Selective Mono-O-acylation of C2V-symmetrical calix[4]arenediols with acylisocyanates

Article abstract of DOI:10.1021/ol049030n

Calix[4]arenedialkyl ethers 3 react with an excess of acylisocyanates to give selectively monoacylated products 4. Intramolecular hydrogen bonds and steric effects of the acylcarbamate fragments are most likely responsible for the high selectivity of this

Full text of DOI:10.1021/ol049030n

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2769-2772
Selective Mono-O-acylation of
C -Symmetrical Calix[4]arenediols with
2V
Acylisocyanates
Anton V. Yakovenko,† Vyacheslav I. Boyko,† Oleg V. Kushnir,† Ivan F. Tsymbal,†
,†
Janusz Lipkowski,‡ Alexander Shivanyuk,† and Vitaly I. Kalchenko*
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
02094 KyiV 02660, Murmanska str. 5, Ukraine, and Institute of Physical Chemistry,
Polish Academy of Sciences, Kasprzaka 44, 01-224 Warsaw, Poland
Vik@bpci.kieV.ua
Received May 26, 2004
ABSTRACT
Calix[4]arenedialkyl ethers 3 react with an excess of acylisocyanates to give selectively monoacylated products 4. Intramolecular hydrogen
bonds and steric effects of the acylcarbamate fragments are most likely responsible for the high selectivity of this monoprotection.
Calixarenes1 are versatile building blocks for the construction
of functional supramolecular systems through conventional
and noncovalent synthesis. Partial protection-deprotection
synthetic procedures have been developed in order to attach
different functional groups (or binding sites) to the calixarene
framework. For example, carefully controlled acylation of
tetraaminocalix[4]arene tetrapentyl ether with BOC an-
hydride afforded mono-, 1,2-di-, and tri-BOC-protected
calixarenes in preparative yields.2 Subsequent acylation-
deprotection procedures gave a wealth of calix[4]arenes
bearing two different kinds of functional groups at the wide
rim. The molecules containing hydrogen bonding frag-
ments (amides, ureas) were shown to form self-assembling
tetramers and dimeric molecular capsules.3 One amine group
of a 1,3-diaminocalix[4]arene tetraether was protected by
BOC anhydride4 in 67% yield. The resulting aminocalixarene
was used for the construction of nanosized molecular
assemblies. Selective protection of four hydroxyls of resor-
cinol-based calixarenes by aroyl, CbZ, and BOC groups
provided a general method for the synthesis of C2V-
symmetrical derivatives.5 Some of these compounds form
highly stable dimeric capsules in the presence of comple-
mentary guests.6
It is known that acylisocyanates readily react with phenols
to produce acylcarbamates,7 which can be easily cleaved
† Institute of Organic Chemistry, NASU.
‡ Institute of Physical Chemistry, PAS.
(1) For reviews, see: Gutsche C. D. Calixarenes ReVisited; Stoddart, J.
F., Ed.; The Royal Society of Chemistry: Cambridge, 1998. Calixarenes
2001; Asfari, Z., Bo¨hmer, V., Harowfield, J., Vicens, J., Eds; Kluwer
Academic Publishers: Dordrecht, 2001. Bo¨hmer, V. Angew. Chem., Int.
Ed. Engl. 1995, 34, 713. Timmerman, P.; Verboom, W.; Reinhoudt, D. N.
Tetrahedron 1996, 52, 2663.
(3) Shivanyuk, A.; Saadioui, M.; Thondorf, I.; Broda, F.; Rissanen, K.;
Vysotsky, M. O.; Kolehmainen, E.; Bo¨hmer, V. Chem. Eur. J. 2004, 10,
2138.
(4) Prins, L. J.; Jolliffe, K. A.; Hulst, R.; Timmerman, P.; Reinhoudt,
D. N. J. Am. Chem. Soc. 2000, 122, 3617.
(5) Shivanyuk, A.; Paulus, E.; Bo¨hmer, V.; Vogt, W. J. Org. Chem. 1998,
63, 6448.
(2) Saadioui, M.; Shivanyuk, A.; Bohmer, V. J. Org. Chem. 1999, 64,
3774.
