CN113444024A - Method for synthesizing polysubstituted ureas, thioureas, chiral ureas and thioureas compounds without catalyst and solvent - Google Patents
Method for synthesizing polysubstituted ureas, thioureas, chiral ureas and thioureas compounds without catalyst and solvent Download PDFInfo
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- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C273/18—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas
- C07C273/1809—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety
- C07C273/1818—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups of substituted ureas with formation of the N-C(O)-N moiety from -N=C=O and XNR'R"
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- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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- C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
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- C07C335/04—Derivatives of thiourea
- C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C335/18—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
The invention discloses a method for synthesizing polysubstituted carbamides, thioureas, chiral carbamides and thioureas compounds without catalyst and solvent, which comprises the following steps: carrying out a first contact reaction on a compound with a structure shown as a formula A and an amine compound with a structure shown as a formula B under the conditions of no catalyst and no solvent to prepare a polysubstituted urea or thiourea compound with a structure shown as a formula C, R1And R2Each independently selected from hydrocarbyl or substituted hydrocarbyl, R3Selected from H, alkyl or substituted alkyl, and X is S or O. The method overcomes the defect that a catalyst and/or a solvent are required in the synthesis of urea compounds and thiourea compounds in the prior art.
Description
Technical Field
The invention relates to synthesis of urea or thiourea compounds, in particular to a method for synthesizing polysubstituted urea, thiourea, chiral urea and thiourea compounds without catalysts and solvents.
Background
The urea and thiourea derivatives are very important organic compounds and are widely applied in the fields of biology, medicine, agriculture, organic synthesis, material science and the like. For example, PKI-587 for anticancer drugs and carmustine for the treatment of brain tumors both have a urea building block, and urea derivatives such as monuron, fennuron, isoprotron, which are widely used as herbicides.
The prior synthesis method of the urea and thiourea derivatives comprises the following steps: (1) reaction of primary amines with phosgene. This method has been abandoned due to the toxicity and environmental issues of phosgene; (2) oxidative carbonylation of amine-based compounds. The method requires the use of gaseous CO or CO2. In 2002, noble metal gold developed by the Dang Yong general topic group is immobilized on a polymer catalyst, and when the loading amount of Au is 0.51 wt%, the noble metal gold acts on oxidative carbonylation of substituted arylamine to realize the synthesis of symmetric urea derivatives (refer to the documents J.Catal.2002,211, 548-551); (3) reductive carbonylation of nitro compounds. In 2012, the group of Vavasori topics used a pd (ii) catalytic system for the reductive carbonylation of nitrobenzene to 1, 3-diphenylurea in acetic acid-methanol medium (ref "Pure appl. chem,2012,84,473, 484"); (4) oxidative cross-coupling of formamide with amines. In 2013, Reddy project group reported that under the action of 5 mol% of CuBr and 1.5 equivalents of TBHP, oxidative coupling of DMF and amine can be realized to generate polysubstituted urea compounds (refer to the literature, "chem688 page "); (5) hydroamination of isocyanates or isothiocyanates. The methods reported in these reaction documents require the addition of a catalyst, such as 3 mol% of an alkaline earth metal (see "chem. Commun,2008,41, 5206. page 5208; chem. Commun,2013,49, 8659-.
As can be seen from the above, in the method (1), phosgene which is toxic is used. In the methods (2) to (4), not only a catalyst is required, but also the most important point is that the atom utilization rate of the chemical reaction is low, and a by-product is separated. The method (5) is a synthesis reaction with 100% atom economy, the methods reported in the literature all need to use a metal catalyst for synthesis, some catalytic systems need to be synthesized by means of dispersion of a solvent, and the use of the catalyst or the solvent increases synthesis cost, increases purification difficulty of products and increases residual risk of heavy metals in the products invisibly. More importantly, the method has adverse effect on environmental protection and is not in accordance with the concept of green chemistry.
Chiral urea and thiourea compounds are widely used in asymmetric syntheses as chiral reagents. In 2005, Juaristi group obtained urea compounds with 2 chiral centers in 79% yield from (R) -1-phenylethylamine and triphosgene in a solvent of triethylamine and chloroform (see "J. Phys. org. chem,2005,18,792-799 page"). In 2016, Lee group tried the synthesis of chiral ureas using Cbz-protected chiral amines and aniline under the action of 2-chloropyridine and trifluoromethanesulfonic anhydride (see "org. Biomol. chem,2016,14, 73457353"). In the same year, the Roesky group used urea and chiral amine to synthesize chiral urea by heating to 130 ℃ in 3-methyl-1-butanol solvent (refer to "Organometallics, 2016,35, 3474-.
Although the above synthesis can obtain chiral urea and thiourea compounds with certain structures, the following defects exist: use of very odorous triethylamine; synthetic routes with low atom economy; the high temperature reaction increases the possibility of racemization of chiral substances; use of a reaction solvent. The use of the solvent increases the synthesis cost and increases the purification difficulty of the product, and more importantly, the hydrophilic solvent such as alcohols and ethers is extremely difficult to completely dry, while the isocyanate compound is easily decomposed when contacting water.
Disclosure of Invention
The invention aims to provide a method for synthesizing polysubstituted urea compounds, thiourea compounds, chiral urea compounds and thiourea compounds without catalysts and solvents, so as to overcome the defect that catalysts and/or solvents are required in the synthesis of urea compounds and thiourea compounds in the prior art.
In order to achieve the purpose, the invention discloses a method for synthesizing polysubstituted urea and thiourea compounds without catalysts and solvents, which comprises the following steps: carrying out a first contact reaction on a compound with a structure shown as a formula A and an amine compound with a structure shown as a formula B under the conditions of no catalyst and no solvent to prepare a polysubstituted urea or thiourea compound with a structure shown as a formula C,
wherein R is1And R2Each independently selected from hydrocarbyl or substituted hydrocarbyl, R3Selected from H, alkyl or substituted alkyl, and X is S or O.
The invention also provides a method for synthesizing bridged chiral urea and thiourea compounds without catalysts and solvents, which comprises the following steps: carrying out a second contact reaction on the bridged diamine with the structure shown in the formula E and the compound with the structure shown in the formula F under the conditions of no catalyst and no solvent to prepare a bridged chiral urea or thiourea compound with the structure shown in the formula D,
wherein R is8、R9And R10Each independently selected from hydrocarbyl or substituted hydrocarbyl, and X is S or O.
According to the technical scheme, on one hand, the compound (isocyanate compound or isothiocyanate compound) with the structure shown in the formula A and the amine compound (primary amine compound or secondary amine compound) with the structure shown in the formula B are directly subjected to nucleophilic addition reaction to prepare the polysubstituted urea or thiourea compound with the structure shown in the formula C, and in the preparation process, a catalyst and a solvent are not needed, so that the defects of high product purification difficulty and high synthesis cost are overcome, and meanwhile, the environment is protected, so that the method conforms to the green chemical concept.
