An isatin cyclooctadiene compound and a preparation method thereof

Abstract

The application discloses an indigoid exocyclic diene compound and a preparation method. N 2' / S N 2” addition, and reaction with (E)-1-benzyl-3-(2-oxo-2-phenylene)indole-2-ketone compounds, a tandem reaction of intermolecular [4+2] / elimination occurs, and an indigoid exocyclic diene structure is obtained in a good yield and high diastereoselectivity. The application has the advantages of good diastereoselectivity, good yield, greenness, high efficiency, mild reaction conditions, convenient operation, relatively short reaction time (20-24h), and less by-products.

Description

TECHNICAL FIELD

[0001] The present application relates to an indigoid ring exo-diene compound and a preparation method. BACKGROUND

[0002] In many fields such as medicinal chemistry, chemical biology, analytical chemistry, material science, cyclic compounds containing exo-double bond have extremely wide and important application value. In many cases, the presence of exo-double bond structure plays a key role in the corresponding biological or physical and chemical activity of the compound. The special properties of exo-double bond structure are also highly valued in chemical biology and analytical chemistry. For example, locked nucleic acid is a synthetic nucleic acid analogue containing a bridged bicyclic sugar group. The antisense oligonucleotide formed by locked nucleic acid modified with exo-double bond can maintain in vivo activity while effectively reducing toxicity, laying a foundation for better treatment and diagnostic applications. The six-membered carbon ring or oxygen ring structure containing exo-unsaturated methylene is a class of characteristic structures existing in many natural products or pharmaceutically active molecules as shown below:

[0003]

[0004] For example, calcitriol is the active form of vitamin D, which plays an important role in regulating blood calcium and phosphorus concentration, and is used for the treatment of osteomalacia, chronic kidney disease, osteoporosis, etc. Correolide derivative has the activity of blocking Kv1.3 potassium ion channel of lymphocytes, can prevent T cell activation, weaken immune response, and can be used as an immunosuppressant for organ transplantation. Ottelione A extracted from the dragon tongue grass produced in the Nile Delta is a competitive inhibitor of colchicine, which has extremely strong anticancer activity. (Hiroshi Araki, Munenori Inoue, Takeyuki Suzuki, Takao Yamori, Michiaki Kohno, Kazuhiro Watanabe, Hideki Abe, and Tadashi Katoh, Enantioselective Total Synthesis of (+)-Ottelione A, (-)-Ottelione B, (+)-3-epi-Ottelione A and Preliminary Evaluation of Their Antitumor Activity, Chem. Eur. J. 2007, 13, 9866-9881.) In addition, cyclic compounds with exo-double bond structure are also important synthetic intermediates, which can participate in diverse transformation reactions through double bond to obtain more synthetic valuable products. Macrolide Δ 2,3 ,Δ 4,26Milbemycin A3 is derived from Streptomyces hygroscopicus, which has acaricidal plant protection activity; Sclerophytin A is a secondary metabolite isolated from soft corals in the waters near the Pacific island nation of Micronesia, which has strong in vitro cytotoxicity; Salvinolin A is a new crocetane diterpene compound, which is a selective kappa receptor antagonist, and its hallucinogenic activity is the strongest among known hallucinogens without nitrogen elements; Eribulin is a synthetic analogue of Halichondrin B developed by Japan's Eisai, which has been approved for the treatment of metastatic breast cancer, etc. These bioactive compounds all have exocyclic double bonds.

[0005] The currently reported synthesis methods of cyclic compounds with exocyclic double bonds can be roughly divided into four categories as follows:

[0006]

[0007] The first category is a linear molecule with an alkyne bond and other functional groups at the end, which undergoes intramolecular bond-forming ring closure reaction on the alkyne bond under the action of metal catalysts such as palladium, ruthenium, rhodium, and copper, to generate ring structure and exocyclic double bond at the same time; the second category is the intermolecular tandem cyclization reaction of two substrates containing double reaction sites under the catalysis of metal or acid-base, in which one substrate already contains a double bond or can generate a double bond in the reaction. A representative example is the tandem addition reaction of homoallyl or homoallyl alcohol with carbonyl compounds under acidic conditions to obtain an oxacyclic structure containing an exocyclic double bond; the third category is the reaction of a substrate with a pre-existing cyclic structure to generate an exocyclic olefin unit, i.e. the olefination reaction of a cyclic substrate; the fourth category is the rearrangement reaction of some relatively special substrates, which can also produce cyclic compounds with exocyclic double bonds. These reactions each have their own characteristics and shortcomings, such as the product type of intramolecular cyclization reaction is limited to the structure of linear molecules, and the preparation of substrates is relatively cumbersome; the intermolecular tandem addition reaction can utilize relatively simple substrates to construct exocyclic double bonds and cyclic structures at the same time, but the substrate type is often limited to specific reaction requirements; the olefination method of cyclic substrates requires the pre-preparation of cyclic structures; the substrate and product structure of rearrangement reaction is often specific, etc. Based on the importance of exocyclic double bond six-membered cyclic structure and the current situation of known synthesis methods, developing a high-efficiency reaction method system that can utilize simple and readily available substrates, adapt to a wide range of structures, and systematically synthesize a variety of exocyclic double bond cyclic products can provide a powerful synthetic means for the research of medicinal chemistry, chemical biology and other disciplines, improve the development efficiency of functional molecules with similar structures, and also provide a reference for the exploration of synthesis methods of related structures.

