CN109535086B - Synthetic method of quinoxaline-2 (1H) -ketone C-3 carboxylate compound - Google Patents
Synthetic method of quinoxaline-2 (1H) -ketone C-3 carboxylate compound Download PDFInfo
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- -1 carboxylate compound Chemical class 0.000 title claims abstract description 49
- 238000010189 synthetic method Methods 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 10
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 7
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical compound NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000005580 one pot reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- FFRYUAVNPBUEIC-UHFFFAOYSA-N quinoxalin-2-ol Chemical class C1=CC=CC2=NC(O)=CN=C21 FFRYUAVNPBUEIC-UHFFFAOYSA-N 0.000 claims description 18
- USHAGKDGDHPEEY-UHFFFAOYSA-L potassium persulfate Chemical group [K+].[K+].[O-]S(=O)(=O)OOS([O-])(=O)=O USHAGKDGDHPEEY-UHFFFAOYSA-L 0.000 claims description 10
- 239000012429 reaction media Substances 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 76
- 239000000047 product Substances 0.000 description 30
- 239000002994 raw material Substances 0.000 description 19
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
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- WFJRIDQGVSJLLH-UHFFFAOYSA-N methyl n-aminocarbamate Chemical compound COC(=O)NN WFJRIDQGVSJLLH-UHFFFAOYSA-N 0.000 description 12
- 238000002474 experimental method Methods 0.000 description 11
- 238000007259 addition reaction Methods 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000007800 oxidant agent Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- CHPVQLYVDDOWNT-UHFFFAOYSA-N 1-methylquinoxalin-2-one Chemical compound C1=CC=C2N=CC(=O)N(C)C2=C1 CHPVQLYVDDOWNT-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- BEFYQUCZRVCEDV-UHFFFAOYSA-N methyl 4-methyl-3-oxoquinoxaline-2-carboxylate Chemical compound CN1C2=CC=CC=C2N=C(C1=O)C(=O)OC BEFYQUCZRVCEDV-UHFFFAOYSA-N 0.000 description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- 238000001228 spectrum Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 2
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- ROOXNKNUYICQNP-UHFFFAOYSA-N ammonium persulfate Chemical compound [NH4+].[NH4+].[O-]S(=O)(=O)OOS([O-])(=O)=O ROOXNKNUYICQNP-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
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- UPUZGXILYFKSGE-UHFFFAOYSA-N quinoxaline-2-carboxylic acid Chemical class C1=CC=CC2=NC(C(=O)O)=CN=C21 UPUZGXILYFKSGE-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
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- JFWAVAHCZRTHLM-UHFFFAOYSA-N 1-methyl-3,4-dihydroquinoxalin-2-one Chemical compound C1=CC=C2N(C)C(=O)CNC2=C1 JFWAVAHCZRTHLM-UHFFFAOYSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- GMDXHYKTWCGQGM-UHFFFAOYSA-N 3-oxo-4-phenylquinoxaline-2-carboxylic acid Chemical compound O=C1C(C(=O)O)=NC2=CC=CC=C2N1C1=CC=CC=C1 GMDXHYKTWCGQGM-UHFFFAOYSA-N 0.000 description 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
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- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
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- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
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- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
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- CQYCEUJAMQTOIB-UHFFFAOYSA-N methyl 3-oxo-4-(3-phenylprop-2-enyl)quinoxaline-2-carboxylate Chemical compound COC(=O)C=1C(N(C2=CC=CC=C2N1)CC=CC1=CC=CC=C1)=O CQYCEUJAMQTOIB-UHFFFAOYSA-N 0.000 description 1
- BOKODRUGBBZDRV-UHFFFAOYSA-N methyl 3-oxo-4-pentylquinoxaline-2-carboxylate Chemical compound COC(=O)C=1C(N(C2=CC=CC=C2N1)CCCCC)=O BOKODRUGBBZDRV-UHFFFAOYSA-N 0.000 description 1
- OYQXKBMWNMHNEC-UHFFFAOYSA-N methyl 3-oxo-4-prop-2-ynylquinoxaline-2-carboxylate Chemical compound COC(=O)C=1C(N(C2=CC=CC=C2N1)CC#C)=O OYQXKBMWNMHNEC-UHFFFAOYSA-N 0.000 description 1
