2838 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 13
Zhang et al.
at -65 °C. The solution was stirred at room temperature for
30 min and then washed with water. The aqueous phase was
extracted three times with EtOAc. The organic layers were
combined, dried, and evaporated to give a solid (3.8 g, 96%),
which was recrystallized from EtOAc; mp 174-175 °C. 1H
NMR: δ 7.13 (d, 1H, J ) 4.1 Hz), 6.83 (d, 1H, J ) 4.1 Hz).
N-[3-(Su b st it u t ed -p yr id in -3-ylm et h yl)-3H -t h ia zol-2-
ylid en e]-2,2,2-tr iflu or oa ceta m id e (23c,d ,g). Gen er a l. A
solution of 22 (1 equiv) in DMF was treated with NaH (1.1
equiv) at 0 °C and stirred until no more hydrogen was
produced. A solution of 5a , 5b, or 5d (0.8 equiv) in DMF was
then added dropwise. The mixture was stirred at room
temperature overnight, and solvent was removed in vacuo.
Chromatography of the residue gave 23c,d ,g, respectively.
N-[3-(5-Azidopyr idin -3-ylm eth yl)-3H-th iazol-2-yliden e]-
2,2,2-tr iflu or oa ceta m id e (23c). Yield, 74%; mp 148-149 °C.
1H NMR: δ 8.41 (br s, 1H), 8.35 (d, 1H, J ) 2.6 Hz), 7.55 (br
s, 1H), 7.21 (d, 1H, J ) 4.6 Hz), 6.94 (d, 1H, J ) 4.6 Hz), 5.44
(s, 2H). 13C NMR: δ 169.4, 164.9 (q, J ) 35.9 Hz), 145.5, 141.9,
137.8, 131.2, 126.5, 126.2, 117.0 (q, J ) 283.0 Hz), 112.0, 49.6.
FAB-HRMS calcd for C11H8F3N6OS(MH+), 329.0432; found,
329.0446.
N-[3-(4-Azidopyr idin -3-ylm eth yl)-3H-th iazol-2-yliden e]-
2,2,2-tr iflu or oa ceta m id e (23d ). Yield, 67%; mp 138-139 °C.
1H NMR: δ 8.56 (s, 1H), 8.27 (d, 1H, J ) 5.6 Hz), 7.37 (d, 1H,
J ) 4.6 Hz), 7.01 (d, 1H, J ) 5.6 Hz), 6.81 (d, 1H, J ) 4.6 Hz),
5.16 (s, 2H). 13C NMR: δ 169.2, 164.7 (q, J ) 35.9 Hz), 153.4,
151.6, 147.5, 127.4, 120.6, 117.1 (q, J ) 283.0 Hz), 112.8, 110.8,
45.8. FAB-HRMS calcd for C11H8F3N6OS(MH+), 329.0432;
found, 329.0449. Anal. (C11H7F3N6OS) C, H, N.
N-[3-(4-Azid o-6-ch lor op yr id in -3-ylm eth yl)-3H-th ia zol-
2-ylid en e]-2,2,2-tr iflu or oa ceta m id e (23g). Yield, 77%; mp
168-169 °C. 1H NMR: δ 8.52 (s, 1H), 7.39 (d, 1H, J ) 4.6
Hz), 7.09 (s, 1H), 6.86 (d, 1H, J ) 4.6 Hz), 5.22 (s, 2H). 13C
NMR: δ 169.0, 164.4 (q, J ) 35.9 Hz), 152.8, 149.9, 127.6,
119.7, 116.9 (q, J ) 283.0 Hz), 113.0, 111.0, 45.3. FAB-HRMS
calcd for C11H7ClF3N6OS(MH+), 363.0043; found, 363.0029.
3-(Su b st it u t ed -p yr id in -3-ylm et h yl)-3H -t h ia zol-2-yli-
d en ea m in e (1c,d ,g). Gen er a l. Compound 23 (100 mg, ∼0.3
mmol) was dissolved in a solution of NH3 in MeOH (10 mL of
a 2.0 M solution, 20 mmol) and stirred overnight. Evaporation
gave the completely deprotected compound, which was purified
by chromatography with CH2Cl2 and 2.0 M NH3 in MeOH
(10:1).
) 1.6, 2.6 Hz), 7.39 (d, 1H, J ) 2.6 Hz), 7.07 (d, 1H, J ) 2.6
Hz), 5.14 (s, 2H). 13C NMR (DMSO-d6): δ 145.6, 145.2, 140.6,
136.7, 132.6, 125.8, 116.8, 113.7, 45.3. FAB-HRMS calcd for
C9H9N8O2(MH+), 261.0848; found, 261.0822. Anal. (C9H8N8O2)
C, H, N.
