Adamantyl-substituted amino alcohols. Synthesis and functionalization at the nitrogen and oxygen nucleophilic centers

Article abstract of DOI:10.1023/B:RUJO.0000010210.89695.79

1-Aminoadamantanes and 1-aminomethyladamantanes were brought into reactions with p-nitrophenyloxirane and 9-carbazolylmethyloxirane. The reactions occurred in a regioselective fashion according to the Krasusky rule, which was confirmed by the ¹H and ¹³C NMR data. The resulting amino alcohols having a p-nitrophenyl moiety were subjected to functionalization at the nitrogen and oxygen nucleophilic centers using p-nitrobenzenesulfonyl chloride, p-nitrobenzoyl chloride, and hexamethyldisilazane, and N,O-bisacyl derivative was synthesized. The structure of the products was proved by IR and ¹H NMR spectroscopy.

Full text of DOI:10.1023/B:RUJO.0000010210.89695.79

Russian Journal of Organic Chemistry, Vol. 39, No. 9, 2003, pp. 1248 1255. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 9, 2003,
pp. 1322 1329.
Original Russian Text Copyright
2003 by L. Kas’yan, Golodaeva, A. Kas’yan.
Adamantyl-Substituted Amino Alcohols.
Synthesis and Functionalization at the Nitrogen and Oxygen
Nucleophilic Centers
L. I. Kas’yan1, E. A. Golodaeva1, and A. O. Kas’yan2
1
Dnepropetrovsk National University, per. Nauchnyi, 13, Dnepropetrovsk, 49005 Ukraine
2
Institut fur organische Chemie, Rheinisch Westfalische Technische Hochschule, Aachen, Germany
Received April 2, 2003
Abstract 1-Aminoadamantanes and 1-aminomethyladamantanes were brought into reactions with p-nitro-
phenyloxirane and 9-carbazolylmethyloxirane. The reactions occurred in a regioselective fashion according
to the Krasusky rule, which was confirmed by the 1H and 13C NMR data. The resulting amino alcohols having
a p-nitrophenyl moiety were subjected to functionalization at the nitrogen and oxygen nucleophilic centers
using p-nitrobenzenesulfonyl chloride, p-nitrobenzoyl chloride, and hexamethyldisilazane, and N,O-bisacyl
derivative was synthesized. The structure of the products was proved by IR and 1H NMR spectroscopy.
Amines and amides having adamantane fragments
exhibit antiviral properties and are active in the treat-
ment of Parkinson’s disease [1, 2]. The biological
activity of aminoadamantanes is believed to originate
from the presence of a bulky and highly lipophilic
cage-like fragment which is capable of directly inter-
acting with biological membranes containing a lipid
layer and also with hydrophobic fragments of proteins,
including those constituting receptor structure [1, 3].
with sulfonyl chlorides [4 6], endic anhydride [7],
aryl isocyanates, aryl isothiocyanates [5, 8], and di-
chlorophosphinoyl isocyanate [9] have been reported.
Their structure and conformations were studied by
molecular mechanics [4], and electron density dis-
tribution in their molecules was analyzed by quantum-
chemical methods [4, 10]. According to the results of
AM1 semiempirical calculations [4], the basicity of
the above amines decreases in the series II > I > IV >
III. However, it was presumed [10] that the reactivity
of these compounds is determined mainly by steric
effects of the bulky cage-like fragments rather than by
electron density distribution in their molecules.
Published data on the reactions of aminoadaman-
tanes with epoxy derivatives are very scanty, though
the spectrum of biological action of amino alcohols
is fairly wide and a number of medicines contain the
above structural fragments [11, 12]. N,N-Bis(1-hy-
droxyethyl)- and N,N-bis(1-hydroxypropyl)-1-ada-
mantylamine hydrochlorides were synthesized by
heating of amine I with 1,2-epoxyethane and
1,2-epoxypropane, respectively (6 h, 70 75 C) [13].
