Anionic condensations of 3,5-di-tert-butyl-4(2)-hydroxybenzaldehydes in the presence of weak bases

Article abstract of DOI:10.1134/S1070428008060043

Products of the reactions of 4- and 2-hydroxy-3,5-di-tert-butyl- benzaldehydes with malonic acid, diethyl malonate, and acetic anhydride in the presence of weak bases were isolated and identified. The reactions of 3,5-di-tert-butyl-4-hydroxybenzaldehyde w

Full text of DOI:10.1134/S1070428008060043

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 6, pp. 803–806. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.B. Vol’eva, I.S. Belostotskaya, N.L. Komissarova, L.N. Kurkovskaya, 2008, published in Zhurnal Organicheskoi Khimii, 2008,
Vol. 44, No. 6, pp. 814–817.
Anionic Condensations of 3,5-Di-tert-butyl-4(2)-hydroxy-
benzaldehydes in the Presence of Weak Bases
V. B. Vol’eva, I. S. Belostotskaya, N. L. Komissarova, and L. N. Kurkovskaya
Emanuel’Institute of Biochemical Physics, Russian Academy of Sciences, ul. Kosygina 4, Moscow, 119991 Russia
e-mail: komissarova@polymer.chph.ras.ru
Received January 17, 2007
Abstract—Products of the reactions of 4- and 2-hydroxy-3,5-di-tert-butyl-benzaldehydes with malonic acid,
diethyl malonate, and acetic anhydride in the presence of weak bases were isolated and identified. The
reactions of 3,5-di-tert-butyl-4-hydroxybenzaldehyde with malonic acid and acetic anhydride in the presence of
sodium acetate and piperidine gave 3,5-di-tert-butyl-4-hydroxycinnamic acid. The reaction of its 2-hydroxy
isomer with acetic anhydride stopped at the stage of formation of the corresponding O-acetyl derivative, while
in the reaction with malonic acid the corresponding substituted cinnamic acid and its lactone (coumarin
derivative) were formed as intermediate products in a transformation sequence finally leading to 3-(3,5-di-tert-
butyl-2-hydroxyphenyl)-3-piperidinopropionic acid and 6,8-di-tert-butyl-2-oxo-3,4-dihydro-2H-chromen-4-
ylacetic acid. Analogous differences were typical of reactions of isomeric 4- and 2-hydroxy-3,5-di-tert-butyl-
benzaldehydes with diethyl malonate. The transformations of the 2-hydroxy isomer were accompanied by
hydrolysis and formation of an adduct of intermediate coumarin derivative with diethyl malonate and
piperidine.
DOI: 10.1134/S1070428008060043
Anionic condensation of aromatic aldehydes, cata-
lyzed by weak bases, such as Knoevenagel and Perkin
reactions and their modifications, are used most fre-
quently for the synthesis of unsaturated aromatic acids
and ketones. Condensations of isomeric 4- and 2-hy-
droxy-3,5-di-tert-butylbenzaldehydes I and II with
malonic acid and acetic anhydride seemed to provide
a convenient route to cinnamic acids having a sterical-
ly hindered phenol fragment. In fact, the reaction of
aldehyde I with malonic acid in the presence of 5–7%
of piperidine smoothly afforded 3,5-di-tert-butyl-4-
hydroxycinnamic acid (III) in high yield (Scheme 1).
and coumarin V are formed as intermediates which
take up piperidine or malonic acid molecule so rapidly
that they could not be detected (Scheme 2). The ratio
of the adducts with malonic acid and piperidine,
6,8-di-tert-butyl-2-oxo-3,4-dihydro-2H-chromen-4-yl-
acetic acid (VI) and 3-(3,5-di-tert-butyl-2-hydroxy-
phenyl)-3-piperidinopropionic acid (VII), respectively,
depends on the initial amount of malonic acid in the
reaction mixture.
Ethyl 6,8-di-tert-butyl-2-oxo-3,4-dihydro-2H-chro-
mene-4-carboxylate (VIII) isolated in the reaction of
aldehyde II with diethyl malonate turned out to be
more stable. The other product formed in this reaction
was diethyl 2-[1-(3,5-di-tert-butyl-2-hydroxyphenyl)-
3-oxo-3-piperidinopropyl]malonate (IX) (Scheme 3).
Obviously, amide IX results from addition of piperi-
dine and diethyl malonate to intermediate coumarin V
Under similar conditions, aldehyde II reacted with
malonic acid along different pathways, and neither
the corresponding cinnamic acid IV nor its lactone,
coumarin V, was obtained. Nevertheless, the structure
of the isolated products suggests that cinnamic acid IV
Scheme 1.
t-Bu
CHO
t-Bu
COOH
HO
OH
+
–H2O, –CO2
HO
HO
O
O
Bu-t
Bu-t
I
III
803

