6712 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 23
Kopka et al.
pyrrolidine-CH/H2); 3.33 (s, 3H, OCH3); 3.52-3.54 and 3.72-
3.75 (m, 2H, OCH2); 3.79 (s, 3H, ArOCH3); 4.90 (s, 2H, NCH2-
4H, ArH); 7.51 (d, 2H, 3JH,H ) 8.1 Hz, SnBu3ArH); 8.00 (dd, 1H,
4JH,H ) 1.8 Hz, 3JH,H ) 8.4 Hz, isatin-H); 8.07 (d, 1H, 4JH,H ) 1.8
Hz, isatin-H). 13C NMR (75 MHz, CDCl3): δ (ppm) 10.0 (SnCH2),
14.0 (SnCH2CH2CH2CH3), 27.7 (SnCH2CH2CH2), 28.2 (SnCH2CH2),
24.6, 29.4, 49.9, 59.1 (pyrrolidine-CH/CH2), 44.8 (NCH2Ar), 69.6
(CH2O), 117.9 (q-ArC(CO)), 114.8, 121.5, 124.6, 127.4, 127.5,
129.9, 133.7, 134.7, 143.4 (q-Ar-C, Ar-CH), 137.5 (q-CSO2), 153.8
(q-CN(CO)), 158.2, 158.6 (q-ArCOH, isatin-N(CO)), 182.1 (N(CO)-
(CO)).
(S)-1-(4-Iodobenzyl)-5-[1-(2-methoxymethylpyrrolidinyl)sul-
fonyl]isatin (25). (S)-5-[1-(2-Methoxymethylpyrrolidinyl)sulfonyl]-
isatin (7) (750 mg, 2.3 mmol) was reacted with sodium hydride
(92 mg, 2.3 mmol, 60% in mineral oil) and p-iodobenzyl bromide
(1.02 g, 3.45 mmol) as described in the general procedure. The
crude dark orange product was purified by silica gel chromatog-
raphy (diisopropyl ether:acetone 8:1) to yield an orange solid.
Yield: 820 mg (1.52 mmol, 66%). Mp: 129-130 °C. MS (EI):
m/e (intensity %) 540 (2) (M)+, 495 (100). Anal. (C21H21N2IO5S)
C, H, N. 1H NMR (300 MHz, CDCl3): δ (ppm) 1.64-1.69, 1.86-
1.91, 3.11-3.13, 3.35-3.41 (m, 7H, pyrrolidine-CH/H2); 3.30 (s,
3H, OCH3); 3.52-3.57, 3.72-3.74 (m, 2H, OCH2); 4.91 (s, 2H,
NCH2Ar); 6.87 (d, 1H, 3JH,H ) 8.4 Hz, isatin-H); 7.08 (d, 2H, 3JH,H
) 8.7 Hz, ArH); 7.69 (d, 2H, 3JH,H ) 8.7 Hz, ArH); 7.97 (dd, 1H,
4JH,H ) 1.8 Hz, 3JH,H ) 8.4 Hz, isatin-H); 8.04 (d, 1H, 4JH,H ) 1.8
Hz, isatin-H). 13C NMR (75 MHz, CDCl3): δ (ppm) 24.1, 28.9,
49.2, 59.1, 59.2 (pyrrolidine-CH/CH2, OCH3), 44.0 (NCH2Ar), 74.8
(CH2O), 94.1 (q-ArCI), 117.6 (q-ArC(CO)), 111.0, 124.6, 129.4,
133.5, 134.5 (Ar-CH and isatin-CH), 137.4 (qCSO2), 138.4 (q-
ArCCH2), 153.0 (q-CN(CO)), 157.8 (isatin-N(CO)), 181.5 (N(CO)-
CO)).
