CN115894378A - Method for synthesizing imidazole derivative by cyclizing methyl ketone, benzylamine and ammonium iodide through [2+ 1] - Google Patents
Method for synthesizing imidazole derivative by cyclizing methyl ketone, benzylamine and ammonium iodide through [2+ 1] Download PDFInfo
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Abstract
The invention discloses a method for preparing ammonium iodide and K 2 S 2 O 8 Under the existence of the solvent DMSO, [2+ 1] between methyl ketone, benzylamine and ammonium iodide]A process for the preparation of imidazoles by cyclization wherein two molecules of acetophenone are provided having 3 carbon atoms in the product imidazole ring and benzylamine and the ammonium salt are each provided having one nitrogen atom in the product imidazole ring. In the product imidazole molecule, a 1-site nitrogen atom and a connected benzyl group are from raw material benzylamine, a 3-site nitrogen atom is provided by inorganic ammonium salt, and raw material methyl ketone provides three carbon atoms at 2,4,5 sites and substituents connected on the carbon atoms at 2,5 sites. The method is applicable to most methyl ketone derivatives. The method for preparing the imidazole has the advantages of wide and easily-obtained raw materials, environmental protection, low price and simple operation, and is beneficial to industrial production.
Description
Technical Field
The invention relates to a preparation method of an imidazole derivative, in particular to a method for preparing an imidazole derivative in ammonium iodide and K 2 S 2 O 8 In the presence of DMSO solvent, methyl ketone and benzylamine react to generate imidazole, belonging to the field of organic synthesis.
Background
Imidazole building blocks are widely present in natural products and drug molecules, such as ketoconazole, etomidate, dexmedetomidine, econazole, nilotinib, and the like. In addition, imidazole compounds are also widely used in functional materials and catalysts. Therefore, the synthesis of imidazole compounds has attracted the attention of the researchers. The Radziszewski reaction is the most classical method for the synthesis of imidazoles. The method uses 1, 2-dicarbonyl compound, ammonia and aldehyde as raw materials to synthesize the imidazole compound through cyclization by [2+1 ]. The reaction requires a substrate of a specific structure, which greatly limits its wide use. Therefore, the cyclizing synthesis of imidazole compounds by means of simple and readily available substrates has received attention from chemists.
Ketone and amine compounds are widely used as the most common reaction raw materials in various cyclization reactions. In recent years, the synthesis of imidazoles by cyclization reactions involving ketones and amines has attracted a great deal of attention from chemists. In 2016, the literature reports a cyclization reaction between methyl ketone, aromatic amine and p-toluenesulfonyl methyl isocyanide mediated by molecular iodine [2+ 1] to synthesize 1,2, 5-trisubstituted imidazole. In this reaction, one molecule of methyl ketone serves as the C2 donor, one molecule of methyl ketone serves as the C1 donor, aniline serves as the N1 donor, and p-toluenesulfonylmethyl isocyanide serves as the N1 donor. However, the starting material p-toluenesulfonylmethylisocyanide is not a common material and fatty amines are not suitable for this reaction.
In recent years, the cyclization of ketones and aliphatic amines has also been studied for the synthesis of imidazoles. In 2017, the literature reports a sodium nitrite-promoted cyclization reaction between methyl ketone and benzylamine [2+1 ]. The reaction takes oxygen as an oxidant and benzonitrile as a solvent to synthesize the 1,2, 4-trisubstituted imidazole at 80 ℃. In this reaction, methyl ketone serves as the C2 donor, one molecule of benzylamine serves as the C1N1 donor, and one molecule of benzylamine serves as the N1 donor. However, aromatic amines are not suitable for this reaction.
In 2018, the literature reports Cu (OTf) 2 And I 2 As catalyst, chalcone and benzylamine as raw materials, toluene as solvent, through [2+1+]The cyclization reaction synthesizes 1,2, 4-trisubstituted imidazole. In this reaction, chalcone acts as a C2 donor, one molecule of benzylamine acts as a C1N1 donor, and one molecule of benzylamine acts as an N1 donor. However, aromatic amines are not suitable for this reaction.
