SmI2-mediated reductive cross-coupling reactions of -cyclopropyl nitrones

Article abstract of DOI:10.1055/s-0030-1258084

Three new α-cyclopropyl nitrones have been synthesized as mechanistic probes for reductive cross-coupling reactions of nitrones. The α-cyclopropylcarbinyl radical intermediate formed by single electron transfer from SmI² to these nitrones is no

Full text of DOI:10.1055/s-0030-1258084

LETTER
1623
SmI2-Mediated Reductive Cross-Coupling Reactions of a-Cyclopropyl
Nitrones
S
a
mI -Mediated Re
l
ductive
g
Cross-Coup
a
ling Reactions of
N
a
-Cyclopropyl
N
i
.
trones Burchak,a Géraldine Masson,b Sandrine Py*a
2
Département de Chimie Moléculaire (SERCO) UMR-5250, ICMG FR-2607, CNRS Université Joseph Fourier,
BP 53, 38041 Grenoble Cedex 09, France
Fax +33(476)635983; E-mail: sandrine.py@ujf-grenoble.fr
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
b
Received 24 February 2010
O
Abstract: Three new a-cyclopropyl nitrones have been synthesized
as mechanistic probes for reductive cross-coupling reactions of
nitrones. The a-cyclopropylcarbinyl radical intermediate formed by
single electron transfer from SmI2 to these nitrones is not prone to
ring opening, due to a unique stabilization by the vicinal N–O–Sm
system. Consequently, b-cyclopropyl hydroxylamines could be pre-
pared in high yield from a-cyclopropyl nitrones.
1)
R4
SmI2
SmIIIO
R1
R3
R2
OH
R5
–O
R1
R3
R2
N
R3
N
OH
R4
+
N
SmI2 (1 equiv)
R2
2) H2O
R1 R5
A
Scheme 1 SmI2-mediated cross-coupling of nitrones and carbonyl
compounds
Key words: nitrone, samarium diiodide, reductive coupling reac-
tion, mechanistic probes, cyclopropyl group
pling reactions of nitrones with aldehydes, ketones9 or
a,b-unsaturated esters.11 To the best of our knowledge, the
reactivity of a-cyclopropyl imine derivatives under reduc-
tive conditions has not been investigated yet.
Samarium(II) iodide is a powerful single electron transfer
agent, that has been used for a vast range of one-step and
cascade transformations.1 Despite the 30 years history of
SmI2 chemistry since its introduction by Kagan,2 the
mechanism of many SmI2-mediated reactions remains
equivocal. Depending on the nature of substrates, the for-
mation of radical, anionic, or organosamarium intermedi-
ates has been postulated or confirmed by mechanistic
studies.3 Cyclopropyl ketones have proved to be conve-
nient mechanistic probes for radical intermediates,4 as the
cyclopropylcarbinyl → homoallyl radical rearrangement
of cyclopropyl-substituted ketyl radical anions is a kineti-
cally favored process.5 Cyclopropyl ring opening has
served for probing the formation of ketyl radical interme-
diates upon treatment of a-cyclopropyl ketones with
SmI2,6 and it has also been used advantageously in the
synthesis of complex natural products.7 However, Handa
et al. demonstrated that SmI2-mediated intramolecular
pinacol coupling of cyclopropyl ketones to form five-
membered rings is such a fast process, that cyclization
competes favorably with ring opening.8
Herein, we present the synthesis of a-cyclopropyl nitrones
1–3 (Scheme 2), as potential mechanistic probes for SmI2-
mediated reactions of nitrones. As the rate of cyclopropyl
ketyl opening depends on the nature of the substituents on
the cyclopropane ring (2-phenyl cyclopropyl ketyl opens
–O
Bn
H
–O
Bn
H
–O
+
N
Bn
H
+
N
+
N
Ph
Ph
Ph
1
2
3
vi 86%
O
vi 82%
O
vi 92%
O
Ph
Ph
Ph
H
H
H
4
5
6
iv, v 72%
O
iv, v
73%
O
Previously, we have reported the chemoselective cross-
coupling of nitrones with carbonyl compounds in the pres-
ence of SmI2 (Scheme 1),9 as an efficient method to access
vicinal amino alcohols derivatives.10 The formation of
radical A was proposed to be the first step of the process.
Ph
Ph
OMe
OEt
Ph
8
7
Intermediate A can be considered as an imino equivalent
of ketyl radical anions. It was thus expected that upon
treatment with SmI2, a-cyclopropyl nitrones could under-
go cyclopropane ring opening during the reductive cou-
i
97%
ii, iii 89%
Ph
Ph
O
Ph
N
NH2
OH
(rac)-9
10
SYNLETT 2010, No. 11, pp 1623–1626
Advanced online publication: 11.06.2010
DOI: 10.1055/s-0030-1258084; Art ID: D04910ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0
Scheme 2 Synthesis of a-cyclopropyl nitrones 1–3. Reagents and
conditions: (i) SOCl2, MeOH, reflux; (ii) MnO2, MgSO4, CH2Cl2; (iii)
ethyl acrylate, pentane; (iv) LiAlH4, THF, 0 °C to r.t.; (v) Dess–
Martin, CH2Cl2; (vi) BnNHOH, MgSO4, CH2Cl2.

