Bis(4-hydroxythiazoles): Novel Functional and Switchable Fluorophores

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 visible spectrum, whereas the emission is shifted bathochromically upon deprotonation. This easy switch makes them suitable for widespread applications, mainly in analysis and supramolecular chemistry. Due to their 1,4-diazadiene substructure, the 2,2′-bithiazoles possess prerequisites for the complexation of metals, however, instead of a copper complex, a dimer which constitutes the 5,5′-C-C coupled product was isolated. In addition, tris(thiazoles) could be constructed.

4-Hydroxythiazoles are well-known compounds [¹] and there are known biologically active derivatives. [²] [³] In contrast to their biological data, there is hardly any information on their physicochemical properties such as color and fluorescence. Therefore, we have been working on the syntheses and applications of 2,5-disubstituted 4-hydroxy­thiazoles. [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 calculations were carried out. [6]

Therefore, we were interested in the synthesis of systems with more than one hydroxythiazole unit as represented in 3 (2,2′-bithiazole-4,4′-diols) and 15 [5,5′-(1,4-phenylene)bis(thiazol-4-ols)]. Molecules containing two or more thiazole rings play an important role in both biochemistry [7] 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 α-mercapto acids, some 2,2′-bis(thiazoles) possessing hydroxy groups in the 4,4′-positions were synthesized. [9] Recently, a new bithiazole chemosensor with phenolic substituents at the 2,2′-positions of the thiazole rings was reported. [¹0]

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 successfully employed for the synthesis of a series of 2,2′-bis(thiazoles), however, without hydroxy groups. [¹¹] According to the conditions of the classical Hantzsch synthesis, dithiooxamide (2) was cyclized with α-aryl-α-bromoacetic acids 1a-c at 80-100 ˚C in the presence of a base, such as pyridine. As depicted in Scheme  [¹] , three different 4,4′-dihydroxy-substituted 2,2′-bithiazoles were prepared 60-75% yields. It should be noted that at higher temperatures (>130 ˚C), considerable amounts of O-alkylation products (monoethyl ether/diethyl ether of 3) were formed as byproducts.

Being typical aromatic hydroxy derivatives (heterocyclic phenols), the bithiazoles 3 can easily be alkylated; for example, 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, starting from pyridine-2,4,6-tricarbothioamide (5b) in good yields.

Alternatively, 9 and 10 can be prepared from 2,5-dicyano­pyridine (7) or 2,6-dicyanopyridine (8) and thiolactic acid esters or thiomalic acid esters, as described earlier. [²] However, attempts to prepare a system with three different thiazole subunits failed, giving only mixtures of all possible isomers. Nevertheless, we finally succeeded in synthesizing mixed thiazoles, such as compound 13b, using a stepwise 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(thia­zoles) is part of our ongoing research.

Furthermore, a new bis(hydroxythiazole) derivative 15 was prepared by the condensation reaction of two molecules of thioamide 5c with bis(bromoacetate) 14 under the reaction conditions mentioned above; the 5,5′-bithiazole 15 was isolated in 22% yield.

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 tetrahydrofuran. 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. Elementary analysis of 3c was performed on a high-vacuum-­sublimed sample (˜260 ˚C, 9 × 10^-6 mbar).

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 fluorescence [3a λ_max = 449 nm, λ_max(em) = 528 nm, t _1/2 = 2.8 ns, Φ = 96% (Rh 6G)]. For fluorescence intensity decay 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, λ_ex = 400 nm. [¹³] Upon deprotonation in dimethyl sulfoxide, the bi(hydroxythiazole) derivatives of type 3 form deep violet solutions of their dianions (3a/dianion: λ_max = 656 nm, Figure  [²] ), which display a deep red fluorescence. Generally, 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.

Apparently, solutions of the anions react rapidly with carbon dioxide from the air with reformation of the OH derivative. ESR data of deprotonated 15 proved the existence of radicals. The first analysis showed one radical 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 reversible two-electron redox system in which the radical represents the SEM-form (extended hydroquinone). Additional research is in progress at the moment and will be reported.

