Adamantylation of nitro-substituted aromatic amines in protic acids

Article abstract of DOI:10.1134/S1070363208090132

Adamantylation of mono-and dinitro-substituted aromatic amines in sulfuric and phosphoric acids and in a mixture of phosphoric and acetic acids gives mainly the corresponding N-adamantyl derivatives. The results of kinetic measurements showed reversible c

Full text of DOI:10.1134/S1070363208090132

ISSN 1070-3632, Russian Journal of General Chemistry, 2008, Vol. 78, No. 9, pp. 1719–1727. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © S.B. Volkova, O.V. Platonova, V.G. Tsypin, V.A. Polukeev, 2008, published in Zhurnal Obshchei Khimii, 2008, Vol. 78, No. 9,
pp. 1487–1495.
Adamantylation of Nitro-Substituted Aromatic Amines
in Protic Acids
S. B. Volkovaa, O. V. Platonovaa, V. G. Tsypina, and V. A. Polukeevb
a Applied Chemistry Russian Research Center, pr. Dobrolyubova 14, St. Petersburg, 197198 Russia
fax: +7(812)3256648; e-mail: vgtsipin@yandex.ru
b Vekton Ltd., St. Petersburg, Russia
e-mail: cyclic@peterlink.ru
Received December 3, 2007
Abstract—Adamantylation of mono- and dinitro-substituted aromatic amines in sulfuric and phosphoric acids
and in a mixture of phosphoric and acetic acids gives mainly the corresponding N-adamantyl derivatives. The
results of kinetic measurements showed reversible character of the process.
DOI: 10.1134/S1070363208090132
Introduction of an adamantane fragment into
organic molecules endows them with practically
important properties. It was found that molecular tubes
on the basis of calix[4]- and thiacalix[4]arenes having
adamantane fragments on the upper rim exhibit
enhanced ionophoric properties. For example, p-tert-
butylcalix[4]-p-(1-adamantyl)thiacalix[4]arene tube is
capable of quantitatively binding potassium and
rubidium ions and retaining them in its cavity [1].
Adapalene-like compounds were shown to exhibit
antiinflammatory and immunoallergenic properties [2].
Therefore, methods for the preparation of adamantane-
containing arenes attract interest. Relevant published
data include mainly alkylation of benzene derivatives
having electron-donating substituents, i.e., those that
are highly reactive in electrophilic replacement
processes. Adamantylation of arenes by the action of
classical Lewis acids or protic acids has been studied
most extensively. Up-to-date methods are based on the
use of Group III metals trifluoromethanesulfonates,
solid acids, Keggin heteropolyacids, as well as of
palladium on charcoal [3–6].
halonitrobenzenes [7–10]. N-(1-Adamantyl)-2-nitro-
aniline (II) is an intermediate product in the synthesis
of 1,5-benzodiazepine derivatives that are used as
gastrin and cholecystokinin antagonists [9]. Prospects
in the application of N-(1-adamantyl)-4-nitroaniline (I)
and N-(1-adamantyl)-2,4-dinitroanilines (III) for the
preparation of organic nonlinear optics materials
deserve special attention [8, 10, 11].
In the present work we examined adamantylation of
2-, 3-, and 4-nitroanilines (V–VII), 4-methyl-2-nitro-
aniline (VIII), N-methyl-2-nitroaniline (IX), 6-nitro-
1,2,3,4-tetrahydroquinoline (X, a structural analog of
nitroanilines, and 2,4- and 3,5-dinitroanilines XI and
XII. These compounds possess reaction centers of
different natures, carbon atoms in the aromatic ring
and exocyclic amino nitrogen atom. On the basis of the
generally accepted views, alkylation of nitro-
substituted aromatic amines could give both N- and C-
alkyl derivatives.
It is known that concentrated sulfuric acid promotes
generation of 1-adamantyl cation (XIII) and is
convenient as catalyst and reaction medium for
alkylation of aromatic and heteroaromatic compounds
with adamantane derivatives, in particular with
adamantan-1-ol (XIV). Using azoles as examples, it
was shown that the selectivity of adamantylation of
heteroaromatic bases depends on the acidity of the
medium. Equilibrium protonation of reaction centers
of the substrate molecule in acid medium may prevent
Adamantylation of nitro-substituted aromatic amines
in the presence of protic acids was not studied
previously. Such known adamantane derivatives as N-
(1-adamantyl)-4-nitroaniline (I), N-(1-adamantyl)-2-
nitroaniline (II), and N-(1-adamantyl)-2,4-dinitro-
aniline (III) were synthesized exclusively by reaction
of adamantan-1-amine (IV) with the corresponding
1719

1720
VOLKOVA et al.
alkylation or force it to occur at a different (unblocked)
center [12–16].
however, the reactions in 92–94% sulfuric acid gave
exclusively the corresponding N-substituted products
I–III and XV in 12.9–33.4% yield. Compounds having
a substituent on the amino nitrogen atom, namely N-
methyl-2-nitroaniline (IX) (pKBH+ –0.62) and 6-nitro-
1,2,3,4-tetrahydroquinoline (X) failed to react with
adamantan-1-ol (XIV) in sulfuric acid over a week.
