Method for preparing azlactone self-coupling body by converting amino acid with sulfur hexafluoride
By using sulfur hexafluoride as an oxidation reagent and a photocatalyst, the cost and cumbersome steps in the prior art are solved, and a safe and inexpensive preparation of azalactone self-coupled body is achieved.
Patent Information
- Application Number
- CN202411685024.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-11-22
- Publication Date
- 2025-02-25
AI Technical Summary
The prior art requires a large amount of metal catalyst and excess oxidizing agent when preparing azlactone self-coupling, resulting in high reaction costs and cumbersome steps.
The amino acids are converted into azlactone self-coupled by photocatalytic reaction, and photocatalysts such as tris(2-phenylpyridine) iridium are used to combine alkaline additives and solvents to react under light conditions.
A safe, cheap and universal preparation of azlactone self-coupling is achieved, avoiding the use of metal catalysts and high oxidants, reducing reaction costs, and simplifying steps.
Smart Images
Figure CN119504598A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for preparing an azlactone self-coupler by converting amino acids with sulfur hexafluoride. Background Art
[0002] α,α disubstituted amino acids are important structures in natural products and bioactive molecules. The synthesis of amino acid derivatives through functionalization reactions at the C-4 site of azlactones is an important means of synthesizing α,α disubstituted amino acids. Many reaction examples have confirmed the existence of azlactone self-coupling active intermediates in the functionalization reactions of azlactones.
[0003] In 2015, the Kozlowski group reported an example of palladium-catalyzed selective coupling of azlactones with alkyl carbon-hydrogen bonds (Curto JM; MC Kozlowski. J. Am. Chem. Soc., 2015, 137, 18-21.). The authors prepared the azlactone self-coupling intermediate in advance and put it into the reaction. Under this condition, the reaction did not require the addition of an oxidant and the reaction yield remained stable.
[0004] In 2018, Ohshima's group used ferric chloride as a catalyst to complete the carbonyl α-position carbon-hydrogen bond activation and azlactone coupling (Tanaka T.; T. Tanaka; T. Tsuji; R. Yazaki; T. Ohshima. Org. Lett., 2018, 20, 3541-3544.). When using tert-butyl peroxide as an oxidant, azlactone self-coupling as a reactant can obtain a cross-coupling product in high yield.
[0005] In 2020, Ohshima's group used oxygen as an oxidant to achieve the coupling of azlactones with heteroaromatic rings under iron catalysis (Tsuji T.; T. Tanaka; T. Tanaka; R. Yazaki; T. Ohshima. Org. Lett., 2020, 22, 4164-4170.). In this reaction, azlactone self-coupled product can be obtained in a small amount in the absence of an oxidant, and the self-coupled product shows higher reactivity in the absence of a ligand.
[0006] The above method requires a large amount of metal catalyst and excess oxidant, and has the problems of high reaction cost and complicated steps, which limits its application. Summary of the invention
[0007] The technical problem to be solved by the present invention is how to prepare azlactone self-couplers safely, cheaply and universally.
[0008] The present invention solves the above technical problems through the following technical means:
[0009] A method for preparing azlactone self-coupler by converting amino acid with sulfur hexafluoride, comprising the following steps: placing a photocatalyst, amino acid and alkaline additive in a reaction device, maintaining a sulfur hexafluoride atmosphere by replacing the gas in the reaction device with sulfur hexafluoride, adding a solvent, sealing the reaction device and reacting under light conditions;
[0010] Wherein, the photocatalyst is a mixture of one or more of tris(2-phenylpyridine)iridium, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, tris(2-(4-trifluoromethylphenyl)pyridine)iridium, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl]phenyl]iridium(III) hexafluorophosphate, tris(4,7-diphenyl-1,10-phenanthroline)ruthenium dichloride, and 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile;
[0011] The amino acid is a mixture of one or more of N-benzoyl valine, N-benzoyl alanine, N-benzoyl phenylalanine and N-benzoyl methionine.
