阅读说明：本技术 一种移除氮杂环化合物取代基中酮片段的方法 (Method for removing ketone fragment in nitrogen heterocyclic compound substituent ) 是由 周锡庚 王圣克 于 2021-04-06 设计创作，主要内容包括：本发明属于化工技术领域,涉及氢解氮杂环侧链非张力非极性碳-碳单键的方法,具体涉及一种简便的移除氮杂环化合物取代基中酮片段的方法。本发明在稀土催化体系下,以二级醇或二级胺或硅氢烷作为氢源,实现高选择性转移氢解氮杂环侧链碳-碳单键的方法,其中所述反应是利用其它已知方法不能或难以实现的；所述方法为复杂天然产物的结构简化和有机合成的逆合成路线设计提供了新策略,可广泛应用；本发明方法具有原子经济性好,操作简便,位置选择性和化学选择性可控等优点,为氮杂环侧链取代基简化提供了实用的新方法。(The invention belongs to the technical field of chemical industry, and relates to a method for hydrogenolysis of a non-tension nonpolar carbon-carbon single bond on a nitrogen heterocyclic side chain, in particular to a simple method for removing a ketone fragment in a nitrogen heterocyclic compound substituent. In the invention, under a rare earth catalytic system, secondary alcohol or secondary amine or silane is used as a hydrogen source to realize the method for highly selectively transferring and hydrogenolyzing the nitrogen heterocyclic side chain carbon-carbon single bond, wherein the reaction can not be or is difficult to realize by other known methods; the method provides a new strategy for the structure simplification of complex natural products and the reverse synthetic route design of organic synthesis, and can be widely applied; the method has the advantages of good atom economy, simple and convenient operation, controllable position selectivity, chemical selectivity and the like, and provides a practical new method for simplifying the side chain substituent of the nitrogen heterocyclic ring.)

1. A method for removing a ketone fragment from a nitrogen heterocyclic compound substituent, comprising the steps of:

under the protection of nitrogen, under a rare earth catalytic system, taking a compound shown as a formula (I) as a reaction substrate, taking alcohol or secondary amine or silane as a hydrogen source, and obtaining hydrogenolysis products (II) and (III) by selectively carrying out hydrogenolysis on a carbon-carbon single bond far away from a carbonyl group; the reaction formula is as follows:

in the above formula, representative heterocycles are listed in the formula;

the catalyst is a rare earth alkyl complex, a rare earth aryl complex, a rare earth amino complex, a rare earth alkoxy complex, a rare earth sulfenyl complex or a rare earth amidino complex;

the rare earth metal is Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb or Lu;

the solvent is benzene, toluene, xylene, tetrahydrofuran or hexane;

the hydrogen source comprises: secondary alcohol, secondary amine, silane.

2. The method of claim 1, wherein the hydrogen source is: diarylcarbinols or arylsilanes.

3. The method according to claim 1, wherein the method comprises, in terms of mole ratios: the ratio of the compound of formula (I)/rare earth catalyst is 1/0.005-0.30, and the ratio of the compound of formula (I)/hydrogen source is 1/0.5-2.0.

4. The process according to claim 1, wherein the reaction temperature for the transfer hydrogenolysis of compound (I) is between 0 ℃ and 120 ℃.

5. The process according to claim 1, wherein the reaction time for the transfer hydrogenolysis of compound (I) is 2 to 48 h.

Technical Field

The invention belongs to the technical field of chemical industry, and relates to a method for hydrogenolysis of a non-tension nonpolar carbon-carbon single bond of a nitrogen heterocyclic side chain, in particular to a simple method for removing a ketone fragment in a nitrogen heterocyclic substituent, especially a method for shortening a carbon chain of the nitrogen heterocyclic substituent.

