H.-J. Lee et al. / Tetrahedron xxx (2018) 1e7
5
3.81e3.79 (m, 1H), 3.20 (dt, J ¼ 12.5, 4.0 Hz, 1H), 3.07 (tt, J ¼ 12.5,
3.0 Hz, 1H), 2.00e1.87 (m, 3H), 1.77e1.67 (m, 2H), 1.62e1.53 (m,
d 174.0, 173.7, 145.7, 128.3, 126.6, 126.2, 51.7, 51.7, 43.7, 41.9, 39.3,
35.2, 33.0, 24.3; IR (neat) 3026, 2949, 1727, 1601, 1494, 1434, 1194,
1156, 1023, 898, 756, 699 cmꢂ1; HRMS (ESI) calcd for C16H20O4Na:
299.1254 ([M þ Na]þ), found: 299.1256.
1H); 13C NMR (125 MHz, DMSO-d6)
d 146.6, 128.2, 126.6, 125.7,
122.3 (q, 1JC,F ¼ 334.0 Hz), 52.0, 51.9, 35.6, 35.6, 31.4, 25.0; IR (neat)
3085, 2948, 1591, 1509, 1449, 1221, 1197, 1147, 1065, 999, 803, 746,
696 cmꢂ1; HRMS (ESI) calcd for C13H18O2N2F3S: 323.1036 ([M þ
H]þ), found: 323.1044.
4.2.8. Hydrolysis of dimethyl ester 16 and 17
To a solution of 17 (0.14 g, 0.5 mmol) in THF (2.0 mL) was added a
2 M aqueous solution of LiOH (2.5 mL, 10 mmol) at room temper-
ature. The mixture was stirried at 40 ꢀC for 10 h. The solution was
diluted with water and extracted with CH2Cl2. The aqueous layer
was acidified to pH 2 with 6 M aqueous solution of HCl and
extracted with ethyl acetate. The combined organic layer was dried
over Na2SO4 and concentrated in vacuo. The solid was washed with
cold CH2Cl2. After the dryness, crude 10 was obtained as a white
solid (0.10 g, 82% yield). For the cis isomer 18: (83% yield): White
4.2.4.2. N-((1S,2R,4S)-2-amino-4-phenylcyclohexyl)-1,1,1-
trifluoromethanes-ulfonamide (8). (47% yield): White solid; M.p.
23
84.5e85.5 ꢀC; [
a
]
¼ ꢂ39.4 (c ¼ 0.8, MeOH); 1H NMR (500 MHz,
D
CD3OD)
d
7.28e7.22 (m, 4H), 7.16 (t, J ¼ 7.0 Hz, 1H), 3.58e3.54 (m,
1H), 3.42e3.40 (m, 1H), 2.81e2.74 (m, 1H), 2.06e1.92 (m, 2H),
1.89e1.81 (m, 2H), 1.71e1.58 (m, 2H); 13C NMR (125 MHz, CD3OD)
d
146.3, 129.5, 127.8, 127.4, 123.1 (q, 1JC,F ¼ 327.5 Hz), 55.8, 55.2, 37.4,
36.8, 33.3, 30.3; IR (neat) 3087, 2933, 1602, 1495, 1453, 1372, 1189,
1079, 973, 754, 698 cmꢂ1; HRMS (ESI) calcd for C13H18O2N2F3S:
323.1036 ([M þ H]þ), found: 323.1030.
