Michael addition initiated carbocyclization sequences with nitroolefins for the stereoselective synthesis of functionalized heterocyclic and carbocyclic systems

Article abstract of DOI:10.1002/chem.200901433

The synthesis of various heterocycles and carbocycles (tetrahydrofurans, pyrrolidines, cyclopentanes) has been achieved by using new and efficient ionic addition/cyclization sequences. Nitroolefins play an important role in the Michael addition induced ring-closing reactions (MIRC) reported in the present article, with various substituted alcohols, amines, Grignard reactants, or malonate derivatives acting as the nucleophile partner. The optimized cascade reactions were high yielding in most cases and highly stereoselective, creating up to three stereogenic centers starting from achiral substrates.

Full text of DOI:10.1002/chem.200901433

DOI: 10.1002/chem.200901433
Michael Addition Initiated Carbocyclization Sequences with Nitroolefins for
the Stereoselective Synthesis of Functionalized Heterocyclic and Carbocyclic
Systems
Estelle Dumez, Anne-Catherine Durand, Martial Guillaume, Pierre-Yves Roger,
Robert Faure, Jean-Marc Pons, Gaꢀtan Herbette, Jean-Pierre Dulcꢁre,
Damien Bonne,* and Jean Rodriguez*[a]
Abstract: The synthesis of various heterocycles and carbocycles (tetrahydrofurans,
pyrrolidines, cyclopentanes) has been achieved by using new and efficient ionic ad-
dition/cyclization sequences. Nitroolefins play an important role in the Michael ad-
dition induced ring-closing reactions (MIRC) reported in the present article, with
various substituted alcohols, amines, Grignard reactants, or malonate derivatives
acting as the nucleophile partner. The optimized cascade reactions were high yield-
ing in most cases and highly stereoselective, creating up to three stereogenic cen-
ters starting from achiral substrates.
Keywords:
cycloaddition · domino reactions ·
Michael addition · nitroolefins
cyclization
·
Introduction
Moreover, the presence of an unsaturated bond available
for further elaboration has stimulated interest in a plethora
of synthetic routes to 3-methylene tetrahydrofurans,[4] as
well as methylene cyclopentanes.[5] For the construction of
these motifs, two major five-membered ring-forming pro-
cesses have been developed in recent years. Although the
transition-metal-catalyzed cycloisomerization of 1,6-dienes
represents an extremely powerful method for the rapid as-
sembly of carbo- and heterocyclic compounds,[6] considera-
ble attention has recently focused on [3+2] annulations,[3a,7]
due to the advantage of creating two carbon–carbon or het-
eroatom–carbon bonds under the same reaction conditions.
Alternatively, regio- and stereoselective cyclizations can
be achieved by intramolecular 1,3-dipolar cycloadditions,[8]
usually for the construction of five-membered heterocycles.
Indeed, two rings are generated during these cycloadditions,
one of which is a five-membered heterocycle that can be
cleaved, thereby leading to the formation of either a carbo-
or a heterocycle, stereospecifically substituted by two new
functional groups.[9]
Heterocycles and carbocycles are key structural features in
many biologically significant compounds. For example, tetra-
hydrofuran and -pyran skeletons are found in several inter-
mediates for the synthesis of numerous polyethers and iono-
phore natural products.[1] Interesting biological activities are
exhibited by several polysubstituted pyrrolidines.[2] Among
carbocycles, five-membered rings are particularly important
building blocks for the synthesis of natural products, for ex-
ample, the prostaglandins.[3] Therefore, the development of
highly stereoselective reactions for the synthesis of function-
alized cyclopentane derivatives remains an important goal
in organic synthesis.[3e]
[a] Dr. E. Dumez, Dr. A.-C. Durand, Dr. M. Guillaume, Dr. P.-Y. Roger,
Dr. R. Faure, Dr. J.-M. Pons, Dr. G. Herbette, Dr. J.-P. Dulcꢀre,
Dr. D. Bonne, Dr. J. Rodriguez
Aix-Marseille Universitꢁ
As part of our sustained interest in one-pot diastereose-
lective cyclizations, we reported some years ago straightfor-
ward entries to functionalized carbocycles and heterocycles,
provided by the Michael addition–intramolecular carbocycli-
zation reaction between unsaturated nucleophiles and a,b-
disubstituted nitroalkenes.[10] Very recently, we reported an
asymmetric version of this efficient sequence that allows the
Institut des Sciences Molꢁculaires de Marseille
iSm2 CNRS UMR 6263, Centre Saint Jꢁrꢂme
service 531-13397 Marseille Cedex 20 (France)
Fax : (+33)491-288-841
E-mail: jean.rodriguez@univ-cezanne.fr
damien.bonne@univ-cezanne.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901433.
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FULL PAPER
synthesis of fused isoxazoline precursors of enantiopure cy-
clopentanoids.[11]
Inspired by the design of new domino reactions, which
have become an attractive area of organic synthesis,[12] we
tried to develop new and improved combinations of cas-
cades, bearing in mind that when cyclizations are involved
in these sequences, the ring closure generally proceeds in a
highly stereoselective fashion. Michael addition induced
ring-closing reactions (MIRC)[13] play a dominant role in
this field. Herein, we report our studies on transformations
initiated by a Michael addition to nitroalkenes 1 coupled
with intramolecular additions to an unactivated double or
triple bond, involving either simple anionic carbocyclization
or 1,3-dipolar cycloaddition (Scheme 1). Unsaturated alco-
hols 2 and amines 5 were chosen to initiate hetero-Michael
additions, and unsaturated Grignard reagents 7 and malo-
nate derivatives 8 provided 1,4-additions of carbon-centered
nucleophiles.
Results and Discussion
A range of nitroalkenes was prepared by adaptation of
known procedures, that is, by the Henry reaction followed
by dehydration of the resulting nitroaldols.[20] Nitroalcohols,
prepared by the reaction of an aldehyde with nitroethane or
-methane and aqueous NaOH in methanol, were dehydrated
to provide E-nitroalkenes 1a–b and 1i.[21] Nitroalkenes 1 f
and 1g were obtained[22] starting from Garnerꢄs aldehyde[23]
and (R)-isopropylidene glyceraldehyde, respectively.[24]
Heating a solution of benzaldehyde and ammonium acetate
at reflux in nitroethane for 12 h afforded 1c in 97% yield,[25]
and nitromercuration of cyclopentene and subsequent b-
elimination provided 1d in 80% yield.[26] 1-Nitrocyclohex-
ene 1e and b-nitrostyrene 1h are commercially available.
