Reaction Of Allenes Research Articles

Pd-Catalyzed/Ligand-Controlled Regioselective Asymmetric Hydrosulfonylation of Alkylallenes or Arylallenes.

The metal-catalyzed hydrofunctionalization reaction of allenes is an efficient approach for the construction of new allyl compounds. This work described a palladium-catalyzed/ligand-controlled asymmetric hydrosulfonylation of simple alkylallenes and arylallenes in the presence of Pd2dba3. Using a Josiphos or Segphos ligand, the alkylallenes or arylallenes could render the corresponding branched chiral allylsulfones with high yields and high enantioselectivities up to 90% and 99% ee, respectively.

Reactivity of Anomalous Aziridines for Versatile Access to High Fsp3 Amine Chemical Space.

ConspectusThe manipulation of strained rings is a powerful strategy for accessing the valuable chemical frameworks present in natural products and active pharmaceutical ingredients. Aziridines, the smallest N-containing heterocycles, have long served as building blocks for constructing more complex amine-containing scaffolds. Traditionally, the reactivity of typical aziridines has been focused on ring-opening by nucleophiles or the formation of 1,3-dipoles. However, over the past decade, our group has pioneered highly chemo-, site-, and stereoselective Ag- and Rh-catalyzed nitrene transfer (NT) reactions of allenes and alkenes to furnish unusual, or "anomalous", aziridines. The unique features of these aziridines, coupled with our ability to control the fate of strained intermediates resulting from diverse reactions of these precursors, allow for their transformation to densely substituted, stereochemically complex N-heterocyclic structures that would otherwise be difficult to access using conventional strategies. Our research is driven by a keen interest in versatile synthetic approaches that explore high Fsp3 (the fraction of sp3 carbons relative to the total number of carbons in a molecule) amine chemical space, which holds promise for uncovering novel bioactivity toward challenging protein targets. We begin by outlining the design and synthesis of selected anomalous aziridines and highlighting the key features that are pertinent to their versatility as synthetic intermediates. We detail chemo-, site-, and stereoselective Rh-catalyzed NT of homoallenic sulfamates leading to the key (E)-methyleneaziridines (MAs) and the development of new Ag catalysts to achieve chemo- and enantioselective aziridinations of homoallenic and homoallylic carbamates/carbamimidates to yield bicyclic (methylene)aziridines. The chemoselective Ag-catalyzed NT of carbamimidates to accomplish intramolecular aza-Büchner reactions via polycyclic aziridine intermediates is also highlighted. Next, we focus on unlocking several modes of reactivity of our anomalous aziridines. These include regioselective ring-opening with nucleophiles and subsequent functionalization to afford amine stereotriads, the stereocontrolled formation and reaction of 2-amidoallyl cations, and alkene oxidation of endo- and exocyclic MAs. Additionally, due to the unusual molecular geometry of bicyclic (methylene)aziridines, the nitrogen lone pair can react with carbenes to generate aziridinium ylides that can be diverted along multiple pathways. From only a handful of anomalous aziridines, our chemistry is capable of delivering amine stereotriads, azetidines, azetidinones, piperidines, aminated cyclopentanes and cycloheptanes, azepines, and azepanes. Finally, we discuss our efforts to leverage this chemistry to explore the complex amine chemical space relevant to the natural products jogyamycin and methyl detoxinine. Ultimately, our goal is to use these methods to generate DNA-encoded libraries of high Fsp3 compounds with potential activity against difficult-to-target proteins.

Synthesis of Indole- and Benzofuran-Based Benzylic Sulfones by Palladium-Catalyzed Sulfonylation of ortho-Iodoaryl Allenes.

A highly efficient palladium-catalyzed domino coupling reaction of ortho-iodoaryl allene with sodium sulfonates under mild conditions is described. This novel method provides a practical protocol to access diverse indole- and benzofuran-containing sulfones by simultaneous construction of C(sp2)-C(sp2) bond and a C(sp3)-S bonds in one pot. The salient features of this transformation include simple operations, broad substrate scope, and good functional group tolerance.