[0008] On the other hand, Morita-Baylis-Hillman reaction derived adducts have become important building blocks for nucleophilic catalytic reactions. People have tried to combine them with different electrophilic or nucleophilic reagents ((a) Ceban, V.; Putaj, P.; Meazza, M.; Pitak, M. B.; Coles, S. J.; Vesely, J.; Rios, R. Chem. Commun. 2014, 50, 7447. (b) Chen, P.; Chen, Z.-C.; Li, Y.; Ouyang, Q.; Du, W.; Chen, Y.-C. Angew. Chem. Int. Ed. 2019, 58, 4036.) or arrange a continuous series of reaction processes (Companyó, X.; Mazzanti, A.; Moyano, A.; Janecka, A.; Rios, R. Chem. Commun. 2013, 49, 1184.) or combined with palladium catalytic reactions and so on (J Liu, Z Han, X Wang, F Meng, Z Wang, & K Ding. Angew. Chem. Int. Ed. 2017, 56 (18), 5050.) to develop a variety of ring-forming or allylation reactions, and some of the methods have been used for the synthesis of some biologically active substances. SUMMARY

[0009] The purpose of the present application is to provide an isatin exo-diene compound and a preparation method thereof, which expands the exo-diene compound and the synthesis method.

[0010] The synthesis method of the isatin exo-diene compound of the present application is to use α-alkenyl MBH adduct and (E)-1-benzyl-3-(2-oxo-2-phenylene) indole-2-ketone compound as shown in formula I as raw materials, and react in the presence of a catalyst and a base, to obtain an isatin exo-diene structure after separation and purification, which has the advantages of simple process, convenient operation, relatively high yield, good diastereoselectivity, wide substrate range, and relatively few by-products. The isatin exo-diene compound is an exo-diene compound, and the exo-diene compound containing a ring in the fields of medicinal chemistry, chemical biology, analytical chemistry, and material science has extremely wide and important application value, and can provide a new metal-free efficient preparation approach for the subsequent application demand of the exo-diene compound containing a ring.

[0011] The isatin exo-diene compound of the present application has a general structure as shown in formula II:

[0012]

[0013] R in formula II 1is hydrogen or halogen or methoxy, R 2 may be Ph, p-FC6H4, p-BrC6H4, p-C3H3C6H4, p-CH3C6H4, m-ClC6H4, o-ClC6H4, 1-naphthyl, 2-thienyl, or -CH3; further, when R 2 is phenyl or naphthyl or thienyl, R 1 may be any one of 5-Br, 5-F, 5-CH3O, 6-Cl, 7-Br, 4-Cl.

[0014] The preparation method of the isatin exocycloalkene compound is to synthesize the α-alkenyl MBH adduct (Shepherd E.D., Hallside M.S., Sutro J.L., Thompson A., Hutchings M., Burton J.W. Synthesis of the cyclopentane core of pepluanin A [J]. Tetrahedron, 2020, 76 (11).) from simple and readily available raw materials in four steps, and the compound shown in formula I (Ben Niu, Yin Wei and Min Shi, Palladium catalyzed divergent cycloadditions of vinylidenecyclopropane-diesters with methyleneindolinones enabled by zwitterionic p-propargyl palladium species, Chem. Commun., 2021, 57, 4783-4786.) can be synthesized from simple and readily available raw materials, and the reaction is carried out under the action of base and catalyst in solvent under reflux, and after separation, the isatin exocycloalkene compound shown in formula II is obtained, and the chemical reaction equation is as follows:

[0015]

[0016] The isatin derivative compound of formula I includes:

[0017] (E)-1-benzyl-3-(2-oxo-2-phenylidenyl)indolin-2-one

[0018] (Z)-1-benzyl-4-chloro-3-(2-oxo-2-phenylidenyl)indolin-2-one,

[0019] (Z)-1-benzyl-5-bromo-3-(2-oxo-2-phenylidenyl)indolin-2-one,

[0020] (Z)-1 -benzyl-6-chloro-3-(2-oxo-2-phenylidenemethyl)-indol-2-one,

[0021] (Z)-1 -benzyl-5-methoxy-3-(2-oxo-2-phenylidenemethyl)-indol-2-one,

[0022] (Z)-1 -benzyl-5-fluoro-3-(2-oxo-2-phenylidenemethyl)-indol-2-one,

[0023] (Z)-1 -benzyl-7-bromo-3-(2-oxo-2-phenylidenemethyl)-indol-2-one,

[0024] (E)-1 -benzyl-3-(2-(4a,8a-dihydronaphthalen-2-yl)-2-oxoethylidene)- indol-2-one, (E)-1 -benzyl-3-(2-oxo-2-(thiophen-2-yl)ethylidene)-indol-2-one,

