Lanthanide triflate catalyzed 1,3-dipolar cycloaddition reactions: Stereoselective synthesis of indenoisoxazolidines

Article abstract of DOI:10.1016/S0040-4039(01)00517-2

Substituted indenones reacted smoothly with a variety of in situ generated nitrones in the presence of lanthanide triflates to give exclusive exo 1,3-dipolar cycloaddition products in high yield. Judicious choice of the nitrone substituents allowed for further modification of the indenoisoxazolidine core to the corresponding indenoisoxazoline and indenoisoxazole analogs in high yield.

Full text of DOI:10.1016/S0040-4039(01)00517-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3545–3547
Lanthanide triflate catalyzed 1,3-dipolar cycloaddition reactions:
stereoselective synthesis of indenoisoxazolidines
David A. Nugiel*
DuPont Pharmaceuticals, Box 80336, Wilmington, DE 19880-0336, USA
Received 28 February 2001; revised 23 March 2001; accepted 26 March 2001
Abstract—Substituted indenones reacted smoothly with a variety of in situ generated nitrones in the presence of lanthanide
triflates to give exclusive exo 1,3-dipolar cycloaddition products in high yield. Judicious choice of the nitrone substituents allowed
for further modification of the indenoisoxazolidine core to the corresponding indenoisoxazoline and indenoisoxazole analogs in
high yield. © 2001 Published by Elsevier Science Ltd.
There have been several recent reports on the properties
and synthesis of indenoisoxazolidines. Synthetic
indenoisoxazolidines with exclusive exo selectivity. In
addition, we could further manipulate the isoxazolidine
core and prepare isoxazolines and isoxazoles depending
on the reaction sequence chosen. We found the reaction
between substituted indenones and in situ generated
nitrones to proceed efficiently and in high yield to give
the corresponding indenoisoxazolidines.
1
approaches to these ring systems rely primarily on
thermal 1,3-dipolar cycloadditions of nitrones with a
partnering olefin. Few examples take advantage of Lewis
acid catalyzed 1,3-dipolar cycloadditions as a means of
preparing these ring systems. There have also been
several recent disclosures of lanthanide triflate catalyzed
1
,3-dipolar cycloaddition reactions as a means to prepare
Preparation of the starting indenone system is shown in
Scheme 1. Condensing 3-nitrophthalic anhydride with
ethylacetoacetate and acetic anhydride gave the desired
carbethoxyindanedione intermediate in 85% yield. The
carbethoxy group was smoothly decarboxylated using
2
a variety of substituted isoxazoline systems. These
reports demonstrate the high endo selective nature of this
reaction in addition to the mild reaction conditions for
preparing the desired targets.
trifluoroacetic acid in CH CN at 70°C to give the
3
We recently disclosed a novel series of cyclin dependen3t
kinase inhibitors based on an indenopyrazole core.
Preparing indenoisoxazoles was a logical extension of the
SAR. To this end we explored new methods for preparing
indenoisoxazoles mediated by lanthanide triflate cata-
lyzed 1,3-dipolar cycloaddition reactions. We were able
to apply this useful reaction towards the preparation of
nitroindanedione 1 in 76% yield. Hydrogenation of this
material using Pd/C reduced both the nitro group and
the eneone double bond to give the corresponding
7-amino-3-hydroxy-indan-1-one in quantitative yield.
Selective acylation of the aniline nitrogen was carried out
using acetyl chloride and K CO in acetone at 60°C.
2
3
The 3-hydroxy group was eliminated using mesyl
O
NO2
NO2
O
O
O
NH
O
a, b
c, d, e
O
O
1
2
Scheme 1. Reagents and conditions: (a) ethylacetoacetate, Ac O, Et N, rt, 85%; (b) TFA, CH CN:water, 70°C, 76%; (c) H , Pd/C,
2
3
3
2
quant.; (d) AcCl, K CO , acetone, 60°C, 88%; (e) MsCl, Et N, CH Cl , reflux, 72%.
2
3
3
2
2
*
0
Corresponding author.
040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)00517-2

