3640 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 15
Bunnelle et al.
ppm (d, J ) 9 Hz, 1H); MS (DCI/NH3) m/z 211 (M + H)+; Anal.-
(C9H11N4Cl‚2C7H8O3S) C, H, N.
1H), 2.36 (s, 3H), 3.20-3.28 (m, 1H), 3.33-3.37 (m, 2H), 3.71
(dd, J ) 11, 3 Hz, 1H), 4.48 (t, J ) 2 Hz, 1H), 4.64 (s, 1H), 6.38-
6.49 (m, 3H), 7.16-7.22 (m, 1H), 7.22 (d, J ) 8 Hz, 2H), 7.70
ppm (d, J ) 8 Hz, 2H) MS (ESI) m/z 193 (M + H). Anal.
(C11H13N2F‚C7H8O3S) C, H, N.
(1S,4S)-2-(4-Chlorophenyl)-2,5-diazabicyclo[2.2.1]heptane p-
Toluenesulfonate (S-60). Prepared from p-bromochlorobenzene and
S-9 according to procedure ‘a’ (32%), followed by deprotection/
salt formation with p-toluenesulfonic acid to provide the title salt
as a pale violet, crystalline solid (83%): 1H NMR (300 MHz, CD3-
OD) δ 2.02 (d, J ) 11 Hz, 1H), 2.28 (d, J ) 11 Hz, 1H), 2.37 (s,
3H), 3.25 (dd, J ) 11, 1 Hz, 1H), 3.31-3.37 (m, 2H), 3.71 (dd, J
) 11, 3 Hz, 1H), 4.41-4.48 (m, 1H), 4.62 (s, 1H), 6.62-6.67 (m,
2H), 7.17-7.22 (m, 2H), 7.22 (d, J ) 8 Hz, 2H), 7.68-7.71 ppm
(m, 2H); MS (DCI/NH3) m/z 209/211 (M + H)+; Anal. (C11H13N2-
Cl‚C7H8O3S) C, H, N.
(1S,4S)-2-(3-Methylisothiazol-5-yl)-2,5-diazabicyclo[2.2.1]-
heptane p-Toluenesulfonate (S-61). Prepared in 3% overall yield
from 5-bromo-3-methylisothiazole67 and S-9 according to coupling
method ‘a,’ followed by deprotection with p-toluenesulfonic acid:
1H NMR (300 MHz, CD3OD) δ 2.14 (d, J ) 11 Hz, 1H), 2.27 (s,
3H), 2.38 (s, 3H), 2.64 (d, J ) 11 Hz, 1H), 3.11-3.18 (m, 2H),
3.23 (dd, J ) 11, 2 Hz, 1H), 3.59 (dd, J ) 10, 2 Hz, 1H), 4.13 (s,
1H), 4.26 (s, 1H), 6.08 (s, 1H), 7.22 (d, J ) 8 Hz, 2H), 7.71 ppm
(d, J ) 8 Hz, 2H); MS (ESI) m/z 196 (M + H). Anal. (C9H13N3S‚
C7H8O3S) C, H, N.
(1R,4R)-2-(3-Methyl-(1,2,4)-thiadiazol-5-yl)-2,5-diazabicyclo-
[2.2.1]heptane Trifluoroacetate (R-62). Prepared from R-9 (40
mg, 0.20 mmol) and 5-chloro-3-methyl-[1,2,4]thiadiazole68 (26 mg,
0.22 mmol) according to Pd-coupling method ‘a,’ followed by
deprotection with Amberlyst resin and purification by HPLC (0.1%
trifluoroacetic acid/water-acetonitrile eluent) to provide the title
salt: 1H NMR (500 MHz, CD3OD) δ 2.12 (d, J ) 11 Hz, 1H),
2.31-2.40 (m, 4H), 3.39-3.50 (m, 2H), 3.57 (d, J ) 11 Hz, 1H),
3.77 (dd, J ) 11, 2 Hz, 1H), 4.60 (s, 1H), 4.75 ppm (s, 1H); MS
(ESI) m/z 197 (M + H).
(1S,4S)-2-(2-Thiazolyl)-2,5-diazabicyclo[2.2.1]heptane p-Tolu-
enesulfonate (S-63). Prepared from S-9 (40 mg, 0.20 mmol) and
2-bromothiazole (32.8 mg, 0.2 mmol) according to thermal coupling
method ‘b’ (35%) followed by deprotection with p-toluenesulfonic
acid in EtOAc to provide the title compound (50%): 1H NMR (300
MHz, CD3OD) δ 2.11 (d, J ) 12 Hz, 1H), 2.34 (d, J ) 12 Hz,
1H), 2.36 (s, 6H), 3.37-3.56 (m, 2H), 3.61 (dd, J ) 11, 1 Hz,
1H), 3.80 (dd, J ) 11, 3 Hz, 1H), 4.59 (s, 1H), 4.76 (s, 1H), 7.23
(d, J ) 4 Hz, 1H), 7.23 (d, J ) 8 Hz, 4H), 7.25 (d, J ) 4 Hz, 1H),
7.69 ppm (d, J ) 8 Hz, 4H); MS (DCI/NH3) m/z 182 (M + H)+;;
Anal. (C8H11N3S‚2 C7H8O3S) C, H, N.
