CN108383803B - Synthetic method of 2, 4-disubstituted oxazole - Google Patents

Abstract

The invention discloses a method for synthesizing 2, 4-disubstituted oxazole, which comprises the step of carrying out cyclization reaction on a methyl ketone compound in a DMSO solution system containing ammonium persulfate and halogen salt and/or a halogen simple substance to obtain the 2, 4-disubstituted oxazole.

Description

Synthetic method of 2, 4-disubstituted oxazole

Technical Field

The invention relates to a synthesis method of oxazole compounds, in particular to a method for synthesizing 2, 4-disubstituted oxazole by constructing an oxazole ring together with methyl ketone compounds, inorganic quaternary ammonium and dimethyl sulfoxide, belonging to the field of synthesis of pharmaceutical intermediates.

Background

The oxazole compound is a compound taking an oxazole ring as a matrix, the oxazole ring is a five-membered heterocycle containing N and O, the oxazole compound is widely present in a plurality of pharmacologically active molecules and natural products and is an important organic compound in the field of medicine, and the common molecular formula with pharmaceutical activity at present is as follows:

in the early days, oxazole compounds have mainly relied on physical extraction from natural products, but have not been able to meet the needs of the existing society by merely physical extraction. A large number of researchers have studied the chemical synthesis method of oxazole compounds, and some achievements have been achieved. More recently, di-substituted oxazoles were synthesized from methyl ketone, such as [1] Jiang, H.F.; Huang, H.W.; Cao, H.J.; Qi, C.R. Org.Lett.2010,12,5561 [2] Gao, Q.H.; Fei, Z.J.; Zhu, Y.P.; Lian, M.J.; Jia, F.C.; Liu, M.C.; She, N.F.; Wu A.X.tetrahedron.2013,69,22.[3] Xue, W.J.; Li, Q.J.; Zhu, Y.P.; Wang, J.G.; Wu A.X.Chem.2012, 48,3485. Xue.W.J.; Zhang, W.J.; Zhu W.J.; Zong.P.; Wang., Wang.; J.; Wu, W.W.W.J.; U.J. Chen U.P.; E.J.; E.35, U.7, U.J.; E.7, U.J.; E.J. J.; E.F.7, U.J.; and U.F.; and U.F.7. F.; Eq.J.; and U.F.; and U.7, U.F.; e.F.F.; and U.F.; e.7, U.J.J.J.P.; and S. A.7, U.A.J.7, U.J.; and U.7, U.J. In addition to the synthesis of oxazole compounds using methyl ketones, a number of methods have been reported for the synthesis of oxazole derivatives, such as ([7] Forsyth, c.j.; Ahemd, f.; Cink, r.d.; Lee, c.s.j.am.chem.soc.1998,120,5597.[8] Feldman, k.s.; Eastman, k.j.; leine, g.org.lei.2002, 4,3525.[8] Burgett, a.w.j.; Li, q.y.; Wei, q., Harran, p.g.angew.chem.int.ed.2003,115,5111.[9] Conqueron, p.y.; dier, c.; diusili, chem.anger.em.e.2003, e.12, c.7, t.7, t.r.t.t.r.11.;. 9. buquetron, p.y.; ne, c.s.t.; eudifulini, chem.a.e.t.t.t.t.t.t.11, r.7, c.7, h.7, c.7, h.7, c.7, h.7, c:

in addition, the synthesis of oxazole compounds reported in the prior art adopts noble metals or heavy metals as catalysts, such as Baander H, W.M., Li, C.Q., Zhang, L.M.J.Am.chem.Soc.2011,133,8482 [14] Peng, H.H., Akhmedov, N.G., Liang, Y.F., Jiano, N.Shi, X.D.J.Am.chem.Soc.2015,137,8912 [15] Mai, S.Y., Rao, C.Q., Chen, M.Su, J.H., Du, J.F., Song, Q.L.chem.C.2017, 53,10366 [16] Grothkop, O.Aad, A.H., Du, J.F., G, Q.L.chem.2017, 53,10366 ] Grotho kopp, Aosh, La.

Disclosure of Invention

Aiming at the defects of high raw material cost, low yield, difficult 2, 4-substituted oxazole obtaining and the like of the existing oxazole ring construction method due to the fact that heavy metal or noble metal is needed as a catalyst, the invention aims to provide a method for synthesizing 2, 4-disubstituted oxazole compounds in high yield by a one-pot method under mild reaction conditions and without the catalytic action of heavy metal or noble metal by using cheap methyl ketone compounds, quaternary ammonium salt, dimethyl sulfoxide and the like as raw materials.

