CN104689849A - Phosphamide-(di) secondary amine dual-functional catalyst and synthesis method thereof - Google Patents

Abstract

The invention discloses a phosphamide-(di) secondary amine dual-functional catalyst and a synthesis method thereof. The structure of the catalyst is represented as follows, and the synthesis method comprises the steps of performing reaction on simple and readily available chiral 1,2-diamine and various phosphoryl chloride, and performing reaction with an aldehyde compound to prepare the phosphamide-(di) secondary amine dual-functional catalyst with chirality and efficient catalysis activity. The prepared catalyst is novel in structure and stable in property; the synthesis method is simple, and the catalysis activity is high; the synthesis method is simple and has the outstanding characteristics of wide application range, mild reaction condition, simplicity and convenience in operation and the like. The structural formula of the catalyst is shown in the description.

Description

One class phosphamide-(primary) secondary amine bifunctional catalyst and synthetic method thereof

Technical field

The invention belongs to organic compound technical field, relate to the novel phosphamide of a class-(primary) secondary amine bifunctional catalyst and synthetic method thereof.

Background technology

Bifunctional catalyst refers to the compound containing Liang Ge functional group in same catalyst molecule.Owing to there is Liang Ge functional group in molecule simultaneously, therefore it just likely in the reaction a functional group to deactivate electrophilic reagent, another nucleopilic reagent that deactivates, both furthered the space length of two reaction substrates, response class is similar to occur in molecule, simultaneously because dual activation makes reaction substrate better be activated, thus improve the activity of reaction and selective.

Hydrogen-bond donor bifunctional catalyst refers to that in catalyst molecule, a functional group is hydrogen-bond donor functional group, as (sulphur) urea, and sulfonamide, acid amides, phosphamide, four directions acid etc.Usually, compared with the hydrogen-bond donor of other types, phosphamide has several obvious feature as hydrogen-bond donor catalyst: 1) phosphamide has two substituting groups of three-dimensional space structure, from two different directions by steric effect, can regulate asymmetric induction effect; 2) by change two substituting groups (as aryl, alkyl, alkoxyl etc.), can be easy to regulate the steric hindrance of catalyst and the pK of acid amides N-H key _avalue, thus the activation of the chiral induction be conducive to reaction and electrophilic reagent; 3) although the synthesis of phosphamide type catalyst is convenient, stable in properties, as hydrogen-bond donor research seldom.[a) East China Normal University's fourth seedling master thesis " 3 asymmetric Michael addition reaction replacing Oxoindole and nitroolefin of unprotect base are studied " in 2012; B) S.E.Denmark, Angew.Chem.Int.Ed.2008,1560.]

Although phosphamide catalyst has above-described advantage, in literature survey, find that the application of phosphamide chiral catalyst in asymmetric catalysis is little.Especially, less as the application report of chirality bifunctional catalyst in organocatalysis in conjunction with phosphamide.Tertiary amine-phosphamide bifunctional catalyst (M.Ding that a class quinine in 2011 is derivative, F.Zhou, Y.-L.Liu, C.-H.Wang, X.-L.Zhao, J.Zhou, Chem.Sci.2011,, and be applied to Oxoindole that 3-replaces and the asymmetric Michael addition reaction of nitroolefin is studied 2,2035.); Although tertiary amine-phosphamide that quinine derives is in the news, but phosphamide-(primary) secondary amine bifunctional catalyst is not almost reported, only have Shi Min group and Song group to report time phosphamide-secondary amine respectively and study [a) M.Shi as metal ligand for the addition reaction of diethyl zinc reagent to imines and aldehyde, W.Zhang, Tetrahedron Asymmetric 2003,14,3407.b) H.Huang, H.Zong, G.Bian, L.Song, J.Org.Chem.2012,77,10427-10434.]; In addition, straight flood and Wang Youming group have developed the phosphamide-secondary amine salt catalyst of sulfo-for the asymmetric Michael addition reaction research (A.Lu of ketone compounds to aromatic nitro alkene, R.Wu, Y.Wang, Z.-H.Zhou, G.Wu, J.Fang, C.Tang, Eur.J.Org.Chem.2010,2057.).And based on chirality 1, phosphamide-(primary) secondary amine bifunctional catalyst that 2-diamines derives still is not reported.

Summary of the invention

The object of this invention is to provide the novel phosphamide of a class-(primary) secondary amine bifunctional catalyst and synthetic method thereof, its catalyst has structure novel, stable in properties, feature that catalytic activity is high; The distinguishing features such as its synthetic method is simple, has applied widely, and reaction condition is gentle, easy and simple to handle.

