CN111393322B - Cyclization synthesis method of naphthalocyanide and derivative thereof - Google Patents

Abstract

The invention relates to a cyclization synthesis method of naphthonitrile and a derivative thereof. A cyclization synthesis method of naphthalene nitrile and derivatives thereof comprises the following steps: under the condition of oxygen isolation, stirring benzonitrile ketene, fluorine-containing substances, a phenylalkyne precursor and anhydrous acetonitrile at room temperature until the reaction is finished; distilling the reaction liquid under reduced pressure to obtain a solid substance; and separating and purifying the solid substance by silica gel column chromatography to obtain the naphthalocyanide and the derivative thereof. The cyclizing synthesis method of the naphthonitrile and the derivative thereof has the advantages of simple and convenient operation, environmental friendliness, high yield, wide substrate application range, no transition metal catalysis and economic process.

Description

A kind of cyclization synthesis method of naphthalene nitrile and derivatives thereof

technical field

The invention relates to the field of chemistry, in particular to a method for cyclization synthesis of naphthalonitrile and derivatives thereof.

Background technique

Polysubstituted naphthalenes are important structures found in many natural products, bioactive compounds, pharmaceuticals, and functional organic materials. Therefore, these naphthalene derivatives have broad application prospects. Because of their importance, organic chemists have devoted enormous efforts to exploit these ubiquitous frameworks in efficient ways.

反应和其他环化反应来制备萘基骨架进行了广泛的研究。而这些反应中经常会存在昂贵的过渡金属催化剂的使用、反应过程的多步进行、一些化学和区域选择性的难以控制的等等困扰。在2007年，Huang和Xue在2007年开发了苯炔，β-酮砜和活化烯烃的无过渡金属多组分反应，通过该反应制得了多取代的萘酚和萘；在2012年，Bi ju及其同事报道了1,2-苯醌和苯炔的先发生Diels-Alder反应，反应产物通过254nm的辐射可进一步转化为萘；2016年，Wu，Shu和他的同事报告了苯炔，酮和炔酸酯的正式[2+2+2]环加成反应，为合成功能化的萘提供了一种新方法。在2018年，Wu，Shu和他的同事又发展了苯炔的串联σ键插入/苯并烷基化反应，得到了两类多取代的萘；同年，Mukher jee和他的同事报道了苯炔和糖基二烯利用Diels-Alder反应构建具有手性侧链的间二取代萘。但是尽管近年来在该领域取得了重大的进展，但是这些反应仍存在着需要多组分参与、多步反应以及需要金属催化等缺点，所以开发高效便捷制备多取代萘的新方法仍迫切需要。In the past decade, people have made use of transition metal catalyzed Diels-Alder reaction,

reaction and other cyclization reactions to prepare naphthyl skeletons have been extensively studied. In these reactions, there are often troubles such as the use of expensive transition metal catalysts, multi-step reaction process, and difficult control of some chemical and regioselectivities. In 2007, Huang and Xue developed a transition metal-free multicomponent reaction of benzynes, β-ketosulfones, and activated alkenes, through which polysubstituted naphthols and naphthalenes were prepared; in 2012, Bi ju and their colleagues reported the first Diels-Alder reaction of 1,2-benzoquinone and benzyne, and the reaction product can be further converted into naphthalene by 254nm radiation; in 2016, Wu, Shu and his colleagues reported that benzyne, ketone The formal [2+2+2] cycloaddition reaction with alkynoate provides a new method for the synthesis of functionalized naphthalene. In 2018, Wu, Shu and their colleagues developed the tandem σ-bond insertion/benzoalkylation reaction of benzyne to obtain two types of multi-substituted naphthalene; in the same year, Mukher jee and his colleagues reported that benzyne Diels-Alder reactions with glycosyl dienes to construct m-disubstituted naphthalenes with chiral side chains. However, although significant progress has been made in this field in recent years, these reactions still have disadvantages such as multi-component participation, multi-step reactions, and metal catalysis. Therefore, it is still urgent to develop new methods for the efficient and convenient preparation of multi-substituted naphthalene.

Contents of the invention

The object of the present invention is to provide a kind of cyclization synthetic method of naphthalene nitrile and its derivative, take benzyne precursor and benzonitrile enone as raw material, easy to operate, environment friendly, high yield, no transition metal catalysis, process economy.

In order to achieve the above purpose, the adopted technical scheme is:

A kind of cyclization synthetic method of naphthalene nitrile and derivative thereof, comprises the following steps:

Under the condition of oxygen barrier, benzonitrile ketene, fluorine-containing substance, benzyne precursor and anhydrous acetonitrile are stirred at room temperature until the reaction is completed;

The reaction solution was distilled under reduced pressure to obtain a solid substance;

The solid matter is separated and purified by silica gel column chromatography to obtain the naphthalonitrile and its derivatives.

Further, the reaction formula of the cyclization synthesis method is:

In the formula, R is a substituent at the 2-, 3-, or 4-position on the benzyne aromatic ring, or a disubstituted or multiple substituent on the aromatic ring; it is selected from one of the following groups: -F, -CH _3. -OCH ₃ , naphthyl;

R ₁ is one of phenyl, phenyl substituted with electron-withdrawing or electron-donating group, part of aliphatic hydrocarbon and heterocyclic group; selected from one of the following groups: -C ₆ H ₅ , 4-CH ₃ C ₆ H ₄ , 4-CH ₃ OC ₆ H ₄ , 4-FC ₆ H ₄ , 4-EtO ₂ CC ₆ H ₄ , CH ₃ , 2-furyl, 2-thienyl;

R ₂ is one of phenyl, phenyl substituted with an electron-withdrawing or electron-donating group, and a heterocyclic group; one of the following groups: -C ₆ H ₅ , 4-CH ₃ C ₆ H ₄ , 3-CH ₃ C ₆ H ₄ , 2-CH ₃ C ₆ H ₄ , 4-CH ₃ OC ₆ H ₄ , 3-CH ₃ OC ₆ H ₄ , 2-CH ₃ OC ₆ H ₄ , 4-ClC ₆ H ₄ , 3-ClC ₆ H ₄ , 3,3-difluorophenyl, 4-BrC ₆ H ₄ , 4-FC ₆ H ₄ , naphthyl, 2-thienyl;

R ₃ is β-ethyl-β-phenyl.