Addition products of p-nitrophenyloxirane (Va),
9-carbazolylmethyloxirane (Vb), and 1,2-epoxycyclo-
hexane to N-methyl-1-adamantylamine (II) were also
reported [5]. The goal of the present work was to
examine reactions of amines I, III, and IV with
oxiranes Va and Vb and to study the reactivity of the
resulting amino alcohols, as well as of previously
described compound VI (Scheme 1).
Compounds I IV are among the most extensively
studied amines of the adamantane series. Amine I and
IV hydrochlorides are known as medical preparations
Amantadine (Midantanum) and Remantadin. Bio-
logical properties of such amines stimulates studies
in the field of further modification of the amino group
therein and search for new compounds with a pro-
nounced biological activity. Reactions of amines I IV
1070-4280/03/3909-1248$25.00 2003 MAIK Nauka/Interperiodica

ADAMANTYL-SUBSTITUTED AMINO ALCOHOLS.
1249
Scheme 1.
VII, R = 1-Ad; VIII, R = 1-AdCH2; IX, R = 1-AdCH(CH3).
1
The aminolysis of epoxy derivatives Va and Vb
was carried out in isopropyl alcohol at room tempera-
ture with equimolar amounts of the reactants [5, 14].
Amino alcohols VII IX were isolated in 71 88%
yield; their properties are given in Table 1. Com-
pounds VII IX are crystalline substances with Rf
values of 0.6 0.9 for those derived from Va and 0.4
0.6 for carbazole derivatives (from Vb). In the IR
spectra of most of the products we observed two
absorption bands in the region 3460 3300 cm ,
which were assigned to stretching vibrations of the
O H and N H bonds; all amino alcohols showed
in the spectra absorption bands belonging to the
aromatic fragment; and compounds VIIa IXa were
also characterized by nitro group absorption at 1523
1518 and 1349 1341 cm 1 [15].
Table 2 contains parameters of the 1H NMR spectra
of the amino alcohol fragments in VII IX, which
Table 1. Yields, melting points, Rf values, IR spectra, and elemental analyses of amino alcohols VII IX and their
N- and O-functionalized derivatives X XV
Comp. Yield,
Rf
(ether)
Found
N, %
Calculated
N, %
1
mp,
C
IR spectrum, , cm
Formula
no.
%
VIIa
VIIb
VIIIa
84.6
82.0
75.3
108 110
97 99
0.68 3430, 3299, 3083, 1518, 1348, 1311,
1227, 1106, 1170
0.40 3420, 3346, 3065, 1640, 1552, 1240,
1146
0.62 3302, 3051, 1604, 1522, 1349, 1212,
1108, 1065
8.82
7.59
8.40
C18H24N2O3
C25H30N2O
C19H26N2O3
8.86
7.49
8.48
145 146
VIIIb
IXa
73.2
71.4
94 96
110 112
0.46 3417, 3293, 3051, 1457, 1124, 1024
0.59 3302, 3051, 1604, 1523, 1346, 1220,
1109, 1072
7.29
8.21
C26H32N2O
C20H28N2O3
7.22
8.14
IXb
Xa
Xb
82.5
88.2
75.0
30.1
76 77
0.45 3460, 3297, 3065, 1465, 1140, 1080
0.46 3430, 3054, 1640, 1525, 1350, 1112
0.40 3471, 3060, 1645, 1520, 1345, 1110
0.43 3420, 3030, 1609, 1530, 1350, 1258,
1125, 1148
6.89
8.97
8.84
8.30
C27H34N2O
C25H27N3O6
C26H29N3O6
C24H27N3O7S
6.96
9.03
8.77
8.38
149 151
122 124
125 126
XIa
XIb
35.4
93.3
101 103
190 191
0.37 3434, 3045, 1600, 1525, 1338, 1246,
1135
0.61 3240, 3064, 1721, 1587, 1525, 1339,
1280
8.21
9.09
C25H29N3O7S
C25H27N3O6
8.15
9.03
XIIb
XIIIb
XIVb
XV
90.1
96.1
80.0
204 210
184 186
143 145
0.67 3060, 1718, 1590, 1530, 1335, 1267
0.60
0.75 1719, 1600, 1535, 1348, 1276
8.81
8.71
9.09
C26H29N3O6
C26H29N3O6
C32H30N4O9
8.77
8.77
9.12
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

1250
KAS’YAN et al.
