Method for synthesizing 3-oxazoline-5-ketone substituted allene compound under catalysis of copper

Abstract

The invention develops a methodological strategy for rapidly constructing a 3-oxazoline-5-ketone skeleton by taking an amino acid derivative and an imine ketone ester as substrates to obtain a compound containing 3-oxazoline-5-ketone substituted allene. The synthesis of the oxazolinone substituted allene compound with potential important biological activity and application value is realized. The oxazolinone is simple in structure, easy to prepare, wide in derivation range and low in price, and the structural diversity of oxazolinone compounds can be better enriched. The method disclosed by the invention can be prepared by a one-pot method, is efficient and rapid, simple to operate, short in reaction step, mild in reaction condition and wide in application range, and overcomes the defects of complex operation, harsh reaction condition, limited substrate, intolerant substrate functional groups, tedious steps and the like of the traditional reaction.

Description

Technical Field

[0001] The invention relates to the field of synthetic pharmaceutical chemistry, and in particular to a method for synthesizing 3-oxazoline-5-one substituted allene compounds by copper catalysis. Background Art

[0002] 3-Oxazolin-5-one has been known to people since the 1960s, but there has been little research on this type of oxazolinone, partly because they are not easy to synthesize using current methods, and partly because they are not commonly found in natural products or drugs. At present, there are four methods for the preparation of 3-oxazolin-5-one. The first is to decompose nitrogen heterocyclic propene by ultraviolet (UV) irradiation to generate nitrile ylide compounds, which undergo cycloaddition reaction with C02; the second is the condensation of α-keto acid with oxime or α-keto acid oxime with aldehyde or ketone to generate 3-oxazolin-5-one-N-oxide, followed by reductive deoxygenation or condensation of α-hydroxyaminocarboxylic acid with aldehyde or ketone; the third is the condensation of α-amino acid with anhydride or acid chloride of perfluorocarboxylic acid; the fourth is the 2-alkylation reaction of 2-oxazolin-5-one, but these reported synthetic methods of 3-oxazolin-5-one have only low or medium yields. To date, the efficient synthesis of 3-oxazolin-5-ones from readily available starting materials has been a challenging task. Summary of the invention

[0003] The present invention provides a methodological strategy for rapidly constructing a 3-oxazolin-5-one skeleton using amino acid derivatives and imino ketoesters as substrates to obtain a target compound containing a 3-oxazolin-5-one substituted allene. This strategy is intended to achieve the synthesis of oxazolinone substituted allene compounds with potentially important biological activity and application value, construct a small molecule library with stereochemical diversity and functional group diversity, and provide important technical support and preliminary theoretical basis for the creation of new drugs for such compounds. The method has the advantages of simple operation, wide application range of functional groups, simple and easy-to-obtain raw materials, and high yield.

[0004] The present invention is achieved through the following technical solutions:

[0005] The present invention provides a multifunctional 3-oxazolin-5-one substituted allene derivative 3, characterized in that: under an inert gas and / or nitrogen atmosphere, compound 1, compound 2, a catalyst, a base, and a solvent are mixed to generate a product structure of: Where R 1 represents phenyl, naphthyl or monosubstituted phenyl, the substituents are halogen, alkyl or alkoxy independently substituted at each position of the ortho, meta or para of the benzene ring, R 2 represents a C1-C3 straight chain alkyl group, R 3 , R 4 is a C1-C3 straight chain alkyl or branched chain alkyl or phenyl;

[0006] The method for copper-catalyzed synthesis of 3-oxazoline-5-one substituted allene compounds of the present invention is characterized in that the synthesis route is as shown in Formula I:

[0007] The copper catalyst is selected from copper acetate, copper chloride, and copper iodide, preferably copper acetate.

[0008] The synthesis reaction time is 6-12h.

[0009] The solvent is one of tetrahydrofuran, dichloromethane and acetonitrile, preferably tetrahydrofuran.

