JPH11302236A - Production of optically active beta-aminoketones and optically active palladium binuclear complex and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To efficiently synthesize the subject compounds useful as an intermediate for producing medicines, etc., by reacting a silyl enol ether with an imine in the presence of a specific catalyst. SOLUTION: A silyl enol ether represented by formula I [R<1> is a substituted silyl; R<2> is a (substituted) alkyl, a (substitute) alkenyl or the like; R<3> and R<4> are each H, a (substituted) alkyl, a (substituted) alkenyl or the like] is reacted with an imine represented by formula II [R<5> is a (substituted) alkyl, a (substituted) alkenyl or the like; R<6> is H, a (substituted) alkyl, a (substituted) alkenyl or the like] in the presence of a catalyst comprising a palladium- optically active phosphine ligand to afford the objective compounds represented by formula III. In the above reaction, e.g. N,N-dimethylformamide is preferably used as a solvent and the reaction is preferably carried out in the presence of a base such as calcium carbonate at a reactional temperature within the range of ambient temperature to 70 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing optically active β-aminoketones, which are intermediates for producing pharmaceuticals and the like, an optically active palladium dinuclear complex, and a method for producing the same.

[0002]

2. Description of the Related Art There are very few reports on the production of β-aminoketones by the reaction of an enolate or silyl enol ether of a ketone with an imine (J. Chem. Soc., C.
hem. Commun., p1053 (1987), J. Org. Chem., 58, p23.
02, p3259 (1993), J. Org.Chem., 62, p232 (199
7)), in particular, no examples have been reported in which optically active β-aminoketones were synthesized by the reaction of a ketone derivative with an imine using an asymmetric catalyst. Optically active β-aminoketones are extremely important as production intermediates for pharmaceuticals and the like. For example, there is an optically active substituted benzoylalanine derivative which is a selective inhibitor of kynureninase or kynurenine-3-hydroxylase, which is expected to be used as a therapeutic agent for cerebral dysfunction ("Recent Advances in Tryptophan Resea"
rch ", Plenum Press, New York, p499, 531 (1996)).
Optically active β-amino alcohols obtained by stereoselective reduction or alkylation of the ketone moiety by known methods can be used for various pharmaceuticals, as well as for asymmetric addition such as alkyl zinc reagents. It is also expected to be used as a catalyst for reactions (Chem. Rev., 92, p833 (199
2)). Therefore, development of a new method for efficiently synthesizing optically active β-aminoketones has been strongly desired. Also, μ
-Hydroxy-type binuclear palladium-phosphine complex has an optically inactive bidentate phosphine ligand.
It has been reported that it may be formed by the reaction of the corresponding palladium chloride-phosphine complex with a silver salt (J. Che
m. Soc. Chem. Commun., p421 (1991)). However, production of the μ-hydroxy dinuclear palladium-optically active bidentate phosphine complex has not been confirmed, and has not been isolated and identified. For example, palladium chloride-BIN in an aqueous solvent
It has been reported that a mononuclear aqua-type complex is formed, not a μ-hydroxy-type dinuclear palladium-BINAP complex, by the reaction of an AP complex with a silver salt (Synlett., P463
(1997)). Therefore, no efficient method for producing a μ-hydroxy-type binuclear palladium-optically active bidentate phosphine complex has been known.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for efficiently synthesizing optically active β-aminoketones.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that optically active β-aminoketones can be synthesized by reacting silyl enol ether and imine in the presence of an optically active palladium catalyst. The present invention has been completed. Further, as a catalyst of the present invention, in addition to a known palladium catalyst, a μ-hydroxy type binuclear palladium-optically active bidentate phosphine complex was found to be useful, and an efficient production method thereof was also found. That is, the present invention provides the following general formula [I]

[0005]

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(Wherein, R ¹ is a substituted silyl group, R ² is an optionally substituted alkyl group, an optionally substituted alkenyl group, and an optionally substituted substituent. An alkynyl group, or an aryl group which may have a substituent, each of R ³ and R ⁴ is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, An alkynyl group which may have a substituent, an alkoxy group which may have a substituent, or an aryl group which may have a substituent, or R ² and R ³ are those (A ring may be formed together with the carbon atom to be bonded.)
And a silyl enol ether represented by the following general formula [II]

[0007]

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(Wherein R ⁵ represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, An optionally substituted aryl group, an optionally substituted alkoxy or aryloxycarbonyl group, an optionally substituted alkyl or arylthiocarbonyl group, an optionally substituted amino A carbonyl group or an acyl group which may have a substituent, R ⁶ represents a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a An optionally substituted alkynyl group, an optionally substituted aryl group, an optionally substituted alkoxy or aryloxycarbonyl group, an optionally substituted alkyl or Arylthiocarbonyl group, an aminocarbonyl group which may have a substituent, or an acyl group which may have a substituent, an aryl or alkylsulfonyl group which may have a substituent, a substituted silyl group, An optionally substituted alkoxy or aryloxy group, an optionally substituted thioalkoxy or thioaryloxy group, or an optionally substituted amino group). Wherein the imine is reacted in the presence of a catalyst comprising a palladium-optically active phosphine ligand, characterized by the following general formula [III]:

[0009]

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Wherein R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as those described above.

In the above method for producing optically active β-aminoketones, the following general formula showing excellent catalytic activity:
[V]

[0012]

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The present invention relates to a complex represented by the formula: wherein A ₂ -PYPB ₂ is an optically active bidentate phosphine ligand and W ^- is a counter anion, and a method for producing the same.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The method for producing optically active β-aminoketones of the present invention is shown in the following scheme.

[0015]

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(Wherein, R ¹ is a substituted silyl group, R ² is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, and a substituent which may have a substituent. An alkynyl group, or an aryl group which may have a substituent, each of R ³ and R ⁴ is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, An alkynyl group which may have a substituent, an alkoxy group which may have a substituent, or an aryl group which may have a substituent, or a carbon atom to which R ² and R ³ are bonded. And R ⁵ may be an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. Alkynyl group, aryl group optionally having substituent (s), optionally having substituent (s) Alkoxy or aryloxy carbonyl group, an optionally substituted alkyl or arylthiocarbonyl group, an optionally substituted amino group or an optionally substituted acyl group,, R ⁶ is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and which may have a substituent Aryl group, optionally substituted alkoxy or aryloxycarbonyl group, optionally substituted alkyl or arylthiocarbonyl group, optionally substituted aminocarbonyl group, or substituted An acyl group which may have a group, an aryl or alkylsulfonyl group which may have a substituent, a substituted silyl group, Which may be an alkoxy or aryloxy group, a thioalkoxy may have a substituent group or thioaryloxy group, or have a substituent is also an amino group)

The substituted silyl groups in the above general formulas [I] to [III] include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, triphenylsilyl group, t-butyldimethylsilyl group, t-butyldiphenylsilyl. Group, trichlorosilyl group, triethoxysilyl group, dimethylchlorosilyl group, dimethoxymethylsilyl group and the like.

The alkyl group in the “alkyl group optionally having substituent (s)” in the above general formulas [I] to [III] may be any of linear, branched or cyclic, and has, for example, 1 to 3 carbon atoms. 3
0 alkyl group, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, s-
Butyl group, t-butyl group, pentyl group, isopentyl group,
Neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, Examples include a hexadecyl group, a 14-methylpentadecyl group, a 6-methylpentadecyl group, an octadecyl group, an icosyl group, and a tetracosyl group.

The alkenyl group in the “optionally substituted alkenyl group” in the above general formulas [I] to [III] is
It may be linear, branched, or cyclic, and has, for example, 2 carbon atoms.
To 30 alkenyl groups, specifically allyl, vinyl, crotyl, cinnamyl, 1-penten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 1 -Hexen-1-yl group, 2-hexen-1-yl group, 3-hexen-1
-Yl group, 2-cyclohexenyl group, 2-cyclopentenyl group, 8-heptadecen-1-yl group, 8,11-heptadecadiene
-1-yl group, 8,11,14-heptadecatrien-1-yl group, 4,
7,10,13-nonadecatetraen-1-yl group and the like.

The alkynyl group in the “optionally substituted alkynyl group” in the general formulas [I] to [III] is
It may be linear, branched, or cyclic, and has, for example, 2 carbon atoms.
To 30 alkynyl groups, specifically ethynyl, propargyl, 1-pentyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 1-octin-1-yl Group, 8-heptadecin-1-yl group and the like.

The alkoxy group in the “optionally substituted alkoxy group” in the general formula [I] may be linear, branched, or cyclic, and has an unsaturated bond. Examples thereof include an alkoxy or aryloxy group having 2 to 30 carbon atoms, specifically, a methoxy group, an ethoxy group, a propyloxy group, a t-butoxy group, and a benzyloxy group.

The aryl group in the “aryl group optionally having substituent (s)” in the above general formulas [I] to [III] also includes a heteroaryl group, for example, a phenyl group, a naphthyl group, an anthranyl group, Pyrenyl group, biphenyl group, indenyl group, tetrahydronaphthyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridanidyl group, piperazinyl group, pyrazolyl group, imidazolyl group, quinilyl group,
Examples include a pyrrolyl group, an indolyl group, and a furyl group.

In the general formula [I], examples of the compound in which R ² and R ³ are united to form a ring include 1-trimethylsilyloxycyclopentene, 1-trimethylsilyloxycyclohexene, and 1-trimethylsilyloxycycloheptene. And 2-trimethylsilyloxyfuran, 1-t-butyldimethylsilyloxy-3,4-dihydronaphthalene and the like, and may further have a substituent on the ring.

The alkoxy or aryloxycarbonyl group in the “optionally substituted alkoxy or aryloxycarbonyl group” in the general formulas [II] to [III] may be linear, branched, cyclic, Saturated, unsaturated aliphatic, or may be aromatic, for example, methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, isopropyloxycarbonyl group,
Butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl, phenyloxycarbonyl, pyridyloxycarbonyl and the like.

The alkyl or arylthiocarbonyl group in the “optionally substituted alkyl or arylthiocarbonyl group” in the general formulas [II] to [III] may be linear, branched, cyclic, Any of saturated or unsaturated aliphatic or aromatic, such as methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, isopropylthiocarbonyl, butylthiocarbonyl, t-butylthiocarbonyl, benzylthiocarbonyl Group, phenylthiocarbonyl group, pyridylthiocarbonyl group and the like.

In the above general formulas [II] to [III], the “aminocarbonyl group optionally having substituent (s)” is an unsubstituted carbamoyl group, an alkyl group optionally having substituent (s), A carbamoyl group substituted with an aromatic group which may have a group, a hydroxyl group, an alkoxy group which may have a substituent, an amino group which may have a substituent, for example, a carbamoyl group , Ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylaminocarbonyl, t-butylaminocarbonyl, benzylaminocarbonyl, phenylaminocarbonyl, pyridylaminocarbonyl, benzyloxyaminocarbonyl and the like. Can be

In the above general formulas [II] to [III], the acyl group in the “optionally substituted acyl group” may be a linear, branched, cyclic, saturated or unsaturated aliphatic, Alternatively, it may be any aromatic group, for example, an acyl group having 2 to 30 carbon atoms, specifically, acetyl, propionyl, isopropionyl, pivaloyl, oleoyl, cyclohexylcarbonyl, acroyl, crotonoyl, benzoyl. , A naphthoyl group, a nicotinoyl group and the like.

