WO2015137417A1

WO2015137417A1 - Synthetic intermediate for producing 3-haloaryne and method for synthesising said synthetic intermediate

Info

Publication number: WO2015137417A1
Application number: PCT/JP2015/057210
Authority: WO
Inventors: 英斗吉岡; 豪人宮部
Original assignee: 学校法人兵庫医科大学
Priority date: 2014-03-13
Filing date: 2015-03-11
Publication date: 2015-09-17
Also published as: JPWO2015137417A1; JP6461914B2

Abstract

[Problem] To provide: an aryne precursor which can be synthesised easily in fewer steps; and a method for synthesising said aryne precursor. [Solution] Provided is an aromatic compound which has: a trialkylsilyl group; a -OSO₂R¹ group [R¹ is a heteroaryl group or an aryl which may be substituted with C_mF_2m+1 (m is an integer) or with an alkyl] in both positions that are adjacent to the trialkylsilyl group; and a -X group [X is F, Cl, or Br].

Description

Synthetic intermediate for producing 3-haloalignment and method for synthesizing the same

The present invention relates to a synthetic intermediate for producing 3-haloalignment and a synthesis method thereof.

Align (1,2-benzyne or o-benzyne, also simply called benzyne) is a general term for highly reactive chemical species having a triple bond on an aromatic ring. Since Align is rich in reactivity, it is used in many fields such as synthesis of biologically active substances such as polycyclic heterocycles and functional molecules (Non-patent Document 1, Patent Documents 1 and 2).
As a method for producing alignment, a method requiring severe reaction conditions such as high temperature and strong basicity has been known. In 1983, as a method for generating alignment under mild conditions, a method using an adjacent trimethylsilyl group and trifluoromethanesulfonic acid ester group on an aromatic ring was reported (Non-patent Document 2). Further, as precursors for generating 3-haloalignment under mild conditions, 6-trimethylsilyl-2-halophenyltrifluoromethanesulfonate (Non-patent Document 3) and 6-bromo-4-trimethylsilyl-1H-indole-5 Although iltrifluoromethanesulfonate (Non-Patent Document 4) has been reported, this precursor is a compound different from the present invention, and its synthesis method is also different.
The following documents are each incorporated herein by reference.
P. M. Tadross and B. M. Stoltz, Chem. Rev., 2012, 112, 3550-3577. H. Kobayashi, et al., Chem. Lett., 1983, 12, 1211-1214. H. Yoshida, et al., Angew. Chem. Int. Ed., 2013, 52, 8629-8632. N. K. Garg, et al., J. Am. Chem. Soc., 2011, 133, 3832-3835. R. C. Larock, et al., Org. Biomol. Chem., 2013, 11, 191-218. S. M. Bronner and N. K. Garg, J. Org. Chem., 2009, 74, 8842-8843. A. E. Goetz and N. K. Garg, Nature Chem., 2013, 5, 54-60. M. F. Greanye, et al., Chem. Commun., 2013, 49, 7602-7604. Japanese Patent Laid-Open No. 10-245367 International Publication No. 2014/024212

In the conventional method for synthesizing the precursor for aligning, since a halogen-lithium exchange reaction is performed, it is necessary to perform an experimental operation in a number of steps of selectively introducing or removing halogen at a target position. It was. Further, it has been known that a halogen-substituted carbon 6-membered ring aromatic compound generates an alignment due to elimination of a halogen atom with the generation of an anion at a position adjacent to the halogen atom. A heterocyclic 6-membered aromatic compound can generate a precursor without going through a halogen-lithium exchange reaction because the anion on the aromatic ring is more stable and more easily generated. It is more difficult to synthesize a carbon six-membered ring alignment precursor than a body compound. From such a background, systematic synthesis of halogen-substituted carbon 6-membered ring-aligned precursor compounds has hardly been performed.

In addition, in the synthesis of various aromatic compounds via alignment, when asymmetric alignment having a substituent is used as a substrate, two regioisomers may be generated, so that the reaction position selectivity is higher. A method was sought.
The present invention succeeded in synthesizing various halogen-substituted align precursors with a smaller number of steps. In addition, by having halogen, the regioselectivity of aligning reaction was improved.

That is, according to the present invention, there is provided an aromatic compound having a trialkylsilyl group, and an —OSO ₂ R ¹ group and an —X group at positions adjacent to the trialkylsilyl group.
In particular, an aromatic compound in which the ring to which the trialkylsilyl group, —OSO ₂ R ¹ group and —X group are directly bonded is a carbon 6-membered ring is preferably provided.
Also provided are uses as synthetic intermediates or synthetic precursors or synthetic intermediates or synthetic precursors for the production of aligns comprising the aromatic compounds.
There is also provided a method for producing alignment, which comprises reacting the aromatic compound with fluoride ions.
Further, according to the present invention, an aromatic compound having a —H (hydrogen) group and a trialkylsilyloxy group and a —X group at both adjacent positions adjacent to the —H group is converted to lithium amide or Provided is a method (synthetic method) for synthesizing an aromatic compound (alignment intermediate), which comprises a step of reacting with an art complex type double salt of magnesium amide or zinc amide and a lithium salt. Here, in a further invention, the aromatic compound (alignment intermediate) is the aromatic compound in which the ring to which the —OSO ₂ R ¹ group and the —X group are directly bonded is a carbon six-membered ring. .

Here, in the above invention, R ¹ is C _m F _{2m + 1} (m is an integer) or an aryl or heteroaryl group which may be substituted with alkyl. X is F, Cl or Br.

Further, according to the present invention, there is further provided the above invention wherein the aromatic moiety contains benzene, naphthalene, indole, benzimidazole, quinoline, isoquinoline or benzofuran. In addition, according to the present invention, there is further provided the aforementioned invention, wherein the aromatic moiety contains benzene, naphthalene, indole, quinoline, isoquinoline or benzofuran. These aromatic moieties may be further substituted.

The present invention provides an align-generating intermediate compound that is easily synthesized with a small number of steps. With this compound, the synthesis reaction via alignment can be performed more easily. In addition, the introduction of a halogen at a specific position makes the alignment reaction generated from this synthetic intermediate compound also regioselective.

[Explanation of terms]
In this specification, the following terms have the following meanings.

The term “halogen” or “halo” means fluorine, chlorine, bromine or iodine, unless otherwise specified.
The term “cyano” means a —CN group.
The term “tertiary amino” means a group in which hydrogen is substituted with a substituent R other than hydrogen in the —NH ₂ group. Preferably, R is an optionally substituted alkyl group.
The term “nitro” means a —NO ₂ group.
The term “sulfonyl” refers to the divalent group —S (═O) ₂ —.
The term “carbonyl” refers to a — (C═O) — group that is a divalent group.

The terms “alkyl”, “alkenyl”, “alkynyl” or “cycloalkyl” mean not only monovalent groups, but in some cases divalent or higher groups. For example, when a divalent group is meant, it is used interchangeably with “alkylene”, “alkenylene”, “alkynylene” or “cycloalkylene”, respectively.
The prefix “C _xy alkyl”, “C _xy alkenyl”, “C _xy alkynyl” or “C _xy cycloalkyl” is prefixed with each of x to y carbon atoms. A group of the specific chain length shown below is representative of “C _xy alkyl”, “C _xy alkenyl”, “C _xy alkynyl” or “C _xy cycloalkyl” It is an example.
Moreover, about arbitrary bivalent or more groups, when substituting in the position which can form a monocycle or a multicycle, unless it specifically limits, the group more than bivalence may form ring structure.

The term “C _1-6 alkyl” or “C _1-6 alkylene” means a branched or straight-chain saturated hydrocarbon group having from 1 to 6 carbon atoms, for example, C _1-3 alkyl , C _1-4 alkyl, C _1-6 alkyl, C _2-6 alkyl, C _3-6 alkyl, and the like. Representative C _1-6 alkyl includes, for example, methyl, ethyl, propyl (eg, propan-1-yl, propan-2-yl [or iso-propyl]), butyl (eg, 2-methylpropane-2) -Yl [or tert-butyl], butan-1-yl, butan-2-yl), pentyl (eg, pentan-1-yl, pentan-2-yl, pentane-3-yl), 2-methylbutane-1 -Yl, 3-methylbutan-1-yl, hexyl (eg, hexane-1-yl) and the like.

The term “C _2-6 alkenyl” or “C _2-6 alkenylene” refers to a linear or branched non-aromatic having 2 to 6 carbon atoms and at least one carbon-carbon double bond. And includes, for example, C _2-3 alkenyl, C _2-4 alkenyl, C _2-6 alkenyl, C _3-6 alkenyl, C _4-6 alkenyl and the like. Representative C _2-6 alkenyl groups include, for example, vinyl, 1-propenyl, 2-propenyl, iso-propenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl- 1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 2,4-hexadienyl, and 5-hexenyl Etc.

The term “C _2-6 alkynyl” or “C _2-6 alkynylene” refers to a linear or branched non-aromatic having 2 to 6 carbon atoms and at least one carbon-carbon triple bond. And includes, for example, C _2-3 alkynyl, C _2-4 alkynyl, C _2-6 alkynyl, C _3-6 alkynyl, C _4-6 alkynyl and the like. Representative C _2-6 alkynyl groups include, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-methyl-1-propynyl, 1-pentynyl, 2- Examples include pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-2-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 5-hexynyl and the like.
The term “C _3-6 cycloalkyl” means a saturated monocyclic carbocycle having from 3 to 6 carbon atoms. Representative C _3-6 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term “alkoxy” or “alkyloxy” means a —O—R group where R is alkyl as previously described. Also, when the term “Roxy” is used, it means a —O—R group that is a monovalent or divalent group.
For example, the term “C _1-6 alkoxy” means a C _1-6 alkyl-O— group, for example, C _1-3 alkoxy, C _1-4 alkoxy, C _1-6 alkoxy, C _2-6. Including alkoxy, C _3-6 alkoxy and the like. Representative C _1-6 alkoxy includes, for example, methoxy, ethoxy, propoxy (eg, 1-prop-oxy, 2-prop-oxy [or iso-propoxy]), butoxy (eg, 1-butoxy, 2-butoxy, 2-methyl-2-propoxy- [or tert-butoxy]), penta-oxy (1-penta-oxy, 2-penta-oxy), hexa-oxy (1-hexa-oxy, 3- Hexa-oxy) and the like.