Table 1 contains the conditions and products of the
reactions of nitroanilines V–IX, XI, and XII with
adamantan-1-ols (XIV). The basicity of the examined
substrates varies over a wide range (pKBH+ 1.00–4.27);
NH2
HN Ad
R1
R1
_
+ Ad OH
H2SO4
R2
R2
XIV
Ad =
R1 = NO2, R2 = H (II, V); R1 = NO2, R2 = CH3 (VIII, XV); R1 = H, R2 = NO2 (I, VII); R1 = R2 = NO2 (III, XI).
I_III, XV
V, VII, VIII, XI
We also examined adamantylation of nitroanilines
V–IX and XII in a mixture of phosphoric and acetic
acids (80:20, by weight). This reaction medium
ensures generation of carbocation XIII, but its acidity
is lower than that of sulfuric acid. The Hammett
acidity function H0 for the above acid mixture is equal
to –1.8 [15, 16] (cf. H0 –9.33 for 92% sulfuric acid
[22]).
Unlike sulfuric acid, 2-nitroaniline (V) in the acid
mixture gives rise to both N-(1-adamantyl)-2-
nitroaniline (II) and dialkylation product, N,4-di(1-
adamantyl)-2-nitroaniline (XVI) (Table 1). In the
reaction of aniline V with 2 equiv of adamantan-1-ol
(XIV), prolonged to 4 days, the major product was
N,4-di(1-adamantyl)-2-nitroaniline
(XVI,
yield
37.7%). Pure N-(1-adamantyl)-2-nitroaniline (II) (its
Table 1. Reactions of adamantan-1-ol (XIV) with nitroanilines V–IX, XI, and XII and N-(1-adamantyl)-2-nitroaniline II
Initial
compound
no.
V
Vc
+
рKВН
Temperature,
Product no., yield, %
Reaction medium
H2SO4
Reaction time
of substratea
°С
–0.31 [17], –0.26 [18]
''
18–20
18–20,
55–60
50–52
50–52
55–60
50–52
16–18
50–52
18–20
58–60
55–60
54–56
54–56
15–20
5–6 days
1 days
21 h
II, 12.9–18.8b
II, XVId
H3PO4–CH3COOH
Ve
''
''
4 days
4 days
1 days
12 h
XVI, 35.5
XVI, 37.7
XIX, 52.3–66.4
XV, 58.4
–
''
II
–0.62 [17]
''
IX
0.40 [19]
''
VIII
VIII
VII
VII
VI
''
H2SO4
6 days
25–30 h
4 days
24–30 h
4 h
XV, 16.9
0.97 [17], 1.00 [18]
H3PO4–CH3COOH
I, 63.6–69.9f
I, 31.4
''
2.46 [20]
0.23 [21]
''
H2SO4
H3PO4–CH3COOH
XX, 14.3–21.5
XXI, 77.0
XXI, 64.2–75.0
III, 81.2
''
H3PO4
''
XII
XII
XI
2 h
–4.27 [18]
''
3 h
H2SO4
6 days
III, 33.4
XI
a
b
c
d
e
Water, 25°C. Yield 29% [9]. Molar ratio V:XIV = 1:1.1. Ratio II:XVI = 26:74 (GLC) or 21:79 (1H NMR). Molar ratio
V:XIV = 1:2. f Yield 67% [7].
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008

ADAMANTYLATION OF NITRO-SUBSTITUTED AROMATIC AMINES
1721
1
purity was confirmed by the H NMR data) also
reacted with adamantan-1-ol (XIV) in 4 days to give
35.5% of compound XVI. According to the TLC data,
the crude product isolated in the two latter reactions
also contained initial 2-nitroaniline (V), N-(1-
adamantyl)-2-nitroaniline (II), and 4-(1-adamantyl)-2-
nitroaniline (XVII). The structure of XVII was
confirmed by independent synthesis via nitration of
accessible N-[4-(1-adamantyl)phenyl]acetamide (XVIII)
[23] and subsequent deacetylation.
HN Ad
NO2
II +
V:XIV = 1:1
Ad
XIV
XVI
V
H3PO4_CH3COOH
XIV
XVI
V:XIV = 1:2
The pKBH+ values of 4-methyl-2-nitroaniline (VIII)
and N-methyl-2-nitroaniline (IX) are 0.40 and –0.62,
respectively. The presence of a methyl group on the
exocyclic nitrogen atom in N-methyl-2-nitroaniline
(IX) forces the alkylation to occur at the C4 atom, so
that the reaction of adamantan-1-ol (XIV) with N-
methyl-2-nitroaniline (IX) in phosphoric–acetic acid
mixture gave 4-(1-adamantyl)-N-methyl-2-nitroaniline
(XIX) in 52.3–66.4% yield. 4-Methyl-2-nitroaniline
(VIII) in the acid mixture is converted exclusively into
N-(1-adamantyl)-4-methyl-2-nitroaniline (XV) in
58.4% yield. The reaction of 6-nitro-1,2,3,4-tetra-
hydroquinoline (X) with adamantan-1-ol (XIV)
resulted in the formation of a mixture of alkylation
products which we failed to isolate and identify, and
the conversion was low.
