Carboxamides and amines having two and three adamantane fragments

Article abstract of DOI:10.1134/S1070428007110103

New carboxamides having two and three adamantane fragments were synthesized from adamantanecarboxylic acid chlorides and adamantane-containing amines. The amides were reduced to the corresponding amines, and the latter were converted into N-p-nitrophenyls

Full text of DOI:10.1134/S1070428007110103

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 11, pp. 1642–1650. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © L.I. Kas’yan, D.V. Karpenko, A.O. Kas’yan, A.K. Isaev, S.A. Prid’ma, 2007, published in Zhurnal Organicheskoi Khimii, 2007,
Vol. 43, No. 11, pp. 1646–1654.
Carboxamides and Amines Having Two and Three
Adamantane Fragments
L. I. Kas’yana, D. V. Karpenkoa, A. O. Kas’yanb, A. K. Isaevc, and S. A. Prid’maa
a Dnepropetrovsk National University, per. Nauchnyi 13, Dnepropetrovsk, 49050 Ukraine
b ProBioGen A.G., Berlin, D-13086 Germany
c Mississippi State University, Jackson MS, 39762 USA
Received October 11, 2006; revised July 31, 2007
Abstract—New carboxamides having two and three adamantane fragments were synthesized from adaman-
tanecarboxylic acid chlorides and adamantane-containing amines. The amides were reduced to the correspond-
ing amines, and the latter were converted into N-p-nitrophenylsulfonyl and N-p-tolylsulfonylcarbamoyl deriva-
tives by treatment with p-nitrobenzenesulfonyl chloride and p-toluenesulfonyl isocyanate, respectively. The
structure of the newly synthesized compounds was confirmed by IR and 1H NMR spectroscopy. Some carbox-
amides turned out to be inactive in the reduction with lithium tetrahydridoaluminate, which was discussed in
terms of the results of semiempirical quantum-chemical calculations.
DOI: 10.1134/S1070428007110103
us previously to prepare amines containing two bi-
cyclic fragments [3], as well as mono- and diamines
having norbornene, epoxynorbornane, and adamantane
fragments [4, 5].
Amines and their derivatives constitute a consider-
able number of adamantane derivatives that have
passed clinical trials and have been introduced into
medical practice. Examples are Amantadine, Rimanta-
dine, Adapromine, Memantine, Dimantine, etc., which
Nowadays, the scope of thorough chemical and bio-
medical studies includes polyamines that are necessary
for the design of medical agents acting on the central
nervous system [1, 2]. Polyamines of the adamantane
series were not studied. Therefore, the goal of the pres-
ent work was to synthesize such amines by reduction
of the corresponding carboxamides obtained from
adamantane-containing amines and adamantanecar-
boxylic acid chlorides. This approach was applied by
O
O
H
NMe2 ·HCl
N
OH
OH
N
O
N
Ph
H
H
O
Ia
Ib
Ic
O
H
Me
Me
S
N
N
H
N
S
O
Br
COOH
O
Id
Ie
NH·HBr
O
H
N
S
NH2
NH2
N
H
O
NH ·HBr
If
Ig
1642

CARBOXAMIDES AND AMINES HAVING TWO AND THREE ADAMANTANE
1643
COOH
COOH
COOH
COOH
COOH
COOH
IIa
IIb
IIc
IId
NH2
Me
NH2
NH2
NHMe
IIIa
IIIb
IIIc
IIId
exhibit anti-influenza, anti-Parkinson, antidepressant,
and anti-herpes activity [1, 6]. Specificity of biological
action of adamantane derivatives is largely determined
by the presence in their molecules of a bulky cage-like
fragment [1, 6, 7] whose lipophilicity (hydrophobicity)
facilitates direct interaction with biological membranes
having a lipid layer, as well as with hydrophobic
domains in proteins, including those constituting
receptor structures. Both N-adamantyl carboxamides,
such as Tromantadine (Ia) and Bemantine (Ib), and
adamantanecarboxamides, such as anti-Parkinson
Dopamantine (Ic) and antibiotic Amantocillin (Id),
have passed clinical trials [1]. In addition to vast data
on biological activity of amides of the adamantane
series, high neuropsychotropic activity of amide Ie was
noted [1]. Analogous biological action of amides
derived from adamantanecarboxylic acids and adaman-
tane-containing amines was proved by comparison of
hypotensive properties of thiuronium salts If and Ig; in
this case, amide If showed a stronger activity which
even exceeded that of novocainamide [8].
