Reactions of 3,5-di-tert-Butyl-4-hydroxybenzyl Acetate with Weakly Basic Nucleophiles

Article abstract of DOI:10.1023/A:1024910004024

The acid dissociation of 3,5-di-tert-butyl-4-hydroxybenzyl acetate in the presence of bases or in dimethylformamide favors reaction of this compound with weakly basic nucleophilies.

Full text of DOI:10.1023/A:1024910004024

Russian Journal of General Chemistry, Vol. 73, No. 3, 2003, pp. 408 412. Translated from Zhurnal Obshchei Khimii, Vol. 73, No. 3, 2003,
pp. 437 441.
Original Russian Text Copyright
2003 by Bukharov, Nugumanova, Mukmeneva.
Reactions of 3,5-di-tert-Butyl-4-hydroxybenzyl Acetate
with Weakly Basic Nucleophiles
S. V. Bukharov, G. N. Nugumanova, and N. A. Mukmeneva
Kazan State Technological University, Kazan, Tatarstan, Russia
Received February 28, 2001
Abstract The acid dissociation of 3,5-di-tert-butyl-4-hydroxybenzyl acetate in the presence of bases or in
dimethylformamide favors reaction of this compound with weakly basic nucleophilies.
3,5-Di-tert-butyl-4-hydroxybenzyl acetate (I) is
a highly active reagent which allows synthesis in mild
conditions and in high yields of compounds compris-
ing sterically congested phenol fragments [1]. Earlier
we found that acetate I readily reacts with primary
and secondary aliphatic amines to form benzylamines
[2]. In the same way acetate I reacts with ammonia,
yielding tris(3,5-di-tert-butyl-4-hydroxybenzyl)amine
rather than bis(3,5-di-tert-butyl-4-hydroxybenzyl) ether
as reported in [2]. At the same time, aromatic amines,
for example, aniline and benzidine, as well as hydr-
azine, fail to react with acetate I in inert solvents,
such as chloroform, carbon tetrachloride, and benzene.
It is known that reactions with nucleophiles of
sterically congested phenols containing a functional
group at the -carbon atom of the para-substituent
proceed via intermediate formation of 2,6-di-tert-
butylmethylenequinone (II) [3, 4].
O
OH
O
O
OH
t-Bu
Bu-t
t-Bu
Bu-t
t-Bu
Bu-t
t-Bu
Bu-t
t-Bu
Bu-t
NuH+
Nu
Nu
NuH+
MeCOO
CH2Nu
CH2Nu
CH2
CH2
CH2
OC(O)Me
OC(O)Me
I
III
II
In view of this scheme we assumed that the inert-
ness of aromatic amines toward acetate I is associated
with their insufficient basicity. It was therefore ex-
pected that addition to the reaction mixture of a
stronger base facilitating formation of phenoxide
anion III and its subsequent transformation into
methylenequinone II but not forming adducts with the
latter would favor benzylation of weakly basic nucleo-
philes. The following circumstance would be born in
mind. It is known that the prevailing reaction route of
methylenequinone II, and, therefore, the selectively
of reaction of acetate I in the presence of bases
depend on the nucleophilicity of the reagent used [4].
In this connection, acetate I and relatively weak
nucleophiles (aromatic amines, phenylhydrazine) are
best reacted in the presence of such basic agents
which ensure a fairly slow formation methylenequi-
none II thus preventing its accumulation in concen-
trations sufficient for dimerization and disproportiona-
tion [3].
It was previously found that alkali additives in a
solution of ester I favor the above transformations of
methylenequinone II [5]. In these conditions, success-
ful benzylation of aniline to form monobenzyl deri-
vative IV is only possible with a great excess of
aniline. The reaction at a 2:1 acetate I:aniline molar
ratio occurs quite unselectively yielding an intractable
mixture containing, by TLC data, benzylated anilines
IV and V, as well as compounds VI and VII formed
by side reactions of methylenequinone II.
