CN108148052B - 3-alkoxy-1, 1-dialkylthiopropene derivative and synthetic method thereof - Google Patents
3-alkoxy-1, 1-dialkylthiopropene derivative and synthetic method thereof Download PDFInfo
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Abstract
The invention discloses a 3-alkoxy-1, 1-dialkylthiopropene derivative and a synthetic method thereof. The dithioketene with structural diversity and multiple reaction centers which is easy to prepare is taken as a raw material, and is promoted by ferric salt to perform oxidative coupling reaction with simple ether, so that a series of 3-alkoxy-1, 1-dialkylthiopropylene derivatives with different structures are synthesized, and the product can be further converted into a functional product. The method has the advantages of easily available raw materials, simple and convenient operation, high reaction efficiency and diversity of functional groups.
Description
Technical Field
The present invention relates to a process for preparing a tetrasubstituted olefin compound, a 3-alkoxy-1, 1-dialkylthiopropene derivative. The 3-alkoxy-1, 1-dialkylthiopropene derivative is prepared by taking dithioketene with structural diversity and multiple reaction centers which is easy to prepare as a raw material and carrying out oxidation cross-coupling reaction on the dithioketene with simple open chain or cyclic ether under the promotion of iron salt. Compared with the existing synthesis method of the polysubstituted olefin derivative, the method has the advantages of easily obtained raw materials, simple and convenient operation and high yield, and takes the iron salt as the catalyst, thereby being environment-friendly; and can avoid the pre-functionalization of the substrate, and has the characteristic of high atom economy.
Background
Polysubstituted olefins are important building blocks and are widely found in natural products and in drug molecules. Such as (Z) -Tamoxifen, which is currently the most important drug for the clinical prevention and treatment of breast cancer. And Vioxx for the treatment of proliferative osteoarthropathy and rheumatoid arthritis. The olefin alkylation reaction is an important synthetic method for preparing polysubstituted olefin derivatives, and is widely applied to the fields of medicines, pesticides, chemical industry and the like.
Currently, many Friedel-Crafts alkylation reactions have been reported. In general, the acid is selected from those capable of reacting with strong Lewis acid and
substrates that generate carbenium ions upon acid activation act as electrophiles, e.g., alcohols, olefins, halides, and the like. However, Friedel-Crafts alkylation reactions all report sp of aromatic or heteroaromatic hydrocarbons2Alkylation of C-H bonds, while less is reported for alkylation of olefins. It can be divided into two main categories: (1) the alkylation reaction of olefin is realized by using the classical Friedel-Crafts reaction, but halogenated hydrocarbon or olefin is required to be used as an alkylating agent, but the atom utilization rate of the reaction is low or the application range of the substrate is narrow, and only aryl olefin can be used as the alkylating agent (C)hem.eur.j.2011,17,8290; hem.eur.j.2012,18,15158; chem.commun.2014,50,6337); (2) the alkylation reaction of olefin is carried out by using transition metal to catalyze the functionalization of C-H bond. Transition metal-catalyzed C — H bond activation and functionalization is one of the most interesting areas of research in recent years, because it avoids pre-functionalization of substrates, reduces synthesis steps, has the advantage of high atom economy, etc. The majority of the olefin alkylation reactions for transition metal catalysis have focused on terminal olefins, while only a few have reported that alkylation reactions of internal olefins have been achieved (ACS cat 2015,5,2882; j. org. chem.2015,80,7251; adv. synth. catayl.2016,358, 2422).
The invention utilizes dithioketene with easy preparation, structural diversity and multiple reaction centers as a raw material to carry out oxidative coupling reaction with simple ether under the promotion of ferric salt, thereby synthesizing a series of 3-alkoxy-1, 1-dialkyl thiopropylene derivatives with different structures.
Disclosure of Invention
The invention aims to synthesize the polysubstituted olefin derivative by using dithioketene 2 which is easy to prepare, has structural diversity and multiple reaction centers as a raw material and realizing the construction of a C-C bond in one step through oxidative coupling.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the oxidative cross-coupling reaction of ketene disulfide 2 and ether 3 is carried out in the presence of an oxidant by taking iron salt as a catalyst to generate the 3-alkoxy-1, 1-dialkylthiopropene derivative 1 (reaction formula 1). And after the reaction is finished, performing product separation and characterization according to a conventional separation and purification method to obtain a target product.
The technical scheme is characterized in that:
1. substituent of dithioketene 2: r1Acetyl, arylformyl, 2-naphthoyl, 2-furoyl, 2-thenoyl, cyano and ethoxycarbonyl; r2Is methyl, ethyl or R2····R2Represents polymethylene (CH)2)nWherein n is 2 or 3.
2. Substituents for ether 3: methyl, R3····R3represents-CH2OCH2-group or R3····R3Represents polymethylene (CH)2)nWherein n is 2 or 3.
3. The catalyst is anhydrous ferric trichloride, ferric tribromide or ferric acetate; wherein, the reaction takes anhydrous ferric trichloride as a catalyst with the best effect, and the optimal molar ratio of the dithioketene 2 to the catalyst is 1: 0.05.
