Preparation method of polysubstituted indolizine derivative
阅读说明：本技术 一种多取代吲哚嗪衍生物的制备方法 (Preparation method of polysubstituted indolizine derivative ) 是由 陈国术 李嘉慧 陈淑杰 张锦辉 于 2021-08-24 设计创作，主要内容包括：本发明属于有机合成领域,公开了一种多取代吲哚嗪衍生物的制备方法。该方法在氮气或惰性气体保护下,将式II所示的N-芳基甲酰甲基溴化吡啶季铵盐、式III所示的联烯酸酯、碱和溶剂置于反应容器中进行反应即得到式I所示的多取代吲哚嗪衍生物。具体反应路线如下所示。该方法相比于目前文献报道的过渡金属催化的吲哚嗪的合成方法,具有以下优点：所用原料容易获取；反应条件相对温和,操作简单,无需昂贵的过渡金属催化剂、氧化剂以及高温条件；能够合成传统方法不易得到的具有多种取代基的吲哚嗪衍生物。所合成的多取代吲哚嗪衍生物在医药、农药领域具有潜在的应用价值。(The invention belongs to the field of organic synthesis, and discloses a preparation method of a polysubstituted indolizine derivative. Under the protection of nitrogen or inert gas, putting N-aryl formyl methyl pyridine quaternary ammonium bromide salt shown in a formula II, allenic acid ester shown in a formula III, alkali and a solvent into a reaction container for reaction to obtain the polysubstituted indolizine derivative shown in the formula I. The specific reaction scheme is shown below. Compared with the synthesis method of indolizine catalyzed by transition metal reported in the literature at present, the method has the following advantages: the used raw materials are easy to obtain; the reaction condition is relatively mild, the operation is simple, and expensive transition metal catalysts, oxidants and high-temperature conditions are not needed; can synthesize indolizine derivatives with various substituents which are not easily obtained by the traditional method. The synthesized polysubstituted indolizine derivative has potential application value in the fields of medicines and pesticides.)
1. A preparation method of polysubstituted indolizine derivatives is characterized by comprising the following steps:
under the protection of nitrogen or inert gas, putting N-aryl formyl methyl pyridine quaternary ammonium bromide salt shown in a formula II, allenic acid ester shown in a formula III, alkali and a solvent into a reaction container for reaction to obtain polysubstituted indolizine derivative shown in a formula I;
the specific reaction scheme is as follows:
wherein R is1Is any one of aromatic condensed ring, aliphatic condensed ring, aryl, halogen, alkyl and hydrogen; r2Is one of aryl and substituted aryl; r3Is any one of benzyl and cycloalkyl.
2. The method for preparing polysubstituted indolizine derivative according to claim 1, wherein the structure of polysubstituted indolizine derivative represented by formula I is one of the following structures:
3. the process for producing a polysubstituted indolizine derivative according to claim 1 or 2, wherein:
the alkali is at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butoxide, DBU and cesium carbonate.
4. The process for producing a polysubstituted indolizine derivative according to claim 1 or 2, wherein:
the alkali is cesium carbonate.
5. The process for producing a polysubstituted indolizine derivative according to claim 1 or 2, wherein:
the solvent is at least one of ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, chlorobenzene, xylene, toluene, ethanol, chloroform, cyclohexane, butanone, acetone, petroleum ether, N-octane, cyclohexane, diethyl ether, dimethyl sulfoxide and N, N-dimethylformamide.
6. The process for producing a polysubstituted indolizine derivative according to claim 1 or 2, wherein:
the solvent is N, N-dimethylformamide.
7. The process for producing a polysubstituted indolizine derivative according to claim 1 or 2, wherein:
the quantity ratio of the N-aryl formyl methyl pyridine quaternary ammonium bromide salt, the allenoic acid ester and the alkali is as follows: 1 (1-1.5) to (1-5), preferably 1:1.2: 2.
8. The process for producing a polysubstituted indolizine derivative according to claim 1 or 2, wherein:
the reaction temperature is 0-50 ℃; the reaction time is 6-12 h.
9. The process for producing a polysubstituted indolizine derivative according to claim 1 or 2, wherein:
the reaction temperature is room temperature; the reaction time is 6 h.
10. The process for producing a polysubstituted indolizine derivative according to claim 1 or 2, wherein:
the method also comprises the steps of separation and purification after the reaction is finished, and specifically comprises the following steps: after the reaction is finished, directly separating by silica gel column chromatography, and separating by using a solution with the volume ratio of ethyl acetate to petroleum ether being 1:49 as an eluent to obtain the polysubstituted indolizine compound shown in the formula I.
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a polysubstituted indolizine derivative.
