A method for rhodium-catalyzed synthesis of unnatural beta-amino acid compounds

Abstract

The application belongs to the technical field of compound synthesis, and discloses a method for rhodium-catalyzed synthesis of unnatural beta-amino acid compounds, which comprises the following steps: taking a compound shown in formula I and a compound shown in formula II as raw materials, and under the action of a rhodium catalyst, an additive and a solvent, a beta-amino acid compound shown in formula III is synthesized through a reaction under the conditions of an inert atmosphere and heating; the rhodium catalyst is dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer. The application uses metal rhodium catalysis, does not need silver additive or external oxidant, and synthesizes various unnatural beta-amino acid compounds through high regioselective spirocyclization reaction of a substrate, conversion of trifluoroacetyl into a carboxylic acid group under the action of a strong base, and carbon-hydrogen activation in one pot, so that the steps are simple and the applicable substrates are wide.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis technology and relates to a method for the rhodium-catalyzed synthesis of non-natural β-amino acid compounds. Background Technology

[0002] Proteins, the basic building blocks of organic life, are mostly composed of α-amino acids, which are naturally occurring in nature. There are about twenty such amino acids found in abundance in nature. In addition to these twenty-odd α-amino acids, there are hundreds of other proteins that contain not only α-amino acids but also another type of β-amino acid.

[0003] Although β-amino acids are not as abundant as naturally occurring α-amino acids, polypeptides composed of them exhibit strong biological activity and are widely used as protease inhibitors, antibacterial agents, and other applications. β-amino acids possess optical activity. Because there are two carbon atoms between the two terminal functional groups of β-amino acids, there are more isomers of β-amino acids than their corresponding α-amino acids, and substitution or polysubstitution of β-amino acids further increases their number. Therefore, the development and synthesis of β-amino acids offers new possibilities for the research and development of novel drugs and treatments. Currently, the synthesis of β-amino acids is largely limited to α-amino acids, and there are relatively few transformations for the efficient construction of β-amino acids.

[0004] In 2009, Feng Xiaoming reported the Michael reaction of bifunctional β-keto esters based on aminoamide skeletons with nitroolefins to synthesize β-amino acids (Angew. Chem. Int. Ed. 2009, 48, 5195-5198). In 2022, Burkhard... Non-natural α-amino acid derivatives were synthesized using imines and abundant alkanes by activating inert sp3 C-H bonds through photo-oxidation (Org. Lett. 2022, 24, 4793-4797). The aforementioned literature reports on amino acid synthesis all pertain to amino acids with relatively simple skeletons. The synthesis of β-amino acids with potentially biologically active rigid spirocyclic skeletons is extremely challenging. Summary of the Invention

[0005] To address the aforementioned technical problems, this invention provides a method for the rhodium-catalyzed synthesis of non-natural β-amino acid compounds. Using metallic rhodium as a catalyst, it eliminates the need for silver additives or external oxidants. Through a highly regioselective spirocyclization reaction of the substrate, and then under strong base conditions, the trifluoroacetyl group is converted to a carboxylic acid group. Following hydrocarbon activation, a variety of non-natural β-amino acid compounds are synthesized in a one-pot process. The method is simple and applicable to a wide range of substrates.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] This invention provides a method for the rhodium-catalyzed synthesis of non-natural β-amino acid compounds, comprising the following steps:

[0008] Using compounds of Formula I and Formula II as starting materials, β-amino acid compounds of Formula III were synthesized by reaction under an inert atmosphere and heating conditions in the presence of a rhodium catalyst, additives, and a solvent. The rhodium catalyst was a dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer. The specific synthetic route is as follows:

[0009]

[0010] Wherein: R1 and R2 are both selected from hydrogen or halogen, and R3 is selected from phenyl, or methyl, ethyl, tert-butyl, halogen, cyano-substituted phenyl, or five-membered heterocyclic group.

