Calix[n]arene/Ti(IV) complexes as active catalysts in aldol reaction of Chan's diene

Article abstract of DOI:10.1016/S0040-4039(03)01529-6

The aldol condensation of Chan's diene with benzaldehyde is catalyzed by only 8% mol of the calix[n]arene/Ti(O-i-Pr)₄ complexes. Studies have revealed that the size of calixarene molecule and the number of hydroxyl groups affected the efficienc

Full text of DOI:10.1016/S0040-4039(03)01529-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6195–6198
Calix[n]arene/Ti(IV) complexes as active catalysts in aldol
reaction of Chan’s diene
Annunziata Soriente,* Marina Fruilo, Luisa Gregoli and Placido Neri*
Department of Chemistry, University of Salerno, Via S. Allende, 43, 84081 Baronissi (SA), Italy
Received 9 June 2003; revised 19 June 2003; accepted 20 June 2003
Abstract—The aldol condensation of Chan’s diene with benzaldehyde is catalyzed by only 8% mol of the calix[n]arene/Ti(O-i-Pr)4
complexes. Studies have revealed that the size of calixarene molecule and the number of hydroxyl groups affected the efficiency
of the reaction. The reaction conditions (solvent and temperature) have been examined.
© 2003 Elsevier Ltd. All rights reserved.
The aldol condensation of Chan’s diene 1,1 the dianion
equivalent of methyl acetoacetate, has emerged as a
powerful preparative reaction because it allows the
formation of a polyfunctional C-5 fragment 3 usable in
the total synthesis of complex molecules2–5 (Scheme 1).
of various functional groups, make them very attractive
ligands for incorporating transition-metals ions.
Metallo-calixarene complexes have been reported by
several authors, including Atwood,12 Pedersen,13 and
Harrowfield.14 Recently, Floriani15 has reported the
synthesis of calix[4]arene/Ti(IV) complexes having very
satisfactory catalytic properties in the epoxidation of
allylic alcohols.16
It is reported that 1 reacts with stoichiometric or cata-
lytic amount of Lewis acids6 to give the adduct 3 in
good yield. Excellent progress in the development of
enantioselective reaction variants has been made. The
most notable achievements concern the addition of
Chan’s diene to aldehydes through catalysis by chiral
Lewis acids.7,8 We have recently described a highly
enantioselective aldol reaction of 1 promoted by cata-
lytic amounts (2–8% mol) of chiral (R)- or (S)-BINOL/
Ti(IV) complexes.9,10
More recently, Miyano et al.17 have reported that a
dinuclear titanium(IV) complex of p-tert-butylthia-
calix[4]arene showed high catalytic activity in the
Mukaiyama aldol reaction of aldehydes with sylyl enol
ethers, while Casolari et al.18 described a very high
activation of the zirconium-BINOL catalyst by p-tert-
In the course of our investigation devoted to efficient
approaches to compounds of type 3, we have investi-
gated the possibility to use calix[n]arene-based Ti(IV)
complexes in the catalytic aldol reaction of Chan’s
diene.
The ready availability of calixarenes,11 in conjunction
to the fine control of their molecular dimensions (by
changing the value of n), and to the easy introduction
Scheme 1.
* Corresponding authors. Fax: ++39-089-965 296; e-mail: titti@unisa.it; neri@unisa.it
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01529-6

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A. Soriente et al. / Tetrahedron Letters 44 (2003) 6195–6198
In order to gain further insight into the calixarene
structural features necessary to give an appreciable
catalytic activity, we extended the above conditions to
other variously substituted calixarenes. In particular,
tert-butyl depleted calix[4]arene 6a23 led to a significant
enhancement of activity (95% yield, entry 5) with respect
to the parent butylated counterpart (77%, entry 1).
Probably this improvement could be ascribed to an
increased solubility of calixarene ligand observed under
the experimental conditions.
butylcalix[4]arene in the enantioselective allylation of
aldehydes.
Herein, we report the first and efficient synthesis of aldol
3a using catalytic amount (8% mol) of calix[n]arene/
Ti(IV) complexes (Scheme 2).
We examined the aldol reaction between the silyloxy
diene 1 and benzaldehyde 2a, as a representative alde-
hyde, (Scheme 2) in the presence of a calix[n]arene/Ti(IV)
complex formed in situ by treating the appropriate
calixarene (Fig. 1) with Ti(O-i-Pr)4. The reaction was
conducted under the conditions [molecular sieves (m.s.),
THF, −78°C (2h), rt (16 h)] recently reported for a
Ti(IV)/BINOL catalytic system.10 The silylated aldol
produced was directly deprotected using Carreira’s
procedure19 to give aldol 3a.
Table 1. Aldol reaction of 2a with 1 to produce 3a via
Scheme 2 [conditions: molecular sieves (m.s.), THF, −78°C
(2 h)+rt (16 h)]
Entry
Calix[n]arene
Yield%a
The experimental results are summarized in Table 1.
Interestingly, a high catalytic activity (77% yield) was
observed using p-tert-butylcalix[4]arene (6)20 as ligand
(entry 1). This activity was even higher (96% yield) using
the larger homologue p-tert-butylcalix[6]arene (7)21
(entry 2), but decreased when the macrocycle size was
increased to the octameric p-tert-butylcalix[8]arene (8)22
(entry 3). It is worthy to note that in all these instances
the catalytic activity of calixarene/Ti(IV) complexes was
clearly superior to that of Ti(O-i-Pr)4, which yielded only
4% of aldol adduct (entry 4). These data indicate that the
complexes act as Lewis acid, enhancing the reactivity of
the aldehyde toward the Chan’s diene.
1
2
3
4
5
6
7
8
6
7
8
77
96
56
4
95
10
17
–
Ti(O-i-Pr)4
6a
6b
6c
6d
6e
8a
8b
9
10
11
69
44
58b
a Yields were obtained by 1H NMR analysis.
b Toluene was used as solvent.
Scheme 2.
Figure 1.

