Piperidyl/ Pyrrolidyl Benzilates as Ligands for mAChR
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 23 4559
NMR (CDCl3, 125 MHz) δ 11.75, 22.38, 29.12, 52.03, 52.47,
56.00, 72.41, 80.73, 127.27, 127.29, 127.68, 127.72, 127.79,
127.85, 142.12, 142.21, 173.52; MS (CI, NH3) m/z 340 (M +
H+, 18). HRMS calcd for C21H26NO3: 340.1913. Found:
340.1906. Anal. (C21H25NO3) C, H, N.
colorless oil, which solidified after 3 days (32.8 mg, 62%): mp
74-76 °C; H NMR (CDCl3, 500 MHz) δ 0.87 (t, J ) 7.4 Hz,
1
3H), 1.43 (sextet, J ) 7.4 Hz, 2H), 1.77 (m, 1H), 2.18 (dq, J )
14.2, 7.1 Hz, 1H), 2.30 (ABqt, J AB ) 11.7 Hz, ∆υ ) 24.1 Hz, J
) 7.6 Hz, 2H), 2.42 (m, 1H), 2.53 (dd, J ) 11.2, 2.5 Hz, 1H),
2.58 (app. q, J ) 7.7 Hz, 1H), 2.81 (dd, J ) 11.2, 6.1 Hz, 1H),
4.53 (bs, 1H), 5.31 (ddt, J ) 7.8, 5.6, 2.6 Hz, 1H), 7.30-7.45
(m, 10H); 13C NMR (CDCl3, 125 MHz) δ 11.84, 21.71, 31.45,
52.50, 57.94, 59.51, 76.67, 80.72, 127.28, 127.84, 127.85,
127.94, 127.96, 14.94, 141.97, 173.90; MS (CI, NH3) m/z 340
(M + H+, 100). HRMS calcd for C21H26NO3: 340.1913. Found:
340.1899. Anal. (C21H25NO3) C, H, N.
(R)-Hyd r oxyd ip h en yla cetic Acid N-P r op ylp ip er id in -
3-yl Ester (21). FC solvent system: EtOAc; yellow oil which
solidified upon standing under vacuum (32.8 mg, 63%): mp
1
70-72 °C; H NMR (CDCl3, 500 MHz) δ 0.89 (t, J ) 7.2 Hz,
3H), 1.48-1.59 (m, 4H), 1.73 (m, 1H), 1.85 (m, 1H), 2.36 (m,
4H), 2.55 (m, 1H), 2.76 (m, 1H), 5.20 (m, 1H), 5.40 (bs, 1H),
7.29-7.53 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ 11.69, 19.48,
21.88, 28.77, 52.90, 53.16, 60.13, 71.88, 80.85, 127.24, 127.30,
127.74, 127.78, 127.85, 127.93, 142.06, 142.21, 173.51; MS (CI,
NH3) m/z 354 (M + H+, 100). HRMS calcd for C22H28NO3:
354.2069. Found: 354.2083. Anal. (C22H27NO3‚0.5H2O) C, H,
N.
(R)-Hyd r oxyd ip h en yla cetic Acid N-(2-F lu or oeth yl)-
p yr r olid in -3-yl Ester (33). FC solvent system: EtOAc; yellow
oil (30.9 mg, 38%): 1H NMR (CDCl3, 500 MHz) δ 1.80 (m, 1H),
2.19 (dq, J ) 14.0, 7.1 Hz, 1H), 2.55-2.73 (m, 5H), 2.95 (dd, J
) 10.8, 6.1 Hz, 1H), 4.47 (dt, J H-F ) 47.5 Hz, J H-H ) 5.9 Hz,
2H), 4.47 (bs, 1H), 5.33 (m, 1H), 7.25-7.45 (m, 10H); 13C NMR
(CDCl3, 125 MHz) δ 31.49, 52.87, (55.21, 55.36; J C-F ) 19.8
Hz), 59.86, 76.59, 80.76, (82.06, 83.39; J C-F ) 167.5 Hz),
127.28, 127.29, 127.99, 128.00, 141.82, 141.86, 173.92; MS (CI,
NH3) m/z 344 (M + H+, 100). HRMS calcd for C20H23FNO3:
