KR20220117789A - Synthesis method ofγ-lactam derivatives andγ-lactam derivatives synthesized by the same - Google Patents

Abstract

The present invention relates to a method for manufacturing γ-lactam derivatives, and γ-lactam derivatives synthesized therefrom, wherein the method for manufacturing γ-lactam derivatives includes the steps of: bringing a γ-lactam compound in contact with a hydrogen transfer catalyst to form a γ-lactam radical intermediate; and introducing a substituent by a radical addition reaction of the γ-lactam radical intermediate and a modifier, a radical-radical coupling reaction, or an intramolecular cyclization reaction.

Description

Method for preparing γ-lactam derivatives and γ-lactam derivatives prepared therefrom

The present invention relates to a novel synthesis method for preparing a γ-lactam derivative through electrolysis and a γ-lactam derivative synthesized thereby.

C-C bond formation by functionalization of inactivated C-H bonds can prevent pre-functionalization of substrates, so intensive studies and efforts are being made. Transition metal catalysts are being developed as a cornerstone for realizing these efforts, but there are limitations such as the use of precious metals, difficulty in removing trace metals, and environmental impact due to waste. Meanwhile, electrochemical synthesis has emerged as a powerful solution to these problems. The use of electricity as a redox reagent to promote chemical reactions has the advantage of reduced environmental pollution, and the reactivity and selectivity can be more easily controlled by simply adjusting the potential.

Previous studies of C(sp ³ )-C(sp ³ ) formation by activation of allylic or benzyl-based C(sp ³ )–H bonds have shown that Pd, Ni, Cu and Fe together with stoichiometric amounts of oxidizing agents It includes a coupling reaction of a nucleophile stabilized using a transition metal catalyst including Other methods for functionalization of allyl-based and benzyl-based C(sp ³ )-H bonds include electrosynthesis and photocatalytic-based hydrogen atom transfer (HAT).

γ-lactams (eg, isoindolinones) are a class of medicinally important compounds with various biological activities, including anti-anxiety, anti-inflammatory and anti-tumor activities. A general approach is to remove the leaving group at the N-α position of the lactam and proceed with a nucleophilic addition reaction to the resulting N-acyliminium (NAI) intermediate. In this regard, a Lewis-Bronsted acid transition metal catalyst and an organic catalyst were used to promote the removal of the leaving group. Harsh but direct C–H bond activation is possible even under strongly basic conditions using palladium-catalyzed bonds with aryl halides.

In addition, electrochemical functionalization of amides and carbamates has been developed mainly based on NAI, which is subsequently captured by nucleophiles. NAIs are generally formed by direct two-electron oxidation of substrates, anodization of electrical aids, azole-mediated HAT followed by anodization and TEMPO-mediated hydride transfer. These methods generally require the use of nucleophiles with high oxidation potentials, including alcohols and azoles, to avoid degradation. To extend the nucleophile range, we have conventionally used a “cation pool” strategy that relies on the pre-formation of NAI by low-temperature electrolysis in divided cells. Thereafter, various coupling reactions were induced by reducing NAI by exchanging an electrode for radical addition or addition of a nucleophile including allyl silane and Grignard reagent under non-electrolytic conditions with an electron-deficient olefin.

Although the electrochemical approach of cation pools for the functionalization of amides and carbamates has shown utility, the mediator of NAI has the limitation of limiting the scope of its coupling partners to nucleophiles. In addition, there is still a need for the development of mild conditions that can be performed in the undivided cell due to the complicated operation of the divided cell along with the requirement for low temperature.

The present invention provides a novel synthesis method for preparing a γ-lactam derivative (eg, a γ-lactam derivative or an isoindolinone derivative) through electrolysis and a γ-lactam derivative synthesized thereby.

According to one aspect, the method comprising: contacting a γ-lactam compound with a hydrogen transfer catalyst to form a γ-lactam radical intermediate; and a step of introducing a substituent by a radical addition reaction of the γ-lactam radical intermediate and a modifier, a radical-radical coupling reaction, or an intramolecular cyclization reaction; do.

According to one embodiment, the method for preparing the γ-lactam derivative may be performed in a single electrolysis cell.

According to one aspect, there is provided a γ-lactam derivative prepared according to the above-described method for preparing a γ-lactam derivative.

According to the method for producing a γ-lactam derivative according to one aspect, it is possible to produce a γ-lactam derivative compound under mild conditions at room temperature, and by controlling the reaction conditions such as the driving voltage of the electrolysis device, the substituents and the substitution rate can be adjusted. It has an adjustable effect.

1 is a table showing the examination results of the optimization conditions of the electrolysis cell.
2 is a view showing various compounds synthesized by a synthesis method according to an embodiment of the present invention.
3 is a view showing various compounds synthesized by a synthesis method according to an embodiment of the present invention.
4 is a view showing various compounds synthesized by a synthesis method according to an embodiment of the present invention.
5 is a view showing various compounds synthesized by a synthesis method according to an embodiment of the present invention.
6 is a view showing various compounds synthesized using γ-lactam derivatives synthesized on a gram-scale.
7 is a reaction scheme confirming the effect of the hydrogen transfer catalyst.
8 is a reaction scheme examining the synthetic reaction mechanism involving N-sulfonyl imine.
9 is a view showing a synthesis mechanism of a method for producing a γ-lactam derivative according to an embodiment of the present invention.

The present invention may be subjected to various transformations and may have various embodiments, and should not be construed as being limited to specific embodiments, and includes all transformations, equivalents and substitutes included in the spirit and scope of the present invention. should be understood In describing the present invention, if it is determined that a detailed description of a related known technology may obscure the gist of the present invention, the detailed description thereof will be omitted.

As used herein, the term “C _x -C _y ” refers to carbon atoms x to y, for example, a C ₁ -C ₂₀ alkyl group refers to an alkyl group having 1 to 20 carbon atoms, for example, a methyl group, an ethyl group, propyl group, butyl group, and the like.

As used herein, the term "C2-C20 alkenyl group" refers to a monovalent hydrocarbon group including at least one C=C bond having 2 to 20 carbon atoms.

As used herein, the term "C2-C20 alkynyl group" refers to a monovalent hydrocarbon group including at least one C≡C bond having 2 to 20 carbon atoms.

In the present specification, the term "C1-C20 alkoxy group" means -OA ₁₀₁ (herein, A101 is an alkyl group having 1 to 20 carbon atoms).

As used herein, the term “C3-C10 cycloalkyl group” refers to a saturated hydrocarbon ring formed from a ring-forming atom having 3 to 10 carbon atoms.

