CN104193667A - Synthesis method of divergently oriented azacycles - Google Patents
Synthesis method of divergently oriented azacycles Download PDFInfo
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- CN104193667A CN104193667A CN201410378274.4A CN201410378274A CN104193667A CN 104193667 A CN104193667 A CN 104193667A CN 201410378274 A CN201410378274 A CN 201410378274A CN 104193667 A CN104193667 A CN 104193667A
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- nitrogen heterocyclic
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- 238000001308 synthesis method Methods 0.000 title abstract 4
- 239000002184 metal Substances 0.000 claims abstract description 8
- 229910052751 metal Inorganic materials 0.000 claims abstract description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- -1 nitrogen heterocyclic aldehyde Chemical class 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000741 silica gel Substances 0.000 claims description 10
- 229910002027 silica gel Inorganic materials 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 125000004494 ethyl ester group Chemical group 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 6
- 150000004702 methyl esters Chemical class 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- NENDHUHGFRLXEN-UHFFFAOYSA-N acetic acid;rhodium Chemical compound [Rh].CC(O)=O NENDHUHGFRLXEN-UHFFFAOYSA-N 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- 239000003921 oil Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052703 rhodium Inorganic materials 0.000 claims description 4
- 239000010948 rhodium Substances 0.000 claims description 4
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- OBASDBHRXUCXKQ-UHFFFAOYSA-N [F].[Br] Chemical compound [F].[Br] OBASDBHRXUCXKQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 239000005749 Copper compound Substances 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 2
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 150000001880 copper compounds Chemical class 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012454 non-polar solvent Substances 0.000 claims description 2
- 150000003284 rhodium compounds Chemical group 0.000 claims description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical class OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 4
- 239000012847 fine chemical Substances 0.000 abstract description 3
- YGRZORIJDZMIPI-UHFFFAOYSA-N 1,2-diazabicyclo[3.1.0]hexane-3-carbaldehyde Chemical compound N12NC(CC2C1)C=O YGRZORIJDZMIPI-UHFFFAOYSA-N 0.000 abstract 3
- YYYYGCMMBVVYLF-UHFFFAOYSA-N 4-sulfonyltriazole Chemical compound O=S(=O)=C1C=NN=N1 YYYYGCMMBVVYLF-UHFFFAOYSA-N 0.000 abstract 1
- JARKCYVAAOWBJS-UHFFFAOYSA-N hexanal Chemical compound CCCCCC=O JARKCYVAAOWBJS-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000003595 spectral effect Effects 0.000 description 3
- 0 **1C=Cc([n](CC=C(*)C=C)cc2)c2C=C1 Chemical compound **1C=Cc([n](CC=C(*)C=C)cc2)c2C=C1 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- OLNJUISKUQQNIM-UHFFFAOYSA-N indole-3-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CNC2=C1 OLNJUISKUQQNIM-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000008204 material by function Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910017464 nitrogen compound Inorganic materials 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a synthesis method of divergently oriented azacycles and belongs to the technical field of chemical pharmaceutics and preparation of fine chemicals. By virtue of the synthesis method of divergently oriented azacycle, polysubstituted N-allyl-3-indolal and 3-diazabicyclo[3,1,0] hexanal can be synthesized at one time; sulfonyl triazole catalyzed by metal is decomposed into metal carbine, subsequently, the metal carbine is cyclized so as to efficiently obtain two types of differently structural azacycles, namely N-allyl-3-indolal and 3-diazabicyclo[3,1,0] hexanal. The invention provides a novel technical route for efficiently preparing derivatives of functionalized N-allyl-3-indolal and 3-diazabicyclo[3,1,0] hexanal derivatives. The synthesis method of divergently oriented azacycles has a wide application range in the field of chemical pharmaceutics and fine chemicals.
