Metal-free synthesis of 1,3,5-trisubstituted benzenes by the cyclotrimerization of enaminones or alkynes in water

Article abstract of DOI:10.1039/c4ra00475b

The cyclotrimerization reactions of enaminones and electron deficient terminal alkynes have been efficiently performed in water in the presence of only a small amount of lactic acid. The reactions led to the green synthesis of a variety of 1,3,5-triacylbenzenes without using any metal as catalyst. Brief investigation on different elaboration of the triacylbenzene product demonstrated the versatile synthetic application of these 1,3,5-triacylbenzenes. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra00475b

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Metal-free synthesis of 1,3,5-trisubstituted
benzenes by the cyclotrimerization of enaminones
Cite this: RSC Adv., 2014, 4, 20499
or alkynes in water†
ab
a
a
ab
*
*
Yunfang Lin, Kaikai Hu and Yunyun Liu
Jie-Ping Wan,
The cyclotrimerization reactions of enaminones and electron deficient terminal alkynes have been
efficiently performed in water in the presence of only a small amount of lactic acid. The reactions led to
the green synthesis of a variety of 1,3,5-triacylbenzenes without using any metal as catalyst. Brief
investigation on different elaboration of the triacylbenzene product demonstrated the versatile synthetic
application of these 1,3,5-triacylbenzenes.
Received 17th January 2014
Accepted 12th March 2014
DOI: 10.1039/c4ra00475b
www.rsc.org/advances
products have restricted these methods from industrial appli-
cations. Accordingly, alternative approaches without relying on
Introduction
transition metal catalyst have attracted chemists' interest.
During the past decades, several different metal-free protocols
have been successfully achieved for providing benzene prod-
ucts. For instance, the acid-catalyzed head-to-tail trimerization
of cyclic ketones,13 thermal induced or organocatalytic trimeri-
zation of alkynyl ketones14 are typical protocols of the category.
Recently, following their interesting work on trimerization
reactions of alkynyl ketones,14f Hiaki and coworkers15 have
investigated the reaction mechanism and discovered that eno-
late 2 was the key intermediate in the trimerization of alkynyl
ketone 1 to give 1,3,5-tribenzoylbenzene 3a under the condi-
The construction of benzene rings is a central issue in modern
organic synthesis due to the prevalent presence of benzene core
in numerous natural products, medicines, agrochemicals, dyes
and functional organic materials. In this regard, benzene
synthesis has been viewed as a fundamental task for the organic
community. Among the presently known approaches towards
benzene synthesis, the transition metal-catalyzed [2 + 2 + 2]
cycloaddition reactions of alkynes have been regarded as the
most classical one for allowing efficient synthesis of benzenes
and analogous aryl derivatives.1 By employing this tactic,
benzene derivatives with broad structural diversity and dense
substitutions could be readily obtained.2,3 Besides this domi-
nant method, other transition metal-catalyzed protocols,
including the oxidative cyclization of olens,4 annulation reac-
tion of cyclobutanols with alkynes,5 intramolecular annulation
of b-iodo-b-silylstyrenes with alkynes,6 methylene transfer
reactions,7 aromatisation of enediynes,8 the coupling reactions
of alkynes and 2-bromoacrylates,9 allylic alkylation of dike-
toester–dioxinones/aromatisation,10 copper,11 titanium or other
metals-catalyzed12 [3 + 3] cycloaddition, etc. have also been
reported as practical protocols for providing benzenes pos-
sessing different functional substructures, respectively.
ꢀ
tions of 150 C and high pressurized hot water. In addition, 4-
methoxy-3-buten-2-one 4 has also been found to similarly tri-
merize to give corresponding benzene derivative 3n (Scheme 1).
These transition-catalyzed methodologies are useful for
synthesizing benzenes containing enriched functionalities, on
the other hand, however, the high cost of transition metal
catalysts as well as the frequently occurred regioisomeric side
aCollege of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P.R. China
bKey laboratory of functional small organic molecules, ministry of education, Jiangxi
Normal University, Nanchang 330022, P.R. China. E-mail: wanjieping@gmail.com;
chemliuyunyun@gmail.com; Fax: +86 791 88120380; Tel: +86 791 88120380
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
of all products. See DOI: 10.1039/c4ra00475b
Scheme 1 Different methods for synthesizing 1,3,5-triacylbenzenes.
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Table
1
Optimizing the reaction conditions of enaminone
Notably, as the aza-analogs of 4, enaminones of type 5 had also
been found to be applicable for providing 1,3,5-triacylbenzenes
3 via cyclotrimerization, usually by performing reactions in
reuxing acetic acid, sometimes with additives such as pyri-
dine.16 Compared with similar alkynyl ketones 1, enaminones
are advantageous for their features of easier availability, better
stability and generally better regioselectivity when used for the
synthesis of benzenes 3. However, besides those few examples
describing the trimerization of enaminones in AcOH, it is
amazing that rather scarce further efforts have been devoted to
improve this methodology, especially by using green media
such as water to alternate AcOH.
