1576
Vol. 56, No. 11
Table 1. Synthesis of Compounds
Table 2. Crystal Data and Structure Refinement for (4c)
Compound
R1
R2
mp (°C)
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
a (Å)
C28H38N2O
418.60
293(2)
0.71073
Trigonal
P65
13.0880(19)
13.0880(19)
25.097(5)
90.00
90.00
120.00
3723.0(11)
1.117
0.067
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
H
H
Ph
195.8
234.6
227.8
152.1
226.2
245.5
208.8
2,5-(CH3)2Ph
p-FPh
o-FPh
2,6-F2Ph
3,5-F2Ph
b (Å)
c (Å)
4g
a (°)
4h
244.4
b (°)
g (°)
V (Å3)
4i
240.4
Density (calculated) (mg mꢁ3
)
)
4j
4k
H
H
iso-Pr
Bu
197.5
171.6
Absorption coefficient (mmꢁ1
F (0 0 0)
1362.0
Crystal size (mm)
q range for data collection (°)
Limiting indices
0.40ꢄ0.20ꢄ0.10
1.80 to 26.00
0ꢅhꢅ13, 0ꢅkꢅ13,
ꢁ30ꢅlꢅ30
30.14 (2C, CH–C); 38.13, 37.79, 35.82, 19.64, 18.95 (5C, CH2–C); 25.01,
24.01, 20.94 (4C, CH3).
4e: C26H33FN2O, IR (cmꢁ1): 3369 (N–H); 2958 (–CH3, –CH2); 1639
(OꢂC–N); 823 (Ar-H); 1H-NMR: (CDCl3, d/ppm, 300 MHz), 7.97—6.87
(7H, CꢂCH–); 6.58 (1H, –NHCO); 4.81 (1H, CO–NH–); 2.82 (1H,
–CH(Me)2); 2.91—1.48 (10H, –CH2–); 1.34 (1H, ꢃCH–); 1.24—1.21 (12H,
–CH3). 13C-NMR: (CDCl3, d/ppm, 300 MHz), 153.81 (1C, CꢂO); 154.47,
146.74, 145.63, 134.52, 127.59, 126.83, 124.45, 123.89, 122.94, 122.84,
121.81, 114.97 (12C, CꢂC); 47.46 (1C, C–N); 33.47 (1C, C–C); 57.31,
30.18 (2C, CH–C); 38.22, 37.72, 19.67, 18.95 (5C, CH2–C); 25.07, 24.01,
23.98, 21.01 (4C, CH3).
Reflections collected/unique
[Rintꢂ0.057]
5492/4852
Completeness to qꢂ25.99 (%)
Max. and min. transmission
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [Iꢃ2s(I)]
wR2ꢂ0.327
99.9
0.9736, 0.9933
4852/4/295
1.001
R1ꢂ0.105
R indices (all data)
R1ꢂ0.1044, wR2ꢂ0.1735
ꢁ5(6)
0.31, ꢁ0.25
4f: C26H32F2N2O, IR (cmꢁ1): 3353 (N–H); 2954 (–CH3, –CH2); 1645
(OꢂC–N); 823 (Ar-H); 1H-NMR: (CDCl3, d/ppm, 300 MHz), 7.33—6.74
(7H, CꢂCH–); 6.07 (1H, –NHCO); 4.51 (1H, CO–NH–); 2.83 (1H,
–CH(Me)2); 2.93—1.69 (10H, –CH2–); 1.32 (1H, ꢃCH–); 1.25—1.21 (12H,
–CH3). 13C-NMR: (CDCl3, d/ppm, 300 MHz), 154.57 (1C, CꢂO); 163.01,
159.78, 146.72, 145.62, 138.04, 134.45, 131.19, 126.79, 124.28, 123.90,
Absolute structure parameter
Largest diff. peak and hole (e·Aꢁ3
)
R1ꢂ∑||Fo|ꢁ|Fc||/∑|Fo|; wR2ꢂ∑[w(Fo2ꢁFc2)2/∑[w(Fo )2]1/2
.
2
116.38, 110.44 (12C, CꢂC); 47.31 (1C, C–N); 33.46 (1C, C–C); 57.12, 18.85 (5C, CH2–C); 25.07, 24.04, 23.98, 23.39, 23.32, 21.29 (6C, CH3).
30.13 (2C, CH–C); 38.17, 37.69, 19.66, 18.98 (5C, CH2–C); 25.02, 24.01,
23.98, 20.99 (4C, CH3).
4k: C25H39N2O, IR (cmꢁ1): 3326 (N–H); 2953 (–CH3, –CH2); 1633
(OꢂC–N); 819 (Ar-H); 1H-NMR: (CDCl3, d/ppm, 300 MHz), 7.14—6.84
(3H, CꢂCH–); 4.32 (1H, –NHCO); 3.78 (1H, –NHCO); 2.82 (1H,
4g: C26H32F2N2O, IR (cmꢁ1): 3362 (N–H); 2955 (–CH3, –CH2); 1628
(OꢂC–N); 826 (Ar-H); 1H-NMR: (CDCl3, d/ppm, 300 MHz), 7.28—6.86 –CH(Me)2); 2.87—1.46 (16H, –CH2–); 1.44 (1H, ꢃCH–); 1.45—1.08 (15H,
(6H, CꢂCH–); 6.65 (1H, –NHCO); 4.87 (1H, CO–NH–); 2.81 (1H,
–CH3). 13C-NMR: (CDCl3, d/ppm, 300 MHz), 157.27 (1C, CꢂO); 146.06,
–CH(Me)2); 2.93—1.68 (10H, –CH2–); 1.34 (1H, ꢃCH–); 1.31—1.19 (12H, 144.32, 133.75, 125.77, 123.26, 122.69 (6C, CꢂC); 46.26 (1C, C–N); 32.45
–CH3). 13C-NMR: (CDCl3, d/ppm, 300 MHz), 155.11 (1C, CꢂO); 146.79, (1C, C–C); 55.03, 31.55 (3C, CH–C); 38.56, 37.14, 36.90, 36.82, 29.25,
145.54, 139.24, 134.53, 129.02, 126.79, 124.29, 123.84, 122.93, 120.28
19.07, 18.83, 17.85 (8C, CH2–C); 24.11, 22.99, 20.28,12.84 (5C, CH3).
