Bis(4-hydroxythiazoles): Novel functional and switchable fluorophores

Article abstract of DOI:10.1055/s-0030-1260670

A series of 2,2- and 5,5-bis(4-hydroxythiazoles) was synthesized according to Hantzsch synthesis. Both phenols and their corresponding anions display a strong fluorescence in the visible spectrum, whereas the emission is shifted bathochromically upon depr

Full text of DOI:10.1055/s-0030-1260670

2334
PAPER
Bis(4-hydroxythiazoles): Novel Functional and Switchable Fluorophores
B
is(4-hydroxyth
r
iazoles)
i
:
N
ove
c
l
Functional and
S
T
w
itchable Fluo
ä
rophores uscher,a Lorena Calderón-Ortiz,a Dieter Weiß,*a Rainer Beckert,*a Helmar Görlsb
a
Institute of Organic and Macromolecular Chemistry, Friedrich-Schiller-University Jena, Humboldtstr. 10, 07743 Jena, Germany
Fax +49(3641)948212; E-mail: C6bera@uni-jena.de
Institute of Inorganic and Analytical Chemistry, Friedrich-Schiller-University Jena, Lessingstr. 8, 07743 Jena, Germany
b
Received 31 March 2011; revised 4 May 2011
successfully employed for the synthesis of a series of 2,2¢-
bis(thiazoles), however, without hydroxy groups.11 Ac-
cording to the conditions of the classical Hantzsch synthe-
sis, dithiooxamide (2) was cyclized with a-aryl-a-
Abstract: A series of 2,2¢- and 5,5¢-bis(4-hydroxythiazoles) was
synthesized according to Hantzsch synthesis. Both phenols and
their corresponding anions display a strong fluorescence in the vis-
ible spectrum, whereas the emission is shifted bathochromically
upon deprotonation. This easy switch makes them suitable for wide- bromoacetic acids 1a–c at 80–100 °C in the presence of a
spread applications, mainly in analysis and supramolecular chemis-
base, such as pyridine. As depicted in Scheme 1, three dif-
try. Due to their 1,4-diazadiene substructure, the 2,2¢-bithiazoles
ferent 4,4¢-dihydroxy-substituted 2,2¢-bithiazoles were
possess prerequisites for the complexation of metals, however, in-
prepared 60–75% yields. It should be noted that at higher
stead of a copper complex, a dimer which constitutes the 5,5¢-C–C
temperatures (>130 °C), considerable amounts of O-alky-
coupled product was isolated. In addition, tris(thiazoles) could be
lation products (monoethyl ether/diethyl ether of 3) were
constructed.
formed as byproducts.
Key words: heterocycles, chromophores, bifunctional compounds,
condensation, thiazole
HO
Ar
N
4-Hydroxythiazoles are well-known compounds1 and
there are known biologically active derivatives.2,3 In con-
trast to their biological data, there is hardly any informa-
tion on their physicochemical properties such as color and
fluorescence. Therefore, we have been working on the
syntheses and applications of 2,5-disubstituted 4-hydroxy-
thiazoles.4 In this context, we found these compounds to
be fluorescent, and recently, highly fluorescent 2-pyridyl-
substituted 4-hydroxythiazoles and related systems have
been reported.5 In order to obtain a better understanding of
structure–property relationships, quantum chemical cal-
culations were carried out.6
NH2
S
S
COOEt
pyridine, 100 °C
60–75%
Ar
S
+
N
Br
S
H2N
Ar
OH
3
1
2
1c, 3c Ar = 4-MeOC6H4
EtO
1a, 3a: Ar = Ph
1b, 3b: Ar = 4-BrC6H4
Ar
N
S
1. NaH, DMSO
2. 2 EtI
S
3a
N
93%
Ar
OEt
4a
Therefore, we were interested in the synthesis of systems
with more than one hydroxythiazole unit as represented in
Scheme 1 Synthetic route for the formation of 2,2¢-bithiazole-4,4¢-
diols 3a–c and alkylation of 3a
3
(2,2¢-bithiazole-4,4¢-diols) and 15 [5,5¢-(1,4-phe-
nylene)bis(thiazol-4-ols)]. Molecules containing two or
more thiazole rings play an important role in both
biochemistry7 and material science.8 Although hydroxy
groups show interesting electronic effects combined with
a variety of chemical variations, only very little data exists
until now for bis(hydroxythiazoles). Thus, starting from
cyanogen and a-mercapto acids, some 2,2¢-bis(thiazoles)
possessing hydroxy groups in the 4,4¢-positions were syn-
thesized.9 Recently, a new bithiazole chemosensor with
phenolic substituents at the 2,2¢-positions of the thiazole
rings was reported.10
Being typical aromatic hydroxy derivatives (heterocyclic
phenols), the bithiazoles 3 can easily be alkylated; for ex-
ample, 4a was synthesized by deprotonation of 3a with
sodium hydride in dimethyl sulfoxide and subsequent
alkylation with ethyl iodide. The molecular structure of
the bis(ethyl ether) 4a obtained by single crystal X-ray
analysis is shown in Figure 1. The structure reveals that
both thiazole subunits are present and almost perfectly
planar.
