One-pot solvent-free synthesis of triaryl- and triheteroarylmethanes by Bi(OTf)3-catalyzed Friedel-Crafts reaction of arenes/heteroarenes with trialkyl orthoformates

Article abstract of DOI:10.1016/j.tet.2018.05.079

A convenient, practical and highly efficient one-pot method has been developed for the synthesis of triaryl- and triheteroarylmethane derivatives by Bi(OTf)₃-catalyzed Friedel-Crafts alkylation of trialkyl orthoformates in combination with a wide variety of arenes/heteroarenes at room temperature under solvent-free conditions and in an air atmosphere. The methodology offers an operational simplicity, high atom economy and environmentally benign procedure. Furthermore, selected compound 3k showed promising anti-inflammatory activity with inhibition nitric oxide and did not exhibit significant cytotoxic effects on macrophage cells.

Full text of DOI:10.1016/j.tet.2018.05.079

Accepted Manuscript
One-pot solvent-free synthesis of triaryl- and triheteroarylmethanes by Bi(OTf) -
3
catalyzed Friedel-Crafts reaction of arenes/heteroarenes with trialkyl orthoformates
Surisa Tuengpanya, Chayamon Chantana, Uthaiwan Sirion, Wipada Siritanyong,
Klaokwan Srisook, Jaray Jaratjaroonphong
PII:
S0040-4020(18)30638-0
10.1016/j.tet.2018.05.079
TET 29586
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 March 2018
Revised Date: 21 May 2018
Accepted Date: 28 May 2018
Please cite this article as: Tuengpanya S, Chantana C, Sirion U, Siritanyong W, Srisook K,
Jaratjaroonphong J, One-pot solvent-free synthesis of triaryl- and triheteroarylmethanes by Bi(OTf) -
3
catalyzed Friedel-Crafts reaction of arenes/heteroarenes with trialkyl orthoformates, Tetrahedron (2018),
doi: 10.1016/j.tet.2018.05.079.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
One-pot solvent-free synthesis of triaryl- and
Leave this area blank for abstract info.
triheteroarylmethanes by Bi(OTf) -catalyzed
3
Friedel-Crafts reaction of arenes/
heteroarenes with trialkyl orthoformates
a
a
a
b
b
Surisa Tuengpanya , Chayamon Chantana , Uthaiwan Sirion , Wipada Siritanyong , Klaokwan Srisook ,
a, ∗
Jaray Jaratjaroonphong
a
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
Department of Biochemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
b
Et
mild condition
HN
OR
Ar/Het
Het/Ar Ar/Het
3
Bi(OTf) (10 mol%)
3
Het/Ar
H
+
3 H OR
+
H H
N
"Novel NO production
inhibition agent"
RO
OR
solvent free
air, rt,
1
2
3
Et
NH
3k
"
Green and facile
synthesis"
up to 99% yield
Et

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
One-pot solvent-free synthesis of triaryl- and triheteroarylmethanes by Bi(OTf)3
catalyzed Friedel-Crafts reaction of arenes/heteroarenes with trialkyl orthoformates
a
a
a
b
b
Surisa Tuengpanya , Chayamon Chantana , Uthaiwan Sirion , Wipada Siritanyong , Klaokwan Srisook ,
a, ∗
Jaray Jaratjaroonphong
a
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
Department of Biochemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
b
ARTICLE INFO
ABSTRACT
Article history:
Received
A convenient, practical and highly efficient one-pot method has been developed for the synthesis
of triaryl- and triheteroarylmethane derivatives by Bi(OTf) -catalyzed Friedel-Crafts alkylation
3
Received in revised form
Accepted
Available online
of trialkyl orthoformates in combination with a wide variety of arenes/heteroarenes at room
temperature under solvent-free conditions and in an air atmosphere. The methodology offers an
operational simplicity, high atom economy and environmentally benign procedure. Furthermore,
selected compound 3k showed promising anti-inflammatory activity with inhibition nitric oxide
and did not exhibit significant cytotoxic effects on macrophage cells.
Keywords:
Triarylmethane
Triheteroarylmethane
Bismuth(III) triflate
Friedel-Crafts reaction
Trialkyl orthoformate
2
009 Elsevier Ltd. All rights reserved.
1
. Introduction
In the past decade, bimuth(III) triflate has become as an
environmentally benign catalyst and has been used as a catalyst
for various types of organic transformations in organic synthesis .
During the last decade, triaryl- and triheteroarylmethanes have
attracted the attention of many scientists due to the broad scope
of their biological activities and their significant applications in
7
1
The catalyst Bi(OTf) is highly tolerant to air as well as moisture
the dye industry and materials science . For instance,
3
symmetrical triindolylmethanes (TIMs) are present in many
products isolated from bacteria and serve as bacterial metabolic
and associated with low cost which make it attractive as a
7
practical catalyst . As part of our ongoing studies in developing
2
simple, convenient and eco-friendly methods for the synthesis of
and cytotoxic agents . Moreover, they show an affinity for
8
hydride ions and dye materials and are effective frameworks for
biologically active compounds , we report here the one-pot
3
the construction of very bulky π-acidic phosphine ligands .
solvent-free synthesis of triaryl- and triheteroarylmethanes via a
triple Friedel-Crafts reaction of trialkyl orthoformates with a
variety of trimethoxybenzene and heteroarenes including furan,
Tripyrrolylmethanes can potentially be utilized as a starting
4
material for the preparation of dendrimers . Trithienylmethane
derivatives find many applications in non-linear optics and
thiophene, pyrrole and indole derivatives using Bi(OTf) as
3
5
catalyst at room temperature under solvent-free conditions and in
an air atmosphere. In an effort to discover a lead compound for
the development of novel non-steroidal anti-inflammatory agents,
the synthesized compounds were further evaluated for their anti-
inflammatory effects on the production of inflammatory factors
NO and cytotoxicity in activated macrophages.
conducting polymer . As a result of their biological and synthetic
importance, a number of methods for the synthesis of
symmetrical triaryl- and triheteroarylmethanes by Lewis acids or
Ønsted acid-catalyzed Friedel-Crafts-type substitution of the
Br
three alkoxy groups in a trialkyl orthofortmate have been
1n,4-6
reported in the literature
. However, most of the examples
reported to date have been limited to reactions of an indole
1n,6
substrate . These suffer from some disadvantages such as the
use of high toxicity or corrosiveness of the promoters
2. Results and discussion
4,6a-d,6f
4,6b,6i
employed
,
high
catalyst
loading
,
elevated
6a-b
6b
Initially, a synthetic plan was designed to access symmetrical
triaryl- and triheteroarylmethanes mediated by Bi(OTf)3
employing 1,2,4-trimethoxybenzene with trimethyl orthoformate
temperature , long duration , low yields of products and
special care for moisture/air sensitive reagents
6b,6f
.
