(Invited) Catalytic Allylation of Aldehydes Using Feedstock Alkenes
Authors: Mitsunuma Harunobu , Tanabe Shun , Kanai Motomu 
Published: July 2021

The efficient production of fine chemicals from simple and readily available bulk materials such as simple alkenes is an important research area in synthetic organic chemistry. Lower alkenes are produced by one of the most common chemical processes (i.e. hydrocarbon cracking) on over 500 million metric tons scale. Development of catalytic methods which enable the direct use of these abundant organic molecules as carbon sources is highly demanded for practical and selective chemical reactions. However, despite several previous examples, the use of feedstock alkenes in synthetically useful transformations remains a challenging task.

Catalytic aldehyde allylation plays an important role in synthetic organic chemistry. Traditionally, nucleophilic allylmetal species as stoichiometric starting materials have contributed to the development of this catalytic process. Despite usefulness of this approach, however, there is room for improvement in the overall efficiency, redox/atom/step economy, and environmental sustainability. The catalytic generation of nucleophilic allylmetal species in situ from simple and feedstock alkenes via allylic sp3 C-H bond activation would be a straightforward approach. We envisioned that radical sp3 C-H bond activation followed by oxidative interception of the resulting carbon-centered radical by a metal complex is a promising strategy for the catalytic generation of organometallic species from inert substrates. We supposed the ternary hybrid catalysis comprising a photoredox catalyst, a hydrogen-atom-transfer (HAT) catalyst, and a metal catalyst would realize catalytic allylation of aldehydes with simple alkenes.

We planned to use a combination of an acridinium photoredox catalyst (Mes-Acr+) and a thiophosphoric imide (TPI) HAT catalyst to activate an allylic C-H bond of the alkenes through the HAT process. Under visible light irradiation, single-electron oxidation of TPI by a photo-excited acridinium catalyst (*Mes-Acr+) generates a sulfur-centered radical (RS•). The RS• radical abstracts the allylic C-H bond of alkenes, affording allyl radicals. Based on the mechanism of Nozaki-Hiyama allylation, we expected that a chromium(II) complex catalyst oxidatively intercepted allyl radicals, giving allylchromium(III) species. This species reacts with aldehydes via a Zimmerman-Traxler transition state to produce chromium alkoxides in an anti-selective fashion. Protonolysis by the proton generated in the HAT catalysis should afford the target homoallylic alcohols and chromium(III) species. Single-electron reduction by the photoredox catalyst (Mes-Acr•) would close the catalytic cycle with regenerating a chromium(II) complex catalyst and the oxidized form of the photoredox catalyst (Mes-Acr+).

Based on this mechanism, we studied the substrate scope with a combination of 5 mol% CrCl2, 10 mol% TPI catalyst (HAT) and 5 mol% acridinium photoredox catalyst (PC). First, the scope of alkenes was investigated. In all cases, the branched constitutional isomer was produced exclusively (>20/1). The reactions of C4 feedstocks, 1-butene and 2-butenes which are annually produced on a 105 metric ton scale, with benzaldehyde afforded the product in 94% and 100% yield, respectively, with high diastereoselectivity (14-16/1). This crotylation reaction using butenes as a starting material will significantly streamline polyketide synthesis. 3-Methyl-1-butene selectively afforded the product containing a quaternary carbon. Branched C6 alkenes were also competent substrates. Other alkenes, including cyclic, halide-containing, and ether-containing, all afforded the product in high yield. The aldehyde scope was then investigated by fixing the alkene substrate to 2-butene. A series of aromatic aldehydes bearing halogens, electron-withdrawing groups, and a boronate ester afforded the corresponding products with high diastereoselectivity. A methyl substituent at the ortho-, meta-, and para positions of the aromatic ring did not affect the results. The reactions of aliphatic aldehydes, including those containing potentially sensitive functional groups (e.g. amine, alkyl halide, sulfide and benzyl oxy moiety), also proceeded efficiently. Next, we investigated the application to highly functionalized substrates. Propranolol derivative bearing free hydroxy group were competent substrate. A dipeptide and a nucleic acid derivative containing coordinating polar functional groups such as amides and an adenine heterocycle did not affect the reaction progress. Therefore, the allylation of aldehydes mediated by the ternary hybrid catalysis realized high functional group compatibility and chemoselectivity using easily available feedstock alkenes.

In conclusion, we developed a ternary hybrid catalysis, enabling catalytic allylation of aldehydes using simple alkenes, under visible light irradiation at room temperature. This hybrid catalysis is applicable to various types of unactivated alkenes including feedstock lower alkenes. Due to the high chemoselectivity and mild conditions, the reaction was applicable to highly functionalized bioactive molecules. The asymmetric variant enabled facile access to enantiomerically and diastereomerically enriched homoallylic alcohols by introducing a chiral ligand to the chromium catalyst. Further studies to expand the scope are ongoing.

Figure 1