WO2010035948A1 - Novel (1,3-butadien-2-yl)methylamine derivatives and preparation method thereof - Google Patents

Novel (1,3-butadien-2-yl)methylamine derivatives and preparation method thereof Download PDF

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WO2010035948A1
WO2010035948A1 PCT/KR2009/004030 KR2009004030W WO2010035948A1 WO 2010035948 A1 WO2010035948 A1 WO 2010035948A1 KR 2009004030 W KR2009004030 W KR 2009004030W WO 2010035948 A1 WO2010035948 A1 WO 2010035948A1
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formula
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mmol
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butadien
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Tae Suk Lee
Phil Ho Lee
Hyunseok Kim
Jaemyung A
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Knu-Industry Cooperation Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/45—Monoamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
    • C07C239/08—Hydroxylamino compounds or their ethers or esters
    • C07C239/18—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to a novel (l,3-butadien-2-yl)methylamine derivative and a preparation method thereof.
  • nucleophilic compound to an imine to form a carbon-carbon bond is an important method for preparing an amine having a biological activity, but due to the poor reactivity of an imine derivative, various organometallic compounds are used as nucleophiles.
  • organoindium (indium) compounds which are stable in air and relatively non-toxic, have been developed to prepare various amines (Tetrahedron Lett. 1992, 33, 5959; Tetrahedron Lett. 1997, 38, 865; Tetrahedron Lett. 2000, 41, 9311; J. Org. Chem. 2001, 66, 7516; Tetrahedron Lett. 2001, 42, 9073; Tetrahedron Lett. 2003, 44, 6755; J. Org. Chem. 2007, 72, 923; and Org. Lett. 2008, 10, 1259). But these methods require the use of aprotic solvents because of the moisture-sensitivity of imines, and generally give unsatisfactorily low yields.
  • 1,3-diene substituent introduced therein is particularly useful for preparing an amine compound having beneficial biological activities.
  • the present inventors have therefore endeavored to develop a novel compound which can be used in preparing an amine having a 1,3-diene substituent, particularly a (l,3-butadien-2-yl)methylamine derivative.
  • A is Ci-Cio alkyl, C 3 -C 9 cycloalkyl, C 6 -C 12 aryl, C r Ci 0 alkoxycarbonyl, or C 3 -C 7 heteroaryl,
  • B is C 6 -C 12 aryl, C 6 -C 12 aryl C r Ci 0 alkyl, or C 6 -Ci 2 aryl C 1 -C 10 alkoxy, and
  • a and B are each optionally substituted by one or more substituents selected from the group consisting of C 1 -C 1O alkyl, Ci-Ci 0 alkoxy, halogen, and hydroxy.
  • a method for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I) which comprises conducting an addition reaction of an organoindium compound of formula (HI) with an imine compound of formula (IV):
  • n is an integer of 0 or 2
  • a and B have the same meanings as defined above.
  • a method for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I) which comprises the steps of (i) conducting a condensation reaction of an aldehyde derivative of formula (V) with an amine derivative of formula (VI) to obtain an imine compound, and (ii) conducting an addition reaction of the imine compound thus obtained with the organoindium compound of formula (IH) in situ without isolating the imine compound after step (i):
  • a and B have the same meanings as defined above.
  • alkyl refers to a straight or branched chain saturated hydrocarbon radical.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and hexyl.
  • alkoxy refers to the group -OR a , wherein R a is an alkyl group as defined above.
  • alkoxy as used herein include, but are not limited to, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
  • cycloalkyl refers to cyclic saturated aliphatic hydrocarbon radicals.
  • examples of “cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • aryl refers to a C 6 -C 12 aromatic hydrocarbon radical.
  • aryl as used herein include, but are not limited to, are phenyl, toluyl, xylyl, biphenyl, and naphthyl.
  • heteroaryl refers to an optionally substituted monocyclic five to six-membered aromatic ring containing one or more heteroatomic substitutions selected from S, SO, SO 2 , O, N, or N-oxide, or refers to such an aromatic ring fused to one or more rings such as heteroaryl rings, aryl rings, heterocyclic rings, or carbocycle rings (e. g., a bicyclic or tricyclic ring system), each having optional subsituents.
  • heteroaryl groups as used herein include, but are not limited to, are benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, imidazolyl, pyridyl, pyrrolyl, tetrazolyl, thiophenyl, triazolyl, and a substituted version thereof.
  • arylalkyl refers to Ci-C 10 alkyl substituted by a C 6 -Ci 2 aryl group, wherein the aryl has the same meaning as defined above.
  • arylalkyl as used herein include, but are not limited to, are benzyl, phenethyl, and phenylpropyl.
  • arylalkoxy refers to Ci-Cio alkoxy substituted by a C 6 -Ci 2 aryl S 1011 P J wherein the aryl has the same meaning as defined above.
  • arylalkoxy as used herein include, but are not limited to, are phenylmethoxy and phenylethoxy.
  • alkoxycarbonyl refers to the group -COOR t , wherein R b is an alkyl group as defined above.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • the (l,3-butadien-2-yl)methylamine derivative of formula (I) according to the present invention may be a compound, wherein A is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl, isopentyl, n-hexyl, cyclohexyl, chlorophenyl, methylphenyl, hydroxyphenyl, bromophenyl, iodophenyl, ethoxycarbonyl, furyl, or pyridyl, and B is iodophenyl,benzyl, methoxybenzyl, or benzyloxy.
  • Examples of the preferred (l,3-butadien-2-yl)methylamine derivative of formula (I) according to the present invention include the compounds of formulae (a) to (o):
  • n is an integer of 0 or 2
  • a and B have the same meanings as defined above.
  • the organoindium compound of formula (HI) may be used in an amount corresponding to 1.5 to 2.5 equivalents based on the indium metal of the imine
  • Example of the organoindium compound of formula (HI) include l,3-butadien-2-yl indium, which may be prepared by conducting a reaction of a l,4-dibromo-2-butyne compound of formula ( II ) with metallic indium (In), as shown in Reaction Scheme 2:
  • n is an integer of 0 or 2.
