Double Elimination Protocol
2000 2004
ature for 2 h, aqueous NH4Cl was poured into the mixture. After usual
work-up with 1n HCl and CH2Cl2, the solvent was evaporated in vacuo, and
the residue was subjected to filtration through a thin pad (silica gel;
CH2Cl2) and recrystallization from CH2Cl2/hexane gave 2 (1.01 g, 78%) as
closed that the final elimination took place completely
(Scheme 7), the yield in the one-pot process [61% in
Scheme 1, Eq. (1)] is recognized as being reminiscent of the
yields of the respective steps.
Now, we are in a position to obtain enough amount of 1 and
thus synthetic utilization of this compound is undertaken in
our laboratories.
1
colorless needles. M.p. 143 1458C; H NMR (300 MHz, CDCl3): d 5.03
(s, 2H,), 7.43 7.48 (m, 3H), 7.55 7.63 (m, 3H), 7.69 7.75 (m, 3H), 9.83 (s,
1H); 13C NMR (75 MHz, CDCl3): d 57.67, 128.68 (2C), 128.82, 128.85
(2C), 129.49, 133.57, 133.83, 133.88, 134.49, 134.61, 138.20, 192.04; MS (EI):
calcd for 260.0507, found: 260.0510 [M] .
Synthesis of 1 from 2: A 100 mL flask was charged with 2 (260 mg,
1.0 mmol), ClP(O)(OEt)2 (0.17 mL, 1.2 mmol) and THF (30 mL), and
LiHMDS (1.0m in THF, 2.0 mL, 2.0 mmol) was added at À788C. After the
mixture had been stirred at À788C for 30 min and, then, at room
temperature for 1.5 h, LDA (1.0m in THF/hexane, 5.0 mL, 5.0 mmol) was
added dropwise at À788C. The reaction mixture was stirred at this
temperature for 2 h, and aqueous NH4Cl was poured into the mixture.
After usual work-up with water and AcOEt, the solvent was evaporated in
vacuo, and the residue was purified by chromatography (CH2Cl2/hexane
2:3) to give 1 (61 mg, 61%) as a yellow solid. 1H NMR (300 MHz, CDCl3):
d 6.71 6.77 (m, 4H), 6.90 6.96 (m, 4H); 13C NMR (75 MHz, CDCl3): d
109.28, 126.68, 129.01, 132.83.
Experimental Section
General: All reactions were carried out under an atmosphere of nitrogen
with freshly distilled solvents, unless otherwise noted. Tetrahydrofuran
(THF) was distilled from sodium/benzophenone. A THF solution of
LiHMDS was purchased from Aldrich and used without titration. A
hexane solution of BuLi was purchased from Aldrich and titrated before
use by Gilman method.[20] A THF/hexane solution of LDA was prepared
from diisopropylamine and a hexane solution of BuLi. Silica gel (Daiso gel
IR-60) was used for column chromatography. NMR spectra were recorded
at 258C on Varian Gemini-300, JEOL Lambda300 and JEOL Lambda500
instruments and calibrated with tetramethylsilane (TMS) as an internal
reference. Mass spectra were recorded on JEOL MStation JMS-700
Shimadzu/Kratos MALDI 4 and Platform II single quadrupole (Micro-
mass, Altrinchan, UK) mass spectrometers. Elemental analyses were
performed by the Perkin Elmer PE2400.
Synthesis of 4: A 100 mL flask was charged with 2 (260 mg, 1.0 mmol),
ClP(O)(OEt)2 (0.17 mL, 1.2 mmol) and THF (30 mL), and LiHMDS (1.0m
in THF, 2.0 mL, 2.0 mmol) was added at À788C. After the mixture had
been stirred at À788C for 30 min and, then, at room temperature for 1.5 h,
the reaction mixture was poured into aqueous NH4Cl. After usual work-up
with water and AcOEt, the solvent was evaporated in vacuo, and the
residue was purified by chromatography (AcOEt/hexane 3:7) to give 4
(157 mg, 65%) as a pale yellow foam. 1H NMR (300 MHz, CDCl3): d
6.97 6.99 (m, 2H), 7.22 7.30 (m, 4H), 7.36 7.50 (m, 12H), 7.61 7.66 (m,
2H); 13C NMR (75 MHz, CDCl3): d 126.89, 128.03, 128.28, 128.81, 128.92,
129.30, 130.70, 133.83, 135.55, 138.79, 138.81, 144.64; elemental analysis
calcd (%) for C28H20O4S2: C 69.40, H 4.16; found: C 69.22, H 4.14.
Recrystallization from AcOEt/EtOH/hexane (2:2:1) gave single crystals
suitable for X-ray analysis: m.p. 195 1998C.
X-ray structure determination: X-ray diffraction measurements were made
on crystals of the appropriate size, which were mounted onto a glass fiber
and transferred to a Rigaku-RAXIS-IV automatic diffractometer using
graphite monochromated MoKa radiation for unit cell determination and
data collection. The data were corrected for Lorentz and polarization
effects. The structures were solved by direct methods (SAPI91)[21] and
subsequently refined by difference Fourier techniques (DIRDIF94).[22] The
non-hydrogen atoms were refined anisotropically. The hydrogen atoms
were found by successive Fourier difference maps and refined. All
calculations were performed using the teXsan crystallographic software
package.[23]
Synthesis of 1 from 4: A 100 mL flask was charged with 4 (485 mg,
1.0 mmol) and THF (30 mL), and LDA (1.0m in THF/hexane, 4.0 mL,
4.0 mmol) was added dropwise at À788C. The reaction mixture was stirred
at this temperature for 2 h, and aqueous NH4Cl was poured into the
mixture. After usual work-up with water and AcOEt, the solvent was
evaporated in vacuo, and the residue was purified by chromatography
(CH2Cl2/hexane 2:3) to give 1 (199 mg, 99%) as a yellow solid.