Anionic domino Michael/carbocyclizations onto unactivated
alkynes: Although the oxa-Michael addition of prop-2-ynyl
alcohols to b-monosubstituted a-nitroalkenes in the pres-
ence of sodium or potassium hydride led to b-nitroprop-2-
ynyl ethers,[27] only few recent preparations of five- or six-
membered heterocycles involve a subsequent intramolecular
addition to the triple bond.[28] Among them, tBuOK-promot-
ed double Michael addition[29] and oxa-Michael/SN2’ substi-
tution[30] with a,b-disubstituted nitroalkenes generate a sta-
bilized nitronate anion, which subsequently adds to the acti-
vated alkyne moiety to provide the heterocycles. The two-
step synthesis of a-methylene g-lactams from 1-nitrocyclo-
hexene, involving the formation of b-nitroamides, which un-
dergo benzyltrimethylammonium hydroxide (Triton B)-pro-
moted carbanion addition to an unactivated terminal alkyne
is also of interest,[31] because it constitutes an unusual report
of the addition of a carbon nucleophile to an unactivated
alkyne moiety. These results underline the crucial effect of
both the nitroalkene substitution pattern and the nature of
the base on the reaction process. Therefore, we propose that
an anionic domino oxa-Michael cyclization sequence with
propargylic alcohols leading to methylenetetrahydrofurans
should be possible by combining an appropriate set of ex-
perimental conditions. Indeed, we were pleased to find that
when nitroalkenes 1b–e were added to a solution of prop-2-
ynyl alcohols 2a–d containing tBuOK, a fast transformation
occurred, leading to 3-methylenetetrahydrofurans 13–25 in
moderate to good yields, which in some cases were accom-
panied by the corresponding dihydropyrans 29–34
(Scheme 2 and Table 1).
Scheme 1. The Michael addition–carbocyclization sequence.
The purpose of this article is to present the extension of
these methodologies, including scope and limitations with
full experimental data.
Michael addition to nitroalkenes:[4] Nitroalkenes constitute
substrates of particular interest in synthesis, either in terms
of their reactivity or their applications as key intermediates
in the construction of complex and/or biologically active
molecules.[15] The powerful electron-withdrawing effect of
the nitro function is the main feature of nitroalkenes, which
are hard electrophiles and therefore good acceptors in Mi-
chael additions.[16] The synthetic utility of these derivatives
also arises from the easy transformation of the nitro group
into many other functionalities.[17] Nitroalkenes are also pre-
cursors of very reactive 1,3-dipolar reagents, such as nitrile
oxides, nitrones, and nitronates.[18] Chiral nitroalkenes are
versatile precursors for 1,2-asymmetric induction. Hence, re-
actions of several nucleophiles in the cyclopropanation with
the appropriate facial diastereoselectivities have been re-
ported.[19] For this purpose, two nitroolefins 1 f and 1g were
elaborated from aldehydes with a stereogenic center in the
alpha position.
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12471

D. Bonne, J. Rodriguez et al.
The best results were obtained when nitroalkenes were
added slowly to a solution of 2 and tBuOK in a mixture of
benzene and tBuOH at À58C; the reaction proceeded with
total diastereoselectivity due to allylic 1,3-strain.[30,32] Unex-
pected regioselectivity was observed when the reactions
were performed on nitroalkenes 1b and 1e: 5-exo adducts
13–15 (Table 1, entries 1–3) and 22–24 (Table 1, entries 10–
12) were isolated along with 3,4-dihydropyrans 29–31 and
32–34, which arise from a disfavored 6-endo cyclization
(ratio 5-exo/6-endo=1.7–20:1). We noticed a drastic effect
of the nature of the unsaturated alcohol nucleophile on the
course of the cyclization. Heterocycles obtained by reaction
with secondary alcohol 2b (Table 1, entries 2, 5, 8, 11) were
obtained as a 0.7–0.9:1 mixture of separable diastereomers
and the observed low facial selectivity with 2-methyl-substi-
tuted alcohols was increased up to 0.25:1 in 25 when alcohol
2d (bearing the large benzyloxymethyl group) was involved
Scheme 2.
in
(Table 1, entry 13). Generally, a
significant Thorpe–Ingold
the
Michael
addition
Table 1. Formation of 3-methylenetetrahydrofurans 13–27 and 3,4-dihydropyrans 29–34.[a]
effect[33] was observed, account-
ing for the increased rate of the
process in the case of 2c
(Table 1, entries 3, 6, 9, 12). On
the other hand, addition of 2 f
to nitroalkenes 1b or 1d result-
ed in a stabilization of the buta-
dienyl anion, which underwent
further cyclization into buta-
dienyl tetrahydrofurans 26 and
27 (Table 1, entries 14–16) along
with the formation of the
opened keto adduct 28a, which
arises from a Nef transforma-
tion, when starting from 1b.
While 27 was isolated in the
1
2
t
Products
Yield [%]
exo/endo
dr[c]
1
1b
2a
12 h
57
20:1
2
3
4
5
1b
1b
1c
1c
2b
2c
2a
2b
1 h
48
32
73
31
10:1
16:1
0.6:1
10 min
12 h
2 h
ratio
E/Z=17:83
(Table 1,
entry 16), total selectivity for
the Z isomer was observed in
the formation of 26 (confirmed
by a NOESY experiment). Fi-
nally, running the reaction with
b-nitrostyrene (1h) resulted in
the decomposition of the start-
ing material (Table 1, entry 17),
highlighting the crucial effect of
the absence of substitution
alpha to the nitro function.
Indeed, the stability of the re-
sulting nitronate intermediate is
probably enhanced, which disfa-
vors the carbocyclization step.
Another interesting observa-
tion concerns the presence of a
methyl group on the alkyne
moiety in 2e. Compound 2e
gives rise exclusively to oxa-Mi-
chael adduct 12 as a 4:1 mixture
of diastereomers (Table 2, en-
0.8:1
6
1c
1d
1d
1d
1e
2c
2a
2b
2c
2a
10 min
24 h
1 h
58
84
80
78
78
7
8
0.6:1
9
0.5 h
21 h
10
1.7:1
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Michael Addition Initiated Carbocyclization
Table 1. (Continued)
FULL PAPER
the reaction of homoallylic al-
cohol 6 with nitroalkene 1b was
unsuccessful, resulting in the
Nef oxidation of Michael
adduct to form 28b exclusively
(Table 2, entry 4).
After these encouraging re-
sults, and to optimize this new
one-pot anionic heterocycliza-
tion, we first decided to study
the effect of the nature of the
base on the yield and selectivi-
ty. The results of reactions be-
tween nitroalkenes 1b and 1e,
propyn-1-ol 2a and different
bases under various reaction
conditions are collected in
Table 3.
When nitrocyclohexene (1e)
was treated with an excess of
the lithium alkoxide obtained
by reaction of n-butyllithium
(1.5m) with propargyl alcohol
(2a), a complex mixture was
obtained and keto compound
9a,[34] resulting from the Nef
oxidation of the Michael adduct
intermediate, was the sole prod-
uct isolated (Table 3, entry 1).