In order to realize the technical purpose, the invention provides a synthesis method of 2, 4-disubstituted oxazole, which comprises the steps of carrying out cyclization reaction on methyl ketone compounds in a DMSO solution system containing ammonium persulfate and halogen salt and/or halogen simple substance;

the methyl ketone compound has a structure shown in a formula 1:

the 2, 4-disubstituted oxazole has the structure of formula 2:

wherein R is alkyl, aryl or aromatic heterocyclic radical.

In a preferred embodiment, R is isobutyl, naphthyl, substituted naphthyl, benzene, substituted phenyl, thienyl, furyl or pyrrolyl. More preferably, R may be an alkyl group, which mainly includes a branched alkyl group, and may also be a cycloalkyl group, and a common alkyl group such as isobutyl, etc. R may be substituted phenyl, including halogen substituted phenyl,Alkyl substituted phenyl, nitro substituted phenyl, alkoxy substituted phenyl or alkylthio substituted phenyl. Halogen-substituted phenyl includes fluoro, chloro, bromo or iodo-substituted phenyl, and fluoro, chloro or bromo-substituted phenyl is common. The number of the substituted groups can be 1-5, the number of the common substituted groups is 1-3, the substituted positions on the benzene ring can be any positions which can be substituted on the benzene ring, and the positions of the substituted groups have little influence on the synthesis of the oxazole ring. Alkyl-substituted phenyl radicals being predominantly short-chain alkyl-substituted phenyl radicals, e.g. C₁～C₅The number of the substituent groups is generally 1-3, the common substituent groups are mono-substituted alkyl substituted phenyl groups, the substitution positions on the benzene ring can be any positions on the benzene ring, and the positions of the substituent groups have little influence on the synthesis of the oxazole ring. Alkoxy-substituted phenyl radicals being predominantly lower-chain alkoxy-substituted phenyl radicals, e.g. C₁～C₅The number of the substituent groups is generally 1-2, the common substituent group is a mono-substituted alkoxy-substituted phenyl group, and the substitution position on the benzene ring can be any position on the benzene ring which can be substituted. The sulfoxy-substituted phenyl radicals being predominantly short-chain sulfoxy-substituted phenyl radicals, e.g. C₁～C₅The number of the substituent groups of the phenoxy substituted phenyl group is generally 1-2, the phenoxy substituted phenyl group is usually mono-substituted, and the substitution position on the benzene ring can be any position on the benzene ring which can be substituted. The nitro-substituted phenyl is usually mono-substituted nitro-substituted phenyl, and the substitution position on the benzene ring can be any position on the benzene ring which can be substituted. The cyano-substituted phenyl is usually mono-substituted cyano-substituted phenyl, and the substitution position on the benzene ring can be any substitutable position on the benzene ring. R can be naphthyl containing substituent groups, which contains at least one substituent group of halogen, alkyl, alkoxy, alkylthio, nitro and cyano. In theory, naphthyl methyl ketones containing these substituents are all suitable for use in the synthesis of the corresponding oxazole rings, and the present invention is illustrated by the typical acetophenone as the synthetic oxazole ring.

In a preferred embodiment, the halogen salt comprises at least one of TBAI, KI, TBAB; the elementary halogen comprises I₂. The most preferred halide salt is TBAI, which is a relative to other alkali metal iodidesThe quaternary ammonium salt of salt or other halogen has better positive effect of promoting the generation of oxazole ring. I is₂It also has promoting effect on the generation of oxazole ring, but the effect is far worse than TBAI.

In a preferable scheme, the molar weight of the ammonium persulfate is 1-2.5 times that of the methyl ketone compound. Most preferably 1.5 times.

In a preferable scheme, the total molar weight of the halogen salt and the halogen simple substance is 10-30% of the molar weight of the methyl ketone compound. Most preferably 15 to 25%.

In a preferable scheme, the concentration of the methyl ketone compound in a DMSO solution system is 0.1-1 mol/L. Most preferably 0.15 to 0.25 mol/L.

Preferably, the DMSO solution system may contain water or other solvents, and the DMSO mixed solution system contains water and/or other organic solvents in a volume ratio of not more than 1/3. However, the pure DMSO system is most beneficial to the synthesis of the oxazole ring, for example, the higher the water content in the water/DMSO mixed solution system is, the lower the yield of the target product is relative to the pure DMSO solution system under the same condition.

