Antioxidant building blocks I. The unexpected C-acetylation of 2,6-Di-tert-butylphenol with isopropenyl acetate

Article abstract of DOI:10.1135/cccc19961244

While the reaction of some 2-substituted and 2,6-disubstituted phenols with isopropenyl acetate resulted in the corresponding phenol acetates, in the reaction of 2,6-di-tert-butylphenol, a useful starting material of antioxidant building blocks, under the same conditions 4-acetyl-2,6-di-tert-butylphenol was the only product.

Full text of DOI:10.1135/cccc19961244

1
244
Gizur, Ferenczy, Agai-Csongor, Domany:
ANTIOXIDANT BUILDING BLOCKS I. THE UNEXPECTED
C-ACETYLATION OF 2,6-DI-tert-BUTYLPHENOL
WITH ISOPROPENYL ACETATE
1
Tibor GIZUR , Gyorgy G. FERENCZY, Eva AGAI-CSONGOR and Gyorgy DOMANY
Chemical Works of Gedeon Richter Ltd., Budapest 10, P.O. Box 27, H-1475 Hungary;
1
e-mail: h11914giz@ella.hu
Received October 20, 1995
Accepted June 5, 1996
While the reaction of some 2-substituted and 2,6-disubstituted phenols with isopropenyl acetate re-
sulted in the corresponding phenol acetates, in the reaction of 2,6-di-tert-butylphenol, a useful start-
ing material of antioxidant building blocks, under the same conditions 4-acetyl-2,6-di-
tert-butylphenol was the only product.
Key words: 2,6-Di-tert-butylphenol acylation; Isopropenyl acetate reaction.
Looking for pharmacophores responsible for antioxidant effect we selected 2,6-di-tert-
butylphenol (1a) as an antioxidant building block for the synthesis of potential neuro-
protective pharmacons. When we attempted to protect the phenolic hydroxyl of 1a with
isopropenyl acetate (2) prior to further functionalization of the molecule only 4-acetyl-
2
,6-di-tert-butylphenol (3) was obtained in good yield (Scheme 1).
Previously we reported some synthetic applications of 2, among others C-acetylation
1
,2
reactions on the pyrrole nucleus . Nevertheless we found the formation of 3 rather
surprising so we decided to study the reaction in detail.
According to the literature the preparation of 3 was first performed under Friedel–
Crafts conditions, using acetyl chloride both as the acetylating agent and the solvent
3
and AlCl as Lewis-acid catalyst . Later other methods were reported for the acetylation
3
4
of 1a at position 4, like with acetic anhydride using HClO as catalyst or with acetic
4
5
acid in trifluoroacetic anhydride .
OH
OH
O
+
O
1a
2
O
3
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Short Communication
1245
We assumed that the steric hindrance around the phenolic OH should play a role in
this reaction, so we reacted different 2-substituted, 2,6-disubstituted and 2,4,6-trisub-
stituted phenols with 2 under identical conditions (Scheme 2).
The results are summarized in Table I. In the case of 2-substituted phenols (1b, 1c)
and 2,6-disubstituted phenols (1d–1f) the corresponding phenol acetates 4b–4f were
4
obtained in good yield. Contrary to the results of Nehoroshev et al. , who used acetic
anhydride with HClO successfully for the O-acetylation of 4-substituted-2,6-di-tert-
4
butylphenols, the isopropenyl acetate/methanesulfonic acid system turned out to be less
reactive, and was not able to produce 2,6-di-tert-butylphenol acetates, starting from 1g
or 3.
Meanwhile we achieved our original goal and were able to prepare (2,6-di-tert-butyl-
phenyl)acetate11 applying a phase-transfer method . We attempted to acetylate it with
12
O
OH
R3
O
R1
R2
R1
R2
O
+
O
2
R3
1b-1g, 3
4b-4f
1
2
3
For R , R , R see Table I
SCHEME 2
TABLE I
Reaction of substituted phenols 1b–1g, 3 with isopropenyl acetate (2)
1
2
3
Compound
R
R
R
Product
Yield, %
b.p. or m.p., °C
a
1
b
CH3
H
H
4b
4c
4d
4e
4f
90
92
93
90
93
210 (101 kPa)
b
d
1
c
C(CH3)3
CH3
H
H
118–120 (0.026 kPa)
c
1
d
CH3
H
70–73 (0.026 kPa)
1
e
CH(CH3)2 CH(CH3)2
H
135–140 (0.026 kPa)
e
1
f
Br
Br
H
42–44
1
3
g
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3
CH3
no reaction
no reaction
COCH3
a
6
b
7
c
8
d
9
e
10
In accordance with literature data: Ref. ; ref. ; ref. ; ref. ; ref. .
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

