CN117304076B - Preparation method of N-sulfonyl amidine compound - Google Patents
Preparation method of N-sulfonyl amidine compound Download PDFInfo
- Publication number
- CN117304076B CN117304076B CN202311599675.8A CN202311599675A CN117304076B CN 117304076 B CN117304076 B CN 117304076B CN 202311599675 A CN202311599675 A CN 202311599675A CN 117304076 B CN117304076 B CN 117304076B
- Authority
- CN
- China
- Prior art keywords
- nmr
- mhz
- dmso
- reaction
- sulfonylamidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 28
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 16
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 150000002825 nitriles Chemical class 0.000 claims abstract description 13
- 239000000654 additive Substances 0.000 claims abstract description 8
- 230000000996 additive effect Effects 0.000 claims abstract description 8
- 239000003054 catalyst Substances 0.000 claims description 11
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- -1 nitro, methoxy, tertiary butyl Chemical group 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 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
- 238000000746 purification Methods 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims 1
- LWRYDHOHXNQTSK-UHFFFAOYSA-N thiophene oxide Chemical compound O=S1C=CC=C1 LWRYDHOHXNQTSK-UHFFFAOYSA-N 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 17
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 125000000524 functional group Chemical group 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 97
- 238000002955 isolation Methods 0.000 description 36
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- HSVFKFNNMLUVEY-UHFFFAOYSA-N sulfuryl diazide Chemical compound [N-]=[N+]=NS(=O)(=O)N=[N+]=[N-] HSVFKFNNMLUVEY-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 7
- 238000009776 industrial production Methods 0.000 description 6
- 230000002194 synthesizing effect Effects 0.000 description 6
- 229910052723 transition metal Inorganic materials 0.000 description 5
- 150000003624 transition metals Chemical class 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000002360 explosive Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000007040 multi-step synthesis reaction Methods 0.000 description 4
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001345 alkine derivatives Chemical group 0.000 description 3
- 150000001409 amidines Chemical class 0.000 description 3
- 150000001412 amines Chemical group 0.000 description 3
- 230000000975 bioactive effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000004880 explosion Methods 0.000 description 3
- 238000005580 one pot reaction Methods 0.000 description 3
- 150000003335 secondary amines Chemical class 0.000 description 3
- 150000003512 tertiary amines Chemical class 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 150000003556 thioamides Chemical class 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000010523 cascade reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 150000002081 enamines Chemical group 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- AEOCXXJPGCBFJA-UHFFFAOYSA-N ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
- C07C311/51—Y being a hydrogen or a carbon atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of an N-sulfonyl amidine compound, which takes commercial primary sulfonamide, alcohol and nitrile as reaction substrates and cheap trifluoro methanesulfonic anhydride as an additive to prepare the N-sulfonyl amidine compound under the mild condition of room temperature. Compared with the prior art, the method has the following advantages: the raw materials for the reaction are commercialized and cheap, the synthesis is not needed by a complicated method, the reaction system is simple, the substrate range is wide, and the method is compatible with various functional groups and complex molecules; the reaction yield is high, the operation is very simple, and the reaction condition is mild. The advantages are very beneficial to industrial practical application.
Description
Technical Field
The invention relates to a preparation method of an N-sulfonyl amidine compound, in particular to a preparation method of a primary sulfonamide-amidine compound, belonging to the technical field of biological medicines.
Background
Amidines contain a unique N-c=n structure that is present in many natural products and bioactive small molecules and is a critical functional group in drug design. In recent years, amidines have become a common framework in heterocyclic construction and synthesis of bioactive natural products, and can be chelated with transition metals, and have wide application and synthesis values in organic synthesis as important transition metal ligands. N-sulfonyl amidines are a special class of amidine compounds, the skeleton of the N-sulfonyl amidines is often found in bioactive compounds, and the N-sulfonyl amidines have wide application in the design of biological medicine molecules and the chemistry of organic synthesis. N-sulfonylamidines have therapeutic effects on a number of diseases and exhibit a variety of biological activities, including anticancer (a), antifungal (b), antiproliferative (c), transporter inhibition (d), etc., as follows.
。
Based on the important application prospect of N-sulfonyl amidine compounds, a plurality of methods for synthesizing the N-sulfonyl amidine compounds exist at present. However, the existing method has the defects of complicated raw material preparation, limited practical value, unstable raw material, danger, noble metal catalyst use, narrow substrate range and the like. For example: (1) Li Xiaonian group reports a method for synthesizing N-sulfonylamidines by accelerating the reaction of a tertiary amine with a sulfonylazide by means of diethyl azodicarboxylate (DEAD). However, this method has special requirements for substrates, i.e., tertiary amines containing an ethyl structure are used as precursors, and more than one non-equivalent ethyl group is present in the amine structure, which can produce by-products resulting from oxidation at different sites during the reaction (see: xu, an Unexpected Diethyl Azodicarboxylate-Promoted Dehydrogenation of Tertiaryamine and Tandem Reaction with Sulfonyl azide. J. Am. chem. Soc. 2008, 130, 14048-14049.). (2) Shannon S.Stahl subject group realized in Cu (OTf) 2 Under catalysis, the terminal alkyne, the sulfanilamide and the secondary amine react to synthesize the N-sulfonyl amidine. However, this method is only applicable to simple secondary amines, has a relatively limited substrate range, and requires the use of toxic metal catalysts (see: stahl, S. Cu-Catalyzed Aerobic Oxidative Three-Component Coupling Route to N-Sulfonyl Amidines via an Ynamine Intermediate. J. Org. Chem. 2015, 80, 2448-2454.). (3) Sukbok Chang group reported earliest methods for one pot synthesis of N-sulfonylamidines with terminal alkynes, sulfonylazides and amines in the presence of a ketolidene catalyst. The method is applicable to a series of primary amine and secondary amine containing fat and aryl structuresSuitable, but still relatively limited substrate ranges. And using as a substrate an explosive sulfonyl azide (see: chang, S. Highly Efficient One-Pot Synthesis of N-Sulfonylamidines by Cu-Catalyzed Three-Component Coupling of Sulfonyl Azide, alkyne, and amine.J. Am. chem. Soc.2005, 127, 2038-2039.). (4) The general problem group is to realize the synthesis of N-sulfonyl amidine compounds in pure water by introducing ester groups into enamine structures, namely adopting the reaction of ethyl enamine ester and sulfonyl azide. However, this type of method requires The use of an explosive Sulfonyl azide as a substrate, which is disadvantageous for industrial production (see: wan, j.—p. The c= C Bond Decomposition Initiated by Enamine-Azide Cycloaddition for Catalyst-and Additive-Free Synthesis of N-sulfolane amino acids, adv. Synth. Catalyst. 2019, 361, 5690-5694.). (5) Yasumaru Hatanaka the task group implements the condensation of sulfonyl azide with thioamides to synthesize fully substituted amidines. However, the sulfonyl azide (explosive) and thioamide starting materials in this reaction generally require one or more steps to prepare, and are expensive to prepare, reducing the practical value of the process (see: hatanaka, Y. Coupling reaction of thioamides with sulfonyl azides: an efficient catalyst-free click-type ligation under mild conditions. Chem. Commun. 2013, 49, 10242-10244.).
