The p-bromodienone route to nucleophilic functionalization of calixarene exo rim

Article abstract of DOI:10.1021/ol8027708

(Chemical Equation Presented) Easily accessible calixarene p-bromodienone derivatives undergo a silver-mediated nucleophilic substitution and a subsequent rearomatization with a range of different 0-nucleophiles (alcohols and carboxyiates) to give p-alkox

Full text of DOI:10.1021/ol8027708

ORGANIC
LETTERS
2009
Vol. 11, No. 3
697-700
The p-Bromodienone Route to
Nucleophilic Functionalization of
Calixarene Exo Rim
Francesco Troisi, Teresa Pierro, Carmine Gaeta, and Placido Neri*
Dipartimento di Chimica, UniVersita` di Salerno, Via Ponte don Melillo, I-84084
Fisciano (Salerno), Italy
neri@unisa.it
Received December 1, 2008
ABSTRACT
Easily accessible calixarene p-bromodienone derivatives undergo a silver-mediated nucleophilic substitution and a subsequent rearomatization
with a range of different O-nucleophiles (alcohols and carboxylates) to give p-alkoxy- or p-acyloxycalixarenes in workable yields. This approach
can be considered a general “p-bromodienone route” to functionalize calixarene exo rim with nucleophiles.
Over the past two decades, the chemical modification of
calixarenes has been largely investigated to change the
chemical and supramolecular properties of the parent mac-
rocycles.1 Among the possible approaches,2 their function-
alization at the para position of the aromatic rings (the upper
or wide or exo rim)3 has received considerable attention
because it was considered the best way to exploit the
preformed calix cavity in recognition processes. The more
common paths to introduce new functionalities at the
calixarene exo rim include a range of electrophilic aromatic
substitutions,4 and the classical “Claisen rearrangement
route”,5 “p-quinone-methide route”,6 and “p-chloromethy-
lation route”7 devised by Gutsche and Ungaro. Obviously,
in all these instances no direct attachment of a nucleophile
to the para aromatic carbon can be obtained, which, on the
other hand, would give access to a range of novel interesting
derivatives.
(1) For comprehensive reviews on calixarenes, see: (a) Bo¨hmer, V.
Angew. Chem., Int. Ed. Engl. 1995, 34, 713. (b) Ikeda, A.; Shinkai, S. Chem.
ReV. 1997, 97, 1713. (c) Gutsche, C. D. Calixarenes ReVisited; Royal Society
of Chemistry: Cambridge, 1998. (d) Calixarenes 2001; Asfari, Z., Bo¨hmer,
V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht, 2001. (e) Bo¨hmer,
V. In The Chemistry of Phenols; Rappoport, Z., Ed.; Wiley: Chichester,
UK, 2003; Chapter 19. (f) Calixarenes in the Nanoworld; Vicens, J.,
Harrowfield, J., Eds.; Springer: Dordrecht, 2007.
In a previous paper, we anticipated that a possible way to
achieve this result is the nucleophilic substitution and the
subsequent rearomatization on easily accessible calixarene
(4) The most common electrophilic aromatic substitutions include
sulfonation,4a acylation,4b nitration,4c halogenation,4d formylation,4e and
chlorosulfonation.4f For general reviews see ref 1, while for representative
or recent examples, see: (a) Shinkai, S.; Koreishi, H.; Ueda, K.; Arimura,
T.; Manabe, O. J. Am. Chem. Soc. 1987, 109, 6371. (b) Gutsche, C. D.;
Lin, L.-G. Tetrahedron 1986, 42, 1633. (c) Verboom, W.; Durie, A.;
Egberink, R. J. M.; Asfari, Z.; Reinhoudt, D. N. J. Org. Chem. 1992, 57,
1313. (d) Gutsche, C. D.; Pagoria, P. F. J. Org. Chem. 1985, 50, 5795. (e)
Arduini, A.; Fanni, S.; Manfredi, G.; Pochini, A.; Ungaro, R.; Sicuri, A. R.;
Ugozzoli, F. J. Org. Chem. 1995, 60, 1448. (f) Casnati, A.; Ting, Y.; Berti,
D.; Fabbi, M.; Pochini, A.; Ungaro, R.; Sciotto, D.; Lombardo, G. G.
Tetrahedron 1993, 49, 9815.
