1-methoxy-1, 3-dihydrobenzo [c] thiophene as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to 1-methoxy-1, 3-dihydrobenzo [c] thiophene as well as a preparation method and application thereof. The preparation method comprises the following specific steps: adding thioether tetra-alkyne and alkali into methanol, uniformly mixing, reacting, washing, extracting and drying the obtained reaction liquid to obtain a crude product, and performing column chromatography on the crude product to obtain the 1-methoxy-1, 3-dihydrobenzo [c] thiophene. The invention provides a brand-new synthetic method of 1, 3-dihydrobenzo [c] thiophene, and a substituted naphthalene derivative can be prepared by taking a thioether tetra-alkyne substrate as an initiator through cyclization, oxidation, [4 + 2] cycloaddition and other reactions in sequence. Compared with the existing synthesis method of 1, 3-dihydrobenzo [c] thiophene, the method has the advantages that the adopted thioether tetraacetylene raw material is convenient to prepare, the operation is simple, the product is easy to purify, the total yield is high, and the industrial production is easy to realize.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to 1-methoxy-1,3-dihydrobenzo[c]thiophene and a preparation method and application thereof. Background Art

[0002] Cycloaddition and cyclization strategies are one of the most powerful methods to create molecular complexity in organic molecules. 1-methoxy-1,3-dihydrobenzo[c]thiophene is an important synthetic building block with a five- and six-membered ring skeleton. Its oxide sulfone undergoes a Diels-Alder reaction with different dienophiles at high temperature to obtain high yields of polycyclic aromatic hydrocarbons. This [4+2] cycloaddition reaction has good tolerance to functional groups and can generate five- and six-membered polycyclic aromatic hydrocarbon systems.

[0003] It is worth noting that the naphthalene ring skeleton is a common group structure in a large number of drugs, natural products and advanced materials. Naphthalene has unique optoelectronic properties and is therefore widely used as an optical and electronic material ((a) McCurdy, CR; LeBourdonnec, B.; Metzger, TG; Kouhen, RE; Zhang, Y.; Law, PY; Portoghese, PS J Med. Chem. 2002, 45, 2887-2890. (b) Watson, MD; Fechtenkotter, A.; Mullen, K. Chem. Rev. 2001, 101, 1267-1300.). For example, using cheap, commercial naphthalene ring compounds (1-bromo-2-naphthol and 1,8-dinaphthol) as raw materials, an aldehyde group is first introduced on the naphthalene ring through a simple functional group conversion. Then, the naphthalene ring regioselective CH methylation reaction is used as the key reaction step to achieve the directional introduction of the methyl group. Finally, after a series of reduction and cyclization reactions, the efficient and simple total synthesis of the natural products dehydrocacalohastine and musizin were achieved (Mao, YJ; Xia, Z.; Hu, LH; Zhang, YN Asian J. Org. Chem. 2022, 11, e202200198). Many naphthalene ring compounds are prepared by the Diels-Alder reaction of 1,3-dihydrobenzo[c]thiophene.

[0004] At present, there are few examples of 1,3-dihydrobenzo[c]thiophene synthesis methods reported, and the thiophene heterocyclic ring has no substituent structure. There are three types of conditions reported: the first type of conditions, in the presence of various catalysts, α-methylbenzyl alcohol and carbon disulfide react at high temperature (up to 500°C) in the gas phase to obtain 1,3-dihydrobenzo[c]thiophene, and the yield can reach 85% (Azizian, F.; Pizey, JS J Chem. Tech. Biofechnol. 1981, 31, 163-166.). This type of condition requires high temperature and high pressure, and has very high requirements for reaction equipment. On the other hand, the heavy metal catalyst used has certain toxicity and pollutes the environment. The second condition is to use sodium sulfide to provide a sulfur source for dichloro or dibromo o-xylene to synthesize 1,3-dihydrobenzo[c]thiophene ((a) Kawabata, K.; Goto, HJ Mater. Chem. 2012, 22, 23514-23524. (b) Borrelli, DC; Gleason, KK Macromolecules. 2013, 46, 6169-6176.). This condition uses the Soxhlet extraction method, and the reflux device is complicated to build; at the same time, the reaction precursor is fixed, which is not conducive to diversified synthesis, and the subsequent conversion to benzo[c]thiophene requires two steps. The third type of conditions is to synthesize 1-aryl-1,3-dihydrobenzo[c]thiophene in three steps starting from 2-[aryl(methoxy)methyl]benzyl alcohol through acid-mediated cyclization (Kobayashi, K.; Shigemura, Y. HETEROCYCLES. 2016, 92, 2261-2270.). This approach has problems such as long reaction time, many experimental steps, and excessive acid, and is not suitable for industrial scale-up.

