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WO2012002913A1 - Procédé de formation d'un imide cyclique - Google Patents

Procédé de formation d'un imide cyclique Download PDF

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WO2012002913A1
WO2012002913A1 PCT/SG2011/000233 SG2011000233W WO2012002913A1 WO 2012002913 A1 WO2012002913 A1 WO 2012002913A1 SG 2011000233 W SG2011000233 W SG 2011000233W WO 2012002913 A1 WO2012002913 A1 WO 2012002913A1
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ruthenium
aromatic
complex
arylaliphatic
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Soon Hyeok Hong
Jian Zhang
Senthilkumar Muthaiah
Subhash Chandra Ghosh
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Nanyang Technological University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B43/00—Formation or introduction of functional groups containing nitrogen
    • C07B43/06—Formation or introduction of functional groups containing nitrogen of amide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/404—2,5-Pyrrolidine-diones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. succinimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/02—Preparation by ring-closure or hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present invention relates to a process of forming a cyclic imide.
  • a primary amine and a primary diol are contacted in the presence of Ruthenium (II) catalyst.
  • Imide derivatives are widely used organic compounds with numerous applications in biological, medicinal, synthetic, and polymer chemistry (Hargreaves, MK, et al., Chem. Rev.
  • cyclic imides are important building blocks for natural products and drugs such as palasimide (Peter, MG, et al., Helv. Chim. Acta (1974) 57, 32;
  • available routes for the synthesis of the cyclic imides from readily available starting materials are limited (Reddy et al., 1997, supra).
  • the typical methods are the dehydrative condensation of an anhydride and an amine at high temperature or with help of a Lewis acid (Hargreaves et al., 1 70, supra; Kamitori et al., 1986, supra; Rad- oghadam & Kheyrkhah, 2009, supra; Abell & Oldham,.1997, supra; Barker et al., 2005, supra; de Figueiredo et al., 2007, supra; Luzzio, 2005, supra; Reddy et al., 1997, supra; Da Settimo, A, et al., Eur. J. Med. Chem.
  • the present invention provides a process that involves subjecting an amine and a diol compound to an intermolecular oxidative coupling reaction, whereby a cyclic imide is formed.
  • the process involves the use of a Ruthenium (II) complex, which may be formed from a Ruthenium (II) precatalyst complex.
  • This Ruthenium (II) complex in the following also termed the Ruthenium (II) catalyst, may involve providing an N-heterocyclic carbene, which may define a ligand of the Ruthenium (II) complex.
  • the invention provides a process of forming a cyclic imide.
  • the process includes providing a primary amine.
  • the process also includes providing a diol compound.
  • the process further includes providing a Ruthenium (II) complex.
  • the Ruthenium (II) complex includes one or more of an alicyclic ligand, an aromatic ligand, an arylalicyclic ligand, an arylaliphatic ligand and a phosphine ligand.
  • the process also includes contacting the primary amine and the diol compound in the presence of the Ruthenium (II) complex. Thereby the formation of a cyclic imide from the primary amine and the diol compound is allowed.
  • Providing the Ruthenium (II) catalyst includes in some embodiments providing an N-heterocyclic carbene. In some embodiments providing the Ruthenium (II) catalyst may involve the formation of one or more Ruthenium (II) complexes of formulae (IV), (V) and
  • R 5 - R 7 and R 9 - R 15 are independently from one another selected from the group consisting of a H, an aliphatic, an alicyclic, an aromatic, an arylaliphatic, and an arylalicyclic group.
  • the aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group includes 0 to about 3 heteroatoms. Such a heteroatom may be selected from N, O, S, Se and Si.
  • X is halogen or -OR 16 .
  • R 16 in this moiety -OR 16 is one of H, an aliphatic group, an alicyclic group, an aromatic group, an arylaliphatic group, and an arylalicyclic group.
  • the aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group includes 0 to about 3 heteroatoms. Such a heteroatom may be selected from N, O, S, Se and Si.
  • L is a solvent molecule, pyridine, acetonitrile or an N-heterocyclic carbene.
  • Figure 1 depicts examples of bioactive compounds containing a cyclic imide moiety.
  • Figure 2 illustrates the synthesis of amides and cyclic imides from alcohols and amines.
  • Figure 3 shows examples of Ru (II) catalysts that can be used in a process of the invention.
  • Figure 4 depicts examples of the reaction of 1,4-butanediol (3a) and benzylamine (4a). Common reaction conditions: 3a (0.5 mmol, 1.0 equiv), 4a (0.55 mmol, 1.1 equiv), a solvent (0.8 mL), reflux, 24 h.
  • Figure 5 illustrates the synthesis of succinimides from 1,4-butanediol.
  • Common reaction conditions 3a (0.5 mmol, 1.0 equiv), amine (1.1 equiv), lc (5 mol %), 1,3- diisopropylimidazolium bromide (2) (5 mol %), NaH (20 mol %), CH 3 CN (5 mol %), toluene (0.5 mL), reflux, 24 h.
  • Figure 6 shows further examples of the synthesis of cyclic imides from diols.
  • Common reaction conditions Diol (0.5 mmol, 1 equiv, 1.0 ), amine (1.1 equiv), lc (5 mol %), 2 (5 mol %), NaH (20 mol %), CH 3 CN (5 mol %), toluene (0.5 mL), reflux, 24 h.
