An unusual synthesis of a spirothioxanthene derivative

Article abstract of DOI:10.1016/j.tetlet.2010.10.048

The reaction of diphenyl sulfone with 2,3-dibromophthalazine-1,4-dione in the presence of n-butyllithium gave a spiro-9H-thioxanthene-10,10-dioxide derivative in 45% yield, the structure of which was proved by X-ray crystallography.

Full text of DOI:10.1016/j.tetlet.2010.10.048

Tetrahedron Letters 51 (2010) 6605–6607
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Tetrahedron Letters
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An unusual synthesis of a spirothioxanthene derivative
⇑
Katja Dahms, Andrei S. Batsanov, Martin R. Bryce
Department of Chemistry, Durham University, Durham DH1 3LE, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of diphenyl sulfone with 2,3-dibromophthalazine-1,4-dione in the presence of n-butyllith-
ium gave a spiro-9H-thioxanthene-10,10-dioxide derivative in 45% yield, the structure of which was
proved by X-ray crystallography.
Received 24 August 2010
Revised 29 September 2010
Accepted 8 October 2010
Available online 14 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
9H-Thioxanthene
Sulfone
2,3-Dibromophthalzine-1,4-dione
Spirolactone
Xanthenes and spiroxanthenes are important and versatile
compounds in organic chemistry. Amongst them are, for example,
rhodamine-based compounds such as 1 and its analogues, which
are used as fluorescent chemosensors,1 electrochromic materials,2
photosensitisers3 and as sensitisers of photopolymer materials.4
The sulfur analogues, spirothioxanthenes, have also been widely
described,3 including thiofluorescein (2)5 and the photochromic
thioxanthene-10,10-dioxide derivative 3,6 which was obtained by
oxidation of the thioxanthene precursor. The spirothioxanthene
skeleton is usually synthesised either starting from thioxanthone,5
or from diphenyl sulfide and phthalic anhydride.7 Herein, we re-
port a novel route to the spirothioxanthene system, as exemplified
by the synthesis of compound 6.
mediation of lead(IV) acetate,9 in the presence of n-butyllithium.10
A single product was obtained in 45% yield, the structure of which
we could not unambiguously assign based on NMR spectroscopic,
mass spectrometric and IR spectroscopic data. X-ray analysis of a
single crystal revealed the spirothioxanthene structure 6 (Fig. 1).11
From directly comparable experiments using 1, 2, 4 and
10 equiv of n-butyllithium, the highest yield was obtained with
4 equiv. A possible mechanism for the formation of 6 is shown in
Scheme 1. Lithiation of 4 and reaction with 5 followed by loss of
bromide, as shown in A, would yield an intermediate which could
undergo a second lithiation followed by spirocyclisation and loss of
dinitrogen and bromide, as shown in B, to give the product 6. The
bromine substituents on 5 are necessary for the reaction to pro-
ceed, which is consistent with the mechanism postulated in
Scheme 1. Using 2,3-dihydrophthalazine-1,4-dione, instead of 5,
gave no product; and unreacted starting materials were recovered.
O
O
O
R
X
R
S
O
O
1 X = O; R = NEt2
2 X = S; R = OH
3
In continuation of our studies on new diarylsulfone building
blocks for conjugated oligomers,8 we reacted diphenyl sulfone (4)
with 2,3-dibromophthalazine-1,4-dione (5), which was previously
synthesised from phthalhydrazide and zinc bromide under the
⇑
Corresponding author. Tel.: +44 191 3342018.
E-mail address: m.r.bryce@durham.ac.uk (M.R. Bryce).
Figure 1. X-ray molecular structures of 6 (left) and 7 (right) (thermal ellipsoids at
50% probability level).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.048

