New crown spirobenzopyrans as light- and ion-responsive dual-mode signal transducers

Article abstract of DOI:10.1021/ja9707668

A new class of crown spirobenzopyrans were designed and synthesized. The crown spirobenzopyrans showed thermally irreversible photochromism only in the presence of alkali-metal cations accompanying cation-selective coloring efficiency. Thus, the new crown

Full text of DOI:10.1021/ja9707668

9160
J. Am. Chem. Soc. 1997, 119, 9160-9165
New Crown Spirobenzopyrans as Light- and Ion-Responsive
Dual-Mode Signal Transducers
Masahiko Inouye,* Kaori Akamatsu, and Hiroyuki Nakazumi
Contribution from the Department of Applied Materials Science, Osaka Prefecture UniVersity,
Sakai, Osaka 599-8531, Japan
ReceiVed March 10, 1997X
Abstract: A new class of crown spirobenzopyrans were designed and synthesized. The crown spirobenzopyrans
showed thermally irreversible photochromism only in the presence of alkali-metal cations accompanying cation-
selective coloring efficiency. Thus, the new crown spirobenzopyrans could transmit information of two different
simultaneous stimuli (ion and photon) to changes in their optical properties. The dual-mode signal transducer molecules
developed here can be considered to perform “AND” gate type signal transduction based on photochromism of
artificial receptors. Molecular recognition abilities and photochromic properties of the new crown spirobenzopyrans
were characterized by use of NMR and FAB mass spectroscopies.
Introduction
tors, which induce a series of chemical and signal transforma-
tions upon light absorption.5 For the vision process in mammals,
light-induced isomerization of retinal linked to opsin triggers a
conformational change of the protein, of which information is
eventually transmitted to the nervous systems by use of various
messenger molecules. Thus, the vision system is referred to as
a highly sophisticated multimode signal transducer system, so
that a mimic of such systems using simple and artificial
molecules may be a worthwhile subject in its own right.
The expectation of application in molecular devices has been
inspiring investigations into furnishing several functional mol-
ecules such as molecular sensors, switches, and signal transduc-
ers.1 In all respects of these functional molecules responding
to external physical and/or chemical stimuli, molecular recogni-
tion processes play a leading role.2,3 The design of molecular
devices principally demands the organization of such signal
transducer molecules. The integration of molecular components
and their coupled functions are also seen in many biological
events.4 For example, the common feature of all light-driven
biosystems is the initial participation of respective photorecep-
Here we present the synthesis of a new type of dual-mode
signal transducer molecule based on photochromism of artificial
receptors, in which only the combination of two simultaneous
“chemical and physical inputs” (ion and UV light) can cause
the receptors to be visible-light active.6 We have previously
reported crown ether-linked spirobenzopyrans 1, isomerization
of which to the open-chain colored merocyanines 1′‚M+ was
induced by recognition of alkali-metal cations as well as by
UV irradiation (Scheme 1).7 An idea that sophisticated signal
transduction at the molecular level also necessitates simultaneous-
type counterparts led us to develop the new crown spiroben-
zopyrans that could only be responsive to the combination of
ionic and photonic stimuli. In searching for an ideal crown
spirobenzopyran for this purpose, the structure 2 was developed.
* To whom correspondence should be addressed. E-mail: inouye@
chem.osakafu-u.ac.jp.
X Abstract published in AdVance ACS Abstracts, September 15, 1997.
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27, 89-112. Lehn, J.-M. Angew. Chem., Int. Ed. Engl. 1990, 29, 1304-
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187-195. Fluorescent Chemosensors for Ion and Molecule Recognition;
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ComprehensiVe Supramolecular Chemistry, Vol. 1; Atwood, J. L., Davies,
J. E. D., MacNicol, D. D., Vo¨gtle, F., Eds.; Elsevier: Oxford, 1996; pp
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L.; Davies, J. E. D.; MacNicol, D. D.; Vo¨gtle, F., Eds.; Elsevier: Oxford,
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(3) Recent examples: Rubinstein, I.; Steinberg, S.; Tor, Y.; Shanzer,
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Chem. Soc. 1997, 119, 7891-7892. Other dual-mode signal transducers:
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S0002-7863(97)00766-X CCC: $14.00 © 1997 American Chemical Society

New Crown Spirobenzopyrans
J. Am. Chem. Soc., Vol. 119, No. 39, 1997 9161
Scheme 1
Figure 1. The possible dominant low-energy binding structure for 2′‚
Li+ obtained by MM2 followed by a PM3 level approximation on
MOPAC.14
sponding iodoarene and alkynylstannane. Other compounds
were commercially available or easily synthesized (Scheme 2).
