Organic & Biomolecular Chemistry
Paper
selective response to Li+ over the other metal ions, exhibiting a was added triethylamine (80 μL, 1.1 mmol) and the solution
stronger relative absorbance and fluorescence spectra. There- cooled in an ice bath. To this mixture was added a solution of
fore in conclusion, these azacrownether spiropyrans have 3-(chloromethyl)-2-hydroxy-5-nitrobenzaldehyde (10) (0.11 g,
potential as new reversible fluorescent probes for investigating 0.51 mmol) in dry THF (5 mL). The solution was allowed to
the concentration of Li+ in biological systems, which will lead warm to r.t. over 1 h followed by reflux for 17 h. The precipitate
to a greater understanding of Li+’s role in diseases such as was removed by filtration and the solvent was removed
manic-depressive illness.
in vacuo to give 11 as a yellow solid (0.19 g). 1H NMR
(500 MHz, DMSO-d6) δ 10.19 (d, J = 0.6 Hz, 1H), 8.27 (dd, J =
0.5, 3.0 Hz, 1H), 8.09 (d, J = 3.0 Hz, 1H), 4.28 (s, 2H), 3.83–3.75
(m, 5H), 3.68–3.51 (m, 11H); 13C NMR (126 MHz, DMSO-d6)
δ 190.1 (s), 178.9 (s), 130.7 (s), 129.9 (s), 126.4 (s), 123.7 (s),
122.3 (s), 70.1 (s), 69.8 (s), 64.6 (s), 56.5 (s), 54.3 (s). MS (m/z)
for C16H22N2O7 + H ([M + H+]+) calcd 355.1505; found
355.1507. A sample of 11 (0.18 g) and 6 (0.18 g, 0.51 mmol)
were dissolved in ethanol (10 mL) and the solution refluxed for
3 h. The solvent was removed in vacuo and the resulting
purple solid (0.36 g) was purified twice by C18 reverse phase
silica chromatography eluting with a gradient of acetonitrile
in water to give 1 (50 mg) in a yield of 18% (based on 7).
mp. 118–121 °C, 1H NMR (500 MHz, DMSO-d6) δ 12.31 (s, 1H),
8.35 (d, J = 2.6 Hz, 1H), 8.13 (d, J = 2.6 Hz, 1H), 7.81 (d, J =
8.2 Hz, 1H), 7.69 (s, 1H), 7.25 (d, J = 10.4 Hz, 1H), 6.70 (d, J =
8.2 Hz, 1H), 6.01 (d, J = 10.4 Hz, 1H), 3.58–3.36 (m, 18H), 2.73
Experimental
Materials and methods
1
All 13C NMR and H NMR spectra were recorded on an Agilent
Technologies 500 MHz NMR with DD2 console in CDCl3 or
DMSO-d6 (Cambridge Isotope Laboratories, Cambridge, MA).
Chemical shifts (δ) are reported in ppm, with CDCl3 (δC
77.1 ppm), DMSO-d6 (δC = 39.52 ppm) or TMS (δH = 0.0 ppm)
used as internal standards. High resolution mass spectrometry
was performed on the Agilent 6230 TOF LC-MS. All commer-
cially available chemicals were reagent grade and used without
further purification.
=
Synthesis of azacrownetherspiropyrans
3,3-Dimethyl-2-methyleneindoline-5-carboxylic acid (5). 4- (s, 3H), 1.25 (s, 3H), 1.14 (s, 3H); 13C NMR (126 MHz, DMSO-
Hydrazinobenzoic acid (4) (5.0 g, 33 mmol) was suspended in d6) δ 167.4 (s), 156.5 (s), 151.2 (s), 140.3 (s), 135.9 (s), 130.8 (s),
ethanol (20 mL) and to this was added 2-methyl-2-butanone 128.7 (s), 127.1 (s), 125.9 (s), 122.9 (s), 121.5 (s), 121.3 (s),
(4 mL, 37 mmol) followed by conc. sulphuric acid (1 mL). The 120.3 (s), 118.4 (s), 106.3 (s), 105.8 (s), 70.9 (s), 69.5 (s), 69.3 (s),
mixture was stirred at reflux for 18 h. After cooling to r.t. the 54.4 (s), 52.4(s), 51.3 (s), 28.4 (s), 25.5 (s), 19.5 (s). MS (m/z) for
precipitate was removed by filtration and washed with aceto- C29H35N3O8 + H ([M + H+]+) calcd 554.2502; found 554.2517
nitrile. The filtrate was quenched with saturated sodium bi-
Aza-18-crown-6-ether spiropyran (3). To a solution of 1-aza-
carbonate solution and washed with DCM 2 × 60 mL. The 18-crown-6-ether (9) (0.25 g, 0.95 mmol) in dry THF (5 mL) was
aqueous layer was carefully acidified to pH 5 (universal indi- added triethylamine (0.16 mL, 2.2 mmol). The solution was
cator paper) with 2 M aqueous hydrochloric acid solution and cooled in an ice bath and to this was added dropwise a solu-
red product was extracted with DCM (3 × 60 mL), dried with tion of 3-(chloromethyl)-2-hydroxy-5-nitrobenzaldehyde (10)
MgSO4 and solvent removed in vacuo to give 5 as a dark red (0.21 g, 0.97 mmol) in dry THF (7 mL). The solution was
solid (4.8 g) in 73% yield. mp. 198–202 °C, 1H NMR (500 MHz, allowed to warm to r.t. over 1 h followed by reflux for 17 h. The
CDCl3) δ 8.16 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 7.67 (d, J = precipitate was removed by filtration and the solvent was
