Trisubstituted hydroxylamine derivatives and methods for their synthesis

Abstract

The present application mainly relates to the efficient synthesis of a kind of tri-substituted hydroxylamine compound by transition metal Pd catalytic C-O bond coupling.The present application realizes the one-pot reaction of tertiary chloroalkane or secondary chloroalkane and O-acyl hydroxylamine compound under the action of catalyst, ligand and base in argon atmosphere, realizes C-O bond coupling in the case of keeping the fragile N-O bond unbroken, and obtains a kind of big steric hindrance N,N,O-trialkyl substituted hydroxylamine derivative with high chemical selectivity.The present application has the characteristics of excellent chemical selectivity to construct C-O bond, simple experimental operation, wide source of raw materials, high yield, wide substrate application range and excellent functional group tolerance, and the synthesized product is suitable for being contained in drug small molecule screening library for the discovery of lead drug.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing N,N,O-trisubstituted hydroxylamine derivatives by transition metal Pd catalyzed C-O bond coupling reaction, belonging to the field of organic synthesis. BACKGROUND

[0002] Hydroxylamine structures widely exist in pesticide molecules, natural products, drug molecules and physiologically active molecules, and have important biological activities. Meanwhile, hydroxylamine is an important reaction intermediate and is widely used in the synthesis of medicines and the like. Therefore, the synthesis method of trisubstituted hydroxylamine derivatives has always been widely valued.

[0003] Synthesis of N,N,O-trisubstituted hydroxylamine compounds usually requires highly functionalized raw materials, multi-step reactions, and harsh reaction conditions such as the use of special or unstable reaction reagents. SUMMARY

[0004] In view of the above, the purpose of the present application is to provide a synthesis method of large steric hindrance N,N,O-trisubstituted hydroxylamine derivatives.

[0005] Another purpose of the present application is to provide a C-O bond coupling product which maintains the integrity of the fragile N-O bond, and to provide a feasible scheme for efficiently synthesizing large steric hindrance N,N,O-trisubstituted hydroxylamine compounds containing α-quaternary carbon centers under mild conditions, which has unique chemical selectivity for constructing C-O bond, simple experimental operation, widely available raw materials, high yield, wide substrate application range and excellent functional group tolerance.

[0006] Therefore, the present application provides a N,N,O-trisubstituted hydroxylamine compound and its derivatives, whose general formula is formula I:

[0007]

[0008] I

[0009] Among them:

[0010] R 1 selected from substituted and unsubstituted aryl groups, indolines, morpholines, tetrahydroquinolines, tetrahydroisoquinolines, anilines, N-alkylanilines, N-alkylbenzylamines, dibenzylamines, cycloalkyl secondary amines;

[0011] R 2 selected from hydrogen atoms, C1-C9 straight-chain and branched-chain alkyl groups;

[0012] R 3 selected from substituted and unsubstituted aryl groups, C1-C9 straight-chain alkyl groups;

[0013] R 4 , R5 selected from the group consisting of hydrogen atom; aryl; heteroaryl; substituted and unsubstituted benzyl; C1-C12 straight chain and branched alkyl; C3-C6 cycloalkyl; and indole; indoline; morpholine; cycloalkyl secondary amine;

[0014] The present application also provides a method for synthesizing large steric N,N,O-trisubstituted hydroxylamine and its derivatives by transition metal palladium catalyzed C-O bond coupling, characterized in that tertiary chloroalkane or secondary chloroalkane and O-acyl hydroxylamine compound are mixed and heated to react under the reaction conditions of palladium catalyst, ligand, base, organic solvent and argon atmosphere, and finally the product is obtained by purification.