N-methyladamantan-1-amine (IIIb), 1-adamantyl-
methanamine (IIIc), and 1-(1-adamantyl)ethanamine
(IIId). Amines IIIa–IIId were used by us previously
to obtain adamatane-containing arensulfonamides, car-
boxamides, phosphonic amides, ureas, thioureas, and
amino alcohols (via reaction with epoxy derivatives)
[9]. The reactivity of adamantane-containing amines
toward p-toluenesulfonyl chloride and diphenyl chloro-
phosphate was estimated by kinetic methods [10].
Amides having several adamantane fragments were
synthesized through intermediate acid chlorides Va–
Vd which were preliminarily isolated [4, 5]. Their
reactions with amines were carried out in chloroform
in the presence of triethylamine at room temperature.
Crystalline amides VIa [11] and VIb were obtained
from adamantane-1-carbonyl chloride (Va) (Scheme 1).
(1-Adamantyl)acetyl chloride (Vc) reacted with
amines IIIa and IIIc to give amides VIIa and VIIb.
Amides VIIIa, VIIIb, IXa, and IXb were synthesized
by treatment of dicarboxylic acid chlorides Vb and Vd
with the same amines, and the reactions of dichloride
Vd with amines IIIb and IIId gave diamides IXc and
IXd, respectively.
For the synthesis of adamantane-containing amides
we used adamantane-1-carboxylic acid (IIa), adaman-
tane-1,3-dicarboxylic acid (IIb), (1-adamantyl)acetic
acid (IIc) and adamantane-1,3-diyldiacetic acid (IId);
the amine components were adamantan-1-amine (IIIa),
In all cases, the reaction conditions were the same
(room temperature), regardless of the number of ada-
mantane fragments in the resulting molecule (two or
Scheme 1.
H
H
N
IIIa
IIIc
N
Cl
O
O
O
VIa
Va
VIb
O
H
N
N
H
O
VIIa
VIIb
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

KAS’YAN et al.
1644
H
H
N
N
HN
HN
O
O
O
O
VIIIa
VIIIb
O
O
O
O
N
N
H
N
H
N
H
H
IXa
IXb
O
O
O
O
Me
Me
N
Me
N
H
N
N
H
Me
IXc
IXd
three) and the presence of additional steric hindrances
(methyl group on the nitrogen atom in amide IXc or at
the neighboring carbon atom in IXd). The structure of
compounds VI–IX was confirmed by the IR data.
Their IR spectra contained absorption bands in the
regions 1650–1622, 1544–1526, and 1273–1270 cm–1,
corresponding to stretching vibrations of the carbonyl
group (amide I), bending vibrations of the NH group
(amide II), and stretching vibrations of the amide C–N
bond (amide III) [12, 13]. Stretching vibrations of the
secondary NH group gave rise to absorption at 3380–
the mixture was quenched with moist diethyl ether and
ice-cold water. According to [14], the reduction of
1 mol of secondary amide requires 0.75 mol of LiAlH4.
Taking into account that some excess of the reducing
agent is necessary to reduce cage-like amides [15], we
used 2 mol of the reagent per mole of monoamide and
4 mol in the reduction of dicarboxamides. Amide VIa
failed to undergo reduction under the above conditions.
Likewise, no reaction occurred in dimethoxyethane at
80°C (the amount of the reducing agent being the
same), and initial amide VIa was recovered from the
reaction mixture. Our further experiments showed that
amides VIb, VIIIa, and VIIIb derived from adaman-
tane-1-carboxylic and adamantane-1,3-dicarboxylic
acids cannot be reduced to the corresponding amides
under the given conditions. Presumably, the reason is
that the reaction center (carbonyl group) in their mole-
cules is directly attached to the adamantane frame-
work. By contrast, 1-adamantylacetamides VIIa and
VIIb and adamantane-1,3-diyldiacetamides IXa and
IXb were smoothly reduced to give amines Xa–Xd;
and in some cases the yields of the latter exceeded
90%. The reduction of amides IXc and IXd obtained
from adamantane-1,3-diyldiacetic acid and N-methyl-
adamantan-1-amine and Rimantadine showed that the
1
3320 cm–1. In the H NMR spectra of amides VIa,
VIb, IXb, and IXd, the NH proton resonated in the
δ range from 2.09 to 3.18 ppm. In the downfield region
(δ 3.40–4.12 ppm) we observed signals from methyl-
ene protons in the CH2CO group of IXa, IXb, and
IXd. Signals from the CH2NH and CHNH protons
appeared at δ 2.85–2.95 ppm, and protons in the
adamantane fragments were characterized by chemical
shifts δ of 1.20–2.10 ppm.
With a view to obtain amines containing several
adamantane fragments, we examined reduction of the
synthesized amides with lithium tetrahydridoaluminate
in boiling diethyl ether. The progress of reactions was
monitored by TLC; when the reaction was complete,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

CARBOXAMIDES AND AMINES HAVING TWO AND THREE ADAMANTANE
1645
Scheme 2.
