阅读说明：本技术 酮与alpha氯代酮一步反应合成呋喃类化合物的方法 (Method for synthesizing furan compound by one-step reaction of ketone and alpha chloroketone ) 是由 唐强 谭林波 于 2021-09-26 设计创作，主要内容包括：本发明提供一种以alpha-氯代酮和甲基酮或环酮为原料,在略微过量的钛酸四异丙酯作用下,无溶剂条件下一步反应制备多取代呋喃化合物的方法。即在惰性气体保护下,将甲基酮或环酮、α-氯代酮和对甲苯磺酸的反应混合物搅拌加热升温后,加入钛酸四异丙酯进行反应,反应结束后再将所得反应混合物进行分离提纯,得到多取代呋喃化合物。本发明所述的合成方法,原料易得,成本低廉,操作简单易控,无需溶剂,有良好的底物普适性和官能团兼容性,适宜于工业化大生产。(The invention provides a method for preparing a polysubstituted furan compound by using alpha-chloroketone and methyl ketone or cyclic ketone as raw materials and carrying out one-step reaction under the action of slightly excessive tetraisopropyl titanate under the solvent-free condition. Under the protection of inert gas, stirring and heating a reaction mixture of methyl ketone or cyclic ketone, alpha-chloroketone and p-toluenesulfonic acid, adding tetraisopropyl titanate for reaction, and separating and purifying the obtained reaction mixture after the reaction is finished to obtain the polysubstituted furan compound. The synthesis method has the advantages of easily available raw materials, low cost, simple and easily-controlled operation, no need of solvent, good substrate universality and functional group compatibility, and suitability for industrial mass production.)

1. The method for synthesizing furan compounds by one-step reaction of ketone and alpha chloroketone is characterized by comprising the following steps: heating alpha-chloroketone shown in general formula (I) or (IV) and ketone shown in general formula (II) or (V) in the presence of tetraisopropyl titanate to react to obtain polysubstituted furan compound shown in general formula (III) or (VI), wherein the chemical reaction formulas (A) and (B) are shown as follows:

wherein R is¹Is C₁-C₄Straight or branched chain alkyl, unsubstituted phenyl, C₁-C₄Straight-chain or branched alkyl-substituted phenyl, chlorophenyl, nitro-substituted phenyl, C₁-C₄Alkoxy-substituted phenyl, phenolic, dimethylamino-substituted phenyl, 1-naphthyl, 2-naphthyl or styryl, R²Is H, C₁-C₄Linear or branched alkyl, phenethyl or styryl groups of (a); or R¹And R²With adjacent carbon atoms thereof bound together to form- (CH)₂)_n-or C₁-C₄Straight or branched chain alkyl substituted- (CH)₂)₄-, where n is 4,5 or 6; r³Is C₁-C₄Straight or branched alkyl of R⁴Is C₁-C₄Linear or branched alkyl of (a); or R³And R⁴With adjacent carbon atoms thereof bound together to form- (CH)₂)_n-, where n is 4,5 or 6; r⁵Is C₁-C₄Linear or branched alkyl of (a); r⁶Is C₁-C₄Linear or branched alkyl of (a); or R⁵And R⁶With adjacent carbon atoms thereof bound together to form- (CH)₂)_n-, where n is 4 or 5.

2. The process for producing a polysubstituted furan compound according to claim 1, wherein said reaction is carried out in the presence of p-toluenesulfonic acid.

3. The method for producing a polysubstituted furan compound according to claim 1 or 2, wherein the molar ratio of said ketone, said α -chloroketone and tetraisopropyl titanate is 1 (1.1-1.4) to (1.1-2).

4. The method for producing a polysubstituted furan compound according to claim 1, wherein said reaction temperature is 60-100 ℃ and the reaction time is 4-72 hours.

5. The process for producing a polysubstituted furan compound according to claim 4, wherein said reaction temperature is 80 ℃ and the reaction time is 4 to 24 hours.

6. The method for producing a polysubstituted furan compound according to claim 1, wherein said reaction is carried out under an inert gas atmosphere.

7. The process for producing a polysubstituted furan compound according to claim 1, wherein said reaction is carried out in the absence of any solvent.

8. The process for producing a polysubstituted furan compound of any one of claims 1-7, which is carried out by the following steps: under the protection of inert gas, stirring and heating a reaction mixture of the ketone and the alpha-chloro ketone or a reaction mixture of the ketone, the alpha-chloro ketone and p-toluenesulfonic acid, adding tetraisopropyl titanate for reaction, quenching the reaction after the reaction is finished, and separating and purifying the obtained reaction mixture to obtain the polysubstituted furan compound.

9. The process for producing a polysubstituted furan compound of claim 8, which comprises the following steps: under the protection of inert gas, heating the reaction mixture of the ketone and the alpha-chloro ketone or the reaction mixture of the ketone, the alpha-chloro ketone and p-toluenesulfonic acid to 80 ℃, stirring for 0.5h, adding tetraisopropyl titanate for reaction, adding saturated ammonium chloride aqueous solution for quenching after the reaction is finished, extracting with dichloromethane, mixing and extracting the obtained dichloromethane solution, drying with anhydrous sodium sulfate, then concentrating under reduced pressure, and finally performing silica gel column chromatography separation on eluent to obtain the polysubstituted furan compound.

10. The process for producing a polysubstituted furan compound according to claim 9, wherein said ketone and p-toluenesulfonic acid are present in a molar ratio of 1 (0.1-0.4).

Technical Field

The invention belongs to the technical field of drug synthesis and chemical product synthesis, and particularly relates to a method for synthesizing a polysubstituted furan compound by directly reacting alpha-chloroketone and methyl ketone or cyclic ketone serving as raw materials under the action of tetraisopropyl titanate.