CCDC-173591 (4) and -173592 (5b) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge via
tallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; (fax:
(44)1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk).
Synthesis of 5a: A 100 mL flask was charged with 2 (260 mg, 1.0 mmol),
PhCOCl (0.14 mL, 1.2 mmol) and THF (30 mL), and LiHMDS (1.0m in
THF, 1.0 mL, 1.0 mmol) was added at À788C. After the mixture had been
stirred at À788C for 30 min and, then, at room temperature for 1.5 h,
aqueous NH4Cl was added. After usual work-up with water and AcOEt,
the solvent was evaporated in vacuo, and the residue was purified by
chromatography (AcOEt/hexane 3:7) to give 5a (256 mg, 82%, 7:3 anti/syn
mixture) as a white solid. 1H NMR (300 MHz, CDCl3): d 4.59, 4.88
(major)/5.95, 5.97 (minor) (each AB, JAB 14.5 (major), 15.8 Hz (minor),
2H), 5.04 (major)/6.41 (minor) (d, J 3.5 Hz (major); s (minor), 1H), 6.24
(major)/6.74 (minor) (d, J 3.5 Hz (major); s (minor), 1H), 6.51 (major) (s,
1H), 6.95 7.95 (major)/7.05 8.24 (minor) (m, 23H (major); m, 24H
(minor)); 13C NMR (75 MHz, CDCl3) (major): d 59.06, 66.93, 70.54,
89.43, 125.71, 126.39, 127.92, 128.27, 128.30, 128.38, 128.56, 128.81, 128.95,
129.14, 129.28, 129.38, 129.88, 130.21, 131.08, 133.51, 133.61, 133.68, 133.82,
137.08, 137.21, 138.67, 165.11; (minor): d 66.96, 69.31, 71.63, 90.31, 124.64,
126.30, 127.79, 128.25, 128.46, 128.55, 128.66, 128.74, 129.00, 129.20, 129.36,
129.50, 129.73, 129.88, 130.35, 131.20, 132.42, 133.03, 133.51, 133.62, 133.14,
134.33, 134.50, 136.30, 137.17, 137.39, 139.18, 165.13, 190.38; elemental
analysis calcd (%) for C35H28O7S2: C 67.29, H 4.52; found: C 67.53, H 4.49.
Preparation of 2
i) a-Bromotolunitrile: A 100 mL flask was charged with ortho-tolunitrile
(2.37 mL, 20.0 mmol), N-bromosuccinimide (3.74 g, 21.0 mmol), AIBN
(328 mg, 2.0 mmol), and CCl4 (30 mL). After the mixture had been stirred
at 808C for 5 min and at 908C for 2 h, the reaction mixture was cooled to
room temperature and filtered. The filtrate was washed with aqueous
NaHCO3, dried over MgSO4 and filtered. The solvent was evaporated in
vacuo, and the residue was purified by chromatography (AcOEt/hexane
1:9) to give a-bromotolunitrile (3.14 g, 80%) as a white solid. 1H NMR
(500 MHz, CDCl3): d 4.64 (s, 2H), 7.43 (dt, J 1.6, 7.5 Hz, 1H), 7.55 7.63
(m, 2H), 7.68 (d, J 7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 29.30,
112.36, 116.70, 128.90, 130.41, 133.13, 133.22, 141.05.
ii) ortho-(Phenylsulfonylmethyl)benzonitrile: A 100 mL flask was charged
with a-bromotolunitrile (3.92 g, 20.0 mmol), benzenesulfinic acid sodium
salt dihydrate (4.80 g, 24.0 mmol), and DMF (30 mL). After the mixture
had been stirred at 808C for 2 h, the reaction mixture was cooled to room
temperature. After usual work-up with water and ethyl acetate, the solvent
was evaporated in vacuo, and the residue was subjected to recrystallization
from AcOEt/hexane to give ortho-(phenylsulfonylmethyl)benzonitrile
1
p-Nitrobenzote 5b was prepared according to the same procedure, and
single crystals were obtained by recrystallization from EtOH/AcOEt/
CH3CN (2:1:1). X-ray analysis of this single crystal suggested that the major
product of benzoate was the anti stereoisomer.
(4.58 g, 89%) as colorless needles. M.p. 157 1608C; H NMR (300 MHz,
CDCl3): d 4.57 (s, 2H), 7.27 7.57 (m, 4H), 7.62 7.73 (m, 5H); 13C NMR
(75 MHz, CDCl3): d 60.46, 114.33, 116.51, 128.67 (2C), 129.25 (2C),
129.36, 131.60, 132.18, 132.77, 132.93, 134.28, 137.48.
iii) ortho-(Phenylsulfonylmethyl)benzaldehyde (2): A 100 mL flask was
charged with ortho-(phenylsulfonylmethyl)benzonitrile (1.29 g, 5.0 mmol)
and CH2Cl2 (15 mL), and DIBAL-H (1.0m in hexane, 11.5 mL, 11.5 mmol)
was added at À788C. After the mixture had been stirred at this temper-
Attempted synthesis of 4 from 5a: A 100 mL flask was charged with 5
(625 mg, 1.0 mmol), ClP(O)(OEt)2 (0.17 mL, 1.2 mmol) and THF (30 mL),
and LDA (1.0m in THF/hexane, 3.0 mL, 3.0 mmol) was added dropwise at
À788C. The reaction mixture was stirred at room temperature for 1.5 h and
Chem. Eur. J. 2002, 8, No. 9
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