[0011] In one technical solution, the methyl, ethyl, tert-butyl, halogen, and cyano groups in R3 are at the para position of the trifluoromethyl-terminated acetylacetonate, and the five-membered heterocyclic group is a thiophene group.

[0012] In one technical solution, the additive is selected from one of pentanoic acid, acetic acid, sodium acetate, and ketone acetate.

[0013] In one technical solution, the solvent is acetonitrile.

[0014] In one technical solution, the molar ratio of the compound represented by Formula I to the compound represented by Formula II is 1:1.5.

[0015] In one technical solution, the molar ratio of the additive to the compound shown in Formula I is 1:1 to 1.5.

[0016] In one technical solution, the ratio of the solvent to the compound shown in Formula I is 1 ml: 0.1 mmol.

[0017] In one technical solution, the reaction temperature is 60°C.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0019] This invention utilizes rhodium catalysis to synthesize a variety of non-natural β-amino acid compounds in a one-pot process via a highly regioselective spirocyclization reaction between phenylbenzoxazine compounds and trifluoromethyl-terminated acetylenes compounds under strong base conditions, without any silver additives or external oxidants.

[0020] The raw materials used in this invention are widely available, easy to synthesize, require minimal processing, and are applicable to a wide range of substrates. Attached Figure Description

[0021] Figure 1 The above is the 1H NMR spectrum of 3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 1 of this invention.

[0022] Figure 2 This is the carbon NMR spectrum of 3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 1 of this invention.

[0023] Figure 3 The above is the 1H NMR spectrum of 3'-(4-ethylphenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 2 of this invention.

[0024] Figure 4 The image shows the carbon NMR spectrum of 3'-(4-ethylphenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 2 of this invention.

[0025] Figure 5 The above is the 1H NMR spectrum of 3'-(4-(tert-butyl)phenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 3 of this invention.

[0026] Figure 6 The image shows the carbon NMR spectrum of 3'-(4-(tert-butyl)phenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 3 of this invention.

[0027] Figure 7 The above is the 1H NMR spectrum of 3'-(4-chlorophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 4 of this invention.

[0028] Figure 8 The image shows the carbon NMR spectrum of 3'-(4-chlorophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 4 of this invention.

[0029] Figure 9 The above is the 1H NMR spectrum of 3'-(4-cyanophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 5 of this invention.

[0030] Figure 10The image shows the carbon NMR spectrum of 3'-(4-cyanophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 5 of this invention.

[0031] Figure 11 The 1H NMR spectrum of 3'-(thiophene-3-yl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 6 of this invention is shown.

[0032] Figure 12 The image shows the carbon NMR spectrum of 3'-(thiophene-3-yl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 6 of this invention.

[0033] Figure 13 The above is the 1H NMR spectrum of 5'-fluoro-3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 7 of this invention.

[0034] Figure 14 The image shows the carbon NMR spectrum of 5'-fluoro-3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid in Example 7 of this invention. Detailed Implementation

[0035] The following embodiments are used to illustrate the present invention, but are not intended to limit the scope of protection of the present invention. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. Unless otherwise specified, the test methods in the following embodiments are conventional methods.

[0036] The ketoimine compounds used in the following examples were synthesized with reference to the following literature: ARhodium-Catalyzed[3+2] Annulation of General Aromatic Aldimines / Ketimines and N-Substituted Maleimides. Org. Lett. 2018, 20, 5960-5963. The trifluoromethyl-terminated ynone compounds were synthesized with reference to: Copper-Mediated Deacylative Coupling of Ynones via CC Bond Activation under Mild Conditions. Org. Lett. 2019, 21, 23, 9487-9492.

[0037] Example 1: Preparation of 3'-(p-Tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid

[0038] In a 25 mL Schlenk tube, add a magnetic stir bar, then add 0.2 mmol of 3-phenyl-2H-1,4-benzoxazine, 0.3 mmol of 1,1,1-trifluoro-4-(p-toluene)but-3-yn-2-one, 0.005 mmol of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (CAS: 12354-85-7), 0.14 mmol of terpentonic acid (CAS: 75-98-9), and finally add 1 mL of acetonitrile (CAS: 75-05-8).

