CN106045804B - A method of based on temperature sensitive type ionic liquid chirality Salen Ti composition catalyst aqueous catalysis thioether asymmetric oxidation reaction - Google Patents

Abstract

The invention discloses a kind of methods based on temperature sensitive type ionic liquid chirality Salen Ti composition catalyst aqueous catalysis thioether asymmetric oxidation reaction；This method is that in an aqueous medium, chiral sulfide compound and hydrogen peroxide carry out asymmetric oxidation reaction under the catalytic action of temperature sensitive type ionic liquid chirality Salen Ti composition catalyst to get chiral sulfoxides；Temperature sensitive type ionic liquid chirality Salen Ti composition catalyst contains chiral Salen Ti composition catalyst unit and temperature sensing material unit simultaneously: compared with traditional chiral Salen Ti catalyst, the catalyst good water solubility, catalysis reaction can be carried out in an aqueous medium, and is easily recycled reuse；Applied to the aqueous catalysis oxidation reaction of chiral thioether, have the characteristics that high catalytic efficiency, chiral sulfoxide are selectively good.

Description

A thermosensitive ionic liquid based chiral Salen Ti complex catalyst for aqueous catalysis Method for Asymmetric Oxidation of Thioether

technical field

The invention relates to an improved chiral Salen Ti complex catalyst, in particular to a temperature-sensitive ionic liquid chiral Salen Ti complex catalyst, and water based on the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst The invention discloses a method for phase-catalyzed asymmetric oxidation reaction of sulfide, belonging to the technical field of catalysis new material preparation and pharmaceutical intermediate synthesis.

Background technique

Optically pure sulfoxide is an important chiral auxiliary, which is widely used in asymmetric synthesis reactions, such as C-C bond formation reaction, C-O bond formation reaction, asymmetric Michael addition reaction, carbonyl reduction reaction, Diels -Alder reaction and radical addition reaction, etc. (Chemical Communications, 2009, 6129-6144). Optically pure chiral sulfoxides are the active groups of many drugs, and they are widely used in the synthesis of biologically active compounds, such as some popular drugs on the market, such as modafinil, sulindac and esola. azoles. Many biologically active molecules contain a chiral sulfinyl unit, and enantiomers with different stereochemical structures have different physiological activities and metabolic effects. At the same time, chiral sulfoxides can also be used as chiral ligands in enantioselective catalytic reactions. Therefore, obtaining sulfoxides with high enantioselectivity has important theoretical significance and practical value. In the past few decades, researchers have made great efforts to develop various methods for preparing optically pure sulfoxides, mainly biological methods and chemical methods. Biological sulfoxide methods include enzymes, microorganisms, etc. to prepare chiral sulfoxides, which have the advantages of substrate specificity, high efficiency, and greenness. Insufficient, its application is limited. Chemical methods can be divided into chiral auxiliary induction, resolution and asymmetric catalytic oxidation. So far, the asymmetric oxidation of thioether is the most practical method for preparing chiral sulfoxide. In 1984, Kagan used a modified Sharpless epoxidation catalyst to achieve the first asymmetric oxidation of thioethers (Synthesis, 1984, 325-326; Tetrahedron Letters, 1984, 25, 1049-1052), after that, researchers have studied this In this field, extensive and in-depth research has been carried out, and a series of catalytic systems based on metals such as titanium, vanadium, aluminum, iron, and copper have been developed (Tanaka, T.; Saito, B.; Katsuki, T. Tetrahedron Lett. 2002, 43, 3259; Katsuki, T.J.Am.Chem.Soc.2007,129,8940; O Mahony, G.E.; Ford, A.; Maguire, A.R.J.Org.Chem.2012,77,3288; T.Chem.Commum.2008, 1704.), and realized the transformation of some simple substrates such as arylalkyl sulfides, but progress for challenging substrates such as cyclic, bulky or long chain thioethers But it was very slow. Until 2013, inspired by metal porphyrins, Gao used a complex formed by a chiral tetradentate nitrogen organic ligand and a metal manganese compound as a catalyst, and hydrogen peroxide as an oxidant, and successfully achieved large steric hindrance, Conversion of long-chain or branched-chain challenging substrates (Dai, W.; Li, J.; Chen, B.; Li, G.; Lv, Y.; Wang, L.; Gao, S. Org. Lett. 2013, 15, 5658). The current literature reports that transition metal catalyzed asymmetric oxidation systems are classified according to chiral ligands, including: chiral diol (phenol)-titanium catalytic system with C2 symmetry, and chiral triolamine-titanium and potassium catalytic system with C3 symmetry , chiral porphyrin metal complex catalytic system, chiral Schiff alkali metal complex catalytic system (Arkivoc, 2011, (i), 1-110; Journal of Sulfur Chemistry, 2013, 34(3), 301-341) . However, this series of catalyst systems are carried out in the non-environmentally friendly solvent dichloromethane, and the selectivity of the product sulfoxide is low, which brings great difficulties to the separation and purification of the product. The existence of these problems greatly increases the synthesis cost of chiral sulfoxides and limits the industrial production of asymmetric thioether oxidation reactions.