[0025] (E)-1 -benzyl-3-(2-(4-bromophenyl)-2-oxoethylidene)-indol-2-one,

[0026] (E)-1 -benzyl-3-(2-(4-fluorophenyl)-2-oxoethylidene)-indol-2-one,

[0027] (E)-1 -benzyl-3-(2-oxo-2-(p-tolyl)ethylidene)-indol-2-one,

[0028] (E)-1 -benzyl-3-(2-(2-chlorophenyl)-2-oxoethylidene)-indol-2-one,

[0029] (E)-1 -benzyl-3-(2-(3-chlorophenyl)-2-oxoethylidene)-indol-2-one,

[0030] (E)-1 -benzyl-3-(2-oxopropylidene)-indol-2-one,

[0031] at least one of the group consisting of

[0032]

[0033]

[0034] The reaction time can be 18-28h, and the reaction temperature can be 40-140℃; the catalyst can be triethylenediamine, triphenylphosphine, tributylphosphine or 4-dimethylaminopyridine, preferably triphenylphosphine. The base can be at least one of potassium carbonate, cesium carbonate, potassium tert-butoxide, potassium hydroxide, lithium hydroxide, preferably potassium tert-butoxide. The molar ratio of the α-alkenyl MBH adduct, the compound of formula I, the catalyst, and the base is 0.8-2:0.8-2:0.8-2:0.8-2, preferably 0.8-1:0.8-1:1.2-2:0.8-1, more preferably 1:1:2:1.

[0035] The present application uses an α-alkenyl MBH adduct as a raw material, and in the presence of a nucleophilic catalyst or a base, a S N 2' / S N 2” addition reaction occurs, and an intermolecular [4+2] / elimination reaction occurs with the (E)-1-benzyl-3-(2-oxo-2-phenylene)indolin-2-one compound, to obtain an isatin exocyclic diene structure with high selectivity (a relatively high yield of 70-90%, and less by-products). The present application has good diastereoselectivity products (dr values are all greater than 9 / 1) and good yield, green, high efficiency, mild reaction conditions, easy operation, relatively short reaction time (24h), and less by-products.

[0036] The present application uses an α-alkenyl MBH adduct and a compound represented by formula I as raw materials, and in the presence of a catalyst and a base, an isatin exocyclic diene structure is obtained after separation and purification, which has the advantages of simple process, easy operation (only one step of reaction), relatively high yield of 70-90%, good diastereoselectivity (dr values are all greater than 9 / 1), wide substrate range (R 1 / R 2 Different aliphatic groups and halogen groups can all react smoothly), and less by-products. The preparation method of the present application has wide substrate applicability, can be compatible with various functional groups, and is suitable for isatin derivative compounds with various substituents. DETAILED DESCRIPTION

[0037] The following examples are further illustrations of the present application and are set forth to aid in the understanding of the technical content of the present application, but the essential content of the present application is not limited to the following examples. Those skilled in the art can and should know that any simple change or replacement based on the essential spirit of the present application should belong to the protection scope required by the present application.

[0038] Example 1:

[0039] A synthesis method of an isatin exocyclic diene structure compound, and the synthesis route is as follows:

[0040]

[0041] Specifically, a 10 mL reaction tube equipped with a magnetic stirrer was added with an alpha-alkenyl MBH adduct (0.1 mmol) synthesized by literature (Shepherd E.D., Hallside M.S., Sutro J.L., Thompson A., Hutchings M., Burton J.W. Synthesis of the cyclopentane core of pepluanin A [J]. Tetrahedron, 2020, 76 (11).), (E)-1-benzyl-3-(2-oxo-2-phenylidene)indolin-2-one (0.1 mmol) synthesized by literature (Ben Niu, Yin Wei and Min Shi, Palladium catalyzed divergent cycloadditions of vinylidene cyclopropane-diesters with methyleneindolinones enabled by zwitterionic p-propargyl palladium species, Chem. Commun., 2021, 57, 4783-4786.), potassium tert-butoxide (0.1 mmol), triphenylphosphine (0.2 mmol), and 1.0 mL of tetrahydrofuran solvent; the reaction tube was fixed on a magnetic stirrer, and the mixture was refluxed for 24 h, and then the reaction was completed; the reaction system was separated and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain the target product (2a) with a yield of 75%, dr = 12:1. The nuclear magnetic resonance data of the compound are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.85 (dd, J = 8.1, 1.3 Hz, 2H), 7.54 (m, 1H), 7.47 (s, 1H), 7.42 (t, J = 8.1 Hz, 2H), 7.30-7.22 (m, 4H), 7.19 (td, J = 7.8, 1.2 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.97 (td, J = 7.5, 0.9 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 5.35 (s, 1H), 5.11 (s, 1H), 4.89 (q, J = 15.7 Hz, 2H), 4.37 (dd, J = 11.6, 5.2 Hz, 1H), 3.85 (s, 3H), 3.16 (dd, J = 18, 5 Hz, 1H), 2.8 (q, J = 11 Hz, 1H). There are two obvious single peaks at δ 5.35 and 5.11, which are the six-membered ring double bonds generated in the reaction. HRMS (APCI): C 30 H 25NO4, MW = 463.5330.

