CN108997431A - The synthetic method and its application of bidentate phosphite ester ligand derived from terephthalyl alcohol - Google Patents

The synthetic method and its application of bidentate phosphite ester ligand derived from terephthalyl alcohol Download PDF

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CN108997431A
CN108997431A CN201811004359.0A CN201811004359A CN108997431A CN 108997431 A CN108997431 A CN 108997431A CN 201811004359 A CN201811004359 A CN 201811004359A CN 108997431 A CN108997431 A CN 108997431A
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ligand
reaction
phosphite ester
bidentate phosphite
synthetic method
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CN108997431B (en
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张攀科
赵洪良
王广柱
张亚娟
李文旗
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Zhengzhou University
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Abstract

The invention discloses a kind of synthetic method of bidentate phosphite ester ligand derived from terephthalyl alcohol and its application, the structural formula of the ligand is as follows:

Description

The synthetic method and its application of bidentate phosphite ester ligand derived from terephthalyl alcohol
Technical field
The invention belongs to technical field of organic synthesis, and in particular to bidentate phosphite ester derived from a kind of terephthalyl alcohol is matched Body and its synthetic method.The present invention is applied to ligand/palladium complex as catalyst in catalysis Suzuki-Miyaura reaction, Synthesize double compound aromatic bases.
Background technique
Constructing for C-C key plays a crucial role in organic synthesis.It is coupled from Suzuki-Miyaura in 1979 Since reaction (Tetrahedron Lett.1979,20,3437) discovery, just wide with substrate applicability due to it, functional group's appearance The advantages that bearing property is strong, by-product is few and easy removing becomes one of the most frequently used and most classic reaction in C-C coupling reaction.It is usually used in Polyene, styrene and connection benzene derivate are synthesized, to be applied in the synthesis of numerous natural products, organic material.
The ligand that design synthesis can form complex compound catalyst with metal realizes that efficient Suzuki-Miyaura reacts Key, the ligand being successfully applied in Suzuki-Miyaura reaction at present are concentrated mainly on monophosphorus ligand, containing n-donor ligand, N- card Guest's ligand etc. (Angew, Chem.Int.Ed.2002,41,4176), (Organometallics.2008,27,4380), (Adv.Synth.Catal.2004,346,595), but reaction generally requires a large amount of catalyst, and these ligands are quick to air Sense is easy failure.Have many advantages, such as to synthesize simple, insensitive to the air and water and close bidentate phosphite ester of metal-chelating Ligand is applied less in the reaction.At practical aspect, bidentate phosphite ester ligand is in asymmetric hydroformylation, asymmetric hydrogenation (Inorg.Chem., 1990,29,5006) is widely used in reaction, (Org.Lett., 2004,69,4031-4040), but palladium is urged Application of the bidentate phosphorous acid ester ligand of change in Suzuki-Miyaura reaction also rarely has people's report.This patent is exactly at this The synthetic method of bidentate phosphite ester ligand derived from terephthalyl alcohol is applied on the basis of sample and its in Suzuki- Application in Miyaura reaction.
Summary of the invention
Aiming at the problems existing in the prior art, the present invention provides bidentate phosphite ester derived from a kind of terephthalyl alcohol and matches The synthetic method of body and its application in Suzuki-Miyaura reaction, i.e. ligand and palladium salt are catalyzed Suzuki-Miyaura altogether Reaction constructs carbon-carbon bond.
