Full Papers
(1S,3R)-3-[2-Hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1-methyl-1-
(cyclohexylmethyl)pyrrolidinium bromide (5a) and (1R,3R)-3-[2-
hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1-methyl-1-(cyclohexyl-
methyl)pyrrolidinium bromide (5c): (Bromomethyl)cyclohexane
(220 mg, 1.24 mmol) was added to a solution of 12a (200 mg,
0.62 mmol) in 2-butanone (0.8 mL) in a sealed tube. The mixture
was stirred at 808C for 40 h. The precipitate was collected by filtra-
tion, washed with 2-butanone (1 mL), and purified by column chro-
matography (CH2Cl2/MeOH=40:1) to afford 5a and 5c, the config-
urations of which were elucidated by 1H, 13C, and ROESY NMR spec-
troscopy. Data for 5a: White solid (85 mg, 27%); mp 62–668C;
[a]2D0 =ꢁ9 (c=0.1, MeOH); 1H NMR (500 MHz, [D6]DMSO): d=7.51
(s, 2H), 7.45 (s, 1H), 7.12 (m, 2H), 7.01 (s, 2H), 5.50 (m, 1H), 3.85
(m, 1H), 3.77 (m, 2H), 3.53 (m, 1H), 3.29 (m, 2H), 2.96 (s,3H), 2.73
(m, 1H), 2.14 (m, 1H), 1.92 (m, 1H), 1.76 (m, 2H), 1.58 (m, 3H), 1.30
(m, 2H), 1.09 ppm (m, 3H); 13C NMR (125 MHz, [D6]DMSO): d=
170.25, 146.61, 126.62, 126.17, 125.71, 125.68, 76.23, 73.40, 70.72,
68.30, 63.22, 48.67, 32.02, 32.00, 29.42, 25.04 ppm; MS (ESI): m/z=
420.2 [MꢁBr]+; HRMS: m/z: calcd for C19H24NO3S2: 420.1667
[MꢁBr]+; found: 420.1670; HPLC (50% aqueous methanol plus
0.1% TFA as the eluent, flow rate 0.6 mLminꢁ1): tR =10.7 min,
purity: 99.3%. Data for 5c: White solid (80 mg, 26%); mp 55–598C;
[a]2D0 =ꢁ6 (c=0.1, MeOH); 1H NMR (500 MHz, [D6]DMSO): d=7.52
(d, J=4.2 Hz, 2H), 7.43 (s, 1H), 7.13 (dd, J=2.25, 13.55 Hz, 2H),
7.01 (m, 2H), 5.52 (m, 1H), 3.97 (m, 1H), 3.64 (m, 3H), 3.13 (s, 5H),
2.70 (m, 1H), 2.11 (m, 1H), 1.87 (m, 1H), 1.62 (m, 5H), 1.27 (m, 2H),
1.12 (m, 1H), 0.97 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=
170.27, 146.60, 146.57, 126.63, 126.21, 125.70, 125.63, 76.22, 73.67,
70.01, 68.83, 63.21, 49.90, 32.16, 32.06, 31.96, 29.24, 25.02 ppm; MS
(ESI): m/z=420.2 [MꢁBr]+; HRMS: m/z: calcd for C19H24NO3S2:
420.1667 [MꢁBr]+; found: 420.1671; HPLC (50% aqueous methanol
plus 0.1% TFA as the eluent, flow rate 0.6 mLminꢁ1): tR =15.2 min,
purity: 96.3%.
0.1% TFA as the eluent, flow rate 0.6 mLminꢁ1): tR =15.2 min,
purity: 95.4%.
(1S,3R)-3-[2-Hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1-methyl-1-
benzylpyrrolidinium bromide (6a) and (1R,3R)-3-[2-hydroxy-2,2-
di(thiophen-2-yl)acetoxy]-1-methyl-1-benzylpyrrolidinium bro-
mide (6c): Benzyl bromide (159 mg, 0.93 mmol) was added to a so-
lution of 12a (150 mg, 0.47 mmol) in 2-butanone (0.6 mL). The
mixture was stirred at room temperature for 2 h and was concen-
trated in vacuo. The residue was purified by column chromatogra-
phy (CH2Cl2/MeOH=40:1) to afford 6a and 6c, the configurations
1
of which were elucidated by H, 13C, and ROESY NMR spectroscopy.
