CN113461578B - Green synthesis method of functionalized sulfoxide compound - Google Patents

Abstract

The invention discloses a green synthesis method of a functionalized sulfoxide compound, which comprises the steps of accurately weighing arylsulfinic acid, 1, 3-eneyne and ytterbium trifluoromethanesulfonate, and then adding the arylsulfinic acid, the 1, 3-eneyne and the ytterbium trifluoromethanesulfonate into a reaction tube filled with an aqueous solution; placing the reaction tube on a stirrer, and stirring and reacting for a plurality of times under the condition of room temperature; after the reaction is finished, extracting, drying the organic phase, and concentrating by a rotary evaporator to obtain a residue; and separating the residue by column chromatography to obtain the target product functionalized sulfoxide compound. The invention adopts the ytterbium trifluoromethanesulfonate catalysis strategy, quickly and efficiently synthesizes novel functionalized sulfoxide compounds in aqueous phase reaction, and has the advantages of simple operation, cheap and easily obtained raw materials, mild and green reaction conditions, short reaction time, easily separated products, good functional group compatibility and the like.

Description

A green synthesis method of functionalized sulfoxide compounds

technical field

The invention relates to a synthesis method of sulfoxide compounds, in particular to a green synthesis method of benzofulvene-functionalized sulfoxide compounds.

Background technique

The sulfoxide group is a sulfur-containing functional group of great value, which widely exists in natural products and clinical therapeutic drugs, such as the commercially available drug omeprazole for the treatment of gastric ulcer and reflux esophagitis, as well as for the treatment of Modafinil for depression, idiopathic hypersomnia, or narcolepsy. In addition, benzofulvenes are a class of molecules having a benzocyclopentadiene skeleton with exocyclic carbon-carbon double bonds. Benzofulvene is not only the core structure skeleton of many drug molecules and natural products, but also an important class of synthetic intermediates. In recent years, benzofulvene has also been used in the research of polymer functional materials. By changing the functional groups, the properties of polymer materials can be changed, and it has broad application prospects in optoelectronic materials. In addition, benzofulvene and its derivatives contain a cyclopentadiene skeleton, which can be used to prepare post-metallocene catalysts and be applied to organic synthesis such as asymmetric olefin polymerization and Diels-Alder reaction. Based on the important role of benzofulvene-functionalized sulfoxide compounds in medicinal chemistry and synthetic chemistry, it can be boldly predicted that benzofulvene-functionalized sulfoxide compounds may have potentially very important application values. However, at present, there is no efficient method for the synthesis of benzofulvene-functionalized sulfoxides. Therefore, it is of great significance to explore new methods for the synthesis of benzofulvene-functionalized sulfoxides that are green, simple, and mild in conditions, in the fields of medicinal chemistry, synthetic chemistry, and materials science.

Contents of the invention

In order to make up for the deficiencies in the prior art, the object of the present invention is to provide a simple and green method to realize the synthesis of benzofulvene-functionalized sulfoxide compounds. Using sulfinic acid and 1,3-enyne as raw materials, the reaction has the advantages of simple operation, short reaction time, green and mild conditions, easy separation of products, and good functional group compatibility.

In order to achieve the above object, the technical means adopted in the present invention is a green synthesis method of a benzofulvene-functionalized sulfoxide compound, the steps of which are as follows:

Step 1. Take arylsulfinic acid, 1,3-enyne, and ytterbium trifluoromethanesulfonate, and add them to a reaction vessel filled with an aqueous solution;

Step 2, the reaction vessel in step 1 is placed on the stirrer, under room temperature condition, stirring reaction several hours;

Step 3. After the reaction is over, pour the reaction mixture into a separatory funnel filled with deionized water, extract and wash with ethyl acetate three times, and combine the organic phases;

Step 4, drying the organic phase obtained in step 3 with magnesium sulfate, suction filtering, removing magnesium sulfate, and concentrating the organic phase with a rotary evaporator to obtain a residue;

Step 5, the residue is separated by column chromatography to obtain the functionalized sulfoxide compound of the target product.

Further, in the first step, the mass ratio of arylsulfinic acid, 1,3-enyne, and ytterbium trifluoromethanesulfonate is 1:0.8-1.4:0.1-0.5.

Further, in the second step, the stirring reaction time is 25-35 minutes.

Further, the separation by column chromatography in the step five refers to silica gel and mobile phase, wherein the mobile phase is composed of petroleum ether and ethyl acetate in a volume ratio of 5:1.