In order to solve the above technical problems, the invention adopts the following technical scheme:
Bidentate phosphite ester ligand derived from terephthalyl alcohol of the invention, structural formula are as follows:
Wherein, R=H or t-Bu.
Work as R=H, bidentate phosphite ester ligand L1It indicates, structural formula is as follows:
Work as R=t-Bu, bidentate phosphite ester ligand L2It indicates, structural formula is as follows:
The synthetic method of the ligand, steps are as follows:
Under anhydrous and oxygen-free inert gas shielding, by 2,2 '-dihydroxybiphenyls or 3,3 ', 5,5 '-tetra-tert -2,2 ' - Dihydroxybiphenyl dissolves in organic solvent, and phosphorous acid is added dropwise, and after being added dropwise, P is added2O5(phosphorus pentoxide) is as dehydration Agent reacts 3-10 hour at 25-160 DEG C.Stop heating, after reaction system is cooled to room temperature, is added under nitrogen protection The pure and mild P of terephthaldehyde2O5, reaction temperature is 50-150 DEG C, and the reaction time is 3-10 hour.Concentrated liquid removes most of molten Agent, then it is recrystallized to give white solid bidentate phosphite ester ligand.The chemical equation of synthetic ligands is as follows:
Wherein R=H, t-Bu.
Above-mentioned reaction step is described as follows:
The molar ratio of 2,2 '-dihydroxybiphenyls or 3,3 ', 5,5 '-tetra-terts -2,2 '-dihydroxybiphenyl and phosphorous acid is 1:1-4, with first step P2O5Molar ratio be 1:1-3, with second step P2O5Molar ratio be 1:1-3, with rubbing for terephthalyl alcohol You than be 1-3:1, wherein organic solvent be benzene,toluene,xylene, methylene chloride, tetrahydrofuran, chloroform, pyridine, DMF or DMSO。
Ligand/palladium catalyst preparation process:
Under inert gas shielding, ligand and palladium salt stir in organic solvent and obtain ligand/palladium catalyst, the palladium salt For Pd (OAc)2、Pd(PPh3)2Cl2、PdCl2Or Pd2(dba), wherein dba is dibenzalacetone；The organic solvent is Methylene chloride, toluene, tetrahydrofuran, chloroform, pyridine, DMF or DMSO；The molar ratio of the palladium salt and ligand is 1:1-3；Instead Answering temperature is 25-100 DEG C；Reaction time 0.1-1h.
The catalyst of above-mentioned preparation can be used for being catalyzed the Suzuki-Miyaura coupling reaction of aryl bromide and aryl boric acid, It is described as follows:
Under inert gas shielding, aryl bromide, aryl boric acid, alkaline agent are sequentially added into ligand/palladium catalyst solution, TLC monitoring, to after reaction, be quenched, column chromatography for separation obtains product.Wherein ligand/copper catalyst: aryl bromide: aryl The molar ratio of boric acid is 1:20-30:30-40；The alkaline agent is sodium tert-butoxide, potassium carbonate, saleratus or triethylamine；The alkali The molar ratio of agent and aryl bromide is 1.4:1；25-140 DEG C of reaction temperature；Reaction time 2-12h.
Beneficial effects of the present invention: the present invention provides bidentate phosphite ester ligands derived from a kind of terephthalyl alcohol to be used for It is catalyzed the new application of Suzuki-Miyaura coupling reaction, reaction realizes high conversion under conditions of catalytic amount is seldom Rate, and substrate universality is wide.Ligand of the present invention has synthesis step simple, insensitive to air and water, tight with metal-chelating The advantages that close.
Specific embodiment
