A new synthetic method for rotaxanes via tandem Claisen rearrangement, diesterification, and aminolysis

Article abstract of DOI:10.1016/S0040-4039(02)01201-7

A novel methodology to make rotaxanes via covalent bond formation has been developed. Rotaxanes composed of crownophanes having two phenolic hydroxy groups as a molecular rotor and an axle having diamide moieties were synthesized in moderate yields via three step processes: tandem Claisen rearrangement, intramolecular diesterification, and aminolysis.

Full text of DOI:10.1016/S0040-4039(02)01201-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5747–5750
A new synthetic method for rotaxanes via tandem Claisen
rearrangement, diesterification, and aminolysis
Kazuhisa Hiratani,a,b,* Jun-ichi Suga,c Yoshinobu Nagawa,b Hirohiko Houjou,b Hideo Tokuhisa,b
Munenori Numatab and Kunihiro Watanabec
aDepartment of Applied Chemistry, Utsunomiya University, 7-1-2 Youtou, Utsunomiya 321-8585, Japan
bNanoarchitectonics Research Center, National Institute of Advanced Industrial Science and Technology, Tsukuba Central 4,
1-1-1 Higashi, Tsukuba 305-8562, Japan
cDepartment of Industrial Chemistry, Tokyo University of Science, Noda, Chiba 278-8510, Japan
Received 10 May 2002; revised 17 June 2002; accepted 20 June 2002
Abstract—A novel methodology to make rotaxanes via covalent bond formation has been developed. Rotaxanes composed of
crownophanes having two phenolic hydroxy groups as a molecular rotor and an axle having diamide moieties were synthesized
in moderate yields via three step processes: tandem Claisen rearrangement, intramolecular diesterification, and aminolysis. © 2002
Elsevier Science Ltd. All rights reserved.
In the last two decades much attention has been paid to
switching devices, memory devices, molecular machines
such as a molecular motor, and so on.4 Several syn-
thetic methods for the preparation of such interlocked
molecules have been reported so far, for example, the
pioneering work via covalent bond formation of Schill,
supramolecular
systems1
such
as
interlocked
molecules2—knots, catenanes, and rotaxanes—which
have topologically interesting structures, that provide a
wealth of potential abilities.3 They could work as
Scheme 1. Synthetic strategy to construct rotaxanes.
Keywords: rotaxanes; crownophanes; tandem Claisen rearrangement; covalent bond formation; aminolysis.
* Corresponding author. Fax: +81-(0)28-689-6146; e-mail: hiratani@cc.utsunomiya-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01201-7

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K. Hiratani et al. / Tetrahedron Letters 43 (2002) 5747–5750
Harrison, and Wassermann,5 Sauvage’s method via for-
mation of coordinated structure,6 Stoddart’s method
utilizing charge transfer interaction and/or p–p stacking
interaction between aromatic rings,7 and a method uti-
lizing hydrogen bond formation between molecules
developed by Vo¨gtle,8 Hunter,9 and Leigh10 as represen-
tative methodologies, which are available and syntheti-
cally excellent. More recently self-assembled formation
of rotaxanes using either the combination of cyclodex-
trin and polymeric linear molecules,11 or transition
metal complexation with acyclic aromatics containing
N atoms12 has been reported. In the 1960s, one sophis-
ticated methodology for preparing rotaxanes via cova-
lent bonding was proposed by Schill.13 However, this
method was not versatile because the synthetic process
is complicated and requires many reaction steps result-
ing in a very low yield of the target interlocked
molecules.
