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

Cyclization synthesis method of naphthalocyanide and derivative thereof Download PDF

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CN111393322B
CN111393322B CN202010211535.9A CN202010211535A CN111393322B CN 111393322 B CN111393322 B CN 111393322B CN 202010211535 A CN202010211535 A CN 202010211535A CN 111393322 B CN111393322 B CN 111393322B
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杜广芬
王强
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Shihezi University
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    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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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

Cyclization synthesis method of naphthalocyanide and derivative thereof
Technical Field
The invention relates to the field of chemistry, in particular to a cyclization synthesis method of naphthalocyanide and derivatives thereof.
Background
Polysubstituted naphthalenes are important structures found in many natural products, bioactive compounds, pharmaceuticals and functional organic materials. Therefore, the naphthalene derivatives have wide application prospects. Because of their importance, organic chemists have made great efforts to develop these ubiquitous frameworks in an efficient manner.
In the past decade, there has been a demand for the use of transition metal catalyzed Diels-Alder reactions,
Figure BDA0002422998500000011
Reactions and other cyclization reactions have been extensively studied to produce naphthyl backbones. These reactions often suffer from the use of expensive transition metal catalysts, multiple steps in the reaction process, some chemical and regioselectivity that is difficult to control, and the like. In 2007, huang and Xue developed transition metal-free multicomponent reactions of phenylalkynes, β -ketosulfones and activated olefins in 2007, by which polysubstituted naphthols and naphthalenes were produced; in 2012, bi ju and coworkers reported 1,2-benzoquinone and phenylalkyne to undergo a Diels-Alder reaction first, and the reaction product can be further converted to naphthalene by radiation at 254 nm; in 2016, wu, shu and his colleagues reported the formalism of [2+2 ] for phenylalkyne, ketone and alkynoate]The cycloaddition reaction provides a new method for synthesizing the functionalized naphthalene. In 2018, wu, shu and his colleagues developedThe serial sigma bond insertion/benzene alkylation reaction of the phenylalkyne obtains two types of polysubstituted naphthalene; in the same year, mukher jee and his colleagues reported that phenylalkyne and glycosyl diene utilized the Diels-Alder reaction to construct meta-disubstituted naphthalenes with chiral side chains. However, despite the great progress in this field in recent years, these reactions still have the disadvantages of requiring multi-component participation, multi-step reactions, and metal catalysis, and thus there is still an urgent need to develop a new method for conveniently and efficiently preparing polysubstituted naphthalenes.
Disclosure of Invention
The invention aims to provide a cyclization synthesis method of naphthalocyanide and derivatives thereof, which takes a benzyne precursor and benzonitrile ketene as raw materials, is simple and convenient to operate, environment-friendly, high in yield, free of transition metal catalysis, and economical in process.
In order to realize the purpose, the adopted technical scheme is as follows:
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 solution 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.
Further, the reaction formula of the cyclization synthesis method is as follows:
Figure BDA0002422998500000021
in the formula, R is a substituent at 2-, or 3-, or 4-position on a benzyne aromatic ring, or a disubstituted or polysubstituent on the aromatic ring; selected from one of the following groups: -F, -CH 3 、-OCH 3 Naphthyl;
R 1 is one of phenyl, phenyl connected with electron withdrawing group or electron donating group for substitution, partial 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 C-C 6 H 4 、CH 3 2-furyl, 2-thienyl;
R 2 is one of phenyl, phenyl connected with electron withdrawing group or electron donating group for substitution and heterocyclic group; selected from 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 beta-ethyl-beta-phenyl.
Further, the oxygen isolation condition is a nitrogen atmosphere.
Further, the fluorine-containing substance is selected from one of the following substances: cesium fluoride, potassium fluoride and 18-crown-6, TBAT, TBAF, TMAF.
Still further, the fluorine-containing species is TBAT.