344.1662. Found: 344.1659. Anal. (C20H22FNO3) C, H, N.
(R)-Hyd r oxyd ip h en yla cetic Acid N-(3-F lu or op r op yl)-
p yr r olid in -3-yl Ester (34). FC solvent system: 2.5% MeOH/
CH2Cl2; yellow oil (50.4 mg, 60%): 1H NMR (CDCl3, 500 MHz)
δ 1.79 (m 3H), 2.17 (dq, J ) 14.1, 7.1 Hz, 1H), 2.39-2.51 (m,
3H), 2.55 (dd, J ) 11.0, 2.0 Hz, 1H), 2.61 (app. q, J ) 7.6 Hz,
1H), 2.80 (dd, J ) 11.1, 6.0 Hz, 1H), 4.43 (dt, J H-F ) 47.2 Hz,
J H-H ) 5.9 Hz, 2H), 4.43 (bs, 1H), 5.30 (m, 1H), 7.24-7.44 (m,
10H); 13C NMR (CDCl3, 125 MHz) δ (29.30, 29.45; J C-F ) 19.6
Hz), 31.41, 51.48, 51.52, 52.40, 59.45, 76.60, 80.72, (81.49,
82.79; J C-F ) 164.2 Hz), 127.26, 127.27, 127.86, 127.89, 127.95,
127.97, 141.89, 173.92; MS (CI, NH3) m/z 358 (M + H+, 100).
HRMS calcd for C21H25FNO3: 358.1818. Found: 358.1826.
Anal. (C21H24FNO3) C, H, N.
(R)-Hyd r oxyd ip h en yla cetic Acid N-(4-F lu or oben zyl)-
p yr r olid in -3-yl Ester (35). FC solvent system: 60% EtOAc/
Hex; yellow oil (45.1 mg, 59%): 1H NMR (CDCl3, 500 MHz) δ
1.80 (m, 1H), 2.19 (dq, J ) 14.0, 7.1 Hz, 1H), 2.41 (m, 1H),
2.55 (dd, J ) 11.1, 2.3 Hz, 1H), 2.63 (app. q, J ) 7.6 Hz, 1H),
2.77 (dd, J ) 11.1, 5.9 Hz, 1H), 3.50 (ABq, J AB ) 13.0 Hz, ∆υ
) 39.8 Hz, 2H), 4.33 (s, 1H), 5.31 (ddt, J ) 7.5, 5.9, 2.8 Hz,
1H), 6.94-7.23 (m, 4H), 7.28-7.48 (m, 10H); 13C NMR (CDCl3,
125 MHz) δ 31.47, 52.24, 58.95, 59.26, 76.76, 80.72, (114.94,
115.11; J C-F ) 21.2 Hz), 127.33, 127.94, 128.01, (129.93,
129.99; J C-F ) 7.9 Hz), 134.31, 134.33, 141.86, 141.90, (160.92,
162.87; J C-F ) 244.8 Hz), 174.02; MS (CI, NH3) m/z 406 (M +
H+, 100). HRMS calcd for C25H25FNO3: 406.1818. Found:
