Efficient synthesis of triarylmethanes via bisarylation of aryl aldehydes with arenes catalyzed by silica gel-supported sodium hydrogen sulfate

Article abstract of DOI:10.1016/j.tetlet.2010.02.157

An efficient synthesis of triarylmethanes has been developed via bisarylation of aryl aldehydes with arenes catalyzed by silica gel-supported sodium hydrogen sulfate in a solvent-free system. The new method features high yield, mild reaction conditions, a

Full text of DOI:10.1016/j.tetlet.2010.02.157

Tetrahedron Letters 51 (2010) 2370–2373
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Tetrahedron Letters
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Efficient synthesis of triarylmethanes via bisarylation of aryl aldehydes
with arenes catalyzed by silica gel-supported sodium hydrogen sulfate
a,b,
Yixin Leng a, , Fang Chen b, , Li Zuo b, , Wenhu Duan
*
*
a School of Pharmacy, East China University of Science & Technology, Shanghai 200237, PR China
b Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of triarylmethanes has been developed via bisarylation of aryl aldehydes with are-
nes catalyzed by silica gel-supported sodium hydrogen sulfate in a solvent-free system. The new method
features high yield, mild reaction conditions, and environmental friendliness.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 January 2010
Revised 22 February 2010
Accepted 26 February 2010
Available online 3 March 2010
Keywords:
Triarylmethane
Bisarylation
Catalyzed
Silica gel-supported sodium hydrogen
sulfate
Triarylmethanes are valuable scaffolds that have been used as
photochromic agents,1 dyes,2 protective groups,3 and building
blocks for dendrimers and NLOs.4 Additionally, they have main-
tained an integral part in a number of bioactive compounds and
pharmaceuticals.5 For instance, substituted triarylmethanes have
been reported to exhibit antioxidant, antivirus, and antitumor
activities.5a–f The available methods for the construction of triar-
ylmethane frameworks are based on the bisarylation of an aryl
aldehyde using various promoting systems. These promoting
systems include (a) acid-catalyzed;5e,6,7 (b) Grignard reagent-assis-
ted;5f (c) microwave-assisted;8,9 (d) inorganic salts-catalyzed;10–12
(e) a reductive system of the combination of tris(pentafluorophe-
nyl)borane and polymethylhydrosiloxane;13 (e) iodine-cata-
lyzed;14 (f) silica sulfuric acid-catalyzed, a useful system for the
synthesis of tri(bis(indolyl) methanes);15 and (g) silica gel-sup-
ported zinc bromide-promoted which features high efficiency
and mild conditions.16 Nevertheless, these approaches are often
hindered by the formation of by-products, high catalyst loading,
long reaction time, and environmental unfriendliness. As a result,
there still exists a need for development of new approaches to
the synthesis of triarylmethanes in more efficient and environmen-
tal friendly way. Herein, we wish to report an efficient synthesis of
triarylmethane via bisarylation of aryl aldehyde catalyzed by silica
gel-supported sodium hydrogen sulfate (NaHSO4ÁSiO2).
Inspired by acid-catalyzed bisarylation of aryl aldehyde, we
envisioned that silica gel-supported NaHSO4 (e.g., NaHSO4ÁSiO2)
could be used as a useful acidic reagent for this transformation
(Scheme 1). Due to the nature of its environmental friendliness,
low cost, and easy preparation,17 NaHSO4ÁSiO2 has gradually be-
come a popular reagent in organic synthesis, and it has therefore
been widely used in a variety of organic transformations such as
nitration, nitrosation, oxidation, halogenation, and coupling of in-
doles.18 Recently, we also found that it was a useful reagent for
debenzylation of aromatic benzyl ethers.19
In an exploratory study, a reaction of 4-methoxybenzaldehyde
(1a) and thiophene (2) in the presence of NaHSO4ÁSiO2 in CHCl3
was carried out. It was found that the reaction proceeded as ex-
pected, but in moderate yield (Table 1, entry 1, 62%). Optimization
of reaction conditions revealed that the reaction efficiency was
highly solvent dependent. No reaction occurred in CH2Cl2, indicat-
ing that the lower boiling point of CH2Cl2 may account for the re-
sult (entry 2). This hypothesis can be further supported by the
result obtained in C4Cl4 (Table 1, entry 3, 64% yield). The reaction
also did not occurr in polar solvent, such as DMF, THF, and 1,4-
dioxane (entries 4–6). Among solvents probed, the highest yield
was achieved in thiophene (entry 8, in this entry thiophene served
as both the reactant and the solvent), which implied that the
NaHSO4·SiO2
Heating
Ar2 Ar2
Ar1
Ar1CHO
+ 2Ar2H
* Corresponding authors. Tel./fax: +86 (21) 5080 6032 (W.D.).
E-mail addresses: lzuo@sibs.ac.cn (L. Zuo), whduan@mail.shcnc.ac.cn (W. Duan).
These authors made equal contributions.
Scheme 1. Bisarylation of aryl aldehydes to produce triarylmethanes.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.157