Michael adduct 10 was isolated
1
2
t
Products
Yield [%]
47
exo/endo
dr[c]
11
12
13
14
15
1e
2b
6 h
3:1
1e
1e
1b
1b
2c
2d
2 f
2 f
10 min
3 h
37
3:1
85
0.25:1
2 h
66 (3.7:1)
12 h
62
37
16
17
1d
1h
2 f
2a
2 h
1 h
(17:83)[b]
ACHTUNGTRENNUNG
decomposition
[a] All reactions were run in the presence of tBuOK (1.7 equiv) with 2 (1.5 equiv) in benzene/tBuOH (2:1,
1
0.4m) at À58C. [b] E/Z ratio. [c] Determined by H NMR spectroscopy of the crude product.
tries 1 and 2). Indeed, in these cases, cyclization would re-
quire the transient formation of a secondary vinyl anion,
which would result in destabilization. Finally, as expected,
the anionic cyclization did not occur on an unactivated
double bond and only Michael adduct 35 was isolated when
allylic alcohol 4a was involved (Table 2, entry 3). Similarly,
in 27% yield when NaH was used as the base (Table 3,
entry 2). Surprisingly, K2CO3 only resulted in the decompo-
sition of the starting material and no product could be iso-
lated (Table 3, entries 3 and 7). The hard base Cs2CO3 dis-
played approximately the same features as tBuOK, both in
terms of products distribution and reaction times (Table 3,
entries 4–6). Although yields were lower, the regioselectivity
in favor of the 5-exo isomer 22 was increased up to 5:1
when three equivalents of propargyl alcohol 2a were em-
ployed (Table 3, entry 5). Conducting the reaction with po-
tassium hydride without the addition of tBuOH for 1 h from
À40 to 08C afforded the Michael adduct 11 in good yield,
according to previously reported results by the groups of
Kurth[27] and Yao[35] (Table 3, entry 8). Lengthening the reac-
tion time to 48 h, starting from À40 to 258C in the absence
of tBuOH had a significant effect, leading to the formation
of the expected cyclized derivatives (13 and 29) as minor
products (Table 3, entry 9) together with the Michael adduct
11. Finally, running the reaction under the same reaction
conditions in the presence of the additive tBuOH resulted in
the exclusive recovery of cyclized adducts 13 and 29 in the
ratio 7:1 and 90% yield (Table 3, entry 10). This clearly
shows the beneficial effect of the tBuOH as the proton
source on the kinetic of the overall process. The carbocycli-
zation step should be a thermodynamically unfavorable pro-
cess because it converts a stabilized nitronate anion into a
nonstabilized vinylic anion. However, when tBuOH is used
Table 2. Michael addition to 1b: Effect of the nature of the unsaturated
alcohol.
Alcohol
Conditions[a]
Products
Yield [%][b]
75 (4:1)[c]
1
2
3
4
2e
258C, 1 h
2e
408C, 2 h
258C, 1 h
258C, 5 h
70 (4:1)[c]
87 (4:1)[c]
68
[a] All reactions were run in the presence of tBuOK (1.7 equiv) with
1.5 equiv of 2 in benzene/tBuOH (2:1, 0.4m) at À58C. [b] Isolated yield.
[c] cis/trans diastereomeric ratio; the assignment was done based on com-
parison of J values of protons a and b to NO2 function.
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D. Bonne, J. Rodriguez et al.
Table 3. Effect of base, solvent, and temperature on the oxa-Michael addition of propargyl alcohol 2a on ni-
troalkene 1b and 1e.
metal enolates to unactivated
triple bonds to give methylene-
cyclopentanes. Such a transfor-
mation usually requires the as-
sistance of a transition metal
catalyst or the use of catalytic
amount of base. In 1953, Eglin-
ton and Whiting reported[39]
that 1,1-dicarboethoxy-2-meth-
ylenecyclopentane was isolated
from the cyclization of diethyl
5-hexyne-1,1-dicarboxylate in
the presence of EtONa at
reflux. This constituted the first
anionic intramolecular cycliza-
tion onto a nonactivated alkyne
to give the methylenecyclopen-
tane skeleton, and similar re-
sults were disclosed a few years
later.[40] Since these pioneering
studies, the most common pro-
cedures for the synthesis of
1
Base ([equiv]) 2a [equiv] Conditions[a]
Products
Yield [%] 5-exo/
6-endo
1
2
1e nBuLi (3)
1e NaH (2)
3
258C, 1 h
20
2
À408C, 1 h
27[c]
–
34
24
19
3
4
5
6
1e K2CO3 (1.7)
1e Cs2CO3 (1.7)
1e Cs2CO3 (1.5)
1e Cs2CO3 (1.5)
1.5
1.5
3
18-C-6 258C, 24 h decomposition
À58C, 22 h
4:1
5:1
4:1
À58C, 22 h
1
À58C, 22 h
7
8
9
1b K2CO3 (1.7)
1b KH (2)
1.5
2
258C, 24 h
decomposition
–
À40 to 08C, 1 h[b]
71[c]
1b KH (2)
2
2
À40 to RT, 48 h[b] (11[c]/13+29) (1.6:1)
81
90
2.5:1
7:1
10 1b KH (2)
À40 to RT, 40 h
13+29
[a] Unless otherwise stated THF/tBuOH (30:1) was used as solvent. [b] THF was used as solvent. [c] Only one
1
diastereomers (cis) was detected by analysis of the H NMR of the crude product (see Experimental Section).
methylenecyclopentanes
in-
volve intramolecular addition
as an additive, the vinylic anion is irreversibly protonated,
which may drive the process to completion (Scheme 3).
Table 4. Formation of 3-methylenepyrrolidines 36–39.[a]
1
t [h]
Product
Yield[b]
84
Scheme 3. Proposed mechanism for the carbocyclization process.
1
2
3
4
1b
1
Interestingly, aza-Michael addition of N-methylprop-2-
ynylamine (3) to nitroalkenes 1b–e also proceeded with in-
tramolecular nucleophilic carbocyclization to provide regio-
and diastereoselectively the corresponding 3-methylenepyr-
rolidines 36–39 (Table 4). Similarly to the formation of the
O-heterocycles described above, cyclization into 3-methyle-
nepyrrolidines proceeded under total 1,3-allylic strain.
Moreover, the intramolecular nucleophilic addition exclu-
sively affords products arising from 5-exo cyclization.
Indeed, the same regioselectivity was reported by Rosen-
berg and Rapoport[36] and Coldham et al.[37] in a study of
anionic cyclization of (2-aza)- and (3-aza)-5-heptenyl sys-
tems.
1c
1d
1e
2
29
63
70
1.5
2
[a] All reactions were run in the presence of tBuOK (1.7 equiv) with
3.0 equiv of 3 in benzene/tBuOH (2:1, 0.4m) at 08C. [b] Isolated yield.
To extend the overall heterocyclization to the synthesis of
the corresponding valuable methylene carbocycles, we envi-
sioned the reactivity of propargyl malonates as Michael
donors. This will provide a Michael adduct intermediate
with a geminal diester group in the hope of utilizing the
Thorpe–Ingold effect[38] to promote the cyclization. In the
literature there are few reports of the addition of stabilized
of organometallic,[41] radical,[42] or anionic[43] centers to a
triple bond and cycloisomerization of enynes,[44] dienes,[45] al-
kynones,[46] or e-acetylenic b-ketoesters.[47] Whereas these
approaches are concerned with a one-bond formation, con-
siderable attention has also been focused on [3+2] annula-
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Michael Addition Initiated Carbocyclization
FULL PAPER
tions.[48] More particularly, encouraged by the interesting
features of anionic [3+2] heterocyclizations that we devel-
oped above, we decided to examine the base-promoted Mi-
chael addition of dimethylpropargyl malonate 8 to nitroal-
kenes 1a–e (Scheme 4 and Table 5). The benzene/tBuOH
solvent system used previously (Tables 1 and 2) was re-
placed by THF/tBuOH for a better solubility of the nitro-
nate intermediates. When nitroalkenes 1a–e were reacted at
08C in THF/tBuOH (30:1) with 8 in the presence of one
equivalent of tBuOK, methylenecyclopentanes 41, 43, and
44 were isolated but in relatively modest yields, not exceed-
ing 40% after a long reaction time, whereas 40 and 42 could
only be detected in the crude reaction mixture (Table 5, en-
tries 1, 3, 5, 7, and 9). Moreover, although total diastereose-
lectivity was observed with nitroalkenes 1c and 1e for deriv-
atives 41 and 43 (which were also the only product formed,
Table 5, entries 3 and 7), product 42 was obtained as a 1.4:1
trans/cis diastereomeric mixture (Table 5, entry 5) and meth-
ylenecyclopentanes 40 and 44 were formed along with the
inseparable Michael adducts 47 and 48 in 12 and 15% yield,
respectively (Table 5, entries 1 and 9). To optimize experi-
mental conditions, a variety of bases were tested with nitro-
cyclohexene 1e. K2CO3, Cs2CO3, KH, NaH, and 1,8-
diazabicycloACTHNUGTRNEUNG[5.4.0]undec-7-ene (DBU) and their solvent sys-
tems proved to be unsuccessful, but revealed once again the
crucial effect of a proton source such as tBuOH.