Still further, the molar ratio of the phenylalkyne precursor to the benzonitrile ketene to the TBAT is 2:1:6.
furthermore, the silica gel column chromatography adopts a method of purifying the silica gel column by using petroleum ether: ethyl acetate: the volume ratio of methanol is 100.
Further, under the condition of oxygen isolation, the concrete operations of stirring the benzonitrile ketene, the fluorine-containing substance, the phenylalkyne precursor and the anhydrous acetonitrile at room temperature until the reaction is finished are as follows:
after adding benzonitrile ketene and fluorine-containing substances into a dried reactor, vacuumizing the reactor and exchanging nitrogen;
under the protection of nitrogen, firstly adding anhydrous acetonitrile, then dropwise adding the phenylalkyne precursor, and stirring at room temperature until the reaction is finished after the dropwise adding is finished.
Still further, the stirring time at room temperature is 24h.
Compared with the prior art, the invention has the advantages that:
the technical scheme of the invention provides a method for cyclizing and synthesizing naphthalocyanide and derivatives thereof (1,3-diphenyl-2-naphthalocyanide) by taking a benzyne precursor and a benzonitrile ketene as raw materials, which has the characteristics of simple operation, short reaction period, wide substrate application range, high yield, no transition metal catalysis, economic process, environmental friendliness and the like. In addition, compared with the same type of reaction reported in the literature, the method effectively solves the harsh reaction conditions of multi-step synthesis, metal catalysis, heating and cooling and the like in the reaction, is more suitable for the requirement of green chemical development, and particularly has the advantages of wide substrate application range, mild reaction conditions, high yield and wide application prospect in the preparation of natural products and biological medicines.
Detailed Description
In order to further illustrate the process for cyclizing synthesis of a naphthonitrile and a derivative thereof according to the present invention, and achieve the intended purpose, the following embodiments, structures, features, and effects thereof will be described in detail with reference to the accompanying drawings. In the following description, different "one embodiment" or "an embodiment" refers to not necessarily the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
The cyclized synthesis method of a naphthonitrile and a derivative thereof according to the present invention will be described in further detail with reference to the following specific examples:
the reaction principle of the invention is as follows: mainly comprises two steps of reaction. (1) Taking ultra-dry anhydrous acetonitrile as a solvent, taking a fluorine-containing substance (preferably organic base TBAT tetra-n-butylammonium difluorotriphenylsilicate) as a fluorine source, converting an benzyne precursor into benzyne under the action of the fluorine-containing substance, and converting benzonitrile ketene into a carbanion intermediate; (2) The benzyne, and the carbanion intermediate interact to carry out a cyclization reaction.
The technical scheme of the invention is as follows:
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 solution 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.
Preferably, the reaction formula of the cyclization synthesis method is as follows:
Figure BDA0002422998500000041
in the formula, R is a substituent at 2-, or 3-, or 4-position on a benzyne aromatic ring, or a disubstituted or polysubstituted group on the aromatic ring; selected from one of the following groups: -F, -CH 3 、-OCH 3 Naphthyl;
R 1 is one of phenyl, phenyl connected with electron withdrawing group or electron donating group for substitution, partial 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 C-C 6 H 4 、CH 3 2-furyl, 2-thienyl;
R 2 is one of phenyl, phenyl connected with electron withdrawing group or electron donating group for substitution and heterocyclic group; selected from 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 beta-ethyl-beta-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, the 18-crown-6 plays a role in fixing potassium ions and avoiding the potassium ions from participating in the reaction )
Further preferably, the fluorine-containing substance is TBAT.
More preferably, the molar ratio of the phenylalkyne precursor to the benzonitrile enone to TBAT is 2:1:6.
preferably, the silica gel column chromatography adopts a mixed solution of petroleum ether, ethyl acetate and methanol with the volume ratio of 100:1 as an eluent.
