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(dq, 2H, J = 2.9 Hz, J = 10.2 Hz), 1.43 (s, 9H); 13C
NMR (CDCl3): d 156.4, 140.3, 140.0, 139.7, 129.3,
129.1, 128.9, 128.8, 127.7, 127.6, 126.6, 80.0, 60.5,
52.3, 50.9, 46.9, 33.6, 31.9, 28.8, 9.41; LRMS (ES+) m/
z 424 [(M+H), 100%].
N-(6-Aminohexyl)-N-(1-phenethylpiperidin-4-yl)propi-
onamide (4d). Trifluoroacetate salt of 4d: brownish hygro-
scopic solid (91%); 1H NMR (CD3OD, 300 MHz) d 7.40–
7.20 (m, 5H), 4.34 (t, 0.5H, J = 11.9 Hz), 4.14 (t, 1H,
J = 11.1 Hz), 3.73 (br d, 2H, J = 11.1 Hz), 3.40–2.80 (m,
10H), 2.60–2.10 (m, 5H), 1.96 (m, 2H), 1.80–1.26 (m,
10H), 1.13 (br t, 3H, J = 7.7 Hz); 13C NMR (CD3OD,
75 MHz) d 176.6, 175.97, 137.6, 130.0, 129.8, 128.3,
59.0, 53.6, 53.1, 52.2, 46.2, 42.8, 40.7, 40.6, 31.7, 31.5,
30.1, 28.9, 28.45, 28.37, 27.9, 27.6, 27.5, 27.3, 27 .0, 26.9,
10.0; LRMS (ES+) m/z 360 [(M+H), 100%]; Anal.
(C22H37N3O 1.6 C2F3HO2) Calcd: C, 55.87; H, 7.11; N,
7.76. Found: C, 55.68; H, 6.99; N, 7.20.
C. Acylation with propionic anhydride. Propionic anhy-
dride (1.5 equiv) was added at room temperature to a
0.2 M solution of amine 1b–9b (1 equiv; typical scale:
5–15 mmol), DMAP catalytic (0.1 equiv) and pyridine
(5 equiv) in dry CH2Cl2. The reaction mixture was stir-
red at room temperature until all the starting material
was consumed. The volatiles were removed under vacu-
um and the crude oil dissolved in EtOAc was extracted
successively with satd NH4Cl aqueous solution and
brine, dried (Na2SO4) and concentrated. The purifica-
tion was carried out as outlined for each compound.
N-(3-(Aminomethyl)benzyl)-N-(1-phenethylpiperidin-
4-yl)propionamide (9d). Trifluoroacetate salt of 9d: yel-
1
lowish oil (99%); H NMR (CDCl3): d 7.68–7.40 (m,
9H), 4.85 (s, 0.8H), 4.81 (s, 1.2H), 4.49 (m, 0.6H), 4.32
(s, 1.2H), 4.27 (s, 0.8H), 3.84 (br d, 2H, J = 12.0 Hz),
3.50 (m, 2H), 3.47–3.28 (m, 4H), 2.86 (q, 0.8H,
J = 7.3 Hz), 2.52 (q, 1.2H, J = 7.3 Hz), 2.32 (q, 2H,
J = 12.5 Hz), 2.12 (br d, 2H, J = 12.9 Hz), 1.40 (t,
1.2H, J = 7.3 Hz), 1.28 (t, 1.8H, J = 7.3 Hz); 13C NMR
(CDCl3): d 177.3, 176.8, 141.5, 140.5, 135.3, 134.7,
130.8, 130.3, 129.9, 129.8, 129.1, 128.2, 127.7, 58.9,
53.6, 53.4, 53.1, 51.9, 45.3, 31.4, 29.0, 27.7, 27.5, 9.9,
9.8; LRMS (ES+) m/z 380 [(M+H), 100%]; Anal.
(C28H35F6N3O5Æ4H2O) Calcd: C, 52.56; H, 6.13; N,
6.99. Found: C, 52.09; H, 6.40; N, 6.51.
tert-Butyl {6-[(1-phenethylpiperidin-4-yl)propionylami-
no]hexyl}carbamate (4c). Following method C. Purifica-
tion by chromatography with CH2Cl2–Et3N (0.5%)/
MeOH–NH3(satd) (100:0 ! 98:2) afforded 4c as a colour-
less oil (73%). Rf = 0.34 (4% MeOH in CH2Cl2); Mix-
ture of two conformers as observed by NMR. 1H
NMR (CDCl3, 400 MHz) d 7.30–7.10 (m, 5H), 4.70–
4.40 (m, 1.5H), 3.57 (br, 0.5H), 3.32 (br d, 1.5H),
3.20–3.00 (m, 4H), 3.00–2.85 (m, 2.5H), 2.85–2.60 (m,
2H), 2.53 (br t, 1H), 2.30 (m, 2H), 2.25–1.65 (m, 4H),
1.60–1.20 (m, 17H), 1.10 (t, 3H, J = 7.3 Hz); 13C
NMR (CDCl3, 100 MHz) d 173.9, 172.9, 156.0, 137.6,
128.7, 128.6, 128.4, 126.7, 126.2, 77.9, 60.0, 59.1, 54.8,
53.0, 52.8, 50.1, 43.7, 41.9, 40.3, 33.3, 31.9, 31.3, 30.3,
29.9, 29.5, 28.3, 27.8, 26.8, 26.6, 26.3, 26.2, 9.6, 9.5;
LRMS (ES+) m/z 460 [(M+H), 100%].
