Palladium(O)-catalyzed allylic alkylation and amination of allylic phosphates

Allyl diethyl phosphates (1) can be easily substituted with malonates and amines in the presence of palladium(O) catalyst. Synthetic utility of the reaction is demonstrated by the sequential amination-amination and alkylation-amination of (Z)-4-acetoxybut-2-enyl diethyl phosphate (1b) with high regio- and stereoselectivity.     

Palladium(0)-catalyzed amination of allylic natural terpenic functionalized olefins

The palladium(0) catalyzed amination of allylic acetates and carbonates derivatives from terpenic olefins was carried out under mild conditions. The reaction offers a very good method for the preparation of allylic amines and thus to provide a useful entry to new functionalized terpenic olefin products. The mechanism involving a formation of p-allyl-palladium intermediate complex is in good agreement with the results obtained with the optically active substrates, as well as via an analysis of the observed regio-and stereoselectivity.      

Cu(I)-catalyzed allylic amination of olefins

The copper(I) complex [Cu(CH₃CN)₄]PF₆ catalyzes the allylic amination of alkenes by aryl hydroxylamine in fair to moderate yields. Unsymmetrical alkenes react with high regioselectivity with N-functionalization occuring at the less substituted vinylic carbon. Trapping experiments indicate that free PhNO is not an intermediate in these reactions.     

Mechanistic studies of copper(I)-catalyzed allylic amination

The reactions of nitrosobenzene and N,N'-diethyl-4-nitrosoaniline with [Cu(CH3CN)4]PF6 provide novel Cu(I) complexes, [Cu(PhNO)3]PF6 (1) and [Cu(Et2NPhNO)3]PF6 (2); in 2 the copper atom is N-coordinated to the nitrosoarenes in a distorted trigonal planar geometry. Complex 1 is strongly implicated as a reactive intermediate in the Cu(I)-catalyzed allylic amination of olefins based on (i) its isolation from the catalytic reaction, (ii) its stoichiometric regioselective allylic amination of alpha-methyl styrene (AMS), (iii) the non-involvement of free PhNO in its amination of AMS, and (iv) its function as a catalyst for the amination of alkenes from phenylhydroxylamine. The reaction between AMS and 1 (80 degrees C, dioxane) is first order in both alkene and 1. Relative rate studies of the reaction of 1 with para substituted AMS derivatives gives a Hammett rho value of -0.035. Alkene adducts isolated from the reaction of 1 with styrene and alpha-methylstyrene are formulated as [(PhNO)3Cu(eta(2)-alkene)]PF6 (7,8) on the basis of spectroscopic characterization and thermolysis. PM3 and DFT MO calculations support the role of [(alkene)Cu(RNO)3]+ and (eta(1)- or eta(3)-allyl)Cu(RNO)2(RNHOH)+ complexes as probable catalytic intermediates and address the origin of the distinctive reaction regioselectivity. A mechanistic scheme is proposed which is consistent with the accumulated experimental and computational results.     

Direct palladium(0)-catalyzed amination of allylic alcohols with aminonaphthalenes

The direct activation of CO bonds in allylic alcohols by palladium complexes has been accelerated by carrying out the reactions in the presence of titanium reagents. The palladium-catalyzed amination of allylic alcohols using aminonaphthalenes gave N-allylic naphthylamines in good yields. The monoallylation products are formed in the main.     

Cu(I)/Cu(II)-catalyzed allylic amination of alkenes

Allylic hydrocarbons are selectively converted to the corresponding allyl amines in good to excellent yield by reaction with aryl hydroxylamines catalyzed by a 1:1 mixture of CuCl and CuCl₂ (10 mol %). Under these conditions unsymmetrical olefins react highly regioselectively with N-functionalization at the less substituted vinylic carbon. Trapping experiments indicate that a free nitrosoarene is not an intermediate in these reactions.     

