CN109053631B - Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol - Google Patents
Synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone through isothiocyanate and 2-sulfonyl alkyl phenol Download PDFInfo
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Abstract
The invention develops a synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by using 2-sulfonyl alkylphenol under alkalescent condition. 2-sulfonyl alkylphenol and isothiocyanate are used as substrates, a multifunctional benzo [1,3] oxazine-2-thioketone containing a nitrogen, oxygen and sulfur heterocyclic structure is synthesized by a one-step method, and the application of the reaction methodology of the isothiocyanate and o-QMs is expanded. The synthesis method provided by the invention can react at room temperature, has mild reaction conditions, good substrate universality, no need of a catalyst, simple and easily obtained alkaline reagent, convenient operation, economy and high efficiency; the method has high reaction activity, the yield reaches 92 percent, and the raw materials are completely converted; the product is convenient to separate, and the reaction is green and economical and environment-friendly.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a synthesis method for synthesizing benzo [1,3] oxazine-2-thioketone by using isothiocyanate and 2-sulfonyl alkylphenol.
Background
The heterocyclic compound has wide biological activity and becomes a hotspot of research and development in the field of pharmaceutical research, wherein the oxazine-2-thione belongs to a polycyclic compound containing nitrogen, oxygen and sulfur heteroatoms, and the compound has biological activities of resisting cancer, resisting tumor, relieving pain, killing insects, sterilizing and the like. For example, the non-steroidal synthetic progestogen Tanaproget, which entered phase II clinical trials in 2010, may be used as an effective contraceptive in the future.
However, the current synthesis methods for oxazine-2-thione include substitution reaction using corresponding oxazine-2-ketone as substrate and Lawesson reagent (bioorg. Med. chem. Lett.2003,13, 1313-.
In 2015, Kazuhiro Kobayashi et al utilized 2- (1-isothiocyanato alkyl ester) phenol to undergo intramolecular cyclization under mild conditions to produce benzoxazine-2-thiones (Heterocycles,2016,93, 63-74). Although this reaction can efficiently synthesize benzoxazine-2-thione, the adoption of a synthetic strategy for intramolecular cyclization results in relatively limited substrates for the convenience of reaction; and the substrate 2- (1-isothiocyanatoalkyl ester) phenol is complicated to operate by a five-step synthetic process.
The isothiocyanate can participate in various organic reactions and is used for synthesizing various compounds containing sulfur, nitrogen and oxygen, in particular heterocyclic compounds. The C in-N ═ C ═ S in the isothiocyanate molecule has high electrophilicity and is capable of nucleophilic addition reaction with a nucleophile. For example, in the above synthetic scheme, the isothiocyanate group undergoes an intramolecular nucleophilic addition cyclization reaction. Because the classical reaction mode of the isothiocyanate is limited to nucleophilic addition reaction and is applied to the total synthesis of natural products containing glycosyl heterocycle and analogues thereof, the development of the isothiocyanate in the pharmaceutical chemical field is limited.
O-methylenequinone (o-QMs) is a transient, highly reactive intermediate that typically exists in two forms: a diradical species or a polarized zwitterion. However, o-QMs participates in catalyzing asymmetric [4+2]]The difficulty of the cycloaddition reaction is not only its short lifetime, but also includes the catalyst and o-QMs being too weak to promote the reaction. Also, among the various mechanisms currently used for the production of o-QMs, Lewis acids and
the acid-catalyzed substituent leaving operation method is simple and convenient, and the application range isThe precursor o-QMs, which contains acid sensitive functional groups (such as phenolic hydroxyl groups), is not suitable for these acidic catalysts. Therefore, under neutral or weakly alkaline conditions, compounds containing hydroxyl groups and the like are subjected to elimination reaction to generate o-QMs, and the type of synthetic reaction in which o-QMs participates can be effectively expanded.
Therefore, in order to realize efficient synthesis of benzoxazine-2-thione compounds and to expand the application of the reaction methodology of isothiocyanate and o-QMs, a new strategy for the synthetic transformation of benzo [1,3] oxazine-2-thione compounds is required.
Disclosure of Invention
The invention aims to provide a synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by using isothiocyanate and 2-sulfonyl alkylphenol. The method has the advantages of simple and practical operation, good yield, green and economical reaction and environmental friendliness.
