阅读说明：本技术 一种2,4-二酰基取代环己醇的氢化去-[2+2+2]环裂解方法 (Method for removing- [2+2+2] ring by hydrogenation of 2, 4-diacyl substituted cyclohexanol ) 是由 周锡庚 王圣克 刘斌 于 2021-04-03 设计创作，主要内容包括：本发明属于化工技术领域,具体涉及2,4-二酰基取代环己醇的氢化去-[2+2+2]环裂解方法。本发明中,在稀土催化体系下,以二级醇(胺)类化合物作为氢源,实现高效高选择性转移氢化裂解取代环己醇,形成相应的酮。本发明涉及的六元碳环的氢化去-[2+2+2]环裂解反应,为取代环己醇衍生物的环裂解建立了新方法和新模式,本发明反应原子经济性好,条件温和,选择性高,操作简便,为天然产物的结构简化、将相关有机废弃物降解为有价值的化学品及逆合成反应路线设计等提供了新策略,应用广泛。(The invention belongs to the technical field of chemical industry, and particularly relates to a method for removing a- [2+2+2] ring by hydrogenation of 2, 4-diacyl substituted cyclohexanol. In the invention, under a rare earth catalytic system, a secondary alcohol (amine) compound is used as a hydrogen source to realize high-efficiency and high-selectivity transfer hydrocracking for substituting cyclohexanol to form corresponding ketone. The invention relates to a hydrogenation de- [2+2+2] ring cleavage reaction of a six-membered carbon ring, which establishes a new method and a new mode for ring cleavage of substituted cyclohexanol derivatives.)

1. A method for removing 2+2+2] ring from 2, 4-diacyl-substituted cyclohexanol by hydrogenation is characterized in that the 2, 4-diacyl-substituted cyclohexanol is subjected to hydrogenation-removal 2+2+2 ring cleavage by rare earth catalysis of continuous carbon-carbon bond hydrogenolysis reaction, and comprises the following steps:

under the protection of nitrogen, taking a compound shown in a formula (I) as a reaction substrate, taking a secondary alcohol (amine) compound as a hydrogen source, and in the presence of a rare earth catalyst, realizing a ring opening removing reaction of- [2+2+2] through continuous Aldol removing reaction/ring carbon-carbon bond hydrogenolysis reaction to obtain hydrogenolysis products (II) and (III); the reaction formula is as follows:

in the above formula, a representative cyclohexanol is represented by 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, DMF, tetrahydrofuran or hexane.

The hydrogen source comprises: secondary alcohols, secondary amines.

2. The method of claim 1, wherein the hydrogen source is diarylmethanol.

3. The method of claim 1, wherein, 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 1/0.8-5.

4. The process as claimed in claim 1, wherein the reaction temperature for the hydrogenolysis of the compound (I) is 20 to 150 ℃.

5. The process as claimed in claim 1, wherein the reaction time for hydrogenolysis of compound (I) is 1 to 72 h.

Technical Field

The invention belongs to the technical field of chemical industry, and relates to a method for removing a- [2+2+2] ring by hydrogenation of 2, 4-diacyl substituted cyclohexanol, in particular to a method for realizing a reaction of removing a- [2+2+2] ring by catalytic hydrogenolysis of 2, 4-diacyl substituted cyclohexanol by rare earth.

Background

The prior art discloses that one of the most important and biggest challenge subjects faced currently in the process of molecular structure optimization of natural lead drugs and degradation and conversion of biomass and harmful wastes into valuable small molecules is the resolution of inert saturated six-membered carbon ring structures (Med. Res. Rev.2004, 24, 182-. Although the concern about carbon-carbon bond activation has attracted considerable research interest to a large number of chemists for decades, a limited number of known de- [2+2+2] cycloaddition reactions are largely limited to the ring-expanding isomerization of strained ring and six-membered carbocyclic rings, such as cis-tris (cyclopropane) and tris (cyclobutane) norcyclohexane, by ring-expanding isomerization to form the corresponding 9-or 12-membered ring annulenes (Angew. chem. int. Ed.2007,46, 6894-. The reaction of simultaneously cleaving three or more carbon-carbon bonds of a non-strained six-membered carbocyclic ring under mild conditions has not been reported so far. The sequential insertion of olefins into M-C bonds has become an important tool for the efficient construction of C-C bonds in the synthesis of carbon backbone polymers and carbocyclic compounds (J.Am.chem.Soc.2012,134, 715-722; J.Am.chem.Soc.2019,141, 12624-12633.). Unfortunately, the reverse reaction, i.e., the continuous β -carbon elimination of metal alkyl complexes, has been rarely reported (chem. eur. j.2013,19, 540-. The release of olefin molecules by beta-C elimination of metal alkyl complexes is a thermodynamically unfavorable process (j.am. chem. soc.2019,141, 18630-18640.).