Wherein in the polysubstituted carbamide or thiourea compound with the structure shown in the formula C, R1And R2The substituted urea compounds or thiourea compounds can be the same or different, and can be symmetrical structures or asymmetrical structures.
In addition, when the compound with the structure shown in the formula A or the amine compound with the structure shown in the formula B is a chiral compound, the prepared polysubstituted urea or thiourea compound with the structure shown in the formula C is also a chiral compound, and the number of chiral centers can be one or more.
On the other hand, the bridged chiral urea or thiourea compound with the structure shown in the formula D can be prepared by directly carrying out nucleophilic addition reaction on the bridged diamine with the structure shown in the formula E and the compound (isocyanate compound or isothiocyanate compound) with the structure shown in the formula F, wherein the bridged chiral urea or thiourea compound has a plurality of chiral centers. In the same way, in the preparation process, a catalyst and a solvent are not needed, so that the defects of high difficulty in product purification and high synthesis cost are overcome, and meanwhile, the method is beneficial to environmental protection, so that the method conforms to the concept of green chemistry.
In addition, in the above two synthetic methods, a small amount of solvent can be added to disperse solid raw materials or gas raw materials, but the inventors have experimentally confirmed that the yield is improved by not more than 5% after the solvent is used, but the difficulty is increased for the subsequent purification of the product, and the product is lost in the purification process.
The inventors emphasize that the two methods provided by the present invention seem to be simple nucleophilic addition reactions, but the invention also goes through a tortuous process. The methods reported in the literature all use catalysts, most of which are solid, and the chemical reaction is more favorable in homogeneous phase, which requires adding solvent to dissolve reactants. The inventors also used 5 mol% rare earth catalyst and solvent when initially making this reaction of aniline and phenyl isocyanate. The addition reaction was inadvertently found to be exothermic when no solvent was used, but in the solvent screen. In a control experiment, it was found that the results were very good when no catalyst was used and no solvent was used. The use of solvents in the prior art not only dilutes the reaction raw materials, but also masks the exothermic reaction. In comparison, isothiocyanates are less reactive than isocyanates, emit heat slowly, and add slowly.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:
FIG. 1 is a nuclear magnetic hydrogen spectrum of the product of example 1;
FIG. 2 is a nuclear magnetic hydrogen spectrum of the product of example 13.
FIG. 3 is a nuclear magnetic carbon spectrum of the product of example 16.
FIG. 4 is a nuclear magnetic hydrogen spectrum of the product of example 18.
Detailed Description
The following describes in detail specific embodiments of the present invention. It should be understood that the detailed description and specific examples, while indicating the present invention, are given by way of illustration and explanation only, not limitation.
The invention discloses a method for synthesizing polysubstituted carbamide and thiourea compounds without catalyst and solvent, which comprises the following steps: carrying out a first contact reaction on a compound with a structure shown as a formula A and an amine compound with a structure shown as a formula B under the conditions of no catalyst and no solvent to prepare a polysubstituted urea or thiourea compound with a structure shown as a formula C,
wherein R is1And R2Each independently selected from hydrocarbyl or substituted hydrocarbyl, R3Selected from H, alkyl or substituted alkyl, and X is S or O.
In the above method, the kind of each substituent is not particularly limited, but preferably R is selected from the viewpoint of the yield of the product and the application of the product1And R2Each independently selected from C1-C20 hydrocarbyl or C1-C20 substituted hydrocarbyl, R3Selected from H, C1-C20 hydrocarbyl or C1-C20 substituted hydrocarbyl; more preferably, R1And R2Each independently selected from C1-C20 hydrocarbyl, C1-C20 halogen substituted hydrocarbyl or C1-C20 oxygen substituted hydrocarbyl, R3Selected from H, C1-C20 hydrocarbyl, C1-C20 halogen substituted hydrocarbyl or C1-C20 oxygen substituted hydrocarbyl; further preferably, R1And R2Each independently selected from phenyl, p-chlorophenyl, p-bromophenyl, p-toluenesulfonyl, tert-butyl, 2, 6-diisopropylphenyl, cyclohexyl, p-methoxyphenyl, p-fluorophenyl, p-tert-butylphenyl, 2-tetrahydrofurylidene, p-methylphenyl, methyl, ethyl or substituted oxyethyl, R3Selected from H, methyl, ethyl, phenyl, p-methoxyphenyl, p-fluorophenyl, cyclohexyl, 2-tetrahydrofuryl methylene, p-tert-butylphenyl, 2, 6-diisopropylphenyl or substituted oxyethyl; even more preferably, when R is2And R3Each independently selected from hydrocarbyl or substituted hydrocarbyl2And R3Is a linear substituent, a substituent with a branched chain or R2、R3And N are connected into a ring.
More preferably, the compound having the structure shown in formula A is at least one selected from phenyl isocyanate, p-chlorophenyl isocyanate, p-bromophenyl isocyanate, p-toluenesulfonyl isocyanate, tert-butyl isocyanate, p-fluorophenyl isothiocyanate, cyclohexyl isothiocyanate, phenyl isothiocyanate and p-tolyl isocyanate; the amine compound with the structure shown in the formula B is selected from at least one of 2, 6-diisopropylaniline, tetrahydropyrrole, p-methoxyphenyl isothiocyanate, 3-methoxyaniline, p-tert-butyl aniline, tetrahydrofurfuryl amine, morpholine, dimethylamine and aniline; more preferably, the polysubstituted urea or thiourea compound of formula C is selected from the group consisting of 1, 3-diphenylurea, 3- (4-chlorophenyl) -1, 1-dimethylurea, 3- (4-chlorophenyl) -1-phenylurea, 3- (4-bromophenyl) -1-phenylurea, 3-p-toluenesulfonyl-1-phenylurea, 3-phenyl-1-tert-butylurea, 3-phenyl-1- (2, 6-diisopropylphenyl) urea, 3-p-methoxyphenyl-1-phenylurea, 3-p-methoxyphenyl-1-phenylthiourea, 3-p-fluorophenyl-1-phenylthiourea, 3-cyclohexyl-1-p-methoxyphenyl thiourea, 3-p-methoxyphenyl thiourea, and mixtures thereof, 3-p-tert-butylphenyl-1-phenylthiourea, -3-phenyl-1- (2-tetrahydrofurylmethylene) thiourea, a thiourea compound of the structure represented by the formula C-3 or a urea compound of the structure represented by the formula C-4,
in the invention, the polysubstituted urea or thiourea compound can be a chiral compound or an achiral compound, and considering that the chiral compound has a wide application range, preferably, the polysubstituted urea or thiourea compound is a chiral compound and has a structure shown as a formula C-1 or a formula C-2; when the structure of the polysubstituted urea or thiourea compound is shown as a formula C-1, the structure of the amine compound is shown as a formula B-1; when the structure of the polysubstituted urea or thiourea compound is as shown in a formula C-2, the structure of the compound with the structure shown in the formula A is as shown in a formula A-1, and the structure of the amine compound is as shown in a formula B-1;
wherein R is4、R5、R6And R7Each independently selected from hydrocarbyl or substituted hydrocarbyl, R1And the aforementioned R1Similarly, no additional description is made herein.
