Synthesis of nitroso- and amino derivatives of N-arylaminoalkyladamantanes

Article abstract of DOI:10.1134/S1070428008050023

By amination of 4-nitrosophenol and 1-nitroso-2-naphthol the corresponding N-arylaminoalkyladamantanes were obtained whose reduction provided 1,4-phenylenediamines and 1,2-naphthylenediamines.

Full text of DOI:10.1134/S1070428008050023

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 5, pp. 647−651. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © E.S. Semichenko, A.L. Gomonova, N.A. Gavrilova, G.S. Suboch, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44,
No. 5, pp. 659−662.
Synthesis of Nitroso- and Amino Derivatives
of N-Arylaminoalkyladamantanes
E. S. Semichenko, A. L. Gomonova, N. A. Gavrilova, and G. S. Suboch
Siberian State Technological University, Krasnoyarsk, 660049 Russia
e-mail: organic@scn.ru
Received September 19, 2007
Abstract—By amination of 4-nitrosophenol and 1-nitroso-2-naphthol the corresponding N-arylamino-
alkyladamantanes were obtained whose reduction provided 1,4-phenylenediamines and 1,2-naphthylenediamines.
DOI: 10.1134/S1070428008050023
Many amines with adamantyl fragments in the
structure exhibit biological activity and are widely used
as drugs [1]. The presence of N-aryl group in the structure
of alkyladamantane amino derivatives should presumably
strengthen the influence on the central dopamine- and
noradrenergic mediator systems [2] important for
preparation of drugs with stimulating psychotropic action.
nitrosoaniline (IIb) in 56 and 45% yield respectively
(Scheme 1).
The amination of 1-nitroso-2-naphthol with amines
Ia and Ib under similar conditions led to the formation
of the corresponding N-[(1-adamantyl)methyl]-1-nitroso-
naphthalene-2-amine (IIIa) and N-[1-(1-adamantyl)-
ethyl]-1-nitrosonaphthalene-2-amine (IIIb) in 41 and
48% yield respectively (Scheme 2).
N-Alkyl- and N-aryl derivatives of adamantanamine
are prepared by amination of adamantine haloderivatives
[3], by alkylation or arylation of adamantanamine [4], or
by reductive amination of carbonyl compounds [5, 6].
Up till now the synthesis of N-aryl-substituted ada-
mantan- and adamantylalkanamines was not performed
by amination of nitrosophenols with sterically hindered
amines, although the 4-nitrosophenols unlike the other
phenols are known to undergo amination with aliphatic
(butyl-, methyl-, benzyl-) amines, cyclohexylamine, and
anilines in the presence of acid catalysts (hydrogen
chloride, boron trifluoride, p-toluenesulfonic acid) or
without catalyst [7].
Scheme 1.
R
NH2
NO
OH
R
Py
_H2O
HN
NO
IIa, IIb
Ia, Ib
R = H (a), Me (b).
Scheme 2.
We investigated the amination of 4-nitrosophenol and
1-nitroso-2-naphthol with sterically hindered amines:
(1-adamantyl)methanamine (Ia), 1-(1-adamantyl)ethan-
amine (Ib), and 1-adamantanamine.
NO
NO
H
N
R
OH
H2O
Amination of 4-nitrosophenol was carried out by
treating with a double excess of amines Ia and Ib in
pyridine at 20°C.After the dilution of the reaction mixture
with water and the extraction of reaction products into
ethyl ether followed by chromatographic purification we
obtained previously unknown N-[(1-adamantyl)methyl-
4-nitrosoaniline (IIa) and N-[1-(1-adamantyl)ethyl]-4-
Py
Ia, Ib
IIIa, IIIb
41_48%
R = H (a), Me (b).
647

SEMICHENKO et al.
648
1-Adamantanamine was not involved in reaction with
protonation of compounds IIa and IIb in 0.1 N HCl
resulted in a blue shift of the short-wave peak to
340 nm.
4-nitrosophenol and 1-nitroso-2-naphthol under the given
conditions. It is evidently due to the steric hindrances
from the bulky adamantyl framework in agreement with
the data on the growing reactivity of amino derivatives
of adamantane with the growing distance of the NH2
group from the adamantine skeleton [8].
The IR spectrum of nitrosoaniline IIb contains the
absorption bands of the stretching vibrations of N–H
bond in the secondary amino group at 3232 cm–1,
aromatic C–H bonds at 3030 cm–1, methyl group at
2921 cm–1 and methylene groups at 2845 cm–1, and bond
C=Carom at 1606, 1543 cm–1; in the IR spectrum of
nitrosonaphthylamine IIIb appear the absorption bands
of the stretching vibrations of N–H bond in the secondary
amino group at 3329–3650 cm–1, aromatic C–H bonds
at 3030 cm–1, methyl group at 2903 cm–1 and methylene
groups at 2846 cm–1, and bond C=Carom at. 1620,
1565 cm–1.