The aryl or alkylsulfonyl group in the “aryl or alkylsulfonyl group optionally having substituent (s)” in the general formulas [II] to [III] may be linear, branched, cyclic, saturated, Any of unsaturated aliphatic or aromatic groups may be used, and examples thereof include a methanesulfonyl group, an ethanesulfonyl group, a benzenesulfonyl group, and a tosyl group.

The alkoxy or aryloxy group in the “optionally substituted alkoxy or aryloxy group” in the general formulas [I] to [III] may be linear, branched, cyclic or saturated. May be any of unsaturated aliphatic or aromatic, for example, an alkoxy or aryloxy group having 2 to 30 carbon atoms, specifically, a methoxy group,
Examples include an ethoxy group, a propyloxy group, a t-butoxy group, a benzyloxy group, a phenoxy group and the like.

The thioalkoxy or thioaryloxy group in the “optionally substituted thioalkoxy or thioaryloxy group” in the general formulas [II] to [III] is linear or branched. May be any of cyclic, saturated, unsaturated, aliphatic or aromatic, such as a thioalkoxy or thioaryloxy group having 2 to 30 carbon atoms, specifically, a methylthio group, an ethylthio group, a propylthio group, a t-butylthio group. Group, benzylthio group, phenylthio group and the like.

The “optionally substituted amino group” in the above general formulas [II] to [III] is an unsubstituted amino group or an amino group substituted with an alkyl group or an aromatic group. And examples thereof include an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a t-butylamino group, a benzylamino group, a phenylamino group and a pyridylamino group.

The above alkyl group, alkenyl group, alkynyl group, aryl group, alkoxy or aryloxycarbonyl group, alkylthio or arylthiocarbonyl group, aminocarbonyl group, acyl group, alkoxy or aryloxy group, thioalkoxy or thioaryloxy group Examples of the substituent which the amino group and the like may have include, for example, an alkyl group, a halogen atom, a nitro group and an amino group (which may have an acyl group, an alkyl group, a cycloalkyl group and the like as a substituent) , Cyano group,
Examples include a hydroxyl group, a carboxyl group, a carbamoyl group, an aryl group, an alkoxy group, and an aralkyl group.

In the present reaction, the catalyst comprising a palladium-optically active phosphine ligand includes, for example, the following general formula:
[V], general formula [VI], general formula [VII], or general formula [VIII]
And a complex represented by

[0034]

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Wherein A ₂ -PYPB ₂ is an optically active bidentate phosphine ligand, W ^- is a counter anion, and L is a neutral ligand having a weak coordination force.

In the above general formulas [V] to [VIII], “optically active
As the `` dentate phosphine ligand '', for example, optically active 2,2'-
Bis (diphenylphosphino) -1,1'-binaphthyl (BINA
P), 2,2'-bis (di-4-methylphenylphosphino) -1,1 '
-Binaphthyl (Tol-BINAP), 2,2'-bis (bis-3,5-dimethyl
Tylphenylphosphino) -1,1'-binaphthyl (3,4-Me_Two-C
₆H _Three-BINAP) and other binaphthyl-type bidentate phosphines
Ligand, (6,6'-dimethylbiphenyl-2,2'-diyl) bis (di
Various biphenyls such as (phenylphosphine) (BIPHEMP)
Type bidentate phosphine ligand, N, N-dimethyl-1- [1 ', 2-bis
(Diphenylphosphino) ferrocenyl] ethylamine (B
PPFA), 1- [1 ', 2-bis (diphenylphosphino) ferrose
Nyl] ethanol (BPPFOH), 1- [1 ', 2-bis (diphenyl
Phosphino) ferrocenyl] ethyl acetate (BPPFAc)
Various ferrocenyl-type bidentate phosphine ligands, such as
4,5-bis (diphenylphosphinomethyl) -2,2-dimethyl
1,3-dioxolane (DIOP), 1,2-bis (trans-2,5
-Dialkylphosphino) benzene (DuPHOS), 2,3-bis
(Diphenylphosphino) bicyclo [2.2.1] hept-5-e
(NORPHOS), 1-t-butoxycarbonyl-4-diphenyl
Phosphino-2-diphenylphosphinomethylpyrrolidine
(BPPM), 1,2-bis (diphenylphosphinomethyl) cyclo
Various optically active bidentate phosphine ligands such as hexane
Is raised.

[0037] As "counter anion" in the above general formula [V] ~ [VIII] ^{are, F -, Br -, Cl} -, I -, OH -, CH 3 COO -, CF 3 C
_{^{OO -, CF 3 CF 2 COO}} -, CF 3 CF 2 CF 2 COO -, CF 3 SO 3 -, p-CH 3 C 6 H 4
_{^{SO 3 -, ClO 4 -,}} NO 3 -, SO 4 2-, CO 3 2-, PO 4 3-, BF 4 -, B (C
^{_{6 H 5) 4 -, B}} (C 6 F 5) 4 -, B [3,5- (CF 3) 2 C 6 H 3] 3 -, PF 6 -, SbF 6
^- , AsF ₆ ^- and so on.

The formula [VIII] represents a complex in which, among the above counter anions (W ⁻ ), those having a high coordinating ability to palladium are directly bonded to palladium, for example, an acetate complex, a trifluoroacetate complex And triflate complexes.

The “neutral ligand having a weak coordination force” in the above general formula [VII] includes N, N-dimethylformamide (DM
F), acetonitrile, benzonitrile, acetone, chloroform, ethylene and the like.

Of these, the complexes represented by the general formulas [VI] to [VIII] can be prepared by a known method (J. Org. Chem., 60, p2648 (19).
95), Synlett, p463 (1997)) or those isolated and prepared by a method analogous thereto, and the following general formula [IV]
A complex prepared by mixing a complex of the above and an appropriate silver salt is used as it is, or if necessary, after filtration, or may be used in a commercially available or known method (eg, “Palladium Reagents
in Organic Syntheses ", Academic Press, New York (19
85), New Laboratory Chemistry 12, Organometallic Chemistry, p230 (1976))
In can also be used to complex and an optically active phosphine ligand represented by PdW ₂ L _n which may be prepared that is formed by mixing in the reaction system. Further, the complex represented by the general formula [V] can be produced by the method of the present invention described in detail below.

As the silyl enol ether represented by the general formula [I], which is a raw material of the present invention, commercially available ones can be used as they are, but known methods (for example, Synthesis,
p1 (1983) and the method described in the cited reference). Further, the imine represented by the general formula [II] can be synthesized by a known method (for example, Synthesis, p439 (1989), Synle
tt.p493 (1994), J. Org.Chem. 54, p4739 (1989),
J. Chem. Res. (M), p1464 (1984)). In addition to using the isolated ones,
What was produced | generated in the reaction container by the dehydration reaction of the corresponding aldehyde and amine can also be used.

The process for producing the optically active β-aminoketones of the present invention comprises reacting the silyl enol ether represented by the general formula [I] and the imine represented by the general formula [II] with the above-mentioned general formula [V],
Reacting in the presence of a palladium-optically active phosphine ligand complex represented by [VI], [VII] or [VIII] or a catalyst comprising a palladium-optically active phosphine ligand prepared in a reaction system; An optically active β-aminoketone represented by [III] is obtained. Solvents used in the reaction include N, N-dimethylformamide (DMF), formamide, N, N-dimethylacetamide (DMA), 1-methyl-2-pyrrolidinone (NMP), hexamethylphosphoric triamide (HM
Amide solvents such as PA), tetramethylurea (TMU)
Urea solvents such as 1,3-dimethyl-2-imidazolidinone (DMI), nitrile solvents such as acetonitrile,
Sulfoxide solvents such as dimethyl sulfoxide, halogenated hydrocarbon solvents such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, and benzotrifluoride; hydrocarbon solvents such as pentane, hexane, benzene, and toluene; or diethyl solvent Ether solvents such as ether, diisopropyl ether, tetrahydrofuran, and 1,4-dioxane, alcohol solvents such as methanol and ethanol, water, and the like, or a mixed solvent thereof are used, preferably amide solvents, urea solvents, and halogens. And hydrocarbon solvents. The amount of the palladium-optically active phosphine ligand catalyst used in the reaction may be a catalytic amount, and 0.1 to 30 mol%, preferably 5 to 20 mol% is used. The reaction is 0
The reaction can be carried out at an appropriate temperature from ℃ to the boiling point of the solvent, and preferably from room temperature to 70 ℃. Also, calcium carbonate,
Inorganic bases such as calcium oxide, barium carbonate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, or organic bases such as triethylamine, N, N-diisopropylethylamine, pyridine, lutidine, or molecular sieves in the reaction system May coexist.

The method for producing the μ-hydroxy type binuclear palladium-optically active bidentate phosphine complex of the present invention is shown in the following scheme.

[0044]

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Wherein A ₂ -PYPB ₂ is an optically active bidentate phosphine ligand, X is a halogen atom, and W ^- is a counter anion.

The "optically active bidentate phosphine ligand" and the "counter anion" in the above general formulas [IV] to [VI] are the same as described above, and the "halogen atom" is a fluorine, chlorine, bromine and iodine atom. And so on.

That is, the complex represented by the general formula [IV] is reacted with a silver salt in a water-containing solvent in the presence of a molecular sieve or a base, or the complex of the general formula [VI] is treated with a molecular sieve or a base. It is manufactured. Solvents used in the reaction include ketone solvents such as acetone, N, N-dimethylformamide (DMF), formamide, amide solvents such as N, N-dimethylacetamide (DMA), tetramethylurea (TMU), 3-Dimethyl-2-
Urea solvents such as imidazolidinone (DMI), nitrile solvents such as acetonitrile, sulfoxide solvents such as dimethyl sulfoxide, hydrocarbon solvents such as pentane, hexane, benzene, and toluene, or diethyl ether, diisopropyl ether, and tetrahydrofuran , Ether solvents such as 1,4-dioxane, alcohol solvents such as methanol and ethanol, ester solvents such as ethyl acetate, dichloromethane, chloroform,
Halogenated hydrocarbon solvents such as 1,2-dichloroethane, carbon tetrachloride, benzotrifluoride and the like, or a mixed solvent thereof are used, and preferred are ketone solvents, halogenated hydrocarbon solvents, alcohol solvents and the like. be able to. The molecular sieves (zeolite) used for the reaction may be of any type, for example, 3A type, 4A type, 5A type, 13X type, etc., and preferred or 3A or 4A type is used. Examples of the base used in the reaction include inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate. And organic bases such as tetramethylammonium hydroxide, potassium t-butoxide and sodium t-butoxide. By using at least one equivalent of the base, the reaction proceeds smoothly. The reaction can be carried out at an appropriate temperature from 0 ° C. to the boiling point of the solvent, preferably room temperature.

