68 (m,
2 H, N—CH2—CH2); 2.92—3.03 (m, 2 H, N—CH2—CH2);
7.04 (t, 1 H, 4ꢀCHPh—C,
3JH,H = 7.3 Hz); 7.22—7.44 (m,
5 H, 3ꢀ, 5ꢀCHPh—C, 3ꢀ, 4ꢀ, 5ꢀCHPh—N); 7.56 (m, 2 H,
2ꢀ, 6ꢀCHPh—N); 8.17 (m, 2 H, 2ꢀ, 6ꢀCHPh—C). 13C NMR
(400 MHz, (CD3)2SO), δ: 23.26 (N—CH2—CH2); 41.19
(N—CH2—CH2); 92.80 (N—CH2—CH2—C); 118.68
(2ꢀ, 6ꢀCHPh—C); 122.52 (4ꢀCHPh—C); 126.68 (4ꢀCHPh—N);
127.51 (2ꢀ, 6ꢀCHPh—N); 128.08 (3ꢀ, 5ꢀCHPh—N); 128.15
(3ꢀ, 5ꢀCHPh—C); 135.92 (1ꢀCPh—N); 141.43 (1ꢀCPh—C); 148.91
(N—C—C=C—N); 162.29 (N—CO).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀphenylꢀ1,2ꢀdiꢀ
hydroꢀ3Hꢀpyrazolꢀ3ꢀone sulfate trihydrate (2). Procedure A.
Yield 93%, m.p. 139—141 °C (decomp.). Found (%): C, 46.67;
H, 5.73. C18H27N3O9S. Calculated (%): C, 46.85; H, 5.90. IR,
ν/cm–1: 2820—2940. 1H NMR (400 MHz, (CD3)2SO), δ:
2.74—2.87 (m, 2 H, N—CH2—CH2); 2.93—3.06 (m, 2 H,
Product
n
R
Method*
Yield
(%)
25
26
27
28
29
1
1
1
1
3
Ph
C
C
D
D
C
89
61
85
78
35
3ꢀBrC6H4
3ꢀPy
4ꢀPy
Ph
N—CH2—CH2); 3.80 (s, 3 H, OMe); 7.07 (d, 2 H, 2ꢀ, 6ꢀCHPh
,
3JH,H = 8.0 Hz); 7.25 (t, 1 H, 4ꢀCHPh, 3JH,H = 7.4 Hz); 7.46 (t,
2 H, 3ꢀ, 5ꢀCHPh, 3JH,H = 7.4 Hz); 7.62 (d, 2 H, 3ꢀ, 5ꢀCHC H
,
6
4
3
3JH,H = 8.0 Hz); 7.79 (d, 2 H, 2ꢀ, 6ꢀCHC H , JH,H = 8.0 Hz);
6
4
* C. H2NOH, H2NOH•HCl, EtOH, H2O, ∆; D. H2NOH•HCl, EtOH, ∆.
7.92 (br.s, 2 H, NH—CH2—CH2). 13C NMR (400 MHz,
(CD3)2SO), δ: 21.05 (N—CH2—CH2); 38.67 (N—CH2—CH2);
55.32
(OMe);
99.29
(N—CH2—CH2—C);
114.37
3ꢀacyllactams under mild conditions to give the target
products in high yields.
(3ꢀ, 5ꢀCHC H ); 120.61 (2ꢀ, 6ꢀCHPh); 123.33 (1ꢀCC H4);
6
4
6
125.57 (4ꢀCHPh); 128.85 (3ꢀ, 5ꢀCHPh); 129.09 (2ꢀ, 6ꢀCHC H );
137.57 (1ꢀCPh); 148.94 (N—C—C=C—N); 157.81 (4ꢀCC H4);
6
6
4
Experimental
160.01 (N—CO).
4ꢀ(2ꢀAminoethyl)ꢀ2ꢀ(4ꢀbromophenyl)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ
1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀone sulfate hydrate (3). Procedure A.
Yield 90%, m.p. 167—169.5 °C (decomp.). Found (%): C, 42.65;
H, 4.48. C18H22BrN3O7S. Calculated (%): C, 42.87; H, 4.40.
IR, ν/cm–1: 2820—2960. 1H NMR (400 MHz, (CD3)2SO), δ:
1
H and 13C NMR spectra were recorded on a Varian
VXRꢀ400 spectrometer (400 and 100 MHz, respectively) in
(CD3)2SO with Me4Si as the internal standard. Chemical shifts
are referenced to Me4Si with an accuracy of 0.01 ppm. IR specꢀ
tra were recorded on a URꢀ20 spectrophotometer (thin film for
liquids and Nujol for solids). TLC analysis was performed on
Silufol UVꢀ254 plates; spots were visualized in an acidified soluꢀ
tion of KMnO4, with a solution of ninhydrin in butanol, in a
chamber with the iodine vapor, and with a UV lamp. Preparaꢀ
tive column chromatography was carried out on silica gel
(63—200 mesh, Merck).
Synthesis of pyrazoles (general procedure). Procedure A. Synꢀ
thesis of pyrazole salts. To a solution of 3ꢀacyllactam (5 mmol)
in 25 mL of 4% H2SO4, 95% N2H4•H2O (0.3 mL) was added
and the mixture was refluxed for 5 to 10 h. The course of the
reaction was monitored by TLC (MeCN—NH3(aq), 95 : 5).
Then the reaction mixture was evaporated to dryness and the
residue was coꢀevaporated with water (5 mL) and recrystallized
from PriOH. Attempted preparation of free pyrazole bases by
alkalization gave thick oils, for which reason we developed anꢀ
other approach to the synthesis of free pyrazoles.
