Amine–Guanidine Switch
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26 6473
1
-Pyrenemethylguanidine Hydrochloride (10). 10 was obtained
from pyrenemethylamine following the general procedure for
guanidylation. Recrystallization from MeOH and Et O gave 10.
Brown solid (yield 56%); mp 271–272 °C; H NMR (300 MHz
1.35–1.52 (m, 2H), 2.74–2.91 (m, 4H), 4.29 (s, 2H), 7.37–7.98 (m,
9H); C NMR (75 MHz, D O) δ 22.64, 24.87, 40.21, 46.34, 47.47,
2
120.88, 122.52, 122.98, 123.16, 124.49, 125.56, 125.68, 126.27,
13
2
1
126.84, 127.88, 128.15, 128.41, 129.66, 130.38, 131.34, 156.44;
1
3
+
CD
CD
3
OD) δ 5.14 (s, 2H), 8.00–8.31 (m, 9H); C NMR (75 MHz
HRMS (FAB) found 345.2053 [M + H] calcd for C22
H
25
N
4
3
OD) δ 44.67, 123.27, 125.72, 126.00, 126.16, 126.64, 126.78,
345.2079.
2
3
1
1
1
27.27, 127.45, 128.38, 128.87, 129.53, 130.01, 130.09, 132.09+,
N ,N -Bis(tert-butoxycarbonyl)-N -[6-[(pyrene-1-ylmethyl)-
amino]hexyl] Guanidine (25). 25 was obtained from 1-amino-6-
[N ,N -bis(tert-butoxycarbonyl)-guanidino]hexane 21 following
32.68, 132.69, 158.69; HRMS (FAB) found 274.1341 [M + H]
2
3
24
calcd for C18
H
16
N
3
274.1344.
[
4-[(Pyrene-1-ylmethyl)amino]butyl]carbamic Acid tert-Bu-
the general procedure for reductive amination. Yellow solid (yield
tyl Ester (19). 19 was obtained from (4-amino-butyl)-carbamic acid
tert-butyl ester following the general procedure for reductive
40%); mp > 100 °C (dec); R
f
) 0.38 (AcOEt/hexane/Et
3
3
N: 40/
4
1
1
60/5); H NMR (300 MHz CDCl ) δ 1.30–1.40 (m, 4H), 1.48 (s,
amination. White solid (yield 59%): mp 105–108 °C; R
f
) 0.27
9H), 1.50 (s, 9H), 1.53–1.67 (m, 4H), 2.77 (t, 2H, J ) 7.2 Hz),
3.38 (dd, 2H, J ) 7.0, 12.4 Hz), 4.48 (s, 2H), 7.94–8.05 (m, 4H),
8.10–8.22 (m, 4H), 8.29 (br t, 1H), 8.35 (d, 1H, J ) 9.3 Hz), 11.5
1
(
(
AcOEt/hexane/Et N: 50/50/5); H NMR (300 MHz CDCl ) δ 1.43
3
3
s, 9H), 1.46–1.70 (m, 4H), 2.43 (br s, 1H), 2.82 (t, 2H, J ) 6.7
1
3
Hz), 3.12 (br dd, 2H), 4.49 (s, 2H), 4.76 (br s, 1H), 7.95–8.06 (m,
3
(s, 1H); C NMR (75 MHz CDCl ) δ 26.85, 27.11, 28.20, 28.45,
1
3
4
H), 8.10–8.24 (m, 4H), 8.35 (d, 1H, J ) 9.2 Hz); C NMR (75
MHz CDCl ) δ 27.20, 27.99, 28.57, 40.52, 49.38, 51.59, 79.21,
23.18, 124.86, 125.00, 125.16, 125.21, 125.30, 126.06, 127.32,
27.58, 127.94, 129.26, 130.94, 130.96, 131.44, 133.08, 156.18;
29.06, 29.80, 40.00, 49.75, 51.63, 79.34, 83.12, 123.20, 124.84,
125.00, 125.16, 125.23, 126.01, 127.24, 127.26, 127.57, 127.87,
3
1
1
129.22, 130.86, 130.95, 131.42, 133.33, 153.45, 156.23, 163.79;
HRMS (FAB) found 573.3431 [M + H] calcd for C34
573.3441.
