Process for the modification of a beta-ketimine ligand precursor and products thereof

Abstract

This invention relates to a simple method for modifying β-ketoimine ligand precursors, wherein L... Ph The reaction involves a lithium compound with H2 solution; then a haloalkane is added for C-C coupling; followed by the addition of an acid solution to complete the modification of the β-ketoimine ligand precursor, yielding a terminally alkylated ketoimine. This invention relates to a simple method for modifying β-ketoimine ligand precursors, specifically involving the removal of the proton at the α-position of the β-ketoimine ligand precursor from commercially available n-butyllithium to form a deprotonated β-ketoimine lithium compound, followed by C-C coupling to achieve alkylation at the α-position of the ketocarbonyl group, thus providing a convenient modification of the β-ketoimine ligand precursor.

Description

Technical Field

[0001] This invention relates to a simple method for modifying β-ketoimine ligand precursors. Background Technology

[0002] β-Ketoimine ligands, as non-cyclohexane ligands, are easily modulated in terms of steric hindrance and charge effects, and are widely used in the synthesis and application of organometallic complexes. To date, the synthesis of β-ketoimine ligand precursors has been achieved through the condensation reaction of β-diketones and primary amines. However, this method is limited by the type of β-diketone and cannot yield precursors with certain special properties, especially those with functional groups. Alkylation at the α-position of the ketone carbonyl group is an important organic reaction, and the alkylation of enols is a crucial process for achieving C-C bond coupling. Armen Zakarian's group previously reported that the direct alkylation of arylacetic acids by enolizing amines can achieve the alkylation of arylacetic acids (Craig E. Stivala and Armen Zakarian). J. Am. Chem. Soc. 2011, 133 Luo achieved C / C bond coupling at the α-position of β-keto carbonyl groups via photocatalysis (Yunbo Zhu, Long Zhang, and Sanzhong Luo). J. Am. Chem. Soc. 2014, 136 (14642). Electrochemically driven processes using rhodium catalysts can enhance the formation of enols, enabling cross-coupling of 2-acylimidazoles with enol silyl ethers (Xiaoqiang Huang, Eric Meggers). Nat Catal. 2019, 2, 34). Summary of the Invention

[0003] This invention relates to a simple method for modifying β-ketoimine ligand precursors. Specifically, it involves removing the proton at the α-position of the β-ketoimine ligand precursor using commercially available n-butyllithium to form a deprotonated β-ketoimine lithium compound, and then alkylating it at the α-position of the ketone carbonyl group via C-C bond coupling, thereby achieving a convenient modification of the β-ketoimine ligand precursor.

[0004] The present invention adopts the following technical solution:

[0005] A method for modifying a β-ketoimine ligand precursor includes the following steps: L Ph H2 solution reacts with lithium compound; then haloalkanes are added for C-C bond coupling reaction, followed by the addition of acid solution to complete the modification of the β-ketoimine ligand precursor.

[0006] The product obtained by the method of modifying the β-ketoimine ligand precursor in this invention is a terminally alkylated ketoimine. Therefore, this invention discloses a method for preparing a terminally alkylated ketoimine, comprising the following steps: L... Ph H2 solution reacts with lithium compounds; then haloalkanes are added for C-C coupling reaction; further, acid solution is added and organic and aqueous phases are taken, the aqueous phase is extracted, and then the extracted organic phase is dehydrated and subjected to column chromatography to obtain terminally alkylated ketimines. The specific operation of this purification method is a conventional technique.

[0007] In this invention, L Ph In H2 solution, L Ph H2 is C6H4[N(CH3)C=CHCOCH3]2H2, the solvent is tetrahydrofuran, and the lithium compound exists in solution form as a commercially available product; under ice bath conditions, the lithium compound solution is added to L Ph The reaction is carried out in H2 solution at room temperature for 10-15 hours; the temperature of the CC bond coupling reaction is -78℃ to 0℃ and the time is 20-30 hours; the CC bond coupling reaction is carried out in an inert atmosphere; after the CC bond coupling reaction is completed, an acid solution is added at room temperature for 10-20 minutes and then the liquid is separated to obtain an organic phase and an aqueous phase solution, and then the aqueous phase solution is extracted; the acid solution is preferably an aqueous hydrochloric acid solution.

