Modular synthesis of functionalized bis-bispidine tetraazamacrocycles

Article abstract of DOI:10.1021/ol202840s

An effective synthesis is reported for the construction of highly rigid and preorganized bis-bispidine tetraazamacrocycles bearing either identical or different functionalities. Using essential building blocks derived from N-Boc-N'-allylbispidinone, the modular approach facilitates independent incorporation of the functional groups to the macrocyclic framework as well as selective derivatization of one functionality in the presence of another.

Full text of DOI:10.1021/ol202840s

ORGANIC
LETTERS
2
011
Vol. 13, No. 24
540–6543
Modular Synthesis of Functionalized
Bis-bispidine Tetraazamacrocycles
6
Zhuo Wang,* Erin J. Miller, and Samantha J. Scalia
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario,
Canada N9B 3P4
zhuowang@uwindsor.ca
Received October 20, 2011
ABSTRACT
An effective synthesis is reported for the construction of highly rigid and preorganized bis-bispidine tetraazamacrocycles bearing either identical
0
or different functionalities. Using essential building blocks derived from N-Boc-N -allylbispidinone, the modular approach facilitates independent
incorporation of the functional groups to the macrocyclic framework as well as selective derivatization of one functionality in the presence of
another.
Macrocyclic compounds are capable of forming stable
complexes with selected metal ions of unusual oxidation
1
states. This is particularly the case for highly rigid and
preorganized frameworks such as bis-bispidine tetraaza-
2
ꢀ6
macrocycles (1) (Figure 1).
Due to the high rigidity
of the structure and the steric hindrance around the
cavity, the macrocycle is considered to have unprecedented
ligand field strength for a tetramine donor and has been
used to encapsulate metal ions to form highly stable com-
plexes which exhibit interesting optical and electronic
Figure 1. Bis-bispidine tetraazamacrocycle.
2
,3
properties.
As part of our research interest to construct polymacro-
cycles which can be used to selectively bind metal ions with
interesting oxidation and electronic states, it was necessary
to incorporate the rigid tetraazamacrocycles into a poly-
mer framework. This requires that the macrocycle pos-
sess suitable functional groups which can be utilized in a
polymerization reaction. For this purpose, we found that
(
1) (a) Constable, E. C. Coordination Chemistry of Macrocyclic
Compounds; Oxford Science Publications: New York, 1999. (b) Ribas
Gispert, J. Coordination Chemistry; Wiley-VCH: Weinheim, 2008. (c)
Dietrich, B.; Viout, P.; Lehn, J.-M. Macrocyclic Chemistry: Aspects of
Organic and Inorganic Supramolecular Chemistry; VCH Weinheim: New
York, 1993. (d) Coordination Chemistry of Macrocyclic Compounds;
Melson, G. A., Ed.; Plenum Press: New York, 1979. (e) Synthetic Multi-
dentate Macrocyclic Compounds; Izatt, R. M., Christensen, J. J., Eds.;
Academic Press, Inc.: New York, 1978.
7
,8
(
2) For recent reviews, see: (a) Comba, P.; Schiek, W. Coord. Chem.
Rev. 2003, 238ꢀ239, 21. (b) Barefield, E. K. Coord. Chem. Rev. 2010,
54, 1607. (c) Hancock, R. D.; Melton, D. L.; Harrington, J. M.;
McDonald, F. C.; Gephart, R. T.; Boone, L. L.; Jones, S. B.; Dean,
N. E.; Whitehead, J. R.; Cockrell, G. M. Coord. Chem. Rev. 2007, 251,
(7) For metal-containing polymers, see: (a) Manners, I. Synthetic
Metal-Containing Polymers; Wiley-VCH Verlag: Weinheim, 2004. (b)
Abd-El-Aziz, A. S. Macromol. Rapid Commun. 2002, 23, 995. (c)
Metal-Containing and Metallosupramolecular Polymers and Materials;
Schubert, U. S., Newkome, G. R., Manners, I., Eds.; ACS Symposium Series
928; American Chemical Society: Washington, D.C., 2006.
(8) For polymacrocycles, see, for example: (a) Zhan, H.; Lamare, S.;
Ng, A.; Kenny, T.; Guernon, H.; Chan, W.-K.; Djurisic, A. B.; Harvey,
P. D.; Wong, W.-Y. Macromolecules 2011, 44, 5155. (b) Delaviz, Y.;
Gibson, H. W. Macromolecules 1992, 25, 4859. (c) Huang, X.; Zhu, C.;
Zhang, S.; Li, W.; Guo, Y.; Zhan, X.; Liu, Y.; Bo, Z. Macromolecules
2008, 41, 6895.
2
1678.
(3) Comba, P.; Pritzkow, H.; Schiek, W. Angew. Chem., Int. Ed. 2001,
0, 2465.
4
(
(
4) Miyahara, Y.; Goto, K.; Inazu, T. Chem. Lett. 2000, 620.
5) Miyahara, Y.; Goto, K.; Inazu, T. Tetrahedron Lett. 2001, 42,
3
097.
6) Galasso, V.; Goto, K.; Miyahara, Y.; Kovac, B.; Klasinc, L.
Chem. Phys. 2002, 277, 229.
(
1
0.1021/ol202840s r 2011 American Chemical Society
Published on Web 11/15/2011

