阅读说明：本技术 一种胺基脂肪族硒氰酸酯类化合物的制备方法 (Preparation method of amino aliphatic selenocyanate compound ) 是由 周云兵 麻洋通 卢立国 刘妙昌 吴华悦 于 2020-11-27 设计创作，主要内容包括：本发明公开了一种胺基脂肪族硒氰酸酯类化合物的制备方法,在无金属、无添加剂的条件下,N-取代的氮丙啶衍生物与单质硒、TMSCN构建获得胺基脂肪族硒氰酸酯类化合物的反应。该新策略具有无金属参与、无需添加剂促进,广泛的底物范围和良好的官能团兼容性,以高度简洁的方式为多种胺基脂肪族硒氰酸酯的制备提供了一个高效和绿色的合成途径。(The invention discloses a preparation method of an amino aliphatic selenocyanate compound, which is characterized in that under the conditions of no metal and no additive, an N-substituted aziridine derivative, elemental selenium and TMSCN are constructed to obtain the amino aliphatic selenocyanate compound through reaction. The new strategy has the advantages of no metal participation, no additive promotion, wide substrate range and good functional group compatibility, and provides an efficient and green synthetic approach for the preparation of various amino aliphatic selenocyanates in a highly concise manner.)

1. A preparation method of an amino aliphatic selenocyanate compound comprises the following steps:

sequentially adding an N-substituted aziridine compound shown in formula I, selenium powder, TMSCN and an organic solvent into a reactor provided with a magnetic stirrer, then replacing the atmosphere in the reactor with an inert atmosphere, heating and stirring for reaction, diluting a reaction mixture with ethyl acetate after the reaction is finished, filtering through a silica gel pad, concentrating the filtrate under reduced pressure, and then purifying the residue through silica gel flash chromatography to obtain an amino aliphatic selenocyanate compound shown in formula II; the reaction formula is as follows:

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

r is selected from C_1-20Acyl radical, C_1-20Alkoxycarbonyl group, C_1-20Alkylsulfonyl radical, C_6-20Arylsulfonyl radical, quilt C_1-20Alkyl substituted C_6-20An arylsulfonyl group;

R₁，R₂，R₃represents substituents on the bonded ring, independently of one another, selected from hydrogen and C_1-20Alkyl radical, C_1-20Haloalkyl, C_6-20Aryl radical, C_3-20Cycloalkyl radical, C_6-20aryl-C_1-20An 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;

the organic solvent is selected from alcohol solvents, preferably methanol, ethanol or isopropanol, and most preferably isopropanol.

2. The method of claim 1, wherein R is selected from C_1-6Alkoxycarbonyl radical, quilt C_1-6Alkyl substituted C_6-14An arylsulfonyl group.

3. The method according to claim 2, wherein R is selected from the group consisting of t-butyloxycarbonyl (Boc) group and p-toluenesulfonyl (Ts) group.

4. The method according to claim 1, wherein R is 0 when n ═ 0₁And R₃One of which is not hydrogen.

5. The method according to claim 1, wherein R is 0 when n ═ 0₁Represents n-hexyl or phenyl, R₃Represents hydrogen; or R₁And R₃To each other and to the carbon atom linking the two substituentsTogether form a cyclopentane, cyclohexane or benzene ring structure;

when n is 1 or 2, R₁，R₂，R₃Are all selected from hydrogen.

6. The process according to any one of claims 1 to 5, wherein the reaction temperature of the heating and stirring reaction is 60 to 120 ℃, preferably 90 to 100 ℃. The reaction time of the heating stirring reaction is 4 to 48 hours, and preferably 12 to 24 hours.

7. The method according to any one of claims 1 to 5, wherein the molar ratio of the N-substituted aziridine compound of formula I to the selenium powder to TMSCN is 1: (2 to 5) and (1 to 3). Preferably, the feeding molar ratio of the N-substituted aziridine compound shown in the formula I to the selenium powder to the TMSCN is 1: 3:2.

8. The method according to any one of claims 1 to 5, wherein the inert gas atmosphere is a nitrogen gas atmosphere or an argon gas atmosphere, preferably a nitrogen gas atmosphere.

Technical Field

The application belongs to the technical field of organic selenium chemistry, and particularly relates to a preparation method of an amino aliphatic selenocyanate compound.

