Synthesis of macrocyclic and linear benzylimidazolidine oligomers from solvent free aromatic Mannich-type reaction

Article abstract of DOI:10.1016/j.tetlet.2015.09.066

The reaction between the phenolic Mannich bases 1,3-bis[2′-hydroxybenzyl]imidazolidines and the Mannich intermediary macrocyclic aminal 1,3,6,8-tetraazatricyclo[4.4.1.1^3,8]dodecane (TATD) was studied under solvent-free conditions. It was establ

Full text of DOI:10.1016/j.tetlet.2015.09.066

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of macrocyclic and linear benzylimidazolidine oligomers
from solvent free aromatic Mannich-type reaction
a,
⇑
b
a
Augusto Rivera , Luz Stella Nerio , Rodolfo Quevedo
a
Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, Departamento de Química, Cra. 30 No. 45-03, Bogotá, Colombia
Universidad de la Amazonia, Programa de Química, Calle 17 Diagonal 17—Carrera 3F, Florencia, Colombia
b
a r t i c l e i n f o
a b s t r a c t
0
Article history:
The reaction between the phenolic Mannich bases 1,3-bis[2 -hydroxybenzyl]imidazolidines and the
Received 27 July 2015
Revised 14 September 2015
Accepted 16 September 2015
Available online xxxx
3,8
Mannich intermediary macrocyclic aminal 1,3,6,8-tetraazatricyclo[4.4.1.1 ]dodecane (TATD) was stud-
ied under solvent-free conditions. It was established that the major product is a heterocalixarene-type
Mannich base, and three linear benzylimidazolidine oligomers were identified as minor products. The
formation of these oligomers is analyzed in the present Letter, and the reaction mechanism is proposed.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Mannich reaction
Heterocalixarene
Cyclic aminal
Solvent-free
Phenol
Introduction
becomes necessary to know the reaction mechanism in depth.
For this reason, a study of the minor products was undertaken
Aminophenol-type Mannich bases are of great chemical and
industrial interest due to their growing applicability for the pro-
duction of new polymeric materials with excellent mechanical,
employing spectroscopic techniques and mass spectrometry.
This work identified several subproducts that provide insight
into the reaction course, justifying the need to perform the
reactions in the absence of a solvent, and the development of a
mechanistic proposal that shows the oligomerization and macro-
cyclization processes (Scheme 1). In addition, the results obtained
make it possible to present the synthesis of benzylimidazoline-
derived macrocycles as a new example of a macrocyclization
reaction assisted by complementary intermolecular hydrogen
bonds between phenolic hydroxyls and amino groups.
1–4
thermal, photophysical, and catalytic properties.
Previous stud-
ies of (aminomethyl)phenol synthesis, both in solution and in the
absence of a solvent, employing the Mannich intermediary macro-
cyclic aminal 1,3,6,8-tetraazatricyclo [4.4.1.13 ]dodecane (TATD) 1
and phenols showed that the formation of benzylimidazoline oli-
gomers, similar to compound 4, plays a decisive role in the reaction
efficiency. In addition, in certain cases, the reaction products in the
,8
5
absence of the solvent differ from those obtained in solution. It
The starting reagents for the experiments were the macrocyclic
aminal TATD 1, synthesized from formaldehyde and ethylenedi-
has also been shown that the solvent-free Mannich-type aromatic
reaction between the macrocyclic aminal TATD 1 and Mannich
7
amine, and the Mannich bases 2a–2d, previously synthesized
0
phenolic bases of the type 1,3-bis[2 -hydroxybenzyl]imidazolidine
from the aminal TATD 1 and the phenols p-chlorophenol (2a), phe-
nol (2b), p-cresol (2c), and methyl p-hydroxybenzoate (2d) by
heating the reactants in aqueous dioxane solution for variable time
at 40–42 °C. The crude product thus obtained was further purified
by CC on silica gel eluting with benzene/ethyl acetate mixtures
2
is a useful synthetic strategy for the high-efficiency production of
heterocalixarene-type macrocyclic compounds 3 and linear oligo-
5
,6
mers 4 formed by three benzylimidazolidine units (Scheme 1).
Considering that aminophenol-type Mannich bases are of inter-
est due to their potential uses, as described above, that the reaction
yields polycondensation products when occurs under solvent-free
conditions and that the formation of linear or macrocyclic oligo-
mers appears to depend exclusively on the stoichiometric ratio, it
8
(Scheme 2).
