Formation and Disproportionation of Xanthenols to Xanthenes and Xanthones and Their Use in Synthesis

Article abstract of DOI:10.1021/acs.joc.0c02694

A facile and versatile strategy employing TiCl4-mediated cyclization followed by a Cannizzaro reaction has been developed for the synthesis of various xanthene derivatives. The reaction proceeded smoothly to afford both xanthenes/xanthones or their sulfur derivatives and tolerated a wide range of electronically diverse substrates. Using this methodology, pranoprofen was synthesized in three steps in 59% overall yield from commercially available starting materials.

Full text of DOI:10.1021/acs.joc.0c02694

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Article
Formation and Disproportionation of Xanthenols to Xanthenes and
Xanthones and Their Use in Synthesis
Zeyu Shi,† Si Chen,† Qiong Xiao,* and Dali Yin
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ABSTRACT: A facile and versatile strategy employing TiCl4-
mediated cyclization followed by a Cannizzaro reaction has been
developed for the synthesis of various xanthene derivatives. The
reaction proceeded smoothly to afford both xanthenes/xanthones
or their sulfur derivatives and tolerated a wide range of
electronically diverse substrates. Using this methodology, prano-
profen was synthesized in three steps in 59% overall yield from
commercially available starting materials.
C−H bond with an aromatic C−H group using tetrabuty-
lammonium bromide (TBAB) as a promoter in aqueous
medium to form xanthones.7 In 2020, Verma reported a Lewis
acid-catalyzed reaction-formed 9H-xanthenes and thioxan-
thenes.8 These methods generally suffer from the use of
strong acids, toxic CO gas, precious metal catalysts, or harsh
reaction conditions. Meanwhile, they represent the limit in
terms of general methods to afford xanthenes directly.
INTRODUCTION
Xanthenes and xanthones (Figure 1) are important structural
motifs and found in the central core of a variety of
■
The Cannizzaro reaction is the disproportionation of
aldehydes to the corresponding alcohols and acids as a 1:1
mixture. Although useful, this named reaction has not been
applied in complex synthesis as it generates a typically
unwanted mixture and leads to the loss of half of the starting
material used. Herein, we reported a novel TiCl4-mediated
cyclization−disproportionation process as an efficient method
to produce xanthenes and xanthones in a 1:1 ratio.
Furthermore, this mixture can be reduced by Et3SiH in a
telescoped strategy to afford xanthenes in one pot, or further
oxidized by CrO3/H5IO6 to afford xanthones.9 We envisage
that this strategy will become a useful and well-exploited
method to form these important scaffolds.
Figure 1. Motif in xanthenes and xanthones.
phytochemicals derived from plants in the families Bonnetia-
ceae, Clusiaceae, and Podostemaceae.1 Xanthene derivatives
are also widely used as dyes and dye precursors. Additionally,
they are privileged scaffolds within medicinal chemistry and
have been shown to possess a wide range of biological
activities, including pronounced antiviral, anti-inflammatory,
and anti-cancer properties.2 As such, the synthesis and
application of these compounds have received much attention
over the past century.
In recent years, efforts have been focused on the
development of practical methods to synthesize xanthones
from readily available starting materials. Pinto’s team reported
some reviews on the synthesis of xanthones during this year.3
In 1958 and 2002, Suschitzky and Gobbi, respectively,
reported that polyphosphoric acid or concentrated sulfuric
acid catalyzed the cyclization of 2-phenoxybenzoic acids to
construct derivatives of xanthones.4 In 2012, Lei and co-
workers developed a Pd(OAc)2-catalyzed double C−H
functionalization/carbonylation of diaryl ethers to produce
functionalized xanthones.5 During the same period, Li and
Studer independently reported a transition metal-catalyzed
cross-dehydrogenative coupling (CDC) strategy to construct
xanthones from 2-aryloxybenzaldehydes.6 Subsequently, Li and
co-workers reported a metal-free oxidative coupling of a formyl
RESULTS AND DISCUSSION
■
We recently developed a telescoped strategy for the synthesis
of tetrahydroisoquinolines (THIQs) via a TiCl4-catalyzed
cyclization and subsequent triethylsilane reduction.10 Therein,
we postulated that 2-aryloxybenzaldehydes could also undergo
Received: November 11, 2020
Published: January 5, 2021
https://dx.doi.org/10.1021/acs.joc.0c02694
© 2021 American Chemical Society
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Scheme 1. Proposed Synthesis Stemming from Our Previous Work
a
Table 1. Optimization of Reaction Conditions
entry
Lewis acid (equiv.)
time (h)
yield (1b:1c)
1
2
3
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (2.0)
TiCl4 (4.0)
TiCl4 (4.0)
AlCl3 (4.0)
Al(OTf)3 (4.0)
BF3·Et2O (4.0)
FeCl3 (4.0)
3
12
12
12
24
24
24
24
24
na
14:18
30:33
32:37
42:45
30:36
na
b
4
5
c
6
7
8
9
na
na
a
b
Reaction conditions: the reactions are carried out with 1a (1.0 mmol) and TiCl4 (1 M solution in DCM) at room temperature. Using 2.0 equiv.
c
or 3.0 equiv. of TiCl4 and then prolonging the reaction time to 36 h cannot convert to the cyclization product completely. Under the refluxing
reaction, there is no obvious improvement compared with the reaction at room temperature.
this cyclization under the same reaction conditions to afford
xanthenols (Scheme 1). To examine this possibility, we began
our study employing commercially available 2-phenoxybenzal-
dehyde (1a) as the model substrate.
xanthenes and xanthones. In most cases, the substrates were
fully converted to the desired xanthenes and xanthones cleanly,
without any apparent side reactions occurring. As mentioned,
the reaction performed well, employing electron-donating
groups (2−4) and mildly electron-withdrawing groups (8−
12). However, upon subjecting substrates bearing more
strongly electron-withdrawing substituents on the aromatic
ring B, we observed no reaction occurring, even under
prolonged reaction times. This process is a kind of aromatic
electrophilic substitution. The strongly electron-withdrawing
functional groups will deactivate this process. Switching the
electron-withdrawing substituent to the aromatic ring A once
again provided the desired products in a moderate overall yield
(14, 15). Expanding the pattern of substitution, we successfully
synthesized the desired heterocycles with substituents on both
the A and B aromatic rings (17-19). It is worth noting here
that using 2-(3-bromophenoxy) benzaldehyde (10a) as the
substrate, a variety of cyclization products were formed.
Theoretically, there would be four products formed in one pot
(10b, 10c, 11b, 11c); however, only three of these (10b, 11b,
11c) were identified. However, we cannot rule out the
possibility of small quantities of 10c being formed and lost
during isolation/purification. Interestingly, 5a only gave 5b
and 5c without 12H-benzo[b]xanthene and 12H-benzo[b]-
xanthen-12-one, indicating that the α-position is more active
than the β-position at naphthalene in this reaction. We have
tried both aniline and protected amine as the substrate.
Unfortunately, these substrates cannot work at all. We
speculated that the lone pair electron of nitrogen may
We began our investigation by treating 1a with 1 equiv. of
TiCl4 (1 M solution in DCM) at room temperature for 3 h. To
our disappointment, we did not observe any of the expected
annulated product (Table 1, entry 1). However, upon stirring
the reaction mixture for 12 h, we observed that two distinct
products had formed. After careful analysis of the reaction
mixture, we identified these products as xanthene (1b) and
xanthone (1c), which were obtained in 14 and 18% yields,
respectively (Table 1, entry 2). Increasing the amount of TiCl4
used, as well as increasing the reaction time, had an
advantageous effect of the isolated yield of the products
obtained (Table 1, entries 3−4). After further optimization,
focusing solely on stoichiometry and reaction times, we found
that running the reaction for 24 h in the presence of 4 equiv. of
TiCl4 provided reproducible yields of 42 and 45%, respectively
(Table 1, entry 5). We then turned our attention to screening
other Lewis acids and observed that AlCl3 afforded the desired
product in reduced yields (Table 1, entry 6). Surprisingly, no
other Lewis acid screened as part of our optimization mediated
the reaction to result in yielder yields of the products (Table 1,
entries 7−9).
