Synthesis of new thioxanthenes by organocatalytic intramolecular Friedel–Crafts reaction

Article abstract of DOI:10.1080/00397911.2018.1482351

An efficient organocatalytic route has been developed to synthesize novel substituted thioxanthenes (2a–2v) starting from diaryl thioether alcohols (1a–1v) using the intramolecular Friedel–Crafts reaction. The starting materials were obtained in two stage

Full text of DOI:10.1080/00397911.2018.1482351

Synthetic Communications
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Synthesis of new thioxanthenes by organocatalytic
intramolecular Friedel–Crafts reaction
Tülay Yildiz
To cite this article: Tülay Yildiz (2018): Synthesis of new thioxanthenes by
organocatalytic intramolecular Friedel–Crafts reaction, Synthetic Communications, DOI:
10.1080/00397911.2018.1482351
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https://doi.org/10.1080/00397911.2018.1482351
Synthesis of new thioxanthenes by organocatalytic
intramolecular Friedel–Crafts reaction
€
Tulay Yildiz
Department of Chemistry, Organic Division, Istanbul University-Cerrahpasa, Istanbul, Avcilar, Turkey
ABSTRACT
ARTICLE HISTORY
Received 5 April 2018
An efficient organocatalytic route has been developed to synthesize
novel substituted thioxanthenes (2a–2v) starting from diaryl thio-
ether alcohols (1a–1v) using the intramolecular Friedel–Crafts reac-
tion. The starting materials were obtained in two stages via a
coupling reaction followed by the Grignard reaction. In this study,
we tried for the first time to use some organic Brønsted acids as
organocatalysts (3a–3h) in the intramolecular Friedel–Crafts cycliza-
tion reaction of thioether alcohols. The synthesis of original substi-
tuted thioxanthenes was achieved within 15minutes by using
N-triflylphosphoramide (3h) with quantitative yields in THF at room
temperature.
KEYWORDS
Brønsted acid catalyst;
Friedel–Crafts reaction;
intramolecular cyclization;
N-triflylphosphoramide;
thioxanthenes
GRAPHICAL ABSTRACT
OO O
O
O
P
S
N
H
CF3
OH
Ar2
Ar2
Ar1
S
S
THF, rt, 15 min.
-HOH
Ar1
2a-2v
1a-1v
Introduction
Thioxanthenes are a significant part of diarylannulated heterocycles, in which the oxy-
gen atom in xanthene is replaced by a sulfur atom. Thioxanthene compounds and their
derivatives have valuable biological properties, such as antiparasitic,[1] anti-cancer[2] and
antitumor,[3] antimicrobial,[4] anti-inflammatory, and antioxidant activities.[5] In add-
ition to these important properties, these substances are used in the development of
neuroleptic and antidepressive drugs. These compounds are utilized in a broad spectrum
€
CONTACT Tulay Yildiz
tulayyil@istanbul.edu.tr
Department of Chemistry, Organic Division, Istanbul University-
Cerrahpasa, Istanbul, Avcilar 34320, Turkey.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