[0010] The base is one of triethylamine, cesium carbonate and diazabicyclic, preferably triethylamine.

[0011] Furthermore, the reaction temperature is 0°C-80°C, preferably 25°C.

[0012] Furthermore, the molar amount of compound 2 is 1-5 times the molar amount of compound 1, preferably 1-3 times, and more preferably 1.2 times.

[0013] The beneficial effects of the present invention are:

[0014] (1) The present invention provides a methodological strategy for rapidly constructing a 3-oxazolin-5-one skeleton using amino acid derivatives and imino ketoesters as substrates to obtain a target compound containing a 3-oxazolin-5-one substituted allene. This strategy is intended to achieve the synthesis of oxazolinone substituted allene compounds with potentially important biological activity and application value, construct a small molecule library with stereochemical diversity and functional group diversity, and provide important technical support and preliminary theoretical basis for the creation of new drugs for such compounds. The method has the advantages of simple operation, wide range of functional group applications, simple and easy-to-obtain raw materials, and high yield.

[0015] (2) The 3-oxazoline-5-one in the present invention has a simple structure, is easy to prepare, has a wide range of derivatization, is cheap, and can better enrich the structural diversity of 3-oxazoline-5-one compounds.

[0016] (3) The method of the present invention can be prepared by a one-pot process, which is efficient and fast, simple to operate, short in reaction steps, mild in reaction conditions, and has a wide range of applications, thus overcoming the shortcomings of traditional reactions such as complex operation, harsh reaction conditions, substrate limitations, and cumbersome steps. DETAILED DESCRIPTION

[0017] The technical solution of the present invention is clearly and completely described below. Obviously, the embodiments described here are only a part of the present invention rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the protection scope of the present invention.

[0018] Compound 1 in the present invention can be synthesized by existing technology, reference:

[0019] [1] Zhang, W; Angew Chem, Int Ed, Org Lett, Nat Comun, 2022, 13, 400.

[0020] Compound 2 in the present invention can be synthesized by existing technology, reference:

[0021] [2]Chan, C.-M.; Org. Lett.2019, 21, 8037-8043.

[0022] Example 1

[0023] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0024] 0.2mol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 89%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0025] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.47 (d, J = 8.1Hz, 2H), 7.35-7.26 (m, 3H), 5.97 (s, 1H), 4. 37-4.22(m, 2H), 2.23(s, 3H), 1.68(s, 3H), 1.46(s, 9H), 1.34(t, J=6.6Hz, 3H). 13C NMR (101MHz, CDCl3) δ177.21, 177.17, 167.08, 166.23, 163.95, 163.64, 154.46, 154.32, 131.99, 128.87, 128.77, 128.25, 128.22, 122.09, 121.90, 72.64, 71.94, 63.05, 28.22, 20.04, 19.56, 15.29, 13.99.HRMS (ESI): calcd.for C 22 H 26 N2O6[M+Na]+: 437.1844.found: 437.1845.

[0026] Embodiment 2:

[0027] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows:

[0028] 0.2mmol of alkynyl imine compound 1, 0.24mol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and vacuum was replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 67%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0029] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.44 (d, J = 11.7Hz, 2H), 7.29 (d, J = 14.4Hz, 3H), 4.38-4.19 (m, 2H), 1.64 ( d,J==12.1Hz,3H),1.47(d,J=4.3Hz,9H), 1.34(dt,J=11.6,7.1Hz,3H),1.24(d,J=2.3Hz,9H). 13C NMR (101MHz, CDCl3) δ172.57, 172.31, 166.72, 154.58, 154.44, 131.99, 131.93, 128.74, 128.64, 128.19, 128.17, 122.20, 1 22.06, 72.44, 71.94, 62.81, 62.34, 34.22, 34.19, 28.24, 28.21, 26.75, 26.70, 20.12, 19.47, 13.97.HRMS(ESI):calccd.for C 25 H 32 N2O6[M+Na]+: 479.2354.found: 479.2355.

