Solid phase synthesis of amides by the Beckmann rearrangement of ketoxime carbonates

Article abstract of DOI:10.1016/j.tetlet.2003.09.113

In the presence of trifluoroacetic acid, ketoxime benzyl carbonates undergo a Beckmann rearrangement to the corresponding amides. This reaction was translated to a solid support by immobilizing oximes in the form of mixed carbonates derived from hydroxymethylpolystyrene in order to produce a diversity of amides with high efficiency.

Full text of DOI:10.1016/j.tetlet.2003.09.113

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8581–8584
Solid phase synthesis of amides by the Beckmann rearrangement
of ketoxime carbonates
a
a
a,
b
b
Sarah His, Christophe Meyer, Janine Cossy, * Gibert Emeric and Alfred Greiner
a
Laboratoire de Chimie Organique, associ e´ au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
b
Bayer Cropscience SA, La Dargoire Research Center, 14-20 rue Pierre Baizet, BP 9163, Lyon Cedex 09, France
Received 22 July 2003; revised 8 September 2003; accepted 16 September 2003
This paper is dedicated to the memory of the late Sarah His
Abstract—In the presence of trifluoroacetic acid, ketoxime benzyl carbonates undergo a Beckmann rearrangement to the
corresponding amides. This reaction was translated to a solid support by immobilizing oximes in the form of mixed carbonates
derived from hydroxymethylpolystyrene in order to produce a diversity of amides with high efficiency.
©
2003 Elsevier Ltd. All rights reserved.
Combinatorial chemistry has become a powerful tool
for the rapid development of novel lead compounds
and optimization of their therapeutic efficiency. In this
context, impressive efforts have been devoted to trans-
fer techniques and reactions originally tuned-up in
liquid phase to solid support with the ultimate goal of
performing the widest array of transformations in solid
oximes to solid support by their oxygen atom in the
form of a suitably chosen oxime derivative, which could
act as an activating group for the Beckmann rearrange-
ment, appeared particularly attractive. A brief screening
first indicated that the benzyl ethers of various
ketoximes were not viable precursors since their Beck-
mann rearrangement failed to occur under various reac-
tion conditions (protic or Lewis acids). The behaviour
of oxime esters was then investigated, and acetophe-
none oxime benzoate 1 and benzophenone oxime
p-methoxybenzoate 2 could indeed be rearranged to
acetanilide 4a (60%) and benzanilide 4b (70%), respec-
tively, by using a large excess of BF ·OEt (5 equiv.) in
1
phase synthesis. The Beckmann rearrangement involv-
ing the transformation of ketoximes into amides is a
fundamental reaction in organic synthesis, and has led
to numerous applications due to the ease with which
nitrogen can be inserted into carbon chains starting
2
from readily available ketones. Herein, we would like
3
2
1
2
to report our results related to the development of a
version of the Beckmann rearrangement on solid sup-
port with the aim of converting a wide variety of
ketoximes to the corresponding amides with high
efficiency.
1,2-dichloroethane (DCE) at room temperature.
Unfortunately, the Beckmann rearrangement of cyclo-
hexanone oxime benzoate 3 under the same conditions
was extremely sluggish and o-caprolactam 4c was
obtained in only 25% yield (Scheme 1).
The Beckmann rearrangement is usually promoted by
strong protic or Lewis acids and its practical impor-
tance has led to the development of improved or cata-
These results led us to consider the behaviour of the
oxime carbonates which were anticipated to exhibit
2
13,14
higher reactivity.
It was reported that BF ·OEt was
3 2
lytic variants based on milder and/or environmentally
3–11
benign conditions.
The role of the different promo-
tors with respect to the mechanism of the Beckmann
rearrangement, is to transform the hydroxyl group of
the ketoximes into a better nucleofuge and induce the
concomitant migration of the organic group usually at
2
the anti position. Therefore, the possibility of attaching
*
Corresponding author. Tel.: +33-1-40-79-44-29; fax: +33-1-40-79-
6-60; e-mail: janine.cossy@espci.fr
4
Scheme 1. Beckmann rearrangement of oxime benzoates.
0
040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.113

