CN110903215B - Polysubstituted benzene compound and its synergistic catalytic preparation method - Google Patents
Polysubstituted benzene compound and its synergistic catalytic preparation method Download PDFInfo
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- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
- C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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Abstract
The invention relates to a polysubstituted benzene compound anda method for preparing the catalyst by concerted catalysis. The method comprises the steps of
And compounds
In AgSbF6Pyrrolidine and a basic agent to produce a compound of formula I:
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a method for synthesizing polysubstituted benzene by carrying out a domino reaction on cinnamyl aldehyde and cyanoacetic acid derivatives under the synergistic catalysis of pyrrolidine and AgSbF 6.
Background
The polysubstituted benzene ring unit is widely existed in natural products, drug molecules and new functional materials, and plays an important role as an important intermediate in organic synthetic chemistry. Meanwhile, polysubstituted benzene compounds are important compounds in organic chemistry, natural product chemistry and polymer chemistry, are used as basic skeletons of a plurality of natural active compounds and synthetic intermediates of a plurality of heterocyclic compounds with pharmacological activity, and play an important role in pharmaceutical chemistry. For example, Chinese patent CN101654401A discloses a liquid crystal display device
A compound of the backbone, which has anti-tumor activity; non-patent document "DABCO-protein one-peptide synthesis of carboxylic-substituted benzenes and the hair biological evaluation, Neelaiah Babu et al," Med. chem. Res., 2014, 23, 2608-
A compound of the backbone having anti-tubercular activity. The synthesis of polysubstituted phenyl rings has been a long challenge for chemists.[1]In general, the synthesis of functionalized benzenes reported in the literature, the usual method comprising the introduction of functional groups onto a preactivated benzene ring by electrophilic/nucleophilic substitution, transition metal-catalyzed coupling reactions[2]And cyclization reactions in which aromatic systems are assembled from acyclic precursors, e.g. [3+3 ]][3a，b]、[4+2][3c，d]、[5+1][3e，f]And [2+2][3g，h]And (4) cycloaddition. However, from the standpoint of atom economy, environmental problems, cumbersome procedures, expensive metal catalysts, toxic by-products, operational complexitiesAs seen, these methods have some drawbacks. Therefore, it is a significant task for chemists to develop a simple and easy-to-use method for synthesizing polysubstituted benzenes.
On the other hand, domino reaction[4]The method has the characteristics of capability of shortening the reaction process, reduction of raw material waste, environmental friendliness and good atom economy, and thus becomes a hotspot. In recent years, several groups have developed efficient methods for synthesizing polysubstituted benzenes by a series of domino methods. For example, in 2007, Deng et al reported a series of tandem reactions of alkyldienmalononitriles with nitroolefins under basic conditions to give polysubstituted benzenes.[5a]In 2011, Fan et al synthesized highly functionalized benzene by the tandem reaction of 1, 2-allene with cyanoacetate.[5b]In 2013, the Li group reported the first phosphine-catalyzed domino reaction with γ -CH3The substituted enolate and the conjugated diene are synthesized into the functionalized benzene.[5c]In 2015, Chi et al reported the first example of NHC catalyzed [4+2 ]]The form of domino reacts to synthesize polysubstituted aromatic hydrocarbons.[5d]
Over the past few decades, chemists developed a variety of multicomponent domino reaction methods for the base-catalyzed synthesis of 2, 6-dicyanobenzene.[7-8]Mechanistically, these strategies can be divided into three main reaction types. One of them is the synthesis of benzene rings from Michael addition and Thorpe-Ziegler cyclization of alpha, beta-unsaturated compounds. Sepiol and Milart[8a]The 2, 6-dicyanoaniline is prepared by taking aryl methylene malononitrile and 1-aryl ethylene malononitrile as raw materials under the condition of piperidine catalysis, and the yield is moderate to good. Using a similar strategy, other chemists[8]Various polysubstituted 2, 6-dicyanoanilides have also been synthesized.