In the above embodiment, for R4、R5、R6And R7Also, the specific species of (A) is not limited, but preferably, R is selected from the viewpoint of the yield of the product and the application of the product4、R5、R6And R7Each independently selected from C1-C20 hydrocarbyl, C1-C20 halogen substituted hydrocarbyl; more preferably, R4、R5、R6And R7Each independently selected from cyclohexyl, phenyl, p-chlorophenyl, p-methylphenyl or methyl; further preferably, the compound having the structure shown in formula a is at least one selected from p-tolyl isothiocyanate, phenyl isocyanate, p-chlorophenyl isocyanate, phenyl isothiocyanate, (S) - α -methylbenzyl isocyanate and p-tolyl isocyanate; the amine compound with the structure shown in the formula B is at least one of (S) -1-phenylethylamine and (S) -1-cyclohexylethylamine; the polysubstituted urea or thiourea compound with the structure shown in the formula C is (S) -1- (1-phenethyl) -3- (p-tolyl) urea, (S) -1- (p-tolyl) -3- (1-cyclohexylethyl) thiourea or a urea compound with the structure shown in the formula C-5,
on the basis of the above embodiment, in order to further ensure the yield, preferably, the molar ratio of the amine compound having the structure shown in formula B to the compound having the structure shown in formula a is 1: (1-1.05). The compound with the structure shown in the formula A is slightly excessive, so that the amine compound can be ensured to react completely as much as possible, and meanwhile, the difficulty caused by the fact that the excessive using amount of the compound with the structure shown in the formula A is large in aftertreatment can be avoided.
On the basis of the above embodiment, in order to further secure the yield, it is preferable that the first contact reaction at least satisfies the following conditions: the reaction temperature is 20-50 ℃, and the reaction time is 5-120 min; more preferably, the first contact reaction satisfies at least the following conditions: the reaction temperature is 25-50 ℃, and the reaction time is 5-60 min; more preferably, the first contact reaction satisfies at least the following conditions: the reaction temperature is 25-50 ℃, wherein, when the substrate is in a liquid state, the reaction temperature is 25-50 ℃; when the substrate contains solid, the reaction temperature is 45-50 ℃; further preferably, the reaction time is 5-40min, wherein when the substrate is in a liquid state, the reaction time is 10-20 min; when the substrate contains a solid state, the reaction temperature is 35-40 min.
Among them, the sterically hindered or aliphatic amines or solid substrates, such as 2, 6-dimethylaniline, 2, 6-diisopropylaniline, tert-butylamine, isopropylamine, cyclohexylamine, amantadine, p-bromophenyl isocyanate, p-chlorophenyl isocyanate are preferably reacted for 20 to 25min, preferably at a temperature of 40 to 45 ℃. More preferably, the reaction time of the urea compound is 5-20min, the reaction time of the thiourea compound is 16-40min, and the preferred reaction time of the chiral urea and the thiourea compound is 28-60 min.
Wherein, in order to improve the yield, the reaction time is properly prolonged, if the conversion rate is not complete after reaching the preset time, the reaction temperature can be properly heated and increased, and the optimal combination between the reaction temperature and the reaction time is searched, preferably not more than 50 ℃.
The invention also provides a method for synthesizing bridged chiral urea and thiourea compounds without catalysts and solvents, which comprises the following steps: carrying out a second contact reaction on the bridged diamine with the structure shown in the formula E and the compound with the structure shown in the formula F under the conditions of no catalyst and no solvent to prepare a bridged chiral urea or thiourea compound with the structure shown in the formula D,
wherein R is8、R9And R10Each independently selected from hydrocarbyl or substituted hydrocarbyl,x is S or O.
In the above process, for R8、R9And R10Is not particularly limited, but preferably R is selected from the viewpoint of yield and application of the product8、R9And R10Each independently selected from C1-C20 aliphatic hydrocarbyl, C1-C20 substituted aliphatic hydrocarbyl, C6-C20 aromatic hydrocarbyl or C6-C20 substituted aromatic hydrocarbyl; more preferably, R8And R9Each independently selected from phenyl, C1-C10 alkyl, R10Selected from p-methoxyphenyl; further preferably, R8And R9Is a linear substituent, a substituent with a branched chain or R8、R9And two C are connected to form a ring; still more preferably, the compound of the structure represented by formula a is selected from at least one of p-methoxyphenyl isothiocyanate and p-methoxyphenyl isocyanate; the bridged diamine with the structure shown in the formula E is at least one selected from (1R,2R) -1, 2-diphenylethylenediamine, (1S,2S) -cyclohexanediamine and 1, 1' -di (2-naphthylamine); still more preferably, the structure of the bridged chiral urea or thiourea compound is shown as a formula D-1 or a formula D-2 or a formula D-3,
on the basis of the above embodiment, in order to further ensure the yield, it is preferable that the bridged diamine is a compound having a structure shown in formula F in a molar ratio (2 to 2.05): 1. the bridged diamine is slightly excessive, so that the compound with the structure shown as the formula F can be ensured to react completely as much as possible, and the difficulty caused by aftertreatment due to excessive use amount of the bridged diamine can be avoided.
On the basis of the above embodiment, in order to further secure the yield, it is preferable that the second contact reaction at least satisfies the following conditions: the reaction temperature is 20-50 ℃, and the reaction time is 5-120 min; more preferably, the second contact reaction satisfies at least the following conditions: the reaction temperature is 25-50 ℃, and the reaction time is 40-60 min. The bridged diamine is mostly solid and, to improve yield, the substituted isocyanate or isothiocyanate is added by heating to a solid near melting. Furthermore, the mixing of the substances leads to a lowering of the melting point. To ensure more complete reaction of the diurea or dithiourea, the amount of isocyanate or isothiocyanate may be increased appropriately, preferably not more than 5% equivalent. Aliphatic isocyanates or isothiocyanates, such as tert-butyl isocyanate (thio) isocyanate, isopropyliso (thio) cyanate and p-bromophenyl isocyanate (thio) cyanate, p-chlorophenyl iso (thio) cyanate, preferably for a reaction time of from 50 to 60min, preferably at a temperature of from 40 to 50 ℃.
Wherein, in order to improve the yield, the reaction time is properly prolonged, if the conversion rate is not complete after reaching the preset time, the reaction temperature can be properly heated and increased, and the optimal combination between the reaction temperature and the reaction time is searched, preferably not more than 50 ℃.