It has been proposed that the initial formation of an
intermolecular hydrogen bond between one of the TATD 1 nitro-
gens and the phenolic hydroxyl is necessary for the formation of
0
1
,3-bis[2 -hydroxybenzyl]imidazolidines 2 through the reaction
between the aminal TATD 1 and phenols. This hydrogen bond
increases the electrophilicity of the aminal carbons and favors
⇑
Corresponding author. Tel.: +57 1 3165000; fax: +57 1 3165220.
E-mail address: ariverau@unal.edu.co (A. Rivera).
http://dx.doi.org/10.1016/j.tetlet.2015.09.066
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0
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2
A. Rivera et al. / Tetrahedron Letters xxx (2015) xxx–xxx
N
OH
HO
N
N
+
N
N
N
R
R
1
2a-d
150 °C
Solvent free
HO
N
N
OH
N
N
R
OH
N
HO
R
N
N
+
HN
NH
N
R
R
6
a-d
3
a-d
+
+
HO
OH
OH
N
N
HO
N
N
N
N
N
N
N
HO
NH
OH
R
R
R
R
4
a-d
7
a-d
R
R
a: R= Cl, b: R= H, c: R= CH , d: R= CO CH
3
3
2
0
Scheme 1. Reaction of TATD 1 with 1,3-bis[2 -hydroxybezyl]imidazolidines 2.
OH
R
OH
HO
N
N
OH
HO
+
N
N
N
N
N
Dioxane/water
40 - 42 °C
N
+
Cl
Cl
N
1
N
N
N
R
R
2a
1
2
a-2d
OH
a: R= Cl, b: R= H, c: R=CH , d: R= CO CH
3
3
2
Cl
0
Scheme 2. Synthesis of 1,3-bis[2 -hydroxybenzyl] midazolidines 2a–2d.
EtOH/H O (1:1)
2
OH
aromatic electrophilic substitution. It is known that (aminomethyl)
phenol-type Mannich bases, such as 2, form very strong
intramolecular hydrogen bonds. In solution, these intramolecular
HO
N
N
OH
9
N
N
hydrogen bonds prevent the intermolecular interaction of 2 with
TATD 1, and consequently formation of imidazolidine containing
products 5 does not occur. When a phenol is present in the reaction
medium in addition to the aminal TATD 1 and the Mannich base 2,
the TATD 1–phenol interaction activates the aminal carbon. Upon
activation, the aminal reacts both with a phenol molecule and with
a Mannich base to form a linear dimer of benzylimidazolidine, con-
Cl
Cl
Cl
5
a
0
0
Scheme 3. Reaction of TATD 1, 1,3-bis[2 -hydroxy-5 -chlorobenzyl]imidazolidine
and p-chlorophenol in solution.
sisting of three aromatic rings joined by two imidazolidines 5
8
(
Scheme 3).
(conventional heating: 3a = 40%; microwave irradiation:
3a = 49%), but the reaction times decreased. In all cases, the neces-
sary time for the full disappearance of the reagents was less than
1 min.
The solvent-free conditions for the reaction between TATD 1
and Mannich bases 2 are necessary to reach higher reaction tem-
peratures, which provide the necessary energy to break the
intramolecular hydrogen bond. After this bond breaks, a new inter-
action appears between the phenolic hydroxyl of the Mannich base
and one of the nitrogens from the TATD 1—nitrogens that are
probably more alkaline than those present in the Mannich base
After the working temperature (150 °C) was established, the
crude products of the reaction between TATD 1 (0.3 mmol) and
the Mannich bases 2a–d (0.3 mmol) were analyzed, both in the
case of conventional heating and in the case of microwave irradia-
2
1
(
Scheme 1).