With these optimized reaction conditions now in hand
(Table 1, entry 5), we turned our attention toward the scope
and limitation of the reaction (Table 2). To our delight, the
reaction successfully afforded in varying yields a range of
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a
Table 2. Synthesis of Xanthenes, Xanthones, and Sulfur Heterocycles
a
b
Reaction conditions: a (1.0 mmol) and TiCl4 (1 M solution in DCM) at room temperature for 24 h. 10c is formed with very little amount, then
c
lost in silica gel column chromatography. 19c is unstable.
coordinate with TiCl4 to form a strong electron-withdrawing
effect, thus deactivating the aromatic system.
improve significantly at a higher substrate concentration
(compared two concentrations at 0.2 and 0.4 M). Addition
of Brønsted acids (like 1 M HCl) or Lewis acids (1 M TiCl4 in
DCM) to 1d accelerated this transformation, which was often
complete within a few hours. In addition, we observed that 1
M HCl was more favorable for disproportionation than TiCl4.
To reveal the intriguing 9-xanthenol 1d disproportionation
mechanism, 1c was reduced by NaBD4 in CD3OD to afford
deuterated 9-xanthenol (1d-D). We then treated 1d-D with
TiCl4 in DCM and observed the formation of 1e. Additionally,
comparing the 1H NMR spectra of 1e and 1b, 1e clearly shows
the absence of the signal corresponding to the hydrogen at 9-
position and plainly shows that the two hydrogen atoms at this
position were replaced by two deuterium atoms. This result
To further expand the substrate scope, the preparation of
thioxanthenes and thioxanthones was also conducted. Under
the same condition, five substrates were converted into the
corresponding sulfur heterocycles (20b/c-24b/c) in good
yields. Also, we tried to get the fluorenene or fluorenone but
failed. The cyclization did not work when there was no
bridging atom at all.
To give us an understanding of a plausible mechanism, some
control experiments were carried out (Figure 2). During the
reaction optimization, we isolated the key intermediate 9H-
xanthen-9-ol (1d) and observed that 1d slowly transformed
into 1b and 1c (−8 °C). We observed that the reaction did not
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Figure 2. Investigations on the mechanism.
Scheme 2. Plausible Mechanism
indicates that one of the deuterium atoms at this position in 1e
is derived from another molecule of 1d-D in the reaction
mixture.
Based on the above investigations, a plausible mechanism for
this TiCl4-mediated cyclization and disproportionation is
provided in Scheme 2. The carbonyl is activated through
TiCl4 complexation, which facilitates the intramolecular
cyclization of A to form 9-xanthenol B, via facile aromatization.
We believe that once the concentration of B reaches a certain
point (explaining the requirement for prolonged reaction
times), a molecule of B undergoes an elimination to afford the
stabilized carbocation C. This subsequently reacts with another
equivalent of B, facilitating the production of E as well as
providing the reduced product D.
We next wanted to explore the applicability of this
disproportionation reaction. Upon completion of the TiCl4-
promoted cyclization of 1a, Et3SiH (4 equiv.) was added after
24 h, and the mixture was stirred for a further 12 h to afford
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Scheme 3. Synthesis of Xanthene 1b or Xanthone 1c
Scheme 4. Synthesis of Pranoprofen
the desired xanthene 1b in 85% yield. Furthermore, xanthone
1c can be obtained in 86% yield through treating the crude
mixture of 1b and 1c with CrO3 in the presence of H5IO6
(Scheme 3).
EXPERIMENTAL SECTION
■
General Information. 1H NMR spectra were recorded on
Mercury-300, Mercury-400, Mercury-500, and Bruker-600 spectrom-
eters. Chemical shifts are referenced to the residual solvent peak and
reported in ppm (δ scale), and all coupling constant (J) values are
given in Hz. The following abbreviations were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, and m =
multiplet. Melting points were determined on a Yanaco MP-J3
microscope melting point apparatus. High-resolution mass spectrom-
etry (HRMS) experiments were performed in electrospray ionization
(ESI) mass spectrometry and measured on a Thermo Exactive
Orbitrap plus spectrometer. Flash column chromatography was
performed on Biotage Isolera one (mesh 300−400). All the solvents
and chemicals were obtained from commercial sources and used
without further purification.
Pranoprofen (PRA) is a nonsteroidal anti-inflammatory drug
(NSAID), which is used as an anti-inflammatory following
strabismus and cataract surgery.11 We wanted to investigate if
our methodology could be used for the synthesis of this
important medicine. As shown (Scheme 4), an Ullmann
condensation employing commercially available 2-fluoronico-
tinaldehyde with ethyl 2-(4-hydroxyphenyl)propanoate in
DMF at 100 °C for 2 h furnished 25 in 92% yield. We then
employed our cyclization/reduction strategy using our
previously discussed conditions to afford 26 in 71% yield.
Finally, hydrolysis of the ester group with LiOH in THF/H2O
(3:1 v/v) produced pranoprofen in 90% yield. Importantly,
this strategy provides a shorter and more efficient way to
prepare pranoprofen than that currently used.12
General Procedure for the Synthesis of Substrate a.6 To a
solution of corresponding benzaldehyde (2.4 mmol, 1 equiv.) in DMF
(3 mL), phenol (2.9 mmol, l.2 equiv.) and potassium carbonate (2.9
mmol, l.2 equiv.) were added, and the mixture was stirred at 100 °C
for 6 h. After adding water, the reaction solution was extracted three
times with dichloromethane, washed with saturated brine, dried over
Na2SO4, filtered, and concentrated. The residue was purified by silica
gel flash column chromatography (PE/EA = 10:1) to afford the
desired product a. Except 14a, 17a, 19a, and 22a, other substrates are
known compounds.6−8
3-Formyl-4-phenoxybenzonitrile (14a). Yellow solid; yield 77.3%
(1.6 g); mp: 60−63 °C; 1H NMR (400 MHz, CDCl3): δ 10.56 (d, J =
1.8 Hz, 1H), 8.22 (dd, J = 4.2, 2.2 Hz, 1H), 7.71 (dd, J = 8.7, 2.3 Hz,
1H), 7.49 (ddd, J = 10.9, 5.7, 2.1 Hz, 2H), 7.32 (td, J = 7.4, 1.4 Hz,
1H), 7.17−7.11 (m, 2H), 6.94−6.81 (m, 1H); 13C {1H} NMR (75
MHz, CDCl3): δ 187.6, 163.5, 154.1, 138.8, 133.3, 130.9, 129.8,
126.4, 120.9, 118.0, 117.7, 115.6, 106.7; HRMS (ESI): m/z calcd for
C14H10O2N [M + H]+, 224.0706; found, 224.0705.
CONCLUSIONS
■
In summary, xanthenes and xanthones can be obtained via a
TiCl4-mediated cyclization from the corresponding aldehydes
as a 1:1 mixture. This mixture can be transformed into a single
product via a telescoped reduction for xanthene or via an
oxidation for xanthone. The method is noteworthy for its wide
substrate tolerance and accommodation of diverse functional
groups on each aromatic ring. This strategy provides a facile
and versatile synthesis of this type of heterocycle, providing a
bespoke synthesis of these important scaffolds. Finally,
pranoprofen was synthesized in three steps using this method
in 59% overall yield.
