CN117586169A - Trisubstituted hydroxylamine derivative and synthesis method thereof - Google Patents

Trisubstituted hydroxylamine derivative and synthesis method thereof Download PDF

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CN117586169A
CN117586169A CN202210959389.7A CN202210959389A CN117586169A CN 117586169 A CN117586169 A CN 117586169A CN 202210959389 A CN202210959389 A CN 202210959389A CN 117586169 A CN117586169 A CN 117586169A
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bis
palladium
substituted
hydroxylamine
diphenylphosphine
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邵稳
陈家兴
徐永卓
邓国军
肖福红
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Xiangtan University
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Xiangtan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/08—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention mainly relates to the realization of the efficient synthesis of a trisubstituted hydroxylamine compound by catalyzing C-O bond coupling through transition metal Pd. Under the action of a catalyst, a ligand and alkali, the invention realizes one-pot reaction of tertiary chloralkane or secondary chloralkane and an O-acyl hydroxylamine compound in an argon atmosphere, realizes C-O bond coupling under the condition of keeping fragile N-O bond not to break, and obtains the technical scheme of the N, N, O-trialkyl substituted hydroxylamine derivative with large steric hindrance with high chemical selectivity. The invention has the characteristics of excellent chemical selectivity to construct C-O bond, simple experimental operation, wide material sources, high yield, wide substrate application range, excellent functional group tolerance and the like, and the synthesized product is suitable for being contained in a drug small molecule screening library for discovering lead drugs.

Description

Trisubstituted hydroxylamine derivative and synthesis method thereof
Technical Field
The invention relates to a method for synthesizing an N, N, O-trisubstituted hydroxylamine derivative through a transition metal Pd-catalyzed C-O bond coupling reaction, and belongs to the field of organic synthesis.
Background
Hydroxylamine structures are widely found in pesticide molecules, natural products, drug molecules and physiologically active molecules because of their important biological activity. Meanwhile, hydroxylamine is an important reaction intermediate and is widely applied to aspects such as medicine synthesis. Therefore, a method for synthesizing trisubstituted hydroxylamine derivatives has been widely paid attention.
The synthesis of N, O-trisubstituted hydroxylamine compounds generally requires highly functionalized starting materials, multi-step reactions, harsh reaction conditions requiring the use of special or unstable reagents, and the like.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for synthesizing a highly hindered N, O-trisubstituted hydroxylamine derivative thereof.
The invention also aims to provide a C-O bond coupling product which can realize the C-O bond coupling under the premise of keeping the fragile N-O bond not to break, provides a feasible scheme for efficiently synthesizing N, N, O-trisubstituted hydroxylamine compounds containing alpha-quaternary carbon centers under mild conditions, and has the characteristics of unique chemical selectivity for constructing the C-O bond, simple experimental operation, wide material sources, high yield, wide substrate application range, excellent functional group tolerance and the like.
Thus, the N, N, O-trisubstituted hydroxylamine compounds and derivatives thereof of the present invention have the general formula I:
wherein:
R 1 selected from substituted and unsubstituted aryl groups; indoline; a morpholine; tetrahydroquinoline; tetrahydroisoquinolines; aniline; n-alkylanilines; n-alkyl benzylamine; dibenzylamine; a secondary cycloalkane amine;
R 2 selected from hydrogen atoms; straight and branched chain alkyl groups of C1-C9;
R 3 selected from substituted and unsubstitutedAryl, C1-C9 linear alkyl;
R 4 ，R 5 selected from hydrogen atoms; an aryl group; a heterocyclic aryl group; substituted and unsubstituted benzyl; C1-C12 straight and branched alkyl; C3-C6 cycloalkyl; indole; indoline; a morpholine; a secondary cycloalkane amine;
the invention also provides a method for synthesizing the N, N, O-trisubstituted hydroxylamine and the derivatives thereof with large steric hindrance by the coupling of the C-O bond catalyzed by the palladium transition metal, which is characterized in that two components of tertiary chloralkane or secondary chloralkane and O-acyl hydroxylamine compound are mixed and heated for reaction under the reaction conditions of palladium catalyst, ligand, alkali, organic solvent and argon atmosphere, and finally the products are obtained by purification.