In all the above embodiments, in order to prevent hydrolysis of the compound having the structure represented by formula a or the compound having the structure represented by formula F and thus ensure the yield, it is preferable that the water content of the raw material is less than 0.1 wt%.
In addition, the urea compound adopts solvent-free addition reaction, after the reaction is finished, the urea compound is washed by a mixed solution of n-hexane and ether (4-6: 1 volume ratio), or the product is recrystallized and purified by ethanol, and the washing scheme is optimized.
The thiourea compound adopts solvent-free addition reaction, and after the reaction is finished, n-hexane is used for washing the thiourea compound to remove unreacted raw materials. Or separating by column chromatography, wherein the volume ratio of the mobile phase to the ethyl ether is 1: 1-1: 30, preferably 1: 5.
the urea compounds have poor solubility, are difficult to dissolve in toluene, chloroform, ethyl acetate and the like, and can be dissolved in alcohols. Its structure can be characterized in deuterated DMSO. The diurea compound has poorer solubility, can be dissolved in DMSO, and is easily dissolved in DMF. The thiourea compound has good solvent property, is difficult to dissolve in hydrocarbon solvents, and is easy to dissolve in polar solvents such as chloroform, ethyl acetate, diethyl ether and the like. The dithioureas compound has solubility similar to that of thiourea compound, and CDCl is used for nuclear magnetic characterization3The compound is dissolved.
The present invention will be described in detail below by way of examples. In the following examples, M.p refers to the melting point, M.p uses the SGWX-4 micro melting pointThe nuclear magnetic resonance instrument adopts a Bruker 400 (or 500) MHz instrument for detection,1the H NMR resonance frequency is 400 (or 500) MHz,13the C NMR resonance frequency was 100 (or 125) MHz.
The specific optical rotation is measured by an SWG-3 full-automatic optical rotator. HRMS (ESI) was detected using a Thermo Scientific LTQ Orbitrap XL instrument. In the examples, the raw material was treated by distillation (or distillation under reduced pressure) before use so that the water content of the raw material was less than 0.1% by weight.
The compounds represented by each chemical formula or the products in each chemical equation in each example described below are the target products of the example.
Example 1
Phenyl isocyanate (0.119g, 1.0mmol, liquid) and aniline (0.093g, 1.0mmol, liquid) were reacted in the absence of catalyst and solvent at a molar ratio of 1:1 mol ratio is rapidly mixed at 25 ℃, the reaction is slightly exothermic, after 5min, the mixed liquid gradually becomes white solid until the stirrer can not rotate, and the temperature of the reaction bottle is restored to 25 ℃. After 10min, the addition reaction was terminated, and the obtained solid powder was washed with a mixed solution of n-hexane and ether (1 mL each, three times), dried under vacuum, and weighed 0.207g to obtain 1, 3-diphenylurea in an isolated yield of 98%. The nuclear magnetic hydrogen spectrum is shown in figure 1.
The characterization results were as follows: white solid, M.p: 239-.
1H NMR(400MHz,DMSO-d6,ppm):δ8.67(br,2H,NH),7.46(d,J＝8.0Hz,4H,ArH),7.28(t,J＝8.0Hz,4H,ArH),6.97(t,J＝7.2Hz,2H,ArH).
13C NMR(100MHz,DMSO-d6,ppm):δ153.0,140.1,129.2,122.2,118.6.
HRMS(ESI):m/z calcd.for C13H12N2O[M+H]+:213.1022,found:213.1024.
Example 2
The procedure is as in example 1, except that the phenyl isocyanate is replaced by 1.0mmol of p-chlorophenyl isocyanate to give 0.236g of a white solid in 96% yield.
The characterization results were as follows: white solid, M.p: 238-.
1H NMR(400MHz,DMSO-d6,ppm):δ8.84(br,1H,NH),8.73(br,1H,NH),7.49-7.44(m,4H,ArH),7.33-7.26(m,4H,ArH),6.97(d,J＝7.2Hz,1H,ArH).
13C NMR(100MHz,DMSO-d6,ppm):δ153.0,139.7,139.0,129.2,129.0,125.9,122.6,120.3,118.9.
HRMS(ESI):m/z calcd.for C13H11ClN2O[M+H]+:247.0633,found:247.0634.
Example 3
The procedure is as in example 1, except that the phenyl isocyanate is replaced by 1.0mmol of p-bromophenyl isocyanate (0.196g, 1.0mmol, solid), heated to melt at 40 ℃ and 1.0mmol of aniline is added with stirring, the mixture is heated for a further 10min and then cooled to 25 ℃. The other processing methods are the same. 0.266g of a white solid is obtained in 92% yield.
The characterization results were as follows: white solid, M.p: 243-.
1H NMR(400MHz,DMSO-d6,ppm):δ8.82(br,1H,NH),8.71(br,1H,NH),7.47-7.45(m,6H,ArH),7.28(d,J＝7.2Hz,2H,ArH),6.97(d,J＝7.2Hz,1H,ArH).
13C NMR(100MHz,DMSO-d6,ppm):δ152.8,139.9,139.6,131.9,129.2,122.4,120.5,118.7,113.6.
HRMS(ESI):m/z calcd.for C13H11BrN2O[M+H]+:291.0128,found:291.0129.
Example 4
The procedure is as in example 1, except that the phenyl isocyanate is replaced by 1.0mmol of p-toluenesulfonyl isocyanate, 0.261g of a white solid is obtained in 90% yield.
The characterization results were as follows: white solid, M.p:169-170 ℃.
1H NMR(400MHz,DMSO-d6,ppm):δ10.62(br,1H,NH),8.83(br,1H,NH),7.85(d,J＝8.0Hz,2H,ArH),7.42(d,J＝8.0Hz,2H,ArH),7.33(d,J＝8.0Hz,2H,ArH),7.25(t,J＝7.6Hz,2H,ArH),7.01(t,J＝7.2Hz,1H,ArH),2.39(s,3H,CH3).
13C NMR(100MHz,DMSO-d6,ppm):δ149.7,144.4,138.3,137.4,129.3,128.0,127.9,123.7,119.5,21.4.
HRMS(ESI):m/z calcd.for C14H14N2O3S[M+H]+:291.0798,found:291.0795.
Example 5
The procedure is as in example 1, except that the phenyl isocyanate is replaced by 1.0mmol of tert-butyl isocyanate and the reaction time is 20 min. 0.165g of a white solid was obtained in 86% yield.
The characterization results were as follows: white solid, M.p: 166-.
1H NMR(400MHz,DMSO-d6,ppm):δ8.21(br,1H,NH),7.34(d,J＝7.6Hz,2H,ArH),7.19(t,J＝7.6Hz,2H,ArH),6.86(t,J＝7.2Hz,1H,ArH),5.97(br,1H,NH),1.28(s,9H,CH3).
13C NMR(100MHz,DMSO-d6,ppm):δ154.8,141.1,129.0,121.2,117.8,49.8,29.4.
