An unusual product obtained from condensation between ethylenediamine and formaldehyde in basic medium

Article abstract of DOI:10.1016/j.tetlet.2005.05.081

Reaction between ethylenediamine and formaldehyde normally affords 1,3,6,8-tetraazatricyclo[4.4.1.1^3.8]dodecane (TATD) but in this case also afforded 3,3′-ethane-1,2-diyl-bis-1,3,5-triazabicyclo[3.2.1]octane (ETABOC), this being an unusual prod

Full text of DOI:10.1016/j.tetlet.2005.05.081

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5001–5004
An unusual product obtained from condensation
between ethylenediamine and formaldehyde in basic medium
*
Augusto Rivera and Jaime R ´ı os-Motta
Departamento de Qu ı´ mica, Universidad Nacional de Colombia, Ciudad Universitaria, Carrera 30 No. 45-03 Bogot a´ DC, Colombia
Received 12 May 2005; revised 18 May 2005; accepted 19 May 2005
Available online 9 June 2005
3
.8
Abstract—Reaction between ethylenediamine and formaldehyde normally affords 1,3,6,8-tetraazatricyclo[4.4.1.1 ]dodecane
0
(
TATD) but in this case also afforded 3,3 -ethane-1,2-diyl-bis-1,3,5-triazabicyclo[3.2.1]octane (ETABOC), this being an unusual
product from such condensation.
2005 Elsevier Ltd. All rights reserved.
ꢀ
3
For a few years now, 1,3,6,8-tetraazatricyclo [4.4.1.1. ]-
,8
Although the reaction for TATD preparation is known
8
dodecane (TATD) 1 a macrocyclic aminal obtained as
1
since 1898 to the best of our knowledge only Hocker
9
10
described by condensing formaldehyde and ethylenedi-
amine with NaOH, has been successfully used in
and Wendisch formerly and later Dale and Sigvartsen
have reported the isolation of compound 3-oxa-1,5-diaza-
bicyclo[3.2.1]octane 3 in addition to TATD.
2
Mannich-type reactions in basic media and in the
synthesis of some heterocyclic compounds, such as
3
1
methyl)imidazolidines,
,3,5-tris-arylhexahydro-1,3,5-triazines, 1,3-bis(cyano-
4
N
N
5
1,3-dinitrosoimidazolidine,
and 1,3,6,8-tetraazatricyclo [4.3.1.1. ]undecane a cage
N
3
,8
N
N
N
6
7
N
amine type compound. A recent report has described
0
N
a solvent-free Mannich-type reaction of 1,3-bis(2 -hydr-
0
N
N
oxy-5 -substituted-benzyl)imidazolidines with TATD to
afford calix[2]imidazolidin[2]arenes.
1
2
Surprisingly low levels (<2.0%) of an unknown impurity
were detected during our ongoing research for the syn-
thetic exploitation of TATD when larger amounts of
sodium hydroxide and lower temperatures than those
N
N
O
1
3
which have been reported were employed. We assigned
0
its structure as 3,3 -ethane-1,2-diyl-bis-1,3,5-triazabicy-
The latter authors have proposed that the reaction for 1
and 3 forming happens via a mechanism implying the
simultaneous presence of imines and methylolamines,
respectively (Scheme 1).
clo[3.2.1.]octane 2 (we named it ETABOC) on the basis
of NMR spectroscopic studies of a small sample isolated
by recrystallization. In view of the apparent ease of for-
mation of this unexpected compound and our own inter-
est in such molecules it was decided to examine its mode
of formation and hopefully, its chemistry.
Our NMR studies allowed us to ascertain the presence
of methylolamines but not that of imines. We were also
able to establish that 1 and 2 production is controlled by
factors such as pH and temperature. Thus, increasing
the amount of NaOH added to an ethylenediamine/
formaldehyde mixture favored producing 2. A contrary
effect was presented on bringing the reaction mixture
into contact with small quantities of ammonium fluo-
ride. Regarding temperature, it was established that
Keywords:
condensation.
Cyclic
aminals;
Ethylenediamine
formaldehyde
*
Corresponding author. Tel.: +57 1 3165000x14464; fax: +57 1
165220; e-mail: ariverau@unal.edu.co
3
0
040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.05.081