Numerous studies have shown that the cleavage of a fragment of 2 or 4 ring carbon atoms from a six-membered carbocyclic ring is an effective method for increasing the biological activity and decreasing the addiction (or toxicity) of certain natural products (Med. Res. Rev.2004, 24, 182. sup. 212; J. Med. chem.2013, 56, 9673. sup. 9682; Nature,2021,589, 474. sup. 479.). However, by continuous hydrogenolysis of non-strained nonpolar C (sp)³)-C(sp³) Method of effecting the hydrogenation of a bond to remove [2+2]-or [2+4 ]]Ring cleavage has not been successful. Studies have revealed that continuous hydrogenolysis of non-strained nonpolar C (sp)³)-C(sp³) The difficulty of bonding is mainly due to three factors: (1) the associated C-C bond energy is high and the reaction is thermodynamically unfavorable; (2) the common catalyst is difficult to directly react withThe target C-C bond is acted; (3) activation of the C-H bond or other functional group often occurs more readily under the desired conditions. Studies have shown that in homogeneous catalysis, the currently common inert C-C bond activating catalysts are late transition metals, whose C-C bond cleavage is mainly achieved by β -carbon elimination reactions of low valence metal species inserted into the C-C bond or metal complex intermediates. Due to the lack of chelation to help the metal to be difficult to access the C-C single bond and the tendency of the intermediate of the late transition alkyl complex to undergo beta-H elimination reaction rather than beta-C elimination reaction, the range of the C-C bond which can be broken is limited and the C-C bond is difficult to be broken continuously. It is well known in the art that the difference in bond energy between the rare earth-hydrogen bond and the rare earth-carbon bond is smaller than that of the corresponding transition metal, which will help prevent the competitive beta-H competitive elimination reaction from occurring; also, the difference in the nature of rare earth metals and transition metals determines the difference in chemoselectivity and regioselectivity between them when reacted with the same substrate. Therefore, the development of a method for activating a C-C bond complementary to a transition metal by using a rare earth metal is expected and will certainly become a new research hotspot in the future. Unfortunately, the study of rare earth catalyzed C-C bond hydrogenolysis under mild conditions is still a blank.

Based on the current situation of the prior art, the inventor of the application intends to provide a method for removing 2+2+2] ring by hydrogenation of 2, 4-diacyl substituted cyclohexanol, in particular to a method for realizing the reaction of removing 2+2+2 ring by rare earth catalytic hydrogenolysis of 2, 4-diacyl substituted cyclohexanol.

Disclosure of Invention

The object of the present invention is to provide a method for producing a plurality of C (sp) s in the presence of an unsaturated functional group having a more reactive intrinsic structure, based on the state of the art³)-C(sp³) The continuous hydrogenolysis strategy of the bond realizes the hydrogenation of the compound shown in the formula (I) to remove the- [2+ 2]]A method of ring cleavage reaction. In particular to a method for removing- [2+ 2] by hydrogenation of 2, 4-diacyl substituted cyclohexanol]A ring cracking method, in particular to a method for removing- [2+ 2] by the catalytic hydrogenolysis of 2, 4-diacyl substituted cyclohexanol by rare earth]A method of ring cleavage reaction. The invention can fill the blank of the rare earth catalysis field and is C (sp)³)-C(sp³) The research of bond activation opens up a new situation, solves organic synthesis and resource circulationThe problem of ring fragmentation is difficult to occur in the process of utilizing the stable six-membered carbon ring.

In particular, the method comprises the following steps of,

the invention relates to a method for removing- [2+2+2] ring by hydrogenation of 2, 4-diacyl-substituted cyclohexanol, 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 a secondary alcohol (amine) compound as a hydrogen source, and realizing a reaction of removing a- [2+2+2] ring cleavage by selective carbon-carbon single bond continuous hydrogenolysis to obtain hydrogenolysis products (II) and (III); the reaction formula is as follows:

in the above formula, a representative cyclohexanol is represented by 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, 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 toluene, xylene, DMF, THF, hexane;

the hydrogen source comprises: secondary alcohols, secondary amines; the hydrogen source is preferably: diaryl carbinols.