Gratifyingly, in the case of nitroalkene 1e, the use of Tri-
ton B as the base provided the expected domino [3+2] an-
nulation into methylenecyclopentane 44 (Table 5, entry 10)
and a substantially improved yield (up to 80%) was attained
when Triton B (1 equiv) was
Scheme 4. Synthesis of 3-methylenecylopentanes.
added at 08C to a solution of
Table 5. Formation of methylenecylopentanes 40–44.
nitroalkene 1e (1.3 equiv) and
Conditions[a]
t [h]
Michael adduct
Cyclization product
8 (1 equiv). The use of a cata-
lytic amount of base resulted in
the recovery of starting materi-
als. With the optimal conditions
in hand, we therefore examined
this new domino reaction with
nitroalkenes 1a–d. The overall
transformation was completed
after a few minutes and the
1
1
2
1a
1a
tBuOK
Triton B
12
24
12% (1:9)[b]
–
<5%
56%
[3+2]
annulation
afforded
methylene cyclopentanes 40–43
in 47–65% yields after purifica-
tion by flash chromatography
on silica gel. It should be noted
3
4
1b
1b
tBuOK
Triton B
21
5
–
–
33%
51%
that
methylenecyclopentanes
40–44 are the sole products iso-
lated when using Triton B,
whereas Michael adducts 47
and 48 were obtained in 12–
15% yield when tBuOK was
employed as the base. The reac-
tion proceeded with total dia-
stereoselectivity for monocyclic
compounds 40 and 41 (Table 5,
entries 2 and 4), due to allylic
1,3-strain as previously reported
in related systems.[30] The
higher diastereoselectivity (9:1)
observed in the formation of 42
(Table 5, entry 6) with respect
to the reaction with tBuOK
(1.4:1) can be accounted for by
an interplay between stereo-
5
6
1c
1c
tBuOK
Triton B
24
16
–
–
<5% (1.4:1)[b]
47% (9:1)[b]
7
8
1d
1d
tBuOK
Triton B
13
1
–
–
35%
65%
9
10
1e
1e
tBuOK
Triton B
18
0.5
15% (1:2)[b]
–
40%
80%
[a] All reactions were run in the presence of tBuOK or Triton B (1.0 to 1.3 equiv) with 8 (1.0 equiv) in THF/
tBuOH (30:1) at 08C. [b] trans/cis diastereomeric ratio.
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D. Bonne, J. Rodriguez et al.
Table 6. Reaction of 1,2-disubstituted nitroalkenes.[a]
chemistry and ion pair forma-
tion. Indeed, the presence of
the large benzyltrimethylammo-
nium cation instead of potassi-
um may affect ion pair forma-
tion[49] and therefore the allylic
1,3-strain effect. The relative
stereochemistry of compounds
40–44 was deduced from their
Base
Nitroalkene
t [h]
Product
Yield [%]
1
2
Triton B
NaH
24
16
32
52
3
4
Triton B
NaH
5
3
63
87
spectral
NOESY
data
experiments)
(1H NMR
and
[a] All reactions were run in the presence of NaH or Triton B (1.0 equiv) with 8 (1.0 equiv) in THF/tBuOH
(30:1) at 08C.
firmly assigned by X-ray struc-
tures for 40, 42, and 44.[50] Fi-
nally, the nature of the substitu-
tion pattern on the nitroalkene
proved to be crucial (Table 6).
Indeed, when 1-nitroheptene
(1h) and nitrostyrene (1i) were
treated with 8 in the presence
of NaH or Triton B, Michael
adducts 49 and 50 were isolated
respectively in 32–52% and 63–
Table 7. Functionalization of g-chiral nitroalkenes 1 f and 1g.[a]
1
T
Products
Yield [%]
1
2
08C to RT
À908C to RT
57
65
3
4
08C to RT
À908C to RT
63
75
87%
yields,
respectively
(tBuOK was unproductive). It
was instructive to note that the
reaction did not proceed with
sequential intramolecular nu-
cleophilic addition. These re-
sults indicate once again that
the absence of a substituent at the a position of the nitroal-
kene has an unfavorable effect on ring closure, certainly due
to a greater stability of the nitronate anion.
[a] All reactions were run in the presence of Triton B (1.0 equiv) with 8 (1.0 equiv) in THF/tBuOH (30:1).
Table 8. Diastereomeric ratios for compounds 45a–d and 46a–d.
1
T [8C]
Diastereomeric ratio [%]
45a
57
60
46a
48
76
45b
34
32
46b
36
15
45c
8
6
46c
13
6
45d
1
2
46d
3
3
1
2
1 f
0
À90
Facial diastereoselectivity: g-Chiral-(E)-nitroalkenes 1 f and
1g were involved in a project on the asymmetric synthesis
of functionalized carbocycles. The most significant data
among the addition of dimethylpropargylmalonate 8 to 1 f
and 1g are collected in Table 7.
3
4
1g
0
À90
Both reactions of 1 f and 1g with 8 afforded methylenecy-
clopentanes 45a–d and 46a–d, respectively, as mixtures of
four diastereomers (Table 8). Reactions were conducted for
12 h in the presence of Triton B, at a temperature range of
08C to room temperature or À908C to room temperature.
Methylenecyclopentanes 45 and 46 were obtained in the
best overall yields (57 and 75%, respectively) at lower tem-
perature ranges. Diastereomers were detected by 1H and
1
13C NMR spectroscopy in a ratio deduced from the H NMR
spectrum of the crude product or by HPLC.
For 1 f, an insignificant effect on the diastereomeric ratio
on varying the reaction temperature was observed. In con-
trast, this effect was drastic with 1g, increasing the initial
48% ratio observed at 08C for 46a up to 76% when the re-
action was carried out at À908C (Table 8, entries 3 and 4).
