Synthesis of a new chiral cyclic aminal derived from rac-1,2-propanediamine

Article abstract of DOI:10.1016/j.tetlet.2012.08.154

The cyclic aminal 4,9-dimethyl-1,3,6,8-tetraazatricyclo[4.4.1.1 ^3,8]dodecane 4c was synthesized by the reaction of commercial rac-1,2-propanediamine with paraformaldehyde in an aqueous solution. ¹H NMR analysis clearly revealed that

Full text of DOI:10.1016/j.tetlet.2012.08.154

Tetrahedron Letters 53 (2012) 6132–6135
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Tetrahedron Letters
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Synthesis of a new chiral cyclic aminal derived from rac-1,2-propanediamine
Augusto Rivera a, , Dency José Pacheco a, Jaime Ríos-Motta a, Karla Fejfarová b, Michal Dušek b
⇑
a Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, Departamento de Química, Carrera 30 No. 45-03, Bogotá, Código Postal 111321, Colombia
b Institute of Physics ASCR, v.v.i., Na Slovance 2, 182 21 Praha 8, Czech Republic
a r t i c l e i n f o
a b s t r a c t
The cyclic aminal 4,9-dimethyl-1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane 4c was synthesized by the
reaction of commercial rac-1,2-propanediamine with paraformaldehyde in an aqueous solution. 1H
NMR analysis clearly revealed that the compound is chiral and racemic with an axis of chirality. To
our knowledge, this is the first example of an azaadamantane derivative having axial chirality. This ami-
nal was used in a Mannich type reaction with p-chlorophenol yielding 2,20-[(4-methylimidazolidine-1,3-
diyl)dimethanediyl]bis(4-chlorophenol) 7 as a racemic mixture. The crystal structure of 7 was deter-
mined by single X-ray diffraction analysis.
Article history:
Received 3 August 2012
Revised 30 August 2012
Accepted 31 August 2012
Available online 10 September 2012
Keywords:
Aminal cage
Axial chirality
Ó 2012 Elsevier Ltd. All rights reserved.
Imidazolidine-bridged bis(phenols)
Mannich condensation
1,2-Propanediamine
Introduction
extensively used as catalyst in many enantioselective reactions.8
Salan ligands (H2[H4]salen, tetrahydrosalen, and N,N0-bis(2-
1,2-Propanediamine is the simplest chiral diamine. 1,2-
Propanediamine is a useful intermediate in the preparation of
N,N0-disalicylidene-1,2-propanediamine, the active ingredient of
the additive approved for use by military specification MIL-T-
5624 and ASTM specification D1655.1 This amine attracts interest
as a useful precursor for the synthesis of non-symmetrical tetra-
dentate di-Schiff base ligands.2 Metal-templated Mannich reac-
tions involving 1,2-propanediamine and formaldehyde have been
employed in the preparation of saturated polyazamacrocyclic com-
plexes.3 Our group has been interested in synthesizing novel N-
containing heterocycles using cyclic aminals for some time. We
previously prepared cyclic aminals by the condensation of formal-
dehyde with 1,2-diamines.4 Some of these cyclic aminal products
have been successfully used in the synthesis of compounds such
as 1 and 2. In fact, in a previous work,5 we reported the successful
synthesis of N,N0-bis(2-hydroxybenzyl)ethylenediamine com-
pounds 1 (salans) by the hydrolysis of 4,40-disubstituted-2,20-[imi-
dazolidine-1,3-diylbis(methylene)]diphenols 2. Compounds such
as 2 are easily synthesized by a Mannich-type condensation of a
hydroxybenzyl)-1,2-diaminoethane) are present in a number of
metal coordination complexes, including complexes containing
elements located in groups 12, 13, and 14.9 These facts prompted
us to synthesize the aminal cage 4,9-dimethyl-1,3,6,8-tetraazatri-
cyclo[4.4.1.13,8]dodecane (DMTATD, 4), the closest analogue of cyc-
lic aminal 3. An extensive literature search revealed that the
synthesis of this molecule has not been reported to date.