In summary, the currently reported methods for preparing N-sulfonylamidines have a number of disadvantages: for example, raw materials are not commercialized, and the cost is high because of multi-step synthesis; part of raw materials (azide and the like) have explosion danger, and are not beneficial to industrial production; the transition metal catalyst is easy to pollute the environment, and the toxicity of the medicine can be influenced by metal residues in the synthesis of the medicine. Therefore, it is important to develop a method for synthesizing N-sulfonyl amidine compounds, which has rich sources of raw materials, no metals, low cost, mildness and high efficiency, and has industrial application potential only when meeting the above requirements.
Disclosure of Invention
The invention aims to provide a novel efficient method for synthesizing N-sulfonyl amidine compounds.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
a process for preparing N-sulfonyl amidine compound from the sulfonic anhydride as additive, sulfonamide and alcohol through reaction in the presence of nitrile. The invention discloses a preparation method of an N-sulfonyl amidine compound, which takes sulfonamide and alcohol as raw materials and takes trifluoro methanesulfonic anhydride as an additive to prepare the N-sulfonyl amidine compound by reaction under the condition of room temperature in the presence of nitrile.
In the technical scheme, the chemical structural formula of the sulfonamide is as follows:
。
the alcohol is R 2 OH; the nitrile is R 3 CN；
The chemical structural formula of the N-sulfonyl amidine compound is as follows:
in the chemical structural formula, R 1 One or more selected from naphthyl, thienyl, benzyl, substituted or unsubstituted aralkyl and substituted or unsubstituted heteroaralkyl, wherein the substituent is one or more of nitro, methoxy, tertiary butyl, ester and chlorine; r is R 2 Selected from alkyl groups; r is R 3 Selected from alkyl, phenyl.
In the present invention, the reaction temperature is 25 to 40℃and the preferred reaction temperature is 25 ℃.
In the present invention, the reaction time is 20 to 48 hours, and the preferable reaction time is 24 hours.
In the invention, the molar ratio of sulfonamide, alcohol and trifluoromethanesulfonic anhydride is 1:1-2:2.5-3.5, and the preferable molar ratio is 1:1.75:3. The ratio of nitrile to sulfonamide is (0.5-2) mL to 0.2mmol, preferably (0.7-1.5) mL to 0.2mmol.
In the invention, the reaction substrates are sulfonamide, alcohol and nitrile compounds, the additive is trifluoromethanesulfonic anhydride, and the materials are cheap commercial raw materials. The reaction of the invention is carried out in air without metal catalysts. After the reaction is finished, the product can be obtained through conventional purification, such as quenching by saturated sodium carbonate solution, drying by anhydrous sodium sulfate, removing solvent by a rotary evaporator, adsorbing by silica gel, and obtaining the N-sulfonyl amidine compound through simple column chromatography.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention uses Tf under the room temperature condition 2 O is used as an additive, sulfonamide and alcohol are used as raw materials, and the N-sulfonyl amidine compound is prepared by reaction without metal in the presence of nitrile. The technology of the invention has the following remarkable advantages: the raw materials are all cheap commodity, multi-step synthesis and preparation are not needed, and the requirements of green chemistry and sustainable development are met; no toxic or harmful metal catalyst is needed; the use of an explosive azide is not required; compared with the prior art, the method can be efficiently carried out at room temperature, high temperature is not needed, the reaction condition is mild, and the operation is very simple; in summary, the present technology has great utility.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound 4 a.
FIG. 2 is a nuclear magnetic resonance spectrum of the compound 4 a.
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of compound 4 y.
FIG. 4 is a nuclear magnetic resonance spectrum of compound 4 y.
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of compound 4 ab.
FIG. 6 is a nuclear magnetic resonance spectrum of compound 4 ab.
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of compound 4 an.
FIG. 8 is a nuclear magnetic resonance spectrum of compound 4 an.
FIG. 9 is a single crystal unit cell structure diagram of compound 4 y.
Detailed Description
The operation method is a conventional method in the field, uses primary sulfonamide, alcohol and nitrile as substrates and trifluoromethanesulfonic anhydride as an additive, and can efficiently obtain the product N-sulfonyl amidine compound in the air under the reaction condition of room temperature without other substances. The invention adopts a mild and efficient strategy to synthesize the N-sulfonyl amidine compound, and the reaction substrate primary sulfonamide, alcohol and nitrile and the additive trifluoromethanesulfonic anhydride are all cheap commercial products. Unless otherwise indicated, the experiments below were carried out in air at room temperature, and the yields were isolated yields.
The present invention employs a mild, efficient scheme for the preparation of N-sulfonylamidine compounds. The reaction can occur in an environment at room temperature; meanwhile, the substrate and the activator of the reaction are cheap and easy to obtain, do not need to be synthesized in advance or carried out in complex reaction conditions, and are green and mild and environment-friendly compared with other reactions; the reaction adopts a one-pot one-step method, and the operation is simple and convenient. The raw materials used in the existing technology for synthesizing the N-sulfonyl amidine compound are not commercialized, multi-step synthesis is needed, the cost is high, part of raw materials have explosion danger, the industrial production is not facilitated, the transition metal catalyst is used, the environment is easy to pollute, and the range of reaction substrates is narrow. Compared with the method, the method has the advantages of wide range of reaction substrates, simple reaction conditions, greenness, mild reaction conditions, higher reaction yield and the like, and is very favorable for industrial production.