[0012] Preferably, the photocatalyst is tris(2-phenylpyridine)iridium.
[0013] Preferably, the alkaline additive is potassium carbonate or potassium carbonate and A mixture of molecular sieves.
[0014] Preferably, the alkaline additive is potassium carbonate and A mixture of molecular sieves.
[0015] Preferably, the solvent is acetonitrile.
[0016] Preferably, the molar amount of the photocatalyst is 1-10% of the molar amount of the amino acid.
[0017] Preferably, the usage ratio of the alkaline additive and the amino acid is 55-105 mg:0.2 mmol.
[0018] Preferably, the usage ratio of the amino acid to the solvent is 0.2 mmol: 1-2 ml.
[0019] Preferably, the light source of the illumination is a 450nm LED blue light source with a power of 3W.
[0020] Preferably, the reaction time is 6-48h.
[0021] The invention also provides an application of sulfur hexafluoride in converting amino acids to prepare azlactone self-couplers.
[0022] Preferably, the amino acid is a mixture of one or more of N-benzoyl valine, N-benzoyl alanine, N-benzoyl phenylalanine and N-benzoyl methionine.
[0023] Preferably, the application process includes the following steps: placing a photocatalyst, an amino acid, and an alkaline additive in a reaction device, using sulfur hexafluoride to replace the gas in the reaction device to maintain a sulfur hexafluoride atmosphere, adding a solvent, and sealing the reaction device to react under light conditions;
[0024] The photocatalyst is a mixture of one or more of tris(2-phenylpyridine)iridium, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, tris(2-(4-trifluoromethylphenyl)pyridine)iridium, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl]phenyl]iridium(III) hexafluorophosphate, tris(4,7-diphenyl-1,10-phenanthroline)ruthenium dichloride, and 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile.
[0025] The advantages of the present invention are:
[0026] In the method of the present invention, amino acids are used as reaction raw materials, sulfur hexafluoride is used as an oxidizing agent to carry out a photocatalytic reaction, and the amino acids are cyclized and self-coupled to prepare azlactone self-couplers. Sulfur hexafluoride is used as a mild oxidant to act on a variety of natural amino acids to synthesize azlactone self-couplers safely, cheaply and universally, and the azlactone self-couplers can be used as drug intermediates. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 is the H NMR spectrum of the product in Example 1 of the present invention;
[0028] Figure 2 is the NMR carbon spectrum of the product in Example 1 of the present invention;
[0029] Figure 3 is the H NMR spectrum of the product in Example 11 of the present invention;
[0030] Figure 4 is the NMR carbon spectrum of the product in Example 11 of the present invention;
[0031] Figure 5 is the H NMR spectrum of the product in Example 12 of the present invention;
[0032] Figure 6 is the NMR carbon spectrum of the product in Example 12 of the present invention;
[0033] Figure 7 is the H NMR spectrum of the product in Example 13 of the present invention;
[0034] Figure 8 This is the NMR carbon spectrum of the product in Example 13 of the present invention. DETAILED DESCRIPTION
[0035] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0036] Unless otherwise specified, the test materials and reagents used in the following examples can be obtained from commercial sources.
[0037] If no specific techniques or conditions are specified in the examples, they can be carried out according to the techniques or conditions described in the literature in the art or according to the product instructions.
[0038] Example 1
[0039] A method for preparing an azlactone self-coupler by converting amino acids using sulfur hexafluoride, comprising the following steps:
[0040] Reaction system photocatalyst screening: tris(2-phenylpyridine)iridium (Ir(ppy)3)
[0041] (1) Photocatalyst and reactants Weigh tris(2-phenylpyridine)iridium (Ir(ppy)3, 1.3 mg, 0.002 mmol), N-benzoylvaline (44.2 mg, 0.2 mmol), and potassium carbonate (55.0 mg, 0.4 mmol) and place them in a dry 25 mL Schlenk tube.
