Site-Selective Ruthenium-Catalyzed C-H Bond Arylations with Boronic Acids: Exploiting Isoindolinones as a Weak Directing Group.

Biologically relevant N-arylisoindolinones efficiently underwent arylation reactions under ruthenium catalysis via C-H bond functionalization. The reactions exclusively led to monoarylated products, and only ortho selectivity was observed in the aromatic ring connected to the nitrogen atom. Interestingly, no C-H bond functionalization was observed in the other benzene ring in the ortho position with respect to the carbonyl group. This ruthenium-catalyzed reaction displayed a high functional group tolerance, and it employed readily available and benchmark stable boronic acid and potassium aryltrifluoroborate derivatives as coupling partners. An appealing late-stage functionalization of indoprofen applying this methodology is showcased.

C-H Bond Alkylation of Cyclic Amides with Maleimides via a Site-Selective-Determining Six-Membered Ruthenacycle.

The first example of a ruthenium-catalyzed C-H bond alkylation via six-membered ruthenacycles is presented. This is disclosed for the C-H bond alkylation of biologically relevant cyclic amides with maleimide derivatives. The cyclic tertiary amide core acted as a directing group (DG) enabling formation of six-membered cycloruthenated species responsible for the control of the regio- and site selectivity of the reaction as well as the excellent functional group tolerance. Unexpectedly, cyclic amides were found to be better DGs than pyridine-containing ones or cyclic imides for this type of C-H bond functionalization.

Ru-Catalyzed Selective C-H Bond Hydroxylation of Cyclic Imides.

We report on cyclic imides as weak directing groups for selective monohydroxylation reactions using ruthenium catalysis. Whereas acyclic amides are known to promote the hydroxylation of the C(sp2)-H bond enabling five-membered ring ruthenacycle intermediates, the cyclic imides studied herein enabled the hydroxylation of the C(sp2)-H bond via larger six-membered ruthenacycle intermediates. Furthermore, monohydroxylated products were exclusively obtained (even in the presence of overstoichiometric amounts of reagents), which was rationalized by the difficulty to accommodate coplanar intermediates once the first hydroxyl group was introduced into the substrate. The same reactivity was observed in the presence of palladium catalysts.

Ruthenium(ii)-catalysed selective C(sp2)-H bond benzoxylation of biologically appealing N-arylisoindolinones.

Site- and regio-selective aromatic C-H bond benzoxylations were found to take place using biologically appealing N-arylisoindolinones under ruthenium(ii) catalysis in the presence of (hetero)aromatic carboxylic acid derivatives as coupling partners. Besides the presence of two potential C(sp2)-H sites available for functionalization in the substrates, exclusive ortho selectivity was achieved in the phenyl ring attached to the nitrogen atom. Notably, the reactions occurred in a selective manner as only mono-functionalized products were formed and they tolerated a large number of functional chemical groups. The ability of the cyclic tertiary amide within the isoindolinone skeleton to act as a weak directing group in order to accommodate six-membered ring ruthenacycle intermediates appears to be the key to reach such high levels of selectivity. In contrast, the more sterically demanding cyclic imides were unreactive under identical reaction conditions.

Ruthenium(II)-Catalyzed C-H (Hetero)Arylation of Alkenylic 1,n-Diazines (n = 2, 3, and 4): Scope, Mechanism, and Application in Tandem Hydrogenations.

A general ruthenium(II)-catalyzed methodology enabling the (hetero)arylation of alkenylic C-H bonds utilizing a series of synthetically appealing diazines as directing groups is presented. Despite the presence of additional nitrogen lone pairs remote from the C-H bond activation site, which could eventually poison the catalyst, the reaction times are short (3 h), thus being suitable for selective double C-H bond arylation. Mixtures of E:Z isomeric products were observed in some cases, which were further hydrogenated in a tandem manner in the presence of the remaining ruthenium catalyst from the first step, representing an alternative approach to more difficult C(sp3)-H bond functionalization. According to mechanistic studies, the unexpected E:Z product formation seems to occur by thermal C═C bond isomerization after the reductive elimination step.

Palladium-Catalysed Cross-Coupling Reactions Controlled by Noncovalent Zn⋠⋠⋠N Interactions.

Non-covalent interactions between halopyridine substrates and catalytically inert building blocks, namely zinc(II)-porphyrins and zinc(II)-salphens, influence the catalytic outcome of Suzuki-Miyaura and Mizoroki-Heck palladium-catalysed cross-coupling reactions. The weak Zn⋅⋅⋅N interactions between halopyridine substrates and zinc(II)-containing porphyrins and salphens, respectively, were studied by a combination of 1 H NMR spectroscopy, UV/Vis studies, Job-Plot analysis and, in some cases, X-ray diffraction studies. Additionally, the former studies revealed unique supramolecular polymeric and dimeric rearrangements in the solid state featuring weak Br⋅⋅⋅N (halogen bonding), C-H⋅⋅⋅π, Br⋅⋅⋅π and π⋅⋅⋅π interactions. The reactivity of halopyridine substrates in homogeneous palladium-catalysed cross-coupling reactions was found to correlate with the binding strength between the zinc(II)-containing scaffolds and the corresponding halopyridine. Such observation is explained by the unfavourable formation of inactive over-coordinated halopyridine⋅⋅⋅palladium species. The presented approach is particularly appealing for those cases in which substrates and/or products deactivate (or partially poison) a transition-metal catalyst.