LiAlH4, Et2O
reflux
HCl, Et2O
·HCl
VIIa
N
N
H
H
Xa
XIa
N
H
N
H
N
H
Xb
Xc
N
N
N
H
N
H
Me
Me
Xd
Xe
Me
Me
N
N
H
H
Xf
The obtained secondary amines were brought into
reactions with some electrophilic reagents, namely
p-nitrobenzenesulfonyl chloride and p-toluenesulfonyl
isocyanate. Sulfonamides XIIa–XIIe were obtained in
chloroform at room temperature in the presence of
an equimolar amount of triethylamine (Scheme 3). In
the reactions with diamines Xc, Xd, and Xf, 2 equiv of
p-nitrobenzenesulfonyl chloride and triethylamine was
used. Sulfonamides XIIa–XIIe were isolated as crys-
talline or oily substances. Their IR spectra contained
absorption bands due to asymmetric and symmetric
stretching vibrations of the nitro groups (1560–1545
and 1330–1320 cm–1 [12]) and sulfonyl groups (1370–
1355 and 1175–1130 cm–1).
presence of a methyl group on the nitrogen atom or on
the neighboring carbon atom does not hinder formation
of the corresponding amines Xe and Xf (Scheme 2).
Amines Xa–Xf were isolated as oily substances
which were purified by conversion into the corre-
sponding hydrochlorides, followed by alkalization,
extraction, and removal of the solvent. The Rf values
of compounds Xa–Xf (0.57–0.87; diethyl ether) were
higher than those of the initial amides; therefore, their
purity can be monitored by TLC. Amines Xa–Xf were
characterized as crystalline hydrochlorides XIa–XId
and XIf which were obtained by passing dry hydrogen
chloride through a solution of amine X in anhydrous
diethyl ether. Spots of hydrochlorides XI remained at
the start of chromatograms after elution.
Sulfonylureas XIIIa–XIIIe were synthesized by
reaction of amines Xa–Xd and Xf with p-toluenesul-
fonyl isocyanate in benzene at room temperature. In
the IR spectra of crystalline ureas XIIIa–XIIIe we ob-
served absorption bands from stretching and bending
vibrations of the NH (3280–3250, 1560–1540 cm–1),
sulfonyl (1355–1350, 1180–1170 cm–1), and carbonyl
groups (1650–1645 cm–1) [12, 13].
The IR spectra of Xa–Xf lacked amide I bands but
contained absorption bands due to NH stretching vi-
brations [12, 13]. In the IR spectra of amine hydro-
chlorides XI we observed no absorption assignable to
free amino groups; instead, absorption bands in the
region 2725–2700 cm–1 were present [νas(NH2),
νs(NH2)] together with medium-intensity bands at
1440 cm–1, belonging to stretching vibrations of the
CH2N+ group [12].
1
Although H NMR spectra of adamantane deriva-
tives are not so informative as the spectra of substitut-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

KAS’YAN et al.
1646
Scheme 3.
4-O2NC6H4SO2Cl
CHCl3, Et3N
Xa
N
O2S
C6H4NO2-4
XIIa
N
N
N
SO2
SO2
SO2
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
XIIc
XIIb
Me
Me
N
N
N
N
O2S
SO2
O2S
SO2
C6H4NO2-4 4-O2NC6H4
C6H4NO2-4 4-O2NC6H4
XIId
XIIe
Scheme 4.
4-MeC6H4SO2NCO
C6H6
N
Xa
SO2C6H4Me-4
O
N
H
XIIIa
N
N
N
4-MeC6H4SO2
4-MeC6H4SO2
N
O
N
O
O
NHSO2C6H4Me-4
H
H
XIIIb
XIIIc
Me
Me
N
N
N
N
HN
O
O
NH
SO2C6H4Me-4
HN
O
O
NH
SO2C6H4Me-4
SO2C6H4Me-4
SO2C6H4Me-4
XIIId
XIIIe
at δ 8.35, 8.03, and 7.91 ppm; signals from protons in
the ortho positions with respect to the methyl group
were observed at δ 7.29 ppm; and the methyl and NH
protons resonated as singlets at δ 2.43 and 4.08 ppm,
respectively. The positions of signals and their intens-
ity ratios were consistent with structures including
three adamantane fragments.