On the other hand, the 1,3,5-triacylbenzenes of type 3 are
known to be highly useful compounds in organic chemistry. For
example, 1,3,5-triacylbenzenes are important hosts in organic
complex molecules,17 they have also been employed as major
precursors in the synthesis of dendrimers of interesting func-
tionality18 as well as the highly branched polymers.19 In addi-
tion, 1,3,5-triacetylbenzenes were the central starting materials
for the photochemical synthesis of C3 symmetrical
cyclophanes.20
Considering the fact that the cyclotrimerization of alkynyl
ketones with transition metal catalysis or under harsh condi-
tions constituted the dominant approaches for synthesizing 3 at
present, it is highly desirable to develop alternative protocols
that overcome the challenges in alkynyl ketones-based
synthesis such as troublesome preparation, short shelf life of
alkynyl ketone substrates 1. In contrast, enaminones of type 5
are easy to prepare from simple aryl/alkyl ketones,21 consider-
ably more stable than terminal alkynes 1. More importantly, no
isomeric side products occur when using enaminones for the
synthesis of target 1,3,5-triacylbenzenes. Therefore, following
our ongoing interest in enaminone-based synthesis,22 we report
herein an authentically simple and green synthesis of 1,3,5-
triacylbenzenes via the trimerization of enaminones in water/
lactic acid (LA) system. This method is attractive not only for
embracing the aforementioned advantages of enaminones, but
also for its signicance in providing a remarkably cleaner
catalytic system by simply carrying out reactions in water23 in
the presence of a small amount of bio-based green chemical
LA24 (Scheme 1).
trimerizationa
Entry
Additive
Solvent
T (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
LA
LA
LA
LA
Toluene
DMSO
Ethyl lactate
H2O
H2O
H2O
H2O
H2O
H2O
H2O
100
100
100
100
100
100
100
100
100
100
110
90
33
26
18
77
0
21
30
Trace
59
74
77
80
64
No
AcOH
p-TSA
L-proline
LA
LA
LA
9c
10c
11
12
13
H2O
H2O
H2O
LA
LA
80
a
General conditions: 0.3 mmol 5a, 0.4 mmol additive, 2 ml solvent, 12
h. b Yields of isolated product. 0.3 mmol LA was used in entry 9, and
c
0.5 mmol LA was used in entry 10.
reaction at 90 ꢀC was discovered to give slightly better yield
(entries 11–13, Table 1). According to the fact that the entry
utilizing 0.4 mmol LA gave evidently better yield than equivalent
entry using 0.3 mmol LA, it can be tentatively concluded that LA
acted not only as acid catalyst, but also as additive to facilitate
the reaction by improving the solubility of substrates in water.
Based on the exploration of reaction conditions, we subse-
quently investigated the application scope by employing
different enaminones under the optimal conditions. Different
triacylbenzenes synthesized by this water mediated system were
listed in Scheme 2. According to the results from this section,
the protocol was generally applicable for synthesizing a broad
array of triacylbenzenes with good to excellent yields. Enami-
nones containing both aroyl, heteroaroyl and alkoyl backbones
could be transformed solely to corresponding 1,3,5-trisubsti-
tuted benzenes. No evident impact of functional groups was
observed in the present examples probably because that the
yields of products were determined simultaneously by elec-
tronic/steric properties of functional groups as well as solubility
of the substrates in water/LA system. However, it is clear that the
alkoyl-based enaminones provided corresponding 1,3,5-tri-
alkoylbenzenes in slightly lower yields than their aroyl equiva-
lents. Under the standard conditions, the cross trimerization
reaction has also been investigated. When two different enam-
inones 5b and 5c were subjected simultaneously for reaction,
the mixed products 3cb and 3bc, together with the homo-tri-
merized products 3b and 3c have all been isolated (Scheme 3).
Encouraged by the results provided by enaminone-based
trimerization, we then attempted to utilize alkynes directly for
Results and discussion
At the beginning, enaminone 5a was subjected to cyclo-
trimerization in different media such as toluene, DMSO, ethyl
lactate and water in the presence of LA additives. Aer being
heated for 12 h at 100 ꢀC (TLC), interestingly, the trimerized
product 3a was obtained in remarkably higher yield in the entry
using water (entries 1–4, Table 1), while a control reaction in the
absence of LA gave no desired product, which suggested the
importance of LA for promoting the reaction (entry 5, Table 1).
Furthermore, low yields of corresponding products have been
observed in the entries employing other acid species such as
AcOH, p-TSA or L-proline (entries 6–8, Table 1). On the other
hand, increasing and decreasing the amount of LA were both
unfavorable (entries 9 and 10, Table 1). Finally, performing the
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Scheme 2 Synthesis of various triaroylbenzenes. All yields are reported based on isolated products, and the reaction time is 16 h for 3e, 3l, 12 h
for all other products.
medium to DMF was found to be capable of achieving the
expected trimerization and affording corresponding 1,3,5-ben-
zenetricarboxylates 7 with good yields (Scheme 4). Based on the
literature survey, presently available methods allowing for the
trimerization of alkynes 6 were dominantly performed with
Scheme 3 Cross-trimerization of enaminones.
similar benzene synthesis in the presence of additional
secondary amine which was expected to activate the alkynes by
forming the enamino ester intermediates 8. In the initial
endeavor of performing the reaction in standard water/LA
system together with secondary amine piperazine, no target
Scheme
terminal alkynes.
4 Metal-free cyclotrimerization of electron deficient
benzenes of type 7 were observed. However, changing the
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transition metal catalysis,3a,25 therefore, realizing identical
transformation under transition-metal free process was of great
signicance. However, attempts on running the trimerization of
unactivated terminal alkynes such as phenylacetylene under
identical conditions was not successful.
Experimental section
General procedure for the synthesis of 1,3,5-triacylbenzenes 3
Enaminone(s) 5 (0.3 mmol)/(0.2 + 0.2 mmol for cross trimeri-
zation experiment) and LA (0.4 mmol) were charged in a 25 ml
round bottom ask equipped with stirring ꢀbar. Water (2 ml) was
added and the mixture was stirred at 90 C for required time
(Scheme 2). Upon completion of the reaction, ethanol was
added dropwise to the homogeneous mixture until complete
dissolvation of the whole mixture. The resulting solution was
then allowed to cool down to room temperature, followed by
further cooling with ice bath until the complete precipitation of
solid. The solid was then collected via ltration and washed
with a small amount of water, dried to provide pure products.