Further, the oxygen isolation condition is a nitrogen atmosphere.

Further, the fluorine-containing substance is selected from one of the following: cesium fluoride, potassium fluoride and 18-crown-6, TBAT, TBAF, TMAF.

Still further, the fluorine-containing substance is TBAT.

Still further, the molar ratio of the benzyne precursor, benzonitrile enone and TBAT is 2:1:6.

Further, the silica gel column chromatography uses a mixed solution composed of petroleum ether: ethyl acetate: methanol with a volume ratio of 100:1:1 as the eluent.

Further, the specific operation of stirring the benzonitrile ketene, fluorine-containing substance, benzyne precursor and anhydrous acetonitrile at room temperature until the reaction ends is as follows:

After adding benzonitrile ketene and fluorine-containing substances into the dry reactor, vacuumize the reactor and change nitrogen;

Then under the protection of nitrogen, first add anhydrous acetonitrile, then dropwise add the benzyne precursor, after the dropwise addition, stir at room temperature until the reaction is completed.

Still further, the time for stirring at room temperature is 24 hours.

Compared with the prior art, the benefits of the present invention are:

The technical scheme of the present invention provides a kind of method that takes benzyne precursor and benzonitrile enone as raw material cyclization synthesis naphthalene nitrile and its derivative (1,3-diphenyl-2-naphthalene nitrile), has It has the characteristics of simple operation, short reaction cycle, wide application range of substrates, high yield, no transition metal catalysis, process economy and environmental friendliness. In addition, compared with the same type of reaction reported in the literature, it effectively solves the multi-step synthesis in the reaction, harsh reaction conditions such as metal catalysis, heating and cooling, and is more in line with the requirements of the development of green chemistry, especially for the substrate The method has wide scope, mild reaction conditions and high yield, and has broad application prospects in the preparation of natural products and biomedicine.

Detailed ways

In order to further elaborate the cyclization synthesis method of a kind of naphthalene nitrile and its derivatives of the present invention, reach the expected purpose of the invention, below in conjunction with preferred embodiment, to the cyclization synthesis method of a kind of naphthalene nitrile and its derivatives proposed according to the present invention , its specific implementation, structure, features and effects are described in detail below. In the following description, different "one embodiment" or "embodiment" do not necessarily refer to the same embodiment. Furthermore, the particular features, structures or characteristics of one or more embodiments may be combined in any suitable manner.

Below in conjunction with specific embodiment, the cyclization synthesis method of a kind of naphthalene nitrile of the present invention and derivative thereof is described in further detail:

The reaction principle of the present invention is: mainly contain two-step reaction. (1) Using ultra-dry anhydrous acetonitrile as a solvent, using a fluorine-containing substance (preferably an organic base TBAT tetra-n-butylammonium difluorotriphenylsilicate) as a fluorine source, under the action of a fluorine-containing substance, benzene Alkyne precursors are transformed into benzynes, and benzonitrile enones are transformed into carbanion intermediates; (2) benzynes interact with carbanion intermediates for cyclization reactions.

Technical scheme of the present invention is:

Under the condition of oxygen barrier, benzonitrile ketene, fluorine-containing substance, benzyne precursor and anhydrous acetonitrile are stirred at room temperature until the reaction is completed;

The reaction solution was distilled under reduced pressure to obtain a solid substance;

The solid matter is separated and purified by silica gel column chromatography to obtain the naphthalonitrile and its derivatives.

Preferably, the reaction formula of the cyclization synthesis method is:

In the formula, R is a substituent at the 2-, 3-, or 4-position on the benzyne aromatic ring, or a disubstituted or multiple substituent on the aromatic ring; it is selected from one of the following groups: -F, -CH _3. -OCH ₃ , naphthyl;

R ₁ is one of phenyl, phenyl substituted with electron-withdrawing or electron-donating group, part of aliphatic hydrocarbon and heterocyclic group; selected from one of the following groups: -C ₆ H ₅ , 4-CH ₃ C ₆ H ₄ , 4-CH ₃ OC ₆ H ₄ , 4-FC ₆ H ₄ , 4-EtO ₂ CC ₆ H ₄ , CH ₃ , 2-furyl, 2-thienyl;

R ₂ is one of phenyl, phenyl substituted with an electron-withdrawing or electron-donating group, and a heterocyclic group; one of the following groups: -C ₆ H ₅ , 4-CH ₃ C ₆ H ₄ , 3-CH ₃ C ₆ H ₄ , 2-CH ₃ C ₆ H ₄ , 4-CH ₃ OC ₆ H ₄ , 3-CH ₃ OC ₆ H ₄ , 2-CH ₃ OC ₆ H ₄ , 4-ClC ₆ H ₄ , 3-ClC ₆ H ₄ , 3,3-difluorophenyl, 4-BrC ₆ H ₄ , 4-FC ₆ H ₄ , naphthyl, 2-thienyl;

R ₃ is β-ethyl-β-phenyl.

Preferably, the oxygen barrier condition is a nitrogen atmosphere.

