Reactions of N,N-bis(siloxy)enamines with trimethylsilyl cyanide: Aliphatic nitro compounds as convenient precursors of 5-aminoisoxazoles

Article abstract of DOI:10.1070/MC2002v012n03ABEH001585

A convenient procedure was developed for the synthesis of 5-aminoisoxazoles by the consecutive double silylation and cyanation of aliphatic nitro compounds.

Full text of DOI:10.1070/MC2002v012n03ABEH001585

Mendeleev Commun., 2002, 12(3), 99–102
Reactions of N,N-bis(siloxy)enamines with trimethylsilyl cyanide:
aliphatic nitro compounds as convenient precursors of 5-aminoisoxazoles
Aleksei V. Lesiv, Sema L. Ioffe,* Yurii A. Strelenko, Igor’ V. Bliznets and Vladimir A. Tartakovsky
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328; e-mail: iof@cacr.ioc.ac.ru
10.1070/MC2002v012n03ABEH001585
A convenient procedure was developed for the synthesis of 5-aminoisoxazoles by the consecutive double silylation and cyanation
of aliphatic nitro compounds.
N,N-Bis(siloxy)enamines (BENA) 1,1,2 double silylation pro-
ducts of available aliphatic nitro compounds, behave as β-C-
electrophiles toward various C- and N-centred nucleophiles3
(the anions of β-dicarbonyl and nitro compounds, silyl nitro-
nates, primary or secondary amines, and silyl derivatives of
N-nitroamines or azoles).
(see also Scheme 1). TMSCN may participate in this process in
a tautomeric isonitrile form.7
It was previously noted8 that the cyanide ion reacts with
nitrosoalkenes A to form 5-aminoisoxazoles 4. In the absence
of Et3N, intermediate A was generated with the use of TMSCN,
however, at a much lower rate.
It was assumed3,4 that conjugated nitrosoalkenes that resulted
from BENA under the action of nucleophiles rather than BENA
are actual intermediates in these reactions.
†
General procedure for the synthesis of silyl derivatives 2a–e.
All reactions with BENA were performed in specially dried solvents
in a dry argon atmosphere.
In this context, it is of interest to use the cyanide ion as a
nucleophile in such reactions because the corresponding α-cyano
oximes (or their silyl derivatives), the probable primary products
of its C,C-cross-coupling reactions with BENA, were not de-
scribed in the literature, although they might be usable in
organic synthesis.
The aim of this work was to study the interaction of the
cyanide ion with BENA 1.
We found that BENA 1b reacted with potassium cyanide
in the presence of dibenzo-18-crown-6 afforded a difficult-to-
separate mixture of unidentified products.
At the same time, trimethylsilyl cyanide (TMSCN) smoothly
reacts with BENA 1 over a wide range of conditions to give
previously unknown trimethylsilyl derivatives of cyanoximes 2.
It is likely that it is optimum to use solutions of equimolar
amounts of reactants in CH2Cl2 in the presence of 10 mol%
Et3N (Scheme 1 and Table 1).† It is well known6 that Et3N
catalysis is required for the C,C-cross-coupling of silyl nitronates
with BENA. However, the reaction BENA + TMSCN can also
be performed without Et3N. In this case, the reaction occurs
without a solvent at 20 °C for several days, and the yields of
target products 2 are close to those given in Table 1.‡
Et3N (0.5 mmol, 0.07 ml) and then BENA 1a–e (5 mmol) were added
to TMSCN5 (5 mmol, 0.67 ml) in freshly distilled CH2Cl2 (7.5 ml) at
20 °C with intense stirring. After an induction period (from a few seconds
to 45 min), the reaction mixture warmed up to boiling; it was allowed to
stand for 1.5 h, volatile components were distilled at 40 °C/20 Torr, and
the residue was fractionated in a vacuum to obtain silyl derivatives 2a–e
(the yields are given in Table 1).
