Synthesis and structural properties of hexaaza[5]helicene containing two [1,2,3]triazolo[1,5-a]pyridine moieties

Article abstract of DOI:10.1016/j.tetlet.2013.06.014

We have synthesized a novel hexaaza[5]helicene in a straightforward way from neocuproine. The crystal structure has been elucidated with direct-space strategy TALP which demonstrates the power of the powder X-ray diffraction technique. In this crystal structure it is possible to see an interplanar angle of 33(1) between the two triazolopyridine rings. The centrosymmetric crystal structure is a racemic mixture, but the resolution was not possible due to a ring-chain isomerization in a solution that produces a dynamic racemization.

Full text of DOI:10.1016/j.tetlet.2013.06.014

Tetrahedron Letters 54 (2013) 4316–4319
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and structural properties of hexaaza[5]helicene containing
q
two [1,2,3]triazolo[1,5-a]pyridine moieties
Rosa Adam , Rafael Ballesteros-Garrido , Oriol Vallcorba , Belén Abarca , Rafael Ballesteros a,
⇑
,
a
b
c
a,
⇑
b
b
d
c,
⇑
Frédéric R. Leroux , Françoise Colobert , José M. Amigó , Jordi Rius
a
Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Valencia, Avd. Vte. Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain
Laboratoire de Stéréochimie, CNRS, Université de Strasbourg (ECPM), 25 rue Becquerel, 67087 Strasbourg, France
Institut de Ciencia de Materials de Barcelona, CSIC, Campus de la UAB, 08193 Bellaterra, Catalunya, Spain
b
c
d
Departamento de Geología, Facultad de Biológicas, Universidad de Valencia, C/Dr. Moliner s/n, 46960 Burjassot, Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
We have synthesized a novel hexaaza[5]helicene in a straightforward way from neocuproine. The crystal
structure has been elucidated with direct-space strategy TALP which demonstrates the power of the pow-
der X-ray diffraction technique. In this crystal structure it is possible to see an interplanar angle of 33(1)°
between the two triazolopyridine rings. The centrosymmetric crystal structure is a racemic mixture, but
the resolution was not possible due to a ring-chain isomerization in a solution that produces a dynamic
racemization.
Received 8 May 2013
Revised 31 May 2013
Accepted 5 June 2013
Available online 13 June 2013
Keywords:
Azahelicenes
Ó 2013 Elsevier Ltd. All rights reserved.
Nitrogen heterocycles
Chirality
X-ray diffraction
Triazolopyridines
Introduction
Results and discussion
When some ortho-fused benzene rings are arranged in non planar
screw-shaped skeletons, the steric hindrance of the terminal rings
and/or the repulsion between the substituents present force the
molecule to adopt a helical conformation.1 These structures are
known as helicenes which present fascinating left- or right-handed
chiral helical structures. This structural motif has generated an enor-
mous work concerning the synthesis, the enantiomeric resolution
and the study of their properties: structural, spectroscopic and opti-
In order to reach this structure, we have employed neocuproine
5 as the starting material. By oxidation with selenium dioxide in
1
0
dioxane, the corresponding dialdehyde 6 was obtained in high
yield (94%), dihydrazone formation and further oxidation with
1
1
manganese dioxide in chloroform led to bis-([1,2,3]triazolo)
0
0
[1,5-a:5 ,1 -k][1,10]phenanthroline
1 in 60% yield by ether
2
cal. Hetero[n]helicenes are a special type of helicenes, where a ben-
2
–4
zene ring is replaced by one or more aromatic heterocyclic rings.
Herein we reportthe preparation and structural properties of a novel
bis-triazolopyridine-based aza[5]helicene 1 with a strong helical
deformation and a torsion angle of 33° (Fig. 1).
N
N
N
N
N
N
R'
N
N
R
1
2
In our previous studies on the chemistry of [1,2,3]triazolo[1,5-
5
a]pyridines 3 we found these compounds as a valuable tool to ob-
Figure 1. Heterohelicenes.
6
tain dimers 4 (Fig. 2). Taking into account the structure of azah-
elicenes 2 reported by Staab and Stará8 we have designed a new
structure with an extra aromatic ring in our dimer 4. This new
compound 1 should adopt a helical conformation.9
7
N
N
N
N
N
N
N
N
N
N
q
R
R
R
R
R
In Memory of Professor José Sepulveda.
N
N
N
N
N
⇑
Corresponding authors. Tel.: +34 963543054.
E-mail addresses: Belen.Abarca@uv.es (B. Abarca), Rafael.Ballesteros@uv.es
3
4
1 R = H
(
R. Ballesteros).
Figure 2. Previous results and target compound.
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.014

