The Mannich reaction in the synthesis of N,S-containing heterocycles. 7. Effective one-pot synthesis of derivatives of spiro[3,5,7,11-tetraazatricyclo- [7.3.1.02,7]tridec-2-ene-13,4′-piperidine]

Article abstract of DOI:10.1007/s10593-007-0224-5

5,11-Disubstituted derivatives of 1′-isopropyl-8-thioxospiro[3,5,7, 11-tetrazatricyclo[7.3.1.0^2,7]tridec-2-ene-13,4′-piperidine]-1, 9-dicar bonitrile was obtained by the interaction of 10-amino-9-aza-3-azonia-7, 11-dicyano-3-isopropylspiro[5,5]undeca-7,10-diene-8-thiolate with 2 equiv. of a primary amine and excess of formaldehyde. An anomalous reaction product was obtained with o-toluidine - 7,9-dicyano-1′-isopropyl-3-(2-methylphenyl)-1, 2,3,4-tetrahydrospiro[pyrido[1,2-a][1,3,5]triazine-8,4′-piper idinium]-6-thiolate.

Full text of DOI:10.1007/s10593-007-0224-5

Chemistry of Heterocyclic Compounds, Vol. 43, No. 11, 2007
THE MANNICH REACTION
IN THE SYNTHESIS OF N,S-CONTAINING
HETEROCYCLES. 7*. EFFECTIVE ONE-
POT SYNTHESIS OF DERIVATIVES OF
SPIRO[3,5,7,11-TETRAAZATRICYCLO-
[7.3.1.02,7]TRIDEC-2-ENE-13,4′-PIPERIDINE]
V. V. Dotsenko1, S. G. Krivokolysko1, and V. P. Litvinov2
5,11-Disubstituted derivatives of 1'-isopropyl-8-thioxospiro[3,5,7,11-tetrazatricyclo[7.3.1.02,7]tridec-
2-ene-13,4′-piperidine]-1,9-dicarbonitrile was obtained by the interaction of 10-amino-9-aza-3-azonia-
7,11-dicyano-3-isopropylspiro[5,5]undeca-7,10-diene-8-thiolate with 2 equiv. of a primary amine and
excess of formaldehyde. An anomalous reaction product was obtained with o-toluidine – 7,9-dicyano-
1′-isopropyl-3-(2-methylphenyl)-1,2,3,4-tetrahydrospiro[pyrido[1,2-a][1,3,5]triazine-8,4′-piperidinium]-
6-thiolate.
Keywords:
10-amino-9-aza-3-azonia-7,11-dicyano-3-isopropylspiro[5,5]undeca-7,1-diene-8-thiolate,
pyridine-2-thiolates, spiro[3,5,7,11]-tetraazatricyclo[7.3.1.02,7]tridec-2-ene-13,4'-piperidine]-1,9-dicarbo-
nitrile, aminomethylation, the Mannich reaction, cyclocondensation.
Functionally substituted derivatives of pyridine-2-(1H)-thione, and their tautomers 2-mercaptopyridines,
and also their partially hydrogenated analogs have been enduring compounds in the arsenal of fine chemical
synthesis for the last twenty years as promising reactive synthons [2-4], opening broad vistas for the preparation
of a series of condensed heterocyclic systems [5-7]. Nevertheless there is only solary reports in the literature on
the problem of aminomethylation of 2-mercaptopyridines [8]. It follows from multitudinous data in the literature
that aminomethylation of 2-mercaptoazoles and -azines is a general method for the preparation of condensed
derivatives of 1,3,5-thiadazines. In particular, derivatives of sym-triazolo[3,4-b][1,3,5]thiadiazine [9-16],
thiazolo[3',4':1,5][1,2,4]triazolo[3,4-b][1,3,5]thiadiazine [17], imidazo[2,1-b][1,3,5]thiadiazine [18, 19],
1,2,4-triazino[3,2-b][1,3,5]thiadiazine [19], and 1,3,5-thiadiazino[3,2-a]benzimidazole [20] have been obtained by
"double" Mannich condensations. We have shown previously with a series of 2-oxo-1,2,3,4-tetrahydropyridine-
6-thiolates that, depending on the structure of the substrate, aminomethylation can lead to the formation of
_______
* For Communication 6, see [1].