4. The additive is 1, 8-diazabicycloundecen-7-ene or triethylene diamine hexahydrate, and the molar ratio of dithioketene 2 to the additive is 1:0.10-1: 0.20; wherein, the reaction takes triethylene diamine hexahydrate as an additive with the best effect, and the molar ratio of dithioketene 2 to triethylene diamine hexahydrate is 1: 0.10.
5. The oxidant is one of tert-butyl hydroperoxide, di-tert-butyl peroxide or tert-butyl peroxybenzoate; among them, di-t-butylperoxy has the best effect as an oxidizing agent.
6. The reaction solvent is the best when the simple ether 3 is selected.
8. The reaction time is 12-48 hours. Wherein the optimal reaction time is 24-48 hours.
9. The reaction temperature is 80-150 ℃, and the optimal reaction temperature is 120-130 ℃.
The invention has the following advantages:
1) the synthon dithioketene 2 has structural diversity and is easy to prepare in large quantity, and can be used for synthesizing 3-alkoxy-1, 1-dialkylthiopropene derivatives 1 with different types and structures.
2) The olefin alkylation reaction can be carried out by direct C-H/C-H oxidative coupling, can avoid the pre-functionalization of a substrate, simplifies the synthesis steps, has the characteristic of high atom economy, and has the characteristic of environmental friendliness by using iron salt as a catalyst.
3) The synthesis reaction has simple steps, high product yield and wide application range.
In a word, the invention utilizes the structural diversity and multiple reaction centers of the dithioketene 2 to efficiently synthesize the 3-alkoxy-1, 1-dialkylthiopropene derivative 1 with different types and structures, the raw materials are easy to obtain, the operation is simple and convenient, the yield of the target product is high, and the derivative can be further derived.
Detailed Description
The invention takes simple dithioketene 2 and simple ether 3 as raw materials to carry out cross coupling reaction under the condition of ferric salt and oxidant (reaction formula 1).
The specific process is as follows: in a glove box, dithioketene 2(0.5mmol), iron salt (0.025mmol) and additive (0.05mmol) were weighed, charged into a 25mL sealed tube with a branch, and reactant 3(3mL) and oxidant (1.5mmol) were added under nitrogen atmosphere, and the mixture was put in an oil bath at 130 ℃ for reaction for 24 hours. After completion of the reaction, it was cooled to room temperature, filtered with celite, evaporated under reduced pressure to remove the solvent, and then subjected to silica gel column chromatography (eluent: petroleum ether (60-90 ℃ C.)/ethyl acetate: 4:1, v/v) to obtain product 3 as a pale yellow solid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
The following examples are provided to aid in the further understanding of the present invention, but the invention is not limited thereto.
Example 1
The specific process is as follows: dithioketene 2a (111.2mg, 0.5mmol), FeCl were weighed in a glove box3(4.1mg，0.025mmol)，DABCO·6H2O (11.0mg, 0.05mmol) was charged into a 25mL sealed tube with a split, 1,4-Dioxane (3mL) and DTBP (219.2mg, 1.5mmol) were added under a nitrogen atmosphere, and the mixture was put in an oil bath at 130 ℃ for reaction for 24 hours. After the reaction was completed, it was cooled to room temperature, filtered with celite, evaporated under reduced pressure to remove the solvent, and then column chromatographed (petroleum ether (60-90 ℃ C.)/ethyl acetate: 8:1, v/v) to give a pale yellow solidProduct 1a (122.5mg, yield 80%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 2
The procedure was as in example 1 except that dithioketene was added in an amount of 2b (150.0mg,0.5mmol) to the reaction system in example 1. The reaction was stopped and worked up to give the title product 1b as a pale yellow solid (146.0mg, yield 76%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 3
The procedure is as in example 1, except that 2c (118.0mg,0.5mmol) is added as dithioketene to the reaction system in example 1. The reaction was stopped and worked up to give the title product 1c as a pale yellow solid (128.0mg, yield 79%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 4
The procedure is as in example 1, except that dithioketene is added to the reaction system in an amount of 2d (80.0mg,0.5 mmol). The reaction was stopped and worked up to give the title product 1d as a pale yellow solid (106.5mg, yield 87%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 5
The procedure was as in example 1 except that 2e (112.0mg,0.5mmol) was used as the dithioketene charged in the reaction system. The reaction was stopped and worked up to give the title product 1e as a pale yellow solid (125.0mg, yield 81%). The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Example 6
The specific process is as follows: 1e (62mg, 0.2mmol), NH was weighed2NH2·H2O (120uL,2.0mmol, 85%) was added to a 25mL sealed tube, 2mL of toluene was added, and the mixture was put in a 120 ℃ oil bath for reaction for 7 d. After completion of the reaction, it was cooled to room temperature, rotary-distilled under reduced pressure to remove the solvent, followed by column chromatography (petroleum ether (60-90 ℃ C.)/ethyl acetate: 8:1, v/v) to give product 4a (52mg, yield 95%) as a white solid. The target product is confirmed by the measurement of nuclear magnetic resonance spectrum and high-resolution mass spectrum.
