Regioselective O-alkylations and acylations of polyphenolic substrates using a calix[4]pyrrole derivative

Article abstract of DOI:10.1016/j.tetlet.2009.04.128

The 10α,20α-bis(4-nitrophenyl)-calix[4]pyrrole 2 can act as a topologically selective protecting group in the O-alkylation and acylation of polyphenolic polycyclic aromatic compounds thanks to the regioselective formation of phenolate-type complexes. Rema

Full text of DOI:10.1016/j.tetlet.2009.04.128

Tetrahedron Letters 50 (2009) 4138–4140
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Tetrahedron Letters
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Regioselective O-alkylations and acylations of polyphenolic substrates using
a calix[4]pyrrole derivative
*
Grazia Cafeo, Franz H. Kohnke , Luca Valenti
Dipartimento di Chimica Organica e Biologica, Università di Messina, Salita Sperone 31, 98166 Messina, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
The 10a,20a-bis(4-nitrophenyl)-calix[4]pyrrole 2 can act as a topologically selective protecting group in
Received 20 March 2009
Revised 22 April 2009
Accepted 29 April 2009
Available online 5 May 2009
the O-alkylation and acylation of polyphenolic polycyclic aromatic compounds thanks to the regioselec-
tive formation of phenolate-type complexes. Remarkably, the host–guest interaction with the anionic
reagents is sufficiently strong and kinetically slow to produce a high degree of selectivity.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Calixpyrroles
Anions
Supramolecular chemistry
Reactivity control
Aromatic compounds
Because of their biological importance, the selective alkylation
and acylation of hydroxy units in polyphenolic compounds are a
topic of considerable practical interest.1 Lipases are currently used
for selective acylations and deacylations as these enzyme-based
methods are compatible with the presence of a range of functional
groups and are generally more efficient than the lengthy protection
and deprotection sequences required by conventional synthetic
techniques.2 Candida antarctica lipase B was recently found to be
an effective biocatalyst for the transfer of acyl groups from vinyl-
propanoate to the hydroxy functions of phenols, hydroquinols,
and resorcinols.3 Chromobacterium viscosum lipase adsorbed on
celite has been found to affect the regioselective esterification of
phenols and dihydroxynaphthalenes in organic solvents,4 whilst
Pseudomanas sp. lipase catalyses the regioselective hydrolysis of
diacetoxynaphthalenes to mono-acetates.5
In this Letter, we demonstrate that 2 can selectively discriminate
between two phenolate-type units within the same molecule
which differ due to their topology, and we present examples prov-
ing that this selective binding can be exploited for the regiocon-
trolled alkylation and acylation of several dihydroxynaphthalenes.
In the course of its development, supramolecular and
host–guest chemistry has addressed the objective of exploiting
molecular recognition phenomena in order to mimic some of the
properties of enzymes to promote selective and/or faster
reactions.6 With the discovery of the anion-binding properties of
calixpyrroles,7 we were encouraged to explore the use of these
receptors in organic syntheses. Thus, we have recently reported
the use of the calix[4]pyrrole derivative 1 as organocatalyst in het-
ero Diels–Alder reactions.8 We have also recently described that 2
is capable of discriminating between different anionic centers
within the same organic molecule (phenolate vs carboxylate).9a
Initially we tested the ability of 2 to bind the anions formed by
treatment of b- and a-hydroxynaphthalene (3 and 4, respectively)
with an excess of Cs2CO3 in CD3CN.10 The 1H NMR spectra (Fig. 1) of
1:1 mixtures show large and diagnostic complexation induced
shifts (CISs). The pyrrole NH resonances are shifted toward higher
ppm values (
D
d 4.6 and 4.2 ppm for [2Á3]À and [2Á4]À, respec-
tively). In both complexes, the naphthalene protons show upfield
CISs, with the protons ortho to the anionic center being the most
affected (ca.
D
d 1.90 ppm for H(1) and H(3) in [2Á3]À and
Dd
1.50 ppm for H(2) in [2Á4]À). These spectral features indicate that
2 binds these aromatic anions with facial selectivity onto the face
containing the p-nitrophenyl units, by a combination of NHÁ Á ÁO
* Corresponding author. Tel.: +39 0906765171; fax: +39 090393895.
E-mail address: franz@unime.it (F.H. Kohnke).
hydrogen bonding and
p–p
interactions.9b Both complexes have
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.128

