4218 J . Org. Chem., Vol. 66, No. 12, 2001
Pawlas et al.
(d), 122.19 (d), 114.55 (s), 114.16 (s), 81.02 (t), 19.94 (q). Anal.
Calcd for C24H19N3O: C, 78.88; H, 5.24; N, 11.50. Found: C,
78.59; H, 5.25; N, 11.29.
n-BuLi in hexanes (0.18 mL, 0.28 mmol) at -78 °C. After 5
min, the aldehyde (0.30 mmol) was added, the solution was
allowed to warm to room temperature, and 5 mL of heptane
was added. Filtration through a pad of silica gel (EtOAc/
heptane, 1:3) was followed by concentration in vacuo and
treatment with NaH (60 mg, 2.5 mmol) in THF (3 mL) at 70
°C for 16 h. The reaction was quenched with EtOAc (5 mL)
and water (10 mL) was added. Extraction with EtOAc (3 × 10
mL), MgSO4 drying, and concentration in vacuo gave the crude
product, which was purified by using the procedure used for
4a -i.
1-Ben zyloxy-4-(4-m eth ylph en yl)-1,4-dih ydr och r om en o-
[4,3-c]p yr a zole (7a ). Following the general procedure using
4-tolualdehyde gave 73 mg (78%) of 7a as yellow crystals, mp
123-124 °C (EtOAc/heptane). Rf (EtOAc/heptane, 1:2) 0.49. δH
(CDCl3): 7.73 (dd, J ) 7.6, 1.7 Hz, 1H), 7.50-6.92 (m, 13H),
6.29 (s, 1H), 5.39 (d, J ) 10.2 Hz, 1H), 5.35 (d, J ) 10.2 Hz,
1H), 2.37 (s, 3H). δC (CDCl3): 153.20, 138.98, 137.60, 136.82,
133.27, 130.19, 130.16, 129.65, 129.58, 128.87, 127.84, 122.91,
121.75, 117.64, 114.29, 113.21, 99.15, 80.84, 21.28, one carbon
signal overlapped.
1-Ben zyloxy-4-(2-th ien yl)-1,4-d ih yd r och r om en o[4,3-c]-
p yr a zole (7b). Following the general procedure using 2-thio-
phenecarboxaldehyde gave 54 mg (60%) of 7b as off-white
crystals, mp 88-89 °C (EtOAc/heptane). Rf (EtOAc/heptane,
1:2) 0.45. δH (CDCl3): 7.75 (dd, J ) 9.1, 1.7 Hz, 1H), 7.46-
6.93 (m, 11H), 6.60 (s, 1H), 5.38 (s, 2H). δC (CDCl3): 152.35,
143.25, 133.05, 130.10, 130.05, 129.53, 128.76, 128.68, 127.06,
127.03, 126.95, 126.78, 122.82, 121.90, 117.71, 114.02, 112.50,
80.76, 71.85. Anal. Calcd for C21H16N2O2S‚40 mol % H2O: C,
68.61; H, 4.61; N 7.62. Found: C, 68.75; H, 4.43; N, 7.61.
1-Ben zyloxy-1,4-d ih yd r och r om en o[4,3-c]p yr a zole (7c).
Following the general procedure using gaseous formaldehyde23
gave 51 mg (63%) of 7c as yellow crystals, mp 111-113 °C
(EtOAc/heptane). Rf (EtOAc/heptane, 1:2) 0.50. δH (CDCl3):
7.69 (dd, J ) 7.3, 1.8 Hz, 1H), 7.42-6.92 (m, 8H), 7.12 (s, 1H),
5.32 (s, 2H), 5.24 (s, 2H). δC (CDCl3): 153.39 (s), 133.10 (s),
129.93 (d), 129.85 (d), 129.42 (d), 128.70 (d), 127.49 (d), 126.77
(s), 122.84 (d), 121.70 (d), 117.16 (d), 114.47 (s), 109.74 (s),
80.66 (t), 64.18 (t).
1-Ben zyloxy-4-(2-flu or op h en yl)p yr a zole (8). Following
the known procedure4 starting with 1-(benzyloxy)-4-iodopyra-
zole (2.6 g, 8.7 mmol) and using 2-iodofluorobenzene as aryl
halide gave 1.79 g (77%) of 8 as colorless crystals, mp 74-75
°C (EtOAc/heptane). Rf (EtOAc/heptane, 1:2) 0.45. δH (CD-
Cl3): 7.66 (t, J ) 1.1 Hz, 1H), 7.50-7.03 (m, 10H), 5.34 (s,
2H). δC (CDCl3): 159.70 (s(d), J ) 248.4 Hz), 133.70 (s), 131.66
(d(d), J ) 3.5 Hz), 129.74 (d), 129.39 (d), 128.77 (d), 127.79
(d(d), J ) 8.4 Hz), 127.25 (d(d), J ) 4.3 Hz), 124.36 (d(d), J )
3.4 Hz), 121.87 (d(d), J ) 8.8 Hz), 119.87 (s(d), J ) 13.9 Hz),
116.08 (d(d), J ) 21.5 Hz), 113.70 (s(d), J ) 1.6 Hz), 80.66 (t).