[0042] Example 2:

[0043] A synthetic method of isatin exo-diene compound is shown in the following scheme:

[0044]

[0045] Specifically, (Z)-l-benzyl-4-chloro-3-(2-oxo-2-phenylidenyl)indolin-2-one (lb) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylidenyl)indolin-2-one (la), and other procedures were the same as Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2b) with a yield of 70%, dr = 10: 1. The NMR data of this compound are as follows: 1H NMR (600 MHz, CDC13) δ 7.80 (s, 1H), 7.74 (d, J = 6.8 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.47 (s, 1H), 7.37 (t, J = 15.7, 7.9 Hz, 1H), 7.30-7.25 (m, 4H), 7.20 (t, J = 15.4, 7.74 Hz, 1H), 7.05 (d, J = 7.44 Hz, 1H), 6.97 (t, J = 15.06, 7.56 Hz, 1H), 6.80 (d, J = 7.86 Hz, 1H), 5.37 (s, 1H), 5.12 (s, 1H), 4.90 (q, J = 15.7 Hz, 2H), 4.30 (dd, J = 11.16, 5.16 Hz, 1H), 3.85 (s, 3H), 3.12 (dd, J = 18.9, 5.1 Hz, 1H), 2.86 (q, J = 11.2 Hz, 1H). There are two obvious singlets at δ 5.37 and 5.12, which are the six-membered exo-double bond generated in the reaction. HRMS (APCI): C 30 H 24 ClNO4, MW = 497.9750.

[0046] Example 3:

[0047] A synthetic method of isatin exo-diene compound is shown in the following scheme:

[0048]

[0049] Specifically, (Z)-l-benzyl-5-bromo-3-(2-oxo-2-phenylidenyl)indolin-2-one (lc) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylidenyl)indolin-2-one (la), and the rest was the same as in Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2c) in 70% yield, dr = 10: 1. The NMR data of this compound were as follows: 1H NMR (600 MHz, CDC13) δ 7.84 (dd, J = 8.2, 1.34 Hz, 2H), 7.55 (m, 1H), 7.45 (t, J = 15.6, 8.1 Hz, 3H), 7.27 (m, 5H), 7.10 (d, J = 1.9 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 5.37 (s, 1H), 5.11 (s, 1H), 4.90 (q, J = 15.7 Hz, 2H), 4.36 (dd, J = 11.1, 5.1 Hz, 1H), 3.85 (s, 3H), 3.12 (dd, J = 18.3, 5.1 Hz, 1H), 2.86 (q, J = 11.4 Hz, 1H). There were two distinct singlets at δ 5.37 and 5.11, which were the six-membered ring exo double bonds generated in the reaction. HRMS (APCI): C 30 H 24 BrNO4, MW = 542.4290.

[0050] Example 4:

[0051] A synthetic method of an indigoid exo-diene compound, the synthetic route being as follows:

[0052]

[0053] Specifically, (Z)-l-benzyl-6-chloro-3-(2-oxo-2-phenylidenyl)indolin-2-one (Id) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylidenyl)indolin-2-one (la), and the rest was the same as Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2d) with a yield of 72%, dr = 12: 1. The nuclear magnetic data of this compound were as follows: 1H NMR (600 MHz, CDC13) δ 7.84 (dd, J = 8.22, 1.02 Hz, 2H), 7.55 (m, 1H), 7.44 (t, J = 15.72, 8.2 Hz, 3H), 7.31-7.24 (m, 4H), 6.97-6.90 (m, 2H), 6.79 (d, J = 1.5 Hz, 1H), 5.36 (s, 1H), 5.10 (s, 1H), 4.90 (q, J = 15.4 Hz, 2H), 4.35 (dd, J = 11.3, 5.2 Hz, 1H), 3.85 (s, 3H), 3.127 (dd, J = 19.14, 4.91 Hz, 1H), 2.80 (q, J = 11.4 Hz, 1H). There were two obvious singlets at δ 5.36 and 5.10, which were the six-membered ring exo double bonds generated in the reaction. HRMS (APCI): C 30 H 24 ClNO4, MW = 497.9750.