—
——
∗
Corresponding author. Tel.: +0-000-000-0000; fax: +0-000-000-0000; e-mail: jaray@buu.ac.th

2
Tetrahedron
ACCEPTED MANUSCRIPT
Table 1
a
Optimization of the reaction conditions .
OMe
MeO
OMe
OMe
OMe
MeO
MeO
MeO
catalyst (x mol%)
OMe
+
OMe
CH(OMe)
3
OMe
OMe
OMe
H
solvent free
air
I
OMe
OMe
O
H
MeO
3a
0.33 mmol)
4a d
5a f
1a
2a
MeO
MeO
(
1 mmol, 1 equiv)
(
1 mmol, 1 equiv)
(1 mmol)
(1 mmol)
(
b
Entry
Catalyst
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
Bi(OTf)
mmol (mol%)
0.033 (10)
0.033 (10)
0.033 (10)
0.016 (5)
Solvent
Temp. (°C)
Time (h)
Yield (%) of 3a
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
3
3
3
−
rt
rt
60
rt
rt
rt
rt
rt
rt
rt
60
rt
rt
rt
rt
rt
rt
rt
rt
3
>99
c
−
3
>99
−
1
>99
80
−
6
0.033 (10)
0.033 (10)
0.033 (10)
0.033 (10)
0.033 (10)
0.033 (10)
0.033 (10)
0.066 (20)
0.33 (100)
0.033 (10)
0.033 (10)
0.20 (60)
Toluene
24
24
24
24
24
24
24
3
90
CH
ClCH
CH CN
2
Cl
2
>99
>99
>99
31
2
CH
2
Cl
3
THF
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
MeOH
10
H
−
−
−
−
−
−
−
−
2
O
trace
73
I
2
d
I
2
3
46 (4a, 45%)
e
InCl
3
ꢀ4H
2
O
24
24
1
−
e
Cu(OAc)
2
−
f
BF
3
⋅OEt
⋅OEt
2
2
46 (5a, 30%)
f
BF
3
1.00 (300)
1.00 (300)
1
44 (5a, 29%)
e
B(OEt)
3
24
24
−
e
1
−
−
−
a
Reaction conditions: 1a (1.0 mmol, 1 equiv), 2a (1.0 mmol, 1 equiv), catalyst (0.033 mmol, 10 mol%), under air atmosphere at room temperature.
b
c
d
e
f
Isolated yields.
Reaction was carried out under N
-Iodo-1,2,6-trimethoxybenzene (4a) was also isolated in 45%.
No reaction based on TLC analysis.
,4,5-trimethoxybenzaldehyde (5a) was isolated as a side product.
2
atmosphere at room temperature.
5
2
as a model reaction to determine the optimum reaction conditions
with longer reaction time (24 h). A lower yield was obtained
when using tetrahydrofuran, methanol or water as a solvent
(entries 9−11). By comparison to the reaction catalyzed by
(Table 1). As anticipated, the reaction in the presence of Bi(OTf)3
10 mol%) produced the symmetrical polymethoxy substituted
(
triphenylmethane 3a in excellent yield under solvent-free and air
atmosphere at room temperature for 3 h (entry 1). The reaction
under nitrogen atmosphere was then performed and gave the
desired product 3a in comparable yield with the case of the
reaction under an air atmosphere (entry 2). Increasing reaction
temperature to 60 °C afforded the compound 3a in excellent yield
within 1 h (entry 3). By lowering the catalyst loading to 5 mol%
Bi(OTf) , the reaction in the presence of molecular iodine (20
3
mol%) gave the lower yield of 3a (entries 1 and 12). Using a
stoichiometric amount of molecular iodine to catalyze the
reaction gave the desired product 3a and iodination adduct, 5-
iodo-1,2,6-trimethoxybenzene (4a) in 46% and 45%, respectively
(entry 13). Three catalysts, InCl ⋅4H O, Cu(OAc) and B(OEt)
3
2
2
3
which have wide applications in organic synthesis failed to
facilitate the reaction transformation (entries 14, 15 and 18).
Interestingly, the reaction in the presence of BF ⋅Et O (60 mol%)
(entry 4), the desired product 3a was also obtained in high yield,
however, a longer reaction time was necessary. The effect of
various solvents was further studied (entries 5−11). Among the
solvents tested, toluene, dichloromethane, dichloroethane and
acetonitrile also produced the product 3a in excellent yield but
3
2
as Lewis acid gave the desired product 3a in 46% yield.
Moreover, 2,4,5-trimethoxybenzaldehyde (5a) was isolated in
30% yield (entry 16). Employing BF ⋅Et O as stoichiometric
3
2

3
amount (1 mmol, 300 mol%) also gave the c
Compounds 3a and 5a were obtained in 44% and 29%,
respectively (entry 17). A control experiment showed that no
reaction was observed in the absence of Bi(OTf) even after a
A
om
C
pa
C
ra
E
blePTres
E
ul
D
ts. MATa
N
bl
U
e
S
2.
C
T
R
heIPre
T
action of 1,2,4-trimethoxybenzene employing
triethyl orthoformate as alkylating agent also proceeded smoothly
to afford the compound 3a in high yield (entry 2). Compared to
1,2,4- trimethoxybenzene, the more sterically electron-rich arene,
1,3,5-trimethoxybenzene gave a lower yield of the desired adduct
3b and unusual bis(2,4,6-trimethoxyphynyl)methane (6) was
obtained as a side-product in modest yield (entries 4-6). Not only
aromatic nucleophiles but also heteroaromatic nucleophiles like
-methylfuran, 2-ethylfuran as well as 2,3-dimethylfuran were
satisfactory in affording trifurylmethane derivatives 3c, 3d and 3e
in excellent yields. The use of 2-methyl- and 2-ethylthiophene,
which is known to be a poorly reactive necleophile , reacted
3
long reaction time (24 h) (entry 19). These experiments led to the
confirmation that Bi(OTf) is highly tolerant to air and is a highly
3
efficient catalyst for the reaction transformation.
