Efficient synthesis of alkylene bridging bisdihydropyridines

Article abstract of DOI:10.1080/00397910903079599

Under microwave irradiation, vanillin was alkylated with α,W-dihaloalkane to give 4,4'-alkylene-bridging vanillins, which in turn underwent one-pot multicomponent reactions with excess of ethyl acetoacetate and ammonium bicarbonate to give 4,4'-alkoxy-bri

Full text of DOI:10.1080/00397910903079599

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Efficient Synthesis of Alkylene Bridging
Bisdihydropyridines
Dong-Mei Liu a , Li-Ting Du a , Jing Sun a & Chao-Guo Yan a
a College of Chemistry and Chemical Engineering, Yangzhou
University , Yangzhou, China
Published online: 07 Apr 2010.
To cite this article: Dong-Mei Liu , Li-Ting Du , Jing Sun & Chao-Guo Yan (2010) Efficient Synthesis of
Alkylene Bridging Bisdihydropyridines, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:9, 1333-1338, DOI: 10.1080/00397910903079599
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Synthetic Communications1, 40: 1333–1338, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903079599
EFFICIENT SYNTHESIS OF ALKYLENE BRIDGING
BISDIHYDROPYRIDINES
Dong-Mei Liu, Li-Ting Du, Jing Sun, and Chao-Guo Yan
College of Chemistry and Chemical Engineering, Yangzhou University,
Yangzhou, China
Under microwave irradiation, vanillin was alkylated with a,x-dihaloalkane to give 4,40-
alkylene-bridging vanillins, which in turn underwent one-pot multicomponent reactions with
excess of ethyl acetoacetate and ammonium bicarbonate to give 4,40-alkoxy-bridging
bisdihydropyridines in moderate yields. The structures of the synthetic bisdihydropyridines
were characterized with 1H NMR, 13C NMR, and high-performance liquic chromato-
graphy/mass spectroscopy.
Keywords: Dihydropyridine; Hantzsch synthesis; microwave irradiation; one-pot reaction; vanillin
1,4-Dihydropyridines and their derivatives are very important bioactive molecules in
the field of pharmaceuticals. These compounds are very well known as calcium
channel modulators and have emerged as one of the most important classes of drugs
for the treatment of hypertension and so on.[1–3] Because of the potential importance
of 1,4-dihydropyridines from pharmaceutical, industrial, and synthetic points of view,
the synthesis of 1,4-dihydropyridyl compounds has attracted much attention, and
various methods have been developed.[4–6] The best known method for the preparation
of 1,4-dihydropyridines is the classical Hantzsch synthesis. Other efficient synthetic
methods such as Menendez synthesis[7] and Ishar synthesis[8] have also developed
recently. It is still challenging to explore new and efficient synthetic routes for this class
of compounds, practically those with clean technologies or environmentally benign
reactions.[9,10] On the other hand, so far attention has been paid mainly to the synthesis
of monofunctional 1,4-dihydropyridine derivatives, while the bifunctional bisdihydro-
pyridines are seldom investigated.[11,12] Herein, we report a facile one-pot multicompo-
nent reaction to prepare alkylene bridging bisdihydropyridine derivatives.
EXPERIMENTAL
Material and Apparatus
Melting points were taken on a hot-plate microscope apparatus. Infrared (IR)
1
spectra were obtained on a Bruker Tensor 27 spectrometer (KBr disc). H and 13C
Received February 3, 2009.
Address correspondence to Chao-Guo Yan, College of Chemistry and Chemical Engineering,
Yangzhou University, Yangzhou 225002, China. E-mail: cgyan@yzu.edu.cn
1333

