4
70 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
Oxidative Rearrangement of 3,5-Di-tert-butyl-4-
hydroxybenzaldehyde Acetals$
Osvalds Pugovics, Valerjans Kauss, Ivars Kalvinsh* and
Ï
1998, 470±471$
a
a
a
b
Markus R. Gold
a
Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga, LV 1006, Latvia
b
Merz Co., GmbH&Co., Frankfurt am Main, PO-box 111353, 60048 Frankfurt/Main, Germany
3,5-Di-tert-butyl-4-hydroxybenzaldehyde acetals rearrange to various esters when oxidized with potassium ferricyanide
in alkaline medium.
During the course of our studies on pharmacologically
active 3,5-di-tert-butyl-4-hydroxybenzyl ethers we started
to investigate the oxidation of both symmetrical and unsym-
metrical 3,5-di-tert-butyl-4-hydroxybenzaldehyde acetals in
order to generate reactive quinone methides.
Here we wish to report a molecular rearrangement of
,5-di-tert-butyl-4-hydroxybenzaldehyde acetals 1 by treat-
3
ment with potassium hexacyanoferrate(III) in benzene±
aqueous sodium hydroxide. A common oxidation pro-
1
cedure gave a mixture of products depending on the
structure of the acetal 1 (Scheme 1 and Table 1).
Scheme 2 Hydrolysis of quinone methide 6
type derivatives, while products 3 and 4 are less prominent
5
in the reaction mixture.
Experimental
1
All
WH-90 instrument. IR spectra were recorded on an Perkin-Elmer
H NMR spectra were recorded on a 90 MHz Bruker
apparatus in Nujol. Acetals 1a±c were prepared from 2,6-di-tert-
butyl-4-[3-(3-pyridyl)-2-oxaprop-1-yl]phenol and 3,5-di-tert-butyl-
6
4
-hydroxybenzaldehyde correspondingly according to known
3
methods. All oxidations were carried out in an argon atmosphere
and solutions were degassed and saturated with argon prior
to use. Column chromatography was performed on Kieselgel 60
using hexane±ethyl acetate. The purity of ®nal products was tested
by TLC on Kieselgel 60 F254 plates (Merck). Eluent: hexane±
ethylacetate, visualisation agent: 15 wt.% solution of phospho-
molybdic acid in ethanol.
General procedure for the oxidation of 3,5-di-tert-butyl-4-hydroxy-
benzaldehyde acetals.ÐAcetal 1 (0.50 mmol) was dissolved in
benzene (5 ml) and under vigorous stirring added in one portion
to a pre-cooled (6 8C) solution of potassium hexacyanoferrate(III)
Scheme 1 Oxidation of 3,5-di-tert-butyl-4-hydroxybenzaldehyde
2
(
500 mg, 1.52 mmol) and sodium hydroxide (300 mg, 7.5 mmol) in
ml of water. The reaction mixture turned green, stirring was
1
2
1
acetals; R R CH
2
(3-Py) a; R Me, R CH
2
(3-Py) b;
5
1
2
R R Me c
continued for 30±60 min until the green color faded and TLC on
Kieselgel 60 showed the disappearance of the starting material.
The organic layer was separated, the aqueous phase washed
with 2Â3 ml of benzene and extracts washed with brine until
neutral pH. The solution was dried over sodium sulfate, evaporated
in vacuo, and products were separated on a 1.5 Â 15 cm column.
We suggest the formation of quinone methide 6 to be the
initial step. Addition of water and subsequent elimination of
2,3
alcohol leads to the formation of the ester 5 (Scheme 2).
Meanwhile quinone methide 6 can undergo Claisen ester
1
Methyl 3,5-di-tert-butyl-4-hydroxybenzoate (5c).Ð H NMR
4
enolate like rearrangement of radical reactions to give
t
(CDCl
OH), 7.89 (s, 2H, C
3
(
(
3
TMS): ꢀ 1.47 (s, 18H, Bu ), 3.88 (s, 3H, OCH
3
), 5.66 (s, 1H,
�
1
H ). IR: 1650, 3620 cm .
rearranged products 2, 3 and 4. The steric eect of tert-
butyl groups facilitate the formation of cyclohexadienone 2
6
2
1
-Pyridylmethyl-3,5-di-tert-butyl-4-hydroxybenzoate (5a).Ð H NMR
t
CDCl
s, 1H, OH), 7.18±7.40 (m, 1H, Py-5H), 7.62±7.82 (m, 1H,
), 8.56 (m, 1H, Py-6H), 8.71 (m, 1H,
3 2
TMS): ꢀ 1.47 (s, 18H, Bu ), 5.36 (s, 2H, CH Py), 5.69
Table 1 Yields of reaction products after oxidation of
3
Py-4H), 7.88 (s, 2H, C
6
H
2
�
1
,5-di-tert-butyl-4-hydroxybenzaldehyde acetals
Py-2H). IR: 1645, 3630 cm
-Pyridylmethyl-3,5-di-tert-butyl-4-(3-pyridylmethoxy)benzoate (4a).
.
3
Ð H NMR (CDCl
a
Yield (%)
1
t
t
3
TMS): ꢀ 1.28 (s, 9H, Bu ), 1.41 (s, 9H, Bu ),
CH Py), 7.11±7.44 (m, 2H,
1
R
2
R
4
.88 (s, 2 H, OCH Py), 5.38 (s, 2H, CO
2
2
2
2
3
4
5
Py-5H), 7.62±7.87 (m, 2H, Py-4H), 7.99 (s, 2H, C
(m, 4H, Py-2H and Py-6H).
2,6-Di-tert-butyl-4-(3-pyridylmethyl)oxycarbonyl-4-(3-pyridylmethyl)-
6 2
H ), 8.49±8.78
CH
Me
Me
2
(3-Py)
CH
CH
Me
2
(3-Py)
(3-Py)
76
90
Ð
2
Ð
Ð
3
Ð
Ð
10
Ð
91
2
1
cyclohexa-2,5-dien-1-one (2a).Ð H NMR (CDCl
3
TMS): ꢀ 1.11
Py), 5.19 (s, 2H, CO CH Py), 6.67
6 2
H ), 6.89±7.69 (m, 4H, Py-5H and Py-4H), 8.18±8.64
t
a
(s, 18H, Bu ), 3.18 (s, 2H, CH
2
2
2
Yields refer to isolated products.
(
(
s, 2H, C
m, 4H, Py-2H and Py-6H). IR: 1235, 1647, 1665, 1732 cm
2,6-Di-tert-butyl-4-methyloxycarbonyl-4-(3-pyridylmethyl)cyclohexa-
�
1
.
*To receive any correspondence.
1
t
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
2,5-dien-1-one (2b).Ð H NMR (CDCl
3.21 (s, 2H, CH Py), 3.79 (s, 3H, OCH
6.96±7.56 (m, 2H, Py-5H and Py-4H), 8.27 (d, J 1.5 Hz, 1H,
3
TMS): ꢀ 1.16 (s, 18H, Bu ),
2
3
), 6.74 (s, 2H, C ),
6 2
H
Pugovics, Osvalds
