CN109574966B - Process for preparing naphthofuran derivatives - Google Patents

Process for preparing naphthofuran derivatives Download PDF

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CN109574966B
CN109574966B CN201910030898.XA CN201910030898A CN109574966B CN 109574966 B CN109574966 B CN 109574966B CN 201910030898 A CN201910030898 A CN 201910030898A CN 109574966 B CN109574966 B CN 109574966B
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titanium tetrachloride
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CN109574966A (en
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唐强
罗娟
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Chongqing Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/92—Naphthofurans; Hydrogenated naphthofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom

Abstract

The invention discloses a method for efficiently synthesizing a naphthofuran derivative in one step under the action of titanium tetrachloride by taking naphthol and alpha-haloketone as raw materials, which comprises the steps of adding naphthol and polyfluorool under the protection of inert gas, heating and stirring until the mixture flows back, adding titanium tetrachloride, finally, dripping a mixed solution of alpha-haloketone and polyfluorool, and separating and purifying after the reaction is finished to obtain the naphthofuran derivative. The synthesis method has the advantages of easily available raw materials, low cost, mild reaction conditions, simple and easily-controlled operation, less side reactions, simple post-treatment, high product yield, great saving of production cost, good economic benefit and suitability for industrial mass production.

Description

Process for preparing naphthofuran derivatives
Technical Field
The invention relates to a preparation method of a naphthofuran derivative, in particular to a method for efficiently synthesizing the naphthofuran derivative in one step under the action of titanium tetrachloride by taking naphthol and alpha-halogenated ketone as raw materials.
Background
Many natural products and synthetic drugs contain a naphthofuran core backbone, and molecules bearing these backbones generally exhibit unique biological properties, such as antibacterial, antifungal, antioxidant, and cytotoxic properties. Furomollugin isolated from Trichinella cunea shows significant cytotoxic activity against mitochondrial and microsomal membrane lipid peroxidation (org. Lett.2005,7 (9), 1765-1768.) in rubiaceae, xylariaphtol-1 isolated from spongiform fungi (bioorg. Med. Chem. Lett.2014, 24 (15), 3389-3391.) and Balsaminolones A isolated from balsamine bark show strong antipruritic activity (J. Am. Chem. Soc.2005, 127 (9), 2870-2871.).
Figure BSA0000177867530000011
At present, a plurality of methods for synthesizing the naphthofuran derivatives exist, such as the coupling of naphthol and alkyne by transition metal catalysis, and the like. However, these processes are often harsh in reaction conditions, require expensive metal catalysts, or are particularly difficult to obtain from the starting materials used. Simple naphthols are readily substituted with α -halo ketones under basic conditions to give phenolic ether products (biorg. Med. Chem.2015, 23 (13), 3852-3859.) which are then cyclized to naphthofuran derivatives under the action of a dehydrating reagent. (Organic & Biomolecular Chemistry 2008,6 (2), 296-307.)
Figure BSA0000177867530000021
Titanium tetrachloride is a typical lewis acid, has a strong affinity for oxygen-containing compounds, and is widely used in various functional group conversion reactions in organic chemistry. In addition, titanium tetrachloride is a very water-absorbing compound and is often used as a dehydrating reagent in the preparation and synthesis of imines or enamines. However, no report has been made in the literature on the use of titanium tetrachloride as a dehydration reagent for naphthofuran derivatives.
Disclosure of Invention
The invention aims to provide a method for efficiently preparing a naphthofuran derivative by taking naphthol and alpha-halogenated ketone as raw materials and carrying out one-step reaction under the action of titanium tetrachloride.
In order to achieve the purpose, the technical scheme provided by the invention is as follows: reacting naphthol represented by (I) or (I ') with α -haloketone represented by general formula (II) in the presence of titanium tetrachloride and a polyfluorool to obtain naphthofuran derivative represented by general formula (III) or (III'), wherein the chemical reaction formulae (A) and (B) are as follows:
Figure BSA0000177867530000022
wherein, R is 1 And R 2 Each independently selected from H or halogen, and R 1 And R 2 Is not halogen at the same time; r 3 Is selected from C 1 -C 6 Alkyl or benzyl of R 4 Selected from H, phenyl or C 1 -C 6 Alkyl groups of (a); or R 3 And R 4 Are linked together to form- (CH) 2 ) n N is 3, 4, 5 or 6; x is bromine or chlorine.
Preferably, R 1 And R 2 Are independent of each otherIs selected from H or halogen, and R 1 And R 2 Is not halogen at the same time, wherein the halogen is chlorine or bromine; r 3 Is selected from C 1 -C 4 Alkyl or benzyl of (a); r 4 Selected from H, phenyl or C 1 -C 4 Alkyl groups of (a); or R 3 And R 4 Are linked together to form- (CH) 2 ) n N is 3, 4, 5 or 6; x is bromine or chlorine.