2-(4-Isopropylphenoxy)-5-methoxybenzaldehyde (17a). Yellow
oil; yield 11.1% (240 mg); 1H NMR (400 MHz, CDCl3): δ 10.41 (s,
1H), 7.39 (d, J = 3.2 Hz, 1H), 7.23−7.16 (m, 2H), 7.11 (dd, J = 9.0,
3.2 Hz, 1H), 6.95−6.89 (m, 3H), 3.84 (s, 3H), 2.90 (p, J = 6.9 Hz,
1H), 1.25 (d, J = 6.9 Hz, 6H); 13C {1H} NMR (125 MHz, CDCl3): δ
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189.5, 155.6, 154.0, 144.3, 127.8, 127.6, 127.4, 123.9, 121.3, 118.1,
115.1, 109.5, 55.9, 33.5, 24.3, 24.2; HRMS (ESI): m/z calcd for
C17H19O3 [M + H]+, 271.1329; found, 271.1349.
121.6, 118.1, 118.0, 33.8, 24.1; HRMS (ESI): m/z calcd for C16H15O2
[M + H]+, 239.1072; found, 239.1060.
2-Methoxy-9H-xanthene (4b).15 Pale yellow solid; yield 47.2%
1
(100 mg); mp: 63−65 °C; H NMR (500 MHz, CDCl3): δ 7.24−
2-Bromo-6-(4-methoxyphenoxy)benzaldehyde (19a). Yellow oil;
1
7.16 (m, 2H), 7.08−6.98 (m, 3H), 6.78 (dd, J = 8.8, 2.9 Hz, 1H), 6.72
(d, J = 2.8 Hz, 1H), 4.06 (s, 2H), 3.82 (s, 3H); 13C {1H} NMR (125
MHz, CDCl3): δ 155.3, 152.3, 146.1, 129.0, 127.7, 122.8, 121.4,
120.1, 117.23, 116.5, 113.5, 113.4, 55.8, 28.4; HRMS (ESI): m/z
calcd for C14H13O2 [M + H]+, 213.0916; found, 213.0902.
yield 76.8% (1.9 g); H NMR (400 MHz, CDCl3): δ 10.50 (s, 1H),
7.33 (dd, J = 8.0, 0.9 Hz, 1H), 7.26−7.19 (m, 1H), 7.02−6.97 (m,
2H), 6.94−6.89 (m, 2H), 6.76 (dd, J = 8.4, 1.0 Hz, 1H), 3.81 (s, 3H);
13C {1H} NMR (125 MHz, CDCl3): δ 189.9, 161.4, 156.8, 148.8,
134.6, 128.3, 124.8, 124.2, 121.4, 116.5, 115.2, 55.8; HRMS (ESI):
m/z calcd for C14H12O3Br [M + H]+, 306.9964; found, 306.9962.
2-((4-Ethylphenyl)thio)benzaldehyde (22a). Yellow oil; yield
2-Methoxy-9H-xanthen-9-one (4c).7 White solid; yield 48.7%
1
(110 mg); mp: 128−130 °C; H NMR (500 MHz, CDCl3): δ 8.35
1
(dd, J = 8.0, 1.5 Hz, 1H), 7.77−7.67 (m, 2H), 7.49 (d, J = 8.1 Hz,
1H), 7.45 (d, J = 9.1 Hz, 1H), 7.42−7.36 (m, 1H), 7.33 (dd, J = 9.1,
3.1 Hz, 1H), 3.92 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3): δ
177.3, 156.3, 156.1, 151.2, 134.8, 126.9, 125.2, 123.9, 122.3, 121.4,
119.6, 118.2, 105.9, 56.2; HRMS (ESI): m/z calcd for C14H11O3 [M
+ H]+, 227.0708; found, 227.0697.
83.2% (1.6 g); H NMR (400 MHz, CDCl3): δ 10.36 (s, 1H), 7.83
(dd, J = 7.5, 1.7 Hz, 1H), 7.39−7.33 (m, 3H), 7.29−7.24 (m, 1H),
7.23−7.20 (m, 2H), 7.02 (d, J = 8.0 Hz, 1H), 2.66 (q, J = 7.6 Hz,
2H), 1.24 (t, J = 7.6 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ
191.6, 145.3, 142.8, 134.0, 133.4, 132.2, 129.5, 129.5, 129.3, 125.8,
28.7, 15.4; HRMS (ESI): m/z calcd for C15H15OS [M + H]+,
243.0838; found, 243.0832.
12H-benzo[a]xanthene (5b).16 Pale red solid; yield 44.8% (104
mg); mp: 90−92 °C; 1H NMR (400 MHz, CDCl3): δ 7.91−7.81 (m,
2H), 7.73 (d, J = 8.9 Hz, 1H), 7.58 (ddd, J = 8.3, 6.9, 1.3 Hz, 1H),
7.44 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.26−
7.21 (m, 2H), 7.13−7.04 (m, 2H), 4.38 (s, 2H); 13C {1H} NMR (100
MHz, CDCl3): δ 151.2, 148.8, 132.2, 130.3, 129.6, 128.6, 128.4,
127.9, 126.8, 124.3, 123.3, 122.4, 119.7, 118.1, 116.6, 111.7, 24.9;
HRMS (ESI): m/z calcd for C17H13O [M + H]+, 233.0966; found,
233.0956.
General Procedure for the Synthesis of Xanthenes and
Xanthones. To a solution of the corresponding substrate a (1.0
mmol, 1 equiv.) in DCM (5 mL) was added TiCl4 (1 M solution in
DCM, 4 mL, 4 equiv.) at room temperature, and the mixture was
stirred at room temperature for 24 h. The reaction was quenched by
the addition of H2O, stirred for 30 min, then was extracted three
times with DCM (20 mL), washed with brine, dried over Na2SO4,
filtered and concentrated. The residue was purified by silica gel flash
column chromatography (PE/EA = 10:1) to afford the desired
products b and c.
12H-benzo[a]xanthen-12-one (5c).7 Yellow solid; yield 46.8%
1
(115 mg); mp: 148−150 °C; H NMR (400 MHz, CDCl3): δ 10.11
(d, J = 8.7 Hz, 1H), 8.48−8.39 (m, 1H), 8.14 (d, J = 9.1 Hz, 1H),
7.91 (d, J = 8.5 Hz, 1H), 7.83−7.70 (m, 2H), 7.65−7.54 (m, 3H),
7.49−7.42 (m, 1H); 13C {1H} NMR (100 MHz, CDCl3): δ 178.7,
157.8, 154.8, 136.8, 134.1, 131.3, 130.3, 129.7, 128.5, 127.1, 126.9,
126.3, 124.5, 123.8, 118.2, 117.7, 114.8; HRMS (ESI): m/z calcd for
C17H11O2 [M + H]+, 247.0759; found, 247.0744.
9H-xanthene (1b).13 White solid; yield 42.0% (72 mg); mp: 99−
1
101 °C; H NMR (400 MHz, CDCl3): δ 7.25−7.14 (m, 4H), 7.09−
7.00 (m, 4H), 4.07 (s, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ
152.1, 129.0, 127.8, 123.1, 120.7, 116.6, 28.0; HRMS (ESI): m/z
calcd for C13H11O [M + H]+, 183.0810; found, 183.0808.
9H-Xanthen-9-one (1c).7 White solid; yield 45.4% (89 mg); mp:
2-Phenyl-9H-xanthene (6b).17 White solid; yield 41.0% (105 mg);
1
172−174 °C; H NMR (400 MHz, CDCl3): δ 8.35 (dd, J = 8.0, 1.4
1
mp: 124−126 °C; H NMR (500 MHz, CDCl3): δ 7.60−7.54 (m,
Hz, 2H), 7.73 (td, J = 7.9, 7.2, 1.6 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H),
7.39 (t, J = 7.5 Hz, 2H); 13C {1H} NMR (100 MHz, CDCl3): δ 177.4,
156.3, 135.0, 126.9, 124.1, 122.2, 118.1; HRMS (ESI): m/z calcd for
C13H9O2 [M + H]+, 197.0603; found, 197.0600.
