A method of constructing a quaternary carbon center

Abstract

The application provides a method for constructing a quaternary carbon center, and belongs to the technical field of organic chemistry. The method is as follows: under the action of potassium bicarbonate, triphenylacetic acid is deprotonated and then deprotonated to generate triphenyl negative ion as a nucleophile to attack Katritzky salt as an alkylating agent, so that a product containing a quaternary carbon center is obtained in a good yield. The method directly constructs a quaternary carbon center from stable and easily prepared Katritzky salt and tertiary carboxylic acid, does not need an oxidant and high-temperature conditions, simultaneously avoids the use of a transition metal, and is simple in process operation, low in reaction condition requirement, and friendly to the environment.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry technology, and specifically relates to a method for constructing quaternary carbon centers. Background Technology

[0002] Compounds with quaternary carbon chiral centers exhibit greater structural diversity and rigidity, thus they are widely found in bioactive compounds such as drugs and natural products, playing a vital role in the biomedical and pharmaceutical fields [see: Hervieu, C.; Kirillova, MS; Suarez, T.; Muller, M.; Merino, E.; Nevado, C. Nat Chem 2021, 13, 327.]. For example, in 2011, 12% of the top 200 best-selling drugs in the United States possessed quaternary carbon chiral centers. Developing efficient methods for constructing quaternary carbon chiral centers is beneficial for synthesizing these bioactive molecules and their analogues, studying the structure-function relationship, and thus promoting new drug development. However, due to steric hindrance, congestion, and conformational flexibility, constructing quaternary carbon chiral centers has always been a significant challenge in organic synthesis [see: Zeng, XP; Cao, ZY; Wang, YH; Zhou, F.; Zhou, J. Chem. Rev. 2016, 116, 7330.].

[0003] The construction of quaternary carbons can be achieved by introducing carbon through alkylation. Various common alkylating agents (such as alkyl halides, carboxylic acids, and esters) are well-developed. We chose Katritzky salts, a hot research topic in the last five years, as our alkylating agent. Katritzky salts use amines, which are widely found in nature, as synthetic raw materials, making them excellent alkylating agents [see: Plunkett, S.; Basch, CH; Santana, SO; Watson, MP J Am. Chem. Soc. 2019, 141, 2257.]. Through nucleophilic substitution, we selected an acid and a Katritzky salt as substrates. After decarboxylation, the acid acted as a nucleophile to attack the Katritzky salt to construct the quaternary carbon center. This reaction is environmentally friendly and simple to operate. Summary of the Invention

[0004] In light of the background information, the purpose of this invention is to provide a method for constructing quaternary carbon centers.

[0005] The reaction synthesis route of this invention is as follows:

[0006]

[0007] This invention provides a method for constructing quaternary carbon centers, comprising the following steps:

[0008] Step 1: Mix Katritzky salt with 2,2,2-triphenylacetic acid, then add potassium bicarbonate. Add the mixture to the solvent under a nitrogen atmosphere.

[0009] Step 2: The system from Step 1 is stirred and reacted at room temperature. After the reaction is complete, water is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic layer is then concentrated and chromatographically analyzed to obtain the product.

[0010] As a preferred option, R in Katritzky salt 1 R 2 The groups are various substituted aryl, alkyl, and hydrogen groups.

[0011] As a preferred option, R in Katritzky salt 1 When the group is a substituted aryl group, R 2 It is hydrogen.

[0012] As a preferred option, R in Katritzky salt 1 The group is -C 10 H 13 At that time, R 2 It is a methyl group.

[0013] Preferably, the molar ratio of Katritzky salt, 2,2,2-triphenylacetic acid and potassium bicarbonate in step one is 1:1:1.

[0014] Preferably, the solvent in step one is 0.2M dimethyl sulfoxide (DMSO).

[0015] Preferably, the stirring reaction time in step two is 6 hours.

[0016] Typical reactions are as follows:

[0017]

[0018] The beneficial effects of this invention are as follows:

[0019] The method of this invention has mild reaction conditions, does not require oxidants or high temperatures, and avoids the use of transition metals, directly constructing quaternary carbon centers from stable and easily prepared Katritzky salts and tertiary carboxylic acids. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below in conjunction with embodiments. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0021] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0022] Synthesis of Katritzky salt used in the examples:

[0023] Following the procedure described by Watson and colleagues [see: Plunkett, S.; Basch, CH; Santana, SO; Watson, MP J Am. Chem. Soc. 2019, 141, 2257.], pyridinium 2,4,6-triphenyltetrafluoroborate (1.0 equiv) and an amine (1.2 equiv) were added to a Schlenk containing a stir bar. Dry EtOH (1.0 M) was then added, resulting in a color change from yellow to dark orange. The mixture was then stirred and refluxed in an oil bath at 90 °C for 5 h. The mixture was then cooled to room temperature. Et₂O (15 mL) was then added and vigorously shaken to form a solid precipitate. The resulting solid was filtered, washed with Et₂O (2 × 15 mL), and dried under high vacuum. If the pyridinium salt failed to precipitate, rapid column chromatography was performed, eluting with a DCM / acetone mixture.

