Intramolecular [3+2] nitrile oxide cycloaddition: Synthesis of tetrahydroisoxazoloindazoles

Article abstract of DOI:10.1016/j.tetlet.2004.04.153

Novel tetrahydroisoxazoloindazoles were synthesized from substituted 1,3-diketones by employing intramolecular [3+2] nitrile oxide cycloaddition [INOC] reaction to alkene as the key step.

Full text of DOI:10.1016/j.tetlet.2004.04.153

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4931–4934
Intramolecular [3+2] nitrile oxide cycloaddition: synthesis of
tetrahydroisoxazoloindazoles
Kyung-Ho Park* and Will J. Marshall
Dupont, Central Research and Development, Material Science and Engineering, Experimental Station, PO Box 80328,
Wilmington, DE 19880-0328, USA
Received 1 April 2004; revised 20 April 2004; accepted 20 April 2004
Available online 18 May 2004
Abstract—Novel tetrahydroisoxazoloindazoles were synthesized from substituted 1,3-diketones by employing intramolecular [3+2]
nitrile oxide cycloaddition [INOC] reaction to alkene as the key step.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Among a great number of heterocycles, pyrazoles1 and
isoxazolines2 are especially important motifs used not
only as key building blocks for the synthesis of their
derivatives in medicinal chemistry, but also as invalu-
able chelating ligands for various transition metals.
While pyrazole derivatives, including celecox,3 have
been the most important drugs as of today, the isoxaz-
oline nucleus not only provides its derivatives with a
variety of biological activities but also modulates vari-
ous other biologically active motifs.4 Although there are
numerous reports for the synthesis of both pyrazoles
and isoxazolines, few routes to construct fused ring
systems with each heterocycle tethered together in the
same molecule are known.5 Those activities mentioned
above, coupled with our program focusing on potential
biological and/or metal chelating ligands, led us to
explore a synthetic pathway to construct novel tetra-
hydroisoxazoloindazoles, pyrazole-isoxazoline hetero-
cycle about central carbocyclic cores. The most common
method to construct pyrazole heterocycles involves the
reaction of 1,3-diketones or their equivalents with
substituted hydrazines.6 Meanwhile isoxazolines are
normally synthesized by employing a 1,3-dipolar cyclo-
addition reaction of a nitrile oxide to an alkene.7 Thus,
we designed the route to our fused tetrahydroisoxazolo-
indazole heterocycles to include intramolecular nitrile
oxide cycloaddition (INOC) as the key step, as depicted
in Scheme 1. We began our studies by preparing acetal
O
O
O
O
O
O
NaH
acetone
KI
Br
OEt
OEt
OEt
OEt
OEt
OEt
R1
R1
+
EtO
R1
toluene
1
2
3
4
R2 NHNH2 2. HCl / H2O
CHCl3
1.
R1
R1
R1
NH2OH
.HCl
NaOAc
R1
NaOCl
CH2Cl2
H
H
N
N
R2
N
R2
+
N
R2
N
N
N
O
R2
N
O
N
N
N
O
OH
7a
7b
6a, 6b
5a, 5b
Scheme 1.
* Corresponding author. Tel.: +1-302-695-1784; fax: +1-302-695-7367; e-mail: kyung-ho.park@usa.dupont.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.153

4932
K.-H. Park, W. J. Marshall / Tetrahedron Letters 45 (2004) 4931–4934
protected diketone8 3 (60–68% yield) from the reaction
of alkylmethylketone 1 with ethyl diethoxyacetate 2,
followed by C-alkylation of compound 3 to give
homoallylated diketone 4 in good yield (74–90%). The
subsequent reaction of compound 4 with hydrazine
derivatives, followed by deprotection of acetal, afforded
aldehyde 5. As expected, when substituted hydra-
zine such as methylhydrazine (R2 ¼ Me) was used,
aldehydes with a regioisomeric mixture (thus the regio-
isomer 5a is corresponding to both 6a and 7a) were
obtained.
