Beckmann rearrangement in the solid state: Reaction of oxime hydrochlorides

Article abstract of DOI:10.1016/S0040-4039(01)01737-3

Several ketoxime hydrochlorides undergo Beckmann rearrangement upon heating below their melting points for 5-48 h, in excellent yields (generally >70%). The absence of a reaction solvent and of by-products (except for HCl) makes for a very simple work-up. Aldoxime hydrochlorides apparently undergo dehydration to the corresponding nitriles under the above conditions. Dibenzyl ketoxime hydrochloride unexpectedly furnished a pyrazine derivative (67%), presumably via further reaction of the intermediate nitrilium ion in the crystal lattice.

Full text of DOI:10.1016/S0040-4039(01)01737-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8123–8125
Beckmann rearrangement in the solid state: reaction of oxime
hydrochlorides
Sosale Chandrasekhar* and Kovuru Gopalaiah
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 7 August 2001; revised 5 September 2001; accepted 14 September 2001
Abstract—Several ketoxime hydrochlorides undergo Beckmann rearrangement upon heating below their melting points for 5–48
h, in excellent yields (generally >70%). The absence of a reaction solvent and of by-products (except for HCl) makes for a very
simple work-up. Aldoxime hydrochlorides apparently undergo dehydration to the corresponding nitriles under the above
conditions. Dibenzyl ketoxime hydrochloride unexpectedly furnished a pyrazine derivative (67%), presumably via further reaction
of the intermediate nitrilium ion in the crystal lattice. © 2001 Elsevier Science Ltd. All rights reserved.
The age-old Beckmann rearrangement remains of prime
synthetic importance even today, essentially because it
allows easy access to a variety of N-substituted car-
boxylic amides. We have recently reported improved
procedures for the reaction,1 and herein report a solid
state version of the reaction.
We then surmised that the above hydrochlorides would
undergo Beckmann reaction in the crystalline lattice
because of the electrophilic activation provided by the
hydrogen chloride—presumably hydrogen bonded to
the oxygen and nitrogen atoms in the lattice network
(Scheme 1). The reaction was indeed observed by heat-
ing the hydrochlorides of a variety of ketoximes (1), at
temperatures ꢀ20°C below their melting points for
periods ranging from 5 to 48 h under nitrogen (Scheme
2 and Table 1; the white solid hydrochlorides often
darkened during the progress of the reaction, but did
not melt). The amide products 2 were isolated and
characterised by their physical constants and spectra
(IR and NMR).† The stereochemistry of the oximes
studied is presumed to be as in 1, as indicated by the
An important feature of the Beckmann reaction is that
it is a rearrangement, so that no additional reagents—
apart from a catalyst—are in principle required. Essen-
tially dehydrating conditions have previously been
employed for the reaction, in order to generate the
intermediate nitrilium species without hydrolysing the
oxime function. However, these requirements may also
be met by employing appropriate acid catalysts in
organic solvents—a solution of dry hydrogen chloride
in ether thus seemed appropriate.
H
O
H
O
Treating ether solutions of several ketoximes with dry
hydrogen chloride gas to saturation at 0–25°C, gener-
ally furnished a precipitate without any evidence of
rearrangement (TLC). The precipitates were difficult to
isolate as they were hygroscopic, and hence were tenta-
tively identified as the oxime hydrochlorides. Removal
of the ether in vacuo furnished the hydrochlorides as
dry powders, the melting points of which could be
determined by careful handling under nitrogen.
H
H
N
N
Cl
Cl
Scheme 1.
OH
70-130 oC
N
R1-NH-CO-R2
or
.HCl
R2
5-48 h
(-HCl)
2
R1
Keywords: Beckmann; nitrile ylide; oxime hydrochlorides; pyrazine;
rearrangement; solid state.
(R1CN/R2CN when R1/R2 = H)
1
* Corresponding author. Fax: (+91 80) 3600 529; e-mail: sosale@
orgchem.iisc.ernet.in
Scheme 2.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01737-3