NMR spectra were measured on a Bruker AM-300 spectrometer (oper-
ating frequency of 300.3 MHz for 1H, 75.47 MHz for 13C and 59.63 MHz
for 29Si, INEPT); TMS was used as an internal standard; CDCl3 was a
solvent, unless otherwise specified.
3-(Trimethylsilyloximino)propionitrile (2a + 2'a; E/Z = 1:2.2): yield 49%,
bp 35–36 °C/0.35 Torr. E: 1H NMR, d: 0.19 (s, 9H, SiMe3), 3.28 (d, 2H,
CH2, 3J 5.1 Hz), 7.41 (t, 1H, CH, 3J 5.1 Hz); 13C NMR, d: –0.9 (SiMe3),
1
19.0 (CH2), 114.9 (CN), 143.8 (CH); 29Si NMR, d: 28.08. Z: H NMR,
d: 0.19 (s, 9H, SiMe3), 3.41 (d, 2H, CH2, 3J 4.4 Hz), 6.96 (t, 1H, CH, 3J
4.4 Hz); 13C NMR, d: –0.9 (SiMe3), 14.8 (CH2), 115.6 (CN), 142.5 (CH);
29Si NMR, d: 28.72.
3-(Trimethylsilyloximino)butyronitrile (2b + 2'b; E/Z = 1.2:1): yield 79%,
bp 28–29 °C/0.35 Torr. E: 1H NMR, d: 0.19 (s, 9H, SiMe3), 2.10 (s, 3H,
Me), 3.38 (s, 2H, CH2); 13C NMR, d: –0.8 (SiMe3), 13.5 (Me), 24.7
1
(CH2), 115.5 (CN), 151.6 (C=N); 29Si NMR, d: 26.65. Z: H NMR, d:
0.19 (s, 9H, SiMe3), 1.98 (s, 3H, Me), 3.50 (s, 2H, CH2); 13C NMR, d:
–0.9 (SiMe3), 17.8 (Me), 19.3 (CH2), 115.6 (CN), 149.7 (C=N); 29Si NMR,
d: 26.80.
Me3SiO
NC
OSiMe
3
2-Methyl-3-(trimethylsilyloximino)propionitrile (2c + 2'c; E/Z = 4:3):
N(OSiMe3)2
+ Me3SiCN
N
N
1
yield 70%, bp 38 °C/0.4 Torr. E: H NMR, d: 0.20 (s, 9H, SiMe3), 1.48
3
3
NC
(d, 3H, Me, J 7.3 Hz), 3.53 (m, 1H, CHMe), 7.41 (d, 1H, HC=N, J
i
R1
R1
R1
5.1 Hz); 13C NMR, d: –0.9 (SiMe3), 16.4 (Me), 26.6 (CHMe), 118.7
(CN), 149.1 (C=N). Z: H NMR, d: 0.21 (s, 9H, SiMe3), 1.43 (d, 3H,
Me, J 7.3 Hz), 4.23 (m, 1H, CHMe), 6.88 (d, 1H, HC=N, J 5.2 Hz).
13C NMR, d: –0.9 (SiMe3), 15.6 (Me), 21.7 (CHMe), 119.1 (CN), 148.3
(C=N).
R2
R2
R2
1
3
3
1a g
–
2a g
–
2'a g
–
42–79%
ii
Methyl 5-cyano-4-(trimethylsilyloxy)pentanoate (2d + 2'd; E/Z = 1:3):
1
yield 61%, bp 84–88 °C/0.20 Torr. E: H NMR, d: 0.12 (s, 9H, SiMe3),
HO
OH
R1
R2
NH2
R1
2.58, 2.69 (m, 4H, CH2CH2), 3.37 (s, 2H, CH2), 3.62 (s, 3H, OMe);
13C NMR: –1.0 (SiMe3), 23.4 (CH2CH2NOSi), 23.8 (CH2CN), 29.8
(CH2CO2), 51.7 (Me), 115.3 (CN), 154.0 (C=N), 172.7 (CO). Z:
1H NMR, d: 0.14 (s, 9H, SiMe3), 2.58, 2.69 (m, 4H, CH2CH2), 3.44 (s,
2H, CH2), 3.62 (s, 3H, OMe); 13C NMR, d: –0.9 (SiMe3), 17.4 (CH2CN),
28.6 (CH2CH2CNOSi), 29.6 (CH2CO2), 51.5 (Me), 115.3 (CN), 150.7
(C=N), 172.4 (CO).