The chromatograms (Figure 1) of products from the reac-
tion between 1 f with propargyl malonate 8 display two
major diastereomers 45a and 45b. When referring to the
strongly favored stereochemistry related to methylenecyclo-
Figure 1. Chromatograms of HPLC analytical separations of stereoiso-
mers 45a–d (for conditions, see the Supporting Information).
pentanes 40–44, we can reasonably assert that the nitro
group and H-Cb are in a cis relationship in these major dia-
stereomers 45a and 45b. This cis relative stereochemistry
was firmly assigned by an X-ray structure in the case of 45a
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Michael Addition Initiated Carbocyclization
FULL PAPER
(Figure 2), but unfortunately, crude 45b–d could not be crys-
tallized. Nevertheless, we should expect the same cis rela-
tionship for 45b, whereas in 45c and 45d, the nitro group
and H-Cb should have a trans relationship.
Scheme 6.
A conformation in which the hydrogen atom occupies the
crowded inside position affords (RS)-anti transient nitronate
H and subsequent cyclization provides (RS)-cis 45b and
(RS)-trans 45d (Scheme 7).
Figure 2. X-ray crystal structure of 45a.
Moreover, the X-ray Ortep plot of 45a (Figure 2) unam-
biguously indicates the favored stereofacial control leading
Structural modifications: To quantify the facial diastereose-
lectivity related to the Michael addition on substrates 1 f
and 1g, we decided to eliminate the stereogenic center with
the functional nitro group. For this purpose, we decided to
transpose allylic nitro compounds through [2,3]-sigmatropic
rearrangement.[52] This rearrangement has received only
little attention in the literature, despite its synthetic poten-
tial. Indeed, allylic alcohols are obtained through hydrolysis
of an allylic nitrite intermediate and the yields are drastical-
ly improved when the thermolysis is performed in the pres-
ence of DABCO.[52a] Thermal reaction conditions[52c] were
optimized on compounds 42 and 44, which provided excep-
tionally stable nitrites 51 and 52 in high yields (Scheme 8).
Encouraged by the effectiveness of this transformation,
the diastereomeric mixture 46a–d was reacted under the
same reaction conditions to un-
À
to the syn stereochemistry with respect to the new C C
bond provided by the Michael addition.
This stereochemical outcome can be explained by Houkꢄs
outside-crowded model and periplanar effect.[22,51] Thus, the
chiral substituent in 1 f is oriented mainly in such a way that
the small hydrogen atom occupies the crowded outside posi-
tion. The addition of the malonate anion to this conforma-
tion occurs antiperiplanar to the alkoxy group to afford the
(R,R)-syn transient nitronate E, a precursor of 45a–b
(Scheme 5).
Conformation F, which is governed by 1,3-allylic strain, af-
À
fords 45a, whereas rotation around the C1 C2 bond pro-
vides 45c through conformation G (Scheme 6).
dergo a [2,3]-sigmatropic rear-
rangement, providing a mixture
of two diastereomers 53a and
53b in 96% yield (Table 9).
Compounds 53 were isolated
as viscous oils that could not be
crystallized and the relative ste-
reochemistry remains undeter-
mined at this time. Neverthe-
less, since cis stereochemistries
have previously been assigned
Scheme 5.
to 46a and 46b, whereas 46c
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12477

D. Bonne, J. Rodriguez et al.
Unfortunately, attempts to
separate the diastereomers re-
sulted in degradation. We then
embarked upon saponification
of the ester groups. LiOH-pro-
moted procedures[54] provided
56 by both saponification of the
ester and deprotection of the
dimethyldioxolane
(Scheme 11).
ring
Formation of 56 most proba-
bly proceeds by deprotection
Scheme 7.
Scheme 9.
Scheme 8.
Scheme 10.
Table 9. ACHTUNGTRENNUNG[2,3]-Sigmatropic rearrangement of 46 into 53.
46
53
46a
48%
76%
46b
36%
16%
46c
13%
5%
46d
3%
3%
53a
61%
81%
53b
39%
19%
1
2
and 46d were presumed to be trans, we could reasonably
assume that 46a and 46c provide 53a, whereas 46b and 46d
are precursors of 53b.
To obtain a crystallized derivative of 53, we envisioned
the formation of a hydrazone or an oxime, but failed to con-
vert the nitrite group into aldehyde in the presence of
BF3·Et2O and oxygen.[53] We therefore changed our strategy
to the formation of a ketone, through ozonolysis of the exo-
methylene group. The reaction was first optimized on sub-
strate 44, which was quantitatively transformed into keto de-
rivative 54 (Scheme 9).
The mixture 46a–d, consisting of four diastereomers (dia-
stereomer ratio of 76:15:6:3; Table 8) was submitted to the
same oxidation conditions to afford the corresponding ke-
tones 55 in a few minutes in a similar ratio (determined by
1H NMR spectroscopy) (Scheme 10).
Scheme 11.
during the acidification step, since the sensitive isopropyli-
dene motif[55] still suffers the same transformation when
treating 46 with p-TsOH to afford 57. Although 56 was iso-
lated in low yield as a colloidal white powder, it could not
be recrystallized. Therefore, the relative stereochemistries of
46a–d could not unambiguously be assigned. Nevertheless, a
stereochemical preference, provided by the Felkin–Anh-like
approach (Scheme 12) should be highly favored and would
be expected to provide 46a.
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Michael Addition Initiated Carbocyclization
FULL PAPER
the nitronate anion acts as a
base to deprotonate a new mal-
onate molecule.
Alkylation of 60 and 61 with
propargyl bromide promoted
by Triton B in THF afforded
adducts 62 and 63 in 80 and
85% yields, respectively. Subse-
quently,
methylenecyclopen-
tanes 64 and 65 were obtained
in 49 and 14% yields, respec-
tively as pure diastereomers
(stereochemistries established
by NOE experiments) by reac-
tion of pure isolated Michael
adduct 62 and 63 with Triton B
in THF (Scheme 14).
Scheme 12.
Multicomponent reactions: To extend the carbocyclization
of a-nitroalkenes to other propargyl malonic-type nucleo-
philes, we envisioned that Michael adduct precursors could
be available by a three-component reaction involving a ma-
lonic derivative, propargyl bromide and a nitroalkene. Ex-
periments were carried out with Triton B as the base
(Table 10).
Scheme 13.
Table 10. Three-component reactions.[a]
Y
Triton B [equiv]
t [h]
Products (yields [%])
(50)
Scheme 14.
1
2
3
4
1
2
1
2
6
12
5
(43)
(38)
(47)
(46)
CO2tBu
CN
60
62
(52)
(32)
(47)
Quenching the cyclization of 63 after 30 min resulted in
the recovery of a large amount of nitroalkene along with
propargyl malononitrile. This result confirms a favored
retro-Michael reaction in the case of these malonate deriva-
tives, which explains the low yield of 65.
61
63
14
[a] All reactions were carried out at 08C.
Indeed, the observed yields in cyclization products are in
agreement with the observed pKa (Table 11), since the great-
er difference of pKa between malonate derivatives and ni-
tronate anions results in the more favored retro-Michael
process.
Starting with 1e and cyanobutylmalonate (58) or maloni-
trile (59), Michael adducts 60 and 61 were isolated along
with the expected d-nitroalkynes 62 and 63 (obtained as
mixtures of diastereomers) in an approximately 1:1 ratio
and good overall yield. Unfortunately, even two equivalents
of base did not promote the one-pot carbocyclization step.
