WO2017193288A1 - Synthèse de ligands de phosphine portant une liaison réglable : procédés pour leur utilisation dans une catalyse - Google Patents

Synthèse de ligands de phosphine portant une liaison réglable : procédés pour leur utilisation dans une catalyse Download PDF

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WO2017193288A1
WO2017193288A1 PCT/CN2016/081589 CN2016081589W WO2017193288A1 WO 2017193288 A1 WO2017193288 A1 WO 2017193288A1 CN 2016081589 W CN2016081589 W CN 2016081589W WO 2017193288 A1 WO2017193288 A1 WO 2017193288A1
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Fuk Yee Kwong
Pui Ying CHOY
Yinuo WU
Qingjing Yang
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Shenzhen Research Institute HKPU
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    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2442—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems
    • B01J31/2447—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • B01J2231/4227—Suzuki-type, i.e. RY + R'B(OR)2, in which R, R' are optionally substituted alkyl, alkenyl, aryl, acyl and Y is the leaving group with Y= Cl
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Definitions

  • the present invention relates to a series of novel linked indolyl phosphine ligands for transition metals, the synthesis thereof and their use in catalytic reactions.
  • the disclosed method provides improvements of transition-metal-catalyzed reactions, including the range of substrates scope, reaction conditions, and efficiency. For examples, remarkable improvements have been realized in the preparation of sterically hindered biaryl compounds by transition-metal-catalyzed cross-coupling reactions.
  • Transition-metal-catalyzed cross-coupling reactions have received significant attention and became an extremely versatile protocol in organic synthesis for the connection of two different fragments via the formation of either carbon-carbon and/or carbon-heteroatom bonds (de Meijere, A. ; Brase, S. ; Oestreich, M. Eds. Metal-Catalyzed Cross-Coupling Reactions, Vol. 3: Wiley-VCH, Weinheim, 2013. Colacot, T.J. Eds. New Trends in Cross-Coupling, Theory and Applications: Royal Society of Chemistry, Cambridge, 2015) .
  • Suzuki-Miyaura coupling is one of the preeminent methods of the formation of carbon-carbon bonds and has been used in the construction of diversified biaryls, and they have a myriad of applications in pharmaceutical, materials, and agricultural chemistry (Miyaura, N. Topics in Current Chemistry, 2002, 219, 11) .
  • Arylamines are frequently encountered in natural and pharmaceutical products.
  • Buchwald-Hartwig amination is a highly valuable method for the formation of carbon-nitrogen bond (Ricci, A Ed Modern Amination Methods: Wiley-VCH, Weinheim, 2000) .
  • ligands play essential roles during each step of the catalytic cycle including oxidative addition, transmetallation, and reductive elimination.
  • the structural features of the ligands can greatly influence the reaction rate, regioselectivity, and stereoselectivity of the cross-coupling reaction.
  • the strategic design of ligands with appropriate steric/electronic natures and great diversity is crucial in dealing with challenging and problematic substrates in this area.
  • sterically hindered substrates and a further decrease of the catalyst loading remain great challenges.
  • the present invention relates to a series of novel and efficient linked indolyl phosphine ligands for transition metals, to their preparation and to their use in catalytic reactions.
  • the disclosed method provides improvements of transition-metal-catalyzed reactions, including the range of substrates scope, reaction conditions, and efficiency.
  • the linked indolyl phosphine ligands several reactions can be effectively handled such as Suzuki-Miyaura, Heck, Sonogashira, Hiyama, Stille cross-coupling reactions; Buchwald-Hartwig amination; direct arylation; and cyanation with aryl halides or vinyl halides.
  • the basic indolyl phosphines bearing tunable linkage can be prepared via traditional Fischer Indolization protocol.