Table 2. 1H NMR parameters (chemical shifts , ppm, and coupling constants J, Hz) of the amino alcohol fragment
in adamantane derivatives VII X, XIIb, XIIIb, XIVb, and XV
Compound
HX
HA, HB
HC, HD
Substituent
NH
OH
no.
3
VIIa
4.59, JX, A = 8.8,
3JX, B = 3.8
2.94, 2.48,
8.13, 7.47
(4H, Harom)
7.16 8.00
(8H, carbazole)
2.02
3.23
3.10
4.19
2JA, B = 12.1
3
VIIb
3.93, JX, A = 8.8,
2.68, 2.45,
4.48, 4.27,
2JC, D = 15.9,
2JD, X = 5.2,
2JC, X = 3.3
3JX, B = 3.8
2JA, B = 12.0
3
VIIIa
VIIIb
4.67, JX, A = 9.5,
2.66, 2.51,
8.13, 7.47
(4H, Harom
7.16 7.99
(8H, carbazole)
2.60
3.00
2.82
3.22
3JX, B = 3.6
2JA, B = 12.2
)
3
4.09, JX, A = 8.8,
2.68, 2.42,
4.26, 4.17,
2JC, D = 15.8,
2JD, X = 5.0,
2JC, X = 3.6
3JX, B = 3.6
2JA, B = 11.9
3
IXa
IXb
4.12, JX, A = 9.9,
3.11, 2.55,
8.13, 7.48
(4H, Harom
7.24 8.09
2.70
1.94
2.85
2.00
3JX, B = 3.6
2JA, B = 12.1
)
3
4.67, JX, A = 9.5,
2.66, 2.51,
4.42, 4.35,
2JC, D = 15.0,
2JD, X = 5.5,
2JC, X = 3.6
3JX, B = 3.6
2JA, B = 12.0
(8H, carbazole)
3
Xa
4.67, JX, A = 9.0
3.12, 2.76,
7.50 8.35
(8H, Harom
8.24, 8.17, 8.01,
7.74 (8H, Harom
3.25
2.82
2JA, B = 12.0
)
3
Xb
4.76, JX, A = 9.3,
3.16, 2.91,
3JX, B = 3.6
2JA, B = 12.3
)
XIIb
XIIIb
XIVb
XV
5.12
3.35, 3.27
3.47, 3.40
3.34, 3.31
3.56, 3.49
8.27, 8.21, 7.89,
3.12
3.24
7.76 (8H, Harom
7.80 8.50
)
5.30
5.25
5.56
(8H, Harom
)
8.26, 8.11, 7.94,
7.84 (8H, Harom
7.70 8.35
)
(12H, Harom
)
support the assigned structures and indicate that
diastereotopicity arising from the presence of a chiral
carbon center between those methylene groups.
the aminolysis of epoxy derivatives Va and Vb occurs
1
Amino alcohols VII IX show in the 13C NMR
according to the Krasusky rule [16]. The H NMR
spectrum of each compound contains a one-proton
multiplet (doublet of doublets) at 4.0 4.7 ppm from
the HX proton on the carbon atom bearing the
hydroxy group, and two signals are observed in the
region 2.4 3.1 ppm from the HA and HB protons
located on the carbon atom attached to the amino
group. Table 2 also gives chemical shifts of the HC
and HD protons of the methylene group neighboring to
the carbazole nitrogen atom in compounds VIIb IXb
( 4.2 4.5 ppm). Protons of the two methylene groups
(HA/HB and HC/HD) are nonequivalent in pairs due to
spectra (Table 3) signals from carbon atoms attached
to the hydroxy group (
71 72 ppm) and amino
group (
47 58 ppm). CThe above spectral data
C
suggest regioselective attack by the amino group of
adamantane derivatives I, III, and IV on the terminal
carbon atoms of the epoxy fragments in compounds
Va and Vb to afford the most substituted carbinols
according to the Krasusky rule. The observed regio-
selectiviety in opening of the oxirane ring in com-
pounds Va and Vb is consistent with the generally
accepted veiws on the mechanism of bimolecular
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

ADAMANTYL-SUBSTITUTED AMINO ALCOHOLS.
