A method for the nickel-catalyzed asymmetric amination synthesis of all-carbon quaternary carbon stereocenter compounds

Abstract

The application discloses a method for efficiently synthesizing a full-carbon quaternary carbon stereogenic center compound by using nickel-catalyzed asymmetric amination. The method comprises the following steps: under the catalysis of a nickel catalyst, an alpha,alpha-dimethylamide compound is reacted with an O-benzoyl hydroxylamine compound in an organic solvent in the presence of an inorganic base, an additive, a molecular sieve and binaphthyl in a 60 DEG C environment for 24 hours or 36 hours, and then the amination product is separated by thin layer silica gel plate chromatography purification; the method has the advantages of mild reaction condition, cheap and easily obtained catalyst, simple process and convenient operation; the amine group can be directly introduced into the alpha,alpha-dimethylamide substrate, and the amination product containing the full-carbon quaternary carbon stereogenic center can be obtained with high stereoselectivity.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for synthesizing a compound with a full carbon quaternary carbon stereogenic center by nickel-catalyzed asymmetric amination, and belongs to the field of directed transition metal-catalyzed asymmetric C-H activation. BACKGROUND

[0002] The full carbon quaternary carbon stereogenic center is a very important structural unit, which widely exists in natural products and pharmaceutically active molecules. Due to its structural diversity, rigidity and crowding, the full carbon quaternary carbon stereogenic center shows unique biological activity in drug design. However, these structural characteristics also make the asymmetric synthesis of its skeleton quite complex and challenging. Therefore, developing new methods for efficiently constructing the full carbon quaternary carbon stereogenic center is of great significance for drug research and design.

[0003] In recent years, transition-metal-catalyzed asymmetric C-H activation strategy with step economy and atom economy has become one of the powerful means for the rapid and efficient construction of all-carbon quaternary stereocenters. Some recent literature reports the synthesis of all-carbon quaternary stereocenter skeleton under different conditions, see a) Albicker, M. R.; Cramer, N. Angew. Chem. Int. Ed. 2009, 48, 9139; b) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 460; c) Wasa, M.; Engle, K. M.; Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598; d) Saget, T.; Cramer, N. Angew. Chem. Int. Ed. 2013, 52, 7865; e) Xiao, K.-J.; Lin, D. W.; Miura, M.; Zhu, R.-Y.; Gong, W.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136, 8138; f) Chan, K. S. L.; Fu, H.-Y.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 2042; g) He, J.; Shao, Q.; Wu, Q.; Yu, J.-Q. J. Am. Chem. Soc. 2017, 139, 3344; h) Grosheva, D.; Cramer, N. Angew. Chem. Int. Ed. 2018, 57, 13644; i) Hu, L.; Shen, P.-X.; Shao, Q.; Hong, K.; Qiao, J. X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2019, 58, 2134; j) Shi, Y.; Gao, Q.; Xu, S. J. Am. Chem. Soc. 2019, 141, 10599; k) Kato, Y.; Lin, L.; Kojima, M.; Yoshino, T.; Matsunaga, S. ACS Catal. 2021, 11, 4271; l) Yang, Y.; Chen, J.; Shi, Y.; Liu, P.; Feng, Y.; Peng, Q.; Xu, S. J. Am. Chem. Soc. 2024, 146, 1635. Although the above methods can construct all-carbon quaternary stereocenter skeleton, they have problems such as limited substrate range, low stereoselectivity and catalytic efficiency, and are severely dependent on palladium, rhodium, iridium and other noble metal catalysts. While the catalytic strategy based on abundant and inexpensive 3d transition metals has been rarely explored.Recently, the asymmetric C-H bond activation catalyzed by 3d transition metals has developed rapidly. Compared with noble metal catalysts, 3d metals have diverse valence states, unique coordination chemistry, and special reactivity, enabling more diverse and green economical reaction transformations, which has significant research value and importance. Our research group has pioneered a nickel / binaphthol-catalyzed asymmetric C-H bond functionalization strategy, achieving the efficient construction of faceted chiral ferrocene compounds (see Yao, Q.-J.; Huang, F.-R.; Chen, J.-H.; Shi, B.-F. Nat. Commun. 2024, 15, 7135). Based on this strategy, we have further developed a nickel / binaphthol-catalyzed asymmetric C(sp) bond activation. 3 )-H amination reaction is used to construct all-carbon quaternary carbon stereocenters with high stereoselectivity. Summary of the Invention