Background

The amino aliphatic 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), can be used as a very useful drug active intermediate (chem.Rev.2015,115,3564-3614) in synthesis, and are extremely widely applied in the fields of synthesis of a plurality of biomolecules, research of new materials, drug molecules and the like. In the past decades, ring-opening reactions of readily available saturated heterocycles based on C-heteroatom bond cleavage have become an effective strategy for building valuable frameworks (chem.soc.rev.2012,41, 643-. After referring to previous work and intensive research on efficient insertion work of elemental selenium similar to that of a subject group (adv.synth.Catal.2018,360, 4336-4340), the inventors continuously and intensively research and provide a high-efficiency synthesis strategy for constructing the amino aliphatic selenocyanate molecules in one step by utilizing N-substituted aziridine derivatives, the elemental selenium and TMSCN, obtaining good yield through ring opening under mild conditions and being compatible with wide range of functional groups, and finally obtaining the amino aliphatic selenocyanate molecules, wherein the yield is high, and the amino aliphatic selenocyanate molecules are convenient and feasible, easy to operate, green and environment-friendly.

Disclosure of Invention

The invention aims to provide a preparation method of an amino aliphatic selenocyanate compound, which is characterized in that under the conditions of no metal and no additive, an N-substituted aziridine derivative, elemental selenium and TMSCN are constructed to obtain the amino aliphatic selenocyanate compound through reaction. The new strategy has the advantages of no metal participation, no additive promotion, wide substrate range and good functional group compatibility, and provides an efficient and green synthetic approach for the preparation of various amino aliphatic selenocyanates in a highly concise manner.

The invention provides a preparation method of an amino aliphatic selenocyanate compound, which comprises the following steps:

sequentially adding an N-substituted aziridine compound shown in formula I, selenium powder, TMSCN and an organic solvent into a reactor provided with a magnetic stirrer, then replacing the atmosphere in the reactor with an inert atmosphere, heating and stirring for reaction, diluting a reaction mixture with ethyl acetate after the reaction is finished, filtering through a silica gel pad, concentrating the filtrate under reduced pressure, and then purifying the residue through silica gel flash chromatography to obtain an amino aliphatic selenocyanate compound shown in formula II; the reaction formula is as follows:

in the above reaction formula, n is 0,1 or 2.

R is selected from C_1-20Acyl radical, C_1-20Alkoxycarbonyl group, C_1-20Alkylsulfonyl radical, C_6-20Arylsulfonyl radical, quilt C_1-20Alkyl substituted C_6-20An arylsulfonyl group.

R₁，R₂，R₃Represents substituents on the bonded ring, independently of one another, selected from hydrogen and C_1-20Alkyl radical, C_1-20Haloalkyl, C_6-20Aryl radical, C_3-20Cycloalkyl radical, C_6-20aryl-C_1-20An alkyl group; or two adjacent (R)₁/R₂，R₂/R₂，R₂/R₃，R₁/R₃) The substituents are linked to each other and, together with the carbon atom linking the two substituents, form a saturated or unsaturated five-to seven-membered carbocyclic ring.

Preferably, when n ═ 0, R₁And R₃One of which is not hydrogen.

Preferably, R is selected from C_1-6Alkoxycarbonyl radical, quilt C_1-6Alkyl substituted C_6-14An arylsulfonyl group.

Herein, said C_1-20Alkyl (including C as referred to in each of the above groups)_1-20Alkyl moieties) may 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, and the like. Said C is_6-20Aryl (including C as referred to in each of the above groups)_6-20Structural part of aryl) can be selected from phenyl, naphthyl, anthryl, phenanthryl. Said C is_3-20Cycloalkyl groups may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The saturated or unsaturated five-to seven-membered carbocyclic ring is selected from cyclopentane, cyclohexane, benzene rings, and the like.

Most preferably, R is t-butyloxycarbonyl (Boc), p-toluenesulfonyl (Ts).

When n is 0, R₁Represents n-hexyl or phenyl, R₃Represents hydrogen; or R₁And R₃Are connected to each other and to bothThe carbon atoms of the substituent groups together form a cyclopentane, cyclohexane or benzene ring structure.

When n is 1 or 2, R₁，R₂，R₃Are all selected from hydrogen.

According to the preparation method of the present invention, the organic solvent is selected from an alcohol solvent, preferably methanol, ethanol, or isopropanol, and most preferably isopropanol.

