CN102872915A - Iron catalyst system for preparation of pyridine derivatives and its application - Google Patents
Iron catalyst system for preparation of pyridine derivatives and its application Download PDFInfo
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- CN102872915A CN102872915A CN2011101975880A CN201110197588A CN102872915A CN 102872915 A CN102872915 A CN 102872915A CN 2011101975880 A CN2011101975880 A CN 2011101975880A CN 201110197588 A CN201110197588 A CN 201110197588A CN 102872915 A CN102872915 A CN 102872915A
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Abstract
The invention provides an iron catalyst system for preparation of pyridine derivatives and its application. The catalyst is composed of a cheap and easily available iron salt, a diphosphine ligand and a reducing agent. Application of the catalyst in synthesis of pyridine derivatives can be carried out under the conditions that: a substrate diyne or monoyne and the catalyst are in a molar ratio of 20-1:1, and the diyne or monoyne and nitrile are in a molar ratio of 1:1-40; the temperature is maintained in a range from room temperature to 100DEG C; tetrahydrofuran, 1, 4-dioxane or the reactant nitrile is adopted as the solvent; the reaction time is 6-48h. The iron catalyst can well catalyze a [2+2+2] cycloaddition reaction of the diyne or monoyne and the nitrile so as to obtain various pyridine derivatives. The iron catalyst system provided in the invention has the advantages of high reaction activity, complete reaction, single product, simple and practical operation, easily available raw materials as well as high yield, and has the characteristics of green atom economy and environment friendliness.
Description
Technical field
The present invention relates to a kind of iron catalyst for preparing pyridine derivate, and be applied to pyridine synthesis derivative in [2+2+2] cycloaddition reaction of diine or single alkynes and nitrile.
Background technology
Pyridine and its derivatives is widely used as organic synthesis reagent, or as medicine, agricultural chemicals and the synthetic intermediate [document: Jones of various types of materials production, G.Comprehensive Heterocyclic Chemistry II, Vol.5 (Eds.:Katritzky, A.R.; Rees, C.W.; Scriven, E.F.V.; McKillop, A.), Pergamon, Oxford, 1996, pp.167-243; Joule, J.A.; Mills, K.Heterocyclic Chemistry, 4th ed., Blackwell Science, Cambridge, 2000; P.63-120; Michael, J.P.Nat.Prod.Rep.2005,22,627-646.].Some natural products are reset derivative Diploclidine such as cholestane, alkaloid Nakinadine A, medicine such as anti-medicine for treating AIDS Atazanavir that success is gone on the market, anticarcinogen Gleevec, blood glucose-control medicine Pioglitazone contains pyridine unit (formula 1) in these materials.And in vitro organic reagent particularly metal ligand and the life in used all kinds of macromolecular materials, pyridine unit also is indispensable part, so the study on the synthesis of pyridine compounds is had great importance.
The pyridine synthesis derivative, except can be by functionalized introducing substituting group on the pyridine ring, the direct construction pyridine ring also be a kind of method commonly used.These methods resolve into different fragments with pyridine ring and are made up (formula 2) again, thereby the synthetic method [documents: Henry such as [5+1], [4+2], [3+3], [3+2+1], [2+2+2], [2+2+1+1] have just been arranged, G.D.Tetrahedron 2004,60, and 6043; Hill, M.D.Chem.Eur.J.2010,16,12052].But most method is under acidity or alkali condition condensation reaction to occur, need to consume acid or the alkali of equivalent, it is many to produce easily a large amount of inorganic salts and accessory substance, can bring the waste of the energy and the pollution of environment, so development environment synthetic method friendly, atom economy has great significance.[2+2+2] cycloaddition reaction has been divided into three diatomic fragments with pyridine ring, and its atom utilization is up to 100%.The characteristics of its maximum be can one the step make up simultaneously two C-C keys and a C-N key and not produce discarded object, meet the requirement of Green Development.Three fragments that mark off can have respectively different substituting groups, can obtain polysubstituted pyridine after the Cheng Huan, but also therefore wayward product regioselectivity, and the temperature of reaction is higher.