[0039] Using a double-row tube, a 25 mL Schlenk tube filled with argon was used. The mixture was heated to 60 °C for 24 h with magnetic stirring, cooled to room temperature, and then 1.6 mmol of NaOH (CAS: 1310-73-2) was added and stirred at room temperature for 12 h to obtain the product: 3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid, with a yield of 76%.

[0040] The above reaction equation is as follows:

[0041]

[0042] The 1H NMR spectrum of 3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 1 The characteristics are as follows: 1 H NMR(400MHz, CDCl3)δ7.38-7.26(m,8H),7.05-7.00(m,1H),6.95-6.89(m,2H), 6.80-6.74(m,1H),4.76(d,J=10.8Hz,1H),3.95(d,J=10.8Hz,1H),2.43(s,3H).

[0043] Carbon NMR spectrum of 3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 2 The characteristics are as follows: 13C NMR (75MHz, DMSO) δ165.78,150.58,150.51,142.28,140.30,137.85,134.15,133.84,130.55,128. 84,128.40,128.30,128.15,123.08,122.24,121.84,116.78,116.00,115.28,68.89,64.64,20.95.

[0044] Example 2: Preparation of 3'-(4-ethylphenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid

[0045] Add a magnetic stir bar to a 25 mL Schlenk tube, then add 0.2 mmol of 3-phenyl-2H-1,4-benzoxazine, 0.3 mmol of 4-(4-ethylphenyl)-1,1,1-trifluorobut-3-en-2-one, 0.005 mmol of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, 0.14 mmol of terpentonic acid, and finally add 1 mL of acetonitrile.

[0046] Using a double-row tube, a 25 mL Schlenk tube was filled with argon gas and stirred with a magnetic stirrer. The mixture was heated to 60 °C for 24 h, cooled to room temperature, and then 1.6 mmol of NaOH was added and stirred at room temperature for 12 h to obtain the product: 3'-(4-ethylphenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid, with a yield of 81%.

[0047] The above reaction equation is as follows:

[0048]

[0049] The 1H NMR spectrum of 3'-(4-ethylphenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 3 The characteristics are as follows: 1 H NMR (400MHz, CDCl3) δ7.41-7.26(m,8H),7.02(dt,J=7.3,3.6Hz,1H),6.94-6.89(m,2H),6.72(dt,J=6.0, 3.7Hz, 1H), 4.74 (d, J = 10.8Hz, 1H), 3.93 (d, J = 10.8Hz, 1H), 2.73 (q, J = 7.6Hz, 2H), 1.31 (t, J = 7.6Hz, 3H).

[0050] Carbon NMR spectrum of 3'-(4-ethylphenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 4 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ166.63,156.90,149.27,145.25,144.03,140.51,130.57,129.62,129.57,128. 69,128.61,127.71,123.82,123.80,122.16,120.90,117.94,117.15,68.66,64.81,28.68,15.08,one carbon was overlapped.

[0051] Example 3 Preparation of 3'-(4-(tert-butyl)phenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid

[0052] Add a magnetic stir bar to a 25 mL Schlenk tube, then add 0.2 mmol of 3-phenyl-2H-1,4-benzoxazine, 0.3 mmol of 4-(4-(tert-butyl)phenyl)-1,1,1-trifluorobut-3-en-2-one, 0.005 mmol of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, 0.14 mmol of tertival acid, and finally add 1 mL of acetonitrile.

[0053] Using a double-row tube, a 25 mL Schlenk tube was filled with argon gas and stirred with a magnetic stirrer. The mixture was heated to 60 °C for 24 h, cooled to room temperature, and then 1.6 mmol of NaOH was added and stirred at room temperature for 12 h to obtain the product: 3'-(4-(tert-butyl)phenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid, with a yield of 68%.