ed norbornenes, we examined the spectra of com-
pounds XIId and XIIId. Sulfonamide XIId displayed
four-proton multiplets at δ 3.20, 2.87, and 2.05 ppm;
the first two signals were assigned to methylene pro-
tons at the nitrogen atom. Analogous signals in the
spectrum of sulfonylurea XIIId are located at δ 3.18,
2.91, and 2.10 ppm. Adamantane protons in both com-
pounds resonated in the regions δ 1.25–1.65, 1.90–
1.98, and 2.16 ppm; protons in the ortho positions with
respect to the nitro and sulfonyl groups gave doublets
As noted above, amides VIa, VIb, VIIIa, and
VIIIb in which the carbonyl group is directly attached
to the adamantane framework were not reduced with
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

CARBOXAMIDES AND AMINES HAVING TWO AND THREE ADAMANTANE
1647
O
O
O
N
H
O
N
N
N
H
H
H
XIVa
XIVb
XVa
XVb
O
H
N
N
Me
Me
O
XVIa
XVIb
lithium tetrahydridoaliminate. Such inertness of secon-
dary amides toward LiAlH4 is a fairly rare case, al-
though it was reported for some bis-crown ethers [16].
On the other hand, structurally related amides XIVa,
XIVb, and XVa [4, 5] having norbornene and adaman-
tane fragments, as well as amide XVb [3] with two
norbornene fragments, are known to undergo reduction
under the same conditions. With a view to rationalize
different behaviors of cage-like amides in the reduc-
tion with LiAlH4 we resorted to quantum-chemical
calculations which were performed using semiempir-
ical PM3 method [17, 18]. In order to facilitate con-
sideration of conformational properties, instead of ada-
mantane-1,3-diacetamides IXc and IXd we examined
structurally simpler amides XVIa and XVIb derived
from 1-adamantylacetic acid. The results of calcula-
tions are given in table. Analysis of these data showed
that charges on the carbonyl carbons cannot be regard-
ed as the main factor responsible for different reactiv-
ities of the amides, for its variation is insignificant. It is
more probable that the reaction is orbital-controlled.
The energies of the lowest unoccupied molecular
orbitals (ELUMO) decrease in the series XIVb > XVb >
XIVa > XVIa > XIIa > XVa > VIb > VIIb > XVIb >
VIa, which generally corresponds to the reactivity
series observed experimentally. In fact, the results of
calculations predict ready reduction of amides contain-
ing only norbornene (XVb) or norbornene and ada-
mantane fragments (XIVa, XIVb) and low reactivity
of amide VIa. An exception is the position in the
above series of inactive amide VIb, which is closer to
the middle of the series than to its end. Presumably, the
inertness of amides VIa and VIb results from spatial
proximity of two adamantane fragments to the car-
bonyl group; these fragments exert electron-donating
effect and simultaneously create steric hindrances to
attack by nucleophile (AlH4–) on the electrophilic car-
bonyl carbon atom.
Calculated (PM3) electronic structure parameters of compounds VI, VII, and XIV–XVI
Charges on atoms q, a.u.
HOMO
localization
LUMO
localization
carb 52.24; O 17.93
Ccarb 53.77; O 27.26
carb 51.88; O 26.86
Compound
no.
N
C
O
E, eV
E, eV
–0.06
–0.06
–0.05
–0.06
–0.06
–0.06
–0.05
–0.10
–0.09
–0.06
0.25
0.24
0.25
0.24
0.25
0.25
0.24
0.27
0.28
0.24
–0.36
–0.37
–0.35
–0.36
–0.36
–0.36
–0.36
–0.34
–0.35
–0.36
–9.613
–9.564
–9.662
–9.612
–9.633
–9.611
–9.606
–9.690
–9.388
–9.684
N 5.68; O 7.93
N 6.93; O 7.71
N 5.19; O 6.34
N 7.92; O 5.09
N 66.17; O 17.11
N 66.29; O 16.33
N 4.76; O 7.01
N 7.67; O 0.34
N 68.64; O 10.01
N 70.48; O 15.73
1.145
1.065
1.019
1.076
0.834
0.746
1.049
0.756
0.972
1.096
C
VIa
VIb
C
VIIa
VIIb
XIVa
XIVb
XVa
Ccarb 53.31; O 27.17
C=C 46.92, 44.19
C=C 47.02, 43.99
C=C 47.20, 45.13
Ccarb 46.40; O 24.88; C=C 9.16, 8.33
XVb
XVIa
XVIb
C
carb 55.43; O 28.18
carb 53.37; O 26.95
C
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

KAS’YAN et al.
1648
Rf 0.69. IR spectrum, ν, cm–1: 3320, 1625, 1541, 1440,
EXPERIMENTAL
1265. Found, %: N 5.47. C34H50N2O2. Calculated, %:
N 5.41.
The IR spectra were recorded in the range from
4000 to 400 cm–1 on a UR-20 spectrometer from
samples prepared as thin films (neat) or KBr pellets.
N,N′-Bis(1-adamantyl)adamantane-1,3-diyldi-
acetamide (IXa). Yield 72%, mp 245–246°C, Rf 0.81.
