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.
Chem. Eur. J. 2009, 15, 12470 – 12488
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12471