  • Diol 0.5 mmol, 1 equiv, 1.0
  • amine 1.1 equiv
  • lc 5 mol %)
  • 2 5 mol %)
  • NaH (20 mol %) CH 3 CN (5 mol %)
  • toluene 0.5 mL
  • reflux 24 h.
  • Isolated yields average of at least two runs.
  • Figure 7 depicts attempts to synthesize imides. Conditions: [Ru] lc (5 mol%), 2 (5 mol%), NaH (20 mol%), CH 3 CN (5 mol%), toluene (0.8 mL), reflux, 24 h.
  • Figure 8 illustrates the proposed mechanism of the formation of the cyclic imide.
  • the process of the invention includes providing a diol compound. Any diol may be used that is capable of undergoing a cyclisation reaction (see scheme 1 below). Accordingly, the diol usually has a distance of at least two atoms, generally carbon atoms, between the two hydroxyl groups of the diol, that is the two hydroxyl groups of the diol are separated by two or more atoms.
  • the diol compound may also be provided in protected form.
  • a large number of protecting groups which are well known to those skilled in the art, is available for various functional groups.
  • hydroxyl groups may be protected by an isopropylidene group.
  • Such a protecting group may easily be removed during or before the process of the invention is carried out and thus the functional group(s) that is/are no longer shielded are available for amide formation.
  • the isopropylidene protective group shielding a hydroxyl group may be removed by acid treatment.
  • Those skilled in the art will furthermore be aware that such protective groups may have to be introduced well in advance during the synthesis of such a bi- or higher functionalized compound.
  • Examples of a suitable hydroxy protecting group include, but are not limited to, methyl ethers; substituted methyl ethers (e.g. methoxymethyl, methylthiomethyl, tert.-butyl- thiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxyme- thyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, tert-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)me- thyl, 2-(1rimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydro- pthiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl
  • the process of the invention includes providing an amine. Any primary amine may be used in the process of the invention.
  • the amino group of the primary amine may in some embodiments also be shielded by a protecting group.
  • a suitable amino protecting group include, but are not limited to, carbamates (methyl and ethyl, 9-fluorenylmethyl, 9(2- sulfo)fluoroenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di-tert-buthyl-[9-(l 0, 10-dioxo- 10, 10,10,10-tetrahydrothioxanthyl)]methyl, 4-methoxyphenacyl); substituted ethyl (2,2,2-tri- choroethyl, 2-trimethylsilylethyl, 2-phenylethyl, l-(l-adamantyl)-l-methylethyl, 1,1-dimethyl- 2-haloeth
  • a process according to the invention includes contacting a diol and an amine compound in the presence of a ruthenium based catalyst and in a suitable solvent.
  • catalyst and “catalyst system” are used interchangeably herein. As used herein, these terms refer to a compound or component, or combination of compounds or components that that is/are capable of increasing the rate of a chemical reaction. Thereby the catalyst or catalyst system generally facilitate(s) or allow(s) the reaction between one or more other compounds, the catalyst remaining in or returning to its original state.
  • a catalyst may be used in any desired amount relative to the other components whose reactions is facilitated or allowed.
  • Suitable solvents include organic solvents such as, but not limited to, toluene, mesitylene and xylene.
  • the method of the invention includes a reaction that can be represented by the following scheme (1):
  • [Ru] is a ruthenium based complex, typically a ruthenium (II) complex.
  • the ruthenium complex includes an alicyclic, aromatic, arylalicyclic or arylaliphatic ligand and/or a phosphine ligand.
  • Illustrative examples such as dichloro-(l,5-cyclooctadiene)ruthenium(II) or dichloro(benzene)ruthenium(II) are depicted in Fig. 3. Further examples are exemplified below.
  • the moieties R 1 to R 4 in scheme 1 above may be H, halogen, a silyl group, an aliphatic, an alicyclic, an aromatic, an arylaliphatic or an arylalicyclic group.
  • the aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group may have a main chain of 1 to about 30 carbon atoms. Further, the main chain of such an aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group may include 0 to about 9 heteroatoms.
  • a respective heteroatom may be N, O, S, Se and Si.
  • one of R 1 and R 2 defines an aliphatic, aromatic or arylaliphatic bridge that is linked to the respective other moiety of R 2 and R l .
  • one of R 3 and R 4 defines an aliphatic, aromatic or arylaliphatic bridge that is linked to the respective other moiety of R 4 and R 3 .
  • the moieties R 1 and R 2 , and/or the moieties R 3 and R 4 may, independent from one another, in some embodiments define one common cyclic structure.
  • R' and R" may be H or a suitable protecting group (supra).
  • R' and R" are in some embodiments different from each other. In some embodiments R' and R" are identical.
  • a suitable protecting group R' and/or R" include, but are not limited to, an ether, a silyl ether, an ester, a carbonate, an aryl carbamate, a phosphinate and a sulfonate.
