KR102779378B1 - 1-allylisochroman derivatives and preparing method thereof - Google Patents

Abstract

The present invention relates to a method for producing a 1-allyl isochromane derivative using a DDQ/TBN system, and according to the method, an allyl isochromane derivative having regioselectivity can be produced in excellent yield through hydride abstraction in an environmentally friendly manner without a metal catalyst.

Description

{1-allylisochroman derivatives and preparing method thereof}

The present invention relates to a 1-allylisochromane derivative and a method for producing the same.

Metal catalysts exhibit high catalytic activity, but they are expensive, and metal ions often contain air and moisture, making them unstable in the reaction environment. In addition, when using metal catalysts, a small amount of metal may remain in the product, and environmental pollution problems may occur due to disposal after use. Therefore, research on stereoselective synthesis using organic catalysts is attracting attention to overcome these shortcomings. Organic catalysts generally contain carbon, hydrogen, nitrogen, etc., and are structurally different from metal catalysts containing metal cores and ligands.

Isochroman can be usefully utilized as an intermediate product of various biologically active substances and therapeutic agents, or an intermediate product for polymeric materials such as industrial resins, and additionally as a stabilizer of organic materials such as fats and fatty oils and synthetic resins.

Under these circumstances, the inventors of the present invention developed a method for substituting an allylic group at position 1 of an isochromane derivative in an environmentally friendly manner without a metal catalyst using a DDQ/TBN catalyst system, thereby completing the present invention.

The purpose of the present invention is to provide a method for producing an allyl isochroman derivative using DDQ/TBN.

Another object of the present invention is to provide an allyl isochroman derivative manufactured by the above manufacturing method.

However, the technical problems to be achieved by the present invention are not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

In order to solve the above problem, the present invention can provide a method for producing an allyl isochromane derivative, including the step of producing a compound represented by [Chemical Formula 2] from a compound represented by [Chemical Formula 1] using DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and TBN (tert-butyl nitrite).

[Chemical Formula 1]

;

[Chemical formula 2]

;

In the above chemical formulas 1 and 2,

A is a C ₃ -C ₁₂ aryl group or heteroaryl group, and at least one hydrogen of the aryl group or heteroaryl group is unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a _hydroxy group, a C 1 -C ₆ chain alkyl group, a C ₁ -C ₆ alkoxy group, and a -OC(O)R ₂ group,

R ₁ is at least one selected from the group consisting of hydrogen, a halogen group, a hydroxy group, a C ₁ -C ₆ chain alkyl group, and a C ₁ -C ₆ alkoxy group,

R ₂ is a C ₁ -C ₆ chain alkyl group,

n can be an integer from 0 to 5.

As one embodiment of the present invention, the manufacturing method may form a compound represented by the following [chemical formula 1'] as an intermediate, i.e., an oxonium ion.

[Chemical formula 1']

;

In the above chemical formula 1', A, R ₁ , and R ₂ are as defined in chemical formulas 1 and 2.

As another embodiment of the present invention, the manufacturing method may be a method of treating DDQ and TBN under oxygen (O ₂ ) conditions. An oxygen balloon (O ₂ balloon) or oxygen bubbling (O ₂ bubbling) may be used to form the oxygen conditions.

As another embodiment of the present invention, the manufacturing method may introduce an allyl group by adding allyltributyl stannane (allyl-SnBu ₃ ).

As another embodiment of the present invention, the manufacturing method may be a method of adding Brønsted acids and additives together with allyltributylstenine.

In another embodiment of the present invention, the acid may be at least one selected from the group consisting of methanesulfonic acid (MSA), trifluoroacetic acid (TFA), chlorobenzenesulfonic acid (CBSA), p-toluenesulfonic acid (PTSA), and combinations thereof, but is not limited thereto.

In another embodiment of the present invention, the additive may be at least one selected from the group consisting of LiPF ₆ , LiClO ₄ , and combinations thereof, but is not limited thereto.

As another embodiment of the present invention, the manufacturing method may be performed in an aprotic polar solvent, a protic polar solvent, or a nonpolar solvent. Non-specific examples of the solvent include, but are not limited to, at least one selected from the group consisting of dichloroethane (DCE), dichloromethane (DCM), tetrahydrofuran (THF), acetone, DMSO, acetonitrile (MeCN), diethyl ether (Et ₂ O), water (H ₂ O), alcohol, toluene, hexane, carbon tetrachloride (CCl ₄ ), and combinations thereof.

As another embodiment of the present invention, the manufacturing method may add DDQ in an amount of 10 to 30 mol%, preferably 20 mol%.

As another embodiment of the present invention, the manufacturing method may be performed within one reactor, i.e., it may be a one-pot process.

As another embodiment of the present invention, the compound represented by the above [Chemical Formula 1] may be at least one selected from the group consisting of compounds represented by the following [Chemical Formula 1-1] to [Chemical Formula 1-16], but is not limited thereto.

(1) Isochroman;

(2) 7-methylisochroman;

(3) 4-methylisochroman;

(4) 3-methylisochroman;

(5) 7-methoxyisochroman;

(6) 6-methoxyisochroman;

(7) 6,7-Dimethoxyisochroman;

(8) 7-Fluoroisochroman;

(9) 7-chloroisochroman;

(10) 7-bromoisochroman;

(11) 6-Fluoroisochroman;

(12) 6-chloroisochroman;

(13) Isochroman-7-yl acetate;

(14) 1,4-Dihydro-2 H -benzo[f]isochroman;

(15) 1,3-dihydroisobenzofuran; and

(16) 4,7-Dihydro-5 H -thieno[2,3-c]pyran.