In a preferable scheme, the temperature of the cyclization reaction is 100-140 ℃, and the reaction time is 1-6 hours. In a more preferable embodiment, the temperature of the cyclization reaction is 110 to 130 ℃ and the reaction time is 1.5 to 2.5 hours. Too high or too low reaction temperature can reduce cyclization products, while the reaction time is prolonged to increase side reactions, the reaction time is too short, and the conversion rate is low.

The synthesis reaction equation of the 2, 4-disubstituted oxazole of the invention is as follows:

in the reaction, α methyl provided by two methyl ketone compound molecules, an ammonium ion provided by an ammonium persulfate molecule and an oxygen provided by a dimethyl sulfoxide molecule are subjected to asymmetric cyclization to synthesize an oxazole ring, wherein 2 and 4 positions of the oxazole ring contain substituents, 5 positions of the oxazole ring are hydrogen, and 2 and 4 positions of the oxazole ring are substituents R introduced by methyl ketone.

The invention also provides a synthesis reaction mechanism of the 2, 4-disubstituted oxazole: to be provided withThe reaction mechanism is explained by coupling acetophenone, ammonium persulfate and dimethyl sulfoxide to construct an oxazole ring: after reviewing and referring to relevant documents, a series of experiments for mechanism research were designed as shown in the following reaction equations (1), (2) and (3). The reaction equation (1) is a radical inhibition experiment. The synthesis of 2, 4-disubstituted oxazole was carried out under standard experimental conditions, and an appropriate amount of 2,2,6, 6-Tetramethylpiperidinyloxy (TEMPO) or Butylated Hydroxytoluene (BHT) was added to the reaction system, and it was found that the target compound 3a of 2, 4-disubstituted oxazole was obtained in good yield by the reaction. Indicating that the reaction does not proceed according to a free radical reaction mechanism. Equation (2) is an experiment for detecting an intermediate, and when the reaction is terminated after 30 minutes under standard conditions, intermediate a, which may be present in the reaction system, is detected by GC-MS, thereby further using intermediate a as a starting material in place of acetophenone. It is noteworthy that intermediate A can only be converted to the final 2, 4-disubstituted oxazole under standard conditions, whereas when I is₂Or S₂O₈ ^2-When removed separately, no final product was obtained, indicating that intermediate a is an essential intermediate in the synthesis of 2, 4-disubstituted oxazol. Then, we further used A and C at S₂O₈ ^2-And DMSO under standard conditions, the desired product can be obtained in good yield, as in equation (3). And as can be seen from b, c and d in equation (3), DMSO and S₂O₈ ^2-Is an indispensable compound for subsequent cyclization reaction, and simultaneously proves that the acetophenone A generates an intermediate C under standard reaction conditions.

Standard reaction conditions: substrate (1.0 eq), (NH)₄)₂S₂O₈(3.0 equiv.), TBAI (20 mol%), DMSO (3mL), was stirred at 120 ℃ for 2 hours.

According to the experiment, a possible reasonable reaction mechanism of the coupling construction of the nitrogen-oxygen heterocyclic ring reaction by the acetophenone, the ammonium persulfate and the dimethyl sulfoxide is provided, and the reaction route is shown as follows. Part (A)-Csp for acetophenone³-H bond is represented by^-Oxidation of formed I₂Activating, and performing substitution reaction to form intermediate A, wherein the intermediate A is at S₂O₈ ^2-Under the action of oxidation, removing a methyl H atom of the intermediate A, attacking the generated carbon negative atom into DMSO for coupling, and removing micromolecular DMS to obtain an intermediate B (which can be detected by GC-MS). Meanwhile, quaternary ammonium ions are heated to release ammonia, part of acetophenone is easy to be condensed with the ammonia to generate an intermediate C, the intermediate C and the intermediate B are subjected to substitution reaction, iodine is substituted by amino, and the substitution reaction product contains unstable hydroxyl and active methyl, so that intramolecular cyclization is easy to occur, and a target product (TM) is obtained.

Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:

1) in the synthesis process of the 2, 4-disubstituted oxazole, heavy metal or noble metal is avoided as a catalyst, and cheap and easily-obtained halogen or halogen salt is adopted as the catalyst, so that the cost is saved, and the environmental pollution is avoided.

2) In the synthesis process of the 2, 4-disubstituted oxazole, methyl ketone, dimethyl sulfoxide, ammonium persulfate and the like are used as basic raw materials, and the raw materials are conventional chemical raw materials, so that the synthesis method is low in cost and beneficial to industrial production.