According to the synthesis method, the catalyst is a transition metal palladium catalyst, and the palladium reagent is selected from the group consisting of: one of palladium chloride, palladium bromide, palladium acetate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, tris (dibenzylideneacetone) dipalladium allyl palladium (II) chloride dimer. The ligand is as follows: one of 2,2 '-bipyridine, 1, 10-phenanthroline, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos), bis (2-diphenylphosphinophenyl) ether (DPEPhos), 1' -binaphthyl-2, 2 '-bis-diphenylphosphine (BINAP), triphenylphosphine, tris (p-benzyl) phosphine, tricyclohexylphosphine, tri-t-butylphosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 4-bis (diphenylphosphine) butane, 1' -bis (diphenylphosphine) ferrocene (DPPF). The alkali is as follows: one or more of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide. The organic solvent is selected from one or more of tetrahydrofuran, diethyl ether, 1, 4-dioxane, toluene, paraxylene, o-xylene, chlorobenzene, acetonitrile, ethyl acetate, dichloromethane, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide. The molar ratio of the tertiary chlorinated alkane or secondary chlorinated alkane, the O-acyl hydroxylamine compound, the catalyst (metal+ligand) and the alkali 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 vessel was: argon atmosphere; the reaction time is 2-48 h.
The general formula of the tertiary chlorinated alkane or secondary chlorinated alkane compound is shown as formula II:
wherein:
R 1 selected from substituted and unsubstituted aryl groups; indoline; a morpholine; tetrahydroquinoline; tetrahydroisoquinolines; aniline; n-alkylanilines; n-alkyl benzylamine; dibenzylamine; a secondary cycloalkane amine;
R 2 selected from hydrogen atoms; straight and branched chain alkyl groups of C1-C9;
R 3 selected from substituted and unsubstituted aryl, C1-C9 linear alkyl.
The general formula of the OH-hydroxylamine or O-acyl hydroxylamine compound in the synthesis method is III:
wherein:
R 4 ，R 5 selected from hydrogen atoms; an aryl group; a heterocyclic aryl group; substituted and unsubstituted benzyl; C1-C12 straight and branched alkyl; C3-C6 cycloalkyl; indole; indoline; a morpholine; a secondary cycloalkane amine;
R 6 selected from hydrogen atoms; substituted and unsubstituted benzoyl; an acetyl group; trifluoroacetyl; pivaloyl group.
The technical scheme of the invention has the following advantages:
(I) Under the action of a catalyst, a ligand and alkali, the invention realizes one-pot reaction of tertiary chloralkane or secondary chloralkane compounds and O-acyl hydroxylamine compounds in an argon atmosphere, and realizes the technical scheme of C-O coupling on the premise of keeping the O-N bond not broken, and the invention has the advantages of mild reaction condition, wide material sources, low price, easy acquisition, simple experimental operation, obviously shortened reaction steps, easy expansion of application and few required instruments and equipment; compared with other hydroxylamine compounds, the synthesis method of the O-acyl hydroxylamine compound serving as a raw material is simpler, the reaction condition is mild, the material sources are wide, and the O-acyl hydroxylamine compound is easy to obtain; the hydroxylamine compound (III) widely exists in drug molecules, can be used in a plurality of industrial production fields of medicines, pesticides, organic functional materials and the like because of important biological activity, can directly construct a target product of the N, N, O-trisubstituted hydroxylamine compound with large steric hindrance in one step with high selectivity, saves a great deal of research time, shortens the production period, has obvious added value increase of the product and high availability, and has foreseeable market commercialization prospect.
Drawings
FIG. 1 shows the reaction chemical formula of the model reaction of the present invention.
FIGS. 1a-7a are partial nuclear magnetic hydrogen spectra of the products of examples 1-21; FIGS. 1b-7b are partial nuclear magnetic carbon spectra of the products of examples 1-21.