[0008] In this invention, L Ph The molar ratio of H2 to haloalkanes is 1:(1-5), preferably 1:(1.5-4).

[0009] This invention utilizes readily available n-butyllithium to react with a β-ketoimine ligand precursor under mild conditions, forming a deprotonated β-ketoimine lithium compound in situ. This compound is then reacted with a haloalkane to achieve alkylation at the ketoimine terminus. This method represents the first time that a convenient modification of the β-ketoimine ligand precursor has been achieved. The reaction diagram is shown below:

[0010]

[0011] To date, the synthesis of β-ketoimine ligand precursors has relied on the condensation reaction of β-diketones and primary amines. However, this method is limited by the type of β-diketone and cannot yield certain β-ketoimine ligand precursors with specific properties, particularly those with functional groups. This invention employs a one-pot, two-step method. Under mild conditions, commercially available n-butyllithium is used to deprotonate the α-position of the β-ketoimine ligand precursor, forming a deprotonated β-ketoimine lithium compound. This compound is then further reacted with an electrophilic haloalkane to conveniently modify the β-ketoimine ligand precursor, yielding a product with alkylation at the ketoimine terminal. Attached Figure Description

[0012] Figure 1The NMR spectrum of the product of Example 1;

[0013] Figure 2 The NMR spectrum of the product in Example 2 is shown. Detailed Implementation

[0014] This invention provides a convenient modification of the β-ketoimine ligand precursor by removing the proton at the α-position from a commercially available n-butyllithium under mild conditions, forming a deprotonated β-ketoimine lithium compound. This compound is then further reacted with an electrophilic haloalkane to yield a product alkylated at the ketoimine terminus, thus achieving a convenient modification of the β-ketoimine ligand precursor. The raw materials used in this invention are existing products, and the specific experimental procedures follow conventional methods, with the n-butyllithium solution being added dropwise over a time of 1 minute.

[0015] Example 1: Synthesis of C6H4[HN(CH3)C=CHCOCH2CH2CH3]2

[0016]

[0017] L Ph H2 (L Ph = C6H4[N(CH3)C=CHCOCH3]2) (0.2744 g, 1 mmol) was dissolved in 50 mL of tetrahydrofuran solution. 4 equivalents of n-BuLi (1.54 mL, 2.6143 M, hexane solution) were added dropwise under ice bath conditions. After reacting at room temperature for 12 hours, a pale orange turbid liquid was obtained. Then, 2 equivalents of bromoethane (0.15 mL, 2 mmol) were added at 0 °C, and the reaction was carried out at 0 °C for 24 hours. All reactions were carried out under argon protection, and subsequent reactions were carried out in air. Afterwards, the reaction flask was removed, and 2 equivalents of hydrochloric acid aqueous solution (1 M) were added at room temperature. After 15 minutes, the reaction solution was poured into a separatory funnel to obtain the organic and aqueous phases. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dehydrated with anhydrous sodium sulfate, mixed with silica gel, and separated by column chromatography to obtain the target product, a pale yellow liquid (PE:EA = 85:15), with a separation yield of 72% (0.2366 g). g, 0.715 mmol). C 20 H 28 N2O2 (Mr=328.46), 1 H NMR (400 MHz, CDCl3) δ 12.55 (s, 2H, N H ), 7.28 (t, J = 8.0 Hz, 1H,Ar H ), 6.92 (dd, J = 8.0, 2.1 Hz, 2H, Ar H ), 6.86 (t,J = 1.9 Hz, 1H, Ar H ),5.20 (s, 2H, C H =C(CH3) N), 2.31 (t, J = 7.3 Hz, 4H, O=CC H 2CH2), 2.03 (s, 6H,C H 3C(NH)=CH), 1.71 – 1.62 (m, 4H, C H 2CH3), 0.96 (t, J = 7.4 Hz, 6H,CH2C H 3). 13 CNMR (101 MHz, CDCl3) δ 199.62, 159.52, 139.73, 129.69, 121.16, 120.13, 97.85, 44.35, 20.05, 19.29, 14.06. Figure 1 Its 1H NMR spectrum and 1C NMR spectrum are shown.