The term “heterocyclic group” means a single atom containing one or more heteroatoms selected from atoms other than carbon (heteroatoms) such as nitrogen, oxygen, sulfur, SO and S (═O) ₂ in the ring. It means a ring, bicyclic or polycyclic saturated or unsaturated non-aromatic group or aromatic group (heteroaryl group). The heterocyclic group includes, for example, a non-aromatic cyclic amino group, and is preferably an aprotic group. The heterocyclic group in the present invention is preferably a 5- to 7-membered ring, more preferably a 5-membered ring or a 6-membered ring. Representative heterocyclic groups include, for example, morpholino, oxazinyl, dihydrooxazinyl, piperazinyl, thiomorpholino, piperidino, pyrrolidinyl, homomorpholino, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, triazinyl, pyridinyl, pyrimidinyl, pyridazinyl, Examples include pyrazinyl, oxazolyl, isoxazolyl, thienyl or furyl.

The term “aryl” means a monocyclic, bicyclic or polycyclic carbocyclic aromatic ring. Representative aryl includes phenyl, naphthalenyl, and the like.
The term “heteroaryl” means a monocyclic, bicyclic or polycyclic heteroaromatic ring containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, SO and S (═O) ₂ . Representative heteroaryls include pyridyl, pyrimidinyl, indolyl, thiazolyl, benzofuranyl, dihydrobenzofuranyl, imidazolyl, pyrazolyl, quinolyl, isoquinolyl, benzothiophenyl, and the like.

The term “saturated or unsaturated” means whether the group in question is a saturated group that does not contain a double or triple bond, or is an unsaturated group that contains at least one double or triple bond. Means either.
The term “optionally substituted” means that the group in question is either unsubstituted or substituted by one or more specific substituents. For example, the number of substitutions is 1, 2, 3, 4, or 5, but preferably, 1, 2, or 3, more preferably 1 or 2, and even more preferably 1 is used. When a target group is substituted with a plurality of substituents, the substituents may be the same or different.

The terms “intermediate”, “synthetic intermediate” or “product intermediate” are produced by reaction from starting materials or previous reactants in the manufacturing process or chemical reaction (organic synthesis) and further reacted. It refers to what gives the final product and is limited by its use. That is, in this case, the final product is synthesized via an intermediate. In particular, in the present application, an intermediate that gives a final product in one step or one reaction, or substantially one step or one reaction (for example, when using a plurality of consecutive reactions) is called a “precursor”. Sometimes (ie, the intermediate includes a precursor). Even if used substantially as a precursor, the final product may be obtained after multiple steps to modify other moieties.

Some of the above terms may be used multiple times in the structural formula, and each term may be in an independent range.
Some of the above terms may be used in combination, in which case the first listed group will be a substituent on the group described later and the point of substitution (addition point) will be at the end of the entire group. It is on the part marked.

BACKGROUND OF THE INVENTION
Most alignment methods require harsh conditions such as high temperature and strong basicity, and are economical for industrial use and effects on other structures in the compound (substituents must be protected). ) Etc.), further improvement was desired.
In addition, conventionally, in the generation of alignment, halogen atoms (F, Cl, Br, and I atoms) on the aromatic ring have been used as leaving groups for alignment generation using strong bases.

Halogen atoms have also been used in alignment methods via Grignard reactions and halogen-metal exchange reactions. For these reasons, it has been difficult to efficiently generate alignments having halogen atoms by conventional methods.

The alignment precursor compound containing a halogen atom has hardly been reported, and the compounds reported so far and their synthesis methods are different from the compounds of the present invention and their synthesis methods.
For example, as a method for synthesizing an align precursor having a chlorine atom (the same applies to a bromine atom), a method of synthesizing via halogen-lithium exchange has been reported as shown in the following formula (1) (Non-patent Document 3).
Further, as a method of directly introducing a substituent into the adjacent position of the phenolic hydroxyl group without using a halogen-lithium exchange reaction, after introducing a protective group / orienting substituent into the phenolic hydroxyl group as shown in Formula (2) A method for synthesizing an align precursor by generating an anion on an aromatic ring has also been reported (Non-patent Document 6). In addition, a method for synthesizing an align precursor having a bromine atom at the adjacent position using the method of Non-Patent Document 6 (Non-Patent Document 4), and a heterocycle align precursor using the heterocycle characteristic that anions are easily generated. Although a synthesis method (Non-patent Document 7) has also been reported, these are all different from the present invention.

It should be noted that the synthesis of the above-mentioned known alignment precursors is generally high in cost, and the generation efficiency is superior to the present invention. For example, in the method of formula (1), the halogen atom in the raw material is removed during the reaction, and the introduction cost of the halogen atom is higher than in the present invention. The introduction and removal of the groups is necessary and the reagent costs are high because an excess amount is used. For example, compared with the method of Formula (1) and the method described in the nonpatent literature 4, the method of this invention is excellent in the production | generation efficiency of alignment.

Embodiment
Embodiments of the present invention will be described below.

In one embodiment of the present invention, a trialkylsilyl group and an —OSO ₂ R ¹ group [where R ¹ is C _m F _{2m + 1} (m is an integer) or alkyl are substituted on both adjacent positions adjacent to the trialkylsilyl group. An aromatic or heteroaryl group] and an —X group [X is F, Cl or Br], wherein the trialkylsilyl group, —OSO ₂ R ¹ group And the ring to which the —X group is directly bonded is an aromatic compound having a six-membered carbon ring.
Another embodiment of the present invention has a —H (hydrogen) group, a trialkylsilyloxy group at a position adjacent to the —H group, and a —X group [X is F, Cl, or Br]. A process for reacting an aromatic compound with lithium amide, or an art complex-type double salt of magnesium amide or zinc amide and a lithium salt. In both adjacent positions, —OSO ₂ R ¹ group [R ¹ is C _m F _{2m + 1} (m is an integer) or an aryl or heteroaryl group optionally substituted with alkyl] and —X group [X Is F, Cl or Br]. (Method of synthesis; or method of production (manufacturing method)).
Another embodiment of the present invention is the method of the above embodiment, wherein the ring to which the trialkylsilyl group, —OSO ₂ R ¹ group and —X group are directly bonded is a carbon 6-membered ring.

The aromatic compound of the present invention can easily generate alignment (3-halo alignment) under mild conditions by reacting with fluoride ions. Alignments produced from the present aromatic compounds react regioselectively with various nucleophiles to give various substituted aromatic compounds. Furthermore, when a diene or the like is added, a polycyclic aromatic compound can also be obtained.
The aromatic compound of the present invention utilizes the characteristic substituent arrangement (an arrangement having an -OSO ₂ R ¹ group and an -X group at positions adjacent to the trialkylsilyl group), Unlike general align-forming intermediate compounds, it can be synthesized more easily with fewer steps. Furthermore, since the number of reagents used is small compared to the conventional method, it can be economical. Furthermore, since the number of steps and the number of reagents used are small, the processing and purification of the product can be made simpler, giving an overall good yield. By these things, the aligning precursor which has various substituents can be supplied on the industrially realizable level.

In particular, a halogen-substituted heterocycle alignment precursor (Non-patent Document 7), which could be synthesized by a conventional method, has a halogen-substituted lane precursor compound having a carbon six-membered ring that is less likely to generate anions than a heterocycle. About (the thing which has the substituent arrangement | positioning of this invention), it was not easy to synthesize | combine by the conventional method, and complicated reaction was required.
Further, this aromatic compound has high storage stability, and can be stored for a long period of time, for example, about -30 ° C. to room temperature for about 1 to 2 years or more. Furthermore, the aromatic compound is preferably stored under conditions free from moisture, but can be stored in normal air.

The align-generating intermediate compound of the above aspect is described as follows: “—H (hydrogen) group, trialkylsilyloxy group, —X group [X is F, Cl, or Br] adjacent to the —H group” Can be synthesized by a method including a step of treating with a specific strong base. Specific strong bases include lithium amide, or an art complex type double salt of magnesium amide or zinc amide and a lithium salt. By the reaction in the above step, an “aromatic compound having a trialkylsilyl group, a hydroxyl group and an —X group [X is F, Cl, or Br] at both positions adjacent to the trialkylsilyl group” (The desired phenolic compound) can be synthesized. This compound may be converted to a haloalkyl sulfonate esterifying reagent or (alkyl-substituted) aryl or heteroaryl sulfonate esterifying reagent (including but not limited to C _m F _{2m + 1} SO ₂ F (eg, trifluoromethanesulfonyl fluoride) , Heptafluoropropylsulfonyl fluoride, perfluorobutanesulfonyl fluoride), Tf ₂ O (trifluoromethanesulfonic anhydride), TsCl (p-toluenesulfonyl chloride), benzenesulfonyl chloride, N, N′-sulfonyldiimidazole, etc. ) And converting to the corresponding sulfonic acid ester according to a conventional method, the target aligning intermediate compound can be synthesized.

It is to be noted that the starting material has an “-H (hydrogen) group, a trialkylsilyloxy group at a position adjacent to the —H group, and an —X group [X is F, Cl or Br]. The “group compound” (starting silyl ether compound) is not limited thereto, but includes a corresponding “—H (hydrogen) group, a hydroxyl group at a position adjacent to the —H group, and —X The aromatic compound having the group [X is F, Cl or Br] (starting phenol compound) is added to a silyl etherification reagent (HMDS (bis (trimethylsilyl) amine (also known as 1,1,1,3)). , 3,3-hexamethyldisilazane)), TMSCl (trimethyl chloride chloride), TBDMSCl (t-butyldimethylsilane chloride), etc.), and silyl etherification according to a conventional method. Can. The silyl ether compound as a starting material is not limited to this, and can be synthesized by various routes by performing a substituent introduction reaction on an aromatic ring.

For the synthesis reaction of the align-forming intermediate compound of the above embodiment, those skilled in the art can appropriately set various conditions such as an appropriate solvent and temperature according to the silyl ether compound to be reacted. Specific reaction conditions can be set with reference to known documents such as Non-Patent Document 5, for example. However, as an example, the reaction conditions are not limited thereto, but a solvent: an aprotic solvent (for example, Tetrahydrofuran, 1,2-dimethoxyethane, diethyl ether and mixed solvents thereof), temperature: -80 ° C to 0 ° C. Furthermore, the reaction is more preferable under moisture-free conditions, for example, in an Ar atmosphere.

The invention of the above embodiment is not limited to this, but can be illustrated as follows (the aromatic compound portion is exemplified using phenyl).

