WO2016011231A1 - Agents de couplage croisé à base de silicium et leurs procédés d'utilisation - Google Patents

Agents de couplage croisé à base de silicium et leurs procédés d'utilisation Download PDF

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WO2016011231A1
WO2016011231A1 PCT/US2015/040709 US2015040709W WO2016011231A1 WO 2016011231 A1 WO2016011231 A1 WO 2016011231A1 US 2015040709 W US2015040709 W US 2015040709W WO 2016011231 A1 WO2016011231 A1 WO 2016011231A1
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mmol
compound
equiv
hexanes
reaction mixture
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PCT/US2015/040709
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Adam T. HOYE
Won-Suk Kim
Dionicio MARTINEZ-SOLORIO
Amos B. Smith Iii
Rongbiao TONG
Minh Huu Nguyen
Luis Sanchez
Bruno MELILLO
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The Trustees Of The University Of Pennsylvania
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Priority to US15/326,069 priority Critical patent/US9850261B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom

Definitions

  • the present invention is directed to silicon-based cross-coupling agents and methods of using them in cross-coupling reactions.
  • CCRs Cross-coupling reactions
  • organometallic/main group reagents with, for example, organic halides permit the construction of carbon-carbon and carbon-nitrogen bonds.
  • CCRs are atom-efficient processes, the known CCRs have drawbacks, including the undesired formation of homo-coupled products and the use of toxic metals. As such, new methods for the cross coupling of organic compounds to form new carbon-carbon bonds and new carbon-nitrogen bonds are needed.
  • the present disclosure is directed to method of cross-coupling a compound of formula NuLi with a compound of formula E-X to form a compound of formula Nu-E comprising contacting the compound of formula NuLi with the compound of formula E-X in the presence of a catalyst system, an ethereal solvent, and a compound of Formula I
  • Y is CH or N
  • R 1 and R 2 are independently C 1-10 straight or branched-chain alkyl optionally substituted with one or more halogen, nitro, C 1-6 alkoxy, or aryl;
  • R 3 is H
  • aryl optionally substituted with one or more nitro, diC 1-6 alkylamino, C 1-6 alkoxy, or C 1-6 alkyl;
  • heteroaryl optionally substituted with one or more nitro, diC 1-6 alkylamino, C 1-6 alkoxy, or C 1-6 alkyl;
  • R 3a is H or C 1-6 alkyl optionally substituted with one or more halogen; and at least one R 4 , wherein each R 4 is independently hydrogen, halogen, nitro, C 1-6 alkoxy, C 1-6 alkyl, aryl, or a resin support;
  • Nu is an aryl compound, a heteroaryl compound, or an alkenyl compound
  • E is an aryl compound, a heteroaryl compound, or an alkenyl compound
  • X is iodo, chloro, or bromo.
  • the present invention is directed to compounds of formula I for use as silicon- based cross-coupling agents in the formation of carbon-carbon and carbon-nitrogen bonds:
  • Y is CH or N
  • R 1 and R 2 are independently C 1-10 straight or branched-chain alkyl optionally substituted with one or more halogen, nitro, C 1-6 alkoxy, or aryl;
  • R 3 is H
  • aryl optionally substituted with one or more halogen, nitro, diC 1-6 alkylamino, C 1-6 alkoxy, or C 1-6 alkyl;
  • heteroaryl optionally substituted with one or more halogen, nitro, diC 1-6 alkylamino,
  • R 3a is H or C 1-6 alkyl optionally substituted with one or more halogen
  • each R 4 is independently hydrogen, halogen, nitro, C 1-6 alkoxy, C 1-6 alkyl, aryl, or a resin support.
  • the compound of formula I is not
  • Compounds of formula I may comprise asymmetrically-substituted carbon atoms, i.e., chiral centers. These compounds may exist, without limitation, as single
  • stereoisomers for example, single enantiomers
  • mixtures of stereoisomers for example, mixture of enantiomers
  • racemic mixtures Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that is substantially free from other stereoisomers (e.g., substantially free from other enantiomers).
  • substantially free it means that at least 80% of the compound in a composition is the described stereoisomer; preferably, at least 90% of the compound in a composition is the described stereoisomer; and more preferably, at least 95%, 96%, 97%, 98% or 99% of the compound in a composition is the described stereoisomer.
  • R 1 and R 2 are independently methyl, ethyl, n-propyl, or isopropyl.
