KR102050066B1 - New 1,1-diboryl-1-metalic alkyl compounds, preparation method thereof and preparation method of 1,1,-diboronate ester compounds using the same - Google Patents

Abstract

The present invention relates to a 1,1-diboron-1-metal-substituted alkyl compound comprising one metal group together with two identical boron groups at the sp ³ carbon center, and specifically, the present invention relates to novel 1, Using 1-diboron-1-metal-substituted alkyl compounds to apply to the production of various molecular libraries that could not be synthesized by the existing methodology to provide useful technologies for the development of new organic reactions, the synthesis of functional molecules, and the synthesis of new drugs. It is for.

Description

New 1,1-diboron-1-metal substituted alkyl compound, preparation method thereof and preparation method of 1,1-diboronate ester compound using the same {New 1,1-diboryl-1-metalic alkyl compounds, preparation method and preparation method of 1,1, -diboronate ester compounds using the same}

The present invention relates to a novel 1,1-diboron-1-metal substituted alkyl compound, a method for preparing the same, and a method for preparing a 1,1-diboronate ester compound using the same.

Transition-metal catalyzed cross-coupling reactions are one of the most powerful and reliable reactions to form carbon-carbon bonds. In one example, lojatan ((2-butyl-4-chloro-1-{[2 '-(1 H -tetrazol-5-yl) biphenyl-4-yl] methyl} -1 H used to treat hypertension - atazanavir imidazole used for 5-yl) methanol) and HIV treatment Birr (methyl N - [(1 S) -1 - {[(2 S, 3 S) -3- hydroxy-4 - [( 2 S ) -2-[(methoxycarbonyl) amino] -3,3-dimethyl- N ' -{[4- (pyridin-2-yl) phenyl] methyl} butanehydrazido] -1-phenylbutane Pharmaceutically active ingredients of drugs such as 2-yl] carbamoyl} -2,2-dimethylpropyl] carbamate) are also synthesized via transition metal-catalytic cross-coupling reactions.

Recently, research has been actively conducted on new protocols for providing complex molecules by repetitive or sequential modification (synthesis) through transition metal-catalytic cross-coupling reactions. For example, Matsubara and Utimoto produce 1,1-dizincborylmethane in a five-step reaction, Negysi cross-coupling using palladium catalyst, and allylation using copper iodide. To suggest a method for preparing highly functionalized molecules (see Scheme below).

The Negishi reaction suggests that two ZnBr substituted on sp ³ carbon can act as a reactive site and finally form two CC bonds. However, a compound in which one ZnBr acts as a reactive site to form one CC bond is an intermediate that is instable and difficult to separate, and is prepared as a sequential product and used as a reactant or applied on a large scale.

In other words, repetitive or sequential modifications in trisubstituted organometallic compounds having organometallic materials containing at least 3 reactive sites on sp ³ carbon and including metals have been hardly studied.

[Preceding technical literature]

(Non-Patent Document 1) Shimada, Y .; Haraguchi, R .; Matsubara, S. Synlett 2015, 26, 2395-2398.

(Non-Patent Document 2) Yoshino, H .; Toda, N .; Kobata, M .; Ukai, K .; Oshima, K .; Utimoto, K .; Matsubara, S. Chem. Eur.J. 2006, 12, 721-726.

New trisubstituted organoboron compounds are provided that can provide new protocols for repetitive or sequential modification through transition metal-catalytic cross-coupling reactions, allyl substitution reactions, and the like.

In one embodiment, a compound represented by Chemical Formula 1 is provided.

[Formula 1]

In Chemical Formula 1,

R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other May form a ring;

R ₃ is hydrogen, C 1 -C 30 alkyl, C 1 -C 30 alkoxy, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, C 3 -C 30 cycloalkyl, C 3 -C 30 heterocycloalkyl, C 6 -C 30 aryl or C 2 -C 30 heteroaryl ego;

M is a zinc group metal;

X ₁ is halogen;

Alkyl, alkoxy and the ring formed by linking with each other of R ₄₁ and R ₄₂ and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ₃ are each independently halogen, hydroxy In cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl May be further substituted with at least one substituent selected;

The heterocycloalkyl and heteroaryl of R ₃ are each independently at least one hetero selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. Contains an atom

R ₁ and R ₂ are each independently hydroxyboronyl, pinacolboronylester, 2-pyrazole-5-nianyanilineboronyl, benzo [1,3,2] dioxaborole or 2,3 -Dihydro-1H-naphtho [1,8-de] [1,3,2] diazabolinin.

The compound may be, for example represented by the following formula (9).

[Formula 9]

In Chemical Formula 9,

R ₃ is hydrogen, C 1 -C 30 alkyl, C 2 -C 30 alkenyl, C 3 -C 30 cycloalkyl or C 3 -C 30 heterocycloalkyl;

M is a zinc group metal;

X ₁ is halogen;

Alkyl, alkenyl, cycloalkyl or heterocycloalkyl of R ₃ is halogen, hydroxy, cyano, C1-C30 alkyl, haloC1-C30 alkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6- May be further substituted with at least one substituent selected from C30 aryl and C2-C30 heteroaryl,

The heterocycloalkyl and heteroaryl of R ₃ are each independently at least one hetero selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. Contains an atom

R ₃ is hydrogen, C 1 -C 7 alkyl or C 2 -C 7 alkenyl,

The alkyl or alkenyl of R ₃ is at least one substituent selected from C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocycloalkyl, C 6 -C 12 aryl and C 6 -C 12 heteroaryl. It may be further substituted with.

M may be Zn.

X ₁ may be Br or Cl.

MX ₁ may be Zn-Br or Zn-Cl.

In another embodiment, a method of preparing a compound represented by Chemical Formula 1 is provided.

The preparation method may include a step of preparing a compound of Chemical Formula 7 by dehydrogenation of the compound of Chemical Formula 6 under a lithium base, and then reacting the compound of Chemical Formula 7 with a compound of Chemical Formula 8.

[Formula 1]

[Formula 6]

[Formula 7]

[Formula 8]

In Chemical Formulas 1 and 6 to 8,

R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other May form a ring;

R ₃ is hydrogen, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl or C2-C30 heteroaryl ego;

M is a zinc group metal;

X ₁ is halogen;

Alkyl, alkoxy and the ring formed by linking with each other of R ₄₁ and R ₄₂ and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ₃ are each independently halogen, hydroxy In cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl May be further substituted with at least one substituent selected;

The heterocycloalkyl and heteroaryl of R ₃ are each independently at least one heteroatom selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. It includes.

The lithium base may be selected from butyl lithium, lithium lithium dicyclohexylamide, lithium lithium tetramethylpiperidide, lithium lithium isopropyl cyclohexylamide and lithium lithium diisopropylamide.

In another embodiment, a halogenated aromatic compound or a vinyl halide compound; A compound of Formula 1; And reacting a coordinating ligand-containing transition metal compound in a solvent to prepare a compound of Chemical Formula 2, which provides a method for preparing a 1,1-diboronate ester compound.

[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2,

R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other To form a ring;

R ₃ is hydrogen, C 1 -C 30 alkyl, C 1 -C 30 alkoxy, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, C 3 -C 30 cycloalkyl, C 3 -C 30 heterocycloalkyl, C 6 -C 30 aryl or C 2 -C 30 heteroaryl ego;

M is a zinc group metal;

X ₁ is halogen;

A is absent or is an aromatic ring;

R ₁₁ is hydrogen, halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C2-C30 heteroaryl, -O-Si (R ₃₁ ) ₃ or —C (O) —R ₃₂ , wherein R ₃₁ and R ₃₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy;

n is an integer of 1 to 3 and when n is 2 or 3, R ₁₁ is the same as or different from each other;

The alkyl, alkoxy and ring formed by linking with each other of R ₄₁ and R ₄₂ and the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ₃ and the aromatic ring of A Alkyl, alkoxy, alkenyl, alkynyl, aryl and heteroaryl of R ₁₁ are each independently halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl May be further substituted with at least one substituent selected from C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl;

The heterocycloalkyl and heteroaryl of R ₃ and the heteroaryl of R ₁₁ are each independently B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. It contains at least one heteroatom selected from.

The reaction can be carried out in the range of 25 to 100 ℃.

The coordinating ligand-containing transition metal compound is [Rh (COD) Cl] ₂ , [Rh (COD) ₂ ] X (X = BF ₄ , ClO ₄ , SbF ₆ or CF ₃ SO ₃ ), [Ir (COD) Cl ] ₂ , [Ir (COD) ₂ ] X (X = OMe, BF ₄ , ClO ₄ , SbF ₆ Or CF ₃ SO ₃ ), Ru (COD) Cl ₂ , [Pd (CH ₃ CN) ₄ [BF ₄ ] ₂ , Pd ₂ (dba) ₃ and [Pd (C ₃ H ₅ ) Cl] ₂ ; And a phosphine-based compound may form a complex.

The phosphine-based compound may be triphenylphosphine, tri- ortho-tolyl phosphine, tri-methol-tolyl phosphine, tri-para-tolyl phosphine, tris (4-trifluoromethylphenyl) phosphine, diphenyl (para) -Tolyl) phosphine, cyclohexyldiphenyl phosphine, tris (2,6-dimethoxyphenyl) phosphine, tris (4-methoxyphenyl) phosphine, trimethylphosphine, tris-3,5-k Silylphosphine, tricyclohexyl phosphine, tribenzyl phosphine, benzyldiphenyl phosphine and diphenyl-normal-propyl phosphine.

In addition, the compound of Formula 5; A compound of Formula 1; And reacting a coordinating ligand-containing transition metal compound in a solvent to prepare a compound represented by the following Chemical Formula 4, which provides a method for preparing a 1,1-diboronate ester compound.