[0024]

[0025] Example 1

[0026] Weigh 48.5 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded onto a dry column and subjected to column chromatography (300-400 mesh silica gel) to obtain 28.2 mg of the product. (Petroleum ether:ethyl acetate = 50:1), yield 84%. 1 H NMR (400MHz, CDCl3) δ7.2–7.1(m,15H),7.0(t,J=7.4Hz,1H),7.0(t,J=7.5Hz,2H),6.6(d,J=7.6Hz,2H),3.9(s,2H).

[0027] Example 2

[0028] Weigh 49.2 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line and reacted at room temperature for 6 h under a nitrogen atmosphere and with 0.5 mL of DMSO. The product was then dry-loaded and subjected to column chromatography (300-400 mesh silica gel) to obtain 25.8 mg of product. (Petroleum ether:ethyl acetate = 50:1), yield 74%, 1H NMR (400MHz, CDCl3) δ 7.2 (dd, J = 4.4, 1.2 Hz, 11H), 7.2–7.1 (m, 3H), 7.2–7.1 (m, 1H), 6.8 (d, J = 7.7 Hz, 2H), 6.5 (d, J = 7.7 Hz, 2H), 3.9 (s, 2H), 2.2 (s, 3H); 13 C NMR (101MHz, CDCl3) δ146.7,135.4,135.3,131.0,129.8,128.0,127.5,125.9,58.4,45.9,20.9.

[0029] Example 3

[0030] Weigh 56.9 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded dry and subjected to column chromatography (300-400 mesh silica gel) to obtain 23.0 mg of the product. (Petroleum ether:ethyl acetate = 50:1), yield 55%, 1H NMR (400MHz, CDCl3) δ 7.3–7.2 (m, 12H), 7.2–7.1 (m, 3H), 6.8 (d, J = 7.5Hz, 2H), 6.6 (d, J = 8.6Hz, 2H), 3.9 (s, 2H); 13 CNMR (101MHz, CDCl3) δ 147.6 (q, J = 2.02Hz), 146.3, 137.3, 132.2, 129.7, 127.7, 126.1, 119.7, 118.2 (q, J = 216.1Hz), 58.5, 45.5.

[0031] Example 4

[0032] Weigh 59.9 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded onto a dry column and purified by column chromatography (300-400 mesh silica gel) to obtain 20.2 mg of the product. (Petroleum ether:ethyl acetate = 50:1), yield 58%, 1 H NMR (400MHz, CDCl3) δ7.2–7.1(m,15H),7.0(t,J=7.3Hz,1H),6.9(d,J=7.4Hz,1H),6.9(d,J=6.4Hz,1H),6.8(t,J=6.7Hz,1H),3.9(s,2H),1.5(s,3H); 13 C NMR (101MHz, CDCl3) δ146.5,138.8,137.1,130.2,129.9,129.7,127.5,126.0,125.9,125.0,58.2,41.6,19.2.

[0033] Example 5

[0034] Weigh 55.3 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line and reacted at room temperature for 6 h under a nitrogen atmosphere and with 0.5 mL of DMSO. The product was then dry-loaded and subjected to column chromatography (300-400 mesh silica gel) to obtain 22.5 mg of product. (Petroleum ether:ethyl acetate = 50:1), yield 56%, 1 H NMR (400MHz, CDCl3) δ7.5(d,J=7.8Hz,1H),7.3–7.1(m,15H),7.1(d,J=7.6Hz,1H),7.0(q,J=8.0Hz,2H),4.3(s,2H); 13 CNMR (101MHz, CDCl3) δ146.7, 137.9 (q, J = 1.01Hz), 131.2 (d, J = 134.3Hz), 130.5, 129.7, 127.8, 126. 3(q, J=3.03Hz), 126.1, 125.8 (q, J=3.03Hz), 125.6, 122.0 (q, J=216.1Hz), 57.4, 41.2 (d, J=2.02Hz).