  • the metallic indium may be used in an amount corresponding to 1 to 2 equivalents based on the l,4-dibromo-2-butyne compound of formula ( II ).
  • inventive (l,3-butadien-2-yl)methylamine derivative of formula (I) may be prepared by subjecting the l,4-dibromo-2-butyne compound of formula ( ⁇ ) to a barbier type reaction with the imine compound of formula (IV) in the presence of metallic indium.
  • the 'barbier type reaction' refers to an one-step procedure for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I) from the
  • the l,4-dibromo-2-butyne compound of formula ( II ) may be used in an amount corresponding to 1.0 to 2.0 equivalents based on the imine compound of formula (IV).
  • the metallic indium may be used in an amount corresponding to 1.5 to 2.5 equivalents based on the indium metal of the imine compound of formula (IV).
  • the reaction may be carried out in the presence of a dry agent which remove moisture formed during the reaction.
  • a dry agent include a magnesium sulfate (MgSO 4 ) and sodium sulfate (Na 2 SO 4 ), which are used in an amount corresponding to 0.5 to 1.5 equivalents based on the imine compound of formula (IV).
  • Example of the reaction solvent includes a C 1 -C 7 lower alcohol such as methanol (MeOH) and ethanol (EtOH), preferably ethanol.
  • a C 1 -C 7 lower alcohol such as methanol (MeOH) and ethanol (EtOH), preferably ethanol.
  • the reaction may be conducted at room temperature, preferably at 25 °C .
  • the reaction time depends on reaction materials, and solvent and its content.
  • the reaction proceeds until no imine compound is detectable by TLC.
  • the resulting material thus obtained is extracted, distilled a reduced pressure to remove the solvent, and the residue is purified by a conventional method such as a column chromatography to obtain the desired material.
  • the inventive (l,3-butadien-2-yl)methylamine derivative of formula (I) may be prepared by conducting a sequence of reaction steps of (i) conducting a condensation reaction of an aldehyde derivative of formula (V) with an amine derivative of formula (VI) in a reaction solvent to obtain an imine compound, and (ii) conducting an addition reaction of the imine compound thus obtained with an organoindium compound of formula (IH) in situ without isolating the imine compound after step (i), as shown in Reaction Scheme 3:
  • n is an integer of 0 or 2
  • a and B have the same meanings as defined above.
  • the amine derivative of formula (VI) may be used in an amount corresponding to 1.0 to 2.0 equivalents based on the aldehyde derivative of formula (V).
  • the organoindium compound of formula (HI) may be used in an amount corresponding to 1 to 3 equivalents based on the indium metal of the aldehyde derivative of formula ( V ).
  • the condensation reaction of the step (i) may be carried out in the presence of an acid which activates the aldehyde derivative of formula ( V ).
  • Example of acid includes acetic acid (AcOH), which is used in an amount corresponding to 0.5 to 1.5 equivalents based on the aldehyde derivative of formula ( V).
  • reaction solvent examples include a Ci-C 7 lower alcohol such as methanol (MeOH) and ethanol (EtOH), preferably ethanol.
  • methanol MeOH
  • EtOH ethanol
  • the reaction temperature and reaction time are the same as described above.
  • (l,3-butadien-2-yl)methylamine derivative of formula (I) can be prepared in a high yield.
  • the inventive (l,3-butadien-2-yl)methylamine derivative is a novel compound having the 1,3-diene substituent at the alpha-position, which can be used in preparing various amine compounds having biochemical activities.
  • N-benzylidene-phenyl-amine (54.4 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere.
  • l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 2 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et 2 O (10 mL * 3).
  • N-(4-methylbenzylidene)-phenyl-amine (58.6 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere.
  • l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 2 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et 2 O (10 mL * 3).
  • N-(3-bromobenzylidene)-phenyl-amine (78 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in
  • N-(2-methylbenzylidene)-phenyl-amine (58.7 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere.
  • EtOH 1.2 mL
  • l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 4 hrs.
  • Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et 2 O (10 mL x 3).
  • N-(2-iodobenzylidene)-phenyl-amine (92.1 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere.
  • l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 5 hrs.
  • Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et 2 O (10 mL x 3).
  • N-((furan-2-yl)methylidene)-phenyl-amine (51.4 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere.
  • 1 ,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 2 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et 2 O (10 mL x 3).
  • N-benzylidene-(4-iodo-phenyl)-amine (92.1 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere.
  • 1 ,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 1 hr.
  • Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et 2 O (10 mL x 3).
  • the combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO 4 , filtered, and distilled under a reduced pressure to remove solvent.
  • the residue thus obtained was purified by column chromatography to obtain
  • N-benzylidene-(4-methoxy-phenyl)-amine (63.4 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere.
  • l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 4 hrs.
  • Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et 2 O (10 mL x 3).
  • the combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO 4 , filtered, and distilled under a reduced pressure to remove solvent.
  • the residue thus obtained was purified by column chromatography to obtain

Abstract

The present invention provides a novel (1,3-butadien-2-yl)methylamine derivative and a preparation method thereof. The (1,3-butadien-2-yl)methylamine derivative having the 1,3-diene substituent at the alpha-position is an useful precursor in preparing various amine compounds having biochemical activities.

Description

NOVEL (1.3-BUTADIEN-2- YL)METHYLAMINE DERIVATIVES AND PREPARATION METHOD THEREOF
FIELD OF THE INVENTION
The present invention relates to a novel (l,3-butadien-2-yl)methylamine derivative and a preparation method thereof.
BACKGROUND OF THE INVENTION
The addition reaction of a nucleophilic compound to an imine to form a carbon-carbon bond is an important method for preparing an amine having a biological activity, but due to the poor reactivity of an imine derivative, various organometallic compounds are used as nucleophiles.
For example, methods using organoindium (indium) compounds, which are stable in air and relatively non-toxic, have been developed to prepare various amines (Tetrahedron Lett. 1992, 33, 5959; Tetrahedron Lett. 1997, 38, 865; Tetrahedron Lett. 2000, 41, 9311; J. Org. Chem. 2001, 66, 7516; Tetrahedron Lett. 2001, 42, 9073; Tetrahedron Lett. 2003, 44, 6755; J. Org. Chem. 2007, 72, 923; and Org. Lett. 2008, 10, 1259). But these methods require the use of aprotic solvents because of the moisture-sensitivity of imines, and generally give unsatisfactorily low yields.