The new crown spirobenzopyran 2 thus synthesized had no
absorption bands above 350 nm in aprotic solvents such as
CHCl3, CH3CN, etc., indicating a closed spiropyran form. The
absorption spectra were scarcely affected upon addition of any
alkali-metal iodides in CH3CN even after several days in the
dark, in contrast to the results for 1. In the 1H NMR spectra of
2 in CD3CN, however, the downfield shifts and split of the
signals for the crown rings in the spiropyran form (3.6-4.2 ppm)
were observed after the addition of LiI (Figure 2a,b). This result
suggested that the lithium cations were bound to the macrocycle
of 2, and that the colorless form was attributed to no isomer-
ization of 2‚Li+ to 2′‚Li+. The complexation was also cor-
roborated on the basis of FAB mass experiments. Before
addition of LiI to 2, ion peaks for (M + H)+, (M + Na)+, and
(M + K)+ were detected; after the addition the signals decreased,
while a peak for (M + Li)+ appeared (Figure 3). Subsequently,
irradiation (360 nm) of the alkali-metal iodide containing CH3-
CN solutions of 2 gave rise to changes in their spectra, and
new absorption bands appeared. Figure 4 showed that small
selective coloration for LiI was observed, and that only
photoirradiation (salt free) of 2 resulted in a little change in its
spectrum, suggesting the suppression of its photochromic
property in the absence of the cations. The same λmax (560
nm) of 2′‚M+ irrespective of all kinds of alkali-metal cations
indicated no interaction of the crown-bound metal cations with
the p-nitrophenolate oxygen of 2′.7,11
Results and Discussion
The design of the new crown spirobenzopyran 2 was based
on the fact that the crown-bound cations could interact with
the ether oxygens of the oxyethylene side arm and not the
phenolate oxygen of the opened merocyanine form 2′. Thus,
we expected that the absence of the strong electrostatic
interaction between crown-bound cations and the phenolate
oxygen of 2′ would prevent ready thermal isomerization of 2
to 2′‚M+ in contrast with 1, and that the photoisomerized, cation-
accommodated merocyanine form 2′‚M+ would be stabilized
by the additional interaction of the lariat oxyethylene side arm
for the cations. In order to determine the appropriateness of
the molecular design of the new crown spirobenzopyran 2,
various computer modelings (MM2, MD, MOPAC) were
performed. Geometry optimization of 2′‚Li+ was carried out
in the form that the lithium cations interacted with both the
crown ring and the oxyethylene side arm of 2′. On the basis of
the comparison of the several dominant low-energy structures,
a possible recognition mode is shown in Figure 1.
The new crown spirobenzopyran 2 was synthesized from two
key intermediates, 3H-indole derivative 5, bearing a benzo-15-
crown-5, and 6-alkynyl-5-nitrosalicylaldehyde 6, by enamine-
passed aldol type cyclization in the final step. For the synthesis
of the bis-crown spirobenzopyran 3, the aldol type cyclization
was followed by Mukaiyama’s amide formation.8 The crown-
linked 3H-indole derivative 5 was prepared by Fisher-indole
synthesis9 from phenylhydrazine and an acetylindan derivative
synthesized from bis(chloromethyl)benzo-15-crown-5 by the
acetoacetate method. Alkynyl-substituted salicylaldehyde de-
rivative 6 was prepared by Stille coupling10 from the corre-
The emerging absorption bands were presumed to be due to
the merocyanine structure 2′ on the basis of the NMR spectrum
(Figure 2c). The interaction of the crown-bound Li+ and the
incoming oxyethylene side arm but not the p-nitrophenolate
oxygen of 2′ was confirmed by the upfield shift (0.25 ppm) of
the propargyl methylene protons by comparison with those of
2 in agreement with the UV spectra. The colored solution was
(10) Stille, J. K. Synthesis 1986, 25, 508-524.
(11) Bertelson, R. C. In Photochromism; Brown G. H., Ed.; Wiley: New
York, 1971; pp 45-294. Guglielmetti, R. In Photochromism, Molecules
and Systems; Du¨rr, H., Bouas-Laurent, H., Eds.; Elsevier: Amsterdam, 1990;
pp 314-466.
(8) Bald, E.; Saigo, K.; Mukaiyama, T. Chem. Lett. 1975, 1163-1166.
(9) Prochazka, M. P.; Carlson, R. Acta Chem. Scand. 1989, 43, 651-
659.

9162 J. Am. Chem. Soc., Vol. 119, No. 39, 1997
Scheme 2. Synthetic scheme for 2 and 3a
Inouye et al.
merization of 3′‚M+ to the colorless spiropyran form 3‚M+ was
observed upon irradiation with >480 nm light. These results
substantiate the interpretation described above.
Conclusions
We designed and synthesized a new class of crown spiroben-
zopyrans 2, in which thermally irreversible photochromism was
observed only in the presence of alkali-metal cations ac-
companying cation-selective coloring efficiency. Thus, the new
crown spirobenzopyran 2 could transmit information of two
different simultaneous stimuli (ion and photon) to changes in
its optical properties. The dual-mode signal transducer mol-
ecules developed here are expected to contribute to molecular-
based device technologies, although significant improvements
including selectivity, response, and fatigue resistance are still
needed.
