Unexpected behavior of 6H,13H-5:12,7:14-dimethanedibenzo[d,i][1,3,6,8]tetraazecine (DMDBTA) toward phenols

Article abstract of DOI:10.1016/j.tetlet.2006.08.045

A new 20-membered octaazamacrocyclic compound named 1:4,6:9,11:14,16:19-tetramethylentetrabenzo[b,g,l,q][1,4,6,9,11,14,16,19 ]octaazaeicocine (TTBOE) (9) has been prepared by means of in situ one-pot synthesis between the aminal 6H,13H-5:12,7:14-dimethane

Full text of DOI:10.1016/j.tetlet.2006.08.045

Tetrahedron Letters 47 (2006) 7467–7471
Unexpected behavior of 6H,13H-5:12,7:14-dimethane-
dibenzo[d,i][1,3,6,8]tetraazecine (DMDBTA) toward phenols
Augusto Rivera* and Mauricio Maldonado
Departamento de Quı´mica, Universidad Nacional de Colombia, Ciudad Universitaria, Carrera 30 No. 45-03, Bogota´ DC, Colombia
Received 13 February 2006; revised 9 August 2006; accepted 11 August 2006
Abstract—A new 20-membered octaazamacrocyclic compound named 1:4,6:9,11:14,16:19-tetramethylentetrabenzo[b,g,l,q]-
[1,4,6,9,11,14,16,19]octaazaeicocine (TTBOE) (9) has been prepared by means of in situ one-pot synthesis between the aminal
6H,13H-5:12,7:14-dimethanedibenzo[d,i][1,3,6,8]tetraazecine (DMDBTA) (3) and electron-deficient phenols. Otherwise, electron-
rich phenols such as 4-chloro-3,5-dimethylphenol or 2-naphthol produce an ortho-regioselective aminomethylation resulting in 2-
(1H-benzimidazol-1-ylmethyl)-4-chloro-3,5-dimethylphenol (7) and 1-(1H-benzimidazol-1-ylmethyl)-2-naphthol (8) in a Mannich
type reaction in a basic medium. Moreover, obtainment of 1,10-methylenbis(1H-benzimidazole) (15) from TTBOE is discussed.
Ó 2006 Elsevier Ltd. All rights reserved.
It is well known that benzyl-benzimidazolines are com-
pounds widely used in medical and pharmaceutical areas
since they show analgesic, hypotensive, anti-inflamma-
tory, and anti-convulsive properties.1 Also, this class
of compounds have been used as fungicides,2 raw mate-
rials in dye synthesis,3 selective reduction of a,b-unsatu-
rated ketones,4 and coordination chemistry to prepare
organometallic compounds for several applications.5
The benzimidazolines can usually be obtained by reduc-
tion of benzimidazole,6 or by direct condensation of
o-phenylendiamines and carbonyl compounds.7
should give the corresponding 1,3-bis(20-hydroxy-50-
substituted-benzyl)benzimidazolines (4) (Scheme 1).
Surprisingly, the products formed during reaction of 3
with phenols12 were not the expected benzyl-benzimid-
azolines (4). Moreover, changing reaction conditions
N
N
N
N
1
R1
R2
R1
R2
HO
OH
N
N
OH
In a previous work,8 using a Mannich type reaction in
basic medium between the macrocyclic aminal 1,3,6,
8-tetraazatricyclo[4.4.1.13,8]dodecane (TATD) (1) and
p-substituted phenols, we synthesized 1,3-bis(20-hydr-
oxy-50-substituted-benzyl)imidazolidines (BISBIAs) (2)
(Scheme 1). BISBIAs have been utilized as powerful
reagents for obtention of salans9 and hetero-
calixarenes.10
2
R3
R3
N
N
N
R1
R3
N
R2
R1
R1
HO
OH
3
5a-f
N
N
R2
R2
R3
R3
4
5
a
R1
R2
R3
On the basis of these consideration, we expected that the
use of 6H,13H-5:12,7:14-dimethanedibenzo[d,i][1,3,6,8]-
tetraazecine (DMDBTA)11 (3) and phenols (5a–f),
-CH3
-Cl
-CH3
b
c
d
-CH=CH-CH=CH-
-H
-H
-H
-H
-H
-H
-H
-H
-CH3
-Cl
e
f
-H
-H
Keywords: Benzimidazoline; Mannich-type reaction; Aminal;
DMDBTA.
-NO2
*
Corresponding author. Tel.: +57 1 3165000x14464; fax: +57 1
3165220; e-mail: ariverau@unal.edu.co
Scheme 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.045

