1. A process for the preparation of 1-N-heterocyclicacyl-1-(2'-N- heterocyclicacylethyl)ethylenes

Abstract

The application relates to a preparation method of 1-N-heterocyclic acyl-1-(2'-N-heterocyclic acetyl ethyl) ethylene. Nitrogen-containing heterocyclic alpha,beta-unsaturated acyl chloride can be rapidly prepared into the product through one-pot two-step reaction. The application has the advantages of mild reaction condition, simple operation, short reaction time, high yield and good product purity. The application effectively improves the defects of the previous synthesis of 1,1'-disubstituted terminal olefin, such as multiple reaction steps, use of noble metal catalyst or dehydrating agent, low temperature, long reaction time and low yield.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and the feature of the present application is to develop a preparation method of 1-N-heterocyclic acyl-1-(2'-N-heterocyclic acetyl) ethylene. BACKGROUND

[0002] Olefins containing iminoacyl and other prosthetic groups have a wide application in the field of organic synthesis. However, there is no report on the compound in which N-acyl and nitrogen heterocyclic alkyl are introduced into one end of the olefin. The synthesis method of such olefins is simple, and the structure simultaneously contains 1) terminal olefin structure, 2) chiral induction function iminoacyl, 3) the end of the saturated alkyl chain contains an easily leaving group, etc. Multiple reaction sites make it have the characteristics of multiple reaction sites, high reaction activity and high stereoselectivity when constructing complex molecules. SUMMARY

[0003] The present application develops a simple preparation method of 1-N-heterocyclic acyl-1-(2'-N-heterocyclic acetyl) ethylene. The method is to mix the nitrogen-containing heterocycle with NaH, then drop α, β-unsaturated acyl chloride, react for 2h, then add a certain proportion of base, react for 30min, and then the product can be obtained.

[0004] The technical scheme provided by the present application is: a preparation method of 1-N-heterocyclic acyl-1-(2'-N-heterocyclic acetyl) ethylene, the reaction equation is as follows, the method comprises the following steps: mixing the nitrogen-containing heterocycle with NaH, then slowly dropping α, β-unsaturated acyl chloride, reacting for 2h, then adding a certain proportion of base in the system, reacting for 30min, then adding saturated brine, and extracting with ethyl acetate to obtain the product. The specific reaction equation is as follows:

[0005]

[0006] The raw materials used in the synthesis process of the above-mentioned 1-N-heterocyclic acyl-1-(2'-N-heterocyclic acetyl) ethylene are nitrogen-containing heterocycle, α, β-unsaturated acyl chloride, NaH, base, and the solvent tetrahydrofuran which must be strictly dehydrated before use.

[0007] The molar ratio of the above-mentioned nitrogen-containing heterocycle, α, β-unsaturated acyl chloride, NaH and base is 1:1.1:1.2:1.

[0008] The above-mentioned reaction process is automatically exothermic, and the reaction temperature is controlled not to exceed 5℃ by controlling the adding speed of α, β-unsaturated acyl chloride.

[0009] The solvent used for recrystallization of the above-mentioned product is a mixed solvent of petroleum ether and ethyl acetate. The volume ratio of petroleum ether to ethyl acetate is 1:5-10:1.

[0010] The above-mentioned α, β-unsaturated acyl chloride is propenoyl chloride.

[0011] The beneficial effects of this invention are:

[0012] 1. After mixing nitrogen-containing heterocycles with NaH, α,β-unsaturated acyl chloride is added. After reacting for 2 hours, a certain proportion of base is added to the system to generate 1-N-heterocyclic acyl-1-(2'-N-heterocyclic acylethyl)ethylene.

[0013] 2. As mentioned above, the method of the present invention rapidly prepares the product from nitrogen-containing heterocyclic α,β-unsaturated acyl chlorides through a one-pot two-step reaction, and the operation is simple and easy to perform.

[0014] 3. The method of this invention has a wide range of applications. The invention uses nitrogen-containing heterocycles, namely pyrazole and 3-methylpyrazole.

