CN102503752A - Method for preparing polysubstituted 2-naphthol - Google Patents
Method for preparing polysubstituted 2-naphthol Download PDFInfo
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- CN102503752A CN102503752A CN201110300963XA CN201110300963A CN102503752A CN 102503752 A CN102503752 A CN 102503752A CN 201110300963X A CN201110300963X A CN 201110300963XA CN 201110300963 A CN201110300963 A CN 201110300963A CN 102503752 A CN102503752 A CN 102503752A
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Abstract
The invention belongs to the field of fine chemical and relates to a pharmaceutical and chemical intermediate and a related chemical technology, in particular to a method for preparing polysubstituted 2-naphthol by synthesizing o-halogen benzyl ketene from o-halogen benzyl halide, tributyl allyl tin and carbon monoxide which are used as raw materials and then carrying out intramolecular Heck reaction. The method for preparing the polysubstituted 2-naphthol is characterized in that the o-halogen benzyl halide, the tributyl allyl tin and, the carbon monoxide and aryl bromide are used as raw materials and the zero-valent or divalent palladium is used as catalyst to carrying out the intramolecular Heck reaction in an organic solvent. The invention mainly provides a novel method for preparing the polysubstituted 2-naphthol, and the novel method has the advantages of good functional group compatibility, a wide range of substrates, environment friendliness, and a single reaction product without isomers, etc.
Description
Technical field
The present invention relates to pharmaceutical-chemical intermediate and relevant technical field of chemistry, relate to a kind of method for preparing polysubstituted beta naphthal.
Background technology
Beta naphthal is claimed β-Nai Fen again, is important Organic Chemicals and medical synthetic intermediate, reaches kind more than 130 by its direct synthetic dyestuff, pigment variety, more than 20 of dyestuff intermediates.Also be widely used at aspects such as medicine, agricultural chemicals, rubber ingredients, spices, leather tanning, textile auxiliary and dressing agents.
Intramolecularly Cheng Huan is one of important method of synthetic polysubstituted beta naphthal, carries out under strong acid, alkaline condition but early stage reaction is many, needs stoichiometric additive to promote reaction, perhaps need higher temperature of reaction, and the substrate scope is narrower.For example, 1-aryl-2,4-cyclohexadione compounds like the vitriol oil, perchloric acid, polyphosphoric acid, phosphoric acid, can molecule inner ring condensation obtain substituted beta naphthal (referring to Tetrahedron Lett.1982,23,3405-3406 under acid system; J.Org.Chem.1988,53,5535-5538; Synthesis, 1998,729-734; WO2008028930,2008.), but this type of reaction substrate scope is narrower.Aryl ketene compounds generation molecule inner ring condensation also can obtain corresponding beta naphthal product (referring to Synthesis, 1985,784-786; Tetrahedron Lett.1996,37,8277-8280; Eur.J.Org.Chem.2000,2605-2611.), but this type of reaction yield is low and have the shortcoming that generates isomer.The Dieckmann ring-closure reaction takes place for substituted adjacent acetylbenzene methyl acetate or adjacent Phenylacetylene methyl acetate can obtain polysubstituted beta naphthal (referring to Chem.Pharm.Bull.1989,37,292-297; Org.Chem.2002,4,1403-1405; J.Org.Chem.2004,69,991-992; Tetrahedron Lett.2005,46,7619-7621; Org.Lett.2005,7,3617-3620; Angew.Chem.Int.Ed.2007,46,7458-7461.), multistep is synthetic just to be obtained but the raw material that is used for Dieckmann reaction needs.
Get into after this century, utilize excessive metalcatalyzing Synthetic 2-naphthols and utilize the method for simple raw material one kettle way Synthetic 2-naphthols to be developed.For example, people such as Liu are that raw material obtains polysubstituted beta naphthal (referring to J.Am.Chem.Soc.2004,126,6895-6899 under ruthenium catalyst catalysis with adjacent ethynyl phenyl epoxide; Org.Lett.2005; 7,1745-1748.), reaction needed is used more expensive ruthenium catalyst of price and large usage quantity (10mol%); In addition, the adjacent ethynyl phenyl epoxide of raw material need utilize adjacent bromobenzaldehyde and trimethylsilyl acetylene just can obtain through polystep reaction.People such as Estevez utilize adjacent aldehyde radical acetophenone compounds for raw material in the presence of alkali, cyclization obtains polysubstituted 3-phenyl-beta naphthal (referring to Tetrahedron Lett.2000,41,2365-2367 through the intramolecularly aldol; Tetrahedron 2005,61,485-492; Tetrahedron 2005,61,1353-1362.).People such as Kozlowski are raw material with polysubstituted toluylic acid, at first generate corresponding acyl chlorides, again with ethyl malonate reaction, the positively charged ion cyclization takes place at last obtain polysubstituted beta naphthal (referring to Org.Lett.2007,9,385-388; Adv.Synth.Catal.2007,349,583-594; Angew.Chem.Int.Ed.2008,47,6877-6880; J.Org.Chem.2010,75,16-29.), but this method reactions step is many, needs strong acid and strong base to carry out smoothly.In sum, the present intramolecularly Cheng Huan that the reports aforesaid method that obtains replacing beta naphthal exists raw material to be difficult for shortcomings such as synthetic, that reactions step is many more.