Data for 6a: White solid (40 mg, 17%); mp 63–668C; [a]2D0 =ꢁ6
(c=0.1, MeOH); 1H NMR (500 MHz, [D6]DMSO): d=7.50 (m, 7H),
7.44 (s, 1H), 7.11 (m, 2H), 6.99 (m, 2H), 5.55 (s, 1H), 4.69 (m, 2H),
4.09 (m, 1H), 3.71 (m, 1H), 3.58 (m, 2H), 2.87 (s, 3H), 2.75 (m, 1H),
2.16 ppm (m, 1H); 13C NMR (125 MHz, [D6]DMSO): d=170.30,
146.57, 146.53, 132.48, 130.31, 129.01, 128.50, 126.66, 126.51,
126.20, 125.95, 125.73, 125.70, 125.40, 76.26, 73.14, 67.03, 66.57,
61.76, 48.42, 29.28 ppm; MS (ESI): m/z=414.1 [MꢁBr]+; HRMS: m/
z: calcd for C23H23F3NO4S2: 414.1198 [MꢁBr]+; found: 414.1202;
HPLC (50% aqueous methanol plus 0.1% TFA as the eluent, flow
rate 0.6 mLminꢁ1): tR =9.5 min, purity: 96.7%. Data for 6c: White
solid (60 mg, 25%); mp 47–508C; [a]2D0 =ꢁ3 (c=0.1, MeOH);
1H NMR (500 MHz, [D6]DMSO): d=7.66 (s, 1H), 7.53 (m, 7H), 7.15
(m, 2H), 7.00 (m, 2H), 5.58 (s, 1H), 4.60 (m, 2H), 3.87 (m, 2H), 3.74
(m, 1H), 3.56 (m, 1H), 3.03 (s, 3H), 2.78 (m, 1H), 2.27 ppm (m, 1H);
13C NMR (125 MHz, [D6]DMSO): d=170.49, 146.74, 132.77, 130.34,
128.96, 128.30, 126.71, 126.68, 126.23, 125.76, 125.67, 76.32, 73.52,
66.39, 65.57, 61.96, 49.21, 29.41 ppm; MS (ESI): m/z=414.1
[MꢁBr]+; HRMS: m/z: calcd for C23H23F3NO4S2: 414.1198 [MꢁBr]+;
found: 414.1201; HPLC (50% aqueous methanol plus 0.1% TFA as
the eluent, flow rate 0.6 mLminꢁ1): tR =10.9 min, purity: 98.6%.
(1R,3S)-3-[2-Hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1-methyl-1-
benzylpyrrolidinium bromide (6b) and (1S,3S)-3-[2-hydroxy-2,2-
di(thiophen-2-yl)acetoxy]-1-methyl-1-benzylpyrrolidinium bro-
mide (6d): Using a procedure similar to that described for 6a and
6c, 6b and 6d were prepared from 11 b and benzyl bromide. The
configurations of 6b and 6d were elucidated by 1H, 13C, COSY,
ROESY, HMBC, and HSQC NMR spectroscopy. Data for 6b: White
solid (110 mg, 34%); mp 62–658C; [a]2D0 = +5 (c=0.1, MeOH);
1H NMR (500 MHz, [D6]DMSO): d=7.58 (m, 2H), 7.51 (m, 4H), 7.44
(s, 1H), 7.11 (m, 2H), 6.98 (m, 2H), 5.55 (s, 1H), 4.69 (m, 2H), 4.10
(m, 1H), 3.74 (m, 1H), 3.74 (m, 2H), 2.87 (s, 3H), 2.75 (m, 1H),
2.15 ppm (m, 1H); 13C NMR (125 MHz, [D6]DMSO): d=170.28,
146.56, 146.52, 132.47, 130.30, 129.00, 128.50, 126.64, 126.50,
126.18, 125.94, 125.72, 125.68, 125.38, 76.25, 73.13, 67.02, 66.55,
61.75, 48.42, 29.27 ppm; MS (ESI): m/z=414.1 [MꢁBr]+; HRMS: m/
z: calcd for C23H23F3NO4S2: 414.1198 [MꢁBr]+; found: 414.1202;
HPLC (50% aqueous methanol plus 0.1% TFA as the eluent, flow
rate 0.6 mLminꢁ1): tR =9.6, 10.9 min; purity: 99.7%. Data for 6d:
White solid (110 mg, 34%); mp 46–508C; [a]2D0 = +3 (c=0.1,
MeOH); 1H NMR (500 MHz, [D6]DMSO): d=7.65 (s, 1H), 7.50 (m,
7H), 7.18 (m, 2H), 7.00 (m, 2H), 5.58 (s, 1H), 4.60 (m, 2H), 3.89 (m,
2H), 3.82 (m, 1H), 3.56 (m, 1H), 3.03 (s, 3H), 2.78 (m, 1H), 2.27 ppm
(m, 1H); 13C NMR (125 MHz, [D6]DMSO): d=170.48, 146.73, 132.77,
130.32, 128.95, 128.31, 126.69, 126.66, 126.21, 125.75, 125.65,
76.32, 73.50, 66.39, 65.57, 66.39, 65.57, 61.95, 49.20, 29.41 ppm; MS
(ESI): m/z=414.1 [MꢁBr]+; HRMS: m/z: calcd for C23H23F3NO4S2:
414.1198 [MꢁBr]+; found: 414.1201; HPLC (50% aqueous methanol
plus 0.1% TFA as the eluent, flow rate 0.6 mLminꢁ1): tR =10.8 min,
purity: 95.2%.
