CN107602418B - Method for synthesizing amidine compound by copper (II) catalyzed aryl methyl ketone oxidation amidation - Google Patents
Method for synthesizing amidine compound by copper (II) catalyzed aryl methyl ketone oxidation amidation Download PDFInfo
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Abstract
The invention discloses a method for synthesizing amidine compounds by oxidizing and amidating aryl methyl ketone under the catalysis of copper (II). The method is carried out in an oxygen-containing atmosphere and in an organic carboxylate/DMSO mixed system; reacting aryl methyl ketone with aryl primary amine under the catalysis of cupric salt, or reacting aryl methyl ketone with aryl primary amine and secondary amine under the catalysis of cupric salt; the amidine compound is obtained. The method takes aryl methyl ketone and amine compounds as raw materials to react in one step to generate amidine compounds, has the characteristics of simple steps, low cost and the like, and is beneficial to industrial production.
Description
Technical Field
The invention relates to a synthetic method of amidine compounds, in particular to a method for generating amidine compounds by taking aryl methyl ketone and amine compounds as raw materials and carrying out one-step reaction under catalysis of copper (II), and belongs to the field of synthesis of organic intermediates.
Background
Amidines are structures in which amino groups and imino groups are simultaneously connected to the same carbon atom, and mainly comprise cyclic amidines or acyclic amidines. Amidines are important structural groups in many natural products and bioactive molecules, and compounds containing amidine structures have wide application in diverse fields such as pharmaceutical chemistry, synthetic intermediates, catalyst design, material science, supramolecular chemistry and coordination chemistry, among others.
In the prior art, the original method for synthesizing the compound containing the amidine structure is obtained by condensing imine chloride and ammonia, the method is difficult in group modification, the cost of the imine chloride raw material is high, the reaction is not easy to control, and the method is gradually eliminated. At present, the method for preparing the compound containing the amidine structure mainly uses isonitrile and an organic azide as raw materials, and the amidation reaction is carried out under the catalytic action of transition metal to obtain the compound containing the imidazole structure. Amidination directly with amines via a C-H bond via dehydrogenation coupling has recently been reported, C-H consisting predominantly of sp2Hybridized C-H or sp3A hybrid C-H bond. The Jiano group has developed a copper-catalyzed oxidative dehydrogenation coupling of aryl aldehydes and aryl amines (reaction 1), primarily the sp remaining after condensation of primary amines with aryl aldehydes2Dehydrogenation of the hybridized C-H is performed with a coupling reaction with an amine (Zhang, C.; Zhang, L.; Jiano, N.Adv. Synth. Catal.2012,354, 1293-1300.). Ihamaide and hum newspaperAdopts the steps of firstly condensing phenylacetaldehyde ketone with primary amine and secondary amine (reaction 2) under the action of no metal catalyst, and then carrying out sp2Coupling of the hybrid C-H dehydrogenation with an amine to give a compound containing an amidine structure (A.Kumar, N.Battini, R.R.Kumar, S.Athimolam, Q.N.Ahmed, Eur.J.Org.chem.2016,3344-3348.) (G.Martinez-Ariza, N.McConnell, C.Hulme, Org.Lett.2016,18, 1864-1867.). recently, secondary SP of α -aminocarbonyl compounds was reported by the Huang team3The reports of (A) α oxoacetamidine (reaction 3) (X. -X.Liu, Z. -Y.Wu, Y. -Q.He., X. -Q.ZHou, T.Hu, C. -W.Ma, G. -S.Huang, adv.Synth.Catal.2016,358,2385-2391.) are mainly based on aryl aldehydes, which are high in cost, poor in stability and not favorable for mass production3Reports on direct amidination of H with amines in one step.
Reaction 1:
reaction 2:
reaction 3:
disclosure of Invention
Aiming at the defect that aryl methyl ketone is difficult to directly react with amine to obtain amidine compounds in the prior art, the invention aims to provide the method for preparing the amidine compounds by taking the aryl methyl ketone and the amine compounds as raw materials and carrying out the next oxidation and amidation reaction under the catalysis of copper (II).
In order to achieve the technical purpose, the invention provides a method for synthesizing amidine compounds by copper (II) catalyzed oxidative amidation of aryl methyl ketone, which comprises the following steps of in an oxygen-containing atmosphere and in an organic carboxylate/DMSO mixed system; reacting aryl methyl ketone with aryl primary amine under the catalysis of cupric salt, or reacting aryl methyl ketone with aryl primary amine and secondary amine under the catalysis of cupric salt; the amidine compound is obtained.