The align-forming intermediate compound of the present invention is the compound of (4) in the figure, and the method of synthesizing the align-generating intermediate compound of the present invention is a reaction from the starting material silyl ether (2) to the phenol compound (3). It is the method characterized by this. An example of a method for synthesizing silyl ether (2) is silyl etherification of a corresponding phenol compound such as the starting phenol compound (1).
In the reaction from the silyl ether (2) to the phenol compound (3), a strong base is used to make the ortho position of the chlorine atom (the 2nd position in the figure) an anion, and the introduction of the silyl group into the 2nd position by the rearrangement reaction and Regeneration of the secondary phenolic hydroxyl group is achieved at once. In this reaction, the introduction of a silyl group is achieved by a rearrangement reaction from a silyl ether group at the meta position (position 1 in the figure) in order to suppress the formation of alignment due to the elimination of halogen atoms. Thus, in the synthesis method of the present invention, a silyl ether group and a halogen atom are utilized, and an anion is generated selectively and a silyl group is introduced without using a halogen-lithium exchange reaction. Yes.

Still another embodiment of the present invention is an alignment synthetic intermediate or synthesis precursor (synthetic intermediate or synthesis precursor for producing alignment) comprising the aromatic compound of the above embodiment.
Yet another embodiment of the present invention is a method for producing an align (3-haloalign), which comprises reacting the compound of the above embodiment with a fluoride ion.
Still another embodiment of the present invention is the alignment obtained by reacting the compound of the above embodiment with fluoride ion or the obtained align (3-haloalign), or the reaction of the fluoride ion to the compound of the above embodiment. Or a reaction mixture or product containing the resulting alignment (3-haloalignment).

The align-forming intermediate compound of the present invention can easily generate aligns (for example, benzyne, naphtholine, pyridyne, etc.) under mild conditions by reacting with fluoride ions. The produced alignment reacts regioselectively with various nucleophiles to give various substituted aromatic compounds and polysubstituted aromatic compounds. Align can be used in many ways, including the synthesis of biologically active substances and functional molecules.
Unlike the general alignment generating intermediate compound, the alignment generating intermediate compound of the present invention can be synthesized more easily with a smaller number of steps, and therefore alignment can be generated more efficiently. Moreover, it can also synthesize | combine by a higher yield by using the synthesis method of this invention in the case of the synthesis | combination. Furthermore, its high storage stability is also convenient when generating an alignment when desired.

For the occurrence of alignment using the alignment-generating intermediate compound of the present invention, for example, by reacting with fluoride ions according to a known method such as the method described in Non-Patent Document 1 or 5, or Patent Document 1, Alignment can be easily generated under mild conditions.
Fluoride ion sources include TBAF (tetra-n-butylammonium fluoride), TBAHF ₂ , CsF, KF, TBAT (tetra-n-butylammonium difluorotriphenyl silicate), TBAH ₂ F ₃ , HF • pyridine HF and triethylamine can be exemplified, and preferably TBAF, TBAHF ₂ , CsF, KF, TBAT, TBAH ₂ F ₃ , more preferably TBAF, TBAHF ₂ , and CsF can be used.

The alignment reaction itself using fluoride ions is a reaction well known to those skilled in the art, and those skilled in the art can appropriately change the reaction conditions according to conventional methods (for example, Non-Patent Document 1 or 5, or Patent Document 1). Can be set. Specifically, the reaction conditions are not particularly limited as long as fluoride ions act, and examples of such conditions include, but are not limited to, solvent: polar aprotic Solvent (for example, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide (reagent and solvent) or a mixed solvent thereof; alcohol solvent is not preferred), temperature: 0 to 100 ° C., more preferably The condition is 20 to 80 ° C. (an ultra-low temperature such as −80 ° C. is not preferable). Furthermore, the reaction is more preferable under moisture-free conditions, for example, in an Ar atmosphere.
About the alignment produced | generated by this invention, it can be made to react with various sphere nucleating agents in a reaction system as it is, and the target compound which has a desired chemical structure can be obtained. Since the generation of align according to the present invention is performed under relatively mild conditions, other substituents present in the compound are not easily affected, and the present invention can be used in the vicinity of the final step of the synthesis step.

The invention of the above embodiment (generation of alignment and subsequent reaction) is not limited to this, but can be illustrated as follows (the aromatic compound portion is exemplified using phenyl, Illustrative representative end products X, Y, Z).

In a preferred aspect of the present invention, the aromatic compound is an aromatic compound in which the trialkylsilyl group, —OSO ₂ R ¹ group, and —X group are bonded to optionally substituted aryl or heteroaryl. An aromatic compound (synthetic intermediate) or method according to any one of the above aspects. Since the alignment precursor synthesis method of the present invention utilizes the arrangement and properties of the trialkylsilyl group, —OSO ₂ R ¹ group, and —X group, even the substituents defined in the present invention have an appropriate arrangement. If it is, it can implement irrespective of the structure and frame | skeleton (For example, a monocyclic ring, a condensed ring, etc.) of another part.

In another preferred embodiment of the present invention, the aromatic compound is an optionally substituted benzene, pyridine, pyrimidine, naphthalene, indole, benzimidazole, quinoline, isoquinoline, benzofuran or benzothiophene or an optionally substituted benzene. , Pyridine, pyrimidine, naphthalene, indole, quinoline, isoquinoline, benzofuran or benzothiophene, which is an aromatic compound in which the trialkylsilyl group, —OSO ₂ R ¹ group and —X group are bonded. An aromatic compound (synthetic intermediate) or method. The aromatic moiety is more preferably benzene, pyridine, naphthale, quinoline, pyrimidine, isoquinoline, and even more preferably benzene, pyridine, naphthalene. In the compound having these portions, the effects of the present invention can be more reliably exhibited.

In addition to industrial usefulness, more reliable progress of reaction or reaction selectivity of aligning, viewpoint of difficulty in synthesis by conventional synthesis methods (point that can be synthesized particularly advantageously by the present invention) The aromatic moiety preferably comprises a benzene ring and is benzene, naphthalene, indole, benzimidazole, quinoline, isoquinoline, benzofuran or benzothiophene or benzene, naphthalene, indole, quinoline, isoquinoline, benzofuran or benzothiophene. More preferably, benzene, naphthalene, indole, benzofuran, and benzothiophene are even more preferable, and benzene and naphthalene are even more preferable.

In the aromatic compound (synthetic intermediate) or method of any of the above embodiments, the ring to which the trialkylsilyl group, —OSO ₂ R ¹ group and —X group are directly bonded is preferably a six-membered ring, More preferably, it is a six-membered ring. According to the present invention, in particular, a carbon 6-membered ring alignment precursor can be synthesized more easily than a conventional method compared to a hetero 6-membered ring alignment precursor.

In addition, the aromatic part (parent ring) of the aromatic compound may be substituted with any substituent according to the structure of the target compound. Since the method for synthesizing an align-generating intermediate compound of the present invention and the method for generating an align from the align-generating intermediate compound are highly specific reactions that proceed under mild conditions, there are few restrictions on substituents. If the functional group is difficult to be deprotonated and hardly rearranged, the reaction can be advantageously advanced.

Specific examples of such one or more substituents R include, but are not limited to, halogen, nitro, cyano, tertiary amino (disubstituted amino), alkyl, haloalkyl, alkene, haloalkene, alkyne. , Haloalkyne, alkoxy, ester (eg, RC (O) O— or ROC (O) —, where R is defined herein), sulfonate ester (eg, ROS (═O) ₂ where R is defined herein) O- and the like), aryl, aryloxy, arylalkyl, arylalkoxy, heterocyclic group and the like. Further, these substituents R may be further substituted with one or more substituents R. The substituent R is preferably halogen, alkyl, haloalkyl, alkoxy, alkene, alkyne, aryl, aryloxy, more preferably halogen, alkyl, haloalkyl, alkoxy. Two or more substituents R may be taken together to form a ring structure.
As the substituent for the aromatic moiety of the align-forming intermediate compound of the present invention, any number of 1 to 3, 1 or 2, or 1 substituents is preferably used.

A certain aspect of the present invention is the aromatic compound (synthetic intermediate) or method according to any one of the above aspects, wherein X is chloro or fluoro. When X is chloro or fluoro, the aligning intermediate compound of the present invention can be synthesized in a higher yield. From the viewpoint of yield and reaction selectivity of alignment, it is advantageous that X is fluoro. In the reaction product using alignment, X is converted to other substituents such as alkyl, aryl, alkoxy, formyl, alkylcarbonyl and the like. From the standpoint of ease of conversion, it is advantageous that X is chloro.

One embodiment of the present invention is the aromatic compound (synthetic intermediate) or method according to any one of the above embodiments, wherein R ¹ is C _m F _{2m + 1} (m is an integer). Although not limited thereto, those having m = 1 to 4 are preferably used, and in particular, the —OSO ₂ R ¹ group in which m is 1 or 4, that is, the trifluoromethane / perfluorobutanesulfonic acid group is It is widely used in the field of organic synthetic chemistry, and the present invention can be carried out more easily. Most preferred is a trifluoromethanesulfonic acid group in which m is 1.

One embodiment of the present invention is the aromatic compound (synthetic intermediate) or method of any of the above embodiments, wherein R ¹ is aryl optionally substituted with alkyl. The aromatic compound (synthetic intermediate) or method according to any one of the above embodiments, wherein aryl is benzene or heteroaryl is imidazole. In particular, the -OSO ₂ R ¹ group in which R ¹ is toluenyl, that is, a toluenesulfonic acid group, is widely used in the field of synthetic organic chemistry, and the present invention can be more easily carried out.

In one embodiment of the present invention, the aromatic compound (synthesis intermediate) according to any one of the above embodiments, wherein the alkylsilyl group is a tri-lower alkylsilyl group, particularly a trimethylsilyl group, a triethylsilyl group, or a tert-butyldimethylsilyl group. Or a method. In these embodiments, the reaction can be carried out more reliably and efficiently, but from the viewpoint of reaction efficiency, a trimethylsilyl group or a triethylsilyl group is preferable, and a trimethylsilyl group is more preferable.

