ACS catalyst: the series C-H reaction of aldoxime ether and heteroarene catalyzed by IR

Phenanthridine is an important polycyclic framework, which is widely found in natural alkaloids, bioactive molecules and organic functional materials At present, the synthesis strategy of phenanthridine mainly depends on the intramolecular cyclization reaction, that is, the formation of C-N or C-C bond of orthofunctionalized diaryl compounds to construct the intermediate pyridine ring However, the long multi-step synthesis and the pre activation of the substrate limit the rapid and diverse synthesis of phenanthridine derivatives Recently, using aromatics as alkyne analogues, Zhu group realized palladium catalyzed cyclization of o-perfluorobenzyloxime and O - (trimethylsilyl) aryltrifluoromethylsulfonate, and prepared a variety of phenanthridine compounds (scheme 1a) However, because aromatics synthons are not easy to prepare and have high reactivity, the scope of application of this reaction is limited Another strategy is to cross couple oxime and (hetero) arenes in series with C-H / C-H, and then cyclize them in one pot The substrate of this strategy is simple and easy to get, and has excellent atom and step economy However, in order to realize two separate C-C and C-N bond formation steps in one pot, it is still challenging to adjust the reaction conditions skillfully Recently, professor you Jinsong's research group of Sichuan University has realized the efficient one-step preparation of phenanthridine derivatives by IR catalyzed C-H / C-H cross coupling / cyclization of aldoxime ether and heteroaromatics in series Relevant research results were published on ACS catalyst (DOI: 10.1021 / acscan 9b04274) (source: ACS catalyst.) at the beginning of the study, the author used (E) - 2-methylbenzaldehyde o-methyloxime 1a and benzothiophene 2A as model substrates and [Cp * ircl2] 2 / agsbf 6 as catalytic system to screen the reaction conditions (Table 1) After a lot of investigation on oxidants, solvents and additives, the author finally determined the optimal conditions for the reaction as follows: under the protection of nitrogen, with [Cp * ircl2] 2 / agsbf 6 as catalyst, Ag 2O as oxidant, Zn (OTF) 2 as additive, 1a and 2A react at 140 ° C in HFIP for 24 hours, and the target product 3A can be obtained with 79% yield (source: ACS catalyst.) under the best reaction conditions, the author investigated the application range of aldoxime ether 1 and benzo heteroarene 2 (Table 2) A variety of aldoxime ether substrates with functional groups (such as alkyl, methoxy, halogen and ester) can react with benzothiophene smoothly and obtain the product (3a-3h) in medium to good yield Polycyclic aromatic (hetero) oxime ether is also a suitable substrate, and the fused ring molecule (3i-3o) is obtained in a moderate yield In addition, the reaction effect of substituted benzothiophene with benzofuran is also good (3p-3s) (source: ACS catalyst.) then, under the improved B condition, the author investigated the universality of aldoxime ether 1 and penta heteroarene 4 (Table 3) A series of thiophenes with functional groups (such as alkyl, halogen, alkoxy and ester) can be directly cyclized with a variety of aldoxime ethers in medium to good yield (5a-5o) In addition to thiophene, N-methylpyrrole and thiophene [3,2-b] thiophene can provide the cyclized products 5q and 5R in 58% and 68% yields, respectively (source: ACS catalyst.) finally, according to the experimental results of relevant mechanisms and previous reports, the author proposed the cyclic mechanism of the reaction (scheme 7) At first, [ircp * Cl 2] 2 and agsbf 6 were exchanged to form an active [Cp * IR III x 2] complex O-methyloxime is activated by the ortho-c-h bond of [Cp * IR III x 2] oriented 1a to form a five membered IR ring IM1, which reacts with benzothiophene 2A or thiophene 3a to form im2 Silver salt oxidizes im2 to form a high valent IR complex IM3, which then undergoes a reduction elimination reaction, releasing C-H / C-H cross coupled intermediates 10 or 10 ʹ and [Cp * IR II x] [Cp * IR II x] is oxidized by silver salt to generate [Cp * IR III x 2] again to enter the next catalytic cycle In this stage, Ag 2O oxidizes the intermediate 10 by single electron, and the cationic radical species IM4 is obtained After intramolecular cyclization, im5 is formed by single electron oxidation of Ag 2O The central pyridine ring was constructed by deprotonation and dearylation of im5 to obtain 6-methoxybenzothiophene [3,2-c] isoquinolinium salt 12 The final product 4a of onium salt 12 is formed by heating and deoxidizing in HFIP The coupling intermediate 10 'of thiophene is activated by IR promoted C-H bond to form a seven membered IR ring 11, which releases 4-methoxythiophene [3,2-c] isoquinolinium salt 12' and [Cp * IR I] through direct reduction elimination The final product 5A was formed by heating and deoxidizing the onium salt 12 'in HFIP AgTFA is necessary in the reaction, probably because trifluoroacetic acid anion can stabilize the seven membered IR ring 11 (source: ACS catalyst.) in summary, the author used the C − H / C − H cross coupling / cyclization strategy of aldoxime ether and heteroaromatics to simply and efficiently realize the one-step preparation of phenanthridine derivatives After fine-tuning the reaction conditions, benzothiophene and simple five component heteroaromatics can be coupled and cyclized with aldoxime ether under similar optimization conditions In-depth mechanism study shows that the first C-H / C-H cross coupling step is involved in the [IR II] - [IR iv] catalytic cycle In the second cyclization step, the reaction modes of different aromatic cyclohydrocarbons are slightly different: for benzo heteroaromatics, the free radical process initiated by Ag 2O forms benzo [3,2-c] isoquinolinium salt; but for simple five membered heteroaromatics, the C-H cyclization process involving [IR I] - [IR III] catalytic cycle produces thiophene [3,2-c] isoquinolinium salt Finally, isoquinolinium salt was heated and deoxidized in HFIP to obtain the target product It is worth noting that Ag 2O and AgTFA are the key to the cyclization of free radicals and C-H, respectively, and they can not be changed.