In a preferred embodiment, the arylmethyl ketone has the structure of formula 1:
wherein Ar is selected from phenyl, phenyl containing substituent, naphthyl or naphthyl containing substituent. Preferred phenyl groups containing substituents are alkylphenyl, alkoxyphenyl, halophenyl, trifluoromethylphenyl or alkoxyacylphenyl. The phenyl group having a substituent is more preferably a 2-methylphenyl group, a 3-methylphenyl group, a 4-tert-butylphenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-iodophenyl group, a 3-chlorophenyl group, a 3-bromophenyl group, a 4-methoxyphenyl group, a 4-trifluoromethylphenyl group or a 4-methoxyacylphenyl group. The naphthyl containing the substituent is alkyl naphthyl, alkoxy naphthyl or halogenated naphthyl.
In a preferred embodiment, the primary arylamine has the structure of formula 2:
wherein R and R1Independently selected from hydrogen, alkyl, alkoxy, halo, trifluoromethyl or alkoxyacyl. The aryl group contained in the aryl primary amine is a phenyl group or a phenyl group containing a meta-or para-substituent, such as a 4-methylphenyl group, a 4-isopropylphenyl group, a 3-methoxyphenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-iodophenyl group, a 3-chlorophenyl group, a 3-bromophenyl group or a 3-iodophenyl group.
Preferably, the secondary amine has the structure of formula 3:
wherein R is2Is C4～C8Or a heteroatom-containing alkane chain. Furthermore, the utility modelPreferred secondary amines are cyclopentylimines, cyclobutylimines or 1-aza-4-oxohexacyclic rings.
In a preferred embodiment, the amidine compound has the structure of formula 4 or formula 5:
wherein the content of the first and second substances,
ar is selected from phenyl, phenyl containing substituent, naphthyl or naphthyl containing substituent;
r and R1Independently selected from hydrogen, alkyl, alkoxy, halo, trifluoromethyl or alkoxyacyl;
R2is C4～C8Or a heteroatom-containing alkane chain.
In a more preferred embodiment, the substituted phenyl group is an alkylphenyl group, an alkoxyphenyl group, a halophenyl group, a trifluoromethylphenyl group or an alkoxyacylphenyl group.
More preferably, the substituted naphthyl group is an alkyl naphthyl group, an alkoxy naphthyl group or a halogenonaphthyl group.
In a preferred embodiment, the organic carboxylate is acetate and/or benzoate. The more preferred organic carboxylate is benzoate; most preferably sodium benzoate.
In a preferred embodiment, the cupric salt is cupric chloride and/or cupric bromide; more preferably copper chloride.
In a preferred embodiment, the reaction conditions are as follows: the temperature is 70-100 ℃, the time is 10-30 h, and the oxygen partial pressure is more than 1 atm. The preferred reaction conditions are: the temperature is 80-90 ℃, the time is 20-30 h, and the oxygen partial pressure is more than 1 atm.
According to the technical scheme, when the aryl methyl ketone and the aryl primary amine react, the theoretical reaction molar ratio of the aryl methyl ketone to the aryl primary amine is 1:2, the aryl primary amine is slightly excessive in the actual reaction process, and the general reaction molar ratio is 1: 2-2.5; the optimal ratio is 1: 2.2. The addition amount of the cupric salt catalyst is 5-30% of the molar amount of the aryl methyl ketone; most preferably 20% of the molar amount of arylmethyl ketone. The dosage of the acetate is generally 0.2 to 1 time of the molar weight of the aryl methyl ketone, and the dosage of the acetate is generally 0.5 time of the molar weight of the aryl methyl ketone.
According to the technical scheme, when the aryl methyl ketone is reacted with the aryl primary amine and the aryl secondary amine, the theoretical reaction molar ratio of the aryl methyl ketone to the aryl primary amine to the aryl secondary amine is 1:1:1, the aryl primary amine and the aryl secondary amine are slightly excessive in the actual reaction process, and the general reaction molar ratio is 1: 1-1.2; the optimal ratio is 1:1.1: 1.1. The addition amount of the cupric salt catalyst is 5-30% of the molar amount of the aryl methyl ketone; most preferably 20% of the molar amount of arylmethyl ketone. The dosage of the acetate is generally 0.2 to 1 time of the molar weight of the aryl methyl ketone, and the optimal dosage is 0.5 time of the molar weight of the aryl methyl ketone.
Compared with the prior art, the technical scheme of the invention has the beneficial technical effects that:
1) the invention first combines three SPs of aryl methyl ketone3The successful direct amidification of-H fills the blank in the prior art.
2) Compared with the existing aryl aldehyde raw materials, the aryl methyl ketone raw material adopted by the invention has the advantages of low cost and good stability.
3) The amidine compound has high yield, and the highest yield can reach 91% according to different introduced groups.
