A method for photoredox nickel-catalyzed Giese addition reaction of alkyl isoureas with Michael receptors

Abstract

This invention discloses a photoredox nickel-catalyzed Giese addition reaction method for alkylisoureas and Michael acceptors. The method uses widely available alcohol-derived alkylisoureas and commercially available Michael acceptors as reactants. In the presence of organic amines, and with inexpensive diaryl ketones as photosensitizers, a nickel-catalyzed radical Giese addition reaction is achieved under ultraviolet light irradiation, efficiently constructing C(sp...)... 3 )-C(sp 3 The method of this invention is applicable to various oxoalkyl isourea substrates derived from primary, secondary, and tertiary alcohols. It exhibits good functional group tolerance, mild reaction conditions, and eliminates the need for precious metal photosensitizers and excessive complex additives. The method is simple to operate and provides an economical and efficient route for the deoxyalkylation of alcohol compounds, showing broad application prospects in the synthesis of pharmaceutical intermediates and functional molecules.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a photoredox nickel-catalyzed Giese addition reaction method for alkyl isoureas with Michael acceptors, and more specifically, to the formation of C(sp) groups using alcohol-derived alkyl isoureas as alkyl radical precursors with Michael acceptors under the synergistic action of photosensitizers and nickel catalysts. 3 )-C(sp 3 The method of the key. Background Technology

[0002] The Giese reaction is the construction of C(sp) 3 )-C(sp 3 One of the most efficient and reliable methods for synthesizing C(sp) bonds (Angew. Chem. 1983, 95, 633-634). In recent years, a series of readily available raw materials, including carboxylic acids (Chem. Soc. Rev. 2022, 51, 1415-1453), amines (Angew. Chem. Int. Ed. 2019, 58, 5697-5701), aldehydes (Angew. Chem. Int. Ed. 2019, 58, 4953-4957) and ketones (Science 2025, 387, 1377-1383), have been developed as efficient alkyl radical precursors, further advancing the development of the Giese reaction. These methods can synthesize various C(sp) bonds under thermally driven, photoredox, or electrochemical conditions. 3 )-C(sp 3 C(sp) bonds are molecules. Although these approaches are effective, alcohols, due to their abundance, structural diversity, and low cost compared to other raw material chemicals, are preferred as C(sp) bonds. 3 Free radical precursors are highly sought after.

[0003] Over the past few decades, researchers have developed various strategies for generating alkyl radicals from alcohols, including methods that directly utilize alcohols as radical precursors, such as in-situ activation or pre-activation strategies. Regarding in-situ activation strategies, some thermal reaction systems, such as titanium-based catalysts (J. Am. Chem. Soc. 2020, 142, 16787-16794) and the CS2 / PPh3 system (Nat. Commun. 2021, 12, 5365), have shown high reactivity in the homolytic cleavage of CO bonds. MacMillan developed an NHC-mediated deoxy-Giese addition method for alcohols (Angew. Chem. Int. Ed. 2022, 61,e202207150). Using alcohols as direct alkyl radical precursors, after in-situ activation with NHC, Giese addition occurs with electron-deficient alkenes under blue light redox conditions. This method eliminates the need to separate activation intermediates, offers mild conditions, and is applicable to primary, secondary, and tertiary alcohols. It also exhibits good functional group tolerance and can be used for the later modification of complex molecules. However, this method requires stoichiometric NHC reagents and bases, as well as expensive iridium photocatalysts, resulting in a complex system and high cost, thus limiting its practicality for large-scale applications. Zuo's group developed a cerium-catalyzed Giese reaction for the dehydroxymethylation of alcohols (J. Am. Chem. Soc. 2019, 141, 10556-10564). This method utilizes inexpensive cerium salts to generate an alkyl radical with one less carbon atom from a free alcohol via ligand-to-metal charge transfer (LMCT), followed by 1,4-addition with a Michael acceptor. The advantages of this method are the direct use of free alcohols, the inexpensive cerium catalyst, mild conditions, and the ability to achieve various transformations. However, it is essentially a dehydroxymethylation reaction, resulting in the loss of a carbon atom. It is mainly suitable for specific primary alcohol substrates; some diols inhibit catalysis, and the yield is low for small molecule substrates such as ethanol. Wu's group developed a xanthate-mediated Giese reaction for the deoxygenation of alcohols (Nat. Commun. 2021, 12, 5365). This method generates xanthate in situ from an alcohol, CS2, and a base, followed by photo-redox / phosphine-mediated fragmentation to generate an alkyl radical, achieving the deoxygenation Giese addition with electron-deficient alkenes. This method is compatible with primary, secondary, and tertiary alcohols, and can even generate methyl radicals, exhibiting a broad substrate range. Diols can be selectively deoxygenated, and the process can be scaled up to gram scale. However, it requires the use of CS2, PPh3, strong bases, and iridium photocatalysts, and produces phosphine sulfides and COS as byproducts. Furthermore, it is not suitable for benzyl alcohol, allyl alcohol, and substrates containing strongly electrophilic groups. A pre-activation strategy aims to efficiently generate C(sp) from alcohols. 3Alkyl oxalate esters offer another pathway. Overman (J. Am. Chem. Soc. 2013, 135, 15342-15345), MacMillan (J. Am. Chem. Soc. 2015, 137, 11270-11273), and Gong (J. Am. Chem. Soc. 2019, 141, 820-824) reported that alkyl oxalate esters are efficient alkyl radical precursors under photoredox or thermally driven conditions. However, the success of these methods largely depends on expensive ruthenium- or iridium-based photocatalysts, or requires the addition of excess zinc reducing agents, MgCl2, and 2-(pyridin-2-yl)-1H-benzo[d]imidazole to achieve efficient catalytic cycling. Furthermore, these methods typically use tertiary alcohols, with limited research on primary and secondary alcohols.

