WO2019208043A1 - Procédé de production d'un composé imine n-protégé - Google Patents

Procédé de production d'un composé imine n-protégé Download PDF

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WO2019208043A1
WO2019208043A1 PCT/JP2019/012006 JP2019012006W WO2019208043A1 WO 2019208043 A1 WO2019208043 A1 WO 2019208043A1 JP 2019012006 W JP2019012006 W JP 2019012006W WO 2019208043 A1 WO2019208043 A1 WO 2019208043A1
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compound
otf
reaction
mmol
producing
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孝志 大嶋
浩之 森本
一宏 森崎
優太 近藤
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国立大学法人九州大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/20—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups being part of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
    • C07C251/24—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to carbon atoms of six-membered aromatic rings
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes 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 in position 9
    • C07D311/88—Nitrogen atoms
    • 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
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods

Definitions

  • the present invention relates to a method for producing (synthesizing) an unprotected imine compound on nitrogen.
  • Patent Document 1 requires a high temperature of reaction temperature of 100 ° C. or higher and an operation of blowing a large amount of ammonia gas that is highly toxic and difficult to handle, and is not easy to implement.
  • the reaction substrate is limited to benzophenone imine, and the substrate generality is poor.
  • An object of the present invention is to provide a method for easily and inexpensively producing various unprotected imine compounds on nitrogen.
  • the present inventors have eliminated various limitations in the conventional method for producing an unprotected imine compound on nitrogen, and can synthesize various unprotected imine compounds on nitrogen easily and inexpensively, As a result of intensive studies, it was found that this can be solved by using a specific catalyst, and the present invention has been completed.
  • the present invention is as follows.
  • the metal salt having Lewis acidity is a triflate salt, nonaflate salt or trifluoromethanesulfonylimide salt of at least one metal selected from rare earth metals, Fe, In, Sn and Bi, or Sc (NO 3 ) 3 or characterized in that it is a BiBr 3 [1] production method of nitrogen on unprotected imine compounds described. [3] The method for producing an unprotected imine compound on nitrogen according to [2], wherein the rare earth metal is Sc, Y, Sm, Eu, Gd, Er, or Yb.
  • the metal salt having Lewis acidity is Sc (OTf) 3 , Y (OTf) 3 , Sm (OTf) 3 , Eu (OTf) 3 , Gd (OTf) 3 , Er (OTf) 3 , Yb (OTf). ) 3 , Fe (OTf) 3 , In (OTf) 3 , Sn (OTf) 2 , Bi (OTf) 3 , Sc (ONf) 3 , and Sc (NTf 2 ) 3
  • the method for producing an unprotected imine compound on nitrogen as described in any one of [1] to [3].
  • a nitrogen source compound (2) represented by Following formula (3) (R 1 and R 2 have the same meanings as those in the ketone compound (1) represented by the formula (1).)
  • the nitrogen compound is characterized by producing the imine compound (3) or a salt thereof. A method for producing a protected imine compound.
  • the method for producing an unprotected imine compound on nitrogen comprises a ketone in the presence of at least one catalyst selected from a catalyst containing a metal salt having Lewis acidity and a catalyst containing a fluorine-containing anion salt of tetraalkylammonium.
  • the imine compound (3) or a salt thereof is produced by reacting the compound (1) with the nitrogen source compound (2).
  • the production method of the present invention has a larger substrate selection range than conventional methods for producing unprotected imine compounds on nitrogen, and various inexpensive unprotected imine compounds on nitrogen can be obtained from commercially available compounds and catalysts that are readily available. It can be manufactured safely. Moreover, since it can implement under a normal pressure, a special reaction instrument and apparatus are not required and the unprotected imine compound on nitrogen can be obtained with a high yield on reaction conditions with easy implementation. In addition, the conventional method generally requires purification of an unprotected imine compound in order to remove a by-product that can inhibit the following reaction, whereas the present invention provides an unprotected imine compound on nitrogen in a high yield.
  • the imine compound can be used as it is in the next reaction without removing it from the reaction system (Example) 6, 7 and 16 (one-pot synthesis)).
  • Catalyst (Catalyst containing metal salt having Lewis acidity)
  • the metal salt having Lewis acid include a rare earth metal and a metal triflate, nonaflate, or trifluoromethanesulfonylimide salt selected from Fe, In, Sn, and Bi, Sc (NO 3 ) 3 , and BiBr 3. it can.