4) The synthetic method has simple steps, is realized through one-pot reaction, has mild reaction conditions, and is beneficial to industrial production.
5) The synthesis method has universality, is beneficial to introducing different functional groups, and can design different organic intermediates according to requirements.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of the imidazole compound prepared in example 1;
fig. 2 is a nuclear magnetic carbon spectrum of the imidazole compound prepared in example 1;
FIG. 3 is a nuclear magnetic hydrogen spectrum of the imidazole compound prepared in example 2;
fig. 4 is a nuclear magnetic carbon spectrum of the imidazole compound prepared in example 2.
Detailed Description
The following examples are intended to further illustrate the present disclosure, but not to limit the scope of the claims.
The substrate starting materials, solvents and the like mentioned in the following examples were all commercial products (analytical reagents) on the market and were not further purified.
The product is separated by chromatography, column silica gel (300-400 mesh).
1H NMR (400MHz/500MHz), 13C NMR (100MHz), DMSO as solvent, TMS as internal standard.
Multiplicity is defined as follows: s (singlet); d (doublet); t (triplet); q (quartet) and m (multiplet). Coupling constant J (Hertz).
Examples 1 to 19 were carried out according to the following methods:
to the sealed tube were added ketone compound (0.5mmol), aniline (1.1mmol), CuCl2(13.4mg, 0.1mmol), PhCOONa (36mg, 0.25mmol) and DMSO (1.0mL), and the reaction mixture was stirred at 80 ℃ under an oxygen atmosphere of 1atm for 30 hours, the organic layers were mixed, Na was added2SO4Drying, filtration and concentration in vacuo and purification by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate) gave the amidine compound.
The specific reaction process is as follows:
example 1
Ketone compound raw material:
and (3) target products:
the target product of 128.4mg is obtained, and the yield is 86%; a yellow solid;1H NMR(400MHz,DMSO)9.79(s,1H),7.85(d,J＝7.9Hz,2H),7.80(d,J＝7.7Hz,2H),7.62(t,J＝7.3Hz,1H),7.48(t,J＝7.4Hz,2H),7.34(t,J＝7.5Hz,2H),7.04(t,J＝7.4Hz,3H),6.78(t,J＝7.2Hz,1H),6.71(d,J＝7.6Hz,2H).13C NMR(101MHz,DMSO)192.00,152.01,148.35,140.11,134.56,133.71,129.28,129.03,128.66,128.44,122.64,122.38,121.81,119.48。
example 2
Ketone compound raw material:
and (3) target products:
obtaining a target product of 105 mg; the yield is 67%; a yellow solid;1H NMR(400MHz,DMSO)9.80(s,1H),7.88(d,J＝7.7Hz,2H),7.69(d,J＝7.7Hz,1H),7.40(t,J＝7.4Hz,1H),7.34(t,J＝7.5Hz,2H),7.29(t,J＝7.6Hz,1H),7.16(d,J＝7.5Hz,1H),7.05(d,J＝7.9Hz,2H),7.00(s,1H),6.77(t,J＝7.1Hz,1H),6.64(d,J＝7.5Hz,2H),2.34(s,3H).13C NMR(101MHz,DMSO)194.22,153.04,148.38,140.22,139.36,133.20,133.17,131.84,131.81,128.64,128.29,126.10,122.56,122.27,121.62,119.39,20.64.
example 3
Ketone compound raw material:
and (3) target products:
116mg of target product is obtained, and the yield is 74%; a yellow solid;1H NMR(400MHz,DMSO)9.76(s,1H),7.85(d,J＝6.9Hz,2H),7.62(d,J＝10.0Hz,2H),7.43(d,J＝7.4Hz,1H),7.38(d,J＝7.5Hz,1H),7.34(d,J＝6.9Hz,2H),7.05(s,3H),6.80(d,J＝6.2Hz,1H),6.72(d,J＝6.8Hz,2H),2.31(s,3H).13C NMR(101MHz,DMSO)191.99,152.00,148.39,140.11,138.44,135.27,133.64,129.31,128.95,128.65,128.44,126.83,122.60,122.34,121.75,119.44,20.69.
example 4
Ketone compound raw material:
and (3) target products:
119mg of a target product is obtained, and the yield is 76%; a yellow solid;1H NMR(400MHz,DMSO)9.76(s,1H),7.86(d,J＝7.1Hz,2H),7.72(d,J＝7.7Hz,2H),7.41–7.25(m,4H),7.05(s,3H),6.83–6.77(m,1H),6.73(d,J＝6.8Hz,2H),2.32(s,3H).13C NMR(101MHz,DMSO)191.45,152.16,148.44,145.36,140.20,131.30,129.62,129.45,128.63,128.43,122.57,122.32,121.79,119.44,21.27.
