Angewandte
Communications
Chemie
Cyanides Very Important Paper
Iridium-Catalyzed Reductive Strecker Reaction for Late-Stage Amide
and Lactam Cyanation
ꢀngel L. Fuentes de Arriba+, Elena Lenci+, Mahendra Sonawane, Odilon Formery, and
Abstract: A new iridium-catalyzed reductive Strecker reaction
for the direct and efficient formation of a-amino nitrile
products from a broad range of (hetero)aromatic and aliphatic
tertiary amides, and N-alkyl lactams is reported. The protocol
exploits the mild and highly chemoselective reduction of the
amide and lactam functionalities using IrCl(CO)[P(C6H5)3]2
(Vaskaꢁs complex) in the presence of tetramethyldisiloxane, as
a reductant, to directly generate hemiaminal species able to
undergo substitution by cyanide upon treatment with TMSCN
(TMS = trimethylsilyl). The protocol is simple to perform,
broad in scope, efficient (up to 99% yield), and has been
successfully applied to the late-stage functionalization of
Scheme 1. Top: Examples of natural products possessing an a-amino
nitrile moiety. Bottom: Catalytic reductive cyanation for the synthesis
amide- and lactam-containing drugs, and naturally occurring
alkaloids, as well as for the selective cyanation of the carbonyl
carbon atom linked to the N atom of proline residues within di-
and tripeptides.
of a-amino nitriles.
2
3
[5]
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and transition-metal-catalyzed sp and sp C H cyanations.
However, significant challenges in relation to improvements
to catalytic turnover, site selectivity, and in particular,
substrate scope and functional-group tolerance remain to be
addressed for this approach to be generally applicable.[4]
We recognized that an alternative, direct, and syntheti-
cally powerful solution for the synthesis of a-amino nitriles
could arise from carboxamides by the development of
a reductive Strecker-type (reductive cyanation) reaction
(Scheme 1, bottom). Owing to the prevalence of amides and
lactams in biologically active compounds, and the vast
numbers of them contained within the suppliersꢀ catalogues
and the compound libraries of pharmaceutical and agro-
chemical companies, a mild reductive method which could
efficiently and chemoselectively target such functional groups
would likely find numerous applications in library generation,
late-stage functionalization, and total synthesis alike.
To this end, in recent years a handful of reports directed
towards reductive cyanation reactions at the amide and
lactam carbonyl carbon functionality have been de-
scribed.[6–11] However, to overcome the low inherent electro-
philicity of the amide/lactam carbonyl group, superstoichio-
metric amounts of powerful metal hydride reducing agents
(such as DIBALH)[9] or strong electrophiles for preactivation
(such as Tf2O) were necessary to achieve reactivity.[10,11] Such
approaches bring with them issues of chemoselectivity and
functional-group intolerance, and therefore we sought to
develop a mild, catalytic, chemoselective, and direct reductive
cyanation reaction of carboxylic amides and lactams, and
herein we report our findings.
N
itrile functionality is found in many bioactive natural
products and, because of its high polarity, characteristic linear
geometry, and hydrogen-bond-acceptor properties, it is
common to numerous pharmaceutical compounds.[1] Further-
more, the nitrile group is a valuable and versatile precursor to
a wide range of functional groups, including amines, amides,
carbonyl compounds, and carboxylic acid derivatives, as well
as five- and six-membered ring heteroaromatics by either
cycloaddition or condensation reactions.[2] In addition, a-
amino nitriles are a recurrent scaffold in many biologically
active molecules and natural compounds.[1,3] Aspidofractinine
and Streptomyces metabolites with antibiotic and antitumoral
activities, for example, saframycin A or cyanocycline A and
lahadinines A and B, extracted from Kopsia pauciflora, all
contain an a-amino nitrile moiety in their structure
(Scheme 1, top).[3] Accordingly in recent years much effort
has been devoted to developing new and efficient ways for
À
their preparation. In particular, direct a-C H functionaliza-
tion reactions of amines has attracted widespread attention as
an alternative approach to classical routes.[4] In fact, great
strides have been made in photochemical, electrochemical,
[*] Dr. ꢀ. L. Fuentes de Arriba,[+] E. Lenci,[+] Dr. M. Sonawane,
O. Formery, Prof. Dr. D. J. Dixon
Department of Chemistry, Chemistry Research Laboratory
University of Oxford
12 Mansfield Road, Oxford OX1 3TA (UK)
E-mail: darren.dixon@chem.ox.ac.uk
[+] These authors contributed equally to this work.
Our group recently reported that Vaskaꢀs complex in the
presence of tetramethyldisiloxane (TMDS) catalyzed the
intramolecular reductive nitro-Mannich reaction of lactam
substrates possessing N-linked nitro-alkyl groups.[12] That
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!