10.1021/ol049030n CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/03/2004

under mild conditions. Therefore we decided to use acyl-
isocyanates as protecting agents for the hydroxy groups of
hydroxycalix[4]arene. Herein we report on the unexpected
selective monoprotection of the 1,3-dialkyl ethers of calix-
[4]arene with acylisocyanates.
in benzene or dichloromethane, in the presence of catalytic
amounts of Et3N, resulted in the selective acylation of one
hydroxy group (Scheme 2). Complete acylation did not occur
The reaction of calix[4]arene 1 with 4 equiv of trifluoro-
acetylisocyanate8 in benzene, in the presence of a catalytic
amount of Et3N, afforded tetracarbamate 2 in 55% yield
(Scheme 1).9
Scheme 2
Scheme 1
even at elevated temperature and in the presence of a large
excess of the acylating agent. Calix[4]areneacylcarbamates
4 were obtained in 44-75% yields by simple crystalliza-
tions.11 Interestingly, the reaction of Cs-symmetrical dipropyl
ether of calix[4]arene 3d (Figure 2) with 2 equiv of
acylisocyanates led to the complete acylation of the hydroxy
groups. The 1H NMR spectrum revealed that the mixture of
cone and partial cone conformers of calixdiacylcarbamates
The 1H NMR spectrum of this product contains one singlet
for the methylene protons of the bridges (δ ) 3.67 ppm)
and one set of signals for the aromatic protons. This pattern
corresponds to the 1,3-alternate conformation of the calix-
arene skeleton that has no intramolecular cavity. Accordingly,
the 13C NMR signal for the carbons of the methylene bridges
appears at 36.96 ppm, which is characteristic of an anti
orientation of adjacent phenolic rings in a 1,3-alternate
conformation.10 The IR spectrum of 2 contains two broadened
bands at 3380 and 1816 cm-1 corresponding to N-H and
CdO bonds, respectively. These bands do not shift upon
dilution, apparently as a result of the formation of intra-
molecular N-H‚‚‚OdC hydrogen bonds.
Surprisingly, the reaction of C2V-symmetrical calix[4]-
arenediols 3a-c with a 2-fold excess of the acylisocyanate
(6) Shivanyuk, A.; Paulus, E. F.; Bo¨hmer, V. Angew. Chem., Int. Ed.
1999, 38, 2906.
(7) Tsuge, O. Acyl and Thioacyl Derivatives of Isocyanates, Thiocyanates
and Isothiocyanates. In The Chemistry of Cyanates and Their Thio
DeriVaties; Patai, S., Ed.; John Willey & Sons: Chichester, New York,
Brisbane, Toronto, 1997.
(8) The reaction of calixarenes with alkylisocyanates has been studied;
see: Ko¨nig, B.; Fricke, T.; Dix, I.; Jones, P. G.; Thondorf, I. Liebigs Ann./
Recueil 1997, 2315.
(9) Calix[4]arenetetracarbamate 2. A solution of trifluoroacetyl iso-
cyanate (0.83 g, 5.94 mmol) in dry benzene (3 mL) was added to a solution
of 0.57 g (1.35 mmol) of calix[4]arene 1 in dry benzene (5 mL). The reaction
mixture was stirred at room temperature for 1 h. Then a drop of triethylamine
was added, and the reaction mixture was stirred for an additional 5 h. After
24 h the solvent and excess isocyanate were removed under reduced
pressure. The crude residue was crystallized from acetone, yielding 55%
of 2 as colorless crystals, mp (complex with acetone) 182-186 °C (decomp).
1H NMR (300 MHz, DMSO-d6) δ ppm: 2.08 (s, 12H, acetone), 3.67 (s,
8H), 6.84 (t, J ) 7.6 Hz, 4H), 7.14 (d, J ) 7.6 Hz, 8H), 10.47 (s, 4H). 19
F
NMR (CH2Cl2) δ ppm: -74.4. 13C NMR (acetone-d6) δ ppm: 36.96, 115.74
(q, JCF ) 284.8 Hz), 127.63 (Ar, C.-H, meta), 130.11, 134.55 (Ar), 148.03,
148.31, 154.82 (q, J ) 40.3 Hz). IR (CH2Cl2) cm-1: 1760 (CF3CdO),
1785 (CdO), 1816 (O-CdO), 3380 (ass. NH). Anal. Calcd for
C40H24F12N4O12‚2 acetone: C 50.28, H 3.49, N 5.10. Found: C 50.44, H
3.40, N 5.30.
