S. Codony, et al.
Bioorganic&MedicinalChemistry27(2019)115078
6′-Hax), 3.86 (dm, J = 13.6 Hz, 1H) and 4.67 (dm, J = 13.6 Hz, 1H) (2′-
Heq and 6′-Heq), 4.10 (m, 1H, 4′-H), 7.06 (dd, J = 1.6 Hz, J′ = 0.8 Hz,
1H, 4-H), 7.29 (broad d, J = 7.6 Hz, 1H, NH), 7.60 (dd, J = 1.6 Hz,
J′ = 1.2 Hz, 1H, 5-H), 8.29 (dd, J = 1.2 Hz, J′ = 0.8 Hz, 1H, 2-H). 13C
NMR (100.6 MHz, CDCl3) δ: 21.5 (CH3, COCH3), 31.4 and 33.1 (CH2,
C3′ and C5′), 40.9 and 45.6 (CH2, C2′ and C6′), 48.2 (CH, C4′), 116.2
(CH, C5), 130.3 (CH, C4), 136.2 (CH, C2), 148.5 (C, NHCNH), 169.2 (C,
COCH3). MS (DIP), m/z (%); significant ions: 169 (10), 168 (100), 153
(19), 126 (53), 125 (31), 85 (19), 84 (42), 83 (20), 82 (23), 81 (21), 68
(98), 57 (40), 56 (56), 55 (16). HRMS-ESI+ m/z [M+H]+ calcd for
[C11H16N4O2+H]+: 237.1346, found: 237.1345.
[broad singlet, 2H, 1′(5′)-H], 2.34 (t, J = 6.8 Hz, 1H, 7′-H), 2.74 (dt,
J = 11.2 Hz , J′ = 2.4 Hz, 1H, 2-Hax or 6-Hax), 3.13 (dt, J = 12 Hz,
J′ = 2.4 Hz, 1H, 6-Hax or 2-Hax), 3.71–3.85 (complex signal, 2H, 2-Heq
or 6-Heq and 4-H), 4.43 (d, J = 13.6 Hz, 1H, 6-Heq or 2-Heq), 4.89 (d,
J = 8.0 Hz, 1H, NH), 5.11 (s, 1H, NH). 13C NMR (100.6 MHz, CDCl3) δ:
21.4 (CH3, COCH3), 32.5 (CH2, C4 or C5), 33.7 (CH2, C5 or C4), 34.8
(CH2, C9′), 37.3 [CH, C1′(5′)], 40.7 (CH2, C2 or C6), 43.4 [CH2,
C6′(8′)], 43.7 (CH, C7′), 45.4 (CH2, C6 or C2), 46.7 (CH, C4), 49.30 and
49.32 (CH2, C2′ and C4′), 64.1 (C, C3′), 157.1 (CO, urea), 169.0 (CO,
COCH3). Elemental analysis: Calcd for C17H27N3O2·0.15C5H12: C 67.42,
H 9.18, N 13.29. Found: C 66.38, H 9.00, N 13.05.
4.1.17. 1-(1-Acetylpiperidin-4-yl)-3-(3,7-dimethyl(tricyclo[3.3.0.03,7
]
4.1.19. 1-(1-Acetylpiperidin-4-yl)-3-(diamant-3-yl)urea (26)
octa-1-yl)urea (24)
Diamantane-3-isocyanate (20) (155 mg, 0.67 mmol) was dissolved
in DCM (3 mL) and 1-acetyl-4-aminopiperidine (115 mg, 0.811 mmol)
dissolved in DCM (2 mL) was added. The mixture was stirred at room
temperature overnight. Evaporation of the solvent gave a white solid
(272 mg). Column chromatography (Dichloromethane/Methanol mix-
tures) gave the urea 26 (160 mg, 65% yield) as a white solid, mp
230–231 °C. IR (ATR) ν: 669, 727, 770, 808, 862, 917, 989, 1047, 1136,
1240, 1319, 1364, 1453, 1560, 1629, 1794, 1855, 1893, 1944, 1977,
2051, 2102, 2153, 2209, 2270, 2352, 2418, 2545, 2596, 2734, 2877,
In a round bottom flask equipped with a condenser apparatus and
magnetic stirrer a solution of 3,7-dimethyltricyclo[3.3.0.03,7]octan-1-
amine hydrochloride (5·HCl) (68 mg, 0.36 mmol) in chloroform (5 mL)
was prepared, to which was added N-(1-acetylpiperidin-4-yl)-1H-imi-
dazole-1-carboxamide (23) (172 mg, 0.73 mmol) followed by triethy-
lamine (0.06 mL, 0.40 mmol). The solution was heated to 50 °C for 25 h,
whereupon the reaction mixture was tempered to room temperature
and evaporated in vacuo to dryness (384 mg). Purification by column
chromatography (SiO2, Dichloromethane/Methanol mixture) afforded
24 (90 mg, 77% yield) as a white solid, mp 165–167 °C. IR (ATR) ν:
3359, 3244, 2947, 2878, 2170, 2034, 1960, 1613, 1556, 1477, 1443,
3020, 3071, 3275, 3316, 3494, 3566, 3688 cm−1
.