Therefore, how through be simple and easy to raw material, utilize less synthesis step, obtaining polysubstituted beta naphthal through intramolecularly Cheng Huan is a significant research work of ten minutes.
Summary of the invention
The invention provides a kind of preparation method of polysubstituted beta naphthal newly, the synthetic route weak point of this method, environmental friendliness, the single no isomer of product; This method with CO as wherein main raw material have be easy to get, advantages of being cheap.
The present invention is to be raw material with adjacent halogen benzyl halogen, at first obtains adjacent halogen benzyl ketenes through three component reaction with CO and tributylallyltin, and then reaction obtains beta naphthal through intramolecularly Heck.Synthetic route is suc as formula shown in (1):
The technical scheme that this method adopts is following:
(1) adjacent halogen benzyl ketenes is synthetic: palladium-containing catalyst, join in the autoclave; Add the solvent of certain volume, adjacent halogen benzyl halogen and tributylallyltin successively; Reaction kettle is connected to CO constant pressure device, charges into CO, place the oil bath heated and stirred that is preheated to design temperature to setting-up time to setting pressure; Be cooled to room temperature then; Remaining CO is discharged, after the reaction solution removal of solvent under reduced pressure, obtain adjacent halogen benzyl ketenes through silica gel column chromatography separation and alkali alumina column chromatography successively.
Wherein, the aromatic ring of adjacent halogen benzyl halogen comprises phenyl ring, naphthalene nucleus, condensed-nuclei aromatics or heterocyclic arene compound;
Substituent R on the adjacent halogen benzyl halogen is hydrogen, halogen, alkyl, alkoxyl group, cyanic acid, acyl group, carboxyl, aldehyde radical, ester group or nitro; X on the adjacent halogen benzyl halogen
1Be fluorine, chlorine, bromine, iodine, X
2Be fluorine, chlorine, bromine, iodine, X
1And X
2Identical or different;
The mol ratio of adjacent halogen benzyl halogen and palladium-containing catalyst is 1: 0.01～1: 0.10;
The mol ratio of tributylallyltin and adjacent halogen benzyl halogen is 1: 1～1: 2, preferred 1: 1;
Palladium-containing catalyst comprises the catalystsystem that tetrakis triphenylphosphine palladium, two (triphenyl phosphorus) palladium chloride or palladium source and tertiary phosphine-ligand are formed.
The palladium source comprises Palladous chloride, palladium, three (dibenzalacetone) two palladiums, two (dibenzalacetone) palladium, palladium acetylacetonate, allyl palladium chloride, two (acetonitrile) palladium chloride, two (benzene nitrile) palladium chloride.Preferred palladium, palladium acetylacetonate or two (acetonitrile) palladium chloride.
Tertiary phosphine-ligand comprises triphenylphosphine, three hexamethylene phosphines, tri-butyl phosphine, 1, two (diphenylphosphine) ethane, 1 of 2-, and two (diphenylphosphine) propane of 2-or 1, two (diphenylphosphine) butane of 2-, two (diphenylphosphine)-1,1 '-dinaphthalene.Triphenylphosphine or 1, two (diphenylphosphine) ethane of 2-.
The mol ratio of palladium source and phosphine part is 1: 1～1: 4.
Solvent comprises benzene, toluene, o-Xylol, 1; 4-dioxane, DMSO 99.8MIN., ethanol, methyl alcohol, the trimethyl carbinol, Virahol, trichloromethane, methylene dichloride, ether, propyl ether, n-butyl ether, tetracol phenixin, dimethyl adipate, ETHYLE ACETATE, sherwood oil, MTBE, THF, hexanaphthene, normal hexane, normal heptane, N; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone; Be one or more mixing wherein, preferred 1,4-dioxane, acetonitrile or THF.
The volume molar ratio of solvent and adjacent halogen benzyl halogen is 1mL/1mmol～10mL/1mmol.Preferred 4mL/1mmol.
CO pressure is 0.1～1.0MPa, preferred 0.2～0.4MPa.
Oil bath temperature is 20～200 ℃, preferred 70～90 ℃.
The heated and stirred time is 1～24h, preferred 2～10h.
The silica gel model of using in the silica gel column chromatography is 100～200 orders or 200～300 orders.
The aluminum oxide model of using in the alkali alumina column chromatography is 100～200 orders or 200～300 orders.
During separating, use on post eluent to be selected from the certain density mix reagent that sherwood oil and ETHYLE ACETATE, normal hexane and ETHYLE ACETATE dispose according to a certain percentage.Concentration ratio is selected from 5: 1,10: 1,20: 1,30: 1,40: 1,1: 0.
(2) beta naphthal is synthetic: palladium-containing catalyst is joined in the Xu Lin gram reactor drum, add the solvent of certain volume, add alkali and adjacent halogen benzyl ketenes again; Closed reactor places the oil bath heated and stirred that is preheated to design temperature to setting-up time, is cooled to room temperature then; Reaction solution is poured in the water, used organic solvent extraction, and then with the saturated aqueous common salt flushing once; Drying, the silica gel column chromatography separation obtains beta naphthal.