2H), 7.46−7.39 (m, 4H), 7.36−7.31 (m, 1H), 7.24−7.16 (m, 2H),
7.12 (d, J = 8.4 Hz, 1H), 7.10−7.02 (m, 2H), 4.13 (s, 2H); 13C {1H}
NMR (125 MHz, CDCl3): δ 152.0, 151.6, 140.7, 136.2, 129.1, 128.9,
127.8, 127.7, 127.1, 126.9, 126.6, 123.2, 120.9, 120.5, 116.9, 116.6,
28.1; HRMS (ESI): m/z calcd for C19H15O [M + H]+, 259.1123;
found, 259.1119.
2-Ethyl-9H-xanthene (2b). White solid; yield 42.9% (90 mg); mp:
1
97−99 °C; H NMR (400 MHz, CDCl3): δ 7.25−7.15 (m, 2H),
2-Phenyl-9H-xanthen-9-one (6c).7 Pale red solid; yield 47.1%
7.13−6.96 (m, 5H), 4.04 (s, 2H), 2.62 (q, J = 7.6 Hz, 2H), 1.25 (t, J =
7.6 Hz, 3H); 13C {1H} NMR (100 MHz, CDCl3): δ 152.3, 150.1,
138.9, 129.0, 128.2, 127.6, 127.1, 122.9, 120.7, 120.3, 116.5, 116.3,
28.3, 28.1, 16.0; HRMS (ESI): m/z calcd for C15H15O [M + H]+,
221.1123; found, 221.1118.
1
(128 mg); mp: 202−204 °C; H NMR (500 MHz, CDCl3): δ 8.57
(d, J = 2.4 Hz, 1H), 8.38 (dd, J = 7.9, 1.6 Hz, 1H), 7.98 (dd, J = 8.7,
2.2 Hz, 1H), 7.78−7.72 (m, 1H), 7.69 (d, J = 7.3 Hz, 2H), 7.58 (d, J
= 8.7 Hz, 1H), 7.55−7.45 (m, 3H), 7.44−7.35 (m, 2H); 13C {1H}
NMR (125 MHz, CDCl3): δ 177.4, 156.3, 155.7, 139.5, 137.2, 135.0,
133.8, 129.1, 127.6, 127.3, 126.9, 124.7, 124.1, 122.1, 121.9, 118.7,
118.2; HRMS (ESI): m/z calcd for C19H13O2 [M + H]+, 273.0916;
found, 273.0899.
2-Ethyl-9H-xanthen-9-one (2c).14 Pale yellow solid; yield 43.0%
(96 mg); mp: 69−71 °C; 1H NMR (400 MHz, CDCl3): δ 8.35 (dd, J
= 8.0, 1.4 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 7.77−7.65 (m, 1H), 7.57
(dd, J = 8.6, 2.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.6 Hz,
1H), 7.40−7.33 (m, 1H), 2.78 (q, J = 7.6 Hz, 2H), 1.31 (t, J = 7.6 Hz,
3H); 13C {1H} NMR (125 MHz, CDCl3): δ 177.5, 156.3, 154.7,
140.2, 135.2, 134.8, 126.9, 124.9, 123.8, 121.9, 121.6, 118.1, 118.0,
28.4, 15.7; HRMS (ESI): m/z calcd for C15H13O2 [M + H]+,
225.0916; found, 225.0904.
4-Phenyl-9H-xanthene (7b).17 Yellow oil; yield 46.5% (120 mg);
1H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 7.1 Hz, 2H), 7.49 (t, J =
7.6 Hz, 2H), 7.40 (t, J = 7.4 Hz, 1H), 7.28 (d, J = 6.1 Hz, 1H), 7.19
(q, J = 7.9 Hz, 3H), 7.12 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.4 Hz, 1H),
6.99 (d, J = 8.1 Hz, 1H), 4.12 (s, 2H); 13C {1H} NMR (125 MHz,
CDCl3): δ 152.2, 149.0, 137.9, 129.9, 129.8, 129.3, 128.7, 128.3,
128.2, 127.6, 127.2, 123.2, 123.0, 121.6, 121.1, 116.7, 28.6; HRMS
(ESI): m/z calcd for C19H15O [M + H]+, 259.1123; found, 259.1116.
4-Phenyl-9H-xanthen-9-one (7c).7 Gray solid; yield 47.8% (130
2-Isopropyl-9H-xanthene (3b). White solid; yield 40.9% (91 mg);
1
mp: 83−85 °C; H NMR (500 MHz, CDCl3): δ 7.19 (dd, J = 12.8,
6.9 Hz, 2H), 7.09−6.95 (m, 5H), 4.04 (s, 2H), 2.96−2.79 (m, 1H),
1.25 (d, J = 7.0 Hz, 6H); 13C {1H} NMR (125 MHz, CDCl3): δ
152.2, 150.1, 143.6, 129.0, 127.7, 126.7, 125.7, 122.9, 120.8, 120.3,
116.5, 116.3, 33.6, 28.2, 24.4; HRMS (ESI): m/z calcd for C16H17O
[M + H]+, 225.1279; found, 225.1284.
1
mg); mp: 137−139 °C; H NMR (500 MHz, CDCl3): δ 8.41−8.32
(m, 2H), 7.77 (dd, J = 7.3, 1.7 Hz, 1H), 7.72−7.64 (m, 3H), 7.54 (t, J
= 7.5 Hz, 2H), 7.51−7.43 (m, 2H), 7.43−7.35 (m, 2H); 13C {1H}
NMR (125 MHz, CDCl3): δ 177.5, 156.1, 153.1, 136.5, 136.0, 134.9,
131.6, 129.8, 128.5, 128.0, 126.8, 126.3, 124.2, 124.0, 122.4, 121.6,
118.3; HRMS (ESI): m/z calcd for C19H13O2 [M + H]+, 273.0916;
found, 273.0910.
2-Isopropyl-9H-xanthen-9-one (3c).14 White solid; yield 40.4%
(96 mg); mp: 80−82 °C; 1H NMR (500 MHz, CDCl3): δ 8.35 (dd, J
= 8.0, 1.6 Hz, 1H), 8.18 (d, J = 2.2 Hz, 1H), 7.72 (ddd, J = 8.6, 7.2,
1.7 Hz, 1H), 7.62 (dd, J = 8.6, 2.3 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H),
7.44 (d, J = 8.6 Hz, 1H), 7.41−7.34 (m, 1H), 3.11−2.98 (m, 1H),
1.33 (s, 3H), 1.31 (s, 3H); 13C {1H} NMR (125 MHz, CDCl3): δ
177.6, 156.3, 154.7, 144.8, 134.8, 133.9, 126.9, 123.8, 123.6, 121.9,
2-Chloro-9H-xanthene (8b).16 White solid; yield 44.7% (96 mg);
1
mp: 110−112 °C; H NMR (400 MHz, CDCl3): δ 7.24−7.12 (m,
4H), 7.08−6.95 (m, 3H), 4.03 (s, 2H); 13C {1H} NMR (125 MHz,
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CDCl3): δ 151.7, 150.6, 129.0, 128.7, 128.0, 127.8, 127.7, 123.4,
122.3, 119.8, 117.9, 116.6, 27.9; HRMS (ESI): m/z calcd for
C13H10OCl [M + H]+, 217.0420; found, 217.0402.
126.9, 124.6, 122.6, 121.3, 120.1, 118.6, 118.2; HRMS (ESI): m/z
calcd for C14H8O3F3 [M + H]+, 281.0420; found, 281.0410.
9H-xanthene-2-carbonitrile (14b).20 White solid; yield 29.2% (60
mg); mp: 123−125 °C; 1H NMR (500 MHz, CDCl3): δ 7.49 (dd, J =
4.2, 2.4 Hz, 2H), 7.23 (t, J = 7.7 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H),
7.12−7.04 (m, 3H), 4.07 (s, 2H); 13C {1H} NMR (125 MHz,
CDCl3): δ 155.3, 151.0, 133.5, 132.1, 129.1, 128.3, 124.2, 122.0,
119.3, 119.0, 117.7, 116.8, 106.5, 27.4; HRMS (ESI): m/z calcd for
C14H10ON [M + H]+, 208.0757; found, 208.0750.