The complex represented by the general formula [IV] can be prepared by a known method (J. Org. Chem., 60, p2648 (1995), Synlett, p463).
(1997)) or those isolated and prepared by a method analogous thereto. Silver salts that can be used in this reaction include, for example, silver tetrafluoroborate, silver tetraphenylborate, silver acetate, silver trifluoroacetate, silver pentafluoropropionate, silver trifluoromethanesulfonate, silver p-toluenesulfonate, Silver perchlorate, silver nitrate, silver sulfate, silver carbonate, silver phosphate, silver hexafluorophosphate, silver hexafluoroantimonate, silver hexafluoroarsenate, silver tetraperfluorophenylborate and the like can be mentioned.

Hereinafter, the present invention will be described in detail with reference to Examples, but it goes without saying that the present invention is not limited to these.

[0050]

Embodiment 1

[0051]

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Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.6 mg, 9.9 μmol, 10.7 mol%)
1-phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to an anhydrous DMF solution (1 mL), and the mixture was stirred at room temperature for 55 minutes. This reaction solution is
Heated to 0 ° C. and adjusted immediately before 4-methoxyphenyliminoacetic acid isopropyl ester (20.3 mg, 0.092 mmol)
Of anhydrous DMF solution (0.5 mL) using a syringe pump
The mixture was slowly added dropwise over a period of time, and the mixture was further heated and stirred at 60 ° C for 2 hours. During the dropping, 1-phenyl-1- (trimethylsilyloxy) ethylene (30 μL, 0.146 mmol) was dropped in three times every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After the desiccant was removed and the solvent was distilled off under reduced pressure, the resulting crude product was subjected to silica gel thin layer chromatography (eluent:
Ethyl acetate / hexane = 1/4) for purification.
(4-Methoxyphenyl) benzoylalanine isopropyl ester (26.7 mg, 85%) was obtained as a pale yellow oil. This enantiomeric excess can be determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIR
ALCEL OG, developing solvent: hexane / 2-propanol = 9 /
It was 67% ee when measured using 1). IR (KBr): 3370, 2355, 2340,1725, 1680, 1515, 1280,
. 1220, 1195, 1110, 820cm -1 1 H-NMR (CDCl 3, 200MHz): δ1.14 (d, J = 6.3Hz, 3H), 1.
19 (d, J = 6.3Hz, 3H), 3.50 (d, J = 5.4Hz, 2H), 3.73
(s, 3H), 4.18 (br s, 1H), 4.50 (br t, J = 5.4Hz, 1
H), 5.03 (sept, J = 6.3Hz, 1H), 6.68 (d, J = 9.1Hz, 2
H), 6.77 (d, J = 9.1Hz, 2H), 7.41-7.61 (m, 3H), 7.94
(d, J = 7.0Hz, 2H). MS (EI): m / e = 341 (27, M ⁺ ), 254 (50), 105 (100) .HRMS: m / e calcd for C ₂₀ H ₂₃ NO ₄ 341.1625.found 34
1.1613.

Embodiment 2

[0054]

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Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.5 mg, 9.7 μmol, 10.0 mol%)
1-Phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to an anhydrous DMF solution (1 mL), followed by stirring at room temperature for 50 minutes. This reaction solution is
After heating to 6 ° C, a solution of phenyliminoacetic acid isopropyl ester (18.6 mg, 0.097 mmol) (0.5 mL) in anhydrous DMF (0.5 mL) was added dropwise slowly using a syringe pump over 4 hours. Stirred for hours. During dripping,
1-phenyl-1- (trimethylsilyloxy) ethylene (30
μL, 0.146 mmol) was added in three portions every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a short silica gel column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. Remove the desiccant,
After the solvent was distilled off under reduced pressure, the resulting crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate /
Hexane = 3/17) and purified with the desired N-phenylbenzoylalanine isopropyl ester (21.5 mg, 71
%) As a pale yellow oil. This enantiomeric excess is
When measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPAK AD, developing solvent: hexane / 2-propanol = 9/1), it was 64% ee. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 1.15 (d, J = 6.3 Hz, 3H), 1.
21 (d, J = 6.3Hz, 3H), 3.55 (d, J = 4.6Hz, 2H), 4.40-
4.65 (m, 2H), 5.05 (sept, J = 6.3Hz, 1H), 6.66-6.79
(m, 3H), 7.12-7.23 (m, 2H), 7.41-7.63 (m, 3H), 7.9
4 (d, J = 7.0Hz, 2H). MS (EI): m / e = 311 (7, M ⁺ ), 268 (2), 224 (27), 105
(100).

Embodiment 3

[0057]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.9 mg, 10 μmol, 10.0 mol%)
1-Phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to an anhydrous DMF solution (1 mL), followed by stirring at room temperature for 40 minutes. The reaction solution is 36 ~
The mixture was heated to 38 ° C, and phenyliminoacetic acid methyl ester (16.3 mg, 0.100 mmol) was added to the solution in three portions every hour, and the mixture was further stirred at 36 to 38 ° C for 3 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether.
The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was subjected to silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane).
= 1/4) to obtain the desired N-phenylbenzoylalanine methyl ester (8.0 mg, 28%) as a pale yellow-white solid. The enantiomeric excess was measured by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OJ, developing solvent: hexane / 2-propanol = 9/1) and was found to be 55% ee. there were. ¹ H-NMR (CDCl ₃ , 400MHz): δ3.59 (d, J = 5.1Hz, 2H), 3.
74 (s, 3H), 4.52 (br d, J = 8.9Hz, 1H), 4.61-4.67
(m, 1H), 6.98 (d, J = 7.7Hz, 2H), 6.73-6.78 (m, 1H),
7.16-7.21 (m, 2H), 7.44-7.49 (m, 2H), 7.56-7.61
(m, 1H), 7.94 (d, J = 7.2Hz, 2H). MS (EI): m / e = 283 (7, M ⁺ ), 224 (20), 105 (100).

Embodiment 4

[0060]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.5 mg, 9.7 μmol, 9.7 mol%)
1-phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) in dry methylene chloride solution (1 mL)
Was slowly added dropwise and stirred at room temperature for 40 minutes. The reaction solution was heated to 34 to 36 ° C, and phenyliminoacetic acid methyl ester (16.3 mg, 0.100 mmol) was added to the solution in three portions every 85 minutes, and the mixture was further stirred at 34 to 36 ° C for 14 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. After evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N-phenylbenzoylalanine methyl ester ( (3.6 mg, 13%)
Was obtained as a pale yellow-white solid. The spectrum data of this was consistent with the data obtained in Example 3. This enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OJ,
When measured using a developing solvent: hexane / 2-propanol = 9/1), it was 70% ee.

Embodiment 5

[0063]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.5 mg, 9.7 μmol, 9.7 mol%)
1-phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to an anhydrous DMF solution (1 mL), and the mixture was stirred at room temperature for 55 minutes. To this solution was added dropwise a solution of 4-methoxyphenyliminoacetic acid methyl ester (18.2 mg, 0.094 mmol) in anhydrous DMF (0.5 mL) prepared using a syringe pump over 3.5 hours. Stirred for hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and then passed through a silica gel short column to remove the catalyst. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate.
After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 3/7) to obtain the desired N- (4-Methoxyphenyl) benzoylalanine methyl ester (22.6 mg, 77%) was obtained as a pale yellow oil. The enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPAK
AD, developing solvent: hexane / 2-propanol = 9/1), it was 28% ee. ¹ H-NMR (CDCl ₃ , 200MHz): δ3.55 (d, J = 5.3Hz, 2H), 3.
72 (s, 3H), 3.74 (s, 3H), 4.10 (br s, 1H), 4.55
(t, J = 5.3Hz, 1H), 6.67 (d, J = 9.0Hz, 2H), 6.78 (d, J
= 9.0Hz, 2H), 7.37-7.62 (m, 3H), 7.94 (d, J = 9.0Hz,
2H) .MS (EI): m / e = 313 (34, M ⁺ ), 254 (39), 134 (3
5), 105 (100).

Embodiment 6

[0066]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.8 mg, 10 μmol, 10.7 mol%)
1- (2-Methoxyphenyl) -1- in anhydrous DMF solution (1 mL)
(Trimethylsilyloxy) ethylene (33 μL, 0.15 mmo
l) was slowly added dropwise, and the mixture was stirred at room temperature for 55 minutes. The reaction solution was heated to 60 ° C., and 4-methoxyphenyliminoacetic acid isopropyl ester (20.7 mg,
(0.094 mmol) in anhydrous DMF (0.5 mL) was slowly added dropwise over 4 hours using a syringe pump, and the mixture was heated with stirring at 60 ° C. for 2 hours. During dropping, 1- (2-methoxyphenyl)
-1- (Trimethylsilyloxy) ethylene (30 μL, 0.14
mmol) was added in three portions every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane = 1: 1).
/ 4) to separate and purify the desired N- (4-methoxyphenyl)-(2-
(Methoxybenzoyl) alanine isopropyl ester (2
4.6 mg, 71%) as a pale yellow oil. The enantiomeric excess was measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPAK AD, developing solvent: hexane / 2-propanol = 9/1) and found to be 41% ee. there were. IR (neat): 3375, 2980, 2930, 1730, 1670, 1600, 151
5, 1485, 1465, 1290, 1240, 1110, 1015, 820, 760cm
^{. -1 1 H-NMR (CDCl} 3, 200MHz): δ1.16 (d, J = 6.3Hz, 3H), 1.
21 (d, J = 6.3Hz, 3H), 3.51 (br d, J = 5.7Hz, 2H), 3.7
3 (s, 3H), 3.90 (s, 3H), 4.19 (br s, 1H), 4.44 (br
t, J = 5.7Hz, 1H), 5.03 (sept, J = 6.3Hz, 1H), 6.65
(d, J = 9.0Hz, 2H), 6.76 (d, J = 9.0Hz, 2H), 6.94-7.05
(m, 2H), 7.42-7.52 (m, 1H), 7.70-7.77 (m, 1H) .MS (EI): m / e = 371 (18, M ⁺ ), 284 (16), 237 (23) , 1
35 (100) .HRMS: m / e calcd for C ₂₁ H ₂₅ NO ₅ 371.1731.found 37
1.1741.