  • R 1 and R 2 are independently methyl or isopropyl.
  • R 1 and R 2 are each methyl.
  • R 1 and R 2 are each isopropyl.
  • R 1 and R 2 are each ethyl.
  • R 1 and R 2 can be optionally substituted with one or more halogen, nitro, C 1-6 alkoxy, or aryl.
  • R 3 is C 1-10 , preferably C 1-6 , straight or branched- chain alkyl optionally substituted with one or more halogen or C 1-6 alkoxy.
  • R 3 is C 1-4 straight or branched-chain alkyl optionally substituted with one or more halogen or
  • R 3 is C 1-6 alkoxy. More preferably, R 3 is C 1-4 straight or branched-chain alkyl. In exemplary embodiments, R 3 is n-butyl, isobutyl, sec-butyl, or tert-butyl. In most preferred embodiments, R 3 is n-butyl. In those embodiments wherein R 3 is C 1-6 alkyl substituted with one or more halogen, R 3 is preferably CF 3 .
  • R 3 is aryl, preferably phenyl, optionally substituted with one or more halogen, nitro, diC 1-6 alkylamino, C 1-6 alkoxy, or C 1-6 alkyl.
  • R 3 is phenyl optionally substituted with one or more diC 1-6 alkylamino, C 1-6 alkoxy, or C 1-6 alkyl.
  • R 3 is unsubstituted phenyl.
  • R 3 is heteroaryl, preferably pyridyl, optionally substituted with one or more halogen, nitro, diC 1-6 alkylamino, C 1-6 alkoxy, or C 1-6 alkyl.
  • R 3 is pyridyl optionally substituted with one or more diC 1-6 alkylamino, C 1-6 alkoxy, or C 1-6 alkyl.
  • R 3 is unsubstituted pyridyl.
  • R 3 is a polymer.
  • this polymer acts as a solid support for the siloxane transfer agent.
  • Such polymers are known in the art per se. Preferred polymers are described herein.
  • R 3 is a resin support.
  • R 3a is H or C 1-6 alkyl optionally substituted with one or more halogen.
  • R 3a is H.
  • exemplary moieties include methyl and ethyl.
  • R 3a is preferably CF 3 .
  • the reactivity of the compound of formula I can be attenuated by manipulation of R 4 .
  • the compounds of formula I can include one, two, three, or four R 4 groups, which can each be the same or different.
  • R 4 is preferably hydrogen, halogen, nitro, C 1-6 alkoxy, C 1-6 alkyl, or aryl. More preferably, R 4 is hydrogen, halogen, for example F, C 1-6 alkoxy, or C 1-6 alkyl.
  • R 4 is hydrogen.
  • R 4 is halogen, for example, F, Cl, or Br, with F being particularly preferred.
  • R 4 can also be a resin support.
  • the resin support is at either R 3 or R 4 . That is, in certain embodiments wherein R 3 is a resin support, each R 4 is independently hydrogen, halogen, nitro, C 1-6 alkoxy, C 1-6 alkyl, or aryl. In those embodiments wherein R 4 is a resin support, R 3 is H; aryl optionally substituted with one or more halogen, nitro, diC 1-6 alkylamino, C 1-6 alkoxy, or C 1-6 alkyl; heteroaryl optionally substituted with one or more halogen, nitro, diC 1-6 alkylamino, C 1-6 alkoxy, or C 1-6 alkyl;
  • aromatic moiety of the compounds of formula I is phenyl, that is, wherein Y is CH or CR 4 .
  • preferred compounds of formula I include, for example:
  • n is about 150 to about 300, preferably about 200 or 250,
  • polymer-supported siloxane transfer agent (saturated), for example, having 20 to 200 repeating units
  • R 3 is a polymer
  • n is independently about 20 to 300, preferably 20 to 200, or 150 to about 300. Most preferably, n is about 200 or 250.
  • R 3 or R 4 is a resin support
  • the aromatic moiety of the compounds of formula I is pyridyl, that is, wherein Y is N.
  • a compound of formula I including a pyridyl group may facilitate removal of the cross-coupling transfer agent from the products of the cross-coupling reaction mixutre by treatment of the crude reaction mixture with Br ⁇ nsted or Lewis acids upon workup.
  • the siloxane motif maybe incorporated into polymers using monomers derived from the silicon transfer agent.
  • This polymeric material may improve the ease of purification following the cross-coupling reaction, and may make the transfer agent easier to handle by altering its physical properties.