Figure 1. Single-crystal X-ray structure of 4b. (Top) Side and
top view in ball-and-stick presentation. Hydrogen bonds are shown
as dashed lines. Only hydrogen atoms of the acetonitrile molecule
are shown for the sake of clarity. (Bottom) Side views in the space
filling presentation. tert-Butyl groups, some hydrogen atoms, and
the included acetonitrile molecule are not shown.
(10) Margans, J. O.; de Mendoza, J.; Pons, M.; Prados, P. J. Org. Chem.
1997, 62, 4518.
2770
Org. Lett., Vol. 6, No. 16, 2004

rim. As shown in Figure 1 (bottom) the hydroxy group of
4b is nearly completely shielded by the two methoxy groups
and the trichloroacetylcarbamate residue.
1
The H NMR spectra of compounds 4 in CDCl3 contain
doublets for the methylene protons of the bridges (J ) 13.2-
13.7 Hz), which indicates the calixarene skeleton exists in a
cone conformation. The pattern of aromatic protons reflects
the Cs-symmetry of the structure with a symmetry plane
passing through the unsubstituted and acylated phenolic rings.
The NH and OH protons emerge as somewhat broadened
singlets at 9.93-10.94 and 7.49-6.85 ppm, respectively.
They do not shift considerably upon dilution, suggesting that
the NH and OH hydrogens are involved in intramolecular
hydrogen bonds in solution as well. Accordingly, the
corresponding IR bands also showed no concentration
dependence.
Figure 2. Line formulas of compounds 3 and 5-7.
Molecular mechanics calculations have been performed
on the basis of the crystallographic coordinates of 4b.14 The
conformation of the calixarene and the hydrogen bonding
pattern do not change considerably during the optimization
procedure. Variations in the orientation of the acylcarbamate
fragment resulted in a sharp increase of the energy and, in
some cases, led to unrealistic distortions of the aromatic rings.
These results in combination with the NMR studies suggest
that the crystal structure of 4b can be considered as a realistic
snapshot of the structure in solution. Fast interconversion
between the two C1-symmetrical enantiomeric arrangements
may explain the average Cs-symmetrical NMR patterns of
compounds 4. The hydroxyl of the optimized structure is
completely shielded by the acylcarbamate fragment and two
methoxy groups (as in the crystal structure). The low
reactivity of compounds 4 and the high selectivity of the
monoprotection of calixdiols 3a-c with acylisocyanates are,
most probably, caused by this steric effect.
The ipso-nitration15 of 4c with 75% HNO3 in CH2Cl2/
AcOH occurs in the most reactive phenolic ring to afford
mononitrocalixarene 5 in 63% yield (Figure 2).16 The
benzoycarbamate group was readily cleaved by KOH in
aqueous methanol to give mononitro calixarene 6 in 68%
yield.17 Catalytic hydrogenation of 6 (H2, Raney-Ni) afforded
aminocalixarene 7 in 83% yield.18 Standard bromination
(NBS, acetone)19 of 4f resulted in a selective monobromi-
nation of the unsubstituted phenol ring.20
was formed. In the case of calixarene monopropyl ether 3e
the acylation with 5-fold excess of acylisocyanates resulted
in a complicated mixture of partially acylated products. Thus
the arrangement of groups at the narrow rim is somehow
responsible for the selective monoacylation of 3a-c with
acylisocyanates. To identify the reason for the low reactivity
of the OH group in monoacylcarbamates 4, single-crystal
X-ray analysis was carried out.