Embodiment 7

[0069]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.7 mg, 10 μmol, 11.3 mol%)
1- (3-Nitrophenyl) -1- (trimethylsilyloxy) ethylene (33 μL, 0.15 mmol) in anhydrous DMF solution (1 mL)
Was slowly added dropwise and stirred at room temperature for 55 minutes. The reaction solution was heated to 60 ° C., and an anhydrous DMF solution (0.5 mL) of phenyliminoacetic acid isopropyl ester (16.8 mg, 0.088 mmol) prepared immediately before was slowly added dropwise using a syringe pump over 4 hours. For 2 hours. During the dropwise addition, 1- (3-nitrophenyl) -1- (trimethylsilyloxy) ethylene (30 μL, 0.14 mmol) was added dropwise in three portions every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Add water (5 mL) to the eluate,
Extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/3, 3 times). N-phenyl-3-nitrobenzoylalanine isopropyl ester (16.1 mg, 51%) was obtained as a pale yellow oil. The enantiomeric excess was measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPAK AD, developing solvent: hexane / 2-propanol = 9/1) and found to be 43% ee. there were. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 1.18 (d, J = 6.3 Hz, 3H), 1.
23 (d, J = 6.3Hz, 3H), 3.60 (br d, J = 4.1Hz, 2H), 4.5
3 (br s, 1H), 4.62 (br t, J = 4.1Hz, 1H), 5.07 (sept,
J = 6.3Hz, 1H), 6.67-6.82 (m, 3H), 7.13-7.72 (m, 2
H), 7.68 (t, J = 8.0Hz, 1H), 8.26 (br d, J = 8.0Hz, 1
H), 8.43 (d, J = 8.0Hz, 1H), 8.75 (br s, 1H).

Embodiment 8

[0072]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (10.0 mg, 10.0μmol, 10.0 mol
%) In anhydrous DMF solution (1 mL) in 1- (3,4-dichlorophenyl)
-1- (Trimethylsilyloxy) ethylene (34 μL, 0.15
mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 80 minutes. The reaction solution was heated to 60 ° C., and 4-methoxyphenyliminoacetic acid isopropyl ester (21.7 mg,
0.098 mmol) in anhydrous DMF (0.5 mL) was slowly added dropwise using a syringe pump over 4 hours, and the mixture was heated and stirred at 60 ° C. for 2 hours. During the addition, 1- (3,4-dichlorophenyl) -1- (trimethylsilyloxy) ethylene (34 μL, 0.
15 mmol) was added dropwise in three portions every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After the desiccant was removed and the solvent was distilled off under reduced pressure, the resulting crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane =
(1/4, twice) to obtain N- (4-methoxyphenyl)-(3,4-dichlorobenzoyl) alanine isopropyl ester (16.0 mg, 40%) as a pale yellow oil.
The enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPA
It was 31% ee when measured using KAD, developing solvent: hexane / 2-propanol = 9/1). IR (neat): 3370, 2980, 2930, 1730, 1690, 1515, 13
. 90, 1240, 1210, 1105,1030 , 820cm -1 1 H-NMR (CDCl 3, 200MHz): δ1.17 (d, J = 6.2Hz, 3H), 1.
20 (d, J = 6.2Hz, 3H), 3.44 (d, J = 5.4Hz, 2H), 3.74
(s, 3H), 4.21 (m, 1H), 4.48 (br t, J = 5.4Hz, 1H),
5.04 (sept, J = 6.2Hz, 1H), 6.67 (d, J = 8.9Hz, 2H),
6.78 (d, J = 8.9Hz, 2H), 7.54 (d, J = 8.4Hz, 1H), 7.75
(dd, J = 8.4, 1.7Hz, 1H), 8.00 (d, J = 1.7Hz, 1H). MS (EI): m / e = 414, 421, 410 (1, 4, 6, M ⁺ ), 322 (5
HRMS: m / e calcd for C ₂₀ H ₂₁ Cl ₂ NO ₄ 409.0846. Found 2), 173 (100).
409.0864.

Embodiment 9

[0075]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.6 mg, 9.8 μmol, 10.7 mol%)
1-Naphthyl-1- (trimethylsilyloxy) ethylene (37 μL, 0.15 mmol) was slowly added dropwise to an anhydrous DMF solution (1 mL), followed by stirring at room temperature for 75 minutes. This reaction solution is
The mixture was heated to 40 ° C., and a solution of 4-methoxyphenyliminoacetic acid isopropyl ester (20.3 mg, 0.092 mmol) in anhydrous DMF (0.5 mL) prepared immediately before was slowly added dropwise using a syringe pump over 4 hours. The mixture was heated and stirred for 2 hours. During the addition, 1-naphthyl-1- (trimethylsilyloxy) ethylene (36 μL, 0.15 mmol) was added in three portions every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After the desiccant was removed and the solvent was distilled off under reduced pressure, the resulting crude product was subjected to silica gel thin layer chromatography (eluent:
Ethyl acetate / hexane = 1/4) for purification.
(4-Methoxyphenyl) -naphthoylalanine isopropyl ester (25.1 mg, 70%) was obtained as a pale yellow oil. This enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CH
IRALPAK AD, developing solvent: hexane / 2-propanol = 9
/ 1) was 53% ee. IR (neat): 3400, 3350, 2980, 2360, 2340, 1730, 166
. 5, 1515, 1235, 1210 , 1110, 825cm -1 1 H-NMR (CDCl 3, 200MHz): δ1.15 (d, J = 6.3Hz, 3H), 1.
19 (d, J = 6.3Hz, 3H), 3.63 (d, J = 5.5Hz, 2H), 3.73
(s, 3H), 4.24 (br s, 1H), 4.56 (br t, J = 5.5Hz, 1
H), 5.04 (sept, J = 6.3Hz, 1H), 6.70 (d, J = 9.1Hz, 2
H), 6.78 (d, J = 9.1Hz, 2H), 7.52-7.67 (m, 2H), 7.85
-8.05 (m, 4H), 8.44 (br s, 1H) .MS (EI): m / e = 391 (4, M ⁺ ), 304 (17), 268 (21), 15
5 (100) .HRMS: m / e calcd for C ₂₄ H ₂₅ NO ₄ 391.1781. Found 39
1.1769.

Embodiment 10

[0078]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (10.0 mg, 10 μmol, 10.3 mol%)
1-Phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to an anhydrous DMF solution (2 mL), and the mixture was stirred at room temperature for 40 minutes. To this solution was added N-benzylidene- (p-toluenesulfonyl) amine (25.9 mg, 0.
After stirring at room temperature for 8 hours, 1-phenyl-1- (trimethylsilyloxy) ethylene (10 μL, 0.0
49 mmol) and stirred at room temperature for 86 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the insolubles derived from the catalyst were separated by filtration using Hyflo Super Cell. Water (5 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After the desiccant was removed and the solvent was distilled off under reduced pressure, the resulting crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane =
1/3) and purify the desired 3-N- (p-toluenesulfonyl) amino-1,3-diphenyl-1-propanone (11.2 mg, 30
%) Was obtained as a white solid. The enantiomeric excess was measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OD, developing solvent: hexane / 2-propanol = 9/1).
It was 9% ee. ¹ H-NMR (CDCl ₃ , 200 MHz): δ2.36 (s, 3H), 3.67 (dd, J
= 17.3, 6.2Hz, 1H), 3.59 (dd, J = 17.3, 5.6Hz, 1H),
4.81-4.91 (m, 1H), 5.74 (d, J = 7.0Hz, 1H), 7.11-7.6
6 (m, 12H), 7.80 (d, J = 7.2Hz, 2H). MS (CI): m / e = 380 (M ⁺ +1).

Embodiment 11

[0081]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.9 mg, 10 μmol, 9.4 mol%)
1-Phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to an anhydrous DMF solution (2 mL), and the mixture was stirred at room temperature for 35 minutes. To this solution was added N-benzylidene- (4-ethoxycarbonyl) aniline (26.8 mg, 0.
After stirring at room temperature for 3 hours, 1-phenyl-1- (trimethylsilyloxy) ethylene (10 μL, 0.04
9 mmol) and stirred at room temperature for 82 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the insolubles derived from the catalyst were separated by filtration using Hyflo Super Cell. Water (5 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After the desiccant was removed and the solvent was distilled off under reduced pressure, the resulting crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane =
1/3, developed twice) to give the desired 3-N- (4-ethoxycarbonylphenyl) amino-1,3-diphenyl-1-propanone (11.2 mg, 28%) as a pale yellow-white solid Obtained. The enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPAK
AS, developing solvent: hexane / 2-propanol = 9/1), it was 34% ee. ¹ H-NMR (CDCl ₃ , 400MHz): δ1.32 (t, J = 7.1Hz, 3H), 3.
47 (dd, J = 16.3, 6.8Hz, 1H), 3.53 (dd, J = 16.3, 4.8H
z, 1H), 4.48 (q, J = 7.1Hz, 2H), 5.05-5.10 (m, 2H),
6.52 (d, J = 8.8Hz, 2H), 7.23-7.48 (m, 7H), 7.55-7.5
9 (m, 1H), 7.79 (d, J = 8.8Hz, 2H), 7.90 (d, J = 7.1Hz,
2H). MS (EI): m / e = 373 (22, M ⁺ ), 328 (7), 297 (4), 269
(10), 254 (100), 120 (75), 105 (95).

Embodiment 12

[0084]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (10.0 mg, 10 μmol, 10.3 mol%)
1-Phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to an anhydrous DMF solution (2 mL), and the mixture was stirred at room temperature for 1 hour. To this solution was added 4-ethoxycarbonyl-N- (4-methylbenzylidene) aniline (38.
After stirring at room temperature for 3.5 hours, 1-phenyl-1- (trimethylsilyloxy) ethylene was added.
(31 μL, 0.151 mmol) was added and the mixture was stirred at room temperature for 63.5 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the insolubles derived from the catalyst were separated by filtration using Hyflo Super Cell. Water (5 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/3, developed twice). To give 3-N- (4-ethoxycarbonylphenyl) amino-1-phenyl-3- (p-tolyl) -1-propanone (25.8 mg, 67%) as a pale yellow-white solid. The enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPAK AS, developing solvent: hexane / 2-propanol).
= 9/1) was 16% ee. ¹ H-NMR (CDCl ₃ , 200 MHz): δ 1.31 (t, J = 7.1 Hz, 3H), 2.
30 (s, 3H), 3.40-3.53 (m, 2H), 4.26 (q, J = 7.1Hz, 2
H), 5.02-5.08 (m, 2H), 6.52 (d, J = 8.8Hz, 2H), 7.12
(d, J = 8.0Hz, 2H), 7.28 (d, J = 8.0Hz, 2H), 7.41-7.4
6 (m, 2H), 7.53-7.58 (m, 1H), 7.78 (d, J = 8.8Hz, 2
H), 7.89 (d, J = 7.2Hz, 2H) .MS (EI): m / e = 387 (4, M ⁺ ), 268 (24), 120 (30), 10
5 (22), 43 (100).

