Synthesis of 4-aminoisoxazole-3-carboxamides using base-promoted nitrosation of N-substituted cyanoacetamides

Article abstract of DOI:10.1023/B:RUCB.0000035646.13790.8a

The reactions of N-substituted cyanoacetamides with EtONO in the presence of an equimolar amount of EtONa afforded the corresponding sodium salts of hydroxyimino derivatives in 70 - 95% yields. The latter were transformed into 4-amino-5-(4-bromobenzoyl)isoxazole-3-carboxamides in 30 - 57% yields using the known method.

Full text of DOI:10.1023/B:RUCB.0000035646.13790.8a

622
Russian Chemical Bulletin, International Edition, Vol. 53, No. 3, pp. 622—625, March, 2004
Synthesis of 4ꢀaminoisoxazoleꢀ3ꢀcarboxamides
using baseꢀpromoted nitrosation of Nꢀsubstituted cyanoacetamides
V. P. Kislyi,ꢀ E. B. Danilova, E. P. Zakharov, 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
The reactions of Nꢀsubstituted cyanoacetamides with EtONO in the presence of an equimoꢀ
lar amount of EtONa afforded the corresponding sodium salts of hydroxyimino derivatives in
70—95% yields. The latter were transformed into 4ꢀaminoꢀ5ꢀ(4ꢀbromobenzoyl)isoxazoleꢀ3ꢀ
carboxamides in 30—57% yields using the known method.
Key words: Nꢀsubstituted cyanoacetamides, baseꢀpromoted nitrosation, 2ꢀ(4ꢀbromophenyl)ꢀ
2ꢀoxoethoxyiminocyanoacetamides, 4ꢀaminoꢀ5ꢀ(4ꢀbromobenzoyl)isoxazoleꢀ3ꢀcarboxamides.
Baseꢀpromoted nitrosation of the αꢀcarbon unit in
Sodium salts of oximes treated with 4ꢀbromophenacyl
bromide (4) are transformed into 4ꢀaminoꢀ5ꢀ(4ꢀbromoꢀ
benzoyl)isoxazoleꢀ3ꢀcarboxamides 5 via the twoꢀstep
method described previously.7 The reactions of sodium
salts 2 with bromoketone 4 in DMF afford Оꢀalkylated
oximes 6a—c, which are transformed into aminoisoxazoles
5a—d under the treatment of LiOH (see Ref. 7) or KOH
in water or aqueous ethanol.
nitriles (i.e., the action of alkyl nitrites in the presence of
bases) has previously1 been used successfully for arylꢀ
acetonitriles. However, nitrosation under acidic condiꢀ
tions (NaNO2 in the presence of AcOH 2,3 or phosphoric
acid) was mainly used for the cyanoacetic acid derivaꢀ
tives.4 Baseꢀpromoted nitrosation of cyanoacetic ester
(amyl nitrite, EtONa) was described5 without indicating
conditions, and only a "low yield" was mentioned.
It should be noted that the typical procedure for
nitrosation of the cyanoacetic acid derivatives (ester,
amide) is inappropriate for Nꢀsubstituted amides 1b—d,
because these compounds are virtually insoluble in
water.6a
R = Me (a), CH2Ph (b), Ph (c), 2ꢀMeOC6H4 (d)
R = Me (a), CH2Ph (b), Ph (c), 2ꢀMeOC6H4 (d)
The presence of the aryl substituent at the amidic
nitrogen atom facilitates ring closure: for instance, under
the reaction conditions, Oꢀsubstituted oxime 6d unꢀ
dergoes spontaneous partial ring closure to form
isoxazole 5d.
We established that the addition of a solution of
EtONO (in ethanol or diethyl ether) to a suspension of
1a—d in ethanol in the presence of an equimolar amount
of EtONa produces rapidly sodium salts of oximes 2a—d
in high yields. The latter can be transformed into oximes
3a—d by acidification (Table 1).
Both the alkylation of sodium salts of oximes and the
reactions with Hꢀforms of oximes in the presence of triꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 594—596, March, 2004.
1066ꢀ5285/04/5303ꢀ0622 © 2004 Plenum Publishing Corporation