OH
OH
OH
OH
NH NH
N
N
R
R
R
R
1
2
N
N
N
N
N
N
N
N
N
H3C
N
O
CH3
phenol
and
the
cyclic
aminal
1,3,6,8-tetraazatricy-
H C
3
clo[4.4.1.13,8]dodecane (TATD) 3,6 which is a product of the con-
densation of ethylenediamine with formaldehyde. Additionally,
chiral salens are one of the most popular and widely used ligands
in asymmetric synthesis, and their metal complexes are now used
as catalysts for various stereoselective processes.7 Salen has been
4a-c
a = 4R,9R
3
5
b = 4 ,9
S
S
S
c = 4 ,9
R
1
2
H C
3
H C
3
3N
N
N
CH
3
N
4
5
10
9
N
N
CH
7
3
6
8
H3C
⇑
Corresponding author. Tel.: +57 1 3165000; fax: +57 1 3165220.
E-mail address: ariverau@unal.edu.co (A. Rivera).
n
6
4c
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.154

A. Rivera et al. / Tetrahedron Letters 53 (2012) 6132–6135
6133
N
ide. To our disappointment, all efforts to obtain the aminal cages
were unsuccessful. Instead, in agreement with Hocker and Wend-
ish,10 only resinous products were obtained. Thus, the cyclization
of two molecules of diamine with the same absolute configuration
to a polycyclic structure failed, which also occurs with trans-1,2-
cyclohexanediamine.12 Interestingly, when experiments were car-
ried out with rac-1,2-propanediamine and paraformaldehyde in
N,N-dimethylformamide, it was apparent that the reaction followed
a different initial condensation pathway. Accordingly, we designed
a series of experiments to optimize these reaction conditions. Dur-
ing our optimization experiments, we found that the condensation
of rac-1,2-propanediamine with paraformaldehyde in water at
60 °C for 4 h yielded a mixture of liquid products from which the
target aminal cage 4c was isolated as a single (R,S) stereoisomer
in 54% yield (Scheme 1). Next, we carried out several experiments
to confirm the chemical structure of this new aminal cage.
(CH2O)n
H2N
NH2
N
N
60 oC, H2O
N
racemic
4R,9S
Scheme 1. Synthesis of chiral cyclic aminal (4c).
To the best of our knowledge, there is only one study in the lit-
erature describing the reaction between 1,2-propanediamine and
formaldehyde.10 According to that study, this reaction does not pro-
duce the expected aminal cage but instead affords a mixture of
liquid products composed of the oxygenated bicycle 6-methyl-3-
oxa-1,5-diazabicyclo[3.2.1]octane 5 and oligomers of type 6, for
which molecular weight determinations indicate that n = 4 or 5.
On the other hand, the reaction of ethylenediamine with parafor-
maldehyde at 80 °C in N,N-dimethylformamide as the solvent has
been reported to produce the cyclic aminal 3.11 Accordingly, we
considered this procedure to be a potential route to obtain the de-
sired aminal cage. These observations influenced us to prepare the
aminal cages (4R,9R)-4,9-dimethyl-1,3,6,8-tetraazatricyclo[4.4.
1.13,8]dodecane (4a) and (4S,9S)-4,9-dimethyl-1,3,6,8-tetraazatri-
cyclo[4.4.1.13,8]dodecane (4b) by reacting enantiopure R- and S-
1,2-propanediamine with formaldehyde in N,N-dimethylformam-
Results and discussion
For the reaction of rac-1,2-propanediamine with paraformalde-
hyde, we chose to use water over N,N-dimethylformamide because
water is known to play the role of a catalyst in many such reac-
tions.13 It is worth mentioning that the complex nature of formal-
2.70 2.68 2.66 2.64 2.62
1.04
1.02
1.00
4.2 4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0
Figure 1. 1H NMR spectrum of 4c.
19.00
73 72 71 70 69 68 67 66 65 64 63 62
140
130
120
110
100
90
80
70
60
50
40
30
20
Figure 2. 13C NMR spectrum of 4c.

6134
A. Rivera et al. / Tetrahedron Letters 53 (2012) 6132–6135
ylene groups of the aminal cage were in different environments.
This process resulted in two axially diastereomeric aminal cages
displaying different NMR signals.
The imaginary chiral axis passes through the mid-point of the
ethylene moieties of aminal cage (4c), and two possible spatial
distributions can be obtained: Ra-(4R,9S)-4,9-dimethyl-1,3,6,8-tet-
raazatricyclo[4.4.1.13,8]dodecane (4cRa) and Sa-(4R,9S)-4,9-di-
methyl-1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (4cSa) (Fig. 3).