According to the preparation method of the invention, the reaction temperature of the heating and stirring reaction is 60-120 ℃, preferably 90-100 ℃. The reaction time of the heating stirring reaction is 4 to 48 hours, and preferably 12 to 24 hours.

According to the preparation method, the feeding molar ratio of the N-substituted aziridine compound shown in the formula I, the selenium powder and the TMSCN is 1: (2 to 5) and (1 to 3). Preferably, the feeding molar ratio of the N-substituted aziridine compound shown in the formula I to the selenium powder to the TMSCN is 1: 3:2.

According to the preparation method of the invention, the inert atmosphere is a nitrogen atmosphere or an argon atmosphere, and preferably a nitrogen atmosphere.

The method of the invention achieves the following beneficial effects:

the invention reports the reaction of constructing and obtaining the amino aliphatic selenocyanate compound by the N-substituted aziridine derivative, elemental selenium and TMSCN under the condition of no metal and no additive for the first time. The new strategy has the advantages of no metal participation, no additive promotion, wide substrate range and good functional group compatibility, and provides an efficient and green synthetic approach for the preparation of various amino aliphatic selenocyanates in a highly concise manner.

Detailed Description

The present invention will be described in further detail with reference to specific examples. In the text, unless otherwise specified, all methods employed are conventional in the art, and the reagents used are commercially available from conventional sources and/or are prepared by known organic synthesis methods.

Examples 1-14 optimization of reaction conditions

The optimal reaction conditions were screened using N-Ts-substituted aziridines as template substrate, as shown in formula 1a (Table 1).

TABLE 1

^[a]1a (0.5mmol), selenium powder (1.5mmol), TMSCN (1.0mmol) in solvent (2mL) at T ℃ and N₂The reaction was carried out for 24 hours.^[b]Yield of isolated product by column chromatography.

Taking example 13 as an example, a typical reaction run is as follows:

a10 mL pressure tube containing a stirring magnet was charged with N-Ts-substituted aziridine compound (0.5mmol) as shown in formula 1a, selenium powder (3.0equiv), TMSCN (2.0equiv) and isopropanol (2 mL). The reaction mixture was stirred at 100 ℃ for 24 hours under nitrogen. After the reaction was complete, the reaction mixture was diluted with 10mL of ethyl acetate, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel to afford the pure target product. White solid (147mg, 82% yield), mp 166.7-166.9 ℃. EtOAc/PE-1/5.¹H NMR(400MHz,CDCl₃):δ7.78(d,J＝6.4Hz,2H),7.34(d,J＝6.4Hz,2H),5.10(d,J＝7.2Hz,1H),3.42-3.37(m,1H),3.25-3.19(m,1H),2.44(s,3H),1.90(d,J＝7.6Hz,1H),1.80-1.70(m,3H),1.63(s,1H),1.31-1.24(m,3H)；¹³C NMR(125MHz,DMSO):δ148.0,144.0,134.9,131.7,108.0,62.0,56.1,39.7,38.9,31.3,29.3,26.2。

The experimental result shows that the template reaction shows different reactivities in various solvents, the yield of the template reaction is generally higher in polar protic solvents, and particularly, the target product is obtained in 82% yield without any additive under the condition that isopropanol is used as a solvent. Finally, considering economic and efficient factors, isopropanol is selected as a reaction solvent, and the reaction is carried out for 24 hours at 100 ℃ under the protection of nitrogen, wherein the optimal condition is.

Example 15

A10 mL pressure tube containing a stirring magnet was charged with N-Ts-substituted aziridine compound (0.5mmol) as shown in formula 1b, selenium powder (3.0equiv), TMSCN (2.0equiv) and isopropanol (2 mL). The reaction mixture was stirred at 100 ℃ for 24 hours under nitrogen. After the reaction was complete, the reaction mixture was diluted with 10mL of ethyl acetate, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel to afford the pure target product. A colorless oily liquid (141mg, 82% yield), EtOAc/PE 1/5.¹H NMR(400MHz,CDCl₃):δ7.79(d,J＝8.4Hz,2H),7.32(d,J＝8.4Hz,2H),5.84(d,J＝7.2Hz,1H),3.61-3.50(m,2H),2.43(s,3H),2.35-2.26(m,1H),1.97-1.80(m,2H),1.75-1.67(m,2H),1.51-1.44(m,1H)；¹³C NMR(125MHz,CDCl₃):δ144.0,136.8,130.0,127.3,101.3,61.2,49.1,32.3,31.2,22.3,21.6。

