1-Alkynyltriazenes as Functional Analogues of Ynamides

Article abstract of DOI:10.1002/anie.201507033

The chemical reactivity of 1-alkynyltriazenes has been investigated and is found to parallel the reactivity of ynamides. The similarity in reactivity of these two classes of compounds is demonstrated by addition reactions with acids, by cycloaddition reactions with ketenes, tetracyanoethene, and cyclopropanes, as well as by intramolecular cyclization reactions. The presence of reactive triazene groups in the products enables subsequent transformations. Overall, our results suggest that 1-alkynyltriazenes should become valuable reagents in synthetic organic chemistry. Cut from the same cloth: 1-Alkynyltriazenes are activated alkynes with a reactivity profile similar to ynamides. A series of different reactions are employed to compare the reactivities of the two compound classes. The triazene functional group in the products facilitates unique subsequent transformations.

Full text of DOI:10.1002/anie.201507033

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507033
German Edition: DOI: 10.1002/ange.201507033
Activated Alkynes
1-Alkynyltriazenes as Functional Analogues of Ynamides
Florian G. Perrin, Gregor Kiefer, Loïc Jeanbourquin, Sophie Racine, Daniele Perrotta,
JØrôme Waser, Rosario Scopelliti, and Kay Severin*
Abstract: The chemical reactivity of 1-alkynyltriazenes has
been investigated and is found to parallel the reactivity of
ynamides. The similarity in reactivity of these two classes of
compounds is demonstrated by addition reactions with acids,
by cycloaddition reactions with ketenes, tetracyanoethene, and
cyclopropanes, as well as by intramolecular cyclization
reactions. The presence of reactive triazene groups in the
products enables subsequent transformations. Overall, our
results suggest that 1-alkynyltriazenes should become valuable
reagents in synthetic organic chemistry.
that 1-alkynyltriazenes are difficult to prepare using the
classic synthetic routes for triazenes.[5] We hypothesized that
1-alkynyltriazenes might display a reactivity similar to
ynamides, because comparable resonance structures can be
formulated for these types of N-atom-substituted alkynes
(Scheme 1).
F
ollowing the development of efficient synthetic routes for
the preparation of ynamides, these compounds have emerged
as extremely useful building blocks for synthetic organic
chemistry.[1] The unique reactivity of ynamides is related to
the nitrogen atom adjacent to the alkyne function, which
renders the triple bond more reactive compared to what is
observed for standard alkynes. On the other hand, ynamides
are significantly more stable than ynamines,[1d] and accord-
ingly are much easier to work with.
Scheme 1. Resonance structures of ynamides and 1-alkynyltriazenes.
EWG=electron-withdrawing group.
The development of functional analogues of ynamides
offers the possibility to further advance the field of alkyne
chemistry.[2] Ideally, these analogues should display the
following characteristics: a) they can be prepared by simple
and atom-economic synthetic routes; b) they should be
reactive enough to enable different chemical transformations
under mild conditions; c) they should be stable enough to
allow easy handling; d) they should provide access to com-
pounds which cannot be prepared with ynamides. Herein, we
demonstrate that 1-alkynyltriazenes possess the character-
istics outlined above.
Research in our laboratory is directed towards the
development of useful synthetic procedures involving nitrous
oxide (N2O, “laughing gas”).[3] Recently, we have discovered
that it is possible to prepare 1-alkynyltriazenes by reaction of
lithium amides with nitrous oxide and alkynyl Grignard
reagents.[4] This simple method allows access to a variety of
1-alkynyltriazenes in good yields. While aromatic triazenes
have been studied extensively in the context of synthetic
organic[5] and medicinal chemistry,[6] the chemistry of
1-alkynyltriazenes is completely unexplored. The lack of
studies on these compounds is as a result of the fact
First, we examined the reaction of 3,3-diisopropyl-1-
(phenylethynyl)triazene with HCl (Scheme 2). Aromatic
triazenes are sensitive to acids and the triazene group is
typically replaced upon addition of strong acids.[5] In contrast,
we observed the 1,2-addition of HCl to the triple bond in the
reaction with the 1-alkynyltriazene. Similar hydrohalogena-
tion reactions are known for ynamides.[7] Hydrohalogenation
reactions with ynamides can be conveniently performed by
utilization of MgX2 in wet organic solvents (HX generated
in situ).[7] This method also worked for our triazenes and
provided the addition products 1–3 in good yields (Scheme 2)
with a preferred formation of the E isomer. The E isomer of
compound 1 was also characterized by X-ray crystallography
(see the Supporting Information).
