Published on Web 03/18/2010
Nucleophilic Acyl Substitution via Aromatic Cation Activation of Carboxylic
Acids: Rapid Generation of Acid Chlorides under Mild Conditions
David J. Hardee, Lyudmila Kovalchuke, and Tristan H. Lambert*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
Received February 12, 2010; E-mail: tl2240@columbia.edu
Recently, we developed a new strategy for the activation of
alcohols toward nucleophilic substitution based on the facile
formation of Breslow-type1 cyclopropenium ethers.2 Given the
broad synthetic importance of carboxylic acid derivatives, we
wondered whether our aromatic cation activation strategy might
also be effective for facilitating nucleophilic acyl substitution
(Scheme 1). Specifically, we hypothesized that treatment of a
carboxylic acid 1 with a cyclopropene 2 bearing geminal leaving
groups (X) would produce a cyclopropenium carboxylate intermedi-
ate 3. Nucleophilic acyl substitution of this intermediate would then
produce a carboxylic acid derivative 4 and cyclopropenone 5.
Although this design had close analogies to our previous work, it
was unclear at the outset whether aromatic cation activation would
be effective in the mechanistically distinct context of acyl substitu-
tion. However, if viable, it seemed clear that such a strategy would
enable the design of powerful new acylation technologies using
simple yet highly modifiable carbon-based reagents. In this Com-
munication, we demonstrate the feasibility of achieving nucleophilic
acyl substitution via aromatic cation activation, in the context of
the rapid conversion of carboxylic acids to acid chlorides.
ature. Within 15 min, we observed (1H NMR, IR) quantitative
conversion to propionyl chloride and 2,3-diphenylcyclopropenone
(eq 1), demonstrating that cyclopropenium formation does in fact
provide a potent means to activate carboxylic acids toward
nucleophilic substitution.
To further probe this reactivity, we next examined the effect of
cyclopropene structure on reaction rate. For this study we chose
the conversion of pivalic acid to pivaloyl chloride, a transformation
we reasoned would offer an observationally convenient (i.e., slower)
reaction rate due to steric encumbrance (Chart 1a). Notably, in this
case the diphenylcyclopropene reagent A was rather inefficient,
providing only ∼20% conversion after 60 min. On the other hand,
replacing the cyclopropenyl phenyl groups with isopropyl substit-
uents (reagent C) resulted in a significantly faster reaction rate,
comparable to that observed using oxalyl chloride E. Since it is
well-known that cyclopropenium ions bearing alkyl substituents
possess higher pKR+ values than those with simple aryl groups,6 it
is worth stressing that in this case the more stable carbocation
provided the faster rate of acyl substitution. We attribute this fact
to the greater propensity for the dialkylcyclopropene to ionize,
thereby accessing the key cyclopropenium carboxylate intermediate.
This trend apparently has its limits, however, because the exceed-
ingly stabilized bisguaiazulenyl cyclopropene D7 resulted in only
13% conversion after 60 min. As expected, use of a mixed phenyl
isopropyl cyclopropene B resulted in a rate of acid chloride
formation approximately intermediate between that provided by A
and C.
Satisfied that aromatic cation activation was a viable means of
acid chloride production, we next decided to investigate the effect
of an amine base additive. In fact, we found that the addition of an
equivalent of Hu¨nig’s base significantly enhanced the rate of
conversion (Chart 1b). Thus for example, using diisopropylcyclo-
propene C in the presence of 1 equiv of Hu¨nig’s base, formation
of pivaloyl chloride was complete within 10 min, proceeding to
78% conversion.8 Interestingly, the relative efficiencies of cyclo-
propenes A and B were now the reverse of those expected based
on relative cyclopropenium ion stabilities. Although conversions
with A and B were significantly lower than that observed with C,
all three cyclopropenes performed better in the presence of base
than did oxalyl chloride (E), the activity of which was significantly
retarded by the presence of amine.
Scheme 1. Nucleophilic Acyl Substitution via Aromatic Cation
Activation
Due to their strong electrophilicity, acid chlorides may be readily
converted to virtually all other acyl derivatives and thus represent
the most powerful means to achieve carboxylic acid functional-
ization. Although traditional methods of acid chloride formation
using oxalyl chloride, thionyl chloride, or phosphorus chlorides have
long been staples of synthetic chemistry,3 the HCl generated with
these procedures renders them incompatible with acid sensitive
substrates. Accordingly, several methods have been developed that
allow for acid chloride synthesis under nonacidic conditions.4
However, many of these protocols are complicated by the use of
undesirable reagents (e.g., PPh3)4a-d or suffer from poor reaction
rates.4a,e Indeed, very few acid chloride forming reagents offer high
reactivity under nonacidic conditions,4f,g and those that do arguably
lack broad structural and electronic versatility of the type desired
for method development. As such, we were especially interested
in the prospect of acid chloride formation via aromatic cation
activation in the presence of amine base.
First, to investigate the possibility of aromatic cation activated
nucleophilic acyl substitution, we examined the readily available
3,3-dichlorocyclopropene that had proven successful in our previous
study.2 Thus, propionic acid was treated with 1.2 equiv of 3,3-
dichloro-1,2-diphenylcyclopropene5 in CDCl3 at ambient temper-
We have found that this method can be employed for the rapid
and mild conversion of carboxylic acids to amides, via the
intermediacy of acid chlorides (Table 1). For these experiments,
1,1-dichloro-2,3-diisopropylcyclopropene C was prepared in situ
9
5002 J. AM. CHEM. SOC. 2010, 132, 5002–5003
10.1021/ja101292a 2010 American Chemical Society