International patents WO91/12221 and WO94/27988 describe methods for the direct resolution of racemic sulfoxides into single enantiomers, with particular reference to the resolution of omeprazole into single enantiomers. Chinese patent CN1087739, international patent applications WO2006/094904, WO2007/013743, etc. describe the use of (S)-binaphthol or tartaric acid to split omeprazole to obtain the inner inclusion of levomeprazole, and then use silica gel column Or the method of alkali dissociation of this inclusion compound to obtain L-omeprazole. Splitting omeprazole with this kind of splitting method will waste half of the omeprazole, causing environmental pollution and economic losses, and the price of optically active splitting agents is also more expensive, so this splitting method is industrially used. large-scale use is limited.

International patent WO96/02535, Chinese patent CN1070489 disclose that in the presence of chiral bidentate ligand diethyl tartrate and titanium metal complex and alkali, use hydrogen peroxide derivatives to oxidize omeprazole sulfide to obtain S- method of omeprazole. International patent WO03/089408 describes the catalysis of chiral monodentate (S)-(+)-mandelate complexes with titanium or vanadium, and simultaneous oxidation of omeprazole sulfide in the presence of a base to obtain levorotene method of meprazole.

Chinese patent CN200380104409.8 and international patent WO2004/052881 describe methods for preparing S-pantoprazole using chiral halide complexes or chiral hafnium complexes. The method is to selectively oxidize sulfide to synthesize S-pantoprazole in the presence of (+)- or (-)-tartaric acid derivatives and alkoxy halide or alkoxy hafnium. CN200610023955 and CN181080803B describe a titanium-containing catalyst formed in situ by the coordination of a metal titanium reagent and a chiral diol, and under the action of tert-butyl hydroperoxide, the sulfide is selectively oxidized.

International Patents WO96/17076 and WO96/17077 describe the use of microorganisms for selective oxidation of thioethers or selective reduction of sulfones to obtain single enantiomers of sulfoxides.

SUMMARY OF THE INVENTION

In view of the defects existing in the prior art, the purpose of the present invention is to provide a temperature-sensitive ionic liquid chiral Salen Ti complex catalyst containing a temperature-sensitive material unit that can realize hydrophilic-hydrophobic conversion through temperature conditions. Water-phase catalysis The method for asymmetric oxidation reaction of sulfide, the catalyst has excellent catalytic activity and selectivity, and realizes the selective oxidation of sulfide compound to sulfoxide in water solvent, and the water solubility of the catalyst is regulated by temperature to realize the catalytic performance of the catalyst. The method is simple, efficient, environmentally friendly, mild in reaction conditions, and meets the requirements of technological production.

In order to achieve the above technical purpose, the present invention provides a method for catalyzing the asymmetric oxidation reaction of thioether in water phase based on a temperature-sensitive ionic liquid chiral SalenTi complex catalyst. The method is that in an aqueous medium, a thioether compound of formula 2 The asymmetric oxidation reaction with hydrogen peroxide is carried out under the catalysis of the thermosensitive ionic liquid chiral Salen Ti complex catalyst of formula 1 to obtain the chiral sulfoxide compound of formula 3:

in,

is a temperature sensitive unit;

X/Y is (1～100):1.

R ₁ , R ₂ , R ₃ are independently selected from hydrogen, alkyl, aryl, aryl-substituted alkyl or alkoxy;

_R4 is n is 0 to 3;

R ₅ is a C ₁ -C ₃ alkyl group or a hydrogen atom;

R6 and _R7 are independently selected from aryl, heterocyclic _- containing group, alkyl or substituted alkyl.

In a preferred solution, in the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst, R ₁ , R ₂ and R ₃ are independently selected from hydrogen, C ₁ -C ₅ alkyl, phenyl, and C containing phenyl substituents ₁ -C ₅ alkyl group or C ₁ -C ₅ alkoxy group; R ₄ is n is 0-2; R ₅ is a hydrogen atom.

In a preferred solution, the range of X is 10-100, and the range of Y is 1-10.

In a preferred solution, X/Y in the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst is (5-50):1.

In a preferred solution, the temperature-sensitive units in the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst are N-isopropylacrylamide units and/or N,N'-dimethylacrylamide units.

In a preferred scheme, R ₆ and R ₇ in the thioether compound and the chiral sulfoxide compound are independently selected from:

C ₆ -C ₁₂ aryl without substituent, or halogen, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl, nitro or cyano substituent Aryl of C ₆ -C ₁₂ ;

or an unsubstituted C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkyl group containing an aryl substituent (wherein, the aryl substituent is preferably an unsubstituted C ₆ -C ₁₂ aryl group) group, or C ₆ -C ₁₂ aryl group containing halogen, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxycarbonyl, nitro or cyano substituent), or containing C ₁ -C ₆ alkyl group of halogen, nitro, hydroxyl or cyano substituent;

Or a pyridine- or imidazole-containing group.

In a more preferred solution, R ₆ and R ₇ in the thioether compound and the chiral sulfoxide compound are independently selected from one of the following substituents:

The most preferred sulfide compounds are: methyl phenyl sulfide (molecular formula C ₇ H ₈ S); 4-bromophenyl methyl sulfide (molecular formula C ₇ H ₇ BrS); 4-methoxyphenyl sulfide (molecular formula C ₈ H ₁₀ OS); 4-nitrophenyl sulfide (molecular formula C ₇ H ₇ NO ₂ S); 2-methoxyphenyl sulfide (molecular formula C ₈ H ₁₀ OS); omeprazole Thioether (5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio-1H-benzimidazole (molecular formula C ₁₇ H ₁₉ N ₃ O 2S ₎ .

