Azacalix[4]arene tetramethyl ether with inherent chirality generated by substitution on the nitrogen bridges

Article abstract of DOI:10.1016/j.tetasy.2009.01.017

The first inherently chiral azacalix[4]arene has been prepared by introducing three benzyl groups onto the nitrogen bridges. The highly enantioenriched compound was easily obtained via a moderately enantioselective cyclization followed by a simple crystal

Full text of DOI:10.1016/j.tetasy.2009.01.017

Tetrahedron: Asymmetry 20 (2009) 375–380
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Azacalix[4]arene tetramethyl ether with inherent chirality generated
by substitution on the nitrogen bridges
*
Koichi Ishibashi, Hirohito Tsue , Hiroki Takahashi, Rui Tamura
Graduate School of Human and Environmental Studies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first inherently chiral azacalix[4]arene has been prepared by introducing three benzyl groups onto
the nitrogen bridges. The highly enantioenriched compound was easily obtained via a moderately enan-
tioselective cyclization followed by a simple crystallization procedure. NMR and X-ray crystallographic
studies revealed that easy access to the enantiomer was permitted by the non-racemizable 1,3-alternate
conformation in solution, up to 110 °C, as well as by the preferential crystallization of a racemic
compound.
Received 20 December 2008
Accepted 15 January 2009
Available online 13 February 2009
This paper is dedicated to Professor
Yoshiteru Sakata on the occasion of his 70th
birthday
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
catalyzed by Pd(0) complex.10,12 Another advantage is the presence
of the easily functionalizable nitrogen bridges, of which the appro-
The term ‘inherent chirality’ is employed for three-dimensional
molecular frameworks that lack a mirror plane, an inversion cen-
ter, or an alternating axis in the molecules.1–4 Certain fullerenes,2
molecular clips,3 and calixarenes with a specific substitution pat-
tern1,4 can show inherent chirality. Of them, inherently chiral
calixarenes have attracted much interest in both fundamental re-
search and application, including enantioselective molecular rec-
ognition and asymmetric catalysis.4 A variety of inherently chiral
calixarenes were prepared in a sophisticated manner by introduc-
ing achiral substituents to the upper- and/or lower-rim in an asym-
metric or dissymmetric fashion.1,4 In contrast, the bridging units5
are less exploited for generating inherent chirality; to the best of
our knowledge, the use of achiral substituents has only been re-
ported for thiacalix[4]arene, of which the inherent chirality was
generated via the partial oxidation of the sulfur bridges.6 In these
foregoing studies, the inherently chiral calixarenes and thiaca-
lix[4]arenes anchoring the achiral substituents on the periphery
were initially prepared as racemates, which were then resolved
into each enantiomer by a direct HPLC separation or through the
derivatizations to the corresponding diastereomer.1,4,6 The direct
enantioselective synthesis has been limited, though highly favor-
able from a synthetic point of view, to three examples in which
inherently chiral calix[4]arenes and resorcinarene are prepared
by lipase-catalyzed transesterification,7 kinetic resolution,8 or ster-
eoselective synthesis exploiting chiral auxiliaries.9
priate N-substitution can generate inherent chirality in the mole-
cule, as shown in Figure 1 where all possible conformations and
N-substitution patterns for creating inherently chiral azaca-
lix[4]arenes are schematically summarized. Herein, in order to ver-
ify this fundamental and widely applicable approach, we have
prepared azacalix[4]arene 1 by introducing three benzyl groups
onto the nitrogen bridges in an AAAB substitution pattern. As a re-
sult, it was found that the direct enantioselective synthesis of
inherently chiral azacalix[4]arene 1 in a 1,3-alternate conforma-
tion was feasible in high yields with moderate enantioselectivities.
More interestingly, simple crystallizations of the resulting enanti-
omerically enriched 1 allowed us to isolate the enantiomer. Herein,
we report the synthesis, molecular structure, and enantiomeric
enrichment of azacalix[4]arene 1, which furnishes the first exam-
ple of an inherently chiral nitrogen-bridged calixarene analog.
