Solvent-free Mannich-type reaction of tetraazatricyclododecane (TATD) with phenols

Article abstract of DOI:10.1016/j.tetlet.2012.12.116

Solvent-free Mannich-type reactions between the macrocyclic aminal 1,3,6,8-tetraazatricyclo [4.4.1.1^3,8]dodecane (TATD) and phenols indicate that the activation of the aromatic ring is critical for controlling the course of reaction. Activated

Full text of DOI:10.1016/j.tetlet.2012.12.116

Tetrahedron Letters 54 (2013) 1416–1420
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent-free Mannich-type reaction of tetraazatricyclododecane (TATD)
with phenols
⇑
Augusto Rivera, Rodolfo Quevedo
Universidad Nacional de Colombia, Sede Bogotá, Facultad de Ciencias, Departamento de Química, Cra. 30 No. 45-03, Bogotá 4-72, Colombia
a r t i c l e i n f o
a b s t r a c t
Article history:
Solvent-free Mannich-type reactions between the macrocyclic aminal 1,3,6,8-tetraazatricyclo
[4.4.1.13,8]dodecane (TATD) and phenols indicate that the activation of the aromatic ring is critical for
controlling the course of reaction. Activated rings form N,N0-bis(2-hydroxybenzyl)ethylenediamine (tetr-
ahydrosalens), and weakly activated rings form Mannich bases consisting of 1,3-bis[20-hydroxyben-
zyl]imidazolidine. When the reaction is conducted using b-naphthol, a Mannich-type reaction occurs
followed by a retro-Mannich-type reaction that forms 1,10-methylene-bis(2-naphthol). The solvent-free
reaction between 1,3-bis[20-hydroxybenzyl]imidazolidine Mannich bases and the macrocyclic aminal
1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD) allows Mannich bases with high molecular weight
to be obtained in a controlled manner.
Received 22 November 2012
Revised 21 December 2012
Accepted 28 December 2012
Available online 5 January 2013
Keywords:
Mannich
Solvent-free
Phenol
Benzoxazine
Aminal
Ó 2013 Elsevier Ltd. All rights reserved.
Aminomethyl phenol derivatives are of great scientific and
industrial interest because of their chemical properties. Benzoxa-
zines are a class of aminomethyl phenol derivatives that are ben-
zo-fused heterocycles, which have an increased usefulness for
the development of new polymeric materials with excellent
mechanical and thermal properties.1,2 In addition, benzoxazines
have recently shown interesting photophysical characteristics,
which indicate promise for developing new materials.3
Aminomethyl phenol derivatives are another class of
benzylamines with differing properties and potential applications
as complexing agents, catalyst components, organic synthetic
intermediates, and bioactive compounds.4 Tetrahydrosalens are
prominent benzylamine compounds that have four active sites in
their structure, two hydroxyls and two amino groups, which can
form coordinate bonds with different metal ions.4 They currently
show a potential for use as ligands in the synthesis of olefin
polymerization catalysts.5 These ligands have improved structural
flexibility over their dehydrogenated analogues (salen ligands).6,7
The Mannich reaction is one of the most popular methods for
synthesizing structurally varied benzoxazines and benzylam-
ines.4,8 A Mannich-type reaction between the macrocyclic aminal
TATD 1 and phenols 2 is a useful tool for synthesizing bis-benzox-
azines and tetrahydrosalens in two steps.
hydrolyzed to the corresponding benzylamine 5.11 These two reac-
tions show good yields (Scheme 1).
