CN105272792A - Difluoromethylene-containing compound and preparation method thereof - Google Patents
Difluoromethylene-containing compound and preparation method thereof Download PDFInfo
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- CN105272792A CN105272792A CN201410334117.3A CN201410334117A CN105272792A CN 105272792 A CN105272792 A CN 105272792A CN 201410334117 A CN201410334117 A CN 201410334117A CN 105272792 A CN105272792 A CN 105272792A
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- 0 CCCC1*CC(C)C1 Chemical compound CCCC1*CC(C)C1 0.000 description 10
- AXFZLFDJAJUPLL-UHFFFAOYSA-N C/[I]=C(/C(F)(F)Cl)\N1CCOCC1 Chemical compound C/[I]=C(/C(F)(F)Cl)\N1CCOCC1 AXFZLFDJAJUPLL-UHFFFAOYSA-N 0.000 description 1
- KXKJSTGRBXOAOS-UHFFFAOYSA-N CC(C1)=CC=NC1c1cc(C)ccn1 Chemical compound CC(C1)=CC=NC1c1cc(C)ccn1 KXKJSTGRBXOAOS-UHFFFAOYSA-N 0.000 description 1
- HUMFGZNXBCEMTM-UHFFFAOYSA-N CC(c1ccc(C(C2)Oc(cccc3)c3C2=O)cc1)O Chemical compound CC(c1ccc(C(C2)Oc(cccc3)c3C2=O)cc1)O HUMFGZNXBCEMTM-UHFFFAOYSA-N 0.000 description 1
- WSAQXVDBTFHGEV-UHFFFAOYSA-N CC(c1ccc(C(c2nc(cccc3)c3[o]2)(F)F)cc1)=O Chemical compound CC(c1ccc(C(c2nc(cccc3)c3[o]2)(F)F)cc1)=O WSAQXVDBTFHGEV-UHFFFAOYSA-N 0.000 description 1
- CKQHAYFOPRIUOM-UHFFFAOYSA-N CC(c1cccc(N)c1)=O Chemical compound CC(c1cccc(N)c1)=O CKQHAYFOPRIUOM-UHFFFAOYSA-N 0.000 description 1
- AUCSDAQGXPNVKX-UHFFFAOYSA-N CCc1ccccc1-c1nc(-c2ccccn2)ccc1 Chemical compound CCc1ccccc1-c1nc(-c2ccccn2)ccc1 AUCSDAQGXPNVKX-UHFFFAOYSA-N 0.000 description 1
- FVSDKEJWCFUORM-UHFFFAOYSA-N C[I](C)c1ccc2[s]c3ccccc3c2c1 Chemical compound C[I](C)c1ccc2[s]c3ccccc3c2c1 FVSDKEJWCFUORM-UHFFFAOYSA-N 0.000 description 1
- NPAXPTHCUCUHPT-UHFFFAOYSA-N Cc(c(C)c1cc2)cnc1c1c2c(C)c(C)cn1 Chemical compound Cc(c(C)c1cc2)cnc1c1c2c(C)c(C)cn1 NPAXPTHCUCUHPT-UHFFFAOYSA-N 0.000 description 1
- GALLWSLKCWDSLT-UHFFFAOYSA-N Cc1c(-c2ncccc2C)nccc1 Chemical compound Cc1c(-c2ncccc2C)nccc1 GALLWSLKCWDSLT-UHFFFAOYSA-N 0.000 description 1
- KPLLFUUUOPHKOT-UHFFFAOYSA-N Cc1c(C)[s]c(C(c2ccccc2)(F)F)n1 Chemical compound Cc1c(C)[s]c(C(c2ccccc2)(F)F)n1 KPLLFUUUOPHKOT-UHFFFAOYSA-N 0.000 description 1
- UWSONZCNXUSTKW-UHFFFAOYSA-N Cc1c(C)[s]cn1 Chemical compound Cc1c(C)[s]cn1 UWSONZCNXUSTKW-UHFFFAOYSA-N 0.000 description 1
- PJQIBTFOXWGAEN-UHFFFAOYSA-N Cc1nc(cccc2)c2[n]1C Chemical compound Cc1nc(cccc2)c2[n]1C PJQIBTFOXWGAEN-UHFFFAOYSA-N 0.000 description 1
- GCBFTAWXXFRJQD-UHFFFAOYSA-N [I-]c(cc1)cc2c1c1ccccc1[o]2 Chemical compound [I-]c(cc1)cc2c1c1ccccc1[o]2 GCBFTAWXXFRJQD-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a difluoromethylene-containing compound and a preparation method thereof. The preparation method of the difluoromethylene-containing compound is characterized in that a Suzuki coupling reaction is carried out on a compound A and a compound B in a solvent in the presence of an alkali, a ligand and a catalyst to obtain a compound C, the catalyst is a nickel salt, and the nickel salt is NiQ2.mH2O, NiLnCl2, NiLnBr2, NiLnI2 or NiLn(OH)2. The preparation method has the advantages of simple and easily available raw materials, few reaction steps, high conversion rate, simple post-treatment operation, low price and low dosage of the catalyst, good compatibility, strong broad spectrum activity, avoiding of use of severely toxic reagents, low production cost and good market application prospect.
Description
Technical field
The present invention relates to the compound and preparation method thereof containing difluoro methylene.
Background technology
The aromatic hydroxy compound that fluoroalkyl replaces has important application at medicine, agricultural chemicals and material science.Although recent years introduces the method for fluoroalkyl to aromatic ring and makes great progress, develop the general method of some transition metal-catalyzed cheapnesss, wide spectrum or very important.
In fluoroalkyl substituted arene compound, what we paid close attention to is the compound of a class containing difluoro methylene.Because difluoro methylene can as the bioisostere of carbonyl, add the reason of fluorine atom uniqueness, change, biological property, this compounds has very important application ((a) J.O.Link at life science, J.G.Taylor, L.Xu, M.Mitchell, H.Guo, H.Liu, D.Kato, T.Kirschberg, J.Sun, N.Squires, J.Parrish, T.Keller, Z.-Y.Yang, C.Yang, M.Matles, Y.Wang, K.Wang, G.Cheng, Y.Tian, E.Mogalian, E.Mondou, M.Cornpropst, J.Perry, M.C.Desai, J.Med.Chem.2014, 57, 2033, (b) JR.T.R.Burke, K.Lee, Acc.Chem.Res.2003,36,426, (c) Z.-Y.Zhang, Acc.Chem.Res.2003,36,385.).The method of crossing this compounds of synthesis of metal catalytic at present makes some progress, but also only has a small amount of several examples ((a) K.Fujikawa, Y.Fujioka, A.Kobayashi, H.Amii, Org.Lett.2011,13,5560; (b) Z.Feng, F.Chen, X.Zhang, Org.Lett.2012,14,1938; (c) Z.Feng, Y.-L.Xiao, X.Zhang, Org.Chem.Front.2014,1,113; (d) Z.Feng, Q.-Q.Min, Y.-L.Xiao, B.Zhang, X.Zhang, Angew.Chem.2014,126,1695; Angew.Chem., Int.Ed.2014,53,1669; (e) Q.-Q.Min, Z.Yin, Z.Feng, W.-H.Guo, X.Zhang, J.Am.Chem.Soc.2014,136,1230; (f) S.Ge, W.Chaladj, J.F.Hartwig, J.Am.Chem.Soc.2014,136,4149; (g) C.Guo, R.-W.Wang, F.-L.Qing, J.FluorineChem.2012,143,135.) and these methods still come with some shortcomings, such as: severe reaction conditions, expensive catalyst, functional group compatibility is bad, and broad spectrum is bad.Reference d is the cross-coupling reaction of aryl boric acid based on palladium chtalyst and Bromodifluoroacetic acid ethyl ester, and this reaction is that palladium catalyst or part xantphos are very expensive, and the substrate spectrum be suitable for is limited, and reaction efficiency has much room for improvement.Therefore, explore a kind of high-efficient simple, the method containing difluoro methylene compound of functional group compatibility is good, catalyzer is cheap and consumption is low, reaction conditions is gentle synthesis functionalization has very important significance.
Summary of the invention
Technical problem to be solved by this invention is the preparation method's severe reaction conditions in order to overcome containing the compound of difluoro methylene in prior art, expensive catalyst, shortcomings such as functional group compatibility is bad, and broad spectrum is bad and provide a kind of containing difluoro methylene compound and preparation method thereof.Preparation method's raw material of the present invention is simple and easy to get, and reactions steps is few, transformation efficiency is high, reaction yield is high, and post-processing operation is simple, catalyzer is cheap, consumption is few, functional group compatibility is good, broad spectrum is strong, can avoid using poisonous reagent, production cost low, has good market application foreground.
The invention provides a kind of preparation method containing difluoro methylene compound, it comprises the following steps: in a solvent, under alkali, part and catalyzer existent condition, compd A and compd B are carried out suzuki linked reaction, obtain Compound C, described catalyzer is nickel salt, and described nickel salt is NiQ
2mH
2o, NiL
ncl
2, NiL
nbr
2, NiL
ni
2or NiL
n(OH)
2;
Wherein, Q is nitrate radical, acetate, trifluoracetic acid root or halogen (such as fluorine, chlorine, bromine or iodine), and 0≤m≤10 (such as 0,1,2,3,4,5,6,7,8,9 or 10), and 0<n<3 (such as 0,1,2 or 3), L is triphenylphosphine, O-methoxy triphenylphosphine, adjacent methyl triphenyl phosphine, tri-butyl phosphine, tricyclohexyl phosphine, three adamantyl phosphines, 1, 2 pairs of (diphenylphosphine) ethane (dppe), 1, two (diphenylphosphine) propane (dppp) of 3-, 1, two (diphenylphosphine) butane (dppb) of 4-, 1, two (diphenylphosphine) ferrocene (dppf) of 1'-, two diphenylphosphine methane (dppm), 1, the two two triphenylphosphine benzene (dppbz) of 2-, dimethyl second diether (DME), diethylene glycol dimethyl ether (Diglyme), " substituted or unsubstituted 1, 10-phenanthroline " (described " unsubstituted 1, 10-phenanthroline " be
) substituted or unsubstituted dipyridyl (preferably
) or " substituted or unsubstituted terpyridyl " (
), described " substituted or unsubstituted dipyridyl ", " substituted or unsubstituted 1,10-phenanthroline " or " replacement " described in " terpyridyl replacing or replace " refer on heteroatomic non-ortho position by C
1~ C
10alkyl (preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) and C
1~ C
10alkoxyl group (preferred C
1~ C
6alkoxyl group, described " C
1~ C
6alkoxyl group " such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy) and in one or morely to replace, when there is multiple substituting group, described substituting group can be identical or different, X is halogen (such as chlorine, bromine or iodine, preferred chlorine or bromine),
R
1for " substituted or unsubstituted C
3~ C
15aryl " (preferably " substituted or unsubstituted C
5~ C
14aryl ", described " substituted or unsubstituted C
5~ C
14aryl " preferably " substituted or unsubstituted phenyl ", " substituted or unsubstituted naphthyl " or " substituted or unsubstituted phenanthryl "; Described " unsubstituted naphthyl " such as
described " unsubstituted phenanthryl " such as
described " phenyl of replacement " preferred 4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl,
4-trifluoromethyl, N, N-3,5-dimethylphenyl, 3-trifluoromethyl, 4-cyano-phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3-nitrophenyl, 4-bromophenyl, 3,5-dichlorophenyls, 3,5-Dimethoxyphenyls, 4-tert-butyl-phenyl, 3-bromophenyl, 4-bromophenyl,
), " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " (preferably " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1
3~ C
10heteroaryl ", it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1
3~ C
10heteroaryl " preferably " substituted or unsubstituted pyridyl ", " substituted or unsubstituted thienyl ", " substituted or unsubstituted furyl ", " substituted or unsubstituted pyrryl ", " substituted or unsubstituted benzofuryl ", " substituted or unsubstituted benzothienyl ", " substituted or unsubstituted benzopyrrole base ",
described " unsubstituted pyridyl " can be 2-pyridyl, 3-pyridyl or 4-pyridyl; Described " unsubstituted thienyl " can be 2-thienyl or 3-thienyl; Described " thienyl of replacement " can be
described " unsubstituted furyl " can be 2-furyl or 3-furyl; Described " furyl of replacement " can be
described " unsubstituted pyrryl " can be 2-pyrryl or 3-pyrryl; Described " pyrryl of replacement " can be
),
described " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by cyano group, hydroxyl, nitro, halogen (such as fluorine, chlorine, bromine or iodine), C
1~ C
10alkyl (preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl), C
1~ C
10alkoxyl group (preferred C
1~ C
6alkoxyl group, described " C
1~ C
6alkoxyl group " such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy), C
1~ C
10alkylthio (preferred C
1~ C
6alkylthio, described " C
1~ C
6alkylthio " such as methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio or tertiary butylthio), C
1~ C
10alkyl silyl (preferred C
1~ C
6alkyl silyl, described " C
1~ C
6alkyl silyl " such as methylsilyl, trimethyl silicon based, ethyl is silica-based, propyl group is silica-based, sec.-propyl is silica-based, butyl is silica-based, isobutyl-is silica-based or the tertiary butyl silica-based), " C of halogen substiuted
1~ C
10alkyl " (described " C of halogen substiuted
1~ C
10alkyl " described in the preferred fluorine of halogen, chlorine or bromine, the number of described halogen is 1-4, and when there is multiple halogen atom, described halogen atom can be identical or different; Described " the C of halogen substiuted
1~ C
10alkyl " described in " C
1~ C
10alkyl " preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " can be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl.Described " the C of halogen substiuted
1~ C
10alkyl " preferred " C of the one or more replacements in fluorine, chlorine and bromine atoms
1~ C
6alkyl ", the described " C of the one or more replacements in fluorine, chlorine and bromine atoms
1~ C
6alkyl " preferred " fluorine, the methyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the ethyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the propyl group of the one or more replacements in chlorine and bromine atoms ", " fluorine, the sec.-propyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the butyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the isobutyl-of the one or more replacements in chlorine and bromine atoms " or " fluorine, the tertiary butyl of the one or more replacements in chlorine and bromine atoms ", described " methyl that fluorine atom replaces " preferably trifluoromethyl, described " methyl that bromine atoms replaces " is preferred
), " hydroxyl replace C
1~ C
10alkyl " (preferably " C that hydroxyl replaces
1~ C
6alkyl ", the described " C that hydroxyl replaces
1~ C
6alkyl " such as " hydroxyl replace methyl ", " ethyl that hydroxyl replaces ", " propyl group that hydroxyl replaces ", " sec.-propyl that hydroxyl replaces ", " butyl that hydroxyl replaces ", " isobutyl-that hydroxyl replaces " or " tertiary butyl that hydroxyl replaces ", ), C
2~ C
10thiazolinyl (preferred C
2~ C
6thiazolinyl, described " C
2~ C
6thiazolinyl " such as vinyl,
), C
2~ C
10alkynyl (preferred C
2~ C
6alkynyl, described " C
2~ C
6alkynyl " such as ethynyl,
), C
3~ C
10aryl (preferred C
3~ C
6aryl, described " C
3~ C
6aryl " preferred phenyl), " C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
6heterocyclylalkyl " (preferably " C that heteroatoms is oxygen or nitrogen-atoms, heteroatoms number is 1-2
3~ C
4heterocyclylalkyl ", the described " C that heteroatoms is oxygen or nitrogen-atoms, heteroatoms number is 1-2
3~ C
4heterocyclylalkyl " preferred morpholinyl, described " morpholinyl " such as
,
(preferably
),
in one or morely to replace, when there is multiple substituting group, described substituting group is identical or different, wherein, R
3, R
4and R
5be independently hydrogen atom, amino, C separately
1~ C
6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) or C
3~ C
6cycloalkyl (such as cyclopropyl, cyclopentyl or cyclohexyl).R
6and R
7be independently C separately
1~ C
6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) or C
3~ C
6cycloalkyl (such as cyclopropyl, cyclopentyl or cyclohexyl).R
8for hydrogen atom, C
1~ C
6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) or C
3~ C
6cycloalkyl (such as cyclopropyl, cyclopentyl or cyclohexyl).
