N=OReduction |Hot Paper|
Direct Reductive N-Functionalization of Aliphatic Nitro
MarianRauser,Christoph Ascheberg, and Meike Niggemann*
Abstract: The first general protocol for the direct reduc-
tive N-functionalizationofaliphatic nitro compounds is
presented.The nitro group is partially reduced to anitre-
noid, with amild and readily available combination of
and zinc organyls. Thereby,the formationofanun-
stable nitroso intermediate is avoided, which has so far se-
verely limited reductivetransformations of aliphatic nitro
compounds. Thereaction is concluded by an electrophilic
amination of zinc organyls.
Nitrogencontaining compounds are valuableand commercial-
ly important bulk chemicals, specialty chemicals, and pharma-
ceuticals. Thus, functionalization of NÀHbonds using nucleo-
philic amination (Buchwald–Hartwig cross-coupling, hydroami-
nation, reductive amination)has been extensively explored.
Nevertheless, the amines’ nucleophilicity often demands alate
stage introductionorcomplexprotection/deprotection se-
quences. Conversely,nitro groups are relativelyinert and one
of the most common nitrogen sources.Their reduction to the
and subsequentfunctionalization is widely utilized.
In some cases, step-economy was improved through acombi-
nation of the reduction to the amine and acondensation with
an aldehyde/nitrile in aone-pot protocol. Nevertheless, even
these reductive amination protocols are scarce and limitedfor
aliphatic nitro compounds.
In addition, it is clearly more ben-
eficial to directly engage apartially reduced nitro group in a
reactionthat requires areagent with oxidized N-atoms. The
only approaches that directly utilize the reactivity of partially
reduced nitro groups for the formation of CÀNbonds, resort
to nitroso intermediates. Hence, traditionally,the O-alkylation
of the nitro group with metal organic reagents yields anitroso
intermediate upon fragmentation, which in turn is alkylated to
the hydroxylamine, and eventually reduced to the amine in a
More recently,inasingle step, the first
direct CÀNalkylationsofnitro compounds with olefins or alkyl
halideshavebeen realized elegantly through radical-mediated
coupling reactions (Scheme1).
These rely on asingle electron
transfer (SET) reduction to the nitroso intermediate, which
then reacts with aconcomitantly generated radical.
Unfortunately,such protocols are severelylimited for (non-
tertiary) aliphatic nitro compounds due to amajor challenge
(Scheme 2): In contrast to nitroarenes,aliphatic nitroso com-
poundsbear aprotoninthe a-position. Therefore, they instan-
taneously tautomerize to oximes
upon their generation, and
further N-functionalizationisprohibited. Thus,adirect reductive
N-functionalization of primaryorsecondary aliphaticnitro com-
pounds must proceedvia anew anddifferent intermediate.
Apart from allowing the first general direct reductive N-func-
tionalization of aliphatic nitro compounds, the presented pro-
tocol is beneficial in severalways. Access to aversatile electro-
philic aminating reagent
is provided by mild and readily
availablereagents in the presence of the nucleophilic reaction
partner.Thereby,not only the isolation and purification of the
reagent are circumvented, but the whole process is merged
into asingle synthetic operation. Aliphatic nitro compounds
are widely used in organocatalytic reactions. The mild condi-
tions and generality of the protocol allows for alate stage con-
version to the amines, thereby eliminating the necessityfor N-
protection strategies. Finally,nucleophilic groups such as NH
or OH are tolerated without protection.
We started our investigation with the reactionconditions for
the electrophilicamination with nitroarenes.Hence, phenylni-
troethane 1a was treated with 1.2 equiv of ZnEt
,and 2.0 equiv of NEt
in toluene. (Table1). Despite full
conversion being achieved, amine 2a was obtained in alow
Scheme1.Recently reported one-stepalkylation of nitro compounds.
Scheme2.Direct alkylation of aliphatic nitro compounds.
[a] M. Rauser,C.Ascheberg, Prof. Dr.M.Niggemann
Institute of Organic Chemistry,RWTH Aachen University
Landoltweg 1, 52072 Aachen (Germany)
Supporting Information and the ORCID number(s) for the author(s) of this
articlecan be foundunder https://doi.org/10.1002/chem.201705986.
Chem. Eur.J.2018, 24,3970 –3974 2018 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim3970