406.1804. Anal. (C25H24FNO3) C, H, N.
(R)-Hyd r oxyd ip h en yla cetic Acid N-(2-F lu or oeth yl)-
p ip er id in -3-yl Ester (22). FC solvent system: 2.5% MeOH/
CH2Cl2; yellow oil (64.4 mg, 67%): 1H NMR (CDCl3, 500 MHz)
δ 1.40 (m, 1H), 1.54 (m, 1H), 1.69 (m, 1H), 1.81 (m, 1H), 2.32
(app. t, J ) 8.5 Hz, 1H), 2.41 (dd, J ) 10.6, 7.8 Hz, 1H), 2.56
(m, 1H), 2.64 (dt, J H-F ) 27.8 Hz, J H-H ) 5.0 Hz, 2H), 2.75
(dd, J ) 11.1, 2.4 Hz, 1H), 4.47 (dt, J H-F ) 47.6 Hz, J H-H
4.9 Hz, 2H), 4.49 (s, 1H), 7.24-7.49 (m, 10H); 13C NMR (CDCl3,
125 MHz) δ 22.25, 28.73, 53.17, 56.68, (57.73, 57.89; J C-F
)
)
20.1 Hz), 72.18, 80.77, (81.22, 82.55; J C-F ) 167.7 Hz), 127.29,
127.31, 127.78, 127.82, 127.87, 127.93, 142.017, 142.140,
173.63; MS (CI, NH3) m/z 358 (M + H+, 100). HRMS calcd for
C
21H25FNO3: 358.1818. Found: 358.1828. Anal. (C21H24FNO3)
C, H, N.
(R)-Hyd r oxyd ip h en yla cetic Acid N-(3-F lu or op r op yl)-
p ip er id in -3-yl Ester (23). FC solvent system: 2.5% MeOH/
CH2Cl2; clear oil which solidified on standing (58.7 mg, 73%):
1
mp 74-75.5 °C; H NMR (CDCl3, 500 MHz) δ 1.44 (dtd, J )
12.9, 8.8, 4.1 Hz, 1H), 1.52 (m, 1H), 1.66 (m, 1H), 1.73-1.83
(m, 3H), 2.21 (m, 1H), 2.30 (m, 1H), 2.40 (t, J ) 7.2 Hz, 2H),
2.42 (m, 1H), 2.64 (m, 1H), 4.41 (dt, J H-F ) 47.2 Hz, J H-H
)
5.9 Hz, 2H), 4.49 (s, 1H), 4.99 (sept, J ) 3.7 Hz, 1H), 7.29-
7.48 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ 22.29, (27.67,
27.83; J C-F ) 19.6 Hz), 28.96, 52.98, (53.83, 53.88; J C-F ) 5.5
Hz), 56.49, 72.35, 80.75, (81.56, 82.86; J C-F ) 164 Hz), 127.28,
127.31, 127.79, 127.83, 127.88, 127.92, 142.00, 142.16, 173.69;
MS (CI, NH3) m/z 372 (M + H+, 100). HRMS calcd for C22H27
-
FNO3: 372.1975. Found: 372.1962. Anal. (C22H26FNO3) C, H,
N.
(R)-Hyd r oxyd ip h en yla cetic Acid N-(4-F lu or oben zyl)-
p ip er id in -3-yl Ester (24). FC solvent system: 2.5% MeOH/
CH2Cl2; yellow oil which partially solidified to a waxy solid
upon standing under vacuum (79.3 mg, 73%): 1H NMR (CDCl3,
500 MHz) δ 1.49 (m, 2H), 1.63 (m, 1H), 1.77 (m, 1H), 2.25 (m,
1H), 2.34-2.40 (m, 2H), 2.60 (m, 1H), 3.40 (ABq, J AB ) 13.3
Hz, ∆υ ) 28.0 Hz, 2H), 4.41 (s, 1H), 5.01 (m, 1H), 6.94-7.16
(m, 4H), 7.30-7.48 (m, 10H); 13C NMR (CDCl3, 125 MHz) δ
22.10, 28.82, 52.58, 56.37, 61.80, 72.42, 80.76, (114.84, 115.01,
J C-F ) 21.2 Hz), 127.31, 127.32, 127.81, 127.82, 127.89, 127.93,
(130.10, 130.16, J C-F ) 7.8 Hz), 133.66, 133.68, 141.98, 142.18,
160.88, 162.83, 173.73; MS (CI, NH3) m/z 420 (M + H+, 21).
