Synthetic studies on azacyclotribenzylenes

Article abstract of DOI:10.3987/COM-04-10249

Azacyclotribenzylene compounds (1, 2) and several of their N-alkyl derivatives (3-6) were synthesized via biarylamines (12, 14) in good yield. Conformational studies of them are also discussed.

Full text of DOI:10.3987/COM-04-10249

HETEROCYCLES, Vol. 65, No. 1, 2005
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HETEROCYCLES, Vol. 65, No. 1, 2005, pp. 1 - 4
Received, 13th October, 2004, Accepted, 7th December, 2004, Published online, 10th December, 2004
SYNTHETIC STUDIES ON AZACYCLOTRIBENZYLENES
Kenta Hayashi, Shoko Inoue, Hanae Shimizu, Akiko Kobayashi, Miyuki Ishizaki,
Yutaka Matsuoka, Kiyoshi Nishitani, and Hiroshi Hara*
Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641,
Yamazaki, Noda-shi, Chiba 278-8510, Japan
Abstract – Azacyclotribenzylene compounds (1, 2) and several of their N-alkyl
derivatives (3-6) were synthesized via biarylamines (12, 14) in good yield.
Conformational studies of them are also discussed.
Much attention has been focused on the synthesis of cyclophanes, such as cyclotriveratrylene (CTV),
crown ether, calixarenes and so on, because of their interesting structures and properties (Figure 1).1,2
However, there is no report involving the usage of cyclophanes as drugs so far. Probably, their bulkiness
and high hydrophobicity are not thought to be adequate for binding receptors or enzymes. Recently, some
biological activities have been found in fullerene derivatives, in spite of their high hydrophobicity. The
fullerene derivatives may break DNA and inhibit cell growth and the activity of enzymes.3-5 These results
suggest that cyclophanes might also have some potential as candidates for drugs. Although, many studies
on the synthesis of oxa- or thiacyclotriveratrylenes have been carried out,6-9 azacyclotribenzylene (1) has
not yet been synthesized. We expected that 1 and its derivatives (2-6) have potential for pharmacological
activities, since an amine group acts as acceptor and donor in a hydrogen bond. Also the
MeO
OMe
MeO
OMe
N
X
(CH2)3NMe2
MeO
MeO
OMe
OMe
N
X
R
7 : X = H
8 : X = Cl
X
1 : R = H, X = H
2 : R = H, X = Cl
3 : R = Me, X = H
4 : R = (CH2)3NMe2, X = H
5 : R = Me, X = Cl
Cyclotriveratrylene (CTV) : X = CH2
Oxacyclotriveratrylene : X = O
Thiacyclotriveratrylene : X = S
Figure 1
6 : R = (CH2)3NMe2, X = Cl
azacyclotribenzylenes have a structure similar to tricyclic anti-depressant drugs, imipramine (7) and
clomipramine (8). Here, we wish to describe our preliminary results on the synthesis of six kinds of

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HETEROCYCLES, Vol. 65, No. 1, 2005
azacyclotribenzylenes (1-6)
At first, synthesis of azacyclotribenzylene (1) was carried out. The Ulluman reaction of 2-aminobenzoic
acid (9) with 2-bromobenzoic acid (10) in the presence of copper iodide and potassium carbonate in 1-
pentanol afforded a diarylamine (11) in a yield of 89%.10,11 Reduction of 11 with BH3-THF gave diol (12)
which was reacted with veratrole under acid conditions successfully to furnish azacyclophane (1)
(Scheme 1). Similarly, a 4-chloro congener (2) of 1 could be synthesized via 14 from Lobenzarit (13) in
three steps.
Previously, we observed that methylene protons in CTV appeared as a couple of doublet (δ 3.65 and 4.87)
1
showing the crown conformation.12 As expected, H NMR spectral data of 1 and 2 also showed their
flexible conformation by the appearance of methylene protons as one singlet peak (δ 4.45) in 1 and two
singlet peaks (δ 3.73 and 3.81) in 2.
With azacyclotribenzylenes (1, 2) in hand, their N-alkylation was examined (Scheme 2). Treatment of 1
with NaH and iodomethane in DMSO easily gave an N-methyl derivative (3) in 80% yield. The
1
conformation of 3 was analyzed to be flexible in the H NMR spectrum, similar to that of 1. A similar
reaction of 1 with N,N-dimethylaminopropyl chloride failed to yield an N-alkyl derivative (4). Despite
treatment under several reaction conditions with various bases and solvents, all attempts for N-alkylation
were not successful.
O
O
HO
O
O
OH
H
N
CuI, K2CO3
OH
OH
OH
NH2
+
1-pentanol
reflux, 89%
Br
10
9
11
MeO
OMe
OMe
HO
OMe
c.H2SO4
H
N
BH3-THF
THF, rt
90%
CF3CF2OH
rt, 82%
N
H
12
1
MeO
OMe
OMe
OMe
NaO
O
O
ONa
HO
OH
H
H
N
N
1) HCl, H2O
c.H2SO4
2) BH3-THF
THF, 0˚C→rt
95%
CF3CF2OH
0˚C, 68%
N
H
2
Cl
Lobenzarit (13)
Scheme 1
Cl
Cl
14