[0015] In the synthetic method of the present application, the catalyst is a transition metal palladium catalyst, and the palladium reagent is selected from one of the following: palladium chloride, palladium bromide, palladium acetate, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium dichloride, tris(dibenzylideneacetone)dipalladium allyl chloride (II) dimer. The ligand is one of the following: 2,2'-bipyridine, 1,10-phenanthroline, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), bis(2-diphenylphosphinophenyl)ether (DPEPhos), 1,1'-binaphthalene-2,2'-bisdiphenylphosphine (BINAP), triphenylphosphine, tri(p-tolyl)phosphine, tricyclohexylphosphine, tri-tert-butylphosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,1'-bis(diphenylphosphino)ferrocene (DPPF). The base is one or more of the following: lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide. The organic solvent is one or more of the following: tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene, p-xylene, o-xylene, chlorobenzene, acetonitrile, ethyl acetate, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide. The molar ratio of the tertiary chloroalkane or secondary chloroalkane, O-acyl hydroxylamine compound, catalyst (metal + ligand), base is 1.0:1.0-2.0:0.005-0.15:0-2.0; the reaction temperature is 25 ℃-100 ℃; the atmosphere of the reaction container is argon atmosphere; the reaction time is 2 h-48 h.

[0016] In the synthetic method of the present application, the general formula of the tertiary chloroalkane or secondary chloroalkane compound is formula II:

[0017]

[0018] II

[0019] wherein:

[0020] R 1selected from substituted and unsubstituted aryl; indoline; morpholine; tetrahydroquinoline; tetrahydroisoquinoline; aniline; N-alkylaniline; N-alkylbenzylamine; dibenzylamine; cycloalkyl secondary amine;

[0021] R 2 selected from hydrogen atom; C1-C9 straight chain and branched alkyl;

[0022] R 3 selected from substituted and unsubstituted aryl; C1-C9 straight chain alkyl.

[0023] The synthetic method of the present application, the general formula of the OH-hydroxylamine or O-acylhydroxylamine compound is III:

[0024]

[0025] III

[0026] wherein:

[0027] R 4 , R 5 selected from hydrogen atom; aryl; heterocyclic aryl; substituted and unsubstituted benzyl; C1-C12 straight chain and branched alkyl; C3-C6 cycloalkyl; and indole; indoline; morpholine; cycloalkyl secondary amine;

[0028] R 6 selected from hydrogen atom; substituted and unsubstituted benzoyl; acetyl; trifluoroacetyl; pivaloyl.

[0029] The technical scheme of the present application has the following advantages:

[0030] (I) The present application realizes one-pot reaction of tertiary chloroalkane or secondary chloroalkane compound and O-acylhydroxylamine compound under the action of catalyst, ligand and base in argon atmosphere, realizes C-O coupling under the premise of keeping O-N bond unbroken, the reaction condition is mild, the raw materials are widely available and cheap, the experimental operation is simple, the reaction steps are obviously shortened, the application is easy to expand, and the required instruments and equipment are less; (II) Compared with other hydroxylamine compounds, O-acylhydroxylamine compound has a simpler synthesis method, mild reaction condition, widely available raw materials, and easy to obtain; (III) Hydroxylamine compounds exist widely in drug molecules, and have important biological activity, which can be used in many industrial production fields such as medicine, pesticide and organic functional material, this method can directly construct the target product of large steric N,N,O-trisubstituted hydroxylamine compound with high selectivity in one step, saves a lot of research time and shortens the production cycle, the product has high added value and high availability, and has foreseeable market commercialization prospect. BRIEF DESCRIPTION OF DRAWINGS

[0031] Figures 1a-7aPart of the nuclear magnetic hydrogen spectrum of the product of Example 1-21; Figures 1b-7b Part of the nuclear magnetic carbon spectrum of the product of Example 1-21.

[0032] Figure 8 Reaction formula of the model reaction of the present application. DETAILED DESCRIPTION

[0033] The present application will now be further described in detail with reference to the following reaction formulae. These are simplified schematic reaction formulae which only schematically illustrate the basic structure of the present application and therefore only show the components relevant to the present application:

[0034]

[0035] Examples 1-21

[0036] The process comprises the following steps:

[0037] (1) adding a tertiary or secondary chloroalkane compound, a benzoyl hydroxylamine compound, a catalyst, a ligand, a base and an organic solvent into a reaction vessel;

[0038] (2) mixing the reactants thoroughly in an inert gas atmosphere, heating and stirring the reaction;

[0039] (3) purifying the product after the reaction.