solid; M.p. 188e189 ꢀC; 1H NMR (500 MHz, DMSO-d6)
d 12.14 (brs,
2H), 7.27 (t, J ¼ 7.5 Hz, 2H), 7.18e7.15 (m, 3H), 3.09e3.06 (m, 1H),
2.59e2.52 (m, 2H), 2.15 (dq, J ¼ 13.0, 3.0 Hz, 1H), 1.99e1.87 (m, 2H),
1.74e1.62 (m, 2H),1.45 (qd, J ¼ 13.0, 3.0 Hz, 1H); 13C NMR (125 MHz,
4.2.5. Synthesis of 15
DMSO-d6) d 174.7, 174.6, 146.6, 128.3, 126.5, 126.0, 42.5, 42.4, 40.2,
To a solution of maleic anhydride (0.98 g, 10 mmol) in toluene
(33 mL) was added 2-phenyl-1,3-butadiene 14 (1.30 g, 10 mmol) at
room temperature. The mixture was stirred at 100 ꢀC for 48 h and
concentrated in vacuo. The residue was dissolved in MeOH (16 mL)
and treated with conc. H2SO4 (0.67 mL). The mixture was stirred at
50 ꢀC for 10 h and concentrated in vacuo. The residue was purified
by silica gel column chromatography (ethyl acetate/hexane ¼ 1:9 as
eluent) to afford dimethyl ester 15 as colorless oil (2.05 g, 75%
31.5, 29.3, 28.0; IR (neat) 3029, 2955, 2594, 1694, 1447, 1422, 1345,
1223, 922, 749, 697 cmꢂ1; HRMS (ESI) calcd for C14H16O4Na:
271.0941 ([M þ Na]þ), found: 271.0942.
4.2.9. Curtius rearrangement of 18
To a solution of 18 (1.24 g, 5.0 mmol) in THF (12.5 mL) was added
Et3N (2.1 mL, 15 mmol) and diphenylphosphoryl azide (2.2 mL,
10.5 mmol) at 0 ꢀC. The mixture was stirred at room temperature
for 4 h. After quenched with NaHCO3, the mixture was extracted
with Et2O and washed with brine. The organic phase was dried over
Na2SO4 and concentrated in vacuo. The oil was dissolved in toluene
(12.5 mL) and stirred at 80 ꢀC for 30 min. After refluxed at 120 ꢀC for
1 h, the mixture was concentrated in vacuo and treated with a 6 M
aqueous solution of HCl (25 mL) at 0 ꢀC. The mixture was stirred at
90 ꢀC for 12 h and then concenterated in vacuo. The residue was
dissolved in ethyl acetate and the precipitate was filtered off. After
the dryness, crude desired product was obtained as a white solid
(1.06 g, 81% yield): M.p. 236e237 ꢀC; 1H NMR (500 MHz, DMSO-d6)
yield): 1H NMR (500 MHz, CDCl3)
d 7.39e7.38 (m, 2H), 7.31 (t,
J ¼ 7.5 Hz, 2H), 7.23 (t, J ¼ 7.5 Hz, 2H), 6.07e6.05 (m, 1H), 3.71 (s,
3H), 3.70 (s, 3H), 3.22e3.19 (m, 1H), 3.13e3.10 (m, 1H), 3.01e2.96
(m, 1H), 2.79e2.72 (m, 2H), 2.58e2.53 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 173.5,173.5,141.2,135.0,128.2,127.0,125.1,122.2, 51.9, 51.8,
40.3, 39.4, 27.9, 26.4; IR (neat) 3023, 2950, 1728, 1434, 1199, 1167,
1025, 994, 746, 695 cmꢂ1; HRMS (ESI) calcd for C16H18O4Na:
297.1097 ([M þ Na]þ), found: 297.1101.
4.2.6. Catalytic hydrogenation for cis-isomer 16
To a solution of 15 (55 mg, 0.2 mmol) in THF (2.0 mL) was added
Pd/BaSO4 (6 mg) at room temperature. The mixture was stirred
under 1 atm of hydrogen gas for 2 h. The catalyst was filtered
through a pad of celite. After removal of the solvent, purification by
silica gel column chromatography (ethyl acetate/hexane ¼ 1:10 as
eluent), 16 was obtained as colorless oil (51 mg, 93% yield, 20.2:1
d 8.66 (brs, 6H), 7.35e7.28 (m, 4H), 7.22e7.19 (m, 1H), 3.76e3.74 (m,
1H), 3.57e3.53 (m, 1H), 2.75e2.69 (m, 1H), 2.08e2.04 (m, 1H),
2.00e1.84 (m, 4H), 1.59e1.55 (m, 1H); 13C NMR (125 MHz, DMSO-
d6)
(neat) 3417, 2924, 2606, 1601, 1518, 1452, 1159, 1057, 1030, 760,
700 cmꢂ1
d 144.8, 128.3, 126.9, 126.4, 50.5, 47.7, 41.5, 31.0, 27.2, 25.1; IR
.
