Synthesis of 5-aminoisoxazoles from 3-trimethylsilylprop-2-ynamides

Article abstract of DOI:10.1016/j.mencom.2017.03.023

Reaction between N,N-disubstituted 3-trimethylsilylprop-2-ynamides and ammonium azide under mild conditions affords hitherto unknown 5-aminoisoxazole derivatives in good yields.

Full text of DOI:10.1016/j.mencom.2017.03.023

Mendeleev
Communications
Mendeleev Commun., 2017, 27, 175–177
Synthesis of 5-aminoisoxazoles from 3-trimethylsilylprop-2-ynamides
Mikhail V. Andreev, Alevtina S. Medvedeva,* Lyudmila I. Larina and Maria M. Demina
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
664033 Irkutsk, Russian Federation. Fax: +7 3952 419 346; e-mail: amedved@irioch.irk.ru
DOI: 10.1016/j.mencom.2017.03.023
i, K2CO3
O
ii, NH4N3
Reaction between N,N-disubstituted 3-trimethylsilylprop-
Me3Si
N
NR1R2
NR1R2
2-ynamides and ammonium azide under mild conditions
affords hitherto unknown 5-aminoisoxazole derivatives in
good yields.
O
NR1R2 = NMe2, NEt2, N
N
O
,
Isoxazoles are bioactive natural products, which are extensively
used in pharmaceutical industry1 and are employed as versatile
building blocks in the synthesis of new biologically potent mole-
cules.2 New strategy for the design of hybrid molecular systems
which combine several pharmacophores, including 1,2-isoxazole
fragment, on the same scaffold, is a well-established pharmaco-
logy-oriented approach to the synthesis of new drugs.3 5-Amino-
isoxazoles exhibiting various biological activities4 generate great
interest. N-Unsubstituted 5-aminoisoxazoles are precursors for
the synthesis of 3-, 4- and N-functionalized derivatives and
isoxazole fused heterocycles.5
The common routes for the preparation of 5-N-unsubstituted
aminoisoxazoles involve the addition of hydroxylamine to func-
tionalized nitriles,4(c),5(b),6 cyanation of N,N-bis(siloxy)enamines
with Me3SiCN.7 N,N-Dialkyl-5-aminoisoxazoles were obtained
by 1,3-dipolar cycloaddition of nitrile oxides to 2-(dialkylamino)-
acrylonitriles8 or substituted ynamines.9
1H-1,2,3-triazoles via the three-component b-catalyzed reaction
of the propynals, trimethylsilyl azide and malononitrile at room
temperature.13 However, the attempt to accomplish 1,3-dipolar
cycloaddition of trimethylsilyl azide to 3-trimethylsilylprop-
2-ynoic acid morpholide 1a under analogous conditions failed.
Instead, only the starting amide 1a was recovered from the
reaction mixture.
The reaction between terminal propynamide 2a, generated
in situ by desilylation of compound 1a with K2CO3 (10 mol%),
and trimethylsilyl azide in water at room temperature for 16 h
unexpectedly afforded a mixture of (Z)-enazide 4a, (E)-enazide 3a,
5-aminoisoxazole 5a along with 2a in a molar ratio of 53:2:4:41,
respectively (1H NMR monitoring) (Scheme 1, Table 1).† The
variation of the starting azide nature, time, temperature and a
ratio of reactants on the model reaction of amide 1a allowed us
to optimize conditions for the synthesis of desired isoxazole 5a
in 70% isolated yield (Table 1, entry 6).
The present paper describes a novel metal-free synthesis of
hitherto unknown 3,4-unsubstituted 5-N,N-dialkylaminoisoxazoles
from available 3-trimethylsilylprop-2-ynamides10 and ammonium
azide.
Recently, we have shown the efficacy of water as a solvent
for efficient metal-free synthesis of 1,2,3-triazolecarbaldehydes
from propynals and trimethylsilyl or benzyl azide11 as compared to
thermal Huisgen processes,12 and in preparation of 5-R-4-alkenyl-
The use of 5-fold excess of more available ammonium azide,
generation of the intermediate (Z)-enazides 4a–d at room tem-
†
The 1H, 13C and 15N NMR spectra were recorded at room temperature
on Bruker DPX-400 and Bruker AV-400 spectrometers (400.13, 100.61
and 40.56 MHz, respectively) in CDCl3 solution with accuracy of 0.01,
0.02 and 0.1 ppm, respectively, and referred to TMS (1H, 13C) and nitro-
methane (15N). The values of the d were obtained through the 2D
15N
1H–15N HMBC experiment. IR spectra were measured on a Bruker IFS-25
spectrometer. Elemental analyses were carried out on a Flash EA 1112
Series CHNS-O analyzer. Melting points were determined on a Kofler
apparatus and were not corrected. The completion of the reaction was
monitored by 1H NMR. Column chromatography was performed on
silica gel [Alfa Aesar, 0.06–0.20 mm (70–230 mesh)] with chloroform–
methanol (100:2) as an eluent.