1251
Table 3. 13C NMR parameters (chemical shifts C) of the amino alcohol fragment in compounds VII IX
Compound
no.
CH2N
(carbazole)
CHOH
NCH2
Substituent
VIIa
VIIb
VIIIa
VIIIb
IXa
71.4
71.5
70.4
72.0
72.1
70.9
51.1
56.4
57.8
57.3
56.9
57.2
150.6, 147.4, 126.7, 123.8
141.1, 126.4, 126.1, 120.6, 119.4, 109.3
150.5, 147.4, 126.7, 123.8
141.0, 126.2, 126.0, 120. 5, 119.6, 109.4
150.5, 150.4, 126.7, 123.8
141.0, 126.2, 126.1, 120.5, 119.5, 109.3
47.6
47.7
47.6
IXb
Table 4. Parameters of the 1H NMR spectra (chemical shifts , ppm, and coupling constants J, Hz) of compounds
VII X, XIIb, XIIIb, XIVb, and XV (adamantane fragment)
Adamantane fragment
Compound
CH3
AdCH2N (AdCHN)
no.
3H (CH)
6H (CH2)
6H (CH2)
VIIa
VIIb
VIIIa
VIIIb
IXa
IXb
Xa
Xb
XIIb
XIIIb
XIVb
XV
2.07
1.90
1.91
1.93
1.92
1.69
2.17
2.04
2.07
2.20
2.01
2.29
2.01
1.52
1.61
1.68
1.61
1.56
2.00
1.71
1.98
2.00
1.69
2.15
1.69
1.40
1.46
1.52
1.41
1.39
1.67
1.60
1.66
1.65
1.54
1.78
2
2.21, 2.19, JH, H = 11.5
2
2.41, 2.31, JH, H = 13.7
0.92
0.89
(2.03)
(1.98)
2
2.47, 2.34, JH, H = 11.3
2.59
2
2.33, 2.25, JH, H = 11.5
Table 5. Parameters of the 13C NMR spectra (chemical shifts C) of compounds VII IX (adamantane fragment)
Comp. no.
Adamantane fragment
CH3
AdCH2N
CH
VIIa
VIIb
VIIIa
VIIIb
IXa
48.2
50.9
37.9
50.8
55.3
52.7
43.2
43.2
33.9
41.7
39.0
39.0
36.8
36.9
30.1
37.1
36.4
36.6
29.8
29.8
28.7
28.5
28.8
28.8
70.4
72.1
14.6
14.3
70.4
70.1
IXb
nucleophilic substitution (SN2) which involves attack
by nucleophile on the most accessible terminal carbon
atom [17].
and contiguous methyl, methylene, and methine
groups. The methylene protons are nonequivalent and
are coupled through a geminal constant of 11.5 and
13.7 Hz for amino alcohols VIIIa and VIIIb, respec-
tively. The substituents in compounds IXa and IXb
1
Tables 4 and 5 contain parameters of the H and
13C NMR spectra for some structural fragments of the
prepared compounds, including adamantane moiety
give rise to quartets at
2.03 and 0.92 ppm and
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

1252
KAS’YAN et al.