  • a suitable ether are a methyl-, a t-butyl-, an isopropyl-, a methoxy- methyl-, a benzyl-, a 2,4-dimethylbenzyl-, a 4-methoxybenzyl-, an o-nitrobenzyl-, a p-nitro- benzyl-, a 2,6-dichlorobenzyl-, a 3,4-dichlorobenzyl-, a 4-(dimethylamino)carbonylbenzyl-, a methylsulfinylbenzyl-, a benzyloxymethyl-, a methoxyethoxymethyl-, a (2-trimethylsilyl)- ethoxymethyl-, a methylthiomethyl-, a phenylthiomethyl-, an azidomethyl-, a cyanomethyl-, a 2,2-dichloro-l,l-difluoro
  • Illustrative examples of a suitable silyl ether are a trimethylsilyl-, a t-butyldimethylsilyl-, a t-butyl- diphenylsilyl- and a triisopropylsilyl ether.
  • Illustrative examples of a suitable ester are a formate-, an acetate-, a levulinate-, a pivaloate-, a benzoate-, a 9-fluorenecarboxylate- and a xanthenecarboxylate group.
  • Illustrative examples of a suitable carbonate are a methyl, a t-butyl-, a vinyl-, a benzyl-, an 1-adamantyl-, a 2,4-dimethylpent-3-yl-, an allyl-, a 4-methylsulfi- nylbenzyl- and a 2,2,2-trichloroethyl carbonate.
  • Illustrative examples of a suitable phosphinate are a dimethylphosphinyl-, a dimethylphosphinothioyl- and a diphenylphosphinothioyl group.
  • Illustrative examples of a suitable sulfonate are a methanesulfonate-, a trifluoromethane- sulfonate-, a 2-formylbenzenesulfonate, a toluenesulfonate- and a benzylsulfonate group.
  • Moiety A in scheme (1) above may be S, Se, O, N-R'", or one of an aliphatic, an alicyclic, an aromatic, an arylaliphatic or an arylalicyclic bridge.
  • the main chain of such an aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic bridge may have 1 to about 30, such as about 2 to about 30, 1 to about 25, about 2 to about 25, about 3 to about 25, 1 to about 20, about 2 to about 20, 1 to about 15, about 2 to about 15, 1 to about 12, about 2 to about 12, 1 to about 10, about 2 to about 10, 1 to about 8, about 2 to about 8, including 3, 4, 5, 6 or 7 carbon atoms.
  • the main chain of such an aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group may include 0 to about 9 heteroatoms.
  • a respective heteroatom may be N, O, S, Se and Si.
  • R'" may be H, a silyl group, an aliphatic, an alicyclic, an aromatic, an arylaliphatic or an arylalicyclic group.
  • R 1 to R 4 , R' and R" are as defined above.
  • R' and R" hydroxy protecting groups may include a substituted methyl ether, a substituted benzyl ether, a silyl ether, and an ester including a sulfonic acid ester, such as a trialkylsilyl ether, a tosylate, a mesylate or an acetate.
  • n is 0, 1 or an integer from 3 to 8, such as 0, 1, 3, 4, 5, 6, 7 or 8.
  • scheme (2) can also be represented as:
  • scheme (2) can also be represented as:
  • aliphatic means, unless stated otherwise, a straight or branched hydrocarbon chain, which may be saturated or mono- or poly-unsaturated and include heteroatoms (see below).
  • An unsaturated aliphatic group contains one or more double and/or triple bonds (alkenyl or alkynyl moieties).
  • the branches of the hydrocarbon chain may include linear chains as well as non-aromatic cyclic elements.
  • the respective hydrocarbon chain which may, unless otherwise stated, be of any length, and contain any number of branches.
  • the hydrocarbon (main) chain includes 1 to 5, to 10, to 15 or to 20 carbon atoms.
  • alkenyl radicals are straight-chain or branched hydrocarbon radicals which contain one or more double bonds.
  • Alkenyl radicals generally contain about two to about twenty carbon atoms and one or more, for instance two, double bonds, such as about two to about ten carbon atoms, and one double bond.
  • Alkynyl radicals normally contain about two to about twenty carbon atoms and one or more, for example two, triple bonds, preferably such as two to ten carbon atoms, and one triple bond. Examples of alkynyl radicals are straight-chain or branched hydrocarbon radicals which contain one or more triple bonds.
  • alkyl groups are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, the n isomers of these radicals, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, neopentyl, 3,3 dimethylbutyl.
  • Both the main chain as well as the branches may furthermore contain heteroatoms as for instance N, O, S, Se or Si, or carbon atoms may be replaced by these heteroatoms.
  • alicyclic may also be referred to as "cycloaliphatic” and means, unless otherwise stated, a non-aromatic cyclic moiety (e.g. hydrocarbon moiety), which may be saturated or mono- or poly-unsaturated.
  • the cyclic hydrocarbon moiety may also include fused cyclic ring systems such as decalin and may also be substituted with non-aromatic cyclic as well as chain elements.
  • the main chain of the cyclic hydrocarbon moiety may, unless otherwise stated, be of any length and contain any number of non-aromatic cyclic and chain elements.
  • the hydrocarbon (main) chain includes 3, 4, 5, 6, 7 or 8 main chain atoms in one cycle.
  • moieties include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. Both the cyclic hydrocarbon moiety and, if present, any cyclic and chain substituents may furthermore contain heteroatoms, as for instance N, O, S, Se or Si, or a carbon atom may be replaced by these heteroatoms.
  • the term "alicyclic” also includes cycloalkenyl moieties that are unsaturated cyclic hydrocarbons, which generally contain about three to about eight ring carbon atoms, for example five or six ring carbon atoms. Cycloalkenyl radicals typically have a double bond in the respective ring system. Cycloalkenyl radicals may in turn be substituted.
