1. A method for decarboxylation of an active ester compound to form a C-S bond is characterized in that:

under the condition of illumination, the general formula is R_a-COONPhth and an active ester of the general formula R_b-S-S-R_cThe disulfide of (a) is reacted in a liquid environment provided by an organic solvent containing an organic base under catalysis of a photocatalyst as follows:

R_a-COONPhth+R_b-S-S-R_c→R_a-S-R_b，

in the above formula, the equivalence ratio of each raw material satisfies: the R is_a-COONPhth: the R is_b-S-S-R_c: 0.5-2: 1-2.5: 1-2.5 in said R_a-S-R_bIn (1), the R_aThe S atom is bonded through C-S;

the photocatalyst is Ru (bpy)₂Cl₂·6H₂O；

The R is_bAnd said R_cIndependently selected from one of alkyl, optionally substituted alkyl, multi-heterocyclic ring or optionally substituted multi-heterocyclic ring, and the R is_bAnd said R_cAll are aromatic groups.

2. A process for decarboxylation of an active ester compound to produce a C-S bond as claimed in claim 1 wherein: the R is_bOr/and said R_cSelected from aryl or said optionally substituted aryl.

3. A process for decarboxylation of an active ester compound to produce a C-S bond as claimed in claim 2 wherein: the substituent on the optionally substituted aryl is selected from one or more of methyl, methoxy, ether or halogen atoms.

4. A process for decarboxylation of an active ester compound to produce a C-S bond as claimed in claim 3 wherein: the halogen atom is selected from one or more of F atom, Cl atom or Br atom.

5. A process for decarboxylation of an active ester compound to produce a C-S bond as claimed in claim 1 wherein: the R is_bOr/and said R_cSelected from a heterocyclic ring or an optionally substituted heterocyclic ring;

each heteroatom in the multinary heterocycle is independently selected from a N atom or an S atom;

each heteroatom in the optionally substituted polyatomic heterocycle is independently selected from a N atom or a S atom.

6. A process for decarboxylation of an active ester compound to produce a C-S bond as claimed in claim 5 wherein: the polyheterocycle is a pyridine ring, and the optionally substituted polyheterocycle is an optionally substituted pyridine ring.

7. A process for decarboxylation of an active ester compound to produce a C-S bond as claimed in claim 1 wherein: the organic solvent is one of dimethylacetamide or acetonitrile.

8. A process for decarboxylation of an active ester compound to produce a C-S bond as claimed in claim 1 wherein: the organic solvent alkali is selected from one of N, N-diisopropylethylamine or triethylamine.

9. A process for decarboxylation of an active ester compound to produce a C-S bond as claimed in claim 1 wherein: the illumination condition is blue light illumination.

10. The method of decarboxylation of an active ester compound to produce a C-S bond according to claim 1, wherein the raw materials are used in an equivalent ratio of: the R is_a-COONPhth: the R is_b-S-S-R_c: the organic base is 1: 2: 2.

Background

C — S bonds are widely present in many common bioactive substances, natural products and functional materials. In particular, in the field of medicinal chemistry, sulfur-containing organic compounds play an important role in the disease types of cancer, diabetes, alzheimer's disease, aids and the like. Therefore, how to conveniently and efficiently construct the C-S bond in synthetic chemistry has important significance.

Over the past several decades, efforts have been made to utilize transition metal catalysis to build C-S bonds, including cross-coupling of aryl halides or borates with thiols or disulfides, and addition reactions of S-S and S-H bonds with alkyne triple bonds. In recent years, photo-redox catalysis has become a powerful and practical strategy in the field of organic synthesis, and the construction of C-S bonds by using the strategy has received much attention. In the prior art, a photocatalyst is typically employed to catalyze the reaction of an aryl halide with a thiol or thiophenol to build a C — S bond. Procopiou et al successfully constructed a C — S bond with thiol under irradiation by two 200w tungsten filament bulbs. However, in the current decarboxylation methods for constructing C-S bonds, the sulfur source is limited to thiols or thiophenols.

