CN106243099B - A kind of novel nitrogen-containing tridentate ligand synthetic method of nickel catalysis - Google Patents
A kind of novel nitrogen-containing tridentate ligand synthetic method of nickel catalysis Download PDFInfo
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- CN106243099B CN106243099B CN201610512161.8A CN201610512161A CN106243099B CN 106243099 B CN106243099 B CN 106243099B CN 201610512161 A CN201610512161 A CN 201610512161A CN 106243099 B CN106243099 B CN 106243099B
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- C07—ORGANIC CHEMISTRY
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- 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
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- C07D—HETEROCYCLIC COMPOUNDS
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- 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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Abstract
This method discloses a kind of novel nitrogen-containing tridentate ligand synthetic method of nickel catalysis, using pyridine bromide imines and chiral oxazoline as raw material, using cheap metal nickel as catalyst, using dppp as ligand, tert-butyl alcohol lithium is as alkali, using toluene as solvent, at a temperature of 120 DEG C, react 24 hours obtained novel nitrogen-containing tridentate ligands, provide the route of an efficient tridentate ligand of the rapid synthesis containing oxazoline, the nickel and ligand of catalytic amount are used, reaction can be with high yield, the progress of high applicability, this reaction is stereocpecificity, the oxazoline class compound of available enantiomer-pure, the target product of synthesis can be directly as the ligand of asymmetry catalysis.
Description
Technical field
This method is related to a kind of ligand synthetic method, specifically, being that a kind of efficiently synthesizing for cheap metal nickel catalysis contains
The method of nitrogen tridentate ligand.
Background technique
Nitrogenous tridentate ligand containing chiral oxazoline in the conversion for realizing high enantioselectivity very efficiently [a)
Tetrahedron:Asymmetry 1998,9,1-45.], current people construct using acid or cyano-containing compound as substrate mostly
This kind of molecule.Several method has been developed to construct this kind of compound [a) in Meyers, Chang et al.
J.Org.Chem.1991,56,1961-1963.b)Org.Lett.2010,12,1868-1871.].For method before making up
Shortcoming, a kind of method of transition metal palladium catalytic coupling has also been developed to construct this kind of compound [a) in our seminars
Org.Lett.2015,17,5939-5941.].However, transition metal palladium belongs to noble metal, earth content is few and expensive,
Therefore, palladium is replaced to go to realize that this reaction is very valuable by the high cheap metal of earth content.Therefore, Wo Menfa
A kind of method for efficiently synthesizing nitrogenous tridentate ligand of cheap metal nickel catalysis is opened up.
The present invention is catalyzed the building that one kettle way is successfully realized nitrogenous tridentate ligand by cheap metal nickel.
Summary of the invention
The problem to be solved in the present invention is to provide the methods that one kind effectively synthesizes nitrogenous tridentate ligand, are by cheap metal
The coupling reaction of nickel catalysis can efficiently construct the tridentate ligand containing chiral oxazoline ring.
The present invention is achieved through the following technical solutions:
The invention discloses a kind of novel nitrogen-containing tridentate ligand synthetic methods of nickel catalysis, with pyridine bromide imines and hand
Property oxazoline be raw material, using cheap metal nickel as catalyst, using dppp as ligand, tert-butyl alcohol lithium is as alkali, using toluene as solvent,
At a temperature of 120 DEG C, 24 hours obtained novel nitrogen-containing tridentate ligands, imines, chiral oxazoline, metallic nickel, dppp, tertiary fourth are reacted
The molar ratio of lithium alkoxide is 1:1.2:0.1:0.2:4, and the structural formula of toluene 4mL, imines areR1For list
Replace or polysubstituted alkyl, the chiral oxazoline are optical voidness, structural formula isWherein R2For methyl, second
Base, isopropyl, tert-butyl, isobutyl group, any one in benzyl.
As a further improvement, imines of the present invention is the substitution of 2,6- dimethylOr 2,
6- diethyl replacesOr 2,6- diisopropyl replaces
As a further improvement, metallic nickel of the present invention is anhydrous nickelous bromide.
As a further improvement, toluene used in the present invention is through overweight steaming Non-aqueous processing.
As a further improvement, the resulting product of the present invention is successively to be subject to by extraction, thin-layer chromatography and column chromatography
It separates.
Present approach provides one kind effectively using cheap metal nickel as catalyst, and efficiently building is containing chiral oxazoline three
The method of tooth ligand.Compared with the conventional method, this method is suitable for a variety of different types of ligands, and reaction condition is mild, operation
Simplicity, metal economy used are higher.In addition, reaction is not necessarily to other any toxic transition metal (such as ruthenium, rhodium, palladium) salts
Addition, on pharmaceutical synthesis have biggish practical application value.And functional group's tolerance of reaction is good, optical purity is high
Also higher.
The invention has the advantages that:
1) route of an efficient tridentate ligand of the rapid synthesis containing oxazoline is provided.
2) nickel and ligand of catalytic amount have been used, reaction can be with high yield, the progress of high applicability.
