CN106045914A - Method for synthesizing tri-substituted imidazole compounds - Google Patents
Method for synthesizing tri-substituted imidazole compounds Download PDFInfo
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- CN106045914A CN106045914A CN201610400867.5A CN201610400867A CN106045914A CN 106045914 A CN106045914 A CN 106045914A CN 201610400867 A CN201610400867 A CN 201610400867A CN 106045914 A CN106045914 A CN 106045914A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/84—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention belongs to the technical field of organic synthetic chemistry, and relates to a method for synthesizing tri-substituted imidazole compounds from isonitrile easy to obtain under catalysis of silver carbonate. The tri-substituted imidazole compounds are prepared from aryl isonitrile and functional group isonitrile in a solvent at a certain reaction temperature. Under the protection of nitrogen, silver carbonate is used as a catalyst, and the reaction temperature is 80 DEG C; the solvent can be selected from dichloromethane, 1,4-dioxane, tetrahydrofuran and dimethyl sulfoxide and is preferably 1,4-dioxane. The method is simple to operate, raw materials and reagents are easy to obtain, conditions are mild, products are easy to separate and purify, and the method is applicable to synthesis of various multi-substituted imidazole compounds, is especially suitable for large-scale industrial production and can be used for preparing the tri-substituted imidazole compounds at high yield efficiently.
Description
Technical field
The invention belongs to technical field of organic synthetic chemistry, be specifically related to a kind of one-step synthesis tri-substituted imidazoles
Method.
Technical background
Imidazoles is the heterocyclic compound that a class is important, is many bioactive natural products, drug molecule and function material
The key structural elements of material.As the pharmacophoric group that a class of drug molecule is important, imidazoles has treatment use widely, as anti-
Cancer, anti-HIV are viral, antibacterial, other is medicinal for antiinflammatory, antiallergic, glucagon receptor antagonist etc..Additionally, imidazoles is in conduct
Metalloenzyme and the part of transition-metal catalyst, organic reaction catalyst, the receptor in supramolecular chemistry reaction, ionic liquid
Body, the synthesis aspect of natural product play the effect of key.Due to extensive at pharmaceutical chemistry and other field of polysubstituted imidazoles
Application, the research of its synthetic method be constantly subjected to the attention of people (Med. Res. Rev.2014, 34, 340; J. Med. Chem.1998, 41, 4744; Nature1994, 372, 739.).
The method of synthesis imidazoles has a lot, common such as 1) Bredereck imidazoles synthetic method, with α-diketone or Alpha-hydroxy
Ketone and Methanamide condensation and cyclization obtain substituted imidazoles, 2) alkali promotes p-toluenesulfonyl methyl isocyanide and aldimine or Asia
The ring-closure reaction of amine acyl chlorides.Up to the present, transition metal-catalyzed isonitrile is directly synthesized miaow with [3+2] cycloaddition reaction of isonitrile
The report of azole compounds only has 3 examples.It is the dimerization cyclization method of the silver catalysis isonitrile of Grigg seminar report respectively,
Yamamoto seminar in the crossed loops additive reaction of Red copper oxide/triphenyl phosphine catalyst aryl isonitrile Yu methyl isocyanide, and
Hong seminar utilizes NHC-copper to make catalyst by isonitrile range expansion to phenyl isonitrile.But, the product of this three example report synthesis
Thing is all 1,4-disubstituted imidazole.
Aryl isonitrile and [3+2] cycloaddition reaction of isonitrile are the sides of an easy synthesis tri-substituted imidazoles
Method, and be first from two kinds of different isonitrile of raw material simple and easy to get, by 1,2-migration directly obtains trisubstituted
Glyoxaline compound.This reaction meets Atom economy, it is possible to efficiently, simply synthesize the imidazoles type with highly functional
Compound.Break away from and synthesize defect in the past: need to use highly basic and high temperature, often have by-product to produce such as acid.
Develop commercial materials synthesis complicated molecule cheap and easy to get, always be vitochemical important research direction.Different
Nitrile molecule, through participating in organic chemical reactions frequently as a class active molecule, is used for efficiently synthesizing some containing nitrogen molecular or heterocycle
Compound, its reaction participated in often has the advantages such as high chemistry, region, stereo selectivity and higher Atom economy
(Chem. Rev., 2015, 115, 2698.).Meanwhile, the structure of isonitrile is similar with carbon monoxide, be important C1 source and
There is strong metal-complexing ability, it is possible to be actively engaged in some transition metal-catalyzed reactions.Up to the present, aryl isonitrile
Reaction with isonitrile synthesis tri-substituted imidazoles yet there are no document report.