N
N
NC
NC
R1
N
R2
3a g
R2
O
4a g
3'a g
–
–
–
36–79%
3-Phenyl-3-(trimethylsilyloximino)propionitrile (2e): yield 72%, bp 92 °C/
1
0.50 Torr. E: H NMR, d: 0.35 (s, 9H, SiMe3), 3.87 (s, 2H, CH2), 7.45,
Scheme 1 Reagents and conditions: i, CH2Cl2, Et3N (cat.), 20–40 °C; ii,
MeOH, Et3N (cat.), 20 °C.
7.70 (m, 5H, Ph); 13C NMR: –0.6 (SiMe3), 14.8 (CH2), 115.3 (CN),
126.2, 128.7, 130.1, 133.5 (Ph), 150.9 (C=N).
‡
TMSCN (2 mmol, 0.27 ml) was added to freshly distilled enamine 1b
Scheme 2 illustrates a conceivable reaction mechanism. We
believe that Et3N, reacting with TMSCN, generates conjugated
nitrosoalkene A from BENA 1. This active intermediate further
reacts with TMSCN to give a mixture of syn- and anti-isomers
of the silyl derivatives of cyano-substituted oximes 2 and 2'
(2 mmol, 0.46 g) with stirring at room temperature, the reaction mixture
was allowed to stand at 20 °C for 48 h, volatile components were distilled
at 20 °C/0.1 Torr, and an aliquot portion of CH2Cl2 was added as an
internal standard to the residue. The yield of mixture of 2b + 2'b was
82%, molar ratio 2b:2'b ~ 1:1.2.
– 99 –

Mendeleev Commun., 2002, 12(3), 99–102
The cross-coupling of TMSCN with BENA 1f is accom-
panied by a considerable contribution of the rearrangement of
BENA 1f into compound 5 (~15%).13 For this reason, TMS
derivative 2f cannot be isolated from the reaction mixture
(Scheme 5).††
The interaction of internal BENA 1g with TMSCN is more
complicated (Scheme 5). Under standard reaction conditions,
only compound 6 was detected, which was transformed by
desilylation into enoxime 7, which is much more stable. How-
ever, the NMR monitoring allowed us to detect the initial for-
mation of cyanoxime 2g, which afforded aminoisoxazole 4g as
a result of rapid desilylation (Table 1). Compound 2g in CH2Cl2
was gradually converted into silyl enoxime derivative 6
(Scheme 5). The reaction 2g ® 6 can include the consecutive
Me3SiCN + NEt3
CN– + Me3SiN+Et3
O
N
N(OSiMe )
3 2
CN–
R1
R1
– (Me3Si)2O
R2
R2
1
A
Me3SiO
N
≡
Me3SiC N
Me3SiN=C (ref. 7)
NC
R1
R2
§
General preparation procedure for aminooximes 4a–e.
2 + 2'
Distilled compound 2 (3 mmol) was dissolved in methanol (5 ml), and
Et3N (0.1 ml) was added; after 24 h, the solvent was evaporated at 50 °C/
20 Torr, and isoxazole 4 of > 90% purity (NMR data) was obtained.
Scheme 2
The role of CH2Cl2 is reduced to the dissolution of reactants
and to the control of reaction temperature by heat removal due
to the boiling of the solvent.