More preferably, R 1 And R 2 Each independently selected from H or halogen, and R 1 And R 2 Not both are halogens, wherein the halogen is bromine; x is chlorine.
Wherein the polyfluorool is selected from hexafluoroisopropanol or trifluoroethanol, and the reaction is carried out under the protection of inert gas.
Wherein the reaction temperature is 0-140 ℃, the reaction time is 1-100 hours, and the molar ratio of the naphthol to the alpha-halogenated ketone to the titanium tetrachloride is 1: 1-2: 0.8-3; preferably, the reaction temperature is 20-80 ℃, the reaction time is 1-24 hours, and the molar ratio of the naphthol to the alpha-halogenated ketone to the titanium tetrachloride is 1: 1-1.5: 1-2.
The method for preparing the polysubstituted furan compound comprises the following operation steps: under the protection of inert gas, reacting naphthol with alpha-halogenated ketone in the presence of polyfluoro alcohol and titanium tetrachloride, and separating and purifying after the reaction is finished to obtain the naphthofuran derivative.
The method for preparing the polysubstituted furan compound comprises the following specific operation steps: under the protection of inert gas, adding the naphthol and the polyfluorool, heating the obtained mixture in stirring until reflux, adding titanium tetrachloride after the naphthol is completely dissolved, then dripping the mixed solution of the alpha-haloketone and the polyfluorool, carrying out reflux reaction, and after the reaction is finished, separating and purifying to obtain the naphthofuran derivative, wherein the polyfluorool is trifluoroethanol.
Wherein, the steps of separating and purifying are as follows: adding saturated ammonium chloride aqueous solution for quenching, extracting by using dichloromethane, mixing and extracting to obtain dichloromethane solution, decompressing and concentrating, and performing silica gel column chromatography separation on the obtained concentrate to obtain the naphthofuran derivative.
Compared with the existing synthetic method of the naphthofuran derivative, the method has the following advantages:
(1) The method uses titanium tetrachloride as a dehydration reagent and polyfluorool as a solvent for preparing the naphthofuran derivative by using naphthol and alpha-halogenated ketone as raw materials for the first time, has wide substrate application range, can smoothly react annular and chain alpha-halogenated ketone to prepare the naphthofuran derivative, and has practical application value.
(2) The method can efficiently synthesize a plurality of naphthofuran derivatives, has mild reaction conditions, simple operation and reduced production cost, and can be used for one-pot reaction.
(3) The synthesis method has the advantages of easily available raw materials, low cost, good regioselectivity, less side reactions, easy product separation, simple post-treatment and good yield (about 80%).
In conclusion, the synthesis method can obtain the series of naphthofuran derivatives only by one-pot reaction, has the advantages of wide substrate application range, good chemical regioselectivity, less side reactions and high product yield, greatly saves the production cost, has better economic benefit and is suitable for industrial mass production.
Detailed Description
The present invention is illustrated in detail by the following examples, but the present invention is not limited to the examples.
Example 1: synthesis of naphthofuran derivative IIIa
Figure BSA0000177867530000041
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ia (2 mmol) and hexafluoroisopropanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ia is completely dissolved, titanium tetrachloride (2 mmol) is added, and finally a mixed solution of alpha-haloketone IIa (2 mmol) and hexafluoroisopropanol (2 mL) is slowly dropped in, the reflux reaction is continued, and the reaction process is monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIa which is yellow oil with the yield of 76%.
1 H NMR(600MHz，CDCl 3 )δ8.07(d，J＝8.2Hz，1H)，7.93(d，J＝8.1Hz，1H)，7.65(d，J＝8.8Hz，1H)，7.60(d，J＝8.9Hz，1H)，7.55(t，J＝7.5Hz，1H)，7.46(t，J＝7.5Hz，1H)，6.87(s，1H)，2.56(s，3H)； 13 C NMR(150MHz，CDCl 3 )δ154.69，151.93，130.25，128.67，127.39，125.92，124.20，124.17，123.78，123.44，112.08，101.74，14.25；GC-MS(m/z)：182.1[M] + .
Example 2: synthesis of naphthofuran derivatives III' a
Figure BSA0000177867530000042
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with α -naphthol I' a (2 mmol) and trifluoroethanol (15 mL), and heated to reflux with stirring. After alpha-naphthol was completely dissolved, titanium tetrachloride (3 mmol) was added, and finally a mixed solution of alpha-haloketone IIa (3 mmol) and trifluoroethanol (2 mL) was slowly dropped in, and the reaction was continued under reflux with TLC monitoring. After completion of the reaction, the mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product III' a which is yellow oil with the yield of 78 percent.
