Improved synthesis of a C3-symmetrical pyridinophane

Article abstract of DOI:10.1016/j.tetlet.2008.01.077

The formation of the C₃-symmetrical 2,11,20-triaza[3.3.3](2,6)pyridinophane 1 was undertaken with the aim of improving the synthesis of this highly desirable macrocycle, with the future aim of functionalizing 1 with amide pendent arms for the recognition of lanthanide ions. The synthesis of 1 involves the stepwise transformation of pyridine-2,6-dicarboxylic acid into two key intermediates; N,N-bis[(6-hydroxymethyl)pyridin-2-yl]-p-tosylamide 7 and 6-bis[(amino-p-tosyl)methyl]pyridine 5. The macrocyclization of these two intermediates gave 8, from which 1 was formed upon deprotection of the three tosyl groups.

Full text of DOI:10.1016/j.tetlet.2008.01.077

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1993–1996
Improved synthesis of a C3-symmetrical pyridinophane
Claire Nolan, Thorfinnur Gunnlaugsson *
School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland
Received 17 October 2007; revised 9 January 2008; accepted 17 January 2008
Available online 20 January 2008
Abstract
The formation of the C3-symmetrical 2,11,20-triaza[3.3.3](2,6)pyridinophane 1 was undertaken with the aim of improving the synthe-
sis of this highly desirable macrocycle, with the future aim of functionalizing 1 with amide pendent arms for the recognition of lanthanide
ions. The synthesis of 1 involves the stepwise transformation of pyridine-2,6-dicarboxylic acid into two key intermediates; N,N-bis[(6-
hydroxymethyl)pyridin-2-yl]-p-tosylamide 7 and 6-bis[(amino-p-tosyl)methyl]pyridine 5. The macrocyclization of these two intermediates
gave 8, from which 1 was formed upon deprotection of the three tosyl groups.
Ó 2008 Elsevier Ltd. All rights reserved.
The design and synthesis of highly structurally orga-
nized molecules or macrocycles as molecular scaffolds or
as ion receptors is of great current interest within the field
of supramolecular chemsitry.1–3 Many classical examples
exist where scaffolds, such as calixarenes,4 azamacrocycles,5
and cyclophens6 have been developed. The use of pyridine
as a coordinating ligand in these structures has been exten-
sively studied.7,8 In particular, such ligands have been used
as hosts for lanthanide ions, which possess valuable photo-
physical and paramagnetic properties, as well as being of
great importance in organic synthesis as catalysts.9
We have been interested in the use of simple macrocyclic
structures as platforms for the development of sensors10
and catalysts11 for biological detection and hydrolysis of
biologically important molecules such as RNA. We have
focused our efforts on the use of the well-known macrocy-
cle, cyclen (1,4,7,10-tetraazacyclododecane)12,13 and fur-
nished this structure with amide pendent arms such as
dipeptides and aromatic antennae for use as chelating
ligands for lanthanide ions. With the aim of developing
other ligands for lanthanide ions, we looked towards syn-
thesizing highly symmetrical and reorganized macrocyclic
structures that could facilitate the incorporation of such
pendent arms that could fulfil the rather high coordination
environments, usually of 9–10.14 We focused on developing
pyridine based ligands, such as 2,11,20-triaza[3.3.3](2,6)-
pyridinophane, 1, which contains three pyridine rings and
three secondary amino moieties in a C3-symmetrical macro-
cycle. This target has previously been synthesized in 2%
yield in a one-pot synthesis by Kaptein15 as well as by
Miyahara and co-workers16 who made the cyclophane via
a number of elegant steps. However, as we were unable
to repeat all these steps successfully in good yield, we
embarked on attempting to improve the synthesis of this
compound, which is the focus of this Letter.
The synthesis of 1 (Scheme 1) began with the synthesis
of dimethyl pyridine-2,6-dicarboxylate from 2,6-pyridine
dicarboxylic acid in 87% yield.17 The diester was then
reduced using NaBH4 in ethanol, to give 2,6-bis(hydroxy-
methyl)pyridine (yield) in 65% after continuous extraction
from aqueous solution. This compound is the starting
material for the two key intermediates, 5 and 7, shown in
Scheme 1.