1
5-Isoxazolamine 4a (lit.9): yield 49%, mp 72–73 °C. H NMR, d: 4.9
(br. s, 2H, NH2), 5.07 (d, 1H, CHCNH2, 3J 1.5 Hz), 7.91 (d, 1H, CHCN,
3J 1.5 Hz); 13C NMR, d: 78.8 (CHCHC), 151.9 (C=N), 168.6 (CNH2).
Found (%): C, 42.82; H, 4.82; N, 33.21. Calc. for C3H4N2O (%): C,
42.86; H, 4.80; N, 33.32.
According to NMR data, derivatives 2a–d are mixtures of Z-
and E-isomers (2 and 2', respectively, in Scheme 1 and Table 1).
Compounds 2e–g were detected as individual isomers with the
Z-configuration of CN and OSiMe3 groups. It is likely that
the Z/E ratios given in Table 1 are thermodynamic values
because they remained unchanged after the vacuum distillation
of these products. Note that compounds 2a–e with > 90% purity
(NMR data) can be isolated by fractionation (the synthesis of
2f,g will be considered below).
3-Methyl-5-isoxazolamine 4b (lit.10): yield 79%, mp 82–84 °C. 1H NMR,
d: 2.12 (s, 3H, Me), 4.5 (br. s, 2H, NH2), 4.94 (s, 1H, CH); 13C NMR, d:
11.7 (Me), 80.6 (CH), 161.6 (C=N), 168.4 (CNH2). Found (%): C, 48.94;
H, 6.16; N, 28.63. Calc. for C4H6N2O (%): C, 48.97; H, 6.16; N, 28.55.
1
4-Methyl-5-isoxazolyloxazole 4c (lit.11): yield 70%, oil. H NMR, d:
1.68 (s, 3H, Me), 4.7 (br. s, 2H, NH2), 7.72 (s, 1H, CH); 13C NMR, d:
6.0 (Me), 87.4 (CMe), 153.2 (CH), 165.7 (CNH2). Found (%): C, 49.20;
H, 6.03; N, 28.31. Calc. for C4H6N2O (%): C, 48.97; H, 6.16; N, 28.55.
Methyl 3-(5-amino-3-isoxazolyl)propionate 4d: yield 61%, mp 65–67 °C.
1H NMR, d: 2.64, 2.82 (t, 4H, CH2CH2, 3J 7.4 Hz), 3.69 (s, 3H, Me), 4.7
(br. s, 2H, NH2), 4.98 (s, 1H, CH); 13C NMR, d: 22.6 (CH2CH2CO2),
29.1 (CH2CO2), 51.4 (Me), 83.7 (CH), 159.8 (C=N), 167.1 (CNH2), 172.9
(CO). Found (%): C, 49.24; H, 5.86; N, 16.21. Calc. for C7H10N2O3 (%):
C, 49.41; H, 5.92; N, 16.46.
The desilylation of derivatives 2a–g by the action of methanol
with Et3N added afforded 5-aminoisoxazoles 4a–g in place of
corresponding free oximes 3a–g (Scheme 1, Table 1).§
Evidently, only isomers 3, in which CN and OH groups are
close to each other, undergo cyclisation. The so-called mild
methanolysis of oxime derivatives 2c + 2'c resulted in the for-
mation of corresponding isoxazole 4c only from isomer 2c,
whereas isomer 2'c was converted into the E-isomer of oxime
3'c. Isomer 3'c in CDCl3 was also very slowly isomerised to
isoxazole 4c in a spectrometer ampoule (Scheme 3). It is
believed that the rate of this cyclisation corresponds to the rate
3-Phenyl-5-isoxazolamine 4e (lit.12): yield 72%, mp 104–108 °C.