The most preferred chiral sulfoxide compounds are: methylphenyl sulfoxide (molecular formula C ₇ H ₈ OS); 4-bromophenylmethyl sulfoxide (molecular formula C ₇ H ₇ BrOS); 4-methoxyphenyl Methyl sulfoxide (molecular formula C ₈ H ₁₀ O ₂ S); 4-nitrophenyl methyl sulfoxide (molecular formula C ₇ H ₇ NO ₃ S); 2-methoxyphenyl methyl sulfoxide (molecular formula C ₈ H ₁₀ O ₂ S); Omeprazole (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl] -1H-benzimidazole, molecular formula C ₁₇ H ₁₉ N ₃ O ₃ S).

In a preferred solution, the hydrogen peroxide solution is slowly added dropwise to the aqueous solution containing the thioether compound and the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst to carry out the asymmetric oxidation reaction.

In a more preferred solution, the molar ratio of the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst to the sulfide compound is 1:50 to 1:1000; more preferably, 1:100 to 1:300.

In a more preferred solution, the molar ratio of hydrogen peroxide to the sulfide compound in the hydrogen peroxide solution is 1:1-2:1; more preferably (1-1.2):1.

In a more preferred solution, the concentration of the hydrogen peroxide solution is 15wt% to 70wt%; more preferably, it is 25wt% to 35wt%.

In a more preferred scheme, the asymmetric oxidation reaction is carried out at a temperature of -50°C to 50°C for 0.1 to 5 hours. A more preferable reaction temperature is -5°C to 20°C. A further preferred reaction time is 1 to 1.5 h.

A more preferred solution is that after the asymmetric oxidation reaction is completed, the temperature of the reaction system is raised to realize the hydrophilic-hydrophobic transition of the thermosensitive ionic liquid chiral Salen Ti complex catalyst, and the thermosensitive ionic liquid chiral Salen Ti complex catalyst is precipitated. , filter recovery.

The preparation method of the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst of the present invention comprises the following steps:

1) The Schiff base compound of formula 4 and the imidazole compound of formula 5 are subjected to substitution reaction to obtain the functionalized chiral Schiff base compound of ionic liquid of formula 6;

2) The chiral Schiff base compound functionalized by the ionic liquid and tetraisopropyl titanate carry out a coordination reaction to obtain the ionic liquid chiral Salen Ti complex of formula 7;

3) A temperature-sensitive ionic liquid chiral Salen Ti complex catalyst is obtained by using a temperature-sensitive monomer and an ionic liquid chiral Salen Ti complex of formula 7 through a controlled radical polymerization method;

in,

R ₁ , R ₂ , R ₃ are independently selected from hydrogen, alkyl, aryl, aryl-substituted alkyl or alkoxy;

_R4 is n is 0 to 3;

R ₅ is a C ₁ -C ₃ alkyl group or a hydrogen atom.

In a preferred embodiment, R ₁ , R ₂ and R ₃ are independently selected from hydrogen, C ₁ -C ₅ alkyl, phenyl, C ₁ -C ₅ alkyl containing phenyl substituents or C ₁ -C ₅ alkoxy; R ₄ is n is 0-2; R ₅ is a hydrogen atom.

In a preferred solution, the molar ratio of the thermosensitive monomer to the ionic liquid chiral Salen Ti complex is (1-100):1; more preferably, (5-50):1.

Relative to the prior art, the beneficial technical effects brought by the technical solution of the present invention:

1) The temperature-sensitive ionic liquid chiral Salen Ti complex catalyst adopted by the technical solution of the present invention mainly comprises a catalyst unit and a temperature-sensitive material unit. The catalyst unit showed high selectivity and high catalytic activity for the asymmetric oxidation of sulfide, and the yield of chiral sulfoxide was as high as 85% to 98%. The temperature-sensitive material unit endows the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst with better water solubility, and realizes the asymmetric oxidation reaction of thioether using water as a solvent. At the same time, the temperature-sensitive material unit has hydrophilic-hydrophobic conversion. It can control the water solubility of the catalyst through temperature, which is beneficial to the recycling of the catalyst.

2) The temperature-sensitive ionic liquid chiral Salen Ti complex catalyst of the present invention forms a hydrophilic shell at the hydrophilic end of the temperature-sensitive material in the aqueous catalyzed asymmetric oxidation reaction of sulfide, and the hydrophobic active center rapidly aggregates to form a micelle , is an ideal nano-reactor. After the hydrophobic thioether reaction substrate is added to the aqueous solution, it will quickly enter the hydrophobic core. When the aqueous solution of hydrogen peroxide is used as the oxygen source, the hydrogen peroxide will slowly enter the hydrophobic core. The ether generates chiral sulfoxide, which greatly improves the selectivity and reaction efficiency of chiral oxidation.

3) The preparation method of the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst of the present invention is simple, the process conditions are mild, and the catalyst unit and the temperature-sensitive material unit in the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst can be arbitrarily selected. A series of block polymers P N _X (IS) _y with different hydrophilic and hydrophobic ratios can be obtained to meet different catalytic application requirements.

4) The present invention based on the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst catalyzes the asymmetric oxidation reaction of sulfide in an aqueous medium, which overcomes the defect of the prior art that the reaction needs to be carried out in an organic solvent.