Disclosure of Invention

The invention aims to provide a method for decarboxylation of an active ester compound to generate a C-S bond, and provides a novel method for constructing the C-S bond.

According to one aspect of the present invention, there is provided a process for decarboxylation of an active ester compound to produce a C-S bond: under the condition of illumination, the general formula is R_a-COONPhth and an active ester of the general formula R_b-S-S-R_cThe disulfide of (a) is reacted in a liquid environment provided by an organic solvent containing an organic base under catalysis of a photocatalyst as follows: r_a-COONPhth+R_b-S-S-R_c→R_a-S-R_bIn the above formula, the equivalence ratio of each raw material satisfies: r_a-COONPhth：R_b-S-S-R_c: organic base ═ 0.5-2: 1-2.5: 1-2.5 at R_a-S-R_bIn, R_aThe S atom is bonded through C-S; the photocatalyst is Ru (bpy)₂Cl₂·6H₂O；R_bAnd R_cIndependently selected from one of alkyl, optionally substituted alkyl, multi-heterocyclic ring or optionally substituted multi-heterocyclic ring, R_bAnd R_cAll are aromatic groups. As used herein, "optionally substituted hydrocarbyl" refers to hydrocarbyl groups in which at least one hydrogen atom on any one carbon atom of the carbon chain is replaced with another group other than hydrogen. As used herein, "optionally substituted polyheterocycles" means that at least one hydrogen atom on a ring-forming carbon atom in the polyheterocycle is replaced with another group other than hydrogen.

Preferably, R_bOr/and R_cSelected from aryl or optionally substituted aryl.

Preferably, the substituents on the optionally substituted aryl group are selected from one or more of methyl, methoxy, ether or halogen atoms.

Preferably, the halogen atoms are selected from one or more of F atoms, Cl atoms or Br atoms.

Preferably, R_bOr/and R_cSelected from a heterocyclic ring or an optionally substituted heterocyclic ring; each heteroatom in the multinary heterocycle is independently selected from a N atom or a S atom; each heteroatom in the optionally substituted polyatomic heterocycle is independently selected from a N atom or a S atom.

Preferably, the polyheterocycle is a pyridine ring and the optionally substituted polyheterocycle is an optionally substituted pyridine ring.

Preferably, the organic solvent is selected from one of dimethylacetamide or acetonitrile.

Preferably, the organic solvent base is selected from one of N, N-diisopropylethylamine or triethylamine.

Preferably, the lighting condition is blue light lighting.

Preferably, the raw materials are in the equivalent ratio: the R is_a-COONPhth：R_b-S-S-R_c: organic base ═ 1: 2: 2.

by utilizing the advantages of easy preparation and higher reaction activity of the alkyl active ester, the invention has R_aThe active ester with the structure of-COONPhth constructs a precursor of a C-S bond and enables the precursor to react in a photocatalyst Ru (bpy)₂Cl₂·6H₂And the decarboxylation coupling reaction is successfully carried out with the disulfide under the catalysis of O, and the compound with the C-S bond is generated. A wide selection of active esters and disulfides, both of which are efficient participants in the decarboxylation coupling reaction, are available. By the above reaction, alkyl sulfides having various structures can be produced.

The yield of the target product of the reaction is effectively improved by further limiting the organic solvent, the organic base or the illumination condition involved in the reaction. Moreover, the optimal reaction conditions required by the reaction are mild, can be carried out at normal temperature and normal pressure, are not harsh on reaction instruments, and have high universality on various reactants. The method for generating the C-S bond by decarboxylation of the active ester compound is expected to be popularized and applied to practical production.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.

In the following examples, use is made of¹⁹F nuclear magnetic resonance spectroscopy, and using fluorobenzene as an internal standard substance to determine the yield.

Example 1

In the present embodiment, a plurality of treatment groups are provided based on the following control treatment method, and the treatment method of each treatment group is strictly consistent with the control treatment method except for the special variable description. The reaction formula is as follows:

in the reaction used for the control treatment, toAs active esters, withAs a sulfur source.