Gold(I)-catalyzed intramolecular amination of allylic alcohols with alkylamines

A 1:1 mixture of (1)AuCl [1 = P(t-Bu)(2)o-biphenyl] and AgSbF(6) catalyzes the intramolecular amination of allylic alcohols with alkylamines to form substituted pyrrolidine and piperidine derivatives. Gold(I)-catalyzed cyclization of (R,Z)-8-(N-benzylamino)-3-octen-2-ol (96% ee, 95% de) led to isolation of (R,E)-1-benzyl-2-(1-propenyl)piperidine in 99% yield with 96% ee, consistent with the net syn addition of the amine relative to the departing hydroxyl group.     

Iridium-catalyzed allylic vinylation and asymmetric allylic amination reactions with o-aminostyrenes

An Ir-catalyzed allylic vinylation reaction of allyl carbonates with o-aminostyrene derivatives has been realized, providing skipped (Z,E)-diene derivatives. With (E)-but-2-ene-1,4-diyl dimethyl dicarbonate as the substrate, an efficient enantioselective synthesis of 1-benzazepine derivatives via an Ir-catalyzed domino allylic vinylation/intramolecular allylic amination reaction has been developed. Mechanistic studies of the allylic vinylation reaction have been carried out, and the results suggest that the leaving group of the allylic precursor plays a key role in directing the reaction pathway. Screening of various allylic precursors showed that Ir-catalyzed reactions of allyl diethyl phosphates with o-aminostyrene derivatives proceed via an allylic amination pathway. A subsequent ring-closing metathesis (RCM) reaction of the amination products led to a series of enantiomerically enriched 1,2-dihydroquinoline derivatives. Their utility is indicated by an asymmetric total synthesis of (-)-angustureine.     

Palladium(0)-catalyzed rearrangement of allyl enol ethers to form chiral quaternary carbon centers via asymmetric allylic alkylation

Herein we report the first palladium(0)-catalyzed asymmetric allylic alkylation (AAA) of allyl enol ether via π-allylpalladium intermediate using Trost chiral diphosphine. This unprecedented reaction produced very rare α-aryl quaternary aldehydes with multi-functional groups. The main novelty in the chemistry demonstrates that enol ethers can be used as precursors for π-allylpalladium intermediates, an observation that is certainly rare and to the best of our knowledge, perhaps without prior precedent. Chiral ligand (R,R)-L3 was found to be optimal in this Pd-AAA reaction and provided good to excellent yield (80–95%) and enantioselectivity (70–90%) with a range of analogs.     

Enantioselective synthesis of acyclic allylic esters catalyzed by a palladium/BINAP(S) system

The synthesis of chiral nonracemic acyclic allylic pivalates via the Pd-catalyzed allylic substitution of racemic allylic carbonates is presented. Good to excellent enantioselectivities (up to 90%) were observed in several cases. An extraordinarily high preference for the production of the branched regioisomeric product is seen when starting from 3-buten-2-yl and crotyl substrates. A significant kinetic resolution (k_rel = 38) of the 1,3-dimethylallyl substrate was also observed, leading to the production of esters of both enantiomers of an allylic alcohol with a single enantiomer of catalyst.     

Ir-catalyzed asymmetric allylic amination using chiral diaminophosphine oxides

An Ir-catalyzed asymmetric allylic amination using chiral diaminophosphine oxide is described. Asymmetric allylic amination of terminal allylic carbonates proceeded in the presence of 2 mol % of Ir catalyst, 2 mol % of chiral diaminophosphine oxide, 5 mol % of NaPF₆, and BSA, affording the chiral branched allylic amines in up to 95% ee.     

New spiro phosphinooxazolines for palladium-catalyzed asymmetric allylic amination

The new conformational rigid spiro phosphinooxazolines 1 were synthesized from 7-bromo-1-indanone. The asymmetric catalytic potential of them was demonstrated in the asymmetric palladium catalyzed allylic amination. High yields and enantioselectivities were obtained with alkylamines.     