[Formula 1]

[Formula 4]

[Formula 5]

In Chemical Formulas 1, 4, and 5,

R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other To form a ring;

R ₃ is hydrogen, C 1 -C 30 alkyl, C 1 -C 30 alkoxy, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl, C 3 -C 30 cycloalkyl, C 3 -C 30 heterocycloalkyl, C 6 -C 30 aryl or C 2 -C 30 heteroaryl ego;

M is a zinc group metal;

X ₁ is halogen;

R ₂₁ is hydrogen, halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C2-C30 heteroaryl, -O-Si (R ₃₁ ) ₃ or —C (O) —R ₃₂ , wherein R ₃₁ and R ₃₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy;

Boc is tert-butoxycarbonyl;

Wherein R ₄₁ and R ₄₂ the alkyl, alkoxy and connected to each other formed alkyl ring and the R _3, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and the alkyl, alkoxy of said R ₂₁ , Alkenyl, alkynyl, aryl and heteroaryl are each independently halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl, C3-C30 cycloalkyl , May be further substituted with at least one substituent selected from C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl;

The heterocycloalkyl and heteroaryl of R ₃ and the heteroaryl of R ₂₁ are each independently B, N, O, S, Se, —P (═O) —, —C (═O) —, Si, and P It contains at least one heteroatom selected from.

The reaction can be carried out in the range of 10 to 35 ℃.

The coordinating ligand-containing transition metal compound is [Rh (COD) Cl] ₂ , [Rh (COD) ₂ ] X (X = BF ₄ , ClO ₄ , SbF ₆ or CF ₃ SO ₃ ), [Ir (COD) Cl ] ₂ , [Ir (COD) ₂ ] X (X = OMe, BF ₄ , ClO ₄ , SbF ₆ Or CF ₃ SO ₃ ), Ru (COD) Cl ₂ , [Pd (CH ₃ CN) ₄ [BF ₄ ] ₂ , Pd ₂ (dba) ₃ and [Pd (C ₃ H ₅ ) Cl] ₂ ; And an aminophosphon-based compound may form a complex.

The aminophosphon-based compound may be L1.

R ₁ and R ₂ are each independently hydroxyboronyl, pinacolboronylester, 2-pyrazole-5-nianyanilineboronyl, benzo [1,3,2] dioxaborole or 2,3 -Dihydro-1H-naphtho [1,8-de] [1,3,2] diazabolinin.

The solvent may be selected from aprotic solvents.

According to the present invention, under very mild process conditions, various organic reactions, such as transition metal-catalytic cross-coupling reactions and allyl substitution reactions, can be carried out. The organic reaction is very economical because it does not require difficult process conditions such as strong acid or strong base conditions, low temperature reaction conditions and anhydrous conditions.

Also according to the invention sp ³ As the reaction is carried out in the presence of a transition metal catalyst from an organic boron compound containing one metal group with two identical boron groups at the carbon center, regardless of the type of substituents of the organoboron compound, stereoselectivity, high yield, and high optical purity It is possible to provide a 1,1-diboronate ester compound having.

In addition, according to the present invention, using a trisubstituted organic boron compound to provide a new protocol for repetitive or sequential modification through transition metal-catalytic cross-coupling reaction, allyl substitution reaction, etc., and at the same time provide a protocol with excellent commercial practicality. Can be.

Therefore, according to the present invention, based on the trisubstituted organic boron compound and the 1,1-diboronate ester compound prepared therefrom, it is possible to provide a number of derivatives that could not be synthesized by the conventional methodology, as well as various applications thereof. It is expected to expand in the direction.

Hereinafter, the present invention will be described in more detail. Unless otherwise defined in the technical terms and scientific terms used at this time, have a meaning commonly understood by those of ordinary skill in the art to which the present invention belongs, unnecessarily obscure the subject matter of the present invention in the following description Description of known functions and configurations that may be omitted.

As used herein, the term "trisubstituted organic boron compound" means a compound represented by the following Formula 1, and has the same meaning as a trisubstituted organic reactant or a 1,1-diboron-1-metal substituted alkyl compound.

As used herein, substituents including alkyl other than "alkyl" and "alkoxy" refer to organic radicals derived from straight chain or pulverized hydrocarbons. In addition, the alkyl and the substituent including the alkyl according to the present invention is preferably a short chain having 1 to 7 carbon atoms, preferably may be selected from methyl, ethyl, propyl and butyl, but is not limited thereto. In addition, said alkoxy means * -O-alkyl.

As used herein, "alkenyl" refers to an organic radical derived from a straight chain or pulverized hydrocarbon containing one or more double bonds, and "alkynyl" refers to a straight chain or pulverized hydrocarbon containing one or more triple bonds. It means an organic radical derived from.

In addition, the term "cycloalkyl" as used herein means a free radical derived from a fully saturated or partially unsaturated hydrocarbon ring of 3 to 9 carbon atoms, including when aryl or heteroaryl is fused, " Heterocycloalkyl "means 3 to 9 ring atoms including one or more heteroatoms selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P, etc. It means a free radical derived from a monocyclic or polycyclic non-aromatic ring containing.

The term "aryl" as used herein also means an organic radical derived from an aromatic hydrocarbon by one hydrogen removal, each ring containing 4 to 7, preferably 5 or 6 ring atoms, as appropriate. It includes a single or fused ring system, and includes a form in which a plurality of aryls are connected by a single bond. Examples include phenyl, naphthyl, biphenyl, terphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, peryleneyl, chrysenyl, naphthacenyl, fluoranthenyl, and the like. It is not limited to this.

In addition, the term "heteroaryl" as used herein means an organic radical derived from an aromatic hydrocarbon by one hydrogen removal, and B, N, O, S, Se, -P (= O)-, -C (= Organic radicals derived from monocyclic or polycyclic aromatic hydrocarbons containing 4 to 7 ring atoms including one or more heteroatoms selected from O)-, Si and P, and the like, suitably 4 to It includes single or fused ring systems containing seven, preferably five or six ring atoms, up to the form in which a plurality of heteroaryls are linked by a single bond. For example, furyl, thiophenyl, pyrrolyl, pyranyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxdiazolyl, triazinyl, tetrazinyl, tria Monocyclic heteroaryl such as zolyl, tetrazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl; And benzofuranyl, benzothiophenyl, isobenzofuranyl, benzoimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzooxazolyl, isoindoleyl, indolyl, indazolyl, benzothiadia Polycyclic heteroaryls such as zolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinolizinyl, quinoxalinyl, carbazolyl, phenanthridinyl, and benzodioxolyl; And the like, but are not limited thereto.

The term "halogen" herein also means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms.

In addition, the term "ring" in the present specification means an alicyclic or aromatic ring formed by linking with C1-C10 alkylene or C2-C10 alkenylene. In addition, one or two or more of the carbons of the alkylene or alkenylene to form a ring is selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P and the like. It may be replaced with a selected heteroatom to form an alicyclic or aromatic ring comprising a heteroatom.

The term "aromatic ring" in this specification also means aryl or heteroaryl formed by linking with C2-C10 alkenylene.

The present inventors have used a tri-substituted organic reactant comprising a boron group and a monosubstituted metal group substituted on sp ³ carbon, that is, a transition metal-catalytic cross-coupling reaction and an allyl substitution reaction using a trisubstituted organic boron compound. In order to provide a new protocol for iterative or sequential modifications, the researchers have repeatedly studied. As a result, a novel compound, ie, trisubstituted organic reactants, containing one metal group with two identical boron groups at the sp ³ carbon center was devised. In addition, the present inventors have found that a new protocol for repetitive or sequential modification, that is, a novel reaction mechanism, may be provided through transition metal-catalytic cross-coupling reactions, allyl substitution reactions, and the like, thereby completing the present invention.

It should also be noted that the protocol of the present invention newly discovers compatibility with catalysts, starting materials (eg, compounds of formula 1), intermediates, solvents, reaction conditions, and the like. In addition, in the present specification, the organoboron compound specifically refers to a compound including one metal group together with two identical boron groups at the sp ³ carbon center, hereinafter 1,1-diboron-1-metal substituted alkyl compound Or a compound of formula (1).

The protocol according to the present invention can realize stereoselectivity, high yield, high optical purity regardless of the type of substituents of the organoboron compound. The protocol according to the invention may also provide a useful approach for asymmetric transformation with a transition metal catalyst. That is, the present invention seeks to provide a novel trisubstituted organic reactant comprising one metal group with two identical boron groups at the sp ³ carbon center and to extend its application.

The 1,1-diboron-1-metal substituted alkyl compound according to one embodiment may be represented by Formula 1 below.

[Formula 1]

In Chemical Formula 1,

R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other To form a ring;

R ₃ is hydrogen, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl or C2-C30 heteroaryl ego;

M is a zinc group metal;

X ₁ is halogen;

Alkyl, alkoxy and the ring formed by linking with each other of R ₄₁ and R ₄₂ and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ₃ are each independently halogen, hydroxy In cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl May be further substituted with at least one substituent selected;

The heterocycloalkyl and heteroaryl of R ₃ are each independently at least one hetero selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. Contains an atom

M of Chemical Formula 1 may be a zinc group metal as described above, and may be, for example, zinc (Zn).

When M in the general formula (1) is a zinc group metal, it exhibits a unique reactivity in the transition metal-catalytic cross-coupling reaction, allyl substitution reaction to be described later, so that the organic reaction using the formula (1) is 1,1-diboro Since it can be applied to repetitive or sequential modification through the nate ester compound, it is possible to prepare complex compounds that could not be synthesized from existing metal substituted compounds.

Details related to this will be described later.

In one embodiment, the 1,1-diboron-1-metal substituted alkyl compound may be represented by the following Formula 9.

[Formula 9]

In Formula 9, M, X ₁ are as described above,

R ₃ may be hydrogen, C 1 -C 30 alkyl, C 2 -C 30 alkenyl, C 3 -C 30 cycloalkyl or C 3 -C 30 heterocycloalkyl.

Pinacol Voronyl Ester (Bpin) is a very stable site for reactions, so it is stable to moisture and easy to handle, so it can be expanded to large scales and used for various carbon-carbon, carbon-oxygen, and carbon-nitrogen reactions utilizing organometallic catalysts. The range of application is wide because it is available.