The invention is further described below in connection with examples which refer to materials which are either currently available products or which are conventionally available according to existing methods, and specific preparation operations and testing are conventional techniques.
The general reaction formula and the method of the preparation method of the N-sulfonyl amidine compound disclosed by the invention are as follows, and the reaction is carried out in air.
Sulfonamide 1 (0.2 mmol), nitrile 3 (1.0 mL), alcohol 2 (0.35 mmol), and trifluoromethanesulfonic anhydride (0.6 mmol,169.3 mg) were sequentially added to the reaction tube; then stirring for 24 hours in air at 25 ℃, quenching the reaction system with saturated sodium carbonate solution, extracting for 3 times with ethyl acetate, combining organic phases, drying with anhydrous sodium sulfate, removing solvent by a rotary evaporator, adsorbing by silica gel, and obtaining the N-sulfonyl amidine compound 4 by simple column chromatography.
Examples
According to the method, different reaction substrates are adopted to obtain different products, and the method is as follows:
according to conventional methods, the product is characterized as follows:
4a, isolation yield was 72%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.68 (t,J= 4.5 Hz, 1H), 7.73 – 7.69 (m, 2H), 7.55 – 7.52 (m, 2H), 3.20 – 3.13 (m, 2H), 2.20 (s, 3H), 1.28 (s, 9H), 1.06 (t,J= 7.2 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.2, 154.2, 141.3, 125.7, 125.5, 36.0, 34.7, 30.8, 19.9, 13.3。
4b, isolation yield was 79%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.55 (d,J= 7.4 Hz, 1H), 7.72 – 7.69 (m, 2H), 7.54 – 7.52 (m, 2H), 3.99 – 3.90 (m, 1H), 2.19 (s, 3H), 1.28 (s, 9H), 1.08 (d,J= 6.6 Hz, 6H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 164.4, 154.2, 141.3, 125.6, 125.5, 42.9, 34.6, 30.8, 21.3, 20.0。
4c, isolation yield 71%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.63 (t,J= 5.4 Hz, 1H), 7.72 – 7.70 (m, 2H), 7.53 – 7.51 (m, 2H), 3.17 – 3.12 (m, 2H), 2.22 (s, 3H), 1.47 – 1.40 (m, 2H), 1.27 (s, 9H), 1.24 – 1.17 (m, 6H), 0.82 (t,J= 6.5 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.3, 154.1, 141.3, 125.6, 125.4, 41.1, 34.6, 30.8, 30.8, 27.6, 26.0, 21.9, 19.9, 13.8。
4d, isolation yield was 73%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (t,J= 5.4 Hz, 1H), 7.73 – 7.71 (m, 2H), 7.53 – 7.51 (m, 2H), 3.57 (t,J= 6.6 Hz, 2H), 3.18 – 3.13 (m, 2H), 2.22 (s, 3H), 1.70 – 1.63 (m, 2H), 1.50 – 1.42 (m, 2H), 1.38 – 1.30 (m, 4H), 1.28 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.4, 154.1, 141.3, 125.6, 125.5, 45.2, 41.0, 34.6, 31.9, 30.8, 27.5, 25.9, 25.5, 19.9。
4e, isolation yield 76%. 1 H NMR (400 MHz, Chloroform-d) δ 7.82-7.80 (m, 2H), 7.45-7.43 (m, 2H), 6.69 ((t,J= 4.6 Hz, 1H), 4.00-3.96 (m, 2H), 2.34 (s, 3H), 1.72 (t, J = 2.6 Hz, 3H), 1.30 (s, 9H). 13 C NMR (100 MHz, Chloroform-d) δ 165.5, 155.2, 140.1, 126.1, 125.5, 80.2, 73.2, 34.9, 32.1, 31.0, 20.6, 3.3。
4f, isolation yield was 60%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.09 (t,J= 5.1 Hz, 1H), 7.77 – 7.73 (m, 2H), 7.54 – 7.51 (m, 2H), 4.05 (d,J= 5.1 Hz, 2H), 2.24 (s, 3H), 1.28 (s, 9H), 0.13 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.4, 154.3, 140.9, 125.7, 125.5, 101.6, 87.3, 34.6, 31.3, 30.8, 19.7, -0.3。
4g, the isolation yield was 70%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.62 (d,J= 6.9 Hz, 1H), 7.73 – 7.71 (m, 2H), 7.54 – 7.52 (m, 2H), 4.12 – 4.04 (m, 1H), 2.20 (s, 3H), 1.88 – 1.80 (m, 2H), 1.64 – 1.59 (m, 2H), 1.50 – 1.38 (m, 4H), 1.27 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 164.9, 154.1, 141.3, 125.6, 125.5, 52.6, 34.6, 31.6, 30.8, 23.5, 19.9。
4h, the yield was 76%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (d,J= 7.5 Hz, 1H), 7.71 – 7.69 (m, 2H), 7.54 – 7.51 (m, 2H), 3.72 – 3.63 (m, 1H), 2.18 (s, 3H), 1.82 – 1.77 (m, 2H), 1.69 – 1.64 (m, 2H), 1.55 – 1.51 (m, 1H), 1.28 (s, 9H), 1.23 – 1.08 (m, 5H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 164.6, 154.2, 141.3, 125.6, 125.6, 49.9, 34.6, 31.3, 30.8, 25.0, 24.3, 19.9。
