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

Article abstract of DOI:10.1002/hc.20458

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

Full text of DOI:10.1002/hc.20458

Heteroatom Chemistry
Volume 19, Number 5, 2008
Synthesis of Organophosphorus Derivatives
of 2,6-Di-tert-butyl-4-methylphenol
Andrey A. Prishchenko, Mikhail V. Livantsov, Olga P. Novikova,
Ludmila I. Livantsova, and Elena R. Milaeva
Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, Russia
Received 20 June 2007
phosphorus acids, which are well known as unique
ABSTRACT: Convenient procedures for the synthesis
organophosphorus synthons [8–10]. In the present
of 2,6-di-tert-butyl-4-methylphenol (ionol) mono-, di-,
study, we found that various trimethylsilyl esters of
and triphosphorus derivatives, starting from the read-
trivalent phosphorus acids react with aldehyde 1 and
ily accessible 3,5-di-tert-butyl-4-hydroxybenzaldehyde,
its derivatives under mild conditions to form new
are proposed, and some properties of the obtained
phosphorus-containing sterically hindered phenols.
ꢀ
C
compounds are presented.
2008 Wiley Periodicals,
Inc. Heteroatom Chem 19:490–494, 2008; Published on-
line in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hc.20458
RESULTS AND DISCUSSION
So bis(trimethylsiloxy)phosphine and trimethylsilyl
phosponites readily add by the carbonyl group of
aldehyde 1 in methylene chloride to afford phos-
phonite 2 or phosphonates 3, 4, respectively, in
high yields (Eq. (1)). Note that under the applied
conditions, the sterically hindered hydroxy group
of aldehyde 1 is not trimethylsilylated with ex-
cess of bis(trimethylsiloxy)phosphine or trimethylsi-
lyl phosphite (cf. [11,12]).
INTRODUCTION
Sterically hindered phenols are widely used
for preparation of stable phenoxyl radicals and
are interesting as biologically active compounds
[1]. Phosphorus derivatives of 2,6-di-tert-butyl-4-
methylphenol (ionol) are effective antioxidants and
promising ligands. However, the methods for syn-
thesis of such compounds are rather complicated
and require rigid conditions [2–6]. In this work,
we propose convenient procedures for synthesis of
a series of ionol phosphorus derivatives with one,
two, or three phosphorus-containing groups, start-
ing from the readily accessible 3,5-di-tert-butyl-4-
hydroxybenzaldehyde 1 prepared by the procedure
described in [7] and trimethylsilyl esters of trivalent
Correspondence to: Andrey A. Prishchenko; e-mail:
aprishchenko@yandex.ru
Contract grant sponsor: Russian Foundation for Basic Re-
search.
Contract grant number: 08-03-00282.
2008 Wiley Periodicals, Inc.
c
ꢀ
490

Synthesis of Organophosphorus Derivatives of 2,6-Di-tert-butyl-4-Methylphenol 491
Treatment of phosphonite 2 with dilute sodium
By the reactions of bisphosphonate 8 and bis-
phosphinates 9, 10 with excess methanol, we also
prepared substituted methylenebisphosphorus acids
11–13 in high yields (Eq. (4)). The products are white
hydroscopic crystals. Under mild methanolysis con-
ditions, the phenolic fragments in compounds 8–10
are preserved, whereas the hydrolysis of compound 7
under heating with HCl results in elimination of the
tert-butyl groups from the phenolic fragment [15].
methoxide in methanol gave sodium phosphonite
5, and the reaction of phosphonate 4 with excess
methanol gave free phosphonic acid 6 as white hy-
groscopic crystals (Eq. (2)). Under similar condi-
tions, phosphonate 3 does not react with methanol.
Reactions of trimethylsilyl esters of trivalent
phosphorus acids with the easily accessible 2,6-
di-tert-butyl-4-(dichloromethyl)phenol A prepared
from aldehyde 1 by the procedure described in
[13] give rise to new methylenediphosphorus com-
pounds, which include sterically hindered phe-
nol fragments. Thus, trimethylsilyl phosphites and
functionally substituted trimethylsilyl phosphonites
readily react with dichloride A in methylene chloride
solution by the Arbuzov reaction scheme to form, re-
spectively, bisphosphonates 7, 8 or bisphosphinates
9, 10 in high yields (Eq. (3)). In these cases, too,
the sterically hindered hydroxy group of dichloride
A is not trimethylsilylated with excess trimethylsilyl
phosphite or trimethylsilyl phosphonites, that is, the
sterically hindered phenolic fragment is preserved
(cf. [14]).
By the oxidation of diphosphonate 7 by the pro-
cedure described in [5], we prepared diphosphorus-
substituted methylenequinone 14, which was fur-
ther used to synthesize triphosphorus-containing
ionol 15. Thus, 1,6-addition of diethyl phosphite
to methylenequinone 14 proceeds readily in the
Heteroatom Chemistry DOI 10.1002/hc