Step (2) can be identical with catalyzer in the step (1), also can be different.Palladium-containing catalyst comprises the catalystsystem that tetrakis triphenylphosphine palladium, two (triphenyl phosphorus) palladium chloride or palladium source and tertiary phosphine-ligand are formed.
The palladium source comprises Palladous chloride, palladium, three (dibenzalacetone) two palladiums, two (dibenzalacetone) palladium, palladium acetylacetonate, allyl palladium chloride, two (acetonitrile) palladium chloride, two (benzene nitrile) palladium chloride.Preferred palladium, palladium acetylacetonate or two (acetonitrile) palladium chloride.
Tertiary phosphine-ligand comprises triphenylphosphine, three hexamethylene phosphines, tri-butyl phosphine, 1, two (diphenylphosphine) ethane, 1 of 2-, and two (diphenylphosphine) propane of 2-or 1, two (diphenylphosphine) butane of 2-, two (diphenylphosphine)-1,1 '-dinaphthalene.Triphenylphosphine or 1, two (diphenylphosphine) ethane of 2-.
The mol ratio of palladium source and phosphine part is 1: 1～1: 4.
The mol ratio of adjacent halogen benzyl ketenes and palladium-containing catalyst is 1: 0.01～1: 0.20.
Alkali comprises yellow soda ash, sodium hydrogencarbonate, salt of wormwood, saleratus, sodium phosphate, sodium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, potassiumphosphate, potassium hydrogen phosphate, potassium primary phosphate, cesium carbonate, sodium tert-butoxide, potassium tert.-butoxide, sodium-acetate, Potassium ethanoate, triethylamine, Tributylamine, diisopropyl ethyl amine, hexamethylenetetramine or N; N; N, the N-Tetramethyl Ethylene Diamine.Preferred sodium hydrogencarbonate, sodium-acetate, Potassium ethanoate.
The mol ratio of adjacent halogen benzyl ketenes and alkali is 1: 1～1: 5.
Step (2) can be identical with solvent in the step (1), also can be different, and can be single solvent, also can be mixed solvent; Solvent comprises benzene, toluene, o-Xylol, 1; 4-dioxane, DMSO 99.8MIN., ethanol, methyl alcohol, the trimethyl carbinol, Virahol, trichloromethane, methylene dichloride, ether, propyl ether, n-butyl ether, tetracol phenixin, dimethyl adipate, ETHYLE ACETATE, sherwood oil, MTBE, THF, hexanaphthene, normal hexane, normal heptane, acetonitrile, N; Dinethylformamide, DMAC N,N, N-Methyl pyrrolidone.Preferred acetonitrile, N, dinethylformamide, N, N-diethyl acetamide or N-Methyl pyrrolidone.
The volume molar ratio of solvent and adjacent halogen benzyl ketenes is 1mL/1mmol～20mL/1mmol, preferred 5～10mL/1mmol.
Oil bath temperature is 20～150 ℃, preferred 100～130 ℃.
The heated and stirred time is 10min～10h, preferred 0.5～5h.
The silica gel model of using during post separates is 100～200 orders or 200～300 orders.
During separating, use on post eluent to be selected from the certain density mix reagent that sherwood oil and ETHYLE ACETATE, normal hexane and ETHYLE ACETATE dispose according to a certain percentage.Concentration ratio is selected from 2: 1,5: 1,10: 1,20: 1,30: 1, preferred 10: 1,20: 1.
Description of drawings
Fig. 1 is 3a among the embodiment 1
1The H nuclear magnetic spectrogram.
Fig. 2 is 3a among the embodiment 1
13The C nuclear magnetic spectrogram.
Fig. 3 is 3b among the embodiment 2
1The H nuclear magnetic spectrogram.
Fig. 4 is 3b among the embodiment 2
13The C nuclear magnetic spectrogram.
Fig. 5 is 3c among the embodiment 3
1The H nuclear magnetic spectrogram.
Fig. 6 is 3c among the embodiment 3
13The C nuclear magnetic spectrogram.
Fig. 7 is 3d among the embodiment 4
1The H nuclear magnetic spectrogram.
Fig. 8 is 3d among the embodiment 4
13The C nuclear magnetic spectrogram.
Fig. 9 is 3e among the embodiment 5
1The H nuclear magnetic spectrogram.
Figure 10 is 3e among the embodiment 5
13The C nuclear magnetic spectrogram.
Embodiment
The preparation method of beta naphthal of the present invention has advantages such as reactions step is few, low in raw material cost is easy to get, product is single, shows good prospects for application.
Below in conjunction with specific embodiment, further set forth the present invention.These embodiment only be used to the present invention is described and be not used in the restriction scope of the present invention.Those skilled in the art to simple replacement that the present invention did or improve within the technical scheme that all belongs to the present invention and protected.
