Fusing triazoles: Toward extending aromaticity

Article abstract of DOI:10.1021/ol201290q

A novel method to extend aromaticity by one benzene and two triazole rings was developed and optimized. This two-step route employs the copper-catalyzed azide-haloalkyne cycloaddition reaction of an ortho-bis(iodoacetylene) system and the subsequent intra

Full text of DOI:10.1021/ol201290q

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3494–3497
Fusing Triazoles: Toward Extending
Aromaticity
ꢀ
´
Michal Jurıcek, Kathleen Stout, Paul H. J. Kouwer, and Alan E. Rowan*
Institute for Molecules and Materials, Radboud University Nijmegen,
Department of Molecular Materials, Heyendaalseweg 135, 6525 AJ Nijmegen,
The Netherlands
a.rowan@science.ru.nl
Received May 13, 2011
ABSTRACT
A novel method to extend aromaticity by one benzene and two triazole rings was developed and optimized. This two-step route employs the
copper-catalyzed azideÀhaloalkyne cycloaddition reaction of an ortho-bis(iodoacetylene) system and the subsequent intramolecular
homocoupling fusion of the neighboring iodotriazoles, a process in which an additional benzene ring is formed. This versatile methodology
allows one to extend the core size of chromophores and, consequently, to tune the material’s properties.
Chromophoric (or dye) molecules, both natural and
synthetic, belong to one of the oldest classes of materials
that have fascinated scientists for more than a century.
Their structure is comprised of a smaller or larger 2D
(hetero)aromatic core, often equipped with solubilizing
substituents on the periphery. A characteristic feature of
a dye core is an extended π-structure, which results in the
red shift of the absorption maximum of these molecules
(usually into the visible or NIR region) and their ability
to self-assemble by means of πÀπ interactions. Polycyclic
aromatic hydrocarbons (PAHs)1 and their analogues re-
present probably the most diverse subclass of dye mole-
cules, with applications varying from fluorescent dyes to
organic semiconductors.2 Other typical examples in-
clude porphyrins,3 phthalocyanines,3,4 perylenes,5 and
BODIPYs,6 among many others.
to extend their (hetero)aromatic cores by one additional
π-conjugated unit, the benzene ring being one of the most
commonly used moieties. The most powerful transforma-
tions to extend aromaticity by an additional fused
benzene unit are the Bergman cyclization7 (A) and the
cyclodehydrogenation8 (B) reactions (Scheme 1).
Scheme 1. Synthetic Transformations of 1À5 Extending the
Core Size by an Extra Benzene Ring: Bergman Cyclization (A),
Cyclodehydrogenation (B), and Homocoupling (C; 4: X = Br;
5: X = I) Reactions
From the perspective of making π-conjugated dye struc-
tures, numerous synthetic strategies have been developed
€
(1) Rieger, R.; Mullen, K. J. Phys. Org. Chem. 2010, 23, 315–325.
€
(2) Wu, J.; Pisula, W.; Mullen, K. Chem. Rev. 2007, 107, 718–747.
(3) The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard, R.,
Eds.; Academic: San Diego, 2003.
(4) (a) Volume on “Functional Phthalocyanine Molecular Materi-
als:” Struct. Bonding (Berlin) 2010, 135, 1À325. (b) de la Torre, G.;
Claessens, C. G.; Torres, T. Chem. Commun. 2007, 2000–2015.
€
(5) Weil, T.; Vosch, T.; Hofkens, J.; Peneva, K.; Mullen, K. Angew.
Chem., Int. Ed. 2010, 49, 9068–9093.
(6) Loudet, A.; Burgess, K. Chem. Rev. 2007, 107, 4891–4932.
