CN105001163B - A kind of synthetic method of four substituted imidazoles - Google Patents
A kind of synthetic method of four substituted imidazoles Download PDFInfo
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- CN105001163B CN105001163B CN201510426231.3A CN201510426231A CN105001163B CN 105001163 B CN105001163 B CN 105001163B CN 201510426231 A CN201510426231 A CN 201510426231A CN 105001163 B CN105001163 B CN 105001163B
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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
- C07D233/64—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 substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Abstract
The invention discloses a kind of synthetic method of four substituted imidazoles, using amidine class and chalcone derivative as raw material, using chlorobenzene as solvent, four substituted imidazoles are synthesized by the reaction of oxidative cyclization as catalyst with ferric trichloride and iodine.There is the inventive method raw material to be easy to get, simple to operate, and reaction condition is gentle, and yield is higher, the advantages of stronger practicality, be suitable for industrialization generation.
Description
Technical field
The present invention relates to a kind of synthetic method of four substituted imidazoles, belong to organic chemistry filed.
Background technology
Imidazoles is a kind of in 1 and 3 five yuan of heteroaromatic structural compounds containing two nitrogen-atoms, using imidazoles as structure
Extensive use of the derivative of primitive in chemistry, pharmacy and industrial circle so that imdazole derivatives turn into nitrogen heterocyclic
Very important class material.Especially four substituted imidazoles find in many natural products and are widely used in functional material
In.Meanwhile, as medicine, agricultural chemicals, dyestuff and with bioactive substance synthesize key intermediate, the application of four substituted imidazoles
It is more and more extensive.In addition, it also has preferable pharmaceutical activity, such as：Four substituted ramification of imidazole have anticancer, antitumor work
Property, analgesia, anti-inflammatory activity, enzyme inhibition, the regulation of cardiovascular and cerebrovascular activity, antifungal activity, antiviral and antiulcer activity,
As the main component of anthelmintic, they are also used as strong, the Cannabined receptor CB1 antagonists of high selectivity.
At present, the synthetic method of four substituted imidazoles is to carry out condensation reaction preparation by 1,2- Determination of Vicinal Diketones and aldehyde and amine, in addition, such as copper
It is catalyzed nitrostyrolene and amidine cycloaddition；Nickel is catalyzed the dehydrogenation reaction of benzyl imines；2- nitrine nitrone and methacrylate
The method such as coupling reaction also have been reported that.But, the method for four substituted imidazoles of existing synthesis all comes with some shortcomings, such as selectivity
Poor, severe reaction conditions, yield are relatively low, raw material is not easy to obtain, the amount of catalyst is more, lack practicality, catalyst complexity etc.
It is not enough.
The content of the invention
It is an object of the invention to provide a kind of technique is simple, reaction condition is gentle, raw material is easily obtained, selectivity is good, real
With the synthetic method of four strong substituted imidazoles of property.
The technical solution adopted by the present invention is as follows：
Structural formula（I）The synthetic method of shown compound,
Wherein, R1Selected from aromatic radical, substituted aromatic base, heterocyclic radical or methyl,
R3And R2Independently selected from aromatic radical or substituted aromatic base,
R4Selected from aromatic radical, substituted aromatic base or heterocyclic radical,
The substitution is alkoxy or the nitro substitution of C1-C4 alkyl, halogen, C1-C4.
Above-mentioned heterocyclic radical is preferably thienyl；Aromatic radical is preferably phenyl.
Above-mentioned synthetic method is with chlorobenzene by the amidine shown in reaction equation, chalcone derivative, ferric trichloride and elemental iodine
Obtain, comprise the concrete steps that for solvent reaction：Amidine, chalcone derivative, ferric trichloride and elemental iodine are added into the circle containing chlorobenzene
In the flask of bottom, 90 ~ 120 are heated tooC, reacts 8 ~ 11h under oxygen atmosphere.Reaction is cooled to room temperature after terminating, with saturation
Hypo solution removes iodine, adds ethyl acetate, then with the brine It of saturation, is removed water with anhydrous sodium sulfate, dense
Ethyl acetate/petroleum ether silica gel column chromatography is used after contracting, yellow product is obtained.
