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Suzuki-Miyaura coupling reaction using alpha-O-alkenyl sulfone as electrophilic reagent and application thereof

An electrophile, alkenyl sulfone technology, applied in the field of chemistry, can solve problems such as limiting synthetic applications

Active Publication Date: 2020-10-23
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Most of the reported methods use Grignard reagents as nucleophiles, which greatly limits their synthetic utility

Method used

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  • Suzuki-Miyaura coupling reaction using alpha-O-alkenyl sulfone as electrophilic reagent and application thereof
  • Suzuki-Miyaura coupling reaction using alpha-O-alkenyl sulfone as electrophilic reagent and application thereof
  • Suzuki-Miyaura coupling reaction using alpha-O-alkenyl sulfone as electrophilic reagent and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Embodiment 1, the preparation of electrophile α-O-alkenyl sulfone of the present invention

[0111] 1. Synthesis of 1-phenylsulfone-3,4,6-tribenzyloxy-D-glucene (8a)

[0112]

[0113] m-Chloroperbenzoic acid (mCPBA, 2.5g, 11.26mmol, 2.2equiv) was added in batches to dichloromethane ( DCM) solution, stirred at room temperature for 2 hours, and filtered with celite. Saturated NaHCO was added to the filtrate 3 and Na 2 S 2 o 3 The solution was stirred for 10 min, extracted with dichloromethane, and distilled under reduced pressure. Subsequent purification by chromatographic column (petroleum ether / ethyl acetate=4:1) gave SI-2 (2.65 g, 3.99 mmol) with a yield of 78%.

[0114] SI-2 (2.65g, 3.99mmol, 1.0equiv) in N 2 Dissolve in tetrahydrofuran (THF, 25mL) under protective conditions, stir at 0°C, then add lithium bistrimethylsilylamide (3.0mL, dissolved in n-hexane solution, concentration 2.0M, 1.5equiv) dropwise . Spot plate monitoring, use saturated NH after th...

Embodiment 2

[0192] Embodiment 2, the influence of different process parameters on the Suzuki-Miyaura coupling reaction

[0193] 1. Effect of ligand on Suzuki-Miyaura coupling reaction

[0194] Taking the following reaction route as the basic reaction route, the influence of different ligands on the Suzuki-Miyaura coupling reaction was studied.

[0195]

[0196] Reaction result is as shown in table 1, and the structural formula of L1, L2, L3 and L4 in the table is as follows:

[0197]

[0198] Table 1 Effect of ligands on Suzuki-Miyaura coupling reaction

[0199]

[0200] a Reaction conditions (unless otherwise specified): 8a (0.05mmol, 1.0equiv), 9 (0.10mmol, 2.0equiv), THF (0.4mL). Yield and conversion were determined by 1 H NMR using 1,3,5-trimethoxybenzene as internal standard. b Ni(cod) 2 instead of Ni(OTf) 2

[0201] From the results in Table 1, it can be seen that the ligand is Cy 3 P·HBF 4 (i.e. Cy in Table 1 3 PHBF 4 ), the yield of the obtained compound is the...

Embodiment 3

[0235] Example 3. Preparation of aryl glycosides and open-chain alkenyl ethers using the α-O-alkenyl sulfone of the present invention as an electrophile in the Suzuki-Miyaura coupling reaction

[0236] The α-O-alkenyl sulfone (1 equivalent) prepared in Example 1, commercially available aryl boronic acid or borate (2 equivalents), Cy 3 P·HBF 4 (0.2 equivalent) was added to a screw-cap bottle with a magnetic stirrer, and the bottle cap was unscrewed before entering the glove box. Add Ni(COD) 2 (0.1 equiv), KOH (2 equiv), THF (0.2M, ie the concentration of α-O-alkenyl sulfone in THF is 0.2M). After tightening the small reaction bottle, remove it from the glove box, and seal the bottle mouth tightly with black tape. The mixed system was stirred at 60-80°C for 8-16 hours. The reaction solution was then cooled to room temperature, diluted with ethyl acetate (10 ml) and saturated with NH 4 After washing with Cl, it was extracted with ethyl acetate (10 mL x 3). Anhydrous Na for ...

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Abstract

The invention provides a Suzuki-Miyaura coupling reaction using alpha-O-alkenyl sulfone as an electrophilic reagent. The reaction comprises the following steps: weighing alpha-O-alkenyl sulfone, an organic boron reagent, a ligand, an alkali and a catalyst, and carrying out reacting in a solvent. The invention also provides application of the coupling reaction. According to the invention, alpha-O-alkenyl sulfone is used as the electrophilic reagent for the Suzuki-Miyaura coupling reaction, and the reaction raw material alpha-O-alkenyl sulfone is simple to prepare and stable in structure, and can overcome the defects of instability, preparation difficulty and the like when organic halide and sulfonic acid are used as electrophilic reagents for the Suzuki-Miyaura coupling reaction. Meanwhile,the reaction are mild in reaction conditions, compatible with a wide range of heterocyclic rings and various functional groups, high in yield and capable of realizing large-scale process production.Since the alpha-O-alkenyl sulfone is used as the electrophilic reagent for the Suzuki-Miyaura coupling reaction, high-yield generation of aryl glucoside and open-chain alkenyl ether can be realized, medicines for treating type 2 diabetes mellitus, namely ipragliflozin and 2-deoxyipragliflozin can also be prepared, and the application scope of the reaction is wide.

Description

technical field [0001] The invention belongs to the field of chemistry, and in particular relates to a Suzuki reaction using α-O-alkenyl sulfone as an electrophile and an application thereof. Background technique [0002] Suzuki reaction, also known as Suzuki-Miyaura coupling reaction, has an irreplaceable position in organic synthesis and medicinal chemistry. It can realize the construction of carbon-carbon bonds and synthesize a large number of molecular skeletons. The readily available and stable organoboron reagents, as affinity reagents, play an important role in this type of reaction. The most commonly used electrophiles in the Suzuki-Miyaura coupling reaction are organic halides and sulfonic acids, but these compounds often have disadvantages such as low reactivity, instability, and difficulty in preparation. It is very important to develop alternative electrophiles. [0003] Sulfone represents a fundamental functional group in chemistry. The versatility and general...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D309/30C07D407/04C07D409/04C07D405/04C07D471/04C07D405/14C07H17/04C07H1/00C07C43/166C07C41/30C07F7/18C07D409/10C07C317/22C07C315/04
CPCC07D309/30C07D407/04C07D409/04C07D405/04C07D471/04C07D405/14C07H17/04C07H1/00C07D409/10C07C315/04C07C43/166C07C41/30C07C317/22Y02P20/584
Inventor 钮大文张霞龚量孙洪宝
Owner SICHUAN UNIV
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