The concrete technical scheme realizing the object of the invention is:

One class phosphamide-(primary) secondary amine bifunctional catalyst, feature is that the structural formula of such catalyst is as follows:

Wherein:

R is aryl or the alkyl of C1-C30, becomes ring or not Cheng Huan between R;

R ¹, R ²for aryl or the alkyl of C1-C30, chirality or achiral; R ¹and R ²between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings;

R ³for the alkyl of H, C1-C50, the aryl of C1-C50 or the alkyl that is connected with support materials;

R ⁴, R ⁵, R ⁶and R ⁷for aryl or the alkyl of C1-C50, chirality or achiral; R ⁴and R ⁵between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings; R ⁶and R ⁷between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings;

R ⁸, R ⁹and R ¹⁰for aryl or the alkyl of C1-C50, it is chirality or achiral; R ⁸and R ⁹between, R ⁹and R ¹⁰between or R ⁸and R ¹⁰between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings; R ⁸, R ⁹and R ¹⁰arbitrarily between the two or between three, become ring or not Cheng Huan, cycloaliphatic ring is become, containing heteroatomic cycloaliphatic ring or become aromatic rings.

A synthetic method for above-mentioned catalyst, this synthetic method is by shown in following reaction equation (I) (II) (III) (IV) (V):

Specifically comprise the following steps:

1) in reaction vessel, add chirality 1, the 2-diamines of X mole, then add the alkali of Y milliliter solvent, Z mole successively, be cooled to-10 DEG C, drip the phosphoryl chloride phosphorus oxychloride of X mole, under room temperature range, be stirred to TLC at-10 degree and show reaction and complete; After column chromatography for separation obtains phosphamide primary amine catalyst, then with the aldehyde of A mole reflux in L milliliter ethanol about 1 little up to primary amine reaction completely after, add the sodium borohydride of B mole under being transferred to-10 degree, stir half an hour TLC display and react completely;

Wherein, X=0.1-100; The consumption Y of solvent is the corresponding scope of application of every mM of (mmol) chirality 1,2-diamines is 20mL; Z=0.2-200; A=0.12-120; B=0.2-200; The volume L of ethanol is the corresponding scope of application of every mM of (mmol) chirality 1,2-diamines is 10mL; Proportionate relationship between its different compound is X:Z:A:B=1:2:1.2:2;

2) target product is obtained by column chromatography for separation; Wherein:

Described different phosphate acyl chlorides is represented by following chemical formula (A) (B) (C) (D) (E) respectively:

Wherein:

R ¹, R ²for aryl or the alkyl of C1-C30, chirality or achiral; R ¹and R ²between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings;

R ³for the alkyl of H, C1-C50, the aryl of C1-C50 or the alkyl that is connected with support materials;

R ⁴, R ⁵, R ⁶and R ⁷for aryl or the alkyl of C1-C50, chirality or achiral; R ⁴and R ⁵between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings; R ⁶and R ⁷between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings;

R ⁸, R ⁹and R ¹⁰for aryl or the alkyl of C1-C50, it is chirality or achiral; R ⁸and R ⁹between, R ⁹and R ¹⁰between or R ⁸and R ¹⁰between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings; R ⁸, R ⁹and R ¹⁰arbitrarily between the two or between three, become ring or not Cheng Huan, cycloaliphatic ring is become, containing heteroatomic cycloaliphatic ring or become aromatic rings.

Described chirality 1,2-diamines has following formula structure:

Wherein, the chiral configuration of diamines is (R, R), (R, S), (S, or (S R), S), by business purchase acquisition or according to document (E.J.Corey, D.-H.Lee, S.Sarshar, Tetrahedron:Asymmetry 1995,6,3-6) simply synthesize; R is aryl or the alkyl of C1-C30, becomes ring or not Cheng Huan between R;

Described solvent is toluene, carrene, ether, ethyl acetate, oxolane, acetone, acetonitrile, DMF, nitromethane or methyl alcohol;

Described alkali is DMAP, triethylamine, diisopropyl ethyl amine, DBU, DABCO, pyridine, nafoxidine, diethylamine, N-methylbenzylamine, potash, cesium carbonate, sodium carbonate, potassium hydroxide or NaOH;

Described aldehyde is aromatic aldehyde or fatty aldehyde.

Catalyst of the present invention has structure novel, stable in properties, feature that catalytic activity is high; Its synthetic method has the distinguishing feature of following several respects:

(1) raw material business is easy to get;

(2) reaction condition is gentle, and simple to operation, synthesis step is short;

(3) the final catalyst synthesized can obtain outstanding productive rate and enantioselectivity in Mukaiyama-Michael addition reaction.

Detailed description of the invention

Illustrate in greater detail the present invention with the following Examples, following examples show different aspect of the present invention, but need by it is emphasised that the present invention is never only limitted to content represented by these embodiments.Meanwhile, also show the application example of such catalyst in the asymmetric Mukaiyama-Michael addition reaction of fluoro silyl enol ether and four substituted olefines in embodiment, wherein enantioselectivity is measured by chirality HPLC.

