Oxidation of Deactivated Cage Substrates in the System H2SO4–HNO3

Article abstract of DOI:10.1134/S1070428020030082

Abstract: The kinetics of oxidation of 16 carboxylic acid esters of the adamantaneseries in the systemH₂SO₄–HNO₃have been studied, and the effective rate constants have been determined. Thereaction is described by the pseudo-first-order kinetic equation. The primarykinetic isotope effect has been estimated at 2.9±0.3. The rate-determining stepof the oxidation process is cleavage of the adamantane C–H bond. The presence ofan ethyl group at the bridgehead position increases the reactivity of adamantanesubstrates toward oxidation, whereas methyl, ethoxycarbonyl, andethoxycarbonylmethyl groups reduce the reactivity.

Full text of DOI:10.1134/S1070428020030082

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 3, pp. 412–421. © Pleiades Publishing, Ltd., 2020.
Russian Text © The Author(s), 2020, published in Zhurnal Organicheskoi Khimii, 2020, Vol. 56, No. 3, pp. 402–413.
Oxidation of Deactivated Cage Substrates
in the System H SO –HNO
2
4
3
a,
a
a
a
E. A. Ivleva *, I. S. Grinʼ , I. S. Uchaev , and Yu. N. Klimochkin
a
Samara State Technical University, Samara, 443100 Russia
*
e-mail: elena.a.ivleva@yandex.com
Received October 3, 2019; revised January 17, 2020; accepted January 17, 2020
Abstract—The kinetics of oxidation of 16 carboxylic acid esters of the adamantane series in the system H SO –
2
4
HNO have been studied, and the effective rate constants have been determined. The reaction is described by
3
the pseudo-first-order kinetic equation. The primary kinetic isotope effect has been estimated at 2.9±0.3. The
rate-determining step of the oxidation process is cleavage of the adamantane C–H bond. The presence of
an ethyl group at the bridgehead position increases the reactivity of adamantane substrates toward oxidation,
whereas methyl, ethoxycarbonyl, and ethoxycarbonylmethyl groups reduce the reactivity.
Keywords: kinetics, kinetic isotope effect, reactivity, adamantane, carboxylic acids, mixture of sulfuric and
nitric acids
DOI: 10.1134/S1070428020030082
Interest in the chemistry of adamantane and its
derivatives increases every year, which is determined
by the unique structure of the adamantane skeleton. Of
particular concern are adamantane derivatives contain-
ing functional groups at the bridgehead positions. They
are important intermediate products for the synthesis
of biologically active [1–6] and organometallic com-
pounds [7, 8] and are also widely used in supramolec-
ular chemistry [9–11] and in the design of high-
technology materials [12–19] and polymers [20–24].
Medical and other applications of adamantane deriv-
atives make it necessary to develop new synthetic
approaches to the activation of C–H bonds therein and
efficient methods for the introduction of functional
groups. Among such methods, the most promising are
those based on transformations of cage structures by
the action of strong acids. At present, the system
H SO –HNO is extensively used in the functionaliza-
possible to predict the reactivity of substrates, and
contribute to understanding the nature of intermediate
species, thus opening ways for intentional control over
the oxidation process.
The problem of C–H bond activation in cage sub-
strates, especially in those containing several electron-
withdrawing substituents at the bridgehead positions,
remains an important field of research [51]. We previ-
ously performed a comprehensive study of the kinetics
of reactions of adamantane, its homologs, and some
functional derivatives with fuming nitric acid [52, 53].
In the present work we focused on the kinetics of
oxidation of deactivated cage substrates with a mixture
of sulfuric and nitric acids with a view to comparing
the obtained results with the data of [54] where the
kinetics of reactions of some substrates were studied
by the microcalorimetric method.
2
4
3
The kinetics of oxidation of lower alkanes with
H SO –HNO were studied by Rudakov et al. [55].
tion of adamantane derivatives [25–37]. Oxidation of
adamantane C–H bond with H SO –HNO is one of
2
4
3
2
4
3
Proper application of the Rudakov method to adaman-
tane substrates requires knowledge of their solubility
parameters in sulfuric acid, which are difficult to
determine. Therefore, we used as substrates carboxylic
acid esters of the adamantane series, which are soluble
in sulfuric acid. Esters 1–15 were synthesized by
esterification of the corresponding mono-, di-, and
tricarboxylic acids of the adamantane series, including
those containing alkyl substituents; their oxidation in
the key stages in the synthesis of vildagliptin [38–40]
and saxagliptin drug substances [41–43] that are used
in the treatment of type II diabetes, as well as of other
biologically active compounds [44–50].
Study of the kinetics of oxidation of adamantane
derivatives in the system H SO –HNO is of both
2
4
3
theoretical and practical importance. It could provide
a deeper insight into the reaction mechanism, make it
4
12

OXIDATION OF DEACTIVATED CAGE SUBSTRATES
413
Scheme 1.
