New method for the synthesis of 1,2,8-triazaspiro[4.5]decane derivatives

Full text of DOI:10.1007/s10593-008-0150-1

Chemistry of Heterocyclic Compounds, Vol. 44, No. 8, 2008
NEW METHOD FOR THE SYNTHESIS
OF 1,2,8-TRIAZASPIRO[4.5]DECANE
DERIVATIVES
V. A. Kovtunenko, L. M. Potikha, A. A. Mishchuk, and A. V. Turov
Keywords: ethyl isonicotinoyl acetate, 1,2,8-triazaspiro[4.5]decane, azo coupling, spirocyclization.
Only one method has been reported for the synthesis of 1,2,8-triazaspiro[4.5]decane derivatives based
on the reaction of esters of 2-(4-piperidinylidene)acetic acid with alkylhydrazines, leading to compounds with
high biological activity [1, 2]. Naito and Ninomiya [3] have reported that some N-alkylisonicotinoyl derivatives
can form spirocondensed systems in the presence of bases. We have found that the reaction of 4-[(Z)-
3-ethoxycarbonyl-1-hydroxy-1-propenyl]-1-methylpyridinium iodide (1) with aryldiazonium salts and
subsequent treatment of the reaction mixture with base leads to ethyl 1-aryl-8-methyl-4-oxo-1,2,8-triazaspiro-
[4.5]deca-2,6,9-triene-3-carboxylates 2a-c.
_
OH
O
I
CO2Et
CO2Et
–
+
ArN2 Cl
_
I
+
+
N
N
N
Me
Me
ArNH
NaOH
1
O
CO2Et
Me
N
N
N
2a–c
Ar
a Ar = C6H5, b Ar = 4-FC6H4, c Ar = 4-ClC6H4
Formation of a spiro system is indicated, in particular, by the signal for the spiro atom C(5) at
1
76.5-76.7 ppm and the pattern for the H NMR spectrum, which is characteristic for 1,4-dihydropyridines [3].
NOESY spectra and heteronuclear 1H13C correlation spectra (HMQC and HMBC), which were taken in addition
1
to H and 13C NMR spectra, prove the structure of compound 2. The experimental results are given in Table 1.
The assignments made for the signals are shown in the scheme for compound 2a; the HMBC and NOESY
correlations, serving as the basis of these assignments, are indicated by arrows.
__________________________________________________________________________________________
Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: potikha l@mail.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1263-1265, August, 2008. Original article
submitted May 22, 2008.
0009-3122/08/4408-1019©2008 Springer Science+Business Media, Inc.
1019