As used herein, the term "C1-C10 heterocycloalkyl group" includes a ring-forming atom having 1 to 10 carbon atoms, and includes at least one heteroatom (eg, N, B, O, S, P, Si, etc.) It means a heterocyclic ring.

As used herein, the term “C5-C20 aryl group” refers to an aromatic ring having 5 to 20 carbon atoms.

As used herein, the term "C1-C20 heteroaryl group" includes a ring-forming atom having 1 to 20 carbon atoms, and includes at least one heteroatom (eg, N, B, O, S, P, Si, etc.) It means a heteroaromatic ring.

As used herein, the term "C6-C20 arylalkyl group" is a monovalent group represented by -A ₁₀₂ A ₁₀₃ (in this case, A ₁₀₂ is a C1-C15 alkyl group, A ₁₀₃ is a C5-C19 aryl group), and the term "C6- "C20 aryloxy group" is a monovalent group represented by -OA ₁₀₄ (in this case, A ₁₀₄ is a C5-C20 aryl group), and the term "C6-C20 arylthio group" is a monovalent group represented by -OA ₁₀₅ ( In this case, A ₁₀₅ is a C5-C20 aryl group).

The terms used in the present application are only used to describe specific embodiments, and are not intended to limit the present invention. The singular expression includes the plural expression unless the context clearly dictates otherwise.

A method for producing a γ-lactam derivative according to an aspect includes the steps of: forming a γ-lactam radical intermediate by contacting a γ-lactam compound with a hydrogen transfer catalyst; and a step of introducing a substituent by a radical addition reaction of the γ-lactam radical intermediate and a modifier, a radical-radical coupling reaction, or an intramolecular cyclization reaction.

According to one embodiment, the γ-lactam compound may be a substituted or unsubstituted γ-lactam, or a substituted or unsubstituted isoindolinone.

According to an embodiment, the hydrogen transfer catalyst may be tetrabutylammonium azide, NaN ₃ , 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, methyl thioglycolate, or a mixture thereof. have. For example, the hydrogen transfer catalyst may be tetrabutylammonium azide.

According to one embodiment, the modifier for the radical addition reaction may be a compound including at least one C═C bond. For example, the compound may further comprise at least one electron withdrawing group.

According to one embodiment, the modifier for the radical addition reaction may include at least one C=C bond and may include an electron withdrawing group at one end. In this case, the electron withdrawing group includes, for example, a halogen group such as -F, -Cl, -Br, -I, a methyl group substituted with at least one halogen group, a cyano group, -C(=O)(Q ₁ ), -C(=O)N(Q ₁ )(Q ₂ ), -C(=O)O(Q ₁ ), -S(=O) ₂ (Q ₁ ), or -P(=O)(Q ₁ ) ) (Q ₂ ), and Q1 and Q2 are referred to below.

According to one embodiment, the modifier for the radical-radical coupling reaction may be a compound including at least one C=N bond. For example, the compound may further include a sulfonyl group.

According to one embodiment, the modifier for the radical-radical coupling reaction may include a C=N bond and further include a sulfonyl group directly bonded to N.

According to one embodiment, the γ-lactam compound may be represented by Formula 1-1 or Formula 1-2 below:

<Formula 1-1> <Formula 1-2>

In Formula 1,

n is an integer selected from 0 to 2, and when n is 0, the carbon (C) of the acyl group and the ring-forming carbon (C) to which R ₄ is bonded are connected by a single bond,

R ₁ To R ₈ are each independently hydrogen, -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group, a C ₁ -C ₂₀ alkyl group unsubstituted or substituted with R ₁₀ , R ₁₀ Substituted or unsubstituted C ₂ -C ₂₀ alkenyl group, R ₁₀ substituted or unsubstituted C ₂ -C ₂₀ alkynyl group, R ₁₀ substituted or unsubstituted C ₁ -C ₂₀ alkoxy group, R ₁₀ substituted or Unsubstituted C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group unsubstituted or substituted with R ₁₀ , C ₅ -C ₂₀ aryl group unsubstituted or substituted with R ₁₀ , substituted or unsubstituted with R ₁₀ A cyclic C ₁ -C ₂₀ heteroaryl group, a C ₆ -C ₂₀ arylalkyl group unsubstituted or substituted with R ₁₀ , a C ₆ -C ₂₀ aryloxy group unsubstituted or substituted with R ₁₀ , unsubstituted or substituted with R ₁₀ cyclic C ₆ -C ₂₀ arylthio group, -C(=O)(Q ₁ ), -C(=O)N(Q ₁ )(Q ₂ ), -C(=O)O(Q ₁ ), -S(=O) ₂ (Q ₁ ), or -P(=O)(Q ₁ )(Q ₂ ),

Among the R ₁ to R ₄ , adjacent groups are optionally bonded to each other, a C ₃ -C ₁₀ cycloalkyl group substituted or unsubstituted with R ₁₀ , C ₁ -C ₁₀ heterocycloalkyl unsubstituted or substituted with R ₁₀ . An alkyl group, a C ₅ -C ₂₀ aryl group substituted or unsubstituted with R ₁₀ , or a C ₁ -C ₂₀ heteroaryl group substituted or unsubstituted with R ₁₀ may be formed,

Wherein R ₁₀ is deuterium (-D), -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group;

Deuterium, -F, -Cl, -Br, -I, hydroxyl group, cyano group, nitro group, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ Alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, a C ₆ -C ₂₀ arylthio group, or an unsubstituted or substituted C ₁ -C ₂₀ alkyl group or a C ₁ -C ₆₀ alkoxy group;

Deuterium, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group C ₁ -C ₂₀ alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryloxy group, C ₆ -C ₂₀ arylthio group, or unsubstituted or substituted with any combination thereof selected, C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, or a C ₆ -C ₂₀ arylthio group; or

N(Q ₃₁ )(Q ₃₂ ), -C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), - S(=O) ₂ (Q ₃₁ ), or -P(=O)(Q ₃₁ )(Q ₃₂ );

Q ₁ , Q ₂ , Q ₃₁ and Q ₃₂ are each independently hydrogen; heavy hydrogen; -F; -Cl; -Br; -I; hydroxyl group; cyano group; nitro group; C ₁ -C ₂₀ alkyl group; C ₂ -C ₂₀ alkenyl group; C ₂ -C ₂₀ alkynyl group; C ₁ -C ₂₀ alkoxy group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, or C ₆ -C ₂₀ arylalkyl group;

According to one embodiment, in Formula 1, n may be 0 or 1.