In the same year, the literature reports a form of KHCO 3 In the presence of oxygen as oxidant, the sulfur promotes [2+ 1] between ketone and fatty amine]Cyclization to synthesize the tetra-substituted imidazole. In this reaction, one ketone serves as the C2 donor, one molecule of the aliphatic amine serves as the C1N1 donor, and one molecule of the aliphatic amine serves as the N1 donor. Aliphatic amines with low boiling points are not suitable for this reaction, such as ethylamine. Also aromatic amines are not suitable for this reaction.
In 2018, the literature also reports a cyclization reaction between methyl ketone and amine [2+1 ]. The reaction synthesizes 1,2, 4-trisubstituted imidazole by an electrochemical oxidation method. In this reaction, methyl ketone serves as the C2 donor, a fatty amine serves as the C1N1 donor, and another molecule of amine serves as the N1 donor. In the above reaction for synthesizing imidazole by cyclization of ketone and aliphatic amine, all reactions start from one molecule of ketone and two molecules of amine, and the formed product is 1,2, 4-trisubstituted imidazole or tetrasubstituted imidazole.
The above methods for synthesizing imidazole by small molecule cyclization have either difficulty in raw material source, or use toxic solvent, or reaction conditions are not suitable for industrial production, or the reaction itself has some insurmountable limitations, such as: special requirements on the structure of raw materials, low reaction yield and the like.
Disclosure of Invention
Aiming at the defects of difficult obtainment of used raw materials, harsh reaction conditions and poor reaction compatibility in the conventional method for synthesizing imidazole by cyclization of small molecules, the invention aims to provide a method for synthesizing imidazole by using K 2 S 2 O 8 Is oxidant, DMSO is solvent, [2+ 1] between methyl ketone, benzylamine and ammonium salt]The method for synthesizing the imidazole in high yield by cyclizing one pot has the advantages of wide and easily obtained raw material source, environmental protection, low price and simple operation, and is beneficial to industrial production.
In order to achieve the technical purpose, the invention provides a reaction for selectively synthesizing imidazole in a [2+ 1] cyclization region between methyl ketone, benzylamine and ammonium salt by taking K2S2O8 as an oxidant and DMSO as a solvent, wherein a nitrogen atom at the 1 position and a connected benzyl group in a product imidazole molecule are from raw benzylamine, a nitrogen atom at the 3 position are provided by inorganic ammonium salt, and raw methyl ketone provides three carbon atoms at the 2,4,5 positions and a substituent connected to the carbon atom at the 2,5 position. The method is applicable to most methyl ketone derivatives.
The methyl ketone has the structure of formula 1:
the imidazole derivative has the structure of formula 2:
in the formula 1, R is an aromatic ring or a hydrocarbon group containing tertiary carbon atoms. The aromatic ring may be phenyl, naphthalene, furan, pyrrole, thiophene, pyridine, quinoline, or substituted derivatives thereof. The substituents on the aromatic ring may contain 1 to 3 substituents, preferably one substituent. The position of the substituent is not limited, and may be ortho, meta or para. The substituents may be selected from benzene, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, fluorine, chlorine, bromine, amino, dimethylamino, trifluoromethyl, alkoxy, methylthio or methoxycarbonyl, ethoxyacyl.
It has been found that this reaction requires the simultaneous presence of an inorganic ammonium salt and an iodide ion, the preferred inorganic salt being NH 4 I; the reaction solvent is DMSO, and the DMSO is used as both the solvent and the oxidant in the reaction process; perdithio sulfideThe acid salt is also necessary for the formation of the reaction product, the preferred peroxodisulfate salt being K 2 S 2 O 8 。
Methyl ketone, benzylamine, ammonium iodide, K 2 S 2 O 8 The molar ratio of (a) affects the reaction yield, and the preferred ratio is 2.
In a preferred embodiment, the reaction conditions are as follows: reacting for 20-120 min at 80-160 ℃ in air or oxygen atmosphere. In a more preferred embodiment, the reaction conditions are as follows: the reaction was carried out at 140 ℃ for 60min under an air atmosphere.
