R-haloesters and nitrite anion is a general way of preparing
R-nitroesters,9 though varying amounts of the corresponding
nitrite esters are obtained (Scheme 2).
half complete, survives unchanged for several days at room
temperature after the resin is filtered. (ii) Pure ethyl nitro-
acetate in acetonitrile (1, R ) Et) undergoes no decomposi-
tion when exposed to the polymer-supported nitrite at room
temperature. (iii) When a catalytic amount (5%) of ethyl
bromoacetate is added to the latter solution, cooled at -15
°C, a comparably small amount of 3 is readily formed and
a slow degradation of the nitroacetate is observed; warming
to room temperature completes the degradation in a few
hours, and during this period, no increase in the level of
hydroxyacetate 3 is observed. From these experiments, it
follows that (i) the nitrite anion and (ii) the byproducts are
both necessary for the degradation to proceed; (iii) only a
catalytic amount of byproducts is sufficient to complete the
degradation, and at -15 °C, the catalytic cycle has a slow
turnover. These observations are summarized in Scheme 3.
Product 1, deprotonated by the nitrite anion, undergoes a
fast nitrosation by the nitrite ester16 to form byproduct 4 and
hydroxyacetate 3. Nitroso derivative 4 can be further
deprotonated to collapse into a series of byproducts,17 some
of which have nitrosating properties, thus closing the catalytic
cycle by slowing the regeneration of the nitrite ester 2 from
3. It is important to stress that this catalytic degradation can
be observed only for activated primary nitroalkanes, since
it requires easy double deprotonation of the carbon bearing
the nitro group.
Attempts to intercept the initially formed nitrite ester by
the use of known scavengers such as phloroglucinol11 and
1,1′-(1,3-phenylen)dipyrrolidine14 only resulted in the reduc-
tion of reaction rates to unacceptable levels. The effect of
the halogen was also investigated, revealing, as expected,
that chloroacetates react very slowly (28% conversion after
48 h at room temperature) and iodoacetates react slightly
faster but with no selectivity (1:1 ratio of nitroacetate and
hydroxyacetate).
The following procedure was then adopted. The dried resin
(2 equiv) was suspended in acetonitrile. The mixture was
cooled to -15 °C, and the bromoacetic acid derivative (1
equiv) was added. After the starting material was consumed,
the resin was quickly filtered. A series of bromoacetic acid
derivatives were tested under these conditions, and the results
are reported in Table 1.
Scheme 2. Synthesis of Nitroalkanes
Although iodoacetates and silver nitrite can sometimes be
used,10 the readily available bromoacetates and sodium nitrite
would represent a more convenient alternative.11 Unfortu-
nately, nitroacetates cannot be prepared by this method.6,12
In this Letter, we report a general method for the
preparation of nitroacetic acid esters and amides from the
corresponding R-bromoacetic acid derivatives and a conve-
nient reusable polymer-supported nitrite anion source. This
method turned out to be much more effective when inserted
into a one-pot multibond-forming process for the preparation
of 4-hydroxy-4,5-dihydroisoxazoles from R,â-epoxy alco-
hols, R-bromo acetates, or acetamides.
We were attracted by the method developed by Gelbard
and Colonna,13 where branched R-bromoesters are treated
with polymer-supported nitrite anion (Amberlite IRA 900,
NO2- form), in anhydrous benzene, at room temperature, to
form the corresponding R-nitroesters.14 Again, the preparation
of no nitroacetic acid ester was reported.
When we applied these reaction conditions15 to ethyl
bromoacetate, an almost instantaneous reaction took place,
leaving ethyl hydroxyacetate as the only detectable product
instead of the expected nitro/nitrite mixture of products. A
coarse screening of solvents and temperatures allowed us to
identify that when the same reaction is performed in
acetonitrile at -15 °C, a mixture of ethyl nitroacetate (1, R
) Et) and the corresponding hydroxyl acetate (3, R ) Et) is
obtained (Scheme 3). Prolonged exposure of the reaction
Scheme 3. Polymer-Supported Nitrite Anion Substitution
Reaction of Bromoacetates
The spent resin can be regenerated by washing it with 1
N NaNO2 until a negative AgCl test of the eluate is achieved.
As an example, in the preparation of ethyl nitroacetate, the
same resin was reused three times with no detectable adverse
effects on reaction times, yields, and selectivity.
(8) Shipchandler, M. T. Synthesis 1979, 666.
(9) Other general methods require the preparation of nitroacetic acid from
its salts by heating nitromethane under strong alkaline conditions.
(10) Kornblum, N.; Chalmers, M. E.; Daniels, R. J. Am. Chem. Soc.
1955, 77, 6654.
(11) Kornblum, N.; Blackwood, R. K.; Powers, J. W. J. Am. Chem. Soc.
1957, 79, 2507.
(12) Kornblum, N.; Eicher, J. H. J. Am. Chem. Soc. 1956, 78, 1494.
(13) Gelbard, G.; Colonna, S. Synthesis 1977, 113.
(14) Use of tetralkylammonium nitrites has also been reported: Munz,
R.; Simchen, G. Liebigs Ann. Chem. 1979, 628.
(15) Polymer-supported nitrite (4 mequiv/g), commercially available from
Fluka Co., was used throughout this work.
mixture to the resin, after the starting material is consumed,
leads to the complete decomposition of the nitro derivative,
leaving only hydroxyacetate.
In the course of our study, we made the following
observations. (i) A reaction mixture, where degradation is
(16) Kornblum, N.; Weaver, W. M. J. Am. Chem. Soc. 1958, 80, 4333.
(17) Jovitschitsch, M. Z. Ber. 1895, 28, 1213; 1906, 39, 785.
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Org. Lett., Vol. 4, No. 6, 2002