铱催化不对称烯丙基取代反应的研究进展

铱催化不对称烯丙基取代反应是一种合成手性支链化合物的重要方法, 综述了近年来铱催化的烯丙基衍生物取代反应的研究进展, 重点讨论了配体和烯丙基衍生物结构, 亲核试剂的类型, 溶剂及添加剂等因素对烯丙基取代反应的影响, 并对烯丙基取代反应的对映选择性和区域选择性进行了探讨.     

A facile highly regio- and stereoselective preparation of N-tosyl allylic amines from allylic alcohols and tosyl isocyanate via Palladium(II)-catalyzed aminopalladation-beta-heteroatom elimination

The high regio- and stereoselectivity have been obtained from the allylic substitution reaction catalyzed by palladium(II) species. From allylic alcohols, one-pot reaction with tosyl isocyanate followed by palladium(II)-catalyzed allylic substitution gives N-tosyl (E)-allylic amines in high yield. The substitution occurs only at the gamma-position of the 1- or 3-substituted allylic alcohols.     

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.     

Iridium‐Catalyzed Regio‐ and Enantioselective Allylic Substitution of Silyl Dienolates Derived from Dioxinones

Reported herein is the iridium‐catalyzed regio‐ and enantioselective allylic substitution reactions of unstabilized silyl dienolates derived from dioxinones. Asymmetric allylic substitution of a variety of allylic trichloroethyl carbonates with these silyl dienolates gave γ‐allylated products selectively in 60–84 % yield and 90–98 % ee.     

Scope and mechanism of formal S(N)2' substitution reactions of a monomeric imidozirconium complex with allylic electrophiles

The zirconium imido complex Cp2(THF)Zr=NSi(t-Bu)Me2 (1) reacts with allylic ethers, chlorides, and bromides to give exclusively the products of the SN2' reaction; i.e., attack at the allylic position remote from the leaving group with migration of the double bond. The primary amine products can be isolated in excellent yields, after in situ Cbz protection, in the presence of variety of functional groups. Good diastereoselectivity and complete stereoselectivity allowed the formation of enantioenriched allylic amines from enantioenriched allylic ethers. Regiospecific substitution with 1 has also been achieved with allylic fluorides, which are notoriously poor substrates in other substitution reactions. On the basis of rate and kinetic isotope effect studies, we propose a general mechanism for the allylic substitution reactions with 1 which involves dissociation of THF and binding of the substrate, followed by the substitution step. In a DFT study of the substitution reaction, we identified a six-membered closed transition state for the substitution step and other relevant stationary points along the reaction coordinate. This study shows that the substitution reaction can be described as a concerted asynchronous [3,3]-sigmatropic rearrangement. This detailed knowledge of the reaction mechanism provides a rationale for the origins of the observed regio-, diastereo-, and stereoselectivity and of the unusual reactivity profile observed in the reaction.     

Zirconium-mediated SN2' substitution of allylic ethers: regio- and stereospecific formation of protected allylic amines

A new zirconium-mediated, regio- and stereospecific SN2' substitution of allylic ethers with a nitrogen nucleophile has been developed. Cbz-protected amine products were isolated in high yield from reactions with a wide range of Z allylic ethers. A mechanism of the allylic substitution consistent with the results of the kinetics and kinetic isotope effect studies was proposed.     

Selective synthesis of allylated oxime ethers and nitrones based on palladium-catalyzed allylic substitution of oximes

[reaction: see text] The viability of oximes as nucleophiles in transition-metal-catalyzed allylic substitution was examined. The oxygen atom of oxime acted as a reactive nucleophile in the reaction of a pi-allyl palladium complex. In the presence of Pd(PPh3)4, the allylic substitution of oximes with allylic carbonate afforded the linear O-allylated oxime ethers selectively without a base. In contrast, the palladium-catalyzed reaction with allylic acetate proceeded smoothly in the presence of K2CO3 or Et2Zn as a base. Selective formation of nitrones was achieved by using palladium(II) catalyst. In the presence of Pd(cod)Cl2, the allylic substitution of oximes with allylic acetate afforded the N-allylated nitrones under solvent-free conditions, as a result of the reaction with the nitrogen atom of oximes.     

Stereodivergent synthesis of 1,4-bifunctional compounds by regio- and diastereoselective Pd-catalyzed allylic substitution reaction

Highly stereoselective synthesis of 1,4-bifunctional compounds was accomplished via 1,2-asymmetric induction to α-oxyaldehyde and α-oxyketone followed by regio- and diastereoselective Pd-catalyzed allylic substitution reaction. We found that trifluoroacetate is a suitable leaving group for the allylic substitution reaction. Various nucleophiles containing carbon, nitrogen, and sulfur can be applied to the method. Both 1,4-syn- and 1,4-anti-adducts were synthesized with high stereoselectivity by using stereodivergent reduction of the propargyl alcohols followed by allylic substitution reaction.     