[0030] Embodiment 3:

[0031] The synthesis of 3-oxazoline-5-one substituted allenes is as follows

[0032] 0.2mol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 66%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0033] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ8.04 (d, J=7.1Hz, 2H), 7.66 (dd, J=7.5, 2.2Hz, 2H), 7.59 (d, J=7 .3Hz, 1H), 7.49 (t, J=7.8Hz, 2H), 7.42 (dd, J=7.6, 2.0Hz, 2H), 7.36-7.30 (m, 5H), 7.26 (s, 1H), 7.25-7.19 (m, 5H), 6.18 (s, 1H), 6.03 (s, 1H), 4.40-4.17 (m, 4H), 2.25 (s, 3H) , 1.78 (s, 3H), 1.46 (s, 9H), 1.43 (s, 9H), 1.38 (t, J = 7.1Hz, 3H), 1.25 (d, J = 7.2Hz, 3H). 13C NMR (101MHz, CDCl3) δ204.05, 176.93, 166.84, 165.32, 164.19, 162.22, 154.39, 136.86, 133.41, 131.99, 129.14, 128.94, 128.88, 128.63, 128.47, 128.41, 128.2 5, 128.15, 128.11, 126.39, 125.12, 122.14, 106.36, 105.08, 86.11, 83.64, 81.26 , 72.75, 62.95, 62.61, 28.20, 20.22, 14.21, 13.97, 13.92.HRMS (ESI): calcd.for C 27 H 28 N2O6[M+Na]+: 499.1944.found: 499.1945.

[0034] Embodiment 4:

[0035] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0036] 0.2mmol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was monitored using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 46%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0037] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.47 (dd, J=7.4, 2.2Hz, 1H), 7.42 (dd, J=7.5, 2.0Hz, 1H), 7.30 (td, J=4.3, 3.9, 2.1Hz, 3H), 5.66 (s, 1H), 4.37-4.19 (m, 2H), 1.46 (d, J = 3.3Hz, 9H), 1.34 (dt, J = 14.0, 7.1Hz, 4H), 1.24 (d, J = 1.8Hz, 9H), 0.92 (dd, J = 11.0, 6.6Hz, 3H), 0.83 (dd, J = 10.9, 6.6Hz, 3H). 13C NMR (101MHz, CDCl3) δ172.43, 172.11, 166.37, 154.73, 154.50, 131.98, 131.90, 128.65, 128.58, 128.16, 62.73, 40.55, 39.7 2, 34.30, 34.25, 29.72, 28.25, 28.22, 26.78, 26.69, 24.68, 24.64, 24.24, 24.11, 23.18, 22.97, 13.96.HRMS (ESI): calcd.for C 27 H 36 N2O6[M+Na]+: 507.2644.found: 507.2645.

[0038] Embodiment 5:

[0039] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0040] 0.2mmol of alkynyl imine compound 1, 0.24mol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and vacuum was replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 70%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0041] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.52 (d, J = 8.5Hz, 2H), 6.88 (d, J = 8.8Hz, 2H), 6.16 (s, 1H), 4.32 -4.22(m,2H),3.81(s,3H),2.23(s,3H),1.80(s,3H),1.44(s,9H),1.32-1.29(m,3H). 13 C NMR (101MHz, CDCl3) δ202.30, 165.34, 164.33, 161.26, 159.72, 130.50, 124.92, 116.00, 113. 87, 105.13, 104.10, 62.42, 55.31, 29.73, 28.22, 24.35, 14.16, 13.90.HRMS (ESI): calcd.for C z3 H 28N2O7[M+Na]+: 467.1797.found: 467.1794.