Embodiment 1

Under nitrogen protection, in 50mL round-bottomed flask, add cinchonidine derivative primary amine Ia (1.0equiv) and anhydrous CH ₂cl ₂, after dissolving completely, add triethylamine (2.0equiv).At 0 DEG C, drip diethoxy phosphoryl chloride phosphorus oxychloride IIa (1.2equiv), stir laggard row post processing of spending the night: add 30mL water, with dichloromethane extraction, column chromatography after anhydrous sodium sulfate drying, takes white solid product IIIa, productive rate 80%. ¹H NMR(400MHz,CDCl ₃):δ4.10-4.04(m,4H),2.63-2.56(m,2H),2.29-2.28(m,1H),2.05-2.02(m,1H),1.94-1.91(m,1H),1.67(s,br,2H),1.59(s,2H),1.31(t,J＝6.8Hz,6H),1.25-1.05(m,4H)； ¹³C NMR(100MHz,CDCl ₃):δ62.46,62.42,58.89,56.66(d,J _C-P＝6.5Hz,1C),34.85,34.67,25.37,24.92,16.26,16.19； ³¹P NMR(161.7MHz,CDCl ₃):δ9.03(s,1P).MS(EI):250(M ⁺,0.4),154(25),126(13),97(100),96(22),44(39)；HRMS(EI):Exact mass calcd for C ₁₀H ₂₃N ₂O ₃P[M] ⁺:250.1446,Found:250.1445。

Embodiment 2

Under nitrogen protection, in 50mL round-bottomed flask, add cinchonidine derivative primary amine Ia (1.0equiv) and anhydrous CH ₂cl ₂, after dissolving completely, add triethylamine (2.0equiv).At 0 DEG C, drip diethoxy phosphoryl chloride phosphorus oxychloride IIa (1.0equiv), stir laggard row post processing of spending the night: add 30mL water, with dichloromethane extraction, column chromatography after anhydrous sodium sulfate drying, takes white solid product IIIa, productive rate 80%.Subsequently under nitrogen protection; anhydrous EtOH is added add IIIa in Schlenk bottle after; at room temperature add 1-naphthaldehyde (1.2equiv); reaction system under reflux conditions stirs (TLC detection reaction is complete) after 1 hour; reaction system is transferred in ice-water bath and cools; slowly add sodium borohydride (2.0equivs) subsequently, in ice-water bath, stir about reacted completely after 2 hours, added NaHCO ₃saturated solution and extraction into ethyl acetate 3 times.Column chromatography after anhydrous sodium sulfate drying organic layer removed under reduced pressure solvent, takes white solid product C1, productive rate 95%. ¹H NMR(400MHz,CDCl ₃):δ8.12(d,J＝8.4Hz,1H),7.84(d,J＝8.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.54-7.38(m,4H),4.38,4.06(AB,J＝12.4Hz,2H),3.98-3.82(m,4H),2.85-2.83(m,2H),2.35-2.27(m,2H),2.14-2.11(m,2H),1.77-1.69(m,2H),1.33-1.18(m,7H),1.04(t,J＝7.2Hz,3H)； ¹³C NMR(100MHz,CDCl ₃):δ136.04,133.79,131.71,128.60,127.69,126.13,126.07,125.57,125.33,123.73,62.65(d,J _C-P＝7.4Hz,1C),62.31(d,J _C-P＝5.9Hz,1C),62.24(d,J _C-P＝6.9Hz,1C),55.51,48.70,34.42,31.23,25.01,24.53,16.11(d,J _C-P＝7.1Hz,1C),15.90(d,J _C-P＝7.2Hz,1C)； ³¹P NMR(161.7MHz,CDCl ₃):δ8.84(s,1P).HRMS(ESI):Exact mass calcd for C ₂₁H ₃₂N ₂O ₃P[M+H] ⁺:391.2145,Found:391.2146。