1-(4-Azid op yr id in -3-ylm eth yl)-1,3-d ih yd r o-2-n itr oim i-
n oim id a zole (2d ). Yield, 23%. 1H NMR (DMSO-d6): δ 8.53
(d, 1H, J ) 5.1 Hz), 8.30 (s, 1H), 7.42 (d, 1H, J ) 5.1 Hz), 7.26
(d, 1H, J ) 2.6 Hz), 7.06 (d, 1H, J ) 2.6 Hz), 5.01 (s, 2H). 13C
NMR (DMSO-d6): δ 150.7, 150.6, 146.7, 145.7, 121.3, 117.2,
114.0, 113.4, 42.2. FAB-HRMS calcd for C9H9N8O2(MH+),
261.0848; found, 261.0867. Anal. (C9H8N8O2‚H2O) C, H; N:
calcd, 40.27; found, 39.72.
1-(5-Azid o-6-ch lor op yr id in -3-ylm eth yl)-1,3-d ih yd r o-2-
1
n itr oim in oim id a zole (2f). Yield, 41%. H NMR: δ 8.17 (d,
1H, J ) 2.1 Hz), 7.84 (d, 1H, J ) 2.1 Hz), 7.28 (d, 1H, J ) 2.6
Hz), 7.06 (d, 1H, J ) 2.6 Hz), 5.20 (s, 2H). 13C NMR (DMSO-
d6): δ 145.9, 144.8, 140.6, 134.8, 132.7, 129.4, 117.3, 114.2,
45.3. FAB-HRMS calcd for C9H8ClN8O2(MH+), 295.0459; found,
295.0462. Anal. (C9H7ClN8O2) C, H; N: calcd, 38.03; found,
37.37.
1-(4-Azid o-6-ch lor op yr id in -3-ylm eth yl)-1,3-d ih yd r o-2-
n itr oim in oim id a zole (2g). Yield, 46%. 1H NMR (CD3OD):
δ 8.34 (s, 1H), 7.32 (s, 1H), 7.07 (d, 1H, J ) 2.6 Hz), 6.95 (d,
1H, J ) 2.6 Hz), 5.05 (s, 2H). 13C NMR (CD3OD): δ 158.0,
152.2, 152.0, 151.5, 121.7, 117.9, 114.6, 114.2, 43.0. FAB-
HRMS calcd for C9H8ClN8O2(MH+), 295.0459; found, 295.0453.
Anal. (C9H7ClN8O2) C, H; N: calcd, 38.03; found, 37.59.
1-(Su b st it u t ed -p yr id in -3-ylm et h yl)-1,3-d ih yd r o-2-n i-
tr oim in oth ia zole (2h ,i). Gen er a l. A solution of 2-nitroimi-
nothiazoline (1.2 equiv), 5c, or 6-chloropyridin-3-ylmethyl
chloride (1 equiv) and K2CO3 (2.0 eq) in DMF was stirred at
50-55 °C overnight. DMF was then evaporated, and the
residue was chromatographed with CH2Cl2 and MeOH (10:1)
to give the desired product.
1-(6-Ch lor op yr id in -3-ylm eth yl)-1,3-d ih yd r o-2-n itr oim i-
n oth ia zole (2h ). Yield, 48%; mp 218-219 °C (reported 219-
1
220 °C 39). H NMR: δ 8.45 (d, 1H, J ) 2.1 Hz), 7.92 (d, 1H, J
) 4.6 Hz), 7.80 (dd, 1H, J ) 2.1, 8.2 Hz), 7.53 (d, 1H, J ) 8.2
Hz), 7.40 (d, 1H, J ) 4.6 Hz), 5.40 (s, 2H). 13C NMR (DMSO-
d6): δ 167.6, 149.6, 139.5, 130.3, 129.9, 127.0, 124.4, 112.6,
49.1.
1-(5-Azid o-6-ch lor op yr id in -3-ylm eth yl)-1,3-d ih yd r o-2-
1
n itr oim in oth ia zole (2i). Yield, 77%. H NMR: δ 8.23 (br s,
3-(5-Azid op yr id in -3-ylm et h yl)-3H -t h ia zol-2-ylid en e-
1H), 7.96 (br s, 1H), 7.93 (d, 1H, J ) 4.6 Hz), 7.41 (d, 1H, J )
4.6 Hz), 5.43 (s, 2H). 13C NMR (DMSO-d6): δ 167.6, 144.8,
140.3, 134.3, 131.4, 129.8, 129.4, 112.5, 48.8. FAB-HRMS calcd
for C9H7ClN7O2S(MH+), 312.0098; found, 312.0070. Anal.
(C9H6ClN8O2S) C, H; N: calcd, 31.52; found, 31.05.
