CN109627164A - A kind of preparation method of high allyl alcohols compound - Google Patents

A kind of preparation method of high allyl alcohols compound Download PDF

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CN109627164A
CN109627164A CN201910053278.8A CN201910053278A CN109627164A CN 109627164 A CN109627164 A CN 109627164A CN 201910053278 A CN201910053278 A CN 201910053278A CN 109627164 A CN109627164 A CN 109627164A
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alkyl
heterocycle
bismuth
aryl
heteroaryl
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CN109627164B (en
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冯雪馨
杨锦明
沈志良
杨子健
王庆东
邱悦
胡朝俊
赵玉军
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Yancheng Jinming Pharmaceutical Co Ltd
Nanjing Tech University
Yancheng Teachers University
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Yancheng Jinming Pharmaceutical Co Ltd
Nanjing Tech University
Yancheng Teachers University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
    • C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms

Abstract

The present invention relates to a kind of preparation methods of high allyl alcohols compound, mainly provide a kind of height cis-selectivity allylation reaction of carbonyls and allyl halide that effective metal mediates, obtain corresponding homoallylic alcohol, yield is good, has excellent cis-selectivity and wide functional group tolerance.

Description

A kind of preparation method of high allyl alcohols compound
Technical field
The invention belongs to chemical and medicine industry fields, are related to a kind of preparation method of high allyl alcohols compound.
Background technique
High allyl alcohols compound is a kind of important chemical substance, be the certain natural products of synthesis, drug, fragrance and The important intermediate of pesticide etc..
There is the method for much preparing high allyl alcohols compound in the prior art, but mostly reaction yield is lower, reacts Post-process it is cumbersome, isolate and purify that difficult, stereoselectivity is poor.Knochel etc. (Angew.Chem., Int.Ed., 2010,49, 8516) carbonyls and preformed cyclic allylic base zinc or aluminon for reporting two kinds of height cis-selectivities exist Allylation reaction under stringent anhydrous condition is produced with excellent stereomeric homoallylic alcohol.
However, although many main metals, such as Li, Mg, Al, Zn, Mn, Sn and In, have been widely used as various organic The medium of conversion, but use ferrous metal as the promotor of organic reaction be fairly limited.With it is every other in periodic table Metal phase ratio, iron are undoubtedly the generally the least expensive metal being widely present in nature.In addition, with other most of metals and its salt (especially tin, lead, chromium etc.) is compared, the Life Cycle of iron and its derivative due to its hypotoxicity and environmental-friendly property and to biology Phase is most important.Therefore, it is badly in need of a kind of effective method, by the activation of ferrous metal, can effectively mediates with good The organic reaction of good chemistry and stereoselectivity.
Summary of the invention
For overcome the deficiencies in the prior art, the purpose of the present invention is to provide a kind of the new of high allyl alcohols compound Preparation method.
One aspect of the present invention provides the preparation method of compound shown in formula I, including by compound shown in Formula II and formula The step of compound shown in III reacts in the presence of metal and metal salt catalyst,
Wherein, R1Selected from alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl,
R2Selected from hydrogen atom, alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein the alkane Base, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl are optionally selected from alkyl, halogen, hydroxyl, amino, oxygroup, carboxylic Replaced one or more substituent groups in base, nitro, cyano, alkoxy, naphthenic base, heterocycle, aryl and heteroaryl, or Person,