Unfortunately remarkable regioselectivity was not
observed regardless of the degree of bulkiness of the
substituent R1. To generate nitrile oxide, we employed
oxime derivative as a precursor to the 1,3-dipole (Hus-
gin method).9 Thus each aldehyde 5 was condensed with
hydroxylamine hydrochloride to afford oxime derivative
6 (79–98%) as a precursor to in situ generated nitrile
oxide. Finally tetrahydroisoxazoloindazole
7
was
obtained from the cycloaddition of nitrile oxide to the
homoallyl group present in the oxime derivative 6
(Table 1).10 As for the unsubstituted tetrahydro-
isoxazoloindazole 7 (R2 ¼ H), X-ray crystallography of
the compound 7-1 (R1 ¼ Me, R2 ¼ H) showed that it
exists as the tautomer 7b and packed in a trimeric form
through hydrogen bonding (Fig. 1). The regiochemistry
of compound 7 (R2 ¼ Me) was also established by X-ray
crystallographic analysis of either isomeric compound
7a or 7b.10 For example the X-ray structure of com-
pound 7-4a (R1 ¼ Me, R2 ¼ H) is illustrated in Figure 2.
Our attempt to make 5-5-5 ring system (pyrazole–
cyclopentane–isoxazoline) as shown in compound 8 did
not work by this route, most likely because of severe
ring strain (Scheme 2).
Figure 1. X-ray crystallography of compound 7-1 (R1 ¼ Me, R2 ¼ H),
disordered positions removed for clarity. Thermal ellipsoids drawn to
the 50% probability level.
In summary, we have developed a synthetic strategy for
the preparation of novel heterocycles of tetra-
hydroisoxazoloindazole 7. The work reported here
secures our program aimed at both the development of
novel ligand for various metals and/or the discovery of
new pharmacophore through the structural diversifica-
tion of the prepared tetrahydroisoxazoloindazole sys-
tem.
Figure 2. X-ray crystallography of compound 7-4a (R1 ¼ Me,
R2 ¼ Me), disordered positions removed for clarity. Thermal ellipsoids
drawn to the 50% probability level.
Table 1. Examples of various tetrahydroisoxazoloindazoles 7 and their
starting materials 5
O
O
O
O
NH NH
2
1.
I
OEt
OEt
2
OEt
OEt
R1
R2
Compound 5
(yieldb %)
H
Compound 7
(yielda %)
N
H
CHCl
3
N
K CO
2
3
2. HCl/H O
2
O
7-1 (51)
7-2 (77)
7-3 (53)
7-4a (74)
7-4b (85)
7-5a (81)
7-5b (77)
7-6a (88)
7-6b (80)
Me
t-Bu
Ph
H
5-1 (83)
5-2 (69)
5-3 (52)
5-4a (55)
5-4b (15)
5-5a (57)
5-5b (20)
5-6a (17)
5-6b (53)
72%
68%
H
NH OH
2
NaOAc
H
.
HCl
Me
Me
t-Bu
t-Bu
Ph
Me
Me
Me
Me
Me
Me
NaOCl
X
N
H
H
N
H
O
CH Cl
N
2
2
N
N
N
Ph
OH
8
91%
a Yield from compound 6.
b Yield from compound 4.
Scheme 2.

K.-H. Park, W. J. Marshall / Tetrahedron Letters 45 (2004) 4931–4934
4933
with hexane to afford 6 g compound 6-1 (R1 ¼ Me, R2 ¼ H,
6 g, 92%). Finally to the solution of oxime (6-1, 5 g,
27.89 mmol) in CH2Cl2 (100 mL) was slowly added bleach
(41 g, 33.47 mmol, 6.15%) dropwise at )10 ꢁC. After
stirring at rt for 5 h, the reaction mixture was extracted
with CH2Cl2, dried (Na2SO4), and concentrated under
reduced pressure. By column chromatography (70% ethyl
acetate in hexane), compound 7-1 (2.51 g, 51%) was
Acknowledgements
We thank Linda M. Longshaw for the technical assis-
tance.
