Carbon-carbon Bond-forming Processes Research Articles

BF3 -Catalyzed Mukaiyama aldol reaction of acetaldehyde with 2-siloxy-1-propene.

The Mukaiyama aldol reaction is a powerful tool for the construction of the carbon-carbon bond and the formation of β-hydroxycarbonyl compounds. In this work, the mechanism of acetaldehyde and 2-siloxy-1-propene both in the absence and presence of the catalyst BF3 was investigated based on density functional theory. The mechanism includes two major steps: the formation of the carbon-carbon bond and the removal of SiH3 /BF2 by water. The energy barrier of the carbon-carbon bond formation process in the presence of BF3 is obviously lower, indicating that BF3 is a good catalyst for this reaction. In terms of molecular configuration, the different tensions between the five-membered-ring and six-membered-ring can be considered as the possible reason for the catalytic effect of BF3 . In terms of charge transfer, the charges of natural population analysis in the carbon atom of the carbonyl group in acetaldehyde becomes more positive, which is easier to attack by nucleophiles and promote the nucleophilic process.

Cobalt-Catalyzed Regio- and Enantioselective Allylic Alkylation of Malononitriles.

Cobalt-catalyzed highly branched- and enantioselective allylic alkylation of malononitriles has been developed. Chiral γ,δ-unsaturated malononitriles could be synthesized with >20:1 branched/linear regioselectivity and up to 99% enantiomeric excess from easily accessible racemic allylic carbonates under mild reaction conditions. The electron-rich and sterically less hindered bisoxazolinephosphine ligand is essential to realize the high reactivity in the carbon-carbon bond formation process.

Electrochemical, Manganese-Assisted Carbon-Carbon Bond Formation between β-Keto Esters and Silyl Enol Ethers.

The electrochemical carbon-carbon bond formation process between β-keto esters and silyl enol ethers was investigated utilizing manganese salts. The tricarbonyl compounds were generated in moderate to good yields under neutral conditions. Control experiments revealed that an electro-generated base at the cathode is important. Electroanalytical measurements with a Mn(TPA) complex suggested that the oxidation of the silyl enol ether is the first step in the oxidation process initiated by a corresponding Mn(IV) species.

Second Generation of Aldol Reaction.

Since the discovery of the Mukaiyama aldol reaction more than 40 years ago, several landmark publications have inspired researchers in the field. The Mukaiyama AR is one of the most significant named reactions in organic synthesis. In the past few decades, development of the modern AR has been at the forefront in addressing the challenges of regio-, chemo-, diastereo-, and enantioselectivity in organic synthesis. All of these selectivity challenges maybe present in a single pair of reactants, thus controlling the outcome of such a process has great practical value. More than 10 years ago, our group became involved in this iconic carbon-carbon bond-forming process and attempted to very closely investigate all possible features of the AR to solve several issues still encountered by chemists, most notably the selectivity challenges mentioned above. In this context, our group initiated the second generation of the AR based on a Lewis or Brønsted acid-catalyzed process in conjunction with the use of a "super silyl" (tris(trimethylsilyl)silyl) directing group, which has demonstrated unrivalled properties in controlling the outcome of the AR. Using the extraordinary power of the super silyl group, we were able to develop new methods and concepts that broadly impacted the ability to control the selectivity attributes and thus allowed for a highly stereoselective construction of polyketide, halogenated polyketide, polypropionate, and polyol scaffolds through inter- and/or intramolecular aldolization protocols. Our diastereoselective ARs of super silyl enol ethers and aldehydes have shown great efficiency and modularity in producing exclusively and preferentially syn- or anti-adducts, creating up to four new adjacent stereocenters in a one-pot sequential manner and under mild reaction conditions. The super silyl-directed AR does not only provide a solution to stereochemistry control challenges, but also offers an efficient, modular and high yielding technique toward nontrivial construction of complex architectures with unprecedented ease. We believe that the new Lewis- or Brønsted-acid-catalyzed super-silyl-directed AR processes chronicled in our laboratories have come to maturity and now offer a "road map" for strategic stereoselective synthesis of polyketide-like units. Herein we report our recent achievements in the diastereoselective C-C bond formation, through the super-silyl-directed AR, toward the synthesis of complex and sophisticated hydroxy aldehydes. We would like to note that due to the extremely broad range of work reported in this field, only stereoselective AR involving aldehyde-derived super SEEs will be discussed in this Account.

