Exploring the anionic reactivity of ynimines, useful precursors of metalated ketenimines

Article abstract of DOI:10.1021/ol500749h

Insights into the reactivity of ynimines under anionic conditions are reported. They were shown to be excellent precursors of metalated ketenimines, which can be generated in situ by the reaction of ynimines with organolithium reagents or strong bases. The metalated ketenimines can then be trapped with various electrophiles and, depending on their substitution pattern, afford original and divergent entries to various building blocks.

Full text of DOI:10.1021/ol500749h

Letter
pubs.acs.org/OrgLett
Exploring the Anionic Reactivity of Ynimines, Useful Precursors of
Metalated Ketenimines
Anouar Laouiti,†,‡ Francois Couty,† Jerome Marrot,† Taoufik Boubaker,‡ Mohamed M. Rammah,‡
̧
́
Mohamed B. Rammah,‡ and Gwilherm Evano*,§
†Institut Lavoisier de Versailles, UMR CNRS 8180, Universite
78035 Versailles Cedex, France
́
de Versailles Saint-Quentin-en-Yvelines, 45, Avenue des Etats-Unis,
‡Laboratoire de Chimie Het
Universite
́
er
́
ocyclique, Produits Naturels et Rea
́
ctivite,
́
Dep
́
artement de Chimie, Faculte
́
des Sciences de Monastir,
́
de Monastir, Avenue de l’Environnement, 5019 Monastir, Tunisia
§Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universite
D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
́
libre de Bruxelles (ULB), Avenue F.
S
* Supporting Information
ABSTRACT: Insights into the reactivity of ynimines under
anionic conditions are reported. They were shown to be
excellent precursors of metalated ketenimines, which can be
generated in situ by the reaction of ynimines with organo-
lithium reagents or strong bases. The metalated ketenimines
can then be trapped with various electrophiles and, depending
on their substitution pattern, afford original and divergent
entries to various building blocks.
ue to the development of efficient methods for their
synthesis,1 ynamides 2, stable surrogates of the more
the emergence of original bond disconnections4 and hetero-
cyclic chemistry.5 In addition, the combination of the
polarization of the triple bond due to the presence of the
nitrogen atom and the possibility to use the electron-
withdrawing group as a directing group makes them ideal
substrates in anionic chemistry. In this context, the inter-/
intramolecular carbocupration, carbolithiation, and carbozinca-
tion of ynamides were recently shown to proceed with high
levels of selectivity and to provide useful entries to quaternary
centers containing aldol products,6 polysubstituted enamides,7
1,4-dihydropyridines,8 pyridines,8 and indoles,9 while an
Ireland−Claisen rearrangement from ynamides provided an
efficient access to highly functionalized allenamides10 and
aminodienes.11
D
labile ynamines 1, have recently emerged as remarkably useful
and versatile building blocks in organic synthesis (Figure 1).2
Besides these developments, new classes of ynamides have
also emerged such as N-phosphoryl-ynamines 3,12 ynimides
4,13 ynehydrazides 5,14 ynesulfoximines 6,15 and ynimines 716
(Figure 1). The development of these new ynamine surrogates
clearly offers new perspectives in the chemistry of ynamides.
For this reason, we recently became interested in the reactivity
of ynimines 7, compounds which have been only scarcely
studied and whose use in organic synthesis is still rather
limited,16a,17 most certainly due to the lack of general methods
for their preparation. These building blocks, which can now be
readily prepared either by a copper-catalyzed alkynylation of
imines with terminal alkynes16a or by their oxidative cross-
coupling with copper acetylides,16b possess a remarkable
Figure 1. Ynamines, ynamides, ynimines, and other stabilized
ynamines.
Their availability combined with their stability and unique
reactivity has attracted the interest of an ever-increasing
number of research groups. These building blocks have indeed
been used for the design and development of an impressive
number of original and efficient transformations including,
among others, cycloadditions, cycloisomerizations, metal-
catalyzed cyclizations, reductive couplings, radical transforma-
tions, ring-closing metathesis, and sigmatropic rearrangements.2
They have also been shown to be excellent substrates in natural
product synthesis,3 a field in which the use of ynamides enabled
Received: March 11, 2014
Published: April 4, 2014
© 2014 American Chemical Society
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sequence of six consecutive reactive sites including nucleo-
philic/basic, electrophilic, and acidic positions (Figure 2).
carbon atoms from readily available ynimines with reasonable
efficiency. Interestingly, no other products resulting from
competitive dimerization of the starting ynimines16a,19 or
carbolithiation were observed.