[0054] Example 5:

[0055] A method for synthesizing an indigo ring exo diene compound, the synthesis route is as follows:

[0056]

[0057] Specifically, (Z)-l-benzyl-5-methoxy-3-(2-oxo-2-phenylidenyl)indolin-2-one (le) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylidenyl)indolin-2-one (la), and the rest was the same as Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2e) with a yield of 73%, dr = 10: 1. The nuclear magnetic data of the compound were as follows: 1H NMR (600 MHz, CDC13) δ 7.86 (dd, J = 8.2, 1.4 Hz, 2H), 7.54 (t, J = 14.7, 7.38 Hz, 1H), 7.4 (m, 3H), 7.30-7.20 (m, 4H), 6.68 (s, 3H), 5.36 (s, 1H), 5.10 (s, 1H), 4.88 (q, J = 15.78 Hz, 2H), 4.37 (dd, J = 11.3, 5.1 Hz, 1H), 3.85 (s, 3H), 3.69 (s, 3H), 3.16 (dd, J = 19.38, 5.28 Hz, 1H) 2.80 (q, J = 11.8 Hz, 1H). There were two obvious singlets at δ 5.36 and 5.10, which were the six-membered ring exo double bonds generated by the reaction. HRMS (APCI): C 31 H 27 NO5, MW = 493.5590.

[0058] Example 6:

[0059] A synthetic method of an indigo ring exo diene compound, the synthetic route being as follows:

[0060]

[0061] Specifically, (Z)-l-benzyl-5-fluoro-3-(2-oxo-2-phenylidenyl)indolin-2-one (If) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylidenyl)indolin-2-one (la), and the other procedures were the same as in Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2f) in 70% yield, dr = 10; 1. The NMR data of this compound were as follows: 1H NMR (600 MHz, CDC13) δ 7.86 (dd, J = 8.4, 1.2 Hz, 2H), 7.56 (t, J = 14.8, 7.44 Hz, 3H), 7.45 (m, 3H), 7.29 (t, J = 14.1, 7.44 Hz, 2H), 7.26 (t, J = 12.9, 5.14 Hz, 2H), 6.87 (td, J = 8.8 2.52 Hz, 1H), 6.80 (dd, J = 8.3 2.46 Hz, 1H) 6.68 (dd, J = 8.6 4.26 Hz, 1H), 5.37 (s, 1H), 5.13 (s, 1H), 4.90 (q, J = 15.7 8 Hz, 2H), 4.38 (dd, J = 11.4, 5.28 Hz, 1H), 3.85 (s, 3H), 3.18 (dd, J = 19.3, 5.16 Hz, 1H), 2.86 (q, J = 11.4 Hz, 1H). There were two obvious singlets at δ 5.37 and 5.3, which were the six-membered ring exo double bonds generated in the reaction. HRMS (APCI): C 31 H 26 FNO4, MW = 481.1689.

[0062] Example 7:

[0063] A synthetic method of an indigoid exo-diene compound, the synthetic route is as follows:

[0064]

[0065] Specifically, (Z)-l-benzyl-7-bromo-3-(2-oxo-2-phenylidenyl)indolin-2-one (lg) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylidenyl)indolin-2-one (la), and the rest was the same as in Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2g), yield 73%, dr = 10: 1. The nuclear magnetic data of this compound is: 1H NMR (600 MHz, CDC13) δ 7.82 (d, J = 7.3 Hz, 2H), 7.54 (t, J = 14.88, 7.5 Hz, 1H), 7.42 (m, 3H), 7.38 (dd, J = 8.16, 0.6 Hz, 1H), 7.26 (t, J = 14.82, 7.44 Hz, 1H), 7.20 (t, J = 13.44, 6.96 Hz, 3H), 7.02 (dd, J = 7.38, 0.6 Hz, 1H), 6.86 (t, J = 15.66, 7.98 Hz, 1H), 5.46 (d, J = 16.46 Hz, 1H) 5.37 (s, 1H), 5.27 (d, J = 16.44 Hz, 1H), 5.07 (s, 1H), 4.35 (dd, J = 11.22, 5.28 Hz, 1H), 3.85 (s, 3H), 3.16 (dd, J = 19.08, 5.2 Hz, 1H), 2.86 (q, J = 11.4 Hz, 1H). There are two obvious singlets at δ 5.37 and 5.07, which are the six-membered ring exo-double bond generated in the reaction. HRMS (APCI): C 31 H 24 BrNO4, MW = 542.4290.

[0066] Example 8:

[0067] A synthetic method of an isatin ring exo-diene compound, the synthetic route is as follows:

[0068]