1 H NMR(600MHz，CDCl 3 )δ8.27(d，J＝8.2Hz，1H)，7.91(d，J＝8.2Hz，1H)，7.74-7.51(m，3H)，7.45(d，J＝7.6Hz，1H)，6.51(s，1H)，2.58(s，3H)； 13 C NMR(150MHz，CDCl 3 )δ154.63，149.86，130.83，128.33，126.11，124.58，124.44，122.96，121.20，119.69，119.29，103.68，14.21.
Example 3: synthesis of naphthofuran derivative IIIb
Figure BSA0000177867530000051
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ib (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ib is completely dissolved, titanium tetrachloride (4 mmol) is added, finally, a mixed solution of alpha-halogenated ketone IIa (3 mmol) and trifluoroethanol (2 mL) is slowly dropped in, the reflux reaction is continued, and the reaction process is monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIb which is yellow oil with 89 percent of yield.
1 H NMR(600MHz，CDCl 3 )δ8.06(d，J＝1.8Hz，1H)，7.90(d，J＝8.7Hz，1H)，7.60(dd，J＝8.8，1.8Hz，2H)，7.53(d，J＝8.9Hz，1H)，6.81(s，1H)，2.55(s，3H)； 13 C NMR(150MHz，CDCl 3 )δ155.27，151.94，131.44，130.63，129.04，125.78，125.16，124.28，122.74，117.77，113.08，101.61，14.21.
Example 4: synthesis of naphthofuran derivative IIIc
Figure BSA0000177867530000052
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with naphthol Ic (2 mmol) and trifluoroethanol (10 mL), and heated to reflux while stirring. After naphthol Ic is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-halogenated ketone IIa (3 mmol) and trifluoroethanol (2 mL), continuing reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is subjected to silica gel column chromatography to obtain the target product IIIc which is yellow oil with the yield of 72 percent.
1 H NMR(600MHz，CDCl 3 )δ8.20(d，J＝1.9Hz，1H)，7.77(d，J＝8.7Hz，1H)，7.59(s，2H)，7.52(dd，J＝8.7，2.0Hz，1H)，6.80(s，1H)，2.55(d，J＝0.8Hz，3H)； 13 C NMR(150MHz，CDCl 3 )δ155.20，152.31，130.28，128.62，128.50，127.46，125.85，123.55，123.51，120.04，112.47，101.57，14.23；HRMS(ESI)calcd for C 13 H 10 BrO(M+H) + ：260.9910，Found：260.9909.
Example 5: synthesis of naphthofuran derivative IIId
Figure BSA0000177867530000061
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ia (2 mmol) and hexafluoroisopropanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ia is completely dissolved, titanium tetrachloride (6 mmol) is added, and finally a mixed solution of alpha-haloketone IIb (4 mmol) and hexafluoroisopropanol (2 mL) is slowly dropped in, the reflux reaction is continued, and the reaction process is monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIId which is yellow oil with 75 percent of yield.
1 H NMR(600MHz，CDCl 3 )δ8.40(d，J＝8.3Hz，1H)，7.96(d，J＝8.1Hz，1H)，7.65(d，J＝8.8Hz，1H)，7.63-7.53(m，2H)，7.53-7.38(m，1H)，2.57(s，3H)，2.49(s，3H)； 13 C NMR(150MHz，CDCl 3 )δ151.26，149.92，130.66，128.94，128.73，125.79，123.97，123.76，123.24，123.04，112.11，111.74，11.77，11.41.
Example 6: synthesis of naphthofuran derivatives III' b
Figure BSA0000177867530000062
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with α -naphthol (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the alpha-naphthol is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIb (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product III' b which is yellow oil with the yield of 76%.
1 H NMR(400MHz，CDCl 3 )δ8.26(d，J＝8.3Hz，1H)，7.92(d，J＝8.2Hz，1H)，7.64(d，J＝8.5Hz，1H)，7.61-7.51(m，2H)，7.51-7.36(m，1H)，2.50(s，3H)，2.24(s，3H)； 13 C NMR(101MHz，CDCl 3 )δ149.84，148.88，130.88，128.34，126.00，125.65，124.30，122.50，121.08，119.74，117.88，110.86，12.00，8.14.
Example 7: synthesis of naphthofuran derivative IIIe
Figure BSA0000177867530000071
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ia (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ia is completely dissolved, titanium tetrachloride (3 mmol) is added, and finally a mixed solution of alpha-haloketone IIc (3 mmol) and trifluoroethanol (2 mL) is slowly dropped in, the reflux reaction is continued, and the reaction process is monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIe which is yellow oily matter with the yield of 8 percent.