Further, in the first step, arylsulfinic acid refers to one of benzenesulfinic acid, p-fluorobenzenesulfinic acid, 2-thiophenesulfinic acid and p-toluenesulfinic acid.

Further, in the first step, 1,3 enyne refers to: ( E )-(3-benzyl-2-en-4-yne-1,2,5-phenylenyne), ( E ) -(3-Benzyl-2-en-4-yne-1,2,5-phenylenyne), ( E )-(3-benzyl-2-en-4-yne-1,2,5 -phenylpentenyne), ( E )-4,4'-(3-benzyl-5-phenyl-3-en-1-yne-1,4-di-p-fluorophenyl-1,3- pentenyne), ( E )-4,4'-(2-phenyl-3-(phenylethyl)but-2-ene-1,4-diyl)bis((trifluoromethyl)benzene ) of a kind.

Further, in the step five, the functionalized sulfoxide compound refers to: (E )-2,3-dibenzyl-1-(phenyl(phenylsulfinyl))methylene- 1H- Indene, ( E )-2,3-dibenzyl-1-(phenyl(p-fluorophenylsulfinyl))methylene- 1H -indene, ( E )-2,3-dibenzyl- 1-(Phenyl(2-thiophenesulfinyl))methylene-1 H -indene, ( E )-2,3-dibenzyl-6-fluoro-1-(4-fluorophenyl(p-methyl phenylsulfinyl))methylene- 1H -indene, ( E )-1-(phenyl(p-methylphenylsulfinyl))methylene-2,3-bis((4-trifluoro methyl)benzyl) -1H -indene.

The beneficial effect of the present invention is: the addition and cyclization reaction of arylsulfinic acid and 1,3-enyne catalyzed by ytterbium trifluoromethanesulfonate is realized by adopting a green, simple, effective, and no external additive strategy, and the obtained A novel sulfoxide compound functionalized with benzofulvene was developed; the reaction uses cheap and easily available arylsulfinic acid and 1,3-enyne as the reaction raw materials, and has the advantages of simple operation, short reaction time, green and mild conditions, The advantages of easy separation of products and good functional group compatibility lay the foundation for the further application of benzofulvene-functionalized sulfoxide compounds in the fields of medicinal chemistry and material science.

Description of drawings

The present invention will be described in detail below in conjunction with drawings and embodiments.

Fig. 1 chemical reaction equation of the present invention;

The hydrogen spectrogram of the compound 3a of Fig. 2 embodiment 1 of the present invention;

The carbon spectrogram of the compound 3a of Fig. 3 embodiment 1 of the present invention;

The hydrogen spectrogram of the compound 3b of Fig. 4 embodiment 2 of the present invention;

The carbon spectrogram of the compound 3b of Fig. 5 embodiment 2 of the present invention;

The hydrogen spectrogram of the compound 3c of Fig. 6 embodiment 3 of the present invention;

The carbon spectrogram of compound 3c of Fig. 7 embodiment 3 of the present invention;

The hydrogen spectrogram of the compound 3d of Fig. 8 embodiment 4 of the present invention;

The carbon spectrogram of the compound 3d of Fig. 9 embodiment 4 of the present invention;

The hydrogen spectrogram of the compound 3e of Fig. 10 embodiment 5 of the present invention;

Figure 11 is the carbon spectrum of compound 3e of Example 5 of the present invention;

Fig. 12 is the yield comparison table of the embodiment of the present invention.

Detailed ways

Example 1

The green synthetic method of the functionalized sulfoxide compound as shown in Figure 1, the method comprises the following steps:

(1) Accurately weigh: 71.0 mg benzenesulfinic acid (1a), 96.0 mg 1,3-enyne (2a), 31.0 mg ytterbium trifluoromethanesulfonate, and then add them into a reaction tube filled with water;

(2) Place the reaction tube in step (1) on a magnetic stirrer, and stir for 30 minutes at room temperature;

(3) After the reaction, pour the reaction mixture into a separatory funnel filled with 10.0 mL of deionized water, extract and wash with ethyl acetate three times, 5.0 mL each time, and combine the organic phases;

(4) the organic phase obtained in the step (3) is dried with magnesium sulfate, suction filtration, removes magnesium sulfate, and the organic phase is concentrated with a rotary evaporator to obtain a residue;

(5) The residue was separated by column chromatography (silica gel, mobile phase: petroleum ether/ethyl acetate=5:1), and 101.3 mg of the target product benzofulvene-functionalized sulfoxide compound (3a) was obtained as a yellow solid , Yield: 80%, the obtained target product crude product is easy to separate by column chromatography.