1
a m in e (1c). H NMR: δ 8.34 (br s, 1H), 8.30 (br s, 1H), 7.35
(br s, 1H), 6.39 (d, 1H, J ) 4.6 Hz), 5.82 (d, 1H, J ) 4.6 Hz),
4.92 (s, 2H). 13C NMR: δ 164.0, 145.1, 140.7, 137.4, 133.7,
126.2, 125.3, 98.6, 46.1. FAB-HRMS calcd for C9H9N6S(MH+),
233.0609; found, 233.0632.
1-(5-Azid o-6-ch lor op yr id in -3-ylm eth yl)-2-n itr om eth yl-
en eim id a zolid in e (3b). A solution of compound 21 (266 mg,
1.2 mmol), 1,1-bis(methylthio)-2-nitroethylene (200 mg, 1.2
mmol), and a catalytic amount of p-toluenesulfonic acid (10
mg) in CH3CN (5.0 mL) was stirred at room temperature for
16 h and then evaporated. The residue was purified by
preparative TLC with CH2Cl2 and MeOH (15:1) to give 3b (62
mg, 18%). 1H NMR (DMSO-d6): δ 8.92 (br s, 1H), 8.15 (s, 1H),
7.84 (s, 1H), 6.79 (s, 1H), 4.49 (s, 2H), 3.58 (m, 4H). 13C NMR
(DMSO-d6): δ 158.5, 144.3, 139.7, 134.2, 132.8, 128.8, 95.8,
48.0, 45.1, 42.3. FAB-HRMS calcd for C10H11ClN7O2(MH+),
296.0663; found, 296.0660. Anal. (C10H10ClN7O2) C, H, N.
Ra d ioliga n d Bin d in g. The affinity of test compounds for
the R4â2 nAChR of M10 cells was determined by displacement
of [3H]nicotine binding.5 The M10 cell line consists of mouse
fibroblasts stably transfected with R4â2 nAChR under the
control of a dexamethasone sensitive promoter.40 The cells
were maintained in Dulbecco’s modified Eagle’s medium
(DMEM) supplemented with 10% fetal bovine serum (FBS),
100 units/mL penicillin, 0.1 mg/mL streptomycin, 2 mM
L-glutamine, and 0.5 mg/mL geneticin (Gibco Life Technolo-
gies, Grand Island, NY) at 37 °C and 5% CO2/95% air
atmosphere. The R4â2 nAChR was induced by replacing the
above medium with one in which the geneticin was deleted
and 1 µM dexamethasone (Sigma) was added. Extracts of M10
3-(4-Azid op yr id in -3-ylm et h yl)-3H -t h ia zol-2-ylid en e-
a m in e (1d ). 1H NMR: δ 8.54 (s, 1H), 8.53 (d, 1H, J ) 5.6
Hz), 7.09 (d, 1H, J ) 5.6 Hz), 6.47 (d, 1H, J ) 5.1 Hz), 5.79 (d,
1H, J ) 5.1 Hz), 4.83 (s, 2H). 13C NMR: δ 164.1, 151.7, 150.5,
147.0, 127.0, 122.8, 112.7, 98.0, 42.5. FAB-HRMS calcd for
C9H9N6S(MH+), 233.0609; found, 233.0623.
3-(4-Azid o-6-ch lor op yr id in -3-ylm et h yl)-3H -t h ia zol-2-
1
ylid en ea m in e (1g). H NMR: δ 8.36 (br s, 1H), 7.11 (s, 1H),
6.48 (d, 1H, J ) 4.6 Hz), 5.79 (d, 1H, J ) 4.6 Hz), 4.78 (s, 2H).
13C NMR: δ 163.8, 152.1, 151.5, 149.2, 126.9, 122.0, 112.9,
98.1, 42.1. FAB-HRMS calcd for C9H8ClN6S(MH+), 267.0220;
found, 267.0219.
1-(Su b st it u t ed -p yr id in -3-ylm et h yl)-1,3-d ih yd r o-2-n i-
tr oim in oim id a zole (2c,d ,f,g). Gen er a l. A solution of 2-ni-
troimino-4-imidazoline (1 equiv) in DMF was treated with NaH
(1.1 equiv) at <5 °C. The mixture was stirred at room
temperature until no hydrogen was produced and then cooled
again to 0 °C. A solution of 5a -d (0.9 equiv) in DMF was added
dropwise. The solution was stirred at room temperature for
4-12 h followed by workup and chromatography with CH2Cl2
and MeOH (10:1) to give the desired product.
1-(5-Azid op yr id in -3-ylm eth yl)-1,3-d ih yd r o-2-n itr oim i-
n oim id a zole (2c). Yield, 34%. 1H NMR (DMSO-d6): δ 8.35
(d, 1H, J ) 2.6 Hz), 8.33 (d, 1H, J ) 1.6 Hz), 7.56 (dd, 1H, J