Embodiment 3

Under nitrogen protection, in 50mL round-bottomed flask, add cinchonidine derivative primary amine Ia (1.0equiv) and anhydrous CH ₂cl ₂, after dissolving completely, add triethylamine (2.0equiv).At 0 DEG C, drip diisopropoxy phosphoryl chloride phosphorus oxychloride IIb (1.0equiv), stir laggard row post processing of spending the night: add 30mL water, with dichloromethane extraction, column chromatography after anhydrous sodium sulfate drying, takes white solid product IIIb, productive rate 57%.Subsequently under nitrogen protection; anhydrous EtOH is added add IIIb in Schlenk bottle after; at room temperature add 1-naphthaldehyde (1.2equiv); reaction system under reflux conditions stirs (TLC detection reaction is complete) after 1 hour; reaction system is transferred in ice-water bath and cools; slowly add sodium borohydride (2.0equivs) subsequently, in ice-water bath, stir about reacted completely after 2 hours, added NaHCO ₃saturated solution and extraction into ethyl acetate 3 times.Column chromatography after anhydrous sodium sulfate drying organic layer removed under reduced pressure solvent, takes white solid product C2, productive rate 83%. ¹H NMR(400MHz,CDCl ₃):δ8.13(d,J＝8.4Hz,1H),7.85(d,J＝8.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.55-7.39(m,4H),4.50-4.39(m,4H),4.39,4.06(AB,J＝12.4Hz,2H),2.88-2.81(m,1H),2.73-2.69(m,1H),2.36-2.27(m,2H),2.16-2.13(m,2H),1.76-1.69(m,2H),1.33-1.24(m,15H),1.04-1.03(m,2H)； ¹³C NMR(100MHz,CDCl ₃):δ136.22,133.83,131.85,128.61,127.69,126.22,126.13,125.60,125.37,123.88,70.87(d,J _C-P＝6Hz,1C),70.73(d,J _C-P＝6Hz,1C),62.97(d,J _C-P＝48Hz,1C),55.51,48.87,34.59,31.32,25.10,24.59,23.81(d,J _C-P＝1.7Hz,1C),23.79,23.64(d,J _C-P＝2.9Hz,1C),23.59(d,J _C-P＝2.1Hz,1C)； ³¹P NMR(161.7MHz,CDCl ₃):δ7.13(s,1P).HRMS(ESI):Exact mass calcd for C ₂₃H ₃₆N ₂O ₃P[M+H] ⁺:419.2458,Found:419.2457。

Embodiment 4

Under nitrogen protection, in 50mL round-bottomed flask, add cinchonidine derivative primary amine Ia (1.0equiv) and anhydrous CH ₂cl ₂, after dissolving completely, add triethylamine (2.0equiv).At 0 DEG C, drip diphenyl phosphoryl chlorine IIc (1.0equiv), stir laggard row post processing of spending the night: add 30mL water, with dichloromethane extraction, column chromatography after anhydrous sodium sulfate drying, takes white solid product IIIc, productive rate 60%.Subsequently under nitrogen protection; anhydrous EtOH is added add IIIc in Schlenk bottle after; at room temperature add 1-naphthaldehyde (1.2equiv); reaction system under reflux conditions stirs (TLC detection reaction is complete) after 1 hour; reaction system is transferred in ice-water bath and cools; slowly add sodium borohydride (2.0equivs) subsequently, in ice-water bath, stir about reacted completely after 2 hours, added NaHCO ₃saturated solution and extraction into ethyl acetate 3 times.Column chromatography after anhydrous sodium sulfate drying organic layer removed under reduced pressure solvent, takes white solid product C3, productive rate 58%. ¹H NMR(400MHz,CDCl ₃):δ8.08-8.05(m,1H),7.87-7.85(m,1H),7.78-7.75(m,1H),7.75-7.47(m,2H),7.37-7.36(m,2H),7.22-7.03(m,10H),4.34,4.02(AB,J＝12.8Hz,2H),3.58-3.56(m,1H),3.06(s,br,1H),2.37-2.22(m,2H),1.78-1.61(m,3H),1.30-1.17(m,4H)； ¹³C NMR(100MHz,CDCl ₃):δ150.94(d,J _C-P＝7Hz,1C),150.80(d,J _C-P＝7Hz,1C),135.92,133.87,131.81,129.58,129.48,128.67,127.77,126.18,126.16,125.68,125.41,124.72,123.77,120.16,120.14,10.11,120.09,62.13(d,J _C-P＝8Hz,1C),56.28,48.50,33.87,31.22,24.86,24.65； ³¹P NMR(161.7MHz,CDCl ₃):δ-0.74(s,1P).HRMS(ESI):Exact mass calcd for C ₂₉H ₃₂N ₂O ₃P[M+H] ⁺:487.2145,Found:487.2143。