To evaluate the scope of the strategy for the synthesis of
corresponding triaryl- and triheteroarylmethanes, a variety of
trimethoxybenzene as well as heteroarenes such as furan,
thiophene, pyrrole and indole derivatives were reacted with
trimethyl or triethyl orthoformates in the presence of 10 mol%
2
9
smoothly with trimethyl or triethyl orthoformate under optimized
reaction condition (Table 1, entry 1) to give symmetrical
Bi(OTf) at room temperature under solvent-free condition and
3
air atmosphere. The experimental results are summarized in
Table 2
a
Bi(OTf) -catalyzed reaction of arenes/heteroarenes with trialkyl orthoformates .
3
Bi(OTf)3 (10 mol%)
Ar/Het
Ar/Het
Het/Ar
H
+
CH(OR)3
solvent free
air, rt,
Het/Ar
1
2a (R = Me)
3
2b (R = Et)
b
Entry
Het/Ar−H (1)
CH(OR)
3
(2)
Product
Time (h)
Yield (%)
OMe
MeO
OMe
1
2
CH(OMe)
3
3a
3a
3
3
>99
86
MeO
OMe
OMe
H
CH(OEt)
3
OMe
OMe
OMe
MeO
MeO
MeO
Me
MeO
OMe
3
4
5
6
CH(OMe)
CH(OMe)
CH(OMe)
3
3
3
3b
3b
3b
3b
24
24
24
24
trace
c,d
c,e
c,f
OMe
MeO
OMe
20 (6, 39%)
22 (6, 40%)
20 (6, 48%)
OMe
H OMe
MeO
OMe
OMe
MeO
CH(OEt)
3
OMe
Me
7
8
CH(OMe)
3
3
3
O
3c
3c
1
1
>99
96
Me
H
O
O
CH(OEt)
3
Me
O
Me
9
CH(OMe)
CH(OEt)
3d
3d
1
1
>99
93
O
Me
O
1
0
3
H
O
Me
O
Me
Me
Me
Me
Me
1
1
1
2
CH(OMe)
CH(OEt)
O
3e
3e
1
1
>99
98
H
O
O
3
Me
Me
Me
O
Me
Me
1
1
1
1
3
4
5
6
CH(OMe)
CH(OMe)
CH(OMe)
3
3
3
3f
3f
3f
3f
24
24
2
53
d
59
S
Me
H
e
S
64
S
Me
CH(OEt)
3
S
24
45
Me

4
Tetrahedron
Table 2 (continued)
ACCEPTED MANUSCRIPT
b
Entry
Het/Ar−H (1)
CH(OR)
3
(2)
Product
Time (h)
Yield (%)
Me
1
1
1
2
7
8
9
0
CH(OMe)
CH(OMe)
CH(OMe)
3
3
3
3g
3g
3g
3g
24
24
2
57
S
d
Me
62
S
H
S
e
Me
67
S
CH(OEt)
3
24
49
Me
g
2
2
2
2
1
2
3
4
CH(OMe)
CH(OMe)
CH(OMe)
3
3
3
3h
3h
3h
3h
1
1
1
1
−
d,g
HN
−
H H
e,g
N
H
N
−
NH
g
CH(OEt)
3
−
2
2
2
2
5
6
7
8
CH(OMe)
CH(OMe)
CH(OMe)
3
3
3
3i
3i
3i
3i
1
1
1
1
32
N
Me
d
Me
30
N
H
N
Me
e
26
N
Me
CH(OEt)
3
43
Me
2
3
3
3
9
0
1
2
CH(OMe)
CH(OMe)
CH(OMe)
3
3
3
3j
3j
3j
3j
1
1
1
1
47
Me
d
HN
Me
49
Me
H H
N
e
Me
N
39
H
Me
NH
CH(OEt)
3
Me
Me
>99
Me
3
3
3
3
3
4
5
6
CH(OMe)
CH(OMe)
CH(OMe)
3
3
3
3k
3k
3k
3k
1
1
1
1
39
Me
HN
NH
d
42
N
H
H H
N
e
Me
33
CH(OEt)
3
76
Me
NH
g
3
3
3
7
8
9
CH(OMe)
3
3
3l
3l
3l
1
1
1
−
H
h
CH(OMe)
87
N
H
h
CH(OEt)
3
N
NH
76
H
F
NH
h
4
4
0
1
CH(OMe)
3
3m
3m
1
1
64
H
F
N
h
F
H
CH(OEt)
3
58
F
N
H
NH
NH
OMe
MeO
MeO
MeO
h
4
4
2
3
CH(OMe)
3
3n
3n
1
1
93
H
N
h
H
CH(OEt)
3
82
N
H
NH
a
b
c
d
e
f
Reaction conditions: 1a (1.0 mmol, 1 equiv), 2a or 2b (1.0 mmol, 1 equiv), Bi(OTf)
3
(0.033 mmol, 10 mol%), under neat condition at room temperature.
Isolated yields.
Bis(2,4,6-trimethoxyphenyl)methane (6) was isolated as a side-product.
The reaction was carried out in in the presence of Bi(OTf)
3
(0.066 mmol, 20 mol%) at room temperature under neat condition.
The reaction was carried out in in the presence of Bi(OTf)
3
(0.033 mmol, 10 mol%) at 70 °C.
2 2 2
The reaction was carried out in ClCH CH Cl (1 mL) under reflux for 24 h.
g
h
Mixtures of products were observed.
2 2
The reaction was carried out in CH Cl (1 mL) at room temperature.

5
ACCEPTED MANUSCRIPT
trithienylmethane derivatives 3f and 3g in modest yields,
although a longer reaction time (24 h) was employed to
accomplish the reaction (Table 2, entries 13, 16, 17 and 20).
Gratifyingly, increasing the catalyst loading to 20 mol% or
increasing reaction temperature to 70 °C can increase the
chemical yields of products 3f and 3g (entries 14-15 and 18-19).
Subsequently, pyrrole and its derivatives were tested for the
construction of tris(pyrrolyl)methane analogs. Unfortunately, the
reaction of unsubstituted pyrrole was unsuccessful, only yielding
a complex mixture (entries 21-24). However, the use of
g, 18 mmol, 1 equiv) was also performed. Notably, we could
reduce the catalyst loading from 10 mol% to 5 mol% without
impacting the yield of the reaction (Scheme 1).