Embodiment 1:
In the 200mL autoclave, add Pd (Ph
3P)
4(555mg, 0.48mmol, 2mol%), adjacent bromobenzyl bromine (1a, 5.7g; 24mmol), 1,4-dioxane (96mL), tributylallyltin (7.9g; 24mmol), and then be connected to the CO constant pressure arrangement, put into 80 ℃ of oil bath heated and stirred 12h (during CO constant pressure at 0.2MPa).Be chilled to room temperature, emit unnecessary gas, after the solvent decompression is removed; Direct silica gel column chromatography, with sherwood oil, sherwood oil: ETHYLE ACETATE=20: 1 is wash-out successively, revolve dried after; The product that obtains is dissolved in 20mL ETHYLE ACETATE and gets 2a (weak yellow liquid 4.4g, yield 76%, Z/E=20/80 through one deck alkali alumina; The GC ratio), further silica gel column chromatography separates the product that can obtain Z and E formula configuration respectively.The 2a-Z formula, weak yellow liquid:
1H NMR (400MHz, CDCl
3) δ 7.57 (dd, J=8.0,0.8Hz, 1H), 7.30-7.21 (m, 2H), 7.15-7.11 (m, 1H), 6.30-6.21 (m, 2H), 3.91 (s, 2H), 2.13 (d, J=5.6Hz, 3H);
13C NMR (101MHz, CDCl
3) δ 197.3,144.6,135.0,132.8,131.7,128.7,127.6,126.9,125.1,51.1,16.1; IR (KBr) 3058,3025,2910,1696,1618,1470,1439,1074,1026,919,742cm
-1HRMS (ESI) calcd for C
11H
11ONaBr:260.9891 [M+Na]
+Found:260.9891.The 2a-E formula, weak yellow liquid:
1H NMR (400MHz, CDCl
3) δ 7.57 (dd, J=8.0,1.0Hz, 1H), 7.29-7.20 (m, 2H), 7.15-7.11 (m, 1H), 6.99 (m, 1H), 6.21 (m, 1H), 3.99 (s, 2H), 1.91 (dd, J=6.9,1.6Hz, 3H);
13C NMR (101MHz, CDCl
3) δ 196.0,143.7,134.9,132.8,131.7,131.0,128.7,127.6,125.1,47.5,18.4; IR (KBr) 3055,2912,1682,1629,1471,1439,1336,1187,1026,968,749cm
-1HRMS (EI) calcd for C
11H
11BrO:237.9993 [M]
+Found:237.9985.
Permitted to add Pd (Ph in the woods gram pipe to 25mL
3P)
4(58mg, 0.05mmol, 10mol%), NaHCO
3(84mg, 1mmol, 2.0equiv.), 1; 4-dioxane (5mL), and the 2a-E formula (120mg, 0.5mmol); After woods gram pipe is permitted in sealing, be chilled to room temperature after putting into 80 ℃ of oil bath heated and stirred 1h, reaction solution is poured in the 20mL water; With ethyl acetate extraction (10mL * 3), merge organic phase again with saturated aqueous common salt flushing (20mL * 1), anhydrous Na
2SO
4Drying is filtered, and choosing is done, and silica gel column chromatography separates (eluent: sherwood oil: ETHYLE ACETATE=20: 1), obtain 3a (incarnadine solid, 68mg, yield 86%).
1H?NMR(400MHz，CDCl
3)δ7.89(d，J＝8.3Hz，1H)，7.65(d，J＝8.1Hz，1H)，7.41(t，J＝7.4Hz，1H)，7.34(t，J＝7.5Hz，1H)，6.98-6.95(m，2H)，5.24(s，1H)，2.63(s，3H)；
13C?NMR(101MHz，CDCl
3)δ152.9，136.9，134.9，128.3，127.1，126.3，124.1，123.5，118.6，107.8，19.3；IR(KBr)3369，3066，2920，2859，1622，1602，1512，1462，1349，1282，1233，1172，1133，1000，857，769，745cm
-1；HRMS(EI)calcd?for?C
11H
10O：158.0732[M]
+；found：158.0737。
Embodiment 2:
In the 200mL autoclave, add Pd (Ph
3P)
4(555mg, 0.48mmol, 2mol%), 1-bromo-2-naphthalene benzyl bromine (1b, 7.6g; 24mmol), toluene (96mL), tributylallyltin (7.9g; 24mmol), and then be connected to the CO constant pressure arrangement, put into 80 ℃ of oil bath heated and stirred 12h (during CO constant pressure at 0.4MPa).Be chilled to room temperature, emit unnecessary gas, after the solvent decompression is removed; Direct silica gel column chromatography, with sherwood oil, sherwood oil: ETHYLE ACETATE=20: 1 is wash-out successively, revolve dried after; The product that obtains is dissolved in 20mL ETHYLE ACETATE and gets 2a (weak yellow liquid 4.4g, yield 63%, Z/E=25/75 through one deck alkali alumina; The GC ratio), further silica gel column chromatography separates the product that can obtain Z and E formula configuration respectively.2b-Z, faint yellow solid:
1H NMR (400MHz, CDCl
3) δ 8.31 (d, J=8.5Hz, 1H), 7.83-7.77 (m, 2H), 7.61-7.49 (m, 2H), 7.33 (d, J=8.4Hz, 1H), 6.29-6.19 (m, 2H), 4.16 (s, 2H), 2.13 (d, J=5.4Hz, 3H);
13C NMR (101MHz, CDCl
3) δ 197.5,144.8,133.7,133.3,132.7,128.7,128.2,127.9,127.7,127.6,127.0,126.5,125.2,52.5,16.2; IR (KBr) 3053,2922,1716,1692,1619,1501,1433,1074,812,759cm
-1HRMS (EI) calcd for C
15H
13BrO:288.0150 [M]
+Found:288.0151.2b-E, white solid:
1H NMR (400MHz, CDCl
3) δ 8.31 (d, J=8.4Hz, 1H), 7.83-7.77 (m, 1H), 7.59 (t, J=7.6Hz, 1H); 7.51 (t, J=7.4Hz, 1H), 7.32 (d, J=8.4Hz, 1H), 7.07-6.98 (m, 1H); 6.24 (d, J=15.5Hz, 1H), 4.24 (s, 2H), 1.90 (d, J=6.8Hz, 3H);
13C NMR (101MHz, CDCl
3) δ 196.3,144.0,133.8,133.2,132.7,131.1,128.7,128.3,127.9,127.7,127.6,126.5,125.1,49.1,18.5; IR (KBr) 3052,2911,1676,1630,1501,1438,1325,1189,968,808,761cm
-1HRMS (EI) calcd for C
15H
13BrO:288.0150 [M]
+Found:288.0149.