In particular, in the case of containing two pinacol voronyl esters, unlike the case where both functional sites are metal halides (such as ZnBr), one pinacol boroyl ester acts as a reactive site, resulting in one CC bond. The formed compound can be separated in a stable state, so that the compound can be prepared as a sequential product to be used as a reactant of a further reaction, and it is easy to apply the compound to expand on a large scale.

More specifically R ₃ is hydrogen, C 1 -C 7 alkyl or C 2 -C 7 alkenyl,

The alkyl or alkenyl of R ₃ is at least one substituent selected from C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocycloalkyl, C 6 -C 12 aryl and C 6 -C 12 heteroaryl. It may be further substituted with.

R ₁ and R ₂ are each independently hydroxyboronyl, pinacolboronylester, 2-pyrazole-5-nianyanilineboronyl, benzo [1,3,2] dioxaborole or 2,3 -Dihydro-1H-naphtho [1,8-de] [1,3,2] diazabolinin.

X ₁ may be Br or Cl,

MX ₁ may be Zn-Br or Zn-Cl.

According to another embodiment, the 1,1-diboron-1-metal substituted alkyl compound may be prepared by dehydrogenation of a compound of Formula 6 under a lithium base to prepare a compound of Formula 7, and then, It may be prepared by a manufacturing method comprising the step of reacting with a compound of formula (8).

[Formula 1]

[Formula 6]

[Formula 7]

[Formula 8]

In Chemical Formulas 1 and 6 to 8, the definitions of R ₁ to R ₃ , M, and X ₁ are as described above.

In the method for preparing a compound of Formula 1 according to an embodiment of the present invention, the compound of Formula 6 may be reacted with the compound of Formula 8 after activating the compound of Formula 6 with a lithium base.

For example, the form in which the compound of Formula 6 is activated with a lithium base may be a compound of Formula 7, and in the present invention, the compound of Formula 7 is an isolable and independent reactant and the compound of Formula 8 Can react.

The inventors have found that in the preparation of the compound of formula 1, the involvement of the compound of formula 7 as an independent reactant can have a significant effect on the reaction selectivity.

For example, in an allyl substitution reaction using Chemical Formula 1, when the compound of Chemical Formula 7 participates in the reaction as an independent reactant (Case I) and in-situ, the selectivity of the (Case II) product It was confirmed that there is a significant difference.

(Case I)

(Case II)

That is, in Case I, only the asymmetric allylic alkylation reaction occurs through the intermediate of Formula 1 while the compound of Formula 7 participates in the reaction as an independent reactant, whereas in Case II, the compound of Formula 7 is in-situ Participation in the furnace was confirmed that the allyl amination reaction was competitive, resulting in allylic amination.

From this, it can be seen that in order to selectively proceed with the allylic alkylation reaction via Formula 1, it is important to include the compound of Formula 7 as an independent reactant in the reaction.

For example, the lithium base is not limited as long as it is a conventional material, and specific examples thereof include those selected from butyl lithium, lithium lithium dicyclohexylamide, lithium lithium methyl piperidide, lithium lithium isopropyl cyclohexylamide, lithium lithium diisopropylamide, and the like. Can be. At this time, the lithium base may be used in a single or a mixture of two or more.

Use of the compound of Formula 1 according to another embodiment is a method of preparing a 1,1-diboronate ester compound represented by the following formula (2).

Method for producing a 1,1-diboronate ester compound according to an embodiment of the present invention is a halogenated aromatic compound or a vinyl halide compound; A compound of Formula 1; And a coordinating ligand-containing transition metal compound; reacting in a solvent to prepare a compound of Formula 2;

[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2,

R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other May form a ring;

R ₃ is hydrogen, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl or C2-C30 heteroaryl ego;

M is a zinc group metal;

X ₁ is halogen;

A is absent or is an aromatic ring;

R ₁₁ is hydrogen, halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C2-C30 heteroaryl, -O-Si (R ₃₁ ) ₃ or —C (O) —R ₃₂ , wherein R ₃₁ and R ₃₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy;

n is an integer of 1 to 3, and when n is 2 or 3, R ₁₁ may be the same or different from each other;

The alkyl, alkoxy and ring formed by linking with each other of R ₄₁ and R ₄₂ and the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ₃ and the aromatic ring of A Alkyl, alkoxy, alkenyl, alkynyl, aryl and heteroaryl of R ₁₁ are each independently halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl May be further substituted with at least one substituent selected from C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl;

The heterocycloalkyl and heteroaryl of R ₃ and the heteroaryl of R ₁₁ are each independently B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. At least one heteroatom selected from:

For example, when A is not present in Formula 2, it may be a compound of Formula 2-1.

[Formula 2-1]

In Formula 2-1, the definition of the substituent is according to the formula (2).

For example, M in Formula 1 may be Zn.

The method for preparing the 1,1-diboronate ester compound according to an embodiment of the present invention is influenced by the starting material (eg, the compound of Formula 1), the catalyst, the solvent, the reaction temperature conditions, and the like.

Hereinafter, the reaction conditions and the like affecting the method according to the present invention will be described in detail.

In the compound of Formula 1, specifically R ₁ and R ₂ are each independently * -B (R ₄₁ ) (R ₄₂ ), and R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy or C 1 -C 30 alkoxy. Or may be linked to each other to form a ring. In this case, the ring may be substituted or unsubstituted.

Specifically, in the compound of Formula 1, R ₁ and R ₂ are each independently hydroxyboronyl, pinacolboronylester, 2-pyrazole-5-nianyanilineboronyl, benzo [1,3,2 ] Dioxaborole or 2,3-dihydro-1H-naphtho [1,8-de] [1,3,2] diazabolinin.

The compound of Formula 1 may specifically be a compound represented by the following Formula 9.

[Formula 9]

In Chemical Formula 9,

R ₃ is hydrogen, C 1 -C 30 alkyl, C 2 -C 30 alkenyl, C 3 -C 30 cycloalkyl or C 3 -C 30 heterocycloalkyl;

M is a zinc group metal;

X ₁ is halogen;

Alkyl, alkenyl, cycloalkyl or heterocycloalkyl of R ₃ is halogen, hydroxy, cyano, C1-C30 alkyl, haloC1-C30 alkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6- It may be further substituted with at least one substituent selected from C30 aryl and C2-C30 heteroaryl, wherein the heterocycloalkyl and heteroaryl of R ₃ are each independently B, N, O, S, Se, -P (= O)-, -C (= 0)-, at least one heteroatom selected from Si and P.

Compounds of formula 9 are specifically R ₃ is hydrogen, C 1 -C 7 alkyl or C 2 -C 7 alkenyl, and alkyl or alkenyl of R ₃ is C 1 -C 7 alkyl, haloC 1 -C 7 alkyl, C 3 -C 12 cyclo It may be further substituted with at least one substituent selected from alkyl, C3-C12 heterocycloalkyl, C6-C12 aryl and C6-C12 heteroaryl.

Compounds of formula 9 are specifically R ₃ is hydrogen, C 1 -C 3 alkyl or C ₂ -C ₃ alkenyl, and alkyl or alkenyl of R ₃ is C 1 -C 7 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 hetero It may be further substituted with at least one substituent selected from cycloalkyl, C6-C10 aryl and C6-C10 heteroaryl.

M in the compound of Formula 1 or Formula 9 may be zinc.

In the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the compound of Formula 1 may be used in 1.0 to 5.0 moles based on 1 mole of the halogenated aromatic compound or vinyl halide compound Specifically, it may be used in 1.0 to 3.0 moles, more specifically 1.0 to 2.0 moles.

The halogenated aromatic compound may be represented by Chemical Formula 3-1, and the vinyl halide compound may be a compound represented by Chemical Formula 3-2.

[Formula 3-1]

[Formula 3-2]

In Chemical Formulas 3-1 and 3-2,

X ₂ is halogen;

Each R ₁₁ is independently hydrogen, halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C2-C30 heteroaryl,- O—Si (R ₃₁ ) ₃ or —C (O) —R ₃₂ may be linked to each other to form a ring, and R ₁₁ may be the same as or different from each other, and in Formula 3-2, R ₁₁ Except when all are hydrogen;

Alkyl, alkoxy, alkenyl, alkynyl, aryl and heteroaryl of R ₁₁ are each independently halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 amino May be further substituted with at least one substituent selected from alkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl, and C2-C30 heteroaryl;

The heteroaryl of R ₁₁ may each independently include at least one heteroatom selected from B, N, O, S, Se, —P (═O) —, —C (═O) —, Si, and P.

The trisubstituted organoboron compounds according to the invention and the 1,1-diboronate ester compounds prepared through the process according to the invention can be applied to repeated and sequential modifications to form potentially more complex molecules. That is, the compounds of the present invention can be applied to the preparation of various molecular libraries that could not be synthesized by the existing methodology.

For example, benzylic 1,1-diboronate ester or allylic 1,1-diboro through a coupling reaction of Chemical Formula 3-1 or Chemical Formula 3-2 with Chemical Formula 1 in the presence of a palladium catalyst and a ligand phosphine ligand Nate ester compounds can be prepared in high yields. The method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention uses a coordinating ligand-containing transition metal compound as a catalyst.

The coordinating ligand-containing transition metal compound is specifically [Rh (COD) Cl] ₂ , [Rh (COD) ₂ ] X (X = BF ₄ , ClO ₄ , SbF ₆ or CF ₃ SO ₃ ), [Ir (COD) Cl] ₂ , [Ir (COD) ₂ ] X (X = OMe, BF ₄ , ClO ₄ , SbF ₆ Or CF ₃ SO ₃ ), Ru (COD) Cl ₂ , [Pd (CH ₃ CN) ₄ [BF ₄ ] ₂ , Pd ₂ (dba) ₃ and [Pd (C ₃ H ₅ ) Cl] ₂ ; It may be a complex formed with a metal-containing compound and a phosphine compound.

For example, the coordination ligand-containing transition metal compound may be a palladium-containing compound selected from [Pd (CH ₃ CN) ₄ [BF ₄ ] ₂ , Pd ₂ (dba) ₃ , [Pd (C ₃ H ₅ ) Cl] _2, and the like. And a complex of phosphine compounds.

