Friedel–Crafts approach to the one-pot synthesis of methoxy-substituted thioxanthylium salts

Article abstract of DOI:10.3762/bjoc.15.208

An efficient synthesis of methoxy-substituted thioxanthylium salts has been developed. The reaction of diaryl sulfides with benzoyl chlorides in the presence of TfOH smoothly proceeded to give the desired thioxanthylium salts in good yields. In their UV–vis spectra, the maximum absorption wavelengths of methoxy-functionalized thioxanthylium salts were observed at around 460 nm, which show a drastic red shift compared to the parent thioxanthylium salts. The present reaction provides a versatile access to functionalized thioxanthylium salts, and therefore it constitutes a promising tool for the synthesis of biologically and photochemically active molecules.

Full text of DOI:10.3762/bjoc.15.208

Friedel–Crafts approach to the one-pot synthesis of
methoxy-substituted thioxanthylium salts
Kenta Tanaka, Yuta Tanaka, Mami Kishimoto, Yujiro Hoshino* and Kiyoshi Honda*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2105–2112.
Graduate School of Environment and Information Sciences,
Yokohama National University, Tokiwadai, Hodogaya-ku, Yokohama
240-8501, Japan
doi:10.3762/bjoc.15.208
Received: 19 June 2019
Accepted: 20 August 2019
Published: 05 September 2019
Email:
Yujiro Hoshino* - hoshino-yujiro-hy@ynu.ac.jp; Kiyoshi Honda* -
honda-kiyoshi-rb@ynu.ac.jp
Associate Editor: D. Y.-K. Chen
* Corresponding author
© 2019 Tanaka et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
Friedel–Crafts reaction; metal-free conditions; one-pot synthesis;
photoredox catalyst; thioxanthylium salt
Abstract
An efficient synthesis of methoxy-substituted thioxanthylium salts has been developed. The reaction of diaryl sulfides with benzoyl
chlorides in the presence of TfOH smoothly proceeded to give the desired thioxanthylium salts in good yields. In their UV–vis
spectra, the maximum absorption wavelengths of methoxy-functionalized thioxanthylium salts were observed at around 460 nm,
which show a drastic red shift compared to the parent thioxanthylium salts. The present reaction provides a versatile access to func-
tionalized thioxanthylium salts, and therefore it constitutes a promising tool for the synthesis of biologically and photochemically
active molecules.
Introduction
Thioxanthylium salts are one of the important structural motifs tion of 4,4’-bis(dimethylamino)diphenylmethane with sulfur in
found in biologically active compounds and photochemical ma- the presence of ZnCl2 [11], and the ring-closure reaction of
terials [1-8]. Owing to these useful properties, several research diaryl sulfide in the presence of a Lewis acid such as SnCl4 and
groups have developed methodologies to synthesize them. The AlCl3 [12-14]. While these reactions were proven to be useful,
typical synthetic methods for thioxanthylium salts include the they require the use of stoichiometric amounts of metals and/or
reaction of thioxanthone with aryl bromide in the presence of toxic metal reagents. Moreover, there are only a few methods
n-butyllithium or Grignard reagents followed by dehydration by for the synthesis of thioxanthylium salts despite their useful
acids such as hexafluorophosphoric acid (Scheme 1a and 1b) active properties. Thus, developing efficient synthetic routes
[3,4,9,10], oxidation of thioxanthene in the presence of PbO2 and more economic approaches is highly desirable. In addition,
followed by dehydration by tetrafluoroboric acid [1], the reac- only amino groups were introduced to the thioxanthylium core
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Scheme 1: The representative synthesis of thioxanthylium salts.
except at the 9-position of the thioxanthylium salt (Scheme 1b), improved to 60% (Table, entry 9). Moreover, when the reaction
and the physical properties of these substituted compounds have temperature was increased to 90 °C, 120 °C, and reflux, higher
not been examined.
yields were observed, especially under reflux conditions provid-
ing the product 3a in 82% yield (Table 1, entries 10–12). De-
We have developed the synthesis of multisubstituted condensed creasing the amount of TfOH did not improve the yield
heterocyclic compounds in the presence of an acid catalyst [15- (Table 1, entry 13). It is suggested that the cyclization and
23]. More recently, we have reported the design and synthesis dehydration were efficiently promoted at high temperature.
of thioxanthylium organophotoredox catalysts, which can work Fortunately, when the reaction was carried out with benzoic
under green light irradiation [24,25]. In the course of this study, acid, which is a more easily available substrate in comparison
we found that these thioxanthylium photocatalysts efficiently with benzyl chloride, the desired product was obtained in good
oxidized styrene derivatives such as trans-anethole, and yield. It was found that the reaction can be applied to not only
promoted radical cation Diels–Alder reactions. Based on the benzoyl chloride but also to benzoic acid.
