A reliable synthesis of 3-amino-5-alkyl and 5-amino-3-alkyl isoxazoles

Article abstract of DOI:10.1055/s-0032-1317935

A reliable procedure that can be used to access a wide range of 3-amino-5-alkyl and 5-amino-3-alkyl isoxazoles was developed. Reaction temperature and pH were key factors that determined the regioselectivity of the two reactions.

Full text of DOI:10.1055/s-0032-1317935

SHORT PAPER
▌171
sAhorRt paepelriable Synthesis of 3-Amino-5-Alkyl and 5-Amino-3-Alkyl Isoxazoles
Synthesis of Substituted Isoxazoles
Leland Johnson, James Powers, Fupeng Ma, Keith Jendza, Bing Wang, Erik Meredith, Nello Mainolfi*
Novartis Institutes for Biomedical Research, Global Discovery Chemistry, 100 Technology Square, Cambridge, MA 02139, USA
Fax +1(617)8717044; E-mail: nello.mainolfi@novartis.com
Received: 24.10.2012; Accepted after revision: 29.11.2012
mation) allowed their regiochemistry to be unequivocally
assigned.
Abstract: A reliable procedure that can be used to access a wide
range of 3-amino-5-alkyl and 5-amino-3-alkyl isoxazoles was de-
veloped. Reaction temperature and pH were key factors that deter-
mined the regioselectivity of the two reactions.
Selected examples (Table 1) highlight the generality of
these methods to access 3- or 5-alkyl amino isoxazoles. It
Key words: heterocycles, regioselectivity, condensation, medici- is worth noting that even enolizable ketones (entries 1–3
nal chemistry, imines
and 6), especially those that are less hindered (entry 6),
provide good yields of both 5-amino and 3-amino isoxa-
zoles. Electron-withdrawing groups (entry 5) do not seem
to have an effect on either the condensation or cyclization
reactions.
5-Amino- and 3-amino-isoxazoles are key building
blocks in many naturally occurring molecules and phar-
maceutically active synthetic compounds.1 They have
2
O
been prepared by different methods; however, most of
O
N
a, 85%
the known preparations are not very reliable, efficient, or
general. A typical problem with synthesizing such amino-
heterocycles is the poor yield and selectivity between for-
mation of 3-amino and 5-amino-isoxazoles. Such amino
isoxazoles became essential building blocks in our medic-
inal chemistry program, therefore, we decided to develop
an efficient, scalable, and predictable methodology with
which to access either the 3-amino or the 5-amino isomer.
A typical readily accessible starting material is ketonitrile
2, which can be obtained from condensation of commer-
cially available cyclobutyl-acetic acid methyl ester 1 and
lithiated acetonitrile (Scheme 1)3 or is available from
commercial sources.4 We explored several reaction condi-
tions involving 2 and hydroxylamine and found that for-
mation of 5-amino isoxazoles was the preferred pathway
regardless of the number of equivalents of hydroxyl-
amine, the base, or the temperature used. Upon careful
monitoring of the reaction,2f we discovered that it was
governed by the pH obtained following mixing the hy-
droxylamine salts, the chosen base, and the temperature.
In fact, these parameters were responsible for directing
the addition of the hydroxylamine either towards the ke-
tone (pH > 8, giving 5-amino-isoxazole; 3a, Scheme 1) or
the nitrile (7 < pH < 8, giving 3-amino-isoxazole; 4a,
Scheme 1), hence, generating the two possible isomers
upon acid-mediated cyclization.2f Towards the synthesis
of the 3-amino isomer, we also found that keeping the
temperature at or below 45 °C (Scheme 1, d), was critical
to allow keto-nitriles bearing a less bulky group to still un-
dergo addition of hydroxylamine to the nitrile, leading to
the desired isomer.5 1D and 2D NMR studies of deriva-
tives of each isoxazole isomer (see the Supporting Infor-
OMe
2
1
N
O
N
H2N OH
2
2
b
H2N
H2N
3
85%
O
H2N OH
c
4
75%
pH controlled addition of hydroxylamine to ketonitrile
OH
O
O
N
N
H+
H2N OH
4
NH2
7 < pH < 8
45 °C
2
4a
–OH
pH > 8
100 °C
H2N OH
HO
N
N
3
+ H2O
3a
Scheme 1 Exploring regioselectivity. Reagents and conditions: (a)
LDA, MeCN, THF, –78 °C to r.t., 2 h; (b) NaOH (pH > 8), H2O,
100 °C, 1.5 h then HCl, 100 °C, 15 min; (c) NaOH (7 < pH < 8), H2O,
45 °C, 72 h, then HCl, 50 °C, 2.5 h.