In addition, there has been developed a method for preparing an amine, which comprises conducting a sequence of reaction steps of conducting a condensation of an aldehyde derivative with an amine derivative to obtain an imine and an addition reaction of the imine thus obtained with an organoindium compound in situ {Tetrahedron Lett. 2004, 45, 3413; and Bull. Korean Chem. Soc. 2007, 28, 139). Among the aforementioned methods, the preparation of an amine having a
1,3-diene substituent introduced therein is particularly useful for preparing an amine compound having beneficial biological activities.
The present inventors have therefore endeavored to develop a novel compound which can be used in preparing an amine having a 1,3-diene substituent, particularly a (l,3-butadien-2-yl)methylamine derivative. SUMMARY OF THE INVENTION
Accordingly, it is a primary object of the present invention to provide a novel (l,3-butadien-2-yl)methylamine derivative. It is another object of the present invention to provide a preparation method of said derivative.
In accordance with one aspect of the present invention, there is provided a (l,3-butadien-2-yl)methylamine derivative of formula (I):
Figure imgf000003_0001
wherein,
A is Ci-Cio alkyl, C3-C9 cycloalkyl, C6-C12 aryl, CrCi0 alkoxycarbonyl, or C3-C7 heteroaryl,
B is C6-C12 aryl, C6-C12 aryl CrCi0 alkyl, or C6-Ci2 aryl C1-C10 alkoxy, and
A and B are each optionally substituted by one or more substituents selected from the group consisting of C1-C1O alkyl, Ci-Ci0 alkoxy, halogen, and hydroxy.
In accordance with another aspect of the present invention, there is provided a method for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I) which comprises conducting an addition reaction of an organoindium compound of formula (HI) with an imine compound of formula (IV):
Figure imgf000003_0002
wherein, n is an integer of 0 or 2, and
A and B have the same meanings as defined above.
In accordance with another aspect of the present invention, there is provided a method for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I), which comprises subjecting a l,4-dibromo-2-butyne compound of formula ( II ) to a barbier type reaction with the imine compound of formula (IV) in the presence of metallic indium:
Br Br ( H )
In accordance with further aspect of the present invention, there is provided a method for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I), which comprises the steps of (i) conducting a condensation reaction of an aldehyde derivative of formula (V) with an amine derivative of formula (VI) to obtain an imine compound, and (ii) conducting an addition reaction of the imine compound thus obtained with the organoindium compound of formula (IH) in situ without isolating the imine compound after step (i):
Figure imgf000004_0001
H2N-B (VI) wherein,
A and B have the same meanings as defined above.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "alkyl" refers to a straight or branched chain saturated hydrocarbon radical. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and hexyl.
As used herein, the term "alkoxy" refers to the group -ORa, wherein Ra is an alkyl group as defined above. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and t-butoxy.
As used herein, the term "cycloalkyl" refers to cyclic saturated aliphatic hydrocarbon radicals. Examples of "cycloalkyl" as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term "aryl" refers to a C6-C12 aromatic hydrocarbon radical. Examples of "aryl" as used herein include, but are not limited to, are phenyl, toluyl, xylyl, biphenyl, and naphthyl.
As used herein, the term "heteroaryl" refers to an optionally substituted monocyclic five to six-membered aromatic ring containing one or more heteroatomic substitutions selected from S, SO, SO2, O, N, or N-oxide, or refers to such an aromatic ring fused to one or more rings such as heteroaryl rings, aryl rings, heterocyclic rings, or carbocycle rings (e. g., a bicyclic or tricyclic ring system), each having optional subsituents. Examples of "heteroaryl" groups as used herein include, but are not limited to, are benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, imidazolyl, pyridyl, pyrrolyl, tetrazolyl, thiophenyl, triazolyl, and a substituted version thereof.
As used herein, the term "arylalkyl" refers to Ci-C10 alkyl substituted by a C6-Ci2 aryl group, wherein the aryl has the same meaning as defined above. Examples of "arylalkyl" as used herein include, but are not limited to, are benzyl, phenethyl, and phenylpropyl. As used herein, the term "arylalkoxy" refers to Ci-Cio alkoxy substituted by a C6-Ci2 aryl S1011PJ wherein the aryl has the same meaning as defined above. Examples of "arylalkoxy" as used herein include, but are not limited to, are phenylmethoxy and phenylethoxy.
As used herein, the term "alkoxycarbonyl" refers to the group -COORt,, wherein Rb is an alkyl group as defined above.
As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
Preferably, the (l,3-butadien-2-yl)methylamine derivative of formula (I) according to the present invention may be a compound, wherein A is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl, isopentyl, n-hexyl, cyclohexyl, chlorophenyl, methylphenyl, hydroxyphenyl, bromophenyl, iodophenyl, ethoxycarbonyl, furyl, or pyridyl, and B is iodophenyl,benzyl, methoxybenzyl, or benzyloxy. Examples of the preferred (l,3-butadien-2-yl)methylamine derivative of formula (I) according to the present invention include the compounds of formulae (a) to (o):
Figure imgf000006_0001
(k) (I) (m) (n) (o)
In accordance with another aspect of the present invention, there is provided a method for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I), which comprises conducting an addition reaction of an organoindium compound of formula (HI) with an imine compound of formula (IV) in a reaction solvent, as shown in Reaction Scheme 1 :
Reaction Scheme 1
Figure imgf000006_0002
( III ) ( IV ) ( I ) wherein, n is an integer of 0 or 2, and A and B have the same meanings as defined above.
The organoindium compound of formula (HI) may be used in an amount corresponding to 1.5 to 2.5 equivalents based on the indium metal of the imine
.* compound of formula (IV). Example of the organoindium compound of formula (HI) include l,3-butadien-2-yl indium, which may be prepared by conducting a reaction of a l,4-dibromo-2-butyne compound of formula ( II ) with metallic indium (In), as shown in Reaction Scheme 2:
Reaction Scheme 2
Figure imgf000007_0001
( I I ) ( III ) wherein, n is an integer of 0 or 2.