In the first case, an additional fused benzene unit is
obtained by the thermal cycloaromatization reaction of an
r
10.1021/ol201290q
Published on Web 06/07/2011
2011 American Chemical Society

enediyne system (1); in the latter case, the benzene ring is
formed upon the Lewis-acid-catalyzed oxidative coupling
of two ortho-localized phenyl rings (2). The second method
is of particular interest and to date, represents the most
efficient tool to access PAHs, as well-defined cut-outs of
graphene.1,2,8a
of this methodology are known in the literature.12,13
Among these, two methods employing a catalytic amount
of the Cu(I) source are of special interest, and these were
tested in the preparation of 4 and 5.
The first procedure employs the CuAHAC reaction of
bromoacetylenes with various azides, using a catalytic
amount of Cu(I)/Cu(II) species without the presence of a
ligand, to obtain 5-bromo-1,4-disubstituted triazoles;12b
the second method employs the CuAHAC reaction of
iodoacetylenes and a catalytic amount of CuI and tris-
(triazolyl)-derived ligand, to obtain 5-iodo-1,4-disubsti-
tuted triazoles.12a For the latter, the three-step one-pot
procedure, including the iodoacetylene formation, CuA-
HAC, and subsequent cross-coupling reactions, proved
also to be very efficient.
The major challenge that needs to be addressed when
building up larger aromatic structures is to retain the
efficiency of each step upon the increase of the core size;
an issue associated with the restricted solubility of larger
cores when solubilizing tails can only be introduced in the
final stage of the synthesis. In the course of our studies on
employing the triazole moiety as an aromaticity-extending
building block,9 it was of interest to probe whether a
bis(triazole) system similar to the bis(phenyl) system 2
could be employed to construct an additional fused
benzene unit. The triazole ring can be obtained using
the powerful Cu-catalyzed azideÀalkyne cycloaddition
(CuAAC) reaction:10 a versatile alternative method.
Initially, three ortho-bis(triazole) systems 3, 4, and 5
were investigated as the precursors for the synthesis of the
fused product 6. Compared with 3À5, aromaticity in 6 is
extended by an additional benzene and two triazole rings,
which, in principle, can be achieved by either the cyclode-
hydrogenation (B) or homocoupling (C) reactions. The
preliminary studies, performed on analogues of 3 by using
method B, did not lead to the formation of the desired
fused products. Thus, method C (4 and 5) was subse-
quently investigated and optimized. The results are
reported below.
The scope and limitations of the CuAHAC reaction of
bis(haloacetylenes) 7 (X = Br) and 8 (X = I) with various
azides (11), to obtain 4 and 5, respectively, were investi-
gated, and the results are summarized in Table 1.
Table 1. CuAHAC Reaction of 7 and 8
Precursors 4 and 5 possess two 1,4,5-trisubstituted tria-
zole rings, bearing a halogen atom (Br or I, respectively) in
the 5-position, and were prepared using the Cu-catalyzed
azideÀhaloalkyne cycloaddition (CuAHAC) method.11
This method employs terminal acetylenes bearing a halo-
genatominsteadofaproton, andtodate, several variations
(7) For examples, see: (a) Nath, M.; Pink, M.; Zaleski, J. M. J. Am.
Chem. Soc. 2005, 127, 478–479. (b) Bowles, D. M.; Anthony, J. E. Org.
Lett. 2000, 2, 85–87.
yield (%)
catalyst
(%)
ligand
(%)
€
(8) (a) Wu, J.; Pisula, W.; Mullen, K. Chem. Rev. 2007, 107, 718–747.
entry
1a
X
azide/R1
4/5
9/10
€
(b) Stabel, A.; Herwig, P.; Mullen, K.; Rabe, J. P. Angew. Chem., Int. Ed.
1995, 34, 1609–1611.
b
Br 11a/C11H23 CuBr (40)
Cu(OAc)2 (40)
Br 11a/C11H23 CuI (10)
Cu(OAc)2 (10)
11a/C11H23 CuI (20)
À
4 (10)
9 (16)
ꢀ
(9) Jurıcek, M.; Kouwer, P. H. J.; Rowan, A. E. Chem. Commun.
