Amino methyl sulfone reagent, preparation method thereof and application of amine methyl sulfone reagent in asymmetric amine methylation sulfonylation reaction of conjugated diene

Abstract

The invention relates to the technical field of organic synthesis, in particular to an amine methyl sulfone reagent, a preparation method of the amine methyl sulfone reagent and application of the amine methyl sulfone reagent in asymmetric amine methylation sulfonylation reaction of conjugated diene. The amine methyl sulfone reagent has a structure shown as a formula I. Both an aminomethyl part and a sulfonyl part of the aminomethyl sulfone reagent can be utilized, and the atom economy of the reaction is 100%. The preparation method is mild in reaction condition and low in energy consumption, and is an environment-friendly reaction. The aminomethyl sulfone reagent can be applied to asymmetric aminomethylation sulfonylation reaction of conjugated diene, and the reaction has good substrate adaptability and is compatible with various functional group substituted aminomethyl sulfone reagents and conjugated diene; in addition, the reaction can obtain high yield and stereochemical selectivity, and a series of chiral 3-sulfonyl amines can be rapidly constructed with extremely high efficiency. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to an aminomethyl sulfone reagent, a preparation method thereof and application thereof in an asymmetric aminomethylation sulfonylation reaction of a conjugated diene. Background Art

[0002] Chiral sulfonyl amide compounds are widely present in a variety of drugs and biologically active natural products, such as dorzolamide·HCl, (-)-agelasidine A, etc.

[0003]

[0004] Currently reported methods for preparing chiral sulfonylamines mainly rely on multi-step synthesis strategies, which require the introduction of amine groups and sulfonyl groups one by one. The methods are cumbersome and uneconomical in terms of atoms and steps. Summary of the invention

[0005] In view of this, the technical problem to be solved by the present invention is to provide an aminomethyl sulfone reagent, a preparation method thereof and an application thereof in the asymmetric amination methylation sulfonylation reaction of conjugated dienes, which can realize the amination sulfonylation reaction in one step.

[0006] To achieve the above object, the present invention provides an aminomethyl sulfone reagent having a structure shown in Formula I:

[0007]

[0008] Among them, R 1 , R 2 independently selected from substituted or unsubstituted C1-C40 aliphatic groups;

[0009] R 4 It is selected from a substituted or unsubstituted C1-C40 aliphatic group, a substituted or unsubstituted C3-C40 alicyclic group, a substituted or unsubstituted C4-C60 heteroaryl group, and a substituted or unsubstituted C6-C40 aromatic group.

[0010] Optionally, the R 1 , R 2 independently selected from substituted or unsubstituted C1-C10 aliphatic groups;

[0011] The R 1 , R 2 The substituents are independently selected from halogen, nitro, amino, C6-C12 aryl, C4-C12 heteroaryl;

[0012] The R 4Selected from substituted or unsubstituted C1-C10 aliphatic groups, substituted or unsubstituted C3-C10 alicyclic groups, substituted or unsubstituted C4-C12 heteroaryl groups, substituted or unsubstituted C6-C14 aromatic groups;

[0013] The R 4 The substituent is selected from halogen, nitro, amino, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryl, and C4-C12 heteroaryl.

[0014] Optionally, the R 1 , R 2 independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl;

[0015] The R 4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, quinolyl, quinoxalinyl, quinazolinyl, anthracenyl, phenanthrenyl, pyridyl;

[0016] The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, quinolyl, quinoxalinyl, quinazolinyl, anthracenyl, phenanthrenyl, pyridyl may be further substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, or amino.

[0017] Optionally, the aminomethyl sulfone reagent has any of the following structures:

[0018]

[0019] The present invention provides a method for preparing the aminomethyl sulfone reagent, comprising the following steps:

[0020] Using the N,O-acetal of formula Ia and the sulfinic acid of formula Ib as raw materials, an aminomethyl sulfone reagent of formula I is synthesized;

[0021]

[0022]

[0023] Among them, R 1 , R 2 , R 3 independently selected from substituted or unsubstituted C1-C40 aliphatic groups;

[0024] R 4 It is selected from a substituted or unsubstituted C1-C40 aliphatic group, a substituted or unsubstituted C4-C60 heteroaryl group, and a substituted or unsubstituted C6-C40 aromatic group.

[0025] Optionally, the solvent of the reaction is selected from one or more of dichloromethane, dichloroethane, chlorobenzene, ether, acetonitrile and toluene.