To optimize the formation of d-nitroalkynes 62 and 63, we
decided first to prepare the Michael adducts 60 and 61 ac-
cording to standard procedures. Subsequent alkylation with
propargyl bromide should provide required d-nitroalkynes.
When nitroalkene 1e was treated with malonate derivative
58 or 59 and a catalytic amount of NaH (1:1:0.1), Michael
adducts were obtained in 91–92% yields as mixtures of dia-
stereomers (Scheme 13). Note that the use of base in a cata-
lytic amount provides adducts in good yields, suggesting that
Carboxycyclopentannulation of
a
nonactivated alkene
through 1,3-dipolar cycloadditions: Although reaction of
propargyl alcohol 2a with nitroalkenes in the presence of
tBuOK/tBuOH provided methylenetetrahydrofurans by in-
tramolecular cyclization of nitronates to the triple bond, we
observed that addition of allylic alcohols 4a and 6 to nitroal-
kene 1b under the same reaction conditions failed to under-
go carbocyclization (see Table 2). Similarly, addition of 4a–c
to nitroalkenes 1a–c, 1e, or 1g also provided oxa-Michael
adducts 35 and 66–71 after hydrolysis of the resulting nitro-
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12479

D. Bonne, J. Rodriguez et al.
Table 11. pKa values of various malonate derivatives.
Malonate derivative
pKa in DMSO
propargylmalonitrile
12–13
14–15
16–17
17–18
2-propargyl-tBu cyanoacetate
dimethylpropargylmalonate
nitronate anion
nates under mild acidic conditions in good to excellent
yields (Table 12).
Scheme 15.
Surprisingly, we found that when aci-nitro anions I (ob-
tained by oxa-Michael addition of allylic alcohol (4a) to ni-
troalkenes 1a–c and 1e with tBuOK in THF/tBuOH (30:1))
were hydrolyzed with excess 2m HCl, an unprecedented
transformation took place leading to the formation of exo-
nitro alcohols 77–80 in 5–23% yields together with the Mi-
chael adducts 35, 66–68 (Scheme 15).
Starting from 68, the corresponding a-alkoxy ketone 9b[56]
(which forms from an in situ Nef reaction) was also isolated
in 5% yield.
To our delight, although yields were not optimized under
these standard reaction conditions, we noticed that tetrahy-
drofuranylnitro alcohols 77–80, which have three stereogenic
centers, were isolated with total
diastereoselectivity. This obser-
vation suggested that an intra-
Table 12. Preparation of b-nitroallyl ethers 35, 66–71.[a]
molecular [3+2] cycloaddition
of nitronic acids followed by an
in situ oxidative ring cleavage
of cycloadduct intermediate
should account for the overall
ionic transformation. Whereas
alkyl or silyl nitronates have
been successfully involved in in-
tramolecular 1,3-dipolar cyclo-
1
Product
Yield [%] (cis/trans ratio)
additions with olefins to give
useful isoxazoline and isoxazoli-
dine intermediates,[18b,9a,c,57] it is
of significant interest to notice
that their nitronic acid precur-
sors, easily obtained by proto-
nation of nitronates, have never
been reported to undergo simi-
lar behavior.[18c]
To confirm that nitro alcohols
77–80 undoubtedly result from
1,3-dipolar cycloaddition and
therefore to enlarge the scope
of this stereoselective carbocyc-
lization that leads to functional-
ized tetrahydrofurans, we decid-
ed to study the reactivity of the
corresponding silyl nitronates
(Table 13).
b-Nitro allyl ethers 35, 66–68,
70 and 71 were first treated
with Me3SiCl (2 equiv) and
DBU (1 equiv) in CH2Cl2 at
08C to smoothly afford N-(tri-
methylsilyloxy)isoxazolidines
84–87, 89 and 90 in 62–86%
yields (Table 13, entries 1, 2, 4,
6, 8, and 10). This [3+2] heter-
1
2
3
4
1b
66 (3:1)
85 (3.3:1)
67 (1:1)
100
1a
1c
1e
5
6
7
1g
1e
1e
81 (mixture of diastereomers)
67 (6:1)
100
[a] All reactions were run in the presence of tBuOK (1.0 equiv), 3 ꢅ molecular sieves with 1.0 equiv of the cor-
responding alcohol in THF/tBuOH (30:1) at 08C for 4 h. The reactions were then quenched by adding 2m HCl
(1–1.5 equiv)
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Michael Addition Initiated Carbocyclization
FULL PAPER
Table 13. Formation of isoxazolidines 84–95.
for the high selectivities ob-
served. Isoxazolidines with 1,3-
trans stereochemistries (related
to hydrogen atoms) are formed
through a proposed transition
state TE1 with minimum allylic
strain and favored overlapping
between C=CH2 and OÀ
(Scheme 16).
TBAF-promoted desilylation
of these oxazolidines led to a
general and unprecedented oxi-
dative cleavage, affording 77–82
(Table 14).
Precursor
Entry
1
Isoxazolidine
Yield
[%]
Entry
–
Isoxazolidine
Yield
[%][c]
35
72[a]
–
–
2
3
62[a]
96[b]
66
67
12
13
93
69
The transformation proved to
be quite general regardless of
the structure of the isoxazoli-
dine, leading to acceptable iso-
lated yields of the expected
nitro alcohol. Note that bicyclic
compound 83a obtained in
66% yield from 1e and croton-
ic alcohol 4c can be totally epi-
merized at the carbon with the
hydroxyl group to give 83b,
probably through an intramo-
4
5
82[a]
98[b]
6
7
84[a]
100[b]
68
70
71
14
15
16
84
31
94
8
9
77[a]
89[b]
lecular
transesterification
during chromatography on
silica gel (Scheme 17).
The crucial point in this un-
expected transformation is the
in situ oxidative ring cleavage
of the isoxazolidine intermedi-
ate, which does not need the
addition of any specific metallic
10
11
86[a]
97[b]
[a] TMSCl/DBU was employed as the silylating agent. [b] Me2N-TMS/DBU. [c] TBDMSCl/DBU.
or
organometallic
oxidant.
From a mechanistic point of
ocyclization is related to the well-documented intramolecu-
lar silylnitronate olefin cycloaddition (ISOC reaction).[9,18c,64]
The tendency of silylnitronates to add smoothly in a 1,3 di-
polar fashion to the alkene moiety was enhanced when
DBU/Me3SiNMe2 was used as the silylating reagent, result-
ing in increased yields (89–100%) and purity obtained
(Table 13, entries 3, 5, 7, 9, 11). Alternatively, the bi- and tri-
cyclic analogues 91–95 could also be easily prepared in mod-
erate to very good yields using the system TBDMSCl/DBU
system (Table 13, entries 12–16).
view, although oxidation of nitroso compounds into the cor-
responding nitro derivatives usually requires powerful oxi-
dants,[59] nitroso compounds are likely to be intermediates in
our transformation (Scheme 18). Indeed, we have been able
to isolate and fully characterize nitroso intermediates 96–98
(10–23% yield). As complementary experimental evidence,
we have shown that pure 96 underwent an uncatalyzed aero-
bic oxidation to furnish the expected hydroxymethyl tetra-
hydrofuran 80 in quantitative yield, the reaction being moni-
tored by NMR.
