Preparation of 2-(N,N-diethylcarboxamido)-6-(1H-pyrazol-3-
yl)-pyridine (VIII).
5.34 (4H, s, CH2), 3.56 (4H, q, CH2CH3), 3.41 (4H, q, CH2CH3),
1.22–1.28 (12H, m, CH3). 13C NMR (125 MHz, CDCl3): d (ppm)
168.4, 154.4, 151.7, 150.6, 137.3, 136.3, 130.8, 128.0, 122.0, 120.2,
105.4, 55.8, 43.3, 40.3, 14.4, 12.8. IR (KBr disk): m (cm−1) 3124
(m), 3016 (w), 2984 (m), 2937 (w), 1627 (s), 1589 (s), 1569 (m),
1519 (w), 1475 (s), 1458 (w), 1433 (m), 1413 (m), 1380 (m), 1361
(w), 1346 (m), 1315 (m), 1297 (m), 1254 (m), 1239 (m), 1201 (w),
1156 (w), 1116 (m), 1091 (w), 1079 (m), 1046 (w), 992 (w), 945 (w),
885 (w), 873 (w), 827 (m), 782 (s), 762 (s), 742 (m), 698 (w), 641 (m)
502 (w). Found: C, 68.04; H, 6.25; N, 18.65%. C34H38N8O2·(H2O)0.5
(599.72) requires C 68.09; H, 6.55; N, 18.68%.
Step 1. A solution of 2-(N,N-diethylcarboxamido)-6-
acetylpyridine VI (20.0 g, 0.091 mol) in dimethylformamide–
dimethylacetal (80 cm3, a large molar excess) was refluxed for
3 days under N2 to yield a brown solution. Removal of excess
dimethylformamide–dimethylacetal in vacuo gave the crude
intermediate VII (see Scheme 1) as an orange–brown solid.
An analytical sample of VII was obtained by recrystallisation
from dichloromethane/hexane. EI MS: m/z 275 (M+). 1H NMR
(250 MHz) CDCl3: d (ppm) 8.15 (1H, dd, pyridine H3), 7.89 (1H,
4
=
d, COCH CH), 7.86 (1H, t, pyridine H ), 7.68 (1H, dd, pyridine
Preparation of L2. A two-phase mixture of VIII (1.20 g,
4.91 mmol), 1,2-bis-(bromomethyl)benzene (0.62 g, 2.35 mmol),
toluene (50 cm3), nBu4NOH (0.2 cm3) and aqueous 10 M NaOH
(7.5 cm3) was heated to 80 ◦C and stirred vigorously at this
temperature for 24 h. After cooling, the mixture was diluted with
water (100 cm3) and the aqueous layer extracted with toluene (2 ×
90 cm3). The combined organic layers were washed with water
and dried (MgSO4). The solvent was removed in vacuo and the
crude product was recrystallised from dichloromethane/hexane
to give 1.19 g of white microcrystalline material. Yield 86%.
EIMS: m/z 590 [M+]. 1H NMR (500 MHz, CDCl3): d (ppm)
8.00 (2H, dd, pyridyl H3), 7.75 (2H, t, pyridyl H4), 7.50 (2H, dd,
pyridyl H5), 7.30–7.33 (4H, m, phenyl, pyrazolyl H5), 7.18 (2H, dd,
phenyl), 6.91 (2H, d, pyrazolyl H4), 5.47 (4H, s, CH2), 3.56 (4H,
q, CH2CH3), 3.41 (4H, q, CH2CH3), 1.22–1.28 (12H, m, CH3).
13C NMR (125 MHz, CDCl3): d (ppm) 168.4, 154.4, 151.7, 150.6,
137.3, 134.5, 130.9, 129.6, 129.0, 122.0, 120.3, 105.5, 53.4, 43.3,
40.3, 14.4, 12.8. IR (KBr disk): m (cm−1) 3115 (w), 3067 (w), 2988
(m), 2936 (m), 1637 (s), 1628 (s), 1614 (s), 1589 (s), 1571 (m), 1517
(w), 1480 (s), 1458 (m), 1432 (m), 1411 (m), 1380 (w), 1363 (w),
1338 (w), 1312 (w), 1297 (m), 1252 (w), 1238 (w), 1230 (w), 1206
(m), 1159 (w), 1115 (m), 1083 (m), 1049 (w), 992 (w), 941 (w), 882
(w), 830 (m), 769 (s), 758 (s), 745 (w), 736 (s), 694 (w), 642 (w) 634
(w). Found: C, 68.17; H, 6.28; N, 18.74%. C34H38N8O2·(H2O)0.5
(599.72) requires C, 68.09; H, 6.55; N, 18.68%.
5
=
H ), 6.44 (1H, d, COCH CH), 3.57 (4H, q, CH2CH3), 3.37 (2H,
q, CH2CH3), 3.16 (3H, s, NCH3), 2.95 (3H, s, NCH3), 1.27 (6H,
t, CH2CH3). 13C NMR (125 MHz, CDCl3): d (ppm) 186.2, 168.3,
154.6, 154.5, 153.5, 137.5, 125.1, 122.4, 91.3, 45.1, 43.2, 40.2,
37.4, 14.4, 12.7. Found: C, 65.43; H, 7.50; N, 15.41%. C15H21N3O2
(275.35) requires 65.43; H, 7.69; N, 15.26%.