To confirm the structure of the product inferred from the spec-
troscopic analysis above, we carried out a Mannich-type reaction
between 4c and p-chlorophenol following the protocol described
previously,6 which afforded 4,40-disubstituted-2,20-[imidazoli-
Figure 3. View of the two possible spatial distributions around the chiral axis. For
dine-1,3-diylbis(methylene)]diphenol
2 as the major product.
clarity only shows the hydrogens of methyl groups.
Based on a similar reaction, we expected to observe ortho-ami-
nomethylation to yield the bis-2-hydroxybencilimida-zolidine
derivative (2). When we carried out this Mannich-type reaction,
(Scheme 2) the expected product, 2,20-[(4-methylimidazolidine-
dehyde solutions makes it difficult to predict the precise effect of
the standard conditions on paraformaldehyde concentration.14 As
such, it was necessary to add a 3-molar excess of paraformalde-
hyde to drive the reaction to completion.15 After solvent evapora-
tion at reduced pressure, a very viscous liquid product was
recovered by chromatography of the crude product on silica gel
(eluent, 8:2 methanol-25% NH4OH). All efforts to obtain a solid
by treating this liquid with different solvents were unsuccessful.
Because of the extreme viscosity of this compound, it was irrele-
vant to measure the boiling point.
1,3-diyl)dimethanediyl]bis(4-chlorophenol)
7 was formed and
was completely characterized by NMR, IR, and MS.19 The structure
of 7 was also determined by X-ray analysis. In the IR spectrum of
Mannich base 7, the absorption band at 3300–2200 cmꢀ1 was
attributed to the O–H stretching vibration, suggesting possible
hydrogen bond interactions between the N atom of heterocyclic
ring and the H atom of phenol residue, which was confirmed by
X-ray analysis. The 1H NMR spectrum showed that all of the meth-
ylene protons were diastereotopic due to the presence of a chiral
carbon atom. Methylene protons adjacent to the chiral center of
heterocyclic ring appeared as two double doublets: one at
d = 2.43 ppm (J = 10, 7.8 Hz) and the other at d = 3.25 ppm (J = 9.9,
7.0 Hz). Both aminalic hydrogens (d = 3.42 ppm, J = 7.1 Hz/
d = 3.63 ppm, J = 7.2 Hz) and benzylic hydrogens (d = 3.58 ppm,
J = 14 Hz/d = 4.11 ppm, J = 13.9 Hz, d = 3.84 ppm, J = 13.8 Hz/
d = 3.77 ppm, J = 13.8 Hz) appeared as doublets due to geminal
coupling.
The spectroscopic evidence showed that the product obtained
was the desired cyclic aminal (4c). The HR-ESI-MS of 4c15 exhibited
a quasi-molecular-ion peak ([M+H]+) at m/z 197.1733 (calculated
197.1761), corresponding to the molecular formula C10H21N4. In
the 1H and 13C NMR spectra of compound 4c, all of the signals could
be assigned and were as expected. One striking feature in both the
1H and 13C spectra was the presence of duplicated signals (Figs. 1
and 2). In our experience, this doubled-signal pattern had not been
observed in other 1H NMR spectra of aminal cages that we previ-
ously synthesized. The 1H NMR spectrum showed two distinct res-
onances at d 1.02 (J = 1.8 Hz) and 1.03 (J = 1.7 Hz) assigned to the
methyl protons, which displayed two close signals at 19.15 and
19.25 ppm in the 13C NMR spectrum. Due to the geometrical rigid-
ity and non-planar structure of 4c, a chiral environment is created
for any pair of geminal protons, resulting in diastereotopy, as ob-
served by chemical no-equivalence of these hydrogens. The 1H
NMR spectrum also contained signals characteristic of the NCH2N
protons between 3.7 and 4.2 ppm. In detail, the proton spectrum
displayed the expected AB splitting pattern for hydrogens 2, 7, 11,
and 12 (diastereotopic geminal protons), with an additional split-
ting into doublets imposed by a long range W-coupling constant
similar to that observed in 1,3,6,8-tetraazatricyclo-[4.3.1.13,8]unde-
cane (TATU), an aminal cage previously synthesized in our labora-
tory.16 In theory, this condensation reaction can result in several
stereoisomers due to the possibility of each possible pair of the
enantiomers reacting. Taking into account the NMR data, it was
possible that at least two possible diastereoisomers were present,
To unambiguously define their structures and to establish the
conformational influence of the methyl substituent, we attempted
to obtain a crystal of 7 suitable for X-ray analysis. Attempts to crys-
tallize 7 from several solvents always resulted in the recovery of
amorphous material. Fortunately, crystals were grown in chloro-
form–methanol using the slow evaporation method. The molecular
structure of 7 (Fig. 4) indicates that the heterocyclic ring adopts a
OH
HO
N
p
-chlorophenol
N
N
N
N
H2O/EtOH, 50
°C
N
H3C
4c
7
Cl
Cl
Scheme 2. Mannich-type reaction leading to 7 from 4c and p-chlorophenol.