R
2for
(preferably
),
(preferably
) or " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " (preferably " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-2
3~ C
8heteroaryl ", described " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-2
3~ C
8heteroaryl " preferably " substituted or unsubstituted benzoxazolyl ", " substituted or unsubstituted benzimidazolyl-" or " substituted or unsubstituted thiazolyl ", described " unsubstituted benzoxazolyl " can be
described " unsubstituted thiazolyl " can be
described " thiazolyl of replacement " can be
described " unsubstituted benzimidazolyl-" can be
described " benzimidazolyl-of replacement " can be
), described " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " refer to by cyano group, halogen (such as fluorine, chlorine, bromine or iodine), C
1~ C
10alkyl (preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl), C
1~ C
10alkoxyl group (preferred C
1~ C
6alkoxyl group, described " C
1~ C
6alkoxyl group " such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy), " C of halogen substiuted
1~ C
10alkyl " (described " C of halogen substiuted
1~ C
10alkyl " described in the preferred fluorine of halogen, chlorine or bromine, the number of described halogen is 1-4, and when there is multiple halogen atom, described halogen atom can be identical or different, described " the C of halogen substiuted
1~ C
10alkyl " preferred " C of the one or more replacements in fluorine, chlorine and bromine atoms
1~ C
6alkyl ", the described " C of the one or more replacements in fluorine, chlorine and bromine atoms
1~ C
6alkyl " preferred " fluorine, the methyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the ethyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the propyl group of the one or more replacements in chlorine and bromine atoms ", " fluorine, the sec.-propyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the butyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the isobutyl-of the one or more replacements in chlorine and bromine atoms " or " fluorine, the tertiary butyl of the one or more replacements in chlorine and bromine atoms ", described " methyl that fluorine atom replaces " preferably trifluoromethyl, described " methyl that bromine atoms replaces " is preferred
), C
2~ C
10thiazolinyl (preferred C
2~ C
6thiazolinyl, described " C
2~ C
6thiazolinyl " such as vinyl,
), C
2~ C
10alkynyl (preferred C
2~ C
6alkynyl, described " C
2~ C
6alkynyl " such as ethynyl,
) in one or morely to replace, when there is multiple substituting group, described substituting group can be identical or different.
Wherein, R
9for C
1~ C
6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) or C
3~ C
6cycloalkyl (such as cyclopropyl, cyclopentyl or cyclohexyl);
R
10for substituted or unsubstituted C
1~ C
10alkyl (preferred substituted or unsubstituted C
1~ C
6alkyl, described " substituted or unsubstituted C
1~ C
6alkyl " can be " substituted or unsubstituted methyl ", " substituted or unsubstituted ethyl ", " substituted or unsubstituted propyl group ", " substituted or unsubstituted sec.-propyl ", " substituted or unsubstituted butyl ", " substituted or unsubstituted isobutyl-" or " the substituted or unsubstituted tertiary butyl "; Described " ethyl of replacement " is preferred
), " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the substituted or unsubstituted C of 1-3
2~ C
15heterocyclylalkyl " (preferably " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1-2
2~ C
6heterocyclylalkyl ", it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1-2
2~ C
6heterocyclylalkyl " preferably heteroatoms be oxygen and/or nitrogen-atoms, heteroatoms number is the C of 2
3~ C
4heterocyclylalkyl, it is described that " heteroatoms is oxygen and/or nitrogen-atoms, and heteroatoms number is the C of 2
3~ C
4heterocyclylalkyl " preferred substituted or unsubstituted morpholinyl, described " unsubstituted morpholinyl " is preferred
), substituted or unsubstituted C
3~ C
15aryl (preferably " substituted or unsubstituted C
5~ C
10aryl ", described " substituted or unsubstituted C
5~ C
10aryl " preferred substituted or unsubstituted phenyl, described " phenyl of replacement " preferably 4-p-methoxy-phenyl, 2-aminomethyl phenyl, 4-trifluoromethyl, 3-trifluoromethyl, 4-cyano-phenyl, 4-fluorophenyl, 4-bromophenyl, 3,5-Dimethoxyphenyls, 4-tert-butyl-phenyl, 3-bromophenyl, 4-bromophenyl, 4-aminomethyl phenyl,
) or C
3~ C
15virtue amino (preferred C
5~ C
10virtue amino, described " C
5~ C
10virtue amino " preferably
); Described R
10described in " substituted or unsubstituted C
1~ C
10alkyl " described in " replacement " refer to by C
3~ C
15aryl (preferred C
5~ C
10aryl, described " C
5~ C
10aryl " preferred phenyl) replaced.
Described R
10described in " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the substituted or unsubstituted C of 1-3
2~ C
15heterocyclylalkyl " described in " replacement " refer to by C
1~ C
10alkyl (preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) and C
3~ C
6cycloalkyl (such as cyclopropyl, cyclopentyl or cyclohexyl) in one or morely to replace, when there is multiple substituting group, described substituting group can be identical or different.
Described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by cyano group, halogen (such as fluorine, chlorine, bromine or iodine), C
1~ C
10alkyl (preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl), C
1~ C
10alkoxyl group (preferred C
1~ C
6alkoxyl group, described " C
1~ C
6alkoxyl group " such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy), " C of halogen substiuted
1~ C
10alkyl " (described " C of halogen substiuted
1~ C
10alkyl " described in the preferred fluorine of halogen, chlorine or bromine, the number of described halogen is 1-4, and when there is multiple halogen atom, described halogen atom can be identical or different, described " the C of halogen substiuted
1~ C
10alkyl " preferred " C of the one or more replacements in fluorine, chlorine and bromine atoms
1~ C
6alkyl ", the described " C of the one or more replacements in fluorine, chlorine and bromine atoms
1~ C
6alkyl " preferred " fluorine, the methyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the ethyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the propyl group of the one or more replacements in chlorine and bromine atoms ", " fluorine, the sec.-propyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the butyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the isobutyl-of the one or more replacements in chlorine and bromine atoms " or " fluorine, the tertiary butyl of the one or more replacements in chlorine and bromine atoms ", described " methyl that fluorine atom replaces " preferably trifluoromethyl, described " methyl that bromine atoms replaces " is preferred
), C
2~ C
10thiazolinyl (preferred C
2~ C
6thiazolinyl, described " C
2~ C
6thiazolinyl " such as vinyl,
), C
2~ C
10alkynyl (preferred C
2~ C
6alkynyl, described " C
2~ C
6alkynyl " such as ethynyl,
),
in one or morely to replace, when there is multiple substituting group, described substituting group is identical or different.
R
11for C
1~ C
6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl), C
3~ C
6cycloalkyl (such as cyclopropyl, cyclopentyl or cyclohexyl) or " C
1~ C
6alkyl silyl " (described " C
1~ C
6alkyl silyl " described in " C
1~ C
6alkyl " preferable methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl, described " C
1~ C
6alkyl silyl " such as trimethyl silicon based, triethyl is silica-based, tripropyl is silica-based or triisopropylsilyl).
R
12for C
1~ C
6alkyl (such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl, preferred sec.-propyl or normal-butyl).
In the present invention, described compd A (
) be preferably as follows arbitrary compound further:
In the present invention, described compd B
be preferably as follows arbitrary compound further:
In the present invention, described Compound C
be preferably as follows arbitrary compound further:
Containing in the preparation method of difluoro methylene compound, described solvent can be the Conventional solvents of such Suzuki linked reaction in this area described, one or more in the present invention particularly preferably in ether solvent and water, preferred ether solvent.One or more in the preferred tetrahydrofuran (THF) of described ether solvent, ether, glycol dimethyl ether (DME), diethylene glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane and methyl tertiary butyl ether, further preferably Isosorbide-5-Nitrae-dioxane and/or tetrahydrofuran (THF).
Described containing in the preparation method of difluoro methylene compound, the Molar of described solvent and described compd B than preferred 1mL/mmol ~ 100mL/mmol, preferred 1mL/mmol ~ 10mL/mmol further.
Contain in the preparation method of difluoro methylene compound described, described alkali can be the conventional alkali of such Suzuki linked reaction in this area, particularly preferably alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate, alkali metal phosphate, " basic metal and C in the present invention
1~ C
4the salt that alcohol is formed " or C
1~ C
4alkylamine (such as triethylamine), one or more in the preferred salt of wormwood of described alkaline carbonate, sodium carbonate and cesium carbonate, further preferably salt of wormwood and/or sodium carbonate, more preferred salt of wormwood further.Described alkali metal phosphate preferably phosphoric acid potassium.Described " basic metal and C
1~ C
4alcohol formed salt " described in " C
1~ C
4alcohol " particular methanol, ethanol, propyl alcohol, Virahol or the trimethyl carbinol; Described " basic metal and C
1~ C
4alcohol formed salt " described in " basic metal " preferred lithium, sodium, potassium, rubidium or caesium; Described described " basic metal and C
1~ C
4the salt that alcohol is formed " one or more in particular methanol sodium, sodium ethylate, sodium tert-butoxide and potassium tert.-butoxide.
Described containing in the preparation method of difluoro methylene compound, the molar ratio of described alkali and described compd B preferably 1 ~ 5, further preferably 2 ~ 3.
Contain in the preparation method of difluoro methylene compound described, described part can be the conventional ligands of such suzuki linked reaction in this area, particularly preferably nitrogenous bitooth ligand or nitrogenous tridentate ligand in the present invention, (described " dipyridyl of replacement " is preferred for described " nitrogenous bitooth ligand " preferred substituted or unsubstituted dipyridyl
), (described " unsubstituted 1,10-phenanthroline " is substituted or unsubstituted 1,10-phenanthroline
) or N, N, N ', N '-tetramethyl-ethamine; (described " unsubstituted terpyridyl " is described nitrogenous tridentate ligand preferred " substituted or unsubstituted terpyridyl "
), described " substituted or unsubstituted dipyridyl ", " substituted or unsubstituted 1,10-phenanthroline " or " replacement " described in " terpyridyl replacing or replace " refer on heteroatomic non-ortho position by C
1~ C
10alkyl (preferred C
1~ C
6alkyl, described " C
1~ C
6alkyl " such as methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl) and C
1~ C
10alkoxyl group (preferred C
1~ C
6alkoxyl group, described " C
1~ C
6alkoxyl group " such as methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy) and in one or morely to replace, when there is multiple substituting group, described substituting group can be identical or different.
Described containing in the preparation method of difluoro methylene compound, the molar ratio of described part and described compd B preferably 0.01 ~ 0.1, further preferably 0.025 ~ 0.05.
Contain in the preparation method of difluoro methylene compound described, described nickel salt preferred dimethyl second diether closes nickelous chloride (NiCl
2dME), 1,2 pairs of (diphenylphosphine) ethane close nickelous chloride (NiCl
2dppe), 1,1'-two (diphenylphosphine) ferrocene closes nickelous chloride (NiCl
2dppf), 1,3-two (diphenylphosphine) propane closes nickelous chloride (NiCl
2dppp), two tricyclohexyl phosphines close nickelous chloride (NiCl
2(PCy
3)
2), dimethyl second diether closes nickelous bromide (NiBr
2dME), diethylene glycol dimethyl ether closes nickelous bromide (NiBr
2diglyme), two triphenylphosphines close nickelous bromide (NiBr
2(PPh
3)
2), two triphenylphosphines close nickelous chloride (NiCl
2(PPh
3)
2), Nickelous nitrate hexahydrate (Ni (NO
3)
26H
2o) and three hydration nickelous bromide (NiBr
23H
2o) one or more in.
Described containing in the preparation method of difluoro methylene compound, the molar ratio of described nickel salt and described compd B preferably 0.01 ~ 0.1, further preferably 0.025 ~ 0.05.
Described containing in the preparation method of difluoro methylene compound, the temperature of described Suzuki linked reaction preferably 20 DEG C ~ 120 DEG C, preferably 60 DEG C ~ 80 DEG C further.
Contain in the preparation method of difluoro methylene compound described, the process of described Suzuki linked reaction can adopt the common detection methods in this area (such as TLC, HPLC or NMR) to monitor, be reaction end when generally disappearing with compd B, preferably 1 hour ~ 48 hours reaction times, preferably 8 hours ~ 24 hours further.
The described preparation method containing difluoro methylene compound can also carry out under promotor existent condition, the preferred mantoquita of described promotor.One or more in described mantoquita preferential oxidation copper, neutralized verdigris, cupric chloride, cupric bromide, cupric iodide, cuprous iodide, cupric fluoride and copper carbonate.
Described containing in the preparation method of difluoro methylene compound, when carrying out under promotor existent condition, the molar ratio of described promotor and described compd B preferably 0 ~ 4, but do not comprise 0.
In the present invention,
synthetic method reference D.Maximilian, etal.PCTInt.Appl., 2013092850,27Jun2013.
synthetic method reference P.Ackermann, H.R.Kaenel, B.Schaub, Eur.Pat.Appl.1989, EP333658A219890920.
synthetic method reference S.Mao, X.Fang, L.Ba, F.Wu, J.FluorineChem., 2007,128,5.
synthetic method reference T.Nihei, N.Twai, T.Matsuda, T.Kitazume, J.Org.Chem., 2005,70,5912.
synthetic method reference Z.-M.Qiu, D.J.Burton, J.Org.Chem., 1995,60,5570.
synthetic method reference W.R.DolbierJr, C.R.Burkholder, M.
j.Fluor.Chem., 1999,95,127.
synthetic method reference C.R.Burkholder, W.R.DolbierJr, J.Org.Chem., 1998,63,5385.
synthetic method reference R.M.Flynn, D.J.Burton, J.Fluor.Chem., 2011,132,815.
synthetic method reference B.Xu; M.S.Mashuta; G.B.Hammond, Angew.Chem., Int.Ed.2006,45,7265.
Present invention also offers such as formula the compound shown in C,
R
1CF
2R
2
C
Wherein, R
1and R
2definition all same as above, but do not comprise following compound:
Present invention also offers the bioisostere of described Compound C as carbonyl at preparation medicine, application in agricultural chemicals or medical material, such as with the situation that Publication about Document is reported: (a) J.O.Link, J.G.Taylor, L.Xu, M.Mitchell, H.Guo, H.Liu, D.Kato, T.Kirschberg, J.Sun, N.Squires, J.Parrish, T.Keller, Z.-Y.Yang, C.Yang, M.Matles, Y.Wang, K.Wang, G.Cheng, Y.Tian, E.Mogalian, E.Mondou, M.Cornpropst, J.Perry, M.C.Desai, J.Med.Chem.2014, 57, 2033, (b) JR.T.R.Burke, K.Lee, Acc.Chem.Res.2003,36,426, (c) Z.-Y.Zhang, Acc.Chem.Res.2003,36,385.
In the present invention, when not having specially appointed, described " alkyl " is comprise the representative examples of saturated aliphatic alkyl having and specify carbonatoms object side chain or straight chain; As at " C
1~ C
20alkyl " in be defined as the group being included in and there is in straight chain or branched structure 1,2,3,4,5,6,7,8,9,11,11,12,13,14,15,16,17,18,19 or 20 carbon atom.Such as, " C
1~ C
10alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group, hexyl, heptyl, octyl group, nonyl and decyl etc.
In the present invention, when not having specially appointed, described " alkoxyl group " represent alkyl be connected with Sauerstoffatom after generation group, namely
r is alkyl.
In the present invention, when not having specially appointed, described " alkylthio " represent alkyl be connected with sulphur atom after generation group, namely
r is alkyl.
In the present invention, when not having specially appointed, described " virtue is amino " refers to " NH
3" in a hydrogen replaced by aryl after amino.
In the present invention, when not having specially appointed, described " alkyl silyl " is structure
in, R
1, R
2and R
3in have one at least for alkyl, all the other are the group of hydrogen.
In the present invention, when not having specially appointed, described " cycloalkyl " refers to full carbon monocycle or polycyclic moiety, and wherein each ring can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.The preferably cycloalkyl of 1 ~ 3 ring that formed of 3 ~ 20 carbon, more preferably 3 ~ 10 carbon, such as: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, cyclodecane and cyclo-dodecyl.
