Selective Derivatizations of Resorcarenes. 4. General Methods for the Synthesis of C2v-Symmetrical Derivatives

Full text of DOI:10.1021/jo981386n

6448
J . Org. Chem. 1998, 63, 6448-6449
Sch em e 1
Selective Der iva tiza tion s of Resor ca r en es. 4.
Gen er a l Meth od s for th e Syn th esis of
C2v-Sym m etr ica l Der iva tives
Alexander Shivanyuk,† Erich F. Paulus,‡
Volker Bo¨hmer,*,† and Walter Vogt†
Institut fu¨r Organische Chemie, J ohannes
Gutenberg-Universita¨t, J .-J .-Becher Weg 34 SB1,
D-55099 Mainz, Germany, and Hoechst-Marion-Roussel
Deutschland GmbH, D-65926 Frankfurt, Germany
Received J uly 16, 1998
Resorcarenes 11 are easily prepared by acid-catalyzed
condensation of resorcinol with various aldehydes. The
bowl-shaped all-cis isomers have been frequently used as
building blocks for the synthesis of covalently linked con-
tainer molecules2 as well as for the construction of self-
assembled structures.3 Although many complete and some
partial derivatizations of resorcinol units have been de-
scribed for compounds 1,4 truly regioselective partial conver-
sions5 are scarce. For example, the tetraphosphorylation
and tetrasulfonylation lead to C2v-symmetrical derivatives6
in reasonable yields. However, neither phosphoryl nor
sulfonyl groups are suitable protecting groups due to dif-
ficulties with their removal.
Sch em e 2
We have now found conditions for the regioselective
tetraacylation of resorcarenes 1 that are applicable to
various aroyl and heteroaroyl chlorides as well as benzyl
chloroformate. The tetraesters obtained are promising
intermediates for the synthesis of C2v-symmetrical tetra-
ethers, aliphatic tetraesters, and resorcarene derivatives
that are selectively substituted in the 2-positions of opposite
resorcinol rings.
Typically, the reaction of octaols 1a -c with acid chlorides
was performed in MeCN in the presence of Et3N as base
(molar ratio 1:4:4). The addition of Et3N to a solution of 1
caused the formation of a pink precipitate, most probably
the complex of 1 with Et3N.7 After addition of the acid
chloride, this complex immediately dissolved, and later a
white precipitate of 2‚2Et3NHCl was formed. Fast addition
of the acid chloride with vigorous stirring of the reaction
mixture is crucial for the purity of the products. A slow,
† University of Mainz.
‡ Hoechst Marion Roussel.
(1) For a recent review see: Timmerman, P.; Verboom, W.; Reinhoudt,
D. N. Tetrahedron 1996, 52, 2663-2704.
(2) (a) Cram, D. J .; Cram, J . M. Container Molecules and Their Guests;
Stoddart, J . F., Ed.; Monographs in Supramolecular Chemistry; The Royal
Society of Chemistry: Cambridge, U.K., 1994. (b) Chopra, N.; Sherman, J .
C. Angew. Chem., Int. Ed. Engl. 1997, 36, 1727-729.
(3) (a) Chapman, R. G.; Sherman, J . C. Tetrahedron 1997, 53, 15911-
15945. (b) MacGillivray, L. R.; Atwood, J . L. Nature 1997, 389, 469-472.
(c) J acopozzi, P.; Dalcanale, E. Angew. Chem., Int. Ed. Engl. 1997, 36, 613-
615.
dropwise addition of the acylating agent usually resulted
in the formation of complicated mixtures that could not be
separated. Tetraesters 2-4 were isolated in 30-50% yield
by simple recrystallization.8 Their structures were unam-
(4) For example see: (a) Xu, W.; Rourke, J . P., Vittal, J . J .; Puddephat,
R. J . J . Am. Chem. Soc. 1993, 115, 6456-6457. (b) Cram, D. J .; Karbach,
S.; Kim, H.-E.; Knobler, C. B.; Maverick, E. F.; Ericson, J . L.; Helgeson, R.
C. J . Am. Chem. Soc. 1988, 110, 2229-2237. (c) Airola, K.; Bo¨hmer, V.;
Paulus, E. F.; Rissanen, K.; Schmidt, C.; Thondorf, I.; Vogt, W. Tetrahedron
1997, 53, 10709-10724. (d) Cram, D. J .; Tunstad, L. M.; Knobler, C. B. J .
Org. Chem. 1992, 57, 528-535. (e) Cram, D. J ., Tanner, M. E.; Bryant, J .
A.; Knobler, C. B. J . Am. Chem. Soc. 1992, 114, 7748-7765. (f) Konishi,
H.; Tamura, T.; Ohkubo, H.; Kobayashi, K.; Morikawa, O. Chem. Lett. 1996,
685-686. (g) Sorrel, T. N.; Richards, J . L. Synlett 1992, 155-156.
