Allylic Reactions Research Articles

Recyclable Silica-Support Taniaphos/Copper(Ⅰ) complex for asymmetric allylic alkylation reactions

The first immobilization of recyclable Taniaphos/copper(Ⅰ) complex on a commercial accessible silica by thiol-ene coupling reaction has been achieved. The immobilization strategy and linker length are found to have significant impact on catalyst selectivities. Furthermore, we have realized the first heterogeneous asymmetric allylic alkylation reactions involving organometallic reagents using this catalyst system, and three types of cinnamyl bromide substrates are found to be suitable with up to 95% enantioselectivity and 96% yield. Notably, the catalyst shows good stability and cyclicity after five recycles without loss of selectivity and the products can be easily isolated with > 95% purity without chromatography purification.

Heterogeneous Single-Atom Zinc on Nitrogen-Doped Carbon Catalyzed Electrochemical Allylation of Imines.

Organometallic reagents are effective for carbon-carbon bond formation; however, consumption of stoichiometric amounts of metals is problematic. We developed electrochemical allylation reactions of imines catalyzed by nitrogen-doped carbon-supported single-atom zinc, which were fixed on a cathode to afford a range of homoallylic amines efficiently. The system could suppress generation of metallic waste, and the catalyst electrode showed advantages over bulk zinc in terms of activity and robustness. An electrochemical flow reaction was also successfully performed to produce the homoallylic amine continuously with minimum amounts of waste.

Constraining and Modifying Peptides Using Pd-Mediated Cysteine Allylation.

Over the past decades, several strategies for inducing and stabilizing secondary structure formation in peptides have been developed to increase their proteolytic stability and their binding affinity to specific interaction partners. Here, we report how our recently introduced chemoselective Pd-catalyzed cysteine allylation reaction can be extended to stapling and how the resulting alkene-containing staples themselves can be further modified to introduce additional probes into such stabilized peptides. The latter is demonstrated by introducing a fluorophore as well as a PEG moiety into different stapled peptides using bioorthogonal thiol-ene and Diels-Alder reactions. Furthermore, we investigated structural implications of our allyl staples when used to replace conformationally relevant disulfide bridges. To this end, we chose a selective binder of integrin α3 β1 (LXY3), which is only active in its cyclic disulfide form. We replaced the disulfide bridge by different stapling reagents in order to increase stability and binding affinity towards integrin α3 β1 .

A theoretical study of the mechanisms, regio- and enantioselectivities associated with rhodium-catalyzed allylic alkylation reactions using hard benzylzinc nucleophiles

A systematic theoretical study of rhodium-catalyzed allylic alkylation reactions using hard benzylzinc nucleophiles was performed. The mechanisms were investigated in detail together with the regioselectivity associated with the branched and linear pathways and the intriguing anti- (as opposed to syn-) diastereoselectivity of this process. The preferred mechanism was found to be initiated by the oxidative addition of the rhodium(I) complex followed by migration of the benzyl nucleophile to the Rh center. The subsequent nucleophilic addition of a benzyl group to the η3-allyl moiety takes place via the formation of a new C–C bond to afford the final allylic benzylation product. This proposed mechanism readily explains the experimental observation that the products obtained from such reactions are branched (as opposed to linear) with an anti-configuration (as opposed to a syn-configuration). This work also provides reasons for the lower regioselectivity observed for a OCO2tBu leaving group or cyanophenyl/secondary amide substituents at the 4-position of the substrate. The present study is expected to assist in the rational design of potential substrates for analogous reactions.

Allylic and Benzylic Alcohol Coupling Reactions Catalyzed by Lithium-Promoted Manganese Oxides

This study reports a novel methodology for the production of allyl acrylate from allyl alcohol solely as the starting substrate. The reaction reported here utilizes a heterogeneous reusable catalyst based on Li-ion-promoted mesoporous manganese oxide. The reaction conditions are mild (ambient pressure and temperature of 80 °C). The catalytic activity, selectivity, and substrate scope of the reaction are reported (60% yield). The system proposed here is composed of an allylic alcohol substrate, O2 as the oxidant, N-hydroxyphthalimide (NHPI) as the promoter, and trichloro acetonitrile (CCl3CN) as the solvent together with the Li-promoted manganese oxide (surface area >150 m2/g) as the catalyst.

