CN108484668A - Organic phosphine compound and its preparation method and application with sulfonyl function - Google Patents

Abstract

The invention discloses an organic phosphine compound with a sulfonyl functional group and its preparation method and application. During preparation, sulfonyl chloride is reacted with a reagent with a leaving group to introduce a functional group that can be left by nucleophilic substitution; then a carbon-phosphine bond is constructed through a nucleophilic substitution reaction or coupling reaction to introduce a phosphine-containing group. The organic phosphine compound with a sulfonyl functional group of the present invention can quickly construct a ligand library through a nucleophilic reaction with a nucleophile, which provides a good technology for the design and synthesis of ligands, accelerates the discovery and optimization of reactions, and can be applied Phosphine-containing compounds are constructed by nucleophilic substitution reactions with nucleophiles.

Description

Organic phosphine compound with sulfonyl functional group and its preparation method and application

technical field

The invention relates to the field of organic synthesis, in particular to an organic phosphine compound with a sulfonyl functional group.

Background technique

Organophosphine compounds with sulfonyl functional groups show excellent catalytic performance in many reactions (Chem. Eur. J. 2015, 21, 2062-2075). In transition metal catalysis, organophosphine compounds are an important class of ligands. The activity and selectivity of the reaction are closely related to the structure and properties of the phosphine ligand. The efficient and concise synthesis of various structurally rich phosphine ligands creates favorable conditions for the optimization of the reaction.

The preparation method that has been reported in the literature at present constructs the phosphine-containing compound route with sulfonamide as follows: 1. Sulfonyl chloride reacts with amine to obtain sulfonamide; 2. The hydrogen atom on the aromatic ring is taken away by n-butyllithium to construct a carbon-phosphine bond. The method is cumbersome to operate, long in steps, low in synthesis efficiency, and limited by the high activity of n-butyllithium, it is difficult to obtain compounds with rich functional groups, and the compatibility of functional groups is not good, which limits the source of catalysts.

Contents of the invention

The object of the present invention is to provide an organic phosphine compound with a sulfonyl functional group, which can directly react with the sulfonyl functional group through a nitrogen-containing nucleophile to construct a sulfonamide-type phosphine-containing compound.

Another object of the present invention is to provide a method for preparing the above organic phosphine compound.

Another purpose of the present invention is to apply the above-mentioned organic phosphine compounds to construct sulfonamide-type phosphine-containing compounds, so as to provide a convenient and economical synthesis idea.

The object of the present invention is achieved like this: a kind of organic phosphine compound with sulfonyl functional group has sulfonyl group and phosphine-containing group, and compound general formula is:

Wherein: ^R1 is selected from functional groups that can be left by nucleophilic substitution; ^R2 can be the same or different, independently selected from hydrogen, halogen, hydroxyl, cyano, carbonyl, substituted carbonyl, keto, alkyl, alkoxy , arylalkoxy, aryloxy, aryl, saturated or partially saturated heterocyclic; X is selected from saturated or unsaturated carbon chains or heteroatom-containing carbon chains, aryl, saturated or partially saturated heterocyclic rings base, or a combination of the aforementioned forms.

Described ^R is selected from a halogen group, an acid anhydride group, an imidazole group, a phenol group, a 2-thiothiazoline group, a heterocyclic functional group or the following structures

Wherein X is selected from a saturated or unsaturated carbon chain or a heteroatom-containing carbon chain, an aryl group, a saturated or partially saturated heterocyclic group, or a combination of the aforementioned forms.

The preparation method of the above-mentioned organophosphine compound with sulfonyl functional group comprises the following steps: a) reaction of sulfonyl chloride with a reagent with a leaving group to introduce ^R functional group; b) through nucleophilic substitution reaction or coupling The reaction builds a carbon-phosphine bond and introduces a phosphine-containing group.

The above-mentioned organophosphine compound having a sulfonyl functional group is used for nucleophilic substitution reaction with a nucleophile to construct a phosphine-containing compound.

The above-mentioned organic phosphine compounds having sulfonyl functional groups are applied to the preparation of sulfonamide phosphine-containing compounds.

The organophosphine compound with a sulfonyl functional group of the present invention can quickly construct a ligand library through a nucleophilic reaction with a nucleophile, which provides a good technology for the design and synthesis of the ligand, and accelerates the discovery and optimization of the reaction.

Detailed ways

The invention is an organic phosphine compound with a sulfonyl functional group, which has a sulfonyl group and a phosphine-containing group, and the two groups are connected together through various chemical forms.