  • aromatic means, unless otherwise stated, a planar cyclic hydrocarbon moiety of conjugated double bonds, which may be a single ring or include multiple fused or covalently linked rings, for example, 2, 3 or 4 fused rings.
  • aromatic also includes alkylaryl.
  • the hydrocarbon (main) chain typically includes 5, 6, 7 or 8 main chain atoms in one cycle.
  • moieties include, but are not limited to, cylcopentadienyl, phenyl, napthalenyl-, [10]annulenyl-(l,3,5,7,9-cyclodecapentaenyl-), [12]annulenyl-, [8]annulenyl-, phenalene (perinaphthene), 1,9-dihydropyrene, chrysene (1,2-benzophenanthrene).
  • An example of an alkylaryl moiety is benzyl.
  • the main chain of the cyclic hydrocarbon moiety may, unless otherwise stated, be of any length and contain any number of heteroatoms, as for instance N, O and S.
  • heteroaromatic moieties include, but are not limited to, furanyl-, thiophenyl-, naphtyl-, naphthofuranyl-, anthrathiophenyl-, pyridinyl-, pyrrolyl-, quinolinyl, naphthoquinolinyl-, quinoxalinyl-, indolyl-, benzindolyl-, imidazolyl-, oxazolyl-, oxoninyl-, oxepinyl-, benzoxepinyl-, azepinyl-, thiepinyl-, selenepinyl-, thioninyl-, azecinyl- (azacyclodecapentaenyl-), dianovanyl-, azacyclododeca- 1,3,5,7,9,1 l-hexaene-5,9
  • arylaliphatic is meant a hydrocarbon moiety, in which one or more aromatic moieties are substituted with one or more aliphatic groups.
  • arylaliphatic also includes hydrocarbon moieties, in which two or more aryl groups are connected via one or more aliphatic chain or chains of any length, for instance a methylene group.
  • the hydrocarbon (main) chain includes 5, 6, 7 or 8 main chain atoms in each ring of the aromatic moiety.
  • arylaliphatic moieties include, but are not limited to, 1 -ethyl-naphthalene, ⁇ , ⁇ -methylenebis-benzene, 9-isopropylanthracene, 1,2,3-trimethyl-benzene, 4-phenyl-2-buten- l-ol, 7-chloro-3-(l-methylethyl)-quinoline, 3-heptyl-furan, 6-[2-(2,5-diethylphenyl)ethyl]-4- ethyl-quinazoline or, 7,8-dibutyl-5,6-diethyl-isoquinoline.
  • arylalicyclic means a hydrocarbon moiety in which an alicyclic moiety is substituted with one or more aromatic groups.
  • arylalicyclic moiety Three illustrative example of an arylalicyclic moiety are "phenylcyclohexyl", “phenylcyclopentyl” or "naphthylcyclohexyl”.
  • an arylalicyclic moiety has a main chain of more than about 10 carbon atoms.
  • an arylalicyclic moiety has a main chain of up to about 30 carbon atoms, such as up to about 28, up to about 25, up to about 22, up to about 20, up to about 18 up or to about 14 carbon atoms.
  • aliphatic alicyclic
  • aromatic arylaliphatic
  • arylalicyclic is meant to include both substituted and unsubstituted forms of the respective moiety.
  • Substituents may be any functional group, as for example, but not limited to, amino, amido, azido, carbonyl, carboxyl, cyano, isocyano, dithiane, halogen, hydroxyl, nitro, organometal, organoboron, seleno, silyl, silano, sulfonyl, thio, thiocyano, trifluoromethyl sul- fonyl, p-toluenesulfonyl, bromobenzenesulfonyl, nitrobenzenesulfonyl, and methane-sulfonyl.
  • a heteroatom is any atom that differs from carbon. Examples include, but are not limited to N, O, P, S, and Se. Where several heteroatoms are present within a moiety of a reactant or product of the process of the invention, they are independently selected.
  • a Ruthenium (II) catalyst is provided.
  • Providing the Ruthenium (II) catalyst in a process according to the invention may in some embodiments include providing an N-heterocyclic carbene.
  • a Ruthenium (II) precatalyst catalyst complex may be provided and an N-heterocyclic carbene, for example together, at the same time or in sequence, e.g. in a preselected order.
  • the N-heterocyclic carbene may be provided as a complex with a metal halogenide or metal oxide, such as a transition metal halogenide or a transition metal oxide, e.g.
  • An illustrative example of a group 11 halogenide is a silver halogenide, e.g. Ag(I)Cl, Ag(I)Br or Ag(I)I.
  • An illustrative example of a group 11 oxide is copper (II) oxide, CuO.
  • N-heterocyclic carbene is known in the art via the understanding of a molecule with a divalent carbon atom that has six valence electrons. While carbenes in general are typically very short lived, an N-heterocyclic carbene is stable as a ligand, generally a two electron ligand. An N-heterocyclic carbene can be understood as being stabilized by the electron lone pair(s) of one or more nitrogen atoms in the molecule, which can contribute to a resonance effect, which can be depicted in the form of mesomer structures, and be taken to lead to a partial multiple bond character of the additional electrons of the carbene moiety.
  • N-heterocyclic carbene generally has to be handled under inert gas atmosphere such as argon or nitrogen, prevented from contact with chlorinated solvents and moisture and is then stable even at elevated temperatures such as 200 °C and higher.