[0015] Good preparation results have been achieved for 4-methylpyrazole, 5-methylpyrazole, 4-bromo-3,5-dimethylpyrazole, 3,5-dimethylpyrazole, indazole, imidazole, pyrrole, piperidine, morpholine, 4-methylimidazolium, 5-methylimidazolium, and 4,5-dimethylimidazolium. Attached Figure Description

[0016] Figure 1 The nuclear magnetic resonance (NMR) of 1-N-3,5-dimethylpyrazolyl-1-(2'-N-3,5-dimethylpyrazolylethyl)ethylene in Example 1 1 HNMR;

[0017] Figure 2 This is the high-resolution mass spectrometry (HRMR) of 1-N-3,5-dimethylpyrazolyl-1-(2'-N-3,5-dimethylpyrazolylethyl)ethylene in Example 1;

[0018] Figure 3 The nuclear magnetic resonance of 1-N-3-methylpyrazolyl-1-(2'-N-3-methylpyrazolylethyl)ethylene in Example 2 1 HNMR;

[0019] Figure 4 The high-resolution mass spectrometry (HRMR) of 1-N-3-methylpyrazolyl-1-(2'-N-3-methylpyrazolylethyl)ethylene in Example 2 is shown.

[0020] Figure 5 The nuclear magnetic resonance of 1-N-indazole acyl-1-(2'-N-indazole acylethyl)ethylene in Example 3 1 HNMR;

[0021] Figure 6 This is the high-resolution mass spectrometry (HRMR) of 1-N-indazole acyl-1-(2'-N-indazole acyl ethyl)ethylene in Example 3.

[0022] Specific embodiments of the present invention:

[0023] Example 1:

[0024] In a three-necked flask equipped with a magnetic stirrer, 0.55 g of 60% NaH was dissolved in 30 ml of purified tetrahydrofuran. Then, 1.82 g of 3,5-dimethylpyrazole was added. Under nitrogen protection, 1.7 ml of acryloyl chloride was slowly added, controlling the addition rate to keep the system temperature below 5°C. After reacting for 2 hours, 2.79 g of DMAP was added. The reaction was monitored by TLC. The starting material spot disappeared. f At a value of 0.47 (eluent: petroleum ether: ethyl acetate = 5:1), a distinct new spot appears, namely 1-N-3,5-dimethylpyrazolyl-1-(2'-N-3,5-dimethylpyrazolylethyl)ethylene. 10 ml of saturated ammonium chloride, 50 ml of ethyl acetate, and 20 ml of distilled water were added to the system for extraction and separation. The product dissolved in the organic layer. The aqueous layer was extracted twice more with 20 ml of ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the crude product. The crude product was recrystallized from petroleum ether: ethyl acetate = 8:1 to give 2.4 g of white crystals, yield: 86%. Structural data: 1 H NMR (300MHz, CDCl3, unit: ppm) δ6.00 (s, 1H), 5.93 (d, 2H), 5.79 (s, 1H), 3.38 (t, J = 9Hz, 2H), 2.96 (t, J = 6Hz, 2H), 2.55 (d, 6H), 2.22 (s, 6H); 13 C NMR (75MHz, CDCl3) δ172.75,169.30,151.90,151.74,144.50,143.83,142.61,124.80,110.94,110.92,34.07,28.29, 14.38,14.09,13.72,13.68; IR(KBr):2958,2923,2847,1722,1683,1617,1580,1376,1350,1331,962,943,816,763cm -1 MS: M + Na = 323.1 (M = 300).

[0025] Example 2:

[0026] In a three-necked flask equipped with a magnetic stirrer, 0.55 g of 60% NaH was dissolved in 30 ml of purified tetrahydrofuran. 1.72 g of 3-methylpyrazole was added. Under nitrogen protection, 1.7 ml of acryloyl chloride was slowly added, controlling the addition rate to keep the system temperature below 5°C. After reacting for 2 hours, 2.79 g of DMAP was added. The reaction was monitored by TLC. The starting material spot disappeared. f At a value of 0.52 (petroleum ether:ethyl acetate = 5:1), a distinct new spot appears, namely 1-N-3-methylpyrazolyl-1-(2'-N-3-methylpyrazolylethyl)ethylene. 10 ml of saturated ammonium chloride, 50 ml of ethyl acetate, and 20 ml of distilled water were added to the system for extraction and separation. The product dissolved in the organic layer. The aqueous layer was extracted twice more with 20 ml of ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the crude product. The crude product was then subjected to column chromatography with petroleum ether:ethyl acetate = 8:1 to give 2.3 g of a pale yellow oily liquid, yield: 80%. Structural data: 1 ¹H NMR (300MHz, CDCl₃, unit: ppm) δ 8.12 (m, 2H), 6.23 (m, 2H), 6.16 (s, 1H), 5.91 (s, 1H), 3.36 (t, J = 6Hz, 2H), 2.99 (t, J = 6Hz, 2H), 2.28 (d, 6H); MS: M + Na = 295.1 (M = 272).