Palladium(0)-catalyzed Mizoroki-Heck reaction and Rh(I)-catalyzed asymmetric hydrogenation of polymer-supported dehydroalanine system

We have developed a practical route for the synthesis of peptides containing unnatural amino acids. Mizoroki-Heck reaction of polymer-supported dehydroalanine, followed by asymmetric hydrogenation was accomplished using Pd(0) and Rh(I)-DuPHOS catalysts, respectively, leading to 36 dipeptides containing phenylalanine derivatives with high stereocontrol.     

Tuneable asymmetric copper-catalysed allylic amination and oxidation reactions

Asymmetric allylic amination or oxidation can be achieved by reaction of an alkene with a peroxycarbamate catalysed by a chiral copper bis-oxazoline complex, and the reaction can be tuned to give either the amination or oxidation product by reagent choice.     

Palladium(II)-catalyzed aerobic intramolecular allylic CH activation for the synthesis of indolines

A method for the preparation of indolines via palladium-catalyzed aerobic intramolecular allylic CH activation was developed. Oxygen was successfully used as oxidant with catalytic amount of 1,4-benzoquinone. 16 examples were reported, the majority of substrates gave moderate to good yields.     

Mechanistic insights into the Pd(BINAP)-catalyzed amination of aryl bromides: kinetic studies under synthetically relevant conditions

Kinetic studies using reaction calorimetry were carried out under synthetically relevant conditions to study the mechanism of the amination of bromobenzene with primary and secondary amines using Pd(2)(dba)(3)/BINAP mixtures as well as preformed (dba)Pd(BINAP), (p-tolyl)(Br)Pd(BINAP), and Pd(BINAP)(2) complexes. The presence of a significant induction period in the reaction was attributed to the slow activation of the catalytic precursor, resulting in an increase in the concentration of active species within the catalytic cycle. The induction period can mask the true kinetics of the reaction, which exhibits positive order dependences on aryl bromide and amine and zero-order dependence on base. It is also determined that the bis-ligand complex Pd(BINAP)(2) does not play a role directly on the catalytic cycle. In addition to the conventionally accepted pathway involving oxidative addition of the aryl halide to (BINAP)Pd as the first step, a pathway initiated by addition of the amine to the catalyst is proposed and supported by kinetic modeling of sequential reaction experiments. A subtle dependence of the reaction mechanism on the relative concentrations of substrates is revealed in these studies. The dependence of the catalyst resting state on reaction conditions is also discussed. This work suggests that conclusions from kinetic studies may be meaningful only for the conditions under which they are carried out, calling into question the use of conventional kinetic methods in this system.     

Palladium(0)-catalyzed direct cross-coupling reaction of allylic alcohols with aryl- and alkenylboronic acids

Allylic alcohols can be used directly for the palladium(0)-catalyzed allylation of aryl- and alkenylboronic acids with a wide variety of functional groups. A triphenylphosphine-ligated palladium catalyst turns out to be most effective for the cross-coupling reaction and its low loading (less than 1 mol%) leads to formation of the coupling product in high yield. The Lewis acidity of the organoboron reagents and poor leaving ability (high basicity) of the hydroxyl group are essential for the cross-coupling reaction. The reaction process is atom-economical and environmentally benign, because it needs neither preparation of allyl halides and esters nor addition of stoichiometric amounts of a base. Furthermore, allylic alcohols containing another unsaturated carbon-carbon bond undergo arylative cyclization reactions leading to cyclopentane formation.     

Palladium/GF-Phos-catalyzed asymmetric carbenylative amination to access chiral pyrrolidines and piperidines

The cross-coupling of N-tosylhydrazones has emerged as a powerful method for the construction of structurally diverse molecules, but the development of catalytic enantioselective versions still poses considerable challenges and only very limited examples have been reported. We herein report an asymmetric palladium/GF-Phos-catalyzed carbenylative amination reaction of N-tosylhydrazones and (E)-vinyl iodides pendent with amine, which allows facile access to a range of chiral pyrrolidines and piperidines in good yields (45–93%) with up to 96.5 : 3.5 er. Moreover, mild conditions, general substrate scope, scaled-up preparation, as well as the efficient synthesis of natural product (−)-norruspoline are practical features of this method.