  • a combination of phenylhydrazines and acetophenones provides a high diversification of the ligand structure.
  • the ligands are suitable to use as scaffolds in metal-ligand complexes, which can serve as catalysts for further reactions.
  • the ligands can be prepared in a large scale, and purified by simple recrystallization. These ligands can exhibit exceptionally high stability in both solid and solution states.
  • the present invention relates to indolyl phosphine ligands bearing tunable linkage, and methods of making such utilizing phenylhydrazine and acetophenones as the starting materials with various linkage reagents.
  • the present invention further includes uses of the ligands in the synthesis of pharmaceuticals, materials, and agriculture.
  • the present invention is achieved according to the novel phosphine ligands structure formula (I) , below:
  • Y independently represents an oxygen atom or C-R 8 group or NR 8 group and R 1 for each of the two R 1 groups independently of the other represents C 1 -C 8 -alkyl; C 3 -C 10 -cycloalkyl, which includes especially both monocyclic and also bi-and tri-cyclic cycloalkyl; (5-to 11-membered) heterocycloalkyl; CF 3 ; ferrocenyl; C 5 -C 20 -aryl, which includes especially the phenyl, naphthyl, fluorenyl; (5-to 11-membered) heteroaryl, wherein the number of hetero atoms, selected from the group N, O, S, may be from 1 to 2; wherein the two R 1 may also be linked to one another; or wherein each such C 3 -C 10 -cycloalkyl, (5-to 11-membered) heterocycloalkyl, C 6 -C 20 -aryl or (5-to 11-membered
  • substituents independently of one another, may be hydrogen, C 1 -C 20 -alkyl, C 2 -C 20 -alkenyl, C 3 -C 8 -cycloalkyl, C 2 -C 9 -heteroalkyl, C 5 -C 10 -aryl, C 2 -C 9 -heteroaryl, wherein the number of heteroatoms, especially from the group N, O, S, may be from 1 to 4; C 1 -C 14 -alkoxy, preferably -O (C 1 -C 6 ) alkyl, particularly preferably OMe; C 1 -C 10 -halo-alkyl, preferably CF 3 , hydroxyl, secondary, tertiary amino groups; wherein two of the mentioned substituents may also bridged with one another to form 4-to 8-membered ring which can be further substituted preferably by linear or branched C 1 -C 10 -alkyl, C 6 -aryl, benzyl
  • R 2 , R 3 , R 4 , and R 5 are each independently selected from the group comprising hydrogen; halogen; C 1 -C 10 -alkyl; hydroxyl; -O (C 1 -C 6 ) alkyl; CF 3 ; C 3 -C 10 -cycloalkyl; (5-to 11-membered) heterocycloalkyl; amino; silyloxy; sulfhydryl; alkylthio; thioalkyl; phosphoryl; phosphonate; phosphine; urea; thiourea; nitrile; carbonyl; carboxyl; carboxamide; C 6 -C 20 -aryl; (5-to 11-membered) heteroaryl, wherein the number of hetero atoms, selected from the group N, O, S, may be from 1 to 2; wherein any two or more adjacent instances of R 2 , R 3 , R 4 , and R 5 , taken together with the carbons to which they are
  • R 9 , R 10 , R 11 , and R 12 are each independently selected from the group comprising hydrogen; halogen; C 1 -C 10 -alkyl; hydroxyl; –O (C 1 -C 6 ) alkyl; CF 3 ; C 3 -C 10 -cycloalkyl; (5-to 11-membered) heterocycloalkyl; amino; silyloxy; sulfhydryl; alkylthio; thioalkyl; phosphoryl; phosphonate; phosphine; urea; thiourea; nitrile; carbonyl; carboxyl; carboxamide; C 6 -C 20 -aryl; (5-to 11-membered) heteroaryl, wherein the number of hetero atoms, selected from the group N, O, S, may be from 1 to 2; wherein any two or more adjacent instances of R 9 , R 10 , R 11 , and R 12 , taken together with the carbons to which they are
  • n is independently for each occurrence an integer in the range 1 to 8 inclusive, and the ligand is achiral or, when chiral, is a single stereoisomer or a mixture of stereoisomers.
  • the invention relates to formula (I) , wherein one of the R 1 is C 1 -C 8 -alkyl selected from –CH 3 , –CH 2 CH 3 , –C (CH 2 ) 2 CH 3 , –CH (CH 3 ) 2 , –C (CH 3 ) 3 , – C (CH 2 CH 3 ) 3 , –C (CH 2 CH 3 ) (CH 3 ) 2 , and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined in the first aspect.
  • the invention relates to formula (I) , wherein one of the R 1 is C 3 -C 10 -cycloalkyl, which includes especially both monocyclic and also bi-and tri-cyclic cycloalkyl, selected from cyclopentyl, cyclohexyl, 1-adamantyl, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined in the first aspect.