[0042] Embodiment 6:

[0043] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0044] 0.2mmol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a pale yellow oily product (yield: 68%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0045] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.39 (d, J = 8.2Hz, 2H), 7.32 (d, J = 8.2Hz, 2H), 5.92 (s, 1H), 4. 36-4.22(m, 2H), 2.23(s, 3H), 1.66(s, 3H), 1.45(s, 9H), 1.34(s, 3H), 1.30(s, 9H). 13 C NMR (101MHz, CDCl3) δ177.14, 167.06, 163.86, 154.31, 152.04, 131.70, 125.21, 119.08, 86.22, 82.77, 81 .18, 72.09, 62.92, 62.65, 34.82, 31.16, 29.72, 28.20, 22.71, 19.96, 15.22, 13.99.HRMS (ESI): calcd.for C 26 H 34 N2O6[M+Na]+: 493.2444.found: 493.2445.

[0046] Embodiment 7:

[0047] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0048] 0.2mmol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 75%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0049] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.38 (d, J=8.0Hz, 2H), 7.13 (d, J=7.9Hz, 2H), 5.93 (s, 1H), 4.36-4.23 (m, 2H), 2.64 (q, J=7.6Hz, 2H), 2.23 (s, 3H), 1.67 (s, 3H), 1.45 (s, 10H), 1.34 (t, J=6.8Hz, 3H), 1.22 (t, J=7.3Hz, 3H). 13 C NMR (101MHz, CDCl3) δ177.16, 167.06, 163.85, 154.31, 145.18, 131.96, 127.76, 119.29, 86.30, 82. 75, 81.16, 72.07, 62.90, 62.69, 28.84, 28.19, 19.98, 15.32, 15.19, 13.98.HRMS (ESI): calcd.forC 24 H 30 N2O6[M+Na]+: 465.2144.found: 465.2145.

[0050] Embodiment 8:

[0051] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0052] 0.2mmol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 63%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0053] The product testing data is as follows; 1 H NMR (400MHz, CDCl3) δ7.91 (d, J = 12.6Hz, 1H), 7.70 (dd, J = 9.7, 7.3Hz, 3H), 7.41 (dd, J = 6.3, 3.3Hz, 3H), 5.92 ( s, 1H), 4.35-4.12 (m, 2H), 1.62 (s, 3H), 1.40 (s, 9H), 1.37-1.29 (m, 3H), 1.24 (d, J = 23.7Hz, 3H), 1.17 (s, 9H). 13 C NMR (101MHz, CDCl3) δ1777.51, 172.64, 166.73, 154.49, 132.96, 132.79, 132 .14, 132.03, 128.48, 127.85, 127.80, 127.77, 126.85, 126.54, 119.50, 119.3 6, 115.92, 81.26, 77.38, 72.50, 72.00, 62.87, 62.47, 34.27, 31.64, 29.73, 29 .66, 28.34, 28.26, 26.79, 26.72, 20.18, 19.53, 14.00.HRMS (ESI): calcd.for C 29 H 34 N2O6[M+Na]+: 529.1841.found: 529.1845.

[0054] Embodiment 9:

[0055] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0056] 0.2mmol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 69%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0057] Product testing data are as follows: 1H NMR (400MHz, CDCl3) δ8.41 (d, J = 7.9 Hz, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 7.0 Hz, 1H), 7.52 (ddd, J = 9.4, 7.8, 1.4 Hz ,2H), 7.43-7.39(m, 1H), 6.01(s, 1H), 4.41-4.30(m, 2H), 2.22(s, 3H), 1.73(s, 3H), 1.47(s, 9H), 1.39(d, J=7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ177.27, 166.28, 163.72, 154.52, 135.24, 133.68, 133.05, 130.94, 129.31, 128.12, 126.93, 126.47, 125.06, 124.23, 119.66, 72.68, 63.11, 62.15, 28.24, 27.83, 19.55, 15.27, 14.01.HRMS (ESI): calcd.for C 26 H 28 N2O6[M+Na]+: 487.1838.found: 487.1845.