1
References and notes
obtained as a white solid. 7-1 51% yield; mp: 190 ꢁC. H
NMR (500 MHz, CDCl3) d 10.49 (s, br, 1H), 4.74 (dd, 1H,
J ¼ 9:5, 7.8 Hz), 3.80 (dd, 1H, J ¼ 13:9, 7.8 Hz), 3.54 (m,
1H), 2.75 (ddd, 1H, J ¼ 1; 7, 5.1, 15.9 Hz), 2.59 (ddd, 1H,
J ¼ 5:2, 12.5, 15.9 Hz), 2.34 (m, 1H), 1.73 (m, 1H). 13C
NMR (125 MHz, CDCl3) d 151.3, 141.7, 133.4, 119.8,
73.5, 48.4, 28.0, 20.0, 10.7. Anal. Calcd for C9H11N3O: C,
61.00; H, 6.26; N, 23.71. Found: C, 60.88; H, 5.98; N,
23.58. Crystal data: C27H33N9O3, from hexane/ethyl ace-
tate, colorless, irregular block, ꢀ0.360 · 0.300 · 0.260 mm,
1. (a) Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A. M. S.
Targets Heterocycl. Systems 2002, 6, 52; (b) Trofimenko,
S. Chem. Rev. 1972, 72, 497.
€
2. (a) Caramella, P.; Grunanger, P. In 1,3-Dipolar Cyclo-
addition Chemistry; Padwa, A., Ed.; J. Wiley and Sons: New
€
York, 1984; pp 291–392; (b) Grunanger, P.; Vita-Finzi, P.
In The Chemistry of Heterocyclic Compounds; Taylor, E.
C. , Ed.; J. Wiley and Sons: New York, 1991; Vol. 49, pp
572–602.
ꢀ
ꢀ
monoclinic, P21/c, a ¼ 7:7566ð8Þ A, b ¼ 25:485ð3Þ A,
3
ꢀ
ꢀ
3. Plount Price, M. L.; Jorgensen, W. L. J. Am. Chem. Soc.
2000, 122, 9455.
c ¼ 13:4743ð14Þ A, beta ¼ 100.578(2)ꢁ, Vol ¼ 2618.3(5) A ,
Z ¼ 4, T ¼ ꢁ100 ꢁC, formula weight ¼ 531.62, den-
sity ¼ 1.349 g/cm3, l (Mo) ¼ 0.09 mmꢁ1 7-2 77% yield;
mp: 223 ꢁC 1H NMR (500 MHz, CDCl3) d 8.75 (s, br,
1H), 4.72 (dd, 1H, J ¼ 8:0, 9.7 Hz), 3.78 (dd, 1H, J ¼ 8:0,
13.6 Hz), 3.52 (m, 1H), 3.00 (ddd, 1H, J ¼ 2:0, 5.3,
16.1 Hz), 2.72 (ddd, 1H, J ¼ 5:0, 12.7, 16.1 Hz), 2.34 m,
1H), 1.75 (m, 1H), 1.39 (s, 9H). 13C NMR (125 MHz,
DMSO-d6) d 156.2, 153.1, 150.1, 146.6, 138.5, 128.4, 118.3,
115.5, 72.6, 72.3, 47.9, 47.3, 32.6, 32.4, 31.5, 30.6, 29.4,
27.8, 21.8, 21.2. M.W calcd for C12H17N3O: 219.14, LC-
MS [M+H]þ ¼ 220.2. 7-3 53% yield; mp: 221 ꢁC. 1H NMR
(500 MHz, CDCl3) d 7.70–7.68 (m, 2H), 7.48–7.45 (m,
2H), 7.40–7.37 (m, 1H), 5.10 (s, br, 1H), 4.77 (dd, 1H,
J ¼ 7:9, 9.1 Hz), 3.82 (dd, 1H, J ¼ 7:9, 13.6 Hz), 3.62 (m,
1H), 3.06 (ddd, 1H, J ¼ 1:6, 5.2, 16.2 Hz), 2.93 (ddd, 1H,
J ¼ 5:0, 12.6, 16.2 Hz), 2.42 (m, 1H), 1.77 (m, 1H). 13C
NMR (125 MHz, DMSO-d6) d 152.9, 149.9, 147.5, 139.2,
138.0, 133.3, 129.1, 128.9, 128.4, 127.9, 127.3, 126.2, 126.0,
119.4, 117.5, 72.6, 72.4, 47.9, 47.2, 27.6, 27.5, 21.4, 20.8.