2.72—2.82 (m,
2 H, N—CH2—CH2); 2.92—3.02 (m,
2 H, N—CH2—CH2); 3.76 (s, 3 H, OMe); 7.06 (d, 2 H,
3
3ꢀ, 5ꢀCH arom., C6H4OMe, JH,H = 8.8 Hz); 7.60 (d, 2 H,
3
2ꢀ, 6ꢀCH arom., C6H4Br, JH,H = 8.7 Hz); 7.64 (d, 2 H,
3
3ꢀ, 5ꢀCH arom., C6H4Br, JH,H = 8.7 Hz); 7.80 (d, 2 H,
3
2ꢀ, 6ꢀCH arom., C6H4OMe, JH,H = 8.8 Hz); 7.91 (br.s, 2 H,
NH—CH2—CH2). 13C NMR (400 MHz, (CD3)2SO), δ: 20.97
(N—CH2—CH2); 38.67 (N—CH2—CH2); 55.13 (OMe); 96.32
(HN—C—C=C—N); 114.07 (3ꢀ, 5ꢀCH arom., C6H4OMe);
116.82 (4ꢀC arom., C6H4Br); 121.49 (3ꢀ, 5ꢀCH arom., C6H4Br);
128.80 (2ꢀ, 6ꢀCH arom., C6H4Br); 131.41 (2ꢀ, 6ꢀCH arom.,
C6H4OMe); 137.44 (1ꢀC arom., C6H4OMe); 143.28 (1ꢀC arom.,
C6H4Br); 146.28 (N—C—C=C—N); 159.66 (4ꢀC arom.,
C6H4OMe); 163.34 (N—CO).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀphenylꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀone
sulfate dihydrate (4). Procedure A. Yield 96%, m.p. 143—146 °C
(decomp.). Found (%): C, 39.05; H, 5.92. C11H19N3O7S. Calꢀ
culated (%): C, 39.16; H, 5.68. IR, ν/cm–1: 2870—3000.
1H NMR (400 MHz, (CD3)2SO), δ: 2.69—2.77 (m, 2 H,
Procedure B. Synthesis of free pyrazole bases. To a solution
of 3ꢀacyllactam (5 mmol) in 20 mL of EtOH, 95% N2H4•H2O
(2 equiv.) was added and the mixture was refluxed for 10 to 20 h.
The course of the reaction was monitored by TLC
(MeCN—NH3(aq), 95 : 5). Then the reaction mixture was
evaporated to dryness, coꢀevaporated with water (5 mL), and
recrystallized from PriOH.
N—CH2—CH2); 2.86—2.97 (m,
2 H, N—CH2—CH2);
7.35—7.41 (m, 1 H, 4ꢀCHPh); 7.43—7.53 (m, 4 H, 2ꢀ, 3ꢀ,
5ꢀ, 6ꢀCHPh). 13C NMR (400 MHz, (CD3)2SO), δ:
20.78 (N—CH2—CH2); 38.77 (N—CH2—CH2); 96.42
(HN—C—C=C—N); 127.05 (2ꢀ, 6ꢀCHPh); 128.21

Synthesis of 4ꢀaminoalkylpyrazolꢀ3ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
223
(4ꢀCHPh); 129.01 (3ꢀ, 5ꢀCHPh); 130.35 (1ꢀCPh); 140.74
(HN—C—C=C—N); 160.45 (HN—CO).
(5ꢀCHC H ); 144.10 (1ꢀCC H4); 144.13 (HN—C—C=C—N);
4 6
156.63 (6HN—C—C=C—N).
5ꢀAdamantylꢀ4ꢀ(2ꢀaminoethyl)ꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀ
one hydrate (5). Procedure B. Yield 88%, m.p. 169—172 °C
(decomp.). Found (%): C, 64.73; H, 8.78. C15H25N3O2. Calcuꢀ
lated (%): C, 64.49; H, 9.02. IR, ν/cm–1: 2830—2920. 1H NMR
(400 MHz, (CD3)2SO), δ: 1.68—1.73 (m, 6 H, 4ꢀ, 6ꢀ, 10ꢀCH2,
Ad); 1.85—1.90 (m, 6 H, 2ꢀ, 8ꢀ, 9ꢀCH2, Ad); 1.95—2.02 (m,
3 H, 3ꢀ, 5ꢀ, 7ꢀCH, Ad); 2.63—2.72 (m, 2 H, N—CH2—CH2);
2.76—2.85 (m, 2 H, N—CH2—CH2). 13C NMR (400 MHz,
(CD3)2SO), δ: 21.25 (N—CH2—CH2); 27.77 (3ꢀ, 5ꢀ, 7ꢀCH,
Ad); 34.07 (1ꢀC, Ad); 35.99 (4ꢀ, 6ꢀ, 10ꢀCH2, Ad); 39.28
(N—CH2—CH2); 40.53 (2ꢀ, 8ꢀ, 9ꢀCH2, Ad); 94.80
(HN—C—C=C—N); 148.91 (HN—C—C=C—N); 160.26
(HN—CO).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀbenzylꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀone
(10). Procedure B. Yield 82%, m.p. 197.5—199 °C (decomp.).
