Hydrogenolysis of geminal diazides

Article abstract of DOI:10.1016/j.tetlet.2017.09.066

The complete hydrogenolysis of compounds containing the geminal diazido functionality is described. Using hydrogen over palladium on charcoal, the diazides are reduced, and primary amines are obtained. For example, aminomalonates and glycines are generated in a straightforward manner. A protocol that provides direct access to acetylated amines derived from 2-amino-1,3-diketones in good to excellent yields, via hydrogenation in the presence of acetic anhydride, is also presented.

Full text of DOI:10.1016/j.tetlet.2017.09.066

Tetrahedron Letters xxx (2017) xxx–xxx
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Tetrahedron Letters
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Hydrogenolysis of geminal diazides
⇑
Phillip Biallas , Stefan F. Kirsch
Organic Chemistry, Bergische Universität Wuppertal, Gaußstraße 20, 42119 Wuppertal, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The complete hydrogenolysis of compounds containing the geminal diazido functionality is described.
Using hydrogen over palladium on charcoal, the diazides are reduced, and primary amines are obtained.
For example, aminomalonates and glycines are generated in a straightforward manner. A protocol that
provides direct access to acetylated amines derived from 2-amino-1,3-diketones in good to excellent
yields, via hydrogenation in the presence of acetic anhydride, is also presented.
Received 8 August 2017
Revised 5 September 2017
Accepted 21 September 2017
Available online xxxx
Ó 2017 Elsevier Ltd. All rights reserved.
Keywords:
Hydrogen
Azides
Amines
Reduction
Heterocycles
Introduction
Results and discussion
The chemistry of compounds containing geminal diazido
groups has been rarely studied: until recently, only a rather small
number of compounds with this motif have been reported in the
literature,1,2 and their synthesis was mostly limited to classical
substitution reactions with dihalides and azide anions.3 With
regard to the reactivity of geminal diazides, the research has
focused on their thermolysis4 and photochemical degradation.5
Over the last couple of years, we have shown in a number of
publications how geminal diazides derived from 1,3-dicarbonyl
compounds can be easily obtained: for example, the use of iodine
and sodium azide in aqueous DMSO allowed the smooth conver-
sion of a broad range of 1,3-dicarbonyl compounds 1 into their dia-
zido congeners 2 (Scheme 1a).6 Other groups have also reported
valuable methods for the synthesis of geminal diazides, thus
expanding the scope of readily available compounds containing
the diazido functionality.7 With powerful methods in hand, we
then started to systematically uncover the reactivity of geminal
diazido compounds, mainly distant from thermolysis and photoly-
sis reactions.8,9 These diazido compounds are potentially haz-
ardous, and gaining knowledge on their controlled reactivity is
important when new methods with diazido intermediates are
envisioned.10 Herein, we report the hydrogenolysis of geminal dia-
zides 2 derived from 1,3-dicarbonyls (Scheme 1b). It was shown
that, under standard hydrogenation conditions, primary amines 3
were formed in a straightforward manner.
We conducted our initial study with the diazide derived from N,
N0-dibenzyl malonamide (2a), a compound that was found to be
reasonably stable towards both thermal decomposition and harsh
hydrolysis conditions. As shown in Table 1, all hydrogenation
attempts resulted in the rapid formation of primary amine 3a.
For example, use of the AlCl3-Fe couple in aqueous ethanol led to
the corresponding amine, albeit with low conversion.11 The reduc-
tion with InCl3 and Et3SiH in acetonitrile gave full conversion and
quantitative yields of the amine; however, we were not able to
purify the product upon work-up.12 The pure amine 3a was
obtained in 70% yield employing ammonium formate and zinc in
methanol.13 Significantly better results were obtained with hydro-
gen over palladium on charcoal:14 complete hydrogenolysis of dia-
zide 2a took place in methanol and in aqueous methanol, at room
temperature and atmospheric hydrogen pressure. When perform-
ing the reaction in CH2Cl2 at room temperature, 100 psi of hydro-
gen were optimal to achieve full conversion of the starting
diazide into the desired amine 3a.
Although not evidenced by experimental data, we speculate
that the initially formed diamino compound A is converted into
imine B upon the loss of ammonia. Alternatively, azide intermedi-
ate A0 may rapidly convert into B via expulsion of the azide anion.
Further reduction with hydrogen may then give rise to amine 3.
Notably, in the presence of Lindlar catalyst, the formation of imine
4a was observed, and the isolation of this intermediate en route to
amine 3a was possible in 35% yield (Scheme 2).
Despite its novelty, the hydrogenolysis of geminal diazides may
have limited applications. Running the reactions on small scales is
⇑
Corresponding author.
E-mail address: p.biallas@uni-wuppertal.de (P. Biallas).
https://doi.org/10.1016/j.tetlet.2017.09.066
0040-4039/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Biallas P., Kirsch S.F. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.09.066

