CN106866541B - A method of preparing benzimidazoles derivative - Google Patents
A method of preparing benzimidazoles derivative Download PDFInfo
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- CN106866541B CN106866541B CN201510920905.5A CN201510920905A CN106866541B CN 106866541 B CN106866541 B CN 106866541B CN 201510920905 A CN201510920905 A CN 201510920905A CN 106866541 B CN106866541 B CN 106866541B
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- nitrone
- aryl
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- derivative
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to a kind of methods for preparing benzimidazoles derivative.Specific method itself occurs cycloaddition reaction by nitrone compound under the cobaltic catalytic condition of transition metal and prepares benzimidazoles derivative.Reactant nitrone can be prepared by starting material cheap and easy to get in this method, and operation is simple, mild condition, wide application range of substrates.
Description
Technical field
The present invention relates to a kind of methods for preparing benzimidazoles derivative.Specific method is the nitre by being simply prepared
Ketone cycloaddition reaction under the catalysis of transition metal trivalent cobalt prepares benzimidazoles derivative.
Background technique
Benzimidazole and its derivative are important one of heterocyclic compound, and such compound is widely present in many natural
In product and drug, there is very important bioactivity and pharmaceutical activity.(document 1:a) Alamgir, M.；Black,
D.S.C.；Kumar,N.Top.Heterocycl.Chem.2007,9,87；b)Bansal,Y.；Silakari,
O.Bioorg.Med.Chem.2012,20,6208；c)Narasimhan,B.；Sharma,D.；Kumar,
P.Med.Chem.Res.2012,21,269；d)Shah,K.；Chhabra,S.；Shrivastava,S.K.；Mishra,
P.Med.Chem.Res.2013,22,5077.) synthesizing benzimidazole analog derivative mainly has following two categories method: method at present
One: preparing (document 2:a) Preston, P.N.In by condensation reaction dehydration by 1,2- diamino benzene-like compounds and carboxylic acid
The Chemistry of Heterocyclic Compounds；Weissberger,A.,Taylor,E.C.,Eds.；John
Wiley&Sons:New York,1981；Vol.40:Benzimidazoles and Cogeneric Tricyclic
Compounds p 6.b)Lin,S.-Y.；Isome,Y.；Stewart,E.；Liu,J.-F.；Yohannes,D.；Yu,
L.Tetrahedron Lett.2006,47,2883)；Two: 1,2- diamino benzene-like compounds of method are under metal catalyzed conditions
Cross-coupling reaction occurs with aldehyde and obtains benzimidazoles derivative.(document 3:a) Chari, M.A.；Shobha,D.；
Sasaki,T.Tetrahedron Lett.2011,52,5575.b)Bahrami,K.；Khodaei,M.M.；Naali,
F.Synlett.2009,569.c)Sharghi,H.；Aberi,M.；Doroodmand,M.M.Adv.Synth.Catal.2008,
350,2380.).This patent is then by the way that in the case where metallic cobalt is catalyzed, cycloaddition reaction occurs for nitrone itself to prepare benzimidazole
Analog derivative is related to the strong activation of C-H in reaction.This method raw material is cheap and easy to get, easy to operate, mild condition.
Summary of the invention
The present invention relates to a kind of methods for preparing benzimidazoles derivative.
Benzimidazoles derivative is prepared under the catalysis of trivalent cobalt by nitrone
A kind of synthesis step of the benzimidazoles derivative of reaction equation 1.
Specific steps are as follows:
It is reacted in reactor, reactor leads to argon gas displacement three times after vacuumizing.Cobalt salt metal precursor [Cp* is added
Co(CO)I2] (0.025 mM, 10.5 milligrams) and silver salt silver hexafluoroantimonate (0.05 mM, 17.2 milligrams), argon gas displacement
2 milliliters of solvents are added afterwards, stir at room temperature after ten minutes, substrate 1 (0.5 mM) is heated to 120 DEG C and reacts 12 hours.Then
Solvent is transferred with Rotary Evaporators, column chromatography for separation obtains pure products.
The present invention has the following advantages:
1. reactant nitrone is obtained by raw material aldehyde cheap and easy to get, nitrobenzene through simple reaction step
2. the reaction of the benzimidazoles derivative 2 generated only needs a kind of reactant and easy to operate, reaction condition is mild.
Detailed description of the invention
Fig. 1 is one of 1 product spectrogram of embodiment；
Fig. 2 is the two of 1 product spectrogram of embodiment；
Fig. 3 is one of 2 product spectrogram of embodiment；
Fig. 4 is the two of 2 product spectrogram of embodiment.
Specific embodiment
Embodiment 1
It is reacted in 10ml Schlenk reaction tube, reaction tube leads to argon gas displacement three times after vacuumizing after, is added
Cp*Co (CO) I of 5mol% (0.025mmol, 11.9mg)2, 10mol%AgSbF6(0.05mmol, 17.2mg) and 2ml's is molten
Agent 1,2- dichloroethanes stir 10min；Then it is small to be heated to 120 DEG C of reactions 12 by the nitrone 1a of addition 0.5mmol (98.6mg)
When.After reaction, after taking out solvent with Rotary Evaporators, solid is dissolved in methylene chloride loading and carries out silica gel column chromatography, uses stone
Oily ether: the eluant, eluent of ethyl acetate=10:1 (volume ratio) rinses pillar, obtains the white solid benzimidazole derivatess of 57.4mg
Object 2a, separation yield 81%.