In recent years, the development of all kinds of transition metal-catalyzed systems improved widely this class reaction activity and selectivity [document:
H.Angew.Chem.Int.Ed.Engl.1985,24,248; Varela, J.A.; Sa á, C.Chem.Rev.2003,103,3787; Chopade, P.R.; Louie, J.Adv.Synth.Catal.2006,348,2307; Heller, B.; Hapke, M.Chem.Soc.Rev.2007,36,1085; Varela, J.A.; Sa á, C.Synlett 2008,2571.].In all kinds of catalyst system and catalyzings, typical representative has the CpCo catalyst system and catalyzing of Sa á group and the development of Vollhardt group, the rhodium of Tanaka group development/pair phosphine system, the Cp*Ru catalyst system and catalyzing that Yamamoto group and Sa á group develop respectively, the Zr/Ni bimetallic system of Takahashi group development, the Ti (O of the nickel of Louie group development/Cabbeen system and the development of Urabe group
iPr)
4/
iThe PrMgCl system, these systems were all done the research of relative system, had obtained good result.Yet,, nontoxic cheapness abundant for this source of iron, eco-friendly metal, the development of its catalyst system and catalyzing is very slow [document: Ferr é, K. but; Toupet, L.; Guerchais, V.Organometallics, 2002,21,2578; Schmidt, U.; Zenneck, U.J.Organomet.Chem.1992,440,187; Knoch, F.; Kremer, F.; Schmidt, U.; Zenneck, U.; Floch, P.L.; Mathey, F.Organometallics, 1996,15,2713.], only reported two examples by Zenneck and these two groups of Guerchais, and employed catalyst iron-phosphine hetero-aromatic ring complex and Cp
*Fe
+ 1(CH
3CN)
3Complex also is difficult for making, and has greatly limited the application of iron catalyst system and catalyzing in pyridine compounds is synthetic.
Summary of the invention
The purpose of this invention is to provide a kind of iron catalyst system for preparing pyridine derivate, and be applied to pyridine synthesis derivative in [2+2+2] cycloaddition reaction of diine or single alkynes.
To achieve these goals, the technical solution used in the present invention:
In the formula: R
1, R
2Be H, Me, Et, Ph or TMS; R
3, R
6Be CH
3(CH
2)
n-(n=0～6), iPr, tBu, Bn, Ph, 2-MeC
6H
4, 1-naphthyl etc.; Z is C (CO
2R), NTs, O ,-(CH
2)
n-(R=Me or Et, n=1～4); R
4, R
5Be H, Me, nPr, Et, Ph or TMS.
Iron catalyst is by molysite, biphosphine ligand, reducing agent and solvent composition.The metal precursor of iron is FeCl
3, FeBr
3, FeBr
2Or FeI
2Biphosphine ligand is 1, two (diphenylphosphine) propane of 3-(are called for short: dppp) or 1, two (diphenylphosphine) ethane of 2-(are called for short: dppe), reducing agent is EtMgBr, Zn, Mn or n-BuLi, the mol ratio of metal precursor and part is 1: 1～3, and the mol ratio of metal precursor and reducing agent is 1: 0.5～2.Organic solvent be oxolane or Isosorbide-5-Nitrae-dioxane or directly with the reactant nitrile as solvent, reactant diine or the concentration of single alkynes in this solution are 0.1～1mol/L.The mol ratio of diine or single alkynes and molysite is 20～1: 1, and the mol ratio of diine or single alkynes and nitrile is 1: 1～40; Reaction temperature: room temperature～100 ℃, reaction time: 6～48 hours.
The pyridine derivate that obtains, its productive rate is 43～98%.
By the pyridine derivate 5 and 6 that the reaction of single alkynes and nitrile obtains, total recovery is 40～80%, both ratios 5: 6 〉=9: 1.
The present invention has the following advantages:
1. reactivity is high, reacts completely, and the product of generation is single-minded.Raw material is easy to get, and productive rate is high, and has the characteristics such as green Atom economy, environmental friendliness.
2. can obtain various types of pyridine derivates, such as 2,3,4,5,6-, five substituted pyridines, 2,3,4,5-substituted pyridyl, 2,4,5-, three substituted pyridines and 2,3,6-, three substituted pyridines.Substituting group on the pyridine is varied, comprises the substituting groups such as alkyl, aryl.
3. catalyst is easy to prepare, and is cheap and easy to get, and operation is simple and practical.
4. reaction condition is gentle, at room temperature can react, and the consumption of catalyst is lower.