In one embodiment of the present invention, lithium amide or an art complex-type double salt of magnesium amide or zinc amide and a lithium salt is magnesium bistetramethylpiperidide.2 lithium salt (Mg (TMP) ₂ .2LiX), Lithium alkylamide, zinc bistetramethylpiperidide dilithium salt (Zn (TMP) ₂ · 2LiX), chloro or bromomagnesium tetramethylpiperidide lithium salt ((TMP) MgX · LiX), or chloro or bromo Zinc tetramethylpiperidide lithium salt ((TMP) ZnX.LiX) is the method according to any of the above embodiments (X is Cl or Br). These strong bases are generally used in the field of organic synthesis, and the reaction of the present invention can be reliably carried out at a lower cost. Among these, Mg (TMP) ₂ · 2LiCl is preferable from the viewpoint of yield, and lithium alkylamide is preferable from the viewpoint of ease of preparation. Examples of lithium alkylamides include, but are not limited to, lithium diisopropylamide (LiN (i-Pr) ₂ ; LDA) and lithium tetramethylpiperidide (Li (TMP)).

The alignment produced from the aromatic compound of the present invention (alignment intermediate compound) reacts with various nucleophiles in a regioselective manner (for example, the meta position relative to the substituent X on the aromatic) to produce a polysubstituted aromatic Give compound. Many reactions are known as reactions using align and nucleophile, and a desired nucleophile and reaction can be used depending on the structure of the target compound. Examples of the reaction include synthesis of polycyclic aromatic rings by Diels-Alder type addition reaction using dienes (eg, cyclopentadiene, cyclohexadiene, anthracene, etc.), and various polycyclic rings by known methods. Synthetic heterocycles (for example, derivatives of isoquinoline, xanthene, coumarin, indoline, chromene, dihydrobenzofuran, benzofuran).

In addition, compounds having F, Cl or Br on the aromatic ring (for example, pharmaceuticals such as efapirenz and sitafuroxane, or agricultural chemicals such as barbamate, cyhalohop butyl and haloxy hop, or derivatives thereof) are produced by the alignment of the present invention. It can also be synthesized utilizing the structure of the intermediate compound.
Moreover, although the actual synthesis example is mentioned later, the synthetic intermediate (tetrahydrobenzodiazepine compound) of a benzodiazepine compound can also be simply synthesize | combined, and it can utilize for the synthesis | combination of various benzodiazepine pharmaceuticals and derivatives.

Furthermore, after introducing substituents via align using the reaction selectivity of the align-forming intermediate compound of the present invention, the substituent X on the aromatic ring is converted to a carbon atom, by various known coupling reactions. By converting to a nitrogen atom, an oxygen atom, etc., a compound having a desired structure can be synthesized by an unprecedented strategy.

It should be noted that the synthetic intermediate compounds and the respective synthesis methods described by the above embodiment are not intended to limit the present invention, but are disclosed for the purpose of illustration. The technical scope of the present invention is defined by the description of the claims, and those skilled in the art can make various design changes within the technical scope of the invention described in the claims.

Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not construed as being limited thereto.

[Synthesis of Aligned Precursor]
Procedure for preparing TMS ether (silyl ether) To a freshly distilled THF (20 mL) solution of the starting phenol compound (20.0 mmol), 1,1,1,3,3,3-hexamethyldisilazane (HMDS) was added. 6.26 mL, 30.0 mmol) was added at room temperature under Ar atmosphere. After stirring at 50 ° C. for 3-12 hours, the reaction mixture was concentrated under reduced pressure. The residue was used in the next reaction without purification.

Reagents MgTMP procedures magnesium metal ₂ · 2LiCl preparation (turnings, 535 mg, 22.0 mmol) of the freshly distilled THF (55 mL) suspension of 1,2-dichloroethane (1.72 mL, 22.0 mmol) Was added at room temperature under an Ar atmosphere and stirred at room temperature for 1 hour to prepare a MgCl ₂ solution. In another two-necked flask, 2,2,6,6-tetramethylpiperidine (TMPH, 7.43 mL, 44.0 mmol) was dissolved in freshly distilled THF (22 mL) at 25 ° C. under an Ar atmosphere. . The solution was cooled to −80 ° C., and n-BuLi (1.6 M hexane solution, 27.5 mL, 44.0 mmol) was added dropwise. After the addition was complete, the reaction mixture was warmed to 0 ° C. and stirred at that temperature for 30 minutes. Then added dropwise the MgCl ₂ solution LiTMP solution, the reaction mixture was stirred for 1 hour at 0 ° _C., was prepared MgTMP 2 · 2LiCl solution.

Preparation of 2-TMS-1-hydroxyallenes (ortho-positioned TMS-modified phenol compound) (1)
MgTMP ₂ · 2LiCl (THF solution, 22.0 mmol or 24.0 mmol) was added to a freshly distilled THF (20 mL) solution of TMS ether (20.0 mmol) at −80 ° C. under Ar atmosphere. After stirring at the same temperature for 1 hour, the reaction mixture was raised to 0 ° C. and stirred at the same temperature for 12 hours. The reaction mixture was diluted with cold 0.5M (+)-sodium tartrate solution and then extracted with hexane or ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (AcOEt: hexane = 0: 1 to 1: 1) to give 2-TMS-1-hydroxyallenes.

Preparation of 2-TMS-1-hydroxyallenes (ortho-positioned TMS-phenol compounds) (2)
To a freshly distilled THF (12 mL) solution of N, N-diisopropylamine (3.4 mL, 24.0 mmol) was added n-BuLi (1.6 M hexane solution, 15.0 mL, 24.0 mmol) at −80 ° C. And dropped in an Ar atmosphere. After the addition was complete, the reaction mixture was warmed to 0 ° C. and stirred at that temperature for 30 minutes to prepare a LiN (i-Pr) ₂ solution. In a separate two-necked flask, the above LiN (i-Pr) ₂ solution was added to a freshly distilled THF (20 mL) solution of TMS ether (20.0 mmol) at −80 ° C. under an Ar atmosphere. After stirring at the same temperature for 1 hour, the reaction mixture was raised to 0 ° C. and stirred at the same temperature for 12 hours. The reaction mixture was diluted with cold saturated brine and then extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (AcOEt: hexane = 0: 1 to 1: 1) to give 2-TMS-1-hydroxyallenes.

Preparation of sulfonate ester (1)
To a solution of 2-TMS-1-hydroxyallenes (6.0 mmol) in anhydrous dichloromethane (15 mL), N, N-diisopropylethylamine (1.20 mL, 6.9 mmol) was added at room temperature under Ar atmosphere. The solution was cooled to −40 ° C. and trifluoromethanesulfonic anhydride or p-toluenesulfonyl chloride (6.6 mmol) was added. After stirring at the same temperature for 3-12 hours, the reaction mixture was diluted with ice water and then extracted with dichloromethane. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (AcOEt: hexane = 0: 1 to 1: 6) to obtain a sulfonic acid ester.

Preparation of sulfonate ester (2)
To a solution of 2-TMS-1-hydroxyallenes (6.0 mmol) in anhydrous pyridine (15 mL), trifluoromethanesulfonic anhydride or p-toluenesulfonyl chloride (6.6 mmol) was added at −20 ° C. in an Ar atmosphere. did. After the addition was complete, the reaction mixture was warmed to 0 ° C. and stirred at the same temperature for 3-12 hours. The reaction mixture was diluted with cold saturated brine and then extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (AcOEt: hexane = 0: 1 to 1: 2) to obtain a sulfonic acid ester.

[Experimental example]
The following align precursors were synthesized according to the above procedure or similar procedures. About the raw material etc. which have no special mention, the commercially available thing was used.

(Synthesis of 3-chloro-aligned precursor)
(Synthesis of silyl ether)
1-Chloro-3- (trimethylsilyloxy) benzene Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.15 (1H, br t, J = 8.0 Hz), 6.95 (1H, ddd, J = 8.0, 2.1, 1.0 Hz), 6.85 (1H, br t, J = 2.1 Hz ), 6.72 (1H, ddd, J = 8.2, 2.1, 1.0 Hz), 0.27 (9H, s).
(Synthesis of phenolic compounds)
3-Chloro-2- (trimethylsilyl) phenol Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.11 (1H, br t, J = 8.0 Hz), 6.91 (1H, d, J = 7.8 Hz), 6.60 (1H, d, J = 8.2 Hz), 5.20 (1H , br s), 0.45 (9H, s).
(Synthesis of Aligned Precursor 1)
3-Chloro-2- (trimethylsilyl) phenyl trifluoromethanesulfonate Colorless oil. . IR (KBr) 2959, 1586 , 1422, 1361 cm -1 1 H-NMR (CDCl 3) δ: 7.37 (1H, dd, J = 7.9, 1.5 Hz), 7.34 (1H, dd, J = 7.9 Hz) , 7.26 (1H, dd, J = 7.9, 1.5 Hz), 0.49 (9H, s) 13 C-NMR δ C:.. 154.5, 142.4, 131.9, 131.2, 129.8, 118.9, 118.6, 1.3 19 F-NMR δ _{F: -73.1 (3F, s)} HRMS (ESI -) calcd for C 7 H 3 35 ClF 3 O 3 S (M-TMS -): 258.9449, Found:. 258.9400; calcd for C 7 H 3 37 ClF 3 O _{3 S (M + 2-TMS} -): 260.9420, Found: 260.9403.
(Synthesis of Aligned Precursor 2)
3-Chloro-2- (trimethylsilyl) phenyl p-toluenesulfonate Colorless crystals. Mp 70-72 ° C (dichloromethane-hexane). IR (KBr) 2956, 2900, 1597, 1581, 1556, 1423, 1374 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 7.70 (2H, br d, J = 8.2 Hz), 7.32 (2H, br d, J = 8.2 Hz), 7.23 (1H, dd, J = 7.8, 1.0 Hz), 7.14 (1H, br t, J = 8.0 Hz), 6.87 (1H, dd , J = 8.2, 1.0 Hz) , 2.45 (3H, s), 0.37 (9H, s) 13 C-NMR δ C:. 154.8, 145.5, 141.9, 132.9, 132.4, 130.5, 129.8, 128.6, 128.5, 119.7, 21.7, 1.4. HRMS (ESI ⁺ ) calcd for C ₁₆ H ₁₉ ³⁵ ClO ₃ SSiNa (M + Na ⁺ ): 377.0405, Found: 377.0351; calcd for C ₁₆ H ₁₉ ³⁷ ClO ₃ SSiNa (M + 2 + Na ⁺ ) : 379.0097, Found: 379.0325.

