An expedient route to 3-chlorothioxanthen-9-one-10,10-dioxide and derivation by palladium-catalyzed coupling

Article abstract of DOI:10.1055/s-2006-951520

Chemistry has been developed that allows for the synthesis of a series of novel tricyclic thioxanthen-9-one-10,10-dioxides. A regioselective synthesis of the novel core substrate 3-chlorothioxanthen-9-one-10,10-dioxide was achieved in 85% yield over three steps without the need for chromatographic purification. Subsequent microwave-assisted coupling methodology afforded the desired novel 3-substituted tricyclic compounds in good to excellent yield. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951520

LETTER
3045
An Expedient Route to 3-Chlorothioxanthen-9-one-10,10-dioxide and
Derivation by Palladium-Catalyzed Coupling
R
oute to 3-Ch
e
d
then-9-one-1
r
0,10-dio
o
xide M. J. Lory, Anton Agarkov, Scott. R. Gilbertson*
Program in Chemical Biology, Department of Pharmacology & Toxicology, University of Texas-Medical Branch, 301 University
Boulevard, Galveston, TX 77555-0650, USA
Fax +1(409)7729700; E-mail: srgilber@utmb.edu
Received 23 February 2006
This paper is dedicated to Professor Richard Heck, a pioneer in palladium-catalyzed carbon–carbon bond formation.
The reported syntheses of similar 3-halo-thioxanthenone
ring systems utilize as their first step the reaction of the
corresponding m-halo-benzenethiol substrate 3 with 2-
halo-benzoic acid 4. Subsequent treatment with mineral
Abstract: Chemistry has been developed that allows for the synthe-
sis of a series of novel tricyclic thioxanthen-9-one-10,10-dioxides.
A regioselective synthesis of the novel core substrate 3-chlorothiox-
anthen-9-one-10,10-dioxide was achieved in 85% yield over three
steps without the need for chromatographic purification. Subse- acid, affords the desired Friedel–Crafts product 3-halo-
thioxanthenone ring system 6 (Scheme 2).2b,d,4 While ef-
fective, this methodology invariably yields a mixture of 3-
and 5-regioisomeric products (6a and 6b) that require te-
dious chromatographic and/or recrystallization in order to
quent microwave-assisted coupling methodology afforded the de-
sired novel 3-substituted tricyclic compounds in good to excellent
yield.
Key words: catalysis, heterocycles, palladium, Suzuki reaction,
thioxanthenone dioxide
obtain the products in pure form. Alternative protocols, al-
though efficient, make use of both reagents and reaction
conditions (e.g. low temperatures, pyrophoric bases such
as t-BuLi, longer reaction times),5 which can be incompat-
The facile assembly of therapeutically valuable molecular
entities such as thioxanthen-9-one-10,10-dioxides is an
important goal. Thioxanthenones as well as thioxanthen-
9-one-10,10-dioxides have been shown to possess potent
antitumor,1 antiallergic2 and monoamine oxidase3 (MAO)
inhibitory activity. A facile approach to this class of mol-
ecules is essential for the development of better drug can-
didates based on this motif. Herein we report a versatile,
expedient and efficient route to this class of molecules and
demonstrate its utility with a small library of novel thiox-
anthen-9-one-10,10-dioxides derivatives 2.
ible with both scale-up and parallel synthesis.
HO2C
base
reflux
+
X
S
X
SH
X
CO2H
5
3
4
X = Cl, Br
H2SO4
O
O
X
+
The approach that has been developed relies on the use of
the Suzuki reaction on a 3-halo-thioxanthen-9-one-10,10-
dioxide (1, Scheme 1). The Suzuki reaction was chosen in
part for the large number of commercial boronic acids and
esters available. For this to be a viable approach to this
class of molecule, a reasonable quantity of the halide was
required. Consequently, the initial goal became the devel-
opment of a practical, efficient and expedient route to the
core halo substrate 1.
S
X
S
6a
6b
Scheme 2
Because of these problems a route starting from thiophe-
nol and 2-iodo-3-chlorobenzoic acid was developed. Un-
der basic conditions the nucleophilic substitution of
thiophenol 7 with the suitably substituted 2-iodo-3-chlo-
robenzoic acid building block 8 in the presence of a cata-
lytic amount of copper6a–c for eight hours affords the
desired coupled sulfide 96b in virtually quantitative yield
(Scheme 3).
O
O
Pd
catalyst
+ RB(OH)2
S
X
S
R
O
O
O
O
The presence of catalytic copper powder is crucial to the
efficiency of this synthetic step, presumably via the in situ
formation of the corresponding cupric benzoate.2c,7
2
1
Scheme 1
Treatment of 9 with concentrated sulfuric acid at 100 °C
over four hours affords the Friedel–Crafts adduct, thiox-
anthenone 10. Upon pouring the reaction mixture onto ice,
the product precipitates out as an off-white solid. No fur-
ther purification is required, although copious amounts of
water were vital to remove adventitious sulfuric acid.