H
OH
H SO –HNO
3
2
4
R1
R3
R1
R3
R2
R2
1
–15
1
2
3
1
2
3
1
2
3
1
2
3
R = COOEt, R = R = H (1), R = COOEt, R = Me, R = H (2), R = COOEt, R = Et, R = H (3), R = COOEt, R = R = Me (4),
1
2
3
1
2
3
1
2
3
1
2
R = R = CH COOEt, R = H (5), R = R = CH COOEt, R = Me (6), R = R = CH COOEt, R = Et (7), R = COOEt, R =
2
2
2
3
1
2
3
1
2
3
1
2
CH COOEt, R = H (8), R = COOEt, R = CH COOEt, R = Me (9), R = COOEt, R = CH COOEt, R = Et (10), R = R = COOEt,
2
2
2
3
1
2
3
1
2
3
1
2
3
1
R = H (11), R = R = COOEt, R = Me (12), R = R = COOEt, R = Et (13), R = R = CH COOEt, R = COOEt (14), R =
2
2
3
R = COOEt, R = CH COOEt (15).
2
the system H SO –HNO can be illustrated by
nitric acid in methylene chloride. The components of
2
4
3
Scheme 1. In order to estimate primary kinetic isotope
effect, we synthesized deuterated ester 16 from car-
boxylic acid 19. Acid 19 was prepared in turn from
hydroxy carboxylic acid 17 through 3-iodo-5,7-di-
methyladamantane-1-carboxylic acid (18) (Scheme 2).
The yield of 19 was 32%, and its isotope purity was
the reaction mixtures were quantitated by the internal
standard method using p-dinitrobenzene. We used
92% sulfuric acid, taking into account that more con-
centrated sulfuric acid (94–96%) promoted appreciable
hydrolysis of esters 1–16. The reactions were carried
out at 22°C, the initial concentrations of esters 1–16
6
7% according to the MS data for its methyl ester
were c = 0.030–0.052 M, and the concentrations of
0
obtained by treatment of 19 with a solution of diazo-
methane in diethyl ether (the intensity of the molecular
ion peak of acid 19 methyl ester was compared with
that of its non-deuterated analog). In the 13C NMR
spectrum of 19, the signal of the carbon atom linked to
deuterium was a triplet with a coupling constant J of
nitric and sulfuric acids were varied in the ranges 0.03–
0
.26 and 18.4–18.5 M, respectively.
Since fuming nitric acid was taken in excess
(5 equiv), change of its concentration during the reac-
tion can be neglected, so that the reaction was pre-
sumed to follow pseudo-first-order kinetics:
13
2
1.0 Hz. The C NMR spectrum of 16 showed a triplet
at δ 28.8 ppm (J = 20.0 Hz) due to the C–D carbon
atom. The isotope purity of 16 was 66% (according to
the GC/MS data).
C
∂
c/∂τ = k[S][HNO ] ; [HNO ] = const;
3 n 3
∂
c/∂τ = k [S], where k = k[HNO ] .
ef ef 3 n
The reaction mixtures were analyzed by GLC after
preliminary quenching by pouring onto crushed ice.
Nitric acid in a mixture with sulfuric acid behaves as
a base which gives rise to nitronium ion, and the latter
directly participates in the activation of tertiary C–H
bond [56, 57]. Stabilization of the intermediate with
sulfuric acid gives protonated sulfonic acid ester which
is deprotonated to sulfonic acid ester. When the reac-
tion mixture is poured onto ice, instantaneous hydrol-
ysis of the sulfonic acid ester yields the corresponding
hydroxy derivative.
In fact, the pseudo-first order of the reaction is
confirmed by the linear character of the semilog kinetic
curves (Fig. 1).
Table 1 contains the effective rate constants for the
oxidation of esters 1–15 in the system H SO –HNO .
2
4
3
We also calculated the relative rate constants with
account taken of the number of C–H bonds capable of
being involved in the reaction. Analysis of the obtained
effective rate constants shows that introduction of
alkyl groups into the bridgehead positions changes the
reactivity of adamantane-containing esters. In partic-
ular, methyl groups in the bridgehead positions slightly
The kinetics of the oxidation of esters 1–16 were
studied using 92% sulfuric acid and 5 equiv of fuming
Scheme 2.
COOH
COOH
COOH
COOEt
EtOH, TsOH
I2, Pcryst, PhMe
Li, n-BuOD
PhMe, Δ
Me
Me
Me
Me
Me
OH
I
D
D
Me
Me
Me
1
7
18
19
16
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

414
IVLEVA et al.