The second mechanism is achieved by Adol condensation, michael addition, Knoevenagel condensation and Thorpe-Ziegler cyclization in sequence, wherein the α, β -unsaturated compound is formed in situ. Yu and Velasco[9a]It is reported that 2, 6-dicyanobenzene can be synthesized when malononitrile is reacted with benzaldehyde and acetaldehyde. Borate (R) is a compound of formula (I)[9b]Reports on various aryl aldehydes in the presence of morpholineAlkyl aldehydes and malononitrile were characterized to give 2, 6-dicyanoaniline as a minor product. Rong et al[9c]It was found that various aldehydes and ketones can be successfully formed into substituted 2, 6-dicyanoanilines together with solid sodium hydroxide after trituration of malononitrile. By the Rong group[9d，e，f，g]Zhou et al[9h]And Shaterian et al also describe similar strategies[9i]For synthesizing the 2, 6-dicyanoaniline needed later. King et al[9j]And Banerjee et al[9k]A microwave and silica nanoparticle, respectively, were reported to promote multicomponent reactions for the parallel synthesis of various substituted dicyanoanilines from aldehydes, ketones and malononitrile.
The third type of mechanism is achieved by Knoevenagel coagulation, Michael addition and Thorpe-Ziegler cyclization in that order. Hassan et al[10a]The synthesis of 2, 6-dicyanoanilines containing 3-thienyl substituents was investigated by using methyl 2-thienylketone, malononitrile and α -cyanocinnamate as starting materials. Similarly, other subject groups[10b-h]A series of 2, 6-dicyanoanilines and derivatives were also synthesized.
A fourth type of mechanism is achieved through Michael addition, Knoevenagel coacervation and Thorpe-Ziegler cyclization in that order. (1) Kandeel et al topic group[11a-c]The reaction of malononitrile with various acetylenic ketones under basic conditions was investigated to give 2, 6-dicyanoanilines and derivatives. (2) Topic group such as Khaidem[11d-i]The reaction of malononitrile with various α, β -unsaturated ketones in the presence of a base was investigated to give 2, 6-dicyanoanilines and derivatives. However, so far, it has been known about α, β -unsaturated aldehydes[11g，11h]The studies of (a) prove that the strategy is not very effective.
More importantly, the above-mentioned methods often suffer from several drawbacks: (1) harmful byproducts such as cyanide salts and HCN, which may cause environmental pollution and harm to the human body; (2) the range of substrates is limited because malononitrile is the only cyano-containing resource; (3) the successful participation of α, β -unsaturated aldehydes in such reactions remains a challenge; (4) the number of alternative highly efficient catalytic systems is limited and it is not satisfactory for the synthesisThe requirement of multi-substituted benzene. In order to overcome the defects, the method hopes that a multi-substituted benzene ring is synthesized for the first time by decarboxylation domino reaction and the synergistic catalysis of an organic catalyst and a transition metal catalyst by selecting a commercially available alpha, beta-unsaturated aldehyde with various cyanoacetic acid esters. The transition metal and the organic molecule are combined to carry out concerted catalysis, and a plurality of chemical bonds can be simultaneously or sequentially activated and recombined by the metal catalyst and the organic catalyst to realize new conversion. This concept has great application prospects in organic synthesis reactions, as demonstrated later in accelerated conversion by metal/organic binary catalyst systems.[13]In this scheme, AgSbF6As metal catalyst and pyrrolidine as organic catalyst. The present application refers to the following documents, which are incorporated herein by reference in their entirety.