- DGPRVEYYFOAKGW-UHFFFAOYSA-N methyl 4-benzyl-3-oxoquinoxaline-2-carboxylate Chemical compound COC(=O)C=1C(N(C2=CC=CC=C2N1)CC1=CC=CC=C1)=O DGPRVEYYFOAKGW-UHFFFAOYSA-N 0.000 description 1
- FFLPPSIOTABPKP-UHFFFAOYSA-N methyl 4-ethyl-3-oxoquinoxaline-2-carboxylate Chemical compound COC(=O)C=1C(N(C2=CC=CC=C2N1)CC)=O FFLPPSIOTABPKP-UHFFFAOYSA-N 0.000 description 1
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- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a method for synthesizing a quinoxaline-2 (1H) -ketone C-3 site carboxylate compound, which is characterized in that quinoxaline-2 (1H) -ketone derivatives, hydrazino carboxylate and persulfate react in one pot to generate the quinoxaline-2 (1H) -ketone C-3 site carboxylate compound in an air atmosphere.
Description
Technical Field
The invention relates to a method for synthesizing a quinoxaline-2 (1H) -ketone C-3 site carboxylate compound, in particular to a method for synthesizing a quinoxaline-2 (1H) -ketone C-3 site carboxylate compound with high selectivity by using hydrazino carboxylate as a carboxylate source and directly oxidizing and removing hydrazine to replace C-3 hydrogen in an air atmosphere, belonging to the technical field of synthesis of organic intermediates.
Background
The quinoxaline-2 (1H) -ketone compound is a common pharmacophore in the field of pharmaceutical research, and the derivative with the parent structure has various physiological and pharmacological activities, is widely used as an anticancer drug, an antitumor drug, an antibacterial drug and the like, is a potential multipurpose lead compound, and has wide development and application prospects. Indeed, the quinoxalinone and modified functional groups on the parent quinoxalinone structure together affect the drug and biological activity of the molecule, not just the parent quinoxalinone structure itself. Therefore, modification of various substituents on the parent quinoxalinone structure and study of the structure-activity relationship are becoming hot points of study. In the past few years, considerable progress has been made in the functionalization of quinoxaline-2 (1H) -ones with C3, including C-H bond alkylation, arylation, acylation, amination, azidation, quinolination, trifluoromethylation, phosphonylation, and the like. Quinoxaline-3-carboxylic acid esters not only have excellent biological and pharmaceutical activity, but also are valuable intermediates for the construction of a variety of functionalized quinoxaline derivatives. The conventional scheme for preparing N-substituted quinoxaline-3-carboxylic acid salts is based on a condensation-cyclization between o-phenylenediamine and a 1, 3-dicarbonyl compound and a subsequent N-substitution reaction in the presence of a base (scheme 1), however, this process is limited by the selection range of o-phenylenediamine, and the use of asymmetric diamines as starting materials inevitably leads to isomeric products. Recently, Yu and colleagues have reported for the first time the one-step synthesis of N-substituted quinoxaline-3-carboxylate compounds by free-radical cyclisation of alkyl 2- (N-substituted carboxy-ethyl) -2-chloroiminoacetates (scheme 2). However, this method still has some disadvantages: if high-activity raw materials are needed, the steps are complicated, and the reaction system is relatively complex and expensive. Given the abundance and ready availability of quinoxalin-2 (1H) -ones, the synthesis of N-substituted quinoxaline-3-carboxylic acid esters by direct introduction of an ester group is undoubtedly a simple strategy. However, at present, no relevant report is found.
Scheme 1:
scheme 2:
disclosure of Invention
Aiming at the defects of the existing synthesis method of the quinoxaline-2 (1H) -ketone C-3 site carboxylate compound, the invention aims to provide the synthesis method of the quinoxaline-2 (1H) -ketone C-3 site carboxylate compound with important physiological activity, and the method has the advantages of high yield, low cost, environmental protection and contribution to industrial production and application.