[0026] The present invention provides application of the aminomethyl sulfone reagent or the aminomethyl sulfone reagent prepared by the preparation method in asymmetric aminomethylation and sulfonylation reaction of conjugated dienes.

[0027] The present invention provides an asymmetric aminomethylation sulfonylation reaction of a conjugated diene, comprising the following steps:

[0028] Using an aminomethylsulfone reagent shown in formula I and a conjugated diene shown in formula II as raw materials, a chiral 3-sulfonylamine shown in formula III is synthesized under the action of a transition metal catalyst and a chiral ligand;

[0029]

[0030] Among them, R 1 , R 2 independently selected from substituted or unsubstituted C1-C40 aliphatic groups;

[0031] R 4 Selected from substituted or unsubstituted C1-C40 aliphatic groups, substituted or unsubstituted C3-C40 alicyclic groups, substituted or unsubstituted C4-C60 heteroaryl groups, substituted or unsubstituted C6-C40 aromatic groups;

[0032] R 5 , R 6 , R 7 Independently selected from H, a substituted or unsubstituted C1-C40 aliphatic group, a substituted or unsubstituted C1-C40 alicyclic group, a substituted or unsubstituted C4-C60 heteroaryl group, and a substituted or unsubstituted C6-C40 aromatic group.

[0033] Optionally, the solvent of the reaction is selected from one or more of tetrahydrofuran, dichloromethane, dichloroethane, chlorobenzene, ether, acetonitrile and toluene;

[0034] The transition metal catalyst is selected from a transition metal catalyst containing palladium element;

[0035] The chiral ligand is selected from (S,R,R)-(+)-(3,5-dioxa-4-phosphocycloheptadien[2,1-a:3,4-a']binaphth-4-yl)bis(1-phenylethyl)amine, (11BS)-2,6-bis[3,5-bis(trifluoromethyl)phenyl]-N,N-bis[(1R)-1-phenylethyl]-binaphthano[2,1-D:1',2'-F][1,3,2]dioxaphosphin-4-amine, (1 One or more of (1BR)-2,6-dimethyl-N,N-bis[(1R)-1-phenylethyl]-dinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphin-4-amine, (11BS)-2,6-bis[3,5-bis(trifluoromethyl)phenyl]-N,N-bis[(1R)-1-phenylethyl]-dinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphin-4-amine.

[0036] Optionally, the amount of the transition metal catalyst used is 0.1% to 10% of the molar amount of the conjugated diene shown in Formula II;

[0037] The amount of the chiral ligand is 0.2% to 20% of the molar amount of the conjugated diene shown in formula II;

[0038] The reaction temperature is 0 to 100° C.; the reaction time is 0 to 24 hours.

[0039] Compared with the prior art, the present invention provides an aminomethyl sulfone reagent having a structure shown in Formula I. Both the aminomethyl part and the sulfonyl part of the aminomethyl sulfone reagent can be utilized, and the atom economy of the reaction is 100%. The preparation method thereof has mild reaction conditions, low energy consumption, and is an environmentally friendly reaction. The aminomethyl sulfone reagent can be applied to the asymmetric aminomethylation and sulfonylation reaction of conjugated dienes, and the reaction has good substrate adaptability and is compatible with aminomethyl sulfone reagents and conjugated dienes substituted with various functional groups; and the reaction can obtain a high yield and stereochemical selectivity, and can quickly construct a series of chiral 3-sulfonylamines with extremely high efficiency. DETAILED DESCRIPTION

[0040] The present invention provides an aminomethyl sulfone reagent having a structure shown in Formula I:

[0041]

[0042] Among them, R 1 , R 2 independently selected from substituted or unsubstituted C1-C40 aliphatic groups;

[0043] R 4It is selected from a substituted or unsubstituted C1-C40 aliphatic group, a substituted or unsubstituted C3-C40 alicyclic group, a substituted or unsubstituted C4-C60 heteroaryl group, and a substituted or unsubstituted C6-C40 aromatic group.

[0044] Preferably, the R 1 , R 2 independently selected from substituted or unsubstituted C1-C10 aliphatic groups; more preferably, the R 1 , R 2 independently selected from substituted or unsubstituted C1-C6 aliphatic groups; in some specific embodiments of the present invention, the R 1 , R 2 Independently selected from substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.

[0045] The R 1 , R 2 The substituent groups are independently preferably one or more of halogen, nitro, amino, C6-C12 aryl, and C4-C12 heteroaryl.