1
doublets of doublets at 1.98 and 0.89 ppm, respec-
tively. Carbon nuclei of the methylene and methine
absorption bands in the region 3471 3420 cm ,
which belong to O H stretching vibrations, while
bands corresponding to sulfonamide and tertiary
amide groups appear (at 1645 and 1640 cm for the
latter; Table 1) [15]. The selective N-acylation is also
confirmed by the H NMR spectra of compounds Xa
and Xb; in particular, signals from protons of the
methylene group on the nitrogen atom (HA and HB
rather than HX) shift appreciably downfield relative to
their position in the spectra of initial amino alcohols
VIIa and VIIIa (Table 2). Also, a downfield shift
of signals from the methylene group contiguous to
the adamantane fragment in Xb was observed. The
signals from the adamantane protons in the spectra of
both acylation products Xa and Xb did not change
their position (Table 4).
groups resonate in the region
70 72 ppm.
C
1
Molecules of amino alcohols contain two nucleo-
philic centers capable of reacting with electrophilic
reagents. The reactions of compounds VIIa and VIIIa
with p-nitrobenzoyl chloride occurred at the more
nucleophilic amino groups of the former to afford
N-p-nitrobenzoyl derivatives Xa and Xb, respectively:
1
Alternative functionalization of the hydroxy group
was effected with amino alcohols VI, VIIa, and VIIIa
via a two-step process including the synthesis of crys-
talline trimethylsilyl ethers XIIa XIVa and their
subsequent transformation into O-acyl derivatives
XIIb XIVb (Scheme 3).
Unlike p-nitrobenzoyl chloride which smoothly
reacts with amino alcohols under mild conditions
(20 C) in the presence of triethylamine (the yields of
Xa and Xb are 88 and 75%), the reaction of VIIa
and VIIIa with p-nitrobenzenesulfonyl chloride in
chloroform in the presence of the same base requires
heating to 40 45 C, and the corresponding sulfon-
amides XIa and XIb are formed in 30 and 35% yield,
respectively (Scheme 2). Our attempt to obtain com-
pound XIa by the procedure reported in [4] (in a two-
phase system using sodium hydroxide as a base; this
procedure turned out to be very advantageous for the
reaction of amines I IV with arenesulfonyl chlorides)
was even less successful: the yield of sulfonamide
XIa was as low as 19%. The structure of N-substi-
tuted amino alcohols follows from analysis of their
spectral parameters. The IR spectra of X and XI retain
Scheme 3.
Scheme 2.
VIIa, XIIa, XIIb, R = 1-Ad, R = H; VI, XIIIa, XIIIb, R =
1-Ad, R = Me; VIIIa, XIVa, XIVb, R = 1-AdCH2, R = H;
HMDS is hexamethyldisilazane.
The silylation of amino alcohols VI, VIIa, and
VIIIa with hexamethyldisilazane (HMDS) in the pres-
ence of a catalytic amount of chlorotrimethylsilane
was performed in toluene under mild conditions [18].
The silyl ethers thus obtained were converted (without
purification) into the corresponding O-acyl derivatives
by treatment with p-nitrobenzoyl chloride in dry
chloroform at room temperature in the absence of
a base. The successful reaction with amino alcohols
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

ADAMANTYL-SUBSTITUTED AMINO ALCOHOLS.
1253
possessing both secondary (VIIa, VIIIa) and tertiary
amino groups (VI) indicates a weak effect of that
group on the silylation of the hydroxy group.
Bis-acylated product XV was synthesized by reac-
tion of O-acyl derivative XIIb with p-nitrobenzoyl
chloride in the presence of triethylamine as shown
in Scheme 4.
tions and the purity of products were monitored by
TLC on Silufol UV-254 plates using diethyl ether as
eluent; spots were visualized by treatment with iodine
vapor. The elemental compositions were determined
using a Carlo Erba analyzer.
Amines I III were synthesized by the procedures
described in [19 21], and amine IV was isolated from
the corresponding hydrochloride. Their properties
were in agreement with published data [9, 19 21].
Scheme 4.
