阅读说明：本技术 一种硫脲烷基化衍生物的制备方法 (Preparation method of thiourea alkylated derivative ) 是由 宋巧 王周玉 张晓梅 张园园 冉小云 龙燕 陈进 王清英 何庆 于 2019-09-29 设计创作，主要内容包括：本发明公开了一种硫脲烷基化衍生物的制备方法,将醛、N-芳基硫脲、三氯氢硅和路易斯碱于有机溶剂中在-10℃～室温搅拌反应,后处理,得到硫脲烷基化衍生物；所述醛和N-芳基硫脲的摩尔比为1：2～2：1；所述醛和路易斯碱的摩尔比为1：(0.01～0.20)；所述醛和三氯氢硅的摩尔比为1：(1～2)。其中,R-1为C-1～C-5的饱和烷基、无取代或取代芳香环；R-2为H、吸电子取代基或供电子取代基。本发明的方法以小分子路易斯碱催化三氯氢硅,实现硫脲的还原烷基化,一锅法即可合成,操作简单,反应时间短,底物毒性小,且低廉易得,反应条件温和,安全性高。(The invention discloses a preparation method of thiourea alkylated derivatives, which comprises the steps of stirring aldehyde, N-aryl thiourea, trichlorosilane and Lewis base in an organic solvent at-10-room temperature for reaction, and carrying out post-treatment to obtain the thiourea alkylated derivatives; the molar ratio of the aldehyde to the N-aryl thiourea is 1: 2-2: 1; the molar ratio of the aldehyde to the lewis base is 1: (0.01 to 0.20); the molar ratio of the aldehyde to the trichlorosilane is 1: (1-2). Wherein R is 1 Is C 1 ～C 5 Saturated alkyl, unsubstituted or substituted aromatic ring; r 2 Is H, an electron withdrawing substituent or an electron donating substituent. The method of the invention uses micromolecule Lewis base to catalyze trichlorosilane to realize the reductive alkylation of thiourea, and adopts a one-pot methodCan be synthesized, has simple operation, short reaction time, small substrate toxicity, low price, easy obtaining, mild reaction condition and high safety.)

1. The preparation method of the thiourea alkylated derivative is characterized by adopting the following synthetic route:

dissolving aldehyde and N-aryl thiourea in a reaction bottle containing an organic solvent, adding Lewis base, stirring and reacting at-10-room temperature for 10 minutes, adding trichlorosilane into reaction liquid for continuous reaction, and performing aftertreatment to obtain thiourea alkylated derivatives;

the molar ratio of the aldehyde to the N-aryl thiourea is 1: 2-2: 1; the molar ratio of the aldehyde to the lewis base is 1: (0.01 to 0.20); the molar ratio of the aldehyde to the trichlorosilane is 1: (1-2);

wherein R is₁Is C₁～C₅Saturated alkyl, unsubstituted or substituted aromatic ring; r₂Is H, an electron withdrawing substituent or an electron donating substituent.

2. The process for the preparation of thiourea alkylated derivatives according to claim 1, characterized in that the unsubstituted or substituted aromatic ring comprises: unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted electron-rich five-membered heterocycle; the electron donating substituents include: alkoxy radical, C₁～C₅Saturated alkyl groups of (a); the electron-withdrawing substituent comprises: and (4) halogenating.

3. The process for the preparation of thiourea alkylated derivatives according to claim 2, characterized in that the substituted phenyl comprises: 4-substituted phenyl.

4. The process for the preparation of thiourea alkylated derivatives according to claim 2, characterized in that R is₂Comprises the following steps: a 4-substituted electron withdrawing substituent or an electron donating substituent.

5. The process for the preparation of thiourea alkylated derivatives according to claim 2, characterized in that the electron rich five-membered heterocycle comprises: furan ring, thiophene ring.

6. The process for the preparation of thiourea alkylated derivatives according to claim 2, characterized in that the substitution comprises: halo, alkoxy, C₁～C₅A saturated alkyl group of,Wherein R is C₁～C₅Is a saturated alkane.