HN R'
NO2
HN CH3
NO2
HN Ad
XIV
XIV
NO2
H3PO4_CH3COOH
H3PO4_CH3COOH
Ad
H3C
R
VIII, IX
XIX
XV
R = CH3, R' = H (VIII); R = H, R' = CH3 (IX).
The corresponding N-adamantyl derivatives I, XX,
and XXI were formed in 14.3–77.0% yield as the only
products in the reactions of 3-nitroaniline (VI), 4-
nitroaniline (VII), and 3,5-dinitroaniline (XII),
respectively, with adamantan-1-ol (XIV) in H3PO4–
AcOH. No alkylation products at the aromatic ring
were detected. The results remained essentially the
same when polyphosphoric acid (PPA, H0 = –5.2) was
used as catalyst and medium. Weakly basic 2,4-
dinitroaniline (XI) reacted with adamantan-1-ol (XIV)
in PPA to produce 81.2% of N-(1-adamantyl)-2,4-di-
nitroaniline (III).
The presence of an alkyl substituent in the amino
group hampers adamantylation in sulfuric acid. In a
less acidic medium, 80:20 phosphoric–acetic acid
mixture, C-alkylation occurs only at the para position
with respect to the amino group. The reaction of 2-
nitroaniline (V) with adamantan-1-ol (XIV) in H3PO4–
AcOH gives both N- and C-substituted products.
Presumably, diadamantyl derivative XVI accumulates
in the reaction mixture mainly through N-(1-
adamantyl)-2-nitroaniline
(II),
whereas
4-(1-
adamantyl)-2-nitroaniline (XVII) is formed via
dealkylation of compound XVI.
Thus the yields of the N-adamantyl derivatives in
The obtained results satisfactorily demonstrate
H3PO4–AcOH and PPA are higher than in sulfuric acid.
exceptionality of N-adamantylation of nitroanilines V,
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008

1722
VOLKOVA et al.
H2N
HN Ad
XIV
H3PO4_CH3COOH
or PPA
R1
R2
R1
R2
XX, XXI
VI, XII
R1 = NO2, R2 = H (VI, XX); R1 = R2 = NO2 (XII, XXI).
H2N
HN Ad
R1
R1
XIV
H3PO4_CH3COOH
or PPA
R2
VII, XI
R2
I, III
R1 = H, R2 = NO2 (I, VII); R1 = R2 = NO2 (III, XI).
VII, VIII, and XI in sulfuric acid and preference of N-
adamantylation of nitroanilines V–VIII, XI, and XII
in a mixture of phosphoric and acetic acids and in
polyphosphoric acid.
pKBH
+
values of both initial substrate and
adamantylation product.
We examined the kinetic relations holding in
adamantylation of nitroanilines in protic acids by
measuring variation in the concentrations of the initial
compounds and final products with time. As reaction
medium we used 89.9–99.6% sulfuric acid (H0 –9.02
to –10.92) [22]. The concentrations of initial
nitroanilines and adamantylation products were
determined by spectrophotometry.
Figure 1 shows plots of the concentration of N-(1-
adamantyl)-2-nitroaniline (II) versus time in the
reactions performed in sulfuric acid having different
concentrations. It is seen that in 89.9% sulfuric aicd
(H0 = –9.02) the curve comes to a plateau in 220–230 h,
i.e., a stationary concentration of II is reached (Fig. 1,
curve 1). An analogous pattern is observed in 95.0%
Logarithm of the ionization ratio (log I = pKBH+ –
H0) [24] can be used as a quantitative parameter
characterizing the reactivity of basic substrates in
adamantylation in protic media. It was believed
previously that azoles with a high log I value either
react in the protonated form or do not react [15, 16,
25]. In our case, N-adamantylation of protonated
nitroanilines is impossible. The log I values for 2- and
4-nitroanilines V and VII in 92–94% sulfuric acid
range from 9.02 to 10.59. As shown above, this range
of logI corresponds to formation N-adamantylation
products. The logI value for 3-nitroaniline (VI) in
83.4% sulfuric acid (H0 = –8.05) is 10.51. It was found
previously that adamantyl cation XIII is generated
even in 71.7% sulfuric acid (H0 = –6.18) [12], i.e.,
83.4% sulfuric acid as reaction medium ensures
conditions necessary for adamantylation of 3-
nitroaniline (VI). Nevertheless, no reaction was
observed over a period of 7 days.
sulfuric acid (H0
=
–9.74) where stationary
concentration of aniline II is reached in 110–120 h
(Fig. 1, curve 2). According to the spectrophotometric
data, the yield of N-(1-adamantyl)-2-nitroaniline (II) in
89.9 and 95.0% sulfuric acid was estimated at 20–
22%. In going to sulfuric acid with a higher
concentration (97.8, 98.1, and 99.6%; H0 = –10.23, –
10.30, and –10.92, respectively), the plots of the yield
of II versus time become U-shaped (Fig. 1, curves 3–
5). The plots of the concentration of initial 2-
nitroaniline (V) versus time for the same sulfuric acid
concentrations (Fig. 2, curves 1–5) are mirror images
of the curves shown in Fig. 1.
