Decarboxylative 1,6-Conjugate Addition of α-Keto Acids with para-Quinone Methides Enabled by Photoredox Catalysis

Abstract

Arylated and α,α'-diarylated carbonyls are an important class of building blocks and widely found in biologically active natural and unnatural molecules. The most popular approach to access α-arylated and α,α′-diarylated carbonyls involves transition-metal-catalyzed cross-coupling reactions and metal-free coupling reactions, which always request harsh conditions or high catalytic loading. Visible-light photoredox catalysis, a novel and green catalytic strategy, has recently received increasing attention from chemists and been widely applied to organic synthesis in the past years. Inspired by the recent process of the visible light photocatalytic generation and exploration of α-keto acids as the precursor for acyl radical in decarboxylative coupling reactions and 1,4-Michael addition reactions, we found that, however, expand their utilization in more complex systems, such as 1,6-conjugate addition with electron deficient olefins, remains underdeveloped, particularly due to the difficult to design the appropriate substrate, and the harsh conditions often required for metal-catalyzed redox neutral decarboxylation. Here, we report a photoredox catalytic CC bond formation reaction that enabled by visible-light. The versatility of this protocol has been portrayed by using a wide range of stable and easily accessible aromatic α-keto acids as well as p-QMs. This synthetic strategy also offers access to 24 kinds of different α-keto-α,α'-diarylated ketones in moderate to excellent yields under mild conditions. A representative procedure for the reaction is as follows: 2-oxo-2-phenylacetic acid 1a (0.10 mmol), the p-QM (2,6-di-tert-butyl-4-(4-methoxybenzylidene)cyclohexa-2,5-dien-1-one) 2a (0.12 mmol), photocatalyst Ir[dF(CF 3)PPy] 2 (dtbbpy)PF 6 (0.001 mmol) and K 2 HPO 4 (0.12 mmol) were dissolved in DCM (1 mL). Then, the resulting mixture was degassed and refilled with N 2 via 'freeze-pump-thaw' procedure (3 times). After that, the solution was stirred at a distance of ca. 5 cm from a 36 W blue LEDs at room temperature for about 12 h with TLC monitoring. Upon completion of the reaction, the crude product was purified by flash chromatography on silica gel (hexane/ethyl acetate) to give the desired product 3.

Visible Light-Driven Radical-Mediated C–C Bond Cleavage/Functionalization in Organic Synthesis

“…Then, acyl radical 191-A is trapped by the Michael acceptor to afford new carbon radical 191-B , which further oxidizes the reduced form of photocatalyst Ir­(II) to regenerate ground-state photocatalyst Ir­(III), together with the formation of 1,4-addition product 200 or 203 after protonation. Unlike the work of Fu and Wang, in Zhou’s work, corresponding anion 191-C would undergo β-fluoride elimination to give the final product 201 . On the other hand, in Zhu’s work, direct fluorine atom transfer from Selectfluor to benzylic radical 191-B and subsequent elimination of HF could deliver α,β-unsaturated ketone 202 .…”

“…In 2015, Fu, Shang, and co-workers reported the addition of α-keto acids 191 to various Michael acceptors 196 , including α,β-unsaturated esters, ketones, amides, aldehydes, nitriles, and sulfones under visible light irradiation (Scheme ). Subsequently, the groups of Zhou, Zhu, and Wang extended the scope of Michael acceptors to α-trifluoromethyl alkenes 197 , aryl alkenes 198 , and para -quinone methides 199 , allowing the synthesis of a wide variety of carbonyl compounds 201 , 202 , and 203 in moderate to good yields. These methodologies exhibited broad substrate scopes and high functional group compatibility.…”

Visible-Light-Triggered Cyanoalkylation of para-Quinone Methides and Its Application to the Synthesis of GPR40 Agonists

“…However, very little further research has been reported . Moreover, the direct radical 1,6-addition of conjugated unsaturated carbonyl compounds is still rare (Scheme b) …”