Permitted to add Pd (Ph in the woods gram pipe to 25mL
3P)
4(58mg, 0.05mmol, 10mol%), K
3PO
4(212.3mg, 1mmol, 2.0equiv); NMP (5mL), and the 2b-E formula (145mg, 0.5mmol); After woods gram pipe is permitted in sealing, be chilled to room temperature after putting into 80 ℃ of oil bath heated and stirred 3h, reaction solution is poured in the 20mL water; With ethyl acetate extraction (10mL * 3), merge organic phase again with saturated aqueous common salt flushing (20mL * 1), anhydrous Na
2SO
4Drying is filtered, and choosing is done, and silica gel column chromatography separates (eluent: sherwood oil: ETHYLE ACETATE=20: 1), obtain 3b (incarnadine solid, 65mg, yield 63%).
1H?NMR(400MHz，CDCl
3)δ8.79(d，J＝8.5Hz，1H)，7.88-7.85(m，1H)，7.66(d，J＝8.8Hz，1H)，7.62-7.48(m，3H)，7.12-7.04(m，2H)，3.07(s，3H)；
13C?NMR(101MHz，CDCl
3)δ152.9，138.0，135.5，132.5，131.8，128.8，127.9，127.3，126.7，125.8，125.0，124.6，120.8，110.9，27.4；IR(KBr)3318，3050，2962，2874，1613，1602，1467，1453，1265，1173，993，866，856，806，744，707cm
-1；HRMS(EI)calcd?for?C
15H
12O：208.0888[M]
+；found：208.0878。
Embodiment 3:
In the 200mL autoclave, add Pd (Ph
3P)
4(555mg, 0.48mmol, 2mo1%), 2-bromo-4 methyl benzyl bromine (1c, 6.7g; 24mmol), MeCN (96mL), tributylallyltin (7.9g; 24mmol), and then be connected to the CO constant pressure arrangement, put into 80 ℃ of oil bath heated and stirred 24h (during CO constant pressure at 0.3MPa).Be chilled to room temperature, emit unnecessary gas, after the solvent decompression is removed; Direct silica gel column chromatography, with sherwood oil, sherwood oil: ETHYLE ACETATE=20: 1 is wash-out successively, revolve dried after; The product that obtains is dissolved in 20mL ETHYLE ACETATE and gets 2c (weak yellow liquid 4.6g, yield 76%, Z/E=21/79 through one deck alkali alumina; The GC ratio), further silica gel column chromatography separates the product that can obtain Z and E formula configuration respectively.2c-Z, weak yellow liquid:
1H NMR (400MHz, CDCl
3) δ 7.41 (s, 1H), 7.17-7.01 (m, 2H), 6.35-6.15 (m, 2H), 3.86 (s, 2H), 2.32 (s, 3H), 2.12 (d, J=5.6Hz, 3H);
13C NMR (101MHz, CDCl
3) δ 197.7,144.4,138.8,133.3,131.8,131.4,128.5,126.8,124.8,50.7,20.7,16.0; IR (KBr) 3025,2920,1693,1620,1492,1435,1317,1074,1040,920,870,819,743,702cm
-1HRMS (ESI) calcd for C12H13ONaBr:275.0047 [M+Na]
+Found:275.0045.2c-E, weak yellow liquid:
1H NMR (400MHz, CDCl
3) δ 7.40 (s, 1H), 7.11-7.06 (m, 2H), 7.03-6.92 (m, 1H), 6.22-6.18 (m, 1H), 3.94 (s, 2H), 2.31 (s, 3H), 1.92-1.90 (m, 3H);
13C NMR (101MHz, CDCl
3) δ 196.3,143.6,138.8,133.2,131.7,131.3,131.0,128.4,124.8,47.1,20.7,18.4; IR (KBr) 3034,2969,2914,2868,1681,1632,1492,1441,1332,1187,1073,1041,968,867,798,674cm
-1HRMS (ESI) calcd for C
12H
13ONaBr:275.0047 [M+Na]
+Found:275.0042.