[0046] Preferably, the R 4 is selected from substituted or unsubstituted C1-C10 aliphatic groups, substituted or unsubstituted C3-C10 alicyclic groups, substituted or unsubstituted C4-C12 heteroaryl groups, substituted or unsubstituted C6-C14 aromatic groups; more preferably, the R 4 It is selected from a substituted or unsubstituted C1-C6 aliphatic group, a substituted or unsubstituted C3-C6 alicyclic group, a substituted or unsubstituted C4-C6 heteroaryl group, and a substituted or unsubstituted C6-C14 aromatic group.

[0047] The R 4 The substituent is preferably halogen, nitro, amino, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryl, or C4-C12 heteroaryl.

[0048] The above-mentioned alicyclic group includes a saturated or unsaturated alicyclic group.

[0049] In some specific embodiments of the present invention, the R 4 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, quinolyl, quinoxalinyl, quinazolinyl, anthracenyl, phenanthrenyl, pyridinyl.

[0050] Preferably, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, quinolyl, quinoxalinyl, quinazolinyl, anthracenyl, phenanthrenyl, pyridyl may be further substituted by one or more of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, and amino.

[0051] In some specific embodiments of the present invention, the aminomethyl sulfone reagent has any of the following structures:

[0052]

[0053] Another aspect of the present invention provides a method for preparing the aminomethyl sulfone reagent, comprising the following steps: using the N,O-acetal represented by formula Ia and the sulfinic acid represented by formula Ib as raw materials to synthesize the aminomethyl sulfone reagent represented by formula I;

[0054]

[0055] Among them, R 1 , R 2 , R 3 independently selected from substituted or unsubstituted C1-C40 aliphatic groups;

[0056] R 4 It is selected from a substituted or unsubstituted C1-C40 aliphatic group, a substituted or unsubstituted C4-C60 heteroaryl group, and a substituted or unsubstituted C6-C40 aromatic group.

[0057] The above R 1 , R 2 , R 4 The range of is the same as that described in Formula I and will not be repeated here.

[0058] Preferably, the R 3 is selected from substituted or unsubstituted C1-C10 aliphatic groups; more preferably, the R 3 is selected from substituted or unsubstituted C1-C6 aliphatic groups; in some specific embodiments of the present invention, the R 3 is selected from substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl.

[0059] The R 3 The substituent group is preferably one or more of halogen, nitro, amino, C6-C12 aryl, and C4-C12 heteroaryl.

[0060] In some specific embodiments of the present invention, the N,O-acetal represented by Formula Ia has any of the following structures:

[0061]

[0062] In some specific embodiments of the present invention, the sulfinic acid represented by Formula Ib has any of the following structures:

[0063]

[0064] Preferably, the solvent of the reaction is selected from one or more of dichloromethane, dichloroethane, chlorobenzene, ether, acetonitrile and toluene.

[0065] The reaction temperature is preferably 0 to 100° C., and the reaction time is preferably 0 to 24 h.

[0066] Another aspect of the present invention provides use of the aminomethyl sulfone reagent or the aminomethyl sulfone reagent prepared by the above preparation method in the asymmetric aminomethylation and sulfonylation reaction of conjugated dienes.

[0067] Specifically, the present invention provides an asymmetric aminomethylation sulfonylation reaction of a conjugated diene, comprising the following steps:

[0068] Using an aminomethylsulfone reagent shown in formula I and a conjugated diene shown in formula II as raw materials, a chiral 3-sulfonylamine shown in formula III is synthesized under the action of a transition metal catalyst and a chiral ligand;

[0069]

[0070] Among them, R 1 , R 2 independently selected from substituted or unsubstituted C1-C40 aliphatic groups;

[0071] R 4 Selected from substituted or unsubstituted C1-C40 aliphatic groups, substituted or unsubstituted C3-C40 alicyclic groups, substituted or unsubstituted C4-C60 heteroaryl groups, substituted or unsubstituted C6-C40 aromatic groups;

[0072] R 5 , R 6 , R 7 Independently selected from H, a substituted or unsubstituted C1-C40 aliphatic group, a substituted or unsubstituted C3-C40 alicyclic group, a substituted or unsubstituted C4-C60 heteroaryl group, a substituted or unsubstituted C6-C40 aromatic group.

[0073] The above R 1 , R 2 , R 4 The range of is the same as that described in Formula I and will not be repeated here.

[0074] Preferably, the R 5 , R 6 , R 7Independently selected from H, substituted or unsubstituted C1-C10 aliphatic groups, substituted or unsubstituted C3-C10 alicyclic groups, substituted or unsubstituted C4-C12 heteroaryl groups, substituted or unsubstituted C6-C14 aromatic groups.

