Pace et al.
JOCNote
SCHEME 2. Diazomethane Acylation with Haloacetyl Halides
in the Presence of CaO
TABLE 1. Hydrohalic Acid Scavenger Effect in the Acylation of
Diazomethane with Bromoacetyl Bromide
entry
CH2N2 (equiv)
HX scavenger (equiv)
yield of 6a (%)
1
2
3
4
5
6
7
8
9
10
1.3
1.3
1.3
1.3
1.3
1.3
1.3
0.7
1.0
1.0
Et3N (1.1)
Et3N (0.7)
complex mixture
complex mixture
NaHCO3 (1.1)
KHCO3 (1.1)
K2CO3 (0.5)
K2CO3 (1.1)
K2CO3 (2.0)
CaO (0.7)
0a
15b
52c
65d
39
64
100
100
application is related to the explosive nature of the reagent,
the use of an excess of diazomethane is highly undesir-
able.15 In this regard, alternatives to the classical use
of diazomethane in such chemistry have been proposed,
for instance, the development of a protocol for the pre-
paration of diazocarbonyl compounds using cyanuric
chloride as promoter and diazomethane.16 However, this
methodology presents the drawback of its limited applic-
ability to aromatic carboxylic acids. Analogously, the more
expensive trimethylsilyldiazomethane (TMSCHN2)17-21 has
been used as a substitute of diazomethane in Arndt-
Eistert reactions, but prior activation of the carboxylic acid
as a mixed anhydride is often required when amino acids are
used as substrates.22 In addition, when the acid is activated
by reaction with DCC, an equimolar ratio of diazoketone
and trimethylsilylmethyl ester is obtained, thus lowering
the chemoselectivity of the process. In general, the use of
trimethylsilyldiazomethane often requires longer reaction
times (>24 h) and results in lower yields as compared
to reactions performed with diazomethane, even when an
excess of TMSCHN2 is used. Alternatively, a two-step
protocol to convert acyl chlorides into R-diazoketones
using N-isocyanotriphenyliminophosphorane via isolable
R-ketohydrazidoyl chlorides has been developed.23
In this paper, the effectiveness of a simple inorganic agent
(i.e., calcium oxide) in scavenging the released hydrohalic
acid and thus cleanly affording the desired R-diazocarbonyl
compound as the only reaction product is reported. Bromo-
acetyl bromide (5a, Scheme 2) was selected as a model
substrate because it possesses a sufficiently acidic hydrogen
that may promote the ketene formation. Furthermore, a
highly efficient synthetic procedure for the preparation of
1-bromo-3-diazopropan-2-one (6a, Scheme 2), as well as the
analogous chloro derivative 6b via the reaction of minimal
amounts of diazomethane with the corresponding acid ha-
lides, is an important goal since diazoketones 6a,b represent
versatile scaffolds in organic synthesis. In fact, diazoketones
6a,b may be employed in a plethora of transformations such
CaO (3.0)
CaO (6.0)
Reactions were carried out at 0°C during 3 h using 1.0 equiv of
bromoacetyl bromide. a1,3-Dibromoacetone was recovered as the
only reaction product in 34% yield. 28% of 1,3-dibromoacetone was
b
detected via 1H NMR. c36% of 1,3-dibromoacetone was detected via 1H
NMR. d15% of 1,3-dibromoacetone was detected via 1H NMR.
as heteroatom alkylation,24-27 Darzens condensation,28 ben-
zene alkylation,29 or diazo displacement reactions.30
In this way, treatment of 5a with a freshly prepared
and titrated (0.27 M) ethereal solution of diazomethane
(1.0 equiv) in the presence of CaO (1.1 equiv) cleanly
afforded the expected R-diazoketone 6a in quantitative
isolated yield, without the formation of any side product
(Scheme 2). Previously, the same ketone 6a has been
prepared in 85% yield with 15% of unidentified impurities
by employing a 3-fold excess of diazomethane,31 while the
use of only 2 equiv of diazomethane lowers the yield (64%)
of 6a.32 It must be stressed that the use of this explosive
reagent in more than stoichiometric ratio requires special
devices for its removal by distillation,31 thus preventing
a large-scale application. Analogously, a quantitative yield
of 1-chloro-3-diazopropan-2-one 6b was obtained from
the reaction of chloroacetyl chloride 5b with CH2N2 and
CaO. Operational details are simple since calcium oxide
was effectively removed by filtration at reduced pressure
(see Experimental Section).
In order to evaluate the effectiveness of CaO as a proton
scavenger, bromoacetyl bromide 5a was treated with diazo-
methane under different conditions. In a first step, the use of
CaO was compared to other commonly employed bases in
organic synthesis, such as triethylamine, sodium bicarbo-
nate, potassium bicarbonate, and potassium carbonate. The
results, shown in Table 1, indicate the superiority of CaO in
the Arndt-Eistert synthesis of R-diazoketones. In fact, using
triethylamine, only complex mixtures were obtained, prob-
ably because of ketene formation (entries 1 and 2). On the
other hand, sodium bicarbonate was completely inefficient
to scavenge the released hydrobromic acid because only 1,3-
dibromoacetone was detected (entry 3). By replacing the
latter with the corresponding potassium salt, only a minimal
amount of R-diazoketone 6a was obtained (entry 4). In the
same way, the use of potassium carbonate did not improve
the process regardless of the amount of this base employed
for the purpose; moreover, when used in excess, the yields
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