Shouyun Yu

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.

Visible-light-mediated fluoroalkylation of isocyanides with ethyl bromofluoroacetates: unified synthesis of mono- and difluoromethylated phenanthridine derivatives.

A practical and unified strategy has been described for the preparation of mono- and difluoromethylated phenanthridine derivatives using a visible-light-promoted alkylation and decarboxylation sequence from biphenyl isocyanides with ethyl bromofluoroacetate (EBFA) or ethyl bromodifluoroacetate (EBDFA). These reactions could be carried out at room temperature in good to excellent chemical yields. Both stepwise and one-pot procedures have been developed, which makes this strategy more attractive.

Visible-Light-Promoted Iminyl-Radical Formation from Acyl Oximes: A Unified Approach to Pyridines, Quinolines, and Phenanthridines†

A unified strategy involving visible-light-induced iminyl-radical formation has been established for the construction of pyridines, quinolines, and phenanthridines from acyl oximes. With fac-[Ir(ppy)3 ] as a photoredox catalyst, the acyl oximes were converted by 1 e(-) reduction into iminyl radical intermediates, which then underwent intramolecular homolytic aromatic substitution (HAS) to give the N-containing arenes. These reactions proceeded with a broad range of substrates at room temperature in high yield. This strategy of visible-light-induced iminyl-radical formation was successfully applied to a five-step concise synthesis of benzo[c]phenanthridine alkaloids.

Direct CH Functionalization of Enamides and Enecarbamates by Using Visible‐Light Photoredox Catalysis

Direct C-H functionalization of various enamides and enecarbamates was realized through visible-light photoredox catalyzed reactions. Under the optimized conditions using [Ir(ppy)(2)(dtbbpy)PF(6)] as photocatalyst in combination with Na(2)HPO(4), enamides such as N-vinylpyrrolidinone could be easily functionalized by irradiation of the reaction mixture overnight in acetonitrile with visible light. The scope of the reaction with respect to enamide and enecarbamate substrates by using diethyl 2-bromomalonate for the alkylation reaction was explored, followed by an investigation of the scope of alkylating reagents used to react with the enamides and enecarbamates. The results indicated that reaction takes place with quite broad substrate scope, however, tertiary enamides with an internal C=C double bond in the E configuration could not be alkylated. Alkylation of N-vinyl tertiary enamides and enecarbamates gave monoalkylated products exclusively in the E configuration. Alkylation of N-vinyl secondary enamides gave doubly alkylated products. Double bond migration was observed in the reaction of electron-deficient bromides such as 3-bromoacetyl acetate with N-vinylpyrrolidinone. A mechanism is proposed for the reaction that is different from reported reactions of SOMOphiles with a nonfunctionalized C=C double bond. Further tests on the trifluoromethylation and arylation of enamides and enecarbamates under similar conditions showed that the reactions could serve as a mild, practical, and environmentally friendly approach to various functionalized enamides and enecarbamates.

Visible-light-promoted redox neutral C-H amidation of heteroarenes with hydroxylamine derivatives.

A room temperature redox neutral direct C-H amidation of heteroarenes has been achieved. Hydroxylamine derivatives, which are easily accessed, have been employed as tunable nitrogen sources. These reactions were enabled by a visible-light-promoted single-electron transfer pathway without a directing group. A variety of heteroarenes, such as indoles, pyrroles, and furans, could go through this amidation with high yields (up to 98%). These reactions are highly regioselective, and all the products were isolated as a single regioisomer.

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.

Visible-Light-Promoted Remote C(sp3)–H Amidation and Chlorination

A visible-light-promoted C(sp(3))-H amidation and chlorination of N-chlorosulfonamides (NCSs) is reported. This remote C(sp(3))-H functionalization can be achieved in weak basic solution at room temperature with as little as 0.1 mol % of a photocatalyst. A variety of nitrogen-containing heterocycles (up to 94% yield) and chlorides (up to 93% yield) are prepared from NCSs. Late-stage C(sp(3))-H functionalization of complex and biologically important (-)-cis-myrtanylamine and (+)-dehydroabietylamine derivatives can also be achieved with excellent yields and regioselectivity.

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.

Visible-Light-Promoted and One-Pot Synthesis of Phenanthridines and Quinolines from Aldehydes and O-Acyl Hydroxylamine

A one-pot synthesis of phenanthridines and quinolines from commercially available or easily prepared aldehydes has been reported. O-(4-Cyanobenzoyl)hydroxylamine was utilized as the nitrogen source to generate O-acyl oximes in situ with aldehydes catalyzed by Brønsted acid. O-Acyl oximes were then subjected to visible light photoredox catalyzed cyclization via iminyl radicals to furnish aza-arenes. A variety of phenanthridines and quinolines have been prepared assisted by Brønsted acid and photocatalyst under visible light at room temperature with satisfactory yields.