Synthesis and conversions of polyhedral compounds. 30*. Synthesis of 2-substituted 6-amino-5,7-dimethyl-1,3-diazaadamantanes

Article abstract of DOI:10.1007/s10593-013-1191-7

A method has been developed for the synthesis of 6-amino-5,7-dimethyl-1,3- diazaadamantanes containing various aliphatic, aromatic, and heterocyclic groups in position 2.

Full text of DOI:10.1007/s10593-013-1191-7

Chemistry of Heterocyclic Compounds, Vol. 48, No. 11, February, 2013 (Russian Original Vol. 48, No. 11, November, 2012)
SYNTHESIS AND CONVERSIONS OF POLYHEDRAL
COMPOUNDS. 30*. SYNTHESIS OF 2-SUBSTITUTED
6-AMINO-5,7-DIMETHYL-1,3-DIAZAADAMANTANES
G. L. Harutyunyan1*, K. A. Gevorkyan1, A. D. Harutyunyan1,
S. P. Gasparyan1, and S. S. Mamyan2
A method has been developed for the synthesis of 6-amino-5,7-dimethyl-1,3-diazaadamantanes
containing various aliphatic, aromatic, and heterocyclic groups in position 2.
Keywords: adamantane, 6-amino-1,3-diazaadamantane, 1,3-diazaadamantane, 3,7-diazabicyclo-
[3.3.1]nonane, oxime, condensation.
Amino derivatives of adamantane (amantadine, rimantadine, gludantan, memantine, etc.) have been known
for a fairly long time, and are widely used in medical practice [2]. Of the amino derivatives of 1,3-diazaadamantane,
only 6-amino-5,7-dimethyl-1,3-diazaadamantane is known, possessing psychotropic activity [3, 4].
Investigation of the biological activity of 2-substituted 1,3-diazaadamantane derivatives, previously
synthesized by us, revealed significant antitumor, psychotropic, antibacterial, and antioxidant action of some of
them. With the aim of further search for biologically active compounds in the 1,3-diazaadamantane series, a method
was developed by us for the synthesis of 2-substituted 6-amino-5,7-dimethyl-1,3-diazaadamantanes.
2-Substituted 6-oxo- and 6-hydroxy-1,3-diazaadamantanes may be synthesized by the condensation of
9-oxo- and 9-hydroxy-3,7-diazabicyclo[3.3.1]nonanes with various aldehydes and ketones [5]. However, it is not
possible to obtain 2-substituted 6-amino-1,3-diazaadamantanes by this method, since the amino group of 9-amino-
3,7-diazabicyclo[3,3.1]nonane (the necessary starting compound for the synthesis of 2-substituted 6-amino-
1,3-diazaadamantanes) also interacts with aldehydes and ketones. Consequently, we chose the 1,5-dimethyl-
3,7-diaza-bicyclo[3.3.1]nonan-9-one oxime (2) as the starting material, which was synthesized by the condensation
of oxime 1 with various aldehydes and ketones led to the corresponding oximes of 2-substituted
1,3-diazaadamantanes 3a-j. 6-Amino-1,3-diazaadamantanes 4a-j were obtained by the reduction of the latter with
LiAlH4.
_______
*For Communication 29, see [1].
**To whom correspondence should be addressed, e-mail: gayane_dam@mail.ru.
1A. L. Mndzhoyan Institute of Fine Organic Chemistry, the Scientific Technological Center of Organic and
Pharmaceutical Chemistry, National Academy of Sciences of the Republic of Armenia, 26 Azatutyan Ave.,
Yerevan 0014, Armenia; e-mail: mamyan@msrc.am.
2Molecular Structure Research Center of the Scientific Technological Center of Organic and Pharmaceutical
Chemistry, National Academy of Sciences of the Republic of Armenia, 26 Azatutyan Ave., Yerevan 0014,
Armenia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1786-1791, November, 2012.
Original article submitted July 22, 2011.
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0009-3122/13/4811-1670©2013 Springer Science+Business Media New York