Furthermore, we were able to construct new bis- and
tris(4-hydroxythiazoles) with pyridine and benzene as the
center core (Schemes 2 and 3). Thus, 6a can be prepared
by the same method using the corresponding dithioamide
5a and two equivalents of ethyl bromoacetate 1a. Even the
tris(thiazole) 6b was prepared in the same manner, start-
ing from pyridine-2,4,6-tricarbothioamide (5b) in good
yields.
Since cyanogen is difficult to obtain and handle, we chose
a different approach based on dithiooxamide (rubeanic
acid). This binucleophilic building block has already been
SYNTHESIS 2011, No. 14, pp 2334–2339
x
x.
x
x
.
2
0
1
1
Advanced online publication: 16.06.2011
DOI: 10.1055/s-0030-1260670; Art ID: T35011SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Bis(4-hydroxythiazoles): Novel Functional and Switchable Fluorophores
2335
Alternatively, 9 and 10 can be prepared from 2,5-dicyano-
pyridine (7) or 2,6-dicyanopyridine (8) and thiolactic acid
esters or thiomalic acid esters, as described earlier.2 How-
ever, attempts to prepare a system with three different thi-
azole subunits failed, giving only mixtures of all possible
isomers. Nevertheless, we finally succeeded in synthesiz-
ing mixed thiazoles, such as compound 13b, using a step-
wise protocol. Accordingly, the first thiazole subunit 12
was synthesized starting from 11; thereafter, the cyano
group was transformed using ammonium sulfide into the
thioamide 13a in very good yields and, finally, the second
thiazole was formed. The overall yield of 13b (three steps)
is moderate. Employing such a step-by-step approach for
the construction of unsymmetrical substituted tris(thia-
zoles) is part of our ongoing research.
Figure 1 X ray crystal structure of 4a. C1–C1A: 1.442(5) Å; C2–
O1: 1.352(3) Å; N1–C1–C1: 124(3)°, torsion angle between thiazole
units: 0.2°; torsion angle between thiazole/phenyl ring: 6.08°; C1–
N1: 1.317(3) Å; N1–C2: 1.358(4) Å; C2–C3: 1.382(4) Å; C3–S1:
1.732(3) Å.
Furthermore, a new bis(hydroxythiazole) derivative 15
was prepared by the condensation reaction of two mole-
cules of thioamide 5c with bis(bromoacetate) 14 under the
reaction conditions mentioned above; the 5,5¢-bithiazole
15 was isolated in 22% yield.
OH
S
n x 1a
N
pyridine, 100 °C
The new hydroxybithiazole derivatives 3 form orange to
reddish powders, derivatives 6, 9, 10, 13b are yellow, and
15 is buff-colored. All 4-hydroxythiazoles are very poorly
soluble in ethanol or acetone and only slightly soluble in
N,N-dimethylformamide, dimethyl sulfoxide, or tetrahy-
drofuran. They can be purified by recrystallization from
dimethyl sulfoxide or N,N-dimethylformamide and form
crystals that bind solvent molecules tenaciously, which
makes elementary analysis almost impossible. Elementa-
ry analysis of 3c was performed on a high-vacuum-
sublimed sample (~260 °C, 9 × 10–6 mbar).
Ph
NH2
S
21–55%
n
N
n
N
5a, n = 2: 2,5-di-
6a, n = 2: 2,5-bis-
6b, n = 3: 2,4,6-tris-
5b, n = 3: 2,4,6-tri-
SH
2
OH
R1
CO2R2
N
CN
pyridine, 100 °C
R1
2
S
N
55–78%
N
2
9: 2,5-bis-, R1 = Me
10: 2,6-bis-, R1 = CH2CO2Me
7: 2,5-di-
8: 2,6-di-
According to NMR data, only the enol (hydroxyl) form
exists in solution,12 which is in agreement with our latest
findings.6 Their solutions show a bright green fluores-
Scheme 2 Synthetic approach for the formation of pyridine based
bis- and tris(thiazoles)
cence [3a
lmax = 449 nm, lmax(em) = 528 nm, t1/2 =
HO
C6H4(4-Br)
2.8 ns, F = 96% (Rh 6G)]. For fluorescence intensity de-
cay measurements, the Chameleon laser was tuned to 950
nm, pulse picked to a 4 MHz repetition rate (Coherent
9200Pulse Picker), and finally frequency doubled (APE-
GmbH SHG Unit) to afford sample excitation, lex = 400
nm.13 Upon deprotonation in dimethyl sulfoxide, the
bi(hydroxythiazole) derivatives of type 3 form deep violet
HO
C6H4(4-Br)
N
S
CSNH2
N
S
1.(NH4)2S
2. 1a
1b
1. 94% 13a
2. 65% 13b
66%
N
CN
OH
CN
S
13b
11
12
Ph
2-Py
N
Br
COOEt
HO
S
pyridine, 100 °C
22%
2
+
S
N
NH2
S
EtOOC
Br
OH
2-Py
N
15
14
5c
Scheme 3 Step-by-step approach to the formation of 13b and syn-
thesis of 5,5¢-bis(thiazole) 15
Figure 2 Varying fluorescence of 3a (excitation: 366 nm diode ar-
ray) from left to right: solution in DMSO, addition of KOH solution,
deprotonated form)
Synthesis 2011, No. 14, 2334–2339 © Thieme Stuttgart · New York

