Alkaline hydrolysis of diethyl N-acetylamino(3,5-di-tert-butyl-4- hydroxybenzyl)malonate

Article abstract of DOI:10.1007/s11172-009-0115-2

Alkaline hydrolysis of diethyl N-acetylamino(3,5-di-tert-butyl-4- hydroxybenzyl)malonate is accompanied by decarboxylation. The efficiency of this process depends on the temperature and ratio of the reactants. A possibility of tautomerism with migration o

Full text of DOI:10.1007/s11172-009-0115-2

Russian Chemical Bulletin, International Edition, Vol. 58, No. 5, pp. 920—925, May, 2009
920
Alkaline hydrolysis of diethyl
Nꢀacetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxybenzyl)malonate
A. A. Volod´kin, S. M. Lomakin, G. E. Zaikov, and N. M. Evteeva
N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences,
4 ul. Kosygina, 119991 Moscow, Russian Federation.
Fax: +7 (499) 137 4101. Eꢀmail: chembio@sky.chph.ras.ru
Alkaline hydrolysis of diethyl Nꢀacetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxybenzyl)malonate
is accompanied by decarboxylation. The efficiency of this process depends on the temperature
and ratio of the reactants. A possibility of tautomerism with migration of the proton of phenolic
hydroxyl and the influence of the structure on the antioxidation properties were considered on
the basis of analysis of the IR spectral data and quantum chemical (PM6) calculation of the
structures. The energies of homolysis of the О—Н bond of phenolic hydroxyl were calculated
for a series of the synthesized compounds. It is proposed to predict the antioxidation activity on
the basis of these values.
Key words: Nꢀacetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxybenzyl)malonate, hydrolysis,
decarboxylation, antioxidants.
The use of malonic acid derivatives in the synthesis of
responding waterꢀsoluble sodium or potassium salts of
this malonic acid. The acidification of these salts results
in the corresponding substituted malonic acid, whose
properties differed from those described earlier.1
tyrosine analogs with tertꢀbutyl substituents in the aroꢀ
matic ring made it possible to consider this method as
optimal for the preparation of waterꢀsoluble antioxidants
promising in biology and medicine. It is known1 that the
formamide group in a molecule of 2ꢀ(Nꢀformylamino)ꢀ
3ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propanoic acid is
deformylated by aniline to form 2ꢀaminoꢀ3ꢀ(3,5ꢀdiꢀtertꢀ
butylꢀ4ꢀhydroxyphenyl)propanoic acid. Alkaline hydrolyꢀ
sis of diethyl Nꢀacetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyꢀ
benzyl)malonate in a water—alcohol solution gives the
corresponding acid in 63% yield. The thermolysis of
the acid at 140—180 °C produces 2ꢀ(Nꢀacetylamino)ꢀ
3ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propanoic acid. It
is insufficient to identify the earlier synthesized comꢀ
Results and Discussion
The alkaline hydrolysis of diethyl Nꢀacetylaminoꢀ
(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxybenzyl)malonate (1) results
in the saponification of ester groups followed by the deꢀ
carboxylation of the substituted malonic acid formed
(Scheme 1). Under the conditions of higher decarboxylaꢀ
tion rates, the tyrosine analogs are formed, whose yield
depends on the reactant ratio and reaction conditions. In
a solution of aqueous dioxane at the mole ratio 1 : NaOH
equal to 1 : 6 and temperature 100 °C, monosodium salt
2a, sodium salt of tyrosine 3а, and sodium salt of moꢀ
noester 2b are formed in the process of conjugated reacꢀ
tions. The rate constants for the conjugated reactions
(Scheme 2) were determined from the data of changing
the composition of the reaction mixtures in time and by
the calculation of the kinetic scheme using modeling of the
system of differential equations (Gear program2).
The kinetic scheme is presented by 12 reactions with
the initial concentrations of compound 1, NaOH, and
Н2О, whose change affects the results of the consumption
of the initial compounds and accumulation of the interꢀ
mediate and final compounds. At the ratio of the initial
molar concentrations of compound 1 and NaOH equal to
1 : 6, the corresponding salts of carboxylic acids are
1
pounds by the Н NMR spectra on the basis of multiplet
signals from the protons of the —CН2—CН— fragment,
because this identification does not allow one to deterꢀ
mine the vicinal and geminal constants. The single
example for the alkaline hydrolysis of this diethyl ester
does not elucidate the regularities of this reaction and its
synthetic potentialities. Therefore, the further study of
alkaline hydrolysis reactions and properties of the comꢀ
pounds formed seems topical.