__________________________________________________________________________________________
1"ChemEx" Laboratory, Vladimir Dal East-Ukrainian National University, Lugansk 91034, Ukraine;
2
e-mail: ksg@lep.lg.ua. N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow
117913; e-mail: vpl@mail.ioc.ac.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11,
1709-1713, November, 2007. Original article submitted September 28, 2006.
0009-3122/07/4311-1455©2007 Springer Science+Business Media, Inc.
1455

derivatives of pyrido[2,1-b][1,3,5]thiadiazine [21,22], 3,7-diazabicyclo[3.3.1]nonane [23], or tricyclic products
[24]. In a continuation of investigation in this area, we paid attention to 10-amino-9-aza-3-azonia-7,11-dicyano-
3-isopropyl-spiro[5,5]undeca-7,10-diene-8-thiolate, which has several active nucleophilic centers and
consequently possesses a series of alternative possibilities for cyclocondensation under the conditions of
aminomethylation.
Me
Me
N
1'
N
4'
N
N
13
9
1
Me
S
4
Me
7
2
+
N
N
H
N
6
R
3
Me
Me
11
N
R
2 RNH2,
HCHO
5
N
N
+
N
H
2a-f
EtOH, ∆
–
N
N
S
H2N
N
H
1
–
HN
S
N
R = 2-MeC6H4
N
Me
3
2 a R = Me, b R = CH2Ph, c R = cyclohexyl,
d R = Ph, e R = 4-BrC6H4, f R = 3-MeC6H4
It has been established that the previously unknown spiro-coupled derivatives of 3,5,7,11-
tetraazatricyclo[7.3.1.02,7]tridec-2-ene (2) are selectively produced in 37-86% yield by the reaction of thiolate 1
with 2 equiv. of a primary amine in the presence of an excess of formaldehyde. So the thiolate 1 did not react as
the expected S,N-binucleophile in the Mannich reaction, but underwent aminomethylation at C-7 and C-11 and
also at the nitrogen atom of the amino and imino groups. Both aliphatic and aromatic primary amines took part
in this reaction. The yield of products did not depend to an important extent on the order of mixing of the
reagents. For example compound 2a was formed in 78.5% yield on successive treatment of the thiolate 1 with
formalin and 40% methylamine solution, but in a yield of 80.5% on treatment of an aqueous alcoholic mixture of
the betaine 1 and MeNH2 with HCHO. An unexpected product, a derivative of pyrido[1,2-a][1,3,5]triazine 3,
was isolated in 25% yield from the reaction of thiolate 1 with 2 equiv of o-toluidine. In our opinion, the reason
for this anomalous course of the reaction is, on the one hand, the sufficiently large volume of the
N-isopropylpiperidine unit and the evident spatial hindrance of the electrophilic component, the product of
hydroxymethylation of o-toluidine, on the other hand. Together these factors hinder electrophilic attack in
positions C-3 and C-5 and thus make ring closing of the 3,7-azabicyclo[3.3.1]nonane system impossible, at the
same time as N-aminomethylation proceeds in the normal way.
All the products have been characterized with the help of 1H NMR and IR spectra and elemental analysis.
