Conjugation of aminoadamantanes by copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition

Article abstract of DOI:10.1007/s11172-018-2231-3

Four variants of conjugation of aminoadamantanes with 1,2,3-triazole- and ditriazolecontaining spacers by copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of azido- and propargyl-containing aminoadamantanes were suggested.

Full text of DOI:10.1007/s11172-018-2231-3

Russian Chemical Bulletin, International Edition, Vol. 67, No. 8, pp. 1401—1405, August, 2018
1401
Conjugation of aminoadamantanes by copper-catalyzed alkyne-azide
1,3-dipolar cycloaddition
V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, and T. V. Goreva
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi pr-d, 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. E-mail: alaks@ipac.ac.ru
Four variants of conjugation of aminoadamantanes with 1,2,3-triazole- and ditriazole-
containing spacers by copper-catalyzed alkyne-azide 1,3-dipolar cycloaddition of azido- and
propargyl-containing aminoadamantanes were suggested.
Key words: 1-aminoadamantanes, N-propynylaminoadamantanes, N-(adamantan-1-yl)-
2-azidoacetamides, terminal diazidoalkanes, 1,4-dipropynylpiperazine, 1,4-substituted 1,2,3-tri-
azoles, 1,3-dipolar cycloaddition, conjugates.
The rational design of known pharmaceutical drugs is
one of the possible approaches to the development of drugs
affecting several targets.1 From this perspective, in this
work we present the data on synthetic approaches to the
combination of adamantan-1-ylamines in one molecule.
The study was prompted by the data on the biological
activity of aminoadamantanes and their derivatives. Thus,
adamantanylamine (amantadine) is used as an antiviral2
and antiparkinsonian dopaminergic agent,3 3,5-dimeth-
yladamantan-1-ylamine (memantine) is one of the main
drugs used in the treatment of Alzheimer´s disease,4 and
its derivatives modified at both the amino group5—8 and
the adamantane core9 are also intensively studied in the
last years.
amines 3a,b and N,N-di(prop-2-yn-1-yl)adamantan-1-
amines 4a,b were formed in 74—84% yield upon heating
aminoadamantanes 1a,b and propargyl bromide in PriOH
in the presence of three equivalents of K2CO3 (Scheme 1).
Scheme 1
Amantadine
Memantine
The purpose of the present work is the studies of synthe-
tic potential of copper-catalyzed alkyne-azide cycloaddi-
tion, which is one of the click-chemistry standards,10,11 for
the combination of azido- and propargyl-containing amino-
adamantanes by triazole- and ditriazole-containing spacers.
The starting objects of the transformations, N-(ada-
mantan-1-yl)-2-azidoacetamides (2a,b), were obtained
using a one-pot method, namely, by sequential addition to
a solution of aminoadamantanes 1a,b and Et3N in DMF
of an equimolar amount of chloroacetyl chloride and, once
the exothermic reaction reached completion, sodium azide
was added with further heating at 50 C for 30 min to
complete the reaction. N-(Prop-2-yn-1-yl)adamantan-1-
1—4: R = H (a), Me (b)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1401—1405, August, 2018.
1066-5285/18/6708-1401 © 2018 Springer Science+Business Media, Inc.

1402
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
Sokolov et al.
Scheme 2
6, 7: R = H, R´ = H (a); Me (b); R = Me, R´ = H (c); Me (d)
8: R = H (a), Me (b)
Conditions: CuSO4•5 H2O, CH2Cl2, sodium ascorbate, 40 С.
Scheme 3
10: n = 0 (a), 2 (b)
The thus obtained azidoacetamides 2a,b were studied
in the cycloaddition reaction with propargyladamantanes
3a,b and 4a,b and 1,4-di(prop-2-yn-1-yl)piperazine (5)
(Scheme 2). It was shown that azidoacetamides 2a,b in
the presence of catalytic amounts of CuI under phase-
transfer conditions (dichloromethane—water) react with
compounds 3a,b, 4a,b, and 5 to form the corresponding
1,2,3-triazoles 6a—d, 7a—d, and 8a,b in high yield. In the
1Н NMR spectra of triazoles 6a—d, 7a—d, and 8a,b,
representing the superposition of the aminoadamantane
fragments, characteristic singlets for the proton of the
triazole ring are observed in the region of  6.8—7.3.