  • inert gas atmosphere such as argon or nitrogen
  • Kirmse Angew. Chem. Int. Ed (2004) 43, 1767-1769
  • the formation, reactivity and theoretical aspects of N-heterocyclic carbenes have for example been reviewed by Hahn & Jahnke (Angew. Chem. Int. Ed. (2008) 47, 3122- 3172).
  • N-heterocyclic carbene examples include, but is not limited to one of the following molecules:
  • an N-heterocyclic carbene can be formed from the corresponding proton- substituted compound using a strong base, i.e. a base such as a metal hydride, e.g. NaH, CaH 2 , LiH or TiH 2 .
  • a strong base include, but are not limited to, lithium diisopropylamide, lithium tetramethylpipendide or lithium hexamethyldisilazide, each of them having a pK a of 30 or more in DMSO.
  • an alkoxide can also be used as the respective base, such as NaOCH 3 , KOtBu, NaOEt.
  • a suitable base are Li[N(SiMe 3 ) 2 ] and K[N(SiMe 3 ) 2 ].
  • at least one equivalent of the base, at least two or at least three equivalents of the base or more, is/are used relative to the proton-substituted compound (e.g. an imidazole or imidazoline compound), typically being an N-heterocyclic compound.
  • the nitrogen atom(s) of the N-heterocyclic carbene is/are included in a 5-membered ring such as an imidazol-based, a triazol-based, a thiazol-based or a benzimidazol-based carbene.
  • An imidazol-based carbene can for example be prepared from an imidazolium salt using a base or by reductive desulfurization of an imidazolin-2-thion (see e.g. chapter 2.3 of Hahn et al., 2008, supra).
  • the respective imidazolium salt can for example be obtained via a cyclisation reaction or by a reaction at an N atom of an imidazol compound, such as alkylation, as summarized by Hahn et al. (ibid.).
  • Imidazol-based N-heterocyclic carbenes have also been reviewed by Ktihl (Chem. Soc. Rev. (2007) 36, 592-607).
  • R 1 1 , R 12 , R 13 and R 14 may independent from one another be H or an aliphatic, an alicyclic, an aromatic, an arylaliphatic, or an arylalicyclic group, which may include 0 to about 3 heteroatoms. Any two of these moieties, where present, such as R 13 and R 14 , R 5 and R 13 or R 12 and R 14 may also be linked to define a bridge, such as an aliphatic, an aromatic, an alicyclic or an arylalicyclic bridge, "ar" in the fourth exemplary compound depicted above represents an aromatic moiety.
  • R 21 , R 22 , R 23 , R 24 , R 25 and R 26 may also be independent from one another, be H or an aliphatic, an alicyclic, an aromatic, an arylaliphatic, or an arylalicyclic group, which may include 0 to about 3 heteroatoms.
  • a respective aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group of any of R 1 1 , R 12 , R 13 , R 14 , R 21 , R 22 , R 23 , R 24 , R 25 and R 26 , where present, is typically of a main chain length of 1 to about 10, to about 15 or to about 20 carbon atoms.
  • R 1 1 , R 12 , Rl5, Rl , R 21 , R 22 , R 23 , R 24 , R 5 and R 26 , may for example include 0 to about 3, such as one or two, heteroatoms selected from the group N, O, S, Se and Si. Any of these aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic groups may be substituted (see also below), for example carrying i silyl group, which may be of the structure:
  • R 33 - R 35 are independently selected aliphatic, alicyclic, aromatic, arylaliphatic, or arylalicyclic groups, typically bonded to the Si-atom via a carbon atom (which is part of the respective group).
  • R 21 and R 22 , R 24 and R 25 , R 22 and R 23 , R 22 and R 26 , R 23 and R 2 * or R 25 and R 26 may also be linked to define a bridge, such as an aliphatic, an aromatic, an alicyclic or an arylalicyclic bridge.
  • a bridge such as an aliphatic, an aromatic, an alicyclic or an arylalicyclic bridge.
  • a further illustrative example of a compound depicted above with a bridge, in which two carbene moieties are present is a molecule with a moiety R 12 that includes an N-heterocyclic carbene moiety such as:
  • Moieties R 23 to R 25 in this example are as defined above, and n may be an integer selected from 1, 2, 3, 4 and 5.
  • the N-heterocyclic carbene may be imidazol- or imidazoline based and have the general formula:
  • Such an N-heterocyclic carbene may be formed from an imidazole or an imidazoline compound and a base (supra).
  • the imidazole compound may be of general formula (I)
  • the imidazoline compound may be of general formula (II):
  • R 1 1 - R 13 are independently selected from H, an aliphatic group, an alicyclic group, an aromatic group, an arylaliphatic group, and an arylalicyclic group.
  • a respective aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group may include 0 to about 3 heteroatoms selected from the group N, O, S, Se and Si.
  • Providing the Ruthenium (II) catalyst in a method according to the invention may include forming the Ruthenium (II) catalyst, for example forming the Ruthenium (II) catalyst in situ.
  • the Ruthenium (II) catalyst may be formed from a Ruthenium (II) precatalyst complex, which may be provided.
  • Forming the Ruthenium (II) catalyst from a Ruthenium (II) precatalyst complex may include allowing a reaction, such as complex formation with the N- heterocyclic carbene.
