Improved synthesis of thiofluorescein

Article abstract of DOI:10.1007/s11178-005-0120-3

Thiofluorescein was synthesized in a preparative yield by successive demethylation of 3,3′-dimethoxydiphenyl sulfide to 3,3′- dihydroxydiphenyl sulfide and condensation of the latter with phthalic anhydride in H₂SO₄. The title compound was also obtained in a higher yield from 3,3′-dimethoxydiphenyl sulfide directly in a one-pot process combining the condensation in H₂SO₄ and demethylation in 2 Py·H₂SO₄. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11178-005-0120-3

Russian Journal of Organic Chemistry, Vol. 41, No. 1, 2005, pp. 57-60. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 1, 2005,
pp. 60-63.
Original Russian Text Copyright Ó 2005 by Russkikh, Konstantinova, Berezhnaya, Gerasimova, Shelkovnikov.
Improved Synthesis of Thiofluorescein
V. V. Russkikh, A. V. Konstantinova, V. N. Berezhnaya,
†
T. N. Gerasimova , and V. V. Shelkovnikov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Division, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: vsh@nioch.nsc.ru
Received June 14, 2004
Abstract—Thiofluorescein was synthesized in a preparative yield by successive demethylation of 3,3'-di-
methoxydiphenyl sulfide to 3,3'-dihydroxydiphenyl sulfide and condensation of the latter with phthalic anhydride
in H SO . The title compound was also obtained in a higher yield from 3,3'-dimethoxydiphenyl sulfide directly in
2
4
a one-pot process combining the condensation in H SO and demethylation in 2Py·H SO .
2
4
2
4
Bromo- and iodo-substituted xanthene dyes are used
in photopolymerization processes [1–4] due to high yield
of the triplet state which gives rise to effective electron
transfer from the donor molecule with formation of free
radicals. Analogous increase in the yield of the triplet
excited state is attained by replacement of the ring oxygen
atom in Fluorescein by sulfur (Thiofluorescein) [5].
The goal of the present work was to experimentally
check the above procedures for the synthesis of Thio-
fluorescein (III) and improve them using both methoxy
sulfide I and hydroxy sulfide II as initial compound. The
first stage in the synthesis of Thiofluorescein (III) is
preparation of sulfides I and II. According to the data of
[5–7], sulfide I was obtained by heating a mixture of
sodium-3-methoxybenzenethiolate with 3-iodo-1-
methoxy-benzene (Scheme 1) above 200°C in the
presence of copper powder [8]. Our attempts to reproduce
this procedure showed that the yield of sulfide I does not
exceed 52%. Schopfer and Schlapback [9] proposed to
A reliable synthesis of Thiofluorescein (3',6'-dihydroxy-
3H-spiro[2-benzofuran-1,9'-[9H]thioxanthen]-3-one) was
reported for the first time in patent [6]. 3,3'-Di-
methoxydiphenyl sulfide (I) obtained by reaction of sodium
3-methoxybenzenethiolate with 3-iodo-1-methoxybenzene
use tris(dibenzylideneacetone)dipalladium Pd (dba) as
was demethylated to 3,3'-dihydroxydiphenyl sulfide (II),
and the latter was brought into condensation with phthalic
anhydride in 80% sulfuric acid. However, neither the yield
nor other parameters of the condensation product were
given. According to Pfoertner [7], the condensation of
sulfide II with phthalic anhydride was performed in molten
2
3
efficient catalyst for analogous condensations. Under the
conditions reported in [9] [100°C, Pd (dba) ], we
2
3
synthesized sulfide I in 80% yield.
Demethylation of I was effected [6, 7] by treatment
with hydrogen iodide in acetic acid. We applied a more
ZnCl , but no experimental procedure was given. El’tsov
2
Scheme 1.
et al. [5] synthesized Thiofluorescein (III) using as
starting compound sulfide I rather than II. The condensa-
tion and demethylation stages were combined into a one-
pot process which was carried out in 80% sulfuric acid.
The target product was isolated in 32% yield after triple
reprecipitation, washing, dissolution, filtration, and
additional purification. The product was characterized only
by the analytical data (C, H) and molar absorption
coefficient in a sodium hydroxide solution.