Synthesis of Aryl‐ and Alkyl‐Containing 3‐Methylene‐5‐hydroxy Esters via a Barbier Allylation Reaction

AbstractThe formation of C−C bonds via the allylation of carbonyl compounds has been widely applied in total syntheses. Amongst the many possible strategies, the Barbier‐type allylation in aqueous media has received only moderate attention over the last decades despite its mild reaction conditions. In this study, we investigated the indium (In0) and zinc (Zn0) mediated Barbier allylation reaction to efficiently synthesize base‐labile 3‐methylene‐5‐hydroxy containing building blocks for natural product total synthesis. As model study we selected the allylation of lipidic undecanal with ethyl 3‐(bromomethyl)but‐3‐enoate in the presence of either Zn0 or In0 and investigated the effects of additives on yields and selectivities. We then applied the optimized reaction conditions to sterically demanding allyl bromides and functionalized aromatic aldehydes yielding eleven new homoallylic alcohols, one of which was further transformed via oxidation and reduction sequences.

Enantioselective Synthesis of N-N Atropisomers by Palladium-Catalyzed C-H Functionalization of Pyrroles.

The catalytic asymmetric construction of N-N atropisomeric biaryls remains a formidable challenge. Studies of them lag far behind studies of the more classical carbon-carbon biaryl atropisomers, hampering meaningful development. Herein, the first palladium-catalyzed enantioselective C-H activation of pyrroles for the synthesis of N-N atropisomers is presented. Structurally diverse indole-pyrrole atropisomers possessing a chiral N-N axis were produced with good yields and high enantioselectivities by alkenylation, alkynylation, allylation, or arylation reactions. Furthermore, the kinetic resolution of trisubstituted N-N heterobiaryls with more sterically demanding substituents was also achieved. Importantly, this versatile C-H functionalization strategy enables iterative functionalization of pyrroles with exquisite selectivity, expediting the formation of valuable, complex, N-N atropisomers.

Enantioselective Synthesis of N‐N Atropisomers by Palladium‐Catalyzed C−H Functionalization of Pyrroles

AbstractThe catalytic asymmetric construction of N−N atropisomeric biaryls remains a formidable challenge. Studies of them lag far behind studies of the more classical carbon‐carbon biaryl atropisomers, hampering meaningful development. Herein, the first palladium‐catalyzed enantioselective C−H activation of pyrroles for the synthesis of N−N atropisomers is presented. Structurally diverse indole‐pyrrole atropisomers possessing a chiral N−N axis were produced with good yields and high enantioselectivities by alkenylation, alkynylation, allylation, or arylation reactions. Furthermore, the kinetic resolution of trisubstituted N−N heterobiaryls with more sterically demanding substituents was also achieved. Importantly, this versatile C−H functionalization strategy enables iterative functionalization of pyrroles with exquisite selectivity, expediting the formation of valuable, complex, N−N atropisomers.

Formation of Isolable Dearomatized [4 + 2] Cycloadducts from Benzenes, Naphthalenes, and N-Heterocycles Using 1,2-Dihydro-1,2,4,5-tetrazine-3,6-diones as Arenophiles under Visible Light Irradiation

We report that the dearomative [4 + 2] cycloaddition between 1,2-dihydro-1,2,4,5-tetrazine-3,6-diones (TETRADs) and benzenes, naphthalenes, or N-heteroaromatic compounds under visible light irradiation affords the corresponding isolable cycloadducts. Several synthetic transformations including transition-metal-catalyzed allylic substitution reactions using the isolated cycloadducts at room temperature or above were demonstrated. Computational studies revealed that the retro-cycloaddition of the benzene-TETRAD adduct proceeds via an asynchronous concerted mechanism, while that of the benzene-MTAD adduct (MTAD = 4-methyl-1,2,4-triazoline-3,5-dione) proceeds via a synchronous mechanism.

Upcycling of Polybutadiene Facilitated by Selenium‐Mediated Allylic Amination

AbstractAccumulation of end‐of‐life plastics presents ongoing environmental concerns. One strategy to solve this grand challenge is to invent new techniques that modify post‐consumer waste and impart new functionality. While promising approaches for the chemical upcycling of commodity polyolefins and polyaromatics exist, analogous approaches to repurpose unsaturated polymers (e.g., polybutadiene) are scarce. In this work, we propose a method to upcycle polybutadiene, one of the most widely used commercial rubbers, via a mild, metal‐free allylic amination reaction. The resulting materials have tunable thermal and surface wetting properties as a function of both sulfonamide identity and grafting density. Importantly, this approach maintains the parent alkene microstructure without evidence of olefin reduction, olefin transposition, and/or chain scission. Based on these findings, we anticipate future applications in the remediation of complex elastomers and vulcanized rubbers.