[0005] In addition, the synthesis of 1,3-dihydrobenzo[c]thiophene can be achieved by rhodium-catalyzed [2+2+2] cycloaddition of 1,6-heptadiyne and acetylene (Grigg, R.; Scott, R.; Stevenson, PJ Chem. Soc., Perkin Trans. 1. 1988, 6, 1357-1364.). This method has substrate diversity, but the sulfur atom will cause catalyst poisoning when preparing thioether substrates, resulting in incomplete reaction of the raw materials and extremely low yield.

[0006] Therefore, it is of great significance to develop a new method for preparing benzo[c]thiophene. Summary of the invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing 1-methoxy-1,3-dihydrobenzo[c]thiophene in view of the deficiencies in the prior art, which will also show a broader application prospect in chemical production and clinical medicine.

[0008] The present invention also provides a method for the diversified transformation of 1-methoxy-1,3-dihydrobenzo[c]thiophene, which generates a series of new condensed ring aromatics through oxidation reaction and Diels-Alder reaction.

[0009] In order to solve the above technical problems, the present invention discloses a method for preparing 1-methoxy-1,3-dihydrobenzo[c]thiophene, which comprises the following specific steps: adding thioether tetrayne and base into methanol, mixing them evenly and reacting them, washing, extracting and drying the obtained reaction solution to obtain a crude product, and subjecting the crude product to column chromatography to obtain the 1-methoxy-1,3-dihydrobenzo[c]thiophene.

[0010] Specifically, the molar ratio of the thioether tetrayne to the base is 1:(0.5-10).

[0011] Specifically, the structural formula of the thioether tetrayne is:

[0012]

[0013] Wherein, R is any one of an alkyl group or an aryl group;

[0014] Preferably, the thioether tetrayne is bis(nona-2,4-diyn-1-yl) sulfide or bis(5-phenylpenta-2,4-diyn-1-yl) sulfide.

[0015] Specifically, the base includes one of potassium carbonate, cesium carbonate, potassium hydroxide, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 2,2,6,6-tetramethylpiperidine;

[0016] Preferably, the base is cesium carbonate or 2,2,6,6-tetramethylpiperidine.

[0017] Specifically, the reaction conditions are as follows: temperature of 0 to 100° C., time of 10 to 20 hours;

[0018] Preferably, the reaction temperature is related to the base, and different bases have different suitable temperatures;

[0019] More preferably, when the base is cesium carbonate, the reaction temperature is room temperature and the reaction time is 17 hours; when the base is 2,2,6,6-tetramethylpiperidine, the reaction temperature is 50° C. and the reaction time is 10 hours.

[0020] Specifically, the washing liquid used in the washing is a saturated ammonium chloride aqueous solution at room temperature.

[0021] Specifically, the eluent of the column chromatography is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:20.

[0022] Furthermore, the 1-methoxy-1,3-dihydrobenzo[c]thiophene prepared by the above preparation method is also within the protection scope of the present invention;

[0023] Wherein, the structural formula of the 1-methoxy-1,3-dihydrobenzo[c]thiophene is:

[0024]

[0025] Wherein, R is any one of an alkyl group and an aryl group.

[0026] Preferably, the R group in the 1-methoxy-1,3-dihydrobenzo[c]thiophene is n-butyl or phenyl.

[0027] Furthermore, the use of the above-mentioned 1-methoxy-1,3-dihydrobenzo[c]thiophene in the preparation of naphthalene derivatives is also within the protection scope of the present invention;

[0028] The specific steps of the application are: mixing the 1-methoxy-1,3-dihydrobenzo[c]thiophene described in claim 7 with an oxidant to obtain 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone, and then using 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone as a diene and a dienophile to obtain the corresponding substituted naphthalene derivative through a Diels-Alder reaction.

[0029] Specifically, the molar ratio of the 1-methoxy-1,3-dihydrobenzo[c]thiophene to the oxidant is 1:(1-3);

[0030] Preferably, the oxidant is one of meta-chloroperbenzoic acid, hydrogen peroxide or sodium periodate;

[0031] More preferably, the oxidant is m-chloroperbenzoic acid.