For example, the phosphine-based compound may be triphenylphosphine, tri-ortho-tolyl phosphine, tri-methol-tolyl phosphine, tri-para-tolyl phosphine, tris (4-trifluoromethylphenyl) phosphine, di Phenyl (para-tolyl) phosphine, cyclohexyldiphenyl phosphine, tris (2,6-dimethoxyphenyl) phosphine, tris (4-methoxyphenyl) phosphine, trimethylphosphine, tris-3, 5-xylylphosphine, tricyclohexyl phosphine, tribenzyl phosphine, benzyldiphenyl phosphine, diphenyl-normal-propyl phosphine, and the like.

As described above, the coordinating ligand-containing transition metal compound according to the present invention is characterized in that it comprises a substance having a coordinating ligand compound. For example, when a substance having two or more ligands other than a substance having a ligand is used as the ligand compound, no transition metal-catalytic cross-coupling reaction is performed. This result is expected to be due to the influence of the oxidative addition reaction due to the narrow binding angle when the ligand is bonded to the transition metal catalyst.

In the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the coordination ligand-containing transition metal compound is a complex in which a transition metal-containing compound and a phosphine-based compound are mixed in a 1: 5 molar ratio. It may be added, specifically, 1: 3 molar ratio, more specifically 1: 1: may be added to the mixed mixture in the molar ratio.

In addition, in the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the coordination ligand-containing transition metal compound is 0.5 to 10 based on 1 mole of the halogenated aromatic compound or vinyl halide compound It may be used in mol%, specifically, it may be used in 0.5 to 8.0 mol%, more specifically 0.5 to 2.0 mol%.

The method for preparing the 1,1-diboronate ester compound according to an embodiment of the present invention is greatly affected by the reactivity according to the type of reaction solvent and the reaction temperature conditions.

In the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the solvent may be an aprotic solvent, but in particular in the tetrahydrofuran can achieve a higher yield in the present invention It takes precedence.

In addition, in the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the amount of the solvent is not limited. Specifically, based on 1 part by weight of the halogenated aromatic compound or vinyl halide compound, It may be used in 10 to 1000 parts by weight, more specifically may be used in 10 to 100 parts by weight.

In addition, in the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the step is characterized in that the reaction is carried out at about warm conditions. That is, the step is carried out at a temperature condition of 25 to 100 ℃. If it is outside the above-mentioned temperature conditions, the reaction is not performed or an excessive amount of by-products are generated during the reaction, which is not preferable.

For example, the step may be performed for 1 to 10 hours at a temperature condition of 45 to 80 ℃.

For example, the step may be performed for 1 to 5 hours at a temperature condition of 50 to 80 ℃.

Use of the compound of Formula 1 according to another embodiment is a method of preparing a 1,1-diboronate ester compound represented by the following formula (4).

Method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention is a compound of formula (5); A compound of Formula 1; And a coordinating ligand-containing transition metal compound; reacting the solvent under a solvent to prepare a compound of Formula 4 below.

[Formula 1]

[Formula 4]

[Formula 5]

In Chemical Formulas 1, 4, and 5,

R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other May form a ring;

R ₃ is hydrogen, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl or C2-C30 heteroaryl ego;

M is a zinc group metal;

X ₁ is halogen;

R ₂₁ is hydrogen, halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C2-C30 heteroaryl, -O-Si (R ₃₁ ) ₃ or —C (O) —R ₃₂ , wherein R ₃₁ and R ₃₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy;

Boc is tert-butoxycarbonyl;

Wherein R ₄₁ and R ₄₂ the alkyl, alkoxy and connected to each other formed alkyl ring and the R _3, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and the alkyl, alkoxy of said R ₂₁ , Alkenyl, alkynyl, aryl and heteroaryl are each independently halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl, C3-C30 cycloalkyl , May be further substituted with at least one substituent selected from C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl;

The heterocycloalkyl and heteroaryl of R ₃ and the heteroaryl of R ₂₁ are each independently B, N, O, S, Se, —P (═O) —, —C (═O) —, Si, and P It contains at least one heteroatom selected from.

According to the above-described method, an allyl substitution reaction having high enantiomer selectivity can be performed. Also, in the allyl substitution reaction, the provision of enantiomer selectivity using a trisubstituted organoboron compound corresponds to a protocol which is not known in the art.

That is, according to the present invention, the compound of Formula 4, which is an enantiomeric excess (ee), can be obtained in high yield. Specifically, Chemical Formula 4 may be one having stereo selectivity represented by the following Chemical Formula 4-1.

[Formula 4-1]

In Chemical Formula 4-1, the definition of the substituent is in accordance with Chemical Formula 4.

In addition, in the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the compound of Formula 1 can be used as a purified compound, as well as a method of preparing a compound of Formula 1 The same reactivity can be achieved even when used without further purification. Thus, when used without further purification in the method for preparing the compound of Formula 1 is good in terms of improving the yield of the final product.

For example, the compound of Chemical Formula 4 may be prepared by reacting a compound of Chemical Formula 7 and a mixture of Chemical Formula 8 instead of the compound of Chemical Formula 1, and then adding a compound of Chemical Formula 5 and a coordinating ligand-containing transition metal compound. have.

[Formula 7]

[Formula 8]

In Chemical Formulas 7 and 8,

R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other May form a ring;

R ₃ is hydrogen, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl or C2-C30 heteroaryl ego;

M is a zinc group metal;

X ₁ is halogen;

Alkyl, alkoxy and the ring formed by linking with each other of R ₄₁ and R ₄₂ and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ₃ are each independently halogen, hydroxy In cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl May be further substituted with at least one substituent selected;

The heterocycloalkyl and heteroaryl of R ₃ are each independently at least one hetero selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. Contains an atom

For example, when the compound of Formula 4 is prepared, the compound of Formula 8 may be in the form of metal chloride or metal bromide.

In addition, in the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the protecting group of Formula 5 also affects the reactivity.

In addition, the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention is influenced by starting materials (eg, the compound of Formula 1), a catalyst, a solvent, reaction temperature conditions, and the like.

Hereinafter, the reaction conditions and the like affecting the method according to the present invention will be described in detail.

The 1,1-diboronate ester compounds prepared through the process according to the invention can be applied to repetitive and sequential modifications to form potentially more complex molecules as well as by enantioselective allyl substitution reactions. It is possible to provide the compound of Formula 4-1, which is an excess of ethylene, in high yield.

The method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention uses a coordinating ligand-containing transition metal compound as a catalyst. In this case, the catalyst is characterized in that it comprises a ligand different from the production method of the 1,1-diboronate ester compound represented by the formula (2).

The coordinating ligand-containing transition metal compound is specifically [Rh (COD) Cl] ₂ , [Rh (COD) ₂ ] X (X = BF ₄ , ClO ₄ , SbF ₆ or CF ₃ SO ₃ ), [Ir (COD) Cl] ₂ , [Ir (COD) ₂ ] X (X = OMe, BF ₄ , ClO ₄ , SbF ₆ Or CF ₃ SO ₃ ), Ru (COD) Cl ₂ , [Pd (CH _3C N) ₄ [BF ₄ ] ₂ , Pd ₂ (dba) ₃ and [Pd (C ₃ H ₅ ) Cl] ₂ ; The metal-containing compound and a ligand compound such as L1 may form a complex.

For example, the coordinating ligand-containing transition metal compound is [Ir (COD) Cl] ₂ , [Ir (COD) ₂ ] X (X = OMe, BF ₄ , ClO ₄ , SbF ₆ Or a complex of an iridium-containing compound selected from CF ₃ SO ₃ ) and the like and an aminophosphon-based compound. For example, the aminophosphon-based compound may be a cyryl ligand.

In particular, when using a coordinating ligand-containing transition metal compound containing L1, it is possible to implement an improved reaction yield and ee value.

In the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the coordination ligand-containing transition metal compound is a mixture of a transition metal-containing compound and a ligand compound such as L1 in a 1:10 molar ratio It may be added to the complex, specifically, 1: 8 molar ratio, more specifically 1: 1: may be introduced into the mixed mixture in the molar ratio.

In addition, in the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the coordination ligand-containing transition metal compound is 1 to 10 mol% based on 1 mol of the compound of Formula 5 It may be used, specifically, it may be used in 1.0 to 8.0 mol%, more specifically 3.0 to 8.0 mol%.

The method for preparing the 1,1-diboronate ester compound according to an embodiment of the present invention is affected by the reactivity according to the type of reaction solvent and the reaction temperature conditions.

In the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the solvent may be an aprotic solvent, but in a higher yield than toluene, dimethyl ether, tetrahydrofuran, etc. , Stereoselectivity and high optical purity can be achieved. In addition, when using the above-mentioned solvent alone, it shows better reactivity than when using two or more mixed solvents.

In addition, in the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the amount of the solvent is not limited. Specifically, based on 1 part by weight of the compound of Formula 5, 10 to 1000 It may be used in parts by weight, more specifically 10 to 100 parts by weight.

In addition, in the method for preparing a 1,1-diboronate ester compound according to an embodiment of the present invention, the step is characterized in that the reaction is carried out at low temperature conditions. Specifically, the step is carried out at a temperature condition of 10 to 35 ℃. If it is outside the above-mentioned temperature conditions, the reaction is not performed or an excessive amount of by-products are generated during the reaction, which is not preferable.

For example, the step may be performed for 5 to 20 hours at a temperature condition of 10 to 30 ℃.

For example, the step may be performed for 8 to 16 hours at a temperature condition of 20 to 30 ℃.

Hereinafter, the present invention will be described in more detail with reference to Examples.

Prior to this, terms or words used in the specification and claims should not be construed as having a conventional or dictionary meaning, and the inventors should properly explain the concept of terms in order to best explain their own invention. Based on the principle that can be defined, it should be interpreted as meaning and concept corresponding to the technical idea of the present invention. Therefore, the embodiments described in the specification and the configuration shown in the drawings are only one of the most preferred embodiments of the present invention and do not represent all of the technical idea of the present invention, these can be replaced at the time of the present application It should be understood that there are various equivalents and variations.