[0004] In summary, existing Giese reaction methods involving alcohols still have the following shortcomings: (1) they rely on expensive precious metal photocatalysts such as iridium and ruthenium; (2) they require stoichiometric or excess activating reagents and additives; (3) some methods have limited substrate applicability, especially poor compatibility with primary and secondary alcohols; and (4) the reaction system is complex and costly, which is not conducive to large-scale industrial applications. Therefore, developing a Giese addition reaction method for alcohol compounds that does not require precious metal photocatalysts, has a wide substrate applicability (compatible with primary, secondary, and tertiary alcohols), is simple to operate, and is cost-effective has important research value and application significance. Summary of the Invention

[0005] The purpose of this invention is to overcome the aforementioned deficiencies in the prior art and provide a photoredox nickel-catalyzed Giese addition reaction method for alkyl isoureas with Michael receptors. This method uses widely available alcohol-derived alkyl isoureas as alkyl radical precursors and inexpensive diaryl ketones as photosensitizers. Under ultraviolet light irradiation and nickel catalysis, the alkyl isoureas undergo a Giese addition reaction with Michael receptors, efficiently constructing C(sp... 3 )-C(sp 3 )key.

[0006] To achieve the above objectives, the technical solution adopted in this invention is as follows: An oxoalkyl isourea of ​​Formula I, a Michael acceptor of Formula II, a nickel catalyst, a ligand, a photosensitizer, and an organic amine are added to an organic solvent, and the mixture is reacted under ultraviolet light irradiation under inert gas protection to obtain C(sp) of Formula III. 3 )-C(sp 3 Coupling products;

[0007]

[0008] In the formula, R represents any one of primary alkyl, secondary alkyl, and tertiary alkyl groups; R1 Represents any one of hydrogen, methyl, ethyl, or fluorine; R 2 EWG represents any one of the following: hydrogen, methyl, ethyl, isopropyl, phenyl, fluorine, C1-C6 alkoxycarbonyl, and protected amino (referring to a group in which the hydrogen atom on the amino group is replaced by an amino protecting group selected from any one of tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and fluorenylmethoxycarbonyl (Fmoc); EWG represents benzyloxycarbonyl, nobutanol-substituted ester group, C1-C6 alkyl group substituted with a lactone ring, C1-C6 alkoxycarbonyl, hydroxyl-substituted C1-C6 alkoxycarbonyl, fluorinated C1-C6 alkoxycarbonyl, C1-C... 12 Any one of the following groups: alkyl acyl, amide, cyano, sulfonyl, pyridyl, phosphate, and pinaborate.

[0009] In the method described in this invention, the oxyalkylisourea used is prepared according to the method disclosed in CN120923407A, by reacting the corresponding alcohol compound with N,N'-diisopropylcarbodiimide in tert-butyl methyl ether under cobalt chloride catalysis and stirring at 90°C under inert gas protection. The amount of cobalt chloride used is 0.01 times the molar amount of the alcohol compound, and the amount of N,N'-diisopropylcarbodiimide used is 1.0 times the molar amount of the alcohol compound.

[0010] In the method of the present invention, the nickel catalyst is selected from any one of nickel chloride, nickel bromide, nickel iodide, nickel fluoride, nickel chloride dimethoxyethane, and nickel bromide dimethoxyethane.

[0011] In the method of the present invention, the ligand is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2':6',2''-terpyridine, 4,4′,4″-tri-tert-butyl-2,2′:6′,2″-terpyridine, and 4'-(4-methoxyphenyl)-2,2':6',2''-terpyridine.

[0012] In the method of the present invention, the photosensitizer is selected from any one of benzoylnaphthalene, benzophenone, 4,4'-dimethylbenzophenone, 4-fluoro-4'-methoxybenzophenone, anthraquinone, 4,4'-dimethoxybenzophenone, and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile.

[0013] In the method described in this invention, the organic amine is selected from any one of diisopropylamine, N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, N,N-diethylcyclohexylamine, dicyclohexylamine, and N-methyldicyclohexylamine.

[0014] In the method of the present invention, the organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

[0015] Furthermore, in the method of the present invention, the amount of Michael receptor used is 1.5 to 3.0 times the molar amount of oxyalkylisourea.

[0016] Furthermore, in the method of the present invention, the amount of nickel catalyst used is 5% to 15% of the molar amount of oxyalkylisourea.

[0017] Furthermore, in the method of the present invention, the amount of the ligand used is 5% to 15% of the molar amount of oxyalkylisourea.

[0018] Furthermore, in the method of the present invention, the amount of photosensitizer used is 5% to 15% of the molar amount of oxyalkylisourea.

[0019] Furthermore, in the method of the present invention, the amount of organic amine used is 2.0 to 4.0 times the molar amount of oxyalkylisourea.

[0020] Furthermore, in the method described in this invention, it is preferable to react under argon protection with ultraviolet light irradiated at a wavelength of 390–395 nm for 10–20 hours.

[0021] This invention utilizes a strategy of photo-redox combined with nickel synergistic catalysis to achieve the deoxy-Giese addition reaction of oxoalkylisoureas. The reaction mechanism is as follows: the oxoalkylisourea undergoes nucleophilic substitution with the bromide anion of the nickel catalyst (using NiBr2 as an example), generating alkyl bromide intermediate A. Simultaneously, a photosensitizer (using 4-fluoro-4'-methoxybenzophenone as an example, PC) is photoexcited to generate a triplet photosensitizer B, which then undergoes a hydrogen atom transfer process with an organic amine (using N,N-diethylcyclohexylamine as an example, CyNEt2), generating a highly active intermediate C. Intermediate C undergoes a single-electron transfer (SET) to the nickel catalyst, generating a low-valent nickel(I) species Ni(I)Br. Subsequently, alkyl bromide intermediate A undergoes a halogen atom transfer (XAT) with Ni(I)Br, generating an alkyl radical D, and regenerating the nickel(II) catalyst Ni(II)Br2. The generated alkyl radical D then adds to the Michael acceptor to form radical intermediate E, which, through a series of single-electron transfer / proton transfer (PT) processes, yields the final Giese addition product F.