  • At least one metal triflate, nonaflate or trifluoromethanesulfonylimide salt selected from Sc, Y, Sm, Eu, Gd, Er, Yb, Fe, In, Sn and Bi, or Sc (NO 3 ) 3 or BiBr 3 is preferred, and is a triflate, nonaflate or trifluoromethanesulfonylimide salt of at least one metal selected from Sc, Y, Sm, Eu, Gd, Er, Yb, Fe, In, Sn and Bi.
  • a triflate salt of at least one metal selected from Sc, Y, Eu, Er, Yb, Fe, Sn, and Bi, or a nonaflate salt is more preferable, and at least one selected from Sc, Er, Sn, and Bi.
  • Some metal triflate or nonaflate salts are particularly preferable.
  • the metal salt having Lewis acidity Sc (OTf) 3 , Y (OTf) 3 , Sm (OTf) 3 , Eu (OTf) 3 , Gd (OTf) 3 , Er (OTf) 3 , Yb (OTf) 3 , Fe (OTf) 3 , In (OTf) 3 , Sn (OTf) 2 , Bi (OTf) 3 , Sc (ONf) 3 , Sc (NTf 2 ) 3 , Sc (NO 3 ) 3 , BiBr 3 etc. can be mentioned.
  • the amount of the catalyst can be appropriately adjusted so that the reaction proceeds appropriately.
  • 0.001 per 1 mol of the ketone compound (1) about 0.3 mol, preferably about 0.002 to 0.2 mol, more preferably about 0.005 to 0.1 mol.
  • the alkyl part of the fluorine-containing anion salt of tetraalkylammonium preferably has 1 to 6 carbon atoms.
  • Specific examples of the fluorine-containing anion salt of tetraalkylammonium include tetrabutylammonium fluoride (TBAF) and tetrabutylammonium dihydrogen trifluoride (TBAH 2 F 3 ). Tetrabutylammonium fluoride Is preferred. It may be an anhydride or a hydrate.
  • the amount of the catalyst can be appropriately adjusted so that the reaction proceeds appropriately, but relative to 1 mol of the ketone compound (1) For example, it is about 0.005 to 0.3 mol, preferably about 0.01 to 0.2 mol, and more preferably about 0.03 to 0.1 mol.
  • the ketone compound (1) used in the production method of the present invention is a compound represented by the following formula (1).
  • R 1 and R 2 each represents an organic group and may be linked to each other to form a ring.
  • examples of R 1 and R 2 include an aromatic group including an aromatic ring, a heterocyclic group including a heterocyclic ring, and an aliphatic group.
  • examples of the aromatic ring of the aromatic group include benzene and naphthalene.
  • examples of the heterocyclic ring of the heterocyclic group include pyridine, pyrazine, quinoline and the like.
  • the aliphatic group may be a linear, branched or cyclic aliphatic group, and may be saturated or unsaturated. In addition, the aliphatic group may be blocked with a heteroatom (a heteroatom may be present between the carbon linkages).
  • aromatic groups, heterocyclic groups and aliphatic groups may have a substituent.
  • substituents include an alkyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom, an alkoxy group having 1 to 4 carbon atoms which may be substituted with a halogen atom, a hydroxyl group and a halogen atom. it can.
  • R 7 to R 11 each represents an aliphatic group, preferably an alkyl group having 1 to 4 carbon atoms.
  • examples of the ketone compound (1) include the following.
  • ketone compounds (1) a ketone compound having the following structure is extremely difficult to synthesize an imine compound by a conventional method using a Grignard reagent, etc., but according to the production method of the present invention, An imine compound can be obtained with a high yield.
  • the nitrogen source compound (2) used in the production method of the present invention is a compound represented by the following formula (2).
  • R 3 and R 4 each represent a hydrogen atom or an aliphatic group.
  • the aliphatic group may be a linear, branched or cyclic aliphatic group, and may be saturated or unsaturated. Among these, a saturated or unsaturated linear aliphatic group having 1 to 4 carbon atoms is preferable.
  • R 5 represents a hydrogen atom, an aliphatic group, or a substituent having the following structure bonded to each other.
  • the aliphatic group is the same as R 3 and R 4 .
  • R 6 represents a hydrogen atom or an aliphatic group, and the aliphatic group is the same as R 3 and R 4 .
  • nitrogen source compound (2) examples include the following.
  • the amount of the nitrogen source compound (2) used in the production method of the present invention is, for example, about 1.0 to 3.0 mol, preferably about 1.0 to 1.5 mol, relative to 1 mol of the ketone compound (1). .