1624
O. N. Burchak et al.
LETTER
significantly faster than unsubstituted cyclopropyl ketyl The SmI2-mediated reductive coupling of nitrones with
radical),12 it was assumed that the rate of ring opening in a,b-unsaturated esters being a slower process when com-
a-cyclopropyl nitrones would also be related to its degree pared to the coupling of nitrones with aldehydes and ke-
of substitution, by analogy.
tones, it was thought that ring opening of the cyclopropyl
group could compete with cross-coupling in this case.11a
Nitrone 2 was thus reacted with ethyl acrylate under sim-
ilar conditions (Scheme 4). However, again the cross-cou-
pling reaction was favored over cyclopropyl opening, and
the g-N-hydroxyamino ester 14 was obtained in 85% yield
(Scheme 4, conditions B).
a-Cyclopropyl nitrones 1–3 were prepared by reaction of
N-benzylhydroxylamine with the corresponding a-cyclo-
propyl carbaldehydes 4–6 (Scheme 2).13 While cyclopro-
pane carbaldehyde (4) is commercially available, its
mono- and disubstituted derivatives 514 and 615 were syn-
thesized from (rac)-trans-2-phenylcyclopropane carbox-
ylic acid (9) and benzophenone hydrazone (10),
respectively.
–O
Bn
H
HO
Bn
+
N
N
(+ recovered 2)
OEt
Ph
Ph
Nitrones 1–3 were first subjected to SmI2-mediated reduc-
tive cross-coupling with cyclohexanone (Scheme 3, con-
ditions A).16 In all cases, only the b-cyclopropyl-b-N-
hydroxyamino alcohols 11–13 were isolated as products,
with no trace of opened-ring products. The reactivity of a-
cyclopropyl nitrones in the presence of samarium diiodide
thus contrasts with the reactivity of the corresponding
a-cyclopropyl carbonyl compounds.6 Disappointingly, in
these reactions, the conversions were reproducibly mod-
est in conditions A. However, as previously observed,9b,11
the introduction of water in reaction media17 led to a sig-
nificant improvement of the yields (82–91%) in b-cyclo-
propyl-b-N-hydroxyamino alcohols 11–13 (Scheme 3,
conditions B).16 Again, no opened-ring product was de-
tected. At this stage, it was assumed that, like in Handa’s
studies,8 the SmI2-mediated reaction of nitrones with car-
bonyl compounds was a fast process that could compete
favorably with the radical ring opening of the cyclopropyl
group.
O
2
conditions A
conditions B
14, 20% (dr 1:6)
14, 85% (dr 1:2)
2, 60%
2, 10%
Scheme 4 SmI2-mediated reductive cross-coupling reactions bet-
ween a-cyclopropyl nitrone 2 and ethyl acrylate. Conditions A: ethyl
acrylate (1.5 equiv), SmI2 (2.2 equiv), THF, –78 °C, 3 h; Conditions
B: ethyl acrylate (1.5 equiv), SmI2 (3.0 equiv), H2O (8.0 equiv), THF,
–78 °C, 3 h.
As noted by Guibé and co-workers,3a the non-observation
of products arising from cyclopropyl opening does not
necessarily mean that radical species are not formed.
Moreover, kinetic studies on cyclopropyl ring opening
have generally been conducted with free radical anions,
and may not transpose to samarium-bound species. In or-
der to evaluate the feasibility of reductive ring opening in
nitrones 1–3, the latter were next treated by SmI2 in the
absence of carbonyl or a,b-unsaturated ester partner, to
avoid the competition of cross-coupling reactions with
a-cyclopropyl ring opening (Scheme 5).
–O
Bn
H
+
N
HO
Bn
N
(+ recovered 1)
HO
Bn
N
HO
1
i
conditions A
conditions B
11, 55%
11, 91%
1, 30%
1, 5%
+
recovered 1, 40%
1
15, 28%
–O
+
N
Bn
HO
Bn
N
HO
Bn
–O
Bn
H
Ph
Ph
+
N
(+ recovered 2)
N
H
i
Ph
2
+
HO
Ph
2
conditions A
conditions B
12, 20% (dr 1:2)
12, 86% (dr 1:3)
2, 70%
2, 0%
16, 15%
17, 35%
–O
Bn
+
N
–O
Bn
HO
Bn
+
N
N
i
Ph
Ph
Ph
Ph
Ph
(+ recovered 3)
3
H
H
Ph
HO
3
18, 35%
conditions A
conditions B
13, 35%
13, 82%
3, 62%
3, 0%
Scheme 5 SmI2-mediated reactions of a-cyclopropyl nitrones 1–3.
Reagents and conditions: (i) SmI2 (3.0 equiv), H2O (16.0 equiv),
THF, –78 °C, 3 h.
Scheme 3 SmI2-mediated reductive cross-coupling of a-cyclo-
propyl nitrones 1–3 with cyclohexanone. Conditions A: cyclohexan-
one (1.5 equiv), SmI2 (2.2 equiv), THF, –78 °C, 3 h; Conditions B:
cyclohexanone (1.5 equiv), SmI2 (3.0 equiv), H2O (16.0 equiv), THF,
–78 °C, 3 h.
In conditions A, no transformation occurred, and starting
nitrones were recovered intact (not shown in Scheme). In
the presence of water (conditions B), nitrones 1–3 exhib-
ited different reactivity pattern, depending on their sub-
Synlett 2010, No. 11, 1623–1626 © Thieme Stuttgart · New York