namely
(4R,9S)-4,9-dimethyl-1,3,6,8-tetraazatricyclo[4.4.1.13,8
]
dodecane (4c) and (4R,9R) or (4S,9S)-4,9-dimethyl-1,3,6,8-tetraaz-
atricyclo[4.4.1.13,8]dodecane (4a–b). However, it was reasonable
to assume that if each of the enantiomerically pure (R)- and (S)-dia-
mines did not afford the respective aminal cage in the self-conden-
sation reactions, the configuration of 4c should be (4R,9S).
The question of the duplicated signals observed in the 1H NMR
spectrum, which suggested the existence of two configurational
isomers, was addressed by considering the existence of a hypothet-
ical chiral axis. It is well known that adamantane and twistane
structures may be chiral compounds due to the presence of a chiral
axis.17,18 Similarly, the incorporation of two methyls in the struc-
ture of TATD (3) broke the symmetry, and consequently, the meth-
Figure 4. The molecular structure of 7. Displacement ellipsoids are drawn at the
50% probability level, and H atoms are shown as small spheres.

A. Rivera et al. / Tetrahedron Letters 53 (2012) 6132–6135
6135
Figure 5. Non-conventional hydrogen bonds linking the pair of enantiomers in the crystal lattice.
13. Hammam, E.; Lee, E. P. F.; Dyke, J. M. J. Phys. Chem. A 2000, 104, 4571.
14. Norris, C. B.; Joseph, P. R.; Mackiewicz, M. R.; Reed, S. M. Chem. Mater. 2010, 22,
3637–3645.
twisted conformation on C2—C3, (Q(2) = 0.3721 (17) Å,
u = 126.8
(3)°),20 whereas a related structure has a twist conformation on
C—N.21 This finding could indicate that the conformational change
of the ethylene bridge is a consequence of methyl substitution on
the heterocyclic ring. Additionally, it was determined that com-
pound 7 crystallized as a racemic mixture, which unequivocally
proves that the configuration of aminal cage 4c is (4R,9S). In the
crystal lattice, a pair of enantiomers was bonded together by
non-classical intermolecular interactions C—Hꢁ ꢁ ꢁCl between H16
and Cl2 (Fig. 5). The crystal structure of 7 confirms the presence
of two intramolecular hydrogen bond interactions. However, no
significant differences in the values observed in a related structure
are observed.
15. Reaction of rac-1,2-propanediamine with paraformaldehyde: Paraformaldehyde
(1026 mg, 34.2 mmol) was added in small portions to a solution of rac-1,2-
propanediamine (1 mL, 11.4 mmol) in water (20.0 mL) with vigorous stirring
for 10 min, at 60 °C. The reaction mixture was stirred for 4 h, and the product
was extracted with CHCl3 (4 ꢂ 5 mL). The organic layer was dried over
anhydrous sodium sulfate and filtered, and the solvent was evaporated under
reduced pressure. The crude product was purified by column chromatography
on silica gel and eluted with methanol–25% NH4OH (8:2) mixture to afford
(4R,9S)-4,9-dimethyl-1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane
4c
(54%
yield) as a viscous liquid: 1H NMR (400.1 MHz, CDCl3): d 1.02 (d, 3H), 1.03
(d, 3H), 2.63 (m, 2H), 3.33 (m, 2H), 3.44 (m, 2H), 3.71–4.13 (m, 8H). 13C NMR
(100.6 MHz, CDCl3): d 19.15, 19.25, 61.86, 62.23, 64.97, 65.37, 67.67, 67.82,
72.98, 73.13. HR-ESI-MS in its positive mode m/z: [M+H]+ calcd for C10H21N4:
197.1761, found: 197.1733.
16. Rivera, A.; Núñez, M. E.; Morales-Rios, M. S.; Joseph-Nathan, P. Tetrahedron Lett.
2004, 45, 7563–7565.
17. Shibuya, M.; Taniguchi, T.; Takahashi, M.; Ogasawara, K. Tetrahedron Lett. 2002,
43, 4145–4147.