In order to realize the technical purpose, the invention provides a synthesis method of a quinoxaline-2 (1H) -ketone C-3 carboxylic ester compound, which comprises the step of carrying out one-pot reaction on a quinoxaline-2 (1H) -ketone derivative, hydrazino carboxylic ester and persulfate in an air atmosphere to generate the quinoxaline-2 (1H) -ketone C-3 carboxylic ester compound.
In a preferred embodiment, the quinoxalin-2 (1H) -one derivative has the structure of formula 1;
the hydrazinocarboxylic acid ester has the structure of formula 2:
the quinoxaline-2 (1H) -one C-3 carboxylate compound has the structure of formula 3:
wherein the content of the first and second substances,
R1selected from H, C1～C10The alkyl group (e.g., a straight-chain alkyl group such as methyl, ethyl, propyl, octyl, etc., and an alkyl group having 3 or more carbon atoms also includes isomers such as a branched alkyl group, specifically, isobutyl, isooctyl, etc.), C2～C10The alkylene group (may be an aliphatic chain containing one or more alkenes, such as ethylene, propylene, etc.), C2～C10Alkynyl (may be aliphatic chain containing one or more alkynyl groups, such as ethynyl, propynyl, etc.), benzyl, C2～C10Ester group (methoxyacyl group, ethoxyacyl group, butoxyacyl group and the like) of (a) or phenyl group;
R2is selected from C1～C10The alkyl group (e.g., a straight-chain alkyl group such as methyl, ethyl, propyl, octyl, etc., and an alkyl group having 3 or more carbon atoms includes isomers such as a branched alkyl group, specifically, isobutyl, isooctyl, etc.), a halogen (e.g., fluorine, chlorine, bromine, or iodine), trifluoromethyl, C2～C10Acyl (formyl, acetyl, propionyl, etc.), C2～C10An ester group (methoxyacyl group, ethoxyacyl group, butoxyacyl group and the like) or a nitro group of (1);
R3is selected from C1～C10The alkyl group of (2) includes straight-chain alkyl groups such as methyl, ethyl, propyl, and octyl, and isomers such as branched alkyl groups, specifically isobutyl, isooctyl, and the like, are also included in the alkyl group having 3 or more carbon atoms.
In a preferred embodiment, the molar ratio of quinoxaline-2 (1H) -one derivative, hydrazinocarboxylic acid ester and persulfate is 1: 1-2: 2 to 4. The most preferred molar ratio is 1: 1.5: 3.
according to the preferable scheme, the persulfate is potassium persulfate, and a large number of experiments show that other common persulfate such as sodium persulfate, ammonium persulfate and the like cannot meet the requirements.
In a preferred embodiment, the reaction conditions are: reacting for 5-15 hours at 80-100 ℃. Most preferably, the reaction is carried out at a temperature of 85 to 95 ℃ for 8 to 10 hours.
In a preferred embodiment, the reaction employs acetonitrile as a reaction medium, the acetonitrile is a benign solvent in the technical scheme of the invention, and other common solvents such as methanol, DCE and DMF are non-benign solvents.
In a preferred scheme, the molar concentration of the quinoxaline-2 (1H) -ketone derivative in an acetonitrile reaction medium is 0.1-0.3 mmol/mL. The most preferred molar concentration is 0.2 mmol/mL.
The route of the addition reaction of the quinoxaline-2 (1H) -ketone derivative, the hydrazinocarboxylic ester and the potassium persulfate is as follows:
the invention also provides a reasonable reaction mechanism. The reaction of methyl carbazate with quinoxalin-2 (1H) -one is illustrated. Methyl carbazate (2) with sulfate anion radical (generated in situ from persulfate anion cleavage) to form ester radical and release HSO4 -Anions and molecular nitrogen. Ester radical attack of C3 into N-methylquinoxaline-2 (1H) -one (1) forms a radical intermediate (A) which is subsequently hydrogen-abstracted/oxidized by sulfate anions to give the desired product (3).
Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
1) the invention firstly synthesizes the C-3 site carboxylate compound of quinoxaline-2 (1H) -ketone by one step of addition reaction of quinoxaline-2 (1H) -ketone derivatives, hydrazino carboxylate and potassium persulfate.
2) The invention adopts the hydrazino carboxylic ester as the esterification reagent and the potassium persulfate as the oxidant, and has the advantages of easily obtained sources and low price;
3) the quinoxaline-2 (1H) -ketone derivative has wide selectivity and good functional group compatibility, and is easy to modify various groups;
4) the invention does not use transition metal and various acid-base additives, has high reaction selectivity, and the product is easy to separate and purify
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 1-methyl-2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid methyl ester;
FIG. 2 is a nuclear magnetic carbon spectrum of methyl 1-methyl-2-oxo-1, 2-dihydroquinoxaline-3-carboxylate.
Detailed Description
The following specific examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.
Comparative example:
the following control experiment groups 1 to 16 all react according to the following reaction equation:
the specific operation steps are as follows: 1-methyl-3, 4-dihydro-2 (1H) -quinoxalinone (1 equivalent, 0.1mmol), methyl carbazinate, potassium persulfate and solvent are sequentially added into a 5mL round-bottom flask, and the obtained mixed solution is reacted in a heating stirring reaction device. The reaction progress is followed by a thin layer chromatography plate, after the reaction is finished, the reaction is cooled to room temperature, 3ml of water is added for dilution, the reactant is extracted by ethyl acetate, and the yield is analyzed by nuclear magnetic crude spectrum.
In the table, experimental groups 1-6 investigate the influence of various oxidants on the addition reaction of the quinoxaline-2 (1H) -ketone derivative and the hydrazinocarboxylic acid methyl ester, and experimental data show that the reaction is very sensitive to the types of the oxidants, and the ideal product yield can be obtained only by using potassium persulfate.
In the table, experimental groups 1 and 7-12 investigate the influence of the reaction medium on the addition reaction of the quinoxaline-2 (1H) -ketone derivative and the hydrazinocarboxylic acid methyl ester, and experiments show that acetonitrile is the optimal reaction medium for the reaction.
In the table, experiment groups 1 and 13-14 investigate the influence of the amount of esterification reagent of methyl hydrazinocarboxylate on the addition reaction of quinoxaline-2 (1H) -one derivatives and methyl hydrazinocarboxylate, and experiments show that the optimal molar amount of methyl hydrazinocarboxylate is 1.5 equivalents, the yield of the target product is not obviously increased when the molar amount is too high, and the yield of the target product is obviously reduced when the molar amount is too low.
In the table, experiment groups 1 and 15-16 investigate the influence of the dosage of potassium persulfate serving as an oxidant on the addition reaction of the quinoxaline-2 (1H) -one derivative and the hydrazinocarboxylic acid methyl ester, and experiments show that the optimal molar dosage of the potassium persulfate is 3 equivalents, the yield of a target product is not obviously increased when the dosage is too high, and the yield of the target product is obviously reduced when the dosage is too low.
In the above table, experiment groups 1 and 17-18 investigate the influence of the molar concentration of the quinoxaline-2 (1H) -ketone derivative on the addition reaction of the quinoxaline-2 (1H) -ketone derivative and the methyl carbazate, and experiments show that the molar concentration of the quinoxaline-2 (1H) -ketone derivative is 0.2mmol/mL, which is the optimum substrate molar concentration for the reaction, when the molar concentration is too high, the yield of the target product is not obviously increased, and when the molar concentration is too low, the yield of the target product is obviously reduced.
In the table, experiment groups 1 and 19-20 investigate the influence of the reaction temperature on the addition reaction of the quinoxaline-2 (1H) -ketone derivative and the hydrazinocarboxylic acid methyl ester, and experiments show that the reaction temperature is the optimum reaction temperature at 90 ℃, the yield of the target product is not obviously increased when the reaction temperature is too high, and the yield of the target product is obviously reduced when the reaction temperature is too low.
