Preparation method of selenium-containing heterocyclic compounds

Abstract

A reaction of azacyclopropane derivative with elemental selenium and TMSCN to construct a selenium-containing heterocycle under metal-free and additive-free conditions is provided. The new strategy features no metal participation, no additive promotion, a wide substrate selection range and a good functional group compatibility, and provides an efficient and green approach to constructing a variety of selenium-containing heterocyclic compounds in a highly concise way.

Claims

1. A preparation method of a selenium-containing heterocyclic compound, comprising the following steps: sequentially adding azacyclopropane derivative of formula I, selenium powder, trimethylsilyl cyanide (TMSCN) and an organic solvent to a reactor equipped with a magnetic stirrer, subsequently replacing atmosphere in the reactor with an inert atmosphere, heating and stirring for reaction to obtain a reaction mixture, diluting the reaction mixture with ethyl acetate after the reaction, and then filtering through a silica gel pad to obtain a filtrate, concentrating the filtrate under a reduced pressure to obtain a residue, and then purifying the residue by silica flash chromatography, thereby obtaining a selenium-containing heterocyclic compound of formula II; wherein a formula for the reaction is as follows: ##STR00007## where n=2; where adjacent two R.sub.1/R.sub.2 substituent groups are connected to each other and form a benzene ring structure together with carbon atoms connecting the adjacent two R.sub.1/R.sub.2 substituent groups, and adjacent two R.sub.2/R.sub.3 substituent groups each are hydrogen group; wherein the organic solvent is one selected from alcoholic solvents.

2. The preparation method according to claim 1, wherein the organic solvent is one selected from the group consisting of methanol, ethanol and isopropanol.

3. The preparation method according to claim 1, wherein the organic solvent is isopropanol.

4. The preparation method according to claim 1, wherein reaction temperature of the heating and stirring for reaction is 80˜120° C., reaction time of the heating and stirring for reaction is 4˜48 hours (h).

5. The preparation method according to claim 4, wherein the reaction temperature is 100° C., and the reaction time is 12˜24 h.

6. The preparation method according to claim 5, wherein the reaction time is 24 h.

7. The preparation method according to claim 1, wherein a molar ratio of the azacyclopropane derivative of the formula I, the selenium powder and the TMSCN is 1:(2˜5):(1˜3).

8. The preparation method according to claim 7, wherein the molar ratio of the azacyclopropane derivative of the formula I, the selenium powder and the TMSCN is 1:3:2.

9. The preparation method according to claim 1, wherein the inert atmosphere is one of nitrogen atmosphere and argon atmosphere.

10. The preparation method according to claim 1, wherein the inert atmosphere is argon atmosphere.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

(1) The disclosure is further described below in combination with specific embodiments. In the illustrated embodiments, unless otherwise specified, the methods adopted are conventional methods in the related art, and the reagents used can be purchased through conventional commercial channels and/or prepared through known organic synthesis methods.

Embodiments 1-14

(2) Using 2-hexylazacyclopropane as a template substrate, optimal reaction conditions are selected (see Table 1).

(3) ##STR00002##

(4) TABLE-US-00001 TABLE 1 Reaction Embodiment.sup.[a] Solvent temperature Yield (%).sup.[b] 1 Dimethyl sulfoxide (DMSO) 90 NR 2 toluene 90 NR 3 Dioxane 90 NR 4 N-Methyl pyrrolidone (NMP) 90 NR 5 acetonitrile 90 NR 6 Dichloroethane (DCE) 90 25 7 Tetrahydrofuran (THF) 90 39 8 Isopropanol (IPA) 90 78 9 Ethanol (EtOH) 90 74 10 IPA 25 NR 11 IPA 60 34 12 IPA 80 66 13 IPA 100 94 14 IPA 120 87

(5) Where, in table 1, [a] represents using the 2-hexylazacyclopropane (0.5 millimole (mmol)), selenium powder (1.5 mmol), trimethylsilyl cyanide (TMSCN) (1.0 mmol) to react in solvent (2 milliliters (mL)) at T ° C. and N.sub.2 for 24 hours (h); [b] represents the yield of products separated by a column chromatography.

(6) Taking the embodiment 13 as an example, typical reaction operations are as follows:

(7) the 2-hexylazacyclopropane (0.5 mmol), the selenium powder (3.0 equiv), the TMSCN (2.0 equivalents (equiv)) and isopropanol (2 mL) are added into a 10 mL pressure tube equipped with a stirring magnet (also referred to as a magnetic stirrer) to obtain a reaction mixture. The reaction mixture is stirred under nitrogen protection at 100° C. for 24 h. After the reaction, the reaction mixture is diluted with 10 mL of ethyl acetate, filtered through a silica gel pad and concentrated under a reduced pressure to obtain a residue. Then the residue is purified by silica gel flash chromatography to obtain a pure target product. Yellow liquid (110 milligrams (mg), 94% yield), CH.sub.3OH/dichloromethane (DCM)=1/10. .sup.1H nuclear magnetic resonance (NMR) (400 MHz, CDCl.sub.3): δ 6.54 (s, 2H), 4.22-4.17 (m, 1H), 3.64 (dd, J=8.0, 5.6 Hz, 1H), 3.27 (dd, J=8.0, 6.0 Hz, 1H), 1.82-1.76 (m, 1H), 1.66-1.59 (m, 1H), 1.33-1.24 (m, 8H), 0.84 (t, J=5.2 Hz, 3H); .sup.13C NMR (125 MHz, deuterated chloroform (CDCl.sub.3)): δ 169.6, 65.0, 34.2, 32.8, 31.6, 29.0, 26.1, 22.6, 14.1.

