Synthesis of thioxanthones through formal C-H thiolation of benzoic acid esters and Acid-mediated Direct Cyclization

Article abstract of DOI:10.1246/CL.200190

An efficient thioxanthone synthesis from benzoic acid esters is disclosed. Various thioxanthones were prepared by iridiumcatalyzed C-H borylation of benzoic acid esters followed by copper-catalyzed deborylthiolation and direct acid-mediated cyclization. We also achieved a synthesis of benzo-fused thioxanthones through a transformation of an aryne intermediate having an ester moiety.

Full text of DOI:10.1246/CL.200190

Advance Publication Cover Page
Synthesis of Thioxanthones through Formal C–H Thiolation of Benzoic Acid Esters
and Acid-mediated Direct Cyclization
Kotaro Mutsuura, Yuki Sakata, Keisuke Uchida, Takamitsu Hosoya, and Suguru Yoshida*
Advance Publication on the web April 9, 2020
doi:10.1246/cl.200190
©
2020 The Chemical Society of Japan
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Publication manuscripts.

1
Synthesis of Thioxanthones through Formal C–H Thiolation of Benzoic Acid Esters
and Acid-mediated Direct Cyclization
Kotaro Mutsuura, Yuki Sakata, Keisuke Uchida, Takamitsu Hosoya, and Suguru Yoshida*
Laboratory of Chemical Bioscience, Institute of Biomaterials and Bioengineering,
Tokyo Medical and Dental University (TMDU), 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062
E-mail: s-yoshida.cb@tmd.ac.jp
1
2
3
4
5
6
7
An efficient thioxanthone synthesis from benzoic acid
4
4
5
8
9
0
thiosulfonates 3a–3c (Figure 2). As a result, after the
selective borylation of benzoic acid esters 1a–1c with a
catalytic amount of [(MeO)Ir(cod)] and SIPBz (Figures 2A
2
esters is disclosed. Various thioxanthones were prepared by
iridium-catalyzed C–H borylation of benzoic acid esters
followed by copper-catalyzed deborylthiolation and direct
acid-mediated cyclization. We also achieved a synthesis of
benzo-fused thioxanthones through a transformation of an
aryne intermediate having an ester moiety.
51 and 2B), a variety of 2-(arylthio)benzoic acid esters 4a–4f
52 were successfully prepared in high to excellent yields (Figure
5
5
5
5
3
4
5
6
2C). Particularly, the copper-catalyzed deborylthiolation
using thiosulfonates having not only electron-donating
methoxy and methyl groups but also electron-withdrawing
chloro, fluoro, and bromo groups took place without a
8
Keywords: Thioxanthone, Thiolation, Cyclization
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
Thioxanthones have gained attention from a broad range
of researchers as synthetic intermediates for organosulfur
compounds, photoredox catalysts, photoinitiators, and
57 significant decrease in the efficiencies.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
58
A
NEt2
O
1
O
O
HN
bioactive compounds such as lucanthone (Figure 1A).
i-Pr
Despite the importance of thioxanthone derivatives, it is not
easy to synthesize thioxaothones by conventional methods