(5) In such a reaction the product should be easily available in yields
distinctly higher than the statistically predicted amount.
(6) (a) Kalchenko, V. I.; Rudkevich, D. M.; Shivanyuk, A. N.; Pirozhenko,
V. V.; Tsymbal, I. F.; Markovsky, L. N. Zh. Obsch. Khim. (Russ.) 1994, 64,
731-742. (b) Lukin, O. V.; Pirozhenko, V. V.; Shivanyuk, A. N. Tetrahedron
Lett. 1995, 36, 7725-7729.
1
biguously proved by H and 13C NMR spectroscopy, by FD-
mass spectrometry, and by single-crystal X-ray analysis (see
1
below).9 The H NMR spectra of compounds 2-4 show four
singlets for the aromatic protons of the calixarene skeleton,
one signal for the hydroxy and methine protons, and one
set of signals for the acyl fragments in accordance with the
C
2v-symmetrical structure.
The regioselectivity observed depends strongly on the
solvent, the base, and the acylating agent. No selective
acylation took place, for instance, with acetyl chloride (as
well as acetic anhydride), acryloyl, pivaloyl, and p-nitroben-
(7) MacGillivray, L. R.; Atwood, J . L. J . Am. Chem. Soc. 1997, 119, 6931-
6932.
S0022-3263(98)01386-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/01/1998

Communications
J . Org. Chem., Vol. 63, No. 19, 1998 6449
tetraether 5c (68%), which on hydrolysis (MeOH/H2O, KOH)
gave quantitatively the resorcarene tetraacid 6c.12
The tetraesters 2 undergo selective electrophilic substitu-
tions in the free resorcinol rings (bromination with NBS,
aminomethylation with primary and secondary amines) to
give derivatives 7a -c in 70-80% yield.13 The alkaline
hydrolysis of the dibromo derivative 7a (MeOH/H2O, KOH,
60 °C) gave the corresponding dibromo resorcarene 8a ,14 but
all attempts to cleave the ester groups in compounds 7b and
7c have failed. However, the regioselective aminomethyla-
tion of the tetracarbonate 6b gave the diamine 7d (78%),
which by cleavage of the BOC groups (TFA, CH2Cl2, rt) was
quantitatively transformed into the 1,3-bis-aminomethylated
resorcarene 8b.15 These results demonstrate the potential
of using the ester functions as protecting groups in the
rational syntheses of C2v-symmetrical resorcarenes.
Single crystals of the p-methylbenzoates 2b and 3b were
obtained from DMSO and MeCN, respectively. Surprisingly,
their molecular conformation is significantly different.
The molecules of 2b assume a boat conformation in which
the acylated resorcinol rings are nearly parallel (dihedral
angle 5.6°) and the unsubstituted rings are coplanar (dihe-
dral angle 168.9°). Each of the four hydroxy groups forms
a hydrogen bond to an individual DMSO molecule (Figure
1a), while a fifth DMSO molecule fills the voids in the
crystalline lattice.
The distortion of the crown (cone) conformation of mol-
ecule 3b is less pronounced and in the opposite direction
(Figure 1b). Here the two unsubstituted resorcinol units are
bent inward, including a dihedral angle of 33.0°, while the
two acylated resorcinol units assume an interplanar angle
of 127.9°. No intramolecular hydrogen bonds were found
between neighboring hydroxy and carboxy groups. Three
hydroxyl groups of 3b are involved in intermolecular hy-
drogen bonds with three acetonitrile molecules, and the one
remaining is hydrogen bonded to the carboxy group of the
next resorcarene molecule (O01-O09A ) 2.857 Å). In this
way, infinite chains of hydrogen bonded molecules 3b are
formed.
This result of the X-ray analysis suggests that the energy
difference between the two possible boat conformations of
tetrabenzoates 2 is rather small. A conformation with either
parallel or coplanar resorcinol units can be “selected” to build
up the crystal depending on packing and solvation effects.16
In conlusion, C2v-symmetrical tetraesters of resorcarenes
are readily available in gram quantities by simple synthetic
and purification procedures. Not only are these compounds
interesting building blocks themselves, but they also open
up the way to synthesize further C2v-symmetrical derivatives
via protection/deprotection strategies.