Table 1. Rate constants for the oxidation of esters 1–16 of the adamantane series in the system H SO –HNO at 22°C
2
4
3
–
1
a –1
krelb
Substrate, R Ad
k , s
ef
k , s
krel
n
ef
–
–
–
–
–
–
–
–
3
3
3
3
3
3
3
3
–3
–3
–3
–3
–3
–3
–3
–3
–4
–4
–4
–5
–5
–5
–5
1
3
3
3
7
1
5
5
3
5
5
1
5
5
3
5
-COOEt (1)
-Me-1-COOEt (2)
-Et-1-COOEt (3)
(3.72±0.47)×10
(3.00±0.32)×10
(4.20±0.47)×10
(1.87±0.41)×10
(1.58±0.49)×10
(1.25±0.36)×10
(1.01±0.33)×10
(1.35±0.38)×10
3.72×10
4.50×10
6.30×10
5.61×10
4.74×10
1.88×10
3.03×10
4.05×10
2.46×10
4.17×10
5.19×10
4.11×10
10.50×10
12.15×10
24.42×10
1
1
0.806
1.129
0.502
0.425
0.336
0.271
0.363
0.044
0.037
0.046
0.007
0.009
0.011
0.022
0.006
1.209
1.693
1.508
1.275
0.504
1.317
1.089
0.066
0.111
0.138
0.011
0.027
0.033
0.066
0.018
,5-Me -1-COOEt (4)
2
-D-3,5-Me -1-COOEt (16)
2
,3-(CH COOEt) (5)
2
2
-Me-1,3-(CH COOEt) (6)
-Et-1,3-(CH COOEt) (7)
2
2
2
2
-CH COOEt-1-COOEt (8)
(1.64±0.11)×10–4
(1.39±0.16)×10–
(1.73±0.11)×10–
2
4
-Me-3-CH COOEt-1-COOEt (9)
2
4
-Et-3-CH COOEt-1-COOEt (10)
2
–
–
–
–
–
5
5
5
5
5
,3-(COOEt) (11)
-Me-1,3-(COOEt) (12)
-Et-1,3-(COOEt) (13)
(2.74±0.27)×10
(3.50±0.14)×10
(4.05±0.13)×10
(8.14±0.61)×10
(2.27±0.25)×10
2
2
2
,5-(CH COOEt) -1-COOEt (14)
2
2
-CH COOEt-1,3-(COOEt) (15)
6.81×10–5
2
2
a
Rate constants calculated with account taken of the number of possible reaction centers.
Ratio of the rate constants calculated with account taken of the number of possible reaction centers.
b
reduce the substrate reactivity. For example, the rate of
oxidation of ethyl 3,5-dimethyladamantane-1-carbox-
ylate (4) is twice as low as that of ethyl adamantane-1-
carboxylate (1). On the other hand, ethyl substitution
at the bridgehead position slightly increases the reac-
tion rate. This is typical of reactions of adamantane
substrates involving formation of a carbocation
ester 1 is 15 times more reactive than diester 8. If the
substrate contains two or more bridgehead substituents,
their effect on the oxidation rate is additive. The pres-
ence of two ethoxycarbonylmethyl groups in triester 14
makes it less reactive than ester 1 by a factor of 15.2
with account taken of the number of possible reaction
centers. Triester 15 containing both ethoxycarbonyl
and ethoxycarbonylmethyl groups is 55 times less reac-
tive than ester 1. The relative oxidation rate constant of
diethyl 2,2′-(adamantane-1,3-diyl)diacetate (5) is only
twice as low as the relative oxidation rate constant
of ester 1.
[52, 53, 58–60].
It is important that the presence of an ethoxycar-
bonyl or ethoxycarbonylmethyl group on the bridge-
head carbon atom sharply reduces the reactivity. The
rate of oxidation of ethyl adamantane-1-carboxylate (1)
is 90 times higher than the rate of oxidation of diethyl
adamantane-1,3-dicarboxylate (11). The deactivating
effect of an ethoxycarbonylmethyl group is weaker:
Our data on the relative reactivity of adamantane-
containing esters do not contradict published data
on the relative reactivity of adamantane derivatives
[52, 54, 59, 60].
1
1
0
0
0
.6
.2
.8
.4
.0
The activation parameters of the oxidation of esters
1 and 4 were determined from the linear temperature
dependences of their effective oxidation rate constants
in the temperature range 2–32°C (Table 2) without
taking into account temperature variation of the state of
ion–molecule equilibria in the reaction medium.
The rate-determining step of the oxidation process
was determined by measuring the primary kinetic
isotope effect in the oxidation of ethyl 3,5-dimethyl-
0
400
800
1200
1600
2
Time, min
[7- H]adamantane-1-carboxylate (16). It was estimated
as the ratio of the effective oxidation rate constants at
22°C of ethyl 3,5-dimethyladamantan-1-carboxylate
Fig. 1. Semilog kinetic curves for the oxidation of carboxylic
acid esters of the adamantane series at 22°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

OXIDATION OF DEACTIVATED CAGE SUBSTRATES
415
Table 2. Rate constants for the oxidation of esters 1 and 4 in the system H SO –HNO at different temperatures
2
4
3
–
1
ΔS, J mol–1 K–1
–32.00±0.57
Ester no.
