Efficient organocatalysis with a calix[4]pyrrole derivative

Article abstract of DOI:10.1016/j.tetlet.2007.10.148

The 10α,20β-bis(4-nitrophenyl)-calix[4]pyrrole was found to act as an effective organocatalyst for the hetero Diels-Alder reaction of Danishefsky's diene with aromatic aldehydes. This discovery is the first reported case of a calixpyrrole that exhibits or

Full text of DOI:10.1016/j.tetlet.2007.10.148

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Tetrahedron Letters 49 (2008) 153–155
Efficient organocatalysis with a calix[4]pyrrole derivative
Grazia Cafeo,a Margherita De Rosa,b Franz H. Kohnke,a,* Placido Neri,b
Annunziata Sorienteb,* and Luca Valentia
a
`
Dipartimento di Chimica Organica e Biologica, Universita di Messina, Salita Sperone 31, 98166 Messina, Italy
b
`
Dipartimento di Chimica, Universita di Salerno, via Ponte don Melillo, I-84084 Fisciano, Salerno, Italy
Received 25 September 2007; revised 25 October 2007; accepted 29 October 2007
Available online 1 November 2007
Abstract—The 10a,20b-bis(4-nitrophenyl)-calix[4]pyrrole was found to act as an effective organocatalyst for the hetero Diels–Alder
reaction of Danishefsky’s diene with aromatic aldehydes. This discovery is the first reported case of a calixpyrrole that exhibits
organocatalytic activity.
Ó 2007 Elsevier Ltd. All rights reserved.
Calixpyrroles1 are a class of molecular receptors that are
receiving considerable attention because of their ability
to bind anions as well as neutral molecules2 bearing
hydrogen-bond acceptor sites. A considerable number
of derivatives have been described, and these have been
exploited in a number of applications including separa-
tion techniques3 and anion optical sensing.4 As hydro-
gen-bond donors, calixpyrroles have the potential to
act as organocatalysts.5 However, no example of their
use in catalysis has appeared in the literature to date.6
natural bio-active compounds.7 The reaction mecha-
nism (Scheme 1) involves either a Diels–Alder cyclo-
addition pathway or a Mukaiyama aldol pathway
depending on the Lewis acid catalyst used.8 Very
recently, carbonyl activation by hydrogen bonding
proved to be an effective choice for several catalytic
reactions9 and, since the pioneering works by Rawal,10
the HDA reaction promoted by hydrogen bonds has
been achieved by using diol compounds as Bronsted
acids.5,11
To test this possibility we decided to investigate the het-
ero Diels–Alder reaction (HDA) of Danishefsky’s diene
1 with carbonyl compounds. This reaction is one of the
most powerful synthetic procedures available for the
construction of pyran derivatives, six-membered hetero-
cycles with important applications in the synthesis of
On the basis of the above considerations, we selected the
HDA reaction of Danishefsky’s diene 1 with p-nitro-
benzaldehyde 2 as a model reaction to test the potential
ability of the recently reported12 stereoisomeric
calix[4]pyrrole derivatives 8 and 9, and dipyrromethane
10 to act as organocatalysts. The results are summarised
Scheme 1. The reaction of Danishefsky’s diene with aldehydes. In the present study R = p-NO2C6H4, macrocycles 8 or 9 or dipyrromethane 10 were
used as the acid catalysts, in DCM solvent.
Keywords: Calixpyrrole; Organocatalysis; Diels–Alder reaction; Hydrogen-bonds.
*
Corresponding authors. Tel.: +39 090 6765171; fax: +39 090 393895 (F.H.K.); tel.: +39 089969584; fax: +39 089 969603 (A.S.); e-mail addresses:
franz@unime.it; titti@unisa.it
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.10.148

