CN106243099A - A kind of method of the novel nitrogen-containing tridentate ligand synthesis of nickel catalysis - Google Patents

A kind of method of the novel nitrogen-containing tridentate ligand synthesis of nickel catalysis Download PDF

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CN106243099A
CN106243099A CN201610512161.8A CN201610512161A CN106243099A CN 106243099 A CN106243099 A CN 106243099A CN 201610512161 A CN201610512161 A CN 201610512161A CN 106243099 A CN106243099 A CN 106243099A
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tridentate ligand
nickel
novel nitrogen
oxazoline
catalysis
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CN106243099B (en
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陆展
吉崇磊
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
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Abstract

This method discloses the method for the novel nitrogen-containing tridentate ligand synthesis of a kind of nickel catalysis, with pyridine bromide imines and chirality oxazoline as raw material, with cheap metal nickel as catalyst, with dppp as part, tert-butyl alcohol lithium is as alkali, with toluene as solvent, at a temperature of 120 DEG C, react 24 hours prepared novel nitrogen-containing tridentate ligands, provide the route of the efficient Fast back-projection algorithm tridentate ligand containing oxazoline, employ nickel and the part of catalytic amount, reaction can be with high yield, the carrying out of the high suitability, this reaction is stereospecificity, the oxazoline compound of enantiomer-pure can be obtained, the target product of synthesis can be directly as the part of asymmetry catalysis.