tion. The H NMR and ESI-(+) MS (using a cone voltage of 10 V, in
The experiments performed showed that when the mixture of
TATD 1 and the Mannich bases 2a–2d at a molar ratio of 1:1 is
heated to 150 °C, the heterocalixarene-type macrocyclic compound
a–3d as major product is obtained in less than 9 min. The reaction
time is reduced with increased activation degree of the aromatic
ring. Reactions at various temperatures from 110 to 200 °C showed
higher efficiencies in the formation of 3 when working in the range
from 140 to 160 °C. The use of microwave radiation (in a CEM
Discover instrument with 250 W maximum power) as a heat
source did not modify the course or the efficiency of the reaction
order to ionize molecules avoiding its fragmentation) spectra
showed that with both heating processes, the major product
obtained is the macrocyclic compound 3a–d. In the 1H NMR
spectrum, in addition to the singlet corresponding to the ethylenic
hydrogens present in 3, appearing at approximately 3 ppm, two
triplets are observed: one at 3.12 ppm (J = 7.2 Hz), and the other
at 2.72 ppm (J = 7.2 Hz). These signals also correspond to ethylenic
hydrogens but, due to their multiplicity, can be attributed to
3
1
0
the presence of linear oligomers.
The analysis of all the
1
lower-intensity signals in the H NMR spectrum led to the
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A. Rivera et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
N
N
NH
N
NH
N
N
N
N
N
H
O
H
O
R
HO
R
OH
R
OH
HO
N
R
N
N
N
N
R
R
N
8
9
3
OH
HO
N
N
+R
R
N
N
N
N
1
2
N
N
HN
NH
NH
NH
N
N
N
N
N
N
H
H
R
HO
R
R
OH
OH
HO
R
O
O
N
N
N
N
N
N
R
R
1
0
11
Scheme 4. Formation of the oligomers 3 and 6.
6
conclusion that in addition to the macrocyclic compound 3, linear
oligomers with different numbers of (hydroxybenzyl)imidazo-
lidine-type units were obtained.
gens of the aminal TATD 1. When the stoichiometric ratio is 1:1,
the hydrogen bonds involve two nitrogens from the same unit of
the aminal TATD 1. If both nitrogens are part of the same ethylene-
diamine unit, a macrocyclization process assisted by the formation
of templates through noncovalent interactions is favored
The fragmentation pattern analysis by mass spectrometry
(
ESI-(+)MS/MS) enabled the determination and identification of
9
,11
the minor compounds present in the crude reaction product. In
the case of the reaction between the aminal 1 and the Mannich
base 2a, an ion was observed at m/z = 449.2, corresponding to
(Scheme 4)
this induces electrophilic aromatic substitution
due to the increased electrophilicity of the aminal carbons for
the formation of the intermediate perhidrotetrazecine 9 or 11.11
This pre-organization is favored by the stoichiometric ratio utilized
(1:1) and by the higher alkalinity of the ethylenic nitrogens due to
the electronic effects characteristic of the 1,2-diamines. If the
intermolecular hydrogen bond is formed by two nitrogens that
belong to different ethylenediamine units, an opening process of
the aminal TATD 1 is favored, which leads to the formation of
the linear oligomer 6 (Scheme 4). The lower alkalinity of the
1,1-diamines does not favor the formation of this hydrogen bond,
and compound 6 is only obtained as a minor product.
The formation of the linear oligomers 4 and 7 follows a similar
mechanism to that proposed for the formation of oligomers 3 and
6. The products are formed when an interaction occurs between
two Mannich base 2 molecules and one aminal TATD 1 molecule.
The intermolecular hydrogen bonds formed with nitrogens from
a 1,2-diamine lead to the formation of 4, and the hydrogen bonds
formed with the nitrogens from a 1,1-diamine lead to the
formation of compound 7 (Scheme 5). Despite using the Mannich
base/TATD ratio (1:1), oligomers 4 and 7 are always formed due
to the fast sublimation of TATD 1 under the selected experimental
conditions, which alter the stoichiometric ratio.
+
5
5
the ion [M+H] of the macrocycle 3a 3 ,7 -dichloro-1,5(1,3)-diim-
2
2
idazolidine-3,7(1,3)-dibenzenacyclooctaphane-3 ,7 -diol. An ion
was observed at m/z = 521.2, corresponding to [M+H] of the
+
2 6 2
molecular formula C25H35Cl N O . The fragmentation pattern in
the ESI-(+)MS/MS spectrum allowed us to determine that the com-
pound has a linear structure formed by three imidazoline and two
5
5
phenol units 3 ,7 -dichloro-1(1),5(1,3)-diimidazolidine-3(1,3),7
2
2
(
1)-dibenzenaheptaphane-3 ,7 -diol 6a (Scheme 1).