According to one embodiment, in Formula 1, R ₁ and R ₂ are each independently hydrogen, a C ₁ -C ₂₀ alkyl group substituted or unsubstituted with R ₁₀ , C ₅ -C ₂₀ substituted or unsubstituted with R ₁₀ It may be an aryl group, or a C ₆ -C ₂₀ arylalkyl group substituted or unsubstituted with R ₁₀ . For example, R ₁ and R ₂ are each independently hydrogen, a C ₁ -C ₂₀ alkyl group; Or it may be a phenyl group or a benzyl group unsubstituted or substituted with at least one of a C ₁ -C ₂₀ alkyl group.

According to one embodiment, in Formula 1, R ₃ and R ₄ are each independently hydrogen, a C ₁ -C ₂₀ alkyl group substituted or unsubstituted with R ₁₀ , C ₁ -C ₂₀ substituted or unsubstituted with R ₁₀ It may be an alkoxy group, a C ₅ -C ₂₀ aryl group unsubstituted or substituted with R ₁₀ , or a C ₆ -C ₂₀ arylalkyl group substituted or unsubstituted with R ₁₀ . For example, R ₃ and R ₄ are each independently hydrogen, a C ₁ -C ₂₀ alkyl group, a C ₁ -C ₂₀ alkoxy group; Or it may be a phenyl group or a benzyl group unsubstituted or substituted with at least one of a C ₁ -C ₂₀ alkyl group and a C ₁ -C ₂₀ alkoxy group.

According to one embodiment, the R ₅ to R ₈ are each independently hydrogen, -F, -Cl, -Br, -I, a cyano group, a C ₁ -C ₂₀ alkyl group unsubstituted or substituted with R ₁₀ , R ₁₀ It may be a C 1 -C 20 alkoxy group substituted or unsubstituted with C ₁ -C ₂₀ alkoxy group, a C ₅ -C ₂₀ aryl group unsubstituted or substituted with R ₁₀ , or a C ₆ -C ₂₀ arylalkyl group unsubstituted or substituted with R ₁₀ . For example, the R ₅ to R ₈ are each independently hydrogen, -F, -Cl, -Br, -I, a cyano group; -F, -Cl, -Br, -I, and a C ₁ -C ₂₀ alkyl group or C ₁ -C ₂₀ alkoxy group unsubstituted or substituted with at least one of a cyano group; Alternatively, it may be a phenyl group or a benzyl group unsubstituted or substituted with at least one of -F, -Cl, -Br, -I, a cyano group, a C ₁ -C ₂₀ alkyl group, and a C ₁ -C ₂₀ alkoxy group.

According to one embodiment, the modifier for the radical addition reaction may be represented by the following Chemical Formula 2-1' or Chemical Formula 2-2':

<Formula 2-1'> <Formula 2-2'>

In Formulas 2-1' and 2-2',

R ₂₁ , R ₂₃ To R ₂₆ are each independently hydrogen, -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group, a C ₁ -C ₂₀ alkyl group unsubstituted or substituted with R ₂₀ , R C ₂ -C ₂₀ alkenyl group substituted or unsubstituted with ₂₀ , C ₂ -C ₂₀ alkynyl group substituted or unsubstituted with R ₂₀ , C ₁ -C ₂₀ alkoxy group substituted or unsubstituted with R ₂₀ , R ₂₀ Substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl group, R ₂₀ substituted or unsubstituted C ₁ -C ₁₀ heterocycloalkyl group, R ₂₀ substituted or unsubstituted C ₅ -C ₂₀ aryl group, R ₂₀ substituted Or an unsubstituted C ₁ -C ₂₀ heteroaryl group, a C ₆ -C _{20 arylalkyl group unsubstituted or substituted with R 20, a C 6 -C 20 aryloxy group unsubstituted or substituted with R 20 , substituted with R 20} or an unsubstituted C ₆ -C ₂₀ arylthio group, a monovalent non-aromatic polycyclic group unsubstituted or substituted with R ₂₀ , or a monovalent non-aromatic heteropolycyclic group unsubstituted or substituted with R ₂₀ ,

R ₂₂ is -F, -Cl, -Br, -I, a cyano group, -C(=O)(Q ₁ ), -C(=O)N(Q ₁ )(Q ₂ ), -C(=O )O(Q ₁ ), -S(=O) ₂ (Q ₁ ), or -P(=O)(Q ₁ )(Q ₂ ),

R ₂₀ is deuterium (-D), -F, -Cl, -Br, -I, a hydroxy group, a cyano group, a nitro group;

Deuterium, -F, -Cl, -Br, -I, hydroxyl group, cyano group, nitro group, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ Alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, a C ₆ -C ₂₀ arylthio group, or an unsubstituted or substituted C ₁ -C ₂₀ alkyl group or a C ₁ -C ₆₀ alkoxy group;

Deuterium, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group C ₁ -C ₂₀ alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryloxy group, C ₆ -C ₂₀ arylthio group, or unsubstituted or substituted with any combination thereof selected, C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, or a C ₆ -C ₂₀ arylthio group; or

-N(Q ₃₁ )(Q ₃₂ ), -C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), -S(=O) ₂ (Q ₃₁ ), or -P(=O)(Q ₃₁ )(Q ₃₂ );

Q ₁ , Q ₂ , Q ₃₁ and Q ₃₂ are each independently hydrogen; heavy hydrogen; -F; -Cl; -Br; -I; hydroxyl group; cyano group; nitro group; C ₁ -C ₂₀ alkyl group; C ₂ -C ₂₀ alkenyl group; C ₂ -C ₂₀ alkynyl group; C ₁ -C ₂₀ alkoxy group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, or C ₆ -C ₂₀ arylalkyl group;

For example, in Formulas 2-1' and 2-2', R ₂₁ is selected from hydrogen, a C ₁ -C ₂₀ alkyl group, and Formulas 2-1 to 2-11, and R ₂₂ is a cyano group, C( =O)(Q ₁ ), -C(=O)N(Q ₁ )(Q ₂ ), -C(=O)O(Q ₁ ), -S(=O) ₂ (Q ₁ ), or - P(=O)(Q ₁ )(Q ₂ ) may be:

In Formulas 2-1 to 2-11,

m2 is an integer selected from 1 to 5,

Z ₂₁ to Z ₂₃ are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, C ₁ -C ₂₀ alkyl group, C ₁ -C ₂₀ alkoxy group, -N(Q ₃₁ )(Q ₃₂ ) , C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), -S(=O) ₂ (Q ₃₁ ) , or -P(=O)(Q ₃₁ )(Q ₃₂ ),

Q ₁ , Q ₂ , Q ₃₁ and Q ₃₂ are each independently a C ₁ -C ₂₀ alkyl group or a C ₅ -C ₂₀ aryl group,

d24 is an integer selected from 1 to 4,

d25 is an integer selected from 1 to 5,

d27 is an integer selected from 1 to 7,

d210 is an integer selected from 1 to 10;

According to an embodiment, R ₂₃ to R ₂₆ are each independently hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, or It may be an n-pentyl group. For example, R ₂₃ to R ₂₆ may all be hydrogen.

