Synthesis method of a phenanthridin-6(5H)-one compound

Abstract

The invention discloses a synthetic method for phenanthridine-6 (5H)-ketone compounds, comprising the following steps: N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide or its derivatives, an oxidant, and a solvent are sequentially added into a round-bottom flask, followed by reacting for 6 to 10 hours at 40-70 DEG C, cooling to room temperature, and concentrating the reaction solution under reduced pressure to remove the solvent, and separating by column chromatography to obtain phenanthridine-6 (5H)-ketone compounds. The synthetic method of the present invention belongs to a free radical reaction as analyzed from the reaction mechanism, and after the raw material is oxidized to remove the hydrazine group, intramolecular free radical cyclization occurs, and phenanthridine-6 (5H)-ketone compounds are finally generated, providing a new synthetic idea for constructing a phenanthridine ketone skeleton; and the synthetic method of the present invention: using a cheap and readily available oxidant, avoiding the use of a metal catalyst, and being environmentally friendly; having better atom economy and higher yield; mild reaction conditions, simple operation, and being convenient for industrialized production.

Description

Technical Field

[0001] The invention belongs to the field of flavors and fragrances, and particularly relates to a method for synthesizing a phenanthridin-6(5H)-one compound. Background Art

[0002] Phenanthridinones are a very important class of alkaloid organic compounds, widely present in complex natural products. Most phenanthridinone alkaloids possess a range of important biological and pharmaceutical activities. Phenanthridinones and their derivatives hold broad research and application prospects in both medicine and biology. However, the availability of naturally occurring phenanthridinone alkaloids is limited. Consequently, rapid, simple, safe, and atom-economical methods for synthesizing phenanthridinone and derivative skeletons have attracted increasing research interest.

[0003] The traditional method is to use 9-fluorenone as raw material, and to produce phenanthridinone compounds by Beckmann rearrangement reaction at high temperature under the action of NaN3 and concentrated H2SO4. [1] This type of method has harsh reaction conditions and uses explosive substances such as azide, which makes the reaction process quite dangerous. In addition, the raw materials are expensive and the types are limited.

[0004]

[0005] To this end, new synthesis methods based on transition metal catalysis have been developed in recent years.

[0006] In 2004, M. Catellani's group [2] The first intermolecular coupling reaction to synthesize a phenanthridinone skeleton is reported. This method uses aryl iodide and o-bromobenzamide as substrates, Pd(OAc)2 as catalyst, and trifurylphosphine as ligand, utilizing norbornene as a guide to achieve a one-pot synthesis of the phenanthridinone skeleton.

[0007]

[0008] In 2007, T.Furuta reported [3] The intermolecular coupling reaction was used to prepare phenanthridinone compounds. Using two molecules of o-bromobenzamide as raw materials, Pd(OAc)2 as catalyst, and monodentate phosphine ligand as the catalyst, the same intermolecular coupling reaction was achieved.

[0009]

[0010] In 2014, J.-C.Hsieh group [4] Using cuprous iodide as a catalyst, under the promotion of strong alkaline sodium hydroxide, the intramolecular coupling of 2'-bromobiphenyl-2-carbonitrile was catalyzed to construct phenanthridinone.

[0011]

[0012] In 2019, Li's group [5] The phenanthridinone skeleton was constructed by carbon-hydrogen activation, with monovalent rhodium as catalyst and triarylphosphine as ligand. Under the condition of one atmosphere of carbon dioxide gas, the carbonyl insertion reaction of 2-phenylaniline was catalyzed to construct the phenanthridinone ring.

[0013]

[0014] The above synthesis methods all have the following problems: the reaction conditions are harsh, requiring high temperature, precious metal or heavy metal catalysts, complex ligands, acid and base additives, etc.

[0015] Therefore, it is very necessary to develop a synthetic method for preparing phenanthridin-6(5H)-one compounds with high efficiency and high selectivity under mild conditions.

[0016] References:

[0017] [1]Walls,LPJChem.Soc.,1935,1405-1410.

[0018] [2] Ferraccioli R, Carenzi D, Catellani M. Org Lett. 2004; 6(25): 4759-4762.

[0019] [3]T Furuta,K Tanaka,T Kan.OrgLett.,2007,9(2),183-186.

[0020] [4]Y.-F.Chen,Y.-S.Wu,J.-C.Hsieh,Org.Chem.Front.,2014,1,253-257.

[0021] [5]Gao Y,Cai Z,Li S,Li G.Org Lett.,2019;21(10):3663-3669. Summary of the Invention

[0022] The object of the present invention is to provide a novel method for synthesizing phenanthridin-6(5H)-one compounds. The method is a free radical reaction. After the raw material is oxidized to remove the hydrazine group, intramolecular free radical cyclization occurs to ultimately generate phenanthridin-6(5H)-one compounds, providing a new synthetic idea for constructing a phenanthridinone skeleton.