As another embodiment of the present invention, the compound represented by the above [Chemical Formula 2] may be at least one selected from the group consisting of compounds represented by the following [Chemical Formula 2-1] to [Chemical Formula 2-16], but is not limited thereto.

(1) 1-allylisochroman;

(2) 1-Allyl-7-methylisochroman;

(3) 1-Allyl-4-methylisochroman;

(4) 1-Allyl-3-methylisochroman;

(5) 1-Allyl-7-methoxyisochroman;

(6) 1-Allyl-6-methoxyisochroman;

(7) 1-Allyl-6,7-dimethoxyisochroman;

(8) 1-Allyl-7-fluoroisochroman;

(9) 1-Allyl-7-chloroisochroman;

(10) 1-Allyl-7-bromoisochroman;

(11) 1-Allyl-6-fluoroisochroman;

(12) 1-Allyl-6-chloroisochroman;

(13) 1-Allylisochroman-7-yl acetate;

(14) 4-Allyl-1,4-dihydro-2 H -benzo[f]isochroman;

(15) 1-allyl-1,3-dihydroisobenzofuran; and

(16) 7-Allyl-4,7-dihydro-5 H -thieno[2,3-c]pyran.

A method for producing an allyl isochroman derivative according to one embodiment of the present invention can produce an allyl isochroman derivative with excellent yield and regioselectivity in an environmentally friendly manner without a metal catalyst using a DDQ/TBN system.

The method for producing an allyl isochroman derivative according to one embodiment of the present invention can stably produce an allyl isochroman derivative because the catalytic cycle is maintained by TBN even when a small amount of DDQ is added, thereby enabling the production of DDQH ₂ .

A method for producing an allyl isochroman derivative according to one embodiment of the present invention can exhibit high reactivity even under neutral, stable conditions by using allyltributyl stannane (allyl-SnBu ₃ ) to introduce an allyl group.

The allyl isochroman derivatives prepared according to one embodiment of the present invention can be usefully utilized as intermediate products for various biologically active substances and therapeutic agents, intermediate products for polymeric materials such as industrial resins, and additionally as stabilizers for organic materials such as fats and fatty oils and synthetic resins.

The effects of the allyl isochroman derivative and the method for producing the same according to one embodiment of the present invention are not limited to those mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description below.

Figure 1 illustrates a proposed mechanism for producing isochromane using DDQ as an organic catalyst according to one embodiment of the present invention.

The present inventors have developed a method for producing an environmentally friendly regioselective allyl isochromane derivative using DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and TBN (tert-butyl nitrite) without a metal catalyst, thereby completing the present invention.

Specifically, DDQ was used as an oxidizing agent, TBN was added to maintain the catalytic cycle of DDQ, and allyltributylsthene was treated to introduce an allyl group, thereby stably substituting an allyl group at position 1 of isochroman.

Accordingly, the present invention provides a method for producing an allyl isochroman derivative, including the step of producing a compound represented by [Chemical Formula 2] from a compound represented by [Chemical Formula 1] using a DDQ/TBN system.

[Chemical Formula 1]

;

[Chemical formula 2]

;

In the above chemical formulas 1 and 2,

A is a C ₃ -C ₁₂ aryl group or heteroaryl group, and at least one hydrogen of the aryl group or heteroaryl group is unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a _hydroxy group, a C 1 -C ₆ chain alkyl group, a C ₁ -C ₆ alkoxy group, and a -OC(O)R ₂ group,

R ₁ is at least one selected from the group consisting of hydrogen, a halogen group, a hydroxy group, a C ₁ -C ₆ chain alkyl group, and a C ₁ -C ₆ alkoxy group,

R ₂ is a C ₁ -C ₆ chain alkyl group,

n can be an integer from 0 to 5.

A manufacturing method according to one embodiment of the present invention is as shown in the following reaction scheme 1, and the proposed mechanism is shown in Figure 1.

[Reaction Formula 1]

At this time, the reaction conditions were as follows: i) chemical formula 1 (0.37 mmol), DDQ (0.074 mmol), TBN (0.074 mmol), O ₂ (atm), DCE (3.7 mL), 0 ℃ or rt, 36 h; ii) allyltributylstenine (0.75 mmol), LiPF ₆ (0.19 mmol), MSA (0.075 mmol), DCE (3.7 mL), 24 h.

In the present invention, the term “substitution” refers to a reaction in which an atom or atomic group included in a molecule of a compound is replaced with another atom or atomic group.

In the present invention, the term “chain-linked alkyl group” refers to a group derived from a straight-chain or branched-chain saturated aliphatic hydrocarbon having a specific number of carbon atoms and having at least one valence. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 2-butyl, 3-butyl, pentyl, n-hexyl, and the like.

In the present invention, the term "aryl group" means an unsaturated aromatic ring compound having 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Examples of such aryls include, but are not limited to, phenyl, naphthyl, and the like.

In the present invention, the term “heteroaryl group” refers to a single ring or multiple condensed rings in which at least one of the atoms constituting the ring has a heteroatom of N, O or S. Examples of such heteroaryl groups include, but are not limited to, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, an oxazolyl group, a furyl group, and the like.