[0058] Embodiment 10:

[0059] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0060] 0.2 mmol of alkynyl imine compound 1, 0.24 mol of amino acid compound 2, 0.02 mmol of copper acetate and a stirrer were added to a 10 ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2 ml of tetrahydrofuran and 0.4 mmol of triethylamine were injected into the reaction tube under nitrogen conditions. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was monitored using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 80%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0061] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.47 (t, J=7.4Hz, 1H), 7.31 (q, J=7.6Hz, 1H), 7.12-7.01 (m, 2H), 5.94 (s, 1H), 4.37-4.23 (m, 2H), 2.24 (s, 3H), 1.45 (s, 9H), 1.34 (t, J==7.2Hz, 3H), 1.26 (s, 3H).13 C NMR (101MHz, CDCl3) δ177.01, 166.75, 164.35, 164.09, 161.84, 154.28, 133.91, 130.58, 130.50, 123.88, 123.84,115.52,115.31,71.93,62.98,62.68,29.70,28.16,19.95,15.12,13.94.HRMS(ESI):calcd.for C 23 H 28 N2O6[M+a]+: 451.1849.found: 451.1845.

[0062] Embodiment 11:

[0063] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0064] 0.2mmol of alkynyl imine compound 1, 0.24mol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and vacuum was replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 71%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0065] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.29 (s, 1H), 7.26 (s, 1H), 7.22-7.16 (m, 1H), 7.13 (d, J = 7.7Hz, 1H), 5.94 (s, 1H), 4.35-4.22 (m, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 1.67 (s, 3H), 1.45 (s, 9H), 1.35 (d, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ181.87, 173.42, 162.27, 161.97, 138.14, 135.28, 132.86, 130.60, 129.35, 128.80, 128.22, 127.26, 124.35, 99.75, 98.06, 62.34, 29.71, 22.70, 21.30, 14.13, 13.78.HRMS (ESI): calcd.for C 23H 28 N2O6[M+Na]+: 451.1846.found: 451.1845.

[0066] Embodiment 12:

[0067] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0068] 0.2mmol of alkynyl imine compound 1, 0.24mol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and vacuum was replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 70%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0069] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.40 (d, J = 7.5Hz, 1H), 7.24-7.16 (m, 2H), 7.14-7.09 (m, 1H), 5.92 (s, 1H) , 4.36-4.23 (m, 2H), 2.45 (s, 3H), 2.22 (s, 3H), 1.67 (s, 3H), 1.45 (s, 9H), 1.34 (t, J = 7.1Hz, 3H). 13 C NMR (101MHz, CDCl3) δ177.06, 166.99, 163.80, 154.28, 141.03, 132.12, 129.38, 128.71, 125.36, 121.94, 8 7.27, 85.07, 81.10, 72.12, 62.89, 62.65, 29.70, 28.18, 20.61, 19.96, 15.17, 13.98.HRMS (ESI): calcd.for C 23 H 28 N2O6[M+Na]+: 451.1837.found: 451.1845.

[0070] Embodiment 13:

[0071] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0072] 0.2mmol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 65%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0073] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.48-7.43 (m, 2H), 7.00 (t, J=8.7Hz, 2H), 5.98 (s, 1H ), 4.34-4.23(m, 2H), 2.23(s, 3H), 1.45(s, 10H), 1.37(s, 3H), 1.33(s, 3H). 13 C NMR (101MHz, CDCl3) δ177.19, 167.04, 164.03, 163.95, 161.55, 154.30, 133.99, 133.91, 124.38, 123.48, 115.65, 1 15.43, 71.82, 63.00, 62.79, 34.99, 34.45, 31.51, 30.15, 29.70, 28.19, 20.12, 15.17, 13.98.HRMS (ESI): calcd.for C 22 H 25 FN2O6[M+Na]+: 455.1593.found: 455.1594.

[0074] Embodiment 14:

[0075] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0076] 0.2mmol of alkynyl imine compound 1, 0.24mol of amino acid compound 2, 0.02mol of copper acetate and a stirrer were added to a 10ml reaction tube, and vacuum was replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was detected using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product (yield: 61%) was obtained by separation using a silica gel (200-300 mesh) column chromatography.