For gummy and liquid products (3g, 3h, 3i and 3o) and the entry
of cross trimerization experiment, 5 ml water was added to the
reaction vessel upon completion of reaction, the resulting
mixture was extracted with EtOAc (3 ꢁ 8 ml), the combined
organic layer was dried over anhydrous Na2SO4. Aer ltration
and removing the solvent, the residue was subjected to silica
column chromatography to give target products by using eluent
of mixed petroleum ether and ethyl acetate (VPET : VEA ¼ 3 : 1).
Benzene-1,3,5-triyltris(phenylmethanone) (3a).16c Yellow
solid; mp: 118–120 ꢀC [lit. 119–120 ꢀC]; 1H NMR (400 MHz,
CDCl3) d ¼ 8.40 (s, 3H), 7.85 (d, 6H, J ¼ 7.6 Hz), 7.63 (t, 3H, J ¼
7.2 Hz), 7.52 (d, 6H, J ¼ 7.2 Hz); 13C NMR (100 MHz, CDCl3) d ¼
194.9, 138.2, 136.5, 134.1, 133.3, 130.1, 128.7; IR (KBr, cmꢂ1):
3088, 3034, 1721, 1224.
Benzene-1,3,5-triyltris((4-methoxyphenyl)methanone) (3b).16a
Pale yellow solid; mp: 186–188 ꢀC [lit. 177 ꢀC]; 1H NMR (400 MHz,
CDCl3) d ¼ 8.14 (s, 3H), 7.72 (d, 6H, J ¼ 8.0 Hz), 6.84 (d, 6H, J ¼ 8.8
Hz), 3.75 (s, 9H); 13C NMR (100 MHz, CDCl3) d ¼ 193.4, 163.3,
138.2, 132.7, 132.1, 128.7, 113.4, 55.1; IR (KBr, cmꢂ1): 3054, 2956,
1676, 1609.
Benzene-1,3,5-triyltris(p-tolylmethanone) (3c).16a Pale yellow
solid; mp: 151–153 ꢀC [lit. 156 ꢀC]; 1H NMR (400 MHz, CDCl3) d
¼ 8.26 (s, 3H), 7.68 (d, 6H, J ¼ 7.6 Hz), 7.23 (d, 6H, J ¼ 7.6 Hz),
2.37 (s, 9H); 13C NMR (100 MHz, CDCl3) d ¼ 193.7, 143.2, 137.4,
Following the examination on reaction scope of this
water-mediated methodology, the application for these
1,3,5-triacyl benzene products for synthesizing different
derivatives was briey investigated. Several examples on
post elaboration of product 3n were outlined in Scheme 4.
Under proper conditions, employing N,N-dimethylforma-
mide dimethyl acetal (DMF-DMA) and benzaldehyde as
reaction partners provided C3 symmetrical enaminone 9
and chalcone 10, respectively. The reactions with Wittig
reagent 11, on the other hand, led to the production of
mixed mono- and double olenated products 12a and 12b
(Scheme 5). These results were able to partially demon-
strated usefulness of the 1,3,5-triacylbenzene products for
the synthesis of useful chemicals.
In conclusion, we have established a green catalytic
method involving water/LA as media for efficient synthesis
1,3,5-triacylbenzenes. This method represents the rst
example of successful water-mediated cyclotrimerization
synthesis of 1,3,5-triacylbenzenes starting from enaminones.
Moreover, this transformation is also one of the few organic
reactions that can be promoted or catalyzed by the nontoxic
bio-based solvents.24 More notably, the simplicity of the
present catalytic conditions, the excellent conversion rate as
well as specic regioselectivity of these reactions allowed
for the purication of most products via chromatography-
free operation (except for gummy and liquid products).
Therefore, as a complement to those known methodologies,
including transition metal-catalyzed alkyne trimerization
and reuxing AcOH/additive promoted enaminone trimeri-
zation, such a green and facile method will reasonably
be attractive for chemists in the synthesis of 1,3,5-
triacylbenzenes.
Scheme 5 Synthesis of different C3 symmetrical and unsymmetrical benzene derivatives.
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132.8, 132.7, 129.3, 128.3, 20.7; IR (KBr, cmꢂ1): 3060, 2956, 1645, DMSO-d3) d ¼ 186.4, 142.4, 138.6, 137.1, 136.9, 132.6, 129.7; IR
1602.
(KBr, cmꢂ1): 3058, 1644.
Benzene-1,3,5-triyltris((4(triuoromethyl)phenyl)methanone)
Benzene-1,3,5-triyltris(naphthalen-2-ylmethanone) (3m).16a
(3d). Dark red solid; mp: 127–129 ꢀC; 1H NMR (400 MHz, CDCl3) Pale yellow solid; mp: 209–210 ꢀC [lit. 225 ꢀC]; 1H NMR (400
d ¼ 8.34 (s, 3H), 7.86 (d, 6H, J ¼ 8.0 Hz), 7.72 (d, 6H, J ¼ 8.0 Hz); MHz, CDCl3) d ¼ 8.51 (s, 3H), 8.18–8.15 (m, 3H), 7.94 (d, 3H, J ¼
13C NMR (100 MHz, CDCl3) d ¼ 192.8, 138.7, 137.3, 133.9, 129.7, 8.0 Hz), 7.86–7.84 (m, 3H), 7.54–7.49 (m, 9H), 7.38 (t, 3H, J ¼ 8.0
125.3 (d, 1C, JC–F ¼ 3.7 Hz), 124.3, 121.6; IR (KBr, cmꢂ1): 3017, Hz); 13C NMR (150 MHz, CDCl3) d ¼ 198.4, 142.0, 138.1, 136.5,
1660, 1599. ESI-HRMS calcd for C30H16F9O3 [M + H]+: 595.0956; 135.2, 133.5, 131.6, 131.6, 131.3, 130.4, 129.4, 128.1, 126.9; IR
found: 595.0947.
