Asymmetric (4+1) Annulations by Cascade Allylation and Transient σ-Alkyl-Pd(II) Initiated Allylic Csp3 -H Activation.

A unique Pd-catalyzed approach for asymmetric (4+1) annulations via cascade allylation and transient σ-alkyl-Pd(II) initiated methylene Csp3 -H activation is reported. The enolate fragment derived from the decarboxylation of vinyl methylene carbonate is crucial to stabilize the key intermediate. These reactions enable the synthesis of various useful dihydrobenzofurans with excellent enantioselectivity, typically >95 : 5 er, and exclusive (Z)-stereoselectivity. Compared with the well-established annulations via Heck-type C-H activations, this protocol showcases a conceptually new way to generate σ-alkyl-Pd(II) species that could initiate challenging asymmetric Csp3 -H activations.

Propargylic Amination Enabled the Access to Enantioenriched Acyclic α-Quaternary α-Amino Ketones.

A propargylic amination approach toward chiral acyclic α-quaternary α-amino ketones is described. This Cu-catalyzed procedure could be performed open to air using commercially available amines as nucleophiles. The key to success is the use of rationally designed propargylic cyclic carbonates as substrates, which can generate a Cu-bonded enolate zwitterionic intermediate upon decarboxylation. This protocol features wide functional group tolerance and high asymmetric induction, with typical ee value higher than 93%, and thus advances a great step forward in the challenging synthesis of acyclic chiral α-quaternary α-amino ketones.

An Update of Transition Metal-Catalyzed Decarboxylative Transformations of Cyclic Carbonates and Carbamates.

Functionalized cyclic organic carbonates and carbamates are frequently used in a number of transition metal-catalyzed decarboxylative reactions for the construction of interesting molecules. These decarboxylative transformations have attracted more and more research attention in recent years mainly due to their advantages of less waste generation and versatile reactivities. On the basis of previous reviews on this hot topic, the present review will focus on the development of transition metal-catalyzed decarboxylative transformations of functionalized cyclic carbonates and carbamates in the last two years.

A Domino Process toward Functionally Dense Quaternary Carbons through Pd-Catalyzed Decarboxylative C(sp3)-C(sp3) Bond Formation.

An efficient protocol was developed to construct functionally dense quaternary carbons with concomitant formation of a new Csp3-Csp3 bond via Pd-catalyzed decarboxylative transformation of vinyl cyclic carbonates. This redox-neutral catalytic system features stereocontrolled formation of multisubstituted allylic scaffolds with an aldehyde functionality generated in situ, and it typically can be performed at room temperature without any additives. DFT calculations provide a rationale toward the selective formation of these compounds and reveal a complex mechanism that with the help of microkinetic models is able to reproduce the nontrivial dependence of the identity of the product on the nature of the substituents in the substrate.

Catalytic Transformations of Functionalized Cyclic Organic Carbonates.

Functionalized cyclic organic carbonates and related heterocycles have emerged as highly versatile heterocyclic substrates for ring-opening and decarboxylative catalytic transformations allowing for the development of new stereo- and enantioselective C-N, C-O, C-C, C-S and C-B bond formation reactions. Transition-metal-mediated conversions have only recently been rejuvenated as powerful approaches towards the preparation of more complex molecules. This minireview will highlight the potential of cyclic carbonates and structurally related heterocycles with a focus on their synthetic value and the mechanistic manifolds that are involved upon their conversion.

Asymmetric Synthesis of α,α-Disubstituted Allylic Amines through Palladium-Catalyzed Allylic Substitution.

The first asymmetric synthesis of important α,α-disubstituted N-alkyl allyl amine scaffolds through allylic substitution is reported. This approach is based on palladium catalysis and features ample scope with respect to both the allylic precursor and amine reagent, and high asymmetric induction with enantiomeric ratios (e.r.) up to 98.5:1.5. The use of less-reactive anilines is also feasible, providing enantioenriched α,α-disubstituted N-aryl allylic amines.

Copper-Catalyzed Synthesis of γ-Amino Acids Featuring Quaternary Stereocenters.

The first general asymmetric synthesis of γ,γ-disubstituted γ-amino acids by copper-catalyzed ring opening of nonstrained lactones with amines is reported. This approach features ample scope, operational simplicity, and wide functional-group diversity. The catalytic process allows access to a series of highly functionalized enantioenriched γ-amino acids featuring quaternary stereocenters with excellent enantiomeric ratios of up to 98:2 and excellent yields of up to 98 %.