Embodiment 13

[0087]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (19 mg, anhydrous DMF solution of 0.02 mmol, 10 mol%) ( 1 mL) 1- phenyl-1- (trimethylsilyloxy) ethylene (61 μL, 0.3 mmol) was slowly added dropwise, followed by stirring at room temperature for 1 hour. Bring the reaction solution to 40 ° C,
An anhydrous DMF solution (0.8 mL) of N-phenacylidene-p-toluidine (44 mg, 0.2 mmol) was slowly added dropwise over 4 hours using a syringe pump. One hour after the start of dropping, 3
After an hour, 1-phenyl-1- (trimethylsilyloxy) ethylene (20 μL, 0.1 mmol) was added. 40 ° C after dropping
The stirring was further continued for 10 hours. The reaction solution was passed through a silica gel column (developing solvent: hexane / ethyl acetate = 2/1) to remove the catalyst. The eluate was concentrated, extracted with ethyl acetate, washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated, and the crude product obtained was subjected to silica gel thin layer chromatography (developing solvent: hexane / ethyl acetate = 4). / 1) to separate and purify the desired 1,4-diphenyl-2
-N- (p-tolyl) aminobutane-1,4-dione (33 mg, 49%)
Was obtained as a pale yellow oil. The enantiomeric excess was measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OJ, developing solvent: hexane / 2-propanol = 9/1).
It was 6% ee. ¹ H-NMR (CDCl ₃ , 200 MHz): δ2.22 (s, 3H), 3.49 (dd, J
= 17.4, 5.8Hz, 1H), 3.52 (dd, J = 17.4, 5.9Hz, 1H),
5.67 (dd, J = 5.9, 5.8Hz, 1H), 6.68-7.10 (m, 4H), 7.
40-7.54 (m, 6H), 7.90-8.07 (m, 4H).

Embodiment 14

[0090]

Embedded image

Under an argon atmosphere, [Pd ((R) -3,4-Me ₂ -C ₆ H _{3
-binap) (H 2 O) 2} ] 2+ (BF 4 -) 2 (10.5 mg, 9.9 μmol, 9.9 m
ol%) in anhydrous DMF (1 mL), 1-phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. This reaction solution was heated to 60 ° C., and 4-methoxyphenyliminoacetic acid isopropyl ester prepared immediately before (22.4 mg, 0.101 mmol)
Of anhydrous DMF solution (0.5 mL) using a syringe pump
The mixture was slowly added dropwise over a period of time, and the mixture was further heated and stirred at 60 ° C for 2 hours. During the dropping, 1-phenyl-1- (trimethylsilyloxy) ethylene (30 μL, 0.149 mmol) was dropped in three times every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-Methoxyphenyl) benzoylalanine isopropyl ester (16.1 mg, 47%) was obtained as a pale yellow oil. The enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CH
IRALCEL OG, developing solvent: hexane / 2-propanol = 9
/ 1) was 26% ee, and its spectral data were consistent with those obtained in Example 1.

Embodiment 15

[0093]

Embedded image

Under an argon atmosphere, [Pd ((R) -binap) (PhCN)
_{^{2] 2+ (BF 4 -)}} 2 (10.9 mg, 9.8 μmol, 9.8 mol%) in anhydrous DM
1-phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to the F solution (1 mL),
Stirred at room temperature for 1 hour. The reaction solution was heated to 60 ° C., and a solution of 4-methoxyphenyliminoacetic acid isopropyl ester (22.4 mg, 0.101 mmol) in anhydrous DMF (0.5 mL) prepared immediately before was slowly added dropwise over 4 hours using a syringe pump. The mixture was further heated and stirred at 60 ° C. for 2 hours. During the addition, 1-phenyl-1- (trimethylsilyloxy) ethylene
(20 μL, 0.10 mmol) was added dropwise twice in one hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. Remove the desiccant,
After the solvent was distilled off under reduced pressure, the resulting crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate /
Hexane = 1/4) for purification and separation of the desired N- (4-methoxyphenyl) benzoylalanine isopropyl ester
7.9 mg, 78%) as a pale yellow oil. The enantiomeric excess was 76% ee when measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG, developing solvent: hexane / 2-propanol = 9/1). , And its spectral data were consistent with those obtained in Example 1.

Embodiment 16

[0096]

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Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.6 mg, 9.8 μmol) in anhydrous DMF
To the solution (1 mL) was slowly added 1-phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) dropwise.
Stirred at room temperature for 60 minutes. Calcium carbonate (10.6 mg, 0.106 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was heated to 60 ° C., and isopropyl ester of 4-methoxyphenyliminoacetic acid adjusted immediately before was heated.
(26.6 mg, 0.120 mmol) in anhydrous DMF (0.5 mL) was added to 5
Then, the mixture was stirred at 60 ° C. for 5 hours. During the reaction, 1-phenyl-1- (trimethylsilyloxy) ethylene
(30 μL, 0.146 mmol) was added dropwise three times every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-Methoxyphenyl) benzoylalanine isopropyl ester (34.4 mg, 84%) was obtained as a pale yellow oil. This enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG,
When measured using a developing solvent: hexane / 2-propanol = 9/1), it was 89% ee, and its spectral data were consistent with those obtained in Example 1.

Embodiment 17

[0099]

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Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.8 mg, 10.0 μmol) in anhydrous DMF
1-Phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to the solution (1 mL), and the mixture was stirred at room temperature for 90 minutes. Triethylamine (2 μL, 0.014 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 25 minutes. The reaction solution was heated to 60 ° C, and a solution of 4-methoxyphenyliminoacetic acid isopropyl ester (21.5 mg, 0.097 mmol) in DMF (0.5 mL) prepared immediately before was heated.
Was slowly added dropwise over 4 hours using a syringe pump, and the mixture was further heated and stirred at 60 ° C. for 8 hours. During the addition, 1-phenyl-1- (trimethylsilyloxy) ethylene (30 μL,
0.146 mmol) was added dropwise in three portions every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether.
The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was subjected to silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane).
= 1/4) and purify the desired N- (4-methoxyphenyl)
Benzoylalanine isopropyl ester (9.4 mg, 26
%) As a pale yellow solid. The enantiomeric excess was measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG, developing solvent: hexane / 2-propanol = 9/1).
78% ee, and its spectrum data is shown in Example 1.
In agreement with the data obtained in.

Embodiment 18

[0102]

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Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.8 mg, 10.0 μmol) in anhydrous DMF
1-Phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol) was slowly added dropwise to the solution (1 mL), and the mixture was stirred at room temperature for 90 minutes. Pyridine is added to this reaction solution.
(4 μL, 0.049 mmol) was added and the mixture was stirred at room temperature for 10 minutes. The reaction solution was heated to 60 ° C.
Methoxyphenyliminoacetic acid isopropyl ester (2
(3.6 mg, 0.107 mmol) in anhydrous DMF (0.5 mL) was slowly added dropwise using a syringe pump over 4 hours.
The mixture was further heated and stirred at 1 ° C. for 1 hour. During the addition, 1-phenyl-1-
(Trimethylsilyloxy) ethylene (30 μL, 0.146mmo
l) was added dropwise three times every hour. After the reaction,
After diluting the reaction solution with diethyl ether, the catalyst was removed through a silica gel short column. Water in the eluate
(5 mL) and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane = 1/1/3).
4) Separate and purify the desired N- (4-methoxyphenyl) benzoylalanine isopropyl ester (31.0 mg, 85%)
Was obtained as a pale yellow solid. The enantiomeric excess was measured by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG, developing solvent: hexane / 2-propanol = 9/1).
It was 0% ee, and its spectral data were consistent with those obtained in Example 1.

Embodiment 19

[0105]

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Under an argon atmosphere, [Pd ((R) -binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 · 2H 2 O (9.8 mg, 10.0 μmol) in anhydrous DMF
To the solution (1 mL) was slowly added 1-phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.151 mmol), and the mixture was stirred at room temperature for 80 minutes. After adding 2,6-lutidine (6 μL, 0.052 mmol) to the reaction solution and stirring at room temperature for 10 minutes, the reaction solution was heated to 60 ° C. and 4-methoxyphenyliminoacetic acid isopropyl ester ( 23.1 mg, 0.10 mmol) in anhydrous DMF (0.5 mL) was slowly added dropwise using a syringe pump over 4 hours.
The mixture was further heated and stirred at 60 ° C. for 2 hours. During dropping, 1-phenyl
-1- (Trimethylsilyloxy) ethylene (30 μL, 0.146
mmol) was added dropwise in three portions every hour. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane = 1: 1).
/ 4) and purified with the desired N- (4-methoxyphenyl) benzoylalanine isopropyl ester (28.9 mg, 81
%) As a pale yellow solid. The enantiomeric excess was measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG, developing solvent: hexane / 2-propanol = 9/1).
75% ee, and its spectrum data is shown in Example 1.
In agreement with the data obtained in.

Embodiment 20

[0108]

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Under an argon atmosphere, [Pd ((R) -tol-binap) (H
^{_{2 O) 2] 2+ (BF}} 4 -) 2 (50 mg, acetone solution of 0.05 mmol)
(5 mL) was added with molecular sieves 4A (300 mg) dried under reduced pressure using a mantle heater, and the mixture was stirred at room temperature for 3 hours. After filtration through celite, vacuum concentration and drying with a vacuum pump are performed to obtain the target dinuclear complex.
[{Pd ((R) -tol -binap) (μ-OH)} 2] 2+ (BF 4 -) 2 (42 mg, 88
%) As a red-orange solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ-3.03 (s, 2H), 1.96 (s, 1
2H), 2.11 (s, 12H), 6.53 (d, J = 8.6Hz, 4H), 6.60-7.
75 (m, 52H). IR (KBr): 3480, 1260, 1030, 810, 510 cm ^-1 . [Α] ²⁰ _D + 590.3 ° (c 0.2, CHCl ₃ ). Mp 247 ° C (decomposition)

Embodiment 21

[0111]

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Under an argon atmosphere, [PdCl ₂ ((R) -tol-bina
p)] (50 mg, 0.058 mmol) in aqueous acetone (5 mL)
And molecular sieves 4A (300 mg) dried under reduced pressure using a mantle heater and silver tetrafluoroborate
(23 mg, 0.116 mmol) was added and the mixture was stirred at room temperature for 3 hours. After filtration through Celite, concentration under reduced pressure, and drying with a vacuum pump, the target binuclear complex [{Pd ((R)
-tol-binap) (μ-OH)} ₂ ] ^{2 +} (BF ₄ ⁻ ) ₂ (48 mg, 93%) was obtained as a red-orange solid. Its spectral data were consistent with those obtained in Example 20.

Embodiment 22

[0114]

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Under an argon atmosphere, [PdCl ₂ ((R) -tol-bina
p)] (100 mg, 0.116 mmol) in aqueous dichloromethane
(10 mL), molecular sieves 4A (1.5 g) and silver tetrafluoroborate (47 mg, 0.232 mmol) dried under reduced pressure using a mantle heater were added, and the mixture was stirred at room temperature for 20 hours. After filtration through celite, vacuum concentration and drying with a vacuum pump are performed to obtain the target dinuclear complex.
[{Pd ((R) -tol -binap) (μ-OH)} 2] 2+ (BF 4 -) 2 (95 mg, 92
%) As a red-orange solid. Its spectral data were consistent with those obtained in Example 20.