In terms of traditional concepts on the reaction
mechanism, N-adamantylation is a reversible process.
This means that N-adamantylation in protic acids
should be governed by the ratio of the rates of
alkylation and dealkylation. The rate of dissociation of
the N–CAd bond in more basic N-adamantyl derivatives
should be higher. Presumably, prospects in using protic
acids for adamantylation of nitrogen-containing
organic bases must be evaluated with account taken of
The alkylation and dealkylation of aromatic amines
in the examined processes involve generation of 1-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008

ADAMANTYLATION OF NITRO-SUBSTITUTED AROMATIC AMINES
1723
2
2
1.9
1.8
1.7
1.6
1.5
0.5
0.4
0.3
0.2
0.1
0
1
3
4
5
1
4
5
2
3
0
50
100
150
200
250
0
50
100
150
200
250
Time, h
Time, h
Fig. 1. Variation of the concentration of N-(1-adamantyl)-2-
nitroaniline (II) in the reaction with adamantan-1-ol (XIV)
in sulfuric acid. Concentration of sulfuric acid, %: (1) 89.9,
(2) 95.0, (3) 97.8, (4) 98.1, and (5) 99.6.
Fig. 2. Variation of the concentration of 2-nitroaniline (V) in
the reaction with adamantan-1-ol (XIV) in sulfuric acid.
Concentration of sulfuric acid, %: (1) 89.9, (2) 95.0, (3)
97.8, (4) 98.1, and (5) 99.6.
adamantyl cation (XIII) which is thermodynamically
stable in acid media. Carbocation XIII is capable of
undergoing oxidation to adamantan-2-one (XXII) by
the action of 94–100% sulfuric acid. The rate of
formation of adamantan-2-one (XXII) increases as the
concentration of sulfuric acid and reaction temperature
rise [26]. Obviously, the observed plateaus on curves 1
and 2 in Figs. 1 and 2 correspond to equilibrium
concentrations of N-(1-adamantyl)-2-nitroaniline (II)
and 2-nitroaniline (V) due to reversible character of the
N-adamantylation of 2-nitroaniline (V) in sulfuric acid.
The U-shaped curves for the reactions in more
concentrated sulfuric acid are related to consumption
of the alkylating agent as a result of concurrent
oxidation with sulfuric acid. The clearly defined
maxima on curves 4 and 5 (Figs. 1, 2) are likely to
correspond to similar rates of adamantylation of 2-
nitroaniline (V), dealkylation of N-(1-adamantyl)-2-
nitroaniline (II), and formation of adamantan-2-one
(XXII).
ol (XIV) in 94.2% sulfuric acid (H0 = –9.62). Figure 4
shows the kinetic curves for initial reactant ratios of
1:1, 1:2, and 1:3. Equilibrium concentrations of
compounds VII and I are attained in 90–95 h. It is seen
that in the reaction with 2 equiv of the alkylating agent
the equilibrium concentration of N-adamantyl
derivative I increases from 8.95×10–2 (1:1) to
1.35×10–1 M, which corresponds to increase in the
yield of I from 46.3 to 70.4%. Further rise of the
amount of adamantan-1-ol (XIV) to 300 mol %
ensured increase in the yield of I only to 76.1%.
Replacement of sulfuric acid n compound by a
mixture of phosphoric and acetic acids in the
adamantylation of 4-nitroaniline (VII) did not change
the results on a qualitative level. Variations of the
concentrations of N-(1-adamantyl)-4-nitroaniline (I)
and 4-nitroaniline (VII) with time are shown in Fig. 5.
2
1.2
We found that pure N-(1-adamantyl)-2-nitroaniline
(II) (the purity of II was confirmed by the H NMR
1
0.8
0.6
1
data) in 94.5% sulfuric acid (H0 = –9.66) was
converted into 2-nitroaniline (V). Figure 3 (curves 1,
2) shows that the concentrations of II and V become
constant in 135–145 h, indicating establishment of
equilibrium in the acid-catalyzed dealkylation of
compound II. The stationary concentrations of N-(1-
adamantyl)-2-nitroaniline (II) and 2-nitroaniline (V)
are 1.88×10–2 and 1.01×10–1 M, respectively. Then the
conversion of II is 84.3%.
1
0.4
0.2
0
0
20 40 60 80 100 120 140 160 180 200 220
Time, h
Fig. 3. Variation of the concentrations of (1) N-(1-
adamantyl)-2-nitroaniline (II) and (2) 2-nitroaniline (V) in
the reaction with adamantan-1-ol (XIV) in 94.5% sulfuric
acid.