Detailed Description
The invention will now be described in further detail with reference to the following figures. These figures are simplified schematic views illustrating the basic structure of the present invention only by way of illustration, and therefore they show only the constitution related to the present invention:
examples 1 to 21
The method comprises the following steps:
adding tertiary chloralkane or secondary chloralkane compound, benzoyl hydroxylamine compound, catalyst, ligand, alkali and organic solvent into a reaction vessel;
the reactants are fully mixed in an inert gas atmosphere, heated and stirred for reaction;
and purifying after the reaction to obtain a product.
The invention is described in further detail below with reference to the drawings and examples.
The tertiary or secondary chlorinated alkane compound, the O-acyl hydroxylamine compound, the reaction conditions, the reaction products and the yields are shown in table 1:
table 1: the reactants and reaction conditions in examples 1-21
The nuclear magnetic data of the products of some examples are:
the nuclear magnetic data of the product of example 1 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.40(d,J＝8.1Hz,1H),7.40–7.32(m,4H),7.30–7.21(m,2H),7.15(dd,J＝7.4,1.4Hz,1H),7.05(td,J＝7.4,1.1Hz,1H),4.34(ddd,J＝10.7,9.4,5.0Hz,1H),3.90(d,J＝11.8Hz,1H),3.82–3.68(m,2H),3.67–3.54(m,1H),3.25(d,J＝10.6Hz,1H),3.09–2.87(m,5H),2.77(td,J＝9.6,4.4Hz,1H),1.85(s,3H).
13 C NMR(100MHz,CDCl 3 )δ170.5,143.7,142.4,131.2,128.6,127.35,127.32,124.4,124.1,124.0,117.9,86.5,66.2,66.1,58.7,56.8,48.4,28.4,27.2.
the nuclear magnetic data of the product of example 2 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.38(d,J＝8.1Hz,1H),7.31(d,J＝6.3Hz,4H),7.28–7.19(m,3H),7.12(d,J＝7.3Hz,1H),7.02(td,J＝7.4,1.1Hz,1H),4.39–4.25(m,1H),3.88(d,J＝11.8Hz,1H),3.77–3.64(m,2H),3.55(td,J＝11.4,2.3Hz,1H),3.23(d,J＝10.6Hz,1H),3.01(d,J＝10.0Hz,1H),2.97–2.80(m,4H),2.78–2.69(m,1H),2.55(dq,J＝14.4,7.2Hz,1H),2.25(dq,J＝14.9,7.5Hz,1H),0.61(t,J＝7.4Hz,3H).
13 C NMR(100MHz,CDCl 3 )δ170.6,143.9,139.7,131.3,128.3,127.5,127.3,125.2,124.4,124.0,118.0,88.9,77.4,77.1,76.7,66.4,66.3,58.5,57.0,48.4,28.8,28.5,8.2.
the nuclear magnetic data of the product of example 3 are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.75–7.65(m,2H),7.38–7.28(m,5H),7.27–7.16(m,3H),3.80(dd,J＝12.0,3.6Hz,1H),3.60–3.43(m,2H),3.26–3.11(m,2H),2.86(td,J＝10.8,3.3Hz,1H),2.43(td,J＝11.0,3.4Hz,1H),2.39–2.23(m,2H),2.05(dq,J＝10.9,2.2Hz,1H),0.64(t,J＝7.4Hz,3H).
13 C NMR(100MHz,CDCl 3 )δ199.4,140.3,136.4,131.9,130.3,128.4,127.7,127.3,125.2,91.1,66.1,66.0,59.2,57.5,28.6,7.4.
the nuclear magnetic data of the product of example 4 are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.84–7.74(m,2H),7.41–7.35(m,3H),7.35–7.29(m,2H),7.28–7.20(m,3H),3.83(d,J＝11.8Hz,1H),3.64–3.50(m,2H),3.36–3.26(m,1H),3.22(d,J＝10.8Hz,1H),2.89(td,J＝10.9,3.3Hz,1H),2.47(td,J＝10.9,3.3Hz,1H),2.17(d,J＝10.8Hz,1H),1.81(s,3H).
