Hatano et al.
JOCArticle
The resulting mixture was quenched by saturatedaqueousNH4Cl
(10 mL), extracted with AcOEt (10 mL ꢀ 3), and washed by brine
(10 mL). The combined extracts were dried over MgSO4. The
organic phase was concentrated under reduced pressure, and the
resultant residue was purified by neutral silica gel column chro-
matography (eluent: n-hexane/AcOEt, v/v = 10/1-5/1) to give
the desired product (2b) (474 mg, 96%).
dried over MgSO4. The organic phase was concentrated under
reduced pressure, and the resultant residue was purified by basic
silica gel column chromatography (eluent: chloroform/MeOH, v/v
= 20/1) to give the desired product (6) (916 mg, >99%): 1H NMR
(400 MHz, CDCl3) δ 0.75 (d, J = 12.8 Hz, 2H), 1.31 (m, 2H), 1.62
(td, J = 12.0, 2.7 Hz, 2H), 2.14 (s, 3H), 2.51 (m, 1H), 2.58 (s, 1H),
2.68 (d, J = 11.1 Hz, 2H), 6.95 (s, 2H), 7.25 (td, J = 7.5, 1.2 Hz,
2H), 7.32 (dd, J = 7.5, 1.5 Hz, 2H), 7.40 (td, J = 8.1, 1.5 Hz, 2H),
7.91 (dd, J= 8.1, 1.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ26.0,
36.1, 46.2, 55.8, 78.3, 125.1, 126.4, 128.6, 129.5, 131.5, 132.3, 141.8;
IR (KBr) 3341, 2931, 2795, 1434, 1377, 1277, 1141 cm-1; HRMS
(FABþ) calcd for C21H22N [M - OH]þ 288.1752, found 288.1758.
Synthesis of Cyproheptadine (7, Scheme 4). To a 30 mL round
flask were added 6 (610 mg, 2.0 mmol) and formic acid (3 mL).
The mixture was heated at 100 °C for 2 h. The resulting mixture
was cooled to 0 °C, diluted with AcOEt (15 mL), and quenched
by aqueous 1 M NaOH. The mixture was extracted with AcOEt
(20 mL ꢀ 3) and washed with brine (10 mL). The combined
extracts were dried over MgSO4. The organic phase was con-
centrated under reduced pressure, and the resultant residue was
purified by basic silica gel column chromatography (eluent:
chloroform/MeOH, v/v = 20/1) to give the desired product
3-Methyl-2-phenylbutan-2-ol (2b): 1H NMR (300 MHz,
CDCl3) δ 0.80 (d, J = 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H),
1.53 (s, 3H), 1.56 (s, 1H), 2.02 (septet, J = 6.9 Hz, 1H), 7.20-7.45
(m, 5H); 13C NMR (75 MHz, CDCl3) δ 17.2, 17.4, 26.7, 38.6,
77.8, 125.2, 126.4, 127.8, 147.8; HRMS (FABþ) calcd for C11H15
[M - OH]þ 147.1174, found 147.1170.
Representative Procedure for ZnCl2-TMSCH2MgCl-LiCl-
Catalyzed Grignard Reaction of Aldehydes (Entries 32-35 in
Table 5). To a Pyrex Schlenk tube was added ZnCl2 (40.8 mg,
0.30 mmol), which was then melt-dried by a heat gun under
reduced pressure (<5 Torr). LiCl (139.9 mg, 3.3 mmol) was
added to the Pyrex Schlenk tube containing melt-dried ZnCl2,
and again the mixture was partially melt-dried by a heat gun
under reduced pressure (<5 Torr). To the mixture was added
(trimethylsilyl)methylmagnesium chloride (1.0 M in Et2O,
0.60 μL, 0.60 mmol) at room temperature. This mixture was
stirred at that temperature for 15 min. i-PrMgBr (0.7 M in THF,
4.71 mL, 3.3 mmol) was added, and the solution was stirred at
that temperature for 45 min. Then, the solution was cooled at
0 °C, and benzaldehyde (305 μL, 3.0 mmol) was added over 1 h
by a syringe pump. The mixture was stirred at 0 °C for 2 h. The
resulting mixture was quenched by saturated aqueous NH4Cl
(10 mL), extracted with AcOEt (10 mL ꢀ 3), and washed by
brine (10 mL). The combined extracts were dried over MgSO4.
The organic phase was concentrated under reduced pressure,
and the resultant residue was purified by neutral silica gel column
chromatography (eluent: n-hexane/Et2O, v/v = 10/1-3/1), to
give the desired product (402 mg, 89%).
1
(7) (575 mg, >99%): H NMR (400 MHz, CDCl3) δ 2.09 (m,
2H), 2.16 (m, 2H), 2.23 (s, 3H), 2.35 (m, 2H), 2.51 (m, 2H), 6.91
(s, 2H), 7.16-7.26 (m, 4H), 7.27-7.35 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 30.1, 46.0, 57.2, 126.2, 127.7, 128.1, 128.4,
130.9, 133.3, 134.7, 135.1, 139.1; HRMS (FABþ) calcd for
C21H21NNa [M þ Na]þ 310.1572, found 310.1570.
