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ISSN 1070-4272, Russian Journal of Applied Chemistry, 2013, Vol. 86, No. 10, pp. 1504−1508. © Pleiades Publishing, Ltd., 2013. Original Russian Text © E.B. Rakhimova, R.A. Ismagilov, R.A. Zainullin, N.F. Galimzyanova, A.G. Ibragimov, 2013, published in Zhurnal Prikladnoi Khimii, 2013, Vol. 86, No. 10, pp. 1547−1551.

ORGANIC SYNTHESIS AND INDUSTRIAL ORGANIC CHEMISTRY

Synthesis of α,ω-Bis-1,5,3-dithiazepanes and Their Fungicidal Properties

E. B. Rakhimovaa, R. A. Ismagilovb, R. A. Zainullinb, N. F. Galimzyanovac, and A. G. Ibragimova

a Institute of Petrochemistry and Catalysis, Russian Academy of Sciences, Ufa, Bashkortostan, Russiae-mail: Rakhimovaelena@mail.ru

b Ufa State University of Economy and Service, Ufa, Bashkortostan, Russiac Institute of Biology, Ufa Scientifi c Center, Russian Academy of Sciences, Ufa, Bashkortostan, Russia

Received September 10, 2013

Abstract—A procedure was developed for preparative synthesis of α,ω-bis-1,5,3-dithiazepanes by heterocycliza-tion of aliphatic α,ω-diamines with N,N,N',N'-tetramethylmethanediamine and 1,2-ethanedithiol. The fungicidal activity of 1,2-bis(1,5,3-dithiazepan-3-yl)ethane and 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepane toward microscopic fungi affecting agricultural plants was studied.

DOI: 10.1134/S1070427213100066

Interest in unsaturated S,N-containing heterocycles is due to the possibility of using them as compounds with bactericidal [1], antimicrobial [2, 3], and fungicidal properties [4, 5].

It was shown previously that condensation of carbon-chain [6] and heterochain [7] α,ω-diamines under the action of CH2O and H2S leads to the formation of α,ω-bis-1,3,5-dithiazinanes exhibiting fungicidal activity [7]. It is known [8, 9] that N-substituted 1,5,3-dithiazepanes can be prepared by ternary condensation of primary amines with formaldehyde and 1,2-ethanedithiol.

Proceeding with studies on synthesis of practically important S,N-heterocycles [10–12], and also aiming to develop a procedure for preparative synthesis of α,ω-bis-1,5,3-dithiazepanes, we studied the heterocyclization of aliphatic α,ω-diamines with N,N,N',N'-tetramethylmethanediamine (bisamine) and

1,2-ethanedithiol.Preliminary experiments showed that noncatalytic

reaction of ethylenediamine with bisamine and 1,2-ethanedithiol occurred nonselectively, with no more than 20% yield of bis(1,5,3-dithiazepan-3-yl)ethane (I). To increase the yield of the desired heterocycle I, the reaction was performed in the presence of catalysts based on salts and complexes of Cu, Pd, Co, Mn, Ti, Hf, V, Fe, and Sm that proved to be active in heterocyclization reactions [13, 14]. Among the catalysts tested, SmCl3·6H2O appeared to be the most active in the heterocyclization reaction under consideration.

We found that aliphatic carbon-chain and heterochain α,ω-diamines under the developed conditions (5 mol % SmCl3·6Н2О, 20°С, 3 h, solvent EtOH–CHCl3) react with N,N,N',N'-tetramethylmethanediamine and 1,2-ethanedithiol to give bis-1,5,3-dithiazepanes I–XII

Scheme 1.

H2NХ

NH2 + Me2N CH2 NMe2 + HS SH[Sm]

_(CH3)2NHS

N

SХ

S

N

SI_ХII

Х = (CH2)n, n = 2–10 (I–IX); (CH2CH2O)nCH2CH2, n = 1, 2 (X, XI); (CH2CH2S)2 (XII).I–XII

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1505SYNTHESIS OF α,ω-BIS-1,5,3-DITHIAZEPANES

in high yields (Scheme 1).The 1Н NMR spectra of I–XII contain broadened

signals of equal intensity at δ 3.03–3.08 and 4.15–4.23 ppm, belonging to methylene protons of bis-1,5,3-dithiazepane rings. In the 13С NMR spectra, the signals at δ = 35.8–36.0 ppm belong to carbon atoms located between the two S atoms, and those at δ = 59.5–60.0 ppm correspond to the methylene groups between the N and S atoms in the dithiazepane rings. The signals in the spectra of bis(1,5,3-dithiazepan-3-yl)alkanes I–IX and 3,3'-[oxa(thia)alkane-α,ω-diyl]bis-1,5,3-dithiazepanes X–XII were assigned using homo- (COSY, NOESY) and heteronuclear (HCQS, HMBC) NMR correlation and MALDI TOF/TOF mass spectrometry.