[0054] The above reaction equation is as follows:

[0055]

[0056] The 1H NMR spectrum of 3'-(4-(tert-butyl)phenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 5 The characteristics are as follows: 1H NMR (400MHz, CDCl3) δ7.47-7.27(m,8H),7.03-6.98(m,1H),6.93-6.86(m,2H), 6.78-6.66(m,1H),4.71(d,J=10.8Hz,1H),3.93(d,J=10.8Hz,1H),1.35(s,9H).

[0057] The carbon NMR spectrum of 3'-(4-(tert-butyl)phenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 6 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ156.64,152.23,148.94,144.20,140.63,130.20,129.61,129.28,129.14,128. 80,128.51,125.16,123.99,123.82,122.24,121.40,118.19,117.26,68.67,64.73,34.78,31.25,one carbon was overlapped.

[0058] Example 4: Preparation of 3'-(4-chlorophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid

[0059] Add a magnetic stir bar to a 25 mL Schlenk tube, then add 0.2 mmol of 3-phenyl-2H-1,4-benzoxazine, 0.3 mmol of 4-(4-chlorophenyl)-1,1,1-trifluorobut-3-en-2-one, 0.005 mmol of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, 0.14 mmol of terpentonic acid, and finally add 1 mL of acetonitrile.

[0060] Using a double-row tube, a 25 mL Schlenk tube was filled with argon gas and stirred with a magnetic stirrer. The mixture was heated to 60 °C for 24 h, cooled to room temperature, and then 1.6 mmol of NaOH was added and stirred at room temperature for 12 h to obtain the product: 3'-(4-chlorophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid, with a yield of 51%.

[0061] The above reaction equation is as follows:

[0062]

[0063] The 1H NMR spectrum of 3'-(4-chlorophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 7 The characteristics are as follows: 1 H NMR (300MHz, CDCl3) δ7.52-7.30 (m, 8H), 7.11-7.06 (m, 1H), 6.96 (s, 2H), 6.87-6.81 (m, 1H), 4.80 (d, J = 10.8Hz, 1H), 4.00 (d, J = 10.8Hz, 1H).

[0064] Carbon NMR spectrum of 3'-(4-chlorophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 8 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ165.37,155.51,148.67,144.34,140.18,135.22,130.70,130.16,130.0 8,129.97,129.05,128.59,123.97,123.66,122.41,121.79,118.37,117.34,68.68,64.85,one carbon was overlapped.

[0065] Example 5 Preparation of 3'-(4-cyanophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid

[0066] Add a magnetic stir bar to a 25 mL Schlenk tube, then add 0.2 mmol of 3-phenyl-2H-1,4-benzoxazine, 0.3 mmol of 4-(4,4,4-trifluoro-3-oxobut-1-yl-1-yl)benzyl nitrile, 0.005 mmol of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, 0.14 mmol of terpentonic acid, and finally add 1 mL of acetonitrile.

[0067] Using a double-row tube, a 25 mL Schlenk tube was filled with argon gas and stirred with a magnetic stirrer. The mixture was heated to 60 °C for 24 h, cooled to room temperature, and then 1.6 mmol of NaOH was added and stirred at room temperature for 12 h to obtain the product: 3'-(4-cyanophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid, with a yield of 29%.

[0068] The above reaction equation is as follows:

[0069]

[0070] The 1H NMR spectrum of 3'-(4-cyanophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 9 The characteristics are as follows: 1 H NMR (400MHz, CDCl3) δ7.77(d,J=8.0Hz,2H),7.56(d,J=8.4Hz,2H),7.41-7.31(m,3H),7.15(d,J=8.0Hz,1H ),7.07-7.01(m,1H),6.99-6.88(m,2H),6.84-6.74(m,1H),4.76(d,J=10.8Hz,1H),3.97(d,J=10.8Hz,1H).

[0071] The carbon NMR spectrum of 3'-(4-cyanophenyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 10 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ164.92,154.61,148.57,144.28,139.59,137.29,132.06,131.12,130.27,129. 74,129.49,129.23,124.17,123.40,122.51,121.96,118.45,118.36,117.40,112.84,68.61,64.93.