The metallic indium may be used in an amount corresponding to 1 to 2 equivalents based on the l,4-dibromo-2-butyne compound of formula ( II ).
The inventive (l,3-butadien-2-yl)methylamine derivative of formula (I) may be prepared by subjecting the l,4-dibromo-2-butyne compound of formula ( π ) to a barbier type reaction with the imine compound of formula (IV) in the presence of metallic indium.
The 'barbier type reaction' refers to an one-step procedure for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I) from the
1 ,4-dibromo-2-butyne compound of formula ( II ), the metallic indium, and the imine compound of formula (IV), without a procedure for preparing the organoindium compound of formula (IE).
The l,4-dibromo-2-butyne compound of formula ( II ) may be used in an amount corresponding to 1.0 to 2.0 equivalents based on the imine compound of formula (IV).
The metallic indium may be used in an amount corresponding to 1.5 to 2.5 equivalents based on the indium metal of the imine compound of formula (IV).
In order to inhibit a hydrolysis of the imine compound of formula (IV) and improve a yield of the (l,3-butadien-2-yl)methylamine derivative of formula (I), the reaction may be carried out in the presence of a dry agent which remove moisture formed during the reaction. Examples of the dry agent include a magnesium sulfate (MgSO4) and sodium sulfate (Na2SO4), which are used in an amount corresponding to 0.5 to 1.5 equivalents based on the imine compound of formula (IV).
Example of the reaction solvent includes a C1-C7 lower alcohol such as methanol (MeOH) and ethanol (EtOH), preferably ethanol.
The reaction may be conducted at room temperature, preferably at 25 °C . The reaction time depends on reaction materials, and solvent and its content. The reaction proceeds until no imine compound is detectable by TLC. After the reaction is over, the resulting material thus obtained is extracted, distilled a reduced pressure to remove the solvent, and the residue is purified by a conventional method such as a column chromatography to obtain the desired material.
The inventive (l,3-butadien-2-yl)methylamine derivative of formula (I) may be prepared by conducting a sequence of reaction steps of (i) conducting a condensation reaction of an aldehyde derivative of formula (V) with an amine derivative of formula (VI) in a reaction solvent to obtain an imine compound, and (ii) conducting an addition reaction of the imine compound thus obtained with an organoindium compound of formula (IH) in situ without isolating the imine compound after step (i), as shown in Reaction Scheme 3:
Reaction Scheme 3
Figure imgf000008_0001
( V ) (Vi ) ( D
wherein, n is an integer of 0 or 2, and A and B have the same meanings as defined above.
The amine derivative of formula (VI) may be used in an amount corresponding to 1.0 to 2.0 equivalents based on the aldehyde derivative of formula (V). The organoindium compound of formula (HI) may be used in an amount corresponding to 1 to 3 equivalents based on the indium metal of the aldehyde derivative of formula ( V ).
In order to improve a yield of the imine compound, the condensation reaction of the step (i) may be carried out in the presence of an acid which activates the aldehyde derivative of formula ( V ). Example of acid includes acetic acid (AcOH), which is used in an amount corresponding to 0.5 to 1.5 equivalents based on the aldehyde derivative of formula ( V).
Examples of the reaction solvent include a Ci-C7 lower alcohol such as methanol (MeOH) and ethanol (EtOH), preferably ethanol. The reaction temperature and reaction time are the same as described above.
In accordance with the inventive preparation methods, the
(l,3-butadien-2-yl)methylamine derivative of formula (I) can be prepared in a high yield. The inventive (l,3-butadien-2-yl)methylamine derivative is a novel compound having the 1,3-diene substituent at the alpha-position, which can be used in preparing various amine compounds having biochemical activities.
The following Preparation Examples and Examples are intended to further illustrate the present invention without limiting its scope.
Example 1: Preparation of
(l-cycIohexyI-2-methylene-but-3-enyl)-phenyl-amine
Figure imgf000009_0001
N-(cyclohexylmethylidene)phenylamine (56.2 mg, 0.3 mmol), indium
(68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in ethanol (EtOH) (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 7 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with diethylether (Et2O) (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous magnesium sulfate (MgSO4), filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain (l-cyclohexyl-2-methylene-but-3-enyl)-phenyl-amine (42 mg, 58 %).
1H NMR (400 MHz, CDC13> 25 0C , TMS): δ 7.12 (t, J- 7.5 Hz, 2H), 6.64 (t, J = 7.5 Hz, IH), 6.51 (d, J= 7.5 Hz, 2H), 6.39 (dd, J= 17.6, J= 11.1 Hz, IH), 5.38 (d, J = 17.6 Hz, IH), 5.17 (s, IH), 5.11 (d, J = 11.1 Hz, IH), 5.09 (s, IH), 3.89 (d, J = 5.6 Hz, IH), 3.85(s, IH), 1.88-1.85(m, IH), 1.81-1.55(m, 5H), 1.31-1.10(m, 4H), 1.06-0.95(m, IH).
Example 2: Preparation of (2-methyIene-l-phenyl-but-3-enyI)-phenyl-amine
Figure imgf000010_0001
N-benzylidene-phenyl-amine (54.4 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 2 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL * 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain (2-methylene-l-phenyl-but-3-enyl)-phenyl-amine (60.7 mg, 86 %).
1H NMR (400 MHz, CDC13> 25 °C , TMS): δ 7.41-7.26 (m, 5H), 7.14 (t, J = 7.6 Hz, 2H), 6.70 (t, J = 7.6 Hz, IH), 6.54 (d, J = 7.6 Hz, 2H), 6.42 (dd, J = 17.8, J = 11.1 Hz, IH) 5.33 (s, IH), 5.29 (s, IH), 5.28 (d, J = 17.8 Hz, IH), 5.16 (s, IH), 5.09 (d, J= 11.1 Hz, IH), 3.99 (s, IH).