2-Chloro-9H-xanthen-9-one (8c).6b White solid; yield 46.6% (107
mg); mp: 170−172 °C; 1H NMR (400 MHz, CDCl3): δ 8.33 (dd, J =
8.0, 1.7 Hz, 1H), 8.30 (d, J = 2.6 Hz, 1H), 7.79−7.72 (m, 1H), 7.67
(dd, J = 8.9, 2.6 Hz, 1H), 7.54−7.45 (m, 2H), 7.45−7.36 (m, 1H).
13C {1H} NMR (125 MHz, CDCl3): δ 176.3, 156.2, 154.6, 135.4,
135.1, 129.8, 126.9, 126.2, 124.4, 122.8, 121.6, 119.9, 118.2; HRMS
(ESI): m/z calcd for C13H8O2Cl [M + H]+, 231.0213; found,
231.0201.
9-Oxo-9H-xanthene-2-carbonitrile (14c).7 White solid; yield
1
35.4% (78 mg); mp: 110−112 °C; H NMR (500 MHz, CDCl3): δ
8.68 (d, J = 2.1 Hz, 1H), 8.34 (dd, J = 8.0, 1.6 Hz, 1H), 7.95 (dd, J =
8.7, 2.1 Hz, 1H), 7.84−7.77 (m, 1H), 7.62 (d, J = 8.7 Hz, 1H), 7.55
(d, J = 8.4 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H); 13C {1H} NMR (125
MHz, CDCl3): δ 175.6, 158.2, 156.0, 137.1, 136.0, 132.6, 127.1,
125.2, 122.3, 121.8, 119.9, 118.3, 117.9, 108.2; HRMS (ESI): m/z
calcd for C14H8O2N [M + H]+, 222.0550; found, 222.05442.
2-Trifluoromethyl-9H-xanthene (15b). White solid; yield 36.8%
2-Bromo-9H-xanthene (9b). White solid; yield 38.9% (101 mg);
1
mp: 118−120 °C; H NMR (500 MHz, CDCl3): δ 7.33−7.27 (m,
2H), 7.21 (t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.0 Hz, 1H), 7.07−7.01 (m,
2H), 6.93 (d, J = 8.8 Hz, 1H), 4.02 (s, 2H); 13C {1H} NMR (125
MHz, CDCl3): δ 151.6, 151.1, 131.6, 130.6, 129.0, 128.0, 123.4,
122.8, 119.75, 118.3, 116.6, 115.1, 27.7; HRMS (ESI): m/z calcd for
C13H10OBr [M + H]+, 260.9915; found, 260.9900.
1
2-Bromo-9H-xanthen-9-one (9c).6b White solid; yield 43.8% (120
mg); mp: 151−153 °C; 1H NMR (500 MHz, CDCl3): δ 8.43 (d, J =
2.4 Hz, 1H), 8.31 (dd, J = 8.0, 1.4 Hz, 1H), 7.78 (dd, J = 8.9, 2.5 Hz,
1H), 7.76−7.71 (m, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.44−7.33 (m,
2H); 13C {1H} NMR (125 MHz, CDCl3): δ 176.1, 156.1, 155.0,
137.8, 135.3, 129.3, 126.9, 124.4, 123.2, 121.6, 120.1, 118.2, 117.2;
HRMS (ESI): m/z calcd for C13H8O2Br [M + H]+, 274.9708; found,
274.9695.
(92 mg); mp: 123−125 °C; H NMR (400 MHz, CDCl3): δ 7.49−
7.43 (m, 2H), 7.25−7.16 (m, 2H), 7.14−7.03 (m, 3H), 4.10 (s, 2H);
13C {1H} NMR (125 MHz, CDCl3): δ 154.4, 151.4, 129.1, 128.2,
126.5, 125.1, 123.8, 121.2, 119.8, 117.0, 116.7, 27.8; HRMS (ESI):
m/z calcd for C14H10OF3 [M + H]+, 251.0684; found, 251.0679.
2-Trifluoromethyl-9H-xanthen-9-one (15c).7 White solid; yield
1
38.3% (101 mg); mp: 110−112 °C; H NMR (400 MHz, CDCl3) δ
8.68−8.61 (m, 1H), 8.36 (dd, J = 8.0, 1.8 Hz, 1H), 7.97−7.93 (m,
1H), 7.81−7.76 (m, 1H), 7.66−7.60 (m, 1H), 7.54 (dd, J = 8.4, 0.9
Hz, 1H), 7.47−7.42 (m, 1H); 13C {1H} NMR (125 MHz, CDCl3): δ
176.5, 157.9, 156.2, 135.7, 131.4, 131.3, 127.1, 125.1, 121.9, 121.8,
119.4, 118.3; HRMS (ESI): m/z calcd for C14H8O2F3 [M + H]+,
265.0476; found, 265.0461.
3-Bromo-9H-xanthene & 1-Bromo-9H-xanthene (10b & 11b).
1
White solid; yield 46.3% (120 mg); H NMR (500 MHz, CDCl3): δ
7.32−7.15 (m, 5H), 7.11−6.99 (m, 4H), 4.02 (s, 2H); 13C {1H}
NMR (125 MHz, CDCl3): δ 152.7, 151.6, 151.2, 130.2, 129.3, 129.1,
128.6, 128.1, 128.0, 126.7, 126.1, 124.6, 123.5, 121.0, 120.4, 120.1,
119.8, 119.7, 116.7, 116.3, 115.8, 29.2, 27.6; HPLC-HRMS (ESI): m/
z calcd for C13H10OBr [M + H]+, 260.9915; found, 260.9910. HPLC
(1260, Agilent) was performed using an Eclipse ZORBAX XDB
column (Agilent; 4.6 × 150 mm) packed with C18 silica (5 μm) and
an eluent of MeCN/H2O = 55:45 at a flow rate of 1.0 mL/min. λ =
254 nm: tR = 15.6 min (major) and tR = 18.7 min (minor).
2-Isopropyl-7-methoxy-9H-xanthene (17b). White solid; yield
36.7% (93 mg); mp: 78−80 °C; 1H NMR (500 MHz, CDCl3): δ 7.04
(dd, J = 8.3, 2.1 Hz, 1H), 7.00 (s, 1H), 6.96 (dd, J = 8.6, 4.4 Hz, 2H),
6.74 (dd, J = 8.8, 3.0 Hz, 1H), 6.69 (d, J = 2.9 Hz, 1H), 4.00 (s, 2H),
3.78 (s, 3H), 2.86 (p, J = 6.9 Hz, 1H), 1.24 (s, 3H), 1.23 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 155.1, 150.3, 146.3, 143.4,
126.6, 125.7, 121.4, 119.7, 117.2, 116.2, 113.4, 55.8, 33.6, 28.6, 24.3;
HRMS (ESI): m/z calcd for C17H19O2 [M + H]+ 255.1385, found
255.1376.
3-Bromo-9H-xanthen-9-one (11c).6b Scarlet solid; yield 29.4%
1
(80 mg); mp: 111−113 °C; H NMR (500 MHz, CDCl3): δ 8.32
(dd, J = 8.0, 1.5 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.78−7.71 (m,
1H), 7.69 (d, J = 1.7 Hz, 1H), 7.54−7.46 (m, 2H), 7.45−7.37 (m,
1H);13C {1H} NMR (125 MHz, CDCl3): δ 176.7, 156.3, 156.1,
135.3, 129.3, 128.3, 127.8, 126.9, 124.5, 121.9, 121.2, 120.9, 118.1;
HRMS (ESI): m/z calcd for C13H8O2Br [M + H]+, 274.9708; found,
274.9698.
