A new method for the synthesis of N-substituted 1,3,5-dithiazinanes via the catalytic recyclization of 1,3,5-trithiane with aryl(benzyl) hydrazines and aryl amines

Article abstract of DOI:10.1016/j.tetlet.2011.05.097

An efficient method for the synthesis of N-substituted 1,3,5-dithiazinanes based on the amination reaction of 1,3,5-trithiane with aryl(benzyl) hydrazines and N-aryl amines in the presence of Ti and Fe catalysts has been developed.

Full text of DOI:10.1016/j.tetlet.2011.05.097

Tetrahedron Letters 52 (2011) 4090–4092
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Tetrahedron Letters
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A new method for the synthesis of N-substituted 1,3,5-dithiazinanes via
the catalytic recyclization of 1,3,5-trithiane with aryl(benzyl) hydrazines
and aryl amines
⇑
Nataliya N. Murzakova , Elena B. Rakhimova, Inna V. Vasil’yeva, Kirill I. Prokof’yev, Askhat G. Ibragimov,
Usein M. Dzhemilev
Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, 141 Prospekt Oktyabrya, Ufa 450075, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of N-substituted 1,3,5-dithiazinanes based on the amination reac-
tion of 1,3,5-trithiane with aryl(benzyl) hydrazines and N-aryl amines in the presence of Ti and Fe cata-
lysts has been developed.
Received 14 March 2011
Revised 12 May 2011
Accepted 20 May 2011
Available online 13 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
N-Substituted 1,3,5-dithiazinanes
N-Aryl(benzyl) hydrazines
Aryl amines
1,3,5-Trithiane
Catalysis
Recyclization
1,3,5-Dithiazinane compounds are widely used as food addi-
tives,1–3 and as adsorbents for noble metals.4 They also exhibit fun-
gicidal activity.5
We assume that 1,3,5-trithiane (1), which contains nucleophilic
centres in the ring, under the influence of substituted hydrazines
and aryl amines, may undergo recyclization9–11 to give the corre-
sponding N-substituted 1,3,5-dithiazinanes (Scheme 1).
According to previous experimental data,6 cyclothiomethyla-
tion of N-aryl(benzyl) hydrazines with CH2O–H2S leads to a mix-
ture of S,N-containing heterocycles. In this case, the yield of the
target N-phenyl(benzyl)-(1,3,5-dithiazinan-5-yl)amines does not
exceed 30%. Nitrophenyl-substituted hydrazines, under these con-
ditions, do not enter into the above reaction giving rise instead to a
mixture of hydrazone, trithiolane, and tetrathiepane.6 Our recent
work7 reported low selectivity for the cyclothiomethylation reac-
tion of primary aryl amines with CH2O and H2S providing appropri-
ate 1,3,5-dithiazinanes. No reports have appeared in the literature
which describe the selective synthesis of N-aryl-1,3,5-dithiazin-
anes, and N-phenyl- and N-benzyl-(1,3,5-dithiazinan-5-yl)amines.
In order to develop an efficient method for synthesizing N-
phenyl(benzyl)-(1,3,5-dithiazinan-5-yl)amines and N-aryl-1,3,5-
dithiazinanes in high yields and selectivity, we have studied the
reaction of aryl(benzyl) hydrazines and aryl amines with commer-
cially available 1,3,5-trithiane, which contains reactive sulfur
atoms in the ring,8 in the presence of transition metal based
catalysts.
Our preliminary experiments revealed that the non-catalytic
reaction between phenyl hydrazine or benzyl hydrazine and an
equimolar amount of 1,3,5-trithiane (1) in MeCN for 3 h (À10 to
60 °C) gave N-phenyl-(1,3,5-dithiazinan-5-yl)amine (2) in yields
not exceeding 10%. To optimize the yield of the product 2, we
investigated the reaction of 1,3,5-trithiane with phenyl hydrazine
in the presence of salts and transition metal based (Cu, Co, Mn,
Ti, Hf, V, Fe, Sm) catalysts, which favor changes in the reactivity
of the initial reagents to form coordination compounds.12 Among
the catalysts tested, the activity of Cp2TiCl2 (7 mol %) in the reac-
tion of hydrazine with 1,3,5-trithiane proved to be the highest. In
this case (MeCN, ꢀ20 °C, 3 h), N-phenyl(benzyl)-(1,3,5-dithiaz-
inan-5-yl)amines 2 and 3 were obtained in 63% and 60% yields,
respectively.13 An excess of phenyl (or benzyl) hydrazine with re-
S
S
S
S
catalyst
S
R N
+
RNH2
1
⇑
Corresponding author.