[0075] Further preferably, the R 5 , R 6 , R 7 Independently selected from H, substituted or unsubstituted C1-C6 aliphatic group, substituted or unsubstituted C3-C6 alicyclic group, substituted or unsubstituted C4-C6 heteroaryl group, substituted or unsubstituted C6-C10 aromatic group.

[0076] The above-mentioned alicyclic group includes a saturated or unsaturated alicyclic group.

[0077] In some specific embodiments of the present invention, the R 5 , R 6 , R 7 independently selected from H, substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, quinolyl, quinoxalinyl, quinazolinyl, anthracenyl, phenanthrenyl, pyridinyl.

[0078] The R 5 , R 6 , R 7 The substituents are independently preferably halogen, nitro, amino, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryl, C4-C12 heteroaryl, and more preferably one or more of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, and amino.

[0079] In some specific embodiments of the present invention, the conjugated diene represented by formula II is selected from any of the following structures:

[0080]

[0081] Preferably, the solvent of the reaction is selected from one or more of tetrahydrofuran, dichloromethane, dichloroethane, chlorobenzene, ether, acetonitrile and toluene;

[0082] Preferably, the transition metal catalyst is selected from transition metal catalysts containing palladium.

[0083] The transition metal catalyst containing the palladium element is preferably one or more of palladium chloride, palladium bromide, palladium iodide, palladium acetate, palladium trifluoroacetate, tri-tert-butylphosphine palladium, tetrakistriphenylphosphine palladium, triphenylphosphine palladium chloride, bisacetonitrile palladium chloride, and allyl palladium chloride.

[0084] Preferably, the chiral ligand is selected from (S,R,R)-(+)-(3,5-dioxa-4-phosphocycloheptadienyl[2,1-a:3,4-a']dinaphth-4-yl)bis(1-phenylethyl)amine, (11BS)-2,6-bis[3,5-bis(trifluoromethyl)phenyl]-N,N-bis[(1R)-1-phenylethyl]-dinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphin-4-amine, One or more of (11BR)-2,6-dimethyl-N,N-bis[(1R)-1-phenylethyl]-dinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphin-4-amine, (11BS)-2,6-bis[3,5-bis(trifluoromethyl)phenyl]-N,N-bis[(1R)-1-phenylethyl]-dinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphin-4-amine.

[0085] The amount of the transition metal catalyst used is preferably 0.1% to 10% of the molar amount of the conjugated diene shown in formula II.

[0086] The amount of the chiral ligand used is preferably 0.2% to 20% of the molar amount of the conjugated diene shown in formula II.

[0087] The reaction temperature is preferably 0 to 100° C. The reaction time is preferably 0 to 24 h.

[0088] In order to further illustrate the present invention, the following is a detailed description in conjunction with the embodiments. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention.

[0089] All raw materials of the present invention have no particular limitation on their sources, and can be purchased from the market or prepared according to conventional methods known to those skilled in the art.

[0090] Example 1 Preparation of aminomethylsulfone reagent 3a

[0091]

[0092] In a glove box, sulfinic acid 1a (1.0 mmol), N,O-acetal 2a (1.0 mmol) and dichloromethane (5.0 mL) were added in a dry Young's tube. The reaction system was then stirred at room temperature for 1 hour. After the reaction was completed, the solvent was dried to obtain a white crude product. The crude product was washed with a small amount of methanol to obtain the target aminomethyl sulfone reagent 3a with a yield of 97%. 1H NMR(400MHz, CDCl3)δ7.79(d,J=1.8Hz,2H),7.43–7.31(m,2H),4.16(s,2H),2.55( d,J=7.3Hz,4H),2.45(s,3H),1.62(dt,J=13.5,6.8Hz,2H),0.77(d,J=6.7Hz,12H). 13 CNMR(100MHz,CDCl3)δ144.47,137.62,129.88,128.48,79.00,62.02,26.55,21.71,20.39.HRMS(ESI)calcd.for C 16 H 28 NO2S[M+H] + :298.1835,found:298.1830.

[0093] Example 2 Preparation of aminomethylsulfone reagent 3b

[0094]

[0095] In a glove box, sulfinic acid 1a (1.0 mmol), N,O-acetal 2b (1.0 mmol) and dichloromethane (5.0 mL) were added in a dry Young's tube. The reaction system was then stirred at room temperature for 1 hour. After the reaction was completed, the solvent was dried to obtain a white crude product. The crude product was washed with a small amount of methanol to obtain the target aminomethyl sulfone reagent 3b with a yield of 99%. 1 H NMR (500MHz, CDCl3) δ7.73--7.50(m,2H),7.23--7.13(m,8H),7.09(dd,J=7.5,2.0Hz,4H),3.97(s,2H),3.92(s,4H),2.35(s,3H). 13 C NMR(126MHz, CDCl3)δ143.52,135.64,128.79,128.11,127.62,127.43,126.45,73.81,55.96,20.72.HRMS(ESI)calcd.for C 22 H 24 NO2S[M+H] + :366.1522,found:366.1525.