The specific embodiment:
Below by example in detail the present invention is described in detail, but the present invention is not limited to following example.
Example 1: the preparation of iron catalyst and screening
In reaction bulb, add ferrous metal precursor (0.05mmol) and biphosphine ligand (0.10mmol), add 1mL oxolane, stirring at room 0.5 hour after the argon replaces.Then add and add again diine 1a (0.25mmol) and nitrile 2a (2.5mmol) after reducing agent Zn (0.10mmol) stirs, react 24h under the room temperature.Desolventizing after reaction finishes, directly column chromatography for separation obtains pure product, confirms its structure by nuclear-magnetism, reaction equation and ligand structure as shown in Equation 4:
Conversion ratio and productive rate are determined (internal standard method) by gas-chromatography, and partial results is listed in table 1:
The screening of table 1. iron catalyst
Example 2: [2+2+2] cycloaddition reaction pyridine synthesis derivative of iron catalysis diine and nitrile
In reaction bulb, add FeI
2(0.05mmol) and dppp (0.10mmol), add 2mL oxolane, stirring at room 0.5 hour after the argon replaces.Then add reducing agent Zn (0.10mmol), diine 1 (0.5mmol) and nitrile 2 (2.5mmol), 24h is stirred in reaction under the room temperature.Desolventizing after reaction finishes, directly column chromatography for separation obtains pure product 3, confirms its structure by nuclear-magnetism, the productive rate of reaction equation and portion of product as shown in Equation 5:
The portion of product nuclear magnetic data is as follows:
3a：
1H?NMR(400MHz，Acetone)δ7.57-7.30(m，5H)，3.76(s，6H)，3.62(s，2H)，3.61(s，2H)，2.40(s，3H)，2.23(s，3H)；
13C?NMR(100MHz，Acetone)δ172.4，157.2，151.0，150.3，141.9，133.3，130.1，128.6，128.2，124.8，60.1，53.4，40.5，39.5，21.9，16.3.
3e：
1H?NMR(400MHz，Acetone)δ7.23(m，4H)，7.14(m，1H)，4.11(s，2H)，3.72(s，6H)，3.55(s，2H)，3.52(s，2H)，2.37(s，3H)，2.14(s，3H)；
13C?NMR(100MHz，CDCl
3)δ172.4，157.3，150.6，149.8，140.9，132.7，129.4，129.0，126.7，125.5，60.0，53.3，42.1，40.3，39.4，21.8，14.9
3j：
1H?NMR(400MHz，CDCl
3)δ6.46(d，J＝11.5Hz，1H)，5.94(dq，J＝12.0，7.0Hz，1H)，3.77(s，6H)，3.56(s，2H)，3.54(s，2H)，2.42(s，3H)，2.14(s，3H)，1.82(d，J＝7.0Hz，3H)；
13C?NMR(100MHz，CDCl
3)δ172.1，153.7，150.0，148.5，131.7，130.7，127.7，124.9，59.5，53.3，40.1，39.3，22.0，15.0，14.9.
3m：
1H?NMR(400MHz，Acetone)δ7.44-7.36(m，3H)，7.34-7.32(m，2H)，3.75(s，6H)，3.71(s，2H)，3.57(s，2H)，2.85(s，3H)，2.41(s，3H)，0.02(s，9H)；
13C?NMR(100MHz，Acetone)δ172.2，164.7，156.9，153.6，145.8，132.5，130.2，128.5，128.4，126.1，60.4，53.4，43.3，38.1，22.0，1.4.
Example 3: [2+2+2] cycloaddition reaction pyridine synthesis derivative of the single alkynes of iron catalysis and nitrile
In reaction bulb, add FeI
2(0.05mmol) and dppp (0.10mmol), add 2mL oxolane, stirring at room 0.5 hour after the argon replaces.Then add reducing agent Zn (0.10mmol), single alkynes 4 (1mmol) and nitrile 2 (2.5mmol), 24h is stirred in reaction under the room temperature.Desolventizing after reaction finishes, directly column chromatography for separation obtains pure product 5 and 6, confirms its structure by nuclear-magnetism, the productive rate of reaction equation and portion of product as shown in Equation 6:
The part of compounds nuclear magnetic data is as follows:
5：
1H?NMR(500MHz，Acetone)δ8.18(dt，J＝8.3，1.7Hz，2H)，7.83(d，J＝7.9Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.53-7.47(m，4H)，7.47-7.40(m，4H)，2.54(s，3H)；
13C?NMR(125MHz，Acetone)δ156.1，155.8，140.9，140.1，138.9，136.3，129.9，129.7，129.5，129.3，128.3，127.5，118.2，23.9.
