CN114014803B - Method for synthesizing urea compound by amidation reaction of amide and amine at room temperature - Google Patents
Method for synthesizing urea compound by amidation reaction of amide and amine at room temperature Download PDFInfo
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- CN114014803B CN114014803B CN202111254357.9A CN202111254357A CN114014803B CN 114014803 B CN114014803 B CN 114014803B CN 202111254357 A CN202111254357 A CN 202111254357A CN 114014803 B CN114014803 B CN 114014803B
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- 150000001412 amines Chemical class 0.000 title claims abstract description 27
- 150000001408 amides Chemical class 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000007112 amidation reaction Methods 0.000 title claims abstract description 15
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 12
- -1 urea compound Chemical class 0.000 title claims description 13
- 239000004202 carbamide Substances 0.000 title claims description 10
- 150000003672 ureas Chemical class 0.000 claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000011259 mixed solution Substances 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 229910052723 transition metal Inorganic materials 0.000 claims abstract description 12
- 150000003624 transition metals Chemical class 0.000 claims abstract description 12
- 238000004440 column chromatography Methods 0.000 claims abstract description 6
- 239000000706 filtrate Substances 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 5
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000007800 oxidant agent Substances 0.000 claims abstract description 4
- 230000001590 oxidative effect Effects 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 238000003756 stirring Methods 0.000 claims abstract description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical group Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 229910000365 copper sulfate Inorganic materials 0.000 claims description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims 1
- 239000000758 substrate Substances 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 239000000376 reactant Substances 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- UPBDTNXNZHJUMB-UHFFFAOYSA-N n-(3-methylpyridin-2-yl)-2,2-diphenylacetamide Chemical compound CC1=CC=CN=C1NC(=O)C(C=1C=CC=CC=1)C1=CC=CC=C1 UPBDTNXNZHJUMB-UHFFFAOYSA-N 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- QPLDLSVMHZLSFG-UHFFFAOYSA-N Copper oxide Chemical class [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 3
- 230000009435 amidation Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- IKDYBHFQQDWWKB-UHFFFAOYSA-N 1-(3-methylpyridin-2-yl)-3-phenylurea Chemical compound CC1=CC=CN=C1NC(=O)NC1=CC=CC=C1 IKDYBHFQQDWWKB-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 239000013132 MOF-5 Substances 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 150000005171 halobenzenes Chemical class 0.000 description 2
- LOOWJHIWKFGSAZ-UHFFFAOYSA-N n-(3-methylpyridin-2-yl)morpholine-4-carboxamide Chemical compound CC1=CC=CN=C1NC(=O)N1CCOCC1 LOOWJHIWKFGSAZ-UHFFFAOYSA-N 0.000 description 2
- 238000007248 oxidative elimination reaction Methods 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 229940076286 cupric acetate Drugs 0.000 description 1
- 229960004643 cupric oxide Drugs 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003337 fertilizer Substances 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000004454 trace mineral analysis Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing urea compounds by amidation reaction of amide and amine at room temperature, which comprises the following steps of dissolving amide, transition metal catalyst and amine in an organic solvent, and stirring for 1-6 hours at room temperature to obtain a mixed solution; filtering the mixed solution, concentrating the filtrate, and performing column chromatography to obtain urea compounds. The method directly uses common non-toxic amide as a substrate, and the substrate range is wide. The reaction uses oxygen in air as an oxidant, the reactants do not need to be excessive, the utilization rate of raw materials is high, the range of substrates is wide, the reaction condition is mild, the operation is simple, the time is short, the yield is high, and the method is suitable for being applied to industrial production.
Description
Technical Field
The invention relates to a method for synthesizing urea compounds, in particular to a method for synthesizing urea compounds by utilizing amidation reaction of amide and amine, belonging to the technical field of preparation of urea compounds.
Background
Urea compounds are widely used as an important compound in chemical fertilizers, pesticides, medicines and fine chemical products. The traditional method for synthesizing urea compounds is to synthesize the urea compounds by utilizing nucleophilic addition reaction of phosgene, isocyanate and amine. However, the requirement for sustainable development is not met due to the highly toxic nature of phosgene, isocyanate, environmental unfriendly and limited substrates. In recent years, chemists have increasingly tended to synthesize urea compounds using transition metal catalyzed processes under mild conditions to increase synthesis yields and substrate versatility. Such as transition metal catalyzed addition of sodium cyanate, halobenzene, and amine, transition metal catalyzed addition of amine to carbon monoxide, transition metal catalyzed addition of azide, amine, and carbon monoxide, transition metal catalyzed addition of halobenzene, sodium azide, aromatic amine, and the like. However, these reactions all require the use of extremely toxic or toxic substances such as isocyanate, sodium cyanate, carbon monoxide, azide compounds or sodium azide, and require high temperatures and other severe conditions, which cannot be applied to industrial production.
At room temperature, the reaction of directly preparing urea compounds by using amide and amine without toxicity has not been reported so far.
Disclosure of Invention
The invention provides a method for synthesizing urea compounds by utilizing amidation reaction of amide and amine at room temperature, which can efficiently prepare various urea compounds.
The method mainly uses various copper salts, copper oxides, supported nano copper catalysts and homogeneous/heterogeneous palladium catalysts as catalysts, oxygen in air is used as an oxidant, and various urea derivatives are prepared through C-C bond oxidative cleavage of amide and addition reaction of amine at room temperature, wherein the reaction adopts a combined strategy of chelation assistance and C-C bond oxidative cleavage, so that the technical barrier that the amide cannot directly react with the amine to prepare urea compounds through the C-C bond cleavage at room temperature is broken.
The chemical reaction equation involved in the method of the invention is as follows:
the method for synthesizing the urea compound by utilizing the amidation reaction of the amide and the amine comprises the following steps:
(1) Dissolving amide, a transition metal catalyst and amine in an organic solvent to obtain a mixed solution A; preferably, the molar ratio of the amide, the transition metal catalyst and the amine is 1:0.02 to 0.5:1-4.
The amide isWherein R is-> (n＝1,2,3,4,5,6)；(n＝1,2,3,4,5,6)；/>(X＝-CN,-NO 2 ,-F,-Cl,-Br,-I,-OH,-OCH 3 ,-OC 2 H 5 ,-SH,-NH 2 ,-SO 3 H,-COOH,-COOCH 3 ,-COOC 2 H 5 ,-CONH 2 ,-CONHCH 3 ,-COCH 3 ,-COC 2 H 5 -CHO); wherein hetAr is->
The transition metal catalyst is copper chloride, copper sulfate, cuprous bromide, cupric acetate, cuprous iodide, cuprous cyanide, cupric oxide, cuprous oxide, and supported nano copper catalyst (Cu/Al) 2 O 3 Cu/C, cu/MOF-5) or palladium acetate, palladium trifluoroacetate, palladium chloride, tetraphenylphosphine palladium, supported nano-palladium catalyst (Pd/Al) 2 O 3 ，Pd/C,Pd/MOF-5)；
The amine is Ar 1 NH 2 Or R is 1 NH 2 Or R is 2 R 3 NH, wherein Ar 1 Is that
Wherein R is 2 R 3 NH is(n＝1,2,3,4,5,6)；
Wherein R is 1 NH 2 Is that(n＝1,2,3,4,5,6,7,8)；/>(n＝1,2,3,4,5,6,7,8)；(n＝0,1,2,3,4,5,6,7,8,9,10,11,12,13)；/>(n＝1,2,3,4,5,6,7,8)；
The organic solvent is acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, toluene, chlorobenzene, chloroform, N-dimethylformamide, dimethyl sulfoxide;
(2) Stirring the mixed solution A for 1-6 hours at room temperature to obtain mixed solution B;
the reaction in the step (2) is not limited in terms of reaction time, and the reaction may be carried out by taking samples at regular time and performing trace analysis by conventional means such as Thin Layer Chromatography (TLC), and the end point of the reaction may be regarded as the end point of the reaction when one or more of the raw materials are reacted.