1334
D.-M. LIU ET AL.
NMR spectra were recorded with a Bruker AV-600 spectrometer with CDCl3 as
solvent and tetramethylsilane (TMS) as internal standard. High-performance liquid
chromatography=mass spectroscopy (HPLC=MS) were measured using a Fennigan
LCQ Deca XP MAX instrument. Microwave heating was conducted with Lingjiang
LMMC-201 microwave reactor (Nanjing, China). Vanillin, ethyl acetoacetate, dibro-
moalkane, and other reagents are commercial reagents and were used as received.
The reaction process was monitored by thin-layer chromatography (TLC).
Synthesis of 4,40-Alkylene Bridging Vanillins (2a–f)
Vanillin (10.0 mmol, 1.50 g), dibromoalkane (4.0 mmol), potassium carbonate
(3.0 g, 25.0 mmol), PEG-400 (0.5 g), and DMF (3.0 mL) were added to a 50-mL flask.
The mixture was put in microwave oven and heated for about 2–3 min (390 W). After
cooling, the reaction mixture was diluted with 50 mL of water. The resulting precipi-
tate was collected with filtration and washed with water. The crude product was
recrystallizated with ethanol to give the solid samples 2a–f, which were pure enough
for analysis.
Compound 2a. White solid, yield 94%, mp 148 ꢀC; 1H NMR (CDCl3,
600 MHz) d: 9.89 (s, 2H, CHO), 7.41–7.47 (m, 6H, ArH), 5.95 (s, 2H, OCH2O),
3.93 (s, 6H, OCH3); IR (KBr) t: 2856, 1688, 1592, 1507, 1466, 1428, 1402, 1269,
1216, 1129, 1007, 865, 806, 734 cmꢁ1; MS (m=z) [M]þ: 316.73.
Compound 2b. White solid, yield 60%, mp 169 ꢀC; 1H NMR (CDCl3,
600 MHz) d: 9.87 (s, 2H, CHO), 7.47 (d, J ¼ 7.8 Hz, 2H, ArH), 7.43 (s, 2H, ArH),
7.11 (d, J ¼ 7.8 Hz, 2H, ArH), 4.56 (s, 4H, OCH2CH2O), 3.92 (s, 6H, OCH3); IR
(KBr) t: 2953, 2856, 1682, 1588, 1512, 1471, 1427, 1138, 1024, 862, 807, 734 cmꢁ1
MS (m=z): 353.80 ([M þ Na]þ) 16.5%.
;
Compound 2c. White solid, yield 90%, mp 130 ꢀC; 1H NMR (CDCl3,
600 MHz) d: 9.85 (s, 2H, CHO), 7.44 (d, J ¼ 7.8 Hz, 2H, ArH), 7.41 (s, 2H, ArH),
7.04 (d, J ¼ 7.8 Hz, 2H, ArH), 4.34 (t, J ¼ 6.0 Hz, 4H, OCH2), 3.92 (s, 6H, OCH3),
2.12 (br, 2H, CH2); IR (KBr) t: 2960, 2837, 1678, 1586, 1509, 1468, 1426, 1401,
1350, 1266, 1160, 1134, 1056, 1029, 1000, 869, 813, 732 cmꢁ1; MS (m=z): 367.60
([M þ Na]þ) 100%.
Compound 2d. White solid, yield 90%, mp 140 ꢀC; 1H NMR (CDCl3,
600 MHz) d: 9.85 (s, 2H, CHO), 7.44 (d, J ¼ 8.4 Hz, 2H, ArH), 7.40 (s, 2H, ArH),
6.99 (d, J ¼ 8.4 Hz, 2H, ArH), 4.22 (br, 4H, OCH2), 3.91 (s, 6H, OCH3), 2.12 (br,
4H, CH2); IR (KBr) t: 2955, 2810, 1679, 1600, 1511, 1454, 1425, 1396, 1264, 1137,
1024, 861, 818, 731 cmꢁ1; MS (m=z): 382.40 ([M þ Na]þ) 100%.
Compound 2e. White solid, yield 85%, mp 103 ꢀC; 1H NMR (CDCl3,
600 MHz) d: 9.83 (s, 2H, CHO), 7.39–7.43 (m, 4H, ArH), 6.95–6.98 (m, 2H, ArH),
4.13 (t, J ¼ 6.0 Hz, 4H, OCH2), 3.91 (s, 6H, OCH3), 1.95–1.99 (m, 4H, CH2),
1.67–1.72 (m, 2H, CH2); IR (KBr) t: 2953, 2837, 1672, 1582, 1511, 1470, 1425,
1401, 1352, 1265, 1241, 1165, 1134, 1055, 1031, 1014, 978, 892, 831,799, 729 cmꢁ1
MS (m=z): 395.60 ([M þ Na]þ) 100%.
;