The versatility of our method was further tested using a
mixture of different arene/heteroarene substrates in the reaction
transformation. A series of experiments were performed as
outlined in Scheme 2. Initially we found that a competitive
reaction between 1,2,4-trimethoxybenzne and 2-methylfuran in
the presence of Bi(OTf)3 under neat conditions delivered a
mixture of three products, 3c, 3o and 3p in 50%, 5% and 43%
yields, respectively (Scheme 2a). Whereas the competition
between indole and 1,2,4-trimethoxybenzene gave exclusively
compound 3l as a sole product in very high yield and within 15
min (Scheme 2b). Finally, the reaction employing a combination
of 2-methylfuran and indole substrates was also carried out. In
this case, the two products derived from two different hetroarene
substrates, 3q and 3r, were observed in modest yields and only a
small amount of 3l was formed (Scheme 2c). The results shown
in Scheme 2 are probably due to the fact that the nucleophilic
reactivity of indole is higher than both 2-methylfuran and 1,2,4-
trimethoxybenzene.
substituted
pyrroles
such
as
N-methylpyrrole,
2,4-
dimethylpyrrole and 2-ethylpyrrole reacted smoothly with
trimethyl or triethyl orthoformate to afford symmetrical
tripyrrolylmethanes 3i, 3j and 3k in moderate to good yields
(
entries 25-36). Bi(OTf) -catalyzed the triple Friedel-Crafts-type
3
reactions of trialkyl orthoformates with both reactive and
unreactive indoles also proceeded well to provide the compounds
3
l, 3m and 3n in high yields, although addition of CH Cl as
2 2
solvent was required in the reaction (entries 37-43).
To demonstrate the scalability and practicality of this method,
a gram scale reaction using 1,2,4-trimethoxybenzene (1a)
(3.0274 g, 18 mmol, 1 equiv) and trimethyl orthoformate (1.9102
OMe
MeO
OMe
CH(OMe)3 2a (1.9102 g, 18 mmol)
MeO
OMe
OMe
H
Bi(OTf)3 (0.30 mmol, 5 mol%)
solvent free
OMe
OMe
MeO
air, rt, 1 h
MeO
MeO
OMe
1
a
(
3.0274 g, 18 mmol)
3a (2.9740 g, 96%)
Scheme 1. Gram-scale reaction.
OMe
OMe
H
OMe
H
Me
MeO
MeO
MeO
OMe
(a)
O
MeO
CH(OMe)3
OMe
OMe
O
OMe
O
+
OMe
H
Me Bi(OTf)3 (10 mol%)
H
+
+
OMe
+
O
O
OMe
solvent free
air, rt, 24h
OMe
OMe
Me
Me
O
Me
Me
O
MeO
MeO
Me
MeO
MeO
MeO
3
1a
1c
a (not observed)
3c (50%)
3o (5%)
3p (43%)
NH
H
OMe
(b)
MeO
CH(OMe)
3
+
Bi(OTf)3 (10 mol%)
N
H
OMe
solvent free
air, rt, 24h
N
H
NH
1a
1l
3l (92%)
Me
Me
O
Me
NH
H
O
O
(c)
CH(OMe)3
H
H
O
+
H
+
+
Me
+
Me
O
N
H
Bi(OTf)3 (10 mol%)
solvent free
air, rt, 30 min
O
O
N
H
NH
N
H
NH
NH
Me
Me
1c
1l
3
c (not observed)
3l (15%)
3q (36%)
3r (44%)
Scheme 2. Competition reaction between two nucleophiles.

6
Tetrahedron
ACCEPTED MANUSCRIPT OR
Bi
RO
OR
OR
OR
Me
H OR
BiIII
OR
Bi(OTf)3
OR
O
RO
1st Arylation
O
OR
Me
O
OR
Bi
OR
OR
Me
2
2
a (R = Me)
b (R = Et)
I
II
III
IV
Me
O
OR
Me
OR
O
BiIII
Me
O
H
O
O
O
Me
2nd Arylation Me
3rd Arylation
O
Me
O
O
Me
O
Me
Me
V
3c
VII
VI
Me
Scheme 3. Proposed mechanism for the synthesis of tris(5-methylfuran-2-yl)methane (3c).
On the basis of the literature information as well as our
include the broad substrate scope, operational simplicity, high
atom economy and the use of inexpensive and environmentally
benign catalyst. In addition, the tris(5-ethyl-1H-pyrrol-2-
yl)methane (compound 3k) showed promising anti-inflammatory
activity with inhibition NO and did not exhibit significant
cytotoxic effects on macrophage cells. The current study provides
a clue for the further development of new types non-steroidal
anti-inflammatory agents (NSAIDs).
experimental results, Bi(OTf) acts as a Lewis acid and plays a
3
significant role in increasing the electrophilic character of the
1a-c
trialkyl orthoformate
. A plausible explanation of the
mechanism is depicted in Scheme 3.
Later the cytotoxic activity of the synthesized compounds was
evaluated by the determination of cell viability using an MTT
8
a-b
assay . The results are shown in Table 3. Most of tested
compounds exhibited little to no cytotoxic effect on cells up to a
concentration of 50 µM, except for tris[3-indolyl]-6-
fluoromethane (3m) and tris[3-indolyl]-5-methoxymethane (3n).
The relative cell viabilities for the latter two compounds were
4
. Experimental section
4
.1. General information
1
6.9% and 21.6%, respectively (entries 16 and 17). These results
revealed that the substitution with methoxy or fluoro in the indole
ring of the triindoylmethane led to a remarkable cytotoxicity to
macrophages.
All synthesized compounds were characterized on the basis of
400 MHz H NMR and 100 MHz C NMR spectroscopic data
(BRUKER AVANC), IR spectra (PERKIN ELMER FT/IR-
1
13
2
000s spectrophotometer) and High-resolution mass spectra
Nitric oxide (NO), a significant pro-inflammatory mediator
which is produced by iNOS, has been implicated in several
1 13
(HRMS) data (Finnigan MAT 95). H NMR and C NMR
8a-b,10
spectra chemical shifts are reported in parts per million (ppm)
using tetramethylsilane (TMS) or the residual nondeuterated
solvent peak as an internal standard. Radial chromatography on a
Chromatotron was performed using Merck silica gel 60 PF254
with CaSO 1/2 H O [E. Merck, Darmstadt, Germany] and was
activated by heating in an oven at 80 °C for 45 min. Thin layer
chromatography (TLC) was performed with Merck silica gel 60
PF254 aluminium plate [E. Merck, Darmstadt, Germany]. Melting
points were measured using a Melting point apparatus (Griffin)
and are uncorrected. All chemicals for synthesis were purchased
from commercial sources such as Sigma Aldrich, Germany,
Merck, Germany or TCI, Japan and purified if required by a
standard technique.
inflammation-related diseases
. Inhibition of NO production
is an important therapeutic target of inflammatory disease.