the existing literature methods developed for the construc-
tion of 1 could not be successfully adapted to the synthesis
of functionalized bis-bispidine macrocycles due to a lack of
tolerance for the functional groups, inefficient transforma-
tion, and/or generation of byproducts which were difficult
Scheme 1. Synthesis of Bispidine Ester 7
3ꢀ5,9,10
to remove by conventional purification methods.
In
this communication, we report an effective synthetic path-
way which provides access to functionalized bis-bispidine
tetraazamacrocycles. The modular approach allows inde-
pendent incorporation of the functionalities to the highly
rigid macrocycle as well as selective derivatization of one
functional group in the presence of another.
0
N-Boc-N -benzylbispidinone were difficult to remove
cleanly in subsequent reactions. Bispidinone 6 was found
to be much superior in this regard.
Scheme 2. Synthesis of Bis(iodoacetamide) 10
Figure 2. Retrosynthetic plan.
The target macrocycle would be constructed via cycli-
zation of functionalized bispidine derivatives 3 and 4
(
Figure 2). Both building blocks could be prepared from
N-Boc-4-piperidone (5) via double Mannich reaction. Thus,
reaction of 5 with paraformaldehyde and allylamine under
0
acidic conditions afforded N-Boc-N -allylbispidinone (6)
1
1,12
in 54% yield (Scheme 1).
Deprotonation of triethyl
phosphonoacetate followed by nucleophilic addition of
the resulting carbanion to bispidinone 6 under Hornerꢀ
WadsworthꢀEmmons conditions generated the desired
1
3
bispidine ester 7 in excellent yield.
0
0
Besides 6, N,N -diallylbispidinone and N-Boc-N -ben-
zylbispidinone had also been investigated as possible sub-
strates for the construction of the tetraazamacrocycles.
Bothcompoundswere prepared ingoodyieldsvia a double
Mannich reaction in a similar fashion to the synthesis
of 6, with the former generated from N-allyl-4-piperidone
and allylamine, and the latter from N-Boc-4-piperidone
The allyl group on bispidine ester 7 was removed
cleanly upon treatment with 1-chloroethyl chloroformate
1
4,15
(
in N,N -diallylbispidinone and the benzyl substituent in
5) and benzylamine. However, the diallyl substituents
0
(Scheme2).
Theresulting1-chloroethyl carbamate was
cleaved efficiently together with the Boc protective group
under acidic conditions to give bispidine hydrochloride 8.
Acetylation of 8 with chloroacetyl chloride provided bis-
(
(
9) Miyahara, Y.; Goto, K.; Inazu, T. Synthesis 2001, 364.
10) Black, D. S. C.; Deacon, G. B.; Rose, M. Tetrahedron 1995, 51,
(
chloroacetamide) 9 in 77% overall yield from bispidine
2
1
2
055.
(11) Ruenitz, P. C.; Smissman, E. E. J. Heterocycl. Chem. 1976, 13,
111.
(14) Olofson, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot,
T. J. Org. Chem. 1984, 49, 2081.
(15) Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
(
12) Huttenloch, O.; Laxman, E.; Waldmann, H. Chem.;Eur. J.
002, 8, 4767.
(
13) Wadsworth, W. Org. React. 1977, 25, 73.
11797.
Org. Lett., Vol. 13, No. 24, 2011
6541