[0018] By changing the temperature or the amount of bromoethane used in the above C-C bond coupling reaction, different separation yields were obtained, as shown in the table below:

[0019] Halogenated hydrocarbons Temperature (°C) <![CDATA[Reactant ratio, L Ph H2∶Halohydrocarbon]]> Yield (%) <![CDATA[CH3CH2Br]]> room temperature 1：2 53% <![CDATA[CH3CH2Br]]> 0℃ 1：2 72% <![CDATA[CH3CH2Br]]> -78℃ 1：2 62% <![CDATA[CH3CH2Br]]> 0℃ 1：1.5 54% <![CDATA[CH3CH2Br]]> 0℃ 1：2.5 73% <![CDATA[CH3CH2Br]]> 0℃ 1：4 70%

[0020] Example 2: Synthesis of C6H4[HN(CH3)C=CHCOCH2CH2CH(CH3)2]2

[0021]

[0022] L Ph H2 (L Ph= C6H4[N(CH3)C=CHCOCH3]2) (0.2744 g, 1 mmol) was dissolved in 50 mL of tetrahydrofuran solution. 4 equivalents of n-BuLi (1.54 mL, 2.6143 M, hexane solution) were added dropwise under ice bath conditions. After reacting at room temperature for 12 hours, a pale orange turbid liquid was obtained. Then, 2 equivalents of BrCH2CH(CH3)2 (0.22 mL, 2 mmol) were added at 0 °C, and the reaction was carried out at 0 °C for 24 hours. All reactions were carried out under argon protection, and subsequent reactions were carried out in air. Afterwards, the reaction flask was removed, and 2 equivalents of hydrochloric acid aqueous solution (1 M) was added at room temperature. After 15 minutes, the reaction solution was poured into a separatory funnel to obtain an organic phase and an aqueous phase. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dehydrated with anhydrous sodium sulfate, mixed with silica gel, and separated by column chromatography to obtain the target product, a pale yellow liquid (PE:EA = 92:8), with a separation yield of 63%. C 24 H 36 N2O2 (Mr=384.56) 1 H NMR (400 MHz, CDCl3) δ 12.50 (s, 2H, N H ), 7.23 (t, J = 8.0 Hz, 1H, Ar H ), 6.86(dd, J = 8.0, 2.0 Hz, 2H, Ar H ), 6.81 (t, J = 1.8 Hz, 1H, Ar H ), 5.16 (s, 2H,C H =C(CH3) N), 2.28 (t, J = 7.8 Hz, 4H, O=CC H 2CH2), 1.98 (s, 6H, C H 3C(NH)=CH),1.60 – 1.52 (m, 2H, C H (CH3)2), 1.51 – 1.45 (m, 4H, O=CCH2C H 2), 0.87 (d, J =6.4 Hz, 12H, CH(C H 3)2). 13C NMR (101 MHz, CDCl3) δ 199.94, 159.51, 139.73, 129.68, 121.09, 120.05, 97.78, 40.38, 34.90, 27.94, 22.47, 20.04. Figure 2 Its 1H NMR spectrum and 1C NMR spectrum are shown.

[0023] Example 3: Synthesis of C6H4[HN(CH3)C=CHCOCH2CH2CH2CH2OSi(CH3)2C(CH3)3]2

[0024]

