CN110964020A - Method for preparing 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] compound - Google Patents

Abstract

The invention relates to a method for preparing 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] derivatives. In particular to a method for preparing 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] derivatives by 3-diazoindoline compounds and ethylene azide compounds under the action of transition metals. The method provided by the invention is used for preparing the 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] derivative from simple and easily available raw materials through simple operation steps.

Description

Method for preparing 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] compound

Technical Field

The invention relates to a method for preparing a 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] compound.

Background

Spiro heterocyclic compounds are common frameworks in natural products, drug molecules and many types of catalysts, and indole spiro pyrrole compounds are a very important type of them as a general synthetic module. Various spiro [ indoline-3, 2' -pyrroles ] have interesting structural properties and highly potent pharmacological activities, including anticancer activity, cholinesterase inhibitors, advanced glycosylation end product activity, antibacterial activity and antidiabetic activity. Its biological activity should be related to the spiro assembly of its two part important modules. Based on their activities, various synthetic methods have been reported in recent years, including 1, 3-dipolar cycloaddition, nucleophilic addition, intramolecular hydroamination, homoenol addition, Buchwald-Hartwig/Michael reaction, aromatization, reductive cyclization, etc., but at present, no method for providing a pyrrole ring structure by a domino reaction with an azidoalkenyl group has been reported. A simple one-step process for preparing 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] compounds from 3-diazoindoline compounds and vinyl azides is described.

Disclosure of Invention

The invention aims to provide a method for synthesizing a 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] compound.

Reaction equation 1: the specific operation steps for synthesizing the 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] compound are as follows (reaction equation 1):

reacting in a reactor, adding 3-diazoindoline 1 and vinyl azide 2, then adding a solvent and a catalyst, and reacting at 0-100 ℃, preferably 60 ℃ for 12-36 hours, preferably 24 hours; after the reaction is finished, separating to obtain the 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] compound 3.

The molar ratio of the vinyl azide 2 to the 3-diazoindoline 1 is 1-10:1, and the preferred ratio is 7: 1.

The catalyst being Rh₂(OAc)₄、Rh₂(Oct)₄、Rh₂(TFA)₄、Rh₂(OAc)₄One or more of rhodium octanoate, rhodium (II) hexanoate dimer, rhodium (II) tetrakis (triphenylacetate) dichlormethane adduct, and rhodium (II) trimethylacetate dimer, preferably Rh₂(TFA)₄(ii) a The amount of the catalyst is 0 to 100mol percent, preferably 5mol percent of the amount of the 3-diazoindoline 1.

The solvent is one or more of 1, 2-dichloroethane, dichloromethane, chloroform, 1,2, 2-tetrachloroethane, chlorobenzene, trifluorotoluene, 1, 4-dioxane and toluene, preferably 1, 2-dichloroethane; the amount of solvent used is 5 to 50 ml, preferably 10 ml, per mmol of 3-diazoindoline 1.

The invention has the following advantages:

1. the synthesis process of the reactants is simple and only needs one to two steps.

2. The reaction is simple and convenient to operate, and compared with the traditional method, the reaction product can be obtained in one step.

3. The reaction yield is high.

Detailed Description

For a better understanding of the present invention, the following examples are set forth.

Reacting in a reactor, adding 3-diazoindoline 1(0.3mmol) and ethylene azide 2(7eq.), and then adding Rh₂(TFA)₄(5 mol%) and 1, 2-dichloroethane (3mL) at 60 ℃ for 24 hours. After the reaction is finished, the solvent is pumped out, the crude sample is dissolved in dichloromethane and loaded for silica gel column chromatography, and the 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole can be obtained]Compound 3.

The reaction materials and results of examples 1-3 are shown in Table 1.

TABLE 1

The characterization data for the products of examples 1-3 are as follows:

1-benzyl-5′-phenyl-3′,4′-dihydrospiro[indoline-3,2′-pyrrol]-2-one：

¹H NMR(400 MHz,CDCl₃)δ7.94–7.91(m,2H),7.47–7.40(m,3H),7.35–7.29(m,4H),7.27–7.23(m,1H),7.19–7.13(m,2H),7.02–6.98(dd,J＝11.0,4.0 Hz,1H),6.74(d,J＝7.8Hz,1H),5.02(d,J＝15.7 Hz,1H),4.83(d,J＝15.7 Hz,1H),3.50(ddd,J＝16.8,9.5,7.2Hz,1H),3.38(ddd,J＝17.0,9.7,4.9 Hz,1H),2.67(ddd,J＝13.4,9.5,4.9 Hz,1H),2.31(ddd,J＝13.1,9.7,7.2 Hz,1H).；¹³C NMR(101 MHz,CDCl₃)δ177.57,177.43,142.87,135.80,133.86,132.31,131.22,129.16,128.87,128.50,128.40,127.67,127.41,123.75,123.17,109.42,81.62,44.04,36.84,33.22.

