Beckmann reaction of oximes catalysed by chloral: Mild and neutral procedures

Article abstract of DOI:10.1016/S0040-4039(02)02644-8

A variety of ketoximes undergo the Beckmann rearrangement when heated with 0.5 molar equiv. of chloral (neat melt/～130°C), to furnish the corresponding amides in excellent yields (generally 80-95%) after simple work-up. (Aromatic aldoximes dehydrated to the corresponding nitriles in excellent yields under similar conditions.) The absence of solvent, Br?nsted acids, strong Lewis acids and by-products, and a simple work-up characterise the procedures.

Full text of DOI:10.1016/S0040-4039(02)02644-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 755–756
Beckmann reaction of oximes catalysed by chloral:
mild and neutral procedures
Sosale Chandrasekhar* and Kovuru Gopalaiah
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 16 October 2002; revised 15 November 2002; accepted 22 November 2002
Abstract—A variety of ketoximes undergo the Beckmann rearrangement when heated with 0.5 molar equiv. of chloral (neat
melt/ꢀ130°C), to furnish the corresponding amides in excellent yields (generally 80–95%) after simple work-up. (Aromatic
aldoximes dehydrated to the corresponding nitriles in excellent yields under similar conditions.) The absence of solvent, Brønsted
acids, strong Lewis acids and by-products, and a simple work-up characterise the procedures. © 2003 Elsevier Science Ltd. All
rights reserved.
We have been interested in developing improved proce-
dures for the historic Beckmann rearrangement in view
of its continuing interest and importance.1 We have
recently reported several new procedures which are
characterised by simplicity, mildness and environmental
compatibility. We report herein another procedure for
this important classical reaction which employs the
readily available chloral as catalyst.
knowledge. It was of interest to investigate the possible
use of chloral (trichloroacetaldehyde) in view of its
ready availability and known Lewis acidic properties.2
(The well-known fact that chloral generally exists as the
hydrate derives from its highly electrophilic nature. In
Table 1. The conversion of the oximes 1/6 to the amides
3 or nitriles 7 with chloral: conditions and yields of the
products (cf. Schemes 1 and 3)a
The search for improved conditions for the Beckmann
reaction essentially involves a search for new elec-
trophilic reagents with the desired characteristics of
mildness, etc. (The reaction occurs under conditions of
electrophilic activation of the oxime hydroxyl group.1)
Generally, a variety of Brønsted and strong Lewis acids
have been employed as reagents, e.g. p-toluenesul-
phonic acid, SnCl4, PCl5, etc. However, mild Lewis
acids have hardly ever been reported to the best of our
Oxime
Conditions: °C/h
Amide/nitrile
Yield (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
6a
6b
6c
6d
125/3
130/6
3a
3b
3c
3d
3e
3f
3g
3h
3i
7a
7b
7c
7d
95
74
84
98
97
89
85
67
89
87
73
94
96
140/6.5
120/3.5
120/1.5
120/3.5
140/5
90/7.5
120/2.5
120/2
120/2.5
140/2.5
135/4.5
a Typical procedure. An intimate mixture of the oxime (1.0 mmol) and
chloral hydrate (0.5 mmol) was heated, first in vacuo (10 Torr) for
0.5 h and then at 760 Torr under N2 as indicated (Table 1). The
mixture was taken into CH2Cl2, washed with water and worked-up
in the usual way.1 The crude products were recrystallised (EtOAc/
ligroin) the resulting pure compounds being identified by their mp’s
and spectral data (IR, 300 MHz 1H NMR and mass spectra). Note
that in the case of cyclohexanone oxime 1h, and of the aldoximes 6
generally, pre-formed chloral (obtained by heating the hydrate at
110°C/0.5 Torr/1 h) was employed to avoid hydrolysis.
Scheme 1. R1/R2 in 1/3: (a) Ph/Me; (b) Ph/Et; (c) Ph/Ph; (d)
4-(MeO)C6H4/Me; (e) p-tolyl/Me; (f) 4-ClC6H4/Me; (g) 4-
BrC6H4/Me; (h) -(CH2)5-; (i) naphth-2-yl/Me.
Keywords: Beckmann rearrangement; catalytic; chloral; environmen-
tally mild.
* Corresponding author. Fax: (+91 80) 3600 529; e-mail: sosale@
orgchem.iisc.ernet.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02644-8

756
S. Chandrasekhar, K. Gopalaiah / Tetrahedron Letters 44 (2003) 755–756
Scheme 2.
from the hydrate as above: and in these cases the
reactions were complete with less than 0.5 molar equiv.
of chloral. Also, the initial in vacuo phase was essential
as otherwise partial hydrolysis of the oximes was
observed, presumably by the water in chloral hydrate.
Thus, by all indications the active reagent species is
chloral, formed by heating the hydrate in vacuo. (This
is easily removed by washing the reaction mixture with
water.)
the present studies chloral was generated in situ by
heating the hydrate in vacuo.)
When a variety of ketoximes 1 was admixed with
chloral hydrate 2 (0.5 molar equiv.) and the mixture
heated (initially at 10 Torr and then under N2) the
Beckmann rearrangement was effected in excellent
yields to afford the expected amides 3 (Scheme 1, Table
1). It is possible that the mechanism (Scheme 2)
involves initial formation of the hemi-acetal intermedi-
ate 4 which breaks down to 5 via nucleophilic participa-
tion of the hydroxyl group as shown;1 5 breaks down to
the amide 3, regenerating chloral in the process and
enabling an overall catalytic process. A few aromatic
aldoximes 6 were also investigated, and were found to
undergo dehydration to the corresponding nitriles 7 in
good yields under the above conditions (Table 1,
Scheme 3; the oximes 1 and 6 had the indicated
stereochemistry.)
Although chloral is known to participate in aromatic
electrophilic substitution reactions, it is generally a
weaker electrophile than the metal halides (SnCl4,
etc.).2 Chloral is less toxic than most other reagents for
the Beckmann reaction, the hydrate having found use
as a sedative in the past.3 It is also inexpensive, easily
stored and effective catalytically. Thus, the Beckmann
rearrangement has been effected under neutral, rela-
tively mild and solvent-free conditions with an exceed-
ingly simple work-up, all of which make it
environmentally mild.
The above reactions could also be effected by heating
the oximes with chloral, which had been pre-formed
References
1. Chandrasekhar, S.; Gopalaiah, K. Tetrahedron Lett. 2002,
43, 2455–2457 and references cited therein.
2. Gill, G. B. In Encyclopedia of Reagents for Organic Syn-
thesis; Paquette, L. A., Ed.; John Wiley: Chichester, 1995;
Vol. 2, pp. 1048–1052.
Scheme 3. Ar in 6/7: (a) p-anisyl; (b) 3-MeO-4-(OH)C6H3; (c)
3,4-(MeO)2C6H3; (d) naphth-1-yl.
3. The Merck Index, 12th ed.; Budavari, S., Ed.; Merck:
Whitehouse Station, NJ, 1996; p. 343.