Permitted to add Pd (Ph in the woods gram pipe to 25mL
3P)
4(58mg, 0.05mmol, 10mol%), NaHCO
3(84mg, 1mmol, 2.0equiv.); Toluene (5mL), and the 2c-E formula (135mg, 0.5mmol); After woods gram pipe is permitted in sealing, be chilled to room temperature after putting into 80 ℃ of oil bath heated and stirred 3h, reaction solution is poured in the 20mL water; With ethyl acetate extraction (10mL * 3), merge organic phase again with saturated aqueous common salt flushing (20mL * 1), anhydrous Na
2SO
4Drying is filtered, and choosing is done, and silica gel column chromatography separates (eluent: sherwood oil: ETHYLE ACETATE=20: 1), obtain 3c (incarnadine solid, 73mg, yield 85%).1H?NMR(400MHz，CDCl
3)δ7.66(s，1H)，7.57(d，J＝8.3Hz，1H)，7.29-7.25(m，1H)，6.97-6.93(m，2H)，4.99(s，1H)，2.63(s，3H)，2.50(s，3H)；
13C?NMR(101MHz，CDCl
3)δ152.4，136.0，133.1，132.8，128.5，128.4，127.0，123.3，118.8，107.8，21.9，19.4；IR(KBr)3373，3048，2920，2858，1634，1612，1512，1440，1395，1287，1139，970，854，732cm
-1；HRMS(EI)calcd?for?C
12H
12O：172.0888[M]
+；found：172.0881。
Embodiment 4:
In the 200mL autoclave, add Pd (OAc)
2(13.5mg, 0.06mmol, 2mol%), PPh
3(63.0mg, 0.240mmol, 8mol%), 2-bromo-4-methoxybenzyl bromine (1d; 6.7g, 24mmol), 1; 4-dioxane (96mL), and tributylallyltin (7.9g, 24mmol); And then be connected to the CO constant pressure arrangement, put into 80 ℃ of oil bath heated and stirred 24h (during CO constant pressure at 0.3MPa).Be chilled to room temperature, emit unnecessary gas, after the solvent decompression is removed; Direct silica gel column chromatography, with sherwood oil, sherwood oil: ETHYLE ACETATE=10: 1 is wash-out successively, revolve dried after; The product that obtains is dissolved in 20mL ETHYLE ACETATE and gets 2d (weak yellow liquid 4.5g, yield 69%, Z/E=13/87 through one deck alkali alumina; The GC ratio), further silica gel column chromatography separates the product that can obtain Z and E formula configuration respectively.2d-Z, white solid:
1H NMR (400MHz, CDCl
3) δ 7.13-7.11 (m, 2H), 6.85-6.82 (m, 1H), 6.28-6.19 (m, 2H), 3.83 (s, 2H), 3.79 (s, 3H), 2.12 (d, J=5.7Hz, 3H);
13C NMR (101MHz, CDCl
3) δ 197.8,159.2,144.3,132.0,126.9,126.8,125.2,118.1,113.8,55.5,50.2,16.0; IR (KBr) 3069,3005,2940,2912,2836,1639,1605,1494,1439,1282,1243,1074,1029,920,862,840cm
-1HRMS (EI) calcd for C
12H
13O
2Br:268.0099 [M]
+Found:268.0105.2d-E, white solid:
1H NMR (400MHz, CDCl
3) δ 7.13-7.10 (m, 2H), 7.13-6.93 (m, 1H), 6.84-6.82 (m, 1H), 6.22-6.18 (m, 1H), 3.91 (s, 2H), 3.79 (s, 3H), 1.91-1.89 (m, 3H);
13C NMR (101MHz, CDCl
3) δ 196.4,159.2,143.5,131.9,130.9,126.8,125.2,118.1,113.7,55.5,46.6,18.3; IR (KBr) 3006,2941,2910,2836,1686,1631,1605,1495,1440,1243,1185,1028,969,864cm
-1HRMS (EI) calcd forC
12H
13O
2Br:268.0099 [M]
+Found:268.0096.
Permitted to add Pd (acac) in the woods gram pipe to 25mL
2(15.2mg, 0.05mmol), PPh
3(52.5mg, 0.20mmol), NaHCO
3(84mg, 1mmol, 2.0equiv); NMP (5mL), and the 2d-E formula (135mg, 0.5mmol); After woods gram pipe is permitted in sealing, be chilled to room temperature after putting into 80 ℃ of oil bath heated and stirred 2h, reaction solution is poured in the 20mL water; With ethyl acetate extraction (10mL * 3), merge organic phase again with saturated aqueous common salt flushing (20mL * 1), anhydrous Na
2SO
4Drying is filtered, and choosing is done, and silica gel column chromatography separates (eluent: sherwood oil: ETHYLE ACETATE=10: 1), obtain 3d (incarnadine solid, 84mg, yield 89%).
