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Synthesis of Adjacent-Bridged Benzo-Annelated Cyclam and Attempted Synthesis of
Cross-Bridged Benzo-Annelated Cyclam
Amanuel B. Ghidey*, Edward H. Wong and Gary R. Weisman
University of New Hampshire, Department of Chemistry, Durham, NH 03824
[email protected]
Introduction
Results and Discussion
Synthesis of Cross-Bridged Benzocyclam
Cyclam is a 14-membered cyclic tetraamine ligand that has the ability to strongly bind metal cations
(1 and 2, Figure 1). Structural modifications were made by Weisman and coworkers1 to the parent
polyazamacrocycles “cyclam” and “cyclen” ligands to form the “cross-bridged” tetraazamacrocycles,
which have nonadjacent nitrogens bridged with an ethylene unit, first reported in 19901 (3 and 4,
Figure 1).
NH HN
NH HN
NH HN
N
NH HN
N
N
R
N
N
N
Cyclam
N
N
R
14
Ar
N
N
R
N
N
N
R
N
R
n
N
N
N
R
7
Target
Figure 2. Proposed structures to decrease the basicity of cross-bridged cyclam.
NH 2 Cu(OAc) 2,
CH 3CN
22%
H
N
N
CH 2 Cl2 ,
5-10 min
90% crude
N
H
N
H
N
NaBH
4
+
N
H
N
2 OTf
N
2 OTf
H
95% EtOH
r.t.
N
Mixture
2 OTf
NaBH4 , AlCl3
THF
NH
NH
61%
CN
O
N
11
N
H
H
H
89%
10
N
H
N
H
EtOH/CH3 CN
NH 2
N
N
H
N
14
H
15
MeI
CH3 CN
N
NaBH 4
MeI
CH3 CN
21 d
51%
N
H
95% EtOH
60%
N
H
17
DIBALH
PhMe
NH
57%
N
H
N
95% EtOH
43%
N
N
N
H
N
+
NaBH4
H
N
N
Br
18
(83:17)
H
N
Br
19
Minor
Major
Br
Mixture of Isomers 18 & 19
CH3 CN, 50 oC
N
N
N
p-TsOH, 10% Pd/C
EtOH/H2 O, reflux
N
4:1
H
34%
20
N
H
N
N
N
Figure 3. Global minima of 21 (MMFF
calculation).
H
N
H
N
N
H
18
N
N
H
Br
19
N
Br
Scheme 4. Isomerization of 18 and 19.
13C{1H}
NMR of 21, C6D6, 500 MHz
N
(40:60)
Scheme 3. Synthesis of novel ligand 21.
1H
H
+
21
NMR of 21, C6D6, 125 MHz
NH HN
H
CH3 CN
O
89%
N
N
N
N
16
N
N
R
2I
NH HN
O
N
N
N
N
1H
13
2I
H
N
NH
12
N
CH 3 CN, r.t. 3 d
99% crud e
N
H
H
O
NH 2
N
N
Br
N
9
H
NH
H
N
H
N
54 h
Reed has synthesized benzocyclam 13 which is the main precursor to get to the target material and
proposed a possible route to synthesize cross-bridged benzocyclam (8, R= Me).3 Condon following
Reed’s methodology has synthesized the adjacent-bridged benzocyclam 16.4
CN
N
+
-78 oC
N
N
N
Initial Attempt Towards the Synthesis of Cross-Bridged Benzo-Annelated Cyclam
and Actual Synthesis of an Adjacent-Bridged Benzo-Annelated Cyclam
CN
H
14
8
NH
2 MeOTf
H
Our approach towards the synthesis of adjacent-bridged benzocyclam 21 involves alkylation using allylbromide and reductive ring
expansion by a mild reducing agent, NaBH4. Finally, deallylation gave the desired product 21. Compound 21 was characterized by 1H and
13C{1H} NMR, 2-D NMR, ESI+ HRMS, IR and melting point. Isomerization of 18 to 19 from (87:13) ratio to (40:60) was also observed
following 54 hours of heating, suggesting 18 is the kinetic product and 19 is the thermodynamically stable product. This isomerization is
explained by an endo anomeric effect which is hypothesized to be the dominant stabilizing interaction with axial substituents having antiperiplanar orientation to the anilino nitrogen lone pair.
n
NH 2
N
Synthesis of Adjacent-Bridged Benzo-Annelated Cyclam (21)
N
Ar
H
N
Scheme 2. Methylation of 14 under kinetic conditions.
A clamshell-shaped cavity or cleft is created as a result of this bridging. These free ligands are
flexible, but when coordinated to metal cations “they adopt a low energy conformation having all
four nitrogen lone pairs convergent upon a cleft for complexation of small metal ions and
encapsulation of protons”.2 As a result of the convergent conformation, these ligands exhibit high
metal ion complexing ability and strong basicity. The strong basicity can hamper their use in metal
ion complexing applications. In order to decrease the strong basic nature, conjugating the amine
lone pairs to a π-system was proposed. Some of the proposed structures are depicted in Figure 2.
N
H
14
4
Figure 1. Structures of cyclam (1) and cyclen (2) and their cross-bridged analogues (3) & (4)
including a low-energy, diamond-lattice-type conformation (5) and metal-coordinated low
energy conformation (6).
N
N
N
Cyclen
N
N
N
N
N
3
2
One of our research goals was to build the benzo-annelated cross-bridged cyclam 8 (R = Me). An alternative synthetic route was
designed under kinetic conditions employing a strong alkylating agent, methyl trifluoromethanesulfonate (magic methyl). Following
Reed’s procedure, the bisaminal 14 was prepared. We were able to achieve the alkylation though it was not selective. Unfortunately the
subsequent reduction gave mixture of products.
R
R
1
Further Attempts Towards the Synthesis of Benzo-Annelated Cross-Bridged Cyclam
R
(R = Me)
NMR, d4-Methanol, 500 MHz
21
Transition metal complexation was investigated with Cu(II) and Zn(II). Zinc coordination
was successful according to its NMR spectroscopy, though further purification is
needed. Unfortunately we were unable to achieve the Cu(II) complexation due to
oxidative decomposition.
8
Scheme 1. First synthesis of benzocyclam 13 and compound 16 .
References
1) Weisman, G. R.; Rogers, M. E.; Wong, E. H.; Jasinski, J. P.; Paight, E. S. J. Am. Chem. Soc. 1990, 112,
8604.
2) Wong, E. H.; Weisman, G. R.; Hill, D. C.; Reed, D. P.; Rogers, M. E.; Condon, J. S.; Fagan, M. A.;
Calabrese, J. C.; Lam, K. C.; Guzei, I. A.; Rheingold, A. L. J. Am. Chem. Soc. 2000, 122, 10561.
3) Reed, D. P. Ph.D. Dissertation, University of New Hampshire, 1998.
4) Condon, J. S. M.S. Thesis, University of New Hampshire, 2002.
Black
Cu(ClO4) 2
MeOH
r.t.
N
N
HN
HN
.
Zn(ClO4 )2 6H 2O
MeOH
r.t.
N
22
HN
Zn(ClO 4)2
N
21
HN
22
Scheme 5. Transition metal complexation attempts.
Acknowledgements
The Department of Chemistry of the University of New Hampshire is acknowledged for financial support and all W-W group members.