EFFICIENT SYNTHESIS OF ALKYLENE BRIDGING BISDIHYDROPYRIDINES
1335
Compound 2f. White solid, yield 87%, mp 145 ꢀC; 1H NMR (CDCl3,
600 MHz) d: 9.85 (s, 2H, CHO), 7.44 (d, J ¼ 8.4 Hz, 2H, ArH), 7.41 (s, 2H, ArH),
6.97 (d, J ¼ 8.4 Hz, 2H, ArH), 4.12 (t, J ¼ 6.6 Hz, 4H, OCH2), 3.93 (s, 6H, OCH3),
1.94 (br, 4H, CH2), 1.59 (br, 4H, CH2); IR (KBr) t: 2949, 1682, 1588, 1510, 1467,
1424, 1398, 1345, 1266, 1135, 1012, 868, 803, 732 cmꢁ1; MS (m=z): 410.27
([M þ Na]þ) 65.0%.
Synthesis of 4,40-Alkylene Bridging Bisdihydropyridines (3a–f)
4,40-Alkylene bridging vanillin (2a–f) (2.0 mmol), ethyl acetoacetate
(7.0 mmol), and ammonium carbonate (3.0 g) were added to a 50-mL flask. The
mixture was heated at 70 ꢀC for 3 days. After cooling, the reaction mixture was
diluted with 50 mL of water, and the resulting precipitate was collected with
filtration. The crude product was recrystallizated with ethanol to give the pure solid
sample 3a–f for analysis.
1
Compound 3a. Light yellow solid, yield 58%, mp 159.0–161.3 ꢀC; H NMR
(CDCl3, 600 MHz) d: 7.08 (d, J ¼ 8.4 Hz, 2H, ArH), 6.88 (s, 2H, ArH), 6.74 (d,
J ¼ 8.4 Hz, 2H, ArH), 5.97 (br, 2H, NH), 5.65, 5.65 (s, s, 2H, OCH2O), 4.93, 4.94
(s, s, 2H, CH), 4.07–4.12 (m, 8H, OCH2), 3.78, 3.79 (s, s, 6H, OCH3), 2.31, 2.32
(s, s, 12H, CH3), 1.22–1.25 (m, 12H, CH3); 13C NMR (CDCl3, 150 MHz) d: 167.8,
149.0, 144.4, 144.3, 143.1, 120.0, 117.2, 112.2, 103.7, 93.2, 59.8, 55.7, 39.0, 19.4,
14.3; IR (KBr) t: 3313, 3237, 3101, 2982, 1689, 1504, 1377, 1330, 1213, 1126,
1018, 870, 815, 761, 690, 585, 475 cmꢁ1; MS (m=z) [M þ Na]: 786.73.
Compound 3b. Yellow solid, yield 49%, mp 88.9–91.8 ꢀC; 1H NMR (CDCl3,
600 MHz) d: 6.74 (s, 2H, ArH), 6.63–6.64 (m, 4H, ArH), 5.63 (s, 2H, NH), 4.79 (s,
2H, CH), 4.18 (s, 4H, OCH2), 3.95–3.97 (m, 12H, OCH2), 3.66 (s, 6H, OCH3), 2.19
(s, 12H, CH3), 1.08–1.10 (m, 12H, CH3); 13C NMR (CDCl3, 150 MHz) d: 167.7,
148.6, 146.4, 143.7, 141.5, 119.976, 113.4, 112.5, 104.1, 67.2, 59.7, 58.5, 55.9, 39.0,
19.6, 14.4; IR (KBr) t: 3434, 3339, 2980, 2935, 1692, 1565, 1508, 1460, 1422, 1383,
1370, 1300, 1269, 1163, 1096, 1024, 941, 865, 784, 754, 728, 699, 570 cmꢁ1; MS
(m=z) [M þ Na]: 801.20.
1
Compound 3c. Light yellow solid, yield 32%, mp 170.6–173.0 ꢀC; H NMR
(CDCl3, 600 MHz) d: 6.86 (s, 2H, ArH), 6.75 (s, 4H, ArH), 5.85 (br, 2H, NH),
4.93 (s, 2H, CH), 4.08–4.15 (m, 12H, OCH2), 3.78 (s, 6H, OCH3), 2.32, 2.33 (s, s,
12H, CH3), 2.26–2.29 (m, 2H, CH2), 1.22–1.24 (m, 12H, CH3); 13C NMR (CDCl3,
150 MHz) d: 167.9, 148.5, 146.6, 144.1, 141.1, 119.9, 113.0, 112.3, 103.9, 65.7,
59.7, 55.9, 39.0, 29.3, 19.4, 14.4; IR (KBr) t: 3369, 3095, 2979, 2594, 1700, 1509,
1376, 1202, 1086, 870, 743 cmꢁ1; MS (m=z) [M þ Na]: 815.67.
1
Compound 3d. Light yellow solid, yield 22%, mp 160.0–162.0 ꢀC; H NMR
(CDCl3, 600 MHz) d: 6.86 (s, 2H, ArH), 6.71–6.75 (m, 4H, ArH), 5.89 (br, 2H,
NH), 4.92 (s, 2H, CH), 4.08–4.11 (m, 12H, OCH2), 3.78, 3.80 (s, s, 6H, OCH3),
2.31, 2.33 (s, s, 12H, CH3), 1.89–1.91 (m, 4H, CH2), 1.22–1.24 (m, 12H, CH3); 13C
NMR (CDCl3, 150 MHz) d: 167.8, 148.5, 146.7, 144.0, 140.9, 119.9, 112.7, 112.3,
104.0, 84.0, 68.4, 59.7, 58.5, 55.9, 39.0, 26.0, 22.3, 19.4, 14.3; IR (KBr) t: 3441,