7. The process for the preparation of thiourea alkylated derivatives according to claim 6, characterized in that the halogenation comprises: chloro, bromo, fluoro; the alkoxy group comprises: methoxy, ethoxy; said C is₁～C₅The saturated alkyl group of (a) comprises: methyl and ethyl.

8. Process for the preparation of thiourea alkylated derivatives according to any of the claims 1-7, characterized in that the lewis base comprises: HMPA, DMF and pyridine.

9. The process for the preparation of thiourea alkylated derivatives according to any of claims 1 to 7, characterized in that the reaction time is 0.5 to 24 h; the organic solvent comprises: any one of dichloromethane, acetonitrile, toluene and chloroform.

10. The preparation method of the thiourea alkylated derivative according to any one of claims 1 to 7, wherein the post-treatment comprises quenching the reaction with water, adjusting the pH to 7-8, extracting with an organic solvent, and performing column chromatography to obtain the thiourea alkylated derivative.

Technical Field

The invention belongs to the field of organic compound synthesis, and particularly relates to a preparation method of a thiourea alkylated derivative.

Background

Thiourea and its derivatives have important applications in natural organic compounds and pharmaceutical chemistry, are important organic reagents, are widely used in organic synthesis, and some thiourea derivatives have biological activities such as antibacterial, anti-AIDS and anticancer.

At present, the preparation method of thiourea derivatives is mainly prepared from commercially available isothiocyanates, and the raw materials have the characteristics of high toxicity, high risk and the like, so that more and more people are concerned about preparing the derivatives of the compounds by reductive alkylation.

Trichlorosilane is an important organosilicon monomer, is mainly used for synthesis of organosilane, alkyl, aryl and organic functional group chlorosilane, and is a main raw material for producing organosilane coupling agents and polycrystalline silicon. And is also a hydrogen source, which is commonly used for reducing imine, enamine, ketone and unsaturated double bonds to prepare compounds such as chiral amine, chiral alcohol and the like. But is not currently used as a hydrogen source for preparing thiourea derivatives.

Disclosure of Invention

The invention aims to provide a preparation method of thiourea alkylated derivatives, which solves the problem that isothiocyanate is dangerous in the prior art, and has relatively low substrate toxicity and mild reaction conditions.

In order to achieve the above object, the present invention provides a method for preparing an alkylated derivative of thiourea, which comprises the following synthetic routes:

dissolving aldehyde and N-aryl thiourea in a reaction bottle containing an organic solvent, adding Lewis base, stirring and reacting at-10-room temperature for 10 minutes, adding trichlorosilane into reaction liquid for continuous reaction, and performing aftertreatment to obtain thiourea alkylated derivatives; the molar ratio of the aldehyde to the N-aryl thiourea is 1: 2-2: 1; the molar ratio of the aldehyde to the lewis base is 1: (0.01 to 0.20); the molar ratio of the aldehyde to the trichlorosilane is 1: (1-2).

Wherein R is₁Is C₁～C₅Saturated alkyl, unsubstituted or substituted aromatic ring; r₂Is H, an electron withdrawing substituent or an electron donating substituent.

Preferably, the unsubstituted or substituted aromatic ring comprises: unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl, unsubstituted or substituted electron-rich five-membered heterocycle; the electron donating substituents include: alkoxy radical, C₁～C₅Saturated alkyl groups of (a); the electron-withdrawing substituent comprises: and (4) halogenating.

Preferably, the substituted phenyl group comprises: 4-substituted phenyl.

Preferably, said R is₂Comprises the following steps: a 4-substituted electron withdrawing substituent or an electron donating substituent.

Preferably, the electron-rich five-membered heterocyclic ring comprises: furan ring, thiophene ring.

Preferably, the substitution comprises: halo, alkoxy, C₁～C₅A saturated alkyl group of,Wherein R is C₁～C₅Is a saturated alkane.

Preferably, the halo comprises: chloro, bromo, fluoro; the alkoxy group comprises: methoxy, ethoxy; said C is₁～C₅The saturated alkyl group of (a) comprises: methyl and ethyl. Specifically, R₁Comprises the following steps: 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl。

Preferably, said lewis base comprises: HMPA, DMF and pyridine.