Upcycling of Polybutadiene Facilitated by Selenium-Mediated Allylic Amination.

Accumulation of end-of-life plastics presents ongoing environmental concerns. One strategy to solve this grand challenge is to invent new techniques that modify post-consumer waste and impart new functionality. While promising approaches for the chemical upcycling of commodity polyolefins and polyaromatics exist, analogous approaches to repurpose unsaturated polymers (e.g., polybutadiene) are scarce. In this work, we propose a method to upcycle polybutadiene, one of the most widely used commercial rubbers, via a mild, metal-free allylic amination reaction. The resulting materials have tunable thermal and surface wetting properties as a function of both sulfonamide identity and grafting density. Importantly, this approach maintains the parent alkene microstructure without evidence of olefin reduction, olefin transposition, and/or chain scission. Based on these findings, we anticipate future applications in the remediation of complex elastomers and vulcanized rubbers.

Expanding Reaction Profile of Allyl Carboxylates via 1,2-Radical Migration (RaM): Visible-Light-Induced Phosphine-Catalyzed 1,3-Carbobromination of Allyl Carboxylates.

Allyl carboxylates are useful synthetic intermediates in a variety of organic transformations, including catalytic nucleophilic/electrophilic allylic substitution reactions and 1,2-difunctionalization reactions. However, the catalytic 1,3-difunctionalization of allyl carboxylates remains elusive. Herein, we report the first photoinduced, phosphine-catalyzed 1,3-carbobromination of allyl carboxylates, affording a range of valuable substituted isopropyl carboxylates (sIPC). The transformation has broad functional group tolerance, is amenable to the late-stage modification of complex molecules and gram-scale synthesis, and expands the reaction profiles of allyl carboxylates and phosphine catalysis. Preliminary experimental and computational studies suggest a non-chain-radical mechanism involving the formation of an electron donor-acceptor complex, 1,2-radical migration (RaM), and Br-atom transfer processes. We anticipate that the 1,2-RaM reactivity of allyl carboxylates and the phosphine-catalyzed radical reaction will both serve as a platform for the development of new transformations in organic synthesis.

Switchable Brønsted Acid‐Catalyzed Ring Contraction of Cyclooctatetraene Oxide Towards the Enantioselective Synthesis of Cycloheptatrienyl‐Substituted Homoallylic Alcohols and Oxaborinanes

AbstractThe ability of cyclooctatetraene oxide to undergo two sequential ring contraction events under mild conditions, using Brønsted acid catalysis, has been studied in detail. We have found that the selectivity can be controlled by the acidity of the catalyst and by the temperature, being able to obtain selectively either the cycloheptatriene carbaldehyde product, arising from a single ring‐contraction event, or phenylacetaldehyde that is formed after a second ring contraction process. A complete mechanistic picture of the reaction and a rationale behind the influence of the catalyst is provided based on both experimental and computational data. Finally, this acid‐catalyzed ring contraction has been coupled with an in situ enantioselective allylation reaction, delivering enantioenriched cycloheptatrienyl‐substituted homoallylic alcohols when it is carried out in the presence of a chiral phosphoric acid catalyst. These homoallylic alcohols have also been converted into enantioenriched oxaborinanes through copper‐catalyzed nucleophilic borylation/cyclization protocol.magnified image

Cluster Preface: Chemical Synthesis and Catalysis in India

Debabrata Maiti (left) received his Ph.D. from Johns Hopkins University in 2008 under the supervision of Prof. Kenneth D. Karlin. After postdoctoral studies at MIT with Prof. Stephen L. Buchwald, he joined the Department of Chemistry at IIT Bombay in 2011. His research interests are focused on the development of new and sustainable synthetic and catalytic methodologies. He is currently an Associate Editor of the ­Journal of Organic Chemistry. Santanu Mukherjee (right) obtained his Ph.D. in 2006, working under the supervision of Prof. Albrecht Berkessel at the Universität zu Köln, Germany. He subsequently worked as a postdoctoral fellow with Prof. Benjamin List at the Max-Planck Institut für Kohlenforschung, and with Prof. E. J. Corey at Harvard University. In 2010, he joined the Department of Organic Chemistry at IISc Bangalore. His research interests revolve around various aspects of asymmetric catalysis, with particular emphasis on organocatalytic enantioselective desymmetrization and transition-metal-catalyzed enantioselective allylic, allenylic and propargylic substitution reactions. He is an Associate Editor of Organic & ­Biomolecular Chemistry.

