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50 ml of dry benzene to dissolve the viscous oil, which was crude CMBP.
After sonication (30 min) followed by stirring (1 h), the mixture was kept at
room temperature without stirring for 3 h to solidify the lithium chloride
cake on the bottom of the flask. The clear and pale yellow supernatant layer
was transferred to another three-necked flask (equipped with a magnetic stir-
ring bar, a three-way stopcock as a gas inlet connected to a vacuum/argon
line, and a rubber septum for each of the remaining inlets) by decantation
via a stainless steel cannula under positive argon pressure through one of the
rubber septa. The solvent in the transferred supernatant was removed under
vacuum (1 mmHg) as quickly as possible to give crude CMBP as a yellow-
ish-brown oil. The residue was purified by bulb-to-bulb distillation
(0.35 mmHg, 120—220 °C) to give 8.37 g of pure CMBP as a light yellow-
ish-brown oil in 95% yield.
Fig. 4
crude CMBP as a yellow-brown oil. Since most of lithium
chloride was removed by this operation, the residue was di-
luted with toluene (or other solvents) to afford a solution of
partially purified CMBP, which could be employed for the
Mitsunobu reaction without additional operations. A reliable
estimate of the concentration of the CMBP toluene solution
was given by the reaction of benzyl alcohol with N-methyl-p-
toluenesulfonamide (Fig. 4).
Handling and Storage of CMBP Since CMBP was
very sensitive to air and moisture, all procedures for the pu-
rification of the product should be carried out under a dry
argon atmosphere, even for NMR, IR, and Mass spectra. The
distilled neat CMBP could be stored in a brown sealed am-
pule for months at 10 °C under an argon atmosphere without
decomposition. CMBP could also be stored as a solution in
dry toluene or THF in a brown sealed ampule for months.
The physical properties were as follows: IR (neat under argon) cmꢁ1
:
2137 (CN). 1H-NMR (300 MHz, CDCl3 under argon) d: 0.79 (br d, 1H,
Jꢂ5.1 Hz), 0.96 (t, 9H, Jꢂ7.2 Hz), 1.36—1.60 (m, 12H), 1.69—1.81 (m,
6H). 13C-NMR (150 MHz, CDCl3 under argon) d: ꢁ7.21 (d, Jꢂ123.0 Hz),
13.36 (s), 23.64 (d, Jꢂ4.4 Hz), 23.82 (d, Jꢂ56.1 Hz), 23.82 (d, Jꢂ14.3 Hz),
128.55 (d, Jꢂ7.8 Hz). 31P-NMR (121.5 MHz, CDCl3 under argon) d: 26.50
(s). CI-MS, m/z (rel intensity) 242 (100%, Mꢃꢃ1). High resolution mass
spectrum, Calcd for C14H29NP, 242.2038. Found 242.2047.
Toluene Solution of CMBP for Large Scale Reaction The salts 4
(30.0 g, 108 mmol) were treated with n-butyllithium following the procedure
described above. The clear and pale yellow supernatant layer was transferred
to another three-necked flask and the solvent was removed. Then, the residue
was dissolved with toluene (100 ml) to afford a solution of CMBP. The con-
centration of CMBP in the solution was estimated as follows. To a solution
of benzyl alcohol (1.5 mmol) and N-methyl-p-toluenesulfonamide (1.5
mmol) in dry toluene (4 ml) was added 1 ml of the CMBP solution under an
argon atmosphere at room temperature. The resulting mixture was stirred at
100 °C for 24 h, and evaporated. The residue was purified by silica gel col-
umn chromatography (eluent: hexane/AcOEt, 10/1—5/1, v/v) to yield N-
benzyl-N-methyl-p-toluenesulfonamide (5) as a colorless solid (209 mg,
0.76 mmol). The reaction gave 0.93 mmol of 5, when using distilled neat
CMBP (1.0 mmol) or a solution of distilled CMBP (1.0 M in toluene, 1.0 ml).
Thus, a solution of CMBP without further purification gave lower yield,
probably because of a small amount of lithium chloride, which could not be
removed. However, this result suggested that the concentration of the solu-
tion was at least up to 0.76 M.
Experimental
General Hexane, benzene and toluene were distilled from calcium hy-
dride under an argon atmosphere before use. 31P-NMR spectra were
recorded on a Varian Unity-600 (121.5 MHz) with 85% H3PO4 as an exter-
nal standard12) in CDCl3.