Preferably, the fluorine-containing substance is selected from one of the following: cesium fluoride, potassium fluoride and 18-crown-6, TBAT, TBAF, TMAF. (Potassium fluoride and 18-crown-6: when fluorine participates in the reaction, 18-crown-6 acts to fix potassium ions and prevent potassium ions from participating in the reaction)

Further preferably, the fluorine-containing substance is TBAT.

Further preferably, the molar ratio of the benzyne precursor, benzonitrile enone and TBAT is 2:1:6.

Preferably, the silica gel column chromatography uses a mixed solution composed of petroleum ether:ethyl acetate:methanol with a volume ratio of 100:1:1 as the eluent.

Preferably, the specific operation of stirring the benzonitrile ketene, fluorine-containing substance, benzyne precursor and anhydrous acetonitrile at room temperature until the end of the reaction is as follows:

After adding benzonitrile ketene and fluorine-containing substances into the dry reactor, vacuumize the reactor and change nitrogen;

Then under the protection of nitrogen, first add anhydrous acetonitrile, then dropwise add the benzyne precursor, after the dropwise addition, stir at room temperature until the reaction is completed.

The present invention carries out the cyclization synthesis of naphthalonitrile and its derivatives in an anhydrous and oxygen-free reaction system, which can prevent water and other substances from participating in the cyclization synthesis reaction, thereby avoiding the generation of by-products and affecting the yield.

Further preferably, the time for stirring at room temperature is 24 hours.

specific embodiment

Example 1.

The synthesis of benzonitrile ketene adopts the following reaction formula:

Ar ¹ = phenyl, phenyl with electron-withdrawing or electron-donating group attached, heterocyclic group

Ar ² = phenyl, phenyl with electron-withdrawing or electron-donating group attached, heterocyclic group

(1) Dry the 50ml reaction tube in an infrared drying oven for about half an hour, take out the reaction tube when it is cooled to room temperature, and add the weighed benzoylacetonitrile (10.0mmol, 1.4516g) into the reaction tube.

(2) Vacuumize the whole device for nitrogen, repeat three times. Under the protection of nitrogen, anhydrous dichloromethane (20ml) was added into the reaction tube, followed by adding acetophenone (10.5mmol, 1.23ml) into the reaction tube and stirring.

After the addition was complete, the reaction device was moved into an ice-water bath, and when the temperature of the reaction system was lowered to 0° C., titanium tetrachloride (10.5 mmol, 1.2 ml) was slowly added within 10 minutes.

After the reaction was carried out for half an hour, pyridine (36 mmol, 3.0 ml) was slowly added to the reaction tube, and the pyridine was added dropwise within 30 minutes, then the ice-water bath was removed, and the reaction was allowed to stir overnight at room temperature. After the reaction was complete, the reaction was quenched with 2.0N HCl (10 ml).

(3) The reaction was transferred to a separatory funnel, and extracted with dichloromethane. The separated water phase was repeatedly washed with dichloromethane several times and then the organic phase was combined, anhydrous sodium sulfate was added to the organic phase to dry and remove water, after filtering and washing through a common funnel, rotary evaporation was carried out with a rotary evaporator, and passed through a column Chromatography for separation and purification to obtain the product benzonitrile enone.

Embodiment 2: the preparation of 1,3-diphenyl-2-naphthalene nitrile

The reaction formula is as follows:

Add the accurately weighed 0.1mmol (E)-2-benzoyl-3-phenylbut-2-enenitrile, 0.6mmolTBAT (tetra-n-butylammonium difluorotriphenyl base silicate), then vacuumize the reaction tube and change the nitrogen gas, and reciprocate three times. Under the protection of nitrogen gas, first add 1ml of acetonitrile, and then add 0.2mmol of the benzyne precursor with a micro-injector dropwise. Into the reaction tube, after the dropwise addition, stir at room temperature for 24 hours, spot plate detection, after the reaction, transfer the reaction solution to a chicken heart bottle, remove the solvent through a vacuum distillation device and complete spin-drying and solidification, and then use petroleum ether : Ethyl acetate: Methanol 100:1:1 was used as the eluent to separate and purify by silica gel column chromatography to obtain a pure white product. The calculated yield was 94%.

1,3-Diphenyl-2-naphthonitrile IR and NMR data, high resolution, melting point data: White solid; mp144.3-144.8℃; IR(KBr,cm ^-1 )υ 3043,2222,1619,1580 ,1488,1444,1410,1371,1332,1182,1075,1026,895,793,696,613,516; ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.96-7.90(m,2H),7.69-7.61(m,4H), 7.60-7.41(m,9H); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm)147.94,139.93,138.76,136.87,134.69,130.83,130.05,129.27,129.08,128.85,128.71,128.661,128 128.28, 127.39, 127.37, 117.95, 109.99; HRMS(ESI) m/z calcd for C ₂₃ H ₁₆ N ⁺ [M+H] ⁺ 306.12773, found 306.12781.

Embodiment 3: the preparation of 1-phenyl-3-p-tolyl-2-naphthalene nitrile

The reaction formula is as follows:

Add 0.1mmol (E)-2-benzoyl-3-p-tolylbut-2-enenitrile, 0.6mmol TBAT (tetra-n-butylammonium difluorotrifluorotri Phenyl silicate), then vacuumize the reaction tube and change the nitrogen, reciprocate three times, under the protection of nitrogen, first add 1ml of acetonitrile, and then draw 0.2mmol of the benzyne precursor drop by drop with a micro-injector Add it into the reaction tube, after the dropwise addition is completed, stir at room temperature for 24 hours, point the plate for detection, after the reaction is completed, transfer the reaction solution to a chicken heart bottle, remove the solvent through a vacuum distillation device and complete the spin-drying and solidification, and then use petroleum Ether: ethyl acetate: methanol 100:1:1 was used as the eluent to separate and purify by silica gel column chromatography to obtain a pure white product. After calculation, the yield is 80%.