7468
A. Rivera, M. Maldonado / Tetrahedron Letters 47 (2006) 7467–7471
such as using different solvents and a different molar
ratio of 3 to 5a–f do not allow finding reaction condi-
tions to obtain the product 4. Thus, using the electron-
rich phenols (5a or 5b), both 1-methylbenzimidazole
(6) and the respective ortho aminomethylation products:
2-(1H-benzimidazol-1-yl-methyl)-4-chloro-3,5-dimethyl-
phenol (7) or 1-(1Hꢀbenzimidazol-1-yl-methyl)-2-naph-
thol (8) were obtained.13 But when electron-deficient
phenols (5c–f) were used, a cyclodimerization product
9 was isolated (Scheme 2).
age forming iminium ion 12 and benzimidazoline 13.
Formation of 6 from 12 involves an intra-molecular hy-
dride transfer to the iminium ion generating the N–Me
group, as it occurs in other cyclic aminals.14 13—a plau-
sible intermediate—afforded benzimidazole derivatives15
(7 or 8) by atmospheric oxygen oxidation being capable
of transferring a hydride.16
On the other hand, 1:4,6:9,11:14,16:19-tetramethyl
entetrabenzo[b,g,l,q][1,4,6,9,11,14,16,19]octaazaeicocine
(TTBOE) 9, a tetramer of benzimidazoline, was ob-
tained when electron-deficient phenols 5c–f were reacted
with DMDBTA.
The question arises as to why only the products of ortho
aminomethylation were isolated in the cases of 4-chloro-
3,5-dimethylphenol (5a) and 2-naphthol (5b). An expla-
nation of this fact is shown in Scheme 3, where hydrogen
bonding between the phenolic hydrogen and any nitro-
gen atom of the aminal 3 would be expected to precede
the formation of the six-membered cyclic transition
state, which would then bring the reactive methylene
group into position for electrophilic attack on the aro-
matic ring in the ortho-position, resulting in adduct 10.
Protonation of 10 is likely accompanied by a ring open-
ing of a strained cycle with a nitrogen lone-pair anti to
the breaking of the C–N bond providing some assis-
tance. In the resulting structure 11, the lone-pair anti
to the C–N bond may labilize that bond regarding cleav-
The possible mechanism for formation of the macro-
cycle 9 is indicated in Scheme 4. As discussed above,
firstly, the hydroxyl group of phenol forms a hydrogen
bond O–Hꢁ ꢁ ꢁN with any one of the N-atoms of 3, which
polarize adjacent methylenes. Secondly, the partially
charged methylenes suffer a nucleophilic attack by any
nitrogen atom from other DMDBTA molecules. It is
reasonable to assume that this reaction is faster than
ring aminomethylation. In fact, electron-deficient phe-
nols afford a corresponding Mannich-type product in
low yields17 and even strongly acid phenols did not form
aminomethylation products.18
The pre-organization of the linear substrate into a
folded conformer is forced by the lone pair repulsion
in the 1,1-diamine units (‘rabbit ears’ effect19), which
brings the proximity of the reactive centers in 14 and en-
hances the chance of a productive interaction suitable
for ring closure. It is interesting to notice that high-dilu-
tion conditions were not necessary for a ring-closing
step since the cyclization was successfully produced
using up to 0.1 mol/L concentrations without contami-
nation detection by polymers or larger ring systems.
The reaction proceeds smoothly and clearly produces 9
in acceptable yield depending on the phenol employed
(Table 1). In addition, by using a large excess of 3
(10 equiv), only 9 was formed with similar yields.
CH
3
N
N
ArOH
N
N
5a-b
+
6
7 or 8
N
N
N
N
N
N
N
N
3
N
N
N
N
5c-f
9
Besides, our experiments showed that a reaction occurs
exclusively with phenols, because by adding acetic acid,
Scheme 2.
H
H
H
H
N
H
N+
N
N+
N
N
N
N
ArOH
N
N
N
H
N
N
N
N
N
ArOH
ArOH
ArOH
O
10
Ar
ArOH = 5a or 5b
CH3
N
H
N
N+
CH2
ArOH
N
HN
HN
N
H
ArOH
N
N
N
N+
N
ArOH
12
6
13
7 or 8
11
7,
8,
5a
ArOH =
ArOH =
5b
Scheme 3.