As shown in Figures 2 and 3, compound 3a is characterized as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ: 7.42 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.8Hz, 1H), 7.33–7.30 (m, 5H), 7.28 (d, J = 4.2 Hz, 4H), 7.25–7.24 (m, 1H), 7.21(t, J = 6.9 Hz, 2H), 7.09–7.05 (m, 4H), 6.92 (t, J = 7.5 Hz, 1H), 6.67 (t, J = 7.5 Hz, 1H), 6.40 (d, J = 7.8 Hz, 2H), 5.91 (d, J = 7.8 Hz, 1H), 5.80 (d, J = 7.8 Hz, 1H), 4.67 (d , J = 17.4 Hz, 1H), 4.53 (d, J = 17.4 Hz, 1H), 4.12 (d, J = 15.6 Hz, 1H), 4.05 (d, J = 15.6 Hz, 1H); ¹³ C NMR (150 MHz, CDCL ₃ ) Δ: 147.9, 145.0, 143.5, 143.1, 140.8, 137.9, 136.4, 134.0, 131.2, 130.7,130.1, 129.2, 128.8, 128.5, 128.3, 128.0, 127.3, 126.5 ,126.4, 125.8, 124.9, 124.6, 119.6, 34.0, 31.5; HRMS (ESI) m/z: [M+H] ⁺ calcdfor C ₃₆ H ₂₉ OS ⁺ 509.1934, found 509.1931.

Example 2

The difference from the preparation method in Example 1 is that the reaction raw material 1a is changed to p-fluorobenzenesulfinic acid (1b), and the addition amount is adjusted, and other conditions are the same as in Example 1; column chromatography separation (silica gel, mobile phase: Petroleum ether/ethyl acetate (3:1)), the target product 3b was obtained (yield: 71%) as a yellow solid.

As shown in Figures 4 and 5, compound 3b is characterized as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ: 7.44 (t, J = 7.5 Hz, 1H), 7.37 (d, J = 7.8Hz, 1H), 7.34–7.26 (m, 10H), 7.23–7.19 (m , 1H), 7.10–7.06 (m, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.73 (t, J = 8.7 Hz, 2H), 6.69–6.67 (m, 1H), 6.27–6.24 ( m,2H), 5.94 (d, J = 7.8 Hz, 1H), 5.82 (d, J = 7.8 Hz, 1H), 4.66 (d, J = 17.4Hz, 1H), 4.52 (d, J = 17.4 Hz, 1H), 4.12 (d, J = 15.6 Hz, 1H), 4.05 (d, J =15.6 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ: 163.8 (d, J = 249.2 Hz), 148.1 , 144.5, 143.5, 143.2, 139.7, 137.9, 136.3, 136.09, 136.08, 133.8, 131.1.130.5, 129.4, 129.1, 128.7, 128.3, 128.1, 126.8 (D, J = 8.6 Hz), 126.5) (d, J = 10.8 Hz), 125.8, 124.9, 119.7, 115.3 (d, J = 22.4 Hz), 34.0, 31.5; HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₆ H ₂₈ FOS ^+539.2039 , found539.2038.

Example 3

The difference from the preparation method in Example 1 is that the reaction raw material 1a is changed to 2-thiophenesulfinic acid (1c), and the addition amount is adjusted, and other conditions are the same as in Example 1. Column chromatography (silica gel, mobile phase: petroleum ether/ethyl acetate (5:1)) gave the target product 3c (yield: 88%) as a yellow solid.

As shown in Figures 6 and 7, compound 3c is characterized as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ: 7.49–7.45 (m, 2H), 7.39 (t, J = 6.9 Hz,1H), 7.32 (t, J = 7.5 Hz, 2H), 7.28–7.24 (m , 8H), 7.18–7.16 (m, 1H), 7.09–7.03 (m, 3H), 6.76 (t, J = 4.2 Hz, 1H), 6.69–6.67 (m, 1H), 6.30 (d, J = 7.8 Hz, 1H), 5.95 (d, J = 3.6 Hz, 1H), 5.89 (d, J = 7.8 Hz, 1H), 4.60 (d, J =17.4 Hz, 1H), 4.45 (d, J = 17.4 Hz, 1H), 4.05 (d, J = 15.6 Hz, 1H), 4.00 (d, J = 16.2 Hz, 1H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ: 148.0, 145.3, 143.7, 143.5, 142.4, 139.5 , 137.8, 136.3, 133.5, 131.0, 130.6, 130.4, 129.5, 129.0, 128.82,128.78, 128.5, 128.17, 127.64, 127.0, 126.3,125.8, 119.6, 31.4.4. (ESI) m/z: [M+H] ⁺ calcd for C ₃₄ H ₂₇ OS ₂ ⁺ 515.1498, found 515.1497.