[0025] L Ph H2 (L Ph = C6H4[N(CH3)C=CHCOCH3]2) (0.2744 g, 1 mmol) was dissolved in 50 mL of tetrahydrofuran solution. 4 equivalents of n-BuLi (1.54 mL, 2.6143 M, hexane solution) were added dropwise under ice bath conditions. After reacting at room temperature for 12 hours, a pale orange turbid liquid was obtained. Then, 2 equivalents of BrCH2CH2CH2OTBS (0.46 mL, 2 mmol) were added at 0 °C, and the reaction was carried out at 0 °C for 24 hours. All reactions were carried out under argon protection, and subsequent reactions were carried out in air. Afterwards, the reaction flask was removed, and 2 equivalents of hydrochloric acid aqueous solution (1 M) were added at room temperature. After 15 minutes, the reaction solution was poured into a separatory funnel to obtain an organic phase and an aqueous phase. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dehydrated with anhydrous sodium sulfate, mixed with silica gel, and separated by column chromatography to obtain the target product as a pale white liquid (PE:EA = 92:8), with a separation yield of 68%. C 34 H 60 N2O4Si2 (Mr=617.03). 1 H NMR (400 MHz, CDCl3) δ 12.52 (s, 2H, N H ), 7.27 (t, J = 8.0 Hz, 1H, Ar H ), 6.90(dd, J = 8.0, 2.0 Hz, 2H, Ar H ), 6.84 (t, J = 1.8 Hz, 1H, Ar H ), 5.18 (s, 2H,C H =C(CH3) N), 3.62 (t, J = 6.4 Hz, 4H, CH 2OSi), 2.33 (t, J = 7.5 Hz, 4H, O=CC H 2CH2), 2.01 (s, 6H, C H 3CNH), 1.67 (m, 4H, C H 2CH2OSi), 1.56 (m, 4H, O=CCH2C H 2), 0.88 (s, 18H, C(C H 3)3), 0.04 (s, 12H, Si(C H 3)2C(CH3)3). 13 C NMR (101MHz, CDCl3) δ 199.42, 159.57, 139.71, 129.68, 121.19, 120.16, 97.78, 63.01,42.02, 32.59, 25.99, 22.25, 20.04, 18.37, -5.26.

[0026] Example 4: Synthesis of C6H4[HN(CH3)C=CHCOCH2CH2CH=CH2]2

[0027]

[0028] L Ph H2 (L Ph = C6H4[N(CH3)C=CHCOCH3]2) (0.2744 g, 1 mmol) was dissolved in 50 mL of tetrahydrofuran solution. 4 equivalents of n-BuLi (1.54 mL, 2.6143 M, hexane solution) were added dropwise under ice bath conditions. After reacting at room temperature for 12 hours, a pale orange turbid liquid was obtained. Then, 2 equivalents of 3-bromopropene (0.18 mL, 2 mmol) were added at 0 °C, and the reaction was carried out at -78 °C for 24 hours. All reactions were carried out under argon protection, and subsequent reactions were conducted in air. The reaction flask was then removed, and 2 equivalents of hydrochloric acid aqueous solution (1 M) were added at room temperature to terminate the reaction. After 15 minutes, the reaction solution was poured into a separatory funnel to obtain the organic and aqueous phases. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dehydrated with anhydrous sodium sulfate, mixed with silica gel, and separated by column chromatography to obtain the target product as a pale yellow liquid (PE:EA = 82:18), with a separation yield of 73%. C 22 H 28 N2O2 (Mr = 352.48). 1H NMR (400 MHz, CDCl3) δ 12.52 (s, 2H, N H ), 7.28 (t, J = 8.0 Hz, 1H, Ar H ),6.92 (dd, J = 8.0, 2.0 Hz, 2H, Ar H ), 6.86 (t, J = 2.0 Hz, 1H, Ar H ), 5.95 –5.81 (m, 2H, CH2C H =CH2), 5.20 (s, 2H, C H =C(CH3) N), 5.06 (dq, J = 17.2, 1.3Hz, 2H, CH2CH=C H 2), 4.98 (dd, J = 10.3, 1.6 Hz, 2H, CH2CH=C H 2), 2.47 – 2.35 (m, 8H, O=CC) H 2C H 2), 2.03 (s, 6H, C H 3CNH). 13 C NMR (101 MHz, CDCl3) δ 198.38,159.73, 139.65, 137.92, 129.71, 121.27, 120.21, 114.74, 97.75, 41.24, 29.64,20.05.

