Chiral sulfinylamine monophosphine, and full-configuration preparation method and application thereof

Abstract

The invention provides a chiral sulfinylamine monophosphine and a preparation method thereof. The preparation method comprises the following steps: carrying out a condensation reaction of 2-disubstituted phosphinoaryl(heteroaryl)formaldehyde (ketone) 2 and chiral sulfonamide 3 to obtain a compound 4, and reacting the compound 4 with a nucleophilic reagent to prepare a compound 1; or carrying out a condensation reaction of aldehyde (ketone) 5 and the chiral sulfonamide 3 to obtain imine 6, and reacting the imine 6 with a 2-disubstituted phosphinoaryl(heteroaryl) metal reagent to obtain the compound 1; or reacting the imine 6 with the 2-disubstituted phosphinoaryl(heteroaryl) metal reagent to obtain a compound, and reducing the compound to obtain the compound 1; or carrying out a condensation reaction of 2-substituted phosphinoaryl(heteroaryl)formaldehyde (ketone) 8 and the chiral sulfonamide 3 to obtain an imine compound 9, reacting the imine compound 9 with the nucleophilic reagent to obtain a compound 7, and reducing the compound 7 to obtain the compound 1. Different chiral sulfenamides and different metal reagents are used to conveniently obtain the optically pure compound of four configurations comprising (R,R), (R,S), (S,S) and (S,R). The above ligand has the advantages of simple skeleton, synthesis convenience and easy reconstruction, can be applied in various metal-catalyzed asymmetric reactions, and has a very high reaction activity and stereoselectivity.

Description

technical field

[0001] The invention relates to the technical field of chemical engineering, in particular to a preparation method of a chiral sulfinamide monophosphine ligand, a metal complex and an application thereof. Background technique

[0002] In asymmetric synthesis, the catalytic system of chiral ligand and metal coordination is the key to the efficient and high enantioselective synthesis of target products, and the ligand is the source of chiral induction and regulation. How to design and synthesize chiral ligands with high selectivity and high catalytic activity is one of the research hotspots of organic chemists today. Chiral phosphine-containing compounds are a very important class of chiral ligands, which are widely used in asymmetric reactions catalyzed by transition metals. At present, a variety of chiral phosphine compounds have been applied to the production and research and development of chiral chemicals. As early as the 1960s, scientists began to study...

Examples

Embodiment 1

[0078] The synthesis of embodiment 1 (Rs, R)-tert-butylsulfinyl-1-(2-diphenylphosphino) phenethylamine [1a (R, R)]

[0079]

[0080] Wherein, THF is tetrahydrofuran; N 2 is nitrogen; Ti( i PrO) 4 For tetraisopropyl titanate.

[0081] Refer to Route 1. The first step: In a 500mL three-necked flask, add 2-diphenylphosphinebenzaldehyde (50mmol) and (R)-(+)-tert-butylsulfinamide (50mmol), add 150mL under nitrogen atmosphere Add tetraisopropyl titanate (100 mmol) to THF, stir at 50° C. for 10 hours, and the yield is 85%. Infrared: 1087cm -1 .Proton NMR (400MHz, CDCl 3 ): δ1.08(s, 9H), 6.94-6.98(m, 1H), 7.23-7.48(m, 12H), 7.98-8.02(m, 1H), 9.11(d, 1H, J=4.8). Phosphine Spectrum NMR (160MHz, CDCl 3 ): δ-11.7. Mass Spectrum (FAB): m / z 394 (MH + ). Elemental analysis theoretical data C 23 h 24 NOPS: C, 70.21; H, 6.15; measured data N, 3.56.: C, 70.03; H, 6.27; N, 3.36.

[0082]

[0083] The second step: add the imine (1.91 g, 5 mmol) prepared in the first step into a ...

Embodiment 2

[0084] Synthesis of Example 2 (Rs, S)-tert-butylsulfinyl-1-(2-diphenylphosphino) phenethylamine [1a(R, S)]

[0085]

[0086] Refer to Route 1. Other operations refer to Example 1, the metal reagent used is methylmagnesium bromide, and the total yield is 60%. Proton NMR (400MHz, CDCl 3 )δ=7.58~7.51(m, lH), 7.41~7.18(m, 12H), 6.96~6.92(m, 1H), 5.49~5.46(m, 1H), 3.58(d, J=3.3Hz , 1 H), 1.38(d, J=6.6Hz, 3H), 1.13(t, 9H); carbon NMR (100MHz, CDCl 3 )δ=23.60, 24.56, 52.21, 53.56, 56.58, 126.10, 127.88, 128.05, 128.60, 129.49, 133.56, 133.99, 134.20; Phosphine NMR (162MHz, CDCl 3 )δ=-17.59ppm. High resolution mass spectrometry theoretical data C 24 h 28 NOPS: 409.5240; experimental data: 409.5233.