[0022]

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0024] This invention utilizes readily available and inexpensive alkyl isoureas derived from alcohols as alkyl radical precursors, providing primary, secondary, and tertiary alkyl sources, thus overcoming the limitation of alkyl sources in existing methods. It employs inexpensive diaryl ketones instead of traditional expensive precious metals such as iridium and ruthenium as photosensitizers, significantly reducing reaction costs. The reaction conditions are mild, allowing it to proceed under room temperature and ultraviolet light irradiation, eliminating the need for high temperature, high pressure, and excessive complex additives, making the operation simple. Furthermore, this method is not only applicable to tertiary alcohol derivatives but also compatible with various primary and secondary alcohol derivatives. The Michael acceptor is tolerant to various electron-withdrawing groups such as ester, ketone carbonyl, amide, cyano, sulfonyl, pyridyl, phosphate, and pinaborate groups, exhibiting good functional group compatibility and a wide range of substrate applications, enabling efficient and highly selective construction of C(sp...) radicals. 3 )-C(sp 3 The deoxyalkylation of alcohols, by removing the alkylation bond, can achieve a partial substrate separation yield of over 80%. Therefore, this invention provides a new, economical, and efficient route for the deoxyalkylation of alcohols, showing promising applications in the synthesis of pharmaceutical intermediates, natural products, and functional molecules. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0026] Example 1

[0027] Under an argon atmosphere, 0.3 mmol of oxyalkylisourea (Formula I-1), 0.6 mmol of Michael acceptor (Formula II-1), 0.03 mmol of nickel bromide trihydrate, 0.03 mmol of 2,2':6',2''-terpyridine (Formula II-1), 0.03 mmol of 4-fluoro-4'-methoxybenzophenone (Formula II-1), 0.75 mmol of N-methyldicyclohexylamine, and 1 mL of N-methylpyrrolidone were sequentially added to a 10 mL reaction tube equipped with a magnetic stirrer. The reaction was carried out under ultraviolet light at 390–395 nm for 16 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography using petroleum ether and ethyl acetate in a volume ratio of 20:1 to obtain a yellow oily product (Formula III-1) in 48% yield.

[0028]

[0029] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.40-7.29 (m, 5H),5.12 (s, 2H), 4.48 (t,J = 6.1 Hz, 1H), 4.36 (t, J = 6.1 Hz, 1H), 2.37 (t, J = 7.5 Hz, 2H), 1.75-1.61 (m, 4H), 1.49-1.32 (m, 4H); 13 C NMR (100 MHz, CDCl3)δ 173.6, 136.2, 128.7, 128.3, 128.3, 84.1 (d, J = 164.3 Hz), 66.3, 34.3, 30.3(d, J = 19.5 Hz), 28.8, 25.0 (d, J = 5.4 Hz), 24.9; 19 F NMR (376 MHz, CDCl3) δ= -217.92-218.43 (m); HRMS (APCI) m / z C 14 H 20 FO2 + [M+H] + Theoretical value: 239.1442, measured value: 239.1450.

[0030] Example 2

[0031] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar oxyalkylisourea as shown in I-2, and the Michael receptor in Example 1 was replaced with an equimolar Michael receptor as shown in II-2. The other steps were the same as in Example 1, and a colorless oily product with the structural formula shown in III-2 was obtained with a yield of 80%.

[0032]

[0033] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 6.5 (dd, J = 14.3,6.8 Hz, 1H), 4.39-4.30 (m, 1H), 4.23-4.11 (m, 2H), 3.97 (dd, J = 6.8, 2.0 Hz, 1H), 3.67 (t, J= 6.4 Hz, 2H), 2.58-2.46 (m, 1H), 2.46-2.35 (m, 1H), 2.01-1.85 (m, 2H), 1.75-1.63 (m, 2H), 1.53-1.38 (m, 5H); 13 C NMR (100 MHz, CDCl3) δ179.6, 152.0, 86.5, 67.9, 66.6, 39.6, 30.4, 29.0, 28.8, 27.2, 26.0; HRMS(APCI) m / z C 11 H 19 O3 + [M+H] + Theoretical value: 199.1329, measured value: 199.1335.

[0034] Example 3

[0035] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar oxyalkylisourea as shown in I-3, and the Michael receptor in Example 1 was replaced with an equimolar Michael receptor as shown in II-3. The other steps were the same as in Example 1, and a yellow oily product with the structural formula shown in III-3 was obtained with a yield of 54%.

[0036]

[0037] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.24 (d, J = 8.4Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 3.66 (s, 3H), 2.59 (t, J = 7.0 Hz, 2H), 2.33 (t, J = 7.0 Hz, 2H), 1.70-1.59 (m, 4H); 13 C NMR (100 MHz, CDCl3) δ 174.1,140.7, 131.6, 129.9, 128.5, 51.7, 35.0, 34.0, 30.9, 24.6; HRMS (APCI) m / zC 12 H 16 ClO2 + [M+H] + Theoretical value: 227.0833, measured value: 227.0835.

[0038] Example 4

[0039] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-4, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-4. The other steps were the same as in Example 1, and a yellow oily product with the structural formula shown in II-4 was obtained with a yield of 84%.

[0040]

[0041] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 5.1Hz, 1H), 6.95-6.89 (m, 1H), 6.78 (d, J = 3.4 Hz, 1H), 4.27-4.18 (m, 2H), 3.81(t, J = 4.6 Hz, 2H), 2.84 (t, J = 7.2 Hz, 2H), 2.58-2.47 (m, 1H), 1.96 (s,1H), 1.75-1.64 (m, 3H), 1.56-1.48 (m, 1H), 1.18 (d, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 177.1, 145.0, 126.9, 124.3, 123.1, 66.1, 61.5, 39.4, 33.2,29.83, 29.5, 17.2; HRMS (APCI) m / z C 12 H 19 O3S + [M+H] + Theoretical value: 243.1049, measured value: 243.1050.

[0042] Example 5

[0043] In this embodiment, the oxyalkylisourea in Example 1 was replaced with equimolar oxyalkylisourea as shown in I-5, and the other steps were the same as in Example 1, to obtain a yellow oily product with the structural formula shown in III-5, with a yield of 49%.

[0044]

[0045] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 1.8Hz, 1H), 7.42-7.28 (m, 6H), 6.24-6.19 (m, 1H), 5.10 (s, 2H), 4.49-4.06 (m,2H), 2.95 (t, J = 6.6 Hz, 0.23 H), 2.35 (t, J = 7.4 Hz, 1.84H), 1.96-1.81 (m,2H), 1.72-1.62 (m, 2H), 1.36-1.27 (m, 2H); 13 HRMS (APCI) m / z C 16 H 21 N2O2 + [M+H] + Theoretical value: 273.1598, measured value: 273.1600.

[0046] Example 6

[0047] In this embodiment, the oxyalkylisourea in Example 1 was replaced with equimolar oxyalkylisourea as shown in I-6, and the other steps were the same as in Example 1, to obtain a yellow solid product with the structural formula shown in III-6, with a yield of 43%.

[0048]

[0049] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 5H),5.12 (s, 2H), 2.38 (t, J = 7.5 Hz, 2H), 1.70-1.64 (m, 2H), 1.51-1.43 (m, 2H), 1.41-1.34 (m, 2H), 1.26 (s, 1H), 1.19 (s, 6H); 13C NMR (100 MHz, CDCl3) δ173.5, 136.1, 128.6, 128.2, 128.2, 70.9, 66.1, 43.5, 34.3, 29.2, 25.4, 23.9; HRMS (APCI) m / z C 15 H 23 O3 + [M+H] + Theoretical value: 251.1642, measured value: 251.1645.

[0050] Example 7

[0051] In this embodiment, the oxyalkylisourea in Example 1 was replaced with equimolar oxyalkylisourea as shown in I-7, and the other steps were the same as in Example 1, to obtain a pale yellow oily product with the structural formula shown in III-7, with a yield of 66%.

[0052]

[0053] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.41-7.26 (m, 5H), 5.11 (s, 2H), 2.42-2.33 (m, 2H), 1.75-1.61 (m, 5H), 1.58-1.51 (m, 2H), 1.23-1.08 (m, 4H), 0.96-0.82 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 174.2, 136.3,128.7, 128.3, 128.3, 66.2, 37.3, 33.1, 32.5, 32.1, 26.7, 26.4; HRMS (APCI) m / z C 16 H 23 O2 + [M+H] + Theoretical value: 247.1693, measured value: 247.1699.

[0054] Example 8

[0055] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-8, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-2. The other steps were the same as in Example 1, and a pale yellow oily product with the structural formula shown in III-8 was obtained with a yield of 50%.

[0056]

[0057] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.37-4.31 (m, 1H), 4.21-4.14 (m, 1H), 3.93 (s, 4H), 2.62-2.52 (m, 1H), 2.46-2.38 (m, 1H), 1.97-1.89 (m, 1H), 1.88-1.81 (m, 1H), 1.76-1.70 (m, 3H), 1.59-1.49 (m, 2H), 1.48-1.41 (m, 1H), 1.37-1.29 (m, 2H), 1.26-1.21 (m, 1H), 1.17-1.06 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 179.8, 108.9, 66.5, 64.4, 37.3, 37.2, 34.5, 34.5, 34.5,30.7, 29.6, 29.5; HRMS (APCI) m / z C 13 H 21 O4 + [M+H] + Theoretical value: 241.1434, measured value: 241.1440.

[0058] Example 9

[0059] In this embodiment, the oxyalkylisourea in Example 1 was replaced with equimolar oxyalkylisourea as shown in I-9, and the other steps were the same as in Example 1, to obtain a light yellow buttery product with the structural formula shown in III-9, with a yield of 58%.

[0060]

[0061] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.52-7.26 (m, 5H), 5.11 (s, 2H), 2.74-2.54 (m, 4H), 2.48-2.33 (m, 2H), 2.09-1.91 (m, 2H), 1.66-1.57 (m, 2H), 1.40-1.24 (m, 4H).; 13C NMR (100 MHz, CDCl3) δ 173.7, 136.1,128.7, 128.4, 66.4, 36.8, 33.9, 32.3, 31.4, 28.7.; HRMS (APCI) m / z C 15 H 21 O2S + [M+H] + Theoretical value: 265.1257, measured value: 265.1260.

[0062] Example 10

[0063] In this embodiment, the oxyalkylisourea in Example 1 was replaced with equimolar oxyalkylisourea as shown in I-10, and the other steps were the same as in Example 1, to obtain a light yellow buttery product with the structural formula shown in III-10, with a yield of 67%.

[0064]

[0065] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.40-7.30 (m, 5H), 5.12 (s, 2H), 3.98-3.87 (m, 2H), 3.40-3.28 (m, 2H), 2.42-2.34 (m, 2H), 1.66-1.54 (m, 4H), 1.52-1.43 (m, 1H), 1.31-1.22 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ173.7, 136.1, 128.7, 128.4, 128.4, 68.0, 66.4, 34.5, 32.8, 31.9, 31.5; HRMS(APCI) m / z C 11 H 19 O3 + [M+H] + Theoretical value 199.1329, measured value 199.1335. HRMS (APCI) m / zC 15 H 21 O3 + [M+H] + Theoretical value: 249.1485, measured value: 249.1488.

[0066] Example 11

[0067] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-3. The other steps were the same as in Example 1, and a yellow solid product with the structural formula shown in III-11 was obtained with a yield of 75%.

[0068]

[0069] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.25-3.94 (m, 2H), 3.66 (s, 3H), 2.78-2.53 (m, 2H), 2.33 (t, J = 7.8 Hz, 2H), 1.68-1.54 (m, 4H), 1.44 (s, 10H), 1.14-1.02 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 174.3, 155.0,79.4, 51.7, 44.0, 35.6, 31.9, 31.5, 31.4, 28.6; HRMS (APCI) m / z C 14 H 26 NO4 + [M+H] + Theoretical value: 271.1856, measured value: 271.1858.

[0070] Example 12

[0071] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar oxyalkylisourea as shown in I-12, and the other steps were the same as in Example 1, to obtain a yellow solid product with the structural formula shown in III-12, with a yield of 54%.

[0072]

[0073] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 5H), 5.11 (s, 2H), 2.49-2.32 (m, 2H), 1.83-1.73 (m, 1H), 1.66-1.61 (m, 1H), 1.55-1.45 (m, 2H), 1.40 (s, 1H), 1.32 (dd, J= 14.3, 6.4 Hz, 1H), 1.21 (s, 6H), 0.97 (d, J = 6.6 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 174.1, 136.2, 128.7,128.4, 128.4, 71.5, 66.3, 50.3, 33.5, 32.1, 30.1, 30.1, 28.8, 21.8; HRMS(APCI) m / z C 16 H 25 O3 + [M+H] + Theoretical value: 268.1798, measured value: 265.1799.

[0074] Example 13

[0075] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-13, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-3. The other steps were the same as in Example 1, and a pale yellow oily product with the structural formula shown in III-13 was obtained with a yield of 26%.

[0076]

[0077] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.27-7.23 (m, 2H),7.20 (d, J = 6.9 Hz, 1H), 7.11 (d, J = 7.4 Hz, 2H), 3.67 (s, 3H), 2.50 (s, 2H), 2.39-2.30 (m, 2H), 1.61-1.56 (m, 2H), 0.86 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 174.9, 138.9, 130.7, 127.9, 126.1, 51.7, 48.5, 36.9, 34.0, 29.7,26.4; HRMS (APCI) m / z C 14 H 21 O2 + [M+H] + Theoretical value: 221.1536, measured value: 221.1540.

[0078] Example 14

[0079] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-14, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-3. The other steps were the same as in Example 1, and a pale yellow oily product with the structural formula shown in III-14 was obtained with a yield of 34%.

[0080]

[0081] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.25-7.22 (m, 2H),7.18-7.10 (m, 3H), 3.64 (s, 3H), 2.55-2.46 (m, 2H), 2.31-2.23 (m, 2H), 1.66-1.58 (m, 2H), 1.51-1.43 (m, 2H), 0.91 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ174.9, 143.3, 128.5, 128.4, 125.8, 51.7, 44.2, 36.6, 32.8, 30.8, 29.6, 26.9; HRMS (APCI) m / z C 15 H 23 O2 + [M+H] + Theoretical value: 235.1693, measured value: 235.1695.

[0082] Example 15

[0083] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-5. The other steps were the same as in Example 1, and a white solid product with the structural formula shown in III-15 was obtained with a yield of 76%.

[0084]

[0085] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.22-3.93 (m, 2H), 2.82-2.58 (m, 2H), 2.22 (t, J = 7.7 Hz, 2H), 1.63 (d, J= 13.1 Hz, 2H), 1.57-1.50 (m, 2H), 1.44 (s, 9H), 1.43 (s, 9H), 1.39-1.32 (m, 1H), 1.13-1.02 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 173.2, 155.0, 80.3, 79.4, 44.1, 35.7, 32.9,32.0, 31.7, 28.6, 28.2; HRMS (ESI) m / z C 17 H 31 NNaO4 + [M+Na] + Theoretical value: 336.2145, measured value: 336.2151.

[0086] Example 16

[0087] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-6. The other steps were the same as in Example 1, and a yellow solid product with the structural formula shown in III-16 was obtained with a yield of 50%.

[0088]

[0089] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.46 (q, J = 8.5Hz, 2H), 4.30-3.89 (m, 2H), 2.80-2.53 (m, 2H), 2.44 (t, J = 7.7 Hz, 2H),1.71-1.56 (m, 4H), 1.49-1.33 (m, 10H), 1.17-1.03 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 172.1, 155.0, 124.5 (q, J = 27.1 Hz), 79.5, 60.3 (q, J = 36.4 Hz),44.0, 35.5, 31.2, 31.0, 28.6; 19 F NMR (376 MHz, CDCl3) δ = -73.85 (t, J= 8.5Hz); HRMS (ESI) m / z C 15 H 24 F3NNaO4 + [M+Na] + Theoretical value: 362.1550, measured value: 362.1554.

[0090] Example 17

[0091] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-7. The other steps were the same as in Example 1, and a yellow solid product with the structural formula shown in III-17 was obtained with a yield of 62%.

[0092]

[0093] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 7.41-7.27 (m, 5H),5.12 (q, J = 12.3 Hz, 2H), 4.26-3.83 (m, 2H), 2.67-2.46 (m, 3H), 1.70-1.61(m, 2H), 1.57-1.49 (m, 1H), 1.44 (s, 9H), 1.31-1.25 (m, 2H), 1.16 (d, J = 7.0Hz, 3H), 1.10-0.96 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 176.7, 154.9, 136.3,128.7, 128.4, 79.4, 66.2, 44.0, 40.8, 36.9, 34.0, 32.0, 28.6, 17.9; HRMS(ESI) m / z C 21 H 31 NNaO4 + [M+Na] + Theoretical value: 384.2145, measured value: 384.2148.

[0094] Example 18

[0095] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-8. The other steps were the same as in Example 1, and a yellow oily product with the structural formula shown in III-18 was obtained with a yield of 62%.

[0096]

[0097] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.09-4.90 (m, 1H), 4.12-4.06 (m, 2H), 3.80 (s, 3H), 2.78-2.59 (m, 2H), 1.98-1.63 (m, 5H), 1.45(s, 9H), 1.21-1.10 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 170.7 (d, J = 23.5 Hz), 154.9, 87.4 (d, J = 184.6 Hz), 79.5, 52.6, 43.8, 39.0 (d, J = 20.7 Hz), 32.4(d, J = 1.9 Hz), 32.0 (d, J = 112.0 Hz), 28.6; 19 F NMR (376 MHz, CDCl3) δ = -191.22 (ddd, J = 51.0, 33.6, 19.5 Hz); HRMS (ESI) m / z C 14 H 24 FNNaO4 + [M+Na] + Theoretical value: 312.1582, measured value: 312.1588.

[0098] Example 19

[0099] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-9. The other steps were the same as in Example 1, and a yellow solid product with the structural formula shown in III-19 was obtained with a yield of 72%.

[0100]

[0101] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.95 (d, J = 8.9Hz, 1H), 4.42-4.19 (m, 1H), 4.10-4.05 (m, 2H), 3.72 (s, 3H), 2.69-2.60 (m,2H), 1.78 (d, J = 12.8 Hz, 1H), 1.69-1.57 (m, 2H), 1.55-1.47 (m, 2H), 1.43(d, J = 2.1 Hz, 18H), 1.21-1.01 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 173.8,155.5, 154.9, 80.1, 79.4, 52.4, 51.2, 43.9, 39.8, 32.4, 31.5, 28.6, 28.4; HRMS (ESI) m / z C 19 H 34 N2NaO6 + [M+Na] + Theoretical value: 409.2309, measured value: 409.2311.

[0102] Example 20

[0103] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-10. The other steps were the same as in Example 1, and a pale yellow oily product with the structural formula shown in III-20 was obtained with a yield of 74%.

[0104]

[0105] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.23-4.08 (m, 6H),3.38 (d, J = 8.7 Hz, 1H), 2.74-2.48 (m, 2H), 2.26-2.16 (m, 1H), 1.57 (t, J =14.2 Hz, 2H), 1.44 (s, 9H), 1.29-1.24 (m, 8H), 1.16-1.09 (m, 1H), 0.92 (d,J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 169.2, 168.8, 154.9, 79.5, 61.5,61.4, 55.5, 44.2, 38.9, 37.9, 28.6, 14.3, 13.1; HRMS (ESI) m / z C 19 H 33 NNaO6 + [M+Na] + Theoretical value: 394.2200, measured value: 394.2203.

[0106] Example 21

[0107] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-11. The other steps were the same as in Example 1, and a yellow solid product with the structural formula shown in III-21 was obtained with a yield of 78%.

[0108]

[0109] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.07 (br, 2H), 3.00 (s, 3H), 2.94 (s, 3H), 2.67 (t, J = 12.8 Hz, 2H), 2.32 (t, J = 7.7 Hz, 2H), 1.67 (d, J = 14.9 Hz, 2H), 1.62-1.54 (m, 2H), 1.44 (s, 10H), 1.16-1.04 (m,2H); 13 C NMR (100 MHz, CDCl3) δ 173.0, 155.0, 79.4, 44.0, 37.4, 35.8, 35.6,31.7, 30.5, 28.6; HRMS (ESI) m / z C 15 H 28 N2NaO3 + [M+Na] + Theoretical value: 307.1992, measured value: 307.1997.

[0110] Example 22

[0111] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-12. The other steps were the same as in Example 1, and a yellow oily product with the structural formula shown in III-22 was obtained with a yield of 62%.

[0112]

[0113] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.17-4.06 (m, 2H), 2.74-2.62 (m, 2H), 2.38 (t, J = 7.0 Hz, 2H), 1.67 (d, J = 13.1 Hz, 2H), 1.64-1.56 (m, 3H), 1.45 (s, 9H), 1.14-1.07 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ154.9, 119.7, 79.6, 43.7, 35.1, 31.8, 31.5, 28.6, 14.6; HRMS (ESI) m / zC 13 H 22 N2NaO2 + [M+Na] + Theoretical value: 261.1573, measured value: 261.1576.

[0114] Example 23

[0115] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-13. The other steps were the same as in Example 1, and a white solid product with the structural formula shown in III-23 was obtained with a yield of 65%.

[0116]

[0117] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.14-4.04 (m, 2H), 3.06-2.87 (m, 4H), 2.78-2.54 (m, 2H), 1.86-1.72 (m, 2H), 1.67 (d, J = 13.6Hz, 2H), 1.60-1.51 (m, 1H), 1.44 (s, 9H), 1.38 (t,J = 7.5 Hz, 3H), 1.18-1.09(m, 2H); 13 C NMR (100 MHz, CDCl3) δ 154.9, 79.6, 49.5, 47.3, 43.8, 35.2, 31.8,28.6, 28.2, 6.8; HRMS (ESI) m / z C 14 H 27 NNaO4S + [M+Na] + Theoretical value: 328.1553, measured value: 328.1557.

[0118] Example 24

[0119] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-14. The other steps were the same as in Example 1, and a pale yellow oily product with the structural formula shown in III-24 was obtained with a yield of 71%.

[0120]

[0121] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.8Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.19-7.06 (m, 2H), 4.08 (s, 2H), 2.84-2.78(m, 2H), 2.69 (t, J = 12.3 Hz, 2H), 1.76-1.65 (m, 4H), 1.50-1.42 (m, 10H), 1.19-1.10 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 162.3, 155.0, 149.4, 136.5,122.7, 121.1, 79.3, 44.1, 36.7, 35.9, 35.6, 32.2, 28.6; HRMS (ESI) m / zC 17 H 26 N2NaO2 + [M+Na] + Theoretical value: 313.1886, measured value: 313.1889.

[0122] Example 25

[0123] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-15. The other steps were the same as in Example 1, and a yellow solid product with the structural formula shown in III-25 was obtained with a yield of 70%.

[0124]

[0125] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 4.70-4.61 (m, 1H),4.29-3.86 (m, 2H), 2.78-2.51 (m, 2H), 2.35-2.24 (m, 2H), 2.00-1.91 (m, 1H),1.88-1.77 (m, 1H), 1.72-1.59 (m, 4H), 1.59-1.45 (m, 3H), 1.43 (s, 9H), 1.39-1.27 (m, 2H), 1.15-0.98 (m, 3H), 0.96-0.81 (m, 8H), 0.73 (d, J = 7.0 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 173.3, 154.9, 79.3, 74.2, 47.1, 44.0, 41.4, 35.6,34.4, 32.0, 31.9, 31.6, 31.5, 28.6, 26.4, 23.5, 22.1, 20.9, 16.4; HRMS (ESI)m / z C 23 H 41 NNaO4 + [M+Na] + Theoretical value: 418.2928, measured value: 418.2930.