G. Cafeo et al. / Tetrahedron Letters 50 (2009) 4138–4140
4139
tioned between the nitrophenyl substituents (the spectrum of 5
2À
in the presence of 2 is shown in Fig. 2b). Unlike what had been
previously reported for several bis-anions of hydroxybenzoic and
phthalic acids,9a there was no evidence for the formation of capsu-
lar-like complexes involving two molecules of 2 and any of the bis-
anions (52À or 62À), even in the presence of an excess of 2, and even
when the bis-anion was the one generated from 2,7-dihydroxy-
naphthalene 7.
Figure 1. Partial 1H NMR spectra in CD3CN of: (a) 2 + 3 (1:1 molar ratio), (b)
2 + 3 + Cs2CO3 in excess as solid, (c) 2 + 4 (1:1 molar ratio), (d) 2 + 4 + Cs2CO3 in
excess as solid, (e) 2 + 3 + 4 (1:1:1 molar ratio) + Cs2CO3 in excess as solid.
Treatment of complex [2Á5]2À with 1 equiv of benzyl bromide
gave the mono-benzyl ether 8 regioselectively in a high proportion.
Under identical conditions, but without receptor 2, a mixture of
mono- and bis-benzyl ethers 8–10 was formed (the proportions
of 8, 9, and 10 were ca. 87%, 0%, and 13% in the presence and
28%, 7%, and 66% in the absence of 2, respectively).12 The same
reactions using 62À or [2Á6]2À gave only complex mixtures in which
we could not detect the expected benzyl ethers. In the absence of 2,
naphthol 7 gave bis-alkylation products 11 although only 1 equiv
of benzyl bromide was added (see Fig. 2 in Supplementary data).
One possible explanation for this result is that the mono-alkylated
12 is more reactive than 7. However, when 2 was present, the
mono-benzyl ether 12 was formed selectively. Encouraged by
these results we decided to test acylation reactions. We used
trans-crotonoyl chloride because its protons provide 1H NMR reso-
nances that are conveniently distant from those of the calix and
naphthols. Unlike bromide (from benzyl bromide) which is only
weakly complexed by 2, the chloride formed during the reaction
a 1:1 stoichiometry and they are kinetically slow on the NMR time
scale. The association constants are too high to be determined by
NMR methods.11
When the two anions derived from 3 and 4 were competing to
bind receptor 2 (1:1.1 molar ratio) the mixture was found to con-
tain the complexes [2Á3]À and [2Á4]À in 87% and 13% ratios, respec-
tively (see the NH resonances in Fig. 1e). Since this indicates that
the ‘b-anion’ moiety is selectively bound with respect to the ‘a-an-
ion’ we were encouraged to investigate if this topological selectiv-
ity would emerge even when the two anionic moieties were
simultaneously present within the same guest.
1,6- and 1,7-dihydroxynaphthalene (5 and 6, respectively) were
identified as suitable substrates to test this hypothesis. The hydro-
xyl units are both sufficiently acidic for the bis-anions to be formed
using Cs2CO3. The 1H NMR spectra of these anions in the presence
of one molar equivalent of 2 are consistent with the formation of
1:1 complexes that are kinetically slow on the NMR time scale,
in which only the ‘b-type’ oxygen atoms are selectively complexed
by the pyrrole NH units, whilst the naphthalene units are posi-
Figure 2. Partial 1H NMR (300 MHz, CD3CN) spectra for: (a) 1:1 mixture of 1,6-
dihydroxynaphthalene 5 and receptor 2 and (b) 1:1 mixture of 1,6-dihydroxy-
naphthalene
5 and receptor 2 with an excess of Cs2CO3, showing the large
complexation induced shifts that indicate the formation of a 1:1 inclusion complex
with the bis-anion.