  • the invention is also directed to methods of cross-coupling compounds of formula NuLi with a compound of formula E-X to form a compound of formula Nu-E.
  • These methods comprise contacting the compound of formula NuLi with the compound of formula E-X in the presence of a a siloxane compound of the invention as described herein, a catalyst or a catalyst system, and an ethereal solvent, for a time and under conditions sufficient to produce the compound of formula Nu-E.
  • Nu is an aryl compound or an alkenyl compound
  • E is an aryl compound or an alkenyl compound
  • X is iodo or bromo or X is iodo, chloro, or bromo.
  • the invention is also directed to methods of cross-coupling compounds of formula Nu-Li with a compound of formula E-X to form a compound of formula Nu-E.
  • These methods comprise contacting the compound of formula NuLi with the compound of formula E-x in the presence of a siloxane compound of the invention as described herein, a catalyst or a catalyst system, and an ethereal solvent, for a time and under conditions sufficient to produce the compound of formula Nu-E.
  • Nu is an aryl compound or an alkeneyl compound
  • E is a disubstituted amine
  • X is–O-benzoyl.
  • aryl compound refers to an organic compound comprising a phenyl or naphthyl group that is optionally substituted with one or more substitutents.
  • substitutents include alkyl, aryl, halogen, nitro, cyano, keto, ester, alkoxy, siloxy, and the like.
  • alkenyl compound refers to an organic compound comprising a carbon-carbon double bond that is optionally substituted with one or more substitutents.
  • substitutents include alkyl, aryl, halogen, nitro, cyano, ester, alkoxy, siloxy, and the like.
  • C 1-10 straight or branched-chain alkyl refers to an aliphatic hydrocarbon including from 1 to 10 carbon atoms. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-penyl, iso-pentyl, n-hexyl, and the like.
  • diC 1-6 alkylamino refers to an amino moiety substituted with two C 1-6 alkyl group.
  • the C 1-6 alkyl groups can be the same or different.
  • diC 1-6 alkylamino groups for use in the invention include dimethylamino, diethylamino, methylethylamino, diisopropylamino, and the like.
  • disubstituted amine refers to a nitrogen atom having two substituents, which are the same or different. Disubstituted amine also refers to compounds wherein the two substituents are joined to form a ring. Examples of disubstituted amines include
  • aryl refers to an aromatic 6-13 membered mono- or bi-cyclic ring such as phenyl or naphthyl.
  • heteroaryl refers to a mono-or bicyclic aromatic ring structure including carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms. Preferred heteroaryl groups include pyridyl and pyrimidinyl.
  • heteroaryl compound refers to a heteroaryl moiety that is optionally substituted with one or more substitutents.
  • substitutents include alkyl, aryl, halogen, nitro, cyano, keto, ester, alkoxy, siloxy, and the like.
  • “resin support” refers to solid supports used in, for example, combinatorial chemistry.“Wang resins” and“Merrifield resin” are examples of such resins. Resin supports and their use and incorporation are known to those skilled in the art, per se.
  • the compounds of formula I can be used in organic synthesis, most preferably as silicon-based cross-coupling agents.
  • the compound of formula I is used in the presence of, for example, an organo-lithium compound and an organo-halogen (or an organo-pseudohalogen) compound to form the resulting cross-coupled organic compound.
  • an organo-lithium compound is an aryl-lithium or alkenyl-lithium compound.
  • the organo-halogen compound is preferably an aryl-halogen compound or an alkenyl-halogen compound.
  • the halogen is preferably iodo, chloro, or bromo.
  • the pseudohalogen is, for example, triflate or mesylate).
  • the resulting cross-coupled organic compounds are thus aryl-aryl compounds, aryl-alkenyl, or alkenyl-alkenyl compounds.
  • the compounds of formula I can be used in the presence of, for example, an organomagnesium reagent (i.e.,“Grignard reagents”).
  • the compounds of formula I can be used in stoichiometric amounts, that is, one molar equivalent, as compared to either the organo-lithium or organo-halogen compound.
  • the compounds of formula I are used in greater than stoichiometric amounts, that is, greater than one molar equivalent as compared to either the organo-lithium or organo-halogen compound.
  • up to three molar equivalents of the compound of formula I, as compared to either the organo-lithium or organo- halogen compound can be used.