[6-[(Pyrene-1-ylmethyl)amino]hexyl] Guanidine Dihydrochlo-
ride (15). 15 was obtained from 25 following the general procedure
for HCl salt formation. The resulted residue was washed with Et O
and lyophilized to give 15. Light brown solid (yield 80%); H NMR
+
45 4 4
H N O
+
HRMS (FAB) found 403.2393 [M + H] calcd for C26
4
H
31
N
2
O
2
03.2386.
1
N -(Pyrene-1-ylmethyl)-1,4-diaminobutane Dihydrochloride
13). 13 was obtained from 19 following the general procedure for
HCl salt formation. Light yellow solid (yield 84%); mp > 246 °C
(
2
1
1
(
dec); H NMR (300 MHz D
2
O) δ 1.44–1.67 (m, 4H), 2.85 (t, 2H,
(300 MHz CD OD) δ 1.35–1.55 (m, 4H), 1.62 (qu, 2H, J ) 6.8
3
J ) 7.2 Hz), 2.95 (t, 2H, J ) 7.5 Hz), 4.30 (s, 2H), 7.35–7.99 (m,
Hz), 1.74–1.91 (m, 2H), 3.18 (t, 2H, J ) 7.0 Hz), 3.22–3.29 (m,
1
3
9
1
1
H); C NMR (75 MHz D
2
O) δ 22.65, 23.91, 38.68, 46.47, 47.74,
2H), 5.00 (s, 2H), 8.03–8.25 (m, 4H), 8.26–8.38 (m, 4H), 8.46 (d,
1
3
20.87, 122.49, 122.90, 123.09, 124.44, 125.53, 125.63, 126.24,
1H, J ) 9.3 Hz); C NMR (75 MHz CD OD) δ 27.05, 27.16,
3
26.80, 127.82, 128.09, 128.31, 129.61, 130.34, 131.29; HRMS
27.27, 29.61, 49.08, 49.37, 123.19, 125.56, 125.59, 126.05, 126.15,
+
(
FAB) found 303.1871 [M + H] calcd for C21
H
23
N
2
303.1861.
126.99, 127.22, 127.71, 128.31, 129.74, 129.89, 130.17, 131.10,
2
3
1
N ,N -Bis(tert-butoxycarbonyl)-N -[4-[(anthracene-9-ylmethyl)
amino]butyl] Guanidine (23). 23 was obtained from 1-amino-4-
131.99, 132.64, 133.88, 158.63; HRMS (FAB) found 373.2402 [M
+
+ H] calcd for C24
29 4
H N 373.2392.
2
3
24
2
3
1
[
N ,N -bis(tert-butoxycarbonyl)-guanidino]butane 20 following
N ,N -Bis(tert-butoxycarbonyl)-N -[3-[[4-[(3-aminopropyl)-
amino]butyl]amino]propyl] guanidine (22). To a solution of
spermine (343 mg, 1.70 mmol) in DMF (15 mL) was added
dropwise a solution of N,N′-bis-Boc-thiourea (235 mg, 0.85 mmol)
in DMF (10 mL). The reaction mixtire was stirred for 1.5 h and
the general procedure for reductive amination. Brown oil (yield
1
6
2%); R
MHz, CDCl
t, 2H, J ) 6.7 Hz), 3.38 (br dd, 2H), 4.79 (s, 2H), 7.40–7.51 (m,
H), 7.51–7.60 (m, 2H), 8.00 (d, 2H, J ) 8.4 Hz), 8.34 (d
f
) 0.45 (AcOEt/hexane/Et
3
3
N: 30/70/5); H NMR (300
) δ 1.47 (s, 9H), 1.51 (s, 9H), 1.56–1.73 (m, 4H), 2.87
(
2
diluted with CHCl (20 mL) and brine (20 mL). The organic layer
3
1
3
overlapped by br s, 3H), 8.42 (s, 1H), 11.5 (br s, 1H); C NMR
75 MHz, CDCl ) δ 26.88, 27.10, 28.19, 28.46, 40.64, 45.37, 49.51,
9.53, 83.21, 124.16, 125.14, 126.50, 127.74, 129.32, 130.57,
31.63, 153.41, 156.34, 163.72; HRMS (FAB) found 521.3138,
was separated, dried over Na SO , and concentrated under vacuum.