The synthesis of this new bisbenzylimidazolidine derivative
represents an expansion of our previous work regarding the use
of cyclic aminals as preformed electrophiles in Mannich condensa-
tions to prepare new ligands with imidazolidinic cores and poten-
tial uses in homogeneous catalysis.22–24
18. Geivandov, R. Ch.; Goncharova, I. V.; Titov, V. V. Mol. Cryst. Liq. Cryst. 1989, 166,
101–103.
19. Synthesis
of
2,20-[(4-methylimidazolidine-1,3-diyl)dimethane-diyl]bis(4-
In summary, we report the first synthesis of the cyclic aminal
4,9-dimethyl-1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane
(DMTATD, 4c). We probed its existence through an ortho-ami-
nomethylation reaction to form the di-Mannich base 7. This finding
could be exploited to produce a range of unprecedented chiral
salans.
chlorophenol) 7: A solution of p-chlorophenol (182 mg, 1,4 mmol) in ethanol
(1 mL) was added dropwise into a solution of (4R,9S)-4,9-dimethyl-1,3,6,8-
tetraazatricyclo[4.4.1.13,8]dode-cane 4c (140 mg, 0.7 mmol) in water (1 mL).
The mixture was stirred for 4 days at 50 °C. The resulting product was purified
by column chromatography on silica gel using gradient elution with benzene/
ethyl acetate to afford the product 7 (mp 117.5–118 °C, 39 % yield): 1H NMR
(400.1 MHz, CDCl3): d 1.26 (d, 3J = 6.2 Hz, 3H), 2.43 (dd, 2Jgem = 10.0, 3J = 7.8 Hz,
1H), 3.10–2.92 (m, 1H), 3.25 (dd, 2Jgem = 9.9, 3J = 7.0 Hz, 1H), 3.42 (d, 3J = 7.1 Hz,
2
1H), 3.58 (d, Jgem = 14.0 Hz, 1H), 3.63 (d, 3J = 7.2 Hz, 1H), 3.77 (d,
2
2
2Jgem = 13.8 Hz, 1H), 3.84 (d, Jgem = 13.8 Hz, 1H), 4.11 (d, Jgem = 13.9 Hz, 1H),
6.77 (d, 3J = 8.7 Hz, 2H), 6.95 (dd, 3J = 6.6, 4J = 2.5 Hz, 2H), 7.13 (dd, 3J = 8.7,
4J = 2.0 Hz 2H). 13C NMR (100.6 MHz, CDCl3): d 18.57, 29.85, 56.64, 57.72,
59.48, 59.64, 74.90, 116.81, 117.75, 117.81, 122.65, 123.07, 124.07, 124.10,
Acknowledgments
We acknowledge the Dirección de Investigaciones, Sede Bogotá
(DIB) de la Universidad Nacional de Colombia and Fundación para
la Promoción de la Investigación y la Tecnología del Banco de la
República for the financial support of this work, as well as the Insti-
tutional research plan No. AVOZ10100521 of the Institute of Phys-
ics and the Praemium Academiae project of the Academy of
Sciences of the Czech Republic.
128.11, 128.11, 129.13, 129.62, 156.20, 156.26. FT-IR (KBr) (m
, cmꢀ1): 3300–
2200 (O–H, broad, st), 2956 (CH3 asym, st), 2924 (CH2 asym, st), 2865 (CH3
sym, st), 2851 (CH2 sym, st), 1607(–C@C, st), 1308 (C–N, st), 643 (C–Cl, st); HR-
ESI-MS in its positive mode m/z: [M+H]+ calcd for C18H21Cl2N2O2: 367.0981,
found: 367.0971.
20. Crystal data for compound 7, C18H20Cl2N2O2, were collected using a goniometer
Xcalibur detector: Atlas (Gemini ultra Cu) diffractometer, M = 367.3, monoclinic,
P21/c, a = 18.3098(7) Å, b = 6.0252(3) Å, c = 16.1039(8) Å, V = 1758.01(14) Å3,
Z = 4, X-ray source Cu Ka (radiation), k = 1.54180 Å, F(0 00) = 768, colorless
prism 0.26 ꢂ 0.13 ꢂ 0.07 mm. The refinement was carried out against all
reflections. The conventional R-factor is always based on F. The goodness of fit
as well as the weighted R-factor are based on F and F2 for refinement carried
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