[0096] Example 3 Preparation of aminomethylsulfone reagent 3c

[0097] The same method as in Example 1 was used to replace the reaction raw materials to prepare aminomethyl sulfone reagent 3c.

[0098]

[0099] Example 4 Preparation of aminomethylsulfone reagent 3d

[0100] The same method as in Example 1 was used to replace the reaction raw materials to prepare aminomethyl sulfone reagent 3d.

[0101]

[0102] Example 5 Preparation of chiral 3-sulfonylamine 5a

[0103]

[0104] In a glove box, [Pd(allyl)Cl]2 (0.0075 mmol), ligand L (0.018 mmol) and dichloromethane (1 mL) were added in sequence to a dry Young's tube. Subsequently, the palladium catalyst was stirred at 45 °C for 30 minutes. After the reaction was completed, it was cooled to room temperature and moved into a glove box. Subsequently, aminomethyl sulfone 3a (0.36 mmol) and 1,3-diene 4a (0.30 mmol) were carefully added to the palladium catalytic system and reacted at room temperature for 12 hours. After the reaction was completed, the solvent was dried to obtain a residue. Finally, the target product chiral 3-sulfonylamine 5a was purified by column chromatography with a yield of 98% and 99% ee. 1 HNMR(500MHz, CDCl3)δ7.70(d,J=8.3Hz,2H),7.39–-7.16(m,7H),6.27(d,J=15. 9Hz,1H),5.91(d,J=9.4Hz,1H),3.95(ddd,J=11.2,9.3,2.3Hz,1H),2.51-–2.23( m,6H),2.06(dd,J=12.5,8.9Hz,2H),1.95(dd,J=12.5,5.4Hz,2H),1.80-–1.68( m,1H),1.60(dq,J=8.9,6.5Hz,2H),0.87(d,J=6.5Hz,6H),0.80(d,J=6.6Hz,6H). 13 C NMR (126MHz, CDCl3) δ144.54,138.42,137.15,134.92,129.57,129.40,128.76,128.41,126 .64,121.51,67.30,63.78,51.84,26.45,25.41,21.76,21.17,21.10.HRMS(ESI)calcd.for C 26 H 38 NO2S[M+H]+ :428.2618, found:428.2629.[99%ee, Chiralcel ID column(n-hexane:isopropanol=90:10,1.0mL / min,254nm,25℃);t(minor peak)=17.0min,t(main peak)=17.9min].

[0105] Example 6 Preparation of Chiral 3-Sulfonylamine 5b

[0106]

[0107] In a glove box, [Pd(allyl)Cl]2 (0.0075 mmol), ligand L (0.018 mmol) and dichloromethane (1 mL) were added in sequence to a dry Young's tube. Subsequently, the palladium catalyst was stirred at 45 °C for 30 minutes. After the reaction was completed, it was cooled to room temperature and moved into a glove box. Subsequently, aminomethyl sulfone 3c (0.36 mmol) and 1,3-diene 4a (0.30 mmol) were carefully added to the palladium catalytic system and reacted at room temperature for 12 hours. After the reaction was completed, the solvent was dried to obtain a residue. Finally, the target product chiral 3-sulfonylamine 5b was purified by column chromatography with a yield of 93% and 97% ee. 1 HNMR(500MHz, CDCl3)δ8.43--8.23(m,2H),8.11--7.91(m,2H),7.39--7.19(m,5H), 6.22(d,J=15.9Hz,1H),5.89(dd,J=15.9,9.5Hz,1H),4.18-–3.91(m,1H),2.56–2.34 (m,3H),2.09(dd,J=12.6,8.9Hz,2H),1.99(dd,J=12.6,5.3Hz,2H),1.83–-1.70(m, 1H), 1.62 (ddd, J=9.2, 4.6, 1.9Hz, 2H), 0.89 (d, J=6.6Hz, 6H), 0.82 (d, J=6.7Hz, 6H). 13 C NMR (126MHz, CDCl3) δ150.83,143.84,139.34,135.48,130.71,128.97,128.95,126.62, 124.04,120.57,67.49,63.84,51.68,26.48,25.05,21.23,21.11.HRMS(ESI)calcd.For C 25 H 35 N2O4S[M+H] +:459.2312, found:459.2329.[97%ee, Chiralcel ID column(n-hexane:isopropanol=95:5,1.0mL / min,254nm,25℃);t(minor peak)=11.2min,t(main peak)=11.7min].

