A bromine-catalysed free-radical oxidation of acetamides from primary and secondary alkylamines by H2O2

Article abstract of DOI:10.1039/b008965f

New procedures based on the oxidation by bromine-catalysed hydrogen peroxide in a two-phase system provide simple and cheap transformations of alkylamines to carbonyl derivatives (aldehydes, ketones, carboxylic acid, imides, lactams) through the corresponding acetamides.

Full text of DOI:10.1039/b008965f

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A bromine-catalysed free-radical oxidation of acetamides from primary and
secondary alkylamines by H2O2
Hans-René Bjørsvik,a Francesca Fontana,b Lucia Liguoric and Francesco Minisci*c
a Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway
b Department of Engineering, University of Bergamo, viale Marconi 5, I-24044 Dalmine (BG), Italy
c
Department of Chemistry, Politecnico di Milano, via Mancinelli 7, I-20131 Milano, Italy.
E-mail: Francesco.Minisci@polimi.it
Received (in Liverpool, UK) 7th November 2000, Accepted 8th February 2001
First published as an Advance Article on the web 26th February 2001
New procedures based on the oxidation by bromine-
catalysed hydrogen peroxide in a two-phase system provide
simple and cheap transformations of alkylamines to car-
bonyl derivatives (aldehydes, ketones, carboxylic acid,
imides, lactams) through the corresponding acetamides.
the a-position. To avoid this limitation we have investigated the
bromine-catalysed H2O2 oxidation of the corresponding acet-
amides.
With primary alkyl groups, the carboxylic acid was easily
obtained, but when the primary alkyl group was benzylic the
corresponding aldehyde was formed instead, with good
selectivity at complete conversion. A free-radical chain is
involved according to Scheme 1.
Classical rearrangement reactions, such as the Hofmann1,2 and
Curtius1,3 rearrangements, allow the transformation of car-
boxylic acids to amines through the corresponding amides or
acyl azides [eqn. (1)], while the Beckmann4,5 rearrangement
involves the formation of amides from ketones through the
oximes [eqn. (2)].
(1)
(2)
In this Communication we report a new simple oxidation
procedure, which allows the reverse transformation of alkyl-
amines to carboxylic acids, aldehydes, ketones and imides
through the intermediates acetamides [eqn. (3)].
Scheme 1
Also in this case, as for alcohol oxidation, the selectivity was
determined by the relative rates of hydrogen abstraction by Br·
from the amide (ka) or from the aldehyde (kAa). Since ka > kAa for
R = aryl, while ka < < kAa for R = alkyl, an opposite behaviour
is observed in the two cases. Polar and enthalpic effects, due to
the different electronic configurations of the alkyl (p-type) and
acyl (s-type) radicals,8 determine this different reactivity, as
previously6,7 discussed for the oxidation of alcohols.
With secondary alkyl groups the corresponding ketones were
obtained, but under the reaction conditions a partial bromination
of the ketones occurs; conversion and selectivity are low with
cyclohexyl derivatives, due to the particular ease of bromination
of cyclohexanone, compared to acyclic ketones.9
By-products of the oxidation according to Scheme 1 are the
imides, formed by further oxidation of a-hydroxyamides before
cleavage. In any case, imides can be easily hydrolysed, so that
high overall yields of carboxylic acids can be obtained by
refluxing the acidic reaction mixture; under the reaction
conditions (room temperature) the imides are not substantially
hydrolysed, supporting the mechanism of Scheme 1 for the
formation of carboxylic acids.
With cyclic amines, such as 1 and 2, the higher stability of a-
hydroxyamides leads to the corresponding imides 3 and 4 with
high yields and to the corresponding lactams 5 and 6 by
hydrolysis [eqns. (6) and (7)].
(3)
Recently we have reported6,7 simple and highly selective
methods for the oxidation of primary alcohols to either
aldehydes or esters, depending on the benzylic or aliphatic
nature of the alcohol, by bromine-catalysed H2O2 [eqns. (4) and
(5)].
(4)
(5)
The selectivity of these reactions is determined by the relative
rates of hydrogen abstraction by bromine atom from the alcohol
(k4) and from the corresponding aldehyde (k5). For benzylic
alcohols k4 > k5 and the reaction gives high selectivity in
aldehyde with complete conversion, whereas for non-benzylic
alcohols k4 < < k5 and the oxidation gives high selectivity in
esters even at very low conversion, without formation of a
significant amount of aldehydes.
Aliphatic amines, in principle, should be more reactive, both
for enthalpic and polar reasons, than the corresponding alcohols
towards hydrogen abstraction by Br·. The acidic medium,
however, deactivates the amines by protonation, which reverses
the polar effect and increases the strength of the C–H bonds in
(6)
DOI: 10.1039/b008965f
Chem. Commun., 2001, 523–524
This journal is © The Royal Society of Chemistry 2001
523