Anal. Calcd for C14H13N3O: C, 70.28; H, 5.48; N, 17.56.
Found: C, 69.97; H, 5.51; N, 17.47. 7-4a 74% yield; mp:
122 ꢁC. 1H NMR (500 MHz, CDCl3) d 4.70 (dd, 1H,
J ¼ 8:1, 9.5 Hz), 4.03 (s, 3H), 3.74 (dd, 1H, J ¼ 8:1,
14.0 Hz), 3.50 (m, 1H), 2.73 (ddd, 1H, J ¼ 2:0, 5.4,
16.0 Hz), 2.58 (ddd, 1H, J ¼ 4:8, 12.5, 16.0 Hz), 2.33 (m,
1H), 2.21 (s, 3H), 1.69 (m, 1H). 13C NMR (125 MHz,
CDCl3) d 150.8, 144.9, 128.9, 120.9, 73.1, 48.8, 38.4, 27.8,
20.4, 11.6. Anal. Calcd for C10H13N3O: C, 62.81; H, 6.85;
N, 21.97. Found: C, 62.94; H, 6.87; N, 22.03. Crystal data:
C10H13N3O, from hexane/ethyl acetate, colorless, irregular
block, ꢀ0.520 · 0.500 · 0.450 mm, orthorhombic, Pbcn,
4. (a) Khalil, M. A.; Maponya, M. F.; Ko, D.-H.; You, Z.;
Oriaku, E. T.; Lee, H. J. Med. Chem. Res. 1996, 6, 52; (b)
Groutas, W. C.; Venkataraman, R.; Chong, L. S.; Yooder,
J. E.; Epp, J. B.; Stanga, M. A.; Kim, E.-H. Bioorg. Med.
Chem. 1995, 3, 125; (c) Park, K.-H.; Kurth, M. J. J. Org.
Chem. 2000, 65, 3520.
5. Kizer, D. E.; Kurth, M. J. Tetrahedron Lett. 1999, 40,
3535.
6. Kost, A. N.; Grandberg, I. I. Adv. Heterocycl. Chem.
1966, 6, 347.
7. For review of nitrile oxide–isoxazoline methodology, see:
(a) Curran, D. P. In Advances in Cycloaddition; Curran, D.
P. , Ed.; JAI: Greenwich, CT, 1988; Vol. 1, pp 129–189; (b)
Torssel, K. B. G. Organic Nitrochemistry Series. In Nitrile
Oxides, Nitrones, and Nitronates in Organic Synthesis.
Novel Strategies in Synthesis; Feuer, H., Ed.; VCH
Publishers: Weinheim, 1988; pp 55–74.
8. Bode, R. H.; Bol, J. E.; Driessen, W. L.; Hulsbergen, F. B.;
Reedijk, J.; Spek, A. L. Inorg. Chem. 1999, 38, 1239.
9. Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
10. Representative procedure: 4-Bromo-1-butene (20 g,
148 mmol) was treated with KI (24.6 g, 148 mmol) in
acetone (200 mL) by reflux overnight. The reaction mix-
ture was filtered, then the filtrate was treated with
compound 3 (R1 ¼ Me, 23 g, 122 mmol) in the presence
of K2CO3 (20 g, 148 mmol) by overnight reflux. The
reaction mixture was filtered, and the filtrate was concen-
trated under reduced pressure, followed by vacuum
distillation (90 ꢁC, 150 mTorr) to afford 22 g of compound
4 (R1 ¼ Me, 74%) as a liquid. Compound 4 (R1 ¼ Me, 11 g,
45.3 mmol) was reacted with hydrazine hydrate (4.15 g,
45.3 mmol, 35%) in chloroform (80 mL) at rt overnight.