3) In the synthesis process of the 2, 4-disubstituted oxazole, inorganic quaternary ammonium ions are used as a nitrogen source for synthesis of an oxazole ring, and compared with organic amines adopted in the prior art, the synthesis method has absolute advantage in cost.

4) The 2, 4-disubstituted oxazole of the invention adopts a one-pot reaction in the synthetic process, and the reaction condition is mild, can react in the air environment, and has simple operation and meets the requirement of industrial production.

5) In the synthesis process of the 2, 4-disubstituted oxazole, the utilization rate of raw materials is high, and the product yield reaches about 80%.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of 2,4 disubstituted oxazole prepared in example 1;

FIG. 2 is a nuclear magnetic carbon spectrum of 2,4 disubstituted oxazole prepared in example 1;

FIG. 3 is a nuclear magnetic hydrogen spectrum of 2,4 disubstituted oxazole prepared in example 4;

FIG. 4 is a nuclear magnetic carbon spectrum of 2,4 disubstituted oxazole prepared in example 4;

FIG. 5 is a nuclear magnetic hydrogen spectrum of 2,4 disubstituted oxazole prepared in example 13;

FIG. 6 is a nuclear magnetic carbon spectrum of 2,4 disubstituted oxazole prepared in example 13;

FIG. 7 is a nuclear magnetic hydrogen spectrum of 2,4 disubstituted oxazole prepared in example 16;

FIG. 8 is a nuclear magnetic carbon spectrum of 2,4 disubstituted oxazole prepared in example 16;

FIG. 9 is a nuclear magnetic hydrogen spectrum of 2,4 disubstituted oxazole prepared in example 18;

FIG. 10 is a nuclear magnetic carbon spectrum of 2,4 disubstituted oxazole prepared in example 18.

Detailed Description

The following examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.

All reactions were carried out in a sealed tube (25mL) at the end of the screw, unless otherwise stated.

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).

All target compounds were characterized based on GC-MS and NMR (1H and 13C) spectral data.

1H NMR (400MHz) and 13C NMR (100MHz) measurements were carried out using a Bruker ADVANCE III spectrometer with CDCl₃As solvent, TMS as internal standard, chemical shifts in parts per million (ppm) and reference shifts of 0.0ppm tetramethylsilane. The following abbreviations (or combinations thereof) are used to explain the multiplicity: s is singlet, d is doublet, t is triplet, q is quartet, m is quartetMultiplet, br ═ broad peak. Coupling constant J is 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.

The GC-MS adopts a GC-MS QP2010 device for detection, the HRMS adopts an Electron Ionization (EI) method for measurement, the type of the mass analyzer is TOF, and the EI is detected by an Esquire 3000plus instrument.

1. Condition optimization experiment:

taking acetophenone as an example of a basic raw material for the reaction, optimum reaction conditions are sought, and various influencing factors such as the type and amount of quaternary ammonium salt, the type and amount of catalyst, reaction temperature and time, reaction solvent and amount are studied.

TABLE 1 optimization of the reaction conditions^a

As can be seen from table 1, compared with other solvents, DMSO is the only effective solvent (table 1, entries 2 to 5) participating in formation of oxazole ring, and the target product cannot be obtained by using common solvents such as DMF, toluene, methanol, acetonitrile, etc. alone, mainly because DMSO is an oxygen source for oxazole ring construction, and thus, a proper amount of DMSO must be contained in the solvent, and oxazole ring can be generated smoothly. Meanwhile, experiments prove that a mixed solvent of DMSO (dimethyl sulfoxide) can be adopted, such as DMSO/H₂O, yield decreased well with increasing water ratio (table 1, entries 6 and 7).

As can be seen from table 1, ammonium persulfate plays a key role in oxazole ring synthesis, and the product structure is changed without ammonium persulfate, so that no oxazole ring product is obtained, and no oxazole ring product is obtained from other quaternary ammonium salts such as ammonium acetate, ammonium iodide, ammonium carbonate and the like (table 1, entries 8 to 10, respectively).

As can be seen from Table 1, TBAI is an important catalyst in the synthesis of oxazole rings, although TBAB, I₂And I^-The isocratic solutions had a certain catalytic effect, but the effect was far worse than using TBAI as catalyst (table 1, entries 11 to 13). In particular, the oxazole ring synthesis reaction of the present invention did not yield the desired product without the addition of a catalyst (table 1, entry 14).