In conclusion, a general and reliable method that can be
used to access both 3-amino-5-alkyl and 5-amino-3-alkyl-
isoxazole isomers is reported. It is anticipated that this
method will allow greater access to more complex varia-
SYNTHESIS 2013, 45, 0171–0173
Advanced online publication: 19.12.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317935; Art ID: SS-2012-M0836-OP
© Georg Thieme Verlag Stuttgart · New York

172
L. Johnson et al.
SHORT PAPER
Table 1 Substrate Scope for the Selective Formation of 3-Amino and 5-Amino Isoxazoles
N
O
O
O
N
(NH2-OH)2H2SO4 (1.1 equiv)
N
R
(NH2-OH)2H2SO4 (1.1 equiv)
R
R
NaOH (>1.25 equiv until pH > 8),
100 °C, 1.5 h
then HCl (1 equiv), 100 °C, 15 min
H2N
NaOH (1.25 equiv), 45 °C, 72 h
7 < pH < 8,
then HCl (1.6 equiv), 50 °C, 2.5 h
H2N
Entry
1
5-Amino yield (%)
R
3-Amino yield (%)
N
O
O
N
H2N
H2N
15
16
2
5 (70)
6 (60)
N
O
O
N
2
H2N
H2N
7 (70)
8 (65)
N
O
O
N
3
H2N
H2N
3 (85)
4 (75)
N
O
O
N
4
H2N
H2N
17
9 (85)
10 (60)
N
O
N
O
5a
F3C
CF3
CF3
H2N
H2N
18
11 (71)
12 (70)
N
O
O
N
6
H2N
H2N
19
13 (90)
14 (60)
a Reaction leading to 12 contained 50% 11.
MeCN (0.63 mL, 11.90 mmol) was added dropwise. The reaction
was stirred at –78 °C for 10 min then warmed to r.t. for 2 h. The re-
action was quenched with 1 M HCl (20 mL), washed again with 1
M HCl (20 mL), extracted with EtOAc (2 × 50 mL), dried with
MgSO4, filtered, and concentrated to give the title compound.
tions of this pharmaceutically relevant heterocycle and
may eventually lead to their commercial availability.
All reagents and solvents were used as supplied. All reactions were
performed under a nitrogen atmosphere unless otherwise stated. 1H
NMR spectra were recorded by using an internal deuterium lock at
ambient temperature with a Bruker 400 Ultrashield spectrometer.
Data are presented as follows: chemical shift (in ppm on the δ scale
relatively to δ = 0 ppm), multiplicity (s = singlet, d = doublet,
Yield: 1.05 g (99%); colorless oil.
1H NMR (400 MHz, DMSO-d6): δ = 4.14 (s, 2 H), 1.65–1.75 (m,
2 H), 1.46–1.55 (m, 2 H).
MS (ESI): m/z = 173.9 [M + 1].
