Synthesis of phosphorus derivatives of 2,6-di-tert-butyl-4-methylphenol

Article abstract of DOI:10.1134/S1070363206110132

Convenient procedures for the synthesis of 2,6-di-tert-butyl-4-methylphenol (ionol) mono-, di-and triphosphorus derivatives, starting from the readily accessible 3,5-di-tert-butyl-4-hydroxybenzaldehyde, are proposed, and some properties of the obtained co

Full text of DOI:10.1134/S1070363206110132

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 11, pp. 1753 1756.
Original Russian Text A.A. Prishchenko, M.V. Livantsov, O.P. Novikova, L.I. Livantsova, D.B. Shpakovskii, E.R. Milaeva, 2006, published in Zhurnal
Obshchei Khimii, 2006, Vol. 76, No. 11, pp. 1834 1838.
Pleiades Publishing, Inc., 2006.
Synthesis of Phosphorus Derivatives
of 2,6-Di-tert-butyl-4-methylphenol
A. A. Prishchenko, M. V. Livantsov, O. P. Novikova,
L. I. Livantsova, D. B. Shpakovskii, and E. R. Milaeva
Moscow State University,
Vorob’evy Gory, Moscow, 119992 Russia
e-mail: liv@org.chem.msu.su
Received July 31, 2006
Abstract Convenient procedures for the synthesis of 2,6-di-tert-butyl-4-methylphenol (ionol) mono-, di-
and triphosphorus derivatives, starting from the readily accessible 3,5-di-tert-butyl-4-hydroxybenzaldehyde,
are proposed, and some properties of the obtained compounds are presented.
DOI: 10.1134/S1070363206110132
Sterically hindered phenols are widely used for
preparation of stable phenoxyl radicals and are inte-
resting as biologically active compounds [1]. Phos-
phorus derivatives of 2,6-di-tert-butyl-4-methylphenol
by the procedure in [6] and trimethylsilyl P(III) acid
esters. We found that the latter add to aldehyde I to
form new phosphorus-containing sterically hindered
phenols. Thus bis(trimethylsiloxy)phosphine and tri-
methylsilyl phosphites readily add by the carbonyl
group of aldehyde I in methylene chloride to afford
phosphinate II or phosphonates III, IV, respectively,
in high yields. Note that under the applied conditions,
the sterically hindered hydroxy group of aldehyde I is
not trimethylsilylated with excess bis(trimethylsiloxy)-
phosphine or trimethylsilyl phosphite (cf. [7]).
(ionol) are effective antioxidants and promising
ligands. However, the methods for synthesis of such
compounds are rather complicated and require rigid
conditions [2 5]. In this work we propose convenient
procedures for synthesis of a series of ionol phos-
phorus derivatives with one, two or three phosphorus-
containing groups, starting from the readily accessible
3
,5-di-tert-butyl-4-hydroxybenzaldehyde (I) prepared
OH
5
t-Bu
Bu-t
Me SiO
(Me SiO) PH
(XO) POSiMe
2 3
3
3
2
4
3
1
1
PC H(OSiMe )Ar
(XO) PC H(OSiMe )Ar
2 3
3
H
O
2
O
1
C HO
II
I
III, IV
Bu-t
3
4
2
5
Ar =
OH, X = Et (III), Me Si (IV).
3
Bu-t
Treatment of phosphinate II with dilute sodium
Reactions of trimethylsilyl esters of P(III) with the
easily accessible 2,6-di-tert-butyl-4-(chloromethyl)-
phenol A prepared from aldehyde I by the procedure
in [8] give rise to new methylenediphosphorus com-
pounds which include sterically hindered phenol
fragments. Thus, trimethylsilyl phosphites and func-
methoxide in methanol gave sodium phosphinate V,
and the reaction of phosphonate IV with excess me-
thanol gave free phosphonic acid VI as white hygro-
scopic crystals. Under similar conditions, phosphonate
III does not react with methanol.
1753