[0040] The present application will now be further described in detail with reference to the following reaction formulae. These are simplified schematic reaction formulae which only schematically illustrate the basic structure of the present application and therefore only show the components relevant to the present application:

[0041] The tertiary or secondary chloroalkane compound, the O-acyl hydroxylamine compound, the reaction conditions, the reaction product and the yield are shown in Table 1:

[0042] Table 1: Reactants and reaction conditions in Examples 1-21

[0043]

[0044] The nuclear magnetic data of the product of some examples are as follows:

[0045] The nuclear magnetic data of the product of Example 1 are as follows:

[0046] 1H NMR (400 MHz, CDC13) δ 8.40 (d, J = 8.1 Hz, 1H), 7.40-7.32 (m, 4H), 7.30-7.21 (m, 2H), 7.15 (dd, J = 7.4, 1.4 Hz, 1H), 7.05 (td, J = 7.4, 1.1 Hz, 1H), 4.34 (ddd, J = 10.7, 9.4, 5.0 Hz, 1H), 3.90 (d, J = 11.8 Hz, 1H), 3.82-3.68 (m, 2H), 3.67-3.54 (m, 1H), 3.25 (d, J = 10.6 Hz, 1H), 3.09-2.87 (m, 5H), 2.77 (td, J = 9.6, 4.4 Hz, 1H), 1.85 (s, 3H).

[0047] 13 C NMR (100 MHz, CDC13) δ 170.5, 143.7, 142.4, 131.2, 128.6, 127.35, 127.32, 124.4, 124.1, 124.0, 117.9, 86.5, 66.2, 66.1, 58.7, 56.8, 48.4, 28.4, 27.2.

[0048] NMR data for the product of Example 2 are as follows:

[0049] 1H NMR (400 MHz, CDC13) δ 8.38 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 6.3 Hz, 4H), 7.28 - 7.19 (m, 3H), 7.12 (d, J = 7.3 Hz, 1H), 7.02 (td, J = 7.4, 1.1 Hz, 1H), 4.39 - 4.25 (m, 1H), 3.88 (d, J = 11.8 Hz, 1H), 3.77 - 3.64 (m, 2H), 3.55 (td, J = 11.4, 2.3 Hz, 1H), 3.23 (d, J = 10.6 Hz, 1H), 3.01 (d, J = 10.0 Hz, 1H), 2.97 - 2.80 (m, 4H), 2.78 - 2.69 (m, 1H), 2.55 (dq, J = 14.4, 7.2 Hz, 1H), 2.25 (dq, J = 14.9, 7.5 Hz, 1H), 0.61 (t, J = 7.4 Hz, 3H).

[0050] 13 C NMR (100 MHz, CDC13) δ 170.6, 143.9, 139.7, 131.3, 128.3, 127.5, 127.3, 125.2, 124.4, 124.0, 118.0, 88.9, 77.4, 77.1, 76.7, 66.4, 66.3, 58.5, 57.0, 48.4, 28.8, 28.5, 8.2.

[0051] The NMR data for the product of Example 3 are as follows:

[0052] 1 H NMR (400 MHz, CDC13) δ 7.75 - 7.65 (m, 2H), 7.38 - 7.28 (m, 5H), 7.27 - 7.16 (m, 3H), 3.80 (dd, J = 12.0, 3.6 Hz, 1H), 3.60 - 3.43 (m, 2H), 3.26 - 3.11 (m, 2H), 2.86 (td, J = 10.8, 3.3 Hz, 1H), 2.43 (td, J = 11.0, 3.4 Hz, 1H), 2.39 - 2.23 (m, 2H), 2.05 (dq, J = 10.9, 2.2 Hz, 1H), 0.64 (t, J = 7.4 Hz, 3H).