Diffraction quality crystals of trichloroacetylcarbamate 4b
were grown from acetonitrile.12,13 The molecule of 4b adopts
a slightly distorted cone conformation whose cavity is filled
with one acetonitrile molecule (Figure 1). The dihedral angles
between the aromatic rings and the main plane of calixarene
(the plane defined by the four bridging carbon atoms) are
74.2°, 54.0°, 67.2°, and 47.5°. The distances between the
methyl group of the included acetonitrile and the centers of
the calixarene aromatic rings (3.5-3.6 Å) clearly indicate
some C-H‚‚‚π interactions. The trichloroacetylcarbamate
fragment forms an intramolecular hydrogen bond with the
methoxy group (N1-O1 distance is 2.8 Å). The hydroxyl is
hydrogen bonded to one of the methoxy groups (O4-O3 )
2.8 Å), while the short distance to the other methoxy
fragment is 3.16 Å. Molecule 4b is chiral as a result of the
orientation of the hydrogen bonding groups at the narrow
(11) Trichloroacetylcarbamate (4b). A solution of trifluoroacetyl,
trichloroacetyl, or benzoyl isocyanate (1.6 mmol) in dry benzene (3 mL)
was added to a benzene solution containing calix[4]arene 3a (0.74 mmol)
and one drop of Et3N. The reaction mixture was stirred for 8 h at room
temperature (288 K). After 24 h the reaction mixture was evaporated in
vacuo. The residue was crystallized from a benzene-hexane mixture,
(14) MMX force field was used as implemented in the PC Model program
PCMODEL for Windows V. 7.50.00, 2000, Serena Software.
(15) (a) Verboom, W.; Durie, A.; Egberink, R. J. M.; Asfari, Z.;
Reinhoudt, D. N. J. Org. Chem. 1992, 57, 1313. (b) Jacobi, R. A.;Bo¨hmer,
V.; Gu¨ttner, C.; Kraft, D.; Vogt, W. New. J. Chem. 1996, 20, 493.
(16) Mononitrocalix[4]arenebenzoylcarbamate 5. Nitric acid (3 mL,
75%) was added dropwise at 0 °C to a solution, containing methylene
chloride (15 mL), glacial acetic acid (15 mL), and calix[4]arene 4c (1 g,
1.21 mmol). The reaction mixture was stirred at room temperature for 2 h
and quenched with water (15 mL). The water layer was separated and
washed with dichloromethane (2 × 5 mL). The combined organic solution
was washed with water again and dried over Na2SO4. The solvent was
removed, and the crude residue was dissolved in dichloromethane and
precipitated with methanol, yielding 63% of 5 as pale yellow crystals: mp
229-231 °C. 1H NMR (300 MHz, CDCl3) δ ppm: 0.84 (s, 18H), 1.36 (s,
9H,), 3.37 (d, J ) 13.3 Hz, 2H), 3.52 (d, J ) 13.7 Hz, 2H), 3.74 (s, 6H),
4.26 (d, J ) 13.3 Hz, 2H), 4.27 (d, J ) 13.7 Hz, 2H), 6.58 (d, J ) 2.2 Hz.
2H), 6.71 (d, J ) 2.2 Hz, 2H), 7.26 (s, 2H), 7.60 (m, 3H), 8.13 (s, 2H),
8.40 (d, 2H), 8.68 (s, 1H), 10.59 (s, 1H). Anal. Calcd for C50H56N2O8: C
73.87, H 6.94. Found: C 74.02, H 6.83.
1
yielding 67% of 4b as colorless crystals, mp 263-265 °C. H NMR (300
MHz, CDCl3) δ ppm.: 0.83 (s, 18H), 1.34 (s, 9H), 1.37 (s, 9H), 3.33 (d, J
) 13.4 Hz, 2H), 3.34 (d, J ) 13.4 Hz, 2H), 3.80 (s, 6H), 4.18 (d, J ) 13.4
Hz, 4H), 6.60 (br s, 4H), 6.95 (s, 1H), 7.12 (br s, 2H). 7.24 (br s, 2H),
10.58 (s, 1H). IR (CCl4) cm-1: 1733 (CCl3CdO), 1809 (O-CdO), 3425
(NH), 3310 (ass. OH). Anal. Calcd for C49H60Cl3NO6: C 68.01 H 6.99, N
1.62. Found: C 68.13, H 6.80, N 1.80.
(12) Crystal data for compound 4b‚2MeCN: monoclinic, P21/n, a )
12.750(3) Å, b ) 12.540(2) Å, c ) 33.750(7) Å, â ) 99.36(3)°, V (Å3) )
5324(2), Z ) 4, Dx (mg cm-3) ) 1.168, 2θmax ) 52.62°, R1 ) 0.0835,
wR2 ) 0.2157 (for 7136 reflns F > 4σ(F)), R1 ) 0.1335, wR2 ) 0.2841
(for 10567 independent reflns), 635 parameters, S ) 1.036, ∆F(min/max)
) -0.82/0.59 e Å-3
(13) (a) Sheldrick, G. M. Acta Crystallogr. A 1990, 46, 467. (b).
