Interaction of 5-methoxy-4-azatricyclo[4.3.1.13,8]-undec-4-ene with nitrogen-containing nucleophiles

Article abstract of DOI:10.1007/s10593-013-1166-8

The interaction of 5-methoxy-4-azatricyclo[4.3.1.1^3,8]undec-4- ene with acid hydrazides has been studied. It has been established that its reaction with methoxycarbonylhydrazine leads to the formation of 6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocin-3-one. Special features of the alkylation of this substrate under various conditions have been studied.

Full text of DOI:10.1007/s10593-013-1166-8

Chemistry of Heterocyclic Compounds, Vol. 48, No. 10, January, 2013 (Russian Original Vol. 48, No. 10, October, 2012)
INTERACTION OF 5-METHOXY-4-AZATRICYCLO[4.3.1.13,8]-
UNDEC-4-ENE WITH NITROGEN-CONTAINING NUCLEOPHILES
E. A. Knyazeva1*, M. Yu. Skomorokhov1, D. V. Osipov1, and Yu. N. Klimochkin1
The interaction of 5-methoxy-4-azatricyclo[4.3.1.13,8]undec-4-ene with acid hydrazides has been
studied. It has been established that its reaction with methoxycarbonylhydrazine leads to the formation
of 6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocin-3-one. Special features
of the alkylation of this substrate under various conditions have been studied.
Keywords: 6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocin-3-one, lactim
ethers, 5-methoxy-4-azatricyclo-[4.3.1.13,8]undec-4-ene, N-methyl lactam, N- and O-alkylation.
The introduction of an adamantane nucleus into compounds possessing marked physiological action
frequently leads to an increase in their biological activity, which is caused by the high lipophilicity of the
adamantane fragment [1, 2]. In particular, certain compounds in the 4-azahomoadamantane series display
antiviral, anti-inflammatory, and antihypertensive action [3-6].
We have chosen 5-methoxy-4-azatricyclo[4.3.1.13,8]undec-4-ene (1), obtained by a modified procedure
[3] from 4-azatricyclo[4.3.1.13,8]undecan-5-one, as the starting material for obtaining heterocyclic systems based
on 4-azahomoadamantane.
It is worth noting that on storage at room temperature or on heating for 3 h the lactim ether 1 undergoes
rearrangement into the N-methyl lactam 2.
O Me
N
O
O
Me2SO4
90°C
25°C, 30 days
N Me
NH
or PhMe, 110°C, 3 h
2
1
H
N
H
N
N
N
N
R
O
MeOH
room temp.
1 day
R
R
1
+
N
O
N
H
NH2
A
3a–d
3 a R = H, b R = Me, c R = 4-BrC6H4, d R = 4-F3CC6H4
_______
*To whom correspondence should be addressed, e-mail: katerina_knyazev@mail.ru.
1Samara State Technological University, 244 Molodogvardeiskaya St., Samara 443100, Russia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1629-1633, October, 2012.
Original article submitted December 31, 2011.
0009-3122/13/4810-1517©2013 Springer Science+Business Media New York
1517

In the continuation of our investigations on lactim ether 1 interaction with acid hydrazides [7], we have
extended the range of condensed triazoles 3a-d obtained. As expected, this reaction proceeds without the
possibility of isolating the amidrazone A formed as an intermediate and leads directly to triazoles 3a-d.
Reaction of the lactim ether 1 with methoxycarbonylhydrazine in refluxing ethanol leads to the
triazolone 4.
H
N
N
O
EtOH
OMe
1
+
N
O
h
H2N
N
H
4
Compound 4 acts as an ambiphilic agent with soft and hard nucleophilic centers. On using certain
methylating agents under various conditions, we have shown the possibility of obtaining products of both O-and
of N-methylation.
The interaction of triazolone 4 with methyl iodide proceeds at the soft nucleophilic center and leads
unambiguously to the N-substituted compound 5a, which is probably the product of thermodynamic control. At
the same time, the reaction of triazolone 4 with dimethyl sulfate enables methoxytriazole 6 to be obtained.
Me
N
N
N
N
N
Me2SO4
90°C
MeI, K2CO3
4
N
OMe
DMF, room temp.