IR spectrum, ν, cm–1: 3355, 1640, 1535, 1445, 1270.
1H NMR spectrum, δ, ppm: 1.23–2.06 m (44H, Ad),
2.09 s (2H, NH), 4.11 s (4H, CH2CO). Found, %:
N 5.45. C34H50N2O2. Calculated, %: N 5.41.
1
The H NMR spectra were measured from solutions
in CDCl3 or DMSO-d6 on a Varian VXR instrument
(300 MHz) using tetramethylsilane as internal refer-
ence. The progress of reactions was monitored, and the
purity of products was checked, by TLC on Silufol
60F254 plates using diethyl ether as eluent; chromato-
grams were developed with iodine vapor. Elemental
analyses were obtained on a Carlo Erba analyzer.
N,N′-Bis(1-adamantylmethyl)adamantane-1,3-
diyldiacetamide (IXb). Yield 75%, oily substance,
Rf 0.85. IR spectrum, ν, cm–1: 3351, 1635, 1535, 1444,
1
1271. H NMR spectrum, δ, ppm: 1.19–2.08 m (44H,
Adamantanecarboxylic acid amides (general
procedure). A solution of 2 mmol of the corresponding
acid chloride in chloroform was added dropwise under
stirring to a mixture of 2 mmol of amine IIIa–IIId and
2 mmol of triethylamine in 5 ml of chloroform, and the
mixture was stirred at room temperature until the
reaction was complete (TLC). The mixture was treated
in succession with water, 5% hydrochloric acid, and
water again, the organic phase was separated and dried
over anhydrous magnesium sulfate, the solvent was
removed, and the residue was purified by recrystalliza-
tion from aqueous isopropyl alcohol.
Ad), 2.94 d (4H, CH2NH), 3.20 t (2H, NH), 4.05 s
and 4.12 s (2H each, CH2CO). Found, %: N 5.20.
C36H54N2O2. Calculated, %: N 5.13.
N,N′-Bis(1-adamantyl)-N,N′-dimethyladaman-
tane-1,3-diyldiacetamide (IXc). Yield 63%, oily sub-
stance, Rf 0.75. IR spectrum, ν, cm–1: 1638, 1442,
1268. Found, %: N 5.23. C36H54N2O2. Calculated, %:
N 5.13.
N,N′-Bis[1-(1-adamantyl)ethyl]adamantane-1,3-
diyldiacetamide (IXd). Yield 81%, mp 173–175°C,
Rf 0.80. IR spectrum, ν, cm–1: 3343, 1654, 1561, 1460,
1
N-(1-Adamantyl)adamantane-1-carboxamide
(VIa). Yield 55%, mp 242–243°C, Rf 0.26. IR spec-
1270, 769. H NMR spectrum, δ, ppm: 0.91 d (6H,
CH3), 1.43–2.10 m (44H, Ad), 2.85 m (2H, CHNH),
3.05 d (2H, NH), 3.40 s and 3.52 s (4H, CH2CO).
Found, %: N 4.95. C38H58N2O2. Calculated, %: N 4.48.
1
trum, ν, cm–1: 3340, 1650, 1531, 1241. H NMR spec-
trum, δ, ppm: 1.37–2.12 m (30H, Ad), 3.18 s (1H, NH).
Found, %: N 4.44. C21H31NO. Calculated, %: N 4.47.
Reduction of amides VIIa, VIIb, and Xa–Xf
(general procedure). A solution of 2 mmol of amide
VIIa, VIIb, or Xa–Xd in 10 ml of anhydrous diethyl
ether was added dropwise under stirring to a suspen-
sion of 4 mmol of lithium tetrahydridoaluminate in
10 ml of anhydrous diethyl ether, and the mixture was
stirred for 10 h, maintaining it moderately boiling
(TLC). Excess reducing agent was decomposed by
treatment with moist diethyl ether and ice water. The
organic layer was separated and dried over calcined
magnesium sulfate, and the solvent was removed.
N-(1-Adamantylmethyl)adamantane-1-carbox-
amide (VIb). Yield 52%, mp 270–272°C, Rf 0.74. IR
spectrum, ν, cm–1: 3363, 1631, 1527, 1450, 1270.
1H NMR spectrum, δ, ppm: 1.48–2.08 m (30H, Ad),
2.95 d (2H, CH2NH), 2.96 t (1H, NH). Found, %:
N 4.35. C22H33NO. Calculated, %: N 4.28.
N-(1-Adamantyl)(1-adamantyl)acetamide
(VIIa). Yield 53%, mp 235–237°C, Rf 0.38. IR spec-
trum, ν, cm–1: 3371, 1627, 1565, 1280. Found, %:
N 4.06. C22H33NO. Calculated, %: N 4.28.