[0042] (2) Gas replacement: Place an A615 polytetrafluoroethylene magnetic stirrer in a 25 mL Schlenk tube containing the weighed drug, screw on the polytetrafluoroethylene stopcock to seal the tube opening, and connect the tube cavity to the branch tube opening. Take a high vacuum three-way gas valve with a stopper, and connect its interfaces to the Schlenk tube, vacuum pump, and sulfur hexafluoride gas. Connect the Schlenk tube and the vacuum pump, and extract the air in the tube (for more than 10 seconds); connect the sulfur hexafluoride gas and the Schlenk tube, and add sulfur hexafluoride gas (for more than 3 seconds). One set of extraction and deflation is a ventilation cycle. Repeat the ventilation 5 times and stay in the deflation state to make the tube have a positive pressure of pure sulfur hexafluoride gas.
[0043] (3) Solvent addition: Open the stopcock of the Schlenk tube, quickly inject ultra-dry acetonitrile (2 mL) in a sulfur hexafluoride gas atmosphere, close the stopcock to completely seal the lumen of the Schlenk tube, and disconnect the vacuum pump and sulfur hexafluoride gas.
[0044] (4) Reaction conditions: Place the sealed Schlenk tube into a parallel light reactor, set the conditions to 450 nm LED blue light source, 3 W power, 800 rpm magnetic stirring speed, and react for 24 h.
[0045] Reaction results: 25.1 mg of N-benzoyl valine, 65% isolation yield, dr = 4:1 to obtain azlactone self-coupling product 4,4'-diisopropyl-2,2'-diphenyl-[4,4'-dioxazole]-5,5'(4H, 4'H)-dione (1), the NMR spectrum of which is shown in Figure 1-2 As shown, the NMR data are as follows: 1 H NMR(600MHz,Chloroform-d)δ7.99(dd,J=8.2,1.4Hz,1H),7.83–7.79(m,3H),7.61–7.54(m,0.4H),7.49–7.39(m,2.6H),7.31(t,J=7.8Hz,3H),2.92(h) ept,J=6.5Hz,0.4H),2.76(hept,J=6.7Hz,1.6H),1.42(d,J=6.7Hz,4.8H), 1.34(d,J=6.6Hz,1.2H), 0.91(d,J=6.7Hz,4.8H), 0.83(d,J=6.8Hz,1.2H).
[0046] 13 C NMR(151MHz,Chloroform-d)δ178.19,176.38,162.45,161.40,133.04,132.94,128.88,128 .68,128.45,128.13,125.13,80.61,32.04,31.82,19.11(d,J=17.8Hz),18.92(d,J=12.9Hz)
[0047] Example 2
[0048] The only difference from Example 1 is that (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate ([Ir(dtBbpy)(ppy)2][PF6], 1.8 mg, 0.002 mmol) is used instead of tris(2-phenylpyridine)iridium (Ir(ppy)3) in Example 1, and the remaining steps are the same as in Example 1.
[0049] Reaction results: N-benzoyl valine was obtained as an azlactone self-coupling product with an isolation yield of 14.7 mg and a yield of 38% and a dr of 4:1.
[0050] Example 3
[0051] The only difference from Example 1 is that tris(2-(4-trifluoromethylphenyl)pyridine)iridium (Ir(4-CF3ppy)3, 1.7 mg, 0.002 mmol) is used instead of tris(2-phenylpyridine)iridium (Ir(ppy)3) in Example 1, and the remaining steps are the same as Example 1.
[0052] Reaction results: N-benzoyl valine was obtained as an azlactone self-coupling product with an isolation yield of 10.0 mg and a yield of 26% and a dr of 4:1.