  • 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.8, 2.0, 2.2, 2.5, or 2.8 molar equivalents of the compound of formula I, as compared to either the organo-lithium or organo-halogen compound, can be used. It is preferred to use 1.6, 1.8, or 2.0 molar equivalents of the compound of formula I. Also preferred is the use of 1.3 or 1.1 molar equivalents of the compound of formulat I. In some embodiments, 1.8 molar equivalents of the compound of formula I is used.
  • the amount of the compound of formula I required for cross-coupling a particular organo-lithium compound with a particular organo- halogen compound can be determined without undue experimentation by someone of skill in the art.
  • the compound of formula I can be used in catalytic amounts, that is, less than one molar equivalent, as compared to either the organo-lithium or organo-halogen compound.
  • the compound of formula I is present at from 1 mol% to 90 mol%, for example, 10, 20, 30, 40, 50, 60, 70, 80, or 90 mol%.
  • cross-coupling of an organo-lithium compound with an organo-halogen compound in the presence of the silicon-based cross-coupling agent compounds of formula I of the invention requires the use of a catalyst or catalyst system.
  • Preferred catalysts or catalyst systems comprise palladium compounds, copper compounds, nickel compounds, or mixtures thereof, optionally in the presence of a phosphate ligand such as cyclohexyl-(2- diphenylphosphanyl-benzylidene)-amine (dpca), XPhos (2-dicyclohexylphosphino-2’,4’,6’- triisopropylbiphenyl), Johnphos ((2-biphenyl)di-tert-butylphosphine), DavePhos (2- Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl), or SPhos (2-Dicyclohexylphosphino- 2′,
  • the palladium compound is PdCl 2 , Pd(PPh 3 ) 4 , or Pd(OAc) 2 .
  • the copper compound is preferably a copper halide, for example, CuI.
  • a preferred catalyst system for use in the methods of the invention comprises PdCl 2 , CuI, and dpca.
  • Another preferred catalyst system includes Pd(OAc) 2 and a phosphate ligand such as XPhos.
  • Yet another catalyst system includes CuI and dpca.
  • Another catalyst system include CuI and Johnphos.
  • the catalyst or component of the catalyst system can be present in an amount of from about 0.1 mol% to about 15 mol% or about 1 mol% to about 15 mol%.
  • the catalyst or component of the catalyst system can be present in an amount of about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or about 15 mol%.
  • the catalyst or component of the catalyst system can be present in an about of from about 0.5 mol% to about 5 mol%.
  • the catalyst or component of the catalyst system can be present in an amount of from about 3 mol% to about 10 mol%.
  • the palladium compound is present in an amount of from about 0.5 mol% to about 5 mol% or about 1 mol% to about 5 mol% or to about 10 mol%.
  • the palladium compound for example, PdCl 2
  • the palladium compound is present at about 3 mol%.
  • the copper compound is present in an amount of from about 0.1 mol% to about 10 mol%. In other embodiments, the copper compound is present in an amount of from about 1 mol% to about 10 mol%. Alternatively, the copper compound is present in an amount of from about 5 mol% to about 12 mol%. More preferably, the copper compound is present in an amount of from about 9 mol% to about 11 mol%. Most preferably, for example when the copper compound is CuI, it is present at about 10 mol%.
  • the dpca is present from about 1 mol% to about 10 mol%.
  • the dpca is present in an amount from about 2 mol% to about 8 mol%.
  • the dpca is used in conjunction with PdCl 2 .
  • Dpca can also be used in conjunction with CuI.
  • the dpca is present in an amount greater than the amount of PdCl 2 or CuI.
  • the dpca is present at about 4 mol% and the PdCl 2 is present at about 3 mol%.
  • the phosphate ligand is present from about 1 mol% to about 50 mol%.
  • the phosphate ligand is present in an amount from about 10 mol% to about 30 mol%.
  • Particularly preferred are embodiments wherein the phosphate ligand is present at about 20 mol%.
  • the Johnphos is present from about 1 mol% to about 20 mol%.
  • the XPhos is present in an amount from about 5 mol% to about 15 mol% or about 5 mol% to about 20 mol%.
  • XPhos is present at about 20 mol% or 10 mol%.
  • Preferred solvents for use in the cross-coupling reactions of the invention include ethereal solvents, for example tetrahydrofuran (THF), tetrahydropyran (THP), diisopropyl ether and diethyl ether, with THF being particularly preferred.