In the present work, we found that decarboxylation
occurs simultaneously with the alkaline hydrolysis of
diethyl Nꢀacetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxybenzyl)ꢀ
malonate, due to which the Nꢀacetyltyrosine derivatives
are formed along with the derivatives of acetylaminoꢀ
malonic acid. The intermediate reaction products are corꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 900—905, May, 2009.
1066ꢀ5285/09/5805ꢀ0920 © 2009 Springer Science+Business Media, Inc.

3´,5´ꢀDiꢀtertꢀbutyltyrosine
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
921
Scheme 1
Ar =
formed, and the evolved CO2 reacts with alkali, decreasꢀ
ing the concentration of NaOH. The kinetic scheme is
presented by three blocks that describe the reactions of
saponification and decarboxylation and the exchange
reactions involving NaOH, Н2О, and CО2. Figure 1 preꢀ
sents the experimental data on the consumption of comꢀ
pound 1 and the accumulation of the reaction products
(after neutralization to pH 4). Figure 2 shows the results
of calculation of the kinetics of this reaction. Satisfactory
coincidence of the experiment and calculation allowed
us to use the kinetic scheme in the development of the
method of synthesis of 2а. It follows from the calculation
of the kinetic scheme of the initial concentrations of comꢀ
pound 1 and NaOH equal to 1 : 1 that more than 50% of
Scheme 2
1 + NaOH
2b + EtOH
(k = 2•10–3 L•mol–1•s–1
(1)
(2)
)
1 + NaOH + H2O
1 + H2O + H2O
2b + H2O
2a + EtOH + EtOH
(k = 1•10–4 L2•mol2•s–1
)
2d + EtOH + EtOH
(k = 8.5•10–5 L2•mol2•s–1
(3)
)
2c + NaOH
(4)
(k = 1 L•mol–1•s–1
)
2c + H2O
2b + H2O
(5)
(k = 10 L•mol–1•s–1
)
C (mol.%)
2a + H2O
2d + NaOH
(6)
100
(k = 1 L•mol–1•s–1
)
1
2d + NaOH
2a + H2O
(7)
80
60
40
20
0
3b
2d
(k = 1•10–2 L•mol–1•s–1
)
2c + H2O
3b + CO2 + EtOH
(8)
(k = 3.1•10–3 L2•mol–2•s–1
)
2a + NaOH + NaOH
3a + Na2CO3 + H2O
(9)
(k = 3•10–2 L•mol–1•s–1
)
3c
2d
3b + CO2
(10)
(11)
(12)
(k = 1.5•10–2 s–1
)
0
0.5
1.0
1.5
2.0
2.5
t/h
NaOH + CO2
NaHCO3
Fig. 1. Experimental data on the consumption of compound 1
and accumulation of 2d, 3b, and 3C under the conditions
of hydrolysis of compound 1 in aqueous dioxane at 100 °C.
(k = 1•102 L•mol–1•s–1
)
[1]0 = 0.357 mol L–1; [NaOH]0 = 2.24 mol L–1; [H2O]0
=
NaHCO3 + NaOH
Na2CO3 + H2O
= 5.95 mol L–1
.
(k = 1•102 L•mol–1•s–1
)

922
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Volod´kin et al.
C (mol.%)
100
compounds and, hence, no reactions occur at the acetylꢀ
amide group under the experimental conditions. The corꢀ
responding signals in the 1Н NMR spectra of the syntheꢀ
sized compounds confirm the presence of the CОCН3
group (δН 1.91—1.75) and NH group (δН 7.69—7.05).
1
3a + 3b
80
60
40
20
0
1
The Н NMR spectra of the tyrosine derivatives indicate
3b
3b
the presence of two nonequivalent hydrogen atoms in the
CН2 group, which are bound to the chiral atom, confirmꢀ
ing the structures of synthesized compounds 3a, 3b, and
1
3c. These protons in the Н NMR spectra appear as a
doublet of doublets with vicinal and geminal constants
that characterize the individual state of each compound.