According to one embodiment, the modifier for the radical-radical coupling reaction may be represented by the following Chemical Formula 3:

<Formula 3>

In Formula 3,

R ₃₁ is hydrogen, -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group, a C ₁ -C ₂₀ alkyl group substituted or unsubstituted with R ₃₀ , C ₂ unsubstituted or substituted with R ₃₀ -C ₂₀ alkenyl group, R ₃₀ substituted or unsubstituted C ₂ -C ₂₀ alkynyl group, R ₃₀ substituted or unsubstituted C ₁ -C ₂₀ alkoxy group, R ₃₀ substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group unsubstituted or substituted with R ₃₀ , C ₅ -C ₂₀ aryl group substituted or unsubstituted with R ₃₀ , C ₁ -C ₂₀ substituted or unsubstituted with R ₃₀ Heteroaryl group, C ₆ -C ₂₀ arylalkyl group substituted or unsubstituted with R ₃₀ , C ₆ -C ₂₀ aryloxy group substituted or unsubstituted with R ₃₀ , C ₆ -C ₂₀ substituted or unsubstituted with R ₃₀ an arylthio group, a monovalent non-aromatic polycyclic group substituted or unsubstituted with R ₃₀ , or a monovalent non-aromatic heteropolycyclic group substituted or unsubstituted with R ₃₀ ,

R ₃₂ is -S(=O) ₂ (Q ₁ ),

R ₃₀ is deuterium (-D), -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group;

Deuterium, -F, -Cl, -Br, -I, hydroxyl group, cyano group, nitro group, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ Alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, a C ₆ -C ₂₀ arylthio group, or an unsubstituted or substituted C ₁ -C ₂₀ alkyl group or a C ₁ -C ₆₀ alkoxy group;

Deuterium, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group C ₁ -C ₂₀ alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryloxy group, C ₆ -C ₂₀ arylthio group, or unsubstituted or substituted with any combination thereof selected, C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, or a C ₆ -C ₂₀ arylthio group; or

-N(Q ₃₁ )(Q ₃₂ ), -C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), -S(=O) ₂ (Q ₃₁ ), or -P(=O)(Q ₃₁ )(Q ₃₂ );

Q ₁ , Q ₃₁ and Q ₃₂ are each independently hydrogen; heavy hydrogen; -F; -Cl; -Br; -I; hydroxyl group; cyano group; nitro group; C ₁ -C ₂₀ alkyl group; C ₂ -C ₂₀ alkenyl group; C ₂ -C ₂₀ alkynyl group; C ₁ -C ₂₀ alkoxy group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, or C ₆ -C ₂₀ arylalkyl group;

For example, in Formula 3, R ₃₁ may be selected from hydrogen, a C ₁ -C ₂₀ alkyl group, and Formulas 3-1 to 3-10 below:

In Formulas 3-1 to 3-10,

m3 is an integer selected from 1 to 5,

Z ₃₁ to Z ₃₃ are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, C ₁ -C ₂₀ alkyl group, C ₁ -C ₂₀ alkoxy group, -N(Q ₃₁ )(Q ₃₂ ) , C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), -S(=O) ₂ (Q ₃₁ ) , or -P(=O)(Q ₃₁ )(Q ₃₂ ),

Q ₃₁ and Q ₃₂ are each independently a C ₁ -C ₂₀ alkyl group or a C ₅ -C ₂₀ aryl group,

d34 is an integer selected from 1 to 4,

d35 is an integer selected from 1 to 5;

d37 is an integer selected from 1 to 7,

d310 is an integer selected from 1 to 10.

According to one embodiment, the method for preparing the γ-lactam derivative may be performed in a single electrolysis cell. For example, the method for producing the γ-lactam derivative is performed in a single electrolysis cell, so the process is simple and easy to control. In addition, the electrolysis cell may be driven at room temperature and in an argon atmosphere.

According to one embodiment, the electrolysis cell may include a glassy carbon anode and a carbon felt cathode. By using such an anode and a cathode, it is possible to introduce a substituent into the γ-lactam compound by electrolysis.

According to one embodiment, the electrolysis cell may include n-Bu ₄ NBF ₄ or n-Bu ₄ NPF ₆ as an electrolyte. By including such an electrolyte, a substituent can be introduced into the γ-lactam compound by electrolysis, and a γ-lactam derivative having a desired yield can be prepared.

According to one embodiment, the electrolysis cell may include MeCN or DMF as a solvent.

According to one embodiment, the electrolysis cell is sufficient to oxidize the hydrogen transfer catalyst, and at the same time, the γ-lactam compound can be operated at a voltage that does not oxidize. For example, the voltage may be 0.7V or more and 2.2V or less.

According to one embodiment, the hydrogen transfer catalyst is tetrabutylammonium azide, and after the azido radical (N ₃ ^- ) is generated at the positive electrode, the azido radical is formed at the β-carbon position of the γ-lactam compound. It can react with hydrogen to form HN ₃ products and γ-lactam-like radical compounds. For a detailed reaction mechanism, refer to the following description.

According to one embodiment, the HN ₃ product may be reduced in the anode to generate an azido radical. Accordingly, a radical addition reaction or a radical-radical coupling reaction may be repeatedly performed.

According to one aspect, there is provided a γ-lactam derivative prepared according to the above-described method for preparing a γ-lactam derivative.

According to one embodiment, the γ-lactam derivative may be selected from the following compounds:

The method for preparing γ-lactam derivatives according to an embodiment of the present invention can be more clearly understood through the following examples, but the present invention is not limited thereto.

[Example]

It should be understood that the symbols and numbers used in the examples relate to the drawings and to the embodiment compounds described above.

1. Review of Optimization Conditions for Electrolysis Cells

Reaction conditions were screened using 0.1 mmol of N-methyl isoindolinone 1a and 0.15 mol of methyl cinnamate 2a as coupling partners (Fig. 1), and catalytic amounts of nBu ₄ NN ₃ 0.03 mmol and nBu ₄ NBF ₄ 0.1M were used as electrolytes. was used to find that the reaction proceeded in 82% yield in 1 hour. (constant current 3mA, glassy carbon (GC) anode and carbon felt (CF) cathode, room temperature, acetonitrile (MeCN) 0.03 M, unseparated cell). Lower yields were obtained at higher currents or constant voltages (Figure 1, items 2 and 3). The choice of electrolyte had a significant effect on the reaction efficiency. nBu ₄ NPF ₆ turned out to be optimal, but no reaction was observed with LiClO ₄ ( FIGS. 1 , items 4 and 5 ). The solvent effect was also investigated.