Description
Technical field
The invention belongs to chemical pharmacy and fine chemistry industry preparing technical field, disperse N-allyl group-3-indolal and the 3-azabicyclic [3 of synthetic guiding, 1,0] hexanal, especially relate to the Cabbeen cyclization of metal catalytic, generate efficiently two kinds of polysubstituted nitrogen heterocyclics, and can effectively control the relative proportion of product.The present invention, for the functionalized nitrogen heterocyclic derivative of efficient preparation provides a new technological line and layout strategy, has wide application at chemical pharmacy and field of fine chemical.
Background technology
Nitrogen heterocyclic is the important organic compound of a large class, and a lot of nitrogen heterocyclics have special chemistry and biological activity, are present in many natural products and drug molecule, are also applied in functional materials.And containing the heterocyclic nitrogen compound organic molecule of high added value especially of aldehyde radical because aldehyde radical can be very easily further derivatize obtain the nitrogen heterocyclic of a lot of other structures.N-allyl group-3-indolal and 3-azabicyclic [3,1,0] hexanal is the very valuable nitrogen heterocyclics of two classes because containing multiple functional group and pharmacophore in its structure, and the preparation method of this two compounds is limited at present, and the method for bibliographical information may be summarized to be following equation substantially:
(1), from indoles 1, through Vilsmeier, formylation obtains 3-indolal 2 (formula 1).
(2), from eneyne 3s, gold catalyst catalyzing oxidation obtains 4 (formulas 2).
(3), from eneyne 5s, metal catalyst catalyzed oxidation obtains 6 (formulas 3).
These methods have certain limitation, are difficult for preparation such as substrate is complicated, and the shortcoming such as substrate narrow range.Consider above shortcoming, the present invention prepares the novel method of two kinds of distinct nitrogen heterocyclics of structure when will setting forth a kind of convenient and general.
Summary of the invention
The object of the invention is to set forth a kind of divergence form nitrogen heterocyclic preparation method, is exactly to have invented an a kind of efficient step to prepare two kinds of nitrogen heterocyclic N-allyl group-3-indolals and 3-azabicyclic [3,1,0] hexanal specifically.
For realizing above-mentioned synthetic object, the present invention adopts following technical scheme, the reaction equation shown in being summarised as: (formula 4).In appropriate solvent, the cyclisation under suitable metal catalyst catalysis of various 1-alkylsulfonyl triazoles 7 obtains N-allyl group-3-indolal 8 and 3-azabicyclic [3,1,0] hexanal 9 after suitable hydrolysis treatment.
R in general formula of molecular structure 7,8,9
1for aryl (being specially phenyl, p-methylphenyl, p-nitrophenyl etc.), the alkyl of various replacements etc. (being specially methyl, trimethyl silicon based ethyl etc.) of various replacements; R
2for the alkyl (being specially methyl, ethyl, benzyl etc.) of the aryl (being specially phenyl, p-methylphenyl etc.) of various replacements, various replacements, various fat base (being specially methyl esters, ethyl ester etc.), various halogen (being specially chlorine, bromine fluorine) etc.; R
3for the aryloxy (being specially phenoxy group) of the alkoxyl group (being specially methoxyl group, 3,5-Dimethoxyphenyl) of the alkyl (being specially methyl) of the aryl (being specially phenyl) of various replacements, various replacements, various replacements, various replacements, nitro (being specially nitro, a nitro), fat base (being specially methyl esters, ethyl ester), itrile group (being specially formonitrile HCN), halogen (being specially chlorine, bromine, iodine, fluorine etc.) etc.
A kind of nitrogen heterocyclic of dispersing guiding synthetic, carries out according to following step:
1-alkylsulfonyl triazole 7, metal catalyst are blended in a kind of organic solvent and stir by a certain percentage, and according to substrate and specificity of reagent, temperature is controlled between certain temperature; after certain hour, stopped reaction, adds appropriate methyl alcohol; salt of wormwood and a small amount of water, stirring is spent the night.With organic solvent ethyl acetate or dichloromethane extraction three times, after merging, organic phase with saturated common salt washing, then uses anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is eluent with ethyl acetate and sherwood oil, and silica gel column chromatogram separating purification obtains corresponding nitrogen heterocyclic aldehyde 8 and 9.Or after having reacted, remove organic solvent under reduced pressure, the direct silica gel chromatographic column of residue separates.