Description

A kind of method of the novel nitrogen-containing tridentate ligand synthesis of nickel catalysis
Technical field
This method relates to a kind of part synthetic method, specifically, is that efficiently synthesizing of a kind of cheap metal nickel catalysis contains The method of nitrogen tridentate ligand.
Background technology
Nitrogenous tridentate ligand containing chirality oxazoline in the conversion realizing high enantioselectivity very efficiently [a) Tetrahedron:Asymmetry 1998,9,1-45.], current people build with acid or cyano-containing compound for substrate mostly This quasi-molecule.Meyers, Chang et al. have been developed several method to build this compounds [a) J.Org.Chem.1991,56,1961-1963.b)Org.Lett.2010,12,1868-1871.].For method before making up Weak point, our seminar have also been developed a kind of method of transition metal palladium catalytic coupling to build this compounds [a) Org.Lett.2015,17,5939-5941.].But, transition metal palladium belongs to noble metal, and earth content is few and expensive, Therefore, it is the most valuable for replacing palladium to go to realize this reaction by the cheap metal that earth content is high.Therefore, Wo Menfa Open up the method efficiently synthesizing nitrogenous tridentate ligand of a kind of cheap metal nickel catalysis.
The present invention is successfully realized the structure of nitrogenous tridentate ligand by cheap metal nickel catalysis one kettle way.
Summary of the invention
The problem to be solved in the present invention is to provide a kind of method of nitrogenous tridentate ligand of effective synthesis, is by cheap metal The coupling reaction of nickel catalysis, it is possible to efficiently build the tridentate ligand containing chirality oxazoline ring.
The present invention is achieved through the following technical solutions:
The method that the invention discloses the novel nitrogen-containing tridentate ligand synthesis of a kind of nickel catalysis, with pyridine bromide imines and hands Property oxazoline is raw material, and with cheap metal nickel as catalyst, with dppp as part, tert-butyl alcohol lithium is as alkali, with toluene as solvent, At a temperature of 120 DEG C, react 24 hours prepared novel nitrogen-containing tridentate ligands, imines, chirality oxazoline, metallic nickel, dppp, tertiary fourth The mol ratio of lithium alkoxide is 1:1.2:0.1:0.2:4, toluene 4mL, and the structural formula of imines isR1For list Replace or polysubstituted alkyl.
As improving further, R of the present invention1Replace for 2,6-dimethylOr 2,6- Diethyl replacesOr 2,6-diisopropyl replaces
As improving further, chirality oxazoline of the present invention is optical voidness, and structural formula isWherein R2For any one in methyl, ethyl, isopropyl, the tert-butyl group, isobutylbenzyl.
As improving further, metallic nickel of the present invention is anhydrous nickelous bromide.
As improving further, toluene used by the present invention is through overweight steaming Non-aqueous processing.
As improving further, of the present inventionHeat 24 hours.
As improving further, the product of gained of the present invention is to sequentially pass through extraction, thin layer chromatography and column chromatography in addition Separation forms.
Present approach provides a kind of effective with cheap metal nickel as catalyst, efficiently build correspondence course property oxazoline three The method of tooth part.Compared with the conventional method, the method is applicable to the part of number of different types, and reaction condition is gentle, operation Simplicity, metal economy used is higher.It addition, reaction is without other any poisonous transition metal (such as ruthenium, rhodium, palladium etc.) salts Addition, pharmaceutical synthesis has bigger actual application value.And functional group's tolerance of reaction is good, optical purity is high The highest.
The invention has the advantages that:
1) route of the efficient Fast back-projection algorithm tridentate ligand containing oxazoline is provided.
2) employing nickel and the part of catalytic amount, reaction can be with high yield, the carrying out of the high suitability.
3) this reaction is stereospecificity, can obtain the oxazoline compound of enantiomer-pure.
4) synthesize target product can be directly as the part of asymmetry catalysis.
Detailed description of the invention
Under nitrogen protection, formula 1 (1mmol, 1equiv) and formula 2 (S)-oxazoline ring (1.2equiv) in 4mL toluene, nothing Water nickelous bromide (10mol%), dppp (20mol%), tert-butyl alcohol lithium (4.0equiv), 120 degree are reacted 24 hours, petroleum ether/second Acetoacetic ester crosses post, obtains the tridentate ligand formula 3 containing chirality oxazoline.
