Use of pyridinium ionic liquids as catalysts for the synthesis
of 3,5-bis(dodecyloxycarbonyl)-1,4-dihydropyridine derivative
Our research group has reported that cationic residue was crystallised from ethanol giving compound
1
amphiphiles comprising 1,4-dihydropyridine cycle 4 as a white powder (440 mg, 72%), mp 55-56°C. H
are good candidates for the development of new NMR spectrum (CDCl3, 200 MHz): δ 0.88 (t, 6H, J=6.6),
gene delivery systems [17]. One of the most potent 1.21-1.30 (m, 36H), 1.51-1.64 (m, 4H), 2.33 (s, 6H), 4.02
and promising compounds with high transfection (t, 4H, J=6.6), 4.99 (s, 1H), 5.59 (br s, 1H), 7.10-7.30
efficiency in vitro is a synthetic cationic lipid – 1,1′-{[3,5- (m, 5H); 13C NMR spectrum (CDCl3, 100 MHz): δ 14.09,
bis(dodecyloxycarbonyl)-4-phenyl-1,4-dihydropyridine- 19.61, 22.67, 26.08, 28.69, 29.30, 29.34, 29.55, 29.61,
2,6-diyl]dimethylene} bispyridinium dibromide (6) 29.63, 29.66, 31.90, 39.49, 63.93, 104.26, 126.08,
[17,18]. In this paper, we report an effective synthetic 127.83, 127.87, 143.76, 147.64, 167.62; IR (film) 3339,
approach to amphiphilic 1,4-DHP6, the key step of which 1700, 1653 cm-1; MS(-ESI) m/z (relative intensity) 608
comprises a two-component Hantzsch-type cyclisation ([M-H]+, 100). Anal. Calcd. for C39H63NO4: C, 76.80; H,
using pyridinium ionic liquid as a catalyst, proceeding 10.41; N, 2.30. Found: C, 76.78; H, 10.50; N, 2.27.
in a substantially higher yields with respect to classical
Hantzsch synthesis.
Method B. A solution of 3-amino-but-2-enoic acid
dodecyl ester 2 (10.80 g, 40.10 mmol) and benzaldehyde
1 (2.16 g, 20.40 mmol) in methanol/acetic acid
(40 mL/10 mL) was refluxed for 8 h, after cooling the
precipitate was filtered off and crystallised from ethanol
giving compound 4 as a light yellow powder (7.80 g,
64%), mp 54-56°C. 1H NMR spectrum (CDCl3, 200 MHz)
2. Experimental Procedure
2.1. General procedures
All reagents were purchased from Acros and used was identical to that described above for 4 in Method A.
without further purification. TLC was performed on
Silica gel 60 F254 Aluminium sheets 20×20 cm (Merck). 2.2.2.
2,6-Di(bromomethyl)-3,5-bis(dodecyloxy-
carbonyl)-4-phenyl-1,4-dihydropyridine (5)
1H NMR spectra were recorded with a Varian Mercury
(200 MHz or 400 MHz) spectrometer. 13C NMR spectra To a solution of compound 4 (3.03 g, 5.00 mmol) in
were recorded with a Varian Mercury (100 MHz) methanol NBS (1.85 g, 10.40 mmol) was added portion-
spectrometer. Chemical shifts are reported in ppm wise. The reaction mixture was stirred at rt for 20 h.
relative to hexamethyldisiloxane (δ 0.055). Multiplicities The yellow precipitate was filtered off, and washed with
are abbreviated as: s, singlet; d, doublet; t, triplet; q, water. The precipitate was crystallised from ethanol
quartet; m, multiplet; br, broad. The coupling constants giving compound 5 as a yellow powder (2.76 g, 72%),
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are expressed in Hertz. Alliance Waters 2695 HPLC mp 87-90°C. H NMR spectrum (CDCl3, 200 MHz): δ
system connected to a Waters 3100 mass detector 0.88 (t, 6H, J=6.6), 1.21-1.33 (m, 36H), 1.61-1.67 (m,
operating in the ESI positive or negative ion mode on a 4H), 4.00 (t, 4H, J=6.6), 4.62 and 4.91 (AB-system, 4H,
Waters Xbridge C18 column (5 µm, 2.1×50 mm) using J=11.4), 5.02 (s, 1H), 6.57 (br s, 1H), 7.17-7.30 (m, 5H);
a gradient elution with methanol/formic acid (0.1% in 13C NMR spectrum (CDCl3, 100 MHz): δ 14.09; 22.66;
water). Infrared spectra were recorded with a FTIR 26.02; 27.32; 28.55; 29.26; 29.34; 29.53; 29.59; 29.62;
spectrometer Prestige-21 (Shimadzu). Melting points 29.65; 31.90; 40.07; 64.77; 106.07; 126.84; 127.91;
weredeterminedonanOptiMelt(SRSStanfordResearch 128.21; 141.60; 145.60; 166.20; IR (film) 3320, 1696,
Systems). Elemental analyses were determined on an 1676 cm-1. Anal. Calcd. for C39H61Br2NO4: C, 61.02; H,
EA 1106 (Carlo Erba Instruments).
8.01; N, 1.82. Found: C, 61.23; H, 8.04; N, 1.73.
2.2. Synthesis of compounds 4-6
2.2.3.
1,1′-{[3,5-Bis(dodecyloxycarbonyl)-4-phenyl-
1,4-dihydropyridine-2,6-diyl]dimethylene}
bispyridinium dibromide (6)
2.2.1.
3,5-Bis(dodecyloxycarbonyl)-2,6-dimethyl-4-
phenyl-1,4-dihydropyridine (4)
MethodA.Toasolutionof3-oxo-2-[1-phenylmethylidene]-
butyric acid dodecyl ester 3 (360 mg, 1.00 mmol) and
3-amino-but-2-enoic acid dodecyl ester 2 (270 mg,
1.00 mmol) in bis(2-hydroxyethyl)ether (5.0 mL) 1-butyl-
4-methylpyridinium chloride (18 mg, 0.10 mmol) was
added and the reaction mixture was heated at 80°C
for 8 h. Then the reaction mixture was poured into ice
water and extracted with ethylacetate (3×20 mL). The
combined organic layers were dried with anhydrous
MgSO4 and the solvent was removed in vacuo. The
To a solution of compound 5 (1.00 g, 1.30 mmol) in dry
acetone (30 mL), pyridine (200 μL, 2.50 mmol) was
added and the reaction mixture was stirred at rt for
48 h. After cooling, the precipitate was filtered off,
washed with dry acetone and crystallised from ethanol
giving compound 6 as a light yellow powder (0.98 g,
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82%), mp 156-158°C (mp 140-145°C [18]). H NMR
spectrum (CDCl3, 200 MHz): δ 0.88 (t, 6H, J=6.6), 1.22-
1.30 (m, 36H), 1.61-1.63 (m, 4H), 4.04 (t, 4H, J=6.6),
5.10 (s, 1H), 5.89 and 6.40 (AB-system, 4H, J=13.5),
144