The yields of Mannich reactions between the macrocyclic ami-
nal TATD 1, and phenols depend on the activation of the phenolic
ring; some products are reactive and form dimerization 6 and olig-
omerization compounds, which creates complex mixtures from
which it is impossible to isolate the pure products.12 Additionally,
when the reaction is conducted using hindered phenols, the corre-
sponding benzoxazine 4 is formed with good yields instead of the
imidazoline (Scheme 2).12
The behaviors observed for this reaction indicate that imidazoli-
dine 3 is formed in low yields and that oligomerization products 6
dominate when working with para-substituted phenols, whereas
when working with highly hindered phenols, the respective ben-
zoxazine 4 is formed, which indicates that the macrocyclic aminal
TATD or some other reaction product acts as the formaldehyde do-
nor under these reaction conditions.12
Previously published results show that the release of formalde-
hyde and formation of benzylimidazolidine oligomers play a deter-
minant role in the yield of Mannich-type reactions between
phenols and the macrocyclic aminal TATD 1.12 To both improve
yields and increase the potential of reactions between macrocyclic
aminals and phenols, the reaction of TATD 1 with various phenols
was studied in this Letter in the absence of a solvent. The results
show that the product depends on the reaction conditions, and
the compounds obtained when the reaction is performed in the
solution are not formed in the absence of a solvent.
In the first step, the corresponding imidazolidine, 3, is obtained
with low yields (20–30%).9 This imidazolidine can react with form-
aldehyde to form the corresponding benzoxazine 4,10 or it can be
For these experiments, we selected o-cresol 2a, m-cresol 2b, and
p-cresol 2c to establish the influence of the substituent position on
⇑
Corresponding author. Fax: +57 1 3165220.
E-mail address: arquevedop@unal.edu.co (R. Quevedo).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.116

A. Rivera, R. Quevedo / Tetrahedron Letters 54 (2013) 1416–1420
1417
OH
OH
HO
N
N
N
N
+
N
N
R
R
3
R
2
1
HCl 10 %
HCHO
R
O
OH
N
R
N
NH
R
R
NH
O
4
5
HO
Scheme 1. Bis-benzoxazine and tetrahydrosalen synthesis from imidazolidines.
R
R
OH
R
R
O
R
N
N
N
N
R
R
R
N
N
R
O
4
1
OH
R
R
R
HO
OH
N
N
OH
HO
N
OH
R
N
+
N
N
R
R
3
6
Scheme 2. Reaction of TATD 1 with phenols.
the course of the reaction; p-chlorophenol 2d, 4-chloro-3-methyl-
phenol 2e, and 4-chloro-3,5-dimethylphenol 2f were used to
establish the effects of the number of substituents on the aromatic
ring; 2,6-dimethylphenol 2g was used to determine if para
aminomethylation occurs under these conditions; and b-naphthol
2h was used to establish the behavior of highly activated aromatic
compounds.
The reactions with 2a–2c were conducted using a 1:2 TATD
1:phenol 2 ratio under the experimental conditions reported by
Rivera and Quevedo.13 In all cases, we obtained the corresponding
imidazolidine 3a–3c in lower yields than for the solution reaction.
One explanation for these low yields is the solidification of the
reaction mixture after product formation, which inhibits the
reaction.14
The stoichiometric ratio was changed to 1:4 (TATD 1:phenol 2)
to prevent solidification. The results allowed for the classification
of the phenols employed into two groups according to the Mannich
base formed. The first group, which consisted of m- and p-cresol
(2b, 2c), formed the corresponding tetrahydrosalens 5b and 5c
(Scheme 3). Additional experiments with 2b at different tempera-
tures (18, 42, 90, and 150 °C) demonstrated that the formation of
tetrahydrosalen 5b was independent of the temperature. They also
indicated that a higher yield is obtained at lower temperatures,
which is most likely because of a reduction in the polymeric prod-
uct formation. A possible mechanism is shown in Scheme 3.14
The second group of phenols consisted of o-cresol 2a, p-chloro-
phenol 2d, 4-chloro-3-methylphenol 2e, 2,6-dimethylphenol
2g, and 4-chloro-3,5-dimethylphenol 2f and formed the imidazoli-
dines 3a, 3d, 3e, 3f, and 3g, respectively, in better yields than for
the solution reactions. The ring is less activated for this second
group of phenols and promotes intramolecular cyclization
(Scheme 4). Intermediate 7 commonly forms tetrahydrosalens 5
and imidazolidines 3; the product formed only depends on the
nucleophilicity of the aromatic ring.14
Once again, the studied phenols can be classified into two
groups according to their yields for the Mannich bases 3 or 5
(Table 1). The first group includes o-cresol 2a, m-cresol 2b, p-cresol
2c, p-chlorophenol 2d, and 4-chloro-3-methylphenol 2e and forms
Mannich bases with close to 50% yields. These low yields were
most likely due to subsequent oligomerization reactions because
the rings had at least two free activated positions. The second
group of phenols includes 4-chloro-3,5-dimethylphenol 2f and
2,6-dimethylphenol 2g and produces Mannich bases with nearly
100% yields. It is impossible to form oligomers with these phenols

1418
A. Rivera, R. Quevedo / Tetrahedron Letters 54 (2013) 1416–1420
OH
N
O
H3C
OH
H3C
H3C
H
HN
N
N
N
N
N
N
2b
N
N
N
N
1
H3C
OH
H3C
O
O
H
H3C
OH
NH
NH
NH
NH
N
H
NH
H
N
H
N
H
H3C
O
CH3
H3C
O
O
CH3
7
H3C
OH
HO
CH3
H3C
OH
NH
2
NH
5b
Scheme 3. Formation of tetrahydrosalens 5 via a solvent-free Mannich-type reaction of TATD 1 with phenols 2a, 2b.
NH
NH
OH
HO
N
H
N
H
N
N
O
O
7
3
Scheme 4. Formation of imidazolidine 3 via the solvent-free Mannich-type reaction of TATD 1 with phenols 2a and 2d–2g.
another b-naphthol unit (Scheme 5).15 This result shows that the
retro-Mannich-type reaction is not restricted to secondary amines
and may occur with other phenols under appropriate experimental
conditions. The reaction of TATD with b-naphthol in a 1:2 ratio
quantitatively formed the corresponding imidazolidine 3h, (94%)
which indicates that an excess of b-naphthol is necessary for the
retro-Mannich-type reaction to occur (Scheme 5).
These results indicated that ring activation is critical for deter-
mining the course of the Mannich reaction between the macrocyclic
aminal TATD and phenols. Oligomer formation appears to be the pri-
mary cause of low yields regardless of the Mannich base obtained.
To determine whether benzylimidazolidine oligomer formation
occurs under the experimental conditions used, the reaction was
conducted between the macrocyclic aminal TATD 1 and the previ-
ously synthesized and characterized imidazolidine 3d. This reac-
tion formed a benzylimidazolidine trimer 9, which is the product
of condensation between one molecule of TATD 1 and 2 of imidaz-
olidine 3d (Scheme 6), in 76% yields.
Table 1
Solvent-free Mannich-type reaction of TATD with phenols
Phenol
Product
Yield (%)
o-Cresol
m-Cresol
p-Cresol
p-Chlorophenol
4-Chloro-3-methylphenol
4-Chloro-3,5-dimethylphenol
2,6-Dimethylphenol
b-Naphthol
3a
5b
5c
3d
3e
3f
44
45
37
59
43
94
91
94
3g
3h
because they are ortho to the occupied hydroxyl or blocked by the
methyl groups.
The reaction with b-naphthol 2h behaved differently than the
other phenols. In the absence of solvent and 1:4 ratio (TATD 1:b-
naphthol 2h), Mannich bases of type 3 or 5 did not form, and 1,10-
methylene-bis(2-naphthol) 8 was obtained in good yields (97%).14
This product may be formed via a retro-Mannich-type reaction be-
tween an electrophilic benzylic carbon and a nucleophilic carbon on
The formation of 9 demonstrated that the reactions of macrocy-
clic aminals with 1,3-bisbenzylimidazolidines depend on the

A. Rivera, R. Quevedo / Tetrahedron Letters 54 (2013) 1416–1420
1419
NH
NH
OH
OH
2
N
H
N
H
O
O
HO
8
OH
HO
N
N
3h
Scheme 5. Solvent-free Mannich-type reaction of TATD 1 with b-naphthol 2h.