Palladium-Catalyzed Regio- and Enantioselective Synthesis of Allylic Amines Featuring Tetrasubstituted Tertiary Carbons.

The first asymmetric synthesis of α,α-disubstituted allylic N-arylamines based on a palladium-catalyzed allylic amination has been developed. The protocol uses highly modular vinyl cyclic carbonates and unactivated aromatic amine nucleophiles as substrates. The catalytic process features minimal waste production, ample scope in reaction partners, high asymmetric induction up to 97% ee, and operational simplicity.

Stereoselective and Versatile Preparation of Tri- and Tetrasubstituted Allylic Amine Scaffolds under Mild Conditions.

Significant progress has been observed in recent years in the synthesis of allylic amines, which are important building blocks in synthetic chemistry. Most of these processes are effective toward the preparation of allylic amines, with limited potential to introduce three or four different substituents on the olefinic unit in a stereocontrolled fashion. Therefore, the discovery of a mild and operationally simple protocol allowing such challenging stereoselective synthesis of multisubstituted allylic amines remains an inspiring target. Herein, we report the first general and practical methodology for the stereoselective synthesis of tri- and tetrasubstituted allylic amines based on Pd-catalyzed conversion of allyl surrogates readily obtained from cyclic vinyl carbonates. These rare conversions are characterized by excellent stereoselectivity, operational simplicity, mild reaction conditions, and wide scope in reaction partners. DFT studies were performed to rationalize the stereocontrol in these allylic amine formation reactions, and evidence is provided that the formation of a six-membered palladacyclic intermediate leads toward the formation of (Z)-configured allylic amine products.

Stereodivergent Carbamate Synthesis by Selective in Situ Trapping of Organic Carbonate Intermediates.

Trans carbamates have been prepared in a diastereoselective approach by a judicious one-pot combination of organic carbonates, prepared in situ, and suitable amine reagents under appropriate reaction conditions. This unprecedented approach allows for stereodivergence from a single oxirane substrate with easy access to both cis and trans carbamate isomers with high stereoselectivity (>19:1 d.r.). Key to the control of the diastereoselective nature of the conversions that lead to the trans carbamates is the in situ formation of trans-configured oligo/polycarbonates through Al catalysis, which provides the targeted products after aminolysis. The present results demonstrate the valorization of a renewable carbon-based reagent (CO2) into new valuable scaffolds and an unusual stereocontrol exerted through carbonate intermediates. A series of control experiments support the proposed mechanistic rationale towards the trans carbamate products, which is based on the trapping of an in situ formed trans-configured oligo/polycarbonate.

Highly Efficient Catalytic Formation of (Z)-1,4-But-2-ene Diols Using Water as a Nucleophile.

The first general catalytic and highly stereoselective formation of (Z)-1,4-but-2-ene diols is described from readily available and modular vinyl-substituted cyclic carbonate precursors using water as a nucleophilic reagent. These 1,4-diol scaffolds can be generally prepared in high yields and with ample scope in reaction partners using a simple synthetic method that does not require the presence of any additive or any special precaution unlike the stoichiometric approaches reported to date. Control experiments support the mechanistic view that hyperconjugation within the catalytic intermediate after decarboxylation plays an imperative role to control the stereoselective outcome of these reactions.

Highly Chemoselective Catalytic Coupling of Substituted Oxetanes and Carbon Dioxide.

The chemoselective coupling of oxetanes and carbon dioxide to afford functional, heterocyclic organic compounds known as six-membered cyclic carbonates remains a challenging topic. Here, an effective method for their synthesis relying on the use of Al catalysis is described. The catalytic reactions can be carried out with excellent selectivity for the cyclic carbonate product tolerating various (functional) groups present in the 2- and 3-position(s) of the oxetane ring. The presented methodology is the first general approach towards the formation of six-membered cyclic carbonates (6MCCs) through oxetane/CO2 coupling chemistry. Apart from a series of substituted six-membered cyclic carbonates, also the unprecedented room-temperature coupling of oxetanes and CO2 is disclosed giving, depending on the structural features of the substrate, a variety of five- and six-membered heterocyclic products. A mechanistic rationale is presented for their formation and support for the intermediary presence of a carbonic acid derivative is given. The presented functional carbonates may hold great promise as building blocks in organic synthesis and the development of new, biodegradable polymers.

A Metal-Free Synthesis of N-Aryl Carbamates under Ambient Conditions.