13 C NMR(100MHz,CDCl 3 )δ99.7,143.0,135.6,132.2,130.6,128.6,127.8,127.4,124.5,88.8,66.1,66.0,59.3,57.4,26.8.
the nuclear magnetic data of the product of example 5 are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.32(d,J＝1.5Hz,1H),7.31–7.29(m,3H),7.28(s,1H),7.26(s,2H),7.17(t,J＝7.8Hz,2H),7.11–7.00(m,4H),6.57–6.42(m,2H),5.43(dd,J＝14.0,1.7Hz,1H),5.25(d,J＝16.3Hz,1H),3.89–3.75(m,2H),3.62(td,J＝11.5,2.1Hz,1H),3.47–3.33(m,2H),3.26(td,J＝11.4,2.2Hz,1H),3.13(d,J＝10.5Hz,1H),2.79(td,J＝11.0,3.4Hz,1H),2.70–2.52(m,2H),2.45(d,J＝10.0Hz,1H),2.31(dq,J＝15.1,7.6Hz,1H),0.50(t,J＝7.4Hz,3H).
13 C NMR(100MHz,CDCl 3 )δ172.4,140.2,137.0,135.9,129.7,128.3,128.2,128.0,127.5,127.1,126.9,126.8,125.0,88.4,66.2,58.5,57.1,50.1,47.8,29.3,8.0.
the nuclear magnetic data of the product of example 6 are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.22(d,J＝8.0Hz,2H),7.10(d,J＝8.0Hz,2H),4.13(d,J＝13.3Hz,1H),3.86(s,2H),3.68(t,J＝10.3Hz,3H),3.51(t,J＝10.2Hz,1H),3.42(d,J＝13.6Hz,1H),3.20(d,J＝12.5Hz,4H),3.04(d,J＝10.0Hz,1H),2.93–2.80(m,2H),2.73(t,J＝10.4Hz,1H),2.45(d,J＝7.2Hz,2H),1.83(dt,J＝13.5,6.8Hz,1H),1.75(s,3H),0.87(dd,J＝6.6,1.9Hz,6H).
13 C NMR(100MHz,CDCl 3 )δ171.2,140.9,140.6,129.2,123.7,85.6,66.7,66.1,65.4,58.7,57.2,47.5,44.9,43.1,30.2,27.6,22.3,22.2.
the nuclear magnetic data of the product of example 7 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.37(d,J＝8.1Hz,1H),7.30–7.18(m,3H),7.12(d,J＝7.3Hz,1H),7.08(d,J＝7.9Hz,2H),7.02(t,J＝7.4Hz,1H),4.31(ddd,J＝11.0,9.5,5.0Hz,1H),3.87(d,J＝11.8Hz,1H),3.80–3.63(m,2H),3.57(t,J＝11.3Hz,1H),3.22(d,J＝10.7Hz,1H),3.08–2.79(m,5H),2.75(dd,J＝9.7,5.1Hz,1H),2.43(d,J＝7.2Hz,2H),1.82(s,3H),0.86(dd,J＝6.6,2.9Hz,6H).
13 C NMR(100MHz,CDCl 3 )δ170.8,143.9,140.9,139.9,131.3,129.3,127.4,124.4,124.1,123.9,118.0,86.7,66.2,48.6,45.0,30.1,28.5,27.2,22.32,22.27.
the nuclear magnetic data of the product of example 8 are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.38–7.30(m,2H),7.30–7.21(m,3H),4.12(dt,J＝13.7,3.8Hz,1H),3.87(t,J＝11.3Hz,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＝14.4,7.2Hz,1H),2.21(dq,J＝15.0,7.5Hz,1H),0.56(t,J＝7.4Hz,3H).
13 C NMR(100MHz,CDCl 3 )δ171.0,140.5,128.2,127.2,124.8,87.9,66.6,66.2,65.2,58.4,57.2,47.5,43.2,29.1,8.1.
the nuclear magnetic data of the product of example 9 are as follows:
1 H NMR(400MHz,CDCl 3 )δ7.68(d,J＝8.2Hz,1H),7.33(d,J＝5.5Hz,4H),7.26(td,J＝6.8,6.0,3.1Hz,1H),7.20–7.13(m,1H),7.10–7.01(m,2H),4.19(dt,J＝13.5,4.0Hz,1H),3.92(d,J＝11.8Hz,1H),3.85–3.69(m,2H),3.64(td,J＝11.4,2.2Hz,1H),3.31–3.17(m,2H),3.01–2.84(m,3H),2.65–2.48(m,3H),2.29(dq,J＝15.0,7.6Hz,1H),1.35–1.23(m,1H),0.99–0.83(m,1H),0.58(t,J＝7.4Hz,3H).