Temperature, °C
2
k , s
eff
Ea, kJ/mol
48.75±0.75
1
(0.73±0.06)×10–3
(1.19±0.13)×10–3
(3.72±0.47)×10–3
(5.00±0.35)×10–3
(0.50±0.34)×10–3
(0.98±0.07)×10–3
(1.87±0.41)×10–3
(3.50±0.34)×10–3
1
2
3
2
2
2
2
2
2
2
–34.91±0.45
4
46.79±0.35
1
2
3
(
4) and ester 16, k /k = 2.9 ± 0.3. This value was
EXPERIMENTAL
H
D
calculated with a correction for the isotope purity of 16
equal to 66%. Thus, the oxidation rate constants
obtained in our kinetic experiments refer to the rate-
determining step which is dissociation of the C–H
bond. It should be noted that the primary kinetic iso-
tope effect in the reaction of 1,3,5-trimethyladamantane
with fuming nitric acid was k /k = 4.4 [52], and in
The IR spectra were recorded on a Shimadzu IR
Affinity-1 spectrometer (Japan) equipped with an ATR
1
13
accessory. The H and C NMR spectra were recorded
on a Jeol NMR-ECX400 spectrometer (Japan) at 400
and 100 MHz, respectively, using tetramethylsilane as
internal standard. The reaction mixtures were analyzed
with a Thermo Scientific Focus gas chromatograph
H
D
the oxidation of 2-methylpropane with a mixture of
(USA) equipped with a DB-5 quartz capillary column,
sulfuric and nitric acids, k /k = 2 [60].
H
D
3
8
0 m×0.32 mm; oven temperature programming from
0 to 340°C at a rate of 20 deg/min; injector tempera-
The effect of electron-withdrawing substituents was
estimated by plotting the logarithms of the relative
effective oxidation rate constants for esters 5–15 versus
Taft inductive constants σ* (r = 0.914, ρ* = –0.53;
Fig. 2). The σ* values were taken from [61]. The
negative sign of ρ* indicates that electron-withdrawing
substituents hamper formation of carbocation, thus
decelerating the reaction:
ture 250°C; carrier gas helium. The mass spectra (elec-
tron impact, 70 eV) were obtained on a Finnigan Trace
DSQ mass spectrometer (USA). The melting points
were measured in capillary tubes using an MPM-H2
melting point apparatus (Germany) and are uncor-
rected. Elemental analysis was performed with
a EuroVector 3000 EA analyzer (Italy) using L-cystine
as standard. Initial adamantanecarboxylic acids were
synthesized according to the procedures described in
logkeff = –(4.22±0.26) – (0.53±0.12)σ*.
[
29] or taken from the collection of chemicals at the
The lack of a satisfactory correlation may be ratio-
nalized assuming that mutual interactions between
several electron-withdrawing substituents could change
geometric structure of the adamantane skeleton.
Figure 3 shows the reactivity series of adamantane
esters in the oxidation with H SO –HNO .
Organic Chemistry Department of the Samara State
Technical University; their purity was ≥95.0%.
3
-Iodo-5,7-dimethyladamantane-1-carboxylic
acid (18). A mixture of 55 g (0.245 mol) of 3-hydroxy-
4
7
6
2
4
3
Presumably, the oxidation of adamantane-contain-
ing esters in the system H SO –HNO involves genera-
3
2
1
0
5
9
8
1
4
10
2
4
3
1
3
12
11
1
5
tion of a tertiary adamantyl cation with dissociation of
the C–H bond as the rate-determining step. Nitronium
cation mediates single-electron transfer with the forma-
tion of adamantyl radical cation and simultaneous
elimination of proton to give adamantyl radical which
is rapidly oxidized with nitronium ion to carbocation.
The latter is stabilized via addition of a nucleophilic
species predominating in the reaction medium.
1
2
3
4
5
Taft constant σ*
Fig. 2. Correlation between the rate constants of oxidation of
esters 5–15 at 22°C and Taft substituent constants σ*.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

416
IVLEVA et al.
>
>
>
COOEt
COOEt
EtOC(O)
COOEt
COOEt
COOEt
COOEt
COOEt
>
>
EtOC(O)
COOEt
COOEt
COOEt
COOEt
Fig. 3. Reactivity series for the oxidation of some adamantanecarboxylic acid esters in the system H SO –HNO at 22°C.
2
4
3
5
2
,7-dimethyladamantane-1-carboxylic acid (17),
75 mL of toluene, 2.05 g (0.066 mol) of red phos-
recrystallization from aqueous methanol. Yield 2.02 g
–
1
(32%), isotope purity 67%. IR spectrum, ν, cm :
1
phorus, and 37.4 g (0.147 mol) of iodine was heated at
0°C with vigorous stirring under argon for 10 h. The
2905–2846 (C–H), 1685 (C=O). H NMR spectrum
8
(CDCl ), δ, ppm: 0.84 s (6H, CH ), 1.15 s (2H, CH ),
3
3
2
mixture was cooled to room temperature and washed
with 350 mL of 10% aqueous sodium thiosulfate, the
organic layer was separated, and the aqueous layer was
extracted with methylene chloride (5×50 mL). The
extracts were combined with the organic phase and
dried over anhydrous sodium sulfate, the solvent was
evaporated under reduced pressure on a rotary evap-
orator, and the residue was purified by recrystallization
from cyclohexane. Yield 56.20 g (69%), colorless
1.28–1.41 m (4H, CH2), 1.57–1.48 m (4H, CH2), 1.72 s
1
3
(2H, CH2), 11.53 br.s (1H, COOH). C NMR spectrum
(CDCl3), δC, ppm: 28.7 t (C–D, J = 21.0 Hz), 30.5
(CH3), 30.9, 37.2 (CH2), 37.3 (CH2), 42.4, 42.6 (CH2),
4
2.7 (CH ), 44.7 (CH ), 50.7 (CH ), 183.9 (C=O).