Background
Indolizine is an important nitrogen-containing aromatic heterocyclic compound, is a core structural unit of a plurality of molecules with biological activity, and has important academic significance and potential application prospect in synthesis and research. Therefore, the search for a method for efficiently constructing indolizine derivatives has been receiving much attention. The currently available synthesis of indolizine derivatives still has more limitations including: the reaction substrate structure is limited; transition metal catalysts and oxidants are needed; the reaction is carried out under high temperature conditions, etc. (for example: Yang, Y.; Xie, C.; Xie, Y.; Zhang, Y. Synthesis of functional induced olefins via coater-Catalyzed analysis of 2-Alkylazaenes with. alpha.,. beta. unreacted Carboxylic acids. org. Lett.,2012,14(4): 957. sub.959; Meng, X.; Liao, P.; Liu, J.; Bi, X. silver-Catalyzed circulation of 2-Pyridyl alkyl carbonates with Isocryanides: Divergent Synthesis of and inductors and minerals, Chem. Commun., 201480): 11839). The high temperature and strong oxidant conditions tend to result in poor tolerance of the functional groups of the reaction, while transition metal catalysis can result in the residue of the biologically toxic transition metal in the product. Therefore, the research on the indolizine derivative synthesis system without transition metal and oxidant under mild conditions has important application value and research significance.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention mainly aims to provide a preparation method of a polysubstituted indolizine derivative.
The purpose of the invention is realized by the following scheme:
a preparation method of a polysubstituted indolizine derivative comprises the following steps:
under the protection of nitrogen or inert gas, putting N-aryl formyl methyl pyridine quaternary ammonium bromide salt shown in a formula II, allenic acid ester shown in a formula III, alkali and a solvent into a reaction container for reaction to obtain the polysubstituted indolizine derivative shown in the formula I.
The specific reaction scheme is as follows:
wherein R is1Is any one of aromatic condensed ring, aliphatic condensed ring, aryl, halogen, alkyl and hydrogen; r2Is one of aryl and substituted aryl; r3Is benzyl, ringAny of alkyl groups.
The quaternary ammonium N-arylformylmethyl pyridinium bromide of the formula II can be synthesized according to the following literature methods (Hu, R.B.; Sun, S.; Su, Y.Angew.chem., int.Ed.2017,56, 10877-10880.).
The diacrylates of formula III can be synthesized according to the following literature methods (Wang., G.; Liu, X.; Chen, Y.; Yang, J.; Li, J.; Lin, L.; Feng, X.ACS Catal.2016,6, 2482-.
The alkali is at least one of sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butoxide, DBU and cesium carbonate, and is preferably cesium carbonate.
The solvent is at least one of ethyl acetate, dichloromethane, acetonitrile, tetrahydrofuran, chlorobenzene, xylene, toluene, ethanol, chloroform, cyclohexane, butanone, acetone, petroleum ether, N-octane, cyclohexane, diethyl ether, dimethyl sulfoxide and N, N-dimethylformamide, and preferably N, N-dimethylformamide.
The quantity ratio of the N-aryl formyl methyl pyridine quaternary ammonium bromide salt, the allenoic acid ester and the alkali is as follows: 1 (1-1.5) to (1-5), preferably 1:1.2: 2.
The reaction temperature is 0-50 ℃, and room temperature is preferred; the reaction time is 6-12h, preferably 6 h.
The method also comprises the steps of separation and purification after the reaction is finished, and specifically comprises the following steps: after the reaction is finished, directly separating by silica gel column chromatography, and separating by using a solution with the volume ratio of ethyl acetate to petroleum ether being 1:49 as an eluent to obtain the polysubstituted indolizine compound (formula I).
Preferably, the structure of the polysubstituted indolizine derivative is one of the following structures:
compared with the prior art, the invention has the following advantages and beneficial effects:
the invention provides a method for synthesizing polysubstituted indolizine compounds by using N-aryl formyl methyl pyridine quaternary ammonium bromide salt and dienoic acid ester as raw materials through [3+2] cycloaddition reaction under the promotion of alkali, and compared with a transition metal catalyzed indolizine synthesis method reported in the current literature, the method has the following advantages: the used raw materials are easy to obtain; the reaction condition is relatively mild, the operation is simple, and expensive transition metal catalysts, oxidants and high-temperature conditions are not needed; can synthesize indolizine derivatives with various substituents which are not easily obtained by the traditional method. The synthesized polysubstituted indolizine derivative has potential application value in the fields of medicines and pesticides.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of an indolizine compound represented by I-1 prepared in example 1;
FIG. 2 is a nuclear magnetic carbon spectrum of the indolizine compound of I-1 prepared in example 1;
FIG. 3 is a nuclear magnetic hydrogen spectrum of the indolizine compound of I-3 prepared in example 3;
FIG. 4 is a nuclear magnetic carbon spectrum of the indolizine compound of I-3 prepared in example 3.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The reagents used in the examples are commercially available without specific reference.