Experimental Section
Instrumentation. 1H and 13C NMR spectra were recorded at 270
and 67.8 MHz, respectively, unless otherwise noted. EI mass spectra
were measured at 70 eV. For FAB mass experiments, Xe was used as
the atom beam accelerated to 8 keV. Melting points are uncorrected.
Materials. The starting materials were all commercially available,
and 3-iodo-4-nitrophenol (14) was prepared according to a literature
procedure.13
Computational Method. Geometry optimization for the binding
structures 2′‚Li+ was carried out by using MM2 (molecular mechanics)
followed by a PM3 level approximation on MOPAC by the CAChe
System (CAChe Scientific, Inc.).14 The dominant binding structure
2′‚Li+ was obtained by varying weight point coordinates and dihedral
angles for several O-Li weak bonds manually.
4,5-Bis(chloromethyl)benzo-15-crown-5 Ether (11). To a CH2-
Cl2 (70 mL) solution of benzo-15-crown-5 ether (13.4 g, 50.0 mmol)
were added a concentrated HCl aqueous solution (10 mL) and
chloromethyl methyl ether (32.2 g, 400 mmol) at room temperature.
The reaction mixture was stirred at that temperature for 12 h. The
reaction mixture was dissolved in water and extracted with CH2Cl2.
The CH2Cl2 extract was evaporated and subjected to column chroma-
tography (silica gel; eluent, AcOEt) to give 11: yield ) 28% (5.11 g,
14.0 mmol); mp 151-153 °C; IR (KBr) 2945, 2883, 1606, 1527, 1367,
a Reagents: (a) MeI; (b) KOH; (c) BrCH2CO2Et; (d) K2CO3; (e)
KOH; (f) monoaza-18-crown-6, 2-chloro-1-methylpyridinium iodide,
n-Bu3N; (g) CH3OCH2Cl, HCl; (h) ethyl acetoacetate, K2CO3; (i) KOH;
(j) PhNHNH2, ZnI2; (k) hexamethylenetetramine, CF3CO2H; (l)
CH3OCH2Cl, NaH; (m) n-Bu3SnC2CH2O(CH2)2OTHP (17), PdCl2(PPh3)2;
(n) HCl.
stable and did not bleach thermally in dark conditions at room
temperature even after 30 days. On the other hand, the
photoisomerized colored form of the parent spirobenzopyran 4
was so labile as to disappear completely for 10 min under
identical conditions. Partial isomerization of 2′‚M+ to the
colorless spiropyran form 2‚M+ was observed upon irradiation
with >480 nm light .12
1
1281, 1234, 1157, 1136, 1080, 866, 677 cm-1; H NMR (CDCl3) δ
3.73-3.76 (s, 8H), 3.89-3.92 (m, 4H), 4.14-4.17 (m, 4H), 4.67 (s,
4H), 6.87 (s, 2H); 13C NMR (CDCl3) δ 43.41, 69.10, 69.13, 69.45,
70.48, 116.00, 129.14, 149.46; MS m/e (rel intensity) 364 (M+, 2).
2-Acetyl-2-(ethoxycarbonyl)-5,6-(1,4,7,10,13-pentaoxatridecyl-
ene)indan (12). To an acetone (70 mL) suspension of finely ground
K2CO3 (6.63 g, 48.0 mmol) was added ethyl acetoacetate (3.12 g, 24.0
mmol) dropwise at room temperature. After stirring at the same
temperature for 30 min, to the suspension was added a DMF (70 mL)
solution of 11 (4.38 g, 12.0 mmol) dropwise. The reaction mixture
was stirred at 50 °C for 5 h. After removal of the solvent, the residue
was dissolved in water and extracted with CH2Cl2. The CH2Cl2 extract
was evaporated and chromatographed (silica gel; eluent, AcOEt) to give
12: yield ) 70% (3.55 g, 8.40 mmol); oil; IR (KBr) 2929, 2870, 1738,
1713, 1608, 1508, 1454, 1234, 1134, 939, 731 cm-1; 1H NMR (CDCl3)
δ 1.27 (t, J ) 7.3 Hz, 3H), 2.21 (s, 3H), 3.42 (d, J ) 16.2 Hz, 2H),
3.45 (d, J ) 16.2 Hz, 2H), 3.75 (s, 8H), 3.87-3.91 (m, 4H), 4.07-
4.09 (m, 4H), 4.22 (q, J ) 7.3 Hz, 2H), 6.70 (s, 2H); 13C NMR (CDCl3)
δ 13.88, 25.87, 38.76, 61.59, 67.21, 69.17, 69.45, 70.40, 70.80, 110.20,
132.07, 148.57, 172.24, 202.62; MS m/e (rel intensity) 422 (M+, 53).