6606
K. Dahms et al. / Tetrahedron Letters 51 (2010) 6605–6607
O
Br
N
O
N
OH
OH
Br
O
O
LiEt3BH, THF
5
0 oC, 74% yield
n-BuLi, THF,
-75 oC, 45% yield
S
S
S
O
O
O
O
O
O
O
4
7
6
O
Br
Br
N
N
N
N
Br
O
-
O
- -
S
O
O
S
O
O
B
A
Scheme 1. Postulated mechanism for the formation of compound 6, followed by reduction to 7.
2. Weng, W.; Higuchi, T.; Suzuki, M.; Fukuoka, T.; Shimomura, T.; Ono, M.;
Radhakrishnan, L.; Wang, H.; Suzuki, N.; Oveisi, H.; Yamauchi, Y. Angew. Chem.,
Int. Ed. 2010, 49, 3956–3959.
3. (a) Pfoertner, K.-H. J. Chem. Soc., Perkin Trans. 2 1991, 523–526; (b) Pfoertner,
K.-H.; Voelker, M. J. Chem. Soc., Perkin Trans. 2 1991, 527–530.
The attempted reduction of 6 with lithium aluminium hydride
gave exclusively the unreacted starting material. Trialkylborohy-
drides are more powerful reducing agents. Compound 6 was, there-
fore, treated with lithium triethylborohydride (Super-Hydride),
which gave the diol product 7 in 74% yield.12 Initial NMR spectro-
scopic and mass spectrometric data did not confirm the structure
of product 7. Only one of the two OH protons gave a visible signal
in the 1H NMR spectrum [dH 4.50 (s, 1H) exchanged with D2O shake]
and the highest observed mass peak was at m/z 334 (EI mode) which
can be attributed to the loss of water from 7. Subsequent mass spec-
tra (ES mode) showed the [M+Na]+ ion for 7. For a reliable determi-
nation of the structure, crystals were grown for X-ray analysis
(Fig. 1), which unambiguously proved the formation of compound
7. This is in agreement with the work of Brown et al., who investi-
gated reactions of trialkylborohydrides, in particular, lithium trieth-
ylborohydride, and showed that lactones rapidly react with up to
2 equiv of hydride and undergo reduction to the diol stage.13
Attempts to brominate spiro compound 6 with NBS and acetic
acid, bromine and acetic acid or bromine and iron (III) bromide
were unsuccessful and resulted only in the recovery of the starting
material.
4. Vasil’ev, E. V.; Shelkovnikov, V. V.; Russkikh, V. V. High Energy Chem. 2010, 44,
204–210.
5. (a) Coelho, P. J.; Carvalho, L. M.; Abrantes, S.; Oliveira, M. M.; Oliveira-Campos,
A. M. F.; Samat, A.; Guglielmetti, R. Tetrahedron 2002, 58, 9505–9511; (b)
Mcheldlov-Petrosyan, N. O.; Vodolazkaya, N. A.; Martynova, V. P.; Samoilov, D.
V.; El’tsov, A. V. Russ. J. Gen. Chem. 2002, 72, 785–792; (c) Coelho, P. J.; Salvador,
M. A.; Oliveira, M. M.; Carvalho, L. M. Tetrahedron 2004, 60, 2593–2599; (d)
Russkikh, V. V.; Vasil’ev, E. V.; Shelkovnikov, V. V. Russ. J. Org. Chem. 2008, 44,
1538–1542; (e) Hafez, H. N.; Hegab, M. I.; Ahmed-Farag, I. S.; El-Gazzar, A. B. A.
Bioorg. Med. Chem. Lett. 2008, 18, 4538–4543.
6. Gabbutt, C. D.; Heron, B. M.; Kolla, S. B.; Kilner, C.; Coles, S. J.; Horton, P. N.;
Hursthouse, M. B. Org. Biomol. Chem. 2008, 6, 3096–3104.
7. Russkikh, V. V.; Konstantinova, A. V.; Berezhnaya, V. N.; Gerasimova, T. N.;
Shelkovnikov, V. V. Russ. J. Org. Chem. 2005, 41, 57–60.
8. Li, H.; Batsanov, A. S.; Moss, K. C.; Vaughan, H. L.; Dias, F. B.; Kamtekar, K. T.;
Bryce, M. R.; Monkman, A. P. Chem. Commun. 2010, 46, 4812–4814 and
references therein.
9. Kim, J.-J.; Kweon, D.-H.; Cho, S.-D.; Kim, H.-K.; Lee, S.-G.; Yoon, Y.-J. Synlett
2006, 194–200.
10. Soltz, B. L.; Corey, J. Y. J. Organomet. Chem. 1979, 171, 291–299.
11. Preparation of spiro[isobenzofuran-1(3H),90-thioxanthen]-3-one-10,10-dioxide
(6): diphenyl sulfone (1.1 equiv) was placed in a flame-dried flask under
argon and dissolved in dry THF (10 ml). The solution was cooled to ꢀ75 °C, n-
butyllithium (4.0 equiv) was added dropwise and the mixture was stirred for
1 h keeping the temperature at ꢀ75 °C. Then, 2,3-dibromophthalazine-1,4-
dione (5) (1.0 equiv) was added and the mixture allowed to warm to rt
gradually overnight under argon. The reaction was quenched by adding H2O
(30 ml) and the aqueous phase extracted with CH2Cl2 (3 ꢁ 50 ml) and EtOAc
(2 ꢁ 30 ml). The product precipitated from the aqueous phase, was filtered and
dried to give 6 (45% yield) as a white solid. Crystals for X-ray analysis were
obtained by slow recrystallisation from EtOH. Mp = 239.5–241.0 °C; 1H NMR
(700 MHz, CDCl3): d = 8.26 (dd, J = 7.8 Hz, J = 1.2 Hz, 2H), 8.02–7.98 (m, 2H),
7.62 (m, 4H), 7.58–7.49 (m, 4H); 13C NMR (176 MHz, CDCl3) d = 170.22, 153.24,
136.67, 135.84, 135.58, 133.42, 130.12, 129.95, 126.37, 126.12, 124.22, 123.88,
122.49, 82.00; HRMS (ASAP) m/z calcd for [C20H12O4S+H]+: 349.0535, found:
In summary, we have developed a new route to an interesting
spiro derivative of the 9H-thioxanthene-10,10-dioxide system in
a synthetically viable yield. There is clearly scope to explore the
functional group tolerance in this process and to explore further
reactions of 6.
Acknowledgement
We thank EPSRC for funding this work.
349.0531; IR (KBr) (
m
max/cmꢀ1): 1782, 1596, 1467, 1300, 1244, 1167, 1147. X-
radiation
20H12O4S, M = 348.36, monoclinic,
space group P21/c (No. 14), a = 13.9202(7), b = 8.0866(4), c = 14.9348(8) Å,
b = 114.34(1)°, U = 1531.7(2) Å3, Z = 4, = 0.24 mmꢀ1, 14,160 reflections with
ray experiment: Bruker SMART 6000 CCD area detector, Mo K
a
Supplementary data
ꢀ
(k = 0.71073 Å), T = 120 K. Crystal data:
C
Supplementary data (copies of spectra of compounds 6 and 7)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.10.048.
l
2h 6 50°, Rint = 0.070, R = 0.039 [2096 data with I P 2r
(I)], wR(F2) = 0.112 (all
2698 unique data). CCDC-781882.
12. Preparation of 9-(2-hydroxyphenyl)-9H-thioxanthen-9-ol-10,10-dioxide (7):
compound 6 (1 equiv) was dissolved in dry THF (10 ml) under argon and the
solution was cooled to 0 °C. An excess of Super-Hydride solution (1 M in THF,
4 equiv) was added carefully. The mixture was kept under argon and stirred at
rt overnight. EtOH (5 ml) was carefully added to quench the excess of Super-
Hydride. CH2Cl2 (50 ml) was added and the organic phase washed with H2O
(3 ꢁ 50 ml). The mixture was purified by column chromatography on silica gel
References and notes
1. Hu, Z.-Q.; Lin, C.-S.; Wang, X.-M.; Ding, L.; Cui, C.-L.; Liu, S.-F.; Lu, H. Y. Chem.
Commun. 2010, 46, 3765–3767.