5002
A. Rivera, J. R ı´ os-Motta / Tetrahedron Letters 46 (2005) 5001–5004
CH O
CH O
2
H N
NH2
2
2
HO
OH
OH
N
N
HN
N
HN
NH
-
H O
-
H O
2
2
N
N
N
N
N
N
N
O
H C
CH2
2
N
1
3
10
Scheme 1. Proposed mechanism for obtaining compounds 1 and 3.
the concentration of 2 decreased if the reaction was car-
ried out at room temperature and, on the contrary, it in-
creased when lower temperatures were used. On the
other hand, the variation in relative yield of products
37% solution (3.6 mL, 48 mmol) cooled using an ice-salt
bath and stirred. After stirring at ꢀ10 ꢁC for 1 h, the
solution was concentrated under reduced pressure.
Crude reaction product was extracted with chloroform
(10 mL · 3) and the chloroformic extract was dried with
anhydrous sodium sulfate and filtered. Removal of the
chloroform under reduced pressure afforded a crude
product which was purified by crystallization (pet. ether)
to give compound 2 (1.04 g) in 51% yield, mp 88–89 ꢁC.
From the residue compound 1 was also isolated (485
mg, 30%).
1
and 2 in crude mixtures of different reactions, led us
to think about the existence of a common intermediary
1
0
for both, different to that proposed in the literature.
In fact, NMR spectra (H O/D O) recorded 5 min after
2
2
mixing ethylenediamine with formaldehyde revealed
the presence of TATD, ETABOC, and methylolamines
in the reaction mixture. It is interesting to note that,
we were never able to detect compound 3 nor imines.
These results led us to suppose that it should be referred
to as equilibrium control (kinetic and thermodynamic)
of product composition formed from a common inter-
mediary. A plausible mechanism involving no imines
but a common intermediary 5 that may rationalize these
results is depicted in Scheme 2.
Compound 2 is stable in the absence of acids and water.
1
13
H NMR and C NMR measurements carried out in
CDCl provide unequivocalevidence for the structure
3
1
1
1
of 2 especially in 2D experiments. The d( H) assign-
ments of AB and AA BB spin system are based on
0
0
2
the characteristic J(H,H), J(H,H) and J(H,H) cou-
3
4
1
pling constants as well as H COSY and NOESY
experiments.
Experimentalconditions in which ETABOC 2 was the
major compound in the reaction mixture and in which
it was isolated with an appreciable yield were established
after carrying out severalassays. Thus, a so lu tion of ethy l-
enediamine (1.6 mL, 24 mmol) in water (2.0 mL) cooled
to 0 ꢁC was slowly added (30 min) to a 25 mL single
neck round bottom flask that contained formaldehyde
1
The H NMR spectrum consist of seven signals having
intensities of 1:2:2:1:2:2:2. A singlet at 2.17 ppm which
is ca. 0.80 ppm more highfield than expected was as-
signed to four protons of ethylenediamine exocyclic
moiety. This signalcorre al ted to a 48.5 ppm signalin
the carbon domain in the HMQC two-dimensionalspec-
OH
OH
N
N
HN
-
2H O
-2H O
2
2
2
CH O
2
NH
NH
N
HO
OH
EDA
N
N
N
H
N
4
5
1
N
N
OH
OH
N
N
4
(-2H O)
-2H O
2
2
N
N
5
HN
N
N
N
N
NH
2
Scheme 2. Proposed mechanism for forming 1 and 2.

A. Rivera, J. R ı´ os-Motta / Tetrahedron Letters 46 (2005) 5001–5004
5003
2
trum. A double–doublet centered on 2.75 ppm ( J =
3
0.6 and J = 4.4 Hz) and a double doublet-of-doublets
1
2
3
4
centered at 3.13 ppm ( J = 10.6, J = 4.4 and J =
.9 Hz) clearly exhibited the general splitting pattern
1
0
0
of an AA BB system which was assigned to ethylenedi-
amine portions conforming the 1,3,5-triaza[3,2,1]octane
bicycle system. Four signals at 3–4 ppm having coupling
constants about 10 Hz, characteristic of coupling be-
tween non-equivalent geminal protons, indicated the
presence of two AB systems. The more shielded aminal
hydrogen signal, centered at 3.30 ppm, corresponded to
2
4
a double–triplet ( J = 10.5 and J = 1.5 Hz); this signal
coupled with the more deshielded signal resonated at d
2
.89 as a double–triplet ( J = 10.5 and J = 1.9 Hz).
4
3
The other AB system showed a doublet at 3.40 ppm
1
3
The C NMR spectrum showed two pairs of secondary
carbon atoms indicating that the molecule has symme-
try. Aminalic carbon appeared at 78.5 and 76.6 ppm
while ethylenic carbon resonated at 51.9 and 48.5 ppm.
This fact was puzzling because at first glance the mole-
cule appeared to be more complex. The ethylene group
binding the two bicycles exhibited a surprisingly chemi-
2
and the other one at 3.62 and both exhibit J = 10.7
4
and J = 1.5 Hz.
It is noteworthy to mention that unequivocalassign-
ments of bridgehead protons was possible because of
J coupling (less than 2.0 Hz) have conformational
dependence and are observable in cycles only when
the ÔWÕ path is available. Additional evidence for struc-
ture elucidation of 2 was obtained from the NOESY
contour plot shown in Figure 1 where it can be seen that
the double–doublet at 3.62 ppm and the singlet at 2.17
corresponded to hydrogens having syn distribution, the
same as that presented with hydrogens appeared at
4
1
3
1
1
2
calequiva el nce of both
C nuclei and H. This fact
especially caught our attention. Such chemical and mag-
netic equivalence is only possible in one of two cases:
when free rotation throughout this bond is not restricted
or when the molecule is symmetric.
An eclipsed 6 conformation presenting a plane of sym-
metry is less stable than an anti conformation 7 present-
ing a C2 axis of symmetry according to stability
calculations for the two possible conformation present-
ing elements of symmetry, based on HF/6-31G* calcula-
3
.17 ppm. Another NOE effect was presented between
the more downfield hydrogens (3.89 ppm) and those at
.40 ppm.
3
1
3
tion employing Gaussian 98 computational software.
The difference in energy between the two conformers
was 8.70 kcal/mol (HF/6-31G*).
The cross-peak in the HMQC two-dimensionalspec-
1
3
trum was taken into account when assigning
NMR signals. The signal at 51.9 ppm presented con-
C
0
0
tours correlating to the AA BB system (2.75 and
.13 ppm), the signala 76.5 ppm corr ea lt ed to the
AB)2 system (3.39 and 3.62 ppm) and the signalat
6.6 ppm presented contours correlating to the AB sys-
tem (3.29 and 3.86 ppm). The highest field signal
48.5 ppm) correlated to the highfield signal (2.17 ppm)
In solution a more Ôstretched outÕ geometry is adapted
by the molecule. The fact that one of these two confor-
mations predominated implies that the molecule is rigid
3
(
7
(
which was assigned to exocyclic ethylene residue.
Figure 1. ETABOC 2 NOESY contour plot.