the ring size of macrocycles used should be appropriate
for the diester moiety to be located inside the cavity,
and (3) the bulky group of amines as a stopper of axles
does not slip out through the ring. We have already
reported a tandem Claisen rearrangement to synthesize
novel macrocycles having plural phenolic hydroxy
groups from the corresponding macrocyclic polyethers
directly by either thermal or Lewis acid-assisted
reaction.15
Consideration of the CPK model of crownophane 2,
which could satisfy conditions (1) and (2), made it our
choice to make rotaxanes. The corresponding rotaxanes
were prepared as shown in Scheme 2. As reported, the
thermal reaction of macrocyclic polyether 1, which can
be prepared by the reaction of 2-[2-(3-hydroxynaphthyl-
2-oxy)methyl]allyloxy-3-naphthol with pentaethylene
glycol ditosylate in the presence of base in DMF, gave
rise to crownophane 2 in good isolated yield.16 The
reaction of 2 with an equimolar succinic acid dichloride
in THF at 50°C overnight gave intramolecularly
cyclized diester 3.17 When malonic acid dichloride was
used instead of succinic acid chloride, we did not
In this paper, the authors report a novel methodology
to make rotaxanes including the process of covalent
bond formation. This versatile method is a convincingly
simpler candidate for the synthesis of rotaxanes.
Scheme 1 illustrates our strategy for preparing rotax-
anes; step 1: synthesis of crownophanes having two
phenolic hydroxy groups from the corresponding
macrocyclic polyethers via tandem Claisen rearrange-
ment,14 step 2: intramolecular diesterification of the
crownophanes with diacid chloride, and step 3: amino-
lysis with amine compounds having a bulky group. To
realize this concept, three important factors should be
pointed out as follows: (1) diacid chloride used should
selectively give rise to intramolecular esterification, (2)
succeed in obtaining
a
diester, but recovered
crownophane 2.
As shown in Scheme 2, the reaction procedure from 3
to 4 is very simple. The mixture of the diester and
excess of amine in a small amount of DMF or without
solvent is stirred at room temperature or 50°C
overnight. The residue after removal of solvent if neces-
sary is subjected to the preparative gel permeation
Scheme 2. Synthetic route of rotaxanes via covalent bond formation from a macrocyclic polyether.

K. Hiratani et al. / Tetrahedron Letters 43 (2002) 5747–5750
5749
Table 1. Yields of rotaxanes by the reaction of 3 with
was confirmed that the slippage of 5b out of the rotor
(2) did not occur at all after the heating of rotaxane 4b
in DMF at 100°C, 2 h. The reaction mechanism of the
rotaxane formation indicates that we could make new
types of rotaxanes having asymmetric axles.
amines
Amine
Conditionsa
Rotaxane (4)
2
Only axle (5)
a
b
b
c
d
d
1
1
2
1
1
3
42
13
26
56
0
44
85
69
28
–
27
71
74
34
–
1
In Fig. 1, H NMR spectra of 2, 5c, and 4c are shown.
The amide protons of the axle 5c in the rotaxane (4c)
are drastically shifted downfield (from 6.03 to 6.93
ppm) compared to those of 5c only. Ethyleneoxy pro-
tons are shifted upfield which imply that anthracenyl
group of the axle is located near these protons, while
OH protons are extremely shifted downfield (from 7.38
to 8.29 ppm) by the formation of hydrogen bonding
with amide oxygens of the axle.19 The ESI mass spec-
trum of rotaxane 4c after the purification by prepara-
tive GPC supports the formation of rotaxane 4c. At the
same time, we can observe peaks due to 2 as a rotor
and 5 as an axle, too, which might be separated by
slippage.
0
–
–
a Reaction conditions: (1) 27 equimolar of amine in DMF, 50°C, 14 h,
then 100°C, 2. (2) 27 equimolar of amine without solvent, rt, 14 h,
then 100°C, 2 h. (3) 27 equimolar of amine in DMF, 100°C, 40 h,
then 100°C, 2 h.