Found (%): C, 66.33; H, 6.73. C12H15N3O. Calculated (%):
C, 66.34; H, 6.96. IR, ν/cm–1: 2865—2985. 1H NMR (400 MHz,
(CD3)2SO), δ: 2.54—2.64 (m, 2 H, N—CH2—CH2); 2.71—2.80
(m, 2 H, N—CH2—CH2); 3.91 (s, 2 H, Ph—CH2); 7.10—7.27
(m, 5 H, Ph). 13C NMR (400 MHz, (CD3)2SO), δ: 20.32
(N—CH2—CH2); 31.84 (Ph—CH2); 39.65 (N—CH2—CH2);
99.81 (HN—C—C=C—N); 129.05 (4ꢀCHPh); 130.1
(3ꢀ, 5ꢀCHPh); 130.69 (2ꢀ, 6ꢀCHPh); 136.94 (1ꢀCPh); 149.22
(HN—C—C=C—N); 156.58 (HN—CO).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ[(methylthio)methyl]ꢀ1,2ꢀdihydroꢀ3Hꢀ
pyrazolꢀ3ꢀone (11). Procedure B. Yield 90%, m.p. 200.5—203 °C
(decomp.). Found (%): C, 45.16; H, 7.13. C7H13N3OS. Calcuꢀ
lated (%): C, 44.90; H, 7.00. IR, ν/cm–1: 2845—2980. 1H NMR
(400 MHz, (CD3)2SO), δ: 1.90 (s, 3 H, CH2—S—Me);
2.63—2.70 (m, 2 H, N—CH2—CH2); 2.89—2.97 (m, 2 H,
N—CH2—CH2); 3.64 (s, 2 H, CH2—S—Me). 13C NMR
(400 MHz, (CD3)2SO), δ: 16.06 (CH2—S—Me); 20.07
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀtertꢀbutylꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀ
one (6). Procedure B. Yield 96%, m.p. 212—215 °C (decomp.).
Found (%): C, 60.17; H, 9.21. C9H17N3O. Calculated (%):
C, 58.99; H, 9.35. IR, ν/cm–1: 2840—3010. 1H NMR
(400 MHz, (CD3)2SO), δ: 1.21 (s, 9 H, CMe3); 2.51 (t, 2 H,
3
N—CH2—CH2, JH,H = 5.6 Hz); 2.75 (t, 2 H, N—CH2—CH2,
3JH,H = 5.6 Hz). 13C NMR (400 MHz, (CD3)2SO), δ: 20.78
(N—CH2—CH2); 29.75 (CMe3); 33.66 (CMe3); 39.15
(N—CH2—CH2); 98.38 (HN—C—C=C—N); 155.54
(HN—C—C=C—N); 155.66 (HN—CO).
(N—CH2—CH2);
26.99
(CH2—S—Me);
39.44
(N—CH2—CH2); 99.67 (HN—C—C=C—N); 147.05
(HN—C—C=C—N); 156.23 (HN—CO).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀmethylꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀone
hydrate (12). Procedure B. Yield 92%, m.p. 145—147.5 °C
(decomp.). Found (%): C, 45.18; H, 8.25. C6H13N3O2. Calcuꢀ
lated (%): C, 45.27; H, 8.23. IR, ν/cm–1: 2860—2960. 1H NMR
(400 MHz, (CD3)2SO), δ: 2.38 (s, 3 H, Me); 2.84 (t, 2 H,
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ(4ꢀfluorophenyl)ꢀ1,2ꢀdihydroꢀ3Hꢀ
pyrazolꢀ3ꢀone (7). Procedure B. Yield 95%, m.p. 268—272 °C
(decomp.). Found (%): C, 59.75; H, 5.41. C11H12FN3O. Calcuꢀ
lated (%): C, 59.72; H, 5.47. IR, ν/cm–1: 2870—3010. 1H NMR
(400 MHz, (CD3)2SO), δ: 2.71—2.81 (m, 2 H, N—CH2—CH2);
2.90—2.98 (m, 2 H, N—CH2—CH2); 7.14—7.23 (m, 2 H,
3ꢀ, 5ꢀCHC H ); 7.43—7.51 (m, 2 H, 2ꢀ, 6ꢀCHC H ); 7.55 (br.s,
3
N—CH2—CH2, JH,H = 7.5 Hz); 3.19 (t, 2 H, N—CH2—CH2,
3JH,H = 7.5 Hz). 13C NMR (400 MHz, (CD3)2SO), δ: 11.06
(Me); 20.10 (N—CH2—CH2); 39.69 (N—CH2—CH2);
99.59 (HN—C—C=C—N); 147.20 (HN—C—C=C—N); 156.16
(HN—CO).
6
4
4
2 H, HN—CH2—CH2). 13C NMR (400 MHz,6(CD3)2SO), δ:
20.64 (N—CH2—CH2); 38.60 (N—CH2—CH2); 96.29
(HN—C—C=C—N); 115.91 (3ꢀ, 5ꢀCHC H ); 126.94 (1ꢀCC H );
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀoxoꢀ3ꢀphenylꢀ2,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ
1ꢀcarboxamide (13). Procedure B. Yield 88%, m.p. 224—227 °C
(decomp.). Found (%): C, 58.81; H, 5.55. C12H14N4O2. Calcuꢀ
lated (%): C, 58.53; H, 5.73. IR, ν/cm–1: 2810—3020, 1610.
1H NMR (400 MHz, (CD3)2SO), δ: 2.69—2.77 (m, 2 H,
129.24 (2ꢀ, 6ꢀCHC H4); 139.72 (HN—6C—C=C—N); 160.30
4
6 4
6
(HN—CO); 160.65 (C—F).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ1,2ꢀdihydroꢀ3Hꢀ
pyrazolꢀ3ꢀone (8). Procedure B. Yield 93%, m.p. 194—197 °C
(decomp.). Found (%): C, 61.96; H, 6.29. C12H15N3O2. Calcuꢀ
lated (%): C, 61.79; H, 6.48. IR, ν/cm–1: 2860—3000. 1H NMR
N—CH2—CH2); 2.86—2.96 (m,
2 H, N—CH2—CH2);
7.35—7.41 (m, 1 H, 4ꢀCHPh); 7.43—7.53 (m, 4 H, 2ꢀ, 3ꢀ, 5ꢀ,
6ꢀCHPh); 7.78 (br.s, 3 H, N—C(=O)—NH2). 13C NMR
(400 MHz, (CD3)2SO), δ: 20.76 (N—CH2—CH2); 38.74
(N—CH2—CH2); 96.40 (HN—C—C=C—N); 127.03
(2ꢀ, 6ꢀCHPh); 128.16 (4ꢀCHPh); 128.95 (3ꢀ, 5ꢀCHPh);
130.34 (1ꢀCPh); 140.73 (HN—C—C=C—N); 160.38
(HN—C—C=C—N); 203.83 (N—C(=O)—NH2).
