A one-step synthesis towards new ligands based on aryl-functionalised thiazolo[5,4-d]thiazole chromophores

Article abstract of DOI:10.1016/j.tetlet.2010.07.172

A general synthesis of disubstituted thiazolo[5,4-d]thiazoles was achieved by condensing two equivalents of an aryl aldehyde with dithiooxamide in nitrobenzene at 130 °C for 24 h. The method is tolerant to a range of aromatic aldehydes including derivativ

Full text of DOI:10.1016/j.tetlet.2010.07.172

Tetrahedron Letters 51 (2010) 5419–5422
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A one-step synthesis towards new ligands based on aryl-functionalised
thiazolo[5,4-d]thiazole chromophores
⇑
Richard C. Knighton, Andrew J. Hallett, Benson M. Kariuki, Simon J. A. Pope
School of Chemistry, Main Building, Cardiff University, Park Place, Cardiff CF10 3AT, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A general synthesis of disubstituted thiazolo[5,4-d]thiazoles was achieved by condensing two equiva-
lents of an aryl aldehyde with dithiooxamide in nitrobenzene at 130 °C for 24 h. The method is tolerant
to a range of aromatic aldehydes including derivatives of pyridine, quinoline, mono- and dihydroxyben-
zene. An X-ray crystal structure of 2,5-bis(2-hydroxy-3,5-di-tert-butylphenyl)thiazolo[5,4-d]thiazole was
obtained confirming the proposed formulation, together with supporting spectroscopic data that sug-
gests that for the 2-hydroxyphenyl derivatives intramolecular hydrogen bonding exists in both solution
and solid states.
Received 2 July 2010
Revised 21 July 2010
Accepted 30 July 2010
Available online 6 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Thiazolo[5,4-d]thiazoles are an important class of bicyclic aro-
matic molecule comprising two fused thiazole rings (Fig. 1).1 Ini-
tially, these compounds were explored for their potential
biological activity,1b but recent effort has focused on their inclusion
in materials for applications such as semi-conducting polymers,2
field-effect transistors3 and optical devices (including electrolumi-
nescence and photovoltaics).4 Thiazolothiazoles have actually been
known for over a century: in 1891, Ephraim first reported the con-
densation of dithiooxamide (also often referred to as rubeanic acid)
with benzaldehyde.5 The product was obtained using excess benz-
aldehyde as the solvent under reflux, however, the precise identity
of the product was mis-assigned, only to be fully characterised in
subsequent studies by Johnson et al.6 From a synthetic perspective
the reported requirement of using the aldehyde as the solvent has
obvious limitations: firstly, the aldehyde must be liquid at the re-
quired temperature to affect cyclisation, and secondly, the large
excess of aldehyde implies cost limitations and restriction to sim-
pler substrates. More recently reported syntheses have utilised sol-
vents with higher boiling points,7 but still reported a need for
excess aldehyde to facilitate thiazolothiazole formation. The syn-
thesis of thiazolothiazoles is not confined to the condensation of
dithiooxamide: Seybold et al.8 reported the synthesis of a di(ace-
tylamino)thiazolothiazole from a functionalised thiazole precursor.
This synthesis provides an alternative route to functionalised
thiazolothiazoles with the advantages of lower reaction tempera-
tures (albeit with relatively poor overall yields) and possible routes
towards asymmetric thiazolothiazoles, something that was not
possible with the aforementioned dithiooxamide condensation.
Our interest in this area stems from the ongoing development of
new chromophoric-ligand scaffolds for supramolecular metallo-
architectures, which have demonstrated potential applications
ranging from biological sensors to photovoltaic devices. Contextu-
ally, thiazolothiazoles represent a fascinating and hitherto un-
tapped class of ligand, with only a handful of reports relating to
their coordination chemistry.7a,9 In this paper we present a general
synthetic route (Scheme 1) towards potential new ligands via the
syntheses of di-substituted thiazolothiazoles from dithiooxamide
and stoichiometric quantities of an appropriate aldehyde. First-
ly,the protocol is tolerant to a variety of aryl aldehydic substrates
and should ultimately lead to the ability to tune the electronic, ste-
ric and donor properties of these comparatively rare heterocyclic
species. Secondly, preliminary studies demonstrate that an unsym-
metrical species can be isolated, wherein two different aldehydes
are utilised in the reaction mixture.