While the use of MeCN gave the highest yield, DMF was inferior and no reaction was observed with DCM and MeOH (Fig. 1, entries 6-8). Replacing the cathode or anode with graphite electrodes decreased the yield (Fig. 1, items 9-11). Other HAT mediators, including NaN ₃ , 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine and methyl thioglycolate, showed that the bond dissociation energy (BDE) was sufficient to promote HAT for 1a. However, the yield was lowered (Fig. 1, items 12-15). Reducing the loading of the HAT mediator nBu ₄ NN ₃ to 5 mol% reduced the conversion (Fig. 1, item 16). In the absence of current or nBu ₄ NN ₃ , the reaction produced no products and air had a detrimental effect. (Fig. 1, items 18-20).

2. Synthesis experiment using various substrates (starting materials)

(Experimental conditions)

1a - 0.1 mmol; 2 - 0.15 mmol; MeCN - 0.03 M; Ar atmosphere; parentheses - ratio of diisomers;

However, in the case of the compound indicated by the superscript c, the experiment was carried out using the amount of alkene 2 as 3 equivalents.

(Experiment result)

A range of substrates was investigated using various alkenes 2 under optimized conditions. As can be seen in Figure 2, a wide range of functionalized isoindolinone 3 can be synthesized in medium to good yield. The electronic effect of alkene 2 was investigated using various substituted cinnamates. The electron-rich substrate showed high conversion (3ab-3af), while the electron-poor cinnamate (3ak) gave a moderate yield. Potential redox functional groups, including amino, bromo and keto groups, were found to be stable under the reaction conditions (3af and 3ah-3aj). We also investigated the reaction compatibility of various aryl and heteroaryl groups, including naphthalene (3am), pyridine (3an), furan (3ao), thiophene (3ap), indole (3aq) and benzothiophene (3ar).

As a result, the same reaction proceeded in this substrate as well, and a substituent was introduced as expected. It has been found that replacing the aryl-substituted alkene with an alkyl group gives the corresponding product in moderate yield (3as-3au). Exclusive formation of beta substitutions was observed for 1,3-diene (3av). In addition to the ester-containing alkenes, various electron withdrawing groups including ketones, amides, nitriles, phosphonates, phenyl sulfones and sulfonamides participated smoothly to yield the desired product in good yield (3aw-3aac). Late stage functionalization where estrone derivatives are well tolerated to give the product of interest (3aad) was investigated.

Tandem C-C bond formation offers great advantages in building reaction efficiency and molecular complexity. With the presence of a quaternary carbon center, the spirocycle presents a unique synthesis problem. Thus, for spirocycle synthesis, the possibility of a double HAT process for formation of two C-C bonds in a single step was investigated. As a result, it was confirmed that the tandem intermolecular cyclization proceeded smoothly to provide the corresponding spirocycle in good yield using the 1,2-divinyl substituted arene as the acceptor (3aae-3aah).

3. Review of reactivity of isoindolinone and α,β-unsaturated lactam

(Experimental conditions)

1 - 0.1 mmol; 2 - 0.15 mmol; MeCN - 0.03 M; Ar atmosphere; parentheses - ratio of diisomers;

However, in the case of the compound denoted by the superscript c, the experiment was carried out using the amount of alkene 2 in 3 equivalents, and in the case of the compound denoted by the superscript d, the experiment was carried out in a constant voltage mode of 2.5V

(Experiment result)

Attention was paid to the electronic effect of the aryl moiety of isoindolinone (Figure 3). Groups with both electron-donating and electron-withdrawing groups were found to give good yields (3ba-3fa). Likewise, a wide range of substituents with varying degrees of electronic effect respond well to the N-substituent (3ga-3ma) of isoindolinone. In addition, the redox labile iodine-substituted isoindolinones provided high yields. To investigate the regioselectivity, we applied N-benzyl isoindolinones to the reaction conditions and found that the complete selectivity of the isoindolinones to N-α methylene surpassed that of the benzyl group (3na-3oa). To investigate the steric effect on C-C bond formation, reaction conditions were applied to substrates with tertiary C-H bonds, including 3-methyl isoindolinone and 3-phenyl isoindolinone, respectively. The methyl substituted isoindolinone reacts smoothly with both the acrylate and the sterically denser phenylacrylate to give the corresponding product with a quaternary center (3pai and 3pa, 60% and 65% respectively), When reacted with phenyl acrylate and acrylonitrile, phenyl substituted acrylates showed moderate yields (3qai and 3qaj, respectively, 47% and 53%). In addition, N-H isoindolinone, phenyl acrylate, and acrylonitrile were respectively reacted to produce coupling products 3ra and 3raj, respectively. Moreover, we found that the reaction with 1,2-dihydroisoquinolinone gave 3sa in 94% yield.

In addition to isoindolinone, various α,β-unsaturated lactams were found to participate smoothly in the reaction. Both α- and β-substituted lactams containing aliphatic and aryl groups gave coupling products in good to medium yields (3ta-3xa). Reaction with the structurally more complex α,β-disubstituted bicyclic lactam also yielded the corresponding coupling product in good yield. We also investigated the possibility of C–C bond formation at the ring junctions of bicyclic lactams. To our delight, various functionalized lactams have been obtained (3ta-3bbak).

4. Review of intramolecular cyclization reaction of γ-lactam derivatives

(Experimental conditions)

4 - 0.1 mmol; MeCN - 0.03 M; Ar atmosphere; parentheses - ratio of diisomers;

However, in the case of the compound denoted by the superscript c, the experiment was carried out using the Mg cathode.

(Experiment result)

As the range of intermolecular coupling was established, it was confirmed whether the protocol could be extended to intramolecular cyclics (Fig. 4). Depending on the tether attachment site, spiro- and fused-cycles were synthesized with moderate to excellent yields. Formation of 5- and 6-membered carbocycles with respect to spirocycles has been demonstrated (5a, 5b). Various fusion ring systems (5c-5f) can be prepared with alternative tether attachments to the N2 position.

5. Coupling reaction between isoindolinone and N-sulfonyl imine

(Experimental conditions)

1a - 0.4 mmol; 6- 1.2 mmol; MeCN - 0.1 M; Ar atmosphere; parentheses - ratio of diisomers;

However, in the case of the compound denoted by the superscript c, the experiment was carried out in the constant voltage mode 6V.