2-Acetyl-5,6-(1,4,7,10,13-pentaoxatridecylene)indan (13). To a
THF (30 mL) solution of 12 (3.55 g, 8.40 mmol) was added 1 N KOH
aqueous solution (15 mL). The reaction mixture was stirred at room
temperature for 12 h. After removal of the solvent, the residue was
dissolved in water and extracted with CH2Cl2. The CH2Cl2 extract was
evaporated and chromatographed (silica gel; eluent, AcOEt) to give
13: yield ) 60% (1.77 g, 5.05 mmol); mp 62-65 °C; IR (KBr) 2927,
Results obtained here show that the crown spirobenzopyran
2 is realized to operate well as dual-mode signal transducer
molecules. At the present moment, although it may be difficult
to determine all of the factors contributing to the thermally
irreversible photochromism of 2‚Li+ and 2′‚Li+ in a striking
contrast to the previous crown spirobenzopyrans 1 and parent
spirobenzopyran 4, we anticipate that the presence of the 3′-
(benzo-15-crown-5) substituent is essential for blocking thermal
isomerization in the presence of Li+. Bis-crown spirobenzopy-
ran 3, which was thought to be a “chimera” of 1 and 2, was
synthesized in order to shed light on this aspect. After addition
of LiI to the CH3CN solution of 3, the absorption spectra of 3
were scarcely affected. Irradiation of the solution containing
LiI caused 3 to isomerize to the colored merocyanine form. The
colored form was identified as the merocyanine structure 3′‚
Li+ by NMR investigations. The order of the coloring efficiency
of LiI, NaI, CsI, RbI, and KI, which decreased in that order,
gave rough agreement for that of 2. In this case, too, reiso-
(12) The nitro-substituted spirobenzopyrans are so liable to fatigue that
substantial decomposition was observed during a few repetitions of the
photochromic cycle.9
(13) Hodgson, H. H.; Moore, F. H. J. Chem. Soc. 1927, 630-635.
(14) Stewart, J. J. P. QCPE 1993, 13, 40-42.

New Crown Spirobenzopyrans
J. Am. Chem. Soc., Vol. 119, No. 39, 1997 9163
Figure 2. 1H NMR spectra (500 MHz) of 2 (0.5 mM) in CD3CN (a) before the addition of LiI (2.5 mM), (b) after the addition, and (c) after
irradiation (360 nm) of (b). The signals marked with “m” are for the merocyanine structure 2′.
Figure 4. Electronic absorption spectra of 2 (0.1 mM) in CH3CN in
the presence of alkali-metal iodides (0.5 mM) after 1 h of irradiation
(360 nm).
153.99, 185.70; FABMS (in 3-nitrobenzyl alcohol) m/e (rel intensity)
446 (M+ + Na, 57).
Figure 3. FAB mass spectra of 2 with 3-nitrobenzyl alcohol matrix
6-Iodo-5-nitrosalicylaldehyde (15). A CF3CO2H (20 mL) suspen-
sion of 3-iodo-4-nitrophenol (14)13 (6.63 g, 25.0 mmol) and hexa-
methylenetetramine (3.15 g, 22.5 mmol) was stirred at 80 °C for 4 h.
After addition of water (5 mL), the mixture was stirred at room
temperature for 30 min. The reaction mixture was dissolved in water
and extracted with CH2Cl2. The CH2Cl2 extract was evaporated and
subjected to column chromatography (silica gel; eluent, CHCl3) to give
15: yield ) 34% (2.49 g, 8.45 mmol); mp 110-112 °C; IR (KBr)
(a) before the addition of LiI and (b) after the addition.
2872, 1701, 1508, 1458, 1244, 1128, 1045, 939 cm-1; 1H NMR (CDCl3)
δ 2.22 (s, 3H), 3.08-3.11 (m, 4H), 3.38-3.53 (m, 1H), 3.76 (s, 8H),
3.92-3.94 (m, 4H), 4.10-4.11 (m, 4H), 6.79 (s, 2H); 13C NMR (CDCl3)
δ 28.41, 34.90, 52.35, 69.45, 69.73, 70.62, 71.03, 110.63, 133.83,
148.53, 209.44; MS m/e (rel intensity) 350 (M+, 24).