Background

The prior art discloses that nitrogen heterocyclic ring structural units are widely present in the molecular structures of natural products and bulk chemical products. In research practice, modification of ring substituents is often required to modulate their biological activity and functional properties, however, traditional methods of modifying nitrogen heterocycles have been largely limitedBased on C-H activation or derivatization of existing functional groups, a new functional substituent is introduced. In contrast, methods for shortening azacyclic side chains have been reported to be less, primarily limited to the cleavage of carbon-heteroatom bonds or the cleavage of heteroatom-substituted carbon-carbon bonds. So far, reports on partial fragment cutting of nitrogen heterocyclic substituent directly through fat non-activated carbon-carbon single bond hydrogenolysis reaction are not seen. The reason for this is mainly due to selective cleavage of the side chain C (sp)³)-C(sp³) Bonds are more challenging than extending carbon chains, and there is no effective general method (Science 2019,364, 681-685; nature 2020,580, 621-627). Hydrogenolysis of nonpolar, non-activated C (sp)³)-C(sp³) The bond tends to result in preferential cleavage of the carbon-nitrogen bond (Nature Commun.2017,8,1866). Therefore, the selective cleavage of C (sp) has been developed³)-C(sp³) The method of bonding, whether it is for structural optimization of natural products or for the design of routes for organic synthesis, will have a major impact (Nature 2018,564, 244-248; nature 2016,537, 214-219). Carbonyl groups are widely found in natural products and organic synthetic molecules and are readily introduced by various conventional reaction routes. It has been shown that the removal of a part of the ketone structural unit in the side chain substituent of the natural heterocyclic compound not only can effectively improve the activity of the natural product, but also can reduce the toxicity of the natural product by the strategy (chem.Rev.2019,119, 4180-4220). Unfortunately, due to the lack of methods for removing ketone building blocks from organic molecules, structurally simplified analogs of such natural products now have to be synthesized using multistep processes or de novo synthetic strategies, which not only reduce the atom economy of synthesis of the target molecule, but are also time-consuming and laborious (J.Am.chem.Soc.2010,132, 1432-1442; J.Am.chem.Soc.2004,126, 1038-1040). Through C (sp)³)-C(sp³) The main reason why the removal of the ketone structural unit by the bond reduction reaction is difficult is that the carbonyl ratio is C (sp)³)-C(sp³) The bond is more easily reduced. Therefore, there is an urgent need to develop a C (sp) having high selectivity away from carbonyl group³)-C(sp³) Bond hydrogenolysis strategies.

Based on the current state of the art, the inventors of the present application propose to provide a method for hydrogenolysis of a non-strained non-polar carbon-carbon single bond on a side chain of an azacyclic compound, and in particular, to a simple method for removing a ketone fragment from a substituent of an azacyclic compound.

Disclosure of Invention

The invention aims to provide a method for hydrogenolysis of a non-tension non-polar carbon-carbon single bond on a side chain of an azacyclic compound based on the current situation of the prior art, and particularly relates to a simple method for removing a ketone fragment in a substituent of the azacyclic compound.

The invention provides a method for obtaining a novel substituted heterocyclic compound by using a compound shown as a formula (I) as a raw material and a diaryl methanol compound as a hydrogen source and carrying out high-selectivity hydrogenolysis on a carbon-carbon single bond on a side chain of an azacyclo. The method has the advantages of good atomic economy, simple and convenient operation and the like.

The invention provides a method for hydrogenolysis of a branched carbon-carbon single bond of an azacyclo, in particular to a simple method for removing a ketone fragment in a substituent of an azacyclo compound, which comprises the following steps:

under the protection of nitrogen, in a rare earth catalytic system, taking a compound shown as a formula (I) as a reactant, taking diaryl methanol or secondary amine or silane as a hydrogen source, and carrying out selective hydrogenolysis on a carbon-carbon single bond far away from a carbonyl group to obtain hydrogenolysis products (II) and (III); the reaction formula is as follows:

in the above formula, representative heterocycles have been listed therein;

the catalyst is a rare earth alkyl complex, a rare earth aryl complex, a rare earth amino complex, a rare earth alkoxy complex, a rare earth sulfenyl complex, a rare earth amidino complex and the like;

the rare earth metals are Sc, Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu;

the solvent is benzene, toluene, xylene, tetrahydrofuran and hexane;

the hydrogen source comprises: diarylcarbinols, secondary amines, hydrosilanes; the hydrogen source is preferably: diaryl carbinols, aryl silanes;

calculated according to molar ratio: the ratio of the compound of the formula (I) to the rare earth catalyst is 1/0.005-0.30, and the ratio of the compound of the formula (I) to the hydrogen source is 1/0.5-2.0;

the reaction temperature of the transfer hydrogenolysis compound (I) is 0-120 ℃;

the reaction time of the transfer hydrogenolysis compound (I) is 2-48 h.