Origins of enantioselectivity during allylic substitution reactions catalyzed by metallacyclic iridium complexes

In depth mechanistic studies of iridium catalyzed regioselective and enantioselective allylic substitution reactions are presented. A series of cyclometalated allyliridium complexes that are kinetically and chemically competent to be intermediates in the allylic substitution reactions was prepared and characterized by 1D and 2D NMR spectroscopies and single-crystal X-ray difraction. The rates of epimerization of the less thermodynamically stable diastereomeric allyliridium complexes to the thermodynamically more stable allyliridium stereoisomers were measured. The rates of nucleophilic attack by aniline and by N-methylaniline on the isolated allyliridium complexes were also measured. Attack on the thermodynamically less stable allyliridium complex was found to be orders of magnitude faster than attack on the thermodynamically more stable complex, yet the major enantiomer of the catalytic reaction is formed from the more stable diastereomer. Comparison of the rates of nucleophilic attack to the rates of epimerization of the diastereomeric allyliridium complexes containing a weakly coordinating counterion showed that nucleophilic attack on the less stable allyliridium species is much faster than conversion of the less stable isomer to the more stable isomer. These observations imply that Curtin-Hammett conditions are not met during iridium catalyzed allylic substitution reactions by η(3)-η(1)-η(3) interconversion. Rather, these data imply that when these conditions exist for this reaction, they are created by reversible oxidative addition, and the high selectivity of this oxidative addition step to form the more stable diastereomeric allyl complex leads to the high enantioselectivity. The stereochemical outcome of the individual steps of allylic substitution was assessed by reactions of deuterium-labeled substrates. The allylic substitution was shown to occur by oxidative addition with inversion of configuration, followed by an outer sphere nucleophilic attack that leads to a second inversion of configuration. This result contrasts the changes in configuration that occur during reactions of molybdenum complexes studied with these substrates previously. In short, these studies show that the factors that control the enantioselectivity of iridium-catalyzed allylic substitution are distinct from those that control enantioselectivity during allylic substitution catalyzed by palladium or molybdenum complexes and lead to the unique combination of high regioselectivity, enantioselectivity, and scope of reactive nucleophile.     

A phosphorimidate rearrangement for the facile and selective preparation of allylic amines

Allylic phosphorimidates, readily prepared from the combination of an allylic alcohol, an azide, and a chlorophosphite, undergo [3,3]-rearrangement under thermal conditions to provide single isomers of allylic phosphoramidates. This new rearrangement is tolerant of a range of substitution patterns on the reactants. Treatment of the products of the rearrangement with ethanethiolate followed by acid produces a protected allylic amine. This strategy thus provides an attractive and versatile procedure for the preparation of key synthetic intermediates, allylic amines.     

Practical Pd/C-mediated allylic substitution in water

Pd/C-mediated allylic substitution in water is described as an interesting alternative to classical homogeneous conditions. The reaction applied to allylic acetates showed a wide range of compatibility with various nitrogen, sulfur, oxygen, and carbon nucleophiles. Notably, the method features inexpensive reagents and a nontoxic solvent. Moreover, measurement of the palladium content in water by ICP-MS shows low palladium contamination (4 ppm) of the solvent, rendering this method safer for the environment compared to homogeneous conditions. The first asymmetric example of Pd/C-mediated allylic substitution is also disclosed.     

Fluorinated alcohols as promoters for the metal-free direct substitution reaction of allylic alcohols with nitrogenated, silylated, and carbon nucleophiles

The direct allylic substitution reaction using allylic alcohols in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and 2,2,2-trifluoroethanol (TFE) as reaction media is described. The developed procedure is simple, works under mild conditions (rt, 50 and 70 °C), and proves to be very general, since different nitrogenated nucleophiles and carbon nucleophiles can be used achieving high yields, especially when HFIP is employed as solvent and aromatic allylic alcohols are the substrates. Thus, sulfonamides, carbamates, carboxamides, and amines can be successfully employed as nitrogen-based nucleophiles. Likewise, silylated nucleophiles such as trimethylsilylazide, allyltrimethylsilane, trimethylsilane, and trimethylsilylphenylacetylene give the corresponding allylic substitution products in high yields. Good results for the Friedel-Crafts adducts are also achieved with aromatic compounds (phenol, anisole, indole, and anilines) as nucleophiles. Particularly interesting are the results obtained with electron-rich anilines, which can behave as nitrogenated or carbon nucleophiles depending on their electronic properties and the solvent employed. In addition, 1,3-dicarbonyl compounds (acetylacetone and Meldrum's acid) are also successfully employed as soft carbon nucleophiles. Studies for mechanism elucidation are also reported, pointing toward the existence of carbocationic intermediates and two working reaction pathways for the obtention of the allylic substitution product.     