2
T. YILDIZ
of applications in medicinal chemistry. For example, they are antipsychotic drugs which
are used in the treatment of schizophrenia and other psychotic disorders.[6] This type of
drugs has also other valuable effects, such as antihistaminic, anesthetic, antinausea, and
antiemetic activities.[7] Moreover, these compounds, found in certain plants, are also
conventional medicines used in the treatment of common conditions, such as fever,
colds, ulcers, diarrhea, itching, and abdominal illnesses.[8]
Several methods for synthesis of thioxanthene derivatives have been reported. The
most conventional approach based on the synthesis of the thioxanthone derivatives and
their reduction.[8,9] The classical way of synthesis of thioxanthones is through the con-
densation of thiosalicylic acids with benzene derivatives, followed by cyclization of the
formed thioether in the presence of sulfuric acid,[10] phosphoric acid,[11] or Lewis acids
such as AlCl3.[3b] However, due to the low yields obtained after the use of sulphuric
acid, the lack of regioselectivity, and the long reaction times, these traditional methods
have not been preferred in recent years.
A different route to obtain thioxanthenes is cross-coupling between an aromatic thio-
ether and aryl halide in the presence of transition metal catalysts, such as Pd or Cu,
and subsequent cyclization.[12] The intramolecular cyclization of biaryls, including
ortho-substituted sulfur-containing functional groups, has been reported as another
pathway for the synthesis of thioxanthenes.[13]
Recently, we reported obtaining 9-arylxanthenes through intramolecular
Friedel–Crafts alkylation (FCA) of appropriate alcohols via the use of an organocata-
lyst.[14] It is noteworthy that the route based on arylation using an FCA protocol has
recently demonstrated new developments. In particular, arylation that does not use any
metals has attracted considerable research interest due to its potential to prevent the dis-
advantages of organometallic chemistry, including the high cost, application of toxic
materials, and difficult purification.[15] These novel methods have significant advantages,
such as using moderate reaction conditions and inexpensive and less poisonous cata-
lysts.[16] Alcohols have recently been reported to be exceedingly useful reagents that can
be utilized in Friedel–Crafts alkylation in contrast to organohalides, which are more
toxic and require harsh conditions.[17] To the best of our knowledge, Panda et al. are
the only research group that used an intramolecular FCA procedure to synthesize some
substituted 9-arylthioxanthenes via Lewis acid (FeCl3)-catalysis.[18]
Although hydroarylation reaction of activated alkenes using FCA was previously
employed with certain Brønsted acids, such as diphenyl hydrogen phosphate as a cata-
lyst,[19] no report exists of intramolecular FCA using organic Brønsted acids as a catalyst
instead of Lewis acids except our newly published work.[14] According to recent studies,
non-chiral, organic Brønsted acids are better than Lewis or inorganic Brønsted acids.[20]
Recently, new Brønsted acids containing –NSO2CF3 or –NSO2F groups were synthesized
to form a new catalyst species named super-acid. These groups, especially the triflate
groups, significantly increased acidity.[21] Because N-triflate groups have lower pKa
values compared to natural organic acids, more acidic N-triflate groups can catalyze
reactions leading to a generally higher yield in a shorter time.[22] More specifically,
N-triflylphosphoramide (3h) (Fig. 1) was used as an organic Brønsted acid as described
in previous reports.[23]
In this work, due to the crucial importance of thioxanthenes as biologically active
compounds, we applied our organocatalytic method for the synthesis of novel

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3
O
O
O
OH
OH
H3C
F3C
OH
OH
O
O
3a
3b
3d
3g
O
P
O
OH
3e
OH
O
O O O
S
O
SO3H.H2O 3h
P
O
N
H
CF3
3c
3f
ClH2C
OH
Figure 1. Organic Brønsted acids used for intramolecular FCA.
thioxanthenes. For this purpose, we modified the technique through new optimization
studies and determined the best reaction conditions for intramolecular cyclization of thi-
oxanthenes. Importantly, using N-triflylphosphoramide (3h), we synthesized sixteen ori-
ginal 9-arylthioxanthenes (2b, 2c, 2e, 2f, 2i, and 2k–2v) with excellent yields.
Based on our previous findings, we first synthesized starting compounds in two steps
through a metal-free coupling reaction[24] and Grignard reaction. Then, we obtained the
desired diaryl alcohols containing a thioether group as reagents (1a–1v) with excellent
yields (95%–100%). All starting materials synthesized in this study are also novel except
1a, 1g, and 1j.
Thioether alcohol 1a was used for intramolecular FCA, and different acid catalysts
were examined as initial optimization tests. Next, certain organic Brønsted acids were
investigated as catalysts for the intramolecular FCA reaction of 1a. Specifically, acetic
acid (3a), trifluoroacetic acid (3b), chloroacetic acid (3c), benzoic acid (3d), salicylic
acid (3e), p-toluenesulfonic acid (3f), diphenyl hydrogen phosphate (3g), and
N-triflylphosphoramide (3h) were used as organocatalysts. To determine the best cata-
lyst, 1a and organic Brønsted acids (3a–3h) were dissolved in dichloromethane.
Furthermore, the mixture was stirred at room temperature until the starting thioether
alcohol was spent. Finally, the new organocatalysts that catalyzed the intramolecular
FCA reaction of thioether alcohols were identified and compared.
As can be seen in Table 1, benzoic acid (3d) did not catalyze the intramolecular
Friedel–Crafts reaction of 1a (Entry 5). Meanwhile, acetic acid (3a), chloroacetic acid
(3c), salicylic acid (3e), and diphenyl hydrogen phosphate (3g) produced meager yields
in the reaction although it lasted 24 h (Entries 2, 4, 6, and 8). In contrast, p-toluenesul-
fonic acid (3f) generated a moderate yield (55%), and excellent yields of 88% and 92%
were obtained by the use of trifluoroacetic acid (3b) and N-triflylphosphoramide (3h)
for 2 h (Entries 3 and 9). When the pKa values of the organic Brønsted acids used are
compared, we can see that the lowest values of pKa in water are with trifluoroacetic
acid and p-toluenesulfonic acid. However, while Brønsted acids are deprotonated, anions
forming may be stabilized more efficiently by some solvents. Eventually, the pKa values
may be measured differently in different solutions. For example, while the pKa value of
salicylic acid is 2.97 in water, it is 8.23[25] in DMF and 6.6[26] in DMSO. In acetonitrile,