R in formula 1 and formula 31For monosubstituted or polysubstituted alkyl etc., such as, 2,6-dimethyl replace2,6-diethyl replaces2,6-diisopropyl replacesDeng, R in formula 2 and formula 32For methyl, ethyl, isopropyl, the tert-butyl group, isobutyl group, benzyl etc..Pd is NiCl2、NiBr2、Ni(OAc)2、Ni(COD)2、Ni(DME)2, preferably NiBr2；Part is monophosphorous ligand and biphosphine ligand, preferably dppp；Alkali is inorganic base, preferably tert-butyl alcohol lithium；Solvent is high boiling point non-polar solven, preferably toluene.
Imines of the present invention, oxazoline, metallic nickel, dppp, the mol ratio of tert-butyl alcohol lithium are 1:1.2:0.1:0.2: 4。
Product 3 of the present invention as the good part of asymmetry catalysis, and can be used widely, such as formula IV-VIII ((a)J.Chen,T.Xi,Z.Lu,Org.Lett.2014,16,6452-6455.(b)J.Guo,J.Chen,Z.Lu, Chem.Commun.2015,51,5725-5727；
Being further described technical scheme below by specific embodiment, following example explain this Bright, responded and carried out in the solvent of airfree argon and degassing, but be not limiting as present invention.
The preparation of formula 2 by known references step synthesize (W.R.Leonard, J.L.Romine, A.I.Meyers, J.Org.Chem.1991,56,1961-1963.)。
Example 1
(S,E)-N-(1-(6-(4-(tert-butyl)-4,5-dihydrooxazol-2-yl)pyridin-2-yl) Ethylidene)-2,6-dim ethylaniline (IIIa): yield 53%；[α]D 20=-45.7 (c=1.09, CHCl3)；1H NMR:(400.1MHz,CDCl3) δ 8.50 (dd, J=8.0,0.8Hz, 1H), 8.22 (dd, J=8.0,0.8Hz, 1H), 7.87 (t, J=8.0Hz, 1H), 7.06 (d, J=7.6Hz, 2H), 6.93 (t, J=7.6Hz, 1H), 4.49 (dd, J= 10.2,8.6Hz, 1H), 4.35 (t, J=8.6Hz, 1H), 4.15 (dd, J=10.2,8.6Hz, 1H), 2.26 (s, 3H), 2.024 (s,3H),2.019(s,3H),1.00(s,9H).
Example 2
(S,E)-N-(1-(6-(4-isopropyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl) Ethylidene)-2,6-dimet hylaniline (IIIb): yiel 57%；[α]D 20=-47.3 (c=1.06, CHCl3)；1H NMR:(400.1MHz,CDCl3) δ 8.50 (dd, J=8.0,0.8Hz, 1H), 8.19 (dd, J=7.6,0.8Hz, 1H), 7.88 (dd, J=8.0,7.6Hz, 1H), 7.06 (d, J=7.6Hz, 2H), 6.94 (t, J=7.6Hz, 1H), 4.55 (dd, J=9.4, 8.2Hz, 1H), 4.29-4.15 (m, 2H), 2.26 (s, 3H), 2.02 (s, 6H), 1.97-1.85 (m, 1H), 1.08 (d, J= 6.8Hz, 3H), 0.97 (d, J=6.8Hz, 3H).
Example 3
(S,E)-N-(1-(6-(4-benzyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl) Ethylidene)-2,6-dimethy laniline (IIIc): yield 60%；[α]D 20=-2.5 (c=0.99, CHCl3)；1H NMR:(400.1MHz,CDCl3) δ 8.51 (dd, J=8.0,0.8Hz, 1H), 8.16 (dd, J=7.6,0.8Hz, 1H), 7.88 (dd, J=8.0,7.6Hz, 1H), 7.36-7.20 (m, 5H), 7.06 (d, J=7.6Hz, 2H), 6.93 (t, J=7.6Hz, 1H), 4.74-4.63 (m, 1H), 4.46 (dd, J=9.2,8.4Hz, 1H), 4.26 (dd, J=8.4,8.0Hz, 1H), 3.32 (dd, J= 14.0,5.2Hz, 1H), 2.78 (dd, J=14.0,9.0Hz, 1H), 2.26 (s, 3H), 2.02 (s, 6H).
Example 4
(S,E)-N-(1-(6-(4-benzyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl) Ethylidene)-2,6-diethyla niline (IIIe): yield 68%；[α]D 20=-1.5 (c=1.02, CHCl3)；1H NMR:(400.1MHz,CDCl3) δ 8.51 (dd, J=8.0,1.2Hz, 1H), 8.16 (dd, J=7.6,1.2Hz, 1H), 7.87 (dd, J=8.0,7.6Hz, 1H), 7.35-7.20 (m, 5H), 7.06-7.11 (m, 2H), 7.00-7.05 (m, 1H), 4.74- 4.64 (m, 1H), 4.46 (dd, J=9.2,8.6Hz, 1H), 4.26 (dd, J=8.6,7.6Hz, 1H), 3.32 (dd, J=13.6, 5.2Hz, 1H), 2.78 (dd, J=13.6,8.8Hz, 1H), 2.46-2.29 (m, 4H), 2.28 (s, 3H), 1.13 (t, J= 7.6Hz,6H).
Example 5
(S,E)-N-(1-(6-(4-benzyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl) Ethylidene)-2,6-diisopro pylaniline (IIIf): yield 79%；[α]D 20=-33.7 (c=1.07, PhCH3)；1H NMR:(500.1MHz,CDCl3) δ 8.52 (dd, J=7.5,0.8Hz, 1H), 8.17 (dd, J=8.0,0.5Hz, 1H), 7.90 (dd, J=8.0,7.5Hz, 1H), 7.35-7.30 (m, 2H), 7.29-7.22 (m, 3H), 7.19-7.14 (m, 2H), 7.10 (dd, J=8.0,6.5Hz, 1H), 4.73-4.65 (m, 1H), 4.48 (dd, J=8.5,8.0Hz, 1H), 4.28 (dd, J= 8.0,7.5Hz, 1H), 3.33 (dd, J=14.0,5.0Hz, 1H), 2.79 (dd, J=14.0,8.5Hz, 1H), 2.75-2.68 (m, 1H), 2.29 (s, 3H), 1.14 (d, J=7.0Hz, 12H).
Example 6
(S,E)-N-(1-(6-(4-benzyl-4,5-dihydrooxazol-2-yl)pyridin-2-yl) Ethylidene)-2-(tert-butyl) aniline (IIIg): yield 61%；[α]D 20=-20.0 (c=0.93, PhCH3)；1H NMR:(400.1MHz,CDCl3) δ 8.44 (dd, J=7.8,1.2Hz, 1H), 8.15 (dd, J=7.8,1.2Hz, 1H), 7.88 (t, J=7.8Hz, 1H), 7.42 (dd, J=7.8,1.2Hz, 1H), 7.35-7.20 (m, 5H), 7.18 (td, J= 7.8,1.2Hz, 1H), 4.73-4.64 (m, 1H), 4.46 (dd, J=9.2,8.6Hz, 1H), 4.26 (dd, J=8.6,7.6Hz, 1H), 3.32 (dd, J=13.6,5.0Hz, 1H), 2.78 (dd, J=13.6,9.2Hz, 1H), 2.44 (s, 3H), 1.35 (s, 9H).
Example 7
(S)-4-benzyl-2-(6'-bromo-[2,2'-bipyridin]-6-yl)-4,5- Dihydrooxoxazoline (IIIt): yield 50%；[α]D 20=-12.0 (c=1.04, CHCl3)；1H NMR: (400.1MHz,CDCl3) δ 8.52 (dd, J=7.6,5.2Hz, 2H), 8.09 (d, J=7.6Hz, 1H), 7.90 (dd, J=8.0, 7.6Hz, 1H), 7.66 (t, J=7.6Hz, 1H), 7.49 (d, J=7.6Hz, 1H), 7.37-7.19 (m, 5H), 4.74-4.62 (m, 1H), 4.47 (dd, J=9.2,8.6Hz, 1H), 4.27 (dd, J=8.6,8.0Hz, 1H), 3.32 (dd, J=13.6, 4.8Hz, 1H), 2.78 (dd, J=13.6,9.0Hz, 1H).
Finally, in addition it is also necessary to be only several specific embodiments of the present invention it is noted that listed above.Obviously, this Bright it is not limited to above example, it is also possible to have many deformation.Those of ordinary skill in the art can be from present disclosure The all deformation directly derived or associate, are all considered as protection scope of the present invention.