The synthesis of all compounds was carried out using standard Schlenk or glove box under nitrogen atmosphere, except where noted, and the organic solvent used in the reaction was refluxed under sodium metal and benzophenone to remove moisture. Distilled and degassed was used. In addition, the glass apparatus used was heated in an oven at 130 ° C. for one day before being put into a glove box, and used in anhydrous state. ¹ H-NMR analysis of the synthesized compounds was performed using Brucker 500 MHz at room temperature. In addition, the optical selectivity (ee) of the synthesized compound was analyzed using gas chromatography.

(Example 1)

Step 1.

1,1-diboronate ester (CH ₂ (Bpin) ₂ , 20 mmol, 5.4 g) and a stirring magnet were placed in a 100 mL round bottom flask. While slowly stirring, the 100 mL round bottom flask was slowly charged with a lithium diisopropyl amide solution (1 mol concentration, tetrahydrofuran / hexane solvent, 1.1 equivalents, 22 mL) cooled to minus 25 ° C. During the injection, a white solid rapidly formed inside the solution, and then rapidly stirred for 20 minutes at room temperature. The resulting solid was separated by filtration under reduced pressure with a glass filter. In the purification process, 50 mL of hexane was poured into the filtered white solid, washed with filtration under reduced pressure, and then transferred to a 100 mL flask. 50 mL of tetrahydrofuran solvent was added to the flask, followed by stirring for 10 minutes. The solid was allowed to settle for 10 minutes, and only the upper liquid portion was removed by a pipette. The procedure of washing with tetrahydrofuran was repeated three times and finally washed once with 50 mL of hexane. In order to remove the organic solvent remaining in the solid, it was placed at room temperature and ultra low pressure for 12 hours. The product was purified 1,1-diborylmethyl lithium in the form of a very fine white solid at room temperature (yield: 5.0 g, 92%). At this time, the 1,1-diborylmethyl lithium was used directly in the next step without further purification.

Step 2.

1,1-diborylmethyl lithium (1.0 equiv, 0.24 mmol, 54 mg) and zinc bromide (1.0 equiv, 0.24 mmol, 66 mg) prepared in step 1 were placed in a 4-drum vial, and 0.24 ml of tetra Hydrofuran was added and stirred for 30 minutes to prepare a 1,1-diborylmethyl zinc bromide solution.

¹ H-NMR (500 MHz, d ₈ -THF) [ppm] δ = 1.22 (s, 6H), 1.21 (s, 6H), 0.47 (s, 1H).

(Example 2)

In a 4-drum vial, containing anhydrous zinc bromide (1.2 equiv., 0.24 mmol, 54 mg) together with purified 1,1-diborylmethyl lithium (1.2 equiv., 0.24 mmol, 66 mg), add tetrahydrofuran (0.24 mL , 1M) was put in the stirring magnet and stirred for 30 minutes to prepare a 1,1-diborylmethyl zinc bromide solution. Next, another 4-dram vial contains tris (dibenzylideneacetone) dipalladium (0) (1.0 mole%, 1.8 mg) and ligand (triphenylphosphine) (2.0 mole%, 1.2 mg). Bromoanisole (0.2 mmol, 37 mg) and tetrahydrofuran (0.5 mL) were added. After holding the stirring magnet, the pre-formed 1,1-diborylmethyl zinc bromide solution was slowly transferred to the vial containing the substrate using a syringe. The lid was closed and taken out of the glove box and reacted at 60 ° C. for 3 hours. After the reaction was completed, the reaction solution was filtered through celite, washed with ethyl acetate (50 mL) to remove the catalyst primarily. The solvent was then removed using a vacuum rotary concentrator, and the product was purified by column chromatography.

¹ H-NMR (500 MHz, CDCl ₃ ) [ppm] δ = 7.18-7.17 (d, J = 8.7 Hz, 2H), 6.78-6.76 (d, J = 8.7 Hz, 2H), 3.76 (s, 3H) , 2.23 (s, 1 H), 1.22-1.21 (d, J = 6.6 Hz, 24 H).

(Example 3-10)

In the preparation method of Example 2, except that the type or solvent of the ligand (phosphine-based compound) was changed, Compound 3a was prepared in a similar manner. Specific reaction conditions are shown in Table 1 below.

(Example 11-12)

In the preparation method of Example 2, except that the amount of the catalyst and ligand (phosphine-based compound) was changed, Compound 3a was prepared in a similar manner. Specific reaction conditions are shown in Table 1 below.

(Comparative Example 1)

In the preparation method of Example 2, the kind of ligand (phosphine-based compound) was changed, and compound 3a was prepared in a similar manner. Specific reaction conditions are shown in Table 1 below.

Ligand menstruum yield(%) Example 2 PPh ₃ THF 53 Example 3 P ( p -CF ₃ C ₆ H ₄ ) ₃ THF 26 Example 4 P ( p -tolyl) ₃ THF 68 Example 5 P ( p -OMeC ₆ H ₄ ) ₃ THF 62 Example 6 P ( o -tolyl) ₃ THF 99 Example 7 PCy ₃ THF 74 Comparative Example 1 dppf THF <1 Example 8 P ( o -tolyl) ₃ 1,4-dioxane 60 Example 9 P ( o -tolyl) ₃ toluene 45 Example 10 P ( o -tolyl) ₃ 1,2-dichloroethylene 15 Reference Example P ( o -tolyl) ₃ THF <1 Example 11 P ( o -tolyl) ₃ THF 99

25℃)
*실시예 11: 0.5 mol% Pd₂(dba)₃ and 1 mol% 리간드(PPh₃)* PPh ₃ : triphenyl phosphine
* P ( p- CF ₃ C ₆ H ₄ ) ₃ : tris (4-trifluoromethylphenyl) phosphine
* P ( p -tolyl) ₃ : tri-para-tolyl phosphine
* P ( p -OMeC ₆ H ₄ ) ₃ : tris (4-methoxyphenyl) phosphine
* P ( o -tolyl) ₃ : tri-ortho-tolyl phosphine
* PCy ₃ : tricyclohexyl phosphine
* dppf: 1,1'-bis (diphenylphosphino) ferrocene
* THF: Tetrahydrofuran
Reference example: Reaction temperature change (60 ℃)

25 ℃)
Example 11: 0.5 mol% Pd ₂ (dba) ₃ and 1 mol% ligand (PPh ₃ )

(Example 12-24)

In the preparation method of Example 11, Compound 3 was prepared in a similar manner except for using the compound of Table 2 below instead of 4-bromo anisole (1a).

The structure of the synthesized compound and ¹ H-NMR are shown in Table 2 below.

Compound 3 Yield (%), ¹ H-NMR Example 12

93% (500MHz, CDCl ₃ ) [ppm] δ = 7.30-7.26 (m, 2H), 7.23-7.20 (dd, J = 10.5Hz, 4.9Hz, 2H), 7.09-7.06 (m, 1H), 2.30 ( s, 1H), 1.23-1.22 (d, J = 7.4 Hz, 24H). Example 13

_{92% (500MHz, CDCl 3)} [ppm] δ = 7.17-7.16 (d, J = 7.9Hz, 2H), 7.03-7.02 (d, J = 7.9Hz, 2H), 2.29 (s, 3H), 2.26 ( s, 1H), 1.23-1.22 (d, J = 6.7 Hz, 24H). Example 14

65% (500 MHz, CDCl ₃ ) [ppm] δ = 7.62-7.60 (dd, J = 8.2 Hz, 1.1 Hz, 2H), 7.49-7.48 (d, J = 8.3 Hz, 1H), 7.43-7.40 (t, J = 7.7 Hz, 2H), 7.37-7.35 (d, J = 8.3 Hz, 1H), 7.32-7.31 (m, 1H). Example 15

60% (500 MHz, CDCl ₃ ) [ppm] δ = 7.46-7.45 (d, J = 8.1 Hz, 2H), 7.36-7.34 (d, J = 8.1 Hz, 1H), 2.37 (s, 2H), 1.24- 1.22 (d, J = 9.5 Hz, 24 H). Example 16

78% (500 MHz, CDCl ₃ ) [ppm] δ = 7.22-7.19 (m, 2H), 6.91-6.87 (t, J = 8.8 Hz, 2H), 2.27 (s, 1H), 1.23-1.21 (dd, J = 21.3 Hz, 7.1 Hz, 24H). Example 17

70% (500 MHz, CDCl ₃ ) [ppm] δ = 7.20-7.16 (m, 4H), 2.26 (s, 12H), 1.22-1.21 (d, J = 8.5 Hz, 24H). Example 18

78% (500 MHz, CDCl ₃ ) [ppm] δ = 7.12-7.11 (d, J = 8.5 Hz, 2H), 6.70-6.68 (d, J = 8.5 Hz, 2H), 2.23 (s, 1H), 1.22- 1.21 (d, J = 6.9 Hz, 24H), 0.96 (s, 9H), 0.17 (s, 3Hz, 6H). Example 19

68% (500 MHz, CDCl ₃ ) [ppm] δ = 7.90-7.88 (d, J = 8.3 Hz, 2H), 7.32-7.31 (d, J = 8.3 Hz, 2H), 4.35-4.31 (q, J = 7.1 Hz, 2H), 2.37 (s, 1H), 1.37-1.34 (t, J = 7.1 Hz, 3H), 1.22-1.20 (d, J = 10.1 Hz, 24H). Example 20

60% (500 MHz, CDCl ₃ ) [ppm] δ = 7.53-7.51 (d, J = 8.3 Hz, 2H), 7.37-7.35 (d, J = 8.2 Hz, 1H), 2.39 (s, 1H), 1.23- 1.21 (d, J = 10.7 Hz, 12H). Example 21

90% (500 MHz, CDCl ₃ ) [ppm] δ = 7.12-7.10 (m, 2H), 7.05 (s, 1H), 6.90-6.89 (dd, J = 3.8 Hz, 1.8 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 1H), 1.24-1.23 (d, J = 6.7 Hz, 24H). Example 22