(KBr, cmꢂ1): 3047, 1651, 1608.
Benzene-1,3,5-triyltris((4-nitrophenyl)methanone)
(3e).26
1,3,5-Acetylbenzene (3n).16c White solid; mp: 167–168 ꢀC [lit.
Pale yellow solid; mp: 196–198 ꢀC [lit. 196–198 ꢀC]; 1H NMR (400 154–155 ꢀC]; 1H NMR (400 MHz, CDCl3) d ¼ 8.61 (s, 3H), 2.63 (s,
MHz, DMSO-d6) d ¼ 8.41 (d, 6H, J ¼ 8.8 Hz), 8.35 (s, 3H), 8.09 (d, 9H); 13C NMR (100 MHz, CDCl3) d ¼ 196.7, 137.9, 131.7, 26.8; IR
6H, J ¼ 8.4 Hz); 13C NMR (100 MHz, DMSO-d6) d ¼ 192.9, 149.9, (KBr, cmꢂ1): 3087, 1689, 1590.
141.2, 136.8, 134.4, 131.1, 123.8; IR (KBr, cmꢂ1): 3086, 1656,
1526, 1337.
1-[3,5-Bis-(3-methyl-butyvyl)-phenyl]-3-methyl-butan-1-one
(3o). Red liquid; 1H NMR (400 MHz, CDCl3) d ¼ 8.58 (s, 3H), 2.85
Benzene-1,3,5-triyltris((4-chlorophenyl)methanone) (3f).16b (d, 6H, J ¼ 7.2 Hz), 2.27–2.20 (m, 3H), 0.93 (d, 18H, J ¼ 6.4 Hz);
White solid; mp: 161–163 C [lit. 180 C]; H NMR (400 MHz, 13C NMR (150 MHz, CDCl3) d ¼ 201.5, 141.0, 133.8, 50.2, 27.5,
1
ꢀ
ꢀ
CDCl3) d ¼ 8.34 (s, 3H), 7.79 (d, 6H, J ¼ 8.4 Hz), 7.50 (d, 6H, J ¼ 25.5; IR (KBr, cmꢂ1): 3015, 1689, 1593. ESI-HRMS calcd for
8.0 Hz); 13C NMR (100 MHz, CDCl3) d ¼ 193.4, 140.1, 138.1,
C
21H31O3 [M + H]+: 331.2273; found: 331.2268.
134.6, 133.9, 131.4, 129.1; IR (KBr, cmꢂ1): 3017, 1668, 1600.
(5-(4-Methoxybenzoyl)-1,3-phenylene)bis(p-tolylmethanone)
1
Benzene-1,3,5-triyltris((3-methoxyphenyl)methanone) (3g).17b (3cb). Yellow gummy; H NMR (400 MHz, CDCl3) d ¼ 8.32 (d,
1
Pale yellow gummy compound; H NMR (400 MHz, CDCl3) d ¼ 3H, J ¼ 5.6 Hz), 7.85 (d, 2H, J ¼ 8.0 Hz), 7.76 (d, 4H, J ¼ 6.8 Hz),
8.32 (s, 3H), 7.33–7.27 (m, 9H), 7.09 (d, 3H, J ¼ 8.0 Hz), 3.79 (s, 7.30 (d, 4H, J ¼ 7.6 Hz), 6.98 (d, 2H, J ¼ 8.0 Hz), 3.89 (s, 3H), 2.44
9H); 13C NMR (100 MHz, CDCl3) d ¼ 194.7, 159.9, 138.2, 137.7, (s, 6H); 13C NMR (150 MHz, CDCl3) d ¼ 195.0, 193.9, 163.9,
134.1, 129.6, 122.9, 119.7, 114.3, 55.5; IR (KBr, cmꢂ1): 3019, 2938, 144.2, 138.8, 138.4, 133.9, 133.5, 132.6, 130.4, 130.3, 129.3,
1663.
129.2, 114.0, 55.4, 21.6; IR (KBr, cmꢂ1): 3010, 1720, 1689; HRMS
Benzene-1,3,5-triyltris((2-bromophenyl)methanone) (3h). calcd for C30H25O4 [M + H]+: 449.1753; found: 449.1740.
Yellow gummy solid; 1H NMR (400 MHz, CDCl3) d ¼ 8.31 (s, 3H),
(5-(4-Methylbenzoyl)-1,3-phenylene)bis((4-methoxyphenyl)
7.57 (d, 3H, J ¼ 8.0 Hz), 7.37–7.30 (m, 9H); 13C NMR (100 MHz, methanone) (3bc). White solid; mp: 175–176 C; H NMR (400
CDCl3) d ¼ 194.1, 139.2, 137.5, 135.3, 133.5, 132.0, 129.4, 127.6, MHz, CDCl3) d ¼ 8.30 (d, 3H, J ¼ 4.0 Hz), 7.85 (d, 4H, J ¼ 8.0 Hz),
119.7; IR (KBr, cmꢂ1): 3017, 1667, 1601. ESI-HRMS calcd for 7.75 (d, 2H, J ¼ 8.0 Hz), 7.30 (d, 2H, J ¼ 8.0 Hz), 6.98 (d, 4H, J ¼
1
ꢀ
C
27H16Br3O3 [M + H]+: 624.8650; found: 624.8671.