Claims (7)

1. a method for the novel nitrogen-containing tridentate ligand synthesis of nickel catalysis, is characterized in that with pyridine bromide imines and chirality azoles Quinoline is raw material, and with cheap metal nickel as catalyst, with dppp as part, tert-butyl alcohol lithium is as alkali, with toluene as solvent, 120 At a temperature of DEG C, react 24 hours prepared novel nitrogen-containing tridentate ligands, described imines, chirality oxazoline, metallic nickel, dppp, uncle The mol ratio of butanol lithium is 1:1.2:0.1:0.2:4, toluene 4mL, and the structural formula of described imines isR1For monosubstituted or polysubstituted alkyl.
The method of the novel nitrogen-containing tridentate ligand synthesis of nickel the most according to claim 1 catalysis, is characterized in that described R1For 2,6-dimethyl replacesOr 2,6-diethyl replacesOr 2,6-diisopropyl Replace
The method of the nitrogenous tridentate ligand of synthesizing new the most according to claim 1 and 2, is characterized in that, described chirality Oxazoline is optical voidness, and structural formula isWherein R2For appointing in methyl, ethyl, isopropyl, the tert-butyl group, isobutylbenzyl Meaning one.
The method of the nitrogenous tridentate ligand of synthesizing new the most according to claim 3, is characterized in that, described metallic nickel is nothing Water nickelous bromide.
5. according to the method for the nitrogenous tridentate ligand of the synthesizing new described in claim 1 or 4, it is characterized in that, toluene used passes through Heavily steam Non-aqueous processing.
The method of the nitrogenous tridentate ligand of synthesizing new the most according to claim 1, is characterized in that, heats 24 hours.
7., according to the method for the nitrogenous tridentate ligand of synthesizing new described in claim 1 or 4 or 6, it is characterized in that, the product of gained It is to sequentially pass through extraction, thin layer chromatography and column chromatography to be separated and form.
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Cited By (1)

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