Therefore, the synthesized compounds were evaluated in vitro for
their inhibitory activity on the production of NO mediators
produced by LPS-stimulated RAW 264.7 macrophage cells by
4
2
10
the Griess reaction . As shown in Table 3 all of the compounds,
except for 3j, significantly inhibited LPS-induced NO production
(P<0.05) when used at 50 µM concentrations. Three compounds
(3k, 3m and 3n) inhibited it by more than 70% as compared to
cells treated with LPS alone. Aminoguanidine (50 µM), a
specific inhibitor of iNOS activity, was used as the positive
control and inhibited induction of nitrite level by LPS (51.8 ± 1.6
%
inhibition). The compound alone and 0.1% (v/v) DMSO did
not stimulate nitric oxide production as compared to the control
cells. Based on the effects on cell viability and inhibition of NO
production shown in Table 3, compound 3k with a 5-ethylpyrrole
moiety could be considered as a lead compound for the further
development of iNOS inhibitors for potential anti-inflammatory
agents.
4
.2. General procedure for the preparation of compounds 3
To a solution of arenes/heteroarenes (1.0 mmol, 1 equiv) and
trialkyl orthoformates (1.0 mmol, 1 equiv) in a test-tube open to
air at room temperature was added Bi(OTf) (0.033 mmol, 10
3
mol%). After the reaction was stirred until completion (TLC
analysis), the reaction mixture was quenched with aqueous
3
. Conclusions
NaHCO (10 mL) and extracted with EtOAc (2 x 10 mL). The
3
combined organic layer was washed with brine (10 mL), dried
over anhydrous Na SO and filtered. The filtrate was evaporated
We have developed a convenient, practical and highly
efficient one-pot method for the synthesis of triaryl- and
2
4
(aspirator then vacuo) to give a crude product, which was
triheteroarylmethanes by Bi(OTf) -catalyzed Friedel-Crafts
3
purified by radial chromatography (SiO , 100% hexane to 70%
2
reaction of arenes/heeroarenes with trialkyl orthoformates as
alkylating agent at room temperature under solvent-free
conditions and air atmosphere. The advantages of this method
EtOAc/hexane as eluent) to give the corresponding symmetrical
triarylmethane 3.

7
Table 3
ACCEPTED MANUSCRIPT
a
In vitro effects of triaryl- and triheteroarylmethanes on LPS-induced NO production and cell viability .
b
c,
e
Entry
Compounds
% Cell viability
100.0 ± 0.0
100.8±0.8
NO production (inhibition, %) *
IC50
(
µM) of NO inhibition
1
2
3
Control
- ± -
-
-
-
DMSO (0.2% v/v)
LPS (1 µg/mL)
- ± -
99.0±1.2
0.0 ± 0.0
d
f
4
5
6
7
8
9
AG (50 µM)
97.1±2.2
100.9 ±3.5
58.8±4.2
97.7±0.5
100.8±1.3
102.8±2.0
99.6±1.7
100.9±2.0
100.7±2.0
100.1±1.2
99.2±2.7
104.8±1.1
16.9±4.5
21.6±10.8
103.5±5.3
98.3±6.1
97.0±5.5
93.7±5.2
100.6±1.9
51.8±1.6
17.1±6.9
15.9±1.3
47.7±3.7
42.6±5.1
39.8±9.3
23.8±6.5
21.4±11.9
29.3±3.0
7.8±11.6
70.7±2.9
39.9±5.9
89.2±6.7
82.2±2.2
68.1±7.3
41.3±7.2
28.0±4.0
58.48±2.8
12.5±3.1
44.5 ± 0.3
3a
-
3b
-
3c
-
3d
-
3e
-
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3f
-
3g
-
3i
-
3j
-
3k
46.0 ± 3.4
3l
-
-
-
-
-
-
-
-
3m
3n
3o
3p
3q
3r
2-ethylpyrrole
a
b
All data are mean ± SD of at least three independent experiments with triplicate samples.
Cell viability of each treatment was presented as percentage of unstimulated cells (control).
c
The percentage inhibition of NO production of each treatment (50 µM) was determined in comparison to LPS-stimulated RAW264.7 macrophage cells (LPS)
for 24 h.
d
AG (Aminoguanidine)-a specific inhibitor of iNOS activity.
e
Concentration of compound was inhibited the production of nitrite with 50%.
f
Under our experimental conditions.
*
p< 0.05 compared to LPS-treated cells.
1
1
12
13
14
15
Spectral data of compounds 3a , 3c , 3d , 3f , 3i ,
4.2.2. Tris(2,4,6-trimethoxyphenyl)methane (3b)
1
6
6h
13
17
3
l , 3n , 3q , and 3r were in agreement with those in the
o
White solid, yield 20% (from 2b); mp 205-209 C; R = 0.22
f
literature.
1
(
3:7 EtOAc/ hexane); H NMR (400 MHz, CDCl ): δ = 6.28 (s,
3
1
3
1
H), 6.11 (s, 6H), 3.78 (s, 9H), 3.48 (s, 18H); C NMR (100
): δ = 159.9, 158.1, 117.2, 92.9, 56.9, 55.1, 28.7; IR
Nujol-mull): νmax 1591, 1492, 1453, 1412, 1225, 1198, 1149,
11b
MHz, CDCl
(
3
4
.2.1. Tris(2,4,5-trimethoxyphenyl)methane (3a)
-
1
White solid, yield >99% (from 2a), 86% (from 2b); mp 183-
87 C; R = 0.18 (4:6 EtOAc/ hexane); H NMR (400 MHz,
1119, 1060, 953, 812 cm ; HRMS (ESI) calcd for C28
[M+Na] 537.2101, found 537.2120.