2336
E. Täuscher et al.
PAPER
Table 1 Absorption and Emission Wavelengths of Thiazoles Mea-
4-MeOC6H4
sured in DMSOa
1. CuCl2, DMSO–H2O
2. air, heat
S
N
O
3c
HO
15%
Compound
Absorption/emission
OH/ether form
Absorption/emission
deprotonated form
N
S
2
16
4-MeOC6H4
l
max (nm)
lmax (nm)
Scheme 4 Dimerization of 3c in the presence of copper(II) chloride
3a
3b
3c
445/528
455/520
466/535
442/500b
400/543
416/533
365/440
365/568
381/426
380/427
432/532
500/564
580/656
530/645
620/649
–
The complex NMR spectra of 16 and the few reliable MS
data gave no further structural information, and only IR
spectra revealed the presence of a carbonyl group, so that
an X-ray structural analysis was the final and unambigu-
ous proof of its structure (Figure 3).
4a
6a
6b
9
540/697
553/630
490/594
no fluorescence
510/621
489/627
620/703
–
10
12
13b
15
16
a Unless otherwise indicated.
b In THF.
Figure 3 ORTEP plot (50% probability ellipsoids) of the solid-state
molecular structure (X-ray crystal structure analysis) of derivative 16.
C3A–C3: 1.553(6) Å; C3–C2: 1.568(4) Å; C3–C4: 1.550(5) Å; C2–
N1: 1.385(4) Å; C1–N1: 1.309(4) Å; C1–S1: 1.470(3) Å; C4–C3–
C3A: 112.9(3)°; C3A–C3–C2: 109.5(3)°.
solutions of their dianions (3a/dianion: lmax = 656 nm,
Figure 2), which display a deep red fluorescence. Gener-
ally, 2-pyridyl-substituted 4-hydroxythiazoles absorb and
emit more bathochromically than 2-phenyl-substituted
derivatives,6 whereas bithiazoles of type 3 display the
longest wavelengths of all examined hydroxythiazoles.
The unexpected structure of 16 consists of two molecules
of the starting material which are linked at the5,5¢-posi-
tions. Simultaneously, a transformation of both hydroxy
groups to carbonyl groups to form thiazolones took place.
Most likely, the formation of 16 is the result of a copper-
mediated oxidative dimerization reaction. This dimeriza-
tion reaction shows remarkable similarity to the oxidative
coupling reaction of 2-naphthol.15
Apparently, solutions of the anions react rapidly with car-
bon dioxide from the air with reformation of the OH de-
rivative. ESR data of deprotonated 15 proved the
existence of radicals. The first analysis showed one radi-
cal species interacting with four equivalent protons of the
symmetrical phenyl unit (1:4:6:4:1; g = 2.0048, hfcc
[G] = 2.4). These findings suggest the existence of a re-
versible two-electron redox system in which the radical
represents the SEM-form (extended hydroquinone). Ad-
ditional research is in progress at the moment and will be
reported.
Reagents were purchased from commercial sources and were used
directly unless otherwise stated in the text. Aq 48% (NH4)2S solu-
tion was obtained from Aldrich. All solvents were of reagent grade
and were dried according to common practice and distilled prior to
use. Reactions were monitored by TLC, carried out on 0.2 mm
Merck silica gel plates (60 F254). 1H and 13C NMR spectra were re-
corded on Bruker AVANCE 250 and 400 spectrometers, shifts (d)
are given relative to signals arising from the solvent. Melting points
were measured with a Galen III apparatus (Boëtius system) and are
corrected.
Due to their 1,4-diazadiene subunit, the bithiazoles 3 furfil
the preconditions for the construction of metal complex-
es.14 Therefore, the reactivity of 3c towards selected metal
ions with regard to the formation of complexes was tested.
When a solution of bithiazole 3c in dimethyl sulfoxide is
added to an aqueous solution of copper(II) chloride, a
deep purple precipitation is formed almost immediately.
The MS data indicated the mass of starting material 3c at-
Crystal structure determination: The intensity data were collected
on a Nonius KappaCCD diffractometer, using graphite-monochro-
mated MoKa radiation. Data were corrected for Lorentz and polar-
ization effects, but not for absorption.16,17
tached to copper(II) chloride, however, due to its low sol- The structure was solved by direct methods (SHELXS)17 and re-
ubility, all attempts to obtain single crystals suitable for
X-ray analysis have failed so far. Treatment of the com-
plex with dimethyl sulfoxide in the presence of air gener-
ated a new compound, 16, in low yields. The latter was
purified by recrystallization from dimethyl sulfoxide as
green-shining, glossy dark red crystals (Scheme 4).