Background

Furans and their derivatives are widely present in almost all classes of terrestrial and marine organisms and are the core structures of many natural products. In particular, certain aryl-substituted or polycyclic fused furan derivatives generally exhibit various biological properties such as antibacterial, anticancer, antispasmodic, anti-inflammatory, antiallergic and immunosuppressive activities, and thus are rapidly becoming hot spots in the field of pharmaceutical research, and many commercially available drugs are polysubstituted furan derivatives. Furthermore, furan derivatives can also be used as flavors and fragrances in food products, as important intermediates in synthetic chemistry.

The polysubstituted furan compounds have a plurality of synthesis methods and can be prepared and synthesized from a plurality of raw materials. The simplest and most direct method is to use ketone and chloroketone as raw materials, and the synthesis strategy is divided into two strategies, namely one-step reaction and multi-step reaction to obtain the target product. Under alkaline conditions, the alpha-chloroketone and the beta-keto ester can react in one step to generate a corresponding furan product, namely a classical Feist-B nary furan synthesis reaction. In the reaction process, the beta-keto ester firstly generates nucleophilic addition reaction with carbonyl carbon of alpha-chloroketone, then intramolecular nucleophilic substitution cyclization is carried out, and finally a molecule of water is removed to generate the 3-furoate. This reaction usually requires a readily enolizable β -dicarbonyl compound as a substrate and the variety of products obtained is very limited.

Another synthesis strategy is a multi-step reaction method, firstly common ketone compounds are converted into stable enol derivatives, then the enol derivatives and alpha-chloroketone are subjected to coupling reaction to generate 1, 4-dicarbonyl compounds, and finally intramolecular cyclization dehydration is carried out to obtain the polysubstituted furan compounds. The multi-step synthesis strategy can obtain more kinds of furan, and is one of the most common methods in furan synthesis at present. However, this synthesis strategy requires a large number of steps and a low overall yield. In particular, in the last step of the reaction (i.e., the Paal-Knorr synthesis), dehydration of some 1, 4-dicarbonyl compounds to form a ring is difficult, requiring strong acid, high temperature and long reaction time, resulting in difficulty in separating many by-products.

Disclosure of Invention

The invention aims to provide a method for preparing a polysubstituted furan compound by using alpha-chloroketone and methyl ketone or cyclic ketone as raw materials and carrying out one-step reaction under the solvent-free condition under the action of slightly excessive tetraisopropyl titanate.

The purpose of the invention can be realized by the following technical scheme:

the method for synthesizing furan compounds by one-step reaction of ketone and alpha chloroketone is characterized by comprising the following steps: heating alpha-chloroketone shown in general formula (I) or (IV) and ketone shown in general formula (II) or (V) in the presence of tetraisopropyl titanate to react to obtain polysubstituted furan compound shown in general formula (III) or (VI), wherein the chemical reaction formulas (A) and (B) are shown as follows:

(A)

(B)wherein R is¹Is C₁-C₄Straight or branched chain alkyl, unsubstituted phenyl, C₁-C₄Straight-chain or branched alkyl-substituted phenyl, chlorophenyl, nitro-substituted phenyl, C₁-C₄Alkoxy-substituted phenyl, phenolic, dimethylamino-substituted phenyl, 1-naphthyl, 2-naphthyl or styryl, R²Is H, C₁-C₄Linear or branched alkyl, phenethyl or styryl groups of (a); or R¹And R²With adjacent carbon atoms thereof bound together to form- (CH)₂)_n-or C₁-C₄Straight or branched chain alkyl substituted- (CH)₂)₄-, where n is 4,5 or 6; r³Is C₁-C₄Straight or branched alkyl of R⁴Is C₁-C₄Linear or branched alkyl of (a); or R³And R⁴Adjacent carbon atom thereofThe subunits being joined together to form- (CH)₂)_n-, where n is 4,5 or 6; r⁵Is C₁-C₄Linear or branched alkyl of (a); r⁶Is C₁-C₄Linear or branched alkyl of (a); or R5 and R6 are linked together with their adjacent carbon atoms to form- (CH)₂)_n-, where n is 4 or 5.

The method for producing a polysubstituted furan compound, wherein the reaction may be carried out in the presence of p-toluenesulfonic acid.

The method for producing a polysubstituted furan compound, wherein the molar ratio of the ketone, the alpha-chloroketone and tetraisopropyl titanate is 1 (1.1-1.4) to (1.1-2); the reaction temperature is 60-100 ℃, the reaction time is 4-72h, preferably the reaction temperature is 80 ℃, and the reaction time is 4-24 h.

The method for preparing the polysubstituted furan compound is characterized in that the reaction is carried out under the protection of inert gas.

The method for producing a polysubstituted furan compound, wherein the reaction is carried out in the absence of any solvent.

The method for preparing the polysubstituted furan compound comprises the following operation steps: under the protection of inert gas, stirring and heating a reaction mixture of the ketone and the alpha-chloro ketone or a reaction mixture of the ketone, the alpha-chloro ketone and p-toluenesulfonic acid, adding tetraisopropyl titanate for reaction, quenching the reaction after the reaction is finished, and separating and purifying the obtained reaction mixture to obtain the polysubstituted furan compound.