E-mail addresses: natali-mnn@mail.ru, ink@anrb.ru (N.N. Murzakova).
Scheme 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.097

N. N. Murzakova et al. / Tetrahedron Letters 52 (2011) 4090–4092
4091
N
NH2
O2N
H
R'
N NH2
S
S
S
S
S
S
H
R
N
NH
R'
N
N
S
O2N
[M], 20 oC, MeCN
[M], 20 oC, MeCN
H
− H2S
− H2S
R
Catalyst = [M] = Cp2TiCl2
R = H (4), NO2 (5)
R' = Ph (2), Bn (3)
Scheme 2.
OH
OH
N
R
NH2
S
S
S
S
NH2
S
R
N
[Fe], −H2S
[Fe], −H2S
S
S
R = OH (7), NH2 (8), SH (9)
6
Scheme 3.
+
+
..
S
RNH2
S
S
S
S
S
S
S
S
S
..
+
N
R
NH
NH
S
S
S
R
R
Met
Met
Met
Scheme 4.
spect to 1,3,5-trithiane did not influence the reactivity of the sec-
ond S atom, which in this reaction remained inert. In each run,
N-substituted 1,3,5-dithiazinanes were formed exclusively
(Scheme 2).
primary aryl amines mediated by Ti- and Fe-based catalysts. This
novel procedure provides an effective route for the selective syn-
thesis of previously inaccessible N-substituted 1,3,5-dithiazinanes.
These positive results on the catalytic recyclization of 1,3,5-tri-
thiane with phenyl (or benzyl) hydrazines into N-substituted 1,3,5-
dithiazinanes 2 and 3 inspired us to implement this reaction with
nitrophenyl hydrazines, which under normal conditions do not un-
dergo the cyclomethylation reaction with CH2O–H2S as the
cyclothiomethylation agent.6 1,3,5-Trithiane reacted with both 4-
nitrophenyl hydrazine and 2,4-dinitrophenyl hydrazine in the
presence of Cp2TiCl2 as the catalyst under optimized conditions
(7 mol %, 20 °C, 3 h, MeCN) to give N-(4-nitrophenyl)-(1,3,5-
dithiazinan-5-yl)amine14 (4) and N-(2,4-dinitrophenyl)-(1,3,5-
dithiazinan-5-yl)amine15 (5) in 69% and 65% yields, respectively.
Aryl amines, like aryl hydrazines, also underwent reaction with
an equimolar amount of 1,3,5-trithiane giving rise to N-aryl-1,3,5-
dithiazinanes16 (Scheme 3). In this reaction, iron(III) chloride
hexahydrate (FeCl3Á6H2O) showed the highest catalytic activity.
Recyclization of 1,3,5-trithiane with 2-aminophenol, 4-aminophe-
nol, 4-phenylenediamine, and 4-aminothiophenol (5 mol %
FeCl3Á6H2O, 60 °C, 6 h, MeCN) allowed the selective synthesis of
2-(1,3,5-dithiazinan-5-yl)phenol17 (6), 4-(1,3,5-dithiazinan-5-
yl)phenol (7), 4-(1,3,5-dithiazinan-5-yl)phenyl amine18 (8), and
4-(1,3,5-dithiazinan-5-yl)phenyl hydrosulfide19 (9) in 60–75%
yield.
Acknowledgments
This work was supported by the Russian Foundation for Basic
Research (Grant 08-03-00789-a) and the President of the Russian
Federation (Sci. School 2349.2008.3).
References and notes
1. Hirai, C.; Herz, K. O.; Pokorny, J.; Chang, S. S. J. Food Sci. 1973, 38, 393.
2. Farka, P.; Sadecka, J.; Kova, M.; Siegmund, B.; Pfannhauserb, W. Food Chem.
1997, 60, 617.
3. Kawai, T.; Ishida, Y. J. Agric. Food Chem. 1989, 37, 1026.
4. Dzhemilev, U. M.; Aleev, R. S.; Dal’nova, Yu. S.; Kunakova, R. V.; Khafizova, S. R.
Pat. 2206726 RF; Byull. Izobret. [Bulletin of Inventions] 2003, 17 (in Russian).