[0069] Specifically, (E)-l-benzyl-3-(2-(4a,8a-dihydronaphthalen-2-yl)-2- oxovinyl)indolin-2-one (1h) was used instead of (E)-l-benzyl-3-(2-oxo-2- phenylvinyl)indolin-2-one (la), and the other procedures were the same as in Example 1. Column chromatography (petroleum ether: ethyl acetate = 5:1) gave the target product (2h) in 85% yield with dr = 10:1. The NMR data of this compound are as follows:1H NMR (600 MHz, CDC13) δ 8.44 (s, 1H), 7.95 (d, J = 8.16 Hz, 1H), 7.85 (d, J = 8.16 Hz, 3H), 7.59 (t, J = 13.98, 6.06 Hz, 1H), 7.55 (m, 2H), 7.26-7.18 (m, 4H), 7.10 (d, J = 7.44 Hz, 1H), 6.99 (td, J = 7.62, 0.72 Hz, 1H), 6.81 (d, J = 7.86 Hz, 1H) 5.37 (s, 1H), 5.15 (s, 1H), 4.88 (dd, J = 35.52, 15.28 Hz, 2H), 4.56 (dd, J = 5.28 Hz, 1H) 3.85 (s, 3H), 3.23 (dd, J = 19.08, 5.1 Hz, 1H), 2.95 (q, J = 11.4 Hz, 1H). The two distinct singlets at δ 5.37 and 5.15 are the six-membered ring exo double bonds formed in the reaction. HRMS (APCI): C 34 H 27 NO4, MW = 513.1940.

[0070] Example 9:

[0071] A synthetic method of an indigoid exo-diene compound, the synthetic route is as follows:

[0072]

[0073] Specifically, (E)-l-benzyl-3-(2-oxo-2-(thiophen-2-yl)ethylidene)indolin-2-one (2i) was synthesized using (E)-l-benzyl-3-(2-oxo-2-(thiophen-2-yl)ethylidene)indolin-2-one (li) instead of (E)-l-benzyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (la) according to the procedure described in Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2i) in 80% yield with dr = 10: 1. The NMR data of this compound are as follows: 1H NMR (600 MHz, CDC13) δ 7.77 (dd, J = 3.84, 0.9 Hz, 1H), 7.63 (dd, J = 4.92, 0.96 Hz, 1H), 7.48 (s, 1H), 7.26 (m, 1H), 7.18 (d, J = 7.38 Hz, 3H), 7.09 (m, 2H), 6.98 (td, J = 7.62, 0.84 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 5.38 (s, 1H), 5.12 (s, 1H), 4.85 (q, J = 15.52, 2H), 4.18 (dd, J = 5.28 Hz, 1H) 3.85 (s, 3H), 3.18 (dd, J = 18.96, 5.1 Hz, 1H), 3.00 (m, 1H). The two distinct singlets at δ 5.38 and 5.12 are the exocyclic double bonds of the six-membered ring formed in the reaction. HRMS (APCI): C 28 H 23 BrNO4S, MW = 469.1348.

[0074] Example 10:

[0075] A synthetic method of an indigoid exocyclic diene compound, the synthetic route is as follows:

[0076]

[0077] Specifically, (E)-l-benzyl-3-(2-(4-bromophenyl)-2-oxoethylidene)indolin-2-one (lj) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (la), and the rest was the same as in Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2j) in 76% yield, dr = 11: 1. The nuclear magnetic data of this compound is: 1H NMR (600 MHz, CDC13) δ 7.71 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.64 Hz, 2H), 7.47 (s, 1H), 7.28 (m, 4H), 7.19 (td, J = 7.74, 1.2 Hz, 1H), 7.05 (dd, J = 7.5,, 0.6 Hz, 2H), 6.97 (td, J = 7.56, 0.9 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 5.38 (s, 1H), 5.12 (s, 1H), 4.85 (q, J = 15.72, 2H), 4.30 (q, J = 5.22 Hz, 1H) 3.85 (s, 3H), 3.10 (dd, J = 18.96, 5.1 Hz, 1H), 2.87 (m, 1H). There are two obvious singlets at δ 5.38 and 5.12, which are the six-membered ring exo double bonds generated by the reaction. HRMS (APCI): C 30 H 24 BrNO5, MW = 541.0889.

[0078] Example 11:

[0079] A method for synthesizing an indigoid exo-diene compound, the synthetic route is as follows:

[0080]

[0081] Specifically, (E)-l-benzyl-3-(2-(4-fluorophenyl)-2-oxoethylidene)indolin-2-one (lk) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (la), and the other procedures were the same as in Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2k) in 74% yield with dr = 11: 1. The NMR data of this compound were as follows: 1H NMR (600 MHz, CDC13) δ 7.87 (dd, J = 8.82, 6 Hz, 2H), 7.47 (s, 1H), 7.28 (m, 4H), 7.19 (td, J = 7.8, 1.02 Hz, 1H), 7.08 (m, 3H), 6.98 (t, J = 15.12, 7.6 Hz, 1H), 6.80 (d, J = 7.86 Hz, 1H), 5.36 (s, 1H), 5.11 (s, 1H), 4.85 (q, J = 15.78, 2H), 4.33 (q, J = 5.22 Hz, 1H) 3.85 (s, 3H), 3.12 (dd, J = 18.96, 5.1 Hz, 1H), 2.90 (m, 1H). There were two distinct singlets at δ 5.36 and 5.11, which were the six-membered ring exo double bonds formed in the reaction. HRMS (APCI): C 30 H 24 FNO4, MW = 481.1689.

