Enantioselective Synthesis of Tertiary Allylic Fluorides by Iridium‐Catalyzed Allylic Fluoroalkylation

Few allylic electrophiles containing two different substituents at a single allyl terminus and none in which one of the two substituents is a heteroatom, have been shown previously to react with iridium catalysts to form substitution products. We report that iridium‐catalysts are uniquely suited to form tertiary allylic fluorides enantioselectively by the addition of a diverse range of carbon‐centered nucleophiles at the fluorine‐containing terminus of 3‐fluoro‐substituted allylic esters. The products contain tertiary stereogenic centers bearing a single fluorine, which are isosteric with common tertiary stereocenters containing a single hydrogen. Computational studies reveal the principal steric interactions influencing the stability of endo and exo π‐allyl intermediates formed from 3,3‐disubstituted allylic electrophiles.     

Nickel‐Catalyzed Allylic Alkylation with Diarylmethane Pronucleophiles: Reaction Development and Mechanistic Insights

Palladium‐catalyzed allylic substitution reactions are among the most efficient methods to construct C?C bonds between sp³‐hybridized carbon atoms. In contrast, much less work has been done with nickel catalysts, perhaps because of the different mechanisms of the allylic substitution reactions. Palladium catalysts generally undergo substitution by a “soft”‐nucleophile pathway, wherein the nucleophile attacks the allyl group externally. Nickel catalysts are usually paired with “hard” nucleophiles, which attack the metal before C?C bond formation. Introduced herein is a rare nickel‐based catalyst which promotes substitution with diarylmethane pronucleophiles by the soft‐nucleophile pathway. Preliminary studies on the asymmetric allylic alkylation are promising.     

Nickel‐Catalyzed Direct Coupling of Allylic Alcohols with Organoboron Reagents

The direct coupling of allylic alcohols with arylboronic acids or their derivatives catalyzed by Ni(cod)₂ in the presence of a catalytic amount of base has been developed. A wide variety of allylic substrates or arylboronic acids turned out to be applicable to this catalytic system. The present method does not require the use of ligands for stabilizing the nickel catalyst in most cases or additional activators for activation of allylic alcohols.     

Palladium‐Catalyzed Substitution of Allylic Fluorides

As unusual substrates for the Tsuji–Trost allylation reaction, allylic fluorides are responsive to palladium‐catalyzed substitution. Their activity towards this reaction fits in the series OCO₂Me>OBz? F ?OAc. The classic stereoretention mechanism that involves sequential inversions does not operate in this case. Several distinct cases are considered.

     

Palladium‐Catalyzed Aminocarbonylation of Allylic Alcohols

A benign and efficient palladium‐catalyzed aminocarbonylation reaction of allylic alcohols is presented. The generality of this novel process is demonstrated by the synthesis of β,γ‐unsaturated amides including aliphatic, cinnamyl, and terpene derivatives. The choice of ligand is crucial for optimal carbonylation processes: Whereas in most cases the combination of PdCl₂ with Xantphos ( L6 ) gave best results, sterically hindered substrates performed better in the presence of simple triphenylphosphine ( L10 ), and primary anilines gave the best results using cataCXium® PCy ( L8 ). The reactivity of the respective catalyst system is significantly enhanced by addition of small amounts of water. Mechanistic studies and control experiments revealed a tandem allylic alcohol amination/C?N bond carbonylation reaction sequence.     

Iridium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution of Trisubstituted Allylic Electrophiles

The first Ir‐catalyzed enantioselective allylation of trisubstituted allylic electrophiles has been developed. Through modification of the leaving group of allylic electrophiles, we found that trisubstituted allylic phosphates are suitable electrophiles for asymmetric allylation. The reaction of allylic phosphates with enol silanes derived from dioxinones gave allylated products in good yields with high enantioselectivities.     

Potassium Amide‐Catalyzed Benzylic C−H Bond Addition of Alkylpyridines to Styrenes

The benzylic functionalization of alkylpyridines is an important pathway for pyridine derivatives synthesis. The reaction partners, however, were mostly limited to highly reactive polar electrophiles. Herein, we report a potassium amide‐catalyzed selective benzylic C?H bond addition of alkylpyridines to styrenes. Potassium bis(trimethylsilyl)amide (KHMDS), a readily available Brønsted base, showed excellent catalytic activity and chemoselectivity. A series of alkylpyridine derivatives, including benzylic quaternary carbon substituted pyridines, were obtained in good to high yield. Preliminary mechanistic studies revealed that the deprotonation equilibrium is probably responsible for the excellent selectivity.     