1 H NMR(400MHz，CDCl 3 )δ8.41(d，J＝8.3Hz，1H)，7.96(d，J＝8.1Hz，1H)，7.74-7.53(m，3H)，7.53-7.41(m，1H)，2.87(q，J＝7.6Hz，2H)，2.59(s，3H)，1.36(t，J＝7.6Hz，3H)； 13 C NMR(101MHz，CDCl 3 )δ155.03，151.28，130.65，128.95，128.86，125.79，123.99，123.74，123.25，123.07，112.21，110.84，19.58，13.20，11.29.
Example 8: synthesis of naphthofuran derivatives III' c
Figure BSA0000177867530000072
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with α -naphthol (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After alpha-naphthol is completely dissolved, titanium tetrachloride (6 mmol) is added, and finally a mixed solution of alpha-haloketone IIc (3 mmol) and trifluoroethanol (2 mL) is slowly dropped in, reflux reaction is continued, and the reaction process is monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product III' c which is yellow oil with the yield of 88 percent.
1 H NMR(600MHz，CDCl 3 )δ8.27(d，J＝8.2Hz，1H)，7.91(d，J＝8.2Hz，1H)，7.63(d，J＝8.4Hz，1H)，7.54(t，J＝7.5Hz，2H)，7.43(t，J＝7.5Hz，1H)，2.86(q，J＝7.6Hz，2H)，2.25(s，3H)，1.36(t，J＝7.6Hz，3H)； 13 C NMR(150MHz，CDCl 3 )δ154.94，148.88，130.91，128.33，125.95，125.67，124.29，122.45，121.17，119.83，117.96，109.90，19.92，13.14，8.00；HRMS(ESI)calcd for C 15 H 15 O(M+H) + ：211.1117，Found：211.1118.
Example 9: synthesis of naphthofuran derivative IIIf
Figure BSA0000177867530000081
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ia (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ia is completely dissolved, adding titanium tetrachloride (2 mmol), finally slowly dropping a mixed solution of alpha-haloketone IId (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIf which is yellow oily matter with the yield of 70%.
1 H NMR(400MHz，CDCl 3 )δ7.90(d，J＝8.2Hz，1H)，7.71(dd，J＝12.8，8.7Hz，2H)，7.63(d，J＝8.9Hz，1H)，7.58-7.44(m，5H)，7.38(t，J＝7.5Hz，1H)，7.35-7.20(m，6H)，4.08(s，2H)； 13 C NMR(101MHz，CDCl 3 )δ152.72，151.66，138.18，133.86，130.74，130.59，128.83，128.74，128.57，128.55，127.84，126.50，125.76，124.98，124.09，123.17，122.19，120.00，112.33，32.6.
Example 10: synthesis of naphthofuran derivatives III' d
Figure BSA0000177867530000082
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with α -naphthol (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the alpha-naphthol is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-haloketone IId (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product III'd which is yellow oil with the yield of 75 percent.
1 H NMR(400MHz，CDCl 3 )δ8.29(d，J＝8.2Hz，1H)，7.92(d，J＝8.1Hz，1H)，7.67(s，2H)，7.56(ddd，J＝8.1，5.1，2.1Hz，3H)，7.53-7.45(m，3H)，7.45-7.19(m，6H)，4.32(s，2H)；LCMS(ESI)calcd for C 25 H 19 O(M+H) + ：335.1，Found：335.0.
Example 11: synthesis of naphthofuran derivative IIIg
Figure BSA0000177867530000091
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ia (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ia is completely dissolved, titanium tetrachloride (2 mmol) is added, and finally a mixed solution of alpha-haloketone IIe (3 mmol) and trifluoroethanol (2 mL) is slowly dropped in, the reflux reaction is continued, and the reaction process is monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIg which is yellow oil with the yield of 83 percent.
1 H NMR(400MHz，CDCl 3 )δ8.24(d，J＝8.1Hz，1H)，7.92(d，J＝8.2Hz，1H)，7.63(d，J＝8.9Hz，1H)，7.62-7.50(m，2H)，7.44(dd，J＝11.1，4.0Hz，1H)，3.03-2.87(m，2H)，2.88-2.69(m，2H)，1.87-1.67(m，4H)，1.42(dd，J＝15.0，7.5Hz，2H)，1.06(t，J＝7.4Hz，3H)，0.96(t，J＝7.4Hz，3H)； 13 C NMR(101MHz，CDCl 3 )δ154.37，151.58，130.68，129.08，128.40，125.90，124.07，123.67，123.16，122.48，116.23，112.30，30.89，27.28，26.02，23.38，22.52，14.10，13.95；HRMS(ESI)calcd for C 19 H 23 O(M+H) + ：267.1743，Found：267.1741.
