Synthesis of the 1,3,4-Oxadiazole Core through Thermolysis of Geminal Diazides

Article abstract of DOI:10.1002/ejoc.201601119

The thermolysis of geminal diazides derived from acylacetate compounds is an efficient tool for the rapid construction of the 1,3,4-oxadiazole core. While a broad range of ethyl esters undergoes smooth transformation to the desired heterocycles that contain the ester moiety in moderate to high yields, the analogous tert-butyl esters give rise to the oxadiazoles with acyl groups, presumably through a pathway of decarboxylation followed by a new acyl transfer.

Full text of DOI:10.1002/ejoc.201601119

DOI: 10.1002/ejoc.201601119
Communication
Organic Azides
Synthesis of the 1,3,4-Oxadiazole Core through Thermolysis of
Geminal Diazides
Hellmuth Erhardt,[a] Fabian Mohr,[b] and Stefan F. Kirsch*[a]
Abstract: The thermolysis of geminal diazides derived from heterocycles that contain the ester moiety in moderate to high
acylacetate compounds is an efficient tool for the rapid con- yields, the analogous tert-butyl esters give rise to the oxa-
struction of the 1,3,4-oxadiazole core. While a broad range of diazoles with acyl groups, presumably through a pathway of
ethyl esters undergoes smooth transformation to the desired decarboxylation followed by a new acyl transfer.
Introduction
ticular, the generation of 1,3,4-oxadiazoles with an ester moiety
at the 2-position, the exact products available through the Rank
route, is significantly hampered when using the traditional cy-
clocondensation strategies.[16]
The chemistry of organic azides has attracted the interest of
researchers since their first discovery by Grieß in 1864.[1] In con-
temporary chemistry, organic azides are one of the synthetically
most valuable classes of compounds[2] with powerful applica-
tions in all kinds of chemical research, spanning from chemical
biology[3] to the synthesis of natural products[4] and nitrogen-
containing heterocycles.[5] For example, the Hemetsberger–
Knittel synthesis provides a straightforward and highly useful
access to indoles through the expulsion of nitrogen under ther-
mal conditions and, most likely, through the formation of react-
ive nitrene intermediates.[6] However, methods regarding the
thermal conversion of azide-containing compounds into
heterocyclic entities are still rare;[7] this lack of interest may have
partly arisen from the supposedly hazardous character of or-
ganic azides.[8]
In the context of our ongoing research efforts, which con-
cern the synthesis and reactivity of geminal di- and triaz-
ides,[9–11] we realized that, in addition to the photochemical
behavior of geminal diazides,[12] a surprisingly small number of
studies on the thermal decomposition of geminal diazides were
reported.[13] As we revised several of the early works on the
thermolysis of geminal diazides, the study by Ogilvie and Rank
reported in 1987 became the focus of our attention: A high-
yielding conversion of 2,2-diazido acyl acetates 1 into 1,3,4-oxa-
diazole-2-carboxylates 2 was described through simple heating
of diazido starting compounds in xylene (Figure 1).[14] The
method does not require additional reagents and thus differs
significantly from the alternative and more wide-spread ap-
proaches toward this heterocyclic core, most of which are based
on the chemistry of highly toxic hydrazides (Figure 1).[15] In par-
Figure 1. Synthesis routes toward 1,3,4-oxadiazoles.
The stunning report by Ogilvie and Rank contains only two
examples of the reaction (R = Me and Ph) and is barely cited,
perhaps because methods for the easy synthesis of the starting
2,2-diazido acyl acetates were rare at the time. However, we
now have an experimentally simple and broadly applicable
method for the synthesis of 2,2-diazido acyl acetates 1 by direct
diazidation of acyl acetates with iodine and sodium azide.[9c]
1,3,4-Oxadiazoles are generally considered attractive target
compounds because they are widely used in pharmaceutically
active compounds (e.g., Raltegravir®, a drug for the treatment
of patients with HIV infectious disease)[17] and as building
blocks for organic light-emitting diodes.[18] These considera-
tions prompted us to carefully reinvestigate the possibilities
and, in particular, the scope of creating 1,3,4-oxadiazole-2-
carboxylates through thermolysis of 2,2-diazido acyl acetates.