3
546
D. A. Nugiel / Tetrahedron Letters 42 (2001) 3545–3547
chloride and triethylamine in refluxing CH Cl to give
the desired indenone system 2 in 63% overall yield.
the reaction stirred at rt for 18 hours. The mixture was
directly purified using silica gel chromatography to give
the desired cycloaddition product in good yield. Both
molecular sieves and the lanthanide catalyst were
required for the reaction to succeed (3g). Both catalysts
worked equally well and gave similar exo/endo product
ratios.
2
2
The indenone system 2 was used in several 1,3-dipolar
cyclization reactions as shown in Table 1. Typical reac-
tion conditions were as follows: activated 3 A
lar sieves were covered with benzene and treated with
.2 equiv. of lanthanide catalyst. After 10 minutes the
,
molecu-
0
4
hydroxylamine and aldehyde were added and allowed
All compounds gave satisfactory analytical data as
1
6
to form the corresponding nitrone at 50°C over 30
determined by H NMR, MS and HPLC. A complete
5
minutes. The indenone 2 was subsequently added and
proton assignment was performed on compound 3e
Table 1. 1,3-Dipolar cycloadditions of 2 with assorted nitrones
O
O
NH
O
NH
O
H
H
R2
N
H
O
R1
2
3
Entry
R1
R2
Catalyst
Yield (%)a
exo:endo (ratio)b
3
3
3
3
3
3
3
a
b
c
d
e
f
C H CH
2
p-MeO
p-MeO
p-MeO
p-MeO
p-NO2
H
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
None
88
84
81
86
78
69
98:2
98:2
98:2
98:2
98:2
98:2
6
5
4-MeOC H CH
6
4
2
3,4-diMeOC H CH
3,4-diMeOC H CH
3,4-diMeOC H CH
3,4-diMeOC H CH
6
3
2
2
2
2
2
6
3
6
3
6
3
c
g
3,4-diMeOC H CH
p-MeO
0
6
3
a
b
c
Yields based on isolated and purified material.
Determined by 1H NMR.
Both starting materials were recovered unchanged.
O
O
NH
O
NH
O
H
H
H
H
a
OMe
OMe
N
NH
O
H
O
H
DMB
3c
4
DMB = Dimethoxybenzyl
b
O
O
NH
NH
O
O
H
c
OMe
OMe
N
N
H
O
O
5
6
Scheme 2. Reagents and conditions: (a) TFA, CH Cl , reflux, 86%; (b) DDQ, CH Cl :water, rt, 94%; (c) 1. NBS, cat. AIBN, CCl ,
2
2
2
2
4
reflux, 2. KOH, MeOH, reflux, 68%.