At the same time, in a chloroform solution of ester
I in the presence of triethylamine, methylenequinone
II is accumulated fairly slowly (Fig. 1). As seen from
1070-3632/03/7303-0408$25.00 2003 MAIK Nauka/Interperiodica

REACTIONS OF 3,5-DI-tert-BUTYL-4-HYDROXYBENZYL ACETATE
409
(a)
(b)
70
65
60
55
50
45 40
35
30 25
20
15 10
, ppm
1
Fig. 1. H NMR spectra of acetate I in CDCl in the presence of triethylamine (a) immediately after prepration and (b) after
3
3 h. c 0.3 M and c
0.8 M.
NEt3
I
1
the H NMR spectra, the intensity of signals of acetate
I { , ppm: 1.40 s (SMe3), 2.03 s [MeC(O)], 4.96 s
(CH2O), 7.13 s (Ar H)} decreases with time com-
pared to those of triethylamine. Simultaneously, the
intensity of signals of methylenequinone II { , ppm:
1.22 s (CMe3), 5.72 s (CH2), 6.91 s (CH)} and of the
acetate methyl group ( , ppm: 1.92 s) increases. The
1H NMR spectra were assigned relying on the che-
mical shifts of compounds II, reported in [6].
Hc Hb
B
PhNH2
Ha
I
MeCOOH + II
RR N
Hc Hb
t-Bu
O
IV, V
R R +
VI
CH
t-Bu
2
In view of the above findings, the synthesis of
benzyl derivatives IV and V in the presence of triethyl-
amine readily occurs at room temperature. Similarly,
the use of triethylamine allows facile reactions of
acetate I with C-nucleophiles.
VII
R = CH2C6H2(Bu-t)2-3,5-OH-4; R = H (IV), CH2C6H2
(Bu-t)2-3,5-OH-4 (V).
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 73 No. 3 2003

410
BUKHAROV et al.
a new absorption band at
425 nm (Fig. 2).
max
D
Acidification of the solution leads to its lightening
and recovery of the initial absorption pattern at 370
480 nm. This finding allows the absorption band at
425 nm to be assigned to phenoxide anion III.
Tmheaxsame band is present in the electronic absorption
spectrum of a fresh solution of ester I in DMF. Within
some time this band is obscured by enhancing absorp-
tion of compound VII.
0.8
0.6
4
0.4
0.2
0
Thus, regardless of the fact that DMF is a weaker
base than aromatic amines, the formation of phen-
oxide anion III is made possible by the high concen-
tration of DMF, which shifts the equilibrium to the
side of this product. In addition, enhanced dissociation
of ion pairs in DMF and its ability to solvation of
delocalized anions should be taken into account [9].
As a result, slow accumulation of compound VII, a
product of methylenequinone II transformations, in a
DMF solution of acetate I takes place, which is de-
tected by electronic spectroscopy.
3
2
1
400
500 600
, nm
Fig. 2. Electronic absorption spectra in acetone.
(1) Compound VII, (2) acetate I (c 0.15 M), (3) the
same solution in the presence of KOH, and (4) DMF
solution of ester I (c 0.2 M).
I
I
Bu-t
The reactions of benzyl acetate I with aniline,
benzidine, and phenylhydrazine in DMF occur under
as mild conditions as in the presence of triethylamine,
and, therewith, the degree of benzylation can be
controlled by varying reactant ratio.
CH2
OH
Bu-t
Bu-t
I + RCCH2CR
RC C CR
O
O
O
O
PhNH2
I
IV
V
CH2
OH
Bu-t
Hb Ha
Ha Hb
VIII X
4-NH2C6H4C6H4NH2-4
RRN
NRR
I
R = Me (VIII, IX), OEt (X); R = Me (VIII), OEt (IX, X).
Hb Ha
Ha Hb
XI
Hc Hb
We found that the role of bases in reactions of ester
I with weak nucleophiles can be played by some
solvents, such as DMF. Dipolar aprotic solvents,
DMF inclusive, can form hydrogen bonds with steri-
cally congested phenols [7], thus facilitating ioniza-
tion of the latter [8].
PhNHNH2
Ha
RR NNR
Hc Hb
XII IV
The electronic absorption spectra of solutions of
acetate I in chloroform, carbon tetrachloride, benzene,
and acetone show no absorption in the visible region
and weak absorption of the 2,6-di-tert-butyl-4-[2-(3,5-
di-tert-butyl-4-oxocyclohexa-2,5-dienylidene)ethyl-
idene]cyclohexa-2,5-dien-1-one (VII) admixture. On
addition of alkalis, the acetone solution of acetate I
immediately acquired a light green color, and in its
electronic absorption spectrum we observed, on the
background of enhanced absorption of compound VII
which is one of the products of dimerization and dis-
proportionation of methylenequinone II [3] readily
formed from acetate I under the action of alkalis [5],
R = CH2C6H2(Bu-t)2-3,5-OH-4 (XI XIV); R = H (XII),
CH2C6H2(Bu-t)2-3,5-OH-4 (XIII, XIV); R = H (XII,
XIII); CH2C6H2(Bu-t)2-3,5-OH-4 (XIV).