The invention relates to a method for shortening side chain substituent of nitrogen heterocyclic compound by hydrogenolysis reaction of non-tension nonpolar carbon-carbon single bond. Compared with the existing process route, the method has the following advantages:

1) the raw material (the compound of formula (I)) and the hydrogen source are widely available or easy to prepare;

2) directly removing ketone fragments of heterocyclic substituent groups through carbon-carbon bond hydrogenolysis reaction, and providing a convenient way for synthesizing another substituted nitrogen heterocyclic ring from one substituted nitrogen heterocyclic ring;

3) the conventional reactivity reversal of the ketone is controlled by the catalyst, so that the reduction of the carbon-carbon single bond-preferential carbonyl is realized for the first time;

4) the protection of carbonyl in the hydrogenolysis process of the carbon-carbon bond is avoided, a large amount of reaction reagents and reaction steps are saved, and the economy and the atom economy are good;

4) the method has the advantages of simple operation, mild reaction conditions, strong reaction selectivity, high product yield, simple preparation process and product separation and purification, and good application prospect.

Compared with the prior art, the invention has the beneficial effects that:

the method can directly cut off the inert carbon-carbon single bond to obtain a corresponding carbon-carbon bond hydrogenolysis product; side chain simplification of numerous types of nitrogen heterocyclic compounds that are otherwise impossible or difficult to achieve is successfully achieved; realizing gram-grade carbon-carbon bond hydrogenolysis reaction; in addition, functional group compatibility is good; the reaction condition is mild, the product is convenient to separate and purify, and the process operation is simple and convenient.

Detailed Description

The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.

Example 1

Synthesis of bis (2-pyridyl) methane in one step from 1, 3-diphenyl-4, 4-bis (2-pyridyl) -1-butanone:

under the protection of nitrogen, 1, 3-diphenyl-4, 4-di (2-pyridyl) -1-butanone (0.50mmol), diphenylmethanol (0.50mmol) and catalyst Y [ N (SiMe)₃)₂]₃(2 mol%) was dissolved in 2mL of toluene and reacted at 110 ℃ for 12 hours, and the isolated yield of the product, bis (2-pyridyl) methane, was 85%.

¹H NMR(400MHz,CDCl₃)δ(ppm)8.58–8.45(m,2H),7.58(t,J＝7.6Hz,2H),7.24(d,J＝7.7Hz,2H),7.11(t,J＝6.5Hz,2H),4.32(s,2H)。

Example 2

Synthesis of bis (2-quinolinyl) methane in one step from 1, 3-diphenyl-4, 4-bis (2-quinolinyl) -1-butanone:

under the protection of nitrogen, raw materials of 1, 3-diphenyl-4, 4-di (2-quinolyl) -1-butanone (0.50mmol), 4-methoxyphenyl benzyl alcohol (0.80mmol) and a catalyst La [ N (SiMe)₃)₂]₃(5 mol%) was dissolved in 2mL of toluene and reacted at 80 ℃ for 24 hours, and the isolated yield of the product, bis (2-quinolyl) methane, was 89%.

¹H NMR(400MHz,CDCl₃)δ(ppm)8.11(d,J＝8.5Hz,2H),8.02(d,J＝8.4Hz,2H),7.74(d,J＝8.2Hz,2H),7.70(t,J＝7.7Hz,2H),7.49(t,J＝7.4Hz,2H),7.40(d,J＝8.4Hz,2H),4.73(s,2H)。

Example 3

Synthesis of bis (2-benzothienyl) methane in one step from 1, 3-diphenyl-4, 4-bis (2-benzothiazolyl) -1-butanone:

under the protection of nitrogenRaw materials of 1, 3-diphenyl-4, 4-bis (2-benzothiazolyl) -1-butanone (0.50mmol), phenylsilane (0.60mmol) and a catalyst Sm (SPh)₃(5 mol%) is dissolved in 2mL xylene and reacted at 110 ℃ for 12h, and the product, bis (2-benzothienyl) methane, is isolated in 59% yield.

¹H NMR(400MHz,CDCl₃)δ(ppm)8.07(d,J＝7.2Hz,2H),7.87(d,J＝7.9Hz,2H),7.51(t,J＝7.6Hz,2H),7.41(t,J＝7.5Hz,2H),4.98(s,2H)。

Example 4

Synthesis of bis (4-isopropyl-4, 5-dihydrooxazolyl) methane from 1, 3-diphenyl-4, 4-bis (4-isopropyl-4, 5-dihydrooxazolyl) -1-butanone in one step:

under the protection of nitrogen, raw materials of 1, 3-diphenyl-4, 4-di (4-isopropyl-4, 5-dihydrooxazolyl) -1-butanone (0.5mmol), diisobutylamine (0.55mmol) and catalyst YPh₃(5 mol%) is dissolved in 2mL toluene, and the reaction is carried out for 12h at 100 ℃, and the separation yield of the product bis (4-isopropyl-4, 5-dihydrooxazolyl) methane is 54%.