Comparison treatment mode: adding 0.1mmol of0.2mmol of0.2mmol of N, N-diisopropylethylamine was added to 1mL of dimethylacetamide (DMAc), and a photocatalyst Ru (bpy) was added to the reaction in an amount of 1 mol%₂Cl₂·6H₂O; the reaction was carried out at room temperature for 20 hours with blue light.

The variable settings and the yields of the target products for each treatment group are shown in table 1.

TABLE 1 influence of the arrangement of the treatment groups of this example on the yield of the target product

The experimental setup of treatment 1 was strictly consistent with the control treatment, with the product yield of the target product prepared by treatment 1 being as high as 99% or more. As can be seen from the comparison of the product yields of treatments 1 to 7, the choice of organic solvent and organic base has a significant effect on the product yield. Selection for organic solvents: treatment 3 with CH₃CN replaces DMAc, so that decarboxylation coupling reaction can be smoothly carried out, however, the yield of the product corresponding to the treatment 3 is obviously lower than that of the treatment 1; and in the treatment 2 and the treatment 4, DCM and THF are respectively used for replacing DMAc to carry out decarboxylation coupling reaction, the reaction is almost completely inhibited, and the target product is hardly obtained. On the other hand, for the selection of organic bases: treatment 5 with NEt₃The decarboxylation coupling reaction can be smoothly carried out by replacing DIPEA, but the yield of the product corresponding to the treatment 5 is obviously lower than that of the treatment 1; treatment 6 and treatment 7 each used HNEt₂、Cs₂CO₃The decarboxylation coupling reaction was performed instead of DIPEA, but treatment 10 did not add an organic base to the reaction system, and the decarboxylation coupling reaction was almost completely inhibited in the three treatment groups, and the target product was hardly obtained. The product yield of each treatment group in table 1 reflects that the photocatalyst, the illumination conditions, the organic base and the organic solvent are important factors for the decarboxylation coupling reaction of this example.

Example 2

In this example, various compounds of the formula R were selected_a-COONPhth and the general formulaAs a reactant (in this example, X is a C atom or a N atom), the decarboxylation coupling reaction was carried out according to the following procedure:

adding 0.2mmol of R_a-COONPhth, 0.4mmol0.4mmol of DIPEA was added to 1mL of DMAc, and the photocatalyst Ru (bpy) was added to the reaction in an amount of 1 mol%₂Cl₂·6H₂O; the reaction was carried out at room temperature for 20 hours with blue light. The reaction formula is as follows:

the various groups of reactants and their corresponding target products used in this example are shown in table 2.

TABLE 2 reactants and their corresponding target products

After the reaction, the product yields of the respective target products were counted, as shown in table 3.

According to tables 2 and 3, the general formula is R_aVarious redox-active esters of-COONPhth successfully react with aromatic disulfides, producing yields of the desired product which are capable of reaching moderate or even high yields. The reaction system shows good functional group compatibility, and aryl ketone active ester (corresponding to product 1 and product 2), alkyl ketone active ester (corresponding to product 4), amide active ester (corresponding to product 5) and diester active ester (corresponding to product 7) are taken as reactants, so that good tolerance is shown. It is particularly noteworthy that the above reaction is carried out using a reactant having a cycloolefin structure, and that, after completion of the reaction, the cycloolefinThe hydrocarbon structure (corresponding to product 9) remains intact and a high yield of the desired product is obtained. In many drugs, the heterocyclic building blocks play an important role in the physiological activity of the drug. In the system, reactants with a thiophene ring structure, a pyridine ring structure and a tetrahydrofuran ring structure are respectively used for reaction, so that the system has good tolerance, and the obtained target products (respectively corresponding to the product 3, the product 8 and the product 6 in sequence) have high yield. In addition, the method can also be used for the later modification of natural products such as gamma-tyrosine (corresponding to a product 7) and abietic acid (corresponding to a product 14).

