Hybrid calix[4]arenes via ionic hydrogenation and transition-metal-mediated processes

Article abstract of DOI:10.1021/ol900714n

We report the first application of ionic hydrogenation for the synthesis of upper-rim urea- or carbamate-derived hybrid calix[4]arenes. Subsequent metal-mediated transformations using 4-iodophenylurea calixarenes afforded structurally unique 1,3-di(biaryl)-, 1,3-di(biarylalkyne)-, or 1,3-(biaryl)(biarylalkyne)-derived hybrid calixarenes.

Full text of DOI:10.1021/ol900714n

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2483-2486
Hybrid Calix[4]arenes via Ionic
Hydrogenation and
Transition-Metal-Mediated Processes
Sean P. Bew,* Rebecca A. Brimage, Glyn Hiatt-Gipson, Sunil V. Sharma, and
Sean Thurston
School of Chemistry, UniVersity of East Anglia, Norwich NR4 7TJ, U.K.
s.bew@uea.ac.uk
Received April 4, 2009
ABSTRACT
We report the first application of ionic hydrogenation for the synthesis of upper-rim urea- or carbamate-derived hybrid calix[4]arenes. Subsequent
metal-mediated transformations using 4-iodophenylurea calixarenes afforded structurally unique 1,3-di(biaryl)-, 1,3-di(biarylalkyne)-, or 1,3-
(biaryl)(biarylalkyne)-derived hybrid calixarenes.
This paper outlines an innovative, generic process (Scheme
1) for synthesizing carbamate or urea substituted (upper-
rim) calix[4]arenes via a protocol that is efficient and
straightforward and employs cheap commercially available
or readily synthesized reagents.
been reported, although on an industrial scale the transforma-
tion of a phenol (or an amine) into a chloroformate (or
isocyanate) is readily accomplished using phosgene; the use
of this highly toxic reagent in a laboratory setting was not
considered appropriate. The second synthesis of N-p-
halophenylurea (bromine or iodine)-derived calix[4]arenes
via reacting upper-rim appended tetra(aminomethylene) or
1,3-di(aminomethylene)calix[4]arenes with p-bromo- or
p-iodophenyl isocyanates was unattractive to us because of
the lachrymatory and moisture-sensitive properties of these
isocyanates and their relative high cost (∼$8/mmol). Interest
in calix[4]arenes,1 their derivatives, and diverse applications
within analytical, supramolecular, inorganic, and biological
chemistry can be attributed to the ease with which it is
The application of “conventional” protocols that are based
on reacting p-halophenyl isocyanates or p-halophenyl chlo-
roformate species with tetra(aminomethylene)- or 1,3-di-
(aminomethylene)-derived calix[4]arenes with the aim of
generating the corresponding N-(p-halophenyl)carbamate- or
-urea-derived calix[4]arenes was problematic. First, one of
the core starting materials, i.e., p-iodophenyl chloroformate,
used for generating the p-iodophenylcarbamate-derived
calixarenes is not commercially available nor has its synthesis
10.1021/ol900714n CCC: $40.75
Published on Web 05/15/2009
 2009 American Chemical Society

