Efficient method for the cycloaminomethylation of glycoluril

Article abstract of DOI:10.1016/j.tetlet.2016.03.013

The efficient method for the cycloaminomethylation of glycoluril to yield 2,6-ditert-butylhexahydro-1H,5H-2,3a,4a,6,7a,8a-hexaazacyclopenta[def]fluorene-4,8-dione is described. The material is synthesized employing water as the solvent, and is isolated by filtration. This is an improvement over the previous reported synthetic method, which relied on the use of samarium trichloride catalysis, as well as silica gel column chromatographic purification to obtain the target product.

Full text of DOI:10.1016/j.tetlet.2016.03.013

Tetrahedron Letters xxx (2016) xxx–xxx
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Tetrahedron Letters
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Efficient method for the cycloaminomethylation of glycoluril
b
c
a,
⇑
Leah A. Wingard , Eric C. Johnson , Jesse J. Sabatini
a
US Army Research Laboratory, Energetics Technology Branch, Aberdeen Proving Ground, MD 21005, United States
Oak Ridge Associated Universities, Belcamp, MD 21017, United States
TKC Global, 13873 Park Center Road, Herndon, VA 20171, United States
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient method for the cycloaminomethylation of glycoluril to yield 2,6-ditert-butylhexahydro-
Received 8 February 2016
Revised 2 March 2016
Accepted 3 March 2016
Available online xxxx
1
H,5H-2,3a,4a,6,7a,8a-hexaazacyclopenta[def]fluorene-4,8-dione is described. The material is
synthesized employing water as the solvent, and is isolated by filtration. This is an improvement over
the previous reported synthetic method, which relied on the use of samarium trichloride catalysis, as well
as silica gel column chromatographic purification to obtain the target product.
Published by Elsevier Ltd.
Keywords:
Synthesis
Cycloaminomethylation
Glycoluril
Introduction
Existing synthesis of bis-1,3,5-triazinane compounds
Glycoluril and/or its derivatives have been used in water treat-
The synthesis of di-tert-butyl-bis-1,3,5-triazinane 2 was previ-
ously synthesized from glycoluril and N,N-bis(methoxymethyl)
1
2
3
ment, paints, and coatings, as a slow-release nitrogen fertilizer,
in the synthesis of the hydrolytically unstable explosives dinitro-
tert-butylhexanamine in the presence of catalytic SmCl
3
Á6H
2
O
4
5
6
glycoluril (DNGU) and tetranitroglycoluril (TNGU). In connection
with an ongoing search to synthesize new energetic materials at
the US Army Research Laboratory (ARL), attention has been
focused on the synthesis of polynitrogen, tetracyclic compounds.
The main compound of interest at this time is the glycoluril-
derived tetracycle 2,6-di-tert-butylhexahydro-1H,5H-2,3a,4a,6,7a,
(Scheme 1) on a 10 mmol scale. Although no procedure and yield
for the synthesis of N,N-bis(methoxymethyl)tert-butylhexanamine
was given, it is assumed that this material was synthesized from
tert-butylamine, formaldehyde, methanol, and KOH at refluxing
7
temperatures. In the Khairullina synthesis, silica gel column chro-
matography was required to obtain 2.
8
a-hexaazacyclopenta[def]fluorene-4,8-dione. Khairullina and co-
Although the target molecule was prepared by this method, the
presence of chlorinated organic solvents, the use of the samarium
trichloride catalyst, and the need to use silica gel chromatography
to purify the compound presents limitations from producing 2 eco-
nomically on a large scale.
workers reported that this aforementioned bis-1,3,5-triazinane
fused aza heterocyclic compound could be synthesized by reacting
glycoluril and N,N-bis(methoxymethyl)tert-butylhexanamine in
the presence of catalytic samarium trichloride (SmCl
3
2
Á6H O) to
obtain the desired product.6
In synthesizing new materials at ARL, it is important that the
materials can be prepared on a large scale in an efficient and
cost-effective manner. Preferably, avoiding the use of organic sol-
vents, expensive catalysts, and flash chromatography on silica gel
would be ideal in achieving a cost-effective synthesis. With this
in mind, we sought to develop an alternative synthesis to make
fused aza heterocycles containing the bis-1,3,5-triazinane core
unit.
O
O
N
N
N
N
MeO
SmCl .
N
OMe (2.0 eq)
O (5 mol%),
2
HN
HN
NH
NH
N
N
6H
3
EtOH:CHCl (2:1), 60 oC, 6 h
3
O
(81%)
O
1
2
Scheme 1. Samarium trichloride-mediated synthesis of di-tert-butyl-bis-1,3,5-
triazinane 2.
⇑
Corresponding author. Tel.: +1 410 278 0235.
E-mail address: jesse.j.sabatini.civ@mail.mil (J.J. Sabatini).
http://dx.doi.org/10.1016/j.tetlet.2016.03.013
040-4039/Published by Elsevier Ltd.
0
Please cite this article in press as: Wingard, L. A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.03.013