The method for synthesizing imidazole provided by the invention has the following reaction equation:
the reaction principle of the above reaction can be illustrated by reacting acetophenone with phenethylamine to produce a (1-benzyl-5-phenylimidazol-2-yl) phenyl methanone (1) compound: first, the iodide ion is covered by K 2 S 2 O 8 Oxidized into iodine simple substance. Then the acetophenone generates alpha-iodo acetophenone A under the action of iodine simple substance. Alpha-iodoacetophenone a is further oxidized by Kornblum to give benzoylaldehyde B under the action of DMSO. The benzoyl formaldehyde B reacts with benzylamine and ammonium salt respectively to generate imine C 1 And imine C 2 . Subsequent imine C 1 And imine C 2 Cyclization to form D, which is dehydrated by aromatization to form the final product (1-benzyl-5-phenylimidazol-2-yl) phenyl methanone (1).
Intermediates A, B, C 1 、C 2 D can be detected from the reaction system, and products can be obtained under the reaction conditions starting from the intermediates A and C, or B and C, respectively.
When the other substituent of the methyl ketone has an alpha-hydrogen, the desired product cannot be obtained.
Compared with the existing synthesis method and technology, the invention has the following advantages and effects:
1) The invention firstly provides a reaction for synthesizing imidazole from methyl ketone, aniline and inorganic ammonium;
2) The invention adopts simple and common methyl ketone, aniline, inorganic ammonium and solvent DMSO which are common chemicals, has wide raw material source and low cost, and meets the requirement of industrial production;
3) The reaction process of the invention has short reaction time and high product yield, and is suitable for industrial production;
4) Toxic raw materials, solvents and additives are not used in the reaction process, special reaction conditions are not needed, and the method meets the requirements of environmental protection;
5) The synthesis process of the invention adopts a one-pot reaction, and has the advantages of few reaction steps and simple operation.
Detailed Description
The present invention will be further specifically described in detail with reference to specific examples, but the embodiments of the present invention are not limited thereto, and may be performed with reference to conventional techniques for process parameters not specifically mentioned.
All reactions were performed in Schlenk tubes unless otherwise noted.
All reaction starting solvents were obtained from commercial sources and used without further purification.
The product is separated by a silica gel chromatographic column and silica gel (the granularity is 300-400 meshes).
1H NMR (400 MHz) and 13C NMR (100 MHz) measurements were performed using a Bruker ADVANCE III spectrometer with CDCl3 as the solvent and TMS as the internal standard with chemical shifts in parts per million (ppm) and 0.0ppm for tetramethylsilane as the reference shift. The following abbreviations (or combinations thereof) are used to explain the multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Coupling constant J is given in Hertz (Hz). Chemical shifts are expressed in ppm, with the center line for the triplet state referenced to deuterated chloroform at 77.0ppm or the center line for the heptad state referenced to deuterated DMSO at 39.52 ppm.
1. Condition optimization experiment:
we systematically optimized the conditions for this reaction using acetophenone and benzylamine as template substrates. We examined the influence of the kind and amount of ammonium salt, the kind and amount of oxidizing agent, reaction solvent, reaction temperature and reaction time on the reaction.
1.1 screening of the type and amount of ammonium salt
First, we investigated the effect of the type and amount of ammonium salt on the reaction, and the results are shown in Table 1.1. The reaction gave the desired product (1-benzyl-5-phenylimidazol-2-yl) phenyl methanone (1) in 71% yield when NH4I was used as ammonium salt, but no NH was added to the reaction 4 No product was obtained at I. We next screened for other ammonium salts, such as NH 4 Br, NH4Cl and NH 4 OAc, but none of them can obtain the target product. This result indicates that ammonium iodide plays a crucial role in this reaction. Further, we used KI/NH 4 Substitution of OAc for NH 4 I, the reaction was able to take place but the reaction yield decreased, 61% yield. Therefore we use NH 4 I as the ammonium salt of the reaction. Next we are dealing with NH 4 The dosage of I is screened. When the amount of NH4I was 0.5mmol, the yield of the desired product was 65%. Increase of NH 4 When the amount of I is 1.0mmol, the reaction effect is best, and the yield of the target product is 71%. Further increase of NH 4 The yield of the reaction is not increased by the amount of I. Therefore, we chose NH 4 The amount of I used was 1.0mmol.