The organic layer was separated, and then concentrated
under reduced pressure. The residue was treated with 1 N
HCl (20 mL) in water (100 mL), then the resultant mixture
was stirred at rt for 6 h. The precipitated white solid was
filtered, and the filter cake was washed with saturated
NaHCO3 solution, then water successively. The solid was
dried under a vacuum to afford compound 5-1 (R1 ¼ Me,
R2 ¼ H, 6.2 g, 83%), then 6 g (36.5 mmol) of which was
reacted with hydroxylamine hydrochloride (5.1 g,
73 mmol) in the presence of NaOAc (9 g, 109 mmol) in
THF/MeOH/H2O (100 mL/50 mL/50 mL) at rt overnight.
After adding water (100 mL) to the reaction mixture, the
reaction mixture was extracted with methylenechloride
(80 mL · 2). The combined organic layer was washed with
saturated NaHCO3, dried (Na2CO3), then concentrated
under reduced pressure. The resultant solid was washed
ꢀ
ꢀ
ꢀ
a ¼ 13:6524ð17Þ A, b ¼ 8:9306ð11Þ A, c ¼ 32:005ð4Þ A,
3
ꢀ
Vol ¼ 3902.2(8) A , Z ¼ 16, T ¼ ꢁ100 ꢁC, formula
weight ¼ 191.23,
density ¼ 1.302 g/cm3,
l
(Mo) ¼
0.09 mmꢁ1 7-4b 85% yield; mp: 133 ꢁC. 1H NMR
(500 MHz, CDCl3) d 4.59 (dd, 1H, J ¼ 7:8, 9.5 Hz), 3.76
(s, 3H), 3.65 (dd, 1H, J ¼ 7:8, 13.7 Hz), 3.43 (m, 1H), 2.61
(ddd, 1H, J ¼ 1:7, 5.1, 15.7 Hz), 2.47 (ddd, 1H, J ¼ 4:7,
13.0, 15.7 Hz), 2.24 (m, 1H), 2.15 (s, 3H), 1.59 (m, 1H). 13
C
NMR (125 MHz, CDCl3) d 151.9, 136.1, 134.3, 118.1,
72.1, 47.9, 35.7, 27.1, 19.2, 8.7. M.W calcd for C10H13N3O;
191.1, LC-MS [M+H]þ ¼ 192.1. 7-5a 81% yield; mp:
147 ꢁC. 1H NMR (500 MHz, CDCl3) d 4.68 (dd, 1H,
J ¼ 8:1, 9.6 Hz), 4.03 (s, 3H), 3.72 (dd, 1H, J ¼ 8:1,
14.4 Hz), 3.44 (m, 1H), 2.99 (ddd, 1H, J ¼ 1:8, 5.1,
16.0 Hz), 2.70 (ddd, 1H, J ¼ 4:9, 12.6, 16.0 Hz), 2.25 (m,
1H), 1.65 (m, 1H), 1.33 (s, 9H). 13C NMR (125 MHz,
CDCl3) d 156.5, 151.0, 129.5, 119.0, 73.2, 48.5, 38.5, 33.0,
29.7, 28.1, 22.7. Anal. Calcd for C13H19N3O: C, 66.92; H,

4934
K.-H. Park, W. J. Marshall / Tetrahedron Letters 45 (2004) 4931–4934
8.21; N, 18.01. Found: C, 67.16; H, 8.02; N, 17.97. Crystal