In the present invention, the term “halogen group” refers to elements belonging to group 17 of the periodic table, such as fluorine (F), chloride (Cl), bromine (Br), or iodine (I).

In the present invention, the term “alkoxy group” means an atomic group C _n H _2n+1 O- formed by bonding an oxygen atom to an alkyl group, and examples of such alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, or phthaloxy.

The terms used in the examples are used for the purpose of description only and should not be construed as limiting. The singular expression includes the plural expression unless the context clearly indicates otherwise. In this specification, the terms "comprises" or "has" and the like are intended to specify the presence of a feature, number, step, operation, component, part or combination thereof described in the specification, but should be understood to not exclude in advance the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts or combinations thereof.

Unless otherwise defined, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments belong. Terms defined in commonly used dictionaries, such as those defined in common dictionaries, should be interpreted as having a meaning consistent with the meaning they have in the context of the relevant art, and shall not be interpreted in an idealized or overly formal sense, unless expressly defined in this application.

In describing components of an embodiment, terms such as first, second, A, B, (a), (b), etc. may be used. These terms are only intended to distinguish the components from other components, and the nature, order, or sequence of the components are not limited by these terms. When it is described that a component is "connected," "coupled," or "connected" to another component, it should be understood that the component may be directly connected or connected to the other component, but another component may also be "connected," "coupled," or "connected" between each component.

Hereinafter, embodiments will be described in detail with reference to the attached drawings. However, since various modifications may be made to the embodiments, the scope of the patent application is not limited or restricted by these embodiments. It should be understood that all modifications, equivalents, or substitutes to the embodiments are included in the scope of the rights.

In addition, when describing with reference to the attached drawings, the same components will be given the same reference numerals regardless of the drawing numbers, and redundant descriptions thereof will be omitted. When describing an embodiment, if it is determined that a specific description of a related known technology may unnecessarily obscure the gist of the embodiment, the detailed description thereof will be omitted.

The present invention can be modified in various ways and has various embodiments, and thus specific embodiments are illustrated in the drawings and described in detail in the detailed description below. However, this is not intended to limit the present invention to specific embodiments, and it should be understood that all modifications, equivalents, and substitutes included in the spirit and technical scope of the present invention are included. In describing the present invention, if it is determined that a specific description of a related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.

Example 1. Preparation of allylisochroman derivative of the present invention

Example 1.1. Preparation of 1-allyl isochromane (chemical formula 2-1)

Isochroman (50 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 h. 2,3-Dichloro-5,6-dicyano-p-benzoquinone (17 mg, 0.074 mmol) and tert-butyl nitrite (8.86 μL, 0.074 mmol) were added to the solution and stirred at room temperature for 36 h. After the solvent was removed from the mixture using a reduced pressure evaporator, it was dissolved again in 1,2-dichloroethane (3.7 mL). To this solution, lithium hexafluorophosphate (28 mg, 0.18 mmol), methanesulfonic acid (6.7 μL, 0.074 mmol), and allyltributyltin (0.23 mL, 0.74 mmol) were added and stirred at 80 °C for 24 h. After cooling to room temperature, the reaction was confirmed using TLC and then sodium bicarbonate aqueous solution (10 mL) was added to terminate the reaction. Dichloromethane (3 x 10 mL) was used for extraction and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allylisochroman (46 mg, 71%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.18-7.16 (m, 2H), 7.11-7.10 (m, 2H), 5.96-5.85 (m, 1H), 5.17-5.07 (m, 2H), 4.84 (dd, J = 7.8, 3.0 Hz, 1H), 4.19-4.14(m, 1H), 3.81-3.75(m, 1H), 3.02-2.96(m, 1H), 2.71-2.66(m, 2H), 2.62-2.55(m, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 137.5, 135.0, 134.0, 129.0, 126.3, 126.1, 124.8, 117.2, 75.5, 63.6, 40.3, 29.0.

Example 1.2. Preparation of 1-allyl-7-methylisochroman (chemical formula 2-2)

7-Methylisochroman (55 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 h. 2,3-Dichloro-5,6-dicyano-p-benzoquinone (17 mg, 0.074 mmol) and tert-butyl nitrite (8.86 μL, 0.074 mmol) were added to the solution and stirred at 0 °C for 36 h. After the solvent was removed from the mixture using a reduced pressure evaporator, it was dissolved again in 1,2-dichloroethane (3.7 mL). To this solution, lithium hexafluorophosphate (28 mg, 0.18 mmol), methanesulfonic acid (6.7 μL, 0.074 mmol), and allyltributyltin (0.23 mL, 0.74 mmol) were added and stirred at 80 °C for 24 h. After cooling to room temperature, the reaction was confirmed using TLC and aqueous sodium bicarbonate solution (10 mL) was added to terminate the reaction. Dichloromethane (3 x 10 mL) was used for extraction and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-7-methylisochroman (53.3 mg, 76%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.01-6.98 (m, 2H), 6.91 (s, 1H), 5.95-5.88 (m, 1H), 5.18-5.07 (m, 2H), 4.80 (dd, J = 8.2, 3.3 Hz, 1H), 4.17-4.12(m, 1H), 3.78-3.72(m, 1H), 2.94(m, 1H), 2.70-2.55(m, 3H), 2.31(s, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 137.5, 135.5, 135.2, 130.9, 128.8, 127.1, 125.3, 116.8, 75.5, 63.4, 40.4, 28.7, 21.2.