Examples 1 to 18
The following examples 1 to 18 were all reacted according to the following reaction equations:
the specific operation steps are as follows: quinoxaline-2 (1H) -one derivative (1 equivalent, 0.2mmol), hydrazinocarboxylic acid ester (1.5 equivalent, 0.3mmol), potassium persulfate (3 equivalent, 0.6mmol) and acetonitrile (1mL) are sequentially added into a 10mL round-bottom flask, and the obtained mixed solution is heated and stirred for reaction at 90 ℃ under the condition of air. The reaction progress is followed by thin-layer chromatography plates, generally for a reaction time of 8 to 12 hours. After the reaction is finished, cooling to room temperature, adding 3ml of water for dilution, extracting a reactant by ethyl acetate, performing nuclear magnetic crude spectrum analysis on the yield, concentrating the filtrate by using a rotary evaporator, and performing column chromatography purification by using Petroleum Ether (PE)/Ethyl Acetate (EA) as an eluent and silica gel (200-mesh and 300-mesh sieve).
Example 1
Raw materials:
and (3) target products:
1-methyl-2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid methyl ester; the yield was 84%.
1H NMR(400MHz,CDCl3):δ＝7.94(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.69–7.64(m,1H),7.41–7.35(m,2H),4.02(s,3H),3.72(s,3H)；
13C NMR(100MHz,CDCl3):δ＝164.0,152.5,148.4,134.1,132.7,131.8,131.3,124.2,113.9,53.2,29.2；
HRMS(ESI)m/z calcd.for C11H11N2O3[M+H]+:219.0764,found 219.0762.
Example 2
Raw materials:
and (3) target products:
1-ethyl-2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid methyl ester; the yield was 87%.
1H NMR(400MHz,CDCl3):δ＝7.95(dd,J1＝8.0Hz,J2＝1.2Hz,1H),7.68–7.64(m,1H),7.40–7.36(m,2H),4.34(q,J＝7.2Hz,2H),4.02(s,3H),1.39(t,J＝7.2Hz,3H)；
13C NMR(100MHz,CDCl3):δ＝164.1,152.1,148.4,133.1,132.6,132.1,131.5,124.0,113.7,53.1,37.6,12.3；
HRMS(ESI)m/z calcd.for C12H13N2O3[M+H]+:233.0921,found 233.0917.
Example 3
Raw materials:
and (3) target products:
1-pentyl-2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid methyl ester; the yield is 92%
1H NMR(400MHz,CDCl3):δ＝7.93(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.66–7.62(m,1H),7.38–7.33(m,2H),4.24(t,J＝8.0Hz,2H),4.01(s,3H),1.79–1.71(m,2H),1.45–1.35(m,4H),0.90(t,J＝7.2Hz,3H)；
13C NMR(100MHz,CDCl3):δ＝164.1,152.2,148.3,133.3,132.5,132.1,131.4,124.0,113.8,53.1,42.5,28.9,26.8,22.2,13.8；
HRMS(ESI)m/z calcd.for C15H19N2O3[M+H]+:275.1390,found 275.1390.
Example 4
Raw materials:
and (3) target products:
1-propenyl-2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid methyl ester; the yield is 82 percent
1H NMR(400MHz,CDCl3):δ＝7.96(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.65–7.61(m,1H),7.41–7.33(m,2H),5.97–5.88(m,1H),5.31–5.19(m,2H),4.94–4.92(m,2H),4.03(s,3H)；
13C NMR(100MHz,CDCl3):δ＝164.0,152.1,148.4,133.4,132.6,132.0,131.4,130.1,124.2,118.8,114.5,53.2,44.7；
HRMS(ESI)m/z calcd.for C13H13N2O3[M+H]+:245.0921,found 245.0925.