(400 MHz, (CD3)2SO), δ: 2.54 (t, 2 H, N—CH2—CH2, 3JH,H
5.1 Hz); 2.80 (t, 2 H, N—CH2—CH2, JH,H = 5.1 Hz); 3.76 (s,
=
3
3 H, OMe); 6.96 (d, 2 H, 3ꢀ, 5ꢀCHC H
,
3JH,H = 8.3 Hz);
6
4
7.34 (d, 2 H, 2ꢀ, 6ꢀCHC H
,
3JH,H = 8.3 Hz). 13C NMR
6
(400 MHz, (CD3)2SO), δ: 420.49 (N—CH2—CH2); 38.73
(HN—CH2—CH2); 56.51 (OMe); 98.63 (N—C—C=C—N);
115.69 (3ꢀ, 5ꢀCHC H4); 119.66 (4ꢀCC H4); 130.87
4ꢀ(2ꢀAminoethyl)ꢀ3ꢀ(3ꢀchlorophenyl)ꢀ5ꢀoxoꢀ2,5ꢀdihydroꢀ
1Hꢀpyrazoleꢀ1ꢀcarbothioamide sulfate (14). Procedure B. Yield
91%, m.p. 141—142 °C (decomp.). Found (%): C, 36.70; H, 3.65.
6
6
(2ꢀ, 6ꢀCHC H4); 146.45 (HN—C—C=C—N); 156.41
6
(HN—CO); 161.74 (C—OMe).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀ[3ꢀ(dimethylamino)phenyl]ꢀ1,2ꢀdihydroꢀ
3Hꢀpyrazolꢀ3ꢀone (9). Procedure B. Yield 91%, m.p.
209.5—213 °C (decomp.). Found (%): C, 63.61; H, 7.50.
C12H15ClN4O5S2. Calculated (%): C, 36.5; H, 3.83. IR, ν/cm–1
:
2810—3020, 1480. 1H NMR (400 MHz, (CD3)2SO), δ:
2.66—2.78 (m, 2 H, NCH2CH2); 2.86—2.97 (m, 2 H,
NCH2CH2); 6.25 (br.s, 3 H, S=C—NH3+); 7.40—7.55 (m, 4 H,
C13H18N4O. Calculated (%): C, 63.39; H, 7.37. IR, ν/cm–1
:
2860—2980. 1H NMR (400 MHz, (CD3)2SO), δ: 2.78—2.91
H arom.); 7.75 (br.s, 3 H, NH2 •HSO4–). 13C NMR (400 MHz,
+
(m, 4 H, N—CH2—CH2); 3.14 (s, 6 H, NMe2); 7.62—7.73 (m,
(CD3)2SO), δ: 20.67 (N—CH2—CH2); 38.57 (N—CH2—CH2);
96.80 (HN—C—C=C—N); 125.75, 126.54, 126.57, 127.97,
130.88, 132.50 (C arom.); 133.60 (N—C(=S)—NH2); 139.32
(HN—C—C=C—N); 160.19 (HN—CO).
4ꢀ(2ꢀAminoethyl)ꢀ5ꢀoxoꢀ3ꢀphenylꢀ2,5ꢀdihydroꢀ1Hꢀpyrazoleꢀ
1ꢀcarboximidamide sulfate (15). Procedure A. Yield 95%, m.p.
3
2 H, 5ꢀ, 6ꢀCHC H ); 7.90 (d, 1 H, 4ꢀCHC H , JH,H = 7.9 Hz);
6
4
6 4
7.97 (s, 1 H, 2ꢀCHC H ). 13C NMR (400 MHz, (CD3)2SO), δ:
20.25 (N—CH2—CH2)4; 38.52 (N—CH2—CH2); 46.43 (NMe2);
99.46 (HN—C—C=C—N); 121.77 (4ꢀCHC H4); 123.43
(3ꢀCC H ); 129.25 (2ꢀCHC H ); 130.07 (6ꢀCHC6 H4); 131.93
6
6
4
6
4
6

224
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
Nenajdenko et al.
259—260 °C (decomp.). Found (%): C, 49.25; H, 5.21.
(N—(CH2)2—CH2—CH2); 27.30 (N—(CH2)3—CH2); 27.80
(N—CH2—CH2—(CH2)2); 40.61 (N—CH2—(CH2)3); 107.70
(HN—C—C=C—N); 126.08 (3ꢀ, 5ꢀCHPy); 140.21 (4ꢀCPy);
143.34 (2ꢀ, 6ꢀCHPy); 147.90 (HN—C—C=C—N); 158.71
(HN—CO).
C24H32N10O6S. Calculated (%): C, 48.97; H, 5.48. IR, ν/cm–1
:
2810—3020, 1660. 1H NMR (400 MHz, (CD3)2SO), δ: 2.59
3
(t, 2 H, NCH2CH2, JH,H = 6.8 Hz); 2.90—2.99 (m, 2 H,
NCH2CH2); 7.37—7.47 (m, 3 H, Ph); 7.75—7.58 (m, 2 H, Ph);
7.98—8.06 (br.s,
2
21.72 (N—CH2—CH2); 39.66 (N—CH2—CH2); 90.02
(N—C—C=C—N); 127.75 (4ꢀCHPh); 128.31 (2ꢀ, 6ꢀCHPh);
128.34 (3ꢀ, 5ꢀCHPh); 133.91 (1ꢀCPh); 153.28 (H2N—C=NH);
155.83 (N—C—C=C—N); 165.55 (N—CO).