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T. YILDIZ
Table 1. Screening of organic Brønsted acids for intramolecular FCA of 1a.a
OH
Organic Brønsted acid
CH2Cl2, rt
S
S
2a
1a
Entry
Organic Brønsted acid (10% equiv.)
Time
Conv. (%)b
1
2
3
4
5
6
7
8
9
None
3a
3b
3c
3d
3e
3f
24 h
24 h
2 h
24 h
24 h
24 h
24 h
24 h
2 h
0
6
88
10
0
5
55
4
3g
3h
92
aCondition: 1a (0.1 mmol) and organic Brønsted acid (10 % equiv.) in CH2Cl2 (2.5 mL) were
stirred at room temperature.
bThe conversion in GC–MS.
Table 2. Screening of solvents for intramolecular FCA of 1a.a
OH
Catalyst
S
solvent, rt
S
2a
1a
Entry
Catalyst
Solvent
Cat. Amount (mol%)
Time
Conv. (%)b
1
2
3
4
5
6
7
8
9
3h
3h
3h
3h
3h
3h
3h
3h
3b
CH2Cl2
Benzene
Toluene
CHCl3
THF
CH3CN
DMSO
THF
10
10
10
10
10
10
10
5
2 h
2 h
2 h
2 h
15 min
15 min
5 h
92
91
93
91
>99
96
57
93
95
15 min
15 min
THF
10
aCondition: 1a (0.1 mmol) and catalyst (10% mmol) in solvent (2.5 mL) were stirred at
room temperature.
bThe conversion in GC–MS.
N-triflylphosphoramides have a pKa value of within the range 6–7,[27] but the pKa value
of benzoic acid is 20.7.[28] Our results indicate that N-triflylphosphoramides are much
more acidic than benzoic acid in acetonitrile. Therefore, N-triflylphosphoramide (3h) is
the best acidic catalyst for the intramolecular FCA reaction of 1a because of its stability
and high acidity in organic solvents. The second best catalyst is trifluoroacetic acid (3b),
but it may not be preferred because of its strongly corrosive nature and certain side
reactions occurring in the long term.
In the next step, we investigated the effect of the solvent on the cyclization reaction
of 1a by using the best catalysts we had established (Table 2). We achieved encouraging

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5
Table 3. Effect of the functional groups on Ar1 used for intramolecular FCA of
thioether alcohols.a
OH
Ar2
3h
Ar2
Ar1
S
S
THF, rt
Ar1
Entry
Product
Ar1
Ar2
Yield (%)b
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
C6H5
C6H5
C6H5
4-MeOC6H4
C6H5
4-MeC6H4
C6H5
99
99
98
35
65
40
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
aCondition: Thioether alcohol (0.1 mmol) and 3h in THF (2.5 mL) were stirred at room
temperature.
bYield of isolated product.
Table 4. Effect of the functional groups on Ar2 for intramolecular FCA of
thioether alcohols.a
OH
Ar2
3h
Ar2
Ar1
S
S
THF, rt
Ar1
Entry
Product
Ar1
Ar2
C6H5
4-MeOC6H4
1-Np
2-MeC6H4
4-MeC6H4
2-Thienyl
Yield (%)b
1
2
3
4
5
6
2a
2g
2h
2i
2j
2k
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
99
99
70
76
96
98
aCondition: Thioether alcohol (0.1 mmol) and 3h (10% mmol) in THF (2.5 mL) were stirred
at room temperature.
bYield of isolated product.
results in this part as the intramolecular FCA reaction of thioether alcohol 1a produced
excellent yields with CH2Cl2, benzene, toluene, and CHCl3 after a two-hour reaction
with catalyst 3h. Interestingly, however, the best yield of 99% was obtained with THF in
just 15 min without any side reaction using 10 mol% of the catalyst 3h (Entry 5). Also,
when we used CH3CN as a solvent, the reaction was completed in 15 min with a yield
of 96% (Entry 6). In addition, the second best catalyst 3b was also examined in THF,
but the yield was lower than the catalyst 3h. Furthermore, a lower yield was obtained
when we used 5 mol% of catalyst 3h in the reaction (Entry 8).
Therefore, we developed a new route for intramolecular FCA cyclization of thioether
alcohols using 10 mol% 3h in THF at room temperature for 15 min to synthesize substi-
tuted thioxanthene derivatives with excellent results. Then, we examined the influence
of the different groups of thioether alcohols on the reaction. For this purpose, differently
substituted thiophenols were used in the first step of the preparation of the starting