SYNLETT 2006, No. 18, pp 3045–3048
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951520; Art ID: S02206ST
© Georg Thieme Verlag Stuttgart · New York
0
3
.1
1
.2
0
0
6

3046
P. M. J. Lory et al.
LETTER
Cl
In-house or readily available catalytic palladium sources
were used under several conditions. When using catalysts
such as Pd2(dba)3, Pd(OAc)2, Pd(dppf)Cl2, Pd/C and Fi-
brecat® (encapsulated palladium; Johnson Matthey Inc.)
isolated yields of coupled product were modest, ranging
from 40–60%. These results were not significantly affect-
ed by variation of solvent, temperature, base used or reac-
tion times. In all cases a substantial amount of unreacted
sulfone 11 was observed and recovered.
HO2C
KOH
+
SH
cat. Cu
120 °C
I
Cl
X
S
8
CO2H
7
9
O
O
S
H2O2–AcOH
H2SO4
The best results were obtained using a combination of
Pd(PPh3)4 as catalyst, EtOH as solvent, Cs2CO3 as base
(1.0 M solution in H2O) and a reaction temperature of
110 °C for a period of 10 minutes (Table 2, entry 6). The
use of Cs2CO3 as a solution rather than a solid reagent
proved to be a significant improvement in the overall
methodology with the yield increasing from 65% to 87%.
90 °C
Cl
100 °C,
4 h
S
Cl
O
O
10
11
Scheme 3
Oxidation of 10 to the desired key sulfone substrate 11 re-
quired fine-tuning of the oxidative protocols reported for
similar deactivated aromatic ring systems (Table 1).8 The
majority of the probed systems led to mixtures of sulfox-
ide and sulfone derivatives ranging from 45:10% to
80:5%. The effects of reaction time, temperature, solvent
and oxidant stoichiometry were monitored for each oxida-
tion method but no significant improvement on the sul-
fone:sulfoxide adduct ratio was evident. Ultimately, the
H2O2–AcOH (1:2 v/v) oxidative system (Table 1, entry 5)
by means of slow addition as well as an optimal reaction
temperature of 90 °C was selected to be the method of
choice. Worth noting is the fact that, previously reported
oxidations of similar thioxanthenone tricyclic systems,8d a
30% H2O2 (v/v) solution, does not effect the oxidation of
this system as efficiently as the 50% H2O2 herein reported.
In addition to being inexpensive and practical this method
afforded 80% of isolated 11 and only a small amount (5%)
of sulfoxide by-product. Sulfone 11 could be purified by
recrystallization from ethyl acetate–hexane, providing
compound 11 in pure form as yellow needles in 70%
yield.
The use of a polymer-supported (PS) surrogate of this cat-
alyst system, PS–Ph3–Pd (Argonaut Technologies;
Table 2, entry 9) resulted in an isolated yield of 78% of
coupled product. In general, the use of PS–Pd catalyst sys-
tems is well known to provide cleaner reaction mixtures in
coupling reactions, such as the Suzuki coupling, due to
higher stability of the former to potential decomposition.10
However, in this case simple Pd(PPh3)4 provided products
of equivalent purity.
In our hands, the use of simultaneous cooling (air stream
at 40 psi) while running this microwave-assisted Suzuki
coupling reaction led to a yield increase of 13 by 10%
when compared to standard reaction conditions.11
Given the efficiency of the reaction, it was decided that
screening of additional catalytic systems known to en-
hance coupling of less reactive chloro Suzuki substrates12
was not necessary. For the same reason, and although it is
known to often play a crucial role in the efficiency of pal-
ladium-catalyzed reactions, it was deemed superfluous to
proceed with the degassing of solvent used for this reac-
tion.
With 11 in hand, conditions for the microwave-assisted
Suzuki coupling to give novel 3-substituted thioxanthen-
9-one-10,10-dioxides were screened.9 This effort utilized
the model reaction of sulfone 11 with commercially avail-
able phenyl boronic acid (Table 2).
The optimized conditions for the synthesis of 13 (Table 2,
entry 6) were utilized in the synthesis of novel analogues,
which were obtained in isolated yields varying from 20–
87% (Table 3). We believe that both the inherent lack re-
activity of 11 and the boronic acid were the chief reason
Table 1 Selected Oxidation Screening Conditions of 10
Entry
Oxidant
Conditions
Yield of 11 (%)a,b
Yield of sulfoxide (%)
1
2
3
4
5
PIFA
CHCl3, r.t.