Me
Me
Me
Me
H2NOH·HCl
NaOH, H2O
O
HON
Me
HON
Me
H2N
Me
RCOR1
LiAlH4
Me
NH
NH
N
N
N
N
NH
2
NH
1
R1
R1
R
R
4a–j
3a–j
3, 4 a R = R1 = Me; b R+R1 = (CH2)5; c–j R = H, c R1 = Ph, d R1 = 2-furyl, е R1 = 2-thienyl,
f R1 = 4-MeOC6H4, g R1 = 4-(i-Pr)C6H4, h R1 = piperonyl, i R1 = 1-naphthyl, j R1 = 1-methylindol-3-yl
TABLE 1. Physicochemical Characteristics of Compounds 3a-j, 4a-j
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Rf (eluent) Yield, %
C
H
N
C12H21N3O
C15H25N3O
C16H21N3O
64.71
64.54
68.23
68.40
71.03
70.82
9.30
9.48
9.71
9.57
7.90
7.80
18.67
18.82
16.07
15.95
15.71
15.48
270-271
(subl.)
210-211
0.35 (A)
0.54 (A)
0.78 (A)
87
92
86
3a
3b
3c
195-196
C14H19N3O2
64.20
64.35
7.08
7.33
15.88
16.08
212-213
0.72 (A)
89
3d
C14H19N3OS*
C17H23N3O2
60.47
60.62
67.48
67.75
7.10
6.90
7.44
7.69
14.92
15.15
13.69
13.94
257-258
(subl.)
260-261
0.27 (B)
0.76 (A)
77
91
3e
3f
C19H27N3O
72.58
72.81
8.87
8.68
13.14
13.41
201-202
0.80 (A)
74
3g
C17H21N3O3
C20H23N3O
C19H24N4O
C12H23N3
64.39
64.74
74.76
74.74
70.65
70.34
68.61
68.85
72.37
72.24
75.02
74.67
68.10
67.98
63.68
63.84
70.79
71.05
76.51
76.21
67.62
67.75
78.01
78.14
6.37
6.71
7.02
7.21
7.25
7.46
10.87
11.07
10.60
10.91
8.76
9.01
8.35
8.56
7.98
8.04
8.66
8.77
9.58
9.76
7.44
7.69
8.43
8.20
13.00
13.32
12.79
13.07
17.37
17.27
20.21
20.07
16.90
16.85
16.60
16.33
17.21
16.99
16.11
15.95
14.52
14.62
13.95
14.03
13.95
13.94
13.81
13.67
260-261
(subl.)
0.73 (A)
0.78 (A)
0.69 (A)
0.24 (A)
0.33 (B)
0.27 (A)
0.33 (A)
0.30 (A)
0.29 (A)
0.21 (A)
0.34 (A)
0.28 (A)
0.38 (B)
67
86
56
55
73
75
72
61
67
72
69
57
61
3h
3i
218-219
257-258
76-77
3j
4а
4b
4c
4d
4e
4f
C15H27N3
85-86
C16H23N3
103-104
77-78
C14H21N3O
C14H21N3S*2
C17H25N3O
C19H29N3
132-133
94-95
92-94
4g
4h
4i
C17H23N3O2
C20H25N3
145-146
95-96
C19H26N4
73.26
73.51
8.60
8.44
18.23
18.05
153-154
4j
_______
*Found, %: S 11.33. Calculated, %: S 11.56.
*2Found, %: S 11.93. Calculated, %: S 12.17.
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TABLE 3. Mass Spectra of the Synthesized Compounds 4b-f,h-j
Com-
pound
m/z (Irel,%)
4b
249 [M]+ (11), 248 [M-H]+ (51), 189 (11), 151 (27), 149 (12), 125 (15), 124 (100),
123 (15), 122 (16), 110 (17), 109 (31), 107 (12), 97 (14), 96 (12), 80 (12), 69 (43)
258 [M+H]+ (20), 257 [M]+ (100), 241 [M-NH2]+ (7), 187 (6), 160 (47), 158 (11), 144 (16),
4c
134 (13), 125 (11), 122 (11), 118 (14), 112 (18), 92 (33), 84 (14), 82 (13), 70 (63)
248 [M+H]+ (16), 247 [M]+ (100), 230 [M-H-NH2]+ (17), 202 (15), 188 (16), 187 (19),
4d
176 (20), 162 (18), 150 (23), 149 (81), 148 (18), 147 (19), 136 (18), 135 (21), 133 (22),
124 (21), 123 (22), 122 (24), 110 (34), 109 (24), 107 (34), 94 (22), 92 (20), 82 (21),
80 (29), 69 (60)
264 [M+H]+ (21), 263 [M]+ (100), 247 [M-NH2]+ (5), 165 (47), 152 (10), 149 (14),
4e
24 (23), 123 (16), 121 (12), 111 (10), 110 (27), 109 (17), 96 (24), 83 (10), 69 (46)
288 [M+H]+ (19), 287 [M]+ (100), 271 [M-NH2]+ (11), 257 (39), 217 (11), 190 (63),
4f
188 (14), 174 (19), 160 (23) 148 (19), 136 (12), 135 (19), 134 (93), 123 (19), 122 (42),
109 (13), 92 (22), 82 (17), 70 (83)
302 [M+H]+ (27), 301 [M]+ (100), 285 [M-NH2]+ (19), 257 (11), 242 (16), 231 (17), 205 (24),
4h
204 (55), 202 (22), 188 (32), 175 (14), 162 (27), 154 (36), 150 (20), 149 (25), 148 (56), 135 (16),
123 (20), 122 (19), 110 (14), 108 (18), 95 (12), 84 (16), 82 (21), 77 (19), 70 (44)
308 [M+H]+ (23), 307 [M]+ (100), 291 [M-NH2]+ (11), 210 (49), 208 (12), 194 (21),
4i
68 (19), 167 (13), 166 (12), 155 (63), 154 (13), 142 (31), 132 (13), 85 (10), 71 (59)
311 [M+H]+ (24), 310 [M]+ (100), 294 [M-NH2]+ (18), 214 (12), 213 (68), 197 (15),
4j
