1490 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 10
Bergeron et al.
N1,N8-Dip r op ylsp er m id in e Tr ih yd r och lor id e (14). HBr
(30% in HOAc, 150 mL), 49 (8.32 g, 10.7 mmol), and phenol
(28 g, 0.29 mol) in CH2Cl2 (125 mL) were reacted, and product
was isolated by the procedure of 2 to produce 2.58 g (71%) of
14 as white plates: NMR (D2O) δ 0.97 and 0.98 (2 t, 6 H, J )
7), 1.63-1.83 (m, 8 H), 2.06-2.19 (m, 2 H), 2.97-3.21 (m, 12
H). Anal. (C13H34Cl3N3) C, H, N.
(50 mL) were reacted and worked up using the procedure of
43. Column chromatography (4:1 hexane/EtOAc) gave 1.26 g
(89%) of 52 as an oil: NMR δ 0.74 (t, 6 H, J ) 7), 1.26-1.45
(m, 12 H), 2.29 (s, 9 H), 2.55 (s, 18 H), 2.98-3.13 (m, 12 H),
6.87 (s, 6 H). Anal. (C41H63N3O6S3) C, H, N.
N1,N9-Dipr opylh om osper m idin e Tr ih ydr och lor ide (19).
HBr (30% in HOAc, 30 mL), 52 (1.24 g, 1.56 mmol), and phenol
(5.4 g, 57 mmol) in CH2Cl2 (25 mL) were reacted, and product
was isolated by the procedure of 2 to give 430 mg (78%) of 19
as plates: NMR (D2O) δ 0.98 (t, 6 H, J ) 7), 1.70 (m, 4 H),
1.76-1.80 (m, 8H), 3.02 (t, 4 H, J ) 7), 3.08-3.12 (m, 8 H).
Anal. (C14H36Cl3N3) C, H, N.
N-(3-Cya n op r op yl)m esitylen esu lfon a m id e (36). NaH
(60%, 2.0 g, 50 mmol), 3533 (10.0 g, 50 mmol), and 4-bromobu-
tyronitrile (4 mL, 40 mol) in DMF (100 mL) were combined.
The mixture was heated at 80 °C overnight and worked up by
the procedure of 43. Column chromatography (4:3 hexane/
EtOAc) gave 5.04 g (38%) of 36 as an oil: NMR δ 1.78 (s, 3 H),
2.25 (s, 3 H), 2.35 (t, 2 H, J ) 7), 2.95 (q, 2 H), 5.05 (br t, 1 H),
6.90 (s, 2 H). Anal. (C13H18N2O2S) C, H, N.
N-(4-Cya n obu tyl)-N-(3-cya n op r op yl)m esitylen esu lfon -
a m id e (38). NaH (60%, 0.90 g, 23 mmol), 36 (5.02 g, 18.85
mmol), and 5-bromovaleronitrile (2.4 mL, 21 mmol) in DMF
were combined and worked up by the method of 43. Column
chromatography (1:1 hexane/EtOAc) provided 5.20 g (79%) of
38 as an oil: NMR δ 1.49-1.66 (m, 4 H), 1.82 (m, 2 H), 2.22 (t,
2 H, J ) 7), 2.25 (t, 2 H, J ) 7), 2.29 (s, 3 H), 2.57 (s, 6 H),
3.19 (t, 2 H, J ) 7), 3.29 (t, 2 H, J ) 7), 6.95 (s, 2 H). Anal.
(C18H25N3O2S) C, H, N.
N,N′-Bis(4-p h th a lim id obu tyl)m esitylen esu lfon a m id e
(37). NaH (60%, 1.6 g, 40 mmol) was added to 3533 (2.72 g,
13.5 mmol) in DMF (60 mL) at 0 °C. After the mixture was
stirred at 0 °C for 30 min, N-(4-bromobutyl)phthalimide (11.51
g, 40 mmol) in DMF (20 mL) was introduced. The mixture
was stirred at room temperature for 1 h and at 60 °C
overnight. Following the workup procedure of 43, column
chromatography (25:1 CHCl3/acetone) gave 3.77 g (46%) of 37
as a white powder: NMR δ 1.51-1.54 (m, 8 H), 2.18 (s, 3 H),
2.57 (s, 6 H), 3.18-3.24 (m, 4 H), 3.55-3.60 (m, 4 H), 6.86 (s,
2 H), 7.69-7.25 (m, 4 H), 7.82-7.85 (m, 4 H); HRMS calcd for
C33H36N3O6S 602.2325 (M + H), found 602.2320 (M + H).
N,N′-Bis(4-am in obu tyl)m esitylen esu lfon am ide (40). Hy-
drazine monohydrate (0.82 g, 16 mmol) was added to a
suspension of 37 (3.5 g, 5.8 mmol) in absolute EtOH (100 mL),
and the mixture was stirred at 65 °C for 24 h. After cooling
the solid was filtered and washed with EtOH (2 × 10 mL).