Representative Procedure for ZnCl2-TMSCH2MgCl-LiCl-
Catalyzed Grignard Reaction of Aldimines (eqs 7-9). To a Pyrex
Schlenk tube was added ZnCl2 (40.8 mg, 0.30 mmol), which was
melt-dried by a heat gun under reduced pressure (<5 Torr). LiCl
(139.9 mg, 3.3 mmol) was added to the Pyrex Schlenk tube
containing melt-dried ZnCl2, and again the mixture was partially
melt-dried by a heat gun under reduced pressure (<5 Torr). To the
mixture was added (trimethylsilyl)methylmagnesium chloride (1.0
MinEt2O, 0.60 μL, 0.60 mmol) at room temperature. This mixture
was stirred at that temperature for 15 min. i-PrMgBr (0.7 M in
THF, 4.71 mL, 3.3 mmol) was added, and the solution was stirred
at that temperature for 45 min. Under N2 flow conditions, N-phe-
nylbenzylideneamine (547 mg, 3.0 mmol) was added. The mixture
was stirred at room temperature for 24 h, and the reaction was
monitored by TLC. The resulting mixture was quenched by satu-
rated aqueous NH4Cl (10 mL), extracted with AcOEt (10 mL ꢀ 3),
and washed with brine (10 mL). The combined extracts were dried
over MgSO4. The organic phase was concentrated under reduced
pressure, and the resultant residue was purified by neutral silica gel
column chromatography (eluent: n-hexane/Et2O, v/v = 25/1-10/1)
to give the desired product (507 mg, 75%).
2-Methyl-1-phenylpropan-1-ol (entry 33 in Table 5): 1H NMR
(400 MHz, CDCl3) δ 0.78 (d, J = 6.6 Hz, 3H), 0.98 (d, J =
6.6 Hz, 3H), 1.92 (septet, J = 6.6 Hz, 1H), 2.26 (bs, 1H), 4.31 (d,
J = 6.9 Hz, 1H), 7.22-7.26 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 18.2, 19.0, 35.2, 80.0, 126.5, 127.3, 128.1, 143.6; HRMS
(FABþ) calcd for C10H13 [M - OH]þ 133.1017, found 133.1020.
Synthesis of 5-(1-Methyl-4-piperidyl)-5H-dibenzo[a,d]cyclo-
hepten-5-ol (6, Scheme 4). To a Pyrex Schlenk tube were added
magnesium turnings (365 mg, 15 mmol), which were dried by a
heat gun under reduced pressure (<5 Torr). N2 was charged
into the Pyrex Schlenk tube, and a piece of I2 (<5 mg) was
added. The mixture was vigorously stirred at room temperature
for 2 h. Then THF (30 mL) and 4-chloro-1-methylpiperidine
(2.0 g, 15 mmol) were added. The mixture was heated at reflux
temperature for 5 h. The solution of (1-methylpiperidin-4-yl)-
magnesium chloride was titrated prior to use against a solution
of 1,10-phenanthoroline/n-BuLi/s-BuOH in benzene. To a Pyrex
Schlenk tube was added ZnCl2 (40.8 mg, 0.30 mmol), which
was melt-dried by a heat gun under reduced pressure (<5 Torr)
within 5 min. LiCl (139.9 mg, 3.3 mmol) was added to the Pyrex
Schlenk tube containing melt-dried ZnCl2, and again the
mixture was partially melt-dried by a heat gun under reduced
pressure (<5 Torr) within 5 min. To the mixture was added
(trimethylsilyl)methylmagnesium chloride (1.0 M in Et2O,
0.60 μL, 0.60 mmol) at room temperature. This mixture was
stirred at that temperature for 15 min. (1-Methylpiperidin-4-yl)-
magnesium chloride (0.5 M in THF, 6.6 mL, 3.3 mmol) was
added, and the solution was stirred at that temperature for 45 min.
Then, the solution was cooled at 0 °C, and 5-dibenzosuberenone
(1c) (619 mg, 3.0 mmol) was added in one portion. The mixture was
stirred at 0 °C for 2 h. The resulting mixture was quenched by
saturated aqueous NH4Cl (10 mL), extracted with AcOEt (10 mL
ꢀ 3), and washed by brine (10 mL). The combined extracts were
N-(2-Methyl-1-phenylpropyl)aniline (eq 7): 1H NMR (400
MHz, CDCl3) δ 0.91 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz,
3H), 2.03 (octet, J = 6.9 Hz, 1H), 4.12 (br, 2H), 6.49 (d, J = 7.2 Hz,
2H), 6.60 (t, J = 7.2 Hz, 1H), 7.05 (t, J = 7.2 Hz, 2H), 7.17-7.34
(m,5H);13C NMR (100 MHz, CDCl3) δ18.5, 19.6, 34.8, 63.6, 113.1,
116.9, 126.7, 127.1, 128.1, 129.0, 142.5, 147.6; HRMS (FABþ) calcd
for C16H19NNa [M þ Na]þ 248.1415, found 248.1416.
Acknowledgment. Financial support for this project was
provided by JSPS KAKENHI (20245022), MEXT KAKEN-
HI (21750094, 21200033), and the Global COE Program of
MEXT. S.S. acknowledges a JSPS Fellowship for Japanese
Junior Scientists.
Supporting Information Available: General information,
characterization data, and copies of 1H and 13C NMR spectra
for products. This material is available free of charge via the
5016 J. Org. Chem. Vol. 75, No. 15, 2010