  • the Ruthenium catalyst is formed in situ from the N-heterocyclic carbene and a [Ru(A)Cl 2 ] 2 precatalyst complex in the presence of the base (supra).
  • Moiety A in formula [Ru(A)Cl 2 ] 2 may be an aromatic, an arylaliphatic or an arylalicyclic compound.
  • A is or includes an aromatic moiety that is free of nitrogen as a heteroatom in the respective aromatic ring(s) of the moiety.
  • the ring of the aromatic moiety consists only of carbon atoms. Any such aromatic ring may carry one or more substituents that may include one or more heteroatoms, e.g.
  • the moiety A is a hydrocarbon moiety that does not include any heteroatom.
  • the moiety A in formula [Ru(A)Cl 2 ] 2 is a benzene based moiety.
  • benzene based refers to a moiety that has a an aromatic moiety, the aromatic moiety being a benzene ring, i.e. an aromatic six-membered ring without a heteroatom.
  • This aromatic ring may carry substituents such as one or more aliphatic or alicyclic groups as well as one or more functional groups such as a hydroxyl group, a seleno group, a thiol group, a silyl group, a silano group, a sulfonyl group, a nitro group, a carboxy group, a halogen, an amino group, an amido group, a cyano group, an isocyano group or a thiocyano group (see also above for examples).
  • the benzene ring may also be linked or fused to an aromatic, an arylaliphatic or an arylalicyclic group.
  • a benzene based moiety has a single aromatic moiety, the aromatic moiety being the benzene ring.
  • the aromatic cycle may nevertheless carry substituents such as one or more aliphatic or alicyclic groups as well as one or more functional groups (supra).
  • R 5 - R 7 and R 9 - R 11 are independently selected from H, an aliphatic group, an alicyclic group, an aromatic group, an arylaliphatic group, and an arylalicyclic group.
  • a respective aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group may include 0 to about 3 heteroatoms selected from the group N, O, S, Se and Si.
  • the benzene based moiety A may be unsubstituted benzene or cymene.
  • providing the Ruthenium catalyst further includes providing a nitrogen containing ligand.
  • a nitrogen containing ligand an atom or a molecule that is or that can be attached to a central atom, in the present case ruthenium (II), in a coordination or complex compound is called a ligand.
  • a ligand is capable of functioning as an electron-pair donor in a coordinate covalent bond (electron-pair bond) formed with the metal atom. Attachment of the ligand to the ruthenium atom may be through a single atom, e.g.
  • L-type ligands are classified as "L-type", "X-type” and "Z-type".
  • L, X, and Z correspond respectively to 2-electron, 1 -electron and 0-electron neutral ligands.
  • X-type ligands are formed from an anionic precursor molecule and L-type ligands from a charge-neutral precursor molecule. Examples of L-type ligands are CO, a phosphine (e.g.
  • a nitrogen containing ligand provided in a method of the invention is an L-type ligand, such as a nitrile and an amine, e.g. acetonitrile or pyridine.
  • ruthenium (II) catalyst is formed from a [Ru(A)Cl 2 ]2 precatalyst complex (supra) and a metal halogenide complex of an N-heterocyclic carbene, a nitrogen containing ligand such as an L-type ligand is not provided.
  • a nitrogen containing ligand such as an L-type ligand.
  • the inventors have found that in such embodiments the formation of an amide proceeds smoothly in the absence of an additional nitrogen containing ligand such as an L-type ligand.
  • providing the Ruthenium (II) compound defining the Ruthenium (II) catalyst includes forming one or more Ruthenium (II) complexes of formulae
  • R 5 - R 7 and R 9 - R 15 are independently from one another H or an aliphatic, an alicyclic, an aromatic, an arylaliphatic or an arylalicyclic group.
  • the respective aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group may have 0 to about 3, including 1 or 2, heteroatoms. Such a heteroatom may be N, O, S, Se or Si.
  • X is halogen or -OR 16 .
  • R 16 in -OR 16 is H or an aliphatic, an alicyclic, an aromatic, an arylaliphatic or an arylalicyclic group.
  • the respective aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group may have 0 to about 3, including 1 or 2, heteroatoms, such as N, O, S, Se or Si.
  • L 1 , L 2 and L 3 are independently selected from a solvent molecule, the L-type ligand (e.g. pyridine or acetonitrile, supra) and the N-heterocyclic carbene (supra).
  • the Ruthenium catalyst that is provided can be represented by one of the above formulae (IV) to (VI).
  • a Ruthenium (II) catalyst of one or more of formulae (IV) to (VI) is provided, including formed, in a process according to the invention.
  • a catalyst of one of formulae (IV) to (VI) is an intermediate that is formed in situ.
  • a catalyst of one of formulae (IV) to (VI) is used in isolated, enriched or purified form.
  • isolated means that a respective Ruthenium (II) catalyst is no longer included in a reaction mixture formed by adding e.g.
  • a Ruthenium (II) precatalyst complex such as a [Ru(A)Cl 2 ] 2 precatalyst complex
  • a solvent for instance together with an N-heterocyclic carbene.
  • the Ruthenium (II) catalyst has been removed from such solvent or solution, for instance the solution in which it was formed.