1H NMR (400 MHz,
CD3OD) δ: 1.32 [complex signal, 2H, 3(5)-Hax], 1.66–1.82 (complex
signal, 16H, diamantane-H), 1.85–1.98 (complex signal, 4H, 3-Heq, 5-
Heq, 2 diamantane-H), 2.10 (s, 3H, COCH3), 2.91 (dt, J = 11.2 Hz,
J′ = 2.8 Hz, 1H, 2-Hax or 6-Hax), 3.25 (dt, J = 11.2 Hz, J′ = 3.2 Hz, 2H,
6-Hax or 2-Hax), 3.71–3.78 (complex signal, 2H, 4-H and 1′-H), 3.85 (dt,
J = 14 Hz, J′ = 2.4 Hz, 2H, 6-Heq or 2-Heq), 4.29 (dt, J = 13 Hz,
J′ = 2.8 Hz, 2H, 2-Heq or 6-Heq). 13C NMR (100.6 MHz, CD3OD) δ: 21.2
(CH3, COCH3), 27.7 (CH), 31.8 (CH), 33.3 (CH2, C3 or C5), 33.4 (CH2),
33.6 (CH2), 34.1 (CH2, C5 or C3), 38.0, 38.1, 38.6, 38.7 (2 carbon),
38.91, 38.94 and 39.0 (3 CH2 and 5 CH, diamantane signals), 41.6
(CH2, C2 or C6), 43.3 (CH, C4′), 46.3 (CH2, C6 or C2), 47.7 (CH, C4),
55.9 (CH, C3′), 159.7 (C, CO urea), 171.5 (C, COCH3). HRMS-ESI+ m/z
[M+H]+ calcd for [C22H33N3O2+H]+: 372.2646, found: 372.2644.
1371, 1318, 1264, 1227, 1151, 1096, 1033, 978, 717, 639 cm−1
.
1H
NMR (400 MHz, CDCl3) δ: 1.11 [s, 6H, 3′(7′)-CH3], 1.22 [complex
signal, 2H, 2(6)-Ha], 1.34 [dd, J = 8.2 Hz, J′ = 3.4 Hz, 2H, 4′(6′)-Ha],
1.54 [dd, J = 7.4 Hz, J′ = 3.4 Hz, 2H, 2′(8′)-Ha], 1.70 [dd, J = 8.2 Hz,
J′ = 2.6 Hz, 2H, 4′(6′)-Hb], 1.75 [d, J = 7.6 Hz, 2H, 2′(8′)-Hb], 1.90 and
2.03 (complex signal, 2H, 3-Hax and 5-Hax), 2.07 (s, 3H, COCH3), 2.27
(t, J = 2.6 Hz, 1H, 5′-H), 2.75 (dt, J = 14.0 Hz, J′ = 2.8 Hz, 1H, 2-Hax
or 6-Hax), 3.14 (dt, J = 11.2 Hz, J′ = 2.8 Hz, 2H, 6-Hax or 2-Hax), 3.73
(broad d, J = 13 Hz, 2H, 6-Heq or 2-Heq), 3.83 (m, 1H, 4-H), 4.42 (broad
d, J = 13 Hz, 2H, 2-Heq or 6-Heq), 4.79 (d, J = 7.6 Hz, 1H, 1-NH), 5.18
(broad s, 1H, 3-NH). 13C NMR (100.6 MHz, CDCl3) δ: 16.5 [CH3,
C3′(7′)-CH3], 21.4 (CH3, COCH3), 33.6 [CH2, C3(5)], 40.6 (CH2, C2),
44.7 (CH, C5′), 45.3 (CH2, C6), 46.1 [C, C3′(7′)], 46.9 (CH, C4), 53.2
[CH2, C4′(6′)], 57.6 [CH2, C2′(8′)], 61.7 (C, C1′), 157.4 (C, CO urea),
169.0 (C, COCH3). MS (DIP), m/z (%); significant ions: 278 (10), 277
(58), 263 (20), 178 (10), 169 (25), 151 (18), 150 (22), 148 (25), 143
(100), 136 (26), 135 (43), 134 (31), 127 (16), 126 (23), 125 (17), 123
(11), 122 (86), 121 (29), 119 (25), 110 (22), 109 (86), 108 (48), 96
(18), 95 (62), 94 (29), 93 (16), 91 (15), 84 (31), 83 (16), 82 (33), 80
(11), 79 (12), 77 (11), 67 (11), 57 (13), 56 (25), 55 (17). Elemental
analysis: Calculated for C18H29N3O2: C 67.68, H 9.15, N 13.15.