492 Prishchenko et al.
presence of the sodium hydride as a reaction ini-
tiator and yields 85% of compound 15 (cf. [6]).
To conclude, we proposed convenient syntheses
of new or hardly accessible ionol derivatives of vari-
ous structures, which are interesting as effective an-
tioxidants, perspective ligands, and biologically ac-
tive compounds. The structures of compounds 1–15
O,O-Diethyl-3,5-di-tert-butyl-4-hydroxyphenyl-
(trimethylsiloxy)methylphosphonate (3)
Aldehyde 1, 3.1 g, was added with stirring to a so-
lution of 6.2 g of diethyl trimethylsilyl phosphite in
30 mL of methylene chloride and 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 mmHg) for 1 h to obtain 5.4 g
of phosphonate 3.
1
were confirmed by the H, 13C, and 31P NMR spec-
tra, which show characteristic signals of the PnC1Hm
fragments and signals of substituted aromatic frag-
ments (see Table 1). As follows from the NMR data,
compounds 2 and 10 are mixtures of two stereoiso-
mers in a 7:3 ratio (measured by 31P NMR); in the
table, data for the predominating isomer are given
first. The methylene proton signals of compounds
9, 10, 12, and 13 are partially overlapping. The ele-
mental analyses data of the synthesized compounds,
confirmatory of the their compositions, are summa-
rized in Table 2.
Phosphonate 4 was prepared similarly.
Sodium 3,5-Di-tert-butyl-4-hydroxyphenyl-
(hydroxy)methylphosphonite (5)
A solution of 3.8 g of phosphonite 2 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 mmHg) for 1 h to obtain
2.6 g of salt 5.
EXPERIMENTAL
1
The H, 13C, and 31P NMR spectra were registered
on a Bruker Avance-400 spectrometer (400, 100, and
162 MHz, respectively) in CDCl3 (1, 2, 4, 7–10, 14,
15), (CD3)2 SO (3, 5, 12, 13), or D2O (5, 11) against
TMS (1H and 13C) and 85% H3PO4 in D2O (31P).
All reactions were performed under dry argon in
anhydrous solvents. Aldehyde 1, dichloride A, and
methylenequinone 14 were prepared according to
the procedures described in [7,13,5], respectively.
3,5-Di-tert-butyl-4-hydroxyphenyl(hydroxy)-
methylphosphonic Acid (6)
Phosphonate 4, 3.8 g, was added with stirring to 30
mL of methanol cooled to 10◦C. The mixture was
heated to boiling, the solvent was distilled off, and
the residue was kept in a vacuum (1 mmHg) for 1 h
to obtain 2.2 g of acid 6.
Acids 11–13 were prepared similarly.
O-Trimethylsilyl-3,5-di-tert-butyl-4-hydroxy-
phenyl(trimethylsiloxy)methylphosphonite (2)
O,O,O,O-Tetraethyl (3,5-di-tert-butyl-4-hydroxy-
phenyl)methylenebisphosphonate (7)
3,5-Di-tert-butyl-4-hydroxybenzaldehyde 1, 2.3 g,
was added with stirring to a solution of 5.3 g of
bis(trimethylsiloxy)phosphine in 30 mL of methy-
lene chloride and cooled to 0◦C. The mixture was
stirred for 0.5 h, the solvent was then distilled off,
and the residue was kept at 40◦C in a vacuum (0.5
mmHg) for 1 h to obtain 3.8 g of phosphinate 2 as
thick oil.
A solution of 3.7 g of dichloride A in 15 mL of methy-
lene chloride was added with stirring to a solution of
6.8 g of diethyl trimethylsilyl phosphite in 20 mL of
methylene 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
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Organophosphorus Derivatives of 2,6-Di-tert-butyl-4-Methylphenol 493