8.0 Hz), 3.89 (s, 6H), 2.44 (s, 3H); 13C NMR (150 MHz, CDCl3) d ¼
Benzene-1,3,5-triyltris((2-hydroxyphenyl)methanone)
(3i). 194.9, 193.8, 163.8, 144.2, 138.8, 138.4, 133.9, 133.4, 132.7,
Red gummy solid; 1H NMR (400 MHz, CDCl3) d ¼ 8.22–8.20 (m, 132.6, 130.4, 129.3, 129.2, 114.0, 55.4, 21.7; IR (KBr, cmꢂ1): 3052,
3H), 7.86 (d, 3H, J ¼ 7.2 Hz), 7.69–7.65 (m, 3H), 7.46–7.38 (m, 1737, 1695; HRMS calcd for C30H25O5 [M + H]+: 465.1702; found:
6H), 6.34 (d, 3H, J ¼ 6.6 Hz); 13C NMR (100 MHz, CDCl3) d ¼ 465.1718.
177.6, 156.5, 155.3, 133.7, 125.8, 125.2, 124.9, 118.2, 113.0; IR
(KBr, cmꢂ1): 3078, 1636, 1598. ESI-HRMS calcd for C27H19O6 [M Synthesis of 1,3,5-benzenetricarboxylates 7
+ H]+: 439.1182; found: 439.1192.
Alkyl propiolates 6 (0.3 mmol), piperazine (0.12 mol) and LA (0.4
mmol) were charged in a 25 ml round bottom ask equipped
with stirring bar. 2 ml DMF was added and the mixture and was
Benzene-1,3,5-triyltris(2-hydroxy-4-methoxyphenyl)methanone
(3j). Red solid; mp: 126–127 C; H NMR (400 MHz, CDCl3) d ¼
1
ꢀ
8.12 (d, 3H, J ¼ 8.0 Hz), 7.78 (d, 3H, J ¼ 6.0 Hz), 6.97 (d, 3H, J ¼ 9.2
Hz), 6.84 (s, 3H), 6.28 (d, 3H, J ¼ 6.0 Hz), 3.90 (s, 9H); 13C NMR
(100 MHz, CDCl3) d ¼ 177.0, 164.1, 158.3, 154.8, 127.2, 118.8,
114.5, 112.9, 100.4, 55.8; IR (KBr, cmꢂ1): 3066, 1632, 1597. ESI-
HRMS calcd for C30H25O9 [M + H]+: 529.1499; found: 529.1507.
Benzene-1,3,5-triyltris((3,4-dichlorophenyl)methanone) (3k).
Pale yellow solid; mp: 189–191 ꢀC; 1H NMR (400 MHz, CDCl3) d
¼ 8.26 (s, 3H), 7.86 (d, 3H, J ¼ 1.6 Hz), 7.56 (t, 6H, J ¼ 3.6 Hz);
13C NMR (150 MHz, CDCl3) d ¼ 194.8, 141.1, 140.5, 138.4, 136.7,
136.5, 134.5, 133.7, 131.7; IR (KBr, cmꢂ1): 3015, 1669, 1607. ESI-
HRMS calcd for C27H13Cl6O3 [M + H]+: 594.8996; found:
594.8987.
stirred at 90 ꢀC for 12 h (TLC). Aer completion of reactions, the
mixture was cooled to room temperature, distilled water was
added dropwise until the solid precipitated completely. The
solid was collected via ltration and washed with a small
amount of water, then dried to give pure products.
Trimethyl benzene-1,3,5-tricarboxylate (7a)27
White solid; mp: 126–129 ꢀC [lit. 144–145 ꢀC]; 1H NMR (400
MHz, CDCl3) d ¼ 8.85 (s, 3H), 3.99 (s, 9H); 13C NMR (150 MHz,
CDCl3) d ¼ 167.8, 137.2, 133.8, 55.3; IR (KBr, cmꢂ1): 3099, 2993,
1713.
Benzene-1,3,5-triyltri(thiophen-2-ylmethanoe) (3l).16c Pale
yellow solid; mp: 200–201 ꢀC [lit. 203–204 ꢀC]; 1H NMR (400
Triethyl benzene-1,3,5-tricarboxylate (7b)26
1
MHz, DMSO-d6) d ¼ 8.42 (s, 3H), 8.20 (d, 3H, J ¼ 4.8 Hz), 7.91 (d, Pale yellow power; mp: 125–126 ꢀC [lit. 127–129 C]; H NMR
ꢀ
3H, J ¼ 3.6 Hz), 7.33 (t, 3H, J ¼ 4.0 Hz); 13C NMR (100 MHz, (400 MHz, CDCl3) d ¼ 8.78 (s, 3H), 4.40–4.34 (m, 6H), 1.36 (t, 9H,
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J ¼ 7.2 Hz); 13C NMR (150 MHz, CDCl3) d ¼ 167.5, 136.8, 134.1, 4H) 2.66 (s, 3H), 2.62 (s, 6H) 1.34 (t, 6H, J ¼ 7.2 Hz); 13C NMR
64.3, 17.1; IR (KBr, cmꢂ1): 3099, 2994, 1715, 1240.
(100 MHz, CDCl3) d ¼ 197.3, 166.4, 154.0, 143.3, 137.6, 128.5,
126.5, 118.7, 60. 1, 26.7, 18.0, 14.3; IR (KBr, cmꢂ1): 3038, 2993,
1711. ESI-HRMS calcd for C20H25O5 [M + H]+: 345.1702; found:
345.1698.
Synthesis of C3 symmetrical enaminone 9
1,3,5-Acetylbenzene 3n (0.9 mmol) was charged in a 10 ml round
bottom ask equipped with stirring bar. DMF-DMA (1 ml) was
added and the mixture was reuxed for 12 h (TLC). Aer cooling
down to room temperature, water (5 ml) was added to the
mixture and the resulting residue was extracted with ethyl
acetate (3 ꢁ 8 ml). The organic layers were combined and dried
over anhydrous Na2SO4. Aer ltering and removing the
solvent, the corresponding product 9 was obtained by subject-
ing the residue to silica gel column chromatography using
EtOH as eluent.