[0053] Example 4
[0054] The only difference from Example 1 is that (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl]phenyl]iridium(III) hexafluorophosphate ([Ir(dFCF3ppy)2dtbpy]PF6, 2.2 mg, 0.002 mmol) is used instead of tri(2-phenylpyridine)iridium (Ir(ppy)3) in Example 1, and the remaining steps are the same as in Example 1.
[0055] Reaction results: N-benzoyl valine was obtained as an azlactone self-coupling product with an isolation yield of 18.1 mg and a yield of 47% and a dr of 4:1.
[0056] Example 5
[0057] The only difference from Example 1 is that tri(4,7-diphenyl-1,10-phenanthroline)ruthenium dichloride ([Ru(4,7-dPh-1,10-phen)3]Cl2, 2.3 mg, 0.002 mmol) is used instead of tri(2-phenylpyridine)iridium (Ir(ppy)3) in Example 1, and the remaining steps are the same as in Example 1.
[0058] Reaction results: N-benzoyl valine was obtained as azlactone self-coupling product with an isolated yield of 6.6 mg and 17%.
[0059] Example 6
[0060] The only difference from Example 1 is that 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile (16.0 mg, 0.02 mmol) is used instead of tris(2-phenylpyridine)iridium (Ir(ppy)3) in Example 1, and the remaining steps are the same as in Example 1.
[0061] Reaction results: N-benzoyl valine was obtained as an azlactone self-coupling product with an isolation yield of 16.6 mg and a yield of 43% and a dr of 4:1.
[0062] Example 7
[0063] The only difference from Example 1 is that the volume of ultra-dry acetonitrile is 1 mL, and the remaining steps are the same as those in Example 1.
[0064] Reaction results: N-benzoyl valine was obtained as an azlactone self-coupling product with 23.2 mg, 60% isolation yield, dr=4:1.
[0065] Example 8
[0066] The only difference from Example 1 is that the reaction time is 48 hours, and the other steps are the same as Example 1.
[0067] Reaction results: N-benzoyl valine was obtained as an azlactone self-coupling product with 27.0 mg, 70% isolation yield, dr=4:1.
[0068] Example 9
[0069] The only difference from Example 1 is that the reaction time is 6 hours, and the other steps are the same as Example 1.
[0070] Reaction results: N-benzoyl valine was isolated in an amount of 4.6 mg and a yield of 12% to obtain an azlactone self-coupling product.
[0071] Example 10
[0072] The difference from Example 1 is that: (1) Photocatalyst and reactants are weighed: Weigh tris(2-phenylpyridine)iridium (Ir(ppy)3, 1.3 mg, 0.002 mmol) and N-benzoylvaline (44.2 mg, 0.2 mmol), potassium carbonate (55.0 mg, 0.4 mmol), Molecular sieves (50 mg) were placed in a dry 25 mL Schlenk tube. The remaining steps were the same as in Example 1.
[0073] Reaction results: N-benzoyl valine was obtained as an azlactone self-coupling product with an isolation yield of 29.3 mg and a yield of 76% and a dr of 4:1.
[0074] Embodiment 11
[0075] The only difference from Example 10 is that N-benzoylalanine (38.4 mg, 0.2 mmol) is used instead of N-benzoylvaline in Example 10, and the remaining steps are the same as Example 10.
[0076] Reaction results: 26.8 mg of N-benzoylalanine was obtained with a 77% isolated yield to obtain the self-coupled product 4,4'-dimethyl-2,2'-diphenyl-[4,4'-dioxazole]-5,5'(4H, 4'H)-dione (2). Its NMR spectrum is shown in Figure 3-4 As shown, the NMR data are as follows:
[0077] 1 H NMR (400MHz, Chloroform-d) δ7.86–7.79(m,4H),7.51–7.41(m,2H),7.38–7.30(m,4H),1.81(s,6H).;
[0078] 13 C NMR (151MHz, Chloroform-d) δ176.83,162.42,133.11,128.77,128.15,125.18,71.81,17.48.