Embodiment 5

Under nitrogen protection, in 50mL round-bottomed flask, add cinchonidine derivative primary amine Ia (1.0equiv) and anhydrous CH ₂cl ₂, after dissolving completely, add triethylamine (2.0equiv).At 0 DEG C, drip diphenyl phosphoryl chlorine IIc (1.0equiv), stir laggard row post processing of spending the night: add 30mL water, with dichloromethane extraction, column chromatography after anhydrous sodium sulfate drying, takes white solid product IIIc, productive rate 60%.Subsequently under nitrogen protection; anhydrous EtOH is added add IIIc in Schlenk bottle after; at room temperature add 1-naphthaldehyde (1.2equiv); reaction system under reflux conditions stirs (TLC detection reaction is complete) after 1 hour; reaction system is transferred in ice-water bath and cools; slowly add sodium borohydride (2.0equivs) subsequently, in ice-water bath, stir about reacted completely after 2 hours, added NaHCO ₃saturated solution and extraction into ethyl acetate 3 times.Column chromatography after anhydrous sodium sulfate drying organic layer removed under reduced pressure solvent, takes white solid product C3, productive rate 58%. ¹H NMR(400MHz,CDCl ₃):δ8.12(d,J＝8.4Hz,1H),7.85(d,J＝8.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.55-7.51(m,1H),7.48-7.46(m,2H),7.43-7.39(m,1H),4.50-4.39(m,4H),4.39,4.09(AB,J＝12.8Hz,2H),3.61(d,J＝11.2Hz,3H),3.51(d,J＝11.2Hz,3H),2.98-2.94(m,1H),2.84-2.80(m,1H),2.33-2.30(m,2H),2.13-2.10(m,1H),2.01(s,br,1H),1.78-1.69(m,2H),1.33-1.14(m,4H),1.04-1.03(m,2H)； ¹³C NMR(100MHz,CDCl ₃):δ135.99,133.83,131.70,128.67,127.75,126.10,126.08,125.62,125.37,123.66,62.35(d,J _C-P＝7.8Hz,1C),55.61,53.08,53.03,48.55,34.19,31.25,24.93,24.59； ³¹P NMR(161.7MHz,CDCl ₃):δ11.42(s,1P).HRMS(ESI):Exact mass calcd for C ₁₉H ₇₂N ₂O ₃P[M] ⁺:362.1759,Found:362.1760。

Embodiment 6

Under nitrogen protection, in 50mL round-bottomed flask, add cinchonidine derivative primary amine Ib (1.0equiv) and anhydrous CH ₂cl ₂, after dissolving completely, add triethylamine (2.0equiv).At 0 DEG C, drip diethoxy phosphoryl chloride phosphorus oxychloride IIa (1.0equiv), stir laggard row post processing of spending the night: add 30mL water, with dichloromethane extraction, column chromatography after anhydrous sodium sulfate drying, takes white solid product IIIe, productive rate 74%.Subsequently under nitrogen protection; anhydrous EtOH is added add IIIe in Schlenk bottle after; at room temperature add 1-naphthaldehyde (1.2equiv); reaction system under reflux conditions stirs (TLC detection reaction is complete) after 1 hour; reaction system is transferred in ice-water bath and cools; slowly add sodium borohydride (2.0equivs) subsequently, in ice-water bath, stir about reacted completely after 2 hours, added NaHCO ₃saturated solution and extraction into ethyl acetate 3 times.Column chromatography after anhydrous sodium sulfate drying organic layer removed under reduced pressure solvent, takes white solid product C5, productive rate 74%. ¹H NMR(400MHz,CDCl ₃):δ7.83-7.73(m,3H),7.46-7.16(m,14H),4.35-4.29(m,1H),4.09,3.84(AB,J＝13.2Hz,2H),3.96-3.88(m,2H),3.82-3.68(m,2H),3.49-3.39(m,2H),1.95(s,br,1H),0.98(t,J＝7.2Hz,3H),0.88(t,J＝6.8Hz,3H)； ¹³C NMR(100MHz,CDCl ₃):δ128.55,128.28,128.07,127.69,127.45,127.13,126.84,125.97,125.78,125.52,125.25,123.38,68.35(d,J _C-P＝8.0Hz,1C),61.93(d,J _C-P＝6.1Hz,1C),61.87(d,J _C-P＝5.6Hz,1C),61.43,15.95(d,J _C-P＝7.5Hz,1C),15.64(d,J _C-P＝7.8Hz,1C)； ³¹P NMR(161.7MHz,CDCl ₃):δ7.59(s,1P).HRMS(ESI):Exact mass calcd for C ₂₉H ₃₄N ₂O ₃P[M+H] ⁺:489.2302,Found:489.2301。