The method for preparing the polysubstituted furan compound comprises the following specific operation steps: under the protection of inert gas, heating the reaction mixture of the ketone and the alpha-chloro ketone or the reaction mixture of the ketone, the alpha-chloro ketone and p-toluenesulfonic acid to 80 ℃, stirring for 0.5h, adding tetraisopropyl titanate for reaction, adding saturated ammonium chloride aqueous solution for quenching after the reaction is finished, extracting with dichloromethane, mixing and extracting the obtained dichloromethane solution, drying with anhydrous sodium sulfate, then carrying out reduced pressure concentration, and finally carrying out silica gel column chromatography separation on eluent to obtain the polysubstituted furan compound; wherein the molar ratio of the ketone to the p-toluenesulfonic acid is 1 (0.1-0.4).

Compared with the existing synthesis method of the polysubstituted furan compound, the synthesis method has the following advantages:

(1) the method prepares the polysubstituted furan compound from the ketone and the alpha-chloroketone under the condition of no solvent, reduces the synthesis cost and the pollution of an organic solvent to the environment, has the advantages of environmental protection, economy, environmental protection, safe and simple operation and the like, and has good application and popularization potentials.

(2) The reaction has good substrate universality and functional group compatibility.

(3) The method can efficiently synthesize a series of polysubstituted furan compounds, the required raw materials and reagents are simple, easy to obtain and low in price, the reaction condition is mild (reaction is 80 ℃), the one-pot reaction is realized, the reaction operation and the post-treatment are simple, the reaction time is short (4-24h), the production cost is reduced, the industrial production is facilitated, and the method has practical application value.

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 2, 3-dimethyl-5-phenylfuran IIIa

To a 10mL two-necked flask with a reflux condenser, 3-chloro-2-butanone Ia (1.2mmol) and acetophenone IIa (1.0mmol) were added under nitrogen. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by the mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product iiia as a colorless oil with a yield of 76%.¹H NMR(600MHz,CDCl₃)δ7.66(d,J＝7.6Hz,2H),7.39(t,J＝7.8Hz,2H), 7.25(dd,J＝12.7,5.2Hz,1H),6.49(s,1H),2.32(s,3H),2.03(s,3H)；¹³C NMR (151MHz,CDCl₃)δ150.96,147.40,131.33,128.64,126.62,123.24,116.20,108.48, 11.55,10.02；HRMS(ESI)calcd for C₁₂H₁₃O(M+H)⁺:173.0961,Found:173.0965.

Example 2: synthesis of 2, 3-dimethyl-5- (2-methylphenyl) furan IIIb

Under the protection of nitrogen, 3-chloro-2-butanone Ia (1.0mmol) and o-methylacetophenone IIb (1.0mmol) were added to a 10mL two-necked flask with a reflux condenser. After the reaction mixture was warmed to 80 ℃ and stirred for 0.5h, tetraisopropyl titanate (1.2mmol) was added and the reaction was monitored by TLC continuously during the reaction. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is dried by anhydrous sodium sulfate, then is concentrated under reduced pressure, and finally is separated by silica gel column chromatography (taking ethyl acetate-hexane as eluent) to obtain the target product 2, 3-dimethyl-5- (2-methylphenyl) furan IIIb as a light yellow oily substance with the yield of 74%.¹H NMR(600MHz,CDCl₃)δ7.70 (d,J＝7.9Hz,1H),7.26–7.20(m,2H),7.17(td,J＝7.5,1.2Hz,1H),6.35(s, 1H),2.50(s,3H),2.30(s,3H),2.03(s,3H)；¹³C NMR(151MHz,CDCl₃)δ150.38, 146.85,133.92,131.07,130.53,126.70,126.37,125.92,115.81,112.20,22.04,11.45, 10.00；HRMS(ESI)calcd for C₁₃H₁₅O₂(M+H)⁺:187.1117,Found:187.1118.

Example 3: synthesis of 2, 3-dimethyl-5- (3-methylphenyl) furan IIIc

Under the protection of nitrogen, 3-chloro-2-butanone Ia (1.0mmol) and m-methyl phenethyl alcohol are added into a 10mL two-neck flask connected with a reflux condenser tubeKetone IIc (1.0 mmol). The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally separated by silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the target product 2, 3-dimethyl-5- (3-methylphenyl) furan iiic as a colorless oil with a yield of 83%.¹H NMR(600MHz,CDCl₃)δ7.90 (s,1H),7.87(d,J＝7.8Hz,1H),7.69(t,J＝7.7Hz,1H),7.48(d,J＝7.5Hz, 1H),6.89(s,1H),2.83(s,4H),2.74(s,3H),2.44(s,3H)；¹³C NMR(151MHz,CDCl₃) δ151.06,147.21,138.13,131.20,128.49,127.41,123.83,120.41,116.08,108.31, 21.51,11.51,9.98；HRMS(ESI)calcd for C₁₃H₁₅O(M+H)⁺:187.1117,Found:187.1112.

Example 4: synthesis of 2, 3-dimethyl-5- (4-methylphenyl) furan IIId

Under the protection of nitrogen, 3-chloro-2-butanone Ia (1.0mmol) and p-methylacetophenone IId (1.0mmol) were added to a 10mL two-necked flask with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product 2, 3-dimethyl-5- (4-methylphenyl) furan IIId as colorless crystals with a yield of 81%.¹H NMR(600MHz,CDCl₃)δ7.58– 7.46(m,2H),7.17(d,J＝8.0Hz,2H),6.40(s,1H),2.36(s,3H),2.28(s,3H), 1.99(s,3H)；¹³C NMR(151MHz,CDCl₃)δ151.13,146.89,136.30,129.26,128.62,123.19, 115.99,107.66,21.23,11.49,9.99；MS(ESI)calcd for C₁₃H₁₅O(M+H)⁺:187.1,Found: 187.0.