N-(1-Adamantylmethyl)(1-adamantyl)acetamide
(VIIb). Yield 57%, mp 210–212°C, Rf 0.65. IR spec-
trum, ν, cm–1: 3371, 1653, 1560, 1461, 1280. Found,
%: N 4.06. C23H35NO. Calculated, %: N 4.11.
N-(1-Adamantyl)-2-(1-adamantyl)ethanamine
(Xa). Yield 83%, oily substance, Rf 0.65. IR spectrum,
ν, cm–1: 3301, 1570, 1462, 1370. Found, %: N 4.55.
C22H35N. Calculated, %: N 4.47. Hydrochloride XIa
was obtained by passing dry hydrogen chloride
through a solution of amine Xa in diethyl ether. Yield
84%, mp 250°C. IR spectrum, ν, cm–1: 2710, 1465.
N,N′-Bis(1-adamantyl)adamantane-1,3-dicar-
boxamide (VIIIa). Yield 59%, mp 191–192°C, Rf 0.32.
IR spectrum, ν, cm–1: 3382, 1641, 1533, 1445, 1270.
Found, %: N 5.65. C32H46N2O2. Calculated, %: N 5.71.
N-(1-Adamantylmethyl)-2-(1-adamantyl)ethan-
amine (Xb). Yield 90%, oily substance, Rf 0.88. IR
spectrum, ν, cm–1: 3354, 1460, 1361, 1058. Found, %:
N,N′-Bis(1-adamantylmethyl)adamantane-1,3-
dicarboxamide (VIIIb). Yield 65%, mp 222–223°C,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

CARBOXAMIDES AND AMINES HAVING TWO AND THREE ADAMANTANE
1649
N 4.20. C23H37N. Calculated, %: N 4.28. Hydrochlo-
ride XIb: yield 73%, mp 231–233°C. IR spectrum, ν,
cm–1: 2700, 1460.
N,N′-Bis(1-adamantyl)-N,N′-[2,2′-(adamantane-
1,3-diyl)diethylene]bis(4-nitrobenzenesulfonamide)
(XIIc). Yield 53%, mp 138–140°C, Rf 0.91. IR spec-
trum, ν, cm–1: 1545, 1460, 1355, 1321, 1200, 1140.
Found, %: N 6.63. C46H60N4O8S2. Calculated, %:
N 6.51.
N,N′-Bis(1-adamantyl)-2,2′-(adamantane-1,3-di-
yl)diethanamine (Xc). Yield 91%, oily substance,
Rf 0.62. IR spectrum, ν, cm–1: 3295, 1581, 1455, 1370,
1115. Found, %: N 5.78. C34H54N2. Calculated, %:
N 5.71. Hydrochloride XIc: yield 91%, mp 230–
231°C. IR spectrum, ν, cm–1: 2710, 1465.
N,N′-Bis(1-adamantylmethyl)-N,N′-[2,2′-(ada-
mantane-1,3-diyl)diethylene]bis(4-nitrobenzenesul-
fonamide) (XIId). Yield 67%, oily substance, Rf 0.82.
IR spectrum, ν, cm–1: 1550, 1465, 1366, 1328, 1175.
Found, %: N 6.20. C48H64N4O8S2. Calculated, %:
N 6.31.
N,N′-Bis(1-adamantylmethyl)-2,2′-(adamantane-
1,3-diyl)diethanamine (Xd). Yield 91%, oily sub-
stance, Rf 0.83. IR spectrum, ν, cm–1: 3345, 1571,
1460, 1360, 1119. Found, %: N 5.53. C36H58N2. Cal-
culated, %: N 5.40. Hydrochloride XId: yield 83%,
mp 225–227°C. IR spectrum, ν, cm–1: 2705, 1464.
N,N′-Bis[1-(1-adamantyl)ethyl]-N,N′-[2,2′-(ada-
mantane-1,3-diyl)diethylene]bis(4-nitrobenzenesul-
fonamide) (XIIe). Yield 62%, oily substance, Rf 0.78.
IR spectrum, ν, cm–1: 1550, 1464, 1361, 1328, 1193,
1130. Found, %: N 6.01. C50H68N4O8S2. Calculated, %:
N 6.11.
N,N′-Bis(1-adamantyl)-N,N′-dimethyl-2,2′-(ada-
mantane-1,3-diyl)diethanamine (Xe). Yield 89%,
oily substance, Rf 0.55. IR spectrum, ν, cm–1: 1480,
1380, 1355, 1120. Found, %: N 5.51. C36H58N2. Cal-
culated, %: N 5.40. Hydrochloride XIe: yield 85%,
oily substance. IR spectrum, ν, cm–1: 2700, 1460.
Sulfonylureas XIIIa–XIIIe (general procedure).