(3) Filtering the mixed solution B, concentrating the filtrate, and performing column chromatography to obtain various urea compounds.
Compared with the prior art, the invention has the following beneficial effects:
the method synthesizes the urea compound through the amidation reaction of the amide and the amine, and the reactants do not need to be excessive. Compared with the prior art, the method directly uses common non-toxic amide as a substrate without using extremely toxic or toxic substances such as isocyanate, sodium cyanate, carbon monoxide, azide compounds or sodium azide and the like as a reaction substrate. At room temperature, oxygen in the air is used as an oxidant, and the method realizes the chemical specificity C-C bond rupture of the amide and further performs amidation reaction with the amine to obtain various urea compounds. The method has the advantages of mild reaction conditions, simple operation, short time and high yield, and is suitable for being applied to industrial production.
Detailed Description
Example 1
This example prepares 1- (3-methylpyridin-2-yl) -3-phenylurea by amidation of N- (3-methylpyridin-2-yl) -2-naphthamide with aniline.
0.1mmol of N- (3-methylpyridin-2-yl) -2-naphthanoacetamide, 0.01mmol of copper chloride and 0.2mmol of aniline are dissolved in 1mL of methylene chloride, and the obtained reaction mixture is stirred at room temperature for 6 hours; the obtained mixed solution is filtered, the filtrate is concentrated, and the 1- (3-methylpyridin-2-yl) -3-phenyl urea can be obtained through column chromatography, and the yield is about 76%.
The nuclear magnetic monitoring data are as follows: 1 HNMR(600MHz,CDCl 3 )δ12.20(s,1H),8.13(d,J＝4.4Hz,1H),7.61(d,J＝7.9Hz,2H),7.47(d,J＝7.2Hz,1H),7.34(t,J＝7.8Hz,2H),7.11(d,J＝13.9Hz,1H),7.08(t,J＝7.4Hz,1H),6.88(dd,J＝7.2,5.1Hz,1H),2.29(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ152.8,151.3,143.5,139.4,138.5,128.9,123.4,120.3,119.2,117.2,17.0.
example 2
This example prepares 1- (3-methylpyridin-2-yl) -3-propyl urea by amidation of N- (3-methylpyridin-2-yl) -2, 2-diphenylacetamide with propylamine.
0.5 mmole of N- (3-methylpyridin-2-yl) -2, 2-diphenylacetamide, 0.05 mmole of palladium acetate, 1 mmole of propylamine were dissolved in 2mL of acetonitrile, and the resulting reaction mixture was stirred for 6 hours; filtering the obtained mixed solution, concentrating the filtrate, and performing column chromatography to obtain the 1- (3-methylpyridin-2-yl) -3-propyl urea with the yield of about 51%.
The nuclear magnetic monitoring data are as follows: 1 H NMR(600MHz,CDCl 3 )δ9.76(s,1H),8.05(d,J＝4.7Hz,1H),7.41(d,J＝7.3Hz,1H),6.81(dd,J＝7.2,5.2Hz,1H),6.77(s,1H),3.37-3.33(m,2H),2.22(s,3H),1.70-1.61(m,2H),0.99(t,J＝7.4Hz,3H)； 13 C NMR(151MHz,CDCl 3 )δ155.5,151.7,143.8,138.8,118.7,116.7,41.7,23.2,17.0,11.6.
example 3
This example prepares N- (3-methylpyridin-2-yl) morpholin-4-carboxamide by amidation of N- (3-methylpyridin-2-yl) -2, 2-diphenylacetamide with morpholin.