  • ethereal solvents for example tetrahydrofuran (THF), tetrahydropyran (THP), diisopropyl ether and diethyl ether, with THF being particularly preferred.
  • the cross-coupling reactions of the disclosure can be performed at or below room temperature, i.e., at or below about 23 °C.
  • cross-coupling reactions of the disclosure can be performed at about 23 °C or at between about 0 °C and 23 °C.
  • the cross-coupling reactions of the disclosure can be performed at or above room temperature.
  • cross-coupling reactions of the disclosure can be performed at about 23 °C or at between about 23 °C and about 50 °C, between about 23 °C and about 60 °C, or between about 23 °C and about 70 °C.
  • Siloxanes of the invention can be prepared according to the methods described herein. Two exemplary methods are shown in Schemes 2A and 2B. Other siloxanes within the scope of the invention can be prepared similarly.
  • Substantially enantiomerically pure compounds are also within the scope of the disclosure.
  • compounds of the disclosure having an ee of at least 90%, preferably at least 96% or 98% ee, can be prepared according to methods known in the art. A preferred method is set forth in the following Scheme 2A:
  • Preferred compounds of formula I have been successfully employed to cross- couple a variety of organo-lithium and organo-halogen compounds, while limiting the amount of homo-coupled product.
  • Scheme 3 depicts the results of several experiments where the organo-halogen compound was 4-iodoanisole and the organo-lithium compound was phenyl lithium.
  • compound 1 is a compound of formula I within the scope of the invention.
  • Good conversion of the aryl iodide occurred when steps a and b were allowed to proceed for longer times (see entry 3).
  • a significant increase in the efficiency of the process was observed when the catalyst system of PdCl 2 , dpca, and CuI was premixed for about 30 minutes in THF at room temperature prior to introduction of the aryl halide, which was followed by immediate addition of a mixture of PhLi and 1 in THF (see entry 4).
  • Using this protocol in conjunction with the use of 2.0 molar equivalents of compound 1 led to complete conversion of 4-iodoanisole with no detectable homocoupled product.
  • organo-halides other than 4-iodoanisole can be used in cross-coupling reactions of the invention using the silicon cross-coupling agents of the present invention, i.e., compounds of formula I.
  • the methods of the claimed invention can also be extended to alkenyl substrates.
  • vinyl halides 9j-l were good coupling partners with 13a, forming styrenes 14a-c with retention of the alkene geometry (see entries 1, 3, and 5).
  • the roles of the coupling partners could be reversed by using the corresponding vinyllithium and aryl halide to access identical coupling products in comparable yields (see entries 2, 4, and 6), demonstrating the flexibility of the methods of the invention with respect to the choice of nucleophilic and electrophilic components.
  • Geminal and vicinal substitution patterns were tolerated in the cross coupling process from silicon, providing coupled products 14c and 14d. Also noteworth was the successful vinyl-vinyl couplings of 13f and 9m and between 13g and (+)-9n to provide dienes 14f and (+)-14g.
  • Scheme 6 details examples demonstrating the scope and utility of the methods of the invention using preferred embodiments of compounds of formula I as silicon cross coupling agents.
  • the synthetic utility of the cross-coupling method may be expanded to include the use of sp3-hybridized organolithium species and alkyl halides.
  • Pd- or Ni-catalysis it may be possible access sp2-sp3 coupled products.
  • sp3-sp3 cross-couplings involving secondary alkyl halides may also be possible. It is preferred, in some examples, that iso-propyl group or groups are present on the silicon in order to avoid competitive transfer of primary alkyl groups from the activated silicon species (e.g., methyl). 7
  • the catalyst system comprises a palladium-based catalysts, for example, PdCl 2 or Pd(OAc) 2 .
  • a phosphate ligand for example, XPhos, SPhos, DavePhos, and Johnphos. Examples of such methods are set forth in Schemes 9A and 9B. See also, Scheme 6. It is noteworthy that in such embodiments, the siloxane reagent can be recovered. 1
  • siloxane compounds are also within the scope of the invention.
  • the siloxane motif may be incorporated into a polymer via ring-opening metathesis polymerization (ROMP).
  • REP ring-opening metathesis polymerization
  • the polymer can be obtained in near quantitative yield without using cross- linking units or co-polymerization agents.
  • the loading of the polymer with siloxane units should be nearly identical to the molarity of the monomer, e.g., 3.9 mmol/g for the example set forth in Scheme 9, with each polymer chain having a relative length of 200-mers.