Amine Xa–Xd or Xf, 0.2 mmol, was dissolved in 5 ml
of benzene, 0.2 mmol of p-toluenesulfonyl isocyanate
was added at room temperature, and the mixture was
stirred until the reaction was complete (TLC). The
precipitate was filtered off, washed with benzene on
a filter, dried, and recrystallized from benzene–hexane.
N,N′-Bis[1-(1-adamantyl)ethyl]-2,2′-(adaman-
tane-1,3-diyl)diethanamine (Xf). Yield 94%, oily
substance, Rf 0.57. IR spectrum, ν, cm–1: 3325, 1564,
1460, 1170. Found, %: N 5.23. C38H62N2. Calculated,
%: N 5.13.
N-(1-Adamantyl)-N-[2-(1-adamantyl)ethyl]-N′-
(4-tolylsulfonyl)urea (XIIIa). Yield 68%, mp 92–
93°C, Rf 0.92. IR spectrum, ν, cm–1: 3274, 1655, 1545,
1460, 1351, 1170. Found, %: N 5.56. C30H42N2O3S.
Calculated, %: N 5.49.
Sulfonamides XIIa–XIIe (general procedure).
A solution of 0.2 mmol of p-nitrobenzenesulfonyl
chloride in 6 ml of chloroform was added dropwise
under stirring at room temperature to a mixture of
0.2 mmol of amine Xa–Xd or Xf and 0.2 mmol of
triethylamine in 10 ml of anhydrous chloroform, and
the mixture was stirred until the reaction was complete
(TLC). The mixture was then treated with water, 15%
hydrochloric acid, and water again, the organic phase
was separated and dried over anhydrous magnesium
sulfate, the solvent was removed, and the residue was
purified by recrystallization from aqueous isopropyl
alcohol.
N-[2-(1-Adamantyl)ethyl]-N-(1-adamantyl-
methyl)-N′-(4-tolylsulfonyl)urea (XIIIb). Yield 70%,
mp 93–94°C, Rf 0.78. IR spectrum, ν, cm–1: 3268,
1650, 1560, 1460, 1355, 1170. Found, %: N 5.40.
C31H44N2O3S. Calculated, %: N 5.34.
N1,N2-[2,2′-(Adamantane-1,3-diyl)diethylene]bis-
[N-(1-adamantyl)-N′-(4-tolylsulfonyl)urea] (XIIIc).
Yield 74%, mp 90–91°C, Rf 0.43. IR spectrum, ν,
cm–1: 3255, 1651, 1541, 1460, 1350, 1170. Found, %:
N 6.45. C50H68N4O6S2. Calculated, %: N 6.33.
N1,N2-[2,2′-(Adamantane-1,3-diyl)diethylene]bis-
[N-(1-adamantylmethyl)-N′-(4-tolylsulfonyl)urea]
(XIIId). Yield 71%, mp 96–97°C, Rf 0.58. IR spec-
trum, ν, cm–1: 3261, 1650, 1561, 1465, 1355, 1171.
Found, %: N 6.25. C52H72N4O6S2. Calculated, %:
N 6.14.
N-(1-Adamantyl)-N-[2-(1-adamantyl)ethyl]-4-ni-
trobenzenesulfonamide (XIIa). Yield 56%, mp 118–
120°C, Rf 0.73. IR spectrum, ν, cm–1: 1559, 1465,
1362, 1184, 1130. Found, %: N 5.70. C28H38N2O4S.
Calculated, %: N 5.62.
N-(1-Adamantylmethyl)-N-[2-(1-adamantyl)-
ethyl]-4-nitrobenzenesulfonamide (XIIb). Yield
64%, oily substance, Rf 0.56. IR spectrum, ν, cm–1:
1558, 1460, 1361, 1325, 1190, 1131. Found, %:
N 5.40. C29H40N2O4S. Calculated, %: N 5.47.
N1,N2-[2,2′-(Adamantane-1,3-diyl)diethylene]bis-
{N-[1-(1-adamantyl)ethyl]-N′-(4-tolylsulfonyl)urea}
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007

KAS’YAN et al.
1650
Kas’yan, L.I., Kas’yan, A.O., and Golodaeva, E.A.,
Russ. J. Org. Chem., 2000, vol. 36, p. 1722; Kas’-
yan, L.I., Danilenko, G.I., and Karpenko, D.V., Vopr.
Khim. Khim. Tekhnol., 2004, no. 3, p. 34; Kas’yan, L.I.,
Golodaeva, E.A., Danilenko, A.L., and Kas’yan, A.O.,
Vopr. Khim. Khim. Tekhnol., 2002, no. 1, p. 31; Kas’-
yan, L.I., Golodaeva, E.A., and Kas’yan, A.O., Vopr.