2. Results and discussion
Inherently chiral azacalix[4]arene 1 was prepared by modifying
our previously reported procedure for the synthesis of achiral 2.13
As shown in Scheme 1, the synthesis started from additional Boc
protection of the terminal amino group of linear tetramer 313 using
Boc2O in the presence of DMAP. The product 4 was subjected to
N-benzylation of the bridging nitrogen atoms, and the subsequent
deprotection of Boc groups afforded N0,N00-tribenzylated acyclic tet-
ramer 5 in 64% yield in two steps. Finally, racemic azacalix[4]arene
( )-1 was obtained in 65% yield (Table 1, entry 1) by intramolecular
cyclization reaction of precursor 5 using a Pd(0)-catalyzed Buch-
wald–Hartwig aryl amination reaction.12 The reaction yield was
improved by switching the ligand from t-Bu3P to ( )-BINAP to
afford ( )-1 in 81% yield (entry 2). The observed high yield is nota-
ble because the nitrogen-bridged calixarene analogs reported thus
We anticipate that the nitrogen-bridged calixarene analogs10,11
would provide an easier access to inherent chirality via direct
enantioselective synthesis because azacalixarenes have been gen-
erally prepared using Buchwald–Hartwig aryl amination reaction
* Corresponding author. Fax: +81 75 753 6722.
E-mail address: tsue@ger.mbox.media.kyoto-u.ac.jp (H. Tsue).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.01.017

376
K. Ishibashi et al. / Tetrahedron: Asymmetry 20 (2009) 375–380
t-Bu
R1
R1
N
N
N
N
OMe
OMe MeO
OMe
1: R1 = Bn, R2 = H
2: R1 = R2 = Me
t-Bu
t-Bu
R2
R1
t-Bu
Partial Cone
A A
1,2-Alternate 1,3-Alternate
A
A
A
A
A
A
A
N
N
N
N
N
N
N
N
N
N
N
N
N
C1
C1
C2
C2
AAAB
N
N
N
B
A B
B
A
A
A
B
A
A
A
N
N
N
N
N
N
C1
C1
AABB
ABAB
N
N
B
A
B
B
B
B
A
B
N
N
N
N
N
N
N
N
C1
D2
B
A
B
A
A
B
A
C
B A
B
A
A
C
B
A
N
N
N
N
N
N
N
N
N
N
N
N
N
N
C1
C1
C2
C2
ABAC
N
N
A C
C
A
Figure 1. Possible conformations and substitution patterns on the nitrogen bridges of inherently chiral azacalix[4]arenes (only one enantiomer shown). A, B, C, and D denotes
N-substituent groups, and black/white rectangles represent the aromatic units pointing upward/downward, respectively. Possible highest point groups are indicated in the
center of each molecule. Substitution patterns AABC and ABCD always generate inherent chirality, irrespective of the conformation, including a cone conformation.
t-Bu
t-Bu
t-Bu
t-Bu
R1
R1
R1
iv
1
(see Table 1)
Br
NR2R3
N
N
N
OMe
OMe
OMe
OMe
1
2
3
3
: R = R = H, R = Boc
4: R1 = H, R2 = R3 = Boc
i
ii, iii
1
2
3
5
: R = Bn, R = R = H
Scheme 1. Synthesis of inherently chiral azacalix[4]arene 1. Conditions: (i) Boc2O, DMAP (cat.), THF, reflux, 83%. (ii) BnBr, NaH, DMF, ꢀ20 °C to 0 °C. (iii) TFA/CH2Cl2 (1:1),
room temperature, 64% in two steps. (iv) Pd(dba)2, Ligand, t-BuONa, PhMe, reflux.
far have been generally synthesized in low yields;10 for example,
fully methylated azacalix[4]arene 2 was prepared in 37% yield.13
The lack of an alkyl group on the reacting terminal nitrogen atom
in 5 precludes the undesirable b-elimination side reaction,12,14
thereby improving the reaction yield of the intramolecular
cyclization.
A single crystal suitable for X-ray crystallography was obtained
from the hexane solution of ( )-1. As shown in Figure 2a, azaca-

K. Ishibashi et al. / Tetrahedron: Asymmetry 20 (2009) 375–380
377
Table 1
Effect of ligands on the Pd(0)-catalyzed intramolecular cyclization reaction of 5a
Entry
Ligand
Product
Yieldb (%)
eec (%)
1d
2
3
4
5
t-Bu3P
( )-BINAP
(R)-BINAP
(R)-SEGPHOS
(R)-DTBM-SEGPHOS
( )-1
( )-1
(+)-1
(+)-1
—
65
81
81
78
0
0
0
21
35
—
a
Conditions: acyclic tetramer 5 (0.10 mmol), 5 mol % Pd(dba)2, 7.5 mol % ligand,
t-BuONa (0.20 mmol), and toluene (20 mL, 5 mM).
b
Isolated yield.
c
Determined by HPLC analysis using a Daicel Chiralpak AD column.
20 mol % Pd(dba)2 and 16 mol % t-Bu3P were used.
d
lix[4]arene 1 adopts a slightly distorted 1,3-alternate conformation
similar to that of 2.13 Two enantiomers of 1 are alternatively
packed in the crystal (Fig. 2b and c), indicating that the crystal of
( )-1 is classified as a racemic compound.