0
H2
6+
,
20H
3
G GED ꢀ'3(SKRVꢁ
0H2
6
20H
Wꢂ%X2.ꢁꢀ3K0Hꢁ
ꢃꢄꢄ &ꢁꢀꢅꢀK
,
†
Deceased.
DPEphos is 2,2'-bis(diphenylphosphino)diphenyl ether.
1070-4280/05/4101-0057Ó2005 Pleiades Publishing, Inc.

58
RUSSKIKH et al.
Scheme 2.
(see table). After washing to remove H SO , the product
2 4
was a mixture of compounds. By column chromatography
we succeeded in isolating Thiofluorescein (III) and its
mono- and dimethyl ethers IV and V in 14, 15, and 7%
yield, respectively (see table, run no. 1). We failed to
raise the fraction of III among the products by varying
the temperature from 150 [6] to 160°C [5] and reaction
time from 1 to 2 h (run nos. 1–3). On the other hand, by
condensation of dihydroxy sulfide II with phthalic
anhydride in 80% sulfuric acid (i.e., under the conditions
described in [6]) we obtained Thiofluorescein in 74% yield
3
\ꢀꢀ+&Oꢁ
,
ꢂꢃꢄ ꢅꢄꢄ &ꢁꢀꢄꢆꢇꢀK
+
2
6
,
2+
,
Scheme 3.
&
2
2
2
ꢀ
ꢁꢂꢃ+ 62
&
2
,
2
(
run no. 4). Thus the main obstacle to prepare Thio-
&
fluorescein in a good yield according to Scheme 3 [5] is
the low efficiency of sulfuric acid as demethylating agent.
Nevertheless, this approach seems to be attractive, for it
ensures preparation of the target product directly from
methoxy sulfide I without isolation of intermediate
hydroxy sulfide II.
5
2
6
25ꢄ
,
,, 9
III, R = R' = H; IV, R = Me, R' = H; V, R = R' = Me.
efficient procedure reported for methyl phenyl ethers [10],
according to which methoxy sulfide I was hydrolyzed
with the system pyridine– HCl; the reaction was
performed at 190–200°C, and hydroxy sulfide was
obtained in 87% yield (Scheme 2). It should be noted
that compound II can be prepared directly from less
expensive and more accessible materials, 3-chlorophenol
and hydrogen sulfide [11] (yield 50–60%). However, this
procedure requires a special apparatus ensuring recycling
through the reaction zone heated to 500–560°C.
In order to improve the yield of compound III ac-
cording to Scheme 3, the resulting mixture of condensa-
tion products III–V was subjected to demethylation by
heating with pyridine hydrochloride for 0.5 h at 190–
200°C. As a result, Thiofluorescein (III) was isolated in
63% yield (run no. 5). Futhermore, we found that the
condensation and demethylation of the condensation
products can be effected in a one-pot process. For this
purpose, it is necessary to add pyridine (in an amount
required to obtain 2Py·H SO ) to the mixture in 80%
2
4
As the second stage in the synthesis of Thiofluorescein
H SO and to heat the mixture for 0.5 h at 190–200°C.
2 4
(
III) we initially examined the condensation of dimethoxy
In such a way we succeeded in isolating 76% of
Thiofluorescein (III) (run no. 6). The purity of the isolated
substances was checked by elemental analysis and
sulfide I with phthalic anhydride in 80% sulfuric acid
according to Scheme 3 (as proposed in [5]) without
preliminary conversion of I into hydroxy derivative II
1
H NMR and electron absorption spectra.
Thus successive demethylation of sulfide I and
Condensation of diphenyl sulfides I and II with phthalic
anhydride and subsequent demethylation of the
condensation products
condensation of sulfide II with phthalic anhydride gives
Thiofluorescein (III) in 74% yield (calculated on sulfide
II; 64% calculated on dimethoxy sulfide I). Thio-
fluorescein (III) can be obtained in 76% yield directly
from sulfide I according to Scheme 3 with additional
demethylation by 2Py·H SO .
