Catalyzed ring transformation of cyclic N-aryl-azadiperoxides with participation of α,ω-dithiols

Abstract

Co(OAc)₂-catalyzed ring transformation reaction of 10-aryl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecanes with α,ω-dithiols (ethane-1,2-, propane-1,3-, butane-1,4-, pentane-1,5-, and hexane-1,6-dithiols, 3,6-dioxaoctane-1,8-dithiol) giving 3-aryl-1,5,3-dithiazacyclanes was studied.

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Cyclic peroxides attract attention for their antimalarial,¹ antibacterial,² and antitumor³ activities. Among numerous cyclic peroxides, heteroatomic cyclic peroxides occupy a special place owing to their high biological activities.⁴ The methods of synthesis of heteroatom-containing cyclic peroxides are limited. Recently,^5–10 nitrogen- and sulfur-containing cyclic di- and triperoxides with antitumor activity have been synthesized.^5–9 The development of efficient methods for the preparation of new cyclic hetero-di(tri)peroxides^5–10 promotes active investigation of their transformations. It was shown that the reduction of silatriperoxycycloalkanes with PPh₃ affords siladiperoxycycloalkanes;¹¹ the reaction of spiro{adamantane-[2,3′]-(pentaoxacane)} with o-phenylenediamine results in the synthesis of benzodioxazocine.⁵ The implemented conversion of pentaoxacane with o-phenylenediamine to benzodioxazocine⁵ suggests that cyclic N-containing peroxides can be involved in reactions with binucleophilic reagents, in particular α,ω-dithiols, to give new heterocycles. In contrast to the previously described methods of synthesis^5–10 and transformation of the peroxide ring,^5,11 this work for the first time discusses the method of catalytic conversion of tetraoxazaspirotridecane to dithiazacycloalkanes.

It was shown by preliminary experiments that the reaction of 10-phenyl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecane 1 with ethane-1,2-dithiol 2 does not proceed without a catalyst. The reaction of azadiperoxide 1 with ethane-1,2-dithiol 2 catalyzed by Sm(NO₃)₃·6H₂O, H₂SO₄ or BF₃·Et₂O in THF as a solvent affords 3-phenyl-1,5,3-dithiazepane 8 in 10–15% yield (Scheme 1, Table 1). It was found that the yield of 3-phenyl-1,5,3-dithiazepane¹² is affected by the nature of the catalyst. When the reaction is carried out in a polar solvent (MeOH) in the presence of catalytic amounts of Sm(NO₃)₃·6H₂O, H₂SO₄ or BF₃·Et₂O, the yield of the target product 8 increases to 30%. In the presence of the Co(OAc)₂ catalyst, the yield of heterocycle 8 is 85%. When AlCl₃ or CuCl catalysts are used, the yields of heterocycle 8 are 55% and 75%, respectively (Table 1). Under these conditions, cyclohexanone is formed and O₂ is released (Scheme 1). All reactions were carried out at room temperature for 20 h.

Scheme 1 Ring transformation reaction of 10-phenyl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecane with α,ω-dithiols.

Table 1 Effect of the catalyst and solvent nature on the yield of 3-phenyl-1,5,3-dithiazacyclanes (∼20 °C, 20 h)

No.	Compound	[Cat]	Solvent	Yield, %
1	8	AlCl3	THF	45
2	8	AlCl3	MeOH	55
3	8	Co(OAc)2	THF	79
4	8	Co(OAc)2	MeOH	85
5	8	BF3·OEt2	THF	15
6	8	BF3·OEt2	MeOH	30
7	8	CuCl	THF	68
8	8	CuCl	MeOH	75
9	8	H2SO4	THF	13
10	8	H2SO4	MeOH	25
11	8	Sm(NO3)3·6H2O	THF	10
12	8	Sm(NO3)3·6H2O	MeOH	20
13	8	—	THF	—
14	8	—	MeOH	—
15	9	Co(OAc)2	MeOH	87
16	10	Co(OAc)2	MeOH	79
17	11	Co(OAc)2	MeOH	83
18	12	Co(OAc)2	MeOH	89
19	13	Co(OAc)2	MeOH	91

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A probable pathway to the synthesis of 3-phenyl-1,5,3-dithiazepane 8 from 10-phenyl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecane 1 includes¹³ coordination of the peroxide oxygen atom to the central atom of the catalyst, nucleophilic addition of ethane-1,2-dithiol to the resulting carbocation,^14,15 and the subsequent ring closure giving heterocycle 8 (Scheme 2).

Scheme 2 Probable synthesis mechanism for 3-phenyl-1,5,3-dithiazepane 8.

Under conditions including 5 mol% of Co(OAc)₂, 20 °C, MeOH, and 20 h, 10-phenyl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecane 1 was allowed to react with propane-1,3- 3, butane-1,4- 4, pentane-1,5- 5, and hexane-1,6-dithiols 6, which furnished the corresponding 3-phenyl-1,5,3-dithiaazacycloalkanes¹⁶ 9–12 in 83–89% yields (Table 1). The ring transformation reaction of azadiperoxide 1 with 3,6-dioxa-1,8-octanedithiol 7 (monooxa derivative is shown in the scheme) under the conditions described above resulted in the synthesis of 6-phenyl-1,11-dioxa-4,8-dithia-6-azacyclotridecane¹⁶ 12 in 91% yield (Scheme 1).

The discovered ring transformation reaction of azadiperoxide 1 with ethane-1,2-dithiol 2 was also carried out for 10-aryl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecanes 14–24, which produced 3-aryl-1,5,3-dithiazepanes¹² 25–35 in 76–90% yields (Scheme 3).

Scheme 3 Ring transformation reaction of 10-aryl-7,8,12,13-tetraoxa-10-azaspiro[5.7]tridecanes with ethane-1,2-dithiol.

In conclusion, we demonstrated that on treatment with α,ω-alkanedithiols and the Co(OAc)₂ catalyst, azadiperoxides are converted to N-aryl-substituted 1,5,3-dithiazamacroheterocycles in high yields.

Conflicts of interest

The authors declare no conflict of interest.

Acknowledgements

The reported study was funded by RFBR according to the research project No. 20-33-90002/20.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d0ra09758f

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