(1S,4S)-2-(3-Quinolinyl)-2,5-diazabicyclo[2.2.1]heptane p-Tol-
uenesulfonate (S-64). Prepared from S-9 and 3-bromoquinoline
by coupling method ‘a’ followed by deprotection with TFA/CH2-
Cl2. The crude TFA salt was eluted through a silica gel column
with CH2Cl2-CH3OH-cNH4OH (90:10:1) to provide the free base
(65% from S-9). This was combined with p-toluenesulfonic acid
and crystallized from EtOAc-EtOH (1:1) to provide the title salt
(72%): 1H NMR (300 MHz, CD3OD) δ 2.13 (d, J ) 11 Hz, 1H),
2.35 (s, 3H), 2.39 (d, J ) 11 Hz, 1H), 3.43 (s, 2H), 3.49 (d, J )
11 Hz, 1H), 3.90 (dd, J ) 11, 3 Hz, 1H), 4.57 (s, 1H), 4.91 (s,
1H), 7.21 (d, J ) 8 Hz, 2H), 7.40 (d, J ) 3 Hz, 1H), 7.43-7.55
(m, 2H), 7.69 (d, J ) 8 Hz, 2H), 7.72-7.80 (m, 1H), 7.82-7.96
(m, 1H), 8.53 (d, J ) 3 Hz, 1H); MS (DCI/NH3) m/z 226 (M +
H)+; Anal. (C14H15N3‚C7H8O3S) C, H, N.
(1S,4S)-2-(2-Quinolinyl)-2,5-diazabicyclo[2.2.1]heptane p-Tol-
uenesulfonate (S-65). Prepared from S-9 and 2-chloroquinoline
by coupling method ‘b,’ followed by deprotection with TFA/CH2-
Cl2. The crude material was purified by flash chromatography on
silica gel, eluting with CH2Cl2-CH3OH-cNH4OH (90:10:1) to
provide the free base, which was combined with p-toluenesulfonic
acid and crystallized from EtOAc-EtOH (5:1) to provide the title
salt as an off-white, crystalline solid (46% overall): 1H NMR (300
MHz, CD3OD) δ 2.09 (d, J ) 11 Hz, 1H), 2.26-2.37 (m, 1H),
2.36 (s, 3H), 3.44 (s, 2H), 3.69-3.77 (m, 1H), 3.83-3.91 (m, 1H),
(1S,4S)-2-(4-Chloro-1-phthalazinyl)-2,5-diazabicyclo[2.2.1]-
heptane Bis(p-toluenesulfonate) (S-53). 1,4-Dichlorophthalazine
was coupled to S-9 according to method ‘a’ (62%) followed by
deprotection/salt formation with p-toluenesulfonic acid to provide
the title salt (83% yield): 1H NMR (300 MHz, CD3OD) δ 2.23 (d,
J ) 12 Hz, 1H), 2.36 (s, 6H), 2.45-2.53 (m, 1H), 3.51-3.60 (m,
1H), 3.91 (dd, J ) 12, 2 Hz, 1H), 4.06 (dd, J ) 11, 2 Hz, 1H),
4.52 (dd, J ) 11, 3 Hz, 1H), 4.65-4.71 (m, 1H), 5.27 (s, 1H),
7.20 (d, J ) 8 Hz, 4H), 7.64 (d, J ) 8 Hz, 4H), 8.07-8.22 (m,
2H), 8.36-8.42 ppm (m, 2H); MS (DCI/NH3) m/z 261(M + H)+;
Anal. (C13H13N4Cl‚2 C7H8O3S) C, H, N.
(1S,4S)-2-(5-Pyrimidinyl)-2,5-diazabicyclo[2.2.1]-
heptanetrifluoroacetate (S-54). Prepared from S-9 and 5-bro-
mopyrimidine according to coupling method ‘a’ (91%) followed
by deprotection/salt formation with trifluoroacetic acid to provide
the title compound after trituration with 10% methanol in ether
(45%): 1H NMR (300 MHz, CD3OD) δ 2.10 (d, J ) 11 Hz, 1 H),
2.31 (d, J ) 12 Hz, 1 H), 3.28-3.33 (m, 2H), 3.35-3.44 (m, 1 H),
3.77 (dd, J ) 11, 3 Hz, 1 H), 4.57 (t, J ) 2 Hz, 1 H), 4.81-4.84
(m, 1 H), 8.27 (s, 2H), 8.55 ppm (s, 1 H); MS (DCI/NH3) m/z 177
(M + H)+; Anal. (C9H12N4‚C2HO2F3‚0.1 H2O) C, H, N.