Khim. Khim. Tekhnol., 2003, no. 4, p. 45; Kas’yan, L.I.,
Golodaeva, E.A., Kas’yan, A.O., and Bondarenko, Ya.S.,
Vopr. Khim. Khim. Tekhnol., 2003, no. 3, p. 59; Kas’-
yan, L.I., Golodaeva, E.A., and Kas’yan, A.O., Russ. J.
Org. Chem., 2003, vol. 39, p. 1248.
(XIIIe). Yield 81%, mp 92–94°C, Rf 0.65. IR spec-
trum, ν, cm–1: 3281, 1660, 1555, 1470, 1362, 1173.
Found, %: N 6.10. C54H76N4O6S2. Calculated, %:
N 5.96.
REFERENCES
1. Morozov, I.S., Petrov, V.I., and Sergeeva, S.A., Farma-
kologiya adamantanov (Pharmacology of Adamantanes),
Volgograd: Volgograd. Med. Akad., 2001.
2. Mashkovskii, M.D., Lekarstvennye sredstva (Drugs),
Khar’kov: Torsing, 1997, vol. 2.
10. Sadovskii, Yu.S., Solomoichenko, T.N., Kas’yan, A.O.,
Golodaeva, E.A., Anikanova, S.V., Kas’yan, L.I., and
Savelova, V.A., Russ. J. Org. Chem., 2004, vol. 40,
p. 50.
3. Kas’yan, L.I., Isaev, A.K., Kas’yan, A.O., Golodae-
va, E.A., Karpenko, D.V., and Tarabara, I.N., Russ. J.
Org. Chem., 2004, vol. 40, p. 1415.
4. Kas’yan, A.O., Karpenko, D.V., Seferova, M.F., and
Kas’yan, L.I., Vіsn. Dnіpropetr. Univ., 2003, no. 9, p. 41.
5. Kas’yan, L.I., Karpenko, D.V., Kas’yan, A.O., and Isa-
ev, A.K., Russ. J. Org. Chem., 2005, vol. 41, p. 678.
6. Bagrii, E.I., Adamantany: poluchenie, svoistva, primene-
nie (Adamantanes: Synthesis, Properties, and Applica-
tions), Moscow: Nauka, 1989.
7. Indulen, M.K., Kalninya, V.A., Ryazantseva, T.M., and
Bubovich, V.I., Mekhanizmy antivirusnogo deistviya pro-
izvodnykh adamantana (Mechanisms of Antiviral Action
of Adamantane Derivatives), Riga: Zinatne, 1981.
11. Danilenko, G.І., Vladimirtsev, І.F., Yurchenko, A.G.,
Galegov, G.A., Leont’єva, N.O., Іsaєv, S.D., Dikolen-
ko, E.І., Boldirєv, І.V., Yurchenko, R.І., and Koten-
ko, S.І., Farm. Zh., 1976, no. 5, p. 36; Kreutzberger, A.
and Schroder, H., Arch. Pharm., 1974, vol. 307, p. 347.
12. Nakanishi, K., Infrared Absorption Spectroscopy. Prac-
tical, San Francisco: Holden-Day, 1962.
13. Bellamy, L.J., Advances in Infra-red Group Fre-
quencies, London: Methuen, 1966.
14. Brown, H.C. and Krishnamurthy, S., Tetrahedron, 1979,
8. Vatsek, G.A., Petrova, I.G., and Kovtun, V.Yu., Abstracts
of Papers, VI Nauchno-prakticheskaya konferentsiya
stran SNG “Perspektivy razvitiya khimii i prakticheskogo
primeneniya karkasnykh soedinenii” (VIth Scientific and
Practical Conf. of UIS Countries “Prospects in the
Development of Chemistry and Practical Applications of
Cage-Like Compounds”), Volgograd, 1995, p. 164.
vol. 35, p. 567.
15. Malinovskii, M.S., Kas’yan, L.I., Ovsyanik, V.D., and
Ivchenko, O.V., Zh. Org. Khim., 1973, vol. 9, p. 2077;
Malinovskii, M.S., Kas’yan, L.I., Ovsyanik, V.D., and
Sil’chenko, L.A., Zh. Org. Khim., 1973, vol. 9, p. 1306.
16. Dugas, H. and Vaugeois, J., Synthesis, 1991, p. 420.
17. Stewart, J.J.P., J. Comput. Chem., 1989, vol. 10, p. 221.
18. Klamt, A., J. Phys. Chem., 1995, vol. 99, p. 2224.
9. Kas’yan, A.O., Okovityi, S.I., Krasnovskaya, O.Yu., and
Kas’yan, L.I., Russ. J. Org. Chem., 1997, vol. 33, p. 985;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 11 2007