(Cyanomethyl)tributylphosphonium Chloride (4) A 3-l, two-necked,
round-bottomed flask was equipped with a magnetic stirring bar, a rubber
septum, and a reflux condenser connected to an argon-filled balloon. The
system was flame-dried, flushed with argon, and charged with tributylphos-
phine (332 ml, 1.32 mol) and nitromethane (1.5 l) using syringes through the
rubber septum. To the stirred mixture was added dropwise neat chloroace-
tonitrile (84 ml, 1.33 mol) over a 1 h period via a syringe changing to a yel-
low homogeneous solution. The process was highly exothermic, and the ad-
dition rate of chloroacetonitrile was adjusted to maintain the mixture at
below 50 °C. The resulting mixture was stirred for 16 h at room temperature,
then concentrated on a rotary evaporator. The residual yellow oil solidified
when a small amount of AcOEt was added. The solid was recrystallized by
dissolution in boiling AcOEt–CHCl3 (2500 ml—30 ml) and cooling to room
temperature to afford 315.9 g (86%) of 4 as colorless needles. The mother
liquor was then concentrated and recrystallized again to afford an additional
19.0 g (5%) of the material.
Acknowledgments This work was supported partially by a Grant-in-
Aid for Scientific Research (C) from MEXT (the Ministry of Education,
Culture, Sports, Science and Technology of Japan). We are also thankful to
MEXT.HAITEKU, 2003—2007.
References and Notes
1) Mitsunobu O., Synthesis, 1981, 1—28 (1981).
2) Hughes D. L., Org. React., 42, 335—656 (1992).
3) Ito S., Tsunoda T., Pure & Appl. Chem., 71, 1053—1057 (1999).
4) Tsunoda T., Itô S., J. Synth. Org. Chem. Jpn., 55, 631—641 (1997).
5) Tsunoda T., Uemoto K., Ohtani T., Kaku H., Itô S., Tetrahedron Lett.,
40, 7359—7362 (1999).
6) Uemoto K., Kawahito A., Matsushita N., Sakamoto I., Kaku H., Tsu-
noda T., Tetrahedron Lett., 42, 905—907 (2001).
7) Tsunoda T., Kaku H., N,N,Nꢄ,Nꢄ-Tetramethylazodicarboxamide, Elec-
tronic Encyclopedia of Reagents for Organic Synthesis, Wiley, 15 Oc-
tober 2003, and references cited therein.
The physical properties were as follows: mp 98—100 °C. IR (KBr) cmꢁ1
:
1
2251 (CN). H-NMR (300 MHz, CDCl3) d: 1.00 (t, 9H, Jꢂ7.5 Hz), 1.47—
1.77 (m, 12H), 2.58—2.74 (m, 6H), 5.27 (d, 2H, Jꢂ15.9 Hz). 13C-NMR
(150 MHz, CDCl3) d: 11.35 (d, Jꢂ49.5 Hz), 13.25 (s), 19.12 (d, Jꢂ45.0 Hz),
23.43 (d, Jꢂ4.5 Hz), 23.83 (d, Jꢂ16.4 Hz), 112.29 (d, Jꢂ8.9 Hz). 31P-NMR
(121.5 MHz, CDCl3) d: 36.17 (s). CI-MS, m/z (rel intensity) 242 (100%,
MꢃꢁClꢁ). High resolution mass spectrum, Calcd for C14H29NP, 242.2038.
Found 242.2033.
(Cyanomethylene)tributylphosphorane (CMBP)
A
300-ml, three-
8) Tsunoda T., Ozaki F., Itô S., Tetrahedron Lett., 35, 5081—5082
(1994).
9) Tsunoda T., Nagino C., Oguri M., Itô S., Tetrahedron Lett., 37, 2459—
2462 (1996).
necked, round-bottomed flask was equipped with a magnetic stirring bar, a
three-way stopcock as a gas inlet connected to a vacuum/argon line, and a
rubber septum for each of the remaining inlets. The system was flame-dried,
flushed with argon, and charged with a suspension of (cyanomethyl)tri- 10) Sakamoto I., Kaku H., Tsunoda T., Chem. Pharm. Bull., 51, 474—476
butylphosphonium chloride (4) (10.0 g, 36.2 mmol) in dry hexane (100 ml).
(2003).
To the cooled (0 °C) and stirred suspension was added dropwise n-butyl- 11) Tsunoda T., Yamamoto H., Goda K., Itô S., Tetrahedron Lett., 37,
lithium (23 ml, 34.5 mmol, 1.5 M in hexane) over a 10 min period via a sy-
ringe through one of the rubber septa. After the addition was completed, the
resulting mixture was allowed to warm to room temperature and was stirred
for 20 h. During the stirring, an insoluble pale yellow viscous oil and a pre-
cipitate of lithium chloride was formed. To the resulting mixture was added
2457—2458 (1996), and references cited therein.
12) 31P-NMR spectra Data of CMMP salt and CMMP reported in ref. 10
should be corrected as follows: 31P-NMR of CMMP salt (121.5 MHz,
DMSO-d6) d: 33.52 (s), 31P-NMR of CMMP (121.5 MHz, CDCl3
under argon) d: 13.16 (s).