Using C-H activation and Rh catalyzed [4 + 1] cyclization to construct various quaternary carbon heterocyclic frameworks

The author: Wan yanlang's heterocyclic skeletons containing quaternary carbon atoms widely exist in natural products and bioactive compounds, but it is still a challenging task to develop efficient and atom economical methods to construct these skeletons The transition metal catalytic cyclization activated by C-H bond is a powerful method to construct and rapidly modify heterocycles Transition metals such as Rh (III), Ru (II), Pd (II) and CO (III) catalyze the C-H bond activation of aromatics, including guide groups and internal alkyne coupling, which have been widely used to prepare various heterocycles Recently, Chang et al Reported that [4 + 1] cyclization between nitroaromatics and alkynes catalyzed by RH (III) was carried out to synthesize indoles (j.am.chem.soc 2015, 137, 4908), in which alkynes acted as a carbon unit (scheme 1, EQ 1) for cyclization; LOH and Feng et al reported that RH (III) catalyzed benzamide and α, Scheme 1, EQ 2 (J am Chem SOC 2017, 139, 1762) is a method for [4 + 1] cyclization between α - difluoromethylene alkynes for the construction of isodihydroindole-1-one derivatives At almost the same time, Liu et al Reported that Ru (II) / Rh (III) without external oxidants catalyzed the cyclization of [4 + 1] between benzamide and propargyl alcohol, in which propargyl alcohol is a rare single carbon unit (scheme 1, eq 3）（ Org Lett 2017 , 19 , 1294）。 Recently, Ji Haitao's team from the drug R & D Department of H Lee Moffitt Cancer Center in the United States reported on J org Chem A method for the synthesis of various fused heterocyclic skeletons (DOI: 10.1021 / ACS Job 8b00397) by cyclization of [4 + 1] aromatics and propargylic alcohols with intrinsic directional groups (such as hydrazide and lactam) catalyzed by RH (III) In the research, the team retained the advantages of propargyl alcohol as a single carbon compound, explored the use of propargyl alcohol in [n + 1] type cyclization, and prepared a new skeleton compound (source: J org Chem.) the author selected compound 1a and propargyl alcohol 2A as substrates to optimize the reaction conditions such as catalyst, solvent, alkali and temperature (Table 1) Finally, it is determined that the catalyst is [Cp * rhcl2] 2, the solvent is chlorobenzene, the base is NaOAc, and the reaction effect is the best at 90 ℃ And the reaction is easy to operate without special attention to humidity and air (source: J org Chem.) after the establishment of the best reaction conditions, the author explored the application scope of heterocyclic substrate (Table 2) Generally speaking, when there are electron donor groups and electron acceptor groups on the benzene ring, they can be coupled with propargyl alcohol 2A The yield is good when electron donating groups (- me and OME) are introduced into the benzene ring of diazapharalenone derivatives, but the yield decreases when bromine substituents are introduced When m or BR is substituted, the substrate has a good reaction effect When methoxy is introduced into the intermediate of benzene ring, the product will produce regional isomer When the o-methyl substituent was used for 1h, the product could not be obtained due to the existence of steric hindrance The cyclization of propargyl alcohol and pyridazinone derivatives can proceed smoothly No matter the electron donor group (MEO -) or electron acceptor group (CL, Br and CF 3) were introduced into the benzene ring of pyridazinone (3j - 3n), the expected product was obtained in high yield In order to extend the range of substrates, we also tried to synthesize pyrazozo [1,2-a] indazolone When the substrates were substituted by Br and me, the expected products could be successfully cyclized Inspired by the above results, the author speculated that the heteroarenes with lactams could also be cyclized with cyclopropanols, which was finally confirmed by experiments In addition, 6-phenylpyridine-2 (1H) - one was coupled with propargyl alcohol 2a to obtain the pyrido [2,1-a] isoindole ketone skeleton It should be noted that the reaction of heterocyclic frameworks containing hydrazide and lactam fragments with propargylic compounds to construct fused heterocyclic compounds containing quaternary carbon is not only efficient, but also has high atomic economy (source: J org Chem.) next, the author also explored the application range of propargylic acid substrate (Table 3), and the corresponding products were obtained from the reaction of substrate 1a and various substituted propargylic acid When the phenyl of propargylic acid derivatives has electron absorbing groups (such as halogen and nitro) and electron supplying groups (me), the reaction tolerance is good When a large alkyl chain is introduced into R1 of propargyl alcohol, the reaction can also proceed smoothly For the substrate of 5-methyl-1-phenylhexyl-2-alkyne-1-ol, the product yield may be significantly reduced due to the existence of steric hindrance (3zb) In addition, when the phenyl part of propargylic acid derivatives is replaced by naphthyl, thiophene, benzyl and ethyl, the substrate can be cyclized to form fused heterocycles (source: J org Chem.) in order to study the possible reaction pathway, the author conducted the following two experiments (scheme 2) First of all, in order to determine whether propanol is oxidized to propionyl ketone under the catalysis of Rh (III), the author has carried out the reaction with propionyl ketone 2AA, but the reaction has not been carried out In addition, deuterium labeled propargylic alcohol 2a-d was used for the reaction, but no obvious deuterization was observed on α - methylene (source: J org Chem.) based on the above experimental results and previous literature, the author proposed a possible response pathway (scheme3) Firstly, the active catalyst Cp * Rh (OAC) 2 is produced by ligand exchange with sodium acetate; secondly, the substrate 1 is activated by C-H bond with rhodium catalyst to obtain pentacyclopentene I; after the coordination of propargyl alcohol 2 with metal, it is transferred and inserted to form intermediate II; subsequently, the intermediate III of malondiene is obtained by rhodium complex by capturing allyl protons At last, the complex of Cp * Rh (I) was oxidized to the active catalyst Cp * Rh (III) in air to complete the catalytic cycle (source: J org Chem.) conclusion: it is a great challenge for synthetic chemistry to construct a fused polycyclic system with quaternary carbon centers Ji Haitao's team reported [4 + 1] cyclization of propargyl alcohol compounds catalyzed by RH (III) and various heterocyclic skeletons in air, and constructed a variety of fused heterocycles containing quaternary carbon centers in good yield And the method has the following characteristics: high atom economy, no need of metal oxidant, simple operation and tolerance with various functional groups.