Yuanzheng Cheng

Synthesis of 6‐Alkylated Phenanthridine Derivatives Using Photoredox Neutral Somophilic Isocyanide Insertion

Isocyanides have been important building blocks in synthetic chemistry since the discovery of the Ugi reaction and related multicomponent reactions. Isocyanides are isoelectronic with carbon monoxide, and thus it is not surprising that isocyanides can undergo insertion reactions (also named imidoylative reactions) to provide N-containing heterocycles which are ubiquitous in pharmaceuticals and biologically active molecules. As depicted in Scheme 1a, palladium-catalyzed isocyanide insertion and somophilic isocyanide insertion represent two typical strategies currently reported for isocyanide insertion reactions. While the palladium-catalyzed isocyanide insertions often require high reaction temperatures and have the tendency to undergo multiple consecutive insertions, the use of isocyanides as somophiles for insertion reactions holds promise for practical synthetic applications under mild reaction conditions. As a convenient approach to generate somophiles, photoredox catalysis, which usually introduces alkenes, alkynes, and aromatic rings as radical acceptors, has been widely used in the synthetic community to construct C C bonds since 2008. However, none of the reported work has employed photoredox catalysis to initiate isocyanide insertion. We consider photoredox-catalyzed isocyanide insertions to be a new synthetic protocol which circumvents the use of stoichiometric oxidants and harsh reaction conditions. As part of our ongoing work on photoredox neutral catalysis, we report herein the first example of photoredox neutral, somophilic isocyanide insertions, which provide 6-alkylated phenanthridine derivatives under mild reaction conditions. Our design of photoredox netural isocyanide insertions is shown in Scheme 1 b. The biphenyl isocyanide 1, which incorporates an isocyanide group and a somophile (phenyl ring) into the same molecule, is selected to react with an alkyl radical RC. It is envisaged that the alkyl radical RC can be generated from an alkyl bromide (2) assisted by an excitedstate photocatalyst. The radical RC adds to 1 to give the imidoyl radical I, which subsequently undergoes intramolecular homolytic aromatic substitution (HAS), oxidation, and deprotonation to afford the phenanthridine 3. Since the intramolecular HAS is faster than intermolecular radical couplings, multiple isocyanide insertions and double alkylation are avoided in this process. The stoichiometric amount of external oxidants can also be avoided because of the overall redox neutral process. It is noteworthy that the phenanthridine framework can be found in a variety of natural products possessing many important biological properties, thus making this strategy more attractive. This design was first examined using 2-isocyanobiphenyl (1a) and ethyl 2-bromopropanoate (2a) as model substrates (Table 1). The complex [fac-Ir(ppy)3] (A) was chosen as the photocatalyst because of its superior oxidation capacity in the excited state. When a solution of 1a and 2a in CH2Cl2 was irradiated with a 3 W blue LED in the presence of A and Na2HPO4 for 10 hours, the desired phenanthridine 3a was isolated in 25 % yield (Table 1, entry 1). Using CH3CN, Scheme 1. Typical isocyanide insertions and our design.

Isocyanide Insertion: De Novo Synthesis of Trifluoromethylated Phenanthridine Derivatives

A mechanistically new strategy has been described for the simple, practical, and environmentally friendly preparation of 6-(trifluoromethyl)phenanthridine derivatives using ionic isocyanide insertion from biphenyl isocyanide derivatives and Umemotos reagent. These reactions were promoted only by inorganic base in good-to-excellent chemical yields without any external stoichiometric oxidants and radical initiators.

Synthesis of isoquinolines via visible light-promoted insertion of vinyl isocyanides with diaryliodonium salts

A synthetic strategy for multi-substituted isoquinoline derivatives has been developed using visible light-promoted vinyl isocyanide insertion with diaryliodonium salts at room temperature. The methodology presented here represents the first example of isoquinoline synthesis via somophilic isocyanide insertion.

De Novo Synthesis of Polysubstituted Naphthols and Furans Using Photoredox Neutral Coupling of Alkynes with 2-Bromo-1,3-dicarbonyl Compounds

A conceptually new strategy has been described for the mild, practical, and environmentally friendly preparation of naphthols and furans using a visible-light promoted photoredox neutral approach. These reactions between accessible electron-deficient bromides and commercially available alkynes could be carried out at room temperature in good-to-excellent chemical yields without any external stoichiometric oxidants.

Direct Aromatic CH Trifluoromethylation via an Electron-Donor–Acceptor Complex

A novel electron-donor-acceptor (EDA) complex-mediated direct C-H trifluoromethylation of arenes with Umemotos reagent has been developed. This transformation has been enabled by an unprecedented EDA complex formed by Umemotos reagent and an amine, which was supported by experiments and theoretical calculations. The radical-based methodology presented here allows to access highly-functionalized trifluoromethyl arenes in up to 81 % chemical yield.

Hydrotrifluoromethylation of Unactivated Alkenes and Alkynes Enabled by an Electron-Donor–Acceptor Complex of Togni’s Reagent with a Tertiary Amine

An electron-donor-acceptor (EDA) complex between Tognis reagent and a tertiary amine has been introduced. The existence of this EDA complex was supported by NMR titration experiments. The hydrotrifluoromethylation of unactivated aliphatic alkenes and alkynes enabled by this EDA complex has also been developed. This hydrotrifluoromethylation protocol is operationally simple and promoted by a tertiary amine.

Radical Alkynyltrifluoromethylation of Alkenes Initiated by an Electron Donor-Acceptor Complex

Radical alkynyltrifluoromethylation of alkenes with actylenic triflones has been achieved. This radical chain reaction is initiated by a catalytic amount of an electron-donor-acceptor complex composed of Tognis reagent and N-methylmorpholine. This transformation proceeds under exceptionally mild and operationally simple conditions. A variety of alkenes are compatible in this protocol including aliphatic alkenes, vinyl ethers, enecarbamates, styrenes, and even acrylates, providing diverse β- trifluoromethyl alkynes in good to excellent yields.

Visible-light-promoted and photocatalyst-free trifluoromethylation of enamides

An efficient and practical method is developed for the trifluoromethylation of enamides using Umemoto’s reagent as the trifluoromethylating reagent. These reactions proceeded under visible light irradiation without any photocatalyst at room temperature in good chemical yields.