7452
J . Org. Chem. 1996, 61, 7452-7454
Efficien t a n d High ly Selective Oxid a tion of P r im a r y Alcoh ols to
Ald eh yd es by N-Ch lor osu ccin im id e Med ia ted by Oxoa m m on iu m
Sa lts
J acques Einhorn,* Cathy Einhorn, Fabien Ratajczak, and J ean-Louis Pierre
Laboratoire de Chimie Biomime´tique, LEDSS/ UMR CNRS 5616, Universite´ J . Fourier,
38041 Grenoble, France
Received May 28, 1996X
2,2,6,6-Tetramethyl-1-piperidinyloxy catalyzes efficient oxidation of primary alcohols to aldehydes
by N-chlorosuccinimide, in a biphasic dichloromethane-aqueous pH 8.6 buffer system in the
presence of tetrabutylammonium chloride. Aliphatic, benzylic, and allylic alcohols are readily
oxidized with no overoxidation to carboxylic acids. Secondary alcohols are oxidized to ketones with
a much lower efficiency. Very high chemoselectivities are observed when primary alcohols are
oxidized in the presence of secondary ones. Primary-secondary diols are selectively transformed
into hydroxy aldehydes, with, in some cases, no detectable formation of the isomeric keto alcohols.
Sch em e 1
As synthetic chemists are concerned with increasingly
sophisticated targets, it is a permanent demand to
develop more and more selective synthetic methods able
to discriminate efficiently various functional groups.
Therefore, selective methods allowing for oxidation of
primary alcohols to aldehydes without overoxidation to
carboxylic acids and without competitive oxidation of
secondary alcohols remain challenging. Relatively few
methods allow this type of selectivity.1 During the past
few years, N-oxoammonium salts have become synthetic
reagents of growing importance, mainly for the oxidation
of alcohols to carbonyl compounds. They can be used
stoichiometrically, either in an isolated form2 or gener-
ated “in situ” via nitroxide dismutation.3 Several cata-
lytic procedures have also been developed, the active
species being regenerated by stoichiometric amounts of
various cooxidants, including m-chloroperbenzoic acid,3c,4
high-valence metal salts,5 sodium bromite,6 sodium or
calcium hypochlorite,7 and electrooxidation.8 Interest-
ingly, a proper choice of the nitroxide catalyst, of the
cooxidant, and of the reaction conditions is able to tune
very finely the selectivity of these oxidizing systems. For
example, several chemoselective systems of preparative
value for the oxidation of primary alcohols have recently
been developed.2a,5c,6,7b,c,8a,b In this paper we describe a
new N-oxoammonium salt based oxidation method where
catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) are used in combination with N-chlorosuccin-
imide (NCS) as the stoichiometric oxidant. This system
operates efficiently at room temperature under biphasic
conditions (CH2Cl2-water) in the presence of tetrabutyl-
ammonium chloride (TBACl) as a phase transfer agent,
the aqueous phase being buffered at pH 8.6 (NaHCO3-
K2CO3) (Scheme 1).
Under these conditions, primary alcohols are quanti-
tatively oxidized to aldehydes (Table 1), without any
noticeable overoxidation to carboxylic acids even with an
excess of NCS (entry 2). Moreover, the TEMPO inhibits
a possible autoxidation of the aldehyde by molecular
oxygen, making unnecessary the use of an inert atmo-
sphere during the reaction.9 No residual oxidation is
observed in the absence of TEMPO (entry 1′),10 whereas
the absence of phase transfer catalyst leads to a much
slower reaction (entry 3′). Under standard reaction
conditions aliphatic and benzylic primary alcohols are
oxidized within 0.5-6 h using 1-1.6 equiv of NCS. The
experiments, usually performed on a 1 mmol scale, can
be scaled up to 0.1 mol without difficuties (entry 3). In
the case of benzylic alcohols, electron-donating groups
slow down the reaction (entry 4) whereas electron-
X Abstract published in Advance ACS Abstracts, September 15, 1996.
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Lett. 1981, 22, 1605-1608. (b) Nakano, T.; Terada, T.; Ishii, Y.; Ogawa,
M. Synthesis 1986, 774-776. (c) Singh, J .; Kolsi, P. S.; J awanda, G.
S.; Chhabra, B. R. Chem. Ind. 1986, 21, 751-752. For examples of
reversed selectivity, see: (d) Stevens, R. V.; Chapman, K. T.; Stubbs,
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4650. (e) Tomioka, H.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1982,
23, 539-542. (f) Kaneda, K.; Kawanishi, Y.; J itsukawa, K.; Teranishi,
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H.; Oshima, K.; Nozaki, H. Bull. Chem. Soc. J pn. 1986, 59, 105-108.
(h) Rozen, S.; Bareket, Y.; Kol, M. Tetrahedron 1993, 49, 8169-8178.
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J .; Mlochowski, J . Tetrahedron Lett. 1990, 31, 2177- 2180. (d) Leanna,
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(9) See ref 7c for similar observations.
(10) Some residual oxidation can be observed when crude com-
mercial NCS is used. It is completely absent when the NCS is
recrystallized from toluene before use.
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