example 5
Ketone compound raw material:
and (3) target products:
119mg of a target product is obtained; the yield is 67%; a yellow solid;1H NMR(500MHz,DMSO)9.77(s,1H),7.90(d,J＝8.0Hz,2H),7.81(d,J＝8.4Hz,2H),7.54(d,J＝8.5Hz,2H),7.34(t,J＝7.7Hz,2H),7.07(t,J＝7.8Hz,2H),7.04(d,J＝10.0Hz,1H),6.80(t,J＝9.4Hz,3H),1.27(s,9H).13C NMR(126MHz,DMSO)191.33,157.93,152.12,148.45,140.21,131.28,129.43,128.65,128.46,125.98,122.57,122.34,121.84,119.43,35.01,30.65.
example 6
Ketone compound raw material:
and (3) target products:
135mg of target product is obtained, and the yield is 85 percent; a yellow solid;1H NMR(400MHz,DMSO)9.83(s,1H),7.89(t,J＝6.5Hz,4H),7.39–7.27(m,4H),7.06(s,3H),6.80(t,J＝7.1Hz,1H),6.73(d,J＝7.4Hz,2H).13C NMR(101MHz,DMSO)190.53,166.87,164.34,151.80,148.31,140.05,132.46,132.36,130.61,130.59,128.68,128.49,122.73,122.47,121.78,119.51,116.42,116.19.
example 7
Ketone compound raw material:
and (3) target products:
133.8mg of the target product is obtained, the yield is 80 percent, and yellow solid is obtained;1H NMR(400MHz,DMSO)9.85(s,1H),7.86(d,J＝7.1Hz,2H),7.81(d,J＝8.2Hz,2H),7.55(d,J＝8.3Hz,2H),7.34(d,J＝6.8Hz,2H),7.06(s,3H),6.81(d,J＝6.5Hz,1H),6.72(d,J＝6.9Hz,2H).13C NMR(101MHz,DMSO)191.01,151.61,148.20,140.00,139.50,132.44,131.03,129.29,128.68,128.51,122.74,122.52,121.77,119.48.
example 8
Ketone compound raw material:
and (3) target products:
142mg of target product is obtained, and the yield is 75%; a yellow solid;1H NMR(400MHz,DMSO)9.84(s,1H),7.85(d,J＝6.6Hz,2H),7.73(d,J＝8.6Hz,2H),7.70(d,J＝8.5Hz,2H),7.34(s,2H),7.06(s,3H),6.81(d,J＝5.7Hz,1H),6.72(d,J＝6.5Hz,2H).13C NMR(101MHz,DMSO)191.24,151.57,148.18,139.99,132.73,132.25,131.07,128.86,128.68,128.52,122.75,122.53,121.77,119.47.
example 9
Ketone compound raw material:
and (3) target products:
106.5mg of a target product is obtained, and the yield is 50%; a yellow solid;1H NMR(400MHz,DMSO)9.81(s,1H),7.89(d,J＝8.2Hz,2H),7.84(d,J＝6.1Hz,2H),7.55(d,J＝8.1Hz,2H),7.34(s,2H),7.06(s,3H),6.81(s,1H),6.71(d,J＝5.7Hz,2H).13C NMR(101MHz,DMSO)191.60,151.59,148.18,139.98,138.11,132.97,130.67,128.67,128.52,122.72,122.51,121.77,119.46,103.90.
example 10
Ketone compound raw material:
and (3) target products:
obtaining 145.5mg of target product; the yield is 87%; a yellow solid;1H NMR(400MHz,DMSO)9.85(s,1H),7.85(d,J＝7.2Hz,2H),7.77(d,J＝7.6Hz,1H),7.69(d,J＝8.2Hz,2H),7.52(t,J＝7.8Hz,1H),7.35(t,J＝6.4Hz,2H),7.07(s,3H),6.81(t,J＝6.8Hz,1H),6.71(d,J＝7.0Hz,2H).13CNMR(101MHz,DMSO)190.96,151.32,148.11,139.91,135.46,134.25,133.82,131.20,128.70,128.55,128.20,128.03,122.82,122.59,121.73,119.50.
example 11
Ketone compound raw material:
and (3) target products:
the target product is obtained, 150mg and the yield is 79 percent; a yellow solid;1H NMR(400MHz,DMSO)9.85(s,1H),7.83(dd,J＝13.9,9.6Hz,5H),7.45(t,J＝7.8Hz,1H),7.35(t,J＝7.3Hz,2H),7.07(s,3H),6.81(t,J＝7.1Hz,1H),6.72(d,J＝7.4Hz,2H).13C NMR(101MHz,DMSO)190.88,151.27,148.10,139.89,137.10,135.60,131.39,130.99,128.70,128.54,128.52,122.82,122.59,122.15,121.72,119.49.
