A green synthesis method for cyanohydrin esters

Abstract

The application discloses a green synthesis method of cyanohydrin ester compounds, which comprises the following steps: mixing acyl cyanide, carboxylic acid, an activating agent and corresponding solvent, and then realizing deoxygenation esterification reaction of the acyl cyanide carbonyl under mild conditions, so as to obtain a series of cyanohydrin ester compounds. The application can efficiently realize efficient synthesis of the cyanohydrin ester compounds under mild conditions, and avoids releasing or converting CN — anions in the traditional reaction process. In addition, the reaction has high yield and simple operation, can realize amplification of the reaction, and has wide application prospect and practical value.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, and specifically relates to a method for synthesizing cyanohydrin esters from acyl nitrile and carboxylic acid in the presence of trivalent phosphine. Background Technology

[0002] Cyanoyl esters are an important component of natural products, pharmaceuticals, and agrochemicals, including commercially significant insecticides such as deltamethrin and mavric, which are considered among the safest and most effective insecticides due to their rapid insecticidal action and low toxicity to mammals. Furthermore, cyanoyl esters play a crucial role in organic synthesis, providing important means for constructing various valuable multifunctional molecules. They possess diverse transformation potentials, such as the synthesis of oxazoles, isocomonasines, and o-carbonyl esters. The most common method for synthesizing cyanoyl esters involves cyaniding aldehydes with cyaniding reagents (such as metal cyanides and TMSCN), followed by carbonylation with acyl halides or acid anhydrides (Tetrahedron Lett. 2015, 56, 7172–7175; Tetrahedron Lett. 2005, 46, 7487–7490). However, the use of toxic cyaniding reagents and the relatively cumbersome two-step reaction introduce significant drawbacks to these methods. To avoid the use of toxic cyanides and simplify processes, attention has been paid to acyl cyanide compounds. In the presence of additives (such as carbonates, amines, phosphine, Bu3SnCN, etc.), acyl cyanide compounds can be synthesized into cyanohydrin esters through in-situ cyanation and esterification processes (Synthesis 1996, 1188–1190; Chem. Eur. J. 2015, 22, 3821–3829; Tetrahedron 2006, 62, 8715–8719; J. Org. Chem. 1995, 60, 6229–6231). However, CN... — In-situ formation of anions remains a key mechanism for initiating the cyanidation-acylation reaction. Even though K3Fe(CN)6 and K4Fe(CN)6 have been developed as environmentally friendly alternatives (Chem. Commun. 2023, 59, 11544–11547; Synlett 2010, 2164–2168), CN... — The release of anions remains an unavoidable risk. Among the numerous synthetic strategies for cyano esters, few do not utilize cyaniding reagents. Furthermore, most reported methods for synthesizing cyano esters are limited to reactive and expensive aldehyde starting materials and acetate or benzoate products. Therefore, developing alternative methods for synthesizing cyano esters is of paramount importance, especially those that do not generate or convert toxic CNG. —In the case of anions, various cyanohydrin esters can be synthesized more efficiently from inexpensive and readily available carboxylic acids, and methods for constructing more diverse compound skeletons are applicable. Summary of the Invention

[0003] Purpose of the invention: The purpose of this invention is to provide a green synthesis method for cyanohydrin ester compounds.

[0004] Technical solution: The present invention provides a green synthesis method for cyanohydrin ester compounds, which, after mixing acyl nitrile, carboxylic acid, activator and corresponding solvent, can realize the deoxyesterification reaction of acyl nitrile carbonyl group under mild conditions, thereby obtaining a series of cyanohydrin ester compounds;

[0005] The specific operating steps are as follows: Add acyl nitrile, carboxylic acid and solvent to the reaction vessel, stir the reaction at room temperature, add activator at the same time, and after the reaction is completed, remove the solvent and obtain the target product lipid compound by simple separation by column chromatography.

[0006] The reaction route for this synthesis method is as follows:

[0007]

[0008] Among them, R 1 R is an alkyl or (hetero)aryl group. 2 It is an alkyl or (hetero)aryl group;

[0009] The activating agent is a trivalent phosphine compound with the following structure:

[0010]

[0011] Among them, R 3 R 4 R 5 It is one of alkyl, aryl, alkoxy, aryloxy, alkylamino, or arylamino, preferably hexamethyltriaminephosphine.

[0012] The solvent is one or a mixture of several of tetrahydrofuran, acetonitrile, 1,2-dichloroethane, dichloromethane, N,N-dimethylformamide, and toluene, preferably tetrahydrofuran.

[0013] Furthermore, the acyl nitrile is an alkyl-substituted acyl nitrile or a (hetero)aryl-substituted acyl nitrile.