187 (13), 172 (17), 160 (14), 159 (23), 158 (76), 156 (13), 145 (44), 71 (30)
The obtained compounds are of interest as potential biologically active substances. The developed method
of synthesis has shown its effectiveness and is versatile for the synthesis of 2-substituted 6-amino-1,3-diazaadaman-
tanes.
The structures of the synthesized compounds were confirmed by data of elemental analysis, IR, 1H NMR,
1
and mass spectra (Tables 1-3). Doubling of all proton signals was observed in the H NMR spectra of oximes
3a-j, which indicated the presence of two stereoisomers in all compounds. In the 1H NMR spectra of 6-amino-
1,3-diazaadamantanes 4a-j there were characteristic broad singlets for amino group protons at 1.08-1.17 ppm,
and a singlet for the proton at the C-6 atom in the region of 2.38-2.56 ppm. In the mass spectra of compounds
4b-f,h-j, the peaks of the molecular ions [M]+ had maximum intensity (with the exception of compound 4b),
which indicated the stability of the molecular ions of these compounds.
A convenient and universal method has therefore been found for the synthesis of previously unavailable
2-substituted 6-amino-1,3-diazaadamantanes.
EXPERIMENTAL
1
The IR spectra were recorded on a UR-20 spectrometer in nujol. The H NMR spectra were recorded
on a Varian Mercury-300 VX instrument (300 MHz) in DMSO-D6, with TMS as internal standard. The mass
spectra were recorded on a MX-1321A instrument with direct sample injection into the ion source, the
ionization voltage was 50 eV. The progress of reactions and the purity of the obtained compounds was
monitored by TLC on Silufol UV-254 plates in the systems: n-PrOH–H2O, 7:3 (A) and n-BuOH–saturated NH3
(B). The starting ketone 1 was synthesized by the procedure of [5].
1,5-Dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one Oxime (2). H2NOH·HCl (16.0 g, 0.23 mol)
dissolved in H2O (70 ml) and NaOH (18.0 g, 0.45 mol) dissolved in H2O (40 ml) were added slowly with
stirring to a solution of compound 1 (28.5 g, 0.17 mol) in H2O (80 ml). The mixture was boiled in an open
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flask for 2 h and left overnight. The solid was filtered off, washed with a small amount of cold water, dried, and
recrystallized from EtOH. Yield 25.0 g (81%). White crystals; mp 190-191°C, Rf 0.33 (B). IR spectrum,
, cm-1: 1660 (C=N), 3180 (OH), 3340 (NH). 1H NMR spectrum, δ, ppm: 0.82 (3H, s, CH3); 1.28 (3H, s, CH3);
2.64-2.70 (2H, m), 2.81-2.90 (4H, m), and 2.98-3.04 (2H, m, 4NCH2); 2.80 (2H, br. s, NH); 9.73 (1H, s, OH).
Found, %: C 58.75; H 9.60; N 22.87. C9H17N3O. Calculated, %: C 58.99; H 9.35; N 22.93.
5,7-Dimethyl-6-oxo-1,3-diazaadamantane Oximes 3a-j (General Method). The corresponding
aldehyde or ketone (0.01 mol) was added to a solution of oxime 2 (1.83 g, 0.01 mol) in EtOH (30 ml) (for
compound 3a in acetone (30 ml)), and the mixture was refluxed for 2-3 h. The precipitate was filtered off, dried,
and recrystallized from EtOH.
6-Amino-5,7-dimethyl-1,3-diazaadamantanes 4a-j (General Method). The corresponding oxime 3a-j
(15 mmol) was added gradually to a mixture of LiAlH4 (1.5 g, 40 mmol) in abs. THF (100 ml). The mixture was
left for 30 min and then carefully heated to reflux (exothermic reaction). Refluxing was continued until
disappearance of the starting oxime (7-10 h). Water (12 ml) was added dropwise with cooling and stirring, then
the same volume of 10% NaOH solution was added, and the mixture was left overnight. The solid was filtered
off and washed with THF. The solvent was distilled off, and the residue recrystallized from hexane.
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