45
60
42
66
80
10
10
15
5
Oxone
DMF, 80 °C
MCPBA
RuCl3–NaIO4
H2O2–AcOH
CH2Cl2, r.t.
CCl4–MeCN–H2O (1:1:2 v/v), r.t.
H2O2–AcOH (1:2 v/v), 90 °C
5
a Reactions were carried out at 0.81 mmol of 10 and using 2.2 equiv of oxidant as starting point whilst screening for optimal stoichiometric
values.
b Isolated yields after reverse-phase preparative HPLC.
Synlett 2006, No. 18, 3045–3048 © Thieme Stuttgart · New York

LETTER
Route to 3-Chlorothioxanthen-9-one-10,10-dioxide
3047
Table 2 Selected Examples of Protocols Screened for Microwave-Assisted Suzuki Coupling Reactiona,b
O
S
O
S
B(OH)2
MW
+
Cl
Ph
O
O
11
13
12
O
O
Entry
Catalyst
Pd(dba)3
Pd(dba)3
Pd(dba)3
Catalyst (mol%) Solvent
Temp (°C)
155
Base
Yield of 13 (%)
1
2
3
3
DMF
DMA
EtOH
DMF
EtOH
EtOH
DMF
DMF
EtOH
EtOH
K2CO3
40
55
52
56
65
87
50
48
78
60
177
Cs2CO3
3
3
110
Cs2CO3
4
Pd(dppf)Cl2
Pd(PPh3)4
Pd(PPh3)4
Pd/C
10
3
155
Cs2CO3
5
110
Cs2CO3
6
3
110
1.0 M soln of Cs2CO3
Cs2CO3
7
10
5
155
8
Fibrecat®
PS-Ph3-Pd
Pd(OAc)2
155
Cs2CO3
9
10
3
110
Cs2CO3
10
110
Cs2CO3
a Reactions were carried out at 0.81 mmol of 10 and using 2.2 equiv of oxidant as starting point whilst screening for optimal stoichiometric
values.
b Isolated yields after reverse-phase preparative HPLC.
Table 3 Synthesis of Novel 3-Substituted Thioxanthen-9-one-
for the lower yield observed for compound 27. Addition-
ally, reported low yields such as with 16 (Table 3) are
10,10-dioxide Analoguesa (continued)
commonly associated with electron-rich boron reagents.
Product
R
Yield (%)b,c
55
In summary, utilizing our strategy, intermediate 11 can be
easily and expediently obtained as a single regioisomer
and in multigram quantities. This key intermediate can
then be used in the synthesis of a wide variety of deriva-
tives of novel tricyclic thioxanthen-9-one-10,10-dioxides
by means of microwave-assisted Suzuki coupling meth-
odology. This methodology makes literally hundreds of
novel thioxanthen-9-one-10,10-dioxides available from a
single precursor. The development of other alternative an-
alogues of 11 such as its 3-boronic acid congener is under
way. Given the wider commercial availability of halides
(vs. boronic acids), the 3-boronic acid substrate will allow
for the introduction of a more diverse set of functionality.
15
t-Bu
16
17
30
56
SMe
NH2
18
19
44
61
NMe2
CO2H
Table 3 Synthesis of Novel 3-Substituted Thioxanthen-9-one-
10,10-dioxide Analoguesa
Product
R
Yield (%)b,c
87
13
20
21
80
40
OMe
OPh
14
59
Me
Synlett 2006, No. 18, 3045–3048 © Thieme Stuttgart · New York

3048
P. M. J. Lory et al.
LETTER
Table 3 Synthesis of Novel 3-Substituted Thioxanthen-9-one-
(2) For representative examples, see: (a) Rokach, J.; Rooney, C.
S.; Cragoe, E. J. US 4536507, 1985; Chem. Abstr. 1985, 104,
19801124. (b) Rokach, J.; Rooney, C. S.; Cragoe, E. J. US
77-773232, 1980; Chem. Abstr. 1980, 93, 46648.
(c) Batchelor, J. F.; Gorvin, J. H. DE 73-2344800, 1974;
Chem. Abstr. 1974, 80, 133449. (d) Hodson, H. F.;
Batchelor, J. F. US 4103015, 1978; Chem. Abstr. 1979, 90,
22816.
10,10-dioxide Analoguesa (continued)
Product
R
Yield (%)b,c
75
22
OH
(3) For selected examples, see: (a) Harfenist, M.; Heuser, D. J.;
Joyner, C. T.; Batchelor, J. F.; White, H. L. J. Med. Chem.
1996, 39, 1857. (b) Harfenist, M.; Joyner, C. T.; Mize, P. D.;
White, H. L. J. Med. Chem. 1994, 37, 2085.
23
42
CF3
(4) (a) Miller, T. C.; Collins, J. C.; Mattes, K. C.; Wentland, M.