Preferably, the specific operation of stirring the benzonitrile ketene, the fluorine-containing substance, the phenylalkyne precursor and the anhydrous acetonitrile at room temperature until the reaction is finished under the oxygen-insulating condition is as follows:
adding benzonitrile ketene and fluorine-containing substances into a dried reactor, vacuumizing the reactor and exchanging nitrogen;
under the protection of nitrogen, firstly adding anhydrous acetonitrile, then dropwise adding the phenylalkyne precursor, and stirring at room temperature until the reaction is finished after the dropwise adding is finished.
The method carries out cyclization synthesis of the naphthalocyanide and the derivative thereof in an anhydrous and oxygen-free reaction system, and can avoid substances such as water and the like from participating in cyclization synthesis reaction, thereby avoiding the generation of by-products and influencing yield.
Further preferably, the stirring time at room temperature is 24h.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1.
The synthesis of the benzonitrile ketene adopts the following reaction formula:
Figure BDA0002422998500000051
Ar 1 = phenyl, phenyl with electron withdrawing or electron donating groups, heterocyclic groups
Ar 2 = phenyl, phenyl with electron withdrawing or electron donating groups, heterocyclic groups
(1) A50 ml reaction tube was dried in an infrared drying oven for about half an hour, taken out when cooled to room temperature, and a weighed amount of benzoylacetonitrile (10.0 mmol, 1.45169g) was added to the reaction tube.
(2) The whole device is vacuumized and nitrogen is exchanged, and the process is repeated three times. Anhydrous dichloromethane (20 ml) was added to the reaction tube under nitrogen blanket, followed by acetophenone (10.5mmol, 1.23ml) and stirring.
After the completion of the addition, the reaction apparatus was transferred to an ice-water bath, and titanium tetrachloride (10.5mmol, 1.2ml) was slowly added over 10 minutes when the temperature of the reaction system was lowered to 0 ℃.
After the reaction had proceeded for half an hour, pyridine (36mmol, 3.0 ml) was then slowly added to the reaction tube and the addition of pyridine was completed over 30 minutes, then the ice water bath was removed and the reaction was allowed to stir at room temperature overnight. After completion of the reaction, the reaction was quenched with 2.0N HCl (10 ml).
(3) The reaction was transferred to a separatory funnel and extracted with dichloromethane. Repeatedly washing the separated water phase with dichloromethane for several times, then combining the organic phases, adding anhydrous sodium sulfate into the organic phases, drying to remove water, filtering and washing through a common funnel, performing rotary evaporation and concentration through a rotary evaporator, and performing separation and purification through column chromatography to obtain the product, namely, the benzonitrile ketene.
Example 2: preparation of 1,3-diphenyl-2-naphthacenitrile
The reaction formula is shown as follows:
Figure BDA0002422998500000061
adding accurately weighed 0.1mmol (E) -2-benzoyl-3-phenylbut-2-enenitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenylsilicate) into a dry 25ml reaction tube in sequence, vacuumizing the reaction tube and exchanging nitrogen for three times, adding 1ml acetonitrile under the protection of nitrogen, then dropwise adding 0.2mmol phenylalkyne precursor absorbed by a microsyringe into the reaction tube, stirring for 24 hours at room temperature after dropwise adding, detecting by using a point plate, transferring the reaction solution into a heart bottle after the reaction is finished, removing the solvent by using a reduced pressure distillation device, drying and curing, and then using petroleum ether: ethyl acetate: methanol 100. The yield was calculated to be 94%.
Infrared and nuclear magnetic data, high resolution, melting point data for 1,3-diphenyl-2-naphthalenecarbonitrile: white solid; mp 144.3-144.8 ℃; 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)147.94,139.93,138.76,136.87,134.69,130.83,130.05,129.27,129.08,128.85,128.71,128.63,128.61,128.45,128.28,127.39,127.37,117.95,109.99；HRMS(ESI)m/z calcd for C 23 H 16 N + [M+H] + 306.12773,found 306.12781.