[0032] Specifically, the molar ratio of the 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone to the dienophile is 1:(3-20);

[0033] Preferably, the dienophile is dimethyl butynedioate or p-benzoquinone.

[0034] Beneficial effects:

[0035] The present invention provides a novel method for synthesizing 1,3-dihydrobenzo[c]thiophene, which can prepare substituted naphthalene derivatives by using a thioether tetrayne substrate as a starting material and sequentially undergoing reactions such as cyclization, oxidation, and [4+2] cycloaddition. Compared with the existing method for synthesizing 1,3-dihydrobenzo[c]thiophene, the thioether tetrayne raw material used in the method is easy to prepare, the operation is simple, the product is easy to purify, the total yield is high, and industrial production is easy to achieve. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments, and the above and / or other advantages of the present invention will become more clear.

[0037] Figure 1 The di(nonane-2,4-diyn-1-yl)sulfide prepared in Example 1 of the present invention 1 H-NMR spectrum;

[0038] Figure 2 The 1-methoxy-1,3-dihydrobenzo[c]thiophene prepared in Example 3 of the present invention 1 H-NMR spectrum;

[0039] Figure 3 The 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone prepared in Example 5 of the present invention 1 H-NMR spectrum;

[0040] Figure 4 The substituted naphthalene derivative obtained by Diels-Alder reaction of the oxide sulfone prepared in Example 6 of the present invention 1 H-NMR spectrum;

[0041] Figure 5 The substituted naphthalene derivative obtained by Diels-Alder reaction of the oxide sulfone prepared in Example 7 of the present invention 1 H-NMR spectrum. DETAILED DESCRIPTION

[0042] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and materials described are commercially available unless otherwise specified.

[0043] Embodiment 1:

[0044] A di(nona-2,4-diyn-1-yl) sulfide, the structure of which is as follows:

[0045]

[0046] Specific preparation method: commercially available 1-bromo-2,4-nonanediyne (100 mmol) and sodium sulfide nonahydrate (50 mmol) are added to a round-bottom flask, methanol is used as solvent, and the reaction is stirred at room temperature for 1 hour, and the reaction product is washed with a saturated aqueous solution of ammonium chloride at room temperature; then extracted with dichloromethane, dried under reduced pressure, and subjected to column chromatography (the volume ratio of ethyl acetate to petroleum ether in the eluent is 1:100) to obtain a yellow oil, namely di(nonane-2,4-diyne-1-yl) sulfide, and the column chromatography yield is 87%.

[0047] Nuclear magnetic resonance (CDCl 3 )The data is as follows: 1 H NMR (CDCl 3 , 400MHz): δ3.48 (s, 4H), 2.27 (t, J = 7.5Hz, 4H), 1.56-1.36 (m, 8H), and 0.9 (t, J = 8.3Hz, 6H).

[0048] Embodiment 2:

[0049] A bis(5-phenylpentane-2,4-diyn-1-yl)sulfide, the structure of which is as follows:

[0050]

[0051] Specific preparation method: commercially available 1-bromo-5-phenyl 2,4-pentadiyne (100 mmol) and sodium sulfide nonahydrate (50 mmol) are added to a round-bottom flask, methanol is used as solvent, and the reaction is stirred at room temperature for 1 hour, and the reaction product is washed with a saturated aqueous solution of ammonium chloride at room temperature; then extracted with dichloromethane, dried under reduced pressure, and subjected to column chromatography (the volume ratio of ethyl acetate to petroleum ether in the eluent is 1:100) to obtain a yellow oil, namely di(5-phenylpentane-2,4-diyn-1-yl) sulfide, and the column chromatography yield is 92%.

[0052] Nuclear magnetic resonance (CDCl 3 )The data is as follows: 1 H NMR (CDCl 3 , 400MHz): δ7.50-7.46(m,4H),7.38-7.28(m,6H),3.64(s,4H).

[0053] Embodiment 3:

[0054] A 1-methoxy-1,3-dihydrobenzo[c]thiophene, the structure of which is as follows:

[0055]

[0056] This embodiment also provides a method for preparing the above 1-methoxy-1,3-dihydrobenzo[c]thiophene:

[0057] Di(nonane-2,4-diyn-1-yl)sulfide (55 mmol) was added to a round-bottom flask, cesium carbonate (55 mmol) was used as a base, methanol was used as a solvent, and the reaction was stirred at room temperature for 17 hours. The reaction product was washed with a saturated aqueous solution of ammonium chloride at room temperature; then extracted with dichloromethane, dried under reduced pressure, and subjected to column chromatography (the volume ratio of ethyl acetate to petroleum ether in the eluent was 1:20) to obtain a yellow oil, namely the above-mentioned 1-methoxy-1,3-dihydrobenzo[c]thiophene, and the column chromatography yield was 82%.

