Preparation of cage amine 1,3,6,8-tetraazatricyclo[4.3.1.1 3,8]undecane

Article abstract of DOI:10.1016/j.tetlet.2004.08.123

Reaction between cage amine 1,3,6,8-tetraazatricyclo[4.4.1.1 ^3,8]dodecane (TATD) and ammonium fluoride affords 1,3,6,8-tetraazatricyclo[4.3.1.1^3,8]undecane, the missing link between 1,3,5,7-tetraazatricyclo[3.3.1.1^3,7]deca

Full text of DOI:10.1016/j.tetlet.2004.08.123

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7563–7565
Preparation of cage amine
1,3,6,8-tetraazatricyclo[4.3.1.13,8]undecane
a
b
Augusto Rivera,a, Martın E. Nu´n˜ez, Martha S. Morales-Rıos and
*
´
´
Pedro Joseph-Nathanb
a
´
´
Departamento de Quımica, Universidad Nacional de Colombia, A.A. 14490 Bogota, D.C., Colombia
b
´ ´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional,
´
´
Apartado 14-740, Mexico, D.F. 07000, Mexico
Received 30 July 2004; revised 18 August 2004; accepted 20 August 2004
Abstract—Reaction between cage amine 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD) and ammonium fluoride affords
1,3,6,8-tetraazatricyclo[4.3.1.13,8]undecane, the missing link between 1,3,5,7-tetraazatricyclo[3.3.1.13,7]decane (urotropine) and
TATD. The structure was established mainly from 2D NMR measurements.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1,3,6,8-Tetraazatricyclo[4.4.1.13,8]dodecane
(1),
or
aromatic amines,12 cyanide anion,13 and electrophiles
such as nitrosonium ion,14 which afford 3,4-dihydro-
3,6-disubstituted-2H-1,3-benzoxazines, 1,3-bis(20-hydr-
oxy-50-substituted-benzyl)-imidazolidines, 1,3-bis(cyano-
methyl)-imidazolidine, 1,3,5-tris-arylhexahydro-1,3,5-
triazines, and 1,3-dinitrosoimidazolidine, respectively.
In continuing our studies, we became interested in
exploring the reactivity of 1 in basic media, which
resulted in the preparation of the new cage amine
[(15.21)]adamanzane (2) that we named TATU. Ana-
logues of 2, substituted at the ethylene residue, were
prepared15 by reaction of 3 with phenacyl bromides.
TATD, known since 1898,1 and 1,3,5,7-tetraazatricy-
clo[3.3.1.13,7]decane (3), or urotropine, known since
1859,2 are important industrial chemicals produced
commercially via reaction of formaldehyde with ethylen-
ediamine1,3 and ammonia,2 respectively. Compound 1
has been used in organic synthesis4 and in the prepara-
tion of resins based on phenol, urea, or melamine, in
which formaldehyde is replaced entirely or partially by
1.5 Compound 3 has been used in organic synthesis,6–9
and in several industrial fields, such as anti-moisture
agent, hardener of resins, accelerator in sulfuration,
pharmaceutical derivation, in the manufacture of high
explosives such as RDX, as urinary antiseptic drug
and in areas of nonlinear optics.10 Surprisingly, during
the long time that has elapsed since the discovery of 1
and 3, no significant efforts were developed for the prep-
aration of 1,3,6,8-tetraazatricyclo[4.3.1.13,8]undecane
(2), hereafter referred to as TATU, despite its interest
due to symmetry considerations and putative industrial
applications.
N
N
N
N
N
N
N
N
N
N
N
N
1
2
3
We initially prepared the macrocyclic aminal cage 2 by
reaction of 1 using either an ammonium hydroxide
(37%) solution obtained from a commercial source, or
by bubbling ammonia gas into the aqueous reaction
medium. However these procedures afforded low yields
(12%) of the desired molecule, and therefore it was
decided to perform the reaction at lower pH values.
Thus, in the final procedure 1 (1.0g, 5.95mmol) was dis-
solved in distilled H2O (5.0mL) and ammonium fluoride
In the course of our studies of the reactivity of aminals,
we described several reactions of TATD (1), a cage
amine type [(14.22)]adamanzane with phenols,11 primary
Keywords: Adamanzanes; Aminals; Cage amines.
*
Corresponding author. Tel.: +57 1 3165000/14464; fax: +57 1
3165220; e-mail: ariverau@unal.edu.co
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.123