example 12
Ketone compound raw material:
and (3) target products:
the target product of 133.6mg is obtained; the yield is 81%; a yellow solid;1H NMR(400MHz,DMSO)9.73(s,1H),7.87(d,J＝6.2Hz,2H),7.79(d,J＝8.4Hz,2H),7.33(s,2H),7.12–7.01(m,4H),7.00(s,1H),6.80(s,1H),6.74(d,J＝5.9Hz,2H),3.80(s,3H).13C NMR(101MHz,DMSO)190.17,164.17,152.33,148.56,140.22,131.88,128.63,128.43,126.70,122.53,122.28,121.75,119.44,114.39,55.66.
example 13
Ketone compound raw material:
and (3) target products:
obtaining 112mg of a target product; the yield is 61%;1H NMR(400MHz,DMSO)9.87(s,1H),7.98(d,J＝7.9Hz,2H),7.85(d,J＝8.0Hz,4H),7.35(t,J＝7.4Hz,2H),7.10–7.02(m,3H),6.79(t,J＝6.9Hz,1H),6.71(d,J＝7.3Hz,2H).13C NMR(101MHz,DMSO)191.45,151.35,148.01,139.87,136.77,133.59,133.27,129.93,128.69,128.63,128.54,128.51,126.07,126.04,126.00,124.80,122.84,122.59,122.09,121.78,120.43,119.49.
example 14
KetonesCompound raw materials:
and (3) target products:
obtaining 114.5mg of a target product with the yield of 64 percent;1H NMR(500MHz,DMSO)9.91(s,1H),8.03(d,J＝8.4Hz,2H),7.92(d,J＝8.3Hz,2H),7.87(s,2H),7.35(s,2H),7.04(s,3H),6.75(d,J＝31.1Hz,3H),3.85(s,3H).13C NMR(126MHz,DMSO)191.91,165.29,151.60,148.09,140.01,136.93,134.21,129.76,129.48,128.63,128.60,122.71,121.85,121.83,119.48,52.55.
example 15
Ketone compound raw material:
and (3) target products:
obtaining 115.5mg of a target product; the yield is 66%;1H NMR(400MHz,DMSO)9.86(s,1H),8.47(s,1H),8.18(d,J＝8.2Hz,1H),7.97(d,J＝3.2Hz,1H),7.95(s,1H),7.89(d,J＝7.7Hz,2H),7.82(d,J＝8.6Hz,1H),7.68(t,J＝7.5Hz,1H),7.60(t,J＝7.5Hz,1H),7.36(t,J＝7.4Hz,2H),7.06(t,J＝7.2Hz,1H),6.99(t,J＝7.3Hz,2H),6.77(d,J＝7.5Hz,2H),6.71(t,J＝7.1Hz,1H).13C NMR(101MHz,DMSO)192.01,152.01,148.53,140.20,135.50,132.62,131.96,131.00,129.92,129.49,128.79,128.67,128.42,127.71,127.24,123.30,122.63,122.30,121.70,119.50.
example 16
Ketone compound raw material:
the target product was not obtained.
Example 17
Ketone compound raw material:
the target product was not obtained.
Examples 18 to 31 were carried out in the following manner:
acetophenone (0.5mmol), primary amine compound (1.1mmol) and CuCl were added into a sealed tube2(13.4mg, 0.1mmol), PhCOONa (36mg, 0.25mmol) and DMSO (1.0mL), and the reaction mixture was stirred at 80 ℃ under an oxygen atmosphere of 1atm for 30 hours, the organic layers were mixed, Na was added2SO4Drying, filtration and concentration in vacuo and purification by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate) gave the amidine compound.