P.; Perni, R. B.; Corbett, T. H.; Guiles, J. W. US 5346917,
1994; Chem. Abstr. 1994, 122, 55895. (b) Mahishi, N. B.;
Sattur, P. B.; Nargund, K. S. J. Karnatak Univ. 1957, 2, 50.
(c) Okabayashi, I.; Fujiwara, H.; Tanaka, C. J. Heterocycl.
Chem. 1991, 23, 1977.
(5) (a) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 4273.
(b) Kristensen, J. L.; Vedsó, P.; Begtrup, M. J. Org. Chem.
2003, 68, 4091. (c) Kwon, C.-H.; He, H.-Z. Synth. Commun.
2003, 33, 2437. (d) Beaulieu, F.; Snieckus, V. J. Org. Chem.
1994, 59, 6508.
CF3
24
25
43
54
S
N
N
(6) (a) Costantino, L.; Ferrari, A. M.; Gamberini, M. C.;
Rastelli, G. Bioorg. Med. Chem. 2002, 10, 3923.
(b) Bonnet, B.; Soullez, D.; Girault, S.; Maes, L.; Landry,
V.; Davioud-Charvet, E.; Sergheraert, C. Bioorg. Med.
Chem. 2000, 8, 95. (c) Slight variation of reported reaction
between 2-iodo-5-methylbenzoic acid and thiophenol:
Valenta, V.; Jílek, J.; Pomykáček, J.; Dlabač, A.; Valcháꢀ,
M.; Metyš, J.; Protiva, M. Collect. Czech. Chem. Commun.
1979, 44, 2677; and references cited therein.
26
87
N
27
28
29
20
53
71
N
O
O
(7) Hodson, H. F.; Batchelor, J. F. GB 1447032, 1976; Chem.
Abstr. 1976, 86, 55284.
(8) (a) Balicki, R. J. Prakt. Chem. 1999, 341, 184. (b) Su, W.
Tetrahedron Lett. 1994, 35, 4955. (c) Denny, W. A.;
Rewcastle, G. W.; Atwell, G. J.; Palmer, B. D.; Boyd, P. D.;
Baguley, B. C. J. Med. Chem. 1991, 34, 491. (d) Carpino,
L. A.; Gao, H.-S.; Ti, G.-S.; Segev, D. J. Org. Chem. 1989,
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(10) Sauer, D. R.; Wang, Y. Org. Lett. 2004, 6, 2793.
(11) For a recent reported example on the use of simultaneous
cooling in microwave-assisted chemistry, see: Arvela, R. K.;
Leadbeater, N. E. Org. Lett. 2005, 7, 2101.
(12) Yields of Suzuki coupling reactions utilizing non-activated
chloro substrates can be often optimized by using
palladacyclic complexes, palladium complexes of phosphine
oxides or di(2-pyridyl)methylamine-based palladium
complexes. For selected reported examples, see: (a) Chen,
C. L.; Liu, Y. H.; Peng, S. M.; Liu, S. T. Tetrahedron Lett.
2005, 46, 521. (b) Miao, G.; Ye, P.; Yu, L.; Baldino, C. M.
J. Org. Chem. 2005, 70, 2332. (c) Nájera, C.; Gil-Moltó, J.;
Karlström, S. Adv. Synth. Catal. 2004, 346, 1798.
(d) Navarro, O.; Kelly, R. A.; Nolan, S. P. J. Am. Chem. Soc.
2003, 125, 16194.
N
H
a Reactions were run using 0.089 mmol of chlorosulfone 11, 0.089
mmol of corresponding boronic acid or boronic ester, 3 mol%
Pd(PPh3)4, 0.107 mmol of Cs2CO3 (1.0 M solution) and 1.5 mL of
EtOH. A microwave irradiation of 200 W was used the temperature
being ramped from r.t. to 110 °C in 1 min where it was then held for
a total reaction time of 10 min. Simultaneous cooling was used (pow-
ermax option on CEM discover microwave unit) for all reactions.
b Isolated yields after chromatography.
c Unoptimized yields except for the case of 13.
Acknowledgment
Financial assistance provided by the Robert A. Welch foundation is
gratefully acknowledged.
References and Notes
(1) For selected examples, see: (a) Azuine, M. A.; Tokuda, H.;
Takayasu, J.; Enjyo, F.; Mukainaka, T.; Konoshima, T.;
Nishino, H.; Kapadia, G. J. Pharm. Res. 2004, 49, 161.
(b) Kostakis, I. K.; Pouli, N.; Marakos, P.; Mikros, E.;
Skaltsounis, A.-L.; Leonce, S.; Atassi, G.; Renard, P.
Bioorg. Med. Chem. 2001, 9, 2793.
Synlett 2006, No. 18, 3045–3048 © Thieme Stuttgart · New York