A linear oligomer formed by three imidazolidine and four phe-
5
5
5
5
nol units 1 ,5 ,9 ,13 -tetrachloro-3,7,11(1,3)-triimidazolidine-1,13
2
2
2
2
(
1),5,9(1,3)-tetrabenzenatridecaphane-1 ,5 ,9 ,13 -tetraol 4a was
recently reported when the reaction between the aminal TATD 1
and the Mannich base 2a was performed solvent-free at a ratio
of 1:2 in the absence of a solvent.5 This antecedent and the frag-
mentation pattern of the ion at m/z = 801.2 showed that the linear
oligomer 4a is also formed when the reaction is performed at the
ratio 1:1 (TATD 1/Mannich base 2). Analysis of the ESI-(+)MS/MS
mass spectrum of the ion at m/z = 437.1 showed the formation of
a
third linear oligomer formed by two phenol and two
5
5
imidazolidine units 3 ,7 -dichloro-1(1),5(1,3)-diimidazolidine-3
2
2
(
1,3),7(1)-dibenzenaheptaphane-3 -7 -diol 7a.
In conclusion, this Letter presents the results of a study on the
0
The results showed that the reaction course and the obtained
solvent-free reaction of 1,3-bis[2 -hydroxybenzyl]imidazolidines-
products are independent of the substituent on the aromatic ring
type Mannich bases 2 and the Mannich intermediary aminal
3
,8
(Scheme 1).
1,3,6,8-tetraazatricyclo [4.4.1.1 ]dodecane (TATD) 1. When
microwave radiation is employed, the reaction times are lower,
the sublimation decreases, the major product corresponds to a
heterocalixarene-type compound 3, and in all cases, unavoidable
formation of oligomeric benzylimidazolidine subproducts was
observed. The products formed depend on the initial interaction
of hydrogen bonds between the phenolic hydroxyls of the Mannich
base with the nitrogens of the aminal TATD 1.
The formation of an intermolecular hydrogen bond between
one of the TATD 1 nitrogens and the phenolic hydroxyl has been
proposed as an initial step for the reaction of TATD 1 and phenols,
which activates the aminal carbons. For the formation of the oligo-
mers presented in this Letter, both cyclic and linear, the first step
also consists of the formation of intermolecular hydrogen bonds
between the two hydroxyls of the Mannich base 2 and two nitro-
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4
A. Rivera et al. / Tetrahedron Letters xxx (2015) xxx–xxx
R
R
R
R
R
R
N
N
N
N
N
N
OH
HO
OH
O
H
OH
HO
N
N
N
N
NH
NH
N
N
N
N
OH
HO
H
O
OH
HO
OH
N
N
N
N
R
R
R
R
N
N
R
R
1
3
4
1
2
N
OH
HO
N
N
+
2
N
N
R
R
N
1
2
R
R
R
R
N
N
N
N
OH
HO
OH
O
H
OH
HO
NH
NH
N
N
N
N
N
N
N
NH
N
N
H
O
R
R
7
OH
OH
HO
N
N
N
N
R
R
R
R
1
4
15
Scheme 5. Formation of oligomers 3 and 6.
3
4
5
.
.
.
Quevedo, R.; Sierra, C. Heterocycles 2011, 83, 2769.
Bujnowski, K.; Adamczyk, A.; Synoradzki, L. Org. Prep. Proced. Int. 2007, 3, 153.
Rivera, A.; Quevedo, R. Tetrahedron Lett. 2013, 54, 1416.
Acknowledgments
We acknowledge the Dirección de Investigaciones, Sede Bogotá
DIB) de la Universidad Nacional de Colombia, for financial support
6. Rivera, A.; Quevedo, R. Tetrahedron Lett. 2004, 45, 8335.
7. Simkins, R. J.; Wright, G. F. J. Am. Chem. Soc. 1955, 77, 3157.
(
8
9
.
.
Rivera, A.; Ríos, J.; Quevedo, R.; Joseph-Nathan, P. Rev. Col. Quím. 2005, 34, 105.
Rivera, A.; Nerio, L. S.; Ríos-Motta, J.; Fejfarová, K.; Dusek, M. Acta Crystallogr.
of this work. L.S.N. acknowledges COLCIENCIAS for a fellowship.
2012, E68, o170.
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Please cite this article in press as: Rivera, A.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.09.066