fined by full-matrix least squares techniques against Fo2 (SHELXL-
97).18 All hydrogen atoms for the compound 4a and for the hydroxy
group O3 for compound 16 were located by difference Fourier syn-
thesis and refined isotropically. XP (Siemens Analytical X-ray In-
struments, Inc.) was used for structure representations.19
Synthesis 2011, No. 14, 2334–2339 © Thieme Stuttgart · New York

PAPER
Bis(4-hydroxythiazoles): Novel Functional and Switchable Fluorophores
2337
Crystal Data for 4a: C22H20N2O2S2, Mr = 408.52 g mol–1, red prism,
size 0.05 × 0.05 × 0.03 mm3, monoclinic, space group P21/c,
a = 4.9317(3), b = 10.1208(9), c = 19.491(2) Å, b = 95.265(5)°,
V = 968.7(1) Å3, T = –140 °C, Z = 2, rcalcd = 1.401 g cm–3,
m(MoKa) = 2.96 cm–1, F(000) = 428, 9060 reflections in h(–5/6),
k(–13/11), l(–25/25), measured in the range 2.10° £ Q £ 27.47°,
5,5¢-Bis(4-methoxyphenyl)-2,2¢-bithiazole-4,4¢-diol (3c)
Following the typical procedure using 1c (1.1 equiv) and 2 (1
equiv); red powder; yield: 70%; mp 348–350 °C.
IR (ATR): 2954, 2553, 1504, 1404, 1246, 1053, 840 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 11.67 (s, 2 H), 7.69 (d, J = 8.8
Hz, 4 H), 6.99 (d, J = 8.8 Hz, 4 H), 3.77 (s, 6 H).
13C NMR (62.5 MHz, DMSO-d6): d = 158.6, 158.0, 151.6, 128.0,
124.1, 114.8, 110.7, 55.6.
MS (EI): m/z (%) = 412 (7) [M+], 233 (11), 151 (100), 108 (41).
completeness Qmax = 99.8%, 2220 independent reflections, Rint
=
0.1459, 1346 reflections with Fo > 4s(Fo), 167 parameters, 0 re-
straints,
R1obs = 0.0539,
wR2obs = 0.1091,
R1all = 0.1165,
wR2all = 0.1317, GOOF = 0.969, largest difference peak and hole:
0.320/–0.488 e Å–3.
UV/Vis (DMSO): lmax = 466 nm; deprotonated (KOH) lmax
=
=
Crystal Data for 16: C40H30N4O8S4 2 C3H7NO, Mr = 969.11 g mol–1,
red-brown prism, size 0.05 × 0.05 × 0.04 mm3, monoclinic, space
group P21/n, a = 10.4220(4), b = 21.1752(9), c = 10.6172(4) Å,
b = 107.599(2)°, V = 2233.42(15) Å3, T = –140 °C, Z = 2,
620 nm.
Fluorescence (DMSO): lmax = 535 nm; deprotonated (KOH) lmax
649 nm.
r
calcd = 1.441 g cm–3, m (MoKa) = 2.8 cm–1, F(000) = 1012, 13706
Anal. Calcd for C20H16N2O4N2: C, 58.24; H, 3.91; N, 6.79; S, 15.55.
Found: C, 58.01; H, 4.05; N, 6.65; S, 15.84.
reflections in h(–13/13), k(–21/27), l(–13/13), measured in the
range 2.26° £ Q £ 27.49°, completeness Qmax = 99.4%, 5101 inde-
pendent reflections, Rint = 0.0577, 3746 reflections with Fo
>
=
4,4¢-Diethoxy-5,5¢-diphenyl-2,2¢-bithiazole (4a)
4s(Fo), 306 parameters, 0 restraints, R1obs = 0.0614, wR2
obs
Compound 3a (1 mmol) was dissolved in DMSO (20 mL). Under
stirring, NaH (1.1 mmol, 60% suspension) was added. After 10 min,
EtI (1.1 mmol) was added dropwise to the deep-violet soln. The
mixture was stirred until the reaction was complete (TLC monitor-
ing, CHCl3). Then, H2O (50 mL) was added and the formed suspen-
sion was filtered off and the crude product was dried in vacuo. The
obtained solid was dissolved in CH2Cl2 and filtered through a short
silica gel column and the solvent was removed; yield: 93%; light-
red crystals; mp 201 °C.
0.1225, R1all = 0.0959, wR2all = 0.1395, GOOF = 1.075, largest dif-
ference peak and hole: 0.604/–0.328 e Å–3.
4-Hydroxythiazoles 3a–c, 6a,b, 9, 10 and 12; Typical Procedure
A mixture of pyridine (0.87 g, 11 mmol), the corresponding thio-
amide 2 or 5 (10 mmol) and the corresponding ethyl bromophenyl-
acetate 1 or sulfanylacetate (11 mmol) was stirred under argon at
100–110 °C until the mixture solidified. After 1 h, EtOH (30 mL)
was added and the mixture was stirred at r.t. for 30 min. After filtra-
tion the crude product was recrystallized (EtOH–DMF) and dried in
vacuo.
IR (ATR): 1519, 1469, 1330, 1060, 760, 686 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.81 (d, J = 8.6 Hz, 4 H), 7.42–
7.36 (m, 4 H), 7.28–7.25 (m, 2 H), 4.61 (q, J = 7.1 Hz, 4 H), 1.52 (t,
J = 7.0 Hz, 6 H).
13C NMR (62.5 MHz, CDCl3): d = 159.1, 153.1, 131.5, 128.7,
126.9, 126.8, 113.9, 66.6, 15.2.
MS (EI): m/z (%) = 408 (89) [M+], 380 (8), 231 (12), 203 (33), 121
(100), 77 (31).