1H NMR, d: 4.8 (br. s, 2H, NH2), 5.41 (s, 3H, CH), 7.43 (m, 2H, Ph),
7.62 (m, 1H, Ph), 7.71 (m, 2H, Ph); 13C NMR, d: 78.26 (CH), 126.16,
126.79, 128.83, 129.87 (Ph), 163.94 (C=N), 169.25 (CNH2). Found (%):
C, 67.38; H, 5.18; N, 17.57. Calc. for C9H8N2O (%): C, 67.49; H, 5.03;
N, 17.49.
of the equilibration 3c
3'c.¶
¶
Distilled derivative 2c (1 mmol, 0.17 g) was dissolved in methanol
(1 ml); after 3 h, the mixture was evaporated at 20 °C/15 Torr. According
to 1H NMR data, the residue contained aminoisoxazole 4c (67%) and
E-2-methyl-3-oximinopropionitrile 3'c (33%), 1H NMR, d: 1.49 (d, 3H,
Me, J 7.2 Hz), 3.53 (m, 1H, CHMe), 7.37 (d, 1H, CH=N, J 5.9 Hz),
9.12 (br. s, 1H, OH). 13C NMR, d: 16.5 (Me), 26.6 (CHMe), 119.2 (CN),
145.2 (C=N). After a week, oxime 3'c in an ampoule was completely
converted into aminoisoxazole 4c.
Me3SiO
N
OH
N
MeOH, 20 °C, 3 h
NC
NC
3
3
N
NH2
O
2c + 2'c
4c
3'c
CDCl3, 1 week
†† Et3N (0.5 mmol, 0.7 ml) was added to TMSCN (5 mmol, 0.67 ml) in
CH2Cl2 (7.5 ml) at 20 °C; next, a solution of BENA 1f (5 mmol, 1.46 g)
in CH2Cl2 (5 ml) was added for 5 min with intense stirring; the reaction
mixture temperature was kept at 20–30 °C. The reaction exhibited an
induction period. The mixture was allowed to stand for 1 h; volatile
components were distilled at 40 °C/20 Torr, and the residue was frac-
tionated at 70–80 °C/0.4 Torr. According to NMR data, the distillate con-
tained compounds 2f (42%, 0.48 g) and 5 (15%, 0.2 g).
Scheme 3
In contrast to the anions of aliphatic nitro compounds and silyl
nitronates, TMSCN readily reacts with both terminal and internal
BENA. All of these reactions are chemoselective; that is, the
corresponding isonitrile derivatives were not detected.
Let us consider the reactions of TMSCN with BENA 1g,f,
containing a CO2Alk group at the α-position, in more detail
(Schemes 4 and 5).
1
E-Ethyl 3-cyano-2-(trimethylsilyloximino)propionate 2f: H NMR, d:
0.29 (s, 9H, SiMe3), 1.31 (t, 3H, Me, 3J 7.4 Hz), 3.60 (s, 2H, CH2CN),
4.29 (q, 2H, CH2Me, 3J 7.4 Hz). 13C NMR, d: –0.9 (SiMe3), 13.8 (Me),
14.0 (CH2CN), 62.4 (CH2Me), 114.1 (CN), 145.9 (C=N), 161.8 (CO).
Ethyl 3-trimethylsiloxy-2-(trimethylsilyloximino)propionate 5 (lit.2):
1H NMR, d: 0.09 (s, 9H, CH2OSiMe3), 0.21 (s, 9H, NOSiMe3), 1.29 (t,
3H, Me, 3J 7.3 Hz), 4.25 (q, 2H, CH2Me, 3J 7.3 Hz), 4.52 (s, 2H,
CH2OSi). 13C NMR, d: –0.9 (CH2OSiMe3), –0.5 (NOSiMe3), 14.1 (Me),
53.8 (CH2C=N), 61.3 (CH2Me), 156.5 (C=N), 163.4 (CO).
Table 1 Product yields in the test reactions.
Yield of 4
Yield of
2 + 2' (%)
(%) on a
BENA
basis
BENA R1
R2
2:2'
The distillate was dissolved in methanol (5 ml) with an additive of
Et3N (0.1 ml), the mixture was allowed to stand for 6 h at 20 °C and then
evaporated at 50 °C/20 Torr. Oily crystals were obtained.