[0126] Example 26

[0127] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-11, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-16. The other steps were the same as in Example 1, and a yellow solid product with the structural formula shown in III-26 was obtained with a yield of 46%.

[0128]

[0129] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.34-5.22 (m, 1H), 4.38-3.77 (m, 4H), 2.65 (t, J 0.81 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 173.8, 155.0, 144.3, 118.9, 79.4,62.8, 45.8, 44.0, 40.9, 38.1, 36.1, 35.6, 32.0, 31.8, 31.7, 31.5, 31.5, 28.6,26.4, 21.2; HRMS (ESI) m / z C 24 H 39 NNaO4 + [M+Na] + Theoretical value: 428.2771, measured value: 428.2775.

[0130] Example 27

[0131] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-12, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-4. The other steps were the same as in Example 1, and a yellow oily product with the structural formula shown in III-27 was obtained with a yield of 85%.

[0132]

[0133] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.19-5.14 (m, 1H),4.23-4.18 (m, 2H), 3.84-3.79 (m, 2H), 2.54-2.42 (m, 1H), 2.37-2.30 (m, 1H),2.28-2.12 (m, 2H), 2.09-2.01 (m, 2H), 2.01-1.89 (m, 3H), 1.69-1.60 (m, 1H), 1.45-1.30 (m, 3H), 1.25 (s, 3H), 1.15 (d,J = 7.0 Hz, 3H), 1.13-1.10 (m, 1H),0.81 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 177.4, 148.1, 116.2, 66.0, 61.6, 45.9(45.9), 41.0, 39.5(39.5), 38.1, 36.8(36.8), 33.7, 31.8, 31.4, 26.5, 24.9,21.3(21.3), 17.2(17.1); HRMS (APCI) m / z C 17 H 29 O3 + [M+H] + Theoretical value: 281.2111, measured value: 281.2112.

[0134] Example 28

[0135] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-13, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-3. The other steps were the same as in Example 1, and a white solid product with the structural formula shown in III-28 was obtained with a yield of 51%.

[0136]

[0137] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.30-5.27 (m,0.38H), 5.26-5.23 (m, 0.62H), 3.66 (s, 3H), 2.55-2.16 (m, 3H), 2.08-1.88 (m,3H), 1.88-1.62 (m, 4H), 1.58 (d, J = 7.6 Hz, 3H), 1.55-1.45 (m, 4H), 1.45-1.35 (m, 3H), 1.31-1.24 (m, 2H), 1.23-1.04 (m, 8H), 0.98 (d, J = 16.1 Hz, 6H), 0.91 (d, J = 6.4 Hz, 3H), 0.88-0.85 (m, 6H), 0.67 (d, J = 1.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.7(174.6), 140.3(143.0), 121.6(119.8), 57.0,56.3, 51.6(51.6), 50.6(50.6), 42.5, 39.7(40.0), 39.6, 39.4, 39.1, 37.6(37.3),36.8, 36.4, 36.0(35.9), 34.1(34.1), 32.4(32.3), 32.0, 31.8, 28.9, 28.2(28.4),26.1(26.1), 24.4, 24.0(24.0), 22.7(23.0), 20.9(21.1), 19.6(19.6), 18.9, 12.0(12.0); HRMS (APCI) m / z C 31 H 53 N3O3 + [M+H] + Theoretical value: 457.4040, measured value: 457.4045.

[0138] Example 29

[0139] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-14, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-3. The other steps were the same as in Example 1, and a white solid product with the structural formula shown in III-29 was obtained with a yield of 59%.

[0140]

[0141] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 5.31-5.26 (m,0.38H), 5.15 (dd, J = 15.2, 8.5 Hz, 1H), 5.07-4.96 (m, 1H), 3.66 (s, 3H), 2.59-2.15 (m, 3H), 2.11-1.88 (m, 4H), 1.87-1.78 (m, 1H), 1.75-1.66 (m, 2H),1.62-1.56 (m, 3H), 1.54-1.48 (m, 4H), 1.47-1.36 (m, 4H), 1.30-1.19 (m, 3H),1.18-1.09 (m, 3H), 1.05-0.96 (m, 9H), 0.85 (d, J= 6.1 Hz, 3H), 0.80 (t, J =7.2 Hz, 6H), 0.69 (d, J = 1.7 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 174.7(174.6), 140.3(143.0), 138.5(138.5), 129.4, 121.6(120.0), 57.1, 56.1(56.1),51.6(51.6), 51.4, 50.6(50.6), 42.4, 40.7(40.7), 39.9(39.1) 39.6, 39.4, 37.6(37.3), 36.8, 34.1(34.1), 32.4(32.3), 32.0, 31.8, 29.1(28.9), 26.1(26.1),25.6, 24.5, 21.4, 21.2, 20.9(21.1), 19.6(19.6), 19.1, 12.4, 12.2(12.2); HRMS(APCI) m / z C 33 H 55 O2 + [M+H] + Theoretical value: 483.4197, measured value: 483.4200.

[0142] Example 30

[0143] In this embodiment, the oxyalkylisourea in Example 1 was replaced with an equimolar amount of the oxyalkylisourea shown in I-15, and the Michael receptor in Example 1 was replaced with an equimolar amount of the Michael receptor shown in II-3. The other steps were the same as in Example 1, and a white solid product with the structural formula shown in III-30 was obtained with a yield of 56%.