2 2 2
Mass spectrum (ethyl ester), m/z (I , %): 223 (14)
rel
+
+
[
M] , 222 (9) [M – 1] , 164 (100), 163 (82), 148 (8),
1
47 (6), 108 (25), 107 (23), 91 (9), 79 (5), 55 (5).
Esters 1–16 (general procedure). A mixture of
–
1
crystals, mp 156–158°C. IR spectrum, ν, cm : 2850,
0.02 mol of the corresponding carboxylic acid, 15 mL
of ethanol, and 5 mol % of p-toluenesulfonic acid in
100 mL of toluene was refluxed in a flask equipped
with a Dean–Stark trap until water no longer separated.
The mixture was cooled and washed with water,
a solution of sodium hydrogen carbonate, and water
again. The organic phase was dried over anhydrous
sodium sulfate and evaporated, and the oily residue
was purified by vacuum distillation.
1
2
922, 2945 (C–H), 1693 (C=O). H NMR spectrum
(
(
DMSO-d ), δ, ppm: 0.79 s (6H, CH ), 1.15–1.23 m
6
3
2H, CH ), 1.44–1.52 m (4H, CH ), 2.10–2.17 m (4H,
2
2
1
3
CH ), 2.41 s (2H, CH ), br.s (1H, COOH). C NMR
2
2
spectrum (DMSO-d ), δ , ppm: 29.5 (2C, CH ), 35.7,
6
C
3
4
3.3 (CH ), 45.8, 48.6 (CH ), 49.4, 51.7 (CH ), 57.1
2 2 2
(
2C, CH ), 176.5. Found, %: C 46.77; H 5.79.
2
C H IO . Calculated, %: C 46.72; H 5.73.
13
19
2
2
Ethyl adamantane-1-carboxylate (1). Yield 3.03 g
73%), bp 70–72°C (0.06 mm Hg); published data [62]:
bp 88–90°C (0.06 mm Hg); purity 99.3% (GLC).
3
,5-Dimethyl[7- H]adamantane-1-carboxylic
acid (19). A solution of 10 g (0.03 mol) of acid 18 in
50 mL of anhydrous dioxane was heated to the boiling
(
1
2
point, and 10 g (0.133 mol) of butan-1-( H)ol was
added with vigorous stirring. Metallic lithium, 1.4 g
0.2 mol), was then added to the boiling mixture, the
mixture was kept until lithium dissolved completely,
and additional 10 g (0.133 mol) of butan-1-( H)ol and
Ethyl 3-methyladamantane-1-carboxylate (2).
Yield 2.93 g (66%), bp 58–59°C (0.015 mm Hg), purity
2
0
–1
(
96.5% (GLC), nD = 1.4890. IR spectrum: ν 1729 cm
1
(C=O). H NMR spectrum (CDCl3), δ, ppm: 0.82 s
(3H, CH3), 1.22 t (3H, CH2CH3, J = 7.1 Hz), 1.56–
1.60 m (4H, CH2), 1.68–1.70 m (2H, CH2), 1.73–
1.83 m (4H, CH2), 1.87 s (2H, CH2), 2.04–2.05 m (2H,
2
1
.4 g (0.2 mol) of lithium were added. The progress of
the reaction was monitored by GLC. After completion
of the reaction, the mixture was poured into water,
acidified to pH 1–2 with concentrated aqueous HCl,
and extracted with methylene chloride (5×30 mL). The
combined extracts were washed with 10% aqueous
sodium thiosulfate (5×40 mL), dried over anhydrous
sodium sulfate, and evaporated on a rotary evaporator
under reduced pressure. The residue was purified by
1
3
CH), 4.07 q (2H, OCH , J = 7.1 Hz). C NMR spec-
2
trum (CDCl ), δ , ppm: 14.3 (CH ), 28.6 (CH), 30.1,
3
C
3
3
4
0.9 (CH ), 36.6 (CH ), 38.2 (CH ), 41.6, 43.6 (CH ),
3 2 2 2
5.6 (CH ), 60.1 (OCH ), 177.9. Found, %: C 75.69;
2
2
H 10.05. C H O . Calculated, %: C 75.63; H 9.97.
14 22
2
Ethyl 3-ethyladamantane-1-carboxylate (3).
Yield 3.40 g (72%), bp 76–77°C (0.012 mm Hg), purity
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

OXIDATION OF DEACTIVATED CAGE SUBSTRATES
417
2
0
–1
9
(
8.4% (GLC), n = 1.4889. IR spectrum: ν 1729 cm
(OCH ), 171.6. Found, %: C 71.44; H 9.65. C H O .
Calculated, %: C 71.39; H 9.59.
D
2
20 32
4
1
C=O). H NMR spectrum (CDCl ), δ, ppm: 0.76 t
3
(
3H, CH , J = 7.6 Hz), 1.15 q (2H, CH , J = 7.6 Hz),
3
2
Ethyl 3-(2-ethoxy-2-oxoethyl)adamantane-1-car-
boxylate (8). Yield 3.12 g (53%), bp 105–106°C
(0.005 mm Hg), purity 99.7% (GLC). The spectral
characteristics of 8 were reported previously [7].
