CN114621148A - Method for introducing dimethylallyl (4, 3-addition) into indazole N1 under action of palladium catalyst - Google Patents

Method for introducing dimethylallyl (4, 3-addition) into indazole N1 under action of palladium catalyst Download PDF

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CN114621148A
CN114621148A CN202011454241.5A CN202011454241A CN114621148A CN 114621148 A CN114621148 A CN 114621148A CN 202011454241 A CN202011454241 A CN 202011454241A CN 114621148 A CN114621148 A CN 114621148A
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indazole
methyl
palladium
butadiene
reaction
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陈庆安
姜文爽
季定纬
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Dalian Institute of Chemical Physics of CAS
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Dalian Institute of Chemical Physics of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Abstract

The invention belongs to the technical field of pharmaceutical and chemical intermediates and related chemistry, and relates to a method for introducing dimethylallyl into an N1 site of indazole and derivatives thereof. Specifically, simple indazole and bulk chemical 2-methyl-1, 3-butadiene are used as starting materials, and dimethylallyl can be introduced at the position of indazole N1 under the condition of promoting a palladium catalyst/phosphine ligand/additive.

Description

Method for introducing dimethylallyl (4, 3-addition) into indazole N1 under action of palladium catalyst
Technical Field
The invention relates to a method for introducing a dimethylallyl group at the position N1 of indazole. Specifically, indazole and 2-methyl-1, 3-butadiene are used as raw materials, and dimethylallyl can be introduced at the position of indazole N1 with high selectivity under the promotion of a palladium catalyst/phosphine ligand/additive. The invention has the advantages of simple and easily obtained raw materials, simple synthesis, environment friendliness, mild conditions and high atom economy, and the compounds are important heterocyclic compounds and synthetic intermediates, have wide pharmacological activities such as anti-inflammation, anti-tumor, antibacterial and various biological enzyme inhibitors, and are common dominant frameworks in drug molecules.
Background
Indazoles and derivatives thereof are widely available in drug molecules and widely used in small molecule inhibitors. For example, Merestinib (MET inhibitor), Granisetron, Benzydamine hydrochloride (prostagladin synthase inhibitor) (formula 1), so that it is important to search for a simple, efficient and atom-economical catalytic system to realize dimethylallyl at the N1 position.
Figure BDA0002827899740000011
Formula 1: active molecules containing indazole structures
Through literature search, it is found (formula 2) that the Breit group reports that indazole and allene realize allylation at the N1 position under the catalysis of palladium or rhodium in 2015 and 2019, but reaction substrates are limited and only occur on indazole without substituents, so that the selection of a proper catalytic system has an important significance for improving universality by performing dimethylallyl substitution at the N1 position of indazole.
Figure BDA0002827899740000012
Formula 2: the allylation of the indazole N1 position is reported in the literature
The 2-methyl-1, 3-butadiene is an industrial bulk chemical, is cheap and easy to obtain, and has high annual yield. The patent develops a reaction of 2-methyl-1, 3-butadiene and indazole under the catalysis of palladium, and dimethylallyl can be introduced at the N1 position with high selectivity.
Disclosure of Invention
The invention aims to develop a palladium catalyst/phosphine ligand/additive system by taking simple chemicals 2-methyl-1, 3-butadiene and indazole as raw materials, and dimethyl allyl can be introduced at the position of indazole N1 with high selectivity.
The invention is realized by the following technical scheme:
indazole 1 and 2-methyl-1, 3-butadiene (or substituted 2-methyl-1, 3-butadiene) can introduce dimethylallyl (or substituted allyl) at position N1 under the action of a palladium catalyst, a phosphine ligand and an additive, and the reaction formula is as follows:
Figure BDA0002827899740000021
the specific operation steps are as follows:
under the atmosphere of argon or nitrogen, a palladium catalyst, a phosphine ligand, an additive and indazole 1 are sequentially added, then a certain amount of solvent is added to dissolve, finally 2-methyl-1, 3-butadiene (or substituted 2-methyl-1, 3-butadiene) 2 is added to react at a certain temperature, a reaction system is monitored by a point plate, after the reaction is finished, the solvent is dried in a spinning mode, and column chromatography (mobile phase V/V: petroleum ether/ethyl acetate: 20/1) is carried out to obtain a target product 3.
The invention has the following advantages:
the invention has the advantages of simple and easily obtained raw materials, simple synthesis, environment friendliness, mild conditions and high atom economy, and the compounds are important heterocyclic compounds and synthetic intermediates, have wide pharmacological activities such as anti-inflammation, anti-tumor, antibacterial and various biological enzyme inhibitors, and are common dominant frameworks in drug molecules.
Detailed Description
The invention will now be illustrated by means of specific examples, without restricting its scope to these examples.
1. Palladium-catalyzed reaction of indazole and 2-methyl-1, 3-butadiene
A palladium catalyst (5 mol% of indazole 1a mol), a phosphine ligand (5 mol% of indazole 1a mol), an additive (75 mol% of indazole 1a mol), and indazole 1a (0.2mmol,23.4mg) were sequentially added to a 2.0mL sealed tube, dissolved in 0.5mL of a solvent, followed by addition of 2-methyl-1, 3-butadiene 2a (1.0mmol, 100. mu.L), reaction at 80 ℃ for 24 hours, and after completion, mesitylene was added as an internal standard,1h NMR detects the yield of the target product 3 a.
Figure BDA0002827899740000031
TABLE 1 influence of factors such as catalyst, ligand, additives, etc. on the reaction
Figure BDA0002827899740000032
Figure BDA0002827899740000041
As can be seen from the results in table 1, when indazole 1a and 2-methyl-1, 3-butadiene 2a were reacted at a molar ratio of 1:5 at 80 ℃, the target product was obtained in a trace amount using palladium ditert-butylphosphine as a catalyst, α, α' -bis (di-tert-butylphosphine) o-xylene as a ligand, and triethylboron as an additive, ethanol as a solvent (example 1). When tetrahydrofuran is used as a solvent, the yield of the target product can reach 16 percent (example 2). The target product was obtained in 6% and 21% yields, respectively, when dichloromethane and dichloroethane were used as solvents (examples 3-4), and the reaction was greatly improved when the solvents were replaced with ethyl acetate, dioxane, tert-butanol and isopropanol as solvents (examples 5-7). When triethylboron was replaced with diethylzinc, trimethylaluminum and diphenyl phosphate, the reaction did not occur or the desired product was obtained in a trace yield (examples 10-12). When the ligands are exchanged for other diphosphine or triphosphon ligands, the effect of the reaction is not ideal (examples 13-18). When the catalyst was changed to palladium chloride and palladium trifluoroacetate, the reaction could not occur (examples 19-20). Thus, it is preferred that the catalyst is palladium bis (tri-tert-butylphosphine), the ligand is α, α' -bis (di-tert-butylphosphine) o-xylene, the additive is triethylboron (75 mol%), the solvent is isopropanol, the reaction temperature is 80 ℃ and the reaction time is 24 h.
2. Type of substrate