[0144]

[0145] The nuclear magnetic resonance (NMR) spectral data of the obtained product are as follows: 1 H NMR (400 MHz, CDCl3) δ 3.66 (d, J= 1.8Hz, 3H), 2.42-2.37 (m, 1H), 2.35-2.25 (m, 2H), 2.12-1.99 (m, 1H), 1.96-1.88(m, 1H), 1.82-1.60 (m, 6H), 1.59-1.35 (m, 5H), 1.31-1.20 (m, 6H), 1.14-1.03(m, 2H), 1.03-0.87 (m, 2H), 0.85 (s, 3H), 0.83-0.75 (m, 3H), 0.76-0.64 (m,1H); 13 C NMR (100 MHz, CDCl3) δ 221.6, 174.7, 54.9(54.9), 51.7(51.7), 48.0(46.7), 40.5(38.6), 37.7(36.8), 36.4(35.4), 35.3(35.2), 33.0(33.3), 32.8(32.7), 32.4(31.9), 36.0(31.7), 31.1(31.1), 28.8(28.8), 28.6, 27.3(25.4),21.9(21.9), 20.4(20.2), 14.0, 12.4(11.9); HRMS (APCI) m / z C 23 H 37 O3 + [M+H] + Theoretical value: 361.2737, measured value: 361.2739.

[0146] Example 31

[0147] In this embodiment, 4-fluoro-4'-methoxybenzophenone in Example 1 was replaced with an equimolar amount of anthraquinone, and the other steps were the same as in Example 1, to obtain a white solid product with the structural formula shown in III-1, with a yield of 48%.

[0148] Example 32

[0149] In this embodiment, equimolar 2,2':6',2''-terpyridine was used to replace 4,4′,4″-tritert-butyl-2,2′:6′,2″-terpyridine in Example 1. The other steps were the same as in Example 1, and a white solid product with the structural formula shown in III-1 was obtained with a yield of 44%.

[0150] Example 33

[0151] In this embodiment, N-methyldicyclohexylamine in Example 1 was replaced with equimolar dicyclohexylamine, and the other steps were the same as in Example 1, to obtain a white solid product with the structural formula shown in III-1, with a yield of 32%.

Claims

1. A method for the photoredox nickel-catalyzed Giese addition reaction of alkyl isoureas with Michael acceptors, characterized in that: The oxyalkylisourea shown in Formula I, along with the Michael acceptor, nickel catalyst, ligand, photosensitizer, and organic amine shown in Formula II, are added to an organic solvent and reacted under ultraviolet light irradiation under inert gas protection to obtain C(sp) shown in Formula III. 3 )-C(sp 3 Coupling products; In the formula, R represents any one of primary alkyl, secondary alkyl, and tertiary alkyl groups; R 1 Represents any one of hydrogen, methyl, ethyl, or fluorine; R 2 Represents any one of hydrogen, methyl, ethyl, isopropyl, phenyl, fluorine, C1-C6 alkoxycarbonyl, or protected amino groups; EWG represents benzyloxycarbonyl, nobutol-substituted ester group, lactone-substituted C1-C6 alkyl group, C1-C6 alkoxycarbonyl group, hydroxyl-substituted C1-C6 alkoxycarbonyl group, fluorinated C1-C6 alkoxycarbonyl group, C1-C6... 12 Any one of the following groups: alkyl acyl, amide, cyano, sulfonyl, pyridyl, phosphate, and pinaborate ester; The nickel catalyst is selected from any one of nickel chloride, nickel bromide, nickel iodide, nickel fluoride, nickel chloride dimethoxyethane, and nickel bromide dimethoxyethane. The ligand is selected from any one of 4,4'-di-tert-butyl-2,2'-bipyridine, 4,4'-dimethyl-2,2'-bipyridine, 4,4'-dimethoxy-2,2'-bipyridine, 1,10-phenanthroline, 4,7-diphenyl-1,10-phenanthroline, 2,2':6',2''-terpyridine, 4,4′,4″-tri-tert-butyl-2,2′:6′,2″-terpyridine, and 4'-(4-methoxyphenyl)-2,2':6',2''-terpyridine; The photosensitizer is selected from any one of benzoylnaphthalene, benzophenone, 4,4'-dimethylbenzophenone, 4-fluoro-4'-methoxybenzophenone, anthraquinone, 4,4'-dimethoxybenzophenone, and 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile; The organic amine is selected from any one of diisopropylamine, N,N-diisopropylethylamine, triethylamine, tripropylamine, tributylamine, N,N-diethylcyclohexylamine, dicyclohexylamine, and N-methyldicyclohexylamine.

2. The method for the photo-redox nickel-catalyzed Giese addition reaction of alkyl isoureas with Michael acceptors according to claim 1, characterized in that: The amount of the Michael receptor used is 1.5 to 3.0 times the molar amount of oxoalkylisourea.

3. The method for the photo-redox nickel-catalyzed Giese addition reaction of alkyl isoureas with Michael acceptors according to claim 1, characterized in that: The amount of nickel catalyst used is 5% to 15% of the molar amount of oxyalkylisourea.

4. The method for the photo-redox nickel-catalyzed Giese addition reaction of alkyl isoureas with Michael acceptors according to claim 1, characterized in that: The amount of the ligand used is 5% to 15% of the molar amount of oxyalkylisourea.

5. The method for the photo-redox nickel-catalyzed Giese addition reaction of alkyl isoureas with Michael acceptors according to claim 1, characterized in that: The amount of photosensitizer used is 5% to 15% of the molar amount of oxyalkylisourea.

6. The method for the photo-redox nickel-catalyzed Giese addition reaction of alkyl isoureas with Michael acceptors according to claim 1, characterized in that: The amount of the organic amine used is 2.0 to 4.0 times the molar amount of the oxyalkylisourea.

7. The method for the photo-redox nickel-catalyzed Giese addition reaction of alkyl isoureas with Michael acceptors according to claim 1, characterized in that: The organic solvent is selected from any one of N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, N,N-dimethylpropenylurea, tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, acetonitrile, toluene, methyl tert-butyl ether, cyclopentyl methyl ether, dichloromethane, dichloroethane, diethyl ether, ethyl acetate, and dimethyl sulfoxide.

8. The method for the photo-redox nickel-catalyzed Giese addition reaction of alkyl isoureas with Michael acceptors according to claim 1, characterized in that: The reaction was carried out under argon protection and irradiated with ultraviolet light with a wavelength of 390–395 nm for 10–20 hours.

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