CN112479958B - Preparation method of hydroxy aliphatic selenocyanate derivative - Google Patents

Abstract

The invention discloses a reaction of epoxy derivatives, elemental selenium and TMSCN to construct hydroxy aliphatic selenocyanate under the condition of no metal and no additives. With metal-free participation, additive-free promotion, broad substrate scope and good functional group compatibility, this new strategy provides an efficient and green route for the preparation of various hydroxyaliphatic selenocyanates in a highly concise manner.

Description

A kind of preparation method of hydroxy aliphatic selenocyanate derivatives

technical field

The application belongs to the technical field of organic selenium chemistry, and in particular relates to a preparation method of hydroxyaliphatic selenocyanate derivatives.

Background technique

Hydroxyaliphatic selenocyanate derivatives have great application value (Eur.J.Org.Chem.2006,22,4979-4988; Synth Commun.2016,46,831-868; Synth Commun.2016,46,1397 -1416.), this type of compound can be used as a class of very useful intermediates in synthesis, and can be used to synthesize a series of very useful products such as hydroxyaliphatic selenocyanate (Chem.Rev.2015,115, 3564-3614.; Synthesis. 1996, 6, 669-686; Curr. Chem. 1997, 190, 1-85; Org. Lett. 2020, 22, 3339-3344.). It is widely used in the synthesis of many biomolecules, the research of new materials, and drug molecules (Chem.Soc.Rev.2012,41,643-665.). Therefore, since the last century, the synthesis and properties of these compounds have been widely concerned by more and more organic synthetic chemists in related fields. After referring to previous work and our research group's in-depth research on the efficient insertion of elemental selenium (Adv.Synth.Catal.2018, 360, 4336-4340.), the inventor hopes to use epoxy derivatives , TMSCN, obtained by ring opening under mild conditions in good yields and compatible with a wide range of functional groups. Finally, a convenient, feasible, easy-to-operate, high-yield, environmentally friendly, and efficient strategy for the one-step construction of such hydroxyaliphatic selenocyanates was obtained.

Contents of the invention

The object of the present invention is to provide a kind of preparation method of hydroxy aliphatic selenocyanate derivatives, under the condition of no metal and no additive, epoxy derivatives, elemental selenium and TMSCN are constructed to obtain hydroxy selenocyanate , the method has metal catalyst-free, additive-free promotion, broad substrate scope and good functional group compatibility, which provides an efficient and green route for the preparation of various hydroxyaliphatic selenocyanates in a highly concise manner .

A kind of preparation method of hydroxy aliphatic selenocyanate derivatives provided by the invention comprises the following steps:

In the reactor that is equipped with magnetic stirrer, add the epoxy compound shown in formula I successively, selenium powder, TMSCN and organic solvent, then the atmosphere in the reactor is replaced with an inert atmosphere, heating and stirring the reaction, after the end of the reaction, the reaction The mixture was diluted with ether, filtered through a silica gel pad, the filtrate was concentrated under reduced pressure, and then the residue was purified by silica gel flash chromatography to obtain the hydroxy aliphatic selenocyanate compound shown in formula II; the reaction formula is as follows:

In the above reaction formula, n=0, 1 or 2.

R ₁ , R ₂ , R ₃ represent substituents on the connected ring, independently selected from hydrogen, C _1-20 alkyl, C _1-20 haloalkyl, C _6-20 aryl, C _3-20 ring Alkyl, C _6-20 aryl-C _1-20 alkyl; or two adjacent (R ₁ /R ₂ , R ₂ /R ₂ , R ₂ /R ₃ , R ₁ /R ₃ ) substituents are connected to each other, and form a saturated or unsaturated five- to seven-membered carbocyclic ring together with the carbon atoms connecting these two substituents.

Preferably, when n=0, one of R ₁ and R ₃ is not hydrogen.

Herein, the C _1-20 alkyl group (including the structural part related to the C _1-20 alkyl group in the above-mentioned groups) can be selected from methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc. The C _6-20 aryl group (including the structural part related to the C _6-20 aryl group in the above-mentioned groups) can be selected from phenyl, naphthyl, anthracenyl, and phenanthrenyl. The C _3-20 cycloalkyl group may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The saturated or unsaturated five- to seven-membered carbon ring is selected from cyclopentane ring, cyclohexane ring, benzene ring and the like.

Most preferably, when n=0, _R1 represents a chloromethyl or phenyl group, _R3 represents hydrogen; or _R1 and _R3 are connected to each other and together with the carbon atom connecting these two substituents form a cyclopenta alkane, cyclohexane or benzene ring structure.

When n=1 or 2, R ₁ , R ₂ and R ₃ are all selected from hydrogen.

According to the aforementioned preparation method of the present invention, wherein, the organic solvent is selected from any one of methanol, ethanol, isopropanol, DMSO, DMF, THF, MeCN, toluene, most preferably isopropanol.

According to the aforementioned preparation method of the present invention, wherein, the reaction temperature of the heating and stirring reaction is 60-120°C, preferably 80-100°C, most preferably 90°C. The reaction time of the heating and stirring reaction is 4-48h, preferably 12-24h, most preferably 24h.