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S. His et al. / Tetrahedron Letters 44 (2003) 8581–8584
successful at promoting the Beckmann rearrangement of
The ketoximes 5a–i were loaded on the resins 10–12 under
optimized conditions involving heating in DCE at 60°C
3a
various ketoxime ethyl carbonates, and for our part, we
studied the Beckmann rearrangement of benzyl carbon-
ates in liquid phase with the aim of performing this
rearrangement on solid support by using a resin having
an activated acyl carbonate anchoring moiety, derived
from benzylic alcohol type resins (hydroxymethyl-
polystyrene or Wang resin). A series of ketoximes 5a–i
were converted to their benzyl carbonates 6a–i (BnO-
COCl, Et N, cat. DMAP, CH Cl , rt) and it was demon-
16
for 72 h. The resulting ketoxime carbonate resins of
type A and B were then treated with a TFA/CH Cl
2
2
(9/1) mixture at 35°C for 16 h and the products were
cleaved from the resins and analyzed by NMR and GC–
MS. The results are summarized in Table 2 and the yields
reported refer to the initial loadings of the commercially
17
available resins 8 and 9.
3
2
2
strated that these compounds underwent a Beckmann
rearrangement when treated with a trifluoroacetic acid/
dichloromethane mixture (9/1 to 1/1) at 30–35°C, afford-
ing the corresponding amides 4a–i in satisfactory yields
(
Table 1).
13
According to literature precedents and our observa-
tions, the greater ability of ketoxime carbonates to
undergo the Beckmann rearrangement was attributed to
the thermodynamically favorable (and detectable) evolu-
tion of carbon dioxide, and not the assistance by the
carbonyl group of the carbonate moiety as recently
Scheme 2. Mechanism of the Beckmann rearrangement of
ketoxime carbonates in the presence of TFA.
3
a
suggested. The rearrangement is therefore accompanied
by the release of benzyl alcohol and the formation of the
labile iminol trifluoroacetates 7a–i, whose subsequent
hydrolysis generates the corresponding amides 4a–i. It is
noteworthy that oximes 5a–i were stable under the
reaction conditions (TFA), thus highlighting the fact that
the carbonates were the actual reactive species and not
the oximes themselves which could have been generated
by an acid-catalyzed hydrolysis (Scheme 2).
The translation of this sequence to solid support was next
investigated. In order to immobilize ketones in the form
of mixed carbonates, several resins bearing an activated
acyl moiety were synthesized. Thus, the Wang resin 8 or
hydroxymethylpolystyrene 9 (cross-linked polymers with
Scheme 3. Preparation of resins 10–12. Reagents and conditions:
(
a)
p-nitrophenylchloroformate,
N-methylmorpholine,
CH Cl , rt, 18 h; (b) carbonyldiimidazole, THF, rt, 3 h.
2
2
1
% of divinylbenzene) were converted to the p-nitro-
Table 2. Beckmann rearrangement of ketoxime carbonates
on solid support
phenylcarbonate resins 10 and 11 respectively by treat-
ment with p-nitrophenylchloroformate in the presence of
N-methylmorpholine in dichloromethane at room tem-
1
4
perature.
On the other hand, hydroxymethyl-
polystyrene 9 was converted to the acylimidazole resin 12
by treatment with carbonyldiimidazole in THF at room
1
5
temperature (Scheme 3).
Table 1. Preparation and Beckmann rearrangement of
ketoxime benzyl carbonates

S. His et al. / Tetrahedron Letters 44 (2003) 8581–8584
8583
The overall sequence was first investigated with two
representative oximes 5a and 5c, respectively, derived
from acetophenone and cyclohexanone. Whatever the
resin used to immobilize the ketoxime 5a, acetanilide 4a
was obtained in satisfactory yields (60–75%). By con-
trast, in the case of cyclohexanone oxime 5c, o-capro-
lactam 4c was obtained in high yield when resins 11 and
fluoroacetic acid, which releases the corresponding
amides in solution. The overall sequence, which affords
in most cases the amides in good yields and in a high
state of purity, may find applications in solid phase
synthesis.
12 derived from hydroxymethylpolystyrene were used
Acknowledgements
for the loading, whereas oxime 5c was the only product
recovered when resin 10 was used. The difference
between both cases could be explained by the presence
of the p-anisyl spacer in resins of type A derived from
the Wang resin, which could induce the direct cleavage
of ketoximes from the solid support (Eq. (1)) and
compete with the Beckmann rearrangement (Eq. (2)) if
the latter occurred at a much slower rate, which was
indeed anticipated to be the case for cyclohexanone
oxime compared to acetophenone oxime derivatives
Financial support from Rhone-Poulenc Agrochimie
and the CNRS (grant to S.H.) is gratefully
acknowledged.
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Scheme 5. Reactivity of the p-methoxybenzyl carbonate of
cyclohexanone oxime.

8
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3a
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3
2
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6
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