Diastereoselective and Enantioselective Hydrophosphinylations of Conjugated Enynes, Allenes and Dienes via Synergistic Pd/Co Catalysis

AbstractDifferent from the reported work focusing on the construction of single P‐ or C‐stereocenter via hydrophosphinylation of unsaturated carbon bonds, the highly diastereo‐ and enantioselective hydrophosphinylation reaction of allenes, conjugated enynes and 1,3‐dienes is achieved via a designed Pd/Co dual catalysis and newly modified masked phosphinylating reagent. A series of allyl motifs bearing both a tertiary C‐ and P‐stereocenter are prepared in generally good yields, >20 : 1 dr, >20 : 1 rr and 99 % ee. The unprecedented diastereo‐ and enantioselective hydrophosphinylation of 1,3‐enynes is established to generate skeletons containing both a P‐stereocenter and a nonadjacent chiral axis. The first stereodivergent hydrophosphinylation reaction is also developed to achieve all four P‐containing stereoisomers. The present protocol features the use of only 3‐minutes reaction time and 0.1 % catalyst, and with the observation of up to 730 TON. A set of mechanistic studies reveal the necessity and roles of two metal catalysts and corroborate the designed synergistic process.

Diastereoselective and Enantioselective Hydrophosphinylations of Conjugated Enynes, Allenes and Dienes via Synergistic Pd/Co Catalysis.

Different from the reported work focusing on the construction of single P- or C-stereocenter via hydrophosphinylation of unsaturated carbon bonds, the highly diastereo- and enantioselective hydrophosphinylation reaction of allenes, conjugated enynes and 1,3-dienes is achieved via a designed Pd/Co dual catalysis and newly modified masked phosphinylating reagent. A series of allyl motifs bearing both a tertiary C- and P-stereocenter are prepared in generally good yields, >20 : 1 dr, >20 : 1 rr and 99 % ee. The unprecedented diastereo- and enantioselective hydrophosphinylation of 1,3-enynes is established to generate skeletons containing both a P-stereocenter and a nonadjacent chiral axis. The first stereodivergent hydrophosphinylation reaction is also developed to achieve all four P-containing stereoisomers. The present protocol features the use of only 3-minutes reaction time and 0.1 % catalyst, and with the observation of up to 730 TON. A set of mechanistic studies reveal the necessity and roles of two metal catalysts and corroborate the designed synergistic process.

Stereoselective rhodium-catalyzed reaction of allenes with organoboronic reagents for diversified branched 1,3-alkadienes.

The terminalisoprene unit, as the simplest branched 1,3-diene unit, exists in a wide range of natural products and bioactive molecules. Herein, we report a stereoselective rhodium-catalyzed reaction of allenes with readily available methyl pinacol boronic ester, providing a straightforward approach to isoprene derivatives with a very high E-stereoselectivity. Its synthetic potential has been illustrated by a concise synthesis of natural product schinitrienin. Such a protocol can be easily extended to aryl and alkenyl boronic reagents affording 2-aryl or -alkenyl substituted 1,3-dienes, which are also of high importance in organic synthesis but remain challenging for their selective synthesis, with a remarkable stereoselectivity. A series of deuterium-labeling experiments indicate a unique mechanism, which involves reversible β-H elimination as well as hydrometalation and isomerization of the allylic rhodium species.

Switchable Chemo‐, Regio‐ and Pseudo‐Stereodivergence in Palladium‐Catalyzed Cycloaddition of Allenes

AbstractHere, we report a strategy enabling triple switchable chemo‐, regio‐, and stereodivergence in newly developed palladium‐catalyzed cycloadditions of allenes. An asymmetric pseudo‐stereodivergent cycloaddition of allenes bearing a primary leaving group at the α‐position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio‐determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di‐substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O‐attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4‐dihydro‐2H‐1,4‐benzoxazines in high efficiency and selectivity.

Switchable Chemo-, Regio- and Pseudo-Stereodivergence in Palladium-Catalyzed Cycloaddition of Allenes.