5,5¢-Diphenyl-2,2¢-bithiazole-4,4¢-diol (3a)
Following the typical procedure using 1a (1.1 equiv) and 2 (1
equiv); orange-red crystals or powder; yield: 40–60%; mp 335–338
°C.
IR (ATR): 2699, 2557, 1411, 1369 1211, 1001, 751 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 11.94 (s, 2 H), 7.78 (d, J = 7.5
Hz, 4 H), 7.44 (dd, J = 7.5 Hz, 4 H), 7.28 (dd, J = 7.3 Hz, 2 H).
13C NMR (62.5 MHz, DMSO-d6): d = 159.1, 158.2, 152.7, 131.7,
129.4, 127.2, 126.6.
MS (EI): m/z (%) = 352 (12) [M+], 203 (13), 121 (100), 77 (19).
UV/Vis (THF): lmax = 442 nm.
Fluorescence (THF): lmax = 500 nm.
Anal. Calcd for C14H10N2OS: C, 64.68; H, 4.93; N, 6.86; S, 15.70.
Found: C, 64.55; H, 5.11; N, 6.99; S, 15.41.
UV/Vis (DMSO):
max = 580 nm.
lmax = 445 nm; deprotonated (KOH)
Pyridine-2,4,6-tricarbothioamide (5b)
l
Pyridine-2,4,6-tricarbonitrile (0.25 g, 1 mmol,) was dissolved in
DMSO (40 mL). Aq (NH4)2S soln (1.5 mL, 48%) was added in one
portion. The mixture was stirred for 30 min and then H2O (125 mL)
was added. After 1 h, the crude product was filtered off, recrystal-
lized (DMF) and dried in vacuo; yellow powder; yield: 56%; mp
>300 °C (decomp.).
Fluorescence (DMSO): lmax = 528 nm; F = 96% (Rh 6G), t1/2
2.8 ns; deprotonated (KOH) lmax = 656 nm. F = 22% (Rh 6G).
=
5,5¢-Bis(4-bromophenyl)-2,2¢-bithiazole-4,4¢-diol (3b)
Following the typical procedure using 1b (1.1 equiv) and 2 (1
equiv); deep red powder; yield: 75%; mp >360 °C.
IR (ATR): 3371, 3263, 3159, 1581, 1420, 1265, 644 cm–1.
IR (ATR): 2654, 2553, 1380, 1423, 1207, 1006, 808 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 11.77 (s, 2 H), 7.73 (d,
J = 8.6 Hz, 2 H), 7.63 (d, J = 8.6 Hz, 2 H).
13C NMR (62.5 MHz, DMSO-d6): d = 159.5, 153.2, 132.2, 131.1,
128.6, 119.6, 110.2.
1H NMR (250 MHz, DMSO-d6): d = 10.51–10.06 (m, 6 H), 8.95 (s,
2 H).
13C NMR (62.5 MHz, DMSO-d6): d = 197.6, 192.6, 149.4, 148.9,
123.9.
MS (EI): m/z (%) = 256 (100) [M+], 239 (16), 222 (58), 206 (20),
180 (19), 60 (58).
MS (EI): m/z (%) = 512 (17), 510 (23), 508 (14), 283 (31), 201
(100), 199 (93), 121 (50), 120 (69).
HRMS (ESI): m/z calcd for C8H8N4S3: 255.9911; found: 255.9921.
UV/Vis (DMSO): lmax = 350 nm.
UV/Vis (DMSO): lmax = 455 nm; deprotonated (KOH) lmax
530 nm.
=
=
2,2¢-Pyridine-2,5-diylbis(5-phenylthiazol-4-ol) (6a)
Following the typical procedure using 1a (2.1 equiv) and 5a (1
equiv); yellow powder; yield: 21%; mp >300 °C (decomp).
Fluorescence (DMSO): lmax = 520 nm; deprotonated (KOH) lmax
645 nm.
Synthesis 2011, No. 14, 2334–2339 © Thieme Stuttgart · New York

2338
E. Täuscher et al.
PAPER
IR (ATR): 3024, 2450, 1540, 1384, 1211, 751 cm–1.
UV/Vis (DMSO): lmax = 365 nm.
1H NMR (250 MHz, DMSO-d6): d = 11.41 (s, 1 H), 11.35 (s, 1 H),
9.10 (s, 1 H), 8.35 (m, 1 H), 8.11 (d, J = 8.3 Hz, 1 H), 7.81 (m, 4 H),
7.44 (m, 4 H), 7.28 (dd, J = 7.4 Hz, 2 H).
13C NMR (62.5 MHz, DMSO-d6): d = 159.8, 159.5, 159.4, 156.4,
151.2, 146.7, 134.3, 132.2, 131.9, 129.9, 129.3, 129.2, 127.0, 126.9,
126.8, 126.8, 119.3, 112.4, 110.2.
Fluorescence (DMSO): lmax = 568 nm.
3-[5-(4-Bromophenyl)-4-hydroxythiazol-2-yl]benzonitrile (12)
Following the typical procedure using 1b (1.1 equiv) and 9 (1
equiv); yellow needles; yield: 66%; mp 207 °C.
IR (ATR): 2970, 2559, 2225, 1566, 1415, 1392, 1064, 803 cm–1.
MS (EI): m/z (%) = lmax 429 (44) [M+], 280 (55), 130 (23), 121
(100).