Y. Leng et al. / Tetrahedron Letters 51 (2010) 2370–2373
2371
Table 1
Table 2
a
Optimization of reaction conditions of thiophene with 4-methoxybenzaldehyde
catalyzed by NaHSO4ÁSiO2
The reaction of thiophene with various aldehydes in the presence of NaHSO4ÁSiO2
a
NaHSO4·SiO2 (3)
+
RCHO
S
S
S
NaHSO4·SiO2 (3)
R
S
S
Neat,reflux
MeO
CHO
+
4
1
2
S
Reflux
4a
1
2
Entry
1
R (1 mmol)
t (h)
4
Mp (°C)
Yieldb (%)
OMe
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
4-MeO–C6H4
3-NO2–C6H4
4-NO2–C6H4
4-Br–C6H4
3
3
2
2.5
2.5
3
3.5
5
4a
4b
4c
4d
4e
4f
4g
4h
4i
88–90
72–74
87–89
62–64
73–74
NAc
94–96
59–61
66–68
50–51
46–47
76
85
84
84
82
66
64
44d
39e
71
58
Entry
2 (mL)
3 (mg)
Solventa
t (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
0.4
0.4
0.4
0.4
0.4
0.4
0.4
3
500
500
500
500
500
500
500
500
200
100
CHCl3
CH2Cl2
CCl4
DMF
THF
1,4-Dioxane
Toluene
Neatd
Neat
7
7
7
7
7
7
7
3
3
5
62
NRc
64
NR
NR
NR
47
73
76
74
C6H5
3-HO–C6H4
3,4-(OCH2O)–C6H3
3-MeO–4-HO–C6H3
3-HO–4-MeO–C6H3
2-Thienyl
5
6
7
10
1j
1k
4j
4k
11f
H
3
3
a
10
Neat
Aldehyde (1 mmol), thiophene (3 mL) and NaHSO4ÁSiO2 (200 mg, 0.5 mmol of
NaHSO4 on SiO2) were used unless specified.
a
1 (1 mmol) and solvent (5 mL) were used unless specified, the content of
b
Isolated yield.
NA (not available), the product is liquid.
Recovered 31% of 1h.
Recovered 27% of 1i.
NaHSO4ÁSiO2 (1 g, 2.5 mmol of NaHSO4 on SiO2).
c
b
Isolated yield.
d
c
NR stands for no reaction.
Neat stands for solvent-free system.
e
d
f
7 mL of thiophene was used, and the aldehyde in this entry was para-
formaldehyde.
reaction could proceed in a solvent-free system. Next, the effect of
the catalyst loading was tested. A good yield was achieved when a
median amount of catalyst loading was used (entry 9). Higher cat-
alyst loading did not improve the yield (entry 8). Reducing the use
of the amount of NaHSO4ÁSiO2 slightly deteriorated the reaction
efficiency in terms of product yield and reaction time (entry 10).
The optimized conditions were used to test a range of aldehydes
(Table 2). Thiophene was combined with various substituted benz-
aldehydes in the presence of NaHSO4ÁSiO2 and the reaction was
carried out at reflux (85 °C). It was demonstrated that the reaction
of the aldehydes with electron-withdrawing groups such as 3-
nitrobenzaldehyde, 4-nitrobenzaldehyde, and 4-bromobenzalde-
hyde went to completion in less than 3 h to afford the expected tri-
arylmethanes in good yields (entries 2–4). However, the reaction of
those aldehydes with electron-donating groups such as 3-hydroxy-
Table 3
Bisarylation of 4-nitrobenzaldehyde with various arenes (ArH) to form triarylmethanesa
Ar Ar
NaHSO4·SiO2 (3)
+
CHO
ArH
O2N
Neat/Heating
1
5
6
NO2
Entry
1
Ar
T (°C)
t (h)
6
Mp (°C)
Yieldb (%)
S
S
Thienyl
Reflux
2
87–89
84
6a or 4c
NO2
2
3
4-Me–C6H4
2,4-Me2–C6H3
Reflux
Reflux
4
4
—
—
—
—
NRc
NR
MeO
OMe
OMe
115
130
5
5
Trace
82
4
5
4-MeO–C6H3
47–49
6d
NO2
MeO
2,4-(MeO)2–C6H3
115
115
3
3
148–149
79
MeO
OMe
6e
NO2
OMe
OMe
OMe
MeO
MeO
6
2,4,5-(MeO)3–C6H2
123–124
95
OMe
6f
NO2
(continued on next page)