IR and NMR data, high resolution, melting point data of 1-phenyl-3-p-tolyl-2-naphthalene nitrile: Whitesolid; mp 149.0-149.8℃; IR(KBr,cm ^-1 )υ 3049,2219,1616, 1512, 1485, 1440, 1373, 1330, 1186, 1026, 896, 815, 756, 702, 621, 522; ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.95-7.87 (m, 2H), 7.65-7.52 (m, 7H), 7.51-7.42 (m,3H),7.35-7.29(m,2H),2.43(s,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm)147.87,139.96,138.34,136.92,135.87,134.73,130.72,130.04 ,129.34,129.12,129.00,128.81,128.61,128.51,128.23,127.34,127.24,118.07,110.08,21.30; HRMS(ESI)m/z calcd for C ₂₄ H ₁₈ N ⁺ [M+H] ⁺ 320.143320.f .

Embodiment 4: the preparation of 3-(3-chlorophenyl)-1-phenyl-2-naphthalene nitrile

The reaction formula is as follows:

Into the dry 25ml reaction tube, add the accurately weighed 0.1mmol (E)-2-benzoyl-3-(3-chlorophenyl)but-2-enenitrile, 0.6mmolTBAT (tetra-n-butylammonium difluorotriphenylsilicate), then vacuumize the reaction tube and change the nitrogen gas, and reciprocate three times. Add the solution dropwise to the reaction tube. After the dropwise addition, stir at room temperature for 24 hours, and spot the plate for detection. After the reaction, transfer the reaction solution to a chicken heart bottle to remove the solvent through a vacuum distillation device and complete spin-drying and solidification. , and then use petroleum ether: ethyl acetate: methanol 100:1:1 as the eluent to separate and purify by silica gel column chromatography to obtain a pure white product. After calculation, the yield is 85%.

3-(3-Chlorophenyl)-1-phenyl-2-naphthalenenitrile IR and NMR data, high resolution, melting point data: Whitesolid; mp 132.0-132.7℃; IR(KBr,cm ^-1 )υ 3055, 2218,1595,1562,1477,1446,1332,1080,881,786,756,709; ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.95 (dd, J = 8.6, 1.2Hz, 1H), 7.92 (s, 1H), 7.69-7.63(m,3H),7.61-7.42(m,9H); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm)148.15,140.49,138.38,136.64,134.58,134.49,131.02,130.00,129.84,129.34 ,129.29,128.96,128.79,128.67,128.57,128.34,127.72,127.53,127.42,117.63,109.67; HRMS(ESI)m/z calcdfor C ₂₃ H ₁₅ ClN ⁺ [M+H] ⁺ 340.08875,found 85

Embodiment 5: the preparation of 3-(naphthalene-2-yl)-1-phenyl-2-naphthalene nitrile

The reaction formula is as follows:

To a dry 25ml reaction tube, add successively 0.1mmol (E)-2-benzoyl-3-(naphthalene-2-yl)but-2-enenitrile, 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenylsilicate), then vacuumize the reaction tube and change the nitrogen gas, and reciprocate three times. Add the solution dropwise to the reaction tube. After the dropwise addition, stir at room temperature for 24 hours, and spot the plate for detection. After the reaction, transfer the reaction solution to a chicken heart bottle to remove the solvent through a vacuum distillation device and complete spin-drying and solidification. , and then use petroleum ether: ethyl acetate: methanol 100:1:1 as the eluent to separate and purify by silica gel column chromatography to obtain a pure white product. The calculated yield was 84%.

3-(Naphthalene-2-yl)-1-phenyl-2-naphthalenenitrile IR and NMR data, high resolution, melting point data: Whitesolid; mp 172.1-172.9℃; IR(KBr,cm ^-1 )υ 3440, 3043, 2223, 1616, 1585, 1442, 1317, 1128, 889, 860, 815, 744, 702; ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 8.14 (s, 1H), 8.04 (s, 1H), 8.01-7.89 (m, 4H ), 7.80 (d, J=8.5Hz, 1H), 7.71-7.63 (m, 2H), 7.62-7.48 (m, 8H); ¹³ C NMR (100MHz, CDCl ₃ ) δ (ppm) 148.05, 139.90, 136.87 ,136.18,134.73,133.25,133.05,130.86,130.06,129.13,129.01,128.87,128.65,128.61,128.38,128.32,127.77,127.44,127.41,126.95,126.60,126.52,118.02,110.15；HRMS(ESI)m/z calcd for C ₂₇ H ₁₈ N ⁺ [M+H] ⁺ 356.14338, found 356.14310.

Embodiment 6: Preparation of 1-phenyl-3-(thiophen-2-yl)-2-naphthalene nitrile

The reaction formula is as follows:

Into the dry 25ml reaction tube, add the accurately weighed 0.1mmol (E)-2-benzoyl-3-(thiophen-2-yl)but-2-enenitrile, 0.6mmolTBAT (tetra-n-butylammonium difluorotriphenylsilicate), then vacuumize the reaction tube and change the nitrogen gas, and reciprocate three times. Add the solution dropwise to the reaction tube. After the dropwise addition, stir at room temperature for 24 hours, and spot the plate for detection. After the reaction, transfer the reaction solution to a chicken heart bottle to remove the solvent through a vacuum distillation device and complete spin-drying and solidification. , and then use petroleum ether: ethyl acetate: methanol 100:1:1 as the eluent to separate and purify by silica gel column chromatography to obtain a pure white product. The calculated yield was 68%.