Here, we report a strategy enabling triple switchable chemo-, regio-, and stereodivergence in newly developed palladium-catalyzed cycloadditions of allenes. An asymmetric pseudo-stereodivergent cycloaddition of allenes bearing a primary leaving group at the α-position, where a dynamic kinetic asymmetric hydroalkoxylation of racemic unactivated allenes was the enantio-determining step, is realized, providing four stereoisomers [(Z,R), (Z,S), (E,S), and (E,R)] containing a di-substituted alkene scaffold and a stereogenic center. By tuning reaction conditions, a mechanistically distinctive cycloaddition is uncovered selectively with the same set of substrates. By switching the position of the leaving group of allenes, a cycloaddition involving an intermolecular O-attack is disclosed. Diverse mechanisms of the cycloaddition reactions of allenes enable rapid access to structurally and stereochemically diverse 3,4-dihydro-2H-1,4-benzoxazines in high efficiency and selectivity.

2,3-Arylacylation of allenes through synergetic catalysis of palladium and N-heterocyclic carbene

An unprecedented 2,3-arylacylation reaction of allenes with aryl iodides and aldehydes was developed by resorting to Pd/NHC synergetic catalysis. It's the first time that allene was introduced into transition metal and NHC synergetic catalysis, which demonstrated a versatile three-component reaction pattern, thus enabling two C-C bonds forged regioselectively in the reaction. The important reaction intermediates were successfully captured and characterized by HRMS analysis, and the migrative insertion of allene to the Ph-Pd species was identified as the reaction rate-limiting step by kinetic experiments.

Recent Advances in Ligand-Controlled Regio- or Stereodivergent Transition-Metal-Catalyzed Hydroelementation (H[E]) (E = H, B, Si, Ge) of C–C Unsaturated Systems

AbstractReductive functionalization of C–C unsaturated systems, including alkenes and alkynes, with a range of hydroelements (H[E]) is one of the most fundamental and highly practical methods for the synthesis of functionalized hydrocarbons. Since the resultant hydrocarbon products have strong applicability as synthetic intermediates, numerous homogeneous organo(metallic) catalysts have been intensively utilized to date for reductive functionalization reactions. In particular, well-defined transition-metal-based catalysts capable of controlling the regio- or stereoselectivity of a product by harnessing the addition of H[E] (E = H, B, Si, Ge) into Cα–Cβ unsaturated bonds have drawn special attention. In this review, we describe recent examples of transition-metal catalytic systems (M = Fe, Co, Rh, Pd, Ni) for regio- or stereodivergent hydroelementation reactions of (conjugated) alkenes, alkynes, and allenes to give a pair of isomeric products in high selectivities from the same starting compounds simply by variation of the ligand. Mechanistic aspects of the ligand-controlled selectivity divergence are discussed in detail on the basis of experimental observations and/or computational insights.1 Introduction2 Hydroelementation of Alkenes and Alkynes3 Hydroelementation of Conjugated Dienes and Diynes4 Hydroelementation of Allenes5 Summary and Outlook

Four-Component Radical 1,2-Selenosulfonylation of Allenes.

Selenosulfones, as pivotal pharmaceutical molecule frameworks, have become a research hotspot in modern organic synthesis due to their vital need for efficient preparation. Herein, we have developed an iron-catalyzed four-component controllable radical tandem reaction of allenes involving cycloketone oxime esters, 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct (DABSO), and diphenyl diselenides for the synthesis of complex selenosulfones. This is the first case of achieving the 1,2-selenosulfonylation of allenes via a radical process, wherein precise control of radical rates and polarity matching enhance high regioselective conversion. The reaction conditions are ecofriendly and mild with step-efficiency by forming two new C-S bonds and one C-Se bond in one pot. Moreover, the 1,2-selenosulfonylation of allenes can be achieved by replacing cycloketone oxime esters with aryldiazonium tetrafluoroborates in this system.

Silanes as a versatile hydride source for Ni–H catalysis: a promising tool for π-hydro functionalization

Nickel-catalyzed hydrofunctionalization of π-substrates is a possibly effective method to synthesize several value-added molecular architectures. This review covers the NiH catalyzed hydrofunctionalization reactions of alkenes, alkynes and allenes.