(12C, CꢂC); 47.45 (1C, C–N); 33.47 (1C, C–C); 56.84, 30.15 (2C, CH–C);
X-Ray Crystallography The crystal structure of 4c was determined by
38.13, 37.77, 37.70, 19.65, 18.95 (5C, CH2–C); 25.04, 24.03, 23.99, 20.88 X-ray single crystal diffraction. XRD data were collected on a Enraf-Nonius
(4C, CH3).
CAD-4 diffractometer equipped with MoKa (lꢂ0.07103) at 293 K. A sin-
4h: C25H38N2O, IR (cmꢁ1): 3358 (N–H); 2955 (–CH3, –CH2); 1626
gle crystal suitable for determination was mounted inside a glass fiber capil-
(OꢂC–N); 1529 (CꢂC); 832 (Ar-H); 1H-NMR: (CDCl3, d/ppm, 300 MHz), lary. The structure of the title compound was solved by direct methods and
7.183—6.875 (3H, CꢂCH–); 4.203 (4H, CONCH2–); 3.682 (4H, OCH2–);
3.290 (4H, NCH2–); 3.237 (1H, –CH(Me)2); 2.829—1.725 (10H, –CH2–);
1.357 (1H, ꢃCH–); 1.278—1.222 (12H, –CH3). 13C-NMR: (CDCl3, d/ppm,
refined by full-matrix least squares on F2. All the hydrogen atoms were
added in their calculated positions and all the non-hydrogen atoms were re-
fined with anisotropic temperature factors. SHELXS97 were used to solve
300 MHz), 156.73 (1C, CꢂO); 146.93, 145.49, 134.45, 126.70, 124.14, the structure and SHELTL were used to refine the structure.11,12) The crystal-
123.76 (6C, CꢂC); 47.04 (1C, C–N); 33.39 (1C, C–C); 56.72, 30.12 (2C, lographic details are summarized in Table 2. The selected bond lengths and
CH–C); 47.04, 45.15, 44.53, 38.09, 37.79, 37.61, 19.72, 18.84 (10C, angles are shown in Table 3.
CH2–C); 23.90, 22.22, 21.37 (4C, CH3).
Pharmacology Test compounds 4a—c were evaluated in vitro, for cyto-
toxicity in SMMC7721 liver cancer cell lines at 1, 10, 15, 25 and 50 mmol/l
4i: C24H36N2O2, IR (cmꢁ1): 3358 (N–H); 2955 (–CH3, –CH2); 1626
(OꢂC–N); 832 (Ar-H); 1H-NMR: (CDCl3, d/ppm, 300 MHz), 7.18—6.87 concentrations using MTT assay, respectively.13)
(3H, CꢂCH–); 4.20 (4H, CONCH2–); 3.68 (4H, O–CH2–); 3.29 (4H,
NCH2–); 3.23 (1H, –CH(Me)2); 2.82—1.72 (10H, –CH2–); 1.35 (1H,
ꢃCH–); 1.28—1.22 (12H, –CH3). 13C-NMR: (CDCl3, d/ppm, 300 MHz),
Results and Discussion
Synthesis As shown in Chart 1, a series of unsymmetri-
cally N,Nꢀ-substituted ureas were synthesized from DHA
through 4 steps of reactions. Although high steric hindrance
156.71 (1C, CꢂO); 146.85, 145.64, 134.40, 126.78, 124.24, 123.89 (6C,
CꢂC); 47.41 (1C, C–N); 33.46 (1C, C–C); 57.02, 30.17 (2C, CH–C); 66.53,
44.24, 43.45, 38.19, 37.78, 19.73, 18.94 (9C, CH2–C); 24.92, 24.03, 21.19
(4C, CH3).
4j: C23H36N2O, IR (cmꢁ1): 3356 (N–H); 2961 (–CH3, –CH2); 1633 of tricycle hydrophethane structure to the carboxylic acid (1),
(OꢂC–N); 826 (Ar-H); 1H-NMR: (CDCl3, d/ppm, 300 MHz), 7.15—6.85
the reaction activity was greatly improved by conversion of
the acid group to chloride intermediate. Previous study re-
vealed that PCl3 is the best chloride reagent. (2) can be ob-
tained from chloride in the presence of NH4OH at room tem-
perature. Through Hoffman degrading reaction, isocyanate
(3H, CꢂCH–); 4.30 (1H, –NHCO); 3.06 (1H, –NHCO); 2.79 (1H,
–CH(Me)2); 2.86—1.67 (10H, –CH2–); 1.43 (2H, ꢃCH–); 1.31—0.88 (18H,
–CH3). 13C-NMR: (CDCl3, d/ppm, 300 MHz), 157.40 (1C, CꢂO); 147.06,
145.35, 134.73, 126.77, 124.30, 123.71 (6C, CꢂC); 47.23 (1C, C–N); 33.46
(1C, C–C); 56.15, 41.48, 30.31 (3C, CH–C); 38.15, 37.94, 37.85, 19.81,