N-(1-Adamantyl)-2-amino-1-(p-nitrophenyl)-
ethanol (VIIa). A mixture of 0.80 g (0.005 mol) of
p-nitrophenyloxirane (Va) and 0.76 g (0.005 mol) of
1-adamantylamine was dissolved in 10 ml of iso-
propyl alcohol. When the reaction was complete
(TLC), the precipitate was filtered off, washed with
isopropyl alcohol on a filter, dried, and recrystallized
from a mixture of isopropyl alcohol and water (2:1).
Amino alcohols VIIIa and IXa were synthesized
by a similar procedure (Table 1).
N-(1-Adamantyl)-1-amino-3-(9-carbazolyl)-2-
propanol (VIIb). A mixture of 0.67 g (0.003 mol) of
N-(2,3-epoxypropyl)carbazole (Vb) and 0.46 g
(0.003 mol) of 1-adamantylamine was dissolved in
10 ml of isopropyl alcohol. The reaction completion
was determined by TLC. The product was purified by
recrystallization from 2-propanol benzene (2:1).
The properties of the crystalline O-acylated prod-
ucts are presented in Table 1. The IR spectra of XIIb,
XIIIb, and XV contain absorption bands at 1721
1
1719 cm due to stretching vibrations of the ester
carbonyl groups [15], while hydroxy group absorption
is lacking. In the IR spectrum of XV we observed
no absorption bands assignable to hydroxy or amino
group, but an amide carbonyl band was present at
Compounds VIIIb and IXb were synthesized in
a similar way (Table 1).
N-(1-Adamantyl)-N-(p-nitrobenzoyl)-2-amino-1-
(p-nitrophenyl)ethanol (Xa). A solution of 0.19 g
(0.001 mol) of p-nitrobenzoyl chloride in 5 ml of dry
chloroform was added dropwise with stirring to
a mixture of 0.31 g (0.001 mol) of amino alcohol
VIIa and 0.30 g (0.003 mol, 0.41 ml) of triethylamine
in 15 ml of dry chloroform. The mixture was stirred
at room temperature until the reaction was complete
(TLC) and washed in succession with three portions
of water, 20% hydrochloric acid, and water again. The
organic layer was separated and dried over calcined
magnesium sulfate. The solvent was removed, and
the residue was recrystallized from 2-propanol water
(2:1). Amide Xb was synthesized by a similar proce-
dure (Table 1).
N-(1-Adamantyl)-2-amino-N-(p-nitrophenylsul-
fonyl)-1-(p-nitrophenyl)ethanol (XIa). a. A solution
of 0.22 g (0.001 mol) of p-nitrobenzenesulfonyl
chloride in 10 ml of dry chloroform was added drop-
wise with stirring to a mixture of 0.31 g (0.001 mol)
of amino alcohol VIIa and 0.31 g (0.003 mol,
0.42 ml) of triethylamine in 15 ml of dry chloroform.
The reaction was slow, so that the mixture was stirred
1
1600 cm . The overall intensity of the aromatic
1
proton signals in the H NMR spectra strictly corre-
sponds to the number of p-substituted benzene rings
in their molecules (8 protons in XIIb, XIIIb, and
XIVb and 12 protons in XV). Change of the position
of the HX, HA, and HB signals with rise in the number
of acyl groups should be noted. For example, the
chemical shifts of HX in compounds Xa (N-acyl
group), XIIb (O-acyl group), XV (two acyl groups),
and VIIa (no acyl group) are as follows: 4.59, 4.67,
5.12, and 5.56 ppm.
EXPERIMENTAL
The IR spectra were recorded on a Specord 75-IR
1
spectrometer from samples pelleted with KBr. The H
NMR spectra were obtained on Varian and Bruker
DRX spectrometers with operating frequencies of 200,
400, and 500 MHz; chloroform-d or DMSO-d6 was
used as solvent, and hexamethyldisiloxane or tetra-
methylsilane, as internal reference. The 13C NMR
spectra were measured on a Varian Gemini-BB instru-
ment operatng at 100.7 MHz. The progress of reac-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

1254
KAS’YAN et al.
at 40 45 C. When the reaction was complete (TLC),
the mixture was washed in succession with three
portions of water, 20% hydrochloric acid, and water
again. The organic layer was separated and dried over
calcined magnesium sulfate. After removal of the
solvent, the residue was purified by recrystallization
from 2-propanol benzene (1:1).