1H NMR (250 MHz, DMSO-d6): d = 11.92 (s, 1 H), 8.24 (s, 1 H),
8.19 (d, J = 8.1 Hz, 1 H), 7.95 (d, J = 7.8 Hz, 1 H), 7.74–7.57 (m, 5
H).
UV/Vis (DMSO): lmax = 400 nm; deprotonated (KOH) lmax
=
=
540 nm.
13C NMR (62.5 MHz, DMSO-d6): d = 159.1, 158.2, 152.7, 131.7,
129.4, 127.2, 126.6.
MS (EI): m/z (%) = 356 (100) [M+], 230 (13), 199 (63), 129 (55).
Fluorescence (DMSO): lmax = 543 nm; deprotonated (KOH) lmax
697 nm.
UV/Vis (DMSO): lmax
=
381 nm; deprotonated (KOH) lmax
=
=
2,2¢,2¢¢-(Pyridine-2,4,6-triyl)tris(5-phenylthiazol-4-ol) (6b)
510 nm.
Following the typical procedure using 1a (3.2 equiv) and 5b (1
Fluorescence (DMSO): lmax = 426 nm; deprotonated (KOH) lmax
621 nm.
equiv); yellow powder; yield: 55%; mp 338 °C.
IR (ATR): 3090, 2557, 1593, 1381, 1207, 752 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 11.89 (s, 1 H), 11.67 (s, 2 H),
8.31 (s, 2 H), 7.82–7.76 (m, 6 H), 7.43–7.37 (m, 6 H), 7.28–7.24 (m,
3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 162.7, 159.6, 159.3, 158.7,
155.6, 151.6, 142.1, 132.0, 131.5, 129.4, 129.2, 127.4, 127.0, 126.8,
126.7, 113.9, 112.4.
3-[5-(4-Bromophenyl)-4-hydroxythiazol-2-yl]thiobenzamide
(13a)
Compound 12 (1 mmol) was dissolved in DMSO (20 mL). Aq
(NH4)2S soln (0.5 mL, 48%) was added in one portion and the mix-
ture was stirred for 30 min. Then H2O (50 mL) was added under
stirring. After 1 h the crude product was filtered off and recrystal-
lized (EtOH–DMF) and dried in vacuo; deep-yellow powder; yield:
94%; mp 300 °C.
MS (EI): m/z (%) = 604 (16) [M+], 305 (8), 196 (22), 163 (100), 121
(93), 91 (86), 79 (43).
IR (ATR): 3282, 3087, 2881, 1651, 1485, 1353, 1300, 1234, 999,
690 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 11.94 (s, 1 H), 10.02 (s, 1 H),
9.68 (s, 1 H), 8.45 (s, 1 H), 7.98 (d, J = 7.9 Hz, 1 H), 7.91 (d, J = 7.9
Hz, 1 H), 7.70–7.51 (m, 5 H).
UV/Vis (DMSO): lmax = 416 nm; deprotonated (KOH) lmax
=
=
553 nm.
Fluorescence (DMSO): lmax = 533 nm; deprotonated (KOH) lmax
630 nm.
13C NMR (62.5 MHz, DMSO-d6): d = 199.7, 159.7, 159.6, 140.9,
2,2¢-Pyridine-2,4-diylbis(5-methylthiazol-4-ol) (9)
132.9, 132.2, 131.5, 129.5, 128.9, 128.2, 128.0, 125.4, 119.3, 107.4.
Following the typical procedure4 using ethyl thiolactate (2.1 equiv)
and 7 (1 equiv); yellow powder; yield: 78%; mp 309 °C.
MS (EI): m/z (%) = 390 (50) [M+], 358 (43), 201 (65), 163 (33), 129
(100), 120 (42).
IR (ATR): 3001, 2665, 1591, 1420, 1126, 775 cm–1.
UV/Vis (DMSO): lmax = 378 nm; deprotonated (KOH) lmax
=
1H NMR (250 MHz, DMSO-d6): d = 10.62 (s, 1 H), 10.4 (s, 1 H),
8.58 (d, J = 4.9 Hz, 1 H), 8.24 (s, 1 H), 7.67 (m, 1 H), 2.26 (s, 3 H),
2.23 (s, 3 H).
13C NMR (62.5 MHz, DMSO-d6): d = 160.2, 159.7, 158.6, 155.0,
151.9, 151.1, 122.5, 119.45, 119.2, 113.0, 106.9, 9.8, 9.8.
480 nm.
5-(4-Bromophenyl)-2-[3-(4-hydroxy-5-phenylthiazol-2-yl)phe-
nyl]thiazol-4-ol (13b)
Following the typical procedure using 13a (1.1 equiv) and 1a (1
equiv); yellow microcrystals; yield: 65%; mp 301 °C.
MS (EI): m/z (%) = 305 (69) [M+], 218 (100), 130 (249), 59 (21).
IR (ATR): 2916, 2553, 1566, 1415, 1392, 1049, 750 cm–1.
UV/Vis (DMSO): lmax = 365 nm; deprotonated (KOH) lmax
=
=
1H NMR (250 MHz, DMSO-d6): d = 11.52 (s, 1 H), 11.29 (s, 1 H),
8.43 (s, 1 H), 7.97 (m, 2 H), 7.77–7.56 (m, 7 H), 7.43 (m, 2 H), 7.26
(dd, J = 7.4 Hz, 1 H).