Thus, the generation of methylenequinone II from
acetate I under the action of bases or dipolar aprotic
solvents, particularly DMF, allow reactions of com-
pound I with weakly basic nucleophiles. Therewith,
reaction success depends on whether the nucleophilic
agent is able to add to methylenequinone II. Thus,
for instance, such a weak nucleophile as urea, because
of its poor reactivity toward methylenequinone II,
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REACTIONS OF 3,5-DI-tert-BUTYL-4-HYDROXYBENZYL ACETATE
411
fails to react with benzyl acetate I even in the pre-
sence of bases or in DMF.
bis(3,5-di-tert-butyl-4-hydroxybenzyl)acetoacetate
(IX), yield 73%, mp 135 137 C. H NMR spectrum
1
(CDCl3), , ppm: 1.13 t (3H, Me), 1.42 s (36H,
CMe3), 1.82 s [3H, Me C(O)], 3.10 s (4H, CH2),
4.03 q (2H, CH2O), 5.02 s (2H, OH), 6.89 s (4H, Ar
H). Found, %: C 76.12; H 9.52. C36H54O5. Calculated,
%: C 76.33; H 9.54. Diethyl 2,2-bis(3,5-di-tert-butyl-
4-hydroxybenzyl)malonate (X), yield 70%, mp
EXPERIMENTAL
1
The H NMR spectra were measured on a Varian
Gemini-200 spectrometer (200 MHz) with reference
to residual proton signals of deuterated solvents. The
electronic absorption spectra were run on a Specord
UV-Vis spectrophotometer.
1
161 C. H NMR spectrum (CDCl3), , ppm: 1.10 t
(6H, Me), 1.42 s (36H, CMe3), 3.18 s (4H, CH2),
4.04 q (4H, CH2O), 5.10 s (2H, OH), 7.03 s (4H,
Ar H). Found, %: C 74.43; H 9.37. C37H56O6.
Calculated, %: C 74.50; H 9.40.
Dimethylformamide was purified as described
in [10].
3,5-Di-tert-butyl-4-hydroxybenzylanilines
(IV, V). A solution of 0.01 mol of acetate I, 0.01 mol
of triethylamine, and 0.25 mol (synthesis of IV) or
0.005 mol (synthesis of V) of aniline in 15 20 ml of
acetone was allowed to stand at room temperature for
5 h, after which it was poured into water. The pre-
cipitate that formed was filtered off, washed with
water, dried, and recrystallized from hexane.
3,5-Di-tert-butyl-4-hydroxybenzylamines IV, V,
and XI XIV. Aniline, benzidine, or phenylhydrazine
was added with stirring to a 25% solution of acetate I
in DMF. The reaction mixture was allowed to stand at
room temperature for 12 h and then poured into water.
The precipitate that formed was filtered off, washed
with water, dried, and recrystallized from hexane.
N-(3,5-Di-tert-butyl-4-hydroxybenzyl)-N-phenyl-
amine (IV), molar ratio I:aniline 1:25,
yield 91%. N,N-Bis(3,5-di-tert-butyl-4-hydroxy-
benzyl)-N-phenylamine (V), molar ratio I:aniline
2.5:1, yield 84%. 4,4 -[N,N,N ,N -Tetra(3,5-di-tert-
butyl-4-hydroxybenzyl)diamino]diphenyl (XI),
molar ratio I:benzidine 4.5:1, yield 89%, mp 265 C.
1H NMR spectrum (C6D5CD3), , ppm: 1.53 s (72H,
CMe3), 4.71 s (8H, CH2), 5.03 s (4H, OH), 7.09 d
N-(3,5-Di-tert-butyl-4-hydrohybenzyl)-N-phenyl-
1
amine (IV), yield 89%, mp 104 105 C. H NMR
spectrum (CDCl3), , ppm: 1.44 s (18H, CMe3),
4.19 s (2H, CH2), 5.21 s (1H, OH), 6.65 6.85 m (3H,
Ha, Hc), 7.18 s (2H, Ar H), 7.21 t (2H, Hb). Found,
%: C 80.87; H 9.31. C21H29NO. Calculated, %: C
81.03; H 9.32. Compound V was obtained in 80%
yield with 1 ml of 20% aqueous KOH instead of tri-
ethylamine.