The 1,3-alternate conformation of 1 is also retained in solution.
The 1H NMR spectrum (Fig. 3a) comprised two sharp singlet signals
(1:1 intensity ratio) for the methoxy protons, four doublet signals
(1:1:1:1) for the skeletal aromatic protons, and two sets of double
doublet signals (1:2) for the diastereotopic N-benzylic protons,
indicating that azacalix[4]arene 1 had a time-averaged C2-symme-
try in solution. The methoxy hydrogens experienced an upfield-
shift characteristic of a 1,3-alternate conformation, as in the case
of 2.13 The conformation was further supported by ROESY measure-
ment, where the close proximity of the methoxy and aromatic
hydrogens was observed (Fig. 3b), implying that azacalix[4]arene 1
adopted a 1,3-alternate conformation in solution.
More important is the conformational stability of 1 in solution
because inherently chiral calix[4]arenes may be racemized by the
macrocyclic ring inversion via the ‘lower rim through the annulus’
pathway.16 To elucidate the molecular flexibility of 1, the 1H NMR
relaxation time (T1) was determined. In our previous report,17 this
technique was successfully applied to 2 to conclude the inflexible
1,3-alternate conformation of 2, on the basis of the small T1 value
(1.03 s) of the aromatic protons as compared to that of conforma-
tionally flexible thiacalix[4]arene (2.51 s).18 The T1 values for each
aromatic proton a, b, c, and d of 1 were determined to be 0.98, 0.74,
0.77, and 0.77 s, respectively. The observed T1 values are compara-
ble to those of 2, eventually demonstrating that the 1,3-alternate
conformation of 1 is also rigid in solution. The conformational sta-
bility of 1 was clearly reflected in the perfect separation of the two
enantiomers by using HPLC analysis (Fig. 4).
Our efforts were next directed to the preparation of enantiome-
rically enriched azacalix[4]arene 1 through a Pd(0)-catalyzed aryl
amination reaction using a chiral ligand. Under the optimized reac-
tion conditions (Table 1), the enantioselective intramolecular cycli-
zation of 5 was examined. The cyclization reaction, catalyzed by
5 mol % Pd(dba)2/(R)-BINAP,19 proceeded smoothly to afford (+)-
enriched 1 in 81% yield, although the enantioselectivity (21% ee)
was unsatisfactory (Table 1, entry 3). The low ee observed seems
to be caused by racemization resulting from the macrocyclic ring
inversion of 1 at a high temperature. However, this was not the
case for 1 because no racemization of 1 took place at 110 °C for
at least 6 h. The enantioselectivity was further improved to 35%
ee by using (R)-SEGPHOS20 (entry 4), whereas no cyclization reac-
tion occurred when using (R)-DTBM-SEGPHOS20 (entry 5), which
was reported to be the most effective ligand in the similar asym-
Figure 2. (a) ORTEP drawing15 of racemic azacalix[4]arene ( )-1 (one enantiomer
shown), and (b) and (c) its crystal packing. In panel (a), the displacement ellipsoids
are drawn at the 50% probability level. All the hydrogen atoms except for the
bridging NH hydrogen atom are omitted for clarity. In panels (b) and (c), each of the
enantiomers is indicated using black or gray color.
metric N-arylation reactions.21 It is likely that 3,5-di-tert-butyl-4-
methoxyphenyl groups on the phosphorus atoms of DTBM-SEG-
PHOS are too bulky to bring about the cyclization reaction of 5.
Although high enantioselectivity was not achieved in the present
study, it is worth noting that the inherently chiral 1 can be pre-
pared with a moderate enantioselectivity by using a chiral Pd
catalyst.
By using (S)-BINAP as the ligand, (ꢀ)-enriched 1 was also ob-
tained with an analogous enantioselectivity (18% ee). Crystalliza-
tion of (ꢀ)-1 of 18% ee from MeCN with a few drops of MeOH
gave crystals of nearly racemic 1 (3% ee), leading to the enantio-
meric enrichment of (ꢀ)-1 to 45% ee in the mother liquor. After
the crystallization was repeated five times, (ꢀ)-1 in 99% ee was ob-
tained. The enantiomeric antipode was also obtained by applying
this process to (+)-enriched 1. As shown in Figure 5, (+)- and (ꢀ)-
X-ray crystallographic analysis revealed that the three bridging nitrogen atoms
with benzyl groups adopted an almost planar geometry as evidenced by the 351.4°,
356.4°, and 356.2° summations of the three CNC bond angles. Nitrogen inversion is
generally rapid in solution, and the local site chirality generated by the slightly
pyramidal nitrogens is thus negligible.