¹H NMR(400MHz,CDCl₃)δ(ppm)4.25(t,J＝8.5Hz,2H),4.02–3.84(m,4H),3.32–3.26(m,2H),1.78–1.70(m,2H),0.93(d,J＝6.7Hz,6H),0.85(d,J＝6.8Hz,6H)；

Example 5

Synthesis of bis (2-quinolinyl) methane in one step from (E) -1, 5-diphenyl-6, 6-bis (2-quinolinyl) -3-alkenyl-1-pentanone:

under the protection of nitrogen, raw material (E) -1, 5-diphenyl-6, 6-di (2-quinolyl) -3-alkenyl-1-pentanone (0.50mmol), diphenylmethanol (0.40mmol) and catalyst Y (OCHPh)₂)₃(3 mol%) was dissolved in 2mL of tetrahydrofuran and reacted at 80 ℃ for 24 hours, and the isolated yield of the product, bis (2-quinolyl) methane, was 73%.

¹H NMR(400MHz,CDCl₃)δ(ppm)8.11(d,J＝8.5Hz,2H),8.02(d,J＝8.4Hz,2H),7.74(d,J＝8.2Hz,2H),7.70(t,J＝7.7Hz,2H),7.49(t,J＝7.4Hz,2H),7.40(d,J＝8.4Hz,2H),4.73(s,2H)。

Example 6

Synthesis of bis (2-benzothienyl) methane in one step from (E) -1, 5-diphenyl-6, 6-bis (2-benzothiazolyl) -3-alkenyl-1-pentanone:

under the protection of nitrogen, raw material (E) -1, 5-diphenyl-6, 6-bis (2-benzothiazolyl) -3-alkenyl-1-pentanone (0.50mmol), diphenyl methanol (0.52mmol) and catalyst Y [ N (SiMe)₃)₂]₃(1 mol%) was dissolved in 2mL of toluene and reacted at 110 ℃ for 6 hours, and the isolated yield of the product, bis (2-benzothienyl) methane, was 84%.

¹H NMR(400MHz,CDCl₃)δ(ppm)8.07(d,J＝7.2Hz,2H),7.87(d,J＝7.9Hz,2H),7.51(t,J＝7.6Hz,2H),7.41(t,J＝7.5Hz,2H),4.98(s,2H)

Example 7

One-step synthesis of bis (2-pyridyl) methane from 1-tert-butyl-3-phenyl-bis (2-pyridyl) -1-butanone:

under the protection of nitrogen, raw materials of 1-tert-butyl-3-phenyl-di (2-pyridyl) -1-butanone (0.50mmol), diphenylmethanol (0.55mmol) and a catalyst Y [ N (SiMe)₃)₂]₃(5 mol%) was dissolved in 2mL of toluene and reacted at 110 ℃ for 6 hours, and the isolated yield of bis (2-pyridyl) methane was 78%.

¹H NMR(400MHz,CDCl₃)δ(ppm)8.58–8.45(m,2H),7.58(t,J＝7.6Hz,2H),7.24(d,J＝7.7Hz,2H),7.11(t,J＝6.5Hz,2H),4.32(s,2H)。

Example 8

One-step synthesis of bis (2-quinolinyl) methane from 1-tert-butyl-3-phenyl-bis (2-quinolinyl) -1-butanone:

under the protection of nitrogen, raw material 1-tert-butyl-3-phenyl-di (2-quinolyl) -1-butanone (0.50mmol), phenylsilanol (2.0mmol) and catalyst Yb [ CH ]₂(TMS)]₃(10 mol%) was dissolved in 2mL of toluene and reacted at 100 ℃ for 48 hours, and the isolated yield of bis (2-quinolyl) methane was 65%.

¹H NMR(400MHz,CDCl₃)δ(ppm)8.11(d,J＝8.5Hz,2H),8.02(d,J＝8.4Hz,2H),7.74(d,J＝8.2Hz,2H),7.70(t,J＝7.7Hz,2H),7.49(t,J＝7.4Hz,2H),7.40(d,J＝8.4Hz,2H),4.73(s,2H)。

Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims.