Method for preparing cyclic lactam derivative through alkene alkyl alkynylation

Abstract

The invention relates to a method for preparing a cyclic lactam derivative through alkene alkyl alkynylation. The method comprises the following steps: adding olefin-bound alpha-carbonyl alkyl bromide, alkyne, a copper catalyst, a ligand, alkali and a solvent into a Schlenk reaction flask, introducing nitrogen, and carrying out a stirring reaction at a certain temperature to obtain the cyclic lactam derivative.

Description

Technical Field

[0001] The present application belongs to the field of organic synthesis, and specifically relates to a terminal alkyne as an alkynylating agent, which induces an olefin-bound α-carbonyl alkyl bromide compound to generate an alkyl radical, which adds to a carbon-carbon double bond to form a cyclic alkyl radical intermediate, which is inserted into an acetylene copper complex, thereby efficiently achieving the alkyl alkynylation of intramolecular olefins under a radical relay strategy, thereby efficiently preparing cyclic lactam derivatives. Background Art

[0002] Some research progress has been made in the di-carbon functionalization of olefins by generating carbon radicals from olefin-bound α-carbonylalkyl bromides, which then undergo cyclization with the intramolecular carbon-carbon double bond. Currently, a C(sp 3 )-C(sp 3 ) and C(sp 3 )-C(sp 2 ) bond, mainly realizes the alkylation and arylation of olefins. However, the construction of C(sp 3 )-C(sp) bonds to achieve dicarbon functionalization of alkenes has not been reported. Although metal-catalyzed cross-coupling strategies are an important method for achieving dicarbon functionalization of olefin-bound α-carbonylalkyl bromides, they usually require the pre-installation of directing groups on the substrate, which usually limits the substrate scope. Therefore, further development of a general strategy to construct C(sp 3 )-C(sp) bonds to achieve the dicarbon functionalization of olefin-bound α-carbonylalkyl bromides is of great research significance.

[0003] Here, the inventors used terminal alkynes as alkynylation reagents to induce the generation of alkyl radicals from α-carbonylalkyl bromides, which then add to carbon-carbon double bonds to form a cyclic alkyl radical intermediate that inserts into an acetylene-copper complex. This method efficiently achieves the alkyl alkynylation of olefins within the olefin-bound α-carbonylalkyl bromide molecule using a radical relay strategy. In this reaction, the more electron-rich tridentate nitrogen ligand 4,4′,4′-tri-tert-butyl-2,2′:6′,2′-tripyridine is used to enhance the reducing power of the copper catalyst, thereby reducing byproducts during the halogen atom transfer radical addition process and stabilizing the acetylene-copper complex intermediate. This promotes the subsequent radical addition process to form a trivalent copper complex intermediate, overcoming the challenges posed by side reactions such as β-H elimination or direct addition to alkyne radicals of the cyclic alkyl radical intermediate formed after the intramolecular cyclization of the α-carbonylalkyl bromide. Furthermore, the lactam derivatives of menthol and clodinafop-butyl backbones prepared by this method have broad application prospects in irritants, carminatives, fragrances, and herbicides. Summary of the Invention

[0004] The present invention aims to overcome the deficiencies of the prior art and to provide a method for preparing cyclic lactam derivatives by alkyl alkynylation of olefins, wherein the method can prepare the target product in a high yield under mild conditions.

[0005] The present invention provides a method for alkyl alkynylation of olefins, which uses olefin-bound α-carbonyl alkyl bromide and alkyne as raw materials and is prepared by the following steps:

[0006] An olefin-bound α-carbonylalkyl bromide represented by Formula 1, an alkyne represented by Formula 2, a copper catalyst, a ligand, a base, and a solvent, dimethyl sulfoxide (DMSO), were added to a Schlenk reaction flask. The flask was filled with nitrogen and stirred at 60° C. to react until the raw materials reacted completely. After post-treatment, a cyclic lactam derivative 3 was obtained, and its chemical reaction formula can be expressed as (the following formula):

[0007]

[0008] The post-treatment operation is as follows: the reaction solution after the reaction is completed is concentrated under reduced pressure, and the residue is separated by column chromatography. The elution solvent is: hexane / ethyl acetate = 8:1-3:1 to obtain a cyclic lactam derivative 3.

[0009] In the compounds represented by formula 2 and formula 3, R is selected from substituted or unsubstituted C6-C 20 Aryl, C6-C 20 alkyl.

[0010] In the reaction of the present invention, the copper catalyst is selected from cuprous iodide, cuprous bromide, cuprous chloride, copper oxide, copper bromide, copper trifluoromethanesulfonate, and copper acetylacetonate, preferably cuprous iodide.

[0011] In the reaction of the present invention, the ligand is selected from 4,4',4'-tri-tert-butyl-2,2':6',2'-tripyridine, 2,2':6',2'-tripyridine, 1,10-phenanthroline, preferably 4,4',4'-tri-tert-butyl-2,2':6',2'-tripyridine.

[0012] In the reaction of the present invention, the base is selected from sodium carbonate, potassium carbonate, potassium tert-butoxide, and triethylamine, preferably sodium carbonate.

[0013] The present invention has the beneficial effect of providing a method for preparing cyclic lactam derivatives by alkyl alkynylation of olefins. The method has the advantages of strong anti-group compatibility and mild reaction conditions, and is particularly suitable for the diversified preparation of cyclic lactam drug molecules. DETAILED DESCRIPTION

[0014] The present invention is further described in detail below with reference to specific embodiments, but the present invention is not limited thereto.

[0015] The experimental methods described in the following examples are conventional methods unless otherwise specified; the reagents and raw materials can be obtained from commercial channels and / or prepared according to known methods unless otherwise specified.

[0016] Examples 1-12 are experiments for optimizing reaction conditions.

[0017] Example 1

[0018]

[0019] To a Schlenk flask were added the olefin-bound α-carbonylalkyl bromide of Formula 1 (71.4 mg, 0.2 mmol), the alkyne of Formula 2a (30.6 mg, 1.5 eq), cuprous iodide (10 mol%), 4,4′,4′-tri-tert-butyl-2,2′:6′,2′-tripyridine (L1, 15 mol%), sodium carbonate (1.5 equiv), and DMSO (1.5 mL). The mixture was then reacted at 60°C under a nitrogen atmosphere for 14 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (elution solvent: petroleum ether / ethyl acetate = 8:1) to obtain the target product 3a (72% yield). The structural characterization data of the product are as follows: 1 H NMR (500MHz, CDCl3) δ: 7.65 (d, J=7.5Hz, 2H), 7.46 (d, J=7.5Hz, 2H), 7.38 (t, J=8.0Hz, 3H), 7.34-7.28 (m, 5H), 7.26 (t, J=4.5Hz, 2 H), 7.11 (t, J=7.5Hz, 1H), 4.09 (d, J=6.5, 1H), 3.94-3.90 (m, 1H), 3.84-3.80 (m, 1H), 2.61-2.56 (m, 1H), 1.36 (s, 3H), 1.02 (s, 3H); 13 C NMR (126MHz, CDCl3) δ: 178.2, 140.0, 139.5, 131.6, 128.8, 128.7, 128.2, 128.1, 128.0, 127.4 , 124.3, 122.9, 119.8, 88.3, ​​85.0, 49.3, 48.5, 44.9, 38.0, 25.0, 19.1; HRMSm / z(ESI)calcdfor C 27 H 25 NONa([M+Na] + )402.1828, found 402.1832.

[0020] Example 2

[0021] The copper catalyst cuprous bromide was used instead of cuprous iodide. Other conditions were the same as those in Example 1. The yield of the target product 3a was 67%.

[0022] Example 3

[0023] The copper catalyst cuprous chloride was used instead of cuprous iodide. Other conditions were the same as those in Example 1. The yield of the target product 3a was 63%.

[0024] Example 4

[0025] The copper catalyst copper oxide replaced cuprous iodide, and the other conditions were the same as in Example 1. The yield of the target product 3a was 28%.

[0026] Example 5

[0027] The copper catalyst copper bromide replaced cuprous iodide, and the other conditions were the same as in Example 1. The yield of the target product 3a was 43%.

[0028] Example 6

[0029] The copper catalyst copper trifluoromethanesulfonate was used instead of cuprous iodide. Other conditions were the same as those in Example 1. The yield of the target product 3a was 41%.

[0030] Example 7

[0031] The copper catalyst copper acetylacetonate was used instead of cuprous iodide. Other conditions were the same as those in Example 1. The yield of the target product 3a was 45%.