Me3Si
CONR1R2
O
Me3SiN3
H2O
Me3Si
N
NH
NR1R2
N
+
1a–d
i
– (Me3Si)2O
Reaction between 1a and Me3SiN3. A mixture of N-[3-(trimethylsilyl)-
2-propynoyl]morpholine 1a (100 mg, 0.47 mmol) and K2CO3 (6 mg,
10 mol%) in H2O (1.5 ml) was stirred for 1.5 h at room temperature and
trimethylsilyl azide (60 mg, 0.52 mmol) was added. The mixture was
stirred at room temperature and small aliquots (0.5 ml) from the reaction
NR1R2
N3
NR1R2
O
ii
H
N3
O
4a–d
O
3a–d
NR1R2
2a–d
mixture were extracted with CDCl3 (2×0.7 ml) after 16 or 40 h and analyze
d
55–60 °C – N2
by 1H NMR spectroscopy. After 40 h along with N-(prop-2-ynoyl)-
morpholine 2a,19 azidovinyl amides 3a, 4a and target aminoisoxazole 5a
were detected in a molar ratio of 9:4:65:22, respectively. According
3' 2'
c NR1R2 = NEt2
a NR1R2 = N 4' 1' O
N
NR1R2
5a–d
64–76%
5' 6'
O
2' 3'
4'
6' 5'
1
to H NMR data, azido alkanes 3a and 4a are stereoisomers (4:65).
b NR1R2 = NMe2
1
2
N 1'
d NR R =
1H NMR, d: 3.47 (br.m, 2H, NCH2), 3.65 (br.m, 6H, NCH2, OCH2), 5.38
(d, 1H, =CHCO, 3J 8.6 Hz, Z-isomer), 5.99 (d, 1H, =CHCO, 3J 12.7 Hz,
E-isomer), 6.46 (d, 1H, N3CH=, 3J 8.6 Hz, Z-isomer), 7.36 (d, 1H,
N3CH=, 3J 12.7 Hz, E-isomer).
Scheme 1 Reagents and conditions: i, K2CO3 (10 mol%), H2O, room tem-
perature; ii, NH4N3 or Me3SiN3, H2O, room temperature.
© 2017 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 175 –

Mendeleev Commun., 2017, 27, 175–177
Table 1 Optimization of the synthesis of 4-(5-isoxazolyl)morpholine 5a
from 1a.
A plausible mechanism for the conversion of (Z)-vinylazides,
bearing a conjugative amide group, involves generation of highly
strained three-membered 2H-azirines via the loss of dinitrogen,
cleavage of the C–N bond, formation of intermediate vinyl
nitrenes and intramolecular cyclization into 5-aminoisoxazoles
with participation of the amide carbonyl moiety (Scheme 2).
Product ratio (1H NMR) Isolated
yield of
Azide
(equiv.)
Reaction
conditions
Entry
2a
3a
4a
5a
5a (%)
1
2
3
4
5
6a
Me3SiN3 (1) 25°C, 16 h
Me3SiN3 (1) 25°C, 40 h
41
9
11
1
–
–
2
4
1
4
1
2
53
65
76
64
96
–
4
22
12
31
3
–
–
–
–
–
70b
NR1R2
NR1R2
NR1R2
NH4N3 (1)
NH4N3 (1)
NH4N3 (5)
NH4N3 (5)
25°C, 16 h
25°C, 40 h
25°C, 4 h
N
O
– N2
N
N3
O
O
N
O
N
25°C, 4 h;
98
NR1R2
then 55°C, 2 h
MW, 80°C,
80 min
7
NH4N3 (1)
–
4
–
96
49c
N
NR1R2
N
O
a Extraction with CH2Cl2, removal of the solvent followed by heating of the
residue at 55–60°C for 2 h. bVacuum distillation. c Column chromatography.