IR and NMR data, high resolution, melting point data of 1-phenyl-3-(thiophen-2-yl)-2-naphthonitrile: Whitesolid; mp 154.7-155.5℃; IR(KBr,cm ^-1 )υ 3047, 2229,1620,1583,1485,1444,1377,1319,1153,1070,954,885,854,837,756,705; ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.05(s,1H),7.93(d,J＝8.2Hz,1H ), 7.67-7.53 (m, 6H), 7.51-7.41 (m, 4H), 7.19 (dd, J=5.1, 3.7Hz, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ (ppm) 148.55, 139.82 , 136.72, 134.63, 132.04 _, 130.92, 129.95, 129.28, 128.92, 128.69, 128.66, 128.27, 128.21, 127.86 _, 127.57, 127.42, 126.84, 117.96, 109.28 ^; [M+H] ⁺ 312.08415, found 312.08408.

Embodiment 7: Preparation of 1-(4-methoxyphenyl)-3-phenyl-2-naphthalenenitrile

The reaction formula is as follows:

In the dry 25ml reaction tube, add the accurately weighed 0.1mmol (E)-2-(4-methoxybenzoyl)-3-phenylbut-2-enenitrile, 0.6mmolTBAT (tetra-n-butyl ammonium difluorotriphenylsilicate), then vacuumize the reaction tube and change the nitrogen, reciprocate three times, under the protection of nitrogen, first add 1ml of acetonitrile, and then suck 0.2mmol of benzene Add the alkyne precursor dropwise to the reaction tube. After the dropwise addition, stir at room temperature for 24 hours, and spot the plate for detection. After drying and curing, petroleum ether: ethyl acetate: methanol 100:1:1 was used as an eluent to separate and purify by silica gel column chromatography to obtain a pure white product. After calculation, the yield is 80%.

1-(4-methoxyphenyl)-3-phenyl-2-naphthonitrile IR and NMR data, high resolution, melting point data: White solid; mp 161.5-162.3℃; IR(KBr,cm ^-1 ) υ 3062,2933,2223,1610,1575,1514,1492,1382,1249,1031,837,773,703; ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.95-7.90 (m, 2H), 7.74-7.60 (m ,4H),7.56-7.40(m,6H),7.13-7.07(m,2H),3.92(s,3H); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm)159.97,147.79,139.96,138.83, _{134.72,131.35,131.10,129.25,129.00,128.94,128.58,128.48,128.39,128.27,127.42,127.29,118.17,114.09,110.15,55.34 _} ^_ ] ⁺ 336.13829, found 336.13806.

Example 8: Preparation of 1-(4-fluorophenyl)-3-phenyl-2-naphthalenenitrile

The reaction formula is as follows:

Add the accurately weighed 0.1mmol (E)-2-(4-fluorobenzoyl)-3-phenylbut-2-enenitrile, 0.6mmolTBAT (tetra-n-butylammonium difluorotriphenylsilicate), then vacuumize the reaction tube and change the nitrogen gas, and reciprocate three times. Add the solution dropwise to the reaction tube. After the dropwise addition, stir at room temperature for 24 hours, and spot the plate for detection. After the reaction, transfer the reaction solution to a chicken heart bottle to remove the solvent through a vacuum distillation device and complete spin-drying and solidification. , and then use petroleum ether: ethyl acetate: methanol 100:1:1 as the eluent to separate and purify by silica gel column chromatography to obtain a pure white product. After calculation, the yield is 85%.

1-(4-fluorophenyl)-3-phenyl-2-naphthalenenitrile IR and NMR data, high resolution, melting point data: Whitesolid; mp 178.8-179.6℃; IR(KBr,cm ^-1 )υ 3057, 2223,1606,1514,1490,1218,1161,896,844,763,752,698; ¹ H NMR (400MHz, CDCl ₃ )δ(ppm)7.97-7.92(m,2H),7.70-7.59(m,4H),7.56-7.43(m ,6H),7.30-7.26(m,2H); ¹³ C NMR(100MHz,CDCl ₃ )δ(ppm)163.07(d,J＝248.4Hz),146.79,139.93,138.61,134.71,132.74(d,J＝ ¹⁹ F NMR ( 376MHz, CDCl ₃ )δ(ppm)-112.54; HRMS(ESI)m/z calcd for C ₂₃ H ₁₅ NF ⁺ [M+H] ⁺ 324.11830, found 324.11813.

Example 9: Preparation of 3-phenyl-1-(thiophen-2-yl)-2-naphthalenenitrile

The reaction formula is as follows:

Into the dry 25ml reaction tube, add the accurately weighed 0.1mmol (E)-3-phenyl-2-(thiophene-2-carbonyl)but-2-enenitrile, 0.6mmolTBAT (tetra-n-butylammonium di Fluorotriphenylsilicate), then vacuumize the reaction tube and change the nitrogen, reciprocate three times, under the protection of nitrogen, first add 1ml of acetonitrile, and then suck 0.2mmol of the benzyne precursor with a micro injector Add dropwise into the reaction tube, after the dropwise addition is completed, stir at room temperature for 24 hours, point the plate for detection, after the reaction is completed, transfer the reaction solution to a chicken heart bottle, remove the solvent through a vacuum distillation device, and complete spin-drying and solidification. Then petroleum ether: ethyl acetate: methanol 100:1:1 was used as the eluent to separate and purify by silica gel column chromatography to obtain a pure white product. The calculated yield was 76%.