Embodiment 23

[0117]

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Under an argon atmosphere, [PdCl ₂ ((R) -tol-bina
p)] (100 mg, 0.116 mmol) in aqueous dichloromethane
(10 mL), molecular sieves 4A (1.5 g) dried under reduced pressure using a mantle heater and silver trifluoromethanesulfonate (62 mg, 0.240 mmol) were added, and the mixture was stirred at room temperature for 30 hours. After filtration through celite, concentration under reduced pressure, and drying with a vacuum pump, the target binuclear complex [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ ₂ (CF ₃ SO ₃ ^- ) ₂
(89 mg, 81%) was obtained as a red-orange solid. Recrystallization from chloroform-ether gave orange needle crystals. ¹ H-NMR (CDCl ₃ , 200 MHz): δ-3.00 (s, 2H), 1.96 (s, 1
2H), 2.11 (s, 12H), 6.53 (d, J = 8.6Hz, 4H), 6.60-7.
75 (m, 52H). IR (CHCl ₃ ): 3620, 2950, 2180, 1270, 1010, 740 c
_{^{m -1. [α] 20 D}} + 628.6 ° (c 0.3, CHCl 3). mp 228 ℃ ( decomposition)

Embodiment 24

[0120]

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[PdCl ₂ ((R) -binap)] under an argon atmosphere
(100 mg, 0.125 mmol) in aqueous dichloromethane (10 m
To L), molecular sieves 4A (1.5 g) and silver tetrafluoroborate (48 mg, 0.25 mmol) dried under reduced pressure using a mantle heater were added, and the mixture was stirred at room temperature for 30 hours. After filtration through celite, concentration under reduced pressure, and drying with a vacuum pump, the target binuclear complex [{Pd
((R) -binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (86 mg, 79%) was obtained as a red-orange solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ-2.90 (s, 2H), 6.55 (d, J
= 8.4Hz, 4H), 6.60-7.75 (m, 60H) .IR (CHCl ₃ ): 3580, 3050, 1430, 1310, 1050, 810, 74
^{0, 690, 500 cm -1.} [Α] 20 D + 735.6 ° (c 0.32, CHCl 3). Mp 217 ℃ ( decomposition).

Embodiment 25

[0123]

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Palladium Aqua Complex [Pd ((R) -tol-bina
p) (H ₂ O) ₂ ] ²⁺ (CF ₃ SO ₃ ⁻ ) ₂ (235 mg, 0.21 mmol) in dichloromethane (3 mL) in water (1 mL), 0.1N aqueous sodium hydroxide solution (2.1 mL) Was added and stirred for 4 hours. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. After removing the desiccant and concentrating, the target binuclear complex [{Pd
((R) -tol-binap) (μ-OH)} 2] 2+ (CF 3 SO 3 -) 2 (173 mg, 87
%) As a red-orange solid. The spectral data of this was consistent with that obtained in Example 23.

Embodiment 26

[0126]

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Palladium Aqua Complex [Pd ((R) -tol-bina
_{p) (H 2 O) 2} ] 2+ (CF 3 SO 3 -) 2 (100 mg, 89μmol) water (1 mL) in dichloromethane (3 mL) of 0.1N sodium hydroxide solution (2.0 mL) The mixture was stirred for 4 hours. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. After removing the drying agent and concentrating, the target binuclear complex [{Pd ((R)-
tol-binap) (μ-OH)} ₂ ] ²⁺ (CF ₃ SO ₃ ⁻ ) ₂ (72 mg, 85%) was obtained as a red-orange solid. The spectral data of this was consistent with that obtained in Example 23.

Embodiment 27

[0129]

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Palladium aqua complex [Pd ((R) -binap) (H _{2
^{O) 2] 2+ (CF 3}} SO 3 -) 2 (1.50g, 1.41 mmol) in dichloromethane (10 mL) of water (10 mL), 1N sodium hydroxide solution (1.4 mL) was stirred for 3 hours added . The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. After removing the desiccant and concentrating, target dinuclear complex [{Pd ((R) -binap)
(μ-OH)} ₂ ] ²⁺ (CF ₃ SO ₃ ⁻ ) ₂ (1.21 g, 92%) was obtained as a red-orange solid. ¹ H-NMR (CDCl ₃ , 200 MHz): δ-2.86 (s, 2H), 6.56 (d, J
= 8.4Hz, 4H), 6.80-7.67 (m, 60H) .IR (KBr): 3500, 3060, 1440, 1260, 1150, 1030, 750,
^{700, 640, 500 cm -1.} [Α] 20 D + 683.6 ° (c 0.50, CHCl 3). Mp 195 ℃ ( decomposition).

Embodiment 28

[0132]

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Palladium aqua complex [Pd ((R) -binap) (H ₂
O) ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (270 mg, 0.27 mmol) in dichloromethane (3 mL) was added with water (1 mL) and a 0.1N aqueous sodium hydroxide solution (2.7 mL) and stirred for 4 hours. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. After removing the desiccant and concentrating, target dinuclear complex [{Pd ((R) -binap)
(μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (182 mg, 81%) was obtained as a red-orange solid. Its spectral data were consistent with those obtained in Example 24.

Embodiment 29

[0135]

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Under an argon atmosphere, the dinuclear complex [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (5.0 m) obtained in Example 20 was obtained.
g, 2.8 μmol) in anhydrous DMF (1 mL).
(Trimethylsilyloxy) ethylene (31 μL, 0.151 mm
ol) was slowly added dropwise, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was heated to 60 ° C, and 4-methoxyphenyliminoacetic acid isopropyl ester (21.0 mg,
(0.095 mmol) in anhydrous DMF (0.5 mL) was slowly added dropwise using a syringe pump over 4 hours, and the mixture was further heated and stirred at 60 ° C. for 1 hour. During the addition, 1-phenyl-1- (trimethylsilyloxy) ethylene (20 μL, 0.097 mmol) was added to 1
The solution was dropped twice in each time. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. Combine the organic layers,
After washing with water and saturated saline solution in that order, it was dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-Methoxyphenyl) benzoylalanine isopropyl ester (26.7 mg, 82%) was obtained as a pale yellow solid. The enantiomeric excess was 80% ee when measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCELOG, developing solvent: hexane / 2-propanol = 9/1). The spectrum data was consistent with the data obtained in Example 1. Further, this was recrystallized from ethyl acetate-hexane to give an enantiomeric excess of 99% ee.
The above colorless plate crystals (10.0 mg) were obtained. mp: 113.0-113.5 ℃ [α] ²⁰ _D + 30.37 ° (c 0.54, CHCl ₃ ) (> 99% ee).

Embodiment 30

[0138]

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The dinuclear complex obtained in Example 20 [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (8.9 m ₂ ) under an argon atmosphere.
g, 5.0 μmol) in anhydrous DMF (1 mL).
(Trimethylsilyloxy) ethylene (41 μL, 0.20 mmo
l) was slowly added dropwise, followed by stirring at room temperature for 40 minutes. To this reaction solution, a solution of 4-methoxyphenyliminoacetic acid isopropyl ester (22.0 mg, 0.10 mmol) prepared immediately before in anhydrous DMF (0.5 mL) was added dropwise over 5 minutes.
Stir for 8.5 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate.
After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-Methoxyphenyl) benzoylalanine isopropyl ester (32.3 mg, 95%) was obtained as a pale yellow solid. This enantiomeric excess can be determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIR
ALCEL OG, developing solvent: hexane / 2-propanol = 9 /
It was 90% ee when measured using 1), and its spectrum data was consistent with the data obtained in Example 1. By recrystallizing this from ethyl acetate-hexane, colorless needles having an enantiomeric excess of 99% ee or more (recovery rate: 75%) were obtained.

Embodiment 31

[0141]

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Under an argon atmosphere, the binuclear complex [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ obtained in Example 20 (8.8 m ₂ )
g, 5.0 μmol) in anhydrous DMF solution (1 mL) was added to 1- (3,4-dichlorophenyl) -1- (trimethylsilyloxy) ethylene (45
μL, 0.20 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 40 minutes. To this reaction solution, 4-methoxyphenyliminoacetic acid isopropyl ester prepared immediately before (22.8 mg,
(0.10 mmol) in anhydrous DMF (0.5 mL) was added dropwise over 5 minutes, and the mixture was further stirred at 25 ° C. for 24 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 m
L) and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-methoxyphenyl)-(3,4-dichlorobenzoyl) alanine isopropyl ester (33.8
mg, 80%) as a pale yellow oil. The enantiomeric excess was 84% ee when measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPACK AD, developing solvent: hexane / 2-propanol = 9/1). , And its spectral data were consistent with those obtained in Example 8. [α] ²⁰ _D + 28.40 ° (c 0.50, CHCl ₃ ) (84% ee).

Embodiment 32

[0144]

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Under an argon atmosphere, the binuclear complex obtained in Example 20 [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (8.9 m
g, 5.0 μmol) in anhydrous DMF (1 mL).
μL, 0.20 mmol) was slowly added dropwise, followed by stirring at room temperature for 40 minutes. 4-Methoxyphenyliminoacetic acid isopropyl ester (22.0 mg, 0.1
0 mmol) in 0.5 ml of anhydrous DMF over 2 minutes.
Stirred at 25 ° C. for a further 17 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. Combine the organic layers,
After washing with water and saturated saline solution in that order, it was dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-Methoxyphenyl)-(2-methoxybenzoyl) alanine isopropyl ester (32.3 mg, 87
%) As a pale yellow oil. This enantiomeric excess is
When measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPACK AD, developing solvent: hexane / 2-propanol = 9/1), it was 71% ee. This was consistent with the data obtained in Example 6. [α] ²⁰ _D + 10.00 ° (c 0.52, CHCl ₃ ) (71% ee).

Embodiment 33

[0147]

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Under an argon atmosphere, the binuclear complex [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ obtained in Example 20 (8.9 m ₂ )
g, 5.0 μmol) in anhydrous DMF (1 mL).
(Trimethylsilyloxy) ethylene (49 μL, 0.20 mmo
l) was slowly added dropwise, followed by stirring at room temperature for 40 minutes. To this reaction solution, an anhydrous DMF solution (0.5 mL) of 4-methoxyphenyliminoacetic acid isopropyl ester (21.8 mg, 0.099 mmol) prepared immediately before was added dropwise over 5 minutes, and the mixture was further stirred at 25 ° C for 17 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate.
After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-Methoxyphenyl) -naphthoylalanine isopropyl ester (31.5 mg, 82%) was obtained as a pale yellow solid. This enantiomeric excess can be determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIR
ALPACK AD, developing solvent: hexane / 2-propanol = 9
/ 1) was 83% ee, and its spectral data were consistent with those obtained in Example 9. Further, this was recrystallized from ethyl acetate-hexane to obtain pale yellow needles having an enantiomeric excess of 99% ee or more (recovery rate: 71%). mp: 105.0-106.0 ℃ [α] ²⁰ _D + 36.79 ° (c 0.50, CHCl ₃ ) (> 99% ee).