Scheme 2
perature in water followed by extraction with CH2Cl2, and final
heating at 55–60°C provided the selective multigram synthesis
of 5-aminoisoxazoles 5a–d in good yields (64–76%) after vacuum
distillation.‡
The intermediate 2H-azirines were never detected by us in the
reaction mixture. The formation of 2H-azirines under thermolysis
of b-aldehyde, ketone, or ester-substituted vinyl azides to afford
isoxazoles is known.14 However, the conversion of carboxamide
vinyl azides into the corresponding 5-aminoisoxazoles has not
been reported until now. It is pertinent to note that the 1H NMR
monitoring confirms the dominant formation of the Z-isomer of
intermediate b-azido enamides 4a–d. The content of the minor
E-isomer 3a–d in the reaction mixture does not exceed 5%.
Note that tandem transformation of trimethylsilylpropynamides
into 3-aminoprop-2-enamides by the action of primary amines in
MeOH gave also the corresponding Z-isomers as major products.15
The reactivity of azide ion in conjugate addition to the triple
bond of in situ generated propynamides 2a–d to form the inter-
mediate azido alkenes substantially depends on the nature of
amide moiety. The 1H NMR monitoring evidences that duration of
the key intermediate Z-isomer formation varies from 4 to 40 h in
the series: N(CH2CH2)2O (a) < NMe2 (b) < N(CH2CH2)2CH2 (d) <
< NEt2 (c) in accordance with the increase of electron-donating
properties of amines.16
Microwave (MW) irradiation can also be successfully employe
d
to prepare 4-(5-isoxazolyl)morpholine 5a from in situ generated
propynamide 2a in water. The MW-assisted reaction with ammo-
nium azide in equimolar ratio (80°C, 80 min) gave the target
isoxazole 5a in 49% isolated yield (see Table 1, entry 7).§
‡
3-Trimethylsilylprop-2-ynamides 1a–d were prepared by published
procedure.12
Compounds 5a–d (general procedure). A mixture of 3-trimetylsilylprop-
2-ynamide 1 (19 mmol) and K2CO3 (240 mg, 10 mol%) in H2O (20 ml)
was stirred for 1.5 h at room temperature, and then solution of NaN3
(6.2 g, 95 mmol) and NH4Cl (5.1 g, 95 mmol) in H2O (40 ml) was added.
The mixture was stirred for 4–40 h at room temperature and extracted
with CH2Cl2 (2×40 ml). The extract was dried over Na2SO4, and the
solvent was removed by distillation at atmospheric pressure using water
bath at 65–70°C followed by heating of the residue at this temperature
until the nitrogen bubbles evolution stopped (ca. 2 h). The oil residue was
distilled in vacuo.
Target compounds 5a–d are well soluble in water and polar
1
organic solvents. Their structure was confirmed by IR and H,
4-(5-Isoxazolyl)morpholine 5a was prepared for 6 h in 70% yield
(2.05 g), white solid, mp 30–31°C, bp 111–114°C (4 mbar). 1H NMR, d:
3.25 (t, 4H, H-3', H-5', 3J 4.9 Hz), 3.72 (t, 4H, H-2', H-6', 3J 4.9 Hz), 4.95
(d, 1H, H-4, 3J 1.9 Hz), 7.93 (d, 1H, H-3, 3J 1.9 Hz). 13C NMR, d: 46.58
(C-3', C-5', 1JCH 138.5 Hz), 65.72 (C-2', C-6', 1JCH 144.1 Hz), 77.68 (C-4,
1JCH 182.1 Hz, 2JCH 9.2 Hz), 151.71 (C-3, 1JCH 182.1 Hz, 2JCH 5.2 Hz),
170.52 (C-5). 15N NMR, d: –313.9 (NCH2), –20.0 (N-2, 2JNH 15.7 Hz).
IR (KBr, n/cm–1): 727, 898, 911, 993, 1072, 1118, 1246, 1269, 1328, 1461,
1504, 1598, 1662, 2858, 2969, 3084, 3110, 3145. Found (%): C, 54.54;
H, 6.52; N, 18.50. Calc. for C7H10N2O2 (%): C, 54.54; H, 6.54; N, 18.17.
N,N-Dimethyl-5-isoxazolamine 5b was prepared for 16 h in 76% yield
(1.62 g), viscous white liquid, bp 86–89°C (17 mbar), n2D0 = 1.4960.
1H NMR, d: 2.89 (s, 6H, Me), 4.77 (d, 1H, H-4, 3J 2.0 Hz), 7.86 (d, 1H,
13C NMR technique and elemental analyses. Their 2D 15N NMR
HMBC {1H–15N} (CDCl3) spectra contain cross-peaks of N-2
atom with H-3 and H-4 protons of the isoxazole cycle at –20.0 to
–26.6 ppm and cross-peaks of the amino group nitrogen with
protons of neighboring N,N-dialkyl substituents at –300.8 to
–329.2 ppm.