3
H, NH=C—NH2); 8.16—8.25 (br.s,
4ꢀ(4ꢀAminobutyl)ꢀ5ꢀphenylꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀone
(20). Procedure B. Yield 92%, m.p. 223—227 °C (decomp.).
Found (%): C, 67.54; H, 7.24. C13H17N3O. Calculated (%):
H, NH2+). 13C NMR (400 MHz, (CD3)2SO), δ:
C, 67.51; H, 7.41. IR, ν/cm–1
:
2860—2980. 1H NMR
(400 MHz, (CD3)2SO), δ: 1.27—1.46 (m,
4
H,
H,
N—CH2—CH2—CH2—CH2); 2.30—2.36 (m,
2
4ꢀ(3ꢀAminopropyl)ꢀ5ꢀ(3ꢀbromophenyl)ꢀ1,2ꢀdihydroꢀ3Hꢀ
pyrazolꢀ3ꢀone (16). Procedure B. Yield 94%, m.p. 231—233 °C
(decomp.). Found (%): C, 48.78; H, 4.73. C12H14BrN3O. Calꢀ
culated (%): C, 48.67; H, 4.76. IR, ν/cm–1: 2880—3020.
1H NMR (400 MHz, (CD3)2SO), δ: 1.66—1.77 (m, 2 H,
N—CH2—CH2—CH2); 2.43—2.51 (m, 2 H, N—(CH2)2—CH2);
N—(CH2)3—CH2); 2.66—2.74 (m, 2 H, N—CH2); 7.32—7.42
(m, 5 H, Ph). 13C NMR (400 MHz, (CD3)2SO), δ: 21.57
(N—(CH2)3—CH2); 27.07 (N—(CH2)2—CH2—CH2); 27.68
(N—CH2—CH2—(CH2)2); 40.64 (N—CH2—(CH2)3); 104.48
(HN—C—C=C—N); 129.51 (2ꢀ, 6ꢀCHPh); 130.74 (1ꢀCPh);
130.96
(3ꢀ,
5ꢀCHPh);
132.41
(4ꢀCHPh);
147.58
3
2.76—2.85 (t, 2 H, N—CH2—(CH2)2, JH,H = 7.7 Hz);
(HN—C—C=C—N); 156.30 (HN—CO).
7.33—7.45 (m, 2 H, 2ꢀ, 5ꢀCHC H4); 7.55—7.66 (m, 2 H,
4ꢀ(4ꢀAminobutyl)ꢀ5ꢀ(4ꢀmethylphenyl)ꢀ1,2ꢀdihydroꢀ3Hꢀ
pyrazolꢀ3ꢀone (21). Procedure B. Yield 88%, m.p. 214—218 °C
(decomp.). Found (%): C, 68.50; H, 7.29. C12H18N4O2. Calcuꢀ
lated (%): C, 68.54; H, 7.81. IR, ν/cm–1: 2840—3010.
1H NMR (400 MHz, (CD3)2SO), δ: 1.26—1.36 (m,
6
4ꢀ, 6ꢀCHC H4). 13C NMR (400 MHz, (CD3)2SO), δ: 19.30
6
(N—CH2—CH2—CH2); 27.92 (N—(CH2)2—CH2); 40.15
(N—CH2—(CH2)2); 103.68 (HN—C—C=C—N); 124.07
(3ꢀCC H ); 128.48 (6ꢀCHC H ); 130.20 (1ꢀCC H4); 131.96
6
4
6
(2ꢀCHC H ); 132.73 (4ꢀCHC H4); 135.09 (5ꢀCHC6 H ); 145.70
2 H, N—CH2—CH2—(CH2)2); 1.68—1.77 (m, 2 H,
6
4
6
4
6 4
(N—C—C=C—N); 157.06 (N—CO).
N—(CH2)2—CH2—CH2); 2.00 (s, 3 H, Me); 2.27—2.39 (m, 2 H,
N—(CH2)3—CH2); 2.98—3.04 (m, 2 H, N—CH2—(CH2)3);
6.95—7.04 (m, 4 H, C6H4). 13C NMR (400 MHz, (CD3)2SO),
δ: 22.08 (Me); 23.91 (N—(CH2)2—CH2—CH2); 27.84
(N—CH2—CH2—(CH2)2); 29.56 (N—(CH2)3—CH2); 49.63
(N—CH2—(CH2)3); 111.24 (HN—C—C=C—N); 126.17
(1ꢀCC H ); 129.34 (2ꢀ, 6ꢀCHC H ); 131.30 (3ꢀ, 5ꢀCHC H4);
4ꢀ(3ꢀAminopropyl)ꢀ5ꢀpyridinꢀ4ꢀylꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ
3ꢀone (17). Procedure B. Yield 93%, m.p. 188—191 °C
(decomp.). Found (%): C, 60.73; H, 6.26. C11H14N4O. Calꢀ
culated (%): C, 60.53; H, 6.47. IR, ν/cm–1: 2870—3040.
1H NMR (400 MHz, (CD3)2SO), δ: 1.67—1.78 (m, 2 H,
N—CH2—CH2—CH2); 2.55 (t, 2 H, N—(CH2)2—CH2, 3JH,H
=
6
6
141.48 4(4ꢀCC H4); 144.69 (H4N—C—C=C—N); 1468.46
3
7.8 Hz); 2.82 (t, 2 H, N—CH2—(CH2)2, JH,H = 7.8 Hz); 8.06
(d, 2 H, 3ꢀ, 5ꢀCHPy, 3JH,H = 6.8 Hz); 8.74 (d, 2 H, 2ꢀ, 6ꢀCHPy
6
,
(HN—CO).
3JH,H = 6.8 Hz). 13C NMR (400 MHz, (CD3)2SO), δ: 19.77
(N—CH2—CH2—CH2); 28.08 (N—(CH2)2—CH2); 40.18
(N—CH2—(CH2)2); 106.30 (HN—C—C=C—N); 126.27
(3ꢀ, 5ꢀCHPy); 140.33 (4ꢀCPy); 143.41 (2ꢀ, 6ꢀCHPy); 147.33
(HN—C—C=C—N); 158.37 (HN—CO).