t = triplet,
q = quartet,
quint = quintuplet,
m = multiplet,
5-Isopropylisoxazol-3-ylamine (6); Typical Procedure
br = broad, dd = doublet of doublet, dt = doublet of triplet,
dq = doublet of quartet), coupling constant (J in Hz) and integra-
tion. Mass spectra were recorded with an Agilent 1200 liquid chro-
matograph. The resolution of the MS system was approximately
11000 (FWHM definition). Keto-nitriles 2, 15–17, and 19 are avail-
able from commercial sources.4
To a mixture of 4-methyl-3-oxopentanenitrile 15 (11 g, 99 mmol)
and H2O (200 mL) was added NaOH (4.95 g, 124 mmol). When the
NaOH pellets had completely dissolved, hydroxylamine sulfate
(8.93 g, 109 mmol) was added and, after 5 min, the pH was mea-
sured (pH 7–8). The reaction is warmed to 45 °C and stirred for 72
h. HCl (13.0 mL, 158 mmol, 37%) was added in one portion and the
reaction was warmed to 50 °C for 2.5 h. The reaction was removed
from the oil bath and allowed to cool to r.t., then a solution of NaOH
(30% in H2O) was added to adjust the solution to pH 11. EtOAc was
then added and the layers separated. The aqueous layer was extract-
ed with EtOAc (3 × 200 mL) until no more product was found in the
3-Oxo-3-[1-(trifluoromethyl)cyclopropyl]propanenitrile (18)
To a solution of diisopropylamine (1.934 mL, 13.68 mmol) in THF
(59.5 mL) at –78 °C, butyllithium (2.7 M in heptane, 5.07 mL,
13.68 mmol) was added. The solution was warmed to r.t. and stirred
for 30 min, then cooled to –78 °C again and a solution of methyl 1-
(trifluoromethyl)cyclopropanecarboxylate (1.0 g, 5.95 mmol) in
Synthesis 2013, 45, 171–173
© Georg Thieme Verlag Stuttgart · New York

SHORT PAPER
Synthesis of Substituted Isoxazoles
173
water layer as measured by LCMS. The combined organics were
dried (Na2SO4) and evaporated to give the title compound.
1H NMR (400 MHz, DMSO-d6): δ = 6.47 (s, 2 H), 4.86 (s, 1 H),
3.22–3.39 (m, 1 H), 1.74–2.28 (m, 6 H).
Yield: 7.5 g (60%); yellow solid.
MS (ESI): m/z = 139.2 [M + 1].
1H NMR (400 MHz, DMSO-d6): δ = 5.52 (s, 1 H), 5.4 (s, 2 H),
2.84–2.87 (m, 1 H), 1.11–1.24 (m, 6 H).
3-(1-Methylcyclopropyl)isoxazol-5-ylamine (9)
Yield: 0.6 g (85%); white solid.
1H NMR (400 MHz, DMSO-d6): δ = 6.41 (br. s., 2 H), 4.64 (s, 1 H),
MS (ESI): m/z = 127.2 [M + 1].
1.28 (s, 3 H), 0.76–0.97 (m, 2 H), 0.63–0.76 (m, 2 H).
5-Cyclopropylisoxazol-3-ylamine (8)
Yield: 4.0 g (65%); pale-yellow solid.
MS (ESI): m/z = 139.2 [M + 1].
1H NMR (400 MHz, DMSO-d6): δ = 5.50 (s, 1 H), 5.37 (s, 2 H),
1.88–1.98 (m, 1 H), 0.87–0.96 (m, 2 H), 0.70–0.77 (m, 2 H).
3-(1-Methylcyclopropyl)isoxazol-5-ylamine (11)
Yield: 1.4 g (71%); pale-yellow solid.
1H NMR (400 MHz, DMSO-d6): δ = 6.71 (br. s., 2 H), 4.9 (s, 1 H),
MS (ESI): m/z = 125.2 [M + 1].
1.21–1.37 (m, 4 H).
5-Cyclobutylisoxazol-3-ylamine (4)
Yield: 2.2 g (75%); pale-yellow solid.
MS (ESI): m/z = 193.2 [M + 1].
1H NMR (400 MHz, DMSO-d6): δ = 5.6 (s, 1 H), 5.4 (s, 2 H), 3.4–
3.5 (m, 1 H), 1.7–2.2 (m, 6 H).
3-(1-Methylcyclopropyl)isoxazol-5-ylamine (13)
Yield: 0.5 g (90%); pale-yellow solid.
1H NMR (400 MHz, DMSO-d6): δ = 6.44 (s, 2 H), 4.78 (s, 1 H),
2.23 (d, J = 7.07 Hz, 2 H), 1.84 (dt, J = 13.64, 6.82 Hz, 1 H), 0.88
(d, J = 6.57 Hz, 6 H).
MS (ESI): m/z = 139.2 [M + 1].
5-(1-Methylcyclopropyl)isoxazol-3-ylamine (10)
Yield: 1.2 g (60%); pale-yellow solid.
MS (ESI): m/z = 141.5 [M – 1].