Example 5
Raw materials:
and (3) target products:
1-cinnamyl-2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid methyl ester; the yield is 78 percent
1H NMR(400MHz,CDCl3):δ＝7.98(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.67–7.63(m,1H),7.46–7.44(m,1H),7.42–7.38(m,1H),7.34–7.27(m,4H),7.25–7.22(m,1H),6.65(d,J＝16.0Hz,1H),6.30–6.23(m,1H),5.09(dd,J1＝5.6Hz,J2＝1.6Hz,2H),4.05(s,3H)；
13C NMR(100MHz,CDCl3):δ＝164.0,152.2,148.4,135.7,134.3,132.7,131.5,128.6,128.2,126.5,124.3,121.3,114.4,53.2,44.4；
HRMS(ESI)m/z calcd.for C19H17N2O3[M+H]+:321.1234,found 321.1236.
Example 6
Raw materials:
and (3) target products:
1- (2-prop-ynyl) -2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid methyl ester; the yield is 83 percent
1H NMR(400MHz,CDCl3):δ＝7.98(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.73–7.69(m,1H),7.53–7.51(m,1H),7.46–7.42(m,1H),5.08(d,J＝2.4Hz,2H),4.03(s,3H),2.31(t,J＝2.4Hz,1H)；
13C NMR(100MHz,CDCl3):δ＝163.7,151.5,148.2,132.8,132.7,132.1,124.6,121.4,114.5,76.1,73.7,53.3,31.6；
HRMS(ESI)m/z calcd.for C13H11N2O3[M+H]+:243.0764,found 243.0769.
Example 7
Raw materials:
and (3) target products:
1-benzyl-2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid methyl ester; the yield is 86 percent
1H NMR(400MHz,CDCl3):δ＝7.95(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.56–7.51(m,1H),7.36–7.25(m,7H),5.51(s,2H),4.04(s,3H)；
13C NMR(100MHz,CDCl3):δ＝164.0,152.6,148.5,134.6,133.5,132.6,132.1,131.4,129.0,127.9,127.0,124.2,114.7,53.2,46.0；
HRMS(ESI)m/z calcd.for C17H15N2O3[M+H]+:295.1077,found 295.1072.
Example 8
Raw materials:
and (3) target products:
1- (2-ethoxy-2-oxoethyl) -2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 74 percent
1H NMR(400MHz,CDCl3):δ＝7.96(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.64–7.60(m,1H),7.41–7.37(m,1H),7.11(dd,J1＝8.4Hz,J2＝0.8Hz,1H),5.03(s,2H),4.23(q,J＝7.2Hz,2H),4.01(s,3H),1.25(t,J＝7.2Hz,3H)；
13C NMR(100MHz,CDCl3):δ＝166.5,163.6,152.1,147.9,133.3,132.9,131.8,131.6,124.5,113.4,62.2,53.2,43.5,14.0；
HRMS(ESI)m/z calcd.for C14H15N2O5[M+H]+:291.0975,found 291.0969.
Example 9
Raw materials:
and (3) target products:
1-phenyl-2-oxo-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 85 percent
1H NMR(400MHz,CDCl3):δ＝7.98(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.63–7.56(m,3H),7.47–7.43(m,1H),7.38–7.34(m,1H),7.30–7.28(m,2H),6.73(dd,J1＝8.4Hz,J2＝1.2Hz,1H),4.02(s,3H)；
13C NMR(100MHz,CDCl3):δ＝163.9,152.2,149.2,135.0,134.9,132.3,131.7,130.8,130.3,129.7,128.1,124.4,115.7,53.2；
HRMS(ESI)m/z calcd.for C16H13N2O3[M+H]+:281.0921,found 281.0922.