R1And R2Carbon atom adjacent thereto is formed together 5 yuan to 10 yuan carbocyclic rings, heterocycle or condensed ring, preferably 6 yuan to 8 yuan carbocyclic rings, Heterocycle or condensed ring, the carbocyclic ring, heterocycle or condensed ring are optionally selected from alkyl, halogen, hydroxyl, amino, oxygroup, carboxyl, nitro, cyanogen Replaced one or more substituent groups in base, alkoxy, naphthenic base, heterocycle, aryl and heteroaryl；
R3, R4It is each independently selected from hydrogen atom, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, wherein institute Alkyl, naphthenic base, heterocycle, aryl, the heteroaryl stated optionally are selected from halogen, hydroxyl, amino, carboxyl, nitro, cyano and alkane Replaced one or more substituent groups in oxygroup, alternatively,
R3And R4Carbon atom adjacent thereto is formed together 5 yuan to 10 yuan carbocyclic rings, preferably 6 yuan to 8 yuan carbocyclic rings, and the carbocyclic ring is appointed Choosing is by selected from alkyl, halogen, hydroxyl, amino, oxygroup, carboxyl, nitro, cyano, alkoxy, naphthenic base, heterocycle, aryl and miscellaneous Replaced one or more substituent groups in aryl；
R5Selected from hydrogen atom, alkyl, halogen, hydroxyl, amino, oxygroup, carboxyl, COOR6, nitro, cyano, alkoxy, cycloalkanes Base, heterocycle, aryl and heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl, heteroaryl are optionally selected from halogen Replaced one or more substituent groups in element, hydroxyl, amino, carboxyl, nitro, alkyl acyl, cyano and alkoxy；
R6Selected from alkyl, alkenyl, alkynyl；
X is selected from fluorine, chlorine, bromine, iodine；
M is selected from 0,1,2,3,4；
Metal is selected from iron or indium, preferably iron；
Metal salt catalyst is selected from metal bismuth salt, preferably bismuth nitrate, bismuth phosphate, bismuth sulfate, chloric acid bismuth, waltherite, bromination Bismuth, bismuth chloride, fluorination bismuth, bismuth acetate, more preferable bismuth chloride, bismuth bromide, fluorination bismuth.
In some embodiments, R1Selected from alkyl, alkenyl, alkynyl, phenyl, naphthalene, thienyl, pyridyl group, ferrocene Base；
In some embodiments, compound shown in formula III is selected from
Wherein
R7Independently selected from alkyl, halogen, hydroxyl, amino, oxygroup, carboxyl, COOR6, nitro, cyano；
N, the integer of p, q 0,1,2 or 3.
In some embodiments, compound shown in the Formula II is selected from
In some embodiments, compound shown in the Formulas I is
The dr value of compound shown in the Formulas I is greater than 80:1, preferably greater than 85:1, more preferably greater than 90:1, most preferably greatly In 95:1.
The molar ratio of compound shown in the Formula II and metal can be 1:0.1~1:10, preferably 1:1~1:5.
The molar ratio of compound shown in the Formula II and metal salt catalyst can be 1:0.01~1:10, preferably 1:0.1 ~1:5, more preferable 1:0.1 or 1:0.2.
The solvent of the reaction can be Conventional solvents, such as can be dimethylformamide, dimethyl acetamide, 1- first Base -2-Pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, dimethylbenzene, dimethyl sulfoxide, ether, isopropyl One of ether, methyl tertiary butyl ether(MTBE), acetonitrile, propionitrile, isopropanol, propyl alcohol, ethyl alcohol, methanol, water are a variety of, preferably dimethyl methyl Amide or dimethyl sulfoxide, more preferable dimethyl sulfoxide.
In some embodiments, 1,2- Bromofume and TMSCl activated metal is added.
The reaction temperature can be 0 DEG C~200 DEG C, preferably 10 DEG C~40 DEG C.
In some embodiments, the method is that iron powder and DMSO are sequentially added into reaction flask.Then pass through addition Glycol dibromide and TMSCl activate iron.BiCl is successively added into reaction mixture3, compound shown in formula III and Formula II institute Show compound, react at room temperature, post-processes to obtain compound shown in Formulas I.
Another aspect of the present invention provides a kind of method for preparing drug, fragrance and pesticide, including Formulas I of the present invention The preparation method of shown compound.
The present invention provides a kind of height of carbonyls and allyl halide that effective metal mediates is diastereomeric Selective allylation reaction obtains corresponding homoallylic alcohol, and yield is good, with excellent cis-selectivity and wide Functional group tolerance.
Unless stated to the contrary, the term used in the specification and in the claims has following meanings.