O
6
5a
In the IR spectra of both compounds intense absorption bands were observed at 2840-2930 cm-1,
indicating the presence of C–H bonds. Compound 5a is characterized by stretching vibration bands of C=N and
C=O bonds at 1684 and 1697 cm-1, while for compound 6 only the stretching vibrations of the aromatic system
1
at 1531 and 1666 cm-1 were characteristic. In the H NMR spectrum of the N-methyl lactam 5a, methyl group
proton signals were displayed at 3.37 ppm, while in the O-methyl derivative 6 at 3.62 ppm. The signal of the
carbonyl carbon atom in compound 5a was observed at 152.9 ppm, while the signal of the carbon atom linked to
the methoxy group in compound 6 is at 148.2 ppm.
When using other alkylating agents in the presence of calcined potassium carbonate, N-alkylation of
triazolone 4 occurs leading to N-substituted triazolones 5b,c.
It is necessary to mention that alkylation of triazolone 4 using 1-bromoadamantane did not permit the
preparation of N-adamantyl-substituted triazolone 5d. Introduction of a 1-adamantyl fragment into triazolone 4
was successfully carried out only by using 1-adamantanol in concentrated H2SO4.
OH
R
O
Ad
O
N
N
N
N
N
RCl, K2CO3
4
N
H2SO4
DMF, room temp.
5d
5b,c
5 b R = Bn, с R = 4-F3CC6H4CH2
1518

EXPERIMENTAL
The IR spectra were recorded on a Shimadzu FTIR-8400S spectrometer in KBr pellets. The 1H and 13C
NMR spectra were recorded on a JEOL JNM-ECX400 spectrometer (at 400 and 100 MHz, respectively) in
CDCl3, internal standard was TMS. Mass spectra were obtained on a Finnigan Trace DSQ instrument, energy of
ionizing electrons 70 eV. Elemental analysis was carried out on an automatic Euro Vector EA3000 CHNS
analyzer. Melting points of the obtained compounds were determined by the capillary method on a PTP-M
instrument.
5-Methoxy-4-azatricyclo[4.3.1.13,8]undec-4-ene (1). A mixture of 4-azatricyclo[4.3.1.13,8]undecan-
5-one (24.15 g, 0.146 mol) and dimethyl sulfate (18.44 g, 13.8 ml, 0.146 mol) was stirred for 6 h at 90oC. After
cooling, the mixture was neutralized with a solution of Na2CO3 (15.50 g) in water (30 ml) until weakly alkaline,
and extracted three times with CHCl3. The organic layers were combined, dried over Na2SO4, and the solvent
was distilled off in vacuum. Yield 23.00 g (89%). Pale-yellow oil, nD 1.6383. IR spectrum, ν, cm-1: 2912,
20
2847 (C–Haliph), 1682 (C=N), 1439, 1362, 1234, 1180, 756. 1H NMR, δ, ppm: 1.34-2.12 (12H, m, 5CH2, 2CH);
2.83-2.85 (1H, m, 6-CH); 3.64-3.66 (1H, m, 3-CH); 3.83 (3H, s, OCH3). Mass spectrum, m/z (Irel, %): 179 [M]+
(100), 164 [M-CH3]+ (53), 148 [M-OCH3]+ (24), 136 (25), 122 [M-NCOCH3]+ (23). Found, %: C 73.61; H 9.48;
N 7.93. C11H17NO. Calculated, %: C 73.70; H 9.56; N 7.81.
N-Methyl-4-azatricyclo[4.3.1.13,8]undecan-5-one (2).
A
solution of 5-methoxy-4-azatricyclo-
[4.3.1.13,8]undec-4-ene (1) (12.0 g, 0.067 mol) in PhMe (40 ml) was refluxed for 3 h. After the end of the
reaction, the solvent was distilled off in vacuum. Yield 11.8 g (98%). Colorless oil, nD20 1.6380. IR spectrum, ν,
1
cm-1: 2916, 2851 (C–Haliph), 1632 (C=O), 1442, 1211, 756. H NMR spectrum, δ, ppm: 1.55-2.18 (12H, m,
5CH2, 2CH); 2.75-2.76 (1H, m, 6-CH); 2.89 (3H, s, NCH3); 3.27-3.28 (1H, m, 3-CH). Mass spectrum, m/z (Irel,
%): 179 [M]+ (100), 164 [M-CH3]+ (18), 151 [M-CO]+ (17), 123 [M-CONCH3]+ (31). Found, %: C 73.64;
H 9.51; N 7.88. C11H17NO. Calculated, %: C 73.70; H 9.56; N 7.81.
6,7,8,9,10,11-Hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocines
3a-d
(General
Method). A mixture of compound 1 (1.00 g, 5.6 mmol) and the hydrazide of the correspoding acid (5.7 mmol)
in MeOH (6 ml) was maintained at room temperature for 1 day. The precipitated solid was filtered off, dried,
and recrystallized.