TABLE 1.1 screening of ammonium salt type and amount a
1.2 selection of the type and amount of oxidizing agent
In determining NH 4 After I is the ammonium salt of the reaction and the amount is 1.0mmol, we further worked up for the reactionThe type and amount of the oxidant were selected and the results are shown in Table 1.2. When K is 2 S 2 O 8 When the compound is used as an oxidizing agent for the reaction, the reaction is most effective, and the yield of the objective product is 71%. Other oxidants, e.g. Na 2 S 2 O 8 And (NH) 4 ) 2 S 2 O 8 It is also applicable to this reaction, but none of them improves the yield of this reaction. H 2 O 2 And TBHP were also used for this reaction tentatively, but neither reaction could proceed. Therefore, we chose K 2 S 2 O 8 As the optimal oxidant for this reaction. In determining K 2 S 2 O 8 As an oxidant for this reaction, we further investigated K 2 S 2 O 8 Influence of the amount on the reaction. When K is 2 S 2 O 8 The yield of the reaction was 71% at 0.5mmol. Reduction of K 2 S 2 O 8 When the amount was 0.25mmol, the reaction yield decreased to 53%. Increase of K 2 S 2 O 8 When the amount was 1mmol, the reaction yield was also reduced to 65%. Therefore, we chose K 2 S 2 O 8 The amount used was 0.5mmol.
TABLE 1.2 selection of oxidant type and amount a
1.3 screening of reaction solvent
Next, we screened the solvent of the reaction systematically and the results are shown in Table 1.3. When DMSO was used as solvent, the reaction gave the desired product in 71% yield. Subsequently, we tried to use toluene, DMF, acetonitrile and 1, 4-dioxane as solvents, and none of the reactions gave the desired product, indicating that DMSO plays a crucial role in the reaction. Therefore, we chose DMSO as the solvent for the reaction.
TABLE 1.3 screening of reaction solvents a
1.4 screening of reaction temperature
After determining the above conditions, we examined the effect of the reaction temperature on the reaction, and the results are shown in table 1.4. The reaction gave the desired product in 71% yield when the reaction temperature was 120 ℃. When the reaction temperature was lowered to 100 ℃, the reaction yield of the reaction was reduced to 60%. When the reaction temperature is increased to 140 ℃, the reaction effect is improved, and the reaction yield is 77%. Next, we continued to raise the reaction temperature to 160 ℃ but the reaction yield decreased. Therefore, we chose 140 ℃ as the optimal reaction temperature for the reaction.
TABLE 1.4 screening of reaction temperatures a
1.5 screening of reaction time
Finally, we investigated the effect of reaction time on the reaction and the results are shown in Table 1.5. When the reaction time is within 1 hour, the reaction yield increases with the increase of the reaction time, and at 1 hour, the reaction yield reaches the highest value of 77%, and the reaction time is further prolonged, and the yield of the target product does not increase any more. Therefore, we chose the reaction time for this reaction to be 1 hour.
TABLE 1.5 screening of reaction time a
In summary, based on the above optimization results, we determined the optimal conditions for synthesizing imidazole by reacting ketone, amine and ammonium salt: ketones (1.0 mmol)Amine (0.5 mmol), NH 4 I(1.0mmol)，K 2 S 2 O 8 (0.5 mmol), DMSO (2.0 mL), 140 deg.C, air, 1h.
2. Carrying out the process
To a 25mL Schlenk reaction tube was added 2.0mL of dimethyl sulfoxide (DMSO), followed by the sequential addition of K 2 S 2 O 8 (0.5mmol,1.0equiv)，NH 4 I (1.0mmol, 2.0equiv), methyl ketone (1.0mmol, 2.0equiv) and benzylamine (0.5 mmol). The reaction mixture was reacted at 140 ℃ for 1 hour. After the reaction was completed, it was cooled to room temperature, diluted with 10mL of ethyl acetate, transferred to a separatory funnel, 10mL of saturated saline was added, the reaction solution was extracted, the upper organic phase was taken, repeated 3 times, and then anhydrous Na was added 2 SO 4 Drying, evaporating solvent under reduced pressure, and separating the crude product by column chromatography using 200-300 mesh silica gel with PE/EA as eluent. And (5) characterizing the separated product.
