Superbase-Promoted Acylation of Hindered Alcohols
J . Org. Chem., Vol. 61, No. 9, 1996 2965
Sch em e 1
acetylation in acetonitrile is consistent with the basicity
order -O2CMe > -O2CPh for the counterions of 2a and
2b, respectively, and also with the proposed reaction
pathway in Scheme 1. In benzene, the benzoylation
intermediate 2a is completely soluble whereas the acety-
lation intermediate 2b is sparingly soluble, thus account-
ing for slower acetylation in the heterogeneous reaction
mixture.
O
C
O
C
R
H
O
O
Ph
Ph
Me
O
Ph
Me
Me
C
P
Me
Me
Me
N
N
N
N
O–
O
P
N
N
PhC
N+
N
According to Table 1 the order of benzoylation of the
relatively hindered alcohols (()-menthol and 6a in the
solvents employed is acetonitrile < pentane < benzene.
Here, solvation of the intermediate cation of 2a and its
anion in acetonitrile may interfere with nucleophilic
attack on the cation by a bulky alcohol, and it may also
inhibit the general base catalysis by the benzoate anion.
Thus benzoylation of these hindered alcohols is faster in
benzene than in acetonitrile, even though the benzoyla-
tion intermediates are soluble in both solvents. Although
pentane and benzene are both nonpolar, the benzoylation
intermediate 2a is quite insoluble in pentane whereas it
is completely soluble in benzene, thus accounting for the
lower yields for all four benzoylated products in Table 1
obtained in pentane. The exceedingly low yield for the
benzoylation of 7a in pentane is undoubtedly due to the
sparing solubility of 7a and intermediate 2a in this
solvent. It is noteworthy that no acidic workup is
required in our preparations as is the case with DMAP6
or Bu3P.7 Hence acid-sensitive alcohols such as 7a can
also be successfully acylated with 1a .
3a + RO2CPh
ming from transannular bond formation (when Z is a
sufficiently strong Lewis acid) play important roles in the
rate of formation and stability, respectively, of cations
of type 2.
We believe that the extensive delocalization of positive
charge in cations of 2a and 2b facilitated by transannular
bond formation permits substantial separation of the ion
pair, thereby making it more reactive. Thus loosely
bound ion pairs of 2a and 2b facilitate the attack of a
nucleophile on the activated acyl group which is then
followed by general base catalysis by the corresponding
anions as shown in Scheme 1. This mechanism is
analogous to that proposed for acylations involving
DMAP.6
The 31P NMR spectrum of a mixture of 0.2 mmol of
Bz2O and 0.2 mmol of 1a in 0.6 mL of C6D6 at 24 °C under
N2 revealed no change in its 2a :1a ratio of 11:9 when
0.2 mmol of DMAP was subsequently added. The same
observation was made when this solution was constituted
by adding 1a last, thus ruling out kinetically slow
achievement of equilibrium. The observed thermody-
namic stability of 2a over the presumed DMAP benzoy-
lation intermediate 10 may be rationalized by the dis-
parate extents of positive charge delocalization in 2a and
10. The resonance structures for the cation of 2a shown
and implied below indicate the possibility of positive
charge delocalization to all four nitrogens, whereas in
DMAP only two nitrogens can be involved in such
delocalization.
In the acylation of the alcohols in Table 1, 70-90% of
3b and 94-98% of 3a were isolated and converted back
to 1a generally in about 30 and 65% yields, respectively,
using 1.1 equiv of KO-t-Bu. The higher solubility of 3b
in ether and the deprotonation of the acetate anion by
KO-t-Bu (paralleling carboxylic acid dianion formation
using LDA16 ) accounts for the generally lower yields of
1a . Hence when 2.5 equiv of KO-t-Bu was used for the
recycling of 3b, the isolated yield of pure 1a increased to
50%. When the acylations described here were carried
out in the atmosphere, the yields of the esters were
slightly lower. It should be noted that halogenated
solvents react with 1a 13 and must be avoided.
Ph
O
Ph
O
C
C
P
Me
Me
Me
Me
Me
Me
+δ
+
N
N
N
P
N
N
N
N
+δ
N
Con clu sion s
PhCOO–
PhCOO–
The exceedingly strong nonionic superbase 1a is a
superior acylation promoter, and it gives rise to the first
detected P-acylation intermediate, namely, 2a . Of the
three solvents used in our acylation reactions, benzene
seems to be optimum for benzoylating alcohols, whereas
acetonitrile is the solvent of choice for acetylating them.
The advantages of using 1a as an acylation promoter are
(1) the yields of acylated alcohols are high, (2) the
byproducts 3a and 3b are easily isolated and recycled to
1a in moderate to high yields, (3) only a slight excess of
the acid anhydride is required, (4) compound 1a is
commercially available (Strem Chemical Co), and (5)
because no acidic (or basic) workup is required, acid-
sensitive alcohols can also be acylated. A minor draw-
back in using 1a as an acylation promoter is that
halogenated solvents cannot be employed.
Although 1a is a stronger base than DMAP and forms
a thermodynamically more stable acylation intermediate
(2a ), this does not imply that 2a is necessarily less
reactive than the acylated intermediate 10 formed from
the weaker base. The relatively high concentration of
2a compared to 10 is undoubtedly also an important
factor here.
From Table 1 it can be inferred that acetylation of a
relatively hindered alcohol such as (()-menthol and 6a
is faster than benzoylation in acetonitrile, whereas in
general, benzoylation of an alcohol is faster than acety-
lation in benzene. These results can be rationalized from
the observation that both acylation intermediates 2a and
2b are completely soluble in acetonitrile. The faster
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