(Synthesis of 3,5-dichloro-aligned precursor)
(Synthesis of silyl ether)
1,3-Dichloro-5- (trimethylsilyloxy) benzene Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 6.98 (1H, t, J = 1.8 Hz), 6.74 (2H, d, J = 1.8 Hz), 0.28 (9H, s).
(Synthesis of phenolic compounds)
3,5-dichloro-2- (trimethylsilyl) phenol A colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 6.93 (1H, d, J = 1.8 Hz), 6.64 (1H, d, J = 1.8 Hz), 5.77 (1H, br s), 0.43 (9H, s).
(Synthesis of aligned precursors)
3,5-dichloro-2- (trimethylsilyl) phenyl trifluoromethanesulfonate Colorless oil. . IR (KBr) 2959, 1579 , 1538, 1429, 1368 cm -1 1 H-NMR (CDCl 3) δ: 7.39 (1H, d, J = 1.8 Hz), 7.28 (1H, d, J = 1.8 Hz) ^{, 0.48 (9H, s) 13} C-NMR δ C:. 154.2, 142.9, 136.4, 130.5, 129.8, 119.6, 118.5 (q, J = 322 Hz), 1.2 19 F-NMR δ F:. -73.0 (3F ^{, s) HRMS (ESI -)} calcd for C 10 H 10 35 Cl 2 F 3 O 3 SSi (MH -): 364.9456, Found:. 364.9396; calcd for C 10 H 10 35 Cl 37 ClF 3 O 3 SSi (M ^{+ 2-H -): 366.9426} , Found: 366.9345 Calcd for C 7 H 2 35 Cl 2 F 3 O 3 S (M-TMS -): 292.9059, Found:. 292.8981; Calcd for C 7 H 2 35 Cl 37 ClF _{_{3 O 3 S (M + 2}} -TMS -): 294.9093, Found: 294.8974.

(Synthesis of 3-chloro-5-trifluoromethyl-align precursor)
(Synthesis of silyl ether)
1-chloro-3- (trimethylsilyloxy) -5- (trifluoromethyl) benzene colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.22 (1H, br s), 7.00 (1H, t, J = 1.8 Hz), 6.96 (1H, br s), 0.30 (9H, s).
(Synthesis of phenolic compounds)
3-Chloro-5-trifluoromethyl-2- (trimethylsilyl) phenol Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.17 (1H, br s), 6.84 (1H, br s), 0.47 (9H, s); Detection of exchangeable OH group protons was unclear.
(Synthesis of aligned precursors)
3-Chloro-5-trifluoromethyl-2- (trimethylsilyl) phenyl trifluoromethanesulfonate Colorless oil. . IR (KBr) 2961, 1554 , 1449, 1431 cm -1 1 H-NMR (CDCl 3) δ: 7.62 (1H, br d, J = 1.0 Hz), 7.48 (1H, br s), 0.51 (9H, ¹³ C-NMR δ _C : 154.1, 143.3, 136.9, 133.6 (q, J = 35 Hz), 126.5 (q, J = 4 Hz), 122.2 (q, J = 273 Hz), 118.5 (q, . J = 322 Hz), 116.1 , 1.1 19 F-NMR δ F:. -63.9 (3F, s), -72.9 (3F, s) HRMS (ESI -) calcd for C 8 H 2 35 ClF 6 O 3 S ^{(M-TMS -): 326.9323} , Found: 326.9303; calcd for C 8 H 2 37 ClF 6 O 3 S (M + 2-TMS -): 328.9294, Found: 328.9269.

(Synthesis of 4-bromo-3,6-dichloro-align precursor)
(Synthesis of silyl ether)
1-Bromo-2,5-dichloro-4- (trimethylsilyloxy) benzene colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.59 (1H, s), 6.99 (1H, s), 0.30 (9H, s).
(Synthesis of phenolic compounds)
4-Bromo-3,6-dichloro-2- (trimethylsilyl) phenol Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.20 (1H, s), 0.56 (9H, s); Detection of exchangeable OH group protons was unclear.
(Synthesis of aligned precursors)
4-Bromo-3,6-dichloro-2- (trimethylsilyl) phenyl trifluoromethanesulfonate Colorless oil. . IR (KBr) 2961, 2901 , 1552, 1434, 1361 cm -1 1 H-NMR (CDCl 3) δ: 7.47 (1H, s), 0.59 (9H, s) 13 C-NMR δ C:. 145.1, .. 144.6, 135.2, 132.4, 130.0, 124.3, 118.5 (q, J = 322 Hz), 3.6 19 F-NMR δ F: -73.8 (3F, s) HRMS (ESI -) calcd for C 10 H 9 79 Br ^{_{_{_{35 Cl 2 F 3 O 3 SSi}}}} (MH -): 442.8560, Found: 442.8544; calcd for C 10 H 9 BrCl 2 F 3 O 3 SSi (M + 2-H -): 444.8536, Found: 444.8517; calcd for C _{_{_{_{10 H 9 BrCl 2 F 3 O}}}} 3 SSi (M + 4-H -):. 446.8509, Found: 446.8502 Calcd for C 7 H 79 Br 35 Cl 2 F 3 O 3 S (M-TMS -): 370.8164, Found _{: 370.8146; calcd for C 7 HBrCl} 2 F 3 O 3 S (M + 2-TMS -): 372.8140, Found: 372.8121; calcd for C 7 HBrCl 2 F 3 O 3 S (M + 4-TMS -): 374.8113 , Found: 374.8145.

Synthesis of 3-chloro-4-methyl-align precursor
(Synthesis of silyl ether)
2-Chloro-1-methyl-4- (trimethylsilyloxy) benzene A colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.06 (1H, d, J = 8.2 Hz), 6.86 (1H, d, J = 2.5 Hz), 6.65 (1H, dd, J = 8.2, 2.5 Hz), 2.29 ( 3H, s), 0.26 (9H, s).
(Synthesis of phenolic compounds)
3-Chloro-4-methyl-2- (trimethylsilyl) phenol A colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.07 (1H, d, J = 8.2 Hz), 6.56 (1H, d, J = 8.2 Hz), 5.19 (1H, br s), 2.27 (3H, s), 0.46 (9H, s).
(Synthesis of aligned precursors)
3-Chloro-4-methyl-2- (trimethylsilyl) phenyl trifluoromethanesulfonate Colorless oil. . IR (KBr) 2959, 1575 , 1422 cm -1 1 H-NMR (CDCl 3) δ: 7.28 (1H, d, J = 8.2 Hz), 7.15 (1H, d, J = 8.2 Hz), 2.38 (3H , s), 0.49 (9H, s) 13 C-NMR δ C:.. 152.4, 134.2, 136.9, 132.5, 131.9, 118.8, 118.5 (q, J = 323 Hz), 20.7, 1.5 19 F-NMR δ F : -73.0 (3F, t, J = 2 Hz) HRMS (ESI -) calcd for C 8 H 5 35 ClF 3 O 3 S (M-TMS -): 272.9605, Found:. 272.9602; calcd for C 8 H 5 ^{_{_{37 ClF 3 O 3 S (M}}} + 2-TMS -): 274.9577, Found: 274.9544.

(Synthesis of 2-chloro-3,4-align precursor)
(Synthesis of silyl ether)
2-Chloro-3- (trimethylsilyloxy) pyridine colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 8.02 (1H, dd, J = 4.6, 1.8 Hz), 7.18 (1H, dd, J = 7.8, 1.8 Hz), 7.13 (1H, dd, J = 7.8, 4.6 Hz ), 0.31 (9H, s).
(Synthesis of phenolic compounds)
2-Chloro-3-hydroxy-4- (trimethylsilyl) pyridine Colorless solid. . IR (KBr) 3059 (br ), 2958, 2634, 1572, 1394 cm -1 1 H-NMR (CDCl 3) δ: 7.93 (1H, d, J = 4.6 Hz), 7.19 (1H, d, J = . 4.6 Hz), 5.81 (1H , br s), 0.33 (9H s) 13 C-NMR δ C:. 151.8, 140.5, 137.5, 136.7, 128.8, -1.7.
(Synthesis of Aligned Precursor 1)
2-Chloro-4- (trimethylsilyl) pyridin-3-yl trifluoromethanesulfonate colorless crystals. Mp 59-60 ° C (dichloromethane-hexane). IR (KBr) 2960, 2905, 1571, 1507, 1415, 1361 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 8.35 (1H, d, J = 4.6 Hz ), 7.40 (1H, d, J = 4.6 Hz), 0.44 (9H, s) 13 C-NMR δ C:. 148.6, 147.6, 145.2, 144.6, 129.4, 118.5 (q, J = 323 Hz), -0.6 ^{_{.. 19 F-NMR δ F}} : -72.0 (3F, s) HRMS (ESI -) calcd for C 9 H 10 35 ClF 3 NO 3 SSi (MH -): 331.9797, Found: 331.9746; calcd for C 9 H 10 ^{_{_{. 37 ClF 3 NO 3 SSi (}}} M + 2-H -): 333.9769, Found: 333.9715 calcd for C 6 H 2 35 ClF 3 NO 3 S (M-TMS -): 259.9402, Found: 259.9352; calcd for C 6 _{^{_{_{H 2 37 ClF 3 NO 3 S}}}} (M + 2-TMS -): 261.9372, Found: 261.9320.
(Synthesis of Aligned Precursor 2)
2-Chloro-4- (trimethylsilyl) pyridin-3-yl toluenesulfonate Colorless crystals. .. Mp 101-102 ℃ (acetone - hexane) IR (KBr) 2956, 2901 , 1597, 1569, 1362 cm -1 1 H-NMR (CDCl 3) δ: 8.22 (1H, dd, J = 4.6, 1.0 Hz ), 7.81 (2H, br d, J = 8.2 Hz), 7.37 (1H, br d, J = 5.0 Hz), 7.35 (2H, br d, J = 8.2 Hz), 2.47 (3H, s), 0.47 ( ¹³ C-NMR δ _C : 149.4, 146.2, 146.1, 145.8, 145.4, 133.5, 129.8, 129.2, 128.7, 21.8, -0.3.HRMS (ESI ⁺ ) calcd for C ₁₅ H ₁₈ ³⁵ ClNO ₃ SSiNa (M + Na ⁺ ): 378.0357, Found: 378.0302; calcd for C ₁₅ H ₁₈ ³⁷ ClNO ₃ SSiNa (M + 2 + Na ⁺ ): 380.0332, Found: 380.0270.