Enantioselective Synthesis of Vicinal All‐Carbon Quaternary Centers via Iridium‐Catalyzed Allylic Alkylation

The development of the first enantioselective transition‐metal‐catalyzed allylic alkylation providing access to acyclic products bearing vicinal all‐carbon quaternary centers is disclosed. The iridium‐catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile‐derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo‐ and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all‐carbon quaternary stereocenters.     

Regio‐ and Enantioselective Synthesis of N‐Allylindoles by Iridium‐Catalyzed Allylic Amination/Transition‐Metal‐Catalyzed Cyclization Reactions

Regio‐ and enantioselective synthesis of N‐allylindoles was realized through an iridium‐catalyzed asymmetric allylic amination reaction with 2‐alkynylanilines and subsequent transition‐metal‐catalyzed cyclization reactions. The highly enantioenriched allylic amines prepared from Ir‐catalysis were treated with catalytic amount of NaAuCl₄ ? 2 H₂O or PdCl₂ providing various substituted N‐allylindoles in excellent yields and enantioselectivities.     

Nickel‐Catalyzed Allylmethylation of Alkynes with Allylic Alcohols and AlMe3: Facile Access to Skipped Dienes and Trienes

We present herein an unprecedented allylative dicarbofunctionalization of alkynes with allylic alcohols. This simple catalytic procedure utilizes commercially available Ni(COD)₂, triphenylphosphine, and inexpensive reagents, and delivers valuable skipped dienes and trienes with an all‐carbon tetrasubstituted alkene unit in a highly stereoselective fashion. Preliminary mechanistic studies support the reaction pathway of allylnickelation followed by transmetalation in this dicarbofunctionalization of alkynes.     

Catalytic Access to Functionalized Allylic gem‐Difluorides via Fluorinative Meyer–Schuster‐Like Rearrangement

An unprecedented approach for efficient synthesis of functionalized allylic gem‐difluorides via catalytic fluorinative Meyer–Schuster‐like rearrangement is disclosed. This transformation proceeded with readily accessible propargylic fluorides, and low‐cost B–F reagents and electrophilic reagents by sulfide catalysis. A series of iodinated, brominated, and trifluoromethylthiolated allylic gem‐difluorides that were difficult to access by other methods were facilely produced with a wide range of functional groups. Importantly, the obtained iodinated products could be incorporated into different drugs and natural products, and could be expediently converted into many other valuable gem‐difluoroalkyl molecules as well. Mechanistic studies revealed that this reaction went through a regioselective fluorination of alkynes followed by a formal 1,3‐fluorine migration under the assistance of the B–F reagents to give the desired products.     

Regio‐ and Enantioselective Synthesis of Sulfone‐Bearing Quaternary Carbon Stereocenters by Pd‐Catalyzed Allylic Substitution

Chiral sulfones are of great importance in medicinal chemistry and chemical synthesis. Efficient methods for preparing enantiomerically enriched sulfone‐containing molecules can therefore be of significant value; such methods, however, are uncommon. Herein, we report the first general palladium‐catalyzed sulfonylation of vinyl cyclic carbonates with sodium sulfinates. A series of enantiomerically enriched tertiary allylic sulfones were synthesized in good yields with excellent enantiomeric ratios. Both aliphatic‐ and aryl‐substituted vinyl cyclic carbonates are suitable reactants with excellent results. This reaction features broad substrates scope, readily available starting materials, excellent regio‐ and enantioselectivity, and synthesis of sulfone‐bearing quaternary carbon stereocenters. Through the sulfonylation of geranyl derived cyclic carbonate 1 h , we achieve the formal total synthesis of (+)‐agelasidine A.     

Ruthenium‐Catalyzed Tandem‐Isomerization/Asymmetric Transfer Hydrogenation of Allylic Alcohols

A one‐pot procedure for the direct conversion of racemic allylic alcohols to enantiomerically enriched saturated alcohols is presented. The tandem‐isomerization/asymmetric transfer hydrogenation process is efficiently catalyzed by [{Ru(p‐cymene)Cl₂}₂] in combination with the α‐amino acid hydroxyamide ligand 1 , and performed under mild conditions in a mixture of ethanol and THF. The saturated alcohol products are isolated in good to excellent chemical yields and in enantiomeric excess up to 93 %.     

Iridium‐Catalyzed Asymmetric Isomerization of Primary Allylic Alcohols

Nothing to sm(Ir)k at : Under appropriate reaction conditions, iridium hydride catalysts promote the isomerization of primary allylic alcohols. The best catalysts, like (R)‐ 1 (P green, O red, N blue, Ir yellow), deliver the desired chiral aldehydes with excellent enantioselectivity and good yields. Mechanistic hypotheses have been developed on the basis of preliminary investigations.