Stepwise synthesis of crownophanes having either one or two hydroxy groups via Claisen rearrangement

Article abstract of DOI:10.1016/S0040-4039(00)01681-6

Bis(naphthyl)crownophanes having an isobutenyl group and different ring size were synthesized. By control of the reaction temperature and time, both the first-step product having one hydroxyl group and the second-step product having two hydroxy groups can

Full text of DOI:10.1016/S0040-4039(00)01681-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9261–9265
Stepwise synthesis of crownophanes having either one or
two hydroxy groups via Claisen rearrangement
Yoshinobu Nagawa,a Naoki Fukazawa,b Jun-ichi Suga,b Michael Horn,a Hideo Tokuhisa,a
Kazuhisa Hiratania,* and Kunihiro Watanabeb
aNational Institute for Advanced Interdisciplinary Research, 1-1-4, Higashi, Tsukuba, Ibaraki 305-8562, Japan
bTokyo University of Science, Faculty of Science and Technology, 2641, Yamazaki, Noda, Chiba 278-8510, Japan
Received 16 June 2000; revised 7 September 2000; accepted 22 September 2000
Abstract
Bis(naphthyl)crownophanes having an isobutenyl group and different ring size were synthesized. By
control of the reaction temperature and time, both the first-step product having one hydroxyl group and
the second-step product having two hydroxy groups can be isolated in high yields. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: macrocyclic polyethers; crownophanes; Claisen rearrangement; naphthol derivatives.
Much attention has recently been paid to crownophanes1 and cryptophanes2, the macrocycles
of which are composed from hybridization of both the aromatic moieties and a flexible polyether
3
chain, because they exhibit some excellent functions such as high ion selectivity, high uptake
property for guest molecules,4 etc. That is, hybridization of both the rigid and flexible parts in
a molecule could result in the development of excellent molecular recognition. Crownophanes
and their analogues having aromatic hydroxy groups would also be attractive for designing and
constructing precise molecular recognition. Aromatic hydroxyl groups could be changed to
various kinds of functional groups by their nucleophilic substitution reaction. Therefore, it could
be meaningful to control the number of aromatic hydroxy groups in a macrocycle.
We have reported the synthesis and the properties of crownophanes having two phenolic
hydroxy groups from the corresponding macrocyclic polyethers in one step via tandem Claisen
rearrangement.5,6 However, in the case of Ref. 5, it was very difficult to control the reaction for
the synthesis of the once-rearranged product, because the rearrangement needs a high tempera-
ture over 180–190°C and a long time. In the case of Ref. 6, on the contrary, the thermal
rearrangement occurs very smoothly at lower temperature, probably because of the release of
the strain energy due to binaphthyl moiety. This could be the reason why the once-rearranged
product was not detected after 120°C, 15 h in two compounds having different chain lengths.
* Corresponding author. Fax: +81 298 61 3029; e-mail: hiratani@nair.go.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01681-6

9262
In this paper, we report the successful control of the reaction to get either a once- or
twice-rearranged product. We used here 2,3-naphthalenediol instead of catechol as the starting
material and tried to control the thermal reaction step and to isolate the products at each step.
Such a stepwise reaction in this study could be of important significance because each compound
is expected to exhibit the drastic change of selectivity towards guest species; that is, the
selectivity could be largely affected both by the ring-size and the number of the proton-ionizable
moiety.7 Macrocyclic polyethers having naphthalene moieties were synthesized by the reaction of
2-[2-(3-hydroxynaphthyl-2-oxy)methyl]allyloxy-3-naphthol with oligo-ethylene glycol ditosylate
in the presence of a base in DMF as shown in Scheme 1. These compounds (1, 2 and 3) were
identified by NMR, IR, and precise mass spectroscopies.8 For comparison, acyclic polyether (4)
was also prepared.9 According to the procedure reported in Ref. 5, the polyethers were obtained
in moderate yields.
Scheme 1. Synthetic route of polyethers (1–4) having an isobutenyl group: (a) DMF, 50°C, overnight, then aq. HCl
in EtOH, 67%; (b) NaH, DMF, 70°C, overnight; (c) NaH, DMF, 70°C, overnight
The thermal rearrangement was tried in the range of 130–180°C, changing the reaction time
either under vacuum without a solvent for a small scale (5–10 mg), such as in an NMR tube,
or under a nitrogen gas atmosphere in decalin for a relatively large scale (more than 0.1 g). All
reactants changed to once- and/or twice-rearranged products according to the Claisen rearrange-
Scheme 2. Tandem Claisen rearrangement of macrocyclic polyethers having an isobutenyl group