HETEROCYCLES, Vol. 65, No. 1, 2005
3
MeO
OMe
MeO
OMe
MeO
OMe
NaH
Me2N(CH2)3Cl
NaH, MeI
DMSO, reflux
80%
DMSO, reflux
N
N
N
H
Me
(CH2)3NMe2
4
3
1
OMe
OMe
c.H2SO4
CF3CF2OH
reflux, 92%
Me2N
MeO
OMe
HO
OH
MeO
OMe
H
H
N
NaH, MeI
NaH, Me2N(CH2)3Cl
N
N
DMSO, rt
90%
DMSO, 120˚C, 67%
12
15
16
Scheme 2
To obtain the imipramine analogue (4), introduction of the N,N-dimethylaminopropyl group onto nitrogen
was carried out before cyclization as an alternative route.13,14 Thus, diol (12) was converted to dimethyl
ether (15), followed by alkylation with N,N-dimethylaminopropyl chloride to afford 16. Acid treatment of
16 with veratrole gave the expected compound (4) in 92% yield as a mixture of two conformational
1
isomers, the ratio of which was estimated to be 4 : 3 by H NMR spectroscopic analysis. Methylene
protons of two isomers are shown as a couple of doublets (δ 3.43 and 5.35, J=12.5Hz) 15 and one singlet
revealing their conformation as crown and flexible types, respectively. Although the two isomers could
be isolated by preparative TLC, each one isomerized gradually at room temperature and completely
reached an equilibrium mixture (4 : 3) in two days (Figure 2).
N(CH2)3NMe2
MeO
MeO
N(CH2)3NMe2
MeO
MeO
X = H or Cl
X
X
Figure 2
In the case of derivarization of 3-chloroazacyclophane (2), not only methylation but also N,N-
dimethylaminopropylation on the nitrogen atom in the cyclic system was successfully performed to
furnish 5 and 6 in moderate yields by direct alkylation (Scheme 3). Two singlet peaks (δ 3.46 and 3.92) of
the 1H NMR spectrum showed that the conformation of 5 was flexible. The product (6) was obtained as a
mixture of two conformational isomers which were separable but liable to come to equilibrium (4 : 3) at
ambient temperature as similar to 4.

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HETEROCYCLES, Vol. 65, No. 1, 2005
MeO
OMe
MeO
OMe
MeO
OMe
NaH, Me2N(CH2)3Cl
DMSO, reflux, 66%
NaH, MeI
DMSO
reflux, 47%
N
N
N
Me
H
Cl
Cl
Cl
(CH2)3NMe2
5
2
6
Scheme 3
In conclusion, we have shown a facile construction of the azacyclotribenzylene system (1, 2) via
biarylamines (12, 14). Four N-alkyl derivatives (3-6) of them were also synthesized. Pharmacological
studies on the obtained azacyclophanes are now in progress.
ACKNOWLEDGEMENTS
The authors are indebted to Chugai Pharmaceutical Co., Ltd. for the supply of Lobenzarit , and to Mrs. F.
Hasegawa of this faculty for her MS spectral measurements.
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