Combined with specific embodiments below, the present invention will be further described.It should be understood that following embodiment is merely to illustrate this The person skilled in the art of the range of invention and is not intended to limit the present invention, the field can make one according to the content of foregoing invention A little nonessential modifications and adaptations.
Embodiment 1: bidentate phosphite ester ligand L is prepared1:
To drying, 2,2'- dihydroxybiphenyl (186mg, 1mmol) is added in clean 50mL three-necked flask, is taken out with oil pump Vacuum simultaneously replaces N2Three times, in N2Protection is lower to be added 7mL dry toluene, phosphorous acid (123mg, 1.5mmol), P2O5(284mg, 2mmol), 6h is stirred under the conditions of 120 DEG C, is stopped heating, is cooled to room temperature to reaction solution in N2Protection is lower to be added terephthaldehyde Alcohol (88mg, 0.8mmol), P2O5(142mg, 1mmol), reaction temperature are 100 DEG C, and the reaction time is 8 hours, filtering, filtrate rotation It is dry to obtain product, 210mg white solid, yield 74% are obtained using recrystallization method.Mp:120-122℃；1H NMR(400MHz, CDCl3,SiMe4): δ 7.75 (d, J=2.5Hz, 4H), 7.35 (t, J=2.0Hz, 4H), 7.21 (d, J=2.2Hz, 4H) 7.02 (t, J=2.3Hz, 4H), 7.00 (d, J=2.5Hz, 4H), 5.00 (d, J=6.7Hz, 4H)；13C NMR(150MHz,CDCl3, SiMe4):δ156.41,138.42,131.73,129.18,127.36,127.24,121.92,116.18,63.34；31P NMR (243MHz,CDCl3,HPO4)δ130.18.HRMS(ESI+)calcd for C32H24O6P2[M+H]+:567.1048,found 567.1048.
Embodiment 2: bidentate phosphite ester ligand L is prepared2。
To drying, 3,3', 5,5'- tetra-tert -2,2'- dihydroxybiphenyls are added in clean 100mL three-necked flask (409mg, 1mmol), is vacuumized with oil pump and replaces N2Three times, in N2The lower addition 7mL dry toluene of protection, phosphorous acid (123mg, 1.5mmol), P2O5(284mg, 2mmol) stirs 6h under the conditions of 120 DEG C, stops heating, be cooled to room temperature to reaction solution in N2 Protection is lower to be added terephthalyl alcohol (88mg, 0.8mmol), P2O5(142mg, 1mmol), reaction temperature are 100 DEG C, the reaction time It is 8 hours, filtering, filtrate is spin-dried for obtaining product, obtains 403mg white solid, yield 79% using recrystallization method.Mp:124-127 ℃；1H NMR(400MHz,CDCl3,SiMe4): δ 7.71 (d, J=2.4Hz, 4H), 7.48 (d, J=2.0Hz, 4H), 7.41 (s, 4H), 4.99 (d, J=6.8Hz, 4H), 1.73 (s, 36H), 1.63 (s, 36H)；13C NMR(150MHz,CDCl3,SiMe4):δ 150.42,142.73,138.18,131.26,130.34,128.92,125.18,124.98,63.34,35.06,34.85, 31.61,31.33；31P NMR(243MHz,CDCl3,HPO4)δ134.18.HRMS(ESI+)calcd for C63H92O6P2[M+ H]+:1015.6056,found 1015.6056.
Application of the bidentate phosphite ester ligand/palladium in catalysis Suzuki-Miyaura coupling reaction
Optimum reaction condition screening:
1) using 4- methoxybromobenzene and phenyl boric acid as template reaction, ligand, palladium source, catalyst amount are sieved Choosing.
The conditional filtering of 1 palladium chtalyst 4- methoxybromobenzene of table and phenyl boric acid reaction[a]
[a] reaction condition: 4- methoxybromobenzene (0.5mmol), phenyl boric acid (1.0mmol), toluene (2.0mL), Pd/L= 1:1, K2CO3(0.7mmol), 110 DEG C of reaction temperature, reaction time 12h, in N2It is separation yield that [b] yield is reacted under atmosphere [c] reaction time for 24 hours
We select 4- methoxybromobenzene and phenyl boric acid as template reaction first, with Pd (OAc)2For metallic catalyst, It selects toluene as solvent, (embodiment 3-5) is screened to ligand, it can be seen that reacting in the case where no ligand is Do not occur, L in the presence of bidentate phosphite ester ligand2Yield highest, reach 83% (embodiment 5), it was demonstrated that Bidentate phosphite ester ligand has activity well in terms of being catalyzed Suzuki-Miyaura coupling reaction.Next to palladium source into It has gone screening (embodiment 5-8), has found Pd (dba)2Catalytic effect it is best.Pass through the amount (embodiment of change catalyst simultaneously It 9-11) demonstrates in the case where catalytic amount is seldom, catalyst still shows higher catalytic activity.