OH
HO
N
N
N
N
+
2
Cl
N
N
Cl
1
3d
Solvent free
OH
Cl
OH
OH
OH
Cl
N
N
N
N
N
N
Cl
Cl
9
Scheme 6. Solvent-free Mannich-type reaction of TATD 1 with benzylimidazolidines 3d.
stoichiometric ratio; when employing a 1:1 (TATD 1:imidazolidine
3) ratio, the most abundant product is a heterocalixarene-type
molecule,13 and when employing a 1:2 (TATD 1:imidazolidine 3)
ratio, the major product is a trimer of benzylimidazolidine 9.
Usually the yield of the Mannich-type reaction between TATD
and phenols is low. These low yields are due to the unavoidable
formation of oligomers; however, the oligomer synthesis can be
directed in a controlled manner toward either cyclic or linear
molecules with high molecular weights, which could be useful
for developing new materials.
macrocyclic aminal 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane
(TATD) 1 allows for the controlled synthesis of Mannich bases with
a high molecular weight.
Acknowledgments
The authors gratefully wish to acknowledge the División de
Investigación Bogotá (DIB) and Departamento de Química of Uni-
versidad Nacional de Colombia.
In conclusion, this paper shows that the products resulting from
the solvent-free Mannich-type condensation between the macro-
cyclic aminal 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD) 1
and phenols depends on the activation of the aromatic ring.
Activated rings form N,N0-bis(2-hydroxybenzyl) ethylenediamine
(tetrahydrosalens) 5. Weakly activated rings form 1,3-bis[20-
hydroxybenzyl]imidazolidines 3, and when the reaction is con-
ducted using b-naphthol, a Mannich-type reaction occurs before
a subsequent retro-Mannich-type reaction that forms the corre-
sponding 1,10-methylenebis(2-naphthol) 8. Oligomer formation is
a major cause of low yields in this reaction independent of which
Mannich base, 3 or 5, was obtained. The reaction between the
References and notes
1. Ishida, H.; Yee Low, H. Macromolecules 1997, 30, 1099–1106.
2. Ishida, D.; Allen, D. J. Polymer 1996, 37, 4487–4495.
3. Quevedo, R.; Sierra, C. Heterocycles 2011, 83, 2769–2772.
4. Bujnowski, K.; Adamczyk, A.; Synoradzki, L. Org. Prep. Proced. Int. 2007, 3(9),
153–184.
5. Tshuva, E.; Goldberg, I.; Kol, M. J. Am. Chem. Soc. 2000, 122, 10706–10707.
6. Balsells, J.; Walsh, P. J. J. Am. Chem. Soc. 2000, 122, 1802–1803.
7. Nuansheng, W.; Yongtao, W.; Junying, L.; Tianduo, L. Chin. J. Org. Chem. 2011,
31, 1703–1706.
8. Bujnowski, K.; Adamczyk-Woz´niak, A.; Synoradzki, L. ARKIVOC 2008, viii, 106–
114.
9. Rivera, A.; Gallo, G.; Gayón, M.; Joseph-Nathan, P. Synth. Commun. 1993, 23,
2921–2930.
Mannich base 1,3 bis[20-hydroxybenzyl]imidazolidine
3 and

1420
A. Rivera, R. Quevedo / Tetrahedron Letters 54 (2013) 1416–1420
10. Rivera, A.; Gallo, G.; Gayón, M.; Joseph-Nathan, P. Synth. Commun. 1994, 24,
2081–2089.
11. Rivera, A.; Quevedo, R.; Navarro, M.; Maldonado, M. Synth. Commun. 2004, 34,
2479–2485.
12. Rivera, A.; Ríos, J.; Quevedo, R.; Joseph-Nathan, P. Rev. Col. Quim. 2005, 34, 105–
115.
1,3-Bis[20-hydroxy-50-chloro-40,60-dimethylbenzyl]imidazolidine 3f:
(C21H26Cl2N2O2) mp 118–120 °C, yield 96%. 1H NMR (CDCl3) d: 2.32 (s, 6H,
CH3), 2.33 (s, 6H, CH3), 3.01 (s, 4H, H-C4, C5), 3.52 (s, 2H, H-C2), 3.96 (s, 4H, Ar-
13
CH2), 6.65 (s, 2H, H-C30). C NMR d: 16.8 (CH3-C60), 21.1 (CH3-C40), 51.1 (C4,
C5), 54.6 (Ar-CH2), 74.4 (C2), 118.3 (C10), 156.1 (C20), 116.5 (C30), 136.8 (C40),
125.5 (C50), 133.7 (C60).
