Shuhei Sumino

Carbonylation Reactions of Alkyl Iodides through the Interplay of Carbon Radicals and Pd Catalysts

Numerous methods for transition metal catalyzed carbonylation reactions have been established. Examples that start from aryl, vinyl, allyl, and benzyl halides to give the corresponding carboxylic acid derivatives have all been well documented. In contrast, the corresponding alkyl halides often encounter difficulty. This is inherent to the relatively slow oxidative addition step onto the metal center and subsequent β-hydride elimination which causes isomerization of the alkyl metal species. Radical carbonylation reactions can override such problems of reactivity; however, carbonylation coupled to iodine atom transfer (atom transfer carbonylation), though useful, often suffers from a slow iodine atom transfer step that affects the outcome of the reaction. We found that atom transfer carbonylation of primary, secondary, and tertiary alkyl iodides was efficiently accelerated by the addition of a palladium catalyst under light irradiation. Stereochemical studies support a mechanistic pathway based on the synergic interplay of radical and Pd-catalyzed reaction steps which ultimately lead to an acylpalladium species. The radical/Pd-combined reaction system has a wide range of applications, including the synthesis of carboxylic acid esters, lactones, amides, lactams, and unsymmetrical ketones such as alkyl alkynyl and alkyl aryl ketones. The design of unique multicomponent carbonylation reactions involving vicinal C-functionalization of alkenes, double and triple carbonylation reactions, in tandem with radical cyclization reactions, has also been achieved. Thus, the radical/Pd-combined strategy provides a solution to a longstanding problem of reactivity involving the carbonylation of alkyl halides. This novel methodology expands the breadth and utility of carbonylation chemistry over either the original radical carbonylation reactions or metal-catalyzed carbonylation reactions.

Synthesis of Alkyl Aryl Ketones by Pd/Light Induced Carbonylative Cross-Coupling of Alkyl Iodides and Arylboronic Acids

Alkyl aryl ketones were synthesized by the carbonylative cross-coupling reaction of alkyl iodides and arylboronic acids under combined Pd/light conditions. In this reaction, it is likely that an acylpalladium species would be formed via carbonylation of the alkyl radical, which would then undergo transmetalation of an arylboronic acid to give the corresponding acyl(aryl)palladium species, ready to undergo reductive elimination to yield the alkyl aryl ketone.

Vicinal C-Functionalization of Alkenes. Pd/Light-Induced Multicomponent Coupling Reactions Leading to Functionalized Esters and Lactones

Under photoirradiation conditions using a xenon light, and in the presence of PdCl(2)(PPh(3))(2) as a catalyst, four-component coupling reactions comprising of α-substituted iodoalkanes, alkenes, carbon monoxide, and alcohols proceeded smoothly to give functionalized esters in good yields. When alkenyl alcohols were used as acceptor alkenes, three-component coupling reactions accompanied by intramolecular esterification proceeded to give lactones in good yields. The present reaction system represents the vicinal C-functionalization of alkenes.

Pd/Light‐Accelerated Atom‐Transfer Carbonylation of Alkyl Iodides: Applications in Multicomponent Coupling Processes Leading to Functionalized Carboxylic Acid Derivatives

The atom-transfer carbonylation reaction of various alkyl iodides thereby leading to carboxylic acid esters was effectively accelerated by the addition of transition-metal catalysts under photoirradiation conditions. By using a combined Pd/hν reaction system, vicinal C-functionalization of alkenes was attained in which α-substituted iodoalkanes, alkenes, carbon monoxide, and alcohols were coupled to give functionalized esters. When alkenyl alcohols were used as acceptor alkenes, three-component coupling reactions, which were accompanied by intramolecular esterification, proceeded to give lactones. Pd-dimer complex [Pd(2)(CNMe)(6)][PF(6)](2), which is known to undergo homolysis under photoirradiation conditions, worked quite well as a catalyst in these three- or four-component coupling reactions. In this metal/radical hybrid system, both Pd radicals and acyl radicals are key players and a stereochemical study confirmed the carbonylation step proceeded through a radical carbonylation mechanism.

Carbonylative Mizoroki–Heck Reaction of Alkyl Iodides with Arylalkenes Using a Pd/Photoirradiation System

A carbonylative Mizoroki-Heck reaction using alkyl iodides was achieved with a Pd/photoirradiation system using DBU as a base. In this reaction, alkyl radicals were formed from alkyl iodides via single-electron transfer (SET) and then underwent a sequential addition to CO and alkenes to give β-keto radicals. It is proposed that DBU would abstract a proton α to carbonyl to form radical anions, giving α,β-unsaturated ketones via SET.

Photoredox-Catalyzed Hydrodifluoroalkylation of Alkenes Using Difluorohaloalkyl Compounds and a Hantzsch Ester

Photoredox-catalyzed hydrodifluoroalkylation of alkenes proceeded smoothly in the presence of a Hantzsch ester as a hydrogen source under visible light irradiation. The reaction was also applicable to the hydrodifluoroalkylation of alkynes, and a continuous photo flow reaction was also successful.

Hydroalkylation of Alkenes Using Alkyl Iodides and Hantzsch Ester under Palladium/Light System

The hydroalkylation of alkenes using alkyl iodides with Hantzsch ester as a hydrogen source occurred smoothly under a Pd/light system, in a novel, tin-free Giese reaction. A chemoselective reaction at C(sp(3))-I in the presence of a C(sp(2))-X (X = Br or I) bond was attained, which allowed for the stepwise functionalization of two types of C-X bonds in a one-pot procedure.

Synthesis of aromatic β-keto esters via a carbonylative Suzuki–Miyaura coupling reaction of α-iodo esters with arylboronic acids

Aromatic β-keto esters were synthesized via a carbonylative cross-coupling reaction of alkyl iodides and arylboronic acids in the presence of a catalytic amount of Pd catalyst. A cooperative radical and Pd-catalyzed mechanism is proposed.

Reductive Bromine Atom-Transfer Reaction

Atom-transfer radical (ATR) reactions of alkenes with R-X usually give products having new C-C and C-X bonds at the adjacent carbons. However, when the reaction was carried out under irradiation using a low-pressure Hg lamp, addition/reduction products were obtained in good yield. Hydrogen bromide, formed by H-abstraction of a bromine radical from alkenes, is likely to play a key role in the reductive ATR reaction.

One-pot synthesis of cyanohydrin derivatives from alkyl bromides via incorporation of two one-carbon components by consecutive radical/ionic reactions

Summary The consecutive radical/ionic reaction consisting of radical formylation of alkyl bromides and nucleophilic addition of a cyanide ion was investigated, which gave moderate to good yields of cyanohydrin derivatives in one-pot.