Oxidative dimerization of 2,6-Di-tert-butyl-4-(2-hydroxyethyl)phenol

Article abstract of DOI:10.1134/S1070428014030117

2,6-Di-tert-butyl-4-(2-hydroxyethyl)phenol undergoes oxidative self-coupling by the action of K₃Fe(CN)₆ in alkaline medium at room temperature to give 7,9-di-tert-butyl-4-(3,5-di-tert-butyl-4- hydroxyphenyl)-1-hydroxymethyl-2-oxaspir

Full text of DOI:10.1134/S1070428014030117

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 3, pp. 367–370. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.P. Krysin, A.M. Genaev, L.M. Pokrovskii, M.M. Shakirov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50,
No. 3, pp. 378–381.
Oxidative Dimerization
of 2,6-Di-tert-butyl-4-(2-hydroxyethyl)phenol
A. P. Krysin, A. M. Genaev, L. M. Pokrovskii, and M. M. Shakirov
Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences,
pr. Akademika Lavrent’eva 9, Novosibirsk, 630090 Russia
e-mail: pokrovsk@nioch.nsc.ru
Received February 11, 2013
Abstract—2,6-Di-tert-butyl-4-(2-hydroxyethyl)phenol undergoes oxidative self-coupling by the action of
K3Fe(CN)6 in alkaline medium at room temperature to give 7,9-di-tert-butyl-4-(3,5-di-tert-butyl-4-hydroxy-
phenyl)-1-hydroxymethyl-2-oxaspiro[4.5]deca-6,9-dien-8-one. The composition of the reaction products has
been determined, and the mechanism of their formation is discussed.
DOI: 10.1134/S1070428014030117
Oxidation of sterically hindered phenols in model
media is used to assess their antioxidant efficiency. In
other words, the antioxidant activity of phenolic com-
pounds is reflected in their oxidation and specific
features of their oxidative transformations which are
disclosed by studying the behavior of initially formed
radicals. Studies in this line are promising from the
viewpoint of synthesis of new phenol derivatives [1].
Oxidation of 4-R-2,6-di-tert-butylphenols (R =
CH2CH2COOMe, CH2CH2COMe [2], CH=CHCO2Me
[3]) yields dimeric products via oxidative β,β′-coupling
of initially formed quinomethanes. In the presence of
bases such products rearrange into dimeric vinyl-
phenols possessing high antioxidant and light-stabiliz-
ing activity [4]. The formation of analogous biologi-
cally active dimers may be expected in oxidative
transformations of some other para-substituted 2,6-di-
alkylphenols containing a functional group in the ali-
phatic chain of the para-substituent.
The ability to undergo oxidative dimerization was
found for a new practically interesting group of
phenolic polymer modifiers, and this reaction has
facilitated the search for their new representatives [5].
The oxidation of the most important commercial phe-
nolic antioxidants, fenozans (irganoxes), leads to
oligomeric products [6]. However, oxidative trans-
formations of phenolic bioantioxidants (flavonoids and
catechins) have not been studied even for model com-
pounds [1]. Such model compounds may be hydroxy-
alkylphenols; the first their representative, 4-(2-hy-
droxyethyl)phenol, constitutes a structural fragment of
many natural phenolic compounds [7].
We previously studied the oxidation of a number of
2,6-di-tert-butyl-4-(ω-hydroxyalkyl)phenols with
excess potassium hexacyanoferrate(III) in alkaline
medium with a view to obtain substituted quino-
methanes. It was found that the first member of this
series, 2-hydroxyethyl-substituted phenol I is con-
verted into quinomethane II in a poor yield [8, 9]. In
the present work we made an attempt to elucidate
whether the low yield of II is related to previously
unknown concurrent processes involving oxidative
dimerization of I.
Our efforts were initially directed toward optimiza-
tion of the reaction conditions for the formation of
quinomethane II and minimization of other processes.
We succeeded in improving the yield of II to 65% by
adhering to the following conditions: rapid addition of
the oxidant to the reaction mixture, short reaction time
(overall reaction time no longer than one hour at
50°C), dilution of the reaction mixture with a solvent,
and high alkalinity of the reaction medium. However,
even these conditions did not ensure complete avoid-
ance of side processes.