H
34
O
9
Na
o
1
+
1
f
CDCl ): δ = 6.55 (s, 3H), 6.42 (s, 3H), 6.23 (s, 1H), 3.89 (s, 9H),
3
13
3
1
.67 (s, 9H), 3.64 (s, 9H); C NMR (100 MHz, CDCl ): δ =
3
51.6, 147.8, 142.7, 124.8, 114.2, 98.7, 57.2, 56.7, 56.0, 36.4; IR
4.2.3. Bis(2,4,6-trimethoxyphenyl)methane (6)
(
1
[
Nujol-mull): νmax 1603, 1511, 1459, 1395, 1318, 1205, 1180,
o
-
1
White solid, yield 48% (from 2b); mp 117-108 C; R
f
= 0.47
116, 1035, 886, 770 cm ; HRMS (ESI) calcd for C H O Na
1
28
34
9
+
(3:7 EtOAc/ hexane); H NMR (400 MHz, CDCl ): δ = 6.12 (s,
3
13
M+Na] 537.2101, found 537.2102.
4
H), 3.87 (s, 2H), 3.79 (s, 6H), 3.73 (s, 12H); C NMR (100
MHz, CDCl ): δ = 159.5, 158.9, 112.2, 91.4, 91.3, 56.2, 55.4,
3
1
6.9; IR (Nujol-mull): νmax 1595, 1495, 1455, 1416, 1226, 1203,

8
Tetrahedron
-
1
13
1
148, 1130, 1059, 949, 808 cm ; HRMS
A
(
C
ES
C
I)
E
c
P
al
T
cd
E
f
D
or MA9.
N
6,
U
1.9
S
H
C
z
R
, 3
I
H), 6.82-6.77 (m, 6H), 6.07 (s, 1H); C NMR (100
P
T
+
1
C H O Na [M+Na] 371.1471, found 371.1487.
MHz, CDCl ): δ = 159.6 ( J = 235.0 Hz), 136.3, 123.3, 123.1
(
19
24
6
3
CF
3
3
2
JCF = 3.0 Hz), 120.3 ( J = 10.0 Hz), 118.8, 107.6 ( J = 24.0
CF CF
2
Hz), 97.0 ( J = 26.0 Hz), 31.0; IR (Nujol-mull): νmax 3415 (N-
CF
4
.2.4. Tris[2-(4,5-dimethylfuryl)]methane (3e)
Brown oil, yield >99% (from 2a), 98% (from 2b); R = 0.61
H), 1706, 1625, 1496, 1456, 1341, 1304, 1213, 1138, 1089, 951,
-
1
+
8
4
36, 804, 749 cm ; HRMS (ESI) calcd for C H F N [M-H]
14.1213, found 414.1214.
25 15 3 3
f
1
(1:9 EtOAc/hexane); H NMR (400 MHz, CDCl ): δ = 5.88 (s,
3
13
3
H), 5.26 (s, 1H), 2.18 (s, 9H), 1.91 (s, 9H); C NMR (100
MHz, CDCl ): δ = 149.6, 146.5, 114.5, 110.1, 39.0, 11.4, 9.9; IR
3
4
(3o)
.2.10. Bis-[(2,4,5-trimethoxyphenyl)-2-(5-methylfuryl)]methane
(
7
Nujol-mull): ν 1674, 1568, 1404, 1222, 1160, 1005, 956, 806,
max
-
1
+
83 cm ; HRMS (ESI) calcd for C H O Na [M+Na] 321.1467,
19 22 3
o
found 321.1464.
Yellow solid, yield 5%; mp 127-129 C; R = 0.13 (2:8 EtOAc/
hexane); H NMR (400 MHz, CDCl ): δ = 6.56 (br d, J = 3.2 Hz,
f
1
3
4
H), 6.03 (s, 1H), 5.85 (br d, 1H, J = 2.8 Hz), 5.65 (br d, 1H, J =
13
4
.2.5. Tris[2-(5-methylthienyl)]methane (3f)
Brown oil, yield 53% (from 2a), 45% (from 2b); R = 0.59
2.8 Hz), 3.90 (s, 6H), 3.75 (s, 6H), 3.72 (s, 6H), 2.26 (s, 3H); C
NMR (100 MHz, CDCl ): δ = 155.2, 151.4, 150.9, 148.3, 142.9,
3
f
1
22.6, 113.8, 108.4, 105.8, 98.6, 57.1, 56.7, 56.1, 36.6, 13.7; IR
1
(1:9 EtOAc/hexane); H NMR (400 MHz, CDCl ): δ = 6.74 (br d,
3
(
1
Nujol-mull): νmax 1721, 1610, 1510, 1464, 1396, 1316, 1260,
J = 2.9 Hz, 3H), 6.61 (br d, J = 2.9 Hz, 3H), 5.87 (s, 1H), 2.46 (s,
-1
213, 1177, 1108, 1036, 876, 764 cm ; HRMS (ESI) calcd for
13
9
1
1
H); C NMR (100 MHz, CDCl ): δ = 145.1, 139.2, 125.4,
+
3
C H O Na [M+Na] 451.1733, found 451.1739.
24
28
7
24.5, 43.1, 15.4; IR (Nujol-mull): νmax 1600, 1552, 1482, 1446,
-
1
379, 1260, 1227, 1167, 1042, 967, 800 cm ; HRMS (ESI) calcd
+
for C H S Na [M+Na] 327.0312, found 327.0311.
16
16 3
4
.2.11. Bis[2-(5-methylfuryl)-2,4,5-trimethoxyphenyl]methane
(3p)
o
4
.2.6. Tris[2-(5-ethylthienyl)]methane (3g)
Yellow solid, yield 43%;; mp 95-97 C; R
f
= 0.31 (2:8 EtOAc/
1
hexane); H NMR (400 MHz, CDCl ): δ = 6.76 (s, 1H), 6.57 (s,
H), 5.89 (br d, J = 2.8 Hz), 5.85 (br d, J = 2.8 Hz, 2H), 5.79 (s,
H), 3.91 (s, 3H), 3.82 (s, 3H), 3.77 (s, 3H), 2.26 (s, 6H);
NMR (100 MHz, CDCl ): δ = 153.4, 151.5, 151.3, 148.9, 143.4,
20.3, 113.8, 108.1, 106.2, 98.4, 57.3, 56.9, 56.4, 37.4, 13.9; IR
Nujol-mull): νmax 1611, 1561, 1509, 1465, 1397, 1315, 1213,
174, 1110, 1036, 1022, 871, 783 cm ; HRMS (ESI) calcd for
C H O Na [M+Na] 365.1365, found 365.1360.