Example 3: Preparation of
[l-(4-chloro-phenyl)-2-methylene-but-3-enyl]-phenyI-amine
Figure imgf000010_0002
N-(4-chlorobenzylidene)-phenyl-amine (64.7 mg, 0.3 mmol), indium
(68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in
EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 2 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
[l-(4-chloro-phenyl)-2-methylene-but-3-enyl]-phenyl-amine (60.7 mg, 75 %).
1H NMR (400 MHz, CDC13> 25 °C, TMS): δ 7.34-7.31 (m, 4H), 7.14 (t, J = 7.7 Hz, 2H), 6.71 (t, J = 7.7 Hz, IH), 6.52 (d, J = 7.7 Hz, 2H), 6.40 (dd, J = 17.8 Hz, J = 11.1 Hz, IH) 5.32 (s, IH), 5.26 (d, J =17.8 Hz, IH), 5.20 (s, IH), 5.14 (s, IH), 5.11 (d, J= 11.1 Hz, IH), 3.96 (s, IH).
Example 4: Preparation of (2-methyIene-l-p-toIyl-but-3-enyl)-phenyl-amine
Figure imgf000011_0001
N-(4-methylbenzylidene)-phenyl-amine (58.6 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 2 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL * 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain (2-methylene-l-/?-tolyl-but-3-enyl)-phenyl-amine (53.9 mg, 72 %).
1H NMR (400 MHz, CDCl3, 25 °C , TMS): δ 7.27 (d, J = 7.6 Hz, 2H), 7.15-7.11 (m, 4H), 6.68 (t, J= 7.6 Hz, IH), 6.52 (d, J= 7.6 Hz, 2H), 6.41 (dd, J = 17.7, J= 11.1 Hz, IH) 5.31 (s, IH), 5.26 (d, J = 17.7 Hz, IH), 5.11 (s, IH), 5.07 (d, J= 11.1 Hz, IH), 3.95 (s, IH), 2.33 (s, 3H).
Example 5: Preparation of 3-(2-methylene-l-phenylamiπo-but-3-enyI)-phenol
Figure imgf000012_0001
3-Phenyliminomethyl-phenol (59.1 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 3 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL * 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain 3-(2-methylene-l-phenylamino-but-3-enyl)-phenol (56.5 mg, 75%). 1H NMR (400 MHz, CDCl3, 25 °C , TMS): δ 7.21-7.09 (m, 3H), 6.95 (d, J
= 7.6 Hz, IH), 6.83 (s, IH), 6.70 (t, J -7.6 Hz, 2H), 6.52 (d, J = 7.6 Hz, 2H), 6.39 (dd, J = 17.6, J = 11.1 Hz, IH), 5.29 (s, IH), 5.27 (d, J = 17.6 Hz, IH), 5.24 (s, IH), 5.09 (s, IH), 5.08 (d, J= 11.1 Hz, IH), 3.98 (br, IH).
Example 6: Preparation of
[l-(3-bromo-phenyl)-2-methylene-but-3-enyl]-phenyI-amine
Figure imgf000012_0002
N-(3-bromobenzylidene)-phenyl-amine (78 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in
EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 3 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
[1 -(3 -bromo-phenyl)-2-methylene-but-3-enyl] -phenyl-amine (56.6 mg, 60 %).
1H NMR (400 MHz, CDC13)25 "C, TMS): δ 7.54 (s, IH), 7.37 (d, J = 7.8 Hz, IH), 7.33 (d, J= 7.8 Hz, IH), 7.20 (t, J= 7.8 Hz, IH) 7.15 (t, J= 7.5 Hz, 2H),
6.72 (t, J= 7.5 Hz, IH), 6.52 (d, J= 7.5 Hz, 2H), 6.40 (dd, J= 17.7, J= 11.1 Hz,
IH), 5.33 (s, IH), 5.26 (d, J = 17.7 Hz, IH), 5.20 (s, IH), 5.13 (s, IH), 5.11 (d, J
= 11.1 Hz, IH), 3.96 (s, IH).
Example 7: Preparation of (2-methylene-l-ø-tolyl-but-3-enyl)-phenyI-amine
Figure imgf000013_0001
N-(2-methylbenzylidene)-phenyl-amine (58.7 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 4 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain (2-methylene-l-o-tolyl-but-3-enyl)-phenyl-amine (50.1 mg, 67 %).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.36 (d, J = 7.1 Hz, IH), 7.21-7.11 (m, 5H), 6.68 (t, J= 7.5 Hz, IH), 6.50 (d, J= 7.5 Hz, 2H), 6.47 (dd, J = 17.7, J = 11.1 Hz, IH), 5.34 (s, IH), 5.28 (s, IH), 5.19 (s, IH), 5.14 (d, J = 17.7 Hz, IH), 5.07 (d, J= 11.1 Hz, IH), 3.87 (s, IH), 2.34 (s, 3H). Example 8: Preparation of
[l-(2-iodo-phenyl)-2-methylene-but-3-enyl]-phenyl-amine
Figure imgf000014_0001
N-(2-iodobenzylidene)-phenyl-amine (92.1 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 5 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain [l-(2-iodo-phenyl)-2-methylene-but-3-enyl]-phenyl-amine (62.9 mg, 58 %).
1H NMR (400 MHz, CDCl3, 25 °C , TMS): δ 7.89 (d, J = 7.6 Hz, IH), 7.44 (d, J = 7.6 Hz, IH), 7.31 (t, J = 7.5 Hz, IH) 7.14 (t, J= 7.5 Hz, 2H), 6.99 (t, J = 7.6 Hz, IH), 6.70 (t, J= 7.6 Hz, IH), 6.49 (d, J= 7.5 Hz, 2H), 6.50-6.43 (m, IH), 5.34 (s, 2H), 5.26 (d, J = 17.7 Hz, IH), 5.14 (d, J = 11.1 Hz, IH), 5.01 (s, IH), 3.96 (s, IH).