Ruthenium Phosphine-Pyridone Catalyzed Cross-Coupling of Alcohols To form α-Alkylated Ketones.

An efficient and green route to access diverse functionalized ketones via dehydrogenative-dehydrative cross-coupling of primary and secondary alcohols is demonstrated. Selective and tunable formation of ketones or alcohols is catalyzed by a recently developed proton responsive ruthenium phosphine-pyridone complex. Light alcohols such as ethanol could be used as alkylating agents in this methodology. Moreover, selective tandem double alkylation of isopropanol is achieved by sequential addition of different alcohols.

Ethenolysis: A Green Catalytic Tool to Cleave Carbon-Carbon Double Bonds.

Remarkable innovations have been made in the field of olefin metathesis due to the design and preparation of new catalysts. Ethenolysis, which is cross-metathesis with ethylene, represents one catalytic transformation that has been used with the purpose of cleaving internal carbon-carbon double bonds. The objectives were either the ring opening of cyclic olefins to produce dienes or the shortening of unsaturated hydrocarbon chains to degrade polymers or generate valuable shorter terminal olefins in a controlled manner. This Review summarizes several aspects of this reaction: the catalysts, their degradation in the presence of ethylene, some parameters driving their productivity, the side reactions, and the applications of ethenolysis in organic synthesis and in potential industrial applications.

Vicinal α,ß-functionalizations of amines: cyclization versus dehydrogenative hydrolysis.

Direct vicinal α,ß-difunctionalization of tertiary cyclic amines is achieved in the presence of ruthenium or iridium transition-metal complexes featuring phosphine-sulfonate chelates. By varying the reaction conditions, α-alkylated lactams were obtained by a formal dehydrogenative hydrolysis in which one molecule of hydrogen is generated from water.

Efficient Domino Hydroformylation/Benzoin Condensation: Highly Selective Synthesis of α-Hydroxy Ketones.

An improved domino hydroformylation/benzoin condensation to give α-hydroxy ketones has been developed. Easily available olefins are smoothly converted into the corresponding α-hydroxy ketones in high yields with excellent regioselectivities. Key to success is the use of a specific catalytic system consisting of a rhodium/phosphine complex and the CO2 adduct of an N-heterocyclic carbene.

Selective ruthenium-catalyzed hydrochlorination of alkynes: one-step synthesis of vinylchlorides.

An unprecedented ruthenium-catalyzed direct and selective alkyne hydrochlorination is reported and leads to vinylchlorides in excellent yields with atom economy. The reaction proceeds at room temperature from terminal alkynes and provides a variety of chloroalkenes. Only the regioisomer resulting from the formal Markovnikov addition is selectively formed. Mechanistic studies show the stereoselective syn addition of HCl to alkynes at room temperature and suggest a chloro hydrido Ru(IV) species as a key intermediate of the reaction.

Cross metathesis of unsaturated epoxides for the synthesis of polyfunctional building blocks.

The cross metathesis of 1,2-epoxy-5-hexene (1) with methyl acrylate and acrylonitrile was investigated as an entry to the synthesis of polyfunctional compounds. The resulting cross metathesis products were hydrogenated in a tandem fashion employing the residual ruthenium from the metathesis step as the hydrogenation catalyst. Interestingly, the epoxide ring remained unreactive toward this hydrogenation method. The saturated compound resulting from the cross metathesis of 1 with methyl acrylate was transformed by means of nucleophilic ring-opening of the epoxide to furnish a diol, an alkoxy alcohol and an amino alcohol in high yields.

Ruthenium-containing phosphinesulfonate chelate for the hydrogenation of aryl ketones.

Various ruthenium(II) complexes that contain phosphinesulfonate chelate have been synthesized. Arene-free complexes were found to be efficient in the base-free hydrogenation of various aryl ketones, whereas the arene-containing precatalysts required the presence of an amine as an additive. The seminal asymmetric hydrogenation reaction by using the new Sulfo-Binepine ligand was also investigated for the possible intervention of a dihydride species.

Ruthenium-catalysed synthesis of functional conjugated dienes from propargylic carbonates and silyl diazo compounds.

Ru being served? The reactions of propargylic carbonates with silyl diazo compounds in the presence of [Cp*RuCl(cod)] as a catalyst precursor led to the formation of dienyl carbonates in excellent yields under mild conditions (see scheme; Y = SiMe(3)).

Autocatalytic intermolecular versus intramolecular deprotonation in C-H bond activation of functionalized arenes by ruthenium(II) or palladium(II) complexes.