In the glove box, to a 2.0mL stopcock, Pd (P) was added in sequencetBu3)2(5 mol%, 5.1mg), α' -bis (di-t-butylphosphino) o-xylene (5 mol%, 4.0mg), BEt3(75 mol%, 150. mu.L) and indazole 1(0.2mmol), in a volume of 0.5mLiDissolving PrOH, adding 2-methyl-1, 3-butadiene 2(5.0equiv), reacting at 80 ℃ for 24 hours, quenching the reaction after the reaction is finished, washing with water, extracting with ethyl acetate, spin-drying, separating by column chromatography, and separating by mobile phase V/V: petroleum ether/ethyl acetate 10: 1.
Figure BDA0002827899740000042
Figure BDA0002827899740000043
acetate＝10/1).1H NMR(400MHz,Chloroform-d)δ8.02(d,J＝1.0Hz,1H), 7.74(dt,J＝8.1,1.1Hz,1H),7.45(dq,J＝8.5,1.0Hz,1H),7.40–7.33(m,1H), 7.14(ddd,J＝7.9,6.8,0.9Hz,1H),5.18(q,J＝6.9Hz,1H),4.97(dt,J＝2.7, 1.3Hz,2H),1.81(d,J＝7.0Hz,3H),1.58(s,3H).13C NMR(101MHz, Chloroform-d)δ145.30,139.40,132.90,126.16,124.59,121.31,120.76,112.47, 109.86,59.85,19.44,18.34.HRMS calculated for C12H15N2[M+H]+ 187.1230,found 187.1229.
Figure BDA0002827899740000051
δ7.91(s,1H),7.48(s,1H),7.33(d,J＝8.6Hz,1H),7.17(d, J＝8.6Hz,1H),5.14(q,J＝7.0Hz,1H),4.95(d,J＝1.6Hz,2H),2.44(s,3H), 1.78(dd,J＝7.0,0.9Hz,3H),1.56(s,3H).13C NMR(100MHz,Chloroform-d) δ145.29,138.00,132.14,130.03,128.14,124.89,120.17,112.24,109.45,59.77, 21.37,19.33,18.18.HRMS calculated for C13H17N2[M+H]+201.1386, found 201.1389.
Figure BDA0002827899740000052
Chloroform-d)δ7.81(s,1H),7.23(d,J＝9.0Hz,1H),6.97 (d,J＝2.4Hz,1H),6.92(dd,J＝9.1,2.3Hz,1H),5.02(q,J＝6.9Hz,1H),4.85 (d,J＝1.3Hz,2H),3.74(s,3H),1.68(d,J＝7.0Hz,3H),1.46(s,3H).13C NMR(100MHz,Chloroform-d)δ154.62,145.31,135.30,131.98,124.75, 118.34,112.30,110.77,100.25,59.97,55.78,19.24,18.21.HRMS calculated for C13H17N2O[M+H]+217.1335,found217.1348.
Figure BDA0002827899740000053
Chloroform-d)δ7.96(s,1H),7.38(dd,J＝9.1,4.1Hz,1H),7.34(dd,J＝8.7, 2.4Hz,1H),7.12(td,J＝9.0,2.4Hz,1H),5.15(q,J＝7.0Hz,1H),4.97(dd,J ＝2.7,1.4Hz,2H),1.79(d,J＝6.9Hz,3H),1.55(s,3H).13C NMR(100MHz, Chloroform-d)δ157.91(d,J＝237.9Hz),145.06,136.31,132.47(d,J＝5.7 Hz),124.41(d,J＝10.2Hz),115.71(d,J＝27.6Hz),112.56,110.82(d,J＝9.6 Hz),105.03(d,J＝23.4Hz),60.20,19.16,18.22.19F NMR(376MHz, Chloroform-d)δ-123.45.HRMS calculated for C12H14FN2[M+H]+205.1136, found 205.1132.
Figure BDA0002827899740000061
Chloroform-d)δ7.95(s,1H),7.69(d,J＝1.9Hz,1H),7.36(d, J＝8.9Hz,1H),7.28(dd,J＝8.9,1.9Hz,1H),5.14(q,J＝7.0Hz,1H),4.96(d, J＝5.5Hz,2H),1.79(d,J＝7.0Hz,3H),1.55(s,3H).13C NMR(100MHz, Chloroform-d)δ144.90,137.77,132.15,126.76,126.36,125.31,120.34,112.64, 110.89,60.18,19.18,18.19.HRMS calculated for C12H14ClN2[M+H]+ 221.0840,found 221.0842.
Figure BDA0002827899740000062
(petroleum ether/ethyl acetate＝10/1).1H NMR(400MHz, Chloroform-d)δ8.11(s,1H),8.05(s,1H),7.58–7.50(m,2H),5.21(q,J＝7.0 Hz,1H),4.99(d,J＝4.0Hz,2H),1.81(d,J＝7.0Hz,3H),1.57(s,3H).13C NMR(100MHz,Chloroform-d)δ144.80,140.24,133.98,124.99(q,J＝271.7 Hz),123.76,123.40(q,J＝32.2Hz),122.80(q,J＝3.2Hz),119.56(q,J＝4.5 Hz),112.96,110.53,60.41,19.31,18.31.19F NMR(376MHz,Chloroform-d)δ -60.91.HRMS calculated for C13H14F3N2[M+H]+255.1104,found 255.1105.
Figure BDA0002827899740000063
(petroleum ether/ethyl acetate＝10/1).1H NMR(400MHz, Chloroform-d)δ8.40(dd,J＝1.5,0.8Hz,1H),8.00(s,1H),7.91(dd,J＝8.9, 1.6Hz,1H),7.33(dd,J＝8.9,1.0Hz,1H),5.07(q,J＝6.9Hz,1H),4.86(dd,J ＝2.8,1.4Hz,2H),3.82(s,3H),1.69(d,J＝7.0Hz,3H),1.46(s,3H).13C NMR (100MHz,Chloroform-d)δ167.41,144.69,141.01,134.51,126.91,124.70, 124.13,123.01,112.73,109.44,60.07,52.15,19.24,18.18.HRMS calculated for C14H17N2O2[M+H]+245.1285,found 245.1289.
Application example 1:
the product 3a can be simply converted into an organic nitrogen polymeric material having flame retardant properties by further polymerization. The specific operation is as follows (formula 2):
Figure BDA0002827899740000064
reaction equation 2: synthesis of organic nitrogen-doped polymers
Under the protection of nitrogen, 3a (0.2mmol) is dissolved in toluene (5.0mL), initiator (1 mmol% of 3 a) is added, and then the mixture is stirred at 100 ℃ for 24h and quenched at normal temperature by adding hydrochloric acid with the mass concentration of 10%. After that, extraction with ethyl acetate, drying over anhydrous sodium sulfate, and rotary evaporation gave a sulfonic acid oil as a liquid. The compound has a molecular weight range of 5000-.