  • the term "enriched" means that a respective Ruthenium (II) catalyst constitutes a significantly higher fraction of the total compounds, including the Ruthenium compounds, present in the matter, typically a solid or solution thereof, than in a reaction mixture in which the process of the invention has been carried out. Examples of other means of enrichment are a filtration or a precipitation.
  • purified means that a respective Ruthenium (II) catalyst constitutes a certain desired portion of the total matter, e.g. solid matter addressed.
  • a purified Ruthenium (II) catalyst may for example be a solid matter, e.g. powder, which contains at least about 50 %, about 60 %, about 60 %, about 70 %, about 80 %, about 90 %, about 95 % or more of Ruthenium (II) catalyst.
  • the Ruthenium (II) catalyst may in some embodiments be provided in catalytic amounts.
  • the term "catalytic amount,” as used herein, includes that amount of the Ruthenium (II) catalyst that is sufficient for a reaction of the process of the invention to occur.
  • the quantity that constitutes a catalytic amount is any quantity that serves to allow or to increase the rate of reaction, with larger quantities typically providing a greater increase.
  • the quantity used in any particular application will be determined to a large part by the individual needs of the manufacturing facility. Factors which enter into such a determination include the catalyst cost, recovery costs, desired reaction time, and system capacity.
  • an amount of Ruthenium (II) catalyst in the range from about Q.001 to about 0.5 equivalents, from about 0.001 to about 0.25 equivalents, from about 0.01 to about 0.25 equivalents, from about 0.001 to about 0.1, from about 0.01 to about 0.1 equivalents, including about 0.005, about 0.05 or about 0.08 equivalents of the primary amine, or in the range from about 0.001 to about 1 equivalents, from about 0.001 to about 0.5 equivalents, from about 0.001 to about 0.25 equivalents, from about 0.001 to about 0.1 equivalents, from about 0.01 to about 0.5 equivalents or from about 0.05 to about 0.1 equivalents, including about 0.015, about 0.02 or about 0.04 equivalents of the diol compound.
  • the Ruthenium (II) catalyst used in the invention includes a phosphine ligand.
  • a phosphine typically has the general formula PR 40 R 41 R 42 .
  • R 40 , R 41 and R 42 are independent from one another an aliphatic, an alicyclic, an aromatic, an arylaliphatic, or an arylalicyclic group.
  • a respective aliphatic, alicyclic, aromatic, arylaliphatic or arylalicyclic group may include 0 to about 3 heteroatoms selected from the group N, O, S, Se and Si.
  • one of R 40 , R 41 and R 42 in a phosphine defines an aliphatic, aromatic or arylaliphatic bridge that is linked to a respective fiirther moiety.
  • R 40 may define a bridge with R 41 or with R 42
  • R 41 may define a bridge with R 40 or R 42 .
  • a suitable phosphine ligand include, but are not limited to, triphenylphosphine, trimethylphosphine, triethylphosphine, tri-n-butylphosphine, tri-n-propyl phosphine, tri-n- butyl phosphine, tri-f-butyl phosphine, tri-p-tolyl phosphin, methyldiphenyl phosphine, phenyldimethyl phosphine (PPh(Me) 2 ), ethyldiphenyl phosphine (P(Et)(Ph) 2 ), tricyclohexyl phosphine (PCy 3 ), (S)-(2-methoxyphenyl)-[2-[(2-methoxyphenyl)-phenylphosphanyl]ethyl]- phenylphosphane (DIP AMP) or tris(di
  • a process according to the present invention may in some embodiments be carried out without adding a phosphine.
  • the Ruthenium (II) catalyst used, including formed in the process of the invention may be free of a phosphine ligand.
  • the process is carried out in the absence of a phosphine.
  • the primary amine and the diol are provided.
  • the amine and the diol may be different molecules, i.e. reactants.
  • the (primary or secondary) amine and the (primary) alcohol are contacted in the presence of the Ruthenium (II) catalyst.
  • the amine and the diol may also be different moieties of the same molecule.
  • the molecule that includes the amine moiety and the alcohol moiety is exposed to the Ruthenium (II) catalyst.
  • Contacting the amine and the diol compound in the presence of the catalyst, or exposing the molecule with the corresponding amine and alcohol moieties, respectively, is typically carried out by adding the corresponding molecules into a suitable solvent.
  • reaction mixture is formed.
  • the reaction mixture may be brought to an elevated temperature, i.e. a temperature above ambient temperature.
  • Ambient temperature is typically about 18 °C or about 20 °C.
  • the reaction mixture may for example be brought to a temperature above about 30 °C, above about 40 °C, above about 60 °C, above about 80 °C, above about 100 °C, above about 120 °C or above about 140 °C.
  • the temperature may for example be selected in the range from about 25 °C to about 200 °C, such as from about 30 °C to about 180 °C, including about 40 °C to about 180 °C, about 30 °C to about 110 °C, about 40 °C to about 160 °C, about 40 °C to about 110 °C, about 50 °C to about 180 °or about 60 °C to about 180 °C.
  • the temperature selected may for example be the boiling point of the reaction mixture, which is largely determined by the boiling point of the solvent used. As an illustrative example, if toluene is used as the solvent, the boiling point that may be selected as the temperature is about 120 °C. As a further example, if mesitylene is used as the solvent, the boiling point is about 163 °C.
