Improved oxidation of active methyl group of N-heteroaromatic compounds by selenium dioxide in the presence of tert-butyl hydroperoxide

Article abstract of DOI:10.3987/com-02-9702

The oxidation of active methyl group of N-heteroaromatic compounds including both of bicyclic and monocyclic compounds using SeO₂ was considerably improved in the presence of tert-butyl hydroperoxde in dioxane to give the corresponding aldehyde or carboxylic acid in the moderate to good yields. The present oxidation proceeds more mildly and more selectively to form aldehyde rather than carboxylic acid, compared with conventional SeO₂ oxidation without tert-butyl hydroperoxide.

Full text of DOI:10.3987/com-02-9702

HETEROCYCLES, Vol. 60, No. 4, 2003, pp. 953 - 957
Received, 24th December, 2002, Accepted, 6th February, 2003, Published online, 10th February, 2003
IMPROVED OXIDATION OF ACTIVE METHYL GROUP OF
N-HETEROAROMATIC COMPOUNDS BY SELENIUM DIOXIDE IN
THE PRESENCE OF tert-BUTYL HYDROPEROXIDE
Yoshinobu Tagawa, Katsuya Yamashita, Yoshitaka Higuchi, and Yoshinobu
Goto*
Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1,
Jonan-ku, Fukuoka 814-0180, Japan
Abstract – The oxidation of active methyl group of N-heteroaromatic compounds
including both of bicyclic and monocyclic compounds using SeO
2
was
considerably improved in the presence of tert-butyl hydroperoxde in dioxane to
give the corresponding aldehyde or carboxylic acid in the moderate to good
yields. The present oxidation proceeds more mildly and more selectively to form
2
aldehyde rather than carboxylic acid, compared with conventional SeO oxidation
without tert-butyl hydroperoxide.
2 2
Selenium dioxide (SeO ) oxidation has been well-documented as mild and selective oxidation and SeO is
particularly used for oxidation of active methyl, methylene and methine groups, alcohols and unsaturated
1
bonds and for dehydrogenation of ethylene compounds. Active methyl group of aromatic and
2
N-heteroaromaic compounds is oxidized by SeO to give the corresponding aldehydes or carboxylic acids,
but in some cases the oxidation has resulted in the low yield of the corresponding aldehydes and
1
carboxylic acids and the formation of undesired by-products.
In order to improve such an inefficient SeO
2
oxidation we examined SeO
2
oxidation of active methyl
2
group of N-heteroaromatic compounds in the presence of t-butyl hydroperoxide (TBHP) and revealed in
this report that SeO
smoothly at lower temperature to afford the corresponding aldehyde or carboxylic acid than the
traditional SeO oxidation without TBHP. The general procedure of the present oxidation is as follows :
To a solution of SeO (23 mmol) in solvent (20 mL) was added dropwise 70%TBHP (10 mmol) and the
mixture was stirred for 0.5 h at room temperature to form the complex. After the starting material (SM)
10 mmol) was added to the mixture, the resulting solution was heated or refluxed according to Tables.
2
oxidation of active alkyl compounds proceeds in the presence of TBHP more
2
2
(

The reaction mixture was filtered and the solvent was evaporated to give the residue which was, after
addition of a little amount of water, extracted with CHCl
3
. The CHCl
3
fraction was purified with silica
3
gel column chromatography to afford the product as shown in Tables. The oxidation of lepidine 1-oxide
2
by SeO / peroxide in search of the optimal reaction conditions was at first investigated in terms of
choosing solvent, peroxide and the molar ratio of SM, peroxide and SeO
2
to give the results as shown in
Table 1, 2, and 3.
Table 1
Effect of peroxide on the yield of aldehyde
CH3
CHO
SeO / peroxide
2
reflux, 3 h, in dioxane
N
O
N
O
a)
SM
Solvent
Peroxide
Temp.(℃)
Time(h)
3
Yield(%)
55
b)
lepidine 1-oxide dioxane
70%TBHP
reflux
c)
MCPBA
reflux
reflux
reflux
reflux
3
3
3
3
46
7
45
55
3
2 2
0%H O
-
80%TBHP
a) starting material
b) tert-butyl hydroperoxide
c) m-chloroperbenzoic acid
Table 2
Effect of molar ratio on the yield of aldehyde
Molar ratio of
a)
b)
SM
Solvent SM : TBHP
: SeO
: 2.3
: 2.3
4
2
Temp.(℃)
reflux
Time(h)
Yield(%)
lepidine 1-oxide
dioxane
1 :
1
0
0
1
2
3
3
3
3
3
55
45
44
25
28
1
1
1
1
:
reflux
reflux
:
:
:
:
1
1
reflux
reflux
a) starting material
b) 70% tert-butyl hydroperoxide
Table 3
Effect of solvent on the yield of aldehyde
Molar ratio of
a)
b)
SM
Solvent
dioxane
acetone
THF
SM : TBHP
: SeO
2
Temp.(℃) Time(h)
Yield(%)
lepidine 1-oxide
1 :
1 :
1 :
1
1
1
:
:
:
2.3
2.3
2.3
reflux
reflux
reflux
3
3
3
55
0
4
c)
DME
1 :
1
1
:
:
2.3
2.3
reflux
reflux
3
3
17
0
dichloromethane 1 :
a) starting material
b) 70% tert-butyl hydroperoxide
c) 1,2-dimethoxyethane