3. Effects of the implementation
The results of the reactions carried out according to the preceding embodiments, using different methyl ketones, are given in Table 3.1.
TABLE 3.1 Effect of different methyl ketones
Reaction conditions were methyl ketone (1.0 mmol), benzylamine (0.5 mmol), NH 4 I(1.0mmol)，K 2 S 2 O 8 (0.5 mmol), DMSO (2.0 mL), 140 deg.C, air, reaction time 1 hour.
4. Hydrogen and carbon spectra of partial products
(1-benzyl-5-phenylimidazol-2-yl) phenyl methanone
(1-benzyl-5-phenyl-1H-imidazol-2-yl)(phenyl)methanone(1)
Yellow solid, melting point: 113.8-116.2 ℃. Yield 77%,130.3mg. 1 H NMR(400MHz,CDCl 3 ):δ8.19(d,J＝7.7Hz,2H),7.57(t,J＝7.2Hz,1H),7.48(t,J＝7.5Hz,2H),7.42(d,J
[ 1-benzyl-5- (4-methylphenyl) imidazol-2-yl ] (4-methylphenyl) methanone
(1-benzyl-5-(p-tolyl)-1H-imidazol-2-yl)(p-tolyl)methanone(2)
Red solid, melting point: 127.7-130.1 ℃. Yield 76%,139.5mg. 1 H NMR
for C 25 H 22 N 2 O,366.1732；found,366.1735.
[ 1-benzyl-5- (3-methylphenyl) imidazol-2-yl ] (3-methylphenyl) methanone
(1-benzyl-5-(m-Tolyl)-1H-imidazol-2-yl)(m-Tolyl)methanone(3)
137.7,133.4,131.0,130.2,129.9,129.1,128.7,128.5,128.5,128.0,127.9,127.3,126.4,126.1,49.2,21.4,21.3.HRMS(EI)m/z:calcd for C 25 H 22 N 2 O,366.1732；found,366.1733.
[ 1-benzyl-5- (2-methylphenyl) imidazol-2-yl ] (2-methylphenyl) methanone
(1-benzyl-5-(o-tolyl)-1H-imidazol-2-yl)(o-tolyl)methanone(4)
127.5,126.9,125.9,125.0,48.9,20.0,19.9.HRMS(EI)m/z:calcd for C 25 H 22 N 2 O,366.1732；found,366.1736.
[ 1-benzyl-5- (4-phenylphenyl) imidazol-2-yl ] (4-phenylphenyl) methanone
[1-benzyl-5-(4-phenylphenyl)imidazol-2-yl](4-phenylphenyl)methanone(5)
Red solid, melting point: 176.3-177.7 ℃. Yield 73%,179.5mg. 1 H NMR
(m,3H),7.02(d,J＝7.0Hz,2H),5.82(s,2H). 13 C{ 1 H}NMR(101MHz,CDCl 3 ):δ183.6,145.3,143.8,141.9,140.2,140.0,138.9,137.7,136.4,131.3,129.8,129.5,128.9,128.8,128.7,128.0,127.8,127.5,127.4,127.4,127.3,127.0,126.8,126.0,49.3.HRMS(EI)m/z:calcd for C 35 H 26 N 2 O,490.2045；found,490.2041.
[ 1-benzyl-5- (4-methoxyphenyl) imidazol-2-yl ] (4-methoxyphenyl) methanone
(1-benzyl-5- (4-methoxyphenyl) -1H-imidozol-2-yl) (4-methoxyphenyl) methanone (6) as a white solid, melting point: 125.5-127.9 ℃. Yield 72%,143.1mg. 1 H NMR(400MHz,CDCl 3 ):
m/z:calcd for C 25 H 22 N 2 O 3 ,398.1630；found,398.1626.
{ 1-benzyl-5- [4- (methylthio) phenyl ] imidazol-2-yl } [4- (methylthio) phenyl ] methanone
(1-benzyl-5-(4-(methylthio)phenyl)-1H-imidazol-2-yl)(4-(methylthio)phenyl)methano ne(7)
Brown solid, melting point: 136.5-137.9 ℃. Yield 70%,150.2mg.