1a
1b
1c
1d
1e
1f
H
Me
H
H
H
Me
H
H
49
79
70
61
72
42
62a
2.2:1
1:1.2
3:4
49
79
70
61
72
36
54
Ethyl 5-amino-3-isoxazolcarboxylate 4f: (36%, 0.28 g), mp 96–98 °C
CH2CH2CO2Me
Ph
CO2Et
3:1
1
3
(from CCl4). H NMR, (C2D5OD) d: 1.40 (t, 3H, Me, J 7.4 Hz), 4.37
(q, 2H, CH2, 3J 7.4 Hz), 5.23 (s, 2H, NH2), 5.41 (s, 1H, CH). 13C NMR,
d: 15.2 (Me), 63.1 (CH2), 79.8 (CH), 158.5 (CN), 162.3 (CO), 174.0
(CNH2). Found (%): C, 45.91; H, 5.07; N, 17.68. Calc. for C6H8N2O3
(%): C, 46.15; H, 5.16; N, 17.94.
only 2e
only 2f
obly 2g
H
Me
1g
CO2Me
aWith respect to an internal standard.
– 100 –

Mendeleev Commun., 2002, 12(3), 99–102
This work was supported by the Russian Foundation for Basic
Research (grant no. 99-03-32015) and the ‘Integratsiya’ Special
Federal Programme (project no. A0082).
N(OSiMe3)2
CH2Cl2/Et3N (cat.)
+ Me3SiCN
20–30 °C
CO2Et
We are grateful to ChemBridge Corporation for providing us
with chemicals for this study.
1f
Me3SiO
N
NOSiMe3
References
NC
Me3SiO
1
A. D. Dilman, A. A. Tishkov, I. M. Lyapkalo, S. L. Ioffe, Yu. A. Strelenko
and V. A. Tartakovsky, Synthesis, 1998, 181.
A. D. Dilman, A. A. Tishkov, I. M. Lyapkalo, S. L. Ioffe, V. V. Kachala,
Yu. A. Strelenko and V. A. Tartakovsky, J. Chem. Soc., Perkin Trans. 1,
2000, 2926.
CO2Et
CO2Et
2f
5 (15%)
2
MeOH
3
4
V. A. Tartakovsky, S. L. Ioffe, A. D. Dilman and A. A. Tishkov, Izv.
Akad. Nauk, Ser. Khim., 2001, 1850 (Russ. Chem. Bull., Int Ed., 2001,
50, 1936).
A. D. Dilman, I. M. Lyapkalo, S. L. Ioffe, Yu. A. Strelenko and V. A.
Tartakovsky, Synthesis, 1999, 1767.
J. K. Rasmussen and S. M. Heilmann, Synthesis, 1979, 523.
A. D. Dilman, A. A. Tishkov, I. M. Lyapkalo, S. L. Ioffe, Yu. A. Strelenko
and V. A. Tartakovsky, Izv. Akad. Nauk, Ser. Khim., 2000, 876 (Russ.
Chem. Bull., Int. Ed., 2000, 49, 874).
J. A. Seckar and J. S. Thayer, Inorg. Chem., 1976, 15, 501.
M. Dines and M. L. Scheinbaum, Tetrahedron Lett., 1969, 54, 4817.
A. Quilico, Gazz. Chim. Ital., 1931, 61, 759.
EtO2C
N
NH2
Scheme 4
O
5
6
4f
1,5-O,O migration of the Me3Si group to the oxygen atom of the
CO2Me unit, the subsequent elimination of Me3SiCN, the 1,5-CO
proton shift14 in resulting intermediate A' and, finally, the sily-
lation of enoxime 7 with the use of Me3SiCN/Et3N. The direct
elimination of HCN from oxime 2g seems to be less probable,
although it cannot be completely excluded (Scheme 5).