13 C NMR(100MHz,CDCl 3 )δ171.3,140.2,139.7,130.4,129.3,128.2,127.1,125.4,124.9,124.7,124.6,88.8,66.4,66.3,58.7,57.3,45.5,29.7,25.6,21.7,8.0.
the nuclear magnetic data of the product of example 10 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝8.1Hz,1H),7.35–7.29(m,2H),7.24(dd,J＝8.4,6.6Hz,2H),7.19–7.11(m,2H),7.07–7.01(m,1H),6.94(td,J＝7.4,1.1Hz,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).
13 C NMR(100MHz,CDCl 3 )δ171.1,143.9,143.5,131.3,128.5,127.3,127.1,124.30,124.28,123.8,117.9,85.9,49.7,48.4,28.5,27.3,10.3.
the nuclear magnetic data of the product of example 11 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.30(d,J＝8.1Hz,1H),7.39–7.12(m,16H),7.04(d,J＝7.3Hz,1H),6.96(t,J＝7.3Hz,1H),4.34–4.19(m,1H),4.11(d,J＝13.2Hz,2H),3.90(d,J＝13.2Hz,2H),2.97(td,J＝10.4,7.8Hz,1H),2.88–2.74(m,1H),2.74–2.60(m,1H),1.67(s,3H).
13 C NMR(100MHz,CDCl 3 )δ170.5,143.7,143.2,136.9,131.2,129.6,129.3,128.5,128.1,127.3,127.2,124.3,124.2,123.8,118.0,86.6,62.0,48.3,28.4,27.4.
the nuclear magnetic data of the product of example 12 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.39(d,J＝8.1Hz,1H),7.38(d,J＝7.3Hz,2H),7.32(t,J＝7.6Hz,2H),7.23(td,J＝8.6,7.9,5.2Hz,2H),7.12(d,J＝7.3Hz,1H),7.01(t,J＝7.4Hz,1H),4.42–4.25(m,1H),3.00–2.79(m,3H),2.73(t,J＝5.4Hz,1H),2.55(s,3H),2.03(d,J＝10.7Hz,2H),1.90–1.76(m,5H),1.64(s,1H),1.34(s,1H),1.28–1.08(m,4H).
13 C NMR(100MHz,CDCl 3 )δ171.1,143.8,143.4,131.3,128.5,127.3,127.2,127.1,124.3,123.8,117.9,85.9,67.3,48.3,39.6,28.5,27.2,26.3,26.0,25.8.
the nuclear magnetic data of the product of example 13 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.40(d,J＝8.1Hz,1H),7.40–7.35(m,2H),7.31(dd,J＝8.5,6.6Hz,2H),7.27–7.19(m,2H),7.12(d,J＝7.3Hz,1H),7.01(t,J＝7.4Hz,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).
13 C NMR(100MHz,CDCl 3 )δ170.8,143.9,143.1,131.3,128.5,127.3,127.1,124.3,123.8,117.9,86.4,59.1,48.4,28.5,27.4,26.4,24.7.
the nuclear magnetic data of the product of example 14 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.34(d,J＝8.1Hz,1H),7.32–7.20(m,4H),7.19–7.13(m,2H),7.08(d,J＝7.3Hz,1H),6.98(q,J＝7.3Hz,2H),6.57(d,J＝50.5Hz,1H),4.32–3.87(m,3H),3.39–2.78(m,6H),2.67(s,1H),1.82(s,3H).
13 C NMR(100MHz,CDCl 3 )δ170.6,143.8,142.6,132.8,132.0,131.3,128.6,127.4,127.3,125.2,124.4,124.2,124.0,123.1,118.0,86.7,55.2,54.5,48.5,28.5,27.1,23.4.
the nuclear magnetic data of the product of example 15 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.41(d,J＝8.2Hz,1H),7.45–7.17(m,11H),7.10(d,J＝7.3Hz,1H),7.00(t,J＝7.5Hz,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).