5
XQꢂ ,QLWLDOꢂ 7HPSHUDWXUHꢀ 7LPH
<LHOGꢀꢁꢂ
QRꢃꢂ VXOILGHꢂ
ƒ&ꢂ
ꢀKꢂ
,
,,ꢀ ,9ꢂ 9ꢂ
ꢄꢂ
,ꢂ
,ꢂ
ꢅꢆꢂWRꢂꢇꢆ ꢂ
ꢄꢇꢆ ꢂ
ꢄꢂ
ꢄꢂ
ꢅꢂ
ꢄꢂ
ꢄꢂ
ꢄꢂ
ꢄꢈꢂ ꢄꢉꢂ ꢊꢂ
ꢄꢇꢂ ꢄꢋꢂ ꢇꢂ
2
4
ꢅꢂ
ꢋꢂ
ꢈꢂ
ꢉꢂ
ꢇꢂ
,ꢂ
ꢄꢇꢆ ꢂ
ꢊ
ꢂ
ꢇꢂ
ꢋꢂ
EXPERIMENTAL
,,ꢂ
,ꢂ
,ꢂ
ꢄꢉꢆ ꢂ
ꢊꢈꢂ
ꢇꢋꢂ
ꢊꢇꢂ
±ꢂ
±ꢂ
ꢄꢂ
±ꢂ
±ꢂ
±ꢂ
ꢄꢉꢆ
ꢂ
The IR spectra were recorded on a Vector 22
ꢄꢉꢆ ꢂ
spectrometer in KBr. The electron absorption spectra
were measured on a Hewlett–Packard 8453 spectro-
ꢂ
a
b
c
8
0% sulfuric acid.
Subsequent demethylation with Py · HCl at 190–200°C (0.5 h).
Subsequent demethylation with 2Py · H SO at 190–200°C
1
photometer. The H NMR spectra were obtained on
a Bruker WP-200SY instrument at 200.13 MHz using
chloroform as internal reference. The mass spectra
2
4
(
0.5 h).
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 1 2005

IMPROVED SYNTHESIS OF THIOFLUORESCEIN
59
(
8
electron impact, 70 eV) were run on a Finnigan MAT
200 mass spectrometer. Column chromatography was
isolated from the third fraction (eluent diethyl ether) by
removal of the solvent and washing of the residue with
chloroform on a filter. The product was dried over P O
at 100°C under reduced pressure. Orange powder,
mp 98–102°C. Electron absorption spectrum, lmax, nm
performed on KSK silica gel. The progress of reactions
and the purity of products were monitored by TLC on
Silufol UV-254 plates.
2
5
(
(
loge): in 0.1 N NaOH: 272 (4.60), 330 (3.71), 512
4.68); in 0.1 N KOH: 513 (4.57) [5]; published data [7],
3
-Methoxybenzenethiol (98%,Aldrich) and 3-iodo-1-
methoxybenzene (98%, Lancaster) were used without
additional purification.
lmax, nm (loge): 512 (4.69) (0.1 N NaOH). IR spectrum,
–
1
1
n, cm : 1726, 1596, 1293, 1216. H NMR spectrum
CD OD), d, ppm: 6.61 d.d (2H, 2'-H, 7'-H, J = 8.7,
3,3'-Dimethoxydiphenyl sulfide (I) was synthesized in
(
3
5
2% yield by the procedure reported in [8] and in 80%
yield by the procedure described in [9]. bp 155°C (2 mm);
published data [8]: bp 214–215°C (10 mm). H NMR
spectrum (CCl ), d, ppm: 3.64 s (6H, OMe), 6.63 d.m
2
4
7
7
.5 Hz), 6.83 d (2H, 1'-H, 8'-H, J = 8.7 Hz), 6.95 d (2H,
'-H, 5'-H, J = 2.5 Hz), 7.57 d.m (1H, 7-H, J = 7.6 Hz),
.58–7.77 m (2H, 5-H, 6-H), 7.96 d (1H, 4-H, J =
1
4
+
.5 Hz). Mass spectrum, m/z (I , %): 348 (3) [M] , 304
rel
(
2
2H, 4-H, 4'-H, J = 7.2, 2.5 Hz), 6.75–6.84 m (4H, 2-H,
'-H, 6-H, 6'-H), 7.07 t (2H, 5-H, 5'-H, J = 7.7 Hz).