We now show that this method is indeed a powerful and
[a] Organic Chemistry, Bergische Universität Wuppertal,
Gaußstraße 20, 42119 Wuppertal, Germany
E-mail: sfkirsch@uni-wuppertal.de
http://www.oc.uni-wuppertal.de/prof-dr-stefan-f-kirsch.html
[b] Inorganic Chemistry, Bergische Universität Wuppertal,
Gaußstraße 20, 42119 Wuppertal, Germany
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201601119.
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Communication
broadly useful alternative to access 1,3,4-oxadiazole-2-carboxyl-
ates. Furthermore, we demonstrate for the first time how the
choice of the ester moiety (i.e., COOEt vs. COOtBu) influences
the reaction pathway, thus allowing for subtle changes in the
structure of the oxadiazole products.
Results and Discussion
All 2,2-diazido acyl acetates 1 were generated through the ex-
perimentally simple diazidation of acyl acetates with iodine and
sodium azide in aqueous DMSO, as previously reported by
us.[9c] This class of diazide compounds 1 were shown to be
reasonably stable at room temperature (up to 150 °C in most
cases), and gram-scale quantities are readily accessible. Never-
theless, diazides should be considered potentially hazardous and
handled accordingly due to their high nitrogen content.[8]
We began our studies with the observation that a smooth
transformation of 2,2-diazido acyl acetates 1 into 1,3,4-oxa-
diazoles 2 was only possible under thermolysis conditions
when heating took place in quite dilute solutions (i.e., ca. 0.1 M).
At higher concentrations, a marked increase of degradation
products was observed, most of which we were not able to
identify. Heating of neat diazides 1 resulted in the rapid and
complete decomposition of the material; not even traces of the
desired oxadiazoles 2 were detected. Best results with regard
to the formation of the desired oxadiazoles 2 were obtained in
refluxing xylene. As shown in Scheme 1, a broad array of 1,3,4-
oxadiazoles with aliphatic substituents was accessible by the
use of these standard conditions: Both small chains and steri-
cally demanding groups were easily attached to the heterocy-
clic core under the reaction conditions (e.g., 2a–2e), and high
yields up to 86 % were obtained in a fully reproducible manner.
As shown in the cases of 2f and 2g, phenyl groups were mostly
well tolerated. However, styrene derivatives (e.g., 2i) were troub-
lesome, and yields were low. We note that other diazide sub-
strates 1, which contain olefin moieties, did not provide traces
of the desired oxadiazole products.
Scheme 1. Thermolysis of geminal diazides 1 for the synthesis of 1,3,4-oxa-
diazoles 2.
The connectivity of the heterocyclic core was unambiguously
proven by the crystal structure of oxadiazole 2e depicted in
Figure 2. Additional 15N NMR measurements of 2e showed two
singlets at δ = –52.5 and –72.4 ppm (relative to nitromethane),
and an HMBC correlation was found between the methyl hydro-
gens and N(a).
While ethyl esters (Y = OEt) were good diazide substrates 1
for the transformation into oxadiazoles 2, we were surprised to
find that most of the other carboxylic acid derivatives tested in
this survey gave markedly reduced yields with regard to the
desired heterocycles.[19] For example, amide 1j with Y = NMeBn
gave oxadiazole 2j with only 22 % yield. When amides with an
acidic proton (Y = NHR or NH2) were refluxed in xylene, com-
plete decomposition was observed, and not even traces of the
corresponding oxadiazole were detected.
