Solid phase synthesis of isoxazole and isoxazoline-carboxamides via [2+3]-dipolar cycloaddition using resin-bound alkynes or alkenes

Article abstract of DOI:10.1016/j.tetlet.2012.02.041

An efficient approach for the parallel solid phase synthesis of isoxazole and isoxazoline derivatives has been developed. The isoxazoles and isoxazolines were constructed through a 1,3-dipolar cycloaddition reaction of nitrile oxides, with resin-bound alkynes or alkenes. The cycloaddition reaction conditions performed on solid phase supports was optimized, and an array of resin-bound carboxylic acid building blocks was utilized for distinct conversions. This methodology presents a new alternative to the diversity oriented synthesis of disubstituted isoxazoles and isoxazolines different from existing routes which are limited in structural diversity.

Full text of DOI:10.1016/j.tetlet.2012.02.041

Tetrahedron Letters 53 (2012) 2096–2099
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solid phase synthesis of isoxazole and isoxazoline-carboxamides via
[2+3]-dipolar cycloaddition using resin-bound alkynes or alkenes
Sureshbabu Dadiboyena a, Adel Nefzi a,b,
⇑
a Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA
b Florida Atlantic University, Boca Raton, FL 33431, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient approach for the parallel solid phase synthesis of isoxazole and isoxazoline derivatives has
been developed. The isoxazoles and isoxazolines were constructed through a 1,3-dipolar cycloaddition
reaction of nitrile oxides, with resin-bound alkynes or alkenes. The cycloaddition reaction conditions per-
formed on solid phase supports was optimized, and an array of resin-bound carboxylic acid building
blocks was utilized for distinct conversions. This methodology presents a new alternative to the diversity
oriented synthesis of disubstituted isoxazoles and isoxazolines different from existing routes which are
limited in structural diversity.
Received 14 December 2011
Accepted 9 February 2012
Available online 16 February 2012
Keywords:
Isoxazoles
Isoxazolines
Heterocycles
Ó 2012 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloadditions
Solid phase synthesis
Combinatorial chemistry
Heterocycles display an array of significant bioactive proper-
ties,1–3 and heterocyclic scaffolds are present in a wide variety of
drugs as well as drug like molecules of pharmaceutical relevance.4,5
Among the family of heterocyclic compounds, isoxazoles and isox-
azolines are an important class of heterocycles displaying a wide
variety of biological properties including antiviral,6 antitubulin,7
as well as anti-inflammatory activity.8 The synthesis of this family
of heterocycles continues to attract the attention of synthetic organ-
ic and medicinal chemists.9 The isoxazoline framework is a preva-
lent feature of several natural products 1–6,10,11 and the isoxazole
structural motif is found in the COX II inhibitors, bextra 7 and parec-
oxib 8 (Fig. 1).9a,12 A plethora of methodologies exist toward the
synthesis of isoxazoles and isoxazolines,13,14 and most of them en-
deavor nitrile oxide cycloaddition (NOC) as a key step.15
On the other hand, combinatorial chemistry and high-throughput
screening have changed the scale on which drug discovery programs
are carried out.4,5 The inherent potential of this technique aids to accel-
erate the drug discovery process through rapid synthesis and subse-
quent screening of much larger numbers of compounds than
previously possible.16 The versatile and potential capability afforded
by the tea-bag approach,17 has led to the isolation and recognition of
an array of bioactive peptides, including antibacterials, antigenic pep-
tides, opioid receptor agonists and antagonist inhibitors, and several
heterocyclic compounds of biomedical importance.18 In continuation
of our research investigation toward the design, and development of
novel heterocycles, we developed a parallel solid phase nitrile oxide
cycloaddition (NOC) strategy to synthesize a variety of isoxazoles
and isoxazolines utilizing 1,3-dipolar cycloaddition chemistry.9,15
The hydroximoyl chlorides 11 for the 1,3-dipolar cycloaddition are
not commercially available and were conveniently synthesized in
two steps utilizing solution phase chemistry.8,9a This methodology
presents a new alternative to the diversity oriented synthesis of disub-
stituted isoxazoles and isoxazolines different from the existing routes
which, are limited in structural diversity.19,20
We envisioned the synthesis of isoxazole 9 and isoxazolines 10
via 1,3-dipolar cycloaddition of in situ generated nitrile oxides
with alkyne 12 or alkenes 13. The required alkyne and alkene pre-
cursors are synthesized from the corresponding resin-bound car-
boxylic acid. The retrosynthetic rationale for the parallel solid
phase synthesis of isoxazoles and isoxazolines is illustrated in
Scheme 1.