6：
1H?NMR(500MHz，Acetone)δ8.76(d，J＝2.3Hz，1H)，7.81(d，J＝2.3Hz，1H)，7.76-7.71(m，2H)，7.55-7.45(m，6H)，7.45-7.37(m，2H)，2.49(s，3H)；
13C?NMR(125MHz，Acetone)δ155.4，146.9，140.9，138.6，137.5，135.8，134.7，129.99，129.96，129.4，128.7，128.4，127.8，23.3.
Claims (4)
1. iron catalyst system for preparing pyridine derivate, it is organic solvent system, its preparation process is: add molysite and biphosphine ligand in organic solvent, then add reducing agent, stir and get final product;
The metal precursor of iron is FeCl
3, FeBr
3, FeBr
2Or FeI
2Biphosphine ligand is 1, two (diphenylphosphine) propane of 3-(are called for short: dppp) or 1, two (diphenylphosphine) ethane of 2-(are called for short: dppe), reducing agent is EtMgBr, Zn, Mn or n-BuLi, the mol ratio of metal precursor and part is 1: 1～3, and the mol ratio of metal precursor and reducing agent is 1: 0.5～2.
2. according to iron catalyst system claimed in claim 1, it is characterized in that: organic solvent be oxolane or Isosorbide-5-Nitrae-dioxane or directly with the reactant nitrile as solvent, reactant diine or the concentration of single alkynes in this solution are 0.1～1mol/L.
3. according to iron catalyst system claimed in claim 1, it is characterized in that: in organic solvent, stirred 0.5～2 hour behind the metal precursor of adding iron and the biphosphine ligand, then add reducing agent.
4. the application of an iron catalyst system claimed in claim 1 is characterized in that:
Iron catalyst system claimed in claim 1 can be used for [2+2+2] cycloaddition reaction pyridine synthesis derivative of diine or single alkynes and nitrile, and reaction equation is as follows:
In the formula: R
1, R
2Be H, Me, Et, Ph or TMS; R
3, R
6Be CH
3(CH
2)
n-(n=0～6), iPr, tBu, Bn, Ph, 2-MeC
6H
4, or 1-naphthyl; Z is C (CO
2R), NTs, O ,-(CH
2)
n-(R=Me or Et, n=1～4); R
4, R
5Be H, Me, Et, nPr, Ph or TMS;
Reaction condition is as follows:
Iron catalyst is the catalyst described in the claim 1, and the mol ratio of diine or single alkynes and molysite is 20～1: 1, and the mol ratio of diine or single alkynes and nitrile is 1: 1～40; Reaction temperature: room temperature～100 ℃, reaction time: 6～48 hours.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382153A (en) * | 2013-07-09 | 2013-11-06 | 安徽师范大学 | Norbornene addition polymerization derivative and its preparation method |
| CN106866673A (en) * | 2015-12-10 | 2017-06-20 | 中国科学院大连化学物理研究所 | A kind of method for preparing azepine heptatomic ring derivative |
-
2011
- 2011-07-14 CN CN2011101975880A patent/CN102872915A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| CHUNXIANG WANG ET AL.: "A Simple and Highly Efficient Iron Catalyst for a [2+2+2] Cycloaddition to Form Pyridines", 《COMMUNICATIONS》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103382153A (en) * | 2013-07-09 | 2013-11-06 | 安徽师范大学 | Norbornene addition polymerization derivative and its preparation method |
| CN103382153B (en) * | 2013-07-09 | 2015-01-07 | 安徽师范大学 | Norbornene addition polymerization derivative and its preparation method |
| CN106866673A (en) * | 2015-12-10 | 2017-06-20 | 中国科学院大连化学物理研究所 | A kind of method for preparing azepine heptatomic ring derivative |
| CN106866673B (en) * | 2015-12-10 | 2018-09-25 | 中国科学院大连化学物理研究所 | A method of preparing azepine heptatomic ring derivative |
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Application publication date: 20130116 |