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A. Rivera et al. / Tetrahedron Letters 45 (2004) 7563–7565
(0.35mg, 9.52mmol) was added, after which the reaction
mixture was left stirring at room temperature for 5h.
The solvent was evaporated under reduced pressure
and the solid residue was extracted with dichlorometh-
ane (3 · 5mL). The organic layer was dried over anhy-
drous sodium sulfate, filtered, and the solvent
evaporated under reduced pressure. The crude reaction
product was purified by column chromatography on
Si-gel, eluting with a dichloromethane–ethanol (1:4)
mixture, to yield 460mg of 2 (63% yield) as a white solid.
Other chromatographic fractions contained yellow res-
ins that could not be characterized. The reaction yield
is calculated taking into account the fact that five mole-
cules of 1 can only afford four molecules of 2, according
to the balance
5C8H16N4 þ 8NH3 ! 4C7H14N4 þ 6H2NCH2CH2NH2
since a carbon–carbon cleavage of an ethylene residue,
to extrude a methylene group, seem extremely unlikely
and therefore the only expected source to generate the
fifth methylene present in 2 appears to be as originated
by decomposition of another molecule of 1.
Figure 1. NOESY contour plot of TATU (2).
The molecular structure of 216 became evident from
NMR measurements (in CDCl3) and in particular from
those performed in two dimensions. Thus, the 13C NMR
spectrum, obtained at 75.4MHz revealed the presence of
only three methylene signals at 57.4, 72.3, and
73.4ppm,17 suggesting that the first signal corresponds
to a CH2 groupdirectly attached to one nitrogen atom,
while the remaining two signals correspond to CH2
groups bonded to two nitrogen atoms in each case.
For comparison purposes, in the case of 1 the ethylene
carbon atoms appear at 58.2ppm, while the NCH2N sig-
nal appears at 73.8ppm.
constant value is due to a long-range W coupling
between the hydrogen atoms at 3.75 and 4.33ppm. Each
hydrogen atom at 4.33ppm is coupled only to two of the
hydrogens at 3.75ppm but virtual coupling makes it ap-
pear as if coupled to all four hydrogens, with the appar-
ent multiplicity of a quintet. This virtual coupling effect
is not so clearly evidenced in the signal at 3.75ppm,
which should appear as a double triplet, but is in fact
observed as a double doublet with a further unresolved
coupling.
The quintet in the hydrogen domain is cross-coupled to
the carbon signal at 72.3ppm, while the AB proton sys-
tem is cross-coupled to the carbon signal at 73.4ppm.
Cogent evidence for the molecular structure of 2 arose
from the NOESY contour plot shown in Figure 1, where
it can be observed that the doublet at 4.67ppm and the
quintet at 4.33ppm correspond to syn distributed hydro-
gens, as is also the case for those protons originating the
signals at 3.75 and 3.20ppm.
4.67
4.33
3.75
3.75
N
4.33
4.67
4.67
N
N
3.20
3.20
N
4.67
Acknowledgements
3.75
3.75
3.20
´
Financial support from Division de Investigacion Bogo-
ta (DIB), Departamento de Quımica, Universidad
´
3.20
´
´
´
Nacional de Colombia and CONACYT, Mexico (Grant
G-32631-N) is acknowledged.
1
The H NMR spectrum exhibits four signals with rela-
tive intensities 2:2:1:2. A singlet at 3.20ppm, having a
cross-peak in the two-dimensional gHSQC contour plot
to the signal at 57.4ppm in the carbon domain, corre-
sponds to the four hydrogen atoms of an ethylene resi-
due. A double doublet at 3.75ppm (J = 13.5, 1.3Hz), a
homonuclear long-range coupled quintet (J = 1.3Hz)
at 4.33ppm and a doublet at 4.67ppm (J = 13.5Hz)
complete the spectrum. The homonuclear small coupling
References and notes
1. Beilsteins Handbuch der Organischen Chemie; Prager, B.,
Jacobson, P., Eds.; Springer: Berlin, 1922; Band IV, p 250.
2. Bulterov, B. Annals 1859, 11, 250; Cited in: Walker, J. F.
Formaldehyde; ACS Monograph Series; Reinhold, 1944;
p278.

A. Rivera et al. / Tetrahedron Letters 45 (2004) 7563–7565
7565
3. Peori, M. B.; Vaughan, K. J. Org. Chem. 1998, 63, 7437.
4. Kuznetsov, A. I.; Kosmakov, B. A.; Moskovkin, A. S.
Khim. Geterotsikl. Soedin 1990, 5, 681.
5. (a) Deutsche Texaco, A.-G. Austrian Patent 327561, 1974;
(b) Chem. Abstr. 1976, 85, 33945v.
6. Galat, A.; Eliot, B. J. Am. Chem. Soc. 1939, 61, 3585.
13. Rivera, A.; Villamil, M.; Nu´n˜ez, M. E.; Joseph-Nathan, P.
Heterocycl. Commun. 2004, 10, 77.
14. Rivera, A.; Gallo, G. I.; Joseph-Nathan, P. Synth.
Commun. 1997, 27, 163.
15. Henry, R. A.; Hollins, R. A.; Lowe-Ma, C.; Moore, D.
W.; Nissan, R. A. J. Org. Chem. 1990, 55, 1796.
16. Compound 2 shows mp213–215 ꢁC (decomposition) when
measured in a capillary tube. EIMS (70eV) m/z (%): 154
(72), 126 (6), 112 (18), 86 (24), 57 (15), 42 (100). Anal.
Calcd for C7H14O4: C, 54.52; H, 9.15; N, 36.33. Found: C,
54.62; H, 8.91; N, 36.47.
´
7. Delepine, M. Bull. Soc. Chim. Fr. 1895, 13, 358.
8. Blazevic, N.; Kolbah, D.; Belin, B.; Sunjic, V.; Kajfez, F.
Synthesis 1979, 3, 161.
9. Smith, W. E. J. Org. Chem. 1972, 37, 3972.
10. Jensen, J. O. Spectrochim. Acta A 2002, 58, 1347.
11. Rivera, A.; Gallo, G. I.; Gayon, M. E.; Joseph-Nathan, P.
17. A proton coupled 13C NMR spectrum showed the signal
at 57.4ppm as a triple triplet (J = 135.8, 9.1Hz), the signal
at 72.3ppm as a triple quintet (J = 148.7, 6.5Hz) and the
signal at 73.4ppm as a triplet (J = 147.5Hz) with further
unresolved long-range spin–spin interactions.
´
Synth. Commun. 1993, 23, 2921.
12. Rivera, A.; Torres, O. L.; Leiton, J. D.; Morales-Rıos,
M. S., P.; Joseph-Nathan, P. Synth. Commun. 2002, 32,
1407.
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