As can be seen from Table 1, temperature is also another important factor affecting the yield of the desired product. The reaction was successfully completed within 2h with sufficient stirring at 120 ℃, but the reaction was over 4h at 100 ℃ and still no conversion of a certain amount of acetophenone was detected, whereas the reaction was over 12h at 80 ℃ and only trace amounts of the target product (table 1, entries 15 and 16, respectively) were obtained, whereas the reaction time was extended to 12h at 120 ℃ and the product yield was significantly reduced. Further reacting respectively at O₂And Ar, similar results were obtained for both (table 1, entries 18 and 19, respectively).

And (3) the optimal reaction conditions for synthesizing the oxazole ring are obtained by optimizing the experiment: acetophenone (0.5mmol), (NH)₄)₂S₂O₈(3.0 equiv., 0.75mmol), TBAI (20 mol%), DMSO (3mL), reaction temperature 120 ℃, reaction time 2 h.

2. Substrate optimization experiment:

after the optimal reaction conditions for synthesizing the oxazole ring are determined, the selection range of acetophenone derivatives is further researched, and the experimental result is shown in table 2, so that the electronic effects of different substituents contained on the benzene ring of the acetophenone derivatives have small influence on the synthesis of the oxazole ring. Meanwhile, the position of a substituent on the benzene ring of the acetophenone derivative has little influence on the synthesis of the oxazole ring, and the oxazole ring can be obtained by various position-substituted acetophenone derivatives in excellent yield. If the substituent is para, the acetophenone derivative can give the oxazole ring (3b to 3g, 70 to 88% respectively) in excellent yields. Acetophenone derivatives containing methyl (3h) and halogen (3i, 3j and 3k) also synthesize oxazole ring well when the position of the substituent is changed from para to meta, giving 85%, 80%, 78% and 62% yields, respectively, while the meta is a strong electron group nitro, the oxazole ring (3l, 47%) can be obtained in moderate yield. When the substituents are positioned ortho, methyl, methoxy, halogen, or the like, all yield the oxazole ring in higher yields, e.g., in 85%, 75% and 78% yields to the desired products 3m, 3n and 3o (3m to 3o), respectively.

TABLE 2 range of acetophenone derivative substrate optimization^a,b

^aReaction conditions are as follows: acetophenone (0.5mmol), (NH)₄)₂S₂O₈(3.0 equiv., 0.75mmol, 170mmg), TBAI (20 mol%), DMSO (3mL), reaction temperature 120 ℃, reaction time 2 h.

^bThe isolation yield.

^cThe X-ray crystal structure of the product shows.

^dThe reaction was carried out for 6 hours.

After studying the selection range of acetophenone derivatives, attempts were made to convert other methyl ketones to 2, 4-disubstituted oxazoles. Numerous experiments have shown that 2-acetonaphthone gives the product 4a in excellent yield (75%) as acetophenone. Surprisingly, the reaction also proceeded well when the heterocyclic methyl ketones (2-furylacetone and 2-acetylthiophene) were investigated under optimal conditions (4b, 58%; and 4c, 52%). Furthermore, in certain reported reactions, aliphatic methyl ketones are not controlled by the desired pathway in the absence of a stable conjugated structure. Whereas pinacolone successfully obtained the target compound 4d in 46% yield under standard conditions.

TABLE 3 ranges for other methyl ketone derivatives^a,b

^aReaction conditions are as follows: acetophenone (0.5mmol), (NH)₄)₂S₂O₈(3.0 equiv., 0.75mmol, 170mmg), TBAI (20 mol%), DMSO (3mL), reaction temperature 120 ℃, reaction time 2 h.

^bThe isolation yield.

The following examples 1 to 18 were all carried out as follows:

methyl ketone compound (0.5mmol), (NH)₄)₂S₂O₈(3 equiv., 0.75mmol, 170mg), TBAI (20 mol%, 18mg), DMSO (3mL) was added to a sealed tube. The reaction was stirred vigorously at 120 ℃ for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, then washed and washed with H₂O and Ethyl Acetate (EA). Finally, the extract was concentrated with a rotary evaporator and purified by column chromatography using silica gel (200-300 mesh size) and Petroleum Ether (PE)/Ethyl Acetate (EA) as eluent.