Summary of the invention
It is an object of the invention to aryl isonitrile and sulfonyloxy, acyloxy and the substituted isonitrile reaction system of carbamoyl
[3+2] type cycloaddition reaction of standby trisubstituted azoles method, such as, uses two kinds of isonitrile simple, that be easy to get to exist
Under conditions of gentleness, direct reaction, one-step synthesis tri-substituted imidazoles, it is provided that a kind of cheap, atom economy
Synthetic method, synthesizes the glyoxaline compound of highly functional more simply, efficiently.
The present invention provides the preparation method of the glyoxaline compound of a kind of highly functional.In the present invention, we are first
Develop the cycloaddition reaction of a kind of two kinds of different isonitrile, be prepared for a series of three substituted azole compounds.
The glyoxaline compound of synthesis highly functional involved in the present invention, its reaction equation is as follows:
Including one aryl isonitrile 1 and functional group's isonitrile 2 are heated to 80 DEG C in nonaqueous solvent reaction obtain trisubstituted pyrrole
Coughing up compounds 3, wherein, TG is sulfonyloxy, acyloxy, carbamoyl, and R is alkyl, phenyl, ester group, thiazolinyl, aryl.
Highly purified tri-substituted imidazoles can be efficiently obtained by by the inventive method.
The preparation method of the tri-substituted imidazoles of the present invention includes that aryl isonitrile is anti-with the cyclization of functional group isonitrile
Should.
Detailed process can be expressed as follows:
(1) in certain reaction temperature and solvent, aryl isonitrile 1 and functional group's isonitrile 2 tri-substituted imidazole class chemical combination is prepared
Thing 3.
The consumption of functional group's isonitrile 2 is 1.2 times of aryl isonitrile consumption, under nitrogen protection, uses Disilver carbonate as urging
Agent, reaction temperature is 80 ° of C.Solvent can select dichloromethane, Isosorbide-5-Nitrae-dioxane, oxolane, dimethyl sulfoxide, its
In best with 1,4-dioxane.
The present invention has simple to operate, and raw material and reagent are easy to get, mild condition, the easily separated purification of product, it is adaptable to synthesis
Various polysubstituted glyoxaline compounds, are particularly well-suited to large-scale commercial production, can prepare three replacements efficiently, with high yield
Glyoxaline compound.
Accompanying drawing explanation
Fig. 1 is imidazoles 3a's1The nuclear magnetic resoance spectrum of H-NMR；
Fig. 2 is imidazoles 3a's13The nuclear magnetic resoance spectrum of C-NMR；
Fig. 3 is imidazoles 3i's1The nuclear magnetic resoance spectrum of H-NMR；
Fig. 4 is imidazoles 3i's13The nuclear magnetic resoance spectrum of C-NMR.
Detailed description of the invention
The following examples will assist in the explanation present invention, but does not limit to its scope.
Embodiment 1
The preparation of imdazole derivatives 3a
P-bromophenyl isonitrile 1a(109.2 mg, 0.6mmol is added in the 10 mL pressure pipes with magnetic stirring apparatus,
1.2 equiv), p-toluenesulfonyl isonitrile (103.1 mg, 0.5 mmol, 1.0 equiv) and Disilver carbonate (27.6 mg, 10
Mol%), stir and be filled with three nitrogen protections, adding Isosorbide-5-Nitrae-dioxane (2 mL) by syringe.At 80 DEG C of oil
Reacting 1 hour in bath, TLC detection substrate disappears, and reaction terminates.Question response liquid is cooled to room temperature, 35 after filtering with silica gel
Degree Celsius decompression distillation obtain mixture, obtain white solid through silica gel column chromatography (eluent is petroleum ether, ethyl acetate)
161.0 mg, turn out to be imdazole derivatives 3a through NMR, MS, and its yield is 82%.