3
3
Ar); 6.87 (d, 1H, JH,H ) 8.1 Hz, isatin-H); 6.94 (d, 2H, JH,H
)
3
8.4 Hz, ArH); 7.25 (d, 2H, JH,H ) 8.4 Hz, ArH); 7.98 (dd, 1H,
4JH,H ) 1.8 Hz, 3JH,H ) 8.1 Hz, isatin-H); 8.02 (d, 1H, 4JH,H ) 1.8
Hz, isatin-H). 13C NMR (75 MHz, CDCl3): δ (ppm) 24.1, 28.9
(pyrrolidine-CH2), 44.0 (NCH2Ar), 49.3, 55.4 (pyrrolidine-CH/CH2),
59.1 (OCH3), 74.9 (OCH2), 111.2, 114.6 (Ar-C), 117.6 (q-
ArC(CO)), 124.4, 125.8, 129.1 (Ar-C), 134.1 (q-ArCCH2), 137.3
(q-ArCSO2), 153.4 (q-ArCN(CO)), 157.8 (q-ArCO), 159.8 (Ar(CO)-
(CO)), 181.9 (Ar(CO)(CO)).
(S)-1-(4-Methoxybenzyl)-5-[1-(2-phenoxymethylpyrrolidinyl)-
sulfonyl]isatin (20). (S)-5-[1-(2-Phenoxymethylpyrrolidinyl)sul-
fonyl]isatin (8) (386 mg, 1 mmol) was converted with sodium
hydride (40 mg, 1 mmol, 60% in mineral oil) and p-methoxybenzyl
chloride (670 mg, 3 mmol) as described in the general procedure.
The crude dark orange product was purified by silica gel chroma-
tography (diisopropyl ether:acetone 8:1) to yield an orange solid.
Yield: 310 mg (0.61 mmol; 61%). Mp: 152 °C. MS (EI): m/e
(intensity %) 506 (17) (M)+, 399 (100). Anal. (C27H26N2O6S) C,
1
H, N. H NMR (300 MHz, CDCl3): δ (ppm) 1.77-1.81, 2.00-
2.04, 3.22-3.26, 3.47-3.51, 4.15-4.19 (m, 7H, pyrrolidine-CH/
H2); 3.80 (s, 3H, OCH3); 3.88-3.98 (m, 2H, ArOCH2); 4.86 (s,
2H, NCH2Ar); 6.81-6.98 (m, 6H, ArH, isatin-H); 7.21-7.28 (m,
4H, ArH); 7.95 (dd, 1H, 4JH,H ) 1.5 Hz, 3JH,H ) 8.4 Hz, isatin-H);
4
8.01 (d, 1H, JH,H ) 1.8 Hz, isatin-H). 13C NMR (75 MHz,
CDCl3): δ (ppm) 26.8, 28.7 (pyrrolidine-CH2), 43.6 (NCH2Ar),
49.2, 55.0 (pyrrolidine-CH/CH2), 58.3, 58.4 (CH2O and OCH3),
110.9, 114.0, 114.3 (Ar-C), 117.1 (q-ArC(CO)), 120.7, 123.9, 125.1,
128.7, 129.2 (ArC), 133.8 (q-ArCCH2), 136.7 (q-ArCSO2), 153.0
(q-ArCN(CO)), 157.4, 157.9 (q-ArCO), 159.4 (Ar(CO)(CO)), 181.4
(Ar(CO)(CO)).