(Synthesis of 5-chloro-3,4-align precursor)
(Synthesis of silyl ether)
5-Chloro-3- (trimethylsilyloxy) pyridine colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 8.20 (1H, d, J = 1.8 Hz), 8.11 (1H, d, J = 2.3 Hz), 7.17 (1H, t, J = 2.3 Hz), 0.30 (9H, s).
(Synthesis of phenolic compounds)
5-Chloro-3-hydroxy-4- (trimethylsilyl) pyridine Colorless solid. IR (KBr) 3133 (br), 2956, 2790, 2640, 1577, 1465, 1406 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 10.79 (1H, br s), 8.04 (1H, s), 7.99 (1H, s), 0.46 ( 9H, s) 13 C-NMR δ C:. 159.9 (d, J = 7 Hz), 139.1 (br), 139.0 (d, J = 4 Hz), 135.5 (d, J = 6 Hz), 133.2 (d, J = 4 Hz), 1.0.
(Synthesis of aligned precursors)
5-Chloro-4- (trimethylsilyl) pyridin-3-yl trifluoromethanesulfonate Colorless oil. . IR (KBr) 2961, 2905 , 1507, 1429, 1305 cm -1 1 H-NMR (CDCl 3) δ: 8.54 (1H, br s), 8.48 (1H, br s), 0.52 (9H, s). ¹³ C-NMR δ _C : 150.4, 148.8, 141.6, 139.9, 138.7, 118.5 (q, J = 322 Hz), 0.56. ¹⁹ F-NMR δ _F : -72.8 (3F, d, J = 2 Hz). HRMS ^{_{(ESI -) calcd for C 9}} H 10 35 ClF 3 NO 3 SSi (MH -): 331.9797, Found: 331.9804; calcd for C 9 H 10 37 ClF 3 NO 3 SSi (M + 2-H -): 333.9769, _{. Found: 333.9732 calcd for C 6} H 2 35 ClF 3 NO 3 S (M-TMS -): 259.9402, Found: 259.9407; calcd for C 6 H 2 37 ClF 3 NO 3 S (M + 2-TMS -): 261.9372, Found: 261.9385.

(Synthesis of 2-chloro-3,4-align precursor)
(Synthesis of silyl ether)
2-Chloro-4- (trimethylsilyloxy) pyridine colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 8.17 (1H, d, J = 5.5 Hz), 6.79 (1H, d, J = 2.3 Hz), 6.69 (1H, dd, J = 5.5, 2.3 Hz), 0.33 ( 9H, s).
(Synthesis of phenolic compounds)
2-Chloro-4-hydroxy-3- (trimethylsilyl) pyridine colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.91 (1H, d, J = 6.0 Hz), 6.57 (1H, d, J = 6.0 Hz), 0.44 (9H, s); Detection of exchangeable OH group protons is It was unclear.
(Synthesis of aligned precursors)
2-Chloro-3- (trimethylsilyl) pyridin-4-yl trifluoromethanesulfonate Colorless oil. . IR (KBr) 2960, 2904 , 1567, 1541, 1427, 1335 cm -1 1 H-NMR (CDCl 3) δ: 8.43 (1H, d, J = 5.5 Hz), 7.29 (1H, d, J = 5.5 Hz), 0.50 (9H, s ) 13 C-NMR δ C:. 162.1, 159.0, 151.5, 127.4, 118.4 (q, J = 323 Hz), 113.7, 0.9 19 F-NMR δ F:. -73.0 (3F ^{, s) HRMS (ESI -)} calcd for C 9 H 10 35 ClF 3 NO 3 SSi (MH -): 331.9797, Found:. 331.9812; calcd for C 9 H 10 37 ClF 3 NO 3 SSi (M + 2-H ^{-): 333.9769, Found: 333.9804} calcd for C 6 H 2 35 ClF 3 NO 3 S (M-TMS -): 259.9401, Found:. 259.9407; calcd for C 6 H 2 37 ClF 3 NO 3 S (M + 2 ^{-TMS -): 261.9372, Found:} 261.9376.

[Synthesis of 3-fluoro-aligned precursor]
(Synthesis of silyl ether)
1-Fluoro-3- (trimethylsilyloxy) benzene A colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.17 (1H, td, J = 8.2, 7.8 Hz), 6.68 (1H, tdd, J = 8.2, 2.3, 1.0 Hz), 6.62 (1H, br dd, J = 8.2 , 2.3 Hz), 6.56 (1H, dt, J = 10.6, 2.3 Hz), 0.27 (9H, s).
(Synthesis of phenolic compounds)
3-Fluoro-2- (trimethylsilyl) phenol colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.16 (1H, td, J = 8.2, 6.9 Hz), 6.57 (1H, td, J = 8.2, 1.0 Hz), 6.48 (1H, dd, J = 8.2, 1.0 Hz) ), 5.15 (1H, br s), 0.37 (9H, d, J = 1.8 Hz).
(Synthesis of aligned precursors)
3-Fluoro-2- (trimethylsilyl) phenyl trifluoromethanesulfonate Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.41 (1H, td, J = 8.2, 6.4 Hz), 7.16 (1H, br d, J = 8.7 Hz), 7.03 (1H, td, J = 8.2, 1.0 Hz) , 0.42 (9H, d, J = 1.8 Hz) 13 C-NMR δ C:. 167.3 (d, J = 247 Hz), 154.1 (d, J = 15 Hz), 131.9 (d, J = 11 Hz), 120.3 (d, J = 35 Hz), 118.5 (q, J = 322 Hz), 166.1 (br), 115.1 (d, J = 27 Hz), 0.3 (d, J = 4 Hz). ¹⁹ F-NMR δ _{F: -73.5 (3F, s)} -94.1 (1F, m) HRMS (ESI -) calcd for C 7 H 3 F 4 O 3 S (M-TMS -):.. 242.9745, Found: 242.9793.

Synthesis of 3-fluoro-6-methoxy-align precursor
(Synthesis of silyl ether)
1-Fluoro-4-methoxy-3- (trimethylsilyloxy) benzene Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 6.77 (1H, dd, J = 8.8, 5.6 Hz), 6.63-6.59 (2H, m), 3.78 (3H, s), 0.25 (9H, s).
(Synthesis of phenolic compounds)
5-Fluoro-2-methoxy-6- (trimethylsilyl) phenol Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 6.77 (1H, dd, J = 8.7, 5.0 Hz), 6.47 (1H, t, J = 8.7 Hz), 5.97 (1H, br d, J = 1.4 Hz), 3.85 (3H, s), 0.35 (9H, d, J = 1.8 Hz).
(Synthesis of aligned precursors)
5-Fluoro-2-methoxy-6- (trimethylsilyl) phenyl trifluoromethanesulfonate colorless crystals. Mp 21-23 ° C (Hexane). IR (KBr) 2960, 1578, 1464, 1417 cm ⁻¹ . ¹ H-NMR (CDCl ₃ ) δ: 7.00 (1H, dd, J = 9.2, 7.6 Hz), 6.97 ( 1H, dd, J = 9.2, 5.5 Hz), 3.84 (3H, s), 0.43 (9H, d, J = 1.8 Hz) 13 C-NMR δ C:. 160.1 (d, J = 239 Hz), 147.3 ( d, J = 3 Hz), 141.6 (d, J = 15 Hz), 122.8 (d, 35 Hz), 118.8 (q, J = 323 Hz), 115.2 (d, J = 29 Hz), 114.3 (d, . J = 10 Hz), 56.1 , 0.3 (d, J = 4 Hz) 19 F-NMR δ F:. -71.9 (3F, m), -105.9 (1F, m) HRMS (ESI -) calcd for C 11 _{_{_{H 13 F 4 O 4 SSi (}}} MH -):. 345.0245, Found: 345.0236 Calcd for C 8 H 5 F 4 O 4 S (M-TMS -): 272.9850, Found: 272.9844.

(Synthesis of 3,4,5-trifluoro-aligned precursor)
(Synthesis of silyl ether)
1,2,3-Trifluoro-5- (trimethylsilyloxy) benzene Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 6.44 (2H, m), 0.26 (9H, s).
(Synthesis of phenolic compounds)
3,4,5-trifluoro-2- (trimethylsilyl) phenol Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 6.34 (1H, ddd, J = 11.0, 5.0, 2.3 Hz), 5.52 (1H, br s), 0.36 (9H, d, J = 1.8 Hz).
(Synthesis of aligned precursors)
3,4,5-trifluoro-2- (trimethylsilyl) phenyl trifluoromethanesulfonate Colorless oil. . IR (KBr) 2963, 1626 , 1496, 1430 cm -1 1 H-NMR (CDCl 3) δ: 7.06 (1H, ddd, J = 9.6, 5.0, 2.3 Hz), 0.43 (9H, d, J = 1.8 ¹³ C-NMR δ _C : 155.0 (ddd, J = 247, 10, 5 Hz), 151.3 (ddd, J = 255, 12, 6 Hz), 147.1 (ddd, J = 16, 12, 5 Hz ), 139.3 (ddd, J = 257, 20, 14 Hz), 118.4 (q, J = 322 Hz), 118.3 (dt, J = 31, 4 Hz), 106.5 (d, J = 21 Hz), 0.2 ( ¹⁹ F-NMR δ _F : -73.4 (3F, s), -117.4 (1F, ddd, J = 23, 7, 2 Hz), -129.6 (1F, dt, J = 20 , 10 Hz), -160.1 (1F , ddd, J = 23, 20, 5 Hz) HRMS (ESI -) calcd for C 10 H 9 F 6 O 3 SSi (MH -):.. 350.9951, Found: 350.9825 calcd _{_{_{for C 7 HF 6 O 3 S}}} (M-TMS -): 278.9556, Found: 278.9551.