(1S,4S)-2-(6-Chloro-1,3-pyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]-
heptane p-Toluenesulfonate (S-55). Prepared in 10% yield from
S-9 and 4,6-dichloropyrimidine according to coupling procedure
‘a,’ followed by deprotection/salt formation with p-toluenesulfonic
acid: 1H NMR (300 MHz, CD3OD) δ 2.06-2.16 (m, 1H), 2.20-
2.33 (m, 1H), 2.37 (s, 3H), 3.35-3.49 (m, 2H), 3.64-3.83 (m,
2H), 4.60 (s, 1H), 5.19 (br.s, 1H), 6.75 (br. s, 1H), 7.23 (d, J ) 8
Hz, 2H), 7.68 (d, J ) 8 Hz, 2H), 8.40 ppm (s, 1H); MS (DCI/
NH3) m/z 211/213 (M + H)+; Anal. C9H11N4Cl‚C7H8O3S‚H2O) C,
H, N.
(1S,4S)-2-(Phenyl)-2,5-diazabicyclo[2.2.1]heptane p-Toluene-
sulfonate (S-56). Prepared in 75% yield from S-9 and bromoben-
zene using coupling procedure ‘a’ (97%) followed by deprotection/
salt formation with p-toluenesulfonic acid to provide the title salt
(76%): 1H NMR (300 MHz, CD3OD) δ 2.03 (d, J ) 11 Hz, 1H),
2.29 (d, J ) 11 Hz, 1H), 2.36 (s, 3H), 3.23-3.41 (m, 3H), 3.73
(dd, J ) 11, 2 Hz, 1H), 4.39-4.51 (m, 1H), 4.64 (s, 1H), 6.67 (d,
J ) 8 Hz, 2H), 6.75 (t, J ) 8 Hz, 1H), 7.17-7.26 (m, 4H), 7.70
ppm (d, J ) 8 Hz, 2H); MS (DCI/NH3) m/z 175; Anal. (C11H14N2‚
C7H8O3S‚0.2H2O) C, H, N.
(1S,4S)-2-(4-Nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane p-
Toluenesulfonate (S-57). Coupling of p-bromonitrobenzene with
S-9 according to method ‘a’ (50%), followed by deprotection/salt
formation with p-toluenesulfonic acid provided the title salt
(78%): 1H NMR (300 MHz, CD3OD) δ 2.10 (d, J ) 12 Hz, 1H),
2.32 (d, J ) 12 Hz, 1H), 2.36 (s, 3H), 3.33-3.44 (m, 2H), 3.48
(dd, J ) 11, 1 Hz, 1H), 3.79 (dd, J ) 11, 2 Hz, 1H), 4.57 (s, 1H),
4.85-4.93 (m, 1H), 6.70-6.79 (m, 2H), 7.22 (d, J ) 8 Hz, 2H),
7.69 (d, J ) 8 Hz, 2H), 8.06-8.20 ppm (m, 2H); MS (DCI/NH3)
m/z 220 (M + H)+; Anal. (C11H13N3O2‚C7H8O3S) C, H, N.
(1S,4S)-2-(3-Nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane p-
Toluenesulfonate (S-58). Coupling of S-9 with 3-bromonitroben-
zene according to method ‘a,’ followed by deprotection/salt
formation with p-toluenesulfonic acid in EtOAc, provided the title
salt as a golden-yellow crystalline powder in 77% overall yield:
1H NMR (300 MHz, CD3OD) δ 2.08 (d, J ) 11 Hz, 1H), 2.32 (d,
J ) 11 Hz, 1H), 2.36 (s, 3H), 3.33-3.43 (m, 3H), 3.79 (dd, J )
11, 3 Hz, 1H), 4.50-4.55 (m, 1H), 4.79 (s, 1H), 7.06 (dd, J ) 8,
2 Hz, 1H), 7.22 (d, J ) 8 Hz, 2H), 7.41-7.49 (m, 2H), 7.58 (dd,
J ) 8, 2 Hz, 1H), 7.69 ppm (d, J ) 8 Hz, 2H); MS (DCI/NH3) m/z
220 (M + H). Anal. (C11H13N3O2‚C7H8O3S) C, H, N.
(1S,4S)-2-(3-Fluorophenyl)-2,5-diazabicyclo[2.2.1]heptane p-
Toluenesulfonate (S-59). Prepared from S-9 and 3-bromofluo-
robenzene according to coupling method ‘a’ (87%), followed by
deprotection/salt formation with p-toluenesulfonic acid to provide
the title salt, which was purified by recrystallization from ethanol
after treatment with decolorizing carbon (27%): 1H NMR (300
MHz, CD3OD) δ 2.05 (d, J ) 12 Hz, 1H), 2.29 (d, J ) 12 Hz,