The structural formula of wherein said 1-alkylsulfonyl triazole 7 is
wherein R
1for aryl (being specially phenyl, p-methylphenyl, p-nitrophenyl etc.), the alkyl of various replacements etc. (being specially methyl, trimethyl silicon based ethyl etc.) of various replacements; R
2for the alkyl (being specially methyl, ethyl, benzyl etc.) of the aryl (being specially phenyl, p-methylphenyl etc.) of various replacements, various replacements, various fat base (being specially methyl esters, ethyl ester etc.), various halogen (being specially chlorine, bromine fluorine) etc.; R
3for the aryloxy (being specially phenoxy group) of the alkoxyl group (being specially methoxyl group, 3,5-Dimethoxyphenyl) of the alkyl (being specially methyl) of the aryl (being specially phenyl) of various replacements, various replacements, various replacements, various replacements, nitro (being specially nitro, a nitro), fat base (being specially methyl esters, ethyl ester), itrile group (being specially formonitrile HCN), halogen (being specially chlorine, bromine, iodine, fluorine etc.) etc.
Wherein said solvent is tetrahydrofuran (THF), toluene, methylene dichloride, trichloromethane, 1, the non-polar solvents such as 2-methylene dichloride.
Wherein said 1-alkylsulfonyl triazole 7, catalyst molar ratio is that 1.0:0.005 is between 1.0:0.05.
Wherein said catalyzer is rhodium compound and the trifluoromethanesulfonic acids such as acetic acid rhodium, sad rhodium, m-phthalic acid rhodium, the silver salt such as copper compound and silver trifluoromethanesulfonate such as trifluoracetic acid copper.
Wherein said temperature of reaction is between 50-120 degree.
The wherein said reaction times is between 10 minutes to 5 hours.
Advantage of the present invention
1, this operation is easy, only needs single step reaction just can prepare efficiently two kinds of nitrogen heterocyclics.
2, the product structure novelty of this reaction, is difficult for preparing with additive method.
3, the method can realize proportion of products regulation and control.
4, the product of this reaction is the compound of high added value.
Embodiment
Below by example, the present invention is described further:
Following non-limiting example 1-3# or comparative example 1-2# are used for the present invention that explains; instead of limit the invention; in the protection domain of spirit of the present invention and claim, any amendment and change that the present invention is made, all belong to protection scope of the present invention.
Raw material used in the present invention, reagent and catalyzer are by reference to pertinent literature preparation, and solvent is through purifying and refining.
Embodiment 1
2 mmole 1-are blended in 10 milliliters of toluene and are stirred toluene sulfo group triazole 7a, 0.01 mmole acetic acid rhodium, and temperature control 120 is spent, and after 2 hours, stops heating, adds 2 ml methanol, 5 mmole salt of wormwood and a water, stirring at room temperature 12 hours.With organic solvent ethyl acetate extraction three times, after organic phase merges, wash with saturated common salt, then use anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is eluent with ethyl acetate and sherwood oil, and silica gel column chromatogram separating purification obtains corresponding nitrogen heterocyclic aldehyde 8a and 9a (in table 1).Or after having reacted, remove organic solvent under reduced pressure, the direct silica gel chromatographic column of residue separates.