HRMS(ESI):m/z calcd.for C11H16N2O[M+H]+:193.1335,found:193.1329.
Example 6
The procedure is as in example 1, except that the aniline is changed to 1.0mmol of 2, 6-diisopropylaniline and the reaction time is 20 min. 0.275g of a white solid is obtained in 93% yield.
The characterization results were as follows: white solid, M.p:256-258 ℃.
1H NMR(400MHz,DMSO-d6,ppm):δ8.75(br,1H,NH),7.64(br,1H,NH),7.44(d,J＝8.0Hz,2H,ArH),7.25(t,J＝8.0Hz,3H,ArH),7.15(d,J＝8.0Hz,2H,ArH),6.91(d,J＝7.6Hz,1H,ArH),3.17(sept,J＝7.2Hz,2H,CH),1.15(d,J＝7.2Hz,12H,CH3).
13C NMR(100MHz,DMSO-d6,ppm):δ154.7,147.1,140.8,132.8,129.1,127.6,123.3,121.7,118.1,28.4,23.8.
HRMS(ESI):m/z calcd.for C19H24N2O[M+H]+:297.1961,found:297.1955.
Example 7
The procedure is as in example 1, except that the aniline is replaced by 1.0mmol of tetrahydropyrrole, giving 0.174g of a white solid in 92% yield.
The characterization results were as follows: white solid, M.p: 134-.
1H NMR(400MHz,DMSO-d6,ppm):δ8.11(br,1H,NH),7.45(d,J＝7.6Hz,2H,ArH),7.19(t,J＝7.6Hz,2H,ArH),6.92(t,J＝7.6Hz,1H,ArH),3.33(t,J＝6.4Hz,4H,CH2),1.82(t,J＝6.4Hz,4H,CH2).
13C NMR(100MHz,DMSO-d6,ppm):δ154.4,140.6,128.7,122.3,120.0,46.2,25.4.
HRMS(ESI):m/z calcd.for C11H14N2O[M+H]+:191.1179,found:191.1172.
Example 8
P-methoxyphenyl isothiocyanate (0.165g, 1.0mmol, liquid) was reacted with aniline (0.093g, 1.0mmol, liquid) in the absence of catalyst and solvent at a molar ratio of 1:1 mol ratio is rapidly mixed at 25 ℃, after 10min, the mixed liquid gradually becomes white solid until the stirring bar can not rotate, and after 20min, the addition reaction is finished. The solid powder obtained was washed with n-hexane (three times per 1 mL), the residual solvent was dried under vacuum, and 0.247g was weighed to obtain the disubstituted thiourea in an isolated yield of 96%.
The characterization results were as follows: white solid, M.p:135-137 ℃.
1H NMR(400MHz,CDCl3,ppm):δ7.98(br,2H,NH),7.38(d,J＝7.2Hz,4H,ArH),7.25(t,J＝7.2Hz,3H,ArH),6.91(d,J＝7.2Hz,2H,ArH),3.80(s,3H,OCH3).
13C NMR(100MHz,CDCl3,ppm):δ180.7,159.1,137.6,137.4,129.8,128.0,127.2,125.6,115.1,55.9.
HRMS(ESI):m/z calcd.for C14H14N2OS[M+H]+:259.0900,found:259.0896.
Example 9
The procedure was followed as in example 8, except that p-methoxyphenyl isothiocyanate was changed to 1.0mmol of p-fluorophenyl isothiocyanate, to obtain 0.231g of a white solid in a yield of 94%.
The characterization results were as follows: white solid, M.p: 192-.
1H NMR(400MHz,DMSO-d6,ppm):δ9.76(br,2H,NH),7.48-7.45(m,4H,ArH),7.34(d,J＝8.0Hz,2H,ArH),7.19-7.11(m,3H,ArH).
13C NMR(100MHz,DMSO-d6,ppm):δ180.4,159.6(d,1JF-C＝237.0Hz),139.8,136.2,128.9,126.7(d,3JF-C＝8.0Hz),124.9,124.1,115.5(d,2JF-C＝22.0Hz).
HRMS(ESI):m/z calcd.for C13H12FN2S[M+H]+:247.0700,found:247.0696.
Example 10
The procedure is as in example 8, except that p-methoxyphenyl isothiocyanate is replaced by 1.0mmol of cyclohexyl isothiocyanate and aniline is replaced by 1.0mmol of 3-methoxyaniline, and the reaction time is 40 min. 0.242g of a white solid is obtained in 92% yield.
The characterization results were as follows: white solid, M.p:120-122 ℃.
1H NMR(400MHz,CDCl3,ppm):δ7.97(br,1H,NH),7.30(t,J＝8.0Hz,1H,ArH),7.10-6.99(m,3H,ArH),5.97(br,1H,NH),4.28(s,1H,CH),2.36(s,3H,OCH3),2.06-2.04(m,2H,Cy),1.66-1.59(m,3H,Cy),1.44-1.36(m,2H,Cy),1.15-1.09(m,3H,Cy).
13C NMR(100MHz,CDCl3,ppm):δ179.0,140.4,136.1,129.9,127.8,125.5,121.8,53.9,32.5,25.4,24.6,21.3.
HRMS(ESI):m/z calcd.for C14H21N2SO[M+H]+:265.1369,found:265.1367.
Example 11
The procedure was followed as in example 8, except that p-methoxyphenyl isothiocyanate was changed to 1.0mmol of phenylisothiocyanate and aniline was changed to 1.0mmol of p-tert-butylaniline, to obtain 0.261g of a white solid in 92% yield.
The characterization results were as follows: white solid, M.p:170-171 ℃.
1H NMR(400MHz,CDCl3,ppm):δ8.20(br,1H,NH),8.08(br,1H,NH),7.42-7.35(m,6H,ArH),7.30-7.22(m,3H,ArH),1.31(s,9H,CH3).
13C NMR(100MHz,CDCl3,ppm):δ179.7,150.3,137.4,134.2,129.4,126.8,126.6,125.3,125.0,34.6,31.3.
HRMS(ESI):m/z calcd.for C17H20N2S[M+H]+:285.1420,found:285.1425.
Example 12
The procedure is as in example 11, except that the aniline is changed to 1.0mmol of 2-tetrahydrofurfuryl amine to give 0.202g of a white solid in 86% yield.
The characterization results were as follows: white solid, M.p: 126-.
1H NMR(400MHz,CDCl3,ppm):δ8.40(br,1H,NH),7.40(t,J＝7.6Hz,2H,ArH),7.28–7.26(m,3H,ArH),6.61(br,1H,NH),4.10-3.98(m,2H,OCH2),3.71-3.69(m,2H,NCH2),3.51(s,1H,OCH),2.01-1.95(m,1H,CH2),1.88-1.84(m,2H,CH2),1.60(s,1H,CH2).
13C NMR(100MHz,CDCl3,ppm):δ179.6,135.4,129.0,125.9,123.8,76.4,67.2,48.1,27.5,24.9.