The bis-1,5,3-dithiazepanes obtained were tested for fungicidal activity. As test cultures we used phytopathogenic fungi Botrytis cinerea and Rhizoctonia solani. It is known [15] that Botrytis cinerea and Rhizoctonia solani induce rot in more than 200 species of agricultural plants. The tests were performed with solutions of the compounds in DMF. Evaluation of the solvent (DMF) effect on the fungus test cultures revealed no negative effect on the development of microscopic fungi.

The biological tests showed (Table 1) that 1,2-bis(1,5,3-dithiazepan-3-yl)ethane (I) at a concentration of ≥0.2%

fully suppressed the development of Botrytis cinerea and Rhizoctonia solani. 3,3'-(3,6-Dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepane (XI) (Table 2) exhibited fungicidal effect with respect to Botrytis cinerea and fungistatic effect with respect to Rhizoctonia solani.

EXPERIMENTAL

Unidimensional (1Н, 13С) and homo- (COSY, NOESY) and heteronuclear (HSQC, HMBC) NMR spectra were recorded with a Bruker Avance 400 spectrometer (400 MHz for 1Н, 100 MHz for 13С) by standard procedures of Bruker, reference TMS; the mass spectra were taken with an Autofl ex III MALDI TOF/TOF device (Bruker). Elemental analysis was performed with a Сarlo Erba 1106 analyzer. The melting points were determined with a PHMK 80/2617 device. The reaction progress was monitored by TLC on Sorbfi l plates (PTSKh-AF-V), visualization with I2 vapor. Column chromatography was performed with KSK silica gel (100–200 μm).

Heterocyclization of α,ω-diamines. General procedure: 0.53 mL (4 mmol) of N,N,N ' ,N ' -tetramethylmethanediamine, 0.17 mL (2 mmol) of 1,2-ethanedithiol in 5 mL of CHCl3, and 0.018 g (0.05 mmol) of SmCl3·6H2O were stirred in an argon atmosphere at room temperature for 30 min, after which

Table 1. Effect of 1,2-bis(1,5,3-dithiazepan-3-yl)ethane (I) on the development of fungus test cultures after 7-day incubation

Fungus speciesConcentration of I in DMF, %

Control0.1 0.2 0.3

Botrytis cinerea No development No development No development Onset of spore formation

Rhizoctoni solani Substrate mycelium The same The same Normal fungus development

Table 2. Effect of 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepane (XI) on the development of fungus test cultures after 7-day incubation

Fungus speciesConcentration of XI in DMF, %

Control0.1 0.2 0.3

Botrytis cinerea No development No development No development Onset of spore formation

Rhizoctoni solani Separate microcolonies beyond the zone of

action

Separate microcolonies beyond the zone

of action

Separate microcolonies beyond the zone

of action

Normal fungus development

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1506 RAKHIMOVA et al.

1 mmol of appropriate α,ω-diamine in 5 mL of EtOH was added dropwise. The reaction mixture was stirred for 3 h at Т ~ 20°С and evaporated; the residue was chromatographed on a column packed with SiO2 to isolate pure heterocycles I–XII.

1,2-Bis(1,5,3-dithiazepan-3-yl)ethane (I). Yield 0.24 g (82%), colorless crystals, mp 144–145°С (CHCl3), Rf 0.5 (Sorbfi l, n-C6H14–EtOAc, 4 : 3). 1H NMR spectrum (CDCl3), δ, ppm: 2.86 br.s (4H, H8,9), 3.06 br.s (8H, H6,6',7,7'), 4.20 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 35.8 (C6,6',7,7'), 47.7 (C8,9), 59.7 (C2,2',4,4'). Mass spectrum, m/z: 297.333 [M + H]+. Found, %: С 40.45, H 6.73, N 9.42, S 43.30. C10H20N2S4.

Calculated, %: С 40.50, H 6.80, N 9.45, S 43.25.1,3-Bis(1,5,3-dithiazepan-3-yl)propane (II). Yield

0.24 g (77%), colorless crystals, mp 73–74°С (CHCl3), Rf 0.5 (Sorbfi l, n-C6H14–EtOAc, 4 : 3). 1H NMR spectrum (CDCl3), δ, ppm: 1.56–1.77 m (2H, H9), 2.63–2.83 m (4H, H8,10), 3.04 br.s (8H, H6,6',7,7'), 4.15 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 24.4 (C9), 35.8 (C6,6',7,7'), 48.6 (C8,10), 59.5 (C2,2',4,4'). Mass spectrum, m/z: 311.052 [M + H]+. Found, %: С 42.50, H 7.09, N 9.03, S 41.35. C11H22N2S4. Calculated, %: С 42.54, H 7.14, N 9.02, S 41.30.