[0004] The purpose of this invention is to provide a nickel-catalyzed asymmetric amination method with mild reaction conditions, convenient operation, and efficient synthesis of all-carbon quaternary carbon stereocenter compounds.

[0005] A method for synthesizing an all-carbon quaternary carbon stereocenter compound by nickel-catalyzed asymmetric amination includes: reacting an α,α-gem-dimethylamide compound with an O-benzoylhydroxylamine compound in the presence of an inorganic base, additives, molecular sieves and binaphthol under nickel catalyst catalysis; and obtaining the all-carbon quaternary carbon stereocenter compound after post-treatment after the reaction.

[0006]

[0007] Among them, R 1 It is independently selected from C2-C6 alkyl, substituted or unsubstituted aryl or heteroaryl, or trifluoromethyl;

[0008] The substituents on the aryl or heteroaryl group are selected from one or more of C1-C6 alkyl, trifluoromethyl, phenyl, halogen, C1-C6 alkoxy, nitro, and methylenedioxy groups;

[0009] R 2 R 3 Independently selected from C1-C6 alkyl, phenyl-substituted C1-C6 alkyl, 9,10-dihydro-9,10-bridged ethylene anthracene-substituted propyl, or R 2 R 3 With connection R 2 R 3 The N atoms together form a substituted or unsubstituted 5- to 8-membered N-containing heterocycle, wherein the substituents on the N-containing heterocycle are selected from one or more of C1- to C4 alkyl, C1- to C4 alkoxy, aryl or heteroaryl, C1- to C4 alkoxycarbonyl, cyano, trifluoromethyl, and ethylenedioxy.

[0010] R is independently selected from H, fluorine, phenyl or substituted phenyl, and the substituent on the phenyl is selected from one or more of C1-C6 alkyl, C1-C6 alkoxy, phenyl, halogen, and trifluoromethyl.

[0011] The aryl groups mentioned above are further preferably C6-C6. 10 Aryl, the above-mentioned heteroaryl group is further preferably C5-C6. 10 Mixed aromatic compounds.

[0012] As a preferred option, R 1 It can be ethyl, n-butyl, isopropyl, trifluoromethyl, phenyl and substituted phenyl, naphthalene and substituted naphthalene or thiophene;

[0013] The substituents on the phenyl or naphthalene are selected from one or more of methyl, isobutyl, trifluoromethyl, phenyl, fluorine, chlorine, bromine, methoxy, and nitro.

[0014] As a preferred option, R 2 R 3 Independently selected from methyl, ethyl, phenyl-substituted ethyl, 9,10-dihydro-9,10-bridged ethylene anthracene-substituted propyl;

[0015] Or R 2 R 3 With connection R 2 R 3 The N atoms together form substituted or unsubstituted 5- to 8-membered N-containing heterocycles, wherein the N-containing heterocycle is morpholine, thiomorpholine, thiomorpholine 1,1-dioxide, piperidine, or 1,4-diazepoxide, and the substituents on the N-containing heterocycle are one or more of methyl, methoxy, phenyl, pyrimidinyl, benzisothiazol, ethoxycarbonyl, tert-butoxycarbonyl, cyano, trifluoromethyl, and ethylenedioxy.

[0016] The types of nickel catalyst, binaphthol, inorganic base, and additives have a significant impact on the enantioselectivity and yield of the reaction. Preferably, the nickel catalyst is bis(tricyclohexylphosphine)nickel chloride.