2
4
(
3
Purification of the resulting residue by silica gel chromatography
1
7
1
(Et N/MeOH 5/95) gave 22. Colorless oil (yield 52%); H NMR
3
(300 MHz CDCl ) δ 1.31–1.55 (m, 22H), 1.55–1.77 (m, 4H),
3
+
[
M + H] calcd for C30
H
41
N
4
O
4
521.3128.
2.48–2.69 (m, 8H), 2.74 (t, 2H, J ) 6.7 Hz), 3.44 (t, 2H, J ) 6.6
1
3
[
4-[(Anthracene-9-ylmethyl)-amino]butyl] guanidine Dihy-
3
Hz), 8.45 (br s, 1H); C NMR (75 MHz CDCl ) δ 27.61, 27.67,
drochloride (12). 12 was obtained quantitatively from 23 following
28.12, 28.36, 29.23, 32.79, 38.99, 40.54, 46.98, 47.81, 49.65, 79.26,
83.07, 153.19, 156.32, 163.57; HRMS (FAB) found 445.3481 [M
1
+
36 °C (dec); H NMR (300 MHz D
O) δ 1.31–1.66 (m, 4H),
+ H] calcd for C21
H
45
O
4
N
6
445.3502.
2
3
1
N ,N -Bis(tert-butoxycarbonyl)-N -[3-[[4-[[3-[(pyrene-1-ylm-
ethyl)-tert-butoxycarbonylamino]propyl]-tert-butoxycarbony-
lamino]butyl]-tert-butoxycarbonylamino]propyl] guanidine (27).
To a solution of compound 22 (140 mg, 0.32 mmol) in MeOH
(0.6 mL) and THF (0.6 mL) was added 1-pyrenecarboxaldehyde
(74 mg, 0.32 mmol) in one portion. The reaction mixture was
allowed to react for 14 h and was then cooled to 0 °C with an ice
bath. After addition of NaBH (34 mg, 0.90 mmol) at 0 °C, the ice
4
bath was removed and the reaction was stirred for 4 h. The mixture
was then diluted with water and AcOEt. The organic layer was
washed with brine, dried over Na SO , and then concentrated in
2
4
vacuo. Purification of the residue by silica gel chromatography
(MeOH/CH Cl /Et N 10/90/5) gave a crude triamine compound 26,
2
2
3
which was used immediately without further purification. To a
solution of crude 26 in CH Cl (2.0 mL) was added a solution of
2
2
2 2 2
Boc O (124 mg, 0.57 mmol) in CH Cl (3.0 mL). The mixture was
stirred for 12 h and then diluted with water and Et O. The organic
2
layer was washed with brine, dried over Na SO , and then
2
4
concentrated in vacuo. Purification of the residue by silica gel
ride (14). 14 was obtained from 24 following the general procedure
for HCl salt formation. Recrystallization of the precipitate from
chromatography (AcOEt/hexane 25/75) gave 27. Colorless oil (yield
1
26% from 22); H NMR (300 MHz CDCl
3
) δ 0.95–1.65 (br m,
MeOH and Et
2
O gave 14. Light yellow solid (yield 81%); mp
51H), 1.65–1.85 (br m, 2H), 2.55–3.54 (br m, 12H), 5.20 (s, 2H),
1
13
2
48–249 °C; H NMR (300 MHz D
2
O) δ 1.19–1.35 (m, 2H),
3
7.80–8.57 (m, 10H), 11.49 (br s, 1H); C NMR (75 MHz CDCl )