7
8
9
10 P. S. Burns, J. Prakt. Chem. [2], 1893, 47, 105.
11 K. Matsumura, T. Saraie, V. Kawano, N. Hashimoto and K. Morita, J.
Takeda Res. Lab., 1971, 30, 486.
12 L. Almirante, A. Biance and V. Zambni, Ann. Chim. (Rome), 1956, 46,
623.
13 H. Feger and G. Simchen, Liebigs Ann. Chem., 1986, 428.
14 I. M. Lyapkalo and S. L. Ioffe, Usp. Khim., 1998, 67, 523 (Russ. Chem.
Rev., 1998, 67, 467).
MeO
NC
O
N
O
OMe
NO
SiMe3
O
Me3Si
NC
15 L. M. Makarenkova, I. V. Bliznets, S. L. Ioffe, Yu. A. Strelenko and
V. A. Tartakovsky, Izv. Akad. Nauk, Ser. Khim., 2000, 1265 (Russ.
Chem. Bull., Int. Ed., 2000, 49, 1261).
16 M. Hesse, H. Meier and B. Zeeh, Spektroskopische Methoden in der
Organischen Chemie, Georg Thieme Verlag, Stuttgart, 1995, p. 200.
2g
– Me3SiCN
Et3N – HCN
OSiMe
OH
O
3
N
N
N
Me3SiCN/NEt3
‡‡ BENA 1g (5 mmol, 1.46 g) was added to a mixture of TMSCN
(5 mmol, 0.67 ml) and Et3N (0.5 mmol, 0.07 ml) for 10 min with intense
stirring (the mixture warmed up in the course of adding BENA; however,
the temperature was kept within a range of 30–40 °C). E-Methyl 2-(tri-
methylsilyloximino)-3-cyanobutyrate 2g was detected by NMR spectro-
scopy (62% yield). 1H NMR, d: 0.31 (s, 9H, SiMe3), 1.53 (d, 3H, CHMe,
3J 7.4 Hz), 3.86 (s, 3H, OMe), 4.40 (q, 1H, CHMe, 3J 7.4 Hz). 13C NMR,
d: –0.9 (SiMe3), 15.5 (Me), 22.1 (CH), 52.9 (OMe), 118.3 (CN), 150.2
(C=N), 162.2 (CO). After 10 min, methanol (5 ml) was added, and the
mixture was allowed to stand for 6 h. Volatile components were distilled
at 50 °C/20 Torr, and oily crystals were obtained.
– HCN
CO2Me
CO2Me
CO2Me
6
7
A'
Scheme 5
Because of this, the general procedure used for the synthesis
of isoxazoles 4a–e was modified for preparing isoxazole 4g.‡‡
The structures of compounds were supported by elemental
analysis and NMR spectroscopy. The configuration of the oxy-
imino group in products 2a–d, 2'a–d, 3'c, 6 and 7 was deter-
mined based on previously published rules,2,15 as illustrated in
Figure 1.
Methyl 5-amino-4-methyl-3-isoxazolcarboxylate 4g: yield 54%, 0.42 g;
1
mp 112–114 °C (from CCl4). H NMR, d: 1.92 (s, 3H, CMe), 3.76 (s,
3H, OMe), 5.26 (br. s, 2H, NH2). 13C NMR, d: 6.2 (CMe), 52.7 (OMe),
89.2 (CMe), 156.2 (C=N), 162.6 (CO), 169.3 (CNH2).
The configuration of the oxyimino group in products 2e–g,
which have only one stereoisomer, was found by comparing the
chemical shifts of their characteristic fragments with the chemi-
cal shifts16 of analogous fragments in isomers 2a–d (Figure 1).