4i, isolation yield was 75%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d,J= 7.5 Hz, 1H), 7.71 – 7.69 (m, 2H), 7.54 – 7.52 (m, 2H), 3.90 – 3.82 (m, 1H), 2.18 (s, 3H), 1.84 – 1.78 (m, 2H), 1.61 – 1.55 (m, 2H), 1.51 – 1.35 (m, 8H), 1.28 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 164.0, 154.1, 141.4, 125.6, 125.5, 51.9, 34.6, 33.2, 30.8, 27.9, 23.5, 19.9。
4j, isolation yield was 76%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.15 (t,J= 4.7 Hz, 1H), 7.70 – 7.68 (m, 2H), 7.53 – 7.51 (m, 2H), 7.34 – 7.31 (m, 2H), 7.28 – 7.25 (m, 3H), 4.39 (d,J= 5.5 Hz, 2H), 2.29 (s, 3H), 1.29 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.6, 154.3, 141.1, 137.3, 128.4, 127.8, 127.2, 125.7, 125.5, 44.6, 34.7, 30.8, 19.9。
4k, isolation yield was 78%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.17 (t,J= 5.3 Hz, 1H), 7.66 – 7.64 (m, 2H), 7.51 – 7.49 (m, 2H), 7.36 – 7.34 (m, 2H), 7.27 – 7.25 (m, 2H), 4.37 (d,J= 5.5 Hz, 2H), 2.30 (s, 3H), 1.28 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.6, 154.3, 141.0, 136.5, 131.8, 129.6, 128.3, 125.6, 125.5, 43.9, 34.6, 30.8, 19.9。
4l, isolation yield 84%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.22 (t,J= 5.7 Hz, 1H), 7.74 – 7.72 (m, 1H), 7.67 – 7.67 (m, 1H), 7.63 – 7.60 (m, 2H), 7.59 – 7.57 (m, 1H), 7.54 – 7.52 (m, 1H), 7.51 – 7.49 (m, 2H), 4.42 (d,J= 5.6 Hz, 2H), 2.30 (s, 3H), 1.28 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.9, 154.4, 140.9, 139.3, 132.6, 131.2, 131.0, 129.6, 125.6, 125.5, 118.7, 111.3, 43.9, 34.7, 30.8, 19.9。
4m, the isolation yield was 95%. 1 H NMR (400 MHz, Chloroform-d) δ 7.98-7.95 (m, 2H), 7.60 (t,J= 5.5 Hz, 1H), 7.58-7.56 (m, 2H), 7.39-7.37 (m, 2H), 7.30-7.27 (m, 2H), 4.46 (d,J= 5.8 Hz, 2H), 2.30 (s, 3H), 1.30 (s, 9H). 13 C NMR (100 MHz, Chloroform-d) δ 166.4, 155.7, 147.0, 144.3, 139.6, 128.6, 125.8, 125.6, 123.4, 44.8, 34.9, 30.9, 20.5。
4n, isolation yield was 90%. 1 H NMR (400 MHz, Chloroform-d) δ 7.69-7.67 (m, 2H), 7.66-7.64 (m, 2H), 7.46 (t,J= 5.3 Hz, 1H), 7.43-7.41 (m, 2H), 7.35-7.33 (m, 2H), 4.48 (d,J = 5.7 Hz, 2H), 2.98 (s, 3H), 2.31 (s, 3H), 1.30 (s, 9H). 13 C NMR (100 MHz, Chloroform-d) δ 166.4, 155.5, 143.3, 139.8, 139.1, 128.8, 127.3, 125.9, 125.6, 44.9, 44.4, 34.9, 31.0, 20.6。
4o, isolation yield 67%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.20 (t,J= 4.8 Hz, 1H), 7.67 – 7.64 (m, 2H), 7.51 – 7.48 (m, 2H), 7.39 – 7.37 (m, 2H), 7.32 – 7.28 (m, 2H), 4.41 (d,J= 5.3 Hz, 2H), 2.31 (s, 3H), 1.27 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.7, 154.3, 147.5, 141.1, 137.0, 129.7, 125.7, 125.5, 120.9, 120.1 (q,J= 256.1 Hz), 43.9, 34.6, 30.8, 19.9. 19 F NMR (376 MHz, DMSO-d 6 ) δ -57.01 (s, 3F)。
4p, isolation yield was 91%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.24 (t,J= 4.9 Hz, 1H), 7.90-7.88 (m, 2H), 7.61-7.59 (m, 2H), 7.48-7.46 (m, 2H), 7.37-7.35 (m, 2H), 4.46 (d,J= 5.6 Hz, 2H), 3.84 (s, 3H), 2.32 (s, 3H), 1.27 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.0, 165.8, 154.3, 143.1, 141.0, 129.2, 128.4, 127.8, 125.6, 125.5, 52.1, 44.3, 34.6, 30.8, 19.9。
4q, isolation yield was 80%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.19 (t,J= 5.7 Hz, 1H), 8.46 (s, 1H), 7.80-7.78 (m, 2H), 7.73 (s, 1H), 7.65-7.63 (m, 2H), 7.49-7.47 (m, 2H), 7.37-7.35 (m, 2H), 6.53 (s, 1H), 4.41 (d,J= 5.6 Hz, 2H), 2.29 (s, 3H), 1.25 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.7, 154.4, 141.1, 141.0, 138.9, 135.4, 129.0, 127.7, 125.7, 125.6, 118.4, 107.9, 44.2, 34.7, 30.9, 20.0。
4r, isolation yield was 77%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.12 (t,J= 5.3 Hz, 1H), 7.68 – 7.65 (m, 2H), 7.63 – 7.60 (m, 1H), 7.53 – 7.50 (m, 2H), 7.38 – 7.30 (m, 2H), 7.26 – 7.22 (m, 1H), 4.43 (d,J= 5.1 Hz, 2H), 2.31 (s, 3H), 1.28 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.9, 154.4, 140.9, 135.9, 132.5, 130.0, 129.5, 127.7, 125.7, 125.5, 123.0, 45.1, 34.7, 30.8, 19.7。
4s, isolation yield was 88%. 1 H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J = 7.7 Hz, 1H), 7.57-7.55 (m, 2H), 7.44-7.41 (m, 2H), 7.34-7.32 (m, 2H), 7.13-7.11 (m, 2H), 5.75-5.70 (m, 1H), 4.88 (dd, J = 13.6, 8.7 Hz, 1H), 4.58 (dd, J = 13.6, 5.2 Hz, 1H), 2.30 (s, 3H), 1.33 (s, 9H). 13 C NMR (100 MHz, Chloroform-d) δ 166.5, 155.8, 139.2, 134.8, 132.1, 128.7, 125.8, 125.7, 122.6, 76.7, 52.8, 35.0, 31.0, 20.4。