Synthesis of 4ꢀaminoisoxazoleꢀ3ꢀcarboxamides
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
623
Table 1. Yields, melting points, and data of IR and 1Н NMR spectra of hydroxyimino derivatives 2a—d and 3a—d
Comꢀ
pound
Yield
(%)
M.p.
/°C
Found
Calculated
Empirical
formula
IR
1Н NMR
(δ, J/Hz)
(%)
C
H
N
CN
CO
2a
2b
95
83
310—312
(decomp.)
245—247
(decomp.)
32.2
32.6
53.3
53.0
2.7 28.2
2.8 28.0
3.6 18.7
3.7 18.9
С4H4N3O2Na 2216
С10H8N3O2Na 2215
1636,
1560
1650,
1550
2.8 (d, 3 H, MeNH, J = 4.2);
7.4 (br.s, 1 H, NHCO)
4.45 (d, 2 H, PhCH2, J = 6.4);
7.2—7.4 (m, 5 H, Ph);
8.00 (1 H, NHCO)
2c
2d
3a
3b
3c
3d
85
70
222—225
(decomp.)
51.2
51.7
2.8 19.9
2.9 19.2
С9H6N3O2Na 2196
С10H8N3O3Na 2200
1668,
1604,
1548
1670,
1550
7.1—7.7 (m, 5 H, Ph);
10.3 (s, 1 H, NHCO)
203—205
(decomp.)
49.8
49.5
3.3 17.4
3.7 17.2
3.9 (s, 3 H, OMe); 6.9 (m, 3 H,
PhOMe); 8.4 (m, 1 H, PhOMe);
9.6 (br.s, 1 H, NH)
2.7 (d, 3 H, MeNH, J = 4.3);
8.3 (br.s, 1 H, NH); 14.4 (br.s,
1 H, OH)
4.4 (d, 2 H, PhCH2, J = 6.3);
7.2—7.4 (m, 5 H, Ph); 9.0 (1 H,
NHCO); 14.5 (br.s, 1 H, NOH)
7.2—7.7 (m, 5 H, Ph); 10.3 (s, 1 H,
NHCO); 14.5 (br.s, 1 H, NOH)
75 208—211*
37.8
37.3
3.4 33.1
4.1 32.9
С4H5N3O2
С10H9N3O2
С9H7N3O2
С10H9N3O3
2244 w 1664,
1552
89
85
79
149—152
229—232
172—174
59.1
59.5
4.4 20.7
4.5 20.6
2242 w 1660,
1550
57.1
57.6
3.7 22.2
3.9 22.0
2240 w 1660,
1600,
1548
54.8
54.3
4.1 19.2
4.0 18.7
2245 w 1665,
1550
3.9 (s, 3 H, OMe); 6.9 (m, 3 H,
PhOMe); 8.4 (m, 1 H, PhOMe);
9.05 (br.s, 1 H, NH); 14.7 (br.s,
1 H, NOH)
* Ref. 6: 212 °C.
ethylamine have been described.7 We attempted to reproꢀ
duce the latter procedure and observed the formation of a
complex mixture of products containing only insignifiꢀ
cant amounts of compounds 5, and, hence, their isolation
was very difficult. The data obtained allow one to conꢀ
clude that these are precisely the sodium salts of oximes,
which are primarily formed by baseꢀpromoted nitrosation,
that should reasonably be used instead of oximes themꢀ
selves in the syntheses of 4ꢀaminoisoxazoles.
The structures of the synthesized compounds were
confirmed by the IR and 1Н NMR spectra (Table 2). The
IR spectra of sodium salts of oximes 2a—d contain a
rather intense absorption band of the CN group, although
its frequency (2216—2196 cm–1) is strongly decreased
compared to that of the CN group in the starting cyanoꢀ
acetamides (2276—2260 cm–1). At the same time, in the
Hꢀforms of oximes 3a—d and Оꢀalkylated oximes 6a—с,
the CN group has an unexpectedly low intensity at the
normal frequency (2235—2245 cm–1), while the intensity
of the absorption band of the nitrile group in the IR specꢀ
tra of some alkylated oximes 6 is close to the "noise" level.
This is rather unusual. The absence of an absorption band
of the CN group has already been mentioned7 for some
compounds of type 6 and is related, probably, to the noꢀ
ticeable conjugation of the CN group in the hydroxyꢀ
iminocyanoacetamide fragment of compounds of type 6.
At the same time, the structures of compounds 6 seem
1
doubtless, because they were confirmed by the Н NMR
spectra and, in addition, oximes 6 served as the starting
compounds for the synthesis of isoxazoles 5. The 1Н NMR
spectra of oximes 6 exhibit a narrow singlet of the CH2CO
group at 5.8—6.0 ppm. However, this signal is absent
from the 1Н NMR spectra of isoxazoles 5, which contain,
by contrast, a noticeably broadened singlet of the amino
group at 6.3—6.5 ppm.
It should be noted that hydroxyiminonitriles 3 can be
used for the synthesis of 4ꢀaminoisoxazoles and also
for syntheses of aminofurazans,8 4ꢀaminoisothiazoles,9
4ꢀaminoimidazoles,10 and 5ꢀaminooxazoles.11 When
oximes 3 were heated with hydroxylamine for many hours
under the conditions indicated in the study,8 we detected
R = H (3e, 7a), CH2Ph (3b, 7b)