Claims (7)

1. A method of palladium-catalyzed indazole incorporating dimethylallyl (4, 3-addition) at position N1, comprising:
under the action of a catalyst and an additive, dimethyl allyl or substituted allyl can be introduced into the position N1 of one or more of indazole (1) and 2-methyl-1, 3-butadiene or substituted 2-methyl-1, 3-butadiene (2);
the specific operation steps are as follows:
under the atmosphere of argon or nitrogen, sequentially adding a palladium catalyst, a phosphine ligand, an additive and indazole 1, then adding a solvent for dissolving, finally adding 2-methyl-1, 3-butadiene 2, and reacting to obtain a target product 3;
the catalyst is a complex of a metal precursor of palladium and a diphosphine ligand;
the metal precursor is palladium bis (tri-tert-butylphosphine);
the diphosphine ligand is alpha, alpha' -bis (di-tert-butylphosphine) o-xylene;
the additive is triethylboron;
the solvent is one or more of ethyl acetate, tert-butyl alcohol and isopropanol, preferably isopropanol.
2. The method of claim 1, wherein:
the reaction formula is shown as follows:
Figure FDA0002827899730000011
the substituent R on the reactant indazole can be one or more of hydrogen, aldehyde group, ester group, halogen, C1-C10 alkyl and the like;
r on dienes1Can be one or more than two of hydrogen, C1-C10 alkyl connected at the 1,3 or 4 position;
wherein the ester group is one of methyl ester and ethyl ester.
3. The method according to claim 1 or 2, characterized in that:
the catalyst is used in an amount of 0.01-0.1:1, preferably 0.03-0.08:1, more preferably 0.05:1, calculated as palladium, based on the molar amount of indazole; the molar ratio of the metal precursor of palladium to the bisphosphine ligand is 1:0.5 to 5, preferably 1:0.8 to 3, more preferably 1: 1.
4. The method according to claim 1 or 2, characterized in that:
the molar ratio of additive to indazole is from 0.01 to 2, preferably in the range of from 0.1 to 1.2, more preferably 0.75.
5. The method according to claim 1 or 2, characterized in that:
the indazole concentration in the solvent is in the range of 0.01-1.5mol/L, preferably 0.1-1mol/L, more preferably 0.25 mol/L.
6. The method according to claim 1 or 2, characterized in that:
one or more of 2-methyl-1, 3-butadiene or substituted 2-methyl-1, 3-butadiene (2) is used in an amount of 0.5 to 10 times, preferably 3 to 7 times, more preferably 5 times the molar amount of indazole;
the reaction temperature is between 25 and 120 ℃, preferably between 60 and 90 ℃, and more preferably 80 ℃;
the reaction time is between 0.5 and 36h, preferably between 12 and 28h, more preferably 24 h.
7. The method according to claim 1 or 2, characterized in that:
and (3) monitoring the reaction system by using a point plate, and after the reaction is finished, spin-drying the solvent and carrying out column chromatography to obtain a target product 3.
CN202011454241.5A 2020-12-10 2020-12-10 Method for introducing dimethylallyl (4, 3-addition) into indazole N1 under action of palladium catalyst Pending CN114621148A (en)

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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ALEXANDER M. HAYDL等: "Regio- and Enantioselective Synthesis of N-Substituted Pyrazoles by Rhodium-Catalyzed Asymmetric Addition to Allenes", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 54, pages 7149 - 7153 *
LUKAS J. HILPERT等: "Palladium- and Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes Towards Chiral Pyrazoles", ANGEWANDTE CHEMIE INTERNATIONAL EDITION, vol. 58, pages 3378 - 3381 *

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