The diffuse reflectance solidꢀphase IR spectra make it
possible to interpret the changes in the positions of the
characteristic frequencies as a consequence of intermoꢀ
lecular interactions.4 Of the synthesized compounds, comꢀ
pound 3с has an analogous property, and in its spectrum
the Н—О frequency of the phenolic hydroxyl shifts to the
longꢀwavelength region of the spectrum (3189 cm–1). In a
solution of compound 3с (CCl4), the Н—О frequency of
the hydroxyl appears at 3435 cm–1. It can be assumed that
in a molecule of compound 3с the hydrogen atom interꢀ
acts with the oxygen atom of the functional group of the
paraꢀsubstituent and this interaction is accompanied
by the enolation of the aromatic bonding system, which
agrees with the IR spectra data of cyclohexadienones.5,6
The IR spectrum of salt 3а contains intense bands at
1667, 1632, and 1596 cm–1, whereas the band at 1550 cm–1
characteristic of the aromatic structure is absent. A simiꢀ
lar effect related to the change in the position of the
characteristic frequencies is manifested in the IR spectra
of compound 2a and corresponding potassium salt 4. The
IR spectra of these compounds contain no frequencies of
the carboxyl group at 1700 cm–1 but have a broad band at
1550—1620 cm–1. These data can be interpreted as a conꢀ
sequence of the interaction of the sodium (potassium)
cation with πꢀelectrons of the atoms of the sixꢀmembered
ring and oxygen atoms of the functional groups. The data
of quantum chemical calculation of structures 2а, 3а, and
4 in the PM6 approximation (Mopac 2007 program)7 conꢀ
firm the participation of the metal cation in the coordinaꢀ
tion bond with the aromatic bonding system and oxygen
atoms of the paraꢀsubstituent (Fig. 4).
0
0.5
1.0
1.5
2.0
2.5
t/h
Fig. 2. Calculated data for the kinetics of the conjugated
reactions under the hydrolysis conditions in aqueous dioxane
at 100 °C; [1]0 = 0.357 mol L–1; [NaOH]0 = 2.24 mol L–1
;
[H2O]0 = 5.95 mol L–1
.
C (mol.%)
100
1
80
60
40
20
0
2a
3b
3c
0
0.5
1.0
1.5
2.0
2.5
t/h
Fig. 3. Calculated data for the kinetics of the conjugated
reactions under the conditions of hydrolysis of compound 1 in
aqueous dioxane at 100 °C; [1]0 = 0.455 mol L–1; [NaOH]0 =
= 0.455 mol L–1; [H2O]0 = 5.05 mol L–1
.
product 2a are formed after 1.5—2 h (Fig. 3). In the
preparative experiment, compound 2а was obtained in
62% yield.
The hydrolysis conditions at room temperature in the
presence of AcONa were developed for the preparation of
compound 2с in the individual form. On heating comꢀ
pound 2с to 175—180 °C, decarboxylation occurs to form
compound 3с.
Thus, the above results show that the functional group
of the paraꢀsubstituent of sterically hindered phenol
exerts a specific effect on the properties of the aromatic
bonding system, which should manifest itself in the
antioxidation properties of the synthesized compounds.
The properties of the antioxidants depend on the reaction
constants of the peroxide radicals with phenol and the
backward reaction of the phenoxyl radical with hydroperꢀ
oxide, which made it possible to use the calculation techꢀ
nologies for the prediction of the efficiency and choice of
optimal structures for the synthesis.8 For this purpose, the
energies of homolysis of the Н—О bond of phenolic
1
The IR and Н NMR spectral data present sufficient
information on the structure and properties of the obtained
compounds. It is known3 that the NН group in αꢀacetylꢀ
amino acids appears in the region of 3390—3260 cm–1,
and vibrations of the C=О bond in the acetylamide group
are observed at 1620—1640 cm–1. These characteristic
bands are observed in the IR spectra of the synthesized

3´,5´ꢀDiꢀtertꢀbutyltyrosine
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
923
([O2]o – [O2]t)/10–3 mol L–1
Na+
1
2
3
4
0.2
0.4
0.6
0.8
1.0
1.2 t/min
Fig. 5. Kinetic curves of oxygen absorption in the initiated oxiꢀ
dation of cumene at 50 °C in the presence of compounds
3c (1), 3b (2), and 2d (3) and azobisꢀisobutyronitrile (AIBN)
(4); Wi = 1.5•10–8 mol L–1 s–1, C0/mol L–1 = 2.4•10–5 (1);
3.1•10–5 (2); 3.3•10–5 (3); f = 1.71 (1); 1.98 (2); 2.42 (3).
