Ketones to amides via a formal Beckmann rearrangement in 'one pot': A solvent-free reaction promoted by anhydrous oxalic acid. Possible analogy with the Schmidt reaction

Article abstract of DOI:10.1016/j.tetlet.2003.08.038

A variety of ketones can be directly converted into the secondary amides expected from a Beckmann rearrangement of the corresponding oximes in high yield, by heating them with hydroxylamine hydrochloride and anhydrous oxalic acid at ～100°C for 4-12 h. (Aromatic aldehydes afforded mixtures of nitrile and amide.) The transformation is apparently (kinetically) driven by the coupled decomposition of oxalic acid (to CO+CO₂) via the fragmentation of an intermediate oxime mono-oxalate. However, an alternative pathway, mechanistically analogous to the Schmidt reaction, is not only equally likely but may well be general for the Beckmann rearrangement.

Full text of DOI:10.1016/j.tetlet.2003.08.038

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7437–7439
Ketones to amides via a formal Beckmann rearrangement in ‘one
pot’: a solvent-free reaction promoted by anhydrous oxalic acid.
Possible analogy with the Schmidt reaction
Sosale Chandrasekhar* and Kovuru Gopalaiah
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 10 July 2003; revised 1 August 2003; accepted 8 August 2003
Abstract—A variety of ketones can be directly converted into the secondary amides expected from a Beckmann rearrangement of
the corresponding oximes in high yield, by heating them with hydroxylamine hydrochloride and anhydrous oxalic acid at ꢀ100°C
for 4–12 h. (Aromatic aldehydes afforded mixtures of nitrile and amide.) The transformation is apparently (kinetically) driven by
the coupled decomposition of oxalic acid (to CO+CO2) via the fragmentation of an intermediate oxime mono-oxalate. However,
an alternative pathway, mechanistically analogous to the Schmidt reaction, is not only equally likely but may well be general for
the Beckmann rearrangement.
© 2003 Elsevier Ltd. All rights reserved.
The Beckmann rearrangement, a most important and
useful transformation in synthetic chemistry,1 is generally
effected starting from an oxime that is derived from the
corresponding ketone. Although the direct conversion of
ketones to secondary amides may be effected via the
classical Schmidt reaction, this employs the hazardous
hydrazoic acid.2 Recent variants have employed ampho-
teric reagents,3 e.g. ZnO, TiO2 or Al2O3/MeSO3H: these
can both generate the oxime in situ (usually requires
base4) and effect its Beckmann reaction (usually requires
acid1). In fact, we have recently reported an improved
oxime synthesis employing either base (pyridine) or acid
(anhydrous oxalic acid).4 This unprecedented synthesis
of oximes under acidic conditions allowed its elaboration
into a ‘one-pot’ method for the conversion of ketones to
secondary amides, as described below.
In the present procedure a mixture of the ketone
1, hydroxylamine hydrochloride 2 and anhydrous
oxalic acid 3 was heated (without a solvent) at 100–
110°C for 4–12 h (Scheme 1). The products 5 formed in
generally high yields (60–96%), were found to be the
secondary amides expected from the Beckmann rear-
rangement of the corresponding ketoximes 4 (Table 1).
The formation of the ketoxime was indicated by TLC
in several cases, and it was shown that the oximes
underwent the Beckmann reaction under similar con-
ditions (Table 1). [However, see below for a discussion
of the possible mechanism. Aromatic aldehydes pro-
vided mixtures of the dehydration (nitrile) and the
rearrangement (amide) products; but note that the
aldoximes furnished only the nitrile (Table 1, entries
i–k).]
Scheme 1.
Keywords: Beckmann rearrangement; ketones; one-pot; oxalic acid; oximes; Schmidt reaction; secondary amides; solvent-free.
* Corresponding author. Fax: (+91 80) 3600 529; e-mail: sosale@orgchem.iisc.ernet.in
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.038

