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J. T. Lai / Tetrahedron Letters 42 (2001) 557–560
Scheme 3.
Scheme 4.
The ketoform reaction, which I refer to as the reaction
among chloroform, a ketone, sodium hydroxide and
nucleophiles, was reported earlier in the literature,
where the nucleophiles are unhindered phenols,5 alco-
hols,6 aniline,7 chloride and hydroxide.8 It was modified
and applied in this laboratory to make totally hindered
amines such as 3,3,5,5-tetraalkyl-2-piperazinones and
3,3,5,5-tetraalkyl-2-morpholones and other molecules.9
and filtered again with 500 ml 20% HCl, and finally
with 500 ml water and filtered. The initial cyclohex-
anone solution filtrate was concentrated to strip off the
solvent and excess dibutylamine, slurred in 500 ml
hexanes and filtered. The two combined solids were
recrystallized from heptane to yield 370 g of colorless
crystals, melting point 135–138°C.
Table 1 lists some of the hindered phenolic amides
made this way, together with their melting points and
the reaction yield.
The mechanism of the ketoform reaction is depicted in
Scheme 2, showing the 1,1-dialkyl-2,2-dichlorooxirane
as the reactive intermediate.
In the absence of the amine, the 2,6-di-t-butyl-4-(1,1-
dialkyl-1-acetic acid)-phenol 2 can be isolated after the
reaction mixture was acidified (Table 2).
When 2,6-di-t-butylphenol participates in the ketoform
reaction as the nucleophile XH, 2,6-di-t-butyl-4-(1,1-
dialkyl-1-acetamide) (1) is formed in decent yield
(Scheme 3), where the 4-carbon on 2,6-di-t-butylphenol
opens the oxirane intermediate (Scheme 4).
The pheoxy radical of 1 can be obtained from the
oxidation of 1 with either potassium ferricyanide4 or
lead dioxide.12
Most dialkyl amines and tertiary alkyl amines work
well because they do not compete against the hindered
phenol for attacking the dialkyl carbon in the oxirane
intermediate. Cyclic amines such as piperidine, mor-
pholine and cyclohexylamine give by-products, so do
dimethylamine and less hindered primary amines.
Methyl alkyl ketones and cyclic ketones usually give
decent conversions. Alkyl aldehydes do not yield the
desired product due to possibly the interference of aldol
condensation, aldimine formation and less favorable
ring closure for making a trisubstituted than a tetra-
substituted oxirane.10
In a typical experiment for estimating the half-life of
the hindered phenoxy radicals, 2.5 mmol K3Fe(CN)6,
2.3 mmol KOH, 5 ml H2O and 50 ml toluene were
mixed in a 250 ml 3-neck flask under a nitrogen atmo-
sphere. Compound 1 (1 mmol) in 50 ml toluene was
added dropwise in 45 minutes. The bluish-colored mix-
ture was stirred for a further 2 hours. A 10 ml aliquot
of the toluene solution was diluted with toluene to 100
ml which was quickly dried over MgSO4. A 3 ml
aliquot was added to an ESR tube capped under air.
The radical shows a singlet in an unresolved hyperfine
ESR spectrum. Spectra were taken at different intervals
The following represents a general procedure: 2,6-Di-t-
butylphenol (206.3 g, 1.0 mol), chloroform (155.2 g, 1.3
mol), dibutylamine (226.2 mol, 1.75 mol) and cyclohex-
anone (785.6 g, 8.0 mol) were mixed at 5–10°C under
nitrogen. Sodium hydroxide beads (180 g, 4.5 mol) were
added at below 15°C during a 4 h period. After stirring
at 10°C overnight, the reaction content was filtered.
The solid was stirred with 750 ml water, filtered, stirred
Lai, John T.