In the present invention, when not having specially appointed, described " Heterocyclylalkyl " is at this separately or when using as the part of another group, refer to 4 ~ 12 yuan of monocycles or the polycyclic moiety that comprise 1 ~ 4 heteroatoms (as one or more in nitrogen, oxygen and sulphur), wherein each ring can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.In addition, any heterocycloalkyl ring can condense on cycloalkyl, aryl, heteroaryl or heterocycloalkyl ring.Heterocyclylalkyl in this range of definition includes but not limited to: oxazoline, oxygen cyclobutyl, pyranyl, THP trtrahydropyranyl, azetidinyl, 1, 4-alkyl dioxin, six hydrogen azatropylidene bases, piperazinyl, piperidyl, pyrrolidyl, morpholinyl, thio-morpholinyl, dihydrofuran base, glyoxalidine base, indolinyl, dihydro-isoxazole base, dihydro isothiazolyl, Er Qing oxadiazolyl, dihydro-oxazole base, dihydro pyrazinyl, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazyl, thiodiazoline base, dihydro-thiazolyl, dihydro-thiophene base, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl and N-oxide compound thereof.Heterocyclylalkyl can be connected with other groups through carbon atom wherein or heteroatoms.
In the present invention, when not having specially appointed, described " thiazolinyl " refers to containing the straight chain specifying number carbon atom and at least one carbon-carbon double bond, side chain or the non-aromatic alkyl of ring-type.Preferred existence carbon-carbon double bond, and can exist up to four non-aromatic carbon-carbon double bonds.Thus, " C
2~ C
12thiazolinyl " refer to the thiazolinyl with 2 ~ 12 carbon atoms." C
2~ C
6thiazolinyl " refer to the thiazolinyl with 2 ~ 6 carbon atoms, comprise vinyl, propenyl, butenyl, 2-methyl butene base and cyclohexenyl.
In the present invention, when not having specially appointed, described " alkynyl " refers to containing the straight chain specifying number carbon atom and at least one carbon carbon triple bond, side chain or cyclic hydrocarbon group.Wherein can exist up to three carbon carbon triple bonds.Thus, " C
2~ C
12alkynyl " refer to the alkynyl with 2 ~ 12 carbon atoms." C
2~ C
6alkynyl " refer to the alkynyl with 2 ~ 6 carbon atoms, comprise ethynyl, proyl, butynyl and 3-methylbutynyl etc.
In the present invention, when not having specially appointed, described " aryl " refer to any stable can up to the monocycle of 7 atoms or bicyclic carbocyclic in each ring, wherein at least one ring is aromatic nucleus; The example of above-mentioned aryl unit comprises phenyl, naphthyl, tetralyl, 2,3-indanyls, xenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).Be appreciated that at aryl substituent be two ring substituents, and one of them ring is in the situation of non-aromatic ring, connection is undertaken by aromatic ring.
In the present invention, when not having specially appointed, described " heteroaryl " represents can up to the stable monocycle of 7 atoms or two rings in each ring, and wherein at least one ring is aromatic nucleus and is selected from the heteroatoms of O, N and S containing 1-4; Heterocyclic aryl in this range of definition includes but not limited to: acridyl, carbazyl, cinnolines base, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl, tetrahydroquinoline.As the definition of following heterocycle, " heterocyclic aryl " it should also be understood that to be the N-oxide derivative comprising any nitrogen-containing hetero aryl.Heterocyclic aryl substituting group is two ring substituents and ring is non-aromatic ring or under not comprising heteroatomic situation wherein, is appreciated that to connect and carries out respectively by aromatic ring or by the heteroatoms comprising ring.
In the present invention, when not having specially appointed, described " heterocycloalkenyl " refers to single heterocycle or many heterocyclic groups, and wherein each ring can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Such as
In the present invention, when not having specially appointed, described " halogen " represents fluorine, chlorine, bromine, iodine or astatine.
In the present invention, the described " C determining carbon number range
x1~ C
y1" substituting group (x1 and y1 is integer), as " C
x1~ C
y1" alkyl, " C
x1~ C
y1" alkoxyl group, " C
x1~ C
y1" aryl, " C
x1~ C
y1" heteroaryl or " C
x1~ C
y1" alkoxy carbonyl, all represent and do not comprise substituent carbon number, such as C
1~ C
10alkyl represents and does not comprise substituent C
1~ C
10alkyl.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material are all commercially.
In the present invention, described room temperature refers to that envrionment temperature is 10 DEG C ~ 35 DEG C.
Positive progressive effect of the present invention is: the present invention take nickel salt as catalyzer, and other metal-salts (silver salt or mantoquita or zinc salt) are promotor, through the short-cut method of the compound containing difluoro methylene of linked reaction synthesis functionalization.It is simple and easy to get that the method has raw material, and reactions steps is few, transformation efficiency is high, reaction yield is high, and post-processing operation is simple, catalyzer is cheap, consumption is few, functional group compatibility is good, broad spectrum is strong, can avoid using poisonous reagent, production cost low, has good market application foreground.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or selects according to catalogue.
Embodiment 1
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
34mL1,4-dioxane, inject 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, stir after 24 hours at 60 DEG C, isolated yield is 87% (during with 0.6mmol chlorine ethyl difluoro, to stir after 24 hours at 80 DEG C, isolated yield is 76%), purity is greater than 95% through the qualification of hydrogen spectrum.
1HNMR(500MHz,CDCl
3)δ7.62(d,J＝7.0Hz,2H),7.53–7.41(m,3H),4.30(q,J＝7.1Hz,2H),1.30(t,J＝7.2Hz,3H).
13CNMR(125.7MHz,CDCl
3)δ164.2(t,J＝35.3Hz),132.8(t,J＝25.5Hz),130.9(t,J＝1.7Hz),128.6,125.4(t,J＝6.2Hz),113.4(t,J＝251.9Hz),63.1,13.8.
19FNMR(376MHz,CDCl
3)δ-103.9(s,2F).
Embodiment 2
To in the reaction tubes of 25mL, add 137mg (0.9mmol) 4-methoxyphenylboronic acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 4-methoxyphenylboronic acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 4-methoxyphenylboronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
34mL1,4-dioxane, inject 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, stir after 24 hours at 60 DEG C, isolated yield is 81% (during with 0.6mmol chlorine ethyl difluoro, to stir after 24 hours at 80 DEG C, isolated yield is 62%), purity is greater than 95% through the qualification of hydrogen spectrum.
1HNMR(400MHz,CDCl
3)δ7.53(d,J＝8.9Hz,2H),6.95(d,J＝8.9Hz,2H),4.29(q,J＝7.1Hz,2H),3.84(s,3H),1.30(t,J＝7.1Hz,3H).
13CNMR(125.7MHz,CDCl
3)δ164.4(t,J＝36.0Hz),161.6,127.0(t,J＝6.1Hz),124.9(t,J＝26.2Hz),114.0,113.5(t,J＝251.5Hz),63.0,55.3,13.8.
19FNMR(376MHz,CDCl
3)δ-102.6(s,2F).
Embodiment 3
To in the reaction tubes of 25mL, add 122mg (0.9mmol) 2-methylphenylboronic acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 2-methylphenylboronic acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 2-methylphenylboronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, inject 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, stir after 24 hours at 80 DEG C, isolated yield is 87% (during with 0.6mmol chlorine ethyl difluoro, isolated yield is 65%), purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.57 (d, J=7.9Hz, 1H), 7.37 (t, J=7.5Hz, 1H), 7.27 (t, J=7.2Hz, 1H), 7.23 (d, J=7.5Hz, 1H), 4.32 (q, J=7.1Hz, 2H), 2.42 (s, 3H), 1.31 (t, J=7.1Hz, 3H).
13cNMR (125.7MHz, CDCl
3) δ 164.2 (t, J=35.1Hz), 136.4 (t, J=3.2Hz), 131.8,131.1 (t, J=23.3Hz), 130.7 (t, J=1.4Hz), 126.1 (t, J=8.8Hz), 125.9,114.2 (t, J=251.6Hz), 63.0,19.6 (t, J=2.7Hz), 13.8.
19fNMR (376MHz, CDCl
3) δ-101.3 (s, 2F) .IR (membrane process) ν
max2986,1767,1462,1290,1255,1112,1018cm
-1.MS (EI): m/z (%) 214 (M
+), 141 (100) .HRMS:Calculatedfor (theoretical value) C
11h
12f
2o
2: 214.0805; Found (measured value): 214.0804.
Embodiment 4
To in the reaction tubes of 25mL, add 171mg (0.9mmol) 4-trifluoromethylbenzene boronic acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 4-trifluoromethylbenzene boronic acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 4-trifluoromethylbenzene boronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
34mL1,4-dioxane, inject 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, stir after 24 hours at 60 DEG C, isolated yield is 74% (during with 0.6mmol chlorine ethyl difluoro, to stir after 24 hours at 80 DEG C, isolated yield is 61%), purity is greater than 95% through the qualification of hydrogen spectrum.
1HNMR(400MHz,CDCl
3)δ7.83–7.57(m,4H),4.31(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H).
13CNMR(125.7MHz,CDCl
3)δ163.5(t,J＝34.7Hz),136.5(t,J＝26.4Hz),133.1(q,J＝32.8Hz),126.2(t,J＝6.1Hz),125.7(q,J＝3.8Hz),123.5(q,J＝272.5Hz),112.7(t,J＝253.0Hz),63.5,13.8.
19FNMR(376MHz,CDCl
3)δ-63.1(s,3F),-104.6(s,2F).
Embodiment 5
To in the reaction tubes of 25mL, add 171mg (0.9mmol) 3-trifluoromethylbenzene boronic acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 3-trifluoromethylbenzene boronic acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 3-trifluoromethylbenzene boronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
34mL1,4-dioxane, inject 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, stir after 24 hours at 60 DEG C, isolated yield is 81% (during with 0.6mmol chlorine ethyl difluoro, to stir after 24 hours at 80 DEG C, isolated yield is 56%), purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.89 (s, 1H), 7.82 (d, J=7.8Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.61 (t, J=7.9Hz, 1H), 4.32 (q, J=7.2Hz, 2H), 1.31 (t, J=7.1Hz, 3H).
13cNMR (125.7MHz, CDCl
3) δ 163.5 (t, J=34.8Hz), 133.9 (t, J=26.2Hz), 131.3 (q, J=33.0Hz), 129.4,129.0 (tq, J=6.0Hz, 1.2Hz), 127.8 (m), 113.5 (q, J=272.5Hz), 122.6 (m), 112.6 (t, J=253.0Hz), 63.5,13.8.
19fNMR (376MHz, CDCl
3) δ-62.9 (s, 3F) ,-104.2 (s, 2F) .IR (membrane process) ν
max1771,1623cm
-1.MS (EI): m/z (%) 268 (M
+), 195 (100) .HRMS:Calculatedfor (theoretical value) C
11h
9f
5o
2: 2268.0523; Found (measured value): 268.0522.
Embodiment 6
To in the reaction tubes of 25mL, add 175mg (0.9mmol) 4-ethoxycarbonyl phenylo boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 4-ethoxycarbonyl phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 4-ethoxycarbonyl phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
34mL1,4-dioxane, inject 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, stir after 24 hours at 60 DEG C, isolated yield is 96% (during with 0.6mmol chlorine ethyl difluoro, to stir after 24 hours at 80 DEG C, isolated yield is 40%), purity is greater than 95% through the qualification of hydrogen spectrum.
1HNMR(400MHz,CDCl
3)δ8.12(d,J＝8.7Hz,2H),7.68(d,J＝8.6Hz,2H),4.40(q,J＝7.1Hz,2H),4.30(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H),1.29(t,J＝7.1Hz,3H).
13CNMR(125.7MHz,CDCl
3)δ165.5,163.5(t,J＝34.8Hz),136.8(t,J＝25.5Hz),132.9,129.7,125.5(t,J＝6.1Hz),112.9(t,J＝252.7Hz),63.3,61.3,14.1,13.7.
19FNMR(376MHz,CDCl
3)δ-104.5(s,2F).
Embodiment 7
To in the reaction tubes of 25mL; add 148mg (0.9mmol) 3-acetylbenzene boric acid; 4.4mg (2.5mol%; refer to the per-cent accounting for 3-acetylbenzene boric acid molar weight) Nickelous nitrate hexahydrate; 2.4mg (2.5mol%; refer to the per-cent accounting for 3-acetylbenzene boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injects 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, and stir after 24 hours at 80 DEG C, isolated yield is 74%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 8.19 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.81 (d, J=7.8Hz, 1H), 7.58 (t, J=7.8Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 2.64 (s, 3H), 1.31 (t, J=7.1Hz, 3H).
13cNMR (101MHz, CDCl
3) δ 196.9,163.8 (t, J=35.0Hz), 137.5,133.5 (t, J=26.0Hz), 130.7 (t, J=1.5Hz), 129.9 (t, J=5.9Hz), 129.1,125.4 (t, J=6.2Hz), 112.9 (t, J=252.9Hz), 63.4,26.6,13.9.
19fNMR (376MHz, CDCl
3) δ-103.9 (s, 2F) .IR (membrane process) ν
max1767,1693,1607cm
-1.MS (EI): m/z (%) 242 (M
+), 169 (100) .HRMS:Calculatedfor (theoretical value) C
12h
12f
2o
3: 242.0755; Found (measured value): 242.0758.
Embodiment 8
To in the reaction tubes of 25mL, add 132mg (0.9mmol) 4-cyanophenylboronic acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 4-cyanophenylboronic acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 4-cyanophenylboronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, inject 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, stir after 24 hours at 80 DEG C, isolated yield is 56% (during with 0.6mmol chlorine ethyl difluoro, isolated yield is 31%), purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.77 (d, J=8.4Hz, 2H), 7.74 (d, J=8.4Hz, 2H), 4.31 (q, J=7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H).
13cNMR (101MHz, CDCl
3) δ 163.2 (t, J=34.5Hz), 137.1 (t, J=26.0Hz), 132.5,126.4 (t, J=6.2Hz), 117.7,115.1 (t, J=1.9Hz), 112.4 (t, J=253.6Hz), 63.6,13.8.
19fNMR (376MHz, CDCl
3) δ-104.9 (s, 2F) .IR (membrane process) ν
max2235,1768cm
-1.MS (EI): m/z (%) 225 (M
+), 152 (100) .HRMS:Calculatedfor (theoretical value) C
11h
9f
2nO
2: 225.0601; Found (measured value): 225.0602.
Embodiment 9
To in the reaction tubes of 25mL; add 180mg (0.9mmol) 3-methylsulfonyl phenylo boric acid; 4.4mg (2.5mol%; refer to the per-cent accounting for 3-methylsulfonyl phenylo boric acid molar weight) Nickelous nitrate hexahydrate; 2.4mg (2.5mol%; refer to the per-cent accounting for 3-methylsulfonyl phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injects 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, and stir after 24 hours at 80 DEG C, isolated yield is 63%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 8.21 (s, 1H), 8.09 (d, J=7.9Hz, 1H), 7.91 (d, J=7.8Hz, 1H), 7.70 (t, J=7.8Hz, 1H), 4.32 (q, J=7.1Hz, 2H), 3.09 (s, 3H), 1.32 (t, J=7.1Hz, 3H).
13cNMR (125.7MHz, CDCl
3) δ 163.2 (t, J=34.5Hz), 141.4,134.5 (t, J=26.3Hz), 130.8 (t, J=5.8Hz), 130.0,129.9 (t, J=1.2Hz), 124.7 (t, J=6.3Hz), 112.3 (t, J=253.6Hz), 63.6,44.3,13.8.
19fNMR (376MHz, CDCl
3) δ-103.7 (s, 2F) .IR (membrane process) ν
max1767,1322,1306,1262,1151,1090,1024cm
-1.MS (EI): m/z (%) 278 (M
+), 126 (100), 205,206.HRMS:Calculatedfor (theoretical value) C
11h
12f
2o
4s:278.0424; Found (measured value): 278.0423.
Embodiment 10
To in the reaction tubes of 25mL, add 126mg (0.9mmol) 4-fluorobenzoic boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 4-fluorobenzoic boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 4-fluorobenzoic boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injects 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, and stir after 24 hours at 80 DEG C, isolated yield is 60%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.61 (dd, J=8.8Hz, 5.2Hz, 2H), 7.14 (t, J=8.8Hz, 2H), 4.30 (q, J=7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H).