9263
1
ment without formation of any by-product in the H NMR spectra. As shown in Scheme 2, the
rearrangement occurred step-by-step. Typical reaction yields of once- and twice-rearranged
compounds with the times are plotted in Fig. 1.
Figure 1. Time course of the tandem Claisent rearrangement of 3 at 160°C13
Fig. 1 shows the time dependence of the yields by the thermal reaction at 160°C in the case
1
of 3. Each yield was determined by the relative change of the proton signals in the H NMR
spectrum. After 15 min at 160°C, the once-rearranged product could be predominantly obtained
at maximum 61%, and could be separated from a relatively small amount of the twice-rearranged
product. After 1.5 h at 160°C the twice-rearranged product could be produced quantitatively. In
other cases, the reaction occurred at lower temperature, compared with the case of phenyl
derivatives5 and almost similar curves were obtained with the reaction time. Therefore, either the
once- or twice-rearranged product could be obtained predominantly by controlling the temper-
ature and time. In Table 1 the representative results of each macrocycle are summarized. In the
case of the acyclic one (4), the rearrangement occurred at the lowest temperature and even at
150°C, 1.5 h, the twice-rearranged product (11) was obtained almost quantitatively.10 The
Table 1
Yields of crownophanes having one or two hydroxyl groups via tandem Claisen rearrangement
Run Polyether
Reaction conditionsa
Temperature (°C) Time (min)
Polyether unreacted (%)
Yield (%)a
CPꢀOHb CPꢀ2OHc
1
2
3
4
5
6
1
1
2
2
3
3
160
180
150
170
140
160
80
90
80
60
45
90
10
1
28
1
17
0
67
6
63
4
61
3
23
93
9
95
22
97
a The reaction was carried out in an NMR tube under vacuum (each polyether: 5 mg) without a solvent. The yields
were determined by the direct comparison of the integral magnitude among the three components in the NMR
spectrum.13
b CPꢀOH: crownophanes (5–7) having one hydroxy group.
c CPꢀ2OH: crownophanes (8–10) having two hydroxy groups.