[0053] 13 C NMR (100 MHz, CDCl3) δ 199.4, 140.3, 136.4, 131.9, 130.3, 128.4,127.7, 127.3, 125.2, 91.1, 66.1, 66.0, 59.2, 57.5, 28.6, 7.4.

[0054] The NMR data for the product of Example 4 are as follows:

[0055] 1 H NMR (400 MHz, CDCl3) δ 7.84-7.74 (m, 2H), 7.41-7.35 (m, 3H), 7.35-7.29 (m, 2H), 7.28-7.20 (m, 3H), 3.83 (d,J = 11.8 Hz, 1H), 3.64-3.50 (m, 2H),3.36-3.26 (m, 1H), 3.22 (d,J = 10.8 Hz, 1H), 2.89 (td,J = 10.9, 3.3 Hz, 1H),2.47 (td,J = 10.9, 3.3 Hz, 1H), 2.17 (d,J = 10.8 Hz, 1H), 1.81 (s, 3H).

[0056] 13 C NMR (100 MHz, CDCl3) δ 99.7, 143.0, 135.6, 132.2, 130.6, 128.6,127.8, 127.4, 124.5, 88.8, 66.1, 66.0, 59.3, 57.4, 26.8.

[0057] The NMR data for the product of Example 5 are as follows:

[0058] 1H NMR (400 MHz, CDC13) δ 7.32 (d, J = 1.5 Hz, 1H), 7.31-7.29 (m, 3H), 7.28 (s, 1H), 7.26 (s, 2H), 7.17 (t, J = 7.8 Hz, 2H), 7.11-7.00 (m, 4H), 6.57-6.42 (m, 2H), 5.43 (dd, J = 14.0, 1.7 Hz, 1H), 5.25 (d, J = 16.3 Hz, 1H), 3.89-3.75 (m, 2H), 3.62 (td, J = 11.5, 2.1 Hz, 1H), 3.47-3.33 (m, 2H),, 3.26 (td, J = 11.4, 2.2 Hz, 1H), 3.13 (d, J = 10.5 Hz, 1H), 2.79 (td, J = 11.0, 3.4 Hz, 1H), 2.70-2.52 (m, 2H), 2.45 (d, J = 10.0 Hz, 1H), 2.31 (dq, J = 15.1, 7.6 Hz, 1H), 0.50 (t, J = 7.4 Hz, 3H).

[0059] 13 C NMR (100 MHz, CDC13) δ 172.4, 140.2, 137.0, 135.9, 129.7, 128.3, 128.2, 128.0, 127.5, 127.1, 126.9, 126.8, 125.0, 88.4, 66.2, 58.5, 57.1, 50.1, 47.8, 29.3, 8.0.

[0060] The NMR data for the product of Example 6 are as follows:

[0061] 1H NMR (400 MHz, CDC13) δ 7.22 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.13 (d, J = 13.3 Hz, 1H), 3.86 (s, 2H), 3.68 (t, J = 10.3 Hz, 3H), 3.51 (t, J = 10.2 Hz, 1H), 3.42 (d, J = 13.6 Hz, 1H), 3.20 (d, J = 12.5 Hz, 4H), 3.04 (d, J = 10.0 Hz, 1H), 2.93-2.80 (m, 2H), 2.73 (t, J = 10.4 Hz, 1H), 2.45 (d, J = 7.2 Hz, 2H), 1.83 (dt, J = 13.5, 6.8 Hz, 1H), 1.75 (s, 3H), 0.87 (dd, J = 6.6, 1.9 Hz, 6H).

[0062] 13 C NMR (100 MHz, CDC13) δ 171.2, 140.9, 140.6, 129.2, 123.7, 85.6, 66.7, 66.1, 65.4, 58.7, 57.2, 47.5, 44.9, 43.1, 30.2, 27.6, 22.3, 22.2.