5) The present invention is based on the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst, making full use of the hydrophobic-hydrophilic conversion performance of its temperature-sensitive material unit, and has hydrophilicity at relatively low temperature and high temperature at relatively high temperature. Hydrophobicity, the recovery of temperature-sensitive ionic liquid chiral Salen Ti complex catalyst can be realized only by controlling the temperature. The defect that the chiral Salen Ti complex catalyst is difficult to recover in the prior art is overcome, and the use cost of the catalyst is greatly reduced.

Description of drawings

[Fig. 1] is the transmission electron microscope (TEM) image of the catalyst in aqueous solution; in the figure b, c, e are three representatives of PN _{60 (} IS) ₂ , PN ₆₈ (IS) ₄ and PN ₆₆ (IS) ₆ respectively Figure 1 shows the transmission electron microscope image of the aqueous solution of the catalyst at room temperature; it can be seen from Figure 1 that the catalysts can form nano-spherical particles in water, and the upper right corner is the aqueous solution of the three catalysts. water, forming micellar nanoparticles. b' is the photo of the catalyst aggregation when the temperature of the bPN ₆₀₍ IS) ₂ aqueous solution is increased to 35 °C. It can be seen from the upper right photo that the catalyst is precipitated from the aqueous phase when the temperature is increased, which achieves "high-efficiency catalysis at room temperature, The effect of heating up and simple separation", so as to realize the simple recovery and efficient repetition of the catalyst.

[Fig. 2] is the infrared characterization (FT-IR) image of several characteristic catalysts, a is the infrared image of the traditional catalyst Salen Ti, b is the infrared image of the catalyst PN ₆₈ (IS) ₄ , b' is the catalyst PN ₆₈ (IS) ) ₄ Infrared images after repeated use. It can be seen from the figure that the catalyst has the characteristic peaks of traditional Salen Ti, and after repeated use of the catalyst, the infrared image does not change, and the catalyst still has a good catalytic effect.

Detailed ways

The present invention will be described in further detail below with reference to examples, which are exemplary descriptions rather than limitations of the present invention.

Example 1

Preparation of temperature-sensitive chiral nano-reaction catalyst (R ₁ , R ₂ , R ₃ are all tert-butyl groups), R ₄ is vinyl, and the selected ionic liquid is vinylimidazole.

At room temperature, the resolved (R,R)-cyclohexanediamine tartrate (11.2mmol) and potassium carbonate (22.5mmol) were dissolved in 20mL of absolute ethanol and deionized water (5/l, V/V ) in the mixed solvent, slowly heat up to 80 °C, reflux for 2 h, and place in the refrigerator. The freed (R,R)-cyclohexanediamine was extracted with chloroform (4×5 mL), and the organic phases were combined. At 0°C, ethereal hydrochloric acid solution (11.2 mmol, 2 mol/L) was slowly added, and the mixture was kept at room temperature overnight. The above single amino-protected (R,R)-cyclohexanediamine (8 mmol) and 3,5-di-tert-butyl salicylaldehyde (8 mmol) were then dissolved in 60 mL of anhydrous methanol and anhydrous ethanol (1/1 , V/V) mixed solvent, add active 4A molecular sieve (1g), and react at room temperature for 4h to obtain a light yellow solid. A mixed solution of 20 mL of 3-tert-butyl-5-chloromethyl salicylaldehyde (8 mmol) and triethylamine (16 mmol) in anhydrous dichloromethane was slowly added dropwise to the above solution, reacted at room temperature for 4 h, filtered, and The crude product was obtained by recrystallization in absolute ethanol. Purification by column chromatography (SiO ₂ , ethyl acetate/n-hexane=1/5, V/V) gave CL (3.57 g, 83%) as a pale yellow powdery solid. Calc. for C ₃₃ H ₄₇ ClN ₂ O ₂ : C, 73.51; H, 8.79; N, 5.20. Found: C, 73.46; H, 8.91; N, 5.12%. ¹ H-NMR (CDCl ₃ , 400 MHz): δppm14.29(s,1H),13.67(s,1H),8.44(s,1H),8.31(s,1H),7.30(d,1H),7.26(d,1H),6.99(d,1H) ,6.89(d,1H),4.43(s,2H),3.55-3.32(m,2H),1.97-1.46(m,8H),1.40(s,9H),1.23(s,18H).FT-IR ( ^KBr ): 3446, 2954, 2862, 1629, 1591, 1479, 1469, 1439, 1391, 1361, 1271, 1252, 1241, 1201, 1174, 1144, 1086, 1040, 981, 934, 879, 828, 803, 772, 731, 711.

