Merging photoredox catalysis with organocatalysis: The direct asymmetric alkylation of aldehydes

D. A. Nicewicz, D. W.C. MacMillan

Research output: Contribution to journalArticlepeer-review


Organocatalysis and photoredox catalysis are two powerful fields of molecule activation in inorganic and organic chemistry, respectively. The marriage of these two areas is exploited in this study to solve long-standing problems in asymmetric chemical synthesis. In particular, the enantioselective catalytic α-alkylation of aldehydes, a previously elusive transformation, can be achieved by employing dual inorganic electron transfer and organic catalysis technique (Fig. 1). In the photoredox catalytic cycle, Ru(bpy) 32+ 1 accepts a photon from a light source to populate high-energy intermediate *Ru(bpy)32+ 2. Intermediate 2 is then reduced by 9 generated from the organocatalytic cycle to provide electron-rich Ru(bpy)3+ 3, which undergoes single-electron transfer (SET) to the α-bromocarbonyl substrate 4. This furnishes electron-deficient alkyl radical 5 as the process returns 1 to the photoredox catalytic cycle (Fig. 2). The organocatalytic cycle begins with condensation of imidazolidinone catalyst 6 and aldehyde substrate 7 to form enamine 8. The two cycles converge upon addition of enamine 8 to radical 5. This is the key alkylation step which produces electron-rich α-amino radical 9 that undergoes SET to 2 to form iminium ion 10. Hydrolysis of 10 reconstitutes 6 to deliver the desired enantioenriched α-alkylated aldehyde. This novel asymmetric alkylation protocol was first examined using octanal and bromodiethylmalonate as coupling partners, the dual catalysts Ru(bpy) 3Cl2 1 and imidazolidinone 6, and a 15-W fluorescent light source (Figure Presented) (Table 1). The results demonstrate the successful α-alkylation of a variety of aldehydes in excellent yield and enantioselectivity (entries 1-6). Bulky groups on α-carbon (entries 4 and 6) and functional groups that are susceptible to oxidation or reduction (entries 2-5) are tolerated under these mild redox conditions. A wide range of electron-deficient α-bromocarbonyls (entries 7-12) can be used as alkylating agents in this tandem catalysis. The enantioselectivity observed in all cases is a result of selective addition of electron-deficient radical 5 to the Si face of the enamine 8. A series of experiments were conducted to validate the proposed dual-cycle pathway. Removal of 1 from standard protocol resulted in only <10% of the product. Thus without 1, only the organocatalytic cycle operates to generate radical 5 via photolytic bond homolysis. In the absence of the light source, neither of the two cycles is operative, and thus no alkylation product was observed. (Figure Presented) The use of a light source specifically tuned to the Ru(bpy)32+ MLCT absorption band (465 ± 20nm) improves the overall rate. However, only traces of products were formed by using a 465-nm photon source in the absence of Ru(bpy) 32+ 1. These results provide strong evidence of *Ru(bpy)32+ 2 participation in the catalytic cycle. Moreover, the opening of the cyclopropylacetaldehyde substrate establishes the SOMO-activated 8 as the organocatalytic intermediate involved in the key alkylation step.

Original languageEnglish (US)
Pages (from-to)73-76
Number of pages4
Issue number2
StatePublished - Mar 2010

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Biochemistry
  • Molecular Biology


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