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A Pd-catalyzed carbonylative double cyclization approach to a novel class of S,O-bicyclic heterocycles is presented. It is based on the reaction between readily available 5-(methylthio)pent-1-yn-3-ols with CO in the presence of the PdI2/KI catalytic system carried out under oxidative conditions with oxygen as external oxidant. The process takes place through an ordered sequence of steps involving an initial 5-exo-dig S-cyclization (by intramolecular nucleoplilic attack by the thiomethyl group to the triple bond activated by coordination to the palladium center), followed by S-demethylation (by attack by the iodide anion), carbon monoxide insertion, O-cyclization (by intramolecular nucleophilic displacement of the hydroxyl group to the ensuing acylpalladium intermediate), and Pd(0) reoxidation. The method allows the construction of previously unreported 6,6a-dihydrothieno[3,2-b]furan-2(5H)-ones starting from simple substrates (5-(methylthio)pent-1-yn-3-ols and CO) with the formation of 3 new bonds and two cycles in one step, and has been successfully applied to the synthesis of variously substituted products (57–81 %, 17 examples).

From simple linear cinnamyl ethers to complex tetrahydropyranes with high diastereocontrol via Ag(i) initiation of a cationic chain.

We present herein the first synthesis of tetrahydropyranes promoted by a silver salt. Cinnamyl ethers undergo a formal dimerization affording the target heterocycle

Trinuclear all-metal aromatic clusters are an original class of molecules with a cyclic and planar metal core. Characterized by peculiar metal-metal delocalized bonds, they represent a new frontier in transition-metal catalysis. We report a study on C-C-forming reactions of polyunsaturated substrates catalyzed by trinuclear all-metal aromatic palladium clusters. The synthesis of two new families of tricyclic compounds was obtained with a broad functional group tolerance under mild reaction conditions. A peculiar regio- and diastereoselectivity characterized the method, demonstrating that trinuclear palladium complexes are complementary to their popular mononuclear peers. Furthermore, preliminary studies on the mechanism of these polycyclization reactions revealed unique features of the homogeneous catalytic system.

Katritzky salts have emerged as effective alkyl radical sources upon metal- or photocatalysis. These are typically prepared from the corresponding triarylpyrylium ions, in turn an important class of photocatalysts for small molecules synthesis and photopolymerization. Here, a flow method for the rapid synthesis of both pyrylium and Katrizky salts in a telescoped fashion is reported. Moreover, several pyrylium salts were tested in the photoinduced RAFT polymerization of vinyl ethers under flow and batch conditions.

The first example of a palladium-catalyzed oxidative carbonylative S-cyclization process carried out under aerobic conditions is reported. The method is based on the use of the PdI2/KI catalytic system and an acetylenic substrate bearing a sulfurated group in suitable position for attacking the coordinated triple bond. To avoid the possible oxidation of a free thiol group, a methylthio group was used as sulfur nucleophile, since the methyl group on sulfur could be removed under the reaction conditions by reaction with the iodide anion to give methyl iodide. In particular, we have employed as substrates 1-(methylthio)-3-yn-2-ols, which, upon S-cyclization, demethylation, and alkoxycarbonylation, led to thiophene-3-carboxylic esters in one step, in alcohols as external nucleophile and solvents, and under 40 atm of a 4:1 mixture of CO-air (air being the source of oxygen, used as external oxidant). The Pd(0) species deriving from the alkoxycarbonylation process was reoxidized back to catalytically active PdI2 by the action of oxygen in combination with the hydrogen iodide ensuing from the alkoxycarbonylation step and from water attack to methyl iodide. This new synthetic transformation could be successfully applied to a variety of differently substituted 1-(methylthio)-3-yn-2-ols, including substrates bearing geminal dialkyl substituents.

A chemoselective method for the carbonylation of allylic substrates CH2=CHCH2X (X= OAc, OC(O)CH2CN, OPh, OEt, OC(O)OPh, OC(O)OiBu, N(H)C(O)Ph, N(Ph)C(O)Ph, N(H)Boc, N(Ph)Boc, Ph, CO2Bn, CN), leading to alkyl succinates with preservation of the X group, under Pd(II)-catalyzed oxidative carbonylation conditions, has been developed. Our method shows a completely different inverse chemoselectivity with respect to the "classical" substitutive carbonylation of the allyl compounds, which is known to provide beta,gamma-unsaturated carbonyl derivatives through the formation of a p-allylpalladium intermediate. An accurate study, carried out using allyl acetate as model substrate, allowed to maximize the selectivity in the envisioned 2-CH2X substituted succinates. The best catalyst is generated in situ by mixing Pd(TFA) 2 (TFA= trifluoroacetate) and the N,N'-di(anthracen-9-yl)butane-2,3-diimine ligand. pBenzoquinone was used as oxidant in presence of benzyl alcohol, which acts as a nucleophile and as a solvent, under 4 bar of CO at 20 degrees C. A combined effect of the ligand and the nucleophile, rationalized through DFT calculations, has been observed both in promoting the bis-alkoxycarbonylation process and in preventing p-allylpalladium-mediated side reactions, allowing the attainment of succinate derivatives with moderate to good yields.