F igu r e 1. (a) Molecular structure of 2b‚5DMSO. Hydrogen bonds
are shown by dotted lines. The non-hydrogen-bonded DMSO
molecule is omitted for clarity. O203-O23 ) 2.604 Å; O204-O24
) 2.642 Å; O207-O27 ) 2.580 Å; O208-O28 ) 2.726 Å. (b)
Molecular structure of 3b‚3MeCN‚H2O. The disordered water
molecule is not shown. O02-N3 ) 2.851 Å, O05-N2 ) 2.850 Å,
O06-N1 ) 2.836 Å.
zoyl chlorides, 1-adamantylcarbonyl chloride, and isobutyl
chloroformate. The tetraacylation with aroyl chlorides was
also regioselective when i-Pr2NEt was used as the base in
contrast to i-Bu3N or pyridine. Although a definite reason
for the selectivity remains as yet unknown, it is clear that
complexation with R3NHCl plays a crucial role.10
It is important that the analogous acylation with benzyl-
chloroformate allows the regioselective protection11 of four
hydroxy groups. The four remaining hydroxy groups can
be further acylated, for instance, with acetic and BOC
anhydrides to give the octaesters 5a ,b. The mild removal
of the Z groups by catalytic hydrogenation (Pd/C, dioxane,
rt) resulted in tetraesters 6a ,b (90%), which are not available
by direct acylation (Scheme 2). Similarly, the alkylation of
2b with ethyl bromoacetate (K2CO3, MeCN) led to the
Ack n ow led gm en t . This work was supported by the
Deutsche Forschungsgemeinschaft and by the Commission
of the European Communities.
(8) General Procedure for the tetraacylation. To a vigorously stirred
suspension or solution of octanol 1 (10 mmol) in dry MeCN (100 mL) was
added Et3N (40 mmol) in one portion. The suspension formed was stirred
at room temperature for 10-15 min, and then the solution of acid chloride
(40 mmol) was added in one portion. The precipitate was completely
dissolved (assistance by vigorous stirring), and within 3-20 min a colorless
precipitate was formed again. The reaction mixture was stirred at room
temperature overnight. The precipitate was filtered off, washed with MeCN
(2 × 10 mL) and H2O (3 × 10 mL), and recrystallized from MeCN, DMSO,
DMSO/H2O, and DMF/H2O.
Su p p or tin g In for m a tion Ava ila ble: Characterization data
and crystallographic details (48 pages).
J O981386N
(9) Selected Crystallographic Data. 2b‚5DMSO: orthorhombic, space
group Pna2(1), a ) 23.547(5) Å, b ) 15.871(3) Å, c ) 40.116 (8) Å, V )
14992(5) Å3, Z ) 8, Dc ) 1.247 g/cm3, R ) 0.0630 (for 10261 reflections I >
(12) The tetraalkylation of 1a by ethyl bromoacetate was possible only
in a rather poor yield of about 10%. The C2v-symmetrical structure of this
tetraether was confirmed by single-crystal X-ray analysis of its tetraac-
etate: Shivanyuk, A.; Bo¨hmer, V.; Paulus E. F. Unpublished results.
(13) Bis-benzoxazine 7c has a C2-symmetrical structure similar to the
analogous derivative from a resorcarene tetratosylate; see: Shivanyuk, A.,
Schmidt, C.; Bo¨hmer, V.; Paulus, E. F.; Lukin, O. V.; Vogt, W. J . Am. Chem.
Soc. 1998, 120, 4319-4326.
2((I)), wR(F2)
) 0.1266 (for all 15802 unique reflections), S ) 1.14.
3b‚3MeCN‚H2O: monoclinic, space group C2/c, a ) 43.1478(3) Å, b ) 16.330
Å, c ) 23.0436 (2) Å, â ) 92.0436 (2)°, V ) 16226.3(3) Å3, Z ) 8, Dc ) 1.132
g/cm3, R ) 0.1280 (for 5883 reflections I > 2((I)), wR(F2) ) 0.2412 (for all
12873 unique reflections), S ) 1.14.
(10) It has been shown that resorcarenes 1 and their tetraanions are
able to complex tri- and tetraalkylammonium salts: (a) Murayama, K.; Aoki,
K. Chem. Commun. 1997, 119-120. (b) Lippmann, T.; Wilde, H.; Pink, M.;
Scha¨fer, A.; Hesse, M.; Mann, G. Angew. Chem., Int. Ed. Engl. 1993, 32,
1195-1197. (c) Schneider, H.-J .; Gu¨ttes, D.; Schneider, U. J . Am. Chem.
Soc. 1988, 110, 6449-6454.
(14) This compound was recently prepared by partial bromination of
1a : Konishi, H.; Nakamaru, H.; Nakatani, H.; Ueyama, T.; Kobayashi, K.;
Morikawa, O. Chem. Lett. 1997, 185-186.
(15) All attempts to synthesize compound 8b by reaction of 1a with 2
equiv of Et2NH and CH2O were unsuccessful.
(16) Tetraester 2d adopts in the crystalline state the boat conformation
with coplanar acylated resorcinol rings, similar to 3b: Paulus, E. F.;
Shivanyuk, A.; Bo¨hmer, V. Unpublished results.
(11) Kocienski, P. J . Protecting Groups; Georg Thieme Verlag: Stuttgart,
New York, 1994.