Convenient access to 1,3,5-triaroylbenzenes

Article abstract of DOI:10.1016/S0040-4039(02)01967-6

The unusual transformation of β-aryl-β-haloacroleins into valuable triaroylbenzenes is reported by the first time. The convenient sequence takes advantage on the one step access to triaroylbenzenes. This work establishes that the presence of amine is required for the trimerization procedure since it is involved in the formation of iminium-enamine intermediate A.

Full text of DOI:10.1016/S0040-4039(02)01967-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8051–8054
Convenient access to 1,3,5-triaroylbenzenes
Delphine Joseph,a,* Raphael Jankowski,a Damien Prim,b Jacqueline Mahuteaua and Ange`le Chiaronic
aBioCIS ESA 8076, Centre d’Etudes Pharmaceutiques, Universite´ Paris-Sud, 5, rue Jean-Baptiste Cle´ment,
F-92296 Chaˆtenay-Malabry Cedex, France
bLaboratoire SIRCOB, UPRES A CNRS 8086, Baˆtiment Lavoisier, Universite´ de Versailles, 45, avenue des Etats-Unis,
F-78035 Versailles Cedex, France
cInstitut de Chimie des Substances Naturelles, CNRS, avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France
Received 29 July 2002; revised 12 September 2002; accepted 13 September 2002
Abstract—The unusual transformation of b-aryl-b-haloacroleins into valuable triaroylbenzenes is reported by the first time. The
convenient sequence takes advantage on the one step access to triaroylbenzenes. This work establishes that the presence of amine
is required for the trimerization procedure since it is involved in the formation of iminium–enamine intermediate A. © 2002
Elsevier Science Ltd. All rights reserved.
The triacylbenzene entity is an aromatic common core
to molecules that exhibit various properties. For exam-
ple, 1,3,5-triacylbenzenes have been isolated from
Cochlospermum tinctorium rhizome known in African
traditional medicine for the treatment of liver diseases.1
Such compounds were found to form crystalline inclu-
sion complexes2 and to induce non linear optical as well
as redox properties.3 They are also key intermediates in
the preparation of super-high-spin organic molecules
with ferro- and opto-magnetic properties.4 Not surpris-
ingly several efforts has been devoted to the develop-
ment of synthetic methodology directed toward the
efficient preparation of triaroylbenzenes. In this regard,
two general strategies have been utilized that rely on
either functionalization of preexisting central benzene
ring5 or cyclotrimerization of b-aminoketones or ben-
zoylacetylenes.2c,4d,6 During the course of studies
devoted to the reactivity of chloroacroleins,7 we discov-
ered that b-aryl-b-haloacroleins successfully cyclotri-
merized, upon heating to afford the 1,3,5-triaroylben-
zene core. The strategy reported herein allows a conve-
nient and rapid access to triaroylbenzenes substituted
by valuable functional groups, that complement the
existing methods. Attempts to clarify the mechanism
evidenced the formation of an iminium–enamine inter-
mediate in the early stage of the reaction. The X-ray
crystal structure of triaroylbenzene 11a (Fig. 1) reveals
an uncommon inclusion like dimer where two
molecules arranged by means of strong hydrogen bonds
involving chlorine atoms rather than the more classical
oxygen atom.2
b-Aryl-b-haloacroleins 1–10 are well known, easy acces-
sible, reactive compounds.8 Their reactivity towards
nucleophiles (N, O, S, Se) has been mostly studied
providing an access to numerous heterocycles through
1,4-addition–elimination mechanisms.7a–c,9 Surprisingly,
refluxing b-(4-chlorophenyl)-b-chloroacrolein
1
in
DMF led to a complete disappearance of the starting
material in 1 h and to the formation of unexpected
triaroylbenzene 11a in 61% yield (Scheme 1). Several
b-aryl-b-haloacrolein derivatives 1–10 have been sub-
jected to identical reaction conditions giving rise to new
1,3,5-triaroylbenzenes substituted by valuable func-
tional groups (Table 1).10 The use of the above-men-
tioned conditions allowed the reaction of either
b-chloro- or b-bromoacrolein leading to the formation
of the desired compound 11a in similar yields and
reaction time (entries 1 and 2).
We next examined the influence of substituent R1 of the
starting acrolein. Triaroylbenzenes substituted by
halides (11a, e and f in entries 1, 6 and 7) and nitro
groups (11c, entry 4) as well as the non substituted
structure (11b, entry 3) could be obtained in 31–71%
yield. Only the well known highly unstable methoxy-
subtituted acrolein did not afford the expected triaroyl-
benzene 11d (entry 5). Whether other substituents R2
such as carboxylic esters were also able to furnish
trimerization products was next examined.