13cNMR (125.7MHz, CDCl
3) δ 164.3 (dt, J=251.1Hz, 1.9Hz), 164.0 (t, J=35.4Hz), 128.9 (td, J=26.2Hz, 3.2Hz), 127.8 (dt, J=9.0Hz, 6.2Hz), 115.8 (d, J=22.2Hz), 113.0 (t, J=252.3Hz), 63.2,13.8.
19fNMR (376MHz, CDCl
3) δ-103.1 (d, J=2.5Hz, 2F) ,-109.1 (m, 1F) .IR (membrane process) ν
max1767,1609cm
-1.MS (EI): m/z (%) 218 (M
+), 145 (100) .HRMS:Calculatedfor (theoretical value) C
10h
9f
3o
2: 218.0555; Found (measured value): 218.0554.
Embodiment 11
To in the reaction tubes of 25mL, add 180mg (0.9mmol) 4-bromobenzeneboronic acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 4-bromobenzeneboronic acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 4-bromobenzeneboronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injects 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, and stir after 24 hours at 60 DEG C, isolated yield is 95%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.60 (d, J=8.8Hz, 2H), 7.48 (d, J=8.7Hz, 2H), 4.30 (q, J=7.1Hz, 2H), 1.30 (t, J=7.1Hz, 3H).
13cNMR (125.7MHz, CDCl
3) δ 163.7 (t, J=35.2Hz), 131.9,131.8 (t, J=26.0Hz), 127.1 (t, J=6.1Hz), 125.6 (t, J=2.2Hz), 113.0 (t, J=252.6Hz), 63.3,13.8.
19fNMR (376MHz, CDCl
3) δ-104.1 (s, 2F) .IR (membrane process) ν
max1767,1597,1489cm
-1.MS (EI): m/z (%) 278 (M
+), 207,205 (100) .HRMS:Calculatedfor (theoretical value) C
10h
9brF
2o
2: 277.9754; Found (measured value): 277.9750.
Embodiment 12
To in the reaction tubes of 25mL, add 189mg (0.9mmol) 4-bromomethyl benzene boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 4-bromomethyl benzene boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 4-bromomethyl benzene boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injects 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters, and stir after 24 hours at 80 DEG C, isolated yield is 58%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.59 (d, J=8.3Hz, 2H), 7.48 (d, J=8.2Hz, 2H), 4.49 (s, 2H), 4.30 (q, J=7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H).
13cNMR (125.7MHz, CDCl
3) δ 163.9 (t, J=35.1Hz), 140.7,132.8 (t, J=25.7Hz), 129.3,126.0 (t, J=6.1Hz), 113.1 (t, J=252.3Hz), 63.2,32.1,13.8.
19fNMR (376MHz, CDCl
3) δ-103.9 (s, 2F) .IR (membrane process) ν
max2985,1766,1268,1104cm
-1.MS (EI): m/z (%) 292 (M
+), 294 (M
+), 140 (100), 213.HRMS:Calculatedfor (theoretical value) C
11h
11brF
2o
2: 291.9910; Found (measured value): 291.9914.
Embodiment 13
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 146mg (0.6mmol) 2,2-bis-fluoro-2-bromo-1-morpholinyl ethyl ketone, stirred at 80 DEG C after 24 hours, isolated yield is 73% (during with 0.6mmol chloro thing, productive rate is 85%), and purity is greater than 95% through the qualification of hydrogen spectrum.Fusing point: 105 DEG C.
1hNMR (400MHz, CDCl
3) δ 7.56-7.53 (m, 2H), 7.50-7.46 (m, 3H), 3.70 (s, 4H), 3.47 (s, 4H).
13cNMR (125.7MHz, CDCl
3) δ 162.0 (t, J=30.3Hz), 133.4 (t, J=24.9Hz), 130.9 (t, J=1.8Hz), 128.8,125.1 (t, J=5.7Hz), 115.5 (t, J=250.7Hz), 66.6,66.3,46.6,43.4.
19fNMR (376MHz, CDCl
3) δ-94.8 (s, 2F) .IR (KBr compressing tablet) ν
max2933,2870,1656,1449,1251,1111,1045,987cm
-1.MS (EI): m/z (%) 241 (M
+), 114 (100), 127.HRMS:Calculatedfor (theoretical value) C
12h
13f
2nO
2: 241.0914; Found (measured value): 241.0917.
Embodiment 14
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, the bromo-phenyl acetanilide,Phenacetylaniline of injection 149mg (0.6mmol) 2,2-bis-fluoro-2-, stir after 24 hours at 80 DEG C, isolated yield is 88%, and purity is greater than 95% through the qualification of hydrogen spectrum.Fusing point: 98 DEG C.
1hNMR (400MHz, CDCl
3) δ 8.14 (s, 1H), 7.69 (d, J=6.9Hz, 2H), 7.58 (d, J=7.7Hz, 2H), 7.54 – 7.43 (m, 3H), 7.36 (t, J=7.9Hz, 2H), 7.19 (t, J=7.4Hz, 1H).
13cNMR (101MHz, CDCl
3) δ 161.8 (t, J=31.3Hz), 136.0 (s), 132.6 (t, J=25.5Hz), 131.1 (t, J=1.8Hz), 129.2 (s), 128.6 (s), 125.6 (s), 125.5 (t, J=6.1Hz), 120.17-120.14 (m), 114.7 (t, J=254.3Hz).
19fNMR (376MHz, CDCl
3) δ-102.3 (s, 2F) .IR (KBr compressing tablet) max3336,1694,1600,1533,1445cm
-1.MS (EI): m/z (%) 247 (M
+), 127,120 (100) .HRMS:Calculatedfor (theoretical value) C
14h
11f
2nO:247.0809; Found (measured value): 247.0811.
Embodiment 15
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, the fluoro-2-bromoacetophenone of injection 140mg (0.6mmol) 2,2-bis-, stirred at 80 DEG C after 24 hours, isolated yield is 93% (during with 0.6mmol chloro thing, productive rate is 65%), and purity is greater than 95% through the qualification of hydrogen spectrum.
1HNMR(400MHz,CDCl
3)δ8.03(d,J＝7.5Hz,2H),7.65–7.56(m,3H),7.51–7.40(m,5H).
13CNMR(125.7MHz,CDCl
3)δ189.0(t,J＝31.0Hz),134.2,133.1(t,J＝25.0Hz),132.2(t,J＝1.3Hz),130.9(t,J＝1.8Hz),130.3(t,J＝3.0Hz),128.8,128.6,125.6(t,J＝6.0Hz),116.9(t,J＝253.2Hz).
19FNMR(376MHz,CDCl
3)δ-97.6(s,2F).
Embodiment 16
To in the reaction tubes of 25mL, add 137mg (0.9mmol) 4-methoxyphenylboronic acid, (2.5mol% refers to the per-cent accounting for 4-methoxyphenylboronic acid molar weight) NiCl
2(dppe), 2.4mg (2.5mol% refers to the per-cent accounting for 4-methoxyphenylboronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, the bromo-1-Phenyl ethyl ketone of injection 140mg (0.6mmol) 2,2-bis-fluoro-2-, stir after 24 hours at 80 DEG C, isolated yield is 52%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1HNMR(400MHz,CDCl
3)δ8.02(d,J＝7.6Hz,2H),7.58(tt,J＝7.4Hz,1.5Hz,1H),7.54(d,J＝8.9Hz,2H),7.44(t,J＝7.8Hz,2H),6.96(d,J＝8.9Hz,2H),3.83(s,3H).
13CNMR(101MHz,CDCl
3)δ189.1(t,J＝31.4Hz),161.4(t,J＝1.7Hz),134.1,132.1(t,J＝1.2Hz),130.2(t,J＝2.9Hz),128.6,127.2(t,J＝5.9Hz),125.1(t,J＝25.7Hz),117.0(t,J＝252.4Hz),114.2,55.3.
19FNMR(376MHz,CDCl
3)δ-96.2(s,2F).
Embodiment 17
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 181mg (0.6mmol) 2,2-bis-fluoro-2-bromo-1-(4-trifluoromethyl) ethyl ketone, stir after 24 hours at 80 DEG C, isolated yield is 73%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 8.14 (d, J=8.2Hz, 2H), 7.72 (d, J=8.4Hz, 2H), 7.61 (d, J=6.6Hz, 2H), 7.54 – 7.44 (m, 3H).
13cNMR (125.7MHz, CDCl
3) δ 188.2 (t, J=32.1Hz), 135.3 (q, J=32.9Hz), 134.9,132.4 (t, J=24.9Hz), 131.2 (t, J=1.8Hz), 130.5 (t, J=3.0Hz), 129.0,125.7 (q, J=3.5Hz), (125.6 t, J=6.0Hz), 123.3 (q, J=272.9Hz), 116.8 (t, J=253.4Hz).
19fNMR (376MHz, CDCl
3) δ-63.5 (s, 3F) ,-98.1 (s, 2F) .IR (membrane process) ν
max1716,1454,1412,1328,1257,1174,1135,1069,901cm
-1.MS (EI): m/z (%) 300 (M
+), 173 (100) .HRMS:Calculatedfor (theoretical value) C
15h
9f
5o:300.0574; Found (measured value): 300.0576.
Embodiment 18
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 157mg (0.6mmol) 1,1-bis-fluoro-1-bromo-4-phenyl fourth-2-ketone, stir after 24 hours at 80 DEG C, isolated yield is 93%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.53 – 7.46 (m, 3H), 7.43 (m, 2H), 7.25 (m, 2H), 7.19 (m, 1H), 7.12 (m, 2H), 3.00 (t, J=6.9Hz, 2H), 2.90 (t, J=7.1Hz, 2H).
13cNMR (125.7MHz, CDCl
3) δ 199.0 (t, J=31.9Hz), 139.9,131.8 (t, J=25.4Hz), 130.9 (t, J=1.6Hz), 128.7,128.5,128.2,126.3,125.4 (t, J=6.3Hz), 115.9 (t, J=254.2Hz), 38.0,28.7.
19fNMR (376MHz, CDCl
3) δ-106.7 (s, 2F) .IR (membrane process) ν
max3065,3030,2931,1746,1497,1453,1262,1126,1057,745,698cm
-1.MS (EI): m/z (%) 260 (M
+), 133,127,105 (100), 91.HRMS:Calculatedfor (theoretical value) C
16h
14f
2o:260.1013; Found (measured value): 260.1008.
Embodiment 19
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 8.8mg (5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 4.8mg (5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 148mg (0.6mmol) 2-bromine difluoro methyl benzoxazoles, stirred at 80 DEG C after 24 hours, and isolated yield is 87% (during with 0.6mmol chloro thing, isolated yield is 88%), purity is greater than 95% through the qualification of hydrogen spectrum.
1HNMR(400MHz,CDCl
3)δ7.84–7.80(m,1H),7.73(dd,J＝5.9Hz,2Hz,2H),7.62–7.58(m,1H),7.56–7.47(m,3H),7.47–7.36(m,2H).
13CNMR(125.7MHz,CDCl
3)δ158.4(t,J＝36.8Hz),150.7,140.0,133.5(t,J＝26.0Hz),131.1(t,J＝1.7Hz),128.7,126.7,125.6(t,J＝5.9Hz),125.2,121.3,114.4(t,J＝243.8Hz),111.3.
19FNMR(376MHz,CDCl
3)δ-95.4(s,2F).
Embodiment 20
To in the reaction tubes of 25mL, add 164mg (0.9mmol) 3,5-dimethoxyphenylboronic, (5mol%, refers to and accounts for 3 8.8mg, the per-cent of 5-dimethoxyphenylboronic molar weight) Nickelous nitrate hexahydrate, 4.8mg (5mol% refers to the per-cent accounting for 3,5-dimethoxyphenylboronic molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 148mg (0.6mmol) 2-bromine difluoro methyl benzoxazoles, stirred at 80 DEG C after 24 hours, and isolated yield is 73% (during with 0.6mmol chloro thing, isolated yield is 84%), purity is greater than 95% through the qualification of hydrogen spectrum.Fusing point: 66 DEG C.
1hNMR (400MHz, CDCl
3) δ 7.81 (m, 1H), 7.57 (m, 1H), 7.40 (m, 1H), 6.85 (d, J=2.2Hz, 2H), 6.57 (t, J=2.1Hz, 1H), 3.80 (s, 6H).
13cNMR (125.7MHz, CDCl
3) δ 160.9,158.3 (t, J=36.8Hz), 150.7,140.0,135.4 (t, J=26.2Hz), 126.7,125.2,121.3,114.1 (t, J=244.6Hz), 111.3,103.7 (t, J=6.1Hz), 103.0,55.4.
19fNMR (376MHz, CDCl
3) δ-95.7 (s, 2F) .IR (KBr compressing tablet) ν
max3006,2941,2842,1601,1453,1430,1353,1335,1310,1291,1238,1207,1159,1092,1055,1014,932,889,846cm
-1.MS (EI): m/z (%) 305 (M
+), 187 (100) .HRMS:Calculatedfor (theoretical value) C
16h
13f
2nO
3: 305.0863; Found (measured value): 305.0862.
Embodiment 21
To in the reaction tubes of 25mL, add 160mg (0.9mmol) 4-tert-butylbenzeneboronic acid, 8.8mg (5mol%, refer to the per-cent accounting for 4-tert-butylbenzeneboronic acid molar weight) Nickelous nitrate hexahydrate, 4.8mg (5mol%, refer to the per-cent accounting for 4-tert-butylbenzeneboronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 148mg (0.6mmol) 2-bromine difluoro methyl benzoxazole, stirred at 80 DEG C after 24 hours, and isolated yield is 83% (during with 0.6mmol chloro thing, isolated yield is 94%), purity is greater than 95% through the qualification of hydrogen spectrum.Fusing point: 58 DEG C.
1hNMR (400MHz, CDCl
3) δ 7.82 (dd, J=6.9Hz, 1.2Hz, 1H), 7.66 (d, J=7.6Hz, 2H), 7.59 (d, J=7.5Hz, 1H), 7.52 (d, J=8.3Hz, 2H), 7.46 – 7.36 (m, 2H), 1.34 (s, 9H).
13cNMR (101MHz, CDCl
3) δ 158.7 (t, J=37.1Hz), 154.4,150.7,140.1,130.6 (t, J=26.2Hz), 126.7,125.7,125.4 (t, J=5.8Hz), 125.2,121.3,114.6 (t, J=243.4Hz), 111.3,34.9,31.1.
19fNMR (376MHz, CDCl
3) δ-94.8 (d, J=5.1Hz, 2F) .IR (KBr compressing tablet) ν
max2966,1614,1454,1293,1266,1238,1112,1080,984cm
-1.MS (EI): m/z (%) 301 (M
+), 286 (100) .HRMS:Calculatedfor (theoretical value) C
18h
17f
2nO
2: 301.1278; Found (measured value): 301.1277.
Embodiment 22
To in the reaction tubes of 25mL, add 175mg (0.9mmol) 4-ethoxycarbonyl phenylo boric acid, 8.8mg (5mol%, refer to the per-cent accounting for 4-ethoxycarbonyl phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 4.8mg (5mol%, refer to the per-cent accounting for 4-ethoxycarbonyl phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 148mg (0.6mmol) 2-bromine difluoro methyl benzoxazoles, stirred at 80 DEG C after 24 hours, and isolated yield is 62% (during with 0.6mmol chloro thing, isolated yield is 95%), purity is greater than 95% through the qualification of hydrogen spectrum.Fusing point 55 DEG C.
1hNMR (400MHz, CDCl
3) δ 8.17 (d, J=8.2Hz, 2H), 7.80 (d, J=8.3Hz, 3H), 7.59 (d, J=7.8Hz, 1H), 7.46 – 7.33 (m, 2H), 4.40 (q, J=7.1Hz, 2H), 1.40 (t, J=7.1Hz, 3H).
13cNMR (101MHz, CDCl
3) δ 165.5,157.8 (t, J=36.3Hz), 150.7,139.9,137.5 (t, J=26.0Hz), 133.0 (t, J=1.6Hz), 129.9,126.9,125.8 (t, J=5.8Hz), 125.3,121.4,114.0 (t, J=244.4Hz), 111.3,61.4,14.2.