Reference documents:
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[13]For reviews：(a)Park，Y.J.；Park，J.-W.；Jun，C.-H.Acc.Chem.Res.，2008，41，222-234.(b)Wasilke，J.-C.；Obrey，S.J.；Baker，R.T.；Bazan，G.C.Chem.Rev.，2005，105，1001-1020.Selected examples：(c)Nakoji，M.；Kanayama，T.；Okino，T.；Takemoto，Y.Org.Lett.，2001，3，3329-3331.(d)ellerichs，B.G.；Kong，J.-R.；Krische，M.-J.J.Am.Chem.Soc.，2003，125，7758-7759.(e)Ibrahem，I.；Cordova，A.Angew.Chem.Int.Ed.，2006，45，1952-1956.(f)Mukherjee，S.；List，B.J.Am.Chem.Soc.，2007，129，11336-11337.(g)Sorimachi，K.；Terada，M.J.Am.Chem.Soc.，2008，130，14452-14453.(h)Zhi-Yong Han，HanXiao，Xiao-Hua Chen，and Liu-Zhu Gong.J.Am.Chem.Soc.，2009，131，9182-9183.(i)Jin Xie and Zhi-Zhen Huang.Angew.Chem.Int.Ed.，2010，49，10181-10185.(j)Jason M.Stevens and David W.C.MacMillan.J.Am.Chem.Soc.，2013，135，11756-11759.(k)Line Nborg，Kim Solm Halskov，Fernando Tur，Sofie M.N.M sted，and Karl Anker Jorgensen.Angew.Chem.Int.Ed.，2015，54，1-6.
[14](a)Gotoh，H.；Ishikawa，H.；Hayashi，Y.，Org.Lett.，2007，9，5307-5309.(b)Product 6 was confirmed by H1-NMR.
[15]Product 7 was confirmed by H1-NMR，C13-NMR and HR-MS.
[16]We performed Sc(OTf)3，Yb(OTf)3，Ce(OTf)3，Sm(OTf)3，La(OTf)3，In(OTf)3Bi(OTf)3and other lewis acid as the additiyes to active the nitrile group，but the yield had not been improved.These experiments indicated that silver salt in the reaction not only active the carbon-nitrogen triple bond，but also play an important role in decarboxylation process(See from the SI).For some examples of decarboxylation catalyzed by silver：(a)Josep Cornella，Carolina Sanchez，David Banawa and Igor Larrosa，Chem.Commun.，2009，7176-7178.(b)Pengfei Lu，Carolina Sanchez，Josep Cornella，and Igor Larrosa，Org.Lett.，2009，11，5710-5713.(c)Sukalyah Bhadra，Wojciech I.Dzik，and Lukas J.Goossen，J.Am.Chem.Soc.，2012，134，9938-9941.
disclosure of Invention
One of the purposes of the invention is to provide a polysubstituted benzene compound.
Another object of the present invention is to provide a process for the preparation of the above polysubstituted compounds.
It is a further object of the present invention to provide the use of the above compounds.
In order to realize the purpose, the invention adopts the following technical scheme:
a polysubstituted benzene compound, the compound being represented by the following formula I:
wherein R is1Selected from methyl, ethyl, propyl or
R3Selected from H, Me, OMe, F, Cl, Br, NO2Or Et; r is2Selected from Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, phenyl or benzyl.
One of the preferred technical solutions is:
preferably R1Is composed of
Preferably, R3Selected from F, Cl, Br; r2Selected from Et;
more preferably, R3Selected from H, Me, OMe; r is2Selected from Et.
Another preferred technical scheme is as follows:
preferably, R1Is composed of
Preferably, R3Selected from H, Me or OMe; r2Selected from Me, n-Pr or i-Pr;
more preferably, R3Is selected from H; r is2Is selected from n-Pr, i-Pr or benzyl.
The compound of formula I is selected from the following specific compounds:
the invention also provides a preparation method of the compound, which comprises the following steps: compound (I)
And compounds
In AgSbF6Pyrrolidine and a basic agent to produce a compound of formula I.
The alkaline reagent is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or DBU; preferably potassium carbonate;
preferably, the reaction temperature is 70-100 ℃; more preferably 75-85 ℃; the reaction time was 12 hours.
Preferably, an organic solvent is also present in the reaction system, said organic solvent being selected from CHCl3One or more of DCE, THF, toluene, EtOH, DMSO or DMF. More preferably CHCl3. Preferably under an inert atmosphere, more preferably under nitrogen.
Preferably, PTBP is also present in the reaction system.