We also examined the effect of the reactant ratio in
the reaction of 4-nitroaniline (VII) with adamantan-1-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008

1724
VOLKOVA et al.
Concentration, M×10–1
After 28–32 h, the concentrations of I and VII attain
constant values, 1.39×10–1 and 5.33×10–2 M, res-
pectively (Fig. 5; curves 1, 2). On the basis of the
equilibrium concentrations, the yield of N-(1-
adamantyl)-4-nitroaniline (I) was estimated at 72.3%.
The reactions considerably slowed down when the
temperature was reduced to 22–24°C (Fig. 6). The
equilibrium in the reaction of 4 nitroaniline (VII)
with adamantan-1-ol (XIV) is set in 60–65 days. The
equilibrium concentrations of I and VII are 1.15×10–1
and 7.68×10–2 M, respectively, and the yield of N-(1-
adamantyl)-4-nitroaniline (I) is 60.0%. In the
adamantylation of 3-nitroaniline (VI), the concentra-
tions of XX and VI become constant (2.40×10–2 and
1.68×10–1 M, respectively) in 22–24 h (Fig. 5; curves
3, 4).
2
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
3
2
4
5
1
6
0
20 40 60 80 100 120 140 160 180 200 220
Time, h
Fig. 4. Variation of the concentrations of (1–3) N-(1-adamantyl)-4-
nitroaniline (I) and (4–6) 4-nitroaniline (VII) in the reaction with
adamantan-1-ol (XIV) in 94.2% sulfuric acid at I:VII molar ratios
of (1, 4) 1:1, (2, 5) 1:2, and (3, 6) 1:3.
Thus the results of our study provide reliable proofs
for the reversible character of N-adamantylation of
nitro-substituted aromatic amines with adamantan-1-ol
in sulfuric acid and in a mixture of phosphoric and
acetic acids.
Concentration, M×10–1
2
1.8
1.6
4
1.4
1.2
1
1
EXPERIMENTAL
1
0.8
0.6
0.4
0.2
0
The H NMR spectra were recorded on a Bruker
2
WM-400 spectrometer from solutions in DMSO-d6
using tetramethylsilane as internal reference. The UV
spectra were measured on a Shimadzu UVmini 1240
spectrophotometer using 1-cm quartz cells. Gas–liquid
chromatography was performed on a Varian Model
3700 instrument (stationary phase Chromaton N-AW-
DMCS, 0.1–0.125 mm, impregnated with 5% of SE-
30; oven temperature programming from 100 to 300°C
at a rate of 10 deg/min, injector temperature 270°C,
detector temperature 270°C; carrier gas helium).
Samples were injected as 1–2% solutions in DMF. The
components were quantitated by the peak area
normalization method with no account taken of
correction factors. The concentration of aqueous
solutions of sulfuric acid was determined with an
accuracy of 0.1%) by volumetric titration with a
0.1 N solution of sodium hydroxide. The elemental
analyses were obtained on a determined Hewlett–
Packard 185 semiautomatic H,N,C-microanalyzer.
3
0
5
10 15
20
Time, h
25
30
35
40
Fig. 5. Variation of the concentrations of (1) N-(1-
adamantyl)-4-nitroaniline (I), (2) 4-nitroaniline (VII), (3) N-
(1-adamantyl)-3-nitroaniline (XX), and (4) 3-nitroaniline
(VI) in the reactions with adamantan-1-ol (XIV) in a mixture
of phosphoric and acetic acids (80:20 by weight) at 50–52°C.
2
1.5
1
1
2
0.5
N-[4-(1-Adamantyl)phenyl]acetamide (XVIII) was
synthesized according to the procedure described in
[23].
0
0
10
20
30
40
50
60
Time, days
Fig. 6. Variation of the concentrations of (1) N-(1-
adamantyl)-4-nitroaniline (I) and (2) 4-nitroaniline (VII) in
the reaction with adamantan-1-ol (XIV) in a mixture of
phosphoric and acetic acids (80:20 by weight) at 22–24°C.
General procedure for the preparation of
adamantyl-substituted nitroanilines I, III, XV, and
XIX–XXI in a mixture of phosphoric and acetic
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008

ADAMANTYLATION OF NITRO-SUBSTITUTED AROMATIC AMINES
1725
acids and in polyphosphoric acid. Adamantan-1-ol
(XIV), 10 mmol, was dissolved under stirring and
heating in 25 ml of a mixture of phosphoric and acetic
acids (80:20 by weight) or polyphosphoric acid.
Nitroaniline VI–IX, XI, or XII, 10 mmol, was added
in one portion, and the mixture was stirred as indicated
in Table 1 and poured into 150 ml of an ice–water
mixture. The mixture was allowed to settle down, and
the precipitate was filtered off, washed with water
(2×50 ml), dried, and recrystallized from appropriate
solvent.
In the synthesis of N-(1-adamantyl)-2,4-dinitro-
aniline (III), the crude product was heated in 20 ml of
acetone for 10–15 min under reflux, the mixture was
cooled, left to stand for 24 h, and filtered, and the
precipitate was recrystallized from 25 ml of toluene.