Example 10
Raw materials:
and (3) target products:
1-methyl-2-oxo-6-fluoro-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 76%
1H NMR(400MHz,CDCl3):δ＝7.65(dd,J1＝8.0Hz,J2＝3.2Hz,1H),7.46–7.41(m,1H),7.36–7.32(m,1H),4.03(s,3H),3.73(s,3H)；
13C NMR(100MHz,CDCl3):δ＝163.8,158.8(d,J＝244.3Hz,1C),152.2,149.9,132.3,130.9(d,J＝2.1Hz,1C),120.6(d,J＝24.1Hz,1C),116.4(d,J＝21.8Hz,1C),115.1(d,J＝8.0Hz,1C),53.3,29.5；
19F NMR(376MHz,CDCl3):δ＝-117.5；
HRMS(ESI)m/z calcd.for C11H10FN2O3[M+H]+:237.0670,found 237.0668.
Example 11
Raw materials:
and (3) target products:
1-methyl-2-oxo-6-chloro-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 92 percent
1H NMR(400MHz,CDCl3):δ＝7.91(d,J＝2.8Hz,1H),7.61(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.30(d,J＝9.2Hz,1H),4.02(s,3H),3.70(s,3H)；
13C NMR(100MHz,CDCl3):δ＝163.6,152.1,149.7,132.8,132.6,132.2,130.3,129.6,115.1,53.2,29.4；
HRMS(ESI)m/z calcd.for C11H10ClN2O3[M+H]+:253.0374,found 253.0367.
Example 12
Raw materials:
and (3) target products:
1-methyl-2-oxo-6-bromo-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 90 percent
1H NMR(400MHz,CDCl3):δ＝8.08(d,J＝2.0Hz,1H),7.74(dd,J1＝8.8Hz,J2＝2.4Hz,1H),7.24(d,J＝8.8Hz,1H),4.02(s,3H),3.70(s,3H)；
13C NMR(100MHz,CDCl3):δ＝163.6,152.1,149.6,135.3,133.5,133.2,132.5,116.8,115.3,53.3,29.4；
HRMS(ESI)m/z calcd.for C11H10BrN2O3[M+H]+:296.9869,found 296.9867.
Example 13
Raw materials:
target product
1-methyl-2-oxo-1, 2-dihydroquinoxaline-3, 6-dicarboxylic acid ester; the yield is 80 percent
NMR(400MHz,CDCl3):δ＝8.63(d,J＝1.6Hz,1H),8.31(dd,J1＝8.4Hz,J2＝1.6Hz,1H),7.41(d,J＝8.8Hz,1H),4.04(s,3H),3.97(s,3H),3.76(s,3H)；
13C NMR(100MHz,CDCl3):δ＝165.5,163.6,152.4,149.3,137.2,133.2,133.1,131.2,126.3,114.0,53.3,52.5,29.5；
HRMS(ESI)m/z calcd.for C13H13N2O5[M+H]+:277.0819,found 277.0816.
Example 14
Raw materials:
target product
1-methyl-2-oxo-6-benzoyl-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 73 percent
1H NMR(400MHz,CDCl3):δ＝8.35(d,J＝2.0Hz,1H),8.26(dd,J1＝8.8Hz,J2＝2.0Hz,1H),7.82–7.79(m,2H),7.65–7.61(m,1H),7.53–7.49(m,3H),4.03(s,3H),3.80(s,3H)；
13C NMR(100MHz,CDCl3):δ＝194.4,163.5,152.4,149.3,137.0,133.9,133.6,133.3,132.8,130.7,129.8,129.6,128.6,114.4,53.3,29.6；
HRMS(ESI)m/z calcd.for C18H15N2O4[M+H]+:323.1026,found 323.1020.
Example 15
Raw materials:
target product
1-methyl-2-oxo-6-nitro-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 73 percent
1H NMR(400MHz,CDCl3)δ8.04(d,J＝8.4Hz,1H),6.84(d,J＝8.4Hz,1H),6.81(d,J＝8.4Hz,1H),6.66(d,J＝2.4Hz,1H),6.60(dd,J＝2.4,8.4Hz,1H),6.01(s,2H).
13C NMR(100MHz,CDCl3)δ167.6,148.2,146.0,144.1,143.9,119.3,113.5,108.1,105.0,103.1,101.9.
