Rapid Access to Free Phenols by Photocatalytic Acceptorless Dehydrogenation of Cyclohexanones at Room Temperature
Lin Min,[a] Jia-Ni Lin,[a]and Wei Shu*,[a,b]
[a] Dr. L. Min, J.-N. Lin, Prof. Dr. W. Shu Shenzhen Grubbs Institute and Department of Chemistry Southern University of Science and Technology Shenzhen 518055, Guangdong (P. R. China) E-mail: shuw@sustech.edu.cn
Abstract: Phenols are ubiquitous substructures in natural products and bioactive compounds. However, practical methods for the direct construction of phenols under mild conditions remains challenging. Herein, a photocatalytic acceptorless dehydrogenative aromatization of cyclohexanones or cyclohexenones at room temperature has been developed. The reaction features the visible-light and cobalt co-catalyzed sequential dehydrogenation of in-situ formed enol silyl ethers, which are regarded as a challenging process. This operationally simple method enables the synthesis of a series of phenols with diverse substitution patterns from cyclohexanones or cyclohexenones. Moreover, diverse substituted 1,2-, 1,3-, and 1,4-benzenediols were obtained from cyclohexanediones, providing a general and straightforward method for the synthesis of phenols from simple starting materials under mild conditions.
Phenol and its derivatives widely exist in drug molecules,[1] pesticide molecules,[2] dyes,[3]flavor components (Fig. 1).[4] Moreover, phenols serve as important precursors for the synthesis of a range of value-added targets.[5] Thus, the synthesis of phenols from diverse precursors has attracted great attention form the community.[6] Industrial production of simple phenol is through Hock (cumene oxidation) process,[7] accounting for annual production of more than 106 tons. On the other hand, synthesis of phenols in laboratory heavily rely on nucleophilic substitution of arenes[8] and transition metal-catalyzed coupling with oxygen-nucleophile reagent.[9] Despite the massive progress, these methods typically require the use of strong bases[10] and high temperatures.[11] Moreover, phenols can also be prepared by oxidation the C-H bond of arenes[12]or arylboron compounds.[13] However, these methods require the use of preformed aromatic compounds as precursors. Thus, developing the synthesis of phenol from non-aromatic compound precursors is attractive.
Figure 1 . Selected natural products and drug molecules containing phenols.
Scheme 1. Dehydrogenative strategies for cyclohexanone.
In 2011, Stahl reported the seminal work on the synthesis of phenols from cyclohexanones via a palladium-catalyzed oxidative aromatization strategy under 1 atm O2 in DMSO at 80 °C.[14] Cyclohexanones undergo α-C-H activation to form Pd(Ⅱ) species, followed by C-H activation and β-H elimination to form cyclohexenones. Subsequently, cyclohexenone undergoes an iterative process to give the phenol product. Recently, Leonori reported the preparation of aniline from cyclohexanone under the dual catalytic conditions of photocatalyst and cobalt catalyst.[15] Mechanistic studies reveal that in situ generated enamine undergoes two SET oxidations, deprotonation, and release of hydrogen. This method has achieved great success in the preparation of various substituted aniline compounds. However, the photocatalytic preparation of phenol from the simple cyclohexanones remains underdeveloped, partially due to the high oxidation of silyl enol ethers and their unproductive competing nucleophilicity. Herein, we reported a photocatalytic acceptorless synthesis of phenols from cyclohexanones at room temperature.[16] The mild conditions allow for the direct dehydrogenative aromatization of cyclohexanones or cyclohexenones under the dual catalysis of light and cobalt, affording a wide range of phenols with diverse substitution patterns.
We started to investigate the feasibility of this proposal using 4-methylcyclohexanone (1a ) as the prototype substrate (Table 1). After extensive evaluation, we define the use of 1 mol% of Ir(dF(CF3)ppy2(4,4dCF3bpy)(E *red= +1.65 V)[17] and 5 mol% of Co(dmgH)2(DMAP)Cl as catalyst, TIPSOTF (1.4 eq) as activating
Table 1 . Condition evaluation for the photocatalytic dehydrogenative phenol synthesis from cyclohexanones.[a]