13. Rivera, A.; Quevedo, R. Tetrahedron Lett. 2004, 45, 8335–8338.
14. Experimental
1,3-Bis[40-hydroxy-30,50-dimethylbenzyl]imidazolidine 3g:
(C21H28N2O2) mp 112–113 °C, yield. 91%. 1H NMR (CDCl3) d: 2.18 (s, 12H, CH3),
2.78 (s, 4H, H-C4, C5), 3.32 (s, 2H, H-C2), 3.51 (s, 4H, Ar-CH2), 6.85 (s, 4H, H-C20,
H-C60). 13C NMR d: 16.7 (CH3), 52.5 (C4, C5), 59.3 (Ar-CH2), 75.9 (C2), 124.1
(C10), 129.6 (C20), 129.9 (C30), 152.4 (C40), 129.9 (C50), 129.6 (C60).
1,10-Methylenebis(2-naphthol) 8:
Reaction of 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD) 1 with phenols 2:
A mixture of TATD 1 (0.5 g, 3 mmol) and the corresponding phenol (12 mmol)
was heated with stirring at 150 °C for 20 min. The reaction mixture was
allowed to cool to room temperature and then suspended in ethanol. The pure
product was isolated by filtration and washed with ethanol.
1,3-Bis[20-hydroxy-30-methylbenzyl]imidazolidine 3a:
(C21H16O2) mp 177–179 °C, yield 97%. 1H NMR (CD3OD) d: 4.80 (s, 4H, Ar-CH2),
7.15 (d, 2H, H-C30, J = 8.8 Hz), 7.54 (d, 2H, H-C40, J = 8.8 Hz), 7.59 (d, 2H, H-C50,
J = 8.0 Hz,), 7.09 (td, 2H, H-C60, J = 8,0 Hz, J = 1,2 Hz), 7.16 (td, 2H, H-C70,
J = 8,0 Hz, J = 8,4 Hz, J = 1,2 Hz), 8.22 (d, 2H, H-C80, J = 8,4 Hz). 13C NMR d: 21.8
(Ar-CH2), 121.0 (C10), 153.0 (C20), 118.7 (C30,), 125.3 (C40), 128.8 (C50), 126.5
(C60), 123,4 (C70), 129.2 (C80), 130.6 (C90), 135.5 (C100).
(C19H24N2O2) mp 118–120 °C, yield 44%. 1H NMR (CDCl3) d: 2.23 (s, 6H, CH3),
2.96 (s, 4H, H-C4, C5), 3.54 (s, 2H, H-C2), 3.88 (s, 4H, Ar-CH2), 7.05 (d, 2H, H-C40,
J = 7.32 Hz), 6.69 (t, 2H, H-C50, J = 7.32 Hz), 6.83 (d, 2H, H-C60, J = 7,32 Hz). 13C
NMR d: 15.6 (CH3), 51.5 (C4, C5), 58.2 (Ar-CH2), 74.5 (C2), 120.7 (C10), 155.7
(C20). 125.1 (C30), 130.3 (C40), 118.8 (C50), 125.9 (C60). Elemental analysis: C,
73.0211; H, 7.8884; N, 9.1932.
Reaction of 1,3,6,8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD 1 with 1,3-bis[20-
hydroxy-50-chlorobenzyl]imidazolidine 3d:
N,N0-Bis(2-hydroxy-4-methylbenzyl)ethylenediamine 5b:
(C18H24N2O2) mp 150–152 °C, yield 45%. 1H NMR (CDCl3) d: 2.27 (s, 6H, CH3),
2.90 (s, 4H, CH2), 3.60 (s, 4H, Ar-CH2), 6.70 (d, 2H, H-C30), 6.60 (d, 2H, H-C60),
6.80 (dd, 2H, H-C50).11
A
mixture of TATD (0.1 g, 0.59 mmol) and 1,3-bis[20-hydroxy-50-
chlorobenzyl]imidazolidine 3d (0.41 g, 1.18 mmol) was heated with stirring
at 150 °C for 20 min and subsequently allowed to cool to room temperature.