Example 1.3. Preparation of 1-allyl-4-methylisochroman (chemical formula 2-3)

4-Methylisochroman (55 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.2. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-4-methylisochroman (56 mg, 80%) as a pure colorless liquid.

diastereomer ratio = 2.2 : 1

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.29-7.10 (m, 4H), 5.99-5.87 (m, 1H), 5.19-5.10 (m, 2H), 4.89 (dd, J = 8.0, 3.6 Hz, 1H), 4.12-4.08 (m, 0.5H), 3.92-3.85(m, 1H), 3.49-3.45(m, 0.5H), 3.08-2.58(m, 3H), 1.26(d, J = 7.0 Hz, 3H).

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.29-7.10 (m, 4H), 5.99-5.87 (m, 1H), 5.19-5.10 (m, 2H), 4.84 (dd, J = 7.6, 3.4 Hz, 1H), 4.12-4.08 (m, 0.5H), 3.92-3.85(m, 1H), 3.49-3.45(m, 0.5H), 3.08-2.58(m, 3H), 1.38(d, J = 7.1 Hz, 3H).

Example 1.4. Preparation of 1-allyl-3-methylisochroman (chemical formula 2-4)

3-Methylisochroman (55 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.2. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-3-methylisochroman (50.2 mg, 72%) as a pure colorless liquid.

diastereomer ratio = 2.9 : 1

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.17-7.13 (m, 2H), 7.09-7.04 (m, 2H), 6.05-5.94 (m, 1H), 5.16-5.11 (m, 2H), 4.89 (dd, J = 9.8, 3.9 Hz, 1H), 4.11-4.03(m, 1H), 2.7-2.61(m, 3H), 2.52-2.46(m, 1H), 1.30(d, J = 6.1 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 137.7, 135.6, 133.5, 128.9, 126.5, 125.9, 125.4, 116.9, 74.6, 63.9, 40.6, 36.0, 21.4.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.20-7.08 (m, 4H), 5.94-5.84 (m, 1H), 5.13 (dd, J = 17.2, 1.5 Hz, 1H), 5.05 (d, J = 10.2 Hz, 1H), 4.88-4.87(m, 1H), 3.83-3.77(m, 1H), 2.8-2.53(m, 4H), 1.35(d, J = 6.2 Hz, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 137.7, 135.1, 134.7, 128.8, 126.3, 126.1, 124.6, 116.8, 76.4, 70.5, 40.3, 36.8, 21.9.

Example 1.5. Preparation of 1-allyl-7-methoxyisochroman (chemical formula 2-5)

7-Methoxyisochroman (55 mg, 0.33 mmol) was dissolved in 1,2-dichloroethane (3.3 mL) in a vial, and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.2. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-7-methoxyisochroman (34.3 mg, 50%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.03 (d, J = 8.3 Hz, 1H), 6.75 (dd, J = 8.4, 2.5 Hz, 1H), 6.64 (d, J = 2.3 Hz, 1H), 5.96-5.85 (m, 1H), 5.16 (dd, J = 17.2, 1.6 Hz, 1H), 5.10 (d, J = 10.2 Hz, 1H), 4.80 (dd, J = 7.7, 3.3 Hz, 1H), 4.17-4.12 (m, 1H), 3.78 (s, 3H), 3.76-3.71 (m, 1H), 2.96-2.88(m, 1H), 2.71-2.54(m, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 157.9, 138.8, 135.1, 129.9, 126.2, 117.1, 112.3, 110.2, 75.6, 63.7, 55.4, 40.4, 28.3.

Example 1.6. Preparation of 1-allyl-6-methoxyisochroman (chemical formula 2-6)

6-Methoxyisochromane (53.6 mg, 0.32 mmol) was dissolved in 1,2-dichloroethane (3.3 mL) in a vial, and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.2. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-6-methoxyisochromane (44.3 mg, 66%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.18-7.16 (m, 2H), 7.11-7.10 (m, 2H), 5.96-5.85 (m, 1H), 5.17-5.07 (m, 2H), 4.84 (dd, J = 7.8, 3.0 Hz, 1H), 4.19-4.14(m, 1H), 3.81-3.75(m, 1H), 3.02-2.96(m, 1H), 2.71-2.66(m, 2H), 2.62-2.55(m, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 158.0, 135.5, 135.2, 130.1, 126.0, 117.0, 113.5, 112.5, 75.4, 63.5, 55.3, 40.5, 29.5.

Example 1.7. Preparation of 1-allyl-6,7-dimethoxyisochroman (chemical formula 2-7)

6,7-Dimethoxyisochroman (72.4 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial, and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.2. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-6,7-dimethoxyisochroman (44.3 mg, 66%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.18-7.16 (m, 2H), 7.11-7.10 (m, 2H), 5.96-5.85 (m, 1H), 5.17-5.07 (m, 2H), 4.84 (dd, J = 7.8, 3.0 Hz, 1H), 4.19-4.14(m, 1H), 3.81-3.75(m, 1H), 3.02-2.96(m, 1H), 2.71-2.66(m, 2H), 2.62-2.55(m, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 158.0, 135.5, 135.2, 130.1, 126.0, 117.0, 113.5, 112.5, 75.4, 63.5, 55.3, 40.5, 29.5.