The parallel solid phase synthesis of all compounds was carried
out utilizing Houghten’s tea-bag approach, wherein the resin is
packed within sealed polypropylene mesh packets.17 The first
position of diversity was introduced by coupling several carboxylic
acids to p-methylbenzhydrylamine resin. The generated secondary
amide 14 was then alkylated in the presence of lithium t-butoxide
and an alkylating agent (allyl bromide or propargyl bromide).21
The parallel synthesis of the resin-bound isoxazoles 9 and isoxaz-
olines 10 was initiated by the nitrile oxide cycloaddition of the
resin-bound alkynes and alkene derivatives. Structurally diverse
combinations of carboxylic acids (cyclopentanecarboxylic acid,
1-cyclopenteneacetic acid, benzoic acid, 2-nitrobenzoic acid,
⇑
Corresponding author. Tel.: +1 772 345 4739; fax: +1 772 345 3649.
E-mail addresses: anefzi@tpims.org, adeln@tpims.org (A. Nefzi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.041

S. Dadiboyena, A. Nefzi / Tetrahedron Letters 53 (2012) 2096–2099
2097
OMe
OMe
OMe
OMe
Br
Br
Br
Br
Br
Br
Br
Br
HO
HO
OH
HO
O
N
O
N
O
N
H
O
N
H
Br
O
N
H
N
N
N
H
n
NH
Me
O
O
N
O
N
O
1
2
n = 2, aerothionin
n = 3, homoaerothionin
Br
Me
3 aerophobin1
4 purealidin Q
O
OMe
O
Br
O
H3C
N
Br
Br
O
O
H3C
N
O
Br
O
O
OH
O
N
H
H
OH
O
N
N
N
R
H
N
N
O
N
H
N
O
S
O
O
OH
O
NH2
S
O
O
HO
Br
O
R = Me, Et, n-Pr
Parecoxib
O
5 epi-fistularin-3
7
Bextra
8
6
calafianin
Br
Br
Br
O
OMe
Figure 1. Naturally occurring isoxazolines and pharmaceutically relevant isoxazoles.
HO
N
O
O
Cl
O
O
O
O
N
R1
N
R1
N
N
11
R2
N
R1
(or)
N
R1
(or)
1,3-Dipolar Cycloaddition
13
12
9
10
R2
R2
Heterocyclic
Pharmacophore
O
O
O
O
Diversity
Site # 1
R1
N
N
R1 Diversity
Site # 1
N
N
Diversity
Site # 2
R2
R2
Scheme 1. Retrosynthetic illustration of structurally diverse isoxazoles and isoxazolines.