HRMS(ESI):m/z calcd.for C12H16N2OS[M+H]+:237.1056,found:237.1049.
Example 13
The procedure is as in example 11, except that the aniline is changed to 1.0mmol of morpholine, giving 0.213g of a white solid in 96% yield. The nuclear magnetic hydrogen spectrum is shown in figure 2.
The characterization results were as follows: white solid, M.p: 134-.
1H NMR(400MHz,CDCl3,ppm):δ7.50(br,1H,NH),7.34(t,J＝8.0Hz,2H,ArH),7.18-7.12(m,3H,ArH),3.79(t,J＝5.2Hz,2H,OCH2),3.70(t,J＝5.2Hz,2H,NCH2).
13C NMR(100MHz,CDCl3,ppm):δ183.5,139.8,129.1,125.4,123.2,66.1,49.6.
HRMS(ESI):m/z calcd.for C11H15N2SO[M+H]+:223.0900,found:223.0907.
Example 14
P-tolyl isocyanate (0.133g, 1.0mmol) and (S) -1-phenylethylamine (0.121g, 1.0mmol) were rapidly stirred at 25 ℃ without catalyst and solvent, the reaction was slightly exothermic, and after 10min, the mixed liquid gradually turned into a white solid until the stirrer could not rotate. After 30min, the addition reaction was terminated, and the obtained solid powder was washed with a mixed solution of n-hexane and ether (three times per 1 mL), dried in vacuo, and weighed 0.243g to obtain (S) -1- (1-phenylethyl) -3- (p-tolyl) urea as a chiral urea substance in an isolated yield of 96%.
The characterization results were as follows: white solid, M.p: 162-.
1H NMR(400MHz,DMSO-d6,ppm):δ8.25(br,1H,NH),7.33-7.23(m,7H,ArH),7.00(d,J＝7.6Hz,2H,ArH),6.55(d,J＝7.6Hz,1H,NH),4.82-4.78(m,1H,CH),2.20(s,3H,CH3),1.37(d,J＝6.8Hz,3H,CH3).
13C NMR(100MHz,DMSO-d6,ppm):δ155.3,146.1,138.6,130.6,129.9,129.1,127.4,126.6,118.4,49.4,23.9,21.1.
HRMS(ESI):m/z calcd.for C16H19N2O[M+H]+:255.1492,found:255.1487.
Example 15
The procedure is as in example 14, except that the chiral amine is changed to 1.0mmol of (S) -1-cyclohexylethylamine and the p-tolylisocyanate is changed to 1.0mmol of p-tolylisothiocyanate, the reaction temperature is 40 ℃ and the reaction time is 40 min. 0.253g of a white solid was obtained in 92% yield.
The characterization results were as follows: white solid, M.p: 117-.
1H NMR(500MHz,CDCl3,ppm):δ7.40(br,1H,NH),7.24(d,J＝8.0Hz,2H,ArH),7.07(d,J＝8.0Hz,2H,ArH),5.77(d,J＝8.5Hz,1H,NH),4.41(s,1H,CH),2.37(s,3H,CH3),1.75-0.91(m,11H,Cy),1.10(d,J＝8.0Hz,3H,CH3).
13C NMR(125MHz,CDCl3,ppm):δ180.1,137.7,133.7,131.1,125.8,56.0,43.2,29.6,29.2,26.7,26.5,26.4,21.4,17.6.
HRMS(ESI):m/z calcd.for C16H25N2S[M+H]+:277.1733,found:277.1740.
Example 16
The procedure is as in example 15, except that p-tolylisothiocyanate is changed to 1.0mmol of (S) - α -methylbenzyl isocyanate, the reaction temperature is 40 ℃ and the reaction time is 30 min. 0.235g of a white solid was obtained in 86% yield. The nuclear magnetic carbon spectrum is shown in figure 3.
The characterization results were as follows: white solid, M.p:194 ℃ and 196 ℃.
1H NMR(400MHz,CDCl3,ppm):δ7.35-7.34(m,5H,ArH),4.64-4.59(m,1H,CH),4.50(d,J＝6.0Hz,1H,NH),3.98(d,J＝8.0Hz,1H,NH),3.62-3.57(m,1H,CH),1.45(d,J＝6.8Hz,3H,CH3),1.00(d,J＝6.8Hz,3H,CH3),1.45-0.53(m,11H,Cy).
13C NMR(100MHz,CDCl3,ppm):δ157.2,144.2,128.8,127.4,125.9,50.8,50.0,43.4,28.8,28.3,26.3,26.2,23.8,18.5.
HRMS(ESI):m/z calcd.for C17H27N2O[M+H]+:275.2118,found:275.2110.
Example 17
(1R,2R) -1, 2-diphenylethylenediamine (0.126g, 0.6mmol) solid was heated to 40 ℃ without catalyst and solvent, p-methoxyphenyl isocyanate (0.183g, 1.23mmol) was added with rapid stirring, and after 10min, white solid appeared, and magneton stirring was difficult. After reacting for 45min at 40 ℃, cooling to 25 ℃. The solid powder was washed with n-hexane and ether, the residual solvent was dried under vacuum, and 0.275g was weighed to obtain the chiral diurea compound in an isolated yield of 90%.
The characterization results were as follows: white solid, M.p: 239-.
1H NMR(400MHz,DMSO-d6,ppm):δ8.43(br,2H,NH),7.26-7.11(m,10H,ArH),7.06(d,J＝7.2Hz,4H,ArH),6.78(d,J＝8.0Hz,4H,ArH),6.74(s,2H,NH),4.99(s,2H,CH),3.66(s,6H,OCH3).
13C NMR(100MHz,DMSO-d6,ppm):δ155.8,154.8,141.7,134.2,128.7,128.3,127.7,120.2,114.6,59.1,55.9.
HRMS(ESI):m/z calcd.for C30H31N4O4[M+H]+:511.2340,found:511.2343.
Example 18
The procedure was followed as in example 17, except that p-methoxyphenyl isocyanate was changed to 1.23mmol of p-methoxyphenyl isothiocyanate, and the product was washed three times with n-hexane to give 0.282g of a white solid in a yield of 87%. The nuclear magnetic hydrogen spectrum is shown in figure 4.
The characterization results were as follows: white solid, M.p:165-167 ℃.
1H NMR(400MHz,CDCl3,ppm):δ7.71(br,2H,NH),7.21-7.16(m,10H,ArH),7.07(s,4H,ArH),6.99(s,2H,NH),6.92(d,J＝8.8Hz,4H,ArH),6.01-6.00(m,2H,CH),3.83(s,6H,OCH3).
13C NMR(100MHz,CDCl3,ppm):δ180.8,158.9,138.1,128.6,128.1,127.9127.8,127.6,115.2,64.2,55.5.