5. Saraç, S.; Ertan, M.; Balkan, A.; Yulug, N. Archiv. Pharm. 1990, 7, 449.
6. Akhmetova, V. R.; Nadyrgulova, G. R.; Tyumkina, T. V.; Starikova, Z. A.;
Golovanov, D. G.; Antipin, M. Yu.; Kunakova, R. V.; Dzhemilev, U. M. Izv. Akad.
Nauk Ser. Khim. 2006, 1758; Russ. Chem. Bull. Int. Ed. 2006, 55, 1824 (Engl.
Transl.).
7. Akhmetova, V. R.; Nadyrgulova, G. R.; Niatschina, Z. T.; Dzhemilev, U. M. Chem.
Heterocycl. Compd. 2009, 45, 1155.
8. Voronkov, M. G.; Deryagina, E. N. Uspekhi Khim. 2000, 69, 90; Russ. Chem. Rev.
2000, 69, 81 (Engl. Transl.).
9. Shvaika, O. P.; Artemov, V. N. Uspekhi Khim. 1972, 41, 1788; Russ. Chem. Rev.
1972, 41, 833 (Engl. Transl.).
10. Aksenov, A. V.; Aksenova, I. V. Chem. Heterocycl. Compd. 2009, 45, 167.
11. Wellmar, U. J. Heterocycl. Chem. 1998, 35, 1531.
A potential mechanism for this trithiane recyclization is shown
in Scheme 4. It can be assumed that 1,3,5-trithiane, under selected
conditions, is activated by the positively charged metal ion. The
subsequent recyclization20,21 of the 1,3,5-trithiane, under the influ-
ence of the catalyst, affords the corresponding N-substituted 1,3,5-
dithiazinanes.
12. Kukushkin, Yu. N. The Reactivity of Coordination Compounds [in Russian];
Khimiya: Leningrad, 1987. p 228.
13. Synthesis of N-phenyl- and N-benzyl-(1,3,5-dithiazinan-5-yl)amines via the
reaction of 1,3,5-trithiane with aryl or benzyl hydrazines (general procedure). A
calcined and argon-filled Schlenk vessel equipped with a magnetic stir bar was
charged with MeCN (5 mL), Cp2TiCl2 (0.7 mmol) and 1,3,5-trithiane (11 mmol).
The mixture was stirred at 20 °C for 1 h. Next, the corresponding aryl(benzyl)
hydrazine (10 mmol) was added dropwise to the mixture which was stirred for
3 h at 20 °C under a dry argon atmosphere. The product mixture was separated
by column chromatography on silica gel (SiO2) with CHCl3:benzene:EtOAc
In conclusion, we have developed a catalytic recyclization reac-
tion of 1,3,5-trithiane with aryl hydrazines, benzyl hydrazines, and

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N. N. Murzakova et al. / Tetrahedron Letters 52 (2011) 4090–4092
(1:5:1) as eluent. The final products 2–5 were identified by means of spectral
methods. Compounds 2 and 3 were further identified by comparison with
known samples.6
9 were identified by means of spectral methods. Compounds 6 and 7 were
further identified by comparison with known samples.17
17. Akhmetova, V. R.; Nadyrgulova, G. R.; Khafizova, S. R.; Tyumkina, T. V.;
Yakovenko, M. Yu.; Antipin, M. Yu.; Khalilov, L. M.; Kunakova, R. V.; Dzhemilev,
U. M. Izv. Akad. Nauk Ser. Khim. 2006, 305; Russ. Chem. Bull. Int. Ed. 2006, 55, 312
(Engl. Transl.).
14. N-(4-Nitrophenyl)-1,3,5-dithiazinan-5-yl amine (4). Mp 140–141 °C. Rf 0.7
(CHCl3:benzene:EtOAc, 1:5:1). Anal. Calcd for C9H11N3O2S2: C, 42.01; H, 4.31;
N, 16.33; S, 24.92. Found: C, 41.95; H, 4.29; N, 16.25; S, 24.88. 1H NMR
(400 MHz, CDCl3): d 3.6 (s, 1H, NH (7)); 3.55 (s, 2H, C(2)H2); 4.28 (s, 4H,
C(4,6)H2); 7.27 (s, 2H, C(10,12)H); 8.19 (s, 2H, C(9,13)H). 13C NMR (100 MHz,
CDCl3): d 29.75 (C(2)), 58.23 (C(6,4)), 112.48 (C(13,9)), 128.68 (C(12,10)),
138.42 (C(11)), 145.93 (C(8)).