background mentioned above, in order to expand the utility of
the synthesis of thioxanthylium salts and investigate their physi- With the optimized conditions in hand, we investigated the
cal properties, we report the Friedel–Crafts approach as an effi- generality of diaryl sulfide 1 and benzoyl chloride 2 (Figure 1).
cient synthetic method of methoxy-substituted thioxanthylium o-Toluoyl chloride smoothly afforded the desired product 3b in
salts (Scheme 1c).
excellent yield. Moreover, the reaction was performed on the
2 mmol scale to furnish the desired product in 73% yield,
suggesting that the reaction can be applied to large scale condi-
Results and Discussion
Initially, we screened the reaction of bis(3,5-dimethoxyphenyl) tions. In addition, 2-methoxy and 2-trifluoromethyl-functionali-
sulfide (1a) with benzoyl chloride (2a) in the presence of zed benzoyl chloride can be applied to the reaction (3c,d). The
Brønsted acids in chlorobenzene at several temperatures 4-methoxy group was also tolerated in the reaction (3e). Sub-
(Table 1). When we used a strong Brønsted acid such as tri- strates with strong electron-withdrawing groups such as 4-tri-
fluoromethanesulfonic acid (TfOH) at room temperature, the fluoromethyl, 4-nitro and 4-cyano groups reacted with moder-
desired thioxanthylium salt 3a was obtained with 21% yield ate to excellent yields (3f–h). The benzoyl chlorides bearing a
while other typical Brønsted acids did not work efficiently variety of halogens were suitable for this reaction (3i–n). Al-
(Table 1, entries 1–8) [2,9,10]. At 60 °C, the yield effectively though naphthalene is a sterically large group, the reaction
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Table 1: Optimization of the reaction conditionsa.
Entry
Brønsted acidb
Temperature (°C)
Yield (%)
1
2
H3PO4
HCl
rt
rt
0
0
3
4
5
6
7
8
9
10
11
12
13c
14d
TsOH
MsOH
HBF4
HPF6
HClO4
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
rt
rt
rt
rt
rt
rt
0
0
0
0
traces
21
60
72
75
82
78
72
60
90
120
reflux
reflux
reflux
aAll reactions were carried out with 1a (0.25 mmol), 2a (0.75 mmol), acid (3.0 equiv) in chlorobenzene (5.0 mL) for 1 h under N2. bH3PO4 (85% aq),
HCl (0.5 M in MeOH), HBF4 (42% aq), HPF6 (65% aq), HClO4 (70% aq). cTfOH (2.0 equiv) was used. dbenzoic acid (0.75 mmol) was used instead of
benzoyl chloride (2a).
proceeded smoothly (3o). The diaryl sulfide with ethoxy sub- maximum absorption wavelength of thioxanthylium salt 3b
stituents furnished the corresponding product in moderate yield (λmax = 464 nm) showed a large red shift compared to thioxan-
(3p). Interestingly, when bis(3,4-dimethoxyphenyl) sulfide was thylium salt 4b (λmax = 383 nm), which has no methoxy groups
used as a substrate, the reaction proceeded to afford the desired (Figure 4 and Figure 5).
2,3,6,7-tetramethoxy-substituted thioxanthylium salt (3q). It
was found that the present reaction can be applied to various Finally, we measured the cyclic voltammograms (CV) of thiox-
benzoyl chlorides bearing either electron-donating or electron- anthylium salts 3b and 4b (Figure 6). The CV data analysis
withdrawing groups.
implies that the reduction potential of 3b (E°’ = −0.79 V vs
Fc/Fc+) afforded a negative shift compared to 4b (E°’ =
Subsequently, we measured the UV–vis spectra of thioxan- −0.56 V vs Fc/Fc+). It is obviously indicated that the methoxy
thylium salts. As shown in Figure 2, almost all measured groups lower the reduction potential by their strong electron-do-
UV–vis spectra are nearly identical in spite of different substitu- nating effect.
ents on the benzene ring at the 9-position of the thioxanthylium
core. Moreover, when the solvent effects were examined using Conclusion
MeCN, CH3NO2, DMSO and MeOH, no substantial shifts of We have developed the Friedel–Crafts approach as an efficient
the main peak at around 460 nm in the UV–vis absorption spec- method to synthesize oxygen-modified thioxanthylium salts.
tra were observed [24], indicating that the main absorption of When the reaction of diaryl sulfide with benzoyl chloride in the
these catalysts would be due to π–π* transition, which is sup- presence of TfOH was carried out under reflux conditions in
ported by DFT calculations (TD-DFT B3LYP method) chlorobenzene, the desired thioxanthylium salt was obtained in
(Figure 3a,b). Based on these calculations, it was found that good yield. A variety of benzoyl chlorides bearing both elec-
tetramethoxy substituents at the thioxanthylium core lead to an tron-donating and electron-withdrawing groups can be applied
up-shift of both HOMO/LUMO energy levels compared to to the reaction. It was found that the main absorption of thiox-
thioxanthylium salts without methoxy groups (Figure 3c,d). The anthylium salts around 460 nm in UV–vis spectra would be due
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Beilstein J. Org. Chem. 2019, 15, 2105–2112.