The conditions for the reactions with nitroanilines
V–IX, XI, and XII and yields of adamantylation
products I–III, XV, XVI, and XIX–XXI are given in
Table 1. The melting points and elemental analyses of
compounds I–III, XV–XVII, and XIX–XXI are
1
collected in Table 2, and Table 3 contains their H
NMR spectra.
In the synthesis of N-(1-adamantyl)-3-nitroaniline
(XX), the reaction mixture was poured into 50 ml of
water without preliminary cooling. The mixture was
filtered, the filtrate was treated at 40–50°C under
stirring with 500 ml of 10% aqueous sodium
hydroxide, and the precipitate was filtered off. The
crude product was stirred in 500 ml of water for 2 h at
50°C, and the precipitate was filtered off and
recrystallized.
4-(1-Adamantyl)-2-nitroaniline (XVII). N-[4-(1-
Adamantyl)phenyl]acetamide (XVIII), 2 g, was added
in portions under stirring to a mixture of 20 ml of
glacial acetic acid and 20 ml of 95.7% nitric acid,
maintaining the temperature at 5–7°C. The mixture
was stirred for 80 min at 10–13°C and poured into 100 ml
of an ice–water mixture, and the precipitate was
filtered off, washed with water (4×50 ml), and dried.
The crude product was transferred into a mixture of 50
ml of methanol and 20 ml of 20% hydrochloric acid,
and the mixture was heated for 2 h under reflux,
cooled, and poured into 200 ml of water. The resulting
suspension was neutralized with 10% aqueous
sodiumm hydroxide, and the precipitate was filtered
off, dried, and recrystallized from 90% aqueous
propan-2-ol. Yield 1.21 g (59.9%).
A mixture of N-(1-adamantyl)-2-nitroaniline (II)
and N,4-di(1-adamantyl)-2-nitroaniline (XVI) was
obtained according to the general procedure from 10
mmol of adamantan-1-ol (XIV) and 11 mmol of 2-
nitroaniline (V). The mixture was diluted with 100 ml
of an ice–water mixture, heated at 95–98°C, and
filtered, and the precipitate was washed on a filter with
water (2×50 ml) heated to 95–98°C and dried. Yield of
the crude product 1.05 g.
The kinetic studies on the adamantylation of
nitroanilines V–VII were performed in a 100-ml flat-
bottom flask equipped with a magnetic stirrer and
thermometer and placed into a temperature-control
unit. The temperature was maintained with an accuracy
of 1°C.
N,4-Di(1-adamantyl)-2-nitroaniline (XVI) was also
synthesized from 20 mmol of adamantan-1ol (XIV)
and 10 mmol of 2-nitroaniline (V) or from 10 mmol of
XIV and 10 mmol of N-(1-adamantyl)-2-nitroaniline
(II) according to the general procedure. The crude
product was mixed with 34 ml of 80% aqueous
propan-2-ol, the mixture was heated for 10–15 min
under reflux, cooled, and filtered, and the precipitate
was recrystallized from 15 ml of DMF.
Reactions of nitroanilines V and VII with
adamantan-1-ol (XIV) in sulfuric acid (general
procedure). Nitroaniline V or VII, 1.38 g, was added
to 50 ml of sulfuric acid with a required concentration,
and the mixture was stirred for 10–15 min (until it
became homogeneous) at a required temperature.
Adamantan-1-ol (XIV), 1.52–4.56 g, was then added,
and the mixture was stirred for 5–7 min until
dissolution. For analysis, a 1-ml sample of the reaction
mixture was withdrawn and mixed with 50 ml of a
0.74 N solution of triethylamine in propan-2-ol. A 1-ml
sample of the resulting solution was diluted with 50 ml
of propan-2-ol.
General procedure for the synthesis of
adamantyl-substituted nitroanilines I–III and XV in
sulfuric acid. Adamantan-1-ol (XIV), 10 mmol, was
dissolved under stirring in 25 ml of 92–94% sulfuric
acid, 10 mmol of nitroaniline V, VII, VIII, or XI was
added in one portion, and the mixture was stirred as
indicated in Table 1 and poured into 200 ml of an ice–
water mixture. The resulting suspension was allowed
to settle down, and the precipitate was filtered off,
washed with water (2×50 ml), dried, and purified by
fractional crystallization.
Reaction of N-(1-adamantyl)-2-nitroaniline (II)
with sulfuric acid. A mixture of 50 ml of 94.5%
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008

1726
VOLKOVA et al.
sulfuric acid and 1.66 g of N-(1-adamantyl)-2-
nitroaniline (II) was stirred for 5–7 min at a required
temperature until it became homogeneous. The
mixture was analyzed as described above.
reaction mixture was withdrawn and mixed with 50 ml
of a 0.9 N solution of triethylamine in propan-2-ol. A
1-ml (in the reaction with VII) or 5-ml (in the reaction
with VI) sample of the resulting solution was diluted
with 50 ml of propan-2-ol and analyzed.