[0017] Preferably, the binaphthol is a chiral pure binaphthol with a 3,5-dimethylphenyl substituent at the 3,3'- position, namely (S)-3,3'-bis(3,5-dimethylphenyl)-1,1'-binaphthol.

[0018] Preferably, the additive is tetrabutylammonium iodide.

[0019] Preferably, the molecular sieve is activated. Molecular sieve.

[0020] In the present application, the reaction is carried out in an organic solvent, which is preferably a mixed binary solvent dimethyl sulfoxide / 1,4-dioxane or dimethyl sulfoxide / ethylene glycol dimethyl ether, with a volume ratio of 2:3.

[0021] In the present application, the reaction temperature is 50-70℃, and the reaction time is 24-36 hours.

[0022] In the present application, the molar ratio of α,α-disubstituted amide, O-benzoylhydroxylamine, nickel catalyst, binaphthol, inorganic base and additive is 1:2-2.2:0.1-0.2:0.1-0.2:2-2.2:2-2.2, and is further preferably 1:2:0.1:0.1:2:2.

[0023] In the present application, the chiral control of binaphthol during the reaction can make the product have an ee value of 67%->99%.

[0024] The post-treatment method of the present application is preferably thin layer silica gel plate chromatography.

[0025] As a preference, the α,α-disubstituted amide compound is selected from any one of Compound 1-Compound 20, and the structural formula is as follows:

[0026]

[0027] As a preference, the O-benzoylhydroxylamine compound is selected from any one of Compound 21-Compound 42, and the structural formula is as follows:

[0028]

[0029] Compared with the prior art, the present application has the following beneficial effects:

[0030] (1) The operation condition is simple, and the post-treatment is easy;

[0031] (2) The metal catalyst and chiral catalyst are cheap and easy to obtain;

[0032] (3) The reaction has good substrate universality;

[0033] (4) The reaction has strong stereoselectivity, and through the chiral control of binaphthol, the product has high enantioselectivity. BRIEF DESCRIPTION OF DRAWINGS

[0034] Figure 1 The HPLC spectrum of Compound 1 obtained in Example 1 and its racemate, wherein the HPLC spectrum conditions are IA, n-hexane / 2-propanol = 80 / 20, rate = 1.0 mL / min, λ = 254 nm.

[0035] Figure 2 HPLC chart of compound 2 obtained from example 2 and its racemate, wherein the conditions of HPLC chart are IA, n-hexane / 2-propanol = 90 / 10, rate = 1.0 mL / min, λ = 254 nm.

[0036] Figure 3 HPLC chart of compound 21 obtained from example 21 and its racemate, wherein the conditions of HPLC chart are IA, n-hexane / 2-propanol = 90 / 10, rate = 1.0 mL / min, λ = 254 nm. DETAILED DESCRIPTION

[0037] The present application will be explained in connection with specific examples, but not limited to them.

[0038] Example 1

[0039] In a reactor, 0.1 mmol of 2-methyl-2-phenylpropionamide, 0.2 mmol of morpholine-derived O-benzoylhydroxylamine, 0.01 mmol of bis(tricyclohexylphosphine) nickel chloride catalyst, 0.01 mmol of (S)-3,3'-bis(3,5-dimethylphenyl)-1,1'-binol, 0.2 mmol of lithium hydroxide, 0.2 mmol of tetrabutylammonium iodide, 50 mg of activated molecular sieves and dimethyl sulfoxide / 1,4-dioxane (0.2 mL / 0.3 mL), the reaction was ended after 24 hours of reaction at 60°C under argon atmosphere, and the post-treatment was carried out, and product 1 with structure as shown in formula 1 was obtained by thin layer silica gel plate chromatography, with a yield of 83% and ee value of 95%.