We report the first example of successful heterogenization of the classical PdI42- carbonylation catalyst, achieved in two simple steps from ionic liquid-functionalized multi-walled carbon nanotubes (MWCNTs). The newly developed materials (PdI4@MWCNT-imi-X, X = Br, I) present the PdI42- anion supported on an imidazolium network (imi) grown on MWCNTs and have been fully characterized. The activity of PdI4@MWCNT-imi-X has been successfully tested in a paradigmatic carbonylation reaction, the oxidative monoaminocarbonylation of 1-alkynes with amines to give high value added 2-ynamides (obtained in good yields, 50–84%, starting from various substrates). The heterogeneous catalyst could be easily recycled and showed a good efficiency even after the fourth recycle, when deactivation began to occur owing to the formation of inactive Pd(0) species, as confirmed by XPS analysis. Hot and cold filtration tests were compatible with an essentially heterogeneous catalytic process, and limited metal contamination in the final organic compounds occurred, as assessed by ICP-MS analysis of representative carbonylation products.

In the article mentioned in the title, the authors have tried to demonstrate that, in the previously reported Pd/iodide-catalyzed oxidative carbonylations of amines to give ureas, the role of iodide ligands was essentially to “etch” the stainless steel autoclaves where the process was performed, releasing in solution small amounts of iron salts. These latter iron species were, in their opinion, the real co-catalysts of the reaction, through the presumed formation of more active Pd/Fe bimetallic species. However, no solid experimental evidence corroborating this hypothesis has been given in the article, while all previous experimental evidences and literature data tend to exclude the involvement of iron co-catalysis in the Pd/iodide-promoted reactions.

A novel and efficient catalytic approach to functionalized furo[3,4-b]indol-1-ones is reported. It is based on a palladium-catalyzed sequential process involving an initial cyclization of 2-(hydroxypropyn-1-yl) anilines to form the indole moiety, followed by insertion of carbon monoxide and a second annulation step to build a lactone ring. In a single transformation, two fused heterocycles and three new bonds (C-N, C-C and C-O) are generated. The present methodology gives direct access to structurally complex molecules starting from readily available reagents.

The combination of a Pd(0) complex with benzoic acid in the presence of D2O enables the synthesis of valuable families of highly deuterated organics through elaborate sequential reactions. The catalytic system can convert 2-butyne fragments into the corresponding d-dienamides, which can then readily deliver labeled polycyclic quinone motifs. Propargylated tryptamines lead to formation of highly enriched tetrahydrocarbolines through the C–H activation of their unprotected indole ring. Mechanistic studies reveal the ordered series of events that regulate the outcome of these complex reactions, which include multiple, sequential and selective H/D scrambling from the cheapest and safest deuterium source.

The abundant and inexpensive carbon monoxide (CO) is widely exploited as a C1 source for the synthesis of both fine and bulk chemicals. In this context, photochemical carbonylation reactions have emerged as a powerful tool for the sustainable synthesis of carbonyl-containing compounds (esters, amides, ketones, etc.). This review aims at giving a general overview on visible light-promoted carbonylation reactions in the presence of metal (Palladium, Iridium, Cobalt, Ruthenium, Copper) and organocatalysts as well, highlighting the main features of the presented protocols and providing useful insights on the reaction mechanisms.

The hydroamination reaction is a convenient alternative strategy for the formation of C–N bonds. Herein, we report a new versatile and convenient protocol for the hydroamination of arylacetylenes with anilines using palladium iodide in the absence of any added ligand as catalyst. Mild conditions, excellent regio- and stereoselectivity, and high functional group tolerance are the main features of this methodology. A subsequent reduction step gives access to a wide variety of secondary aromatic amines.

The first example of the bis-alkoxycarbonylation of acrylic esters and acrylic amides, leading to differently substituted 1,1,2-ethanetricarboxylate compounds and 2-carbamoylsuccinates respectively, is reported. The catalyst is formed in situ by mixing Pd(TFA)2 (TFA=trifluoroacetate) and the ligand bis(2,6-dimethylphenyl)butane-2,3-diimine. The reaction, that proceeds using p-benzoquinone as oxidant and p-toluenesulfonic acid as additive, has been applied to variously substituted electron-poor alkenes, employing different alcohols as nucleophiles, under very mild reaction conditions (4 bar of carbon monoxide at 20 °C). Remarkably, this catalytic system is able to promote the carbonylation of both the β- and the generally unreactive α-positions of acrylic esters and amides, allowing the formation of bis-alkoxycarbonylated products in good to excellent yields (up to 98%). The trend of reactivity, observed with the different electron-deficient olefins, has been rationalized on the basis of the proposed catalytic cycle and DFT calculations. (Figure presented.).