Benzo-15-crown-5-Substituted 3H-Indole 5. To a p-xylene (40
mL) suspension of 13 (1.75 g, 5.00 mmol) and ZnI2 (1.69 g, 5.00 mmol)
was added phenylhydrazine (1.35 g, 12.5 mmol) dropwise at room
temperature. The reaction mixture was stirred at 110 °C for 7 h. After
removal of the solvent, the residue was dissolved in 1 N HCl aqueous
solution and extracted with CH2Cl2. The CH2Cl2 extract was evaporated
and chromatographed (silica gel; eluent, CH2Cl2:EtOH ) 30:1) to give
5: yield ) 60% (1.27 g, 3.00 mmol); mp 133-135 °C; IR (KBr) 3433,
3390, 2910, 2872, 1576, 1504, 1456, 1311, 1207, 1120, 1105, 1053,
939, 758 cm-1; 1H NMR (CDCl3) δ 2.16 (s, 3H), 3.13 (s, 4H), 3.67-
3.80 (m, 8H), 3.92-3.94 (m, 4H), 4.10-4.11 (m, 4H), 6.79 (s, 2H),
7.11 (d, J ) 3.7 Hz, 1H), 7.27-7.32 (m, 2H), 7.53 (d, J ) 7.9 Hz,
1H); 13C NMR (CDCl3) δ 16.18, 40.78, 63.67, 68.20, 68.62, 69.37,
69.85, 110.12, 119.76, 120.94, 125.48, 127.91, 134.20, 144.83, 147.58,
1653, 1568, 1525, 1443, 1329, 1277, 1263, 1176 cm-1 1H NMR
;
(CDCl3) δ 7.08 (d, J ) 9.2 Hz, 1H), 7.90 (d, J ) 9.2 Hz, 1H), 10.29
(s, 1H), 12.72 (s, 1H); 13C NMR (CDCl3) δ 96.50, 119.00, 119.64,
132.18, 165.89, 203.47; MS m/e (rel intensity) 293 (M+, 100).
2-Iodo-6-(methoxymethoxy)-3-nitrobenzaldehyde (16). To a THF
(20 mL) suspension of NaH (480 mg, 12.0 mmol; commercial 60%
dispersion was washed thoroughly with hexane prior to use) was added
a THF (15 mL) solution of 15 (2.34 g, 7.99 mmol) dropwise at 0 °C.
After stirring at that temperature for 30 min, to the solution was added
chloromethyl methyl ether (3.22 g, 40.0 mmol) dropwise at the same
temperature. After stirring for an additional 2 h at room temperature,
the reaction mixture was neutralized to pH 7 with 1 N NaOH aqueous
solution and evaporated. The residue was dissolved in water and
extracted with CH2Cl2. The CH2Cl2 extract was evaporated and

9164 J. Am. Chem. Soc., Vol. 119, No. 39, 1997
Inouye et al.
subjected to column chromatography (silica gel; eluent, CH2Cl2:AcOEt
) 5:1) to give 16: yield ) 70% (1.89 g, 5.61 mmol); mp 92-94 °C;
IR (KBr) 2962, 1701, 1653, 1578, 1527, 1523, 1450, 1331, 1261, 1161,
amount of concentrated HCl aqueous solution (several drops) was
refluxed for 1 h. The reaction mixture was neutralized to pH 7 with
1 N NaOH aqueous solution and evaporated. The residue was dissolved
in water and extracted with CH2Cl2. The CH2Cl2 extract was evaporated
to give 6: yield ) 75% (249 mg, 0.94 mmol); mp 52-54 °C; IR (KBr)
2926, 2873, 1655, 1606, 1570, 1522, 1456, 1336, 1300, 1221, 1178,
1107, 1076, 1022, 928, 770 cm-1; 1H NMR (CDCl3) δ 3.50-3.83 (m,
4H), 4.58 (s, 2H), 7.06 (d, J ) 9.2 Hz, 1H), 8.27 (d, J ) 9.2 Hz, 1H),
10.56 (s, 1H), 12.38 (s, 1H); 13C NMR (CDCl3) δ 59.20, 61.85, 71.87,
102.36, 118.95, 132.74, 166.01, 196.70; MS m/e (rel intensity) 265
(M+, 20).
Benzo-15-crown-5-Substituted exo-Methyleneindoline 7. To a
CH3CN (5 mL) solution of 5 (169 mg, 0.40 mmol) was added methyl
iodide (284 mg, 2.0 mmol) dropwise at room temperature. The reaction
mixture was stirred at 50 °C for 7 h. After removal of the solvent, the
residue was dissolved in water. The aqueous solution was washed with
ether in order to remove the unreacted starting materials and basified
to pH 9-10 by the addition of 1 N KOH aqueous solution. The
aqueous solution was extracted with CH2Cl2, and the CH2Cl2 extract
was evaporated. The residue was chromatographed (silica gel; eluent,
CHCl3:hexane:Et3N ) 20:30:1) to give 7: yield ) 45% (79 mg, 0.18
mmol); oil; 1H NMR (CDCl3) δ 3.05 (s, 3H), 3.20 (s, 4H), 3.79-3.86
(m, 9H), 3,87 (s, 1H), 3.91-3.94 (m, 4H), 4.12-4.15 (m, 4H), 6.55
(d, J ) 7.9 Hz, 1H), 6.64 (t, J ) 6.7, 1H), 6.76 (s, 2H), 6.84 (d, J )
6.7 Hz, 1H), 7.13 (t, J ) 7.9 Hz, 1H); 13C NMR (CDCl3) δ 28.84,
49.96, 54.93, 69.31, 69.71, 70.52, 71.01, 73.65, 104.91, 110.63, 118.59,
121.42, 127.85, 134.42, 137.35, 146.51, 148.47, 162.07; MS m/e (rel
intensity) 437 (M+, 94).