3
Brown oil, yield 57% (from 2a), 49% (from 2b); R = 0.63
f
1
1
1
(1:9 EtOAc/hexane); H NMR (400 MHz, CDCl ): δ = 6.76 (br d,
13
3
C
J = 3.0 Hz, 3H), 6.64 (br d, J = 3.0 Hz, 3H), 5.89 (s, 1H), 2.82 (q,
J = 7.5 Hz, 6H), 1.30 (t, J = 7.4 Hz, 9H); C NMR (100 MHz,
CDCl ): δ = 147.0, 144.9, 125.4, 122.8, 43.5, 23.8, 16.0; IR
13
3
1
3
(
1
(Nujol-mull): ν 1667, 1619, 1456, 1403, 1261, 1223, 1020,
-1
max
-
1
+
8
06 cm ; HRMS (ESI) calcd for C H S Na [M+Na] 369.0781,
+
19
22 3
20
22
5
found 369.0786.
4
4
.3 Biological activity evaluation
4
.2.7. Tris[2-(3,5-dimethylpyrroyl)]methane (3j)
Brown oil, yield 47% (from 2a), >99% (from 2b); R = 0.66
.3.1 Cell culture
f
1
(2:8 EtOAc/hexane); H NMR (400 MHz, CDCl ): δ = 7.41 (br s,
3
Murine macrophage cell line RAW 264.7 was provided by.
3
9
1
1
H, 3xNH), 5.72 (br d, J = 1.9 Hz, 3H), 5.42 (s, 1H), 2.19 (s,
13
Cells were cultured in DMEM-containing 100 U/mL of
penicillin, 100 µg/mL of streptomycin, 4 mM L-glutamine, 25
mM D-glucose, 1 mM sodium pyruvate and 10% heat-inactivated
fetal bovine serum (FBS) at 37 ºC in humidified air containing
H), 1.86 (s, 9H); C NMR (100 MHz, CDCl ): δ = 125.7,
3
15.0, 108.9, 32.9, 13.4, 11.0; IR (Nujol-mull): νmax 3363 (N-H),
-
1
691, 1599, 1509, 1456, 1375, 1260, 1147, 952, 750 cm ;
+
HRMS (ESI) calcd for C H N Na [M+Na] 318.1946, found
3
19
25
3
5
% CO . Cells were subcultured by scrapping.
2
18.1957.
4
.3.2 Measurement of the production of NO
4
.2.8. Tris[2-(5-ethylpyrroyl)]methane (3k)
Cells (5×105 cells/well) were incubated with tested compound
Brown solid, yield 39% (from 2a), 76% (from 2b); mp 139-141
o
1
and 1 μg/mL LPS for 24 h. Conditioned media was collected to
determine the level of nitrite, an oxidation product of NO.
Briefly, nitrite concentration was examined by Griess reagent.
The percentage of NO production is expressed as: (nitrite
C; R = 0.44 (2:8 EtOAc/ hexane); H NMR (400 MHz, CDCl ):
f
3
δ = 7.75 (br s, 3H), 5.94 (br t, J = 2.6 Hz, 3H), 5.86 (br d, J = 2.6
Hz, 3H), 5.42 (s, 1H), 2.58 (q, J = 7.6 Hz, 6H), 1.22 (t, J = 7.6
13
Hz, 9H); C NMR (100 MHz, CDCl ): δ = 133.9, 130.0, 106.4,
3
concentration of treated sample/ nitrite concentration of LPS
1
1
04.0, 37.6, 20.9, 13.5; IR (Nujol-mull): νmax 3344 (N-H), 1684,
10
-
1
treatment)×100
.
579, 1501, 1428, 1375, 1328, 1177, 1032, 1007, 769 cm ;
+
HRMS (ESI) calcd for C H N [M-H] 294.1963, found
19
24
3
2
94.1972.
4
.3.3 Cell viability test using MTT assay
Cell viability was evaluated by MTT assay as described by
10
4
.2.9. Tris[3-indolyl]-6-fluoromethane (3m)
Srisook et al. . This assay is based on the reduction of
tetrazolium salt (MTT) to formazan by viable cells containing
mitochondrial dehydrogenase activity. Cells were exposed to
tested compounds for 24 h and media containing 0.1 mg/ml MTT
was added, and further incubated for 4 h. The MTT-formazan
Orange solid, yield 64% (from 2a), 58% (from 2b); mp 205-207
o
1
C; R = 0.55 (100% CH Cl ); H NMR (400 MHz, CDCl ): δ =
f
2
2
3
7
.94 (br s, 3H, 3xNH), 7.39 (dd, J = 8.6, 5.4 Hz), 7.07 (dd, J =

9
(
c) Garbe TR, Kobayashi M, Shimizu N, Takesue N, Ozewa M,
was dissolved by DMSO. Absorbance of sol
A
ubi
C
liz
C
ed
E
f
P
or
TED
an MANUSCRIPT
m
az
Yukawa H. J. Nat. Prod. 2000; 63:596−598.
d) Li J, Wang L, Li B, Zhang G. Heterocycles 2003; 60:1307−1315.
solution was measured at 550 nm. The percentage of cell
viability is expressed as: (absorbance of treated well/absorbance
of control well)×100.
(
3
. (a) Preobrazhenskaya MN, Korolev AM, Rozhkov II, Yudina LN, Lazhko
EI, Aiello E, Almerico A-M, Mingoia F. II Farmaco.1999; 54:265−274.
(
(
b) Muthyala R, Katritzky AR, Lan X. Dyes Pigments. 1994; 25:303−324.
c) Mason MR, Barnard TS, Segla MF, Xie B, Kirschbaum K. J. Chem.
Crystalogr. 2003; 33:531−540.
. Reese CB, Yan H. Tetrahedron Lett. 2001; 42:5545−5547.
. Cherioux F, Guyard L, Audebert P. Adv. Mater. 1998; 10:1013−1018.
Acknowledgments
4
5
This work was financially supported by a Research Grant
from Burapha University through the National Research Council
of Thailand (Grant nos. 20/2556 and 60/2557) and the Center of
Excellence for Innovation in Chemistry (PERCH-CIC),
Commission on Higher Education, Ministry of Education,
Thailand. The authors are grateful to Dr. Ron Beckett, Faculty of
Science, Burapha University, Thailand for his comments and
English proofreading as well as thank to Ms. Petcharat Sawai and
Ms. Kanjana Duangkate for valuable technical assistance.