Figure 1: The generality of diaryl sulfide 1 and benzoyl chloride 2. aThe reaction was carried out with 1a (2.0 mmol), 2a (6.0 mmol), TfOH (3.0 equiv)
in chlorobenzene (40.0 mL) at reflux for 1 h under N2. b2 (2.0 equiv) and TfOH (2.0 equiv) were used at 120 °C. c2 (2.0 equiv) and TfOH (2.0 equiv)
were used. d20 h. e2 h.
to π–π* transitions, which was supported by DFT calculations. DRX-300 (300 MHz) spectrometer, a Bruker DRX-500
The present reaction provides a versatile access to functionali- (500 MHz) spectrometer or a JEOL JNM ECA-500 (500 MHz)
zed thioxanthylium salts, and therefore constitutes a promising spectrometer with tetramethylsilane (TMS) as internal standard.
tool for the synthesis of biologically and photochemically active Chemical shifts are reported in ppm from TMS. Data are re-
molecules.
ported as follows: chemical shift, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet), coupling con-
stants, integration. 13C NMR spectra were recorded on a Bruker
DRX-500 (126 MHz) or a JEOL JNM ECA-500 (126 MHz)
Experimental
General
Infrared (IR) spectra were recorded on a JASCO FT/IR-4100 spectrometer with complete proton decoupling. Chemical shifts
spectrophotometer. 1H NMR spectra were recorded on a Bruker are reported in ppm with the solvent resonance as the internal
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Figure 2: The UV–vis spectra of thioxanthylium salt (0.1 mM) in CH3CN.
Elemental Analyzer Vario ELIII Elemental (Elementar Co.).
Column chromatography was carried out with Cicareagent
silica gel 60 N (spherical, particle size 63–210 mm). Thin-layer
chromatography (TLC) was carried out with Merck TLC plates
with silica gel 60 F254. Unless otherwise noted, reagents were
commercially available and were used without further purifica-
tion. The UV absorption spectra were measured with a JASCO
V-630 spectrometer. Cyclic voltammetry measurements were
carried out with a computer-controlled potentiostat Model 660C
(ALS Co., Ltd.).
General procedure for the synthesis of
thioxanthylium salt 3
Analogously as described in [24] thioxanthylium salts 3a–q
were prepared according to the following procedure.
A solution of diaryl sulfide 1 (0.25 mmol) and benzoyl chloride
2 (0.75 mmol) in chlorobenzene (5.0 mL) was placed in a
50 mL recovery flask under N2. Trifluoromethanesulfonic acid
(0.75 mmol) was slowly added to the solution, which was
heated to reflux for 1 h. The solution was cooled to room tem-
perature and excess Et2O was added to precipitate a solid. After
stirred for 1 h, the mixture was filtered. The solid was washed
with Et2O and dried in vacuo, affording the desired thioxan-
thylium salt 3.
Figure 3: Frontier orbitals of thioxanthylium salts, calculated by DFT at
the B3LYP/6-31G(d,p) level of Orca. (a) LUMO localization of 3a
(energy level: −5.745 eV), (b) HOMO localization of 3a (energy level:
−8.842 eV), (c) LUMO localization of 4a (energy level: −6.812 eV), (d)
HOMO localization of 4a (energy level: −9.788 eV).
standard (CDCl3: δ 77.0). 19F NMR spectra were recorded on a
JEOL JNM AL-400 (376 MHz) or a JEOL JNM ECA-500
9-Phenyl-1,3,6,8-tetramethoxythioxanthylium
(471 MHz) spectrometer with hexafluorobenzene (C6F6: trifluoromethanesulfonate (3a)
δ −164.9 ppm) as internal standard. High-resolution mass spec- Red solid (0.1109 g, 82% yield). 1H NMR (500 MHz, CDCl3) δ
tra (HRMS) were obtained with a Hitachi Nanofrontier LD 7.51 (d, J = 2.2 Hz, 2H), 7.44–7.38 (m, 3H), 7.14–7.10 (m, 2H),
Spectrometer (ESI/TOF). Elemental analyses of carbon, hydro- 6.51 (d, J = 2.5 Hz, 2H), 4.15 (s, 6H), 3.37 (s, 6H); 13C NMR
gen, nitrogen, and sulfur were performed with a CHNOS (126 MHz, CDCl3) δ 168.3. 165.5. 165.2. 147.8. 142.2. 127.2.