8.1 Hz, 1H), 2.38 (s, 3H), 1.38 (s, 6H); 13C NMR (126 MHz, removed in vacuo to give 13 as a thick orange oil (0.48 g).
CDCl3) δ 192.4 (s), 171.3 (s), 157.6 (s), 145.6 (s), 130.9 (s), 1H NMR (500 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.27 (d, J =
126.6 (s), 123.2 (s), 119.7 (s), 53.9 (s), 22.9 (s), 15.6 (s). MS (m/z) 3.1 Hz, 1H), 8.13 (d, J = 3.1 Hz, 1H), 4.38 (s, 2H), 3.84–3.79
for C12H13NO2 + H ([M + H+]+) calcd 204.1025; found 204.1025. (m, 4H), 3.56 (s, 8H), 3.53 (s, 8H), 3.33–3.27 (m, 5H); 13C NMR
1,3,3-Trimethyl-2-methyleneindoline-5-carboxylic acid (126 MHz, DMSO-d6) δ 189.9 (s), 178.6 (s), 130.7 (s), 130.6 (s),
(6). 3,3-Dimethyl-2-methyleneindoline-5-carboxylic acid (5) 126.0 (s), 123.8 (s), 122.2 (s), 69.9 (s), 69.8 (s), 69.7 (s), 69.4 (s),
(3.9 g, 19 mmol) was dissolved in a solution of 2 : 1 toluene : 64.6 (s), 56.0 (s), 52.0 (s). MS (m/z) for C20H30N2O9 + H
acetonitrile (100 mL). To this was added iodomethane (1.3 mL, ([M + H+]+) calcd 443.2030; found 443.2009. A sample of 13
21 mmol) and the solution was stirred at 95 °C for 24 h. The (0.47 g) and 6 (0.24 g, 1.1 mmol) were dissolved in ethanol
solution was cooled to r.t. and the precipitate was collected by (15 mL), and the solution refluxed for 18 h. Solvent was
filtration and washed with acetonitrile to give 6 (3.0 g) in 72% removed in vacuo to give purple crude solid (0.68 g, 1.1 mmol)
yield. mp. 154–157 °C, 1H NMR (500 MHz, DMSO-d6) δ 8.36 of which 0.34 g was purified by C18 reverse phase silica chrom-
(s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 4.00 atography eluting with a gradient of acetonitrile in water to
(s, 3H), 2.82 (s, 3H), 1.57 (s, 6H); 13C NMR (126 MHz, DMSO- give 3 (120 mg) in a yield of 20% (based on 10). mp. 95–99 °C,
d6) δ 199.0 (s), 166.5 (s), 145.2 (s), 141.9 (s), 131.6 (s), 130.3 (s), 1H NMR (500 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.15–8.11
124.2 (s), 115.4 (s), 54.3 (s), 35.2 (s), 21.5 (s), 14.8 (s). MS (m/z) (m, 2H), 7.81 (d, J = 8.2 Hz, 1H), 7.68 (s, 1H), 7.24 (d, J =
for C13H16NO2 ([M]+) calcd 218.1181; found 218.1184.
10.3 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.00 (d, J = 10.3 Hz, 1H),
Aza-12-crown-4-ether spiropyran (1). To a solution of 1-aza- 3.57–3.46 (m, 12H), 3.46–3.42 (m, 5H), 3.41 (s, 2H), 3.37–3.33
12-crown-4-ether (7) (90 mg, 0.51 mmol) in dry THF (3 mL) (m, 2H), 3.29–3.26 (m, 5H), 2.71 (s, 3H), 1.26 (s, 3H),
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