1
1
2
.21 t (3H, CH , J = 7.8 Hz), 1.39–1.43 m (4H, CH ),
3
2
.54–1.61 m (4H, CH ), 1.76–1.79 m (4H, CH ), 2.04–
2
2
.05 m (2H, CH), 4.08 q (2H, OCH , J = 7.8 Hz).
2
1
3
C NMR spectrum (CDCl ), δ , ppm: 7.0 (CH ), 14.3
3
C
3
Ethyl 3-(2-ethoxy-2-oxoethyl)-5-methyladaman-
(
4
CH ), 28.5 (CH), 32.6, 36.2, 36.3 (CH ), 38.6 (CH ),
3 2 2
tane-1-carboxylate (9). Yield 4.75 g (77%), bp 155–
1.0 (CH ), 41.5, 43.2 (CH ), 60.1 (OCH ), 177.9.
20
2
2
2
1
1
56°C (0.1 mm Hg), purity 97.2% (GLC), n
=
D
Found, %: C 76.28; H 10.29. C H O . Calculated, %:
C 76.23; H 10.24.
–1
1
1
5
24
2
.4799. IR spectrum: ν 1730 cm (C=O). H NMR
spectrum (CDCl ), δ, ppm: 0.83 s (3H, CH ), 1.22 t
3
3
Ethyl 3,5-dimethyladamantane-1-carboxylate
(
6H, CH , J = 7.1 Hz), 1.28–1.35 m (4H, CH ), 1.49–
3
2
(4). Yield 3.30 g (70%), bp 70–71°C (0.017 mm Hg),
1
.52 m (4H, CH ), 1.63–1.66 m (2H, CH ), 1.67–
2 2
2
0
purity 99.5% (GLC), n = 1.4910. IR spectrum:
D
1.71 m (2H, CH ), 2.10 s (2H, CH ), 2.11–2.14 m (1H,
2 2
CH), 4.06–4.10 m (4H, OCH2). C NMR spectrum
ν 1730 cm–1 (C=O). H NMR spectrum (CDCl ), δ,
1
1
3
3
ppm: 0.83 s (6H, CH ), 1.14 s (2H, CH ), 1.22 t (3H,
CH , J = 7.8 Hz), 1.28–1.37 m (4H, CH ), 1.45–1.54 m
3
2
(CDCl ), δ , ppm: 14.3 (CH ), 14.4 (CH ), 29.0 (CH ),
3
C
3
3
3
3
2
30.4 (CH), 30.9, 33.8, 37.5 (CH ), 40.6 (CH ), 42.3,
2 2
(4H, CH ), 1.69–1.70 m (2H, CH ), 2.06–2.11 m
2 2
42.7 (CH ), 42.9 (CH ), 44.9 (CH ), 48.1 (CH ), 48.3
2 2 2 2
1
3
(1H, CH), 4.08 q (2H, OCH , J = 7.8 Hz). C NMR
2
(CH ), 60.0 (OCH ), 60.3 (OCH ), 171.5, 177.2.
2 2 2
spectrum (CDCl ), δ , ppm: 14.3 (CH ), 29.3 (CH),
3
4
Found, %: C 76.30; H 10.28. C H O . Calculated, %:
C 76.23; H 10.24.
3
C
3
Found, %: C 70.14; H 9.23. C H O . Calculated, %:
18 28 4
C 70.10; H 9.15.
0.5 (2C, CH ), 31.0, 37.6 (CH ), 42.5, 42.9 (CH ),
3 2 2
5.0 (CH ), 50.8 (CH ), 60.1 (OCH ), 177.7.
2
2
2
Ethyl 3-(2-ethoxy-2-oxoethyl)-5-ethyladaman-
1
5
24
2
tane-1-carboxylate (10). Yield 3.54 g (55%), bp 161–
20
1
62°C (0.1 mm Hg), purity 97.9% (GLC), n
=
D
–
1
1
Diethyl 2,2′-(adamantane-1,3-diyl)diacetate (5).
1.4848. IR spectrum: ν 1728 cm (C=O). H NMR
spectrum (CDCl ), δ, ppm: 0.79 t (3H, CH , J =
Yield 4.93 g (80%), bp 161–162°C (0.1 mm Hg), purity
9
reported previously [7].