Example 1.8. Preparation of 1-allyl-7-fluoroisochroman (chemical formula 2-8)

7-Fluoroisochroman (56.7 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.1. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-7-fluoroisochroman (13.0 mg, 18%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.08-7.04(m, H), 6.87(td, J = 8.5, 2.5 Hz, 1H), 6.81(dd, J = 9.8, 24 Hz, 1H), 5.93-5.83(m, 1H), 5.15(dd, J) = 17.2, 1.6 Hz, 1H), 5.10(d, J = 10.2 Hz, 1H), 4.79(dd, J = 7.5, 3.3 Hz, 1H), 4.18-4.13(m, 1H), 3.77-3.71(m, 1H), 2.98-2.90(m, 1H), 2.71 - 2.66(m, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 161.2 (d, ¹ J = 243.5 Hz), 139.6 (d, ³ J = 6.1 Hz), 134.6, 130.4 (d, ³ J = 7.7 Hz), 129.7 (d, ⁴ J = 3.0 Hz), 117.4, 113.6 (d, ² J = 21.2 Hz), 111.6 (d, ² J = 22.0 Hz), 75.4 (d, ⁴ J = 2.2 Hz), 63.6, 40.2, 28.4.

Example 1.9. Preparation of 1-allyl-7-chloroisochroman (chemical formula 2-9)

7-Chloroisochroman (62.8 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.1. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-7-chloroisochroman (25.3 mg, 33%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.14-7.03 (m, 3H), 5.91-5.84 (m, 1H), 5.17-5.09 (m, 2H), 4.78 (dd, J = 7.8, 3.3 Hz, 1H), 4.17-4.12 (m, 1H), 3.77-3.70(m, 1H), 2.96-2.90(m, 1H), 2.71-2.54(m, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 139.6, 134.6, 132.6, 131.7, 130.3, 126.6, 125.0, 117.4, 75.3, 63.4, 40.2, 28.5.

Example 1.10. Preparation of 1-allyl-7-bromoisochromane (chemical formula 2-10)

7-Bromoisochromane (79.4 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial, and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.1. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-7-bromoisochromane (31.7 mg, 34%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.29-7.25 (m, 2H), 6.99 (d, J = 8.1 Hz, 1), 5.91-5.84 (m, 1H), 5.18-5.08 (m, 2H), 4.78 (dd, J = 7.9, 3.4 Hz, 1H), 4.17-4.12(m, 1H), 3.76-3.70(m, 1H), 2.95-2.88(m, 1H), 2.72-2.52(m, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 140.0, 134.6, 133.1, 130.7, 129.5, 127.9, 119.7, 117.5, 75.2, 63.3, 40.2, 28.6.

Example 1.11. Preparation of 1-allyl-6-fluoroisochroman (chemical formula 2-11)

6-Fluoroisochroman (56.7 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.1. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-6-fluoroisochroman (29.6 mg, 41%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.06 (q, J = 4.7 Hz, 1H), 6.88 (td, J = 8.5, 2.6 Hz, 1H), 6.81 (dd, J = 9.3, 2.5 Hz, 1H), 5.93-5.83 (m, 1H), 5.16-5.07(m, 2H), 4.80(dd, J = 7.3, 2.9 Hz, 1H), 4.17-4.12(m, 1H), 3.78-3.72(m, 1H), 3.02-2.95(m, 1H), 2.72-2.63(m, 2H), 2.60-2.52(m, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 161.2 (d, ¹ J = 244.9 Hz), 136.4 (d, ³ J = 7.3 Hz), 134.8, 133.5 (d, ⁴ J = 2.9 Hz), 126.5 (d, ³ J = 8.2 Hz), 117.2, 115.2(d, ² J = 20.5 Hz), 113.3(d, ² J = 21.2 Hz), 75.2, 63.1, 40.3, 29.1.

Example 1.12. Preparation of 1-allyl-6-chloroisochroman (chemical formula 2-12)

6-Chloroisochroman (62.8 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.1. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-6-chloroisochroman (28.8 mg, 37%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.15-7.10(m, 2H), 7.03(dd, J = 8.5, 2.6 Hz, 1H), 5.92-5.82(m, 1H), 5.15-5.07(m, 2H), 4.79(dd, J = 7.6, 3.4 Hz, 1H), 4.17-4.12(m, 1H), 3.77-3.71(m, 1H), 3.00-2.93(m, 1H), 2.71-2.52(m, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 136.3, 136.1, 13.6, 132.0, 128.8, 126.4, 126.4, 117.4, 75.3, 63.2, 40.3, 29.0.

Example 1.13. Preparation of 1-allylisochroman-7-yl acetate (chemical formula 2-13)

Isochroman-7-yl acetate (71.6 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.1. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 1-allylisochroman-7-yl acetate (10.4 mg, 12%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.12 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 8.2, 2.1 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 5.94-5.83 (m, 1H), 5.16-5.08(m, 2H), 4.81(dd, J = 7.7, 3.3 Hz, 1H), 4.18-4.13(m, 1H), 3.78-3.72(m, 1H), 3.00-2.93(m, 1H), 2.71-2.53(m, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 169.7, 148.8, 139.1, 134.7, 131.8, 130.0, 119.8, 117.9, 117.3, 75.5, 63.5, 40.2, 28.6, 21.2.