R. Adam et al. / Tetrahedron Letters 54 (2013) 4316–4319
4317
precipitation.12 As a result, compound 1 was obtained from neo-
cuproine 5 in three steps (Scheme 1), in global yield of 56%.
The characterization of compound 1 was realized initially by
a
b
N
N
N
N
N
N
H
H
H
H
6
standard procedures such as NMR in DMSO-d , HRMS, TCR-FTIR,
H C
CH3
3
O
O
NNH2 H NN
2
and UV, (see the Supplementary data). It is a stable solid that
decomposes exothermically at 200 °C (see DSC and TG study in
Supplementary data S4, S5).
5
6
c
Compound 1 is highly insoluble in many organic solvents mak-
ing it difficult to grow suitable crystals for single-crystal diffraction
studies. Consequently, a transmission powder X-ray diffraction
experiment with the sample included in a capillary was carried
out to confirm the helical structure of 1.
N
N
N
N
N
N
1
Scheme 1. Reagents and conditions: (a) SeO
h, 94%; (b) H NNH , MeOH, 25 °C, 20 h, 75%; (c) MnO
2
, dioxane/water (95:5 vol/vol) reflux
, Cl CH, reflux, 24 h, 80%.
The structure was solved from powder data using the direct-
2
2
2
2
3
1
3
space method TALP. Bond, angle and plane restraints were taken
1
4
from the reported structure DBPHEN02 and low weights were as-
signed to allow model distortion during structure solution. Crystal
data from final restrained Rietveld refinement with RIBOLS15 are
given in Ref. 16. The resulting helical structure shows an interpla-
nar angle of 33(1)° and confirms the structure of hexaaza[5]heli-
0
0
cene as bis([1,2,3]triazolo)[1,5-a:5 ,1 -k][1,10] phenanthroline 1
1
6
(
Fig. 3). This distortion is similar to those described in other
a
N
N
N
N
O O
N
N
N
O S
N
N
N
O
1
7
Figure 3. Molecular structure of 1 from powder X-ray diffraction data showing the
interplanar angle of 33(1)° between the two triazolopyridine rings.
Scheme 2. Triazolo ring opening with loss of N
acid in DMSO.
2
. a = (1R)-(ꢀ)-10-camphorsulfonic
Figure 4. Crystal packing obtained for 1: (a) general view showing the two enantiomers (P)-1 and (M)-1 and the p-stacking. (b) c-Axis and (c) b-axis projections of the crystal
structure.