Example 1

(phenyl)(4-phenyloxazol-2-yl)methanone(3a)

52.9mg, 85% yield, dark yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.60(d,J＝7.7Hz,2H),8.15(s,1H),7.85(d,J＝7.5Hz,2H),7.68(t,J＝7.3Hz,1H),7.56(d,J＝15.1Hz,2H),7.46(d,J＝7.5Hz,2H),7.39(t,J＝7.2Hz,1H).

¹³C NMR(101MHz,CDCl₃)δ178.71,157.52,142.68,136.22,134.94,134.03,131.03,129.91,128.89,128.86,128.49,125.83.

Example 2

(4-methylphenyl)(4-(4-methylphenyloxazol)-2-yl)methanone(3b)

60.9mg, 88% yield, orange solid.

¹H NMR(400MHz,CDCl₃)δ8.49(d,J＝7.6Hz,2H),8.08(s,1H),7.72(d,J＝7.1Hz,2H),7.34(d,J＝7.8Hz,2H),7.25(d,J＝5.3Hz,2H),2.45(s,3H),2.39(s,3H).

¹³C NMR(101MHz,CDCl₃)δ178.40,157.59,145.10,142.64,138.77,135.67,132.49,131.16,129.54,129.22,127.17,125.73,21.81,21.32.

Example 3

(4-methoxylphenyl)(4-(4-methoxylphenyloxazol)-2-yl)methanone(3c)

63.5mg, 82% yield, yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.64(d,J＝7.7Hz,2H),8.04(s,1H),7.77(d,J＝7.4Hz,2H),7.00(dd,J＝17.3,7.6Hz,2H),3.91(s,3H),3.85(s,3H).

¹³C NMR(101MHz,CDCl₃)δ177.11,164.37,160.02,157.67,142.29,134.90,133.56,127.97,127.16,122.70,114.26,113.80,55.52,55.32.

Example 4

(4-fluorophenyl)(4-(4-fluorolphenyloxazol)-2-yl)methanone(3d)

60.6mg, 85% yield, yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.77–8.56(m,2H),8.11(s,1H),7.87–7.77(m,2H),7.22(d,J＝8.7Hz,2H),7.16(t,J＝8.4Hz,2H).

¹³C NMR(101MHz,CDCl₃)δ176.87,166.45(d,J＝257.1Hz),163.04(d,J＝248.9Hz),157.37,141.84,135.94,133.88(d,J＝9.6Hz),132.78(d,J＝9.9Hz),131.21(d,J＝2.8Hz),130.64(d,J＝9.3Hz),127.65(d,J＝8.3Hz),115.89(t,J＝22.4Hz).

Example 5

(4-chlorophenyl)(4-(4-chlorophenyloxazol)-2-yl)methanone(3e)

61.2mg, 77% yield, as a tan solid.

¹H NMR(400MHz,CDCl₃)δ8.55(d,J＝8.2Hz,2H),8.14(s,1H),7.76(d,J＝8.1Hz,2H),7.53(d,J＝8.2Hz,2H),7.43(d,J＝8.1Hz,2H).

¹³C NMR(101MHz,CDCl₃)δ177.16,157.31,141.75,140.86,136.47,134.79,133.09,132.39,129.17,128.90,128.25,127.07.

Example 6

(4-iodophenyl)(4-(4-iodophenyloxazol)-2-yl)methanone(3f)

91.5mg, 73% yield, light yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.29(d,J＝7.6Hz,2H),8.16(s,1H),7.92(d,J＝7.9Hz,2H),7.79(d,J＝7.2Hz,2H),7.56(d,J＝7.5Hz,2H).

¹³C NMR(101MHz,CDCl₃)δ177.73,157.31,141.89,138.56,138.05,137.91,134.05,132.22,131.04,129.44,129.27,127.45,115.48,102.91,94.62.

Example 7

(4-sulfurmethylphenyl)(4-(4-sulfurmethylphenyloxazol)-2-yl)methanone(3g)

59.7mg, yield 70%, yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.45(d,J＝8.2Hz,2H),8.01(s,1H),7.65(d,J＝8.0Hz,2H),7.36–7.09(m,4H),2.46(s,3H),2.43(s,3H).

¹³C NMR(101MHz,CDCl₃)δ177.30,157.51,147.62,142.07,139.52,135.73,131.30,131.00,126.57,126.43,126.09,124.60,15.46,14.54.

