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M.-Y. Chang et al. / Tetrahedron 68 (2012) 3283e3287
4.3. 4-Methyl-N-(5-oxo-10,11-dihydro-5H-dibenzo[a,d]
cyclohepten-10-yl)-benzenesulfonamide (4)
Found: C, 73.81; H, 5.82, N, 4.03. Single-crystal X-ray diagram:
crystal of compound 6 was grown by slow diffusion of EtOAc into
a solution of compound 6 in DCM to yield colorless prism. The
compound crystallizes in the orthorhombic crystal system, space
Palladium on activated carbon (10%, 10 mg) was added to a so-
lution of compound 3 (375 mg, 1.0 mmol) in MeOH (40 mL) at rt.
Then hydrogenwas bubbled into the mixture for 10 min, and stirring
occurred at rt for 10 h. The reaction mixture was filtered and evap-
orated to yield crude product. Purification on silica gel (hexanes/
EtOAc¼4/1e2/1) afforded compound 4 (336 mg, 89%) as a white
solid. Mp¼157e158 ꢁC (recrystallized from hexanes and EtOAc);
HRMS (ESI, Mþþ1) calcd for C22H20NO3S 378.1164, found 378.1162;
ꢀ
ꢀ
ꢀ
group P 1 21/n 1, a¼9.6183(4) A, b¼11.5389(5) A, c¼16.8837(8) A,
3
V¼1869.27(14) A , Z¼4, Dcalcd¼1.334 g/cm3, F(000)¼792, 2
q
range
ꢀ
2.14e26.50ꢁ, R indices (all data) R1¼0.0673, wR2¼0.1356.
4.6. 5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-
5,10-imine (1, dizocilpine)
1H NMR (400 MHz, CDCl3):
d
7.93 (dd, J¼1.6, 7.6 Hz, 1H), 7.85 (dd,
Mg (48 mg, 2.0 mmol) was added to a mixture of compound 6
(75 mg, 0.2 mmol) in MeOH (10 mL) at rt. Then, Et3N (1.0 mL) was
added to the reaction mixture at rt. The reaction mixture was
stirred at reflux for 10 h. The reaction mixture was cooled to rt. The
solvent was evaporated under vacuum to give crude product. A
mixture of the resulting crude product in MeOH (5 mL) and aque-
ous maleic acid solution (70 mg, 0.6 mmol, 5 mL) was refluxed for
10 h. The solvent was evaporated under reduced pressure and the
resulting residue was triturated in the co-solvent of dioxane-DCM
(v/v¼1/1, 10 mL) yielding dizocilpine-meleate 1 (53 mg, 79%) as
a colorless solid. The 1H NMR spectral data were in accordance with
those reported in the literature.3b 1H NMR (400 MHz, CDCl3/
J¼1.6, 7.6 Hz,1H), 7.64 (d, J¼8.4 Hz, 2H), 7.43e7.32 (m, 4H), 7.27e7.21
(m, 3H), 6.87 (d, J¼7.2 Hz, 1H), 4.93 (dt, J¼1.6, 8.4 Hz, 1H), 4.78 (d,
J¼8.4 Hz, 1H), 3.44 (d, J¼15.2 Hz, 1H), 3.16 (dd, J¼6.4, 15.2 Hz, 1H),
2.43 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 194.2, 143.6, 139.9, 139.0,
137.6, 137.1, 134.2, 132.9, 132.6, 131.0, 130.9, 123.0, 129.8, 129.6 (2ꢀ),
128.3, 127.6, 127.1 (2ꢀ), 55.8, 39.2, 21.5; Anal. Calcd for C22H19NO3S:
C, 70.00; H, 5.07; N, 3.71. Found: C, 70.32; H, 5.20, N, 3.93.