[0040] The structure of product 1 is as follows:

[0041]

[0042] The structural characterization data are as follows:

[0043] 1 HNMR (400 MHz, CDC13) δ 11.63 (s, 1H), 8.93 (dd, J = 7.5, 1.6 Hz, 1H), 8.75 (dd, J = 4.2, 1.7 Hz, 1H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.51 (dd, J = 8.3, 1.6 Hz, 1H), 7.48 - 7.44 (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 7.34 - 7.30 (m, 2H), 7.26 - 7.21 (m, 1H), 3.79 - 3.59 (m, 4H), 3.10 (d, J = 13.9 Hz, 1H), 2.99 (d, J = 13.9 Hz, 1H), 2.52 - 2.30 (m, 4H), 1.75 (s, 3H); 13 CNMR (101 MHz, CDC13 ) δ 174.7, 148.1, 143.7, 139.3, 136.2, 135.4, 128.5, 128.1, 127.4, 126.9, 126.8, 121.7, 121.4, 117.6, 67.5, 66.8, 55.5, 52.1, 24.6; HRMS (ESI) calcd for C 23 H 26 N3O2[M+H] + : 376.2020, Found: 376.2022;

[0044] HPLC with a Daicel Chiralpak IA, Figure 1 , n-hexane / 2-propanol = 80 / 20, v = 1.0 mL / min, λ = 254 nm, t(minor) = 7.132 min, t(major) = 8.987 min, 95% ee;

[0045] Examples 2-20

[0046] The procedure was the same as Example 1, except that the substituents on the starting material α,α-dimethyl amide were changed, and different all-carbon quaternary carbon stereocenter compounds were obtained (see Table 1).

[0047] Table 1 Experimental results of synthesis of all-carbon quaternary carbon stereocenter compounds in Examples 2-20

[0048]

[0049] Example 21 is taken as an example, the process is as follows:

[0050] In a reactor, 0.1 mmol of 2-methyl-2-(o-tolyl)propanamide, 0.2 mmol of morpholine-derived O-benzoylhydroxylamine, 0.01 mmol of bis(tricyclohexylphosphine)nickel chloride catalyst, 0.01 mmol of (S)-3,3'-bis(3,5-dimethylphenyl)-1,1'- binaphthyl, 0.2 mmol of lithium hydroxide, 0.2 mmol of tetrabutylammonium iodide, 50 mg of activated molecular sieves and dimethylsulfoxide / 1,4-dioxane (0.2 mL / 0.3 mL), the reaction was completed after 24 hours at 60 °C under argon atmosphere, and the reaction was worked up to give the product 2 of structure as shown in Formula 2 in 40% yield with an ee value of >99% by thin layer silica gel plate chromatography.

[0051] The structure of product 2 is as follows:

[0052]

[0053] The structure characterization data are as follows:

[0054] 1 HNMR (400 MHz, CDC13 ) δ 10.33 (s, 1H), 8.76 (dd, J = 7.6, 1.4 Hz, 1H), 8.59 (dd, J = 4.4, 1.6 Hz, 1H), 8.10 (dd, J = 8.3, 1.7 Hz, 1H), 7.55 - 7.51 (m, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.36 (dd, J = 8.3, 4.2 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 7.4 Hz, 1H), 3.61 - 3.52 (m, 4H), 3.12 (d, J = 14.0 Hz, 1H), 3.04 (d, J = 14.0 Hz, 1H), 2.49 - 2.35 (m, 2H), 2.30 (s, 3H), 2.27 - 2.23 (m, 2H), 1.87 (s, 3H); 13 CNMR (101 MHz, CDC13 ) δ 176.4, 148.2, 140.4, 138.9, 137.3, 136.1, 135.0, 131.9, 128.0, 127.7, 127.3, 127.3, 126.0, 121.5, 121.4, 116.5, 67.2, 64.3, 55.7, 52.6, 25.1, 20.9; HRMS (ESI) calcd for C 24 H 28 N3O2[M+H] + : 390.2176, Found: 390.2174;