Due to their 1,4-diazadiene subunit, the bithiazoles 3 furfil the preconditions for the construction of metal complexes. [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 attached to copper(II) chloride, however, due to its low solubility, all attempts to obtain single crystals suitable for X-ray analysis have failed so far. Treatment of the complex with dimethyl sulfoxide in the presence of air generated 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] ).

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 unambiguous proof of its structure (Figure  [³] ).

The unexpected structure of 16 consists of two molecules of the starting material which are linked at the5,5′-positions. 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 dimerization reaction shows remarkable similarity to the oxidative coupling reaction of 2-naphthol. [¹5]

Reagents were purchased from commercial sources and were used directly unless otherwise stated in the text. Aq 48% (NH₄)₂S solution 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 recorded on Bruker AVANCE 250 and 400 spectrometers, shifts (δ) are given relative to signals arising from the solvent. Melting points were measured with a Galen III apparatus (Boëtius system) and are corrected.

Crystal structure determination: The intensity data were collected on a Nonius KappaCCD diffractometer, using graphite-monochromated MoKα radiation. Data were corrected for Lorentz and polarization effects, but not for absorption. [¹6] [¹7]

The structure was solved by direct methods (SHELXS) [¹7] and refined by full-matrix least squares techniques against Fo^² (SHELXL-97). [¹8] All hydrogen atoms for the compound 4a and for the hydroxy group O3 for compound 16 were located by difference Fourier synthesis and refined isotropically. XP (Siemens Analytical X-ray Instruments, Inc.) was used for structure representations. [¹9]

Crystal Data for 4a: C₂₂H₂₀N₂O₂S₂, M _r  = 408.52 g mol^-¹, red prism, size 0.05 × 0.05 × 0.03 mm^³, monoclinic, space group P2₁/c, a = 4.9317(3), b = 10.1208(9), c = 19.491(2) Å, β = 95.265(5)˚, V = 968.7(1) Å^³, T = -140 ˚C, Z = 2, ρ_calcd = 1.401 g cm^-³, µ(MoKα) = 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˚ ≤ Θ ≤ 27.47˚, completeness Θ_max = 99.8%, 2220 independent reflections, R _int = 0.1459, 1346 reflections with F _o > 4σ(F _o), 167 parameters, 0 restraints, R1_obs = 0.0539, wR ^² _obs = 0.1091, R1_all = 0.1165, wR ^² _all = 0.1317, GOOF = 0.969, largest difference peak and hole: 0.320/-0.488 e Å^-³.

Crystal Data for 16: C₄₀H₃₀N₄O₈S₄ 2 C₃H₇NO, M _r  = 969.11 g mol^-¹, red-brown prism, size 0.05 × 0.05 × 0.04 mm^³, monoclinic, space group P2₁/n, a = 10.4220(4), b = 21.1752(9), c = 10.6172(4) Å, β = 107.599(2)˚, V = 2233.42(15) Å^³, T = -140 ˚C, Z = 2, ρ_calcd = 1.441 g cm^-³, µ (MoKα) = 2.8 cm^-¹, F(000) = 1012, 13706 reflections in h(-13/13), k(-21/27), l(-13/13), measured in the range 2.26˚ ≤ Θ ≤ 27.49˚, completeness Θ_max = 99.4%, 5101 independent reflections, R _int = 0.0577, 3746 reflections with F _o > 4σ(F _o), 306 parameters, 0 restraints, R1_obs = 0.0614, wR ^² _obs = 0.1225, R1_all = 0.0959, wR ^² _all = 0.1395, GOOF = 1.075, largest difference 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 thio­amide 2 or 5 (10 mmol) and the corresponding ethyl bromophenyl­acetate 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 filtration the crude product was recrystallized (EtOH-DMF) and dried in vacuo.

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-d ₆): δ = 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-d ₆): δ = 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 (DMSO): λ_max = 445 nm; deprotonated (KOH) λ_max = 580 nm.

Fluorescence (DMSO): λ_max = 528 nm; Φ = 96% (Rh 6G), t _1/2 = 2.8 ns; deprotonated (KOH) λ_max = 656 nm. Φ = 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): 2654, 2553, 1380, 1423, 1207, 1006, 808 cm^-¹.