154
G. Cafeo et al. / Tetrahedron Letters 49 (2008) 153–155
in Table 1. The reactions were run at room temperature
for 24 h using 115 mg (0.67 mmol) of 1 in dichlorometh-
ane (DCM) solvent (2 or 4 mL). The crude mixtures
were extracted with water and the organic phase ana-
Calixpyrrole a,a-isomer 9 (entry 7) was totally inactive
as catalyst, despite having been reported to be a stronger
ligand for anions than its a,b-isomer 8.12 Binding con-
stants of 8 or 9 with neutral hydrogen-bond acceptors,
such as p-nitrobenzaldehyde, are expected to be consid-
erably lower than those observed with negatively
charged guests,12,13 although their relative magnitudes
should reflect the ones observed for anionic guests.
Therefore, the lack of catalytic activity of 9 is puzzling.
A possible explanation is that 9 binds the aldehyde on
the face of the macrocycle bearing the p-nitrophenyl
units, and these shield the complexed aldehyde from
the approach of the diene. This would not be possible
in the complex with 8 in which only one face of the car-
bonyl p-system can be shielded by the p-nitrophenyl
units.
1
lysed by H NMR.
No dihydropyrone 5 was observed when using a diene/
aldehyde ratio 1:2 and 10 mol % of the calixpyrrole
a,b-isomer 8 but, interestingly, a mixture of aldolic ad-
duct 6 and cycloadduct 7 was produced (entries 2–4).
The relative amounts of 6 and 7 depended on the con-
centration of the reaction system and provide useful
information about the reaction pathway.
By using 2 mL of solvent (entry 2) the reaction provided
7 as the major product, hence suggesting a concerted
cycloaddition mechanism as the main path. On the other
hand, when the reaction was performed in 4 mL of sol-
vent (entry 3), the predominant formation of 6 was con-
sistent with Mukaiyama aldol condensation as the main
pathway. In both cases reaction efficiency was low (25–
36%). By increasing the catalyst loading (entry 4) to
20 mol % cycloadduct 7 was isolated in 57% yield and
the total conversion was good (60%).
Dipyrromethane 10 was used as reference compound
because it represents a half calixpyrrole. However, it
was also inactive as organocatalyst (entry 8), demon-
strating that a macrocyclic structure is required for cat-
alytic activity.
Calix[4]pyrrole has been shown2 (at least in the solid
state) to bind acetone by adopting a 1,3-alternate con-
formation in which two hydrogen bonds are formed
by two distal pyrrole NH units. In contrast, the carbonyl
unit of DMF was found to form hydrogen bonds with
the NH units of adjacent pyrrole rings whilst the calix
adopted a 1,2-alternate conformation. The lack of
organocatalytic activity for 10 could originate from a
preferred distal binding mode of p-nitrobenzaldehyde
similar to the one observed for acetone. Therefore, 10
cannot provide a ‘complete’ binding unit that is similar
to the one responsible for the catalytic activity of 8.
On the basis of our previous studies on organocatalysed
reactions,9h we performed the reaction using 5 equiv of
aldehyde (entries 5–6). With 20 mol % of the catalyst
in 2 mL of solvent (entry 5), the reactants were fully con-
verted: products 5 and 7 were obtained in 33% and 50%
yield, respectively, consistent with a predominant cyclo-
addition pathway.
This work proves that calixpyrroles can be effective
organocatalysts. These macrocycles can be extensively
functionalised and a vast number of calixpyrrole-based
receptors have appeared in the literature over recent
years,14 including several examples of chiral deriva-
tives.15 We believe that many of these compounds can
find applications in organocatalysis and we are actively
pursuing this goal by screening a variety of reactions
that are known to be affected by hydrogen-bonding
interactions.5,16
Table 1. Conversion data for the cycloaddition of silyloxydiene 1 to
the p-nitrobenzaldehyde 2 in the presence of 8, 9 and 10a
Entry
2:1b
Solvc
Catalystd
Conv.e
5f
6f
7f
1
2
3
4
5
6
7
8
2
2
2
2
5
5
5
5
2
2
4
2
2
4
2
2
—
—
36
25
60
90
51
—
—
—
—
—
—
33
47
—
—
—
11
20
3
7
4
—
25
5
57
50
—
—
—
8 (10)
8 (10)
8 (20)
8 (20)
8 (20)
9 (20)
10 (20)
—
—
a All reactions were performed with 0.67 mmol of diene 1.
b Molar ratio of the reagents.
c Volume of solvent (mL).
Acknowledgement
d Amount of catalyst (mol %).
e Conversion (mol %) determined on the isolated compounds.
f Yield based on isolated product.
This work was sponsored solely by the Universities of
Messina and Salerno.

G. Cafeo et al. / Tetrahedron Letters 49 (2008) 153–155
155
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Supplementary data
Experimental procedures for the preparation of catalysts
8, 9 and 10, for the cycloaddition reactions, for the iso-
lation of the adducts 5, 6 and 7, and their characterisa-
tion. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2007.10.148.
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