Term " alkyl " refers to saturated aliphatic hydrocarbons group, is the linear chain or branched chain group comprising 1 to 20 carbon atom, excellent Select the alkyl containing 1 to 12 carbon atom.Non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl Base, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl third Base, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethyl Butyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- first Base amyl, 4- methyl amyl, 2,3- dimethylbutyl, n-heptyl, 2- methylhexyl, 3- methylhexyl, 4- methylhexyl, 5- first Base hexyl, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2- ethyl penta Base, 3- ethylpentyl, n-octyl, 2,3- dimethylhexanyl, 2,4- dimethylhexanyl, 2,5- dimethylhexanyl, 2,2- dimethyl Hexyl, 3,3- dimethylhexanyl, 4,4- dimethylhexanyl, 2- ethylhexyl, 3- ethylhexyl, 4- ethylhexyl, 2- methyl -2- Ethylpentyl, 2- methyl -3- ethylpentyl, n-nonyl, 2- methyl -2- ethylhexyl, 2- methyl -3- ethylhexyl, 2,2- bis- Ethylpentyl, positive decyl, 3,3- diethylhexyl, 2,2- diethylhexyl and its various branched isomers etc..More preferably Low alkyl group containing 1 to 6 carbon atom, non-limiting embodiment include methyl, ethyl, n-propyl, isopropyl, normal-butyl, Isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- second Base propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- bis- Methyl butyl, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..Alkyl can be it is substituted or non-substituted, when substituted, Substituent group can be substituted on any workable tie point, and the substituent group is preferably one or more following groups, Independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkanes Base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo base, carboxyl or Carboxylate.
Term " naphthenic base " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, cycloalkyl ring include 3 to 20 carbon atoms, preferably comprise 3 to 12 carbon atoms, more preferably include 3 to 6 carbon atoms.Monocyclic cycloalkyl it is non-limiting Example includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptyl Trialkenyl, cyclooctyl etc.；Polycyclic naphthene base includes the naphthenic base of loop coil, condensed ring and bridged ring.
Term " heterocycle " refers to the unsaturated monocycle of saturation or part or polycyclic cyclic hydrocarbon substituent, and it includes 3 to 20 rings Atom, wherein one or more annular atoms are selected from nitrogen, oxygen or S (O)mThe hetero atom of (wherein m is integer 0 to 2), but do not wrap The loop section of-O-O- ,-O-S- or-S-S- are included, remaining annular atom is carbon.3 to 12 annular atoms are preferably comprised, wherein 1~4 It is hetero atom；It more preferably include 3 to 6 annular atoms.The non-limiting example of monocyclic heterocycles base includes pyrrolidinyl, imidazolidine Base, tetrahydrofuran base, tetrahydro-thienyl, glyoxalidine base, dihydrofuryl, pyrazoline base, pyrrolin base, piperidyl, Piperazinyl, morpholinyl, thio-morpholinyl, high piperazine base etc., preferably piperidyl, pyrrolidinyl.Multiring heterocyclic includes loop coil, thick The heterocycle of ring and bridged ring.
Term " aryl " refers to that 6 to 14 yuan of full carbon monocycles of the pi-electron system with conjugation or fused polycycle are (namely shared The ring of adjacent carbon atoms pair) group, preferably 6 to 10 yuan, such as phenyl and naphthalene.
Aryl can be substituted or non-substituted, and when substituted, substituent group is preferably one or more following groups, It is independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, cyano, ring Alkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl or carboxylic acid Ester group, preferably phenyl.
Term " heteroaryl " refers to the heteroaromatic system comprising 1 to 4 hetero atom, 5 to 14 annular atoms, and wherein hetero atom selects From oxygen, sulphur and nitrogen.Heteroaryl is preferably 5 to 12 yuan, such as imidazole radicals, furyl, thienyl, thiazolyl, pyrazolyl, oxazole Base, pyrrole radicals, tetrazole radical, pyridyl group, pyrimidine radicals, thiadiazoles, pyrazinyl etc., preferably imidazole radicals, pyrazolyl, pyrimidine radicals or thiophene Oxazolyl；More preferably pyrazolyl or thiazolyl.
Heteroaryl can be it is optionally replacing or non-substituted, when substituted, substituent group be preferably it is one or more with Lower group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, nitro, Cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, carboxyl Or carboxylate.