6,7,8,9,10,11-Hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocine (3a). Yield 0.30 g
(19%). Colorless crystals, mp 66-69oC (PhMe). IR spectrum, , cm-1: 2916, 2851 (C–Haliph), 1632, 1512, 1442,
1
1389, 1192. H NMR spectrum, δ, ppm: 1.75-2.25 (12H, m, 5CH2, 2CH); 3.55-3.56 (1H, m, CH–C=N); 4.36-
4.37 (1H, m, N=C–N–CH); 7.95 (1H, s, H-3). 13C NMR spectrum, δ, ppm: 26.6; 27.0; 29.6; 30.7; 32.6; 34.6;
35.2; 36.5; 50.0; 142.5; 160.5. Mass spectrum, m/z (Irel, %): 189 [M]+ (100), 161 [M-N2]+ (7), 148 [M-H-CN2]+
(10). Found, %: C 69.90; H 7.91; N 22.19. C11H15N3. Calculated, %: C 69.81; H 7.99; N 22.20.
3-Methyl-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocine (3b). Yield
0.97 g (40%). Colorless crystals, mp 166-169oC (PhMe). IR spectrum, , cm-1: 2928, 2854 (C–Haliph), 1623,
1
1531, 1439, 1392. H NMR spectrum, δ, ppm: 1.78-2.22 (12H, m, 5CH2, 2CH); 2.39 (3H, s, CH3); 3.48-3.50
(1H, m, CH–C=N); 4.23-4.25 (1H, m, N=C–N–CH). Mass spectrum, m/z (Irel, %): 203 [M]+ (100), 175 [M-N2]+
(7), 160 [M-N2-CH3]+ (11). Found, %: C 70.82; H 8.49; N 20.69. C12H17N3. Calculated, %: C 70.90; H 8.43;
N 20.67.
3-(4-Bromophenyl)-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocine
(3c). Yield 1.25 g (65%). White crystals, mp 254-256oC (o-xylene). IR spectrum, , cm-1: 2912, 2847 (C–Haliph),
1
1593, 1512, 1470, 1443, 848. H NMR spectrum, δ, ppm (J, Hz): 1.80-2.26 (12H, m, 5CH2, 2CH); 3.61-3.63
(1H, m, CH–C=N); 4.41-4.42 (1H, m, N=C–N–CH); 7.39 (2H, d, J = 12.1, H-3',5'); 7.63 (2H, d, J = 12.1,
H-2',6'). Mass spectrum, m/z (Irel, %): 344 (100); 265 [M-Br]+ (14), 252 (34). Found, %: C 59.43; H 5.35;
N 12.28. C17H18BrN3. Calculated, %: C 59.31; H 5.27; N 12.21.
3-(4-Trifluoromethylphenyl)-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azo-
cine (3d). Yield 0.56 g (30%). White crystals, mp 263-265oC (o-xylene). IR spectrum, , cm-1: 2923, 2854
1519

1
(C–Haliph), 1620, 1477, 1450, 1326, 1165, 1111, 852. H NMR spectrum, δ, ppm (J, Hz): 1.80-2.30 (12H, m,
5CH2, 2CH); 3.61-3.63 (1H, m, CH–C=N); 4.42-4.44 (1H, m, N=C–N–CH); 7.62 (2H, d, J = 11.8, H-3',5'); 7.65
(2H, d, J = 11.8, H-2',6'). Mass spectrum, m/z (Irel, %): 333 [M]+ (100), 240 (56), 252 (34). Found, %: C 64.79;
H 5.53; N 12.64. C18H18F3N3. Calculated, %: C 64.86; H 5.44; N 12.61.
6,7,8,9,10,11-Hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocin-3-one (4). A mixture of
compound 1 (6.4 g, 0.036 mol) and methoxycarbonylhydrazine (3.2 g, 0.036 mol) in EtOH (20 ml) was refluxed
for 3 h. The solvent was distilled off in vacuum, and the residue was crystallized from PhMe. Yield 4.1 g (56%).