Tandem Isomerization/α,β-Site-Selective and Enantioselective Addition Reactions of N-(3-Butynoyl)-3,5-dimethylpyrazole Induced by Chiral π-Cu(II) Catalysts.

Allenes are important building blocks, and derivatization of products via cycloadditions of allenes could become a powerful strategy for constructing carbocyclic and heterocyclic rings. However, the development of catalytic site-selective and enantioselective cycloaddition reactions of allenes still presents significant challenges. Here, we report chiral π-Cu(II)-complex-catalyzed isomerization of N-(3-butynoyl)-3,5-dimethyl-1H-pyrazole to generate N-allenoylpyrazole in situ and subsequent α,β-site-selective and enantioselective [3 + 2], [4 + 2], or [2 + 2] cycloaddition or conjugate addition reactions. The asymmetric environment created by the intramolecular π-Cu(II) interactions provides the corresponding adducts in moderate to high yield with excellent enantioselectivity. To the best of our knowledge, this is the first successful method for chiral-Lewis-acid-catalyzed tandem isomerization/α,β-site-selective and enantioselective cycloaddition or conjugate addition reactions of latent non-γ-substituted allenoyl derivative.

Experimental and Theoretical Study of Phosphine-Catalyzed Reaction Modes in the Reaction of α-Substituted Allenes with Aryl Imines.

A new phosphine-catalyzed reaction of α-substituted allenes with aryl imines, in stark contrast to classic cycloaddition reactions, has been developed. This reaction delivers valuable highly functionalized itaconimides with excellent stereoselectivities by a new uncyclized reaction mode involving β'-carbon of α-substituted allenes. Moreover, the present uncyclized reaction can also be carried out in a one-pot fashion and scaled up to the gram scale by using aryl aldehydes, without the need to isolate the aryl imines. Mechanistic studies and control experiments reveal the crucial role of H2CO3 for the present reaction mode. In addition, density functional theory (DFT) calculations were performed to understand the possible mechanism.

Unveiling the Chemistry and Synthetic Potential of Catalytic Cycloaddition Reaction of Allenes: A Review.

Allenes with two carbon-carbon double bonds belong to a unique class of unsaturated hydrocarbons. The central carbon atom of allene is sp hybridized and forms two σ-bonds and two π-bonds with two terminal sp2 hybridized carbon atoms. The chemistry of allenes has been well documented over the last decades. They are more reactive than alkenes due to higher strain and exhibit significant axial chirality, thus playing a vital role in asymmetric synthesis. Over a variety of organic transformations, allenes specifically undergo classical metal catalyzed cycloaddition reactions to obtain chemo-, regio- and stereoselective cycloadducts. This review briefly describes different types of annulations including [2+2], [2+2+1], [3+2], [2+2+2], [4+2], [5+2], [6+2] cycloadditions using titanium, cobalt, rhodium, nickel, palladium, platinum, gold and phosphine catalyzed reactions along with a mechanistic study of some highlighted protocols. The synthetic applications of these reactions towards the synthesis of natural products such as aristeromycin, ent-[3]-ladderanol, waihoensene(-)-vindoline and (+)-4-epi-vindoline have also been described.

Divergent Reactivity of Phosphorylated and Related Allenes: [4 + 2] Cycloaddition with 3,6-Diphenyltetrazine, Self-Addition Leading to Dimers and [Pd]-Complex Formation.

Phosphorus-based naphthalenes are formed by self-dimerization-cum-cyclization of α-aryl allenylphosphonates or allenylphosphine oxides using catalytic Pd(OAc)2in the presence of PPh3 and Et3N . This reaction involves [4 + 2]-cycloaddition with the (β,γ) double bond of one allene as the dienophile; the double bonds at the α-aryl-(β',γ') group and (α,β)-carbons of the second allene act as the diene part. A subsequent proton shift also takes place. Upon treating allenylphosphine oxides with Pd(OAc)2 [stoichiometry 2:1] in the presence of PPh3/Ag2CO3, a [Pd]-complex is isolated and structurally characterized. This complex can be used as a catalyst for C-C bond-forming reactions of phosphorus-based allenes with 2-iodophenol. Densely substituted 3,6-diphenylpyridazines are conveniently obtained in excellent yields by a thermally induced regioselective Inverse Electron Demand Diels-Alder (IEDDA) reaction of allenes with 3,6-diphenyltetrazine, followed by a [1,3]-H shift.