Fig. 4. Structure of compound 2а according to the data of the
PM6 calculation.
hydroxyl (DOH) were calculated: DOH = ΔH(AlkArO) +
+ ΔH(H) – ΔH(AlkArOH), where ΔH(AlkArO) is
the energy of formation of the phenoxyl radical, and
ΔH(AlkArOH) is the energy of formation of phenol (comꢀ
pounds 2а, 2d, 3b, 3c, and 4). The results are listed in
Table 1.
Cumeneꢀsoluble compounds 2d, 3b, and 3с were used
in the estimation of the influence of the intramolecular
interaction on the antioxidation parameters: the period of
oxidation inhibition involving the antioxidant (τ) and the
chain termination factor (f) at the constant initiation rate
Wi = 1.5•10–8 m L–1 s–1. These parameters were related
by the expression: f = τWi[InH]–1, where InH are comꢀ
pounds 3b, 3c, or 2d. The results of determination of the
induction period of cumene oxidation in the presence of
InH are shown in Fig. 5. It follows from these results that
the antioxidation properties (by the f value) increase in
the series of compounds 2d > 3b > 3c, whereas similar
values of the f factor for compounds 2d and 3c should be
expected from the results of calculation of the energy of
homolysis of the О—Н bond. In our opinion, this contraꢀ
diction is due to tautomerism of compound 3с between
the aromatic and spirocyclic structures (Fig. 6), resulting
A
Table 1. Energies of homolysis of the O—H bond of phenolic
hydroxyl in 2d, 3a—c, and 4 and cumene hydroperoxide
B
Compound
D(OH)/kcal mol–1
D(OH)/kJ mol–1
Fig. 6. Structures of tautomers 3C (A and B) according to the
data of quantum chemical calculations in the PM6 approxiꢀ
mation.
3b
2d
3c
3a
80.0
76.6
76.6
71.7
74.6
75.2
334.7
320.5
320.5
300.0
312.1
314.6
in a decrease in the concentration of the aromatic strucꢀ
ture under the experimental conditions. It follows from
the energies of formation of aromatic structure 3с (А)
(–883.544 kJ) and spirocyclic structure 3с (B) (–841.748 kJ)
4
Cumene
hydroperoxide

924
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
Volod´kin et al.
1
data,1 m.p. 203 °C. Н NMR (acetoneꢀd6), δ: 1.42 (s, 18 Н,
But); 1.96 (s, 3 H, CОCН3); 2.94 (dd, 1 Hа, J = 7.6 Hz); 3.11
(dd, 1 Hb, J = 5.0 Hz); 4.63—4.69 (m, 1 НC); 5.90 (s, 1 H, OH);
that the difference is 41.796 kJ mol–1 (9.98 kcal mol–1).
In the nonpolar solvent (cumene) structure 3с (B) is more
stable, because the dipole moment (D) of structure 3c (В)
is 3.47 D, which is lower than D 3c (A) = 6.13 D.
The data in Table 1 show that compounds 2d, 3b, and
3с are insufficiently efficient antioxidants, whereas comꢀ
pounds 3а and 4 can be interest as waterꢀsoluble and
efficient antioxidants.
7.05 (s, 2 H, Ar); 7.45 (d, 1 H, NH, J = 5.0 Hz). IR, ν/cm–1
:
3639 (ОН); 3332 (NHCОCН3); 2954, 2913, 2872 (CH); 1715
(COОН); 1624 (HNCO); 1550 (C=C), 1433, 1269, 1218, 1188,
1157, 1120. Found (%): C, 67.84; H, 8.85; N, 4.16. C19H29NO4.
Calculated (%): C, 68.03; H, 8.72; N, 4.18.
Ethyl hydrogen Nꢀacetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyꢀ
benzyl)malonate (2c). A mixture of compound 1 (43.6 g, 0.1 mol)
and AcONa (8.2 g, 0.1 mol) in water (30 mL) and propanꢀ2ꢀol
(200 mL) was stored for 3 days at room temperature, after which
10% HCl (35 mL) was added. Compound 2c was obtained in a
yield of 26.1 g (64%), m.p. 175—176 °C (from toluene).
