Selective functionalization of a resorcin[6]arene

Article abstract of DOI:10.1016/j.tet.2011.10.043

The Mannich-type condensation of hexaethylresorcin[6]arene with achiral primary amines results in S₆-symmetrical hexadihydro-1,3-oxazine derivatives, which are mesoforms. The reaction with individual enantiomers of α-phenylethylamine leads to C

Full text of DOI:10.1016/j.tet.2011.10.043

Tetrahedron 67 (2011) 9715e9718
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Selective functionalization of a resorcin[6]arene
,
c
,
b
Andriy Tarnovskiy a, Alexander Shivanyuk b , Vladimir V. Rozhkov
*
a The Institute of Organic Chemistry, The National Academy of Science of Ukraine, 5 Murmanska Str., Kyiv, Ukraine
b The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov St., Kyiv 03187, Ukraine
c The Institute of Pharmacology and Toxicology, The National Academy of Medical Sciences, 14 Ejen Pottier Str., Kyiv 03680, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2011
Received in revised form 22 September 2011
Accepted 10 October 2011
Available online 19 October 2011
The Mannich-type condensation of hexaethylresorcin[6]arene with achiral primary amines results in S6-
symmetrical hexadihydro-1,3-oxazine derivatives, which are mesoforms. The reaction with individual
enantiomers of
a-phenylethylamine leads to C3-symmetrical enantiomeric hexaoxazines, which crys-
tallize from reaction mixtures in an analytically pure form.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Resorcin[6]arene
Selective functionalization
Asymmetric synthesis
1. Introduction
hydrogen bonds. The present research was undertaken in order to
develop a method for a regioselective cyclocondensation of resorcin
[6]arene 2 with primary amines and formaldehyde.
Reaction of r-tctct resorcin[6]arene 2 with primary amines and
formaldehyde gives hexaoxazines 5 in a 40% yield (Scheme 1).
Compounds 5 precipitate from the reaction mixtures and can be
easily purified by simple recrystallization. Unlike the parent
dodecaol 2, hexaoxazines 5 are very soluble in nonpolar solvents,
such as chloroform, dichloromethane, benzene, toluene, and in-
soluble in polar DMSO and methanol.
Resorcin[4]arenes 11 (Fig. 1) are excellent building blocks for
rational design of container molecules,2 ion receptors,3 self-
assembling molecular capsules,4 and hollow crystal structures.5
Compounds 1 are readily available through the thermodynami-
cally controlled acid-catalyzed condensation of resorcinol or its 2-
substituted derivatives with various aldehydes.6 In some cases,
the reaction of 2-alkylresorcinol with formaldehyde affords resor-
cin[5]- and resorcin[6]arenes.7 Acid-catalyzed condensation of
resorcinol with propionic aldehyde resulted in resorcin[6]arene 2
as a minor product (5% yield),8 which could be purified by simple
crystallization.
Single crystal X-ray analysis revealed that compound 2 has r-
trans-cis-trans-cis-trans (r-tctct) configuration and adopts a S6-
symmetrical wreath-like conformation in which the OH groups do
not form intramolecular hydrogen bonds but are solvated by polar
solvent molecules (acetone, DMSO). Only one derivative 3 was
originally synthesized through the aminomethylation of 2 with n-
dibutylamine and formaldehyde. In the crystalline state, compound
3 has r-tctct configuration and adopts a S6-symmetrical wreath-like
conformation stabilized through OeH/O and N/HeO intra-
molecular hydrogen bonds.
The 1HNMRspectrum ofcompound5ameasured in CDCl3 at 295 K
(500 MHz)contains one setof singlets for the protons of the resorcinol
rings and hydroxyl groups, whereas the diastereotopic methylene
protons of the oxazine rings emerge as pairs of AB doublets at 4.9 ppm
(Fig. 2a). The signal centered at 4.1 ppm corresponds to the protons of
the methine bridges. It arises as an ABB0 quartet apparently due to the
spinespin coupling with diastereotopic protons of the adjacent
methylene groups. The protons of the OH groups emerge as a sharp
singlet at 7.4 ppm. The double doublet with J¼23.0 Hz at 3.9 ppm
appears to be a signal of an AB system of the diastereotopic hydrogen
atoms of benzyl fragments of the dihydro-1,3-oxazine rings.
This pattern corresponds to S6-symmetrical structure A (meso-
form), in which the methine carbon atoms of the bridges have al-
ternating R- and S-configurations (Fig. 3). The 13C NMR spectrum of
compound 4a contains 14 sharp signals in accordance with the
anticipated S6-symmetrical structure A. Since the amino-
methylation with n-dibutylamine does not change the conforma-
tion of the resorcin[6]arene skeleton it seems very likely that
compounds 5 exist in a conformation similar to that of hexamine 3
(Figs. 1 and 3).
Regio- and stereoselective aminomethylation of resorcin[4]are-
nes 1 with primary amines and formaldehyde afforded a number of
cyclochiral C4-symmetrical tetraoxazine derivatives 49 possessing
extended molecular cavities stabilized by four intramolecular
* Corresponding author. Tel.: þ380 442270889; fax: þ380 4453732; e-mail ad-
dress: a.shivanyuk@gmail.com (A. Shivanyuk).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.043