Preferably, the method comprises the compound
And compounds
AgSbF in a molar amount of 5% to 20% of the molar amount of cinnamaldehyde substrate6Pyrrolidine in a molar amount of 10% to 30% of the molar amount of the cinnamaldehyde substrate, PTBP in a molar amount of 5% to 20% of the molar amount of the cinnamaldehyde substrate, K in a molar amount of 100% to 300% of the molar amount of the cinnamaldehyde substrate2CO3In the presence of CHCl3In the step (1), generating a compound shown in the formula I at the temperature of 70-100 ℃;
more preferably, the method comprises AgSbF at a molar amount of 10% of the molar amount of cinnamaldehyde substrate6Pyrrolidine in a molar amount of 20% of the molar amount of the cinnamaldehyde substrate, PTBP in a molar amount of 10% of the molar amount of the cinnamaldehyde substrate, and K in a molar amount of 200% of the molar amount of the cinnamaldehyde substrate2CO3In the presence of CHCl3At 80 ℃ to produce the compound of formula I.
The invention has the following advantages
1. High reaction activity, complete reaction, convenient separation and high yield.
2. The metal catalyst and the organic catalyst are used cooperatively, so that the reaction efficiency is improved, and the operation is simple and convenient.
3. The domino reaction condition is mild, and the reaction is carried out at 70-100 ℃.
4. Compared with the traditional synthetic method, the method adopts a small amount of silver catalyst and pyrrolidine as a synergistic catalyst, can obtain a large amount of polysubstituted benzene derivatives, and has the advantages of short synthetic route, high atom economy, wide substrate application range and high practical value.
The invention also provides application of the compound in preparing a polysubstituted benzene compound.
Examples
The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All the starting materials and solvents used in the examples are commercially available products.
Example 1: preparation of compound 3 aa:
in a 25 ml round bottom flask was added cinnamaldehyde 1a (0.25 mmol, 33 mg), ethyl cyanoacetate 2a (2 mmol, 226 mg), potassium carbonate (0.5 mmol, 69 mg), silver hexafluoroantimonate (0.05 mmol, 17 mg), tetrahydropyrrole (0.05 mmol, 4 mg), p-tert-butylphenol (0.025 mmol, 4 mg), dissolved in 3 ml of chloroform and stirred at 80 ℃ under nitrogen for 12 hours. After completion of the reaction, the mixed solution was cooled to room temperature, extracted 3 times (10 ml/time) with saturated brine and dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. Finally, the polysubstituted benzene 3aa (yield 63%) is obtained by silica gel column chromatography separation (eluent is petroleum ether and ethyl acetate, and the volume ratio is 30: 1-20: 1).
According to a similar preparation method to example 1, different reaction conditions were changed to investigate the optimum reaction conditions. The results are shown in Table 1.
TABLE 1 optimization of the domino reaction between cinnamaldehyde 1a and ethyl cyanoacetate 2a
a) The reaction conditions are as follows: 1a (0.25 mmol), 2a (2 mmol), [ M ] (0.05 mmol), organic catalyst (0.05 mmol), base (0.5 mmol), nitrogen protection, reaction temperature 80 ℃, reaction time 12 hours.
b) Isolated yield.
c) Under an oxygen atmosphere.
d) PTBP (0.025 mmol) was added to the reaction system; PTBP ═ p-tert-butylphenol.
e)1a (10 mmol, 1.32 g).
