Triple condensation of aryl methyl ketones catalyzed by amine and trifluoroacetic acid: Straightforward access to 1,3,5-triarylbenzenes under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2012.03.008

An efficient triple condensation reaction of aryl methyl ketones catalyzed by ethylenediamine and trifluoroacetic acid was reported. A broad scope of 1,3,5-triarylbenzenes was obtained in good to excellent yields. The reaction provides a novel and practical approach to access organic materials of polycyclic aromatic hydrocarbons under mild conditions.

Full text of DOI:10.1016/j.tetlet.2012.03.008

Tetrahedron Letters 53 (2012) 2436–2439
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Triple condensation of aryl methyl ketones catalyzed by amine and
trifluoroacetic acid: straightforward access to 1,3,5-triarylbenzenes
under mild conditions
⇑
Shao-Liang Zhang, Zhao-Feng Xue, Ya-Ru Gao, Shuai Mao, Yong-Qiang Wang
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry & Materials Science, Northwest University,
Xi’an 710069, PR China
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, CAS, Shanghai 200032, 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 triple condensation reaction of aryl methyl ketones catalyzed by ethylenediamine and triflu-
oroacetic acid was reported. A broad scope of 1,3,5-triarylbenzenes was obtained in good to excellent
yields. The reaction provides a novel and practical approach to access organic materials of polycyclic aro-
matic hydrocarbons under mild conditions.
Received 12 December 2011
Revised 15 February 2012
Accepted 2 March 2012
Available online 9 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Amine
Triple condensation
Aryl methyl ketones
1,3,5-Triarylbenzenes
Polycyclic aromatic hydrocarbons
Polycyclic aromatic hydrocarbons (PAHs) have attracted much
attention due to their potential application in organic semiconduc-
tors, nanomaterials, and photovoltaics.1,2 As key building blocks for
the preparation of PAHs, the 1,3,5-triarylbenzenes have also been
used for developing organic light emitting diodes (OLEDs)3 and
synthesis of dendrimers4 and fullerene fragments.5 Traditionally,
1,3,5-triarylbenzenes were synthesized via acid-catalyzed triple
condensation of aryl methyl ketones,6 Suzuki coupling reaction,7
and [2+2+2] cycloaddition of arylacetylenes(arylethynes)8 (Scheme
1). It is well known that ketones and aldehydes can be activated
through iminium or enamine with amines. Therefore, we envis-
aged that amines could catalyze the triple condensation of aryl
methyl ketones to accomplish 1,3,5-triarylbenzenes. In 1936, Clapp
and Morton realized the cyclotrimerization of three aryl methyl ke-
tones using catalytic amount of aniline hydrochloride in aniline as
the solvent to form the products in low yields (18–23%).9 To our
knowledge, a general and efficient process has not been reported
for amine/acid-catalyzed triple condensation of aryl methyl ke-
tones. Herein, we wish to report, for the first time, an efficient tri-
ple condensation reaction catalyzed by ethylenediamine and
trifluoroacetic acid (TFA), which is sustainable for aryl methyl ke-
tones of various electronic properties.
Initially, we investigated primary, secondary, and tertiary
amines for their ability to promote the triple condensation reaction
using acetophenone as a substrate and trifluoroacetic acid (TFA) as
an additive at reflux in benzene (Table 1). The reaction was found
to proceed in low yield (34%) with aniline (entry 1). There was no
remarkable improvement in yield when increasing aniline loading
or using substituted anilines with electron-donating group or elec-
tron-withdrawing group (entries 2 and 3). To our delight, when
ethylenediamine was used as catalyst, acetophenone was con-
verted into the desired product in good yield (70%) (entry 4), and
o-phenylenediamine as catalyst to give moderate yield (57%) (en-
try 5). In contrast, n-butylamine, piperidine, diisopropylamine,
and triethylamine were almost inactive for the triple condensation
reaction (entries 6–9). Notably, the desired 1,3,5-triphenylbenzene
was not observed in the absence of ethenediamine or TFA (entries
10 and 11). Then using ethenediamine as catalyst and TFA as addi-
tive, a range of solvents were examined, polar solvents were
Ar BY2
+
Suzuki
coupling
Ar
Ar
X
O
traditional
Ar
this report
amine / acid
Ar
[2+2+2]
cycloaddition
Ar
Ar
R
⇑
Corresponding author.
E-mail address: wangyq@nwu.edu.cn (Y.-Q. Wang).
Scheme 1. Synthesis of 1,3,5-triarylbenzene.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.008