The synthesis of both 5 and 7 involved the bromination
of the diol, by simply reacting it with 48% HBr solution
under reflux. After cooling to room temperature, and sub-
sequent neutralization using 40% NaOH solution, a pink
precipitate was formed upon cooling to 0 °C. This solid
was shown to contain a mixture of two products; the bis-
bromo derivative 2 and the bromo-alcohol 3. Both of these
*
Corresponding author. Tel.: +353 1 896 3459; fax: +353 1 671 2826.
E-mail address: gunnlaut@tcd.ie (T. Gunnlaugsson).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.077

1994
C. Nolan, T. Gunnlaugsson / Tetrahedron Letters 49 (2008) 1993–1996
Ts
N
TsNH2, K2CO3
+
O
O
N
N
N
N
N
Br
Br
OH
OH
Br
OH
2
OH
OH
3
6
O
K+
K2CO3, KI
N
PBr3
CH2Cl2
O
1. H2N-NH2
2. HCl
Ts
N
K2CO3, H2O
TsCl
+
N
N
N
N
Br
Br
NH2
NH2
NHTs
NHTs
.2HCl
7
5
4
Cs2CO3, KI
CH3CN
N
N
N
Ts
Ts
N
N
N
NH
N
HN
N
H2SO4
N
H
N
Ts
8
1
Scheme 1. The synthesis of 1 from pyridine-2,6-dicarboxylic acid.
compounds are central to the synthesis of 1. From this
mixture, compound 2 was isolated by flash silica chromato-
graphy, using CH2Cl2 as eluent, in 27% yield. By simply
changing the eluent (gradually) to 98:2 CH2Cl2/CH3OH,
compound 3 could be isolated in 41% yield. Attempts to
make 2 in high yield, as described in the work of Rabjohn18
by using 2,6-lutidine and N-bromosuccinimide, failed to
give the desired product in more than 5% yield. However,
it was possible to improve the yield of 2 to 87% by reacting
the pyridine diol with PBr3 instead of HBr. Compound 2
was transformed into the corresponding di-amine 4 using
the classical Gabriel synthesis, by first refluxing 2 overnight
with potassium phthalimide in the presence of K2CO3
and KI, in dry DMF under an inert atmosphere. This gave
2,6-bis(phthalimomethyl)pyridine in 78% yield, which
could be carried forward, without the need of further puri-
fication, to give compound 4. This was achieved by reflux-
ing the bisphthalimide for 5 h in a mixture of hydrazine
monohydrate and ethanol in 92% yield, followed by aque-
ous HCl workup after cooling to room temperature. The
transformation of this product into the di-tosyl amide 5
was unsuccessful using several literature procedures.19
However, the desired product 5 was eventually formed in
55% yield as a grey solid, by refluxing 4 in water with
K2CO3 and p-tosyl chloride, for 12 h, after which a black
precipitate was formed that was collected, washed with
water, methanol and diethyl ether, and finally dried in
the presence of P2O5 under vacuum. Despite its low yield,
this reaction could easily be scaled-up to give 5 in multi-
gram quantities.
The synthesis of the second intermediate, 7, in the syn-
thesis of 1, was achieved in two steps from 3, by firstly
making 6 (N,N-bis[(6-hydroxymethyl)pyridin-2-yl]-p-tosyla-
mide) from the condensation of 2 equiv of 3 with p-tosyla-
mide in acetone in the presence of K2CO3. After refluxing
the mixture for four days, the reaction was cooled to room
temperature and the resulting precipitate removed by filtra-
tion. The filtrate was then evaporated (collected), giving a
brown oil. This brown residue was then dissolved in CHCl3
and washed with 10% aqueous K2CO3 solution and evap-
orated to dryness to give 6 as brown crystals in 62% yield,
which did not require any further purification. This prod-
uct was characterized by conventional methods, as well
as by using X-ray crystallography. Interestingly, using sev-
eral other solvents such as CH3CN instead of acetone in
the above synthesis did not give rise to the formation of
6. Converting the two methyl alcohols of 6 into the corre-
sponding dibromide, 7, was achieved using PBr3 in CH2Cl2
over 12 h. The reaction was neutralized with 40% NaOH
and the organic layer collected, giving 7 as pink crystals in
97% yield.