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Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Kislyi et al.
Table 2. Yields, melting points, and data of elemental analyses and 1Н NMR spectra of isoxazoles 5a—d and amides 6a—c
Comꢀ Yield
pound (%)
M.p.
/°C
Found
Calculated
Empirical
formula
IR
1Н NMR (δ, J/Hz)
(%)
N
C
H
CO
Y*
X**
BrPh
Other signals
5a
5b
72
63
180—182 44.4 3.1 13.0
44.5 3.2 12.9
С12H10BrN3O3 1720,
1660
3488, 6.3 (br.s, 7.7—8.05 2.90 (d, 2 H, MeNH,
3364 2 Н)
(m, 4 H) J = 4.6); 8.55 (br.s,
1 H, NHCO)
3375, 6.3 (br.s, 7.7—8.07 4.50 (d, 2 Н, CH2Ph,
160—162 54.0 3.5 10.5
54.1 3.2 10.3
С18H12BrN3O3 1725,
1680
3300 2 Н)
(m, 4 H) J = 6.2); 9.20 (br.s,
1 H, NHCO); 7.2—7.4
(m, 5 H, Ph)
5c
5d
55
30
205—207 52.9 3.1 10.9
52.7 3.0 10.1
158—162 51.9 3.4 10.1
52.9 3.9 10.1
С17H12BrN3O3 1740,
3450, 6.42 (br.s, 7.7—8.07 7.2—7.7 (m, 5 H, Ph);
3350 2 Н) (m, 4 H) 10.7 (s, 1 H, NHCO)
3455, 6.38 (br.s, 7.7—8.1
1694
С18H14BrN3O4 1735,
1690
7.1—8.3 (m, 4 H,
MeOPh); 3.97 (s, 3 H,
MeOPh); 9.22 (s, 1 H,
NHCO)
3310 2 Н)
(m, 4 H)
6a
6b
80
64
160—162 44.4 3.1 13.0
44.9 3.0 13.8
С12H10BrN3O3 1692,
2240 5.82 (s,
2 H)
7.7—7.93 2.70 (d, 3 Н, MeNHCO,
1584 w
(4 H)
J = 4.7); 8.3 (br.s,
1 H, NHCO)
7.7—7.93 4.4 (d, 2 Н, CH2NH,
162—164 54.0 3.5 10.5
53.7 3.6 10.2
С18H14BrN3O3 1690,
1587 w
2240 5.82 (s,
2 H)
(4 H)
J = 6.4); 7.2—7.3 (5 Н,
Ph); 8.9 (br.s, 1 H,
NHCO)
6c
32
194—197 52.8 3.1 10.9
51.5 3.7 10.2
С17H12BrN3O3 1688,
1604 w
2235 6.0 (s,
2 H)
7.7—7.93 7.1—7.7 (m, 5 H,Ph);
(m, 4 H) 10.45 (s, NHCO)
* Y = NH (5a—d), CN (6a—c).
** X = COCH2 (5a—d), NH2 (6a—c).
The yields, melting points, and 1Н NMR spectra of the
products are presented in Table 1.
no aminofurazans 7 (TLC analysis using as references
authentic amides 7a,b obtained from methyl aminoꢀ
furazanꢀ3ꢀcarboxylate8).
Synthesis of hydroxyiminocyanoacetamides 3a—d (general
procedure). Sodium salt of Nꢀsubstituted isonitrosoacetamide 2
(0.05 mol) was suspended in water (30 mL), the suspension was
acidified with hydrochloric acid to pH 5—6 and stirred for 30 min
at ~20 °C, and the product was filtered off. The yields, melting
points, and 1Н NMR spectra of the products are presented in
Table 1.
Experimental
1
Н NMR spectra were recorded on Bruker АМꢀ300 and
Bruker DRXꢀ500 instruments with working frequencies of
300.13 and 500.13 MHz, respectively, in a mixture of DMSOꢀd6
and CCl4 (1 : 3). IR spectra were obtained on a Specord Mꢀ80