Example 1.14. 4-Allyl-1,4-dihydro-2 H - Manufacture of benzo[f]isochromane (chemical formula 2-14)

1,4-Dihydro-2 H -benzo[f]isochromane (68.6 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.1. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 4-allyl-1,4-dihydro-2 H -benzo[f]isochromane (71.5 mg, 86%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.94 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.54 (td, J = 11.9, 1.2 Hz, 1H), 7.49 (d, J = 7.4, 1.0 Hz, 1H), 7.24 (d, J = 8.6 Hz, 1H), 5.97-5.87 (m, 1H), 5.17 (dd, J = 17.2, 1.7 Hz, 1H), 5.09 (d, J = 10.2 Hz, 1H), 5.0-4.9(m, 1H); 4.37-4.32(m, 1H), 3.95-3.89(m, 1H), 3.28-3.20(m, 1H), 3.13-3.07(m, 1H), 2.83-2.77(m, 1H), 2.69-2.62(m, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 135.0, 134.8, 132.1, 132.0, 129.5, 128.5, 126.4, 125.6, 123.2, 122.9, 117.1, 75.8, 63.0, 40.3, 25.7.

Example 1.15. Preparation of 1-allyl-1,3-dihydroisobenzofuran (chemical formula 2-15)

1,3-Dihydroisobenzofuran (44.8 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 h. 2,3-Dichloro-5,6-dicyano-p-benzoquinone (17 mg, 0.074 mmol) and tert-butyl nitrite (8.86 μL, 0.074 mmol) were added to the solution and stirred at room temperature for 36 h. After the solvent was removed from the mixture using a reduced pressure evaporator, it was dissolved again in 1,2-dichloroethane (3.7 mL). To this solution, lithium hexafluorophosphate (28 mg, 0.18 mmol), methanesulfonic acid (6.7 μL, 0.074 mmol), and allyltributyltin (0.12 mL, 0.37 mmol) were added and stirred at room temperature for 10 h. After confirming the reaction using TLC, the reaction was terminated by adding aqueous sodium bicarbonate solution (10 mL). Dichloromethane (3 x 10 mL) was used for extraction and washed with water and brine. The organic layer was dried over anhydrous MgSO ₄ and the solvent was removed under reduced pressure. The mixture was purified by silica gel column chromatography (Ether:Hexane = 1:50) to obtain the target compound 1-allyl-1,3-dihydroisobenzofuran (17.9 mg, 30%) as a pure colorless liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.28-7.18 (m, 2H), 5.92-5.82 (m, 1H), 5.31-5.28 (m, 1H), 5.18-5.17 (m, 0.5H), 5.15-5.10 (m, 2H), 5.09-5.08(m, 0.5H), 5.07-5.04(m, 1H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 141.6, 139.5, 134.2, 127.5, 127.2, 121.4, 121.0, 117.7, 83.3, 72.7, 40.8.

Example 1.16. 7-Allyl-4,7-dihydro-5 H - Preparation of thieno[2,3-c]pyran (chemical formula 2-16)

4,7-Dihydro-5 H -thieno[2,3-c]pyran (52.2 mg, 0.37 mmol) was dissolved in 1,2-dichloroethane (3.7 mL) in a vial and oxygen was injected for 1 hour, and then synthesized using the same method as in Example 1.2. The mixture was purified by silica gel column chromatography separation method (Ether:Hexane = 1:50) to obtain the target compound 7-allyl-4,7-dihydro-5 H -thieno[2,3-c]pyran (19.5 mg, 29%) as a pure yellow liquid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.14 (d, J = 5.0 Hz, 1H), 6.81 (d, J = 5.0 Hz, 1H), 5.98-5.88 (m, 1H), 5.22-5.13 (m, 2H), 4.85 (td, J = 4.6, 2.1 Hz, 1H), 4.23 (qd, J = 5.7, 2.0 Hz, 1H), 3.76 (td, J = 14.0, 7.8 Hz, 1H), 2.92-2.83 (m, 1H), 2.67-2.52 (m, 3H). ¹³ C-NMR (100 MHz, CDCl ₃ ) δ 134.7, 134.0, 133.6, 127.1, 122.7, 117.8, 74.7, 64.5, 41.4, 26.2.

Experimental Example 1. Preparation of allylisochroman derivatives according to various Bronsted acids

Allyl isochroman derivatives were prepared by treating with various Bronsted acids as shown in the following reaction scheme 2 (Table 1).

[Reaction Formula 2]

At this time, the reaction conditions were as follows: i) compound 1a (chemical formula 1-1, 0.37 mmol), DDQ (0.37 mmol), H ₂ O (0.41 mmol), DCE (3.7 mL), RT, 24 h; ii) allyltributylstenine (0.75 mmol), LiClO ₄ (0.37 mmol), acid (0.075 mmol), DCE (3.7 mL), 24 h.

Entry Acid Temp(℃) Yield(%) ^[a] Time 1 TFA 25 10 24h / 24h 2 TFA 80 28 24h / 24h 3 MSA 80 59 24h / 24h 4 CBSA 80 58 6h / 24h [a] Calculated by separation yield.

In the presence of trifluoroacetic acid (TFA), the yield of target compound 2a (chemical formula 2-1) was higher (28%) at 80 °C than at 25 °C (entry 1-2). When methanesulfonic acid (MSA) was treated to the reaction mixture, the yield of compound 2a increased to 59% (entry 3). At this time, the yield was calculated as the isolated yield.