[0063] NMR data for the product of Example 7 are as follows:

[0064] 1H NMR (400 MHz, CDC13) δ 8.37 (d, J = 8.1 Hz, 1H), 7.30-7.18 (m, 3H), 7.12 (d, J = 7.3 Hz, 1H), 7.08 (d, J = 7.9 Hz, 2H), 7.02 (t, J = 7.4 Hz, 1H), 4.31 (ddd, J = 11.0, 9.5, 5.0 Hz, 1H), 3.87 (d, J = 11.8 Hz, 1H), 3.80-3.63 (m, 2H), 3.57 (t, J = 11.3 Hz, 1H), 3.22 (d, J = 10.7 Hz, 1H), 3.08-2.79 (m, 5H), 2.75 (dd, J = 9.7, 5.1 Hz, 1H), 2.43 (d, J = 7.2 Hz, 2H), 1.82 (s, 3H), 0.86 (dd, J = 6.6, 2.9 Hz, 6H).

[0065] 13 C NMR (100 MHz, CDC13) δ 170.8, 143.9, 140.9, 139.9, 131.3, 129.3, 127.4, 124.4, 124.1, 123.9, 118.0, 86.7, 66.2, 48.6, 45.0, 30.1, 28.5, 27.2, 22.32, 22.27.

[0066] The NMR data for the product of Example 8 are as follows:

[0067] 1 H NMR (400 MHz, CDC13) δ 7.38-7.30 (m, 2H), 7.30-7.21 (m, 3H), 4.12 (dt, J = 13.7, 3.8 Hz, 1H), 3.87 (t, J = 11.3 Hz, 2H), 3.76-3.58 (m, 3H), 3.53-3.40 (m, 2H), 3.26-3.09 (m, 4H), 3.10-3.00 (m, 1H), 2.96–2.75 (m, 2H), 2.68-2.54 (m, 1H), 2.46 (dq, J = 14.4, 7.2 Hz, 1H), 2.21 (dq, J = 15.0, 7.5 Hz, 1H), 0.56 (t, J = 7.4 Hz, 3H).

[0068] 13 C NMR (100 MHz, CDCl3) δ 171.0, 140.5, 128.2, 127.2, 124.8, 87.9,66.6, 66.2, 65.2, 58.4, 57.2, 47.5, 43.2, 29.1, 8.1.

[0069] The NMR data for the product of Example 9 are as follows:

[0070] 1 H NMR (400 MHz, CDCl3) δ 7.68 (d,J = 8.2 Hz, 1H), 7.33 (d,J = 5.5 Hz,4H), 7.26 (td,J = 6.8, 6.0, 3.1 Hz, 1H), 7.20-7.13 (m, 1H), 7.10-7.01 (m,2H), 4.19 (dt,J = 13.5, 4.0 Hz, 1H), 3.92 (d,J = 11.8 Hz, 1H), 3.85-3.69 (m,2H), 3.64 (td,J = 11.4, 2.2 Hz, 1H), 3.31-3.17 (m, 2H), 3.01-2.84 (m, 3H),2.65-2.48 (m, 3H), 2.29 (dq,J = 15.0, 7.6 Hz, 1H), 1.35-1.23 (m, 1H), 0.99–0.83 (m, 1H), 0.58 (t,J = 7.4 Hz, 3H).

[0071] 13 C NMR (100 MHz, CDCl3) δ 171.3, 140.2, 139.7, 130.4, 129.3, 128.2,127.1, 125.4, 124.9, 124.7, 124.6, 88.8, 66.4, 66.3, 58.7, 57.3, 45.5, 29.7,25.6, 21.7, 8.0.