19fNMR (376MHz, CDCl
3) δ-96.0 (s, 2F) .IR (KBr compressing tablet) max1715,1453,1276,1101,1077,1003cm
-1.MS (EI): m/z (%) 317 (M
+), 199 (100) .HRMS:Calculatedfor (theoretical value) C
17h
13f
2nO
3: 317.0863; Found (measured value): 317.0862.
Embodiment 23
To in the reaction tubes of 25mL; add 148mg (0.9mmol) 4-acetylbenzene boric acid; 8.8mg (5mol%; refer to the per-cent accounting for 4-acetylbenzene boric acid molar weight) Nickelous nitrate hexahydrate; 4.8mg (5mol%; refer to the per-cent accounting for 4-acetylbenzene boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 148mg (0.6mmol) 2-bromine difluoro methyl benzoxazoles, stirred at 80 DEG C after 24 hours, and isolated yield is 87% (during with 0.6mmol chloro thing, isolated yield is 86%), purity is greater than 95% through the qualification of hydrogen spectrum.Fusing point: 78 DEG C.
1hNMR (400MHz, CDCl
3) δ 8.07 (d, J=7.4Hz, 2H), 7.83 (d, J=7.0Hz, 2H), 7.79 (dd, J=8.8Hz, 1.2Hz, 1H), 7.59 (dd, J=7.8Hz, 1.7Hz, 1H), 7.48 – 7.36 (m, 2H), 2.63 (m, 3H).
13cNMR (125.7MHz, CDCl
3) δ 197.0,157.7 (t, J=36.2Hz), 150.7,139.9,139.1,137.6 (t, J=26.0Hz), 128.6,127.0,126.1 (t, J=5.7Hz), 125.4,121.4,113.9 (t, J=244.3Hz), 111.3,26.7.
19fNMR (376MHz, CDCl
3) δ-96.0 (d, J=10.9Hz, 2F) .IR (KBr compressing tablet) max3071,1670,1610,1452,1265,1078cm
-1.MS (EI): m/z (%) 287 (M
+), 272 (100) .HRMS:Calculatedfor (theoretical value) C
16h
11f
2nO
2: 287.0758; Found (measured value): 287.0754.
Embodiment 24
To in the reaction tubes of 25mL, add 171mg (0.9mmol) 4-trifluoromethylbenzene boronic acid, 8.8mg (5mol%, refer to the per-cent accounting for 4-trifluoromethylbenzene boronic acid molar weight) Nickelous nitrate hexahydrate, 4.8mg (5mol%, refer to the per-cent accounting for 4-trifluoromethylbenzene boronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 148mg (0.6mmol) 2-bromine difluoro methyl benzoxazoles, stirred at 80 DEG C after 24 hours, and isolated yield is 93% (during with 0.6mmol chloro thing, isolated yield is 87%), purity is greater than 95% through the qualification of hydrogen spectrum.Fusing point: 66 DEG C.
1hNMR (400MHz, CDCl
3) δ 7.88 (d, J=8.2Hz, 2H), 7.82 (d, J=7.7Hz, 1H), 7.78 (d, J=8.0Hz, 2H), 7.61 (d, J=8.0Hz, 1H), 7.49 – 7.37 (m, 2H).
13cNMR (125.7MHz, CDCl
3) δ 157.7 (t, J=36.1Hz), 150.8,139.9,137.1 (t, J=26.3Hz), 133.2 (q, J=32.9Hz), 127.1,126.4 (t, J=5.8Hz), 125.8 (q, J=3.7Hz), 125.4,123.5 (q, J=272.5Hz), 121.5,113.8 (t, J=244.4Hz), 111.4.
19fNMR (376MHz, CDCl
3) δ-63.1 (s, 3F) ,-95.9 (s, 2F) .IR (KBr compressing tablet) max1616,1452,1412,1324,1254,1180,1085cm
-1.MS (EI): m/z (%) 313 (M
+), 195 (100), 145.HRMS:Calculatedfor (theoretical value) C
15h
8f
5nO:313.0526; Found (measured value): 313.0529.
Embodiment 25
To in the reaction tubes of 25mL, add 180mg (0.9mmol) 3-bromobenzeneboronic acid phenylo boric acid, 8.8mg (5mol%, refer to the per-cent accounting for 3-bromobenzeneboronic acid molar weight) Nickelous nitrate hexahydrate, 4.8mg (5mol%, refer to the per-cent accounting for 3-bromobenzeneboronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 148mg (0.6mmol) 2-bromine difluoro methyl benzoxazoles, stir after 24 hours at 80 DEG C, isolated yield is 68%, and purity is greater than 95% through the qualification of hydrogen spectrum.Fusing point: 62 DEG C.
1hNMR (400MHz, CDCl
3) δ 7.88 (s, 1H), 7.82 (dd, J=7.0Hz, 1.0Hz, 1H), 7.66 (d, J=7.9Hz, 2H), 7.61 (d, J=7.7Hz, 1H), (7.46 td, J=7.8Hz, 1.4Hz, 1H), (7.42 dd, J=7.7Hz, 1.3Hz, 1H), (7.38 t, J=7.6Hz, 1H).
13cNMR (125.7MHz, CDCl
3) δ 157.8 (t, J=36.5Hz), 150.7,140.0, (135.5 t, J=26.4Hz), 134.3,130.3,128.9 (t, J=6.0Hz), 126.9,125.4,124.4 (t, J=5.8Hz), 122.8,121.4, (113.5 t, J=244.8Hz), 111.4.
19fNMR (376MHz, CDCl
3) δ-95.6 (s, 2F) .IR (KBr compressing tablet) ν
max3072,1617,1573,1476,1449,1424,1348,1252,1130,1108,1070,1004cm
-1.MS (EI): m/z (%) 323 (M
+), 325 (M
+), 205,207 (100) .HRMS:Calculatedfor (theoretical value) C
14h
8brF
2nO:322.9757; Found (measured value): 322.9760.
Embodiment 26
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 8.8mg (5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 4.8mg (5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 145mg (0.6mmol) 2-bromine difluoro methyl-4,5-dimethyl-benzothiazole, stir after 24 hours at 80 DEG C, isolated yield is 85%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.64 (m, 2H), 7.52 – 7.34 (m, 3H), 2.37 (s, 3H), 2.33 (s, 3H).
13cNMR (101MHz, CDCl
3) δ 159.3 (t, J=36.1Hz), 149.7, (135.5 t, J=27.2Hz), 130.3 (t, J=1.7Hz), 129.2 (t, J=1.2Hz), 128.3,125.7 (t, J=5.7Hz), 117.1 (t, J=241.9Hz), 14.6,11.1.
19fNMR (376MHz, CDCl
3) δ-85.5 (s, 2F) .IR (membrane process) max3419,1548,1452,1273,1215,1047,903cm
-1.MS (EI): m/z (%) 239 (M
+, 100), 127.HRMS:Calculatedfor (theoretical value) C
12h
11f
2nS:239.0580; Found (measured value): 239.0582.
Embodiment 27
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 8.8mg (5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 4.8mg (5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, injection 156mg (0.6mmol) 2-bromine difluoro methyl-1-methyl isophthalic acid H-benzoglyoxaline, stir after 24 hours at 80 DEG C, isolated yield is 69%, and purity is greater than 95% through the qualification of hydrogen spectrum.(during with 0.6mmol chloro thing, isolated yield is 77%).
1hNMR (400MHz, CDCl
3) δ 7.86 (d, J=8.0Hz, 1H), 7.65 (d, J=6.5Hz, 2H), 7.55 – 7.45 (m, 3H), 7.38 (m, 2H), 7.34-7.30 (m, 1H), 3.86 (s, 3H).
13cNMR (101MHz, CDCl
3) δ 147.2 (t, J=33.0Hz), 141.2,136.3,134.4 (t, J=25.7Hz), (130.7 t, J=1.9Hz), 128.5, (125.9 t, J=5.6Hz), 124.2,122.7,121.1,117.1 (t, J=240.0Hz), 109.7,30.9.
19fNMR (376MHz, CDCl
3) δ-89.0 (s, 2F) .IR (membrane process) max3055,1474,1395,1274,1249,1073,1016,967,761,745cm
-1.MS (EI): m/z (%) 258 (M
+), 257 (M
+-1,100), 127.HRMS:Calculatedfor (theoretical value) C
15h
12f
2n
2: 258.0969; Found (measured value): 258.0968.
Embodiment 28
To in the reaction tubes of 25mL, add 107mg (0.4mmol) flavones phenylo boric acid, (5mol%, refer to the per-cent accounting for brass boric acid molar weight) Nickelous nitrate hexahydrate, (5mol%, refer to the per-cent accounting for brass boric acid molar weight) bpy (2,2 '-dipyridyl), 48mg (0.4mmol) K
2cO
3, 2mL1,4-dioxane, injects 26 μ L (0.2mmol) Bromodifluoroacetic acid ethyl esters, and stir after 24 hours at 80 DEG C, isolated yield is 53%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.93 (dd, J=7.8Hz, 1.7Hz, 1H), 7.69 (d, J=8.3Hz, 2H), 7.59 (d, J=8.3Hz, 2H), 7.56 – 7.49 (m, 1H), 7.10-7.05 (m, 2H), 5.54 (dd, J=13.1Hz, 3.0Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 3.05 (dd, J=16.9Hz, 13.1Hz, 1H), 2.91 (dd, J=16.9Hz, 3.1Hz, 1H), 1.32 (t, J=7.1Hz, 3H).
13cNMR (101MHz, CDCl
3) δ 191.3,164.0 (t, J=35.1Hz), 161.2,141.8 (t, J=1.7Hz), 136.3,133.1 (t, J=25.8Hz), 127.1,126.3,126.1 (t, J=6.1Hz), 121.9,120.8,118.0,113.1 (t, J=252.3Hz), 78.6,63.3,44.6,13.9.
19fNMR (376MHz, CDCl
3) δ-103.9 (d, J=3.0Hz) .IR (membrane process) max2985,1765,1694,1607,1465,1305cm
-1.MS (EI): m/z (%) 346 (M
+), 120 (100) .HRMS:Calculatedfor (theoretical value) C
19h
16f
2o
4: 346.1017; Found (measured value): 346.1020.
Embodiment 29
To in the reaction tubes of 25mL, add 107mg (0.4mmol) flavones phenylo boric acid, (5mol%, refer to the per-cent accounting for brass boric acid molar weight) Nickelous nitrate hexahydrate, (5mol%, refer to the per-cent accounting for brass boric acid molar weight) bpy (2,2 '-dipyridyl), 48mg (0.4mmol) K
2cO
3, 2mL1,4-dioxane, injection 49mg (0.2mmol) 2-bromine difluoro methyl benzoxazoles, stir after 24 hours at 80 DEG C, isolated yield is 65%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.94 (dd, J=8.1Hz, 1.4Hz, 1H), 7.86 – 7.77 (m, 3H), 7.63 (d, J=8.2Hz, 2H), 7.61 – 7.57 (m, 1H), 7.54 – 7.50 (m, 1H), 7.45 (td, J=7.6Hz, 1.2Hz, 1H), 7.40 (td, J=7.6Hz, 1.2Hz, 1H), 7.09 – 7.05 (m, 2H), 5.55 (dd, J=13.1Hz, 2.9Hz, 1H), 3.06 (dd, J=16.8Hz, 13.1Hz, 1H), 2.92 (dd, J=16.9Hz, 3.1Hz, 1H).
13cNMR (125.7MHz, CDCl
3) δ 191.2,161.2,158.2 (t, J=36.7Hz), 150.7,141.9 (t, J=1.7Hz), 140.0,136.3,133.9 (t, J=26.2Hz), 127.1,126.9,126.4, (126.3 t, J=5.8Hz), 125.3,121.9,121.4,120.9,118.0,114.2 (t, J=244.0Hz), 111.3,78.8,44.6.
19fNMR (376MHz, CDCl
3) δ-95.3 (s, 2F) .IR (membrane process) max2926,1694,1607,1464,1306cm
-1.MS (EI): m/z (%) 391 (M
+), 153,120 (100) .HRMS:Calculatedfor (theoretical value) C
23h
15f
2nO
3: 391.1020; Found (measured value): 391.1022.
Embodiment 30
To in the reaction tubes of 25mL, add 134mg (0.45mmol) oestrone boric acid, (5mol%, refer to the per-cent accounting for oestrone phenylo boric acid molar weight) Nickelous nitrate hexahydrate, (5mol%, refer to the per-cent accounting for oestrone phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 83mg (0.6mmol) K
2cO
3, 2mL1,4-dioxane, injection 74mg (0.3mmol) 2-bromine difluoro methyl benzoxazoles, stir after 24 hours at 80 DEG C, isolated yield is 56%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.81 (d, J=7.5Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 7.52 – 7.35 (m, 5H), 2.97 (m, 2H), 2.62 – 2.39 (m, 2H), 2.33 (s, 1H), 2.24 – 1.92 (m, 4H), 1.73 – 1.36 (m, 6H), 0.90 (s, 3H).
13cNMR (101MHz, CDCl
3) δ 220.6,158.6 (t, J=37.1Hz), 150.6,143.0,139.9,137.2,130.8 (t, J=26.0Hz), 126.7,126.0 (t, J=5.6Hz), 125.8,125.2,122.9 (t, J=5.7Hz), 121.3,114.4 (t, J=243.4Hz), 111.3,50.3,47.8,44.3,37.7,35.7,31.4,29.3,26.1,25.5,21.5,13.7.
19fNMR (376MHz, CDCl
3) δ-94.9 (s, 2F) .IR (membrane process) max2933,2249,1736,1453,1259cm
-1.MS (EI): m/z (%) 421 (M
+, 100) and .HRMS:Calculatedfor (theoretical value) C
26h
25f
2nO
2: 421.1853; Found (measured value): 421.1857.
Embodiment 31
To in the reaction tubes of 25mL, add 110mg (0.9mmol) phenylo boric acid, 4.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, the fluoro-3-propargyl bromide of injection 186mg (0.6mmol) 1-triisopropylsilyl-3,3-bis-, stir after 24 hours at 80 DEG C, isolated yield is 77%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.71 (d, J=7.8Hz, 2H), 7.54 – 7.34 (m, 3H), 1.26 – 0.95 (m, 21H).
13cNMR (125.7MHz, CDCl
3) δ 136.2 (t, J=27.9Hz), 130.6 (t, J=1.8Hz), 128.4,125.4 (t, J=4.5Hz), 111.6 (t, J=231.0Hz), 98.9 (t, J=40.0Hz), 92.5 (t, J=5.0Hz), 18.5,11.0.
19fNMR (376MHz, CDCl
3) δ-74.5 (s, 2F) .IR (membrane process) max2946,2868,2186,1455,1263cm
-1.MS (EI): m/z (%) 308 (M
+), 265,115 (100) .HRMS:Calculatedfor (theoretical value) C
18h
26f
2si:308.1772; Found (measured value): 308.1777.
Embodiment 32
To in the reaction tubes of 25mL, add 122mg (0.9mmol) 4-methylphenylboronic acid, 4.4mg (2.5mol%, refer to the per-cent accounting for 4-methylphenylboronic acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (2.5mol%, refer to the per-cent accounting for 4-methylphenylboronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, the fluoro-3-propargyl bromide of injection 186mg (0.6mmol) 1-triisopropylsilyl-3,3-bis-, stir after 24 hours at 80 DEG C, isolated yield is 60%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.59 (d, J=8.0Hz, 2H), 7.24 (d, J=7.9Hz, 2H), 2.40 (s, 3H), 1.19 – 1.04 (m, 21H).
13cNMR (125.7MHz, CDCl
3) δ 140.8 (t, J=1.9Hz), 133.4 (t, J=28.0Hz), 129.1 (s), 125.4 (t, J=4.5Hz), 111.7 (t, J=230.3Hz), (99.0 t, J=40.1Hz), 92.1 (t, J=4.9Hz), 21.3 (s), 18.5 (s), 11.0 (s).
19fNMR (376MHz, CDCl
3) δ-73.7 (s, 2F) .IR (membrane process) max2946,2868,2375,2292,1464,1266,1149,1003cm
-1.MS (EI): m/z (%) 322 (M
+), 279,129 (100) .HRMS:Calculatedfor (theoretical value) C
19h
28f
2si:322.1928; Found (measured value): 322.1933.