The above solid CL (3.2 mmol, 1.725 g) and vinylimidazole (3 mmol, 0.28 g) were added to 50 mL of dry toluene, and the mixture was refluxed at 110 °C for 48 h under the protection of N ₂ . The solvent was distilled under reduced pressure, dried in vacuo, the above product was dissolved in CH ₂ Cl ₂ at room temperature, and an equimolar amount of tetraisopropyl titanate (Ti(O ⁱ Pr) ₄ , 3.2 mmol, 0.91 mol) was added thereto. g), react at room temperature for 3 h to obtain a yellow product IL/Ti (salen). FT-IR(KBr): γ _max /cm ^-1 3437,3310,3073,2973,2933,2882,1653,1540,1458,1384,1365,1263,1172,1130,1051,986,922,881,838,626,518cm ^{-1 .1} H NMR (500MHz, CD ₃ Cl ₃ ): δ8.11～7.65 (s, 2H, CH=N), 7.18～7.59 (m, 4H, ArH), 6.05 (m, 1H, N-CH=CH ₂ ) 4.15 (s, 1H, C=NCH), 3.87 (m, 1H, C=NCH), 3.56 (m, 4H, N-CH=CH ₂ and-N-CH ₂ -N-), 2.36～2.65 (m, 2H, CH ₃ -CH-CH ₃ in ⁱ PrO-), 1.46 (m, 8H, cyclohexyl-H), 1.23～1.37 (m, 27H, H-in t-butyl), 1.31 (m, 12H, CH ₃ -CH-CH ₃ in ⁱ PrO-).

In Schlenk, different proportions of temperature-sensitive materials and IL/Ti(salen) were added, which were dissolved in anhydrous methanol, and the initiator azobisisobutylcyanide (AIBN, 0.5mmol, 0.082g) was added thereto. and chain transfer agent propanethiol (n-Propanethiol, 1mmol, 0.076g), under the condition of N ₂ protection, react at 60°C for 24h, cool to room temperature, remove the solvent under reduced pressure, then dissolve in tetrahydrofuran, precipitate with ether, vacuum Drying yields a yellow solid product PN _x (IS) _y , (x represents the polymer of thermosensitive units, y represents the degree of polymerization of ionic liquid-functionalized Salen Ti units). x and y were obtained by NMR characterization.

Other catalysts were prepared as described above. Four examples are listed:

PN ₆₀₍ IS) ₂ : FT-IR(KBr): γ _max /cm ^-1 3436, 3313, 3075, 2971, 2942, 2891, 1653, 1542, 1457, 1386, 1368, 1263, 1170, 1131, 1054, 985, 927, 880, 836, 806, 709, 624, 519 cm ^-1 . ¹ H NMR (500MHz, CDCl ₃ ): δ6.24～6.89 (m, 60H, HC-NH-C=O), 6.08 (m, 2H, N-CH-CH ₂ -of N- vinyl), 4.18 (m, 2H, C=NCH), 3.99 (m, 60H, -CH- _CH2 in NIPAAm), 3.88 (m, 2H, C=NCH), 3.67 (m, 8H, -CH- _CH2 -of N-vinyl in IL and -N-CH ₂ -N-), 3.45 (m, 60H, CH ₃ -CH-CH ₃ in NIPAAm), 3.06 (m, 12H, -N-CH ₂ -CH ₂ - N-and-N-CH ₂ -Ph-), 2.84(m,2H,SH-CH ₂ -CH ₂ -CH ₃ ),2.64～2.73(m,4H,CH ₃ -CH-CH ₃ of ⁱ PrO- in Ti(salen)), 2.38(m, 2H, SH-CH ₂ -CH ₂ -CH ₃ ), 1.86～2.12 (m, 120 H, -CH ₂ -CH-in NIPAAm), 1.71(s, 3 H , SH-CH ₂ -CH ₂ -CH ₃ ), 1.43 (16 H, cyclohexyl-H), 1.13～1.33 (54H, H-in t-butyl), 1.09～1.16 (m, 384 H, CH ₃ -CH -CH ₃ in ⁱ PrO-and NIPAAm);

PN ₆₈ (IS) ₄ : FT-IR (KBr): γ _max /cm ^-1 965, 920, 882, 834, 809, 709, 635, 624, 509 cm ^-1 . ¹ HNMR (500 MHz, CD ₃ Cl ₃ ): δ8.15～7.68 (m, 8 H, CH=N), 7.14～7.64 (m, 16 H, ArH), 6.24～6.89 (m , 68 H, HC-NH-C=O), 6.05 (m, 4H, N-CH-CH ₂ -of N-vinyl), 4.14 (m, 4 H, C=NCH), 3.99 (m, 68 H , -CH-CH ₂ -in NIPAAm), 3.85 (m, 4 H, C=NCH), 3.58 (m, 16 H, -CH-CH ₂ -of N-vinyl inIL and-N-CH ₂ -N- ), 3.26 (m, 68 H, CH ₃ -CH-CH ₃ in NIPAAm), 2.90 (m, 24 H, -N-CH ₂ -CH ₂ -N-and-N-CH ₂ -Ph-), 2.78 (m, 2 H, SH-CH ₂ -CH ₂ -CH ₃ ), 2.34～2.68 (m, 8 H, CH ₃ -CH-CH ₃ of ⁱ PrO-inTi(salen)), 2.10 (m, 2 H , SH-CH ₂ -CH ₂ -CH ₃ ), 1.78～1.98(m, 136 H, -CH-CH ₂ in NIPAAm), 1.73(s, 3H, SH-CH ₂ -CH ₂ -CH ₃ ), 1.47 (m,32H,cyclohexyl-H),1.21～1.38(m,108H,H-int-butyl),1.06～1.15(m,456H,CH ₃ -CH-CH ₃ in ⁱ PrO-and NIPAAm) ;