3
(4H, Hb, J 8.8 Hz), 7.34 s (8H, Ar H), 7.58 d (4H,
3
N,N-Bis(3,5-di-tert-butyl-4-hydroxybenzyl)-N-
Ha, J 8.8 Hz). Found, %: C 81.50; H 9.44. C72H100
1
phenylamine (V), yield 81%, mp 166 168 C. H
N2O4. Calculated, %: C 81.82; N 9.47. N-(3,5-Di-tert-
NMR spectrum (CDCl3), , ppm: 1.38 s (36H, CMe3), butyl-4-hydroxybenzyl)-N -phenylhydrazine (XII),
4.49 s (4H, CH2), 5.10 s (2H, OH), 6.69 t (1H, Ha),
6.84 d (2H, Hc), 7.02 s (4H, Ar H), 7.19 t (2H, Hb).
Found, %: C 81.46; N 9.62. C36H51NO2. Calculated,
%: C 81.66; H 9.64.
molar ratio I:phenylhydrazine 1:25, yield 77%, mp
100 102 C. 1H NMR spectrum (CDCl3), , ppm:
1.46 s (18H, CMe3), 3.44 s (2H, NH), 4.50 s (2H,
CH2), 5.17 s (1H, OH), 6.80 t (1H, Ha), 7.08 s (2H,
Ar H), 7.10 7.35 m (4H, Hb, Hc). Found, %: C
77.21; H 9.19. C21H30N2O. Calculated, %: C 77.30;
H 9.20. N,N-Bis(3,5-di-tert-butyl-4-hydroxybenzyl)-
N -phenylhydrazine (XIII), molar ratio I:phenylhyd-
Di(3,5-di-tert-butyl-4-hydroxybenzyl)-substi-
tuted C-nucleophiles VIII X. A solution of 0.02 mol
of ester I, 0.04 mol of triethylamine, and 0.01 mol of
acetylacetone or 0.01 mol of acetoacetic ester, or 0.01
mol of malonic ester in 20 ml of acetone was allowed
to stand at room temperature for 5 h. The reaction
mixture was then poured into 150 of water and acidi-
fied with 5 ml of acetic acid. The precipitate that
formed was filtered off, washed with water, dried, and
recrystallized from methanol.
1
razine 1.5:1, yield 76%, mp 167 168 C. H NMR
spectrum (CDCl3), , ppm: 1.47 s (36H, CMe3),
3.78 s (4H, CH2), 4.62 s (1H, NH), 5.08 s (2H, OH),
6.74 t (1H, Ha), 6.88 d (2H, Hc), 7.10 7.35 m (6H, Hb,
Ar H). Found, %: C 79.29; H 9.53. C36H52N2O2.
Calculated, %: C 79.41; H 9.56. N,N,N -Tris(3,5-di-
tert-butyl-4-hydroxybenzyl)-N -phenylhydrazine
(XIV), molar ratio I:phenylhydrazine 3.5:1, yield
2,2-Bis(3,5-di-tert-butyl-4-hydroxybenzyl)-
1
1
acetylacetone (VIII), yield 75%, mp 154 156 C. H
79%, mp 160 162 C. H NMR spectrum (CDCl3), ,
NMR spectrum (CDCl3), , ppm: 1.39 s (36H, CMe3),
2.05 s (6H, Me), 3.20 s (4H, CH2), 5.03 s (2H, OH),
6.78 s (4H, Ar H). Found, %: C 78.11; H 9.68.
C35H52O4. Calculated, %: C 78.36; H 9.70. Ethyl 2,2-
ppm: 1.27 s (18H, CMe3), 1.40 s (36H, CMe3), 3.90 s
(4H, CH2), 4.54 s (2H, CH2), 4.96 s (1H, OH), 4.99 s
(2H, OH), 6.75 t (1H, Ha), 6.91 s (2H, Ar H), 7.13 s
(4H, Ar H), 7.14 7.35 m (4H, Hb, Hc). Found, %:
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BUKHAROV et al.
C 80.23; H 9.70. C51H74N2O3. Calculated, %: C 80.31;
H 9.71.
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