[0014] Furthermore, the carboxylic acid is an alkyl-substituted primary, secondary, or tertiary carboxylic acid or a (hetero)arylic carboxylic acid.

[0015] Furthermore, the activating agent is a trivalent phosphorus compound, preferably hexamethyltriaminephosphine.

[0016] Furthermore, the molar ratio of the acyl nitrile, carboxylic acid and activating reagent is 1.0-1.2:1.0:1.0-1.3, preferably 1.1:1.0:1.1.

[0017] Furthermore, the reaction temperature for the carboxylic acid esterification is 25–50°C, preferably 25°C.

[0018] Furthermore, the reaction time for the carboxylic acid esterification is 2 to 12 hours, preferably 2 hours.

[0019] Beneficial effects: The specific advantages of this invention are as follows:

[0020] 1. This invention enables efficient and green synthesis of cyanohydrin esters under mild conditions.

[0021] 2. This invention avoids the release or transformation of CN, which is biotoxic and environmentally harmful, during traditional reaction processes. — In the case of anions; furthermore, the present invention develops a method for preparing a variety of cyanohydrin ester compounds from inexpensive and readily available carboxylic acid raw materials, without the need for the traditionally used active and expensive aldehydes as raw materials.

[0022] 3. The synthesis method of the present invention has high yield and simple operation, and can realize the scale-up of the reaction, and has broad application prospects and practical value. Attached Figure Description

[0023] Figure 1 The structure of Example 1 prepared according to the present invention 1 H NMR spectrum. Detailed Implementation

[0024] The technical solutions in the embodiments of the present invention will be clearly and completely described below, so that those skilled in the art can better understand the advantages and features of the present invention, thereby making a clearer definition of the scope of protection of the present invention. The embodiments described in this invention are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0025] Example 1

[0026]

[0027] In a 25 mL reaction tube, benzoyl nitrile (0.55 mmol), benzoic acid (0.5 mmol), and tetrahydrofuran (2 mL) were added sequentially, followed by hexamethyltriaminephosphine (0.55 mmol). The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction system was concentrated and separated by column chromatography to obtain the target product (89%). 1 H NMR (400MHz, Chloroform-d) δ8.06 (d, J = 7.6Hz, 2H), 7.65-7.57 (m, 3H), 7.50-7.42 (m, 5H), 6.67 (s, 1H).

[0028] Example 2

[0029]

[0030] In a 25 mL reaction tube, benzoyl nitrile (5.5 mmol), 4-fluorobenzoic acid (5.0 mmol), and tetrahydrofuran (20 mL) were added sequentially, followed by hexamethyltriaminephosphine (5.5 mmol). The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction system was concentrated and separated by column chromatography to obtain the target product (83%). 1 H NMR (400MHz, Chloroform-d) δ 8.15-8.04 (m, 2H), 7.65-7.59 (m, 2H), 7.52-7.46 (m, 3H), 7.14 (t, J = 8.6Hz, 2H), 6.66 (s, 1H).

[0031] Example 3

[0032]

[0033] In a 25 mL reaction tube, benzoyl nitrile (5.5 mmol), 3-methoxybenzoic acid (5.0 mmol), and tetrahydrofuran (20 mL) were added sequentially, followed by hexamethyltriaminephosphine (5.5 mmol). The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction system was concentrated and separated by column chromatography to obtain the target product (90%). 1 H NMR(400MHz,Chloroform-d)δ7.68-7.60(m,3H),7.58-7.55(m,1H),7.50-7.45(m,3H ), 7.36 (t, J = 8.0Hz, 1H), 7.15 (ddd, J = 8.3, 2.7, 1.0Hz, 1H), 6.67 (s, 1H), 3.84 (s, 3H).

[0034] Example 4

[0035]

[0036] In a 25 mL reaction tube, benzoyl nitrile (0.55 mmol), 3,4-dichlorophenylacetic acid (0.5 mmol), and tetrahydrofuran (2 mL) were added sequentially, followed by hexamethyltriaminephosphine (0.55 mmol). The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction system was concentrated and separated by column chromatography to obtain the target product (82%). 1 H NMR (400MHz, Chloroform-d) δ = 7.52-.43 (m, 5H), 7.39 (d, J = 8.3Hz, 1H), 7.35 (d, J = 2.1Hz, 1H), 7.09 (dd, J = 8.2, 2.1Hz, 1H), 6.41 (s, 1H), 3.74-3.61 (m, 2H).