4t, isolation yield was 69%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.18 (t,J= 5.7 Hz, 1H), 7.67 – 7.63 (m, 2H), 7.49 – 7.45 (m, 2H), 7.39 – 7.31 (m, 3H), 7.15 – 7.11 (m, 1H), 7.06 – 7.03 (m, 1H), 6.99 – 6.94 (m, 3H), 6.91 – 6.88 (m, 1H), 4.39 (d,J= 5.7 Hz, 2H), 2.28 (s, 3H), 1.26 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.7, 156.6, 156.5, 154.3, 141.0, 139.8, 130.0, 130.0, 125.6, 125.5, 123.4, 122.8, 118.5, 117.9, 117.3, 44.3, 34.6, 30.8, 19.9。
4u, isolation yield 88%. 1 H NMR (400 MHz, Chloroform-d) δ 7.63-7.61 (m, 2H), 7.55-7.53 (m, 2H), 7.49-7.47 (m, 1H), 7.34-7.32 (m, 2H), 7.18 (t,J= 5.6 Hz, 1H), 6.98-6.98 (m, 1H), 6.95-6.93 (m, 2H), 6.80 (dd,J = 8.6, 2.9 Hz, 1H), 4.45 (d,J = 5.7 Hz, 2H), 2.30 (s, 3H), 1.27 (s, 9H). 13 C NMR (100 MHz, Chloroform-d) δ 166.3, 160.7, 155.3, 153.9, 139.8, 137.9, 134.2, 134.1, 125.8, 125.4, 121.9, 120.8, 118.7, 118.5, 117.9, 106.0, 45.8, 34.8, 31.0, 20.5。
4v, isolation yield 86%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.36 (s, 1H), 8.69 (t,J= 2.1 Hz, 1H), 8.47 – 8.47 (m, 2H), 7.55 – 7.52 (m, 2H), 7.43 – 7.40 (m, 2H), 4.61 (s, 2H), 2.34 (s, 3H), 1.27 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.0, 154.4, 147.8, 142.6, 140.6, 128.1, 125.5, 125.3, 117.2, 43.6, 34.6, 30.7, 19.9。
4w, isolation yield was 91%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.19 (t,J= 5.8 Hz, 1H), 7.69 – 7.65 (m, 2H), 7.50 – 7.47 (m, 2H), 7.10 – 7.04 (m, 1H), 6.98 – 6.92 (m, 2H), 4.41 (d,J= 5.6 Hz, 2H), 2.34 (s, 3H), 1.27 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.9, 162.4 (dd,J= 246.5, 13.3 Hz), 154.4, 142.3 (t,J= 9.1 Hz), 140.9, 125.6, 125.5, 111.2 – 110.4 (m), 102.5 (t,J= 25.8 Hz), 43.8, 34.6, 30.8, 19.9. 19 F NMR (376 MHz, DMSO-d 6 ) δ -109.86 (s, 2F)。
4x, isolation yield 73%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (t,J= 5.5 Hz, 1H), 8.09 – 8.07 (m, 2H), 7.65 – 7.63 (m, 2H), 7.52 – 7.49 (m, 2H), 7.42 – 7.40 (m, 2H), 3.49 – 3.45 (m, 2H), 2.91 (t,J= 7.0 Hz, 2H), 2.17 (s, 3H), 1.27 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.8, 154.5, 147.4, 146.2, 141.1, 130.0, 125.7, 125.6, 123.4, 41.8, 34.7, 33.5, 30.9, 19.9。
4y, isolation yield 74%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.77 (t,J= 5.0 Hz, 1H), 7.66 – 7.63 (m, 2H), 7.55 – 7.53 (m, 2H), 7.45 – 7.41 (m, 2H), 7.13 – 7.09 (m, 2H), 3.39 – 3.36 (m, 2H), 2.75 (t,J= 7.1 Hz, 2H), 2.17 (s, 3H), 1.29 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) Delta 165.6, 154.3, 141.2, 138.4, 131.2, 130.9, 125.6, 125.6, 119.3, 42.2, 34.7, 32.9, 30.9, 19.9; the structure of the product was further confirmed by single crystals, see fig. 9.
4z, isolation yield was 93%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.18 (t,J= 5.4 Hz, 1H), 7.87 – 7.85 (m, 2H), 7.71 – 7.69 (m, 2H), 7.55 – 7.53 (m, 2H), 7.50 – 7.48 (m, 2H), 7.41 – 7.37 (m, 2H), 7.30 – 7.26 (m, 2H), 4.23 (t,J= 7.1 Hz, 1H), 3.57 (t,J= 6.1 Hz, 2H), 2.39 (s, 3H), 1.25 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.0, 154.3, 144.6, 141.1, 140.4, 127.5, 127.1, 125.6, 125.5, 124.8, 120.1, 45.4, 44.7, 34.6, 30.8, 19.9。
4ab, isolation yield 84%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.13 (t,J= 5.7 Hz, 1H), 7.65 – 7.63 (m, 2H), 7.39 – 7.36 (m, 2H), 7.27 – 7.25 (m, 2H), 7.03 – 7.00 (m, 2H), 4.35 (d,J= 5.5 Hz, 2H), 3.81 (s, 3H), 2.25 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.5, 161.4, 136.6, 135.8, 131.8, 129.6, 128.3, 127.8, 113.8, 55.5, 43.8, 19.8。
4ac, isolation yield was 80%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.30 (t,J= 5.6 Hz, 1H), 7.74 – 7.70 (m, 2H), 7.58 – 7.54 (m, 2H), 7.39 – 7.35 (m, 2H), 7.26 – 7.23 (m, 2H), 4.36 (d,J= 5.4 Hz, 2H), 2.29 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.9, 142.7, 136.4, 136.3, 131.9, 129.6, 128.9, 128.3, 127.7, 44.0, 20.0。
4ad, isolated in 79%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.48(t,J= 5.6 Hz, 1H), 8.33 – 8.29 (m, 2H), 7.96 – 7.92 (m, 2H), 7.38 – 7.34 (m, 2H), 7.26 – 7.23 (m, 2H), 4.37 (d,J= 5.0 Hz, 2H), 2.32 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.2, 149.1, 149.0, 136.3, 131.9, 129.6, 128.4, 127.3, 124.2, 44.2, 20.2。
4ae, isolated in 82%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.28 (t,J= 5.8 Hz, 1H), 8.36 – 8.35 (m, 1H), 8.10 – 8.08 (m, 1H), 8.04 – 7.99 (m, 2H), 7.73 – 7.71 (m, 1H), 7.68 – 7.61 (m, 2H), 7.35 – 7.32 (m, 2H), 7.27 – 7.25 (m, 2H), 4.38 (d,J= 5.6 Hz, 2H), 2.32 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.9, 140.9, 136.5, 133.8, 131.8, 131.7, 129.6, 129.1, 128.8, 128.3, 128.3, 127.7, 127.3, 125.7, 122.4, 44.0, 20.0。