Example 4

The difference from the preparation method in Example 1 is that the reaction raw material 1a is changed to p-methyl sulfinic acid (1d), and the addition amount is adjusted, the raw material 2a is adjusted to 2b, and the addition amount is adjusted, and other conditions are the same as in Example 1 .

Separation by column chromatography (silica gel, mobile phase: petroleum ether/ethyl acetate (5:1)), the target product (3d) was obtained as a yellow solid, yield: 85%.

As shown in Figures 8 and 9, compound 3d is characterized as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ: 7.36–7.31 (m, 3H), 7.29–7.24 (m, 7H), 7.20–7.18 (m, 1H), 7.15–7.12 (m, 1H), 6.98– 6.96 (m, 1H), 6.90 (d, J = 7.8 Hz, 2H), 6.74 (t, J = 8.4 Hz, 1H), 6.70–6.67 (m, 1H), 6.26 (d, J = 7.8 Hz, 2H ), 5.93–5.91 (m, 1H), 5.55 (d, J = 10.2 Hz, 1H), 4.64 (d, J = 17.4 Hz, 1H), 4.50 (d, J = 16.8 Hz, 1H), 4.09 (d , J = 15.6 Hz, 1H), 4.00 (d, J = 15.6 Hz, 1H), 2.24(s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ: 163.0 (d, J = 247.8 Hz), 161.2 (d, J =242.4 Hz), 147.3, 145.2, 142.2, 140.7, 139.30, 139.26, 139.25, 138.2, 138.1, 137.5, 137.0, 133.69, 133.67, 132.8, 132.8 ( d1, J = Hz) J = 8.1 Hz), 128.9, 128.8, 128.6, 128.1, 126.25 (d, J = 77.1 Hz), 126.17 (d, J = 60.6 Hz), 124.4, 120.2, 120.1, 115.2 (d, J = 21.3 Hz), 115.0 (d, J = 22.7 Hz), 114.8, 114.6, 113.0, 112.9, 33.9, 31.5, 21.1; HRMS (ESI) m/z: [M+H] ⁺ calcd for C ₃₇ H ₂₉ F ₂ OS ⁺ 559.1902, found 559.1899.

Example 5

The difference from the preparation method in Example 1 is that the reaction raw material 1a is changed to p-methyl sulfinic acid (1d), and the addition amount is adjusted, the raw material 2a is adjusted to 2c, and the addition amount is adjusted, and other conditions are the same as in Example 1 .

Column chromatography (silica gel, mobile phase: petroleum ether/ethyl acetate (5:1)) gave the target product 3e (yield: 75%) as a yellow solid.

As shown in Figures 10 and 11, compound 3e is characterized as follows:

¹ H NMR (600 MHz, CDCl ₃ ) δ: 7.57 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 7.8Hz, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.39– 7.33 (m, 6H), 7.11 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 6.6 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz,2H), 6.73 (t, J = 7.5 Hz, 1H), 6.28 (d, J = 7.8 Hz, 2H), 6.00 (d, J = 7.8 Hz,1H), 5.86 (d, J = 8.4 Hz, 1H), 4.73 (d, J = 18.0 Hz, 1H), 4.54 (d, J = 17.4Hz, 1H), 4.15 (d, J = 16.2 Hz, 1H), 4.11 (d, J = 16.2 Hz, 1H) , 2.26 (s, 3H); ¹³ C NMR (150 MHz, CDCl ₃ ) δ: 147.2, 146.1, 143.7, 142.9, 142.5, 141.9, 140.9,137.0, 136.3, 133.5, 131.0, 130.5, 129.3 ( q, J = 32.3 Hz), 129.00, 128.97 (q, J = 32.3 Hz), 128.7, 128.5, 128.1, 127.5, 126.3, 125.70, 125.67, 125.65, 125.62, 125.2, 124.3 , 20 J. ), 124.06 (q, J = 270.4 Hz), 119.5, 34.1, 31.3, 21.2; HRMS (ESI) m/z: [M+H] ⁺ calcd forC ₃₉ H ₂₉ F ₆ OS ⁺ 659.1838, found 659.1839.