  • the nitrogen source compound may be used in the same amount or slightly more, and it is not necessary to use it excessively.
  • the imine compound (3) to be produced is a compound represented by the following formula (3).
  • the imine compound (3) may be in the form of a salt.
  • the kind of salt is not particularly limited, and examples thereof include halides (fluorides, chlorides, bromides, iodides), sulfonates, and the like.
  • Solvents used in the production method of the present invention include chlorobenzene (preferably monochlorobenzene), toluene, tetrahydrofuran, dioxane (preferably 1,4-dioxane), fluorobenzene, dichloroethane, acetononitrile, alcohol, N, N-dimethyl.
  • Formamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), N, N-dimethylpropylene urea (DMPU) ), 1,3-dimethyl-2-imidazolidinone (DMI) and the like, and these may be used as a mixture.
  • DMF dimethyl sulfoxide
  • NMP N-methyl-2-pyrrolidone
  • DMA N-dimethylacetamide
  • HMPA hexamethylphosphoric triamide
  • DMPU N-dimethylpropylene urea
  • DI 1,3-dimethyl-2-imidazolidinone
  • chlorobenzene, toluene, tetrahydrofuran, fluorobenzene and acetononitrile are preferred.
  • chlorobenzene, toluene, tetrahydrofuran, fluorobenzene, N, N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N, N-dimethylacetamide, hexamethyl Phosphoric triamide, N, N-dimethylpropyleneurea and 1,3-dimethyl-2-imidazolidinone are preferred, N, N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, N, N-dimethyl Polar solvents such as acetamide, hexamethylphosphoric triamide, N, N-dimethylpropyleneurea and 1,3-dimethyl-2-imidazolidinone are more preferred.
  • the reaction can be promoted by adding a polar solvent as an additional solvent to the nonpolar solvent.
  • reaction accelerator in the present invention, a reaction accelerator can be used.
  • the reaction accelerator include water, alcohol, silanol and the like.
  • the alcohol include methanol, ethanol, butanol and the like.
  • silanols include trimethylsilanol.
  • the addition amount of the reaction accelerator is, for example, about 0.01 to 1.0 mol, preferably about 0.02 to 0.8 mol, preferably 0.05 to 0, per 1 mol of the ketone compound (1). More preferably, it is about 5 mol.
  • the temperature (reaction temperature) for reacting the ketone compound (1) and the nitrogen source compound (2) in the production method of the present invention is preferably about 0 to 150 ° C.
  • a metal salt having Lewis acidity it is more preferably from room temperature (25 ° C.) to about 150 ° C., more preferably from about 50 to 100 ° C.
  • a catalyst containing a fluorine-containing anion salt of tetraalkylammonium is used, it is more preferably about 10 to 100 ° C, and further preferably about 15 to 70 ° C.
  • the reaction in the production method of the present invention does not require an extremely low temperature or high temperature, and the production cost is low.
  • the reaction time depends on other conditions such as the reaction temperature, but is, for example, about 0.25 to 48 hours, preferably about 0.5 to 24 hours, and more preferably about 0.75 to 15 hours. Preferably, about 5 to 15 hours is more preferable.
  • the conditions of reaction temperature and reaction time can be determined optimally while confirming the yield.
  • the yield is preferably 40 mol% or more, more preferably 60 mol% or more, further preferably 80 mol% or more, particularly preferably 90 mol% or more, and 95 mol% or more. Is most preferred.
  • the reaction of the ketone compound (1) and the nitrogen source compound (2) can be carried out substantially without using a solvent.
  • performing the reaction substantially without using a solvent means that the reaction is performed without using a general solvent amount of the solvent, for example, a reaction using a small amount of solvent that dissolves the catalyst. Is included in the reaction substantially using no solvent.
  • the amount of solvent in the reaction using substantially no solvent in the production method of the present invention is, for example, 0.1 mL or less with respect to 1 mmol of the ketone compound (1).
  • the yield exceeded 20% in all cases.
  • Sc (OTf) 3 , Y (OTf) 3 , Sm (OTf) 3 , Eu (OTf) 3 , Gd (OTf) 3 , Er (OTf) 3 , Yb (OTf) 3 , Fe (OTf) 3 , In (OTf) 3 , Sn (OTf) 2 , Bi (OTf) 3 , Sc (ONf) 3 , and Sc (NTf 2 ) 3 were able to achieve a yield of 40% or more.