2011, DOI: 10.1039/c1031cc10685f.
b
2a
À
4 (16)
9 (23)
(10) (a) Themed issue (4) on “Applications of Click Chemistry:”
Chem. Soc. Rev. 2010, 39, 1221À1408. (b) Click Chemistry for Biotech-
nology and Materials Science; Laham, J., Ed.; Wiley: Chichester, 2009. (c)
Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952–3015. (d) Wu, P.;
Fokin, V. V. Aldrichimica Acta 2007, 40, 7–17. (e) Moses, J. E.;
Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249–1262. (f) Tornøe,
C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057–3064.
(g) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599.
(11) For reviews, see: (a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev.
2010, 39, 1302–1315. (b) Spiteri, C.; Moses, J. E. Angew. Chem., Int. Ed.
2010, 49, 31–33.
(12) (a) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.;
Fokin, V. V. Angew. Chem., Int. Ed. 2009, 48, 8018–8021. (b) Kuijpers,
B. H. M.; Dijkmans, G. C. T.; Groothuys, S.; Quaedflieg, P. J. L. M.;
Blaauw, R. H.; van Delft, F. L.; Rutjes, F. P. J. T. Synlett 2005, 3059–
3062. (c) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005, 1314–
1318.
3c
4c
5c
6c
7c
I
I
I
I
I
12b (20) 5a (47) n.i.d
12a (20) 5a (54) n.i.d
12a (20) 5a (48)e n.i.d
12b (20) 5b (39) n.i.d
12a (20) 5c (82) n.i.d
11a/C11H23 CuI (20)
11a/C11H23 CuI (20)
11b/Ph
11c/TEGf
CuI (20)
CuI (20)
a 7 (1 equiv), azide (6 equiv), THF, 50 °C, 5 d. b CuX is acting as a
heterogeneous catalyst; Cu(OAc)2 is soluble under these conditions. c
8
(1 equiv), azide (2.2 equiv), THF, rt, 65 h. d Not isolated. e 43 h. f TEG =
CH2O(CH2CH2O)2CH3.
Bis(haloacetylenes) 77b and 8 were prepared starting
from 1,2-diethynylbenzene (1) or its protected analogue
(13) Additionally, other methods for the preparation of 1,4,5-trisub-
stituted triazoles are known in the literature; for a review, see:
Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8,
4503–4513.
(14) (a) Lee, T.; Kang, H. R.; Kim, S.; Kim, S. Tetrahedron 2006, 62,
4081–4085. (b) Leroy, J. Synth. Commun. 1992, 22, 567–572.
Org. Lett., Vol. 13, No. 13, 2011
3495

(see the Supporting Information) in one step following
literature procedures.14 Compared with literature, longer
reaction times (>65 h) for the CuAHAC reactions were
applied and moderate to good yields of the desired prod-
ucts were obtained, most likely due to the partial decom-
position of the starting materials 7 and 8 under the applied
reaction conditions.15
Scheme 2. Intermolecular Homocoupling Reaction of 14
To compare the efficiencies of the two previously de-
scribed CuAHAC protocols using either 7 and Cu(I)/
Cu(II)12b or 8 and CuI/1212a as catalytic systems, 1-azido-
dodecane (11a) was used as an azide precursor (Table 1,
entries 1À5). From the yields of the desired product 4/5 and
its monoclicked side product 9/10, it can be concluded that
the efficiency of the CuAHAC reactions using 8 is signifi-
cantly higher (entries 3À5), when compared with 7 (entries 1
and 2), with the highest yield obtained when 12a was used as
a ligand (entry 4). The yield of this reaction was still
increasing after the period of 43 h; thus, a prolonged
reaction time (65 h) was applied when using this method
(entries 4 and 5).
