Samarium(II) iodide reduction of isoxazolidines

Article abstract of DOI:10.1016/j.tetlet.2004.09.050

SmI₂ was used as reducing agent for the N-O bond cleavage in isoxazolidines. The procedure revealed is general and particularly useful for the transformation of 5-spirocyclopropane isoxazolidines to the corresponding β-aminocyclopropanols, a tr

Full text of DOI:10.1016/j.tetlet.2004.09.050

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8375–8377
Samarium(II) iodide reduction of isoxazolidines
Julia Revuelta, Stefano Cicchi and Alberto Brandi*
`
Dipartimento di Chimica Organica ‘Ugo Schiff’ Universita degli Studi di Firenze, Polo Scientifico, Via della Lastruccia 13,
I-50019 Sesto Fiorentino, Italy
Received 16 August 2004; revised 6 September 2004; accepted 7 September 2004
Available online 25 September 2004
Abstract—SmI2 was used as reducing agent for the N–O bond cleavage in isoxazolidines. The procedure revealed is general and
particularly useful for the transformation of 5-spirocyclopropane isoxazolidines to the corresponding b-aminocyclopropanols, a
troublesome transformation with other known reagents.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Samarium(II) iodide has found a widespread use as a
reducing agent.1 Several functional groups are easily
reduced by this reagent while the radical intermediates
produced in the process gave access to an important ser-
ies of new reactions.2 Particularly efficient is the reduc-
tion of the N–O bond which has found application in
the reduction of nitrocompounds,3 hydroxylamines
and hydroxamic acids,4 1,2-oxazine,5 isoxazoles6 and
isoxazolines.7 Furthermore this reactivity has found an
interesting application in a traceless release strategy
for solid-phase synthesis.8 Even if the use of SmI2 for
the reduction of isoxazolidinyl derivatives appears a
logic consequence, there are only two examples of the
use of SmI2 for the reduction of an isoxazolidinone
derivative9 and of isoxazolidines fused with a hetero-
cyclic ring.10 This is probably due to the availability of
a large number of reduction procedures for these com-
pounds which allowed the N–O bond reduction in the
presence of the most common functional groups and
reaction conditions. Nevertheless, the development of
new N–O bond reduction procedures is still useful since
modern organic synthesis always requires more selective
and mild procedures to cope with the simultaneous
assembly of reacting functional groups on the same
molecule.
R1
R1
SmI2
R2
R3
R2
R3
R
NH
N
R
O
1
HO
2
Scheme 1.
bond (Scheme 1, R2–R3 = –CH2–CH2–).11 This is, gen-
erally, a very simple and straightforward transforma-
tion, but the presence of a spirofused cyclopropyl ring
next to the oxygen atom made this reaction trouble-
some. As a matter of fact several of the most common
reagents used in the literature for the reduction of the
N–O bond were tested, like H2/Pd/C,12 Zn/H+,13 Zn/
Cu(OAc)2,14 Mo(CO)6,15 In,16 but all invariably failed
to afford the expected aminoalcohol. Only the use of
Pd(OH)2/C and H2 afforded aminoalcohols 19 and 20
in acceptable yields.11 However the extension of this
methodology to other substrates failed. We presume
that the difficulties encountered in this transformation
were due to the scarce stability of the final product.
Cyclopropane derivatives are known to be very reactive
both under acidic and basic conditions,17 as well as
under reducing conditions,18 leading to open chain
products. On the other hand the same 5-spirocyclopro-
pane isoxazolidines are thermally labile since they easily
undergo thermal rearrangement to afford, as main prod-
uct, tetrahydropyridones.19 We decided, then, to verify
the use of SmI2 as a reducing agent, considering the mild
reaction condition usually needed. Furthermore the use
of SmI2 on cyclopropane substituted substrates posed
some interesting questions about the reactivity of the
intermediate radicals that are known to be formed in
this kind of reaction.1,2 Examples are reported in the
During our ongoing research for the synthetic exploita-
tion of 5-spirocyclopropane isoxazolidines it was needed
to transform these compounds into the corresponding b-
aminocyclopropanols through the reduction of the N–O
Keywords: Samarium iodide; Reduction; Isoxazolidine.
*
Corresponding author. Tel.: +39 0554573485; fax: +39
0554573531; e-mail: alberto.brandi@unifi.it
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.050