[0108] Example 7 Preparation of chiral 3-sulfonylamine 5c

[0109]

[0110] In a glove box, [Pd(allyl)Cl]2 (0.0075 mmol), ligand L (0.018 mmol) and dichloromethane (1 mL) were added in sequence to a dry Young's tube. Subsequently, the palladium catalyst was stirred at 45 °C for 30 minutes. After the reaction was completed, it was cooled to room temperature and moved into a glove box. Subsequently, aminomethyl sulfone 3d (0.36 mmol) and 1,3-diene 4a (0.30 mmol) were carefully added to the palladium catalytic system and reacted at room temperature for 12 hours. After the reaction was completed, the solvent was dried to obtain a residue. Finally, the target product chiral 3-sulfonylamine 5c was purified by column chromatography with a yield of 98% and 98% ee. 1 HNMR (500MHz, CDCl3) δ8.85--8.70(m,1H),8.22--8.17(m,1H),8.03(d,J=8.2Hz,1H),7.91(dd,J=8.2,1.4Hz,1H),7.63(dd d,J=8.6,6.8,1.5Hz,1H),7.60--7.53(m,1H),7.47(t,J=7.8Hz,1H),7.26--7.16(m,3H),7.06(dd,J=7.4,2.1Hz,2H),5.97 (d,J=15.9Hz,1H),5.88(dd,J=15.9,9.2Hz,1H),4.26(td,J=9.9,9.1,2.3Hz,1H),2.56-–2.27(m,3H),2.04(dd,J=12.5,9. 0Hz, 2H), 1.95 (d, J = 5.3Hz, 2H), 1.89 (d, J = 5.0Hz, 1H), 1.55 (t, J = 7.2Hz, 2H), 0.81 (d, J = 6.5Hz, 6H), 0.76 (d, J = 6.7Hz, 6H). 13C NMR (126MHz, CDCl3) δ138.33,135.93,135.03,134.17,133.08,131.92,129.43,129.18,128.56,128.49,128.29, 126.92,126.48,124.83,124.22,121.64,67.10,63.95,52.12,26.42,25.16,21.07,21.05.HRMS(ESI)calcd.for C 29 H 38 NO2S[M+H] + :464.2618, found:464.2650.[98%ee,ChiralcelAD-H column(n-hexane:isopropanol:trifluoroacetic acid:diethylamine=80:20:0.1:0.05,1.0mL / min,254nm,25℃);t(minor peak)=8.9min,t(main peak)=10.4min].

[0111] Example 8 Preparation of Chiral 3-Sulfonylamine 5d

[0112]

[0113] In a glove box, [Pd(allyl)Cl]2 (0.0075 mmol), ligand L (0.018 mmol) and dichloromethane (1 mL) were added in sequence to a dry Young's tube. Subsequently, the palladium catalyst was stirred at 45 °C for 30 minutes. After the reaction was completed, it was cooled to room temperature and moved into a glove box. Subsequently, aminomethyl sulfone 3a (0.36 mmol) and 1,3-diene 4b (0.30 mmol) were carefully added to the palladium catalytic system and reacted at room temperature for 12 hours. After the reaction was completed, the solvent was dried to obtain a residue. Finally, the target product chiral 3-sulfonylamine 5d was purified by column chromatography with a yield of 72% and 98% ee. 1 HNMR (500MHz, CDCl3) δ7.70–7.47(m,2H),7.30–-7.15(m,7H),6.18(d,J=16.3Hz,1H),6.09(d,J=16.3H z,1H),2.41–2.24(m,5H),2.16–1.94(m,6H),1.57-–1.47(m,2H),1.38(s,3H),0.77(d,J=6.6Hz,12H). 13C NMR (126MHz, CDCl3) δ144.63,136.26,134.75,132.43,130.84,129.23,128.63,128.39,126 .73,126.71,67.64,63.70,49.84,29.72,26.78,21.75,20.98,17.42.HRMS(ESI)calcd.for C 27 H 40 NO2S[M+H] + :442.2774, found:442.2785.[98%ee, ChiralcelID column (n-hexane:isopropanol=95:5,1.0mL / min,254nm,25℃); t(minor peak)=12.3min, t(main peak)=13.6min].