378
K. Ishibashi et al. / Tetrahedron: Asymmetry 20 (2009) 375–380
Figure 5. CD and UV–vis spectra of inherently chiral azacalix[4]arene 1 in hexane.
Enantiomeric excesses of the samples were 87% ee for (+)-1 and 99% ee for (ꢀ)-1.
calixarenes.3 As a result, the easy access to both enantiomers of 1
was accomplished by its inflexible and thereby non-racemizable
structure, as well as the preferential deposition of the racemic
compound crystal (Fig. 2b and c), the stability of which is sup-
ported by the experimental result that the melting point of ( )-1
is ca. 90 °C higher than that of (ꢀ)-1 of 99% ee.
3. Conclusion
In conclusion, we have clearly demonstrated that the first inher-
ently chiral azacalix[4]arene 1 can be prepared in high yields by
the direct enantioselective synthesis using a chiral Pd(0) catalyst.
Although the enantioselectivity was unsatisfactory, the enantio-
mer of 1 was easily obtained by a simple crystallization procedure
owing to the non-racemizable 1,3-alternate conformation in solu-
tion as well as the preferential crystallization of the racemic com-
pound. Our efforts are now being directed toward preparing a
single crystal of the isolated enantiomers of 1 in order to determine
the absolute configuration.
Figure 3. (a) 1H NMR and (b) ROESY spectra of inherently chiral azacalix[4]arene 1
in CDCl3 at room temperature.
4. Experimental
4.1. General
Melting points were determined on a Yanaco MP-J3 apparatus
and are uncorrected. NMR spectra were recorded on a JEOL JNM-
A500 instrument using tetramethylsilane (1H NMR) and solvent
resonance (13C NMR) as internal standards. 1H NMR relaxation
time measurements were performed on
a JEOL JNM-EX270
Figure 4. HPLC analysis of racemic azacalix[4]arene ( )-1 using a CD detector.
Separation conditions: Daicel Chiralpak AD; mobile phase, 5% 2-PrOH/hexane; flow
rate, 0.2 mL minꢀ1; detection at 254 nm; temperature, 25 °C.
instrument. Infrared spectra were obtained on a Shimadzu IRPres-
tige-21 spectrometer. UV–vis spectra were recorded on a Shima-
dzu UV-3101PC spectrometer. CD spectra were measured in a
1 mm path-length cell on a JASCO J-805 spectropolarimeter. Spe-
cific rotations were measured in a 1 dm path-length cell on a JAS-
CO P-1030 polarimeter. HPLC analyses (mobile phase, 5% 2-PrOH/
hexane; flow rate, 0.2 mL minꢀ1; detection at 254 nm; tempera-
ture, 25 °C) were carried out using the following two instruments
A and B. Instrument A is a JASCO HPLC system equipped with a
CD-2095 Plus detector, a PU-2080 Plus pump, a CO-2060 Plus col-
1 display mirror image CD spectra, demonstrating conclusively
that azacalix[4]arene 1 is inherently chiral. The present enantio-
meric resolution based on simple crystallization is favorable be-
cause neither HPLC separation nor derivatization to the
corresponding diastereomers is required, both of which were typ-
ically used in the enantiomeric resolution of the inherently chiral

K. Ishibashi et al. / Tetrahedron: Asymmetry 20 (2009) 375–380
379
umn oven, and a ChromNAV recorder. Instrument B is constituted
with a JASCO 870-UV detector, a JASCO 880-PU pump, a Shima-
dzu CTO-10AS column oven, and a Shimadzu C-R6A recorder. Dai-
cel Chiralpak AD (/ 0.46 cm ꢁ 25 cm) was used as a chiral
stationary-phase column. Mass spectra were recorded at the
GC–MS and NMR Laboratory, Faculty of Agriculture, Hokkaido
University, Japan. Elemental analyses were conducted at the
Microanalytical Center, Kyoto University, Japan. Flash column
chromatography was performed with Kanto Chemical Silica gel
60N. DMF and THF were refluxed over, and then distilled from
CaH2 and benzophenone ketyl, respectively, under Ar before
use. Other chemicals were purchased from commercial suppliers
and were used as received.