[0027] Example 3:

[0028] In a three-necked flask equipped with a magnetic stirrer, 0.55 g of 60% NaH was dissolved in 30 ml of purified tetrahydrofuran. 2.23 g of indazole was added. Under nitrogen protection, 1.7 ml of acryloyl chloride was slowly added, controlling the addition rate to keep the system temperature below 5°C. After reacting for 2 hours, 2.79 g of DMAP was added. The reaction was monitored by TLC. The starting material spot disappeared. f At a concentration of 0.53 (petroleum ether:ethyl acetate = 5:1), a distinct new spot appears, representing 1-N-indazoleyl-1-(2'-N-indazoleylethyl)ethylene. The system was treated with 10 ml of saturated ammonium chloride, 50 ml of ethyl acetate, and 20 ml of distilled water for extraction and separation. The product dissolved in the organic layer. The aqueous layer was extracted twice more with 20 ml of ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the crude product. Recrystallization from the crude product using petroleum ether:ethyl acetate = 8:1 yielded 2.7 g of white crystals, with a yield of 82%. Structural characterization data. 1HNMR (300MHz, CDCl3, unit: ppm) δ8.45 (q, J=9Hz, 2H), 8.10 (d, 2H), 7.73 (t, J=9Hz, 2H), 7.57 (m, 2 H), 7.38 (m, 2H), 5.97 (d, 2H), 3.56 (t, J = 9Hz, 2H), 3.18 (t, J = 9Hz, 2H); MS: M+Na = 367.1 (M = 344).

[0029] Example 4:

[0030] Add 0.55 g of 60% NaH to a three-necked flask equipped with a magnetic stirrer, dissolved in 30 ml of purified tetrahydrofuran. Add 1.36 g of pyrazole. Under nitrogen protection, slowly add 1.7 ml of acryloyl chloride, controlling the addition rate to keep the system temperature below 5°C. After reacting for 2 hours, add 2.79 g of DMAP. Monitor the reaction by TLC. When the starting material spot disappears, the reaction proceeds. f At a concentration of 0.56 (eluent: petroleum ether: ethyl acetate = 5:1), a distinct new spot appears, representing 1-N-pyrazolyl-1-(2'-N-pyrazolylethyl)ethylene. The system was further treated with 10 ml of saturated ammonium chloride, 50 ml of ethyl acetate, and 20 ml of distilled water for extraction and separation. The product dissolved in the organic layer. The aqueous layer was extracted twice more with 20 ml of ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the crude product. Recrystallization from the crude product using petroleum ether: ethyl acetate = 8:1 yielded 1.9 g of white crystals, with a yield of 77%. Structural characterization data: 1 HNMR (300MHz, CDCl3, unit: ppm) δ8.27(m,2H),7.61(d,2H),6.46(m,2H),6.23(s,1H) ,6.00(s,1H),3.44(t,J=9Hz,2H),3.04(t,J=6Hz,2H); HRMS:M+Na=267.1(M=244).

[0031] Example 5:

[0032] In a three-necked flask equipped with a magnetic stirrer, 0.55 g of 60% NaH was dissolved in 30 ml of purified tetrahydrofuran. 1.72 g of 5-methylpyrazole was added, and under nitrogen protection, 1.7 ml of acryloyl chloride was slowly added, controlling the addition rate to keep the system temperature below 5°C. After reacting for 2 hours, 2.79 g of DMAP was added. The reaction was monitored by TLC. The starting material spot disappeared. fAt a pH of 0.54 (petroleum ether:ethyl acetate = 5:1), a distinct new spot appears, representing 1-N-5-methylpyrazolyl-1-(2'-N-5-methylpyrazolylethyl)ethylene. 10 ml of saturated ammonium chloride, 50 ml of ethyl acetate, and 20 ml of distilled water were added to the system for extraction and separation. The product dissolved in the organic layer. The aqueous layer was extracted twice more with 20 ml of ethyl acetate. The organic layers were combined and washed with saturated brine. After drying with anhydrous magnesium sulfate, the crude product was concentrated. The crude product was then subjected to column chromatography with petroleum ether:ethyl acetate = 8:1 to give 2.2 g of a white oily liquid, yield: 78%. 1 HNMR (300MHz, CDCl3, unit: ppm) δ8.15(m,2H),6.25(m,2H),6.18(s,1H),5.94(s,1H) ,3.38(t,J=9Hz,2H),3.01(t,J=9Hz,2H),2.31(d,6H); HRMS:M+Na=295.1(M=272).