4.4. N-(5-Hydroxy-5-methyl-10,11-dihydro-5H-dibenzo[a,d]
cyclohepten-10-yl)-4-methyl-benzenesulfonamide (5)
A solution of methylmagnesium bromide (1.0 M in THF, 2 mL,
2.0 mmol) was added to a stirred solution of compound 4 (189 mg,
0.5 mmol) in THF (10 mL) at ice bath. The reaction mixture was
stirred at rt for 10 h. Water (5 mL) was added to the reaction
mixture and the mixture was filtered through a short plug of Celite.
The filtrate was concentrated under reduced pressure. The residue
was extracted with EtOAc (3ꢀ50 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to afford
crude product under reduced pressure. Purification on silica gel
(hexanes/EtOAc¼4/1e2/1) afforded compound 5 (136 mg, 69%) as
a white solid with cis-form isomer and trans-form isomer (a ratio of
1:1). HRMS (ESI, Mþþ1) calcd for C23H24NO3S 394.1477, found
CD3OD): d 7.45e7.43 (m, 1H), 7.36e7.22 (m, 5H), 7.18e7.16 (m, 1H),
7.10e7.08 (m,1H), 6.14 (s, 2H), 5.28 (d, J¼5.6 Hz,1H), 3.76 (dd, J¼5.6,
17.6 Hz,1H), 3.01 (d, J¼17.6 Hz,1H), 2.21 (s, 3H); 13C NMR (100 MHz,
CDCl3/CD3OD):
d
169.4 (2ꢀ), 144.7, 137.4, 136.0 (2ꢀ), 135.3 (2ꢀ),
130.1,129.3 (2ꢀ), 129.0, 127.2, 122.5, 121.8,119.1, 66.9, 57.8, 31.7,17.2.
4.7. 5-Methyl-10,11-dihydro-5H-5,10-epoxydibenzo[a,d][7]
annulen-11-yl-4-methyl-benzenesulfonamide (7)
A solution of methylmagnesium bromide (1.0 M in THF, 4 mL,
4.0 mmol) was added to a stirred solution of compound 3 (375 mg,
1.0 mmol) in THF (10 mL) at ice bath. The reaction mixture was
stirred at rt for 10 h. Water (5 mL) was added to the reaction
mixture and the mixture was filtered through a short plug of Celite.
The filtrate was concentrated under reduced pressure. The residue
was extracted with EtOAc (3ꢀ20 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to afford
crude product under reduced pressure. Purification on silica gel
(hexanes/EtOAc¼4/1e1/1) afforded compound 7 (313 mg, 80%) as
a white solid. Mp¼112e113 ꢁC (recrystallized from hexanes and
EtOAc); HRMS (ESI, Mþþ1) calcd for C23H22NO3S 392.1320, found
394.1452; One isomer: 1H NMR (400 MHz, CDCl3):
d
7.93 (dd, J¼1.2,
8.4 Hz, 1H), 7.82e7.79 (m, 2H), 7.75e7.71 (m, 2H), 7.42e7.05 (m,
6H), 6.82 (dd, J¼1.6, 6.8 Hz, 1H), 5.20 (dt, J¼4.4, 13.6 Hz, 1H), 4.70 (d,
J¼9.2 Hz, 1H), 3.69 (dd, J¼4.0, 14.8 Hz, 1H), 3.03e2.97 (m, 1H), 2.48
(s, 3H), 2.36 (s, 1H), 2.05 (s, 3H). Another isomer 1H NMR (400 MHz,
CDCl3): 7.82e7.79 (m, 2H), 7.75e7.71 (m, 2H), 7.60 (dd, J¼1.6, 7.6 Hz,
1H), 7.42e7.05 (m, 6H), 6.75 (dd, J¼1.2, 7.6 Hz, 1H), 4.90 (ddd, J¼4.0,
6.0, 9.6 Hz, 1H), 4.61 (d, J¼9.6 Hz, 1H), 3.53 (dd, J¼3.6, 14.8 Hz, 1H),
3.03e2.97 (m, 1H), 2.46 (s, 3H), 2.21 (s, 1H), 1.79 (s, 3H).