Example 12: synthesis of naphthofuran derivatives III' e
Figure BSA0000177867530000101
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with α -naphthol (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the alpha-naphthol is completely dissolved, adding titanium tetrachloride (2 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIe (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product III' e which is yellow oil with the yield of 85 percent.
1 H NMR(400MHz，CDCl 3 )δ8.26(d，J＝8.3Hz，1H)，7.90(d，J＝8.2Hz，1H)，7.57(ddd，J＝17.6，16.0，8.2Hz，3H)，7.50-7.36(m，1H)，2.82(dt，J＝9.9，7.5Hz，2H)，2.68(dd，J＝15.8，7.9Hz，2H)，1.91-1.72(m，2H)，1.67(dd，J＝15.7，7.6Hz，2H)，1.51-1.33(m，2H)，0.98(ddt，J＝16.3，8.9，7.4Hz，6H)； 13 C NMR(101MHz，CDCl 3 )δ154.11，149.12，130.80，128.28，125.93，125.02，124.30，122.32，121.23，119.82，118.30，115.78，23.46，23.41，22.60，22.47，22.12，14.05，13.92；HRMS(ESI)calcd for C 19 H 23 O(M+H) + ：267.1743，Found：267.1744.
Example 13: synthesis of naphthofuran derivative IIIh
Figure BSA0000177867530000102
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ia (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ia is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIf (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is subjected to silica gel column chromatography to obtain the target product IIIh which is yellow oil with the yield of 74 percent.
1 H NMR(400MHz，CDCl 3 )δ8.05(d，J＝8.1Hz，1H)，7.90(d，J＝8.1Hz，1H)，7.59(s，2H)，7.51(t，J＝7.4Hz，1H)，7.43(t，J＝7.5Hz，1H)，3.16-2.99(m，2H)，2.91(t，J＝7.2Hz，2H)，2.73-2.52(m，2H)； 13 C NMR(101MHz，CDCl 3 )δ162.04，157.29，130.35，128.45，127.54，125.76，124.23，124.11，123.11，122.21，121.74，113.02，27.91，25.00，23.94；HRMS(ESI)calcd for C 15 H 13 O(M+H) + ：209.0961，Found：209.0960.
Example 14: synthesis of naphthofuran derivative IIIi
Figure BSA0000177867530000111
In a 50mL two-neck flask under the protection of nitrogen, adding beta-naphthol Ia (2 mmol) and trifluoroethanol (15 mL), stirring at room temperature, adding titanium tetrachloride (3 mmol) after the beta-naphthol Ia is completely dissolved, finally slowly dropping a mixed solution of alpha-haloketone IIg (2 mmol) and trifluoroethanol (2 mL), continuing the reaction at room temperature, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIi which is yellow oil with the yield of 86%.
1 H NMR(400MHz，CDCl 3 )δ8.25(d，J＝8.2Hz，1H)，7.94(d，J＝8.1Hz，1H)，7.75-7.60(m，2H)，7.60-7.50(m，1H)，7.50-7.37(m，1H)，3.21-3.03(m，2H)，2.85(t，J＝4.8Hz，2H)，2.14-1.86(m，4H)； 13 C NMR(150MHz，CDCl 3 )δ153.30，151.48，130.55，129.48，128.73，125.68，123.82，123.65，123.52，122.51，114.34，112.29，23.75，23.16，23.12，22.62.
Example 15: synthesis of naphthofuran derivative IIIj
Figure BSA0000177867530000112
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ia (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ia is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIh (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIj which is yellow oil with the yield of 76%.
1 H NMR(400MHz，CDCl 3 )δ8.46(d，J＝8.4Hz，1H)，7.94(d，J＝8.1Hz，1H)，7.63(d，J＝8.8Hz，1H)，7.61-7.52(m，2H)，7.45(t，J＝7.5Hz，1H)，3.37-3.17(m，2H)，3.03(d，J＝5.9Hz，2H)，2.13-1.77(m，6H)； 13 C NMR(101MHz，CDCl 3 )δ155.81，150.72，130.82，129.10，128.81，125.64，124.05，123.65，123.12，123.04，118.30，112.18，29.63，28.51，27.97，26.06，25.75；HRMS(ESI)calcd for C 17 H 17 O(M+H) + ：237.1274，Found：237.1276.
