Regioselective syntheses of bis-(2-haloalkyl) selenides and dihalo[bis-(2-haloalkyl)]- λ 4 -selanes from selenium dihalides and 1-alkenes, and the methoxyselenenylation reaction

Regioselective syntheses of bis-(2-haloalkyl) selenides in excellent yields were developed based on selenium dihalides and terminal alkenes (1-hexene, 1-heptene and 1-octene). The addition of selenium dichloride and dibromide to the alkenes occurred via the intermediate formation of kinetic products, anti-Markovnikov bis-(1-haloalk-2-yl) selenides, which were further transformed into thermodynamically stable Markovnikov products presumably via seleniranium intermediates. Preparations of dihalo[bis-(2-haloalkyl)]- λ 4 -selanes in 95-99% yields were accomplished by halogenation of bis-(2-haloalkyl) selenides. The system MeOH / NaHCO 3 / CH 2 Cl 2 was developed for methoxyselenenylation of the alkenes using selenium dibromide leading to bis-(2-methoxyalkyl) and bis-(1-methoxyalk-2-yl) selenides in 68-80% total yields.

Methoxyselenenylation reactions have many useful applications in modern organic synthesis allowing simultaneous introduction of the selenium atom and methoxy group into double bonds. 2 Seleniranium cations are regarded as intermediates in these reactions. 2ecently we studied the methoxy-and ethoxy-selenenylation of selenium dihalides with styrene and its derivatives. 36The reaction proceeded regioselectively, affording bis-(2-alkoxy-2-phenylethyl) selenides in high yields.
We found that addition of selenium dichloride to alkenes 1a-c proceeds efficiently in chloroform at -60 o C, while favorable solvent for the reactions of selenium dibromide is carbon tetrachloride (at -20 o C).It is necessary to mix the reagents and to carry out the reactions at low temperature (at -60 o C in chloroform and at -20 o C in carbon tetrachloride).When the reactions were carried out at room temperature, halogenation of the double bond with the formation of 1,2-dihaloalkanes and precipitation of elemental selenium were also observed.
It is necessary to carry out the reactions by addition of selenium dichloride or dibromide to a solution of alkenes 1a-c at low temperature (a 1 : 2 ratio molar ratio of selenium dihalide and alkene).With inverse addition, i.e. when a solution of alkene was added to a solution of selenium dihalide, the formation of compounds with 4-valent selenium, dihalo[bis-(2-haloalkyl)]-λ 4 -selanes 6a-c and 7a-c, as by-products in up to 15% yield were observed.In these cases the selenium dichloride and dibromide, present in excess, behave as halogenating agents, converting the selenides 2a-c and 3a-c into the corresponding selanes 6a-c and 7a-c (Scheme 3).
Efficient synthesis of selanes 6a-c and 7a-c in near quantitative yields (95-99%) was developed based on the reaction of selenides 2a-c and 3a-c with sulfuryl chloride or bromine in hexane at 0 o C (Scheme 3).Selanes 6a-c and 7a-c precipitated from the reaction mixture under these conditions and can easily be isolated.
Synthesis of compound 6a by addition of SeCl4 to 1-hexene was previously reported in old works 37,38 without NMR data.We found that addition of selenium dihalides to alkenes 1a-c initially led to anti-Markovnikov products, bis-(1-haloalk-2-yl) selenides 8a-c and 9a-c (Scheme 4), which were detected in the reaction mixture by 1 H and 13 C NMR in CCl4 (the content of selenides 8a-c or 9a-c in the mixture with corresponding 2a-c or 3a-c was about 65-90%).Compounds 8a-c and 9a-c are kinetic products which could not be isolated in pure form since they undergo rearrangement to thermodynamic Markovnikov products 2a-c and 3a-c at room temperature.
The content of compounds 8a-c or 9a-c predominated over the corresponding 2a-c or 3a-c at the beginning of the reactions (carbon tetrachloride, -20 o C, 1-2 h).However, if the reactions were carried out at room temperature, the Markovnikov products 2a-c and 3a-c predominated.For example, the ratio of compounds 2c/8c was about 3:2 when the reaction was carried out for 1 h in carbon tetrachloride at room temperature (NMR data).
The rearrangement is suggested to proceed via seleniranium intermediates A and B. This reaction went slowly in low-polarity solvents (carbon tetrachloride, hexane) and faster in more polar solvents such as chloroform, methylene chloride or acetonitrile.It was found that the rearrangement proceeded faster with bromo derivatives than with the chlorine-containing analogs.On heating the rate of the rearrangement increased.
We found that methoxyselenenylation of alkenes 1a-c with selenium dibromide in the system MeOH / NaHCO3 / CH2Cl2 (or CHCl3) led to a mixture of Markovnikov-type bis-(2-methoxyalkyl) selenides 4a-c and anti-Markovnikov bis-(1-methoxyalk-2-yl) selenides 5a-c (Scheme 5).The compounds 4a-c were the major products in all cases (a ratio of 4a-c/5a-c was about 3 : 1-2).The total yields of compounds 4a-c and 5a-c after purification by column chromatography were 68-80%.In contrast to the results of our previous work, 24 compounds 5a-c were isolated in a pure form by column chromatography.Some unidentified by-products, presumably unsymmetrical (2-methoxyalkyl)-(1-methoxyalk-2-yl) selenides (10a-c), were also formed in the reaction.© ARKAT USA, Inc The methoxy derivatives can be also obtained by nucleophilic substitution of the halide atom by methanol.The methanolysis of selenide 3c in MeOH/NaHCO3/CH2Cl2 was studied.It was found that the methanolysis of 3c led to the formation of the same products 4c and 5c in the same ratio (3 : 2) as in the methoxyselenenylation reaction.This fact indicates that the methoxyselenenylation reactions as well as the methanolysis proceeded via the same intermediates, seleniranium cations.The formation of anti-Markovnikov methanolysis product 5c from Markovnikov adducts 3b can be rationalized via assuming the generation of seleniranium intermediates C and D (Scheme 6).Structural assignment of the synthesized compounds was made by 1 Н and 13 С NMR spectra and confirmed by analytical data.The values of the 13 C- 77 Se coupling constants (65-70 Hz) corresponding to the direct coupling ( 1 JC-Se) was observed for the CH2-group, indicating that the selenium atom added to the terminal carbon of alkenes 1a-c.The products are approximately equimolar mixtures of two diastereomers (d,l-and meso-forms, SR/RS and RR/SS), which exhibit different signals of the SeCH2, SeCH, CH2X, CHX (X = Cl, Br, OMe) groups in NMR spectra (in some cases the signals of two diastereomers coincided). 77