In the 1H NMR spectra of nitrosoanilines IIa and IIb
the signals of aromatic protons are observed in the region
6.5–8.0 ppm. The aromatic protons of naphthylamines
IIIa and IIIb give rise to signals in the 1H NMR spectra
in the region 7.05–9.06 ppm. The proton signals of the
methylene groups of the adamantyl fragment of com-
pounds IIa, IIb and IIIa, IIIb appear as a multiplet in
the region 1.38–1.80 ppm, the resonances of methine
groups protons, at 1.9–2.1 ppm. These findings are
consistent with the known data on the chemical shifts of
β-, γ-, and δ-protons of the adamantyl framework of
1-monosubstituted alkyladamantanes [12]. The broaden-
ed signal of the NH group proton in the spectrum of
nitrosoanilines IIa and IIb is observed in the region 4.8–
5.3 ppm.
In the amination of 4-nitrosophenol with amine Ib in
alcohol in the presence of p-toluenesulfonic acid the
conversion into 4-nitrosoaniline IIb was close to that in
pyridine, 94%. The conversion into nitrosoaniline IIb
was estimated spectrophotometrically at the absorption
maximum in the region 410 nm corresponding to the
π−π* transition in the nitrosoanilines.
The composition of compounds IIa, IIb, and IIIb
was established by elemental analysis, of compounds IIb
and IIIa, by mass spectrometry. The mass spectra of
compounds IIb and IIIa contain molecular ion peaks
corresponding to the calculated values, m/z 284 and 320
respectively. The maximum abundant (100%) peak in
the mass spectra of compounds IIb and IIIa is the
fragment ion, m/z 135, corresponding to the adamantyl-
cation A. Further fragmentation of the adamantyl-cation
results im ions B–D.
H
CH2
m/z: 135
135
B
A
One of the most important properties of nitroso
compounds are acid-catalyzed conversions, therefore we
One of the protonation sites is the oxygen of the nitroso
group [10, 11] (Scheme 3), for in the acid environment
the electronic spectra of amines IIa and IIb lack the
CH2
93
C
93
D
Scheme 3.
This fragmentation is characteristic of 1-alkyl-sub-
stituted adamantanes and is weakly affected by the
structure of the alkyl group [9].
H
O +
OH
O
N
N
N
N
N
The structure of amines IIa, IIb and IIIa, IIIb was
established based on the complex of analytical and
spectral data. In the electronic spectra of ethanol solutions
of nitrosoanilines IIa and IIb and nitrosonaphthylamines
IIIa and IIIb absorption band is observed in the region
650–700 nm (π−π* transition of aromatic NO group). In
the short-wave region the p-nitrosoanilines IIa and IIb
have an absorption band at 410-430 nm (π−π* transition
of nitrosoaniline). This finding is in agreement with the
published data for p-nitrosoanilines [10, 11]. The
H+
R
N+
R
R
H
H
H
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SYNTHESIS OF NITROSO- AND AMINO DERIVATIVES
649
absorption at 650–750 nm corresponding to the π−π*
Scheme 4.
HN
transition of the nitroso group.
The evaluation of pK of compounds IIa and IIb was
performed in buffer solutions spectrophotometrically.
Nitrosoanilines IIa and IIb are insufficiently soluble in
weak acid medium, therefore the pKBH+ was measured
in 50% alcohol.
NH2
[H]
[H]
IIa
IV
NH2
NH
The pKBH+ values of compounds IIa and IIb (3.62
and 3.44 respectively) are less than the pKBH+ of
unsubstituted p-nitrosoaniline (3.90). This decrease in
basicity may be due to the use 50% aqueous ethanol as
solvent [13], and also probably because of the distortion
of the conjugation of the amino group with the aromatic
ring effected by the presence of a spatially bulky
substituent resulting in decreased contribution of the
resonance structure stabilizing the protonated form.
IIIa
V
on silica gel of the grade Silicagel L 100/400 (Chemapol).
Analytic TLC was carried out on the plates Sorbfil of
the grade PTSKh-AF-V (Krasnodar) with a UV indicator.
Mass spectra were measured on a mass spectrometer
MAT-8200 Finnigan. IR spectra were taken on Vector
22 instrument from pellets with KBr.