  • the number of repeating siloxane units on each polymer chain can be adjusted by changing the amount of Grubbs catalyst used during the polymerization process.
  • polymers of the invention are generally soluble in common organic solvents such as those used in the cross-coupling reaction.
  • the silicon transfer reagent may also be incorporated into a solid support, for example a resin, using "click chemistry," which is understood by those in the art to include, for example, the reaction of an alkyne and an azide to produce a 1,2,3-triazole. See Scheme 11.
  • the reaction is between an alkyne-capped resin, such as those known in the art, and an azido-siloxane, which can be prepared according to known methods. (Scheme 11).
  • the compounds of formula I can be tethered to a resin via a triazoyl linker.
  • These embodiments of the inventions may facilitate removed of the transfer reagent from the reaction mixture by mechanical means such as filtration. Additionally, the transfer agent may be regenerated and reused.
  • STA-I 200 one embodiment of the invention, was used to mediate the cross-coupling of phenyl lithium and 1-iodoanisole. See Scheme 12.
  • the polymeric siloxanes of the invention have utility in, for example, the cross- coupling between ary organolithiums and aryl or alkenyl iodides. Examples of such cross- coupling reactions are set forth in Scheme 13.
  • Polymeric siloxanes of the invention are also recyclable and retain activity through multiple cross-coupling reaction cycles, using the same nucleophile for each transformation. See, e.g., Scheme 14.
  • Mn number average molecule weight
  • Polymeric siloxanes of the invention can also transfer different nucleophiles in repeated cycles. See, e.g., Scheme 15.
  • n-Butyllithium (2.0 M in hexane, 13.3 mL, 26.6 mmol) was added dropwise and the resulting solution was allowed to warm to–30 o C over 1 hr and stirred for an additional 30 min at–30 o C. The solution was then cooled to–78 o C and
  • reaction mixture was quenched by addition of t-BuOH (20 mL) and stirred for 5 h, followed by the addition of H 2 O (20 ml) and stirred for another 2 h.
  • the aqueous phase was then extracted with Et 2 O (2 x 25 mL) and the combined organic layers were washed with brine, dried (MgSO 4 ), and concentrated under reduced pressure.
  • Phenylmagnesium bromide (11.7 mL, 3.00 M in Et 2 O, 35.1 mmol, 1.20 equiv) was added dropwise to a vigorously stirred solution of isobutyraldehyde (2.11 g, 29.3 mmol, 1.00 equiv) in Et 2 O (50 mL) at 0 °C.
  • the reaction mixture was warmed to room temperature and stirred for 12 h, then quenched with sat. aq. NH 4 Cl (25 mL).
  • the aqueous phase was extracted with Et 2 O (2 x 25 mL) and the combined organic layers were washed with brine, dried (MgSO 4 ) and concentrated under reduced pressure.
  • the reaction mixture was allowed to slowly warm to room temperature and stirred for 12 h. The resulting orange slurry was then quenched with H 2 O (100 mL) with vigorous evolution of H 2 gas observed.
  • the reaction mixture was allowed to stir for 5 h and extracted with Et 2 O (3 ⁇ 50 mL).
  • the combined organic layers were collected and washed with 1M aq. HCl (3 ⁇ 50 mL).
  • the acidic aqueous layers were collected and neutralized to pH 8-9 with 1M aq. NaOH (150 mL) producing a white turbid mixture that was extracted with Et 2 O (3 ⁇ 100 mL).
  • the combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • the reaction mixture was allowed to slowly warm to room temperature and stirred for 12 h. The resulting red-brown solution was then quenched with H 2 O (100 mL) with vigorous evolution of H 2 gas observed. The reaction mixture was allowed to stir for 5 h and extracted with Et 2 O (3 ⁇ 50 mL). The combined organic layers were collected and washed with 1M aq. HCl (3 ⁇ 50 mL). The acidic aqueous layers were collected and neutralized to pH 8-9 with 1M aq. NaOH (150 mL) producing a white turbid mixture that was extracted with Et 2 O (3 ⁇ 100 mL). The combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • reaction mixture was then quenched with H 2 O (20 mL) with evolution of H 2 gas observed.
  • the reaction mixture was allowed to stir for 5 h and extracted with EtOAc (3 ⁇ 20 mL).
  • the combined organic layers were collected and washed with 1M aq. HCl (3 ⁇ 40 mL).