0.1 mmole of N- (3-methylpyridin-2-yl) -2, 2-diphenylacetamide, 0.005 mmole of copper acetate, 0.1 mmole of morpholin were dissolved in 1mL of dichloroethane, and the resulting reaction mixture was stirred at room temperature for 1.5 hours; filtering the obtained mixed solution, concentrating the filtrate, and performing column chromatography to obtain the N- (3-methylpyridin-2-yl) morpholin-4-carboxamide with the yield of about 93%.
The nuclear magnetic monitoring data are as follows: 1 H NMR(600MHz,CDCl 3 )δ8.78(s,1H),8.17(d,J＝3.5Hz,1H),7.58(d,J＝7.3Hz,1H),7.10(dd,J＝7.2,4.9Hz,1H),3.64–3.56(m,4H),3.47–3.38(m,4H),2.12(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ155.3,152.0,145.1(d,J＝9.2Hz,1C),138.7(d,J＝8.0Hz,1C),128.0,120.3(d,J＝18.9Hz,1C),66.0,44.3,17.6.
examples 4 to 13
In examples 4 to 13, only the types of the amide and the amine were changed by using the reaction conditions and the material ratios of example 3, and the raw materials used in each example and the obtained products and the product yields were shown in Table 1.
TABLE 1
The nuclear magnetic resonance monitoring data of the target products in examples 4 to 13 are as follows:
example 4:1- (3-methylpyridin-2-yl) -3- (4-methylphenyl) urea
1 H NMR(600MHz,CDCl 3 )δ12.05(s,1H),8.13(d,J＝4.2Hz,1H),7.48(t,J＝9.3Hz,3H),7.14(d,J＝8.2Hz,2H),6.92(s,1H),6.88(dd,J＝7.3,5.1Hz,1H),2.33(s,3H),2.27(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ152.8,151.33,143.6,139.2,135.9,133.0,129.4,120.4,119.1,117.1,20.9,17.0.
Example 5:1- (3-methylpyridin-2-yl) -3- (2-isopropylphenyl) urea
1 H NMR(600MHz,CDCl 3 )δ12.08(s,1H),8.08(d,J＝2.8Hz,1H),8.02(d,J＝6.3Hz,1H),7.49(d,J＝5.2Hz,1H),7.31(d,J＝6.8Hz,1H),7.23(t,J＝7.2Hz,1H),7.13(t,J＝7.4Hz,1H),6.99(s,1H),6.92-6.87(m,1H),3.34-3.28(m,1H),2.29(s,3H),1.33(d,J＝6.8Hz,6H)； 13 C NMR(151MHz,CDCl 3 )δ153.2,151.4,143.4,139.3,139.0,135.5,126.3,125.2,124.4,123.0,119.1,117.1,28.2,23.0,17.0.
Example 6:1- (3-methylpyridin-2-yl) -3- (4-phenylphenyl) urea
1 H NMR(600MHz,CDCl 3 )δ12.01(s,1H),8.45(d,J＝8.3Hz,1H),7.46(d,J＝4.5Hz,4H),7.45-7.42(m,1H),7.38(t,J＝7.1Hz,1H),7.33(d,J＝7.2Hz,1H),7.23-7.19(m,2H),7.12(t,J＝7.3Hz,1H),6.85(s,1H),6.65(dd,J＝7.1,5.2Hz,1H),2.19(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ152.8,150.6,143.2,139.6,138.9,136.6,132.7,130.3,130.0,128.6,128.3,127.4,123.0,121.0,118.4,116.7,16.8.
Example 7:1- (3-methylpyridin-2-yl) -3- (4-ethoxyphenyl) urea
1 H NMR(600MHz,CDCl 3 )δ11.97(s,1H),8.11(d,J＝4.2Hz,1H),7.49(d,J＝8.9Hz,2H),7.46(d,J＝7.0Hz,1H),7.04(s,1H),6.90-6.85(m,3H),4.02(q,J＝7.0Hz,2H),2.27(s,3H),1.41(t,J＝7.0Hz,3H)； 13 C NMR(151MHz,CDCl 3 )δ155.3,153.0,151.4,143.5,139.2,131.5,122.1,119.1,117.1,114.9,63.7,17.0,14.9.