Example 1
Synthesis of indolizine compounds of formula I-1:
at room temperature and N2Under protection, II-1(0.1mmol, 31.3mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was chromatographed directly on silica gel column (eluent: EtOAc/P.E.,1:49) to give I-1 as a yellow oily viscous liquid (21.8mg, yield 54%).1H NMR(400MHz,CDCl3)δ9.45(d,J＝7.1Hz,1H),8.32(d,J＝9.0Hz,1H),7.65-7.59(m,2H),7.47-7.42(m,4H),7.35(qd,J＝8.2,1.2Hz,4H),6.94(td,J＝7.0,1.3Hz,1H),5.37(s,2H),2.22(s,3H).13C NMR(100MHz,CDCl3) Delta 186.44,164.72,139.82,139.42,138.36,137.92,136.52,130.45,129.00,128.73,128.29,128.23,128.09,127.53,122.68,119.44,114.67,105.12,65.88 and 15.34, and the specific nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum are respectively shown in fig. 1 and fig. 2.
Example 2
Synthesizing indolizine compounds shown in the formula I-2:
at room temperature and N2Under protection, II-2(0.1mmol, 30.2mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was chromatographed directly on silica gel column (eluent: EtOAc/P.E.,1:49) to give I-2 as a yellow oily viscous liquid (20.1mg, 51% yield).1H NMR(400MHz,CDCl3)δ9.63(d,J＝7.0Hz,1H),8.36(d,J＝9.0Hz,1H),7.76(q,J＝8.2Hz,4H),7.45(d,J＝7.1Hz,2H),7.37(ddd,J＝11.9,7.5,3.6Hz,4H),7.02(td,J＝7.0,1.1Hz,1H),5.39(s,2H),2.17(s,3H).13C NMR(100MHz,CDCl3)δ＝185.41,164.44,145.02,140.15,138.74,136.31,132.50,129.12,128.68,128.32,128.25,128.18,126.99,122.21,119.45,118.11,115.11,115.02,105.71,65.94,15.25.
Example 3
Synthesizing indolizine compounds shown in the formula I-3:
at room temperature and N2Under protection, II-3(0.1mmol, 38.7mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was separated by direct silica gel column chromatography (eluent: EtOAc/P.E.,1:49) to give I-3 as a yellow solid (16.0mg, 36% yield).1H NMR(400MHz,CDCl3)δ9.51(d,J＝7.3Hz,1H),8.58(d,J＝1.2Hz,1H),7.63(t,J＝6.9Hz,4H),7.54-7.33(m,11H),7.25(dd,J＝6.9,2.4Hz,1H),5.39(s,2H),2.26(s,3H).13C NMR(10MHz,CDCl3) Delta 186.19,164.62,140.08,139.77,139.39,138.59,138.26,137.88,136.38,130.34,129.11,128.94,128.82,128.72,128.42,128.23,128.19,126.82,122.49,116.19,113.68,105.47,66.07 and 15.23, and the specific nuclear magnetic hydrogen spectrum and the nuclear magnetic carbon spectrum are respectively shown in fig. 3 and fig. 4.
Example 4
Synthesizing indolizine compounds shown in the formula I-4:
at room temperature and N2Under protection, II-4(0.1mmol, 32.4mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was chromatographed directly on silica gel column (eluent: EtOAc/P.E.,1:49) to give I-4 as a yellow oily viscous liquid (35.9mg, 86% yield).1H NMR(400MHz,CDCl3)δ8.32(d,J＝8.9Hz,1H),7.86(d,J＝8.4Hz,2H),7.46(t,J＝8.1Hz,4H),7.39-7.30(m,3H),7.28-7.22(m,1H),6.74(d,J＝6.9Hz,1H),5.38(s,2H),2.30(s,3H),2.27(s,3H).13C NMR(100MHz,CDCl3)δ＝186.46,164.89,140.79,139.86,138.06,137.52,136.74,134.93,131.54,129.28,128.68,128.20,128.12,126.18,123.49,117.27,115.99,104.02,65.71,23.32,13.92.
Example 5
Synthesizing indolizine compounds shown in the formula I-5:
at room temperature and N2Under protection, II-1(0.1mmol, 31.3mg,1equiv), III-2(0.12mmol, 19.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was chromatographed directly on silica gel column (eluent: EtOAc/P.E.,1:49) to give I-5 as a yellow viscous oily liquid (17.4mg, 44% yield).1H NMR(400MHz,CDCl3)δ9.48(d,J＝7.1Hz,1H),8.37(d,J＝9.0Hz,1H),7.68-7.60(m,2H),7.49-7.44(m,2H),7.36(ddd,J＝8.9,6.8,1.0Hz,1H),6.96(td,J＝7.0,1.3Hz,1H),5.21-5.01(m,1H),2.24(s,3H),2.04-1.95(m,2H),1.84-1.74(m,2H),1.66-1.55(m,3H),1.53-1.33(m,3H).13C NMR(100MHz,CDCl3)δ＝186.33,164.43,139.68,139.49,138.19,137.70,130.35,128.91,127.98,127.18,122.49,119.39,114.45,105.93,72.14,31.99,25.53,23.84,15.25.