Term " condensed ring radical ", which refers to, independently to be selected by the group selected from naphthenic base, heterocycle, aryl and heteroaryl with 1~2 It is formed from the group of naphthenic base, heterocycle, aryl and heteroaryl is condensed, non-limiting example includes:
Term " alkenyl " refers to thering is 2-20 carbon on main chain, preferably 2-12 carbon and more preferable 2-8 carbon The group of linear chain or branched chain includes one or more double bonds, such as vinyl, 2- acrylic, 3- cyclobutenyl, 2- on main chain Cyclobutenyl, 4- pentenyl, 3- pentenyl, 2- hexenyl, 3- hexenyl, 2- pentenyl, 3- pentenyl, 4- pentenyl, 3- octene Base, 3- nonenyl, 4- decene base, 4- laurylene base, 4,8,12- ten four carbon triolefins, etc.." alkenyl replaced " includes optionally choosing The alkenyl replaced with one or more substituent groups, the substituent group is for example including " alkyl replaced " and " ring replaced above Alkyl " definition in substituent group.
Term " alkynyl " refers on main chain with 2-20 carbon, preferably 2-12 carbon and more preferable 2-8 carbon The group of linear chain or branched chain, includes one or more three keys on main chain, for example, 2-propynyl, 3- butynyl, 2- butynyl, 4- pentynyl, 3- pentynyl, 2- hexin base, 3- hexin base, 2- heptynyl, 3- heptynyl, 4- heptynyl, 3- octynyl, 3- nonyl Alkynyl, 4- decynyl, 3-^ alkynyl, 4- dodecyne base, etc.." alkynyl replaced " includes optionally with one or more substituent groups Substituted alkynyl, the substituent group is for example including the substitution above in the definition of " alkyl replaced " and " naphthenic base replaced " Base.
Term " alkoxy " refers to-O- (alkyl) and-O- (non-substituted naphthenic base), and wherein alkyl is as defined above. The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, propoxyl group, butoxy, cyclopropyl oxygroup, cyclobutoxy group, penta oxygen of ring Base, cyclohexyloxy.Alkoxy can be optionally replacing or non-substituted, and when substituted, substituent group is preferably one or more A following group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, sulfydryl, hydroxyl, Nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkane sulphur Base, carboxyl or carboxylate.
Term " hydroxyalkyl " refers to the alkyl being optionally substituted by a hydroxyl group, and wherein alkyl is as defined above.
Term " halogenated alkyl " refers to the alkyl being optionally substituted by halogen, and wherein alkyl is as defined above.
Term " deuteroalkyl " refers to the alkyl replaced by D-atom, and wherein alkyl is as defined above.
Term " hydroxyl " refers to-OH group.
Term " halogen " refers to fluorine, chlorine, bromine or iodine.
Term " amino " refers to-NH2。
Term " cyano " refers to-CN.
Term " nitro " refers to-NO2。
Term " carboxyl " refers to-C (O) OH.
Term " aldehyde radical " refers to-CHO.
Term " carboxylate " refers to-C (O) O (alkyl) or-C (O) O (naphthenic base), and wherein alkyl, naphthenic base are as above determined Justice.
Term " carboxylic acid halides " refers to the compound containing-C (O)-halogen group.
" optional " or " optionally " mean event or environment described later can with but need not occur, which includes The occasion that the event or environment occur or do not occur.For example, meaning that alkyl can be with " optionally by alkyl-substituted heterocyclic group " But necessarily exist, the explanation include heterocyclic group by alkyl-substituted situation and heterocyclic group not by alkyl-substituted situation.
" substituted " refers to one or more hydrogen atoms in group, preferably at most 5, more preferably 1~3 hydrogen atom Replaced independently of one another by the substituent group of respective number.Self-evident, substituent group is only in their possible chemical position, this Field technical staff, which can determine in the case where not paying excessive make great efforts and (pass through experiment or theoretical), may or impossible take Generation.It may be unstable when for example, amino or hydroxyl with free hydrogen are in conjunction with the carbon atom with unsaturated (such as olefinic) key Fixed.
Specific embodiment
The present invention is explained in detail below with reference to specific example, so that this hair is more fully understood in those skilled in the art Bright specific example is only used to illustrate the technical scheme of the present invention, and does not limit the present invention in any way.