2) using 4- methoxybromobenzene and phenyl boric acid as template reaction, solvent, temperature and alkali are screened.
The conditional filtering of 2 palladium chtalyst 4- methoxybromobenzene of table and phenyl boric acid reaction[a]
[a] reaction condition: 4- methoxybromobenzene (0.5mmol), phenyl boric acid (1.0mmol), solvent (2.0mL), Pd/L= 1:1, catalyst 2mol%, alkali (0.7mmol), reaction time 12h, in N2It is separation yield [c] that [b] yield is reacted under atmosphere Reaction time for 24 hours
Next we are with L2As ligand with Pd (dba)2The influence of solvent, alkali and temperature to reaction has been probed into for palladium source (table 2) is selected different solvents (embodiment 13-17) at a reflux temperature, and discovery toluene is optimum solvent.When reaction is used instead NaOH、KHCO3、NaOtBu、NEt3When (embodiment 18-21), find effect without K2CO3It is good.Change reaction temperature (embodiment 21-24), yield also can accordingly change, and reaction is not reacted substantially at normal temperature, even if after attempting to extend the reaction time.Work as liter Yield increases when high-temperature, and when temperature reaches reflux temperature, yield reaches 89%, it is thus determined that reaction temperature is 110 ℃。
By the screening to 4- methoxybromobenzene and phenyl boric acid reaction condition, we select optimum reaction condition i.e.: in nitrogen Under atmosphere is enclosed, 110 DEG C, with Pd (dba)2(2mol%)/L2(2mol%) is used as catalyst, 1.4 equivalent K2CO3As alkali, in first Suzuki-Miyaura coupling reaction is catalyzed in benzene solvent, bromobenzene and phenyl boric acid to different structure, which have been done, expands (table 3)
Chemical formula Pd (dba)2/L2It is catalyzed the Suzuki-Miyaura coupling reaction of different substrates
Table 3Pd (dba)2/L2It is catalyzed the Suzuki-Miyaura coupling reaction result of different substrates
Reaction condition: aryl bromide (0.5mmol), aryl boric acid (1.0mmol), toluene (2.0mL), Pd (dba)2 (2mol%), L ligand (2mol%), K2CO3(0.7mmol), reaction time 12h, in N2It is reacted under atmosphere.Yield is that separation is received Rate.
From the point of view of reaction result, we select catalyst system for aryl bromide and aryl boric acid Suzuki- When Miyaura coupling reaction, whole catalytic effect is all fine, and yield is mostly all 80% or more.And the catalyst system is being urged Aryl bromide and aryl boric acid in the case where agent amount very bottom for 4 containing donor residues or electron-withdrawing group have urges well Change effect.And wide application range of substrates, also have to certain heterocyclic arenes such as 2- bromopyridine or 2- thienyl boric acid etc. and preferably urges Change effect
Therefore by above embodiment show bidentate phosphite ester ligands derived from terephthalyl alcohol to catalysis Suzuki- Miyaura coupling reaction has good activity and regioselectivity, and substrate universality is strong.
Basic principles and main features and advantages of the present invention of the invention have been shown and described above.The skill of the industry Art personnel it should be appreciated that the present invention is not limited to the above embodiments, the above embodiments and description only describe The principle of the present invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these Changes and improvements all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and Its equivalent thereof.