Having achieved the synthesis of the two key intermedi-
ates, the next step involved the macrocyclization of 5 and 7
to give 8. This was achieved using a method discussed by
Parker et al. for the synthesis of azacrown ethers.20 We
hoped that using a mild base and KI would both increase

C. Nolan, T. Gunnlaugsson / Tetrahedron Letters 49 (2008) 1993–1996
1995
the rate of the SN2 reaction between 5 and 7, and that K+
would function as a template in the formation of the
desired 18-membered macrocycle 8. The synthesis involved
adding 7 in CH3CN to a stirring CH3CN solution of 5,
which also contained Cs2CO3 and KI over 20 min. This
solution was then stirred for further two days under an
inert atmosphere and finally refluxed for a further 12 h.
This led to the formation of a precipitate that was removed
by filtration; the filtrate was reduced to dryness and the
resulting residue taken up into CHCl3 and washed with
10% K2CO3. This gave the desired macrocycle 8 as a solid
in 59% yield after recrystallization from a mixture of CHCl3
and diethyl ether.21 The 1H NMR spectrum of 8 (400 MHz,
CDCl3) showed that the product had high symmetry, with a
singlet resonating at 2.44 ppm for the methyl group of the
tosyl moiety, a singlet appearing at 4.30 ppm for the CH2
group and a doublet and a multiplet resonating at
7.68 ppm and 7.29 ppm, respectively, for the tosyl group
and a doublet and triplet at 7.14 and 7.44 ppm, respectively,
for the pyridine protons. The final step was the deprotection
of the tosylamide units of 8 to give the desired free amines.
This was achieved using concd H2SO4, and refluxing the
mixture for 2 h. The reaction was then cooled to room tem-
perature before adding the reaction mixture to an ice/water
mixture and adjusting the pH to 14 using 40% NaOH and
extracting 1 into diethyl ether, giving the C3-symmetrical
pyridinophane in 89% yield.22,23 The 1H NMR of 1
recorded in CDCl3 is shown in Figure 1, which clearly dem-
onstrated the expected C3-symmetry of 1. The spectrum
showed the presence of two resonances for the aryl protons
and a characteristic singlet for the methylene spacers.
In summary, we have synthesized the C3-symmetrical
pyridinophane 1 by improving the synthesis of Miyahara
and co-workers16 The key transformations were the forma-
tion of 5, which was achieved in water, the high yield of 6
and the use of Parker’s macrocyclization, which gave pre-
cursor 8 in both high yield and high purity. The transfor-
mation of this product to 1 was then achieved using hot
acid, which allows for the further functionalization of the
three amino moieties to give additional donor moieties
for the complexation of lanthanide ions such as Eu(III)
and Tb(III). This work will be reported in due course.
Acknowledgements
We thank TCD, School of Chemistry, Kinerton Ltd
(now Ibsen Ltd) and Higher Education Authority PRTLI
Cycle 1 for financial support, Dr. John E. O’Brien for
assisting with NMR and Professor Clive Williams for his
support during the course of this project.
References and notes
1. Pentecost, C. D.; Peters, A. J.; Chichak, K. S.; Cave, G. W. V.;
Cantrill, S. J.; Stoddart, J. F. Angew. Chem., Int. Ed. 2006, 45, 4099;
Chichak, K. S.; Cantrill, S. J.; Pease, A. R.; Chui, S.-H.; Cave, G. W.
V.; Atwood, J. L.; Stoddart, J. F. Science 2004, 304, 1308.
2. Leonard, J. P.; Jensen, P.; McCabe, T.; O’Brien, J. E.; Peacock, R. D.;
Kruger, P. E.; Gunnlaugsson, T. J. Am. Chem. Soc. 2007, 129, 10986;
Nitschke, J. R. Acc. Chem. Res. 2007, 40, 103; Goetz, S.; Kruger, P. E.
