Professor Jiang Huanfeng, South China University of science and technology research group: synthesis of 3-trifluoromethyl-3-hydroxy-1-cyclohexanone by intermolecular [4 + 2] cyclization promoted by internal oxidants catalyzed by copper

Source: Professor Jiang Huanfeng's research group cyclohexanone is a kind of structural unit widely existing in many natural products, bioactive molecules and reaction intermediates In general, the construction of C (SP 3) - C (SP 3) bond by intermolecular [4 + 2] cyclization catalyzed by small organic molecules is one of the direct and effective methods for the synthesis of these compounds In recent years, transition metal catalyzed oxidation of C (SP 3) - H functional groups for the construction of C (SP 3) - C (SP 3) bonds has attracted widespread attention, usually requiring stoichiometric exogenous oxidants to promote the reaction However, this strategy has not been reported for the construction of cyclohexanone derivatives Generally speaking, the more acidic C (SP 3) - H bond will preferentially undergo functional transformation under the condition of exogenous oxidants Therefore, it is challenging to realize the functionalization of two different acidic C (SP 3) - H bonds in the same reaction and to construct two different C (SP 3) - C (SP 3) bonds The key difficulty lies in how to realize the selective functionalization of weak acid C (SP 3) - H bonds under the condition of strong acid C (SP 3) - H bonds In recent years, Professor Jiang Huanfeng's research group of South China University of technology has carried out systematic research on the promotion of carbon hydrogen functionalization strategy by endogenous oxidants (chem SOC Rev 2015, 44, 1155; acc chem Res 2018, 51, 1092; angelw Chem Int ed 2014, 53, 4205; angelw Chem Int.ed 2017, 56, 13324; angelw Chem Int.ed 2018, 57, 17215) In this work, the author uses the endogenous oxidant α, β - unsaturated ketoxime ester derivatives as C4 synthons instead of the traditional c3n1 synthons to realize the non enantioselective [4 + 2] cyclization reaction with trifluorone and synthesize a series of 3-trifluoromethyl substituted cyclohexanone compounds (Fig 1) The results were published in org Lett (org Lett 2019, 21, 4900) Fig 1 After determining the optimal reaction conditions for the functionalization of C (SP 3) - h by transition metal catalytic oxidation (source: org Lett.), the author first investigated the substrate application range of α, β - unsaturated ketoxime ester, studied the effect of electronic effect and steric effect of substituent groups on the reaction effect, and determined the spatial structure of the product by X-ray single crystal diffraction The results show that the reaction has good compatibility with α, β - unsaturated ketoxime ester derivatives (Fig 2) Figure 2 Application range of α, β - unsaturated ketoxime ester (source: org Lett.) then the author also examined the substrate application range of trifluoromethylketone (Figure 3) Through simple modification, the author further constructed a variety of trifluoromethyl substituted cyclic compounds with high efficiency by using the products obtained (Fig 4) Fig 3 Application scope of trifluoromethylketone (source: org Lett.) Fig 4 Application of product (source: org Lett.) in order to study the reaction mechanism, the author has done a series of control experiments Studies have shown that α, As an endogenous oxidant, β - unsaturated ketoxime ester derivatives are crucial to the reaction (Fig 5, a); air or oxygen atmosphere is fatal to the reaction (Fig 5, b); the reaction is unlikely to experience the reaction process of free radicals (Fig 5, c); 18 O standard records show that the oxygen atom of carbonyl in the product comes from the H 2O produced in situ in the reaction system , and trifluorone 2a is not the only oxygen source for in situ production of H 2O (Fig 5) Fig 5 Controlled experiment (source: org Lett.) based on this, the author speculated the possible reaction mechanism (Fig 6) It is suggested that the reaction may go through the catalytic cycle of Cu (I) / Cu (III) At the same time, the coordination of copper catalyst and trifluorone is propitious to produce good enantioselectivity Figure 6 Possible reaction mechanism (source: org Lett.) this achievement was recently published in org Lett (org Lett 2019, 21, 4900) The authors of this paper are: chuanlezhu, * Hao Zeng, Chi Liu, Fulin Chen and Huanfeng Jiang *.