[0033] Example 6:

[0034] Add 0.55 g of 60% NaH to a three-necked flask equipped with a magnetic stirrer, dissolved in 30 ml of purified tetrahydrofuran. Add 1.27 g of 4-methylpyrazole. Under nitrogen protection, slowly add 1.7 ml of acryloyl chloride, controlling the addition rate to keep the system temperature below 5°C. After reacting for 2 hours, add 2.79 g of DMAP. Monitor the reaction by TLC. The starting material spot disappears. f At a concentration of 0.52 (eluent: petroleum ether: ethyl acetate = 5:1), a distinct new spot appears, representing 1-N-4-methylpyrazolyl-1-(2'-N-4-methylpyrazolylethyl)ethylene. 10 ml of saturated ammonium chloride, 50 ml of ethyl acetate, and 20 ml of distilled water were added to the system for extraction and separation. The product dissolved in the organic layer. The aqueous layer was extracted twice more with 20 ml of ethyl acetate. The organic layers were combined and washed with saturated brine. After drying with anhydrous magnesium sulfate, the crude product was concentrated. Recrystallization from the crude product using petroleum ether: ethyl acetate = 15:1 yielded 1.7 g of white crystals, with a yield of 74%. Structural characterization data: 1 H NMR (300MHz, CDCl3, unit: ppm) δ8.01(d,2H),7.53(d,2H),6.12(s,1H),5.92(s,1H) ,3.38(t,J=9Hz,2H),3.01(t,J=9Hz,2H),2.12(d,6H); HRMS:M+Na=295.1(M=272).

[0035] Example 7:

[0036] In a three-necked flask equipped with a magnetic stirrer, 0.55 g of 60% NaH was dissolved in 30 ml of purified tetrahydrofuran. Then, 1.62 g of 4-bromo-3,5-dimethylpyrazole was added. Under nitrogen protection, 1.7 ml of acryloyl chloride was slowly added, controlling the addition rate to keep the system temperature below 5°C. After reacting for 2 hours, 2.79 g of DMAP was added. The reaction was monitored by TLC. The starting material spot disappeared. f At a value of 0.48 (eluent:petroleum ether:ethyl acetate = 5:1), a distinct new spot appears, namely 1-N-4-bromo-3,5-dimethylpyrazolyl-1-(2'-N-4-bromo-3,5-dimethylpyrazolylethyl)ethylene. 10 ml of saturated ammonium chloride, 50 ml of ethyl acetate, and 20 ml of distilled water were added to the system for extraction and separation. The product dissolved in the organic layer. The aqueous layer was extracted twice more with 20 ml of ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the crude product. The crude product was recrystallized from petroleum ether:ethyl acetate = 10:1 to give 2.1 g of white crystals, yield: 79%. Structural characterization data: 1 HNMR (300MHz, CDCl3, unit: ppm) δ5.90 (s, 1H), 5.82 (s, 1H), 3.36 (t, J = 9Hz, 2H), 2.95 (t, J = 9Hz, 2H), 2.56 (d, 6H), 2.24 (s, 6H); HRMS: M + Na = 478.9 (M = 456).

Claims

1. 1 A method for preparing 1-N-heterocyclic acyl-1-(2'-N-heterocyclic acylethyl)ethylene involves mixing a nitrogen-containing heterocycle (HcyNH) with NaH, then adding α,β-unsaturated acyl chloride dropwise. After reacting for 2 hours, a certain proportion of alkali is added, and the reaction is continued for 30 minutes. Finally, saturated brine is added, and the mixture is extracted with ethyl acetate. The α,β-unsaturated acyl chloride is acryloyl chloride. The reaction formula is as follows: The raw materials used in the synthesis of 1-N-heterocyclic acyl-1-(2'-N-heterocyclic acylethyl)ethylene are nitrogen-containing heterocycles, α,β-unsaturated acyl chlorides, NaH, and bases. The solvent tetrahydrofuran must be strictly dehydrated before use. The molar ratio of nitrogen-containing heterocycle, α,β-unsaturated acyl chloride, NaH, and base is 1:1.1:1.2:1; The above structural formula of 1-N-heterocyclic acyl-1-(2'-N-heterocyclic acylethyl)ethylene is: In the structural formula, NHcy is: Nitrogen-containing heterocycles (HcyNH) are pyrazole, 3-methylpyrazole, 4-methylpyrazole, 5-methylpyrazole, 4-bromo-3,5-dimethylpyrazole, and 3,5-dimethylpyrazole; The base mentioned above is DMAP.

2. The method according to claim 1, wherein the reaction temperature is -5 to 20°C.

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