490 nm.
Fluorescence (DMSO): lmax = 440 nm; deprotonated (KOH) lmax
594 nm.
13C NMR (62.5 MHz, DMSO-d6): d = 159.5, 157.9, 134.2, 133.9,
132.2, 131.2, 131.1, 130.1, 129.0, 128.3, 119.6, 118.6, 112.9,
108.45.
MS (EI): m/z (%) = 508 (34) [M+], 557 (12), 279 (53), 201 (24), 121
(100).
Dimethyl 2,2¢-[2,2¢-(Pyridine-2,6-diyl)bis(4-hydroxythiazole-
5,2-diyl)]diacetate (10)
The standard procedure was applied using dimethyl mercaptosuc-
cinic acid (2.1 equiv) and 8 (1 equiv); yellow-orange powder; yield:
55%; mp 286 °C.
UV/Vis (DMSO): lmax = 380 nm; deprotonated (KOH) lmax
=
=
IR (ATR): 2954, 2619, 1731, 1558, 1404, 1203, 1064, 823 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 10.77 (s, 2 H), 8.05–8.00 (m,
1 H), 7.93 (d, J = 7.1 Hz, 2 H), 4.10 (s, 4 H), 3.65 (s, 6 H).
13C NMR (62.5 MHz, DMSO-d6): d = 171.1, 160.8, 160.6, 150.7,
139.8, 118.9, 103.9, 61.1, 30.2.
489 nm.
Fluorescence (DMSO): lmax = 427 nm; deprotonated (KOH) lmax
627 nm.
Anal. Calcd for C24H15BrN2O2S2: C, 56.81; H, 2.98; N, 5.52; S,
12.64; Br, 15.74. Found: C, 56.52; H, 3.11; N, 5.43; S, 12.62; Br,
16.04.
MS (EI): m/z (%) = 412.2 (94) [M+], 362 (92), 276.3 (45), 216
(100), 87.3 (55).
Synthesis 2011, No. 14, 2334–2339 © Thieme Stuttgart · New York

PAPER
Bis(4-hydroxythiazoles): Novel Functional and Switchable Fluorophores
2339
5,5¢-(1,4-Phenylene)bis[2-(pyridin-2-yl)thiazol-4-ol] (15)
A mixture of 14 (0.41 g, 1 mmol), 5c (0.276 g, 2 mmol), and pyri-
dine (1 mL) was stirred in DMF (5 mL) and heated to 100 °C for 2
h. After cooling, EtOH (25 mL) was added and the slurry was fil-
tered off. The pure compound was obtained after recrystallization
(hot DMSO); buff-colored powder; yield: 22%; mp >360 °C.
IR (ATR): 2978, 2549, 1562, 1458, 1408, 1101, 817, 771 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 11.32 (s, 2 H), 8.62 (s, 2 H),
8.01–7.96 (m, 6 H), 7.83 (s, 2 H), 7.46 (s, 2 H).
(2) Kedersky, F. A. J.; Holms, J. H.; Moore, J. L.; Bell, R. L.;
Dyer, R. D.; Carter, G. W.; Brooks, D. W. J. Med. Chem.
1991, 34, 2158.
(3) Rzasa, R. M.; Kaller, M. R.; Lia, G.; Magal, E.; Nguyen, T.
T.; Osslund, T. D.; Powers, D.; Satora, V. S.; Viswanadhan,
V. N.; Wang, H.-L.; Xiong, X.; Zhong, W.; Norman, H. M.
Bioorg. Med. Chem. 2007, 15, 6574.
(4) (a) Stippich, K.; Weiß, D.; Güther, A.; Görls, H.; Beckert, R.
J. Sulfur Chem. 2009, 30, 109. (b) Grummt, U.-W.; Weiss,
D.; Birckner, E.; Beckert, R. J. Phys. Chem. A 2007, 111,
1104.
(5) Täuscher, E.; Weiß, D.; Beckert, R.; Görls, H. Synthesis
2010, 1603.
13C NMR (62.5 MHz, DMSO-d6): d = 160.8, 159.3, 150.8, 150.2,
138.0, 130.4, 127.0, 125.2, 118.9, 111.3.
MS (EI): m/z (%) = 430 (100) [M+], 309 (6), 204 (11), 121 (9), 105
(6) Täuscher, E.; Weiß, D.; Beckert, R.; Fabian, J.; Assumpção,
A.; Görls, H. Tetrahedron Lett. 2011, 52, 2292.
(7) (a) Ma, Q.; Xu, Z.; Schroeder, B. R.; Sun, W.; Wei, F.;
Hashimoto, S.; Konishi, K.; Leitheiser, C. J.; Hecht, S. M.
J. Am. Chem. Soc. 2007, 129, 12439. (b) Claussen, C. A.;
Long, E. C. Chem. Rev. 1999, 99, 2797. (c) Ninomiya, K.;
Satoh, H.; Sugiyama, T.; Shinomiya, M.; Kuroda, R. Chem.