[0055] HPLC with a Daicel Chiralpak IA, Figure 2 n-hexane / 2-propanol = 90 / 10, v = 1.0 mL / min, λ = 254 nm, t(major) = 11.552 min, t(minor) = 16.216 min, >99% ee;

[0056] Examples 21-41

[0057] Examples 21-41 were operated according to the procedure of Example 1, except that the substituents on the starting material O-benzoylhydroxylamine were changed, and in some examples the reaction conditions were slightly adjusted (see footnotes), to produce different all-carbon quaternary stereocenter products (see Table 2).

[0058] Table 2. Experimental results for synthesis of all-carbon quaternary stereocenter compounds in Examples 21-41

[0059]

[0060] [a] Reaction time 36 hours; [b] Reaction solvent dimethyl sulfoxide / glyme (0.2 mL / 0.3 mL); [c] 0.02 mmol bis(tricyclohexylphosphine) nickel chloride catalyst and 0.02 mmol (S)-3,3'-bis(3,5-dimethylphenyl)-1,1'-binol were used.

[0061] Using Example 21 as an example, the procedure was as follows:

[0062] In a reactor, 0.1 mmol 2-methyl-2-phenylpropionamide, 0.2 mmol 2,6-dimethylmorpholine-derived O-benzoylhydroxylamine, 0.01 mmol bis(tricyclohexylphosphine) nickel chloride catalyst, 0.01 mmol (S)-3,3'-bis(3,5-dimethylphenyl)-1,1'-binol, 0.2 mmol lithium hydroxide, 0.2 mmol tetrabutylammonium iodide, 50 mg activated molecular sieves and dimethyl sulfoxide / 1,4-dioxane (0.2 mL / 0.3 mL) were added, and the reaction was allowed to proceed under an argon atmosphere at 60 °C for 36 hours. The reaction was then worked up and the product 21, having the structure of Formula 3, was obtained by thin layer silica gel plate chromatography in 73% yield and 95% ee.

[0063] The structure of product 21 was as follows:

[0064]

[0065] Structural characterization data were as follows:

[0066] 1 HNMR (400 MHz, CDC13) δ 11.66 (s, 1H), 8.93 (dd, J = 7.4, 1.6 Hz, 1H), 8.72 (dd, J = 4.2, 1.7 Hz, 1H), 8.14 (dd, J = 8.3, 1.7 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.51 (dd, J = 8.3, 1.6 Hz, 1H), 7.47 - 7.39 (m, 3H), 7.31 (t, J = 7.6 Hz, 2H), 7.26 - 7.21 (m, 1H), 3.94 - 3.86 (m, 1H), 3.75 - 3.67 (m, 1H), 3.04 (d, J = 13.9 Hz, 1H), 2.96 (d, J = 13.9 Hz, 1H), 2.65 - 2.61 (m, 1H), 2.30 - 2.27 (m, 1H), 1.94 (t, J = 10.6 Hz, 1H), 1.75 (s, 3H), 1.69 (t, J = 10.7 Hz, 1H), 1.07 (d, J = 6.3 Hz, 3H), 0.94 (d, J = 6.3 Hz, 3H); 13 C NMR (101 MHz, CDC13 ) δ 174.8, 148.1, 143.8, 139.3, 136.2, 135.4, 128.5, 128.1, 127.4, 126.9, 126.8, 121.7, 121.4, 117.6, 71.2, 71.2, 67.1, 61.5, 60.9, 52.1, 24.7, 19.1, 19.0; HRMS (ESI) calcd for C 25 H 30 N3O2[M+H] + :404.2333, Found:404.2334;

[0067] HPLC with a Daicel Chiralpak IA, Figure 3 , n-hexane / 2-propanol = 90 / 10, v = 1.0 mL / min, λ = 254 nm, t(minor) = 7.424 min, t(major) = 8.009 min, 95% ee.