A. Rivera, M. Maldonado / Tetrahedron Letters 47 (2006) 7467–7471
7469
N
N
N
N
N
N
N
N
N
N
N
+
N
N
N
N
N
N
HN
N
O
CH
2
R
+
H
N
CH
NH
2
5c-f
N
N
N
14
3
5
c
d
e
f
R
H
CH
Cl
NO
2
3
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
+
HN
CH
2
9
Scheme 4.
Table 1.
in dissolution occurs. Thus, by registering again spec-
trum H NMR from 9 over 1–2 days in chloroform-d1,
1
Entry Phenol
Reaction time (h) Yield TTBOE (%)
5c
5d
5e
5f
Phenol
4-Methyl phenol 10
4-Chlorophenol
4-Nitrophenol
12
13
19
47
65
the spectrum showed marked differences compared with
those formerly taken. As observed, aminal signals at
4.52 and 4.55 for 9 were decreased in intensity and
replaced by signals at d 8.18 and 8.05. Over the same
period, aromatic proton signals of 9 were replaced by
new multiplet sets. Then a sample of 9 dissolved in
CDCl3 was monitored by 1H NMR. In measures on
chloroform-d1 after 5 min of preparation, the spectrum
showed small quantities of 1,10-methylenbis(1H-benz-
imidazole) (15) and 1-methylbenzimidazole (6) in almost
equal amounts. After 3–4 h, the same solution contained
6 and 15 in substantially increased amounts as the pre-
dominant species detected. The tetramer 9 was not
observed.
4.5
2
p-toluensulfonic acid, or mineral acids in place of phe-
nol, in all cases, o-phenylendiamine and formaldehyde
were obtained.
On the other hand, 9 is poorly soluble in most solvents
including dimethyl sulfoxide, but a sample of enough
concentration in chloroform-d1 was obtained by NMR
1
spectroscopy.20 The H NMR spectrum of 9 in this sol-
vent shows two signals distinctive for aminal’s resonance
at d 4.52 and 4.55, as well as the aromatic protons. How-
ever, the data from H NMR are insufficient to design
1
These experiments suggested that upon dissolution in
the possible conformer: cone (I), partial cone (II), 1,2-
alternate (III), and 1,3-alternate (IV). Preliminary con-
formational analysis per-formed through computational
calculations using Gaussian 98 software,21 B3-LYP-3-
21G basis set, showed that the most stable conformation
for TTBOE is the 1,3-alternated ring of benzimidazoline
(IV) (Fig. 1).
chloroform, 9 began a rearrangement in two cyclic
1
structures. H NMR22 spectrum showed peculiar benz-
imidazole resonances at d 8.18 for 15 and d 8.05 for 6
(Scheme 5). Thus we suggest that TTBOE is decom-
posed by traces of oxygen present in chloroform,23
which induces a dealkylation of the cyclic tertiary amine
function making therefore the generation of 15 and
formaldehyde on a similar fashion to aromatic N-re-
placed amines. Later, a slower stage involves a decom-
position of 15 by an oxide-reduction reaction with
Under strict exclusion of air and moisture, 9 is thermally
stable and can be stored indefinitely, but decomposition
Figure 1. Four main conformations of TTBOE: cone (I), partial cone (II), 1,2-alternate (III), 1,3-alternate (IV).