  • the invention relates to formula (I) , wherein one of the R 1 is C 6 -C 20 -aryl selected from phenyl, 2-methylphenyl, 4-methylphenyl, 3, 5-dimethylphenyl, 3, 5-di (fluoromethyl) phenyl, 3, 5-di-tert-butylphenyl, 4-methoxyphenyl, 2-trifluoromethylphenyl, 2, 4, 6-trimethylphenyl, 3, 5-di-tert-butyl-4-methoxyphenyl, and naphthyl, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are as defined in the first aspect.
  • the present invention provides a process for the preparation of the above-described ligands of formula (I) .
  • the ligands can be prepared by traditional Fischer Indolization followed the general reaction scheme 1 below.
  • the novel phosphine ligands bearing tunable linkage are used as catalysts in combination with transition metal complexes.
  • the transition metal compounds used are particularly preferably palladium compounds.
  • the ligands according to the invention can generally be added in situ to corresponding transition metal precursor compounds and accordingly used for catalytic applications. However, it may occasionally be advantages for specific phosphine complexes of the mentioned transition metals to be prepared first and subsequently used as catalyst to increase the catalytic activity.
  • the phosphine ligands bearing tunable linkage prepared in accordance with the invention have proved suitable especially as the ligand component for the biaryl synthesis from aryl halides or vinyl halides.
  • catalyst compositions contain a ligand described herein and a transition metal compound.
  • transition metal compounds include those of palladium, rhodium, ruthenium, platinum, gold, cobalt, iridium, copper, and nickel, as well as combinations.
  • the transition metal compound and the ligand are provided in the catalyst composition in stoichiometric amounts with respect to one other.
  • the optimum ligand to metal ratio depends on the metal source used as well as the specifics of the transformation being attempted.
  • the transition metal compound is provided in the catalyst composition as a salt of a central atom.
  • a non-limiting example of such a salt is an acetate salt.
  • a preferred transition metal compound is palladium acetate, or Pd (OAc) 2 .
  • a catalyst composition is then formed of a mixture of palladium acetate and a ligand compound coordinated as a complex as described herein.
  • Other embodiments of palladium sources formally in the 2+ oxidation state include but are not limited to PdCl 2 , Pd (TFA) 2 , Pd (CH 3 CN) 4 (BF 4 ) 2 and PdCl 2 (CH 3 CN) 2 .
  • the transition metal compound is in zero valence state.
  • An example is tris (dibenzylideneacetone) dipalladium (0) , commonly abbreviated as Pd 2 (dba) 3 .
  • Other palladium sources in formally the zero or other valence states may also be suitable. Examples include but are not limited to Pd (dba) 2 .
  • the ligands described herein exhibit utility in transition metal catalyzed reactions.
  • the disclosed ligands may be combined with a variety of transition metal compounds to catalyze a range of chemical transformations.
  • compositions containing a transition metal compound and a disclosed ligand can be used to catalyze a variety of organic reactions.
  • a non-limiting example of a reaction catalyzed by a disclosed ligand is given in Scheme I, illustrating the catalysis of a C-N reaction.
  • Other reactions of interest include carbon-oxygen, carbon-carbon.
  • the catalysts can be used to catalyze Suzuki-Miyaura type C-C bond-forming reactions, Buchwald-Hartwig Amination C-N bond forming reactions, direct arylation C-C bond forming reactions, and Hiyama type C-C bond forming reactions.
  • a combination of a ligand with a transition metal compound catalyzes the following reactions:
  • the present invention provides a process for the preparation of the above-described ligands.
  • These ligands may be prepared in the manner depicted in the general reaction Scheme 1.