4
318
R. Adam et al. / Tetrahedron Letters 54 (2013) 4316–4319
[
5]helicenes17 and, in this case, may be helped by repulsion be-
Several strategies were performed in order to isolate both enan-
tiomers. First, chiral HPLC, decomposition being the major ob-
served phenomena. In order to avoid this, we tried to form
1
8
tween electron lone pairs of nitrogen atoms.
The centrosymmetric crystal structure of 1 is a racemic mixture,
and the two enantiomers (P)-1 and (M)-1 can be identified (Fig. 4).
The most significant intermolecular interaction which establishes
diastereomeric salts. We treated compound 1 with L-ascorbic acid,
L
-tartaric acid and (R)-(ꢀ)-camphorsulfonic acid, following the
1
the crystal packing is the
p-stacking between central phenyl rings
behaviour of 1 by H NMR. (Supplementary data Fig. S8). In the
cases of treatment with ascorbic and tartaric acids no changes in
the spectra were observed, while in the case of using camphorsul-
fonic acid a fast gas evolution was observed, and a new compound,
identified as 7, was formed by a triazolo ring opening with loss of
with a distance of 3.668(6) Å between ring centroids. This powder
X-ray diffraction technique used must be outlined as a powerful
tool for structure resolution in highly insoluble compounds which
are difficult to crystallize (like compound 1).
2
N (see Scheme 2). This behaviour is well known in triazolopyri-
1
9
dines. Interestingly compound 7 was obtained as a unique enan-
tiomer, the absence of one of the two triazolo moieties makes the
aromatic part of the molecule planar.
1
(P)
1(M)
N
N
Also it is known that [1,2,3]triazolo[1,5-a]pyridines or [1,2,3]
triazolo[1,5-a]quinolines present in solution a tautomeric equilib-
rium between an open form, that can be considered as a diazo
N
N
N
2
8
5
a,20
Scheme 3. Racemization based on the tautomeric equilibrium of compound 1 in
compound, and the corresponding heterocycle,
demonstrated for triazolopyridines.
as Wentrup
2
1
solution.
We presume that compound 1 must also have this property,
and, as a consequence, a dynamic conversion between P and M
enantiomers in solution could exist. (Scheme 3) Our hypothesis
H
D
2
D O
N
N
is that, the triazolo ring opening must lead to a planar struc-
N
N
N
N
N
7a,22
ture,
to obtain intermediate 8 that should be responsible of
the enantio conversion.
Wentrup demonstrated the ring-chain equilibrium in [1,2,3]
triazolo[1,5-a]pyridines by deuteration experiments (Scheme 4).
In our case, we performed deuteration experiments of com-
pound 1 demonstrating also the presence of this equilibrium. In
H
H
D
D
21
N
N
N
N
N
N
N
N
a solution of D
change of protons by deuterium in 3 and 10 positions (compound
-d , Scheme 5, Fig. 5). This exchange has shown to be strongly cat-
alysed by the addition of NaOD. The presence of 1-d is considered
2 7
O/DMF-d compound 1 suffers a complete ex-
Scheme 4. General mechanism for the deuteration in triazolo pyridines.
1
2
2
as a direct proof of the existence of open forms, thus the planar
structure and a dynamic enantio conversion at 25 °C.
a
N
N
N
N
N
N
N
N
Elguero and co-workers have demonstrated for 1-aza[5]helic-
enes, that these compounds have low racemization barriers.4 The
fact that compound 1 is a [5]helicene with two five member rings,
and the slow kinetics of deuteration process, do demonstrate that
D
D
N
N
N
N
1
1-d2
Scheme 5. Deuteration of compound 1 in solution ((a): D
2
7
O/ DMF-d with NaOD).
Figure 5. 1H NMR of compound 1 in d
-DMF/D O at different times.
7 2