The effect of the R group of the azide on the yield of
the desired product 5 during the CuAHAC reaction
using 8 was also studied (entries 3/6 and 4/7). The use
of (azidomethyl)benzene (11b) led to a small decrease
(8%) in yield compared with 11a (entries 3 and 6);
the use of 1-azido-2-(2-(2-methoxyethoxy)ethoxy)ethane
(11c) led to a significant increase in yield (28 and 43%)
compared with both 11a and 11b, respectively (entries 4/
7 and 6/7). The reason for such a dramatic difference in
the reactivity of this series of azides attached to a
primary carbon is not known; the decrease in yield in
the case of 11b compared to 11a, however, is tentatively
attributed to the steric reasons.
not afford the desired product 15. Instead, the product of
protodehalogenation 16 and the recovered starting material
14 were obtained in 82% and 18% yield, respectively. This
was possibly due to the steric hindrance of the bulky
substituents in the 1- and 4-positions (both ortho relative
to the iodine substituent in the 5-position); the protodeha-
logenation product 16 was possibly formed from the oxida-
tive-addition intermediate via the β-H-atom elimination/
reductive elimination mechanism (DIPEA being the source
of the β-H-atom when coordinated to Pd(II)).
Interestingly, when the intramolecular homocoupling re-
action of bis(iodotriazoles) 5aÀ5c was carried out to afford
the key intermediate 6 using the same reaction conditions,
the desired products 6aÀ6c were formed in moderate to
good yields (Table 2); possibly, this reaction was partially
inhibited by protodehalogenation as the side reaction.
In the literature, several examples of the homocoupling
reactions of aryl halides are known, usually employing
morereactivehalideelectrophiles, namely, aryliodides and
aryl bromides.16 Since the CuAHAC reaction of bis-
(iodoacetylene) 8 proceeds significantly faster and more
efficiently compared to bis(bromoacetylene) 7, an intra-
molecular homocoupling reaction of bis(iodotriazoles)
5aÀ5cwas studied. An efficient method for the preparation
of biaryls, using a homocoupling reaction of aryl iodides
catalyzed by palladacycle catalyst 13, was previously de-
scribed in the literature;17 this methodology, however, was
not applied to the heteroaromatic systems. To test the
reactivity of 5-iodo-1,4-disubstituted triazoles in this reac-
tion, the intermolecular homocoupling reaction of iodo-
triazole 14 was first carried out (Scheme 2).
Table 2. Intramolecular Homocoupling Reaction of 5a
starting
compd
catalyst
(%)
product
(%)b
entry
R
1
2
3
4
5
6
7
5a
5a
5a
5b
5c
5c
5c
C11H23
1
6a (47)
C
C
11H23
11H23
2
6a (52)
4
6a (40)
Ph
1
6b (36)
Despite the electron-withdrawing character of the triazole
moiety, that is expected to facilitate the insertion of the Pd(0)
into the CÀI bond,17,18 the homocoupling reaction of 14 did
TEGc
TEGc
TEGc
1
6c•HX (71)d
6c•HX (80)d
6c•HX (66)d
0.5
0.5e
a 5 (1 equiv), DMF (c(5) = 0.40 M), DIPEA (1.2 equiv), 110 °C, 17 h.
b Isolated yield. c CH2O(CH2CH2O)2CH3. d Yield calculated for X = I.
e c(5) = 0.13 M.
(15) Both 7 and 8 are unstable, and upon their preparation, they were
immediately used in the next step or stored in the freezer. Compared with
relatively stable 8, compound 7 is significantly less stable and slowly
decomposes even at lower temperatures (freezer).
ꢁ
(16) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359–1469.
(17) Luo, F.-T.; Jeevanandam, A.; Basu, M. K. Tetrahedron Lett.
1998, 39, 7939–7942.