Ynamides are sufficiently reactive to allow the addition of
simple carboxylic acids.[8] Similarly, benzoic acid or acetic acid
could be added to 3,3-diisopropyl-1-(phenylethynyl)triazene
[*] F. G. Perrin, Dr. G. Kiefer, L. Jeanbourquin, S. Racine, D. Perrotta,
Prof. J. Waser, Dr. R. Scopelliti, Prof. K. Severin
Institut des Sciences et IngØnierie Chimiques
École Polytechnique FØdØrale de Lausanne (EPFL)
1015 Lausanne, (Switzerland)
E-mail: kay.severin@epfl.ch
Scheme 2. Addition of acids to 1-alkynyltriazenes. Reaction conditions
for HX=HCl, HBr, or HI: MgX2, wet CH3CN, RT, 24 h. Reaction
conditions for HX=HO2CR: toluene, 1008C, 24 h.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507033.
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(toluene, 1008C, 24 h) to give products 4 (91% yield) and 5
(94% yield). Again, the E isomer was obtained as the major
product isomer (Scheme 2).
Encouraged by these first test reactions, we have exam-
ined more complex transformations. Ynamides[9] and their
analogues, such as N-alkynylated sulfoximines,[10] are known
to undergo [2++2] cycloaddition reactions with ketenes to
afford functionalized cyclobutenones. We have investigated
the reaction of 3,3-diisopropyl-1-(phenylethynyl)triazene
with dimethylketene (generated in situ by dehydrohalogena-
tion of isobutyryl chloride). As in the case of ynamides, we
observed the formation of a cyclobutenone (6), which was
isolated in 80% yield (Scheme 3). It should be noted that
Scheme 4. Reactions of 1-alkynyltriazenes with tetracyanoethylene.
well as aromatic alkynes, and variations of the dialkylamine
component are also possible.
Donor–acceptor cyclopropanes are useful building blocks
in Lewis acid catalyzed [3+n] cycloadditions to yield hetero-
cycles or carbocycles.[14] Recently, Johnson et al. described
a Sc(OTf)3-catalyzed [3+2] annulation of activated cyclo-
propanes with ynamides.[15] However, versatile aminocyclo-
propanes[16] as reaction partners were not employed. Cyclo-
pentene derivatives 18 (42% yield) and 19 (80% yield) were
obtained by reaction of 1-alkynyltriazenes with an amino-
cyclopropane (Scheme 5). The regioselectivity of the prod-
Scheme 3. Synthesis of substituted cyclobutenones by reaction of
1-alkynyltriazenes with ketenes. The ketenes were generated in situ
from acyl chlorides.
cycloaddition reactions between non-activated ketenes
and alkynes are difficult to achieve.[11] The clean formation
of cyclobutenone 6 thus confirms the high reactivity of
1-alkynyltriazenes. As evident by the successful formation of
cyclobutenone derivatives 7–13, it possible to vary the
triazene as well as the ketene coupling partner, even though
a low yield of isolated product was obtained in some cases
(Scheme 3). In all cases, we obtained only one isomer. The
trans position of the keto group and the triazene group was
confirmed by a X-ray crystallographic analysis of a crystal of
compound 9 (see the Supporting Information).
Activated alkynes (for example N,N-dimethylanilino-
substituted alkynes) are known to react with tetracyano-
ethylene (TCNE) to give 1,1,4,4-tetracyanobuta-1,3-diene
derivatives.[12] The products have received considerable
interest because of their optical properties. Recently, it was
reported that ynamides are also able to react with TCNE to
give tetracyanobutadienes.[13] This report prompted us to
examine the reaction of 1-alkynyltriazenes with TCNE
(Scheme 4). As in the case of ynamides, a clean transforma-
tion into the corresponding tetracyanobutadienes (14–17) was
obtained when the starting materials were mixed in dry
dichloromethane (DCM) at room temperature. The reactions
can be performed with triazenes derived from aliphatic as
Scheme 5. Synthesis of substituted cyclopentenes by reactions of
1-alkynyltriazenes with cyclopropanes.
ucts, with the triazene functional group next to the ester
groups, was confirmed by single-crystal X-ray analysis of
a crystal of 18 (for details see the Supporting Information).
These results demonstrate that 1-alkynyltriazenes are com-
patible with a strong Lewis acid such as Sc(OTf)3.