Table 1
Isoxazoles from resin-bound alkynes
Entry
R1
R2
Mass calcd/found
Yieldsa (%)
15a
15b
15c
15d
15e
15f
15g
15h
15i
Piperonyl
Cyclopentyl
1-Cyclopenteneacetyl
4-Biphenyl
Syringyl
1-Phenyl-1-cyclopropyl
Diphenylacetyl
Phenyl
Piperonyl
Cyclopentyl
1-Cyclopenteneacetyl
2-Nitrophenyl
4-Biphenyl
1-Phenyl-1-cyclopropyl
Diphenylacetyl
Syringyl
1-Napthyl
2-Nitrophenyl
Piperonyl
Phenyl
Cyclopentyl
1-Phenyl-1-cyclopentyl
4-Biphenyl
H
H
H
H
H
H
H
322.3/323.2 (MH+)
270.3/271.4 (MH+)
282.3/283.2 (MH+)
354.4/355.2 (MH+)
354.4/356.0 (MH+)
318.3/319.6 (MH+)
368.4/369.5 (MH+)
354.4/355.2 (MH+)
398.4/399.3 (MH+)
346.4/347.4 (MH+)
358.4/359.2 (MH+)
399.4/400.4 (MH+)
430.5/431.4 (MH+)
394.5/395.3 (MH+)
444.5/445.3 (MH+)
430.4/453.2 (MH+)
404.5/405.4 (MH+)
392.2/393.5 (MH+)
391.2/392.4 (MH+)
347.4/349.3 (MH+)
415.4/416.3 (MH+)
415.3/438.2 (MNa+)
423.3/446.1 (MNa+)
87
66
91
63
54
52
75
90
83
93
94
55
63
75
62
63
73
70
91
92
79
75
86
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
2,6-diCl
2,6-diCl
2,6-diCl
2,6-diCl
2,6-diCl
2,6-diCl
15j
15k
15l
15m
15n
15o
15p
15q
15r
15s
15t
15u
15v
15w
The products were run on a Vydac column, gradients 5–95% formic acid in Acetonitrile in 7 min.
a
The yields are based on the weight of purified products and are relatives to the initial loading of the resin. (The purity of the purified compounds is higher than 95% for all
the compounds).

2098
S. Dadiboyena, A. Nefzi / Tetrahedron Letters 53 (2012) 2096–2099
Table 2
Isoxazolines from resin-bound alkenes
Entry
R1
R2
Mass calcd/found
Yieldsa (%)
16a
16b
16c
16d
16e
16f
16g
16h
16i
Cyclopentyl
1-Cyclopenteneacetyl
4-Biphenyl
1-Phenyl-1-cyclopropyl
Syringyl
Piperonyl
H
H
H
H
272.3/273.1 (MH+)
284.1/285.1 (MH+)
356.4/357.3 (MH+)
320.3/321.2 (MH+)
356.3/357.2 (MH+)
400.4/423.2 (MNa+)
348.4/349.3 (MH+)
360.4/361.3 (MH+)
401.5/402.4 (MH+)
356.3/357.3 (MH+)
396.5/397.4 (MH+)
446.4/447.4 (MH+)
432.4/433.2 (MH+)
406.5/429.3 (MNa+)
432.5/455.5 (MNa+)
424.5/447.3 (MNa+)
349.2/372.3 (MNa+)
394.2/417.1 (MNa+)
393.2/417.2 (MNa+)
417.3/440.2 (MNa+)
417.3/440.1 (MNa+)
425.3/447.4 (MNa+)
96
92
67
87
77
63
93
88
84
84
77
82
87
71
61
72
96
95
96
87
77
78
H
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
4-Ph
2,6-diCl
2,6-diCl
2,6-diCl
2,6-diCl
2,6-diCl
2,6-diCl
Cyclopentyl
1-Cyclopenteneacetyl
2-Nitrophenyl
Phenyl
1-Phenyl-1-cyclopropyl
Diphenylacetyl
Syringyl
1-Napthyl
4-Biphenyl
1-Phenyl-1-cyclopentyl
Phenyl
2-Nitrophenyl
Piperonyl
16j
16k
16l
16m
16n
16o
16p
16q
16r
16s
16t
16u
16v
Cyclopentyl
1-Phenyl-1-cyclopentyl
4-Biphenyl
The products were run on a Vydac column, gradients 5–95% formic acid in Acetonitrile in 7 min.
a
The yields are based on the weight of purified products and are relatives to the initial loading of the resin (The purity of the purified compounds is higher than 95% for all
the compounds).