Example 16: synthesis of naphthofuran derivative IIIk
Figure BSA0000177867530000121
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ia (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ia is completely dissolved, titanium tetrachloride (3 mmol) is added, and finally a mixed solution of alpha-haloketone IIi (2 mmol) and trifluoroethanol (2 mL) is slowly dropped in, the reflux reaction is continued, and the reaction process is monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIk which is yellow oil with the yield of 78 percent.
1 H NMR(400MHz，CDCl 3 )δ8.37(d，J＝8.3Hz，1H)，7.95(d，J＝8.1Hz，1H)，7.62(q，J＝8.8Hz，2H)，7.58-7.52(m，1H)，7.50-7.42(m，1H)，3.30-3.12(m，2H)，3.12-2.88(m，2H)，1.96(dt，J＝12.6，6.3Hz，2H)，1.89-1.73(m，2H)，1.68-1.53(m，2H)，1.46(dd，J＝11.2，5.5Hz，2H)； 13 C NMR(101MHz，CDCl 3 )δ154.96，151.33，130.64，128.98，128.58，125.83，123.80，123.76，123.04，122.55，115.64，112.39，29.58，28.14，26.67，25.96，25.75，23.25；HRMS(ESI)calcd for C 18 H 19 O(M+H) + ：251.1430，Found：251.1435.
Example 17: synthesis of naphthofuran derivatives III' f
Figure BSA0000177867530000131
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with α -naphthol (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the alpha-naphthol is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIg (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product III' f which is yellow oil with the yield of 92 percent.
1 H NMR(400MHz，CDCl 3 )δ8.29(d，J＝8.3Hz，1H)，7.93(d，J＝8.2Hz，1H)，7.65(d，J＝8.4Hz，1H)，7.61-7.50(m，2H)，7.51-7.37(m，1H)，2.99-2.81(m，2H)，2.81-2.61(m，2H)，2.14-1.96(m，2H)，1.96-1.80(m，2H)；LCMS(ESI)calcd for C 16 H 15 O(M+H) + ：223.1，Found：223.3.
Example 18: synthesis of naphthofuran derivatives III' g
Figure BSA0000177867530000132
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with α -naphthol (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the alpha-naphthol is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIh (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product III' g which is yellow oil with the yield of 85 percent.
1 H NMR(400MHz，CDCl 3 )δ8.25(d，J＝8.3Hz，1H)，7.91(d，J＝8.2Hz，1H)，7.63(d，J＝8.5Hz，1H)，7.54(ddd，J＝8.5，5.5，2.0Hz，2H)，7.43(ddd，J＝8.1，6.9，1.2Hz，1H)，3.14-2.97(m，2H)，2.89-2.71(m，2H)，2.00-1.75(m，6H)； 13 C NMR(101MHz，CDCl 3 )δ155.84，148.15，130.78，128.34，125.99，125.66，124.24，122.47，121.22，119.76，117.70，117.15，30.77，29.35，28.42，26.54，23.47.
Example 19: synthesis of naphthofuran derivatives III' h
Figure BSA0000177867530000141
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with α -naphthol (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the alpha-naphthol is completely dissolved, adding titanium tetrachloride (2 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIi (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product III' h which is yellow oily matter with the yield of 87 percent.
1 H NMR(400MHz，CDCl 3 )δ8.29(d，J＝8.3Hz，1H)，7.93(d，J＝8.2Hz，1H)，7.65(d，J＝8.5Hz，1H)，7.57(t，J＝8.1Hz，2H)，7.45(t，J＝7.4Hz，1H)，3.18-2.99(m，2H)，2.99-2.82(m，2H)，2.03-1.72(m，4H)，1.68-1.44(m，4H)； 13 C NMR(101MHz，CDCl 3 )δ154.31，148.79，130.84，128.38，126.01，125.18，124.26，122.48，121.30，119.80，117.69，114.96，28.34，27.60，26.46，26.10，25.58，21.61.
Example 20: synthesis of naphthofuran derivative IIIl
Figure BSA0000177867530000142
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ib (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ib is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIf (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIl which is yellow oil with the yield of 72 percent.
1 H NMR(600MHz，CDCl 3 )δ8.06(s，1H)，7.93(d，J＝8.7Hz，1H)，7.60(dd，J＝18.5，8.8Hz，2H)，7.51(d，J＝8.9Hz，1H)，3.06(t，J＝6.8Hz，2H)，3.00-2.89(m，2H)，2.77-2.56(m，2H)； 13 C NMR(150MHz，CDCl 3 )δ162.72，157.31，131.53，130.44，128.92，125.91，125.81，122.09，122.02，121.83，117.87，114.03，27.87，25.00，23.82；HRMS(ESI)calcd for C 15 H 12 BrO(M+H) + ：287.0066，Found：287.0068.