N-(1-Adamantylmethyl)-2-amino-N-(p-nitro-
phenylsulfonyl)-1-(p-nitrophenyl)ethanol (XIb) was
synthesized in a similar way (Table 1).
was separated and dried over calcined magnesium
sulfate, the solvent was removed, and the product was
recrystallized from aqueous ethanol (1:1).
REFERENCES
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2001.
2. Moiseev, I.K., Makarova, N.V., and Zemtsova, M.N.,
Usp. Khim., 1999, vol. 68, p. 1102; Moiseev, I.K.,
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b. A solution of 0.22 g (0.001 mol) of p-nitroben-
zenesulfonyl chloride in 10 ml of diethyl ether was
added dropwise with stirring to a mixture of 0.31 g
(0.001 mol) of amino alcohol VIIa in 10 ml of ether
and 2 ml of a 20% aqueous solution of sodium
hydroxide. The mixture was stirred at room tempera-
ture until the reaction was complete (TLC). The
organic layer was separated and dried over calcined
magnesium sulfate, the solvent was removed, and
the product was purified by recrystallization from
benzene. Yield 19.4%.
N-(1-Adamantyl)-2-amino-1-(p-nitrophenyl)-
ethyl p-nitrobenzoate (XIIb). A solution of 0.16 g
(0.001 mol, 0.21 ml) of hexamethyldisilazane in 10 ml
of anhydrous toluene containing a catalytic amount
of chlorotrimethylsilane was added dropwise with
stirring at room temperature to a solution of 0.31 g
(0.001 mol) of amino alcohol VIIa in 10 ml of
anhydrous toluene. The mixture was stirred until
the reaction was complete (TLC), the solvent was
removed under reduced pressure, and the product,
silyl ether XIIa, was washed with dry benzene on
a glass filter. A solution of 0.19 g (0.001 mol) of
p-nitrobenzoyl chloride in 5 ml of dry chloroform was
added dropwise with stirring to a mixture of 0.42 g
(0.001 mol) of silyl ether XIIa and 15 ml of dry
chloroform. The mixture was stirred at room tem-
perature until the reaction was complete (TLC), the
solvent was removed, and the product was purified
by recrystallization from 2-propanol water (2:1).
3. Bagrii, E.M., Adamantany: poluchenie, svoistva,
primenenie (Adamantanes: Synthesis, Properties, and
Application), Moscow: Nauka, 1989; Indulen, M.K.,
Kalninya, V.A., Ryazantsava, G.M., and Bubo-
vich, V.I., Mekhanizmy antivirusnogo deistviya
proizvodnykh adamantana (Mechanisms of Antiviral
Action of Adamantane Derivatives), Riga: Zinatne,
1981.
4. Kas’yan, A.O., Okovityi, S.I., Krasnovskaya, O.Yu.,
and Kas’yan, L.I., Russ. J. Org. Chem., 1997,
vol. 33, p. 985.
5. Kas’yan, L.I., Kas’yan, A.O., and Golodaeva, E.A.,
Russ. J. Org. Chem., 2000, vol. 36, p. 1722.
6. Ivanov, A.I., Shmar’yan, M.I., and Skoldinov, A.P.,
Khim.-Farm. Zh., 1969, no. 3, p. 13; Zakrewski, S.F.,
Bloch, A., and Nichol, C.A., J. Med. Chem., 1968,
vol. 11, p. 885; US Patent no. 3501511, 1970; Ref.
Zh., Khim., 1971, no. 9N267P.
7. Kas’yan, A.O., Krishchik, O.V., Krasnov-
skaya, O.Yu., and Kas’yan, L.I., Russ. J. Org.
Chem., 1998, vol. 34, p. 1731.