Typical compound characterization data
3-alkoxy-1, 1-dialkylthiopropene derivative (1a) as a pale yellow solid, melting point 129-.1H NMR(400MHz,CDCl3)7.69(d,J＝7.1Hz,2H,aromatic CH),7.48(t,J＝7.3Hz,1H,aromatic CH),7.40(t,J＝7.4Hz,2H,aromatic CH),4.71(dd,J＝10.5,3.0Hz,1H,OCHOCH2),4.12(t,J＝11.1Hz,1H,OCH2),3.89(d,J＝9.3Hz,1H,OCH2),3.72(m,2H,SCH2),3.62(t,J＝9.2Hz,1H,OCH2),3.53(dd,J＝11.7,2.9Hz,1H,OCH2),3.42(m,1H,OCH2),3.31(m,2H,SCH2),3.16(m,1H,OCH2).13C{H}NMR(100MHz,CDCl3)193.17(Cq,C＝O),163.07(Cq,CSMe),138.58(Cq of Ph),131.75,128.52,and 128.42(aromatic CH),121.93(Cq,C＝CCH),76.67(OCH),67.24,66.65and 65.70(OCH2),37.42and 37.22(SCH2CH2S).C15H16O3S2HRMS theoretical value of ([ M + H ]]+) 309.0619; measured value 309.0617.
3-alkoxy-1, 1-dialkylthiopropene derivative (1b) as a pale yellow solid, melting point 141-.1H NMR(400MHz,CDCl3)7.56(q,J＝8.5Hz,4H,aromatic CH),4.64(dd,J＝10.4,2.9Hz,1H,OCH),4.10(t,J＝11.1Hz,1H,OCH2),3.87(d,J＝9.3Hz,1H,OCH2),3.72(m,2H,SCH2),3.62(t,J＝9.8Hz,1H,OCH2),3.52(dd,J＝11.7,2.8Hz,1H,OCH2),3.42(m,1H,OCH2),3.32(m,1H,OCH2),3.17(m,1H,SCH2).13C{H}NMR(100MHz,CDCl3)192.17(Cq,C＝O),163.55(Cq,CSMe),137.42126.75(Cq of Ph),131.76and 130.31(aromatic CH),126.75(Cq of Ph),121.68(Cq,C＝CCH),76.77(OCH),67.36,66.78and 65.80(OCH2),37.56and 37.36(SCH2CH2S).C15H15O3S2HRMS theoretical value of Br ([ M + H)]+) 386.9724; measured value 386.9722.
Claims (6)
1. A method for synthesizing 3-alkoxy-1, 1-dialkylthiopropene derivatives is characterized by comprising the following steps: the molecular structural formula 1 is as follows:
R1acetyl, benzoyl, 2-naphthoyl, 2-furoyl, 2-thenoyl, cyano or ethoxycarbonyl; r2Selected from the following groups: methyl, ethyl or R2....R2Represents polymethylene (CH)2)nWherein n = 2 or 3; r3Is methyl, R3....R3represents-CH2OCH2-group or R3....R3Represents polymethylene (CH)2)nWherein n = 2 or 3;
the synthesis method of the 3-alkoxy-1, 1-dialkylthiopropylene derivative comprises the following steps:
taking dithioketene 2 as a starting material, taking iron salt as an accelerant, adding an additive, and generating C (sp) under the action of an oxidant2)-C(sp3) Bond coupling reaction to generate 3-alkoxy-1, 1-dialkyl thio propylene derivative 1 in one step;
the molecular structural formula of dithioketene 2 is shown in the specification,
the synthetic route is shown in the following reaction formula,
wherein the catalyst is one or more of anhydrous ferric trichloride, ferric tribromide or ferric acetate, the molar ratio of the dithioketene 2 to the catalyst is 1:0.05-1:0.10, the additive is one or two of 1, 8-diazabicycloundecene-7-ene or triethylene diamine hexahydrate, and the molar ratio of the dithioketene 2 to the catalyst is 1:0.10-1: 0.20; the oxidant is one or more than two of tert-butyl hydroperoxide, di-tert-butyl peroxide or tert-butyl peroxybenzoate; the reaction solvent is simple ether 3; the reaction temperature is 80-150 ℃; the reaction time is 12-48 hours.
2. A method of synthesis according to claim 1, characterized in that: the catalyst in the reaction for generating 1 from dithioketene dimer 2 is anhydrous ferric chloride, and the molar ratio of dithioketene 2 to anhydrous ferric chloride is 1: 0.05.
3. A method of synthesis according to claim 1, characterized in that: in the reaction for generating 1 from dithioketene 2, the additive is triethylene diamine hexahydrate, and the molar ratio of dithioketene 2 to the additive is 1: 0.10.
4. A method of synthesis according to claim 1, characterized in that: the oxidant in the reaction of dithioketene dimer 2 to form 1 is di-tert-butyl peroxide.
5. A method of synthesis according to claim 1, characterized in that: the reaction time in the reaction of dithioketene 2 to 1 is 24 to 48 hours.
6. A method of synthesis according to claim 1, characterized in that: the reaction temperature in the reaction for generating 1 from dithioketene 2 is 120 ℃ to 130 ℃.
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