ester 7. Further conversion of 9 to bis(iodoacetamide) 10
was achieved in high yield.
Macrocyclization of bispidine hydrochloride 8 with bis-
The tetraazamacrocyclic diol 12 possesses two primary
hydroxyl groups that extend away from the ring system.
This is expected to render them sterically favorable for
further reactions and functionalizations. However, deriva-
tization seems to be limited to the generation of identical
functionalities as our attempt to monosilylate 12 led to a
mixture of mono- and diprotected products as well as
(
iodoacetamide) 10 proceeded smoothly at room tempera-
ture to afford bisamide 11 in 68% yield (Scheme 3). In
comparison, cyclization of 8 with the chloro substrate 9
did not proceed after a prolonged reaction at reflux.
The bromo substrate, which can be prepared from 8
and bromoacetyl bromide in a similar way to the synthesis
of 9, was also unsuitable as its reaction with 8 was very
sluggish.
1
7,18
unprotected diols.
In order to incorporate different functional groups on
each end of the tetraazamacrocylic framework, it is more
straightforward to introduce the functionalities to the bis-
pidine building blocks prior to macrocyclization. To this
end, DIBALH reduction of bispidine ester 7 followed by
1
9
TBS-protection afforded silyl ether 13 (Scheme 4). Sub-
sequent removal of the allyl, Boc, and TBS groups pro-
vided hydroxybispidine 14 in 70% overall yield.
Scheme 3. Formation of Dihydroxy Tetraazamacrocycle 12
Scheme 4. Synthesis of Hydroxybispidine 14
Macrocyclization of 14 and 10 generated bisamide 15
which was then reduced to give the desired monoprotected
hydroxy tetraazamacrocycle 16 (Scheme 5). In the DIBALH
reduction of 15, it was found that solvents played an
important role. At ambient temperature, reduction of the
amide groups in 15 proceeded sluggishly in THF. When
toluene was used, the amide groups could be successfully
1 13
The H and C NMR spectra of the macrocyclic bis-
1
6
20
amide 11 are unusually complex. Similar results have
been obtained for bisamide 15. However, upon DIBALH
reduction of 11, the resultant tetraazamacrocycle 12 de-
monstrates straightforward NMR data in accordance with
the proposed structure. Likewise, tetraazamacrocycle 16
displays clear-cut spectra. These results seem to suggest
that bisamide 11 (and 15) possesses different conforma-
tions which may not interconvert quickly on the NMR
time scale due, in part, to a significant restriction to bond
rotations imposed by the bispidine rings and the amide
groups. As each conformer may exhibit distinctive reso-
reduced. However, the TBS protective group was also
completely cleaved. The best solvent system for this reduc-
tion seems to be a mixture of toluene and diethyl ether
which facilitated the reduction of the amide and ester
2
1
groups while keeping the TBS group intact.
The tetraazamacrocycles 12 and 16 possess a highly
basic tetramine core which can bind readily to normal-
phase silica gel and therefore could not be purified on a
(
17) McDougal, P. G.; Rico, J. G.; Oh, Y.-I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388.
(18) Yu, C.; Liu, B.; Hu, L. Tetrahedron Lett. 2000, 41, 4281.
1
13
nance peaks, it is possible that the H and C NMR spec-
tra represent a collection of resonances produced by the
different conformers.
(
19) TBS protection was necessary as the hydroxyl group can react
with 1-chloroethyl chloroformate and interfere with the allyl group
removal in the next step.
(
20) Yoon, N. M.; Gyoung, Y. S. J. Org. Chem. 1985, 50, 2443.
21) Taniguchi, T.; Ogasawara, K. Angew. Chem., Int. Ed. 1998, 37,
(
1136.
(
16) See Supporting Information.
6
542
Org. Lett., Vol. 13, No. 24, 2011

difficulty by column chromatography using commercially
available reversed-phase silica gel.
Scheme 5. Formation of Hydroxy Tetraazamacrocycle 16
It should be noted that the hydroxyl group in the mono-
protected macrocycle 16 can be selectively transformed in
the presence of the silyl ether group when further deriva-
tization is desired. This will enable independent introduc-
tion of various functionalities to either side of the tetra-
azamacrocyclic structure if necessary.
In summary, an effective synthetic pathway has been
developed for the construction of functionalized bis-bispi-
dine tetraazamacrocycles. Using essential building blocks
derived from bispidinone 6, the modular approach facil-
itates independent incorporation of either identical or dif-
ferent functionalities to the highly rigid and preorganized
macrocycle. The synthesis offers the opportunity for further
derivatization after the formation of the tetraazamacro-
cyclic framework, including selective transformation of one
functional group in the presence of another. This makes
it possible to introduce a variety of functional groups, in
particular those which may be labile throughout the macro-
cycle formation, onto the ring system. Currently, this synthetic
approach is being employed in the preparation of polytetra-
azamacrocycles which will be reported in due course.
Acknowledgment. We thank the Natural Science and
Engineering Research Council (NSERC) of Canada for
funding. We also thank Dr. Jiaxi Wang at Queen’s University,
Canada, for HRMS analysis.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
conventional column. Sublimation of the compounds was
unsuccessful due, in part, to strong intermolecular hy-
drogen bonding. However, they can be purified without
Org. Lett., Vol. 13, No. 24, 2011
6543