Calculated according to molar ratio: 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 1/0.8-5.

The reaction temperature for hydrogenolysis of compound (I) is 20 to 150 deg.C, preferably 60 to 110 deg.C.

Characterized in that the reaction time of hydrogenolysis compound (I) is 1-72 h.

Compared with the existing process route, the method for catalytic transfer hydrocracking of 2, 4-diacyl-substituted cyclohexanol has the following advantages:

1) conventional cyclohexanol ring-opening reactions are generally only capable of cleaving 1 carbon-carbon bond, and the ring-opening of 2-acyl substituted cyclohexanols (desol reactions) requires a multi-step reaction process to be achieved (chem.rev.2021, 121, 300-phase 326; angew.chem.int.ed.2016, 55, 15319-15322; eur.j.org.chem.2020, 420-423); the method realizes the simultaneous breakage of 3 ring carbon-carbon bonds of cyclohexanol for the first time, and the method is also the first reaction for removing- [2+2+2] cracked rings by hydrogenation of six-membered carbon rings.

2) The hydrogenation reaction method for removing the- [2+2+2] split ring has the advantages of simple operation, good functional group compatibility, high selectivity, no need of additional additives, simple product separation and purification, and easy obtaining or preparation of the catalyst.

3) The cyclohexanol structure unit is widely existed in natural products and artificial chemical synthetic products, and the method has better potential application prospect for simplifying and modifying the existing natural products or complex drug molecules through ring cleavage reaction.

By adopting the method, gram-grade carbon-carbon bond hydrogenolysis reaction can be realized to obtain a corresponding reduction product; in addition, the reaction condition is mild, the operation is simple and convenient, and the controllability of the reaction selectivity is strong.

Detailed Description

The invention is further illustrated by the following examples, which do not limit the scope of the invention.

Example 1

Hydrocracking of 1-phenyl-3, 5-diphenyl-2, 4-dibenzoyl-1-cyclohexanol:

under the protection of nitrogen, the raw material 1-phenyl-3, 5-diphenyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), (4-methoxyphenyl) benzyl alcohol (0.55mmol) and catalyst Y [ N (SiMe) were added₃)₂]₃(1 mol%) and reacted in 2mL toluene at 100 ℃ for 24h, and the separation yields of hydrogenolysis products acetophenone and 1,3 diphenyl-1-acetone were 62% and 67%, respectively.

EXAMPLE 2 starting Material 1-phenyl-3, 5-diphenyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), diphenylmethanol (0.55mmol) and catalyst Y [ CH ] were added under nitrogen₂(SiMe₃)]₃(5 mol%) and reacted in 2mL xylene at 60 ℃ for 72h, the isolated yields of acetophenone and 1, 3-diphenyl-1-propanone were 67% and 70%, respectively.

Example 3 starting material 1-phenyl-3, 5-diphenyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), benzhydrol (0.55mmol) and catalyst Y (OCHPh) were added under nitrogen protection₂)₃(5 mol%) and reacted in 2mL xylene at 100 ℃ for 12h, the isolated yields of acetophenone and 1, 3-diphenyl-1-propanone were 71% and 72%, respectively.

EXAMPLE 4 starting material 1-phenyl-3, 5-diphenyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), benzhydrol (0.40mmol) and catalyst La (OCHPh) were added under nitrogen blanketing₂)₃(10 mol%) and reacted in 2mL xylene at 120 ℃ for 12h, the isolated yields of acetophenone and 1, 3-diphenyl-1-propanone were 67% and 70%, respectively.

Example 5 starting material 1-phenyl-3, 5-diphenyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), benzhydrol (2.5mmol) and catalyst Y (SPh) were added under nitrogen blanketing₃(5 mol%) and reacted in 2mL xylene at 120 ℃ for 24h, the isolated yields of acetophenone and 1, 3-diphenyl-1-propanone were 47% and 45%, respectively.