Results and discussion:
cinnamaldehyde 1a and ethyl cyanoacetate 2a were initially selected as model substrates to explore and optimize a series of domino reactions. When reacting, use 15% Ag2When O and 20% pyrrolidine (based on cinnamaldehyde substrate) were reacted in DCE at 80 ℃ for 12 hours as a catalyst, we wisely found that the desired poly-substituted benzene ring 3aa was produced in a yield of 38% (entry 1, Table 1). Then, useOther transition metal catalysts, e.g. CuBr, CuBr2、Pd(OAc)2、Rh(PPh3)Cl2、Ir(cod)2Cl2、Sc(OTf)3And Yb (OTf)3Discovery of AgSbF6The yields were highest among these transition metal salts (entry 5 compared to entries 1-4, table 1). The desired product 3aa was not observed in the absence of silver catalyst (entry 6, table 1). Next, we screened the organic catalysts (entries 7-9, table 1) and experiments showed that pyrrolidine provided the best yield of 48% of the desired product 3aa (entry 7, table 1). In the absence of the organic catalyst, the yield of 3aa was significantly reduced (entry 15, table 1). When other bases than K are used2CO3When the yield of 3aa was lower (entries 10-13, table 1). In addition, if the base is removed from the reaction system, the yield of the desired product 3aa is reduced to a trace amount (item 14, table 1). The influence of the solvent on the domino reaction is also examined, and CHCl is proved3Superior to DCE, THF, toluene, EtOH, DMSO and DMF (entry 16, table 1). Next, we are at O2The reaction was carried out under the conditions that the yield of 3aa was slightly decreased (Table 1; entry 17). When PTBP (p-tert-butylphenol) was added to the reaction system at 10% (based on the cinnamaldehyde substrate), the yield was as high as 63% (Table 1; entry 18). After screening the reaction conditions, it can be concluded that the optimal conditions for the reaction are 10% AgSbF620% pyrrolidine as catalyst, 10% PTBP as additive, 2 equivalents of K2CO3With 1a, 1b in CHCl3The reaction temperature was 80 ℃.
Example 2: preparation of compound 3ba compound:
in a 25 ml round bottom flask was added p-methoxycinnamaldehyde 1b (0.25 mmol, 41 mg), ethyl cyanoacetate 2a (2 mmol, 226 mg), potassium carbonate (0.5 mmol, 69 mg), silver hexafluoroantimonate (0.05 mmol, 17 mg), tetrahydropyrrole (0.05 mmol, 4 mg), p-tert-butylphenol (0.025 mmol, 4 mg), dissolved in 3 ml of chloroform and stirred at 80 ℃ under nitrogen for 12 hours. After completion of the reaction, the mixed solution was cooled to room temperature, extracted 3 times with saturated brine and dichloromethane (10 ml/time), and the organic phases were combined and dried over anhydrous sodium sulfate. Finally, the product is separated by silica gel column chromatography (eluent is petroleum ether and ethyl acetate, the volume ratio is 30: 1-20: 1) to obtain the target product, namely the polysubstituted benzene 3ba (yield is 68%).
The compounds in Table 2 were prepared according to a similar preparation to example 2, following the following reaction scheme, using different starting materials.
TABLE 2 Compounds prepared starting from different alpha, beta-unsaturated aldehydes
a) Reaction conditions are as follows: 1(0.25 mmol), 2(2 mmol), AgSbF6(0.05 mmol), pyrrolidine (0.05 mmol), K2CO3(0.25 mmol), PTBP (0.025 mmol), in the presence of nitrogen, 80 ℃ for 12h, isolated in yield.
Results and discussion:
under optimized reaction conditions, we examined the versatility and the applicable scope of the method. We have found that a series of cinnamaldehyde derivatives 1a-j can be smoothly domino reacted with ethyl cyanoacetate 2a to give the desired products 3aa-ja in 39-68% yield (Table 2). In this reaction, it seems to be sensitive to the electron density of the functional group on cinnamaldehyde. Having an electron radical in the p-position (e.g. CH)3O-and CH3-) cinnamic aldehydes are superior performing than compounds having electron groups (e.g., F-and NO)2-) cinnamic aldehyde. It is worth mentioning that when aliphatic alpha, beta-unsaturated aldehydes 1h-j are used, the desired polysubstituted benzenes are successfully constructed, which provides a new strategy for the synthesis of various alkylated benzenes. This method is a good complement to the Friedel-Crafts reaction, because the Friedel-Crafts reaction is difficult to carry out when the group on the aromatic ring is electronically inactivated.
Example 3: preparation of compound 3 ac:
in a 25 ml round bottom flask was added cinnamaldehyde 1a (0.25 mmol, 33 mg), propyl cyanoacetate 2c (2 mmol, 254 mg), potassium carbonate (0.5 mmol, 69 mg), silver hexafluoroantimonate (0.05 mmol, 17 mg), tetrahydropyrrole (0.05 mmol, 4 mg), p-tert-butylphenol (0.025 mmol, 4 mg), dissolved in 3 ml of chloroform and stirred at 80 ℃ under nitrogen for 12 hours. After completion of the reaction, the mixed solution was cooled to room temperature, extracted 3 times with saturated brine and dichloromethane (10 ml/time), and the organic phases were combined and dried over anhydrous sodium sulfate. Finally separating by silica gel column chromatography (eluent is petroleum ether and ethyl acetate, the volume ratio is 30: 1-20: 1) to obtain the target product, namely the polysubstituted benzene 3ac (yield is 65%).
