CN111333507B - Synthesis method of beta-hydroxy ester compound - Google Patents
Synthesis method of beta-hydroxy ester compound Download PDFInfo
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- CN111333507B CN111333507B CN202010037659.XA CN202010037659A CN111333507B CN 111333507 B CN111333507 B CN 111333507B CN 202010037659 A CN202010037659 A CN 202010037659A CN 111333507 B CN111333507 B CN 111333507B
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Abstract
The invention belongs to the technical field of medicine and organic chemical synthesis, and discloses a method for synthesizing beta-hydroxy ester compounds. The synthetic method of the invention has safe and simple operation, easily obtained raw materials, low price and high reaction efficiency, and the yield can reach more than 90 percent and even up to 98 percent; good adaptability to functional groups, wide adaptability to substrates, environmental protection, contribution to industrial production and wide application in medicine and organic synthesis.
Description
Technical Field
The invention belongs to the technical field of medicine and organic chemical synthesis, and particularly relates to a method for synthesizing beta-hydroxy ester compounds.
Background
Beta-hydroxy ester compounds are widely present in various natural products and are basic structural units of many natural products, bioactive molecules and drug molecules. In the field of pharmaceutical chemistry, it has a wide range of uses, such as antipsychotics, antidepressants, antihypertensives, anti-inflammatory drugs, etc. (s.ibrayim, x.fang, d.zhang, l.liu, f.wu, chi.j.chem.2011, 29, 2713-2716, p.p.reddy, k.f.yen, b.j.uang, j.org.chem.2002,67,1034-1035, j.i.degraw, p.h.christie, r.l.kisluk, y.gaumont, f.m.sirotnak, j.med.1990, 33,212-215 s.yamakoshi, e.kawanishi, tehetran lett.2014tt.20141175-547, t.547, y.yh, hesanchi, hedron. Because of the potential medicinal value of the compounds, the compounds attract great interest of chemists in research of the compounds in various countries in the world (S.Reformatsky, ber.Dtsch. Chem.Ges.1887,20,1210-1211 b) S.Choppin, L.Ferreiro-Medeeiros, M.Barbarotto, F.Colobert, chem.Soc.Rev.2013,42,937-949; c) P.g. cozzi, angelw.chem.int.ed.2007, 46, 2568-2571).
In recent years, chemists have developed effective methods for constructing beta-hydroxy ester compounds through Reformatsky reaction, which are mainly realized through zinc powder or metal zinc reagent promotion and different metal catalysis, and the methods include the following methods: (1) [ RhCl (PPh) 3 ) 3 ]Catalytic, reformatsky reaction promoted with dimethylzinc (k.kanai, h.wakabayashi, t.honda, org.lett.2000,2, 2549-2551); (2) Metal nickel is used for catalyzing, and the asymmetric Reformatsky reaction of aldehyde, amine and bromo-ester under the action of a chiral ligand is promoted by dimethyl zinc (P.G. Cozzi, E.Rivalta, angew.chem.int.Ed.2005,44, 3600-3603); (3) The beta-hydroxy ester compound is synthesized by the Reformatsky reaction of aldehyde and bromo-ester under the promotion of iodine elementary substance catalysis and iron powder (X. -Y.Liu, X. -R.Li, C.Zhang, X. -Q.Chu, W.Rao, T. -P.Loh, Z. -L.Shen, org.Lett. 2019,21, 5873-5878); (4) Free radical asymmetric Reformatsky reactions of aldehydes with bromo-or iodo-esters promoted with zinc dimethyl (p.g. cozzi, angel.chem.int.ed.2006, 45,2951-2954, p.g. cozzi, a. Miggnona, l.zoli, synthesis 2007,17,2746-2750
B.Maciá,A.J. Minnaard,B.L.Feringa,Angew.Chem.Int.Ed.2008,47,1317–1319；b)M.A. Fernández-
B.Maciá,A.J.Minnaard,B.L.Feringa,Chem.Commun.2008,2571–2573；P. G.Cozzi,Adv.Synth.Catal.2006,348,2075–2079；P.G.Cozzi,F.Benfatti,M.Guiteras Capdevila,A.Mignogna,Chem.Commun.2008,3317–3318；A.Tarui,H.Nishimura,T.Ikebata, A.Tahira,K.Sato,M.Omote,H.Minami,Y.Miwa,A.Ando,Org.Lett.2014,16,2080-2083.