High diversity on simple substrates: 1,4-dihalo-2-butenes and other difunctionalized allylic halides for copper-catalyzed S(N)2' reactions

Enantioselective allylic alkylation with an organomagnesium reagent catalyzed by copper thiophene carboxylate (CuTC) was carried out on difunctionalized substrates, such as commercially available 1,4-dichloro-2-butene and 1,4-dibromo-2-butene, and on similar compounds of higher substitution pattern of the olefin for the formation of all-carbon chiral quaternary centers. The high regioselectivity obtained throughout the reactions favored good regiocontrol for the addition of phenyl Grignard reagents. Other difunctionalized substrates (allylic ethers and allylic alcohols) also underwent asymmetric S(N)2' substitution.     

Stereoselective and diversity-oriented synthesis of trisubstituted allylic alcohols and amines

Stereoselective and diversity-oriented synthesis of trisubstituted olefins was achieved by using ortho-diphenylphosphanyl benzoate (o-DPPB) as a directing group for allylic substitution. The starting point of this methodology was a set of α-methylene aldehydes derived from Baylis-Hillman adducts. Subsequent addition of different organometallic reagents led to a variety of allylic alcohol substrates. After introduction of the reagent-directing o-DPPB group, copper-mediated allylic substitution with a wide range of Grignard reagents enabled the stereoselective construction of a large number of E-configured trisubstituted allylic alcohols and amines in excellent yields and stereoselectivities. Remarkable is the synthetic flexibility, which allows a wide range of permutations starting from an aldehyde followed by successive introduction of the substituents R(2) and R(3) from organometallic Grignard based reagents. Thus, starting from only a few precursors, a diversity-oriented synthesis of stereodefined trisubstituted allylic alcohols and amines becomes possible.     

Iridium‐Catalyzed Enantioselective Allylic Substitution of Unstabilized Enolates Derived from α,β‐Unsaturated Ketones

We report Ir‐catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β‐unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62–94 % yield with 90–98 % ee and >20:1 branched‐to‐linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI‐9826.     

Synthesis of chiral oxime ethers based on regio- and enantioselective allylic substitution catalyzed by iridium-pybox complex

The oxygen atom of oximes acts as a reactive nucleophile in the iridium-catalyzed allylic substitution of unsymmetrical substrates to give the branched oxime ethers. Among several chiral ligands evaluated, the iridium complex of pybox ligand having phenyl group catalyzed the allylic substitution of phosphates with high activity to form the branched oxime ethers with good enantioselectivities.     

Strategy for employing unstabilized nucleophiles in palladium-catalyzed asymmetric allylic alkylations

We report a strategy for the employment of highly unstabilized anions in palladium-catalyzed asymmetric allylic alkylations (AAA). The "hard" 2-methylpyridyl nucleophiles studied are first reacted in situ with BF3.OEt2; subsequent deprotonation of the resulting complexes with LiHMDS affords "soft" anions that are competent nucleophiles in AAA reactions. The reaction is selective for the 2-position of methylpyridines and tolerates bulky aryl and alkyl substitution at the 3-, 4-, and 5-positions. Investigations into the reaction mechanism demonstrate that the configuration of the allylic stereocenter is retained, consistent with the canonical outer sphere mechanism invoked for palladium-catalyzed allylic substitution processes of stabilized anions.     

Ir‐Catalysed Asymmetric Allylic Substitutions with Cyclometalated (Phosphoramidite)Ir Complexes—Resting States,Catalytically Active (π‐Allyl)Ir Complexes and Computational Exploration

Mechanistic aspects of allylic substitutions with iridium catalysts derived from phosphoramidites by cyclometalation were investigated. The determination of resting states by ³¹P NMR spectroscopy led to the conclusion that the cyclometalation process is reversible. A novel, one‐pot procedure for the preparation of (π‐ allyl)Ir complexes was developed, and these complexes were characterised by X‐ray crystal structure analyses and spectral data. They are fully active catalysts of the allylic substitution reaction. DFT calculations on the allyl complexes, transition states of the allylic substitution and product olefin complexes gave further mechanistic insight.     

Palladium-catalyzed substitution reactions of 4-allylimidazole derivatives

In the context of synthetic studies toward the oroidin family of pyrrole-imidazole alkaloids, we required an efficient method for conducting substitution reactions of allylic alcohols derived from urocanic acid. While in some cases this could be accomplished quite readily by classical nucleophilic substitution, it was complicated by allylic transposition in others. Application of Pd-catalyzed π-allyl chemistry provided a convenient solution, giving substitution without allylic transposition. Herein we describe the scope of this reaction in imidazole-containing substrates, and the elaboration of one adduct into a homologated histidine derivative, and into a cyclic homohistidine derivative.     

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.