Research group of Professor Mo Dongliang, Guangxi Normal University: synthesis of AZA nine membered ring compounds by using the strategy of [3 + 2] cycloaddition / [3,3] rearrangement in series

The author: Professor Mo Dongliang's research group has been one of the most challenging front topics in organic synthesis due to the adverse effects of ring tension and entropy increase Aza-9-membered ring compounds are not only the core framework of natural products or alkaloids, but also a kind of very important organic synthesis intermediates There are many reports on the synthesis of aza-9-membered ring compounds by intramolecular cyclization, but few reports on the synthesis of aza-9-membered ring skeleton by intermolecular reactions At present, researchers mainly synthesize this kind of skeleton through [6 + 3], [5 + 4], [4 + 4 + 1], [4 + 3 + 2] and other cycloaddition strategies Although all of these strategies can be successfully used to construct nine membered ring compounds, the range of substrates is very limited As 1,3-dipoles, nitrone has been successfully applied to [3 + 2], [3 + 1 + 1], [3 + 3], [4 + 3], [2 + 2 + 3], [5 + 2] and many other cycloaddition reactions to construct five seven membered heterocyclic compounds The method of directly constructing nine membered cyclic compounds by intermolecular [7 + 2] cycloaddition involving nitrone has not been reported so far Aromatic alkynes are a kind of common dipole like compounds, which have high reactivity under mild conditions Many reactions involving aromatic alkynes have been successfully applied to the synthesis of natural products In recent decades, there have been many reports on the cycloaddition reaction of nitrone with aryl alkyne In 2012, Professor Larock synthesized benzoisoxazolines (scheme 1a) by the [3 + 2] cycloaddition reaction of n-alkyl / arylnitrone with phenylyne In 2015, Professor Xie Zuowei of the Chinese University of Hong Kong first developed the [5 + 2] cycloaddition reaction of n-arylnitrone and carboxyalkyne, and constructed the fused cyclocarboboron seven membered heterocyclic compound (scheme 1b) In these studies, nitrone is involved in the reaction as 3 or 5 units, and then five or seven membered heterocyclic compounds are constructed N-alkenylnitrone has been used as an intermediate or by-product of the reaction It is one of the least studied nitrone types, and its involvement in the reaction is still rarely reported In recent years, the research group of Professor Mo Dongliang of Guangxi Normal University has been devoted to the study of the synthesis and reactivity of n-alkenylnitrones, and has developed new methods for the synthesis of n-alkenylnitrones and their series of series reactions (J org Chem 2017, 82, 6417; adv synth Catalyst 2017, 359, 3545; green chem 2017, 19, 5761; green chem 2018, 20, 2722) and studied the new strategies of n − O bond breaking (J org Chem 2017, 82, 502; J org Chem 2017, 82, 4407; adv synth Catalyst 2017, 359, 4129; org Lett 2018, 20, 3527) Recently, Professor Mo Dongliang's research group reported the latest achievements on the basis of previous research: under mild conditions, n-alkenyl-a, β - unsaturated nitrone and aryl alkyne were used as raw materials to synthesize scheme 1C through [3 + 2] cycloaddition / [3,3] rearrangement This method is characterized by easy access to raw materials, wide range of substrates, gram scale preparation, nitrone as a seven unit synthon and the diversity of n − O bond breaking of AZA nine membered ring This paper is entitled "formal [7 + 2] cycloaddition of arynes with n-vinyl-a, β - unsaturatednitrones: synthesis of benzoxazones and their N-O bond cleavage", published in org Lett (DOI: 10.1021 / ACS Orglett 8b01761) The first author is Ma Xiaopan, a doctoral student, and Professor Mo Dongliang is the corresponding author Scheme 1 The reaction of nitrone with aryl alkyne (source: org Lett.) firstly, the author uses n-alkenyl-α, β - unsaturated nitrone 1a and phenylalkyne precursor 2A were used as raw materials, CSF as base and THF as solvent The reaction was tried at room temperature It was found that the target compound 3AA could be obtained in 14% yield The single crystal diffraction results further confirmed the structure of 3AA, in which the methyl and phenyl on the nine membered ring were in cis structure Then the solvent, alkali and temperature of the reaction were optimized It was found that when 1,4-dioxane, toluene and DCE were used as solvent, almost no nine membered ring compounds were obtained At room temperature, with MeCN as solvent and CSF as base, nine membered ring compounds can be obtained in 91% yield At the same time, the author prepared the nine membered ring compound (Table 1) in gram scale with 86% yield A reaction conditions: 1A (0.2 mmol), 2A (0.4 