E. Synthesis of the Boc-protected guanidines. HgCl2
(190 mg, 0.7 mmol, 1.2 equiv) was added to a solution
of amine 1d–8d (0.58 mmol, 1 equiv), N,N0-di(tert-butoxy-
carbonyl)thiourea(191 mg, 0.7 mmol, 1.2 equiv) and Et3N
(0.4 mL, 2.9 mmol, 5 equiv) in dry CH2Cl2, under a N2
atmosphere. After 3 h stirring at room temperature, the
darkgreyreactionmixturewasdilutedwithCH2Cl2 andfil-
tered on a pad of Celite. The filter cake was rinsed with
CH2Cl2 (2· 15 mL). The combined organic phases were
washed with water, dried (Na2SO4) and concentrated un-
der vacuum. The crude oil was chromatographed on a
short plug of silica (2.5 · 2.5 cm) eluting with cyclohex-
ane/EtOAc (50:50).
tert-Butyl {3-[(N-(1-phenethylpiperidin-4-yl)propion-
amido)methyl]benzyl} carbamate (9c). Method C. The
crude product was pre-purified on silica gel by flash
chromatography eluting with CH2Cl2/MeOH–NH3
(100:0 ! 98:2), then it was purified on silica gel eluting
with CH2Cl2/ Et3N (100:1) to give 9c as a colourless oil
1
(63%); H NMR (CDCl3): d 8.5 (br, 2H), 7.32–7.08 (m,
9H), 4.90–4.0 (m, 5H), 4.12 (br, 2H), 3.80–3.50 (m, 2H),
3.25–2.65 (m, 5H), 2.47 (m, 2H), 2.10–1.70 (m, 3H),
1.30–1.10 (m, 3H). 13C NMR (CDCl3): d 174.7, 155.8,
140.2, 139.6, 139.1, 128.9, 128.6, 128.4, 126.1, 126.0,
125.8, 124.5, 79.6, 60.4, 55.9, 53.1, 51.7, 46.3. 33.8,
29.7, 28.4, 27.1, 9.2; LRMS (ES+) m/z 480 [(M+H),
100%].
N-[N2,N3-(Bis-tert-butoxycarbonyl)guanidinohexyl]-N-
[1-phenethyl-4-piperidyl]propanamide (4e). Yellowish oil
1
(57%); H NMR (CDCl3, 300 MHz) d 11.43 (br, 1H),
8.22 (br, 1H), 7.30–7.05 (m, 5H), 4.40 (m, 0.5H), 3.50
(m, 0.5H), 3.34 (m, 2H), 3.20–2.95 (m, 4H), 2.74 (m, 2H,
1/2 A2B2), 2.54 (m, 2H, 1/2 A2B2), 2.27 (quint, 2H), 2.06
(m, 2H), 1.93–1.57 (m, 4H), 1.55–1.40 (m, 22H), 1.27 (br
m, 4H), 1.08 (m, 3H); 13C NMR (CDCl3, 75 MHz) d
173.6 (s), 172.9 (s), 164.4 (s), 155.9 (s), 153.16 (s), 153.10
(s), 139.8 (s), 128.5 (d), 128.2 (d), 125.9 (d), 82.88 (s),
82.76 (s), 79.06 (s), 78.95 (s), 60.2 (t), 55.0 (d), 53.05 (t),
52.98 (t), 51.1 (d), 43.2 (t), 41.9 (t), 40.7 (t), 40.5 (t), 33.5
(t), 33.4 (t), 31.3 (t), 30.5 (t), 29.5 (t), 29.4 (t), 28.8 (t),
28.4 (t), 28.1 (q), 27.9 (q), 26.72 (t), 26.67 (t), 26.56 (t),
26.49 (t), 26.37 (t), 9.62 (q), 9.46 (q); LRMS (ES+) m/z
602.5 [(M+H)]; Anal (C33H55N5O5) C, H, N.
D. Removal of the Boc-protecting groups with TFA. A
solution of the Boc-protected amine 1c–9c in 50%
TFA/CH2Cl2 was stirred for 30 min at room tempera-
ture. The volatiles were removed under vacuum. Et2O
was added to the crude residue and rotatory evaporation
was repeated. The crude oil was dissolved in a little
quantity of EtOH (ca 5 mL) and Et2O was added until
a precipitate formed. The product was allowed to stand
in the freezer for 2 h. The mother liquor was discarded
and the oily residue that settled at the bottom of the
flask was collected and dried under high-vacuum,
affording the TFA salt of the product as a highly hygro-
scopic solid.
N-[Guanidinohexyl]-N-[1-phenethyl-4-piperidyl]pro-
panamide (4f).11 Following method D (1 h at room