through copper-mediated S-arylation with aryl halides
followed by cyclization of carboxylic acids under acidic
S
S
MeO
S
OMe
Me
lucanthone
acetylcholine inhibitor
2
-ITX
photoredox catalyst
photoinitiator
1
,2
conditions (Figure 1B). In particular, a synthesis of
multisubstituted thioxanthones including p-extended ring-
fused thioxanthones is quite limited due to the poor
accessibility of the corresponding thiols, the narrow substrate
scope of S-arylation, and the harsh reaction conditions
requiring an excess amount of strong acids. Therefore, a
facile synthetic method enabling to prepare diverse
thioxanthones from simple starting materials is desired.
Herein, we describe a thioxanthone synthesis from easily
available benzoic acid esters through formal ortho-C–H
thiolation followed by direct trifluoromethanesulfonic acid
(TfOH)-mediated cyclization (Figure 1C).
B
Conventional methods
Ar2
O
X
Cu
Cu
OH
O
PPA
20 °C
O
Ar1
1
OH
SH
Ar2
or
Ar1
Ar2
Ar1
S
conc. H2SO4
0 °C
S
O
8
OH
Ar1
X
Ar2
HS
C
This work
O
1
2
. B2pin2
cat. Ir
O
Based on our continuous efforts on the organosulfur
TfOH
O
OMe
3
chemistry, we planned to develop a novel synthetic route for
Ar1
OMe
Ar1
Ar2
Ar1
Ar2
. TsSAr2
cat. Cu
formal
HFIP
65 °C
S
thioxanthones from benzoic acid esters and thiosulfonates.
Recently, an odorless user-friendly diaryl sulfide synthesis
catalyzed by copper has been developed using a thiosulfonate
S
C–H thiolation
5
9
3
a,3c
as a sulfur surrogate.
Considering the broad substrate
60 Figure 1. Synthesis of thioxanthones. (A) Useful thioxanthones. (B)
6
1
Conventional methods. (C) This work.
scope of the sulfide synthesis, we envisioned that the iridium-
4
62
catalyzed ortho-borylation of benzoic acid esters followed
6
6
3
4
We then screened the reaction conditions for direct
cyclization from 2-(arylthio)benzoic acid esters to
by the copper-catalyzed deborylthiolation and direct
cyclization would afford a wide variety of thioxanthone
5
–7
65 thioxanthones without obtaining benzoic acids (Table 1). The
derivatives. Since halogeno groups would be tolerated in
these transformations, combination between this
8
6
6
6
6
7
6
7
8
9
0
results showed that TfOH facilitated the direct construction
a
of the thioxanthone skeleton from ester 4a. We found that
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP)
promoted the TfOH-mediated intramolecular Friedel–Crafts-
type reaction among various solvents tested (entry 6 vs
thioxanthone synthesis and subsequent cross-coupling
chemistry will remarkably expand synthesizable
thioxanthones.
9
dramatically
Firstly, we conducted ortho-borylation of benzoic acid
4
71 entries 1–5). It is worthy to note that the cyclization also
esters 1a–1c according to the report by Smith and coworkers
7
7
2
3
proceeded at room temperature (entry 7). On the other hand,
the cyclization using concentrated sulfuric acid or
and attempted the copper-catalyzed deborylthiolation of the
resulting arylboronic acid pinacol esters 2a–2c with