_{89% (500MHz, CDCl 3)} [ppm] δ = 7.47-7.46 (d, J = 7.7Hz, 1H), 7.12-7.08 (dd, J = 12.4Hz, J = 6.8Hz, 2H), 7.03-6.99 ( m, 1H), 2.41 (s, 1H), 2.26 (s, 3H), 1.25-1.24 (d, J = 5.4 Hz, 24H). Example 23

98% (500 MHz, CDCl ₃ ) [ppm] δ = 7.77-7.68 (m, 4H), 7.48-7.46 (dd, J = 8.5 Hz, J = 1.8 Hz, 1H), 7.41-7.34 (m, 1H), 2.48 (s, 1 H), 1.25-1.23 (d, J = 10.3 Hz, 12H). Example 24

_{75% (500MHz, CDCl 3)} [ppm] δ = 5.37-5.35 (d, J = 9.1Hz, 1H), 1.83-1.81 (d, J = 9.0Hz, 1H), 1.68 (s, 3H), 1.54 ( s, 3 H), 1.21 (s, 24 H). Example 25

75%, (500 MHz, CDCl ₃ ) δ 5.37 -5.35 (d, J = 9.4 Hz, 1H), 1.99-1.96 (t, J = 7.4 Hz, 2H), 1.84- 1.82 (d, J = 9.4 Hz, 1H), 1.52 (s, 3H), 1.35-1.31 (m, 2H), 1.28-1.23 (m, 6H), 1.22 (s, 12H), 1.21 (s, 12H), 0.87-0.85 (t, J = 6.9 Hz, 3H). Example 26

78%, (500 MHz, CDCl ₃ ) δ 5.44-5.43 (d, J = 9.0 Hz, 1H), 1.80 -1.78 (d, J = 9.0 Hz, 1H), 1.55 (s, 3H), 1.21 (s, 12H), 1.20 (s, 12H), 1.01 (s, 9H). Example 27

71%, (500 MHz, CDCl 3) δ 5.40 -5.38 (d, J = 9.1 Hz, 1H), 1.92 - 1.87 (m, 1H), 1.82 - 1.80 (d, J = 9.1 Hz, 1H), 1.71 - 1.69 (m, 2H), 1.64-1.59 (m, 3H), 1.50-1.50 (d, J = 0.7 Hz, 3H), 1.28-1.23 (m, 2H), 1.21 (s, 12H), 1.20 (s, 12H), 1.18-1.08 (m, 3H). Example 28

76%, (500 MHz, CDCl ₃ ) δ 7.42-7.40 (m, 2H), 7.29-7.26 (m, 2H), 7.18-7.15 (m, 1H), 6.11-6.09 (m, 1H), 2.09-2.07 (d, J = 9.9 Hz, 1H), 1.99-1.99 (d, J = 1.3 Hz, 3H), 1.25 (s, 12H), 1.24 (s, 12H). Example 29

85%, (500 MHz, CDCl 3) δ 5.33-5.31 (d, J = 8.7 Hz, 1H), 2.08 - 2.03 (m, 4H), 1.85 - 1.83 (d, J = 8.7 Hz, 1H), 1.48 - 1.46 (d, J = 7.8 Hz, 6H), 1.22 (s, 24H). Example 30

79%, (500 MHz, CDCl ₃ ) δ 5.41 -5.39 (d, J = 9.5 Hz, 1H), 2.21-2.14 (m, 4H), 1.82-1.80 (d, J = 9.5 Hz, 1H), 1.54- 1.49 (m, 4H), 1.46-1.45 (d, J = 2.7 Hz, 4H), 1.22 (s, 12H), 1.21 (s, 12H). * TBSO:

* Bpin:

, Pinacolboronyl Ester
Example 12-24: 1 mol% Pd ₂ (dba) ₂ , 2 mol% ligand (P ( o- tolyl) ₃ ), THF, 60 ° C., 3hr

(Example 25)

Anhydrous zinc bromide (1.2 equiv., 0.24 mmol, 54 mg) and purified 1,1-diborylmethyl lithium (1.2 equiv., 0.24 mmol, 66 mg) are added to the 4-drum vial together with 1,2-dimethy. Toxyethane (0.5 mL) was added and stirred for 30 minutes to prepare a 1,1-diborylmethyl zinc bromide solution. Next, bis (1,5-cyclooctadiene) diiridium (I) dichloride (2.0 mol%, 4.0 vmol, 2.7 mg) and phosphorus containing chiral ligand (L1, 8.0 mol%, 16) νmol, 8.1 mg) were added together and toluene (0.5 mL) was added thereto, followed by stirring for 15 minutes to form a catalyst. Finally, another 4-dram vial contains tert -butyl- (1-phenylallyl) carbonate (0.2 mmol, 47 mg) and a stirring magnet, followed by a pre-produced catalyst solution and 1,1-dibo The ylmethyl zinc bromide solution was transferred to a vial containing the substrate. The reaction proceeded for 12 hours in dark and room temperature conditions. When the reaction was completed, the reaction solution was filtered through silica and washed with diethyl ether (40 mL) to remove the catalyst primarily. After removing the solvent by filtration under reduced pressure, the product was purified by column chromatography. The optical selectivity of the reaction was determined from HPLC (CHIRALPAK IA, Hexane: IPrOH = 98: 2, 1 mL / min) (yield = 89% (99% ee)).

¹ H-NMR (500 MHz, CDCl ₃ ) [ppm] δ = 7.24-7.20 (m, 4H), 7.12-7.09 (m, 1H), 5.99-5.93 (ddd, J = 17.3, 10.1, 7.3 Hz, 1H ), 5.02-4.98 (dt, J = 17.0, 1.5 Hz, 1H), 4.89-4.86 (dt, J = 10.1, 1.4 Hz, 1H), 3.76-3.72 (dd, J = 12.4, 7.3 Hz, 1H), 1.46-1.44 (d, J = 12.4 Hz, 1H), 1.24 (s, 6H), 1.22 (s, 6H), 0.96 (s, 6H), 0.90 (s, 6H).

(Example 26)

In the preparation method of Example 25, Compound 7a was prepared by a similar method except that 5.0 mmol of tert -butyl- (1-phenylallyl) carbonate was used (yield = 82% (99% ee)).

(Example 27-30)

In the preparation method of Example 25, except that the reaction conditions of the following Table 3, Compound 7a was prepared in a similar manner.

(Comparative Example 2-6)

In the preparation method of Example 25, except that the reaction conditions of the following Table 3, Compound 7a was prepared in a similar manner.

(Comparative Example 7)

In the preparation method of Example 25, the compound 7a was prepared in a similar manner except for following the following reaction conditions.

The reaction with MgCl _{2 shows} that when magnesium-substituted diboron compound is used as a reactant, it is responsive to the basic reaction substrate, but ee% is significantly decreased.

(Comparative Example 8)

In the preparation method of Example 25, the compound 7a was prepared in a similar manner except for following the following reaction conditions.

When 1,1-diboryl (methyl) trimethylsilane was used as the reactant, the reaction did not proceed at all and it was confirmed that all of the reactant remained.

Protecting
Group menstruum additive Ligand yield(%) ee (%) Example 27 Boc DME / toluene ZnBr ₂ L1 90 99 Example 28 Boc THF / toluene ZnBr ₂ L1 70 99 Example 29 Boc DME / toluene ZnCl ₂ L1 81 99 Example 30 Boc DME / toluene ZnBr ₂ L1 82 99 Comparative Example 2 Boc DME / toluene ZnI ₂ L1 <1 - Comparative Example 3 Ac DME / toluene ZnBr ₂ L1 23 99 Comparative Example 4 OP (OEt) ₂ DME / toluene ZnBr ₂ L1 <1 - Comparative Example 5 Boc DME / toluene ZnBr ₂ L2 <1 - Comparative Example 6 Boc DME / toluene ZnBr ₂ L3 <1 - Comparative Example 7 Boc DME / toluene MgCl ₂ L1 43 85 Comparative Example 8 Boc DME / toluene Si (X) Me ₃ L1 <1 -

*Boc: tert-Butoxy carbonyl
*실시예 29: 2.0 mol% [Ir(cod)Cl₂], 8.0 mol% L1
*X: Cl or Br

Boc: tert-Butoxy carbonyl
Example 29: 2.0 mol% [Ir (cod) Cl ₂ ], 8.0 mol% L 1
* X: Cl or Br

(Example 31-41)

In the preparation method of Example 25, Compound 5 was used instead of Compound 5a, and Compound 7 was prepared in a similar manner.

(Comparative Example 9)

In the preparation method of Example 25, Compound 7 was prepared using Compound 5 instead of Compound 5a and Compound 6b instead of Compound 6.

The structure and ¹ H-NMR of the synthesized compound are shown in Table 4 below.