2
P. Biallas, S.F. Kirsch / Tetrahedron Letters xxx (2017) xxx–xxx
Scheme 1. Synthesis5 and hydrogenation of geminal diazides.
Table 1
Hydrogenolysis of diazide 2a.
Scheme 3. Hydrogenolysis of diazides.
recent alternative is the direct amination of 1,3-dicarbonyls.16
Yet the direct -amination of malonates is barely feasible, in con-
a
trast to the smooth amination of 1,3-diketones and 3-oxo esters.
We point out that our diazidation-hydrogenation sequence repre-
sents a simple method to accomplish the synthesis of aminated
malonates. Under standard hydrogenation conditions using
15 mol% of palladium on charcoal with 100 psi of hydrogen in CH2-
Cl2 at room temperature, diazides derived from malonates
smoothly gave the corresponding amines, as exemplified by the
conversion of diester 2b (Scheme 3). In this particular case, CH2Cl2
was the solvent of choice since the alternative use of methanol led
to transesterification. When reducing diazides from 3-oxo esters
(e.g., 2c and 2d), the corresponding pyrazine heterocycles 5a and
5b were generally obtained as the main products through classical
dimerization in moderate yields.17
Entry
Conditions
Yield of 3a [%]
1
2
3
4
5
6
Fe, AlCl3 EtOH-H2O, 23 °C
9
InCl3, Et3SiH MeCN, 23 °C
Quant. yield
Zn, H4N+HCOꢀ2 MeOH, 23 °C
70
91
96
91
H2 (1 atm), 15 mol% Pd-C MeOH-H2O, 23 °C
H2 (1 atm), 15 mol% Pd-C dry MeOH, 23 °C
H2 (100 psi), 15 mol% Pd-C CH2Cl2, 23 °C
We then focused on a more practical reaction, with the goal of
supressing the pyrazine-forming dimerization during the reduc-
tion of diazides derived from 3-oxo esters.18 To this end, the hydro-
Scheme 2. Proposed mechanism.
strictly advised since the diazido starting materials are potentially
explosive compounds. However, the standard method for the pro-
duction of compounds containing the amino functionality between
two carbonyls, such as 3, is reduction of the corresponding oximes
(e.g., via the reduction of 2-hydroxylimino 1,3-dicarbonyls); and
the generation of oximes also has some safety issues.15 A more
Scheme 4. Hydrogenolysis of diazides in the presence of acetic anhydride.
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P. Biallas, S.F. Kirsch / Tetrahedron Letters xxx (2017) xxx–xxx
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and the acetylated amines 6a–6d were obtained. As shown in
Scheme 4, this method is a useful tool for the synthesis of N-acety-
lated 3-oxo 2-amino esters, and the yields were typically high.
Additionally, the reduction of other diazido compounds not pos-
sessing a 1,3-dicarbonyl motif was feasible. For example, diazide
7 with a single carbonyl group in proximity to the diazido unit gave
the acetylated amine 8 in good yields while the reduction of diazi-
dated ethyl acetate 9 resulted in the formation of the acetylated
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Conclusion
In conclusion, we have shown that readily available geminal
diazides undergo complete hydrogenolysis when treated with
hydrogen in the presence of palladium on charcoal. The yields for
formation of the corresponding amino-containing products are
typically high. The straightforward reduction of diazides 2, which
are directly accessed from 1,3-dicarbonyl compounds through sim-
ple diazidation, may attract particular interest. This reaction pro-
vides amines with the amino group positioned between the two
carbonyls and, thus, represents a possible alternative to the classi-
cal synthesis of those amines via reduction of the corresponding
oximes.15 We hope that this reaction will further enrich the knowl-
edge on the diverse chemistry of geminal diazido compounds.
Acknowledgments
The supporting work from Kristina Holzschneider (BUW) and
Fabia Mittendorf (BUW) is gratefully acknowledged.
A. Supplementary data
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Please cite this article in press as: Biallas P., Kirsch S.F. Tetrahedron Lett. (2017), https://doi.org/10.1016/j.tetlet.2017.09.066