K. Dahms et al. / Tetrahedron Letters 51 (2010) 6605–6607
[C20H16O4S+Na]+: 375.0667, found: 375.0663; IR (KBr)
6607
eluting with EtOAc/petroleum ether (bp 40–60) in a 1:1 (v/v) ratio to give 7
(74% yield) as a white solid. Crystals for X-ray analysis were obtained by slow
recrystallisation from a mixture of CH2Cl2 and hexane. Mp = 107.5–108.5 °C;
1H NMR (400 MHz, CDCl3): d = 8.18 (dd, J = 7.7 Hz, J = 1.2 Hz, 2H), 7.98–7.88 (m,
1H), 7.61–7.52 (m, 4H), 7.49–7.47 (m, 4H), 7.15 (d, J = 7.9 Hz, 1H), 4.50 (s, 1H),
3.86 (d, J = 5.3 Hz, 2H), (1H not observed); 13C NMR (101 MHz, CDCl3):
d = 188.56, 143.33, 139.51, 137.93, 136.38, 133.33, 129.62, 129.26, 129.08,
128.97, 128.26, 127.74, 123.69, 73.70, 62.97; HRMS (ES): m/z calcd
(m
max/cmꢀ1): 1442,
1289, 1160, 1146, 1003. X-ray experiment: Bruker SMART 1000 CCD area
ꢀ
detector, Mo K
M = 352.39, monoclinic, space group P21/n (No. 14), a = 7.679(1), b = 27.580(4),
c = 7.951(1) Å, b = 108.01(1)°, U = 1601.3(4) Å3, Z = 4, = 0.23 mmꢀ1, 16,060
a radiation (k = 0.71073 Å), T = 120 K. Crystal data: C20H16O4S,
l
reflections with 2h 6 57.5°, Rint = 0.044, R = 0.039 [3457 data with I P 2
r(I)],
wR(F2) = 0.099 (all 3838 unique data). CCDC-789461.
13. Brown, H. C.; Kim, S. C.; Krishnamurthy, S. J. Org. Chem. 1980, 45, 1–12.