HRMS(ESI):m/z calcd.for C30H31N4O2S2[M+H]+:543.1883,found:543.1888.
Example 19
The procedure is as in example 17, except that (1R,2R) -1, 2-diphenylethylenediamine is changed to 0.6mmol of (1S,2S) -cyclohexanediamine and p-methoxyphenyl isocyanate is changed to 1.23mmol of p-methoxyphenyl isothiocyanate, and the product is washed three times with n-hexane to give 0.221g of a white solid in 83% yield.
The characterization results were as follows: white solid, M.p: 134-.
1H NMR(500MHz,CDCl3,ppm):δ7.58(br,2H,NH),7.19(d,J＝9.0Hz,4H,ArH),6.91(d,J＝9.0Hz,4H,ArH),6.27(d,J＝7.0Hz,2H,NH),4.37-4.33(m,2H,CH),3.80(s,6H,OCH3),2.09-2.07(m,2H,Cy),1.70(s,2H,Cy),1.28-1.19(m,4H,Cy).
13C NMR(125MHz,CDCl3,ppm):δ176.1,154.5,123.6,123.4,110.9,54.5,51.1,27.8,20.2.
HRMS(ESI):m/z calcd.for C22H29N4O2S2[M+H]+:445.1726,found:445.1732.
Comparative example 1
Para-bromophenyl isocyanate (0.196g, 1.0mmol, solid) was dissolved in 2mL of toluene solvent that was soaked with sodium wool and redistilled before use, and aniline (0.093g, 1.0mmol, liquid) was added. After stirring the reaction at 40 ℃ for 10min, a white solid slowly precipitated from the solution. Due to the solvent reaction, the concentration of the raw materials is reduced, and the reaction is finished after 30min in order to ensure the reaction to be complete. The reaction mixture was heated under reduced pressure to remove the solvent toluene. The obtained white solid powder was washed with a mixture of n-hexane and diethyl ether (1 mL each time, three times). The residual solvent in the solid was dried under vacuum and weighed 0.275g to give the desired product in 95% isolated yield.
The characterization of the product is the same as in example 3.
Comparative example 2
1.0mmol of (S) -1-cyclohexylethylamine and 1.0mmol of p-tolylisocyanate were dissolved in 2mL of a toluene solvent which was soaked with sodium thread and redistilled before use, and heated to 40 ℃ for reaction without a catalyst. Because the reaction is a solvent homogeneous reaction, the concentration of the raw materials is reduced, and the reaction is finished after 60min to ensure the reaction to be complete. The toluene solvent was removed from the reaction mixture under vacuum. The obtained white solid powder was washed three times with n-hexane. The residual solvent in the solid was removed in vacuo and 0.253g was weighed to give the chiral urea compound in 92% isolated yield.
The characterization of the product is the same as in example 15.
Comparative example 3
Without catalyst, (1S,2S) -cyclohexanediamine (0.068g, 0.6mmol) as a solid was dissolved in 2mL tetrahydrofuran solvent which was soaked with sodium and redistilled before use, and a slight excess of p-methoxyphenyl isothiocyanate (0.202g, 1.23mmol) was added and the reaction stirred at 40 ℃. Because the reaction is a solvent homogeneous reaction, the concentration of the raw materials is reduced, and the reaction is finished after 60min to ensure the reaction to be complete. The tetrahydrofuran solvent was removed from the reaction mixture under vacuum. The obtained white solid powder was washed three times with n-hexane. The residual solvent in the solid was removed in vacuo and 0.226g was weighed to give the chiral bis-thiourea material in 88% isolated yield.
The characterization of the product is the same as in example 19.
As can be seen from the comparison of the above examples with comparative examples 1 to 3, when the substrate is a solid, the addition of the solvent enables the reaction mixture to be completed in a homogeneous phase, but the solvent must be removed by water and distilled before use, and although the yield can be improved to some extent, the improvement is limited to no more than 5%, especially the yield of comparative example 2 is not improved at all relative to example 15. When the reaction substrate is liquid, insufficient drying of the solvent increases the risk of hydrolysis of the iso (thio) cyanate, and the yield remains substantially unchanged or decreases. Dilution of the solvent results in a reduced chance of contact between the starting materials, requiring a longer reaction time than in the absence of the solvent. Furthermore, an additional solvent removal step is required after the end of the reaction, and for high boiling solvents such as toluene (b.p. 110 ℃), DMF (b.p. 153 ℃) and DMSO (b.p. 189 ℃) add to the risk of residual high boiling solvent in the product.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Claims (10)
1. A method for synthesizing polysubstituted urea and thiourea compounds without catalysts and solvents is characterized by comprising the following steps: carrying out a first contact reaction on a compound with a structure shown as a formula A and an amine compound with a structure shown as a formula B under the conditions of no catalyst and no solvent to prepare a polysubstituted urea or thiourea compound with a structure shown as a formula C,
wherein R is1And R2Each independently selected from hydrocarbyl or substituted hydrocarbyl, R3Selected from H, alkyl or substituted alkyl, and X is S or O.