Embodiment 33
To in the reaction tubes of 25mL, add 175mg (0.9mmol) 4-ethoxycarbonyl phenylo boric acid, (2.5mol% refers to the per-cent accounting for 4-ethoxycarbonyl phenylo boric acid molar weight) NiCl
2(dppe), 2.4mg (2.5mol% refers to the per-cent accounting for 4-ethoxycarbonyl phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, the fluoro-3-propargyl bromide of injection 186mg (0.6mmol) 1-triisopropylsilyl-3,3-bis-, stir after 24 hours at 80 DEG C, isolated yield is 92%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 8.12 (d, J=8.6Hz, 2H), 7.76 (d, J=8.6Hz, 2H), 4.40 (q, J=7.1Hz, 2H), 1.41 (t, J=7.1Hz, 3H), 1.19 – 0.96 (m, 21H).
13cNMR (125.7MHz, CDCl
3) δ 165.7,140.2 (t, J=28.1Hz), 132.5,129.7,125.4 (t, J=4.4Hz), 110.9 (t, J=232.2Hz), (98.4 t, J=39.8Hz), 93.5 (t, J=4.9Hz), 61.3,18.4,14.3,10.9.
19fNMR (376MHz, CDCl
3) δ-76.1 (s, 2F) .IR (membrane process) max2946,2868,2189,1725,1277,1153cm
-1.MS (EI): m/z (%) 380 (M
+), 337 (100) .HRMS:Calculatedfor (theoretical value) C
21h
30f
2o
2si:380.1983; Found (measured value): 380.1986.
Embodiment 34
To in the reaction tubes of 25mL, add 148mg (0.9mmol) 4-acetylbenzene boric acid, (2.5mol% refers to the per-cent accounting for 4-acetylbenzene boric acid molar weight) NiCl
2(dppe), 2.4mg (2.5mol% refers to the per-cent accounting for 4-acetylbenzene boric acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, the fluoro-3-propargyl bromide of injection 186mg (0.6mmol) 1-triisopropylsilyl-3,3-bis-, stir after 24 hours at 80 DEG C, isolated yield is 82%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 8.03 (d, J=8.5Hz, 2H), 7.79 (d, J=8.5Hz, 2H), 2.64 (s, 3H), 1.24 – 0.96 (m, 21H).
13cNMR (125.7MHz, CDCl
3) δ 197.2,140.3 (t, J=28.2Hz), 138.7,128.4,125.7 (t, J=4.4Hz), 110.8 (t, J=232.2Hz), 98.3 (t, J=39.7Hz), 93.6 (t, J=4.9Hz), 26.7,18.4,10.9.
19fNMR (376MHz, CDCl
3) δ-76.1 (s, 2F) .IR (membrane process) max2946,2868,2187,1694,1464,1262,1151cm
-1.MS (EI): m/z (%) 350 (M
+), 307,43 (100) .HRMS:Calculatedfor (theoretical value) C
20h
28f
2oSi:350.1878; Found (measured value): 350.1877.
Embodiment 35
To in the reaction tubes of 25mL, add 181mg (0.9mmol) 4-bromobenzeneboronic acid, (2.5mol% refers to the per-cent accounting for 4-bromobenzeneboronic acid molar weight) NiCl
2(dppe), 2.4mg (2.5mol% refers to the per-cent accounting for 4-bromobenzeneboronic acid molar weight) bpy (2,2 '-dipyridyl), 166mg (1.2mmol) K
2cO
3, 4mL1,4-dioxane, the fluoro-3-propargyl bromide of injection 186mg (0.6mmol) 1-triisopropylsilyl-3,3-bis-, stir after 24 hours at 80 DEG C, isolated yield is 77%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.63 – 7.50 (m, 4H), 1.23 – 0.99 (m, 21H).
13cNMR (101MHz, CDCl
3) δ 135.2 (t, J=28.5Hz), 131.7, (127.1 t, J=4.4Hz), 125.2 (t, J=2.2Hz), 111.0 (t, J=231.6Hz), 98.3 (t, J=41.3Hz), 93.1 (t, J=4.9Hz), 18.4,10.9.
19fNMR (376MHz, CDCl
3) δ-75.0 (s, 2F) .IR (membrane process) max2945,2868,2187,1904,1597,1464,1263cm
-1.MS (EI): m/z (%) 386 (M
+), 345,155 (100) .HRMS:Calculatedfor (theoretical value) C
18h
25brF
2si:386.0877; Found (measured value): 386.0881.
Example 36
To in the reaction tubes of 25mL, add 80mg (0.4mmol) flavones boric acid, 3mg (5mol%, refer to the per-cent accounting for brass boric acid molar weight) Nickelous nitrate hexahydrate, 1.6mg (2.5mol%, refer to the per-cent accounting for brass boric acid molar weight) bpy (2,2 '-dipyridyl), 55mg (0.2mmol) K
2cO
3, 2mL1,4-dioxane, the fluoro-3-propargyl bromide of injection 62mg (0.2mmol) 1-triisopropylsilyl-3,3-bis-, stir after 24 hours at 80 DEG C, isolated yield is 58%, and purity is greater than 95% through the qualification of hydrogen spectrum.
1hNMR (400MHz, CDCl
3) δ 7.94 (dd, J=8.1Hz, 1.7Hz, 1H), (7.78 d, J=8.3Hz, 2H), (7.58 d, J=8.2Hz, 2H), 7.53 (ddd, J=8.9Hz, 7.3Hz, 1.7Hz, 1H), 7.10 – 7.06 (m, 2H), 5.54 (dd, J=13.1Hz, 2.8Hz, 1H), 3.07 (dd, J=16.9Hz, 13.2Hz, 1H), 2.92 (dd, J=16.9Hz, 3.1Hz, 1H), 1.24 – 0.95 (m, 21H).
13cNMR (125.7MHz, CDCl
3) δ 191.4,161.3,141.4 (t, J=1.2Hz), (136.6 t, J=28.1Hz), 136.3,127.1,126.2,126.0 (t, J=4.4Hz), 121.9,120.9,118.1,111.2 (t, J=231.2Hz), 98.6 (t, J=39.7Hz), 92.9 (t, J=5.0Hz), 79.0,44.7,18.5,11.0.
19fNMR (376MHz, CDCl
3) δ-74.4 (s, 2F) .IR (membrane process) max2945,2867,2187,1694,1607,1464,1305cm
-1.MS (EI): m/z (%) 454 (M
+), 411,224,120 (100) .HRMS:Calculatedfor (theoretical value) C
27h
32f
2o
2si:454.2140; Found (measured value): 454.2138.
Embodiment 37-50
To in the reaction tubes of 25mL, add phenylo boric acid (0.45mmol), nickel salt, part, alkali, solvent (2mL), injection 0.3mmol Bromodifluoroacetic acid ethyl ester, stirs at 80 DEG C after 8 hours and terminates reaction.
The respective reaction conditions of embodiment 37-50 and product fluorine spectrum yield as shown in table 1, obtaining target compound is colourless transparent liquid; Described fluorine spectrum yield refers to that with Trifluoromethyl phenyl ether be interior target fluorine spectrum yield.
Table 1
Embodiment 51-82
To in the reaction tubes of 25mL, add phenylo boric acid (0.45mmol), nickel salt, part, alkali, solvent (2mL), injection 0.3mmol Bromodifluoroacetic acid ethyl ester, stirs at 80 DEG C after 8 hours and terminates reaction.
The respective reaction conditions of embodiment 51-82 and product yield as shown in table 2, obtaining target compound is colourless transparent liquid.
Table 2
Embodiment 83-87
To in the reaction tubes of 25mL, add phenylo boric acid (0.45mmol), nickel salt, part, salt of wormwood (200%), 1,4-dioxane (2mL), injection 0.3mmol Bromodifluoroacetic acid ethyl ester, stirs at 40-70 DEG C after 8-24 hour and terminates reaction.
The respective reaction conditions of embodiment 83-87 and product yield as shown in table 3, obtaining target compound is colourless transparent liquid.
Table 3
Example 88-100
To in the reaction tubes of 25mL, add phenylo boric acid (0.45mmol), nickel salt, part, alkali, solvent (2mL), the fluoro-3-propargyl bromide of injection 0.3mmol1-triisopropylsilyl-3,3-bis-, stir at 80 DEG C after 16 hours and terminate reaction.
The respective reaction conditions of embodiment 88-100 and product yield as shown in table 4, obtaining target compound is colourless transparent liquid.
Table 4
Example 101-104
To in the reaction tubes of 25mL, add phenylo boric acid (0.45mmol), nickel salt, part, alkali, solvent (2mL), the fluoro-3-propargyl bromide of injection 0.3mmol1-triisopropylsilyl-3,3-bis-, stir at 80 DEG C after 24 hours and terminate reaction.
The respective reaction conditions of embodiment 101-104 and product yield as shown in table 5, obtaining target compound is colourless transparent liquid.
Table 5
Example 105-111
To in the reaction tubes of 25mL, add 4-ethoxycarbonyl phenylo boric acid (0.45mmol), nickel salt, part, alkali, solvent (2mL), the fluoro-3-propargyl bromide of injection 0.3mmol1-triisopropylsilyl-3,3-bis-, stirs at 80 DEG C after 24 hours and terminates reaction.
The respective reaction conditions of embodiment 105-111 and product yield as shown in table 6, obtaining target compound is colourless transparent liquid.
Table 6
Example 112-115
To in the reaction tubes of 25mL; add 4-acetylbenzene boric acid (0.45mmol), nickel salt, part, alkali, solvent (2mL); the fluoro-3-propargyl bromide of injection 0.3mmol1-triisopropylsilyl-3,3-bis-, stirs at 80 DEG C after 24 hours and terminates reaction.
The respective reaction conditions of embodiment 112-115 and product yield as shown in table 7, obtaining target compound is colourless transparent liquid.
Table 7
Example 116-126
To in the reaction tubes of 25mL, add phenylo boric acid (0.45mmol), nickel salt, part, alkali, solvent (2mL), injection 0.3mmol2-bromine difluoro methyl benzoxazoles, stirs at 80 DEG C after 12 hours and terminates reaction.
The respective reaction conditions of embodiment 116-126 and product yield as shown in table 8, obtaining target compound is colourless transparent liquid.
Table 8
Example 127-141
To in the reaction tubes of 25mL, add phenylo boric acid (0.45mmol), nickel salt, part, alkali, solvent (2mL), injection 0.3mmol bromine difluorophosphoric acid diisopropyl ester, stirs at 80 DEG C after 24 hours and terminates reaction.
The respective reaction conditions of embodiment 127-141 and product yield as shown in table 9, obtaining target compound is colourless transparent liquid.
Table 9
Embodiment 142-152
To in the reaction tubes of 25mL, add the phenylo boric acid of 1 to 0.9mmol phenylo boric acid or replacement, catalyzer, alkali, solvent (4mL), the humorous difluoromethyl reagent of injection 0.6mmol functionalization, stirs at 60-80 DEG C after 24 hours and terminates reaction.
In embodiment 142-152, adopt phenylo boric acid or the phenylo boric acid of replacement, humorous difluoromethyl reagent that respective product is corresponding, obtained product and yield as shown in table 10, obtaining target compound is colourless transparent liquid or solid.
Table 10
Embodiment 153
To in the reaction tubes of 25mL, add 55mg (0.45mmol) phenylo boric acid, 4.4mg (5mol%, refer to the per-cent accounting for phenylo boric acid molar weight) Nickelous nitrate hexahydrate, 2.4mg (5mol% refers to the per-cent accounting for phenylo boric acid molar weight) bpy (2,2 '-dipyridyl), 2.9mg (5mol% refers to the per-cent accounting for phenylo boric acid molar weight) cuprous iodide, 83mg (0.6mmol) K
2cO
3, 2mL1,4-dioxane, injection 38ul (0.3mmol) chlorine ethyl difluoro, stir after 24 hours at 80 DEG C, isolated yield is 52%.
Material synthesis method:
Embodiment 154
250mLschlenk bottle, add heterocycle 4,5-dimethylthiazole (2g, 17.7mmol), anhydrous THF100ml, dry ice ethanol bath is cooled to-78 degree, adds n-Butyl Lithium (2.5Minhexane, 7.8ml) lentamente,-78 degree stir 30min, add difluoro dibromo 10ml fast, solution becomes orange red, continues-78 degree and stirs 2h.But thin-layer chromatography detects raw material and disappears, and has product generate also have a large amount of by product to generate, stopped reaction.Concentrated, cross silicagel column separated product, pure sherwood oil wash-out, obtains 1.4g product 15e, productive rate: 33%.
1HNMR(400MHz,CDCl
3)δ2.41(s,3H),2.38(s,3H).
19FNMR(376MHz,CDCl
3)δ-41.21(s,2F).
Embodiment 155
20mL single port bottle adds Bromodifluoroacetic acid (75mmol, 16g), the aqueous hydrochloric acid 40mL of 4M, amine salt (37.5mmol, 7.3g), reflux 5h.Stopped reaction, is neutralized to neutrality with aqueous sodium hydroxide solution, extraction into ethyl acetate, which floor has with anhydrous sodium sulfate drying, filters, concentrated, crosses silicagel column separated product, obtains 2.5g white solid product.Productive rate 25%.Fusing point 81 DEG C.
1hNMR (500MHz, CDCl
3) δ 7.86 (d, J=8.0Hz, 1H), 7.41 (s, 2H), 7.36 (t, J=5.9Hz, 1H), 3.95 (s, 3H).
13cNMR (125.7MHz, CDCl
3) δ 144.31 (t, J=31.6Hz), 140.7,136.3,125.2,123.6,121.5,120.8 (t, J=287.5Hz), 110.0,31.1 (t, J=2.7Hz).
19fNMR (376MHz, CDCl
3) δ-50.5 (s, 2F) .IR (KBr compressing tablet) max1588,1483,1401,1213,1076,935,745cm
-1.MS (EI): m/z (%) 262 (M
+), 181 (100) .HRMS:Calculatedfor (theoretical value) C
9h
7brF
2n
2: 259.9761; Found (measured value): 259.9763.
Embodiment 156
20mL single port bottle adds chlorine difluoroacetic acid (30mmol, 3.92g), the aqueous hydrochloric acid 20mL of 4M, amine salt (15mmol, 2.96g), reflux 5h.Stopped reaction, is neutralized to neutrality with aqueous sodium hydroxide solution, extraction into ethyl acetate, which floor has with anhydrous sodium sulfate drying, filters, concentrated, crosses silicagel column separated product, obtains 2.6g white solid product.Productive rate 80%.Fusing point 81 DEG C.
1hNMR (400MHz, CDCl
3) δ 7.86 (dd, J=8.1Hz, 0.8Hz, 1H), 7.45 – 7.39 (m, 2H), 7.39 – 7.33 (m, 1H), 3.95 (s, 3H).
13cNMR (125.7MHz, CDCl
3) δ 145.1 – 144.0 (m), 140.7,136.3,125.2,123.6 – 123.5 (m), 121.6 – 121.4 (m), 120.9 (t, J=287.6Hz), 110.0 (s), 31.1 – 31.0 (m).