[0082] Example 12:

[0083] A synthetic method of an indigoid exo-diene compound, the synthetic route is as follows:

[0084]

[0085] Specifically, (E)-l-benzyl-3-(2-oxo-2-(p-tolyl)ethylidene)indolin-2-one (2I) was synthesized by replacing (E)-l-benzyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (2a) in Example 2. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2I) in 74% yield, dr = 10: 1. The NMR data of this compound are as follows: 1H NMR (600 MHz, CDC13) δ 7.76 (d, J = 8.22, 2H), 7.47 (s, 1H), 7.28 (m, 6H), 7.17 (td, J = 7.8, 1.08 Hz, 1H), 7.05 (d, J = 6.9 Hz, 1H), 6.96 (td, J = 7.62, 0.84 Hz, 1H), 6.79 (d, J = 7.68 Hz, 1H), 5.35 (s, 1H), 5.13 (s, 1H), 4.90 (q, J = 15.72, 2H), 4.33 (q, J = 5.28 Hz, 1H) 3.85 (s, 3H), 3.15 (dd, J = 19.02, 4.98 Hz, 1H), 2.85 (m, 1H), 2.40 (s, 3H). There are two distinct singlets at δ 5.35 and 5.13, which are the six-membered ring exo double bonds generated in the reaction. HRMS (APCI): C 31 H 27 NO4, MW = 477.1940.

[0086] Example 13:

[0087] A synthetic method of an indigoid exo-diene compound, the synthetic route is as follows:

[0088]

[0089] Specifically, (E)-l-benzyl-3-(2-(2-chlorophenyl)-2-oxoethylidene)indolin-2-one (1m) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (la), and the rest was the same as in Example 1. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave the target product (2m) in 74% yield, dr = 12: 1. The NMR data of this compound were as follows: 1H NMR (600 MHz, CDC13) δ 7.79 (s, 1H), 7.74 (d, J = 7.86 Hz, 1H), 7.51 (dd, J = 7.98, 1.86 Hz, 1H), 7.47 (s, 1H), 7.37 (t, J = 15.84, 7.92 Hz, 1H), 7.28 (m, 4H), 7.19 (t, J = 15.48, 7.74 Hz, 1H) 7.04 (d, J = 7.5 Hz, 1H), 6.97 (t, J = 15.12, 7.56 Hz, 1H) 6.80 (d, J = 7.86 Hz, 1H), 5.37 (s, 1H), 5.12 (s, 1H), 4.90 (q, J = 15.72, 2H), 4.30 (q, J = 5.28 Hz, 1H) 3.85 (s, 3H), 3.15 (dd, J = 18.92, 5.22 Hz, 1H), 2.85 (m, 1H). There were two distinct singlets at δ 5.37 and 5.12, which were the six-membered ring exo double bonds generated in the reaction. HRMS (APCI): C 30 H 24 ClNO4, MW = 497.1394.

[0090] Example 14:

[0091] A synthetic method of an indigoid exo-diene compound, the synthetic route being as follows:

[0092]

[0093] Specifically, (E)-l-benzyl-3-(2-(3-chlorophenyl)-2-oxoethylidene)indolin-2-one (1m) was used instead of (E)-l-benzyl-3-(2-oxo-2-phenylethylidene)indolin-2-one (la), and the rest was the same as in Example 1. Column chromatography (petroleum ether: ethyl acetate = 5:1) gave the target product (2m) in 74% yield with dr = 12:1. The NMR data of this compound were as follows:1H NMR (600 MHz, CDC13) δ 7.42 (s, 1H), 7.37 (d, J = 7.92 Hz, 4H), 7.32 (t, J = 15.12, 7.38 Hz, 1H), 7.27 (m, 2H), 7.18 (td, J = 7.74, 1.14 Hz, 1H), 7.03 (d, J = 7.44 Hz, 1H), 6.95 (td, J = 7.56, 0.78 Hz, 1H) 6.82 (d, J = 7.8 Hz, 1H), 5.30 (s, 1H), 5.10 (s, 1H), 5.09 (d, J = 15.72 Hz, 1H), 4.95 (d, J = 15.72 Hz, 1H), 4.28 (q, J = 6.06 Hz, 1H) 3.85 (s, 3H), 3.02 (dd, J = 18.92, 5.52 Hz, 1H), 2.85 (m, 1H). There were two distinct singlets at δ 5.30 and 5.10, which were the six-membered ring exo double bonds formed in the reaction. HRMS (APCI): C 30 H 24 ClNO4, MW = 497.1394.