3
3
9.8% (GLC). The spectral characteristics of 5 were
7.3 Hz), 1.22 t (6H, CH , J = 7.8 Hz), 1.28–1.33 m
3
(4H, CH ), 1.36 q (2H, CH , J = 7.3 Hz), 1.49–1.52 m
2
2
(
4H, CH ), 1.63–1.66 m (2H, CH ), 1.67–1.71 m (2H,
Diethyl 2,2′-(5-methyladamantane-1,3-diyl)di-
acetate (6). Yield 4.18 g (65%), bp 164–165°C
2 2
CH ), 2.10 s (2H, CH ), 2.11–2.14 m (1H, CH), 4.09 q
2
2
1
3
2
0
(4H, OCH , J = 7.8 Hz). C NMR spectrum (CDCl ),
(
0.1 mm Hg), purity 98.2% (GLC), n = 1.4894. IR
2
3
D
–
1
1
δ , ppm: 7.0 (CH ), 14.3 (CH ), 14.4 (CH ), 28.9
spectrum: ν 1727 cm (C=O). H NMR spectrum
CDCl ), δ, ppm: 0.82 s (3H, CH ), 1.20 t (6H, CH ,
C
3
3
3
(CH ), 33.5, 33.7, 35.9 (CH), 37.9 (CH ), 40.1 (CH ),
(
3 2 2
1.0 (CH ), 42.2, 42.6 (CH ), 43.3 (CH ), 45.9 (CH ),
2 2 2 2
3
3
3
4
4
J = 7.1 Hz), 1.22–1.40 m (12H, CH ), 1.92–1.95 m
2
8.2 (CH ), 60.0 (OCH ), 60.3 (OCH ), 171.6, 177.4.
(
7
1H, CH), 2.05 s (4H, CH ), 4.03 q (4H, OCH , J =
2
2
2
2
2
.1 Hz). 13C NMR spectrum (CDCl ), δ , ppm: 14.1
Found, %: C 70.84; H 9.44. C H O . Calculated, %:
C 70.77; H 9.38.
19 30
4
3
C
(
CH ), 29.3 (CH), 33.9, 34.0, 36.0 (CH ), 40.5 (CH ),
3 2 2
4
1.3 (CH ), 45.8 (CH ), 46.9 (CH ), 48.2 (CH ), 60.0
Diethyl adamantane-1,3-dicarboxylate (11). Yield
4.54 g (81%), bp 107–108°C (0.02 mm Hg); 176–
178°C (3 mm Hg) [63]; purity 99.8% (GLC).
2
2
2
2
(OCH ), 171.7. Found, %: C 70.83; H 9.45. C H O .
2 19 30 4
Calculated, %: C 70.77; H 9.38.
Diethyl 2,2′-(5-ethyladamantane-1,3-diyl)di-
acetate (7). Yield 4.64 g (69%), bp 172–173°C
Diethyl 5-methyladamantane-1,3-dicarboxylate
(12). Yield 3.65 g (62%), bp 116–117°C (0.03 mm Hg),
2
0
20
(
0.1 mm Hg), purity 96.5% (GLC), n = 1.4892. IR
purity 95.5% (GLC), n = 1.4824. IR spectrum:
D
D
–
1
1
–1
1
spectrum: ν 1727 cm (C=O). H NMR spectrum
ν 1730 cm (C=O). H NMR spectrum (CDCl ), δ,
3
(
CDCl ), δ, ppm: 0.71 t (3H, CH , J = 7.4 Hz), 1.09 t
ppm: 0.87 s (3H, CH ), 1.22 t (6H, CH , J = 7.8 Hz),
3
3
3
3
(
2H, CH , J = 7.4 Hz), 1.18 t (6H, CH , J = 7.1 Hz),
1.39–1.41 m (2H, CH ), 1.48–1.59 m (4H, CH ), 1.66–
2
3
2 2
1
.20–1.37 m (12H, CH ), 1.91–1.93 m (1H, CH),
1.88 m (4H, CH ), 1.91–1.99 m (2H, CH ), 2.16–
2 2
2
2
.03 s (4H, CH ), 4.05 q (4H, OCH , J = 7.1 Hz).
2.19 m (1H, CH), 4.09 q (4H, OCH , J = 7.8 Hz).
2
2
2
1
3
13
C NMR spectrum (CDCl ), δ , ppm: 7.0 (CH ), 14.4
C NMR spectrum (CDCl ), δ , ppm: 14.3 (CH ),
3
C
3
3
C
3
(
CH ), 29.2 (CH), 33.8, 34.0, 35.8 (CH ), 40.2 (CH ),
28.6 (CH), 30.4 (CH ), 30.6, 37.4 (CH ), 38.0 (CH ),
3
2
2
3 2 2
4
1.1 (CH ), 46.0 (CH ), 46.9 (CH ), 48.2 (CH ), 59.9
41.9, 42.5 (CH ), 44.8 (CH ), 60.4 (OCH ), 176.9.
2 2 2
2
2
2
2
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 3 2020

418
IVLEVA et al.
Found, %: C 69.42; H 8.94. C H O . Calculated, %:
C 69.36; H 8.90.
60.1 (OCH ), 177.6 (C=O). Mass spectrum, m/z
(I , %): 237 (10) [M] , 236 (3) [M – 1] , 164 (100),
rel
1
7
26
4
2
+
+
1
63 (70), 148 (8), 147 (4), 108 (79), 107 (80), 91 (52),
Diethyl 5-ethyladamantane-1,3-dicarboxylate
(
13). Yield 3.70 g (60%), bp 126–127°C (0.018 mm
79 (46), 55 (52).