BSENA 1g (2 mmol, 0.58 g) was added to a solution of TMSCN
(2 mmol, 0.27 ml) and NEt3 (0.5 mmol, 0.07 ml) in 3 ml of CH2Cl2 at
20 °C. The mixture was allowed to stand for 24 h and then distilled at
51 °C/0.9 Torr. The yield of enoxime 6 was 47% (0.19 g). Compound 6 is
very unstable, and it completely decomposed at 20 °C in 1 h. Therefore,
methanol (2 ml) was immediately added to the distillate, and the solution
was chromatographed on silica gel (eluent: ethyl acetate–light petroleum,
1:1). Rf 0.68 (Z-isomer) or 0.44 (E-isomer). Compound 7: Z: 13%
(0.034 g), E: 28% (0.072 g).
HO
OH
HO
OH
N
C
N
C
N
C
N
C
'
Cα
Cα
H
H'
Methyl 2-(trimethylsilyloximino)but-3-enoate (6 + 6'; E/Z = 7:4): E:
d 13Cα < d 13Cα
d 1H > d 1H'
1H NMR, d: 0.25 (s, 9H, SiMe3), 3.84 (s, 3H, OMe), 5.67 (dd, 1H, CH2,
'
2
3
2
3J 11.7 Hz, J 2.1 Hz), 6.13 (dd, 1H, CH2, J 17.7 Hz, J 2.1 Hz), 6.94
(dd, 1H, CH, J 17.7 Hz, J 11.7 Hz); 13C NMR, d: –0.8 (SiMe3), 52.3
(OMe), 122.6 (CH2), 128.8 (CH), 152.4 (C=N), 163.4 (CO). Z: 1H NMR,
d: 0.25 (s, 9H, SiMe3), 3.88 (s, 3H, OMe), 5.43 (d, 1H, CH2, 3J 17.7 Hz),
5.58 (d, 1H, CH2, 3J 11.2 Hz), 6.46 (dd, 1H, CH, 3J 17.7 Hz, 3J 11.2 Hz);
13C NMR, d: –0.9 (SiMe3), 52.3 (OMe), 122.3 (CH2), 125.4 (CH), 152.4
(C=N), 163.4 (CO).
3
3
HO
OH
N
C
N
H
H'
C
C
C
Methyl 2-oximinobut-3-enoate (7, 7'): E: 1H NMR, d: 3.84 (s, 3H,
d 1
d 1
H >
H
'
3
2
OMe), 5.78 (dd, 1H, CH2, J 11.8 Hz, J 2.0 Hz), 6.38 (dd, 1H, CH2,
2
3
3
3J 17.7 Hz, J 2.0 Hz), 6.82 (dd, 1H, CH, J 17.7 Hz, J 11.5 Hz), 10.1
Figure 1
(br. s, 1H, OH); 13C NMR, d: 52.6 (OMe), 121.8 (CH2), 127.2 (CH),
Thus, we proposed a convenient method for the synthesis of
5-aminoisoxazoles 4, which may exhibit biological activity,17
using the simplest aliphatic compounds as starting substrates.
1
146.5 (C=N), 163.1 (CO). Z: H NMR, d: 3.91 (s, 3H, OMe) 5.54 (d,
1H, CH2, 3J 17.7 Hz), 5.63 (d, 1H, CH2, 3J 11.2 Hz), 6.46 (dd, 1H, CH,
3
3J 17.7 Hz, J 11.2 Hz), 9.1 (br. s, 1H, OH); 13C NMR, d: 52.4 (OMe),
122.6 (CH2), 128.3 (CH), 152.0 (C=N), 163.1 (CO).
– 101 –

Mendeleev Commun., 2002, 12(3), 99–102
17 P. D. Stein, D. M. Floyd, S. Bisaha, J. Dickey, R. N. Girotra, J. Z.
Gougoutas, M. Kozlowski, V. G. Lee, E. C.-K. Liu, M. F. Malley,
D. McMullen, C. Mitchell, S. Moreland, N. Murugesan, R. Serafino,
M. L. Webb, R. Zhang and J. T. Hunt, J. Med. Chem., 1995, 38, 1344.
Received: 26th March 2002; Com. 02/1911
– 102 –