Iodine-catalyzed efficient synthesis of xanthene/thioxanthene-indole derivatives under mild conditions

Article abstract of DOI:10.1039/d0ra05217e

An iodine-catalyzed nucleophilic substitution reaction of xanthen-9-ol and thioxanthen-9-ol with indoles has been developed, providing an efficient procedure for the synthesis of xanthene/thioxanthene-indole derivatives with good to excellent yields. This protocol offers several advantages, such as short reaction times, green solvent, operational simplicity, easily available catalyst and mild reaction conditions. Moreover, this method showed good tolerance of functional groups and a wide range of substrates.

Full text of DOI:10.1039/d0ra05217e

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Iodine-catalyzed efficient synthesis of xanthene/
thioxanthene-indole derivatives under mild
conditions†
Cite this: RSC Adv., 2020, 10, 25165
Weihang Miao,‡a Pingting Ye,‡a Mengjiao Bai,a Zhixin Yang,a Suyue Duan,a
a
Hengpan Duanb and Xuequan Wang
*
An iodine-catalyzed nucleophilic substitution reaction of xanthen-9-ol and thioxanthen-9-ol with indoles
has been developed, providing an efficient procedure for the synthesis of xanthene/thioxanthene-indole
derivatives with good to excellent yields. This protocol offers several advantages, such as short reaction
times, green solvent, operational simplicity, easily available catalyst and mild reaction conditions.
Moreover, this method showed good tolerance of functional groups and a wide range of substrates.
Received 13th June 2020
Accepted 26th June 2020
DOI: 10.1039/d0ra05217e
rsc.li/rsc-advances
in the formation of xanthene-indole derivatives. Therefore,
there is considerable interest in exploring superior catalyst
Introduction
systems which are cheap, stable, environmentally friendly and
easy to access.
Xanthenes and their analogues including thioxanthenes are
important biologically active heterocycles.1 Natural and
synthetic products possessing xanthene moieties exhibit a wide
range of biological activities such as antitumor,2 antibacterial,3
antifungal,4 analgesic and antiinammatory5 activities. Pres-
ently, a number of methods for the functionalized xanthene
derivatives have been investigated, some methods particularly
for the synthesis of 9-substituted xanthene derivatives.6 Notably,
substitution of the xanthenyl-9-position with an indolyl
substituent has received much attention due to the widespread
biological and pharmacological activities of indole derivatives.7
Recently, xanthene-indole derivatives were explored by the
nucleophilic substitution of xanthen-9-ol in the presence of
catalysts such as AcOH,8 DDQ,9 CAN,10 In(DS)3,11 BmimBF4,12
gluconic acid13 and 1,3-dichloro-tetra-n-butyl-distannoxane.14
Cozzi also reported the direct substitution of xanthen-9-ol ‘on
water’ without Brønsted or Lewis acid or surfactants, but this
reaction must be carried out at 80 ꢀC for long time.15 However,
many of these procedures suffer from certain drawbacks
including strong acidic conditions, long reaction times, low
yields of products and harsh reaction conditions. In addition,
Tsuchimoto reported an indium-catalyzed reductive alkylation
of indoles by using carbonyl compounds to obtain alkylindoles
with structural diversity.7d However, this method was not used
In recent years, molecular iodine has drawn considerable
attention, and been used frequently in many organic reactions.
It is widely available, nontoxic, relatively inexpensive, environ-
mentally friendly and highly stable to air and moisture.16 Iodine
catalyzed reactions have resulted in the formation of new C–C,17
C–O,18 C–N (ref. 19) and C–S (ref. 20) bonds, and have been
recognized as a powerful tool for the synthesis of pharmaco-
logically important heterocyclic compounds.21 Several method-
ologies have been reported for the reactions involving the
iodine-mediated nucleophilic addition of indole to aldehydes
and ketones.22 However, the reactions about iodine-mediated
nucleophilic substitution of alcohols with indoles are seldom.
With these in our mind, we report an efficient synthesis of
xanthene/thioxanthene-indole derivatives by iodine-catalyzed
nucleophilic substitution of alcohols with indoles under mild
conditions in a very short time (Scheme 1). Moreover, this
protocol was also used in the substitution of secondary alcohols
with indoles or other nucleophiles such as pyrrole, furan and
1,3-dicarbonyl compounds. To the best of our knowledge, there
aKey Laboratory of Natural Pharmaceutical and Chemical Biology of Yunnan Province,
School of Science, Honghe University, Mengzi, Yunnan 661100, China. E-mail:
huolixuanfeng@126.com
bInternational Academy of Targeted Therapeutics and Innovation, School of Pharmacy,
Chongqing University of Arts and Sciences, Chongqing, 402160, China
† Electronic supplementary information (ESI) available: Detailed experimental
procedures. 1H NMR and 13C NMR spectra for synthesized compounds or other
electronic format. See DOI: 10.1039/d0ra05217e
Scheme 1 I2-catalyzed synthesis of xanthene/thioxanthene-indole
derivatives.
‡ The two authors contributed equally to this paper.