Embodiment 34

[0150]

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Under an argon atmosphere, the binuclear complex obtained in Example 20 [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (5.0 m
g, 2.8 μmol) in anhydrous DMF (1 mL) was added to 1- (3-nitrophenyl) -1- (trimethylsilyloxy) ethylene (33 μL).
L, 0.15 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 50 minutes. 4-Methoxyphenyliminoacetic acid isopropyl ester (22.5 mg, 0.10
Anhydrous DMF solution (0.5 mL) was slowly added dropwise over 4 hours using a syringe pump, and the mixture was further stirred at 25 ° C. for 9 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 3/10) to obtain the desired N- (Four-
(Methoxyphenyl) -3-nitrobenzoylalanine isopropyl ester (24.2 mg, 62%) was obtained as a red solid. This enantiomeric excess can be determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIR
ALPACK AD, developing solvent: hexane / 2-propanol = 9 /
It was 60% ee when measured using 1). IR (KBr): 3375, 2360, 2340, 1715, 1690, 1615, 1525,
. 1515, 1350,1240, 1210, 1110 , 820cm -1 1 H-NMR (CDCl 3, 200MHz): δ1.18 (d, J = 6.3Hz, 3H), 1.
21 (d, J = 6.3Hz, 3H), 3.55 (d, J = 5.4Hz, 2H), 3.74
(s, 3H), 4.18 (br s, 1H), 4.53 (br t, J = 5.4Hz, 1
H), 5.05 (sept, J = 6.3Hz, 1H), 6.68 (d, J = 9.0Hz, 2
H), 6.78 (d, J = 9.0Hz, 2H), 7.68 (t, J = 8.0Hz, 1H),
8.26 (d, J = 8.0Hz, 1H), 8.43 (d, J = 8.0Hz, 1H), 8.75
(s, 1H). MS (EI): m / e = 386 (31, M ⁺ ), 343 (5), 299 (100) .HRMS: m / e calcd for C ₂₀ H ₂₂ N ₂ O ₆ 386.1476. found 38
6.1456. [Α] ²⁰ _D + 14.06 ° (c 0.52, CHCl ₃ ) (60% ee).

Embodiment 35

[0153]

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The dinuclear complex [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (8.9 m ₂ ) obtained in Example 20 under an argon atmosphere.
g (5.0 μmol) in anhydrous DMF (0.8 mL), 2- (trimethylsilyloxy) propene (50 μL, 0.30 mmol) was slowly added dropwise, followed by stirring at room temperature for 40 minutes. To this reaction solution, a solution of 4-methoxyphenyliminoacetic acid isopropyl ester (21.8 mg, 0.099 mmol) prepared immediately before in anhydrous DMF (0.7 mL) was added dropwise using a syringe pump over 7 hours, and further added at room temperature for 17 hours. Stirred. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 m
L) and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-Methoxyphenyl) acetylalanine isopropyl ester (21.8 mg, 79%) was obtained as a pale yellow oil. The enantiomeric excess was measured by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPAKAD, developing solvent: hexane / 2-propanol = 9/1), and was 53%.
was ee. IR (neat): 3360, 2980, 2930, 1720, 1510, 1240, 110
^{. 5, 1035, 820cm -1 1} H-NMR (CDCl 3, 200MHz): δ1.20 (d, J = 6.2Hz, 3H), 1.
21 (d, J = 6.2Hz, 3H), 2.18 (s, 3H), 2.94 (br d, J =
5.7Hz, 2H), 3.74 (s, 3H), 4.04 (br s, 1H), 4.30 (b
rt, J = 5.7Hz, 1H), 5.02 (sept, J = 6.2Hz, 1H), 6.64
(d, J = 9.0Hz, 2H), 6.77 (d, J = 9.0Hz, 2H). MS (EI): m / e = 279 (30, M ⁺ ), 192 (100), 150 (65). Anal.Calcd for C ₁₅ H ₂₁ NO ₄ : C, 64.50; H, 7.58; N,
5.01. Found: C, 64.36; H, 7.78; N, 4.91. [Α] ²⁰ _D -4.95 ° (c 0.525, CHCl ₃ ) (53% ee).

Embodiment 36

[0156]

Embedded image

In an argon atmosphere, the dinuclear complex [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (9.7 m) obtained in Example 20 was obtained.
g, 5.5 μmol) in 1 mL of anhydrous DMF.
(Trimethylsilyloxy) ethylene (41 μL, 0.20 mmo
l) was slowly added dropwise, and the mixture was stirred at room temperature for 45 minutes. To this reaction solution was added 4-methoxyphenyliminoacetic acid benzyl ester (26.9 mg, 0.10 mmol) prepared immediately before in anhydrous DM.
F solution (0.5 mL) was added dropwise over 5 minutes, and an additional 24
Stirred for hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 3/10) to obtain the desired N-
(4-Methoxyphenyl) -benzoylalanine benzyl ester (24.8 mg, 64%) was obtained as a pale yellow solid. This enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPACK A
D, using developing solvent: hexane / 2-propanol = 9/1), it was 77% ee. IR (KBr): 3325, 2360, 1735, 1680, 1515, 1240, 835 c
^{. m -1 1 H-NMR (} CDCl 3, 200MHz): δ3.53 (d, J = 5.3Hz, 2H), 3.
73 (s, 3H), 4.22 (br s, 1H), 4.60 (br t, J = 5.3Hz,
1H), 5.14 (s, 2H), 6.66 (d, J = 9.1Hz, 2H), 6.76 (d,
J = 9.1Hz, 2H), 7.18-7.35 (m, 5H), 7.38-7.62 (m, 3
H), 7.91 (d, J = 7.1Hz, 2H) .MS (EI): m / e = 389 (29, M ⁺ ), 254 (34), 160 (78), 1
05 (100) .HRMS: m / e calcd for C ₂₄ H ₂₃ NO ₄ 389.1625.found 38
9.1611. [Α] ²⁰ _D + 14.11 ° (c 0.51, CHCl ₃ ) (77% ee).

Embodiment 37

[0159]

Embedded image

In an argon atmosphere, the dinuclear complex [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ obtained in Example 20 (8.8 m ₂ )
g, 4.9 μmol) in anhydrous DMF (1 mL).
(Trimethylsilyloxy) ethylene (31 μL, 0.151 mm
ol) was slowly added dropwise, followed by stirring at room temperature for 60 minutes. N-benzylidene- (p-toluenesulfonyl) amine
(25.9 mg, 0.100 mmol) was added, and the mixture was stirred at room temperature for 48 hours. Then, 1-phenyl-1- (trimethylsilyloxy) ethylene (10 μL, 0.049 mmol) was added, and the mixture was stirred at room temperature for 96 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the insolubles derived from the catalyst were separated by filtration using Hyflo Super Cell. Water (5 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/3) to give the desired 3- N- (p-Toluenesulfonyl) amino-1,3-diphenyl-1-propanone (20.8 mg, 55%) was obtained as a white solid. The enantiomeric excess was measured by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OD, developing solvent: hexane / 2-propanol = 9/1) and found to be 30% ee. there were. The spectral data was consistent with the data obtained in Example 10.

Embodiment 38

[0162]

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Under an argon atmosphere, the binuclear complex obtained in Example 20 [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (8.8 m
g, 4.9 μmol) in 1 mL of anhydrous DMF solution.
(Trimethylsilyloxy) ethylene (41 μL, 0.20 mmo
l) was slowly added dropwise, and the mixture was stirred at room temperature for 65 minutes. To this solution was added N-benzylidene-4-methoxyaniline (21.1 mg,
0.10 mmol) and stirred at room temperature for 48 hours, and then 1-phenyl-1- (trimethylsilyloxy) ethylene (10 μL,
0.049 mmol) and stirred at room temperature for 22 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the insolubles derived from the catalyst were separated by filtration using Hyflo Super Cell. Water (5 mL) was added to the filtrate, and the mixture was extracted with diethyl ether.
The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After the desiccant was removed and the solvent was distilled off under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/3, developed twice). The desired 3-N- (4-methoxyphenyl) amino-1,3-diphenyl-1-propanone (1
8.0 mg, 54%) as a pale yellow-white solid. The enantiomeric excess was measured by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALPAK AD, developing solvent: hexane / 2-propanol = 98/2) and was found to be 16% ee. there were. IR (KBr): 3375, 2360, 2340, 1665, 1515, 1280, 815 c
^{. m -1 1 H-NMR (} CDCl 3, 200MHz): δ3.32-3.54 (m, 2H), 3.68
(s, 3H), 4.02 (br s, 1H), 4.87-4.96 (m, 1H), 6.52
(d, J = 8.9Hz, 2H), 6.68 (d, J = 8.9Hz, 2H), 7.22-7.60
(m, 8H), 7.91 (d, J = 7.0Hz, 2H). MS (CI): m / e = 331 (M ⁺ ).

Embodiment 39

[0165]

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Under an argon atmosphere, the binuclear complex [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (TfO ⁻ ) ₂ obtained in Example 23 (9.5 m ₂ )
g, 5.0 μmol) in anhydrous DMF (1 mL).
(Trimethylsilyloxy) ethylene (41 μL, 0.20 mmo
l) was slowly added dropwise, followed by stirring at room temperature for 60 minutes. To this reaction solution, a solution of 4-methoxyphenyliminoacetic acid isopropyl ester (21.6 mg, 0.098 mmol) prepared immediately before in anhydrous DMF (0.5 mL) was added dropwise over 5 minutes, and the mixture was further stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-Methoxyphenyl) benzoylalanine isopropyl ester (26.5 mg, 80%) was obtained as a pale yellow solid. This enantiomeric excess can be determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIR
ALCEL OG, developing solvent: hexane / 2-propanol = 9 /
It was 89% ee when measured using 1), and its spectral data were consistent with those obtained in Example 1.

Embodiment 40

[0168]

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Under an argon atmosphere, the binuclear complex obtained in Example 24 [{Pd ((R) -binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (5.0 mg, 3.
(0 μmol) in anhydrous DMF (1 mL) was slowly added dropwise with 1-phenyl-1- (trimethylsilyloxy) ethylene (31 μL, 0.15 mmol) and stirred at room temperature for 60 minutes. To this reaction solution was added 4-methoxyphenyliminoacetic acid isopropyl ester (22.8 mg, 0.103 mmol) prepared immediately before in anhydrous DMF.
The solution (0.5 mL) was added dropwise over 3 minutes, and the mixture was stirred at room temperature for 3 hours. To this reaction solution was added 1-phenyl-1- (trimethylsilyloxy) ethylene (10 μL, 0.049 mmol), and the mixture was further stirred at room temperature for 21 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Add water (5 mL) to the eluate,
Extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4),
The desired N- (4-methoxyphenyl) benzoylalanine isopropyl ester (30.7 mg, 87%) was obtained as a pale yellow solid. The enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CH
IRALCEL OG, developing solvent: hexane / 2-propanol = 9
/ 1) was 83% ee, and its spectral data were consistent with those obtained in Example 1.