Reactions of nitroanilines VI and VII with
adamantan-1-ol (XIV) in a mixture of phosphoric
and acetic acids (general procedure). Adamantan-1-ol
(XIV), 1.52 g, was added to 50 ml of a mixture of
phosphoric and acetic acids (80:20 by weight), the
mixture was stirred for 0.5–1.0 h at a required
temperature until it became homogeneous, 1.38 g of
nitroaniline VI or VII was added, and the mixture was
stirred until complete dissolution. A 1-ml sample of the
The current concentrations of components of
reaction mixtures were calculated according to
Vierordt [27]. The working wavelengths were λ 407
and 438 nm for the reaction with 2-nitroaniline (V), λ
361 and 418 nm for the reaction with 3-nitroaniline
(VI), and λ 368 and 435 nm for the reaction with 4-
nitroaniline (VII).
Table 2. Melting points and elemental analyses of adamantyl-substituted nitroanilines I–III, XV–XVII, and XIX–XXI
Found, %
Calculated, %
Comp. no.
mp, °С (solvent)
Formula
C
–
H
–
N
–
C
–
H
–
N
–
188.5–189а (ethanol–ethyl acetate,
80:20, vol %)
С16H20N2O2
I
155.5–156.0 (80% aqueous propan-2-
ol)
>250 (toluene)
–
–
–
С16H20N2O2
–
–
–
–
–
II
–
–
–
С16H19N3O4
С17H22N2O2
С26H34N2O2
С16H20N2O2
–
III
172–173.5 (ethanol)
71.51
77.11
70.73
7.41
8.07
7.07
9.95
7.03
10.50
71.33
76.85
70.59
7.69
8.37
9.79
6.90
XV
248.5–250 (DMF)
XVI
XVII
225–226.5 (90% aqueous propan-2-
ol)
7.35 10.29
152.0–153.5 (propan-2-ol)
121.5–123.0 (80% aqueous propan-2-
ol)
70.95
70.58
7.67
7.24
9.87
С17H22N2O2
С16H20N2O2
71.33
70.59
7.69 9.79
XIX
XX
10.43
7.35 10.29
5.99 13.25
229–231 (80% aqueous acetone)
60.77
6.20
13.04
С16H19N3O4
60.56
XXI
a
Published data [7]: mp 188–189°C.
Table 3. 1H NMR spectra of adamantyl-substituted nitroanilines I–III, XV–XVII, and XIX–XXI
Comp.
δ, ppm
no.
1.71, 1.98, 2.13 m (15Н, Ad), 6.61 s (1Н, NH), 6.75 d (2Н, Нarom, J 7.32 Hz), 7.87 d (2Н, Нarom, J 4.27 Hz)
I
1.73, 2.08, 2.15 m (15Н, Ad), 6.61 тр (1Н, Нarom, J 14.77 Hz), 7.28 d (1Н, Нarom, J 7.88 Hz), 7.41 тр (1Н, Нarom, J 13.78 Hz),
8.04 d (1Н, Нarom, J 6.89 Hz), 8.18 с (1Н, NH)
II
1.76, 2.13, 2.20 m (15Н, Ad), 7.48 d (1Н, Нarom, J 9.16 Hz), 8.16 d (1Н, Нarom, J 9.77 Hz), 8.65 s (1Н, Нarom), 8.93 s (1Н, NH)
1.72, 2.04, 2.14 m (15Н, Ad), 2.22 c (3Н, Ме), 7.20–7.26 m (2Н, Нarom), 7.84 s (1Н, Нarom), 8.09 s (1Н, NH)
1.73, 1.81, 2.06, 2.14 m (30Н, Ad), 7.25 d (1Н, Нarom, J 8.86 Hz), 7.47 d (1Н, Нarom, J 8.86 Hz), 7.91 s (1Н, Нarom), 8.10 br.s
(1Н, NH)
III
XV
XVI
1.73, 1.81, 2.06 m (15Н, Ad), 6.95 d (1Н, Нarom, J 8.86 Hz), 7.21 br.s (2Н, NH), 7.42 d (1Н, Нarom, J 8.86 Hz), 7.77 s (1Н, Нarom
)
XVII
XIX
1.73, 1.82, 2.07 m (15Н, Ad), 2.95 d (3Н, J 2.96 Hz, Ме), 6.92 d (1Н, Нarom, J 9.84 Hz), 7.59 d.d (1Н, Нarom, J 11.81 Hz), 7.89 d
(1Н, Нarom, J 2.95 Hz), 8.04 br.s (1Н, NH)
1.69, 1.92, 2.11 m (15Н, Ad), 5.74 br.s (1Н, NH), 7.09 d (1Н, Нarom, J 7.88 Hz), 7.19–7.29 m (2Н, Нarom.), 7.51 s (1Н, Нarom
)
XX
1.72, 1.96, 2.15 m (15Н, Ad), 6.66 с (1Н, NH), 7.83 d (2Н, Нarom, J 1.97 Hz), 7.89 s (1Н, Нarom
)
XXI
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008

ADAMANTYLATION OF NITRO-SUBSTITUTED AROMATIC AMINES
1727
12. Saraev, V.V., Kanakina, T.P., Pevzner, M.S., Golod, E.L.,
Ugrak, B.I., and Kachala, V.V., Khim. Geterotsikl.