^¹H NMR (250 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 159.5, 153.2, 132.2, 131.1, 128.6, 119.6, 110.2.

MS (EI): m/z (%) = 512 (17), 510 (23), 508 (14), 283 (31), 201 (100), 199 (93), 121 (50), 120 (69).

UV/Vis (DMSO): λ_max = 455 nm; deprotonated (KOH) λ_max = 530 nm.

Fluorescence (DMSO): λ_max = 520 nm; deprotonated (KOH) λ_max = 645 nm.

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-d ₆): δ = 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-d ₆): δ = 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).

UV/Vis (DMSO): λ_max = 466 nm; deprotonated (KOH) λ_max = 620 nm.

Fluorescence (DMSO): λ_max = 535 nm; deprotonated (KOH) λ_max = 649 nm.

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.

4,4′-Diethoxy-5,5′-diphenyl-2,2′-bithiazole (4a)

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 monitoring, CHCl₃). Then, H₂O (50 mL) was added and the formed suspension 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.

IR (ATR): 1519, 1469, 1330, 1060, 760, 686 cm^-¹.

^¹H NMR (250 MHz, CDCl₃): δ = 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): δ = 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).

UV/Vis (THF): λ_max = 442 nm.

Fluorescence (THF): λ_max = 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.

Pyridine-2,4,6-tricarbothioamide (5b)

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, recrystallized (DMF) and dried in vacuo; yellow powder; yield: 56%; mp >300 ˚C (decomp.).

IR (ATR): 3371, 3263, 3159, 1581, 1420, 1265, 644 cm^-¹.

^¹H NMR (250 MHz, DMSO-d ₆): δ = 10.51-10.06 (m, 6 H), 8.95 (s, 2 H).

^¹³C NMR (62.5 MHz, DMSO-d ₆): δ = 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).

HRMS (ESI): m/z calcd for C₈H₈N₄S₃: 255.9911; found: 255.9921.

UV/Vis (DMSO): λ_max = 350 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).

IR (ATR): 3024, 2450, 1540, 1384, 1211, 751 cm^-¹.

^¹H NMR (250 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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.

MS (EI): m/z (%) = λ_max 429 (44) [M⁺], 280 (55), 130 (23), 121 (100).

UV/Vis (DMSO): λ_max = 400 nm; deprotonated (KOH) λ_max = 540 nm.

Fluorescence (DMSO): λ_max = 543 nm; deprotonated (KOH) λ_max = 697 nm.

2,2′,2′′-(Pyridine-2,4,6-triyl)tris(5-phenylthiazol-4-ol) (6b)

Following the typical procedure using 1a (3.2 equiv) and 5b (1 equiv); yellow powder; yield: 55%; mp 338 ˚C.

IR (ATR): 3090, 2557, 1593, 1381, 1207, 752 cm^-¹.

^¹H NMR (250 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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.

MS (EI): m/z (%) = 604 (16) [M⁺], 305 (8), 196 (22), 163 (100), 121 (93), 91 (86), 79 (43).

UV/Vis (DMSO): λ_max = 416 nm; deprotonated (KOH) λ_max = 553 nm.

Fluorescence (DMSO): λ_max = 533 nm; deprotonated (KOH) λ_max = 630 nm.

2,2′-Pyridine-2,4-diylbis(5-methylthiazol-4-ol) (9)

Following the typical procedure [4] using ethyl thiolactate (2.1 equiv) and 7 (1 equiv); yellow powder; yield: 78%; mp 309 ˚C.

IR (ATR): 3001, 2665, 1591, 1420, 1126, 775 cm^-¹.

^¹H NMR (250 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 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.

MS (EI): m/z (%) = 305 (69) [M⁺], 218 (100), 130 (249), 59 (21).

UV/Vis (DMSO): λ_max = 365 nm; deprotonated (KOH) λ_max = 490 nm.

Fluorescence (DMSO): λ_max = 440 nm; deprotonated (KOH) λ_max = 594 nm.

Dimethyl 2,2′-[2,2′-(Pyridine-2,6-diyl)bis(4-hydroxythiazole-5,2-diyl)]diacetate (10)

The standard procedure was applied using dimethyl mercaptosuccinic acid (2.1 equiv) and 8 (1 equiv); yellow-orange powder; yield: 55%; mp 286 ˚C.