[0079] Example 12
[0080] The only difference from Example 10 is that N-benzoylphenylalanine (53.8 mg, 0.2 mmol) is used instead of N-benzoylvaline in Example 10, and the remaining steps are the same as Example 10.
[0081] Reaction results: 28.5 mg of N-benzoylphenylalanine was obtained with a 57% isolated yield to obtain the self-coupled product 4,4'-dibenzyl-2,2'-diphenyl-[4,4'-dioxazole]-5,5'(4H, 4'H)-dione (3). Its NMR spectrum is shown in Figure 5-6 As shown, the NMR data are as follows:
[0082] 1 H NMR(600MHz,Chloroform-d)δ7.63–7.59(m,4H),7.38(tt,J=7.3,1.3Hz,2H),7.24(t,J=7.7Hz,4H),7. 22–7.19(m,4H),7.18–7.13(m,4H),7.13–7.09(m,2H),4.02(d,J=13.1Hz,2H),3.57(d,J=13.1Hz,2H);
[0083] 13C NMR(151MHz,Chloroform-d)δ176.19,162.13,133.33,132.86,130.69,128.57,128.34,127.97,127.52,124.94,76.72,36.45,
[0084] Example 13
[0085] The only difference from Example 10 is that N-benzoylmethionine (50.6 mg, 0.2 mmol) is used instead of N-benzoylvaline in Example 10, and the remaining steps are the same as Example 10.
[0086] Reaction results: 35.3 mg of N-benzoylmethionine was obtained with a 72% isolated yield to obtain the self-coupled product 4,4'-di(2-(methylthio)ethyl)-2,2'-diphenyl-[4,4'-dioxazole]-5,5'(4H, 4'H)-dione (4). Its NMR spectrum is shown in Figure 7-8 As shown, the NMR data are as follows:
[0087] 1 H NMR(600MHz,Chloroform-d)δ7.98(dd,J=8.3,1.4Hz,1H),7.83–7.78(m,3H),7. 63–7.57(m,0.5H),7.48(t,J=7.8Hz,1H),7.46–7.41(m,1.5H),7.31(t,J=7.8Hz, 3H),2.95(ddd,J=13.7,8.6,3.9Hz,1.5H),2.66(dd,J=8.8,6.7Hz,1H),2.52–2.4 6(m,1.5H),2.46–2.37(m,2H),2.29(ddt,J=17.0,13.2,8.5Hz,2H),2.06(s,6H);
[0088] 13 C NMR(151MHz,Chloroform-d)δ176.72,163.53,133.21,128.74,128.17,124.99,75.05,29.27,28.25,15.17,
[0089] Comparative Example 1
[0090] The operation steps and results were compared with those of the Kozlowski group (J.Am.Chem.Soc.2015,137,18-21). The article used a metal palladium catalyst and an equivalent amount of silver oxide as an oxidant to synthesize azlactone self-coupling.
[0091] (1) Operation steps: Add phenylglycine azlactone (0.23 mmol), palladium acetate (2.5 mg, 0.011 mmol), silver oxide (52 mg, 0.23 mmol) and toluene (2.3 mL) into an 8 mL vial and stir the reaction for 5 hours.
[0092] (2) Effect: Phenylglycine azlactone was obtained as azlactone self-coupled product with an isolated yield of 50.0 mg and 83%.
[0093] (3) Comparison: The present invention uses sulfur hexafluoride as a mild oxidant to directly convert amino acids into azlactone self-couplers. The reagent price is low and it is applicable to a variety of substrates. The metal palladium catalyst and silver oxide reagent used in the comparative example are expensive. In addition, the method requires the amino acid to be prepared into azlactone before being put into the reaction, which is cumbersome.
[0094] Comparative Example 2
[0095] The only difference from Example 1 is that tris(2,2'-bipyrazine)ruthenium di(hexafluoroborate) salt (1.4 mg, 0.002 mmol) is used to replace tris(2-phenylpyridine)iridium (Ir(ppy)3) in Example 1, and the remaining steps are the same as Example 1.