* Corresponding author. Tel.: 33(0)1 46835730; fax: 33(0)1 46835652;
e-mail: delphine.joseph@cep.u-psud.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01967-6

8052
D. Joseph et al. / Tetrahedron Letters 43 (2002) 8051–8054
Requisite carboxylic ester 8 was prepared from acrolein
1 as reported7d and subjected to identical reaction
conditions. No traces of triaroylbenzene could be
detected and starting compound was recovered
unchanged. This experiment revealed that the carbox-
aldehyde moiety was strictly required for this transfor-
mation (Table 1, entry 8). It was also established that
the presence of an additional substituent on the acro-
lein moiety precludes the formation of triaroylbenzenes
(entry 9 and 10). Surprisingly, in DMSO at 150°C or in
refluxing THF for 1 h, acrolein 2 did not afford com-
pound 11a. Since dimethylamine may be produced by
heating DMF and dialkylamines have been shown to
catalyze cyclotrimerization of ethynylketones,6a the
aforementioned reactions, were run in the presence of 1
and 2 equiv. of diethylamine. In fact, triaroylbenzene
11a was produced in 63% yield when acrolein 2 was
heated at 150°C in DMSO in presence of 2 equiv. of
diethylamine. The same reaction conducted in refluxing
THF in presence of 2 equiv. of diethylamine was also
successful, indicating that high temperatures are not
required. If decreasing the initial amount of diethyl-
amine to 1 equiv. lead to a small decrease of the
reaction rate, attempts to use catalytic amount of
diethylamine failed. Consequently the presence of
diethylamine is strictly required in the trimerization of
b-aryl-b-haloacroleins. In the light of these results, one
can expect the formation of intermediate such as A by
two iterative nucleophilic attack at both b-haloacroleins
reactive sites, in an early stage of the reaction (Scheme
2).11 Despite our efforts, we were not able to isolate
intermediate A from reaction mixtures. The structure of
A was however undoubtedly confirmed by NMR analy-
sis. The characteristic deshielding/shielding alternate
along the diene chain (169.3–92.3–159.4 ppm) is consis-
tent with the formation of both iminium and enamine
moieties.12 An 11 Hz coupling constant confirmed a Z
configuration of the enamine double bond. Moreover
NOE experiments evidenced the diene conformation
shown in Scheme 2.
Figure 1. ORTEP drawing of the X-ray crystal structure of
11a showing dimerization via two CH···Cl hydogen bonds in
the solid state. Displacement ellipsoids are shown at the 30%
level. Estimation of the dimer cavity dimensions: O24···Cl4=
To show that A was one of the intermediates of the
tranformation, it was dissolved in deuterated DMSO
and heated at 60 and 130°C. The reaction was then
3.810(5),
O54···Cl1=3.768(5),
O24···O54=6.770(8),
1
C7···Cl4=8.535(6), C37···Cl1=8.525(7), Cl1···Cl4=9.461(4),
monitored by H NMR. Surprisingly, A was recovered
,
C7···C37=11.291(9) and C30···C60=11.909(13) A.
unchanged, showing high degree of stability even under
hard conditions and prolonged heating time. Therefore,
a rapid decrease of intermediate A with concomitant
formation of triaroylbenzene 11a was obtained after
stepwise addition of 1 and 2 equiv. of starting acrolein
1 (Scheme 2). Thus, these findings showed that A is one
of the intermediates formed during the reaction. How-
ever, at this stage, the way to produce the triaroylben-
zene core from A in the reaction conditions is still
unclear.13
The crystal structure of compoud 11a is shown in Fig.
1.14 It is worth noting that the two molecules of the
unit-cell labelled (C1–C30) and (C31–C60) are assem-
bled in a nearly centrosymmetric dimer, by means of
two strong hydrogen bonds involving the chlorine
atoms Cl1 and Cl4 with the nearest C-H groups, C60-H
and C30-H, respectively (distances Cl1···C60=3.750(8)
Scheme 1.
,
,
A, Cl1···H60=2.88 A, angle Cl1···HꢀC60=157.1°;

D. Joseph et al. / Tetrahedron Letters 43 (2002) 8051–8054
Table 1. Cyclotrimerization of acroleins 1–11
8053
Entry
R1
R2
X
R3
Acrolein
Time (h)
Compound
Yield (%)
1
2
3
4
5
6
7
8
9
Cl
Cl
H
NO2
MeO
Br
F
Cl
H
H
H
H
H
H
H
H
OEt
H
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
1
2
3
4
5
6
7
8
9
1
0.5
1
2
0.5
3
11a
11a
11b
11c
11d
11e
11f
11g
11h
11i
61
59
31
45
a
–
65
71
4
b
24
24
24
–
–
–
b
Me
Ph
b
10
H
H
10
a Severe resinification occurred.
b Starting material recovered unchanged.
