Synthesis and study of 2-(2-thienyl)benzazole type fluorophores

Article abstract of DOI:10.1081/SCC-120018752

Reaction of 2-(mercaptomethyl)benzazoles 2a-c or isothiouronium salt 4 with acetyleneketone 5 or β-halogeno-α,β-unsaturated aldehyde 7 gives highly fluorescent heterocycles 6a-c or 8a-d. The fluorescence properties of these compounds and their aromatised

Full text of DOI:10.1081/SCC-120018752

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Synthesis and Study of 2-(2-Thienyl)benzazole Type
Fluorophores
c
Tamás Kálai a , József Jekő , Erzsébet Ősz b & Kálmán Hideg a
a Department of Organic and Medicinal Chemistry , University of Pécs , Pécs, Hungary
b Department of Biochemistry and Medical Chemistry , University of Pécs , Pécs, Hungary
c ICN Hungary , Tiszavasvári, Hungary
Published online: 16 Aug 2006.
To cite this article: Tamás Kálai , József Jekő , Erzsébet Ősz & Kálmán Hideg (2003) Synthesis and Study of 2-(2-
Thienyl)benzazole Type Fluorophores, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:9, 1433-1442, DOI: 10.1081/SCC-120018752
To link to this article: http://dx.doi.org/10.1081/SCC-120018752
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 9, pp. 1433–1442, 2003
Synthesis and Study of 2-(2-Thienyl)benzazole
Type Fluorophores
00
00
Tamas Kalai,1 Jozsef Jeko,3 Erzsebet Osz,2
and Kalman Hideg1,
*
1Department of Organic and Medicinal Chemistry, and
2Department of Biochemistry and Medical Chemistry
University of Pecs, Pecs, Hungary
3ICN Hungary, Tiszavasvari, Hungary
ABSTRACT
Reaction of 2-(mercaptomethyl)benzazoles 2a–c or isothiouronium
salt
4 with acetyleneketone 5 or b-halogeno-a,b-unsaturated
aldehyde 7 gives highly fluorescent heterocycles 6a–c or 8a–d. The
fluorescence properties of these compounds and their aromatised
derivatives 9a,b were investigated.
Key Words: Benzazoles; Vilsmeyer-Hack reaction; Fluorescent
dye; Fiesselmann reaction.
*Correspondence: Kalman Hideg, Department of Organic and Medicinal
Chemistry, University of Pecs, H-7602 Pecs, P.O. Box 99, Szigeti st. 12.
Hungary; Fax: 36 72 536-219; E-mail: kalman.hideg@aok.pte.hu.
1433
DOI: 10.1081/SCC-120018752
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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1434
Kalai et al.
Benzazoles have been found to exhibit unique properties in pharma-
cology[1,2] and they are also important building blocks of different
dyes,[3–5] herbicides and polymers.[6] In our laboratory a new method was
developed for the synthesis of 2-(2-thienyl)benzimidazoles[7–9] starting
from 2-(mercaptomethyl)benzimidazole and b-electrophilic esters. 2-(2-
Thienyl)benzimidazoles exhibited strong fluorescence,[8] therefore we
found desirable to extend this method for benzothiazoles, benzoxazoles
as starting thiols and b-halogeno-a,b-unsaturated aldehydes as electro-
philic partners. b-Halogeno-a,b-unsaturated aldehydes are easily avail-
able by Vilsmeier-Hack reaction[10] of ketones ensuring high variability.
Our aimwas to evaluate the structure and steady-state fluorescence
relationship of these compounds to develop new fluorescent dyes.
The polyaromatic compounds presented here are also available by the
reaction of thiophene-2-carboxylic acid of thiophene-2-carbaldehyde
derivatives with ortho-substituted anilines[11] but sometimes under harsh
conditions or using more expensive palladium catalysed cross-coupling
reactions.[12]
The 2-chloromethylbenzoxazole (1a) and 2-chloromethylbenzothia-
[14]
zole (1b)[13] were treated with Na2CS3
to give 2-mercaptomethyl-
benzoxazole (2a) and 2-mercaptomethylbenzothiazole 2b,[15] respectively.
Compounds 2a and 2b proved to be unstable in our hands, thus these
derivatives were converted into thienyl derivatives immediately after
isolation. Reaction of 2-amino-4-methyl-benzenethiol (3)[16] with chloro-
acetyl chloride in EtOAc[17] followed by treatment with thiourea afforded
a more conveniently handle isothiouronium salt (4) fromwhich a thiol
can be liberated in situ.
The 2-mercaptomethylbenzimidazole (2c) was obtained by Phillips
reaction[18] (Sch. 1). Reaction of 2a or 2b with 4-phenyl-3-butyn-2-one
(5) in acetonitrile in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) catalyst at 82ꢀC gave 2-(3-methyl-5-phenyl-2-thienyl)benzoxazole
(6a) and 2-(3-methyl-5-phenyl-2-thienyl)benzothiazole (6b), respectively.
Reactions of thiols (2a–c) and 4 with 1-chloro-3,4-dihydro-6-methoxy-
naphthalene-2-carboxaldehyde (7)[19] in the presence of 1.1 or 2.1 (in case
of 4) equivalent DBU at r.t. gave 2-(7-methoxy-4,5-dihydro-naphtho[1,2-
b]-thien-2-yl)benzoxazole (8a), 2-(7-methoxy-4,5-dihydro-naphtho[1,2-b]-
thien-2-yl)benzothiazole (8b), 2-(7-methoxy-4,5-dihydro-naphtho[1,2-b]-
thien-2-yl)benzimidazole (8c), and 5-methyl-2-(7-methoxy-4,5-dihydro-
naphtho[1,2-b]thien-2-yl)benzothiazole (8d), respectively.
Aromatization of compounds 8b and 8d with 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone (DDQ) in benzene gave 2-(7-methoxy-
naphtho[1,2-b]thien-2-yl)benzothiazole 9a and 5-methyl-2-(7-methoxy-
naphtho[1,2-b]thien-2-yl)benzothiazole 9b (Sch. 2).