1.03 (s, 9H, t-Bu); 13C NMR (125 MHz, CDCl3) d 148.1, 147.4,
146.6, 145.9, 145.7, 145.2, 145.0, 143.3, 142.7, 142.62, 142.59,
142.3, 140.1, 139.9, 139.8, 139.4, 138.5, 128.04, 128.00, 127.88,
126.5, 126.3, 126.2, 123.2, 119.9, 117.5, 117.4, 117.1, 117.0,
116.7, 111.5, 107.5, 59.9, 59.2, 58.7, 56.9, 56.84, 56.80, 34.4,
34.29, 34.27, 34.24, 31.2, 31.13, 31.09; IR (KBr) 3447, 3368 (mN–
H) cmꢀ1; Anal. Calcd for C65H79BrN4O4: C, 73.63; H, 7.51; N, 5.28.
Found: C, 73.78; H, 7.75; N, 5.00.
4.2.3. General procedure for the synthesis of 2,8,14-tribenzyl-
5,11,17,23-tetra-tert-butyl-25,26,27,28-tetramethoxy-2,8,14,20-
tetraazacalix[4]arene 1 (Table 1, entry 3)
After a mixture of 5 (106.4 mg, 0.100 mmol), Pd(dba)2 (2.9 mg,
5.0 lmol), and (R)-BINAP (4.7 mg, 7.5 lmol) in anhydrous toluene
4.2. Synthesis
(20 mL) was refluxed for 5 min, t-BuONa (19.2 mg, 0.200 mmol)
was added, and the mixture refluxed for 6 h. The mixture was
then cooled to room temperature, filtered through Celite, and
evaporated. Flash column chromatography on silica gel (hexane/
CH2Cl2 = 3:2, v/v) gave (+)-1 (79.2 mg, 81% yield, 21% ee) as a col-
orless solid, 1H NMR (500 MHz, CDCl3) d 7.38ꢀ7.16 (m, 15H, ArH),
6.75 (d, J = 2.3 Hz, 2H, ArH), 6.73 (d, J = 2.3 Hz, 2H, ArH), 6.53 (d,
J = 2.3 Hz, 2H, ArH), 6.37 (d, J = 2.3 Hz, 2H, ArH), 5.09 (d,
J = 16.0 Hz, 2H, CH2), 5.08 (d, J = 15.3 Hz, 1H, CH2), 4.79 (s, 1H,
NH), 4.66 (d, J = 16.0 Hz, 2H, CH2), 4.58 (d, J = 15.3 Hz, 1H, CH2),
2.96 (s, 6H, OMe), 2.82 (s, 6H, OMe), 1.13 ppm (s, 36H, t-Bu);
13C NMR (125 MHz, CDCl3) d 146.7, 144.6, 144.4, 143.3, 142.8,
142.5, 141.4, 140.28, 140.24, 137.6, 128.2, 128.11, 128.09, 127.6,
126.6, 126.5, 114.31, 114.29, 111.1, 110.7, 59.6, 59.5, 59.3,
4.2.1. N-{3-[3-(3-Bromo-5-tert-butyl-2-methoxyanilino)-5-tert-
butyl-2-methoxyanilino]-5-tert-butyl-2-methoxyphenyl}-N0,N0-
di(tert-buthoxycarbonyl)-5-tert-butyl-2-methoxy-1,3-
phenylenediamine 4
A
suspension of 312 (5.34 g, 6.00 mmol), Boc2O (2.62 g,
12.0 mmol), and DMAP (73 mg, 0.60 mmol) in anhydrous THF
(60 mL) was refluxed for 13 h. After cooling to room temperature,
the reaction mixture was concentrated, extracted with EtOAc,
and washed with brine three times. The organic layer was dried
over anhydrous MgSO4, filtered, and evaporated. The residue was
washed with MeOH to afford 4 (4.96 g, 83%) as a colorless solid,
mp 192ꢀ194 °C; 1H NMR (500 MHz, CDCl3) d 7.48 (d, J = 2.2 Hz,
1H, ArH), 7.47 (d, J = 2.2 Hz, 1H, ArH), 7.17 (d, J = 2.2 Hz, 1H,
ArH), 7.13 (d, J = 2.2 Hz, 1H, ArH), 7.07 (d, J = 2.2 Hz, 1H, ArH),
7.03 (d, J = 2.2 Hz, 1H, ArH), 7.02 (d, J = 2.2 Hz, 1H, ArH), 6.70 (d,
J = 2.2 Hz, 1H, ArH), 6.56 (s, 1H, NH), 6.50 (s, 1H, NH), 6.42 (s, 1H,
NH), 3.87 (s, 3H, OMe), 3.80 (s, 6H, OMe), 3.77 (s, 3H, OMe), 1.47
(s, 18H, t-Bu), 1.32 (s, 9H, t-Bu), 1.31 (s, 18H, t-Bu), 1.30 (s, 9H, t-
Bu); 13C NMR (125 MHz, CDCl3) d 152.0, 148.8, 147.43, 147.37,
146.7, 143.8, 143.1, 137.1, 136.5, 136.2, 136.04, 135.95, 135.6,
135.5, 135.1, 132.5, 120.8, 117.9, 116.6, 114.2, 112.6, 106.4,
106.1, 106.0, 105.6, 82.4, 60.24, 60.23, 59.9, 59.8, 34.88, 34.86,
34.75, 34.6, 31.5, 31.4, 31.3, 27.9; IR (KBr) 3426, 3393 (mN–
H) cmꢀ1; Anal. Calcd for C54H77BrN4O8: C, 65.51; H, 7.84; N, 5.66.