Example 3: preparation of 1-phenyl-3-p-tolyl-2-naphthalenecarbonitrile
The reaction formula is shown as follows:
Figure BDA0002422998500000071
adding accurately weighed 0.1mmol (E) -2-benzoyl-3-p-tolylbut-2-enenitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenylsilicate) into a dry 25ml reaction tube in sequence, vacuumizing the reaction tube and exchanging nitrogen for three times, adding 1ml acetonitrile under the protection of nitrogen, then sucking 0.2mmol phenylalkyne precursor by a microsyringe dropwise into the reaction tube, stirring for 24 hours at room temperature after dropwise adding, detecting by a point plate, transferring the reaction solution into a heart bottle after the reaction is finished, removing the solvent by a reduced pressure distillation device, drying and curing, and then using petroleum ether: ethyl acetate: methanol 100. The yield was calculated to be 80%.
Infrared and nuclear magnetic data, high resolution, melting point data for 1-phenyl-3-p-tolyl-2-naphthalenecarbonitrile: white solid; 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] + 320.14338,found 320.14325.
Example 4: preparation of 3- (3-chlorophenyl) -1-phenyl-2-naphthacenitrile
The reaction formula is shown as follows:
Figure BDA0002422998500000081
adding accurately weighed 0.1mmol (E) -2-benzoyl-3- (3-chlorphenyl) butyl-2-alkene nitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenyl silicate) into a dry 25ml reaction tube in sequence, then vacuumizing the reaction tube and exchanging nitrogen for three times, under the protection of nitrogen, firstly adding 1ml acetonitrile, then sucking 0.2mmol of phenylalkyne precursor by a microsyringe dropwise into the reaction tube, stirring for 24 hours at room temperature after dropwise addition, detecting a point plate, transferring the reaction liquid into a heart-shaped bottle after the reaction is finished, removing the solvent by a reduced pressure distillation device, and completing spin drying and solidification, and then using petroleum ether: ethyl acetate: methanol 100. The calculated yield was 85%.
Infrared and nuclear magnetic data, high resolution, melting point data for 3- (3-chlorophenyl) -1-phenyl-2-naphthalenecarbonitrile: white solid；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 calcd for C 23 H 15 ClN + [M+H] + 340.08875,found 340.08856.
Example 5: preparation of 3- (naphthalen-2-yl) -1-phenyl-2-naphthalenecarbonitrile
The reaction formula is shown as follows:
Figure BDA0002422998500000082
adding accurately weighed 0.1mmol (E) -2-benzoyl-3- (naphthalene-2-yl) butyl-2-ene nitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenyl silicate) into a dry 25ml reaction tube in sequence, vacuumizing the reaction tube and exchanging nitrogen for three times, adding 1ml acetonitrile under the protection of nitrogen, sucking 0.2mmol of phenylalkyne precursor by a microsyringe dropwise into the reaction tube, stirring at room temperature for 24 hours after dropwise addition, detecting a point plate, transferring the reaction liquid into a heart-shaped bottle after the reaction is finished, removing the solvent by a reduced pressure distillation device, drying and solidifying, and then using petroleum ether: ethyl acetate: methanol 100. The calculated yield was 84%.
Infrared and nuclear magnetic data, high resolution, melting point data for 3- (naphthalen-2-yl) -1-phenyl-2-naphthalenecarbonitrile: white solid; 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.
Example 6: preparation of 1-phenyl-3- (thien-2-yl) -2-naphthalenecarbonitrile
The reaction formula is shown as follows:
Figure BDA0002422998500000091
adding accurately weighed 0.1mmol (E) -2-benzoyl-3- (thiophene-2-yl) butyl-2-alkene nitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenyl silicate) into a dry 25ml reaction tube in sequence, vacuumizing the reaction tube and exchanging nitrogen for three times, adding 1ml of acetonitrile under the protection of nitrogen, sucking 0.2mmol of phenylalkyne precursor by a microsyringe dropwise into the reaction tube, stirring for 24 hours at room temperature after dropwise addition, performing plate counting detection, transferring the reaction liquid into a heart-shaped bottle after the reaction is finished, removing the solvent by a reduced pressure distillation device, performing spin-drying solidification, and then using petroleum ether: ethyl acetate: methanol 100. The calculated yield was 68%.