Example 5: synthesis of 2, 3-dimethyl-5- (3, 4-dimethylphenyl) furan IIIe

Under nitrogen protection, 3-chloro-2-butanone Ia (1.2mmol) and 3, 4-dimethylacetophenone IIe (1.0mmol) were added to a 10mL two-necked flask with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is dried by anhydrous sodium sulfate, then is concentrated under reduced pressure, and finally is separated by silica gel column chromatography (taking ethyl acetate-hexane as eluent) to obtain the target product 2, 3-dimethyl-5- (3, 4-dimethylphenyl) furan III e as a white solid with the yield of 78%.¹H NMR(600MHz,CDCl₃)δ7.41 (s,1H),7.36(d,J＝7.8Hz,1H),7.12(d,J＝7.8Hz,1H),6.39(s,1H),2.30(s, 3H),2.29(s,3H),2.27(s,3H),1.99(s,3H)；¹³C NMR(151MHz,CDCl₃)δ151.21, 146.76,136.64,135.03,129.82,128.99,124.46,120.75,115.92,107.55,19.83,19.52, 11.47,9.97；HRMS(ESI)calcd for C₁₄H₁₇O(M+H)⁺:201.1274,Found:201.1271.

Example 6: synthesis of 2, 3-dimethyl-5- (4-isopropylphenyl) furan IIIf

Under nitrogen protection, 3-chloro-2-butanone Ia (1.0mmol) and p-isopropylacetophenone IIf (1.0mmol) were added to a 10mL two-necked flask with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After the reaction was complete, saturated aqueous ammonium chloride (10mL) was added to quenchAnd extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (with ethyl acetate-hexane as an eluent) to obtain the objective product IIIf as a colorless oil in a yield of 72%.¹H NMR(600MHz,CDCl₃)δ7.57–7.47(m,2H),7.19(d,J＝ 8.2Hz,2H),6.37(s,1H),2.88(dt,J＝13.8,6.9Hz,1H),2.25(s,3H),1.96(s, 3H),1.24(d,J＝7.0Hz,6H)；¹³C NMR(151MHz,CDCl₃)δ151.14,147.29,146.89, 129.00,126.59,123.26,115.94,107.68,33.86,23.92,11.46,9.96；HRMS(ESI)calcd for C₁₅H₁₉O(M+H)⁺:215.1430,Found:215.1433.

Example 7: synthesis of 2, 3-dimethyl-5- (4-chlorophenyl) furan III g

Under the protection of nitrogen, 3-chloro-2-butanone Ia (1.0mmol) and p-chloroacetophenone IIg (1.0mmol) were added to a 10mL two-necked flask with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC throughout the reaction. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by the mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the target product III g as a white solid in a yield of 75%.¹H NMR(600MHz,CDCl₃)δ7.52(d,J＝8.1Hz,2H),7.30(d,J＝8.1Hz, 2H),6.43(s,1H),2.27(s,3H),1.98(s,3H)；¹³C NMR(151MHz,CDCl₃)δ149.85, 147.75,132.04,129.74,128.74,124.38,116.33,108.87,11.50,9.93；MS(ESI)calcd for C₁₂H₁₂ClO(M+H)⁺:207.1,Found:207.0.

Example 8: synthesis of 2, 3-dimethyl-5- (4-nitrophenyl) furan IIIh

Under the protection of nitrogen, 3-chloro-2-butanone Ia (1.0mmol) and p-nitroacetophenone IIh (1.0mmol) were added to a 10mL two-necked flask connected with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally separated by silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the target product ih as a yellow solid with a yield of 53%.¹H NMR(600MHz,CDCl₃)δ8.19(d,J＝8.9Hz,2H),7.68(d,J＝ 8.9Hz,2H),6.67(s,1H),2.31(s,3H),2.00(s,3H)；¹³C NMR(151MHz,CDCl₃)δ 150.34,148.75,145.71,136.79,124.35,123.05,117.46,112.71,11.69,9.88；HRMS (ESI)calcd for C₁₂H₁₂NO₃(M+H)⁺:218.0812,Found:218.0810.

Example 9: synthesis of 2, 3-dimethyl-5- (4-methoxyphenyl) furan IIIi

Under the protection of nitrogen, 3-chloro-2-butanone Ia (1.0mmol) and p-methoxyacetophenone IIi (1.0mmol) were added to a 10mL two-necked flask with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally separated by silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the target product iiii as a white solid with a yield of 83%.¹H NMR(600MHz,CDCl₃)δ7.58–7.47(m,2H),6.89(d,J＝8.7 Hz,2H),6.31(s,1H),3.82(s,3H),2.26(s,3H),1.97(s,3H)；¹³C NMR(151MHz, CDCl₃)δ158.48,150.92,146.53,124.60,124.46,115.90,114.02,106.80,55.28,11.44, 9.97；MS(ESI)calcd for C₁₃H₁₅O₂(M+H)⁺:203.1,Found:203.3.

Example 10: synthesis of 2, 3-dimethyl-5- (4-hydroxyphenyl) furan III j

Under nitrogen protection, 3-chloro-2-butanone Ia (1.2mmol) and p-hydroxyacetophenone IIj (1.0mmol) were added to a 10mL two-necked flask with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is dried by anhydrous sodium sulfate, then is concentrated under reduced pressure, and finally is separated by silica gel column chromatography (taking ethyl acetate-hexane as eluent) to obtain the target product IIIj as a light yellow solid with the yield of 76%.¹H NMR(600MHz,CDCl₃)δ7.56–7.44(m,2H),6.90–6.73(m, 2H),6.30(s,1H),5.23(s,1H),2.26(s,3H),1.97(s,3H)；¹³C NMR(151MHz,CDCl₃) δ154.47,154.46,150.86,146.54,124.82,124.60,115.53,106.79,11.43,9.96；HRMS (ESI)calcd for C₁₂H₁₃O₂(M+H)⁺:189.0910,Found:189.0914.