Found: C, 65.24; H, 7.90; N 5.42.
58.02, 34.2, 34.1, 31.34, 31.33; IR (KBr) 3408 (m
N–H) cmꢀ1; MS
(FD) m/z 978 [M+]; Anal. Calcd for C65H78N4O4: C, 79.72; H,
8.03; N 5.72. Found: C, 79.88; H, 7.84; N 5.55. mp (of ( )-1)
171ꢀ173 °C.
In entries 1, 2, 4, and 5 of Table 1, the experiments were con-
ducted according to the above protocol. Entry 1: ( )-1 (64.1 mg,
65% yield) was obtained from 5 (105.9 mg, 0.100 mmol), Pd(dba)2
(11.5 mg, 20.0
16 mol), t-BuONa (19.3 mg, 0.201 mmol), and anhydrous toluene
(20 mL). Entry 2: ( )-1 (79.0 mg, 81% yield) was obtained from 5
(106.1 mg, 0.100 mmol), Pd(dba)2 (2.9 mg, 5.0 mol), and ( )-BIN-
AP (4.7 mg, 7.5 mol), t-BuONa (19.2 mg, 0.200 mmol), and anhy-
lmol), and t-Bu3P (10 wt % hexane solution, 50 lL,
l
l
l
drous toluene (20 mL). Entry 4: (+)-1 (76.4 mg, 78% yield, 35% ee)
was obtained from 5 (106.4 mg, 0.100 mmol), Pd(dba)2 (2.9 mg,
4.2.2. N-Benzyl-N-{3-[N-benzyl-3-(N-benzyl-3-bromo-5-tert-
butyl-2-methoxyanilino)-5-tert-butyl-2-methoxyanilino]-5-
tert-butyl-2-methoxyphenyl}-5-tert-butyl-2-methoxy-1,3-
phenylenediamine 5
5.0 lmol), and (R)-SEGPHOS (4.6 mg, 7.5 lmol), t-BuONa
(19.1 mg, 0.199 mmol), and anhydrous toluene (20 mL). Entry 5:
Compound 1 was not obtained from 5 (105.8 mg, 0.100 mmol),
Pd(dba)2 (2.9 mg, 5.0
7.5 mol), t-BuONa (19.2 mg, 0.200 mmol), and anhydrous toluene
(20 mL).
lmol), and (R)-DTBM-SEGPHOS (8.8 mg,
To a solution of 4 (4.95 g, 5.00 mmol) in anhydrous DMF
(100 mL) was added 60% NaH (800 mg, 20.0 mmol) at ꢀ20 °C un-
der Ar. After stirring for 15 min, BnBr (1.85 mL, 15.5 mmol) was
added. Stirring was continued at 0 °C for 8 h, and then Et2O and
H2O were added to the reaction mixture. The organic layer was
washed with brine, dried over MgSO4, filtered, and evaporated.