Although research on Reformatsky reactions is currently in progress, there are a number of deficiencies. The reported methods have low reaction efficiency, long reaction time and low yield; the substrate applicability is not good enough; enantioselectivity is not good enough; expensive transition metal catalyst such as palladium, gold, rhodium and the like is used as the catalyst, the dosage of the catalyst is large, and the reaction cost is high. Therefore, the method for synthesizing the beta-hydroxy ester compound by the Reformatsky reaction with cheap and easily obtained raw materials, simple operation, simplicity and high efficiency still has a certain challenging subject.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides a method for synthesizing beta-hydroxy ester compounds, which has the advantages of easily available raw materials, high yield, low price, high atom economy and safe and simple operation.
The principle of the invention is that aldehyde and iodo-ester are used as raw materials, and intermolecular Reformatsky reaction is carried out under the catalysis of nickel salt and the promotion action of manganese powder to generate the beta-hydroxy ester compound. All the raw materials of the method are cheap and easy to obtain, the reaction yield is high, the method is simple and easy to implement, and the operation is safe, so that the method has potential practical value.
The purpose of the invention is realized by the following technical scheme:
a method for synthesizing beta-hydroxy ester compounds comprises the steps of taking an aldehyde compound and an iodoacetate compound as raw materials, taking manganese powder as an accelerator, taking metal nickel salt as a catalyst, taking an organic solvent as a reaction medium, adding organic protonic acid, stirring and reacting under the protection of inert gas, cooling to room temperature after the reaction is finished, carrying out reduced pressure distillation and concentration to obtain a crude product, and purifying by column chromatography to obtain the beta-hydroxy ester compounds; the aldehyde compound is aromatic aldehyde, oxygen-containing aromatic miscellaneous aldehyde, sulfur-containing aromatic miscellaneous aldehyde, nitrogen-containing aromatic miscellaneous aldehyde or aliphatic aldehyde.
The above reaction is represented by the following formula:
preferably, the iodoacetate compound is ICH 2 COOEt。
Preferably, the molar ratio of the catalyst to the aldehyde compound is from 0.05 to 0.2:1.
preferably, the catalyst is nickel iodide, nickel bromide, nickel chloride, nickel acetate, potassium hexafluoro nickel (IV), nickel (II) triflate or nickel (II) bis (hexafluoroethyl acetone).
Preferably, the molar ratio of the manganese powder to the aldehyde compound is 2-4: 1.
preferably, the molar ratio of the iodoacetate compound to the aldehyde compound is 1-2: 1;
preferably, the molar ratio of the organic protonic acid to the aldehyde compound is 0.1 to 0.5:1.
preferably, the organic protonic acid is pivalic acid, p-toluenesulfonic acid, trifluoroacetic acid, glacial acetic acid.
Preferably, the organic solvent is one of dimethyl sulfoxide, N-dimethylformamide, N-hexane, dichloromethane, toluene or 1, 4-dioxane, diethyl ether, tetrahydrofuran, acetonitrile and N, N-dimethylacetamide.
Preferably, the aldehyde compound is benzaldehyde, p-chlorobenzaldehyde, p-fluorobenzaldehyde, p-methyloxybenzaldehyde, 2, 3-dimethylbenzaldehyde, 2,4, 6-trimethylbenzaldehyde, 2, 6-difluorobenzaldehyde, 2-naphthaldehyde, 2-thiophenecarboxaldehyde, furfural, cyclohexylaldehyde, cinnamaldehyde, neral.