[0114] Example 9 Preparation of chiral 3-sulfonylamine 5e

[0115]

[0116] In a glove box, [Pd(allyl)Cl]2 (0.0075 mmol), ligand L (0.018 mmol) and dichloromethane (1 mL) were added in sequence to a dry Young's tube. Subsequently, the palladium catalyst was stirred at 45 °C for 30 minutes. After the reaction was completed, it was cooled to room temperature and moved into a glove box. Subsequently, aminomethyl sulfone 3a (0.36 mmol) and 1,3-diene 4c (0.30 mmol) were carefully added to the palladium catalytic system and reacted at room temperature for 12 hours. After the reaction was completed, the solvent was dried to obtain a residue. Finally, the target product chiral 3-sulfonylamine 5e was purified by column chromatography with a yield of 42% and 95% ee. 1 HNMR (500MHz, CDCl3) δ7.73--7.50(m,2H),7.38-7.01(m,2H),5.43(dd,J=15.8,1.2Hz,1H),5.30(d,J=6.8Hz,1H),2.43(s,3H),2.40-2.23(m,2H),2 .13–1.90(m,7H),1.67(ddt,J=41.5,13.4,5.2Hz,7H),1.31–1.21(m,5H), 1.14(tt,J=12.8,3.3Hz,1H),1.05--0.93(m,2H),0.85(d,J=6.7Hz,12H). 13C NMR (126MHz, CDCl3) δ144.36,142.04,132.32,130.95,128.87,124.83,67.05,63.51,49.52, 41.01,32.69,32.49,28.79,26.71,26.14,25.96,21.73,20.95,17.28.HRMS(ESI)calcd.for C 27 H 46 NO2S[M+H] + :448.3244, found:448.3245.[95%ee, ChiralcelID column(n-hexane:isopropanol=90:10,1.0mL / min,254nm,25℃);t(minor peak)=6.9min,t(main peak)=7.5min].

[0117] Example 10 Preparation of chiral 3-sulfonylamine 5f

[0118]

[0119] In a glove box, [Pd(allyl)Cl]2 (0.0075 mmol), ligand L (0.018 mmol) and dichloromethane (1 mL) were added in sequence to a dry Young's tube. Subsequently, the palladium catalyst was stirred at 45 °C for 30 minutes. After the reaction was completed, it was cooled to room temperature and moved into a glove box. Subsequently, aminomethyl sulfone 3b (0.36 mmol) and 1,3-diene 4a (0.30 mmol) were carefully added to the palladium catalytic system and reacted at room temperature for 12 hours. After the reaction was completed, the solvent was dried to obtain a residue. Finally, the target product chiral 3-sulfonylamine 5f was purified by column chromatography with a yield of 95% and 99% ee. 1 HNMR(500MHz,CDCl3)δ7.66(d,J=8.3Hz,2H),7.33–-7.15(m,15H),7.15-–7.01(m,2H),5.84(d,J=15.9Hz,1H),5.71(dd,J=15.9,9 .2Hz,1H),3.85–3.72(m,1H),3.68(d,J=13.4Hz,2H),3.30(d,J=13.3Hz,2H),2.64–-2.41(m,3H),2.38(s,3H),1.85-–1.65(m,1H). 13C NMR (126MHz, CDCl3) δ144.53,139.34,138.00,136.06,134.85,129.56,129.20,129.14,128.52,1 28.32,128.25,127.09,126.69,121.06,67.21,58.30,49.82,25.60,21.72.HRMS(ESI)calcd.for C 32 H 34 NO2S + [M+H] + :496.2305, found:496.2305.[99%ee, Chiralcel ID column (n-hexane:isopropanol=90:10, 0.6mL / min, 254nm, 25℃); t(minor peak)=49.2min, t(main peak)=50.4min].

[0120] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. An aminomethyl sulfone reagent having the structure shown in Formula I: in, R 1 , R 2 independently selected from substituted or unsubstituted C1-C40 aliphatic groups; R 4 It is selected from a substituted or unsubstituted C1-C40 aliphatic group, a substituted or unsubstituted C3-C40 alicyclic group, a substituted or unsubstituted C4-C60 heteroaryl group, and a substituted or unsubstituted C6-C40 aromatic group.