Commun. 1996, 1825. (d) Glover, C.; Merritt, E. A.; Bagley,
M. C. Tetrahedron Lett. 2007, 48, 7027. (e) Chen, H.-J.;
Wang, W.-L.; Wang, G.-F.; Shi, L.-P.; Gu, M.; Ren, Y.-D.;
Hou, L.-F.; He, P.-L.; Zhu, F.-H.; Zhong, X.-G.; Tang, W.;
Zuo, J.-P.; Nan, F.-J. ChemMedChem 2008, 3, 1316.
(8) (a) Ando, S.; Murakami, R.; Nishida, J.; Tada, H.; Inoue, Y.;
Tokito, S.; Yamashita, Y. J. Am. Chem. Soc. 2005, 127,
14996. (b) Nakagawa, T.; Atsumi, K.; Nakashima, T.;
Hasegawa, Y.; Kawai, T. Chem. Lett. 2007, 36, 372.
(c) MacLean, B. J.; Pickup, P. G. J. Mater. Chem. 2001, 11,
1357.
(9) Mutha, S. C.; Ketcham, R. J. Org. Chem. 1969, 34, 2053.
(10) Helal, A.; Lee, S. H.; Kim, S. H.; Kim, H.-S. Tetrahedron
Lett. 2010, 51, 3531.
(11) Tomalia, D. A.; Paige, J. N. J. Org. Chem. 1973, 38, 3949.
(12) Elguero, J.; Marzin, C.; Katritzky, A. R.; Linda, P. In
Advances in Heterocyclic Chemistry; Katritzky, A. R.;
Boulton, A. J., Eds.; Academic Press: San Diego, 1976, 369;
and references therein.
(23).
UV/Vis (DMSO): lmax = 432 nm; deprotonated (KOH) lmax
620 nm.
=
=
Fluorescence (DMSO): lmax = 532 nm; deprotonated (KOH) lmax
703 nm.
2,2¢-Bis[4-hydroxy-5-(4-methoxyphenyl)thiazol-2-yl]-5,5¢-bis(4-
methoxyphenyl)-5,5¢-bithiazole-4,4¢(5H,5¢H)-dione (16)
Compound 3b (0.41 g, 1 mmol) was dissolved in DMSO (50 mL),
then a soln of CuCl2 (1.7 g 10 mmol) in H2O (5 mL) was added in
one portion. The resulting deep blue-lilac mixture was stirred for 30
min and then filtered off. The compound obtained was dissolved in
hot DMSO. Upon slow cooling to r.t. the pure compound was ob-
tained; green-shining, glossy dark red crystals; yield: 15%; mp 300–
305 °C.
IR (ATR): 1697, 1624, 1473, 1374, 1150, 1026, 7, 808 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 12.32 (s, 2 H), 7.95–7.76 (m,
8 H), 7.03–6.91(m, 8 H), 3.79 (s, 6 H), 3.67 (s, 6 H).
13C NMR (62.5 MHz, DMSO-d6): d = due to the low solubility of
this compound no spectra could be recorded.
MS (EI): m/z (%) = 412 (52) [M/2+], 397 (9), 232 (67), 151 (77), 73
(100).
UV/Vis (DMSO): lmax = 500 nm.
(13) Singh-Rachford, T. N.; Nayak, A.; Muro-Small, M. L.;
Goeb, S.; Therien, M. J.; Castellano, F. N. J. Am. Chem. Soc.
2010, 132, 14203.
Fluorescence (DMSO): lmax = 564 nm.
(14) Menzel, R.; Täuscher, E.; Weiß, D.; Beckert, R.; Görls, H. Z.
Anorg. Allg. Chem. 2010, 636, 1380.
Acknowledgment
(15) Toda, F.; Tanaka, K.; Iwata, S. J. Org. Chem. 1989, 54,
3007.
(16) COLLECT, Data Collection Software, Nonius B.V.,
Netherlands, 1998.
We are very grateful for the financial support by DAAD (grant for
Lorena Calderón-Ortiz). We are grateful for the measurement and
discussion of: ESR spectra (Dr M. Friedrich)b, MS-spectra (Dr. D.
Berg and Dr W. Poppitz)b, fluorescence measurement (Dr. E. Birck-
ner and E. Kielmann; FSU Jena, IPC, Jena 07743, Germany) and
NMR spectra (Dr. W. Günther)a. A special thanks goes to Prof. Fe-
lix. N. Castellano and Dr. Jörg Blumhoff (Department of Chemistry
& Center for Photochemical Sciences, Bowling Green State Univer-
sity Bowling Green, Ohio 43403, USA) for the measurement of the
fluorescence life time.
(17) Otwinowski, W.; Minor, W. Methods Enzymol. 1997, 276,
307.
(18) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 46, 112.
(19) Supporting Information Available: Crystallographic data
deposited at the Cambridge Crystallographic Data Centre
under CCDC-813194 for 4a, and CCDC-813195 for 16
contain the supplementary crystallographic data excluding
structure factors; this data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html, or from the
Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44(1223)336033; or
deposit@ccdc.cam.ac.uk.
References
(1) Liebscher, J. Houben-Weyl, 4th ed., Vol. E8b; Georg
Thieme: Stuttgart, 1993, 1; and references therein.
Synthesis 2011, No. 14, 2334–2339 © Thieme Stuttgart · New York