Embodiment 7

Under nitrogen protection, in 50mL round-bottomed flask, add cinchonidine derivative primary amine Ia (1.0equiv) and anhydrous CH ₂cl ₂, after dissolving completely, add triethylamine (2.0equiv).At 0 DEG C, drip diethoxy phosphoryl chloride phosphorus oxychloride IIa (1.0equiv), stir laggard row post processing of spending the night: add 30mL water, with dichloromethane extraction, column chromatography after anhydrous sodium sulfate drying, takes white solid product IIIa, productive rate 80%.Subsequently under nitrogen protection; anhydrous EtOH is added add IIIa in Schlenk bottle after; at room temperature add 1-pyrene aldehyde (1.2equiv); reaction system under reflux conditions stirs (TLC detection reaction is complete) after 1 hour; reaction system is transferred in ice-water bath and cools; slowly add sodium borohydride (2.0equivs) subsequently, in ice-water bath, stir about reacted completely after 2 hours, added NaHCO ₃saturated solution and extraction into ethyl acetate 3 times.Column chromatography after anhydrous sodium sulfate drying organic layer removed under reduced pressure solvent, takes yellow solid product C7, productive rate 83%. ¹h NMR (400MHz, CDCl ₃): δ 8.38 (d, J=8.4Hz, 1H), 8.19-8.11 (m, 4H), 8.03-7.97 (m, 4H), 4.64,4.35 (AB, J=12.8Hz, 2H), 3.93-3.79 (m, 4H), 2.89-2.81 (m, 2H), 2.36-2.35 (m, 2H), 2.14-2.11 (m, 1H), 1.78-1.69 (m, 2H), 1.31-1.24 (m, 5H), 1.15 (t, J=7.2Hz, 3H), 0.97 (t, J=7.2Hz, 3H); ¹³c NMR (100MHz, CDCl ₃): δ 134.05,131.31,130.87,130.68,129.12,127.66,127.45,127.18,127.06,125.88,125.07,125.02,124.89,124.70,123.31,62.62,62.54,62.34,55.58,48.88,34.44,31.38,25.05,24.63,16.11 (d, J=7.1Hz, 1C), 15.90 (d, J=6.9Hz, 1C); ³¹p NMR (161.7MHz, CDCl ₃): δ 8.85 (s, 1P) .MS (EI): 464 (M ⁺, 8), 230 (100), 215 (77), 122 (32), 96 (12), 44 (15); HRMS (EI): Exact mass calcd for C ₂₇h ₃₃n ₂o ₃p [M] ⁺: 464.2229, Found:464.2226.

Embodiment 8

Under nitrogen protection, in 50mL round-bottomed flask, add cinchonidine derivative primary amine Ia (1.0equiv) and anhydrous CH ₂cl ₂, after dissolving completely, add triethylamine (2.0equiv).At 0 DEG C, drip diethoxy phosphoryl chloride phosphorus oxychloride IIa (1.0equiv), stir laggard row post processing of spending the night: add 30ml water, with dichloromethane extraction, column chromatography after anhydrous sodium sulfate drying, takes white solid product IIIa, productive rate 80%.Subsequently under nitrogen protection; anhydrous EtOH is added add IIIa in Schlenk bottle after; at room temperature add P-methoxybenzal-dehyde (1.2equiv); reaction system under reflux conditions stirs (TLC detection reaction is complete) after 1 hour; reaction system is transferred in ice-water bath and cools; slowly add sodium borohydride (2.0equivs) subsequently, in ice-water bath, stir about reacted completely after 2 hours, added NaHCO ₃saturated solution and extraction into ethyl acetate 3 times.Column chromatography after anhydrous sodium sulfate drying organic layer removed under reduced pressure solvent, takes white solid product C8, productive rate 83%. ¹h NMR (400MHz, CDCl ₃): δ 7.23 (d, J=8.4Hz, 2H), 6.84 (d, J=8.4Hz, 2H), 4.08-3.95 (m, 4H), 3.78 (s, 3H), 3.85,3.58 (AB, J=12.8Hz, 2H), 2.89-2.80 (m, 2H), 2.19-2.09 (m, 4H), 1.71-1.66 (m, 2H), 1.33-1.07 (m, 10H) ¹³c NMR (100MHz, CDCl ₃): δ 158.53,132.51,129.27,113.72,62.43 (d, J _c-P=5.6Hz, 1C), 62.29 (d, J _c-P=5.5Hz, 1C), 61.69 (d, J _c-P=7.5Hz, 1C), 55.49,55.23,50.12,34.39,31.04,24.98,24.49,16.20 (d, J _c-P=6.9Hz, 1C), 16.13 (d, J _c-P=6.7Hz, 1C); ³¹p NMR (161.7MHz, CDCl ₃): δ 8.95 (s, 1P) .HRMS (ESI): Exact mass calcd for C ₁₈h ₃₂n ₂o ₄p [M+H] ⁺: 371.2094, Found:371.2093.