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Synthesis and Study of Fluorophores
1435
Scheme 1. Reagents and conditions: (a) Na2CS3 (2.0 equiv.), H2O, r.t. 1.5 h, then
NH4Cl (25–40%); (b) ClCH2COCl (1 equiv.), Et3N, EtOAc, 0ꢀC ! r.t. 1.5 h, then
(NH2)2CS (1.0 equiv.), EtOH, 78ꢀC, 3 h, (76%).
Scheme 2. Reagents and conditions: (a) DBU (0.1 equiv.), acetonitrile, 82ꢀC, 2 h,
(40–52%); (b) DBU (1.1 equiv.) or (2.1 equiv. in case of 4), acetonitrile, r.t. 1 h, then
82ꢀC, 30 min. (35–50%); (c) DDQ (1.0 equiv.), benzene, 78ꢀC, 1 h, (74–81%).
Steady-state fluorescence properties of compounds 6, 8, and 9
(Table 1) suggest that inserting a C2H4 bridge between the thiophene and
the benzene ring (8a–d) as well as OCH3 substituent increase the quantum
yield and result batochromic shift compared to compounds without

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1436
Kalai et al.
Table 1. Fluorescence properties of compounds 6, 8, and 9.
Compound
ꢀex
ꢀem
ꢁ
6a
6b
6c
8a
8b
8c
9a
344
362
344
374
384
372
362
416
430
418
444
462
432
434
0.88
0.65
0.66
0.78
0.93
0.77
0.43
bridge (6a–c). This presumably can be justified by a decrease in rotational
freedomdegree and better conjugation. We have found the best quantum
yields and longest emission wavelengths in the case of benzothiazoles in
comparison with other benzazoles which is in complete accordance with
Costa and co-worker’s findings.[20] However, aromatization of benzo-
thiazole (8b, 8d) caused decrease in quantumyield (about 50%) and
caused blue shift (about 30 nm).
In conclusion, a new, simple and mild procedure was developed for
the synthesis of benzazole type fluorophores and polycyclic 2-(2-thienyl)-
benzazoles. Among the studied compounds, partially saturated, 2-(2-
thienyl)benzothiazole type fluorophores were found to exhibit the most
advantageous fluorescence properties.
EXPERIMENTAL
Melting points were determined with a Boetius micro melting point
apparatus and are uncorrected. Elemental analyses (C, H, N, S) were
performed on Carlo Erba EA 1110 CHNS elemental analyser. The IR
(Specord 75) spectra were in each case consistent with the assigned struc-
ture. Mass spectra were recorded on a VG TRIO-2 instrument in the EI
1
mode (70 eV, direct inlet). H NMR spectra were recorded with Varian
Unity Inova 400 WB spectrometer, chemical shifts referenced to Me4Si.
The purity of compounds was checked by HP-1100 HPLC (water/MeOH
65/35, hypersyl BDS-C18 column). Absorption spectra were collected
with Hewlett-Packard 8451A diode array spectrophotometer (2 nm
resolution), while fluorescence spectra were recorded with SLM AB2 in
acetonitrile employing 2/2 exitation–emission bandpasses. The quantum
yields are referred to quinine sulphate in 0.2 M aqueous H2SO4.[21]