The characterize data of 2a is as follows:
1H NMR (400MHz, Acetone) δ 7.64 (d, J=7.8Hz, 1H), 7.48-7.40 (m, 4H), 7.33-7.02
(m,9H)；(spectrogram is shown in Figure of description 1)
13C NMR(101MHz,Acetone)δ152.1,143.2,137.2,130.4,123.0,129.4,129.3,
(128.7,128.2,127.6,123.2,122.7,119.6,110.4. spectrogram is shown in Figure of description 2)
Embodiment 2
It is reacted in 10ml Schlenk reaction tube, reaction tube leads to argon gas displacement three times after vacuumizing after, is added
Cp*Co (CO) I of 5mol% (0.025mmol, 11.9mg)2, 10mol%AgSbF6(0.05mmol, 17.2mg) and 2ml's is molten
Agent 1,2- dichloroethanes stir 10min；Then it is small to be heated to 120 DEG C of reactions 12 by the nitrone 1b of addition 0.5mmol (120.7mg)
When.After reaction, after taking out solvent with Rotary Evaporators, solid is dissolved in methylene chloride loading and carries out silica gel column chromatography, uses stone
Oily ether: the eluant, eluent of ethyl acetate=10:1 (volume ratio) rinses pillar, obtains the yellow oily benzimidazole derivatess of 62.4mg
Object 2b, separation yield 78%.
The characterization number of 2b is as follows:
1H NMR(400MHz,CDCl3)δ7.77–7.63(m,4H),7.38–7.26(m,6H),7.24–7.15(m,3H),
6.33(s,1H),4.39(s,2H),4.21(s,2H),2.92(s,2H),2.42(s,3H),2.18(s,3H)；(spectrogram is shown in explanation
Book attached drawing 3)
13C NMR(100MHz,CDCl3)δ160.4,152.0,140.9,138.5,137.5,134.6,133.0,130.8,
130.5,128.9,127.3,124.3,122.5,118.9,113.7,110.2,55.3,21. (spectrogram is shown in specification to 8,21.3.
Attached drawing 4).
Claims (6)
1. a kind of method for preparing benzimidazoles derivative,
Shown in following formula by nitrone (1) be raw material silver salt and transition metal trivalent cobalt catalysis under synthesizing benzimidazole derivative
(2), reaction equation is as follows:
Wherein Ar1For heteroaryl perfume base or aryl containing hetero atom O or S, aryl is that substituent group is had on phenyl, naphthalene or phenyl ring
Aryl；R1Heteroaryl perfume base or aryl for C1-C10 alkyl, containing hetero atom O or S, aryl are on phenyl, naphthalene or phenyl ring
Aryl with substituent group；
The transition metal trivalent cobalt derives from Cobalt salts [Cp*Co (CO) I2] or [Cp*Co (CO) Cl2], silver salt is hexafluoro antimony
Sour silver or silver trifluoromethanesulfonate；The amount of Cobalt salts and silver salt and the molar ratio of nitrone being added are respectively 0.05:1-0.1:
1。
2. according to the method for claim 1, it is characterised in that:
Specific steps are as follows:
Reactor leads to argon gas displacement after vacuumizing, catalyst cobalt salt, silver salt and solvent is added, then addition nitrone 1, and last 50
Reaction 12h-is for 24 hours at DEG C -120 DEG C；After reaction, take out solvent with Rotary Evaporators, solid be dissolved in methylene chloride loading into
Row silica gel column chromatography obtains benzimidazoles derivative 2.
3. method according to claim 1 or 2, it is characterised in that:
Heteroaryl perfume base containing hetero atom O or S is thienyl or furyl.
4. method according to claim 1 or 2, it is characterised in that: solvent 1,2- dichloroethanes, methylene chloride, toluene, four
One of hydrogen furans, 1,4- dioxane and N,N-dimethylformamide or two kinds or more.
5. method according to claim 1 or 2, it is characterised in that: range of reaction temperature is at 50 DEG C -120 DEG C；Reaction time
For 12 h-24 h.
6. method according to claim 1 or 2, it is characterised in that: the dosage of solvent is 10 ml/mmol nitrones (1) -20
Ml/mmol nitrone (1).
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1847231A (en) * | 2005-04-15 | 2006-10-18 | 沈阳化工研究院 | Process of preparing aromatic ring substituted ixooxazoline compound |
| CN102408376A (en) * | 2011-10-21 | 2012-04-11 | 浙江工业大学 | Synthesis method of tetra-substituted iminazole |
| CN105061304A (en) * | 2015-06-05 | 2015-11-18 | 沈阳科创化学品有限公司 | Method for preparing isoxazoline compound and intermediate thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1847231A (en) * | 2005-04-15 | 2006-10-18 | 沈阳化工研究院 | Process of preparing aromatic ring substituted ixooxazoline compound |
| CN102408376A (en) * | 2011-10-21 | 2012-04-11 | 浙江工业大学 | Synthesis method of tetra-substituted iminazole |
| CN105061304A (en) * | 2015-06-05 | 2015-11-18 | 沈阳科创化学品有限公司 | Method for preparing isoxazoline compound and intermediate thereof |
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