Spectrum elucidation data 3a:
1H-NMR (500 MHz, CDCl3) δ = 7.48 (d, J = 8.5 Hz, 2H), 7.43 (s, 1H), 7.30
(d, J = 8.5 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 2.67
(s, 3H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3) δ =147.09, 144.42, 140.34,
138.75, 133.84, 131.94, 129.51, 129.45, 127.12, 126.53, 123.93, 21.56, 14.96。
Embodiment 2
Replacing the 1e in example 1 with 1i, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 3i:
1H NMR (500 MHz, CDCl3) δ = 8.00 (d, J = 8.5 Hz, 2H), 7.49 (s, 1H), 7.29
(d, J = 8.5 Hz, 2H), 7.15 (dd, J = 13.0, 8.5 Hz, 2H), 4.42 (q, J = 7.0 Hz,
1H), 2.68 (s, 3H), 2.37 (s, 3H), 1.42 (t, J=7.0, 3H); 13C NMR (125 MHz, CDCl3)
δ = 165.24, 147.16, 144.40, 140.19, 138.59, 138.43, 131.57, 129.94, 129.48,
127.75, 126.97, 126.43, 61.46, 21.50, 14.91, 14.21。
Embodiment 3
Replacing the 1e in example 1 with 1j, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 3j:
1H NMR (500 MHz, DMSO) δ = 8.29 (d, J = 8.0 Hz, 2H), 8.07 (s, 1H), 7.48
(d, J = 8.5 Hz, 2H), 7.34 (dd, J = 21.1, 7.5 Hz, 4H), 2.54 (s, 3H), 2.36 (s,
3H);13C NMR (125 MHz, DMSO) δ 147.77, 146.53, 144.59, 141.96, 140, 03, 138.30,
130. 01, 129.28, 126.63, 125.49, 123.99, 21.09, 14.66。
Embodiment 4
Replacing the 1e in example 1 with 1q, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 3j:
1H NMR (500 MHz, CDCl3) δ = 7.71 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 7.0
Hz,, 1H), 7.53 (td, J = 7.5, 3.5 Hz, 1H), 7.46-7.41 (m, 4H0, 7.24 (dd, J =
6.5. 0.5 Hz, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.5 Hz, 2H), 6.71
(d, J = 16.0 Hz, 1H), 6.64 (d, J = 16.0 Hz, 1H), 2.71 (s, 3H), 2.12 (s, 3H);13C NMR (125 MHz, CDCl3) δ = 189.54, 146.80, 144.47, 140.65, 138.35, 137.34,
133.95, 133.30, 132.96, 130.57, 130.47, 130.26, 129.41, 128.60, 128.37,
127.65, 127.25, 126.86, 124.57, 21.35, 14.97。
Embodiment 5
Replacing the methyl isocyanide in example 1 with benzyl isonitrile, other conditions are with example 1, and experimental result is shown in Table 1.
Spectrum elucidation data 3t:
1H NMR (500 MHz, CDCl3) δ = 7.49-7.46 (m, 5H), 7.34 (t, J = 7.5 Hz, 2H),
7.27- 7.24 (m, 2H), 7.08 (dd, J = 8.5 Hz, 4H), 6.93 (d, J = 8.5 Hz, 2H), 4.47
(s, 2H), 2.36 (s, 3H);13C NMR (125 MHz, CDCl3) δ = 149.43, 144.46, 140.83,
139.10, 138.40, 133.67, 131.93, 129.63, 129.43, 129.29, 128.49, 127.32,
126.41, 124.05, 34.34, 21.58。
Embodiment 6
Replace the substituted isonitrile of tolysulfonyl chloro in example 1 with the substituted isonitrile of acyloxy, other conditions with example 1,
Experimental result is shown in Table 1.
Spectrum elucidation data 4a:
1H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.5 Hz,
2H), 7.70 (s,1H), 7.64 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.0 Hz, 4H), 4.41
(q, J = 7.0 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.5 Hz,3H), 1.04
(t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ = 166.51, 159.83, 147.91,
140.61, 137.92, 135.94, 132.34, 130.17, 129.35, 129.07, 127.72, 123.05,
120.67, 61.10, 61.04, 14.37, 13.69。
Embodiment 7
The substituted isonitrile of p-toluenesulfonyl in example 1, the same example of other conditions is replaced with the substituted isonitrile of carbamoyl
1, experimental result is shown in Table 1.