3-Phenyl-1-(thiophen-2-yl)-2-naphthalenenitrile IR and NMR data, high resolution, melting point data: Whitesolid; mp 125.3-126.0℃; IR(KBr,cm ^-1 )υ 3064, 2219, 1614, 1589, 1488, 1440, 1369, 1326, 1288, 1224, 1145, 1072, 902, 846, 767, 700, 624; ¹ H NMR (400MHz, CDCl ₃ ) δ (ppm) 7.95 (s, 1H), 7.92 (d, J = 8.2Hz, 1H), 7.88(d, J=8.5Hz, 1H), 7.68-7.62(M, 3H), 7.60(dd, J=5.1, 1.2Hz, 1H), 7.57-7.43(m, 4H), 7.31 (dd, J=3.5, 1.1Hz, 1H), 7.27-7.25 (m, 1H); ¹³ C NMR (100MHz, CDCl ₃ ) δ (ppm) 140.29, 140.02, 138.53, 136.39, 134.54, 131.87, 129.88, 129.64,129.27,129.26,128.65,128.55,128.24,127.86,127.75,127.43,127.14,117.59,111.89; HRMS(ESI)m/z calcd for C ₂₁ H ₁₄ NS ⁺ [M+H] ⁺ 312.083415.found

Embodiment 10: Preparation of 1-methyl-3-phenyl-2-naphthalene nitrile

The reaction formula is as follows:

Add the accurately weighed 0.1mmol (E)-2-acetyl-3-phenylbut-2-enenitrile, 0.6mmolTBAT (tetra-n-butylammonium difluorotriphenyl Silicate), then vacuumize the reaction tube and change the nitrogen, reciprocate three times, under the protection of nitrogen, first add 1ml of acetonitrile, then add 0.2mmol of the benzyne precursor dropwise to the In the reaction tube, after the dropwise addition is completed, stir at room temperature for 24 hours, and point the plate for detection. After the reaction is completed, transfer the reaction solution to a heart-shaped bottle to remove the solvent through a vacuum distillation device and complete spin-drying and solidification, and then use petroleum ether: Ethyl acetate:methanol 100:1:1 was used as the eluent to separate and purify by silica gel column chromatography to obtain a pure white product. After calculation, the yield is 50%.

IR and NMR data, high resolution, melting point data of 1-methyl-3-phenyl-2-naphthalene nitrile: White solid; mp112.1-112.8℃; IR(KBr,cm ^-1 )υ 3058,2219,1625 ,1586,1494,1445,1410,1379,1326,1181,1072,1028,927,883,777,764,751,698,676,615; ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)8.11(m,1H),7.91-7.84,(m,1H) 7.77(s,1H),7.68-7.58(m,4H),7.54-7.40(m,3H),3.03(s,3H); ¹³ CNMR(100MHz,CDCl ₃ )δ(ppm)142.77,139.80,139.00, 134.40,130.72,129.15,128.94,128.87,128.55,128.35,127.47,127.34,124.89,118.37,110.16,18.14; HRMS( ^ESI )m/zcalcd for C ₁₈ H ₁₄ N ⁺ [M+H]1 1204.4,found .

Example 11: Preparation of 6,7-dimethyl-1,3-diphenyl-2-naphthalenenitrile

The reaction formula is as follows:

Add the accurately weighed 0.1mmol (E)-2-benzoyl-3-phenylbut-2-enenitrile, 0.6mmolTBAT (tetra-n-butylammonium difluorotriphenyl base silicate), then vacuumize the reaction tube and change the nitrogen gas, and reciprocate three times. Under the protection of nitrogen gas, first add 1ml of acetonitrile, and then suck 0.2mmol of 4,5-dimethyl- 2-(Trimethylsilyl)phenyl trifluoromethanesulfonate was added dropwise to the reaction tube. After the addition was completed, it was stirred at room temperature for 24 hours, and detected by spotting. After the reaction was completed, the reaction solution was Transfer to a chicken heart bottle, remove the solvent through a vacuum distillation device, spin dry and solidify, and then use petroleum ether: ethyl acetate: methanol 100:1:1 as an eluent to separate and purify through silica gel column chromatography to obtain pure white product. The calculated yield was 75%.

6,7-Dimethyl-1,3-diphenyl-2-naphthonitrile IR and NMR data, high resolution, melting point data: Whitesolid (25.0mg, 75%, yield); mp 173.4-174.2℃; IR (KBr,cm ^-1 )υ 3440,3060,2916,2219,1623,1591,1494,1450,1375,1024,902,761,698,613; ¹ H NMR(400MHz,CDCl ₃ )δ(ppm)7.80(s,1H), 7.69-7.63(m,3H),7.61-7.40(m,8H),7.36(s,1H),2.46(s,3H),2.33(s,3H); ¹³ CNMR(100MHz,CDCl ₃ )δ(ppm )146.95,139.51,139.13,139.06,137.55,137.20,133.68,130.04,129.63,129.26,128.67,128.57,128.53,128.23,127.81,127.71,126.56,118.28,108.92,20.44,20.32；HRMS(ESI)m/z calcd for C ₂₅ H ₂₀ N ⁺ [M+H] ⁺ 334.15903, found 334.15897.

Example 12: Preparation of 6,7-difluoro-1,3-diphenyl-2-naphthalenenitrile

The reaction formula is as follows:

Add the accurately weighed 0.1mmol (E)-2-benzoyl-3-phenylbut-2-enenitrile, 0.6mmolTBAT (tetra-n-butylammonium difluorotriphenyl base silicate), then vacuumize the reaction tube and change the nitrogen gas, and reciprocate three times. Under the protection of nitrogen gas, first add 1ml of acetonitrile, and then suck 0.2mmol of 4,5-difluoro-2 -(Trimethylsilyl)phenyl trifluoromethanesulfonate was added dropwise to the reaction tube, after the dropwise addition was completed, and stirred at room temperature for 24 hours, spot plate detection, after the reaction was completed, the reaction solution was transferred to Remove the solvent in the chicken heart bottle through a vacuum distillation device and complete spin-drying and solidification, then use petroleum ether: ethyl acetate: methanol 100:1:1 as the eluent to separate and purify through silica gel column chromatography to obtain a pure white product . The calculated yield was 78%.