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G. Cafeo et al. / Tetrahedron Letters 50 (2009) 4138–4140
was found to compete with the anionic naphthols for the binding
with 2. In fact, when using 1 equiv of 2, we were able to observe
the displacement of the phenolic anions occurring to an extent cor-
related to the progress of the acylation and the related release of
chloride ions in the reaction medium. The formation of the chloride
complex with the calix 2 was also evident.8b Therefore, we com-
pared the compositions of reaction mixtures in which receptor 2
was either absent or used in a twofold molar excess with respect
to the trans-crotonoyl chloride and the naphthols. Acylation of
52À without 2 gave a mixture of mono- and bis-acyl derivatives
13 and 15, respectively. We were unable to detect any mono-acyl
derivative 14 in this crude mixture. The same reaction in the pres-
ence of 2 gave the mono-acyl derivative 14 as the main product. It
should be noted that this mono-acyl derivative is not accessible in
the absence of 2. Identical reactions using naphthol 6 gave only
complex mixtures from which we were unable to isolate any of
the expected acylation products.
These preliminary results on the use of calixpyrrole complexes
for the selective O-alkylation and O-acylation of polyphenolic com-
pounds demonstrate that calixpyrroles can behave as a topologi-
cally sensitive protecting group whose on/off reaction requires
just a pH change. Receptor 2 was found to be unaffected by the
reactions described here and could be recovered and recycled if
necessary. We are actively investigating the extension of these
principles to a larger number of reactions involving a broader
range of starting materials.
References and notes
1. (a) Pandey, J.; Mishra, M.; Bisht, S. S.; Sharma, A.; Tripathi, R. P. Tetrahedron Lett.
2008, 49, 695–698; (b) Yamada, S.; Sugaki, T.; Matsuzaki, K. J. Org. Chem. 1996,
61, 5932–5938.
2. For reviews see: (a) Faber, K. Biotransformations in Organic Chemistry, 5th ed.;
Springer: Berlin, 2004. pp 94–123; (b) Gais, H. J.; Theil, F. In Enzyme Catalysis in
Organic Syntheses; Drauz, K., Waldmann, H., Eds., 2nd ed.; Wiley-VHC:
Weinheim, 2002; pp 335–578.
3. Miyazawa, T.; Hamada, M.; Morimoto, R.; Murashima, T.; Yamada, T.
Tetrahedron Lett. 2008, 49, 175–178.
4. Lambusta, D.; Nicolosi, G.; Piattelli, M.; Sanfilippo, C. Indian J. Chem. 1993, 32B,
58–60.
5. Ciuffreda, P.; Casati, S.; Santaniello, E. Tetrahedron 2000, 56, 317–321.
6. (a) Pluth, M. D.; Bergman, R. G.; Raymond, K. N. J. Org. Chem. 2009, 74, 58–63;
(b) Koblenz, T. S.; Wassenaar, J.; Reek, J. N. H. Chem. Soc. Rev. 2008, 37, 247–262;
(c) Schmuck, C. Angew. Chem., Int. Ed. 2007, 46, 5830–5833; (d) Sanders, J. K. M.
Chem. Eur. J. 1998, 4, 1378–1383.
7. (a) Gale, P. A.; Sessler, J. L.; Kràl, V. Chem. Commun. 1998, 1–8; (b) Gale, P. A.;
Sessler, J. L.; Kràl, V.; Lynch, V. J. Am. Chem. Soc. 1996, 118, 5140–5141; (c) Gale,
P. A.; Anzembacher, P., Jr.; Sessler, J. L. Coord. Chem. Rev. 2001, 222, 57–102; (d)
Cafeo, G.; Kohnke, F. H.; La Torre, G. L.; Parisi, M. F.; Nascone, R. P.; White, A. J.
P.; Williams, D. J. Chem. Eur. J. 2002, 8, 3148–3156; (e) Sessler, J. L.; Camiolo, S.;
Gale, P. A. Coord. Chem. Rev. 2003, 240, 17–55.
8. (a) Cafeo, G.; De Rosa, M.; Kohnke, F. H.; Neri, P.; Soriente, A.; Valenti, L.
Tetrahedron Lett. 2007, 49, 153–155; For the description of the synthesis of
compounds 1 and 2 see: (b) Bruno, G.; Cafeo, G.; Kohnke, F. H.; Nicolo, F.
Tetrahedron 2007, 63, 10003–10010.
9. (a) Cafeo, G.; Kohnke, F. H.; Valenti, L.; White, A. J. P. Chem. Eur. J. 2008, 14,
11593–11600; (b) This mode of binding was also observed in Ref. 9a.
10. Complexation studies were conducted by means of 1H NMR spectrometry
(20 °C, 300 MHz) using 5 Â 10À3 M solutions of receptor 2 and of the naphthols
in CD3CN (700 lL) and an excess of solid Cs2CO3. All resonances were assigned
on the basis of their multiplicity and of double irradiation experiments.
Alkylation reactions were conducted at 40 °C in either CD3CN or CH3CN both in
the absence and in the presence of 1 M equiv of 2, using 1 equiv of benzyl
bromide and an excess of solid Cs2CO3. Acylation reactions were conducted in a
similar manner, but using twice the amount of 2 with respect to that of trans-
crotonoyl chloride. All reactions were monitored (1H NMR) for the
disappearance of the starting materials, and excess base was neutralized
with trifluoroacetic acid before recording the NMR spectra.
Acknowledgment
This work was sponsored by the University of Messina.
Supplementary data
11. (a) Fielding, L. Tetrahedron 2000, 56, 6151–6170; (b) The association constants
for the complexations between the mono- and bis-anions of the
hydroxynaphthalenes might be measured by UV methods. However, these
measurements were not considered a priority at this stage of the work and will
be addressed in a full paper. In fact, these binding constants are sufficiently
high to produce the regioselective control of the reactions described here.
12. The benzyl signals corresponding to 8–10 were assigned by comparison with
those reported in the literature for these compounds. See: Asakawa, M.; Ashton,
P. R.; Boyd, S. E.; Brown, C. L.; Gillard, R. E.; Kocian, O.; Raymo, F. M.; Stoddart, J. F.;
Tolley, M. S.; White, A. J. P.; Williams, D. J. J. Org. Chem. 1997, 62, 26–37.
Supplementary data (supplementary material contains 1H NMR
spectra for the 1:1 host–guest complexes of the dihydroxynaph-
thalenes and receptor 2 and of the crude reaction mixture for alkyl-
ation and acylation reactions both in the presence and in the
absence of receptor 2) associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2009.04.128.