[0058] Nuclear magnetic resonance (CDCl 3 )The data is as follows: 1 H NMR (CDCl 3 , 400MHz): δ7.26(d,1H),7.16(d,1H),6.44(q,1H),4.38(d,1H),4.21(d,1H),3.30(s,3H),2.8 1(t,2H),2.52(td,2H),1.65-1.60(m,4H),1.57-1.51(m,2H),1.43-1.36(m,2H),0.98(q,6H).

[0059] Embodiment 4:

[0060] A 1-methoxy-1,3-dihydrobenzo[c]thiophene, the structure of which is as follows:

[0061]

[0062] This embodiment also provides a method for preparing the above 1-methoxy-1,3-dihydrobenzo[c]thiophene:

[0063] 1-Bromo-5-phenyl-2,4-pentadiyne (32 mmol) was added to a thick-walled pressure-resistant tube, 2,2,6,6-tetramethylpiperidine (320 mmol) was used as a base, methanol was used as a solvent, and the mixture was stirred in an oil bath at 50°C for 10 hours. The reaction product was washed with a saturated aqueous solution of ammonium chloride at room temperature; then extracted with dichloromethane, dried under reduced pressure, and subjected to column chromatography (the volume ratio of ethyl acetate to petroleum ether in the eluent was 1:20) to obtain a yellow oily substance, namely 1-methoxy-1,3-dihydrobenzo[c]thiophene, with a column chromatography yield of 87%.

[0064] Nuclear magnetic resonance (CDCl 3 )The data is as follows: 1 H NMR (CDCl 3 , 400MHz): δ7.69-7.67(m,1H),7.66-7.64(m,1H),7.50-7.40(m,5H),7.37-7.28(m,5H),6.51(d,1H),4.54(dd,1H),4.39(d,1H),3.36(s,3H).

[0065] Embodiment 5:

[0066] The 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone prepared based on 1-methoxy-1,3-dihydrobenzo[c]thiophene in Example 1 has the following structure:

[0067]

[0068] The specific preparation method is as follows:

[0069] 1-Methoxy-1,3-dihydrobenzo[c]thiophene (40 mmol) prepared in Example 3 was added to a round-bottom flask, and dichloromethane was used as solvent. The mixture was reacted in an ice bath at 0°C. Then, m-chloroperbenzoic acid (80 mmol) was added as an oxidant. The mixture was stirred and reacted at room temperature for 0.5 hours. The reaction product was washed with a saturated sodium bicarbonate aqueous solution at room temperature. The mixture was then extracted with dichloromethane, dried under reduced pressure, and subjected to column chromatography (the volume ratio of ethyl acetate to petroleum ether in the eluent was 1:10) to obtain a light yellow oily substance, i.e., the above-mentioned 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone. The column chromatography yield was 83%.

[0070] Nuclear magnetic resonance (CDCl 3 )The data is as follows: 1 H NMR (CDCl 3 , 400MHz): δ7.28(d,1H),7.23(d,1H),5.26(s,1H),4.40(d,1H),4.33(d,1H),3.82(s,3H),2 .80-2.73(m,2H),2.47(t,2H),1.61-1.56(m,4H),1.51-1.46(m,2H),1.38-1.32(m,2H),and 0.94(dt,6H).

[0071] Embodiment 6:

[0072] The substituted naphthalene derivative obtained by Diels-Alder reaction of 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone in Example 5 has the following structure:

[0073]

[0074] The specific preparation method is as follows:

[0075] The 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone (3 mmol) obtained in Example 3 was added to a thick-walled pressure-resistant tube, dimethyl butynedioate (60 mmol) was used as a dienophile, chlorobenzene was used as a solvent, and the reaction was stirred in an oil bath at 100°C for 3 hours. The reaction product was washed with a saturated sodium bicarbonate aqueous solution at room temperature; then extracted with dichloromethane, dried under reduced pressure, and subjected to column chromatography (the volume ratio of ethyl acetate to petroleum ether in the eluent was 1:10) to obtain a yellow oily substance, i.e., a substituted naphthalene derivative obtained by Diels-Alder reaction of the oxide sulfone, and the column chromatography yield was about 90%.