Example 9: Preparation of
(l-furan-2-yl-2-methylene-but-3-enyl)-phenyl-amine
Figure imgf000014_0002
N-((furan-2-yl)methylidene)-phenyl-amine (51.4 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. 1 ,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 2 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain (l-fiiran-2-yl-2-methylene-but-3-enyl)-phenyl-amine (45.3 mg, 67 %).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.38 (dd, J = 3.3 Hz, J =1.8
Hz, IH), 7.16 (t, J = 7.5 Hz, 2H), 6.73 (t, J = 7.5 Hz, IH), 6.57 (d, J = 7.5 Hz, 2H),
6.44 (dd, J = 17.7, J = I Ll Hz, IH), 6.32 (dd, J = 1.8 Hz, J = 3.3 Hz, IH), 6.24(d, J = 3.3 Hz, IH), 5.33 (d, J = 17.7 Hz, IH), 5.31 (s, IH), 5.28 (s, IH), 5.13 (d, J =
11.1 Hz, IH), 4. l l (s, IH).
Example 10: Preparation of
(4-iodo-phenyI)-(2-methylene-l-phenyl-but-3-enyl)-amine
N-benzylidene-(4-iodo-phenyl)-amine (92.1 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. 1 ,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 1 hr. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
(4-iodo-phenyl)-(2-methylene-l-phenyl-but-3-enyl)-amine (80.2 mg, 74 %).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.39-7.33 (m, 6H), 7.32-7.29 (m, IH), 6.40 (dd, J = 17.6, J = 11.1 Hz, IH), 6.31 (d, J = 8.9 Hz, 2H), 5.32 (s, IH), 5.25 (d, J = 17.6 Hz, IH), 5.23 (s, IH), 5.10 (s, IH), 5.09 (d, J = 11.1 Hz, IH), 4.02 (s , IH).
Example 11: Preparation of (4-methoxy-phenyI)-(2-methyIene-l-phenyl-but-3-enyl)-amine
Figure imgf000016_0001
N-benzylidene-(4-methoxy-phenyl)-amine (63.4 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 4 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
(4-methoxy-phenyl)-(2-methylene-l-phenyl-but-3-enyl)-amine (60.5 mg, 76 %). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.40-7.25 (m, 5H), 6.74 (d, J
= 8.9 Hz, 2H), 6.49 (d, J- 8.9 Hz, 2H), 6.41 (dd, J= 17.8, J= 11.1 Hz, IH), 5.31 (s, IH), 5.29 (s, IH), 5.28 (d, J- 17.8 Hz, IH), 5.08 (d, J= 11.1 Hz, IH), 5.08 (s, IH), 3.77 (br, IH), 3.71 (s, 3H).
Example 12: Preparation of benzyl-(2-methyIene-l-phenyI-but-3-enyl)-amine
Figure imgf000016_0002
Benzyl-benzylidene-amine (58.6 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 6 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain benzyl-(2-methylene-l-phenyl-but-3-enyl)-amine (44.1 mg, 59 %). 1H NMR (400 MHz, CDCl3, 25 °C , TMS): δ 7.40 (d, J = 7.2 Hz, 2H),
7.33-7.29 (m, 6H), 7.26-7.22 (m, 2H), 6.31 (dd, J= 17.7, J= 11.1 Hz, IH) 5.40 (s, IH), 5.30 (s, IH), 5.26 (d, J = 17.7 Hz, IH), 5.00 (d, J = 11.1 Hz, IH), 4.52 (s, IH), 3.7-3.69 (m, 2H).
Example 13: Preparation of 2-benzyloxyamino-3-methylene-pent-4-enoic acid ethyl ester
Figure imgf000017_0001
Benzyloxyimino acetic acid ethyl ester (62.2 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 6 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain 2-benzyloxyamino-3-methylene-pent-4-enoic acid ethyl ester (60.4 mg, 77 %). 1H NMR (400 MHz, CDCl3, 25 0C , TMS): δ 7.38-7.28 (m, 5H), 6.29 (dd, J
= 17.5, J= 11.0 Hz, IH), 6.04 (d, J= 9.0 Hz, IH), 5.25 (d, J= 17.5 Hz, IH), 5.23 (s, IH), 5.16 (s, IH), 5.09 (d, J= 11.0 Hz, IH), 4.78-4.70 (m, 2H), 4.45 (d, J= 9.0 Hz, IH), 4.24 (q, J= 7.2 Hz, 2H), 1.27 (t, J= 7.2 Hz, 3H).
Example 14: Preparation of
2-(4-methoxy-phenylamino)-3-methylene-pent-4-enoic acid ethyl ester
Figure imgf000018_0001
(4-Methoxy-phenylimido) acetic acid ethyl ester (62.2 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 6 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
2-(4-methoxy-phenylamino)-3-methylene-pent-4-enoic acid ethyl ester (51 mg, 65 %). 1H NMR (400 MHz, CDCl3, 25 °C , TMS): δ 6.76 (d, J = 8.9, Hz 2H), 6.56
(d, J= 8.9 Hz, 2H), 6.42 (dd, J= 17.6, J= 11.2 Hz, IH), 5.54 (d, J= 17.6 Hz, IH), 5.36 (s, IH), 5.31 (s, IH), 5.21 (d, J = 11.2 Hz, IH), 4.74 (s, IH), 4.35 (s, IH), 4.21 (q, J= 7.1 Hz, 2H), 3.73 (s, 3H), 1.25 (t, J= 7.1Hz, 3H).
Example 15: Preparation of
4-(2-methylene-l-phenylamino-but-3-enyl)-benzoic acid methyl ester
Figure imgf000018_0002
4-Phenyliminomethyl-benzoic acid methyl ester (71.8 mg, 0.3 mmol), indium (68.9 mg, 0.6 mmol) and magnesium sulfate (36 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere. l,4-Dibromo-2-butyne (95.4 mg, 0.45 mmol) was added to the resulting mixture, and stirred at room temperature for 1 hr. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain 4-(2-methylene-l-phenylamino-but-3-enyl)-benzoic acid methyl ester (57.2 mg, 65 %).