Embodiment 41

[0171]

Embedded image

In an argon atmosphere, the dinuclear complex [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (4.7 m) obtained in Example 20 was obtained.
g, 2.6 μmol) in anhydrous dichloromethane (1 mL).
Phenyl-1- (trimethylsilyloxy) ethylene (31 μ
L, 0.15 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 45 minutes. To this reaction solution, 4-methoxyphenyliminoacetic acid isopropyl ester prepared immediately before (22.0 mg, 0.10
mmol) in anhydrous dichloromethane (0.5 mL) was slowly added dropwise over 4 hours using a syringe pump. After completion of the dropwise addition, the mixture was stirred at room temperature for 86 hours, 1-phenyl-1- (trimethylsilyloxy) ethylene (10 μL, 0.049 mmol) was added, and the mixture was further stirred at room temperature for 63 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Add water (5
mL) and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-Methoxyphenyl) benzoylalanine isopropyl ester (16.1 mg, 45%) was obtained as a pale yellow solid. The enantiomeric excess was measured by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG, developing solvent: hexane / 2-propanol = 9/1), and was 53% e.
e. The spectral data was consistent with the data obtained in Example 1.

Embodiment 42

[0174]

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Under an argon atmosphere, the binuclear complex obtained in Example 20 [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (5.0 m
g, 2.8 μmol) in anhydrous tetrahydrofuran (1 mL)
1-phenyl-1- (trimethylsilyloxy) ethylene (3
(1 μL, 0.15 mmol) was slowly added dropwise, followed by stirring at room temperature for 40 minutes. To this reaction solution, 4-methoxyphenyliminoacetic acid isopropyl ester (21.6 mg,
0.098 mmol) in anhydrous tetrahydrofuran (0.5 mL)
Was slowly dropped over 4 hours using a syringe pump. After completion of the dropwise addition, the mixture was stirred at room temperature for 48 hours.
-1- (trimethylsilyloxy) ethylene (10 μL, 0.049
mmol) and stirred at room temperature for a further 54 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After the desiccant was removed and the solvent was distilled off under reduced pressure, the resulting crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane =
1/4) to separate and purify the desired N- (4-methoxyphenyl) benzoylalanine isopropyl ester (20.0 mg, 60
%) As a pale yellow solid. The enantiomeric excess was measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG, developing solvent: hexane / 2-propanol = 9/1).
The spectrum data was 7% ee, and the spectrum data was consistent with the data obtained in Example 1.

Embodiment 43

[0177]

Embedded image

Under an argon atmosphere, the binuclear complex obtained in Example 20 [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (6.0 m
g, 3.4 μmol) in anhydrous DMI solution (1 mL).
(Trimethylsilyloxy) ethylene (31 μL, 0.15 mmo
l) was slowly added dropwise, followed by stirring at room temperature for 60 minutes. An anhydrous DMI solution (0.5 mL) of 4-methoxyphenyliminoacetic acid isopropyl ester (22.1 mg, 0.10 mmol) prepared immediately before was slowly added dropwise to this reaction solution over 4 hours using a syringe pump. After dropping, 1-phenyl-1-
(Trimethylsilyloxy) ethylene (10 μL, 0.049 mm
ol), and the mixture was further stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane = 1: 1).
/ 4) and purify the desired N- (4-methoxyphenyl) benzoylalanine isopropyl ester (25.7 mg, 75%)
Was obtained as a pale yellow solid. The enantiomeric excess was measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG, developing solvent: hexane / 2-propanol = 9/1).
% Ee, and its spectral data were consistent with those obtained in Example 1.

Embodiment 44

[0180]

Embedded image

Under an argon atmosphere, the binuclear complex obtained in Example 20 [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (5.0 m
g, 2.8 μmol) in anhydrous TMU solution (1 mL).
(Trimethylsilyloxy) ethylene (31 μL, 0.15 mmo
l) was slowly added dropwise, followed by stirring at room temperature for 40 minutes. To this reaction solution, an anhydrous TMU solution (0.5 mL) of 4-methoxyphenyliminoacetic acid isopropyl ester (21.9 mg, 0.099 mmol) prepared immediately before was added dropwise over 5 minutes. 7 at room temperature
After stirring for 1 hour, 1-phenyl-1- (trimethylsilyloxy) ethylene (10 μL, 0.049 mmol) was added, and the mixture was further stirred at room temperature for 14.5 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Add water (5 mL) to the eluate,
Extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4),
The desired N- (4-methoxyphenyl) benzoylalanine isopropyl ester (20.0 mg, 59%) was obtained as a pale yellow solid. The enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CH
IRALCEL OG, developing solvent: hexane / 2-propanol = 9
/ 1) was 82% ee, and its spectral data were consistent with those obtained in Example 1.

Embodiment 45

[0183]

Embedded image

In an argon atmosphere, the dinuclear complex obtained in Example 20 [{Pd ((R) -tol-binap) (μ-OH)} ₂ ] ²⁺ (BF ₄ ⁻ ) ₂ (5.1 m
g, 2.9 μmol) in anhydrous NMP (1 mL).
(Trimethylsilyloxy) ethylene (31 μL, 0.15 mmo
l) was slowly added dropwise, followed by stirring at room temperature for 40 minutes. To this reaction solution, an anhydrous NMP solution (0.5 mL) of 4-methoxyphenyliminoacetic acid isopropyl ester (22.1 mg, 0.10 mmol) prepared immediately before was added dropwise over 5 minutes. 2.5 at room temperature
After stirring for 1 hour, 1-phenyl-1- (trimethylsilyloxy) ethylene (10 μL, 0.049 mmol) was added, and the mixture was further stirred at room temperature for 12.5 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether, and the catalyst was removed through a silica gel short column. Water (5 mL) was added to the eluate, and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure,
The obtained crude product was separated and purified by silica gel thin-layer chromatography (developing solvent: ethyl acetate / hexane = 1/4) to give the desired N- (4-methoxyphenyl) benzoylalanine isopropyl ester (27.1 mg, 79% ) Was obtained as a pale yellow solid. The enantiomeric excess was determined by high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG, developing solvent: hexane / 2-propanol)
= 9/1) and was 83% ee.
The spectrum data was consistent with the data obtained in Example 1.

Embodiment 46

[0186]

Embedded image

Under an argon atmosphere, a solution of glyoxylic acid isopropyl ester (23 mg, 0.20 mmol) in anhydrous DMF (2
mL), p-anisidine (26 mg, 0.20 mmol) and molecular sieves 4A (100 mg) were added, and the mixture was stirred at room temperature for 3 hours. 1-phenyl-1- (trimethylsilyloxy) ethylene
(60 μL, 0.30 mmol) was added dropwise and ({Pd ((R) -tol-binap)
(μ-OH)} ₂ ] ²⁺ (CF ₃ SO ₃ ⁻ ) ₂ (19.0 mg, 10.0 μmol) was added, and the mixture was stirred at room temperature for 40 hours. After the completion of the reaction, the catalyst was removed through a silica gel short column. Water in the eluate
(5 mL) and extracted with diethyl ether. The organic layers were combined, washed sequentially with water and saturated saline, and then dried over anhydrous sodium sulfate. After removing the desiccant and evaporating the solvent under reduced pressure, the obtained crude product was subjected to silica gel thin layer chromatography (developing solvent: ethyl acetate / hexane = 1/1/3).
Separate and purify in 4) to obtain the desired N- (4-methoxyphenyl) benzoylalanine isopropyl ester (51.0 mg, 74%)
Was obtained as a pale yellow oil. The enantiomeric excess was measured using high performance liquid chromatography using an optical isomer separation column (column: Daicel CHIRALCEL OG, developing solvent: hexane / 2-propanol = 9/1).
% Ee and its spectral data were consistent with those obtained in Example 1.

[0188]

According to the production method of the present invention, optically active β-
Amino ketones can be produced efficiently. In addition, the novel μ- is a catalyst excellent in the reaction according to the present invention, and has a possibility of being used as a catalyst in various other asymmetric synthesis reactions.
The present invention can provide a hydroxy-type binuclear palladium-optically active bidentate phosphine complex and an efficient production method thereof.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07C 229/18 C07C 229/18 229/60 229/60 303/36 303/36 311/16 311/16 C07F 15/00 C07F 15/00 C // C07B 61/00 300 C07B 61/00 300 C07M 7:00

Claims (4)

[Claims] [Claim 1] The following general formula [I] (Wherein, R ¹ is a substituted silyl group, R ² is an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, Or an aryl group which may have a substituent, R ³ and R ⁴ each represent a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, An alkynyl group which may have, an alkoxy group which may have a substituent, or an aryl group which may have a substituent, or R ² and R ³ are carbon atoms to which they are bonded. Which may form a ring together with the atom) and a silyl enol ether represented by the following general formula [II]: (Wherein, R ⁵ represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, May be an aryl group, an optionally substituted alkoxy or aryloxycarbonyl group, an optionally substituted alkyl or arylthiocarbonyl group, an optionally substituted aminocarbonyl group, Or an acyl group which may have a substituent, R ⁶ is a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, Alkynyl group, aryl group which may have a substituent, alkoxy or aryloxycarbonyl group which may have a substituent, alkyl or arylthioca which may have a substituent Bonyl group, aminocarbonyl group which may have a substituent, or acyl group which may have a substituent, aryl or alkylsulfonyl group which may have a substituent, substituted silyl group, substituent Which is an alkoxy or aryloxy group which may have a thioalkoxy or thioaryloxy group which may have a substituent, or an amino group which may have a substituent) Is reacted in the presence of a catalyst comprising a palladium-optically active phosphine ligand, characterized by the following general formula [III]: (Wherein R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as described above). 2. A compound represented by the following general formula [IV]: Wherein A ₂ -PYPB ₂ is an optically active bidentate phosphine ligand and X is a halogen atom, and a silver salt is reacted in a water-containing solvent in the presence of a molecular sieve or a base. Characterized by the following general formula [V] (Wherein, A ₂ -PYPB ₂ is the same as above, and W ⁻ is a counter anion). 3. The following general formula [VI] Wherein A ₂ -PYPB ₂ and W ^- are the same as described above, wherein the complex is treated with a molecular sieve or a base, wherein the complex is represented by the following general formula [V]: (Wherein, A ₂ -PYPB ₂ and W ^- are the same as described above). 4. The following general formula [V] (Wherein, A ₂ -PYPB ₂ and W ^- are the same as described above).