8376
J. Revuelta et al. / Tetrahedron Letters 45 (2004) 8375–8377
literature of cyclopropane ring cleavage in reaction of
20
gen atom. In any case, except for entry 3, the yields
are comparable, if not higher, with precedent meth-
ods.12–16 The low yield for compound 15 was ascribed
to a partial hydrolysis of the ester group in the basic
work-up. The reduction of isoxazolidines 9–12 was
then examined using the reaction conditions tuned
before. Every 5-spirocyclopropane isoxazolidine tested
afforded the corresponding aminoalcohol in good to
excellent yield (see entries 7–10).25 The presence of the
spirocyclopropane ring in the final aminoalcohols
bromo-substituted cyclopropanes with SmI2 as well
as in the reduction of cyclopropyl ketones.21
SmI2 has never been used as a general reducing agent
with isoxazolidines besides the two cited examples,9,10
for this reason the reaction was initially tested on isoxaz-
olidines lacking the spirofused cyclopropane ring, to
verify its general applicability and to tune the reaction
conditions (Scheme 1).
1
was easily determined by H and 13C NMR spectro-
As expected the reduction of simple isoxazolidines effi-
ciently afforded the corresponding aminoalcohols or lac-
tams (Table 1). The reaction proceeded despite the steric
hindrance (entries 4 and 6) and proved selective also to-
wards benzylic substitution (entries 1–3). Such selectiv-
ity was already demonstrated in precedent examples.4
The presence of a spirocyclopropane group on the C4
position of the isoxazolidinyl ring, as in isoxazolidine
7, is compatible with the reaction conditions (entry 5).
The synthesis of compound 18 demonstrated the stabil-
ity of a four-membered cyclic ring adjacent to the oxy-
scopy due to the high field resonance typical of both
hydrogen atoms (d 0.8–0.3ppm) and carbon atoms (d
13–5ppm) of the cyclopropane ring.
This successful transformation suggests some considera-
tions about the reaction mechanism. It is well known
that SmI2 act as a single electron donor affording, in
the first step, radical anion species such as 24.1 However
the isolation of the aminoalcohol with the cyclopropyl
group suggests the formation of the alkoxysamarium
species 26 stabilizing the intermediate radical anion
Table 1. SmI2 reduction of some representative isoxazolidinesa
Entry
Isoxazolidine
Product (yield)
Entry
2
Isoxazolidine
Product (yield)
1
(95%)b
(98%)b
NH OH
NH OH
N
O
4
N
Ph
O
13
14
3
CO2Me
CO2Me
CO2Me
N
O
(87%)d
N
O
3
(55%)c
4
N
N
N
OH
O
5
CO2Me
HO
6
16
O
15
N
N
O
N
e
5
7
H
(80%)c
6
8
(90%)
H
O
HO
17
HO
7
8
18
NH
OH
N
(80%)c
O
(70%)c
N
NH OH
19
O
9
10
20
NH OH
O
N
Ot-Bu
Ot-Bu
H
H
9
(90%)c
10
(95%)c
N
H
N
N
SO2
N
O
HO
21
SO2
Ph
Ph
11
12
22
a General procedure: a 100mL Schlenck flask charged with the isoxazolidine (0.5mmol) was added, under nitrogen atmosphere, with 17.5mL of a
commercial 0.1M THF solution of SmI2 (3.5equiv) at rt. The resulting blue solution was stirred for 2h. A 1M solution of NH3 in MeOH (8.5mL)
was added and left under stirring for 20min. Finally 17mL of water were added and the resulting solution was brought to pH9 by addition of a 1M
solution of NaOH. The mixture was then saturated with Na2S2O3 and extracted with diethyl ether (3 · 15mL). The organic phase was then dried
with Na2SO4, filtered and concentrated to afford the crude product.
b See Ref. 22.
c See Ref. 25.
d See Ref. 23.
e See Ref. 24.

J. Revuelta et al. / Tetrahedron Letters 45 (2004) 8375–8377
8377
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N
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O
O
23
O
25
24
SmI2
SmI2
H2O/NH3
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SmI3
+
NH
N
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I2SmO
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I
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28
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for the reduction of isoxazolidines and solved the syn-
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spirocyclopropane isoxazolidines affording also an alter-
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b-aminocyclopropanols.17a
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`
MIUR (Ministero dellÕUniversita, Istruzione e Ricerca-
Italy) is acknowledged for financial contribution. Dr.
Federica Pisaneschi is acknowledged for kindly provid-
ing a sample of isoxazolidine 12.
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1
19: Rf (CH2Cl2–CH3OH 14:1); H NMR: d 7.42–7.22 (m,
5H); 3.87 (dd, J = 10.5, 2.9Hz, 1H); 2.38 (dd, J = 14.2,
10.5Hz, 1H); 2.32 (s, 3H); 1.35 (dd, J = 14.2, 2.9Hz, 1H);
0.84–0.72 (m, 2H), 0.52–0.27 (m, 2H). 13C NMR: d 128.0
(d, 2C); 127.9 (s); 126.6 (d, 2C); 125.8 (d); 64.5 (d); 55.6 (s);
43.4 (t); 32.8 (q); 12.7 (t); 12.1 (t).