Studies of Stoichiometric Monobenzylation of Cross-bridged Cyclam by SN2
Alkylation and Reductive Alkylation!
Brian J. Kispert, Gary R. Weisman and Edward H. Wong
Department of Chemistry, University of New Hampshire, Durham, NH 03824
[email protected]
Introduction
N
step synthesis outlined in Scheme
1.1
NH
H
H
N
BnBr
N
N
PhCH3
N
H
H
N
N
Bn
Br
N
H
N
Bn
MeCN
N
Br
H
N
2Br
NaBH(OAc)3 (10 eq)
N
N
MeCN
Reflux, 24h
N
N
Bn
Pd/C, TsOH
N
N
EtOH/H2O
reflux
NH
N
Bn
N
N
in radiopharmaceutical applications. Such ligands can be
N
N
linked to a biologically-active target molecule and
Scheme 2. Bioconjugates, like 4, are potentially useful for
H
linker
N
N
N
N
OH
P OH
O
1) peptide
conjugation
2) 64Cu labeling
peptide
N
N
N
II
O
P
O
O
4
Scheme 2: Formation of second generation ligands
from 1.
N
N
Bn
N
1
2
N
N
N
N
+
65%
Bn
N
Bn
+
HN
Bn
achieved.2
N
N
N
HN
Bn
N
N
NH
5
N
N
1
5
2
59%
2%
Bn
N
N
N
N
Bn
N
HN
+
Bn
NH
5
N
2
to 5 was determined by comparing the normalized
Figure 3: 1H NMR spectrum of 1, 2, and 5 in C6D6 (400
MHz) for reductive alkylation
integrations of the resonances at δ 3.53 and 4.00 in
Figure 3. The ratio of 2 was determined using the
multiplets from δ 1.10-1.60, which contain protons
from each compound in the final mixture. Based
N
N
NH
N
Bn
N
N
N
N
+
Bn
N
HN
+
Bn
1
5
NH
N
2
upon total integrations and integrations of 1 and 5,
13C{1H}
NMR spectrum showed very small amounts
of starting material (2), but was not clear enough to
confirm the final ratio.
HN
+
Bn
NH
N
These data show that SN2 alkylation and reductive
5
2
23%
12%
The SN2 alkylation (Scheme 3) involved treating CBcyclam (2) with 1 equivalent of benzyl bromide to form a
alkylation are not effective methods for producing high
yields of monobenzyl CB-cyclam (1) when compared to
Figure 1: 1H NMR spectrum of 1, 2, and 5 in C6D6 (400
MHz) for SN2 alkylation
mixture of 1, 5, and leftover 2 in a ratio of 0.65: 0.23:
N
0.12, respectively. This ratio was determined by
N
Bn
N
N
+
NH
integration of specifically-denoted resonances (green = 1,
13C{1H}
N
calculated or supported by 1H and 13C{1H} NMR
previous methods of synthesis; thus, these methods would
blue = 5, orange = 2) in the
N
NH
2
Scheme 3: SN2 alkylation of 1 with benzyl bromide
1H
N
+
NH
+
1
Bn
N
+
spectra (Figures 3 and 4, respectively). The ratio of 1
64Cu
N
3
NH
N
Bn
the quantity of leftover 2 was established. The
Results and Discussion
N
N
the presence of excess sodium triacetoxyborohydride
secondary amines of CB-cyclam (2) so that efficient monofunctionalization of the other secondary amine can be
NH
N
N
CB-cyclam (2) with 1 equivalent of benzaldehyde in
2
Positron Emission Tomography-based tumor detection (PET). The benzyl group of 1 functions to protect one of the
N
N
to form a mixture of 1, 5, and 2 in a ratio of ~0.39:
1
subsequently complexed with 64Cu (II), as shown in
MeCN
Bn
~0.59: ~0.02, respectively. These ratios were
N
BnBr (1 eq.)
N
The reductive alkylation (Scheme 4) involved treating
N
linker
for synthesis of second generation ligands that are useful
N
N
NH
39%
HN
NH
Monobenzyl CB-cyclam (1) is an important intermediate
HN
N
1
Scheme 1: Previous synthesis of monobenzyl CB-cyclam (1).1
NH
DCE
NaBH(OAc)3
Scheme 4: Reductive alkylation of 1 with benzaldehyde
1
N
PhCHO (1 eq.)
2
suitable for large scale production of 1. If not, the previous approach is validated as necessary.
N
N
The goal of this research project was to explore whether 1 could be synthesized
from CB-cyclam (2) through SN2 alkylation or reductive alkylation. If successful, this direct synthesis would be more
N
HN
+
Production of monobenzyl cross-bridged (CB) cyclam (1) in high yields has previously been accomplished through a four-
N
1
Bn
N
HN
+
Bn
N
N
5
NH
N
2
Figure 4: 13C{1H} NMR spectrum of 1, 2, and 5 in C6D6
(100 MHz) for reductive alkylation
not be appropriate for large-scale synthesis of compound 1.
The reductive alkylation will be repeated using freshly purified PhCHO and dried 2.
Conclusions
In summary, SN2 alkylation and reductive alkylation of CB-cyclam are not efficient methods for producing high yields of
NMR spectrum (Figure 1).
the desired product 1. These reactions produce mixtures of 1, 2, and 5, and would require intensive separation and
NMR relative peak heights (Figure 2) were
consistent with the 1H results. In Figure 1, the integrations
purification. Therefore, it can be concluded that the most efficient route to date for preparation of desired synthetic
of the resonances at δ 3.50, 4.00 and 1.15 were
intermediate 1 is the procedure previously designed and realized (Scheme 1).
compared to give the ratio of 1:5:2. The resonances
Acknowledgements
representing 2 and 5 were normalized due to the ligands’
C2 symmetry.
13C{1H}
Figure 2:
NMR spectrum of 1, 2, and 5 in C6D6 (100
MHz) for SN2 alkylation
References
This work was supported by Award Number R01CA093375 from the National Cancer Institute. The content is solely the responsibility of the
authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. BJK thanks
Leon Wong, Barbara Li, Amanuel Ghidey, and Justin Fleming for help and support in the lab.
1. 
G. R. Weisman, personal communication; route is the work of Shanta Bist, Matthew Young, Kaitlyn Dugan, Leon Wong, and David Wilk.
2. 
Wadas, T.J.; Wong, E.H.; Weisman, G.R.; Anderson, C.J. Chem. Rev. 2010, 110, 2858-2902.