According to the aforementioned preparation method of the present invention, wherein, the molar ratio of the epoxy compound shown in formula I, selenium powder, and TMSCN is 1:(2-5):(1-3). Preferably, the molar ratio of the epoxy compound shown in formula I, selenium powder, and TMSCN is 1:3:2.

According to the aforementioned preparation method of the present invention, wherein the reaction atmosphere of the heating and stirring reaction is not particularly limited, it may be an inert atmosphere, an air atmosphere or an oxygen atmosphere, preferably an inert atmosphere. Wherein, the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, preferably a nitrogen atmosphere.

Method of the present invention has obtained following beneficial effect:

The present invention reports for the first time the synthesis strategy of obtaining hydroxyselenocyanate by constructing epoxy derivatives, elemental selenium and TMSCN under the condition of no metal and no additives. The substrate scope and good functional group compatibility provide an efficient and green synthetic route for the preparation of various hydroxyaliphatic selenocyanates in a highly concise manner.

Detailed ways

Below in conjunction with specific embodiment, the present invention is described in further detail. In the text, unless otherwise specified, the methods used are conventional methods in the art, and the reagents used can be purchased through conventional commercial channels and/or prepared by known organic synthesis methods.

Embodiment 1-13 reaction condition optimization experiment

Using epoxycyclohexane represented by formula 1a as a template substrate, the optimal reaction conditions were screened out.

Wherein embodiment 1 reaction operation is as follows:

In a 10mL pressure tube equipped with a stirring magnet, put the formula 1a cyclohexane (0.5mmol), selenium powder (3.0equiv, 1.5mmol), TMSCN (2.0equiv, 1.0mmol) and isopropanol (2mL) . The reaction mixture was stirred at 90° C. for 24 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with 10 mL of ether, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography to obtain the pure target product represented by formula 2a. Yellow liquid (136 mg, 83% yield), EtOAc/PE=1/5.1 H NMR (400 MHz, CDCl ₃ ): δ3.62-3.57 (m, ^1H ), 3.30-3.24 (m, 1H), 2.73 ( s,1H),2.37-2.34(m,1H),2.13-2.10(m,1H),1.82-1.75(m,3H),1.39-1.28(m,3H); ¹³ C NMR(125MHz,CDCl ₃ ) : δ101.3, 73.9, 54.0, 35.8, 34.1, 26.7, 24.2.

Basically consistent with the method of Example 1, only the reaction conditions shown in Table 1 were changed, and the influence of the reaction on the yield of the target product under different conditions was investigated, and the results are shown in Table 1.

Table 1 is as follows:

The experimental results show that the template reaction exhibits different reactivity in various solvents. In the case of isopropanol as the solvent without any additives, the target product is obtained with a yield of 83%. Finally, considering the factors of economy and high efficiency, choose isopropanol as the reaction solvent, and react at 90℃ for 24h under the protection of nitrogen as the optimal condition.

Example 14

Cyclopentane (0.5mmol), selenium powder (3.0equiv, 1.5mmol), TMSCN (2.0equiv, 1.0mmol) and isopropanol were charged into a 10mL pressure tube equipped with a stirring magnet (2 mL). The reaction mixture was stirred at 90° C. for 24 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with 10 mL of ether, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography to obtain the pure target product represented by formula 2b. Colorless liquid (73 mg, yield 76%), EtOAc/PE=1/ ^5.1 H NMR (400 MHz, CDCl ₃ ): δ4.35-4.31 (m, 1H), 3.52 (q, J=5.2 Hz, 1H), 2.95(d, J=2.8Hz, 1H), 2.38-2.31(m, 1H), 2.11-2.06(m, 1H), 1.89-1.75(m, 3H), 1.69-1.63(m, 1H) ; ¹³ C NMR (125MHz, CDCl ₃ ): δ101.6, 79.1, 51.4, 32.7, 31.4, 22.0.

Example 15

In a 10mL pressure tube equipped with a stirring magnet, chloromethyl oxirane (0.5mmol) shown in formula 1c, selenium powder (3.0equiv, 1.5mmol), TMSCN (2.0equiv, 1.0mmol) and Isopropanol (2 mL). The reaction mixture was stirred at 90° C. for 24 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with 10 mL of ether, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography to obtain the pure target product represented by formula 2c. Yellow liquid (68 mg, 80% yield), EtOAc/PE=1/ ^5.1 H NMR (400 MHz, CDCl ₃ ): δ4.20 (s, 1H), 3.71-3.65 (m, 2H), 3.34 ( dd, J=10.0, 3.6Hz, 1H), 3.24(dd, J=9.6, 6.0Hz, 1H), 3.14(d, J=2.8Hz, 1H); ¹³ C NMR (125MHz, CDCl ₃ ): δ101. 8, 70.1, 47.7, 32.9.