(Experiment result)

Next, N-sulfonyl imine was investigated as a coupling partner (FIG. 5). Initial attempts using 1a and N-sulfonyl imine (6a) as substrates gave sulfonamide 7aa in 33% yield under standard conditions for reaction with alkenes, but much improved when performed at higher concentrations of 0.1 M 75 % yield was obtained. A range response was investigated under optimized conditions. The electron deficient imine, methyl benzoate sulfonamide (7ag), was found to be poorly tolerated, while various substituted imines gave the corresponding sulfonamides in good to moderate yields. We also investigated the reactivity of heteroaryl imines, including thiophenes and furans, in which thiophenes show good reactivity towards furans. Also, despite the low yield, the corresponding product 7ak was obtained using the alkyl imine.

6. Synthesis Reaction at Gram-Scale

(Experimental conditions)

parentheses - ratio of diisomers;

(Experiment result)

We investigated the method for the reaction at the gram-scale by conducting the reaction with 1.03 g of 1a, which gave 3aa in 77% yield (Fig. 6A). The usefulness of functionalized isoindolinone was demonstrated by facile conversion into dihydroari-stolactam and aristolactam scaffolds 8a and 8b (Fig. 6B). In addition, pyrrolizidines are known to have various important biological activities capable of producing 8d from isoindoli-none 3ja (FIG. 6C).

7. Review of Effects of Hydrogen Transfer Catalysts

After observing a significant concentration dependence of the reaction efficiency between alkenes and imines, we speculated that a distinct reaction mechanism might be at work. Several control experiments and density functional theory (DFT) calculations were performed to explain the mechanisms related to alkenes, and the reaction is shown in FIG. 7 . First, to confirm that activation of 1a involves HAT by azido radicals formed by anodic oxidation of azide rather than direct oxidation of 1a, the reaction was performed in the absence of nBu ₄ NN ₃ and no conversion was found (Fig. 7A). -i). Cyclic voltammetry (CV) was performed for 1a, 2a and HAT mediator azide to gain insight into the redox process.

Based on this information, voltage control experiments were performed. When the reaction was performed at 1.8 V sufficient to oxidize the azide (Ep/2ox = 0.7 V vs. SCE) but not to oxidize 1a (Ep/2ox = 2.25 V vs. SCE), the formation of 3aa was observed. . (Fig. 7 A-ii). This observation supports that the reaction proceeds through the HAT mechanism. HAT of 1a by azido radical is calculated BDE (DFT calculation result from B3LYP-D3/6-31G(d) of SMD (MeCN), 78.7 kcal/mol for 1a vs 88.4 kcal/mol for HN ₃ ) It seems to be an advantageous process based on it. In addition, by observing that addition of 2,6-Di-tert-butyl-4-methylphenol (BHT) as a radical scavenger completely inhibits the reaction with the identification of 1a-BHT adducts confirmed by HRMS, existence was confirmed. (Fig. 7B).

8. Review of Synthetic Reaction Mechanisms involving N-sulfonyl imine

Next, we investigated the reaction mechanism associated with N-sulfonyl imine (Fig. 8). Similar to the reaction with alkene, the reaction without azide gave only traces of 7aa. More importantly, we observed the formation of imine dimer 6'aa in 18% yield, suggesting the formation of a radical species derived from 6a (Fig. 8A). This was further confirmed by performing the reaction in the absence of 1a, which resulted in the formation of 6'aa in 29% yield (Fig. 8B). In addition, the formation of radical species derived from 1a was confirmed by observing the corresponding BHT adduct ( FIG. 8C ). These results strongly suggest a reaction involving an N-sulfonyl radical anion (C) and a 1a radical intermediate (A).

9. Review of Reaction Mechanism

A reaction mechanism is proposed in FIG. 9 based on control experiments and DFT calculations. Anodization of the azide provides an azido radical, which mediated HAT in 1a to form A. Subsequent addition of A to 2a gave B with dG‡ = 20 kcal/mol. B provided the coupling product 3aa after HAT ( FIG. 9A ).

On the other hand, a distinct mechanism is proposed for the reaction with N-sulfonyl imine involving radical-radical cross-linking based on control experiments (Fig. 9B, 9C). Thus, radical species A initially formed by HAT underwent coupling with radical anion C formed by cathodic reduction of 6a (Fig. 9D). To corroborate the mechanism, we performed DFT calculations where barrierless coupling leads to a highly vigorous reaction with dG = -24.8 kcal/mol. We also investigated an alternative reaction pathway involving the radical addition of A to 6a, which turned out to be undesirable at dG‡ = 24.2 kcal/mol (Fig. 9C).

10. Conclusion

In conclusion, functionalization of γ-lactam compounds was possible based on the electrochemical activation of C(sp3)-H bond through HAT, and by using catalytic amount of nBu ₄ NN ₃ as a HAT mediator, Coupling reactions of alkenes and N-sulfonyl imines proceeded over a wide range of substrates. Moreover, it can be confirmed through the mechanism that the structuring of the quaternary carbon center from the methylene group in an intermolecular manner was achieved based on the double HAT process. Detailed mechanistic studies, including experiments and DFT calculations, elucidated the reaction pathway.

Claims (20)

contacting a γ-lactam compound with a hydrogen transfer catalyst to form a γ-lactam radical intermediate; and
introducing a substituent by a radical addition reaction of the γ-lactam radical intermediate and a modifier, a radical-radical coupling reaction, or an intramolecular cyclization reaction;
A method for producing a γ-lactam derivative comprising a. According to claim 1,
The method for producing a γ-lactam derivative, wherein the γ-lactam compound is a substituted or unsubstituted γ-lactam, or a substituted or unsubstituted isoindolinone. According to claim 1,
The hydrogen transfer catalyst is tetrabutylammonium azide, NaN ₃ , 1,4-diazabicyclo[2.2.2]octane (DABCO), quinuclidine, methyl thioglycolate or a mixture thereof, a γ-lactam derivative manufacturing method. According to claim 1,
The modifier for the radical addition reaction is a compound containing at least one C=C bond, a method for producing a γ-lactam derivative. 5. The method of claim 4,
The method of claim 1, wherein the compound further comprises at least one electron withdrawing group. According to claim 1,
The radical-modifier for the radical coupling reaction is a compound including at least one C=N bond, a method for producing a γ-lactam derivative. 7. The method of claim 6,
The method for producing a γ-lactam derivatives, wherein the compound further comprises a sulfonyl group. According to claim 1,
The γ-lactam compound is a method for producing a γ-lactam derivative represented by the following Chemical Formula 1-1 or 1-2:
<Formula 1-1><Formula1-2>