The specific reaction process is as follows:
example 18
Primary amine raw materials:
and (3) target products:
92mg of target product is obtained, and the yield is 56%;1H NMR(400MHz,DMSO)9.62(s,1H),7.80(d,J＝7.7Hz,2H),7.72(d,J＝7.8Hz,2H),7.62(t,J＝7.3Hz,1H),7.48(t,J＝7.5Hz,2H),7.13(d,J＝7.8Hz,2H),6.84(d,J＝7.6Hz,2H),6.60(d,J＝7.6Hz,2H),2.27(s,3H),2.09(s,3H).13CNMR(101MHz,DMSO)192.31,151.88,145.80,137.65,134.50,133.67,131.40,130.87,129.22,129.00,128.97,128.92,121.63,119.43,20.41,20.19。
example 19
Primary amine raw materials:
and (3) target products:
132.5mg of a target product is obtained, and the yield is 69%;1H NMR(400MHz,DMSO)9.65(s,1H),7.79(t,J＝9.8Hz,4H),7.59(t,J＝7.2Hz,1H),7.47(t,J＝7.5Hz,2H),7.19(d,J＝7.0Hz,2H),6.90(d,J＝6.7Hz,2H),6.64(d,J＝6.6Hz,2H),2.85(d,J＝5.5Hz,1H),2.68(d,J＝5.7Hz,1H),1.20(d,J＝5.5Hz,6H),1.05(d,J＝5.6Hz,6H).13C NMR(101MHz,DMSO)192.40,151.82,146.15,142.62,142.02,137.98,134.39,133.92,129.21,128.96,126.27,126.20,121.65,119.54,32.90,32.57,23.97,23.83.
example 20
Primary amine raw materials:
and (3) target products:
106mg of target product is obtained, and the yield is 59%;1H NMR(400MHz,DMSO)9.80(s,1H),7.84(d,J＝7.5Hz,2H),7.63(t,J＝6.9Hz,2H),7.50(t,J＝7.4Hz,2H),7.37(s,1H),7.25(s,1H),6.95(s,1H),6.65(d,J＝4.8Hz,1H),6.38(d,J＝5.1Hz,1H),6.32(s,2H),3.74(s,3H),3.57(s,3H).13C NMR(101MHz,DMSO)191.93,159.52,159.39,152.05,149.65,141.17,134.59,133.76,129.44,129.33,129.21,129.05,114.31,111.95,108.40,107.90,107.42,105.67,54.95,54.74.
example 21
Primary amine raw materials:
and (3) target products:
123.5mg of a target product is obtained, and the yield is 74%;1H NMR(400MHz,DMSO)9.90(s,1H),7.89(dd,J＝7.7,5.1Hz,2H),7.82(d,J＝7.7Hz,2H),7.63(t,J＝7.3Hz,1H),7.50(t,J＝7.6Hz,2H),7.19(t,J＝8.6Hz,2H),6.87(t,J＝8.5Hz,2H),6.76–6.68(m,2H).13C NMR(101MHz,DMSO)192.03,159.19,158.92,156.82,156.54,152.48,144.74,144.72,136.41,136.39,134.75,133.57,129.28,129.15,123.22,123.14,121.23,121.16,115.35,115.13,114.92。
example 22
Primary amine raw materials:
and (3) target products:
142mg of target product is obtained, and the yield is 73%;1H NMR(400MHz,DMSO)10.06(s,1H),7.90(d,J＝8.3Hz,2H),7.83(d,J＝7.7Hz,2H),7.64(t,J＝7.3Hz,1H),7.50(t,J＝7.5Hz,2H),7.40(d,J＝8.3Hz,2H),7.09(d,J＝8.0Hz,2H),6.74(d,J＝8.0Hz,2H).13C NMR(101MHz,DMSO)191.46,152.28,147.11,138.77,134.86,133.43,129.31,129.18,128.56,128.35,126.62,126.47,123.44,121.09。
example 23
Primary amine raw materials:
and (3) target products:
the target product of 208mg is obtained, and the yield is 91%;1H NMR(400MHz,DMSO)10.07(s,1H),7.83(d,J＝6.8Hz,4H),7.64(t,J＝7.3Hz,1H),7.53(d,J＝6.9Hz,2H),7.49(d,J＝7.6Hz,2H),7.22(d,J＝8.0Hz,2H),6.69(d,J＝8.0Hz,2H).13C NMR(101MHz,DMSO)191.37,152.17,147.49,139.15,134.89,133.39,131.47,131.25,129.32,129.20,123.89,121.48,114.71,114.48。
example 24
Primary amine raw materials:
and (3) target products:
the target product is 210mg, and the yield is 76%;1H NMR(400MHz,DMSO)10.01(s,1H),7.81(d,J＝7.6Hz,2H),7.67(s,4H),7.64(d,J＝7.6Hz,1H),7.51(t,J＝7.5Hz,2H),7.37(d,J＝7.9Hz,2H),6.54(d,J＝7.9Hz,2H).13C NMR(101MHz,DMSO)191.31,152.01,147.90,139.58,137.29,137.08,134.89,133.36,129.30,129.20,124.24,121.77,86.43,86.20.