Under similar conditions, N-(prop-2-yn-1-yl)ada-
mantan-1-amine (3a) reacted with terminal diazido-
alkanes 9a,b to form the corresponding conjugates 10a,b
in 83 and 87% yield (Scheme 3).
The 1Н NMR spectra of conjugates 10a,b contain the
singlets for the proton of the triazole ring in the region of
 6.8—7.3 and the multiplets for the protons of the spacer
methylene groups.
In conclusion, we suggested four variants for the com-
bination of aminoadamantanes in one molecule by tri-
azole- and ditriazole-containing spacers, using the click-
reaction of 1,3-dipolar cycloaddition, allowing obtaining
a variety of potential multitarget neuroprotectors.
Experimental
1H NMR spectra were recorded on a Bruker DPX 200 spec-
trometer at 200.13 МHz relative to SiMe4 (an internal standard).
Melting points were measured in a glass capillary tube. 1,4-Di-
(prop-2-yn-1-yl)piperazine (5) was obtained according to the

Conjugates of aminoadamantane
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1403
described procedure,12 diazidoalkanes 9a,b (see Ref. 13), ami-
noadamantanes 1a,b, copper sulfate and sodium ascorbate
(Aldrich) were used without additional purification.
for 5 h at 70 C, cooled, poured into H2O (100 mL), extracted
with chloroform, and dried with Na2SO4. The solvent was
evaporated in vacuo, the residue was purified by column chrom-
atography on silica gel (chloroform—hexane, 5 : 1).
N,N-Di(prop-2-yn-1-yl)adamantan-1-amine (4а) and 3,5-di-
methyl-N,N-di(prop-2-yn-1-yl)adamantan-1-amine (4b) were
obtained similarly to 3a,b from aminoadamantane 1a,b (0.2 mmol)
and propargyl bromide (0.4 mmol).
Synthesis of N-(adamantan-1-yl)-2-{4-[(adamantan-1-yl-
amino)methyl]-1Н-1,2,3-triazol-1-yl}acetamide (6a), N-(ada-
mantan-1-yl)-2-{4-[(3,5-dimethyladamantan-1-ylamino)methyl]-
1Н-1,2,3-triazol-1-yl}acetamide (6b), 2-{4-[(adamantan-1-
ylamino)methyl]-1Н-1,2,3-triazol-1-yl}-N-(3,5-dimethyladaman-
tan-1-yl)acetamide (6c), N-(3,5)-dimethyladamantan-1-yl)-2-{4-
[(3,5-dimethyladamantan-1-ylamino)methyl]-1Н-1,2,3-triazol-
1-yl}acetamide (6d) (general procedure). The corresponding
N-propenyaminoadamantane 3a,b (0.1 mmol), CuSO4•5H2O
Synthesis of N-(adamantan-1-yl)-2-azidoacetamide (2а) and
2-azido-N-(3,5-dimethyladamantan-1-yl)acetamide (2b) (gen-
eral procedure). Chloroacetyl chloride (0.2 mmol) was added to
a solution of aminoadamantane 1a,b (0.2 mmol) and Et3N
(0.2 mmol) in DMF (30 mL) with stirring, the reaction mixture
was stirred for 30 min, followed by the addition of NaN3
(0.21 mmol), stirring for 30 min at 50 C, and pouring into H2O
(100 mL). The precipitate formed was collected by filtration and
recrystallized from 50% ethanol.