1
2
3
4
5
6
7
trifluoroacetic acid instead of TfOH resulted in failure
(entries 8 and 9). Good accessibility of benzoic acid esters 4
is a significant advantage of this method, while benzoic acids
possessing arylthio groups at the ortho position have been
used in the conventional methods for the formation of
thioxanthone skeleton.
19 (Figure 3). Indeed, the cyclization of 2-(4-anisylthio)-6-
20 methoxybenzoic acid ester 4b proceeded smoothly to afford
21 thioxanthone 5b in good yield. Benzoic acid ester 4c having
22 electron-deficient 4-chlorophenylthio group was also
23 applicable providing 2-chloro-8-methoxythioxanthone (5c)
24 in moderate yield. Treatment of fluoro- and bromo-
25 substituted 2-(4-tolylthio)benzoic acid esters 4d and 4e with
26 TfOH furnished the corresponding thioxanthones 5d and 5e,
27 respectively, in high yields. Furthermore, thioxanthone 5f
28 having a transformable chloro and bromo groups was
29 successfully synthesized in high yield leaving these
30 functional groups untouched.
A
Ar2
Ts
B
cat. Ir
cat. L
2
pin
2
S
3
O
CuSO
4
O
O
(10 mol %)
OMe
Ar2
OMe
Bpin
OMe
Ar1
Ar1
Ar1
THF
NaHCO3
MeOH, rt
S
4
8
0 °C
1
(ref 4)
2
3
1
O
O
B
TfOH
OMe
X
O
L = SIPBz
Si(H)i-Pr
X
O
Ar2
Y
Ar1
Ar2
Ar1
HFIP
65 °C
OMe
2
OMe
S
S
5
Ts
X = OMe : 1a
F : 1b
S
4
Bpin
P(p-Tol)
2
Y = Me : 3a
OMe : 3b
Cl : 3c
X = OMe : 2a
F : 2b
O
OMe O
OMe O
F
O
Br
O
OMe
Cl
Me
OMe
Br
1
c
OMe
S
S
S
Bpin 2c
5
b
5c
5d
7
9%
49%
76%
O
O
C
O
O
O
Br
Me
Br
Cl
MeO
MeO
MeO
OMe
OMe
OMe
Me
OMe
Cl
S
S
S
S
S
5e
5f
4
a
4b
85%
4c
94%
32
70%
64%
8
7%
(
from 2a, 3a)
(from 2a, 3b)
(from 2a, 3c)
33
34
Figure 3. Synthesis of thioxanthones 5b–5f.
O
O
O
F
OMe
OMe
OMe
S
Me Br
Me Br
Cl
S
S
S
B(OH)
6a
2
S
O
4
d
4e
4f
cat. (amphos) PdCl
2
2
Cl
9
1%
90%
(from 2c, 3a)
97%
(from 2c, 3c)
5f
(
from 2b, 3a)
K
3
PO
,4-dioxane, H
00 °C
4
8
7
1
2
O
S
7
8%
1
9
0
1
Figure 2. Synthesis of 2-(arylthio)benzoic acid esters 4. (A) General
scheme. (B) Structures of 1–3 and L. (C) Synthesized 2-
(arylthio)benzoic acid esters.
1
1
(
HO)
2
B
Me
6
b
XPhos Pd G2
XPhos Pd G2 (10 mol %)
PO (2.0 equiv)
THF, 40 °C
12
K
3
4
13
Table 1. Optimization of the reaction conditions
Cl Pd
N H
H
Me
Acid
(2.0 equiv)
OMe O
O
XPhos
S
O
MeO
OMe
Me
Me
Solv.
Temp.
8
8%
S
S
S
8
2
1 h
35
4
a
5a
14
3
6
a
Entry
Acid
Solv.
Temp. Yield/%
3
3
7
8
Figure 4. Consecutive cross-coupling using thioxanthone 5f. amphos =
4-(t-Bu P)C NMe . XPhos = 2-(c-Hex P)-2’,4’,6’-i-Pr biphenyl.
1
2
3
4
5
6
7
8
9
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
MeCN
MeNO
ClCH CH
toluene
CF CH
100 °C
100 °C
13
38
2
6
H
4
2
2
3
2
3
4
4
4
4
4
4
4
4
4
4
9
0
1
2
3
4
5
6
7
8
9
2
2
Cl 100 °C
100 °C
21
Consecutive
palladium-catalyzed
cross-coupling
36
reactions of thioxanthone 5f bearing a chloro and a bromo
3
2
OH
65 °C
65 °C
rt
13
1
0
group were accomplished (Figure 4). Treatment of
thioxanthone 5f with 3-thienylboronic acid (6a) in the
presence of potassium phosphate and a catalytic amount of
b
HFIP
HFIP
HFIP
HFIP
98 (97)
80
conc. H
2
SO
4
65 °C
65 °C
0
2 2
(amphos) PdCl in dioxane and water resulted in the selective
CF CO
3
2
H
0
11
C–C bond formation at the bromo group in good yield. The
second cross-coupling of resulting thioxanthone 7 with 4-
tolylboronic acid (6b) was prompted by a second-generation
a 1
b
1
1
1
1
5
6
7
8
H NMR yields. Isolated yield.
A
variety of disubstituted thioxanthones were
12
Pd–XPhos precatalyst to yield thioxanthone 8 efficiently.
successfully prepared by the acid-mediated ring-closure