[0023] To achieve the above object, the present invention adopts the following technical solutions:

[0024] A method for synthesizing a phenanthridin-6(5H)-one compound, wherein the general reaction formula of the synthesis method is:

[0025]

[0026] In the formula, R1 is hydrogen, halogen, methyl, ethyl, isopropyl, methoxy, trifluoromethyl, etc.; R2 is hydrogen, halogen, methoxy, cyano, trifluoromethyl, trifluoromethoxy, etc.

[0027] The method for synthesizing a phenanthridin-6(5H)-one compound comprises the following steps: sequentially adding N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide or a derivative thereof, an oxidant, and a solvent to a round-bottom flask, followed by reacting at 40-70°C for 6-10 hours and cooling to room temperature. The reaction solution is concentrated under reduced pressure to remove the solvent, and then separated by column chromatography to obtain a phenanthridin-6(5H)-one compound.

[0028] Furthermore, the oxidant is at least one of DTBP, TBPB, 70% TBHP, Oxone, K2S2O8, 30% H2O2 and PhI(OAc)2, preferably 70% TBHP.

[0029] Furthermore, the molar ratio of N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide or its derivative to the oxidant is 1:1 to 3, preferably 1:2.

[0030] Furthermore, the solvent is at least one of tetrahydrofuran, dioxane, dichloroethane, acetonitrile, ethyl acetate, N,N-dimethylformamide, and dimethyl sulfoxide, and the total volume of the solvent is 2 to 6 times (mL / mmol) the molar amount of the starting material (N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide or a derivative thereof). Preferably, a mixed solvent of acetonitrile and dichloroethane (volume ratio of 1:1) is selected, and the solvent volume is 3 times the molar amount of the starting material.

[0031] Furthermore, the reaction temperature is 40-70° C., and the reaction time is 6-10 hours, preferably 50° C. for 8 hours.

[0032] Furthermore, the column chromatography separation conditions are: 200-300 mesh silica gel column, and a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:1-5 as the eluent.

[0033] Furthermore, when R1 and R2 are H, the synthesis mechanism of phenanthridin-6(5H)-one is:

[0034]

[0035] N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide removes two hydrogen atoms under the action of tert-butoxy radicals and hydroxyl radicals (derived from the decomposition of TBHP under heating) to produce azo compound A, which then removes hydrogen atoms to generate azo radical B. In the reaction system, nitrogen atoms are removed to produce carbamoyl radical C. Radical 3.7 then attacks the benzene ring to generate aryl radical D, which, under the action of tert-butanol radicals (tBuO·), ultimately gives the cyclized product phenanthridin-6(5H)-one.

[0036] Compared with the prior art, the beneficial effects of the present invention are embodied in:

[0037] 1. The synthesis method of the present invention: uses cheap and readily available oxidants, avoids the use of metal catalysts, and is environmentally friendly; has good atom economy and high yield; has mild reaction conditions, simple operation, and is convenient for industrial production.

[0038] 2. The synthesis method of phenanthridin-6(5H)-one compounds provided by the present invention is a free radical reaction. After the raw materials are oxidized to remove the hydrazine group, intramolecular free radical cyclization occurs to finally generate phenanthridin-6(5H)-one compounds, providing a new synthetic idea for constructing the phenanthridinone skeleton. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The phenanthridin-6 (5H) -one prepared in Example 1 1 H NMR spectrum.

[0040] Figure 2 The phenanthridin-6 (5H) -one prepared in Example 1 13 C NMR spectrum. DETAILED DESCRIPTION

[0041] To make the above-mentioned objects, features, and advantages of the present invention more clearly understood, the following detailed description of the specific embodiments of the present invention is provided in conjunction with the accompanying drawings. The following is merely an example and illustration of the concept of the present invention. Persons skilled in the art may make various modifications, additions, or substitute similar methods for the specific embodiments described. As long as these modifications or additions do not deviate from the concept of the invention or exceed the scope defined by the claims, they shall fall within the scope of protection of the present invention.

[0042] N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide and its derivatives used in the following examples were prepared from 2-biarylamine, phenyl chloroformate and hydrazine hydrate according to the method of reference (Hron R, Jursic B S. Tetrahedron Letters, 2014, 55(9):1540-1543).

[0043] Example 1

[0044] In this embodiment, phenanthridin-6(5H)-one was prepared according to the following steps. The reaction equation is as follows:

[0045]

[0046] To a 100 mL round-bottom flask, N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide (10 mmol), MeCN / DCE (15 mL / 15 mL), and 70% TBHP (20 mmol) were added in sequence. The reaction was stirred at 50°C for 8 hours and then stopped. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and separated by silica gel column chromatography (eluent V 石油醚 :V 乙酸乙酯 The reaction mixture was reacted at a ratio of 2:1) to afford phenanthridin-6(5H)-one (white solid, yield 87%).