Colorless crystals, mp 238-240oC. IR spectrum, , cm-1: 3167 (NH), 2928, 2851 (C–Haliph), 1701 (C=O), 1674,
1
1585, 1381, 748. H NMR spectrum, δ, ppm: 1.76-2.15 (12H, m, 5CH2, 2CH); 3.01-3.03 (1H, m, CH–C=N);
4.39-4.41 (1H, m, N=C–N–CH); 10.22 (1H, s, NH). 13C NMR spectrum, δ, ppm: 27.1; 31.1; 33.2; 34.6; 35.1;
45.3; 154.8; 154.9. Mass spectrum, m/z (Irel, %): 205 [M]+ (100), 190 [M-NH]+ (6), 177 [M-CO]+ (8). Found, %:
C 64.40; H 7.15; N 20.32. C11H15N3O. Calculated, %: 64.37; H 7.37; N 20.47.
N-Methyl-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocin-3-one (5a).
MeI (0.15 ml, 2.4 mmol) was added to a mixture of compound 4 (0.50 g, 2.4 mmol) and calcined K2CO3
(0.67 g, 4.9 mmol) in DMF (5 ml) and stirred for 3 h at room temperature. The reaction mixture was poured into
water, and twice extracted with EtOAc. The organic layers were combined, dried over Na2SO4, and the solvent
distilled off in vacuum. The residue was crystallized from PhMe. Yield 0.16 g (30%). Colorless crystals, mp
1
92-94oC. IR spectrum, ν, cm-1: 2927, 2847 (C–Haliph), 1697 (C=O), 1684 (C=N), 1578, 1477, 1381. H NMR
spectrum, δ, ppm: 1.71-2.15 (12H, m, 5CH2, 2CH); 2.94-2.97 (1H, m, CH–C=N); 3.37 (3H, s, CH3); 4.37-4.39
(1H, m, N=C–N–CH). 13C NMR spectrum, δ, ppm: 27.1; 31.2; 32.1; 33.3; 34.7; 35.1; 45.8; 152.9; 153.0. Mass
spectrum, m/z (Irel, %): 219 [M]+ (100), 204 [M-CH3]+ (6), 176 [M-CH3-CO]+ (12), 140 (26), 79 (42). Found, %:
C 65.90; H 7.19; N 19.12. C12H17N3O. Calculated, %: C 65.73; H 7.81; N 19.16.
N-Benzyl-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocin-3-one (5b)
was obtained analogously to compound 5a using benzyl chloride as alkylating agent. Yield 0.35 g (49%).
Colorless crystals, mp 84-86oC (PhMe). IR spectrum, , cm-1: 2927, 2858 (C–Haliph), 1712 (C=O), 1693, 1578,
1
1466, 1396, 721. H NMR spectrum, δ, ppm: 1.75-2.16 (12H, m, 5CH2, 2CH); 2.94-3.00 (1H, m, CH–C=N);
4.42-4.44 (1H, m, N=C–N–CH); 4.88 (2H, s, CH2Ph); 7.25-7.33 (5H, m, H Ph). 13C NMR spectrum, δ, ppm:
27.1; 31.2; 33.3; 34.7; 35.2; 45.9; 49.0; 127.7; 128.2; 128.7; 136.8; 153.0; 153.2. Mass spectrum, m/z (Irel, %):
295 [M]+ (48), 218 [M-C6H5]+ (36), 148 (12), 91 (100), 79 (18). Found, %: C 73.30; H 7.06; N 14.12.
C18H21N3O. Calculated, %: C 73.19; H 7.17; N 14.23.
N-(4-Trifluoromethylbenzyl)-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azo-
cin-3-one (5c) was obtained analogously to compound 5a, using 4-trifluoromethylbenzyl chloride as alkylating
agent. Yield 0.48 g (27%). Light-yellow crystals, mp 157-158oC (PhMe). IR spectrum, , cm-1: 2923, 2854 (C–
1
H
aliph), 1705 (C=O), 1697, 1585, 1327, 1119. H NMR spectrum, δ, ppm (J, Hz): 1.74-2.16 (12H, m, 5CH2,
2CH); 2.97-3.00 (1H, m, CH–C=N); 4.42-4.44 (1H, m, N=C–N-CH); 4.93 (2H, s, CH2Ar); 7.43 (2H, d, J = 8.0,
H-3',5'); 7.57 (2H, d, J = 8.0, H-2',6'). 13C NMR spectrum, δ, ppm: 27.0; 31.2; 33.2; 34.6; 35.2; 46.0; 48.5;
125.7; 125.8; 128.4; 130.2; 140.7; 153.0; 153.7. Mass spectrum, m/z (Irel, %): 363 [M]+ (100), 344 [M-F]+ (12),
218 [M-C6H5-CF3]+ (48), 159 (52). Found, %: C 62.90; H 5.39; N 11.42. C19H20F3N3O. Calculated, %: C 62.80;
H 5.55; N 11.56.