(2) Besides to functionalization at the para positions, these approaches
include modification at the lower rim,2a,b bridging methylenes,2c,d aromatic
walls,2e,f and meta positions.2h For general accounts see ref 1, while for
representative or recent examples, see: (a) Gutsche, C. D. Tetrahedron 1986,
42, 1633. (b) Iwamoto, K.; Araki, K.; Shinkai, S. Tetrahedron 1991, 47,
4325. (c) Columbus, I.; Biali, S. E. J. Org. Chem. 2008, 73, 2598. (d) Kogan,
K.; Columbus, I.; Biali, S. E. J. Org. Chem. 2008, 73, 7327, and references
therein. (e) Troisi, F.; Mogavero, L.; Gaeta, C.; Gavuzzo, E.; Neri, P. Org.
Lett. 2007, 9, 915. (f) Troisi, F.; Citro, L.; Gaeta, C.; Gavuzzo, E.; Neri, P.
Org. Lett. 2008, 10, 1393, and references therein. (h) Mascal, M.; Warmuth,
R.; Naven, R. T.; Edwards, R. A.; Hursthouse, M. B.; Hibbs, D. E. J. Chem.
Soc., Perkin Trans. 1 1999, 3435.
(5) Gutsche, C. D.; Levine, J. J. Am. Chem. Soc. 1982, 104, 2652.
(6) Gutsche, C. D.; Nam, K. C. J. Am. Chem. Soc. 1998, 110, 6153.
(7) Almi, M.; Arduini, A.; Casnati, A.; Pochini, A.; Ungaro, R.
Tetrahedron 1989, 45, 2177.
(3) Gutsche, C. D. Calixarenes, An Introduction; Royal Society of
Chemistry: Cambridge, UK, 2008, pp 25-26, and following chapters.
10.1021/ol8027708 CCC: $40.75
Published on Web 12/29/2008
2009 American Chemical Society

Scheme 1
Scheme 2
arene 2a, selectively obtainable in 81% yield from tripro-
poxy-p-tert-butylcalix[4]arene 1 (Scheme 1),8 was treated
with a methanolic solution of AgClO4 for 2 h at 0 °C. Soon
after the addition, a yellow precipitate of AgBr was formed.13
Column chromatography on silica gel of the reaction mixture
unexpectedly afforded p-methoxycalix[4]arene derivative 5a
in 60% yield with respect to 2a (Table 1, entry 1).13,14
The structure of 5a was easily assigned by means of
spectral analysis. In particular, the presence of a pseudomo-
lecular ion peak at m/z 749 in the ESI(+) mass spectrum
confirmed the molecular formula. The Cs symmetry was
p-bromodienone derivatives (exemplified by 2a,b in Scheme
1) recently reported by us.8 Here, we wish to report on a
study on these reactions, which can be considered as a
general “p-bromodienone route” to functionalize the calix-
arene exo rim with nucleophiles.9
The first examples of calixarene p-bromodienones were
unexpectedly obtained,8 in good yields, under conditions
usually used for the preparation of monospirodienones,10 by
treatment of the appropriate substrate with trimethylpheny-
lammonium tribromide and a saturated solution of NaHCO3
(Scheme 1). Alternatively, they can also be prepared by using
Br2/AcOH as brominating agent.11 The results of our studies8
showed that calixarene p-bromodienones are of general
accessibility when isolated, nonproximal, phenol rings are
present in the starting macrocycle.8
1
confirmed by pertinent signals in the H and 13C NMR
spectra. In particular, two 2:1 tert-butyl singlets at 0.86 and
0.94 ppm, respectively, and one OMe signal at 3.79 ppm
were a clear evidence of the displacement of a t-Bu group
by a methoxyl one, while bromine was precipitated as
AgBr.13 The absence of dienone resonances both in 1H and
13C NMR spectra and the presence of the pertinent aromatic
ones were a clear proof of the rearomatization of dienone
system. Obviously, this was also confirmed by the disap-
pearance of the typical dienone yellow color and by UV
measurements. Clearly, the complication of exo/endo ster-
eoisomerism of the starting p-bromodienone derivative 2a
was overcome in the rearomatization step.
On the basis of this result, we decided to test the reaction
directly on the mixture of exo/endo isomers of 2 to avoid an
useless isolation step. Thus, the mixture of stereoisomers 2a
and 2b, obtained by oxidation of 1 with trimethylphenylam-
monium tribromide (Scheme 1), was directly treated with a
methanolic solution of AgClO4 for 2 h at 0 °C. Column
To verify the feasibility of nucleophilic substitution of
bromine on calixarene p-bromodienones we tested the silver
ion mediated displacement with alcohols reported by Omura
for 4-bromo-2,6-di-tert-butylcyclohexa-2,5-dienone.12 Thus,
the exo stereoisomer of p-bromodienone-tripropoxycalix[4]-
(8) Gaeta, C.; Martino, M.; Neri, P. Tetrahedron Lett. 2003, 44, 9155.