1H?NMR(400MHz，CDCl
3)δ7.58(d，J＝8.9Hz，1H)，7.17-7.11(m，2H)，6.96(d，J＝6.3Hz，2H)，4.95(s，1H)，3.92(s，3H)，2.61(s，3H)；
13C?NMR(101MHz，CDCl
3)δ155.9，151.5，135.2，130.1，128.9，128.6，119.1，118.4，108.0，103.3，55.4，19.5；IR(KBr)3404，2933，2833，1608，1514，1444，1397，1249，1160，1036，851cm
-1；HRMS(EI)calcd?for?C
12H
12O
2：188.0837[M]
+；found：188.0835。
Embodiment 5:
In the 200mL autoclave, add PdCl
2(10.6mg, 0.06mmol, 2mol%), PPh
3(63.0mg, 0.240mmol, 8mol%), 2-bromo-3,4-dimethoxy benzyl bromine (1e; 7.4g, 24mmol), MeCN (96mL), tributylallyltin (7.9g; 24mmol), and then be connected to the CO constant pressure arrangement, put into 80 ℃ of oil bath heated and stirred 24h (during CO constant pressure at 0.3MPa).Be chilled to room temperature, emit unnecessary gas, after the solvent decompression is removed; Direct silica gel column chromatography, with sherwood oil, sherwood oil: ETHYLE ACETATE=10: 1 is wash-out successively, revolve dried after; The product that obtains is dissolved in 20mL ETHYLE ACETATE and gets 2e (weak yellow liquid 4.5g, yield 62%, Z/E=29/71 through one deck alkali alumina; The GC ratio), further silica gel column chromatography separates the product that can obtain Z and E formula configuration respectively.2e-Z, white solid:
1H NMR (400MHz, CDCl
3) δ 7.04 (s, 1H), 6.72 (s, 1H), 6.30-6.20 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.83 (s, 2H), 2.13 (d, J=5.7Hz, 3H);
13C NMR (101MHz, CDCl
3) δ 197.8,148.6,148.5,144.6,126.8,126.7,115.5,115.0,113.9,56.2,56.0,50.7,16.0; IR (KBr) 3077,3002,2935,2909,2839,1692,1619,1508,1464,1439,1381,1259,1219,1165,1075,1032,967,924,852,801cm
-1HRMS (EI) calcd for C
13H
15O
3Br:298.0205 [M]
+Found:298.0211.2e-E, white solid:
1H NMR (400MHz, CDCl
3) δ 7.04 (s, 1H), 7.02-6.95 (m, 1H), 6.71 (s, 1H), 6.23-6.18 (m, 1H), 3.91 (s, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 1.92-1.90 (m, 3H);
13C NMR (101MHz, CDCl
3) δ 196.3,148.6,148.4,143.7,130.8,126.6,115.4,114.9,113.9,56.1,56.0,47.0,18.3; IR (KBr) 2935,2840,1685,1630,1507,1439,1382,1259,1218,1165,1031,969,807cm
-1HRMS (EI) calcd for C
13H
15O
3Br:298.0205 [M]
+Found:298.0207.
Permitted to add Pd (dba) in the woods gram pipe to 25mL
3(22.9mg, 0.025mmol), PPh
3(52.5mg, 0.20mmol), Et
3N (101.2mg, 1mmol, 2.0equiv.); Add MeCN (5mL) again, and the 3e-E formula (150mg, 0.5mmol); After woods gram pipe is permitted in sealing, be chilled to room temperature after putting into 80 ℃ of oil bath heated and stirred 2h, reaction solution is poured in the 20mL water; With ethyl acetate extraction (10mL * 3), merge organic phase again with saturated aqueous common salt flushing (20mL * 1), anhydrous Na
2SO
4Drying is filtered, and choosing is done, and silica gel column chromatography separates (eluent: sherwood oil: ETHYLE ACETATE=2: 1), obtain 3e (incarnadine solid, 88mg, yield 81%).
1H?NMR(400MHz，CDCl
3)δ7.13(s，1H)，6.98(s，1H)，6.92(d，J＝2.3Hz，1H)，6.83(d，J＝1.6Hz，1H)，4.80(s，1H)，3.99(s，3H)，3.98(s，3H)，2.60(s，3H).；
13CNMR(101MHz，CDCl
3)δ152.1，149.8，147.5，135.0，130.6，123.18，116.5，107.1，105.9，103.3，55.82，55.79，19.6.；IR(KBr)3452，3002，2956，2829，1633，1510，1399，1272，1250，1162，1063，862，771cm
-1；HRMS(EI)calcd?for?C
13H
14O
3：218.0943[M]
+；found：218.0934。
Claims (5)
1. method for preparing polysubstituted beta naphthal; With adjacent halogen benzyl halogen, tributylallyltin and carbon monoxide is the at first synthetic adjacent halogen benzyl ketenes of raw material; And then the method for the polysubstituted beta naphthal of process intramolecularly Heck prepared in reaction, it is characterized in that synthetic route is following:
(1) adjacent halogen benzyl halogen, palladium-containing catalyst, solvent, tributylallyltin are joined in the autoclave, charge into CO then, 20 ℃～200 ℃ of temperature of reaction; Reaction times 1～24h; Reaction pressure 0.1MPa～1.0MPa; With the reaction solution that obtains, make adjacent halogen benzyl ketenes through silicagel column and the separation of alkali alumina post;
Wherein, the aromatic ring of adjacent halogen benzyl halogen comprises phenyl ring, naphthalene nucleus, condensed-nuclei aromatics or heterocyclic arene compound;
Substituent R on the adjacent halogen benzyl halogen is hydrogen, halogen, alkyl, alkoxyl group, cyanic acid, acyl group, carboxyl, aldehyde radical, ester group or nitro; X on the adjacent halogen benzyl halogen
1Be fluorine, chlorine, bromine, iodine, X
2Be fluorine, chlorine, bromine, iodine, X
1And X
2Identical or different;
The mol ratio of adjacent halogen benzyl halogen and palladium-containing catalyst is 1: 0.01～1: 0.10;
The mol ratio of tributylallyltin and adjacent halogen benzyl halogen is 1: 1～1: 2;
(2) palladium-containing catalyst, solvent, adjacent halogen benzyl ketenes and alkali are added in the reactor drum 20 ℃～150 ℃ of temperature of reaction; Reaction times 10min～10h; With the reaction solution that obtains, make polysubstituted beta naphthal through the silicagel column separation; The mol ratio of adjacent halogen benzyl ketenes and palladium-containing catalyst is 1: 0.01～1: 0.20.
