Synthesis of Substituted Pyrazolylpyridine Ligands
J . Org. Chem., Vol. 63, No. 2, 1998 239
130.56, 137.16, 140.35, 142.83, 148. 86, 152. 56, 166.72 ppm;
MS m/z (%) 559 (67, M•+), 515 (15, M•+ - CO2), 467 (18), 439
(5, M•+ + H - C6H4COOH), 368 (5), 319 (5, M•+ - 2C6H4COO‚),
280 (11), 236 (15), 187 (10), 137 (37), 97 (54), 81 (81), 69 (100,
C3H7CN), 57 (74), 43 (65). Anal. Calcd for C33H29N5O4‚CF3
COOH‚H2O: C, 60.69; H, 4.80; N, 10.11. Found: C, 60.56; H,
4.92; N, 10.10.
Bis(tetr a m eth yla m m on iu m ) 2,6-Bis[1-(4-ca r boxyla to-
ph en yl)-4,5,6,7-tetr ah ydr oin dazol-3-yl]pyr idin e (1d). Fr om
1b. A mixture of 0.308 g (0.5 mmol) of diester 1b and Me4-
NOH‚5H2O (0.181 g, 1 mmol) in EtOH was heated to reflux
overnight. The volatiles were removed, and the crude yellow
solid was washed with CHCl3 and then vacuum-dried to leave
a quantitative yield of salt 1d in nearly pure form: mp 276-8
°C; 1H NMR (D2O): δ 1.33 (m, 8H), 2.34 (m, 4H), 2.47 (m, 4H),
3.13 (s, 24H), 7.28 (bd, 4H, J ) 8.2 Hz), 7.49 (bd, 2H), 7.52
(bt, 1H), 7.88 (d, 4H) ppm; 13C NMR (D2O): δ 23.17, 23.40,
23.76, 24.27, 56.32, 117.98, 121.34, 123.60, 131.21, 136.57,
138.32, 141.56, 141.82, 149.73, 152.90, 174.79 ppm; MS m/z
(%) 705 (0.1, M•+), 602 (1), 560 (3), 481 (6), 368 (42), 334 (6),
313 (8), 257 (25), 236 (46), 110 (82), 71 (100), 56 (85).
Calcd for C20H23N5‚0.5 H2O: C, 70.15; H, 7.06; N, 20.45.
Found: C, 70.78; H, 7.39; N, 20.66.
2-[1-[4-(Eth oxyca r bon yl)p h en yl]-4,5,6,7-tetr a h yd r oin -
d a zol-3-yl]-6-(2H -4,5,6,7-t e t r a h yd r oin d a zol-3-yl)p yr i-
d in e (4b). In the same fashion as for diester 1b, a 2 d
arylation in DMSO at 70 °C, using bis(pyrazolyl)pyridine 3
(0.106 g, 0.33 mmol), K metal (0.028 g, 0.716 mmol), and ethyl
4-fluorobenzoate (0.061 g, 0.36 mmol), gave two products.
Isolation as before provided diester 1b (0.040 g, 20%) and the
desired monoester 4b (0.062 g, 40%). The spectra and melting
points of these materials were identical with those previously
reported.4
2-[1-(4-Ca r b oxyp h en yl)-4,5,6,7-t et r a h yd r oin d a zol-3-
yl]-6-(2H-4,5,6,7-tetr a h yd r oin d a zol-3-yl)p yr id in e (4c). As
for diacid 1c, 0.234 g (0.5 mmol) of monoester 4b gave 0.160
g (73%) of white solid acid 4c, after recrystallization from
THF: mp > 300 °C; 1H NMR (DMSO-d6); δ 1.78 (m, 8H), 2.65
(m, 2H), 2.89 (m, 4H), 3.10 (m, 2H), 7.80 (m, 3H), 7.90 (m,
2H), 8.09 (d, 2H, J ) 8.5 Hz); 13C NMR: δ 20.79, 21.60, 22.38,
22.54, 23.21, 23.63, 113.67, 114.76, 117.81, 119.36, 122.02,
122.29, 124.55, 128.62, 130.472, 130.71, 140.33, 143.82, 148.90,
152.52, 158.59, 166.76 ppm; MS m/z (%) 439 (100, M•+), 410
(20), 395 (10, M•+ - CO2), 303 (4), 256 (4), 241 (9), 220 (19),
170 (13), 149 (16), 129 (19), 95 (16), 81 (37), 69 (70, C3H7CN),
55 (27, C2H5CN), 41 (24). Anal. Calcd for C26H25N5O2: C,
71.05; H, 5.73; N, 15.93. Found: C, 70.65; H, 6.10; N, 15.52.