The combined filtrate was concentrated and purified by column
chromatography (6:1 MeOH/concentrated NH4OH) to produce
1.50 g (76%) of 40 as a viscous oil: NMR δ 1.37 (quintet, 4 H),
1.52 (quintet, 4 H), 2.30 (s, 3 H), 2.54 (t, 4 H, J ) 7), 2.58 (s,
6 H), 3.20 (t, 4 H, J ) 7), 7.04 (s, 3 H).
Hom osp er m id in e Tr ih yd r och lor id e (15). HBr (30% in
HOAc, 30 mL), 40 (1.50 g, 4.39 mmol), and phenol (4.49 g, 48
mmol) in CH2Cl2 (20 mL) were reacted, and product was
isolated by the procedure of 2 to afford 0.86 g (73%) of 15 as
white crystals: NMR (D2O) δ 1.73-1.80 (m, 8 H), 3.03-3.14
(m, 8 H). Anal. (C8H24Cl3N3) C, H, N.
6-(Mesit ylen esu lfon yl)-1,6,12-Tr ia za d od eca n e
(41).
Raney nickel (W-2 grade, 7.60 g) and concentrated NH4OH
(10 mL) were successively added to 38 (5.06 g, 14.6 mmol) in
CH3OH (30 mL) and THF (30 mL) in a 200 mL Parr bottle,
and a slow stream of NH3 was bubbled through the mixture
for 30 min at 0 °C. After hydrogenation in a Parr bottle was
carried out at 50-55 psi for 8 h, the suspension was filtered
through Celite, and the solvents were removed in vacuo to give
4.70 g (91%) of 41 as an oil: NMR δ 1.14-1.24 (m, 10 H), 2.25
(s, 3 H), 2.6 (s, 6 H), 3.05-3.25 (m, 8 H), 3.45 (s, 4 H), 6.9 (s,
2 H).
1,6,12-Tr ia za d od eca n e Tr ih yd r och lor id e (20). HBr
(30% in HOAc, 33 mL), 41 (2.43 g, 6.83 mmol), and phenol (6
g, 60 mmol) in CH2Cl2 were reacted, and product was isolated
by the procedure of 2 to give 0.97 g (50%) of 20 as a hygroscopic
solid: NMR (D2O) δ 1.47 (m, 2 H), 1.70-1.80 (m, 8 H), 3.00-
3.10 (m, 8 H). Anal. (C9H26Cl3N3) C, H, N.
1,6,12-Tr is(m e sit yle n e su lfon yl)-1,6,12-Tr ia za d od e -
ca n e (33). Mesitylenesulfonyl chloride (4.29 g, 19.6 mmol)
and 41 (3.17 g, 8.92 mmol) in CH2Cl2 (40 mL) and 1 N NaOH
(20 mL) were combined and worked up by the method of 31.
Column chromatography (4:3 hexane/EtOAc) generated 5.66
g (88%) of 33 as an oil: NMR δ 1.12-1.17 (m, 2 H), 1.34-1.51
(m, 8 H), 2.29 (s, 3 H), 2.30 (s, 6 H), 2.55 (s, 6 H), 2.60-2.62
(2s, 12 H), 2.77-2.81 (m, 4 H), 3.06 (t, 2 H, J ) 7), 3.11 (t, 2
H, J ) 7), 4.50-4.60 (m, 2 H), 6.92 (s, 2 H), 6.95 (s, 2 H). Anal.
(C36H53N3O6S3) C, H, N.
N1,N5,N9-Tr is(m esitylen esu lfon yl)h om osper m idin e (32).
Mesitylenesulfonyl chloride (6.71 g, 30.7 mmol) and 40 (4.76
g, 14 mmol) in CH2Cl2 (30 mL) and 1 N NaOH (35 mL) were
combined and worked up by the method of 31. Column
chromatography (4:1 toluene/EtOAc) produced 3.06 g (31%) of
32 as a white foam: NMR δ 1.32-1.38 (m, 4 H), 1.44-1.54
(m, 4 H), 2.28-2.29 (2 s, 9 H), 2.54 (s, 6 H), 2.60 (s, 12 H),
2.79 (quartet, 4 H), 3.09 (t, 4 H, J ) 7), 4.70-4.80 (br s, 2 H),
6.90 (s, 2 H), 6.92 (s, 4 H). Anal. (C35H51N3O6S3) C, H, N.