Embodiment 2
2 mmole 1-are blended in 10 milliliters of ethylene dichloride and are stirred toluene sulfo group triazole 7b, 0.1 mmole acetic acid rhodium, and temperature control 50 is spent, and after 5 hours, stops heating, adds 2 ml methanol, 5 mmole salt of wormwood and a water, stirring at room temperature 8 hours.With organic solvent ethyl acetate extraction three times, after organic phase merges, wash with saturated common salt, then use anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is eluent with ethyl acetate and sherwood oil, and silica gel column chromatogram separating purification obtains corresponding nitrogen heterocyclic aldehyde 8b and 9b (in table 1).Or after having reacted, remove organic solvent under reduced pressure, the direct silica gel chromatographic column of residue separates.
Embodiment 3
2 mmole 1-are blended in 10 milliliters of toluene and are stirred toluene sulfo group triazole 7c, 0.04 mmole acetic acid rhodium, and temperature control 120 is spent, and after 10 minutes, stops heating, adds 2 ml methanol, 5 mmole salt of wormwood and a water, stirring at room temperature 12 hours.With organic solvent ethyl acetate extraction three times, after organic phase merges, wash with saturated common salt, then use anhydrous sodium sulfate drying, remove solvent under reduced pressure, residue is eluent with ethyl acetate and sherwood oil, and silica gel column chromatogram separating purification obtains corresponding nitrogen heterocyclic aldehyde 8c and 9c (in table 1).Or after having reacted, remove organic solvent under reduced pressure, the direct silica gel chromatographic column of residue separates.
The preparation of table 1. divergence form N-allyl group-3-indolal and 3-azabicyclic [3,1,0] hexanal
8a:79％；The?spectral?data?matched?that?reported?by?Black?and?co-workers
2.
1H?NMR(400MHz,CDCl
3)δ10.36(s,1H),7.73(s,1H),6.41(d,J＝1.8Hz,1H),6.39(d,J＝1.8Hz,1H),5.98(ddd,J＝22.5,10.6,5.5Hz,1H),5.29(dd,J＝10.3,0.8Hz,1H),5.14(dd,J＝17.1,0.7Hz,1H),4.68(d,J＝5.4Hz,2H),3.95(s,3H),3.85(s,3H).
8b:17%;
1h NMR (400MHz, CDCl
3) δ 10.44 (s, 1H), 7.85 (s, 1H), 7.22 (t, J=8.1Hz, 1H), 7.00 (d, J=8.2Hz, 1H), 6.73 (d, J=7.9Hz, 1H), 5.99 (ddd, J=22.6,10.6,5.5Hz, 1H), 5.29 (dd, J=10.2,0.8Hz, 1H), 5.16 (dd, J=17.1,0.7Hz, 1H), 4.74 (d, J=5.5Hz, 2H), 4.00 (s, 3H);
13c NMR (125MHz, CDCl
3) δ 188.0,154.7,138.2,131.8,131.2,123.9,119.0,118.5,117.0,103.9,102.59,55.49,49.98; HRMS (ESI) m/z theoretical value C
13h
14nO
2 +[M+H]
+216.1019, measured value 216.1015.
8b ': 48%;
1h NMR (400MHz, CDCl
3) δ 9.89 (s, 1H), 8.16 (d, J=8.7Hz, 1H), 7.60 (s, 1H), 6.94 (dd, J=8.7,2.2Hz, 1H), 6.77 (d, J=2.2Hz, 1H), 5.99 (ddt, J=17.0,10.6,5.5Hz, 1H), 5.30 (dd, J=10.3,0.9Hz, 1H), 5.16 (dd, J=17.1,0.8Hz, 1H), 4.70 (dt, J=5.4,1.5Hz, 2H), 3.84 (s, 3H);
13c NMR (100MHz, CDCl
3) δ 184.5,157.7,138.3,138.1,131.7,122.8,119.3,119.0,118.4,112.1,94.2,55.7,49.5; HRMS (ESI) m/z theoretical value C
13h
14nO
2 +[M+H]
+216.1019, measured value 216.1016.
8c:53％；The?spectral?data?matched?that?reported?by?Wilson?and?co-workers
3.