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A. Tarnovskiy et al. / Tetrahedron 67 (2011) 9715e9718
Fig. 1. Structures of compounds 1e4 and a molecular structure of hexaamine 3 in the crystalline state (bottom right). Hydrogen bonds are shown in dashed lines; disordered parts
of n-butyl chains are omitted for clarity.
of the resorcinol rings and N-acetal methylene protons of the
dihydro-1,3-oxazine rings (Fig. 2b). The other protons emerge as
a complicated set of signals. The 13C NMR spectra of 5c and 5d
contain a double set of sharp signals in 1:1 ratio for all the carbon
atoms in keeping with C3-symmetrical structure B (Fig. 3) whose
Scheme 1.
The 1H NMR spectra of compounds 5a and 5b are nearly iden-
tical to those of tetraoxazines 4a and 4b. The protons in the 5-
positions of the resorcinol rings emerge at 6.6 and 7.2 ppm for
compounds 5 and 4, respectively, apparently owing to different
disposition of the resorcinol rings in the r-cccc crown and the r-tctct
wreath conformations.
Molecular mechanics calculations suggested that the r-tctct
wreath-like conformation of molecule 5 is likely to be stabilized by
six intramolecular OH/O hydrogen bonds. This type of intra-
molecular hydrogen bonding was observed for resorcin[4]arenes 4
both in the crystalline state and in solution. Accordingly, the pro-
tons of the OH groups of compounds 4 and 5 emerge in 1H NMR
spectra as slightly broadened singlets at 7.4e7.45 ppm whose shape
and position do not considerably depend on the concentration
(10ꢀ2e10ꢀ3 M, CDCl3).
The 1H NMR spectra of compounds 5c and 5d bearing six chiral
(S) and (R)-
a-phenyl-ethylamino groups, respectively, are identical
and contain a double set of signals for the protons at the 5-positions
Fig. 2. The 1H NMR spectra (500 MHz, CDCl3, 295 K) of: (a) 5a; (b) 5c and 5d.