Example 11: synthesis of 2, 3-dimethyl-5- (4-dimethylaminophenyl) furan IIIk

Under nitrogen protection, 3-chloro-2-butanone Ia (1.0mmol) and 4' -dimethylaminoacetophenone IIk (1.0mmol) were added to a 10mL two-necked flask with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After the reaction is finished, saturated chlorine is addedAqueous ammonium hydroxide (10mL) was quenched and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is dried by anhydrous sodium sulfate, then is concentrated under reduced pressure, and finally is separated by silica gel column chromatography (taking ethyl acetate-hexane as eluent) to obtain the target product IIIk as a white solid with the yield of 56%.¹H NMR(600MHz,CDCl₃)δ7.49(d,J＝8.9Hz,2H),6.73(d,J ＝8.9Hz,2H),6.24(s,1H),2.97(s,6H),2.26(s,3H),1.97(s,3H)；¹³C NMR(151 MHz,CDCl₃)δ151.72,149.38,145.81,124.45,115.75,112.61,105.56,40.63,11.46, 10.03；HRMS(ESI)calcd for C₁₄H₁₈NO(M+H)⁺:216.1383,Found:216.1380.

Example 12: synthesis of 2, 3-dimethyl-5- (1-naphthyl) furan III

Under the protection of nitrogen, 3-chloro-2-butanone Ia (1.0mmol) and 1-naphthylethanone IIl (1.0mmol) were added to a 10mL two-necked flask with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the target product ill as a yellow oil with a yield of 70%.¹H NMR(600MHz,CDCl₃)δ8.50(d,J＝8.4Hz,1H),7.95–7.85 (m,1H),7.81(d,J＝8.2Hz,1H),7.73(d,J＝7.2Hz,1H),7.60–7.44(m,3H), 6.56(s,1H),2.38(s,3H),2.09(s,3H)；¹³C NMR(151MHz,CDCl₃)δ150.26,147.65, 134.00,130.15,128.94,128.45,127.80,126.28,125.74,125.69,125.35,125.33, 115.89,112.74,11.56,9.99；HRMS(ESI)calcd for C₁₆H₁₅O(M+H)⁺:223.1117,Found: 223.1114.

Example 13: synthesis of 2, 3-dimethyl-5- (2-naphthyl) furan IIIm

Under the protection of nitrogen, 3-chloro-2-butanone Ia (1.0mmol) and 2-naphthylethanone IIm (1.0mmol) were added to a 10mL two-necked flask connected with a reflux condenser. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is dried by anhydrous sodium sulfate, then is concentrated under reduced pressure, and finally is separated by silica gel column chromatography (taking ethyl acetate-hexane as eluent) to obtain the target product IIIm as a white solid with the yield of 72 percent.¹H NMR(600MHz,CDCl₃)δ8.09(s,1H),7.86(d,J＝8.1Hz,1H), 7.81(t,J＝7.6Hz,2H),7.73(dd,J＝8.6,1.5Hz,1H),7.48(dd,J＝7.9,7.0Hz, 1H),7.44(t,J＝7.5Hz,1H),6.59(s,1H),2.35(s,3H),2.04(s,3H)；¹³C NMR(151 MHz,CDCl₃)δ150.96,147.72,133.68,132.34,128.55,128.19,128.00,127.70,126.30, 125.45,122.13,121.03,116.34,109.14,11.56,9.97；HRMS(ESI)calcd for C₁₆H₁₅O(M+H)⁺: 223.1117,Found:223.1119.

Example 14: (E) synthesis of (E) -2, 3-dimethyl-5-styryl furan III n

To a 10mL two-necked flask with a reflux condenser, 3-chloro-2-butanone Ia (1.0mmol) and (E) 4-phenyl-3-buten-2-one IIn (1.0mmol) were added under nitrogen. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). Mixing the dichloromethane solution obtained by extraction, drying with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by silica gel column chromatography (with ethyl acetate-hexane as eluent) to obtainThe desired product IIIn is obtained in 63% yield as a yellow solid.¹H NMR(600MHz,CDCl₃)δ7.44(d,J＝7.6Hz,2H),7.32 (t,J＝7.7Hz,2H),7.22(d,J＝7.3Hz,1H),6.92(d,J＝16.2Hz,1H),6.79(d, J＝16.2Hz,1H),6.15(s,1H),2.26(s,3H),1.95(s,3H)；¹³C NMR(151MHz,CDCl₃) δ150.38,147.75,137.45,128.61,127.09,126.09,125.05,116.66,116.25,112.46, 11.56,9.85；MS(ESI)calcd for C₁₄H₁₅O(M+H)⁺:199.1,Found:199.0.

Example 15: synthesis of 2-methyl-3-ethyl-5-phenyl furan IIIo

To a 10mL two-necked flask with a reflux condenser, 2-chloro-3-pentanone Ib (1.0mmol) and acetophenone IIa (1.0mmol) p-toluenesulfonic acid (0.2mmol) were added under nitrogen protection. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by the mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIo as a colorless oil with a yield of 67%.¹H NMR(600MHz,CDCl₃)δ7.63(d,J＝7.5Hz, 2H),7.36(t,J＝7.5Hz,2H),7.22(d,J＝7.2Hz,1H),6.52(s,1H),2.40(dd,J ＝14.9,7.4Hz,2H),2.30(s,3H),1.19(t,J＝7.5Hz,3H)；¹³C NMR(151MHz,CDCl₃) δ151.03,146.63,131.30,128.55,126.53,123.18,122.92,106.79,18.14,14.92, 11.59；HRMS(ESI)calcd for C₁₃H₁₅O(M+H)⁺:187.1117,Found:187.1114.