1H?NMR(400MHz,CDCl
3)δ9.92(s,1H),7.79(s,1H),7.65(s,1H),7.23(m,2H),6.94(d,J＝8.9Hz,1H),6.06–5.87(m,1H),5.30(d,J＝10.2Hz,1H),5.17(d,J＝17.1Hz,1H),4.72(d,J＝5.4Hz,2H),3.87(s,3H).
8d:41%;
1h NMR (400MHz, CDCl
3) δ 9.96 (s, 1H), 8.12 (s, 1H), 7.67 (s, 1H), 7.29 – 7.20 (m, 1H), 7.15 (d, J=8.4Hz, 1H), 6.00 (ddd, J=22.4,10.6,5.5Hz, 1H), 5.30 (d, J=10.3Hz, 1H), 5.17 (d, J=17.1Hz, 1H), 4.74 (d, J=5.5Hz, 2H), 2.48 (s, 3H);
13c NMR (100MHz, CDCl
3) δ 184.6,138.5,135.7,132.8,131.8,125.7,125.6,121.9,119.0,118.0,110.0,49.6,21.5; HRMS (ESI) m/z theoretical value C
13h
14nO
+[M+H]
+200.1070, measured value 200.1064.
8e:33％；The?spectral?data?matched?that?reported?by?Chen?and?co-workers
4.
1H?NMR(400MHz,CDCl
3)δ9.99(s,1H),8.36–8.25(m,1H),7.74(s,1H),7.43–7.27(m,3H),6.02(ddd,J＝22.3,10.6,5.5Hz,1H),5.33(d,J＝10.2Hz,1H),5.20(d,J＝17.1Hz,1H),4.79(d,J＝5.4Hz,2H).
8f:29%;
1h NMR (400MHz, CDCl
3) δ 9.92 (s, 1H), 8.27 (s, 1H), 7.71 (s, 1H), 7.25 (m, 2H), 6.07 – 5.91 (m, 1H), 5.33 (d, J=10.2Hz, 1H), 5.17 (d, J=17.1Hz, 1H), 4.75 (d, J=4.9Hz, 2H);
13c NMR (101MHz, CDCl3) δ 184.4,139.1,135.6,131.4,129.0,126.3,124.4,121.7,119.4,117.8,111.4,49.8; HRMS (ESI) m/z theoretical value C
12h
11clNO
+[M+H]
+220.0524, measured value 220.0520.
8g:13%;
1h NMR (400MHz, CDCl
3) δ 10.07 (s, 1H), 9.21 (d, J=2.0Hz, 1H), 8.23 (dd, J=9.0,2.0Hz, 1H), 7.90 (s, 1H), 7.43 (d, J=9.1Hz, 1H), 6.05 (ddd, J=22.2,10.5,5.4Hz, 1H), 5.40 (d, J=10.2Hz, 1H), 5.22 (d, J=17.0Hz, 1H), 4.86 (d, J=5.3Hz, 2H);
13c NMR (125MHz, CDCl
3) δ 184.2,144.2,140.4,140.0,131.0,125.0,120.0,119.7,119.1,110.6,100.1,50.1; HRMS (ESI) m/z theoretical value C
12h
11n
2o
3 +[M+H]
+231.0764, measured value 231.0766.
8i:12％；
1H?NMR(400MHz,CDCl
3)δ7.77(d,J＝8.2Hz,2H),7.39(d,J＝7.9Hz,1H),7.29-7.27(m,3H),7.20(t,J＝7.2Hz,1H),7.06(t,J＝7.4Hz,1H),6.90(s,1H),4.69(t,J＝5.4Hz,1H),4.28(d,J＝5.4Hz,2H),4.12-4.06(m,4H),2.44(s,3H),2.23(t,J＝7.1Hz,2H),2.07(p,J＝7.0Hz,2H),1.23(t,J＝7.1Hz,3H)；
13C?NMR(100MHz,CDCl
3)δ172.7,143.4,136.9,136.4,129.7,127.3,127.0,126.8,126.4,122.2,119.6,118.9,109.7,109.6,60.7,45.2,38.9,31.1,25.4,21.6,14.2.