[0032] Example 8

[0033] The ligand 2,2':6',2'-tripyridine replaced 4,4',4'-tri-tert-butyl-2,2':6',2'-tripyridine. The other conditions were the same as those in Example 1. The yield of the target product 3a was 65%.

[0034] Example 9

[0035] The ligand 1,10-phenanthroline replaced 4,4′,4′-tri-tert-butyl-2,2′:6′,2′-tripyridine. Other conditions were the same as those in Example 1. The yield of the target product 3a was 53%.

[0036] Example 10

[0037] Alkali potassium carbonate was used instead of sodium carbonate. Other conditions were the same as in Example 1. The yield of target product 3a was 64%.

[0038] Example 11

[0039] Potassium tert-butoxide was used instead of sodium carbonate. Other conditions were the same as in Example 1. The yield of target product 3a was 5%.

[0040] Example 12

[0041] The base triethylamine was used instead of sodium carbonate, and the other conditions were the same as in Example 1. The yield of the target product 3a was 5%.

[0042] As can be seen from Examples 1-12 above, the most suitable reaction conditions are those of Example 1: cuprous iodide (10 mol%), 4,4',4'-tri-tert-butyl-2,2':6',2'-tripyridine (15 mol%), sodium carbonate (1.5 equiv), and DMSO (1.5 mL). The reaction flask was filled with nitrogen and stirred at 60°C. Based on these optimal reaction conditions, the inventors further developed highly selective alkyl alkynylation methods to prepare cyclic lactam derivatives using alkynes with different substituents as starting materials.

[0043] Example 13

[0044]

[0045] To a Schlenk flask were added the olefin-bound α-carbonylalkyl bromide of Formula 1 (71.4 mg, 0.2 mmol), the alkyne of Formula 2b (85.2 mg, 1.5 eq), cuprous iodide (10 mol%), 4,4′,4′-tri-tert-butyl-2,2′:6′,2′-tripyridine (L1, 15 mol%), sodium carbonate (1.5 equiv), and DMSO (1.5 mL). The mixture was then reacted at 60°C under a nitrogen atmosphere for 14 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (elution solvent: petroleum ether / ethyl acetate = 5:1) to obtain the desired product 3b (73% yield). The structural characterization data of the product are as follows: 11H NMR (500 MHz, CDCl3) δ: 7.94 (d, J = 8.0 Hz, 2H), 7.67 - 7.66 (m, 1H), 7.65 - 7.64 (m, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.38 (t, J = 8.0 Hz, 4H), 7.34 - 7.30 (m, 3H), 7.10 (t, J = 7.5 Hz, 1H), 4.95 - 4.90 (m, 1H), 4.12 (d, J = 6.5 Hz, 1H), 3.93 - 3.89 (m, 1H), 3.81 - 3.78 (m, 1H), 2.61 - 2.57 (m, 1H), 2.13 - 2.09 (m, 1H), 1.96 - 1.91 (m, 1H), 1.73 - 1.70 (m, 2H), 1.57 - 1.52 (m, 2H), 1.36 (s, 3H), 1.10 (t, J = 11.5 Hz, 2H), 1.04 (s, 1.7H), 1.03 (s, 1.3H), 0.92 (t, J = 2.5 Hz, 3H), 0.91 (t, J = 3.0 Hz, 3H), 0.79 (t, J = 6.5 Hz, 3H); 13 13C NMR (126 MHz, CDCl3) δ: 178.0, 165.3, 139.4, 139.3, 131.4, 130.0, 129.2, 128.8, 128.6, 127.9, 127.4, 127.3, 124.2, 119.6, 91.2(2), 84.3, 74.9, 71.2, 49.9, 49.0, 48.2, 47.1, 44.9, 44.8, 40.8, 38.0, 34.4, 34.1, 31.5, 31.3, 26.4, 25.6, 25.0(2), 23.5, 23.0, 22.1, 21.9, 20.9, 20.6, 19.0, 16.4, 16.0; HRMS m / z (ESI) calcd for C 38 H 43 NO3Na ([M+Na] + ) 584.3135, found 584.3139.