1H NMR (400 MHz, DMSO-d6): δ = 5.52 (s, 1 H), 5.38 (s, 2 H), 1.3
(s, 3 H), 0.81–0.95 (m, 2 H), 0.72–0.8 (m, 2 H).
MS (ESI): m/z = 139.2 [M + 1].
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
5-[1-(Trifluoromethyl)cyclopropyl]isoxazol-3-amine (12)
Yield: 0.2 g (70%); pale-yellow solid; contained 50% 11. Data for
compound 12.
1H NMR (400 MHz, DMSO-d6): δ = 5.63 (s, 1 H), 5.43 (s, 2 H),
References
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1.38–1.45 (m, 4 H).
MS (ESI): m/z = 193.2 [M + 1].
5-Isobutylisoxazol-3-ylamine (14)
Yield: 0.6 g (60%); pale-yellow solid.
1H NMR (400 MHz, DMSO-d6): δ = 4.91 (s, 1 H), 4.83 (s, 2 H),
2.31 (d, J = 7.07 Hz, 2 H), 1.86–1.93 (m, 1 H), 0.93–0.96 (m, 6 H).
MS (ESI): m/z = 141.5 [M – 1].
(2) (a) Quilico, A. Gazz. Chim. Ital. 1931, 61, 759. (b) Iwai, I.;
Nakamura, N. Chem. Pharm. Bull. 1966, 14, 1277.
(c) Haruki, E.; Hirai, Y.; Imoto, E. Bull. Chem. Soc. Jpn.
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Reiner, R.; Bader, G. Monatsh. Chem. 1970, 101, 1109.
(e) Stachel, H. D. Chem. Ber. 1963, 96, 1088. (f) Takase, A.;
Murabayashi, A.; Sumimoto, S. Heterocycles 1991, 32,
1153. (g) Elnagdi, M. H.; Elmoghayar, M. R. H.; Hafez, E.
A. A.; Alnima, H. H. J. Org. Chem. 1975, 40, 2604.
(h) Rowbottom, M. W.; Faraoni, R.; Chao, W.; Campbell, B.
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(3) Ji, N.; Meredith, E.; Liu, D.; Adams, C. M.; Artman, G. D.
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(4) CAS numbers: 118431-89-3 (2), 29509-06-6 (15), 118431-
88-2 (16), 88485-78-3 (17), and 64373-43-9 (19).
(5) Takase and co-workers in ref. 2f report the formation, with
reasonable yields, of only 5-aminoisoxazole for any group
smaller than t-Bu at 100 °C.
3-Isopropylisoxazol-5-ylamine (5); Typical Procedure
A solution of hydroxylamine sulfate (1.72 g, 20.9 mmol) in H2O (4
mL) was added to a solution of 5-methyl-3-oxo-hexanenitrile (2.38
g, 19.0 mmol) and NaOH (0.837 g, 20.9 mmol) in H2O (10 mL) at
r.t. The mixture was adjusted to pH > 8 (between pH 8 and 11) with
5% NaOH, then heated to 100 °C for 1.5 h. Concentrated HCl (1.73
mL, 17.1 mmol) was added and the mixture was heated at 100 °C
for 15 min. After cooling, the pH was adjusted to 11 with 30%
NaOH and the mixture was extracted with EtOAc (3 × 20 mL). The
organic extracts were dried with Na2SO4 and concentrated to give
the title compound.
Yield: 1.7 g (70%); yellow solid.
1H NMR (400 MHz, DMSO-d6): δ = 6.44 (s, 2 H), 4.81 (s, 1 H),
2.73 (quint, J = 6.88 Hz, 1 H), 1.02–1.23 (m, 6 H).
MS (ESI): m/z = 127.2 [M + 1].
3-Cyclopropylisoxazol-5-ylamine (7)
Yield: 0.6 g (70%); white solid.
1H NMR (400 MHz, DMSO-d6): δ = 6.43 (s, 2 H), 4.61 (s, 1 H),
1.73 (tt, J = 8.43, 4.96 Hz, 1 H), 0.80–0.95 (m, 2 H), 0.52–0.68 (m,
2 H).
MS (ESI): m/z = 123.2 [M – 1].
3-Cyclobutylisoxazol-5-ylamine (3)
Yield: 1.1 g (85%); pale-yellow solid.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 171–173