N-(1-Adamantyl)-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocin-3-one
(5d). Adamantan-1-ol (0.5 g, 3.3 mmol) was dissolved with stirring in conc. H2SO4 (3 ml) and compound 4
(0.67 g. 3.3 mmol) was added. The mixture was heated at 60oC for 1 h. The reaction mixture was poured into
water, the precipitated solid was filtered off and recrystallized from toluene. Yield 0.60 g (54%). Colorless
crystals, mp > 340oC (decomp.). IR spectrum, , cm-1: 2908, 2851 (C–Haliph), 1690 (C=O), 1589, 1477, 1358.
1H NMR spectrum, δ, ppm: 1.66-2.27 (27H, m, 11CH2, 5CH); 2.98-3.02 (1H, m, CH–C=N); 4.36-4.40 (1H, m,
N=C–N–CH). 13C NMR spectrum, δ, ppm: 27.1; 27.5; 29.6; 31.2; 33.4; 34.8; 35.2; 36.3; 40.4; 45.0; 47.1;
151.7; 152.1. Mass spectrum, m/z (Irel, %): 339 [M]+ (66), 282 (42), 135 [Ad]+ [100]. Found, %: C 74.43;
H 8.39; N 12.22. C21H29N3O. Calculated, %: C 74.30; H 8.61; N 12.38.
1520

3-Methoxy-6,7,8,9,10,11-hexahydro-5H-5,9:7,11-dimethano[1,2,4]triazolo[4,3-a]azocine (6).
A
mixture of compound 4 (0.5 g, 2.4 mmol) and dimethyl sulfate (0.23 ml, 0.3 g, 2.4 mmol) was stirred at 90oC
for 5 h, then cooled to room temperature and dissolved in CHCl3 (5 ml). The obtained solution was added
slowly to a saturated NaHCO3 solution (20 ml). After the end of gas evolution, the organic layer was separated,
and the aqueous layer was extracted twice with CHCl3. The organic layers were combined, dried over Na2SO4,
and the solvent distilled off in vacuum. Yield 0.19 g (36%). Colorless crystals, mp 326-328oC (CHCl3). IR
1
spectrum, ν, cm-1: 2904, 2847 (C–Haliph), 1666 (C=N), 1597, 1531, 752, 675. H NMR spectrum, δ, ppm: 1.76-
2.19 (12H, m, 5CH2, 2CH); 3.20-3.23 (1H, m, CH–C=N); 3.62 (3H, s, CH3); 4.64-4.66 (1H, m, N–CH).
13C NMR spectrum, δ, ppm: 26.8; 28.0; 32.1; 34.2; 34.3; 35.8; 45.5; 148.2; 158.9. Mass spectrum, m/z (Irel, %):
219 [M]+ (1), 205 (100). Found, %: C 65.90; H 7.49; N 19.12. C12H17N3O. Calculated, %: C 65.73; H 7.81;
N 19.16.
The work was carried out with the financial support of the Ministry of Education and Science of the
Russian Federation with the use of the scientific equipment of the Collective Use Center of the Samara State
Technological University "Investigation of the Physicochemical Properties of Substances and Materials".
REFERENCES
1.
N. Tsuzuki, T. Hama, M. Kawada, A. Hasui, R. Konoshi, S. Shiwa, Y. Ochi, S. Futaki, and
K. Kitagawa, J. Pharm. Sci., 83, 481 (1994).
2.
3.
4.
5.
N. Lomadze and H.-J. Schneider, Tetrahedron Lett., 43, 4403 (2002).
V. G. Keizer and J. G. Korsloot, J. Med. Chem., 14, 411 (1971).
K. V. Bolshakov, D. B. Tikhonov, V. E. Gmiro, and L. G. Magazanik, Neurosci. Lett., 291, 101 (2000).
G. Zoidis, I. Papanastasiou, I. Dotsikas, A. Sandoval, R. G. Dos Santos, Z. Papadopoulou-Daifoti,
A. Vamvakides, N. Kolocouris, and R. Felix, Bioorg. Med. Chem., 13, 2791 (2005).
Z. Kazimierczuk, A. Gorska, T. Switaj, and W. Lasek, Bioorg. Med. Chem. Lett., 11, 1197 (2001).
E. A. Knyazeva, M. Yu. Skomorokhov, and Yu. N. Klimochkin, Khim. Geterotsikl. Soedin., 1731
(2010). [Chem. Heterocycl. Compd., 46, 1407 (2010).]
6.
7.
1521