3
1
3,14
1
2
The wide viability of the cross-coupling chemistry will serve
in the rapid construction of diverse thioxanthone library.
15 intermediate (I) (Figure 5).
16 reports, treatment of a mixture of 4-(methoxycarbonyl)-2-
iodophenyl triflate (9) and 2,5-dimethylfuran (10) with
According to our previous
1
7
3
15
1
.
Me
O
18 trimethylsilylmagnesium
chloride
and
following
A
1
2
2
9
0
1
aromatization with sodium iodide and trimethylsilyl
1
6
chloride
afforded
methoxycarbonyl-substituted
1
0
Me
naphthalene 11 in good yields. The resulting ester 11 was
22 successfully borylated by the iridium-catalyzed C–H
Me
Me
O
O
3 2
Me SiCH MgCl
THF, –30 °C; 77%
I
OMe
OMe
2
2
2
3
4
5
activation in
a
regioselective manner. Following
deborylthiolation with thiosulfonates 3a–3c afforded sulfides
12a–12c efficiently. Finally, TfOH-promoted cyclization of
2
. NaI, Me3SiCl
MeCN, CH2Cl2;
7%
9
11
TfO
7
O
1
. B2pin2
cat. Ir,
cat. SIPBz
THF, reflux;
2. TsSAr 3
cat. CuSO4
NaHCO3
26 sulfides 12a–12c occurred smoothly to furnish a range of
27 benzothioxanthones 13a–13c having methyl, methoxy, and
chloro groups in good yields. In addition, benzothioxanthone
29 13a emitted significant blue-green fluorescence under
0 excitation at 440 nm. Considering the versatility of aryne
31 intermediates by a wide variety of transformations, various
32 multisubstituted thioxanthones would be synthesized via
OMe
MeOH, rt
I
46%
2
8
O
Me
O
Me
OMe
17
TfOH
HFIP
3
Ar
Ar
S
S
6
5 °C
12
Me
13
Me
3
3
3
4
aryne reactions with diverse arynophiles.
In summary, we have developed a novel method to
B
O
O
Me
OMe
Me
OMe
35 prepare thioxanthone derivatives from benzoic acid esters
3
3
Me
OMe
6
7
and thiosulfonates. The synthetic utility of this method was
clearly shown by the thioxanthone synthesis on the basis of
S
S
1
8
2a
6%
12b
63%
Me
Me
38 the consecutive cross-coupling approach and synthetic aryne
chemistry. Further studies are underway to disclose the
40 detailed scope and limitations of this thioxanthone synthesis,
3
9
O
Me
OMe
Cl
4
4
43
1
2
examine structure–fluorescence relationship, and synthesize
highly p-extended compounds.
S
1
9
2c
3%
Me
4
4
4
4
4
4
4
5
6
7
8
9
This work was supported by JSPS KAKENHI Grant
Numbers JP19K05451 (C; S.Y.), JP17J08217 (JSPS
Research Fellow; K.U.), JP18H02104 (B; T.H.), and
JP18H04386 (Middle Molecular Strategy; T.H.); the Naito
Foundation (S.Y.); the Japan Agency for Medical Research
and Development (AMED) under Grant Number
C
Me
O
Me
Me
O
Me
O
Me
OMe
Cl
S
S
S
Me
Me
1
3a
13b
63%
13c
71%
50 JP19am0101098 (Platform Project for Supporting Drug
6
6%
4
5
5
5
5
5
55
5
5
1
2
3
4
Discovery and Life Science Research, BINDS); and the
Cooperative Research Project of Research Center for
Biomedical Engineering.
D
5
4
3
2
1
0000
0000
0000
0000
0000
0
40000ꢀ
30000ꢀ
20000ꢀ
10000ꢀ
Supporting Information is available on http://dx.doi.org/
10.1246/cl.xxxxxx.
6
7
5
8 References and Notes
59
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6
6
6
6
6
6
6
6
6
6
7
7
7
7
0
1
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3
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6
7
8
9
0
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0ꢀ
2
50
350
450
550
650
750
Wavelength (nm)ꢀ
6
7
8
9
0
1
2
Figure 5. Synthesis of benzothioxanthones 13. (A) General scheme.
(B) Synthesized diaryl sulfides 12. (C) Synthesized thioxanthones 13.
(D) The UV/Vis absorption (solid line; lmax = 441 nm, e = 3350) and
emission (dashed line; lem = 490, lex = 440 nm, f = 0.76) spectra of
13a in chloroform.
1
1
1
1
1
3
4
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2
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