6,7-difluoro-1,3-diphenyl-2-naphthalene nitrile IR and NMR data, high resolution, melting point data: Whitesolid mp 175.1-175.8℃; IR(KBr,cm ^-1 )υ 3070,2216 , _{1724,1598,1580,1515,1493,1458,1441,1388,1306,1275,1253,1201,1311,1075,1035,905,870,822,761,739,700,613,569,508} ^; 1H),7.71-7.62(m,3H),7.61-7.56(m,3H),7.55-7.44(m,5H),7.39(dd,J＝11.7,8.0Hz,1H); ¹³ C NMR(100MHz, CDCl ₃ ) δ (ppm) 151.89 (dd, J = 255.1, 15.9 Hz), 150.69 (dd, J = 251.5, 15.4 Hz), 147.33-147.05 (m), 140.74 (d, J = 2.2 Hz), 138.16, 136.21,132.18-131.84(m),129.78,129.30,129.17,128.93,128.74,128.71,128.07(d,J=6.8Hz),127.86-127.67(m),117.44,114.08(d,J=20.6Hz), 113.90(d, J=22.1Hz), 110.55(d, J=2.8Hz); ¹⁹ F NMR(376MHz, CDCl ₃ )δ-131.66(d, J=20.8Hz), -133.10(d, J=20.8Hz ); HRMS(ESI) m/z calcd for C ₂₃ H ₁₄ F ₂ N ⁺ [M+H] ⁺ 342.10888, found.

Comparative example 1.

Let α-cyano-β-methylene ketone 1a be 1.2 times the equivalent of benzyne precursor 2a, use THF as the reaction solvent, and react at room temperature with 2.0 equivalents of KF/18-C-6 as the additive . After reacting for 48 hours, it was found through TLC spot plate monitoring that although there were products in the reaction, the reaction was relatively weak, and there were many remaining α-cyano-β-methylene ketones, and finally separated by column chromatography with less than 10% product The product was obtained at a high rate (see Entry 1 in Table 1 for specific results).

Comparative example 2.

On the basis of Comparative Example 1, the α-cyano-β-methylene ketone 1a was reduced to 1.1 times the equivalent of the benzyne precursor 2a, and the reaction was continued on the basis of keeping other conditions unchanged. After the reaction was carried out for 48 hours, it was found by means of TLC spot plate monitoring that the concentration of the target product became larger, and the target product was finally obtained with a yield of 14% through column chromatography separation and purification (see Entry 2 in Table 1 for specific results).

Comparative example 3.

On the basis of Comparative Example 2, the reaction solvent was optimized, keeping other conditions unchanged.

In the case of using toluene, DMF, and DMSO as solvents, the reaction obtained products with a yield of less than 10% (see Entry 3-5 in Table 1 for specific results); and when using ClCH ₂ CH ₂ Cl, 1,4- When dioxane, CH ₂ Cl ₂ , and DME were used as solvents, the reaction obtained the target product with yields of 14%, 15%, 19%, and 20%, respectively. Although the yield was improved, there was no significant change (see Table Entry 6-9 in 1); when CH ₃ CN was used as the reaction solvent, the product was obtained with a yield of 32% (see Entry 10 in Table 1 for specific results).

Comparative example 4.

On the basis of Comparative Example 3, with CH ₃ CN as the solvent, the reaction was heated to reflux for 48 hours. After the reaction, the product was obtained by column chromatography with a yield of 38% (see Entry 11 in Table 1 for specific results).

Then continue to add 1.5 times the equivalent of Cs ₂ CO ₃ at the same time under the condition of reflux, and react for 48 hours. It was found by column chromatography that the reaction yield not only did not increase as expected, but decreased to some extent. As a result, the product was only obtained with a yield of 34% (see Entry 12 in Table 1 for specific results).

Summary: Under the condition of CH ₃ CN as the solvent, although the yield has been improved, the reaction cycle is long and the conditions are harsh. At the same time, there is a large amount of α-cyano-β-methylene ketone remaining, which makes the reaction uneconomical.

Comparative example 5.

Increase the amount of benzyne precursor to 1.5 times that of α-cyano-β-methylene ketone 1a, while replacing the fluorine source used in the previous reaction with CsF and increase the amount of fluorine source to 4.5 times that of 1a, with the previous optimal Solvent CH ₃ CN under yield conditions Try to react at room temperature, that is, the reaction of α-cyano-β-methylene ketone 1a with 1.5 equivalents of benzyne precursor 2a as a model reaction, using CH ₃ CN as solvent, Using 4.5 equivalents of CsF as a fluorine source, the reaction was carried out at room temperature. After the reaction was carried out for 24 hours, the crude product was separated and purified by column chromatography, and finally the benzene cyclization product 3a naphthalonitrile was successfully obtained with a yield of 37% (see Entry 13 in Table 1 for specific results).

Comparative example 6.

On the basis of Comparative Example 5, the additive (ie fluorine-containing substance or fluorine source) was optimized, keeping other conditions unchanged.

When other fluorine sources KF/18-crown-6, TBAF, TMAF, and TBAT were used as additives, the specific results are shown in Entry 14-17 in Table 1. Among them, KF/18-crown-6 obtained the desired product with an isolated yield of 39% (see Entry 14 in Table 1 for specific results), and TBAF and TMAF promoted the reaction with moderate yields of 40% and 47%, respectively (see Entry 15-16 in Table 1 for specific results); and when TBAT was used as a fluorine source, the yield was significantly increased to 81% (see Entry 17 in Table 1 for specific results).