Next, TFA (10 mL) and CH2Cl2 (10 mL) were added to the residue,
and the mixture was stirred for 3 h at room temperature. After
cooling to 0 °C, the mixture was made basic to pH 11 with 5%
NaOH, then extracted with CH2Cl2, and washed with saturated
aqueous NaHCO3. The organic layer was dried over MgSO4, filtered,
and evaporated. Flash column chromatography on silica gel (hex-
ane/EtOAc = 9:1, v/v) gave 5 (3.38 g, 64%) as a colorless solid, mp
72ꢀ74 °C; 1H NMR (500 MHz, CDCl3) d 7.31ꢀ7.10 (m, 15H, ArH),
7.06 (d, J = 2.3 Hz, 1H, ArH), 6.87 (d, J = 2.3 Hz, 1H, ArH), 6.71 (d,
J = 2.3 Hz, 1H, ArH), 6.67 (d, J = 2.3 Hz, 1H, ArH), 6.65 (d,
J = 2.3 Hz, 1H, ArH), 6.59 (d, J = 2.3 Hz, 1H, ArH), 6.40 (s, 2H, ArH),
4.84 (s, 2H, CH2Ph), 4.82 (s, 2H, CH2Ph), 4.80 (s, 2H, CH2Ph), 3.62
(s, 6H, NH2), 3.50 (s, 3H, OMe), 3.483 (s, 3H, OMe), 3.479 (s, 3H,
OMe), 3.41 (s, 3H, OMe), 1.12 (s, 18H, t-Bu), 1.04 (s, 9H, t-Bu),
l
4.3. General procedure for the enantiomeric enrichment of (+)-
and (ꢀ)-1
A solution of (ꢀ)-1 of 18% ee (582 mg, 0.594 mmol) in MeCN
(ca. 20 mL) with a few drops of MeOH was sonicated at ambient
temperature for 10 min. The resulting suspension was filtered to
afford a colorless powder of (ꢀ)-1 of 3% ee (381 mg). The mother
liquor was evaporated to yield (ꢀ)-1 of 45% ee (199 mg) as col-
orless solid. After similar crystallization procedures were re-
peated four times, (ꢀ)-1 in 82% ee (100 mg) was obtained.
Recrystallization from MeCN with
a few drops of water at
ꢀ15 °C deposited (ꢀ)-1 of 10% ee (20 mg) as colorless solid
and left (ꢀ)-1 of 99% ee in the mother liquor, from which color-
less solid of (ꢀ)-1 (70 mg) was obtained. An analogous proce-
dure was applied for (+)-1. (+)-1 (87% ee): mp 79–83 °C,
½
a 2D7
a 2D7
ꢂ
¼ þ106:5 (c 0.1, CHCl3); (ꢀ)-1 (99% ee): mp 77–82 °C,
½
ꢂ
¼ ꢀ122:5 (c 0.1, CHCl3).

380
K. Ishibashi et al. / Tetrahedron: Asymmetry 20 (2009) 375–380
4.4. 1H NMR relaxation time (T1) measurements
References
1. (a) Böhmer, V.; Kraft, D.; Tabatabai, M. J. Inclusion Phenom. Mol. Recognit. Chem.
1994, 19, 17; (b) Vysotsky, M.; Schmidt, C.; Böhmer, V. In Advances in
Supramolecular Chemistry; Gokel, G. W., Ed.; JAI Press: Stamford, 2000; Vol. 7,
pp 139–233.
2. (a) Hawkins, J. M.; Meyer, A. Science 1993, 260, 1918; (b) Thilgen, C.; Diederich,
F. Chem. Rev. 2006, 106, 5049. and references therein.
3. Fukuhara, G.; Madenci, S.; Polkowsa, J.; Bastkowski, F.; Klärner, F.-G.; Origane,
Y.; Kaneda, M.; Mori, T.; Wada, T.; Inoue, Y. Chem. Eur. J. 2007, 13, 2473.
4. (a) Dieleman, C.; Steyer, S.; Jeunesse, C.; Matt, D. J. Chem. Soc., Dalton Trans.
2001, 2508; (b) Shirakawa, S.; Moriyama, A.; Shimizu, S. Org. Lett. 2007, 9,
3117; (c) Xu, Z.-X.; Li, G.-K.; Chen, C.-F.; Huang, Z.-T. Tetrahedron 2008, 64,
8668.
5. Functionalizations of the bridging units of calixarenes have been reported, see:
(a) Biali, S. E.; Böhmer, V.; Cohen, S.; Ferguson, G.; Grüttner, C.; Grynszpan, F.;
Paulus, E. F.; Thondorf, I.; Vogt, W. J. Am. Chem. Soc. 1996, 118, 12938; (b)
Middel, O.; Greff, Z.; Taylor, N. J.; Verboom, W.; Reinhoudt, D. N.; Snieckus, V. J.
Org. Chem. 2000, 65, 667; (c) Biali, S. E. Synlett 2003, 1; (d) Columbus, I.; Biali, S.
E. J. Org. Chem. 2008, 73, 2598.
The relaxation time (T1) values of ( )-1 were determined in de-
gassed CDCl3 at 270 MHz and 23 °C by using the inversion recovery
method. Since the aromatic protons c and d were not resolved so
well in the 1H NMR spectra (270 MHz), those signals were assumed
as a single one in the T1 calculation.
4.5. Racemization experiment of (+)-1
A solution of (+)-1 of 93% ee (2.2 mg) in toluene (5 mL) was
heated at 110 °C in a thermostat-controlled bath. The changes in
the enantiomeric excess were followed at appropriate intervals
by using a chiral HPLC. No change of the ee value (93% ee) of (+)-
1 was observed at this temperature for 6 h.