Embodiment 3

[0087] Synthesis of Example 3 (Ss, R)-tert-butylsulfinyl-1-(2-diphenylphosphino) phenethylamine [1a(S, R)]

[0088]

[0089] Refer to Route 1. Other operations refer to Example 1, the metal reagent used is methylmagnesium bromide, and the total yield is 60%. Proton NMR (400MHz, CDCl 3 )δ=7.58~7.51(m, 1H), 7.41~7.18(m, 12H), 6.96~6.92(m, 1H), 5.49~5.46(m, 1H), 3.58(d, J=3.3Hz, 1H) , 1.38(d, J=6.6Hz, 3H), 1.13(t, 9H); carbon NMR (100MHz, CDCl 3 )δ=23.60, 24.56, 52.21, 53.56, 56.58, 126.10, 127.88, 128.05, 128.60, 129.49, 133.56, 133.99, 134.20; Phosphine NMR (162MHz, CDCl 3 )δ=-17.59ppm. High resolution mass spectrometry theoretical data C 24 h 28 NOPS: 409.5240; experimental data: 409.5233.

technical field

[0001] The invention relates to the technical field of chemical engineering, in particular to a preparation method of a chiral sulfinamide monophosphine ligand, a metal complex and an application thereof. Background technique

[0002] In asymmetric synthesis, the catalytic system of chiral ligand and metal coordination is the key to the efficient and high enantioselective synthesis of target products, and the ligand is the source of chiral induction and regulation. How to design and synthesize chiral ligands with high selectivity and high catalytic activity is one of the research hotspots of organic chemists today. Chiral phosphine-containing compounds are a very important class of chiral ligands, which are widely used in asymmetric reactions catalyzed by transition metals. At present, a variety of chiral phosphine compounds have been applied to the production and research and development of chiral chemicals. As early as the 1960s, scientists began to study...

Examples

Embodiment 1

[0078] The synthesis of embodiment 1 (Rs, R)-tert-butylsulfinyl-1-(2-diphenylphosphino) phenethylamine [1a (R, R)]

[0079]

[0080] Wherein, THF is tetrahydrofuran; N 2 is nitrogen; Ti( i PrO) 4 For tetraisopropyl titanate.

[0081] Refer to Route 1. The first step: In a 500mL three-necked flask, add 2-diphenylphosphinebenzaldehyde (50mmol) and (R)-(+)-tert-butylsulfinamide (50mmol), add 150mL under nitrogen atmosphere Add tetraisopropyl titanate (100 mmol) to THF, stir at 50° C. for 10 hours, and the yield is 85%. Infrared: 1087cm -1 .Proton NMR (400MHz, CDCl 3 ): δ1.08(s, 9H), 6.94-6.98(m, 1H), 7.23-7.48(m, 12H), 7.98-8.02(m, 1H), 9.11(d, 1H, J=4.8). Phosphine Spectrum NMR (160MHz, CDCl 3 ): δ-11.7. Mass Spectrum (FAB): m / z 394 (MH + ). Elemental analysis theoretical data C 23 h 24 NOPS: C, 70.21; H, 6.15; measured data N, 3.56.: C, 70.03; H, 6.27; N, 3.36.

[0082]

[0083] The second step: add the imine (1.91 g, 5 mmol) prepared in the first step into a ...

Embodiment 2

[0084] Synthesis of Example 2 (Rs, S)-tert-butylsulfinyl-1-(2-diphenylphosphino) phenethylamine [1a(R, S)]

[0085]

[0086] Refer to Route 1. Other operations refer to Example 1, the metal reagent used is methylmagnesium bromide, and the total yield is 60%. Proton NMR (400MHz, CDCl 3 )δ=7.58~7.51(m, lH), 7.41~7.18(m, 12H), 6.96~6.92(m, 1H), 5.49~5.46(m, 1H), 3.58(d, J=3.3Hz , 1 H), 1.38(d, J=6.6Hz, 3H), 1.13(t, 9H); carbon NMR (100MHz, CDCl 3 )δ=23.60, 24.56, 52.21, 53.56, 56.58, 126.10, 127.88, 128.05, 128.60, 129.49, 133.56, 133.99, 134.20; Phosphine NMR (162MHz, CDCl 3 )δ=-17.59ppm. High resolution mass spectrometry theoretical data C 24 h 28 NOPS: 409.5240; experimental data: 409.5233.

Embodiment 3

[0087] Synthesis of Example 3 (Ss, R)-tert-butylsulfinyl-1-(2-diphenylphosphino) phenethylamine [1a(S, R)]

[0088]

[0089] Refer to Route 1. Other operations refer to Example 1, the metal reagent used is methylmagnesium bromide, and the total yield is 60%. Proton NMR (400MHz, CDCl 3 )δ=7.58~7.51(m, 1H), 7.41~7.18(m, 12H), 6.96~6.92(m, 1H), 5.49~5.46(m, 1H), 3.58(d, J=3.3Hz, 1H) , 1.38(d, J=6.6Hz, 3H), 1.13(t, 9H); carbon NMR (100MHz, CDCl 3 )δ=23.60, 24.56, 52.21, 53.56, 56.58, 126.10, 127.88, 128.05, 128.60, 129.49, 133.56, 133.99, 134.20; Phosphine NMR (162MHz, CDCl 3 )δ=-17.59ppm. High resolution mass spectrometry theoretical data C 24 h 28 NOPS: 409.5240; experimental data: 409.5233.

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