Example 8

(3-methylphenyl)(4-(3-methylphenyloxazol)-2-yl)methanone(3h)

58.9mg, 85% yield, dark yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.44(d,J＝7.3Hz,1H),8.30(s,1H),8.13(s,1H),7.71–7.60(m,2H),7.46(q,J＝7.9Hz,2H),7.35(t,J＝7.5Hz,1H),7.20(d,J＝7.5Hz,1H),2.48(s,3H),2.43(s,3H).

¹³C NMR(101MHz,CDCl₃)δ179.02,157.60,142.77,138.62,138.32,136.14,134.99,134.86,131.16,129.84,129.63,128.79,128.49,128.37,126.46,122.96.

Example 9

(3-fluorophenyl)(4-(3-fluorophenyloxazol)-2-yl)methanone(3i)

58.9mg, yield 80%, yellow white solid.

¹H NMR(400MHz,CDCl₃)δ8.42(d,J＝7.8Hz,1H),8.30(d,J＝9.6Hz,1H),8.17(s,1H),7.65–7.48(m,3H),7.40(dt,J＝16.1,7.5Hz,2H),7.08(t,J＝8.3Hz,1H).

¹³C NMR(101MHz,CDCl₃)δ177.04(d,J＝2.6Hz),164.03(d,J＝66.1Hz),161.58(d,J＝67.4Hz),157.18,141.74(d,J＝2.7Hz),136.94,136.53(d,J＝7.0Hz),131.85(d,J＝8.3Hz),130.58(d,J＝8.3Hz),130.21(d,J＝7.7Hz),126.83(d,J＝3.0Hz),121.42(d,J＝2.9Hz),121.20(d,J＝21.5Hz),117.69(d,J＝23.5Hz),115.83(d,J＝21.2Hz),112.86(d,J＝23.2Hz).

Example 10

(3-chlorophenyl)(4-(3-chlorophenyloxazol)-2-yl)methanone(3j)

62mg, yield 78%, pink yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.52(d,J＝7.0Hz,2H),8.18(s,1H),7.83(s,1H),7.71(d,J＝7.0Hz,1H),7.65(d,J＝7.9Hz,1H),7.52(t,J＝7.4Hz,1H),7.43–7.31(m,2H).

¹³C NMR(101MHz,CDCl₃)δ177.09(s),157.20(s),141.63(s),136.98(s),136.19(s),135.01(s),134.81(s),134.06(s),131.48(s),130.77(s),130.25(s),129.88(s),129.22(s),129.02(s),125.91(s),123.92(s).

Example 11

(3-bromophenyl)(4-(3-bromophenyloxazol)-2-yl)methanone(3k)

63.1mg, 62% yield, dark yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.68(s,1H),8.58(d,J＝7.8Hz,1H),8.18(s,1H),7.99(s,1H),7.79(dd,J＝17.3,7.9Hz,2H),7.53(d,J＝7.9Hz,1H),7.46(t,J＝7.8Hz,1H),7.34(t,J＝7.8Hz,1H).

¹³C NMR(101MHz,CDCl₃)δ177.11,157.20,141.53,136.99,136.41,133.68,131.97,131.74,130.52,130.14,129.70,128.83,127.20,124.40,123.12,122.77.

Example 12

(3-nitrophenyl)(4-(3-nitrophenyloxazol)-2-yl)methanone(3l)

39.8mg, 47% yield, dark yellow solid.

¹H NMR(400MHz,CDCl₃)δ9.54(s,1H),8.93(d,J＝7.7Hz,1H),8.67(s,1H),8.55(d,J＝8.2Hz,1H),8.38(s,1H),8.24(dd,J＝17.7,7.9Hz,2H),7.82(t,J＝7.9Hz,1H),7.70(t,J＝8.0Hz,1H).

¹³C NMR(101MHz,CDCl₃)δ175.92,157.09,148.75,148.33,141.04,137.99,136.31,135.74,131.59,131.27,130.24,129.94,128.34,126.08,123.75,120.70.

Example 13

(2-methylphenyl)(4-(2-methylphenyloxazol)-2-yl)methanone(3m)

59.0mg, 85% yield, bright yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.09(d,J＝7.6Hz,1H),7.97(s,1H),7.75(d,J＝32.5Hz,1H),7.45(t,J＝7.4Hz,1H),7.32(t,J＝7.6Hz,5H),2.54(s,3H),2.47(s,3H).

¹³C NMR(101MHz,CDCl₃)δ182.13,182.13,157.38,142.02,139.56,138.06,135.71,134.94,132.20,131.59,131.55,130.92,129.19,128.85,128.64,126.14,125.29,21.61,20.73.