[0029] Example 5: Synthesis of C6H4[HN(CH3)C=CHCOCH2CH2C6H5]2

[0030]

[0031] L Ph H2 (L Ph= C6H4[N(CH3)C=CHCOCH3]2) (0.2744 g, 1 mmol) was dissolved in 50 mL of tetrahydrofuran solution. 4 equivalents of n-BuLi (1.54 mL, 2.6143 M, hexane solution) were added dropwise under ice bath conditions. After reacting at room temperature for 12 hours, a pale orange turbid solution was obtained. Then, 2 equivalents of PhCH2Br (0.24 mL, 2 mmol) were added at 0 °C, and the reaction was carried out at -78 °C for 24 hours. All reactions were carried out under argon protection, and subsequent reactions were conducted in air. The reaction flask was then removed, and 2 equivalents of hydrochloric acid aqueous solution (1 M) were added at room temperature to terminate the reaction. After 15 minutes, the reaction solution was poured into a separatory funnel to obtain an organic phase and an aqueous phase. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dehydrated with anhydrous sodium sulfate, mixed with silica gel, and separated by column chromatography to obtain the target product as a pale yellow solid (PE:EA = 81:19), with a separation yield of 74%. C 30 H 32 N2O2, (Mr = 452.60). 1 HNMR (400 MHz, CDCl3) δ 12.53 (s, 2H, N H ), 7.32 -7.28 (m, 5H, Ar H ), 7.25 –7.17 (m, 6H, Ar H ), 6.94 (dd, J = 8.0, 2.0 Hz, 2H, Ar H ), 6.88 (t, J = 1.9 Hz, 1H, Ar H ), 5.21 (s, 2H, C H =C(CH3) N), 2.97 (t, J = 7.6 Hz, 4H, O=CC H 2CH2), 2.67(t, J = 8.4 Hz, 4H, O=CCH2C H 2), 2.03 (s, 6H, C H 3CNH). 13 C NMR (101 MHz, CDCl3)δ 198.07, 159.92, 141.78, 139.64, 129.76, 128.40, 128.34, 125.90, 121.38,120.29, 97.77, 43.73, 31.67, 20.06.

Claims

1. A method for modifying a β-ketoimine ligand precursor, comprising the following steps: L Ph H2 solution reacts with lithium compounds; then a haloalkane is added for C-C bond coupling; finally, an acid solution is added to complete the modification of the β-ketoimine ligand precursor; L Ph In H2 solution, L Ph H2 is C6H4[N(CH3)C=CHCOCH3]2H2, the solvent is tetrahydrofuran, and the lithium compound exists in solution form; L Ph The molar ratio of H2 to haloalkanes is 1:(1-5); the C-C bond coupling reaction is carried out at 0°C for 20-30 hours; the lithium compound is n-butyllithium; the reaction is illustrated below: ； R is one of the following groups: 。 2. The method for modifying the β-ketoimine ligand precursor according to claim 1, characterized in that, Under ice bath conditions, a lithium compound solution was added to L Ph The mixture was placed in an H2 solution and then reacted at room temperature for 10–15 hours.

3. A method for preparing a terminally alkylated ketimine, comprising the following steps: L Ph H2 solution reacts with a lithium compound; then a haloalkane is added for C-C bond coupling; followed by the addition of an acid solution to yield a terminally alkylated ketimine; L Ph In H2 solution, L Ph H2 is C6H4[N(CH3)C=CHCOCH3]2H2, the solvent is tetrahydrofuran, and the lithium compound exists in solution form; L Ph The molar ratio of H2 to haloalkanes is 1:(1-5); the C-C bond coupling reaction is carried out at 0°C for 20-30 hours; the lithium compound is n-butyllithium; the reaction is illustrated below: ； R is one of the following groups: 。 4. The method for preparing the terminally alkylated ketimine according to claim 3, characterized in that, After adding acid solution, the organic phase and aqueous phase solution were taken. The aqueous phase was extracted, and then the extracted organic phase was dehydrated and subjected to column chromatography to obtain terminally alkylated ketimine.

5. The method for preparing the terminally alkylated ketimine according to claim 3, characterized in that, After the C-C bond coupling reaction is complete, add acid solution at room temperature, and separate the layers after 10-20 minutes.

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