,3'-Dihydroxydiphenyl sulfide (II) was obtained by
(31), 303 (48), 104 (20), 76 (24), 45 (20), 32 (25), 31 (50),
2
8 (100). Found, %: C 68.61; H 3.40; S 9.20. C H O S.
20 12 4
3
Calculated, %: C 68.95; H 3.47; S 9.21.
demethylation of sulfide I under the conditions reported
in [10]. Yield 87%, mp 128–129°C (from CHCl );
published data [11]: mp 129–130°C. H NMR spectrum
CDCl ), d, ppm: 4.6–6.1 br.s (2H, OH), 6.67 d.m (2H,
-H, 4'-H, J = 8.6, 2.4 Hz), 6.76 t (2H, 2-H, 2'-H, J =
.8 Hz), 6.90 d.m (2H, 6-H, 6'-H, J = 7.9 Hz), 7.17 t
2H, 5-H, 5'-H, J = 7.9 Hz).
3
'-Hydroxy-6'-methoxy-3H-spiro[2-benzofuran-
3
1
,9'-[9H]thioxanthen]-3-one (IV) was isolated from
1
the second fraction by removal of the solvent and washing
of the residue with carbon tetrachloride on a filter. The
product was dried over P O at 100°C under reduced
pressure. Yellow powder, mp 115–120°C. Electron
absorption spectrum, lmax, nm (loge): in 0.1 N KOH:
2
2
1
(
4
1
3
2
5
(
Condensation of compounds I and II with
89 (4.04), 417 (3.52), 491 (3.58), 511 (3.59); in EtOH:
phthalic anhydride. Compound I, 2.46 g (0.01 mol), or
II, 2.16 g (run no. 4), and 1.48 g (0.01 mol) of sublimed
phthalic anhydride were dissolved in 5 ml of 80% sulfuric
acid, and the mixture was heated for 1 h at 20 to 160°C
run no. 1) or kept for 1 or 2 h at 150 or 160°C (run nos.
–4). The mixture was cooled to room temperature and
poured into 100 ml of water. The brown precipitate was
filtered off, washed with 70 ml of water, and dried in air.
The product, 3.5 g, was ground in a mortar with 5 g of
silica gel (0–140 mm) and washed with 50 ml of diethyl
ether on a filter; this procedure was repeated three times.
The solvent was distilled off, and the residue was ground
in a mortar with 5 g of silica gel, and the resulting material
was applied to a column charged with silica gel (140–
–
1
89 (4.07). IR spectrum, n, cm : 1724, 1598, 1288, 1246.
H NMR spectrum (CD OD), d, ppm: 3.76 s (3H, OMe),
3
6
6
7
.61 d.d and 6.69 d.d (2H, 2'-H, 7'-H, J = 8.7, 2.5 Hz),
.85 d and 6.91 d (2H, 1'-H, 8'-H, J = 8.6 Hz), 6.94 d and
.04 d (2H, 4'-H, 5'-H, J = 2.5 Hz), 7.57 d.m (1H, 7-H,
(
2
J = 7.6 Hz), 7.60–7.77 m (2H, 5-H, 6-H), 7.95 d (1H,
4
-H, J = 7.5 Hz). Mass spectrum, m/z (I , %): 362 (14)
rel
+
[M] , 319 (25), 318 (59), 317 (100), 303 (26), 287 (42),
2
6
%
74 (44), 45 (36), 31 (75), 28 (55). Found, %: C 69.53,
9.23; H 3.60, 3.67; S 8.82, 8.50. C H O S. Calculated,
2
1
14
4
: C 69.60; H 3.89; S 8.85.