The general formula of the compound is:

Wherein: ^R1 is selected from functional groups that can be left by nucleophilic substitution; ^R2 can be the same or different, independently selected from hydrogen, halogen, hydroxyl, cyano, carbonyl, substituted carbonyl, keto, alkyl, alkoxy , arylalkoxy, aryloxy, aryl, saturated or partially saturated heterocyclic; X is selected from saturated or unsaturated carbon chains or heteroatom-containing carbon chains, aryl, saturated or partially saturated heterocyclic rings base, or a combination of the aforementioned forms.

Described ^R is selected from halogen group, acid anhydride group, imidazole group, phenol group, 2-thiothiazoline group, heterocyclic functional group and subordinate structure

The preparation method of the above-mentioned organic phosphine compound with a sulfonyl functional group comprises the following steps: a) reacting a sulfonyl chloride with a reagent with a leaving group to introduce a ^R functional group; b) constructing a carbon phosphine through a nucleophilic substitution reaction or a coupling reaction bond, introducing a phosphine-containing group.

The above organic phosphine compounds having sulfonyl functional groups can be applied to the preparation of sulfonamide phosphine-containing compounds. Sulfonamide-type phosphine-containing compounds can be constructed by directly reacting nitrogen-containing nucleophiles with sulfonyl functional groups (see below). This route has mild reaction conditions and good functional group compatibility, which provides a quick way to construct a ligand library, which is much better than the prior art, and the obtained sulfonamide phosphine-containing compounds can be used as catalysts. Preferably, the nitrogen-containing nucleophile is a nucleophile containing -NH or -NH ₂ groups.

The present invention is further explained below in conjunction with the examples, but the specific examples do not limit the present invention in any form.

Embodiment 1 benzenesulfonyl chloride is raw material synthesis compound III

1. Pentafluorophenol 2-iodo-5-methylbenzenesulfonate (II) (R=I)

Pentafluorophenol and dry dichloromethane (-0.13-1 M) were added to the reaction flask, and triethylamine (2-3 equiv) was added dropwise to the solution. After stirring at room temperature for 30-120 minutes, a solution of compound III in dichloromethane (1-2 equiv, 0.5M) was added dropwise to the mixture. After the addition was complete, the reaction continued to stir at room temperature for 12-48 hours. Dichloromethane was then added for dilution, and the organic phase was washed sequentially with 1N aq HCl, 2N aq. NaOH and brine. After the obtained organic phase was dried over anhydrous sodium sulfate, the solvent was removed to obtain the white target product II with a yield of 85-90%. The test results are: ¹ H NMR (400MHz, CDCl ₃ ) δ: 2.41(s, 3H), 7.20(d, J=8Hz, 1H), 7.87(s, 1H), 7.76(t, J=8Hz, 1H) ; ¹³ C NMR (100MHz, CDCl ₃ ) δ: 20.91, 88.44, 132.26, 136.54, 138.50, 139.12, 139.33, 141.02, 141.67, 143.16, 143.61; ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ: -160.98(t, J=19.8Hz, 2F), -155.09(t, J=21.8Hz, 1F), -149.99(d, J=17.8Hz, 2F).

2. 2-(diphenylphosphine)-5-methylbenzenesulfonic acid pentafluorophenol ester (III)

Add compound II and anhydrous tetrahydrofuran (0.5-1M) into the reaction flask, and cool the solution to zero. To this solution was then added isopropylmagnesium chloride solution (1.5-2 equiv, 1M in tetrahydrofuran) with stirring. The resulting reaction mixture was stirred at zero degrees for 2-10 hours. Diphenylphosphine chloride (1.2-3 equiv) was then added. The reaction was then stirred for 12-48 hours at room temperature. Finally, saturated aqueous ammonium chloride solution was added to quench the reaction.

The organic phase was separated and the aqueous phase was catalyzed with ethyl acetate. The organic phases were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After removing the desiccant and solvent, the target product is obtained as a white powder with a yield of 60-70% after purification by column chromatography.

The test results are: ¹ H NMR (400MHz, CDCl ₃ ) δ: 2.45(s, 3H), 7.18(d, J=8Hz, 1H), 7.43-7.26(m, 11H), 7.92(s, 1H); ¹⁹ F NMR (282MHz, CDCl3) δ: -161.38 (m, 2F), -155.79 (t, J = 21.9Hz, 1F), -149.94 (dd, J = 18.1, 8.6Hz, 2F); ³¹ P NMR (162MHz , CDCl ₃ )δ: -8.84.

Example 2 Application of compound IV to construct sulfonamide phosphine-containing compound V

The preparation method of compound IV is the same as that of compound III in Example 1, except that the methyl group on the benzene ring is replaced by a methoxy group.