4ꢀ(4ꢀAminobutyl)ꢀ5ꢀcyclohexylꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ3ꢀ
one (22). Procedure B. Yield 84%, m.p. 152—154 °C (decomp.).
Found (%): C, 65.91; H, 7.50. C13H23N3O. Calculated (%):
C, 65.79; H, 9.77. IR, ν/cm–1: 2860—2970. 1H NMR (400 MHz,
(CD3)2SO), δ: 0.97—1.38, 1.42—1.69 (m, 14 H, CH2,
cyclohexyl, N—(CH2)2—CH2—CH2); 2.22—2.29 (m, 2 H,
N—CH2—CH2—(CH2)2); 2.59—2.65 (m, 1 H, CH, cyclohexyl);
2.69—2.77 (m, 2 H, N—CH2—(CH2)3). 13C NMR (400 MHz,
(CD3)2SO), δ: 21.10 (N—(CH2)2—CH2—CH2); 26.31
(N—(CH2)3—CH2); 26.81 (3ꢀ, 5ꢀCH2, cyclohexyl); 27.54, 27.65
(4ꢀCH2, cyclohexyl, N—CH2—CH2); 32.49 (2ꢀ, 6ꢀCH2, cycloꢀ
hexyl); 35.70 (1ꢀCH, cyclohexyl); 40.18 (N—CH2—CH2);
102.69 (HN—C—C=C—N); 154.07 (HN—C—C=C—N);
155.59 (HN—CO).
4ꢀ(3ꢀAminopropyl)ꢀ5ꢀ[4ꢀ(dimethylamino)phenyl]ꢀ1,2ꢀdiꢀ
hydroꢀ3Hꢀpyrazolꢀ3ꢀone (18). Procedure B. Yield 87%, m.p.
196.5—198.5 °C (decomp.). Found (%): C, 64.68; H, 7.67.
C14H20N4O. Calculated (%): C, 64.59; H, 7.74. IR, ν/cm–1
:
2830—2980. 1H NMR (400 MHz, (CD3)2SO), δ: 1.64—1.75
(m, 2 H, N—CH2—CH2—CH2); 2.49 (t, 2 H, N—(CH2)2—CH2,
3JH,H = 7.8 Hz); 2.78 (t, 2 H, N—CH2—(CH2)2, 3JH,H = 7.8 Hz);
3.19 (s, 6 H, NMe2); 7.64—7.73 (m, 4 H, C6H4). 13C NMR
(400 MHz, (CD3)2SO), δ: 19.26 (N—CH2—CH2—CH2); 27.90
(N—(CH2)2—CH2); 40.21 (N—CH2—(CH2)2); 47.88 (NMe2);
4ꢀ[2ꢀ(Methylamino)ethyl]ꢀ2,5ꢀdiphenylꢀ1,2ꢀdihydroꢀ3Hꢀ
pyrazolꢀ3ꢀone hydrate (23). Procedure B. Yield 88%, m.p.
168—170 °C (decomp.). Found (%): C, 69.52; H, 6.62.
104.12 (HN—C—C=C—N); 123.26 (3ꢀ, 5ꢀCHC H ); 130.20
6
(1ꢀCC H ); 131.89 (2ꢀ, 6ꢀCHC H ); 144.96 (4ꢀCC H4); 145.63
6
4
6
4
6 4
(HNꢀC—C=C—N); 156.79 (HN—CO).
C18H21N3O2. Calculated (%): C, 69.43; H, 6.80. IR, ν/cm–1
2840—3010. H NMR (400 MHz, (CD3)2SO), δ: 2.53 (s, 3 H,
:
1
4ꢀ(4ꢀAminobutyl)ꢀ5ꢀpyridineꢀ4ꢀylꢀ1,2ꢀdihydroꢀ3Hꢀpyrazolꢀ
3ꢀone hydrate (19). Procedure B. Yield 90%, m.p. 179—183.5 °C
(decomp.). Found (%): C, 57.72; H, 7.37. C12H18N4O2. Calꢀ
culated (%): C, 57.58; H, 7.25. IR, ν/cm–1: 2870—3035.
1H NMR (400 MHz, (CD3)2SO), δ: 1.36—1.56 (m,
4 H, N—CH2—CH2—CH2—CH2); 2.44—2.53 (m, 2 H,
N—(CH2)3—CH2); 2.59—2.66 (m, 2 H, N—CH2); 7.49—7.55
(m, 2 H, 2ꢀ, 6ꢀCHPy); 8.51—8.57 (m, 2 H, 3ꢀ, 5ꢀCHPy).
Me); 2.69—2.75 (m, 2 H, N—CH2—CH2); 2.96—3.02 (m, 2 H,
N—CH2—CH2); 7.04 (t, 1 H, 4ꢀCHPh—C
7.26—7.42 (m, 5 H, 3ꢀ, 5ꢀCHPh—C, 3ꢀ, 4ꢀ, 5ꢀCHPh—N); 7.52
(d, 2 H, 2ꢀ, 6ꢀCHPh—N
3JH,H = 7.5 Hz); 8.09 (d, 2 H,
2ꢀ, 6ꢀCHPh—C
3JH,H = 8.1 Hz). 13C NMR (400 MHz,
,
3JH,H = 7.2 Hz);
,
,
(CD3)2SO), δ: 21.89 (N—CH2—CH2); 31.99 (Me); 50.21
(N—CH2—CH2); 92.85 (HN—C—C=C—N); 118.80
(2ꢀ, 6ꢀCHPh—N); 122.79 (4ꢀCHPh—C); 126.81 (4ꢀCHPh—N);
13C
NMR
(400
MHz,
(CD3)2SO),
δ:
22.14

Synthesis of 4ꢀaminoalkylpyrazolꢀ3ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 1, January, 2005
225
127.55 (2ꢀ, 6ꢀCHPh—C); 128.13, 128.22 (3ꢀ, 5ꢀCHPh—C
,
was refluxed for 5 to 10 h. The course of the reaction was moniꢀ
3ꢀ, 5ꢀCHPh—N); 135.64 (1ꢀCPh—C); 141.16 (1ꢀCPh—N); 148.80
(HN—C—C=C—N); 161.40 (HN—CO).
tored by TLC (MeCN—NH3(aq), 95 : 5). The resulting mixture
was cooled and the product was filtered off.