[0072] The NMR data for the product of Example 10 are as follows:

[0073] 1H NMR (400 MHz, CDC13) δ 8.31 (d, J = 8.1 Hz, 1H), 7.35-7.29 (m, 2H), 7.24 (dd, J = 8.4, 6.6 Hz, 2H), 7.19-7.11 (m, 2H), 7.07-7.01 (m, 1H), 6.94 (td, J = 7.4, 1.1 Hz, 1H), 4.30-4.20 (m, 1H), 2.99-2.77 (m, 6H), 2.70-2.60 (m, 1H), 1.74 (s, 3H), 1.01-0.95 (m, 4H).

[0074] 13 C NMR (100 MHz, CDC13) δ 171.1, 143.9, 143.5, 131.3, 128.5, 127.3, 127.1, 124.30, 124.28, 123.8, 117.9, 85.9, 49.7, 48.4, 28.5, 27.3, 10.3.

[0075] The NMR data for the product of Example 11 are as follows:

[0076] 1 H NMR (400 MHz, CDC13) δ 8.30 (d, J = 8.1 Hz, 1H), 7.39-7.12 (m, 16H), 7.04 (d, J = 7.3 Hz, 1H), 6.96 (t, J = 7.3 Hz, 1H), 4.34-4.19 (m, 1H), 4.11 (d, J = 13.2 Hz, 2H), 3.90 (d, J = 13.2 Hz, 2H), 2.97 (td, J = 10.4, 7.8 Hz, 1H), 2.88 - 2.74 (m, 1H), 2.74 - 2.60 (m, 1H), 1.67 (s, 3H).

[0077] 13 C NMR (100 MHz, CDC13) δ 170.5, 143.7, 143.2, 136.9, 131.2, 129.6, 129.3, 128.5, 128.1, 127.3, 127.2, 124.3, 124.2, 123.8, 118.0, 86.6, 62.0, 48.3, 28.4, 27.4.

[0078] The nuclear magnetic data for the product of Example 12 are as follows:

[0079] 1 H NMR (400 MHz, CDCl3) δ 8.39 (d,J = 8.1 Hz, 1H), 7.38 (d,J = 7.3 Hz,2H), 7.32 (t,J = 7.6 Hz, 2H), 7.23 (td,J = 8.6, 7.9, 5.2 Hz, 2H), 7.12 (d,J =7.3 Hz, 1H), 7.01 (t,J = 7.4 Hz, 1H), 4.42-4.25 (m, 1H), 3.00-2.79 (m, 3H),2.73 (t,J = 5.4 Hz, 1H), 2.55 (s, 3H), 2.03 (d,J = 10.7 Hz, 2H), 1.90-1.76(m, 5H), 1.64 (s, 1H), 1.34 (s, 1H), 1.28-1.08 (m, 4H).

[0080] 13 C NMR (100 MHz, CDCl3) δ 171.1, 143.8, 143.4, 131.3, 128.5, 127.3,127.2, 127.1, 124.3, 123.8, 117.9, 85.9, 67.3, 48.3, 39.6, 28.5, 27.2, 26.3,26.0, 25.8.

[0081] The nuclear magnetic data for the product of Example 13 are as follows:

[0082] 1 H NMR (400 MHz, CDCl3) δ 8.40 (d,J = 8.1 Hz, 1H), 7.40-7.35 (m, 2H),7.31 (dd,J = 8.5, 6.6 Hz, 2H), 7.27-7.19 (m, 2H), 7.12 (d,J = 7.3 Hz, 1H),7.01 (t,J = 7.4 Hz, 1H), 4.40-4.22 (m, 1H), 3.46-2.81 (m, 6H), 2.80-2.61 (m,1H), 1.82 (s, 3H), 1.78-1.49 (m, 8H).

[0083] 13C NMR (100 MHz, CDC13) δ 170.8, 143.9, 143.1, 131.3, 128.5, 127.3, 127.1, 124.3, 123.8, 117.9, 86.4, 59.1, 48.4, 28.5, 27.4, 26.4, 24.7.