Crude 84–87, 89 and 90 were stable enough[58] to provide
satisfactory spectroscopic data without purification, and 91–
95 (Table 13, entries 12–16) could be easily purified by flash
chromatography on silica gel.
Facial diastereoselectivity: To evaluate p-facial diastereose-
lection, we applied the overall sequence to nitroalkene 1g,
which has the chiral substituent attached to the b-carbon of
the double bond. Michael adducts 69 were obtained in 81%
yield by addition of allylic alcohol to chiral nitroalkene 1g,
and 1H NMR spectroscopy indicated the presence of two
major diastereomers in a ratio of 5:3 (Scheme 19). Indeed,
due to the presence of the stereogenic center, the two faces
of nitroalkene 1g are diastereotopic, allowing the oxa-Mi-
Whereas isoxazolidines 89 and 94 were isolated as 1:1 epi-
meric mixtures (Table 13), compounds 84–87, 90–93 and 95
were diastereomerically pure and their stereochemistries
were assigned by NOESY experiments.
Both required stereochemistries of the intramolecular cy-
cloaddition together with allylic 1,3-strain control account
Chem. Eur. J. 2009, 15, 12470 – 12488
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12481

D. Bonne, J. Rodriguez et al.
Scheme 17. Epimerization of 83a.
Hassnerꢄs results, which are based on a correlation between
1
the stereochemistry and H NMR J values in a series of oxa-
Michael adducts of allylic alcohol on nitroalkenes.[60] The
observed J values between H4 and H7 are in the range of 8–
10 Hz for an anti stereochemistry, whereas this value falls to
2–4 Hz for a syn stereochemistry.
An enriched mixture of 69a/69b (5:1) was isolated by
chromatography and was converted into silyl nitronate.
which spontaneously cyclized in
Scheme 16. Favored and unfavored (E) and (Z)-nitronate transition
states leading to the observed trans stereochemistry of isoxazolidines.
Table 14. Oxidative cleavage of isoxazolidines.
situ to afford 88 as two diaste-
reomers in the same ratio of
5:1. Although their configura-
tions could not be assigned, the
same hypothesis could indicate
the relative stereochemistries of
these diastereomers. Therefore,
the 8.1 Hz J value observed for
the major diastereomer 88
should be indicative of anti ste-
reochemistry.
Entry
1
Isoxazolidine
Yield [%]
Entry
4
Isoxazolidine
Yield [%]
This observed stereochemical
preference can be interpreted
by invoking a Felkin—Anh-like
approach[61] to provide an
highly preferred conformation
in which the g-oxygen almost
overlaps the “inside” position
of the alkene bond. Then, the
steric approach of alkoxide on
nitroalkene 1g affords the
major anti Michael adduct,
which upon reaction with
TMSCl undergoes an ISOC re-
action to provide anti isoxazoli-
dine 88 (Scheme 20).
84
87, 93
2
3
85, 91
86, 92
5
6
89, 94
90, 95
One-pot desilylation with tet-
rabutylammonium
fluoride
À
chael addition to proceed either on the si or on the re face,
leading to anti 69a or syn 69b. The anti stereochemistry of
the major diastereomer has been assigned on the basis of
(TBAF) and concomitant N O bond cleavage (which cer-
tainly proceeds through an alkoxynitroso intermediate) pro-
vides a diastereomeric mixture of tetrahydrofurans 99 in the
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Michael Addition Initiated Carbocyclization
FULL PAPER
pared b-(allylamino)nitroalkanes 72–75 according to Stur-
gessꢄ conditions,[63] by heating an excess of allylmethyl-
amines 5a,b at reflux in dichloromethane containing nitroal-
kene 1c, e, or g (Scheme 22). Nitroalkene 1g derived from
(R)-2,3-isopropylidene glyceraldehyde was an efficient Mi-
chael acceptor, affording 74 in 53% yield as an inseparable
mixture of diastereomers. b-Nitrotosylamine 76 was pre-
pared in 59% yield by tosylation of adduct 75.
Scheme 18.
Scheme 19.
Scheme 22. Preparation of b-nitrotosylamine 72–76. 72: 66% (trans/cis
4.2:1); 73: 97%; 74: 53% (mixture of isomers). Reaction conditions:
a) TsCl, NEt3, CH2Cl2, RT.
Unsaturated amino silyl nitronates have been shown to be
efficient precursors to the highly selective ISOC sequence.[64]
Indeed, the reaction of 72–74 and 76 in the presence of
DBU/ trimethylsilyl chloride (TMSCl) in CH2Cl2 at 08C af-
forded 100–103 in 31–96% yield (Scheme 23).
Scheme 20.
ratio of anti/syn 5:1 in 58% yield. Stereochemistries were
1
assigned by H NMR spectroscopy: coupling constants be-
tween Cb-H and Cg-H of 8.9 Hz for the anti isomer and of
1.5 Hz for the syn isomer were observed (Scheme 21).
Scheme 23.
Trimethylsilyl isoxazolidine 102, isolated in 96% yield,
was obtained as a mixture of two diastereomers, in a ratio of
5:1 (determined by 1H NMR spectroscopy). The coupling
constant of 9.1 Hz between H7 and H4 suggests a facial dif-
ferentiation in favor of the anti isomer (Scheme 24).
Scheme 21.
Stereoselective synthesis of functionalized pyrrolidines: The
procedure developed for the preparation of functionalized
tetrahydrofurans through an ISOC sequence was extended
to the synthesis of pyrrolidines. Although the aza-Michael
addition of a secondary amine to a conjugated nitroalkene
suffers from a competitive retro-Michael reaction,[62] we pre-
Surprisingly, TBAF-promoted desilylation of 100–102 was
unproductive. Extensive degradation was observed, except
in the case of compound 100, which underwent an unexpect-
ed ring-opening/-closing rearrangement to give 105 in 24%
yield. The donating effect of the N-methyl group combined
with the presence of the phenyl substituent required for the
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12483

D. Bonne, J. Rodriguez et al.
et al.[69c,d] developed a highly stereoselective strategy for the
construction of carbocycles based on Michael addition of
Grignard reagents to aromatic a-unsubstituted nitroalkenes.
Although initial reports of attempted Michael addition of
Grignard reagents to monosubstituted aliphatic nitroalkenes
were not encouraging,[69a,b,70] in our hands, addition of a 0.5m
solution of Grignard reagent (prepared from homoallylbro-
mide) to nitroalkenes 1b, 1c, 1e, or 1g afforded Michael ad-
ducts 106–109 in 7–98% yields (Table 15). These products
were always isolated as undetermined mixtures of diastereo-
mers, which is not detrimental to the carbocyclization step.
Scheme 24.
stabilization of an iminium intermediate seems to be crucial
in this unexpected transformation (Scheme 25).
Table 15. Condensation of homoallyl Grignard reagent to 1,2-disubstitut-
ed nitroalkenes.
Entry
1
Adducts
Yields [%][a]
93
dr[c]
1.1:1
2
3
71
98
1.8:1
6:1
Scheme 25.
In contrast, the presence of the N-tosyl function in 103 al-
À
lowed the expected in situ diastereoselective N O oxidative
bond cleavage to form 104 in 52% yield (Scheme 26).