VOL’EVA et al.
804
Scheme 2.
OH
t-Bu
CHO
OH
t-Bu
COOH
HO
OH
Pyridine
+
–H2O, –CO2
O
O
Bu-t
Bu-t
II
IV
Bu-t
Bu-t
O
O
O
O
CH2(COOH)2
–H2O
t-Bu
t-Bu
COOH
V
VI
H
·
·
·
O
N
Piperidine
t-Bu
COOH
Bu-t
VII
Scheme 3.
Bu-t
Bu-t
O
O
OH
EtO
OEt
Pyridine, piperidine
II
+
+
N
O
O
t-Bu
COOEt
t-Bu
O
EtOCO
COOEt
VIII
IX
whose formation requires hydrolysis of at least one
ester group in diethyl malonate (Scheme 4).
zylidene)malonate (X). Such a fast reaction of water
in situ indicates its high activity, which may be related
to complex formation with diester X.
It is reasonable to presume participation of water
molecule liberated in the first condensation stage
yielding diethyl 2-(3,5-di-tert-butyl-2-hydroxyben-
Presumably, retention of water molecule in the
reaction complex is a specific property of ester X. In
Scheme 4.
Bu-t
OH
EtO
OEt
COOEt
COOEt
II
+
O
O
t-Bu
X
Bu-t
V
–EtOH, –CO2
–H2O
OH
COOEt
COOH
VIII
t-Bu
XI
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 6 2008

ANIONIC CONDENSATIONS OF 3,5-Di-tert-BUTYL-4(2)-HYDROXYBENZALDEHYDES
805
H
Scheme 7.
O
Bu-t
OH
O
H
OAc
Me
O
Me
t-Bu
NaOAc
OEt
COOEt
II
+
O
O
t-Bu
CHO
XIII
t-Bu
X
Bu-t
OAc
fact, the reaction of diethyl malonate with isomeric
4-hydroxy aldehyde I was not accompanied by hy-
drolysis, and the only product was diethyl 2-(3,5-di-
tert-butyl-4-hydroxybenzylidene)malonate (XII)
(Scheme 5). We have found no examples of analogous
hydrolysis among vast published data on anionic con-
densations of diethyl malonate with various carbonyl
compounds (for review, see, e.g., [1]).
t-Bu
COOH
XIV
lyzed by TLC using Silufol UV-254 plates (eluent
hexane–diethyl ether, 15:1).
3-(3,5-di-tert-Butyl-4-hydroxyphenyl)prop-2-
enoic acid (III). a. A mixture of 5 g (21 mmol) of
aldehyde I, 6.7 g (60 mmol) of malonic acid, and
0.7 ml of piperidine in 18 ml of anhydrous pyridine
was heated for 1.5 h on a water bath. The mixture was
cooled, poured into water acidified with hydrochloric
acid, and extracted with diethyl ether. The extract was
washed with water and dried, the solvent was removed,
and the residue was recrystallized from hexane–chloro-
form (5 : 1). Yield 4.2 g (71%), mp 213–214°C
(sublimes). 1H NMR spectrum (CDCl3), δ, ppm: 1.46 s
(18H, t-Bu), 5.55 br.s (1H, OH), 6.31 d (1H, CH),
7.73 d (1H, CH, Jtrans = 16.1 Hz), 7.40 s (2H, Harom).
Found, %: C 73.87; H 8.75. C17H24O3. Calculated, %:
C 73.80; H 8.75.
Scheme 5.
EtO
OEt
I
+
O
O
Bu-t
HO
COOEt
COOEt
t-Bu
XII
An alternative method for the synthesis of cinnamic
acids and related compounds is based on the con-
densation of aromatic aldehydes with acetic anhydride
according to Perkin. Following this procedure, alde-
hyde I was converted into substituted cinnamic acid
III (Scheme 6).
b. A mixture of 0.23 g (1 mmol) of aldehyde I,
0.16 g (1.5 mmol) of acetic anhydride, 0.1 g (1 mmol)
of calcined sodium acetate, and 2 ml of pyridine was
heated for 3 h on an oil bath at 180–190°C. The mix-
ture was then treated as described above in a to isolate
0.12 g (48%) of compound III.
Scheme 6.
Ac2O
I
III
Reaction of 3,5-di-tert-butyl-2-hydroxybenzalde-
hyde with malonic acid. a. A mixture of 1.4 g
(6 mmol) of aldehyde II, 2 g (20 mmol) of malonic
acid, and 0.21 ml of piperidine in 6 ml of anhydrous
pyridine was heated for 3 h on a water bath, the
progress of the reaction being monitored by TLC. The
mixture was then treated as described above to isolate
6,8-di-tert-butyl-2-oxo-3,4-dihydro-2H-chromen-4-
ylacetic acid (VI). Yield 1.1 g (51%), mp 149–150°C
However, the reaction of aldehyde II with acetic
anhydride under analogous conditions resulted only in
acetylation of the hydroxy group to give aldehyde
XIII. Elevated temperature and prolonged reaction
time resulted in oxidation of aldehyde XIII to 3,5-di-
tert-butylsalicylic acid (XIV) [2] (Scheme 7).
EXPERIMENTAL
1
1
The H NMR spectra were measured on a Bruker
(from hexane). H NMR spectrum (DMSO-d6), δ,
WM-250 spectrometer at 250 MHz relative to tetra-
methylsilane as internal reference. The mass spectra
(electron impact, 70 eV) were recorded on a Hitachi
M-80A instrument. The reaction mixtures were ana-
ppm: 1.27 s (9H, t-Bu), 1.37 s (9H, t-Bu), 2.55 d (2H,
3
CH2), 2.71 d.d and 2.98 d.d (1H each, CH2, J = 6.8,
2
3
8.5, J = 16.6 Hz), 3.43 m (1H, 4-H, J = 5.1 Hz),
3
7.20 d (1H, Harom), 7.24 d (1H, Harom, J = 2.1 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 6 2008