O
O
O
O
HO
N
R1
N
R1
O
N
N
N
H
Br
b
c
+
R1
N
Cl
15
12
9
11
R2
O
R2
R2
N
a
N
H
R1
O
O
14
O
HO
O
N
R1
N
N
H
R1
N
O
b
c
Br
Cl
+
R1
N
10
11
13
16
R2
R2
R2
Scheme 2. Solid phase synthesis of structurally diverse isoxazoles and isoxazolines. Reagents and conditions: (a) tBuOLi, DMSO, 5 h; (b) (C2H5)3N, CH2Cl2, rt overnight; (c)
anhydrous HF, 90 min, 0 °C.
piperonylic acid, syringyl, 4-biphenylcarboxylic acid, 1-napthalen-
ecarboxylic, diphenylacetic acid, 1-phenyl-1-cyclopropylcarboxylic
acid, and 1-phenyl-1-cyclopentanecarboxylic acid) were selected.
To investigate the feasibility of nitrile oxide cycloadditions
(NOC) on solid support, three different hydroximoyl chlorides were
freshly prepared and were treated with triethylamine to generate
the corresponding nitrile oxides9,13c,f,14i,5a,b Treatment of resin-
bound dipolarophiles 12, 13 with the generated nitrile oxides pro-
ceeded in a 1,3-dipolar fashion and furnished diversified isoxazoles
and isoxazolines.22 In case of resin coupled with piperonylic acid,
we also observed the formation of a diol (partially cleaved pro-
tected diol) in addition to the main product. All of the cycloaddi-
tions occurred in good yields and were isolated in high purities
(Tables 1 and 2). The protocol for the parallel synthesis of structur-
ally diverse isoxazoles and isoxazolines is outlined in Scheme 2.
In conclusion, we have developed an efficient parallel solid phase
methodology to construct the diversity oriented isoxazoles and
isoxazolines via 1,3-dipolar cycloaddition reaction.22 Coupling of
carboxylic acids to the resin introduced the first position of diversity
in which, following N-alkylation with allyl bromide or propargyl
bromide furnished several resin-bound alkenes and alkynes. 1,3-
Dipolar cycloaddition of the resin-bound alkenes or alkynes with
nitrile oxides led to the formation of the corresponding disubsti-
tuted isoxazole and isoxazolines.
Acknowledgements
The authors would like to thank the State of Florida Funding,
NIH (1R03DA025850-01A1, Nefzi; 5P41GM081261-03, Houghten;
3P41GM079590-03S1, Houghten) for providing generous financial
support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.041.
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22. General procedure for the 1,3-Dipolar cycloaddition: Resin-bound carboxylic acid
coupling and N-alkylation using allyl bromide or propargyl bromide were
performed according to the literature precedents.21 Resin-bound alkyne
(alkene) and the hydroximoyl chloride (10 equiv) in 10 mL of dry
dichloromethane (DCM) was treated with triethylamine (0.16 mL, 10 equiv)