9264
larger the macrocyclic polyethers become, the more appropriate the lower temperature or the
shorter time for rearrangement becomes. Furthermore, the conditions at lower temperature and
shorter time give once-rearranged crownophanes (5–7)11 as the major products, while the higher
temperature and longer time give twice-rearranged crownophanes (8–10)12 as the major prod-
ucts, respectively. The products were isolated by column chromatography on silica gel with
chloroform as eluent.
In summary, both once- and twice-rearranged products having naphthyl moieties can success-
fully be obtained in high yields by controlling the reaction temperature and time. We were able
to design high-performance crownophanes based on thermally once- or twice-rearranged macro-
cycles. Furthermore, we are now applying this methodology to the synthesis of macrocycles
having plural isobutenyl groups.
References
1. Inokuma, S.; Sakai, S.; Nishimura, J. Top. Curr. Chem. 1994, 172, 87–118.
2. Gokel, G. Crown Ethers and Cryptands; The Royal Society of Chemistry, 1994; pp. 115–120.
3. Yamamoto, H.; Sasaki, T.; Shinkai, S. Chem. Lett. 1994, 469–472; Yamamoto, H.; Shinkai, S. ibid. 1994,
1115–1118.
4. Kubo, Y.; Maeda, S.; Tokita, S.; Kubo, M. Nature 1996, 382, 522–524.
5. Hiratani, K.; Kasuga, K.; Goto, M.; Uzawa, H. Tetrahedron Lett. 1997, 38, 8993–8996.
6. Tokuhisa, H.; Nagawa, Y.; Uzawa, H.; Hiratani, K. Tetrahedron Lett. 1999, 40, 8007–8010.
7. For example, as a preliminary result, compound 5 exhibits the selectively fluorescent increase at 421 nm toward
sodium ion in acetonitrile among alkali and alkaline earth metal ions, when exposed to UV light of 280 nm.
8. Synthesis: typical procedure: to 200 ml of DMF with suspended NaH (0.24 g, 10 mmol), which was maintained
at 70°C under stirring, was added 50 ml of DMF solution containing 2-[2-(3-hydroxynaphthyl-2-
oxy)methyl]allyloxy-3-naphthol (1.5 g, 4 mmol) and triethylene glycol di-p-tosylate (1.85 g, 4 mmol) dropwise
over a period of 12 h at 70°C. The dark solution was heated at 70°C overnight and then treated carefully with
some drops of water to hydrolyze the excess of NaH. After the solvent was evaporated under reduced pressure,
the residue was extracted with dichloromethane and the extractant was washed with water. After drying over
sodium sulfate, the solvent was removed. The crude product was purified by column chromatography on silica
gel with chloroform as eluent and then recrystallized from toluene to give 1.3 g of compound 1: colorless crystal;
1
yield 52%; mp 138–139°C; H NMR (500 MHz, in CD2Cl2/CDCl3 9:1, l (ppm)) 3.76 (s, 4H), 3.90 (m, 4H), 4.23
(m, 4H), 4.84 (s, 4H), 5.57 (s, 2H), 7.13 (s, 2H), 7.26 (s, 2H), 7.31 (m, 4H), 7.62 (dd, J=7, 2 Hz, 2H), 7.66 (dd,
J=7, 2 Hz, 2H); IR (KBr, cm−1) 3055, 2929, 1627, 1600, 1507, 1257, 1165, 1116; Precise mass, calcd for C30H30O6
486.204, found 486.201. Compound 2: colorless crystal; yield 64%; mp 164–165°C; 1H NMR (500 MHz, in
CD2Cl2/CDCl3 9:1, l (ppm) 3.61 (m, 4H), 3.71 (m, 4H), 3.87 (m, 4H), 4.23 (m, 4H), 4.86 (s, 4H), 5.47 (s, 2H),
7.15 (s, 2H), 7.20 (s, 2H), 7.32 (m, 4H), 7.63 (dd, J=7, 3 Hz, 2H), 7.67 (dd, J=6, 3 Hz, 2H); IR (KBr, cm−1
)
3050, 2902, 2864, 1626, 1600, 1508, 1485, 1260, 1174, 1118; precise mass, calcd for C32H34O7 530.230, found
1
530.230. Compound 3: colorless crystal; mp 108–109°C; yield 48%; H NMR (500 MHz, in CD2Cl2/CDCl3 9:1,
l (ppm)) 3.54 (s, 4H), 3.56 (m, 4H), 3.67 (m, 4H), 3.88 (m, 4H), 4.23 (m, 4H), 4.86 (s, 4H), 5.50 (s, 2H), 7.15 (s,
2H), 7.20 (s, 2H), 7.32 (m, 4H), 7.62 (d, J=7, 2 Hz, 2H), 7.67 (d, J=7, 2 Hz, 2H); IR (KBr, cm−1) 3052, 2909,
2864, 1626, 1600, 1509, 1487, 1261, 1172, 1114; precise mass, calcd for C34H38O8 574.256, found 574.249.
1
9. Compound 4: colorless oil; yield 65%; H NMR (500 MHz, CD2Cl2, l (ppm)) 1.17 (t, J=7.0 Hz, 6H), 3.56 (q,
J=7.0 Hz, 4H), 3.81 (m, 4H), 4.21 (m, 4H), 4.87 (s, 4H), 5.51 (s, 2H), 7.16 (s, 2H), 7.21 (s, 2H), 7.31 (m, 4H),
7.60 (dd, J=7, 2 Hz, 2H), 7.67 (dd, J=7, 2 Hz, 2H); IR (KBr, cm−1) 3056, 2974, 2927, 2869, 1663, 1627, 1600,
1583, 1508, 1486, 1257, 1173, 1117; precise mass, calcd for C32H36O6 516.251, found 516.246.
1
10. Compound 11: colorless crystal; isolated yield 80% (150°C, 90 min); mp 73–75°C; H NMR (500 MHz, CDCl3,
l (ppm)) 1.26 (t, J=7 Hz, 6H), 3.62 (q, J=7 Hz, 4H), 3.84 (t, J=5 Hz, 4H), 3.95 (s, 4H), 4.31 (t, J=4 Hz, 4H),
4.49 (s, 2H), 6.54 (s, 2H), 7.12 (s, 2H), 7.25 (m, 4H), 7.64 (d, J=8 Hz, 2H), 7.69 (d, J=8 Hz, 2H); IR (KBr, cm−1
)
3420, 3066, 2976, 2927, 2871, 1627, 1604, 1510, 1475, 1448, 1282, 1185, 1110; precise mass, calcd for C32H36O6
516.251, found 516.244.