When the reaction temperature was reduced to am-
bient with simultaneous increase of the reaction time
and reactant concentration, the yield of quinomethane
II decreased from 65 to 5%. According to the GLC and
GC/MS data, the product mixture contained 50% of
unreacted initial compound I, 5% of II, 3% of alde-
367

KRYSIN et al.
368
Scheme 1.
OH
O
OH
O
14, 15
t-Bu
Bu-t
t-Bu
Bu-t
t-Bu
Bu-t
1t2-,B13u
Bu-t
16t,-1B7u
8
7
K3Fe(CN)6, KOH
9
5'
6'
+
+
4'
3'
HO
10
6
1'
11
5
4
1
16, 17
OH
OH
OH
3
2
2'
t-Bu
CHO
O
I
II
III
IVa
O
Bu-t
6'
12
t-Bu
Bu-t
t-Bu
t-Bu
8
7
O
5'
4'
6
1'
2'
3
9
2
1
+
+
4
OH
HO
5
O
HO
3'
11 10
OH
Bu-t
t-Bu
t-Bu
O
IVb
Va, Vb
hyde III, and four compounds (20, 11, 5, and 3%) with
a molecular weight of 496 which corresponds to prod-
ucts of oxidative dimerization of phenol I.
pounds IV and V are shown in Schemes 2 and 3,
respectively.
We failed to separate stereoisomers Va and Vb
which were obtained at a ratio of 2:1. Their structure
was assigned on the basis of differences in their mass
and NMR spectra. The singlet at δC 105.6 ppm in the
13C NMR spectrum was attributed to aliphatic carbon
atom linked to two oxygen atoms. The other signals
in the 13C NMR spectrum were consistent with the
assumed structures of Va and Vb.
Presumably, initially formed quinomethane II
reacts with phenol I to produce ether VI. Easy forma-
tion of analogous ethers in reactions of quinomethanes
with alcohols in the presence of bases was reported in
[10]. As shown in Scheme 2, stereoisomeric dienones
IVa and IVb are formed as a result of oxidation of
both aromatic rings in ether VI to give radical VIII
and intramolecular ring closure of the latter. This
By column chromatography we isolated two groups
of products, each containing (according to the NMR
data) two diastereoisomers. One group was a mixture
of stereoisomeric dienones IVa and IVb, and the other,
a mixture of two bisphenols Va and Vb (structures
IV and V possess two asymmetric carbon atoms;
Scheme 1). The stereoisomeric products had equal
molecular weights and displayed similar UV spectra,
but they differed by GC/MS retention times. The major
product, dienone IVa, was isolated as individual sub-
stance by repeated recrystallization. The steric struc-
ture of isomers IVa and Vb was determined by NMR
spectroscopy with the aid of two-dimensional NOESY,
COSY, COLOC, and HXCO techniques. Probable
mechanisms of formation of stereoisomeric com-
Scheme 2.
OH
OH
t-Bu
Bu-t
t-Bu
Bu-t
Bu-t
Bu-t
[O]
I
+ II
OH
O
HO
HO
O
O
Bu-t
O
Bu-t
VI
VII
O
t-Bu
Bu-t
t-Bu
Bu-t
Bu-t
Bu-t
[O]
IV
·
O
O
·
HO
HO
Bu-t
O
Bu-t
O
VIII
IX
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

OXIDATIVE DIMERIZATION OF 2,6-DI-tert-BUTYL-4-(2-HYDROXYETHYL)PHENOL
369
Scheme 3.
HO
Bu-t
Bu-t
t-Bu
O
II
+
III
V
O
Bu-t
OH
X
transformation may be regarded as C-alkylation of
phenols with compounds possessing an activated
double bond. Although the mechanism of such pro-
cesses in the presence of bases remains unclear [11],
we believe that in our case radical path shown in
Scheme 2 is operative.