Preferably, the reaction temperature is 10-35 ℃, and the reaction time is 6-36 h;
preferably, the eluent of the column chromatography is pure hexane or a mixed solvent, and the mixed solvent is a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of the petroleum ether to the ethyl acetate is 5-50.
The inert gas includes nitrogen, argon, helium, and the like.
Compared with the prior art, the invention has the following advantages and effects:
(1) The method greatly improves the reaction efficiency, and the yield of the beta-hydroxy ester compound can reach more than 90 percent and even up to 98 percent.
(2) The synthesis method of the beta-hydroxy ester compound has the advantages of safe and simple operation, low price of raw materials, easy obtainment, good adaptability to functional groups, wide adaptability to substrates, environmental friendliness and good industrial application prospect.
Drawings
FIG. 1 is a hydrogen spectrum of the product obtained in example 10;
FIG. 2 is a carbon spectrum of the product obtained in example 10;
FIG. 3 is a hydrogen spectrum of the product obtained in example 11;
FIG. 4 is a carbon spectrum of the product obtained in example 11;
FIG. 5 is a hydrogen spectrum of the product obtained in example 12;
FIG. 6 is a carbon spectrum of the product obtained in example 12;
FIG. 7 is a hydrogen spectrum of the product obtained in example 13;
FIG. 8 is a carbon spectrum of the product obtained in example 13;
FIG. 9 is a hydrogen spectrum of the product obtained in example 14;
FIG. 10 is a carbon spectrum of the product obtained in example 14;
FIG. 11 is a hydrogen spectrum of the product obtained in example 15;
FIG. 12 is a carbon spectrum of the product obtained in example 15;
FIG. 13 is a hydrogen spectrum of the product obtained in example 16;
FIG. 14 is a carbon spectrum of the product obtained in example 16;
FIG. 15 is a hydrogen spectrum of the product obtained in example 17;
FIG. 16 is a carbon spectrum of the product obtained in example 17;
FIG. 17 is a hydrogen spectrum of the product obtained in example 18;
FIG. 18 is a carbon spectrum of the product obtained in example 18.
Detailed Description
The present invention will be described in further detail with reference to the following specific examples and drawings, but the embodiments and the substrates to be used in the present invention are not limited thereto.
Example 1
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, 22 mg NiBr 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH, tetrahydrofuran as solvent, in N 2 And (2) under the protection of gas, stirring and reacting at room temperature for 36 hours, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 90%.
1 H NMR(400MHz,CDCl 3 ):δ7.41–7.28(m,5H),5.19–5.11(m,1H),4.20(q,J＝7.1Hz, 2H),3.39(d,J＝3.4Hz,1H),2.77–2.73(m,2H),1.28(t,J＝7.1Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.41,142.60,128.55,127.79,125.70,70.34,60.88,43.40, 14.16.
The structure of the resulting product is deduced from the above data as follows:
example 2
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, and 13 mg NiCl 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH, tetrahydrofuran as solvent, in N 2 Stirring at room temperature under protection of gas for 36 hr, stopping heating and stirring, cooling to room temperature, vacuum distilling to obtain crude product, and purifying by column chromatography to obtain target product, wherein the eluent of column chromatography is petroleum ether/ethyl acetateThe ester is 10:1, yield 23%.
Example 3
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, 31 mg NiI 2 83 mg manganese powder, 15. Mu.L CF 3 COOH, tetrahydrofuran as solvent, in N 2 And under the protection of gas, stirring and reacting at room temperature for 36 hours, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 92%.
1 H NMR(400MHz,CDCl 3 ):δ7.41–7.28(m,5H),5.19–5.11(m,1H),4.20(q,J＝7.1Hz, 2H),3.39(d,J＝3.4Hz,1H),2.77–2.73(m,2H),1.28(t,J＝7.1Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.41,142.60,128.55,127.79,125.70,70.34,60.88,43.40, 14.16.