1,4-Bis(1,5,3-dithiazepan-3-yl)butane (III). Yield 0.27 g (84%), colorless crystals, mp 122–123°С (CHCl3), Rf 0.5 (Sorbfi l, n-C6H14–EtOAc, 4 : 3). 1H NMR spectrum (CDCl3), δ, ppm: 1.48 br.s (4H, H9,10), 2.68 br.s (4H, H8,11), 3.03 br.s (8H, H6,6',7,7'), 4.15 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 24.6 (C9,10), 35.9 (C6,6',7,7'), 50.6 (C8,11), 59.5 (C2,2',4,4'). Mass spectrum, m/z: 325.051 [M + H]+. Found, %: С 44.42, H 7.46, N 8.60, S 39.47. C12H24N2S4. Calculated, %: С 44.41, H 7.45, N 8.63, S 39.51.

1,5-Bis(1,5,3-dithiazepan-3-yl)pentane (IV). Yield 0.24 g (70%), colorless oil, Rf 0.5 (Sorbfi l, n-C6H14–EtOAc, 4 : 3). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.30–1.40 m (2H, H10), 1.44–1.54 m (4H, H9,11), 2.67 t (4H, H8,12, J = 7.2), 3.04 br.s (8H, H6,6',7,7'), 4.16 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 25.0 (C10), 26.7 (C9,11), 35.9 (C6,6',7,7'), 50.8 (C8,12), 59.5 (C2,2',4,4'). Mass spectrum, m/z: 377.011 [M + K]+.

Found, %: С 46.05, H 7.70, N 8.29, S 37.90. C13H26N2S4. Calculated, %: С 46.11, H 7.74, N 8.27, S 37.88.

1,6-Bis(1,5,3-dithiazepan-3-yl)hexane (V). Yield 0.24 g (68%), colorless crystals, mp 84–86°С (CHCl3), Rf 0.45 (Sorbfil, n-C6H14–EtOAc, 4 : 3). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.35 br.s (4H, H10,11), 1.46 br.s (4H, H9,12), 2.62–2.69 m (4H, H8,13), 3.05 d (8H, H6,6',7,7', J = 10.4), 4.17 d (8H, H2,2',4,4', J = 10.4). 13С NMR spectrum (CDCl3), δ, ppm: 26.9 (C10,11), 27.1 (C9,12), 35.9 (C6,6',7,7'), 50.9 (C8,13), 59.5 (C2,2',4,4'). Mass spectrum, m/z: 375.241 [M + Na]+. Found, %: С 47.63, H 7.97, N 7.90, S 36.40. C14H28N2S4.

Calculated, %: С 47.68, H 8.00, N 7.94, S 36.38.1,7-Bis(1,5,3-dithiazepan-3-yl)heptane (VI). Yield

0.27 g (75%), colorless crystals, mp 69–70°С (CHCl3), Rf 0.45 (Sorbfil, n-C6H14–EtOAc, 4 : 3). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.33 br.s (8H, H9,10,12,13), 1.45 br.s (2H, H11), 2.66 t (4H, H8,14, J = 8.8), 3.05 br.s (8H, H6,6',7,7'), 4.17 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 26.9 (C10,12), 27.2 (C9,13), 29.3 (C11), 35.9 (C6,6',7,7'), 50.9 (C8,14), 59.5 (C2,2',4,4'). Mass spectrum, m/z: 389.271 [M + Na]+. Found, %: С 49.10, H 8.21, N 7.60, S 35.00. C15H30N2S4. Calculated, %: С 49.13, H 8.25, N 7.64, S 34.98.

1,8-Bis(1,5,3-dithiazepan-3-yl)octane (VII). Yield 0.27 g (72%), colorless crystals, mp 70–71°С (CHCl3), Rf 0.45 (Sorbfi l, n-C6H14–EtOAc, 4 : 3). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.32 br.s (8H, H10,11,12,13), 1.58 br.s (4H, H9,14), 2.67 t (4H, H8,15, J = 7.2), 3.06 br.s (8H, H6,6',7,7'), 4.18 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 27.0 (C10,13), 27.2 (C9,14), 29.4 (C11,12), 35.9 (C6,6',7,7'), 51.0 (C8,15), 59.5 (C2,2',4,4'). Mass spectrum, m/z: 381.319 [M + H]+. Found, %: С 50.43, H 8.42, N 7.34, S 33.71. C16H32N2S4. Calculated, %: С 50.48, H 8.47, N 7.36, S 33.69.