Scheme 1. Possible Mechanism for the Transformation of
Ynimines to Alkanenitriles
Figure 2. Schematic overview of the reactivity of ynimines.
Provided that the reactivity of ynimines can be finely
controlled, they should therefore behave as remarkably useful
and versatile building blocks, especially in anionic chemistry.
We indeed report in this manuscript that, upon reaction with
organolithium reagents or strong bases, ynimines are readily
transformed into a wide array of products including
alkanenitriles, alkenenitriles, ketenimines, and α,β-unsaturated
amides.
A possible mechanism that accounts for this transformation
is shown in Scheme 1. Addition of the organolithium reagent to
the starting ynimine 7 would provide a lithiated ynamine A,
which would be in equilibrium with the lithiated ketenimine
form B. Trapping this intermediate with the electrophile would
afford a transient unstable ketenimine C which would then
rearrange, as previously documented from related keteni-
mines,20 via a radical pathway involving radical intermediates
D and E/E′,21 to the corresponding nitrile 8.22,23 In this case,
the generation of a stabilized benzhydryl radical D would
account for the rapid rearrangement of C to 8.
Based on these results, we envisioned that N-vinyl-metalated
ketenimines G (Scheme 2) analogous to B might be obtained
by deprotonation starting from enolizable ynimines 7 instead of
addition of an organolithium reagent to the imine moiety.
Upon protonation, a transient N-vinyl-ketenimine H would be
Figure 3. Reaction with alkyllithiums: from ynimines to alkanenitriles
via ketenimines.
Scheme 2. Generation of Metalated N-Vinyl-Ketenimines by
Deprotonation of Ynimines and Their in Situ
Transformation to Allylic/Vinylic Nitriles
We started our investigations on the reactivity of ynimines
under anionic conditions by examining the outcome of the
reaction between non-enolizable benzophenone-derived yni-
mines 7a,b and organolithium reagents (Figure 3). These
reagents could potentially either perform a carbolithiation of
the triple bond18 or add to the imine moiety to generate
lithiated enamines or ynamines, respectively, the latter being
potentially in equilibrium with the corresponding lithiated
ketenimine, compounds that could all be trapped by an
appropriate electrophile. Ynimine 7a was therefore reacted with
1 equiv of methyllithium in THF at −78 °C followed by the
addition of allyl bromide and furnished, to our surprise, the
corresponding alkanenitrile 8a which could be isolated in 47%
yield. The nature of this unexpected rearranged product could
be confirmed by replacing allyl bromide with p-nitrobenzyl
bromide, which gave the corresponding adduct 8b whose
structure could be elucidated by X-ray diffraction analysis.
Benzyl bromide and iodomethane were found to be equally
efficient terminal electrophiles and gave the corresponding
nitriles 8c and 8d in fair yields. Methyllithium could in addition
be replaced by n-butyllithium with similar efficiency (8e,f), and
electron-rich ynimine 7b was also found to be a suitable
substrate. In all cases, the one-pot sequence gave the
corresponding nitriles possessing two consecutive quaternary
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formed that should then rearrange to allylic nitriles 9. To test
this hypothesis, ynimine 7c was treated with KHMDS, which
was found to be more efficient than LiHMDS, in THF at −78
°C followed by hydrolysis. To our delight, the expected allylic
nitrile 9a24 could be isolated, although with a modest yield
(33%), from the reaction mixture along with conjugated nitrile
10a resulting from the isomerization of 9a. This isomerization
was found to be complete starting from ynimine 7d which gave
a mixture of diasteroisomeric conjugated nitriles 10b24 and
10b′24 resulting from a deprotonation/isomerization/hydrol-
ysis/rearrangement/isomerization sequence.