References
1. Diallo, B.; Vanhaelen-Fastre´, R.; Vanhaelen, M. Phyto-
chemistry 1991, 30, 4153.
2. (a) Pigge, F. C.; Zheng, Z. Tetrahedron Lett. 2001, 42,
8259; (b) Pigge, F. C.; Ghasedi, F.; Zheng, Z.; Rath, N.
P.; Nichols, G.; Chickos, J. S. J. Chem. Soc., Perkin
Trans. 2 2000, 2458; (c) Pigge, F. C.; Zheng, Z.; Rath, N.
P. N. J. Chem. 2000, 24, 183; (d) Pigge, F. C.; Ghasedi, F.
Tetrahedron Lett. 2000, 41, 6545; (e) Pigge, F. C.;
Ghasedi, F.; Rath, N. P. Tetrahedron Lett. 1999, 40,
8045.
3. Lambert, C.; No¨ll, G.; Schma¨lzlin, E.; Meenholz, K.;
Brau¨chle, C. Chem. Eur. J. 1998, 4, 2129.
Scheme 2.
4. See for example: (a) Kwak, S. Y.; Ahn, D. U. Macro-
molecules 2000, 33, 7557; (b) Wienk, M. M.; Janssen, R.
A. J. J. Am. Chem. Soc. 1997, 119, 5398; (c) Matsuda, K.;
Nakamura, N.; Inoue, K.; Koga, N.; Iwamura, H. Bull.
Chem. Soc. Jpn. 1996, 69, 1483; (d) Matsuda, K.; Naka-
mura, N.; Takahashi, K.; Inoue, K.; Koga, N.; Iwamura,
H. Chem. Eur. J. 1996, 2, 259; (e) Matsuda, K.; Naka-
mura, N.; Takahashi, K.; Inoue, K.; Koga, N.; Iwamura,
H. J. Am. Chem. Soc. 1995, 117, 5550; (f) Matsuda, K.;
Inoue, K.; Koga, N.; Nakamura, N.; Iwamura, H. Mol.
Cryst. Liq. Cryst. 1994, 253, 33.
,
,
Cl4···C30=3.736(9) A, Cl4···H30=2.84 A, angle
Cl4···H-C30=160.5°). The mean values of the interpla-
nar distances between the phenyl rings (C1–C6) and
(C31–C36), (C9–C14) and (C39–C44), (C25–C30) and
,
(C55–C60) are 11.224, 8.546 and 13.943 A, respectively.
In contrast to inclusion complexes recently described by
Pigge , the distances O24···C41 of 4.057(8) A and
O54···C11 of 4.046(9) A are too long to allow classical
hydrogen bonding. The dihedral angles between the
central benzene ring (C1–C6) and the three other
phenyl rings are 54.0° for ring (C9–C14), 48.5° for ring
(C17–C22) and 123.0° for ring (C25–C30), respectively.
Similar values are found in the second monomer: 54.2,
45.6 and 122.5°, respectively.
2
,
,
5. Ju¨tz, C.; Wagner, R.-M.; Kraatz, A.; Go¨bering, H.-G.
Liebigs Ann. Chem. 1975, 874.
6. (a) Matsuda, K.; Nakamura, N.; Iwamura, H. Chem.
Lett. 1994, 1765; (b) Murahashi, S.-I.; Mitsue, Y.;
Tsumiyama, T. Bull. Chem. Soc. Jpn. 1987, 60, 3285; (c)
Balasubramanian, K. K.; Selvaraj, P. S.; Venkataramani,
P. S. Synthesis 1980, 29; (d) Harmish, H. Liebigs Ann.
Chem. 1972, 765, 8; (e) Croxall, W. J.; Van Hook, J. O.
J. Am. Chem. Soc. 1949, 71, 2422.
7. (a) Kirsch, G.; Prim, D.; Leising, F.; Mignani, G. J.
Heterocyclic Chem. 1994, 31, 1005; (b) Prim, D.; Joseph,
D.; Kirsch, G. Liebigs Ann. 1996, 239; (c) Prim, D.;
Joseph, D.; Kirsch, G. Phosphorus, Sulfur, Silicon 1994,
91, 137; (d) Prim, D.; Fuss, A.; Kirsch, G.; Silva, A. M.