5004
A. Rivera, J. R ı´ os-Motta / Tetrahedron Letters 46 (2005) 5001–5004
0
and Ôfree rotationÕ around N3–CH –CH –N3 bonds are
7. Rivera, A.; Quevedo, R. Tetrahedron Lett. 2004, 45, 8335.
2
2
8
. Beilsteins Handbuch der Organischen Chemie; Prager, B.,
Jacobson, P., Eds.; Springer: Berl ´ı n, 1922, p 250, Band IV.
. Hocker, J.; Wendisch, D. J. Chem. Res. (S) 1977, 236.
restricted. The NOESY contour diagram experiment of
2
was supported because a cross-peak between ethylene
hydrogens (2.17 ppm) and (AB)2 system hydrogens can
be seen (Fig. 1).
9
1
1
0. Dale, J.; Sigvartsen, T. Acta Chem. Scand. 1991, 45, 1064.
1
1. pf 88 ꢁC, H NMR (400 MHz, CDCl
3
) d ppm (J Hz): 2.17
0
0
(
NCH CH N, s, 4H); 2.79 (H6b, H7b, H6 b, and H7 b,
dd; 10.6; 4.4); 3.17 (H6a, H7a, H6 a, and H7 a, ddd; 10.6;
.4; 1.9) 3.30 (H8b and H8 b, dt: 10.5;1.5); 3.40 (H2b,
H4b, H2 b, and H4 b, d; 10.7); 3,62 (H2a, H4a, H2 a, and
+
The M peak in HR-EIMS at 252.2062 further con-
2
2
0
0
firmed the structure. In conclusion, we have discovered
an unknown product from condensation reaction be-
tween ethylediamine and formaldehyde and developed
a mild method to obtain it in good yields.
0
4
0
0
0
0
0
13
H4 a, dd: 10.7;1.5); 3.89 (H8a and H8 a, dt; 10.5; 1.9).
C
0
NMR (100 MHz, CDCl
0
3
0
) d ppm: 76.6 (C-8 and C-8 ); 76.5
0
0
(
C-2, C-4, C-2 , and C-4 ); 51.9 (C-6, C-7, C-6 , and C-7 );
+
8.5 (NCH CH N). HR-EIMS: m/z (%) [M ]: (1.71) calcd
4
2
2
for C12
H
24
N
6
: 252.3653. Found: 252.2062; 182.1564
Acknowledgements
(10.10); 126.1030 (87.2), 85.0728 (100).
2. Barfield, M.; Dean, A. M.; Fallick, C. J.; Spear, R. J.;
1
Financialsupport from Direccio´n Nacionalde Investi-
gaciones (DINAIN) and Departamento de Qu ´ı mica,
Universidad Nacionalde Co ol mbia is acknow el dged.
Stermhell, S.; Westerman, P. W. J. Am. Chem. Soc. 1975,
7, 1481.
9
1
3. Frisch, M. J.; Trucks, G. W.; Robb, M. A.; Schlegel, H.
B.; Scuseria, G. E.; Cheeseman, J. R.; Zakrzewski, V. G.;
Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J.
C.;Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K.
N.;Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.;
Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo,
C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P.
Y.;Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A.
D.;Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.;
Martin, R. L.; Fox, D. J.; Keith, T. M.; Al-Laham, A.;
Peng, C. Y.; Nanayakkara, A.; Challacombe, M. P.; Gill,
M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J.
L.;Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.;
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Pittsburgh, PA, 1998.
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