The compounds in Table 3 were prepared according to the similar preparation method of example 3, according to the following reaction formula, using different starting materials.
TABLE 3 Compounds prepared starting from different alkyl cyanoacetates
a) Reaction conditions are as follows: 1(0.25 mmol), 2(2 mmol), AgSbF6(0.05 mmol), pyrrolidine (0.05 mmol), K2CO3(0.25 mmol), PTBP (0.025 mmol), in the presence of nitrogen, 80 ℃ for 12h, isolated in yield.
b) Reaction 2 was 1.25 mmol.
c) The amount of 2 in the reaction was 0.75 mmol.
In addition, the domino reaction of different alkyl cyanoacetates 2 with cinnamaldehyde and its derivative 1 was investigated. Experiments show that the reaction has good tolerance to different esters such as methyl ester, propyl ester, isopropyl ester, n-butyl ester, tert-butyl ester, benzyl ester and the like. In this reaction, when cinnamaldehyde having a methoxy group at the 4-position is subjected to a coordination reaction with an alkyl cyanoacetate, the desired product 3 can be obtained smoothly.
The nuclear magnetic data of some of the compounds prepared in this application are shown below:
1H NMR(CDCl3，400MHz)δ：8.12(d，J＝8.0Hz，1H)，7.57-7.55(m，2H)，7.51-7.45(m，3H)，6.73(d，J＝8.0Hz，2H)，4.41-4.35(m，2H)，1.43(t，J＝7.2Hz，3H).
1H NMR(CDCl3，400MHz)δ：8.09(d，J＝8.0Hz，1H)，7.53(d，J＝8.0Hz，2H)，7.26(s，1H)，7.01(d，J＝8.0Hz，2H)，6.70(d，J＝8.0Hz，2H)，4.38(d，J＝8.0Hz，2H)，3.86(s，3H)，1.42(t，J＝8.0Hz，3H).
1H NMR(CDCl3，400MHz)δ：8.12(d，J＝8.0Hz，1H)，7.47(d，J＝8.0Hz，2H)，7.12(d，J＝16.0Hz，2H)，6.62(d，J＝8.0Hz，3H)，4.34-4.28(m，2H)，1.36(t，J＝8.0Hz，3H).
1H NMR(CDCl3，400MHz)δ：8.04(d，J＝8.0Hz，1H)，7.48(t，J＝8.0Hz，4H)，6.74(t，J＝8.0Hz，2H)，4.41-4.36(m，2H)，1.43(t，J＝8.0Hz，3H).
1H NMR(CDCl3，400MHz)δ：8.12(d，J＝8.0Hz，1H)，7.62(d，J＝8.0Hz，2H)，7.41(d，J＝6.0Hz，2H)，6.74(m，3H)，4.41-4.36(m，2H)，1.43(t，J＝8.0Hz，3H).
1H NMR(CDCl3，400MHz)δ：8.36(d，J＝8.0Hz，1H)，8.18(d，J＝8.0Hz，1H)，7.74(d，J＝8.0Hz，2H)，6.79(m，3H)，4.43-4.38(m，2H)，1.44(t，J＝8.0Hz，3H).
1H NMR(CDCl3，400MHz)δ：7.84(s，1H)，6.39(s，2H)，4.37-4.31(m，2H)，2.83(m，2H)，2.23(s，3H)，1.41(t，J＝8.0Hz，3H)，1.23(t，J＝8.0Hz，3H).
1H NMR(CDCl3，400MHz)δ：7.97(d，J＝8.0Hz，1H)，6.54(d，J＝8.0Hz，3H)，4.37-4.31(m，2H)，2.48(s，3H)，1.40(m，J＝8.0Hz，3H).