Embodiment 1
To sequentially adding iron powder (83.8mg, 1.5mmol) and DMSO (1mL) in Schlenk bottles of 10mL.Then by adding Enter 1,2- Bromofume (14.1mg, 5mol%) and TMSCl (8.1mg, 5mol%) activation iron.Stirring is successively mixed to reaction BiCl is added in object3(31.5mg, 0.1mmol), 2a (241.5mg, 1.5mmol) and 1a (82mg, 0.5mmol).By the suspension Liquid is vigorously mixed at room temperature for 24 hours, then with saturation NaHCO3Aqueous solution is quenched.Use NH4Cl solution (30mL) washing, is used in combination Ethyl acetate (20mL × 3) extraction.Combined extract liquor is washed with salt water (30mL), it is dense with the dry simultaneously vacuum of anhydrous sodium sulfate Contracting.Gained residue is purified by silica gel column chromatography, uses ethyl acetate/petroleum ether as eluant, eluent, it is total to obtain 3a 118.08mg, yield 96%, dr value > 99:1.
Embodiment 2
According to the method for embodiment 1, preparation 3a is carried out using the catalyst in table.
Embodiment 3
According to the method for embodiment 1, using the made of metal in table for 3a.
Metal Yield (%)
Mg 32
Al <5
Zn <5
Cr <5
Sm <5
In 80
Embodiment 4
According to the method for embodiment 1, solvent is replaced with into DMF, the yield for preparing 3a is 88%.
Embodiment 5
According to the method for embodiment 1,3b, yield 94%, dr value > 99:1 are prepared.
Embodiment 6
According to the method for embodiment 1,3c, yield 85%, dr value > 99:1 are prepared.
Embodiment 7
According to the method for embodiment 1,3d, yield 90%, dr value > 99:1 are prepared.
Embodiment 8
According to the method for embodiment 1,3e, yield 93%, dr value > 99:1 are prepared.
Embodiment 9
According to the method for embodiment 1,3f, yield 86%, dr value > 99:1 are prepared.
Embodiment 10
According to the method for embodiment 1,3g, yield 94%, dr value > 99:1 are prepared.
Embodiment 11
According to the method for embodiment 1,3h, yield 93%, dr value > 99:1 are prepared.
Embodiment 12
According to the method for embodiment 1,3i, yield 84%, dr value > 99:1 are prepared.
Embodiment 13
According to the method for embodiment 1,3j, yield 88%, dr value > 99:1 are prepared.
Embodiment 14
According to the method for embodiment 1,3k, yield 98%, dr value > 99:1 are prepared.
Embodiment 15
According to the method for embodiment 1,3l, yield 83%, dr value > 99:1 are prepared.
Embodiment 16
According to the method for embodiment 1,3m, yield 85%, dr value > 99:1 are prepared.
Embodiment 17
According to the method for embodiment 1,3n, yield 65%, dr value > 99:1 are prepared.
Embodiment 18
According to the method for embodiment 1,4a, yield 67%, dr value > 99:1 are prepared.
Embodiment 19
According to the method for embodiment 1,4b, yield 73%, dr value > 99:1 are prepared.
Due to describing the present invention according to its specific embodiment, certain modifications and equivalent variations are for being proficient in this neck The technical staff in domain is obvious and is included within the scope of the invention.