D. A. Nugiel / Tetrahedron Letters 42 (2001) 3545–3547
3547
1
using 2D H NMR experiments. The preferred exo
(c) Kobayashi, S.; Akiyama, R.; Kawamura, M.; Ishitani,
H. Chem. Lett. 1997, 10, 1039–1040; (d) Minakata, S.;
Ezoe, T.; Nakamura, K.; Ryu, I.; Komastu, M. Tetra-
hedron Lett. 1998, 39, 5205–5208.
orientation seen in the products was determined by
NOE experiments. Irradiating the C-3a proton adjacent
to the indeno carbonyl induces a signal enhancement of
the two protons at C-3 and C-8a. Subsequent sequential
irradiation of the two protons at C-3 and C-8a causes a
signal enhancement of the C-3a proton, indicating all
three protons are on the same face of the indenoisoxa-
zolidine core and confirming the exo product
preference.
3. Nugiel, D. A.; Etzkorn, A. M.; Vidwans, A.; Benfield, P.
A.; Boisclair, M.; Burton, C. R.; Cox, S.; Czerniak, P. M.;
Doleniak, D.; Seitz, S. P. J. Med. Chem. 2001, 44, in press.
4. (a) Baldwin, J. E.; Cha, J. K.; Kruse, La. I. Tetrahedron
1985, 41, 5241–5260; (b) Dagoneau, C.; Denis, J. N.;
Vallee, Y. Synlett 1999, 5, 602–604.
. TLC showed disappearance of the starting aldehyde and
hydroxylamine concurrent with the formation of the
desired nitrone.
5
Indenoisoxazolidine 3 can be further converted to the
corresponding indeonisoxazoline 5 and indenoisoxazole
as shown in Scheme 2. The DMB protecting group
6
6. Analytical data for select compounds: 3a: mp 169–171°C;
1
was removed by treating with TFA in refluxing CH Cl2
H NMR (300 MHz, CDCl ) 10.0 (bs, 1H), 8.5 (d, J=9
2
3
to give the desired product 4 in 86% yield. Alterna-
tively, the DMB group could be removed using an
oxidation protocol. Treating 3c with DDQ gave the
desired indenoisoxazoline 5 in 94% yield. Attempts at
further oxidizing this isoxazoline intermediate directly
to the isoxazole using a variety of oxidants failed. A
two-step protocol proved to work very well. Treating
the isoxazoline 5 with NBS gave the desired brominated
Hz, 1H), 7.7 (t, J=7.5 Hz, 1H), 7.3 (d, J=7.7 Hz, 1H), 7.1
(m, 4H), 6.9 (m, 5H), 5.6 (d, J=6.6 Hz, 1H), 4.1 (m, 1H),
3.9 (d, J=15 Hz, 1H); 3.8 (s, 3H), 3.6 (s, 2H), 2.2 (s, 3H);
HRMS calcd for C H N O (M+H): 429.1814, found:
26
25
2
4
1
429.1823; 3b: mp 173–175°C; H NMR (300 MHz, CDCl )
3
10.0 (bs, 1H), 8.5 (d, J=9 Hz, 1H), 7.7 (t, J=7.5 Hz, 1H),
7.3 (d, J=7.7 Hz, 1H), 7.1 (m, 4H), 6.9 (d, J=9 Hz, 2H),
6.8 (d, J=9 Hz, 2H), 5.6 (d, J=6.6 Hz, 1H), 4.1 (m, 1H),
3.9 (d, J=15 Hz, 1H), 3.8 (2×s, 2×3H), 3.6 (s, 2H), 2.2 (s,
3H); HRMS calcd for C H N O (M+H): 459.1920,
7
intermediate, which was treated directly with KOH in
MeOH at reflux to give the desired indenoisoxazole 6 in
2
7
27
2
5
1
68% yield for the two steps.
found: 459.1925; 3c: mp 169–170°C; H NMR (300 MHz,
CDCl ) 10.0 (bs, 1H), 8.5 (d, J=9 Hz, 1H), 7.7 (t, J=7.5
3
In conclusion, we have shown that lanthanide triflate-
mediated 1,3-dipolar cycloadditions of nitrones with
indenones is an efficient route to complex indeonisoxa-
zolidine systems. The reaction is exo specific and con-
structs three contiguous asymmetric centers with a
single reaction. In addition, these isoxazolidine interme-
diates can be further manipulated to give the corre-
sponding isoxazolines or isoxazoles in good yield.
Hz, 1H), 7.4 (d, J=7.7 Hz, 1H), 7.3 (d, J=9 Hz, 2H), 7.1
(m, 3H), 6.8 (d, J=9 Hz, 2H), 6.4 (dd, J=9, 2 Hz, 1H),
6.3 (d, J=2 Hz, 1H), 5.6 (d, J=6.6 Hz, 1H), 4.1 (m, 2H),
3.8 (2×s, 2×3H), 3.6 (s, 3H), 2.2 (s, 3H); HRMS calcd for
C H N O (M+H): 489.2026, found: 489.2010; 3e: mp
28
29
2
6
1
165–167°C; H NMR (600 MHz, CDCl ) 9.9 (bs, 1H), 8.5
3
(d, J=8.2 Hz, 1H), 8.1 (d, J=8.8 Hz, 2H), 7.7 (t, J=7.9
Hz, 1H), 7.4 (d, J=7.5 Hz, 1H), 7.3 (d, J=8.8 Hz, 2H),
7.1 (d, J=8.4 Hz, 1H), 6.4 (dd, J=8.4, 2.4 Hz, 1H), 6.3 (d,
J=2.4 Hz, 1H), 5.6 (d, J=6.4 Hz, 1H), 4.2 (d, J=9.2 Hz,
1H), 3.9 (s, 2H), 3.8 (s, 3H), 3.7 (dd, J=9.2, 6.4 Hz, 1H),
References
3
.6 (s, 3H), 2.1 (s, 3H); HRMS calcd for C H N O
27 26 3 7
1
1
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3
1H), 8.1 (d, J=9 Hz, 2H), 7.4 (t, J=7.5 Hz, 1H), 7.1 (d,
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19
15
2
4
found: 335.1022.
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1
2
indenone carbonyl. H NMR indicates the process was
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.