Together with a number of characteristic signals observed in the 1H NMR spectra of compounds 2, the signals of the
protons of the tetrahydro-1,3,5-triazine ring should be noted: a doublet of doublets (or a multiplet) of 2H-4 at
δ 5.65-5.13 (2J = 12.1-13.5) and a doublet of doublets of 2H-6 at δ 4.41-5.13 ppm (2J = 16,7-17.0 Hz). The protons
2H-10 and 2H-12 resonate in the range δ 3.83-2.90 ppm and are observed as two doublets of doublets with
1456

2J = 11.6-13.0 Hz. Also characteristic is the presence of two sets of signals of the aromatic protons and a doublet
1
at δ = 0.98-0.94 ppm (2J = 6.2-6.6 Hz) assigned to the methyl groups of NCH(CH3)2. In the H NMR spectrum
of compound 3 a broad singlet of the NH group is present at δ 8.85, a group of signals of protons in the region
δ 7.24-7.03 ppm, indicating the presence of one 2-methylphenyl substituent and also two doublets of doublets
for the protons of the 1,3,5-triazine ring. It is characteristic that the signal of the methyl groups of the NH(CH3)2
is shifted by 0.25-0.30 ppm to weaker field relative to the analogous signals in the spectra of compounds 2,
evidently as a result of the positive charge on the nitrogen atom. In the IR spectra of compounds 2a-f there are
weak absorption bands at ν = 2243-2237 cm-1 (unconjugated CN groups) and intensive absorption bands in the
1660-1640 cm-1 range (C=N stretching vibrations). In the IR spectrum of compound 3 the absorption bands of
the unconjugated nitrile groups are absent, but on the other hand there are absorptions in the 3430-3295 (N–H)
and an intense broad band at ν = 2167 cm-1 (conjugated cyanide groups).
EXPERIMENTAL
1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded on Varian Mercury
VX-200 (200 MHz) instrument. IR spectra of nujol mulls were recorded with an IKS-29 spectrometer, elemental
analyses were determined with a Perkin-Elmer C,H,N-analyzer. The course of reactions and the purity of
compounds were monitored by TLC on Silufol UV-254 plates, with 1:1 acetone–heptane as eluent, and
development with iodine vapor or UV light. Melting points were measured on a Kofler stage. The 10-amino-
9-aza-3-azonia-7,11-dicyano-3-isopropylspiro[5,5]undeca-7,10-diene-8-thiolate (1) starting material was
synthesized in 72% yield from a three component condensation of α-cyanothioacetamide, N-isopropylpiperidin-
4-one, and malononitrile according to a known method [25].
Spiro[3,7,5,11-tetraazatricyclo[7.3.1.02,7]tridec-2-ene-13,4′-piperidine]-1,9-dicarbonitriles 2a-f and
Spiro[pyrido[1,2-a][1,3,5]triazine-8,4'-piperidinium]-6-thiolate (3) (General Method). A mixture of thiolate
1 (0.6 g, 2.07 mmol) was ground with an excess of 37% aqueous formaldehyde (3-4 ml), EtOH (10-15 ml) was
added and the mixture was heated until homogenization was complete, and the corresponding primary amine
(4.2 mmol) was added in one piece. The mixture was boiled for 3 min and stirred for 8 h at ~20°C. The
precipitate was filtered off, washed with EtOH, and recrystallized from a suitable solvent.
1'-Isopropyl-5,11-dimethyl-8-thioxospiro[3,5,7,11-tetraazatricyclo[7.3.1.02,7]tridec-2-ene-13,4′-
piperidine]-1,9-dicaronitrile (2a). Yield 0.65 g (78.5%), light-yellow crystals, mp 216-218°C (dec., Me2CO).
1
2
IR spectrum, ν, cm-1: 2242 (2C≡N), 1655 (C=N). H NMR spectrum, δ, ppm (J, Hz): 5.13 (2H, dd, J = 12.1,
2
2
2
H-4); 4.41 (2H, dd, J = 16.8, H-6); 3.08 (2H, dd, J = 12.8, H-10 or H-12); 2.95 (2H, br. d, J = 11.8, H-12 or
H-10); 2.92-2.69 (5H, m (CH2)2NCHMe2); 2.38 (3H, s, NCH3); 2.27 (3H, s, NCH3); 2.22 and 1.83 (each 2H,
3
both m, H-3' and H-5'); 0.95 (6H, d, J = 6.4, NCH(CH3)2). Found, %: C 59.50; H 7.37; N 24.42. C20H29N7S
(M = 399.57). Calculated, %: C 60.12; H 7.32; N 24.54.