A. Soriente et al. / Tetrahedron Letters 44 (2003) 6195–6198
6197
The number of OH groups also plays a major role with
respect to catalytic activity. In fact, tripropoxy-p-tert-
butylcalix[4]arene 6b,24 blocked in the cone conforma-
tion and possessing only a single free phenolic OH,
showed only a modest activity (10%, entry 6). Only a
slight improvement (17 and 12%, entries 7 and 8) was
observed with two distally- or proximally-positioned
OH groups, respectively, by using 1,3-dimethoxy-p-
tert-butylcalix[4]arene 6c25 or 1,2-dimethoxy-p-tert-
butylcalix[4]arene 6d.26 However, a significant burst in
activity was observed with monomethoxy-p-tert-butyl-
calix[4]arene 6e,27 containing three contiguous OH
groups, which showed an activity (69%, entry 9)
approaching that of the parent unsubstituted
calix[4]arene 6 (77%, entry 1). These results suggest that
three contiguous phenolic OH groups, very likely, are a
minimal requirement in order to strongly tricoordinate
Ti(IV) cation. This conclusion seems to be confirmed
by the finding that calix[8]arenes 8a28 and 8b,29 distally-
bridged with tetramethylene and crown-3 moieties,
respectively, showed a catalytic activity (44 and 58%,
respectively, entries 10 and 11) similar to that of the
parent calix[8]arene 8 (56%, entry 3), probably only
limited by solubility factor. In the attempt to improve
the results, we also investigated the influence of reac-
tion conditions (Table 2). By using the conditions
recently reported for Ti(IV)/BINOL,10 the aldol adduct
was obtained in 77% yield using 8% mol of the p-tert-
butylcalix[4]arene/Ti(IV) complex (entry 1). Since
calix[4]arene 6 has a low solubility in THF, we used
toluene as reaction medium, but the aldol adduct was
obtained only in 36% yield (entry 2).
In conclusion, the collected data show that the calix-
arene/Ti(IV) complexes can be used as efficient catalyst
in aldol reaction of Chan’s diene. In addition the
procedure is simple and no particular drying is required
for calixarene ligands. Future work in our laboratory
will be addressed to extend this procedure to different
aldehydes and to examine asymmetric or dissymmetric
calix[n]arenes in order to produce chiral aldol adducts.
A typical experimental procedure is described for the
aldol reaction of 1 with benzaldehyde using the p-tert-
butylcalix[4]arene/Ti(IV) complex. A mixture of Ti(O-i-
Pr)4 (0.08 mmol), p-tert-butylcalix[4]arene 6 (0.08
mmol), and molecular sieves (340 mg) in THF (5 mL)
was stirred at rt for 1 h. The mixture was cooled to
−78°C and then benzaldehyde (1 mmol) was added
dropwise. After 30 min, silyloxydiene 1 (2 mmol) was
added in a similar way. The resulting solution was
stirred under an N2 atmosphere at −78°C for 2 h. After
warming at rt the mixture was stirred overnight (16 h).
The mixture was cooled to −78°C and TFA (0.4 mL)
was added. Then the solution was warmed to rt and
stirred for 1 h after which desilylation was complete.
The reaction mixture was diluted with ether and a
saturated aqueous solution of NaHCO3 (2 mL) was
added dropwise. The mixture was stirred until the
evolution of gas ceased (30 min), then the organic layer
was separated, washed with brine, dried over MgSO4,
and concentrated in vacuo to afford a yellow oil con-
taining 3a with traces of reagents.
Acknowledgements
The temperature strongly influences the outcome of
aldol reaction. In fact, when the reaction was analyzed
after the 2 h stirring period at −78°C, no 3a could be
detected (entry 3). Instead, omission of the low-temper-
ature step and carrying out the reaction for 16 h at
room temperature (entry 4) led to a good yield (65%).
Financial support from the Italian MIUR (Supramolec-
ular Devices Project) is gratefully acknowledged.
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