3-(3,5-Diacetyl-phenyl)-but-2-enoic acid ethyl ester (12b).
1
Red liquid; H NMR (400 MHz, CDCl3) d ¼ 8.41 (t, 1H, J ¼ 1.6
Hz), 8.16 (d, 2H, J ¼ 1.6 Hz), 6.13 (d, 1H, J ¼ 1.2 Hz), 4.20–4.14
(m, 2H), 2.61 (s, 6H), 2.55 (s, 3H), 1.26 (t, 3H, J ¼ 7.2 Hz); 13C
NMR (100 MHz, CDCl3) d ¼ 197.1, 166.5, 153.4, 143.5, 137.8,
130.1, 128.3, 119.2, 60.2, 26.8, 18.0, 14.3; IR (KBr, cmꢂ1): 3035,
2997, 1714. ESI-HRMS calcd for C16H19O4 [M + H]+: 275.1283;
found: 275.1283.
1-[3,4-Bis-(3-dimethylamino-acryloyl)-phenyl]-3-dimethyl
Acknowledgements
1
amino-propenone (9). Yellow solid; mp: 266–268 ꢀC; H NMR
(400 MHz, CDCl3) d ¼ 8.54 (s, 3H), 7.84 (d, 3H, J ¼ 12.0 Hz), 5.87
(d, 3H, J ¼ 12.0 Hz), 3.16 (s, 9H), 2.95 (s, 9H); 13C NMR (150
MHz, CDCl3) d ¼ 190.5, 157.2, 142.9, 131.5, 94.9, 47.8, 40.1; IR
(KBr, cmꢂ1): 1630, 1595, 1539. ESI-HRMS calcd for C21H28N3O3
[M + H]+: 370.2131; found: 370.2128.
This work was nancially supported by NSFC (no. 21102059 and
21202064), a project from the Department of Education of
Jiangxi Province (GJJ13245) as well as NSF of Jiangxi province
(20114BAB213005). The authors also thank Dr Yaqin Liu in the
Department of Chemistry, Zhejiang University for her help in
NMR tests.
Synthesis of C3 symmetrical chalcone 10
1,3,5-Acetylbenzene 3n (0.3 mmol), benzaldehyde (0.9 mmol)
and EtOH (2 ml) were charged in a 25 ml round bottom ask
equipped with stirring bar. NaOH 20% aqueous solution (0.2
ml) was then slowly added. The mixture was stirred at room
temperature for 10 min (TLC). Upon completion, 5 ml water was
added to the mixture and the resulting residue was extracted
with ethyl acetate (3 ꢁ 8 ml). The organic layers were combined
and dried over anhydrous Na2SO4. Aer ltration and removing
the solvent, product 10 was puried by silica gel column chro-
matography with the elution of mixed petroleum ether and
ethyl acetate (VPET : VEA ¼ 5 : 1).
Notes and references
1 For pioneer examples on transition metal-catalyzed [2 + 2 + 2]
benzene synthesis, see: (a) P. E. M. Bertholet, C. R. Hebd.
Seances Acad. Sci., 1866, 63, 515; (b) W. Reppe and
W. J. Sweckendiek, Justus Liebigs Ann. Chem., 1948, 560, 104.
2 For reviews, see: (a) M. Lautens, W. Klute and W. Tam, Chem.
Rev., 1996, 96, 49; (b) S. Saito and Y. Yamamoto, Chem. Rev.,
2000, 100, 2901; (c) D. L. J. Broere and E. Ruijter, Synthesis,
2012, 44, 2639; (d) Y. Shibata and K. Tanaka, Synthesis,
2012, 44, 323.
3 For selected examples on [2 + 2 + 2] cyclotrimerization for
benzene synthesis, see: (a) V. Cadierno, S. E. Garcia-
Garrido and J. Gimeno, J. Am. Chem. Soc., 2006, 128, 15094;
(b) V. Gevorgyan, U. Radhakrishnan, A. Takeda, M. Rubina,
M. Rubin and Y. Yamamoto, J. Org. Chem., 2001, 66, 2835;
(c) J.-S. Cheng and H.-F. Jiang, Eur. J. Org. Chem., 2004,
643; (d) M. R. Shaaban, R. El-Sayed and A. H. M. Elwahy,
Tetrahedron, 2011, 67, 6095; (e) M. Kawatsura,
M. Yamamoto, J. Namioka, K. Kajita, T. Hirakawa and
T. Itoh, Org. Lett., 2011, 13, 1001; (f) Y.-H. Wang,
S.-H. Huang, T.-C. Lin and F.-Y. Tsai, Tetrahedron, 2010, 66,
7136; (g) T. Konno, K. Moriyasu, R. Kinugawa and
T. Ishihara, Org. Biomol. Chem., 2010, 8, 1718; (h)
B. R. Galan and T. Rovis, Angew. Chem., Int. Ed., 2009, 48,
2830; (i) K. Yoshida, I. Morimoto, K. Mitsudo and
H. Tanaka, Tetrahedron, 2008, 64, 5800; (j) K. Murayama,
Y. Sawada, K. Noguchi and K. Tanaka, J. Org. Chem., 2013,
78, 6202; (k) K. Tanaka, H. Hara, G. Nishida and
M. Hirano, Org. Lett., 2007, 9, 1907.
1,3,5-Tris(3-phenylpropenoyl)benzene (10).20 White solid;
mp: 174–175 ꢀC [lit. 179 ꢀC]; 1H NMR (400 MHz, CDCl3) d ¼ 8.86
(s, 3H), 7.94 (d, 3H, J ¼ 15.2 Hz), 7.73–7.71 (m, 6H), 7.67 (d, 3H, J
¼ 15.6 Hz), 7.47–7.44 (m, 9H); 13C NMR (100 MHz, CDCl3) d ¼
189.0, 146.5, 139.1, 134.5, 131.8, 131.1, 129.1, 128.9, 121.1; IR
(KBr, cmꢂ1): 3038, 1642, 1593.