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Table 2 Scope of the reaction of indoles 3 with xanthen-9-ol 1a,b
are no reports concerning the iodine employed in the substi-
tution of xanthen-9-ol or thioxanthen-9-ol.
Results and discussion
The reaction of 9H-xanthen-9-ol 1a and indole 3a was chosen as
a model reaction to optimize the reaction conditions. The
results were listed in the Table 1. Initially, we investigated the
reaction at room temperature under different amounts of
iodine in CH3CN. In the absence of iodine, the reaction could
not proceed in CH3CN at room temperature even prolonging
reaction time to 1 h (entry 1). To our delight, the reaction pro-
ceeded rapidly in the presence of iodine to afford the corre-
sponding substituted product in good yield (entries 2–4), and
the investigation indicated that the optimal amount of catalyst
was 5 mol% in 85% yield (entry 2). Next, different solvents were
also examined in the presence of 5 mol% I2. Interestingly, EtOH
and CH2Cl2 are tolerated in this reaction (entries 5 and 6). Only
H2O is turned out to be incompatible for the poor solubility of
1a in H2O (entry 7). Different oxidizing agents including NBS
and tBuOOH were also examined, but did not show any
improvement in the generation of 4aa. Therefore, the reaction
with 5 mol% I2 in EtOH at room temperature for 5 minutes was
found to be the optimal condition.
Under the above optimum reaction conditions, we investi-
gated the substrate scope of the iodine-catalyzed nucleophilic
substitution of xanthen-9-ol. Firstly, xanthen-9-ol
1 with
different indoles were investigated, and the representative
results were listed in Table 2. All substituted indoles with
electronic-withdrawing groups or electronic-donating groups
proceeded smoothly to afford the desired xanthene-indole
derivatives with high or excellent yield. Surprisingly, not only
Table 1 Optimization of the reaction conditionsa
a
Reaction conditions: 1 (1.0 mmol) and 3 (1.0 mmol) in EtOH (5 mL) at
b
c
rt under air. Isolated yield. The product was recrystallized from
petroleum ether and ethyl acetate.
Entry
Catalyst (mol%)
Solvent
Time (min)
Yieldb (%)
1
2
3
4
I2 (0)
I2 (5)
I2 (10)
I2 (15)
I2 (5)
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
60
5
5
5
5
n.d.c
85
81
80
87
1- or 2-substituted indoles but also 3-, 4-, 5- or 6-substituted
indoles showed high reactivity in our methodology. Moreover,
for methyl 1H-indole-2-carboxylate, the desired product could
be afforded with 90% yield. Substitution of xanthen-9-ol with
different substituents such as halogen atoms, CH3, CH3O,
CH3CH2O and NO2 groups was conducted, and the targeted
products were obtained in good yields.
Subsequently, the reactivity of 9H-thioxanthen-9-ol 2 with
indoles was also tested for synthesis of thioxanthene-indole
derivatives. As shown in Table 3, the reaction proceeded
5
6
7
8
I2 (5)
I2 (5)
I2 (5)
I2 (5)
CH2Cl2
H2O
EtOH
EtOH
EtOH
5
5
30
5
5
77
n.d.
86
84
84
9d
10
11
NBS (5)
tBuOOH (5)
EtOH
60
82
a
Reaction conditions: 1a (1.0 mmol) and 3a (1.0 mmol) in solvent (5 mL)
at rt under air. b Isolated yield. c Not detected. d Reaction temperature was
50 ꢀC.
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Table 3 Scope of the reaction of indoles 3 with 9H-thioxanthen-9-ol
Interestingly, the use of 0.5 equiv. of pyrrole or furan gave 2,5-
disubstituted pyrrole or 2,5-disubstituted furan in good yields.
However, the use of 8 equiv. of pyrrole or furan afforded 2-
substituted pyrrole (83%) or 2-substituted furan (81%). 1,3-
dicarbonyl compounds such as 2,4-pentanedione, dimedone,
1,3-indanedione, 1,3-dimethylbarbituric acid and 4-hydrox-
ycoumarin were found to be compatible with the reaction
conditions, giving the desired products with good to excellent
yields.
2a,b
In addition, the reactivity of other secondary alcohols
including benzhydrols and ferrocenyl alcohols were also
investigated (Table 5). Diphenylmethanol was not reactive even
prolonging reaction time to 12 h. Bis(4-methoxyphenyl)
methanol and bis(4-(dimethylamino)phenyl)methanol were
suitable substrates and the corresponding products 8b and 8d
could be obtained in 99% and 84% respectively. The substitu-
tion of bis(4-(dimethylamino)phenyl)methanol with pyrrole (0.5
equiv.) also proceeded smoothly to give 2,5-disubstituted
pyrrole in 80% yield. To our delight, the heterocyclic derived
a
Reaction conditions: freshly prepared 2 (1.0 mmol) and 3 (1.0 mmol)
in EtOH (5 mL) at rt under air. b Isolated yield.
Table 5 Scope of the reaction of other secondary alcoholsa,b
smoothly and afforded corresponding substituted product with
high yield.