Example 14

(2-chlorophenyl)(4-(2-chlorophenyloxazol)-2-yl)methanone(3n)

62mg, yield 78%, yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.56(s,1H),8.09(d,J＝7.6Hz,1H),7.78(d,J＝7.5Hz,1H),7.51(s,2H),7.44(dd,J＝14.2,5.9Hz,2H),7.38–7.27(m,2H).

¹³C NMR(101MHz,CDCl₃)δ180.26,156.51,140.28,139.49,135.67,132.90,132.74,131.76,130.93,130.58,130.28,130.17,129.56,128.54,127.12,126.57.

Example 15

(naphthyl)(4-naphthyl-2-yl)methanone(4a)

65.4mg, 75% yield, yellow solid.

¹H NMR(400MHz,CDCl₃)δ9.37(s,1H),8.50(d,J＝7.6Hz,1H),8.41(s,1H),8.28(s,1H),8.10(d,J＝5.9Hz,1H),8.03–7.83(m,6H),7.74–7.58(m,2H),7.54(s,2H).

¹³C NMR(101MHz,CDCl₃)δ178.61,157.81,142.78,136.53,136.01,134.16,133.44,132.39,132.27,130.25,130.25,129.14,128.72,128.38,128.30,127.80,127.27,126.83,126.66,126.55,125.51,125.01,123.43,119.07.

Example 16

(furan)(4-furan-2-yl)methanone(4b)

33.2mg, 58% yield, brown-black solid.

¹H NMR(400MHz,CDCl₃)δ8.20(s,1H),8.06(s,1H),7.81(s,1H),7.48(s,1H),6.85(s,1H),6.68(s,1H),6.52(s,1H).

¹³C NMR(101MHz,CDCl₃)δ165.50,156.71,150.03,149.10,145.62,142.89,135.85,135.15,124.64,112.91,111.52,108.33.

Example 17

(thiophene)(4-thiophene-2-yl)methanone(4c)

33.9mg, yield 52%, yellow solid.

¹H NMR(400MHz,CDCl₃)δ8.72(s,1H),8.04(s,1H),7.83(d,J＝4.5Hz,1H),7.48(s,1H),7.37(d,J＝4.7Hz,1H),7.26(s,1H),7.12(s,1H).

¹³C NMR(101MHz,CDCl₃)δ170.41,156.78,140.48,137.82,137.41,136.69,135.39,132.33,128.64,127.85,126.03,125.24.

Example 18

(tert-butyl)(4-tert-butyl-2-yl)methanone(4d)

24mg, yield 46%, yellow liquid.

¹H NMR(400MHz,CDCl₃)δ7.41(s,1H),1.43(s,9H),1.29(s,9H).¹³C NMR(101MHz,CDCl₃)δ193.72,155.81,152.07,133.69,43.85,31.14,29.18,26.86.

Claims (3)

1. A synthetic method of 2, 4-disubstituted oxazole is characterized in that: carrying out cyclization reaction on the methyl ketone compound in a DMSO solution system containing ammonium persulfate and halogen salt and/or halogen simple substance to obtain the methyl ketone compound;

the methyl ketone compound has a structure shown in a formula 1:

the 2, 4-disubstituted oxazole has the structure of formula 2:

wherein R is isobutyl, naphthyl, benzene, phenyl containing substituent, thienyl, furyl or pyrrolyl;

the substituent in the phenyl containing the substituent is halogen and C₁～C₅Alkyl of (C)₁～C₅Alkoxy group of (C)₁～C₅At least one of alkylthio, nitro and cyano;

the halogen salt is at least one of TBAI, KI and TBAB; the elementary halogen is I₂；

The using amount of the ammonium persulfate is 1-2.5 times of the molar weight of the methyl ketone compound;

the concentration of the methyl ketone compound in a DMSO solution system is 0.1-1 mol/L;

the temperature of the cyclization reaction is 100-140 ℃, and the reaction time is 1-6 hours;

the DMSO solution system comprises water and/or other organic solvents in a volume ratio of no more than 1/3.

2. The synthesis method of 2, 4-disubstituted oxazole according to claim 1, characterized in that: the total molar weight of the halogen salt and the halogen simple substance is 10-30% of the molar weight of the methyl ketone compound.

3. The synthesis method of 2, 4-disubstituted oxazole according to claim 1, characterized in that: the temperature of the cyclization reaction is 110-130 ℃, and the reaction time is 1.5-2.5 hours.

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