13 C NMR(100MHz,CDCl 3 )δ170.6,143.8,142.9,136.5,131.3,129.7,128.6,128.3,127.5,127.4,127.2,124.33,124.29,123.9,118.0,86.7,66.0,48.5,45.4,28.5,27.2.
the nuclear magnetic data of the product of example 16 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.40(d,J＝8.1Hz,1H),7.38(d,J＝7.3Hz,2H),7.31(dd,J＝8.5,6.6Hz,2H),7.24(ddd,J＝11.9,6.1,3.5Hz,2H),7.13(d,J＝7.3Hz,1H),7.02(td,J＝7.4,1.0Hz,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).
13 C NMR(100MHz,CDCl 3 )δ170.9,143.9,143.1,131.4,128.5,127.3,127.1,124.3,123.8,117.9,86.2,59.2,57.2,48.4,28.5,27.1,25.5,25.2,23.5.
the nuclear magnetic data of the product of example 17 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.40(d,J＝8.1Hz,1H),7.41–7.35(m,2H),7.31(dd,J＝8.4,6.6Hz,2H),7.28–7.19(m,2H),7.12(d,J＝7.3Hz,1H),7.02(t,J＝7.4Hz,1H),4.32(q,J＝7.0,5.0Hz,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＝6.9Hz,3H).
13 C NMR(100MHz,CDCl 3 )δ170.8,143.9,143.1,131.3,128.5,127.3,127.2,124.29,124.26,123.8,118.0,86.2,62.1,48.4,45.6,31.8,29.4,29.1,28.5,27.4,27.3,26.4,22.6,14.1.
the nuclear magnetic data of the product of example 18 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.43(d,J＝8.1Hz,1H),7.38–7.28(m,4H),7.28–7.19(m,2H),7.14(d,J＝7.3Hz,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).
13 C NMR(100MHz,CDCl 3 )δ171.0,144.0,142.6,131.2,128.5,127.4,127.2,124.29,124.27,123.8,118.0,86.6,48.3,29.7,28.5,27.9,21.3.
the nuclear magnetic data of the product of example 19 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.31(d,J＝8.2Hz,1H),7.40–7.24(m,6H),7.23(s,1H),7.18(d,J＝7.7Hz,3H),7.12(t,J＝7.8Hz,2H),6.99(d,J＝7.3Hz,1H),6.90(t,J＝7.4Hz,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).
13 C NMR(100MHz,CDCl 3 )δ170.4,150.5,143.8,143.1,142.2,136.6,131.3,129.6,128.5,128.3,127.4,127.3,127.2,124.4,124.3,123.9,118.0,110.3,110.2,86.9,61.2,53.0,48.5,28.5,27.0.
the nuclear magnetic data of the product of example 21 are as follows:
1 H NMR(400MHz,CDCl 3 )δ8.28(d,J＝8.1Hz,1H),7.20(t,J＝7.4Hz,2H),7.03(t,J＝7.4Hz,1H),4.63(q,J＝6.6Hz,1H),4.29(td,J＝9.8,7.3Hz,1H),4.07(td,J＝9.9,7.1Hz,1H),3.89–3.77(m,2H),3.58–3.45(m,2H),3.33(d,J＝10.7Hz,1H),3.26–3.11(m,3H),2.82–2.68(m,2H),1.40(d,J＝6.6Hz,3H).
13 C NMR(100MHz,CDCl 3 )δδ170.7,143.0,131.0,127.5,124.5,123.9,117.5,75.4,66.2,66.1,56.9,56.4,47.6,28.2,16.5。
with the above-described preferred embodiments according to the present invention as an illustration, the above-described descriptions can be used by persons skilled in the relevant art to make various changes and modifications without departing from the scope of the technical idea of the present invention. The technical scope of the present invention is not limited to the description, but must be determined according to the scope of claims.