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T. YILDIZ
Table 5. Scope of substrates for intramolecular FCA of 1a-1v and their yields.
OH
Ar2
3h
Ar2
Ar1
S
S
THF, rt
Ar1
1a-1v
2a-2v
OMe
OMe
S
S
S
2a 99%
2b 99%
2c 98%
F
Cl
Br
S
S
S
2d 35%
2e 65%
2f 40%
OMe
S
S
S
2g 99%
2h 70%
2i 76%
S
Br
S
S
S
2j 96%
OMe
2k 98%
2l 45%
Br
Br
S
S
S
2m 31%
2n 55%
2o 85%
OMe
OMe
OMe
OMe
Cl
S
S
S
2p 82%
2r 80%
2s 72%
OMe
Cl
F
F
S
S
S
2t 73%
2u 87%
2v 68%

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7
materials. Varying substituted thiophenols (Ar1) having Me, MeO, Br, Cl, or F groups
were utilized in the experiments for the coupling reaction step. We reached this decision
because in the electrophilic aromatic substitution reactions, especially the Friedel-Crafts
reactions, electron-attracting and donating groups attached to the ring considerably
affect the yield of the reaction. To understand the effect of the Ar1 group on the intra-
molecular FCA, different substituted Ar1 units were used while the other aromatic ring
(Ar2) was kept as a phenyl or a substituted phenyl ring. The results of the impacts of
the screening reactions of the different functional groups on the aromatic thioether
(Ar1) are presented in Table 3.
As can be seen in Table 3, electron-donating groups activating the ring, such as
methoxy- and methyl-substituted phenyl and phenyl groups (Table 3, entries 1–3),
increased the yield of the electrophilic aromatic substitution. On the other hand, the
units that slightly deactivated the ring, such as halogen-substituted phenyl rings (Entries
4–6) reduced the yield of the intramolecular FCA of thioether alcohols.
Furthermore, we used different arylmagnesium bromides (Ar2) in the Grignard reac-
tion. However, as known, the range of substituents that can be used in the Grignard
reaction is limited. When Ar1 was kept as a phenyl group, and Ar2 group was replaced
by different groups and in varying positions (Table 4), we observed that the phenyl or
4-Me and 4-MeO that substituted the phenyl and thenyl groups generated excellent
yields within the range 96%–99% (Entries 1, 2, 5, and 6). However, the 2-Me substituted
phenyl, and 1-naphthyl groups produced slightly lower yields of 70% and 76% (Entries
3 and 4), which was likely due to the possible steric hindrance. As a result, the Ar1
group was more active than the Ar2 group in the electrophilic aromatic substitution
reaction because the Ar1 group plays an essential role in the mechanism of the reaction.
As known, the mechanism of the reaction is the electrophilic aromatic substitution
mechanism, and the proposed mechanism was shown in our previous report[14] about
the synthesis of xanthene derivatives by an intramolecular Friedel-Crafts reaction.
Moreover in recent works, when it was looked at the similar reaction mechanism with
chiral Brønsted acids, it is shown that an ortho-quinone methide (o-QM) intermediate
may occur in acidic medium.[29]
Conclusion
Herein, we applied an organocatalytic method we had previously developed for the syn-
theses of novel substituted thioxanthenes via intramolecular Friedel–Crafts cyclisation
starting from thioether diaryl alcohol compounds in the absence of transition-metal cat-
alysts. In this study, we investigated new reaction conditions to synthesize thioxanthenes
and obtained excellent yields. Furthermore, the function of certain organic Brønsted-
acids as catalysts was explored. Importantly, N-triflylphosphoramide (3h) was established
as the best organocatalyst among the studied ones.
Therefore, we, for the first time to our knowledge, developed a new intramolecular
FCA route for the synthesis of certain novel substituted arylthioxanthenes in the pres-
ence of 3 h as an organocatalyst with excellent yields. This new protocol does not
require inert reaction conditions or any protection. The novel substituted thioxanthenes
2a–2v (Table 5) may be used as bioactive compounds in the pharmaceutical chemistry