1H NMR(CDCl3，400MHz)δ：7.92(d，J＝8.0Hz，1H)，6.48(d，J＝8.0Hz，3H)，4.30-4.24(m，2H)，2.68(t，J＝8.0Hz，2H)，1.65-1.60(m，2H)，1.33(t，J＝8.0Hz，3H)，0.93(t，J＝8.0Hz，3H).
1H NMR(CDCl3，400MHz)δ：8.10(d，J＝8.0Hz，1H)，7.57-7.55(m，2H)，7.51-7.45(m，3H)，6.73(d，J＝8.0Hz，3H)，3.92(s，3H).
1H NMR(CDCl3，400MHz)δ：8.12(d，J＝8.0Hz，1H)，7.57-7.55(m，2H)，7.50-7.45(m，3H)，6.73(d，J＝8.0Hz，3H)，4.30(t，J＝8.0Hz，2H)，1.83-1.78(m，2H)，1.06(t，J＝8.0Hz，3H).
1H NMR(DMSO-d6，400MHz)δ：8.07(d，J＝8.0Hz，1H)，7.55(t，J＝8.0Hz，5H)，7.26(s，2H)，6.78(d，J＝8.0Hz，1H)，5.20-5.12(m，1H)，1.35(d，J＝8.0Hz，6H).
1H NMR(DMSO-d6，400MHz)δ：8.04(d，J＝8.0Hz，1H)，7.55(d，J＝8.0Hz，2H)，7.22(s，2H)，7.10(d，J＝12.0Hz，2H)，6.76(d，J＝12.0Hz，1H)，5.20-5.11(m，1H)，3.83(s，3H)，1.34(d，J＝8.0Hz，6H).
1H NMR(CDCl3，400MHz)δ：8.11(d，J＝8.0Hz，1H)，7.56(t，J＝8.0Hz，2H)，7.50-7.45(m，2H)，6.73(d，J＝8.0Hz，3H)，4.34(t，J＝8.0Hz，2H)，1.80-1.73(m，2H)，1.51-1.46(m，2H)，1.01(t，J＝8.0Hz，3H).
1H NMR(CDCl3，400MHz)δ：8.07(d，J＝8.0Hz，1H)，7.53(d，J＝8.0Hz，2H)，7.01(d，J＝8.0Hz，2H)，6.71(d，J＝8.0Hz，2H)，3.91(d，J＝20.0Hz，6H).
1H NMR(CDCl3，400MHz)δ：8.15(d，J＝8.0Hz，1H)，7.55-7.36(m，9H)，6.72(d，J＝8.0Hz，2H)，5.36(d，J＝8.0Hz，2H).
1H NMR(CDCl3，400MHz)δ：8.11(d，J＝8.0Hz，1H)，7.53-7.35(m，7H)，7.00(d，J＝8.0Hz，2H)，6.80-6.66(m，3H)，5.34(s，2H)，3.85(s，3H).
1H NMR(CDCl3，400MHz)δ：8.10(d，J＝8.0Hz，1H)，7.42-7.40(m，3H)，7.33-7.31(m，2H)，7.10(d，J＝8.0Hz，2H)，6.65(d，J＝8.0Hz，2H)，4.41-4.36(m，2H)，1.43(t，J＝8.0Hz，3H).
control experiment: preparation without pyrrolidine under standard conditions (eq.1):
to a 25 ml round bottom flask was added cinnamaldehyde 1a (0.25 mmol, 33 mg), ethyl cyanoacetate 2a (2 mmol, 226 mg), potassium carbonate (0.25 mmol, 35 mg), silver hexafluoroantimonate (0.025 mmol, 9 mg), dissolved in 3 ml of chloroform and stirred under nitrogen at 80 ℃ for 12 hours. After the reaction is finished, cooling the mixed solution to room temperature, and detecting by a liquid chromatography-mass spectrometry technology, wherein the corresponding target product poly-substituted benzene 3aa is not found.
According to a similar preparation method of (eq.1), the corresponding compound is prepared by adopting different raw materials and conditions according to the following reaction formula, and the optimal conditions are discussed.