1Н NMR (DMSOꢀd6), δ: 1.24 (t, 3 Н, CН2CН3, J = 7.1 Hz);
1.34 (s, 18 Н, But); 1.89 (s, 3 H, COCH3); 3.22 (s, 2 H, CН2);
4.13 (2 Н, CН3CН2, J = 7.1 Hz); 6.34 (s, 1 H, OH); 6.76 (s,
2 H, Ar); 7.39 (s, 1 H, NH). IR, ν/cm–1: 3633 (ОН); 3345
(NHCОCН3); 2954 (CH); 1749 (CООC2Н5); 1714 (COОН);
1619 (HNCОCН3); 1533 (C=C); 1435, 1235, 1212, 1149.
Found (%): C, 64.89; H, 8.33; N, 3.31. C22H33NO6. Calcuꢀ
lated (%): C, 64.85; H, 8.16; N, 3.44.
Ethyl 2ꢀ(Nꢀacetylamino)ꢀ3ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyꢀ
phenyl)propanoate (3c) is formed on heating monoethyl ester 2c
to temperatures higher than 176 °C due to decarboxylation.
M.p. 135—136 °C (from toluene). 1Н NMR (acetoneꢀd6), δ:
1.68 (t, 3 Н, CН3CН2, J = 7.1 Hz); 1.42 (s, 18 Н, But); 1.91
(s, 3 H, COCH3); 2.02 (dd, 1 Hа, J = 6.2 Hz); 3.11 (dd, 1 Hb,
J = 6.3 Hz); 4.09 (2 Н, CН3CН2, J = 7.1 Hz); 4.60—4.64 (m,
1 НC); 5.98 (s, 1 H, OH); 6.95 (s, 2 H, Ar); 7.34 (d, 1 H, NH,
J = 7.15 Hz). IR, ν/cm–1: 3354 (NHCОCН3); 3189 br (OH);
2948 (CH); 1732 (COOC2Н5); 1647 (HNCO); 1548 (C=C);
1435; 1253; 1211; 1039. Found (%): C, 69.59; H, 9.13; N, 3.94;
C21H33NO4. Calculated (%): C, 69.40; H, 9.15; N, 3.85.
NꢀAcetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxybenzyl)malonate
(2d). A solution of compound 2a (4.2 g, 0.01 mol) in water
(50 mL) was treated with 10% HCl (5 mL). The precipitate
formed was separated, dried at 25—30 °C, and crystallized from
a toluene—EtOH (9 : 1, vol.) mixture. The yield was 92—96%,
m.p. 198—200 °C (from toluene). According to the literature
data,1 m.p. 148 °C. 1Н NMR (DMSOꢀd6), δ: 1.34 (s, 18 Н,
But); 1.87 (s, 3 H, COCH3); 3.22 (s, 2 H, CН2); 6.74 (s, 2 H, Ar);
7.69 (s, 1 H, NH). IR, ν/cm–1: 3637 (ОН); 3338 (NHCОCН3);
2954, 2913, 2872 (CH), 1716 (COOН); 1623 (HNCОCН3);
1536 (C=C), 1435, 1214, 1155, 1121. Found (%): C, 63.24; H,
7.95; N, 3.86. C20H29NO6. Calculated (%): C, 63.31; H, 7.70;
N, 3.69.
Experimental
The parameters of the structures of the synthesized comꢀ
pounds were calculated using the Mopacꢀ2007, Version 8.288W
program in the РМ6 approximation. 1Н NMR spectra were
recorded on a Bruker WMꢀ400 instrument (400 MHz) relative
to the signal of residual protons of the deuterated solvent
(acetoneꢀd6 or DMSOꢀd6). IR diffuse reflectance spectra were
recorded on a PerkinꢀElmer 1725ꢀX spectrometer for crystals.
The antioxidation parameters of the synthesized compounds
were determined by a known method9 under the conditions of
inhibited oxidation of cumene with oxygen at 50 °C in the
presence of the oxidation initiator (azodiisobutyronitrile).
Diethyl Nꢀacetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxybenzyl)ꢀ
malonate (1) was synthesized by a known procedure,6 m.p. 130 °C.
1Н NMR (acetoneꢀd6), δ: 1.25 (t, 6 Н, CН2CН3, J = 7.1 Hz);
1.40 (s, 18 Н, But); 2.07 (s, 3 H, COCH3); 2.89 (s, 1 H, CH2);
4.20—4.23 (m, 4 Н, CH2CH3); 6.01 (s, 1 H, OH); 6.82 (s, 2 H,
Ar); 7.29 (br.s, 1 H, NH).