  • the yield is 50% or more, and for Sm (OTf) 3 , the yield is 60% or more.
  • Y (OTf), Eu (OTf) 3 the yield is 80% or more, and Sc (OTf) 3 , Er (OTf) 3 , Sn (OTf) 2 , Bi (OTf) 3 and Sc (ONf)
  • the yield was 95% or more.
  • Sc (OTf) 3 achieves a yield of 80% or more despite being a low temperature and short time reaction condition of 70 ° C. for 1 hour, and is a particularly excellent catalyst. I understand.
  • Example 4-6 Synthesis of di-p-tolylmethanimine
  • the reaction was carried out using 0.20 mmol of 4,4′-dimethylbenzophenone under the above basic reaction conditions for 3 hours.
  • Example 4-19-2 Synthesis of 2,2,2-trifluoro-1-phenylethaneimine on a large scale (10 mmol)
  • a 50 mL flask was charged with scandim (III) trifluoromethanesulfonate (49.2 mg, 0.10 mmol, 1.0 mol%), 2,2,2-trifluoroacetophenone ( 1.4 mL, 10 mmol), fluorobenzene (10 mL, 1.0 M), bis (trimethylsilyl) amine (2.3 mL, 11 mmol, 1.1 equivalents) were added, and the mixture was heated and stirred at 90 ° C. for 24 hours.
  • scandim (III) trifluoromethanesulfonate 49.2 mg, 0.10 mmol, 1.0 mol
  • 2,2,2-trifluoroacetophenone 1.4 mL, 10 mmol
  • fluorobenzene 10 mL, 1.0 M
  • bis (trimethylsilyl) amine 2.3
  • reaction accelerator [Examination of reaction accelerator] A stir bar was placed in a 4 mL vial, scandium (III) trifluoromethanesulfonate (0.010 mmol, 5.0 mol%) as a catalyst was added, and the mixture was heated and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, benzophenone (0.20 mmol) as the ketone compound (1), monochlorobenzene (1.0 mL, 1.0 M) as the solvent, nitrogen source compound (2) (0.22 mmol, 1 0.1 equivalent), a reaction accelerator (0.010 mmol, 5.0 mol%) was added. Trimethylsilanol (TMSOH) and methanol (MeOH) were used as reaction accelerators. After the mixture was stirred at 50 ° C., the yield of the product was determined by 1 H NMR measurement of the reaction crude product. The results are shown in Table 7.
  • the imine was obtained as a yellow oil (162 mg, 90% yield).
  • unprotected ketimine on nitrogen was produced by using a catalyst containing a fluorine-containing anion salt of tetraalkylammonium.
  • TBAF was able to achieve a yield of 80% or more.
  • Additional solvents include N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), N, N-dimethylpropyleneurea (DMPU) and 1,3-dimethyl-2-imidazolidinone (DMI) were used.
  • the mixture was stirred at room temperature for 24 hours, and the yield was determined by 1 HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The results are shown in Table 10.
  • N, N-dimethylformamide (DMF) is improved by the addition of 10 mol% to 200 mol% (0.1 to 2 equivalents), and 100 mol% is particularly excellent.
  • Additional solvents include N, N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), N, N-dimethylpropylene Urea (DMPU) and 1,3-dimethyl-2-imidazolidinone (DMI) were used. After the mixture was stirred at room temperature for 2 hours, the yield of the product was determined by 1 H NMR measurement of the reaction crude product. The results are shown in Table 11.
  • N N-dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP), N, N-dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPA), N, N -An improvement in yield was observed by adding dimethylpropyleneurea (DMPU) and 1,3-dimethyl-2-imidazolidinone (DMI). In particular, it can be seen that DMF and DMPU are excellent.
  • the reaction proceeded even at a low temperature of 0 ° C.
  • the reaction proceeded particularly well at room temperature (25 ° C.).
  • Example 14-1 (Synthesis of cyclohexyl (phenyl) methanimine) Stirring was performed for 6 hours using 1.0 mmol of cyclohexyl (phenyl) ketone under the above basic reaction conditions. From 1 HNMR measurement, it was confirmed that the desired cyclohexyl (phenyl) methanimine was produced in a yield of> 99%.
  • Example 14-2 (Synthesis of cyclobutyl (phenyl) methanimine) Stirring was performed for 6 hours using 1.0 mmol of cyclobutyl (phenyl) ketone under the above basic reaction conditions. From 1 HNMR measurement, it was confirmed that the desired cyclobutyl (phenyl) methanimine was produced in a yield of> 99%.