mmol, 2.0 equiv), solvent (2.0ml), additive (2.0 equiv), 5 − 20 h; B isolated yield; C 1a (1.0 g, 3.3 mmol); D CSF (1.0 equiv) Table 1 Optimization of reaction conditions (source: org Lett.) Next, n-alkenyl-a, The applicability of β - unsaturated nitrone 1 was investigated (scheme 2) When there are donor and acceptor groups on the ortho, meta and para positions of the aromatic ring of symmetric or asymmetric n-alkenyl-α, β - unsaturated nitrones, the corresponding nine membered heterocyclic compounds can be obtained in medium to excellent yields, and the heterocyclic alkenyl nitrone substrate can be well compatible When there are chain or ring alkenyl groups on the nitrogen, the target compound can also be obtained in good yield The nine membered heterocyclic compound 3YA can be obtained in 75% yield when the six membered ring is connected with alkenylnitrone protected by acetal When tert butyl was attached to the six membered ring, the target compound 3za was obtained in 54% yield with a Dr value of 1.6:1 A reaction conditions: 1 (0.2 mmol), 2A (0.4 mmol, 2.0 equiv), CSF (0.4 mmol, 2.0 equiv), MeCN (2.0 ml), 25 ° C, 5 − 48 h; B isolated yield Scheme2 N-alkenyl-a, β - unsaturated nitrone 1 substrate range (source: org Lett.) at the same time, the author also investigated the applicability of arylacetylene precursor substrate 2 (scheme 3) No matter whether the substrate 2 generates symmetrical or asymmetric aryl alkynes, the corresponding aza nine membered ring compounds can be obtained in medium to good yields When the 5-position of aryl alkyne precursor is methoxy and the 6-position is methyl, it shows very high regioselectivity and can obtain a single target compound When the 5-position of aryl alkyne precursor is methyl, 3aC can be obtained with 73% yield and good regioselectivity a Reactionconditions: 1a (0.2 mmol), 2 (0.4 mmol, 2.0 equiv), CsF (0.4 mmol,2.0 equiv), MeCN (2.0 mL), 25 °C, 8-48 h; b Isolated yield ; C the regioselectivity for aryne cycloaddition Scheme3 The range of substrate of aryl alkyne precursor substrate 2 (source: org Lett.) subsequently, the author studied the n-o-cleavage of nine membered heterocyclic compounds (scheme 4) It was found that 20 mol% of FeCl3 and 40 mol% of Cu (OAC) 2.1 were used, When 10 phen was used as co catalyst, et 2O as solvent and R 1 as vinyl group, benzopyran substituted by pyrrole could be obtained in medium yield at 80 ℃ When R 1 is an aryl group, pyrrolidine phenols can be obtained Scheme 4 Study on N − o cleavage of nine membered heterocyclic compounds (source: org Lett.) the author further reduced aza nine membered ring compound 3 by Zn / Hoac, and made 3 react at 40 ° C to form ketone substituted phenol derivative 6 (scheme 5) containing two chiral carbons Nine membered heterocyclic compounds with different substituents can be converted into corresponding phenol 6 in medium to good yields, and the Dr value of the product is 1:1-20:1 Some of the carbonyl or substituents of the substrate underisomerized (6Aa, 6ha, 6va and 6ae) Scheme 5 The reductive N-O bond was broken by Zn / Hoac (origin: org Lett.) finally, the author carried out the gram level preparation of aza-9-membered ring 3ja (scheme 6), the yield can reach 81%, and the Dr value is more than 20:1 By reducing 3ja with Zn / Hoac, the ketone substituted phenolic compound 6ja with a yield of 59% was obtained In addition, 6ja was reacted with NaBH 4, memgbr, NBS and phi (OAC) 2 respectively The products of reduction, addition and oxidation were obtained in good to excellent yields, and the Dr value was 3:1-20:1 This study provides a simple method for the construction of complex intermediates containing multiple chiral carbon Scheme 6 Gram level preparation of aza-9-membered ring 3ja (source: org Lett.) conclusion: Professor Mo Dongliang's group of Guangxi Normal University took n-alkenyl-a, β - unsaturated nitrone and aryl alkyne as raw materials and carried out [3 + 2] cycloaddition under mild conditions / [3, 3] The aza nine membered ring compounds were synthesized by rearrangement series reaction, and the [7 + 2] cycloaddition reaction of nitrone was realized This method is characterized by easy access to raw materials, wide range of substrates, large-scale preparation at the gram level, the synthesis of nitrones as seven units, and the diversity of n ￣ O bond breaking of AZA nine membered ring Professor Mo Dongliang and Professor Su Guifa of Guangxi Normal University: n-alkenyl-a, The selective synthesis of polysubstituted pyridine and isooxazoline compounds with β - unsaturated nitrone under the catalysis of iron report by the research group of Professor Mo Dongliang of Guangxi Normal University on the synthesis of 2- aminobenzonitrile derivatives by the breaking of new C - C bond of 2- arylindole catalyzed by iron