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Beilstein J. Org. Chem. 2019, 15, 2105–2112.
Figure 4: UV–vis spectra of thioxanthylium salts 3b and 4b (0.1 mM) in CH3CN.
393.1155; found, 393.1171; anal. calcd for C24H21F3O7S2: C,
53.13; H, 3.90. found: C, 52.80; H, 4.001.
For the synthesis of 9-(naphthalene-1-yl)-
1,3,6,8-tetramethoxythioxanthylium trifluoro-
methanesulfonate (3o)
To a solution of 1-naphthoic acid (0.1746 g, 1.0 mmol) in dry
CH2Cl2 (2.5 mL) at 0 °C under N2 (COCl)2 (0.100 mL,
1.2 mmol) was dropwise added. After the addition of a catalyt-
ic amount of dry DMF (2 drops), the solution was allowed to
warm to room temperature, and stirred at that temperature for
2 h. The reaction mixture was concentrated in vacuo to afford
the corresponding crude acid chloride. After the residue was
dissolved in chlorobenzene, bis(3,5-dimethoxyphenyl) sulfide
1a (0.1005 g, 0.33 mmol) and trifluoromethanesulfonic acid
Figure 5: Structure of thioxanthylium salt 4.
127.0. 125.6. 116.9. 101.8. 101.4. 57.7. 56.7; 19F NMR
(376 MHz, CDCl3) δ −81.3; IR (ATR): 1585, 1219, 1143, 1026,
634 cm−1; HRMS (ESI+) m/z: [M]+ calcd for C23H21O4S,
Figure 6: Cyclic voltammograms of thioxanthylium salts 3b and 4b.
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Beilstein J. Org. Chem. 2019, 15, 2105–2112.
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(0.087 mL, 0.99 mmol) were added. The reaction temperature
was increased to reflux and the solution was stirred for 1 h. The
solution was cooled to room temperature and excess Et2O was
added. After stirring for 1 h, the solution was filtered, and the
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7.36–7.32 (m, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.93 (dd, J = 7.1,
1.1 Hz, 1H), 6.43 (d, J = 2.2 Hz, 2H), 4.15 (s, 6H), 2.96 (s, 6H);
13C NMR (126 MHz, CDCl3) δ 168.4, 165.2, 164.7, 147.6,
140.7, 132.1, 132.0, 128.2, 127.5, 126.4, 125.9, 125.0, 124.4,
121.3, 117.6, 102.0, 101.5, 57.7, 56.6; 19F NMR (376 MHz,
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Copies of 1H and 13C NMR spectra, procedures for the
synthesis of diaryl sulfides and thioxanthylium 4,
computational data, absorption spectra, and cyclic
voltammetry data.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-208-S1.pdf]
18.Tanaka, K.; Sukekawa, M.; Kishimoto, M.; Hoshino, Y.; Honda, K.
Heterocycles 2019, 99, 145–170. doi:10.3987/com-18-s(f)5
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21.Tanaka, K.; Hoshino, Y.; Honda, K. Heterocycles 2017, 95, 474–486.
doi:10.3987/com-16-s(s)38
Acknowledgements
We thank Prof. Mahito Atobe of Yokohama National Univer-
sity for cyclic voltammetry measurements.
ORCID® iDs
Kenta Tanaka - https://orcid.org/0000-0001-8253-3561
Yujiro Hoshino - https://orcid.org/0000-0002-8373-8013
Kiyoshi Honda - https://orcid.org/0000-0001-7216-7676
22.Tanaka, K.; Hoshino, Y.; Honda, K. Tetrahedron Lett. 2016, 57,
2448–2450. doi:10.1016/j.tetlet.2016.04.086
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Tetrahedron Lett. 2016, 57, 5914–5918.
doi:10.1016/j.tetlet.2016.11.076
24.Tanaka, K.; Kishimoto, M.; Sukekawa, M.; Hoshino, Y.; Honda, K.
Tetrahedron Lett. 2018, 59, 3361–3364.
Preprint
A non-peer-reviewed version of this article has been previously published
as a preprint doi:10.3762/bxiv.2019.41.v1
doi:10.1016/j.tetlet.2018.07.058
25.Tanaka, K.; Omata, D.; Asada, Y.; Hoshino, Y.; Honda, K.
J. Org. Chem. 2019. doi:10.1021/acs.joc.9b01156
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