Example 21: synthesis of naphthofuran derivative IIIm
Figure BSA0000177867530000151
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ib (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ib is completely dissolved, adding titanium tetrachloride (4 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIg (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is subjected to silica gel column chromatography to obtain the target product IIIm which is yellow oily matter with the yield of 78 percent.
1 H NMR(400MHz，CDCl 3 )δ8.04(dd，J＝9.2，5.4Hz，2H)，7.68-7.53(m，2H)，7.49(d，J＝8.9Hz，1H)，3.00(t，J＝4.8Hz，2H)，2.83(t，J＝5.0Hz，2H)，2.04-1.84(m，4H)； 13 C NMR(101MHz，CDCl 3 )δ153.90，151.49，131.77，130.66，128.77，126.83，125.16，122.65，122.60，117.46，114.14，113.28，23.72，23.02，23.01，22.54；HRMS(ESI)calcd for C 16 H 14 BrO(M+H) + ：301.0223，Found：301.0220.
Example 22: synthesis of naphthofuran derivative IIIn
Figure BSA0000177867530000152
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ib (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ib is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIh (2 mmol) and trifluoroethanol (2 mL), continuing reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIn which is yellow oily matter with the yield of 70%.
1 H NMR(400MHz，CDCl 3 )δ8.29(d，J＝9.0Hz，1H)，8.06(d，J＝2.0Hz，1H)，7.56(ddd，J＝25.1，13.7，5.5Hz，3H)，3.34-3.09(m，2H)，3.01(d，J＝6.1Hz，2H)，2.06-1.76(m，6H)； 13 C NMR(101MHz，CDCl 3 )δ156.41，150.74，132.13，130.98，128.68，127.17，124.81，123.20，123.00，118.09，117.23，113.21，29.51，28.46，27.87，25.97，25.70；HRMS(ESI)calcd for C 17 H 16 BrO(M+H) + ：315.0379，Found：315.0381.
Example 23: synthesis of naphthofuran derivative IIIo
Figure BSA0000177867530000161
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ib (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ib is completely dissolved, adding titanium tetrachloride (2 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIi (2 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIo which is yellow oil with the yield of 72 percent.
1 H NMR(600MHz，CDCl 3 )δ8.20(s，1H)，8.07(s，1H)，7.60(s，2H)，7.52(s，1H)，3.13(s，2H)，2.98(s，2H)，1.93(s，2H)，1.78(s，2H)，1.58(s，2H)，1.45(s，2H)； 13 C NMR(150MHz，CDCl 3 )δ155.53，151.36，131.97，130.89，128.89，126.97，124.71，122.76，122.71，117.36，115.51，113.39，29.46，27.98，26.64，25.96，25.66，23.25；HRMS(ESI)calcd for C 18 H 18 BrO(M+H) + ：329.0536，Found：329.0534.
Example 24: synthesis of naphthofuran derivative IIIp
Figure BSA0000177867530000171
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ic (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ic is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIf (3 mmol) and trifluoroethanol (2 mL), continuing the reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is subjected to silica gel column chromatography to obtain the target product IIIp which is yellow oil with the yield of 76%.
1 H NMR(600MHz，CDCl 3 )δ8.18(d，J＝1.9Hz，1H)，7.78(d，J＝8.7Hz，1H)，7.59(dd，J＝22.5，8.9Hz，2H)，7.52(dd，J＝8.7，2.0Hz，1H)，3.15-3.02(m，2H)，3.02-2.84(m，2H)，2.68(dd，J＝14.2，7.4Hz，2H)；HRMS(ESI)calcd for C 15 H 12 BrO(M+H) + ：287.0066，Found：287.0069.
Example 25: synthesis of naphthofuran derivative IIIq
Figure BSA0000177867530000172
A50 mL two-necked flask equipped with a reflux condenser and under nitrogen protection was charged with β -naphthol Ic (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ic is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-halogenated ketone IIg (3 mmol) and trifluoroethanol (2 mL), continuing reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIq which is yellow oil with the yield of 78 percent.
1 H NMR(400MHz，CDCl 3 )δ8.31(d，J＝1.8Hz，1H)，7.76(d，J＝8.7Hz，1H)，7.64-7.53(m，2H)，7.50(dd，J＝8.7，1.9Hz，1H)，3.04(t，J＝4.7Hz，2H)，2.83(t，J＝4.9Hz，2H)，1.96(dd，J＝6.7，3.9Hz，4H)； 13 C NMR(101MHz，CDCl 3 )δ153.76，151.87，130.31，129.49，128.89，127.12，125.79，123.42，121.82，119.84，114.12，112.68，23.71，22.97，22.92，22.53；HRMS(ESI)calcd for C 16 H 14 BrO(M+H) + ：301.0223.Found：301.0220.