  • the acidic aqueous layers were collected and neutralized to pH 8-9 with 1M aq. NaOH (120 mL) producing a white turbid mixture that was extracted with Et 2 O (3 ⁇ 75 mL).
  • the combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • This Grignard reagent was then allowed to cool to room temperature and added to a cooled solution of 2-bromobenzaldehyde (4.00 g, 21.6 mmol, 1.00 equiv) in THF (32 mL) at 0 °C via cannula over 10 min.
  • the reaction mixture was then allowed to reach room temperature and stirred for 12 h and quenched with sat. aq. NH 4 Cl (75 mL).
  • the aqueous phase was then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • the slurry was quenched with H 2 O (75 mL) with vigorous evolution of H 2 gas observed.
  • the reaction mixture was allowed to stir for 5 h and extracted with EtOAc (3 ⁇ 50 mL).
  • the combined organic layers were collected and washed with 3M aq. HCl (3 ⁇ 50 mL).
  • the acidic aqueous layers were collected and neutralized to pH 8-9 with 1M aq. NaOH producing a white turbid mixture that was extracted with Et 2 O (3 ⁇ 75 mL).
  • the combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • This Grignard reagent was then allowed to cool to room temperature and added to a cooled solution of 2-bromobenzaldehyde (8.00 g, 43.2 mmol, 1.00 equiv) in THF (87 mL) at 0°C via cannula over 10 min. The reaction was then allowed to reach room temperature and stirred for 12 h and quenched with sat. aq. NH 4 Cl (100 mL). The aqueous phase was then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure.
  • the slurry was quenched with H 2 O (50 mL) with vigorous evolution of H 2 gas observed.
  • the reaction mixture was allowed to stir for 5 h and extracted with EtOAc (3 ⁇ 25 mL).
  • the combined organic layers were collected and washed with 3M aq. HCl (3 ⁇ 25 mL).
  • the acidic aqueous layers were collected and neutralized to pH 8-9 with 1M aq. NaOH producing a white turbid mixture that was extracted with Et 2 O (3 ⁇ 75 mL).
  • the combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • the slurry was quenched with H 2 O (100 mL) with vigorous evolution of H 2 gas observed.
  • the reaction mixture was allowed to stir for 5 h and extracted with EtOAc (3 ⁇ 50 mL).
  • the combined organic layers were collected and washed with 3M aq. HCl (3 ⁇ 50 mL).
  • the acidic aqueous layers were collected and neutralized to pH 8-9 with 1M aq. NaOH (300 mL) producing a white turbid mixture that was extracted with Et 2 O (3 ⁇ 100 mL).
  • the combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure.
  • the aryl halide (0.45 mmol, 1.0 equiv) was added to the orange slurry, followed by addition of the siloxane/PhLi reaction mixture by cannula (flask rinsed with 0.5 mL of THF). After 2 h at room temperature, the reaction mixture was diluted with Et 2 O (2 mL) and quenched according to the siloxane used in the reaction; 1, 1a-f, 2a-d quenched with sat. aq. NH 4 Cl (5 mL); 3a-b and 3d-e quenched with 1M aq. HCl (5 mL); 3c and 3f-g quenched with 3M aq. HCl (5 mL).
  • siloxanes 3a-g the organic layer was washed with either 1M or 3M aq. HCl (3 ⁇ 5 mL) (according to siloxane, see above), and the acidic aqueous layers were collected. The organic layer was then washed with sat. aq. NaHCO 3 (5 mL), dried (MgSO 4 ), filtered, and concentrated under reduced pressure. Flash chromatography provided the cross-coupled product. The acidic aqueous layer was then basified to pH 8-9 with 1M aq. NaOH, producing a white turbid mixture that was then extracted with Et 2 O 3 ⁇ 50 mL). The combined organic layers were dried (MgSO 4 ), filtered, and concentrated under reduced pressure to provide the recovered siloxane. Example 26. Preparation of fluorinated siloxanes.
  • the alkenyl halide or aryl iodide (0.45 mmol, 1.00 equiv) was added as a solution in THF (0.3 mL) to the orange slurry, immediately followed by addition of the siloxane reaction mixture by cannula (flask rinsed with 0.5 mL of THF). After 2-12 h at room
  • reaction mixture was diluted with Et 2 O (2 mL) and quenched according to the siloxane used in the reaction; 1, 1a-f, 2a-d quenched with sat. aq. NH 4 Cl (5 mL); 3a-b and 3d-e quenched with 1M aq. HCl (5 mL); 3c and 3f-g quenched with 3M aq. HCl (5 mL).