Infrared and nuclear magnetic data, high resolution, melting point data of 1-phenyl-3- (thiophen-2-yl) -2-naphthanil are White solid; 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；HRMS(ESI)m/z calcd for C 21 H 14 NS + [M+H] + 312.08415,found 312.08408.
Example 7: preparation of 1- (4-methoxyphenyl) -3-phenyl-2-naphthacenitrile
The reaction formula is shown as follows:
Figure BDA0002422998500000101
accurately weighed 0.1mmol (E) -2- (4-methoxybenzoyl) -3-phenylbut-2-enenitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenylsilicate) are sequentially added into a dry 25ml reaction tube, then the reaction tube is vacuumized and changed with nitrogen for three times, under the protection of nitrogen, 1ml acetonitrile is added firstly, then a microsyringe is used for absorbing 0.2mmol of a phenylalkyne precursor and is dripped into the reaction tube dropwise, after the dropwise addition is finished, the reaction tube is stirred for 24 hours at room temperature, a point plate is detected, after the reaction is finished, the reaction liquid is transferred into a heart-shaped bottle, a solvent is removed through a reduced pressure distillation device, spin drying and solidification are finished, and then petroleum ether is used: ethyl acetate: methanol 100. The calculated yield was 80%.
Infrared and nuclear magnetic data, high resolution, melting point data of 1- (4-methoxyphenyl) -3-phenyl-2-naphthanil are 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；HRMS(ESI)m/z calcd for C 24 H 18 NO + [M+H] + 336.13829,found 336.13806.
Example 8: preparation of 1- (4-fluorophenyl) -3-phenyl-2-naphthonitrile
The reaction formula is shown as follows:
Figure BDA0002422998500000111
adding accurately weighed 0.1mmol (E) -2- (4-fluorobenzoyl) -3-phenylbut-2-enenitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenylsilicate) into a dry 25ml reaction tube in sequence, vacuumizing the reaction tube and exchanging nitrogen for three times, adding 1ml of acetonitrile under the protection of nitrogen, then sucking 0.2mmol of phenylalkyne precursor by a microsyringe dropwise into the reaction tube, stirring for 24 hours at room temperature after dropwise adding, detecting by a point plate, transferring the reaction liquid into a heart-shaped bottle after the reaction is finished, removing the solvent by a reduced pressure distillation device, drying and curing, and then using petroleum ether: ethyl acetate: methanol 100. The calculated yield was 85%.
Infrared and nuclear magnetic data, high resolution, melting point data of 1- (4-fluorophenyl) -3-phenyl-2-naphthanil are White solid; 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＝3.5Hz),131.89(d,J＝8.3Hz),130.85,129.23,129.18,128.91,128.64,128.52,128.39,127.56,127.08,117.89,115.85(d,J＝21.7Hz),110.24； 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- (thien-2-yl) -2-naphthalenecarbonitrile
The reaction formula is shown as follows:
Figure BDA0002422998500000121
adding accurately weighed 0.1mmol (E) -3-phenyl-2- (thiophene-2-carbonyl) butyl-2-enenitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenylsilicate) into a dry 25ml reaction tube in sequence, vacuumizing the reaction tube and exchanging nitrogen for three times, adding 1ml of acetonitrile under the protection of nitrogen, sucking 0.2mmol of phenylalkyne precursor by a microsyringe dropwise into the reaction tube, stirring for 24 hours at room temperature after dropwise adding, detecting by using a point plate, transferring the reaction liquid into a heart-shaped bottle after the reaction is finished, removing the solvent by using a reduced pressure distillation device, drying and curing, and then using petroleum ether: ethyl acetate: methanol 100. The calculated yield was 76%.