6. (a) Morohashi, N.; Iki, N.; Onodera, T.; Kabuto, C.; Miyano, S. Tetrahedron Lett.
2000, 41, 5093; (b) Morohashi, N.; Naito, R.; Iki, N.; Miyano, S. Isr. J. Chem. 2001,
41, 303.
4.6. X-ray crystallographic analysis
7. Browne, J. K.; McKervey, M. A.; Pitarch, M.; Russell, J. A.; Millership, J. S.
Tetrahedron Lett. 1998, 39, 1787.
Measurement was made by using graphite-monochromated Mo
a radiation (k = 0.71075 Å). All the crystallographic calculations
K
8. Xu, Z.-X.; Zhang, C.; Chen, C.-F.; Huang, Z.-T. Org. Lett. 2008, 10, 477.
9. Page, P. C. B.; Heaney, H.; Sampler, E. P. J. Am. Chem. Soc. 1999, 121, 6751.
10. For a review on nitrogen-bridged calixarene analogues, see: Tsue, H.; Ishibashi,
K.; Tamura, R. In Heterocyclic Supramolecules I; Matsumoto, K., Ed.; Topics in
Heterocyclic Chemistry; Springer-Verlag: Berlin Heidelberg, Germany, 2008;
Vol. 17, pp 73–96.
11. For reviews on heteroatom-bridged calixarene analogues, see: (a) König, B.;
Fonseca, M. H. Eur. J. Inorg. Chem. 2000, 2303; (b) Lhotäk, P. Eur. J. Org. Chem.
2004, 1675; (c) Morohashi, N.; Narumi, F.; Iki, N.; Hattori, T.; Miyano, S. Chem.
Rev. 2006, 106, 5291; (d) Maes, W.; Dehaen, W. Chem. Soc. Rev. 2008, 37, 2393;
(e) Wang, M.-X. Chem. Commun. 2008, 4541.
12. For reviews on the palladium(0)-catalyzed aryl amination reaction, see: (a)
Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805; (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852; (c) Hartwig, J. F. Angew.
Chem., Int. Ed. 1998, 37, 2046; (d) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 133; (e) Hartwig, J. F. Synlett 2006, 1283.
13. Tsue, H.; Ishibashi, K.; Takahashi, H.; Tamura, R. Org. Lett. 2005, 7, 2165.
14. Ishibashi, K.; Tsue, H.; Tokita, S.; Matsui, K.; Takahashi, H.; Tamura, R. Org. Lett.
2006, 8, 5991.
were performed by using a crystallographic software package, Crys-
talStructure version 3.8.2.22 The crystal structure was solved by
direct methods and refined by full-matrix least-squares. All non-
hydrogen atoms were refined anisotropically, and the hydrogen
atoms were refined using the riding model. Crystal data for ( )-1:
Mr = 979.36, monoclinic, space group P21/a (No. 14), a = 18.721(1),
b = 15.116(1), c = 21.688(1) Å, b = 109.796(1)°, V = 5775(1) Å3,
Z = 4,
independent reflections, 664 refined parameters. R1 = 0.1234
(I > 2 (I)), wR2 = 0.4116 (all reflections), S = 0.975. Crystallographic
q , l
calcd = 1.126 g cmꢀ3 = 0.695 cmꢀ1, T = 113(1) K, 13,102
r
data for the structure in this paper have been deposited with the
Cambridge Crystallographic Data Center as supplementary publica-
tion number CCDC-706406. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44(0)-1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk].
15. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
16. Iwamura, K.; Araki, K.; Shinkai, S. J. Org. Chem. 1991, 56, 4955.
17. Tsue, H.; Ishibashi, K.; Tokita, S.; Matsui, K.; Takahashi, H.; Tamura, R. Chem.
Lett. 2007, 36, 1374.
18. Sone, T.; Ohba, Y.; Moriya, K.; Kumada, H.; Ito, K. Tetrahedron 1997, 53, 10689.
19. Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
Acknowledgments
20. Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumobayashi,
H. Adv. Synth. Catal. 2001, 343, 264.
21. Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.; Takahashi, M.; Dobashi, Y.;
Taguchi, T. J. Am. Chem. Soc. 2006, 128, 12923.
22. CrystalStructure, version 3.8.2, Program for the Solution of Crystal Structures,
Rigaku and Rigaku Americas, The Woodlands, TX, 2000–2007.
This work was supported by the Grant-in-Aid for Scientific Re-
search (C) No. 19550037 (to H.T.) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan. We also appreciate
JASCO Corporation for the HPLC analyses using a CD detector.