1,9-Bis(1,5,3-dithiazepan-3-yl)nonane (VIII). Yield 0.30 g (77%), colorless crystals, mp 60–62°С (CHCl3), Rf 0.45 (Sorbfi l, n-C6H14–EtOAc, 4 : 3). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.31 br.s (8H, H9,10,14,15), 1.40–1.50 m (4H, H11,13), 1.58 br.s (2H, H12), 2.67 t (4H, H8,16, J = 7.2), 3.06 br.s (8H, H6,6',7,7'), 4.18 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 27.0 (C10,14), 27.3 (C9,15), 29.4 (C11,13), 29.5 (C12), 35.9 C6,6',7,7'), 51.0 (C8,16), 59.5 (C2,2',4,4'). Mass spectrum, m/z: 395.075 [M + H]+. Found, %: С 51.69, H 8.62, N 7.05, S 32.52. C17H34N2S4. Calculated, %: С 51.73, H 8.68, N 7.10, S 32.49.

1,10-Bis(1,5,3-dithiazepan-3-yl)decane (IX). Yield 0.28 g (70%), colorless crystals, mp 77–78°С (CHCl3),

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1507SYNTHESIS OF α,ω-BIS-1,5,3-DITHIAZEPANES

Rf 0.45 (Sorbfil, n-C6H14–EtOAc, 4 : 3). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.29 br.s (12H, H10,11,12,13,14,15), 1.46 t (4H, H9,16, J = 7.2), 2.67 t (4H, H8,17, J = 7.4), 3.08 br.s (8H, H6,6',7,7'), 4.19 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 26.9 (C9,16), 27.3 (C10,15), 29.4 (C11,14), 29.4 (C12,13), 36.0 (C6,6',7,7'), 51.1 (C8,17), 59.4 (C2,2',4,4'). Mass spectrum, m/z: 409.346 [M + H]+. Found, %: С 52.85, H 8.82, N 6.83, S 31.42. C18H36N2S4. Calculated, %: С 52.89, H 8.88, N 6.85, S 31.38.

3,3'-(3-Oxapentan-1,5-diyl)bis-1,5,3-dithiazepane (X). Yield 0.18 g (52%), colorless crystals, mp 53–55°С (CHCl3), Rf 0.7 (Sorbfi l, n-C6H14–EtOAc, 1 : 2). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.88–2.97 m (4H, H8,8'), 3.06 br.s (8H, H6,6',7,7'), 3.59 t (4H, H9,9', J = 5.4), 4.22 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 35.8 (С6,6',7,7'), 50.3 (С8,8'), 60.0 (С2,2',4,4'), 68.6 (С9,9'). Mass spectrum, m/z: 341.216 [M + H]+. Found, %: С 42.27, H 7.02, N 8.16, S 37.72. C12H24N2OS4. Calculated, %: С 42.32, H 7.10, N 8.22, O 4.70, S 37.66.

3,3' - (3 ,6-Dioxaoctane-1,8-diyl )bis-1 ,5 ,3-dithiazepane (XI). Yield 0.25 g (65%), colorless crystals, mp 74–75°С (CHCl3), Rf 0.8 (Sorbfi l, n-C6H14–EtOAc, 1 : 2). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.93 t (4H, H8,8', J = 5.4), 3.06 br.s (8H, H6,6',7,7'), 3.59–3.64 m (8H, H9,9',10,10'), 4.23 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 35.8 (С6,6',7,7'), 50.4 (С8,8'), 59.9 (С2,2',4,4'), 68.8 (С9,9'), 70.4 (C10,10'). Mass spectrum, m/z: 385.321 [M + H]+. Found, %: С 43.65, H 7.30, N 7.25, S 33.42. C14H28N2O2S4. Calculated, %: С 43.72, H 7.34, N 7.28, O 8.32, S 33.34.

3,3′-(3,4-Dithiahexane-1,6-diyl)bis-1,5,3-di-thiazepane (XII). Yield 0.19 g (50%), colorless oil, Rf 0.75 (Sorbfil, n-C6H14–EtOAc, 1 : 2). 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 2.81–2.91 m (4H, H9,9'), 2.90 t (4H, H8,8', J = 5.2), 3.06 br.s (8H, H6,6',7,7'), 4.18 br.s (8H, H2,2',4,4'). 13С NMR spectrum (CDCl3), δ, ppm: 35.8 (С6,6',7,7'), 36.7 (С9,9'), 50.0 (С8,8'), 59.4 (С2,2',4,4'). Mass spectrum, m/z: 387.173 [M – H]+. Found, %: С 37.00, H 6.15, N 7.20, S 49.55. C12H24N2S6. Calculated, %: С 37.08, H 6.22, N 7.21, S 49.49.