[0077] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.58 (d, J=6.5Hz, 2H), 7.48 (d, J=14.2Hz, 2H), 7.32 (q, J=3.2, 2.6Hz, 3H), 6.90 (t, J=7.8Hz, 2 H), 6.27 (s, 1H), 4.35 (dddd, J = 39.4, 11.3, 7.0, 3.6Hz, 2H), 2.43-2.35 (m, 3H), 1.45 (s, 9H), 1.38 (t, J = 7.2Hz, 3H). 13 CNMR (101MHz, CDCl3) 6164.96, 163.95, 163.73, 161.54, 161.25, 151.37, 136.56, 130.83, 130.75, 129.38, 1 28.49, 126.98, 116.32, 115.29, 115.08, 105.72, 81.10, 62.59, 28.22, 14.22, 14.12.HRMS (ESI): calcd.for C 27 H 27 FN2O6[M+Na]+: 517.1944.found: 517.1945.

[0078] Embodiment 15:

[0079] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0080] 0.2mmol of alkynyl imine compound 1, 0.24mol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was monitored using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a pale yellow oily product was obtained by separation using a silica gel (200-300 mesh) column chromatography (yield: 60%).

[0081] Product testing data are as follows: 1H NMR (400MHz, CDCl3) δ7.48 (t, J=7.4Hz, 1H), 7.31 (dd, J=14.2, 6.9Hz, 1H), 7.11-7.02 (m, 2H), 5.95 (s, 1H), 4.36-4.24 (m, 2H), 2.25 (s, 3H), 1.68 (s, 3H), 1.45 (s, 9H), 1.34 (t, J=6.9Hz, 3H). 13 C NMR(101 MHz, CDCl3) δ177.02, 166.78, 164.34, 164.11, 161.84, 154.29, 133.92, 130.58, 130.51, 123.89, 123.85, 115.52, 115.3 1, 110.86, 110.71, 88.67, 81.32, 79.46, 71.91, 63.00, 62.68, 29.70, 28.16, 19.96, 15.13, 13.94.HRMS (ESI): calcd.for C 22 H 25 FN2O6[M+Na]+: 455.1595.found: 455.1594.

[0082] Embodiment 16:

[0083] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0084] 0.2mmol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was monitored using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a pale yellow oily product was obtained by separation using a silica gel (200-300 mesh) column chromatography (yield: 68%).

[0085] Product testing data are as follows: 1H NMR (400MHz, CDCl3) δ7.62 (s, 1H), 7.46 (d, J = 8.2Hz, 1H), 7.41 (d, J = 7.7Hz, 1H), 7.18 (t, J = 7.9Hz, 1H), 5.65 (s, 1 H), 4.35-4.23 (m, 2H), 2.22 (d, J = 1.9Hz, 3H), 1.67 (d, J = 2.0Hz, 3H), 1.47 (d, J = 1.9Hz, 9H), 1.32 (t, J = 7.2Hz, 3H). 13 C NMR (101MHz, CDCl3) δ171.47, 170.64, 168.38, 154.88, 134.74, 131.93, 130.64, 129.63, 124.08, 12 1.94, 84.90, 84.61, 63.49, 63.35, 61.44, 31.59, 28.25, 23.36, 19.00, 13.97.HRMS (ESI): calcd.for C 22 H 25 BrN2O6[M+Na]+: 515.0802.found: 515.0794.

[0086] Embodiment 17:

[0087] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0088] 0.2mmol of alkynyl imine compound 1, 0.24mmol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mmol of triethylamine were injected into the reaction tube under nitrogen conditions. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was monitored using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a light yellow oily product was obtained by separation using a silica gel (200-300 mesh) column chromatography (yield: 73%).