Compound 7 Yield (%), ee (%), ¹ H-NMR Comparative Example 9

<1% Example 31

87%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.15-7.13 (d, J = 8.7 Hz, 2H), 6.79-6.77 (d, J = 8.7 Hz, 2H), 5.97-5.90 (ddd , J = 17.2 Hz, 10.1 Hz, 7.2 Hz, 1H), 4.99-4.95 (dt, J = 16.9 Hz, 1.5 Hz, 1H), 4.86-4.84 (dt, J = 10.2 Hz, 1.3 Hz, 1H), 3.75 (s, 3H), 3.72-3.68 (dd, J = 12.4 Hz, 7.3 Hz, 1H), 1.41-1.39 (d, J = 12.4 Hz, 1H), 1.24 (s, 6H), 1.22 (s, 6H), 0.98 (s, 6H), 0.93 (s, 6H). Example 32

95%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.12-7.10 (d, J = 8.2 Hz, 2H), 7.04-7.02 (d, J = 7.8 Hz, 2H), 5.98-5.91 (ddd , J = 17.2 Hz, 10.1 Hz, 7.3 Hz, 1H), 5.02-4.98 (dt, J = 17.1 Hz, 1.5 Hz, 1H), 4.87-4.84 (dt, J = 10.1 Hz, 1.3 Hz, 1H), 2.26 (s, 3H), 1.43-1.41 (d, J = 12.4 Hz, 1H), 1.24 (s, 6H) , 1.22 (s, 6H), 0.97 (s, 6H), 0.92 (s, 6H). Example 33

46%, 80% ee (500MHz, CDCl₃[ppm] δ = 5.82-5.75 (ddd,J= 17.5 Hz, 10.2 Hz, 7.6 Hz, 1H), 4.98-4.94 (dt,J= 17.1 Hz, 1.5 Hz, 1H), 4.81-4.79 (dd,J= 10.2 Hz, 1.8 Hz, 1H), 2.62-2.54 (dt,J= 10.5 Hz, 6.8 Hz, 1H), 1.23 (s, 6H), 1.22 (s, 6H), 1.20 (s, 6H), 1.19 (s, 6H), 1.04 (d,J= 6.7 Hz, 3H), 0.77 (d,J= 10.6 Hz, 1H). Example 34

42%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.50-7.48 (d, J = 8.1 Hz, 2H), 7.35-7.33 (d, J = 8.0 Hz, 2H), 5.97-5.90 (ddd , J = 17.2Hz, 10.2Hz, 7.2Hz, 1H), 5.03-5.00 (m, 1H), 4.94-4.91 (dd, J = 10.2Hz, 1.3Hz, 1H), 3.83-3.79 (dd, J = 12.4 Hz, 7.2 Hz, 1H), 1.45-1.42 (d, J = 12.3 Hz, 1H), 1.24 (s, 6H), 1.22 (s, 6H), 0.97 (s, 6H), 0.90 (s, 6H). Example 35

81%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.36-7.33 (m, 2H), 7.12-7.09 (m, 2H), 5.94-5.87 (ddd, J = 17.2 Hz, 10.1 Hz, 7.2 Hz, 1H), 5.00-4.96 (dt , J = 17.0Hz, 1.5Hz, 1H), 4.90-4.87 (dt, J = 10.1Hz, 1.3Hz, 1H), 3.73-3.69 (dd, J = 12.3Hz, 7.2 Hz, 1H), 1.39-1.37 (d, J = 12.3 Hz, 1H), 1.23 (s, 6H), 1.21 (s, 6H), 0.99 (s, 6H), 0.93 (s, 6H). Example 36

87%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.20-7.16 (m, 2H), 6.94-6.89 (m, 2H), 5.96-5.89 (ddd, J = 17.2 Hz, 10.2 Hz, 7.2 Hz, 1H), 4.99-4.95 (dt , J = 17.1Hz, 1.5Hz, 1H), 4.89-4.86 (dt, J = 10.1Hz, 1.4Hz, 1H), 3.75-3.71 (m, 1H), 1.40- 1.38 (d, J = 12.4 Hz, 1H), 1.24 (s, 6H), 1.22 (s, 6H), 0.98 (s, 6H), 0.92 (s, 6H). Example 37

58%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.91-7.90 (d, J = 8.3 Hz, 2H), 7.30-7.28 (d, J = 8.3 Hz, 2H), 5.96-5.89 (ddd , J = 17.2Hz, 10.2Hz, 7.3Hz , 1H), 5.01-4.98 (d, J = 17.1Hz, 1H), 4.91-4.89 (d, J = 10.1Hz, 1H), 3.87 (s, 3H), 3.82-3.78 (dd, J = 12.3 Hz, 7.3 Hz, 1H), 1.45-1.43 (d, J = 12.3 Hz, 1H), 1.24 (s, 6H), 1.21 (s, 6H), 0.97 (s, 6H ), 0.89 (s, 6H). Example 38

92%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.15-7.11 (t, J = 7.9 Hz, 1H), 6.83-6.79 (m, 2H), 6.67-6.65 (m, 1H), 5.98 -5.91 (ddd, J = 17.3 Hz, 10.1 Hz, 7.4 Hz, 1H), 5.03-4.99 (dt, J = 17.0 Hz, 1.5 Hz, 1H), 3.75 (s, 3H), 3.73-3.69 (dd, J = 10.1 Hz, 1.3 Hz, 1H), 4.88-4.86 (dt, J = 10.1Hz, 1.3Hz, 1H), 3.75 (s, 3H), 3.73-3.69 (dd, J = 12.4Hz, 7.4Hz, 1H), 1.44-1.41 (d, J = 12.4 Hz, 1H), 1.23 (s, 6H), 1.21 (s, 6H), 0.98 (s, 6H), 0.92 (s, 6H). Example 39

49%, 99% ee (500MHz, CDCl ₃ ) [ppm] δ = 7.19-7.17 (dd, J = 7.5Hz, 1.7Hz, 1H), 7.11-7.08 (td, J = 7.7Hz, 1.7Hz, 1H) , 6.87-6.83 (td, J = 7.5 Hz, 1.1 Hz, 1H), 6.79-6.77 (dd, J = 8.2 Hz, 1.1 Hz, 1H), 6.03-5.96 (ddd, J = 17.2 Hz, 10.1 Hz, 7.2 Hz, 1H), 4.98-4.94 (dt, J = 17.0 Hz, 1.7 Hz, 1H), 4.84-4.81 (ddd, J = 10.1Hz, 1.9Hz, 1.1Hz, 1H), 4.20-4.16 (dd, J = 12.6Hz, 7.3Hz, 1H), 3.80 (s, 3H), 1.63-1.60 (d, J = 12.6Hz, 1H) , 1.24 (s, 6H), 1.22 (s, 6H), 0.98 (s, 6H), 0.86 (s, 6H). Example 40

84%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.77-7.70 (m, 4H), 7.43-7.36 (m, 3H), 6.08-6.01 (ddd, J = 17.2 Hz, 10.1 Hz, 7.2 Hz, 1H), 5.09-5.05 (dt , J = 17.0Hz, 1.5Hz, 1H), 4.95-4.92 (dt, J = 10.2Hz, 1.4Hz, 1H), 3.97-3.93 (dd, J = 12.3Hz, 7.2 Hz, 1H), 1.58-1.55 (d, J = 12.4 Hz, 1H), 1.27 (s, 6H), 1.25 (s, 6H), 0.90 (s, 6H), 0.83 (s, 6H). Example 41

93%, 99% ee (500MHz, CDCl ₃ ) [ppm] δ = 7.17-7.15 (dd, J = 4.9Hz, 3.0Hz, 1H), 7.00-6.99 (dd, J = 3.0Hz, 1.2Hz, 1H) , 6.95-6.94 (dd, J = 5.0 Hz, 1.3 Hz, 1H), 5.97-5.90 (ddd, J = 17.3 Hz, 10.1 Hz, 1H), 4.89-4.86 (dt, J = 10.0 Hz, 1.3 Hz, 1H ), 3.88-3.85 (dd, J = 12.2 Hz, 7.4 Hz, 1H), 1.38-1.36 (d, J = 12.2 Hz, 1H), 1.23 (s, 6H), 1.21 (s, 6H), 1.04 (s , 6H), 0.99 (s, 6H). Example 42

75%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.28-7.24 (m, 3H), 6.28 (dd, J = 1.8, 0.9 Hz, 1H), 5.95-5.88 (ddd, J = 17.2, 10.1, 7.4 Hz, 1H), 5.04-5.00 (dt, J = 17.0, 1.5 Hz, 1H), 4.91-4.88 (dt, J = 10.1, 1.3 Hz, 1H), 3.68-3.64 (dd, J = 12.0, 7.4 Hz, 1H), 1.26 (m, 1H), 1.23 (s, 6H), 1.21 (s, 6H), 1.10 (s, 6H), 1.06 (s, 6H) Example 43

67%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.24-7.23 (m, 1H), 7.17-7.14 (m, 1H), 7.11-7.08 (m, 2H), 5.96-5.89 (ddd, J = 17.2, 10.1, 7.2 Hz, 1H), 5.03-4.99 (dt, J = 17.2, 1.5 Hz, 1H), 4.93-4.90 (dt, J = 10.1, 1.3 Hz, 1H), 3.74-3.70 (dd, J = 12.3, 7.2 Hz, 1H), 1.39-1.37 (d, J = 12.3 Hz, 1H), 1.24 (s, 6H), 1.21 (s, 6H), 1.00 (s, 6H), 0.94 (s, 6H ) Example 44

70%, 99% ee (500 MHz, CDCl ₃ ) [ppm] δ = 7.98-7.96 (d, J = 8.2 Hz, 1H), 7.78-7.76 (d, J = 8.4 Hz, 2H), 7.61-7.59 (d , J = 7.9 Hz, 1H), 7.41 (s, 1H), 7.30-7.26 (m, 1H), 7.22-7.18 (m, 3H), 5.95-5.88 (ddd, J = 17.4, 10.1, 7.6 Hz, 1H ), 5.05-5.01 (dt, J = 17.0, 1.4 Hz, 1H), 4.93-4.91 (dt, J = 10.1, 1.3 Hz, 1H), 4.00-3.96 (dd, J = 11.9, 7.6 Hz, 1H), 2.35 (s, 3H), 1.51-1.49 (d, J = 11.9 Hz, 1H), 1.27 (s, 6H), 1.26 (s, 6H), 1.03 (s, 6H), 0.91 (s, 6H) * Me: methyl
* MeO: methoxy
* Ts: para-toluenesulfonyl

The 1,1, -diboronate ester compound of Compound 7 prepared in one embodiment of the present invention may be applied to various known synthesis methods, for example, Compound 7a may be modified into various compounds as follows according to reaction conditions. Can be.

(Application example)

Reaction conditions

[a] NaO t Bu, MeOH, THF; RT, 6hr

[b] quinolone- N- oxide, NaOMe, toluene; 120 ℃, 3hr

[c] cat. Pd / c, H ₂ , MeOH; RT, 2hr

[d] H ₂ O ₂ , NaHCO ₃ , THF / H ₂ O; 0 ℃ → RT, 3hr

[e] LDA, 3-phenylpropyl bromide, THF; 0 ℃ → RT, 6hr

[f] LDA, CH ₂ I ₂ , THF; 0 ℃ → 60 ℃, 48hr

[g] NaBO _{3 ·} 4H ₂ O, THF / H ₂ O; 0 ℃ → RT, 3hr

[h] cat. Pd (PPh ₃ ) ₄ , 4-iodoanisole, NaOH, 1,4-dioxane / H ₂ O; 100 ℃, 6hr

Although described in detail with respect to embodiments of the present invention as described above, those of ordinary skill in the art, without departing from the spirit and scope of the invention as defined in the appended claims Various modifications may be made to the invention. Therefore, changes in the future embodiments of the present invention will not be able to escape the technology of the present invention.