Example 16

A10 mL pressure tube containing a stirring magnet was charged with N-Ts-substituted aziridine compound (0.5mmol) as shown in formula 1c, selenium powder (3.0equiv), TMSCN (2.0equiv) and isopropanol (2 mL). The reaction mixture was stirred at 100 ℃ for 24 hours under nitrogen. After the reaction was complete, the reaction mixture was diluted with 10mL of ethyl acetate, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel to afford the pure target product. Yellow liquid (173mg, 89% yield), EtOAc/PE 1/5.¹H NMR(400MHz,CDCl₃):δ7.79(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),5.50(d,J＝7.2Hz,1H),3.48-3.42(m,1H),3.23(d,J＝5.6Hz,2H),2.44(s,3H),1.57-1.40(m,2H),1.29-1.02(m,8H),0.82(t,J＝7.2Hz,3H)；¹³C NMR(125MHz,CDCl₃):δ143.9,136.9,129.8,127.1,102.0,53.5,35.5,33.9,31.4,28.5,25.2,22.3,21.5,13.9。

Example 17

A10 mL pressure tube containing a stirring magnet was charged with N-Ts-substituted aziridine compound (0.5mmol) as shown in formula 1d, selenium powder (3.0equiv), TMSCN (2.0equiv) and isopropanol (2 mL). The reaction mixture was stirred at 100 ℃ for 24 hours under nitrogen. After the reaction was complete, the reaction mixture was diluted with 10mL of ethyl acetate, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel to afford the pure target product. Yellow liquid (127mg, 67% yield), EtOAc/PE 1/5.¹H NMR(400MHz,CDCl₃):δ7.73(d,J＝7.6Hz,2H),7.36-7.32(m,5H),7.26(d,J＝3.2Hz,2H),4.96(s,1H),4.69(t,J＝7.2Hz,1H),3.78-3.65(m,2H),2.45(s,3H)；¹³C NMR(125MHz,CDCl₃):δ144.2,136.5,135.6,130.0,129.6,129.5,127.8,127.1,101.0,48.9,47.7,21.6。

Example 18

A10 mL pressure tube containing a stirring magnet was charged with N-Ts-substituted azetidine (0.5mmol) as shown in formula 1e, selenium powder (3.0equiv), TMSCN (2.0equiv) and isopropanol (2 mL). The reaction mixture was stirred at 100 ℃ for 24 hours under nitrogen. After the reaction was complete, the reaction mixture was diluted with 10mL of ethyl acetate, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel to afford the pure target product. Yellow liquid (40mg, 25% yield), EtOAc/PE 1/5.¹H NMR(400MHz,CDCl₃):δ7.76-7.71(m,2H),7.35-7.29(m,2H),5.41-5.39(m,1H),3.15-3.04(m,4H),2.45(s,3H),2.09-2.02(m,2H)；¹³C NMR(125MHz,CDCl₃):δ143.8,136.4,129.9,127.0,101.9,41.5,30.5,26.4,21.5。

Example 19

A10 mL pressure tube equipped with a stirring magnet was charged with N-Boc-substituted azetidine (0.5mmol) as shown in formula 1f, selenium powder (3.0equiv), TMSCN (2.0equiv) and isopropanol (2 mL). The reaction mixture was stirred at 100 ℃ for 24 hours under nitrogen. After the reaction was complete, the reaction mixture was diluted with 10mL of ethyl acetate, filtered through a pad of silica gel and concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel to afford the pure target product. Yellow liquid (20mg, 30% yield), EtOAc/PE-1/10.¹H NMR(400MHz,CDCl₃):δ4.78(s,1H),3.33-3.28(m,2H),3.13-3.07(m,2H),2.13-2.06(m,2H),1.44(s,9H)；¹³C NMR(125MHz,CDCl₃):δ156.0,102.2,79.7,39.2,31.5,28.4,27.1。

The embodiments described above are only preferred embodiments of the inventors determined after extensive experimental screening and are not exhaustive of the possible implementations of the invention. Any obvious modifications to the present invention, which do not depart from the synthetic route of the present invention, should be construed as being included within the scope of the present invention as set forth in the appended claims.