Furthermore, other nucleophiles such as pyrrole, furan and
1,3-dicarbonyl compounds were examined (Table 4).
Table 4 Scope of the reaction of other nucleophiles with xanthen-9-
ol 1a,b
a
Reaction conditions: 1 (1.0 mmol) and NuH (1.0 mmol) in EtOH (5 mL)
b
c
a
at rt under air. Isolated yield. The reaction was performed with 0.5
equiv. of pyrrole or furan. The reaction was performed with 8 equiv. at rt under air. Isolated yield. The reaction was performed with 0.5
of pyrrole or furan. The product was recrystallized from petroleum equiv. of pyrrole. The product was recrystallized from petroleum
Reaction conditions: 7 (1.0 mmol) and NuH (1.0 mmol) in EtOH (5 mL)
d
b
c
e
d
ether and ethyl acetate.
ether and ethyl acetate.
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substrates such as di(benzofuran-2-yl)methanol, benzofuran-2-
yl(4-methoxyphenyl)methanol
and
(9-ethyl-9H-carbazol-3-
yl)(phenyl)methanol could proceed smoothly in this reaction,
affording the desired products with excellent yields. Ferrocenyl
alcohols were also good candidate in this transformation to give
the desired products 8j (92%) and 8k (98%).
The structures of synthesized compounds were conrmed on
1
the basis of IR, H, 13C NMR spectra as well as by comparison
with previous reports. For example, compound 4aa was ob-
tained as white solid. Its molecular formula was determined to
be C21H15NO from the HR-MS at m/z 320.1046 [M + Na]+ (calcd
320.1047). Absorption bands at 3425 cmꢁ1 in the IR spectrum of
1
4aa were assigned to N–H of indolyl unit. The H NMR data of
4aa indicated the presence of a 3-substituted indolyl unit based
on the characteristic signals at dH 7.92 (s, 1H), 7.35 (d, J ¼
8.0 Hz, 1H), 7.30 (d, J ¼ 8.0 Hz, 1H), 7.18 (dd, J ¼ 8.8, 1.6 Hz,
1H), 7.03 (d, J ¼ 2.4 Hz, 1H) and 6.97–6.94 (m, 1H). The 13C NMR
data of 4aa showed 15 carbon signals. dC 151.33 (2 C), 129.50 (2
CH), 127.73 (2 CH), 124.44 (2 C), 123.13 (2 CH), 116.35 (2 CH)
and 35.53 (CH) suggested the existence of 9-substituted xan-
thenyl moiety.
In order to probe the mechanism of this reaction, control
experiments were further conducted (Scheme 2). A 9-ethoxy-9H-
xanthene 6k was obtained when 9H-xanthen-9-ol 1a was treated
solely under the optimized reaction conditions. Subsequently,
9-ethoxy-9H-xanthene was reacted with indole 3a under the
standard conditions; 86% of 4aa was obtained (Scheme 2b).
However, when 9H-xanthen-9-ol 1a was treated solely under I2
(5% mmol) in CH3CN, 9H-xanthen-9-one and 9H-xanthene
formed immediately (Scheme 2c). Meanwhile, the reaction of
bis(3-methoxyphenyl)methanol with indole could not proceed
under the optimized reaction conditions from room tempera-
ture to reux even prolonging reaction time to 12 h (Scheme 2d).
On the basis of the above experimental outcomes and the
previous literature reports,11,22 a plausible reaction mechanism
is presented in Scheme 3. The rst step of the process is the
coordination of iodine to the hydroxyl function of compound A,
Scheme 3 Proposed mechanisms.
thus causing its elimination to give the pyrylium ion B. And the
I2 is transformed to HIO and Iꢁ. Then, nucleophile attacks the
pyrylium ion to generate the corresponding product. On the
other hand, EtOH as nucleophile can react with pyrylium ion B
to give C, which can transform to pyrylium ion under HI.
Importantly, the formation of C can prevent the redox reaction
between A and pyrylium ion B. Liberated HI is further reacted
with HIO to regenerate I2 and complete the catalytic cycle by
releasing H2O. For other secondary alcohols, the results could
be explained by the higher stabilization of the generated
carbocation.
Conclusions
In conclusion, I2 in ethanol was found to be effective and green
catalyst for the electrophilic substitution reactions of xanthen-9-
ol and thioxanthen-9-ol with indoles giving xanthene/
thioxanthene-indole derivatives. Using 5 mol% I2, the reac-
tions could proceed efficiently at room temperature in ve
minutes and afford xanthene/thioxanthene-indole derivatives
with good to excellent yield. Moreover, the reactions of xanthen-
9-ol with other nucleophilic reagents such as pyrrole, furan and
1,3-dicarbonyl compounds could proceed smoothly. The scope
of substrate was also extended to other secondary alcohols such
as benzhydrols and ferrocenyl alcohols.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (No. 21602050), Applied Basic Research
Project of Yunnan (2017FD154), and Yunnan Province Depart-
ment of Education Fund (2016ZZX218).
Scheme 2 Control experiments.
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