Example 8:1- (3-methylpyridin-2-yl) -3- (2-fluorophenyl) urea
1 H NMR(600MHz,CDCl 3 )δ12.57(s,1H),8.33(t,J＝7.7Hz,1H),8.17(d,J＝4.5Hz,1H),7.49(d,J＝7.0Hz,1H),7.15-7.10(m,2H),7.07-6.98(m,2H),6.91(dd,J＝7.0,5.3Hz,1H),2.30(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ153.9,152.7,151.0,143.7,139.4,127.2(d,J＝9.9Hz,1C),124.4(d,J＝3.5Hz,1C),123.3(d,J＝6.9Hz,1C),121.7,119.0,117.4,114.78(d,J＝19.0Hz,1C),16.9.
Example 9:1- (3-methylpyridin-2-yl) -3- (3-trifluoromethylphenyl) urea
1 H NMR(600MHz,CDCl 3 )δ12.51(s,1H),8.16(d,J＝4.2Hz,1H),7.93(s,1H),7.80(d,J＝8.0Hz,1H),7.51(d,J＝7.2Hz,1H),7.44(t,J＝7.9Hz,1H),7.33(d,J＝7.7Hz,2H),6.92(dd,J＝7.2,5.2Hz,1H),2.33(s,3H)； 13 C NMR(151MHz,CDCl 3 )δ152.9,151.1,143.5,139.6,139.2,131.3(q,J＝32.1Hz,1C),129.4,124.1(q,J＝271.5Hz,1C),119.8(q,J＝3.8Hz,1C),119.6,117.5,116.8(q,J＝4.1Hz,1C),17.0.
Example 10:1- (3-methylpyridin-2-yl) -3- (3-methylpyridin-2-yl) urea
1 H NMR(600MHz,CDCl 3 )δ12.39(s,2H),8.25(s,2H),7.53(d,J＝7.2Hz,2H),6.98(s,2H),2.36(s,6H)； 13 C NMR(151MHz,CDCl 3 )δ152.2,150.7,144.8,139.4,118.8,17.6.
Example 11: n- (3-methylpyridin-2-yl) tetrahydropyrrole-1-carboxamide
1 H NMR(600MHz,CDCl 3 )δ8.17(d,J＝4.3Hz,1H),7.51(d,J＝5.6Hz,1H),7.09-6.96(m,1H),6.73(s,1H),3.54-3.44(m,4H),2.31(s,3H),2.02-1.91(m,4H)； 13 C NMR(151MHz,CDCl 3 )δ154.1,151.2,145.4,139.5,128.2,120.6,46.1,25.6,18.4.
Example 12:1- (3-methylpyridine-2)-group) -3-n-octyl urea
1 H NMR(600MHz,CDCl 3 )δ9.73(s,1H),8.04(d,J＝4.3Hz,1H),7.42(d,J＝7.2Hz,1H),6.81(dd,J＝7.2,5.2Hz,1H),6.78(s,1H),3.42-3.35(m,2H),2.22(s,3H),1.66-1.57(m,2H),1.42-1.36(m,2H),1.35-1.25(m,8H),0.88(t,J＝6.9Hz,3H)； 13 C NMR(151MHz,CDCl 3 )δ155.4,151.8,143.7,138.8,118.7,116.7,40.031.8,30.0,29.3,29.3,27.1,22.7,17.0,14.1
Example 13:1- (3-methylpyridin-2-yl) -3-serotonin urea
1 H NMR(600MHz,DMSO)δ10.47(s,1H),9.44(s,1H),8.51(s,1H),8.00(s,1H),7.91(d,J＝4.1Hz,1H),7.51(d,J＝7.0Hz,1H),7.13(d,J＝8.6Hz,1H),7.09(d,J＝1.9Hz,1H),6.90–6.82(m,2H),6.60(dd,J＝8.6,2.2Hz,1H),3.54–3.45(m,2H),2.84(t,J＝7.0Hz,2H),2.20(s,3H)； 13 C NMR(151MHz,DMSO)δ155.3,152.2,150.7,143.6,139.6,131.4,128.3,123.9,120.7,117.3,112.1,111.8,111.2,102.8,40.426.0,17.4.