4af, isolation yield 91%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.35 (t,J= 5.7 Hz, 1H), 7.82 – 7.80 (m, 1H), 7.48 – 7.47 (m, 1H), 7.40 – 7.38 (m, 2H), 7.31 – 7.29 (m, 2H), 7.10 – 7.08 (m, 1H), 4.40 (d,J= 5.7 Hz, 2H), 2.30 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.1, 145.4, 136.3, 131.9, 131.2, 129.7, 129.7, 128.4, 127.0, 43.9, 19.7。
4ag, isolation yield was 78%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.45 (t,J= 5.6 Hz, 1H), 7.40 – 7.38 (m, 2H), 7.32 – 7.30 (m, 2H), 7.30 – 7.28 (m, 1H), 7.23 – 7.22 (m, 1H), 4.40 (d,J= 5.6 Hz, 2H), 2.31 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.2, 146.5, 136.2, 131.9, 130.6, 130.0, 129.6, 128.4, 116.9, 44.1, 19.9。
4ah, isolated yield 76%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.97 (t,J= 5.8 Hz, 1H), 7.43 – 7.40 (m, 2H), 7.32 – 7.30 (m, 2H), 7.28 – 7.20 (m, 3H), 7.17 – 7.14 (m, 2H), 4.39 (d,J= 5.6 Hz, 2H), 3.36 (s, 2H), 2.14 (s, 3H), 1.24 – 1.18 (m, 4H), 0.77 (t,J= 6.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.6, 141.4, 137.1, 131.6, 129.2, 128.5, 128.3, 128.0, 126.7, 49.8, 43.7, 29.5, 19.6, 19.2, 13.5。
4ai, isolated in 88%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (t,J= 5.7 Hz, 1H), 8.15 – 8.13 (m, 2H), 7.92 – 7.89 (m, 2H), 7.36 – 7.34 (m, 2H), 7.26 – 7.24 (m, 2H), 5.18 (s, 2H), 4.38 (d,J= 5.5 Hz, 2H), 2.31 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.1, 163.3, 148.5, 136.3, 131.8, 130.7, 130.1, 129.6, 128.3, 126.4, 95.1, 73.9, 44.1, 20.1。
4aj, isolated in 79%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.36 (t,J= 5.7 Hz, 1H), 8.13 – 8.09 (m, 2H), 8.08 – 8.03 (m, 2H), 7.82 – 7.80 (m, 2H), 7.69 – 7.65 (m, 1H), 7.49 – 7.46 (m, 1H), 7.31 – 7.29 (m, 2H), 7.22 – 7.20 (m, 2H), 7.00 (s, 2H), 4.34 (d,J= 5.6 Hz, 2H), 2.28 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.0, 163.9, 148.3, 145.3, 136.3, 132.8, 131.8, 130.8, 130.1, 129.5, 128.4, 128.3, 126.2, 124.7, 119.4, 111.0, 69.3, 44.1, 20.1。
4ak, isolation yield 80%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.35 (t,J= 5.6 Hz, 1H), 7.79 – 7.75 (m, 2H), 7.49 – 7.45 (m, 2H), 7.35 – 7.31 (m, 2H), 7.25 – 7.23 (m, 2H), 7.22 – 7.20 (m, 4H), 7.17 (s, 1H), 4.36 (d,J= 5.5 Hz, 2H), 2.31 (s, 3H), 2.29 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.9, 145.2, 143.7, 142.2 (q,J= 37.5 Hz), 140.9, 139.1, 136.4, 131.9, 129.6, 129.4, 128.7, 128.3, 126.9, 125.8, 125.4, 121.3 (q,J= 268.9 Hz), 106.0, 44.0, 20.8, 20.0. 19 F NMR (376 MHz, DMSO-d 6 ) δ -60.91 (s, 3F)。
4al, isolation yield 92%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.27 (t,J= 5.7 Hz, 1H), 7.81 – 7.78 (m, 2H), 7.39 – 7.31 (m, 4H), 7.29 – 7.24 (m, 4H), 7.05 – 7.02 (m, 2H), 7.00 – 6.94 (m, 1H), 5.31 (q,J= 6.8 Hz, 1H), 4.37 (d,J= 5.6 Hz, 2H), 2.30 (s, 3H), 1.71 (d,J= 6.8 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.2, 165.8, 157.1, 152.0, 141.7, 136.4, 131.9, 129.7, 129.6, 128.3, 127.6, 122.0, 121.5, 115.0, 71.5, 44.0, 20.0, 18.1。
4am, isolation yield 64%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (t,J= 5.6 Hz, 1H), 8.20 – 8.16 (m, 2H), 7.78 – 7.74 (m, 2H), 7.62 – 7.58 (m, 2H), 7.38 – 7.35 (m, 2H), 7.27 – 7.23 (m, 2H), 7.23 – 7.20 (m, 2H), 4.36 (d,J= 5.6 Hz, 2H), 3.14 – 3.10 (m, 2H), 3.06 – 3.02 (m, 2H), 2.29 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 170.6, 165.8, 152.4, 148.5, 146.1, 141.3, 136.4, 131.9, 129.7, 129.7, 128.3, 127.5, 123.5, 122.2, 44.0, 34.2, 29.8, 20.0。
4an, isolation yield was 90%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.09 (t,J= 5.6 Hz, 1H), 8.23 – 8.19 (m, 2H), 7.51 – 7.48 (m, 2H), 7.29 – 7.23 (m, 5H), 4.49 (d,J= 5.8 Hz, 2H), 4.21 (s, 2H), 2.15 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 )δ 165.9, 146.6, 145.8, 131.1, 130.9, 128.6, 127.9, 127.6, 123.6, 59.8, 43.7, 19.8。
4ao, isolated in 85% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.26 (t,J= 5.9 Hz, 1H), 8.13 – 8.10 (m, 2H), 7.96 – 7.93 (m, 1H), 7.70 – 7.68 (m, 1H), 7.63 – 7.58 (m, 1H), 7.40 – 7.38 (m, 2H), 7.35 – 7.31 (m, 1H), 4.85 (s, 2H), 4.39 (d,J= 5.8 Hz, 2H), 2.29 (s, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.2, 162.5, 151.0, 146.6, 145.2, 130.3, 128.5, 123.7, 123.4, 123.3, 121.0, 109.5, 50.6, 43.8, 20.0。