R. Adam et al. / Tetrahedron Letters 54 (2013) 4316–4319
4319
we cannot reject another possible mechanism of racemization
based on its flexibility.
Strained Hydrocarbons: Beyond the van’t Hoff and Le Bel Hypothesis; Dodziuk, H.,
Ed.; Wiley-VCH, 2009; pp 166–176. Chapter 4; (f) Collins, S. K.; Vachon, M. P.
Org. Biomol. Chem. 2006, 4, 2518–2524; (g) Urbano, A. Angew. Chem., Int. Ed.
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Dumitrascu, F.; Dumitrescu, D. G.; Aron, I. ARKIVOC 2010, 1–32.
Alkorta, I.; Blanco, F.; Elguero, J.; Schroeder, D. Tetrahedron: Asymmetry 2010,
Conclusions
2
1, 962–968. and references cited herein.
In summary, we have synthesized a novel hexaaza[5]helicene in
a straightforward way as a racemic mixture, being the first azahe-
licene containing two triazolopyridine moieties. The crystal struc-
ture has been elucidated with direct-space strategy TALP13 which
demonstrates the power of the powder X-ray diffraction technique.
This compound could be one of the rare examples of dynamic con-
version between enantiomers of helicenes. A theoretical study will
be performed in the future to calculate the energy implied in the
racemization process, trying to understand better the mechanism
of the enantio conversion of this compound.
5. The chemistry of [1,2,3]triazolo[1,5-a]pyridines has been revised (a) Jones, G.;
Sliskovic, D. R. Adv. Heterocycl. Chem. 1983, 34, 79–143; (b) Jones, G. Adv.
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002, 17, 359–367; (d) Jones, G.; Abarca, B. Adv. Heterocycl. Chem. 2010, 100,
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6. (a) Jones, G.; Pitman, M. A.; Lunct, E.; Lythgoe, D. J.; Abarca, B.; Ballesteros, R.;
Elmasnaouy, M. Tetrahedron 1997, 53, 8257–8268; (b) Abarca, B.; Ballesteros,
R.; Elmasnaouy, M. Tetrahedron 1998, 54, 15287–15292.
7
8
9
.
.
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(a) Krieger, C.; Newsom, I.; Zirnstein, M. A.; Staab, H. A. Angew. Chem., Int. Ed.
1989, 28, 84–86; (b) Staab, H. A.; Zirnstein, M. A.; Krieger, C. Angew. Chem., Int.
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1
994, 35, 8357–8360.
(a) Mísek, J.; Tepl y´ , F.; Stará, I. G.; Tich y´ , M.; Saman, D.; Cisarroá, I.; Vojtísek, P.;
Stary, I. Angew. Chem., Int. Ed. 2008, 47, 3188–3191; (b) Songis, O.; Misek, J.;
Schmid, M. B.; Kollarovie, A.; Stara, I. G.; Saman, D.; Cisarova, I.; Stary, I. J. Org.
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In similar manner as N,N’-phenantrolinium dioxide Rozen, S.; Dayan, S. Angew.
Chem., Int. Ed. 1999, 38, 3472–3473.
0. Abusshamled, A. S.; Goodwin, H. A. Aust. J. Chem. 1980, 33, 2171–2179.
1. Standard method for preparation of [1,2,3]triazolo[1,5-a]pyridines, see Ref. 6b.
2. Compound 1 decomposes partially under chromatographic conditions, either
in silica or alumina. In chiral reverse phase HPLC analytical columns also
decomposes.
Acknowledgments
We are grateful to the Ministerio de Ciencia e Innovación
1
1
1
(
0
Spain) (Projects CONSOLIDER-INGENIO SUPRAMED CSD 2010-
0065 and MAT2009-07967), to Generalitat Valenciana (Valencia,
Spain) (project PROMETEO 2011/008) for its financial support,
and to the SCSIE for the realization of HRMS spectra and prelimin-
ary XRD. R.A. thanks Generalitat Valenciana for a doctoral fellow-
ship and O.V. thanks CSIC for a contract (PIE 201060E068). The
transmission XRPD pattern was collected at the CCiT of University
of Barcelona.
1
3. Vallcorba, O.; Rius, J.; Frontera, C.; Miravitlles, C. Acta Crystallogr. 2011, A67,
C272.
14. Kuroda, R. J. Chem. Soc., Perkin Trans. 2 1982, 789–794.
15. Rius, J. RIBOLS18 A Computer Program for Least-Squares Refinement from Powder
Diffraction Data; Institut de Ci e` ncia de Materials de Barcelona (CSIC):
Barcelona, Spain, 2009.
16. Crystal data for 1: C14H8N6, MW = 260.26, monoclinic, space group P21/a,
a = 15.2222(13), b = 10.0823(8), c = 7.5904(3) Å, b = 99.796(3)°,
Supplementary data
3
V = 1147.95(14) Å , Z = 4, T = 298 K. Refinement details: 70 parameters, 106
restraints, 500 reflections, Rwp = 0.115, goodness of fit = 3.534. CCD886043
contains the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via: www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
0
6.014.
1
1
1
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8. CHIRALPACK IC column or a CHIRACEL ODH column in reverse phase, iPrOH/
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012, 112, 1463–1535; (d) Stara, I.; Stary, I. G. In Aromatic Ring Assemblies,
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