[0084] The NMR data for the product of Example 14 are as follows:

[0085] 1 H NMR (400 MHz, CDC13) δ 8.34 (d, J = 8.1 Hz, 1H), 7.32-7.20 (m, 4H), 7.19-7.13 (m, 2H), 7.08 (d, J = 7.3 Hz, 1H), 6.98 (q, J = 7.3 Hz, 2H), 6.57 (d, J = 50.5 Hz, 1H), 4.32-3.87 (m, 3H), 3.39-2.78 (m, 6H), 2.67 (s, 1H), 1.82 (s, 3H).

[0086] 13 C NMR (100 MHz, CDC13) δ 170.6, 143.8, 142.6, 132.8, 132.0, 131.3, 128.6, 127.4, 127.3, 125.2, 124.4, 124.2, 124.0, 123.1, 118.0, 86.7, 55.2, 54.5, 48.5, 28.5, 27.1, 23.4.

[0087] The NMR data for the product of Example 15 are as follows:

[0088] 1 H NMR (400 MHz, CDC13) δ 8.41 (d, J = 8.2 Hz, 1H), 7.45-7.17 (m, 11H), 7.10 (d, J = 7.3 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 4.60-3.67 (m, 3H), 3.03-2.82 (m, 2H), 2.79-2.67 (m, 1H),, 2.56 (s, 3H), 1.84 (s, 3H).

[0089] 13C NMR (100 MHz, CDC13) δ 170.6, 143.8, 142.9, 136.5, 131.3, 129.7, 128.6, 128.3, 127.5, 127.4, 127.2, 124.33, 124.29, 123.9, 118.0, 86.7, 66.0, 48.5, 45.4, 28.5, 27.2.

[0090] The NMR data for the product of Example 16 are as follows:

[0091] 1 H NMR (400 MHz, CDC13) δ 8.40 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.3 Hz, 2H), 7.31 (dd, J = 8.5, 6.6 Hz, 2H), 7.24 (ddd, J = 11.9, 6.1, 3.5 Hz, 2H), 7.13 (d, J = 7.3 Hz, 1H), 7.02 (td, J = 7.4, 1.0 Hz, 1H), 4.43 - 4.28 (m, 1H), 3.46 - 3.23 (m, 1H), 3.22 - 3.04 (m, 1H), 3.04 - 2.81 (m, 2H), 2.81 - 2.47 (m, 3H), 1.82 (s, 3H), 1.78 - 1.42 (m, 6H).

[0092] 13 C NMR (100 MHz, CDC13) δ 170.9, 143.9, 143.1, 131.4, 128.5, 127.3, 127.1, 124.3, 123.8, 117.9, 86.2, 59.2, 57.2, 48.4, 28.5, 27.1, 25.5, 25.2, 23.5.

[0093] The NMR data for the product of Example 17 are as follows:

[0094] 1H NMR (400 MHz, CDC13) δ 8.40 (d, J = 8.1 Hz, 1H), 7.41-7.35 (m, 2H), 7.31 (dd, J = 8.4, 6.6 Hz, 2H), 7.28-7.19 (m, 2H), 7.12 (d, J = 7.3 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 4.32 (q, J = 7.0, 5.0 Hz, 1H), 3.01-2.69 (m, 5H), 2.61 (s, 3H), 1.82 (s, 3H), 1.52-1.40 (m, 2H), 1.30-1.14 (m, 10H), 0.87 (t, J = 6.9 Hz, 3H).

[0095] 13 C NMR (100 MHz, CDC13) δ 171.0, 144.0, 142.6, 131.2, 128.5, 127.4, 127.2, 124.29, 124.27, 123.8, 118.0, 86.6, 48.3, 29.7, 28.5, 27.9, 21.3.

[0096] The NMR data for the product of Example 18 are as follows:

[0097] 1 H NMR (400 MHz, CDC13) δ 8.43 (d, J = 8.1 Hz, 1H), 7.38-7.28 (m, 4H), 7.28-7.19 (m, 2H), 7.14 (d, J = 7.3 Hz, 1H), 7.06-6.99 (m, 1H), 4.42-4.23 (m, 1H), 3.43-2.87 (m, 6H), 2.83-2.67 (m, 1H), 1.85 (s, 3H), 1.82-1.65 (m, 4H).