The synthesis method provided by the invention specifically comprises the following steps:
2-sulfonyl alkyl phenol and isothiocyanate react under the action of an alkaline reagent to generate the benzo [1,3] oxazine-2-thioketone.
The benzo [1,3] oxazine-2-thioketone is a compound shown as a formula I:
in formula I, the dotted line represents an optional single bond;
R1any one of methyl, methoxy and halogen; and is
R2、R3Each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethylphenyl, cyanophenyl, halogen-substituted phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one of alkoxy substituted phenyl.
The above-mentioned 2-sulfonylalkylphenol is a compound represented by the formula II, and the above-mentioned isothiocyanate is a compound represented by the formula III:
in the formulas II and III, the dotted line represents an optional single bond;
R1any one of methyl, methoxy and halogen; and is
R2、R3Each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethylphenyl, cyanophenyl, halogen-substituted phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one of alkoxy substituted phenyl.
The alkaline reagent is any one of cesium carbonate, potassium carbonate, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and tetramethylguanidine.
The reaction is carried out in a solvent selected from dichloromethane, tetrahydrofuran and dioxane.
The molar ratio of the 2-sulfonylalkylphenol to the isothiocyanate is 2: 3.
The molar ratio of the alkaline reagent to the 2-sulfonyl alkylphenol is 2.5: 1; the amount of the solvent is 10L per mole of 2-sulfonylalkylphenol.
The above reaction was carried out at 25 ℃.
The reaction time is 1-16 h.
The invention provides a synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by isothiocyanate and 2-sulfonyl alkylphenol, which comprises the following steps:
adding 0.2mmol of 2-sulfonylalkylphenol to 2mL of a solvent, followed by adding 0.3mmol of isothiocyanate and 0.5mmol of a basic agent to the solvent; controlling the temperature of the system to be 25 ℃ at room temperature, continuously stirring, and carrying out sample application tracking reaction by a thin layer chromatography plate until the reaction of the raw materials is complete;
after reacting for 12h, separating a reaction product in the solution by using a silica gel column, and performing rotary evaporation and concentration to obtain a product.
The compounds to which the present invention relates may exist in the form of one or more stereoisomers. The various isomers include enantiomers, diastereomers, geometric isomers. It is within the scope of the present invention for these isomers to include mixtures of these isomers.
The technical scheme of the invention has the following beneficial effects: under the alkaline condition, p-toluenesulfonyl is removed from 2-sulfonyl alkyl phenol to generate o-QMs in situ, and the o-QMs and isothiocyanate undergo a [4+2] cycloaddition reaction. The reaction is subjected to a series cyclization reaction because isothiocyanate is a strong electron-deficient system and the difficulty of generating a reverse electron-demanding hetero Diels-Alder reaction is high. Since the properties of isothiocyanates are greatly influenced by substituent effects, different substituents result in reactions yielding different products, not just benzo [1,3] oxazine-2-thiones. The concrete expression is as follows: firstly, removing p-toluenesulfonyl from 2-sulfonylalkylphenol to generate o-QMs in situ, then attacking oxygen atom of o-QMs to the carbon of an electricity-deficient center of isothiocyanate to form two resonant transition state zwitterions TS2 and TS 2', and generating a product 3 in the form of TS2 when R is methoxy, methyl, fluorine, chlorine, bromine and trifluoromethyl substituted phenyl; when R is p-nitrophenyl, the product 4 is generated in the form of TS 2'; when R is p-cyanophenyl, both forms exist, and a mixed product is obtained. However, when R is an ester group, o-QMs is not undergone, but the phenolic hydroxyl group directly acts as a nucleophile to perform an addition reaction on the isothiocyanate to produce product 5.
The invention develops a synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by using 2-sulfonyl alkylphenol under alkalescent condition. 2-sulfonyl alkyl phenol and isothiocyanate are used as substrates, and a multifunctional benzo [1,3] oxazine-2-thioketone containing a nitrogen, oxygen and sulfur heterocyclic structure is synthesized by a one-step method. The method has the advantages of convenient and easily obtained reaction substrates, good substrate universality and no obvious influence of the position of a substrate substituent on the reaction yield. The alkaline reagent is simple and easy to obtain, convenient to operate, economical and efficient; the reaction activity is higher, and the raw material conversion is complete; the product is convenient to separate, and the reaction is green and economical and environment-friendly.