Preferably, the reaction time is 0.5-24 h; the organic solvent comprises: any one of dichloromethane, toluene, acetonitrile and chloroform.

Preferably, the post-treatment comprises quenching the reaction with water, adjusting the pH to 7-8, extracting with an organic solvent, and performing column chromatography to obtain the thiourea alkylated derivative.

The preparation method of the thiourea alkylated derivative solves the problem that isothiocyanate is dangerous in the prior art, and has the following advantages:

the preparation method provided by the invention has the advantages that the trichlorosilane is catalyzed by the micromolecule Lewis base to realize the reductive alkylation of the thiourea, and compared with the traditional hydrogen source, the trichlorosilane is used as the hydrogen source, and the preparation method has the advantages of no toxicity, mild reaction conditions, high chemical selectivity and the like. The method can be synthesized by a one-pot method, and has the advantages of simple operation, short reaction time, low substrate toxicity, low cost, easy obtainment, mild reaction conditions and high safety. In addition, the preparation method has the characteristic of high universality on a substrate, and provides a feasible synthetic path for the subsequent reductive alkylation of thiourea.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

A process for preparing the alkylated derivative of thiourea includes such steps as adding aldehyde, N-arylthiourea and HMPA to a reactor, adding solvent, stirring for 10min, adding trichlorosilane to the mixture, stirring at-10 deg.C to room temp for reaction, and chromatography by silica gel column.

Specifically, according to the above synthesis method, 0.05eq of HMPA is used as lewis base, and the molar ratio of benzaldehyde to trichlorosilane is 1: 1.5, reacting for 12h at room temperature, and adopting aldehydes and N-phenylthiourea in different molar ratios, wherein the reaction results are shown in Table 1.

TABLE 1 reaction results of the present invention using different molar ratios of aldehyde (A) and N-arylthiourea (B)

Specifically, according to the above synthesis method, 0.05eq of HMPA is used as lewis base, and the molar ratio of benzaldehyde to trichlorosilane is 1: 1.5, the reaction time is 12h, the molar ratio of benzaldehyde to N-phenylthiourea is 2: 1, reacting at different reaction temperatures, and obtaining the reaction results shown in table 2.

Table 2 reaction results of the present invention at different reaction temperatures

Specifically, according to the above synthesis method, 0.05eq of HMPA is used as lewis base, and the molar ratio of benzaldehyde to trichlorosilane is 1: 1.5, the molar ratio of benzaldehyde to N-phenylthiourea is 2: 1, reacting at room temperature, and reacting at different reaction times, wherein the reaction results are shown in table 3.

TABLE 3 results of the reactions of the invention at different reaction times

Specifically, according to the above synthesis method, 0.05eq HMPA is used as lewis base, and the molar ratio of benzaldehyde to N-phenylthiourea is 2: 1, the reaction time is 4h, the reaction is carried out at room temperature, the reaction is carried out under different trichlorosilane dosages, and the reaction results are shown in Table 3.

Table 4 reaction results of the present invention at different amounts of trichlorosilane

In order to explain the preparation method of the thiourea alkylated derivative provided by the invention in detail, the following is specifically described by taking examples 1 to 14 as examples.

Example 1

Selecting N-phenylthiourea and benzaldehyde as substrates to react, sequentially adding N-phenylthiourea (0.2mmol, 1eq) and 2mL of dried Dichloromethane (DCM) into a reaction test tube, then adding 7.2 mu L (0.05eq) of HMPA (hexamethylphosphoric triamide) into the test tube, then adding 0.4mmol (2eq) of benzaldehyde, reacting for 10min in an ice bath, then adding 1.2eq of trichlorosilane, reacting for 12h, and monitoring the reaction condition.

After the reaction is completed, quenching unreacted trichlorosilane by water, adding saturated sodium bicarbonate solution to adjust the pH to be 7-8, then transferring the reaction solution into a separating funnel, extracting by ethyl acetate, taking supernatant and using anhydrous Na₂SO₄Drying, filtering, removing the solvent under reduced pressure, and performing column chromatography (volume ratio, petroleum ether: ethyl acetate: 5:1, eluent) to obtain the product N-benzyl-N' -phenylthiourea as a white solid.