Scalable Total Synthesis of Leucascandrolide A Macrolactone Using a Chiral Phosphoric Acid/CuX Combined Catalytic System

A scalable total synthesis of leucascandrolide A macrolactone has been accomplished with a longest linear sequence of 17 steps from readily available feedstocks in 31.2% yield. The key steps in this synthesis are the enantioselective allylation reaction by chiral phosphoric acid (CPA)/CuBr cooperative catalysis and the diastereoselective catalytic crotylation in the presence of CPA with CuCl. These catalytic reactions can be performed on a gram scale to afford the desired products with excellent stereoselectivities.

Metal-Free Allylic C-H Amination

Allylic amination reactions of alkenes are useful tools to construct N-functionalized molecules and now one of the main research targets in the field of allylic oxidation reaction. Although many reactions using transition metal catalysts have been developed, the examples of metal-free systems are relatively limited. This short review focuses on recent reports about metal-free allylic C-H amination, and three types of the reactions, (1) enantioselective reactions using organobase catalysts, (2) iodine-mediated reaction systems, and (3) selenium-catalyzed reactions will be described.

Copper-Catalyzed Visible-Light-Induced Allylic Difluoromethylation of Unactivated Alkenes Using Difluoroacetic Acid.

We herein describe a straightforward allylic difluoromethylation reaction of unactivated alkenes. Compared to cross-couplings of prefunctionalized allylic substrates for the construction of allylic CF2H bonds, this reaction employs readily available alkenes as substrates under mild conditions. Difluoroacetic acid is used as an inexpensive and easy-to-handle source of CF2H radical under visible light irradiation with PIDA. The copper catalyst plays an important role of diverting the reaction pathway toward allylic difluoromethylation as opposed to previously found hydrodifluoromethylation.

Simultaneous Dual Cu/Ir Catalysis: Stereodivergent Synthesis of Chiral β-Lactams with Adjacent Tertiary/Quaternary/Tertiary Stereocenters

A stereodivergent synthesis of chiral β-lactams with contiguous tertiary/quaternary/tertiary stereocenters has been achieved by a Cu/Ir-catalyzed three-component interrupted Kinugasa allylic alkylation reaction. The two catalysts independently exert high local stereocontrol, providing access to four of the eight possible stereoisomers in high yields with >99% ee. The features of this strategy are the asymmetric simultaneous dual metal-catalyzed cascade reactions with stereoselective coupling of highly transient organometallic intermediates.

Stereodivergent Construction of 1,3‐Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction

AbstractHerein, we report a synthesis of cyclohexanones bearing multi‐continuous stereocenters by combining copper‐catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic enones with iridium‐catalyzed asymmetric allylic substitution reaction. Good to excellent yields, diastereoselectivity and enantioselectivity can be obtained. Unlike the stereodivergent construction of adjacent stereocenters (1,2‐position) reported in the literature, the current reaction can achieve the stereodivergent construction of nonadjacent stereocenters (1,3‐position) by a proper combination of two chiral catalysts with different enantiomers.

Stereodivergent Construction of 1,3-Chiral Centers via Tandem Asymmetric Conjugate Addition and Allylic Substitution Reaction.

Herein, we report a synthesis of cyclohexanones bearing multi-continuous stereocenters by combining copper-catalyzed asymmetric conjugate addition of dialkylzinc reagents to cyclic enones with iridium-catalyzed asymmetric allylic substitution reaction. Good to excellent yields, diastereoselectivity and enantioselectivity can be obtained. Unlike the stereodivergent construction of adjacent stereocenters (1,2-position) reported in the literature, the current reaction can achieve the stereodivergent construction of nonadjacent stereocenters (1,3-position) by a proper combination of two chiral catalysts with different enantiomers.