ChemInform Abstract: Tandem Bond‐Forming Reactions of 1‐Alkynyl Ethers

AbstractReview: 54 refs.

Tandem Bond-Forming Reactions of 1-Alkynyl Ethers.

Electron-rich alkynes, such as ynamines, ynamides, and ynol ethers, are functional groups that possess significant potential in organic chemistry for the formation of carbon-carbon bonds. While the synthetic utility of ynamides has recently been expanded considerably, 1-alkynyl ethers, which possess many of the reactivity features of ynamides, have traditionally been far less investigated because of concerns about their stability. Like ynamides, ynol ethers are relatively unhindered to approach by functional groups present in the same or different molecules because of their linear geometry, and they can potentially form up to four new bonds in a single transformation. Ynol ethers also possess unique reactivity features that make them complementary to ynamides. Research over the past decade has shown that ynol ethers formed in situ from stable precursors engage in a variety of useful carbon-carbon bond-forming processes. Upon formation at -78 °C, allyl alkynyl ethers undergo a rapid [3,3]-sigmatropic rearrangement to form allyl ketene intermediates, which may be trapped with alcohol or amine nucleophiles to form γ,δ-unsaturated carboxylic acid derivatives. The process is stereospecific, takes place in minutes at cryogenic temperatures, and affords products containing (quaternary) stereogenic carbon atoms. Trapping of the intermediate allyl ketene with carbonyl compounds, epoxides, or oxetanes instead leads to complex α-functionalized β-, γ-, or δ-lactones, respectively. [3,3]-Sigmatropic rearrangement of benzyl alkynyl ethers also takes place at temperatures ranging from -78 to 60 °C to afford substituted 2-indanones via intramolecular carbocyclization of the ketene intermediate. tert-Butyl alkynyl ethers containing pendant di- and trisubstituted alkenes and enol ethers are stable to chromatographic isolation and undergo a retro-ene/[2 + 2] cycloaddition reaction upon mild thermolysis (90 °C) to afford cis-fused cyclobutanones and donor-acceptor cyclobutanones in good to excellent yields and diastereoselectivities. This process, which takes place under neutral conditions and proceeds through an aldoketene intermediate, obviates the need to employ moisture-sensitive and/or unstable acid chlorides under basic conditions for intramolecular [2 + 2] cycloaddition reactions. Furthermore, Lewis acid-catalyzed intramolecular condensations of both ethyl and tert-butyl ynol ethers with tethered acetals efficiently provide protected five-, six-, and seven-membered cyclic Baylis-Hilman adducts. Metalated ethoxyacetylene can also participate in multiple bond-forming reactions that avoid isolation of the alkynyl ether intermediate. Lewis acid-promoted tandem additions employing epoxides/oxetanes and carbonyl compounds give rise to (Z)-α-alkylidene and α-benzylidene lactones stereoselectively in high overall yields. Three new carbon-carbon bonds and a ring are formed in this atom-economical single-flask transformation, resulting in a significant increase in molecular complexity. This Account provides a detailed overview of these useful transformations with the intention of stimulating further interest in and research on ynol ethers and their application in organic synthesis.

Multicomponent Strategy for the Synthesis of Prostaglandin E2 Methyl Ester under Anion Relay Chelation Control.

Starting with four components, the enantioselective synthesis of prostaglandin E2 methyl ester has been achieved through a highly stereoselective heteroatom-directed conjugate addition reaction and cyclopentanone ring cyclization as the key steps. This asymmetric strategy includes (i) an asymmetric Reformatsky reaction; (ii) conjugate addition of a chiral vinyllithium reagent; (iii) cyclization to form a sulfonylated cyclopentanone in one-pot; followed by (iv) allylation of the side chain. Four carbon-carbon bond-forming processes and three stereogenic centers were established, with the steps from (ii) to (iii) being achieved in a one-pot process.

