Angewandte
Communications
Chemie
Synthetic Methods
Direct Conversion of Nitriles to Alkene “Isonitriles”
Abstract: The sequenced addition of RLi to nitriles, trapping
with isopropylformate, and dehydration with phosphoryl
chloride provides an efficient, direct synthesis of alkene
isocyanides. The one-pot sequence involves a series of carefully
orchestrated steps: addition, formylation, tautomerization, and
dehydration, with CuCN catalyzing a key equilibration of
a formyl imine to an N-formyl enamine. The resulting aromatic
alkeneisocyanides, that are otherwise challenging to synthesize,
engage in an unusual [4+2]-type cycloaddition/1,3-H shift/
decyanation sequence to afford substituted naphthalenes.
I
socyanides are exceptionally versatile synthetic precursors
Scheme 1. Nitrile to alkeneisocyanide conversion.
that react with nucleophiles, electrophiles, radicals, and
transition metals to rapidly generate complex molecules.[1]
The ambident reactivity of isocyanides stems from the unique
electronic configuration of the formal carbene carbon that
often serves as a central connection point in heterocycle
synthesis.[2]
Despite the demonstrable value of isocyanides, few are
commercially available in gram quantities.[3] Access to
alkeneisocyanides is particularly acute because few methods
exist for their synthesis[4] though an exception is the recent use
of isocyanomethylenetriphenylphosphorane.[5] Classic car-
bonyl condensations of activated alkylisocyanides are com-
plicated by concomitant hydrolysis to the corresponding
formamide.[6] The paucity of methods to synthesize alkenei-
socyanides currently limits their use in synthesis and is stifling
the discovery of new reactions. Described below is a direct,
one-pot method that addresses the challenge of synthesizing
alkeneisocyanides and the disclosure of a new [4+2]-type
cycloaddition with alkeneisocyanides.
The alkeneisocyanide synthesis is predicated on a method
for synthesizing N-acyl enamines 5a (Scheme 1).[7] The N-acyl
enamines 5a were generated by nucleophilic addition of
organolithiums to a nitrile (1) followed by acylation of
metalloimine 2 and isomerization to the N-acyl enamine 5a.
Conceptually, an analogous formylation of metalloimine 2,
isomerization of 4b to the N-formyl enamine 5b, and
dehydration should generate the alkeneisocyanide 6. Coaxing
2 to the reversed sequence: equilibration (2!3), formylation
(3!5), and dehydration, would also provide alkeneisocya-
nide 6.
Scheme 2. Direct conversion of benzonitrile to 1-phenyl alkeneisocya-
nide.
and formylation of lithio imine 2c (Scheme 2).[8] 1H NMR
analysis of the crude reaction mixture indicated the formation
of the N-formyl enamine 5c, acetophenone (7), and a species
tentatively assigned as the formyl imine 4c; identification of
4c implies that formylation (2c!4c, Scheme 2) precedes
equilibration (cf. 2b!3b, Scheme 1). Presumably acetophe-
none (7) arose from adventitious protonation of the metal-
loimine 2c followed by hydrolysis. Raising the molar ratio of
methyl formate from 2 to 5 equivalents, to out-compete
protonation of the imine 2c, increased conversion to the N-
formyl enamine 5c.
The equilibration of 4c to 5c is likely triggered by the
lithium methoxide released upon formylation, with the
methanol, formed upon deprotonation, facilitating the
proton transfers. Reasoning that methanol might prematurely
protonate the metalloimine 2c, the formylation was per-
formed with isopropyl formate with the expectation that the
less basic isopropanol would minimize protonation of 2c. An
increase in the ratio of 5c:7 to 7:1 is consistent with this
mechanistic understanding. Conversion to the N-formyl
enamine 5c was further improved by performing the reaction
at 508C (> 99:1 ratio of 5c:7).
Initial forays to convert benzonitrile (1a) to the alkene-
isocyanide 6a explored sequential addition of methyllithium
[*] Dr. Y. Li, Prof. F. F. Fleming
Department of Chemistry, Drexel University
32 S. 32 nd Street, Philadelphia, PA 19104-2875 (USA)
E-mail: fleming@drexel.edu
Further optimization was performed after dehydration of
the formyl enamine 5c to the alkeneisocyanide 6a because 5c
was strongly adsorbed on silica gel during purification.
Supporting information and the ORCID identification number(s) for
Angew. Chem. Int. Ed. 2016, 55, 1 – 5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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