Communication
doi.org/10.1002/chem.202100889
Chemistry—A European Journal
Metal-Free Deoxygenation of Chiral Nitroalkanes: An Easy
Entry to α-Substituted Enantiomerically Enriched Nitriles
variable amounts, heavily depending on the experimental
conditions (nature and the stoichiometry of the base, temper-
Abstract: A metal-free, mild and chemodivergent trans-
formation involving nitroalkanes has been developed.
ature, and the structural features of the aliphatic substrate).
Under optimized reaction conditions, in the presence of
Therefore, we decided to further investigate the reaction, in the
trichlorosilane and a tertiary amine, aliphatic nitroalkanes
attempt to develop an efficient protocol to convert nitro
were selectively converted into amines or nitriles. Further-
compounds in nitriles, under mild conditions.
more, when chiral β-substituted nitro compounds were
Due to their unique reactivity and activating ability, nitriles
reacted, the stereochemical integrity of the stereocenter
are important functional groups in organic synthesis,[6] valuable
was maintained and α-functionalized nitriles were obtained
with no loss of enantiomeric excess. The methodology was
precursors for the preparation of carboxylic acids, amides,
aldehydes, ketones, amidines, amines, N-containing hetero-
successfully applied to the synthesis of chiral β-cyano
cycles, or as directing groups for remote CÀ H activation through
esters, α-aryl alkylnitriles, and TBS-protected cyanohydrins,
weak coordination. Moreover, cyanated compounds frequently
including direct precursors of four active pharmaceutical
find applications in medicinal, biological, physical organic, and
ingredients (ibuprofen, tembamide, aegeline and denop-
materials chemistry.[7]
amine).
Reactions that forms CÀ CN bonds includes mostly substitu-
tions and rearrangements, often requiring the use of highly
toxic and difficult-to-handle metal-cyanides; also, dehydration
reactions represent an important alternative.[6] However, most
Nitro derivatives are a valuable and versatile class of com-
pounds in organic synthesis. The transformations of nitro
groups into other functionalities,[1] such as their reduction or
the Nef reaction[2] are therefore of primary importance, as they
potentially broaden the application of nitro derivatives as useful
intermediates in organic synthesis.
Our group has reported an unprecedented metal-free
protocol for the reduction of nitro derivatives into amines based
on the use of trichlorosilane (HSiCl3),[3] an inexpensive and
readily commercially available bulk chemical, widely used in the
silicon industry.[4] It was observed that nitro compounds could
be reduced to the corresponding amines when reacted in the
presence of HSiCl3 and a tertiary amine under mild reaction
conditions. A systematic screening of substrates revealed that
this reduction protocol is applicable to both aryl and aliphatic
nitro compounds and was successfully employed in the total
synthesis of complex molecules.[5]
of these methods suffer from drawbacks such as harsh reaction
conditions, as traditionally they require strongly acidic dehy-
drating reagents; therefore, the development of a robust
strategy for the synthesis of diverse functional-group-rich
nitriles is highly desirable.
An interesting method for the synthesis of nitriles is the
deoxygenation of nitroalkanes. Only few examples in the
literature for this transformation exist, which involve different
phosphorus compounds such as P2I4,[8] and PCl3,[9] sulfur
[8]
compounds like Me3SiSSiMe3 and Na2S2O4,[10] or silyl deriva-
tives such as Me3SiI.[11] Transformation of optically active nitro-
alkanes into chiral nitriles by using benzyl bromide, KOH and
nBu4NI was reported by Carreira et al.[12]
Therefore, the development of an efficient method to
transform chiral nitro derivatives in the corresponding nitriles,
operating under mild experimental conditions, and respectful
of the stereochemical integrity of the molecule, would
represent a useful entry to the synthesis of enantiomerically
pure nitriles.
However, with aliphatic nitro derivatives, the corresponding
nitrile could be observed as a substantial reaction by-product in
Herein, we report a convenient chemodivergent trans-
formation for the selective formation of nitriles or amines
starting from an aliphatic nitroalkane (Scheme 1A). Furthermore,
focusing on the conversion of nitroalkanes into nitriles, we
expanded reaction scope also to optically active substrates to
obtain chiral enantioenriched cyano derivatives (Scheme 1B).
Our work started with the optimization of a benchmark
reaction involving 2-phenylnitroethane 2a as model substrate,
in the presence of trichlorosilane (HSiCl3) and diisopropylethyl-
amine (iPr2EtN) as a base (Scheme 2). Preliminary studies
revealed that 3 equivalents of base are the minimum required
[a] Dr. M. Pirola, Dr. C. Faverio, Prof. Dr. M. Benaglia
Dipartimento di Chimica,
Università degli Studi di Milano
Via Golgi, 19, 20133 Milano (Italy)
E-mail: maurizio.benaglia@unimi.it
[b] Dr. M. Orlandi
Dipartimento di Scienze Chimiche
Università degli Studi di Padova
Via Marzolo, 1, 35131, Padova (Italy)
Supporting information for this article is available on the WWW under
Chem. Eur. J. 2021, 27, 1–5
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