How Low Does Iron Go? Chasing the Active Species in Fe-Catalyzed Cross-Coupling Reactions

The catalytic cross-coupling reactions of organic halides or related substrates with organometallic nucleophiles form the cornerstone of many carbon-carbon bond-forming processes. While palladium-based catalysts typically mediate such reactions, there are increasing concerns about the long-term sustainability of palladium in synthesis. This is due to the high cost of palladium, coupled with its low natural abundance, environmentally deleterious extraction (∼6 g of metal are produced per ton of ore), toxicity, and competition for its use from the automotive and consumer electronics sectors. Therefore, there is a growing interest in replacing palladium-based catalysts with those incorporating more earth-abundant elements. With its low cost, high natural abundance, and low toxicity, iron makes a particularly appealing alternative, and accordingly, the development of iron-catalyzed cross-coupling is undergoing explosive growth. However, our understanding of the mechanisms that underpin the iron-based catalytic cycles is still very much in its infancy. Mechanistic insight into catalytic reactions is not only academically important but also allows us to maximize the efficiency of processes or even to develop entirely new transformations. Key to the development of robust mechanistic models for cross-coupling is knowing the lowest oxidation state in the cycle. Once this is established, we can explore subsequent redox processes and build the catalytic manifold. Until we know with confidence what the lowest oxidation state is, any cycles proposed are largely just guesswork. To date, Fe(-II), Fe(-I), Fe(0), Fe(I), and Fe(II) have been proposed as contenders for the lowest-oxidation-state species in the cycle in iron-catalyzed cross-coupling; the aim of this Account is to pull together the various pieces of evidence in support, or otherwise, of each of these suggestions in turn. There currently exists no direct evidence that oxidation states below Fe(0) are active in the catalytic cycle. Meanwhile, the reactivity required of the lowest-oxidation-state species has been observed with model compounds in higher oxidation states, implying that there is no need to invoke such low oxidation states. While subzero-valent complexes do indeed act as effective precatalysts, it is important to recognize that this tells us that they are efficiently converted to an active catalyst but says nothing about the oxidation states of the species in the catalytic cycle. Zero-valent heterogeneous iron nanoparticles can be formed under typical catalytic conditions, but there is no evidence to suggest that homogeneous Fe(0) complexes can be produced under comparable conditions. It seems likely that the zero-valent nanoparticles act as a reservoir for soluble higher-oxidation-state species. Fe(II) complexes can certainly be formed under catalytically relevant conditions, and when bulky nucleophilic coupling partners are exploited, potential intermediates can be isolated. However, the bulky reagents act as poor proxies for most nucleophiles used in cross-coupling, as they give Fe(II) organometallic intermediates that are kinetically stabilized with respect to reductive elimination. When more realistic substrates are exploited, reduction or disproportionation to Fe(I) is widely observed, and while it still has not been conclusively proved, this oxidation state currently represents a likely candidate for the lowest one active in many iron-catalyzed cross-coupling processes.

Sm(II)-Mediated Electron Transfer to Carboxylic Acid Derivatives: Development of Complexity-Generating Cascades

Reductive electron transfer (ET) to organic compounds is a powerful method for the activation of substrates via the formation of radicals, radical anions, anions, and dianions that can be exploited in bond-cleaving and bond-forming processes. Since its introduction to the synthetic community in 1977 by Kagan, SmI2 has become one of the most important reducing agents available in the laboratory. Despite its widespread application in aldehyde and ketone reduction, it was widely accepted that carboxylic acid derivatives could not be reduced by SmI2; only recently has our work led to this dogma being overturned, and the reduction of carboxylic acid derivatives using SmI2 can now take its place alongside aldehyde/ketone reduction as a powerful activation mode for synthesis. In this Account, we set out our studies of the reduction of carboxylic acid derivatives using SmI2, SmI2-H2O, and SmI2-H2O-NR3 and the exploitation of the unusual radical anions that are now accessible in unprecedented carbon-carbon bond-forming processes. The Account begins with our serendipitous discovery that SmI2 mixed with H2O is able to reduce six-membered lactones to diols, a transformation previously thought to be impossible. After the successful development of selective monoreductions of Meldrum's acid and barbituric acid heterocyclic feedstocks, we then identified the SmI2-H2O-NR3 reagent system for the efficient reduction of a range of acyclic carboxylic acid derivatives that typically present a significant challenge for ET reductants. Mechanistic studies have led us to propose a common mechanism for the reduction of carboxylic acid derivatives using Sm(II), with only subtle changes observed as the carboxylic acid derivative and Sm(II) reagent system are varied. At the center of our postulated mechanism is the proposed reversibility of the first ET to the carbonyl of carboxylic acid derivatives, and this led us to devise several strategies that allow the radical anion intermediates to be exploited productively in efficient new processes. First, we have used internal directing groups in substrates to "switch on" productive ET to esters and amides and have exploited such an approach in tag-removal cyclization processes that deliver molecular scaffolds of significance in biology and materials science. Second, we have exploited external ligands to facilitate ET to carboxylic acid derivatives and have applied the strategy in telescoped reaction sequences. Finally, we have employed follow-up cyclizations with alkenes, alkynes, and allenes to intercept radical anion intermediates formed along the reaction path and have employed this strategy in complexity-generating cascade approaches to biologically significant molecular architectures. From our studies, it is now clear that Sm(II)-mediated ET to carboxylic acid derivatives constitutes a general strategy for inverting the polarity of the carbonyl, allowing nucleophilic carbon-centered radicals to be formed and exploited in novel chemical processes.