Detailed Description
The foregoing aspects of the present invention are further illustrated by the specific embodiments provided in the following examples, which should not be construed as limiting the scope of the above-described subject matter of the present invention to the following examples by those skilled in the art; all the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials, instruments and the like used in the following examples are commercially available unless otherwise specified.
Example 1
Taking 0.2mmol of 2- (α -phenyl p-toluenesulfonyl) phenol to a reaction bottle, sequentially adding 2mL of solvent, 0.3mmol of phenyl isothiocyanate and finally 0.5mmol of alkaline reagent, controlling the temperature of the system to be 25 ℃, continuously stirring, and carrying out sample application tracking reaction by a thin layer chromatography plate until the raw materials are completely reacted.
After the reaction is finished, separating and purifying by using a silica gel column, and performing rotary evaporation on the purified product to obtain the target product.
Using the above reaction formula, 10 sets of parallel test groups were set up, using different alkaline reagents, solvents and reaction times. The alkaline reagents are respectively cesium carbonate Cs2CO3Potassium carbonate K2CO3Triethylamine TEA, 1, 8-diazabicyclo [5.4.0]]Undec-7-ene DBU, tetramethylguanidine TMG. The solvents are dichloromethane DCM, tetrahydrofuran THF and Dioxane respectively. The specific alkaline reagents, solvent types and concentrations used in the test groups are shown in table 1:
TABLE 1 reaction yield of 2- (α -Phenylp-toluenesulfonyl) phenol with phenylisothiocyanate
| Serial number | Alkaline reagent | Solvent(s) | Reaction time (h) | Yield (%) |
| 1 | Cs2CO3 | DCM | 12 | 92 |
| 2 | Cs2CO3 | Dioxane | 12 | 86 |
| 3 | Cs2CO3 | THF | 12 | 79 |
| 4 | TEA | DCM | 12 | 63 |
| 5 | DBU | DCM | 12 | 54 |
| 6 | TMG | DCM | 12 | 62 |
| 7 | K2CO3 | DCM | 12 | 75 |
| 8 | Cs2CO3 | DCM | 1 | 19 |
| 9 | Cs2CO3 | DCM | 8 | 72 |
| 10 | Cs2CO3 | DCM | 16 | 80 |
Note: the yield is an isolated yield.
According to the analysis of the results of the parallel tests, the reduction or increase of the reaction time can lead to the reduction of the yield of the reactant, and the selection of the metal salt reagent and the organic alkaline reagent in the reaction can obtain higher yield of the target product.
Example 2
According to the procedure of example 1, 2- (α -phenyl-p-toluenesulfonyl) phenol was reacted with 4-cyanophenyl isothiocyanate, 4-nitrophenyl isothiocyanate and ethyl isothiocyanatecarboxylate, respectively, in the same reaction system as the reagents, in the presence of 0.5mmol of cesium carbonate in 2mL of DCM as a solvent, under continuous stirring at 25 ℃ for 12 hours, to complete the reaction.
According to the analysis of the test results, one of the reaction raw materials is isothiocyanate with different electric substituents, and the yield of benzo [1,3] oxazine-2-thioketone is obviously reduced due to different addition products obtained by the [4+2] cycloaddition of the isothiocyanate and o-QMs in the reaction process.
In the following examples 3 to 16, according to the procedure of example 1, the starting material 1-sulfonylalkylphenol and isothiocyanate were 0.2mmol and 0.3mmol, respectively, the amount of the basic agent was 0.5mmol of cesium carbonate, and 2mL of DCM was used as a solvent, and the reaction was continued with stirring at 25 ℃ for 12 hours to complete the reaction.