[0089] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) δ7.48 (t, J=7.3Hz, 1H), 7.31 (q, J=7.0Hz, 1H), 7.07 (dt, J=16.8, 8.2Hz, 2H), 5.94 (s , 1H), 4.30 (ddd, J=24.1, 10.9, 5.5Hz, 2H), 2.24 (s, 3H), 1.68 (s, 3H), 1.45 (s, 9H), 1.33 (d, J=7.0Hz, 3H).13 C NMR (101MHz, CDCl3) δ177.02, 166.77, 164.35, 164.10, 161.84, 154.29, 133.92, 130.58, 130.50, 123. 89,123.85, 115.52, 115.31, 71.92, 62.99, 62.69, 28.16, 19.95, 15.12, 13.93.HRMS (ESI): calcd.for C 22 H 25 BrN2O6[M+Na]+: 515.0786.found: 515.0794.

[0090] Embodiment 18:

[0091] The synthesis of 3-oxazoline-5-one substituted allene compounds is as follows

[0092] 0.2mmol of alkynyl imine compound 1, 0.24mol of amino acid compound 2, 0.02mmol of copper acetate and a stirrer were added to a 10ml reaction tube, and the mixture was evacuated and replaced with nitrogen three times. 2ml of tetrahydrofuran and 0.4mol of triethylamine were injected into the reaction tube under nitrogen. The reaction tube was placed on a magnetic stirrer for stirring. The reaction progress was monitored using a TLC plate, and the reaction was stopped when the raw material 1 was completely consumed. The solvent was removed using a rotary evaporator, and a pale yellow oily product was obtained by separation using a silica gel (200-300 mesh) column chromatography (yield: 89%).

[0093] Product testing data are as follows: 1 H NMR (400MHz, CDCl3) 67.46 (dd, J=7.5, 2.1Hz, 2H), 7.32 (q, J=5.3Hz, 3H), 5.93 (s, 1H), 4.27-4.11 (m, 2H), 2.22 (d, J = 3.8Hz, 3H), 1.73 (q, J = 7.1Hz, 2H), 1.46 (d, J = 7.8Hz, 9H), 0.99 (td, J = 7.4, 4.3Hz, 3H). 13 C NMR (101MHz, CDCl3) δ177.17, 167.07, 163.88, 154.26, 131.96, 128.73, 128.22, 122.14, 86.05, 83.43, 81.19, 71.99, 68.52, 68.45, 62.78, 28.23, 28.20, 21.80, 20.02, 15.22, 10.41.HRMS (ESI): calcd.forC 23 H28 N2O6[M+Na]+: 451.1844.found: 451.1845.

Claims

1. A method for preparing an oxazolinone substituted allene derivative 3, characterized in that In an inert gas and / or nitrogen atmosphere, compound 1, compound 2, a copper catalyst, a base, and a solvent are mixed to generate a product structure of: R 1 represents phenyl, naphthyl or monosubstituted phenyl, the substituents are halogen, alkyl or alkoxy independently substituted at each position of the ortho, meta or para of the benzene ring, R 2 represents a C1-C3 straight chain alkyl group, R 3 , R 4 is a C1-C3 straight chain alkyl or branched chain alkyl or phenyl; its synthesis route is as shown in Formula I 2. The preparation method according to claim 1, characterized in that: The copper catalyst is selected from copper acetate, copper chloride, and copper iodide, preferably copper acetate.

3. The preparation method according to claim 1, characterized in that: The synthesis reaction time is 6-12h.

4. The preparation method according to claim 1, characterized in that: The solvent is one of tetrahydrofuran, dichloromethane and acetonitrile, preferably tetrahydrofuran.

5. The preparation method according to claim 1, characterized in that: The base is one of triethylamine, cesium carbonate and diazabicyclic, preferably triethylamine.

6. The preparation method according to claim 1, characterized in that: The temperature is 0°C-80°C, preferably 25°C.

7. The preparation method according to claim 1, characterized in that: The molar amount of the compound 2 is 1-5 times the molar amount of the compound 1, preferably 1-3 times, more preferably 1.2 times.

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