2. according to the method described in claims 1, it is characterized in that the palladium-containing catalyst in step (1) and the step (2) is identical or different; Palladium-containing catalyst comprises the catalystsystem that tetrakis triphenylphosphine palladium, two (triphenyl phosphorus) palladium chloride or palladium source and tertiary phosphine-ligand are formed.
3. according to the method described in claims 2; It is characterized in that described palladium source comprises Palladous chloride, palladium, three (dibenzalacetone) two palladiums, two (dibenzalacetone) palladium, palladium acetylacetonate, allyl palladium chloride, two (acetonitrile) palladium chloride, two (benzene nitrile) palladium chloride;
Tertiary phosphine-ligand comprises triphenylphosphine, three hexamethylene phosphines, tri-butyl phosphine, 1, two (diphenylphosphine) ethane, 1 of 2-, and two (diphenylphosphine) propane of 2-or 1, two (diphenylphosphine) butane of 2-, two (diphenylphosphine)-1,1 '-dinaphthalene; The mol ratio of described palladium source and tertiary phosphine-ligand is 1: 1～1: 4.
4. according to the method described in claims 1, it is characterized in that the solvent in step (1) and the step (2) is identical or different; Solvent comprises benzene, toluene, o-Xylol, 1; 4-dioxane, DMSO 99.8MIN., ethanol, methyl alcohol, the trimethyl carbinol, Virahol, trichloromethane, methylene dichloride, ether, propyl ether, n-butyl ether, tetracol phenixin, dimethyl adipate, ETHYLE ACETATE, sherwood oil, MTBE, THF, hexanaphthene, normal hexane, normal heptane, N; Dinethylformamide, N; N-N,N-DIMETHYLACETAMIDE, N-Methyl pyrrolidone are one or more mixing wherein; Volume (mL) mole (mmol) ratio of solvent and adjacent halogen benzyl halogen is 1～10: 1; Volume (mL) mole (mmol) ratio of solvent and adjacent halogen benzyl ketenes is 1～20: 1.
5. according to the method described in claims 1; It is characterized in that; Described alkali comprises yellow soda ash, sodium hydrogencarbonate, salt of wormwood, saleratus, sodium phosphate, sodium hydrogen phosphate, SODIUM PHOSPHATE, MONOBASIC, potassiumphosphate, potassium hydrogen phosphate, potassium primary phosphate, cesium carbonate, sodium tert-butoxide, potassium tert.-butoxide, sodium-acetate, Potassium ethanoate, triethylamine, Tributylamine, diisopropyl ethyl amine, hexamethylenetetramine, N; N, N, one or more mixing in the N-Tetramethyl Ethylene Diamine; The mol ratio of adjacent halogen benzyl ketenes and alkali is 1: 1～1: 5.
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| CN107253903A (en) * | 2016-06-20 | 2017-10-17 | 北京海步医药科技股份有限公司 | Prepare a kind of method that can combine S1P acceptor compounds and its intermediate |
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| CN101781172A (en) * | 2010-01-04 | 2010-07-21 | 曲靖众一精细化工股份有限公司 | Novel process for efficiently and continuously synthesizing 2-naphthol |
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| CN1740129A (en) * | 2005-08-30 | 2006-03-01 | 湖南大学 | Prepn process of hydroquinone and phenol |
| CN101781172A (en) * | 2010-01-04 | 2010-07-21 | 曲靖众一精细化工股份有限公司 | Novel process for efficiently and continuously synthesizing 2-naphthol |
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| CN107253903A (en) * | 2016-06-20 | 2017-10-17 | 北京海步医药科技股份有限公司 | Prepare a kind of method that can combine S1P acceptor compounds and its intermediate |
| CN106187835A (en) * | 2016-07-14 | 2016-12-07 | 江苏扬农化工集团有限公司 | 2,3 dihydroxy naphthlene 1,6 disulfonic acid chemical intermediate synthetic methods |
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