[0035] Example 6

[0036] Weigh 51.9 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded dry and subjected to column chromatography (300-400 mesh silica gel) to obtain 25.0 mg of the product. (Petroleum ether:ethyl acetate = 50:1), yield 68%. 1 H NMR (400MHz, CDCl3) δ7.3–7.2(m,12H),7.2(m,3H),7.0(d,J=8.7Hz,1H),6.9(t,J=7.8Hz,1H),6.5(d,J=9.9Hz,2H),3.9(s,2H); 13 C NMR (101MHz, CDCl3) δ146.2,140.5,133.0,131.2,129.7,129.2,128.4,127.7,126.1,126.1,58.5,45.9.

[0037] Example 7

[0038] Weigh 54.5 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded onto a dry column and purified by column chromatography (300-400 mesh silica gel) to give 25.2 mg of the product. (Petroleum ether:ethyl acetate = 50:

[0039] 1) Yield 64%, 1 H NMR (400MHz, CDCl3) δ7.2 (d, J = 4.1Hz, 12H), 7.2 (h, J = 4.1Hz, 3H), 6.2 (s, 1H), 5.8 (s, 2H), 3.9 (s, 2H), 3.5 (s, 6H); 13 C NMR (101MHz, CDCl3) δ159.6,146.6,140.7,129.8,127.6,125.9,108.9,99.0,58.4,55.0,46.7.

[0040] Example 8

[0041] Weigh 53.7 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded onto a dry column and purified by column chromatography (300-400 mesh silica gel) to obtain 22.0 mg of the product. (Petroleum ether:ethyl acetate = 50:1), yield 57%. 1 H NMR (400MHz, CDCl3) δ7.3–7.1(m,15H),6.7(t,J=8.7Hz,1H),6.6–6.5(m,2H),3.8(s,2H); 13 C NMR (101MHz, CDCl3) δ156.6, (d, J = 46.5Hz), 146.1, 135.4 (d, J = 4.0Hz), 133.0, 130.5 (d, J = 7.07Hz) ,129.6,128.8(d,J=10.1Hz),127.7,126.2,119.5(d,J=17.2Hz),115.2(d,J=21.2Hz),58.5,45.2.

[0042] Example 9

[0043] Weigh 49.1 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded dry and subjected to column chromatography (300-400 mesh silica gel) to obtain 23.5 mg of the product. (Petroleum ether:ethyl acetate = 40:1), yield 69%. 1 H NMR (400MHz, CDCl3) δ7.2(m,J=7.7,7.0Hz,15H),6.9(d,J=5.1Hz,1H),6.7(t,J=4.1Hz,1H),6.3(d,J=3.4Hz,1H),4.1(s,2H); 13 C NMR (101MHz, CDCl3) δ146.5,140.7,129.6,127.9,127.7,126.2,125.7,124.3,58.1,41.8.

[0044] Example 10

[0045] Weigh 48.6 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded dry and subjected to column chromatography (300-400 mesh silica gel) to obtain 24.5 mg of the product. (Petroleum ether:ethyl acetate = 50:1), yield 73%. 1 H NMR (400MHz, CDCl3) δ8.3(d,J=3.6Hz,1H),7.3(d,J=7.7Hz,6H),7.3–7.1(m,10H),6.9(dd,J=7.5,5.0Hz,1H),6.3(d,J=7.9Hz,1H),4.2(s,2H); 13 C NMR (101MHz, CDCl3) δ158.9,148.3,146.7,135.0,129.7,127.7,126.0,125.0,121.0,58.2,49.0.

[0046] Example 11

[0047] Weigh 50.0 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded dry and subjected to column chromatography (300-400 mesh silica gel) to obtain 26.5 mg of the product. (Petroleum ether:ethyl acetate = 10:1), yield 76%. 1 H NMR(400MHz, CDCl3)δ7.3(d,J=7.8Hz,6H),7.2(dd,J=7.5Hz,6H),7.2(t,J=7.3Hz,3H), 7.1(t,J=7.8Hz,1H),6.8(d,J=7.6Hz,1H),6.1(d,J=7.9Hz,1H),4.2(s,2H),2.4(s,3H); 13 C NMR (101MHz, CDCl3) δ158.1,156.7,146.8,135.3,129.8,127.6,125.9,121.7,120.3,58.1,49.0,24.3.

[0048] Example 12

[0049] Weigh 48.7 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded onto a dry column and subjected to column chromatography (300-400 mesh silica gel) to obtain 13.8 mg of the product. (Petroleum ether:ethyl acetate = 10:1), yield 41%, 1 H NMR (400MHz, CDCl3) δ8.3(d,J=4.9Hz,2H),7.3(d,J=8.0Hz,6H),7.2(t,J=7.4Hz,6H),7.1(t,J=7.2Hz,3H),6.9(t,J=4.9Hz,1H),4.4(s,2H); 13 C NMR (101MHz, CDCl3) δ168.8,155.9,147.0,129.6,128.2,127.4,125.8,118.0,58.2,49.9.