Example 16

Phenyloxirane (0.5mmol), selenium powder (3.0equiv, 1.5mmol), TMSCN (2.0equiv, 1.0mmol) and isopropyl are charged into a 10mL pressure tube equipped with a stirring magnet. Alcohol (2 mL). The reaction mixture was stirred at 90° C. for 24 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with 10 mL of ether, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel to obtain the pure target product of formula 2d. Colorless liquid (59mg, yield 52%), EtOAc/PE= ¹ /5.1H NMR (400MHz, CDCl ₃ ): δ7.40-7.36(m, 5H), 4.82(t, J=7.2Hz, 1H), 4.23-4.20 (m, 2H), 2.77 (s, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ136.3, 129.3, 129.2, 128.1, 102.0, 65.4, 52.6.

Example 17

Oxetane (0.5mmol), selenium powder (3.0equiv, 1.5mmol), TMSCN (2.0equiv, 1.0mmol) and isopropanol were charged into a 10mL pressure tube equipped with a stirring magnet (2 mL). The reaction mixture was stirred at 90° C. for 24 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with 10 mL of ether, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel to give the pure target product of formula 2e. Colorless liquid (29 mg, yield 35%), EtOAc/PE=1/2. ¹ H NMR (400 MHz, CDCl ₃ ): δ3.80 (s, 2H), 3.24-3.21 (m, 2H), 2.17- 2.11 (m, 2H), 1.98 (s, 1H); ¹³ C NMR (125 MHz, CDCl ₃ ): δ 102.6, 61.1, 32.7, 26.6.

Example 18

Put formula 1f (2mL), selenium powder (1.5mmol) and TMSCN (1.0mmol) into a 10mL pressure tube equipped with a stirring magnet. The reaction mixture was stirred at 120° C. for 24 hours under nitrogen protection. After the reaction was complete, the reaction mixture was diluted with 10 mL of ether, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography to obtain the pure target product represented by formula 2f. Yellow liquid (48mg, yield 54%), EtOAc/PE= ¹ /5.1H NMR (400MHz, _CDCl3 ): δ3.70(t, J=4.8Hz, 2H), 3.10(t, J=6.0 Hz,2H),2.05-1.99(m,2H),1.80(s,1H),1.74-1.69(m,2H); ¹³ C NMR(125MHz,CDCl ₃ ):δ101.7,61.8,31.8,29.5, 27.6.

The above-mentioned embodiments are only the preferred embodiments determined by the inventor after a large number of tests and screenings, and are not an exhaustive list of feasible implementations of the present invention. For those skilled in the art, on the premise of not departing from the synthesis route of the present invention, any obvious changes made to it should be considered to be included in the protection scope of the claims of the present invention.

Claims (10)

1. A preparation method of a hydroxy aliphatic selenocyanate derivative is characterized by comprising the following steps:

sequentially adding the epoxy compound shown in the formula I, selenium powder, TMSCN and an organic solvent into a reactor provided with a magnetic stirrer, heating and stirring for reaction, diluting a reaction mixture with diethyl ether after the reaction is finished, filtering through a silica gel pad, concentrating filtrate under reduced pressure, and purifying residues through silica gel flash chromatography to obtain the hydroxy aliphatic selenocyanate compound shown in the formula II; the reaction formula is as follows:

in the above reaction formula, n =0,1 or 2;

R ₁ ，R ₂ ，R ₃ represents substituents on the bonded ring, independently of one another, selected from hydrogen and C _1-20 Alkyl radical, C _1-20 Haloalkyl, C _6-20 Aryl radical, C _3-20 Cycloalkyl, C _6-20 aryl-C _1-20 An alkyl group; or two adjacent substituents are linked to each other and form, together with the carbon atom linking the two substituents, a saturated or unsaturated five-to seven-membered carbocyclic ring.

2. The method according to claim 1, wherein R is R when n =0 ₁ And R ₃ One of which is not hydrogen.

3. The method according to claim 1, wherein R is R when n =0 ₁ Represents chloromethyl or phenyl, R ₃ Represents hydrogen; or R ₁ And R ₃ Are linked to each other and form, together with the carbon atoms linking the two substituents, a cyclopentane, cyclohexane or benzene ring structure;

when n =1 or 2, R ₁ ，R ₂ ，R ₃ Are all selected from hydrogen.

4. The method according to any one of claims 1 to 3, wherein the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, DMSO, DMF, THF, meCN, and toluene.

5. The method according to claim 4, wherein the organic solvent is isopropyl alcohol.

6. The process according to any one of claims 1 to 3, wherein the reaction temperature of the heating and stirring reaction is 60 to 120 ℃; the reaction time of the heating stirring reaction is 4-48h.

7. The preparation method according to claim 6, wherein the reaction temperature of the heating stirring reaction is 80-100 ℃; the reaction time of the heating stirring reaction is 12-24h.

8. The method according to claim 7, wherein the reaction temperature of the heating and stirring reaction is 90 ℃; the reaction time of the heating stirring reaction is 24h.

9. The preparation method according to any one of claims 1 to 3, wherein the epoxy compound represented by formula I, the selenium powder and the TMSCN are fed in a molar ratio of 1: (2-5) and (1-3).

10. The preparation method according to claim 9, wherein the feeding molar ratio of the epoxy compound shown in formula I, the selenium powder and the TMSCN is 1:3:2.