Synthesis of olens 12a and 12b
1,3,5-Acetylbenzene 3n (0.3 mmol) and Witting reagent 11 (0.9
mmol) were charged with DMF (2 ml) in a 25 ml round bottom
ask equipped with stirring bar. The mixture was stirred at 100
ꢀC for 12 h (TLC). Aer cooling down to room temperature,
water (5 ml) was added to the mixture and the resulting residue
was extracted with ethyl acetate (3 ꢁ 8 ml). The organic layers
were combined and dried over anhydrous Na2SO4. Aer ltra-
tion and removing the solvent, the residue was subjected to
silica gel column chromatography with elution of mixed
petroleum ether and ethyl acetate (VPET : VEA ¼ 10 : 1) to provide
12a and 12b.
3-[3-Acetyl-5-(2-ethoxycarbonyl-1-methyl-vinyl)-phenyl]-but-
2-enoic acid ethyl ester (12a). Red liquid; H NMR (400 MHz,
CDCl3) d ¼ 8.02 (s, 2H), 7.72 (s, 1H) 6.18 (s, 2H), 4.27–4.22 (m,
4 (a) K.-I. Tamaso, Y. Hatamoto, S. Sakaguchi, Y. Obora and
Y. Ishii, J. Org. Chem., 2007, 72, 3603; (b) H.-F. Jiang,
Y.-X. Shen and Z.-Y. Wang, Tetrahedron Lett., 2007, 48,
1
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Paper
7542; (c) H.-F. Jiang, Y.-X. Shen and Z.-Y. Wang, Tetrahedron,
RSC Advances
and B. Z. Tang, Sci. China, Ser. B: Chem., 2008, 51, 705–
708; (c) H. Dong, A. Qin, C. K. W. Jim, J. W. Y. Lam,
M. Haussler and B. Z. Tang, J. Inorg. Organomet. Polym.,
2008, 18, 201–205.
2008, 64, 508.
5 T. Matsuda and N. Miura, Org. Biomol. Chem., 2013, 11, 3424.
6 H. Kinoshita, H. Takahashi and K. Miura, Org. Lett., 2013, 15,
2962.
7 J.-J. Lian, A. Odedra, C.-J. Wu and R.-S. Liu, J. Am. Chem. Soc.,
2005, 127, 4186.
20 (a) H. Meier and E. Karpouk, Tetrahedron Lett., 2004, 45,
4477; (b) E. Karpouk, D. Schollmeyer and H. Meier, Eur. J.
Org. Chem., 2007, 1983.
8 A. Odedra, C.-J. Wu, T. B. Pratap, C.-W. Huang, Y.-F. Ran and 21 F. M. A. A. El-Taweel and M. H. Elnagdi, J. Heterocycl. Chem.,
R.-S. Liu, J. Am. Chem. Soc., 2005, 127, 3406.
9 C. Xi, C. Chen, J. Lin and X. Hong, Org. Lett., 2005, 7, 347.
10 J. Cordes, S. Laclef, A. J. P. White and A. G. M. Barrett, J. Org.
Chem., 2012, 77, 3524.
11 L. Li, M.-N. Zhao, Z.-H. Ren, J.-L. Li and Z.-H. Guan, Org.
Lett., 2012, 14, 3506.
12 For an excellent review on [3 + 3] cyclization providing
benzene derivatives, see: H. Feist and P. Langer, Synthesis,
2007, 327.
2001, 38, 981.
22 For our previous works on enamione-based organic
synthesis, see: (a) J.-P. Wan and Y.-J. Pan, Chem. Commun.,
2009, 2768; (b) J.-P. Wan, S.-F. Gan, G.-L. Sun and Y.-J. Pan,
J. Org. Chem., 2009, 74, 2862; (c) J.-P. Wan, C. C. J. Loh,
F. Pan and D. Enders, Chem. Commun., 2012, 48, 10049; (d)
J.-P. Wan, C. Wang and Y. Pan, Tetrahedron, 2011, 67, 922;
(e) J.-P. Wan, R. Zhou, Y. Liu and M. Cai, RSC. Adv., 2013,
3, 2477.
13 (a) M. M. Boorum and L. T. Scott, in Modern Arene Chemistry, 23 For recent references on water-mediated organic synthesis,
´
ed. D. Astruc, Wiley, New York, 2002, ch. 1; (b) O. De Frutos,
B. Gomez-Lor, T. Granier, M. A. Monge, E. Gutierrez-Puebla
and A. M. Echavarren, Angew. Chem., Int. Ed., 1999, 38, 204;
(c) W. Zhang, X.-Y. Cao, Z. Hong and J. Pei, Org. Lett., 2005, 7,
959; (d) M.-S. Yuan, Q. Fang, Z.-Q. Liu, J.-P. Guo, H.-Y. Chen,
W.-T. Yu, G. Xue and D.-S. Liu, J. Org. Chem., 2006, 71, 7858;
(e) A. W. Amick and L. T. Scott, J. Org. Chem., 2007, 72, 3412;
(f) S. Hagen and L. T. Scott, J. Org. Chem., 1996, 61, 7198.