The reduction of nitrosoaniline IIa and nitroso-
naphthylamine IIIa with hydrazine hydrate on a catalyst
Pd/C gave rise respectively to N-[(1-adamantyl)methyl]-
1,4-phenylenediamine (IV) and N2-[(1-adamantyl)-
methyl]-1,2-naphthylenediamine (V) (Scheme 4).
N-[1-(1-Adamantyl)alkyl]-4-nitrosoanilines IIa
and IIb. a. A mixture of 0.02 mol of amine Ia or Ib and
1.23 g (0.01 mol) of 4-nitrosophenol in 45 ml of pyridine
was maintained at 20°C for 96 h, then it was poured into
250 ml of ice water and extracted with ethyl ether (3 ×
15 ml). The extract was washed with 5% HCl (2 × 15
ml), 5% NaOH (2 × 15 ml), and then with water (50 ml).
The ether was evaporated, and the oily residue was
washed with petroleum ether till it turned into green
crystals. The analytically pure sample was obtained by
column chromatography (2 × 100 cm, 100 g of silica
gel, eluent ethyl acetate).
The composition and structure of diamines IV and V
were established from elemental analyses and 1H NMR
spectra. In the 1H NMR spectrum of phenylenediamine
IV two doublet signals at 6.48 and 6.58 ppm belong to
the aromatic protons. The value JA,Β 8 Hz coincides with
the typical value of coupling constant JA,Β in benzene
derivatives [14]. In the 1H NMR spectrum of naphthyl-
enediamine V the aromatic protons give rise to a multiplet
in the region 7.11–7.75 ppm.
The proton signals of the methylene groups of the
adamantyl framework of compounds IV and V appear
in their spectra as a multiplet in the region 1.5–1.79 ppm,
protons of methine groups, at 1.96–2.01 ppm. The
broadened signal of the protons of NH and NH2 groups
of diamines IV and V is observed in the region 2.69–
3.40 ppm. In compounds IV and V the protons of
methylene groups not included into the adamantyl
skeletone give signals at 2.69 and 2.86 ppm respectively.
N-[1-(1-Adamantyl)methyl]-4-nitrosoaniline (IIa).
Yield 1.5 g (56%), mp 191°C (ethyl acetate). UV
spectrum, λmax, nm (å), alcohol: 270 (4400), 420 (27000),
650 (119); 0.1 N HCl: 360 (11600). 1H NMR spectrum
(CDCl3), δ, ppm: 1.58–1.80 m (12H, CH2), 2.00–2.05 m
(3H, CH), 2.97 (J 6.4 Hz), (2H, CH2), 4.88 br.m (1H,
NH), 6.60 d (J 8.2 Hz), (2Harom), 7.5–8.0 br.m (2Harom).
Found, %: C 75.80; H 8.76; N 9.85. C17H22N2O.
Calculated, %: C 75.52; H 8.20; N 10.36.
N-[1-(1-Adamantyl)ethyl]-4-nitrosoaniline (IIb).
Yield 37%, mp 179°C. Electronic spectrum, λmax, nm
(å), alcohol: 285 (5700), 420 (30000), 660 (88); 0.1 N
HCl: 340 (20000). IR spectrum, ν, cm–1: 3232 (NH), 3030
(CHarom), 2921 (CH3), 2845 (CH2), 1606, 1543 (C=Carom).
1H NMR spectrum (CDCl3), δ, ppm: 1.14 d (3H, CH3,
J 6.4 Hz), 1.38–1.67 m (12H, CH2), 1.89–1.95 m (3H,
CH), 3.26 m (1H, CH), 5.24 br.d (1H, NH, J 6.6 Hz),
6.54 d (2Harom, J 8 Hz), 7.6–8.2 br.m (2Harom). Mass
EXPERIMENTAL
Electronic spectra were recorded on a spectro-
photometer SF-26 in a cell 1 cm thick at solution
concentration 5 × 10–5 mol l−1 in the region 200–500
nm, 10–2 mol l−1 in the region 600–800 nm. H NMR
1
spectra were registered on a spectrometer BrukerAvance
DRX-200 (operating frequency 200 Hz) from solutions
in CDCl3. The column chromatography was performed
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

SEMICHENKO et al.
650
spectrum, m/z (Irel, %): 284 (55) [M]+, 270 (19), 149 (79),
135 (100), 119 (44), 107 (10), 93 (14), 77 (13). Found,
%: C 75.80; H 8.76; N 9.15 C18H24N2O. Calculated, %:
C 76.02; H 8.51; N 9.85.
(1Harom). Found, %: C 79.03; H 8.85; N 8.90. C22H26N2O.
Calculated, %: C 79.00; H 7.84; N 8.38.