Stereoisomers Va and Vb are likely to be formed
via reaction of quinomethane II with aldehyde III,
followed by dioxolane ring closure in intermediate
adduct X (Scheme 3). Scheme 3 is analogous to the
scheme proposed by us previously [8] for the oxidation
of 2,6-di-tert-butyl-4-(4-hydroxybutyl)phenol to
phenol derivative containing a five-membered ring.
a period of 45 min under stirring at 50°C. Immediately
after addition, the mixture was washed with water until
neutral reaction, the organic layer was separated and
evaporated, the oily residue (7.8 g) was treated with
2 mL of petroleum ether, and the resulting solution was
kept at –20°C. The precipitate was filtered off and
washed with 10 mL of petroleum ether cooled to
–20°C. Yield 4.5 g (60%), light yellow substance,
mp 98–100°C; published data [7]: mp 100–101°C.
The filtrate was evaporated to isolate 3.0 g of a red
oily material which solidified on prolonged storage.
According to the GLC and GC/MS data, it contained
50% of unreacted phenol I, 15% of dienone IVa,
25% (overall yield) of five isomeric compounds with
a molecular weight of 496, 2% of 2,6-di-tert-butyl-1,4-
benzoquinone, 3% of aldehyde III, 5% of II, and
a product with a molecular weight of 743.5 (assuming-
ly, trimer of II).
The new path of oxidative transformations of
phenol I disclosed in the present work should be taken
into account while determining the structure of prod-
ucts resulting from oxidation of natural phenolic com-
pounds at room temperature.
(1RS,4RS)-7,9-Di-tert-butyl-4-(3,5-di-tert-butyl-
4-hydroxyphenyl)-1-hydroxymethyl-2-oxaspiro[4.5]-
deca-6,9-dien-8-one (IVa). A solution of 6.58 g
(0.02 mol) of K3Fe(CN)6 in 25 mL of water was added
to a solution of 5.0 g (0.02 mol) of compound I in
25 mL of benzene, and an aqueous solution of 1.2 g
(0.021 mol) of potassium hydroxide was added drop-
wise over a period of 60 min under vigorous stirring.
The mixture was kept for 12 h at room temperature,
and the organic layer was separated, washed with
water, and evaporated. The residue, 5.0 g, contained
(GLC) 62% of initial compound I and 28% of dimers
IVa and IVb (M 496). The product mixture was
dissolved in petroleum ether on heating, and 1.5 g of
phenol I separated therefrom on cooling and was
filtered off. The filtrate was evaporated, and the oily
residue (3.5 g) was subjected to silica gel column chro-
matography using petroleum ether–chloroform (1:1)
as eluent to isolate 1.4 g (28%) of a mixture of stereo-
isomers IVa and IVb at a ratio of 2:1 as a white solid.
EXPERIMENTAL
The IR spectra were recorded on a Bruker Tensor-
27 instrument. The NMR spectra were measured on
Bruker AM-400 and AV-600 spectrometers. Gas chro-
matographic–mass spectrometric analyses were carried
out on an HP 5890 Series II gas chromatograph
coupled with an HP 5971 mass-selective detector. The
molecular weights were determined from the high-
resolution mass spectra which were obtained on
a Thermo Electron Corporation DFS instrument. The
melting points were determined using a Mettler Toledo
FP 900 melting point apparatus.
2,6-Di-tert-butyl-4-(2-hydroxyethyl)phenol (I),
mp 99–101°C, was prepared by reaction of 2,6-di-tert-
butylphenol with ethylene oxide [12].
2,6-Di-tert-butyl-4-(2-hydroxyethylidene)cyclo-
hexa-2,5-dien-1-one (II). A solution of 7.5 g
(0.03 mol) of phenol I in 120 mL of benzene was
mixed with a solution of 20 g (0.06 mol) of K3Fe(CN)6
in 80 mL of water, and 4.0 g (0.072 mol) of pelletized
potassium hydroxide was added in small portions over
Stereoisomer IVa was isolated by triple recrystal-
lization from hexane. Yield 0.7 g, fine needles,
mp 120.1°C. UV spectrum, λmax, nm (logε): 232 (4.07),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014

KRYSIN et al.