Titanium‐Catalyzed Intermolecular Hydroaminoalkylation of Allenes and Methylenecyclopropanes

AbstractIntermolecular hydroaminoalkylation reactions of 1,1‐ and 1,3‐disubstituted allenes as well as methylenecyclopropanes with secondary amines can be achieved in the presence of a 2,6‐bis(phenylamino)pyridinato titanium catalyst at 140 °C within 2–8 h. Corresponding reactions of allenes with N‐benzylanilines deliver branched allylamine products in very good yields (up to 83 %) and with branched‐linear‐ratios between 75 : 25 and 95 : 5. In contrast, bicyclic methylenecyclopropanes undergo hydroaminoalkylation with N‐benzylanilines or N‐alkylbenzylamines to give linear products in good to excellent yields (up to 98 %) with perfect regio‐ and diastereoselectivity. The corresponding 1,2,3‐trisubstituted (2‐aminoethyl)cyclopropane products exhibit a structurally interesting cis‐orientation of all three cyclopropane hydrogen atoms.

Theoretical insight into the mechanism of palladium-catalyzed oxidative cascade reaction of phenylacetylene and allenes with different assisting groups

The reaction mechanisms of the palladium-catalyzed oxidative cascade reaction of phenylacetylene and allenes with different assisting groups have been theoretically investigated with the aid of density functional theory calculations (DFT) calculations. Both reactions A (Pd(OAc)2-catalyzed cascade reactions of phenylacetylene with the allene bearing hydroxyl group) and B (Pd(OAc)2-catalyzed cascade reactions of phenylacetylene with the allene bearing p-toluenesulfonamide) involve sp3 CH activation processes, but the specific reaction mechanism is different due to allenes bearing different α-nucleophilic functionality in the substrate. On the basis of these mechanistic foundations, the influence of electronic effect and steric effect on chemoselectivity was illustrated. The present study provided more universal and deeper mechanistic insights into Pd-catalyzed oxidative cascade reaction of phenylacetylene and allenes with different α-nucleophilic functionality (e.g., OH, NHR).

Catalytic Asymmetric Syntheses of Alkylidenecyclopropanes from Allenoates with Donor-Acceptor and Diacceptor Diazo Reagents.

The first diastereo- and enantioselective cyclopropanation reactions of electron-deficient allenes with donor-acceptor and diacceptor diazo reagents are described. The desired enantioenriched alkylidenecyclopropanes (ACPs) were obtained in high yields with high diastereo- and enantioselectivities in the presence of Rh2 ((S)-TCPTAD)4 or Rh2 ((R)-BTPCP)4 catalysts (up to 95 % yield, >95 : 5 d.r. and 99 : 1 e.r.). This methodology gave a direct access to ACPs bearing multiple electron-deficient substituents and allows to further expand the availability of ACPs chemistry. Interestingly, during the examination of the scope of this reaction, the asymmetric intramolecular C-H insertion reaction into tert-butyl group was observed as a side reaction with up to 94 : 6 e.r.

Copper-catalyzed regio- and stereo-selective hydrosilylation of terminal allenes to access (E)-allylsilanes

Regioselectivity and stereoselectivity control in hydrosilylation of terminal allenes is challeging. Although the selective synthesis of vinylsilanes, branched allylsilanes or linear (Z)-allylsilanes have been achieved, transition-metal catalyzed hydrosilylation of terminal allenes to access (E)-allylsilane is difficult. Herein, we report a copper-catalyzed selective hydrosilylation reaction of terminal allenes to access (E)-allylsilanes under mild reaction conditions. The reaction shows broad substrate scope, representing an efficient method to prepare trisubstituted (E)-allylsilanes through hydrosilylation reaction of allenes and can also be applied in the synthesis of disubstituted (E)-allylsilanes. The mechanism study reveals that the E-selectivity is kinetically controlled by the catalyst but not by the thermodynamically isomerization of the (Z)-isomer.