3) this reaction is stereocpecificity, the oxazoline class compound of available enantiomer-pure.
4) target product synthesized can be directly as the ligand of asymmetry catalysis.
Specific embodiment
Under nitrogen protection, formula 1 (1mmol, 1equiv) and formula 2 (S)-oxazoline ring (1.2equiv) are 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 column, obtains the tridentate ligand formula 3 containing chiral oxazoline.
R in formula 1 and formula 31For monosubstituted or polysubstituted alkyl etc., for example, 2,6- dimethyl replace2,6- diethyl replaces2,6- diisopropyl replacesDeng R in formula 2 and formula 32For methyl, ethyl, isopropyl, tert-butyl, isobutyl group, benzyl etc..Ni is
NiCl2、NiBr2、Ni(OAc)2、Ni(COD)2、Ni(DME)2, preferably NiBr2；Ligand be monophosphorous ligand and biphosphine ligand, preferably
dppp；Alkali is inorganic base, preferably tert-butyl alcohol lithium；Solvent is higher boiling nonpolar solvent, preferably toluene.
Imines of the present invention, oxazoline, metallic nickel, dppp, tert-butyl alcohol lithium molar ratio be 1:1.2:0.1:0.2:
4。
Product 3 of the present invention can be used as the good ligand of asymmetry catalysis, and 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；
Technical solution of the present invention is further described below by specific embodiment, following embodiment explains this hair
Bright, all reactions carry out in airfree argon gas and the solvent of degassing, but are not intended to limit the content of present invention.
The preparation of formula 2 by known references step synthesis (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-dimethylaniline (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-dimethylaniline (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-dimethylaniline (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-diethylaniline (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-diisopropylaniline (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)
The above list is only a few specific embodiments of the present invention for finally, it should also be noted that.Obviously, this hair
Bright to be not limited to above embodiments, acceptable there are many deformations.Those skilled in the art can be from present disclosure
All deformations for directly exporting or associating, are considered as protection scope of the present invention.
Claims (5)
1. a kind of nitrogenous tridentate ligand synthetic method of nickel catalysis, it is characterized in that being with pyridine bromide imines and chiral oxazoline
Raw material, using metallic nickel as catalyst, using dppp as ligand, tert-butyl alcohol lithium is as alkali, using toluene as solvent, at a temperature of 120 DEG C,
Nitrogenous tridentate ligand, the molar ratio of the imines, chiral oxazoline, metallic nickel, dppp, tert-butyl alcohol lithium is made for 24 hours in reaction
For 1:1.2:0.1:0.2:4, toluene 4mL, the structural formula of the imines isR1To be monosubstituted or
Polysubstituted alkyl, the chiral oxazoline are optical voidness, and structural formula isWherein R2For methyl, ethyl, isopropyl
Base, tert-butyl, isobutyl group, any one in benzyl.
2. the nitrogenous tridentate ligand synthetic method of nickel catalysis according to claim 1, it is characterized in that the imines is
2,6- dimethyl replacesOr 2,6- diethyl replacesOr 2,6- diisopropyl
Replace
3. the method for the nitrogenous tridentate ligand of synthesis according to claim 1, characterized in that the metallic nickel is anhydrous bromine
Change nickel.
4. the method for the nitrogenous tridentate ligand of synthesis according to claim 1, characterized in that toluene used is anhydrous through overweight steaming
Processing.
5. the method for the nitrogenous tridentate ligand of synthesis according to claim 1, characterized in that resulting product is successively to pass through
Extraction, thin-layer chromatography and column chromatography are separated.
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| CN104447725A (en) * | 2014-10-22 | 2015-03-25 | 浙江大学 | Chiral compound comprising iminopyridyl oxazoline and preparation method thereof |
| CN105384731A (en) * | 2015-10-16 | 2016-03-09 | 浙江大学 | Chiral compound containing aminomethyl oxazoline pyridine and preparation method therefor |
| CN105601626A (en) * | 2015-11-04 | 2016-05-25 | 浙江大学 | Preparation method of 2-substituted oxazoline-containing derivative |
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| CN104447725A (en) * | 2014-10-22 | 2015-03-25 | 浙江大学 | Chiral compound comprising iminopyridyl oxazoline and preparation method thereof |
| CN105384731A (en) * | 2015-10-16 | 2016-03-09 | 浙江大学 | Chiral compound containing aminomethyl oxazoline pyridine and preparation method therefor |
| CN105601626A (en) * | 2015-11-04 | 2016-05-25 | 浙江大学 | Preparation method of 2-substituted oxazoline-containing derivative |
Non-Patent Citations (2)
| Title |
|---|
| HBF_4·SiO_2催化β-二羰基化合物的烯胺化反应以及NiCl_2（dppp）催化Suzuki-Miyaura偶联反应的研究;高焓;《中国博士学位论文全文数据库-工程科技Ⅰ辑》;20110915(第9期);第42页 |
| Ni催化的碳(sp~2)-碳和碳(sp~2)-杂交叉偶联反应;李哲，等;《有机化学》;20051225;第25卷(第12期);1508-1529 |
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