Infrared and nuclear magnetic data, high resolution, melting point data of 3-phenyl-1- (thiophen-2-yl) -2-naphthanil are White solid; 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] + 312.08415,found 312.08398.
Example 10: preparation of 1-methyl-3-phenyl-2-naphthacenitrile
The reaction formula is shown as follows:
Figure BDA0002422998500000122
adding accurately weighed 0.1mmol (E) -2-acetyl-3-phenylbut-2-enenitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenylsilicate) into a dry 25ml reaction tube in sequence, vacuumizing the reaction tube and exchanging nitrogen for three times, adding 1ml acetonitrile under the protection of nitrogen, then dropwise adding 0.2mmol phenylalkyne precursor absorbed by a microsyringe into the reaction tube, stirring for 24 hours at room temperature after dropwise adding, detecting by using a point plate, transferring the reaction solution into a heart bottle after the reaction is finished, removing the solvent by using a reduced pressure distillation device, drying and curing, and then using petroleum ether: ethyl acetate: methanol 100. The calculated yield was 50%.
Infrared and nuclear magnetic data, high resolution, melting point data of 1-methyl-3-phenyl-2-naphthanil are White solid; mp 112.1-112.8 ℃; 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 C NMR(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/z calcd for C 18 H 14 N + [M+H] + 244.11208,found 244.11206.
Example 11:6,7-dimethyl-1,3-diphenyl-2-naphthalenecarbonitrile preparation
The reaction formula is shown as follows:
Figure BDA0002422998500000131
adding accurately weighed 0.1mmol (E) -2-benzoyl-3-phenylbut-2-enenitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenylsilicate) into a dry 25ml reaction tube in sequence, vacuumizing the reaction tube and exchanging nitrogen for three times, adding 1ml acetonitrile under the protection of nitrogen, sucking 0.2mmol 4,5-dimethyl-2- (trimethylsilyl) phenyl trifluoromethanesulfonate by a microsyringe, dropwise adding into the reaction tube, stirring at room temperature for 24 hours after dropwise adding, detecting by a point plate, transferring the reaction liquid into a heart bottle after the reaction is finished, removing the solvent by a reduced pressure distillation device, drying and curing, and then adding petroleum ether: ethyl acetate: methanol 100. The yield was calculated to be 75%.
5363 Infrared and nuclear magnetic data, high resolution, melting point data of 6,7-dimethyl-1,3-diphenyl-2-naphthalenecarbonitrile White solid (25.0 mg,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 C NMR(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 12:6,7-difluoro-1,3-diphenyl-2-naphthalenenitrile preparation
The reaction formula is shown as follows:
Figure BDA0002422998500000141
adding accurately weighed 0.1mmol (E) -2-benzoyl-3-phenylbut-2-enenitrile and 0.6mmol TBAT (tetra-n-butylammonium difluorotriphenylsilicate) into a dry 25ml reaction tube in sequence, vacuumizing the reaction tube and exchanging nitrogen for three times, adding 1ml acetonitrile under the protection of nitrogen, sucking 0.2mmol 4,5-difluoro-2- (trimethylsilyl) phenyl trifluoromethanesulfonate by a microsyringe, dropwise adding into the reaction tube, stirring at room temperature for 24 hours after dropwise adding, detecting by a point plate, transferring the reaction liquid into a heart bottle after the reaction is finished, removing the solvent by a reduced pressure distillation device, drying and curing, and then adding petroleum ether: ethyl acetate: methanol 100. The yield was calculated to be 78%.
5363 infrared and nuclear magnetic data, high resolution, melting point data of 6,7-difluoro-1,3-diphenyl-2-naphthalenecarbonitrile White solid 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； 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.86(s,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＝255.1,15.9Hz),150.69(dd,J＝251.5,15.4Hz),147.33-147.05(m),140.74(d,J＝2.2Hz),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.