VOL’EVA et al.
806
12.45 br.s (1H, COOH). Mass spectrum: m/z 318 [M]+.
Found, %: C 71.37; H 8.18. C19H26O4. Calculated, %:
C 71.60; H 8.29. The mother liquor contained unre-
acted aldehyde II (TLC).
3-carboxylate (VIII), mp 118–119°C (from MeOH).
1H NMR spectrum (CDCl3), δ, ppm: 1.36 s (9H, t-Bu),
1.51 s (9H, t-Bu), 1.41 t (3H, CH3CH2), 4.41 q (2H,
CH2CH3, J = 7.0 Hz), 7.41 d (1H, Harom), 7.68 (1H,
3
H
arom, J = 2.2 Hz), 8.51 s (1H, CH). Found, %:
When the reaction was carried out under analogous
conditions but at an aldehyde II–malonic acid ratio of
1 :1.5, we isolated 3-(3,5-di-tert-butyl-2-hydroxy-
phenyl)-3-piperidinopropionic acid (VII). Yield 46%,
C 72.58; H 7.89. C20H26O4. Calculated, %: C 72.66;
H 7.93.
Diethyl 2-(3,5-di-tert-butyl-4-hydroxybenzyli-
dene)malonate (XII). A mixture of 1 g (4 mmol) of
aldehyde I, 2 g (12 mmol) of diethyl malonate, and
0.14 ml of piperidine in 4 ml of anhydrous pyridine
was heated for 1.5 h on a water bath. The mixture was
treated with water acidified with hydrochloric acid and
extracted with diethyl ether, and the extract was dried
and evaporated to isolate 0.92 g (67%) of compound
XII, mp 116–117°C (from MeOH). 1H NMR spectrum
(CDCl3), δ, ppm: 1.33 t (6H, CH3CH2), 1.43 s (18H,
t-Bu), 4.29 q (2H, CH2CH3), 4.35 q (2H, CH2CH3, J =
7.3 Hz), 5.57 s (1H, OH), 7.34 s (2H, Harom), 7.65 s
(CH). Found, %: C 69.92; H 8.66. C22H32O5. Calculat-
ed, %: C 70.00; H 8.51.
1
mp 151–152°C (from octane). H NMR spectrum
(CDCl3), δ, ppm: 1.28 s (9H, t-Bu), 1.42 s (9H, t-Bu),
1.5 m (6H, CH2), 3.4 m (4H, CH2N), 2.65 d.d and
3
2
2.87 d.d (1H each, CH2, AB system, J = 3.0, 5.6, J =
16.0 Hz), 4.06 m (1H, CH), 6.92 d (1H, Harom), 7.19 d
(1H, Harom, 3J = 2.3 Hz), 9.06 br.s (1H, OH), 12.07 br.s
(1H, COOH); the position of the OH proton signal
at δ 9.06 ppm did not change upon replacement of
CDCl3 as solvent by DMSO-d6, indicating formation
of a strong intramolecular hydrogen bond OH···N.
Found, %: C 76.45; H 9.37. C22H33NO2. Calculated,
%: C 76.92; H 9.67. From the mother liquor we isolat-
ed lactone VI in 19% yield.
Reaction of 3,5-di-tert-butyl-2-hydroxybenzal-