Acetophenone:¹H NMR(400MHz,CDCl₃)δ7.98-7.95(m,2H),7.58-7.55(m,1H),7.48-7.44(m,2H),2.61(s,3H)；

1, 3-diphenyl-1-propanone:¹H NMR(400MHz,CDCl₃)δ7.99-7.97(m,2H),7.59-7.56(m,1H),7.49-7.46(m,2H),7.34-7.21(m,5H),3.33(t,J＝7.7Hz,2H),3.11-3.07(m,2H)。

example 6

Hydrocracking of 1-phenyl-3, 5-di-p-tolyl-2, 4-dibenzoyl-1-cyclohexanol:

under the protection of nitrogen, the raw material 1-phenyl-3, 5-di-p-tolyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), (4-methoxyphenyl) benzyl alcohol (0.56mmol) and catalyst Y [ N (SiMe)₃)₂]₃(5 mol%) and reacted in 2mL DMF at 110 ℃ for 12h, the separation yields of acetophenone and 1-phenyl-3-p-methylphenyl-1-acetone were 76% and 78% of hydrogenolysis product, respectively.

EXAMPLE 7 starting material 1-phenyl-3, 5-di-p-tolyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), benzhydrol (0.56mmol) and catalyst Y (OCHPh) were added under nitrogen₂)₃(5 mol%) and reacted at 60 ℃ in 2mL THF for 72h, the isolated yields of acetophenone and 1-phenyl-3-p-methylphenyl-1-propanone were 52% and 60%, respectively.

1, 3-diphenyl-1-propanone:¹H NMR(400MHz,CDCl₃)δ(ppm)7.99(d,J＝7.48Hz,2H),7.59(t,J＝7.24Hz,1H),7.49(t,J＝7.68Hz,2H),7.20–7.14(m,4H),3.32(t,J＝7.36Hz,2H),3.07(t,J＝7.84Hz,2H),2.36(s,3H)。

example 8

Hydrocracking of 1-phenyl-3, 5-di-p-bromophenyl-2, 4-dibenzoyl-1-cyclohexanol:

under the protection of nitrogen, adding raw materials of 1-phenyl-3, 5-di-p-bromophenyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), diisobutylamine (2.5mmol) and catalyst Sm [ N (SiMe)₃)₂]₃(10 mol%) and reacted at 80 ℃ in 2mL of hexane for 72h, the isolated yields of hydrogenolysis products acetophenone and 1-phenyl-3-p-bromophenyl-1-propanone were 65% and 71%, respectively.

Example 9 charging under nitrogen protection starting materials 1-phenyl-3, 5-di-p-bromophenyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), benzhydrol (0.50mmol) and catalyst Cp₂YPh (3 mol%), 110 ℃ in 2mL dimethylbenzene for 24h, the separation yields of acetophenone and 1-phenyl-3-p-bromophenyl-1-propanone are 75% and 78%, respectively.

1 phenyl-3-p-bromophenyl-1-propanone:¹H NMR(400MHz,CDCl₃)δ(ppm)7.99(d,J＝7.48Hz,2H),7.59(t,J＝7.24Hz,1H),7.49(t,J＝7.68Hz,2H),7.20–7.14(m,4H),3.32

example 10

Hydrocracking of 1-phenyl-3, 5-di-p-tolyl-2, 4-dibenzoyl-1-cyclohexanol:

under the protection of nitrogen, the raw materials of 1-phenyl-3, 5-di-p-tolyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), benzhydrol (0.55mmol) and catalyst Lu [ CH ]₂C₆H₄(NMe₂-o)]₃(2 mol%) and reacting at 80 deg.C in 2mL toluene for 48h, the separation yields of acetophenone and 1-phenyl-3-p-methoxyphenyl-1-propanone are 73% and 71%, respectively.

EXAMPLE 11 starting materials 1-phenyl-3, 5-di-p-tolyl-2, 4-dibenzoyl-1-cyclohexanol (0.50mmol), diisopropylamine (2.0mmol) and catalyst YPh were added under nitrogen₃(20 mol%) and reacted at 110 ℃ in 2mL of toluene for 72h, the isolated yields of acetophenone and 1-phenyl-3-p-methoxyphenyl-1-propanone were 41% and 45%, respectively.

1-phenyl-3-p-methoxyphenyl-1-propanone:¹H NMR(400MHz,CDCl₃)δ7.99–7.96(m,2H),7.59–7.55(m,1H),7.49–7.45(m,2H),7.20–7.18(m,2H),6.85(d,J＝8.6Hz,2H),3.81(s,3H),3.28(t,J＝7.7Hz,2H),3.02(t,J＝7.7Hz,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.