7470
A. Rivera, M. Maldonado / Tetrahedron Letters 47 (2006) 7467–7471
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O2
O
O
N
CDCl3
9
CH3
N
N
NH
N
N
N
N
N
O2
2 CO2
2
2
+
2 HCHO
+
2
+
6
16
15
Scheme 5.
9. Rivera, A.; Quevedo, R.; Navarro, M.; Maldonado, M.
Synth. Commun. 2004, 34, 2479.
10. Rivera, A.; Quevedo, R. Tetrahedron Lett. 2004, 45, 7563.
11. DMDBTA is obtained by direct condensation between
o-phenylendiamine and formaldehyde.
12. General procedure for the synthesis of 7, 8, and 9: A
solution of 6H,13H-5:12,7:14dimethanedibenzo[d,i] [1,3,6,8]-
tetraazecine (DMDBTA) (3) (0.25 mmol) and the appro-
priate phenol (5a–f) (0.5 mmol) in 15 mL of propan-2-ol
was placed in a round-bottomed flask equipped with a
water-cooled condenser. The reaction mixture was heated
at 74 °C for different times (see Table 1). In all cases, the
precipitates were collected by filtration and washed with
propan-2-ol. The solids residues 7 or 8 were chromato-
graphed on a column of silica gel with ethyl acetate as
eluent solvent. The crude product 9 was purified by
recrystallization from propan-2-ol.
formaldehyde formed participation to produce carbon
dioxide, 1-methylbenzimidazole 6, and benzimidazole 16.
In conclusion, we discovered an innovative route for an
efficient one-pot synthesis of 1:4,6:9,11:14,16:19-tetra-
methylentetrabenzo[b,g,l,q][1,4,6,9,11,14,16,19]octaazaeico-
cine (TTBOE) (9) from DMDBTA and phenols.
Depending on the phenol employed, Mannich-type
bases could be obtained instead of 9. Now that the util-
ity of this methodology for synthesis of TTBOE and
some derivatives has been established, further studies
are underway to investigate the role of phenols in the
reaction and to explore its applications in synthesis of
benzimidazole derivatives.
13. 2-(1H-benzimidazol-1-ylmethyl)-4-chloro-3,5-dimethylphe-
nol (7): Mp 232–235 °C (uncorrected), yield 35%; 1H
NMR (400 MHz, CD3OD) d: 2.34 (6H, s, –CH3), 5.49
(2H, s, N–CH2–Ar), 6.77 (1H, s, H–C60), 7.27 (1H, t,
J = 6 Hz, H–C6), 7.30 (1H, t, J = 6 Hz, H–C7), 7.63 (1H,
d, J = 6 Hz, H–C5), 7.66 (1H, d, J = 6 Hz, H–C8), 7.94
(1H, s, N@CH–N). 13C NMR: (100 MHz, CD3OD) d:
19.7 (–CH3), 40.5 (N–CH2–Ar), 110.3 (C5), 115.0 (C60),
118.6 (C8), 119.1 (C20), 122.0 (C7), 122.7 (C6), 125.4 (C30,
C50), 133.7 (C4), 136.3 (C40), 137.6 (C9), 142.9 (C2), 154.4
(C10). 1-(1H-benzimidazol-1-ylmethyl)-2-naphthol (8): Mp
180–182 °C (uncorrected), yield 46%. 1H NMR (400 MHz,
CD3OD) d: 5.88 (2H, s, N–CH2–Ar), 7.24 (1H, d,
J = 7.4 Hz, H–C13), 7.27 (2H, t, J = 6.6 Hz, H–C7 and
H–C8), 7.32 (1H, dt, J1 = 8.92 Hz, J2 = 0.9 Hz, H–C19),
7.46 (1H, dt, J1 = 8.6 Hz, J2 = 1.1 Hz, H–C18), 7.62 (1H,
d, J = 7.1 Hz, H–C6), 7.76 (1H, dd, J1 = 8.32 Hz,
J2 = 1.1 Hz, H–C20), 7.81 (1H, d, J = 7.44 Hz, H–C14),
7.83 (1H, d, J = 6.9 Hz, H–C9), 7.95 (1H, d, J = 9 Hz, H–
C17), 7.97 (1H, s, H–C2). 13C NMR: (100 MHz, CD3OD)
d: 38.9 (N–CH2–Ar), 110.5 (C20), 111.8 (C11), 117.3
(C13), 118.5 (C6), 122.0 (C19), 122.7 (C7), 122.7 (C8),
126.9 (C18), 127.4 (C17), 128.5 (C14), 129.0 (C16), 130.6
(C9), 133.3 (C5), 133.9 (C15), 142.5 (C4), 143.0 (C2), 154.2
(C12).
Acknowledgements
The authors acknowledge financial support for this
´
research from Direccion Nacional de Investigaciones
(DINAIN) of Universidad Nacional de Colombia. We
are also grateful to Departamento de Quımica, Univers-
idad Nacional de Colombia.
´
References and notes
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N–CH2–N bridge), 4.55 (8H, s, N–CH2–N cyclic); 6.33
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C7); 7.29 (2H, t, J = 7.16 Hz, H–C6); 7.65 (2H, d,
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