IR (ATR): 2954, 2619, 1731, 1558, 1404, 1203, 1064, 823 cm^-¹.

^¹H NMR (250 MHz, DMSO-d ₆): δ = 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-d ₆): δ = 171.1, 160.8, 160.6, 150.7, 139.8, 118.9, 103.9, 61.1, 30.2.

MS (EI): m/z (%) = 412.2 (94) [M⁺], 362 (92), 276.3 (45), 216 (100), 87.3 (55).

UV/Vis (DMSO): λ_max = 365 nm.

Fluorescence (DMSO): λ_max = 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.

^¹H NMR (250 MHz, DMSO-d ₆): δ = 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).

^¹³C NMR (62.5 MHz, DMSO-d ₆): δ = 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).

UV/Vis (DMSO): λ_max =  381 nm; deprotonated (KOH) λ_max = 510 nm.

Fluorescence (DMSO): λ_max = 426 nm; deprotonated (KOH) λ_max = 621 nm.

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 mixture was stirred for 30 min. Then H₂O (50 mL) was added under stirring. After 1 h the crude product was filtered off and recrystallized (EtOH-DMF) and dried in vacuo; deep-yellow powder; yield: 94%; mp 300 ˚C.

IR (ATR): 3282, 3087, 2881, 1651, 1485, 1353, 1300, 1234, 999, 690 cm^-¹.

^¹H NMR (250 MHz, DMSO-d ₆): δ = 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).

^¹³C NMR (62.5 MHz, DMSO-d ₆): δ = 199.7, 159.7, 159.6, 140.9, 132.9, 132.2, 131.5, 129.5, 128.9, 128.2, 128.0, 125.4, 119.3, 107.4.

MS (EI): m/z (%) = 390 (50) [M⁺], 358 (43), 201 (65), 163 (33), 129 (100), 120 (42).

UV/Vis (DMSO): λ_max = 378 nm; deprotonated (KOH) λ_max = 480 nm.

5-(4-Bromophenyl)-2-[3-(4-hydroxy-5-phenylthiazol-2-yl)phenyl]thiazol-4-ol (13b)

Following the typical procedure using 13a (1.1 equiv) and 1a (1 equiv); yellow microcrystals; yield: 65%; mp 301 ˚C.

IR (ATR): 2916, 2553, 1566, 1415, 1392, 1049, 750 cm^-¹.

^¹H NMR (250 MHz, DMSO-d ₆): δ = 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).

^¹³C NMR (62.5 MHz, DMSO-d ₆): δ = 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).

UV/Vis (DMSO): λ_max = 380 nm; deprotonated (KOH) λ_max = 489 nm.

Fluorescence (DMSO): λ_max = 427 nm; deprotonated (KOH) λ_max = 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.

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 pyridine (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 filtered 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-d ₆): δ = 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).

^¹³C NMR (62.5 MHz, DMSO-d ₆): δ = 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 (23).

UV/Vis (DMSO): λ_max = 432 nm; deprotonated (KOH) λ_max = 620 nm.

Fluorescence (DMSO): λ_max = 532 nm; deprotonated (KOH) λ_max = 703 nm.

2,2′-Bis[4-hydroxy-5-(4-methoxyphenyl)thiazol-2-yl]-5,5′-bis(4-methoxyphenyl)-5,5′-bithiazole-4,4′(5 H ,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 obtained; 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-d ₆): δ = 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-d ₆): δ = 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): λ_max = 500 nm.

Fluorescence (DMSO): λ_max = 564 nm.

Acknowledgment

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. Birckner and E. Kielmann; FSU Jena, IPC, Jena 07743, Germany) and NMR spectra (Dr. W. Günther)^a. A special thanks goes to Prof. Felix. N. Castellano and Dr. Jörg Blumhoff (Department of Chemistry & Center for Photochemical Sciences, Bowling Green State University Bowling Green, Ohio 43403, USA) for the measurement of the fluorescence life time.

References

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COLLECT, Data Collection Software, Nonius B.V., Netherlands, 1998.