The crude product was dissolved in methanol and precipitated by changing the
polarity with water. The precipitate was purified by column chromatography
eluting with ethanol:ethyl acetate mixtures.
N,N0-Bis(2-hydroxy-5-methylbenzyl) ethylenediamine 5c:
(C18H24N2O2) mp 140–142 °C, yield 47%. 1H NMR (CDCl3) d: 2.23 (s, 6H, CH3),
2.96 (s, 4H, CH2), 3.87 (s, 4H, Ar-CH2), 6.75 (d, 2H, H-C30), 6.99 (dd, 2H, H-C40),
6.77 (d, 2H, H-C60).11
1,3-Bis[20-hydroxy-30-(300-(2000-hydroxy-5000-chlorobenzyl)-100-methyleneimidaz-
olidin)-50-chloro-bencyl]imidazolidine 9:
1,3-Bis[20-hydroxy-50-chlorobenzyl]imidazolidine 3d:
(C39H44Cl4N6O4) mp 69 °C, yield 76%. 1H NMR (CDCl3) d: 2.95 (s, 4H, H-C4 and
H-C5), 2,97 (s, 8H, H-C400 and H-C500), 3.53 (s, 2H, H-C2), 3.54 (s, 4H, H-C200),
3.83 (s, 4H, H-C6 and H-C7), 3.89 (s, 4H, H-C600), 3.79 (s, 4H, H-C700), 7.05 (d, 2H,
H-C60, J = 2.4 Hz), 7.11 (d, 2H, H-C40, J = 2.4 Hz), 6.79 (d, 2H, H-C3000, J = 8.8 Hz),
7.14 (dd, 2H, H-C4000, J = 8.8 Hz, J = 2.4 Hz), 6.98 (d, 2H, H-C6000, J = 2.4 Hz). 13C
NMR d: 51.9 (C4 and C5), 51.6 (C400), 51.8 (C500), 75.1 (C2), 75.0 (C200), 55.8 (C6
and C7), 58.0 (C600), 54.4 (C700), 125.2 (C10), 154.4 (C20), 124.5 (C30), 128.3 (C40),
123.6 (C50), 127.9 (C60), 123.6 (C1000), 156.5 (C2000), 117.6 (C3000), 128.8 (C4000),
123.2 (C5000), 127.9 (C6000), MALDITOF-MS: m/z 801.2.
(C17H18Cl2N2O2) mp 80–82 °C, yield 59%. 1H NMR (CDCl3) d: 2.97 (s, 4H, HC-4,
C5), 3.52 (s, 2H, H-C2), 3.82 (s, 4H, Ar-CH2), 7.12 (d, 2H, H-C40), 6.96 (t, 2H, H-
C50), 6.75 (d, 2H, H-C60).10
1,3-Bis[20-hydroxy-50-chloro-40-methylbenzyl]imidazolidine 3e:
(C19H22Cl2N2O2) mp 134–135 °C, yield 43%. 1H NMR (CDCl3) d: 2.28 (s, 6H,
CH3), 2.98 (s, 4H, H-C4, C5), 3.53 (s, 2H, H-C2), 3.84 (s, 4H, Ar-CH2), 6.72 (s, 2H,
H-C30), 6.93 (s, 2H, H-C60).
13C NMR d: 19.8 (CH3), 51.5 (C4, C5), 57.4 (Ar-CH2), 74.5 (C2), 120.2 (C10), 155.9
(C20), 118.6 (C30), 136.7 (C40), 124.1 (C50), 128.2 (C60). Elemental analysis: C,
59.931; H, 5.779; N, 7.478.
15. Bulman, P.; Heaney, H.; McGrath, M.; Sampler, E.; Wilkins, R. Tetrahedron Lett.
2003, 44, 2965–2970.