(9) After the submission of this paper, a related alkoxy/de-tert-butylation
transformation based on a calixarene spirodienone derivative was reported
by Varma and co-workers (Thulasi, S.; Bhagavathy, G. V.; Eliyan, J.;
Varma, L. R. Tetrahedron Lett. 2009, 50, doi: 10.1016/j.tetlet.2008.11.118).
(10) Agbaria, K.; Aleksiuk, O.; Biali, S. E.; Bo¨hmer, V.; Frings, M.;
Thondorf, I. J. Org. Chem. 2001, 66, 2891.
(13) See the Supporting Information for additional details.
(14) In addition to 5a, tripropoxy-p-tert-butylcalix[4]arene 1 and the
corresponding tripropoxycalix[4]monoquinone were also isolated in 28%
and 9% yield, respectively.
(11) Paquette, L. A.; Hefferon, G. J.; Samodral, R.; Hanzawa, Y. J. Org.
Chem. 1983, 48, 1262.
(12) Omura, K. J. Org. Chem. 1996, 61, 7156.
698
Org. Lett., Vol. 11, No. 3, 2009

Table 1. p-Alkoxy- or p-Acyloxycalix[4]Arenes Obtained in the Silver-Mediated Nucleophilic Substitution on p-Bromodienones 2a,b
(Compounds 5a-k) and Bis(p-bromodienones) 7a-c (Compounds 8a,b).
entry
substrate
nucleophile
solvent
isolated compd (yield, %)
1
2
3
4
5
6
7
8
2a
MeOH
MeOH
EtOH
i-PrOH
PhCH2OH
MeOH
MeOH
EtOH
i-PrOH
PhCH2OH
1-octanol
allylic alcohol
propargylic alcohol
AcOH
(R)-2-butanol
DME
DME
5a (60a)
5a (42b)
5b (42b)
5c (42b)
5d (42b)
5e (42b)
5f (51b)
5g (45b)
5h (44b)
5i (46b)
5j (33b)
5k (46b)
8a (67c)
8a (40d)
8a (46e)
8b (35e)
2a,b
2a,b
2a,b
2a,b
2a,b
2a,b
2a,b
2a,b
2a,b
2a,b
2a,b
7a
1-octanol
allylic alcohol
propargylic alcohol
AcO-
(R)-2-butanol
(-)-myrtenol
N-benzyl-L-serine benzyl ester
MeOH
MeOH
MeOH
PhCH2OH
9f
10
11
12
13
14
15
16
MeOH
MeOH
MeOH
PhCH2OH
7b
7a-c
7a-c
a Yield is given with respect to 2a as starting material. b Yield is given with respect to tripropoxycalix[4]arene 1 as starting material. c Yield is
given with respect to 7a as starting material. d Yield is given with respect to 7b as starting material. e Yield is given with respect to dipropoxycalix[4]arene
6 as starting material. f This reaction was conducted in the absence of AgClO4.
chromatography on silica gel of the reaction mixture afforded
p-methoxycalix[4]arene derivative 5a in 42% yield with
respect to 1 (Table 1, entry 2).13 Clearly, in this way the
entire procedure is made more expeditious.
butoxy derivative could be traced. This difficulty could be
explained either by the steric crowding of the intermediate
p-tert-butoxydienone as well as by the lability of the final
tert-butyl ether linkage.
The formation of 5a can be explained by the silver-
mediated initial formation of carbocation 3 (aryloxenium
cation),15,16 which reacts with methanol to give intermediate
p-methoxydienone derivative 4a. This latter then undergoes
acidic de-tert-butylation to give rearomatized p-methoxy-
calix[4]arene 5a.