The 2,5-disubstituted thiazolo[5,4-d]thiazoles 1–7 (Fig. 2) were
synthesised according to the general procedure shown in Scheme 1,
whereby 2 equiv of the aldehyde were stirred with dithiooxamide
in nitrobenzene at 130 °C (for compound 8, better results were ob-
N
S
S
N
Figure 1. Thiazolo[5,4-d]thiazole.
H2N
S
S
N
S
S
N
H
O
R
R
+
R
NH2
⇑
Corresponding author. Tel.: +44 29 2087 9316; fax: +44 29 2087 4030.
E-mail address: popesj@cardiff.ac.uk (S.J.A. Pope).
Scheme 1. General route to the symmetrical thiazolo[5,4-d]thiazoles. Typical
conditions: PhNO2, 130 °C, 24 h.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.172

5420
R. C. Knighton et al. / Tetrahedron Letters 51 (2010) 5419–5422
In the context of designing ditopic ligand architectures with
S
N
N
S
tunable electronic properties, the isolation of unsymmetrical thiaz-
olo[5,4-d]thiazoles would be attractive from a coordination chem-
istry as well as a chromophoric perspective. Preliminary studies
(Scheme 2) into the synthesis of unsymmetrical hetero-substituted
thiazolo[5,4-d]thiazoles were undertaken using two aldehydes
which were assumed to possess similar reactivity (2-pyridinecar-
boxaldehyde and 2-quinolinecarboxaldehyde). Thin layer chro-
matographic analysis (silica gel; 99:1 CH2Cl2/MeOH) of the
reaction mixture revealed the presence of three species: two Rf val-
ues consistent with compounds 3 and 4 and a new species with an
Rf value intermediate between the two. Following chromato-
graphic purification of the crude reaction mixture (i.e., removal
of compounds 3 and 4) the new brown band (overall yield 13%;
statistical yield 26%) was characterised as compound 9, hetero-
substituted, unsymmetrical 2-(2-pyridyl)-5-(2-quinolyl)thiazol-
o[5,4-d]thiazole.
R
R
N
N
N
N
1
2
3
4
OH
OH
OH
OH
OH
OH
Yellow needle-like single crystals of compound 2,5-di(2-hydro-
xy-3,5-di-tert-butylphenyl)thiazolo[5,4-d]thiazole (8) were ob-
tained from the crude reaction mixture. The parameters
associated with the data collection11 are collated in Table 1. The
obtained pictorial representation of the structure is shown in Fig-
ure 3 and reveals the expected formulation of the new compound.
The molecule adopts a distorted planar conformation, with the
phenol group and azole nitrogen functionalities syn to each other.
The planarity is supported by the presence of two intramolecular
H-bonding interactions between the azole nitrogens and phenol
protons with d(Nꢀ ꢀ ꢀH) at just 1.855 Å and therefore, typical of a
strong interaction. The key bond-lengths and angles are collected
in the Supplementary data, Table S1; the parameters associated
with the thiazolo[5,4-d]thiazole core correlate very well with those
obtained from 2,5-di(2-pyridyl)thiazolo[5,4-d]thiazole.9
5
6
7
8
Figure 2. The various symmetrical aryl-derived thiazolo[5,4-d]thiazoles used in
this study.
tained using DMF at 153 °C) for 24 h.10 All reactions were per-
formed under a dinitrogen atmosphere to avoid oxidation of start-
ing materials. The reaction mixture was then cooled and diethyl
ether was added resulting in precipitation of the desired product
[if required further purification could be undertaken using column
chromatography (silica gel; 99:1 CH2Cl2/MeOH)]. Compound 8 was
intentionally exceptional in this regard, since the tert-butyl groups
impart much greater solubility to the product. However, an initial
crop of crystalline material was obtained upon cooling the reaction
mixture and further product was isolated via recrystallisation; lay-
ering hexane upon a concentrated DMSO solution resulted in the
production of additional crystals, which were filtered and dried.