dr): 1H NMR (500 MHz, CDCl3)
d 7.30e7.27 (m, 2H), 7.22e7.17 (m,
3H), 3.70 (s, 3H), 3.68 (s, 3H), 3.32e3.29 (m, 1H), 2.63e2.59 (m, 1H),
2.57e2.51 (m, 1H), 2.36e2.32 (m, 1H), 2.25e2.20 (m, 1H), 2.10e2.03
(m, 1H), 1.80e1.74 (m, 1H), 1.73e1.68 (m, 1H), 1.48 (dq, J ¼ 12.5,
4.2.10. Resolution of rac-19ꢃ2HCl
To a solution of crude rac-19ꢃ2HCl (1.31 g, 5.0 mmol) in water
(12.5 mL) was added NaOH (0.66 g, 16.5 mmol) at room tempera-
ture. The mixture was extracted with CH2Cl2, dried over Na2SO4 and
concentrated in vacuo. The solid was dissolved in MeOH (25 mL)
and added to a solution of (S,S)-benzoyltartaric acid (1.79 g,
5.0 mmol) in EtOH (25 mL) at 0 ꢀC. The mixture was stirred at room
temperature for overnight. Then, the precipitate was filtered off and
washed with cold EtOH. The white solid was re-suspended in
MeOH/CHCl3 (1:2) and the mixture was stirred at 70 ꢀC for 1 h. After
cooled to 0 ꢀC, the precipitate was filtered off and washed with
CHCl3. The process was repeated three times, and the optically pure
(1S,2R,4R)-19ꢃ(S,S)-DBTA was obtained as a white solid. This solid
was suspended CH2Cl2 (100 mL), basified with 2 M aqueous solu-
tion of NaOH (25 mL) and extracted with CH2Cl2. The organic layer
was dried over Na2SO4 and concentrated in vacuo to afford optically
3.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d 173.9, 173.7, 146.0, 128.3,
126.7, 126.1, 51.7, 51.6, 43.9, 43.5, 40.7, 31.3, 29.6, 28.3; IR (neat)
3026, 2949, 1727, 1600, 1494, 1434, 1196, 1145, 1022, 778, 700 cmꢂ1
;
HRMS (ESI) calcd for C16H20O4Na: 299.1254 ([M þ Na]þ), found:
299.1252.
4.2.7. Catalytic hydrogenation for trans isomer 17
To a solution of 15 (55 mg, 0.2 mmol) in CH2Cl2 (2.0 mL) was
added Crabtree's catalyst (24 mg, 0.03 mmol) at room temperature.
The mixture was stirred under 1 atm of hydrogen gas for 72 h. After
removal of the solvent and purification by silica gel column chro-
matography (ethyl acetate/hexane ¼ 1:15 as eluent), 17 was ob-
tained almost exclusively as colorless oil (49 mg, 89% yield): 1H
NMR (500 MHz, CDCl3)
d
7.31e7.28 (m, 2H), 7.21e7.18 (m, 3H), 3.71
pure (1S,2R,4R)-4-phenylcyclohexane-1,2-diamine (19) as a color-
23
(s, 6H), 3.41e3.39 (m, 1H), 2.63e2.56 (m, 1H), 2.54e2.49 (m, 1H),
2.41e2.36 (m, 1H), 2.19e2.14 (m, 1H), 2.06e1.97 (m, 2H), 1.75 (td,
J ¼ 13.0, 5.0 Hz, 1H), 1.52e1.43 (m, 1H); 13C NMR (125 MHz, CDCl3)
less oil (0.794 g, 29% yield): [
1H NMR (500 MHz, CD3OD)
3.02e3.00 (m, 1H), 2.85 (dt, J ¼ 12.0, 3.5 Hz, 1H), 2.61e2.54 (m, 1H),
a
]
¼ þ9.9 (c ¼ 0.5, MeOH; 99% ee);
D
d
7.27e7.21 (m, 4H), 7.16e7.11 (m, 1H),
Please cite this article in press as: Lee H-J, et al., Practical synthesis of four different pseudoenantiomeric organocatalysts with both cis- and
trans-substituted 1,2-cis-cyclohexanediamine structures from
j.tet.2018.05.035