The activation of the C-H bond of 1-phenylpyrazole (2) and 2-phenyl-2-oxazoline (3) by [Ru(OAc)2(p-cymene)] is an autocatalytic process catalyzed by the co-product HOAc. The reactions are indeed faster in the presence of acetic acid and water but slower in the presence of a base K2CO3. A reactivity order is established in the absence of additives: 2-phenylpyridine>2-phenyl-2-oxazoline>1-phenylpyrazole (at RT). The accelerating effect of added acetate ions reveals an intermolecular deprotonation after C-H bond activation by a cationic Ru(II) center (SE 3 mechanism). The reactions of 1-phenylpyrazole and 2-phenyl-2-oxazoline first lead to the neutral cyclometalated complexes A2 and A3 ligated by one acetate. The latter dissociate to the cationic complexes B2(+) and B3(+), respectively, and acetate. A slow incorporation of one or two D atoms into 2, 3, and 2-phenylpyridine (1) was observed in the presence of deuterated acetic acid. The "reversibility" of the C-H bond activation/deprotonation takes place from the cationic complexes Bn(+) (n=1-3). They are also involved in oxidative additions to PhI, which are rate-determining and lead to the mono- and bis-phenylated products at high temperatures. A general mechanism is proposed for the arylation of arenes 1-3 catalyzed by [Ru(OAc)2(p-cymene)]. In contrast, the reaction of Pd(OAc)2 with 2-phenylpyridine (1), is much faster: Pd(OAc)2>[Ru(OAc)2(p-cymene)]. Since the kinetics is not affected by added acetates, the reaction proceeds through a CMD mechanism assisted by a ligated acetate (intramolecular process) and is irreversible. A bis-cyclometalated Pd(II)^Pd(II) dimer D'1 is formed whose bielectronic electrochemical oxidation leads to a [Pd(III)^Pd(III)](2+) dimer, in agreement with the result of a reported chemical oxidation used in arene functionalizations catalyzed by Pd(OAc)2.

Synthesis of heteroarylated polyfluorobiphenyls via palladium-catalyzed sequential sp2 C-H bonds functionalizations.

The higher reactivity of C5-H bonds of heteroarenes as compared to C-H bonds of bromopolyfluorobenzenes for palladium-catalyzed direct arylation allows the selective synthesis of the polyfluoroaryl-heteroarenes in moderate to high yields, without C-H bond functionalization of the polyfluorobenzene ring. In most cases, low loading of Pd(OAc)2 catalyst (0.5-1 mol %) was employed. Then, from these heteroarylated polyfluorobenzenes, the palladium-catalyzed C-H bond functionalization of the polyfluorobenzene ring allows the synthesis of heteroarylated polyfluorobiphenyls.

Transition metal catalyzed nucleophilic allylic substitution: activation of allylic alcohols via π-allylic species.

Modern organic synthesis now requires efficient atom economical synthetic methods operating under greener pathways to achieve C-C and C-heteroatom bond formation. Direct activation of allylic alcohols in the presence of transition metal catalysts leading to electrophilic π-allyl metal intermediates represents such a promising target in the field of nucleophilic allylation reactions. During the last decade, this topic of recognized importance has become an emerging area, and selected transition metals, sometimes associated with alcohol activators, have brought elegant solutions for performing allylic substitution directly from alcohols in a regio, stereo and enantioselective manner.

N-Heterocyclic carbene-palladium catalysts for the direct arylation of pyrrole derivatives with aryl chlorides.

New Pd-NHC complexes have been synthesized and employed for palladium-catalyzed direct arylation of pyrrole derivatives by using electron-deficient aryl chlorides as coupling partners. The desired coupling products were obtained in moderate to good yields by using 1 mol % of these air-stable palladium complexes. This is an advantage compared to the procedures employing air-sensitive phosphines, which have been previously shown to promote the coupling of aryl chlorides with heteroarenes.

Palladium-catalyzed direct arylation of 5-chloropyrazoles: a selective access to 4-aryl pyrazoles.

The use of a temporary protection by a chloro group at C5 of pyrazoles allows the synthesis of the 4-arylated pyrazoles, which were previously inaccessible by palladium-catalyzed direct arylation, with complete regioselectivity and in high yields using in most cases as little as 0.5-0.1 mol % Pd(OAc)(2) as the catalyst with electron-deficient aryl bromides. Moreover, from 5-chloro-1,3-dimethylpyrazole, sequential catalytic C4 arylation, dechlorination, catalytic C5 arylation reactions allowed the synthesis of a 4,5-diarylated pyrazole derivative.

Isoquinoline derivatives via stepwise regioselective sp(2) and sp(3) C-H bond functionalizations.

Efficient and practically attractive stepwise ruthenium- and palladium-catalyzed regioselective C-H bond functionalizations were achieved to produce 4-substituted tetrahydroisoquinoline derivatives featuring various heteroaromatic substructures in moderate to good yields. Both ruthenium- and palladium-based catalytic processes generated nontoxic and easily separable side products.