dehyde with diethyl malonate. A mixture of 1 g
(4 mmol) of aldehyde II, 2 g (12 mmol) of diethyl
malonate, and 0.14 ml of piperidine in 4 ml of anhy-
drous pyridine was heated for 2 h on a water bath until
complete conversion of aldehyde II. The mixture was
poured into acidified water and extracted with diethyl
ether. The extract was evaporated, and the crystals
were separated and washed with hexane. Yield of di-
ethyl 2-[1-(3,5-di-tert-butyl-2-hydroxyphenyl)-3-oxo-
3-piperidinopropyl]malonate (IX) 0.4 g (21%),
Perkin reaction of acetic anhydride with alde-
hyde II. A mixture of 0.47 g (2 mmol) of aldehyde II,
0.31 g (3 mmol) of acetic anhydride, 0.2 g of calcined
sodium acetate, and 3 ml of anhydrous pyridine was
heated for 4 h at 180–190°C on an oil bath. The
mixture was cooled, treated with water acidified with
hydrochloric acid, and extracted with diethyl ether.
The extract was evaporated, and the residue was re-
crystallized from hexane. Yield of 4,6-di-tert-butyl-2-
formylphenyl acetate (XIII) 0.7 g (91%), mp 88–89°C.
1H NMR spectrum (CDCl3), δ, ppm: 1.36 s (9H, t-Bu),
1.39 s (9H, t-Bu), 2.42 s (3H, CH3), 7.68 d (1H, Harom),
1
mp 191–192°C (from MeOH). H NMR spectrum
3
(pyridine-d5), δ, ppm: 0.87 t (3H, CH3CH2), 1.14 t 3H,
CH3CH2), 1.38 s (9H, t-Bu), 1.62 s (9H, t-Bu), 1.40 m
(6H, CH2), 3.3 m (4H, NCH2), 3.06 d.d and 3.19 d.d
7.70 d (1H, Harom, J = 2.4 Hz), 9.91 s (1H, CHO).
Found, %: C 73.65; H 8.54. C17H24O3. Calculated, %:
C 73.87; H 8.75.
2
(1H each, COCH2, AB system, J = 16.2 Hz), 3.91 m
(2H, OCH2), 4.21 q (2H, OCH2, J = 7.0 Hz), 4.53 d
REFERENCES
3
(1H, CHCO), 4.95 m (1H, 1′-H, J = 11.2 Hz), 7.40 d
3
(1H, Harom), 7.44 d (1H, Harom, J = 2.2 Hz), 10.21 s
1. Organic reactions, Adams, R., Ed., New York: Wiley,
(1H, OH). Mass spectrum: m/z 503 [M]+. Found, %:
C 68.81; H 8.49. C29H45NO6. Calculated, %: C 69.10;
H 8.94. Evaporation of the mother liquor gave 0.78 g
(57%) of ethyl 6,8-di-tert-butyl-2-oxo-2H-chromene-
1967, vol. 15.
2. Vol’eva, V.B., Belostotskaya, I.S., Komisarova, N.L.,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 6 2008