[0096] Reaction results: This photocatalyst failed to catalyze the reaction to obtain azlactone self-coupling product.
[0097] Comparative Example 3
[0098] The only difference from Example 10 is that N-benzoylphenylglycine (51.0 mg, 0.2 mmol) is used instead of N-benzoylvaline in Example 10, and the remaining steps are the same as Example 10.
[0099] Reaction results: N-benzoylphenylglycine was not successfully obtained as a reaction product.
[0100] The structural formula and yield of the products of Examples 10-13 are shown in Table 1:
[0101] Table 1
[0102]
[0103]
[0104] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.
Claims
1. A method for preparing azlactone self-couplers by converting amino acids using sulfur hexafluoride, characterized in that: The following steps are involved: A photocatalyst, an amino acid, and an alkaline additive are placed in a reaction device, the gas in the reaction device is replaced by sulfur hexafluoride to maintain a sulfur hexafluoride atmosphere, a solvent is added, and the reaction device is sealed to react under light conditions; Wherein, the photocatalyst is a mixture of one or more of tris(2-phenylpyridine)iridium, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridyl)phenyl]iridium(III) hexafluorophosphate, tris(2-(4-trifluoromethylphenyl)pyridine)iridium, (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl]phenyl]iridium(III) hexafluorophosphate, tris(4,7-diphenyl-1,10-phenanthroline)ruthenium dichloride, and 2,4,5,6-tetrakis(diphenylamino)-isophthalonitrile; The amino acid is a mixture of one or more of N-benzoyl valine, N-benzoyl alanine, N-benzoyl phenylalanine and N-benzoyl methionine.
2. The method for preparing azlactone self-couplers by converting amino acids using sulfur hexafluoride according to claim 1, characterized in that: The photocatalyst is tris(2-phenylpyridine)iridium.
3. The method for preparing azlactone self-coupler by converting amino acid with sulfur hexafluoride according to claim 1, characterized in that: The alkaline additive is potassium carbonate or potassium carbonate and A mixture of molecular sieves.
4. The method for preparing azlactone self-coupler by converting amino acid with sulfur hexafluoride according to claim 3, characterized in that: The alkaline additive is potassium carbonate and A mixture of molecular sieves.
5. The method for preparing azlactone self-coupler by converting amino acid with sulfur hexafluoride according to claim 1, characterized in that: The solvent is acetonitrile.
6. The method for preparing azlactone self-coupler by converting amino acid with sulfur hexafluoride according to claim 1, characterized in that: The molar amount of the photocatalyst is 1-10% of the molar amount of the amino acid.
7. The method for preparing azlactone self-coupler by converting amino acid with sulfur hexafluoride according to claim 1, characterized in that: The dosage ratio of the alkaline additive and the amino acid is 55-105 mg: 0.2 mmol.
8. The method for preparing azlactone self-coupler by converting amino acid with sulfur hexafluoride according to claim 1, characterized in that: The usage ratio of the amino acid to the solvent is 0.2mmol:1-2ml.
9. The method for preparing azlactone self-coupler by converting amino acid with sulfur hexafluoride according to claim 1, characterized in that: The light source of the illumination is a 450nm LED blue light source with a power of 3W.
10. The method for preparing azlactone self-coupler by converting amino acid with sulfur hexafluoride according to any one of claims 1 to 9, characterized in that: The reaction time is 6-48h.
11. Use of sulfur hexafluoride in converting amino acids to prepare azlactone self-couplers.
12. The use of sulfur hexafluoride according to claim 11 in converting amino acids to prepare azlactone self-couplers, characterized in that: The amino acid is a mixture of one or more of N-benzoyl valine, N-benzoyl alanine, N-benzoyl phenylalanine and N-benzoyl methionine.