1754
PRISHCHENKO et al.
tionally substituted trimethylsilyl phosphonites readily
Bu-t
3
4
4
NaO
H
react with chloride A in methylene chloride medium
by the Arbuzov reaction scheme to form, respectively,
bisphosphonates VII, VIII or bisphosphinates IX, X
in high yields. In these cases, too, the sterically hin-
dered hydroxy group of chloride A is not trimethyl-
silylated with excess trimethylsilyl phosphite or tri-
methylsilyl phosphonites, that is, the sterically hin-
dered phenolic fragment is preserved (cf. [9]).
MeONa, MeOH
2
2
5
1
II
II
P C H
OH
2
Me SiOMe
3
O OH
Bu-t
Bu-t
V
3
3
MeOH
5
1
(HO)2 P C H
O OH
OH
3
Me SiOMe
3
Bu-t
VI
OH
t-Bu
Bu-t
Me SiO
3
2
(XO) POSiMe
2(Me SiO) PY
3 2
2
3
C1HAr
1
P
[
(XO) P] C HAr
2 2
2
Me SiCl
2Me3SiCl
Y
3
O
O
2
CHCl2
VII, VIII
A
IX, X
Bu-t
O
3
4
1
3
2
5
8
9
6
7
Ar =
OH, X = Et (VII), Me Si (VIII); Y = C H C H
(IX), C H N
12 (X).
3
2
2
2
1
0 11
Bu-t
By the reactions of bisphosphonate VIII and bis-
diphosphonate VII by the procedure in [4] we pre-
pared diphosphorus-substituted methylenequinone
XIV which was further used to synthesize triphos-
phorus-containing ionol XV. Thus, 1,6-addition of
diethyl phosphite to methylenequinone XIV proceeds
readily in the presence of the sodium hydride reaction
initiator and yields 85% of compound XV (cf. [5]).
phosphinates IX, X with excess methanol we also
prepared substituted methylenebisphosphorus acids
XI XIII in high yields. The products are white hyd-
roscopic crystals.
Bu-t
4
MeOH
VIII
[(HO) P] CH
OH
Bu-t
Bu-t
OH
2
2
4
Me SiOMe
3
To conclude, we proposed convenient syntheses of
new or hardly accessible ionol derivatives of various
structures, which are interesting as effective anti-
oxidants, prospective ligands, and biologically active
compounds. The structures of compounds I XV were
O
XI
HO
Y
3
MeOH
II
P
CH
1
13
31
3
Me SiOMe
confirmed by the H, C and P NMR spectra which
3
1
O
show characteristic signals of the P C H fragments
2
Bu-t
n
m
and signals of substituted aromatic fragments (see
table). As follows from the NMR data, compounds II
and X are mixtures of two stereoisomers in a 7:3 ratio
XII, XIII
O
(
measured by 31P NMR); in the table, data for the
Y = CH CH Ph (XII), CH N
(XIII).
2
2
2
predominating isomer are given first). The methylene
proton signals of compounds IX, X, XII, and XIII
are partially overlapping. The elemental analyses of
the synthesized compounds, confirmatory of the
proposed compositions, have also been reported in
preliminary communications [11].
Under mild methanolysis conditions, the phenolic
fragments in compounds VIII X are preserved, while
the hydrolysis of compound VII under heating with
HCl results in elimination of the tert-butyl groups
from the phenolic fragment [10]. By the oxidation of
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 11 2006

SYNTHESIS OF PHOSPHORUS DERIVATIVES
1755
Physicochemical constants and NMR spectral data ( , ppm, J, Hz) of comopounds I XVa
3
(C4),
s
(C5),
s
mp,
C
(C H), (OH),
P,
s
(
C1H) 2JPH
(C1) 1JPC
(C2) 2JPC
(C3) 3JPC
s
s
I
II
80 189 9.87 s
7.75
7.13
7.12
7.19
7.21
5.90 191.85 s
127.68 s
128.75 s
136.55 159.70
b
85
4.84 d
8
5.27
5.27
6.93
5.d16
73.59 d 119 123.38 s
74.23 d 118 123.88 s
71.74 d 170 124.21 s
72.62 d 180 124.17 s
73.90 d 105 123.96 s
71.25 d 159 124.47 s
45.19 t 132 120.12 t 6
48.79 t 140 122.89 t 8.5 127.31 t
49.98 t 78.5 120.98 t 7
50.17 t 78 118.60 t 7
126.13 s
125.81 s
128.45 s
128.33 s
129.70 s
131.08 s
127.25 t
135.83 153.71 24.30
135.95 153.89 24.65
138.94 153.91 20.49
125.34 153.40 4.93
139.74 152.55 29.42
138.51 153.75 19.17
135.87 153.35 19.39
135.70 153.16 0.17
136.34 153.63 37.96
136.78 153.70 29.91
135.99 153.63 29.18
4
.72 d 12
III
IV
V
92 102 4.97 d 12
85 98 4.81 d 16
c
95 159 4.48 d
8.1 7.16
c
d
VI
97 198 4.54 d 16
7.17
7.24
7.17
7.14
7.40
7.40
7.22
7.36
7.27
8.24
7.89
VII 90 140 3.62 t 24
VIII 89 156 3.40 t 26
IX
X
5.45
5.16
5.20
5.30
5.d30
6
6
6
91 119 3.29 t 18
94 71 3.94 t 17
127.10 t
126.25 s
3
.94 t 17
50.97 t 77 119.52 t 5.5 127.72 s
45.85 t 126 123.42 t 7.5 127.04 t 5.5 139.87 152.26 18.35
49.27 t 75 123.14 t 5.5 127.63 t
49.36 t 74 121.57 t 5.5 127.84 s
XI
97 201 3.60 t 26
d
d
XII 95 202 3.82 t 18
XIII 96 122 3.64 t 20
XIV 91 74
6
139.47 153.40 43.20
138.76 153.30 35.01
e
127.08 t 161 153.61 s
57.65 q 116 119.74 q 7
130.38 t 15 151.03 186.33 14.01
128.81 q 134.43 152.79 16.12
XV
85 162
5.18
7
a
1
1
1
PH fragment. H NMR spectrum, , ppm (J, Hz): compound II: 6.91 d ( J
552) and 6.83 d ( J 552); compound V: 6.67 d
PH
6 1
PH
7 2
1
13
8 3
(
J
510.3). C NMR spectrum, , ppm (J, Hz). Compound IX: 33.17 d (C , J 96), 28.66 d (C , J 4), 141.29 d (C , J
PH
PC
11
PC
PC
9
1
10
12
13 3
1
6); compound X, first isomer: 43.61 d (C , J 108), 48.47 s (C ), 17.79 s (C ), 30.00 s (C ), 174.66 d (C , J 3); second
isomer: 43.50 d (C , J 106), 48.40 s (C ), 17.72 s (C ), 30.00 s (C ), 174.46 s (C ); compound XII: 31.59 d (C , J 94),
PC
PC
6 1
9
1
10
11
12
13
PC
PC
7
2
8 3
9 1
10
11
12
2
1
7.96 d (C , J 3), 142.26 d (C , J 17); compound XIII: 42.75 d (C , J 106), 48.08 s (C ), 17.94 s (C ), 30.15 s (C ),
PC PC PC
74.31 s (C ).
1
3
b
c
d
e
Oily substance.
Broad signal.
With decomposition.
Orange crystals.
EXPERIMENTAL
hyde I, 3.1 g, was added with stirring to a solution of
.2 g of diethyl trimethylsilyl phosphite in 30 ml of
6
The H, 13C and 31P NMR spectra were registered
on a Bruker Avance-400 instrument (400, 100, and
1
methylene chloride, cooled to 10 C. The mixture was
stirred for 0.5 h, the solvent was then distilled off, the
residue was diluted with 20 ml of hexane, and the
mixture was cooled to 0 C. The white crystals that
dropped were filtered off and kept in vacuum (0.5 mm
Hg) for 1 h to obtain 5.4 g of phosphonate III. Found,
1
62 MHz, respectively) in CDCl (I, II, IV, VII X,
3
XIV, and XV), (CD ) SO (III, VI, XII, and XIII), or
3
2
1
13
D O (V and XI) against TMS ( H and C) and 85%
H PO in D O ( P). All reactions were performed
2
3
1
3
4
2
%
: C 59.09; H 9.22. C H O PSi. Calculated, %: C
under dry argon in water-free solvents. Aldehyde I,
chloride A, and methylenequinone XIV were prepared
according to the procedures in [6, 8, 4], respectively.
22 41 5
5
9.43; H 9.29.
Phosphonate IV was prepared similarly.
Trimethylsilyl [3,5-di-tert-butyl-4-hydroxy-
phenyl(trimethylsiloxy)methyl]phosphonite (II).
Sodium [(3,5-di-tert-butyl-4-hydroxyphenyl)-
(hydroxy)methyl]phosphinate (V). A solution of
3.8 g of phosphinate II in 20 ml of methanol was
added with stirring to a solution of 0.46 g of sodium
methoxide in 10 ml of methanol. The solvent was
then distilled off, and the residue was kept in a
vacuum (1 mm Hg) for 1 h to obtain 2.6 g of salt V.
Found, %: C 55.65; H 7.46. C H NaO P. Calcu-
3
,5-Di-tert-butyl-4-hydroxybenzaldehyde (I), 2.3 g,
was added with stirring to a solution of 5.3 g of bis-
trimethylsiloxy)phosphine in 30 ml of methylene
chloride, cooled to 0 C. The mixture was stirred for
.5 h, the solvent was then distilled off, and the re-
sidue was kept at 40 C in a vacuum (0.5 mm Hg) for
(
0
1
5
24
4
1
h to obtain 3.8 g of phosphinate II as a thick oil.
lated, %: C 55.90; H 7.50.
Diethyl [(3,5-di-tert-butyl-4-hydroxyphenyl)-
trimethylsiloxy)methyl]phosphonate (III). Alde-
[(3,5-Di-tert-butyl-4-hydroxyphenyl)(hydroxy)-
methyl]phosphonic acid (VI). Phosphonate IV,
(
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 11 2006