Claims (10)

1. a kind of preparation method of compound shown in formula I, including by compound shown in compound shown in Formula II and formula III in gold The step of being reacted in the presence of category and metal salt catalyst,
Wherein, R1Selected from alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl,
R2Selected from hydrogen atom, alkyl, alkenyl, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl, wherein the alkyl, alkene Base, alkynyl, naphthenic base, heterocycle, aryl and heteroaryl are optionally selected from alkyl, halogen, hydroxyl, amino, oxygroup, carboxyl, nitre Replaced one or more substituent groups in base, cyano, alkoxy, naphthenic base, heterocycle, aryl and heteroaryl, alternatively,
R1And R2Carbon atom adjacent thereto is formed together 5 yuan to 10 yuan carbocyclic rings, heterocycle or condensed ring, preferably 6 yuan to 8 yuan carbocyclic rings, heterocycles Or condensed ring, the carbocyclic ring, heterocycle or condensed ring optionally by selected from alkyl, halogen, hydroxyl, amino, oxygroup, carboxyl, nitro, cyano, Replaced one or more substituent groups in alkoxy, naphthenic base, heterocycle, aryl and heteroaryl；
R3、R4It is each independently selected from hydrogen atom, alkyl, alkoxy, naphthenic base, heterocycle, aryl, heteroaryl, wherein described Alkyl, naphthenic base, heterocycle, aryl, heteroaryl are optionally selected from halogen, hydroxyl, amino, carboxyl, nitro, cyano and alkoxy In one or more substituent groups replaced, alternatively,
R3And R4Carbon atom adjacent thereto is formed together 5 yuan to 10 yuan carbocyclic rings, preferably 6 yuan to 8 yuan carbocyclic rings, the carbocyclic ring optionally quilt Selected from alkyl, halogen, hydroxyl, amino, oxygroup, carboxyl, nitro, cyano, alkoxy, naphthenic base, heterocycle, aryl and heteroaryl In one or more substituent groups replaced；
R5Selected from hydrogen atom, alkyl, halogen, hydroxyl, amino, oxygroup, carboxyl, COOR6, nitro, cyano, alkoxy, naphthenic base, Heterocycle, aryl and heteroaryl, wherein the alkyl, naphthenic base, heterocycle, aryl, heteroaryl are optionally selected from halogen, hydroxyl Replaced one or more substituent groups in base, amino, carboxyl, nitro, alkyl acyl, cyano and alkoxy；
R6Independently selected from alkyl, alkenyl, alkynyl；
X is selected from fluorine, chlorine, bromine, iodine；
M is selected from 0,1,2,3,4；
Metal is selected from iron or indium, preferably iron；
Metal salt catalyst is selected from metal bismuth salt, preferably bismuth nitrate, bismuth phosphate, bismuth sulfate, chloric acid bismuth, waltherite, bismuth bromide, chlorine Change bismuth, fluorination bismuth, bismuth acetate, more preferable bismuth chloride, bismuth bromide, fluorination bismuth, most preferably bismuth chloride.
2. preparation method according to claim 1, which is characterized in that R1Selected from alkyl, alkenyl, alkynyl, phenyl, naphthalene, thiophene Pheno base, pyridyl group, ferrocenyl.
3. preparation method according to claim 1, which is characterized in that compound shown in formula III is selected from
Wherein
R7Independently selected from alkyl, halogen, hydroxyl, amino, oxygroup, carboxyl, COOR6, nitro, cyano；
N, the integer of p, q 0,1,2 or 3.
4. preparation method according to claim 1, which is characterized in that compound shown in the Formula II is selected from
5. preparation method according to claim 1, which is characterized in that compound shown in the Formulas I is
6. preparation method according to claim 5, which is characterized in that the dr value of compound shown in the Formulas I is greater than 80:1, Preferably greater than 85:1, more preferably greater than 90:1, most preferably greater than 95:1.
7. preparation method according to claim 1, which is characterized in that the molar ratio of compound shown in the Formula II and metal For 1:0.1~1:10, preferably 1:1~1:5.
8. preparation method according to claim 1, which is characterized in that compound shown in the Formula II and metal salt catalyst Molar ratio be 1:0.01~1:10, preferably 1:0.1~1:5, more preferable 1:0.1 or 1:0.2.
9. preparation method according to claim 1, which is characterized in that the solvent of the reaction be selected from dimethylformamide, Dimethyl acetamide, 1-Methyl-2-Pyrrolidone, tetrahydrofuran, methyltetrahydrofuran, dioxane, toluene, dimethylbenzene, two One of first sulfoxide, ether, isopropyl ether, methyl tertiary butyl ether(MTBE), acetonitrile, propionitrile, isopropanol, propyl alcohol, ethyl alcohol, methanol, water or It is a variety of, preferably dimethylformamide or dimethyl sulfoxide, more preferable dimethyl sulfoxide.
10. a kind of method for preparing drug, fragrance or pesticide, including chemical combination shown in Formulas I described in any one of claim 1-9 The preparation method of object.
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