Example 3
The raw materials are 2- (α -phenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H15NOS
Molecular weight: 318.4126
Structural formula (xvi):
yield: 92 percent of
1H NMR(500MHz,CDCl3)δ7.39–7.31(m,8H),7.21–7.14(m,3H),7.04(d,J＝7.1Hz,3H),5.69(s,1H).13C NMR(125MHz,CDCl3)δ＝182.9,147.9,143.8,140.2,129.6,129.5,129.2,128.9,128.5,127.6,127.4,126.2,125.5,121.8,116.5,67.1.HRMS(ESI)Calcd forC20H15NOS[M+H]+:318.4121,Found:318.4126.
Example 4
The raw materials are 4-methyl-2- (α -phenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4386
Structural formula (xvi):
yield: 81 percent of
1H NMR(500MHz,CDCl3)δ7.39–7.30(m,6H),7.21-7.15(m,4H),7.02(s,2H),6.81(s,1H),5.63(s,1H),2.28(s,3H).13C NMR(125MHz,CDCl3)δ＝183.1,146.0,143.9,140.3,135.3,130.2,129.5,129.2,128.9,128.4,127.6,127.4,126.3,121.4,116.2,67.2,20.8.HRMS(ESI)Calcdfor C21H17NOS[M+H]+:332.4381,Found:332.4386.
Example 5
The raw materials are 2-methoxy-6- (α -phenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NO2S
Molecular weight: 348.4386
Structural formula (xvi):
yield: 62 percent of
1H NMR(500MHz,CDCl3)δ7.31-7.26(m,6H),7.20(s,2H),7.08–7.02(m,3H),6.90(d,J＝8.0Hz,1H),6.58(d,J＝7.6Hz,1H),5.65(s,1H),3.94(s,3H).13C NMR(125MHz,CDCl3)δ＝182.5,147.0,143.8,140.1,137.6,129.4,129.1,128.8,128.3,127.5,127.2,125.5,122.8,117.0,111.5,66.9,56.0.HRMS(ESI)Calcd for C21H17NO2S[M+H]+:348.4381,Found:348.4386.
Example 6
The raw materials are 4-chloro-2- (α -phenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H14ClNOS
Molecular weight: 352.8577
Structural formula (xvi):
yield: 71 percent of
1H NMR(500MHz,CDCl3)δ7.39–7.30(m,7H),7.26(d,J＝3.2Hz,1H),7.16(dd,J＝6.5,3.0Hz,2H),7.00(d,J＝2.2Hz,3H),5.62(s,1H).13C NMR(125MHz,CDCl3)δ＝182.4,146.4,143.6,139.5,130.5,129.7,129.6,129.4,129.2,128.6,127.5,127.3,126.0,123.3,118.0,66.7.HRMS(ESI)Calcd for C20H14ClNOS[M+H]+:352.8572,Found:352.8577.
Example 7
The raw materials are 2- (α -m-methylphenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
Structural formula (xvi):
yield: 83 percent
1H NMR(500MHz,CDCl3)δ7.38–7.28(m,5H),7.21–7.10(m,3H),7.02(d,J＝7.2Hz,3H),6.96(d,J＝8.7Hz,2H),5.62(s,1H),2.29(s,3H).HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
Example 8
The raw materials are 2- (α -p-benzyloxy-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NO2S
Molecular weight: 348.4386
Structural formula (xvi):
yield: 86 percent of the total weight
1H NMR(500MHz,CDCl3)δ7.32–7.14(m,5H),7.04(t,J＝7.2Hz,1H),6.96(d,J＝8.7Hz,2H),6.90(d,J＝7.7Hz,3H),6.72(d,J＝8.6Hz,2H),5.55(s,1H),3.67(s,3H).HRMS(ESI)Calcd for C21H17NO2S[M+H]+:348.4381,Found:348.4386.