Next, we have investigated intramolecular cyclization
reactions. The iodocyclization of alkynes is an efficient
method for the synthesis of heterocycles.[17] Recently, it was
shown that ynamides are suitable substrates for this type of
chemistry, providing access to amide-functionalized benzo-
furans.[18] 1-Alkynyltriazenes can be used in similar fashion.
To demonstrate this reactivity, we first synthesized the new
2-methoxyphenyl-substituted alkynyltriazene 20 using our
N2O procedure.[4] In the presence of iodine, the triazene is
cleanly converted into the corresponding benzofuran 21,
which was isolated in 62% yield (Scheme 6).
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ring closure. It should be noted that spirocyclic butenolides
such as 26 are of significant interest because this kind of
subunit is found in numerous biologically active compounds,
such as in the synthetic insecticides spirodiclofen and
spiromesifen,[19] as well as in the natural products lambertellol
A/B,[20] chlorothricolide,[21] and andirolactone.[22] The success-
ful synthesis of butenolides 25 and 26 suggests that it is
possible to access this important class of compounds in two
steps starting from 1-alkynyltriazenes.
Scheme 6. Iodocyclization of an 1-alkynyltriazene.
Aromatic triazenes can be successfully employed in
a variety of reactions because they are very stable under
basic conditions and towards organometallic reagents, yet it is
possible to substitute the triazene by a variety of functional
groups using an appropriate activation method.[5] This intri-
guing mix of stability and reactivity is also found for the
reaction products of 1-alkynyltriazenes. For example, it is
possible to use the 3-iodobenzofuran 21 in a Pd-catalyzed
cross-coupling reaction with phenylboronic acid to give the
arylated product 22 in 90% yield. The triazene function can
then be removed by treatment with HCl/Et2O or I2/MeI to
give benzofurans 23 and 24 (Scheme 7).
Another demonstration of the reactivity imparted by the
triazene function is the successful conversion of the cyclo-
butenones 7 and 10 into the lactones 25 and 26. This
transformation was accomplished by heating the cyclobute-
none in the microwave for 35 minutes in the presence of HBr
(Scheme 7). The following mechanism seems plausible: an
initial retro-electrocyclization gives a ketene, which is hydro-
The cleavage of the triazene function can also be
accomplished for simple olefinic triazenes such as 3. For
example, heating of 3 with iodine in MeI provides the
diiodostyrene 27 in 55% yield (Scheme 7).
To conclude, we have started to examine the chemical
reactivity of 1-alkynyltriazenes, which can be prepared easily
by a recently developed method.[4] On purpose, we have not
performed a detailed study on scope and limitations for one
or two selected reactions. Instead, we have examined differ-
ent types of reactions in order to obtain a first impression
of the general reactivity. The results show that 1-alkynyl-
triazenes are activated alkynes, which undergo a variety of
chemical transformations. The reactivity observed so far is
reminiscent of what has been reported for ynamides. The
extent of the similarity between 1-alkynyltriazene and
ynamide reactivities needs to be examined in future studies,
but it seems likely that the transformations reported herein
are merely the tip of the iceberg with respect to possible
reactions of 1-alkynyltriazenes. One interesting aspect of
these reactions is the possibility to access triazenes, which
would be otherwise difficult to synthesize. For example, it is
unlikely that the olefinic triazenes described above (1–19) can
be prepared by the standard synthetic route for triazenes. In
view of the fact that aromatic triazenes have been inves-
tigated extensively as potential antitumor agents, it will be
interesting to perform biological tests with these new olefinic
triazenes. A second noteworthy point is the intrinsic reactivity
of triazene-containing compounds. Despite the fact that the
relative stability of the compounds means that handling and
purification (for example, by chromatography) are quite
straightforward, it is possible to substitute the triazene
functionality with other groups, as demonstrated by the
formation of compounds 23–27. Taken together, our results
suggest that 1-alkynyltriazenes should become valuable
reagents for synthetic organic chemistry.
À
lyzed to a carboxylic acid. Acid-induced rupture of the N N
single bond leads to the formation of a vinyl diazonium
compound, which releases dinitrogen after intramolecular
Acknowledgements
The work was supported by the Ecole Polytechnique FØdØrale
de Lausanne (EPFL) and the Swiss National Science Foun-
dation.
Keywords: alkynes · cyclization · cycloaddition reactions ·
triazenes · ynamides
How to cite: Angew. Chem. Int. Ed. 2015, 54, 13393–13396
Angew. Chem. 2015, 127, 13591–13594
Scheme 7. Reactions of olefinic triazenes.
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Received: July 29, 2015
Published online: September 16, 2015
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