[0098] 13 C NMR (100 MHz, CDC13) δ 171.0, 144.0, 142.6, 131.2, 128.5, 127.4, 127.2, 124.29, 124.27, 123.8, 118.0, 86.6, 48.3, 29.7, 28.5, 27.9, 21.3.

[0099] The NMR data for the product of Example 19 is as follows:

[0100] 1 H NMR (400 MHz, CDCl3) δ 8.31 (d,J = 8.2 Hz, 1H), 7.40-7.24 (m, 6H),7.23 (s, 1H), 7.18 (d,J = 7.7 Hz, 3H), 7.12 (t,J = 7.8 Hz, 2H), 6.99 (d,J =7.3 Hz, 1H), 6.90 (t,J = 7.4 Hz, 1H), 7.02-6.85 (m, 2H), 4.20 (s, 1H), 4.00(s, 2H), 3.81 (s, 2H), 2.96-2.71 (m, 2H), 2.62 (ddd,J=15.2, 9.3, 4.2Hz, 1H),1.72 (s, 3H).

[0101] 13 C NMR (100 MHz, CDCl3) δ 170.4, 150.5, 143.8, 143.1, 142.2, 136.6,131.3, 129.6, 128.5, 128.3, 127.4, 127.3, 127.2, 124.4, 124.3, 123.9, 118.0,110.3, 110.2, 86.9, 61.2, 53.0, 48.5, 28.5, 27.0.

[0102] The NMR data for the product of Example 21 is as follows:

[0103] 1H NMR (400 MHz, CDC13) δ 8.28 (d, J = 8.1 Hz, 1H), 7.20 (t, J = 7.4 Hz, 2H), 7.03 (t, J = 7.4 Hz, 1H), 4.63 (q, J = 6.6 Hz, 1H), 4.29 (td, J = 9.8, 7.3 Hz, 1H), 4.07 (td, J = 9.9, 7.1 Hz, 1H), 3.89-3.77 (m, 2H), 3.58-3.45 (m, 2H), 3.33 (d, J = 10.7 Hz, 1H), 3.26-3.11 (m, 3H), 2.82-2.68 (m, 2H), 1.40 (d, J = 6.6 Hz, 3H).

[0104] 13 C NMR (100 MHz, CDC13) δ 170.7, 143.0, 131.0, 127.5, 124.5, 123.9, 117.5, 75.4, 66.2, 66.1, 56.9, 56.4, 47.6, 28.2, 16.5.

[0105] The above-described embodiments according to the present application are merely exemplary and illustrative, and thus should not be used in a limiting sense. The scope of the present application should be determined by the appended claims, rather than by the embodiments described above.

Claims

1. A method for synthesizing sterically hindered N,N,O-trisubstituted hydroxylamines and their derivatives by CO bond coupling catalysis using transition metal palladium, characterized in that, Two components, a tertiary or secondary chloroalkane and an O-acylhydroxylamine compound, are mixed and heated under reaction conditions of palladium catalyst, ligand, base, organic solvent, and argon atmosphere, and finally purified to obtain the product. The tertiary or secondary chloroalkane is selected from any of the following structural formulas: The O-acylhydroxylamine compound is selected from any one of the following structural formulas: The palladium catalyst is palladium chloride; The ligand is 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene; The alkali is sodium tert-butoxide; The organic solvent is tetrahydrofuran; The product is selected from any one of the following structural formulas:

2. The method according to claim 1, characterized in that, The molar ratio of the tertiary or secondary chloroalkanes, O-acylhydroxylamine compounds, palladium catalyst, and ligand is 1.0:1.0-2.0:0.005-0.15; the reaction temperature is 50℃-100℃; the atmosphere of the reaction vessel is argon; and the reaction time is 2h-48h.

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