2. The aminomethyl sulfone reagent according to claim 1, characterized in that The R 1 , R 2 independently selected from substituted or unsubstituted C1-C10 aliphatic groups; The R 1 , R 2 The substituents are independently selected from halogen, nitro, amino, C6-C12 aryl, C4-C12 heteroaryl; The R 4 Selected from substituted or unsubstituted C1-C10 aliphatic groups, substituted or unsubstituted C3-C10 alicyclic groups, substituted or unsubstituted C4-C12 heteroaryl groups, substituted or unsubstituted C6-C14 aromatic groups; The R 4 The substituent is selected from halogen, nitro, amino, C1-C10 alkyl, C1-C10 alkoxy, C6-C12 aryl, and C4-C12 heteroaryl.

3. The aminomethyl sulfone reagent according to claim 2, characterized in that The R 1 , R 2 independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or benzyl; The R 4 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, quinolyl, quinoxalinyl, quinazolinyl, anthracenyl, phenanthrenyl, pyridyl; The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, quinolyl, quinoxalinyl, quinazolinyl, anthracenyl, phenanthrenyl, pyridyl may be further substituted by halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, or amino.

4. The aminomethyl sulfone reagent according to claim 3, characterized in that The aminomethyl sulfone reagent has any of the following structures:

5. The method for preparing the aminomethyl sulfone reagent according to any one of claims 1 to 4, comprising the following steps: Using the N,O-acetal of formula Ia and the sulfinic acid of formula Ib as raw materials, an aminomethyl sulfone reagent of formula I is synthesized; Among them, R 1 , R 2 , R 3 independently selected from substituted or unsubstituted C1-C40 aliphatic groups; R 4 It is selected from a substituted or unsubstituted C1-C40 aliphatic group, a substituted or unsubstituted C4-C60 heteroaryl group, and a substituted or unsubstituted C6-C40 aromatic group.

6. The preparation method according to claim 5, characterized in that: The solvent of the reaction is selected from one or more of dichloromethane, dichloroethane, chlorobenzene, ether, acetonitrile and toluene.

7. Use of the aminomethyl sulfone reagent according to any one of claims 1 to 4 or the aminomethyl sulfone reagent prepared by the preparation method according to any one of claims 5 to 6 in the asymmetric aminomethylation sulfonylation reaction of conjugated dienes.

8. An asymmetric aminomethylation sulfonylation reaction of a conjugated diene, comprising the following steps: Using an aminomethylsulfone reagent shown in formula I and a conjugated diene shown in formula II as raw materials, a chiral 3-sulfonylamine shown in formula III is synthesized under the action of a transition metal catalyst and a chiral ligand; Among them, R 1 , R 2 independently selected from substituted or unsubstituted C1-C40 aliphatic groups; R 4 Selected from substituted or unsubstituted C1-C40 aliphatic groups, substituted or unsubstituted C3-C40 alicyclic groups, substituted or unsubstituted C4-C60 heteroaryl groups, substituted or unsubstituted C6-C40 aromatic groups; R 5 , R 6 , R 7 Independently selected from H, a substituted or unsubstituted C1-C40 aliphatic group, a substituted or unsubstituted C1-C40 alicyclic group, a substituted or unsubstituted C4-C60 heteroaryl group, and a substituted or unsubstituted C6-C40 aromatic group.

9. The asymmetric aminomethylation sulfonylation reaction of conjugated dienes according to claim 8, characterized in that: The solvent of the reaction is selected from one or more of tetrahydrofuran, dichloromethane, dichloroethane, chlorobenzene, ether, acetonitrile and toluene; The transition metal catalyst is selected from a transition metal catalyst containing palladium element; The chiral ligand is selected from (S,R,R)-(+)-(3,5-dioxa-4-phosphocycloheptadien[2,1-a:3,4-a']binaphth-4-yl)bis(1-phenylethyl)amine, (11BS)-2,6-bis[3,5-bis(trifluoromethyl)phenyl]-N,N-bis[(1R)-1-phenylethyl]-binaphthano[2,1-D:1',2'-F][1,3,2]dioxaphosphin-4-amine, (1 One or more of (1BR)-2,6-dimethyl-N,N-bis[(1R)-1-phenylethyl]-dinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphin-4-amine, (11BS)-2,6-bis[3,5-bis(trifluoromethyl)phenyl]-N,N-bis[(1R)-1-phenylethyl]-dinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphin-4-amine.

10. The asymmetric aminomethylation sulfonylation reaction of conjugated dienes according to claim 8, characterized in that: The amount of the transition metal catalyst used is 0.1% to 10% of the molar amount of the conjugated diene shown in formula II; The amount of the chiral ligand is 0.2% to 20% of the molar amount of the conjugated diene shown in formula II; The reaction temperature is 0 to 100° C.; the reaction time is 0 to 24 hours.

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