[0094] Example 15:

[0095] A synthetic method of an isatin ring exo diene compound, the synthetic route is as follows:

[0096]

[0097] Specifically, (E)-1 -benzyl-3-(2-oxo-2-phenylene)indolin-2-one (1a) was replaced by (E)-1 -benzyl-3-(2-oxopropylidene)indolin-2-one (1o), and others were the same as Example 1. Column chromatography (petroleum ether: ethyl acetate = 5:1) gave the target product (2o) with a yield of 74%, dr = 12:1. The nuclear magnetic number of this compound:1H NMR (600 MHz, CDCI3) δ 7.39 (d, J = 7.26 Hz, 3H), 7.34 (t, J = 15.3, 7.62 Hz, 2H), 7.15 (td, J = 7.98, 1.38 Hz, 1H), 6.93 (m, 2H), 6.77 (d, J = 7.86 Hz, 1H), 5.30 (s, 1H), 5.10 (s, 1H), 5.09 (d, J = 15.72 Hz, 1H), 4.91 (d, J = 15.78 Hz, 1H), 3.85 (s, 3H), 3.02 (dd, J = 18.72, 5.46 Hz, 1H), 2.85 (m, 1H), 2.11 (s, 3H). There are two obvious singlets at δ 5.37 and 5.12, which are the six-membered ring outside double bonds generated by the reaction. HRMS (APCI): C 25 H 23 NO4, MW = 401.1627.

[0098] It should be noted that the above technical content of the present application is only an explanation and clarification to enable those skilled in the art to understand the essence of the present application, so the technical content is not used to limit the scope of the essential protection of the present application. The essential protection scope of the present application should be subject to the description in the claims. Those skilled in the art should know that any modification, equivalent replacement and improvement made on the basis of the essential spirit of the present application should be within the essential protection scope of the present application.

Claims

1. A method for preparing an indigo exocyclic diene compound, comprising reacting an α-alkenyl MBH adduct with a compound of formula... The compound shown is used as a raw material. After separation by reflux reaction in a solvent under the action of alkali and catalyst, the product of formula is obtained. The chemical reaction equation for the indigo exocyclic diene compound shown is as follows: ； wherein R 1 is hydrogen or halogen or methoxy, R 2 is Ph, p-FC6H4, p-BrC6H4, p-CH3C6H4, m-ClC6H4, o-ClC6H4, 1-naphthyl, 2-thienyl, or -CH3; Nbz is ; the base is potassium t-butoxide, the catalyst is triphenylphosphine, and the solvent is tetrahydrofuran.

2. The method of preparing isatin cycloocta-diene compounds according to claim 1, wherein, The molar ratio of the α-alkenyl MBH adduct, the compound of formula I, the catalyst, and the base is 0.8-2:0.8-2:0.8-2:0.8-2.

3. The method for preparing the indigo exocyclic diene compound as described in claim 1, characterized in that, said alpha-alkenyl MBH adduct, formula The amount of substance of compound, catalyst, base = 1 : 1 : 2 :

1.

4. The method of preparing isatin cycloocta-diene compounds as claimed in claim 1, wherein, The isatin derivative of formula I is at least one of: (E)-1-benzyl-3-(2-oxo-2-phenylethylidene)indolin-2-one, (Z)-1-benzyl-4-chloro-3-(2-oxo-2-phenylethylidene)indolin-2-one, (Z)-1-benzyl-5-bromo-3-(2-oxo-2-phenylethylidene)indolin-2-one, (Z)-1-benzyl-6-chloro-3-(2-oxo-2-phenylethylidene)indolin-2-one, (Z)-1-benzyl-5-methoxy-3-(2-oxo-2-phenylethylidene)indolin-2-one, (Z)-1-benzyl-5-fluoro-3-(2-oxo-2-phenylethylidene)indolin-2-one, (Z)-1-benzyl-7-bromo-3-(2-oxo-2-phenylethylidene)indolin-2-one, (E)-1-benzyl-3-(2-(4a,8a-dihydronaphthalen-2-yl)-2-oxoethylidene)indolin-2-one, (E)-1-benzyl-3-(2-(4-fluorophenyl)-2-oxoethylidene)indolin-2-one, (E)-1-benzyl-3-(2-(4-bromophenyl)-2-oxoethylidene)indolin-2-one, (E)-1-benzyl-3-(2-(4-fluorophenyl)-2-oxoethylidene)indolin-2-one, (E)-1-benzyl-3-(2-(4-fluorophenyl)-2-oxoethylidene)indolin-2-one, (E)-1-benzyl-3-(2-(4-fluorophenyl)-2-oxoethylidene)indolin-2-one, (E)-1-benzyl-3-(2-(4-fluorophenyl)-2-oxoethylidene)indolin-2-one, (E)-1-benzyl-3-(2-oxopropylidene)indolin-2-one. The reaction time is 18-28 h, and the reaction temperature is 40-140 °C.

5. The method for preparing the indigo exocyclic diene compound as described in claim 1, characterized in that, The separation is performed by column chromatography using petroleum ether: ethyl acetate = 5:1 ~ 4:1, v / v as eluent.

6. The method of preparing isatin cycloocta-diene compounds as claimed in claim 1, wherein, The separation is performed by column chromatography using petroleum ether: ethyl acetate = 5:1 ~ 4:1, v / v as eluent.

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