392.1329; 1H NMR (400 MHz, CDCl3):
d
7.91 (d, J¼8.4 Hz, 2H), 7.40
4.5. 12-(4-Methylphenylsulfonyl)-5-methyl-10,11-dihydro-5H-
dibenzo[a,d]cyclohepten-5,10-imine (6)
(d, J¼8.4 Hz, 2H), 7.22e7.19 (s, 1H), 7.15e7.10 (m, 5H), 7.03e7.00 (m,
1H), 6.96e6.94 (m, 1H), 5.37 (d, J¼9.2 Hz, 1H), 5.10 (s, 1H), 4.23 (d,
J¼9.2 Hz, 1H), 2.47 (s, 3H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3):
A solution of BF3$OEt2 (142 mg, 1.0 mmol) in DCM (5 mL) was
added to a stirred solution of the compound 5 (393 mg,1.0 mmol) in
DCM (50 mL) at 0 ꢁC. The reaction mixture was stirred at rt for 10 h.
Saturated aqueous NaHCO3 solution (10 mL) was added to the re-
action mixture and the solvent was concentrated under reduced
pressure. The residue was extracted with EtOAc (3ꢀ30 mL). The
combined organic layers were washed with brine, dried, filtered,
and evaporated to afford crude product under reduced pressure.
Purification on silica gel (hexanes/EtOAc¼4/1e2/1) afforded com-
pound 6 (290 mg, 77%) as a white solid. Mp¼200e201 ꢁC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for
C23H22NO2S 376.1371, found 376.1376; 1H NMR (400 MHz, CDCl3):
d
150.7, 143.8, 143.7, 139.2, 138.3, 131.1, 130.8, 130.0 (2ꢀ), 128.2,
128.0, 127.9, 127.2 (2ꢀ), 127.1, 121.9, 120.8, 118.6, 83.5, 82.4, 53.5,
21.6, 18.9; Anal. Calcd for C23H21NO3S: C, 70.56; H, 5.41; N, 3.58.
Found: C, 70.76; H, 5.80, N, 3.65. Single-crystal X-ray diagram:
crystal of compound 7 was grown by slow diffusion of EtOAc into
a solution of compound 7 in CHCl3 to yield colorless prism. The
compound crystallizes in the monoclinic crystal system, space
ꢀ
ꢀ
ꢀ
group P 1 21/n 1, a¼10.1969(5) A, b¼19.8386(7) A, c¼11.9163(5) A,
V¼2408.62(18) A , Z¼4, Dcalcd¼1.406 g/cm3, F(000)¼1052, 2
q
range
3
ꢀ
1.99e26.39ꢁ, R indices (all data) R1¼0.1233, wR2¼0.2404.
4.8. N-(4-Methylphenylsulfonyl)-10,11-dihydro-5-hydroxy-
dibenzo[a,d]cyclohepten-10,11-aziridine (8)
d
7.58 (d, J¼8.4 Hz, 2H), 7.30 (d, J¼6.4 Hz,1H), 7.21e6.96 (m, 8H), 6.69
(d, J¼7.6 Hz, 1H), 5.50 (d, J¼5.6 Hz, 1H), 3.57 (dd, J¼5.6, 17.6 Hz, 1H),
2.64 (d, J¼17.6 Hz, 1H), 2.30 (s, 3H), 2.14 (s, 3H); 13C NMR (100 MHz,
NaBH4 (103 mg, 3.0 mmol) was added to a solution of compound
3 (375 mg, 1.0 mmol) in the co-solvent of MeOH (10 mL) and THF
(5 mL) at rt. The reaction mixture was stirred at rt for 10 h. Satu-
rated aqueous NaHCO3 solution (2 mL) was added to the reaction
CDCl3):
d
149.7, 142.7, 141.7, 140.0, 138.6, 131.7, 130.1, 128.9 (2ꢀ),
127.4,127.3 (2ꢀ),127.2 (2ꢀ),126.1,121.4,121.0,118.3, 67.5, 62.0, 33.2,
21.4, 18.0; Anal. Calcd for C23H21NO2S: C, 73.57; H, 5.64; N, 3.73.