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.  p.1 ; and references therein
  Search in Google Scholar
• 2 Kedersky FAJ. Holms JH. Moore JL. Bell RL. Dyer RD. Carter GW. Brooks DW. J. Med. Chem.  1991,  34:  2158 
  CrossrefSearch in Google Scholar
• 3 Rzasa RM. Kaller MR. Lia G. Magal E. Nguyen TT. Osslund TD. Powers D. Satora VS. Viswanadhan VN. Wang H.-L. Xiong X. Zhong W. Norman HM. Bioorg. Med. Chem.  2007,  15:  6574 
  CrossrefSearch in Google Scholar
• 4a Stippich K. Weiß D. Güther A. Görls H. Beckert R. J. Sulfur Chem.  2009,  30:  109 
  Search in Google Scholar
• 4b Grummt U.-W. Weiss D. Birckner E. Beckert R. J. Phys. Chem. A  2007,  111:  1104 
  Search in Google Scholar
• 5 Täuscher E. Weiß D. Beckert R. Görls H. Synthesis  2010,  1603 
  Thieme Connect
• 6 Täuscher E. Weiß D. Beckert R. Fabian J. Assumpção A. Görls H. Tetrahedron Lett.  2011,  52:  2292 
  CrossrefSearch in Google Scholar
• 7a Ma Q. Xu Z. Schroeder BR. Sun W. Wei F. Hashimoto S. Konishi K. Leitheiser CJ. Hecht SM. J. Am. Chem. Soc.  2007,  129:  12439 
  Search in Google Scholar
• 7b Claussen CA. Long EC. Chem. Rev.  1999,  99:  2797 
  Search in Google Scholar
• 7c Ninomiya K. Satoh H. Sugiyama T. Shinomiya M. Kuroda R. Chem. Commun.  1996,  1825 
• 7d Glover C. Merritt EA. Bagley MC. Tetrahedron Lett.  2007,  48:  7027 
  Search in Google Scholar
• 7e 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 
  Search in Google Scholar
• 8a Ando S. Murakami R. Nishida J. Tada H. Inoue Y. Tokito S. Yamashita Y. J. Am. Chem. Soc.  2005,  127:  14996 
  Search in Google Scholar
• 8b Nakagawa T. Atsumi K. Nakashima T. Hasegawa Y. Kawai T. Chem. Lett.  2007,  36:  372 
  Search in Google Scholar
• 8c MacLean BJ. Pickup PG. J. Mater. Chem.  2001,  11:  1357 
  Search in Google Scholar
• 9 Mutha SC. Ketcham R. J. Org. Chem.  1969,  34:  2053 
  CrossrefSearch in Google Scholar
• 10 Helal A. Lee SH. Kim SH. Kim H.-S. Tetrahedron Lett.  2010,  51:  3531 
  CrossrefSearch in Google Scholar
• 11 Tomalia DA. Paige JN. J. Org. Chem.  1973,  38:  3949 
  CrossrefSearch in Google Scholar
• 12 Elguero J. Marzin C. Katritzky AR. Linda P. In Advances in Heterocyclic Chemistry   Katritzky AR. Boulton AJ. Academic Press; San Diego: 1976.  p.369 ; and references therein
• 13 Singh-Rachford TN. Nayak A. Muro-Small ML. Goeb S. Therien MJ. Castellano FN. J. Am. Chem. Soc.  2010,  132:  14203 
  CrossrefSearch in Google Scholar
• 14 Menzel R. Täuscher E. Weiß D. Beckert R. Görls H. Z. Anorg. Allg. Chem.  2010,  636:  1380 
  CrossrefSearch in Google Scholar
• 15 Toda F. Tanaka K. Iwata S. J. Org. Chem.  1989,  54:  3007 
  CrossrefSearch in Google Scholar
• 17 Otwinowski W. Minor W. Methods Enzymol.  1997,  276:  307 
  PubMedSearch in Google Scholar
• 18 Sheldrick GM. Acta Crystallogr., Sect. A  2008,  46:  112 
  Search in Google Scholar

COLLECT, Data Collection Software, Nonius B.V., Netherlands, 1998.

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.