Above-mentioned amidine and the mol ratio of chalcone derivative are 1:1~1:2, the mol ratio of amidine and ferric trichloride and iodine is 1:
0.1:0.05~1:0.3:0.2, the mol ratio of amidine and chlorobenzene is 1:25~1:35.
Above-mentioned reaction temperature is preferably 110oC, the reaction time is preferably 10 hours.
The present invention proposes a kind of letter for being catalyzed amidine and chalcone reaction four substituted imidazoles of synthesis altogether with ferric trichloride and iodine
Folk prescription just cheap synthetic method, this method is bright to have advantages below：
1st, technological process is simple, and reaction condition is gentle, with preferable selectivity, is conducive to industrialized production；
2nd, the present invention used in catalyst be ferric trichloride and iodine, it is cheap and easy to get, be relatively easy to after the completion of reaction remove.
Embodiment
The present invention is described in detail below by embodiment, but the present invention is not limited to these embodiments.
The synthesis of the substituted imidazole of embodiment 1 four：With 1a, 1n is described in detail exemplified by 2a.
1,2,4- triphenyl -5- benzoyl imidazoles（1a）Synthesis
0.6mmol N- phenyl benzenecarboximidamide, 0.5mmol chalcones, 0.01mmol ferric trichlorides and 0.05mmol iodine are added
Enter into the round-bottomed flask of the 25mL containing 2mL chlorobenzenes, be heated to 110oC, 10h is reacted under oxygen atmosphere.Reaction terminates
Afterwards（TLC is monitored）It is cooled to room temperature.Iodine is removed with the hypo solution of saturation, ethyl acetate (15 mL are added in three times
× 3), then with the brine It of saturation, removed water with anhydrous sodium sulfate, ethyl acetate/petroleum ether (1 is used after concentration:5) silicon
Plastic column chromatography, obtains yellow solid 170mg, and yield is 85%.
Characterize data：Mp 183−184 °C;1H NMR (400 MHz,DMSO) δ 7.68 (t, J = 8.5 Hz,
3H), 7.51 – 7.43 (m, 5H), 7.33 (dd, J = 17.8,10.0 Hz, 4H), 7.21 (dd, J =
12.2, 5.9 Hz, 8H); 13C NMR (101 MHz, DMSO) δ 188.20, 149.04, 144.40, 137.73,
136.98, 133.91, 133.56, 129.95, 129.87, 129.66, 129.60, 129.49, 129.44,
129.23, 128.91, 128.71, 128.58, 128.48, 128.15; HRMS Calcd (ESI) m/z for
C28H21N2O: [M+H]+ 401.1654, Found: 401.1660。
1,4- diphenyl -2- thienyl -5- benzoyl imidazoles（1n）Synthesis
By 0.6mmol N- tolylthiophene bases carbonamidine, 0.5mmol chalcones, 0.01mmol ferric trichlorides and 0.05mmol
Iodine is added in the round-bottomed flask of the 25mL containing 2mL chlorobenzenes, is heated to 110oC, 10h is reacted under oxygen atmosphere.Reaction
After end（TLC is monitored）It is cooled to room temperature.Iodine is removed with the hypo solution of saturation, ethyl acetate (15 is added in three times
ML × 3), then with the brine It of saturation, removed water with anhydrous sodium sulfate, ethyl acetate/petroleum ether (1 is used after concentration:5)
Silica gel column chromatography, obtains yellow solid 150mg, and yield is 74%.