9a:9%;
1h NMR (400MHz, CDCl
3) δ 9.06 (s, 1H), 5.93 (s, 1H), 5.77 (d, J=1.6Hz, 2H), 3.80-3.74 (m, 7H), 3.61 (d, J=9.3Hz, 1H), 3.58 (d, J=9.4Hz, 1H), 3.35 (dd, J=9.3,4.4Hz, 1H), 2.36-2.31 (m, 1H), 1.66 (dd, J=8.5,5.1Hz, 1H), 1.33 (t, J=5.3Hz, 1H);
13c NMR (125MHz, CDCl
3) δ 198.0,161.7,149.8,91.7,89.6,55.3,49.4,47.9,40.6,26.8,18.7; HRMS (ESI) m/z theoretical value C
14h
18nO
3 +[M+H]
+248.1281, measured value 248.1270.
9b:23%;
1h NMR (400MHz, CDCl
3) δ 9.07 (s, 1H), 7.14 (t, J=8.2Hz, 1H), 6.32 (dd, J=8.1,2.1Hz, 1H), 6.22 (dd, J=8.2,2.0Hz, 1H), 6.15 (t, J=2.3Hz, 1H), 3.79 (s, 3H), 3.75 (d, J=9.5Hz, 1H), 3.64 (d, J=9.3Hz, 1H), 3.60 (d, J=9.5Hz, 1H), 3.34 (dd, J=9.3,4.4Hz, 1H), 2.34 (dt, J=8.8,5.0Hz, 1H), 1.66 (dd, J=8.5,5.1Hz, 1H), 1.35 (t, J=5.2Hz, 1H);
13c NMR (100MHz, CDCl
3) δ 198.0,160.7,149.2,130.0,105.6,102.4,99.0,55.2,49.3,47.9,40.6,26.8,18.7; HRMS (ESI) m/z theoretical value C
13h
16nO
2 +[M+H]
+218.1176, measured value 218.1167.
9c:31%;
1h NMR (400MHz, CDCl
3) δ 9.06 (s, 1H), 6.84 (d, J=8.8Hz, 2H), 6.59 (d, J=8.2Hz, 2H), 3.75 (s, 3H), 3.62 (dd, J=19.5,9.2Hz, 3H), 3.25 (dd, J=9.0,4.1Hz, 1H), 2.38 – 2.26 (m, 1H), 1.63 (dd, J=8.3,5.1Hz, 1H), 1.47 (s, 1H);
13c NMR (100MHz, CDCl
3) δ 198.1,152.1,142.4,115.0,113.8,55.9,50.0,48.5,40.8,26.9,18.2; HRMS (ESI) m/z theoretical value C
13h
16nO
2 +[M+H]
+218.1176, measured value 218.1160.
9d:46%;
1h NMR (400MHz, CDCl
3) δ 9.07 (s, 1H), 7.06 (d, J=8.2Hz, 2H), 6.57 (d, J=8.3Hz, 2H), 3.74 – 3.56 (m, 3H), 3.30 (dd, J=9.2,4.3Hz, 1H), 2.37 – 2.31 (m, 1H), 2.26 (s, 3H), 1.65 (dd, J=8.4,5.1Hz, 1H), 1.46 (t, J=5.0Hz, 1H);
13c NMR (100MHz, CDCl
3) δ 198.0,145.6,129.9,112.9,49.8,48.3,40.7,26.9,20.4,18.4; HRMS (ESI) m/z theoretical value C
13h
16nO
+[M+H]
+202.1226, measured value 202.1214.
9e:53%;
1h NMR (300MHz, CDCl
3) δ 9.05 (s, 1H), 7.30 – 7.13 (m, 2H), 6.73 (t, J=7.3Hz, 1H), 6.62 – 6.52 (m, 2H), 3.65 (dt, J=14.1,9.5Hz, 3H), 3.31 (dd, J=9.2,4.4Hz, 1H), 2.38 – 2.23 (m, 1H), 1.64 (dd, J=8.5,5.1Hz, 1H), 1.34 (t, J=5.2Hz, 1H);
13c NMR (100MHz, CDCl
3) δ 198.0,147.9,129.3,117.2,112.4,49.2,47.7,40.6,26.9,18.6; HRMS (ESI) m/z theoretical value C
12h
14nO
+[M+H]
+188.1070, measured value 188.1061.
9f:54%;
1h NMR (400MHz, CDCl
3) δ 9.04 (s, 1H), 7.15 (d, J=8.5Hz, 2H), 6.49 (d, J=8.5Hz, 2H), 3.70 (d, J=9.4Hz, 1H), 3.57 (dd, J=20.3,9.3Hz, 2H), 3.30 (dd, J=9.2,4.3Hz, 1H), 2.40 – 2.28 (m, 1H), 1.66 (dd, J=8.1,5.4Hz, 1H), 1.34 (t, J=5.2Hz, 1H);
13c NMR (100MHz, CDCl
3) δ 197.7,146.4,129.0,122.0,113.6,49.4,48.0,40.6,26.7,18.6; HRMS (ESI) m/z theoretical value C
12h
13clNO
+[M+H]
+222.0680, measured value 222.0669.
9g:72%;
1h NMR (400MHz, CDCl
3) δ 9.05 (s, 1H), 8.08 (d, J=9.2Hz, 2H), 6.49 (d, J=9.2Hz, 2H), 3.98 (d, J=10.2Hz, 1H), 3.71 (d, J=10.0Hz, 1H), 3.66 – 3.55 (m, 2H), 2.49 – 2.42 (m, 1H), 1.79 (dd, J=8.3,5.6Hz, 1H), 1.27 (t, J=5.5Hz, 1H);
13c NMR (100MHz, CDCl
3) δ 197.1,129.7,126.4,126.1,111.1,49.6,48.1,40.5,26.4,19.4; HRMS (ESI) m/z theoretical value C
12h
13n
2o
3 +[M+H]
+233.0921, measured value 233.0908.
9h:87%;
1h NMR (400MHz, CDCl
3) δ 9.07 (s, 1H), 7.50 (dd, J=8.0,1.9Hz, 1H), 7.33-7.29 (m, 2H), 6.83 (dd, J=8.2,2.4Hz, 1H), 3.83 (d, J=9.5Hz, 1H), 3.68 (d, J=9.4Hz, 1H), 3.61 (d, J=9.5Hz, 1H), 3.45 (dd, J=9.3,4.5Hz, 1H), 2.46-2.42 (m, 1H), 1.76 (dd, J=8.5,5.3Hz, 1H), (1.33 t, J=5.4Hz, 1H);
13c NMR (100MHz, CDCl
3) δ 197.3,149.0,148.3,129.7,118.0,111.4,106.3,49.4,47.9,40.4,26.4,18.8; HRMS (ESI) m/z theoretical value C
12h
13n
2o
3 +[M+H]
+233.0921, measured value 233.0917.
9i:65％；
1H?NMR(400MHz,CDCl
3)δ7.74(d,J＝8.0Hz,2H),7.29-7.25(m,3H),7.20(d,J＝8.0Hz,2H),6.94(d,J＝8.4Hz,2H),5.88(d,J＝6.1Hz,1H),4.53(s,1H),4.12(q,J＝7.1Hz,2H),3.30(dd,J＝12.8,6.2Hz,1H),3.12(td,J＝12.4,4.5Hz,1H),2.89(dd,J＝9.1,4.9Hz,1H),2.62(dt,J＝13.4,5.5Hz,1H),2.43(d,J＝8.5Hz,1H),2.38(s,3H),2.14(dd,J＝13.7,9.3Hz,1H),2.01(d,J＝9.4Hz,1H),1.47(d,J＝13.6Hz,1H),1.22(t,J＝7.0Hz,3H)；
13C?NMR(100MHz,CDCl
3)δ172.5,148.1,143.4,138.1,129.4,129.4,127.8,120.5,116.9,75.1,61.4,59.1,46.7,40.9,31.7,28.4,21.6,14.2.
Claims (6)
1. the nitrogen heterocyclic of a divergence form guiding is synthetic, it is characterized in that carrying out according to following step:
1-alkylsulfonyl triazole, metal catalyst are blended in a kind of organic solvent and stir by a certain percentage, according to substrate and specificity of reagent, temperature is controlled between certain temperature, after certain hour, stopped reaction, add appropriate methyl alcohol, salt of wormwood and a small amount of water, stirring is spent the night, and uses organic solvent ethyl acetate or dichloromethane extraction three times, after merging, organic phase washes with saturated common salt, use anhydrous sodium sulfate drying again, remove solvent under reduced pressure, residue is eluent with ethyl acetate and sherwood oil, silica gel column chromatogram separating purification, obtains corresponding nitrogen heterocyclic aldehyde 8 and 9; Or after having reacted, remove organic solvent under reduced pressure, the direct silica gel chromatographic column of residue separates.
2. the nitrogen heterocyclic of a kind of divergence form guiding according to claim 1 is synthetic, it is characterized in that the structural formula of wherein said 1-alkylsulfonyl triazole is
, aryl (being specially phenyl, p-methylphenyl, p-nitrophenyl etc.), the alkyl of various replacements etc. (being specially methyl, trimethyl silicon based ethyl etc.) that wherein R1 is various replacements; R2 is alkyl (being specially methyl, ethyl, benzyl etc.), various fat base (being specially methyl esters, ethyl ester etc.), various halogen (being specially chlorine, bromine fluorine) of the aryl (being specially phenyl, p-methylphenyl etc.) of various replacements, various replacements etc.; R3 is aryloxy (being specially phenoxy group), nitro (being specially nitro, a nitro), fat base (being specially methyl esters, ethyl ester), itrile group (being specially formonitrile HCN), halogen (being specially chlorine, bromine, iodine, fluorine etc.) of the alkoxyl group (being specially methoxyl group, 3,5-Dimethoxyphenyl) of the alkyl (being specially methyl) of the aryl (being specially phenyl) of various replacements, various replacements, various replacements, various replacements etc.
3. the nitrogen heterocyclic of a kind of divergence form guiding according to claim 1 is synthetic, it is characterized in that wherein said solvent is tetrahydrofuran (THF), toluene, methylene dichloride, trichloromethane, 1, the non-polar solvents such as 2-methylene dichloride.
4. the nitrogen heterocyclic of a kind of divergence form guiding according to claim 1 is synthetic, it is characterized in that wherein said 1-alkylsulfonyl triazole 7, catalyst molar ratio are that 1.0:0.005 is between 1.0:0.05.
5. the nitrogen heterocyclic of a kind of divergence form guiding according to claim 1 is synthetic, it is characterized in that wherein said catalyzer is rhodium compound and the trifluoromethanesulfonic acids such as acetic acid rhodium, sad rhodium, m-phthalic acid rhodium, the silver salt such as copper compound and silver trifluoromethanesulfonate such as trifluoracetic acid copper.
6. the nitrogen heterocyclic of a kind of divergence form guiding according to claim 1 is synthetic, it is characterized in that wherein said the first step temperature of reaction is between 50-120 degree, and second step is room temperature; The wherein said the first step reaction times is between 10 minutes to 5 hours, and the second step reaction times is 8-12 hour.
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| CN109336730A (en) * | 2018-09-28 | 2019-02-15 | 南京林业大学 | Bicyclic [ 3.3.1 ] nonyl vinyl compound of one kind and preparation method thereof |
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