8124
S. Chandrasekhar, K. Gopalaiah / Tetrahedron Letters 42 (2001) 8123–8125
Table 1. Beckmann rearrangement of solid ketoxime hydrochlorides (1·HCl) to amides/lactams 2: melting points of 1·HCl,
reaction conditions and yields of 2
R1
R2
1·HCl
Mp (°C)
(°C)/ha
2
Yield (%)
Ph
Ph
p-Tolyl
Ph
Me
Me
a
b
c
d
e
f
125–128
108–110
120–122
85–87
135–137
108–110
140–141
148–150
105/8
85/16
105/15
70/48
100/8
90/12
110/20
130/5
a
b
c
d
e
f
96
83
90
−(CH2)5−
Vanillin
72b
92c
1-Naphthaldehyde
PhCH2 PhCH2
78d
67e
g
h
g
h
(+)-Camphor
ꢀ60f
a Reaction conditions (temperature/hours).
b Caprolactam from cyclohexanone oxime hydrochloride.
c 4-Hydroxy-3-methoxybenzonitrile.
d 1-Naphthonitrile.
e 2,5-Dibenzyl-3,6-diphenylpyrazine identified by elemental analysis and comparison with reported data:2 mp 152–153°C (lit.2a 151–153°C); wmax
MeOH
(KBr) 3081, 1600 cm−1; umax
(log m) 247 (3.89), 297 (3.86) nm; lH (300 MHz, CDCl3) 4.27 (s, 4H, 2×PhCH2), 7.10–7.25 (m, 10H, ArH),
7.43–7.53 (m, 10H, ArH); lC (125 MHz, CDCl3) 41.15, 126.64, 128.76, 128.80, 129.08, 129.27, 129.68, 139.04, 139.67, 150.51, 152.32; m/e 412
(M+), 411.
f Complex mixture indicating fragmentation to nitriles.3
solution phase Beckmann reaction:1 the present results
thus also indicate the migration of the group anti to the
oxime hydroxyl group.
oxidation of the resulting dihydropyrazine 5 most likely
during work-up (Scheme 3). This sequence of events
indicates the power of the solid state method in effecting
unusual transformations, under the control of the crystal
lattice.
The oxime hydrochlorides of vanillin (1e) and 1-naph-
thaldehyde (1f) dehydrated to the corresponding nitriles
(2e and 2f, respectively) in good yields under the above
conditions. Dibenzyl ketoxime hydrochloride furnished
what is apparently 2,5-dibenzyl-3,6-diphenylpyrazine
(2g):2 this may form via the dimerisation of the nitrile
ylide (4) obtained by the deprotonation of the nitrilium
species (3) initially formed upon rearrangement, and the
The oxime hydrochloride of (+)-camphor furnished a
complex mixture of products when subjected to the above
conditions. IR and NMR spectra indicated the presence
of nitriles: the fragmentation of camphor oxime to
nitriles under Beckmann conditions is well known,3 and
the above mixture was not analysed further.
OH
N
(-H+)
110 o
20 h
C
[Bn
Bn]
N
+
C
.HCl
N
+
C-Bn]
[Ph-CH
Bn
Bn
3
4
1g
Bn = PhCH2
Ph
Bn
Ph
N
Bn
C
Ph
N
Bn
Ph
[O]
+N
H
+
N+
C
N
Ph
Bn
Bn
N
H
Bn
Ph
5
2g
4
4
Scheme 3.
† Typical procedure: A stirred solution of the oxime 1 (1 g) in dry diethyl ether (20 ml), in a 100 ml two-necked round-bottomed flask protected
by a CaCl2 guard tube, was saturated with dry hydrogen chloride gas via an inlet. A white solid precipitated out, which was allowed to settle
and collected by pipetting out the supernatant ether under nitrogen, and removing trace volatiles in vacuo. A pinch was transferred under
nitrogen to a melting point capillary, which was then fully sealed before the determination of the mp. The rest was heated under nitrogen as
indicated (Table 1), the reaction being followed by TLC. The darkened solid was cooled and taken into ether; the resulting solution was washed
successively with NaHCO3 solution and water, dried (MgSO4) and the solvent evaporated in vacuo. The products 2 were purified by
recrystallisation and identified by their mp’s, and IR and 1H NMR spectra.

S. Chandrasekhar, K. Gopalaiah / Tetrahedron Letters 42 (2001) 8123–8125
8125
References
The present method employs no solvent in the rear-
rangement step per se and the work-up is simple—
washing an ether solution of the reaction mixture
with bicarbonate solution to remove the hydrogen
chloride, etc. The absence of by-products also adds to
the overall simplicity of the procedure. There are two
previous reports of the solid-state Beckmann reac-
tion,‡ involving the oxime picrates4 and the admixing
of oximes and p-toluenesulphonic acid.5 However, the
present method is apparently advantageous as it
employs the simple and inexpensive hydrogen chlo-
ride.
1. Anilkumar, R.; Chandrasekhar, S. Tetrahedron Lett. 2000,
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‡ We are grateful to a referee for kindly bringing these to our
attention.