[0046] Example 14

[0047]

[0048] To a Schlenk flask were added the olefin-bound α-carbonylalkyl bromide of Formula 1 (71.4 mg, 0.2 mmol), the alkyne of Formula 2c (104.7 mg, 1.5 eq), cuprous iodide (10 mol%), 4,4′,4′-tri-tert-butyl-2,2′:6′,2′-tripyridine (L1, 15 mol%), sodium carbonate (1.5 equiv), and DMSO (1.5 mL). The mixture was then reacted at 60°C under a nitrogen atmosphere for 14 hours. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to remove the solvent. The residue was separated by column chromatography (elution solvent: petroleum ether / ethyl acetate = 3:1) to obtain the target product 3c (66% yield). The structural characterization data of the product are as follows: 1 H NMR (500MHz, CDCl3) δ: 7.81 (t, J=2.0Hz, 1H), 7.65-7.63 (m, 2H), 7.45-7.43 (m, 1H), 7.34-7. 32 (m, 5H), 7.27-7.23 (m, 2H), 7.10 (t, J=7.5Hz, 1H), 7.01-6.95 (m, 2H), 6.88-6.83 (m, 2H), 4 .73(d, J=2.0Hz, 2H), 4.71-4.65(m, 1H), 3.87-3.85(m, 1H), 3.84-3.81(m, 1H), 3.68-3.61(m , 1H), 2.50-2.45 (m, 1H), 1.57 (t, J=6.5Hz, 3H), 1.22 (d, J=5.5Hz, 3H), 0.92 (d, J=6.0Hz, 3H); 13 C NMR (126MHz, CDCl3) δ: 177.8, 171.1, 154.5(2), 151.0(d, J C-F =11.2Hz), 146.8, 146.6 (d, J C-F =266.6Hz), 139.8(d, J C-F =6.0Hz), 139.2, 139.0, 128.6(2), 127.7(d, J C-F =3.8Hz), 127.3, 124.8, 124.7, 124.6, 124.1, 122.0, 119.5(2), 115.8(d, J C-F =9.1Hz), 86.4, 86.3, 77.9, 72.7, 72.6, 52.9(2), 48.7, 48.6, 48.3(2), 44.5(2), 37.1(2), 24.6, 18.8, 18.7, 18.3; 19F NMR(471MHz, CDCl3)δ: -134.02; HRMSm / z(ESI)calcd for C 36 H 32 ClFN2O5Na([M+Na] + )649.1876, found 649.1871.

[0049] The above embodiments are only preferred embodiments of the present invention and are not exhaustive of the feasible implementations of the present invention. For those skilled in the art, any obvious modifications made thereto without departing from the principles and spirit of the present invention should be considered to be included in the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a cyclic lactam derivative by alkyl alkynylation of an olefin, characterized in that: The steps include: An olefin-bound α-carbonylalkyl bromide of Formula 1, an alkyne of Formula 2, a copper catalyst, a ligand, a base, and dimethyl sulfoxide (DMSO) solvent were added to a Schlenk reaction flask. The flask was filled with nitrogen and stirred at 60°C until the reaction of the raw materials was complete. After post-treatment, a cyclic lactam derivative 3 was obtained. In the compounds represented by formula 2 and formula 3, R is selected from substituted or unsubstituted C6-C 20 Aryl, C6-C 20 alkyl.

2. The method according to any one of claim 1, characterized in that The copper catalyst is selected from cuprous iodide, cuprous bromide, cuprous chloride, copper oxide, copper bromide, copper trifluoromethanesulfonate, and copper acetylacetonate, and is preferably cuprous iodide.

3. The method according to any one of claim 1, characterized in that The ligand is selected from 4,4',4'-tri-tert-butyl-2,2':6',2'-tripyridine, 2,2':6',2'-tripyridine, 1,10-phenanthroline, preferably 4,4',4'-tri-tert-butyl-2,2':6',2'-tripyridine.

4. The method according to any one of claim 1, characterized in that The base is selected from sodium carbonate, potassium carbonate, potassium tert-butoxide, and triethylamine, preferably sodium carbonate.

5. The method according to any one of claims 1 to 4, characterized in that The post-treatment operation is as follows: the reaction solution after the reaction is completed is concentrated under reduced pressure, and the residue is separated by column chromatography. The elution solvent is: hexane / ethyl acetate = 8:1-3:1 to obtain a cyclic lactam derivative 3.

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