370
248 (4.01), 285 (3.48). IR spectrum (CCl4), ν, cm–1:
[(CH3)3C]; 34.2, 34.88, 34.91 [(CH3)3C]; 52.3 (C12),
59.5 (C4), 73.6 (C5), 105.5 (C2), 124.0 and 124.1 (C2′,
C6′, C7, C11), 130.3 and 130.5 (C6, C1′), 135.7 and
135.8 (C3′, C5′, C8, C10), 152.4 (C4′, C9).
1
3644 (OH), 1841 and 1658 (C=C, C=O). H NMR
spectrum (CDCl3–CCl4), δ, ppm: 1.00 s (9H, 7-t-Bu),
1.21 s (9H, 9-t-Bu), 1.34 s (18H, 3′-t-Bu, 5′-t-Bu),
1.70 br.s (1H, CH2OH), 3.31 d.d (1H, CH2OH, J =
11.8, 3.0 Hz), 3.52 d.d (1H, CH2OH, J = 11.8, 7.8 Hz),
3.80 t (1H, 4-H, J = 9 Hz), 4.16 d.d (1H, 1-H, J = 7.8,
3.0 Hz), 4.44 t and 4.53 t (1H each, 3-H, J = 9 Hz),
5.06 s (1H, 4′-OH), 6.51 and 6.52 (2H, 6-H, 10-H, AB
system, J = 2.9 Hz), 6.76 s (2H, Harom). 13C NMR spec-
trum (CDCl3–CCl4), δC, ppm: 29.1 (C13), 29.5 (C15),
30.1 (C17), 34.2 (C16), 34.88 (C12), 34.91 (C14), 53.6
(C5), 56.2 (C4), 62.4 (CH2OH), 70.4 (C3), 87.6 (C1),
123.9 (C2′, C6′), 125.2 (C1′), 135.4 (C3′, C5′), 136.8 (C6),
140.2 (C10), 148.0 (C7), 150.3 (C9), 152.9 (C4′), 185.9
(C8). Found: m/z 496.3563 [M]+. C32H48O4. Calculated:
[M]+ 496.3552.
1
Stereoisomer Vb. H NMR spectrum (CDCl3), δ,
ppm: 1.36 s and 1.39 s (36H, t-Bu), 2.48 d (1H, 12-H,
J = 3.0 Hz), 3.40–3.60 m (1H, 12-H), 3.80–4.00 (1H,
5-H), 4.12–4.19 d.d (1H, 5-H, J = 7.8, 3.0 Hz), 4.55 t
(1H, 4-H, J = 7.8 Hz), 4.60 s (1H, OH), 4.80 s (1H,
OH), 7.01 s and 7.10 s (2H each, Harom). 13C NMR
spectrum (CDCl3–CCl4), δC, ppm: 30.1 and 30.2
[(CH3)3C], 34.2 [3′-C(CH3)3, 5′-C(CH3)3], 34.88 and
34.91 [8-C(CH3)3, 10-C(CH3)3], 45.7 (C12), 56.7 (C4),
74.7 (C5), 99.8 (C2), 125.5 and 125.8 (C2′, C5′, C7, C11),
129.4 and 130.3 (C6, C1′), 135.5 and 135.7 (C3′, C5′, C8,
C10), 152.5 (C4′, C9).
(1RS,4SR)-7,9-Di-tert-butyl-4-(3,5-di-tert-butyl-
REFERENCES
4-hydroxyphenyl)-1-hydroxymethyl-2-oxaspiro-
1
1. Fenol’nye soedineniya: fundamental’nye i prikladnye
aspekty (Phenolic Compounds. Fundamental and
Applied Aspects). Zagoskin, N.V. and Burlakova, E.B.,
Moscow: Nauchnyi Mir, 2010, p. 400.
[4.5]deca-6,9-dien-8-one (IVb). H NMR spectrum
(CDCl3–CCl4), δ, ppm: 0.95 s (9H, 7-t-Bu), 1.24 s (9H,
9-t-Bu), 1.37 s (18H, 3′-t-Bu, 5′-t-Bu), 1.9 br.s (1H,
CH2OH), 3.48 d.d (1H, CH2OH, J = 11.8, 3.0 Hz),
3.64 d.d (1H, CH2OH, J = 11.8, 7.8 Hz), 3.55 t (1H,
4-H, J = 9 Hz), 4.00 d.d (1H, 1-H, J = 7.8, 3.0 Hz),
4.35 t and 4.53 t (1H each, 3-H, J = 9 Hz), 5.11 s (1H,
4′-OH), 6.12 and 6.75 (2H, 6-H, 10-H, AB system, J =
2.9 Hz), 6.88 s (2H, Harom). 13C NMR spectrum
(CDCl3–CCl4), δC, ppm: 29.07, 29.52, 30.11, 34.20,
34.57, 34.90, 52.45, 55.90, 62.97, 71.62, 86.20,
124.12, 127.25, 135.84, 140.21, 140.47, 147.16,
147.60, 185.89.
2. Titova, T.F. and Krysin, A.P., Zh. Org. Khim., 1987,
vol. 23, p. 597.
3. Sarkanen, K.V. and Wallis, A.F.A., J. Chem. Soc.,
Perkin Trans. 1, 1973, no. 17, p. 1878.
4. Titova, T.F., Krysin, A.P., Rusov, V.P., Ovsyannik, N.V.,
Ken’ko, L.A., Sitnikova, I.V., and Balykina, N.V., Plast.
Massy, 1990, p. 23.
5. Nikulicheva, O.N., Krysin, A.P., and Fadeeva, V.P.,
Zh. Prikl. Khim., 2008, vol. 81, p. 1517.
6. Titova, T.F. and Krysin, A.P., Izv. Sib. Otd. Akad. Nauk
Subsequent column chromatography on silica gel
using petroleum ether–chloroform as eluent (gradient
elution) gave 0.3 g of a mixture of stereoisomeric
2,6-di-tert-butyl-4-[2-(3,5-di-tert-butyl-4-hydroxyben-
zyl)-1,3-dioxan-4-yl]phenols Va and Vb at a ratio of
2:1, mp 185–187°C. UV spectrum: λmax 278 nm. Mass
spectrum: m/z (Irel, %): 496 (2) [M]+, 290 (1), 248 (2)
[M]2+, 232 (100), 219 (12), 217 (38), 57 (30). Found:
m/z 496.35 [M]+. C32H48O4. Calculated: [M]+ 496.3552.
SSSR, Ser. Khim., 1987, vol. 19, no. 6, p. 140.
7. Korul’kin, D.Yu., Abilov, Zh.A., Muzychkina, R.A., and
Tolstikov, G.A., Prirodnye flavonoidy (Natural
Flavonoids), Novosibirsk: Geo, 2007, p. 232.
8. Krysin, A.P. and Fedorenko, A.N., Izv. Akad. Nauk
SSSR, Ser. Khim., 1989, p. 1671.
9. Volod’kin, A.A., Doctoral (Chem.) Dissertation,
Moscow, 1978.
10. Ershov, V.V., Volod’kin, A.A., Kudinova, L.I., and
Vol’eva, V.B., USSR Inventor’s Certificate no. 727614,
1980; Byull. Izobret., 1980, no. 14.
11. Volod’kin, A.A., Zaitsev, A.S., Rubailo, V.A., Belya-
kov, V.A., and Zaikov, G.E., Izv. Akad. Nauk SSSR, Ser.
Khim., 1989, p. 1829.
1
Stereoisomer Va. H NMR spectrum (CDCl3), δ,
ppm: 1.37 s and 1.40 s (36H, t-Bu), 2.87 d (1H, 12-H,
J = 3.0 Hz), 3.40–3.60 m (1H, 12-H), 3.80–4.00 (1H,
5-H), 4.12–4.19 d.d (1H, 5-H, J = 7.8, 3.0 Hz), 4.30 t
(1H, 4-H, J = 7.8 Hz), 4.75 s (1H, OH), 4.80 s (1H,
OH), 7.01 s and 7.07 s (2H each, Harom). 13C NMR
spectrum (CDCl3–CCl4), δC, ppm: 30.1 and 30.2
12. Krysin, A.P., Kusov, S.Z., and Malykhin, E.V., Russian
Patent no. 2385858, 2008; Byull. Izobret., 2010, no. 10.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 3 2014