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Synthesis and Study of Fluorophores
1437
Flash column chromatography was performed on Merck Kieselgel 60
(0.040–0.063 mm). Qualitative TLC was carried out on commercially
prepared plates (20 Â 20 Â 0.02 cm) coated with Merck Kieselgel GF254
.
Compounds 1a, 1b,[13] 2c,[17] 3,[16] 6c,[9] 7,[19] were prepared according to
published procedures, compound 5 was purchased fromAldrich.
Synthesis of 2-Mercaptomethylbenzoxazole (2a) and
2-Mercaptomethylbenzothiazole (2b)
To a stirred solution of Na2CS3 (made from Na2SÁ9 H2O (4.80 g,
20.0 mmol), CS2 (1.8 mL, 30.0 mmol) and 8 mL H2O) compound 1a
(1.67 g, 10.0 mmol) or compound 1b (1.83 g, 10.0 mmol) was added and
the mixture was allowed to react for 1.5 h. The mixture was filtered, the
filtrate was poured onto 10 mL aq. saturated NH4Cl solution. The amor-
phous brownish-grey precipitate was filtered, dissolved in CHCl3
(20 mL), the aqueous phase was extracted with further CHCl3 portions
(2 Â 15 mL), the combined organic phase was dried (MgSO4), filtered and
evaporated to give a brown solid residue 2a 660 mg (40%) or 2b 452 mg
(25%) which was converted further immediately in the next step.
Synthesis of
5-Methyl-2-isothiouroniummethylbenzothiazole Chloride (4)
Mixture of chloroacetyl chloride (1.13 g, 10.0 mmol), 2-amino-4-
methylbenzenethiol (3) (1.39 g, 10.0 mmol) and Et3N (1.01 g, 10.0 mmol)
in dry EtOAc (15 mL) was stirred at 0ꢀC for 1 h then 30 min at r.t. The
mixture was filtered, evaporated in vacuo, the residue was dissolved in
EtOH (20 mL), thiourea (761 mg, 10.0 mmol) was added and the mixture
was refluxed for 3 h. After cooling the solvent was evaporated, the residue
was crystallized fromacetone/EtOH to give compound 4 2.07 g (76%) as
a pale pink solid, m.p. 143–145ꢀC. Calcd. for C10H12ClN3S2: C 43.87, H
4.42, N 15.35, S 23.42; found: C 43.81, H 4.57, N 15.23, S 23.27. The
isothiouroniumsalt was used without further purification.
Reaction of 2-Mercaptomethylbenzazoles with
Acetyleneketone; General Procedure
A mixture of 2a (495 mg, 3.0 mmol) or 2b (543 mg, 3.0 mmol),
4-phenyl-3-butyn-2-one (432 mg, 3.0 mmol) and DBU (45 mg, 0.3 mmol)