Experimental Example 2. H ₂ Preparation of allylisochroman derivatives with or without addition of O or additives

Allyl isochroman derivatives were prepared by additionally treating with water (H ₂ O) or additives as shown in the following reaction scheme 3 (Table 2).

[Reaction Formula 3]

At this time, the reaction conditions were as follows: i) compound 1a (0.37 mmol), DDQ (10 mol%), TBN, H ₂ O, O ₂ bubbling (1 h), blue LED (18 W), DCE (3.7 mL), RT, 36 h; ii) allyltributylstenine (0.75 mmol), additive (0.19 mmol), acid (0.075 mmol), DCE (3.7 mL), 24 h.

Entry TBN(equiv) H ₂ O(equiv) Additive(equiv) Acid Temp(℃) Yield(%) ^[a] 1 ^[b] 2.0 2.0 LiClO ₄ 1.0 MSA 80 12 2 ^[b] 2.0 MeOH 2.0 LiClO ₄ 1.0 MSA 80 3 3 ^[b] 1.0 2.0 LiClO ₄ 1.0 MSA 80 12 4 1.0 2.0 LiClO ₄ 1.0 MSA 80 25 5 1.0 2.0 LiClO ₄ 1.0 CBSA 80 14 6 1.0 2.0 LiClO ₄ 1.0 PTSA 80 20 7 1.0 2.0 LiClO ₄ 1.0 CSA 80 25 8 1.0 2.0 LiClO ₄ 0.5 MSA 80 25 9 1.0 2.0 LiClO ₄ 1.0 MSA 0 22 10 1.0 - LiClO ₄ 0.5 MSA 80 22 11 1.0 - LiPF ₆ 0.5 MSA 80 37 [a] Calculated by separation yield.
[b] Both steps used the same solvent bubbled with O ₂ .

First, compound 2a was synthesized by adding water and LiClO ₄ , obtaining a yield of 12% (entry 1). When methanol was added instead of water, the yield decreased (entry 2). In the second step, when the solvent bubbled with O ₂ was replaced with a new solvent, the reaction yield increased (entry 4). When various Brønsted acids were tested under the same reaction conditions, the best yield was observed when methanesulfonic acid (MSA) was added (entries 5-7). This is the same result as Experimental Example 1. When LiPF ₆ was added instead of LiClO ₄ as an additive, the yield increased to 37% (entry 11).

Experimental Example 3. Equivalent amount and O of DDQ/TBN ₂ Preparation of allylisochroman derivatives according to conditions

To optimize the reaction conditions, the amounts of DDQ, TBN, water (H ₂ O), and oxygen (O ₂ ) were screened as shown in the following reaction scheme 4 (Table 3).

[Reaction Formula 4]

At this time, the reaction conditions were as follows: i) compound 1a (0.37 mmol), DDQ, TBN, H ₂ O, O ₂ bubbling (1 h), O ₂ balloon, DCE (3.7 mL), RT, 36 h; ii) allyltributylstenine (0.75 mmol), additive (0.19 mmol), MSA (0.075 mmol), DCE (3.7 mL), 80 °C, 24 h.

Entry DDQ(mol%) TBN(equiv) O ₂ H ₂ O(equiv) Yield(%) ^[a] 1 ^[b] 20 1.0 bubbling 2.0 39 2 ^[b] 20 0.2 bubbling 2.0 63 3 ^[b] 30 0.2 bubbling 2.0 51 4 20 0.2 Air 2.0 55 5 20 0.2 balloon(x) 2.0 55 6 20 0.2 bubbling(x) 2.0 50 7 20 0.2 bubbling - 71 8 10 1.0 bubbling - 42 9 ^[b] 20 0.2 bubbling - N.R [a] Calculated by separation yield.
[b] LiPF ₆ and MSA were not added.

Under the conditions of DDQ (20 mol%), TBN (0.2 equiv.), LiPF ₆ (0.5 equiv.), and methanesulfonic acid (MSA, 0.2 equiv.), compound 2a was obtained in a yield of 63% after O ₂ bubbling for 1 h (entry 2). The yield decreased when the amount of DDQ increased (entry 3). The yield also decreased when air was used instead of O ₂ , when the O ₂ balloon was not inserted, or when O ₂ was not bubbling (entries 4-6). Interestingly, the desired compound 2a was produced in a yield of 71% when H ₂ O was not added (entry 7). This is probably because even a very small amount of H ₂ O remaining in the solvent can act as a protic additive, so that water does not need to be removed in the reaction. In addition, when NO ₂ oxidizes DDQH ₂ to DDQ, H ₂ O is released, which also serves as a water source for the catalytic cycle. On the other hand, the desired compound 2a could not be obtained when LiPF ₆ and MSA were not added (entry 8).

Although the embodiments have been described with limited drawings as described above, those skilled in the art can apply various technical modifications and variations based on the above. For example, even if the described techniques are performed in a different order than the described method, and/or the components of the described system, structure, device, circuit, etc. are combined or combined in a different form than the described method, or are replaced or substituted by other components or equivalents, appropriate results can be achieved.

Therefore, other implementations, other embodiments, and equivalents to the claims are also included in the scope of the claims described below.