Example 9
The raw materials are 2- (α -o-methylphenyl-p-toluenesulfonyl) phenol and phenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
Structural formula (xvi):
yield: 71 percent of
1H NMR(500MHz,CDCl3)δ7.36–7.28(m,5H),7.24–7.14(m,4H),7.14–7.02(m,3H),6.90(d,J＝7.6Hz,1H),6.05(s,1H),1.97(s,3H).HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
Example 10
The raw materials are 2- (α -phenyl-p-toluenesulfonyl) phenol, p-toluene isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
Structural formula (xvi):
yield: 83 percent
1H NMR(500MHz,CDCl3)δ7.38–7.27(m,5H),7.22–7.09(m,5H),7.01(d,J＝7.5Hz,1H),6.89(d,J＝7.0Hz,2H),5.65(s,1H),2.34(s,3H).13C NMR(125MHz,CDCl3)δ＝183.0,147.9,141.3,140.3,138.5,130.2,129.5,129.2,128.9,127.4,127.2,126.2,125.4,121.8,116.5,67.1,21.2.HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
Example 11
The raw materials are 2- (α -phenyl-p-toluenesulfonyl) phenol and m-toluene isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
Structural formula (xvi):
yield: 73 percent
1H NMR(500MHz,CDCl3)δ7.29–7.17(m,6H),7.17–7.02(m,5H),6.94(d,J＝7.3Hz,1H),6.74(d,J＝34.9Hz,2H),5.58(s,1H),2.20(s,3H).13C NMR(125MHz,CDCl3)δ＝182.8,147.9,143.7,140.2,139.6,129.5,129.2,129.2,129.1,128.8,127.8,127.3,126.1,125.4,124.6,121.8,116.4,67.0,21.2.HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
Example 12
The raw materials are 2- (α -phenyl p-toluenesulfonyl) phenol, 4-methoxyphenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NO2S
Molecular weight: 348.4386
Structural formula (xvi):
yield: 74 percent
1H NMR(500MHz,CDCl3)δ7.39–7.28(m,5H),7.21–7.11(m,3H),7.01(d,J＝7.2Hz,1H),6.92(s,2H),6.83(d,J＝8.7Hz,2H),5.64(s,1H),3.79(s,3H).13C NMR(125MHz,CDCl3)δ＝183.2,159.1,147.9,140.3,136.7,129.5,129.2,128.9,128.6,127.5,126.2,125.4,121.8,116.5,114.6,67.3,55.4.HRMS(ESI)Calcd for C21H17NO2S[M+H]+:348.4381,Found:348.4386.
Example 13
The raw material is 2- (α -phenyl-p-toluenesulfonyl) phenol, 4-fluorophenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H14FNOS
Molecular weight: 336.4031
Structural formula (xvi):
yield: 85 percent of
1H NMR(500MHz,CDCl3)δ7.39–7.29(m,5H),7.17–7.14(m,3H),7.01(d,J＝7.8Hz,5H),5.64(s,1H).13C NMR(125MHz,CDCl3)δ＝183.0,161.9(d,J＝249.1Hz),147.7,139.7(d,J＝2.5Hz),139.6,129.6,129.5(d,J＝7.0Hz),129.2,129.0,127.4,126.2,125.5,121.5,116.6,116.4,67.1.HRMS(ESI)Calcd for C20H14FNOS[M+H]+:336.4026,Found:336.4031.
Example 14
Starting materials 2- (α -phenyl-p-toluenesulfonyl) phenol, 4-chlorophenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H14ClNOS
Molecular weight: 352.8577
Structural formula (xvi):
yield: 94 percent of
1H NMR(500MHz,CDCl3)δ7.38–7.29(m,7H),7.17–7.13(m,3H),7.01(d,J＝7.6Hz,1H),6.95(d,J＝7.5Hz,2H),5.63(s,1H).13C NMR(125MHz,CDCl3)δ＝182.9,147.8,142.2,139.9,134.3,129.8,129.7,129.3,129.1,127.4,126.3,125.6,121.5,116.5,67.1.HRMS(ESI)Calcd forC20H14ClNOS[M+H]+:352.8572,Found:352.8577.
Example 15
The raw materials are 2- (α -phenyl p-toluenesulfonyl) phenol, 4-bromophenyl isothiocyanate
The product is as follows: the chemical formula is as follows: c20H14BrNOS
Molecular weight: 397.3087
Structural formula (xvi):
yield: 81 percent of
1H NMR(500MHz,CDCl3)δ7.47(d,J＝7.9Hz,2H),7.40–7.27(m,5H),7.24–7.12(m,3H),7.03(d,J＝7.5Hz,1H),6.90(d,J＝6.8Hz,2H),5.65(s,1H).13C NMR(125MHz,CDCl3)δ＝182.8,147.7,142.7,139.8,132.8,129.7,129.4,129.3,129.1,127.3,126.2,125.6,122.4,121.4,116.4,67.0.HRMS(ESI)Calcd for C20H14BrNOS[M+H]+:397.3082,Found:397.3087.