Step 2. The entire crude batch of VII from the previous step was
dissolved in ethanol (100 cm3), and hydrazine hydrate (40 cm3, a
large molar excess) was added to the solution which was then re-
fluxed in air for 2 h. The pale orange solution was cooled and added
to ice/water (800 cm3) resulting in a pale orange precipitate. The
mixture was refrigerated overnight to allow precipitation of the
product to complete. The solid was filtered off, washed with cold
water (50 cm3) and hexane (50 cm3) and dried in vacuo. Subsequent
recrystallisation from dichloromethane/hexane afforded pure 2-
(N,N-diethylcarboxamido)-6-(1H-pyrazol-3-yl)-pyridine VIII as
a pale orange crystalline material (12.5 g). A second crop was
obtained by extracting the aqueous mixture with dichloromethane
(3 × 100 cm3). These combined organic extracts were dried
(MgSO4), the solvent removed in vacuo and the residue recrys-
tallised from dichloromethane/hexane to give a further 4.2 g of
1
product. Total yield: 16.7 g (75%). EI MS: m/z 244 (M+). H
NMR (500 MHz) CDCl3: d (ppm) 9.71 (1H, br s, NH), 7.85 (1H,
d, pyridyl H3), 7.80 (1H, t, pyridyl H4), 7.64 (1H, s, pyrazolyl H5),
7.48 (1H, d, pyridine H5), 6.84 (1H, d, pyrazolyl H4), 3.57 (2H,
q, CH2), 3.37 (2H, q, CH2), 1.26 (3H, t, CH3), 1.20 (3H, t, CH3).
13C NMR (125 MHz, CDCl3): d (ppm) 168.4, 154.6, 151.7, 148.7,
137.8, 130.8, 121.9, 120.4 103.9, 43.3, 40.2, 14.4, 12.8. Found: C,
63.61; H, 6.52; N, 23.06%. C13H16N4O (244.29) requires 63.91; H,
6.60; N, 22.93%.
Preparation of L3. A two-phase mixture of VIII (2.36 g,
9.66 mmol), 1,3-bis-(bromomethyl)benzene (1.22 g, 4.62 mmol),
toluene (150 cm3), nBu4NOH (0.90 cm3) and aqueous 10 M NaOH
(15 cm3) was heated to 80 ◦C and stirred vigorously at this
temperature for 24 h. After cooling, the mixture was diluted with
water (100 cm3) and the aqueous layer extracted with toluene (2 ×
100 cm3). The combined organic layers were washed with water
and dried (MgSO4). The solvent was removed in vacuo and the
crude product purified by column chromatography (alumina, 2%
methanol in dichloromethane) to give 2.40 g of white foam. Yield
88%. EIMS: m/z 590 [M+]. 1H NMR (250 MHz, CDCl3): d (ppm)
8.00 (2H, dd, pyridyl H3), 7.77 (2H, t, pyridyl H4), 7.51 (2H, dd,
pyridyl H5), 7.39 (2H, d, pyrazolyl H5), 7.32 (1H, t, phenyl H5),
7.13–7.22 (3H, m, phenyl H2, H4), 6.93 (2H, d, pyrazolyl H4), 5.34
(4H, s, CH2), 3.57 (4H, q, CH2CH3), 3.43 (4H, q, CH2CH3), 1.21–
1.32 (12H, m, CH3). 13C NMR (125 MHz, CDCl3): d (ppm) 168.4,
154.3, 151.7, 150.6, 137.2, 137.0, 130.8, 129.2, 127.2, 126.7, 121.8,
120.2, 105.3, 55.8, 43.2, 40.2, 14.3, 12.8 ppm. IR (KBr disk): m
(cm−1) 3017 (w), 2973 (m), 2934 (w), 2873 (w), 1630 (s), 1588 (s),
1570 (m), 1519 (w), 1479 (s), 1461 (m), 1429 (m), 1413 (m), 1379
(w), 1361 (w), 1346 (m), 1314 (m), 1295 (m), 1250 (m), 1231 (m),
1205 (m), 1154 (w), 1113 (m), 1080 (m), 1045 (m), 992 (m), 943
Preparation of L1. A two-phase mixture of VIII (1.42 g,
5.81 mmol), 1,4-bis(bromomethyl)benzene (0.77 g, 2.92 mmol),
toluene (150 cm3), nBu4NOH (0.50 cm3) and aqueous 10 M
NaOH (7 cm3) was heated to 80 ◦C and stirred vigorously
at this temperature for 24 h. After cooling, the mixture was
diluted with water (100 cm3) and the aqueous layer extracted
with toluene (2 × 100 cm3). The combined organic layers
were washed with water and dried (MgSO4). The solvent was
removed in vacuo and the crude product was recrystallised twice
from dichloromethane/hexane to give 1.07 g of white crystalline
material. A second crop (0.13 g) was obtained by column
chromatography (alumina, 2% methanol in dichloromethane) of
the remaining material (total yield 1.20 g, 70%). EIMS: m/z 590
[M+]. 1H NMR (500 MHz, CDCl3): d (ppm) 8.00 (2H, dd, pyridyl
H3), 7.75 (2H, t, pyridyl H4), 7.50 (2H, dd, pyridyl H5), 7.38 (2H,
d, pyrazolyl H5), 7.22 (4H, s, phenyl), 6.92 (2H, d, pyrazolyl H4),
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The Royal Society of Chemistry 2007
Dalton Trans., 2007, 1006–1022 | 1017
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