A. Tarnovskiy et al. / Tetrahedron 67 (2011) 9715e9718
9717
groups for the ring closing reaction with formaldehyde to give
a concerted orientation of the six dihydro-1,3-oxazine rings.
In conclusion, a Mannich-type aminomethylation of r-tctct res-
orcin[6]arenedodecaol 2 with primary amines and formaldehyde
results in the formation of the hexadihydro-1,3-oxazine derivatives
whose conformations are stabilized by intramolecular hydrogen
bonds between hydroxyl groups and oxygen atoms of dihydro-1,3-
oxazine rings. This reaction results in complete functionalization of
the resorcinol rings at the 5-position and a selective alkylation of
six OH-groups. Apparently, this procedure can be used for synthesis
of wreath-like r-tctct resorcin[6]arenes bearing six functional
groups attached to the 5-positions or (and) to the oxygen atoms of
the resorcinol rings.11
2. Experimental part
2.1. General
All reactions were carried out under open atmosphere with no
precautions taken to exclude ambient moisture. Melting points
measured with a Buchi melting points apparatus are uncorrected.1H
and 13C NMR spectra were measured on a Bruker Avance DRX 500
(500 and 125 MHz, respectively) with TMS as an internal standard.
IR spectra were measured on a Vertex 70 spectrometer. HPLC anal-
yses were carried out on Agilent 1100, column EC 125/4.6 Nucleosil
100-5 (Macherey-Nagel), eluent hexaneeisopropanol 85:15 v/v.
Chiral HPLC analyses were carried outon CHIRALPAK IB 0.46ꢁ25 cm,
cellulose tris (3,5-dimethylphenylcarbamate immobilized on 15
m
silica) eluent hexaneei-PrOH (gradient 85:15 up to 70:30).
2.2. General procedure for the synthesis of compounds 5
Fig. 3. Energy-minimized structures of compounds 5a, b (A) and 5c, d (B). Time av-
eraged conformations of dihydro-1,3-oxazine rings are shown. Hydrogen bonds are
indicated by broken lines.
To a solution of resorcin[6]arene 2 (0.5 g, 0.56 mmol) in ethanol
(20 ml), formaldehyde (1 ml, 37% in H2O,14 mmol CH2O) and amine
(5 mmol) were added upon stirring. The reaction mixture was stir-
red for 8 h at ambient temperature, the precipitate was filtered off,
washed with ethanol, recrystallized from CH2Cl2$MeOH, and dried
in vacuo. Yields are not optimized. Analytical data for 5bed are
consistent with the previously reported data.10
‘asymmetric unit’ contains two diastereomeric fragments. Specific
optical rotations of compounds 5c and 5d are equal in amount and
opposite in sign. The above results indicate that dihydro-1,3-
oxazines 5c and 5d are individual enantiomers.
Compound 5a: yield 48%. Mp >300 ꢂC. 1H NMR (500 MHz,
The HPLC chromatograms of 5c and 5d (silica gel, hexaneei-
PrOH) were identical and contained one broad signal with re-
tention time 4.6 min. Unfortunately all attempts to analyze com-
pounds 5c and 5d on chiral cellulose column have failed (see
Experimental part).
CDCl3) d (ppm): 7.39 (s, 6H, OH), 6.53 (s, 6H, CH), 4.90e4.80 (m, 6H,
OCH2N), 4.08 (dd, J 9.4 Hz, 6H, CH), 3.89 (dd, J 23.0 Hz, 12H, NCH2),
2.55e2.42 (m, 12H, NCH2), 2.23e2.09 (m, 6H, CH), 2.00e1.84 (m,
6H, CH),1.84e1.70 (m, 6H, CH), 0.95e0.84 (m, 36H, CHMe2), 0.74 (t, J
7.5 Hz,18H, Me). 13C NMR (125 MHz, CDCl3)
d (ppm): 149.29,149.01,
The reaction of compound 2 with formaldehyde and racemic
a
-
124.24, 122.86, 121.64, 107.83, 83.95, 59.72, 46.51, 34.12, 28.85,