A consequence of the straightforward synthesis of tetra- and
1,3-diformylcalix[4]arenes, in addition to the ease of ex-
perimental design associated with undertaking ionic hydro-
genations, should, when these two protocols are dovetailed
together, afford a powerful procedure for the synthesis of
urea- or carbamate-derived calix[4]arenes.
Scheme 1. Synthesis of Calix[4]arenes via Ionic Hydrogenation
To initiate our work, a series of model reactions were
performed using 1. Utilizing reaction conditions reported by
Dube and Scholte6 (Scheme 2), we were delighted that
Scheme 2. Synthesis of N,O-Substituted Carbamate
Calix[4]arenes 2-8 and Bis(amine) 9
possible to chemoselectively append structurally diverse
moieties onto the upper and/or lower rim of the calix[4]arene
macrocycle.
Given the chemical and structural versatility of the
calixarene motif, it is not surprising that upper-rim appended
N,N′-disubstituted urea or N,O-disubstituted carbamate
derived calix[4]arenes are of considerable utility. With this
in mind, however, it is interesting to note that relatively few
strategies for their efficient synthesis have been reported.2
Thus, Ungaro et al. published a multistep synthesis of upper-
rim anchored 1,3-di(thio)urea calix[4]arenes in an overall
∼25% yield (over six steps).3 Furthermore, the same authors
communicated an alternative, but lower yielding, procedure
(15% overall yield for four steps) that also generated N,N′-
disubstituted (thio)ureas. Ungaro’s latter procedure employed,
as a critical step, an experimentally inconvenient 200 °C
cyanation reaction (CuCN) of p-bromocalix[4]arene that was
relatively low yielding, i.e., 56%.
Searching for an alternative protocol that did not require
high reaction temperatures or the synthesis/use of chloro-
formates or isocyanate intermediates, we considered the
possibility of performing a one-pot condensation-ionic
hydrogenation reaction between an O- or N-substituted
carbamate or urea and a formylcalix[4]arene. Ionic hydro-
genations routinely employ a binary mixture of TFA (H+
donor) and triethylsilane (H- donor) for the efficient reduc-
tion of a variety of functional groups, i.e., alkenes, dienes,
aldehydes, imines, and saturated and unsaturated ketones.4
To the best of our knowledge, there are no reports of any
ionic hydrogenation protocols being used for the synthesis
of upper-(or lower-)rim urea-functionalized calix[4]arenes.5
O-benzyl carbamate afforded the corresponding upper-rim
appended N,O-disubstituted carbamate 2 in an excellent 74%
yield. Similarly, O-tert-butyl carbamate afforded 3 in a 72%
yield. It is worthy of note that the use of TFA, a reagent
well-known for its ability to cleave N- and O-Boc groups,7
was not a concern, the tert-butyl group on 3 remaining intact
during the reaction; similarly O-allyl carbamate afforded 4
in an 81% yield. Increasing the steric bias on the upper rim,
we incorporated 5 into the ionic hydrogenation protocol.
Gratifyingly, 5 reacted with O-benzyl carbamate, O-tert-butyl
carbamate, and O-allyl carbamate to afford the corresponding
N,O-disubstituted carbamate-derived calix[4]arenes 6-8 in
unoptimized but respectrable 89%, 71%, and 76% yields.
Utilizing our efficient, one-pot synthesis of 2, it seemed
entirely plausible that cleavage of the Cbz groups off the
nitrogen atoms of 2 would generate 9. Subjecting 2 to
hydrogenation (1 atm of H2, 10 mol % of Pd/C) afforded
tetra-n-propoxy-1,3-di(aminomethylene)calix[4]arene 9 in an
excellent 89% yield (66% overall yield from 1). Thus, a
combination of ionic hydrogenation with subsequent low-
pressure hydrogenation represents an improvement, not only
in experimental design but also reaction efficiency.
As previously affirmed by Ungaro et al., upper-rim
appended 1,3-(N,N-disubstituted urea)calix[4]arenes are at-
tractive synthetic targets; however, their widespread applica-
tion and use is limited by their ease of synthesis and
availability. Utilizing fewer chemical steps via a procedure
that employed readily generated 1, an arylurea, and our ionic
hydrogenation procedure, we pondered the possibility of
efficiently synthesizing N-arylurea calix[4]arenes. Gratify-
(1) Gutsche, C. D.; Dhawan, B.; No, K. N.; Murthukrishan, R. J. Am.
Chem. Soc. 1983, 103, 3782. (a) Bo¨hmer, V. Angew. Chem., Int. Ed. Engl.
1995, 34, 713. (b) Bo¨hmer, V. Chemistry of Phenols; Rappoport, Z., Ed.;
Wiley: Chichester, England, 2003; p 1369.
(2) Rudzevich, Y.; Vysotsky, M. O.; Bohmer, V.; Brody, M. S.; Rebek,
J., Jr.; Broda, F.; Thondorf, I. Org. Biomol. Chem. 2004, 2, 3080.2.
Castellano, R. K.; Craig, S. L.; Nuckolls, C.; Rebek Jr, J. J. Am. Chem.
Soc. 2000, 122, 7876. Moon, K.; Kaifer, A. E. J. Am. Chem. Soc. 2004,
126, 15016. Gaeta, C.; Vysotsky, M. O.; Bogdan, A.; Bo¨hmer, V. J. Am.
Chem. Soc. 2005, 127, 13136.
(5) We thank one of the reviewers for bringing to our attention the
following publications: Kuno, L.; Seri, N.; Bialli, S. E. Org. Lett. 2007, 9,
1577. Agbaria, K.; Biali, S. E. J. Org. Chem. 2001, 66, 5482. Van Gelder,
J. M.; Brenn, J.; Thondorf, I.; Biali, S. E. J. Org. Chem. 1997, 62, 3511.
(6) Dube, D.; Scholte, A. A. Tetrahedron. Lett 1999, 40, 2295.
(7) Greeene, T. W.; Wuts, P. G. M. ProtectiVe Groups In Organic
Synthesis; Wiley-Interscience: Chichester, West Sussex, 1991.
(3) Casnati, A.; Fochi, M.; Minari, P.; Pochini, A.; Reggiani, M.; Ungaro,
R.; Reinhoudt, D. N. Gazz. Chim. Ital. 1996, 126, 99.
(4) Kursanor, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1973, 633.
2484
Org. Lett., Vol. 11, No. 12, 2009