In Formula 1,
n is an integer selected from 0 to 2, and when n is 0, the carbon (C) of the acyl group and the ring-forming carbon (C) to which R ₄ is bonded are connected by a single bond,
R ₁ To R ₈ are each independently hydrogen, -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group, a C ₁ -C ₂₀ alkyl group unsubstituted or substituted with R ₁₀ , R ₁₀ Substituted or unsubstituted C ₂ -C ₂₀ alkenyl group, R ₁₀ substituted or unsubstituted C ₂ -C ₂₀ alkynyl group, R ₁₀ substituted or unsubstituted C ₁ -C ₂₀ alkoxy group, R ₁₀ substituted or Unsubstituted C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group unsubstituted or substituted with R ₁₀ , C ₅ -C ₂₀ aryl group unsubstituted or substituted with R ₁₀ , substituted or unsubstituted with R ₁₀ A cyclic C ₁ -C ₂₀ heteroaryl group, a C ₆ -C ₂₀ arylalkyl group unsubstituted or substituted with R ₁₀ , a C ₆ -C ₂₀ aryloxy group unsubstituted or substituted with R ₁₀ , unsubstituted or substituted with R ₁₀ cyclic C ₆ -C ₂₀ arylthio group, -C(=O)(Q ₁ ), -C(=O)N(Q ₁ )(Q ₂ ), -C(=O)O(Q ₁ ), -S(=O) ₂ (Q ₁ ), or -P(=O)(Q ₁ )(Q ₂ ),
Among the R ₁ to R ₄ , adjacent groups are optionally bonded to each other, a C ₃ -C ₁₀ cycloalkyl group substituted or unsubstituted with R ₁₀ , C ₁ -C ₁₀ heterocycloalkyl unsubstituted or substituted with R ₁₀ . An alkyl group, a C ₅ -C ₂₀ aryl group substituted or unsubstituted with R ₁₀ , or a C ₁ -C ₂₀ heteroaryl group substituted or unsubstituted with R ₁₀ may be formed,
Wherein R ₁₀ is deuterium (-D), -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group;
Deuterium, -F, -Cl, -Br, -I, hydroxyl group, cyano group, nitro group, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ Alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, a C ₆ -C ₂₀ arylthio group, or an unsubstituted or substituted C ₁ -C ₂₀ alkyl group or a C ₁ -C ₆₀ alkoxy group;
Deuterium, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group C ₁ -C ₂₀ alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryloxy group, C ₆ -C ₂₀ arylthio group, or unsubstituted or substituted with any combination thereof selected, C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, or a C ₆ -C ₂₀ arylthio group; or
N(Q ₃₁ )(Q ₃₂ ), -C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), - S(=O) ₂ (Q ₃₁ ), or -P(=O)(Q ₃₁ )(Q ₃₂ );
Q ₁ , Q ₂ , Q ₃₁ and Q ₃₂ are each independently hydrogen; heavy hydrogen; -F; -Cl; -Br; -I; hydroxyl group; cyano group; nitro group; C ₁ -C ₂₀ alkyl group; C ₂ -C ₂₀ alkenyl group; C ₂ -C ₂₀ alkynyl group; C ₁ -C ₂₀ alkoxy group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, or C ₆ -C ₂₀ arylalkyl group; According to claim 1,
The modifier for the radical addition reaction is a method for producing a γ-lactam derivative represented by the following Chemical Formula 2-1' or Chemical Formula 2-2':
<Formula 2-1'><Formula2-2'>

In Formulas 2-1' and 2-2',
R ₂₁ , R ₂₃ To R ₂₆ are each independently hydrogen, -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group, a C ₁ -C ₂₀ alkyl group unsubstituted or substituted with R ₂₀ , R C ₂ -C ₂₀ alkenyl group substituted or unsubstituted with ₂₀ , C ₂ -C ₂₀ alkynyl group substituted or unsubstituted with R ₂₀ , C ₁ -C ₂₀ alkoxy group substituted or unsubstituted with R ₂₀ , R ₂₀ Substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl group, R ₂₀ substituted or unsubstituted C ₁ -C ₁₀ heterocycloalkyl group, R ₂₀ substituted or unsubstituted C ₅ -C ₂₀ aryl group, R ₂₀ substituted Or an unsubstituted C ₁ -C ₂₀ heteroaryl group, a C ₆ -C _{20 arylalkyl group unsubstituted or substituted with R 20, a C 6 -C 20 aryloxy group unsubstituted or substituted with R 20 , substituted with R 20} or an unsubstituted C ₆ -C ₂₀ arylthio group, a monovalent non-aromatic polycyclic group unsubstituted or substituted with R ₂₀ , or a monovalent non-aromatic heteropolycyclic group unsubstituted or substituted with R ₂₀ ,
R ₂₂ is -F, -Cl, -Br, -I, a cyano group, -C(=O)(Q ₁ ), -C(=O)N(Q ₁ )(Q ₂ ), -C(=O )O(Q ₁ ), -S(=O) ₂ (Q ₁ ), or -P(=O)(Q ₁ )(Q ₂ ),
R ₂₀ is deuterium (-D), -F, -Cl, -Br, -I, a hydroxy group, a cyano group, a nitro group;
Deuterium, -F, -Cl, -Br, -I, hydroxyl group, cyano group, nitro group, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ Alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, a C ₆ -C ₂₀ arylthio group, or an unsubstituted or substituted C ₁ -C ₂₀ alkyl group or a C ₁ -C ₆₀ alkoxy group;
Deuterium, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group C ₁ -C ₂₀ alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryloxy group, C ₆ -C ₂₀ arylthio group, or unsubstituted or substituted with any combination thereof selected, C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, or a C ₆ -C ₂₀ arylthio group; or
-N(Q ₃₁ )(Q ₃₂ ), -C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), -S(=O) ₂ (Q ₃₁ ), or -P(=O)(Q ₃₁ )(Q ₃₂ );
Q ₁ , Q ₂ , Q ₃₁ and Q ₃₂ are each independently hydrogen; heavy hydrogen; -F; -Cl; -Br; -I; hydroxyl group; cyano group; nitro group; C ₁ -C ₂₀ alkyl group; C ₂ -C ₂₀ alkenyl group; C ₂ -C ₂₀ alkynyl group; C ₁ -C ₂₀ alkoxy group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, or C ₆ -C ₂₀ arylalkyl group; 10. The method of claim 9,
In Formula 2, R ₂₁ is selected from hydrogen, a C ₁ -C ₂₀ alkyl group, and Formulas 2-1 to 2-11, and R ₂₂ is a cyano group, C(=O)(Q ₁ ), -C(= O)N(Q ₁ )(Q ₂ ), -C(=O)O(Q ₁ ), -S(=O) ₂ (Q ₁ ), or -P(=O)(Q ₁ )(Q ₂ ) ), and the preparation method of γ-lactam derivatives:

In Formulas 2-1 to 2-11,
m2 is an integer selected from 1 to 5,
Z ₂₁ to Z ₂₃ are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, C ₁ -C ₂₀ alkyl group, C ₁ -C ₂₀ alkoxy group, -N(Q ₃₁ )(Q ₃₂ ) , C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), -S(=O) ₂ (Q ₃₁ ) , or -P(=O)(Q ₃₁ )(Q ₃₂ ),
Q ₁ , Q ₂ , Q ₃₁ and Q ₃₂ are each independently a C ₁ -C ₂₀ alkyl group or a C ₅ -C ₂₀ aryl group,
d24 is an integer selected from 1 to 4,
d25 is an integer selected from 1 to 5,
d27 is an integer selected from 1 to 7,
d210 is an integer selected from 1 to 10; According to claim 1,
The modifier for the radical-radical coupling reaction is represented by the following Chemical Formula 3, a method for producing a γ-lactam derivative:
<Formula 3>

In Formula 3,
R ₃₁ is hydrogen, -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group, a C ₁ -C ₂₀ alkyl group substituted or unsubstituted with R ₃₀ , C ₂ unsubstituted or substituted with R ₃₀ -C ₂₀ alkenyl group, R ₃₀ substituted or unsubstituted C ₂ -C ₂₀ alkynyl group, R ₃₀ substituted or unsubstituted C ₁ -C ₂₀ alkoxy group, R ₃₀ substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group unsubstituted or substituted with R ₃₀ , C ₅ -C ₂₀ aryl group substituted or unsubstituted with R ₃₀ , C ₁ -C ₂₀ substituted or unsubstituted with R ₃₀ Heteroaryl group, C ₆ -C ₂₀ arylalkyl group substituted or unsubstituted with R ₃₀ , C ₆ -C ₂₀ aryloxy group substituted or unsubstituted with R ₃₀ , C ₆ -C ₂₀ substituted or unsubstituted with R ₃₀ an arylthio group, a monovalent non-aromatic polycyclic group substituted or unsubstituted with R ₃₀ , or a monovalent non-aromatic heteropolycyclic group substituted or unsubstituted with R ₃₀ ,
R ₃₂ is -S(=O) ₂ (Q ₁ ),
R ₃₀ is deuterium (-D), -F, -Cl, -Br, -I, a hydroxyl group, a cyano group, a nitro group;
Deuterium, -F, -Cl, -Br, -I, hydroxyl group, cyano group, nitro group, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ Alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, a C ₆ -C ₂₀ arylthio group, or an unsubstituted or substituted C ₁ -C ₂₀ alkyl group or a C ₁ -C ₆₀ alkoxy group;
Deuterium, C ₁ -C ₂₀ alkyl group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group C ₁ -C ₂₀ alkoxy group C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryloxy group, C ₆ -C ₂₀ arylthio group, or unsubstituted or substituted with any combination thereof selected, C ₃ -C ₁₀ cycloalkyl group, C ₁ -C ₁₀ heterocycloalkyl group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, C ₆ -C ₂₀ arylalkyl group, C ₆ -C ₂₀ aryl an oxy group, or a C ₆ -C ₂₀ arylthio group; or
-N(Q ₃₁ )(Q ₃₂ ), -C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), -S(=O) ₂ (Q ₃₁ ), or -P(=O)(Q ₃₁ )(Q ₃₂ );
Q ₁ , Q ₃₁ and Q ₃₂ are each independently hydrogen; heavy hydrogen; -F; -Cl; -Br; -I; hydroxyl group; cyano group; nitro group; C ₁ -C ₂₀ alkyl group; C ₂ -C ₂₀ alkenyl group; C ₂ -C ₂₀ alkynyl group; C ₁ -C ₂₀ alkoxy group, C ₅ -C ₂₀ aryl group, C ₁ -C ₂₀ heteroaryl group, or C ₆ -C ₂₀ arylalkyl group; 12. The method of claim 11,
In Formula 3, R ₃₁ is hydrogen, a C ₁ -C ₂₀ alkyl group, and a method for producing a γ-lactam derivative selected from Formulas 3-1 to 3-10:

In Formulas 3-1 to 3-10,
m3 is an integer selected from 1 to 5,
Z ₃₁ to Z ₃₃ are each independently hydrogen, deuterium, -F, -Cl, -Br, -I, C ₁ -C ₂₀ alkyl group, C ₁ -C ₂₀ alkoxy group, -N(Q ₃₁ )(Q ₃₂ ) , C(=O)(Q ₃₁ ), -C(=O)N(Q ₃₁ )(Q ₃₂ ), -C(=O)O(Q ₃₁ ), -S(=O) ₂ (Q ₃₁ ) , or -P(=O)(Q ₃₁ )(Q ₃₂ ),
Q ₃₁ and Q ₃₂ are each independently a C ₁ -C ₂₀ alkyl group or a C ₅ -C ₂₀ aryl group,
d34 is an integer selected from 1 to 4,
d35 is an integer selected from 1 to 5;
d37 is an integer selected from 1 to 7,
d310 is an integer selected from 1 to 10. According to claim 1,
The method for preparing the γ-lactam derivative is performed in a single electrolysis cell. 14. The method of claim 13,
The electrolysis cell comprises a glassy carbon anode and a carbon felt cathode, a method for producing a γ- lactam derivatives. 14. The method of claim 13,
The electrolysis cell comprises n-Bu ₄ NBF ₄ or n-Bu ₄ NPF ₆ as an electrolyte, a method for producing a γ-lactam derivative. 14. The method of claim 13,
The electrolysis cell comprises MeCN or DMF as a solvent, γ- lactam derivatives manufacturing method. 14. The method of claim 13,
wherein the electrolysis cell is operated at a voltage sufficient to oxidize the hydrogen transfer catalyst and at the same time not oxidize the γ-lactam compound. 15. The method of claim 14,
wherein the hydrogen transfer catalyst is tetrabutylammonium azide,
After the azido radical (N ₃ ⁻ ) is generated at the positive electrode, the azido radical reacts with hydrogen at the β-carbon position of the γ-lactam compound to generate a HN ₃ product and a γ-lactam radical compound, A method for producing γ-lactam derivatives. 19. The method of claim 18,
A method for producing a γ-lactam derivative, wherein the HN ₃ product is reduced in the anode to generate an azido radical. A γ-lactam derivative prepared according to any one of claims 1 to 19.

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