Alpha-cyano-beta-methanone 1a is 1.2 times of the equivalent of the benzyne precursor 2a, THF is used as a reaction solvent, and the reaction is carried out at normal temperature under the condition that 2.0 equivalent of KF/18-C-6 is used as an additive. After 48 hours of reaction, the reaction was weak although the product was produced, and a large amount of α -cyano- β -methanone remained as monitored by TLC plates, and finally the product was obtained in less than 10% yield by column chromatography (see Entry1 in table 1).
Comparative example 2.
On the basis of comparative example 1, the alpha-cyano-beta-methanone 1a was reduced to 1.1 times the equivalent of the phenylalkyne precursor 2a, and the reaction was continued while keeping the other conditions unchanged. After the reaction was carried out for 48 hours, the concentration of the objective product was found to become large by monitoring with a TLC spot plate, and the objective product was finally obtained in a yield of 14% by purification by column chromatography (see Entry2 in Table 1 for specific results).
Comparative example 3.
The reaction solvent was optimized on the basis of comparative example 2, keeping the other conditions unchanged.
In the case of using tolumen, DMF and DMSO as solvents, the reaction can obtain the product with the yield less than 10% (see En in Table 1 for specific results)try 3-5); when using ClCH 2 CH 2 Cl、1,4-dioxane、CH 2 Cl 2 When DME is used as a solvent, the target product is obtained by the reaction in the yield of 14%, 15%, 19% and 20%, and the yield is improved but is not obviously changed (the specific result is shown in Entry6-9 in Table 1); when using CH 3 CN as the reaction solvent, the reaction yielded the product in 32% yield (see Entry10 in Table 1).
Comparative example 4.
Based on comparative example 3, with CH 3 CN as solvent, the reaction was heated to reflux for 48h. After the reaction was completed, the product was obtained in a yield of 38% by column chromatography (see Entry11 in table 1 for specific results).
Then continuously adding 1.5 times of equivalent of Cs under the condition of reflux 2 CO 3 The reaction was carried out for 48 hours. It was found by column chromatography that the reaction yield was not only unexpectedly increased but rather decreased, resulting in a product of only 34% (see Entry12 in table 1).
To summarize: in CH 3 Under the condition that CN is used as a solvent, although the yield is improved, the reaction period is long, the conditions are harsh, and simultaneously, a large amount of alpha-cyano-beta-methanone remains, so that the reaction is not economical.
Comparative example 5.
Increasing the amount of the benzyne precursor to 1.5 times that of the α -cyano- β -methanone 1a, while replacing the fluorine source used in the previous reaction with CsF and increasing the amount of the fluorine source to 4.5 times that of 1a, with solvent CH at the previous optimum yield conditions 3 CN attempted to react at room temperature, a model reaction of alpha-cyano-beta-methanone 1a with 1.5 equivalents of the phenylalkyne precursor 2a, using CH 3 CN as a solvent, and CsF as a fluorine source in an amount of 4.5 equivalents, and the reaction was carried out at room temperature. After the reaction was carried out for 24 hours, the crude product was purified by column chromatography, and finally, the benzene cyclized product 3a naphthonitrile was successfully obtained in a yield of 37% (see Entry13 in Table 1).
Comparative example 6.
The additive (i.e., the fluorine-containing species or the fluorine source) was optimized on the basis of comparative example 5, keeping the other conditions unchanged.
The specific results of the addition of KF/18-crown-6, TBAF, TMAF and TBAT as other fluorine sources are shown in Entry14-17 in Table 1. In which KF/18-crown-6 gave the desired product in 39% isolated yield (see Entry14 in Table 1), TBAF and TMAF promoted the reaction in moderate yields of 40% and 47%, respectively (see Entry15-16 in Table 1); while when TBAT was used as the fluorine source, the yield increased significantly to 81% (see Entry17 in Table 1 for specific results).
Comparative example 7.