Example 16: synthesis of 2-propyl-3-butyl-5-phenyl furan IIIp

To a 10mL two-necked flask with a reflux condenser, 4-chloro-5-nonanone Ic (1.0mmol), acetophenone IIa (1.0mmol), and p-toluenesulfonic acid (0.2mmol) were added under nitrogen. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by the mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIp as a colorless oil with a yield of 63%.¹H NMR(600MHz,CDCl₃)δ7.61(d,J＝7.4Hz, 2H),7.34(t,J＝7.8Hz,2H),7.19(t,J＝7.4Hz,1H),6.48(s,1H),2.59(t,J ＝7.4Hz,2H),2.35(t,J＝7.6Hz,2H),1.69(dd,J＝14.8,7.4Hz,2H),1.55–1.51(m,2H),1.36(dd,J＝15.0,7.4Hz,2H),0.95(dt,J＝22.5,7.4Hz,6H)；¹³C NMR(151MHz,CDCl₃)δ151.15,150.93,131.39,128.53,126.47,123.19,121.41,107.08, 32.78,28.10,24.48,22.37,22.14,13.96,13.83；HRMS(ESI)calcd for C₁₇H₂₃O(M+H)⁺: 243.1743,Found:243.1740.

Example 17: synthesis of 1,2,3,4,6,7,8, 9-octahydrodibenzo [ b, d ] furaniiiq

To a 10mL two-necked flask with a reflux condenser, 2-chlorocyclohexanone Ic (1.0mmol) and cyclohexanone IIq (1.0mmol) were added under nitrogen protection. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIq as a colorless oil with a yield of 65%.¹H NMR(600MHz,CDCl₃)δ2.55(t,J＝6.3Hz,4H),2.31(tt,J＝6.0,1.7Hz, 4H),1.87–1.77(m,4H),1.76–1.67(m,4H)；¹³C NMR(151MHz,CDCl₃)δ148.17, 116.78,23.23,23.18,23.05,20.64.

Example 18: synthesis of 2,3,4,6,7,8,9, 10-octahydro-1H-cycloheptane [ b ] benzofuran IIIr

To a 10mL two-necked flask with attached reflux condenser, 2-chlorocyclohexanone Id (1.0mmol) and cycloheptanone IIp (1.0mmol) were added under nitrogen blanket. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by the mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIr as a colorless oil with a yield of 67%.¹H NMR(600MHz,CDCl₃)δ2.78–2.68(m,2H),2.52(t,J＝6.1Hz,2H),2.37 –2.31(m,2H),2.31–2.24(m,2H),1.85–1.63(m,10H)；¹³C NMR(151MHz,CDCl₃) δ150.72,146.74,120.09,118.23,30.80,28.98,28.71,26.81,23.72,23.08,23.05, 20.71；HRMS(ESI)calcd for C₁₃H₁₉O(M+H)⁺:191.1430,Found:191.1435.

Example 19: synthesis of 2,3,4,6,7,8,9, 10-octahydro-1H-cycloheptane [ b ] benzofuran IIIr

To a 10mL two-necked flask with attached reflux condenser was added 2-chlorocycloheptanone Ie (1.0mmol) and cyclohexanone IIo (1.0mmol) under nitrogen. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by the mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIr as a colorless oil with a yield of 58%.

Example 20: synthesis of 1,2,3,4,6,7,8,9,10, 11-decahydrocyclooctane [ b ] benzofuran IIIs

To a 10mL two-necked flask with a reflux condenser, 2-chlorocyclohexanone Id (1.0mmol) and cyclooctanone IIq (1.0mmol) were added under nitrogen blanket. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIs as a colorless oil with a yield of 70%.¹H NMR(600MHz,CDCl₃)δ2.80–2.70(m,2H),2.54(t,J＝6.2Hz,2H),2.50 –2.39(m,2H),2.29(ddd,J＝6.0,4.2,1.9Hz,2H),1.88–1.77(m,2H),1.77 –1.69(m,4H),1.69–1.62(m,2H),1.50(dt,J＝8.4,3.7Hz,4H)；¹³C NMR(151 MHz,CDCl₃)δ148.94,147.20,117.76,117.71,28.11,27.44,26.10,25.99,25.61, 23.19,23.15,23.10,21.69,20.59；HRMS(ESI)calcd for C₁₄H₂₁O(M+H)⁺:205.1587,Found: 205.1586.

Example 21: synthesis of 1,2,3,4,6,7,8,9,10, 11-decahydrocyclooctane [ b ] benzofuran IIIs

To a 10mL two-necked flask with a reflux condenser, 2-chlorocyclooctanone If (1.0mmol) and cyclohexanone IIo (1.0mmol) were added under nitrogen. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the target product IIIs with a yield of 61%.

Example 22: synthesis of 4-methyl-1, 2,3,4,6,7,8, 9-octahydrodibenzo [ b, d ] furan IIIt

To a 10mL two-necked flask with attached reflux condenser, 2-chlorocyclohexanone Id (1.0mmol) and 2-methylcyclohexanone IIr (1.0mmol) were added under nitrogen blanket. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIt as a colorless oil with a yield of 66%.¹H NMR(600MHz,CDCl₃)δ2.86–2.75(m,1H),2.56(d,J ＝6.1Hz,2H),2.30(dt,J＝7.3,4.0Hz,4H),2.00–1.91(m,1H),1.82(dd,J＝ 11.6,6.4Hz,3H),1.72(dd,J＝5.1,3.6Hz,2H),1.66–1.60(m,1H),1.46–1.34 (m,1H),1.21(d,J＝6.8Hz,3H)；¹³C NMR(151MHz,CDCl₃)δ152.41,148.30,116.60, 116.27,32.45,29.10,23.23,23.04,21.78,21.00,20.70,19.20；HRMS(ESI)calcd for C₁₃H₁₉O(M+H)⁺:191.1430,Found:191.1435.