Reduction of compounds IIa and IIIa. To 1.8 mmol
of nitroso compound IIa or IIIa and 0.5 g of 0.5% Pd/C
in 120 ml of alcohol was added 0.4 ml (8 mmol) of 96%
hydrazine hydrate. After 1 h the catalyst was filtered off,
the colorless solution was evaporated on a rotary
evaporator in a vacuum of a water-jet pump.
b. A mixture of 0.0896 g (0.5 mmol) of amine Ib and
0.0307 g (0.25 mmol) of 4-nitrosophenol in 4 ml of
pyridine was maintained at 20°C for 96 h. Then the
reaction mixture was diluted with alcohol to 10 ml, an
aliquot of 0.5 ml was transferred into a volumetric flask
of 25 ml capacity, filled to the mark with alcohol, and
the solution was used to register the electronic spectrum.
The conversion of amine Ib into 4-nitrosoaniline IIb was
96% (λ 420 nm, å 30000).
c. A mixture of 0.0896 g (0.5 mmol) of amine Ib,
0.0307 g (0.25 mmol) of p-nitrosophenol, and 0.006 g
(0.035 mmol) of 4-toluenesulfonic acid in 4 ml of alcohol
was maintained at 20°C for 96 h. Then the reaction
mixture was subjected to workup described for procedure
a. Amine Ib conversion 94%.
N-[(1-Adamantyl)methyl]-1,4-phenylenediamine
(IV). Yield 0.43 g (90%), mp 110ºC. 1H NMR spectrum
(CDCl3), δ, ppm: 1.54–1.75 m (12H, CH2), 1.96 m (3H,
CH), 2.69 s (2H, CH2), 2.69–2.96 br.s (3H, NH, NH2),
6.58 d (2Harom, JA,Β 8.7 Hz), 6.48 d (2Harom, JA,Β 8.7 Hz).
Found, %: C 79.13; H 9.06; N 10.70. C17H24N2.
Calculated, %: C 79.64; H 9.44; N 10.93.
N2-[(1-Adamantyl)methyl]-1,2-naphthylene-
diamine (V). Yield 0.31 g (65%), mp 130ºC. 1H NMR
spectrum (CDCl3), δ, ppm: 1.64–1.79 m (12H, CH2),
2.01 s (3H, CH), 2.86 (2H, CH2), 3.1–3.4 br.s (3H, NH,
NH2), 7.11–7.42 m (4Harom), 7.75–7.65 m (2Harom).
Found, %: C 82.03; H 8.13; N 9.83. C21H26N2. Calculat-
ed, %: C 82.31; H 8.55; N 9.14.
N-[1-(1-Adamantyl)alkyl]-1-nitrosonaphthalene-
2-amines IIIa and IIIb. A mixture of 3.3 g (0.02 mol)
of amine Ia and 1.73 g (0.01 mol) of 1-nitroso-2-naphthol
in 75 ml of pyridine was maintained at 20°C for 96 h,
then it was poured into 250 ml of ice water and extracted
with ethyl ether (3×15 ml). The extract was washed with
5% HCl (2 × 15 ml), 5% NaOH (2 × 15 ml), and then
with water (50 ml). The ether was evaporated, and the
oily residue was washed with petroleum ether till it turned
into green crystals.
The pKBH+ values were estimated by spectro-
photometric procedure [13]. Electronic spectra were
taken of SF-26 instrument at the layer thickness 1 cm
and concentration 2.5 × 10–5 mol l−1, at 25ºC.
NMR measurements were carried out on the
equipment of the Krasnoyarsk Center of Joint Use of
Siberian Division, Russian Academy of Sciences.
N-[(1-Adamantyl)methyl]-1-nitrosonaphthalene-
2-amine (IIIa). Yield 1.3 g (41%), mp 175–176°C
The study was performed under a financial support
of a grant of the President of the Russian federation for
the State support of young Russian scientists MQ-
7348.2006.3.
(hexane–chloroform, 1:1). UV spectrum (CHCl3), λmax
,
nm (å): 295 sh (5600), 370 (6600), 450 (7900), 660 (84).
1H NMR spectrum (CDCl3), δ, ppm: 1.65–1.83 m (12H,
CH2), 1.95–2.10 m (3H, CH), 3.14 d (2H, CH2, J 6 Hz),
7.04 d (1Harom, J 9.6 Hz) , 7.48–7.40 m (1Harom), 7.63–
7.59 m (2Harom), 7.73 d (1Harom, J 9.6 Hz), 9.01–9.13 m
(1Harom). Mass spectrum, m/z (Irel, %): 320 (3) [M]+, 164
(5), 135 (100), 107 (10), 93 (20), 79 (23), 67 (10), 55
(5).
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