4ap, isolation yield 84%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (t,J= 5.8 Hz, 1H), 8.23 – 8.20 (m, 2H), 7.54 – 7.51 (m, 2H), 4.47 (d,J= 5.7 Hz, 2H), 2.93 – 2.89 (m, 4H), 2.30 (s, 3H), 1.64 – 1.57 (m, 4H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 166.0, 146.5, 146.4, 128.2, 123.5, 48.2, 43.9, 24.6, 19.6。
4aq, isolated in 72% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.85 (t,J= 5.8 Hz, 1H), 8.22 – 8.19 (m, 2H), 7.55 – 7.52 (m, 2H), 6.45 (t,J= 6.1 Hz, 1H), 4.48 (d,J= 5.8 Hz, 2H), 2.63 – 2.58 (m, 2H), 2.30 (s, 3H), 1.38 – 1.28 (m, 2H), 0.73 (t,J= 7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.2, 146.5, 146.3, 128.4, 123.5, 44.8, 43.6, 22.2, 19.3, 11.3。
4ar, isolation yield 91%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.11 (t,J= 5.7 Hz, 1H), 7.65 – 7.61 (m, 2H), 7.50 – 7.47 (m, 2H), 7.35 – 7.31 (m, 2H), 7.25 – 7.21 (m, 2H), 4.35 (d,J= 5.6 Hz, 2H), 2.70 – 2.66 (m, 2H), 1.69 – 1.59 (m, 2H), 1.28 (s, 9H), 0.88 (t,J= 7.4 Hz, 3H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 168.5, 154.1, 141.5, 136.7, 131.7, 129.4, 128.2, 125.4, 125.3, 43.8, 34.9, 34.6, 30.8, 21.1, 13.6。
4as, isolated in 63%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.18 (t,J= 5.7 Hz, 1H), 7.55 – 7.53 (m, 2H), 7.44 – 7.42 (m, 2H), 7.31 – 7.29 (m, 2H), 7.28 – 7.21 (m, 5H), 7.21 – 7.19 (m, 2H), 4.38 (d,J= 5.6 Hz, 2H), 4.16 (s, 2H), 1.28 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.7, 154.2, 141.1, 136.7, 135.3, 131.7, 129.5, 128.8, 128.3, 128.2, 126.7, 125.4, 125.3, 44.1, 38.0, 34.6, 30.8。
4at, isolation yield was 85%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (t,J= 5.1 Hz, 1H), 7.52 – 7.47 (m, 1H), 7.44 – 7.41 (m, 4H), 7.40 – 7.39 (m, 4H), 7.36 – 7.33 (m, 2H), 7.30 – 7.27 (m, 2H), 4.46 (d,J= 5.3 Hz, 2H), 1.28 (s, 9H). 13 C NMR (100 MHz, DMSO-d 6 ) δ 165.2, 154.1, 141.2, 136.7, 134.0, 131.6, 130.5, 129.3, 128.3, 127.9, 127.8, 125.5, 125.2, 44.4, 34.6, 30.9。
The raw materials used in the existing technology for synthesizing the N-sulfonyl amidine compound are not commercialized, multi-step synthesis is needed, the cost is high, part of raw materials have explosion danger, the industrial production is not facilitated, the transition metal catalyst is used, the environment is easy to pollute, and the range of reaction substrates is narrow. Compared with the method, the method has the advantages of wide range of reaction substrates, no need of metal catalysts, simple reaction conditions, green temperature, high reaction yield and the like, and is very favorable for industrial production.
Claims (8)
1. A preparation method of an N-sulfonyl amidine compound is characterized in that the N-sulfonyl amidine compound is prepared by taking sulfonic anhydride as an additive, sulfonamide and alcohol as raw materials and reacting in the presence of nitrile;
the chemical structural formula of the sulfonamide is as follows:
；
the alcohol is R 2 OH；
The nitrile is R 3 CN；
The chemical structural formula of the N-sulfonyl amidine compound is as follows:
；
in the structural formula, R 1 Selected from naphthyl, thiopheneOne of a group, a benzyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted heteroaralkyl group; r is R 2 Selected from alkyl groups; r is R 3 Selected from alkyl or phenyl; in the substituted aralkyl and the substituted heteroaralkyl, the substituent is one or more of nitro, methoxy, tertiary butyl, ester and chlorine;
the sulfonic anhydride is trifluoromethanesulfonic anhydride.
2. The process for producing an N-sulfonylamidine compound according to claim 1, wherein the ratio of the nitrile to the sulfonamide is (0.5 to 2) mL/0.2 mmol.
3. The method for producing an N-sulfonylamidine compound according to claim 1, wherein the reaction temperature is 25 to 40℃and the reaction time is 20 to 48 hours.
4. The method for producing an N-sulfonylamidine compound according to claim 1, characterized in that the nitrile is a liquid.
5. The process for producing an N-sulfonylamidine compound according to claim 1, wherein the molar ratio of the sulfonamide, the alcohol and the sulfonic anhydride is 1:1 to 2:2.5 to 3.5.