5′-phenyl-1-tosyl-3′,4′-dihydrospiro[indoline-3,2′-pyrrol]-2-one：

¹H NMR(400 MHz,CDCl₃)δ8.00(d,J＝8.4 Hz,2H),7.95(d,J＝8.2 Hz,1H),7.84–7.82(m,2H),7.48–7.45(m,1H),7.41–7.36(m,3H),7.31(d,J＝8.1 Hz,2H),7.20–7.12(m,2H),3.44–3.29(m,2H),2.61(ddd,J＝13.4,8.8,4.7 Hz,1H),2.41(s,3H),2.21(ddd,J＝13.4,9.4,8.3 Hz,1H).；¹³C NMR(101 MHz,CDCl₃)δ178.75,175.43,145.81,139.04,135.26,133.41,131.61,131.24,129.97,129.93,128.61,128.45,128.12,125.49,124.16,113.85,81.64,36.59,34.73,21.83.

1-benzoyl-5′-phenyl-3′,4′-dihydrospiro[indoline-3,2′-pyrrol]-2-one：

¹H NMR(400 MHz,CDCl₃)δ7.95–7.89(m,3H),7.77–7.75(m,2H),7.57–7.53(m,1H),7.49–7.39(m,6H),7.24(d,J＝3.7 Hz,2H),3.47–3.33(m,2H),2.67(ddd,J＝13.7,8.4,5.4Hz,1H),2.38–2.30(m,1H).；¹³C NMR(101 MHz,CDCl₃)δ178.00,176.99,169.46,140.18,134.24,133.58,132.89,131.79,131.54,129.69,129.48,128.64,128.46,128.30,125.66,123.92,115.50,82.13,36.98,33.87.

comparative example 1:

the operation process is the same as that of example 1, except that the catalyst is PPh₃AuCl/AgSbF₆(1/1, 3 mol%) and yield of product 3 was 0%.

Comparative example 2:

the procedure was as in example 1, except that in example 1, the yield of product 3 was 0% without using any catalyst.

Claims (5)

1. A process for preparing a 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] derivative, characterized in that:

3-diazoindoline 1 and vinyl azide 2 shown in the following formula are used as raw materials to generate a 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] compound 3, and the reaction formula is as follows:

wherein R is¹、R²、R³Respectively selected from fluorine, chlorine, bromine, trifluoromethyl, nitro, alkylsulfonyl, arylsulfonyl, C1-C5 alkyl, unsubstituted phenyl, or phenyl substituted by 1-5 of C1-C5 alkyl, fluorine, chlorine, bromine, trifluoromethyl, nitro, phenyl or acetyl.

2. The process for preparing a 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] derivative according to claim 1, wherein:

the specific operation steps are as follows:

reacting in a reactor, adding 3-diazoindoline 1 and vinyl azide 2, then adding a solvent and a catalyst, and controlling the temperature at 0-100 ℃, preferably 60 ℃; the reaction is carried out for 12 to 36 hours, preferably 24 hours; after the reaction is finished, separating to obtain the 3 ', 4 ' -dihydrospiro [ indoline-3, 2 ' -pyrrole ] compound 3.

3. The method of claim 2, wherein:

the molar ratio of the vinyl azide 2 to the 3-diazoindoline 1 is 1-50:1, and the preferred ratio is 7: 1.

4. The method of claim 2, wherein:

the catalyst being Rh₂(OAc)₄、Rh₂(Oct)₄、Rh₂(TFA)₄、Rh₂(OAc)₄One or more of rhodium octanoate, rhodium (II) hexanoate dimer, rhodium (II) tetrakis (triphenylacetate) dichlormethane adduct, and rhodium (II) trimethylacetate dimer, preferably Rh₂(TFA)₄(ii) a The amount of the catalyst is 0 to 100mol percent, preferably 5mol percent of the amount of the 3-diazoindoline 1.

5. The method of claim 2, wherein:

the solvent is one or more of 1, 2-dichloroethane, dichloromethane, chloroform, 1,2, 2-tetrachloroethane, chlorobenzene, trifluorotoluene, 1, 4-dioxane and toluene, preferably 1, 2-dichloroethane; the amount of solvent used is 5 to 50 ml, preferably 10 ml, per mmol of 3-diazoindoline 1.