1336
D.-M. LIU ET AL.
3333, 3101, 2980, 1690, 1502, 1377, 1274, 1212, 1102, 1029, 869, 795, 753 cmꢁ1; MS
(m=z) [M þ 1]: 805.00.
Compound 3e. Light yellow, yield 56%, mp 173.0–176.3 ꢀC; 1H NMR (CDCl3,
600 MHz) d: 6.87 (s, 2H, ArH), 6.76 (d, J ¼ 7.8 Hz, 2H, ArH), 6.71 (d, J ¼ 7.8 Hz, 2H,
ArH), 5.77 (br, 2H, NH), 4.93 (s, 2H, CH), 4.07–4.13 (m, 8H, OCH2), 3.96 (t,
J ¼ 7.2 Hz, 4H, OCH2), 3.81 (s, 6H, OCH3), 2.33 (s, 12H, CH3), 1.84–1.88 (m, 4H,
CH2), 1.56–1.61 (m, 2H, CH2), 1.23 (t, J ¼ 7.2 Hz, 12H, CH3); 13C NMR (CDCl3,
150 MHz) d: 167.8, 148.5, 146.8, 143.7, 140.8, 119.9, 112.6, 112.3, 104.2, 68.7, 59.7,
55.9, 39.0, 29.0, 22.5, 19.6, 14.4; IR (KBr) t: 3330, 3100, 2943, 1694, 1504, 1377,
1273, 1210, 1098, 1027, 870, 748, 616, 472 cmꢁ1; MS (m=z) [M þ Na]: 842.80.
1
Compound 3f. Yellow solid, yield 28%, mp 85.2–91.5 ꢀC; H NMR (CDCl3,
600 MHz) d: 6.87 (s, 2H, ArH), 6.77 (d, J ¼ 8.4 Hz, 2H, ArH), 6.71 (d, J ¼ 8.4 Hz,
2H, ArH), 5.98 (br, 2H, NH), 4.93 (s, 2H, CH), 4.09–4.11 (m, 8H, OCH2), 3.94 (t,
J ¼ 6.6 Hz, 4H, OCH2), 3.80 (s, 6H, OCH3), 2.31, 2.32 (s, s, 12H, CH3), 1.81 (br,
4H, CH2), 1.49 (br, 4H, CH2), 1.23 (t, J ¼ 6.6 Hz, 12H, CH3); 13C NMR (CDCl3,
150 MHz) d: 167.9, 148.4, 146.8, 140.9, 119.9, 112.5, 112.3, 103.8, 68.7, 59.7, 55.8,
38.9, 29.2, 25.8, 19.3, 19.3, 14.3; IR (KBr) t: 3342, 3100, 2940, 1690, 1502, 1377,
1273, 1265, 1214, 1104, 1025, 867, 791 cmꢁ1; MS (m=z) [M þ Na]: 856.80.
X-Ray Structure Determination of 3f
A single crystal of 3f suitable for x-ray structural analysis was obtained from a
chloroform and ethanol mixed solution. The diffraction data were collected at 296(2)
K on a Bruker Smart-CCD diffractometer (graphite-monochromated MO K a radi-
ation: k ¼ 0.071073 nm). The structure was solved by the direct method and refined
by full-matrix least-squares on F2. All calculations were performed using SHELXTL
crystallographic software package. Crystal data for C98H136Cl0N4O28, M ¼ 1818.11,
crystal system: monoclinic, space group: P21=n, a ¼ 8.292(2), b ¼ 19.836(5),
c ¼ 15.919(4), b ¼ 92.819(4), V ¼ 2615.1(12), Z ¼ 1, F(000) ¼ 976, Dcalc ¼ 1.154 g=
cm3, h range ¼ 1.64–25.00ꢀ, reflection collected 4601, unique 3015, R1 ¼ 0.0798,
wR2 ¼ 0.2259; R1 ¼ 0.1210, wR2 ¼ 0.2602, CCDC 699581.
RESULTS AND DISCUSSION
The alkylation of phenolic hydroxyl group assisted with microwave irradiation
has been proven to be an efficient method for the preparation of aromatic ethers.
Using this procedure, we carried out the alkylation reaction of vanillin with a series
of a,x-dihaloalkanes, 1a–f. With microwave irradiation, the alkylation reaction can
be finished efficiently in 2–3 min (Scheme 1). After workup, the 4,40-alkylene bridged
vanillins 2a–f were obtained in satisfactory yields, but the yield of product 2b was
less (60%), which might due to the alkylating reagent 1,2-dibromoethane having a
lower boiling point and some being lost in the course of heating. The structures of
1
compound 2a–f were characterized with IR, H NMR, and HPLC-MS spectra. The
IR spectra of 2a–f show one stronger peak of the aldehyde group at 1670–1680 cmꢁ1
.
In 1H NMR spectra, the two protons of aldehyde groups usually displayed one peak at
about 9.85 ppm, which also indicates that the two aldehyde groups exist in nearly the