3',6'-Dimethoxy-3H-spiro[2-benzofuran-1,9'-
[9H]thioxanthen]-3-one (V) was isolated from the first
3
15 mm, 2´30 cm). The column was eluted in succes-
fraction by removal of the solvent (CHCl +C H ) and
3
6
6
sion with benzene, chloroform, and diethyl ether (run
nos. 1–3) or with diethyl ether (run no. 4). The separation
process was monitored by TLC using diethyl ether–
benzene (4 :1, by volume) as eluent. Three fractions were
collected (benzene–chloroform, chloroform–diethyl ether,
and diethyl ether), which corresponded to one yellow and
two orange spots on Silufol plates. In run no. 4, only one
fraction was obtained (orange spot).
washing of the residue with methanol on a filter.
Colorless powder, mp 191–193°C. Electron absorption
spectrum (EtOH), lmax, nm (loge): 204 (4.72), 230
–1
(
1
4.68), 274 (3.99). IR spectrum, n, cm : 1777, 1597,
1
578, 1486, 1461, 1440, 1404, 1288, 1265. H NMR
spectrum (CDCl ), d, ppm: 3.78 s (6H, OMe), 6.67 d.d
3
(
2H, 2'-H, 7'-H, J = 8.5, 2.7 Hz), 6.98 d (2H, 4'-H, 5'-H,
J = 2.7 Hz), 7.04 d (2H, 1'-H, 8'-H, J = 8.5 Hz), 7.49–
7.65 m (3H, 5-H, 6-H, 7-H), 7.93 d.m (1H, 4-H, J =
Thiofluorescein (3',6'-dihydroxy-3H-spiro[2-
benzofuran-1,9'-[9H]thioxanthen]-3-one) (III) was
+
7.5 Hz). Mass spectrum, m/z (I , %): 376 (19) [M] ,
rel
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 1 2005

60
RUSSKIKH et al.
3
32 (63), 331 (52), 317 (52), 301 (100), 245 (31), 28 (69).
03-333-3336 and 03-333-3345), by the Siberian Division,
Russian Academy of Sciences (Integration project
no. 84), and by the Russian Academy of Sciences
Found, %: C 70.14; H 4.33; S 8.40. C H O S.
Calculated, %: C 70.21; H 4.26; S 8.51.
2
2
16
4
(
program nos. 8-3 and 5-2).
Demethylation of compounds IV and V. a. Run
no. 5. A 3.5-g portion of the crude condensation product
obtained from dimethoxy sulfide I and phthalic anhydride
was mixed with 10 g of Py·HCl [10], and the mixture
was stirred for 0.5 h at 190–200°C in a stream of argon.
The mixture was cooled and diluted with 100 ml of water,
and the red–brown precipitate was filtered off, washed
with water, and dried in air. The product, 3.2 g, was ground
in a mortar with 5 g of silica gel and extracted with diethyl
ether to isolate Thiofluorescein (III).
REFERENCES
1
. Krasovitskii, B.M. and Bolotin, B.M., Organicheskie
lyuminofory (Organic Luminophores), Leningrad: Khimiya,
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krasitelyakh, Moscow: Mir, 1976, p. 172.
..
3
4
5
. Daviason, R.S., J. Photochem. Photobiol. A, 1993, vol. 73,
p. 81.
b. Run no. 6. A mixture of 2.46 g (0.01 mol) of
compound I and 1.48 g (0.01 mol) of phthalic anhydride
in 5 ml of 80% sulfuric acid was heated for 1 h at 150°C.
The mixture was cooled to room temperature, and 13 ml
of pyridine was added dropwise under vigorous stirring.
The mixture was heated to 190–200°C, kept for 0.5 h at
that temperature in a stream of argon, cooled, and diluted
with 150 ml of water. The precipitate was filtered off,
washed with water, and dried in air. Yield of the crude
product 3.5 g. Thiofluorescein (III) was isolated from
the crude product as described above. Methyl ether IV
was isolated by evaporation of the chloroform filtrate
obtained by washing of compound III.
. Padon, K.S. and Scranton,A.B., Recent Res. Devel. Polym.
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. Pfoertner, K.H., J. Chem. Soc., Perkin Trans. 2, 1991,
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. Schopfer, U. and Schlapback, A., Tetrahedron, 2001,
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1
1967, p. 1138.
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RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 1 2005