chromatography (GPC) with chloroform as an eluent
to give rotaxane (4),18 crownophane (2), and diamide
(5), which can be isolated completely. In Table 1, the
yields of rotaxane formation are summarized. As axles,
we used 2-triphenylmethylaminoethyl amine (a), 3-
diphenylpropyl amine (b), 9-(aminomethyl)anthracene
(c), and 4-triphenylmethylaniline (d). As shown in
Table 1, the reactions of 3 with amines (a–c) proceeded
under mild conditions to give moderate yields of the
rotaxanes, which are surprisingly high compared with
the results via covalent bond formation reported so
far.13 Only aniline derivative (d) did not react with 3
even under the more severe conditions. The best yield
of rotaxane reached 56% in the reaction of 3 with
9-(aminomethyl)anathracenne (c). In the formation of
the rotaxane 4a, crownophane 2 and 1,2-bis[2-(N,N%-
Thus, we successfully demonstrated the synthesis of
novel rotaxanes by using the method of intramolecular
diester formation proposed in this paper. This method
could potentially be a candidate for the synthesis of a
series of supramolecular systems such as rotaxanes, as
well as catenanes and others. We will now pursue this
research in due course.
References
triphenylmethylamino)-ethylaminocabonyl)ethane
5a
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were obtained in 28% and 34%, respectively. As
expected, the formation of rotaxanes 4 would result
from two amines attacking from opposite sides of the
macrocyclic ring. On the other hand, in the formation
of 2 and 5 it can be considered that the second amine
attacked the remaining ester group from the same side
as the first aminolysis. Using amine b, which has a
relatively small stopper (diphenylmethyl group), the
yield of the rotaxane (4b) decreased. The reason might
come from the second attack of amine b occurring
more easily from the same side as the first attack than
in the case of other amines having a bulkier stopper. It
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M. D. Angew. Chem., Int. Ed. Engl. 1995, 34, 1209.
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Harada, A.; Li, J.; Kamachi, M. Nature 1992, 356, 325.
Figure 1. 1H NMR spectra of crownophane 2, axle 5c, and
rotaxane 4c in CDCl3.

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12. Fujita, M.; Ogura, K. Coord. Chem. Rev. 1996, 148, 249
and references cited therein.
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and stirred at 50°C (or 100°C in the case of amine d) for
14 h. Then DMF was evaporated under vacuum by
Kugelrohr apparatus, and the residue was heated at
100°C for 2 h. The residue was directly subjected to a
preparative GPC with chloroform as eluent to give 2, 4,
and 5 as main products. The yields of each component
are shown in Table 1. Compound 4a: 1H NMR (500
MHz, CDCl3, ppm) 2.10 (m, 4H, N-CH2), 2.41 (s, 4H,
C(ꢀO)-CH2), 3.19 (m, 4H, N-CH2), 3.39 (s, 4H, OCH2),
3.45 (m, 4H, OCH2), 3.52 (m, 4H, OCH2), 3.74 (m, 4H,
OCH2), 3.90 (s, 4H, Ar-CH2), 4.09 (m, 4H, OCH2), 4.20
(s, 2H, H2CꢀC), 6.50 (broad, 2H, C(ꢀO)-NH), 6.89 (s,
2H, Ar-H), 7.05 (m, 20H, Ar-H), 7.33 (m, 14H, Ar-H),
7.4 (broad, 2H, C-NH), 7.60 (m, 2H, Ar-H), 7.93 (m, 2H,
Ar-H); IR (KBr, cm−1) 1639 (amide); ESI mass, calcd for
C80H84N4O10 1260.62, found 1283.2 (+Na+). Compound
4b: 1H NMR (500 MHz, CDCl3, ppm) 1.99 (m, 4H,
15. Uzawa, H.; Hiratani, K.; Minoura, N.; Takahashi, T.
Chem. Lett. 1999, 307.
16. Nagawa, Y.; Fukazawa, N.; Suga, J.; Horn, M.;
Tokuhisa, H.; Hiratani, K.; Watanabe, K. Tetrahedron
Lett. 2000, 41, 9261.