The structure of the resulting product is deduced from the above data as follows:
example 4
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, and 15.6 mg NiI 2 83 mg manganese powder, 15. Mu.L CF 3 COOH, tetrahydrofuran as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 92%.
1 H NMR(400MHz,CDCl 3 ):δ7.41–7.28(m,5H),5.19–5.11(m,1H),4.20(q,J＝7.1Hz, 2H),3.39(d,J＝3.4Hz,1H),2.77–2.73(m,2H),1.28(t,J＝7.1Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.41,142.60,128.55,127.79,125.70,70.34,60.88,43.40, 14.16.
The structure of the resulting product is deduced from the above data as follows:
example 5
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, and 15.6 mg NiI 2 83 mg of manganese powder, 21.5 mg of p-toluenesulfonic acid and tetrahydrofuran as solvents in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 56%.
Example 6
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, and 15.6 mg NiI 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH,1, 4-dioxane as solvent in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 90%.
1 H NMR(400MHz,CDCl 3 ):δ7.41–7.28(m,5H),5.19–5.11(m,1H),4.20(q,J＝7.1Hz, 2H),3.39(d,J＝3.4Hz,1H),2.77–2.73(m,2H),1.28(t,J＝7.1Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.41,142.60,128.55,127.79,125.70,70.34,60.88,43.40, 14.16.
The structure of the resulting product is deduced from the above data as follows:
example 7
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, and 15.6 mg NiI 2 83 mg manganese powder, 15. Mu.L CF 3 COOH, toluene as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 78%.
Example 8
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, and 15.6 mg NiI 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH, dichloromethane as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 80%.
Example 9
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, and 15.6 mg NiI 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH, N-hexane as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 85%.
Example 10
A25 mL reaction tube was charged with 0.5 mmol benzaldehyde, 0.75 mmol ethyl iodoacetate, and 15.6 mg NiI 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH, acetonitrile as solvent, in N 2 Stirring at room temperature under gas protection for 12 hr, stopping heating and stirring, cooling to room temperature, vacuum distilling to obtain crude product, and separating and purifying by column chromatography to obtain targetThe product, the eluent of column chromatography is petroleum ether/ethyl acetate 10:1, yield 98%.
The structural characterization data for the product obtained in example 10 are shown below (as shown in FIGS. 1 and 2):
1 H NMR(400MHz,CDCl 3 ):δ7.41–7.28(m,5H),5.19–5.11(m,1H),4.20(q,J＝7.1Hz, 2H),3.39(d,J＝3.4Hz,1H),2.77–2.73(m,2H),1.28(t,J＝7.1Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.41,142.60,128.55,127.79,125.70,70.34,60.88,43.40, 14.16.
the structure of the resulting product is deduced from the above data as follows:
example 11
A25 mL reaction tube was charged with 0.5 mmol of p-fluorobenzaldehyde, 0.75 mmol of ethyl iodoacetate, and 15.6 mg of NiI 2 83 mg manganese powder, 15. Mu.L CF 3 COOH, acetonitrile as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 95%.
The structural characterization data of the product obtained in example 11 are shown below (as shown in figures 3 and 4):
1 H NMR(400MHz,CDCl 3 ):δ7.41–7.33(m,2H),7.09–7.01(m,2H),5.17–5.09(m,1H), 4.20(q,J＝7.1Hz,2H),3.41(d,J＝2.6Hz,1H),2.78–2.65(m,2H),1.28(t,J＝7.1Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.33,163.52,161.08,138.31,138.28,127.43,127.35, 115.49,115.27,69.69,60.97,43.33,14.14.
the structure of the resulting product is deduced from the above data as follows:
example 12
A25 mL reaction tube was charged with 0.5 mmol of p-methoxybenzaldehyde, 0.75 mmol of ethyl iodoacetate, and 15.6 mg of NiI 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH, acetonitrile as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate, and is 5:1, yield 92%.