1H NMR (400 MHz, CDCl3, 25 °C , TMS): δ 8.01 (d, J = 8.3 Hz, 2H), 7.47
(d, J = 8.3 Hz, 2H), 7.14 (t, J= 7.5 Hz, 2H), 6.71 (t, J= 7.5 Hz, IH), 6.52 (d, J =
7.5 Hz, 2H), 6.41 (dd, J = 17.7 Hz, J = 11.1 Hz, IH), 5.33 (s, IH), 5.28 (d, J = 17.7 Hz, IH), 5.22 (s, IH), 5.17 (s, IH), 5.11 (d, J = 11.1 Hz, IH), 4.03 (s, IH),
3.90 (s, 3H).
Example 16: Preparation of
(l-cyclohexyl-2-methylene-but-3-enyI)-phenyl-amine
Figure imgf000019_0001
4-Cyclohexanecarbaldehyde (33.7 mg, 0.3 mmol), aniline (41.1 mg, 0.45 mmol) and acetic acid (18 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere for 1 hr. Indium (68.9 mg, 0.6 mmol) and l,4-dibromo-2-butyne (95.4 mg, 0.45 mmol) were added to the reaction mixture, and stirred at room temperature for 6 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
(l-cyclohexyl-2-methylene-but-3-enyl)-phenyl-amine (31.1 mg, 43 %).
1H NMR (400 MHz, CDCl3, 25 °C , TMS): δ 7.12 (t, J= 7.5 Hz, 2H), 6.64 (t, J = 7.5 Hz, IH), 6.51 (d, J = 7.5 Hz, 2H), 6.39 (dd, J = 11.6, J = 1 1.1 Hz, IH), 5.38 (d, J = 17.6 Hz, IH), 5.17 (s, IH), 5.11 (d, J = 11.1 Hz, IH), 5.09 (s, IH), 3.89 (d, J = 5.6 Hz, IH), 3.85(s, IH), 1.88-1.85(m, IH), 1.81-1.55(m, 5H), 1.31-1.10(m, 4H), 1.06-0.95(m, IH). Example 17: Preparation of (2-methylene-l-phenyI-but-3-enyl)-phenyl-amine
Figure imgf000020_0001
Benzaldehyde (31.8 mg, 0.3 mmol), aniline (41.1 mg, 0.45 mmol) and acetic acid (18 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere for 1 hr. Indium (68.9 mg, 0.6 mmol) and l,4-dibromo-2-butyne (95.4 mg, 0.45 mmol) were added to the reaction mixture, and stirred at room temperature for 2 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
(2-methylene-l-phenyl-but-3-enyl)-phenyl-amine (41.7 mg, 59 %). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.41-7.26 (m, 5H), 7.14 (t, J
= 7.6 Hz, 2H), 6.70 (t, J = 7.6 Hz, IH), 6.54 (d, J = 7.6 Hz, 2H), 6.42 (dd, J = 17.8, J= 11.1 Hz, IH) 5.33 (s, IH), 5.29 (s, IH), 5.28 (d, J = 17.8 Hz, IH), 5.16 (s, IH), 5.09 (d, J= 11.1 Hz, IH), 3.99 (s, IH).
Example 18: Preparation of
[ 1 -(4-chloro-phenyl)-2-methy lene-but-3-eny 1] -phenyl-amine
Figure imgf000020_0002
4-Chlorobenzaldehyde (42.2 mg, 0.3 mmol), aniline (41.1 mg, 0.45 mmol) and acetic acid (18 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere for 1 hr. Indium (68.9 mg, 0.6 mmol) and l,4-dibromo-2-butyne (95.4 mg, 0.45 mmol) were added to the reaction mixture, and stirred at room temperature for 5 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
[l-(4-chloro-phenyl)-2-methylene-but-3-enyl]-phenyl-amine (48.4 mg, 60 %). 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.34-7.31 (m, 4H), 7.14 (t, J
= 7.7 Hz, 2H), 6.71 (t, J = 7.7 Hz, IH), 6.52 (d, J = 7.7 Hz, 2H), 6.40 (dd, J = 17.8 Hz, J = 11.1 Hz, IH) 5.32 (s, IH), 5.26 (d, J =17.8 Hz, IH), 5.20 (s, IH), 5.14 (s, IH), 5.11 (d, J= 11. I Hz, IH), 3.96 (s, IH).
Example 19: Preparation of
(3-(2-methylene-l-phenylamino-but-3-enyI)-phenol
Figure imgf000021_0001
3-Hydroxybenzaldehyde (36.6 mg, 0.3 mmol), aniline (41.1 mg, 0.45 mmol) and acetic acid (18 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere for 1 hr. Indium (68.9 mg, 0.6 mmol) and l,4-dibromo-2-butyne (95.4 mg, 0.45 mmol) were added to the reaction mixture, and stirred at room temperature for 5 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
3-(2-methylene-l-phenylamino-but-3-enyl)-phenol (40.7 mg, 54 %). 1H NMR (400 MHz, CDCl3, 25 °C , TMS): δ 7.21-7.09 (m, 3H), 6.95 (d, J
= 7.6 Hz, IH), 6.83 (s, IH), 6.70 (t, J =7.6 Hz, 2H), 6.52 (d, J= 7.6 Hz, 2H), 6.39
(dd, J = 17.6, J = 11.1 Hz, IH), 5.29 (s, IH), 5.27 (d, J = 17.6 Hz, IH), 5.24 (s,
IH), 5.09 (s, IH), 5.08 (d, J= 11.1 Hz, IH), 3.98 (br, IH).
Example 20: Preparation of
(4-methoxy-phenyI)-(2-methyIene-l-phenyl-but-3-enyl)-amine
Figure imgf000022_0001
Benzaldehyde (31.8 mg, 0.3 mmol), />-anisidine (55.4 mg, 0.45 mmol) and acetic acid (18 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere for 1 hr. Indium (68.9 mg, 0.6 mmol) and l,4-dibromo-2-butyne (95.4 mg, 0.45 mmol) were added to the reaction mixture, and stirred at room temperature for 6 hrs. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
(4-methoxy-phenyl)-(2-methylene-l-phenyl-but-3-enyl)-amine (40.6 mg, 51 %).