(Synthesis of 3-bromo-aligned precursor)
(Synthesis of silyl ether)
1-Bromo-3- (trimethylsilyloxy) benzene colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.09 (2H, m), 7.01 (1H, br t, J = 1.6 Hz), 6.76 (1H, m), 0.27 (9H, s).
(Synthesis of phenolic compounds)
3-Bromo-2- (trimethylsilyl) -phenol colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.13 (1H, dd, J = 7.8, 1.0 Hz), 7.03 (1H, br t, J = 7.8 Hz), 6.64 (1H, dd, J = 7.8, 1.0 Hz) , 5.35 (1H, br s), 0.48 (9H, s).
(Synthesis of aligned precursors)
3-Bromo-2- (trimethylsilyl) phenyl trifluoromethanesulfonate Colorless oil. . IR (KBr) 2960, 1583 , 1552, 1421 cm -1 1 H-NMR (CDCl 3) δ: 7.58 (1H, dd, J = 7.8, 1.4 Hz), 7.34-7.23 (2H, m), 0.52 ( ^{... 9H, s) 13} C-NMR δ C: 155.2, 134.9, 134.4, 132.3, 132.2, 120.4, 119.4, 2.5 19 F-NMR δ F: -73.1 (3F, s) HRMS (ESI -) calcd for _{_{^{_{C 10 H 11 79 BrF 3 O}}}} 3 SSi (MH -): 374.9339, Found:. 374.9281; calcd for C 10 H 11 81 BrF 3 O 3 SSi (M + 2-H -): 376.9319, Found: 376.9253 calcd for _{_{^{_{C 7 H 3 79 BrF 3 O}}}} 3 S (M-TMS -): 302.8944, Found: 302.8868; calcd for C 7 H 3 81 BrF 3 O 3 S (M + 2-TMS -): 304.8923, Found: 304.8881.

[Examination of strong bases in the alignment precursor synthesis reaction]
With respect to the synthesis reaction of the above-mentioned 3-chloroaline precursor (reaction from the following silyl ether (2) to the phenol compound (3)), the yield when each strong base was used was examined, and the results are shown in Table 1 below. It was shown to.
As shown in Table 1, Mg (TMP) ₂ · 2LiCl had the best yield. On the other hand, the target phenol (3) could be obtained in a moderate yield by using this reaction even with LDA which was easily prepared.

(The reaction time was about 6 to 16 hours for (1) → (2) and about 16 hours for (2) → (3).)

[Generating Alignment from Aligned Precursor]
Regarding the generation of alignment from the align precursor, for example, alignment can be easily generated under mild conditions by reacting with fluoride ions according to a known method such as the method described in Non-Patent Document 5. . In addition, the generated alignment reacts with various nucleophiles in a regioselective manner to give a polysubstituted aromatic compound. As described in Non-Patent Document 5, many reactions are known for the reaction using align and nucleophile, and a desired nucleophile and reaction may be used depending on the structure of the target compound. it can.
Examples of typical alignment generating reactions and generated alignment reactions are shown below, but the present invention is not limited thereto, and alignment is generated according to a known method such as Non-Patent Document 5, This can be used.

[Comparison with conventional align precursors]

In the drawing, the conventional align precursor compound is indicated by 1a, and the align precursor compound of the present invention is indicated by 1b.
In generating alignment from 1a and b, it has been reported that the conventional alignment precursor compound 1a produces a dimer 2a in which a rearrangement produced as a side reaction reacts with the desired 3-chloroalignment. (Non-patent document 8). On the other hand, from the alignment precursor compound 1b of the present invention, the generated alignment reacts with acetonitrile as a solvent without generating the dimer 2b via the side reaction even under the same experimental conditions, 3 and 4 occurred.

N- (3-chlorophenyl) acetamide: Compound 3
Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.62 (1H, s), 7.34 (1H, d, J = 7.8 Hz), 7.27 (1H, br s), 7.23 (1H, t, J = 7.8 Hz), 7.08 (1H, d, J = 7.8 Hz), 2.18 (3H, s) 13 C-NMRδ C:.. 168.3, 139.0, 134.6, 130.0, 124.3, 119.8, 117.7, 24.6 HRMS (ESI +) calcd for C 8 H ₈ ³⁵ ClNONa (M + Na ⁺ ): 192.0187, Found: 192.0191; calcd for C ₈ H ₈ ³⁷ ClNONa (M + 2 + Na ⁺ ): 194.0159, Found: 194.0169.
N, N-bis (3-chlorophenyl) acetamide: Compound 4
Colorless oil. ^{_{1 H-NMR (CDCl 3)}} δ: 7.32-7.25 (6H, br m), 7.16 (2H, br d, J = 7.8 Hz), 2.07 (3H, s) 13 C-NMRδ C:. 170.1, 154.6 ( br), 135.0 (br), 130.4 (br), 127.6 (br), 125.4 (br), 23.8; One aryl carbon peak was missing due to overlapping with other aryl carbon peak.HRMS (ESI ⁺ ) calcd for C ₁₄ H ₁₁ ³⁵ Cl ₂ NONa (M + Na ⁺ ): 302.0110, Found: 302.0123; calcd for C ₁₄ H ₁₁ ³⁵ Cl ³⁷ ClNONa (M + 2 + Na ⁺ ): 304.0082, Found: 304.0087.

Moreover, when generating alignment from 1a and b by a reaction different from the above, it was reported that compound 5 as a result of reaction of the generated alignment was obtained from conventional alignment precursor compound 1a in a yield of 41%. (Non-Patent Document 3). On the other hand, when the align precursor 1b of the present invention was used, Compound 5 was obtained in a higher yield (91%) using the same experimental conditions.
(2-Chloro-6-fluorophenyl) tributyltin: Compound 5
Colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 7.20 (1H, td, J = 7.8, 6.9 Hz), 7.13 (1H, d, J = 7.8 Hz), 6.88 (1H, br t, J = 7.8 Hz), 1.58 -1.48 (6H, m), 1.33 (6H, sex, J = 7.3 Hz), 1.28-1.12 (6H, m), 0.89 (9H, t, J = 7.3 Hz). ¹³ C-NMRδ _C : 167.3 (d , J = 240 Hz), 142.7 (d, J = 17 Hz), 130.9 (d, J = 9 Hz), 128.6 (d, J = 50 Hz), 124.8 (d, J = 3 Hz), 112.7 (d , J = 30 Hz), 28.9 (t, J = 10 Hz), 27.2 (t, J = 33 Hz), 13.6, 12.0 (d, J = 3 Hz). ¹⁹ F-NMR δ _F : -91.0 (1F , t, J = 7 Hz) HRMS (ESI -) calcd for C 14 H 21 35 ClFSn (M-Bu -): 363.0339, Found:. 363.0352; calcd for C 14 H 21 37 ClFSn (M + 2-Bu - ): 365.0330, Found: 365.0375.

As described above, it was confirmed that the alignment precursor compound of the present invention has higher reaction selectivity and yield when producing alignment, compared with the alignment precursor compound having a conventional structure.

[Alignment generation and alignment reaction (amine addition reaction)]
To a solution of CsF (91 mg, 0.60 mmol) in anhydrous acetonitrile (2 mL), secondary amine (0.40 mmol) was added at room temperature under Ar atmosphere. Then, the triflate compound (0.20 mmol) which is the align precursor compound of this invention was added, and it stirred at the same temperature for 3 hours. The reaction mixture was diluted with ice water and then extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC (AcOEt: hexane = 1: 10 to 1: 2) to obtain an amine adduct.
[Experimental example]
According to the above procedure or a procedure similar thereto, the alignment reaction was performed so as to obtain the following product. About the raw material etc. without special mention, the commercially available thing was used.

1- (3-Chlorophenyl) pyrrolidine (the ratio of this product: addition reaction regioisomer = 88: 12)
Colorless oil. . IR (KBr) 2969, 2839 , 1596, 1497, 1485 cm -1 1 H-NMR (CDCl 3) δ: 7.12 (1H, t, J = 8.2 Hz), 6.62 (1H, ddd, J = 7.8, 1.8 , 1.0 Hz), 6.53 (1H, br t, J = 2.1 Hz), 6.43 (1H, dd, J = 8.2, 2.3 Hz), 3.26 (4H, br t, J = 6.7 Hz), 2.01 (4H, m ¹³ C-NMRδ _C : 148.8, 134.9, 129.9, 115.0, 111.3, 109.8, 47.5, 25.4.HRMS (ESI ⁺ ) calcd for C ₁₀ H ₁₃ ³⁵ ClN (M + H ⁺ ): 182.0731, Found: 182.0748; calcd for C ₁₀ H ₁₃ ³⁷ ClN (M + 2 + H ⁺ ): 184.0703, Found: 184.0720.

1- (2-Chlorophenyl) pyrrolidine colorless oil. . IR (KBr) 2969, 2874 , 1592, 1481, 1440 cm -1 1 H-NMR (CDCl 3) δ: 7.29 (1H, dd, J = 7.8, 1.4 Hz), 7.14 (1H, ddd, J = 8.2 , 7.3, 1.4 Hz), 6.89 (1H, dd, J = 8.2, 1.4 Hz), 6.78 (1H, br td, J = 7.6, 1.4 Hz), 3.37 (4H, m), 1.95 (4H, m). ¹³ C-NMRδ _C : 147.1, 131.2, 127.1, 123.4, 120.1, 117.0, 30.69, 25.2.HRMS (ESI ⁺ ) calcd for C ₁₀ H ₁₃ ³⁵ ClN (M + H ⁺ ): 182.0731, Found: 182.0693; calcd for C ₁₀ H ₁₃ ³⁷ ClN (M + 2 + H ⁺ ): 184.0703, Found: 184.0749.

1- (3,5-dichlorophenyl) pyrrolidine white solid. . IR (KBr) 2971, 2846 , 1585, 1551, 1475, 1461 cm -1 1 H-NMR (CDCl 3) δ: 6.60 (1H, t, J = 1.8 Hz), 6.38 (2H, d, J = 1.8 Hz), 3.24 (4H, m ), 2.01 (4H, m) 13 C-NMRδ C:.. 149.0, 135.2, 114.8, 109.8, 47.6, 25.4 HRMS (ESI +) calcd for C 10 H 12 35 Cl 2 N (M + H ⁺ ): 216.0341, Found: 216.0204; calcd for C ₁₀ H ₁₂ ³⁵ Cl ³⁷ ClN (M + 2 + H ⁺ ): 218.0313, Found: 218.0238.

[Alignment generation and alignment reaction ([3 + 2] cycloaddition reaction)]
To a solution of CsF (76 mg, 0.50 mmol) in anhydrous acetonitrile (2 mL), an azide compound (0.20 mmol) was added at room temperature under Ar atmosphere. Then, the triflate compound (0.20 mmol) which is the align precursor compound of this invention was added, and it stirred at the same temperature for 3 hours. The reaction mixture was diluted with ice water and then extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC (AcOEt: hexane = 1: 6) to obtain a benzotriazole derivative.
[Experimental example]
According to the above procedure or a procedure similar thereto, the alignment reaction was performed so as to obtain the following product. About the raw material etc. which have no special mention, the commercially available thing was used.