2-[1-[[4-(Meth oxyca r bon yl)p h en yl]m eth yl]- 4,5,6,7-tet-
r a h yd r oin d a zol-3-yl]-6-(1H-4,5,6,7-tetr a h yd r oin d a zol-3-
yl)p yr id in e (4d ). A mixture of bis(pyrazolyl)pyridine 3 (0.160
g, 0.5 mmol) and NaH (0.014 g, 0.6 mmol) was stirred under
Ar in anhydrous DMF at room temperature for 2 h until the
solution became clear and the evolution of H2 had stopped.
The mixture was treated with methyl 4-(bromomethyl)ben-
zoate (0.115 g, 0.5 mmol) and allowed to stir under Ar at room
temperature for 24 h. The solvent was removed, and the
resulting oil was washed with H2O and extracted into CHCl3.
Further purification was carried out by column chromatogra-
phy on alumina, using MeOH:EtOAc (2:98) as eluent. After
liberation from solvents, the first isolated fraction yielded the
disubstituted diester 1e as a white solid (0.080 g, 26%), and
the second fraction, a clear oil, was the desired monoester 4d .
This was crystallized from EtOAc:PE to yield a white solid
(0.110 g, 47%), mp: 105-107 °C; 1H NMR: δ 1.80 (m, 4H),
1.90 (m, 4H), 2.50 (t, 2H, J ) 5.6 Hz), 2.78 (m, 2H), 2.87 (m,
2H), 3.05 (t, 2H, J ) 5.4 Hz), 3.92 (s, 3H), 5.38 (s, 2H), 7.22 (d,
2H, J ) 7.96 Hz), 7.41 (d, 1H, J ) 7.70 Hz), 7.76 (dd, 1H),
7.92 (d, 1H, J ) 7.90 Hz), 8.00 (d, 2H, J ) 8.05 Hz) ppm; 13C
NMR: δ 21.73, 22.36, 22.41, 23.01, 23.10, 23.31, 23.52, 23.69,
52.13, 52.76, 113.61, 116.80, 117.74, 119.27, 126.80, 129.61,
130.10, 137.05, 138.02, 140.38, 142.05, 146.96, 147.96, 150.60,
153.74, 166.72 ppm; MS m/z (%) 467 (21, M•+), 448 (4), 411
(3), 368 (5), 318 (13, M•+ - CH2C6H4COOCH3), 301 (3), 284
(5), 249 (23), 2218 (17), 181 (18), 167 (12), 137 (48), 111 (57),
91 (96), 81 (84), 69 (96, C3H7CN), 55 (85), 43 (100). Anal. Calcd
for C28H29N5O2‚0.5 H2O: C, 70.57; H, 6.34; N, 14.70. Found:
C, 70.45; H, 6.15; N, 14.25.
Fr om 1c. An EtOH solution of diacid salt 1c‚CF3COOH‚H2O
(0.063 g, 0.091 mmol) was treated with Me4NOH‚5H2O (0.055
g, 0.303 mmol). Workup as above provided nearly pure 1d
(0.060 g, 93%).
2,6-Bis[1-[[4-(m eth oxyca r bon yl)p h en yl]m eth yl]-4,5,6,7-
tetr a h yd r oin d a zol-3-yl]p yr id in e (1e). Solid NaH (0.053 g,
2.2 mmol) was added to a solution of 0.319 g (1 mmol) of bis-
(pyrazolyl)pyridine 3 in dry THF. H2 evolution was immediate,
and the solution became milky-white. The mixture was stirred
under Ar for 2 h and then treated with methyl 4-(bromo-
methyl)benzoate (0.504 g, 2.2 mmol). After heating to reflux
overnight, THF was removed, and the light yellow solid residue
was dissolved in CHCl3 and washed with water. After the
removal of CHCl3, the resulting oil was purified by column
chromatography on alumina, using EtOAc as eluent, to yield
the solid diester 1e (0.536 g, 87%), mp: 147-149 °C; 1H
NMR: δ 1.79 (m, 8H), 2.47 (t, 4H, J ) 5.90 Hz), 2.99 (t, 4H, J
) 5.75 Hz), 3.90 (s, 6H), 5.35 (s, 4H), 7.20 (d, 4H, J ) 8.01
Hz), 7.70 (t, 1H, J ) 7.97 Hz), 7.86 (d, 2H, J ) 7.85 Hz), 7.98
(d, 4H, J ) 8.50 Hz) ppm; 13C NMR: δ 21.73, 22.43, 22.97,
23.23, 52.10, 52.67, 116.47, 119.44, 126.83, 129.49, 130.03,
136.48, 139.83, 142.32, 148.00, 153.33, 166.78 ppm; MS m/z
(%) 616 (10, M•+ + H), 524 (5), 466 (5, M•+ - CH2C6H4-
COOCH3), 336 (44), 350 (20), 313 (13), 257 (16), 236 (28), 218
(59), 129 (34), 97 (82), 83 (83), 43 (100). Anal. Calcd for
C
37H37N5O4: C, 72.18; H, 6.06; N, 11.37. Found: C, 72.19; H,
6.00; N, 11.29.