9265
11. Compound 5: to 20 ml of decalin was added 0.40 g of polyether 1 and the mixture was stirred at 160°C, 80 min
under N2 atmosphere. Then, decalin was removed at 100°C under vacuum and the residue was subjected to
column chromatography on silica gel with chloroform as eluent to give 0.195 g of 5 as a main product (colorless
crystal recrystallized from acetonitrile; isolated yield 49%); mp 131–132°C; 1H NMR (500 MHz, CDCl3, l (ppm))
3.83 (m, 6H), 4.09 (s, 2H), 4.10 (t, J=5 Hz, 2H), 4.21 (m, 2H), 4.37 (t, J=5 Hz, 2H), 4.57 (s, 2H), 5.09 (s, 1H),
5.31 (s, 1H), 7.14 (s, 1H), 7.17 (s, 1H), 7.22 (s, 1H), 7.30 (m, 3H), 7.37 (dd, J=7, 7 Hz, 1H), 7.64 (m, 4H), 7.92
(d, J=9 Hz, 1H); IR (KBr, cm−1) 3435, 3057, 2922, 2871, 1627, 1601, 1508, 1483, 1259, 1173, 1118; precise mass,
calcd for C30H30O6 486.204, found 486.209. Compound 6: colorless crystal; isolated yield 52% (150°C, 80 min);
1
mp 78–83°C; H NMR (500 MHz, CDCl3, l (ppm)) 3.76 (s, 4H), 3.90 (m, 4H), 4.23 (m, 4H), 4.84 (s, 4H), 5.57
(s, 2H), 7.13 (s, 2H), 7.26 (s, 2H), 7.31 (m, 4H), 7.62 (dd, J=7, 2 Hz, 2H), 7.66 (dd, J=7, 2 Hz, 2H); IR (KBr,
cm−1) 3435, 3058, 2924, 2871, 1627, 1601, 1508, 1260, 1175, 1116; precise mass, calcd for C32H34O7 530.230,
1
found 530.229. Compound 7: colorless crystal; isolated yield 45% (140°C, 45 min); mp 75–78°C; H NMR (500
MHz, CDCl3, l (ppm)) 3.62 (s, 4H), 3.66 (m, 4H), 3.73 (s, 2H), 3.95 (m, 4H), 4.08 (m, 4H), 4.31 (m, 4H), 4.61
(s, 1H), 4.75 (s, 2H), 5.15 (s, 1H), 7.06 (s, 1H), 7.18 (m, 2H), 7.31 (m, 4H), 7.66 (m, 3H), 7.73 (d, J=8 Hz, 1H),
8.48 (s, 1H); IR (KBr, cm−1) 3490, 3064, 2923, 2867, 1627, 1601, 1508, 1477, 1260, 1176, 1115; precise mass, calcd
for C34H38O8 574.256, found 574.260.
1
12. Compound 8: colorless crystal; isolated yield 77% (180°C, 90 min); mp 140–144°C; H NMR (500 MHz, CDCl3,
l (ppm)) 3.74 (s, 4H), 3.75 (s, 4H), 3.88 (m, 4H), 4.28 (m, 4H), 5.20 (s, 2H), 6.6 (broad, 2H), 7.33 (dd, J=7, 7
Hz, 2H), 7.63 (d, J=8 Hz, 2H), 8.12 (d, J=9 Hz, 2H); IR (KBr, cm−1) 3448, 3066, 2922, 2871, 1627, 1601, 1509,
1475, 1283, 1184, 1120; precise mass, calcd for C30H30O6 486.204, found 486.196. Compound 9: colorless crystal;
1
isolated yield 81% (170°C, 60 min); mp 165–170°C; H NMR (500 MHz, CDCl3, l (ppm)) 3.61 (m, 4H), 3.71 (m,
4H), 3.87 (m, 4H), 4.23 (m, 4H), 4.86 (s, 4H), 5.47 (s, 2H), 7.15 (s, 2H), 7.20 (s, 2H), 7.32 (m, 4H), 7.63 (dd, J=7,
3 Hz, 2H), 7.67 (dd, J=7, 3 Hz, 2H); IR (KBr, cm−1) 3393, 3064, 2914, 2876, 1626, 1602, 1511, 1473, 1262, 1187,
1118; precise mass, calcd for C32H34O7 530.230, found 530.222. Compound 10: colorless crystal; isolated yield
1
75% (160°C, 90 min); mp 165–167°C; H NMR (500 MHz, CDCl3, l (ppm)) 3.56 (m, 12H), 3.87 (m, 4H), 3.93
(s, 4H), 4.29 (m, 4H), 4.49 (s, 2H), 4.86 (s, 4H), 7.22 (s, 2H), 7.26–7.34 (m, 4H), 7.65 (d, J=7 Hz, 2H), 7.78 (d,
J=7 Hz, 2H); IR (KBr, cm−1) 3359, 3069, 2903, 2874, 1628, 1604, 1509, 1477, 1288, 1192, 1119; precise mass,
calcd for C34H38O8 574.256, found 574.249.
13. In NMR spectra, any other species was never observed except the three components, and all of the sample
solutions in CDCl3 are clear without any precipitate.
.