1-Benzyl-4-chloro-1,2,3-benzotriazole colorless crystals. Mp 78-80 ° C (AcOEt-hexane). IR (KBr) 3067, 3033, 1609, 1581, 1494, 1454, 1424 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 7.37-7.23 (8H, m) ^{, 5.86 (2H, s) 13} C-NMRδ C:.. 144.0, 134.2, 134.1, 129.1, 128.6, 127.9, 127.6, 125.5, 123.8, 108.5, 52.7 HRMS (ESI +) calcd for C 13 H 11 35 ClN 3 (M + H ⁺ ): 244.0636, Found: 244.0637; calcd for C ₁₃ H ₁₁ ³⁷ ClN ₃ (M + 2 + H ⁺ ): 246.0609, Found: 246.0610.

[Alignment generation and alignment reaction (three-component ligation reaction)]
To a solution of CsF (91 mg, 0.60 mmol) in anhydrous DMF (2 mL), an active methylene compound (0.30 mmol) was added at room temperature under Ar atmosphere. Then, the triflate compound (0.20 mmol) which is the align precursor compound of this invention was added, and it stirred at the same temperature for 3 hours. The reaction mixture was diluted with ice water and then extracted with ethyl acetate. The organic phase was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by preparative TLC (AcOEt: hexane = 1: 6 to 1: 1) to obtain coumarins.
(Basic skeleton of Coumarin)

[Experimental example]
According to the above procedure or a procedure similar thereto, the alignment reaction was performed so as to obtain the following product. About the raw material etc. which have no special mention, the commercially available thing was used.

5-chloro-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester pale yellow crystals. .. Mp 140-143 ℃ (AcOEt- hexane) IR (KBr) 3087, 2980 , 1766, 1719, 1595, 1562, 1451 cm -1 1 H-NMR (CDCl 3) δ: 8.84 (1H, s), 7.55 (1H, t, J = 8.2 Hz), 7.37 (1H, dd, J = 8.2, 1.0 Hz), 7.26 (1H, br d, J = 8.7 Hz), 4.43 (2H, q, J = 7.1 Hz), 1.41 (3H, t, J = 7.1 Hz) 13 C-NMRδ C:.. 162.7, 155.9, 155.8, 144.6, 134.2, 134.0, 125.4, 119.0, 116.6, 115.6, 62.2, 14.2 HRMS (ESI +) calcd for C ₁₂ H ₉ ³⁵ ClO ₄ Na (M + Na ⁺ ): 275.0082, Found: 275.0121; calcd for C ₁₂ H ₉ ³⁷ ClO ₄ Na (M + 2 + Na ⁺ ): 277.0056, Found: 277.0065.

5-Fluoro-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester Pale yellow crystals. Mp 124-126 ° C (dichloromethane-hexane). ¹ H-NMR (CDCl ₃ ) δ: 8.73 (1H, s), 7.60 (1H, br td, J = 8.4, 6.0 Hz), 7.16 (1H, br d, J = 8.2 Jz ), 7.04 (1H, br t , J = 8.4 Hz), 4.43 (2H, q, J = 7.2 Hz), 1.42 (3H, t, J = 7.2 Hz) 13 C-NMRδ C:. 162.6, 159.3 (d , J = 260 Hz), 155.9, 155.4 (d, J = 5 Hz), 141.4 (d, J = 4 Hz), 134.9 (d, J = 11 Hz), 118.4, 112.6 (d, J = 4 Hz) , 110.6 (d, J = 19 Hz), 108.3 (d, J = 18 Hz), 62.2, 14.2. ¹⁹ F-NMRδ _F : -117.0 (1F, dd, J = 9, 6 Hz). HRMS (ESI ⁺ ) calcd for C ₁₂ H ₉ FO ₄ Na (M + Na ⁺ ): 259.0377, Found: 259.0372.

5-Bromo-2-oxo-2H-1-benzopyran-3-carboxylic acid, ethyl ester brown crystals. Mp 113-114 ° C (dichloromethane-hexane). ¹ H-NMR (CDCl ₃ ) δ: 8.82 (1H, s), 7.56 (1H, d, J = 8.2 Hz), 7.48 (1H, t, J = 8.2 Hz), 7.32 ( 1H, d, J = 8.2 Hz ), 4.44 (2H, q, J = 7.2 Hz), 1.42 (3H, t, J = 7.2 Hz) 13 C-NMRδ C:. 162.7, 156.1, 155.7, 147.1, 134.5, 128.9, 123.9, 119.4, 118.1, 116.3, 62.3, 14.2.HRMS (ESI ⁺ ) calcd for C ₁₂ H ₉ ⁷⁹ BrO ₄ Na (M + Na ⁺ ): 318.9576, Found: 318.9597; calcd for C ₁₂ H ₉ ⁸¹ BrO ₄ Na (M + 2 + Na ⁺ ): 320.9557, Found: 320.9584.

[Alignment generation and alignment reaction (benzodiazepine compounds)]
To a solution of CsF (91 mg, 0.60 mmol) in anhydrous DMI (1 mL), the triflate compound (0.20 mmol), which is an align precursor compound of the present invention, was added and stirred at the same temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, MgSO ₄ was added, and filtered to obtain an organic phase. This was concentrated under reduced pressure, and the residue was purified by preparative TLC (AcOEt: hexane = 2: 1) to obtain benzodiazepines.
(An example of the basic skeleton of benzodiazepine)

[Experimental example]
According to the above procedure or a procedure similar thereto, the alignment reaction was performed so as to obtain the following product. About the raw material etc. without special mention, the commercially available thing was used.

6-chloro-1,2,3,4-tetrahydro-1,4-dimethyl-5H-1,4-benzodiazepin-5-one colorless crystals. Mp 166-168 ¹ H-NMR (CDCl ₃ ) δ: 7.23 (1H, br t, J = 8.0 Hz), 7.06 (1H, dd, J = 7.8, 1.0 Hz), 6.81 (1H, d, J = 7.8 Hz), 3.41 ( 2H, br m), 3.22 (3H, s), 3.18 (2H, br m), 2.79 (3H, s) 13 C-NMRδ C:. 167.1, 148.1, 132.7, 131.0, 128.8, 124.1, 116.2, 57.1, 47.8, 10.1, 33.4.HRMS (ESI ⁺ ) calcd for C ₁₁ H ₁₄ ³⁵ ClN ₂ O (M + H ⁺ ): 225.0789, Found: 225.0734; calcd for C ₁₁ H ₁₄ ³⁷ ClN ₂ O (M + 2 + H ⁺ ): 227.0762, Found: 227.0693.

6-Chloro-8-trifluoromethyl-1,2,3,4-tetrahydro-1,4-dimethyl-5H-1,4-benzodiazepin-5-one colorless crystals. Mp 139-140 ° C (dichloromethane-hexane). ¹ H-NMR (CDCl ₃ ) δ: 7.31 (1H, br d, J = 1.0 Hz), 7.01 (1H, br s) 3.44 (2H, br s), 3.24 (2H, br s), 3.22 (3H, s ), 2.84 (3H, s) 13 C-NMRδ C:. 165.9, 148.4, 133.7, 133.2 (q, J = 33 Hz), 131.5, 123.1 (q, J = 274 Hz) , 120.6 (q, J = 4 Hz), 113.1 (q, J = 4 Hz), 56.9, 47.6, 10.1, 33.5. ¹⁹ F-NMR δ _F : -63.7 (3F, s). HRMS (ESI ⁺ ) calcd for C ₁₂ H ₁₂ ³⁵ ClF ₃ N ₂ ONa (M + Na ⁺ ): 315.0482, Found: 315.0502; calcd for C ₁₂ H ₁₂ ³⁷ ClF ₃ N ₂ ONa (M + 2 + Na ⁺ ): 317.0456, Found: 317.0473 .

In the above, this invention was demonstrated based on the Example. It is to be understood by those skilled in the art that this embodiment is merely an example, and that various modifications are possible and that such modifications are within the scope of the present invention.
It should be noted that the disclosures of patents, patent applications, and publications cited in this specification are all incorporated herein by reference.

Alignment produced according to the present invention can react regioselectively with various nucleophiles to give various substituted aromatic compounds and polycyclic aromatic compounds. Therefore, the present invention can be used in various fields such as synthesis of functional molecules such as biologically active substances, pharmaceuticals, pharmaceutical intermediates, and electronic device materials (insulating films).

Claims

An aromatic compound having a —H (hydrogen) group, a trialkylsilyloxy group, and a —X group [X is F, Cl, or Br] at both positions adjacent to the —H group is Reacting with an amide, or an art complex type double salt of magnesium amide or zinc amide and a lithium salt,
A trialkylsilyl group, and a -OSO 2 R 1 group [R 1 is C m F 2m + 1 (m is an integer) or an aryl or hetero group optionally substituted with an alkyl at both adjacent positions adjacent to the trialkylsilyl group. A method for synthesizing an aromatic compound having an aryl group] and an —X group [X is F, Cl, or Br].
The method according to claim 1, wherein the ring to which the trialkylsilyl group, -OSO 2 R 1 group and -X group are directly bonded is a carbon 6-membered ring.
The aromatic compound is an aromatic compound in which the trialkylsilyl group, —OSO 2 R 1 group, and —X group are bonded to optionally substituted benzene, naphthalene, indole, quinoline, isoquinoline, or benzofuran. The method according to claim 1 or 2.
A trialkylsilyl group, and a -OSO 2 R 1 group [R 1 is C m F 2m + 1 (m is an integer) or an aryl or hetero group optionally substituted with an alkyl at both adjacent positions adjacent to the trialkylsilyl group. Is an aryl group] and -X group [X is F, Cl or Br], wherein the trialkylsilyl group, -OSO 2 R 1 group and -X group are directly bonded An aromatic compound in which the ring is a six-membered carbon ring.
5. The aromatic compound according to claim 4, wherein the trialkylsilyl group, —OSO 2 R 1 group, and —X group are bonded to optionally substituted benzene, naphthalene, indole, quinoline, isoquinoline, or benzofuran. Aromatic compounds.
An intermediate for the production of an align consisting of the compound according to claim 4 or 5.
A method for producing alignment, comprising reacting the compound according to claim 4 or 5 with fluoride ions.