Compounds 1–8 were obtained in moderate-to-good yields (30–
80%). As a demonstration of the utility of this synthetic approach,
it is important to note that compound 3, 2,5-di(2-pyridyl)thiazol-
o[5,4-d]thiazole, has been previously reported9 to be obtained in
a 19% yield, using 2-pyridinecarboxaldehyde as solvent. The meth-
odology reported herein, dramatically improves this yield to 60%,
whilst only requiring stoichiometric aldehyde. Generally, with
the exception of compound 8, the new compounds possessed rela-
tively poor solubility in common organic solvents. However, all
compounds were characterised by 1H NMR and where solubility al-
lowed, 13C{1H} NMR spectroscopy. LR and HRMS, IR and UV–vis
spectra were also obtained.
Mass spectra generally showed the parent ion {M}+ of each li-
gand as well as occasionally showing (usually in EI mode) charac-
teristic fragmentation due to the cleavage of the C–C bond joining
the central thiazolothiazole moiety with the appended aromatic
unit. More usefully, 1H NMR spectroscopy was used to confirm
the proposed formation of the products, in each case displaying
aromatic resonances, which were slightly shielded in comparison
to the relevant aldehyde starting materials as well as the obvious
absence of the downfield aldehyde proton. With reference to the
spectra of the relevant homo-substituted species 3 and 4, the 1H
NMR spectrum of 9 revealed that the chemical shifts of the quino-
line proton resonances matched very closely to those of compound
4 suggesting a very similar electronic environment. In contrast,
although possessing comparable chemical shifts, the pyridyl reso-
nances were much broader than in 3 and indicative of rotameric
N
N
N
H2N
S
S
N
S
S
N
S
N
S
S
H
O
N
S
H
O
N
+
+
+
+
N
NH2
N
N
N
N
N
9
Scheme 2. Synthetic route to compound 9. Typical conditions: PhNO2, 130 °C, 24 h.

R. C. Knighton et al. / Tetrahedron Letters 51 (2010) 5419–5422
5421
Table 1
8.75 and 10.44 ppm. The broadened downfield resonances are
more characteristic of non-H-bonded hydroxy protons, correlat-
ing with those obtained for compound 7 where no intramolecu-
larly H-bonded conformations are possible, but the sharper
upfield resonance at 8.75 ppm can be attributed to an H-bonded
(and thus more shielded) hydroxy proton. Analogous intramolec-
ular H-bonding interactions have been well documented in sys-
tems based upon, for example, 2-(20-hydroxyphenyl)pyridine.12
More specifically, the behaviour of the very closely related spe-
cies 2-(20-hydroxyphenyl)thiazole has been studied from a theo-
retical perspective13 revealing that, in the ground state, the
normal form (phenol syn to N) is energetically favoured over
either the rotameric (phenol syn to S) or tautomeric forms. Fur-
ther, the calculations show that the thiazole differs significantly
from the related oxazole and imidazole analogues, with signifi-
cant single bond character between the phenol and azole ring.
Additional evidence of this intramolecular interaction was also
provided by the 13C{1H} NMR spectrum of compound 8, which
showed sixteen unique aromatic carbon resonances, again indic-
ative of inequivalence and a loss of symmetry across the thiazol-
o[5,4-d]thiazole core. Therefore, whilst the solid-state structure
revealed a double and thus symmetrical intramolecular H-bond-
ing interaction, the subsequent NMR spectroscopic characterisa-
tion of the 2-hydroxyphenyl derivatives suggests that, on
average, one hydroxyl group participates in H-bonding to the
N-azole ring in solution (Fig. 4).