Claims (10)

1. bidentate phosphite ester ligand derived from a kind of terephthalyl alcohol, structural formula are as follows:
Wherein, R=H or t-Bu.
2. the synthetic method of ligand according to claim 1, which is characterized in that steps are as follows: in anhydrous and oxygen-free indifferent gas Under body protection, by 2,2 '-dihydroxybiphenyls or 3,3 ', 5,5 '-tetra-tert -2,2 '-dihydroxybiphenyls are dissolved in organic solvent In, phosphorous acid is added dropwise, is eventually adding P2O5As dehydrating agent, at 25-160 DEG C, 1-10 hour is reacted；Stop heating, instead After answering system to be cooled to room temperature, the pure and mild P of terephthaldehyde is added under nitrogen protection2O5, it is warming up to 50-150 DEG C of reaction 3-10h；It is dense Contracting liquid removes most of solvent, then being recrystallized to give white solid is bidentate phosphite ester ligand.
3. the synthetic method of ligand according to claim 2, it is characterised in that: described 2,2 '-dihydroxybiphenyls or 3,3 ', The molar ratio of 5,5 '-tetra-terts -2,2 '-dihydroxybiphenyl and phosphorous acid is 1:1-4.
4. the synthetic method of ligand according to claim 2, it is characterised in that: the P being added for the first time2O5With 2,2 '-dihydroxies Base biphenyl or 3,3 ', 5,5 '-tetra-tert -2, the molar ratio of 2 '-dihydroxybiphenyls are 1-3:1, second of P being added2O5With 2, 2 '-dihydroxybiphenyls or 3,3 ', 5,5 '-tetra-terts -2,2 '-dihydroxybiphenyl molar ratio are 1-3:1.
5. the synthetic method of ligand according to claim 2, it is characterised in that: described 2,2 '-dihydroxybiphenyls or 3,3 ', The molar ratio of 5,5 '-tetra-terts -2,2 '-dihydroxybiphenyl and terephthalyl alcohol is 1-3:1.
6. the synthetic method of ligand according to claim 2, it is characterised in that: the organic solvent is benzene, toluene, diformazan Benzene, methylene chloride, tetrahydrofuran, chloroform, pyridine, DMF or DMSO.
7. application of the bidentate phosphite ester ligand described in claim 1 in palladium chtalyst Suzuki-Miyaura reaction.
8. the application of bidentate phosphite ester ligand according to claim 7, it is characterised in that:, will under inert gas shielding Bidentate phosphite ester ligand first reacts to obtain ligand/palladium catalyst in organic solvent with palladium salt, and the palladium salt is Pd (OAc)2、 PdCl2Or Pd2(dba), wherein dba is dibenzalacetone；The organic solvent be methylene chloride, toluene, tetrahydrofuran, Chloroform, pyridine, DMF or DMSO；The molar ratio of the palladium salt and ligand is 1:1-3；Reaction temperature is 25-100 DEG C；When reaction Between 0.1-1h.
9. the application of bidentate phosphite ester ligand according to claim 8, it is characterised in that:, should under inert gas shielding Catalyst is for being catalyzed Suzuki-Miyaura reaction；Aryl bromide, aryl are sequentially added into ligand/palladium catalyst solution Boric acid, alkaline agent, TLC monitoring, to after reaction, be quenched, column chromatography for separation obtains product.
10. the application of bidentate phosphite ester ligand according to claim 9, it is characterised in that: ligand/palladium catalyst: bromine For aromatic hydrocarbons: the molar ratio of aryl boric acid is 1:(20-30): (30-40)；The alkaline agent is sodium tert-butoxide, potassium carbonate, saleratus Or triethylamine；The molar ratio of the alkaline agent and aryl bromide is 1.4:1；25-140 DEG C of reaction temperature；Reaction time 2-12h.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103990495A (en) * 2014-04-24 2014-08-20 上海华谊（集团）公司 Olefin hydroformylation catalyst
CN105801625A (en) * 2016-05-30 2016-07-27 郑州大学 Preparation method of novel bidentate phosphite ligand and application thereof in Buchwald-Hartwig reaction
JP2016155065A (en) * 2015-02-24 2016-09-01 三菱化学株式会社 Catalyst composition

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103990495A (en) * 2014-04-24 2014-08-20 上海华谊（集团）公司 Olefin hydroformylation catalyst
JP2016155065A (en) * 2015-02-24 2016-09-01 三菱化学株式会社 Catalyst composition
CN105801625A (en) * 2016-05-30 2016-07-27 郑州大学 Preparation method of novel bidentate phosphite ligand and application thereof in Buchwald-Hartwig reaction

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