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1438
Kalai et al.
in acetonitrile (10 mL) was refluxed for 2 h. After cooling the precipitated
product 6a or 6b was filtered, the filtrate was evaporated and the residue
was purified by flash column chromatography (hexane/Et2O) to give a
further crop of thienyl compound.
2-(3-Methyl-5-phenyl-thien-2-yl)benzoxazole (6a): 350 mg (40%), m.p.
131–132ꢀC. Calcd. for C18H13NOS: C 74.20, H 4.50, N 4.81, S 11.00;
found: C 74.27, H 4.57, N 4.96, S 11.20. IR (nujol) ꢂ: 1605, 1560 cmÀ1
(C¼C, C¼N).
1
MS (m/z, %): 307 (Mþ, 100), 262 (5), 171 (10). H NMR (CDCl3):
ꢃ aromatic region: 7.74 (1H), 7.65 (2H), 7.55 (1H), 7.41 (2H), 7.37–7.29
(3H), 7.21 (1H); CH3: 2.75 (3H).
2-(3-Methyl-5-phenyl-thien-2-yl)benzothiazole (6b): 480 mg (52%),
m.p. 118–120ꢀC. Calcd. for C18H13NS2: C 70.32, H 4.26, N 4.56, S
20.86 found C 70.40, H 4.30, N 4.52, S 20.61. IR (nujol) ꢂ: 1600,
1550 cmÀ1 (C¼C, C¼N). MS (m/z, %): 307 (Mþ, 100), 273 (9), 171 (8).
1H NMR (CDCl3): ꢃ aromatic region: 8.06 (1H), 7.89 (1H), 7.66 (2H),
7.49 (1H), 7.41 (2H), 7.36 (1H), 7.33 (1H), 7.20 (1H); CH3: 2.64 (3H).
Reaction of 2-Mercaptomethylbenzazoles with
1-Chloro-3,4-dihydro-6-methoxynaphthalene-
2-carboxaldehyde; General Procedure
To a solution of compound 7 (666 mg, 3.0 mmol) and 2a (495 mg,
3.0 mmol) or 2b (543 mg, 3.0 mmol) or 2c (492 mg, 3.0 mmol) or 4
(821 mg, 3.0 mmol) in acetonitrile (20 mL) DBU (501 mg, 3.3 mmol or
957 mg, 6.3 mmol in case of 4) was added and the mixture was allowed
to react at r.t. for 1 h. The precipitated product was filtered, the filtrate
was refluxed further for 30 min., after cooling the solvent was evaporated
in vacuo, the residue dissolved in CH2Cl2 (20 mL), washed with brine
(15 mL), the organic phase was dried (MgSO4), filtered and evaporated.
The residue was purified by flash chromatography (hexane/Et2O) to give
further crops of compounds 8a–d.
2-(7-Methoxy-4,5-dihydro-naphtho[1,2-b]thien-2-yl)benzoxazole (8a):
349 mg (35%), m.p. 142–144ꢀC. Calcd. for C20H15NO2S: C 72.05,
H 4.53, N 4.20, S 9.62; found: C 72.20, H 4.51, N 4.40, S 9.70. IR
(nujol) ꢂ: 1605, 1565 cmÀ1 (C¼C, C¼N). MS (m/z, %): 333 (Mþ, 100),
1
318 (38), 288 (10). H NMR (CDCl3): ꢃ aromatic region: 7.71 (1H), 7.69
(1H), 7.52 (1H), 7.38 (1H), 7.32 (2H), 6.81 (2H); CH3O: 3.84 (3H);
CH2: 2.98 (2H) and 2.88 (2H).
2-(7-Methoxy-4,5-dihydro-naphtho[1,2-b]thien-2-yl)benzothiazole (8b):
419 mg (40%), m.p. 184–186ꢀC. Calcd. For C20H15NOS2: C 68.74, H 4.33,