Example 26: synthesis of naphthofuran derivative IIIr
Figure BSA0000177867530000181
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ic (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ic is completely dissolved, adding titanium tetrachloride (2 mmol), finally slowly dropping a mixed solution of alpha-haloketone IIh (2 mmol) and trifluoroethanol (2 mL), continuing reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIr which is yellow oily matter with the yield of 70%.
1 H NMR(400MHz，CDCl 3 )δ8.54(d，J＝1.7Hz，1H)，7.78(d，J＝8.7Hz，1H)，7.66-7.45(m，3H)，3.31-3.10(m，2H)，3.01(d，J＝6.2Hz，2H)，2.10-1.73(m，6H)； 13 C NMR(101MHz，CDCl 3 )δ156.27，151.14，130.62，129.83，129.18，126.93，125.48，123.80，122.35，119.86，118.06，112.59，29.51，28.47，27.88，25.97，25.58；HRMS(ESI)calcd for C 17 H 16 BrO(M+H) + ：315.0379，Found：315.0377.
Example 27: synthesis of naphthofuran derivative IIIs
Figure BSA0000177867530000182
A50 mL two-necked flask equipped with a reflux condenser and protected with nitrogen was charged with β -naphthol Ic (2 mmol) and trifluoroethanol (10 mL), and heated to reflux with stirring. After the beta-naphthol Ic is completely dissolved, adding titanium tetrachloride (3 mmol), finally slowly dropping a mixed solution of alpha-halogenated ketone IIi (3 mmol) and trifluoroethanol (2 mL), continuing reflux reaction, and monitoring the reaction process by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is decompressed and concentrated, and then is separated by silica gel column chromatography to obtain the target product IIIs which is yellow oily matter with the yield of 72 percent.
1 H NMR(600MHz，CDCl 3 )δ8.45(d，J＝1.8Hz，1H)，7.78(d，J＝8.7Hz，1H)，7.58(d，J＝1.9Hz，2H)，7.51(dd，J＝8.7，1.9Hz，1H)，3.22-3.09(m，2H)，3.09-2.86(m，2H)，2.07-1.90(m，2H)，1.88-1.73(m，2H)，1.58(d，J＝6.3Hz，2H)，1.52-1.40(m，2H)； 13 C NMR(150MHz，CDCl 3 )δ155.33，151.73，130.53，129.68，129.05，127.06，125.39，123.59，121.90，120.03，115.53，112.77，29.39，27.87，26.66，26.02，25.61，23.22；HRMS(ESI)calcd for C 18 H 18 BrO(M+H) + ：329.0536，Found：329.0538。

Claims (3)

1. A process for producing a naphthofuran derivative, characterized in that: reacting naphthol represented by (I) or (I ') with α -haloketone represented by general formula (II) in the presence of titanium tetrachloride and a polyfluorool to obtain naphthofuran derivative represented by general formula (III) or (III'), wherein the chemical reaction formulae (A) and (B) are as follows:
Figure FSB0000201477730000011
wherein R is 1 And R 2 Each independently selected from H or halogen, and R 1 And R 2 Is not simultaneously halogen, wherein the halogen is chlorine or bromine; r 3 Is selected from C 1 -C 4 Alkyl or benzyl of (a); r 4 Selected from H, phenyl or C 1 -C 4 Alkyl groups of (a); or R 3 And R 4 Are linked together to form- (CH) 2 ) n -n is 3, 4, 5 or 6; x is bromine or chlorine; the polyfluorool is selected from hexafluoroisopropanol or trifluoroethanol; the molar ratio of the naphthol to the alpha-halogenated ketone to the titanium tetrachloride is 1 to (1-1.5) to (1-2);
the specific operation steps are as follows: under the protection of inert gas, adding the naphthol and the polyfluorool, heating the obtained mixture in stirring until refluxing, after the naphthol is completely dissolved, adding titanium tetrachloride, then dripping the mixed solution of the alpha-haloketone and the polyfluorool, carrying out reflux reaction, and after the reaction is finished, separating and purifying to obtain the naphthofuran derivative.
2. The method of claim 1, wherein R is 1 And R 2 Each independently selected from H or halogen, and R 1 And R 2 Not both are halogens, wherein the halogen is bromine; x is chlorine.
3. The method according to claim 1, wherein the step of separating and purifying comprises: adding saturated ammonium chloride aqueous solution for quenching, extracting by using dichloromethane, mixing and extracting to obtain dichloromethane solution, decompressing and concentrating, and performing silica gel column chromatography separation on the obtained concentrate to obtain the naphthofuran derivative.
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