Chemistry Reference
In-Depth Information
Typical procedure. 2,2-Dimethyl-5-(trimethylsilyl)-4-pentynal 1795 [1377]:
A solution
of dimethyl sulfoxide (62 mL, 68.3 g, 0.874 mol) in dichloromethane (200 mL)
was added dropwise over a period of 2 h to a solution of oxalyl chloride (36.6 mL,
53.2 g, 0.420 mol) in dichloromethane (500 mL) cooled to
60
C. The mixture
was stirred for an additional 30 min, and then a solution of 2,2-dimethyl-5-(trime-
thylsilyl)-4-pentyn-1-ol (66.3 g, 0.360 mol) in dichloromethane (200 mL) was added
dropwise over 2.5 h. The resulting solution was stirred for a further 40 min, and
then triethylamine (251 mL, 182 g, 1.80 mol) was added dropwise over 1 h. The
solution was stirred for an additional 45 min and then allowed to warm to room
temperature, whereupon water (400 mL) was added. The aqueous layer was sepa-
rated and extracted with dichloromethane (3
75 mL), and the combined organic
layers were washed with 1 n hydrochloric acid (3
200 mL) and then with water.
The individual washes were successively extracted with dichloromethane (3
50
mL) and all the organic layers were combined, washed with saturated sodium
chloride solution, and dried over magnesium sulfate. The dried solution was con-
centrated and passed through a florosil column eluting with 10% diethyl ether in
hexane and the solvent was removed from the eluate. The crude product was
transferred in a vacuum train at room temperature, and small scale (2-4 g)
medium-pressure liquid chromatography on silica gel using 3% diethyl ether in
hexane afforded pure product 1795 in 80% yield.
Reactivity-selectivity relationships in the Swern oxidation of alcohols using di-
methyl sulfoxide/oxalyl chloride have been investigated [1378]. The competititive
oxidation of a mixture of two alcohols by a sub-stoichiometric amount of oxidant
under the conditions developed by Swern (reaction of the alcohols at
60
C with
Me
2
SCl
รพ
Cl
generated from (COCl)
2
and Me
2
SO in CH
2
Cl
2
followed by reaction
with Et
3
N) showed significant selectivity, with sterically crowded alcohols and those
bearing electron-withdrawing substituents being less reactive. Experiments in
which the order of mixing of the alcohols and the oxidant was reversed and the
time of reaction varied established that the process involves initial fast formation of
a mixture of alkoxydimethylsulfonium ions, which equilibrate at a slower rate with
the residual alcohols. Addition of Et
3
N rapidly converts the existing mixture of
alkoxydimethylsulfonium ions to carbonyl products. Intramolecular and inter-
molecular H/D isotope effects are consistent with this mechanistic scheme. In a
practical application of these reactivity principles, pregnenol 1796, with a crowded
11b-OH group, was smoothly oxidized in 58% yield to ketone 1797, whereas the
9a-fluoro substituent in fluoropregnenol 1798 inhibited the reaction and the corre-
sponding ketone was formed in only 5% yield.
A synthetic approach to 2-piperidylglycine using Swern oxidation as a synthetic
step has been reported [1379]. Protection and Swern oxidation of 2-piperidine-
methanol 1799 gave the corresponding N-protected aldehydes 1800, which formed
diastereomeric cyanohydrins 1801 on reaction with KCN. Treatment of these cya-
nohydrins with ammonia in methanol gave a-amino-2-piperidineace-tonitriles 1802.
An improved preparation of (S)-N-(Boc)-cyclohexylalaninal by application of the
Moffatt-Swern oxidation of a-amino alcohols has been described [1346]. Moffatt-
Swern oxidation of protected (S)-alcohol 1803 with DMSO/(COCl)
2
/Et
3
N/