Claims (4)
1. A method for synthesizing urea compounds by utilizing amidation reaction of amide and amine at room temperature is characterized in that: the method comprises the following steps: s1, dissolving amide, a transition metal catalyst and amine in an organic solvent to obtain a mixed solution A, wherein the chemical reaction equation is as follows:
ar in the urea compound 1 、R 1 、R 2 、R 3 HetAr is as defined in the starting materials;
the amide isWherein R is-> n＝1,2,3,4,5,6；/>n＝1,2,3,4,5,6；/>X＝-CN,-NO 2 ,-F,-Cl,-Br,-I,-OH,-OCH 3 ,-OC 2 H 5 ,-SH,-NH 2 ,-SO 3 H,-COOH,-COOCH 3 ,-COOC 2 H 5 ,-CONH 2 ,-CONHCH 3 ,-COCH 3 ,-COC 2 H 5 -CHO; wherein hetAr is
The amine is Ar 1 NH 2 Or R is 1 NH 2 Or R is 2 R 3 NH, wherein Ar 1 Is that
Wherein R is 2 R 3 NH isn＝1,2,3,4,5,6；
Wherein R is 1 NH 2 Is thatn＝1,2,3,4,5,6,7,8；/>n＝1,2,3,4,5,6,7,8；n＝0,1,2,3,4,5,6,7,8,9,10,11,12,13；/>n＝1,2,3,4,5,6,7,8；
S2, stirring the mixed solution A at room temperature for 1-6 hours to obtain mixed solution B;
s3, filtering the mixed solution B, concentrating the filtrate, and performing column chromatography to obtain the urea compound;
the reaction uses oxygen in the air as an oxidant; the transition metal catalyst is copper chloride, copper acetate, palladium acetate, copper sulfate, palladium trifluoroacetate or palladium chloride.
2. The method for synthesizing urea-based compounds by amidation reaction of amide and amine at room temperature according to claim 1, wherein: the organic solvent is acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, toluene, chlorobenzene, chloroform, N-dimethylformamide, and dimethyl sulfoxide.
3. The method for synthesizing urea-based compounds by amidation reaction of amide and amine at room temperature according to claim 1, wherein: the molar ratio of the amide to the transition metal catalyst is 1:0.02 to 0.5.
4. The method for synthesizing urea-based compounds by amidation reaction of amide and amine at room temperature according to claim 1, wherein: the molar ratio of the amide to the amine is 1:1 to 4.
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| CN102503860A (en) * | 2011-11-14 | 2012-06-20 | 武汉大学 | Synthetic method of 1, 3-two substituted ureas and carbamate |
| CN104744356A (en) * | 2015-03-24 | 2015-07-01 | 上海大学 | Synthesis method of disubstituted urea compounds |
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| CN102503860A (en) * | 2011-11-14 | 2012-06-20 | 武汉大学 | Synthetic method of 1, 3-two substituted ureas and carbamate |
| CN104744356A (en) * | 2015-03-24 | 2015-07-01 | 上海大学 | Synthesis method of disubstituted urea compounds |
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| Sen Li等."Selective C–C bond cleavage of amides fused to 8-aminoquinoline controlled by a catalyst and an oxidant".《Chem. Commun.》.2020,第56卷13820-13823. * |
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