26.76, 20.60, 20.55, 12.71. IR (KBr): 3379.09 (83%), 3072.22 (82%),
2964.42 (68%), 2929.23 (73%), 2670.48 (%), 1971.09 (86%), 1601.05
(75%), 1470.37 (55%). Anal. found %: C, 72.64; H, 8.50; N, 5. 67; anal.
calcd for C90H126O12N6%: C, 72.87; H, 8.65; N, 5.52.
phenylethylamine gave a 1:1 mixture of compounds 5c and 5d. The
solution of the product did not rotate the plane of polarized light
and had 1H and 13C NMR spectra identical to those of individual
enantiomers 5c and 5d. These results indicate the remarkable
diastereoselectivity of the reaction between 2,
a
-phenylethylamine,
Compound 5b: yield 32%. Mp >300 ꢂC. 1H NMR (500 MHz,
and formaldehyde.
CDCl3) d (ppm): 7.47 (s, 6H, OH), 7.40e7.20 (m, 30H, Ph), 6.55 (m,
Compounds 5b and 5c were also prepared from compound 2
and the corresponding bisaminol ethers.10 They were postulated to
exist as 1:1 mixtures of enantiomers or diastereoisomers, re-
spectively, differing in a clock- and anti-clockwise orientation of
dihydro-1,3-oxazine fragments. It should be noted that the r-ctctct
wreath-like structures of 5b and 5c have only one concerted ori-
entation of the dihydro-1,3-oxazine rings . It is in contrast to C4-
symmetrical rccc resorcin[4]arenes 4a and 4c in which the clock
and anti-clockwise orientations of the dihydro-1,3-oxazine rings
are enantio- and diastereomeric, respectively.
6H, CH), 4.87 (s, 12H, OCH2N), 4.13 (q, J 5.0 Hz, 6H, CH), 4.00 (s, 12H,
NCH2), 3.88 (s, 12H, NCH2Ph), 2.31e2.15 (m, 6H, CH), 2.08e1.93 (m,
6H, CH), 0.82 (t, J 7.2 Hz, 18H, Me). 13C NMR (125 MHz, CDCl3)
d
(ppm): 149.43, 148.79, 137.92, 129.06, 128.54, 127.47, 124.54,
122.94, 121.85, 107.55, 82.13, 55.84, 46.63, 34.20, 28.95, 12.86. Anal.
found %: C, 76.72; H, 6.84; N, 4. 98; anal. calcd for C108H114O12N6%:
C, 76.86; H, 6.76; N, 4.81.
Compounds 5c and 5d: yield 40%. Mp 160e163 ꢂC (dec). 1H NMR
(500 MHz, CDCl3)
d (ppm): 7.45 (s, 6H, OH), 7.39e7.15 (m, 30H, Ph),
6.59 (s, 3H, CH), 6.52 (s, 3H, CH), 5.03 (d, J¼9.8 Hz, 6H, OCH2N), 4.81
and 4.78 (d, J 16.2 Hz, 6H, OCH2N), 4.16e3.84 (m, 24H, CH, NCH2,
CHPh), 2.30e2.12 (m, 6H, CHH), 2.06e1.90 (m, 6H, CHH),1.42 (m,18H,
The regioselective formation of compounds 5 can be explained
by intramolecular hydrogen bonding involving six aminomethyl
groups in the intermediate hexaminomethylated resorcin[6]arenes
(like in hexaamine 3) that preorganize the amino and hydroxyl
Me), 0.87e0.73 (m, 18H, Me). 13C NMR (125 MHz, CDCl3)
d
(ppm):
149.37, 149.32, 149.34, 144.26, 144.16, 128.56, 128.50, 127.44, 127.32,

9718
A. Tarnovskiy et al. / Tetrahedron 67 (2011) 9715e9718
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127.25, 124.27, 123.13, 122.85, 121.67, 121.50, 107.96, 107.86, 81.05,
80.91, 58.02, 57.99, 44.54, 44.33, 34.19, 28.93, 28.82, 21.72, 21.62,
12.99, 12.90; 5c [
a
]
293K ꢀ81ꢃ1 (c 0.03, CHCl3). Anal. found %: C, 77.13;
D
H, 6.98; N, 4. 63; anal. calcd for C114H126O12N6%: C, 77.28; H, 7.12; N,
4.75. 5d[
a
]
293K 82ꢃ2(c0.03, CHCl3).Anal. found%:C,77.23;H, 7.04;N,
D
4, 58; anal. calcd for C114H126O12N6%: C, 77.28; H, 7.12; N, 4.75.
3. Molecular mechanics calculations
MMX force field was used as implemented in PCMODEL
7.50.00.12 Crystallographic coordinates of hexamine 3 were used for
generating the initial structures.
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