Example 16
The raw materials are 2- (α -phenyl-p-toluenesulfonyl) phenol and benzyl isothiocyanate
The product is as follows: the chemical formula is as follows: c21H17NOS
Molecular weight: 332.4392
Structural formula (xvi):
yield: 73 percent
1H NMR(500MHz,CDCl3)δ7.40–7.31(m,6H),7.30–7.20(m,4H),7.05(t,J＝7.6Hz,1H),6.90(d,J＝7.2Hz,1H),6.32(d,J＝15.1Hz,1H),5.34(s,1H),4.10(d,J＝15.2Hz,1H).13CNMR(125MHz,CDCl3)δ＝183.6,147.6,140.0,134.6,129.5,129.4,129.0,128.3,128.2,126.9,126.4,126.3,126.3,125.3,116.3,61.2,56.2.HRMS(ESI)Calcd for C21H17NOS[M+H]+:332.4387,Found:332.4392.
The foregoing is directed to preferred embodiments of the present invention, other and further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. However, any simple modification, equivalent change and modification of the above embodiments according to the technical essence of the present invention are within the protection scope of the technical solution of the present invention.
Claims (6)
1. A synthetic method for synthesizing benzo [1,3] oxazine-2-thioketone by isothiocyanate and 2-sulfonyl alkyl phenol is characterized in that: 2-sulfonyl alkyl phenol and isothiocyanate react under the action of an alkaline reagent to generate the benzo [1,3] oxazine-2-thioketone;
the benzo [1,3] oxazine-2-thioketone is a compound shown in a formula I:
in formula I, the dotted line represents an optional single bond;
R1any one of methyl, methoxy and halogen; and is
R2、R3Each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethylphenyl, cyanophenyl, halogen-substituted phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one of alkoxy substituted phenyl;
the 2-sulfonyl alkyl phenol is a compound shown as a formula II, and the isothiocyanate is a compound shown as a formula III:
in the formulas II and III, the dotted line represents an optional single bond;
R1any one of methyl, methoxy and halogen; and is
R2、R3Each independently selected from C1-C3Alkyl, phenethyl, phenyl, trifluoromethylphenyl, cyanophenyl, halogen-substituted phenyl, C1-C3Alkyl-substituted phenyl, C1-C3Any one of alkoxy substituted phenyl;
the alkaline reagent is any one of cesium carbonate, potassium carbonate, triethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene and tetramethylguanidine.
2. The method of synthesis according to claim 1, characterized in that: the reaction is carried out in a solvent, wherein the solvent is any one of dichloromethane, tetrahydrofuran and dioxane.
3. The method of synthesis according to claim 2, characterized in that: the molar ratio of the 2-sulfonylalkylphenol to the isothiocyanate is 2: 3.
4. The method of synthesis according to claim 3, characterized in that: the molar ratio of the alkaline reagent to the 2-sulfonyl alkylphenol is 2.5: 1; the amount of the solvent is 10L per mole of 2-sulfonylalkylphenol.
5. The method of synthesis according to claim 4, characterized in that: the reaction is carried out at 25 ℃.
6. The method of synthesis of any one of claims 1-5, wherein: the method specifically comprises the following steps: adding 0.2mmol of 2-sulfonylalkylphenol to 2mL of a solvent, followed by adding 0.3mmol of isothiocyanate and 0.5mmol of a basic agent to the solvent; controlling the temperature of the system to be 25 ℃ at room temperature, continuously stirring, and carrying out sample application tracking reaction by a thin layer chromatography plate until the reaction of the raw materials is complete;
after reacting for 12h, separating a reaction product in the solution by using a silica gel column, and performing rotary evaporation and concentration to obtain a product.
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| Three-Component Aminoalkylations Yielding Dihydronaphthoxazine-Based Sirtuin Inhibitors: Scaffold Modification and Exploration of Space for Polar Side-Chains;S. Vojacek et al.;《Arch. Pharm. Chem. Life Sci.》;20171231;第350卷;第e1700097页 * |
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