Copper-Catalyzed Three-Component Carboboration of Alkynes and Alkenes

Carboboration of alkynes was found to take place efficiently by a three-component coupling reaction with diboron and carbon electrophiles under copper catalysis to afford diverse multisubstituted borylalkenes in a stereoselective manner. The carboboration was also applicable to alkenes, leading to the formation of multisubstituted borylalkanes via regioselective carbon-boron and carbon-carbon bond-forming processes.

Unconventional Titania Photocatalysis: Direct Deployment of Carboxylic Acids in Alkylations and Annulations

Under dry, anaerobic conditions, TiO(2) photocatalysis of carboxylic acid precursors resulted in carbon-carbon bond-forming processes. High yields of dimers were obtained from TiO(2) treatment of carboxylic acids alone. On inclusion of electron-deficient alkenes, efficient alkylations were achieved with methoxymethyl and phenoxymethyl radicals. In reactions with maleic anhydride or maleimides, phenoxyacetic acid produced chromenedione derivatives in addition to adducts. These photocatalytic reactions are simple and cheap to perform, and the TiO(2) is easily removed by filtration. The anaerobic photocatalysis strategy offers a range of synthetic possibilities.

An Efficient Low‐Temperature Stille–Migita Cross‐Coupling Reaction for Heteroaromatic Compounds by Pd–PEPPSI–IPent

The reactivity of Pd-PEPPSI (Pyridine, Enhanced, Precatalyst, Preparation, Stabilization, and Initiation) precatalysts in the Stille-Migita cross-coupling reaction between heteroaryl stannanes and aryl or heteroaryl halides was evaluated. In general, Pd-PEPPSI-IPent (IPent=diisopentylphenylimidazolium derivative) demonstrated high efficiency over a variety of challenging aryl or heteroaryl halides with thiophene-, furan-, pyrrole-, and thiazole-based organostannanes when compared with Pd-PEPPSI-IPr (IPr=diisopropylphenylimidazolium derivative). The transformations proceeded at appreciably lower temperatures (30-80 degrees C) than triarylphosphine-based Pd catalysts, improving the scope of this useful carbon-carbon bond-forming process.

Enantioselective Alkenylation via Nickel-Catalyzed Cross-Coupling with Organozirconium Reagents

A new family of organometallic compounds, organozirconium reagents, are shown to serve as suitable partners in cross-coupling reactions of (activated) secondary alkyl electrophiles. Thus, the first catalytic method for coupling secondary alpha-bromoketones with alkenylmetal reagents has been developed, specifically, a mild, versatile, and stereoconvergent carbon-carbon bond-forming process that generates potentially labile beta,gamma-unsaturated ketones with good enantioselectivity.