[0047] The product was characterized by NMR spectroscopy, and the data are as follows:

[0048] 1 H NMR (500 MHz, DMSO-d 6 )δ8.52(d,J=8.1Hz,1H),8.40(d,J=7.9Hz,1H),8.34(d,J=7.8Hz,1H),7.89–7.84(m,1H), 7.66(dd,J=11.1,3.9Hz,1H),7.53–7.48(m,1H),7.39(d,J=8.0Hz,1H),7.31–7.25(m,1H); 13 C NMR (125 MHz, DMSO-d 6 )δ166.0,141.8,139.5,138.0,134.8,133.2,132.7,130.9,128.5,127.9,127.5,122.8,121.3.

[0049] Example 2

[0050] In this embodiment, 2-methylphenanthridin-6(5-hydrogen)-one was prepared according to the following steps. The reaction equation is as follows:

[0051]

[0052] To a 100 mL round-bottom flask, N-([5-methyl-1,1'-biphenyl]-2-yl)-carbamoylhydrazide (10 mmol), MeCN / DCE (15 mL / 15 mL), and 70% TBHP (20 mmol) were added in sequence. The reaction was stirred at 50°C for 8 hours and then stopped. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and separated by silica gel column chromatography (eluent V 石油醚:V 乙酸乙酯 The reaction mixture was stirred at 2:1) to give 2-methylphenanthridin-6(5-hydrogen)-one (light yellow solid, yield 79%).

[0053] The product was characterized by NMR spectroscopy, and the data are as follows:

[0054] 1 H NMR (500 MHz, DMSO-d 6 )δ8.47(d,J=8.1Hz,1H),8.31(dd,J=7.9,1.1Hz,1H),8.18(s,1H),7.86–7.80(m,1H) ,7.65–7.59(m,1H),7.30(dd,J=8.3,1.3Hz,1H),7.26(d,J=8.2Hz,1H),2.41(s,3H); 13 C NMR (125 MHz, DMSO-d 6 )δ160.7,134.4,134.2,132.7,131.2,130.6,127.7,127.5,125.73,123.0,122.5,117.4,115.9,20.7.

[0055] Example 3

[0056] In this embodiment, 9-chlorophenanthridin-6(5-hydrogen)-one was prepared according to the following steps. The reaction equation is as follows:

[0057]

[0058] To a 100 mL round-bottom flask, N-([3'-chloro-1,1'-biphenyl]-2-yl)-carbamoylhydrazide (10 mmol), MeCN / DCE (15 mL / 15 mL), and 70% TBHP (20 mmol) were added in sequence. The reaction was stirred at 50°C for 8 hours and then stopped. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and separated by silica gel column chromatography (eluent V 石油醚 :V 乙酸乙酯 The reaction mixture was stirred at 2:1) to give 9-chlorophenanthridin-6(5-hydrogen)-one (light yellow solid, yield 84%).

[0059] The product was characterized by NMR spectroscopy, and the data are as follows:

[0060] 1 H NMR (500 MHz, DMSO-d 6)δ8.52(d,J=8.8Hz,1H),8.35(d,J=8.0Hz,1H),8.23(d,J=2.4Hz,1H),7.87(dd, J=8.7,2.4Hz,1H),7.54–7.47(m,1H),7.36(d,J=8.1Hz,1H),7.30–7.24(m,1H); 13 C NMR (125 MHz, DMSO-d 6 )δ159.7,136.5,133.1,132.7,132.7,129.9,127.2,126.6,125.2,123.4,122.5,116.9,116.2.

[0061] The above are merely exemplary embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing a phenanthridin-6(5H)-one compound, characterized in that: The general reaction formula of the synthesis method is: In the formula, R1 is hydrogen, halogen, methyl, ethyl, isopropyl, methoxy or trifluoromethyl, R2 is hydrogen, halogen, methoxy, cyano, trifluoromethyl or trifluoromethoxy; the raw material I is N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide or its derivatives, the product II is a phenanthridin-6(5H)-one compound; and the oxidant is DTBP, TBPB or 70% TBHP.

2. The method for synthesizing phenanthridin-6(5H)-one compounds according to claim 1, wherein The following steps are involved: N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide or its derivative, an oxidant, and a solvent are added sequentially to a round-bottom flask, followed by reaction at 40-70°C for 6-10 hours, cooling to room temperature, and concentrating the reaction solution under reduced pressure to remove the solvent, followed by column chromatography separation to obtain a phenanthridin-6(5H)-one compound.

3. The method for synthesizing a phenanthridin-6(5H)-one compound according to claim 2, wherein: The molar ratio of N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide or its derivative to the oxidant is 1:1-3.

4. The method for synthesizing a phenanthridin-6(5H)-one compound according to claim 2, wherein: The solvent is at least one of tetrahydrofuran, dioxane, dichloroethane, acetonitrile, ethyl acetate, N,N-dimethylformamide and dimethyl sulfoxide, and the ratio of the total volume of the solvent to the molar amount of N-([1,1'-biphenyl]-2-yl)-carbamoylhydrazide or its derivative is 2 to 6 mL / mmol.

5. The method for synthesizing a phenanthridin-6(5H)-one compound according to claim 2, wherein: The conditions for column chromatography separation are: 200-300 mesh silica gel column, using a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:1-5 as the eluent.

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