Spectrum elucidation data 4e:
1H NMR (500 MHz, CDCl3) δ 7.58-7.55 (m, 3H), 7.31 (d, J = 7.0 Hz, 2H),
7.27 (d, J = 3.0 Hz, 1H), 7.24-7.21 (m, 3H), 7.16 (t, J = 7.0 Hz, 1H), 4.02
(s, 2H), 3.38 (t, J = 7.0 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H), 1.70 (t, J = 7.0
Hz, 1H), 1.52 (t, J = 7.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ = 161.13,
142.09, 139.44, 135.89, 135.29, 132.92, 128.84, 128.34, 126.18, 124.61,
124.37, 121.84, 47.40, 45.48, 34.21, 25.38, 24.10。
Claims (2)
1. a synthetic method for tri-substituted imidazoles, is characterized in that its reaction equation is as follows:
Being prepared tri-substituted imidazoles 3 by aryl isonitrile 1 and functional group's isonitrile 2, functional group's isonitrile 2 is aryl isonitrile 1
1.2 times of quality consumption, under nitrogen protection, use Disilver carbonate as catalyst, and reaction temperature is 80 ° of C, and solvent selects dichloro
Methane, 1,4-dioxane, oxolane, dimethyl sulfoxide one of them.
2., according to the synthetic method of a kind of tri-substituted imidazoles described in claim 1, it is characterized in that its reactional equation
Formula is as follows:
Concrete steps: add p-bromophenyl isonitrile 1a109.2 mg in the 10 mL pressure pipes with magnetic stirring apparatus,
0.6mmol, 1.2 equiv, p-toluenesulfonyl isonitrile 103.1 mg, 0.5 mmol, 1.0 equiv and Disilver carbonate 27.6
Mg, 10 mol%, stir and be filled with three nitrogen protections, adding Isosorbide-5-Nitrae-dioxane 2 mL by syringe, at 80 DEG C
In oil bath pan react 1 hour, TLC detection substrate disappear, reaction terminates, and question response liquid is cooled to room temperature, with silica gel filter after
35 degrees Celsius of decompression distillations obtain mixture, are that petroleum ether, the silica gel column chromatography of ethyl acetate obtain white through eluent solid
Body 161.0 mg, through NMR, to obtain MS be imdazole derivatives 3a, and its yield is 82%.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111592497A (en) * | 2020-05-29 | 2020-08-28 | 浙江农林大学暨阳学院 | Method for preparing N-phenyl-4-benzenesulfonyl imidazole compound by copper catalysis |
| CN111825594A (en) * | 2020-08-18 | 2020-10-27 | 商丘师范学院 | (Z) -beta-trifluoromethyl dehydrotryptophan compound and synthetic method and application thereof |
| CN115536592A (en) * | 2022-09-28 | 2022-12-30 | 江苏建筑职业技术学院 | Synthesis method of 2,3, 5-trisubstituted imidazole derivative |
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| CN103145600A (en) * | 2013-03-06 | 2013-06-12 | 东北师范大学 | Synthesis method of silver-catalyzed polysubstitued pyrrole compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103145600A (en) * | 2013-03-06 | 2013-06-12 | 东北师范大学 | Synthesis method of silver-catalyzed polysubstitued pyrrole compounds |
Non-Patent Citations (3)
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| CHIKASHI KANAZAWA ET AL.,: "Synthesis of Imidazoles through the Copper-Catalyzed Cross-Cycloaddition between Two Different Isocyanides", 《J. AM. CHEM. SOC.》 * |
| JIANQUAN LIU ET AL.,: "Silver-Catalyzed Isocyanide-Alkyne Cycloaddition: A General and Practical Method to Oligosubstituted Pyrroles", 《ANGEW. CHEM. INT. ED.》 * |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111592497A (en) * | 2020-05-29 | 2020-08-28 | 浙江农林大学暨阳学院 | Method for preparing N-phenyl-4-benzenesulfonyl imidazole compound by copper catalysis |
| CN111825594A (en) * | 2020-08-18 | 2020-10-27 | 商丘师范学院 | (Z) -beta-trifluoromethyl dehydrotryptophan compound and synthetic method and application thereof |
| CN111825594B (en) * | 2020-08-18 | 2022-03-29 | 商丘师范学院 | (Z) -beta-trifluoromethyl dehydrotryptophan compound and synthetic method and application thereof |
| CN115536592A (en) * | 2022-09-28 | 2022-12-30 | 江苏建筑职业技术学院 | Synthesis method of 2,3, 5-trisubstituted imidazole derivative |
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