Example 6
Synthesizing indolizine compounds shown in the formula I-6:
at room temperature and N2Under protection, II-5(0.1mmol, 38.8mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was chromatographed directly on silica gel column (eluent: EtOAc/P.E.,1:49) to give I-6 as a yellow viscous oily liquid (28.9mg, 60% yield). GC-MS (EI) 481.
Example 7
Synthesizing indolizine compounds shown in the formula I-7:
at room temperature and N2Under protection, II-6(0.1mmol, 35.1mg,1equiv), III-1(0.12mmol,20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was chromatographed directly on silica gel column (eluent: EtOAc/P.E.,1:49) to give I-7 as a yellow viscous oily liquid (12.8mg, 29% yield). GC-MS (EI) 443.
Example 8
Synthesizing indolizine compounds shown in the formula I-8:
at room temperature and N2Under protection, II-7(0.1mmol, 36.1mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was chromatographed directly on silica gel column (eluent: EtOAc/P.E.,1:49) to give I-8 as a yellow viscous oily liquid (10.0mg, 22% yield). GC-MS (EI) 453.
Example 9
Synthesizing indolizine compounds shown in the formula I-9:
at room temperature and N2Under protection, II-8(0.1mmol, 38.7mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was chromatographed directly on silica gel column (eluent: EtOAc/P.E.,1:49) to give I-9 as a yellow viscous oily liquid (34.0mg, 71% yield). GC-MS (EI) 479.
Example 10
Synthesis of indolizines of formula I-1 (using a different base from example 1):
at room temperature and N2II-1(0.1mmol, 31.3mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and DBU (0.2mmol,30.4mg,2equiv) were dissolved in DMF (1mL) under protection, and after 24h of reaction, the reaction was directly chromatographed on silica gel (eluent: EtOAc/P.E.,1:49) to give viscous liquid I-1 as a yellow oil (17.3mg, 43% yield). The nuclear magnetic data substantially agreed with those of example 1, and it was demonstrated that the technical effects of the present invention can be achieved even when the base is DBU.
Example 11
Synthesis of indolizine type compound represented by formula I-1 (using a different solvent from example 10):
at room temperature and N2II-1(0.1mmol, 31.3mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and DBU (0.2mmol,30.4mg,2equiv) were dissolved in EtOAc (1mL) under protection, reacted for 12h, and then the reaction solution was distilled under reduced pressure to dryness and then purified on an adsorption column surface layer filled with silica gel (eluent: EtOAc/P.E.,1:49) to obtain viscous liquid I-1(18.5mg, yield 46%) as a yellow oil. The nuclear magnetic data is substantially consistent with example 1, indicating that the technical effect of the present invention can also be achieved when the solvent is EtOAc.
Example 12
Synthesis of indolizines of formula I-1 (using different times than in example 1):
at room temperature and N2Under protection, II-1(0.1mmol, 31.3mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 24h of reaction, the reaction was purified directly on the surface of an adsorption column packed with silica gel (eluent: EtOAc/P.E.,1:49) to obtain viscous liquid I-1 as a yellow oil (21.0mg, yield 52%). The nuclear magnetic data are substantially the same as in example 1, indicating that the reaction time is prolonged to 24 hoursThe technical effect of the invention is realized.
Example 13
Synthesis of indolizines of formula I-1 (using different temperatures than in example 1):
at 0 ℃ and N2Under protection, II-1(0.1mmol, 31.3mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was purified directly on the surface of an adsorption column packed with silica gel (eluent: EtOAc/P.E.,1:49) to obtain viscous liquid I-1 as a yellow oil (18.1mg, yield 45%). The nuclear magnetic data are substantially consistent with example 1, indicating that the reaction at 0 ℃ can also achieve the technical effects of the present invention.
Example 14
Synthesis of indolizines of formula I-1 (using different temperatures than in example 1):
at 50 ℃ and N2Under protection, II-1(0.1mmol, 31.3mg,1equiv), III-1(0.12mmol, 20.9mg,1.2equiv) and Cs2CO3(0.2mmol,65.2mg,2equiv) was dissolved in DMF (1mL) and after 6h of reaction, the reaction was purified directly on the surface of an adsorption column packed with silica gel (eluent: EtOAc/P.E.,1:49) to obtain viscous liquid I-1 as a yellow oil (19.3mg, yield 48%). The nuclear magnetic data are substantially consistent with example 1, indicating that the reaction at 50 ℃ can also achieve the technical effects of the present invention.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.