example 25
Primary amine raw materials:
and (3) target products:
136mg of target product is obtained, and the yield is 74%;1H NMR(400MHz,DMSO)10.17(s,1H),8.13(s,1H),7.84(d,J＝7.7Hz,2H),7.65(dd,J＝14.4,7.3Hz,2H),7.52(t,J＝7.6Hz,2H),7.37(t,J＝8.1Hz,1H),7.13(d,J＝7.9Hz,1H),7.07(t,J＝7.9Hz,1H),6.86(d,J＝7.9Hz,1H),6.78(s,1H),6.69(d,J＝7.8Hz,1H).13C NMR(101MHz,DMSO)191.03,152.48,149.64,141.09,135.00,133.39,133.08,132.81,130.37,130.06,129.38,129.24,122.66,122.50,121.65,120.53,119.06,118.06.
example 26
Primary amine raw materials:
and (3) target products:
176mg of target product is obtained, and the yield is 77%;1H NMR(400MHz,DMSO)10.15(s,1H),8.25(s,1H),7.84(d,J＝7.7Hz,2H),7.66(t,J＝7.2Hz,2H),7.52(t,J＝7.6Hz,2H),7.31(t,J＝8.0Hz,1H),7.26(d,J＝7.6Hz,1H),7.00(s,2H),6.92(s,1H),6.73(d,J＝5.7Hz,1H).13CNMR(101MHz,DMSO)191.00,152.46,149.76,141.21,134.99,133.39,130.67,130.34,129.37,129.23,125.57,125.36,124.48,121.89,121.55,121.31,120.89,118.44.
example 27
Primary amine raw materials:
and (3) target products:
the target product is obtained, 152mg and the yield is 55 percent;1H NMR(400MHz,DMSO)10.04(s,1H),8.37(s,1H),7.83(d,J＝7.5Hz,2H),7.74(d,J＝7.0Hz,1H),7.65(t,J＝7.3Hz,1H),7.51(t,J＝7.5Hz,2H),7.43(d,J＝7.0Hz,1H),7.13(d,J＝11.2Hz,2H),7.09(s,1H),6.85(t,J＝7.1Hz,1H),6.74(d,J＝7.0Hz,1H).13C NMR(101MHz,DMSO)191.08,152.33,149.62,141.08,134.90,133.48,131.49,131.20,130.70,130.37,129.32,129.18,127.71,127.69,121.31,118.92,94.52,94.37.
example 28
Primary amine raw materials:
the target product was not obtained.
Example 29
Raw materials:
the target product was not obtained.
Example 30
Primary amine raw materials:
the target product was not obtained.
Example 31
Primary amine raw materials:
the target product was not obtained.
Examples 32 to 37 were carried out in the following manner:
acetophenone (0.5mmol), aniline (0.55mmol), secondary amine compound (0.55mmol), CuCl were added to the sealed tube2(13.4mg, 0.1mmol), PhCOONa (36mg, 0.25mmol) and DMSO (1.0mL), and the reaction mixture was stirred at 80 ℃ under an oxygen atmosphere of 1atm for 30 hours, the organic layers were mixed, Na was added2SO4Drying, filtration and concentration in vacuo and purification by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate) gave the amidine compound.
The specific reaction process is as follows:
example 32
Secondary amine compound starting material:
and (3) target products:
the target product 83.5mg is obtained, and the yield is 57%;1H NMR(400MHz,CDCl3)7.81(d,J＝7.6Hz,2H),7.52(t,J＝7.4Hz,1H),7.39(t,J＝7.6Hz,2H),6.99(t,J＝7.6Hz,2H),6.75(t,J＝7.4Hz,1H),6.69(d,J＝7.7Hz,2H),3.48(s,4H),1.68(s,6H).13C NMR(101MHz,DMSO)193.83,155.12,148.80,134.83,134.05,129.24,128.86,128.18,122.03,121.64,54.90,25.16,24.01。
example 33
Secondary amine compound starting material:
and (3) target products:
the target product is 77mg, and the yield is 55%;1H NMR(400MHz,CDCl3)7.80(d,J＝7.6Hz,2H),7.51(t,J＝7.3Hz,1H),7.38(t,J＝7.5Hz,2H),6.99(t,J＝7.5Hz,2H),6.75(t,J＝6.9Hz,3H),3.49(d,J＝183.6Hz,4H),1.97(s,4H).13C NMR(101MHz,CDCl3)194.49,154.67,148.92,134.26,133.96,129.34,128.76,128.25,122.76,122.08,46.52,26.86,25.87,24.24。
example 34
Secondary amine compound starting material:
and (3) target products:
98.5mg of a target product is obtained, and the yield is 67%;1H NMR(400MHz,CDCl3)7.80(d,J＝7.6Hz,2H),7.52(t,J＝7.4Hz,1H),7.39(t,J＝7.6Hz,2H),7.00(t,J＝7.6Hz,2H),6.77(t,J＝7.3Hz,1H),6.70(d,J＝7.7Hz,2H),3.75(s,4H),3.53(s,4H).13C NMR(101MHz,CDCl3)193.99,156.04,148.05,134.57,134.38,129.17,128.86,128.36,122.51,122.17,66.53,45.23。
example 35
Secondary amine compound starting material:
and (3) target products:
the target product 52mg is obtained, and the yield is 34%;1H NMR(500MHz,DMSO)7.77(d,J＝7.6Hz,2H),7.58(t,J＝7.3Hz,1H),7.49(d,J＝5.6Hz,2H),7.46(d,J＝7.6Hz,1H),6.98(t,J＝7.5Hz,2H),6.71(t,J＝7.2Hz,1H),6.63(d,J＝7.7Hz,2H),3.93(s,1H),2.08(d,J＝9.4Hz,2H),1.75(d,J＝11.9Hz,2H),1.61(d,J＝12.0Hz,1H),1.39–1.28(m,4H),1.24–1.16(m,1H).13CNMR(126MHz,DMSO)193.43,153.95,149.54,134.21,134.02,129.12,128.87,128.24,122.20,121.45,48.93,31.95,25.46,24.67.
