ACS catalyst: RhCl3 · 3H2O catalyzed C (SP2) - H alkoxycarbonylation to prepare indole and pyrrole-2-carboxylate

Indole skeleton is the dominant structural unit of natural products, drugs, agricultural chemicals and other functional molecules, among which indole-2-carboxylate and its derivatives are commonly found in many active natural alkaloids and drugs (scheme 1a) Recently, the transition metal catalyzed direct C-H carbonylation of indole skeleton has become a new way to prepare carbonyl functionalized indole derivatives due to its atomic economy and simplicity Compared with the complete C3 selective C-H carbonylation of indole and Co, the direct regioselective C2 carbonylation is still less studied Up to now, only two cases of C-H carbonylation at C2 to synthesize ketone or amide (scheme 1b) have been reported Recently, Yang Lei, associate researcher of Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, reported for the first time the C2 selective alkoxycarbonylation of CO, alcohol and indole (scheme 1c) catalyzed by RhCl 3 · 3H 2O Relevant research results were published on ACS catalyst (DOI: 10.1021 / acscalal 9b01193) (source: ACS catalyst.) the author previously reported an efficient Rh / O 2 catalytic system to promote the selective oxidation of C 2-alkenylation of indoles (adv synth Catalyst 2014, 356, 1509 − 1515) In this process, the author obtained a key five element Rh (III) complex intermediate, which undergoes migration and insertion of olefins, and then reduction elimination to form the final product It is assumed that the five membered Rh (III) complex can undergo co migration and insertion, and then be attacked by nucleophiles to produce new complex molecules For this reason, the ring metallized Rh (III) complex a was synthesized first, and then in the presence of Cu (OAC) 2, a stoichiometric reaction was carried out with 1 atm CO and n-BuOH (2a, 5 equivalent) with complex a (1) Interestingly, the ester 3AA was obtained in 19% yield This shows that the alkoxycarbonylation of 1A with CO is possible (source: ACS catalyst.) subsequently, the author explored the catalytic C-H alkoxycarbonylation of 1a and 2A (5-11 equivalent) using readily available rhodium catalysts (Table 1) The results show that the required product 3AA (entry 1) can be obtained quantitatively by reaction of [Cp * RhCl 2] 2 (2.5 mol%) as catalyst, Cu (OAC) 2 (2 equivalent) as oxidant, 1a and 2A (5-11 equivalent) in DMF at 110 ℃ for 14 h in CO (1 ATM) atmosphere When the simple inorganic salt RhCl3 · 3H 2O or RhCl3 is introduced into the reaction, 1A can be completely converted into 3AA Because it is cheap and easy to obtain, the author chooses it as the best catalyst It is worth noting that the yield of the reaction is still high with the reduction of catalyst loading and 2A content (entry 19) The control experiment showed that the reaction could not be carried out without Co or rhodium catalyst (source: ACS catalyst.) after obtaining the best reaction conditions, the author first investigated the scope of application of coupling alcohol (scheme 2) N-pyrimidinyindole 1A can be successfully carbonylated with a variety of primary, secondary and tertiary alcohols at C2, and the corresponding indole-2-carboxylate (3aa-3az, 3AA '- 3aC') can be obtained The yield is good to excellent Different functional groups such as aryl, cyclopropyl, methoxy and tert butyl Dimethylsilyl ether have good tolerance This method can also be extended to the late functionalization of complex molecules, such as diosgenin and (±) - menthol reacted with 1a to obtain 3AA 'and racemic product 3az, respectively After that, the author investigated the reaction range of indole derivatives (scheme 2) Indole derivatives with electron withdrawing or electron donating substituents at different positions can successfully undergo alkoxycarbonylation with n-BuOH and Co, and the corresponding products (3ba-3sa) can be obtained in medium to excellent yields However, 3-substituted indoles are more sensitive to the electrical properties of substituents (3ba vs 3CA) In addition, 3ta can also be obtained by the reaction of benzoindole with 2a, and the yield is 80% (source: ACS catalyst.) in addition, the method can also be used to prepare ester functionalized pyrrole derivatives (scheme 4) As expected, when 2 - (1 h-pyrrole-1-yl) pyrimidine 9A was used as the substrate, the product 10aa was formed and the yield was 90% On the contrary, the C2 substituted pyrrole derivatives obtained corresponding pyrrole-2-carboxylate products 10ba and 10Ca in good yields (source: ACS catalyst.) finally, based on mechanism experiments and previous reports, the author proposed a reasonable reaction mechanism (scheme 7) At first, a five membered rhodium ring compound I was produced by the coordination of the nitrogen guiding group in 1a with the Rh (III) catalyst Then, a molecule of CO combines with rhodium ring I, and CO is inserted into rh-c bond through 1,1-migration to produce intermediate II Subsequently, alcohol 2A lost one molecule of Hoac and produced intermediate III through ligand exchange and coordination with II The intermediate III was eliminated by reduction to obtain the required products 3AA and Rh (I), which were oxidized to enter the catalytic cycle again (source: ACS catalyst.) Summary: Yang Lei's research group developed RhCl 3.3h 2O to catalyze the C-H carbonylation of indole with alcohol and Co, and synthesized a variety of indole-2-carboxylate compounds In addition, the same RH catalytic system can also be used to synthesize pyrrole-2-carboxylate and indole δ - lactone derivatives This method is the first example of transition metal catalyzed C2 selective C-H alkoxycarbonylation of indole and Co, and also the first example of rhcl3.3h 2O catalyzed direct carbonylation of C-H bond of aromatic hydrocarbon with Co.