Claims (19)

Compound represented by the following formula (1):
[Formula 1]

In Chemical Formula 1,
R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other To form a ring;
R ₃ is hydrogen, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl or C2-C30 heteroaryl ego;
M is a zinc group metal;
X ₁ is halogen;
Alkyl, alkoxy and the ring formed by linking with each other of R ₄₁ and R ₄₂ and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ₃ are each independently halogen, hydroxy In cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl May be further substituted with at least one substituent selected;
The heterocycloalkyl and heteroaryl of R ₃ are each independently at least one hetero selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. Contains an atom The method of claim 1,
R ₁ and R ₂ are each independently hydroxyboronyl, pinacolboronylester, 2-pyrazole-5-nianyanilineboronyl, benzo [1,3,2] dioxaborole or 2,3 -Dihydro-1H-naphtho [1,8-de] [1,3,2] diazabolinin. The method of claim 1,
A compound represented by the following formula (9):
[Formula 9]

In Chemical Formula 9,
R ₃ is hydrogen, C 1 -C 30 alkyl, C 2 -C 30 alkenyl, C 3 -C 30 cycloalkyl or C 3 -C 30 heterocycloalkyl;
M is a zinc group metal;
X ₁ is halogen;
Alkyl, alkenyl, cycloalkyl or heterocycloalkyl of R ₃ is halogen, hydroxy, cyano, C1-C30 alkyl, haloC1-C30 alkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6- May be further substituted with at least one substituent selected from C30 aryl and C2-C30 heteroaryl,
The heterocycloalkyl and heteroaryl of R ₃ are each independently at least one hetero selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. Contains an atom The method of claim 1,
R ₃ is hydrogen, C 1 -C 7 alkyl or C 2 -C 7 alkenyl, or
The alkyl or alkenyl of R ₃ is at least one substituent selected from C 1 -C 7 alkyl, C 1 -C 7 haloalkyl, C 3 -C 12 cycloalkyl, C 3 -C 12 heterocycloalkyl, C 6 -C 12 aryl and C 6 -C 12 heteroaryl. Further substituted with. The method of claim 1,
M is Zn. The method of claim 1,
X ₁ is Br or Cl. The method of claim 1,
Wherein MX ₁ is Zn-Br or Zn-Cl. Dehydrogenation of a compound of Formula 6 to produce a compound of Formula 7 by dehydrogenation under a lithium base, and then reacting the compound of Formula 7 with a compound of Formula 8 to produce a compound of Formula 1
[Formula 1]

[Formula 6]

[Formula 7]

[Formula 8]

In Chemical Formulas 1 and 6 to 8,
R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other To form a ring;
R ₃ is hydrogen, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl or C2-C30 heteroaryl ego;
M is a zinc group metal;
X ₁ is halogen;
Alkyl, alkoxy and the ring formed by linking with each other of R ₄₁ and R ₄₂ and alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ₃ are each independently halogen, hydroxy In cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl May be further substituted with at least one substituent selected;
The heterocycloalkyl and heteroaryl of R ₃ are each independently at least one heteroatom selected from B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. It includes. The method of claim 8,
Wherein said lithium base is selected from butyl lithium, lithium dicyclohexylamide, lithium tetramethylpiperidide, lithium isopropylcyclohexylamide and lithium diisopropylamide. Halogenated aromatic compounds or vinyl halide compounds; A compound of Formula 1; And reacting a coordinating ligand-containing transition metal compound in a solvent to prepare a compound represented by the following Chemical Formula 2, wherein the 1,1-diboronate ester compound is prepared by:
[Formula 1]

[Formula 2]

In Chemical Formulas 1 and 2,
R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other To form a ring;
R ₃ is hydrogen, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl or C2-C30 heteroaryl ego;
M is a zinc group metal;
X ₁ is halogen;
A is absent or is an aromatic ring;
R ₁₁ is hydrogen, halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C2-C30 heteroaryl, -O-Si (R ₃₁ ) ₃ or —C (O) —R ₃₂ , wherein R ₃₁ and R ₃₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy;
n is an integer of 1 to 3 and when n is 2 or 3, R ₁₁ is the same as or different from each other;
The alkyl, alkoxy and ring formed by linking with each other of R ₄₁ and R ₄₂ and the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl of R ₃ and the aromatic ring of A Alkyl, alkoxy, alkenyl, alkynyl, aryl and heteroaryl of R ₁₁ are each independently halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl May be further substituted with at least one substituent selected from C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl;
The heterocycloalkyl and heteroaryl of R ₃ and the heteroaryl of R ₁₁ are each independently B, N, O, S, Se, -P (= 0)-, -C (= 0)-, Si and P. It contains at least one heteroatom selected from. The method of claim 10,
The reaction is carried out in the range of 25 to 100 ℃, how to prepare a 1,1-diborate ester compound. The method of claim 10,
The coordinating ligand-containing transition metal compound is [Rh (COD) Cl] ₂ , [Rh (COD) ₂ ] X (X = BF ₄ , ClO ₄ , SbF ₆ or CF ₃ SO ₃ ), [Ir (COD) Cl ] ₂ , [Ir (COD) ₂ ] X (X = OMe, BF ₄ , ClO ₄ , SbF ₆ Or CF ₃ SO ₃ ), Ru (COD) Cl ₂ , [Pd (CH ₃ CN) ₄ [BF ₄ ] ₂ , Pd ₂ (dba) ₃ and [Pd (C ₃ H ₅ ) Cl] ₂ ; And a phosphine-based compound is a complex, the method for producing a 1,1-diboronate ester compound. The method of claim 12,
The phosphine-based compound may be triphenylphosphine, tri- ortho-tolyl phosphine, tri-methol-tolyl phosphine, tri-para-tolyl phosphine, tris (4-trifluoromethylphenyl) phosphine, diphenyl (para) -Tolyl) phosphine, cyclohexyldiphenyl phosphine, tris (2,6-dimethoxyphenyl) phosphine, tris (4-methoxyphenyl) phosphine, trimethylphosphine, tris-3,5-k A method for producing a 1,1-diboronate ester compound, which is selected from silylphosphine, tricyclohexyl phosphine, tribenzyl phosphine, benzyldiphenyl phosphine and diphenyl-normal-propyl phosphine. A compound of Formula 5; A compound of Formula 1; And reacting a coordinating ligand-containing transition metal compound in a solvent to prepare a compound represented by the following Chemical Formula 4, wherein the method for preparing a 1,1-diboronate ester compound comprising:
[Formula 1]

[Formula 4]

[Formula 5]

In Chemical Formulas 1, 4, and 5,
R ₁ and R ₂ are each independently * —B (R ₄₁ ) (R ₄₂ ), wherein R ₄₁ and R ₄₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy or are linked to each other To form a ring;
R ₃ is hydrogen, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C3-C30 cycloalkyl, C3-C30 heterocycloalkyl, C6-C30 aryl or C2-C30 heteroaryl ego;
M is a zinc group metal;
X ₁ is halogen;
R ₂₁ is hydrogen, halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 alkoxy, C2-C30 alkenyl, C2-C30 alkynyl, C6-C30 aryl, C2-C30 heteroaryl, -O-Si (R ₃₁ ) ₃ or —C (O) —R ₃₂ , wherein R ₃₁ and R ₃₂ are each independently hydrogen, hydroxy, C 1 -C 30 alkyl or C 1 -C 30 alkoxy;
Boc is tert-butoxycarbonyl;
Wherein R ₄₁ and R ₄₂ the alkyl, alkoxy and connected to each other formed alkyl ring and the R _3, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl and the alkyl, alkoxy of said R ₂₁ , Alkenyl, alkynyl, aryl and heteroaryl are each independently halogen, hydroxy, cyano, C1-C30 alkyl, C1-C30 haloalkyl, C1-C30 alkoxy, C1-C30 aminoalkyl, C3-C30 cycloalkyl , May be further substituted with at least one substituent selected from C3-C30 heterocycloalkyl, C6-C30 aryl and C2-C30 heteroaryl;
The heterocycloalkyl and heteroaryl of R ₃ and the heteroaryl of R ₂₁ are each independently B, N, O, S, Se, —P (═O) —, —C (═O) —, Si, and P It contains at least one heteroatom selected from. The method of claim 14,
The reaction is carried out in the range of 10 to 35 ℃, how to prepare a 1,1-diboron ester compound. The method of claim 14,
The coordinating ligand-containing transition metal compound is [Rh (COD) Cl] ₂ , [Rh (COD) ₂ ] X (X = BF ₄ , ClO ₄ , SbF ₆ or CF ₃ SO ₃ ), [Ir (COD) Cl ] ₂ , [Ir (COD) ₂ ] X (X = OMe, BF ₄ , ClO ₄ , SbF ₆ Or CF ₃ SO ₃ ), Ru (COD) Cl ₂ , [Pd (CH ₃ CN) ₄ [BF ₄ ] ₂ , Pd ₂ (dba) ₃ and [Pd (C ₃ H ₅ ) Cl] ₂ ; The aminophosphone compound and a complex form a method for producing a 1,1-diborate ester compound. The method of claim 16,
The aminophosphon compound is a method of producing a 1,1-diboronate ester compound, L1:

. The method according to claim 10 or 14,
R ₁ and R ₂ are each independently hydroxyboronyl, pinacolboronylester, 2-pyrazole-5-nianyanilineboronyl, benzo [1,3,2] dioxaborole or 2,3 -Dihydro-1H-naphtho [1,8-de] [1,3,2] diazaborinine, A method for producing a 1,1-diboronate ester compound. The method according to claim 10 or 14,
The solvent is selected from an aprotic solvent, the method for producing a 1,1-diboronate ester compound.