PN ₆₆ (IS) ₆ : FT-IR (KBr): γ _max /cm ^-1 963, 920, 883, 836, 805, 708, 625, 504 cm ^-1 . ¹ H NMR (500 MHz, CD ₃ Cl ₃ ): δ8.13～7.72 (m, 12 H, CH=N), 7.18～7.69 (m, 24 H, ArH), 6.21～6.92 ( m, 66 H, HC-NH-C=O), 6.16 (m, 6 H, N-CH-CH ₂ -of N-vinyl), 4.04 (m, 6H, C=NCH), 3.97 (m, 66 H, -CH-CH ₂ -in NIPAAm), 3.81 (m, 6 H, C=NCH), 3.56 (m, 24 H, -CH-CH ₂ -of N-vinyl inIL and -N-CH ₂ -N -), 3.23 (m, 66 H, CH ₃ -CH-CH ₃ in NIPAAm), 3.09 (m, 36 H, -N-CH ₂ -CH ₂ -N-and-N-CH ₂ -Ph-), 2.75(m, 2 H, SH-CH ₂ -CH ₂ -CH ₃ ), 2.41～2.61(m, 12 H, CH ₃ -CH-CH ₃ of ⁱ PrO-in Ti(salen)), 2.23(m, 2 H,SH-CH ₂ -CH ₂ -CH ₃ ),1.76～1.82(m,132 H,-CH-CH ₂ in NIPAAm),1.75(s,3 H,SH-CH ₂ -CH ₂ -CH ₃ ), 1.41(m, 48 H, cyclohexyl-H), 1.22～1.31(m, 162 H, H-in t-butyl), 1.01～1.12(m, 469 H, CH ₃ -CH-CH ₃ in ⁱ PrO -and NIPAAm);

PN ₆₄ (IS) ₈ : FT-IR (KBr): γ _max /cm ^-1 967,924,882,839,806,709,634,625,507cm ^-1 . ¹ HNMR (500 MHz, CD ₃ Cl ₃ ): δ8.11～7.62(m,16H,CH=N),7.13～7.67(m,32H,ArH),6.24～6.87(m , 64 H, HC-NH-C=O), 6.22 (m, 8 H, N-CH-CH ₂ -of N-vinyl), 4.46 (m, 8H, C=NCH), 4.05 (m, 64H, -CH-CH ₂ -in NIPAAm), 3.78 (m, 8H, C=NCH), 3.58 (m, 32H, -CH-CH ₂ -of N-vinylin IL and-N-CH ₂ -N-), 3.18 (m, 64H, CH ₃ -CH-CH ₃ in NIPAAm), 2.86 (m, 48H, -N-CH ₂ -CH ₂ -N-and-N-CH ₂ -Ph-), 2.75 (m, 2H, SH-CH ₂ -CH ₂ -CH ₃ ), 2.45～2.63(m,16H,CH ₃ -CH-CH ₃ of ⁱ PrO-inTi(salen)),2.12(m,2H,SH-CH ₂ -CH ₂ -CH ₃ ), 1.75～1.87(m, 128H, -CH-CH ₂ -in NIPAAm), 1.73(s, 3H, SH-CH ₂ -CH ₂ -CH ₃ ), 1.41(m, 64H, cyclohexyl-H ), 1.22～1.31 (m, 216H, H-in t-butyl), 1.01～1.12 (m, 480H, CH ₃ -CH-CH ₃ in ⁱ PrO-and NIPAAm).

According to the above method, a series of catalysts were prepared with different temperature-sensitive materials.

Example 2

The reaction conditions were optimized using methyl phenyl sulfide as a model substrate, and the results were as follows.

Reaction route:

Add 1 mmol of substrate (methyl phenyl sulfide), 0.5 mmol% of catalyst PN ₆₈ (IS) 4, 1 mL of H ₂ O as solvent to a 10 mL reaction flask, and slowly dropwise add it within 15 min under the condition of 25° C. _1.2 mmol of 30 _% H2O2 and the reaction continued for 45 min. After the reaction is completed, the catalyst is automatically precipitated, the water phase is separated, the catalyst is washed with n-hexane, dried and reused, the water phase is extracted with dichloromethane to obtain a product, and the product is subjected to gas chromatography analysis to detect the conversion rate and selectivity, liquid phase. The ee value was obtained by chromatographic analysis, the product was obtained by column chromatography, the yield was calculated, and the structure of the product was determined by NMR characterization.

Four comparative catalysts and conventional Salen Ti catalysts were used to catalyze the oxidation of methylphenyl sulfide to sulfoxide, and the results are shown in the following table:

[a]Yield of the isolated product.[b]Determined by HPLC.

It can be seen from the table that the ratio of hydrophilic and hydrophobic substituents will affect the catalytic effect, showing regular changes. PN ₆₈ (IS) ₄ is the most moderate hydrophilic-hydrophobic ratio. When the hydrophilic group is too long (PN ₆₀ (IS) ₂ ), the active center will be greatly reduced, and the catalytic efficiency is lower than that of PN ₆₈ (IS) ₄ (yield). only 75%). When the hydrophilic-hydrophobic ratio is less than 17, the catalytic activity also decreases (89% for PN ₆₆ (IS) ₆ , 86% for PN ₆₄ (IS) ₈ ), and the ee value also changes regularly.