19fNMR (376MHz, CDCl
3) δ-50.5 (s, 2F) .IR (KBr compressing tablet) max1588,1483,1076,935,745cm
-1.MS (EI): m/z (%) 216 (M
+), 181 (100) .HRMS:Calculatedfor (theoretical value) C
9h
7clF
2n
2: 216.0266; Found (measured value): 216.0267.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (21)
1. the preparation method containing difluoro methylene compound, it is characterized in that comprising the following steps: in a solvent, under alkali, part and catalyzer existent condition, compd A and compd B are carried out suzuki linked reaction, obtain Compound C, described catalyzer is nickel salt, and described nickel salt is NiQ
2mH
2o, NiL
ncl
2, NiL
nbr
2, NiL
ni
2or NiL
n(OH)
2;
Wherein, Q is nitrate radical, acetate, trifluoracetic acid root or halogen, 0≤m≤10,0<n<3, L is triphenylphosphine, O-methoxy triphenylphosphine, adjacent methyl triphenyl phosphine, tri-butyl phosphine, tricyclohexyl phosphine, three adamantyl phosphines, 1, 2 pairs of (diphenylphosphine) ethane, 1, two (diphenylphosphine) propane of 3-, 1, two (diphenylphosphine) butane of 4-, 1, two (diphenylphosphine) ferrocene of 1'-, two diphenylphosphine methane, 1, the two two triphenylphosphine benzene of 2-, dimethyl second diether, diethylene glycol dimethyl ether, substituted or unsubstituted dipyridyl, " substituted or unsubstituted 1, 10-phenanthroline " or " substituted or unsubstituted terpyridyl ", described " substituted or unsubstituted dipyridyl ", " substituted or unsubstituted 1, 10-phenanthroline " or " replacement " described in " replace or replace terpyridyl " refer on heteroatomic non-ortho position by C
1~ C
10alkyl and C
1~ C
10alkoxyl group in one or morely to replace, when there is multiple substituting group, described substituting group can be identical or different, X is halogen,
R
1for " substituted or unsubstituted C
3~ C
15aryl ", " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl ",
described " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by cyano group, hydroxyl, nitro, halogen, C
1~ C
10alkyl, C
1~ C
10alkoxyl group, C
1~ C
10alkylthio, C
1~ C
10the alkyl silyl, " C of halogen substiuted
1~ C
10alkyl ", " hydroxyl replace C
1~ C
10alkyl ", C
2~ C
10thiazolinyl, C
2~ C
10alkynyl, C
3~ C
10the aryl, " C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
6heterocyclylalkyl ",
in one or morely to replace, when there is multiple substituting group, described substituting group is identical or different; R
3, R
4and R
5be independently hydrogen atom, amino, C separately
1~ C
6alkyl or C
3~ C
6cycloalkyl; R
6and R
7be independently C separately
1~ C
6alkyl or C
3~ C
6cycloalkyl; R
8for hydrogen atom, C
1~ C
6alkyl or C
3~ C
6cycloalkyl;
R
2for
or " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl ", described " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " refer to by cyano group, halogen, C
1~ C
10alkyl, C
1~ C
10the alkoxyl group, " C of halogen substiuted
1~ C
10alkyl ", C
2~ C
10thiazolinyl, C
2~ C
10alkynyl in one or morely to replace, when there is multiple substituting group, described substituting group can be identical or different; R
9for C
1~ C
6alkyl or C
3~ C
6cycloalkyl;
R
10for substituted or unsubstituted C
1~ C
10alkyl, " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the substituted or unsubstituted C of 1-3
2~ C
15heterocyclylalkyl ", substituted or unsubstituted C
3~ C
15aryl or C
3~ C
15virtue amino; Described R
10described in " substituted or unsubstituted C
1~ C
10alkyl " described in " replacement " refer to by C
3~ C
15aryl replaced; Described R
10described in " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the substituted or unsubstituted C of 1-3
2~ C
15heterocyclylalkyl " described in " replacement " refer to by C
1~ C
10alkyl and C
3~ C
6cycloalkyl in one or morely to replace, when there is multiple substituting group, described substituting group can be identical or different;
Described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by cyano group, halogen, C
1~ C
10alkyl, C
1~ C
10the alkoxyl group, " C of halogen substiuted
1~ C
10alkyl ", C
2~ C
10thiazolinyl, C
2~ C
10alkynyl,
in one or morely to replace, when there is multiple substituting group, described substituting group is identical or different; R
11for C
1~ C
6alkyl, C
3~ C
6cycloalkyl or " C
1~ C
6alkyl silyl "; R
12for C
1~ C
6alkyl.
2. the preparation method containing difluoro methylene compound as claimed in claim 1, it is characterized in that: when described X is halogen, described halogen is chlorine or bromine;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " for being optionally substituted by halogen time, described " halogen " is fluorine, chlorine, bromine or iodine;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by C
1~ C
10alkyl replace time, described " C
1~ C
10alkyl " be C
1~ C
6alkyl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by C
1~ C
10alkoxyl group replace time, described " C
1~ C
10alkoxyl group " be C
1~ C
6alkoxyl group;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by C
1~ C
10alkylthio when replacing, described " C
1~ C
10alkylthio " be C
1~ C
6alkylthio;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " C
1~ C
10alkyl silyl " when replacing, described " C
1~ C
10alkyl silyl " be C
1~ C
6alkyl silyl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " the C of halogen substiuted
1~ C
10alkyl " when replacing, the described " C of halogen substiuted
1~ C
10alkyl " described in " halogen " be fluorine, chlorine or bromine, the number of described halogen is 1-4, and when there is multiple halogen atom, described halogen atom can be identical or different, the described " C of halogen substiuted
1~ C
10alkyl " described in " C
1~ C
10alkyl " be C
1~ C
6alkyl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " hydroxyl replace C
1~ C
10alkyl " when replacing, the described " C that hydroxyl replaces
1~ C
10alkyl " be " and hydroxyl replace C
1~ C
6alkyl ";
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " C
2~ C
10thiazolinyl " when replacing, described " C
2~ C
10thiazolinyl " be C
2~ C
6thiazolinyl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " C
2~ C
10alkynyl " when replacing, described " C
2~ C
10alkynyl " be C
2~ C
6alkynyl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " C
3~ C
10aryl " when replacing, described " C
3~ C
10aryl " be C
3~ C
6aryl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " the C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
6heterocyclylalkyl " when replacing, the described " C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
6heterocyclylalkyl " be " C that heteroatoms is oxygen or nitrogen-atoms, heteroatoms number is 1-2
3~ C
4heterocyclylalkyl ";
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " by by " halogen " replaced time, described " halogen " is fluorine, chlorine, bromine or iodine;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " C
1~ C
10alkyl " when replacing, described " C
1~ C
10alkyl " be C
1~ C
6alkyl;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " C
1~ C
10alkoxyl group " when replacing, described " C
1~ C
10alkoxyl group " be C
1~ C
6alkoxyl group;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " the C of halogen substiuted
1~ C
10alkyl " when replacing, the described " C of halogen substiuted
1~ C
10alkyl " described in " halogen " be fluorine, chlorine or bromine, the number of described halogen is 1-4, and when there is multiple halogen atom, described halogen atom can be identical or different, the described " C of halogen substiuted
1~ C
10alkyl " described in " C
1~ C
10alkyl " be C
1~ C
6alkyl;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " C
2~ C
10thiazolinyl " when replacing, described " C
2~ C
10thiazolinyl " be C
2~ C
6thiazolinyl;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " C
2~ C
10alkynyl " when replacing, described " C
2~ C
10alkynyl " be C
2~ C
6alkynyl;
As described R
10described in " substituted or unsubstituted C
1~ C
10alkyl " described in " replacement " refer to by " C
3~ C
15aryl " when replacing, described " C
3~ C
15aryl " be C
5~ C
10aryl;
As described R
10described in " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the substituted or unsubstituted C of 1-3
2~ C
15heterocyclylalkyl " described in " replacement " refer to by " C
1~ C
10alkyl " when replacing, described " C
1~ C
10alkyl " be C
1~ C
6alkyl;
As described R
10described in " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the substituted or unsubstituted C of 1-3
2~ C
15heterocyclylalkyl " described in " replacement " refer to by " C
3~ C
6cycloalkyl " when replacing, described " C
3~ C
6cycloalkyl " be cyclopropyl, cyclopentyl or cyclohexyl;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " by by " halogen " replaced time, described " halogen " is fluorine, chlorine, bromine or iodine;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by C
1~ C
10alkyl when replacing, described " C
1~ C
10alkyl " C
1~ C
6alkyl;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by C
1~ C
10alkoxyl group when replacing, described " C
1~ C
10alkoxyl group " be C
1~ C
6alkoxyl group;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by " the C of halogen substiuted
1~ C
10alkyl " when replacing, the described " C of halogen substiuted
1~ C
10alkyl " described in " halogen " be fluorine, chlorine or bromine, the number of described halogen is 1-4, and when there is multiple halogen atom, described halogen atom can be identical or different, the described " C of halogen substiuted
1~ C
10alkyl " described in " C
1~ C
10alkyl " be C
1~ C
6alkyl;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by " C
2~ C
10thiazolinyl " when replacing, described " C
2~ C
10thiazolinyl " be C
2~ C
6thiazolinyl;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by " C
2~ C
10alkynyl " when replacing, described " C
2~ C
10alkynyl " be C
2~ C
6alkynyl.
3. the preparation method containing difluoro methylene compound as claimed in claim 2, is characterized in that:
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by C
1~ C
6alkyl replace time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by C
1~ C
6alkoxyl group replace time, described " C
1~ C
6alkoxyl group " be methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by C
1~ C
6alkylthio when replacing, described " C
1~ C
6alkylthio " be methylthio group, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio or tertiary butylthio;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by C
1~ C
6alkyl silyl when replacing, described " C
1~ C
6alkyl silyl " for methylsilyl, trimethyl silicon based, ethyl is silica-based, propyl group is silica-based, sec.-propyl is silica-based, butyl is silica-based, isobutyl-is silica-based or the tertiary butyl is silica-based;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " the C of halogen substiuted
1~ C
6alkyl " when replacing, the described " C of halogen substiuted
1~ C
6alkyl " in, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " hydroxyl replace C
1~ C
6alkyl " when replacing, the described " C that hydroxyl replaces
1~ C
6alkyl " be " hydroxyl replace methyl ", " ethyl that hydroxyl replaces ", " propyl group that hydroxyl replaces ", " sec.-propyl that hydroxyl replaces ", " butyl that hydroxyl replaces ", " isobutyl-that hydroxyl replaces " or " tertiary butyl that hydroxyl replaces ";
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " C
2~ C
6thiazolinyl " when replacing, described " C
2~ C
6thiazolinyl " for vinyl,
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " C
2~ C
6alkynyl " when replacing, described " C
2~ C
6alkynyl " for ethynyl,
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " C
3~ C
6aryl " when replacing, described " C
3~ C
6aryl " be phenyl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " the C that heteroatoms is oxygen or nitrogen-atoms, heteroatoms number is 1-2
3~ C
4heterocyclylalkyl " when replacing, the described " C that heteroatoms is oxygen or nitrogen-atoms, heteroatoms number is 1-2
3~ C
4heterocyclylalkyl " be morpholinyl;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " C
1~ C
6alkyl " when replacing, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " C
1~ C
6alkoxyl group " when replacing, described " C
1~ C
6alkoxyl group " be methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " the C of halogen substiuted
1~ C
6alkyl " when replacing, the described " C of halogen substiuted
1~ C
6alkyl " in, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " C
2~ C
6thiazolinyl " when replacing, described " C
2~ C
6thiazolinyl " for vinyl,
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " C
2~ C
6alkynyl " when replacing, described " C
2~ C
16alkynyl " for ethynyl,
As described R
10described in " substituted or unsubstituted C
1~ C
10alkyl " described in " replacement " refer to by " C
5~ C
10aryl " when replacing, described " C
5~ C
10aryl " be phenyl;
As described R
10described in " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the substituted or unsubstituted C of 1-3
2~ C
15heterocyclylalkyl " described in " replacement " refer to by " C
1~ C
6alkyl " when replacing, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by C
1~ C
6alkyl when replacing, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by C
1~ C
6alkoxyl group when replacing, described " C
1~ C
6alkoxyl group " be methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by " the C of halogen substiuted
1~ C
6alkyl " when replacing, the described " C of halogen substiuted
1~ C
6alkyl " in, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by " C
2~ C
6thiazolinyl " when replacing, described " C
2~ C
6thiazolinyl " for vinyl,
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by " C
2~ C
6alkynyl " when replacing, described " C
2~ C
6alkynyl " for ethynyl,
4. the preparation method containing difluoro methylene compound as claimed in claim 3, is characterized in that:
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be by " the C of halogen substiuted
1~ C
6alkyl " when replacing, the described " C of halogen substiuted
1~ C
6alkyl " be " fluorine, the methyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the ethyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the propyl group of the one or more replacements in chlorine and bromine atoms ", " fluorine, the sec.-propyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the butyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the isobutyl-of the one or more replacements in chlorine and bromine atoms " or " fluorine, the tertiary butyl of the one or more replacements in chlorine and bromine atoms ",
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " by being replaced by morpholinyl time, described " morpholinyl " is
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " be by " the C of halogen substiuted
1~ C
6alkyl " when replacing, the described " C of halogen substiuted
1~ C
6alkyl " be " fluorine, the methyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the ethyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the propyl group of the one or more replacements in chlorine and bromine atoms ", " fluorine, the sec.-propyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the butyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the isobutyl-of the one or more replacements in chlorine and bromine atoms " or " fluorine, the tertiary butyl of the one or more replacements in chlorine and bromine atoms ",
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " be by " the C of halogen substiuted
1~ C
6alkyl " when replacing, the described " C of halogen substiuted
1~ C
6alkyl " be " fluorine, the methyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the ethyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the propyl group of the one or more replacements in chlorine and bromine atoms ", " fluorine, the sec.-propyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the butyl of the one or more replacements in chlorine and bromine atoms ", " fluorine, the isobutyl-of the one or more replacements in chlorine and bromine atoms " or " fluorine, the tertiary butyl of the one or more replacements in chlorine and bromine atoms ".
5. the preparation method containing difluoro methylene compound as claimed in claim 4, is characterized in that:
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " by being replaced by " fluorine atom replace methyl " time, described " methyl of fluorine atom replacement " is trifluoromethyl;
As described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " by being replaced by " bromine atoms replace methyl " time, described " methyl of bromine atoms replacement " is
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " by being replaced by " fluorine atom replace methyl " time, described " methyl of fluorine atom replacement " is trifluoromethyl;
As described R
2described in " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " described in " replacement " by being replaced by " bromine atoms replace methyl " time, described " methyl of bromine atoms replacement " is
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " by being replaced by " fluorine atom replace methyl " time, described " methyl of fluorine atom replacement " is trifluoromethyl;
As described R
10described in " substituted or unsubstituted C
3~ C
15aryl " described in " replacement " by being replaced by " bromine atoms replace methyl " time, described " methyl of bromine atoms replacement " is
6. the preparation method containing difluoro methylene compound as claimed in claim 1, is characterized in that: as described R
1described in " substituted or unsubstituted C
3~ C
15aryl " or " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " described in " replacement " be quilt
when replacing, described
for
As described R
1for " substituted or unsubstituted C
3~ C
15aryl " time, described " substituted or unsubstituted C
3~ C
15aryl " be " substituted or unsubstituted C
5~ C
14aryl ";
As described R
1for " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is that 1-3 is individual, substituted or unsubstituted C
2~ C
15heteroaryl " time, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is 1-3, substituted or unsubstituted C
2~ C
15heteroaryl " be that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1
3~ C
10heteroaryl ";
As described R
3, R
4and R
5be independently " C separately
1~ C
6alkyl " time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
3, R
4and R
5be independently C separately
3~ C
6cycloalkyl time, described " C
3~ C
6cycloalkyl " be cyclopropyl, cyclopentyl or cyclohexyl;
As described R
6and R
7be independently " C separately
1~ C
6alkyl " time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
6and R
7be independently C separately
3~ C
6cycloalkyl time, described " C
3~ C
6cycloalkyl " be cyclopropyl, cyclopentyl or cyclohexyl;
As described R
8be independently " C separately
1~ C
6alkyl " time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
8be independently C separately
3~ C
6cycloalkyl time, described " C
3~ C
6cycloalkyl " be cyclopropyl, cyclopentyl or cyclohexyl;
As described R
2for
time, described
for
As described R
2for
time, described
for
As described R
2for " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " time, described " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-3
2~ C
15heteroaryl " be " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-2
3~ C
8heteroaryl ";
As described R
9for C
1~ C
6alkyl time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
9for C
3~ C
6cycloalkyl time, described " C
3~ C
6cycloalkyl " be cyclopropyl, cyclopentyl or cyclohexyl;
As described R
10for " substituted or unsubstituted C
1~ C
10alkyl " time, described " substituted or unsubstituted C
1~ C
10alkyl " be " substituted or unsubstituted C
1~ C
6alkyl ";
As described R
10for " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the substituted or unsubstituted C of 1-3
2~ C
15heterocyclylalkyl " time, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the substituted or unsubstituted C of 1-3
2~ C
15heterocyclylalkyl " be that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1-2
2~ C
6heterocyclylalkyl ";
As described R
10for " substituted or unsubstituted C
3~ C
15aryl " time, described " substituted or unsubstituted C
3~ C
15aryl " be " substituted or unsubstituted C
5~ C
10aryl ";
As described R
10for C
3~ C
15virtue amino time, described " C
3~ C
15virtue amino " be C
5~ C
10virtue amino;
As described R
11for C
1~ C
6alkyl time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
11for C
3~ C
6cycloalkyl time, described " C
3~ C
6cycloalkyl " be cyclopropyl, cyclopentyl or cyclohexyl;
As described R
11for C
1~ C
6alkyl silyl time, described " C
1~ C
6alkyl silyl " described in " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
As described R
12for C
1~ C
6alkyl time, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl.