Parameters associated with the single crystal diffraction data collection for 2,5-di(2-
hydroxy-3,5-di-tert-butylphenyl)thiazolo[5,4-d]thiazole, 8
Formula
Molecular weight
Wavelength (Å)
Temperature (K)
Crystal system
Space group
Unit cell dimensions
a
b
c
a
b
C32H42N2O2S2
550.8
0.71073
150
Triclinic
P-1
5.9428(3) Å
9.7978(4) Å
13.5783(5) Å
75.466(2) °
85.973(2) °
80.694(2) °
754.88(6)
c
Volume (Å3)
Z
1
Density (calculated)
F(0 0 0)
Crystal size
Absorption coefficient
Range for data collection
All reflections collected
Independent reflections
Observed reflections
Goodness-of-fit
1.212
296
0.45 ꢂ 0.10 ꢂ 0.04 mm3
0.207 mmꢁ1
3.48–27.50°
4735
3399
2562
1.068
Final R indices [I >2
R indices (all data)
r
(I)]
R1 = 0.0591, wR2 = 0.1321
R1 = 0.0867, wR2 = 0.1482
The UV–vis absorption properties of compounds 1–9 were as-
sessed in aerated MeCN solution (10ꢁ4 M). Each chromophore
absorbs in the long-wavelength UV region with
a weaker
absorption tailing into the visible region. In each case this band
*
is assigned to a
p–p
transition. With reference to previous
*
studies into related systems,14 although n–
p transitions cannot
be ruled out as a component of the absorptions, the magnitude
of the recorded extinction coefficients
(
e
>2 ꢂ 104 Mꢁ1 cmꢁ1
)
would seem to preclude their observation. The precise position-
ing of the longest wavelength absorption was subtly modulated
by the nature of the terminating aryl units. For example, 2,5-
di(2-quinolyl)thiazolo[5,4-d]thiazole (4) absorbed at a lower en-
ergy compared to the related pyridyl analogues (1–3), suggest-
ing that good electronic communication occurs across the
fused bicyclic core. The hetero-substituted species 9 possessed
kmax = 373 nm, which is intermediate between
3 and 4 and
therefore, consistent with the proposed structure. In the cases
of the hydroxyphenyl derivatives (5–8) the variation in absorp-
tion maxima was far less-pronounced, each absorbing with a
kmax at ca. 360 nm.
Figure 3. X-ray crystal structure of compound 8. Top: side view with t-Bu groups
and H atoms removed for clarity.
In summary, this Letter discusses a general method for synthes-
ising 2,5-disubstituted thiazolo[5,4-d]thiazole derivatives together
with supporting spectroscopic and structural data. Future work
will focus upon the exploitation of these functionalised heterocy-
cles, including their incorporation into metallo-containing arrays
as well as fully elucidating their electronic characteristics and
photophysical behaviour, with particular focus upon the excited
state proton-coupled electron transfer phenomena of the 2-
hydroxyphenyl (5, 6 and 8) derivatives.
behaviour about the C–C bond adjoining the thioazole and pyridyl
rings.
The 1H NMR spectra of the 2-hydroxyphenyl-substituted com-
pounds (5, 6 and 8) displayed proton resonances indicative of
inequivalent terminal 2-hydroxyphenyl rings. The number of res-
onances and range of chemical shifts are suggestive of an intra-
molecular interaction between one of the phenol groups and the
azole nitrogen, thus inducing a loss of symmetry about the C2
axis of the molecule (Fig. 4). For example, the 1H NMR spectrum
of compound 6, 2,5-di(2,3-dihydroxyphenyl)thiazolo[5,4-d]thia-
zole, showed that there are four unique OH resonances between
Acknowledgement
The authors thank the EPSRC for funding together with Cardiff
University.
H
O
OH
HO
OH
N
S
S
Supplementary data
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.172.
Figure 4. Suggested mode of solution state intramolecular hydrogen bonding for 6.

5422
R. C. Knighton et al. / Tetrahedron Letters 51 (2010) 5419–5422
9. Zampese, J. A.; Keene, F. R.; Steel, P. J. Dalton Trans. 2004, 4124.
10. representative synthesis of compound (7):
References and notes
A
2,5-bis(3,4-
dihydroxyphenyl)thiazolo[5,4-d]thiazole. The title compound was prepared
by adding dithiooxamide (250 mg, 2.0 mmol) and 3,4-dihydroxybenzaldehyde
(575 mg, 4.0 mmol) to nitrobenzene (10 mL). The reaction mixture was heated
at 130 °C for 24 h under a dinitrogen atmosphere. Following cooling to room
temperature, Et2O (50 mL) was added and the resultant precipitate was filtered
and dried in vacuo to give 7 as a dark brown solid. Yield = 586 mg (79%). 1H
NMR (250 MHz; DMSO-d6): dH 9.73 (2H, br s, OH), 9.52 (2H, br s, OH), 7.41 (2H,
1. For a general overview of thiazole-containing heterocycles, see: (a) Smirnova,
N. G.; Zavarzin, I. V.; Krayushkin, M. M. Chem. Heterocycl. Compd. 2006, 42, 144;
For biological aspects, see: (b) Ketcham, R.; Mah, S. J. Med. Chem. 1971, 14, 743.