1H NMR (400 MHz, CDC13>25 "C, TMS): δ 7.40-7.25 (m, 5H), 6.74 (d, J = 8.9 Hz, 2H), 6.49 (d, J = 8.9 Hz, 2H), 6.41 (dd, J= 17.8, J = 11.1 Hz, IH), 5.31 (s, IH), 5.29 (s, IH), 5.28 (d, J= 17.8 Hz, IH), 5.08 (d, J= 11.1 Hz, IH), 5.08 (s, IH), 3.77 (br, IH), 3.71 (s, 3H).
Example 21: Preparation of (4-(2-methylene-l-phenylamino-but-3-enyl)-benzoic acid methyl ester
Figure imgf000022_0002
Methyl 4-formylbenzoate (49.3 mg, 0.3 mmol), aniline (41.1 mg, 0.45 mmol) and acetic acid (18 mg, 0.3 mmol) were dissolved in EtOH (1.2 mL), and stirred under a nitrogen atmosphere for 1 hr. Indium (68.9 mg, 0.6 mmol) and l,4-dibromo-2-butyne (95.4 mg, 0.45 mmol) were added to the reaction mixture, and stirred at room temperature for 1 hr. Water (3 mL) was added to the reaction mixture to quench the reaction, and the resulting mixture was extracted with Et2O (10 mL x 3). The combined organic layer thus obtained was washed with saturated NaCl (10 mL), dried over anhydrous MgSO4, filtered, and distilled under a reduced pressure to remove solvent. The residue thus obtained was purified by column chromatography to obtain
4-(2-methylene-l-phenylamino-but-3-enyl)-benzoic acid methyl ester (46.6 mg, 53 %).
1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 8.01 (d, J= 8.3 Hz, 2H), 7.47
(d, J= 8.3 Hz, 2H), 7.14 (t, J= 7.5 Hz, 2H), 6.71 (t, J= 7.5 Hz, IH), 6.52 (d, J =
7.5 Hz, 2H), 6.41 (dd, J = 17.7 Hz, J = 11.1 Hz, IH), 5.33 (s, IH), 5.28 (d, J =
17.7 Hz, IH), 5.22 (s, IH), 5.17 (s, IH), 5.11 (d, J = 11.1 Hz, IH), 4.03 (s, IH), 3.90 (s, 3H)
While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A (1 ,3-butadien-2-yl)methylamine derivative of formula (I):
Figure imgf000024_0001
wherein,
A is C1-C10 alkyl, C3-C9 cycloalkyl, C6-C12 aryl, C1-C10 alkoxycarbonyl, or (C3-C7)heteroaryl,
B is C6-C12 aryl, C6-C12 aryl C1-C10 alkyl, or C6-Ci2 aryl C1-C10 alkoxy, and
A and B are each optionally substituted by one or more substituents selected from the group consisting of C1-C10 alkyl, Ci-C10 alkoxy, halogen, and hydroxy.
2. The (l,3-butadien-2-yl)methylamine derivative of claim 1, wherein A is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, pentyl, isopentyl, n-hexyl, cyclohexyl, chlorophenyl, methylphenyl, hydroxyphenyl, bromophenyl, iodophenyl, ethoxycarbonyl, furyl, or pyridyl, and B is iodophenyl,benzyl, methoxybenzyl, or benzyloxy.
3. The (l,3-butadien-2-yl)methylamine derivative of claim 2, which is a compound selected from the group consisting of the compounds of formulae (a) to (o):
Figure imgf000025_0001
4. A method for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I) of claim 1, which comprises conducting an addition reaction of an organoindium compound of formula (HI) with an imine compound of formula (IV):
Figure imgf000025_0002
wherein, n is an integer of 0 or 2, and A and B have the same meanings as defined in claim 1.
5. The method of claim 4, wherein the organoindium compound of formula (W) is used in an amount corresponding to 1.5 to 2.5 equivalents based on the indium metal of the imine compound of formula (IV).
6. The method of claim 4, wherein the organoindium compound of formula (HI) is prepared by conducting a reaction of a l,4-dibromo-2-butyne compound of formula ( II ) with metallic indium:
/
Br Br (H)
7. A method for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I) of claim 1, which comprises subjecting a l,4-dibromo-2-butyne compound of formula ( II ) to a barbier type reaction with an imine compound of formula (IV) in the presence of metallic indium:
Figure imgf000026_0001
Br Br ( π )
Figure imgf000026_0002
wherein,
A and B have the same meanings as defined in claim 1.
8. The method of claim 7, wherein the metallic indium is used in an amount corresponding to 1.5 to 2.5 equivalents based on the imine compound of formula (IV).
9. The method of claim 7, wherein the 1 ,4-dibromo-2-butyne compound of formula ( II ) is used in an amount corresponding to 1.0 to 2.0 equivalents based on the imine compound of formula (IV).
10. The method of claim 4 or 7, wherein the reaction is carried out in the presence of added magnesium sulfate (MgSO4) or sodium sulfate (Na2SO4) in an amount corresponding to 0.5 to 1.5 equivalents based on the imine compound of formula (IV).
11. A method for preparing the (l,3-butadien-2-yl)methylamine derivative of formula (I) of claim 1 , which comprises the steps of (i) conducting a condensation reaction of an aldehyde derivative of formula (V) with an amine derivative of formula (VI) to obtain an imine compound, and (ii) conducting an addition reaction of the imine compound thus obtained with an organoindium compound of formula (HI) in situ without isolating the imine compound after step (i):
Figure imgf000027_0001
wherein, n is an integer of 0 or 2, and A and B have the same meanings as defined in claim 1.
12. The method of claim 11, wherein the amine derivative of formula (VI) is used in an amount corresponding to 1.0 to 2.0 equivalents based on the aldehyde derivative of formula (V).
13. The method of claim 11, wherein step (i) is carried out in the presence of acetic acid in an amount corresponding to 0.5 to 1.5 equivalents based on the aldehyde derivative of formula (V).
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US10743533B2 (en) 2007-11-14 2020-08-18 Stratatech Corporation Cold storage of organotypically cultured skin equivalents for clinical applications
US11911444B2 (en) 2009-05-21 2024-02-27 Stratatech Corporation Use of human skin substitutes expressing exogenous IL-12 to treat a wound bed

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