ingly, 1 reacted with phenylurea (TFA, triethylsilane, MeCN,
rt) affording 10 in an isolated and unoptimized 39% yield.3
Extending the utility of the procedure, we wanted to generate
alternative N-arylcalix[4]arenes that could be further manipu-
lated via transition-metal-mediated transformations. When 1 was
reacted with 4-iodophenylurea (TFA, triethylsilane, acetonitrile,
rt), the corresponding adduct 11 was afforded in a 44% yield.
Interestingly, changing the solvent from acetonitrile to toluene
returned 11 in a significantly improved 63% yield. When
toluene was used as solvent, 4-bromophenylurea afforded 12
(47% yield), and switching to alkylureas, i.e., benzylurea,
4-pyridylmethyleneurea, and 3-chlorobenzylurea, returned the
corresponding N-alkylcalix[4]arenes 13-15 in unoptimized
57%, 76%, and 57% yields, respectively. Incorporating a
bicyclic heterocycle such as the 2-substituted benzimidazole
shown in Scheme 3 afforded the desired hybrid8 calixarene,
i.e., 16 in a 69% yield.
Scheme 4. Synthesis of
1-N-Boc-3-N-Cbz-diaminomethylenecalix[4]arene 18 and
Chemoselective N-Cbz Deprotection of 18
sponding disubstituted urea calix[4]arene 21 in a 63%
isolated yield (Scheme 5).
Scheme 3
.
Synthesis of Urea-Derived Calix[4]arenes 10-16 via
Ionic Hydrogenation of 1
Scheme 5. Synthesis of
1-N-(4-Iodophenylurea)-3-formylcalix[4]arene 20 and
1-N-(4-Iodophenylurea)-3-N-(4-chlorophenylurea)calix[4]arene
21
Notwithstanding the undoubted potential that calixarenes
appended on the upper rim with two or more different
structural motifs have, we considered the possibility of
employing our ionic hydrogenation protocol for the chemose-
lective appendage of two disparate moieties onto 1. Using a
similar process, 1 was reacted with O-benzyl carbamate (1.5
equiv, TFA, Et3SiH) and the corresponding mono-N-Cbz-
calix[4]arene 17 was returned in a 47% yield (Scheme 4).
Subsequent reaction of 17 with tert-butyl carbamate (1.5
equiv, TFA, Et3SiH) afforded orthogonally (Cbz and Boc)
N-diprotected 18 in an excellent 91% yield. Chemoselective
cleavage of the N-Cbz group on 18 via low-pressure
hydrogenation removed the N-Cbz group returning the
corresponding amine 19.
The synthesis of monourea 20 was attempted utilizing the
slightly modified reaction strategy, i.e., use of toluene as
solvent, 1, and 4-iodophenylurea. The desired monosubsti-
tuted urea derived hybrid calix[4]arene (20) appended with
a 4-iodophenyl group was returned in an unoptimized 54%
yield. Subjecting 20 to a second essentially identical ionic
hydrogenation procedure, this time substituting the 4-io-
dophenylurea for 4-chlorophenylurea, afforded the corre-
Performing a Sonogashira reaction incorporating 11 and
phenylacetylene resulted in a 79% yield of the diphenylalkyne-
derived calix[4]arene 22. The use of microwave irradiation,
DMF as solvent, piperidine, and tert-butylphosphine was found
to be critical for high yields of product. Employing these
optimized conditions, we were delighted that 11 reacted with
the R-amino acid N-Boc-O-propargyl-(S)-tyrosine methyl ester
23 affording a 71% yield of 24. Interestingly, 11 reacted with
1 equiv of N-Boc-ꢀ-alanine propargyl ester affording the
corresponding upper-rim appended ꢀ-amino acid derived hybrid
calix[4]arene 25 in 37% yield (Scheme 6).9
With the Sonogashira results in hand, we wanted to further
extend the versatility of 11 and utilize it within a Suzuki
coupling procedure for the synthesis of biaryl-appended
hybrid calix[4]arenes based on 26. After extensive prelimi-
nary investigations using alternative palladium sources, i.e.,
(8) Hybrid calixarenes have the potential to display mutiple chemical
characteristics. For example, 10 is known to bind anions,3 i.e., Cl-, while
the calix[4]arene cavity could retain a solvent molecule, i.e., toluene.
(9) Bew, S. P.; Brimage, R. A.; Sharma, S.; L’Hermite, N. Org. Lett.
2007, 9, 3713.
Org. Lett., Vol. 11, No. 12, 2009
2485