To verify the influence of the alcoholic moiety on the
reaction outcome, methanol was substituted by other alcohols
and, for convenience, the reaction was performed directly
on the mixture of 2a and 2b. Thus, it was evidenced that
primary (ethanol) and secondary (isopropyl alcohol) alcohols
behave in the same way giving p-ethoxy- and
p-isopropoxycalix[4]arene, 5b and 5c, both in 42% yield with
respect to 1 (Table 1, entries 3 and 4).13 On the other hand,
by using tert-butyl alcohol under various conditions no tert-
Interestingly, the reaction with an heavier primary alcohol,
namely benzylic alcohol, was successful giving
p-benzyloxycalix[4]arene 5d also in 42% yield (Table 1,
entry 5).13 Long-chain alcohols such as 1-octanol gave very
similar results (5e in 42% yield, Table 1, entry 6). Analo-
gously, unsaturated allylic and propargylic alcohols gave the
corresponding derivatives 5f and 5g in 51% and 45% yield,
respectively (Table 1, entries 7 and 8).13
To expand the potentiality of the p-bromodienone route
we decided to test acetate anion as an additional oxygen
nucleophile. Therefore, an exo/endo mixture of p-bromodi-
enones 2a,b was reacted with CH3COOK using acetic acid
as a solvent. Also in this instance, usual workup of reaction
mixture afforded p-acetoxycalix[4]arene 5h in 44% yield
(Table 1, entry 9).13
(15) Aryloxenium cations, also named as phenoxonium15a,b and
aryloxylium,15c have been frequently invoked as key intermediates in
synthetically useful oxidations of phenols.15a,b Evidence for the existence
of these cations has been often based on proposed mechanistic pathways,15d
trapping experiments,15e or the detection of UV-vis spectra of transients
from laser flash photolysis experiments,15f but examples of stable, isolatable,
highly delocalized specie are known.15g-i (a) Taylor, W. I.; Battersby, A. R.
OxidatiVe Coupling of Phenols; Marcel Dekker: New York, 1967. (b)
Swenton, J. S.; Callinan, A.; Chen, Y.; Rohde, J. L.; Kerns, M. L.; Morrow,
G. L. J. Org. Chem. 1996, 61, 1267. (c) Hegarty, A. F.; Keogh, J. P. J. Chem.
Soc., Perkin Trans. 2 2001, 758. (d) Eickhoff, H.; Jung, G.; Rieker, A.
Tetrahedron 2001, 57, 353. (e) Glover, S. A.; Novak, M. Can. J. Chem.
2005, 83, 1372. (f) Wang, Y.-T.; Wang, J.; Platz, M. S.; Novak, M. J. Am.
Chem. Soc. 2007, 129, 14566. (g) Williams, L. L.; Webster, R. D. J. Am.
Chem. Soc. 2004, 126, 12441. (h) Lee, S. B.; Lin, C. Y.; Gill, P. M.;
Webster, R. D. J. Org. Chem. 2005, 70, 10466. (i) Peng, H. M.; Webster,
To verify the p-bromodienone route on substrates bearing
two p-bromodienone systems, we decided to prepare a distal
bis(p-bromodienone) calix[4]arene derivative. Therefore,
distal dipropoxycalix[4]arene 617 was treated with trimeth-
ylphenylammonium tribromide, under conditions similar to
those used for the preparation of 2a,b, to give a mixture of
products 7a-c, which clearly originated from the exo or endo
ipso-attack of bromine to the para positions (Scheme 2).
Interestingly, repeated treatment with diethyl ether of this
reaction mixture allowed the selective precipitation of each
stereoisomer, namely exo,exo-7a (38%), exo,endo-7b (56%),
R. D. J. Org. Chem. 2008, 73, 2169
.
(16) Intermediate calixarene carbocations have been recently proposed
by Biali for the functionalization of methylene bridges under SN1 conditions
performed on the corresponding bromocalixarene derivatives.2c,d
(17) Iwamoto, K.; Shinkai, S. Tetrahedron 1991, 47, 4325.
Org. Lett., Vol. 11, No. 3, 2009
699

and endo,endo-7c (2%), which were fully characterized.13,18
At this point, exo,exo-bis(p-bromodienone) 7a was treated
with a methanolic solution of AgClO4, as described above
for 2a to give distal p-dimethoxycalix[4]arene derivative 8a
in 67% yield (Table 1, entry 13).13 As expected, the
analogous treatment of exo,endo-7b afforded 8a in a 40%
yield (Table 1, entry 14). This clearly demonstrated that
p-bromodienone route can be also applied to calixarenes
bearing two p-bromodienone systems. In addition, the
absence of exo/endo stereoisomerism in the final product 8a
induced us to test the nucleophilic substitution reaction
directly on the stereoisomeric mixture 7a-c. As expected,
good yields of 8a (46%, Table 1, entry 15) were obtained
also in this instance, making faster the entire procedure.
Substitution reaction on stereoisomeric mixture 7a-c was
also extended to the larger benzylic alcohol, which also gave
the corresponding p-dibenzyloxycalix[4]arene 8b in 35%
yield (Table 1, entry 16).