17. Synthesis of macrocyclic diester (3): To 100 ml of THF
solution of crownophane 2 (1.15 g, 2.0 mmol), potassium
t-butoxide (0.51 g, 4.5 mmol) was added and stirred for 5
h at room temperature. The solution became turbid grad-
ually. After 250 ml of THF were added to it, succinyl
dichloride (0.31 g, 2.0 mmol) was then added to make the
mixture clear at once. The solution was stirred overnight
at room temperature. After the solvent was removed by
evaporation, the residue was extracted with chloroform
and the chloroform layer was washed with water and
dried over anhydrous magnesium sulfate. The solvent was
removed and the residue was subjected to a preparative
GPC with chloroform as eluent to give 0.80 g of macro-
cyclic diester 3 as a main product together with the
reactant (2) and dimeric succinate ester. Diester 3 was
identified by NMR, IR, and mass spectroscopic methods.
Without further purification, 3 was used in the reaction
with amines. Compound 3: yield 62.0%; mp 164°C; 1H
NMR (500 MHz, CDCl3, ppm) 3.16 (m, 2H, C(ꢀO)-
CH2), 3.29 (m, 2H, C(ꢀO)CH2), 3.67–3.77 (m, 14H, Ar-
CH2(2H), OCH2(12H)), 3.88 (m, 4H, OCH2), 3.94–4.03
(m, 2H, Ar-CH2), 4.24 (m, 4H, OCH2), 4.35 (s, 2H,
H2CꢀC), 7.15 (s, 2H, Ar-H), 7.42 (m, 4H, Ar-H), 7.73 (m,
2H, Ar-H), 8.01 (m, 2H, Ar-H); IR (KBr, cm−1) 1759
(ester); ESI mass, calcd for C38H40O10 656.26, found
679.0 (+Na+).
CH-CH6 2-CH2-N), 2.47 (s, 4H, C(ꢀO)-CH2), 2.97 (m, 4H,
CH2-N), 3.54 (m, 8H, OCH2), 3.59 (m, 4H, OCH2), 3.71
(m, 6H, OCH2(4H), C-CH(2H)), 3.92 (s, 4H, Ar-CH2),
4.01 (m, 4H, OCH2), 4.34 (s, 2H, H2CꢀC), 6.65 (broad,
2H, C(ꢀO)-NH), 6.86 (s, 2H, Ar-H), 6.97 (m, 8H, Ar-H),
7.07–7.30 (m, 14H, Ar-H), 7.67 (m, 2H, Ar-H), 7.62 (m,
2H, Ar-H), 8.18 (m, 2H, Ar-H), 8.19 (broad, 2H, Ar-
OH); IR (KBr, cm−1) 1654 (amide); ESI mass, calcd for
C68H74N2O10 1078.54, found 1099.2 (+Na+). Compound
4c: 1H NMR (500 MHz, CDCl3, ppm) 2.52 (s, 4H,
C(ꢀO)-CH2), 2.88 (s, 4H, OCH2), 2.99 (m, 4H, OCH2),
3.04 (m, 8H, OCH2), 3.27 (m, 4H, OCH2), 3.70 (m, 4H,
OCH2), 3.83 (s, 4H, Ar-CH2), 4.06 (s, 2H, H2CꢀC), 5.22
(s, 4H, CH2-anthryl), 6.60 (s, 2H, Ar-H), 6.93 (broad,
2H, C(ꢀO)-NH), 7.26 (m, 2H, Ar-H), 7.33 (m, 6H, Ar-H),
7.39 (m, 4H, Ar-H), 7.54 (m, 2H, Ar-H), 7.88 (m, 2H,
Ar-H), 7.92 (m, 4H, Ar-H), 8.21 (m, 4H, Ar-H), 8.29 (s,
2H, Ar-OH), 8.30 (s, 2H, Ar-H); IR (KBr, cm−1) 1647
(amide); ESI mass, calcd for C68H66N2O10 1070.48, found
1093.3 (+Na+).
19. In the NOESY spectrum of 4c at 298 K in CDCl3,
significant NOE cross peaks were observed between the
anthryl protons and oxyethylene protons. This indicates
that the anthracene ring of the axle (5c) exists in close
proximity to the macrocyclic ring of the rotor (2).
18. General procedure for rotaxane synthesis via intramolecu-
lar diester of crownophane: To 5 ml of DMF, 110 mg
(0.18 mmol) of 3 and then 27 equiv. of amine were added