Synthesis of N-(prop-2-yn-1-yl)adamantan-1-amine (3а) and
3,5-dimethyl-N-(prop-2-yn-1-yl)adamantan-1-amine (3b) (gen-
eral procedure). Potassium carbonate (0.6 mmol) was added to a
solution of aminoadamantane 1a,b (0.2 mmol) and propargyl
bromide (0.2 mmol) in PriOH (30 mL). The mixture was stirred
Table 1. Yields, melting points, and elemental analysis data for compounds 2a,b, 3a,b, 4a,b,
6a—d, 7a—d, 8a,b, and 10a,b
Com-
pound
Yield
(%)
M.p./С
Found
Calculated
H
Molecular
formula
(%)
C
N
2a
2b
3a
3b
4a
4b
6a
6b
6c
6d
7a
7b
7c
7d
8a
8b
10a
10b
91
88
76
74
82
84
80
81
85
86
81
88
91
87
86
85
83
87
96—98
83—85
61.31
61.52
64.28
64.09
82.27
82.48
83.11
82.89
84.71
84.53
84.82
84.65
70.71
70.89
72.03
71.80
71.63
71.80
72.43
72.61
68.82
69.03
69.49
69.68
70.11
70.27
71.08
70.82
64.92
64.73
66.22
66.44
68.69
68.54
69.27
69.46
7.93
7.74
8.66
8.45
10.30
10.12
10.48
10.67
9.50
9.31
10.05
9.87
8.68
8.80
8.99
9.15
9.33
9.15
9.62
9.46
8.06
8.26
8.27
8.49
8.56
8.71
9.11
24.12
23.91
21.07
21.36
7.22
C
12H18N4O
C14H22N4O
56—57
C13H19
C15H23
C16H21
C18H25
N
N
N
N
7.40
An oil
6.29
6.44
85—84
6.05
6.16
An oil
5.31
5.48
118—120
111—113
102—103
95—97
6.72
C25H37N5O
C27H41N5O
C27H41N5O
C29H45N5O
C40H57N9O2
C42H61N9O2
C44H65N9O2
C46H69N9O2
C34H50N10O2
C38H58N10O2
C28H42N8
6.53
15.72
15.51
15.33
15.51
14.45
14.60
18.30
18.11
17.63
17.41
16.52
16.76
16.34
16.16
22.41
22.20
20.21
20.39
22.66
22.84
21.79
21.60
267—269
251—252
244—245
233—235
162—164
137—139
140—142
146—147
8.92
8.17
7.99
8.70
8.51
8.84
8.63
9.15
8.94
C30H46N8

1404 Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
Sokolov et al.
Table 2. 1Н NMR spectra of compounds 2a,b, 3a,b, 4a,b, 5a—d, 6a—d, 8a,b, and 10a,b
Compound
 (J/Hz)
2a
2b
1.69 (s, 6 H, CAdH2); 2.01 (s, 6 H, CAdH2); 2.09 (br.s, 3 H, CAdH); 3.87 (s, 2 H, CH2N); 5.94 (s, 1 H, NH)
0.86 (s, 6 H, Me); 1.16 (s, 2 H, CAdH2); 1.22—1.48 (m, 4 H, CAdH2); 1.55—1.76 (m, 4 H, CAdH2);
1.84 (s, 2 H, CH2); 2.16 (septet, 1 H, CAdH, JH,H = 3.0); 3.85 (s, 2 H, CH2N); 5.78 (s, 1 H, NH)
3a
3b
1.52—1.78 (m,13 H, NH + CAdH2); 2.01—2.17 (m, 3 H, CAdH); 2.19 (t, 1 H, CH, JH,H = 2.5);
3.41 (d, 2 H, CH2N, JH,H = 2.5)
0.84 (s, 6 H, Me); 1.08—1.15 (m, 2 H, CAdH2); 1.21—1.33 (m, 4 H, CAdH2); 1.35 (s, 1 H, NH);
1.46—1.52 (m, 4 H, CAdH2); 1.80 (s, 2 H, CH2); 2.14 (septet, 1 H, CAdH, JH,H = 3.1); 2.19 (t, 1 H,
CH, JH,H = 2.5); 3.41 (d, 2 H, CH2N, JH,H = 2.5)
4a
4b
1.63 (s, 6 H, CAdH2); 1.83 (s, 6 H, CAdH2); 2.08 (br.s, 3 H, CAdH); 2.21 (t, 2 H, CH, JH,H = 2.3);
3.69 (d, 4 H, CH2N, JH,H = 2.3)
0.87 (s, 6 H, Me); 1.08—1.17 (m, 2 H, CAdH2); 1.25—1.35 (m, 4 H, CAdH2); 1.36—1.56 (m, 4 H, CAdH2);
1.8—34 (s, 2 H, CH2); 2.17 (septet, 1 H, CAdH, JH,H = 3.2); 2.22 (t, 2 H, CH, JH,H = 2.0);
3.70 (d, 4 H, CH2N, JH,H = 2.0)
6a
6b
1.60—1.75 (m, 18 H, CAdH2); 1.98 (s, 6 H, CAdH2); 2.05—2.20 (m, 7 H, CAdH + NH); 3.99 (s, 2 H,
CH2C(O)); 4.97 (s, 2 H, CH2NH); 5.91 (s, 1 H, NHC(O)); 7.71 (s, 1 H, CH=)