[0072] Example 6 Preparation of 3'-(thiophene-3-yl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid

[0073] Add a magnetic stir bar to a 25 mL Schlenk tube, then add 0.2 mmol of 3-phenyl-2H-1,4-benzoxazine, 0.3 mmol of 1,1,1-trifluoro-4-(thiophen-3-yl)but-3-en-2-one, 0.005 mmol of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, 0.14 mmol of terpentonic acid, and finally add 1 mL of acetonitrile.

[0074] Using a double-row tube, a 25 mL Schlenk tube was filled with argon gas and stirred with a magnetic stirrer. The mixture was heated to 60 °C for 24 h, cooled to room temperature, and then 1.6 mmol of NaOH was added and stirred at room temperature for 12 h to obtain the product: 3'-(thiophene-3-yl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid, with a yield of 58%.

[0075] The above reaction equation is as follows:

[0076]

[0077] The 1H NMR spectrum of 3'-(thiophene-3-yl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 11 The characteristics are as follows: 1 H NMR(400MHz, CDCl3)δ7.69(s,1H),7.47-7.28(m,6H),7.07-7.00(m,1H),6.97- 6.89 (m, 2H), 6.82-6.76 (m, 1H), 4.73 (d, J = 10.8Hz, 1H), 3.95 (d, J = 10.8Hz, 1H).

[0078] Carbon NMR spectrum of 3'-(thiophene-3-yl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 12 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ165.72,150.63,148.52,144.33,140.26,131.95,130.01,129.73,129.23, 128.97,128.75,127.24,125.19,123.86,123.82,122.32,121.69,118.36,117.29,68.64,64.70.

[0079] Example 7 Preparation of 5'-fluoro-3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid

[0080] Add a magnetic stir bar to a 25 mL Schlenk tube, then add 0.2 mmol of 3-phenyl-2H-1,4-benzoxazine, 0.3 mmol of 1,1,1-trifluoro-4-(p-toluene)but-3-yn-2-one, 0.005 mmol of dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, 0.14 mmol of terpentonic acid, and finally add 1 mL of acetonitrile.

[0081] Using a double-row tube, a 25 mL Schlenk tube was filled with argon gas and stirred with a magnetic stirrer. The mixture was heated to 60 °C for 24 h, cooled to room temperature, and then 1.6 mmol of NaOH was added and stirred at room temperature for 12 h to obtain the product: 3'-(thiophene-3-yl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid, with a yield of 38%.

[0082] The above reaction equation is as follows:

[0083]

[0084] The 1H NMR spectrum of 5'-fluoro-3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 13 The characteristics are as follows: 1 H NMR (400MHz, CDCl3) δ7.35-7.27(m,5H),7.04-6.90(m,5H),6.81-6.75(m,1H),4.75(d,J=10.8Hz,1H),3.93(d,J=10.8Hz,1H),2.43(s,3H).

[0085] Carbon NMR spectrum of 5'-fluoro-3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid (see spectrum) Figure 14 The characteristics are as follows: 13 C NMR (101MHz, CDCl3) δ165.57,163.45(d,J=247.5Hz),155.54,144.38,144.18,142.83(d,J=9.1Hz),139.54,131.08,130.15,129.15,12 8.81, 128.52, 125.01 (d, J = 9.1Hz), 122.41, 121.57, 118.26, 117.31, 116.21 (d, J = 23.2Hz), 111.06 (d, J = 24.2Hz), 68.79, 64.36, 21.47.

[0086] Optimization of reaction conditions in Examples 8-11

[0087] Examples 8-11 are basically the same as Example 1, except that the additives are replaced by acetic acid, sodium acetate, and copper acetate, respectively, and the amount of each additive is adjusted to 0.2 mmol. That is, when the molar ratio of 3-phenyl-2H-1,4-benzoxazine to pivalic acid is 1:1, the yields of the product 3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid under different additive conditions are shown in Table 1.