In this contribution, we report novel palladium-catalyzed carbonylative cascade approaches to highly functionalized polyheterocyclic structures. The Pd-catalyzed carbonylative process involves the regioselective insertion of one to three CO molecules and the sequential ordered formation of up to eight new bonds (one C-O, two C-C, five C-N). The exclusive formation of six-membered heterocycles is elucidated by detailed modeling studies.

We report the first example of cooperative catalysis by DBU and CuCl2, which allows the carboxylation of homopropargylic amines to high value added 6-methylene-1,3-oxazin-2-ones. This reaction also represents the first efficient method for the catalytic incorporation of CO2 into an acyclic substrate to give oxazinones. DFT calculations are in agreement with a mechanism involving: a) deprotonation of the substrate by DBU; b) CO2 capture with formation of a copper carbamate; c) 6-exo-dig cyclization through intramolecular triple bond insertion; and d) protonolysis, with regeneration of DBU and CuCl2 catalysts. The structure of a representative product has been confirmed by XDR analysis.

Summary: The development of efficient synthetic strategies for the discovery of novel antitumor molecules is a major goal in current research. In this context, we report here a catalytic double cyclization process leading to bicyclic heterocycles with significant antitumor activity on different human breast cancer (BC) cell lines. The products, 6,6a-dihydrofuro[3,2-b]furan-2(5H)-ones, were obtained in one step, starting from simple substrates (4-yne-1,3-diols, CO, and O2), under the catalytic action of PdI2 in conjunction with KI. These compounds have significant antiproliferative activity in vitro on human BC cell lines, both hormone receptor positive (MCF-7) and triple negative (triple-negative breast cancer [TNBC]; MDA-MB-231 and MDAMB-468), while exhibiting practically no effects on normal MCF-10A (human mammary epithelial) and 3T3-L1 (murine fibroblasts) cells. Thus, these compounds have the potential to expand the therapeutic options against BC, and in particular, against its most aggressive forms (TNBCs). Moreover, the present synthetic approach may provide an economic benefit for their production. : Drugs; Organic Synthesis; Toxicology Evaluation Subject Areas: Drugs, Organic Synthesis, Toxicology Evaluation

The front cover picture supplied by Carla Carfagna and co‐workers depicts an efficient process for the diastereospecific bis‐alkoxycarbonylation of 1,2‐disubstituted olefins, leading to the synthesis of 2,3‐disubstituted‐succinic diesters. Using Pd(TFA)2 as palladium source, bis‐(2,6‐dimethylphenyl)‐2,3‐dimethyl‐1,4‐diazabutadiene as ligand and p‐benzoquinone as oxidant, aliphatic, aromatic, cyclic olefins and unsaturated fatty acid methyl esters, have been successfully converted in the presence of different alcohols, under mild reaction conditions (PCO =4 bar, T = 20 °C). Further details can be found in the full paper on pages 3507–3517 (D. Olivieri, F. Fini, R. Mazzoni, S. Zacchini, N. Della Ca′, G. Spadoni, B. Gabriele, R. Mancuso, V. Zanotti, C. Carfagna, Adv. Synth. Catal. 2018, 360, 3507–3517: DOI 10.1002/adsc.201701597).

A novel methodology to easily access imidazolidin-2-ones from propargylamines, primary amine and CO 2 with TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) or MTBD (7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene) as catalysts under solvent-free conditions is here reported. Bicyclic guanidines, able to catalyze the formation of oxazolidinones from secondary propargylamines and CO 2 , are now presented for the first time as effective organocatalysts for the chemical fixation of CO 2 into linear and cyclic ureas. Plausible reaction pathways are proposed on the basis of experimental findings.

A new protocol for the alkoxycarbonylation of α-olefins to the corresponding unsaturated esters has been developed. Differently substituted styrenes were selectively converted to cinnamate derivatives, via C H bond functionalization. Various palladium sources, including heterogeneous ones, in combination with CuI exhibited a high catalytic efficiency using oxygen as the most cheap oxidant. Monocarbonylated products were obtained in good yields and high chemoselectivity working with a low CO pressure (2 atm) and an excess of air (35 atm) avoiding in this way explosion risks. Commercial cinnamate derivatives were prepared in good to excellent yields by this very simple one-pot procedure.

Herein, we report a novel catalytic synthesis of substituted 9H-fluoren-9-ols starting from aryl iodides and secondary ortho-bromobenzyl alcohols in the presence of palladium/norbornene as a catalytic system. The present protocol exhibits high functional group tolerance, mild reaction conditions and moderate to good yields. This transformation is based on two sequential pathways: (i) Pd(II)-mediated oxidation of the secondary alcohol to the corresponding ketone and (ii) Pd(0)/norbornene-catalyzed reaction of the in situ generated ortho-bromoacetophenone with the aryl iodide.

The first organo-catalyzed synthesis of imidazolidin-2-ones and imidazol-2-ones via intramolecular hydroamidation of propargylic ureas is reported. The phosphazene base BEMP turned out to be the most active organo-catalyst compared with guanidine and amidine bases. Excellent chemo- and regioselectivities to five-membered cyclic ureas have been achieved under ambient conditions, with a wide substrate scope and exceptionally short reaction times (down to 1 min). A base-mediated isomerization step to an allenamide intermediate is the most feasible reaction pathway to give imidazol-2-ones, as suggested by DFT studies.

A catalytic carbonylative double cyclization method for the synthesis of furo[3,4-b]benzofuran-1(3H)-ones is reported. It is based on the reaction between readily available 2-(3-hydroxy-1-yn-1-yl)phenols, CO, and oxygen carried out in the presence of catalytic amounts of PdI2 (1 mol %) in conjunction with KI (20 mol %) and 2 equiv of diisopropylethylamine at 80 degrees C for 24 h under 30 atm of a 1:4 mixture of CO-air. Interestingly, the process was not selective when carried out in classical organic non-nucleophilic solvents (such as MeCN or DME), leading to a mixture of the benzofurofuranone derivative and the benzofuran ensuing from simple cycloisomerization, whereas it turned out chemoselective toward the formation of the double cyclization compound in BmimBF(4) as the reaction medium. Moreover, the ionic liquid solvent containing the catalyst could be easily recycled several times without appreciable loss of activity.

The first example of the oxidative carbonylation of 2-ethynylbenzoic acid derivatives, leading to alkyl (Z)-2-[3-oxoisobenzofuran-1-(3H)-ylidene]acetates in a regio- and stereoselective manner, is reported. Under the catalytic action of PdI2 (2 mol%) in conjuction with KI (20 mol%), different 2-[(trimethylsilyl)ethynyl]benzoic acids were converted into the corresponding isobenzofuranones in high to excellent yields (70–98%). The proposed reaction mechanism involves syn 5-exo-dig cyclization, carbon monoxide insertion, and nucleophilic displacement by an alcohol. Desilylation occurred under the reaction conditions. The structure of a representative product, that is, methyl (Z)-2-[3-oxoisobenzofuran-1(3H)-ylidene]acetate, was confirmed by XRD analysis. (Figure presented.).

A practical homogeneous and gas‐liquid palladium‐catalyzed Catellani‐type reaction using a continuous‐flow platform is described. The implementation of continuous‐flow technology allowed the acceleration of the transformation and, for the first time, expansion of the chemical space to gaseous olefins (i.e., ethylene, propylene and 3,3,3‐trifluoropropene), thus providing a safe and practical approach to sterically hindered ortho‐disubstituted styrenes and vinyl arenes. The complete control over the stoichiometry of gaseous reagents through flow technology proved essential for directing the selectivity of the Catellani reaction to the desired products.

The front cover picture, provided by Carla Carfagna et al., shows the first example of an oxidative bis‐alkoxycarbonylation of acrylic esters and acrylic amides, leading to 2‐EWG‐substituted succinates. Despite the low reactivity of electron‐deficient olefins in carbonylation reactions, the aryl α‐diimine palladium(II) catalyst is able to promote the carbonylation of both the β‐ and the generally non‐reactive α‐positions of electron‐poor alkenes, under mild reaction conditions (PCO=4 bar, T=20 °C). Further details of this work can be found in the full paper on pages 533–544

(S)-4-Isopropyl-5,5-diphenyloxazolidin-2-one has been synthesized for the first time by the enantiospecific oxidative carbonylation of commercially available (S)-2-amino-3-methyl-1,1-diphenylbutan-1-ol. The cyclocarbonylation reaction was carried out at 100 °C in 1,2-dimethoxyethane (DME) as the solvent for 15 h, under 20 atm of a 4:1 mixture of CO–air and in the presence of the catalytic system PdI2/KI (substrate:KI:PdI2 molar ratio = 100:10:1), to give the oxazolidinone derivative in 81% isolated yield.