Judging from these experimental results, we adopted TBHP (70%) as a peroxide, dioxane as a solvent,
and the molar ratio of 1 : 1 : 2.3 ( = SM : TBHP : SeO ). Using the above-mentioned reaction conditions
we carried out the oxidation of active methyl group on the various types of N-heteroaromatic compounds
2
(
Table 4 and 5).
Table 4
Oxidation of active methyl group on bicyclic N-heteroaromatic compound
a)
SM
Reaction Conditions
Product (%)
CHO
A , 1.5 h , 50 ℃
85
N
B , 1.5 h , 50 ℃
no reaction
4
CH3
N
SeO
2
, AcOH-Ac
2
O
CHO
1
.5 h , 85-90 ℃
5
0-60
or
5
N
SeO
2
, xylene , 1 h , 135 ℃
6
SeO
2
2
, H O-dioxane
8
9
1
h , reflux
N
CH=CH
N
A , 1 h , 50 ℃
B , 1 h , 50 ℃
80
N
CHO
no reaction
7
2
SeO , pyridine
7
5
1
N
CH3
70 min , 115 ℃
N
COOH
8
SeO
2
2
, H O-dioxane
9
N
C
O
C
O
N
1
h , reflux
N
9
A , 1 h , 50 ℃
B , 1 h , 50 ℃
quant.
33
N
N
N
N
CHO
CHO
CH3
N
a) starting material
A : SM : 70%TBHP : SeO = 1 : 1 : 2.3 and dioxane as a solvent.
2
B : SM : SeO = 1 : 2.3 and dioxane as a solvent.
2

Table 5 Oxidation of active methyl group on monocyclic N-heteroaromatic compound
a)
SM
Reaction Conditions
Product (%)
CHO
COOH
CH3
A , reflux , 24 h
34
11
19
72
N
N
CHO
COOH
B , reflux , 24 h
2
N
N
N
CHO
10
A , 50 ℃ , 0.5 h
N
CH3
N
COOH
1
1
N
B , 50 ℃ , 0.5 h
N
N
18
72
11
N
COOH
SM : 70% TBHP : SeO
1 : 10 : 2.3 , 50 ℃ , 0.5 h
2
=
N
dioxane
N
N
N
N
b), 12
A , reflux , 3 h
N
CHO
CH3
B , reflux , 3 h
no reaction
a) starting material
b) The aldehyde was obtained as 2,4-dinitrophenylhydrazone.
A : SM : 70%TBHP : SeO = 1 : 1 : 2.3 and dioxane as a solvent.
B : SM : SeO = 1 : 2.3 and dioxane as a solvent.
2
2
Table 4 and 5 show that the oxidation of active methyl group on both of monocyclic and bicyclic
N-heteroaromatic compounds proceeds more smoothly under reaction conditions A (with TBHP) than the
oxidation under reaction conditions B (without TBHP) to give the corresponding aldehydes and
carboxylic acids in better yields. Furthermore, reaction conditions A is much milder one than conditions
B to give larger amount of aldehyde than carboxylic acid and facilitated selective oxidation suppressing
the formation of by-products. We suggest the plausible mechanism shown in the Scheme.
O-Bu-tert
O
HO Se OH
CH3
H2C
CHO
O
tert-BuO Se OH
N
O
SeO /tert-BuOOH
2
N
O
N
O
(
C)
Scheme

Selenium tert-butyl peroxo complex reacts with active methyl group to form the intermediate C which
1
3
rearrange to aldehyde . This mechanism is supported by the fact that the gelatinous precipitate obtained
by the reaction of 4-methyl pyridine with SeO / TBHP at 50 ℃ showed CH proton and carbon signals
2
2
in the NMR spectrum and that it was transformed into the corresponding aldehyde when it was refluxed
for a few hours.
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