S.-L. Zhang et al. / Tetrahedron Letters 53 (2012) 2436–2439
2437
Table 1
Optimizing reaction conditionsa
O
amine, additive
+
3H2O
solvent, reflux
Entry
Amine
Additive
Solvent
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16d
17
18
19
20
21
22
23
24
25
Aniline
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
—
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
AcOH
Formic acid
Oxalic acid
Benzoic acid
PTSA
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Toluene
CH3OH
C2H5OH
CH3CN
CH3NO2
THF
EtOAc
DMF
DMSO
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
80
80
80
80
80
80
80
80
80
80
80
110
64
78
81
101
66
34c
42
35
70
57
<5
4-Methoxyaniline
4-Nitroaniline
Ethylenediamine
o-Phenylenediamine
n-Butylamine
Piperidine
Diisopropylamine
Et3N
<5
<5
NR
NR
NR
19
Trace
<5
15
87
NR
NR
NR
NR
29
NR
9
—
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
Ethylenediamine
77
152
189
101
101
101
101
101
26
42
TFA: trifluoroacetic acid; PTSA: p-toluenesulfonic acid.
a
Reaction conditions: 1a (1.5 mmol), amine (0.3 mmol), and additive (0.6 mmol) in solvent (1.5 mL) reacted for 60 h at corresponding temperature.
Isolated yield.
Aniline increased to 0.6 mmol, the yield is 35%.
Reacted for 48 h.
b
c
d
unsuitable for the condensation reaction, while CH3NO2 gave the
best yield (87%) (entries 12–20). For additive, weaker acids, such
as acetic acid, formic acid, oxalic acid, and benzoic acid, were not
efficient to promote the condensation reaction, while p-toluenesul-
fonic acid (PTSA) gave moderate yield (42%) (entries 21–25).
With the optimal reaction conditions in hand, we then exam-
ined the substrates scope, and the results are summarized in Table
2. Various substituted aromatic methyl ketones were examined.
Both electron-withdrawing and electron-donating groups on the
aromatic ring were tolerated, yielding the desired products in
moderate to high yields (60–93%) (entries 1–10). 2-Furyl and
2-thiophene methyl ketones gave the corresponding products in
46% and 90% yields, respectively, (entries 11 and 12). Furthermore,
acetylnaphthalenes were found to serve as suitable substrates for
the triple condensation reaction and afforded good yields (entries
13 and 14).
A plausible mechanism for ethylenediamine catalyzed triple
condensation of aryl methyl ketones for preparation of 1,3,5-tria-
rylbenzenes is depicted in Scheme 2. Aryl methyl ketones react
with ethylenediamine and TFA to form intermediates iminium
(3). Intramolecular addition affords b-amino iminium (4) which re-
leases an amine, followed by tautomerization to give conjugated
diene (6). Diene (6) condenses with aryl methyl ketone to give
iminium (7), which is subjected to similar intramolecular addition,
elimination and tautomerization to obtain conjugated triene (10),
Table 2
Scope of ethylenediamine and TFA catalyzed triple condensation of aryl methyl
ketonesa
Ar
O
Ethylenediamine, TFA
CH3NO2, reflux
+
3H2O
Ar
Ar
Ar
1
2
Entry
Ar
Ph (2a)
4-FC6H4 (2b)
4-ClC6H4 (2c)
4-BrC6H4 (2d)
4-IC6H4 (2e)
4-MeC6H4 (2f)
4-AllylOC6H4 (2g)
2-ClC6H4 (2h)
2-BrC6H4 (2i)
3-BrC6H4 (2j)
2-Furyl (2k)
2-Thiophene (2l)
1-Naphthalene (2m)
2-Naphthalene (2n)
2-PhC6H4 (2o)
Time (h)
48
Mp (lit.c) (°C)
Yieldb (%)
87
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
171–173 (170–172)
241–243 (238–240)
246–248 (246–248)
260–262 (260–261)
264–265 (262–263)
177–178 (179–180)
83–84 (83–85)
161–163 (162–164)
161–163 (159–160)
170–171 (167–168)
126–128 (125–126)
158–159 (156–158)
156–157 (155–156)
222–223 (222–223)
211–212 (—)
36
36
48
48
36
36
36
48
36
24
24
48
48
4d
92
90
69
60
92
83
72
61
93
46
90
72
66
90
a
Reaction conditions:
1 (1.5 mmol), ethylenediamine (0.3 mmol), and TFA
(0.6 mmol) in CH3NO2 (1.5 mL) at 101 °C.
b
then 6p-electrocyclization and elimination of ethylenediamine
Isolated yield.
Mp in parentheses was reported in literature.
c
catalyst to produce 1,3,5-triarylbenzene.

2438
S.-L. Zhang et al. / Tetrahedron Letters 53 (2012) 2436–2439
H2O
O
H2N
H2N
H
HN
NH
Ar
NH
Ar
HN
NH
NH
Ar
1
Ar
Ar
Ar
Ar
Ar
Ar
Ar
3
5
4
+
6
TFA
H2N
NH2
H2N
1
H
NH2
NH
H
N
H2N
Ar
Ar
Ar
N
Ar
Ar
6π -electro
H
-cyclization
NH
NH
NH
HN
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
Ar
2
11
8
Ar
9
10
7
Scheme 2. Plausible mechanism for primary amine catalyzed triple condensation of aryl methyl ketones.
O
FeCl3
CH3NO2 / CH2Cl2
Ethylenediamine, TFA
CH3NO2, reflux
4 days, 90%
rt, 1 h, 86%
1o
2o
Scheme 3. Preparation of hexabenzocoronene (HBC).
HBC
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The present reaction is potentially useful in the synthesis of or-
ganic materials. For example, in the presence of ethylenediamine
and TFA, 2-phenyl-acetophenone (1o) was refluxed to give the cor-
responding triple condensation product (2o) in excellent yield (en-
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2 and Scheme 3). Compound 2o was readily
cyclodehydrogenated with FeCl3 in a mixture of dichlorometh-
ane-nitromethane to obtain hexabenzocoronene (HBC),10c which
has been the focus of considerable research for materials chemis-
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In summary, we have developed the general and efficient triple
condensation reaction of aryl methyl ketones catalyzed by ethy-
lenediamine and trifluoroacetic acid. The reaction proceeds in a
broad range of substrates to afford 1,3,5-triarylbenzenes under
mild conditions in good yields. A plausible mechanism was pro-
posed. The reported method represents a novel and practical ap-
proach to access organic materials of polycyclic aromatic
hydrocarbons. Further investigations on the application of the con-
densation reaction are in progress.
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Acknowledgments
This research was supported by National Natural Science Foun-
dation of China (NSFC-20872183, 20972126), the Program for New
Century Excellent Talents in University of the Ministry of Educa-
tion China (NCET-10-0937), and Education Department of Shaanxi
Provincial Government (09JK776).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.03.008.
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