8. Kreutzberger, A. and Schroders, H.-H., Arch.
Pharm., 1975, vol. 308, p. 748; Kreutzberger, A. and
Schroders, H.-H., Tetrahedron Lett., 1969, p. 5101;
Stetter, H. and Wulff, C., Chem. Ber., 1962, vol. 95,
p. 2302; Swiss Patent no. 424767, 1974; Ref. Zh.,
Khim., 1975, no. 12O81P.
Trimethylsilyl ethers XIIIa and XIVa and the cor-
responding O-acyl derivatives XIIIb and XIVb were
synthesized in a similar way (Table 1).
9. Kas’yan, L.I., Golodaeva, E.A., Danilenko, A.L.,
and Kas’yan, A.O., Vopr. Khim. Khim. Tekhnol.,
2002, no. 1, p. 31.
N-(1-Adamantyl)-2-amino-N-(p-toluoyl)-1-(p-
nitrophenyl)ethyl p-nitrobenzoate (XV). A solution
of 0.19 g (0.001 mol) of p-toluoyl chloride in 5 ml
of dry chloroform was added dropwise with stirring
to a mixture of 0.48 g (0.001 mol) of compound XIIb
and 0.30 g (0.003 mol, 0.41 ml) of triethylamine in
15 ml of dry chloroform. The mixture was stirred at
room temperature until the reaction was complete
(TLC). After appropriate treatment, the organic layer
10. Novakov, I.A., Orlinson, B.S., Sabirov, Z.M.,
Urazbaev, V.N., and Monakov, Yu.B., Vysokomol.
Soedin., 1993, vol. 35, p. 2053.
11. Bergmeier, S.C., Tetrahedron, 2000, vol. 56,
p. 2561; Lukevits, E.Ya., Libert, L.I., and Voron-
kov, M.G., Usp. Khim., 1970, vol. 29, p. 2005.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003

ADAMANTYL-SUBSTITUTED AMINO ALCOHOLS.
1255
12. Mashkovskii, M.D., Lekarstvennye sredstva (Medi-
cines), Moscow: Novaya Volna, 2002, 14th ed.,
vols. 1, 2.
18. Birgele, I.S., Kemme, A.A., and Kupge, E.L., Krem-
niiorganicheskie proizvodnye aminospirtov: fiziko-
khimicheskie issledovaniya (Organosilicon Deriva-
tives of Amino Alcohols: Physicochemical Studies),
Riga: Zinatne, 1987; Kashutin, M.V., Ioffe, S.L.,
and Tartakovskii, V.A., Usp. Khim., 1973, vol. 34,
p. 1621; Kovalev, G.V., Rakhimov, A.I., and
Sazhik, A.A., Khim.-Farm. Zh., 1990, no. 5, p. 17.
13. USSR Inventor’s Certificate no. 368236, 1973; Ref.
Zh., Khim., 1973, no. 22N302P.
14. Kas’yan, A.O., Golodaeva, E.A., Tsygankov, A.V.,
and Kas’yan, L.I., Russ. J. Org. Chem., 2002,
vol. 38, p. 1606.
19. USSR Inventor’s Certificate no. 408546, 1977; Ref.
Zh., Khim., 1978, no. 20O46P.
15. Nakanishi, K., Infrared Absorption Spectroscopy.
Practical, San Francisco: Holden-Day, 1962.
20. USSR Inventor’s Certificate no. 2008066, 1976;
16. Kirk, D.N., Chem. Ind., 1973, p. 109; Krasus-
kii, K.A., Zh. Obshch. Khim., 1936, vol. 6, p. 460.
Ref. Zh., Khim., 1977, no. 4N129P.
21. Korolev, B.A., Khardin, A.P., Radchenko, S.S.,
Novakov, I.A., and Orlinson, B.S., Zh. Org. Khim.,
1978, vol. 14, p. 1632.
17. Parker, R.N. and Isaacs, N.S., Chem. Rev., 1959,
vol. 59, p. 737.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 9 2003