N1,N9-Dim et h yl-N1,N5,N9-t r is(m esit ylen esu lfon yl)h o-
m osp er m id in e (50). NaH (60%, 0.17 g, 4.2 mmol), 32 (1.28
g, 1.8 mmol), and iodomethane (0.25 mL, 4.0 mmol) in DMF
(50 mL) were reacted and worked up as was 43. Column
chromatography (2:1 toluene/EtOAc) gave 1.14 g (86%) of 50
as an oil: NMR δ 1.38-1.44 (m, 8 H), 2.28 (s, 3 H), 2.30 (s, 6
H), 2.57 (s, 18 H), 2.62 (s, 6 H), 3.03-3.14 (m, 8 H), 6.93-6.94
(2 s, 6 H). Anal. (C37H55N3O6S3) C, H, N.
N1,N9-Dim eth ylh om osper m idin e Tr ih ydr och lor ide (16).
HBr (30% in HOAc, 30 mL), 50 (1.12 g, 1.52 mmol), and phenol
(5.4 g, 57 mmol) in CH2Cl2 (25 mL) were reacted, and product
was isolated by the procedure of 2 to provide 354 mg (79%) of
16 as plates: NMR (D2O) δ 1.78 (m, 8 H), 2.73 (s, 6 H), 3.08-
3.12 (m, 8 H). Anal. (C10H28Cl3N3) C, H, N.
2,7,13-Tr is(m esit ylen esu lfon yl)-2,7,13-Tr ia za t et r a d e-
ca n e (53). NaH (60%, 0.28 g, 6.9 mmol), 33 (2.16 g, 3.0 mmol),
and iodomethane (6.1 mL, 9.8 mmol) in DMF (30 mL) were
combined and worked up by the method of 43. Column
chromatography (7:3 hexane/EtOAc) gave 1.90 g (85%) of 53
as an oil: NMR δ 1.08-1.16 (m, 2 H), 1.38-1.50 (m, 8 H),
2.28-2.29 (2s, 9 H), 2.57-2.58 (2 s, 18 H), 2.63 (s, 3 H), 2.65
(s, 3 H), 3.02-3.14 (m, 8 H), 6.95 (s, 6 H); HRMS calcd for
C38H58N3O6S3 748.3487 (M + H), found 748.3483 (M + H).
2,7,13-Tr ia za tetr a d eca n e Tr ih yd r och lor id e (21). HBr
(30% in HOAc, 45 mL), 53 (1.85 g, 2.47 mmol), and phenol
(8.5 g) in CH2Cl2 (20 mL) were reacted, and product was
isolated by the procedure of 2 to give 529 mg (69%) of 21 as
crystals: NMR (D2O) δ 1.42-1.52 (m, 2 H), 1.69-1.81 (m, 8
N1,N9-Dieth yl-N1,N5,N9-tr is(m esitylen esu lfon yl)h om o-
sp er m id in e (51). NaH (80%, 0.264 g, 8.8 mmol) was added
to 3533 (0.796 g, 4 mmol) in DMF (60 mL) at 0 °C. After the
mixture was stirred at 0 °C for 30 min, 5815 (3.19 g, 8.8 mmol)
in DMF (15 mL) was added. The mixture was heated at 75
°C overnight and worked up by the procedure of 43. Column
chromatography (3:1 hexane/EtOAc) gave 2.82 g (93%) of 51
as an oil: NMR δ 0.96 (t, 6 H), 1.20-1.40 (m, 8 H), 2.25 (s, 9
H), 2.55 (s, 18 H), 2.85-3.20 (m, 12 H), 6.90 (s, 6 H). Anal.
(C39H59N3O6S3) C, H, N.
N1,N9-Dieth ylh om osp er m id in e Tr ih yd r och lor id e (17).
HBr (30% in HOAc, 20 mL), 51 (1.87 g, 2.45 mmol), and phenol
(4.4 g, 49 mmol) in CH2Cl2 (20 mL) were reacted, and product
was isolated by the procedure of 2 to give 493 mg (62%) of 17
as plates: NMR (D2O) δ 1.30 (s, 6 H), 1.55-1.90 (m, 8 H), 2.95-
3.20 (m, 12 H). Anal. (C12H32Cl3N3) C, H, N.
H), 2.73-2.74 (2 s, 6 H), 3.03-3.12 (m, 8 H). Anal. (C11H30
Cl3N3) C, H, N.
-
4,9,15-Tr is(m esit ylen esu lfon yl)-4,9,15-Tr ia za oct a d e-
ca n e (54). NaH (60%, 0.273 g, 6.84 mmol), 33 (2.24 g, 3.11
mmol), and 1-iodopropane (0.67 mL, 6.9 mmol) in DMF (30
mL) were combined and worked up by the method of 43.
Column chromatography (3:1 hexane/EtOAc) provided 2.01 g
N1,N9-Dip r op yl-N1,N5,N9-t r is(m esit ylen esu lfon yl)h o-
m osp er m id in e (52). NaH (60%, 0.17 g, 4.2 mmol), 32 (1.28
g, 1.8 mmol), and 1-iodopropane (0.39 mL, 4.0 mmol) in DMF