LETTER
SmI2-Mediated Reductive Cross-Coupling Reactions of a-Cyclopropyl Nitrones
1625
stituents on the cyclopropyl ring. Under treatment with
SmI2 (3 equiv) in the presence of water (16 equiv) at –78
°C, nitrone 1 was partially reduced to the corresponding
N-hydroxylamine 15 (28%); no opened-ring product was
detected in the reaction mixture, and 40% of starting ma-
terial was recovered. Under the same conditions, the phe-
nyl-substituted nitrone 2 was transformed into N-
hydroxylamine 16 (15%) and nitrone 17 (35%); nitrone 3
yielded nitrone 18 (35%) as the only identified product.
Nitrones 17 and 18 do result from a-cyclopropyl ring
opening from SmI2-mediated reduction of nitrones 2 and
3, respectively, and their isolation supports the formation
of a radical intermediate of type A (see Scheme 1). How-
ever, it appears that the ring opening of this radical is not
favored, presumably due to stabilization by delocalization
on the neighboring heteroatomic centers. Stabilization of
radicals a to nitrogen atoms has been documented.18 In the
present system, a unique sharing of p-electrons in the
semi-occupied and lone pair orbitals can be admitted not
only between the C and N centers, but also with the O and
Sm centers, resulting in increased stabilization of the
a-cyclopropyl radical I versus homoallyl radical II
(Scheme 6). Consequently, the predominant formation of
b-N-hydroxyamino cyclopropyl derivatives from SmI2-
mediated reduction of nitrones could be related to the pre-
dominance of intermediate I over II ([I] >> [II],
Scheme 6). Only in cases where II benefits from stabiliza-
tion of the homoallyl radical by substitution with phenyl
group(s) the products resulting from the cyclopropyl →
homoallyl radical rearrangement (i.e. 17 and 18) could be
isolated. This result is surprising in light of the Curtin–
Hammet principle that would predict that I and II being in
rapid equilibrium, the proportion of the products should
depend only on the kinetic rate of their respective bimo-
lecular coupling (or reduction) towards the products. In
such case, one would reasonably expect that II, which is
less stabilized, would react faster than I, and that opened-
ring products would predominate.
I2SmIIIO
Bn
H
–O
Bn
H
I2SmIIIO
Bn
H
+
N
N
SmI2
N
R2
R2
R1
R2
R1
R1
I
II
1) SmI2
2) H2O
HO
Bn
H
N
HO
Bn
N
R2
R2
R1
R1
–O
Bn
H
+
N
R2
R1
Scheme 6 Proposed mechanism for the SmI2-mediated reduction of
a-cyclopropyl nitrones
Acknowledgment
The CNRS, the Université Joseph Fourier, and the Agence Nationa-
le pour la Recherche (grant ANR-05-JCJC-0130-01) are acknowl-
edged for financial support.
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http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 11, 1623–1626 © Thieme Stuttgart · New York

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O. N. Burchak et al.
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Synlett 2010, No. 11, 1623–1626 © Thieme Stuttgart · New York