1
1107, 1091, 964, 935, 800 cm-1; H NMR (CDCl3) δ 3.51 (s, 3H),
5.32 (s, 2H), 7.33 (d, J ) 9.2 Hz, 1H), 7.85 (d, J ) 9.2 Hz, 1H), 10.09
(s, 1H); 13C NMR (CDCl3) δ 56.98, 87.95, 95.14, 115.30, 129.01,
159.71, 191.48; MS m/e (rel intensity) 337 (M+, 75).
2-[1,4-Dioxa-7-(tri-n-butylstannyl)hept-6-ynyl]tetrahydropyran
(17). To an Et2O (100 mL) solution of ethylene glycol (9.31 g, 150
mmol) containing a small amount of concentrated HCl aqueous solution
(several drops) was added 3,4-dihydro-2H-pyran (DHP) (13.44 g, 160
mmol) at room temperature. The reaction mixture was stirred at this
temperature for 2 h. After addition of finely ground K2CO3 (2.0 g),
the reaction mixture was stirred for an additional 10 min and filtered.
The filtrate was evaporated, and the residue was subjected to column
chromatography (silica gel; eluent, AcOEt) to give 2-(2-hydroxy-
ethoxy)tetrahydropyran: yield ) 41% (9.00 g, 61.6 mmol); oil; IR
(KBr) 3435, 2943, 2871, 1456, 1351, 1201, 1161, 1124, 1072, 1033,
1
985, 870 cm-1; H NMR (CDCl3) δ 1.51-1.86 (m, 6H), 2.81 (br s,
1H), 3.51-3.59 (m, 1H), 3.69-3.81 (m, 4H), 3.89-3.98 (m, 1H), 4.56-
4.59 (m, 1H); 13C NMR (CDCl3) δ 20.04, 25.24, 30.82, 62.33, 63.32,
70.82, 100.22; MS m/e (rel intensity) 146 (M+, 8). To a THF (50 mL)
suspension of NaH (2.00 g, 50 mmol; commercial 60% dispersion was
washed thoroughly with hexane prior to use) was added 2-(2-
hydroxyethoxy)tetrahydropyran (9.00 g, 61.6 mmol) dropwise at 0 °C,
and the reaction mixture was stirred for 30 min at the same temperature.
Propargyl bromide (7.14 g, 60.0 mmol) was added dropwise to the
solution at the same temperature. The reaction mixture was stirred at
room temperature for an additional 15 h. After removal of the solvent,
the residue was dissolved in water and extracted with CHCl3. The
CHCl3 extract was evaporated and distilled under reduced pressure to
give 2-(1,4-dioxahept-6-ynyl)tetrahydropyran: yield ) 57% (6.45 g,
35.0 mmol); bp 90-95 °C (4 mmHg); oil; IR (KBr) 3290, 3255, 2943,
2872, 1442, 1354, 1201, 1124, 1076, 1036, 985, 930, 872, 814, 673
Crown Spirobenzopyran 2. To an EtOH (1.5 mL) solution of 6
(48 mg, 0.18 mmol) was added an EtOH (1.5 mL) solution of 7 (79
mg, 0.18 mmol) dropwise at room temperature. The reaction mixture
was refluxed for 3 h. After removal of the solvent, the residue was
chromatographed (silica gel; eluent, CHCl3:EtOH ) 15:1) to give 2:
yield ) 43% (53 mg, 0.077 mmol); mp 117-120 °C; IR (KBr) 3359,
1
cm-1; H NMR (CDCl3) δ 1.49-1.99 (m, 6H), 2.43 (t, J ) 2.4 Hz,
1
2870, 1564, 1506, 1454, 1327, 1288, 941, 748 cm-1; H NMR (500
1H), 3.47-3.55 (m, 1H), 3.59-3.69 (m, 1H), 3.73 (t, J ) 4.1 Hz, 2H),
3.84-3.94 (m, 2H), 4.23 (d, J ) 2.4 Hz, 2H), 4.64 (t, J ) 4.1 Hz,
1H); 13C NMR (CDCl3) δ 19.50, 25.46, 30.58, 58.45, 62.31, 66.50,
69.15, 74.44, 79.80, 98.98; MS m/e (rel intensity) 184 (M+, 2). To a
THF (60 mL) solution of 2-(1,4-dioxahept-6-ynyl)tetrahydropyran (2.76
g, 15.0 mmol) was added an n-hexane solution of n-BuLi (13.5 mmol)
dropwise at 0 °C. After stirring at that temperature for 30 min, to the
solution was added tri-n-butyltin chloride (3.91 g, 12.0 mmol) at the
same temperature. The reaction mixture was stirred at room temper-
ature for an additional 15 h. After removal of the solvent, the residue
was dissolved in brine and extracted with CHCl3. The CHCl3 extract