The structural characterization data for the product obtained in example 12 are shown below (as shown in figures 5 and 6):
1 H NMR(400MHz,CDCl 3 ):δ7.32(d,J＝8.6Hz,2H),6.91(d,J＝8.7Hz,2H),5.11(dt,J ＝8.8,3.4Hz,1H),4.20(q,J＝7.1Hz,2H),3.82(s,3H),3.22(d,J＝3.3Hz,1H),2.73(m,2H), 1.34(dt,J＝14.3,13.6Hz,4H).
13 C NMR(100MHz,CDCl 3 ):δ172.46,159.22,134.73,126.98,113.92,69.98,60.85,55.30, 43.34,14.17.
the structure of the resulting product is deduced from the above data as follows:
example 13
Into a 25mL reaction tube were added 0.5 mmol of 2-naphthaldehyde, 0.75 mmol of ethyl iodoacetate, and 15.6 mg of NiI 2 83 mg manganese powder, 15. Mu.L CF 3 COOH in acetonitrile as solvent, N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 96%.
The structural characterization data for the product obtained in example 13 are shown below (as shown in figures 7 and 8):
1 H NMR(400MHz,CDCl 3 ):δ8.09(d,J＝8.2Hz,1H),7.92–7.88(m,1H),7.81(d,J＝8.2 Hz,1H),7.73(d,J＝7.1Hz,1H),7.57–7.47(m,3H),5.95(dd,J＝9.2,2.7Hz,1H),4.24(q,J＝ 7.1Hz,2H),3.63(s,1H),2.89(qd,J＝16.4,6.3Hz,2H),1.30(t,J＝7.2Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.71,138.19,133.78,130.01,129.02,128.27,126.29, 125.63,125.54,123.00,122.85,67.35,61.01,42.83,14.21.
the structure of the resulting product is deduced from the above data as follows:
example 14
Into a 25mL reaction tube were added 0.5 mmol of 2-furaldehyde, 0.75 mmol of ethyl iodoacetate, and 15.6 mg of NiI 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH, acetonitrile as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 93%.
The structural characterization data for the product obtained in example 14 are shown below (as shown in FIGS. 9 and 10):
1 H NMR(400MHz,CDCl 3 ):δ7.40(dd,J＝1.8,0.8Hz,1H),6.36(dd,J＝3.2,1.8Hz,1H), 6.30(d,J＝3.3Hz,1H),5.16(dt,J＝8.6,4.4Hz,1H),4.25–4.19(m,2H),3.25(d,J＝5.0Hz, 1H),2.96–2.83(m,2H),1.32–1.30(m,3H).
13 C NMR(100MHz,CDCl 3 ):δ171.97,154.72,142.26,110.26,106.32,64.22,60.98,39.77, 14.15.
the structure of the resulting product is deduced from the above data as follows:
example 15
To a 25mL reaction tube were added 0.5 mmol of cinnamaldehyde, 0.75 mmol of ethyl iodoacetate, and 15.6 mg of NiI 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH, acetonitrile as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 94%.
The structural characterization data of the product obtained in example 15 are shown below (as shown in figures 11 and 12):
1 H NMR(400MHz,CDCl 3 ):δ7.40(d,J＝7.4Hz,2H),7.34(t,J＝7.3Hz,2H),7.29–7.25 (m,1H),6.68(d,J＝15.9Hz,1H),6.25(dd,J＝15.9,6.0Hz,1H),4.75(dd,J＝11.4,6.0Hz,1H), 4.21(q,J＝7.1Hz,2H),2.71–2.60(m,2H),1.30(t,J＝7.1Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.30,136.44,130.78,129.94,128.61,127.83,126.56, 68.90,60.90,41.52,14.21.
the structure of the resulting product is deduced from the above data as follows:
example 16
A25 mL reaction tube was charged with 0.5 mmol of cyclohexylformaldehyde, 0.75 mmol of ethyl iodoacetate, and 15.6 mg of NiI 2 83 mg of manganese powder, 15. Mu.l of CF 3 COOH, acetonitrile as solvent, in N 2 Stirring and reacting for 12 hours at room temperature under the protection of gas, stopping heating and stirring, cooling to room temperature, distilling under reduced pressure to obtain a crude product, separating and purifying by column chromatography to obtain a target product,the eluent of the column chromatography is petroleum ether/ethyl acetate 10:1, yield 90%.