2
0
Hg), purity 96.7% (GLC), n = 1.4922. IR spectrum:
D
Kinetic measurements. Nitric acid (100%, d =
ν 1730 cm–1 (C=O). H NMR spectrum (CDCl ), δ,
1
3
3
1.522 g/cm ) was distilled under reduced pressure
ppm: 0.79 t (3H, CH , J = 7.3 Hz), 1.23 t (6H, CH , J =
3
3
(20 mm Hg) just before use. Methylene chloride was
purified according to standard procedure [64]. The
components of the reaction mixtures were quantitated
by the internal standard method [65].
7
(
.8 Hz), 1.36 q (2H, CH , J = 7.3 Hz), 1.38–1.40 m
2
2H, CH ), 1.50–1.58 m (4H, CH ), 1.76–1.80 m (4H,
2 2
CH ), 1.93–1.95 m (2H, CH ), 2.18–2.20 m (1H, CH),
2
2
1
3
4
.10 q (4H, OCH , J = 7.8 Hz). C NMR spectrum
2
A 100-mL three-necked flask equipped with a ther-
mometer, stirrer, and dropping funnel was charged
with 8 mL of 92% sulfuric acid and 0.025 g of 1,4-di-
nitrobenzene (internal standard), 5 equiv of fuming
nitric acid was added on cooling, and a mixture of 0.2 g
of ester 1–16 and 10 mL of 92% sulfuric acid was
added over a period of 10 s, maintaining the required
temperature with an accuracy of ± 1°C. Samples of
the reaction mixture were withdrawn at definite time
intervals. A 2-mL sample was poured onto 4 g of
crushed ice and extracted with methylene chloride
(
3
4
CDCl ), δ , ppm: 7.0 (CH ), 14.3 (CH ), 28.5 (CH),
3.2, 35.8 (CH ), 37.8 (CH ), 39.6 (CH ), 39.9 (CH ),
2 2 2 2
3 C 3 3
1.8, 42.5 (CH ), 60.4 (OCH ), 177.1. Found, %:
2
2
C 70.15; H 9.21. C H O . Calculated, %: C 70.10;
H 9.15.
Diethyl 2,2′-[5-(ethoxycarbonyl)adamantane-1,3-
diyl]diacetate (14). Yield 5.47 g (72%), bp 210–211°C
(
IR spectrum: ν 1728 cm (C=O). H NMR spectrum
(
1
1
8
28
4
2
0
0.1 mm Hg), purity 97.7% (GLC), n = 1.4813.
D
–
1
1
CDCl ), δ, ppm: 1.14 t (9H, CH , J = 7.1 Hz), 1.36–
3
3
.47 m (6H, CH ), 1.54–1.64 m (6H, CH ), 2.03 s (4H,
2 2
(
2×2 mL), and the combined extracts were washed
with a solution of sodium hydrogen carbonate
3×4 mL) and water (3×4 mL), dried over anhydrous
CH ), 2.06–2.07 m (1H, CH), 3.97–4.02 m (6H,
OCH2). C NMR spectrum (CDCl ), δ , ppm: 14.2
(
2
1
3
3
C
(
CH ), 14.3 (CH ), 28.6 (CH), 33.6, 37.4 (CH ), 40.4
3 3 2
sodium sulfate, and analyzed by GLC. Each experiment
was performed at least in triplicate, and the rate con-
stant was calculated as the mean value.
(CH ), 42.0, 42.7 (CH ), 60.0 (OCH ), 60.3 (OCH ),
2 2 2 2
71.1, 176.6. Found, %: C 66.35; H 8.54. C H O .
21 32 6
1
Calculated, %: C 66.29; H 8.48.
Diethyl 5-(2-ethoxy-2-oxoethyl)adamantane-1,3-
ACKNOWLEDGMENTS
dicarboxylate (15). Yield 4.03 g (55%), bp 190–191°C
2
0
(
0.1 mm Hg), purity 93.5% (GLC), n = 1.4828.
The spectral and analytical data were obtained using the
facilities of the joint center “Study of Physicochemical
Properties of Compounds and Materials.”
D
–
1
1
IR spectrum: ν 1729 cm (C=O). H NMR spectrum
(
CDCl ), δ, ppm: 1.17 t (9H, CH , J = 7.1 Hz), 1.51 s
3 3
(
2H, CH ), 1.61–1.73 m (8H, CH ), 1.83–1.88 m (2H,
2
2
FUNDING
CH ), 2.08 s (2H, CH ), 2.11–2.15 m (1H, CH), 4.02–
4
ppm: 14.2 (CH ), 14.3 (CH ), 28.2 (CH), 33.3, 37.2
(
2
2
1
3
.05 m (6H, OCH2). C NMR spectrum (CDCl ), δ ,
3 C
This study was performed under financial support by the
Russian Foundation for Basic Research (project no. 18-33-
3
3
CH ), 39.3 (CH ), 40.2 (CH ), 41.5, 42.6 (CH ), 47.7
2 2 2 2
0
0881).
(
CH ), 60.1 (OCH ), 60.4 (OCH ), 171.1, 176.4.
2
2
2
Found, %: C 65.61; H 8.32. C H O . Calculated, %:
2
0
30
6
CONFLICT OF INTEREST
C 65.55; H 8.25.
2
Ethyl 3,5-dimethyl[7- H]adamantane-1-carbox-
The authors declare the absence of conflict of interest.
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