was evaporated and distilled under reduced pressure to give 17: yield
) 80% (5.68 g, 12.0 mmol); bp 210-215 °C (4 mmHg); IR (KBr)
2927, 2852, 1524, 1464, 1342, 1201, 1124, 1076, 1036, 962, 874, 816,
MHz, CD3CN) δ 2.60 (d, J ) 15.5 Hz, 1H), 2.73 (s, 3H), 2.81 (br s,
1H), 3.13 (d J ) 15.5 Hz, 1H), 3.15 (d, J ) 15.5 Hz, 1H), 3.42 (d, J
) 15.5 Hz, 1H), 3.60-3.70 (m, 12H), 3.71-3.83 (m, 4H), 3.92-4.08
(m, 4H), 4.51 (s, 2H), 6.06 (d, J ) 10.6 Hz, 1H), 6.64 (d, J ) 7.3 Hz,
1H), 6.71 (s, 1H), 6.74 (t, J ) 7.3 Hz, 1H), 6.76 (s, 1H), 6.78 (d, J )
9.2 Hz, 1H), 6.84 (d, J ) 7.3 Hz, 1H), 7.18 (t, J ) 7.3 Hz, 1H), 7.28
(d, J ) 10.6 Hz, 1H), 7.93 (d, J ) 9.2 Hz, 1H); 13C NMR (CDCl3) δ
28.98, 29.71, 38.36, 42.00, 59.26, 61.81, 64.58, 69.06, 69.19, 69.49,
70.32, 70.80, 71.55, 79.25, 98.62, 105.11, 107.29, 110.20, 115.36,
115.86, 119.88, 121.34, 122.80, 125.66, 126,76, 128.23, 133.31, 134.08,
135.43, 143.01, 147.82, 148.41, 158.51; FABMS (in 3-nitrobenzyl
alcohol) m/e (rel intensity) 685 (MH+, 100).
Benzo-15-crown-5-Substituted exo-Methyleneindoline 8. To a
CH3CN (10 mL) solution of 5 (318 mg, 0.75 mmol) was added ethyl
bromoacetate (626 mg, 3.75 mmol) dropwise at room temperature. The
reaction mixture was stirred at 50 °C for 12 h. After removal of the
solvent, the residue was dissolved in water. The aqueous solution was
washed with ether in order to remove the unreacted starting materials
and basified to pH 9-10 by the addition of K2CO3 aqueous solution.
The aqueous solution was extracted with CH2Cl2, and the CH2Cl2 extract
was evaporated. The residue was chromatographed (silica gel; eluent,
AcOEt:Et3N ) 30:1) to give 8: yield ) 45% (171 mg, 0.34 mmol);
oil; 1H NMR (CDCl3) δ 1.25 (t, J ) 3.1 Hz, 3H), 3.22 (s, 4H), 3.75-
3.80 (m, 9H), 3.87-3.99 (m, 4H), 4.06-4.24 (m, 7H), 6.53 (d, J )
6.7 Hz, 1H), 6.64 (t, J ) 6.7 Hz, 1H), 6.76 (s, 2H), 6.84 (d, J ) 6.7
Hz, 1H), 7.12 (t, J ) 6.7 Hz, 1H); MS m/e (rel intensity) 509 (M+,
26).
1
671 cm-1; H NMR (CDCl3) δ 0.90 (t, J ) 6.8 Hz, 9H), 0.99 (t, J )
7.3 Hz, 6H), 1.26-1.40 (m, 6H), 1.47-1.77 (m, 12H), 3.47-3.54 (m,
1H), 3.60-3.69 (m, 1H), 3.70-3.78 (m, 2H), 3.83-3.93 (m, 2H), 4.24
(d, J ) 1.1 Hz, 2H), 4.64 (t, J ) 3.2 Hz, 1H); 13C NMR (CDCl3) δ
11.07, 13.64, 19.48, 25.50, 26.98, 28.88, 30.58, 59.38, 62.21, 66.52,
68.68, 89.78, 98.90, 105.92.
6-(Methoxymethoxy)-3-nitro-2-[4-oxa-6-(tetrahydropyranyloxy)-
hex-1-ynyl]benzaldehyde (18). To a toluene (3.0 mL) suspension of
16 (505 mg, 1.50 mmol) and (PPh3)2PdCl2 (42 mg, 0.06 mmol) was
added 17 (1065 mg, 2.25 mmol) dropwise at room temperature. The
reaction mixture was stirred at 80 °C for 3 h. The reaction mixture
was chromatographed (silica gel; eluent, CH2Cl2:AcOEt ) 5:1) to give
18: yield ) 83% (490 mg, 1.25 mmol); oil; IR (KBr) 2870, 1709,
1574, 1462, 1352, 1279, 1201, 1097, 1036, 1020, 949, 926, 908, 872,
810, 731 cm-1; 1H NMR (CDCl3) δ 1.48-1.88 (m, 6H), 3.53 (s, 3H),
3.50-3.54 (m, 1H), 3.65-3.72 (m, 1H), 3.84-3.99 (m, 4H), 4.56 (d,
J ) 1.6 Hz, 2H), 4.67 (t, J ) 3.8 Hz, 1H), 5.37 (s, 2H), 7.31 (d, J )
9.2 Hz, 1H), 8.16 (d, J ) 9.2 Hz, 1H), 10.57 (s, 1H); 13C NMR (CDCl3)
δ 19.44, 25.42, 30.50, 56.94, 59.08, 62.23, 66.46, 69.45, 94.94, 98.86,
101.39, 114.89, 120.59, 127.06, 130.11, 145.07, 160.84, 188.66; MS
m/e (rel intensity) 393 (M+, 9).