(8) The experimental results in Table 1 show that the template reaction shows different reactivity in various solvents. In polar proton solvents, the yield of template reaction is generally high, especially in the case of isopropanol as solvent, the target product is obtained in 94% yield without any additives. Finally, considering factors of economy and efficiency, the isopropanol is selected as the reaction solvent and reacted at 100° C. for 24 hours under the protection of nitrogen.

Embodiment 15

(9) ##STR00003##

(10) 2-benzylazacyclopropane (0.5 mmol), selenium powder (3.0 equiv), TMSCN (2.0 equiv) and isopropanol (2 mL) are added into a 10 mL pressure tube equipped with a stirring magnet to obtain a reaction mixture. The reaction mixture is stirred under nitrogen protection at 100° C. for 24 h. After the reaction, the reaction mixture is diluted with 10 mL of ethyl acetate, filtered through a silica gel pad and concentrated under a reduced pressure to obtain a residue. Then the residue is purified by silica gel flash chromatography to obtain a pure target product. Yellow liquid (64.8 mg, yield 54%), CH.sub.3OH/DCM=1/10. .sup.1H NMR (400 MHz, CDCl.sub.3): δ 7.32-7.28 (m, 2H), 7.24-7.20 (m, 3H), 5.64 (s, 2H), 4.38-4.33 (m, 1H), 3.46-3.40 (m, 1H), 3.28-3.21 (m, 1H), 3.08-3.01 (m, 1H), 2.81-2.75 (m, 1H); .sup.13C NMR (125 MHz, CDCl.sub.3): δ 158.7, 138.6, 129.2, 128.6, 126.5, 73.3, 41.1, 36.4.

Embodiment 16

(11) ##STR00004##

(12) Azacyclobutane (0.5 mmol), selenium powder (3.0 equiv), TMSCN (2.0 equiv) and isopropanol (2 mL) are added into a 10 mL pressure tube equipped with a stirring magnet to obtain a reaction mixture. The reaction mixture is stirred under nitrogen protection at 100° C. for 24 h. After the reaction, the reaction mixture is diluted with 10 mL of ethyl acetate, filtered through a silica gel pad and concentrated under a reduced pressure to obtain a residue. Then the residue is purified by silica gel flash chromatography to obtain a pure target product. Yellow liquid (46 mg, yield 56%), CH.sub.3OH/DCM=1/10. .sup.1H NMR (400 MHz, hexadeuteroacetone (CD.sub.3COCD.sub.3)): δ 3.68-3.64 (m, 2H), 3.46-3.42 (m, 2H), 2.34-2.30 (m, 2H), 2.12 (s, 2H); .sup.13C NMR (125 MHz, CD.sub.3COCD.sub.3): δ 166.9, 43.9, 23.3, 23.2.

Embodiment 17

(13) ##STR00005##

(14) Tetrahydropyrrole (0.5 mmol), selenium powder (3.0 equiv), TMSCN (2.0 equiv) and isopropanol (2 mL) are added into a 10 mL pressure tube equipped with a stirring magnet to obtain a reaction mixture. The reaction mixture is stirred under nitrogen protection at 100° C. for 24 h. After the reaction, the reaction mixture is diluted with 10 mL of ethyl acetate, filtered through a silica gel pad and concentrated under a reduced pressure to obtain a residue. Then the residue is purified by silica gel flash chromatography to obtain a pure target product. Colorless liquid (71 mg, yield 80%), CH.sub.3OH/DCM=1/10. .sup.1H NMR (400 MHz, CD.sub.3COCD.sub.3): δ 4.18-4.15 (m, 4H), 2.26-2.23 (m, 4H), 2.09 (s, 2H); .sup.13C NMR (125 MHz, CD.sub.3COCD.sub.3): δ 186.5, 55.5, 46.3, 25.5, 24.9.

Embodiment 18

(15) ##STR00006##

(16) Dihydroindole (0.5 mmol), selenium powder (3.0 equiv), TMSCN (2.0 equiv) and isopropanol (2 mL) are added into a 10 mL pressure tube equipped with stirring magnet to obtain a reaction mixture. The reaction mixture is stirred under nitrogen protection at 100° C. for 24 h. After the reaction, the reaction mixture is diluted with 10 mL of ethyl acetate, filtered through a silica gel pad and concentrated under a reduced pressure to obtain a residue. Then the residue is purified by silica gel flash chromatography to obtain a pure target product. Yellow liquid (39 mg, yield 34%), CH.sub.3OH/DCM=1/10. .sup.1H NMR (400 MHz, DMSO): δ 8.91 (s, 1H), 8.22 (s, 2H), 7.25-7.23 (m, 1H), 7.18-7.13 (m, 1H), 7.05-7.00 (m, 1H), 4.12-4.07 (m, 2H), 3.09-3.05 (m, 2H); .sup.13C NMR (125 MHz, DMSO): δ 174.0, 143.0, 134.0, 125.8, 125.0, 123.5, 116.7, 53.1, 26.2.

(17) The above illustrated embodiments are only preferred embodiments determined by the inventor after a large number of tests and screening, and are not an exhaustive list of feasible embodiments of the disclosure. For those skilled in the art, any obvious changes made to the synthetic route of the disclosure without departing from the synthetic route of the disclosure shall be considered to be included in the protection scope of the claims of the disclosure.