Application examples 1

Catalyst C1 (0.025mmol) is added in 5mL reaction bulb, the alkene (0.25mmol) that isatin is derivative and solvent acetone 2.5mL stirred at ambient temperature are after 10 minutes, add difluoro silyl enol ether (0.375mmol), reaction detects through TLC, after raw material disappears, be spin-dried for, take target product through column chromatography, productive rate 98%; HPLC analysis (Chiralpak AD-H, ⁱprOH/hexane=20/80,1.0mL/min, 230nm; t _r(minor)=22.501min, t _r(major)=27.828min) gave the isomeric composition of the product:94%ee, [] ²⁰ _d=-4.3 (c=0.5, acetone); ¹h NMR (400MHz, CDCl ₃): δ 8.37 (s, br, 1H), 8.01-7.99 (m, 2H), 7.68-7.64 (m, 2H), 7.50-7.42 (m, 3H), 7.18-7.14 (m, 1H), 7.06-7.04 (m, 1H), 4.92 (s, 1H); ¹³c NMR (100MHz, CDCl ₃): δ 185.43 (t, J=31Hz, 1C), 170.30 (d, J=7.6Hz, 1C), 141.72,135.44,131.96,130.52,130.35 (t, J=3.3Hz, 1C), 128.89,125.85 (d, J=3.3Hz, 1C), 123.95, (120.78 d, J=3.6Hz, 1C), (116.87 t, J=271Hz, 1C), 111.31,109.66,108.79, (55.45 t, J=20Hz, 1C), (26.92 d, J=8.6Hz, 1C); ¹⁹f NMR (376MHz, CDCl ₃): δ-96.87 (d, J=309Hz, 1F) ,-98.67 (d, J=309Hz, 1F).

Application examples 2

Catalyst C7 (0.025mmol) is added in 5mL reaction bulb, the alkene (0.25mmol) that isatin is derivative and solvent acetone 2.5mL stirred at ambient temperature are after 10 minutes, add difluoro silyl enol ether (0.375mmol), reaction detects through TLC, after raw material disappears, be spin-dried for, take target product through column chromatography, productive rate 99%yield; HPLC analysis (Chiralpak IC, ⁱprOH/hexane=20/80,1.0mL/min, 230nm; t _r(minor)=6.910min, t _r(major)=8.244min) gave the isomeric composition of the product:94%ee, [] ²⁰ _d=+5.3 (c=0.7, acetone); ¹h NMR (400MHz, CDCl ₃): δ 8.20 (s, br, 1H), 8.02-8.00 (m, 2H), 7.68-7.64 (m, 1H), 7.50-7.46 (m, 3H), 7.26-7.23 (m, 1H), 6.95-6.93 (m, 1H), 4.90 (s, 1H), 2.34 (s, 3H); ¹³c NMR (100MHz, CDCl ₃): δ 185.45 (t, J=31Hz, 1C), 170.34 (d, J=7.6Hz, 1C), 139.20,135.38,133.79,132.37,130.61,130.37 (t, J=3.3Hz, 1C), 128.87,126.38 (d, J=3.2Hz, 1C), 120.79 (d, J=3.5Hz, 1C), 116.84 (t, J=270Hz, 1C), 111.02,109.74,108.85,55.54 (t, J=20Hz, 1C), 26.97 (d, J=8.5Hz, 1C), 21.18; ¹⁹f NMR (376MHz, CDCl ₃): δ-96.87 (d, J=308Hz, 1F) ,-98.67 (d, J=308Hz, 1F).

Application examples 3

Catalyst C8 (0.025mmol) is added in 5mL reaction bulb, the alkene (0.25mmol) that isatin is derivative and solvent acetone 2.5mL stirred at ambient temperature are after 10 minutes, single fluorine silyl enol ether (0.375mmol) is added at 0 DEG C, reaction detects through TLC, after raw material disappears, be spin-dried for, take target product through column chromatography, productive rate 95%yield (m.p.75-77 DEG C). ¹h and ¹⁹f NMR of crude mixture indicated the dr value is 17:1.HPLC analysis (Chiralpak AS-H, ⁱprOH/hexane=30/70,1.0mL/min, 230nm; Major diastereomer:t _r(minor)=12.580min, t _r(major)=15.913min) gave the isomeric composition of the product:90%ee, [] ²⁵ _d=+302.5 (c=1.0, acetone); ¹h NMR for major diastereomer (400MHz, CDCl ₃): δ 8.10 (s, br, 1H), 7.85 (d, J=7.6Hz, 1H), 7.81-7.79 (m, 1H), 7.63-7.59 (m, 1H), 7.43 (t, J=7.2Hz, 1H), 7.28-7.26 (m, 1H), 6.79-6.76 (m, 1H), 6.54 (d, J=2.4Hz, 1H), 5.86 (s, 1H), 3.86 (s, 3H), 3.11 (dd, J=26Hz, J=18.8Hz, 1H), (2.88 t, J=18Hz, 1H); ¹³c NMR for major diastereomer (100MHz, CDCl ₃): δ 197.32 (d, J=18Hz, 1C), 171.38 (d, J=11Hz, 1C), 162.43,148.52 (d, J=1.8Hz, 1C), 142.16,137.08,134.07,128.85,127.56,126.23,125.46,114.69,110.94,110.59,109.23,98.37,94.94 (d, J=195Hz, 1C), 57.21 (d, J=22Hz, 1C), 55.69,37.55 (d, J=24Hz, 1C), 24.89 (d, J=3.2Hz, 1C); ¹⁹f NMR (376MHz, CDCl ₃): δ-160.57 (s, 1F) .IR (ATR): 3310,2924,1717,1629,1466,1158,749,728; MS (EI): 375 (M ⁺, 3), 355 (3), 310 (11), 225 (35), 198 (15), 150 (100), 122 (66), 101 (32), 7631); HRMS (EI): Exact mass calcd for C ₂₁h ₁₄n ₃o ₃f [M] ⁺: 375.1019, Found:75.1016.