Claims (9)

1. An N, O-trisubstituted hydroxylamine and its derivatives of the formula i:
wherein:
R 1 selected from substituted and unsubstituted aryl groups; indoline; a morpholine; tetrahydroquinoline; tetrahydroisoquinolines; aniline; n-alkylanilines; n-alkyl benzylamine; dibenzylamine; a secondary cycloalkane amine;
R 2 selected from hydrogen atoms; straight and branched chain alkyl groups of C1-C9;
R 3 a linear alkyl group selected from substituted and unsubstituted aryl groups, C1-C9;
R 4 ，R 5 selected from hydrogen atoms; an aryl group; a heterocyclic aryl group; substituted and unsubstitutedBenzyl of (a); C1-C12 straight and branched alkyl; C3-C6 cycloalkyl; indole; indoline; a morpholine; a secondary cycloalkane amine.
2. A method for synthesizing the large steric hindrance N, N, O-trisubstituted hydroxylamine and derivatives thereof by coupling C-O bond through the catalysis of transition metal palladium according to claim 1 is characterized in that two components of tertiary chloralkane or secondary chloralkane and O-acyl hydroxylamine are mixed and heated for reaction under the reaction conditions of palladium catalyst, ligand, alkali, organic solvent and argon atmosphere, and finally purified to obtain the product.
3. The method of claim 2, wherein the palladium catalyst is: one of palladium chloride, palladium bromide, palladium acetate, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium dichloride, tris (dibenzylideneacetone) dipalladium allyl palladium (II) chloride dimer.
4. The method of claim 2, wherein the ligand is: one of 2,2 '-bipyridine, 1, 10-phenanthroline, 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (Xantphos), bis (2-diphenylphosphinophenyl) ether (DPEPhos), 1' -binaphthyl-2, 2 '-bis-diphenylphosphine (BINAP), triphenylphosphine, tris (p-benzyl) phosphine, tricyclohexylphosphine, tri-t-butylphosphine, 1, 2-bis (diphenylphosphine) ethane, 1, 3-bis (diphenylphosphine) propane, 1, 4-bis (diphenylphosphine) butane, 1' -bis (diphenylphosphine) ferrocene (DPPF).
5. The method according to claim 2, wherein the base is: one or more of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide and potassium ethoxide.
6. The method according to claim 2, wherein the organic solvent is selected from one or more of tetrahydrofuran, diethyl ether, 1, 4-dioxane, toluene, p-xylene, o-xylene, chlorobenzene, acetonitrile, ethyl acetate, dichloromethane, N-dimethylformamide, N-dimethylacetamide, and dimethylsulfoxide.
7. The method according to claim 2, wherein the molar ratio of tertiary or secondary chloroalkanes, O-acyl hydroxylamines, catalysts (transition metals and ligands), 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 vessel was: argon atmosphere; the reaction time is 2-48 h.
8. The method according to claim 2, wherein the tertiary chlorinated alkane or secondary chlorinated alkane compound has the general formula ii:
wherein:
R 1 selected from substituted and unsubstituted aryl groups; indoline; a morpholine; tetrahydroquinoline; tetrahydroisoquinolines; aniline; n-alkylanilines; n-alkyl benzylamine; dibenzylamine; a secondary cycloalkane amine;
R 2 selected from hydrogen atoms; straight and branched chain alkyl groups of C1-C9;
R 3 selected from substituted and unsubstituted aryl, C1-C9 linear alkyl.
9. The method according to claim 2, wherein the OH-hydroxylamine or O-acyl hydroxylamine compound has the general formula III:
wherein:
R 4 ，R 5 selected from hydrogen atoms; an aryl group; a heterocyclic aryl group; substituted and unsubstituted benzyl; C1-C12 straight and branched alkyl; C3-C6 cycloalkyl; indole; indoline; a morpholine;a secondary cycloalkane amine;
R 6 selected from hydrogen atoms; substituted and unsubstituted benzoyl; an acetyl group; trifluoroacetyl; pivaloyl group.
CN202210959389.7A 2022-08-10 2022-08-10 Trisubstituted hydroxylamine derivative and synthesis method thereof Pending CN117586169A (en)

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