  • Method A follows the general procedures of Fischer-indole synthesis, compound II can be obtained from corresponding substituted acetophenone (100 mmol) , corresponding substituted phenylhydrazine (110 mmol) and polyphosphoric acid (PPA) as an off-white solid.
  • Compound II from Method A may be made in the manner described by Kwong, Organic Syntheses 2016, 93, 14-28.
  • Method B According to the literature, compound II can be obtained from corresponding substituted oxindole (50 mmol) , 2-chloropyridine (60 mmol) , trifluoromethanesulfonic anhydride (60 mmol) and corresponding substituted 2-naphthol (50 mmol) as a grey solid.
  • Compound II from Method B may be made in the manner described by Ghandi, Tetrahedron Letters 2011, 270-273; and Shibata, Organic Letters 2013, 15, 686-689.
  • Example 5-6 Catalysis Examples –Suzuki-Miyaura Couplings
  • Pd (II) source and ligand were loaded into a Schlenk tube equipped with a Teflon-coated magnetic stir bar. The tube was evacuated and flushed with nitrogen for three cycles. Precomplexation was applied by adding freshly distilled dichloromethane and Et 3 N into the tube. The palladium complex stock solution was stirred and warmed using hair drier for about 1 to 2 minutes until the solvent started boiling. The solvent was then evaporated under high vacuum.
  • Aryl chloride (0.5 mmol) , boron source (1.0 mmol) , and base (1.5 mmol) were then added to Schlenk tubes. 1.0 mL of solvent was added (to rinse the tube wall) with stirring at room temperature for several minutes. The tube was then placed in a preheated oil bath and stirred for 12-24 hours. After the completion of reaction as judged by GC or TLC analysis, the reaction was cooled down to room temperature and quenched with water and diluted with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (230-400 mesh) to afford the desired product.
  • a stock solution of Pd 2 (dba) 3 (1.0 mol%, 0.0023 g) with L3 (4.0 mol%, 0.0099 g) in freshly distilled dioxane (5.0 ml) was initially prepared by continuously stirring at room temperature for 10 min. 1 ml of the stock solution was transferred to another nitrogen-filled tube for further dilution. Freshly distilled dioxane was then added to the tube to give the needed concentration of palladium complex in total 4 ml final solution volume.
  • 2-Chloro-1, 3-dimethylbenzene 0.5 mmol, 0.07 g)
  • (2-ethylphenyl) boronic acid 1.0 mmol, 0.15 g, 2.0 equiv.
  • Table 1 Summary of the optimaization of the results of Catalysis Experiment 1 a
  • Pd 2 (dba) 3 (1.0 mol%, 0.0023 g) and L3 (4.0 mol%, 0.0099 g) were loaded into a Schlenk tube equipped with a magnetic stir bar. The tube was carefully evacuated and backfilled with nitrogen (3 cycles) . Precomplexation was applied by adding freshly distilled dioxane (0.5 ml) into the tube. The palladium complex stock solution was continuously stirred at room temperature for 10 min. 2-Chloro-1, 3, 5-trimethylbenzene (0.5 mmol, 0.077 g) , potassium 2, 6-dimethylphenyltrifluoroborate (1.0 mmol, 0.21 g, 2.0 equiv.
  • Example 7-10 Catalysis Examples –General Cross-Couplings
  • Example 8 Catalytic Hiyama Cross-coupling Reaction of aryl chlorides and aryl trialkoxysilanes
  • Example 9 Catalytic direct arylation of aryl chlorides and polyfluoroarene
  • Example 10 Catalytic Borylation of aryl chlorides and boron reagents

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Abstract

L'invention concerne une série de nouveaux ligands d'indolyle phosphine liés pour des métaux de transition, leur synthèse et leur utilisation dans des réactions de couplage catalytique. Les ligands permettent d'obtenir des améliorations de réactions catalysées par le métal de transition, comprenant la plage des substrats, des conditions de réaction et de l'efficacité.
PCT/CN2016/081589 2016-05-10 2016-05-10 Synthèse de ligands de phosphine portant une liaison réglable : procédés pour leur utilisation dans une catalyse Ceased WO2017193288A1 (fr)

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CN116396302A (zh) * 2023-04-10 2023-07-07 南京工业大学 一种吲哚类化合物及其制备方法
CN117062822A (zh) * 2021-03-25 2023-11-14 西格马-奥尔德里奇有限责任公司 带有庞大二(金刚烷基)膦基基序的新型基于二茂铁的不对称配体及其金属催化剂

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