1-(5-Isoxazolyl)piperidine 5d was prepared for 30 h in 64% yield
(1.85 g), white solid, mp 28–29°C, bp 101–102°C (4 mbar). 1H NMR, d:
1.59–1.69 (m, 6H, H-3', H-4', H-5'), 3.28 (t, 4H, H-2', H-6', 3J 5.6 Hz),
4.93 (d, 1H, H-4, 3J 2.0 Hz), 7.98 (d, 1H, H-3, 3J 2.0 Hz). 13C NMR, d:
23.81 (C-4', 1JCH 128.6 Hz, 2JCH 4.9 Hz), 24.81 (C-3', C-5', 1JCH 128.6 Hz,
2JCH 3.4 Hz), 47.71 (C-2', C-6', 1JCH 136.8 Hz, 2JCH 2.8 Hz), 76.78 (C-4,
1JCH 181.3 Hz, 2JCH 9.4 Hz), 151.91 (C-3, 1JCH 181.3 Hz, 2JCH 5.4 Hz),
170.89 (C-5). 15N NMR, d: –306.8 (NCH2), –25.3 (N-2, 2JNH 15.2 Hz).
IR (KBr, n/cm–1): 717, 759, 892, 909, 985, 1029, 1064, 1136, 1193, 1225,
1255, 1327, 1355, 1389, 1452, 1505, 1598, 2855, 2939, 3081, 3102,
3137. Found (%): C, 63.28; H, 7.90; N, 18.13. Calc. for C8H12N2O (%):
C, 63.13; H, 7.95; N, 18.41.
3
1
3
H-3, J 2.0 Hz). 13C NMR, d: 38.46 (Me, JCH 137.7 Hz, JCH 3.6 Hz),
1
2
1
75.82 (C-4, JCH 180.9 Hz, JCH 9.5 Hz), 151.86 (C-3, JCH 180.9 Hz,
2JCH 5.3 Hz), 170.73 (C-5). 15N NMR, d: –329.2 (NMe), –24.1 (N-2,
2JNH 14.3 Hz). IR (microlayer, n/cm–1): 707, 916, 1001, 1052, 1143, 1240,
1360, 1430, 1519, 1619, 2811, 2923, 3097, 3150. Found (%): C, 53.37;
H, 6.91; N, 24.77. Calc. for C5H8N2O (%): C, 53.56; H, 7.19; N, 24.98.
N,N-Diethyl-5-isoxazolamine 5c was prepared for 42 h in 71% yield
(1.89 g), viscous white liquid, bp 78–79°C (3 mbar), nD20 = 1.4903.
1H NMR, d: 1.19 (t, 6H, Me, 3J 7.2 Hz), 3.35 (q, 4H, CH2, 3J 7.2 Hz),
4.80 (d, 1H, H-4, 3J 2.0 Hz), 7.94 (d, 1H, H-3, 3J 2.0 Hz). 13C NMR, d:
§
MW-assisted synthesis of 5a. A mixture of 1a (400 mg, 1.88 mmol) and
K2CO3 (24 mg, 10 mol%) in H2O (2.0 ml) was stirred in a sealed 10 ml
Pyrex vial at room temperature for 1 h, then solution of NaN3 (124 mg,
1.88 mmol) and NH4Cl (100 mg, 1.88 mmol) in H2O (4.0 ml) was added.
The vial was placed in the cavity of an Anton Paar Monowave 300 reactor
and irradiated for 80 min at 80°C. After cooling to room temperature, the
mixture was extracted with CH2Cl2 (2×4 ml) and the extract was dried over
Na2SO4. The solvent was evaporated in vacuo, and column chromato-
graphy of the residue afforded the target compound 5a, white solid,
mp 30–31°C, yield 142 mg (49%).
1
1
2
13.10 (Me, JCH 127.2 Hz), 43.95 (CH2, JCH 136.7 Hz, JCH 4.1 Hz),
1
2
1
75.11 (C-4, JCH 181.3 Hz, JCH 9.6 Hz), 152.10 (C-3, JCH 181.3 Hz,
2JCH 5.5 Hz), 169.62 (C-5). 15N NMR, d: –300.8 (NEt), –26.6 (N-2,
2JNH 15.3 Hz). IR (microlayer, n/cm–1): 704, 786, 910, 1027, 1054, 1080,
1097, 1181, 1217, 1273, 1362, 1380, 1450, 1518, 1603, 2876, 2936,
2976, 3092, 3149. Found (%): C, 60.13; H, 8.82; N, 20.00. Calc. for
C7H12N2O (%): C, 59.98; H, 8.63; N, 19.98.