Characterize data：Mp 197−198 °C;1H NMR (400 MHz, DMSO) δ 7.64 (dd, J = 12.2,
6.4 Hz, 3H), 7.52 (s, 5H), 7.46 – 7.39 (m, 3H), 7.26 (t, J = 7.5 Hz, 2H),
7.19 (d, J = 3.8 Hz, 3H), 7.01 – 6.95 (m, 1H), 6.63 (d, J = 3.6 Hz, 1H); 13C
NMR (101 MHz, DMSO) δ 187.40, 145.20, 144.66, 137.79, 136.59, 133.72, 133.28,
131.99, 130.30, 129.97, 129.94, 129.48, 129.32, 129.00, 128.80, 128.70,
128.52, 128.28, 128.20, 127.57; HRMS Calcd (ESI) m/z for C26H19N2OS: [M+H]+
407.1218, Found: 407.1204。
1,2,4- triphenyls -5-（2- methyl benzoyls）Imidazoles（2a）Synthesis
By 0.6mmol N- phenyl benzenecarboximidamide, 0.5mmol (2E) -1- (2- aminomethyl phenyls) -3- phenyl -2- acrylic -1-
Ketone, 0.01mmol ferric trichlorides and 0.05mmol iodine are added in the round-bottomed flask of the 25mL containing 2mL chlorobenzenes, are heated to
110 oC, 10h is reacted under oxygen atmosphere.After reaction terminates（TLC is monitored）It is cooled to room temperature.With the sodium thiosulfate of saturation
Solution removes iodine, and ethyl acetate (15 mL × 3) is added in three times, then with the brine It of saturation, is removed with anhydrous sodium sulfate
Water, uses ethyl acetate/petroleum ether (1 after concentration:5) silica gel column chromatography, obtains yellow solid 166mg, and yield is 80%.
Characterize data：Mp 141−142 °C;1H NMR (400 MHz, DMSO) δ 7.48 – 7.45 (m, 2H),
7.42 – 7.32 (m, 10H), 7.31 – 7.29 (m, 1H), 7.24 – 7.17 (m, 4H), 7.07 (d, J =
7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 2.31 (s, 3H); 13C NMR (101 MHz, DMSO) δ
189.13, 149.21, 146.03, 138.29, 138.11, 137.17, 133.68, 131.97, 131.33,
130.92, 130.75, 129.83, 129.66, 129.54, 129.33, 129.26, 128.69, 128.62,
128.45, 128.30, 128.20, 125.81, 20.22; HRMS Calcd (ESI) m/z for C29H23N2O: [M+
H]+ 415.1810, Found: 415.1788。
Claims (7)
1. structural formula（I）The synthetic method of shown compound, it is characterised in that：
Wherein, R1Selected from aromatic radical, substituted aromatic base, heterocyclic radical or methyl,
R3And R2Independently selected from aromatic radical or substituted aromatic base,
R4Selected from aromatic radical, substituted aromatic base or heterocyclic radical,
The substitution is alkoxy or the nitro substitution of C1-C4 alkyl, halogen, C1-C4.
2. synthetic method according to claim 1, it is characterised in that：The heterocyclic radical is thienyl.
3. synthetic method according to claim 1, it is characterised in that：The aromatic radical is phenyl.
4. the synthetic method according to claim 1-3 is one of any, it is characterised in that：By the amidine shown in reaction equation, Cha Er
Ketone derivatives, ferric trichloride and elemental iodine are obtained by solvent reaction of chlorobenzene.
5. synthetic method according to claim 4, it is characterised in that：Reaction temperature is 90 ~ 120oC, under oxygen atmosphere
Reaction, reaction is cooled to room temperature after terminating, and removes iodine with the hypo solution of saturation, adds ethyl acetate, then with full
The brine It of sum, is removed water with anhydrous sodium sulfate, and ethyl acetate/petroleum ether silica gel column chromatography is used after concentration, obtains yellow production
Thing.
6. synthetic method according to claim 4, it is characterised in that：Described amidine and the mol ratio of chalcone derivative are
1:1~1:2, the mol ratio of amidine and ferric trichloride and iodine is 1:0.1:0.05~1:0.3:0.2.
7. synthetic method according to claim 4, it is characterised in that：Reaction temperature is preferably 110oC, the reaction time is preferred
For 10 hours.
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