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S. Chandrasekhar, K. Gopalaiah / Tetrahedron Letters 44 (2003) 7437–7439
Table 1. The conversion of the ketones 1 to the amides 5 (Scheme 1): conditions and yieldsa
Entry
Ketone 1/amide 5
Reaction conditions:b
Yield of 5 (%)b
temperature (°C)/time (h)
R
R%
a
b
c
d
e
f
g
h
i
p-Anisyl
Ph
Naphth-2-yl
Me
Ph
Me
100/4.0 (125/5.0)
110/12.5 (130/9.0)
110/6.0 (130/7.0)
80/12.0 (80/12.0)
110/8.5
110/8.0 (108/14.0)
110/6.5 (120/6.0)
110/11.5 (120/15.0)
110/11.5 (125/12.0)
110/3.5 (120/3.0)
110/8.0 (115/7.0)
91 (89)
96 (93)
79 (79)
60 (64)
67
69 (73)
74 (86)
79 (82)
96d (92)
92d (95)
90d (86)
-(CH2)5-c
PhCH2
Ph
Ph
p-Tolyl
p-Anisyl
3,4-(MeO)2C6H3
Naphth-1-yl
PhCH2
Me
Et
Me
H
j
k
H
H
a Typical procedures. The carbonyl compound (1.0 mmol), NH2OH·HCl (1.3 mmol) and anhydrous oxalic acid (from the dihydrate over P2O5 at
100°C/2 h 0.5 Torr; 2.5 mmol) were heated together under N2 as indicated in Table 1. The residue was dissolved in CH2Cl2 (20 ml), the solution
washed successively with saturated NaHCO3 (30 ml) and water (30 ml×2), dried (Na2SO4) and evaporated in vacuo. The resulting residue was
recrystallised from EtOAc/hexane to obtain the pure amide 5, which was characterised by melting point and spectral data (IR, 300 MHz 1H
NMR and MS). Note: With oxime 4 (1.0 mmol) as substrate, 1.5 mmol of the oxalic acid was used and the reaction conducted as above. The
reactions were incomplete if less than the indicated amounts of reagents were employed. The decomposition of oxalic acid during the reaction
was indicated by the presence of CO2 in the gaseous effluents, which turned Ca(OH)2 solution turbid.
b The data in parenthesis refer to the reaction with the oxime 4 as substrate.
c Cyclohexanone“o-caprolactam.
d The aldehydes furnished mixtures (unresolved) of the corresponding nitrile and amide (by IR and NMR) in the following ratios (by GCMS):
1i (1.0:6.6); 1j (1.0:1.1); 1k (1.0:0.3). The spectra of the mixtures did not permit a clear distinction between the two possible amide products,
ArCONH2 and ArNHCHO. (The aldoximes furnished only the corresponding nitriles.)
Although the above transformation apparently occurs
via the oxime, the mechanism of its formation is
unclear. It is possible that the mono-oxalate ester 6
(Scheme 2) of hydroxylamine hydrochloride 2 is an
intermediate: 6 would be more acidic than 2 and may
thus provide a small but finite concentration of the
corresponding conjugate base 7 for nucleophilic reac-
tion with ketone 1. Thus, we are essentially proposing
that the esterification of 2 to 7 reduces the basicity
more than the nucleophilicity of the nitrogen centre.
The resulting oxime mono-oxalate 8 probably rear-
ranges via the decomposition of the oxalate moiety to
CO and CO2 as shown formally in 9. Thus, although
the overall transformation is thermodynamically con-
trolled, it is apparently kinetically driven by the decom-
position of the oxalate 8. (Note the gaseous
by-products which simplify purification; oxalic acid
derivatives are well known to decompose as shown.5)
In fact, the rather unusual reaction conditions
employed above raise the fascinating question as to
whether a classical Beckmann reaction is being effected
at all. Note that the water by-produced in the forma-
tion of the putative oxalate ester 8 is not removed, the
reaction presumably being driven by the thermody-
namic stability of the final amides 5. This leads us to
propose an alternative pathway, that may well occur at
least in parallel with the above mechanism. This
involves the decomposition of the tetrahedral interme-
diate 10 (Scheme 3), which is also derived by the
reversible hydration of the oxime oxalate 8. In fact, not
only is this route analogous to the Schmidt reaction,
but also, the transition state 11 derived from 10 appears
to be more stable than the classical Beckmann transi-
tion state 12: This contains an unsaturated three-mem-
bered ring, and bears a partial positive charge at an sp2
centre adjacent to the electronegative nitrogen centre!
Scheme 2.

S. Chandrasekhar, K. Gopalaiah / Tetrahedron Letters 44 (2003) 7437–7439
7439
Scheme 3.
Furthermore, if in 10 rotation around the CꢀN bond is
much slower than either the migration of the alkyl
group or dehydration to 8, the overall reaction would
display the anti stereochemistry expected of the Beck-
mann reaction: If 10 forms from 8 the (presumed) anti
relationship between R and the N-oxalate moiety
would be retained (as shown); the same conformer of
10 may also be derived from 1 and 7 by invoking
kinetic control, on the basis that its relatively fast
dehydration leads to 8. Therefore, 10 would be
stereoelectronically set up for the migration of the
group R (antiperiplanar to N-oxalate) rather than R%
(evidence for analogous stereoelectronic control has
been reported6). These arguments, of course, explain
how the same amides are formed starting either from
the ketones 1 or the oximes 4. And intriguingly, they
imply that the Beckmann reaction could generally
occur via a mechanism of the Schmidt type: Analogs of
10 and 11 may be reached via nucleophilic (‘Nu’)
addition to a suitably activated oxime (R(R%)C=NX),
leading to the ‘nitrenoid’ transition state 13, nucle-
ophiles or bases being generally present during the
Beckmann reaction.
ondary amides, via a formal oximation-Beckmann rear-
rangement sequence. High yields, an inexpensive
reagent (oxalic acid), gaseous by-products (CO+CO2)
and the absence of solvent characterise the process. We
have also proposed that the Beckmann and Schmidt
reactions are mechanistically analogous.
References
1. Craig, D. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I.; Ley, S. V., Eds.; Pergamon Press: Oxford,
1991; Vol. 7, pp. 689–702.
2. Shioiri, T. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I.; Winterfeldt, E., Eds.; Pergamon Press:
Oxford, 1991; Vol. 6, pp. 820–821.
3. Sharghi, H.; Sarvari, M. H. J. Chem. Res. (S) 2003,
176–178 and references cited therein.
4. Chandrasekhar, S.; Gopalaiah, K. Tetrahedron Lett., in
press.
5. Sustmann, R. In Comprehensive Organic Synthesis; Trost,
B. M.; Fleming, I.; Winterfeldt, E., Eds.; Pergamon Press:
Oxford, 1991; Vol. 6, p. 304.
6. Milligan, G. L.; Mossman, C. J.; Aube´, J. J. Am. Chem.
Soc. 1995, 117, 10449–10459.
In conclusion, we have presented a simple and effective
method for the direct conversion of ketones to sec-