Anal. Calcd for C16H13FN2O: C, 71.63; H, 4.88; N 10.44.
Found: C, 71.84; H, 5.02; N, 10.34.
1-Ben zyloxy-4-(2-m eth oxyp h en yl)p yr a zolo[4,3-c]qu in -
olin e (4h ). Following the general procedure using 2-meth-
oxybenzonitrile gave 51 mg (27%) of 4h as colorless crystals,
mp 119-120 °C (EtOAc/heptane). Rf (EtOAc/heptane, 1:4) 0.30.
δH (CDCl3): 8.56 (dd, J ) 9.1, 1.5 Hz, 1H), 8.30 (d, J ) 7.7 Hz,
1H), 7.80 (s, 1H), 7.74 (dt, J ) 8.5, 1.5 Hz, 1H), 7.66 (dt, J )
7.5, 1.3 Hz, 1H), 7.66-6.92 (m, 9H), 5.53 (s, 2H), 3.82 (s, 3H).
δC (CDCl3): 157.16 (s), 133.21 (s), 132.82 (s), 131.50 (d), 131.01
(d), 129.96 (d), 129.60 (d), 129.21 (d), 128.87 (d), 126.65 (d),
122.14 (d), 121.26 (d), 114.69 (s), 114.45 (s), 111.40 (d) 80.93
(t), 55.41 (q), five carbon signals overlapped. Anal. Calcd for
C
24H19N3O2: C, 75.57; H, 5.02; N, 11.02. Found: C, 76.10; H,
5.14; N, 10.76.
1-Ben zyloxy-4-(2-ch lor op h en yl)p yr a zolo[4,3-c]q u in o-
lin e (4i). Following the general procedure using 2-chloroben-
zonitrile gave 66 mg (35%) of 4i as colorless crystals, mp 130-
131 °C (EtOAc/heptane). Rf (EtOAc/heptane, 1:2) 0.31. δH
(CDCl3): 8.57 (dd, J ) 7.1, 1.0 Hz, 1H), 8.27 (d, J ) 8.3 Hz,
1H), 7.80-7.34 (m, 11H), 7.78 (s, 1H), 5.55 (s, 2H). δC
(CDCl3): 153.19 (s), 145.44 (s), 137.42 (s), 133.05 (s), 132.95
(s), 132.70 (s), 131.36 (d), 130.48 (d), 130.32 (d), 130.12 (d),
130.03 (d), 129.66 (d), 129.64 (d), 129.45 (d), 128.86 (d), 127.19
(d), 127.03 (d), 122.24 (d), 114.48 (s), 114.20 (s), 81.06 (t).
1-(Ben zyloxy)-4-cya n o-5-(2-flu or op h en yl)p yr a zole (5).
To a solution of 3 (1.05 g, 2.7 mmol) in THF (10 mL) was added
dropwise 1.6 M n-BuLi in hexanes (1.8 mL, 2.9 mmol) at -78
°C. After 5 min, 4-toluenesulfonyl cyanide (0.63 g, 3.4 mmol)
was added and the reaction mixture was allowed to warm to
room temperature. The crude mixture was concentrated in
vacuo, adsorbed on a silica gel plug (5 g), and purified by
vacuum filtration using EtOAc/heptane, 1:8, to give 547 mg
(70%) of 5 as colorless oil. Rf (EtOAc/heptane, 1:2) 0.46. δH
(CDCl3): 7.74 (s, 1H), 7.49-6.92 (m, 9H), 5.24 (s, 2H). δC
(CDCl3): 159.41 (d, J ) 253.9 Hz), 137.10 (d, J ) 1.3 Hz),
136.14 (d, J ) 0.7 Hz), 132.45 (d, J ) 8.4 Hz), 132.05, 131.29
(d, J ) 1.8 Hz), 129.75 (d, J ) 15.1 Hz), 128.64, 124.31, (d, J
) 3.8 Hz), 116.38, 116.10, 112.97 (d, J ) 0.6 Hz), 112.95 (d, J
) 14.6 Hz), 90.94 (d, J ) 1.1 Hz), 80.89. Anal. Calcd for C17H12
-
FN3O: C, 69.62; H, 4.12; N, 14.33. Found: C, 69.31; H, 4.29;
N, 14.10.