Nuclear magnetic data for N-benzyl-N' -phenylthiourea are characterized by:

¹H NMR(400MHz,DMSO–d₆)δ9.65(s,1H),8.18(s,1H),7.44(d,J＝7.6Hz,2H),7.35(t,J＝4.0Hz,6H),7.30–7.24(m,1H),7.13(t,J＝7.2Hz,1H),4.75(d,J＝5.6Hz,2H).

the mass spectrometry data for N-benzyl-N' -phenylthiourea were characterized as:

HRMS(ESI)Calcd for[C₁₄H₁₄N₂S+H]⁺243.0950；Found:243.0948。

the melting point of N-benzyl-N' -phenylthiourea is: m.p 145.4-146.0 ℃.

Example 2

The same procedure as in example 1 was followed, the solvent was changed to acetonitrile, the aldehyde used was 4-chlorobenzaldehyde, and the product obtained was N- (4-chlorobenzyl) -N' -phenylthiourea as a white solid.

Nuclear magnetic data for N- (4-chlorobenzyl) -N' -phenylthiourea are characterized by:

¹H NMR(400MHz,DMSO–d₆)δ9.68(s,1H),8.21(s,1H),7.41(d,J＝8.4Hz,4H),7.39–7.31(m,4H),7.14(t,J＝7.3Hz,1H),4.74(d,J＝5.6Hz,2H)。

the melting point of N- (4-chlorobenzyl) -N' -phenylthiourea is: m.p 135.3.3-136.4 ℃.

Example 3

The same procedure as in example 1 was followed, the solvent was changed to chloroform, the aldehyde used was 4-bromobenzaldehyde, and the product obtained was N- (4-bromobenzyl) -N' -phenylthiourea.

Nuclear magnetic data for N- (4-bromobenzyl) -N' -phenylthiourea are characterized as:

1H NMR(400MHz,DMSO–d6)δ9.67(s,1H),8.20(s,1H),7.53(d,J＝8.4Hz,2H),7.40(d,J＝7.4Hz,2H),7.37–7.26(m,4H),7.13(t,J＝7.3Hz,1H),4.71(d,J＝5.7Hz,2H)。

the melting point of N- (4-bromobenzyl) -N' -phenylthiourea is: m.p 141.5-142.3 ℃.

Example 4

The solvent was changed to toluene in the same manner as in the preparation of example 1, the aldehyde used was 4-methylbenzaldehyde, and the product obtained was N- (4-methylbenzyl) -N' -phenylthiourea.

Nuclear magnetic data for N- (4-methylbenzyl) -N' -phenylthiourea are characterized by:

¹H NMR(400MHz,DMSO–d₆)δ9.59(s,1H),8.11(s,1H),7.43(d,J＝7.8Hz,2H),7.33(t,J＝8.0Hz,2H),7.24(d,J＝8.0Hz,2H),7.19–7.09(m,3H),4.86–4.57(m,2H),2.30(s,3H)。

the melting point of N- (4-methylbenzyl) -N' -phenylthiourea is: m.p 140.2.2-141.1 ℃.

Example 5

In the same manner as in the preparation of example 1, the Lewis base was changed to DMF, the aldehyde used was 4-methoxybenzaldehyde, and the product obtained was N- (4-methoxybenzyl) -N' -phenylthiourea as a white solid.

Nuclear magnetic data for N- (4-methoxybenzyl) -N' -phenylthiourea are characterized by:

¹H NMR(400MHz,DMSO–d₆)δ9.42(s,1H),7.96(s,1H),7.34–7.29(m,4H),7.25(d,J＝8.8Hz,3H),6.91(d,J＝8.9Hz,2H),4.72(d,J＝5.6Hz,2H),3.73(s,3H)。

the melting point of N- (4-methoxybenzyl) -N' -phenylthiourea is: m.p 106.7.7-107.3 ℃.