Dalton Trans. 2006, 1277; Fujita, M.; Tominaga, M.; Hori, A.;
Therrien, B. Acc. Chem. Res. 2005, 38, 371.
´
3. Gunnlaugsson, T.; Glynn, M.; Tocci (nee Hussey), G. M.; Kruger, P.
E.; Pfeffer, F. M. Coord. Chem. Rev. 2006, 250, 3094; Callan, J. F.; de
Silva, A. P.; Magri, D. C. Tetrahedron 2005, 36, 8551; Faulkner, S.;
Pope, S. J. A.; Burton-Pye, B. P. Appl. Spectrosc. Rev. 2004, 40, 1; de
Silva, A. P.; McCaughan, B.; McKinney, B. O. F.; Querol, M. Dalton
Trans. 2003, 1902.
4. Quinlan, E.; Matthews, S. E.; Gunnlaugsson, T. J. Org. Chem. 2007,
72, 7497; Quinlan, E.; Matthews, S. E.; Gunnlaugsson, T. Tetrahedron
Lett. 2006, 47, 9333; Matthews, S. E.; Beer, P. D. Supramol. Chem.
2005, 17, 411; Cao, Y. D.; Wang, L. Y.; Bolte, M.; Vysotsky, M. O.;
Bo¨hmer, V. Chem. Commun. 2005, 3132.
5. Parker, D.; Dickins, R. S.; Puschmann, H.; Cossland, C.; Howard, J.
A. K. Chem. Rev. 2002, 102, 1977; Gunnlaugsson, T.; Bichell, B.;
Nolan, C. Tetrahedron Lett. 2002, 43, 4989; Gunnlaugsson, T.;
Nieuwenhuyzen, M.; Richard, L.; Thoss, V. Tetrahedron Lett. 2001,
42, 4725.
6. Serreli, V.; Lee, C. F.; Kay, E. R.; Leigh, D. A. Nature 2007, 445, 523;
Kay, E. R.; Leigh, D. A.; Zerbetto, F. Angew. Chem., Int. Ed. 2007,
46, 72.
7. Galaup, C.; Couchet, J. M.; Picard, C.; Tisnes, P. Tetrahedron Lett.
2001, 42, 6275; Galaup, C.; Carrie, M. C.; Azema, J.; Picard, C.
Tetrahedron Lett. 1998, 39, 1573.
8. Gunnlaugsson, T.; Leonard, J. P. Dalton Trans. 2005, 3204; Alexan-
der, V. Chem. Rev. 1995, 95, 273.
9. Gunnlaugsson, T.; Stomeo, F. Org. Biomol. Chem. 2007, 5, 1999;
Ha
Hb
Bunzli, J.-C. G.; Piguet, C. Chem. Rev. 2002, 102, 1897; Sammes, P.
¨
Hb
Hc
G.; Yahioglu, G. Nat. Prod. Rep. 1996, 13, 1.
N
10. Gunnlaugsson, T.; Leonard, J. P. Chem. Commun. 2005, 3114;
Leonard, J. P.; Gunnlaugsson, T. J. Fluoresc. 2005, 15, 585.
11. Fanning, A.-M.; Plush, S. E.; Gunnlaugsson, T. Chem. Commun.
2006, 3791; Gunnlaugsson, T.; Harte, A. J. Org. Biomol. Chem. 2006,
4, 1572; Gunnlaugsson, T.; Davies, R. J. H.; Kruger, P. E.; Jensen, P.;
McCabe, T.; Mulready, S.; O’Brien, J. E.; Stevenson, C. S.; Fanning,
A.-M. Tetrahedron Lett. 2005, 46, 376; Gunnlaugsson, T.; Davies, R.
J. H.; Nieuwehuyzen, M.; O’Brien, J. E.; Stevenson, C. S.; Viguier, R.;
Mulready, S. Polyhedron 2003, 22, 711; Gunnlaugsson, T.; Davies, R.
J. H.; Nieuwehuyzen, M.; Stevenson, C. S.; Viguier, R.; Mulready, S.
Chem. Commun. 2002, 2136.