The above examples are only some of the examples we listed to verify the applicability of this method to different reaction substrates. This method can realize the reaction of arylsulfinic acid containing different substituents with 1,3-enyne to obtain Benzofulvene-functionalized sulfoxides with different functional groups.

The yield comparison table of the examples is shown in Figure 12. Due to the influence of different substituents, the yields of the obtained target products are different.

It is not difficult to find out from the foregoing embodiments that the present invention has the following advantages:

1. The green synthesis of benzofulvene-functionalized sulfoxide compounds was realized for the first time.

2. The preparation of benzofulvene-functionalized sulfoxide compounds containing different substituents (methyl, fluorine, trifluoromethyl) was achieved by a simple, mild and green method, using water as the reaction solvent without other With the addition of additives, a novel functionalized sulfoxide compound was obtained, which was confirmed by NMR and high-resolution mass spectrometry.

3. The present invention has readily available raw materials, low price and cost, short reaction time, green and mild conditions, easy separation of products, simple preparation process and process, and easy operation.

4. The benzofulvene-functionalized sulfoxide compound prepared by the present invention provides a source of raw materials for the screening of pharmaceutically active molecules, and also lays a foundation for further transformation of drugs and materials.

The embodiments disclosed in the present invention are only for explaining the working process of the present invention, and are not intended to limit the technology of the present invention. Those skilled in the art have no creative changes in the present invention, which are all within the protection scope of the present application.

Claims (6)

1. A green synthesis method of a functionalized sulfoxide compound comprises the following steps:

step one, adding aryl sulfinic acid, 1, 3-eneyne and ytterbium trifluoromethanesulfonate into a reaction container containing an aqueous solution;

step two, placing the reaction container in the step one on a stirrer, and stirring and reacting for a plurality of times under the condition of room temperature;

step three, after the reaction is finished, pouring the reaction mixed solution into a separating funnel filled with deionized water, extracting and washing with ethyl acetate for three times, and combining organic phases;

step four, drying the organic phase obtained in the step three by using magnesium sulfate, carrying out suction filtration to remove the magnesium sulfate, and concentrating the organic phase by using a rotary evaporator to obtain a residue;

step five, separating the residue by column chromatography to obtain a target product functionalized sulfoxide compound;

in the fifth step, the functionalized sulfoxide compound refers to: (E) -2, 3-dibenzyl-1- (phenyl (benzenesulfinyl)) methylene-1H-indene, (E) -2, 3-dibenzyl-1-, (Phenyl (p-fluorophenyl) methylene-1H-indene, (E) -2, 3-dibenzyl-1- (phenyl (2-thiophenesulfinyl)) methylene-1H-indene, (E) -2, 3-dibenzyl-6-fluoro-1- (4-fluorophenyl (p-methylbenzenesulfinyl)) methylene-1H-indene, (E) -1- (phenyl (p-methylbenzenesulfinyl)) methylene-2, 3-bis ((4-trifluoromethyl) benzyl) -1H-indene.

2. The green synthesis method of functionalized sulfoxides according to claim 1, wherein: in the first step, the mass ratio of the aryl sulfinic acid, the 1, 3-eneyne and the ytterbium trifluoromethanesulfonate is 1.

3. The green synthesis method of functionalized sulfoxides according to claim 1, wherein: and in the second step, stirring for reaction for 25-35 minutes.

4. The green synthesis method of functionalized sulfoxides as claimed in claim 1, wherein: and in the fifth step, column chromatography separation refers to silica gel and a mobile phase, wherein the silica gel is an adsorbent, and the mobile phase is composed of petroleum ether and ethyl acetate according to a volume ratio of 5.

5. The green synthesis method of functionalized sulfoxides according to claim 1, wherein: in the first step, the aryl sulfinic acid refers to: one of benzene sulfinic acid, p-fluorobenzene sulfinic acid, 2-thiophene sulfinic acid and p-methyl benzene sulfinic acid.

6. The green synthesis method of functionalized sulfoxides as claimed in claim 1, wherein: in the first step, the 1,3 eneyne means: (E) - (3-benzyl-2-en-4-yne-1, 2, 5-phenylalkynes), (b), (c)E) -4,4' - (3-benzyl-5-phenyl-3-en-1-yne-1, 4-di-p-fluorophenyl-1, 3-pentyne), (b)E) -4,4' - (2-phenyl-3- (phenylethyl)But-2-en-1, 4-diyl) bis ((trifluoromethyl) benzene).

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