Example 6

In the same manner as in the preparation of example 1, the Lewis base was changed to pyridine, the aldehyde used was 2-naphthaldehyde, and the product obtained was N- (naphthyl-2-methyl) -N' -phenylthiourea.

Nuclear magnetic data for N- (naphthyl-2-methyl) -N' -phenylthiourea are characterized by:

¹H NMR(400MHz,DMSO–d₆)δ9.70(s,1H),8.30(s,1H),7.95–7.87(m,3H),7.82(s,1H),7.57–7.43(m,5H),7.35(t,J＝7.8Hz,2H),7.14(t,J＝7.4Hz,1H),4.93(d,J＝5.4Hz,2H)。

the melting point of N- (4-bromobenzyl) -N' -phenylthiourea is: m.p 163.7-164.3 ℃.

Example 7

The same procedure used in example 1 was followed, using N-arylthiourea as N- (4-fluorophenyl) thiourea and the product obtained was N-benzyl-N' - (4-fluorophenyl) thiourea.

Nuclear magnetic data for N-benzyl-N' - (4-fluorophenyl) thiourea were characterized as:

¹HNMR(400MHz,DMSO–d₆)δ9.57(s,1H),8.14(s,1H),7.42(dd,J＝8.9,5.0Hz,2H),7.36–7.30(m,4H),7.29–7.23(m,1H),7.20–7.13(m,2H),4.73(d,J＝5.5Hz,2H)。

the melting point of N-benzyl-N' - (4-fluorophenyl) thiourea is: m.p 142.3.3 to 143.0 ℃.

Example 8

The same procedure used in example 1 was followed, using N-arylthiourea as N- (4-methoxyphenyl) thiourea and the product obtained as N-benzyl-N' - (4-methoxyphenyl) thiourea.

The nuclear magnetic data of N-benzyl-N' - (4-methoxyphenyl) thiourea are characterized as follows:

¹HNMR(400MHz,DMSO–d₆)δ9.42(s,1H),7.96(s,1H),7.34–7.29(m,4H),7.25(d,J＝8.8Hz,3H),6.91(d,J＝8.9Hz,2H),4.72(d,J＝5.6Hz,2H),3.73(s,3H)。

the melting point of N-benzyl-N' - (4-methoxyphenyl) thiourea is: m.p 107.8.8-109.5 ℃.

Example 9

In the same manner as in example 1, 4-chlorobenzaldehyde was used as the aldehyde, N- (4-methoxyphenyl) thiourea was used as the N-arylthiourea, and N- (4-chlorobenzyl) -N' - (4-methoxyphenyl) thiourea was obtained as the product.

The nuclear magnetic data of N- (4-chlorobenzyl) -N' - (4-methoxyphenyl) thiourea are characterized as follows:

¹H NMR(400MHz,DMSO–d₆)δ9.47(s,1H),7.98(s,1H),7.39(d,J＝8.5Hz,2H),7.33(d,J＝8.6Hz,2H),7.23(d,J＝8.9Hz,2H),6.91(d,J＝8.9Hz,2H),4.70(d,J＝5.7Hz,2H),3.74(s,3H)。

the melting point of N- (4-chlorobenzyl) -N' - (4-methoxyphenyl) thiourea is: m.p 134.8.8-135.8 ℃.

Example 10

The same procedure as in example 1 was followed, using N-propionaldehyde as the aldehyde, and N-propyl-N' -phenylthiourea as the product.

Nuclear magnetic data for N-propyl-N' -phenylthiourea are characterized by:

¹H NMR(400MHz,DMSO–d₆)δ9.45(s,1H),7.75(s,1H),7.40(d,J＝7.5Hz,2H),7.31(t,J＝7.9Hz,2H),7.09(t,J＝7.3Hz,1H),3.47–3.36(m,2H),1.60–1.48(m,2H),0.88(t,J＝7.4Hz,3H)。

the melting point of N-N-propyl-N' -phenylthiourea is: m.p 80.0.0-80.3 ℃.

Example 11

The same procedure used in example 1 was followed, using the aldehyde ethyl 4- (5-formyl-2-furyl) benzoate, and the product obtained was ethyl 4- (5- ((3-phenylthioureido) methyl) -2-furyl) benzoate.