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Table 1 Oxidation of R1R2NCOMe (1 mmol) by H2O2 and Br2 in a two-phase system (H2O–DCEa)
H2O2/
mmol
Solvent ml
H2O–DCE
#
R1
R2
Br2/mmol
Conv. %
Reaction products (%)
Carboxylic acid (68)
Imide (26)
Carboxylic acid (72)
Imide (24)
Carboxylic acid (63)
Imide (25)
Carboxylic acid (72)
Imide (23)
Carboxylic acid (66)
Imide (28)
Carboxylic acid (61)
Imide (23)
Carboxylic acid (48)
Imide (45)
Carboxylic acid (47)
Imide (48)
Carboxylic acid (44)
Imide (43)
Carboxylic acid (46)
Imide (44)
Ketone (70)
a-Br-ketone (12)
Ketone (69)
1b n-C4H9
H
0.4
0.4
0.4
0.4
0.8
0.8
2.2
2.2
2.2
1.8
1.8
1.8
1.8
3.6
3.6
—
1/4
1/4
1/4
1/4
1/4
1/4
4/8
4/8
4/8
4/8
4/8
4/8
4/8
4/8
4/8
1/4
4/8
> 99
97
2b n-C6H13
H
3b Me2CH-CH2
4b n-C12H23
5b n-C4H9
H
95
H
98
n-C4H9
98
6b n-C6H13
n-C6H13
92
7c n-C4H9
H
H
H
H
H
H
H
H
H
H
H
> 99
> 99
96
8c n-C6H13
—
9c n-C12H23
10d n-C4H9
—
HBr
4.4
H2O2
2.2
93
11c Me2CH-n-C5H11
12c (n-Bu)2CH
13c Ph-CH-Me
14c Cyclohexyl
15c Cyclohexyl
16b (n-Bu)2CH
17d (n-Bu)2CH
1.3
1.3
1.3
1.3
2.2
0.3
—
—
—
—
—
1
95
93
a-Br-ketone (13)
Ketone (73)
> 99
26
a-Br-ketone (13)
Cyclohexanone (49)
a-Br-cyclohexanone (51)
Cyclohexanone (46)
a-Br-cyclohexanone (53)
Ketone (56)
a-Br-ketone (41)
Ketone (71)
a-Br-ketone (12)
3 (96)
4 (95)
35
41
HBr
2.6
2.2
2.2
1.2
1.3
89
18c
19c
20b
1
2
2
1
2
2
—
—
0.8
4/8
4/8
1/1
98
100
100
4 (98)
Aldehyde (95)
Imide (5)
Aldehyde (81)
Imide (12)
Aldehyde (73)
Imide (4)
Aldehyde (82)
Imide (6)
21c PhCH2
H
H
H
H
H
0.5
1.0
0.3
—
2/2
49
83
22c p-Me-C6H4-CH2
23b p-Me-C6H4-CH2
24d p-Me-C6H4-CH2
25b p-Cl-C6H4-CH2
—
4/4
1.2
1.2
0.8
1/6
96
HBr
2.4
4/4
85
Aldehyde (89)
Imide (4)
0.4
0.6/3
100
a DCE = 1,2-dichloroethane. b Procedure: the aqueous solution of H2O2 was added dropwise to the mixture of the other reagents and solvents reported in
the Table, at rt and under effective stirring for 3 h. c Procedure: the mixture of the reagents and solvents reported in the Table 1 was effectively stirred for
3 h at rt. d Procedure: as in c but 2 mol of HBr and 1 mol H2O2 were used instead of 1 mol Br2. All the reaction products were known and characterised by
comparison with authentic samples (GLC-MS and NMR); quantitative yields were determined by GLC using as internal standards n-C7H15COOH for
carboxylic acids, p-MeO-C6H4-CHO for aromatic aldehydes, n-Pr-CO-Pr-n for ketones and n-C6H13CONHCOMe for imides.
amount of Br2 by electrophilic bromination and inhibits the
free-radical oxidation.
(7)
Notes and references
1 J. R. Molpass, Comprehensive Organic Chemistry, vol. 2, ed. I. O.
Sutherland, 1979, p. 17.
2 D. V. Banthorpe, The chemistry of the amino group, ed. S. Patai, 1968,
p. 630.
3 D. V. Banthorpe, The chemistry of the amino group, ed. S. Patai, 1968,
p. 623.
4 B. C. Chollis and J. A. Chollis, Comprehensive Organic Chemistry, vol.
2, ed. I. O. Sutherland, 1979, p. 966.
5 D. V. Banthorpe, The chemistry of the amino group, ed. S. Patai, 1968,
p. 623.
6 A. Amati, G. Dosualdo, F. Fontana, F. Minisci and H.-R. Bjørsvik, Org.
Process Res. Dev., 1998, 2, 261 and references therein.
7 F. Minisci and F. Fontana, Chim. Ind. (Milan), 1998, 80, 1309 and
references therein.
The reactions, carried out in a two-phase system (H2O–
ClCH2CH2Cl), are initiated by ambient light and the active
oxidant is Br2, which acts in the organic phase; the formed HBr
is extracted by the aqueous phase and oxidised to Br2 by H2O2
making the process catalytic in Br2. Two procedures were
utilised as reported in Table 1. In both cases the overall process
is catalytic in Br2, but a higher concentration of Br2 makes the
overall process faster; an aqueous solution of HBr and H2O2 can
be utilised instead of Br2 in a two-phase system. Procedure a)
gives better results for the synthesis of carboxylic acids because
a higher concentration of Br2 accelerates the oxidation of a-
hydroxyamides to imides, while procedure b) is more suitable
for the synthesis of ketones, which consumes the catalytic
8 F. Minisci, Top. Curr. Chem., 1976, 62, 1.
9 A. J. Waring, Ref. 1, pp. 1027, 1036, vol. 1.
524
Chem. Commun., 2001, 523–524