Comparative example 7.

On the basis of Comparative Example 5, under the optimal fluorine source conditions, the solvent for the reaction was simply screened (see Entry 18-25 in Table 1 for specific results). Among all the solvents screened, it was found that the effect of DME was relatively good, but the yield was only 65% (see Entry 19 in Table 1 for specific results), thus confirming that CH ₃ CN was the optimal solvent for the reaction.

Comparative example 8.

On the basis of Comparative Example 7, the amount of benzyne precursor was increased to 2.0 equivalents, and it was found that the yield of the reaction could reach 94% (see Entry 26 in Table 1 for specific results). However, further increasing the benzyne precursor to 2.5 equivalents unfortunately did not produce a significant change in the reaction yield (see Entry 27 in Table 1 for specific results).

Through comparative examples 1-8, the optimal conditions for the reaction were determined, that is, using 6.0 equivalents of TBAT as the fluorine source, CH ₃ CN as the solvent for the reaction, and allowing 2.0 equivalents of the benzyne precursor to react with 1a at room temperature for 24 hours. .

The reaction formula is as follows:

Table 1

Standard conditions: 1a (0.10mmol), 2a (0.15mmol), solvent: 1.0mL, room temperature. ^b Isolated yield. ^c 1a (0.12mmol), 2a (0.10mmol), KF/18-crown-6 (0.2mmol) ,solvent:1.0mL,room temperature.d ^1a (0.11mmol),2a(0.10mmol),KF/18-crown-6(0.2mmol),solvent:1.0mL,room ^{temperature.e} 1a(0.11mmol),2a (0.10mmol), KF/18-crown-6(0.2mmol), solvent: 1.0mL, 82℃. ^f 1a(0.11mmol), 2a(0.10mmol), KF/18-crown-6(0.2mmol), Cs ₂ CO ₃ (0.15mmol),solvent:1.0mL,82℃. ^g 1a(0.10mmol),2a(0.20mmol),TBAT(0.60mmol) ^.h 1a(0.10mmol),2a(0.25mmol),TBAT (0.75 mmol).

The invention provides a method for synthesizing naphthalene derivatives by cyclization with simple operation, environmental friendliness, high yield, no transition metal catalysis and process economy. Wherein, the fluorine-containing substance is used as the fluorine source (preferably TBAT), the benzyne precursor and benzonitrile enone are the reaction raw materials, and the solvent is ultra-dry anhydrous acetonitrile. Under these conditions, the benzyne precursor and The benzonitrile enone is reacted with stirring at room temperature under the action of a fluorine-containing substance (preferably TBAT), and finally naphthalonitrile and its derivatives are obtained with a yield of 50-94%. The reaction system is free of transition metal catalysis, has a wide range of substrates and mild conditions, and has broad application prospects in the preparation of natural products and biomedicine.

The above is only a preferred embodiment of the embodiment of the present invention, and does not limit the embodiment of the present invention in any form. Any simple modification, equivalent change and Modifications still fall within the scope of the technical solutions of the embodiments of the present invention.

Claims (6)

1. a cyclization synthesis method of naphthalonitrile and derivatives thereof, is characterized in that, comprises the following steps: Under the condition of oxygen barrier, benzonitrile ketene, fluorine-containing substance, benzyne precursor and anhydrous acetonitrile are stirred at room temperature until the reaction is completed; The reaction solution was distilled under reduced pressure to obtain a solid substance; The solid matter is separated and purified by silica gel column chromatography to obtain the naphthalonitrile and its derivatives; Wherein, the fluorine-containing substance is selected from one of the following: cesium fluoride, potassium fluoride and 18-crown-6, TBAT, TBAF, TMAF; Described cyclization synthetic method adopts following reaction formula to represent:

In the formula, R is a substituent at the 2-, 3-, or 4-position on the benzyne aromatic ring, or a disubstituted or multiple substituent on the aromatic ring; it is selected from one of the following groups: -F, -CH ₃ , -H; R ₁ is selected from one of the following groups: -C ₆ H ₅ , 4-CH ₃ OC ₆ H ₄ , 4-FC ₆ H ₄ , -CH ₃ , 2-thienyl; R ₂ is selected from one of the following groups: -C ₆ H ₅ , 4-CH ₃ C ₆ H ₄ , 4-ClC ₆ H ₄ , naphthyl, 2-thienyl; _R3 is -H. 2. cyclization synthesis method according to claim 1, is characterized in that, The oxygen barrier condition is a nitrogen atmosphere. 3. cyclization synthesis method according to claim 1, is characterized in that, The fluorine-containing substance is TBAT. 4. cyclization synthesis method according to claim 3, is characterized in that, The molar ratio of the benzyne precursor, benzonitrile enone and TBAT is 2:1:6. 5. cyclization synthesis method according to claim 1, is characterized in that, The silica gel column chromatography uses a mixed solution composed of petroleum ether:ethyl acetate:methanol with a volume ratio of 100:1:1 as the eluent. 6. cyclization synthesis method according to claim 1, is characterized in that, The specific operation of stirring benzonitrile ketene, fluorine-containing substance, benzyne precursor and anhydrous acetonitrile at room temperature until the reaction ends is as follows: After adding benzonitrile ketene and fluorine-containing substances into the dry reactor, vacuumize the reactor and change nitrogen; Then under the protection of nitrogen, first add anhydrous acetonitrile, then dropwise add the benzyne precursor, after the dropwise addition, stir at room temperature until the reaction is completed.