4
5
7
32[b]
n.d.[d]
[a] Grignard reagent (1,5 equiv) was added slowly to a solution of nitroal-
kene (1 equiv) in THF (0.2m) under argon atmosphere at 08C. [b] Ad-
dition of Grignard reagent (2.0 equiv) and CeCl3 (2.0 equiv). [c] cis and
trans isomers have not been assigned. [d] n.d.=not determined.
Scheme 26.
The low yield obtained in the case of 109 (Table 15,
entry 4) was increased up to 32% by the addition of
CeCl3[71] to the reaction mixture (Table 15, entry 5).
In our case, a,b-disubstitution of nitroalkenes 1b, 1c, 1e,
and 1g certainly accounts for the fair to good yields ob-
tained in these Grignard Michael additions.
Unfortunately, neither the use of chlorotrimethylsilane
nor N,N-dimethylsilylamine with DBU as the base gave iso-
xazolidine products and only starting materials were recov-
ered. Addition of hexamethylphosphoramide (HMPA) as a
stabilizing and solubilizing additive did not affect the course
of the reaction. Heating the reaction at 608C in toluene was
also ineffective. Finally, the starting Michael adducts were
recovered by treatment with Et3N and TMSCl in the pres-
ence of HMPA as performed by Hassner et al.[7d] for the
construction of isoxazolines from substrates unsubstituted at
the a position of the nitro group. Undoubtedly, in our cases,
Synthesis of functionalized cyclopentanes: Our results ob-
tained in the anionic [3+2] heterocyclization prompted us
to investigate the addition of unsaturated carbon-centered
nucleophiles to nitroolefins, to extend the overall methodol-
ogy to the synthesis of carbocycles. The most widely used
carbon nucleophiles in Michael additions are organometal-
lics such as alkylstannanes,[65] organoaluminium etherates,[66]
cuprates, or organolithiums,[67] organozincs,[68] or Grignard
reagents.[18b,69] Grignard reagents are the most important of
the Group IIA organometallics used as nucleophiles in con-
jugate additions, due to the high electron density on the
carbon atom.
Provided the Michael adducts obtained incorporate a suit-
ably located double bond, a predictable 1,3-dipolar cycload-
dition with the nitronate moiety should generate a carbocy-
cle. Indeed, recently, Dehaen and Hassner[58] and Yao
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Michael Addition Initiated Carbocyclization
FULL PAPER
Table 16. Formation of bicyclic isoxazolidines.
the a substitution of the nitro group prevents the [3+2] cy-
cloaddition. Some years ago, Veselovsky and co-workers re-
ported the synthesis of natural (+)-iridomyrmecin and its
unnatural enantiomer according to an intramolecular [3+
2]-dipolar cycloaddition of silylnitronate by using two differ-
ent procedures.[72] In the first method, the reaction was con-
ducted in hexamethyldisilazane (HMDS) and Et3N at
1108C, whereas in the second procedure N,O-bis(trimethyl-
silyl)acetamide (BSA) and the unsaturated nitro compound
were reacted at 858C in benzene/acetonitrile. Both proce-
dures afforded the same ratio of N,O-silylated diastereo-
meric oxazolidines in 50 and 68% yields, respectively.
Entry
1
Michael adduct
Isoxazolidine
Yield [%]
69
106
2
3
107
108
92
99
When Michael adducts 106–108 were treated with
HMDS/Et3N at 1108C according to the first procedure, we
observed the formation of 110–112 along with remaining
starting materials (80–96% overall yield; Scheme 27).
4
109
100 (1.2:1)[a]
Scheme 27.
[a] Diastereomeric ratio determined by 1H NMR spectroscopy of the
crude product.
The best yield was obtained for the transformation of 107,
but the conversion did not exceed 6.9:1. We therefore tested
more drastic conditions, but heating 106 and 108 at reflux in
HMDS resulted in degradation. The unsatisfactory yields
obtained in these transformations prompted us to investi-
gate the second procedure reported by Veselovsky et al.[72]
and we were delighted to observe high yields for the conver-
sion of Michael adducts 106–109 into the corresponding iso-
xazolidines 110–113 in 69–100% yields (Table 16). Isoxazoli-
dines 110–112 were isolated as pure diastereomers starting
from a cis/trans isomer mixture of Michael adduct starting
materials. Both the stereochemistry of intramolecular cyclo-
addition together with 1,3-allylic strain stereocontrol ac-
count for the total diastereoselectivity of the reaction, as we
observed previously in the heterocyclic series. In the particu-
lar case of chiral nitroalkene 1g, due to a low facial stereo-
selectivity, a 1.2:1 diastereomeric ratio was observed in the
formation of 113 (Table 16, entry 4).
Desilylation of oxazolidines 110–113 was performed with
TBAF in CH2Cl2 at room temperature and subsequent in
situ oxidation allowed the formation of sensitive hydroxy-
methyl nitrocyclopentanes 114–117, isolated as crude prod-
ucts in 69–100% yield (Table 17). Purification of all of these
compounds by flash chromatography on silica gel provided
partial nitrous acid elimination and separable cyclopentenes
118–121 were always produced as minor components.
scopic data obtained for 117 were insufficient to assign the
configuration of these diastereomers. However, according to
an analogous pathway encountered in the oxygenated series,
we can reasonably predict that the 1.2:1 facial diastereose-
lectivity of the Michael addition is in favor of the anti
isomer (Scheme 28).
Conclusion
We have developed new Michael addition initiated anionic
sequences that provide stereoselective preparations of a va-
riety of highly functionalized carbo- and heterocyclic com-
pounds starting from simple achiral nitroolefins.
Upon reaction with propargyl alcohols or amines, nitroal-
kenes acted as excellent Michael acceptors, with the option
to undergo subsequent ring closure onto nonactivated al-
kynes, which lead to exo-methylene heterocycles for
tBuOK-promoted domino reactions. According to a similar
MIRC process, Triton B-promoted addition of propargyl
malonate afforded methylene cyclopentanes.
Finally, highly stereoselective intramolecular 1,3-dipolar
cycloadditions to give isoxazolidines were initiated by con-
version of unsaturated nitro compounds into silylnitronates.
The unprecedented in situ oxidative ring cleavage of the iso-
xazolidines was the key step of this new sequential carbohy-
droxy cyclopentannulation, which resulted in the diastereo-
selective formation of five-membered-ring carbocycles and
heterocycles with up to four consecutive stereogenic centers.
Compounds 114–116 were isolated as pure diastereomers,
whereas 117 was obtained as a 1.2:1 diastereomeric mixture
of anti and syn diastereomers, which were separable by
chromatography on silica gel. Unfortunately, the spectro-
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12485

D. Bonne, J. Rodriguez et al.
Table 17. Formation of hydroxymethyl five-membered rings.
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Entry
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Isoxazoline
Cyclopentane
Yield [%]
54
Cyclopentene
Yield [%]
15
110
2
3
111
112
55
29
11
15
4
113
42 (1.2:1)[a]
25
[a] Diastereomeric ratio determined by proton NMR of the crude product.
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Scheme 28.
Experimental Section
Full experimental procedures and characterization data are given in the
Supporting Information.
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Acknowledgements
Financial support from the French Research Ministry, the Universitꢁ
Paul Cꢁzanne, the Centre National de la Recherche Scientifique (CNRS)
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Received: May 28, 2009
Published online: October 15, 2009
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