15. N-(2,4-Dinitrophenyl)-1,3,5-dithiazinan-5-yl amine (5). Mp 153–154 °C. Rf 0.6
(CHCl3:benzene:EtOAc, 1:5:1). Anal. Calcd for C9H10N4O4S2: C, 35.75; H, 3.33;
N, 18.53; S, 21.22. Found: C, 35.63; H, 3.27; N, 18.36; S, 21.09. 1H NMR
(400 MHz, CDCl3): d 3.39 (s, 1H, N(7)H); 4.09 (s, 2H, C(2)H2); 4.43 (s, 4H,
C(4,6)H2); 7.98 (d, J = 8.1 Hz, 1H, C(13)H); 8.34 (d, J = 8.1 Hz, 1H, C(12)H); 9.14
(s, 1H, C(10)H). 13C NMR (100 MHz, CDCl3): d 34.27 (C(2)), 58.23 (C(6,4)),
114.56 (C(13)), 121.91 (C(12)), 127.67 (C(9)), 130.18 (C(12)), 139.42 (C(11)),
153.93 (C(8)).
16. Recyclization of 1,3,5-trithiane with aryl amines (general procedure). A calcined
and argon-filled Schlenk vessel equipped with a magnetic stir bar was charged
with MeCN (5 mL), FeCl3Á6H2O (0.5 mmol) and 1,3,5-trithiane (11 mmol). The
mixture was stirred at 20 °C for 1 h. Next, the corresponding aryl amine
(10 mmol) in MeCN (5 mL) was added dropwise to the mixture which was
stirred for 6 h at 60 °C under a dry argon atmosphere. The product mixture was
separated by column chromatography on silica gel (SiO2). The final products 6–
18. (1,3,5-Dithiazinan-5-yl)phenyl amine (8). Mp 240–242 °C. Rf 0.6 (benzene:EtOH,
9:1). IR (m
, cmÀ1): 720, 1100, 1600, 1650, 2900, 3300. HRMS (RP) C9H12N2S2
[M++H] calcd: 213.345, found: 213.379. 1H NMR (400 MHz, CDCl3): d 4.25 (br s,
2H, C(2)H2); 4.97 (br s, 4H, C(4,6)H2); 6.70 (d, J = 8.8 Hz, 2H, C(8,12)H); 7.70 (d,
J = 8.8 Hz, 2H, C(9,11)H). 13C NMR (100 MHz, CDCl3): d 36.5 (C(2)), 52.7 (C(4,6)),
114.7 (C(8,12)), 124.3 (C(9,11)), 145.8 (C(10)), 148.5 (C(7)).
19. 4-(1,3,5-Dithiazinan-5-yl)phenyl hydrosulfide (9). Mp 185–187 °C. Rf 0.5
(CHCl3:benzene:EtOAc, 1:5:1). IR (m,
cmÀ1): 720, 1100, 1600, 2600, 2900,
3300. Anal. Calcd for C9H11NS3: C, 47.12; H, 4.83; N, 6.11; S, 41.94. Found: C,
47.10; H, 4.75; N, 6.07; S, 41.93. GC–MS (m/z): 197 [M+ÀS] (35), 136
[M+ÀCH3SCH2S] (100), 109 [M+ÀSPh] (35). 1H NMR (400 MHz, CDCl3): d 4.25
(br s, 2H, C(2)H2); 4.93 (br s, 4H, C(4,6)H2); 6.66–7.49 (m, 4H, C(8,9,11,12)H).
13C NMR (100 MHz, CDCl3): d 33.23 (C(2)), 55.02 (C(4,6)), 114.70 (C(8,12)),
118.03 (C(9,11)), 131.96 (C(10)), 137.72 (C(7)).
20. Mokrov, G. V.; Likhosherstov, A. M.; Lezina, V. P.; Gudasheva, T. A.;
Bushmarinov, I. S.; Antipin, M. Yu. Izv. Akad. Nauk Ser. Khim. 2010, 1228;
Russ. Chem. Bull. Int. Ed. 2010, 59 (Engl. Transl.).
21. Krohn, K.; Cludius-Brandt, S. Synthesis 2010, 1344.