Add triethylamine (2-4 equivalents), 1-phenylethylamine (1-2 equivalents) and 4-dimethylaminopyridine (0.1-0.5 equivalents) to IV acetonitrile solution (1-2M), then mix the mixture After stirring for 12-24 hours, the reaction temperature ranged from room temperature to reflux. After the reaction, the acetonitrile was removed, and the obtained residue was purified by column chromatography to obtain the target product V in the form of white powder.

The test results are: ¹ H NMR (400MHz, CDCl ₃ ) δ: 1.57(d, J=6.9Hz, 3H), 3.86(s, 3H), 4.52(p, J=6.8Hz, 1H), 6.94-7.35( m,16H),7.60(t,J=3.0Hz,1H); ¹³ C NMR(101MHz,CDCl3)δ:160.00,146.99,146.73,141.97,137.76,136.25,136.19,135.75,135.69,133.61,133.43,133.24 , 128.86, 128.82, 128.64, 128.54, 128.49, 128.46, 128.43, 127.60, 126.34, 125.48, 125.29, 118.02, 114.70, _114.65 , 55.69 ^, 54.41, 23.78.

Example 3 Synthesis of Compound VII

Cool the solution of VI in dichloromethane (0.2-0.5M) to zero degree and add pentafluorophenol (1-2 equivalents), and the resulting mixture reacts at zero degree for 1-2 hours. To this mixture was then added Hendrickson's Reagent (2-3 eq.) dropwise. After the addition was complete, the reaction continued to stir at room temperature for 12-48 hours. After the reaction, the white solid was filtered off, and dichloromethane in the filtrate was removed to obtain a crude product. Further purified by column chromatography to obtain white VII with a yield of 75-85%.

Example 4 Synthesis of Compound VIII

To a solution of IV in acetonitrile (1-2M) was added cesium fluoride (2-4 equivalents), and the mixture was stirred for 12-24 hours at room temperature to reflux. After the reaction, the insoluble matter and solvent were removed, and the obtained residue was purified by column chromatography to obtain the target product VII in the form of white powder with a yield of 70-90%.

Claims (8)

1. An organic phosphine compound with a sulfonyl functional group has a sulfonyl group and a phosphine-containing group, and the general formula of the compound is: Wherein: ^R1 is selected from functional groups that can be left by nucleophilic substitution; ^R2 can be the same or different, independently selected from hydrogen, halogen, hydroxyl, cyano, carbonyl, substituted carbonyl, keto, alkyl, alkoxy , arylalkoxy, aryloxy, aryl, saturated or partially saturated heterocyclic; X is selected from saturated or unsaturated carbon chains or heteroatom-containing carbon chains, aryl, saturated or partially saturated heterocyclic rings base, or a combination of the aforementioned forms. 2. the organic phosphine compound with sulfonyl functional group according to claim ¹ , is characterized in that: described R is selected from halogen group, acid anhydride group, imidazole group, phenolic group, 2-thiothiazoline group, heterocyclic functional group or the following structure Wherein X is selected from a saturated or unsaturated carbon chain or a heteroatom-containing carbon chain, an aryl group, a saturated or partially saturated heterocyclic group, or a combination of the aforementioned forms. 3. The organophosphine compound having a sulfonyl functional group according to claim 1, characterized in that: the atoms in the general formula of the compound are selected from isotopic forms. 4. the preparation method of the organophosphine compound with sulfonyl functional group described in claim 1,2 or 3, comprises the following steps: a) sulfonyl chloride reacts with the reagent of band leaving group, introduces R ¹ functional group; b) by Nucleophilic substitution reactions or coupling reactions construct carbon-phosphine bonds and introduce phosphine-containing groups. 5. The organophosphine compound having a sulfonyl functional group as claimed in claim 1, 2 or 3 is used in a nucleophilic substitution reaction with a nucleophile to construct a phosphine-containing compound. 6. The organic phosphine compound having a sulfonyl functional group described in claim 1, 2 or 3 is applied to the preparation of sulfonamide phosphine-containing compounds. 7. The organic phosphine compound with sulfonyl functional group according to claim 6 is applied to the preparation of sulfonamide phosphine-containing compounds, characterized in that: directly react with the sulfonyl functional group of the organic phosphine compound by nitrogen-containing nucleophile, Construct sulfonamide phosphine-containing compounds. 8. According to claim 7, the organic phosphine compound with sulfonyl functional group is applied to the preparation of sulfonamide phosphine-containing compounds, and it is characterized in that: the nitrogen-containing nucleophile is containing -NH or -NH ₂ groups nucleophile.