0.86 (s, 6 H, Me); 1.14 (s, 2 H, CAdH2); 1.24—1.47 (m, 8 H, CAdH2); 1.52—1.72 (m, 8 H, CAdH2);
1.90—2.10 (m, 11 H, CAdH2 + CAdH); 3.93 (s, 2 H, CH2C(O)); 4.96 (s, 2 H, CH2NH);
6.30 (s, 1 H, NHC(O)); 7.71 (s, 1 H, CH=)
6c
6d
0.83 (s, 6 H, Me); 1.13 (s, 2 H, CAdH2); 1.20—1.41 (m, 4 H, CAdH2); 1.47—1.84 (m, 18 H, CAdH + CAdH2);
2.05—2.18 (m, 4 H, CAdH2); 2.27 (s, 1 H, NH); 3.95 (s, 2 H, CH2C(O)); 4.92 (s, 2 H, CH2NH);
5.95 (s, 1 H, NHC(O)); 7.66 (s, 1 H, CH=)
0.83 (s, 6 H, Me); 0.87 (s, 6 H, Me); 1.14 (s, 4 H, CAdH2); 1.24—1.47 (m, 12 H, CAdH2); 1.49—1.70
(m, 5 H, NH + CAdH2); 1.74—1.82 (m, 2 H, CAdH2); 2.09—2.20 (m, 4 H, CAdH2 + CAdH); 3.94 (s, 2 H,
CH2C(O)); 4.92 (s, 2 H, CH2NH); 5.93 (s, 1 H, NHC(O)); 7.65 (s, 1 H, CH=)
7a
7b
1.50—1.77 (m, 22 H, CAdH2); 1.85—2.15 (m, 23 H, CAdH2 + CAdH); 3.81 (s, 4 H, CH2C(O));
4.97 (s, 4 H, CH2N); 7.77 (s, 2 H, CH=); 7.86 (s, 2 H, NHC(O))
0.84 (s, 6 H, Me); 1.14 (s, 2 H, CAdH2); 1.21—1.53 (m, 8 H, CAdH2); 1.57—1.73 (m, 21 H, CAdH2);
1.85—2.15 (m, 12 H, CAdH2 + CAdH); 3.97 (s, 4 H, CH2C(O)); 4.92 (s, 4 H, CH2N); 5.82 (s, 2 H, NHC(O));
7.65 (s, 2 H, CH=)
7c
7d
0.81 (s, 12 H, Me); 1.10 (s, 4 H, CAdH2); 1.18—1.39 (m, 8 H, CAdH2); 1.57—1.80 (m, 23 H, CAdH2);
1.95—2.13 (m, 6 H, CAdH2 + CAdH); 3.62 (s, 4 H, CH2C(O)); 4.65 (s, 4 H, CH2N); 7.77 (s, 2 H, CH=);
7.87 (s, 2 H, NHC(O))
0.81 (s, 18 H, Me); 1.10 (s, 6 H, CAdH2); 1.17—1.46 (m, 12 H, CAdH2); 1.48—1.80 (m, 16 H, CAdH2);
2.00—2.13 (m, 5 H, CAdH2 + CAdH); 3.61 (s, 4 H, CH2C(O)); 4.95 (s, 4 H, CH2N); 7.76 (s, 2 H, CH=);
7.88 (s, 2 H, NHC(O))
8a
8b
1.51—1.70 (m, 12 H, CAdH2); 1.80—2.10 (m, 18 H, CAdH2 + CAdH); 2.20—2.56 (m, 8 H, NCH2CH2);
3.50 (s, 4 H, CH2C(O)); 4.94 (s, 4 H, CH2N); 7.83 (s, 4 H, CH= + NHC(O))
0.81 (s, 12 H, Me); 1.10 (s, 4 H, CAdH2); 1.17—1.46 (m, 8 H, CAdH2); 1.48—1.80 (m, 12 H, CAdH2);
2.00—2.13 (m, 2 H, CAdH); 2.18—2.54 (m, 8 H, NCH2CH2); 3.50 (s, 4 H, CH2C(O)); 4.93 (s, 4 H, CH2N);
7.78 (s, 2 H, CH=); 7.83 (s, 2 H, NHC(O))
10a
10b
1.53—1.82 (m, 18 H, CAdH2); 1.86—2.17 (m, 14 H, NH + CAdH + CAdH2); 3.85 (s, 4 H, CH2CH2);
4.86 (s, 4 H, CH2NH); 7.30 (s, 2 H, CH=)
1.54—1.84 (m, 22 H, NCH2CH2 + CAdH2); 1.86—2.01 (m, 6 H, CAdH2); 2.01—2.20 (m, 8 H, NH + CAdH);
3.85 (s, 4 H, NCH2CH2); 4.86 (s, 4 H, CH2NH); 7.30 (s, 2 H, CH=)
(0.002 g, 0.01 mmol) in water (0.5 mL), and sodium ascorbate
(0.008 g, 0.04 mmol) in water (0.25 mL) were added to a solution
of azidoacetamide 2a,b (0.1 mmol) in dichloromethane (20 mL)
with vigorous stirring. The reaction mixture was stirred for 7 h at
40 C, cooled to room temperature, diluted with dichlorometh-
ane (10 mL), and washed with 2% aqueous ammonia (10 mL)
and water. The organic layer was separated and dried with
Na2SO4, The solvent was evaporated in vacuo, the residue was
subjected to chromatography on silica gel (60 mesh, eluent
methanol—chloroform, 1 : 10).