Claims

1. A method for the synthesis of all-carbon quaternary carbon stereocenter compounds by nickel-catalyzed asymmetric amination, characterized in that, comprising the following steps: an α,α-disubstituted amide compound is reacted in the presence of a nickel catalyst to form a compound of formula (II) O a benzoyl hydroxylamine compound is reacted in the presence of an inorganic base, an additive, a molecular sieve and a chiral pure binaphthol, and after the reaction is completed, the compound is subjected to post-treatment to obtain the all-carbon quaternary carbon stereocenter compound. ； wherein R 1 is independently selected from C2-C6alkyl, substituted or unsubstituted phenyl, or trifluoromethyl, the substituents on phenyl being selected from one or more of C1-C6alkyl, trifluoromethyl, halogen, C1-C6alkoxy, nitro; R 2 , R 3 is independently selected from the group consisting of C1-C6alkyl, or R 2 , R 3 and the N to which R 2 , R 3 are attached together form a substituted or unsubstituted 5-8 membered N-containing heterocycle, the substituents on the N-containing heterocycle being selected from one or more of C1-C4alkyl, C1-C4alkoxy, cyano, trifluoromethyl, ethylenedioxy; The nickel catalyst is acetylacetone nickel, nickel triflate, nickel chloride, bis(tricyclohexylphosphine) nickel chloride, bis(triphenylphosphine) nickel chloride or nickel (II) chloride ethylene glycol dimethyl ether complex. The chiral pure binaphthol has the following structural formula: R is independently selected from H, fluorine, phenyl or substituted phenyl, the substituents on the phenyl being selected from one or more of C1-C6 alkyl, C1-C6 alkoxy, phenyl, halogen, trifluoromethyl; The additive is tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide or tetrabutylammonium acetate.

2. The method of synthesis of all-carbon quaternary carbon stereogenic compounds by nickel-catalyzed asymmetric amination according to claim 1, characterized in that, R 1 is ethyl, n-butyl, isopropyl, trifluoromethyl, phenyl and substituted phenyl; The substituents on the phenyl group are selected from one or more of methyl, isobutyl, trifluoromethyl, fluorine, chlorine, bromine, methoxy, and nitro.

3. The method of synthesis of all-carbon quaternary carbon stereocenter compounds by nickel-catalyzed asymmetric amination according to claim 1, characterized in that, The inorganic base is sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide or potassium hydroxide.

4. The method of synthesis of all-carbon quaternary carbon stereogenic compounds by nickel-catalyzed asymmetric amination according to claim 1, characterized in that, The molecular sieve is activated 3A molecular sieve, activated 4A molecular sieve or activated 5A molecular sieve.

5. The method of synthesis of all-carbon quaternary carbon stereogenic compounds by nickel-catalyzed asymmetric aminylation according to claim 1, characterized in that, The reaction is carried out in an organic solvent, which is dimethyl sulfoxide, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, acetonitrile or dichloroethane.

6. The method of synthesis of all-carbon quaternary carbon stereogenic compounds by nickel-catalyzed asymmetric aminylation according to claim 1, characterized in that, The reaction temperature is 50-70 o C, and the reaction time is 24-36 hours. α,α-disubstituted amides, O - the molar ratio of benzoyl hydroxylamine, nickel catalyst, chiral pure binaphthol, inorganic base and additive is 1 : 2-2.2 : 0.1-0.2 : 0.1-0.2 : 2-2.2 : 2-2.

2.

7. The method of synthesis of all-carbon quaternary carbon stereogenic compounds by nickel-catalyzed asymmetric amination according to claim 1, characterized in that, The α,α-disubstituted amide compound is selected from any one of compounds 1-15, which have the following structural formulas: ， The O - the benzoyl hydroxylamine compound is selected from any one of compounds 16 to 27, having the following structural formula: 。

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