1756
PRISHCHENKO et al.
3
.8 g, was added with stirring to 30 ml of methanol
REFERENCES
cooled to 10 C of. The mixture was heated to boiling,
the solvent was distilled off, and the residue was kept
in a vacuum (1 mm Hg) for 1 h to obtain 2.2 g of
acid VI. Found, %: C 56.78; H 7.89. C H O P.
1. Nonhebel, D., Tedder, J., and Walton, J., Radicals,
Cambridge: Cambridge Univ. Press, 1979.
1
5
25
5
2
. Mukmeneva, N.A., Kadyrova, V.Kh., and Zharko-
va, V.M., Zh. Obshch. Khim., 1992, vol. 62, no. 7,
p. 1670; Mukmeneva, N.A., Cherezova, E.N., and
Zhukova, R.S., Zh. Obshch. Khim., 1994, vol. 64,
no. 6, p. 1049.
Calculated, %: C 56.95; H 7.97.
Acids XI XIII were prepared similarly.
Tetraethyl (3,5-di-tert-butyl-4-hydroxyphenyl)-
methylenebis(diethyl phosphonate) (VII). A solu-
tion of 3.7 g of chloride A in 15 ml of methylene
chloride was added with stirring to a solution of 6.8 g
of diethyl trimethylsilyl phosphite in 20 ml of me-
thylene chloride, cooled to 0 C. The mixture was
stirred for 0.5 h, heated to boiling, the solvent was
distilled off, the residue was diluted with 20 ml of
hexane and cooled to 0 C. The white crystals that
dropped were filtered off and kept in a vacuum
3
4
5
. Gross, H., Seibt, H. and Keitel, I., J. Prakt. Chem.,
1
975, vol. 317, p. 890.
. Ismagilov, R.K., Moskva, V.V., and Kopylova, R.Yu.,
Zh. Obshch. Khim., 1989, vol. 59, no. 7, p. 1686.
. Gross, H., Ozegowski, S., and Costisella, B., Phos-
phorus, Sulfur, Silicon, Relat. Elem., 1990, vol. 47,
nos. 1 2, p. 7.
(
0.5 mm Hg) for 1 h to obtain 5.7 g of compound VII
6. Coppinger, G.M. and Campbell, T.W., J. Am. Chem.
Soc., 1953, vol. 75, no. 3, p. 734.
(cf. [3]).
Compounds VIII X were prepared similarly.
7. Prishchenko, A.A., Livantsov, M.V., Novikova, O.P.,
Livantsova, L.I., and Kashulin, I.A., Zh. Obshch.
Khim., 2005, vol. 75, no. 10, p. 1748; Prishchen-
ko, A.A., Livantsov, M.V., Novikova, O.P., Livan-
tsova, L.I., and Maryashkin, A.V., Zh. Obshch. Khim.,
(
3,5-Di-tert-butyl-4-hydroxyphenyl)tris(dieth-
oxyphosphinoyl)methane (XV). Diethyl phosphite,
.5 g, was added with stirring to a mixture of 3.3 g of
7
methylenequinone XIV and 0.01 g of sodium hydride.
When the mixture decolorized, 30 ml of hexane and
2
005, vol. 75, no. 12, p. 2055.
8
9
. Popov, L.K., Egidis, F.M., and Ershov, V.V., Izv.
Akad. Nauk SSSR., Ser. Khim., 1968, no. 4, p. 902.
3
ml of water were added. The mixture was stirred
for 0.5 h, the organic layer was separated, heated to
boiling, and cooled to 10 C. The white crystals that
dropped were filtered off and kept in a vacuum
. Friedman, S., Kaufman, M.L., and Wender, I., J. Org.
Chem., 1962, vol. 27, no. 2, p. 664.
(
0.5 mm Hg) for 1 h to obtain 3.6 g of compound XV.
1
1
0. Gross, H. and Ozegowski, S., Phosphorus, Sulfur,
Silicon, Relat. Elem., 1990, vol. 47, nos. 1 2, p. 1.
Found, %: C 51.47; H 8.09. C H O P . Calculated,
2
7
51 10 3
%
: C 51.59; H 8.18.
1. Prishchenko, A.A., Livantsov, M.V., Novikova, O.P.,
Livantsova, L.I., Shpakovskii, D.B., and Milaeva, E.R.,
Zh. Obshch. Khim., 2005, vol. 75, no. 12, p. 2058;
Prishchenko, A.A., Livantsov, M.V., Novikova, O.P.,
Livantsova, L.I., Shpakovskii, D.B., and Milaeva, E.R.,
Zh. Obshch. Khim., 2006, vol. 76, no. 5, p. 868.
ACKNOWLEDGMENTS
The work was financially supported by the Russian
Foundation for Basic Research (project nos. 05-03-
2864 and 06-03-32731).
3
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 11 2006