CO2_2016 - page 45

Chimica Oggi - Chemistry Today
- vol. 34(2) March/April 2016
coupled to cyclic and acyclic enones, enals, and acrylamides
with good yields. The new ligand proposed for iron is a good
compromise between reactivity and selectivity, as Fe(acac)
certain cases gives rise to the formation of secondary products
due to its major Lewis acidity. Alkyl or aryl vinyl ethers,
endocyclic enol ethers, enecarbamates, and enamides are all
suitable substrates. The presence of protected nitrogen,
halogen, sulphur, and boron substitutions are tolerated. A first
attempt in controlling the stereochemistry of the adduct was,
however, quite disappointing due to the radical nature of the
reaction. For proving the consistency of the radical mechanism
proposed, some experiments were conducted using suitable
cyclopropyl derivatives. In fact, if radicals are formed, the
cyclopropyl group can undergo a fast ring opening reaction,
as was indeed observed. It is also worth mentioning that in this
chemistry species like silyl enol ethers or enamides, normally
considered reactive nucleophiles in their
position in Lewis
acid catalysed reactions, are becoming
nucleophiles. This
peculiar behaviour, thanks to the availably of many different
alkenes, is opening a new way for the construction of a large
variety of C–C bonds in a rapid, and practical fashion. A
spectacular further development of this chemistry was again
described by Baran when in the 2015 he reported an easier
solution to the classic unsolved problem of olefin
hydromethylation. A methyl group is rarely view as a substituent
for the decoration of a molecule due to the few
methodologies available for its installation, but its introduction
in the early or in the late stages of a synthesis can enable
access to modified natural products, medicinally relevant
molecules, and isotopically labelled structures. In order to use
this Fe(III) hydride for a selective introduction of a methyl group,
a suitable Michael acceptor, able to be transformed into the
corresponding methyl group needed to be found. Baran
discovered that the hydrazone derived from formaldehyde
could be an interesting option. If the addition of the radical to
sulfinyl hydrazone leads to an alkyl hydrazide, and this
subsequently decomposes through the elimination of sulfinic
acid and nitrogen, the desired product could be obtained (7).
After a long optimization, a multistep protocol was established.
Thus, in the first step the Fe-mediated radical addition of the
olefin to the hydrazone formed
in situ
from formaldehyde and
sulfinyl hydrazine gave the corresponding hydrazide. In the
second step the solvent was switched to methanol and
heating at 60°C allowed the reductive C
N bond cleavage.
The transformation can tolerate a variety of functional groups
and can furthermore open a new direction in
intercepting the radical species formed by iron
mediated reactions.
In considering a retrosynthetic approach for a
substituted amine functional group, the cross-
coupling reaction realized by Buchwald-Hartwig
chemistry promoted by palladium(8) or copper(9) is
often selected. In this disconnection, one of the
coupled precursor is usually an halogenated
compound (aliphatic or aromatic). The introduction
of halides in an aromatic ring or in an aliphatic chain
can be problematic and incompatible with the
presence of many other functional groups. A radical
pathway can be instead considered for the
formation of a new C-N bond. Indeed, if an alkyl
radical is generated, this specie is able to react with
a nitroso group (Scheme 2, a) to give an
hydroxylamine. As the iron hydridic specie is able to
reduce the nitro group to the corresponding nitroso
for initiation of the olefin oxidation”, as remarked by Boger.
Is generating the hydride iron complex responsible for
initiating the reaction. Based on this observation, Baran raised
the questions if more suitable and easily conditions could be
found for generating relatively stable hydridic iron species from
stable and available precursors, and if the radical obtained
from the electron rich olefin could be intercepted by Michael
acceptors. Clearly, NaBH
employed by Boger to generate the
hydride iron complex is posing severe limitation in the
realization of this idea. In fact, common Michael acceptors
generally contain carbonyl groups (aldehydes or ketones) not
compatible with NaBH
. Baran found that employing the
cheap, stable, and available iron complex Fe(acac)
combination with silyl hydrides, reactive radicals were
generated compatibly with the presence of carbonyl groups.
In a brief analysis of the catalytic cycle proposed for this
reaction, the key intermediate is an iron hydride complex that
is formed from the reaction of silyl hydrides with the Fe(acac)
(Scheme 1). Although the exact nature of this species is still not
clear, nucleophilic alkenes present in the reaction mixture are
able to abstract an hydrogen radical from this Fe(III) hydride
complex, (Scheme 1, a). The reaction with the alkene
produces Fe(II) species and a tertiary nucleophilic radical. This
radical is then able to react with Michael acceptors, and a
new radical specie, stabilized by the presence of an electron
withdrawing group, is formed. This new radical specie is
reduced by Fe(II) complexes through a single electron transfer
to a new stabilized anion, that is protonated by the alcoholic
solvent. This is an “innate radical reaction”, that was described
with other suitable metals and conditions many times in the
past (3). However the scope of the reaction found by Baran is
wide and can be used for intra- or intermolecular reactions
(Scheme 1, b). Hindered bicyclic systems or vicinal quaternary
centres can be created with this chemistry in good yields.
Moreover the reaction is not sensitive to oxygen or moisture
although radical species are involved, and can be performed
on gram-scale using alcoholic solvents or co-solvents. The
formation of radicals, mediated by iron needs to be
highlighted, as it gives the possibility to establish an efficient
chemistry with a cheap metal in convenient reaction
The reaction was further optimized(6) and was applied to a
wider variety of donor and acceptor olefins. By using a simple
prepared and stable iron complex, Fe(dibm)
(dibm =
diisobutyrylmethane) in 5 mol%, silyl enol ethers could be
Scheme 1.
a) Catalytic cycle for iron promoted radical reaction; b) Examples
of the acceptor scope for the reaction.
1...,35,36,37,38,39,40,41,42,43,44 46,47,48,49,50,51,52,53,54,55,...68
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