Claims (2)

1. a class phosphamide-(primary) secondary amine bifunctional catalyst, is characterized in that the structural formula of such catalyst is as follows:

Wherein:

R is aryl or the alkyl of C1-C30, becomes ring or not Cheng Huan between R;

R ¹, R ²for aryl or the alkyl of C1-C30, chirality or achiral; R ¹and R ²between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings;

R ³for the alkyl of H, C1-C50, the aryl of C1-C50 or the alkyl that is connected with support materials;

R ⁴, R ⁵, R ⁶and R ⁷for aryl or the alkyl of C1-C50, chirality or achiral; R ⁴and R ⁵between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings; R ⁶and R ⁷between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings;

R ⁸, R ⁹and R ¹⁰for aryl or the alkyl of C1-C50, it is chirality or achiral; R ⁸and R ⁹between, R ⁹and R ¹⁰between or R ⁸and R ¹⁰between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings; R ⁸, R ⁹and R ¹⁰arbitrarily between the two or between three, become ring or not Cheng Huan, cycloaliphatic ring is become, containing heteroatomic cycloaliphatic ring or become aromatic rings.

2. a synthetic method for catalyst described in claim 1, is characterized in that, this synthetic method is by shown in following reaction equation (I) (II) (III) (IV) (V):

Specifically comprise the following steps:

1) in reaction vessel, add chirality 1, the 2-diamines of X mole, then add the alkali of Y milliliter solvent, Z mole successively, be cooled to-10 DEG C, drip the phosphoryl chloride phosphorus oxychloride of X mole, under room temperature range, be stirred to TLC at-10 degree and show reaction and complete; After column chromatography for separation obtains phosphamide primary amine catalyst, then with the aldehyde of A mole reflux in L milliliter ethanol about 1 little up to primary amine reaction completely after, add the sodium borohydride of B mole under being transferred to-10 degree, stir half an hour TLC display and react completely;

Wherein, X=0.1-100; The consumption Y of solvent is the corresponding scope of application of every mM of (mmol) chirality 1,2-diamines is 20mL; Z=0.2-200; A=0.12-120; B=0.2-200; The volume L of ethanol is the corresponding scope of application of every mM of (mmol) chirality 1,2-diamines is 10mL; Proportionate relationship between its different compound is X:Z:A:B=1:2:1.2:2;

2) target product is obtained by column chromatography for separation; Wherein:

Described different phosphate acyl chlorides is represented by following chemical formula (A) (B) (C) (D) (E) respectively:

Wherein:

R ¹, R ²for aryl or the alkyl of C1-C30, chirality or achiral; R ¹and R ²between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings;

R ³for the alkyl of H, C1-C50, the aryl of C1-C50 or the alkyl that is connected with support materials;

R ⁴, R ⁵, R ⁶and R ⁷for aryl or the alkyl of C1-C50, chirality or achiral; R ⁴and R ⁵between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings; R ⁶and R ⁷between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings;

R ⁸, R ⁹and R ¹⁰for aryl or the alkyl of C1-C50, it is chirality or achiral; R ⁸and R ⁹between, R ⁹and R ¹⁰between or R ⁸and R ¹⁰between become ring or not Cheng Huan, become cycloaliphatic ring, containing heteroatomic cycloaliphatic ring or become aromatic rings; R ⁸, R ⁹and R ¹⁰arbitrarily between the two or between three, become ring or not Cheng Huan, cycloaliphatic ring is become, containing heteroatomic cycloaliphatic ring or become aromatic rings.

Described chirality 1,2-diamines has following formula structure:

Wherein, the chiral configuration of diamines is (R, R), (R, S), (S, R) or (S, S), is bought obtain or obtain through simple synthesis by business; R is aryl or the alkyl of C1-C30, becomes ring or not Cheng Huan between R;

Described solvent is toluene, carrene, ether, ethyl acetate, oxolane, acetone, acetonitrile, DMF, nitromethane or methyl alcohol;

Described alkali is DMAP, triethylamine, diisopropyl ethyl amine, DBU, DABCO, pyridine, nafoxidine, diethylamine, N-methylbenzylamine, potash, cesium carbonate, sodium carbonate, potassium hydroxide or NaOH;

Described aldehyde is aromatic aldehyde or fatty aldehyde.