4ꢀ[3ꢀ(Methylamino)propyl]ꢀ5ꢀphenylꢀ1,2ꢀdihydroꢀ3Hꢀ
pyrazolꢀ3ꢀone (24). Procedure B. Yield 92%, m.p. 192—194.5 °C
(decomp.). Found (%): C, 67.69; H, 7.26. C13H17N3O. Calꢀ
culated (%): C, 67.51; H, 7.41. IR, ν/cm–1: 2810—3020.
1H NMR (400 MHz, (CD3)2SO), δ: 1.63—1.75 (m, 2 H,
N—CH2—CH2—CH2); 2.39—2.47 (m, 5 H, N—(CH2)2—CH2,
NMe); 2.73—2.83 (m, 2 H, N—CH2—(CH2)2); 7.40—7.44 (m,
5 H, Ph). 13C NMR (400 MHz, (CD3)2SO), δ: 19.33
(N—CH2—CH2—CH2); 26.69 (N—(CH2)2—CH2); 34.08
(NMe); 49.39 (N—CH2—(CH2)2); 102.94 (HN—C—C=C—N);
127.67 (4ꢀCHPh); 129.34 (2ꢀ, 6ꢀCHPh); 130.91 (3ꢀ, 5ꢀCHPh);
132.28 (1ꢀCPh); 147.07 (HN—C—C=C—N); 156.31 (HN—CO).
Synthesis of isoxazoles 25, 26, and 29. Procedure C.
Hydroxylamine hydrochloride (10 mmol) and KOH (5 mmol)
in water (5 mL) were added to a solution of 3ꢀacyllactam
(5 mmol) in EtOH (15 mL). The reaction mixture was refluxed
for 10 to 20 h. The course of the reaction was monitored by TLC
(MeCN—NH3(aq), 95 : 5). The resulting mixture was evapoꢀ
rated to dryness and diluted with cold water (5 mL) and aqueous
NH3 (5 mL) with stirring and cooling; the precipitate was filꢀ
tered off.
4ꢀ(2ꢀAminoethyl)ꢀ3ꢀpyridinꢀ3ꢀylisoxazolꢀ5(2H )ꢀone hydroꢀ
chloride (27). Yield 85%, m.p. 195—198 °C (decomp.).
Found (%): C, 49.76; H, 4.71. C10H12ClN3O2. Calculated (%):
C, 49.70; H, 5.00. IR, ν/cm–1: 1630—3270. 1H NMR (400 MHz,
(CD3)2SO), δ: 2.61—2.69 (m, 2 H, N—CH2—CH2); 2.88—2.99
(m, 2 H, N—CH2—CH2); 7.64 (dd, 1 H, 5ꢀCHPy, =
3JH,H
8.0 Hz, JH,H = 4.9 Hz); 8.04 (br.s, 2 H, NH2+); 8.13 (dt, 1 H,
4ꢀCHPy, 3JH,H = 8.0 Hz, 4JH,H = 2.1 Hz); 8.78 (d, 1 H, 6ꢀCHPy
3JH,H = 4.9 Hz); 8.84 (d, 1 H, 2ꢀCHPy 4JH,H = 2.1 Hz).
3
,
,
13C NMR (400 MHz, (CD3)2SO), δ: 20.06 (N—CH2—CH2);
37.23 (N—CH2—CH2); 92.17 (O=C—C=C—N); 124.06
(3ꢀCPy); 124.28 (5ꢀCHPy); 136.05 (4ꢀCHPy); 147.66 (2ꢀCHPy);
151.11 (6ꢀCHPy); 159.28 (O=C—C=C—N); 171.91 (C=O).
4ꢀ(2ꢀAminoethyl)ꢀ3ꢀpyridinꢀ4ꢀylisoxazolꢀ5(2H )ꢀone hydroꢀ
chloride (28). Yield 78%, m.p. 182—184.5 °C (decomp.).
Found (%): C, 49.53; H, 4.88. C10H12ClN3O2. Calculated (%):
C, 49.70; H, 5.00. IR, ν/cm–1: 1650—3240. 1H NMR (400 MHz,
(CD3)2SO), δ: 2.65—2.76 (m, 2 H, N—CH2—CH2); 2.93—3.03
(m, 2 H, N—CH2—CH2); 8.15 (d, 2 H, 3ꢀ, 5ꢀCHPy, =
3JH,H
3
5.8 Hz); 8.85 (d, 2 H, 2ꢀ, 6ꢀCHPy, JH,H = 5.8 Hz). 13C NMR
(400 MHz, (CD3)2SO), δ: 20.73 (N—CH2—CH2); 38.93
4ꢀ(2ꢀAminoethyl)ꢀ3ꢀphenylisoxazolꢀ5(2H )ꢀone (25). Yield
89%, m.p. 200.5—201 °C (decomp.). Found (%): C, 64.51;
H, 6.07. C11H12N2O2. Calculated (%): C, 64.69; H, 5.92. IR,
ν/cm–1: 1620, 3250. 1H NMR (400 MHz, (CD3)2SO), δ: 2.46
(N—CH2—CH2);
(3ꢀ, 5ꢀCHPy); 143.65 (2ꢀ, 6ꢀCHPy); 146.06 (4ꢀCPy); 159.33
(O=C—C=C—N); 174.47 (C=O).