The structural characterization data for the product obtained in example 16 are shown below (as shown in figures 13 and 14):
1 H NMR(400MHz,CDCl 3 ):δ4.16(q,J＝7.1Hz,2H),3.76(dd,J＝10.3,4.5Hz,1H), 2.81(s,1H),2.43(dt,J＝16.2,12.8Hz,2H),1.86(d,J＝12.6Hz,1H),1.75(d,J＝9.3Hz,2H), 1.66(d,J＝12.0Hz,2H),1.41–1.32(m,1H),1.29–1.11(m,6H),1.08–0.96(m,2H).
13 C NMR(100MHz,CDCl 3 ):δ173.53,77.41,77.09,76.77,72.11,60.63,43.06,38.61, 28.77,28.22,26.40,26.14,26.03,14.15.
the structure of the resulting product is deduced from the above data as follows:
example 17
A25 mL reaction tube was charged with 0.5 mmol of 2,4, 6-trimethylbenzaldehyde, 0.75 mmol of ethyl iodoacetate, and 15.6 mg of NiI 2 83 mg manganese powder, 15. Mu.L CF 3 COOH, acetonitrile as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 83%.
The structural characterization data for the product obtained in example 17 are shown below (as shown in fig. 15 and 16):
1 H NMR(400MHz,CDCl 3 ):δ6.85(s,2H),5.63(dd,J＝10.6,2.1Hz,1H),4.23(q,J＝7.1 Hz,2H),3.08(dd,J＝16.5,10.7Hz,1H),2.59–2.50(m,1H),2.44(d,J＝10.2Hz,6H),2.27(s, 3H),1.32(t,J＝7.2Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.71,137.00,136.12,134.62,130.18,67.52,60.87,40.08, 20.76,20.68,14.21.
the structure of the resulting product is deduced from the above data as follows:
example 18
To a 25mL reaction tube were added 0.5 mmol neral, 0.75 mmol ethyl iodoacetate, 15.6 mg NiI 2 83 mg manganese powder, 15. Mu.L CF 3 COOH, acetonitrile as solvent, in N 2 Under the protection of gas, stirring and reacting for 12 hours at room temperature, stopping heating and stirring, cooling to room temperature, carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography separation and purification to obtain a target product, wherein the eluent of the column chromatography is petroleum ether/ethyl acetate of 10:1, yield 88%.
The structural characterization data for the product obtained in example 18 are shown below (as shown in fig. 17 and 18):
1 H NMR(400MHz,CDCl 3 ):δ5.21(d,J＝8.6Hz,1H),5.13–5.03(m,1H),4.77(qd,J＝ 9.0,4.1Hz,1H),4.16(q,J＝7.1Hz,2H),2.94–2.59(m,1H),2.56–2.41(m,2H),2.09(dt,J＝ 13.6,6.0Hz,3H),2.02–1.96(m,1H),1.73–1.66(m,6H),1.59(d,J＝3.5Hz,3H),1.26(t,J＝7.0 Hz,3H).
13 C NMR(100MHz,CDCl 3 ):δ172.49,172.45,139.52,139.32,132.37,131.72,126.47, 125.49,123.82,123.79,65.13,64.75,60.66,60.63,41.88,41.76,39.43,32.35,26.44,26.31, 25.65,23.30,17.68,17.65,16.64,14.18.