5,11-Dibenzyl-1′-isopropyl-8-thioxospiro[3,5,7,11-tetraazatricyclo[7.3.1.02,7]tridec-2-ene-13,4′-piperi-
dine]-1,9-dicarbonitrile (2b). Yield 0.98 g (86%); yellow crystals, mp 101-103°C (1:1 EtOH-Me2CO).
IR spectrum, ν, cm-1: 2237 (2C≡N), 1657 (C=N). 1H NMR spectrum, δ, ppm (J, Hz): 7.34-7.21 (10H, m, 2C6H5);
5.16 (2H, dd, 2J =13.0, H-4); 4.48 (2H, dd, 2J = 16.7, H-6); 3.84-3.63 (4H, m, two overlapping dd, CH2Ph); 3.22
2
(2H, m, H-10 or H-12); 3.07 (2H, dd, J = 11.6, H-12 or H-10); 2.83-2.72 (5H, m, (CH2)2NCHMe2); 2.20 and
1.85 (each 2H, both m, H-3′ and H-5′); 0.95 (6H, d, 3J = 6.4, NCH(CH3)2). Found, %: C 70.61; H 6.87; N 17.49.
C32H37N7S (M = 551.76). Calculated, %: C 69.66; H 6.76; N 17.77.
5,11-Dicyclohexyl-1′-isopropyl-8-thioxospiro[3.5.7.11-tetraazatricyclo[7.3.1.02,7]tridec-2-ene-13,4'-
piperidine]-1,9-dicarbonitrile (2c). Yield 0.56 g (50%); light-yellow crystals, mp 144-146°C (1:1 EtOH–
1
Me2CO). IR spectrum, ν, cm-1: 2243 (2C≡N), 1645 (C=N). H NMR spectrum, δ, ppm (J, Hz): 5.28 (2H, dd,
2
2
2J = 13.5, C(4)H2); 4.56 (2H, m, H-6); 3.20 (2H, dd, J =11.6, H-10 or H-12); 3.05 (2H, dd, J = 11.8, H-12
1457

or H-10); 2.81-2.69 (7H, m, (CH2)2N and 3 N-CH); 2.32-2.08 (4H, m, H-3′ and H-5′); 1.77-1.12 (2 H, m, H-2);
0.94 (6H, d, 3J = 6.4, NCH(CH3)2). Found, %: C 67.67, H 8.50, N 18.19. C30H45N7S (M =535.80). Calculated, %:
C 67.25, H 8.47, N 18.30.
1′-Isopropyl-5,11-diphenyl-8-thioxo-spiro[3,5,7,11-tetrazatricyclo[7.3.1.02,7]tridec-2-ene-13,4′-
piperidine]-1,9-dicarbonitrile (2d). Yield 0.84 g (77%); light-yellow crystals, mp 202-204°C (1:3 EtOH–
1
Me2CO). IR spectrum, ν, cm-1: 2240 (2C≡N), 1640 (C=N). H NMR spectrum, δ, ppm (J, Hz): 7.20-6.71 (10H,
2
2
m, 2C6H5); 5.63 (2H, dd, J = 13.5, H-4); 5.10 (2H, dd, J =17.0, H-6); 3.82 (2H, m, H-10 or H-12); 3.73 (2H,
2
dd, J = 13.0, H-12 or H-10); 2.82-2.65 (5H, m, (CH2)2NCHMe2); 2.32-2.20, 1.73 (each 2H, both m, H-3' and
H-5′); 0.94 (6H, d, J = 6.2, NCH(CH3)2). Found, %: C 69.01; H 6.36; N 18.62. C30H33N7S (M = 523.71).
3
Calculated; %: C 68.80; H 6.35; N 18.72.