Similarly to the CuAHAC reaction, the homocoupling
reaction proceeded more efficiently (66À80%) in the case of
Org. Lett., Vol. 13, No. 13, 2011
(18) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
3496

5c (entries 5À7); in the case of 5a and 5c (entries 1À4), the
efficiencies were significantly lower (36 and 40À52%,
respectively). For 5a (entries 2À4) and 5c (entries 5À7),
optimization of the reaction conditions by varying the
amount of the catalyst was also carried out. In both cases,
a maximum efficiency was reached at a certain amount of
the catalyst (entries 3 and 6, respectively) that decreased
after further increase or decrease of the catalyst loading. To
favor the intramolecular reaction of 5c and suppress the
intermolecular reactions leading to oligomeric side pro-
ducts, the homocoupling reaction under dilute conditions
was carried out (entry 7). This, however, did not improve the
efficiency of this reaction and led to a 14% decrease in yield.
In the case of 5c, the desired product 6c was repeatedly
isolated as the monoprotonated salt 6c•HX, the counter-
anion most likely being iodide (X = I). We suggest that the
proton was possibly obtained from DIPEA via the same
reaction mechanism as in the case of the formation of 16,
when an inactive Pd(II) catalyst, obtained after one homo-
coupling cycle employing Pd(IV), was reduced to active
Pd(0). Washing of the organic solution of 6c•HX by strong
alkaline aqueous solutions did not afford the desired
deprotonated product 5c; probably, the protonation of
the N-2 nitrogen of the triazole was highly favored due to
the efficient stabilization of the proton by the three oxygen
atoms of the ethylene glycol tail through hydrogen bond-
ing (Table 2 figure). Protonation of the second triazole
moiety in 6c•HX was never observed, most likely due tothe
decreased electron density of the system caused by the first
protonation.
As mentioned before, our methodology allows one
to extend the aromaticity of a (hetero)aromatic core (by
one benzene and two triazole rings); this effect can clearly
Figure 1. (a) 1H NMR spectra in CDCl3 (7.26 ppm) of 5a and 6a:
insets of the aromatic region (the corresponding protons are
marked in the structure by using an “H” symbol); (b) Overlay of
the UVÀvis spectra of 5a and 6a in CHCl3 at 40 μM.
1
be observed in the H NMR and UVÀvis spectra of
compounds 5 and 6 (Figure 1). Compared with 5, the
aromatic-core 1H NMR signals of the fused product 6 are
significantly shifted downfield and a red-shifted shoulder
appears in the UVÀvis spectrum of 6.
three steps (iodoacetylene formation/CuAHAC/homo-
coupling). This methodology is of interest for the prepara-
tion of extended functional chromophoric materials with
potential applications in (opto)electronic devices.
Apart from extending aromaticity, our approach offers
another opportunity: the two fused triazole rings can, in
principle, serve to coordinate metals or as hydrogen-bond
acceptors and, thus, allow for a further tuning of the
material’s properties upon doping. As an example, this
synthetic approach has been applied by us in extending
functional chromophores based on phthalocyanines to
substituted napthalocyanines.9,19
Acknowledgment. The Nederlandse Organisatie voor
Wetenschappelijk Onderzoek (Netherlands Organisation
for Scientific Research, NWO), NanoNed, Vici (A.E.R.),
The Council for the Chemical Sciences of The Netherlands
Organisation for Scientific Research, and the European
ITNs (CHEXTAN, SUPERIOR and HIERARCHY) are
kindly acknowledged for financial support.
In summary, a novel approach to extend aromaticity
of (hetero)aromatic systems by one benzene and two
triazole rings was developed and optimized. The crucial
steps of this approach, the CuAHAC and the intramo-
lecular homocoupling reactions affording the key inter-
mediate 6, were optimized on a model system to proceed
in moderate to good overall yields (14À64%; over the
Supporting Information Available. Synthetic and char-
acterization details for each compound, and copies of the
1H and 13C NMR spectra for compounds 4, 5aÀ5c, 9, and
6aÀ6c. This material is available free of charge via the
Internet at http://pubs.acs.org.
ꢀ
(19) Jurıcek, M.; Stout, K.; Kouwer, P. H. J.; Rowan, A. E.
J. Porphyrins Phthalocyanines 2011, in press.
Org. Lett., Vol. 13, No. 13, 2011
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