and the reaction mixture was stirred overnight. The excess solution was
decanted, and the resin was washed with DCM (2 Â 5 mL). The resin was
cleaved with anhydrous HF (10 mL) for 90 min at 0 °C, and the desired
isoxazole (isoxazoline) was obtained following extraction with 95% AcOH in
H2O and lyophilization as a colorless powder. The isoxazole (isoxazoline) was
purified by preparative reverse-phase HPLC. Cyclopentanecarboxylic acid (3-
phenyl-isoxazol-5-ylmethyl)-amide (15b): 1H NMR (500 MHz; DMSO-d6):
d
1.50–1.52 (m, 2H), 1.61–1.67 (m, 4H), 1.77–1.79 (m, 2H), 2.61–2.64 (m, 1H),
4.44 (d, J = 6.0 Hz, 2H), 6.81 (s, 1H), 7.49–7.52 (m, 3H), 7.84–7.87 (m, 2H), 8.49
(t, J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C16H18N2O2 [M+H+]: 270.3; found:
271.4. Benzo[1,3]dioxole-5-carboxylic acid (3-biphenyl-4-yl-isoxazol-5-ylmethyl)-
amide (15i): 1H NMR (500 MHz; DMSO-d6): d 1.23 (s, 2H), 4.64 (d, J = 5.5 Hz,
2H), 6.55 (s, 1H), 7.02 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 7.0 Hz, 1H), 7.45 (s, 1H), 7.50
(q, J = 8.0 Hz, 3H), 7.74 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.97 (d,
J = 8.0 Hz, 2H), 9.07 (t, J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C24H18N2O4
[M+H+]: 398.4; found: 399.3. Cyclopentanecarboxylic acid (3-biphenyl-4-yl-
isoxazol-5-ylmethyl)-amide (15j): 1H NMR (500 MHz; DMSO-d6): d 1.23 (s, 4H),
1.50–1.52 (m, 1H), 1.63–1.68 (m, 2H), 1.77–1.80 (m, 1H), 2.62–2.65 (m, 1H),
4.46 (t, J = 5.8 Hz, 2H), 6.88 (s, 1H), 7.41 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 8.0 Hz,
2H), 7.74 (t, J = 9.5 Hz, 2H), 7.81 (t, J = 8.1 Hz, 2H), 7.95 (t, J = 10.5 Hz, 2H), 8.49–
8.51 (m, 1H); MS (ESI) m/z calcd for C22H22N2O2 [M+H+]: 346.4; found: 347.4.
Benzo[1,3]dioxole-5-carboxylic acid [3-(2,6-dichloro-phenyl)-isoxazol-5-ylmethyl]-
amide (15s): 1H NMR (500 MHz; DMSO-d6): d 4.69 (d, J = 5.5 Hz, 2H), 6.10 (s,
2H), 6.59 (s, 1H), 7.01 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.50 (d, J = 10.0 Hz, 1H),
7.54–7.63 (m, 1H), 7.64–7.65 (m, 2H), 9.1 (t, J = 5.5 Hz, 1H); MS (ESI) m/z calcd
for C17H12Cl2N2O4 [M+H+]: 391.2; found: 393.2. Biphenyl-4-carboxylic acid [3-
(2,6-dichloro-phenyl)-isoxazol-5-ylmethyl]-amide (15w): 1H NMR (500 MHz;
DMSO-d6):
d 4.75 (d, J = 4.5 Hz, 2H), 6.62 (s, 1H), 7.41 (m, 1H), 7.50 (t,
J = 7.0 Hz, 2H), 7.56 (t, J = 8.0 Hz, 1H), 7.64 (t, J = 8.5 Hz, 2H), 7.74 (d, J = 8.5 Hz,
2H), 7.80 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.5 Hz, 2H), 9.31 (t, J = 6.0 Hz, 2H); MS
(ESI) m/z calcd for
C
23H16Cl2N2O2 [M+Na+]: 423.2; found: 446.1.