Calculated for C18H29N3O2·1.0 H2O: C 64.07, H 9.26, N 12.45. Found: C
64.00, H 9.31, N 12.40.
4.1.20. Diamantane-4-isocyanate (27)
Diamantane-4-amine hydrochloride (9·HCl) (110 mg, 0.458 mmol)
was suspended in DCM (2 mL) and aq. NaHCO3 was added, followed by
triphosgene (68 mg, 0.23 mmol). The biphasic mixture was stirred at
room temperature for 30 min. The two phases were separated and the
organic layer was washed with brine. The organics were dried over anh.
Na2SO4, filtered and evaporated until 1 mL. The solution of isocyanate
(27) in DCM was used in the next step without further purification.
4.1.21. 1-(1-Acetylpiperidin-4-yl)-3-(diamant-4-yl)urea (28)
To the solution of diamantane-4-isocyanate (27) (105 mg,
0.46 mmol) in DCM (1 mL) from the previous step is added 1-acetyl-4-
aminopiperidine hydrochloride (22·HCl) (98 mg, 0.55 mmol) and DCM
(1 mL), followed by Et3N. The mixture was stirred at room temperature
overnight. DCM was added to the mixture and it was washed with 2 N
HCl (30 mL). The organics were dried over anh. Na2SO4, filtered and
evaporated to obtain a residue (48 mg). Column chromatography
(Dichloromethane/Methanol mixture) gave the desired urea (28)
(33 mg, 21% overall yield) as a beige solid, mp 195–196 °C. IR (ATR): ν:
3364, 2906, 2881, 2847, 1686, 1601, 1550, 1480, 1462, 1444, 1429,
1374, 1348, 1322, 1305, 1267, 1221, 1138, 1105, 1048, 1002, 986,
4.1.18. 1-(1-Acetylpiperidin-4-yl)-3-(tricyclo[3.3.1.03,7]non-3-yl)urea
(25)
Under argon atmosphere, tricyclo[3.3.1.03,7]nonane-3-isocyanate
(18) (360 mg, 2.20 mmol) was dissolved in anh. DCM (10 mL). 1-acetyl-
4-aminopiperidine (375 mg, 2.64 mmol) and Et3N (445 mg, 4.40 mmol)
were added. The reaction mixture was stirred at room temperature
overnight. The solvent was removed in vacuo and the residue was dis-
solved in EtOAc and washed with 2 N HCl. The organics were dried over
anh. Na2SO4, filtered and evaporated in vacuo affording a white yel-
lowish solid which was washed with acetone and EtOAc affording the
urea 25 as a yellowish solid (240 mg, 36% yield), mp 164–165 °C. IR
(ATR) ν: 638, 705, 783, 860, 904, 974, 992, 1059, 1139, 1230, 1269,
1318, 1361, 1429, 1555, 1620, 1659, 2351, 2919, 3328 cm−1. 1H NMR
(400 MHz, CDCl3) δ: 1.16–1.29 (complex signal, 2H, 4-Hax and 5-Hax),
1.47–1.61 [complex signal, 4H, 9′-H2 and 6′(8′)-Hax], 1.80 [dd,
J = 10.0 Hz, J′ = 2.8 Hz, 2H, 2′(4′)-Hax], 1.84–2.01 [complex signal,
6H, 6′(8′)-Heq, 2′(4′)-Heq, 4-Heq and 5-Heq], 2.07 (s, 3H, 8-H), 2.23
976, 918, 613, 597, 576 cm−1
.
1H NMR (400 MHz, CDCl3) δ: 1.19
(complex signal, 2H, 3-Hax and 5-Hax), 1.69–1.78 (complex signal, 10H,
diamantane-H), 1.83–1.94 (complex signal, 11H, 3-Heq, 5-Heq, 9 dia-
mantane-H), 2.08 (s, 3H, COCH3), 2.73 (dt, J = 11.6 Hz, J′ = 3.2 Hz, 1
H, 2-Hax or 6-Hax), 3.13 (dt, J = 11.6 Hz, J′ = 3.2 Hz, 2H, 6-Hax or 2-
H
ax), 3.71–3.85 (complex signal, 2H, 4-H and 6-Heq or 2-Heq), 4.36
(broad s, NH, urea), 4.42–4.50 (complex signal, 2H, 2-Heq or 6-Heq and
NH). 13C NMR (100.6 MHz, CDCl3) δ: 21.4 (CH3, COCH3), 25.6 (CH,
7