On the basis of comparative example 5, the solvent for the reaction was simply screened under the optimum fluorine source conditions (see Entry18-25 in Table 1 for specific results). The CH was determined by finding that DME was found to work well in all solvents screened, but only in 65% yield (see Entry19 in Table 1 for specific results) 3 CN is the optimal solvent for the reaction.
Comparative example 8.
On the basis of comparative example 7, increasing the amount of the benzyne precursor to 2.0 equivalents, it was found that the yield of the reaction reached 94% (see Entry26 in table 1 for specific results). However, increasing the benzyne precursor further to 2.5 equivalents unfortunately produced no significant change in reaction yield (see Entry27 in Table 1 for specific results).
By comparative examples 1 to 8, the optimum conditions for the reaction were determined, i.e. 6.0 equivalents of TBAT as fluorine source, CH 3 CN is a solvent for reaction, and 2.0 equivalent of the benzyne precursor and 1a are reacted for 24 hours at normal temperature.
The reaction formula is shown as follows:
Figure BDA0002422998500000171
TABLE 1
Figure BDA0002422998500000172
Figure BDA0002422998500000181
Standard conditions 1a (0.10 mmol), 2a (0.15 mmol), 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(0.75mmol)。
The invention provides a method for cyclizing and synthesizing a naphthalene derivative, which is simple and convenient to operate, environment-friendly, high in yield, free of transition metal catalysis and economical in process. Under the condition that a fluorine-containing substance is used as a fluorine source (preferably TBAT), a phenylalkyne precursor and a benzonitrile ketene are used as reaction raw materials, and a solvent is ultra-dry anhydrous acetonitrile, the phenylalkyne precursor and the benzonitrile ketene are stirred and react at room temperature under the action of the fluorine-containing substance (preferably TBAT), and the naphthanitrile and the derivative thereof are finally obtained with the yield of 50-94%. The reaction system has no transition metal catalysis, wide substrate application range and mild conditions, and has wide application prospect in the preparation of natural products and biological medicines.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention in any way, and any simple modification, equivalent change and modification made to the above embodiments according to the technical spirit of the present invention are within the scope of the technical solution of the present invention.

Claims (6)

1. The cyclization synthesis method of the naphthalonitrile and the derivative thereof is characterized by comprising 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;
separating and purifying the solid substance by silica gel column chromatography to obtain the naphthalocyanide and the derivative thereof;
wherein the fluorine-containing substance is selected from one of the following substances: cesium fluoride, potassium fluoride and 18-crown-6, TBAT, TBAF, TMAF;
the cyclization synthesis method is represented by the following reaction formula:
Figure FDA0004063443690000011
in the formula, R is a substituent at 2-, or 3-, or 4-position on a benzyne aromatic ring, or a disubstituted or polysubstituted group on the aromatic ring; selected from one of the following groups: -F, -CH 3 、-H；
R 1 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 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;
R 3 is-H.
2. The cyclized synthesis method according to claim 1,
the oxygen isolation condition is nitrogen atmosphere.
3. The cyclized synthesis method according to claim 1,
the fluorine-containing substance is TBAT.
4. The cyclized synthesis method according to claim 3,
the molar ratio of the phenylalkyne precursor to the benzonitrile ketene to the TBAT is 2:1:6.
5. the cyclized synthesis method according to claim 1,
the silica gel column chromatography adopts a method that petroleum ether: ethyl acetate: the volume ratio of methanol is 100.
6. The cyclized synthesis method according to claim 1,
under the condition of oxygen isolation, the concrete operations of stirring the benzonitrile ketene, the fluorine-containing substance, the phenylalkyne precursor and the anhydrous acetonitrile at room temperature until the reaction is finished are as follows:
adding benzonitrile ketene and fluorine-containing substances into a dried reactor, vacuumizing the reactor and exchanging nitrogen;
and under the protection of nitrogen, firstly adding anhydrous acetonitrile, then dropwise adding the benzyne precursor, and stirring at room temperature until the reaction is finished after the dropwise adding is finished.
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