NH
N
HN
N
Ha
Hc
H
N
7.70
7.60
7.50
7.40
7.30
7.20
7.10
(ppm)
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
(ppm)
12. Massue, J.; Plush, S. E.; Bonnet, C. S.; Moore, D. A.; Gunnlaugsson,
T. Tetrahedron Lett. 2007, 48, 8052; Harte, A. J.; Gunnlaugsson, T.
Fig. 1. The 1H NMR (400 MHz) of 1 recorded in CDCl3.

1996
C. Nolan, T. Gunnlaugsson / Tetrahedron Letters 49 (2008) 1993–1996
Tetrahedron Lett. 2006, 47, 6321; Gunnlaugsson, T.; Brougham, D.
F.; Fanning, A.-M.; Nieuwehuyzen, M.; O’Brien, J. E.; Viguier, R.
17. Newcomb, M.; Timoko, J.; Walba, D.; Cram, D. J. J. Am. Chem. Soc.
1977, 99, 1875.
Org. Lett. 2004, 6, 4805.
13. Leonard, J. P.; de Santos, C. M. G.; Plush, S. E.; McCabe, T.;
Gunnlaugsson, T. Chem. Commun. 2007, 129; dos Santos, C. M. G.;
18. Rabjohn, W. Org. Synth. 1963, Coll. Vol. IV, 921–923.
19. Hosseini, M. W.; Camarmond, J.; Lehn, J. M. Helv. Chim. Acta 1989,
72, 1066; Che, C.-M. Polyhedron 1994, 13, 771.
´
Fernandez, P. B.; Plush, S. E.; Leonard, J. P.; Gunnlaugsson, T.
20. Macrocyclic Synthesis—A Practical Approach; Parker, D., Ed.;
Oxford University Press, 1996; Chapters 1–3. See also: Gerbeleu, N.
V., Arion, V. B., Burgess, J., Eds.; Template Synthesis of Macrocyclic
Compounds, S.M. Nelson, Wiley-VCH, 1998; Chapter 3.
21. Analyses were in agreement with those reported by Miyahara and co-
workers16 1H NMR (400 MHz, CDCl3): d 7.68 (6H, d, J = 8.04 Hz,
Ar–CH(tosyl)), 7.44 (3H, t, J = 7.52 Hz, Ar–CH(pyridine)), 7.29 (6H,
m), 7.14 (6 H, d, J = 7.52, Ar–CH(pyridine)), 4.30 (12H, s, CH2), 2.44
(9H, s, CH3); ES-MS: m/z 822.7 (M+).
Chem. Commun. 2007, 3389; Plush, S. E.; Gunnlaugsson, T. Org. Lett.
2007, 9, 1919; McCoy, C. P.; Stomeo, F.; Plush, S. E.; Gunnlaugsson,
T. Chem. Mater. 2006, 18, 4336–4343; Seneshal-David, K.; Pope, S. J.
A.; Quinn, S.; Faulkner, S.; Gunnlaugsson, T. Inorg. Chem. 2006, 45,
10040; Harte, A. J.; Jensen, P.; Plush, S. E.; Kruger, P. E.;
Gunnlaugsson, T. Inorg. Chem. 2006, 45, 9465; Gunnlaugsson, T.;
Harte, A. J.; Leonard, J. P.; Nieuwenhuyzen, M. Supramol. Chem.
2003, 15, 505.
´ ´
14. Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Chem. Rev.
1999, 99, 2293.
15. Kaptein, G. J. Org. Chem. 1990, 55, 811.
16. Lee, G.; Oka, M.; Takemura, M.; Miyahara, Y.; Shimizu, N.; Inazu,
T. J. Org. Chem. 1996, 61, 8304; Lee, G.; Miyahara, Y.; Inazu, T.
Chem. Lett. 1996, 873.
22. Analyses were in agreement with those reported by Miyahara and co-
workers:16 1H NMR (400 MHz, CDCl3): d 7.57 (3H, t, J = 7.56 Hz,
Ar–CH), 7.12 (6H, d, J = 7.52 Hz, Ar–CH), 3.97 (12H, s, CH2), 2.01
(3H, s, b, NH); ES-MS: m/z 361.4 (M+).
23. This product was very pure when the reaction was carried out using a
low concentration of 8.