instrument in KBr pellets.
Alkylation of sodium salts of the hydroxyimino derivatives
(synthesis of 6a—d, general procedure). A mixture of 4ꢀbromoꢀ
phenacyl bromide (4) (1.4 g, 5 mmol), the corresponding soꢀ
dium salt 2a—d (5 mmol), and a solvent (8 mL, DMF for 1a or
ethanol for 1b—d) was stirred for 8 h at ~20 °C and left for 16 h.
Then the solvent was evaporated on a rotary evaporator, and
water was added to the residue. ОꢀSubstituted oxime was filꢀ
tered off, washed with water and hexane on the filter, and
dried in vacuo. In the case of salt 2d, a mixture of Оꢀalkyꢀ
lated oxime 6d and the corresponding isoxazole 5d (∼1 : 1) was
formed.
Baseꢀpromoted nitrosation of cyanoacetamides (general proꢀ
cedure). A mixture of concentrated H2SO4 (8 mL, d = 1.84),
ethanol (10.4 mL), and water (84 mL) was slowly added dropwise
to a solution of NaNO2 (21.2 g, 0.3 mol) in a mixture of ethanol
(92 mL) and water (84 mL) with gradual heating (30—45 °C)
and absorption of the released gas (ethyl nitrite) with ethanol
(30 mL). An ethanolic solution of EtONO was rapidly added to
a suspension of sodium salt of oxime 2, which was obtained by
mixing of Nꢀsubstituted cyanoacetamide 1a—d (0.07 mol) with
a solution of sodium ethoxide (6.8 g, 0.1 mol) in ethanol (50 mL)
and stirring of the resulting mixture for 1 h. The mixture was
stored for 16 h (in the case of 1b—d, complete dissolution was
observed) and concentrated on a rotary evaporator. Toluene was
added to the residue, and sodium salt of hydroxyiminocyanoꢀ
acetamide 2 was filtered off.
The yields, melting points, and 1Н NMR spectra of the
products are presented in Table 2.
Synthesis of 4ꢀaminoisoxazoleꢀ3ꢀcarboxamides 5a—d (genꢀ
eral procedure). A suspension of compounds 6a—с (5 mmol) or
a 5d + 6d mixture (see above) in a solution of LiOH•H2O (0.6 g)
in 40 mL of water (for 6а) or 40 mL of 50% ethanol (for 6b,с)
was stirred for 8 h. The product was filtered off, washed with
water on the filter, and dried in vacuo.

Synthesis of 4ꢀaminoisoxazoleꢀ3ꢀcarboxamides
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
625
The yields, melting points, and 1Н NMR spectra of the
products are presented in Table 2.
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7. K. Gewald, P. Bellmann, and H.ꢀJ. Jaensch, Liebigs. Ann.
Chem., 1980, 1623.
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Received October 13, 2003;
in revised form February 11, 2004