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Synthesis and Study of Fluorophores
1439
N 4.01, S 18.35; found: C 68.94, H 4.17, N 4.20, S 18.17. IR (nujol) ꢂ:
1605, 1575 cmÀ1 (C¼C, C¼N). MS (m/z, %): 349 (Mþ, 100), 334 (41),
304 (10). 1H NMR (CDCl3): ꢃ aromatic region: 8.00 (1H), 7.83 (1H), 7.46
(1H), 7.45 (1H), 7.37 (1H), 7.34 (1H), 6.80 (2H); CH3O: 3.84 (3H); CH2:
2.97 (2H) and 2.86 (2H).
2-(7-Methoxy-4,5-dihydro-naphtho[1,2-b]thien-2-yl)benzimidazole(8c):
498 mg (50%), m.p. 242–243ꢀC. Calcd. for C20H16N2OS: C 72.26, H 4.85,
N 8.43, S 9.64 found 72.31, H 4.99, N 8.52, S 9.77. IR (nujol) ꢂ: 1600,
1560 cmÀ1 (C¼C, C¼N). MS (m/z, %): 332 (Mþ, 100), 317 (46), 287 (11).
1H NMR (CDCl3): ꢃ aromatic region: 7.60 (2H), 7.44 (1H), 7.32 (1H),
7.25 (2H), 6.78 (1H), 6.77 (1H); CH3O: 3.82 (3H); CH2: 2.95 (2H) and
2.83 (2H).
5-Methyl-2-(7-methoxy-4,5-dihydro-naphtho[1,2-b]thien-2-yl)benzothia-
zole (8d): 468 mg (43%), m.p. 189–191ꢀC. Calcd. for C21H17NOS2: C
69.39, H 4.71, N 3.85, S 17.64, found C 69.31, H 4.61, N 4.02, S 17.82.
IR (nujol) ꢂ: 1605, 1560 cmÀ1 (C¼C, C¼N). MS (m/z, %): 363 (Mþ, 100),
1
348 (40), 318 (11). H NMR (CDCl3): ꢃ aromatic region: 7.80 (1H), 7.69
(1H), 7.42 (1H), 7.37 (1H), 7.17 (1H), 6.79 (2H); CH3O: 3.83 (3H); CH2:
2.96 (2H) and 2.85 (2H); CH3: 2.49 (3H).
Aromatization of Benzazole Derivatives; General Procedure
To a solution of compound 8b (349 mg, 1.0 mmol) or 8d (363 mg,
1.0 mmol) in benzene (20 mL) DDQ (227 mg, 1.0 mmol) was added and
the mixture was refluxed for 1 h. After cooling, the mixture was filtered,
the filtrate was evaporated, the residue was dissolved in EtOAc (20 mL),
washed with 10% aq. K2CO3 (10 mL), dried (MgSO4), filtered, evapo-
rated and the residue was purified by flash column chromatography
(hexane/Et2O) to give compound 9a or 9b.
2-(7-Methoxy-naphtho[1,2-b]thien-2-yl)benzothiazole (9a): 281 mg
(81%), m.p. 208–210ꢀC. Calcd. for C20H13NOS2: C 69.14, H 3.77, N
4.03, S 18.45; found C 69.32, H 3.97, N 4.02, S 18.60. IR (nujol) ꢂ:
1605, 1580, 1550 cmÀ1 (C¼C, C¼N). MS (m/z, %): 347 (Mþ, 100), 332
(17), 304 (62). 1H NMR (CDCl3): ꢃ aromatic region: 8.09 (1H), 8.07 (1H),
7.96 (1H), 7.89 (1H), 7.78 (1H), 7.67 (1H), 7.50 (1H), 7.39 (1H), 7.27
(2H); CH3O: 3.96 (3H).
5-Methyl-2-(7-methoxy-naphtho[1,2-b]thien-2-yl)benzothiazole (9b):
268 mg (74%), m.p. 189–191ꢀC. Calcd. for C21H15NOS2: C 69.78, H
4.18, N 3.87, S 17.74; found C 69.60, H 4.11, N 4.00, S 17.91. IR
(nujol) ꢂ: 1605, 1575, 1550 cmÀ1 (C¼C, C¼N). MS (m/z, %): 361 (Mþ,
100), 346 (15), 318 (40). 1H NMR (CDCl3): ꢃ aromatic region: 8.06 (1H),

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1440
Kalai et al.
7.94 (1H), 7.88 (1H), 7.76 (2H), 7.66 (1H), 7.27 (2H), 7.22 (1H); CH3O:
3.96 (3H); CH3: 2.51 (3H).
ACKNOWLEDGMENT
This work was supported by grant fromHungarian National
Research Foundations (OTKA T34307 and M 028226). The authors
thank to Prof. Neil V. Blough (Univeristy of Maryland, College Park,
USA) for the possibility and helpful discussions in fluorescence measure-
ments and M. Szabo for mass spectral measurements (ICN, Hungary).
One of authors (T. K.) thanks for Eotvos fellowship for Hungarian
Ministry of Education.
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Received in the Netherlands May 22, 2002