Scheme 6
.
Synthesis of Alkyne-Derived Hybrid Calix[4]arenes 22,
Scheme 8. Synthesis of Glucose-Derived Hybrid Calix[4]arene 35
via an Ionic Hydrogenation and Sonogashira Reaction Process
24, and 25 via Transition-Metal-Mediated Sonogashira Couplings
processes for generating structurally diverse calix[4]arenes.
Performing a Sonogashira coupling on 11 using 1 equiv of
phenylacetylene afforded an inseparable mixture of 22 and
36. Subjecting this mixture to a Suzuki reaction using boronic
acid 37 afforded 38 in a 35% overall yield (two steps from
11). This important result is the first example of two
sequential transition-metal-mediated reaction processes being
performed on a calix[4]arene affording a structurally diverse
product (Scheme 9).
Pd(PPh3)4, Pd(OAc)2, Pd2(DBA)3, bases, i.e., K2CO3,
Cs2CO3, CsF, solvents, and phosphines, we eventually settled
on the conditions outlined in Scheme 7. Utilizing the
Scheme 9. Synthesis of Dansyl-Appended Hybrid Calix[4]arene 38
Scheme 7. Synthesis of Biaryl-Appended Hybrid Calix[4]arenes
27-31 via Transition-Metal-Mediated Suzuki Reactions
In summary, we have demonstrated the ionic hydrogena-
tion procedure to be a convenient and experimentally
straightforward method for generating structurally diverse
urea- or carbamate-derived calix[4]arenes. Furthermore, we
have shown these important adducts can be efficiently
transformed into structurely diverse calix[4]arenes via metal-
mediated processes. This work paves the way for hybrid
calixarenes to be readily accessible and their potential within
synthetic and supramolecular chemistry to be fully explored.
conditions shown and a variety of aryl and heterocyclic
boronic acids, the synthesis of the hybrid calix[4]arenes
27-31 were achieved in good yields.
Utilizing 1, we investigated the synthesis of carbamate-
derived calixarene hybrid 35. Employing readily synthesized
32 and 1 within our standard ionic hydrogenation reaction
conditions, we isolated a partially separable mixture of a
monoreacted adduct and 33 (50%) in a combined 78% yield.
Enhancing the structural diversification of the hybrid
calix[4]arenes, we attempted to append a carbohydrate
species onto 33. Subjecting 34 and 33 to our previously
employed Sonogashira reaction conditions, we were delighted
to isolate carbohydrate derived carbamate 35 in a 45% yield
(Scheme 8).
Acknowledgment. Support from the University of East
Anglia and the EPSRC is acknowledged.
Supporting Information Available: Experimental pro-
cedures and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Confident that our protocol was robust we wanted to
exemplify our strategy of using transition-metal mediated
OL900714N
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Org. Lett., Vol. 11, No. 12, 2009