The first chemo- and site-selective process for the formation of N-aryl-carbamates from cyclic organic carbonates and aromatic amines is reported. The reactions proceed smoothly under extremely mild reaction conditions using TBD (triazabicyclodecene) as an effective and cheap organocatalyst, thus providing a sustainable and new methodology for the formation of a wide variety of useful N-aryl carbamate synthons in good to excellent yields. Computational investigations have been performed and show the underlying reason for the observed unique reactivity as related to an effective proton-relay mechanism mediated by the bicyclic guanidine base.

Merging of Palladium and Organocatalysis Enabled Asymmetric Decarboxylative (2+1) Cycloadditions toward Cyclopropanes.

A cascade reaction enabling enantio- and diastereoselective construction of strained cyclopropanes is described. This asymmetric (2+1) annulation process uses vinyl methylene carbonate and 2-cyanoacrylate as reaction partners in the presence of Pd(PPh3)4 as a precatalyst and an enantioenriched phosphoramidite ligand featuring a morpholine functionality. Mechanistic investigations unveil that the PPh3 derived from the Pd(PPh3)4 and the morpholine-containing phosphoramidite work as cooperative phosphorus and Brønsted base catalysts to promote the reaction.

Direct arylation of oligonaphthalenes using PIFA/BF3·Et2O: from double arylation to larger oligoarene products.

Direct dehydrogenative coupling between the linear ter- and quaternaphthalenes and substituted benzenes was achieved under the Kita conditions using the hypervalent PIFA/BF3 reagent. Products resulting from either the double arylation of the naphthalenic substrate or the formal dimerizative arylation have been prepared. For example, in the latter mode, ternaphthalene was converted into a series of linear octiarenes (counting the capping Ar). The process represents an alternative to the cross-coupling methodologies employed in related syntheses and proceeds via a selective functionalization of six relatively inert aromatic CH bonds.

Modular Divergent Synthesis of Functionalized Indoles via TFA-Promoted Amino-Claisen Rearrangement at Room Temperature.

A conceptually novel approach for the modular and divergent synthesis of highly functionalized indoles via trifluoroacetic acid-promoted amino-Claisen rearrangement is reported. This metal-free protocol could be performed at room temperature with wide functional group tolerance. The substitution type of the resultant indoles could be easily adjusted by the variation of the starting propargyl amines. The resultant products could be easily transformed into different value-added indole derivatives with simple experimental operations.

Practical asymmetric amine nucleophilic approach for the modular construction of protected α-quaternary amino acids.

We report the first amine nucleophilic approach for the modular construction of enantioenriched protected α-quaternary amino acids. The key to success is the use of an alcohol solvent, which makes a rationally designed COOMe-bonded Cu-allenylidene electrophilic intermediate stable enough to couple with amine nucleophiles before its decomposition. The reaction features wide functional group tolerance with high enantioselectivity, typically >90% ee, and is amenable to the modification of commercially available bioactive molecules. The resultant protected α-amino acids could be readily converted into a number of precious enantioenriched amines featuring α-hindered tertiary carbon centers, which are otherwise synthetically quite challenging, including those of α-amino aldehyde, peptides or α-vinyl amino ester with >92% ee in excellent yields. This protocol could be utilized for the synthesis of the protected bioactive α-ethylnorvaline in 3 steps, a significant advancement in comparison to an 11-step sequence reported previously.

Kinetically Controllable Construction of Nine-Membered Carbocycles via Pd-Catalyzed Decarboxylative Cycloaddition.

A kinetically controllable strategy toward the construction of otherwise challenging nine-membered carbocycles is reported. This Pd-catalyzed decarboxylative procedure utilizes vinyl methylene cyclic carbonates as the C5-dipole and allylidenemalononitriles as C4-building blocks. The protocol features user-friendly operations with controllable regioselectivity and generates CO2 as the sole byproduct. The formation of synthetically valuable and thermodynamically favored seven-membered carbocycles was also investigated.

Modular Domino Process toward Highly Functionalized Pyrroles via Pd-Catalyzed [4 + 1] Annulation under Mild Conditions.

A Pd-catalyzed decarboxylative approach for the modular synthesis of highly functionalized pyrroles is presented. This protocol utilizes readily available cyclic carbonates and amines as reaction partners and only generates CO2 and H2O as byproducts. This methodology could be operated at room temperature and open to air, thus serving as an ideal means for the derivatization of bioactive compounds. Mechanism investigations suggested that the stereoselective formation of the (Z)-configured γ-amino ketone intermediate is crucial for the success of the reaction.