  • siloxanes 1, 1a-f, 2a-d the aqueous layer was extracted with Et 2 O (3 ⁇ 5 mL) and the combined organic layers were dried (MgSO 4 ), filtered, and concentrated under reduced pressure. Flash chromatography provided the cross-coupled product and the recovered siloxane (where possible as with siloxanes 2a-d).
  • siloxanes 3a-g the organic layer was washed with either 1M or 3M aq. HCl (3 ⁇ 5 mL) (according to siloxane, see above), and the acidic aqueous layers were collected. The organic layer was then washed with sat. aq. NaHCO 3 (5 mL), dried (MgSO 4 ), filtered, and concentrated under reduced pressure. Flash chromatography provided the cross-coupled product. The acidic aqueous layer was then basified to pH 8-9 with 1M aq. NaOH, producing a white turbid mixture which was then extracted with Et 2 O 3 ⁇ 50 mL).
  • Grubbs’ 1 st generation catalyst (6.1 mg, 7.4 ⁇ mol) was dissolved in CH 2 Cl 2 (0.5 mL) and the solution was stirred for 30 min. The catalyst solution was then introduced via cannula to another flask containing 22 (378 mg, 1.48 mmol) in CH 2 Cl 2 (1 mL), and the resulting solution was then stirred at room temperature. After 17 h, the reaction mixture was heated to reflux. After 19 h, the reaction was quenched with ethylvinylether (0.5 mL) in CH 2 Cl 2 (1.5 mL), and heating of the mixture at 50 o C was continued for another 2 h. The solution was then cooled to room temperature and diluted with CH 2 Cl 2 (5 mL).
  • Example 36 Polymer-Mediated Cross-Coupling
  • Example 40 Alternative procedure for siloxane-mediated cross-coupling of 4-chloroanisole and phenyllithium.

Abstract

L'invention concerne des compositions et des procédés utilisant des agents de couplage croisé à base de silicium dans la formation de liaisons carbone-carbone et carbone-azote.
PCT/US2015/040709 2012-06-08 2015-07-16 Agents de couplage croisé à base de silicium et leurs procédés d'utilisation WO2016011231A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023123126A1 (fr) * 2021-12-29 2023-07-06 苏州大学 Matériau composite d'un polymère organique poreux azoté et procédé de préparation et application associés

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4447628A (en) * 1982-07-12 1984-05-08 E. I. Du Pont De Nemours And Company Nonhygroscopic, anionic pentacoordinate silicate
US20080177112A1 (en) * 2005-03-17 2008-07-24 Daihatsu Motor Co., Ltd. Method of Synthesizing Compound
US20090069577A1 (en) * 2005-04-14 2009-03-12 Yoshiaki Nakao Silicon-Based Cross-Coupling Reagent and Production Method of Organic Compound Using the Same
WO2013159229A1 (fr) * 2012-04-24 2013-10-31 Dalhousie University Ligand à la silanyloxyaryle phosphine et ses utilisations dans le couplage croisé c-n
WO2013185021A2 (fr) * 2012-06-08 2013-12-12 The Trustees Of The University Of Pennsylvania Agents de couplage croisé à base de silicium et leurs procédés d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4447628A (en) * 1982-07-12 1984-05-08 E. I. Du Pont De Nemours And Company Nonhygroscopic, anionic pentacoordinate silicate
US20080177112A1 (en) * 2005-03-17 2008-07-24 Daihatsu Motor Co., Ltd. Method of Synthesizing Compound
US20090069577A1 (en) * 2005-04-14 2009-03-12 Yoshiaki Nakao Silicon-Based Cross-Coupling Reagent and Production Method of Organic Compound Using the Same
WO2013159229A1 (fr) * 2012-04-24 2013-10-31 Dalhousie University Ligand à la silanyloxyaryle phosphine et ses utilisations dans le couplage croisé c-n
WO2013185021A2 (fr) * 2012-06-08 2013-12-12 The Trustees Of The University Of Pennsylvania Agents de couplage croisé à base de silicium et leurs procédés d'utilisation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023123126A1 (fr) * 2021-12-29 2023-07-06 苏州大学 Matériau composite d'un polymère organique poreux azoté et procédé de préparation et application associés

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