NOE
CO2Et
O
4.42
199.2
NOE
6.45
129.1
95.9
6
76.5
N
2
8
N
5
41.6
N
1
H C
3.22
3
135.3
4.42
Ph
6.45
2a
TABLE 1. 1H13C Correlations for Compounds 2a and 2b
2a
2b
Signal 1Н,
δ, ppm
Signal 1Н,
δ, ppm
HMBC
HMBC
7.51
7.33
7.18
6.45
140.3, 125.8, 118.6
140.3, 129.1
7.47
7.03
6.47
4.41
161.9, 159.5, 136.7, 120.5
161.9, 159.5, 136.7, 116.0
135.5, 95.7, 76.7, 41.6
118.6
135.3, 95.9, 76.5, 41.6
199.0, 161.9, 135.5, 95.7, 76.7,
14.6
4.42
3.22
1.41
199.2, 162.0, 95.9, 76.5, 14.6
3.22
1.40
135.5, 95.7
61.3
135.3, 95.9
61.3
1
The IR spectra were taken on a Pye-Unicam SP3-300 spectrometer with KBr plates. The H and
13C NMR spectra were taken on a Varian Mercury 400 spectrometer at 400 and 100 MHz, respectively, in
CDCl3 using TMS as the internal standard. 4-[(Z)-3-ethoxycarbonyl-1-hydroxy-1-propenyl]-1-methylpyridinium
iodide was prepared according to Bunting and Kanter [4].
Ethyl 1-Aryl-8-methyl-4-oxo-1,2,8-triazaspiro[4.5]deca-2,6,9-triene-3-carboxylates 2a-c. Aniline
(3 mmol) and 21% aq. sodium nitrite (1 ml) were added with stirring to 2 N hydrochloric acid (5 ml) cooled to
0°C. The mixture was maintained for 30 min and, then, sodium acetate (1.3 g) and ethyl N-methylisonicotinoyl
acetate 1 (1 g, 3 mmol) were added. The mixture was stirred for 2 h at room temperature and 10% aq. sodium
hydroxide was added to bring the pH to 9. The crystalline precipitate formed was filtered off and washed with
ethanol.
Ethyl Ester 2a was obtained in 54% yield (0.5 g); mp 199-201°C (ethyl acetate). IR spectrum, ν, cm-1:
1
1735 (C=O), 1685 (C=N), 1450, 1335 (C–O), 1155 (C–O), 1098, 755, 658. H NMR spectrum, δ, ppm (J, Hz):
3
3
3
7.51 (2H, d, J = 8.0, H-2', H-6'); 7.33 (2H, t, J = 8.0, H-3', H-5'); 7.18 (1H, t, J = 8.0, H-4'); 6.45 (2H, d,
3J = 7.6, H-7, H-9); 4.42 (4H, m, CH2CH3, H-6, H-10); 3.22 (3H, s, N–CH3); 1.41 (3H, t, J = 7.0, CH2CH3).
3
13C NMR spectrum, δ, ppm: 199.2 (C-4); 162.0 (CO2Et); 140.3 (C-1'); 135.3 (C-7, C-9); 129.1 (C-3, C-3', C-5');
125.8 (C-4'); 118.6 (C-2', C-6'); 95.9 (C-6, C-10); 76.5 (C-5); 61.3 (CH2); 41.6 (N–CH3); 14.6 (C–CH3). Found,
%: C 65.51; H 5.45; N 13.52. C17H17N3O3. Calculated, %: C, 65.58; H 5.50; N 13.50.
Ethyl Ester 2b was obtained in 66% yield (0.65 g); mp 215-217°C (ethanol). IR spectrum, ν, cm-1: 1738
1
(C=O), 1685 (C=N), 1458, 1331 (C–O), 1231 (C–F), 1155 (C–O), 1098, 910, 840. H NMR spectrum, δ, ppm
3
(J, Hz): 7.47 (2H, m, H-2', H-6'); 7.03 (2H, m, H-3', H-5'); 6.47 (2H, d, J = 7.6, H-7, H-9); 4.41 (4H, m,
CH2Me, H-6, H-10); 3.22 (3H, s, N–CH3); 1.40 (3H, t, J = 7.0, CH2CH3). 13C NMR spectrum, δ, ppm: 199.0
3
(C-4); 161.9 (CO2Et); 159.5 (C-4'); 136.7 (C-1'); 135.5 (C-7, C-9); 129.3 (C-3); 120.5 (C-2', C-6'); 116.1 (C-3',
C-5'); 95.7 (C-6, C-10); 76.7 (C-5); 61.3 (CH2); 41.6 (N–CH3); 14.6 (C–CH3). Found, %: C 61.95; H 4.83;
N 12.78. C17H16FN3O3. Calculated, %: C 62.00; H 4.90; N 12.76.
1020

Ethyl Ester 2c was obtained in 45% yield (0.47 g), mp 202-203°C (ethanol), IR spectrum, ν, cm-1: 1740
(C=O), 1685 (C=N), 1460, 1400, 1331 (C–O), 1160 (C–O), 1098, 910, 830. 1H NMR spectrum, δ, ppm (J, Hz):
7.43 (2H, d, 3J = 8.5, H-2', H-6'); 7.30 (2H, d, 3J = 8.5, H-3', H-5'); 6.40 (2H, d, 3J = 7.2, H-7, H-9); 4.42 (4H, m,
3
CH2Me); H-6, H-10); 3.23 (3H, s, N–CH3); 1.40 (3H, t, J = 7.2, CH2CH3). 13C NMR spectrum, δ, ppm: 199.0
(C-4); 161.9 (CO2Et); 138.9 (C-1'); 135.6 (C-7, C-9); 131.2 (C-4'); 129.8 (C-3); 129.3 (C-2', C-6'); 119.7 (C-3',
C-5'); 95.7 (C-6, C-10); 76.5 (C-5); 61.5 (CH2); 41.7 (N–CH3); 14.7 (C-CH3). Found, %: Cl 10.28; N 12.16.
C17H16ClN3O3. Calculated, %: Cl 10.25; N 12.15.
REFERENCES
1.
2.
S. Tsukamoto, H. Nagaoka, S. Igarashi, F. Wanibuchi, K. Hidaka, and T. Tamura, Chem. Pharm.
Bull., 43, 1523 (1995).
P. W. Smith, A. W. J. Anthony, R. Bell, I. J. M. Beresford, P. M. Gore, A. B. McElroy,
J. M. Pritchard, V. Saez, N. R. Taylor, R. L. Sheldrick, and P. Ward, J. Med. Chem., 38, 3772
(1995).
3.
4.
T. Naito and I. Ninomiya, Heterocycles, 15, 735 (1981).
J. W. Bunting and J. P. Kanter, J. Am. Chem. Soc., 115, 11705 (1993).
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