TABLE 1 Yields, Product Constants and NMR Spectral Data (δ, ppm, J, Hz) of Compounds 1–15a
Yield mp
2
No (%) (◦C) δ C1H JPH
δ
C3H (s) δ OH (s) δ (C1) 1JPC δ(C2) 2JPC δ(C3) 3JPC δ(C4) (s) δ(C5) (s) δ (s)
H H P
H
1
2
80 189 9.87 s
–
8
7.75
7.13
7.12
7.19
7.21
7.16
7.17
7.24
7.17
7.14
7.40
7.40
7.22
7.36
7.27
8.24
7.89
5.90
5.27
5.27
6.93
191.85 s
–
127.68 s
–
–
–
–
–
–
–
6
128.75 s
126.13 s
125.81 s
128.45 s
128.33 s
129.70 s
131.08 s
127.25 t
–
–
–
–
–
–
–
6
6
6
–
–
136.55 159.70
–
b
85
4.84 d
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
48.79 t 140 122.89 t 8.5 127.31 t
49.98 t 78.5 120.98 t
50.17 t 78 118.60 t
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
127.08 t 161 153.61 s
57.65 q 116 119.74 q
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
92 102 4.97 d 12
85 98 4.81 d 16
3
4
5
6
7
8
9
5.16
95 159c 4.48 d 8.1
97 198c 4.54 d 16
90 140 3.62 t 24
89 156 3.40 t 26
91 119 3.29 t 18
d
d
5.45
5.16
5.20
5.30
7
7
127.10 t
126.25 s
10 94
71 3.94 t 17
3.94 t 17
5.30
d
11 97 201 3.60 t 26
12 95 202 3.82 t 18
13 96 122 3.64 t 20
d
d
6
–
139.47 153.40 43.20
138.76 153.30 35.01
14 91 74e
15 85 162
–
–
–
–
–
5.18
–
7
130.38 t 15 151.03 186.33 14.01
128.81 q 134.43 152.79 16.12
7
aAll signals of the trimethylsilyl, tert-butyl, and ethoxy groups are in the standard area. PH fragment. 1H NMR spectrum, δ, ppm (J, Hz): 2:
6.91 d (1JPH 552) and 6.83 d (1JPH 552); 5: 6.67 d (1JPH 510.3). 13C NMR spectrum, δ, ppm (J, Hz). 9: 33.17 d (C6, 1JPC 96), 28.66 d (C7, 2JPC
3
1
4), 141.29 d (C8, JPC16); 10, first isomer: 43.61d (C9, JPC 108), 48.47s (C10), 17.79s (C11), 30.00s (C12), 174.66 d (C13 3JPC 3); 10, second
,
isomer: 43.50 d (C9, 1JPC 106), 48.40s (C10), 17.72 s (C11), 30.00 s (C12), 174.46 s (C13); 12: 31.59d (C6, 1JPC 94), 27.96 d (C7, 2JPC 3), 142.26
d (C8, 3JPC 17); 13: 42.75 d (C9, 1JPC 106), 48.08 s (C10), 17.94 s (C11), 30.15 s (C12), 174.31 s (C13).
bOily substance.
cWith decomposition.
dBroad signal.
eOrange crystals.
TABLE 2 Elemental Analyses Data of Compounds 2–15
Calcd (%)
Found (%)
No
Empirical Formula
Formula Weight
C
H
C
H
2
C21H41O4PSi2
C22H41O5PSi
C24H49O5PSi3
444.69
444.62
532.88
322.32
316.34
492.53
669.05
700.99
686.91
380.33
556.62
542.56
490.52
628.61
56.72
59.43
54.09
55.90
56.95
56.09
48.47
63.40
54.21
47.37
66.89
55.35
56.32
51.59
9.29
9.29
9.27
7.50
7.97
8.59
8.74
8.34
8.22
6.89
7.60
7.43
8.22
8.18
56.59
59.09
53.94
55.65
56.78
55.92
48.26
63.28
54.03
47.19
66.68
55.26
56.15
51.47
9.16
9.22
9.20
7.46
7.89
8.49
8.68
8.23
8.16
6.97
7.69
7.52
8.13
8.09
3
4
5
C15H24NaO4P
6
C15H25O5P
C23H42O7P2
C27H58O7P2Si4
C37H58O5P2Si2
C31H56N2O7P2Si2
7
8
9
10
11
12
13
14
15
C15H26O7P2
C31H42O5P2
C
25H40N2O7P2
C23H40O7P2
C27H51O10P3
dropped were filtered off and were kept in a vacuum
(0.5 mmHg) for 1 h to obtain 5.7 g of compound 7
(cf. [4]).
30 mL of hexane and 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
were kept in a vacuum (0.5 mmHg) for 1 h to obtain
3.6 g of compound 15 (cf. [6]).
Compounds 8–10 were prepared similarly.
3,5-Di-tert-butyl-4-hydroxyphenyltris(diethoxy-
phosphinoyl)methane (15)
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