7. the preparation method containing difluoro methylene compound as claimed in claim 6, is characterized in that:
As described R
1for " substituted or unsubstituted C
5~ C
14aryl " time, described " substituted or unsubstituted C
5~ C
14aryl " be " substituted or unsubstituted phenyl ", " substituted or unsubstituted naphthyl " or " substituted or unsubstituted phenanthryl ";
As described R
1for " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1
3~ C
10heteroaryl " time, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1
3~ C
10heteroaryl " preferably " substituted or unsubstituted pyridyl ", " substituted or unsubstituted thienyl ", " substituted or unsubstituted furyl ", " substituted or unsubstituted pyrryl ", " substituted or unsubstituted benzofuryl ", " substituted or unsubstituted benzothienyl ", " substituted or unsubstituted benzopyrrole base ",
As described R
2for " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-2
3~ C
8heteroaryl " time, described " the substituted or unsubstituted C that heteroatoms is oxygen, sulphur or nitrogen-atoms, heteroatoms number is 1-2
3~ C
8heteroaryl " be " substituted or unsubstituted benzoxazolyl ", " substituted or unsubstituted benzimidazolyl-" or " substituted or unsubstituted thiazolyl ";
As described R
10for " substituted or unsubstituted C
1~ C
6alkyl " time, described " substituted or unsubstituted C
1~ C
6alkyl " be " substituted or unsubstituted methyl ", " substituted or unsubstituted ethyl ", " substituted or unsubstituted propyl group ", " substituted or unsubstituted sec.-propyl ", " substituted or unsubstituted butyl ", " substituted or unsubstituted isobutyl-" or " the substituted or unsubstituted tertiary butyl ";
As described R
10for " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1-2
2~ C
6heterocyclylalkyl " time, it is described that " heteroatoms is oxygen, sulphur or nitrogen-atoms, and heteroatoms number is the C of 1-2
2~ C
6heterocyclylalkyl " be that " heteroatoms is oxygen and/or nitrogen-atoms, and heteroatoms number is the C of 2
3~ C
4heterocyclylalkyl ";
As described R
10for " substituted or unsubstituted C
5~ C
10aryl " time, described " substituted or unsubstituted C
5~ C
10aryl " be substituted or unsubstituted phenyl;
As described R
10for C
5~ C
10virtue amino time, described " C
5~ C
10virtue amino " be
As described R
11for C
1~ C
6alkyl silyl time, described " C
1~ C
6alkyl silyl " for trimethyl silicon based, triethyl is silica-based, tripropyl is silica-based or triisopropylsilyl.
8. the preparation method containing difluoro methylene compound as claimed in claim 7, is characterized in that:
As described R
1during for unsubstituted naphthyl, described " unsubstituted naphthyl " is
As described R
1during for unsubstituted phenanthryl, described " unsubstituted phenanthryl " is
As described R
1for replace phenyl time, described " phenyl of replacement " is 4-p-methoxy-phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl,
4-trifluoromethyl, N, N-3,5-dimethylphenyl, 3-trifluoromethyl, 4-cyano-phenyl, 4-fluorophenyl, 2,4-difluorophenyl, 3-nitrophenyl, 4-bromophenyl, 3,5-dichlorophenyls, 3,5-Dimethoxyphenyls, 4-tert-butyl-phenyl, 3-bromophenyl, 4-bromophenyl,
As described R
1during for " unsubstituted pyridyl ", described " unsubstituted pyridyl " is 2-pyridyl, 3-pyridyl or 4-pyridyl;
As described R
1during for " unsubstituted thienyl ", described " unsubstituted thienyl " is 2-thienyl or 3-thienyl;
As described R
1during for " thienyl of replacement ", described " thienyl of replacement " is
As described R
1during for " unsubstituted furyl ", described " unsubstituted furyl " is 2-furyl or 3-furyl;
As described R
1during for " furyl of replacement ", described " furyl of replacement " is
As described R
1during for " unsubstituted pyrryl ", described " unsubstituted pyrryl " is 2-pyrryl or 3-pyrryl;
As described R
1during for " pyrryl of replacement ", described " pyrryl of replacement " is
As described R
2during for " unsubstituted benzoxazolyl ", described " unsubstituted benzoxazolyl " is
As described R
2during for " unsubstituted thiazolyl ", described " unsubstituted thiazolyl " is
As described R
2during for " thiazolyl of replacement ", described " thiazolyl of replacement " is
As described R
2during for " unsubstituted benzimidazolyl-", described " unsubstituted benzimidazolyl-" is
As described R
2during for " benzimidazolyl-of replacement ", described " benzimidazolyl-of replacement " is
As described R
10during for " ethyl of replacement ", described " ethyl of replacement " is
As described R
10for " heteroatoms is oxygen and/or nitrogen-atoms, and heteroatoms number is the C of 2
3~ C
4heterocyclylalkyl " time, it is described that " heteroatoms is oxygen and/or nitrogen-atoms, and heteroatoms number is the C of 2
3~ C
4heterocyclylalkyl " be substituted or unsubstituted morpholinyl;
As described R
10during for " phenyl of replacement ", described " phenyl of replacement " is 4-p-methoxy-phenyl, 2-aminomethyl phenyl, 4-trifluoromethyl, 3-trifluoromethyl, 4-cyano-phenyl, 4-fluorophenyl, 4-bromophenyl, 35-Dimethoxyphenyl, 4-tert-butyl-phenyl, 3-bromophenyl, 4-bromophenyl, 4-aminomethyl phenyl,
9. the preparation method containing difluoro methylene compound as claimed in claim 1, is characterized in that: described compd A is following arbitrary compound:
Described compd B is following arbitrary compound:
Described Compound C is following arbitrary compound:
10. the preparation method containing difluoro methylene compound as claimed in claim 1, is characterized in that: contain in the preparation method of difluoro methylene compound described, described part is nitrogenous bitooth ligand or nitrogenous tridentate ligand.
11. as claimed in claim 10 containing the preparation method of difluoro methylene compound, it is characterized in that: contain in the preparation method of difluoro methylene compound described, described nitrogenous bitooth ligand is substituted or unsubstituted dipyridyl, substituted or unsubstituted 1,10-phenanthroline or N, N, N ', N '-tetramethyl-ethamine; Described nitrogenous tridentate ligand is " substituted or unsubstituted terpyridyl "; Described " substituted or unsubstituted dipyridyl ", " substituted or unsubstituted 1,10-phenanthroline " or " replacement " described in " terpyridyl replacing or replace " refer on heteroatomic non-ortho position by C
1~ C
10alkyl and C
1~ C
10alkoxyl group in one or morely to replace, when there is multiple substituting group, described substituting group can be identical or different.
12. as claimed in claim 11 containing the preparation method of difluoro methylene compound, it is characterized in that: when " replacement " described in described " substituted or unsubstituted dipyridyl ", " substituted or unsubstituted 1,10-phenanthroline " or " terpyridyl replacing or replace " refers on heteroatomic non-ortho position by C
1~ C
10alkyl when replacing, described " C
1~ C
10alkyl " be C
1~ C
6alkyl;
When " replacement " described in described " substituted or unsubstituted dipyridyl ", " substituted or unsubstituted 1,10-phenanthroline " or " terpyridyl replacing or replace " refers on heteroatomic non-ortho position by C
1~ C
10alkoxyl group when replacing, described " C
1~ C
10alkoxyl group " be C
1~ C
6alkoxyl group.
13., as claimed in claim 12 containing the preparation method of difluoro methylene compound, is characterized in that:
When " replacement " described in described " substituted or unsubstituted dipyridyl ", " substituted or unsubstituted 1,10-phenanthroline " or " terpyridyl replacing or replace " refers on heteroatomic non-ortho position by C
1~ C
6alkyl when replacing, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
When " replacement " described in described " substituted or unsubstituted dipyridyl ", " substituted or unsubstituted 1,10-phenanthroline " or " terpyridyl replacing or replace " refers on heteroatomic non-ortho position by C
1~ C
6alkoxyl group when replacing, described " C
1~ C
6alkoxyl group " be methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy.
14. as claimed in claim 11 containing the preparation method of difluoro methylene compound, it is characterized in that: contain in the preparation method of difluoro methylene compound described, when described nitrogenous bitooth ligand is " dipyridyl of replacement ", described " dipyridyl of replacement " is
Contain in the preparation method of difluoro methylene compound described, when described nitrogenous bitooth ligand is " substituted or unsubstituted 1,10-phenanthroline ", described " unsubstituted 1,10-phenanthroline " is
Contain in the preparation method of difluoro methylene compound described, when described nitrogenous tridentate ligand is " unsubstituted terpyridyl ", described " unsubstituted terpyridyl " is
15., as claimed in claim 1 containing the preparation method of difluoro methylene compound, is characterized in that: contain in the preparation method of difluoro methylene compound described, when described Q is halogen, described " halogen " is fluorine, chlorine, bromine or iodine;
Contain in the preparation method of difluoro methylene compound described, described m is 0,1,2,3,4,5,6,7,8,9 or 10;
Contain in the preparation method of difluoro methylene compound described, described n is 0,1,2 or 3;
Contain in the preparation method of difluoro methylene compound described, when " replacement " described in " the substituted or unsubstituted dipyridyl " described in described L, " substituted or unsubstituted 1,10-phenanthroline " or " terpyridyl replacing or replace " refers on heteroatomic non-ortho position by C
1~ C
6alkyl when replacing, described " C
1~ C
6alkyl " be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-or the tertiary butyl;
When " replacement " described in " the substituted or unsubstituted dipyridyl " described in described L, " substituted or unsubstituted 1,10-phenanthroline " or " terpyridyl replacing or replace " refers on heteroatomic non-ortho position by C
1~ C
6alkoxyl group when replacing, described " C
1~ C
6alkoxyl group " be methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy or tert.-butoxy.
16., as claimed in claim 15 containing the preparation method of difluoro methylene compound, is characterized in that: contain in the preparation method of difluoro methylene compound described, when described L is " dipyridyl of replacement ", described " dipyridyl of replacement " is
Contain in the preparation method of difluoro methylene compound described, when described L is substituted or unsubstituted 1,10-phenanthroline, described " unsubstituted 1,10-phenanthroline " is
Contain in the preparation method of difluoro methylene compound described, when described L is " unsubstituted terpyridyl ", described " unsubstituted terpyridyl " is
17., as claimed in claim 1 containing the preparation methods of difluoro methylene compound, is characterized in that: described containing in the preparation method of difluoro methylene compound, and described solvent is one or more in ether solvent and water;
And/or,
Contain in the preparation method of difluoro methylene compound described, described solvent is 1mL/mmol ~ 100mL/mmol with the Molar ratio of described compd B;
And/or,
Contain in the preparation method of difluoro methylene compound described, described alkali is alkali metal hydroxide, alkaline carbonate, alkali metal hydrocarbonate, alkali metal phosphate, " basic metal and C
1~ C
4the salt that alcohol is formed " or C
1~ C
4alkylamine;
And/or,
Contain in the preparation method of difluoro methylene compound described, the molar ratio of described alkali and described compd B is 1 ~ 5;
And/or,
The molar ratio of described part and described compd B is 0.01 ~ 0.1;
And/or,
Contain in the preparation method of difluoro methylene compound described, the molar ratio of described nickel salt and described compd B is 0.01 ~ 0.1;
And/or,
Contain in the preparation method of difluoro methylene compound described, the temperature of described Suzuki linked reaction is 20 DEG C ~ 120 DEG C.
18. as claimed in claim 17 containing the preparation method of difluoro methylene compound, it is characterized in that: contain in the preparation method of difluoro methylene compound described, when described solvent is ether solvent, described ether solvent is one or more in tetrahydrofuran (THF), ether, glycol dimethyl ether, diethylene glycol dimethyl ether, Isosorbide-5-Nitrae-dioxane and methyl tertiary butyl ether;
And/or,
Described containing in the preparation method of difluoro methylene compound, when described alkali is alkaline carbonate, described " alkaline carbonate " is salt of wormwood, one or more in sodium carbonate and cesium carbonate;
And/or,
Contain in the preparation method of difluoro methylene compound described, when described alkali is alkali metal phosphate, described " alkali metal phosphate " is potassiumphosphate;
And/or,
Contain in the preparation method of difluoro methylene compound, when described alkali is " basic metal and C described
1~ C
4the salt that alcohol is formed " time, described " basic metal and C
1~ C
4alcohol formed salt " described in " C
1~ C
4alcohol " be methyl alcohol, ethanol, propyl alcohol, Virahol or the trimethyl carbinol, described " basic metal and C
1~ C
4alcohol formed salt " described in " basic metal " be lithium, sodium, potassium, rubidium or caesium;
And/or,
Contain in the preparation method of difluoro methylene compound described, the molar ratio of described alkali and described compd B is 2 ~ 3;
And/or,
The molar ratio of described part and described compd B is 0.025 ~ 0.05;
Contain in the preparation method of difluoro methylene compound described, the molar ratio of described nickel salt and described compd B is 0.025 ~ 0.05;
Contain in the preparation method of difluoro methylene compound described, the temperature of described Suzuki linked reaction is 60 DEG C ~ 80 DEG C.
19., as claimed in claim 1 containing the preparation method of difluoro methylene compound, is characterized in that: the described preparation method containing difluoro methylene compound carries out under promotor existent condition, and described promotor is mantoquita; The molar ratio of described promotor and described compd B is 0 ~ 4, but does not comprise 0.
20., as claimed in claim 19 containing the preparation methods of difluoro methylene compound, is characterized in that: described mantoquita is one or more in cupric oxide, neutralized verdigris, cupric chloride, cupric bromide, cupric iodide, cuprous iodide, cupric fluoride and copper carbonate.
21. 1 kinds such as formula the compound shown in C,
R
1CF
2R
2
C
Wherein, R
1and R
2definition as described in any one of claim 1 ~ 9, but do not comprise following compound:
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| CN106674067A (en) * | 2016-12-09 | 2017-05-17 | 南京理工大学 | Method for compounding sulfur-difluoromethylene compound from thiol |
| CN106699532A (en) * | 2016-12-28 | 2017-05-24 | 浙江师范大学 | Preparing method of 1,1-difluoro tetrahydronaphthalene compound |
| CN106748771A (en) * | 2016-12-28 | 2017-05-31 | 浙江师范大学 | A kind of preparation method of 6 fluoroalkyl ketone |
| CN109704914A (en) * | 2019-01-19 | 2019-05-03 | 山东理工大学 | A kind of facile syntheesis new method of 1,1- bis-fluoro ethyls aromatic compound |
| CN109879733A (en) * | 2019-04-03 | 2019-06-14 | 上海应用技术大学 | A kind of synthetic method of list fluorine bromo acetone derivatives |
| CN110668941A (en) * | 2019-09-16 | 2020-01-10 | 江苏三美化工有限公司 | Compound with trifluoromethyl benzyl halide structure efficiently synthesized by nickel salt catalysis and conversion application thereof |
| CN111548269A (en) * | 2020-04-29 | 2020-08-18 | 兰州大学 | Preparation method of diarylmethane structure compound |
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| HAIZHEN JIANG等: "Enhancement of Neighbouring-Group Participation in Cu0-Promoted Cross-Coupling gem-Difluoromethylenation of Aryl/Alkenyl Halides with 1,3-Azolic Difluoromethyl Bromides", 《CHEM. EUR. J.》 * |
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