[0076] Nuclear magnetic resonance (CDCl 3 )The data is as follows:1 H NMR (CDCl 3 , 400MHz): δ8.69(s,1H),8.21(s,1H),7.75(d,1H),7.46(d,1H),3.97(s,3H),3.95(s,3H),3 .01-2.93(m,2H),2.63(t,2H),1.75-1.65(m,4H),1.62-1.56(m,2H),1.44-1.37(m,2H),and 0.98(dt,6H).

[0077] Embodiment 7:

[0078] The substituted naphthalene derivative obtained by Diels-Alder reaction of 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone in Example 5 has the following structure:

[0079]

[0080] The specific preparation method is as follows:

[0081] The 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone (3 mmol) obtained in Example 4 was added into a thick-walled pressure-resistant tube, p-benzoquinone (9 mmol) was used as a dienophile, chlorobenzene was used as a solvent, and the reaction was stirred in an oil bath at 100°C for 7 hours. The reaction product was washed with a saturated sodium bicarbonate aqueous solution at room temperature; then extracted with dichloromethane, dried under reduced pressure, and subjected to column chromatography (the volume ratio of ethyl acetate to petroleum ether in the eluent was 1:10) to obtain a bright yellow oily substance, i.e., a substituted naphthalene derivative obtained by the DA reaction of the oxide sulfone, and the column chromatography yield was about 85%.

[0082] Nuclear magnetic resonance (CDCl 3 )The data is as follows: 1 H NMR (CDCl 3 , 400MHz): δ9.06(s,1H),8.51(s,1H),7.85(d,1H),7.51(d,1H),7.04(q,2H),3.03-2 .91(m,2H),2.67(t,2H),1.77-1.66(m,4H),1.64-1.58(m,2H),1.47-1.37(m,2H),and 1.00(dt,6H).

[0083] The present invention provides a 1-methoxy-1,3-dihydrobenzo[c]thiophene and a method for preparing and using the same. There are many methods and approaches to implement the technical solution. The above is only a preferred embodiment of the present invention. It should be noted that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be considered as the scope of protection of the present invention. All components not specified in this embodiment can be implemented using existing technologies.

Claims

1. A method for preparing 1-methoxy-1,3-dihydrobenzo[c]thiophene, characterized in that: The specific steps are: adding thioether tetrayne and base to methanol, mixing them evenly and reacting them, washing, extracting and drying the obtained reaction solution to obtain a crude product, and the crude product is subjected to column chromatography to obtain the 1-methoxy-1,3-dihydrobenzo[c]thiophene.

2. The preparation method according to claim 1, characterized in that: The molar ratio of the thioether tetrayne to the base is 1:(0.5-10).

3. The preparation method according to claim 2, characterized in that: The structural formula of the thioether tetrayne is: Wherein, R is any one of an alkyl group or an aryl group.

4. The preparation method according to claim 2, characterized in that: The base includes one of potassium carbonate, cesium carbonate, potassium hydroxide, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene and 2,2,6,6-tetramethylpiperidine.

5. The preparation method according to claim 1, characterized in that: The specific conditions of the reaction are: temperature of 0 to 100° C. and time of 10 to 20 hours.

6. The preparation method according to claim 1, characterized in that: The eluent of the column chromatography is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:

20.

7. 1-Methoxy-1,3-dihydrobenzo[c]thiophene prepared by any one of the preparation methods described in claims 1 to 6, characterized in that: The structural formula of the 1-methoxy-1,3-dihydrobenzo[c]thiophene is: Wherein, R is any one of an alkyl group or an aryl group.

8. Use of 1-methoxy-1,3-dihydrobenzo[c]thiophene according to claim 7 in the preparation of naphthalene derivatives, characterized in that: The specific steps of the application are: mixing the 1-methoxy-1,3-dihydrobenzo[c]thiophene described in claim 7 with an oxidant to obtain 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone, and then using 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone as a diene and a dienophile to obtain the corresponding substituted naphthalene derivative through a Diels-Alder reaction.

9. The use according to claim 8, characterized in that: The molar ratio of the 1-methoxy-1,3-dihydrobenzo[c]thiophene to the oxidant is 1:(1-3); the molar ratio of the 1-methoxy-1,3-dihydrobenzo[c]thiophene oxide sulfone to the dienophile is 1:(3-20).

10. The use according to claim 8, characterized in that: The dienophile is dimethyl butynedioate or p-benzoquinone.

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