93.61
(O=C—C=C—N);
127.11
3
(t, 2 H, NCH2CH2, JH,H = 5.6 Hz); 2.96 (t, 2 H, NCH2,
References
3JH,H = 5.6 Hz); 7.33—7.43 (m, 5 H, Ph); 8.61 (br.s, 2 H, NH2).
13C NMR (400 MHz, (CD3)2SO), δ: 21.34 (NCH2CH2); 40.85
(NCH2CH2); 78.71 (O=C—C=C); 127.46 (4ꢀCHPh); 127.94
(2ꢀ, 6ꢀCHPh); 128.26 (3ꢀ, 5ꢀCHPh); 133.02 (1ꢀCPh); 162.49
(O=C—C=C); 178.01 (O=C).
1. J. Elguero, Pyrazoles, in Comprehensive Heterocyclic Chemisꢀ
try II, Eds A. R. Katritzky, C. W. Rees, and E. F. V. Scriven,
Pergamon, New York, 1995, Vol. 3, Ch. 3.01.
2. E. Vedejs, J. G. Reid, J. D. Rodjers, and S. J. Wittenberger,
J. Am. Chem. Soc., 1990, 112, 4351.
3. V. J. Lee, A. R. Branfman, T. R. Herrin, and K. L.
Rinehart, Jr., J. Am. Chem. Soc., 1978, 100, 4225.
4. K. L. Sorgi, A. C. Maryanoff, D. F. McComsey, and B. E.
Maryanoff, Org. Synth., 1997, 75, 215.
4ꢀ(2ꢀAminoethyl)ꢀ3ꢀ(3ꢀbromophenyl)isoxazolꢀ5(2H )ꢀone
(26). Yield 69%, m.p. 168—169 °C (decomp.). Found (%):
C, 46.82; H, 4.05. C11H11BrN2O2. Calculated (%): C, 46.66;
H, 3.92. IR, ν/cm–1: 1645, 3230. 1H NMR (400 MHz,
(CD3)2SO), δ: 2.45 (t, 2 H, NCH2CH2, 3JH,H = 5.5 Hz); 2.96 (t,
3
2 H, NCH2, JH,H = 5.5 Hz); 7.35—7.58 (m, 4 H, C6H4); 8.54
(br.s, 2 H, NH2). 13C NMR (400 MHz, (CD3)2SO), δ: 21.21
(NCH2CH2); 40.64 (NCH2CH2); 78.56 (O=C—C=C); 121.63
(C—Br); 126.53 (6ꢀCHC H ); 129.79 (4ꢀCHC H4); 130.56
5. A. G. M. Barrett, J. Head, M. L. Smith, N. S. Stock, A. J. P.
White, and D. J. Williams, J. Org. Chem., 1999, 64, 6005.
6. M. L. Rueppel and H. Rapoport, J. Am. Chem. Soc., 1970,
92, 5781.
7. A. H. Jackson, P. V. R. Shannon, and D. J. Wilkins, Tetraꢀ
hedron Lett., 1987, 28, 4901.
8. F. Baburi, F. Ciminale, L. Di Nunno, and S. Florio, Tetraꢀ
hedron, 1982, 38, 557.
9. J.ꢀP. Bouillon, C. Ates, Z. Janousek, and H. G. Viehe, Tetraꢀ
hedron Lett., 1993, 34, 5075.
10. N. Tamura, Y. Matsushita, T. Iwama, S. Harada,
S. Kishimoto, and K. Itoh, Chem. Pharm. Bull., 1991,
39, 1199.
11. V. G. Nenajdenko, A. M. Gololobov, E. P. Zakurdaev, and
E. S. Balenkova, Izv. Akad. Nauk, Ser. Khim., 2003, 2338
[Russ. Chem. Bull., Int. Ed., 2003, 52, 2473].
4
6
(2ꢀCHC H ); 130.78 (1ꢀCC6 H ); 135.44 (5ꢀCHC H4); 161.07
6
4
6
6
(O=C—C=C); 178.04 (C=O).4
4ꢀ(4ꢀAminobutyl)ꢀ3ꢀphenylisoxazolꢀ5(2H )ꢀone (29). Yield
35%, m.p. 169—170 °C (decomp.). Found (%): C, 67.47; H, 6.71.
C13H16N2O2. Calculated (%): C, 67.22; H, 6.94. IR, ν/cm–1
:
1650, 3280. 1H NMR (400 MHz, (CD3)2SO), δ: 1.42—1.53 (m,
2 H, NCH2CH2CH2CH2); 2.19 (t, 2 H, N(CH2)3CH2, 3JH,H
=
3
6.5 Hz); 2.78 (t, 2 H, NCH2, JH,H = 6.5 Hz); 7.30—7.49 (m,
5 H, Ph); 8.06 (br.s, 2 H, NH2). 13C NMR (400 MHz,
(CD3)2SO), δ: 21.34 (N(CH2)2CH2CH2); 25.86 (N(CH2)3CH2);
27.32 (NCH2CH2(CH2)2); 40.13 (NCH2CH2); 80.09
(O=C—C=C); 126.97 (4ꢀCHPh); 127.71 (2ꢀ, 6ꢀCHPh);
128.25 (3ꢀ, 5ꢀCHPh); 134.01 (1ꢀCPh); 162.03 (O=C—C=C);
177.70 (C=O).
Synthesis of isoxazoles 27 and 28. Procedure D. Hydroxylꢀ
amine hydrochloride (5 mmol) was added to a solution of
3ꢀacyllactam (5 mmol) in EtOH (10 mL). The reaction mixture
Received September 10, 2004;
in revised form November 19, 2004