5,11-Di(4-bromophenyl)-1′-isopropyl-8-thioxospiro[3,5,7,11-tetraazatricyclo[7.3.1.02,7]tridec-2-ene-
13,4′-piperidine]-1,9-dicarbonitrile (2e). Yield 0.52 g (37%); light-yellow crystals, mp 270°C (dec., 1:10
1
DMF–Me2CO. IR spectrum, ν, cm-1: 2139 (2C≡N), 1650 (C=N). H NMR spectrum, δ, ppm (J, Hz): 7.01 and
6.82 (each 4H, both dd, 2J = 8.8, 2C6H4Br-4); 5.57 (2H, dd, 2J = 13.5, H-4); 5.12 (2H, pseudo-t, 2J = 17.0, H-6);
2
3.78 (2H, m, H-10 or H-12); 3.68 (2H, dd, J = 12.4, H-12 or H-10); 2.88-2.74 (5H, m, (CH2)2NCHMe2);
3
2.39-2.17, 1.83 (2H, both m, H-3' and H-5'); 0.98 (6H, d, J = 6.6, NCH(CH3)2). Found, %: C 52.07, H 4.63,
N 14.42. C30H31Br2N7S (M = 681.50). Calculated, %: C 52.87, H 4.59, N 14.39.
1′-Isopropyl-5,11-di(3-methylphenyl)-8-thioxospiro[3,5,7,11-tetraazatricyclo[7.3.1.02,7]tridec-2-ene-
13,4′-piperidine]-1,9-dicarbonitrile (2f). Yield 0.90 g (79%); pale-yellow crystals, mp 174-175°C (1:1 EtOH–
Me2CO). IR spectrum, ν, cm-1: 2237 (2C≡N), 1660 (C=N). 1H NMR spectrum, δ, ppm (J, Hz): 7.05-6.46 (8H, m,
2Ar); 5.65 (2H, m, H-4); 5.11(2H, dd, 2J = 17.0, H-6); 3.77 (2H, m, H-10 or H-12); 3.70 (2H, dd, 2J = 12.4, H-
12 or H-10); 2.83-2.64 (5H, m, (CH2)2NCHMe2); 2.40-2.20, 1.74 (each 2H, both m, H-3' and H-5'); 2.15 and
3
1.97 (each 3H, both s, 2CH3); 0.94 (6H, d, J = 6.6, NCH(CH3)2). Found, %: C 70.18; H 6.73; N 17.92.
C32H37N7S (M = 551.76). Calculated, %: C 69.66; H 6.76; N 17.77.
7,9-Dicyano-1′-isopropyl-3-(2-methylphenyl)-1,2,3,4-tetrahydrospiro[pyrido[1.2-a][1,3,5]triazine-
8,4′-piperidinium)-6-thiolate (3). Yield 0.23 g (26,5%); beige powder, mp 235-240°C (dec.). IR spectrum,
ν, cm-1: 3430-3295 (NH); 2167 (C≡N), 1667 (2C=C). 1H NMR spectrum, δ, ppm (J, Hz): 8.85 (1H, br. s, H-1);
2
2
7.24-7.03 (4H, m, Ar); 4.35 (2H, dd, J = 15.2, 2H-2 or 2H-4); 3.68 (br. s, H+, H2O); 3.49 (2H, dd, J = 11.2,
2H-4 or 2H-2); 3.77 (2H, m, 2H-10 or 2H-2); 3.30-2.71 (5H, m, (CH2)2N+CHMe2); 2.30 (3H, s, CH3); 2.09-1.58
3
(4H, m, H-3' and H-5'); 1.23 (6H, d, J = 6.4, NCH(CH3)2). Found, %: C 65.48, H 6.70, N 20.12. C23H28N6S
(M = 420.58). Calculated, %: C 65.68, H 6.71, N 19.98.
This work was carried out under an agreement for scientific and technical cooperation between the
Vladimir Dalya Eastern Ukrainian University (Lugansk, Ukraine) and the N. D. Zelinskii Institute of Organic
Chemistry of the Russian Academy of Science with financial support of the RFFI (project 05-03-32031).
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