Example 23: synthesis of 2-tert-butyl-1, 2,3,4,6,7,8, 9-octahydrodibenzo [ b, d ] furan IIIu

To a 10mL two-necked flask with attached reflux condenser, 2-chlorocyclohexanone Id (1.0mmol) and 4-tert-butyl-cyclohexanone IIs (1.0mmol) were added under nitrogen blanket. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by the mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIu as a colorless oil with a yield of 68%.¹H NMR(600MHz,CDCl₃)δ2.64(d,J＝14.3Hz,1H),2.56(t, J＝6.0Hz,3H),2.42–2.27(m,3H),2.13–1.99(m,2H),1.87–1.78(m,2H), 1.73(dd,J＝12.1,6.1Hz,2H),1.46–1.34(m,2H),1.00–0.90(m,9H)；¹³C NMR (151MHz,CDCl₃)δ148.57,148.22,117.05,116.94,45.43,45.08,32.49,29.54,27.57, 27.53,23.25；HRMS(ESI)calcd for C₁₆H₂₅O(M+H)⁺:233.1900,Found:233.1902.

Example 24: synthesis of 2-phenyl-4, 5,6, 7-tetrahydrobenzofuran IIIv

To a 10mL two-necked flask with a reflux condenser, 2-chlorocyclohexanone Id (1.0mmol) and acetophenone IIa (1.0mmol) were added under nitrogen blanket. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIv as a colorless oil with a yield of 71%.¹H NMR(600MHz,CDCl₃)δ7.64(d,J＝7.7Hz,2H),7.36(t,J＝7.7Hz,2H), 7.22(t,J＝7.4Hz,1H),6.49(s,1H),2.68(t,J＝6.2Hz,2H),2.48(t,J＝6.0 Hz,2H),1.97–1.84(m,2H),1.84–1.69(m,3H)；¹³C NMR(151MHz,CDCl₃)δ151.56, 150.79,131.41,128.54,126.53,123.22,118.97,106.00,23.28,23.13,23.07,22.14； HRMS(ESI)calcd for C₁₄H₁₅O(M+H)⁺:199.1117,Found:199.1120.

Example 25: synthesis of 2- (4-chlorophenyl) -4,5,6, 7-tetrahydrobenzofuran IIIw

To a 10mL two-necked flask with a reflux condenser, 2-chlorocyclohexanone Id (1.0mmol) and p-chloroacetophenone IIg (1.0mmol) were added under nitrogen blanket. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC throughout the reaction. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by the mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIw as a colorless oil with a yield of 73%.¹H NMR(600MHz,CDCl₃)δ7.59–7.47(m,2H),7.38–7.28(m,2H),6.45 (s,1H),2.72–2.57(m,2H),2.45(tt,J＝6.1,1.7Hz,2H),1.86(ddd,J＝8.7, 7.7,4.4Hz,2H),1.75(dtd,J＝9.0,6.1,2.8Hz,2H)；¹³C NMR(151MHz,CDCl₃)δ 151.21,150.54,132.04,129.94,128.76,124.44,119.20,106.51,23.30,23.10,23.05, 22.12；MS(ESI)calcd for C₁₄H₁₄ClO(M+H)⁺:233.1,Found:233.2.

Example 26: synthesis of 2-butyl-4, 5,6, 7-tetrahydrobenzofuran IIIx

To a 10mL two-necked flask with attached reflux condenser, 2-chlorocyclohexanone Id (1.0mmol) and 2-hexanone IIp (1.0mmol) were added under nitrogen blanket. The reaction mixture is heated to 80 ℃ and stirred for 0.5h,tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIx as a colorless oil with a yield of 69%.¹H NMR(600MHz,CDCl₃)δ5.78(s,1H),2.55(dd,J＝15.6,7.9Hz,4H), 2.40–2.33(m,2H),1.83–1.77(m,2H),1.74–1.67(m,2H),1.63–1.58(m, 2H),1.38(dd,J＝14.9,7.4Hz,2H),0.93(t,J＝7.4Hz,3H)；¹³C NMR(151MHz,CDCl₃) δ154.21,148.61,117.11,105.99,105.57,105.29,104.87,30.45,27.87,27.52,23.21, 23.12,22.74,22.36,22.16,13.88.

Example 27: synthesis of 2-phenethyl-4, 5,6, 7-tetrahydrobenzofuran IIIy

To a 10mL two-necked flask with a reflux condenser, 2-chlorocyclohexanone Id (1.0mmol) and 4-phenyl-2-butanone IIv (1.0mmol) were added under nitrogen blanket. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product IIIy as a colorless oil with a yield of 66%.¹H NMR(600MHz,CDCl₃)δ7.30(t,J＝7.6Hz,2H),7.25– 7.21(m,3H),5.82(s,1H),2.99–2.92(m,2H),2.92–2.84(m,2H),2.58(t,J ＝6.2Hz,2H),2.38(t,J＝6.0Hz,2H),1.87–1.80(m,2H),1.75–1.68(m,2H)；¹³C NMR(151MHz,CDCl₃)δ153.08,148.95,141.54,128.38,128.36,125.99,117.23,105.96, 34.69,30.16,23.25,23.22,23.14,22.15；HRMS(ESI)calcd for C₁₆H₁₉O(M+H)⁺:227.1430, Found:191.1427.