This invention was made possible with the support of the project (2021.07.01 ~ 2022.06.30.) on research on hydrogen storage technology based on liquid organic hydrogen carrier (LOHC) as part of the Gyeonggi Regional Cooperation Research Center Project (GRRC) / GRRC basic project hosted by the Gyeonggi Provincial Government.

Claims (13)

A method for producing an allyl isochromane derivative, comprising the steps of producing a compound represented by [Chemical Formula 2] from a compound represented by [Chemical Formula 1] using DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and TBN (tert-butyl nitrite):
[Chemical Formula 1]
;
[Chemical formula 2]
;
In the above chemical formulas 1 and 2,
A is a C ₃ -C ₁₂ aryl group or heteroaryl group, and at least one hydrogen of the aryl group or heteroaryl group is unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a _hydroxy group, a C 1 -C ₆ chain alkyl group, a C ₁ -C ₆ alkoxy group, and a -OC(O)R ₂ group,
R ₁ is at least one selected from the group consisting of hydrogen, a halogen group, a hydroxy group, a C ₁ -C ₆ chain alkyl group, and a C ₁ -C ₆ alkoxy group,
R ₂ is a C ₁ -C ₆ chain alkyl group,
n is an integer from 0 to 5.
In the first paragraph,
The above manufacturing method is a manufacturing method characterized in that it forms a compound represented by the following [chemical formula 1'] as an intermediate.
[Chemical formula 1']
;
In the above chemical formula 1',
A is a C ₃ -C ₁₂ aryl group or heteroaryl group, and at least one hydrogen of the aryl group or heteroaryl group is unsubstituted or substituted with at least one selected from the group consisting of a halogen group, a _hydroxy group, a C 1 -C ₆ chain alkyl group, a C ₁ -C ₆ alkoxy group, and a -OC(O)R ₂ group,
R ₁ is at least one selected from the group consisting of hydrogen, a halogen group, a hydroxy group, a C ₁ -C ₆ chain alkyl group, and a C ₁ -C ₆ alkoxy group,
R ₂ is a C ₁ -C ₆ chain alkyl group,
n is an integer from 0 to 5.
In the first paragraph,
The above manufacturing method is characterized by treating DDQ and TBN under oxygen (O ₂ ) conditions.
In the first paragraph,
The above manufacturing method is a manufacturing method characterized in that an allyl group is introduced by adding allyltributyl stannane (allyl-SnBu ₃ ).
In paragraph 4,
The above manufacturing method is characterized by adding Brønsted acids and an additive together with allyltributylstenine.
In paragraph 5,
A manufacturing method, characterized in that the acid is at least one selected from the group consisting of methanesulfonic acid (MSA), trifluoroacetic acid (TFA), chlorobenzenesulfonic acid (CBSA), p-toluenesulfonic acid (PTSA), and combinations thereof.
In paragraph 5,
A manufacturing method, characterized in that the additive is at least one selected from the group consisting of LiPF ₆ , LiClO ₄ , and combinations thereof.
In the first paragraph,
A manufacturing method, characterized in that the above manufacturing method is performed in at least one solvent selected from the group consisting of dichloroethane (DCE), dichloromethane (DCM), tetrahydrofuran (THF), acetone, DMSO, acetonitrile (MeCN), diethyl ether (Et ₂ O), water (H ₂ O), alcohol, toluene, hexane, carbon tetrachloride (CCl ₄ ), and combinations thereof.
In the first paragraph,
The above manufacturing method is a manufacturing method characterized by adding DDQ in an amount of 10 to 30 mol%.
In the first paragraph,
A manufacturing method, characterized in that the above manufacturing method is performed within one reactor.
In the first paragraph,
A manufacturing method, characterized in that the compound represented by the above [chemical formula 1] is at least one selected from the group consisting of compounds represented by the following [chemical formula 1-1] to [chemical formula 1-16].
[Chemical Formula 1-1]
;
[Chemical Formula 1-2]
;
[Chemical Formula 1-3]
;
[Chemical Formula 1-4]
;
[Chemical Formula 1-5]
;
[Chemical Formula 1-6]
;
[Chemical Formula 1-7]
;
[Chemical Formula 1-8]
;
[Chemical Formula 1-9]
;
[Chemical Formula 1-10]
;
[Chemical Formula 1-11]
;
[Chemical Formula 1-12]
;
[Chemical Formula 1-13]
;
[Chemical Formula 1-14]
;
[Chemical Formula 1-15]
; and
[Chemical Formula 1-16]
.
In the first paragraph,
A manufacturing method, characterized in that the compound represented by the above [chemical formula 2] is at least one selected from the group consisting of compounds represented by the following [chemical formula 2-1] to [chemical formula 2-16].
[Chemical Formula 2-1]
;
[Chemical Formula 2-2]
;
[Chemical Formula 2-3]
;
[Chemical Formula 2-4]
;
[Chemical Formula 2-5]
;
[Chemical Formula 2-6]
;
[Chemical Formula 2-7]
;
[Chemical Formula 2-8]
;
[Chemical Formula 2-9]
;
[Chemical Formula 2-10]
;
[Chemical Formula 2-11]
;
[Chemical Formula 2-12]
;
[Chemical Formula 2-13]
;
[Chemical Formula 2-14]
;
[Chemical Formula 2-15]
; and
[Chemical Formula 2-16]
.
delete