49.2,15.3,14.8.HRMS(EI)m/z:calcd for C 25 H 22 N 2 OS 2 ,430.1174；found,430.1177.
[ 1-benzyl-5- (3, 5-dimethylphenyl) imidazol-2-yl ] (3, 5-dimethylphenyl) methanone
(1-benzyl-5-(3,5-dimethylphenyl)-1H-imidazol-2-yl)(3,5-dimethylphenyl)methanone(8)
Yellow oily liquid, yield 70%,138.5mg. 1 H NMR(400MHz,CDCl 3 )
C 25 H 22 N 2 OS 2 ,430.1174；found,430.1178.
[ 1-benzyl-5- (4-fluorophenyl) imidazol-2-yl ] (4-fluorophenyl) methanone
(1-benzyl-5-(4-fluorophenyl)-1H-imidazol-2-yl)(4-fluorophenyl)methanone(9)
White solid, melting point: 175.4-177.2 ℃. Yield 68%,127.4mg. 1 H NMR
127.5,125.9,124.6(d,J＝3.6Hz),116.0(d,J＝21.8Hz),115.2(d,J＝21.8Hz),49.3.HRMS(EI)m/z:calcd for C 23 H 16 F 2 N 2 O,374.1231；found,374.1232.
[ 1-benzyl-5- (4-chlorophenyl) imidazol-2-yl ] (4-chlorophenyl) methanone
(1-benzyl-5-(4-chlorophenyl)-1H-imidazol-2-yl)(4-chlorophenyl)methanone(10)
White solid, melting point: 178.3-179.5 ℃. Yield 71%,143.9mg. 1 H NMR
calcd for C 23 H 16 Cl 2 N 2 O,406.0640；found,406.0636.
[ 1-benzyl-5- (3-chlorophenyl) imidazol-2-yl ] (3-chlorophenyl) methanone
(1-benzyl-5-(3-chlorophenyl)-1H-imidazol-2-yl)(3-chlorophenyl)methanone(11)
127.5,126.0,49.5.HRMS(EI)m/z:calcd for C 23 H 16 Cl 2 N 2 O,406.0640；found,406.0642.
[ 1-benzyl-5- (4-bromophenyl) imidazol-2-yl ] (4-bromophenyl) methanone
(1-benzyl-5-(4-bromophenyl)-1H-imidazol-2-yl)(4-bromophenyl)methanone(12)
White solid, melting point: 174.9 to 176.5 ℃. Yield 70%,172.3mg. 1 H NMR
HRMS(EI)m/z:calcd for C 23 H 16 Br 2 N 2 O,493.9629；found,493.9630.
{ 1-benzyl-5- [4- (trifluoromethyl) phenyl ] imidazol-2-yl } [4- (trifluoromethyl) phenyl ] methanone
(1-benzyl-5-(4-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)(4-(trifluoromethyl)phenyl)methanone(13)
7.5,3.7Hz),125.8,125.0(q,J＝3.5Hz),122.4,49.6.HRMS(EI)m/z:calcd for C 25 H 16 F 6 N 2 O,474.1167；found,474.1165.
{ 1-benzyl-5- [3- (trifluoromethyl) phenyl ] imidazol-2-yl } [3- (trifluoromethyl) phenyl ] methanone
(1-benzyl-5-(3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)(3-(trifluoromethyl)phenyl)methanone(14)
130.7(d,J＝32.9Hz),130.2,129.5,129.3,129.1(dd,J＝6.9,3.3Hz),128.9,128.6,127.8,127.7,126.4(dd,J＝7.7,3.8Hz),126.0(dd,J＝7.4,3.8Hz),125.9,125.0(d,J＝27.4Hz),122.3(d,J＝27.4Hz),49.6.HRMS(EI)m/z:calcd for C 25 H 16 F 6 N 2 O,474.1167；found,474.1164.