(1R,3S)-3-[2-Hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1-methyl-1-
(cyclohexylmethyl)pyrrolidinium bromide (5b) and (1S,3S)-3-[2-
hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1-methyl-1-(cyclohexyl-
methyl)pyrrolidinium bromide (5d): Using a procedure similar to
that described for 5a and 5c, 5b and 5d were prepared from 12b
and (bromomethyl)cyclohexane. The configurations of 5b and 5d
were elucidated by 1H, 13C, COSY, ROESY, HMBC, and HSQC NMR
spectroscopy. Data for 5b: White solid (110 mg, 36%); mp 62–
668C; [a]2D0 = +11 (c=0.1, MeOH); 1H NMR (500 MHz, [D6]DMSO):
d=7.51 (d, J=3.4 Hz, 2H), 7.45 (s, 1H), 7.14 (dd, J=2.3, 18.2 Hz,
2H), 7.01 (m, 2H), 5.50 (m, 1H), 3.87 (m, 1H), 3.77 (m, 2H), 3.54 (m,
1H), 3.30 (m, 2H), 2.96 (s,3H), 2.72 (m, 1H), 2.12 (m, 1H), 1.93 (m,
1H), 1.76 (m, 2H), 1.61 (m, 3H), 1.30 (m, 2H), 1.09 ppm (m, 3H);
13C NMR (125 MHz, [D6]DMSO): d=170.25, 146.61, 146.60, 126.62,
126.17, 125.71, 125.68, 76.22, 73.39, 70.72, 68.30, 63.22, 48.67,
32.03, 32.00, 31.98, 29.41, 25.04 ppm; MS (ESI): m/z=420.2
[MꢁBr]+; HRMS: m/z: calcd for C19H24NO3S2: 420.1667 [MꢁBr]+;
found: 420.1670; HPLC (50% aqueous methanol plus 0.1% TFA as
the eluent, flow rate 0.6 mLminꢁ1): tR =10.7 min, purity: 97.8%.
Data for 5d: White solid (110 mg, 36%); mp 55–598C; [a]2D0 = +4
(c=0.1, MeOH); 1H NMR (500 MHz, [D6]DMSO): d=7.52 (dd, J=
4.2 Hz, 2H), 7.43 (s, 1H), 7.13 (dd, J=2.25, 13.55 Hz, 2H), 7.01 (m,
2H), 5.52 (m, 1H), 3.97 (m, 1H), 3.64 (m, 3H), 3.13 (s, 5H), 2.70 (m,
1H), 2.11 (m, 1H), 1.87 (m, 1H), 1.62 (m, 5H), 1.27 (m, 2H), 1.12 (m,
1H), 0.97 ppm (m, 2H); 13C NMR (125 MHz, [D6]DMSO): d=170.27,
146.60, 146.57, 126.63, 126.21, 125.70, 125.63, 76.22, 73.67, 70.01,
68.83, 63.21, 49.90, 32.16, 32.06, 31.96, 29.24, 25.02 ppm; MS (ESI):
m/z=420.2 [MꢁBr]+; HRMS: m/z: calcd for C19H24NO3S2: 420.1667
[MꢁBr]+; found: 420.1671; HPLC (50% aqueous methanol plus
ChemMedChem 2017, 12, 1 – 11
7
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