Methylphenyl sulfoxide, white solid, separated by silica gel column chromatography (methanol:dichloromethane=20:80 (volume ratio)) (93% yield, 98% ee). ¹ H NMR (CDCl ₃ , 500MHz): δ (ppm): 2.56 (s, 3H, Me), 7.37-7.52 (m, 5H, ArH). ¹³ C NMR (CDCl ₃ , 125 MHz): δ (ppm): 43.8 (SCH ₃ ), 123.4, 129.3, 131.0, 145.5; conversion and selectivity were measured by gas chromatography (Agilent Co, HP19091G-B213, column temperature 180°C, flow rate: 1.6mL/min),

The ee value was measured by chiral high performance liquid chromatography (chromatographic column: Daicel chiralpak AD, mobile phase: isopropanol/n-hexane=10:90 (volume ratio), flow rate: 1.0 mL/min, wavelength: 254 nm, temperature 25 °C).

Example 3

PN ₆₈ (IS) ₄ was selected for the examination of different substrates.

Reaction route:

Reaction steps and processing mode are as above embodiment 2

Catalyst PN ₆₈ (IS) ₄ and conventional Salen Ti catalysts were used to catalyze the oxidation of four other thioethers to sulfoxides, and the results are shown in the table below:

It can be seen from the table that the catalytic effect of the catalyst PN ₆₈ (IS) ₄ is obviously better than that of the traditional catalyst, and it has huge advantages in yield and ee value.

The characterization data of some products are as follows:

4-Bromophenylmethyl sulfoxide, yellow solid, separated by silica gel column chromatography (methanol:dichloromethane=20:80 (volume ratio)) (yield 82%, ee value>99%). ¹ H NMR (CDCl ₃ , 500MHz): δ (ppm): 3.07 (s, 3H, SCH ₃ ), 7.84 (d, 2H, ArH), 7.74 (d, 2H, ArH). ¹³ C NMR (CDCl ₃ , 125MHz): δ (ppm): 44.5 (SCH ₃ ), 129.0, 132.7, 139.5; ee value was measured by chiral high performance liquid chromatography (chromatographic column: Daicelchiralpak AD, mobile phase: isopropanol/n-hexane=50: 50 (volume ratio), flow rate: 1.0mL/min, wavelength: 254nm, temperature 25℃)

4-Methoxyphenylmethyl sulfoxide, colorless liquid, separated by silica gel column chromatography (methanol:dichloromethane=20:80 (volume ratio)) (yield 90%, ee value 94%). ¹ H NMR (CDCl ₃ , 500MHz): δ (ppm): 3.01 (s, 3H, SCH ₃ ), 3.91 (s, 3H, OCH ₃ ), 7.04 (d, 2H, ArH), 7.89 (d, 2H, ArH). ¹³ C NMR (CDCl ₃ , 125MHz): δ (ppm): 44.9 (SCH ₃ ), 55.7 (OCH ₃ ), 114.5, 129.6, 132.3, 163.7; ee values were measured by chiral high performance liquid chromatography ( Chromatographic column: Daicelchiralpak AD, mobile phase: isopropanol/n-hexane=20:80 (volume ratio), flow rate: 1.0mL/min, wavelength: 254nm, temperature 25°C)

4-Nitrophenylmethyl sulfoxide, yellow solid, separated by silica gel column chromatography (methanol:dichloromethane=20:80 (volume ratio)) (yield 97%, ee value 88%). ¹ H NMR(CDCl ₃ , 500MHz): δ(ppm): 2.57(s, 3H, SCH ₃ ), 7.30(d, 2H, ArH), 8.16(d, 2H, ArH). ¹³ C NMR(CDCl ₃ , 125MHz): δ (ppm): 43.9 (SCH ₃ ), 113.9, 125.0, 144.7, 148.9; ee value was measured by chiral high performance liquid chromatography (chromatographic column: Daicel chiralpak AD, mobile phase: isopropanol/n-hexane =30:70 (volume ratio), flow rate: 1.0mL/min, wavelength: 254nm, temperature 25℃)

2-Methoxyphenylmethyl sulfoxide, colorless liquid, separated by silica gel column chromatography (methanol:dichloromethane=20:80 (volume ratio)) (yield 88%, ee value 99%). ¹ H NMR (CDCl ₃ , 500MHz): δ (ppm): 2.67 (s, 3H, SCH ₃ ), 3.78 (s, 3H, OCH ₃ ), 6.84-7.37 (m, 4H, ArH). ¹³ C NMR ( CDCl ₃ , 125MHz): δ (ppm): ¹³ C NMR (CDCl ₃ , 125MHz): δ (ppm): 41.1 (SCH ₃ ), 55.7 (OCH ₃ ), 118.6, 121.5, 124.3, 132.0, 154.7; ee values Measured by chiral high performance liquid chromatography (chromatographic column: Daicel chiralpak AD, mobile phase: isopropanol/n-hexane = 20:80 (volume ratio), flow rate: 1.0 mL/min, wavelength: 254 nm, temperature 25 °C)

Omeprazole, white powder, was separated by silica gel column chromatography (methanol:dichloromethane=20:80 (volume ratio)) (yield 80%, ee value 87%). ¹ H NMR (DMSO, 500MHz): δ (ppm): 2.15 (s, 6H), 3.65 (s, 3H), 3.78 (s, 3H), 4.66 and 4.75 (AB-system, 2H), 6.90 (dd, 1H), 7.08(s, 1H), 7.53(d, 1H), 8.15(s, 1H); ee values were measured by chiral high performance liquid chromatography (chromatographic column: Daicel chiralpak AD, mobile phase: isopropanol/ n-hexane=20:80 (volume ratio), flow rate: 1.0mL/min, wavelength: 254nm, temperature 25℃)

The temperature sensitivity of the catalyst is reflected in that after the reaction is completed, the catalyst is precipitated from the reaction system. When the temperature is raised, the catalyst is completely precipitated and separated. Under the condition of room temperature, the catalyst is soluble in water. When the temperature is raised, the catalyst is released from water. Phase precipitation aggregates. The specific pattern can be seen by transmission electron microscope.