Ester-Substituted Crown Spirobenzopyran 9. To an EtOH (4 mL)
solution of 6 (80 mg, 0.30 mmol) was added a CH2Cl2 (4 mL) solution
of 8 (152 mg, 0.30 mmol) dropwise at room temperature. The reaction
mixture was stirred at 50 °C for 4 h. After removal of the solvent, the
residue was chromatographed (silica gel; eluent, CH2Cl2:MeOH ) 15:
1) to give 9: yield ) 46% (104 mg, 0.14 mmol). This compound was
used for the next reaction without further purification and identification.
Carboxylic Acid-Substituted Crown Spirobenzopyran 10. To a
THF (10 mL) solution of 9 (104 mg, 0.14 mmol) was added 1 N KOH
aqueous solution (3 mL). The reaction mixture was stirred at room
6-(6-Hydroxy-4-oxahex-1-ynyl)-5-nitrosalicylaldehyde (6).
A
MeOH (30 mL) solution of 18 (490 mg, 1.25 mmol) containing a small

New Crown Spirobenzopyrans
J. Am. Chem. Soc., Vol. 119, No. 39, 1997 9165
temperature for 10 h. The reaction mixture was neutralized to pH 7
with 1 N HCl aqueous solution and evaporated. The residue was
dissolved in water and extracted with CH2Cl2. The CH2Cl2 extract was
evaporated to give 10: yield ) 100% (100 mg, 0.14 mmol). This
compound was used for the next reaction without further purification
and identification.
Bis-Crown Spirobenzopyran 3. To a CH3CN (4 mL) solution of
monoaza-18-crown-6 ether (53 mg, 0.20 mmol), 2-chloro-1-methylpy-
ridinium iodide (52 mg, 0.20 mmol), and n-Bu3N (70 mg, 0.69 mmol)
was added a CH2Cl2 (4 mL) solution of 10 (100 mg, 0.14 mmol)
dropwise at room temperature. The reaction mixture was stirred at 50
°C for 4 h. After removal of the solvent, the residue was dissolved in
water and extracted with CH2Cl2. The CH2Cl2 extract was evaporated
and chromatographed (silica gel; eluent, CH2Cl2:MeOH ) 20:1; then
ODS reversed-phase silica gel; eluent, MeOH:H2O ) 4:1) to give 3:
yield ) 29% (39 mg, 0.040 mmol); mp 77-80 °C; IR (KBr) 3340,
1635, 1506, 1456, 1261, 1097, 802 cm-1; 1H NMR (500 MHz, CD3CN)
δ 2.79 (d, J ) 15.5 Hz, 1H), 3.00 (br s, 1H), 3.25 (d J ) 15.5 Hz, 1H),
3.31 (d, J ) 15.5 Hz, 1H), 3.42-3.82 (m, 33H), 3.83-3.94 (m, 6H),
4.01-4.17 (m, 6H), 4.25 (s, 2H), 4.59 (s, 2H), 6.14 (d, J ) 10.6 Hz,
1H), 6.58 (d, J ) 6.7 Hz, 1H), 6.76 (s, 1H), 6.81 (t, J ) 6.7 Hz, 1H),
6.88 (s, 1H), 6.90 (d, J ) 9.1 Hz, 1H), 6.98 (d, J ) 6.7 Hz, 1H), 7.21
(t, J ) 6.7 Hz, 1H), 7.26 (d, J ) 10.6 Hz, 1H), 8.01 (d, J ) 9.1 Hz,
1H); 13C NMR (CDCl3) δ 38.22, 42.50, 45.15, 47.03, 48.91, 59.28,
61.61, 65.51, 68.59, 69.13, 69.17, 69.83-71.67, 79.07, 98.80, 105.17,
107.01, 109.76, 110.67, 115.50, 115.78, 119.66, 121.34, 121.38, 123.50,
126.23, 126.58, 128.27, 133.81, 134.16, 134.36, 142.95, 147.01, 147.80,
158.27, 169.32; FABMS (in 3-nitrobenzyl alcohol) m/e (rel intensity)
974 (MH+, 93), 996 (M+ + Na, 100).
Acknowledgment. This work was partly supported by the
Mazda Foundation’s Research Grant.
JA9707668