  • Example 14-7 (Synthesis of 1-phenylpentane-1-imine) Stirring was performed for 24 hours using 1.0 mmol of valerophenone under the above basic reaction conditions. From 1 HNMR measurement, it was confirmed that the target 1-phenylpentane-1-imine was produced in a yield of 81%, and 10% of unreacted valerophenone remained.
  • Example 14-8 (Synthesis of dicyclopropylmethanimine) Stirring was carried out for 24 hours using 1.0 mmol of dicyclopropyl ketone under the above basic reaction conditions. From 1 HNMR measurement, it was confirmed that the target dicyclopropylmethanimine was produced in a yield of 60%, and 35% of unreacted dicyclopropylketone remained.
  • reaction proceeded without any problem even when the cyano source was reduced to 1.5 equivalents.
  • reaction proceeded similarly when TMSCN was used as the cyano source.
  • reaction accelerator (1) A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol) as the ketone compound (1), bis (trimethylsilyl) amine (2.0 mmol, 2.0 equivalents) as the nitrogen source compound (2), reaction Accelerator (1.0 mmol, 1.0 eq) and tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 0.10 mL, 0.10 mmol, 10 mol%) as catalyst were added.
  • argon cyclohexyl (phenyl) ketone
  • bis (trimethylsilyl) amine 2.0 mmol, 2.0 equivalents
  • reaction Accelerator 1.0 mmol, 1.0 eq
  • TBAF tetrabutylammonium fluoride
  • TMSOH trimethylsilanol
  • MeOH methanol
  • EtOH ethanol
  • the reaction is accelerated (the yield is improved) by adding trimethylsilanol, methanol, and ethanol, and it can be seen that ethanol is particularly excellent. It can be seen that the yield is improved when the amount of ethanol is 10 to 50 mol%, and particularly 10 mol% is excellent. Moreover, it turns out that a yield improves by making the quantity of a nitrogen source into 1.5 equivalent. Further, it can be seen that the reaction proceeds almost quantitatively by extending the reaction time to 24 hours. It can be seen that trimethylsilanol gives better results when extended to 24 hours.
  • reaction accelerator (2) [Examination of reaction accelerator (2)] A stir bar was placed in a 4 mL vial and dried with a heat gun under reduced pressure. After cooling, the vial was filled with argon, cyclohexyl (phenyl) ketone (1.0 mmol) as the ketone compound (1), bis (trimethylsilyl) amine (2.0 mmol, 2.0 equivalents) as the nitrogen source compound (2), solvent As N, N-dimethylformamide (1.0 mmol), tetrabutylammonium fluoride (TBAF, 1.0 M in THF, 0.10 mL, 0.10 mmol, 10 mol%) as a catalyst, and H 2 O (0 .10 mmol, 10 mol%) was added. The mixture was stirred at room temperature for 6 hours, and the yield was determined by 1 HNMR measurement of a crude product using 1,2,4,5-tetramethylbenzene as an internal standard substance. The results are shown in Table 18.
  • the present invention is industrially useful because an unprotected imine compound on nitrogen can be produced.

Abstract

Le problème à résoudre par la présente invention est de fournir un procédé de production simple de divers composés imines N-protégés de manière peu coûteuse et sans danger. La solution selon l'invention concerne un procédé de production d'un composé imine N-protégé consistant à faire réagir un composé cétone et un composé source d'azote en présence d'au moins un catalyseur choisi parmi : un catalyseur contenant un sel métallique d'acide de Lewis tel que des sels triflate de Sc, Y, Sm, Eu, Gd, Er, Yb, Fe, In, Sn, et Bi ; et un catalyseur contenant un sel d'anion contenant du fluor de tétraalkylammonium.
PCT/JP2019/012006 2018-04-24 2019-03-22 Procédé de production d'un composé imine n-protégé WO2019208043A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113372238A (zh) * 2021-06-30 2021-09-10 上海科技大学 一种亚胺类化合物及其合成方法和用途
WO2024071178A1 (fr) * 2022-09-28 2024-04-04 積水メディカル株式会社 Procédé de production d'un composé benzylamine à substitution alkylsilyloxy

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WO2024071178A1 (fr) * 2022-09-28 2024-04-04 積水メディカル株式会社 Procédé de production d'un composé benzylamine à substitution alkylsilyloxy

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