[0037] Example 5

[0038]

[0039] In a 25 mL reaction tube, benzoyl nitrile (0.55 mmol), 2-methylphenylacetic acid (0.5 mmol), and tetrahydrofuran (2 mL) were added sequentially, followed by hexamethyltriaminephosphine (0.55 mmol). The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction system was concentrated and separated by column chromatography to obtain the target product (71%). 1 H NMR (400MHz, Chloroform-d) δ7.37-7.32 (m, 2H), 7.29-7.12 (m, 8H), 6.31 (s, 1H), 3.73 (p, J = 7.1Hz, 1H), 1.45 (dd, J = 11.5, 7.2Hz, 3H).

[0040] Example 6

[0041]

[0042] In a 25 mL reaction tube, benzoyl nitrile (0.55 mmol), oxaprazine (0.5 mmol), and tetrahydrofuran (2 mL) were added sequentially, followed by hexamethyltriaminephosphine (0.55 mmol). The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction system was concentrated and separated by column chromatography to obtain the target product (74%). 1H NMR(400MHz,Chloroform-d)δ7.52-7.46(m,2H),7.45-7.40(m,2H),7.39-7.34(m, 2H), 7.26-7.15 (m, 9H), 6.34 (s, 1H), 3.07 (t, J = 7.7Hz, 2H), 2.88 (t, J = 7.7Hz, 2H).

[0043] Example 7

[0044]

[0045] In a 25 mL reaction tube, benzoyl nitrile (0.55 mmol), isocolic acid (0.5 mmol), and tetrahydrofuran (2 mL) were added sequentially, followed by hexamethyltriaminephosphine (0.55 mmol). The mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction system was concentrated and separated by column chromatography to obtain the target product (76%). 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J=2.4Hz,1H),7.85(dd,J=7.6,1.3Hz,1H),7. 54-7.31(m,9H),7.00(d,J=8.4Hz,1H),6.42(s,1H),5.13(s,2H),3.77-3.66(m,2H).

[0046] Example 8

[0047]

[0048] In a 25 mL reaction tube, 2-fluorobenzoyl nitrile (0.55 mmol), benzoic acid (0.5 mmol), and tetrahydrofuran (2 mL) were added sequentially, followed by hexamethyltriaminephosphine (0.55 mmol). The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction system was concentrated and separated by column chromatography to obtain the target product (91%). 1 H NMR(400MHz,Chloroform-d)δ8.11-8.03(m,2H),7.73(td,J=7.5,1.7Hz,1H),7.62(t,J =7.5Hz,1H),7.52-7.43(m,3H),7.29(t,J=7.6Hz,1H),7.21-7.15(m,1H),6.87(s,1H).

[0049] Example 9

[0050]

[0051] In a 25 mL reaction tube, 2-chlorobenzoyl nitrile (0.55 mmol), benzoic acid (0.5 mmol), and tetrahydrofuran (2 mL) were added sequentially, followed by hexamethyltriaminephosphine (0.55 mmol). The mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction system was concentrated and separated by column chromatography to obtain the target product (94%). 1 H NMR (400MHz, Chloroform-d) δ8.07 (dd, J=8.1, 1.5Hz, 2H), 7.84-7.78 (m, 1H), 7.66-7.58 (m, 1H), 7.50-7.41 (m, 5H), 6.94 (s, 1H).

Claims

1. A green synthesis method for cyanohydrin ester compounds, characterized in that: The process includes the following steps: adding acyl nitrile, carboxylic acid and solvent to a reaction vessel, stirring the reaction at room temperature, adding an activator at the same time, removing the solvent after the reaction is complete, and obtaining the target product lipid compound by simple separation by column chromatography; The reaction route of the synthesis method is as follows: ； Among them, R 1 For aryl or substituted aryl, R 2 It is aryl, substituted aryl, or alkyl; The activator is hexamethyltriaminephosphine; The solvent is one or a mixture of several of tetrahydrofuran, acetonitrile, 1,2-dichloroethane, dichloromethane, N,N-dimethylformamide, or toluene.

2. The method for synthesizing cyanohydrin ester compounds as described in claim 1, characterized in that: The acyl nitrile is an aryl acyl nitrile.

3. The method for synthesizing cyanohydrin ester compounds as described in claim 1, characterized in that: The carboxylic acid mentioned is an aryl carboxylic acid.

4. The method for synthesizing cyanohydrin ester compounds as described in claim 1, characterized in that: The molar ratio of the acyl nitrile, carboxylic acid and activator is 1.0-1.2:1.0:1.0-1.

3.

5. The method for synthesizing cyanohydrin ester compounds as described in claim 1, characterized in that: The concentration of the carboxylic acid is 0.25–1.0 M.

6. The method for synthesizing cyanohydrin ester compounds as described in claim 1, characterized in that: The reaction temperature is 25–50℃.

7. The method for synthesizing cyanohydrin ester compounds as described in claim 1, characterized in that: The reaction time is 2 to 12 hours.

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