2372
Y. Leng et al. / Tetrahedron Letters 51 (2010) 2370–2373
Table 3 (continued)
Entry
Ar
T (°C)
t (h)
6
Mp (°C)
Yieldb (%)
HO
OH
7
8
4-HO–C6H4
130
5
NAd
39e
6g
NO2
Me2N
MeO
NMe2
6h
4-(Me2N)–C6H4
130
130
4
3
182–183
132–134
84
82
NO2
OMe
9
4-Methoxynaphthyl
6i
NO2
a
1 (1 mmol), arene (6 mmol), and NaHSO4ÁSiO2 (200 mg, 0.5 mmol of NaHSO4 on SiO2) were used.
Isolated yield.
NR stands for no reaction.
NA (not available), the product is liquid.
39% of 6g and 44% of regioisomer 2-hydroxyphenyl-4-hydroxyphenyl-4-nitrophenylmethane.
b
c
d
e
benzaldehyde, piperonal, vanilline and isovanilline led to lower
turing Program’ (Nos. 2009ZX09103-065, 2009ZX09301-001), Ma-
jor Project of Chinese National Programs for Fundamental Research
and Development (No. 2009CB918404), and National Science
Foundation of China (Nos. 30721005, 90813034, 03772648).
reaction yields and required longer time as well (entries 6–9). In
some cases the reaction did not reach completion even after a pro-
longed reaction time. For example, the reaction of vanilline after
5 h provided the desired product 4h in 44% yield along with 31%
of unreacted aldehyde 1h (entry 8), and reaction of isovanilline
with thiophene afforded 4i in 39% yield along with 27% of unre-
acted aldehyde 1i (entry 9). Notably, triheteroarylmethanes could
also be prepared using this method as trithienylmethane 4j was
afforded in 71% yield (entry 10). Additionally, the reaction of p-
formaldehyde with thiophene afforded dithiophen-2-ylmethane
in 58% yield, but with lower efficacy in term of reaction time and
yield (entry 11).
Supplementary data
Supplementary data (detailed experimental procedures and the
analytical data of all final products) associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2010.02.157.
References and notes
We finally examined the scope of the arenes (Table 3).20 The re-
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uene and 1,3-xylene were used (entries 2 and 3). A reaction of 4-
nitrobenzaldehyde with anisole in the presence of NaHSO4ÁSiO2
proceeded smoothly at 130 °C in good yield (82%), but only a trace
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perature of 115 °C (entry 4). Substrates such as 2,4-dimethoxyben-
zene and 1,2,4-trimethoxybenzene bearing more electron-rich
groups significantly produced the products at a lower temperature
of 115 °C and in a shorter reaction time (compared with substrate
anisole of entry 4) with yields of 79% and 95%, respectively (entries
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normal product and a regioisomer (entry 7). Notably, the naphtha-
lene derivative was also prepared using substrate 1-methoxynaph-
thalene in a good yield (entry 9).
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In summary, a new approach to access multi-substituted triar-
ylmethanes has been developed via a bisarylation of various aryl
aldehydes with electron-rich arenes in the presence of NaHSO4ÁSiO2.
This new approach features high yield, mild reaction conditions, and
environmental friendliness, and proves to be an efficient method for
the synthesis of valuable triarylmethane derivatives.
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Acknowledgements
We are grateful for financial support from National Science &
Technology Major Project ‘Key New Drug Creation and Manufac-

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20. The preparative procedure of 4a is given as a representative example of general
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