Example 28: synthesis of 2-styryl-4, 5,6, 7-tetrahydrobenzofuran IIIz

To a 10mL two-necked flask with attached reflux condenser, 2-chlorocyclohexanone Id (1.0mmol) and (E) 4-phenyl-3-buten-2-one IIn (1.0mmol) were added under nitrogen blanket. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the target product IIIz as a pale yellow oil with a yield of 57%.¹H NMR(600MHz,CDCl₃)δ7.45(d,J＝7.7Hz,2H), 7.33(t,J＝7.7Hz,2H),7.21(t,J＝7.3Hz,1H),6.95(d,J＝16.2Hz,1H),6.83 (d,J＝16.2Hz,1H),6.17(s,1H),2.65(t,J＝6.3Hz,2H),2.43(t,J＝6.1Hz, 2H),1.92–1.80(m,2H),1.80–1.68(m,2H)；¹³C NMR(151MHz,CDCl₃)δ151.21, 151.08,137.49,128.64,127.10,126.12,125.07,119.13,116.88,110.12,23.36,23.09, 23.03,22.07.

Example 29: synthesis of 2, 3-dimethyl-4, 5-dihydronaphtho [1,2-b ] furan VIa

To a 10mL two-necked flask with a reflux condenser, 3-chloro-2-butanone Ia (1.0mmol) and 1-tetralone V (1.0mmol) were added under nitrogen. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC throughout the reaction. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). Mixing the dichloromethane solution obtained by extraction, drying with anhydrous sodium sulfate, andthen, the mixture was concentrated under reduced pressure and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the objective product VIa as a colorless oil in 67% yield.¹H NMR(600MHz,CDCl₃)δ7.44(d,J＝7.6Hz,1H),7.26–7.21(m,1H), 7.19(d,J＝7.1Hz,1H),7.10(td,J＝7.5,1.2Hz,1H),2.98(t,J＝7.9Hz,2H), 2.64(t,J＝7.9Hz,2H),2.33(s,3H),1.96(d,J＝0.7Hz,3H)；¹³C NMR(151MHz, CDCl₃)δ147.42,147.17,134.06,128.54,127.82,126.67,125.54,121.19,118.49, 114.59,29.12,19.73,11.76,8.20；HRMS(ESI)calcd for C₁₄H₁₅O(M+H)⁺:199.1117,Found: 199.1114.

Example 30: synthesis of 5,6,7,8,9, 10-hexahydronaphtho [1,2-b ] benzofuran VIb

To a 10mL two-necked flask with a reflux condenser, 2-chlorocyclohexanone Id (1.0mmol), 1-tetralone V (1.0mmol), and p-toluenesulfonic acid (0.2mmol) were added under nitrogen blanket. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by the mixed extraction was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and finally subjected to silica gel column chromatography (using ethyl acetate-hexane as an eluent) to obtain the target product VIb as a yellow oil with a yield of 53%.¹H NMR(600MHz,CDCl₃)δ7.43(dd,J＝7.5,0.5 Hz,1H),7.22(t,J＝7.5Hz,1H),7.18(d,J＝7.4Hz,1H),7.08(td,J＝7.4,1.3 Hz,1H),2.96(t,J＝7.9Hz,2H),2.70(ddd,J＝6.3,4.0,1.7Hz,2H),2.64(t, J＝7.9Hz,2H),2.42(tt,J＝6.0,1.8Hz,2H),1.95–1.85(m,2H),1.85–1.73 (m,2H)；¹³C NMR(151MHz,CDCl₃)δ150.78,147.55,134.01,128.58,127.73,126.59, 125.42,119.52,118.45,117.55,29.02,23.46,23.07,22.90,20.71,19.57；HRMS(ESI) calcd for C₁₆H₁₇O(M+H)⁺:225.1274,Found:225.1273.

Example 31: synthesis of 5,7,8,9,10, 11-hexahydro-6H-cyclohepta [ b ] naphtho [2,1-d ] furan VIc

To a 10mL two-necked flask with attached reflux condenser was added 2-chlorocycloheptanone Ie (1.0mmol) and 1-tetralone V (1.0mmol) under nitrogen. The reaction mixture was warmed to 80 ℃ and stirred for 0.5h, then tetraisopropyl titanate (1.5mmol) was added and the reaction was monitored by TLC throughout the reaction. After completion of the reaction, the reaction mixture was quenched by addition of saturated aqueous ammonium chloride (10mL) and extracted with dichloromethane (3X 10 mL). The dichloromethane solution obtained by mixed extraction is dried by anhydrous sodium sulfate, then is concentrated under reduced pressure, and finally is separated by silica gel column chromatography (taking ethyl acetate-hexane as eluent) to obtain the target product VIc as brown oil with the yield of 45%.¹H NMR(600MHz,CDCl₃)δ7.41(d,J＝7.6Hz,1H),7.23–7.12(m,3H), 7.06(t,J＝7.4Hz,1H),2.96(t,J＝7.9Hz,2H),2.92–2.83(m,2H),2.61(t, J＝7.9Hz,2H),2.47–2.38(m,2H),1.87–1.80(m,2H),1.75(d,J＝4.7Hz, 4H)；¹³C NMR(151MHz,CDCl₃)δ153.58,146.19,133.96,128.61,127.75,126.62,125.43, 121.17,121.07,118.48,30.95,29.28,29.15,28.55,26.67,23.85,19.66；HRMS(ESI) calcd for C₁₇H₁₉O(M+H)⁺:239.1430,Found:239.1428。