6. The method for producing an N-sulfonylamidine compound according to claim 1, characterized in that the reaction is carried out in air.
7. The method for producing an N-sulfonylamidine compound according to claim 1, characterized in that the reaction is carried out without a metal-based catalyst.
8. The method for producing an N-sulfonylamidine compound according to claim 1, wherein the N-sulfonylamidine compound is obtained by a purification treatment after the completion of the reaction.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311599675.8A CN117304076B (en) | 2023-11-28 | 2023-11-28 | Preparation method of N-sulfonyl amidine compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311599675.8A CN117304076B (en) | 2023-11-28 | 2023-11-28 | Preparation method of N-sulfonyl amidine compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN117304076A CN117304076A (en) | 2023-12-29 |
| CN117304076B true CN117304076B (en) | 2024-02-20 |
Family
ID=89255613
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311599675.8A Active CN117304076B (en) | 2023-11-28 | 2023-11-28 | Preparation method of N-sulfonyl amidine compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117304076B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2008810A6 (en) * | 1988-07-18 | 1989-08-01 | Marga Investigacion | A process for the preparation of N-sulfamyl-propionamidine derivatives. |
| CN1050873A (en) * | 1989-10-10 | 1991-04-24 | 拜尔公司 | The alkylsulfonyl guanylhydrazones that replaces |
| JPH09309877A (en) * | 1996-05-20 | 1997-12-02 | Teijin Ltd | Cyclic diamine derivative and its production and use |
| CN1167484A (en) * | 1994-12-02 | 1997-12-10 | 山之内制药株式会社 | Novel amidinonaphthyl derivative or salt thereof |
| CN116283678A (en) * | 2023-03-01 | 2023-06-23 | 中国农业大学 | Preparation method of C-fluoroalkyl substituted amidine compound and application of C-fluoroalkyl substituted amidine compound in resisting fungal diseases |
-
2023
- 2023-11-28 CN CN202311599675.8A patent/CN117304076B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2008810A6 (en) * | 1988-07-18 | 1989-08-01 | Marga Investigacion | A process for the preparation of N-sulfamyl-propionamidine derivatives. |
| CN1050873A (en) * | 1989-10-10 | 1991-04-24 | 拜尔公司 | The alkylsulfonyl guanylhydrazones that replaces |
| CN1167484A (en) * | 1994-12-02 | 1997-12-10 | 山之内制药株式会社 | Novel amidinonaphthyl derivative or salt thereof |
| JPH09309877A (en) * | 1996-05-20 | 1997-12-02 | Teijin Ltd | Cyclic diamine derivative and its production and use |
| CN116283678A (en) * | 2023-03-01 | 2023-06-23 | 中国农业大学 | Preparation method of C-fluoroalkyl substituted amidine compound and application of C-fluoroalkyl substituted amidine compound in resisting fungal diseases |
Non-Patent Citations (3)
| Title |
|---|
| Cu-Catalyzed Aerobic Oxidative Three-Component Coupling Route to N‑Sulfonyl Amidines via an Ynamine Intermediate;Jinho Kim et al;《J. Org. Chem.》(第80期);2448-2454 * |
| Debashish Mishra et al.Unprecedented 1,3-tert-butyl migration via the C–N single bond scission of isonitrile: an expedient metal-free route to N-sulfonyl amidines.《Chem. Commun》.2020,(第56期),8408-8411. * |
| N-氨基（磺）酰脒类化合物的合成及结构表征;伍悦瑄;《中国优秀硕士学位论文全文数据库 工程科技I辑》(第5期);B016-144 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN117304076A (en) | 2023-12-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108033922B (en) | Preparation method of 3-acyl quinoxalinone derivative | |
| CN106588897A (en) | New preparation method of Pranlukast | |
| CN110590635A (en) | Preparation method of levetiracetam and intermediate thereof | |
| CN115490697B (en) | Asymmetric synthesis method of chiral azaspiro [4,5] -decylamine | |
| CN107382820B (en) | Synthetic method of 3-aryl isoindole derivative | |
| CN112062712A (en) | Preparation method of 2- (5-bromo-3-methylpyridin-2-yl) acetic acid hydrochloride | |
| CN117304076B (en) | Preparation method of N-sulfonyl amidine compound | |
| CN109180601B (en) | Organic amine catalyzed CO2Method for synthesizing 2, 4-oxazolidinedione compound | |
| CN110041274B (en) | Method for preparing 5-fluoroalkyl triazole compound by air oxidation multi-component one-pot method | |
| CN109232282B (en) | Synthetic method of 2-aminobenzophenone compound | |
| CN108440378B (en) | Preparation method of iodine-hydrogen peroxide promoted 3-amino-2-indolone derivative at room temperature | |
| CN111205202A (en) | Quaternary carbon center-containing symmetric gem-difluoroolefin derivative and synthesis method thereof | |
| CN110950865B (en) | Synthetic method of medical intermediate 8-chloro-1, 7-naphthyridine-3-formaldehyde | |
| CN115536494B (en) | Synthesis method of 1- (4-bromophenyl) -1, 4-butanediol | |
| CN115466238B (en) | Dihydrofuran-2 (3H) -imine bridged ring derivative and synthetic method thereof | |
| CN109331876B (en) | Sodium-magnesium bimetallic catalyst and preparation method and application thereof | |
| CN110590641B (en) | Green preparation method of 3-hydroxyisoindole-1-ketone series compounds | |
| CN114751800B (en) | Synthesis method of 5-sulfonyl-penta-2, 3-diene nitrile compound | |
| CN115304557B (en) | Enamine derivative and preparation method thereof | |
| CN113861093B (en) | Synthesis method of polysubstituted gamma-butyrolactam | |
| CN117229187B (en) | Synthesis method of thioimine ester compound | |
| CN110423224B (en) | Synthesis method of 2-aminopyrimidine type antiplatelet compound | |
| CN111423354B (en) | Synthesis method of 1H-3-pyrrolidone compound | |
| CN110156676B (en) | 3, 4-dihydroquinoline-2 (1H) -ketone derivative and preparation method and application thereof | |
| CN110078746B (en) | 2-carbonyl thiazolothiophene compound with luminescent property and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |