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An improved carbonylation method allowing amide bond formation between aryl iodides and aromatic amines is presented. In contrast to usual methods based on Pd catalysis, this method does not require a phosphine ligand. The catalyst system simply employs bis(dibenzylideneacetone)palladium (0.5 mol %) and DBU (10 mol %). The method was applied to the synthesis of various aromatic amides from aryl iodides and amines, and was scaled to gram order synthesis under as low as 1 atm of carbon monoxide.

In this article, we discuss how effective photo-induced organic reactions became when applied evolving photo flow technologies through our experiences over these two last decades. We started with the flow update of traditional [2 + 2] cycloaddition using Mikroglas Dwell device as a flow reactor and a compact light source, such as blacklight, instead of a high-pressure mercury lamp. Then we examined Barton nitrite reaction using a photo flow reactor consisting of stainless-steel channels and a quartz glass top provided by DNS. Again the use of blacklight was successful. However, the energy profile of these reactions was improved further by the use of LED lights. We used a photo-flow set-up, consisting of stainless steel engraved microchannels covered by a quartz top (MiChS L-1) and a sodium lamp, for the isomerization of a fulleroid to PCBM. Photo-redox-catalyzed alkene alkylation proceeded within a shortened reaction time when the same photo flow reactor and white LED were used instead of a batch reactor. Photo-induced reductive 5-exo-dig radical cyclization and reduction of alkenyl halides proceeded smoothly, thanks to the combination of a photo flow reactor and low-pressure Hg lamp. We also applied flow technologies for photo-bromination and chlorination of C-H bonds. Photocatalytic oxidation of benzyl alcohol by molecular oxygen became quick when high-power LED irradiation was employed.

Aminocarbonylation of alkenyl iodides with CO and amines proceeded under heating to produce α,β-unsaturated amides in good yields (23 examples, 71% average yield). This catalyst-free method exhibited good functional-group tolerance, and open a straightforward access to functionalized acrylamides, as illustrated by the synthesis of Ilepcimide. A hybrid radical/ionic mechanism involving chain electron transfer is proposed for this transformation.

This Feature Article summarizes our current efforts to develop new strategies for radical carbonylation, which include electron-transfer carbonylation, site-selective C(sp3)–H carbonylation by a photocatalyst and ring-opening carbonylation.

A broad variety of unactivated acyclic and alicyclic substrates cleanly undergo site-selective alkenylation of unactivated C(sp3 )-H bonds with 1,2-bis(phenylsulfonyl)ethene in the presence of persulfate. This simple transformation furnishes (E)-2-alkylvinylphenylsulfones in up to 88 % yield. In contrast with the previously reported decatungstate protocol, the current method is applicable to alkenylation of sterically hindered C-H bonds. This important advantage significantly broadens the substrate scope, and is attributed to the compact size of the sulfate radical employed in the C-H activation and cleavage.

Diarylethenes were obtained from the corresponding ethenyl sulfones by photocatalyzed desulfonylation using UV or blue LEDs. When perylene and i-Pr2NEt were used as a photocatalyst and a sacrificin...

We report flash C-H chlorination of ethylene carbonate, which gives chloroethylene carbonate, a precursor to ethylene carbonate. A novel photoflow setup designed for a gas-liquid biphasic reaction turned out to be useful for the direct use of chlorine gas in flow. The setup employed sloped channels so as to make the liquid phase thinner, ensuring high surface to volume ratio. When ethylene carbonate was introduced to the reactor, the residence time was measured to be 15 or 30 sec, depending on the slope of the reactor to be 15 or 5 °C, respectively. Such short time exposition sufficed the photo C-H chlorination. The partial irradiation of the flow channels sufficed for the C-H chlorination, which is consistent with the requirement of photoirradiation for the purpose of radical initiation. We also found that the contaminated water negatively influenced the performance of C-H chlorination. The 100% selectivity for single chlorination required the low conversion of ethylene carbonate such as 9%, which was controlled by limited introduction of chlorine gas. At a higher conversion of ethylene carbonate such as 63%, the selectivity for mono-chlorinated ethylene carbonate over di-chlorinated ethylene carbonate was 86%. We found that the contaminated water negatively influenced the performance of the C-H chlorination.

High-power UV-LED irradiation (365 nm) effectively accelerated the decatungstate-anion-catalyzed oxidation of benzyl alcohol 1 to benzoic acid 3 via benzaldehyde 2. As the power of the UV-LED light increased, both the selectivity and yield of benzoic acid also increased. The reaction was finished within 1 h to give 3 in a 93% yield using 2 mol% of decatungstate anion catalyst. The combination of a flow photoreactor and high-power irradiation accelerated the oxidation reaction to an interval of only a few minutes.

Our previous work established a continuous-flow synthesis of pristane, which is a saturated branched alkane obtained from a Basking Shark. The dehydration of an allylic alcohol that is the key to a tetraene was carried out using a packed-bed reactor charged by an acid–silica catalyst (HO-SAS) and flow hydrogenation using molecular hydrogen via a Pd/C catalyst followed. The present work relies on the additional propensity of Pd/C to serve as an acid catalyst, which allows us to perform a flow synthesis of pristane from the aforementioned key allylic alcohol in the presence of molecular hydrogen using Pd/C as a single catalyst, which is applied to both dehydration and hydrogenation. The present one-column-two-reaction-flow system could eliminate the use of an acid catalyst such as HO-SAS and lead to a significant simplification of the production process.

A radical chain addition of allyl bromides 2 to alkenylcyclopropanes 1 resulted in [3+2] annulation to give 2-bromomethyl-alkenylcyclopentanes 3 in good yields (16 examples). In this reaction, two kinetically fast radical reactions, cyclopropylcarbinyl radical-ring-opening and 5-exo-radical cyclization, preceded the β-fragmentation of a bromine radical to make the formal cycloaddition possible.

Since photoreactions are advantageously carried out using flow microreactors due to their very narrow and shallow reactor channels, a variety of photoreactions can be carried out effectively using photo-microreactors. In this chapter, efficient flow photoreactions using a photo-microreactor, which was developed by our research group are introduced.

A broad variety of unactivated acyclic and alicyclic substrates cleanly undergo site-selective alkenylation of unactivated C(sp

Kinetically controlled Fischer glycosidation was achieved under flow conditions. β-Hydroxy-substituted sulfonic acid functionalized silica (HO-SAS) was used as an acid catalyst. This reaction directly converted aldohexoses into kinetically favored furanosides to enable the practical synthesis of furanosides. After optimization of the reaction temperature and residence time, glucofuranosides, galactofuranosides, and mannofuranosides were synthesized in good yields.

The C(sp3)–H allylation of alkanes is investigated by using allyl bromides under radical reaction conditions. In many cases, methine C–H allylation preceded methylene and methyl C–H allylation with complete or a high degree of site selectivity. The C–H allylation of allylic compounds, such as allylbenzene, gives 1,5-dienes with the SH2′ reactions of the allyl radicals occurring at the less hindered carbon.

A metal-catalyst-free intramolecular Heck carbonylation reaction of benzyl alcohols and benzyl amines with carbon monoxide under heating at 250 °C affords the corresponding benzolactones and benzolactams in good to excellent yields. A hybrid radical/ionic chain mechanism, involving electron transfer from radical anions generated by nucleophilic attack of alcohols or amines on intermediate acyl radicals, is proposed.

An efficient approach to the synthesis of perinaphthenones via the rhodium-catalyzed dehydrative annulation of 1-naphthoic acids with internal alkynes was developed. Norbornadiene can act as an acetylene equivalent to give unsubstituted perinaphthenones at the 2- and 3-positions via dehydrative annulation followed by a retro Diels-Alder reaction.

The synergistic control of the SH2 transition states of hydrogen abstraction by polar and steric effects provides a promising strategy in achieving site-selective C(sp3)–H functionalization under decatungstate anion photocatalysis. By using this photocatalytic approach, the C–H bonds of alkanes, alcohols, ethers, ketones, amides, esters, nitriles, and pyridylalkanes were functionalized site-selectively. In the remarkable case of a 2,4-disubstituted cyclohexanone bearing five methyl, five methylene, and three methine C–H bonds, one methine C–H bond in the isoamyl tether was selectively functionalized.

Tetrabutylammonium decatungstate (TBADT)-photocatalyzed C–H functionalization of alkylpyridines was investigated. Unlike alkylbenzene counterparts, alkylation of α-C–H bonds did not proceed for the reaction of 2- and 4-alkylpyridines and reluctantly proceeded for 3-alkylpyridines, which allow site-selective C(sp3)–H functionalization at nonbenzylic positions. The observed nonbenzylic site selectivities are rationalized by the polar inductive effects of pyridyl groups in the SH2 transition states. Consecutive γ-functionalization and α-bromofunctionalization were successfully carried out in selected cases.

We investigated the anionic ring opening polymerization of ethylene oxide using a microflow system with a tubular reactor. Employing alkoxy anions as an initiator, the monoalkyl-ether terminated polyethylene glycols were obtained by the microfluidic system within 30 min of residence time, which is a remarkably shortened reaction time compared with a batch system. The use of a suitable micromixer is important to obtain monoalkyl-ether terminated PEGs in high yields and small PDIs. By comparison with a batch system, the anionic ROP in the microflow was quite smooth and the distribution of the obtained polymer was narrow with the use of MeONa as a catalyst.

The bromine-radical-mediated allylation reaction of aldehydes was studied. In the presence of V-65 as radical initiator, the reaction of aldehydes with allyl bromides gave β,γ-unsaturated ketones in good yields (13 examples, 45–84%). The reaction is triggered by hydrogen abstraction from the aldehyde by bromine radical to form an acyl radical, which undergoes an SH2′-type addition–elimination reaction with allyl bromides to give coupling products with liberation of bromine radical. Three-component coupling reactions comprising aldehydes, electron-deficient alkenes, and methallyl bromide also proceeded to give δ,ε-unsaturated ketones.

Flow Fischer esterification of carboxylic acids using hydroxy-substituted sulfonic acid-functionalized silica (HO-SAS) packed into a stainless steel column reactor was investigated. HO-SAS well catalyzed flow esterification of long chain carboxylic acids with methanol within 3 min of residence time at 110 °C, and the methyl esters were quantitatively obtained. The flow esterification protocol was applied to the synthesis of a variety of esters (19 examples) and scalable synthesis was also successful.

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.

Hydroxy-substituted sulfonic acid functionalized silica (HO-SAS) in combination with THF containing a small amount of water as a solvent proved to be a reliable system for the dehydration of allylic alcohols. This process generally caused dehydration within 1 min through a column reactor charged with HO-SAS. The flow dehydration was sequenced by flow hydrogenation, which resulted in the synthesis of pristane. A scalable flow synthesis of pristane was successfully performed and afforded 10 g of pristane after an operation of 2 h. We also performed dehydration and hydrogenation by using a mixed column of HO-SAS and 10 % Pd/C.

DFT calculations were carried out to elucidate the 1,4-hydrogen shift of 1-hydroxyallyl radicals to give α-keto radicals. The 1,4-H shift is predicted to be exothermic with large energy barriers. H...

Aminocarbonylation of aromatic iodides with CO and amines gives aromatic amides under photoirradiation conditions. DFT calculations predict that methylamine adds to benzoyl radical to give a zwitte...

Site-selectivity in C(sp3)–H functionalization of aliphatic alcohols and alkanes was studied using the decatungstate anion as a photocatalyst. In the case of aliphatic alcohols, C–H bond α to the hydroxy group was preferentially functionalized. The α-site-selectivity is rationalized by polar effects imparted by the hydroxy group in the SH2 transition states. In contrast, C–H functionalization of alkanes was largely affected by steric effects.

Photoredox-catalyzed allylation of α-gem-difluorinated organohalides with allyl sulfones proceeded smoothly under visible light irradiation to give 4,4-difluoroalkenes in good yields. In the presence of catalytic Ru(bpy)3Cl2, Hantzsch ester, and diisopropylethylamine, the reaction was complete within 2 h. Using the same methodology, three-component cascade reactions to give 6,6-difluoroalkenes were carried out successfully.

The ionic liquids bearing an aromatic vinylic C–H moiety are not innocent during Pd-catalyzed cross-coupling reactions of aryl halides. Palladium-catalyzed direct C–H arylation of thiazolium and imidazolium ionic liquids took place to give arylated ionic liquids.

The full scope (30 examples) of the radical bromoallylation of alkynes using allyl bromides was studied. In this reaction, bromine radical adds to alkynes to form vinyl radicals, which then undergo an S H 2′ reaction with allyl bromides to produce good yields of 1-bromo-1,4-dienes with the liberation of a bromine radical, which creates a radical chain. The sp 2 -carbon–bromine bond of the product dienes was further functionalized via cross-coupling and carbonylation reactions.

A radical-chain addition of allyl bromides to aryl alkenes, vinyl ester, and vinyl phthalimide was studied in which elusive β-bromoalkyl radicals were trapped efficiently to give 5-bromo-1-pentenes in good to high yields (16 examples). A subsequent carbonylative radical cyclization with AIBN/Bu3SnH/CO was successful in giving the corresponding 3,5-disubstituted cyclohexanone derivatives in moderate yields. Synthesis of a piperidine ring was also successful by subsequent reaction with primary amine.

An efficient flow system was constructed for the synthesis of PCBM, which involves flow [2+1] addition of C60 and the subsequent flow photo isomerization of the resulting fulleroid to PCBM by using a flow photo-reactor in combination with a Na lamp. With the present flow system, the scalable synthesis of PCBM (0.79 g/3.3 h) was achieved by the continuous operation for 3.3 h.

Four-component coupling reactions between xanthogenates, alkenes, CO, and sulfonyl oxime ethers were studied. In the presence of hexabutylditin, working as a propagating radical reagent, the chain reaction proceeds, as expected, taking into account reagents polarities, affording the corresponding functionalized α-keto oximes. Although yields are modest, this rare one-pot four-component process is easy to carry out and the resulting compounds, bearing multiple functionalities, have the potential for further elaboration.

International audience; Primary, secondary and tertiary alkyl radicals, formed by photocatalyzed oxidation of organosilicates, can be involved efficiently in radical carbonylation with carbon monoxide (CO), which leads to a variety of unsymmetrical ketones. This work constitutes the first example of radical carbonylation under a photooxidative regime.