Alkaline hydrolysis of compound 1. Compound 1 (4.36 g,
0.01 mol) was added to a solution of NaOH (0.84 g, 0.06 mol) in
dioxane (25 mL) and water (3 mL) at 100 °C in an argon flow,
and samples for analysis were taken at an interval of 30 min for
3 h under the temperatureꢀcontrolled conditions. The comꢀ
position of the reaction mixtures was monitored (after neutralꢀ
ization to pH 4) using the comparison of the 1Н NMR spectra in
an acetoneꢀd6 solution by the signals from metaꢀprotons of the
aromatic ring of the initial ester 1 (δ 6.820) and reaction
Н
products: δН 7.05 (3b), δН 6.95 (3c), and δН 6.92 (2d).
Synthesis of monosodium salt of Nꢀacetylamino(3,5ꢀdiꢀtertꢀ
butylꢀ4ꢀhydroxybenzyl)malonic acid (2a) and 2ꢀ(Nꢀacetylamino)ꢀ
3ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)propanoic acid (3b).
A mixture of compound 1 (43.6 g, 0.1 mol), NaOH (4 g,
0.1 mol), water (20 mL), and dioxane (200 mL) was heated for
2 h at 85—90 °C in an argon flow. Then the reaction mixture
was cooled down, and the precipitate formed was separated and
recrystallized from aqueous ethanol (8 : 2). Crystalline hydrate
of salt 2a was obtained in a yield of 23.4 g (62%), m.p. 258—260 °C
NꢀAcetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxybenzyl)malonic
acid diammonium salt (2e). Ammonia (2.2 mL, 0.1 mol) was
added to a solution of acid 2d (3.37 g, 0.01 mol) in EtOH (15 mL).
The reaction mixture was stirred for 30 min, and ammonia and
solvent excess were distilled off. Water (10 mL) was added to the
residue, and the mixture was heated and filtered. The filtrate
was cooled to 5—6 °C and stored until precipitation, and the
precipitate was separated by filtration. Compound 2e was
obtained in a yield of 3.1 g (83%), m.p. 177—178 °C (from
1
(with decomp.). Н NMR (DMSOꢀd6), δ: 1.26 (s, 18 Н, But);
1.79 (s, 3 Н, CОCН3); 3.37 (s, 2 Н, CН2); 3.40—3.48 (br.s,
НОН); 6.42—6.46 (br.s, 1 H, OH); 6.79 (s, 2 H, Ar); 7.20—7.27
(br.s, 1 H, NH). IR, ν/cm–1: 3643 (ОН); 3550—3100 br (НОH);
3321 (NHCОCН3); 2957 (CH); 1550—1615 br (HNCО, CОО–,
C=C); 1507; 1433; 1417; 1287; 1234; 1215; 1156; 1123. Found (%):
C, 56.96; H, 7.37; N, 3.52; Na, 5.55. C20H28NO6Na•H2O.
Calculated (%): C, 57.27; H, 7.20; N, 3.34; Na, 5.48.
EtOH). Н NMR (DMSOꢀd6), δ: 1.29 (s, 18 Н, But); 1.75 (s,
1
The mother liquor was treated with 10% HCl to pH 4, the
solvent was evaporated, and the residue was crystallized from
acetone. Compound 3b was obtained in a yield of 5.37 g (17%),
m.p. 205—206 °C (from EtOH). According to the literature
3 H, COCH3); 2.52 (s, 2 H, CН2); 3.85—4.01 (br.s,. 8 H, NH4);
6.80 (s, 2 H, Ar); 7.04—7.06 (br.s, 1 H, NH). Found (%):
C, 57.95; H, 8.71; N, 10.26. C20H35N3O6. Calculated (%):
C, 58.01; H, 8.53; N, 10.16.

3´,5´ꢀDiꢀtertꢀbutyltyrosine
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 5, May, 2009
925
NꢀAcetylamino(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxybenzyl)malonic
acid monopotassium salt (4) was synthesized similarly to
References
1
2a in 56% yield, m.p. 250—252 °C (with decomp.). Н NMR
1. H. J. Teuder, H. Rrause, V. Berariu, Lieb. Ann., 1978, 757.
2. C. W. Gear, Numerical Initial Value Problems in Ordinary
Differential Equations, Prentice Hall, New York, 1971, 158.