The fungicidal activity was evaluated by diffusion into agar [16]. The culture medium (potato–glucose agar) was placed in 20–25-mL portions into standard Petri dishes (d 90 mm). The surface of the medium was sown with a suspension of fungus test culture spores. Then three holes were drilled in the medium with a drill 10 mm in diameter,

and 100-μL portions of the test solutions were placed in these holes. The fungicidal activity was evaluated by the diameter of the zone in which the micromycete growth was suppressed, and also by monitoring of the development of test cultures with a Leica DM-100 optical microscope. The fungus development in the culture medium served as control. The incubation time was 7 days at 28°С.

CONCLUSIONS

(1) A procedure is suggested for preparative synthesis of α,ω-bis-1,5,3-dithiazepanes, based on heterocycliza-tion of α,ω-diamines with N,N,N',N'-tetramethylmethane-diamine and 1,2-ethanedithiol.

(2) 1,2-Bis(1,5,3-dithiazepan-3-yl)ethane and 3,3'-(3,6-dioxaoctane-1,8-diyl)bis-1,5,3-dithiazepane ex-hibit fungicidal activity with respect to phytopathogenic fungi Botrytis cinerea and Rhizoctonia solani.

ACKNOWLEDGMENTS

The study was fi nancially supported by the Russian Foundation for Basic Research (project nos. 11-03-00101-а, 11-03-97011r_Povolzh’e_а).

REFERENCES

1. Kunakova, R.V., Khafi zova, S.R., Dal’nova, Yu.S., et al., Neftekhimiya, 2002, vol. 42, no. 5, pp. 382–385.

2. Bialy Serry, A.A., Abdelal, A.M., El-Shorbagi, A., and Kheira Samy, M.M., Arch. Pharm., 2005, vol. 338, no. 1, pp. 38–43.

3. Saraç, S., Ertan, M., Balkan, A., and Yulug, N., Arch. Pharm., 1991, vol. 324, no. 7, pp. 449–453.

4. Ambrogi, V., Grandolini, G., Perioli, L., et al., Eur. J. Med. Chem., 1990, vol. 25, no. 5, pp. 403–411.

5. Ameta, K.L., Pawar, R.P., and Domb, A.J., Bioactive Heterocycles: Synthesis and Biological Evaluation, Nova Science, 2013.

6. Akhmetova, V.R., Vagapov, R.A., Nadyrgulova, G.R., et al., Tetrahedron, 2007, vol. 63, no. 47, pp. 11702–11709.

7. Akhmetova, V.R., Rakhimova, E.B., Minnebaev, A.B., et al., Russ. J. Org. Chem., 2012, vol. 48, no. 2, pp. 202–208.

8. Ito, K. and Sekiya, M., Chem. Pharm. Bull., 1979, vol. 27, no. 7, pp. 1691–1694.

RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 86 No. 10 2013

1508 RAKHIMOVA et al.

9. Murzakova, N.N., Prokof’ev, K.I., Tyumkina, T.V., and Ibragimov, A.G., Zh. Org. Khim., 2012, vol. 48, no. 4, pp. 590– 595.

10. Niatshina, Z.T., Murzakova, N.N., Vasilieva, I.V., et al., ARKIVOC, 2011, no. 8, pp. 141–148.

11. Murzakova, N.N., Rakhimova, E.B., Vasilieva, I.V., et al., Tetrahedron Lett., 2011, vol. 52, no. 32, pp. 4090–4092.

12. Rakhimova, E.B., Vasil’eva, I.V., Khalilov, L.M., et al., Khim. Geterotsikl. Soedin., 2012, no. 7, pp. 1132–1139.

13. Rakhimova, E.B., Efremova, E.A., Bushmarinov, I.S., et al., Tetrahedron Lett., 2012, vol. 53, no. 32, pp. 4225–4227.

14. Rakhimova, E.B., Ismagilov, R.A., Zainullin, R.A., et al., Khim. Geterotsikl. Soedin., 2013, no. 8, pp. 1325–1330.

15. Bilai, V.I., Mikroorganizmy – vozbuditeli boleznei rastenii (Microorganisms Inducing Plant Diseases), Kiev: Naukova Dumka, 1988.

16. Egorov, N.S., Praktikum po mikrobiologii (Practical Course of Microbiology), Moscow: Mosk. Gos. Univ., 1976.