Example 4

Examination of the reusability of catalysts

By heating the solution after the above reaction, the catalyst can be separated out from the reaction system, and then through the steps of filtration, washing, drying and the like, the catalyst is used in the next catalytic reaction system, and its repeated use effect is shown in the following table:

[a]Yield of the isolated product.[b]Determined by HPLC.

It can be seen from the above data that the catalyst has good reusability. The reaction system uses water as the solvent for the reaction, which is green and environmentally friendly, and provides a method for enterprises to mass-produce chiral sulfoxides.

Claims (8)

1. a method based on temperature-sensitive ionic liquid chiral Salen Ti complex catalyst aqueous catalysis sulfide asymmetric oxidation reaction, it is characterized in that: in aqueous medium, formula 2 structure sulfide compound and hydrogen peroxide are in formula The asymmetric oxidation reaction is carried out under the catalysis of the thermosensitive ionic liquid chiral Salen Ti complex catalyst of structure 1, and the chiral sulfoxide compound of formula 3 is obtained: in, is N-isopropylacrylamide polymer unit and/or N,N'-dimethylacrylamide polymer unit; X/Y is (1～100):1; R ₁ , R ₂ and R ₃ are independently selected from hydrogen, C ₁ -C ₅ alkyl, phenyl, C ₁ -C ₅ alkyl containing a phenyl substituent, or C ₁ -C ₅ alkoxy ; _R4 is n is 0 to 3; R ₅ is a C ₁ -C ₃ alkyl group or a hydrogen atom; R ₆ and R ₇ are independently selected from: unsubstituted C ₆ -C ₁₂ aryl, or halogen-containing, C _1-4 alkyl, C _1-4 alkoxy, C _2-5 alkoxy C ₆ -C ₁₂ aryl groups of carbonyl, nitro or cyano substituents; Or unsubstituted C ₁ -C ₆ alkyl group, or C ₁ -C ₆ alkyl group containing aryl substituent, or C ₁ -C ₆ alkyl group containing halogen, nitro, hydroxyl or cyano substituent alkyl; or The aryl substituent in the C ₁ -C ₆ alkyl group containing an aryl substituent is a C ₆ -C ₁₂ aryl group without a substituent, or a halogen-containing, C _1-4 alkyl, C _{1- 4} alkoxy, C _2-5 alkoxycarbonyl, nitro or cyano substituent C ₆ -C ₁₂ aryl group. 2. the method based on the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst water-phase catalyzed sulfide asymmetric oxidation reaction according to claim 1, is characterized in that: R ₄ is n is 0-2; R ₅ is a hydrogen atom. 3 . The method for water-phase catalyzed sulfide asymmetric oxidation reaction based on a temperature-sensitive ionic liquid chiral Salen Ti complex catalyst according to claim 1 , wherein: X/Y is (5～50):1. 4 . 4. the method based on the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst water-phase catalyzed thioether asymmetric oxidation reaction according to claim 1, is characterized in that: R ₆ and R ₇ are independently selected from the following substituents One of: 5. The method for water-phase catalyzed asymmetric oxidation reaction of thioether based on a temperature-sensitive ionic liquid chiral Salen Ti complex catalyst according to any one of claims 1 to 4, wherein the hydrogen peroxide solution is slowly dripped Adding the sulfide compound and the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst to an aqueous solution to carry out asymmetric oxidation reaction. 6. the method based on temperature-sensitive ionic liquid chiral Salen Ti complex catalyst water-phase catalyzed sulfide asymmetric oxidation reaction according to claim 5, it is characterized in that: described temperature-sensitive ionic liquid chiral Salen Ti is coordinated The molar ratio of the physical catalyst to the sulfide compound is 1:50～1:1000; The molar ratio of hydrogen peroxide to the sulfide compound in the hydrogen peroxide solution is 1:1 to 2:1; The concentration of the hydrogen peroxide solution is 15wt%-70wt%. 7. The method for water-phase catalyzed sulfide asymmetric oxidation reaction based on temperature-sensitive ionic liquid chiral Salen Ti complex catalyst according to any one of claims 1 to 4, characterized in that: the asymmetric oxidation reaction Under the condition that the temperature is -50℃～50℃, the reaction is carried out for 0.1～5h. 8. the method based on the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst water-phase catalyzed sulfide asymmetric oxidation reaction according to claim 7, is characterized in that: after the asymmetric oxidation reaction is completed, the reaction system is raised The temperature realizes the hydrophilic-hydrophobic transition of the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst, and the temperature-sensitive ionic liquid chiral Salen Ti complex catalyst is precipitated, which can be reused after filtration and recovery.