1-Ben zyloxy-4-m eth ylp yr a zolo[4,3-c]qu in olin e (6a ). To
a solution of 5 (45 mg, 0.15 mmol) in THF (3 mL) was added
dropwise 1.6 M MeLi in ether (0.10 mL, 0.17 mmol) at -78
°C. After 5 min, the reaction mixture was allowed to warm to
room temperature, quenched with saturated aqueous NH4Cl
(20 mL), taken up with CH2Cl2 (3 × 20 mL) and dried with
MgSO4, and concentrated in vacuo. Preparative TLC purifica-
tion (EtOAc/heptane, 1:2) gave 31 mg (70%) of 6a as yellow
crystals, mp 129-131 °C (ether/heptane). Rf (EtOAc/heptane,
1:2) 0.34. δH (CDCl3): 8.47 (ddd, J ) 9.1, 1.5, 0.6 Hz, 1H), 8.09
(d, J ) 8.1 Hz, 1H), 7.98 (s, 1H), 7.69 (dt, J ) 8.5, 1.5 Hz, 1H),
7.54 (dt, J ) 8.3, 1.3 Hz, 1H), 7.50-7.32 (m, 5H), 5.51 (s, 2H),
2.88 (s, 3H). δC (CDCl3): 154.36, 145.48, 132.98, 132.56, 129.98,
129.62, 129.23, 129.02, 128.84, 128.35, 126.03, 122.17, 114.77,
114.15, 80.90, 22.15. Anal. Calcd for C18H15N3O: C, 74.72; H,
5.23; N, 14.52. Found: C, 74.51; H, 5.29; N, 14.38.
1-Ben zyloxy-4-n -b u t ylp yr a zolo[4,3-c]q u in olin e (6b ).
Likewise, n-BuLi (0.12 mL, 0.19 mmol) was added to a solution
of 5 (50 mg, 0.17 mmol) in THF (4 mL), and the protocol
described for 6a was followed to give 32 mg (56%) of 6b as
off-white crystals, mp 84-85 °C (EtOAc/heptane). Rf (EtOAc/
heptane, 1:2) 0.41 δH (CDCl3): 8.48 (dd, J ) 9.1, 1.5 Hz, 1H),
8.12 (d, J ) 9.0 Hz, 1H), 7.98 (s, 1H), 7.69 (dt, J ) 8.6, 1.5 Hz,
1H), 7.54 (dt, J ) 8.3, 1.3 Hz, 1H), 7.50-7.35 (m, 5H), 5.51 (s,
2H), 3.16 (t, J ) 7.8 Hz, 3H), 1.96-1.84 (m, 2H), 1.56-1.44
(m, 2H), 0.99 (t, J ) 7.3 Hz, 3H). δC (CDCl3): 158.52, 145.55,
133.02, 132.78, 129.98, 129.61, 129.21, 129.16, 128.84, 128.25,
125.99, 122.15, 114.34, 114.17, 80.91, 36.18, 31.48, 22.78,
13.84.
N -[2-(1-B e n zy lo x y p y r a zo l-4-y l)p h e n y l]b e n zo p h e -
n on eim in e (10). A mixture of benzophenone (3.7 mmol), 4-(2-
aminophenyl)-1-(benzyloxy)pyrazole (13)4 (3.4 mmol), Si(OEt)4
(4.4 mmol), and one drop of concentrated H2SO4 was placed
in a flask equipped with a still head. The solution was heated
at 160 °C under nitrogen overnight. The distillate (EtOH) was
discarded, and the residue was dissolved in Et2O (20 mL),
washed with a saturated NaHCO3 solution and H2O (10 mL
each), and dried with MgSO4, and the solvents were removed.
FC (heptane/EtOAc 10:1) gave 1.1 g (75%) of 10 as a thick
yellow oil. Rf (EtOAc/heptane, 1:2) 0.42. δ (CDCl3): 7.80-
H
7.74 (m, 2H), 7.63 (d, J ) 1.1 Hz, 1H), 7.57-7.38 (m, 4H), 7.31
(d, J ) 1.1 Hz, 1H), 7.28-6.83 (m, 12H), 6.42-6.36 (m, 1H),
5.25 (s, 2H). δC (CDCl3): 167.82, 148.14, 138.86, 136.07, 133.83,
131.86, 131.06, 129.60, 129.49, 129.25, 128.76, 128.69, 128.64,
128.41, 127.91, 126.63, 126.34, 123.54, 123.41, 122.00, 120.50,
117.71, 80.32.
(22) Prepared according to: Molina, P.; Alajarin, M.; Vidal, A.;
Sanchez-Andrada, P. J . Org. Chem. 1992, 57, 929.
(23) Lu¨ning, U.; Baumgartner, H.; Manthey, C.; Meynhardt, B. J .
Org. Chem. 1996, 61, 7922.
P r epar ation of Dih ydr och r om en opyr azoles 7a -c. Gen -
er a l P r oced u r e. To a stirred solution of 3 (100 mg, 0.25
mmol) in 4 mL of THF at -78 °C was added dropwise 1.6 M