S. J. Chem. Soc., Perkin Trans. 2 1999, 1175.
In conclusion, we have shown that a fast and conve-
nient preparation of valuable 1,3,5-triaroylbenzenes is
now available starting from b-aryl-b-haloacroleins. The
crucial role played by the amine in the trimerization
procedure has been outlined and an enamine–iminium
salt intermediate has been characterized. The X-ray
crystal structure of triaroylbenzene 11a showed an
unusual dimeric arrangement of the triaroylbenzene
units.
8. b-Aryl-b-haloacroleins can be readily prepared in one
step by addition of Vilsmeier–Haack reagent to commer-
cially available a-methylene ketones (see Ref. 7a) or
acetylenic compounds, see: Ziegenbein, W.; Franke, W.
Angew. Chem. 1959, 71, 573.
Acknowledgements
9. Marson, C. M.; Giles, P. R. Synthesis using Vilsmeier
The authors thank the CNRS for financial support.
Reagents; CRC Press, 1994 and references cited therein.

8054
D. Joseph et al. / Tetrahedron Letters 43 (2002) 8051–8054
10. All new compounds showed satisfactory spectroscopic
and analytical data. Typical procedure for triaroylben-
zene 11a: b-aryl-b-haloacroleins (1 mmol), diethylamine
(2 mmol) were refluxed in degassed THF for the time
indicated in Table 1. The reaction mixture was poured
into ice cold water and the precipitate collected by filtra-
tion. Compound 11a was purified by flash column chro-
matography using petroleum ether/diethylether 7:3 as
eluent. 11a: 1H NMR (250 MHz, CDCl3): l 7.51 (d,
3×2H), 7.77 (d, 3×2H), 8.34 (s, 3×1H). 13C NMR (100
MHz, CDCl3): l 129.1, 131.4, 133.8, 134.5, 138.1, 140.1,
193.4. IR (CH2Cl2) w (CO): 1664 cm−1. UV (CH2Cl2)
tem, racemic space group Pca21, Z=8: so, there are two
molecules in the asymmetric unit. Cell parameters: a=
3
,
,
10.396(7), b=9.300(8), c=48.014(34) A, V=4642 A ;
D
,
calcd=1.413 g cm−3, F(000)=2016, u (CuKa)=1.5418
A, v=3.80 mm−1, no decay, absorption ignored. Intensity
data were collected with a Nonius CAD4 diffractometer
up to q=67° (h: 0–12, −105k511, l: 0–57). From the
7657 reflections measured, 4201 were independent (Rint
=
0.047) of which 2677 were considered as observed having
I]2|(I). The structure was solved by direct methods
using program SHELXS8615 and refined by full-matrix
least-squares based upon unique F2 with program
SHELXL93.16 Hydrogen atoms were fitted at theoretical
positions and assigned an isotropic displacement parame-
ter equivalent to 1.20 that of the bonded atom. Refine-
ment converged to R1(F)=0.0482 for the 2677 observed
reflections and wR2(F2)=0.1267 for all the 4201 data
with goodness-of-fit S=1.035. Residual electron density
umax: 267 nm. Mass: m/z=492.1. Anal. calcd for
C27H15Cl3O3: C, 65.68; H, 3.06. Found: C, 65.59; H,
3.01%.
11. Nucleophilic attack from amines on b-haloacroleins can
occur at C-4 and/ or at the carboxaldehyde group leading
to enamines and/or imines or iminium salts, respectively.
Weissenfels, M. Z. Chem. 1964, 4, 458. Terent’ev, A. P.;
Volotina, M. A.; Kudryashova, V. A. Dokl. Akad. Nauk
SSR 1965, 164, 115. Chem. Abs. 1965, 63, 16290c.
12. Breitmaier, E.; Voelter, W. Carbon-13 NMR Spec-
troscopy; 3rd ed.; VCH: Weinheim, 1987; p. 238.
13. The presence of other possible intermediates such as
a-formylacetophenones, also known to trimerize6d and
which could arose from addition of released water on 1
or A could not be evidenced.
was found between −0.25 and 0.24 e A−3. In the crystal,
,
the molecules are closely packed, no channel was
observed. Crystallographic results have been deposited
with the Cambridge Crystallographic Data Centre, UK
as supplementary publication number CCDC No.
190303.
15. Sheldrick, G. M. SHELXS86. Acta Crystallogr. A 1990,
46, 467–473.
16. Sheldrick, G. M. SHELXL93. Program for the Refine-
ment of Crystal Structures; University of Go¨ttingen, Ger-
many, 1993.
14. Crystallographic data. Small colorless crystal (0.26×33×
0.36 mm). C27H15Cl3O3, Mw=493.74. Orthorhombic sys-