Sheldrick, G. M SHELXL-97-A program for crystal structure refinement;
University of Go¨ttingen, Germany, 1997.
Org. Lett., Vol. 6, No. 16, 2004
2771

In conclusion, acylisocyanates are efficient agents for
selective protection of one hydroxyl group in calixarenediols
3a-c. It seems that this selectivity is caused by a low
reactivity of the hydroxyl group in the monocarbamate 4,
which is in turn the result of intramolecular hydrogen bonds21
and steric effects.
Supporting Information Available: Characterization
details for compounds 4a,c-f and details of crystal structure
solution and refinement in cif format. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL049030N
(18) Monoaminocalixarene 7. To a suspension of mononitrocalix[4]-
arene 6 (31.4 mg, 0.0472 mmol) in 5 mL of ethanol (96%) was added 0.5
mL of hydrazine hydrate. The mixture was heated to 35 °C, and Raney-Ni
catalyst, as water suspension, (0.2 mL) was added dropwise. An immediate
release of gas was observed. After the essential part of the gas had dissipated
the reaction mixture was refluxed for 30 min. The solid disappeared, and
the solution became colorless. The catalyst was filtered off. The water-
ethanol solution was evaporated in a vacuum. The residue was washed with
water and filtered off. After drying in a vacuum calixarene 7 was obtained
as pale-pink solid: yield 83%, mp 154-156 °C. 1H NMR (CDCl3) δ ppm.:
1.00 (s, 18H), 1.28 (s, 9H), 3.24 (d, 2H, J ) 13.0 Hz), 3.34 (d, 2H, J )13.0
Hz), 3.94 (s, 6H), 4.26 and 4.30 (2d, 4H, J )13.0 Hz each), 6.48 (bs, 2H),
6.80 (d, 2H, J ) 2.5 Hz), 6.85 (d, 2H, J ) 2.5 Hz), 7.05 (bs, 2H), 7.40 (bs,
1H). Anal. Calcd for C42H53NO4: C 79.33, H 8.40 N 2.20. Found: C 79.44,
H 8.36, N 2.17.
Acknowledgment. This research was financially sup-
ported by STCU (grant RUS-09). A.V.Y. thanks foundation
Scientific Partnership for a scholarship. We thank Professor
Darren Johnson (University of Oregon) and Dr. Vadim
Timoshenko (IOC, NASU) for discussion.
(17) Mononitrocalix[4]arene 6. A water solution of KOH (0.4 mL, 0.772
mmol of KOH) was added to a solution of calix[4]arene 5 (0.2 g, 0.234
mmol) in methanol (5 mL). The reaction mixture was refluxed for 12 h.
The reaction mixture was diluted with water (2 mL) and acidified with
concentrated sulfuric acid until the yellow color of the suspension
disappeared. The precipitate was filtered off, washed with water (3 × 25
mL) and dried: yield 68%, mp 273-275 °C (decomp), white solid. 1H
NMR (300 MHz, CDCl3) δ ppm: 0.98 (s, 18H,), 1.29 (s, 9H), 3.37 (d, J
) 13.4 Hz, 2H), 3.47 (d, J ) 13.4 Hz, 2H), 3.78 (s, 6H), 4.28 (d, J ) 13.4
Hz, 4H), 6.78 and 6.90 (two m, 2H each), 7.08 (s, 2H), 7.40 (s, 1H), 8.06
(s, 2H), 8.84 (s, 1H). Anal Calcd for C42H51NO6: C 75.76, H 7.72 N 2.10.
Found: C 73.10, H 7.46, N 2.19.
(19) Casnati, A.; Fochi, M.; Minari, P.; Pochini, A.; Reggiani, Ungaro,
R. Gazz. Chem. Ital. 1996, 126, 99-106.
(20) Selective transformations of the monoacycarbamates of type 4f will
be published in a due course.
(21) Rudkevich, D. M. Chem. Eur. J. 2000, 6, 2679-2686.
2772
Org. Lett., Vol. 6, No. 16, 2004