2. (a) Van Mierloo, S.; Chambon, S.; Boyukbayram, A. E.; Adriaensens, P.; Lutsen,
L.; Cleij, T. J.; Vanderzande, D. Magn. Reson. Chem. 2010, 48, 362; (b) Naraso;
Wudl, F. Macromolecules 2008, 41, 3169; (c) Osaka, I.; Zhang, R.; Sauve, G.;
Smilgies, D. M.; Kowalewski, T.; McCullough, R. D. J. Am. Chem. Soc. 2009, 131,
2521.
3. (a) Osaka, I.; Sauve, G.; Zhang, R.; Kowalewski, T.; McCullough, R. D. Adv. Mater.
2007, 19, 4160; (b) Ando, S.; Kumaki, D.; Nishida, J.; Tada, H.; Inoue, Y.; Tokito,
S.; Yamashita, Y. J. Mater. Chem. 2007, 17, 553; (c) Ando, S.; Nishida, J.; Inoue, Y.;
Tokito, S.; Yamashita, Y. J. Mater. Chem. 2004, 14, 1787; (d) Kumaki, D.; Ando, S.;
Shimono, S.; Yamashita, Y.; Umeda, T.; Tokito, S. Appl. Phys. Lett. 2007, 90,
053506.
3
d, JHH = 2.3 Hz, ArH), 7.32 (2H, dd, JHH = 8.5 Hz and 2.3 Hz, ArH), 6.88 (2H, d,
3JHH = 8.4 Hz, ArH) ppm. 13C{1H} NMR (62.5 MHz; DMSO-d6): dC 168.24, 148.82,
148.62, 145.87, 124.79, 118.17, 116.17, 112.93 ppm. LRMS (EI) found m/
z = 358.0; calculated 358.4 for {M}+. HRMS (EI): found 358.0081; cal 358.0082
for C16H10N2O4S2. IR (solid): mmax 3213, 1596, 1173, 1024, 788 cmꢁ1. UV–vis
(CH3CN): kmax (Mꢁ1 cmꢁ1) 274 (93000), 356 (24000) nm.
11. Crystallographic data including bond lengths and bond angles associated with
compound (782893) have been deposited with the Cambridge
8
4. (a) Peng, Q.; Peng, J. B.; Kang, E. T.; Neoh, K. G.; Cao, Y. Macromolecules 2005, 38,
7292; (b) Jung, I. H.; Jung, Y. K.; Lee, J.; Park, J. H.; Woo, H. Y.; Lee, J.; Chu, H. Y.;
Shim, H. K. J. Polym. Sci., Part A 2008, 46, 7148; (c) Jung, I. H.; Yu, J.; Jeong, E.;
Kim, J.; Kwon, S.; Kong, H.; Lee, K.; Woo, H. Y.; Shim, H. K. Chem. Eur. J. 2010, 16,
3743.
Crystallographic Data Centre.
12. (a) Basaric, N.; Wan, P. Photochem., Photobiol. 2006, 5, 656; (b) Sitkowski, J.;
Stfaniak, L.; Kaczmarek, L.; Webb, G. A. J. Mol. Struct. 2002, 385, 65; (c) Korth, H.
G.; de Heer, M. I.; Mulder, P. J. Phys. Chem. A 2002, 106, 8779; (d) Brauer, M.;
Mosquera, M.; Perez-Lustres, J. L.; Rodriguez-Prieto, F. J. Phys. Chem. A 1998,
102, 10736.
13. Purkayastha, P.; Chattopadhyay, N. J. Mol. Struct. 2002, 604, 87.
14. LeGourrierec, D.; Kharlanov, V.; Brown, R. G.; Rettig, W. J. Photochem. Photobiol.,
A 1998, 117, 209.
5. Ephraim, J. Ber. 1891, 94, 1027.
6. Johnson, J. R.; Ketcham, R. J. Am. Chem. Soc. 1960, 82, 2719.
7. (a) Falcao, E. H. L.; Naraso; Feller, R. K.; Wu, G.; Wudl, F.; Cheetham, A. K. Inorg.
Chem. 2008, 47, 8336; (b) Mamada, M.; Nishida, J. I.; Kumaki, D.; Tokito, S.;
Yamashita, Y. Chem. Mater. 2007, 19, 5404.
8. Seybold, G.; Eilingsfeld, H. Liebigs Ann. Chem. 1979, 1271.