[0050] Example 13

[0051] Weigh 48.7 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times through a vacuum line and reacted at room temperature for 6 h under a nitrogen atmosphere and with 0.5 mL of DMSO. The product was then dry-loaded and subjected to column chromatography (300-400 mesh silica gel) to obtain 19.8 mg of product. (Petroleum ether:ethyl acetate = 10:1), yield 59%. 1 H NMR (400MHz, CDCl3) δ8.3–8.3(m,1H),8.2(d,J=2.6Hz,1H),7.5(d,J=1.6Hz,1H),7.4–7.3(m,6H),7.3–7.2(m,6H),7.2–7.1(m,3H),4.2(s,2H); 13 CNMR (101MHz, CDCl3) δ154.9,146.4,146.2,143.0,141.6,129.5,127.8,126.2,58.4,46.3.

[0052] Example 14

[0053] Weigh 52.7 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line. The reaction was carried out under a nitrogen atmosphere with 0.5 mL of DMSO at room temperature for 6 h. The sample was then loaded onto a dry column and subjected to column chromatography (300-400 mesh silica gel) to obtain 11.3 mg of the product. (Petroleum ether:ethyl acetate = 50:1), yield 30%. 1 H NMR (400MHz, CDCl3) δ7.3(t,J=7.4Hz,5H),7.2(t,J=6.4Hz,7H),7.1(d,J=7.8Hz,6H),7.1–6.9(m,2H),3.3(dt,J=12.8,6.5Hz,1 H),2.8(ddd,J=14.0,9.4,4.9Hz,1H),2.7–2.6(m,1H),2.1–1.9(m,1H),1.0(d,J=6.4Hz,3H),0.8(dtd,J=13.8,9.3,4.8Hz,1H); 13 C NMR (101MHz, CDCl3) δ142.3,129.4,129.4,128.7,128.3,126.9,126.2,125.8,61.9,35.3,35.1,34.2,16.1.

[0054] Example 15

[0055] Weigh 44.9 mg (0.1 mmol), 2,2,2-triphenylacetic acid (28.8 mg, 0.1 mmol), and KHCO3 (10.0 mg, 0.1 mmol) were added to the reaction tube. The tube was evacuated three times using a vacuum line and reacted at room temperature for 6 h under a nitrogen atmosphere and with 0.5 mL of DMSO. The product was then dry-loaded and subjected to column chromatography (300-400 mesh silica gel) to give 29.1 mg of product. (Petroleum ether:ethyl acetate = 50:1), yield 98%. 1 H NMR (400MHz, CDCl3) δ7.2 (dd, J = 13.7, 6.6Hz, 12H), 7.2–7.1 (m, 3H), 4.7 (s, 1H), 4.3 (s, 1H), 3.4 (s, 2H), 1.4 (s, 3H).

[0056] The embodiments described above are merely preferred embodiments of the present invention, and while the descriptions are specific and detailed, they are not intended to limit the present invention. It should be noted that various changes and modifications can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the concept and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for constructing quaternary carbon centers, characterized in that, Includes the following steps: Step 1: Mix Katritzky salt with 2,2,2-triphenylacetic acid, then add potassium bicarbonate. Add the mixture to the solvent under a nitrogen atmosphere. Step 2: The system from Step 1 is stirred and reacted at room temperature. After the reaction is complete, water is added to quench the reaction, and the mixture is extracted with ethyl acetate. The organic layer is then concentrated and chromatographically analyzed to obtain the product. The reaction synthesis route is as follows: ； Where R 1 When the group is a substituted aryl group, R 2 It is hydrogen; when R 1 Group is At that time, R 2 It is hydrogen; when R 1 Group is , , or At that time, R 2 It is hydrogen; when R 1 Group is Or vinyl, R 2 It is a methyl group.

2. The method for constructing quaternary carbon centers according to claim 1, characterized in that, The molar ratio of the Katritzky salt, 2,2,2-triphenylacetic acid, and potassium bicarbonate in step one is 1:1:

1.

3. The method for constructing quaternary carbon centers according to claim 1, characterized in that, The solvent used in step one is 0.2 M dimethyl sulfoxide.

4. The method for constructing quaternary carbon centers according to claim 1, characterized in that, The stirring reaction time in step two is 6 hours.

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