Cyclopentanecarboxylic acid (3-phenyl-4,5-dihydro-isoxazol-5-ylmethyl)-amide
(16a): 1H NMR (500 MHz; DMSO-d6): d 1.44–168 (m, 8H), 2.54 (t, J = 7.5 Hz,
1H), 3.13 (dd, J = 7.0 Hz, 17 Hz 1H), 3.22–3.24 (m, 1H), 3.44 (dd, J = 11.0 Hz,
17 Hz 1H), 4.72–4.78 (m, 1H), 7.43–7.46 (m, 3H), 7.62–7.65 (m, 2H), 8.04 (t,
J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C23H16Cl2N2O2 [M+H+]: 272.3; found:
273.1. Benzo[1,3]dioxole-5-carboxylic acid (3-biphenyl-4-yl-4,5-dihydro-isoxazol-
5-ylmethyl)-amide (16f): 1H NMR (500 MHz; DMSO-d6): d 3.40 (dd, J = 7 Hz,
17.5 Hz, 1H), 3.61–3.70 (m, 1H), 3.77–3.81 (m, 1H), 4.34 (dd, J = 5.5 Hz, 12 Hz,
1H), 4.43 (dd, J = 3.5 Hz, 12 Hz, 1H), 5.07–5.13 (m, 1H), 6.11 (s, 2H), 6.80–6.82
(m, 1H), 6.98–7.00 (m, 2H), 7.09–7.10 (m, 1H), 7.32 (s, 1H), 7.40–7.42 (m, 1H),
7.48–7.54 (m, 4H), 7.72–7.74 (m, 2H); MS (ESI) m/z calcd for C24H20N2O4
[M+Na+]: 400.4; found: 423.2. Cyclopentanecarboxylic acid (3-biphenyl-4-yl-4,5-
dihydro-isoxazol-5-ylmethyl)-amide (16g): 1H NMR (500 MHz; DMSO-d6):
d
1.45–1.69 (m, 6H), 2.55–2.58 (m, 1H), 3.15–3.19 (m, 1H), 3.24–3.32 (m, 1H),
3.46–3.51 (m, 1H), 4.74–4.80 (m, 1H), 7.4 (t, J = 8.0 Hz, 1H), 7.49 (t, J = 7.5 Hz,
2H), 7.71–7.73 (m, 4H), 7.77–7.78 (m, 2H), 8.05 (t, J = 6.0 Hz, 1H); MS (ESI) m/z
calcd for C22H24N2O2 [M+H+]: 348.4; found: 349.3. N-[3-(2,6-Dichloro-phenyl)-
4,5-dihydro-isoxazol-5-ylmethyl]-2-nitro-benzamide (16r): 1H NMR (500 MHz;
DMSO-d6): d 3.14 (dd, J = 6.5 Hz, 17.5 Hz, 1H), 3.41–3.55 (m, 3H), 4.96–5.00 (m,
1H), 7.52–7.55 (m, 1H), 7.61–7.64 (m, 3H), 7.8 (t, J = 7.5 Hz, 1H), 8.05 (d,
J = 10 Hz, 1H), 9.06 (t, J = 6.0 Hz, 1H); MS (ESI) m/z calcd for C17H13Cl2N3O4
[M+Na+]: 394.20; found: 417.1. Benzo[1,3]dioxole-5-carboxylic acid [3-(2,6-
dichloro-phenyl)-4,5-dihydro-isoxazol-5-ylmethyl-]-amide (16s): 1H NMR (500
MHz; DMSO-d6): d 3.14 (dd, J = 6.5 Hz,17.5 Hz, 2H), 3.64–3.48 (m, 2H), 3.55–
3.61 (m, 1H), 4.98–5.0 (m, 1H), 6.1 (s, 2H), 6.99 (d, J = 10 Hz, 2H), 7.43 (s, 1H),
7.48–7.58 (m, 2H), 7.60 (d, J = 5.0 Hz, 2H), 8.65 (t, J = 6.0 Hz, 1H); MS (ESI) m/z
calcd for C18H14Cl2N2O4 [M+Na+]: 393.22; found: 417.2.
16. Yu, Y.; Nefzi, A.; Ostresh, J. M.; Houghten, R. A. In Innnovations and Perspectives
in Solid Phase Synthesis and Combinatorial Libraries; Epton, R., Ed.; Mayflower
Worldwide: London, UK, 2004.
17. Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 5131.
18. (a) Houghten, R. A.; Wilson, D. B.; Pinilla, C. Drug Discovery Today 2000, 5, 276;
(b) Houghten, R. A.; Pinilla, C.; Appel, J. R.; Blondelle, S. E.; Dooley, C. T.; Eichler,
J.; Nefzi, A.; Ostresh, J. M. J. Med. Chem. 1999, 42, 3743.