Figure 2. 15N NMR signals in CDCl3; crystal structure of 2e, thermal ellipsoids
are drawn at 50 % probability.[23]
20, 4b in 29, and 4c in 33 % yield), albeit in low to moderate
The thermolysis of geminal diazides 3 that bear tert-butyl yields. We reasoned that the acylation of the oxadiazole core
esters was particularly astonishing because it gave rise to 1,3,4- most likely proceeds through an intermolecular acyl-transfer
oxadiazoles 4 acylated at the C2 position, besides the expected step, and the diazido starting material not only enables hetero-
oxadiazoles with the ester moiety. As shown in Scheme 2, it cyclization, but in addition presumably acts as acylation agent.
was possible to generate several oxadiazoles of this type (4a in Currently, this unprecedented acyl-transfer step is under further
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Communication
investigation in our laboratory. As one might expect, more con- experiment in refluxing xylene with a 1:1 mixture of 3a and 3c
centrated solutions were required to generate the acylated oxa- (tert-butyl 2,2-diazido-3-oxo-5-phenylpentanoate) showed an
diazoles 4 (i.e., > 0.5 M), and it was important to carefully moni- intermolecular exchange of the acyl groups. This is indicated by
tor the product formation since elongated reaction times led to the formation of the acetylated oxadiazole derived from 3c, that
complete decomposition. The standard oxadiazole product with is, 1-(5-phenethyl-1,3,4-oxadiazol-2-yl)ethanone, besides 4a and
the tert-butyl ester moiety still attached was obtained under 4c.[22] However, our experiments provide no indication of how
reflux in xylene at a 0.1
M
concentration, as exemplified through the diazido compound 3 is transformed in the course of the
the conversion of 3a into 5 in 43 % yield (Scheme 3).
acyl-transfer step. We note that some degree of decomposition
takes place because the crude product does not even contain
traces of remaining azides in the IR spectrum.
Scheme 5. Synthesis of 1,3,4-oxadiazole 7.
Conclusions
We presented insights into the thermolysis of 2,2-diazido acyl
acetates: The scope of this reaction was significantly expanded,
and the methodology was shown to be of broad use for the
synthesis of substituted 1,3,4-oxadiazoles. Ethyl acyl acetates
were found to be the ideal substrates for accessing 1,3,4-oxadi-
azoles with the carboxy group still attached to the heterocyclic
nucleus. tert-Butyl esters, in stark contrast to ethyl esters, un-
dergo decarboxylation at elevated reaction temperatures: A
new subsequent acylation with the 2,2-diazido acyl acetate
starting compound gives rise to a subtly different oxadiazole
product. This interesting result adds to the understanding and
development of the chemistry associated with geminal diaz-
ides.
Scheme 2. Synthesis of acetylated 1,3,4-oxadiazoles 3.
Scheme 3. Synthesis of 1,3,4-oxadiazole 5.
We currently assume that the acylated oxadiazoles 4 are gen-
erated through the initial formation of oxadiazole product 5
(Scheme 4).[20] Thermal stress then leads to the cleavage of the
tert-butyl ester and subsequent decarboxylation.[21] The hetero-
cycle A is finally acylated under the reaction conditions by
diazido compound 3 to give 4. This hypothesis was supported
by the fact that we were able to detect the formation of the
decarboxylated oxadiazole A under the reaction conditions:
when submitting diazide 6, which contains a 4-chlorophenyl
group, to refluxing xylene, 1,3,4-oxadiazole 7 was obtained as
the only product, albeit in poor yield (Scheme 5). A crossover
Acknowledgments
We thank M.Sc. Janis Derendorf for support with the X-ray struc-
ture of compound 2e.
Keywords: 1,3,4-Oxadiazoles · Heterocycles · Thermolysis ·
Organic azides · Acylation · Cyclization
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Received: September 9, 2016
Published Online: ■
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Communication
Organic Azides
H. Erhardt, F. Mohr,
S. F. Kirsch* .......................................... 1–5
Synthesis of the 1,3,4-Oxadiazole
Core through Thermolysis of Gemi-
nal Diazides
Simple heating of easily generated oxadiazoles were observed: the direct
geminal diazides derived from ꢀ-keto heterocyclization product and, in the
esters affords the corresponding 1,3,4- case of tert-butyl esters, the product in
oxadiazoles in a straightforward man- which the ester moiety was replaced
ner. Depending on the nature of the through further acylation.
ester functionality, two types of 1,3,4-
DOI: 10.1002/ejoc.201601119
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