Palladium-Catalyzed Ligand-Directed C−H Functionalization Reactions

1.1 Introduction to Pd-catalyzed directed C–H functionalization The development of methods for the direct conversion of carbon–hydrogen bonds into carbon-oxygen, carbon-halogen, carbon-nitrogen, carbon-sulfur, and carbon-carbon bonds remains a critical challenge in organic chemistry. Mild and selective transformations of this type will undoubtedly find widespread application across the chemical field, including in the synthesis of pharmaceuticals, natural products, agrochemicals, polymers, and feedstock commodity chemicals. Traditional approaches for the formation of such functional groups rely on pre-functionalized starting materials for both reactivity and selectivity. However, the requirement for installing a functional group prior to the desired C–O, C–X, C–N, C–S, or C–C bond adds costly chemical steps to the overall construction of a molecule. As such, circumventing this issue will not only improve atom economy but also increase the overall efficiency of multi-step synthetic sequences. Direct C–H bond functionalization reactions are limited by two fundamental challenges: (i) the inert nature of most carbon-hydrogen bonds and (ii) the requirement to control site selectivity in molecules that contain diverse C–H groups. A multitude of studies have addressed the first challenge by demonstrating that transition metals can react with C–H bonds to produce C–M bonds in a process known as “C–H activation”.1 The resulting C–M bonds are far more reactive than their C–H counterparts, and in many cases they can be converted to new functional groups under mild conditions. The second major challenge is achieving selective functionalization of a single C–H bond within a complex molecule. While several different strategies have been employed to address this issue, the most common (and the subject of the current review) involves the use of substrates that contain coordinating ligands. These ligands (often termed “directing groups”) bind to the metal center and selectively deliver the catalyst to a proximal C–H bond. Many different transition metals, including Ru, Rh, Pt, and Pd, undergo stoichiometric ligand-directed C–H activation reactions (also known as cyclometalation).2,3 Furthermore, over the past 15 years, a variety of catalytic carbon-carbon bond-forming processes have been developed that involve cyclometalation as a key step.1b–d,4 The current review will focus specifically on ligand-directed C–H functionalization reactions catalyzed by palladium. Palladium complexes are particularly attractive catalysts for such transformations for several reasons. First, ligand-directed C–H functionalization at Pd centers can be used to install many different types of bonds, including carbon-oxygen, carbon-halogen, carbon-nitrogen, carbon-sulfur, and carbon-carbon linkages. Few other catalysts allow such diverse bond constructions,5,6,7 and this versatility is predominantly the result of two key features: (i) the compatibility of many PdII catalysts with oxidants and (ii) the ability to selectively functionalize cyclopalladated intermediates. Second, palladium participates in cyclometalation with a wide variety of directing groups, and, unlike many other transition metals, promotes C–H activation at both sp2 and sp3 C–H sites. Finally, the vast majority of Pd-catalyzed directed C–H functionalization reactions can be performed in the presence of ambient air and moisture, making them exceptionally practical for applications in organic synthesis. While several accounts have described recent advances, this is the first comprehensive review encompassing the large body of work in this field over the past 5 years (2004–2009). Both synthetic applications and mechanistic aspects of these transformations are discussed where appropriate, and the review is organized on the basis of the type of bond being formed.

Palladium−Pincer Complex Catalyzed C−C Coupling of Allyl Nitriles with Tosyl Imines via Regioselective Allylic C−H Bond Functionalization

A mechanistically new palladium-pincer complex catalyzed allylation of sulfonimines is presented. This reaction involves C-H bond functionalization of allyl nitriles under mild conditions. The reaction proceeds with a high regioselectivity, without allyl rearrangement of the product. Modeling studies indicate that the carbon-carbon bond formation process proceeds via (eta (1)-allyl)palladium pincer complex intermediates.

Enantioselective Radical Cyclizations: A New Approach to Stereocontrol of Cascade Reactions

Stereocontrol in a cascade radical addition-cyclization-trapping reaction was achieved by a new approach, which utilizes a hydroxamate ester moiety as a coordinating chiral Lewis acid tether between two radical acceptors. A remarkable feature of this reaction is the construction of three bonds and tertiary and quaternary stereogenic centers through both inter- and intramolecular carbon-carbon bond-forming processes. The chiral Lewis acid mediated reaction of oxime ethers also proceeded smoothly with good enantio- and diastereoselectivities, indicating the usefulness of the cascade approach for the asymmetric synthesis of various gamma-lactams.

Zinc-mediated carbon radical addition to glyoxylic imines in aqueous media for the synthesis of α-amino acids

The addition of carbon radicals to glyoxylic imines was studied using zinc dust as a radical initiator. The zinc-mediated radical reaction of glyoxylic oxime ethers and hydrazones proceeded smoothly to give the alkylated products via a carbon-carbon bond-forming process in aqueous media. The reaction of the oxime ethers and hydrazones having an Oppolzer's camphorsultam group provided the corresponding alkylated products, which could be converted into enantiomerically pure alpha-amino acids. The diastereoselectivities observed in the reaction of hydrazones were better than those obtained in the reaction of oxime ethers.

Development of Radical Reactions in Water Aimed at Environmentally Benign Synthetic Reactions

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stannyl Radical Addition—Cyclization of Oxime Ethers Connected with Olefins.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Free Radical‐Mediated Tandem Reaction of Dehydroamino Acid Derivative with π‐Allyl Palladium Complex: Synthesis of α,α‐Disubstituted Amino Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.