[0088] Table 1. Product yield under different additive conditions

[0089] Serial Number additive Mole ratio Yield (%) Example 8 pivalic acid 1：1 69 Example 9 Acetic acid 1：1 55 Example 10 Sodium acetate 1：1 59 Example 11 Acetate ketone 1：1 58

[0090] As can be seen from Table 1, the product can be obtained under different additive conditions, and the yield of the product is the highest when the additive is pentanoic acid.

[0091] Optimization of Additive Dosage in Examples Twelve to Fourteen

[0092] Examples 12-14 are essentially the same as Example 1, except that the amount of the additive tervastatin was changed to 0.1 mmol, 0.24 mmol, and 0.3 mmol, respectively. Table 2 shows the yields of the product 3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid under different molar ratios of 3-phenyl-2H-benzo[b][1,4]oxazine-3,1'-indene.

[0093] Table 2 Product yield under different additive dosages

[0094] Serial Number Mole ratio Yield (%) Example 1 1：0.7 76 Example 8 1：1 69 Example 12 1：0.5 65 Example 13 1：1.2 70 Example 14 1：1.5 59

[0095] As shown in Table 2, the product can be obtained under different additive dosages. The product yield is highest when the molar ratio of 3-phenyl-2H-benzo[b][1,4]oxazine to pivalic acid is 1:0.7.

[0096] Examples 15-17: Optimization of Metal Catalysts

[0097] Examples 15-17 are essentially the same as Example 1, except that the catalyst is replaced by rhodium trichloride trihydrate, rhodium trichloride tri(triphenylphosphine)chloride, and rhodium cyclooctadienyl chloride dimer, respectively. Specifically, when the molar ratio of 3-phenyl-2H-1,4-benzoxazine to the metal catalyst is 1:0.025, the yields of the product 3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid under different metal catalyst conditions are shown in Table 3.

[0098] Table 3 Product yields under different catalyst conditions

[0099]

[0100]

[0101] As can be seen from Table 3, under different catalytic conditions, only dichloro(pentamethylcyclopentadienyl)rhodium dimer can promote the formation of the product 3'-(p-tolyl)-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-indene]-2'-carboxylic acid; the reaction does not proceed under other catalysts.

[0102] The embodiments described above are merely preferred embodiments of the present invention and are only used to explain the present invention. They are not intended to limit the scope of the present invention. For those skilled in the art, other implementation methods can be easily made by substitution or modification based on the technical content disclosed in this specification. Therefore, all changes and improvements made on the principle of the present invention should be included within the scope of the patent application of the present invention.

Claims

1. A method for the rhodium-catalyzed synthesis of non-natural β-amino acid compounds, characterized in that, Includes the following steps: Using compounds of Formula I and Formula II as starting materials, β-amino acid compounds of Formula III were synthesized by reaction under an inert atmosphere and heating conditions in the presence of a rhodium catalyst, additives, and a solvent. The rhodium catalyst was a dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, the additives were selected from pentovalinic acid, acetic acid, sodium acetate, and ketone acetate, and the solvent was acetonitrile. The specific synthetic route is as follows: ， Wherein: R1 and R2 are both selected from hydrogen or halogen, and R3 is selected from phenyl, or methyl, ethyl, tert-butyl, halogen, cyano-substituted phenyl, or five-membered heterocyclic group.

2. The method according to claim 1, characterized in that, In R3, methyl, ethyl, tert-butyl, halogen, and cyano groups are at the para position of the trifluoromethyl-terminated acetylene, and the five-membered heterocyclic group is a thiophene group.

3. The method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to the compound shown in Formula II is 1:1.

5.

4. The method according to claim 1, characterized in that, The molar ratio of the additive to the compound shown in Formula I is 1:1 to 1.

5.

5. The method according to claim 1, characterized in that, The ratio of the solvent to the compound shown in Formula I is 1 ml: 0.1 mmol.

6. The method according to claim 1, characterized in that, The reaction temperature is 60℃.

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