In order to understand the mechanism of the domino reaction, a series of experiments were performed. The substrates of 2a and 1a were treated under standard conditions without pyrrolidine (eq.1) and the desired product 3aa was not detected. Similarly, we separately in the absence of AgSbF6(eq.2) and K2CO3(eq.3) the reaction was carried out to give 3aa in low or no yield. These experiments show that pyrrolidine, AgSbF6And K2CO3Plays an important role in this reaction. Then, using 4 and 2b under standard conditions (eq.4), the desired product was not found to be 3 aa. From the above experiments we conclude that the reaction may involve first a michael addition, followed by a Knoevenagel condensation and Thorpe-Ziegler cyclization. To validate our hypothesis, we used 1a and nitromethane to obtain the Michael addition product 6 according to the literature,[14]then 1a (8eq) was injected without isolation into the reaction system under standard conditions to yield the desired product 7[15]The yield was 40%.
Based on the above-mentioned preparation of the different compounds and optimization of the different reaction conditions, we conclude that the mechanism of the reaction described in this application is as follows:
based on the above-mentioned experimental results and the literature,[8，9]the possible mechanism of the domino reaction is described in the above equation. Initially, 1a and 2a may be at K2CO3In the presence of a Michael addition product 8. Knoevenagel condensation between 8 and 1b then occurred with pyrrolidine as the organic catalyst to give 9. When AgSbF6Upon activation of the nitrile group, the intermediate 10 is readily formed 11 by an intramolecular Thorpe-Ziegler reaction. Then, at K2CO3Or AgSbF6 [16]In the presence of (a), 11 is converted to 12, while HCOOEt is eliminated. Finally, intermediate 12 was involved in the aromatization process and produced 3 aa.
As mentioned above, the organic catalyst is pyrrolidine, and AgSbF is used6As the transition metal catalyst, Michael addition, Knoevenagel condensation, and Thorpe-Ziegler type cyclization decarboxylation are carried out. The raw materials are alpha, beta-unsaturated aldehyde and various cyanoacetic acid esters sold in the market, and a method with more environmental protection, simple operation and practical feasibility is provided for synthesizing the polysubstituted benzene.
Claims (6)
1. A method for producing a polysubstituted benzene compound, characterized by comprising the steps of: compound (I)
And compounds
In AgSbF6Pyrrolidine and a basic agent to form a compound of formula I
R1Selected from methyl, ethyl, propyl or
R3Selected from H, Me, OMe, F, Cl, Br, NO2Or Et; r2Selected from Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, phenyl or benzyl.
2. The production method according to claim 1, characterized in that: the alkaline reagent is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, triethylamine or DBU; the reaction temperature is 70-100 ℃; the reaction time is 8-16 hours.
3. The method of claim 1, wherein: an organic solvent is also present in the reaction system, and is selected from CHCl3One or more of DCE, THF, toluene, EtOH, DMSO or DMF; under an inert atmosphere.
4. The method of claim 1, wherein: PTBP is also present in the reaction system.
5. The method of claim 1, comprising the steps of: compound (I)
And compounds
AgSbF in a molar amount of 5% to 20% of the molar amount of cinnamaldehyde substrate6Pyrrolidine in a molar amount of 10 to 30% of the molar amount of the cinnamaldehyde substrate, PTBP in a molar amount of 5 to 20% of the molar amount of the cinnamaldehyde substrate, K in a molar amount of 100 to 300% of the molar amount of the cinnamaldehyde substrate2CO3In the presence of CHCl3And in the reaction, generating the compound shown in the formula I at the temperature of 70-100 ℃.
6. The production method according to claim 5, characterized in that: AgSbF at a molar mass of 10% of the molar mass of the cinnamaldehyde substrate6Pyrrolidine in a molar amount of 20% of the molar amount of the cinnamaldehyde substrate, PTBP in a molar amount of 10% of the molar amount of the cinnamaldehyde substrate, and K in a molar amount of 200% of the molar amount of the cinnamaldehyde substrate2CO3In the presence of CHCl3Formation of the formula I at medium to 80 ℃A compound (I) is provided.
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