3. N. B. Colthup, L. H. Daly, S. E. Wiberley, Introduction to
Infrared and Raman Spectroscopy, Аcademic Press, New York—
London, 1990, 319.
(DMSOꢀd6), δ: 1.27 (s, 18 Н, But); 1.80 (s, 3 H, COCH3); 2.48
(s, 2 H, CН2); 3.41—3.46 (br.s, 3 H, НОН); 6.42—6.47 (br.s, 1
Н, ОН); 6.79 (s, 2 H, Ar); 7.22—7.26 (br.s, 1 H, NH). IR, ν/cm–1
:
3644 (ОН); 3550—3100 br. (НОH); 3323 (NHCОCН3);
1550—1620 br. (HNCО, CОО–, C=C). Found (%): C, 54.04;
H, 7.03; N, 3.15; К, 8.60. C20H22КNO6•1.5Н2О. Calcuꢀ
lated (%): C, 54.32; H, 7.21; N, 3.06; К. 8.75.
4. V. A. Russell, Lian Yu, J. Chem. Soc., Perkin Trans. 2, 2000,
913.
Sodium 2ꢀ(Nꢀacetylamino)ꢀ3ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyꢀ
phenyl)propanoate (3a). А. Sodium hydroxide (0.4 g, 0.01 mol)
was added to a solution of compound 3b (3.16 g, 0.01 mol) in
water (10 mL). The mixture was heated until the precipitate
dissolved, and then the solvent was distilled in vacuo. Ethanol
(10 mL) was added to the residue, NaCl was separated by
filtration, the mother liquor was evaporated, and the crystals of
compound 3a were washed with EtOH and dried in a desiccator
over P2O5. Compound 3a decomposes on heating above 250 °C.
1Н NMR (DMSOꢀd6), δ: 1.32 (s, 18 Н, But); 1.75 (s, 3 H,
CОCН3); 2.69 (dd, 1 Hа, J = 7.6 Hz); 2.94 (dd, 1 Hb, J = 5.0 Hz);
4.01—4.06 (m, 1 НC); 3.52—3.57 (br.s, Н, H2O); 6.96—6.98
(br.s, 1 H, ОН); 6.87 (s, 2H, Ar); 7.43—7.45 (br.s, 1 H, NH).
IR, ν/cm–1: 3646 (ОН); 3285 br. (НОН); 3103 (NHCОCН3);
2956, 2914, 2874 (CH); 1667 (C=O); 1632 (HNCОCН3);
1596 (C=C); 1435; 1400; 1316; 1400; 1316; 1234; 1158;
1121. Found (%): C, 55.64; H, 8.15; N, 3.46; Na, 5.64.
C19H28NO4Na•3H2O. Calculated (%): C, 55.45; H, 8.34;
N, 3.40; Na, 5.59.
5. A. A. Volod´kin, R. D. Malysheva, V. V. Ershov, Izv. Akad.
Nauk SSSR, Ser. Khim., 1982, 1594 [Bull. Acad. Sci. USSR,
Div. Chem. Sci. (Engl. Transl.), 182, 1633].
6. R. M. Guerra, I. Duran, P. Ortiz, Chemical Reaction: Quantiꢀ
tative Level of Liquid and Solid Phase, Nova Science Publishers,
Inc., New York, 1992, pp. 59—74.
7. J. J. P. Stewart Computational, J. Mol. Mod., 2007, 13, 1173.
8. D. V. Berdyshev, V. P. Glazunov, V. L. Novikov, Izv. Akad.
Nauk, Ser. Khim., 2007, 400 [Russ. Chem. Bull., Int. Ed.,
2007, 56, 413].
9. N. M. Emanuel, E. T. Denisov, Z. K. Maizus, Tsepnye reaktsii
okisleniya uglevodorodov v zhidkoi faze [Chain Reactions of
Hydrocarbon Oxidation in the Liquid Phase], Nauka, Moscow,
1965 (in Russian).
B. A solution of compound 2a (4.2 g, 0.01 mol) in water
(20 mL) was heated to boiling and stored for 35—40 min, then
the solvent was evaporated, and the residue was crystallized
from an EtOH—water (1 : 1) mixture. The yield of compound
3a was 3.78 g (92%). The 1Н NMR spectrum of the sample
coincides with that of compound 3a obtained by method A.
Received June 17, 2008;
in revised form March 17, 2009