The inventors adoptThe active ester is used for participating in the reaction according to the parameters and the dosage set on the reaction formula, the reaction progress is good, and the yield of the obtained target product (corresponding product 12) can reach 89%. Further, the inventors carried out the above reaction in gram order, the progress of the reaction and the yield were still good, and the yield of the target product could reach 79%. Thus, the method for constructing the C-S key has good practicability and expandability.

TABLE 3 product yield of the target product prepared in this example

Product numbering	Product yield	Product numbering	Product yield	Product numbering	Product yield
						1	81％	6	70％	11	59％
2	92％	7	82％	12	89％
						3	68％	8	75％	13	64％
4	92％	9	89％	14	32％
						5	87％	10	96％

Example 3

This example shows the general formulaAnd amino acid active esters of (A) and (B)As a reactant, the decarboxylation coupling reaction was carried out according to the following procedure:

adding 0.2mmol of0.4mmol of0.4mmol of DIPEA was added to 1mL of DMAc, and the photocatalyst Ru (bpy)2Cl2 & 6H2O was added to the reaction in an amount of 1 mol%; the reaction was carried out at room temperature for 20 hours with blue light. The reaction formula is as follows:

the groups of reactants used in this example and their corresponding target products and product yields are shown in table 4. All of the reference amino acid-based active esters of this example were able to produce the desired product by performing the above reaction, and the yield of the desired product was able to reach a moderate to excellent grade. As shown in Table 4, various natural and unnatural amino acids such as phenylalanine (corresponding product 15), leucine (corresponding product 16), valine (corresponding product 17), alanine (corresponding product 18), methionine (corresponding product 19), proline (corresponding product 20), and tryptophan (corresponding product 21) can be used as suitable substrates for the above reactions. As can be seen from comparison of the product yields of the product 18 and the product 24, in the active ester as a reactant, the use of t-butyloxycarbonyl group (-Boc) instead of benzyloxycarbonyl group (-Cbz) as a nitrogen-protecting group is advantageous in increasing the product yield.

TABLE 4 types of active esters used in this example and their corresponding target products and product yields

Example 4

In this example, various compounds of the formula R were selected_a-COONPhth and the general formulaAs a reactant, the decarboxylation coupling reaction was carried out according to the following procedure:

adding 0.2mmol of R_a-COONPhth, 0.4mmol0.4mmol of DIPEA was added to 1mL of DMAc, and the photocatalyst Ru (bpy) was added to the reaction in an amount of 1 mol%₂Cl₂·6H₂O; the reaction was carried out at room temperature for 20 hours with blue light. The reaction formula is as follows:

。

the various sets of reactants and their corresponding target products used in this example are shown in table 5.

TABLE 5 reactants and their corresponding target products

After the reaction, the product yields of the respective target products were counted, as shown in table 6. This example uses disulfide as a reactant to perform a decarboxylation coupling reaction with an active ester. In products 25 and 28, the ortho-substituted aryl groups crosslink with the fluorine groups, thus enabling higher target product yields with high yields of C-S bonds. Comparing the yields of product 26 and product 29 and comparing the yields of product 27 and product 30, it is clear that the coupling reaction of aryl disulfides having electron donating groups (Me, OMe) with amino acid active esters is significantly more efficient. Furthermore, heterocyclic disulfides such as thiophene and pyridine react smoothly, and the product yield is moderate (corresponding to product 31 and product 32). It is noted that the C-S bond (corresponding to the product 34) can be constructed by using dialkyl sulfide as a reactant, and although the coupling reaction is not efficient, the decarboxylation coupling reaction of dialkyl sulfide by using a photo-oxidation-reduction method is not reported in the prior art.

TABLE 6 product yield of the target product prepared in this example

Product numbering	Product yield	Product numbering	Product yield
				25	89％	30	70％
26	45％	31	36％
				27	38％	32	77％
28	94％	33	24％
				29	83％	34	31％

Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the true spirit and scope of the present invention.