see: (a) M. B. Gawande, V. D. B. Bonifacio, R. Luque,
P. S. Branco and R. S. Varma, Chem. Soc. Rev., 2013, 42,
5522; (b) B. Li and P. H. Dixneuf, Chem. Soc. Rev., 2013, 42,
5744; (c) M.-O. Simon and C.-J. Li, Chem. Soc. Rev., 2012,
41, 1415; (d) Y. Gu, Green Chem., 2012, 14, 2091; (e)
R. N. Nuler and A. G. Goyne, Chem. Rev., 2010, 110, 6302;
(f) K. Kumaravel and G. Vasuki, Green Chem., 2009, 11,
1945; (g) W. W. Y. Leong, X. Chen and Y. R. Chi, Green
Chem., 2013, 15, 1505; (h) D. J. Yeung, T. Gao, J. Huang,
S. Sun, H. Guo and J. Wang, Green Chem., 2013, 15, 2384;
(i) G.-X. Li and J. Qu, Chem. Commun., 2010, 46, 2653; (j)
J.-L. Cao, S.-L. Shen, P. Yang and J. Qu, Org. Lett., 2013, 15,
3856; (k) E. Feng, Y. Zhou, F. Zhao, X. Chen, L. Zhang,
H. Jiang and H. Liu, Green Chem., 2012, 14, 1888.
14 (a)
K.
Balasubramanian,
P.
S.
Selvaraj
and
P. S. Venkataramani, Synthesis, 1980, 29; (b) J. Yang and
J. G. Verkade, J. Am. Chem. Soc., 1998, 120, 6834; (c) J. Yang
and J. G. Verkade, J. Am. Chem. Soc., 2000, 19, 893; (d)
Z.-K. Yao and Z.-X. Yu, J. Am. Chem. Soc., 2011, 133, 10864;
(e) Q.-F. Zhou, F. Yang, Q.-X. Guo and S. Xue, Synlett, 2007,
215; (f) M. Tanaka, K. Nakamura, T. Iwado, T. Sato, 24 For representative references on lactic acid mediated green
M. Okada, K. Sue, H. Iwamura and T. Hiaki, Chem. – Eur.
J., 2011, 17, 606.
synthesis, see: (a) J. Yang, J.-N. Tang and Y. Gu, Green
´ ˆ
Chem., 2012, 14, 3304; (b) Y. Gu and F. Jerome, Chem. Soc.
15 T. Iwado, K. Hasegawa, T. Sato, M. Okada, K. Sue,
H. Iwamura and T. Hiaki, J. Org. Chem., 2013, 78, 1949.
16 (a) B. Al-Saleh, M. M. Abdelkhalik, A. M. Eltoukhy and
M. H. Elinagdi, J. Heterocycl. Chem., 2002, 39, 105; (b)
I. Elghamry, Synthesis, 2003, 2301; (c) M. M. Abdel-Khalik
and M. H. Elnagdi, Synth. Commun., 2002, 32, 159.
17 (a) F. C. Pigge, F. Ghasedi and N. P. Rath, Tetrahedron Lett.,
1999, 40, 8045; (b) F. C. Pigge, F. Ghasedi, Z. Zheng,
N. P. Rath, G. Nichols and J. S. Chickos, J. Chem. Soc.,
Perkin Trans. 2, 2000, 2458; (c) F. C. Pigge, Z. Zheng and
N. P. Rath, New J. Chem., 2000, 24, 183; (d) F. C. Pigge,
F. Ghasedi and N. P. Rath, J. Org. Chem., 2002, 67, 4547.
18 (a) K. Matsuda, N. Nakamura, K. Takahashi, K. Inoue,
N. Koga and H. Iwamura, J. Am. Chem. Soc., 1995, 117,
5550; (b) K. Matsuda, N. Nakamura, K. Inoue, N. Koga and
H. Iwamura, Chem. – Eur. J., 1996, 2, 259–264.
Rev., 2013, 42, 9550, For examples on bio-based solvent
mediated synthesis from our group, see: (c) Y. Liu,
C. Wang, R. Zhou and J.-P. Wan, RSC Adv., 2012, 2, 8789;
(d) Y. Liu, H. Wang, C. Wang, J.-P. Wan and C. Wen, RSC.
Adv., 2013, 3, 21369.
25 For selected known references on transition metal-catalyzed
cyclotrimerization of eletron decient terminal alkynes, see:
´
(a) A. Leyva-Perez, J. Oliver-Mesaguer, J. R. Cabrero-
´
Antonino, P. Rubio-Marques, P. Serna, S. I. Al-Resayes and
A. Corma, ACS Catal., 2013, 3, 1865; (b) K. Abdulla,
B. L. Booth and C. Stacey, J. Organomet. Chem., 1985, 293,
103; (c) J. Cheng, L. Tang and J. Li, J. Nanosci.
Nanotechnol., 2011, 11, 5159; (d) M. S. Sigman,
A. W. Fatland and B. E. Eaton, J. Am. Chem. Soc., 1998, 120,
5130; (e) M. Herberhold, H. Yan, W. Milius and
B. Wrackmeyer, Organometallics, 2000, 19, 4289.
19 (a) A. Vandendriessche, J. Thomas, C. Van Oosterwijck, 26 K. M. Al-Zayd, L. M. Nhari, R. M. Borik and M. H. Elnagdi,
J. Huybrechts, B. Dervaux, S. D'hollander, F. Du Prez, Green Chem. Lett. Rev., 2010, 2, 93.
W. Dehaen and M. Smet, Eur. Polym. J., 2009, 45, 3196; (b) 27 M. P. Castaldi, S. E. Gibson, M. Rudd and A. J. P. White,
C. K. W. Jim, A. Qin, J. W. Y. Lam, J.-Z. Liu, M. Haeussler
Chem. – Eur. J., 2006, (12), 138.
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RSC Adv., 2014, 4, 20499–20505 | 20505