8
T. YILDIZ
or as photoelectric materials in material chemistry. Nevertheless, further research is
required of their pharmacological and photoelectric effects and activities.
Experimental details
The majority of the chemicals used in this work were commercially available from
Merck or Aldrich. The starting carbinols 1a–1v were prpared by coupling reaction of 2-
fluorobenzaldehyde and substituted thiophenols and then Grignard reaction of 2-thioe-
therbenzaldehydes and some arylmagnesium bromides. All substrates were purified by
1
crystallization or column chromatography and were characterized by IR, H NMR, 13C
NMR, elementel analysis and GC-MS. 2a,[18] 2d,[30] 2g,[18] 2h,[31] and 2j[32] were synthe-
sized and characterized before with different procedures. All novel products were char-
1
acterized by IR, H NMR, 13C NMR, elementel analysis and GC–MS. The reactions
were monitored by TLC using silica gel plates and the products were purified by flash
column chromatography on silica gel (Merck; 230–400 mesh), eluting with hexane-ethyl
1
acetate (v/v 9:1). NMR spectra were recorded at 500 MHz for H and 125 MHz for 13C
using Me4Si as the internal standard in CDCl3. GC–MS were recorded on Shimadzu/
QP2010 Plus. IR spectra were recorded on a Bruker Vertex 70 IR spectrometer.
General procedure for intramolecular Friedel Crafts cyclization
To a stirred solution of a starting alcohol compound (1a–1v) (0.1 mmol) in dry THF
(2.5 mL) was added N-triflylphosphoramide (3h) (10 mol%) at room temperature and
the reaction was stirred for 15 min. After the completion of the reaction as observed on
TLC, the mixture was concentrated in vacuo and was extracted with ethylacetate. After
usual reaction workup and concentration, the product was charged on silica gel.
Spectral data for selected products
9-(4-Methoxy-phenyl)-2-methyl-9H-thioxanthene 2c
98% Yield as colorless oily. IR (cmꢀ1) ꢀ 3057, 3028, 2959, 2836, 1606, 1579, 1246, 1180,
1060, 806, 742. 1 H NMR (500 MHz, CDCl3) d 7.46-7.41 (m, 2H), 7.35 (d, 1H,
J ¼ 10 Hz), 7.29–7.22 (m, 3H), 7.08 (d, 1H, J ¼ 9.5 Hz), 6.97 (d, 2H, J ¼ 8.5 Hz), 6.76
(d, 2H, J ¼ 9 Hz), 5.26 (s, 1H), 3.75 (s, 3H), 2.33 (s, 3H), 2.38 (s, 3H). 13C NMR
(150 MHz, CDCl3) d 158.1, 137.8, 137.5, 136.4, 133.4, 133.1, 130.1, 129.6, 129.4, 128.8,
127.6, 127.1, 127.0, 126.6, 124.4, 113.5, 55.1, 52.8, 21.1. MS (m/z) ¼ 41, 63, 77, 92, 113,
129, 152, 165, 178, 211, 241, 259, 273, 287, 303, 318 (Mþ). Anal. Calcd. for C21H18OS:
C, 79.21; H, 5.70; S, 10.07. Found: C, 79.32; H, 5.83; S, 9.96.
9-Thiophen-2-yl-9H-thioxanthene 2k
98% Yield as yellow oily. IR (cmꢀ1) ꢀ 3104, 3058, 2922, 2869, 1670, 1581, 1475, 1365,
1023, 733, 687. 1 H NMR (500 MHz, CDCl3) d 7.30-7.24 (m, 2H), 7.18–7.08 (m, 7H),
6.80 (dd, J1 ¼ 3.5 Hz, J2 ¼ 5.5 Hz, 1H), 6.73 (ddd, J1 ¼ J2 ¼ 1.0 Hz, J3 ¼ 3.5 Hz, 1H), 5.19
(s, 1H). 13C NMR (150 MHz, CDCl3) d 147.3, 144.6, 136.3, 133.9, 132.5, 129.9, 129.2,

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9
129.1, 128.6, 128.5, 127.3, 126.7, 126.6, 125.4, 125.3, 125.2, 45.8. MS (m/z) ¼ 45, 51, 69,
75, 88, 101, 123, 152, 165, 197, 205, 231, 234, 247, 280 (Mþ). Anal. Calcd. for C17H12S2:
C, 72.82; H, 4.31; S, 22.87. Found: C, 72.93; H, 4.46; S, 22.60.
Supplementary information
1
Experimental details, analytical data for all compounds and copies of H NMR, 13C NMR spec-
tra, GC-MS and elemental analysis are provided.
Acknowledgments
This work was supported by Istanbul University, Scientific Research Projects, project number
BYP-2017-24039.
Disclosure statement
No potential conflict of interest was reported by the author.
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