Scheme 3
The usefulness of p-bromodienone route can be increased
by a subsequent chemical modification of the introduced
nucleophile. Thus, p-benzyloxycalix[4]arene 5d can be fully
propylated (Scheme 3) to give 9 (54% yield) and then
subjected to hydrogenolysis (H2, Pd/C, Scheme 3) to give
p-hydroxycalix[4]arene 10 in 95% yield,13 which would be
more difficult to prepare by different routes.19
p-Bromodienone route can also be conveniently exploited
for introducing chirality into the calixarene structure by
appending appropriate chiral substituents. Therefore, an exo/
endo mixture of calix[4]arene p-bromodienones 2a,b was
treated with (R)-2-butanol in the presence of AgClO4 to give
the corresponding p-sec-butoxycalix[4]arene 5i in 46% yield
(Table 1, entry 10).13 In a similar way, calix[4]arene 5j,
bearing a chiral myrtenyl group, was obtained in 33% yield
by treatment with myrtenol using dimethoxyethane (DME)
as solvent (Table 1, entry 11).13
chiral derivative 5k (Table 1, entry 12), which can be
considered a novel type of “calixarene-amino acid”. Differ-
ently from other known examples of calixarene amino acid
derivatives,20 in this instance, peptide chains can be equally
grown either from the C- or the N-side.21
In conclusion, we have reported a convenient procedure
for the functionalization of calixarene exo rim by direct
attachment of a nucleophile to the para aromatic carbon. This
result was achieved through the nucleophilic substitution and
the subsequent rearomatization on easily accessible calix-
arene p-bromodienone derivatives. This approach can be
considered as a novel “p-bromodienone route” to function-
alize the calixarene exo rim with nucleophiles. In order to
expand the potentiality of this route, future work will be
directed to the use of other nucleophiles including N-, S-,
and C-nucleophiles and aromatic rings.
Supporting Information Available: Synthetic details, 1D
Under similar conditions the reaction with a serine
protected both at the amino and carboxy group, namely
N-benzyl-L-serine-benzyl ester, gave the very interesting
1
and 2D H and 13C NMR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL8027708
(18) The stereoisomeric nature of derivatives 7a-c was readily evidenced
by MS and elemental analysis data. 1H and 13C NMR spectra of more
abundant stereoisomer 7b, reported in Figure S31 and S32, evidenced the
presence of a single plane of symmetry (Cs-symmetry) and, therefore, are
only compatible with the exo,endo stereochemistry of structure 7b. The
second more abundant stereoisomer 7a, showed more symmetrical 1H and
13C NMR spectra (Figures S27-S30) indicative of the presence of two
orthogonal symmetry planes (C2V-symmetry) compatible with both exo,exo
or endo,endo stereochemistry. In addition to favorable thermodynamic and
kinetic considerations, the exo,exo stereochemistry was assigned to 7a on
the basis of a ROESY experiment (Figure S38). Consequently, the endo,endo
stereochemistry was assigned by exclusion to the far less abundant
stereoisomer 7c.
(20) Several examples of calixarenes bearing N-, or C-linked amino acid
or peptides are known: (a) Sansone, F.; Barboso, S.; Casnati, A.; Fabbi,
M.; Pochini, A.; Ugozzoli, F.; Ungaro, R. Eur. J. Org. Chem. 1998, 897.
(b) Lazzarotto, M.; Sansone, F.; Baldini, L.; Casnati, A.; Cozzini, P.; Ungaro,
R. Eur. J. Org. Chem. 2001, 595. (c) Francese, S.; Cozzolino, A.; Caputo,
I.; Esposito, C.; Martino, M.; Gaeta, C.; Troisi, F.; Neri, P. Tetrahedron
Lett. 2005, 46, 1611. In addition, a peculiar example of calixarene bearing
both an amino and a carboxy group directly bound to two distal aromatic
rings has been also reported. (d) Sansone, F.; Baldini, L.; Casnati, A.;
Chierici, E.; Faimani, G.; Ugozzoli, F.; Ungaro, R. J. Am. Chem. Soc. 2004,
126, 6204.
(21) Conceptually related calix[4]arenes constructed with L-tyrosine units
have been mentioned in a very preliminary communication: Bew, S. P.;
Sharma, S. V.; Brimage, R. A. In Abstracts of 9th International Conference
on Calixarene Chemistry (Calix 2007); College Park, MD, Aug 6-9, 2007,
SL-5.
(19) For other examples of p-hydroxycalixarenes, see ref 2h and: (a)
Morita, Y.; Agawa, T.; Nomura, E.; Taniguchi, H. J. Org. Chem. 1992,
57, 3658. (b) Gaeta, C.; Procida, G.; Gavuzzo, E.; Neri, P. J. Incl. Phenom.
Macrocycl. Chem. 2008, 60, 115.
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Org. Lett., Vol. 11, No. 3, 2009