  • Solvents used may be polar or non-polar liquids that are compatible with the catalyst used. Due to the sensitivity of the ruthenium (II) compound used, it may be disadvantageous to use protic polar liquids, which may in some embodiments be avoided. In some embodiments it may also be disadvantageous to use a chlorinated liquid (supra), which may thus in some embodiments be avoided. Accordingly, in some embodiments a non-polar liquid is used that does not have a chlorine substituent. In addition the liquid used is in some embodiments free of substituents, which are capable of coordinating to ruthenium (II) due to the presence of electron lone pair(s).
  • the liquid used as a solvent is free of substituents that have nitrogen, sulfur or oxygen atoms.
  • non-polar liquids include, but are not limited to mineral oil, pentane, hexane, heptane, cyclohexane, cyclooctane, benzene, toluene, mesitylene, carbon disulfide, and a non-polar ionic liquid.
  • non-polar ionic liquid examples include, but are not limited to, l-ethyl-3- methylimidazolium bis[(trifluoromethyl)sulfonyl]amide bis(triflyl)amide, l-ethyl-3-methyl- imidazolium bis[(trifluoromethyl)sulfonyl]amide trifluoroacetate, l-butyl-3-methylimida- zolium hexafluorophosphate, l-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, l-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, trihexyl(tetradecyl)phospho- nium bis[oxalate (2-)]borate, l-hexyl-3 -methyl imidazolium tris(pentafluoroethyl)trifluoro
  • the solvent used is an aromatic liquid that is free of halogen substituents.
  • a respective aromatic liquid include, but are not limited to, benzene, toluene, mesitylene, p-xylene, m-xylene, ethylbenzene, propylbenzene, an ethyl toluene, p-cymene, o-cymene, cumene, naphthalene, phenanthrene or pyrene.
  • the strategy for the amide synthesis is to oxidize alcohol to aldehyde first and then further oxidize the hemiaminal, formed from the aldehyde and the amine, to amide evolving two equivalents of hydrogen gas.
  • RuH 2 (PPh 3 ) 4 (lc) for the synthesis of cyclic lactam from ⁇ , ⁇ -aminoalcohols by Naota and Murahashi (Synlett (1991) 693).
  • RuH 2 (PPh 3 ) 4 showed good activity (70%) with the help of the NHC precursor 2 (entry 5).
  • Further optimization has been attempted by applying different NHC precursors, however, the reported condition using 2 has been identified most active, see Muthaiah et al. (J. Org. Chem. (2010) 75, 3002) for more detailed screening conditions.
  • NHC promoted RuH 2 (PPh 3 ) 4 based catalyst was recently reported to be active on the synthesis of amides from either alcohols or aldehydes with amines (ibid.).
  • lactones either in low yielding reactions or in lower concentrations can be explained as an intramolecular reaction of an aldehyde intermediate as reported (Murahashi et al., 1981, supra; Murahashi et al, 1987, supra; Ishii et al., 1986, supra; Blum & Shvo, 1984, supra; Zhao & Hartwig, 2005, supra; Ito et al., 2007, supra; Murahashi et al., 1982, supra; Abbenhuis et al., 1998, supra).
  • Tetramethylsilane was used as reference, and the chemical shifts were reported in ppm and the coupling constants in Hz.
  • GC yield were obtained on a Agilent 7890A instrument equipped with an HP-5 column using dodecane as an internal standard. Mass spectrometry was performed by Waters Q-Tof Premier Micromass instrument, using Electro Spray Ionization (ESI) mode. 1,3-diisopropylimidazolium bromide (Starikova, OV, et al., Russ. J. Org. Chem. (2003) 39, 1467), RuH 2 (PPh 3 ) 4 (Levison, JJ, & Robinson, SD, J. Chem. Soc.
  • ESI Electro Spray Ionization

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Abstract

La présente invention concerne un procédé de synthèse d'un imide cyclique. Une amine primaire et un diol sont mis en contact en présence d'un complexe de ruthénium (II). Le catalyseur au ruthénium (II) inclut au moins l'un des éléments du groupe constitué par un ligand alicyclique, un ligand aromatique, un ligand arylalicyclique, un ligand arylaliphatique et un ligand phosphine.
PCT/SG2011/000233 2010-07-02 2011-07-01 Procédé de formation d'un imide cyclique Ceased WO2012002913A1 (fr)

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US9932315B2 (en) 2014-08-08 2018-04-03 Massachusetts Institute Of Technology Persistent carbene adducts and related methods
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014100218A1 (fr) 2012-12-21 2014-06-26 Exxonmobil Chemical Patents Inc. Synthèse améliorée de succinimides et d'ions ammonium quaternaires destinée à être utilisée dans la fabrication de tamis moléculaires
US10035762B2 (en) 2012-12-21 2018-07-31 Exxonmobil Chemical Patents Inc. Synthesis of succinimides and quaternary ammonium ions for use in making molecular sieves
WO2015016521A1 (fr) * 2013-07-29 2015-02-05 서울대학교산학협력단 Procédé de préparation d'amide et d'imide à partir d'alcool et de composé hétérocyclique azoté
US9932315B2 (en) 2014-08-08 2018-04-03 Massachusetts Institute Of Technology Persistent carbene adducts and related methods
CN104496880A (zh) * 2014-12-24 2015-04-08 东华大学 一种n-甲基-3-苯基琥珀酰亚胺化合物及其制备方法
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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