2. The catalyst-free and solvent-free process for synthesizing polysubstituted urea and thiourea compounds according to claim 1, wherein R is1And R2Each independently selected from C1-C20 hydrocarbyl or C1-C20 substituted hydrocarbyl, R3Selected from H, C1-C20 hydrocarbyl or C1-C20 substituted hydrocarbyl;
preferably, R1And R2Each independently selected from C1-C20 hydrocarbyl, C1-C20 halogen substituted hydrocarbyl or C1-C20 oxygen substituted hydrocarbyl, R3Selected from H, C1-C20 hydrocarbyl, C1-C20 halogen substituted hydrocarbyl or C1-C20 oxygen substituted hydrocarbyl;
more preferably, R1And R2Each independently selected from phenyl, p-chlorophenyl, p-bromophenyl, p-toluenesulfonyl, tert-butyl, 2, 6-diisopropylphenyl, cyclohexyl, p-methoxyphenyl, p-fluorophenyl, p-tert-butylphenyl, 2-tetrahydrofurylidene, p-methylphenyl, methyl, ethyl or substituted oxyethyl, R3Selected from H, methyl, ethyl, phenyl, p-methoxyphenyl, p-fluorophenyl, cyclohexyl, 2-tetrahydrofuryl methylene, p-tert-butylphenyl, 2, 6-diisopropylphenyl or substituted oxyethyl;
further preferably, when R is2And R3Each independently selected from hydrocarbyl or substituted hydrocarbyl2And R3Is a linear substituent, a substituent with a branched chain or R2、R3And N are connected to form a ring;
still more preferably, the compound having the structure shown in formula a is selected from at least one of phenyl isocyanate, p-chlorophenyl isocyanate, p-bromophenyl isocyanate, p-toluenesulfonyl isocyanate, tert-butyl isocyanate, p-fluorophenyl isothiocyanate, cyclohexyl isothiocyanate, phenyl isothiocyanate and p-tolyl isocyanate; the amine compound with the structure shown in the formula B is selected from at least one of 2, 6-diisopropylaniline, tetrahydropyrrole, p-methoxyphenyl isothiocyanate, 3-methoxyaniline, p-tert-butyl aniline, tetrahydrofurfuryl amine, morpholine, dimethylamine and aniline;
still more preferably, the polysubstituted urea or thiourea compound of formula C is selected from the group consisting of 1, 3-diphenylurea, 3- (4-chlorophenyl) -1, 1-dimethylurea, 3- (4-chlorophenyl) -1-phenylurea, 3- (4-bromophenyl) -1-phenylurea, 3-p-toluenesulfonyl-1-phenylurea, 3-phenyl-1-tert-butylurea, 3-phenyl-1- (2, 6-diisopropylphenyl) urea, 3-p-methoxyphenyl-1-phenylurea, 3-p-methoxyphenyl-1-phenylthiourea, 3-p-fluorophenyl-1-phenylthiourea, 3-cyclohexyl-1-p-methoxyphenyl thiourea, 3-p-methoxyphenyl thiourea, and mixtures thereof, 3-p-tert-butylphenyl-1-phenylthiourea, 3-phenyl-1- (2-tetrahydrofurylmethylene) thiourea, a thiourea compound having a structure represented by the formula C-3 or a urea compound having a structure represented by the formula C-4,
3. the catalyst-free and solvent-free method for synthesizing polysubstituted urea and thiourea compounds according to claim 1, wherein the polysubstituted urea and thiourea compounds are chiral compounds having a structure represented by formula C-1 or formula C-2;
when the structure of the polysubstituted urea or thiourea compound is shown as a formula C-1, the structure of the amine compound is shown as a formula B-1;
when the structure of the polysubstituted urea or thiourea compound is as shown in a formula C-2, the structure of the compound with the structure shown in the formula A is as shown in a formula A-1, and the structure of the amine compound is as shown in a formula B-1;
wherein R is4、R5、R6And R7Each independently selected from hydrocarbyl or substituted hydrocarbyl;
preferably, R4、R5、R6And R7Each independently selected from C1-C20 hydrocarbyl, C1-C20 halogen substituted hydrocarbyl;
more preferably, R4、R5、R6And R7Each independently selected from cyclohexyl, phenyl, p-chlorophenyl, p-methylphenyl, methyl;
further preferably, the compound having the structure shown in formula a is at least one selected from p-tolyl isothiocyanate, phenyl isocyanate, p-chlorophenyl isocyanate, phenyl isothiocyanate, (S) - α -methylbenzyl isocyanate and p-tolyl isocyanate; the amine compound with the structure shown in the formula B is at least one of (S) -1-phenylethylamine and (S) -1-cyclohexylethylamine; the polysubstituted urea or thiourea compound with the structure shown in the formula C is (S) -1- (1-phenethyl) -3- (p-tolyl) urea, (S) -1- (p-tolyl) -3- (1-cyclohexylethyl) thiourea or a urea compound with the structure shown in the formula C-5,
4. the method for synthesizing polysubstituted urea and thiourea compound without catalyst and solvent as claimed in claim 1, wherein the molar ratio of the amine compound with the structure shown in formula B to the compound with the structure shown in formula A is 1: (1-1.05).
5. The catalyst-free and solvent-free process for the synthesis of polysubstituted urea and thiourea compounds according to claim 1, wherein the first contact reaction at least satisfies the following conditions: the reaction temperature is 20-50 ℃, and the reaction time is 5-120 min;
more preferably, the first contact reaction satisfies at least the following conditions: the reaction temperature is 25-50 ℃, wherein, when the substrate is in a liquid state, the reaction temperature is 25-50 ℃; when the substrate contains solid, the reaction temperature is 45-50 ℃;
more preferably, the reaction time is 5-60min, wherein when the substrate is in a liquid state, the reaction time is 10-20 min; when the substrate contains solid, the reaction temperature is 35-40 min; the preferred reaction time for the chiral urea and thiourea compounds is 28-60 min.
6. A method for synthesizing bridged chiral urea and thiourea compounds without catalysts and solvents is characterized by comprising the following steps: carrying out a second contact reaction on the bridged diamine with the structure shown in the formula E and the compound with the structure shown in the formula F under the conditions of no catalyst and no solvent to prepare a bridged chiral urea or thiourea compound with the structure shown in the formula D,
wherein R is8、R9And R10Each independently selected from hydrocarbyl or substituted hydrocarbyl, and X is S or O.
7. The catalyst-free and solvent-free synthesis method of bridged chiral ureas and thioureas according to claim 6, wherein R8、R9And R10Each independently selected from C1-C20 aliphatic hydrocarbyl, C1-C20 substituted aliphatic hydrocarbyl, C6-C20 aromatic hydrocarbyl or C6-C20 substituted aromatic hydrocarbyl;
preferably, R8And R9Each independently selected from phenyl, C1-C10 alkyl, R10Selected from p-methoxyphenyl;
more preferably, R8And R9Is a linear substituent, a substituent with a branched chain or R8、R9And two C are connected to form a ring;
further preferably, the compound having the structure represented by formula a is selected from at least one of p-methoxyphenyl isothiocyanate and p-methoxyphenyl isocyanate; the bridged diamine with the structure shown in the formula E is at least one selected from (1R,2R) -1, 2-diphenylethylenediamine, (1S,2S) -cyclohexanediamine and 1, 1' -di (2-naphthylamine);
still more preferably, the structure of the bridged chiral urea or thiourea compound is shown as a formula D-1 or a formula D-2 or a formula D-3,
8. the catalyst-free and solvent-free synthesis method of bridged chiral ureas and thioureas according to claim 6, wherein the bridged diamine and the compound having the structure shown in formula F are in a molar ratio of (2-2.05): 1.
9. the catalyst-free and solvent-free synthesis method of bridged chiral ureas and thioureas according to claim 6, wherein the second contact reaction at least satisfies the following conditions: the reaction temperature is 20-50 ℃, and the reaction time is 5-120 min;
more preferably, the second contact reaction satisfies at least the following conditions: the reaction temperature is 40-50 ℃, and the reaction time is 30-60 min.
10. A process according to any one of claims 1 to 9, wherein the moisture content of the feedstock is less than 0.1% by weight.
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| CN114349674A (en) * | 2022-01-17 | 2022-04-15 | 华南理工大学 | Thiourea compound and preparation method thereof |
| CN115368282A (en) * | 2022-08-09 | 2022-11-22 | 吉安宏达秋科技有限公司 | Method for synthesizing 1, 3-disubstituted thiourea in aqueous phase |
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| CN115368282A (en) * | 2022-08-09 | 2022-11-22 | 吉安宏达秋科技有限公司 | Method for synthesizing 1, 3-disubstituted thiourea in aqueous phase |
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