(S)-1-(4-Iodobenzyl)-5-[1-(2-phenoxymethylpyrrolidinyl)sul-
fonyl]isatin (26). (S)-5-[1-(2-Phenoxymethylpyrrolidinyl)sulfonyl]-
isatin (8) (385 mg, 1 mmol) was reacted with sodium hydride (40
mg, 1 mmol, 60% in mineral oil) and p-iodobenzyl bromide (445
mg, 1.5 mmol) as described in the general procedure. The crude
dark orange product was purified by silica gel chromatography
(diisopropyl ether:acetone 4:1) to yield an orange solid. Yield: 400
mg (0.66 mmol; 66%). Mp: 88-90 °C. MS (ESI): m/e (intensity
%) 657 (100) (M + MeOH + Na)+, 625 (25) (M + Na)+, 603
(S)-5-[1-(2-Methoxymethylpyrrolidinyl)sulfonyl]-1-(4-(tribu-
tylstannyl)benzyl)isatin (23). (S)-5-[1-(2-Methoxymethylpyrro-
lidinyl)sulfonyl]isatin (7) (324 mg, 1 mmol) was reacted with
sodium hydride (60 mg, 1.5 mmol, 60% in mineral oil) and
p-tributylstannylbenzyl methanesulfonate (22) (680 mg, 1.4 mmol)
as described in the general procedure. The crude orange product
was purified by silica gel chromatography (petroleum ether:ethyl
acetate 4:1) to yield an orange oil. Yield: 378 mg (0.54 mmol,
54%). HRMS (ESI-EM) m/e: 759.2460 (M + Na + CH3OH)+
calcd for C34H52N2NaO6SSn 759.2466. 1H NMR (300 MHz,
CDCl3): δ (ppm) 0.80 (t, 9H, 3JH,H ) 7.5 Hz, SnBu-CH3); 0.94-
1.00, 1.16-1.28, 1.39-1.48 (m, 18H, SnCH2), 1.58-1.61, 1.78-
1.83, 3.02-3.09, 3.45-3.50, 3.64-3.69 (m, 7H, pyrrolidine-CH/
H2); 3.25 (s, 3H, CH3OCH2); 3.27-3.35 (m, 2H, OCH2); 4.87 (s,
2H, NCH2Ar); 6.86 (d, 2H, 3JH,H ) 8.4 Hz, isatin-H); 7.20 (d, 2H,
1
(10) (M + H)+. Anal. (C26H23IN2O5S) C, H, N. H NMR (300
MHz, CDCl3): δ (ppm) 1.71-1.74, 1.91-1.98, 3.13-3.18, 3.39-
3.43, 4.05-4.09 (m, 7H, pyrrolidine-CH/H2); 3.81-3.91 (m, 2H,
ArOCH2); 4.78 (s, 2H, NCH2Ar); 6.72-6.76 (m, 3H, isatin-H and
ArH); 6.83-6.87 (m, 1H, ArH); 6.98-7.01 (m, 2H, ArH); 7.13-
4
7.19 (m, 2H, ArH); 7.61-7.63 (m, 2H, ArH); 7.86 (dd, 1H, JH,H
3
4
) 1.5 Hz, JH,H ) 7.8 Hz, isatin-H); 7.93 (d, 1H, JH,H ) 1.5 Hz,
isatin-H). 13C NMR (100 MHz, CDCl3): δ (ppm) 24.1, 28.9, 49.4,
58.6 (pyrrolidine-CH and CH2), 43.8 (NCH2Ar), 69.1 (OCH2), 94.0
(q-ArCI), 117.4 (q-ArC(CO)), 114.3, 120.9, 124.3, 124.4, 129.2,
129.4, 133.4, 134.4 (ArCH, isatin-CH), 137.0 (qCSO2), 138.3 (q-
ArCCH2), 152.8 (q-CN(CO)), 158.1 (isatin-N(CO)), 181.3 (N(CO)-
CO)).
3
3JH,H ) 7.2 Hz, SnBu3ArH); 7.38 (d, 2H, JH,H ) 7.2 Hz, SnBu3-
4
3
ArH); 7.91 (dd, 1H, JH,H ) 1.8 Hz, JH,H ) 8.4 Hz, isatin-H);
7.97 (d, 1H, JH,H ) 1.8 Hz, isatin-H). 13C NMR (75 MHz,
4
CDCl3): δ (ppm) 9.6 (SnCH2), 13.6 (SnCH2CH2CH2CH3), 27.3
(SnCH2CH2CH2), 28.8 (SnCH2CH2), 24.1, 29.0, 49.3, 59.2 (pyr-
rolidine-CH/CH2), 44.4 NCH2Ar, 60.3 (OCH3), 74.8 (CH2O), 117.5
(q-ArC(CO)), 111.2, 124.4, 126.9, 133.2, 143.0 (q-ArC, ArCH),
137.3 (q-CSO2), 153.4 (q-CN(CO)), 157.8, 158.1 (q-ArCOH, isatin-
N(CO)), 180.0 (N(CO)(CO)).