2,2´-{4,4´-[(Adamantan-1-ylazanediyl)bis(methylene)bis-
(1Н-1,2,3-triazole-4,1-diyl)]bis(N-adamantan-1-yl)acetamide}
(7a), 2,2´-{4,4´-[(3,5-dimethyladamantan-1-ylazanediyl)bis-
(methylene)bis(1Н-1,2,3-triazole-4,1-diyl)]bis(N-adamantan-1-

Conjugates of aminoadamantane
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 8, August, 2018
1405
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tsova, A. Yu. Abramov, D. V. Vinogradova, M. E. Neganova,
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8. V. B. Sokolov, A. Yu. Aksinenko, T. V. Goreva, T. A. Epishina,
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(methylene)bis(1Н-1,2,3-triazole-4,1-diyl)]bis(N-3,5-dimethyl-
adamantan-1-yl)acetamide} (7c), and 2,2´-{4,4´-[(3,5-dimethyl-
adamantan-1-ylazanediyl)bis(methylene)bis(1Н-1,2,3-triazole-
4,1-diyl)]bis(N-3,5-dimethyladamantan-1-yl)acetamide} (7d) were
obtained similarly to 6a—d from azidoacetamide 2a,b (0.1 mmol)
and N.N-dipropenylaminoadamantane 4a,b (0.2 mmol).
1,4-Bis({1-[2-(adamantan-1-ylamino)-2-oxoethyl]-1,2,3-
triazol-4-yl}methyl)piperazine (8a) and 1,4-bis({1-[2-(3,5-di-
methyladamantan-1-ylamino)-2-oxoethyl]-1,2,3-triazol-4-yl}-
methyl)piperazine (8b) were obtained similarly to 6a—d from
azidoacetamide 2a,b (0.2 mmol) and 1,4-dipropenylpiperazine 5
(0.1 mmol).
N,N´-{[1,1´-(Ethane-1,2-diyl)bis(1H-1,2,3-triazole-4,1-di-
yl)]bis(methylene)}bis(adamantan-1-amine) (10a) and N,N´-
{[1,1´-(butane-1,2-diyl)bis(1H-1,2,3-triazole-4,1-diyl)]bis(me-
thylene)}bis(adamantan-1-amine) (10b) were obtained similarly
to 6a—d from N-propenylaminoadamantane 3a (0.2 mmol) and
diazidoalkanes 9 (0.1 mmol).
Yields, melting points, elemental analysis data, and spectral
characteristics of compounds 2a,b, 3a,b, 4a,b, 6a—d, 7a—d, 8a,b,
and 10a,b are given in Tables 1 and 2.
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This work was financially supported by the Russian
Science Foundation (Project No. 14-23-00160-P: synthe-
sis of conjugates 6a—d, 7a—d, 8a,b, and 10a,b) and within
the State Assignment for 2018 (Theme No. 0090-2017-
0023: synthesis of compounds 2a,b, 3a,b, and 4a,b).
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References
Received April 20, 2018;
in revised form May 29, 2018;
accepted May 31, 2018
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