Nuclear magnetic data for ethyl 4- (5- ((3-phenylthioureido) methyl) -2-furyl) benzoate are characterized by:

¹H NMR(400MHz,DMSO–d₆)δ9.68(s,1H),8.22(s,1H),8.00(d,J＝8.5Hz,2H),7.82(d,J＝8.5Hz,2H),7.46(d,J＝7.6Hz,2H),7.34(dd,J＝10.7,5.1Hz,2H),7.13(dd,J＝8.9,5.4Hz,2H),6.51(d,J＝3.4Hz,1H),4.82(d,J＝5.3Hz,2H),4.37–4.28(m,2H),1.33(t,J＝7.1Hz,3H).¹³C NMR(100MHz,DMSO–d6)δ181.23,165.83,153.67,151.55,134.74,130.34,129.10,128.56,124.84,123.57,110.55,109.78,61.20,14.67。

the melting point of ethyl 4- (5- ((3-phenylthioureido) methyl) -2-furyl) benzoate was: m.p, 149.5-155.2 ℃.

Example 12

In the same manner as in example 1, 2-thiophenecarboxaldehyde was used as the aldehyde, and 1-phenyl-3- (thienyl-2-methyl) thiourea was obtained as the product.

Nuclear magnetic data for 1-phenyl-3- (thienyl-2-methyl) thiourea are characterized by:

¹H NMR(400MHz,DMSO–d₆)δ9.63(s,1H),8.19(s,1H),7.42–7.37(m,3H),7.35–7.29(m,2H),7.12(t,J＝7.3Hz,1H),7.05(dd,J＝3.4,1.0Hz,1H),6.97(dd,J＝5.1,3.4Hz,1H),4.90(d,J＝5.7Hz,2H)。

the melting point of 1-phenyl-3- (thienyl-2-methyl) thiourea is: 121.6-130.1 ℃.

Example 13

In the same manner as in example 1, furfural was used as the aldehyde, and 1-phenyl-3- (furyl-2-methyl) thiourea was obtained as the product.

Nuclear magnetic data for 1-phenyl-3- (furanyl-2-methyl) thiourea are characterized as:

¹H NMR(400MHz,DMSO–d₆)δ9.59(s,1H),8.08(s,1H),7.61(dd,J＝1.8,0.8Hz,1H),7.44(dd,J＝8.4,0.8Hz,2H),7.36–7.28(m,2H),7.11(t,J＝7.4Hz,1H),6.42(dd,J＝3.2,1.9Hz,1H),6.33(dd,J＝3.2,0.6Hz,1H),4.72(d,J＝5.4Hz,2H)。

the melting point of 1-phenyl-3- (furyl-2-methyl) thiourea is: m.p at 133.3-134.5 deg.C.

The yields of the compounds prepared in examples 1-13 above are given in Table 5 below.

TABLE 5 yields of the compounds prepared in inventive examples 1-13

Note: a represents that the yield is more than or equal to 90 percent; b represents that the yield is more than or equal to 80 percent and less than 90 percent; c represents that the yield is more than or equal to 70 percent and less than 80 percent; d represents that the yield is more than or equal to 60 percent and less than 70 percent; e represents that the yield is more than or equal to 20 percent and less than 60 percent; f represents that the yield is more than or equal to 20 percent and less than 40 percent; j represents a yield < 20%; n indicates no product.

As can be seen from Table 5, the yield of the reaction product is good whether the electron donating substitution or the electron withdrawing substitution is performed on the aromatic ring of the substituted aldehyde/substituted thiourea; the aldehydes of heterocyclic, naphthalene and chain alkane react with N-phenylurea sulfur to obtain better yield. Therefore, the method has the advantage that the reductive alkylation conditions for the thiourea adopted by the invention have high universality on the substrate, and provides a feasible synthetic path for the subsequent reductive alkylation of the thiourea.

While the present invention has been described in detail with reference to the preferred embodiments, it should be understood that the above description should not be taken as limiting the invention. Various modifications and alterations to this invention will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, the scope of the invention should be determined from the following claims.