In order to block the radical rearrangement of the
intermediate ketenimines, we next envisioned stabilizing both
these ketenimines and their metalated form by incorporating a
silicon substituent at the terminal carbon atom. Silylated
ynimine 7e was therefore successively reacted with various
alkyllithium reagents and electrophiles under the standard
reaction conditions used for the formation of alkanenitriles
(Scheme 1). The presence of the silyl substituent indeed
strongly modified the reactivity since stable ketenimines 11a−
Figure 5. Synthesis of α,β-unsaturated amides from silylated ynimines.
f
25,26 could now be isolated in good to excellent yields without
the need for any purification (Figure 4).27 Methyllithium and n-
butyllithium gave similar results for these reactions, and the
intermediate lithiated ketenimines could be conveniently
trapped with a variety of electrophiles including allyl, benzyl,
p-nitrobenzyl bromides and methyl iodide. Compared to other
methods for the synthesis of ketenimines, which typically
involve an elimination from imidoyl halides, a Staudinger aza-
Wittig reaction, or an isonitrile-based process,28 our sequence,
which is however limited to the preparation of silylated
ketenimines, provides a useful entry to these building blocks.
−78 °C followed by reaction with an aldehyde and warming the
reaction mixture to room temperature. These results, which
further demonstrate the synthetic utility of ynimines as
precursors of metalated keteniminescompounds which can
hardly be generated using other methodsalso represent the
first examples of a Perterson olefination yielding to [3]-
azacumulenes.
In conclusion, we have shown that ynimines, compounds
that are readily prepared by direct alkynylation of imines with
terminal alkynes or copper acetylides, are excellent precursors
of metalated ketenimines. They can be generated in situ by the
reaction of ynimines with organolithium reagents or strong
bases and trapped with various electrophiles including water,
alkyl iodides, allyl/benzyl bromides, and aldehydes. Substitution
of the triple bond in the starting ynimines by alkyl or aryl
groups allow for the formation of unstable ketenimines which
spontaneously rearrange to highly substituted saturated and
unsaturated nitriles. In sharp contrast, a dramatic change in
reactivity was observed starting from silyl-substituted ynimines
which, upon transformation to the corresponding lithiated
ketenimines, afford stable silylketenimines or conjugated
amides upon reaction with alkyl halides and aldehydes,
respectively.
Altogether, these results bring useful insights into the
reactivity of ynimines under anionic conditions and further
expand the synthetic utility of these underrated building blocks.
Figure 4. Synthesis of stable ketenimines from silylated ynimines.
To bring these studies one step further and in order to fully
exploit the presence of the trimethylsilyl group, we finally
evaluated the possibility of trapping the intermediate lithiated
silylketenimines K (Figure 5) with aromatic aldehydes. The
nucleophilic addition of K to these aldehydes should indeed
allow for the formation of α-alkoxysilylketenimines L, which
could potentially evolve through either a [1,3]-Brook rearrange-
ment, a nucleophilic addition of the alkoxide to the central
carbon atom of the ketenimine moiety, or a Peterson-type
olefination. The latter, which was found to be operative in our
case, would yield to [3]-azacumulene M29 which, upon
hydrolysis, would generate α,β-unsaturated amides 12. As
shown by results summarized in Figure 5, ynimine 7e could
indeed be transformed to conjugated amides 12a−d upon
reaction with 1 equiv of an organolithium reagent in THF at
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures, characterization, copies of H and
13C NMR spectra for all new compounds, and cif files for
compounds 8b and 11b. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gevano@ulb.ac.be.
Notes
The authors declare no competing financial interest.
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Bourdreux, F.; Rammah, M. M.; Rammah, M. B.; Evano, G. Synthesis
2012, 44, 1491.
ACKNOWLEDGMENTS
■
We thank the CNRS, the Universities of Brussels, Versailles and
Monastir, the ANR (project DYNAMITE ANR-2010-BLAN-
704), and the CMCU/PHC Utique (Grant No. 10G1025) for
support.
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suppressed by rapidly adding the organolithium reagent in order to
avoid the concomitant presence of the lithiated ynamine and the
starting ynimine.
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