data: C13H19N3O, from hexane/ethyl acetate, colorless,
5.0, 16.1 Hz), 2.92 (ddd, 1H, J ¼ 4:7, 11.9, 16.1 Hz), 2.40
(m, 1H), 1.76 (m, 1H). 13C NMR (125 MHz, CDCl3) d
150.8, 147.8, 133.1, 129.9, 128.6, 127.7, 126.8, 120.1, 73.3,
48.6, 39.0, 28.0, 22.3. Anal. Calcd for C15H15N3O: C,
71.13; H, 5.97; N, 16.59. Found: C, 71.07; H, 5.81; N,
16.74. 7-6b 80% yield; mp: 201 ꢁC. 1H NMR (500 MHz,
CDCl3) d 7.48–7.42 (m, 3H), 7.33–7.32 (m, 2H), 4.69 (dd,
1H, J ¼ 7:9, 9.5 Hz), 3.87 (s, 3H), 3.75 (dd, 1H, J ¼ 7:9,
13.7 Hz), 3.56 (m, 1H), 2.66 (m, 2H), 2.28 (m, 1H), 1.69
(m,1H). 13C NMR (125 MHz, CDCl3) d 152.7, 140.3,
137.7, 129.4, 129.2, 128.9, 119.9, 73.3, 48.8, 37.9, 28.2,
20.9. Anal. Calcd for C15H15N3O: C, 71.13; H, 5.97;
N, 16.59. Found: C, 70.92; H, 5.77; N, 16.64. Crystal
data: C15H15N3O, from hexane/ether, colorless,
prism, ꢀ0.250 · 0.200 · 0.120 mm, monoclinic, P21/c,
irregular block, ꢀ0.230 · 0.230 · 0.200 mm, monoclinic,
ꢀ
ꢀ
P21/c,
a ¼ 9:6755ð11Þ A,
b ¼ 10:4034ð12Þ A,
c ¼
3
ꢀ
ꢀ
12:8949ð15Þ A, beta ¼ 105.542(2)ꢁ, Vol ¼ 1250.5(2) A ,
Z ¼ 4, T ¼ ꢁ100 ꢁC, formula weight ¼ 233.31, den-
sity ¼ 1.239 g/cm3, l (Mo) ¼ 0.08 mmꢁ1 7-5b 77% yield;
1
mp: 176 ꢁC. H NMR (500 MHz, CDCl3) d 4.64 (dd, 1H,
J ¼ 8:0, 9.8 Hz), 4.02 (s, 3H), 3.71 (dd, 1H, J ¼ 8:0,
13.0 Hz), 3.41 (m, 1H), 3.03 (ddd, 1H, J ¼ 1:9, 4.9,
16.1 Hz), 2.66 (ddd, 1H, J ¼ 4:8, 12.9, 16.1 Hz), 2.25 (m,
1H), 1.65 (m, 1H), 1.41 (s, 9H). 13C NMR (125 MHz,
CDCl3) d 153.0, 146.1, 137.2, 117.6, 73.4 ,47.9, 41.3, 33.1,
30.5, 28.5, 23.5. Anal. Calcd for C13H19N3O: C, 66.92; H,
8.21; N, 18.01. Found: C, 67.09; H, 8.06; N, 18.16. 7-6a
88% yield; mp: 152 ꢁC. 1H NMR (500 MHz, CDCl3) d
7.72-7.70 (m, 2H), 7.46–7.43 (m, 2H), 7.37–7.35 (m, 1H),
4.76 (dd, 1H, J ¼ 8:1, 9.2 Hz), 4.18 (s, 3H), 3.79 (dd, 1H,
J ¼ 8:1, 13.8 Hz), 3.60 (m, 1H), 3.06 (ddd, 1H, J ¼ 1:9,
ꢀ
ꢀ
ꢀ
a ¼ 7:2409ð15Þ A,
b ¼ 9:633ð2Þ A,
c ¼ 17:930ð4Þ A,
3
ꢀ
beta ¼ 96.381(4)ꢁ,
l (Mo) ¼ 0.09 mmꢁ1
Vol ¼ 1242.9(5) A ,
Z ¼ 4,
T ¼
ꢁ100 ꢁC, formula weight ¼ 253.30, density ¼ 1.354 g/cm3,
.