EFFICIENT SYNTHESIS OF ALKYLENE BRIDGING BISDIHYDROPYRIDINES
1337
Scheme 1. Synthesis of 4,40-alkylene bridging bisdihydropyridine.
same chemical environment. The proton signs of bridging alkylene groups usually
show simple peak patterns for the whole molecule, which were symmetric. For
example, 2b displayed one singlet at 4.56 ppm for the OCH2CH2O unit, and 2d showed
two broad peaks at 4.22, 2.12ppm for the O(CH2)4O bridging unit. In their HPLC-MS
spectra, the peak of [Mþ Na] was observed usually as the most abundant peak.
For preparation of bisdihydropyridines, at first we heated the prepared 4,40-
alkylene bridging vanillin (2a–f) and excess of ethyl acetoacetate and ammonium
carbonate in a microwave oven. The bisdihydropyridine was formed in a short time,
but it contained a lot of by-products, which made it difficulty to purify by recrystal-
lization. Thus the classical Hantzsch procedure was carried out with a little devi-
ation. The reaction mixture without any solvent or catalyst was heated at about
70 ꢀC using a conventional method for 3 days. The desired bisdihydropyridines
3a–f were produced in moderate to lower yields. By this procedure, the obtained bis-
dihydropyridines 3a–f were pure enough for analysis after recrystallization from
ethanol. The structures of compound 3a–f were characterized with IR, 1H NMR,13C
NMR, and HPLC-MS spectra and was confirmed by x-ray single-crystal diffraction
determination of one representative compound 3f (Fig. 1). For example, in the IR
Figure 1. Crystal structure of 3f. (Hydrogen atoms are omitted for clarity.)

1338
D.-M. LIU ET AL.
spectra of 3b, the stronger peak at 1690 cmꢁ1 belongs to the ester carbonyl group. In
its 1H NMR spectra, the two protons of NH groups in dihydropyrdine rings display
one singlet at about 5.63 ppm; the two protons of methine groups show one singlet at
4.79 ppm. The bridging OCH2CH2O group also displays one singlet at 4.18 ppm,
whereas the four ethyl ester groups show two mixed peaks at 3.95–3.97 and
1.08–1.10 ppm. The four methyl groups on the dihydropyridine ring show one singlet
at 2.19 ppm. In HPLC-MS spectra, the peak of [M þ Na] ¼ 801.20 was observed as
the most abundant peak.
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