6. (a) Akgün E, Pindur U, Müller J. J. Heterocycl. Chem. 1983; 20:1303−
1305.
(b) Pindur U, Müller J. J. Heterocycl. Chem. 1987; 24:289−290.
(c) Witzel H, Pindur U. J. Heterocycl. Chem. 1988; 25:907−910.
(d) Chakrabarty M, Sarkar S, Linden A, Stein BK. Synth. Commun.
2
004; 34:1801−1810.
(e) Chang Z-H, Lin J. Synth. Commun. 2007; 37:209−215.
(f) Sato T, Higuchi S, Ito K. Lett. Org. Chem. 2007; 4:595−600.
(g) Zeng X-F, Ji S-J, Su X-M. Chin. J. Chem. 2008; 26:413−416.
(h) Khaksar S, Vahdat SM, Gholizadeh M, Talesh SM. J. Fluorine Chem.
2
012; 136:8−11;
(i) Singh NG, Kathing C, Rani JWS, Nongkhlaw RL. J. Chin. Chem.
Soc. 2014; 61:442−446.
7
8
.
.
(a) Ollevier, T. In Bismuth-mediated organic reaction; Springer-Verlag:
Heidelberg, 2012.
Supplementary Material
(b) Suzuki, H.; Matano, Y. In Organobismuth Chemistry; Elsevier:
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.xxxx.xx.xxx.
Amsterdam, 2002.
(c) Ollevier T. Org. Biomol. Chem. 2013; 11:2740−2755.
(a) Jaratjaroonphong J, Tuengpanya S, Saeeng R, Udompong S, Srisook
K. Eur. J. Med. Chem. 2014; 83:561−568.
References
(b) Udompong S, Mankhong S, Jaratjaroonphong J, Srisook K. Int.
Immunopharmacol. 2017; 50:6−13.
c) Jaratjaroonphong J, Tuengpanya S, Ruengsangtongkul S. J. Org.
Chem. 2015; 80:559−567.
1
. For selected examples, please see: (a) Xie QW, Cho HJ, Calaycay J,
Mumford RA, Swiderek KM, Lee TD, Ding A, Troso T, Nathan C.
Science 1992; 256−225.
(
d) Ruengsangtongkul S, Taprasert P, Sirion U, Jaratjaroonphong J. Org.
Biomol. Chem. 2016; 14:8493−8502.
e) Senapak W, Saeeng R, Jaratjaroonphong J, Kasemsuk T, Sirion U.
Org. Biomol. Chem. 2016; 14:1302−1210.
f)) Jaratjaroonphong J, Sathalalai S, Techasauvapak P, Reutrakul V.
Tetrahedron Lett. 2009; 50:6012−6015.
g) Jaratjaroonphong J, Krajangsri S, Reutrakul V. Tetrahedron Lett.
012; 53:2476−2479.
Mayr H, Kempf B, Ofial AR. Acc. Chem. Res. 2003; 36:66−77.
(b) Medzhitov R, Nature 2008; 454:428−435.
(c) Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G,
(
Huber C. Gastroenterology 1992; 103:264− 274.
(
(
(
d) IIsomaki P, Punnonen J. Ann. Med. 1997; 29:499−507.
e) Coker RK, Laurent GJ. Eur. Respir. J. 1998; 11:1218−1221.
f) Guzik TJ, Korbut R, Adamek-Guzik T. J. Physiol. Pharmacol. 2003;
(
(
2
5
4:469−487.
(
(
g) Wright CE, Rees DD, Moncada S. Cardiovasc. Res. 1992; 26:48−57.
h) Latham KA, Whittington KB, Zhou R, Qian Z, Rosloniec EF. J
9
1
.
0. Srisook K, Srisook E, Nachaiyo W, Chan-In M, Thongbai J, Wongyoo
K, Chawsuanthong S, Wannasri K, Instasuwan S, Watcharanawee K. J
Enthnopharmacol. 2015; 165: 94−102.
Immunol. 2005; 174:3978−3985.
(i) Duxbury DF. Chem. Rev. 1993; 93:381−433.
(j) Brüne B, Von Knethen A, Sandau KB. Eur. J. Pharmacol. 1998;351:
1
1. (a) Sánchez-Viesca F, Gómez MR, Berros M. Org. Prep. Proc. Int.
2
61−272.
2
004; 36:135−140.
(
(
k) Shchepinov MS, Korshun VA. Chem. Soc. Rev. 2003;32:170−180;
l) Nair V, Thomas S, Mathew SC, Vidya N, Rath NP. Tetrahedron
(b) Kantlehner W, Anders E, Mezger J, Stoyanov EV, Kreß R, Wermann
K, Frey W, Görls H. Z. Naturforsch. B 2008: 63:395−406.
2
(
6
(
005; 61:9533−9540.
m) Nair V, Thomas S, Mathew SC, Abhilash KG. Tetrahedron 2006;
2:6731−6747.
n) Shiri M, Zolfigol MA, Kruger HG, Tanbakouchian Z. Chem. Rev.
010; 110:2250− 2293.
1
2. Hashmi SK, Schwarz L, Rubenbauer P, Blanco MC. Adv. Synth. Catal.
2
006; 348:705−708.
1
1
1
3. Nair V, Abhilash KG, Vidya N. Org. Lett. 2005; 7:5857−5859.
4. Dhiman S, Ramassastry SSV. Org. Biomol. Chem. 2013; 11:8030−8035.
5. Singh K, Sharma S, Sharma A. J. Mol. Catal. A: Chem. 2011;
2
(o) Mondal S, Panda G. RSC Adv. 2014; 4:28317−28358.
3
47:34−37.
(p) Beija M, Afonso CAM, Martinho JMG. Chem. Soc. Rev. 2009; 38:
1
1
6. El Sayed MT, Ahmed KM, Mahmoud K, Hilgeroth A. Eur. J. Med.
Chem. 2015; 90:845−859.
7. An L-T, Ding F-Q, Zou J-P, Lu XH, Zhang LL. Chin. J. Chem. 2007;
2
410−2433.
2
. For selected examples, please see: (a) Mansson M, Gram L, Larsen TO.
Mar. Drugs. 2011; 9:1440−1468.
2
5:822−827.
(b) Veluri R, Oka I, Wagner-Dobler I, Laatsch H. J. Nat. Prod.
2
003; 66:1520−1523.