example 36
Secondary amine compound starting material:
the target product was not obtained.
Example 37
Secondary amine compound starting material:
the target product was not obtained.
Control experimental group:
taking the reaction of acetophenone and aniline as an example, a control experiment is performed on the selection of the catalyst and the solvent and the selection of the reaction conditions to further illustrate the content of the present invention, the specific experimental data are shown in the following table, and the specific experimental process is shown in example 1.
Reaction conditions are as follows: 1a (0.5mmol), 2a (1.1mmol), catalyst (0.1mmol), and base (0.25mmol), solvent (1mL), O2(1atm)，30h，bIsolated yields，cPhCOONa(0.5mmol).d10h.e20h.
As can be seen from the above table, the catalysts having better catalytic activity for the reaction are mainly halogen-containing copper salts, wherein cuprous salts have poor catalytic effect, but copper salts containing chlorine and bromine have better effect than other halogen-containing copper salts. While other organic copper salts and complex copper salts exhibit relatively poor catalytic activity for the reaction.
The organic carboxylate is a weakly alkaline substance, the reaction can be carried out in the presence of weakly alkaline substances such as benzoate, acetate, carbonate, bicarbonate and the like, but the reaction can obtain higher yield in the presence of the organic carboxylate, and particularly, the reaction effect can reach the best under the action of the benzoate.
The reaction solvent is mainly selected from strongly polar aprotic dimethyl sulfoxide, and the reaction can be carried out in DMF, but the effect is not ideal, and the reaction can hardly be carried out in solvents with smaller polarity such as DCE, 1,4-dioxane and the like.
The reaction temperature is around 80 ℃ with the best reaction effect, while the reaction effect is not good at lower or higher temperature.
In addition, the reaction needs to be carried out in an oxygen atmosphere, and the reaction is difficult to carry out under an atmosphere having no oxygen or a low oxygen content.
Claims (1)
1. A method for synthesizing amidine compounds by oxidizing and amidating aryl methyl ketone under the catalysis of copper (II) is characterized by comprising the following steps: in an oxygen-containing atmosphere with an oxygen partial pressure of 1atm or more and in an organic carboxylate/DMSO mixed system; reacting aryl methyl ketone with aryl primary amine under the catalysis of cupric salt, or reacting aryl methyl ketone with aryl primary amine and secondary amine under the catalysis of cupric salt to obtain amidine compounds;
the aryl methyl ketone has the structure of formula 1:
the primary arylamine has the structure of formula 2:
the secondary amine has the structure of formula 3:
the amidine compound has a structure shown in formula 4 or formula 5:
wherein the content of the first and second substances,
ar is selected from 2-methylphenyl, 3-methylphenyl, 4-tert-butylphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 3-chlorophenyl, 3-bromophenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl or 4-methoxylphenyl;
r and R1Independently selected from hydrogen, methyl, methoxy, halo or trifluoromethyl;
R2is C4～C8An alkane chain of (a) or an alkane chain containing a heteroatom;
the organic carboxylate is acetate and/or benzoate;
the cupric salt is cupric chloride and/or cupric bromide;
when the aryl methyl ketone and the aryl primary amine react, the molar ratio of the aryl methyl ketone to the aryl primary amine is 1: 2-2.5;
when the aryl methyl ketone is reacted with aryl primary amine and aryl secondary amine, the reaction molar ratio of the aryl methyl ketone to the aryl primary amine and the aryl secondary amine is 1: 1-1.2;
the reaction conditions are as follows: the temperature is 70-100 ℃, and the time is 10-30 h.
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