2-Isopropyl-7-methoxy-9H-xanthen-9-one (17c).21 White solid;
yield 38.7% (103 mg); mp: 90−92 °C; 1H NMR (500 MHz, CDCl3):
δ 8.23−8.12 (m, 1H), 7.70 (d, J = 3.1 Hz, 1H), 7.60 (dd, J = 8.6, 2.2
Hz, 1H), 7.45−7.42 (m, 1H), 7.41 (s, 1H), 7.31 (dd, J = 9.1, 3.1 Hz,
1H), 3.92 (s, 3H), 3.05 (p, J = 6.9 Hz, 1H), 1.32 (s, 3H), 1.31 (s,
3H); 13C{1H} NMR (125 MHz, CDCl3): δ 177.4, 155.9, 154.7,
151.1, 144.6, 133.7, 124.9, 123.4, 122.1, 121.0, 119.5, 118.0, 105.9,
56.1, 33.8, 24.1; HRMS (ESI): m/z calcd for C17H17O3 [M + H]+,
269.1178; found, 269.1170.
4-Bromo-9H-xanthene (12b).18 Yellow solid; yield 44.3% (115
1
mg); mp: 114−116 °C; H NMR (400 MHz, CDCl3): δ 7.46−7.41
(m, 1H), 7.26−7.15 (m, 3H), 7.13−7.09 (m, 1H), 7.09−7.03 (m,
1H), 6.89 (t, J = 7.7 Hz, 1H), 4.06 (s, 2H); 13C {1H} NMR (125
MHz, CDCl3): δ 151.8, 148.9, 131.5, 128.1, 127.9, 123.7, 122.7,
120.5, 117.0, 110.9, 28.4; HRMS (ESI): m/z calcd for C13H10OBr [M
+ H]+, 260.9915; found, 260.9907.
2,7-Dimethoxy-9H-xanthene (18b). White crystal; yield 40.8%
(98 mg); mp: 127−129 °C; 1H NMR (400 MHz, CDCl3): δ 6.91 (d,
J = 8.7 Hz, 2H), 6.84−6.58 (m, 4H), 3.95 (s, 2H), 3.73 (s, 6H); 13C
{1H} NMR (100 MHz, CDCl3): δ 155.2, 146.4, 120.9, 117.2, 113.5,
113.4, 55.8, 28.9; HRMS (ESI): m/z calcd for C15H15O3 [M + H]+,
243.1021; found, 243.1010.
4-Bromo-9H-xanthen-9-one (12c). Yellow solid; yield 45.0% (123
1
mg); mp: 110−112 °C; H NMR (400 MHz, CDCl3): δ 8.33−8.28
(m, 2H), 7.97−7.96 (m, 1H), 7.78−7.74 (m, 1H), 7.62−7.60 (m,
1H), 7.43−7.39 (m, 1H), 7.26−7.25 (m, 1H); 13C {1H} NMR (150
MHz, CDCl3): δ 176.7, 156.0, 152.7, 138.3, 135.3, 126.8, 126.2,
124.6, 124.5, 123.2, 121.4, 118.3, 111.6.; HRMS (ESI): m/z calcd for
C13H8O2Br [M + H]+, 274.9702; found, 274.9690.
2,7-Dimethoxy-9H-xanthen-9-one (18c).5 White solid; yield
1
42.1% (107 mg); mp: 181−183 °C; H NMR (400 MHz, CDCl3):
δ 7.70 (s, 2H), 7.59−7.24 (m, 4H), 3.93 (s, 6H); 13C{1H} NMR (125
MHz, CDCl3) δ 177.0, 155.9, 151.1, 125.0, 121.5, 119.5, 105.6, 56.1;
HRMS (ESI): m/z calcd for C15H13O4 [M + H]+, 257.0814; found,
257.0801.
2-Trifluoromethoxy-9H-xanthene (13b). White solid; yield 23.8%
1
(63 mg); mp: 110−112 °C; H NMR (400 MHz, CDCl3): δ 7.23−
7.12 (m, 2H), 7.08−6.99 (m, 5H), 4.04 (s, 2H); 13C{1H} NMR (125
MHz, CDCl3): δ 151.7, 150.5, 144.3, 129.0, 128.1, 123.5, 122.1,
121.7, 120.8, 119.6, 117.6, 116.6, 28.1; HRMS (ESI): m/z calcd for
C14H10O2F [M + H]+, 267.0627; found, 267.0620.
1-Bromo-7-methoxy-9H-xanthene (19b). White crystal; yield
1
27.0% (78 mg); mp: 127−129 °C; H NMR (500 MHz, CDCl3): δ
7.27−7.24 (m, 1H), 7.06 (t, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0, 3.0 Hz,
2H), 6.80−6.65 (m, 2H), 4.04 (s, 2H), 3.80 (s, 3H); 13C {1H} NMR
(125 MHz, CDCl3): δ 155.6, 153.0, 145.3, 128.6, 126.4, 124.6, 120.4,
120.3, 117.1, 115.7, 114.0, 113.3, 55.8, 29.7; HRMS (ESI): m/z calcd
for C14H12O2Br [M + H]+, 291.0015; found, 291.0008.
2-Trifluoromethoxy-9H-xanthen-9-one (13c).19 White solid; yield
1
24.6% (69 mg); mp: 170−172 °C; H NMR (400 MHz, CDCl3): δ
8.34 (dd, J = 8.0, 1.4 Hz, 1H), 8.19 (dt, J = 2.5, 0.9 Hz, 1H), 7.83−
7.70 (m, 1H), 7.63−7.48 (m, 3H), 7.45−7.38 (m, 1H); 13C {1H}
NMR (125 MHz, CDCl3): δ 176.5, 156.2, 154.3, 145.2, 135.5, 128.3,
9H-thioxanthene (20b).22 White solid; yield 39.0% (77 mg); mp:
1
129−131 °C; H NMR (400 MHz, CDCl3): δ 7.47−7.41 (m, 2H),
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7.34−7.28 (m, 2H), 7.24−7.19 (m, 2H), 7.19−7.16 (m, 2H), 3.85 (s,
2H); 13C {1H} NMR (125 MHz, CDCl3): δ 136.3, 133.9, 128.1,
127.0, 126.7, 126.6, 39.3; HRMS (ESI): m/z calcd for C13H11S [M +
H]+, 199.0582; found, 199.0574.
128.0, 127.7, 126.8, 126.2, 120.4; HRMS (ESI): m/z calcd for
C13H8OSBr [M + H]+, 290.9479; found, 290.9462.
Telescoped Procedure for the Synthesis of Xanthene (1b).
To a solution of corresponding substrate 1a (198 mg, 1.0 mmol 1
equiv.) in DCM (5 mL) was added TiCl4 (1 M solution in DCM, 4
mL, 4 equiv.) at room temperature, and the mixture was stirred at
room temperature for 24 h, then with added Et3SiH (465 mg, 4.0
mmol, 4 equiv.) for another 12 h. The reaction was quenched by the
addition of H2O (10 mL), then was extracted three times with DCM
(20 mL), washed with brine, dried over Na2SO4, filtered, and
concentrated. The residue was purified by silica gel flash column
chromatography (PE/EA = 10:1) to afford the desired product 1b
(155 mg, 85%).
Procedure for the Synthesis of Xanthone (1c). To a solution
of corresponding substrate 1a (198 mg, 1.0 mmol, 1 equiv.) in DCM
(5 mL) was added TiCl4 (1 M solution in DCM, 4 mL, 4 equiv.) at
room temperature, and the mixture was stirred at room temperature
for 24 h. The reaction was quenched by the addition of H2O (10 mL),
then was extracted three times with DCM (20 mL), washed with
brine, dried over Na2SO4, filtered, and concentrated. The crude
products were treated to acetonitrile (5 mL), which dissolved H5IO6
(399 mg, 1.75 mmol, 1.75 equiv.) and CrO3 (2.5 mg, 0.025 mmol,
equiv. 2.5%) for 1 h. The residue was extracted with DCM (20 mL)
three times, washed with brine, dried over Na2SO4, filtered, and
concentrated. The residue was purified by silica gel flash column
chromatography (PE/EA = 10:1) to afford the desired product 1c
(168 mg, 86%).