(S)-1-(4-(2-Bromoethoxy)benzyl)-5-[1-(2-methoxymethylpyr-
rolidinyl)sulfonyl]isatin (29). (S)-5-[1-(2-Methoxymethylpyrro-
lidinyl)sulfonyl]isatin (7) (800 mg, 2.46 mmol) was reacted with
sodium hydride (98 mg, 2.46 mmol, 60% in mineral oil) and p-(2-
bromoethoxy)bromomethylbenzene (28) (1.4 g, 4.92 mmol) as
described in the general procedure. The crude orange product was
purified by silica gel chromatography (petroleum ether:ethyl acetate
3:1 to 1:2) and yielded 29 as a yellow foam. Yield: 1.02 g (1.9
mmol, 77%). Mp: 61-62 °C. MS (EI): m/e (intensity %) 538 (42),
536 (42) (M)+, 493 (100), 491 (100). Anal. (C23H25BrN2O6S) C,
(S)-5-[1-(2-Phenoxymethylpyrrolidinyl)sulfonyl]-1-(4-(tribu-
tylstannyl)benzyl)isatin (24). (S)-5-[1-(2-Phenoxymethylpyrro-
lidinyl)sulfonyl]isatin (8) (385 mg, 1 mmol) was reacted with
sodium hydride (60 mg, 1.5 mmol, 60% in mineral oil) and
p-tributylstannylbenzyl methanesulfonate (22) (1.42 g, 3 mmol) as
described in the general procedure. The crude orange product was
purified by silica gel chromatography (petroleum ether:ethyl acetate
6:1) to yield an orange oil. Yield: 410 mg (0.53 mmol, 53%).
HRMS (ESI-EM) m/e: 821.2592 (M + Na + CH3OH)+ calcd for
C39H54N2NaO6SSn 821.2624. 1H NMR (300 MHz, CDCl3): δ
(ppm) 0.92 (t, 9H, 3JH,H ) 7.5 Hz, SnBu-CH3); 1.07-1.13, 1.31-
1.43, 1.53-1.60 (m, 18H, SnCH2), 1.81-1.89, 2.04-2.11, 3.28-
3.34, 3.50-3.56 (m, 7H, pyrrolidine-CH/H2); 3.94-4.04, 4.19-
1
H, N. H NMR (300 MHz, CDCl3): δ (ppm) 1.66-1.70, 1.86-
1.90, 3.10-3.13, 3.53-3.57, 3.71-3.73 (m, 7H, pyrrolidine-CH/
H2); 3.33 (s, 3H, OCH3); 3.35-3.39 (m, 2H, CH3OCH2); 3.63 (t,
3
3
2H, JH,H ) 5.7 Hz, ArCH2CH2Br); 4.28 (t, 2H, JH,H ) 5.7 Hz,
ArCH2CH2Br); 4.91 (s, 2H, NCH2Ar); 6.89-6.97 (m, 3H, ArH and
isatin-H); 7.27-7.30 (m, 2H, ArH); 7.97 (dd, 1H, 4JH,H ) 1.8 Hz,
3JH,H ) 8.4 Hz, isatin-H); 8.02 (d, 1H, JH,H ) 1.5 Hz, isatin-H).
4
3
4.23 (m, 2H, ArOCH2); 4.94 (s, 2H, NCH2Ar); 6.86 (d, 2H, JH,H
13C NMR (75 MHz, CDCl3): δ (ppm) 24.5, 29.2, 29.4, 49.7, 59.4
(pyrrolidine-CH/ CH2, CH2CH2Br), 44.3 (NCH2Ar), 59.3 (OCH3),
) 8.1 Hz, SnBu3ArH); 6.91-6.99 (m, 2H, ArH); 7.23-7.34 (m,