[ 1-benzyl-5- (thien-2-yl) imidazol-2-yl ] (thien-2-yl) methanone
(1-benzyl-5-(thiophen-2-yl)-1H-imidazol-2-yl)(thiophen-2-yl)methanone(15)
128.7,128.7,128.3,127.9,127.8,127.8,127.4,125.8,49.3.HRMS(EI)m/z:calcd for C 19 H 14 N 2 OS 2 ,350.0548；found,350.0550.
[ 1-benzyl-5- (thien-3-yl) imidazol-2-yl ] (thien-3-yl) methanone
(1-benzyl-5-(thiophen-3-yl)-1H-imidazol-2-yl)(thiophen-3-yl)methanone(16)
137.5,136.2,134.3,129.3,128.9,128.8,128.6,127.9,127.4,126.7,125.7,125.0,124.9,49.5.HRMS(EI)m/z:calcd for C 19 H 14 N 2 OS 2 ,350.0548；found,350.0543.
[ 1-benzyl-5- (furan-2-yl) imidazol-2-yl ] (furan-2-yl) methanone
(1-benzyl-5-(furan-2-yl)-1H-imidazol-2-yl)(furan-2-yl)methanone(17)
127.4,126.3,123.0,112.4,111.7,110.2,49.7.HRMS(EI)m/z:calcd for C 19 H 14 N 2 O 3 ,318.1004；found,318.1009.
[ 1-benzyl-5- (naphthalen-2-yl) imidazol-2-yl ] (naphthalen-2-yl) methanone
(1-benzyl-5-(naphthalen-2-yl)-1H-imidazol-2-yl)(naphthalen-2-yl)methanone(18)
139.2,137.7,135.4,134.9,133.2,133.2,133.0,132.4,130.0,129.7,129.1,128.7,128.6,128.3,128.2,127.8,127.8,127.6,127.4,127.0,126.8,126.6,126.4,126.2,126.1,125.9,49.5.HRMS(EI)m/z:calcd for C 31 H 22 N 2 O,438.1732；found,438.1729.
1- [ 1-benzyl-5- (tert-butyl) imidazol-2-yl ] -2, 2-dimethylpropan-1-one
1-(1-benzyl-5-(tert-butyl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-one(19)
calcd for C 19 H 26 N 2 O,298.2045；found,298.2040.
Claims (4)
1. A mixture of methyl ketone, benzylamine and ammonium iodide [2+ 1]]A process for the cyclic synthesis of imidazole derivatives, characterized in that: at ammonium iodide and K 2 S 2 O 8 In the presence of DMSO solvent, methyl ketone reacts with benzylamine to generate imidazole, and the position 1 in the imidazole molecule of the productThe nitrogen atom and the attached benzyl group are from the raw material benzylamine, the nitrogen atom at the 3-position is provided by inorganic ammonium salt, and the raw material methyl ketone provides three carbon atoms at the 2,4, 5-position and a substituent attached to the carbon atom at the 2, 5-position;
the methyl ketone has the structure of formula 1:
the imidazole derivative has the structure of formula 2:
in formula 1, R is an aromatic ring or a hydrocarbon group containing a tertiary carbon atom. The aromatic ring may be phenyl, naphthalene, furan, pyrrole, thiophene, pyridine, quinoline, or substituted derivatives thereof. The substituents on the aromatic ring may contain 1 to 3 substituents, preferably one substituent. The position of the substituent is not limited, and may be ortho, meta or para. The substituents may be selected from benzene, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, fluorine, chlorine, bromine, amino, dimethylamino, trifluoromethyl, alkoxy, methylthio or methoxycarbonyl, ethoxyacyl.
2. The method for cyclizing imidazole derivative from methyl ketone, benzylamine and ammonium iodide by [2+ 1] according to claim 1, which comprises the following steps: the reaction requires the presence of both iodine and an inorganic amine species, preferably ammonium iodide.
3. The method for cyclizing imidazole derivative from methyl ketone, benzylamine and ammonium iodide by [2+ 1] according to claim 1, which comprises the following steps: the reaction temperature is from 120 ℃ to 160 ℃, preferably 140 ℃.
4. The method of claim 1 for cyclizing imidazole derivative from methyl ketone, benzylamine and ammonium iodide through [2+ 1], which is characterized in that: the reaction time is 20 to 120 minutes, preferably 60 minutes.
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