9H-Thioxanthen-9-one (20c).23 White solid; yield 42.7% (90 mg);
1
mp: 214−216 °C; H NMR (400 MHz, CDCl3): δ 8.66−8.59 (m,
2H), 7.66−7.54 (m, 4H), 7.53−7.44 (m, 2H); 13C {1H} NMR (125
MHz, CDCl3): δ 180.1, 137.4, 132.4, 130.0, 129.3, 126.4, 126.1;
HRMS (ESI): m/z calcd for C13H9OS [M + H]+, 213.0374; found,
213.0367.
12H-Benzo[a]thioxanthene (21b).24 Gray solid; yield 40.1% (99
mg); mp: 114−116 °C; 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J =
8.3 Hz, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.59
(t, J = 7.7 Hz, 1H), 7.54−7.39 (m, 4H), 7.23 (s, 2H), 4.29 (s, 2H);
13C {1H} NMR (125 MHz, CDCl3): δ 135.6, 134.1, 132.7, 131.5,
131.4, 130.7, 129.0, 128.4, 126.8, 126.8, 126.7, 126.7, 126.6, 125.3,
125.3, 122.6, 33.6; HRMS (ESI): m/z calcd for C17H13S [M + H]+,
249.0738; found, 249.0731.
12H-Benzo[a]thioxanthen-12-one (21c). Yellow crystal; yield
1
45.8% (120 mg); mp: 127−129 °C; H NMR (400 MHz, CDCl3):
δ 9.90 (d, J = 8.8 Hz, 1H), 8.66 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 8.7
Hz, 1H), 7.89 (dd, J = 8.0, 1.4 Hz, 1H), 7.79−7.72 (m, 1H), 7.65−
7.51 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.3, 140.1,
135.2, 133.7, 132.9, 132.5, 132.3, 131.6, 130.0, 129.3, 128.7, 127.0,
126.9, 126.8, 125.4, 124.2, 123.9; HRMS (ESI): m/z calcd for
C17H11OS [M + H]+, 263.0531; found, 263.0521.
2-Ethyl-9H-thioxanthene (22b). Yellow wax; yield 42.0% (95 mg);
1H NMR (400 MHz, CDCl3): δ 7.46−7.42 (m, 1H), 7.36 (d, J = 7.9
Hz, 1H), 7.34−7.29 (m, 1H), 7.23−7.15 (m, 3H), 7.04 (dd, J = 7.9,
1.9 Hz, 1H), 3.84 (s, 2H), 2.64 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6
Hz, 3H); 13C {1H} NMR (125 MHz, CDCl3): δ 143.1, 136.5, 136.4,
134.3, 130.7, 128.0, 127.7, 127.0, 126.9, 126.6, 126.6, 126.3, 39.4,
28.6, 15.9; HRMS (ESI): m/z calcd for C15H15S [M + H]+, 227.0895;
found, 227.0889.
Procedure for the Synthesis of Pranoprofen. Ethyl 2-(4-((3-
Formylpyridin-2-yl)oxy)phenyl)propanoate (25). To a solution of 2-
fluoronicotinaldehyde (309 mg, 2.47 mmol, 1 equiv.) and ethyl 2-(4-
hydroxyphenyl)propanoate (400 mg, 2.06 mmol, 1.2 equiv.) in 4 mL
of DMF, K2CO3 (284 mg, 2.06 mmol, 1 equiv.) was added. The
mixture was heating at 100 °C for 2 h (oil bath). After cooling to
room temperature, water was added to the reaction mixture and
extracted with AcOEt. The combined organic layer was washed with
water and brine, dried over Na2SO4, filtered, and evaporated. The
residue was purified by silica gel flash column chromatography (PE/
EA = 10:1) to afford 25 (566 mg, 92%).
2-Ethyl-9H-thioxanthen-9-one (22c). Yellow solid; yield 48.2%
1
(115 mg); mp: 111−113 °C; H NMR (400 MHz, CDCl3): δ 8.63
(d, J = 9.5 Hz, 1H), 8.46 (s, 1H), 7.64−7.54 (m, 2H), 7.55−7.43 (m,
3H), 2.79 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.7 Hz, 3H); 13C {1H}
NMR (125 MHz, CDCl3): δ 180.2, 142.9, 137.6, 134.5, 132.8, 132.2,
130.0, 129.3, 129.2, 128.6, 126.2, 28.8, 15.6; HRMS (ESI): m/z calcd
for C15H13OS [M + H]+, 241.0687; found, 241.0677.
1
Oil; yield 92.0% (566 mg); H NMR (400 MHz, CDCl3): δ 8.36
(dd, J = 4.6, 1.6 Hz, 1H), 8.25 (dd, J = 7.5, 1.7 Hz, 1H), 7.39 (d, J =
8.4 Hz, 2H), 7.22−7.03 (m, 3H), 4.24−4.01 (m, 2H), 3.75 (q, J = 7.1
Hz, 1H), 1.54 (t, J = 11.6 Hz, 4H), 1.24 (t, J = 7.1 Hz, 3H); 13C {1H}
NMR (150 MHz, CDCl3): δ 188.8, 174.4, 164.0, 153.1, 152.1, 138.2,
137.6, 128.9, 121.5, 119.6, 119.1, 60.8, 45.0, 18.7, 14.1; HRMS (ESI):
m/z calcd for C17H18O4N [M + H]+, 300.1230; found, 300.1227.
Ethyl 2-(5H-Chromeno[2,3-b]pyridin-7-yl)propanoate (26).12 To
a solution of 25 (500 mg, 1.67 mmol, 1 equiv.) in DCM (5 mL) was
added TiCl4 (1 M solution in DCM, 6.69 mL, 4 equiv.) at room
temperature, and the mixture was stirred at room temperature for 24
h, then with added Et3SiH (1.07 mL, 6.69 mmol, 4 equiv.) for another
3 h. The reaction was quenched by the addition of H2O (10 mL),
then was extracted three times with DCM (20 mL), washed with
brine, dried over Na2SO4, filtered, and concentrated. The residue was
purified by silica gel flash column chromatography (PE/EA = 10:1) to
afford 26 (335 mg, 71%).
2-Methoxy-9H-thioxanthene (23b).25 White solid; yield 39.3%
1
(90 mg); mp: 104−106 °C; H NMR (400 MHz, CDCl3): δ 7.46−
7.40 (m, 1H), 7.38−7.27 (m, 2H), 7.24−7.14 (m, 2H), 6.91 (d, J =
2.7 Hz, 1H), 6.76 (dd, J = 8.5, 2.7 Hz, 1H), 3.83 (s, 2H), 3.81 (s,
3H); 13C {1H} NMR (100 MHz, CDCl3): δ 159.1, 138.1, 136.4,
134.7, 128.0, 127.8, 127.0, 126.6, 125.0, 114.0, 112.4, 55.6, 39.8;
HRMS (ESI): m/z calcd for C14H13OS [M + H]+, 229.0687; found,
229.0670.
2-Methoxy-9H-thioxanthen-9-one (23c).7 Pale white solid; yield
1
40.8% (99 mg); mp: 131−133 °C; H NMR (400 MHz, CDCl3): δ
8.64 (dd, J = 8.7, 0.9 Hz, 1H), 8.09 (d, J = 2.9 Hz, 1H), 7.65−7.56
(m, 2H), 7.53−7.43 (m, 2H), 7.30−7.26 (m, 1H), 3.95 (s, 3H); 13C
{1H} NMR (100 MHz, CDCl3): δ 179.9, 158.6, 137.7, 132.2, 130.4,
130.0, 129.3, 128.8, 127.5, 126.3, 126.2, 122.9, 110.5, 55.9; HRMS
(ESI): m/z calcd for C14H11O2S [M + H]+, 243.0474; found,
243.0478.