HRMS calcd for C26H27FNO3: 420.1975. Found: 420.1981.
Anal. (C26H26FNO3) C, H, N.
(R)-Hyd r oxyd ip h en yla cet ic Acid N-E t h ylp yr r olid in -
3-yl Ester (31). FC solvent system: 5% MeOH/CH2Cl2; yellow
oil which solidified on standing (56.6 mg, 70%): mp 74-77.5
°C; 1H NMR (CDCl3, 500 MHz) δ 1.02 (t, J ) 7.2 Hz, 3H), 1.77
(m, 1H), 2.17 (dq, J ) 14.0, 7.1 Hz, 1H), 2.31-2.45 (m, 3H),
2.51 (dd, J ) 11.3, 2.7 Hz, 1H), 2.55 (app. q, J ) 8.2 Hz, 1H);
2.83 (dd, J ) 11.2, 6.2 Hz, 1H), 4.70 (bs, 1H), 5.31 (ddt, J )
7.1, 6.2, 2.7 Hz, 1H), 7.29-7.45 (m, 10H); 13C NMR (CDCl3,
125 MHz) δ 13.47, 31.45, 49.72, 52.10, 59.14, 76.44, 80.73,
127.24, 127.25, 127.80, 127.90, 141.95, 142.00, 173.79; MS (CI,
NH3) m/z 326 (M + H+, 100). HRMS calcd for C20H24NO3:
326.1756. Found: 326.1753. Anal. (C20H23NO3) C, H, N.
Hyd r oxyd ip h en yla cetic Acid N-(2-F lu or o-1-m eth yl-
eth yl)p ip er id in -4-yl Ester (10). To a suspension of piperidyl
benzilate 3a (130 mg, 0.417 mmol) in 50% acetone/MeOH (2
mL) was added 1 M HCl in ether (0.420 mL, 0.420 mmol). The
reaction became homogeneous, and the solvent was evaporated
to a yellow foam. The foam was dissolved in MeOH (3.5 mL),
and to it was added fluoroacetone (0.120 mL, 1.67 mmol) and
NaCNBH3 (39.3 mg, 0.626 mmol). After stirring overnight, 1
mL of water was added, resulting in a white precipitate. The
MeOH was evaporated and the residue purified by flash
chromatography (7.5% MeOH/CH2Cl2) to give 10 as a clear oil
(40 mg, 26%): 1H NMR (CDCl3, 500 MHz) δ 0.967 (d, J ) 5.7
Hz, 3H), 1.70 (m, 2H), 1.87 (m, 2H), 2.43-2.49 (m, 4H), 2.83
(m, 1H), 4.23-4.42 (m, 3H), 4.99 (m, 1H), 7.25-7.44 (m, 10H);
13C NMR (CDCl3, 125 MHz) δ (11.23, 11.29; J C-F ) 7.1 Hz),
30.71, 45.77, (58.67, 58.82; J C-F ) 18.6 Hz), 72.97, 80.82,
(84.19, 85.55; J C-F ) 172.0 Hz), 127.40, 127.92, 128.17, 142.03,
173.86; MS (CI, NH3) m/z 372 (M + H+, 100). HRMS calcd for
C
22H27FNO3: 372.1975. Found: 372.1977.
(R)-Hyd r oxyd ip h en yla cetic Acid N-Meth ylp ip er id in -
3-yl Ester (25). To a solution of 19 (57.1 mg, 0.183 mmol) in
MeOH (2 mL) was added 37% aqueous H2CO (45 µL, 0.550
mmol). To this was added a solution of ZnCl2 (25.0 mg, 0.183
mmol) and NaCNBH3 (23.0 mg, 0.366 mmol) in MeOH (2 mL).
(R)-Hyd r oxyd ip h en yla cetic Acid N-P r op ylp yr r olid in -
3-yl Ester (32). FC solvent system: 5% MeOH/CH2Cl2;