2
L. A. Wingard et al. / Tetrahedron Letters xxx (2016) xxx–xxx
O
O
O
O
HO
HO
OH
OH
Paraformaldehyde (4.05 eq),
NaOH (cat.), pH = 8-10,
H N
NH2 (2.5 eq)
N
N
N
N
O
H
O
H
2
HN
HN
NH
NH
H O, 70 oC, 12 h
2
H SO (cat.), H O,
2
4
2
o
9
0 C, 12 h
O
1
(92%)
O
O
N
N
N
N
t-BuNH2 (2.5 eq),
0 oC, 16 h
N
N
4
2
(61%)
Scheme 2. Samarium-free synthesis of 2.
Optimized synthesis of di-tert-butyl-bis-1,3,5-triazinane 2
Acknowledgments
The optimized synthesis commenced with an acid-catalyzed
condensation of glyoxal and urea to afford glycoluril (1) in high
Research was sponsored by the Army Research Laboratory was
accomplished in part under Cooperative Agreement Number
W911NF-12-2-0019. The views and conclusions contained in this
document are those of the authors and should not be interpreted
as representing official policies, either expressed or implied, of
the Army Research Laboratory or the U.S. Government. The U.S.
Government is authorized to reproduce and distribute reprints
for Government purposes notwithstanding any copyright notation
herein.
yield after filtration. Rather than employing SmCl
3 2
Á6H O in the
presence of N,N-bis(methoxymethyl)tert-butylhexanamine, gly-
coluril and paraformaldehyde were suspended in water, treated
with a catalytic amount of NaOH, and heated to produce tetram-
ethylol glycoluril. This material was not isolated, though addition
of tert-butylamine and gentle heating led to the formation of 2.
Gratifyingly, this material did not require column chromatography
for purification, but could simply be isolated by filtration without
the need for further purification. The synthesis of 2 was carried
out on a 176 mmol scale to yield 36 g of product on multiple occa-
sions (see Scheme 2).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.03.
When synthesizing the tetramethylolglycoluril intermediate,
pH control is essential. A pH of 8–10 is the best to achieve optimal
yields. No reaction occurred if the pH was 7 and below. When the
pH rose to 11 and above, poor yields of 2 were obtained.
0
13.
References and notes
1
2
3
.
.
.
Karcher, S.; Kornmuller, A.; Jekel, M. Water Res. 2001, 35, 3309–3316.
Parekh, G. G. US Patent 4,105,708, 1978.
Shimizu, T. Soil Sci. Plant Nutr. 1987, 33, 291–298.
Conclusions
In summary, an optimized and cost-efficient synthesis of 2 is
described. Unlike the previous synthetic methodology, the new
method detailed in this paper allows 2 to be synthesized from
inexpensive commercially available starting materials. The use of
4. (a) Franchimont, A. P. N.; Klobbie, E. A. Recueil Trav. Chim. 1888, 7, 12–24; (b)
Franchimont, A. P. N.; Klobbie, E. A. Recueil Trav. Chim. 1888, 7, 236–257; (c)
Franchimont, A. P. N.; Klobbie, E. A. Recueil Trav. Chim. 1889, 8, 283–306.
5.
(a) Boileau, J.; Emeury, J. M. L.; Kehren, J. P. A. German Patent 2,435,651, 1975;
(b) Boileau, J.; Emeury, J. M. L.; Kehren, J. P. A. US Patent 4,487,938, 1984; (c)
Boileau, J.; Carail, M.; Wimmer, E.; Gallo, R.; Pierrot, M. Propellants Explos.
Pyrotech. 1985, 10, 118–120.
N,N-bis(methoxymethyl)tert-butylhexanamine, SmCl
3
2
Á6H O, chlo-
rinated organic solvents and silica gel column chromatography is
avoided. The aforementioned compound has been reproducibly
synthesized on a 36 g scale. Although outside the scope of our cur-
rent research interests, it is believed that the new methodology
could be applied toward synthesizing other bis-1,3,5-triazinanes
through the employment of other primary amines during the
cyclization step.
6
.
Khairullina, R. R.; Geniyatova, A. R.; Meshcheryakova, E. S.; Khalilov, L. M.;
Ibragimov, A. G.; Dzhemilev, U. M. Russ. J. Org. Chem. 2015, 51, 116–120.
7. Farzaliev, V. M.; Mustafaev, I. I.; Nabiev, O. G.; Nabizade, Z. O. Kimya Problemari
010, 1, 40–44.
2
Please cite this article in press as: Wingard, L. A.; et al. Tetrahedron Lett. (2016), http://dx.doi.org/10.1016/j.tetlet.2016.03.013