HRMS Calcd(EI)m/z for C11H7NO4Se:[M]+296.9540,found:296.9534.
Example 16
Raw materials:
target product
1-methyl-2-oxo-7-trifluoromethyl-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 77 percent
1H NMR(400MHz,CDCl3):δ＝8.06(d,J＝8.4Hz,1H),7.64–7.60(m,2H),4.03(s,3H),3.76(s,3H)；
13C NMR(100MHz,CDCl3):δ＝163.5,152.1,150.9,134.1,134.0,133.7,132.0,123.2(q,J＝271.2Hz,1C),120.6(q,J＝3.7Hz,1C),111.4(q,J＝4.3Hz,1C),53.4,29.4；19FNMR(376MHz,CDCl3):δ＝-62.7；
HRMS(ESI)m/z calcd.for C12H10F3N2O3[M+H]+:287.0638,found 287.0644.
Example 17
Raw materials:
target product
1,6, 7-trimethyl-2-oxo-6-chloro-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 85 percent
1H NMR(400MHz,CDCl3):δ＝7.67(s,1H),7.09(s,1H),4.00(s,3H),3.68(s,3H),2.43(s,3H),2.33(s,3H)；
13C NMR(100MHz,CDCl3):δ＝164.2,152.6,146.7,143.3,133.4,132.3,131.1,130.3,114.3,53.0,29.1,20.8,19.1；
HRMS(ESI)m/z calcd.for C13H15N2O3[M+H]+:247.1077,found 247.1076.
Example 18
Raw materials:
target product
1-methyl-2-oxo-6, 7-dichloro-1, 2-dihydroquinoxaline-3-carboxylic acid ester; the yield is 78 percent
1H NMR(400MHz,CDCl3):δ＝8.00(s,1H),7.45(s,1H),4.01(s,3H),3.68(s,3H)；
13C NMR(100MHz,CDCl3):δ＝163.4,151.3,137.1,133.4,131.8,131.2,130.7,128.3,115.5,53.3,29.5；
HRMS(ESI)m/z calcd.for C11H9Cl2N2O3[M+H]+:286.9985,found 286.9976。
Claims (4)
1. A method for synthesizing a quinoxaline-2 (1H) -ketone C-3 site carboxylate compound is characterized by comprising the following steps: under the air atmosphere, quinoxaline-2 (1H) -ketone derivative, hydrazino carboxylic ester and persulfate react in one pot to generate quinoxaline-2 (1H) -ketone C-3 site carboxylic ester compound; the persulfate is potassium persulfate; the reaction adopts acetonitrile as a reaction medium;
the quinoxaline-2 (1H) -one derivative has a structure shown in a formula 1;
the hydrazinocarboxylic acid ester has the structure of formula 2:
the quinoxaline-2 (1H) -one C-3 carboxylate compound has the structure of formula 3:
wherein the content of the first and second substances,
R1selected from H, C1～C10Alkyl of (C)2～C10Alkenyl group of (C)2～C10Alkynyl, benzyl, C2～C10Ester group of (a) or phenyl group;
R2is selected from C1～C10Alkyl, halogen, trifluoromethyl, C2～C10Acyl group of (1), C2～C10Ester group or nitro group of (1);
R3is selected from C1～C10Alkyl group of (1).
2. The method for synthesizing a quinoxaline-2 (1H) -one C-3 carboxylate compound according to claim 1, wherein: the molar ratio of the quinoxaline-2 (1H) -one derivative, the hydrazino carboxylic acid ester and the persulfate is 1: 1-2: 2 to 4.
3. The method for synthesizing a C-3 carboxylate compound of quinoxaline-2 (1H) -ketone according to any one of claims 1 to 2, wherein: the reaction conditions are as follows: reacting for 5-15 hours at 80-100 ℃.
4. The method for synthesizing a quinoxaline-2 (1H) -one C-3 carboxylate compound according to claim 1, wherein: the molar concentration of the quinoxaline-2 (1H) -ketone derivative in an acetonitrile reaction medium is 0.1-0.4 mmol/mL.
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