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Gizur, Ferenczy, Agai-Csongor, Domany:
isopropenyl acetate but the starting material did not change, the 1-acetoxy group
prevented the C-acetylation in position 4.
From these observations one can conclude that in the proton-catalyzed reaction of
phenols with isopropenyl acetate the corresponding phenol acetates are the normal
products unless the bulk of substituents in positions 2 and 6 reaches the size of the
tert-butyl group. When position 4 is blocked in 2,6-di-tert-butylphenol derivatives no
reaction occurs. The lack of reaction in the case of (2,6-di-tert-butylphenyl)acetate sug-
gests that the formation of 3 is not a Fries-type reaction starting with the corresponding
O-acetate.
Summarising, there are two prerequisites for the C-acylation of phenol derivatives.
First, the prevention of O-acylation as exemplified by the steric hindrance exerted by
the 2,6-di-tert-butyl substitution. Second, the activation of the C-4 atom as the effect of
the conjugation between the lone pair of the O-atom and the electrons of the ring. This
2
conjugation requires an essentially sp O-atom and thus a planar arrangement of the
connecting atoms. These conclusions were supported by the results of the calculations
1
3
performed with the semiempirical AM1 Hamiltonian .
EXPERIMENTAL
Proton NMR spectra were recorded in CDCl solution on a Varian VXR-300 (300 MHz) instrument
3
and proton chemical shifts are reported in ppm downfield from TMS as internal reference. Infrared
spectra were recorded using KBr pellets on a Nikolet 20 DXC FT-IR spectrophotometer. Melting
point was determined on a Büchi 510 apparatus.
General Procedure for the O-Acetylation of Phenols 1b–1f
A solution of the phenol (0.05 mol), isopropenyl acetate (6.0 ml, 0.055 mol) and methanesulfonic
acid (0.5 ml) in 1,2-dichloroethane (50 ml) was refluxed for 30 min. After cooling the reaction mix-
ture was washed with 5% aqueous sodium bicarbonate solution (30 ml), then with water (30 ml). The
organic layer was dried and evaporated under reduced pressure. The oily residue was purified by
distillation (yield and b.p. or m.p. in Table I).
4
-Acetyl-2,6-di-tert-butylphenol (3)
To a solution of 2,6-di-tert-butylphenol (1a; 10.3 g, 0.05 mol) in 1,2-dichloroethane (150 ml)
methanesulfonic acid (0.5 ml) and isopropenyl acetate (6.0 ml, 0.055 mol) was added. The reaction
mixture was refluxed for 1 h and after cooling it was washed with 5% aqueous sodium bicarbonate
solution (30 ml), then with water (30 ml). The organic layer was dried and evaporated under reduced
pressure. The residue was crystallized from diisopropyl ether to yield 3 (9.92 g, 80%) as white crystalls,
3
m.p. 144–146 °C, identical with a sample prepared by a known procedure .
The authors are grateful to Mr B. Hegedüs for the IR and Mr Cs. Szántay, jr. for the NMR spectra.
Collect. Czech. Chem. Commun. (Vol. 61) (1996)

Short Communication
1247
REFERENCES
1
2
3
4
5
6
7
8
9
. Gizur T., Harsanyi K.: Synth. Commun. 20, 2365 (1990).
. Gizur T., Harsanyi K.: J. Heterocycl. Chem. 31, 361 (1994).
. Cook C. D., Gilmour N. D.: J. Org. Chem. 25, 1429 (1960).
. Nehoroshev M. V., Ivahnenko E. P., Ohlobistin O. Y.: Zh. Org. Khim. 13, 662 (1977).
. Nishinaga A., Shimizu T., Toyoda Y., Matsuura T.: J. Org. Chem. 47, 2278 (1982).
. Nord S., Sjoberg B.: Acta Chem. Scand. 11, 1752 (1957).
. Santori G., Casnati G., Bigi F.: J. Org. Chem. 55, 4371 (1990).
. Benington F., Morin R. D., Clark L. C., jr., Phyllis Fox R.: J. Org. Chem. 23, 1979 (1958).
. Zimmer W. F., jr.: U.S. 3,028,410; Chem. Abstr. 57, 8503 (1962).
1
1
1
0. Joshi G. G., Shah N. M.: J. Indian Chem. Soc. 31, 20 (1954).
1. Liu K. T., Kuo M. Y.: J. Chin. Chem. Soc. (Taipei) 28, 209 (1981).
2. Gold M. R., Peteri D., Quack G. P., Strohmeier J., Wuelfroth P. M.: PCT Int. Appl. WO 93
1
2,089 (1993); Chem. Abstr. 119, 225836 (1993).
3. Dewar M. J. S., Zoebisch E. G., Healy E. F., Stewart J. J. P.: J. Am. Chem. Soc. 107, 3902
1985).
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