the structure of the resulting product is deduced from the above data as follows:
Claims (9)
1. a synthetic method of beta-hydroxy ester compounds is characterized in that aldehyde compounds and iodoacetate compounds are used as raw materials, manganese powder is used as an accelerator, metal nickel salt is used as a catalyst, an organic solvent is used as a reaction medium, organic protonic acid is added, the mixture is stirred and reacts under the protection of inert gas, the mixture is cooled to room temperature after the reaction is finished, the mixture is subjected to reduced pressure distillation and concentration to obtain a crude product, and the crude product is purified by column chromatography to obtain the beta-hydroxy ester compounds; the aldehyde compound is aromatic aldehyde, oxygen-containing aromatic heterocyclic aldehyde, sulfur-containing aromatic heterocyclic aldehyde, nitrogen-containing aromatic heterocyclic aldehyde or aliphatic aldehyde;
the catalyst is nickel iodide, nickel bromide or nickel chloride;
the organic protonic acid is trifluoroacetic acid.
2. The method of claim 1, wherein said iodoacetate is ICH 2 COOEt。
3. The synthesis process according to claim 1, characterized in that the molar ratio of the catalyst to the aldehyde compound is between 0.05 and 0.2:1.
4. the synthesis method according to claim 1, wherein the molar ratio of the manganese powder to the aldehyde compound is 2-4: 1.
5. the synthesis method according to claim 4, wherein the molar ratio of the iodoacetate compound to the aldehyde compound is 1-2: 1.
6. the synthesis method according to claim 5, wherein the molar ratio of the organic protic acid to the aldehyde compound is 0.1 to 0.5:1.
7. the synthesis method according to any one of claims 1 to 6, wherein the organic solvent is one of dimethyl sulfoxide, N, N-dimethylformamide, N-hexane, dichloromethane, toluene or 1, 4-dioxane, diethyl ether, tetrahydrofuran, acetonitrile, N, N-dimethylacetamide;
the aldehyde compounds are benzaldehyde, p-chlorobenzaldehyde, p-fluorobenzaldehyde, p-methyloxybenzaldehyde, 2, 3-dimethylbenzaldehyde, 2,4, 6-trimethylbenzaldehyde, 2, 6-difluorobenzaldehyde, 2-naphthaldehyde, 2-thiophenecarboxaldehyde, furfural, cyclohexyl aldehyde, cinnamaldehyde and neral.
8. The synthesis method according to any one of claims 1 to 6, characterized in that the reaction temperature is 10 to 35 ℃ and the reaction time is 6 to 36 hours.
9. The synthesis method according to any one of claims 1 to 6, wherein the eluent of the column chromatography is pure hexane or a mixed solvent, the mixed solvent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to the ethyl acetate is 5 to 50.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB762041A (en) * | 1953-07-07 | 1956-11-21 | Roche Products Ltd | Novel hydroxy-esters and the manufacture and conversion thereof |
| GB782354A (en) * | 1953-01-22 | 1957-09-04 | Philips Nv | Improvements in or relating to the manufacture of vitamin a |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB782354A (en) * | 1953-01-22 | 1957-09-04 | Philips Nv | Improvements in or relating to the manufacture of vitamin a |
| GB762041A (en) * | 1953-07-07 | 1956-11-21 | Roche Products Ltd | Novel hydroxy-esters and the manufacture and conversion thereof |
Non-Patent Citations (5)
| Title |
|---|
| Activation of Manganese Metal by a Catalytic Amount of PbCl2 and Me3SiCl;Kazuhiko Takai;《Tetrahedron Letters》;19961231;第37卷(第39期);第7049-7052页 * |
| Direct Formation of Organomanganese Bromides using Rieke Manganese;Seung-Hoi Kim等;《Tetrahedron Letters》;19961231;第37卷(第13期);第2197-2200页 * |
| Iron-Catalysed Reformatsky-Type Reactions;Muriel Durandetti等;《SYNTHESIS》;20061231;第9卷;第1542-1548页 * |
| Synthesis ofb-hydroxy esters using highly active manganese;YoungSung Suh等;《Tetrahedron Letters》;20041231;第45卷;第1807-1809页 * |
| 锰参与的催化不对称Reformatsky反应研究;梁大成等;《中国化学会第六届有机化学学术会议》;20091231;第414页 * |
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