– 176 –

Mendeleev Commun., 2017, 27, 175–177
5 (a) W. S. Hamama, M. E. Ibrahim and H. H. Zoorob, Synth. Commun.,
We have recently elaborated an efficient one-pot synthesis of
3-trimethylsilylprop-2-ynamides from accessible and environ-
mentally benign trimethylsilylpropynoic acid.10 It should be
noted that application of 3-trimethylsilylprop-2-ynamides as the
starting substrates in the synthesis of the target 5-aminoisoxazoles
is more advantageous as compared to terminal propynamides.
Known methods for the preparation of terminal propynamides17
are based on the use of highly toxic, flammable (inflammation
temperature 58°C) and skin-irritating propynoic acid.18 Highly
efficient procedure for the synthesis of terminal propynamides
from trimethylsilylated analogues catalyzed by KF–Al2O3 has
been reported earlier.19
2013, 43, 2393; (b) A. Davoodnia, M. Bakavoli, N. Pooryaghoobi and
M. Roshani, Heterocycl. Commun., 2007, 13, 323; (c) G. J.Yu, B.Yang,
A. S. Verkman and M. J. Kurth, Synlett, 2010, 1063; (d) S. B. Alyabiev,
D. V. Kravchenko and A. V. Ivachtchenko, Mendeleev Commun., 2008,
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Sen’ko, T. J. J. Müller, E. V. Vashchenko and V. A. Chebanov, Arkivoc,
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6 (a) L. Johnson, J. Powers, F. Ma, K. Jendza, B. Wang, E. Meredith
and N. Mainolfi, Synthesis, 2013, 45, 171; (b) J. Khalafy, K. Akbari
Dilmaghani, L. Soltani and A. Poursattar-Marjani, Chem. Heterocycl.
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Sobenina, V. N. Drichkov, A. I. Mikhaleva, O. V. Petrova, I. A. Ushakov
and B. A. Trofimov, Tetrahedron, 2005, 61, 4841.
In summary, we have implemented a novel facile metal-free
selective synthesis of so far unknown N,N-substituted 5-amino-
isoxazoles using available amides of 3-(trimethylsilyl)propynoic
acid and ammonium azide under mild conditions. It has been
shown for the first time that successive conversion of generated
in water (Z)-azidovinylamides as key intermediates into 5-amino-
isoxazoles occurs with the involvement of the CO moiety of
the amide group. New 3,4-unsubstituted 5-N,N-dialkylisoxazol-
amines are potential biologically active substances, polydentate
7 A
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Mendeleev Commun., 2002, 99.
,
8 A. Saad, M. Vaultier and A. Derdour, Molecules, 2004, 9, 527.
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10 A. S. Medvedeva, M. V. Andreev and L. P. Safronova, Russ. J. Org.
Chem., 2010, 46, 1466 (Zh. Org. Khim., 2010, 46, 1463).
11 (a) M. M. Demina, T. L. H. Nguyen, N. S. Shaglaeva, A. V. Mareev and
A. S. Medvedeva, Russ. J. Org. Chem., 2012, 48, 1582 (Zh. Org. Khim.,
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T. D. Vu, D. A. Bulanov and V. V. Novokshonov, Russ. J. Org. Chem.,
2013, 49, 1221 (Zh. Org. Khim., 2013, 49, 1236).
12 M. M. Demina, P. S. Novopashin, G. I. Sarapulova, L. I. Larina, A. S.
Smolin, V. S. Fundamenskii, A. A. Kashaev and A. S. Medvedeva, Russ.
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13 A. S. Medvedeva, M. M. Demina, T. D.Vu, M.V.Andreev, N. S. Shaglaeva
and L. I. Larina, Mendeleev Commun., 2016, 26, 326.
14 (a) T. M. V. D. Pinho e Melo, C. S. J. Lopes, A. M. d’A. Rocha Gonsalves
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15 M. V. Andreev, A. S. Medvedeva and L. P. Safronova, Russ. J. Org. Chem.,
2013, 49, 822 (Zh. Org. Khim., 2013, 49, 839).
ligands, and reagents for synthesis of new heterocyclic compounds
.
An alternative approach to the synthesis of these 5-amino-
isoxazoles via the cycloaddition of nitrile oxides to terminal
ynamines9,20 is difficult to implement because of instability of
unsubstituted nitrile oxide (fulminic acid)21 and less accessibility
of ynamines22 in comparison with trimethylsilylpropynamides.
The main results were obtained using the equipment of Baikal
Analytical Center of Collective Use SB RAS.
16 Tablitsy konstant skorostei i ravnovesiya geteroliticheskikh organiche-
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