Conclusions
The addition of selenium dihalides to terminal alkenes occurred in a regioselective mode affording selenides 2ac and 3a-c in quantitative yield.The reaction proceeded via initially formed kinetic anti-Markovnikov products 8a-c and 9a-c, which underwent rearrangement to thermodynamically stable Markovnikov products 2a-c and 3a-c.The rearrangement was supposed to proceed via seleniranium intermediates.Efficient synthesis of selanes 6a-c and 7a-c in 95-99% yield was accomplished by halogenation of selenides 2a-c and 3a-c.The methoxyselenenylation reaction of alkenes with selenium dibromide was carried out in the system MeOH/NaHCO3/CH2Cl2 leading to bis-(2-methoxyalkyl) 4a-c and bis-(1-methoxyalk-2-yl) selenides 5a-c in 68-80% total yields.The methanolysis of bis-(2-bromoheptyl) selenide leads to the formation of bis-(2methoxyheptyl) selenide 4c and bis-(1-methoxyhept-2-yl) selenide 5c in the same ratio (3 : 2) as this was observed in the methoxyselenenylation reaction, thus indicating that both methoxyselenenylation and methanolysis reactions proceed through the same seleniranium intermediates.The synthesized compounds are valuable starting material for preparation of novel organoselenium compounds and intermediates for organic synthesis.Potential biological activity (e.g., glutathione peroxidase-like activity [14][15][16][17] ) can be supposed for the methoxy derivatives 4a-c and 5a-c.

Experimental Section
General.NMR spectra were recorded on a Bruker DPX-400 instrument. 1 H NMR spectra were acquired at operating frequencies 400.13 MHz and chemical shifts were recorded relative to SiMe4 (δ 0.00) or solvent resonance (CDCl3 δ 7.26). 13C NMR spectra were acquired at 100.61 Hz and chemical shifts were recorded relative to solvent resonance (CDCl3 δ 77.23 or CCl4 δ 96.70). 77Se NMR spectra were obtained at 76.3 MHz and chemical shifts were recorded relative to Me2Se (δ 0.00).Elemental analysis of carbon and hydrogen was performed on the THERMO Flash EA1112 analyzer.Analytical determination of chlorine, bromine and selenium was made by known methods. 39Dried and freshly distilled solvents were used in the reactions.