2-(1-Meth yl-4,5,6,7-tetr ah ydr oin dazol-3-yl)-6-(2H-4,5,6,7-
tetr a h yd r oin d a zol-3-yl)p yr id in e (4a ). Solid NaH (0.030 g,
1.26 mmol) was added to a solution of 0.190 g (0.6 mmol) of
bis(pyrazolyl)pyridine 3 in anhydrous DMF. H2 evolution was
immediate, and the solution became yellow. The mixture was
stirred under Ar for 2 h and then treated with CH3I (0.085 g,
0.6 mmol). After stirring overnight at room temperature, DMF
was removed, and the light yellow solid residue was dissolved
in CHCl3 and washed with water. After the removal of CHCl3,
the resulting oil was purified by column chromatogrsphy on
alumina, using EtOAc as eluent. The first fraction was the
N,N′-dimethyl compound 1a (0.050 g, 24%), whose spectra and
melting point were identical with those previously reported.4
Subsequent fractions, eluted with MeOH:EtOAc (1:99), con-
tained the desired N-monomethyl compound 4a (0.096 g, 48%)
and unreacted bis(pyrazolyl)pyridine 3 (0.031 g, 16%). Re-
crystallization of crude 4a from EtOAc:PE gave a white solid,
mp: 130-132 °C; 1H NMR: δ 1.79 (m, 4H), 1.89 (m, 4H), 2.62
(t, 2H, J ) 6.2 Hz), 2.76 (m, 2H), 2.84 (m, 2H), 2.99 (t, 2H, J
) 5.75 Hz), 3.81 (s, 3H), 7.38 (d, 1H, J ) 7.7 Hz), 7.73 (dd,
1H), 7.83 (d, 1H, J ) 7.86 Hz) ppm; 13C NMR: δ 21.69, 22.43,
23.02, 23.16, 23.28, 23.52, 23.70, 35.20, 108.20, 113.53, 116.00,
117.53, 118.96, 136.99, 137.60, 140.28, 147.20, 148.80, 153.80
ppm; MS m/z (%) 333 (62, M•+), 318 (7, M•+ - CH3), 304 (13),
279 (16), 256 (14), 241 (14), 213 (14), 185 (14), 149 (42), 129
(84), 111 (30), 81 (63), 69 (100, C3H7CN), 57 (39), 43 (23). Anal.
Bis[3-[2-(1-m eth yl-4,5,6,7-tetr ah ydr oin dazol-3-yl)pyr id-
6-yl]-4,5,6,7-tetr a h yd r oin d a zol-1-yl]m eth a n e (5a ). A mix-
ture of mono-N-methyl derivative 4a (0.040 g, 0.12 mmol) and
NaH (0.009 g, 0.38 mmol) was stirred under Ar in CH2Cl2 at
room temperature for 2 h until evolution of H2 stopped. The
mixture was heated to reflux overnight and then washed with
H2O. After separation of the organic phase and removal of
solvent, the clear oily residue was purified by column chro-
matography on alumina using EtOAc as the eluent. The white
solid residue was subsequently recrystallized from MeOH,
yielding 0.038 g (93%) of ditopic ligand 5a as white solid, mp
1
238-240 °C; H NMR: δ 1.78 (m, 8H), 1.89 (m, 8H), 2.63 (m,
6H), 2.95 (m, 10H), 3.81 (s, 6H), 6.26 (s, 2H), 7.70 (dd, 2H),
7.83 (d, 4H) ppm; 13C NMR: δ 21.72, 21.88, 22.43, 22.52, 22.87,
22.93, 23.11, 23.28, 35.75, 61.07, 115.67, 116.73, 118.93,
119.22, 136.41, 139.78, 140.83, 148.49, 153.00, 153.28, 153.44
ppm; MS m/z (%) 679 (6, M•+), 604 (6), 578 (3), 538 (4), 524
(6), 510 (4), 403 (5), 346 (28, M•+ - C20H22N5 (4a - H)), 333
(46, C20H22N5 (4a - H)), 264 (16), 236 (22), 211 (16), 135(23),