Oil; yield 92.0% (335 mg); 1H NMR (400 MHz, CD3OD): δ 8.09
(dd, J = 4.9, 0.9 Hz, 1H), 7.80−7.69 (m, 1H), 7.24−7.13 (m, 3H),
7.05 (d, J = 9.1 Hz, 1H), 4.22−4.02 (m, 4H), 3.73 (q, J = 7.1 Hz,
1H), 1.49−1.42 (m, 3H), 1.22−1.15 (m, 3H); 13C {1H} NMR (150
MHz, CD3OD): δ 176.2, 159.6, 151.8, 146.9, 140.8, 138.1, 129.0,
128.3, 121.5, 121.3, 117.8, 117.7, 62.0, 28.6, 19.0, 14.5; HRMS (ESI):
m/z calcd for C17H18O3N [M + H]+, 284.1281; found, 284.1281.
Pranoprofen.12 Compound 26 (320 mg, 1.13 mmol, 1 equiv.) was
diluted with THF/H2O = 3:1 (v/v) (4 mL); then, LiOH (135 mg,
5.56 mmol, 5 equiv.) was added, and the reaction was stirred at room
temperature for 3 h. Then, water was added to the reaction mixture
and extracted with CH2Cl2. The combined organic layer was washed
with water and brine, dried over Na2SO4, filtered, and evaporated.
The residue was purified by silica gel flash column chromatography
(PE/EA = 5:1−1:1) to afford pranoprofen (259 mg, 90%).
2-Bromo-9H-thioxanthene (24b). White solid; yield 41.5% (114
mg); mp: 103−105 °C; 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H),
7.43 (dd, J = 7.0, 1.7 Hz, 1H), 7.34−7.16 (m, 5H), 3.82 (s, 2H); 13C
{1H} NMR (100 MHz, CDCl3): δ 138.5, 135.5, 133.5, 133.3, 130.9,
129.6, 128.3, 128.2, 127.0, 126.9, 120.4, 39.0; HRMS (ESI): m/z
calcd for C13H10SBr [M + H]+, 276.9687; found, 276.9684.
2-Bromo-9H-thioxanthen-9-one (24c). Pale white solid; yield
45.0% (130 mg); mp: 165−166 °C; 1H NMR (400 MHz, CDCl3): δ
8.75 (d, J = 2.2 Hz, 1H), 8.61 (dd, J = 8.1, 1.4 Hz, 1H), 7.72 (dd, J =
8.6, 2.3 Hz, 1H), 7.68−7.61 (m, 1H), 7.61−7.55 (m, 1H), 7.53−7.48
(m, 1H), 7.47 (d, J = 8.6 Hz, 1H); 13C {1H} NMR (125 MHz,
CDCl3): δ 179.0, 137.0, 136.1, 135.4, 132.8, 132.6, 130.6, 130.2,
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J. Org. Chem. 2021, 86, 3334−3343

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Article
1
White solid; yield 90.0% (259 mg); mp: 180−183 °C; H NMR
(400 MHz, CDCl3): δ 8.25−8.14 (m, 1H), 7.61−7.49 (m, 1H), 7.18
(dd, J = 8.4, 2.2 Hz, 1H), 7.12 (dd, J = 10.3, 5.2 Hz, 2H), 7.04 (dd, J
= 7.4, 4.9 Hz, 1H), 4.09 (s, 2H), 3.85−3.60 (m, 1H), 1.51 (d, J = 7.2
Hz, 3H); 13C {1H} NMR (150 MHz, CDCl3): δ 179.3, 158.3, 150.9,
146.5, 138.6, 135.4, 127.6, 127.4, 119.9, 119.7, 117.4, 115.4, 44.6,
28.1, 18.3; HRMS (ESI): m/z calcd for C15H14O3N [M + H]+,
256.0968; found, 256.0966.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02694.
1H and 13C spectra of all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Qiong Xiao − Department of Medicinal Chemistry, State Key
Laboratory of Bioactive Substance and Function of Natural
Medicines & Beijing Key Laboratory of Active Substances
Discovery and Drugability Evaluation, Institute of Materia
Medica, Peking Union Medical College and Chinese Academy
of Medical Sciences, Beijing 100050, China; orcid.org/
0000-0001-7881-1362; Email: xiaoqiong@imm.ac.cn
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Authors
Zeyu Shi − Department of Medicinal Chemistry, State Key
Laboratory of Bioactive Substance and Function of Natural
Medicines & Beijing Key Laboratory of Active Substances
Discovery and Drugability Evaluation, Institute of Materia
Medica, Peking Union Medical College and Chinese Academy
of Medical Sciences, Beijing 100050, China
Si Chen − Department of Medicinal Chemistry, State Key
Laboratory of Bioactive Substance and Function of Natural
Medicines & Beijing Key Laboratory of Active Substances
Discovery and Drugability Evaluation, Institute of Materia
Medica, Peking Union Medical College and Chinese Academy
of Medical Sciences, Beijing 100050, China
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coupling via base-promoted homolytic aromatic substitution (BHAS):
synthesis of fluorenones and xanthones. Org. Lett. 2013, 15, 928−931.
(b) Wang, P.; Rao, H.; Hua, R.; Li, C.-J. Rhodium-catalyzed xanthone
formation from 2-aryloxybenzaldehydes via cross-dehydrogenative
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(7) Rao, H.; Ma, X.; Liu, Q.; Li, Z.; Cao, S.; Li, C.-J. Metal-free
oxidative coupling: xanthone formation via direct annulation of 2-
aryloxybenzaldehyde using tetrabutylammonium bromide as a
promoter in aqueous medium. Adv. Synth. Catal. 2013, 355, 2191−
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(8) Verma, S. K.; Prajapati, A.; Saini, M. K.; Basak, A. K. Lewis acid
catalyzed reductive cyclization of 2-aryloxybenzaldehydes and 2-
(arylthio)benzaldehydes to unsubstituted 9H-xanthenes and thio-
xanthenes in diisopropyl ether. Adv. Synth. Catal. 2020,
DOI: 10.1002/adsc.202000836.
Dali Yin − Department of Medicinal Chemistry, State Key
Laboratory of Bioactive Substance and Function of Natural
Medicines & Beijing Key Laboratory of Active Substances
Discovery and Drugability Evaluation, Institute of Materia
Medica, Peking Union Medical College and Chinese
Academy of Medical Sciences, Beijing 100050, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02694
(9) Yamazaki, S. Chromium (VI) oxide-catalyzed benzylic oxidation
with periodic acid. Org. Lett. 1999, 1, 2129−2132.
(10) Shi, Z.; Xiao, Q.; Yin, D. Synthesis of tetrahydroisoquinolines
through TiCl4-mediated cyclization and Et3SiH reduction. Chin.
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Author Contributions
†Z.Y.S. and S.C. contributed equally.
Notes
The authors declare no competing financial interest.
(11) Abrego, G.; Alvarado, H.; Souto, E. B.; Guevara, B.; Bellowa, L.
H.; Parra, A.; Calpena, A.; Garcia, M. L. Biopharmaceutical profile of
pranoprofen-loaded PLGA nanoparticles containing hydrogels for
ocular administration. Eur. J. Pharm. Biopharm. 2015, 95, 261−270.
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CN 103864804 A, 2014. (b) Deng, J.; Ye, Q.; Luo, R.; Huang, C.;
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ACKNOWLEDGMENTS
■
This work was financially supported by the National Key R&D
Program of China (no. 2018YFC1706403), Drug Innovation
Major Project (no. 2018ZX09711-001-005, China), CAMS
Innovation Fund for Medical Sciences (no. 2017-I2M-2-004,
China), and Disciplines Construction Project (no.
201920200802, China).
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