Soedin., 1996, no. 8, p. 1078.
ACKNOWLEDGMENTS
This study was performed in the framework of the
Federal Scientific and Technical Program “Studies and
Developments in the Priority Fields of Science and
Technics” for 2002–2006 (state contract no.
02.442.11.7471, March 6, 2006).
13. Saraev, V.V. and Golod, E.L., Russ. J. Org. Chem.,
1997, vol. 33, no. 4, p. 571.
14. Saraev, V.V., Gavrilov, A.S., and Golod, E.L., Russ. J.
Org. Chem., 1999, vol. 35, no. 7, p. 1093.
15. Gavrilov, A.S., Golod, E.L., Kachala, V.V., and Ugrak, B.I.,
REFERENCES
Russ. J. Org. Chem., 2001, vol. 37, no. 12, p. 1741.
16. Gavrilov, A.S. and Golod, E.L., Russ. J. Org. Chem.,
1. Khomich, E.V., Kashapov, M.N., Vatsuro, I.M.,
Shokova, E.A., and Kovalev, V.V., Russ. J. Org. Chem.,
2007, vol. 43, no. 2, p. 192.
2. Shroot, B., Eustache, J., and Bernardon, J.M., Eur. Pat.
Appl. no. EP 199636; Chem. Abstr., 1987, vol. 106, no.
84197.
3. Prakash, G.K.S., Yan, P., Török, B., Bucsi, I., Tanaka, M.,
and Olah, G.A., Catal. Lett., 2003, vol.85, nos. 1–2, p. 1.
4. Olah, G.A., Török, B., Shamma, T., Török, M., and
Prakash, G.K.S., Catal. Lett., 1996, vol. 42, nos. 1–2, p. 5.
1999, vol. 35, no. 8, p. 1234.
17. Eastes, J.W., Aldridge, M.H., and Kamlet, M.J., J.
Chem. Soc. B, 1969, no. 8, p. 922.
18. Tickle, P., Briggs, A.G., and Wilson, J.M., J. Chem. Soc.
B, 1970, no. 1, p. 65.
19. Robinson, R.A., J. Res. NBS, Sec. A, 1967, vol. 71, no. 3,
p. 213.
20. Bolton, P.D. and Hall, F.M., Aust. J. Chem., 1968, vol. 21,
no. 4, p. 939.
21. Bolton, P.D. and Hall, F.M., J. Chem. Soc. B, 1970, no. 7,
5. Beregszaszi, T., Török, B., Molnar, A., Olah, G.A., and
Prakash, G.K.S., Catal. Lett., 1997, vol. 48., nos. 1–2, p. 83.
6. Bräse, S., Waegell, B., and de Meijere, A., Synthesis,
1998, no. 2, p. 148.
p. 1247.
22. Ryabov, R.S., Medvetskaya, I.M., and Vinnik, M.I., Zh.
Fiz. Khim., 1966, vol. 40, no. 2, p. 339.
23. Stetter, H., Weber, J., and Wulff, C., Chem. Ber., 1964,
vol. 97, no. 12, p. 3488.
24. Hammett, L., Physical Organic Chemistry, New York:
McGraw–Hill, 1970, 2nd ed.
25. Tsypin, V.G., Kachala, V.V., Ugrak, B.I., and Golod, E.L.,
Russ. J. Org. Chem., 2002, vol. 38, no. 1, p. 90.
26. Geluk, H.W. and Schlatmann, J.L.M.A., Tetrahedron,
1968, vol. 24, no. 15, p. 5361.
7. Lednicer, D., Heyd, W.E., Emmert, D.E., TenBrink, R.E.,
Schurr, P.E., and Day, C.E., J. Med. Chem., 1979, vol. 22,
no. 1, p. 69.
8. Tomaru, A., Kaino, T., Kurihara, T., and Matsumoto, S.,
JPN Patent Appl. no. 89-124834, 1989; Chem. Abstr.,
1990, vol. 112, no. 45281.
9. Tranquillini, M.E. and Finizia, G., PCT Int. Appl. WO
9425445; Chem. Abstr., 1995, vol. 122, no. 133229.
10. Takeya, Y., JPN Patent no. 93-61082, 1993; Chem.
Abstr., 1993, vol. 119, no. 149204.
27. Bershtein, I.Ya. and Kaminskii, Yu.L., Spektro-
fotometricheskii analiz
v
organicheskoi khimii
11. Nicoud, J.F., Mol. Cryst. Liq. Cryst., 1988, vol. 156,
p. 257.
(Spectrophotometric Analysis in Organic Chemistry),
Leningrad: Khimiya, 1975.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 78 No. 9 2008