An efficient asymmetric palladium/GF-Phos-catalyzed carbenylative amination reaction to access structurally diverse chiral pyrrolidines and piperidines in good yields with high chemo-, regio- and enantioselectivities has been developed.

N-tosylhydrazones, readily prepared from aldehydes or ketones, served as a safe source of carbene precursors and have attracted much attention of chemists.¹N-tosylhydrazone-mediated applications have been continuously developed, such as cyclopropanation or cyclopropenation, X–H insertion, ylide formation, cycloaddition, aza-Wacker-type cyclization, asymmetric allylic substitution, etc.² Among them, transition-metal-catalyzed cross-coupling is one of the powerful protocols for C–X or C C bond formation in organic synthesis involving versatile intermediates, of which in situ generation of diazo compounds and carbene migratory insertion are considered key steps.^3–5 Over the past decades, considerable progress has been made in the asymmetric cross-coupling reactions of N-tosylhydrazones with various coupling partners, including cyclobutanols, terminal alkynes, silacyclobutanes and so on.⁴ Relatively, only a few examples focus on the cross-coupling reactions of aryl halides with N-tosylhydrazones involving benzyl metal intermediates [Scheme 1A, eqn. (a)].⁶ For example, Gu,^6a Wu,^6b Lassaletta^6c and coworkers have developed a palladium-catalyzed asymmetric synthesis of axial chiral compounds from aryl bromides and N-tosylhydrazones, ending with β-H elimination. Very recently, we realized palladium/GF-Phos catalyzed asymmetric three component cross-coupling reactions of aryl halides, N-tosylhydrazones, with terminal alkynes.^6f In contrast, much less progress has been made in N-tosylhydrazone-based carbenylative insertions from vinyl halides, which would generate a π-allylic metal intermediate followed by nucleophile attack, providing a unique approach for building C–X bonds, especially for N-heterocyclic compounds [Scheme 1A, eqn. (b)].⁷N-heterocycles are important structural motifs for the development of various types of valuable chemicals and materials.⁸ Importantly, optically active 2-substituted pyrrolidine and piperidine derivatives are privileged scaffolds in many natural products and pharmaceuticals with a wide range of biological activities,⁹ as well as the backbone of organocatalysts in asymmetric catalysis (Fig. 1).¹⁰Open in a separate windowScheme 1Asymmetric transition-metal-catalyzed carbenylative cross-coupling reactions.Open in a separate windowFig. 1Selected natural products and pharmaceuticals containing chiral 2-substituted pyrrolidine and piperidine units.Notably, Van Vranken and coworkers reported an elegant palladium-catalyzed carbenylative amination reaction of N-tosylhydrazones and (E)-vinyl iodides pendent with amine, providing facile access to pyrrolidine and piperidine ring systems that are common to alkaloid natural products (Scheme 1B).¹¹ Unfortunately, only up to 58.5 : 41.5 er was obtained after they made a lot of efforts to screen a series of chiral phosphine ligands, indicating that this asymmetric reaction indeed poses considerable challenges in addition to competitive side reactions such as the dimerization of vinyl iodides,¹² the formation of diene via the palladatropic rearrangement/β-H elimination or allene via β-H elimination from C_sp²,¹³ and the π-allylpalladium intermediate trapped by the byproduct sulfinic acid salt.¹⁴ Given the significance of chiral pyrrolidines and piperidines as core structures in alkaloid natural products, the development of an asymmetric version of this elegant carbenylative amination reaction is highly desirable. In recent years, our group has developed a series of chiral sulfinamide phosphine ligands (so-called Sadphos), which showed unique potential in asymmetric transition-metal catalysis,^6f,15 so we wondered whether Sadphos could address this challenging asymmetric carbenylative amination reaction (Scheme 1C).Initially, our study began with (E)-vinyl iodide 1a and N-tosylhydrazone 2a in the presence of Pd₂(dba)₃, t-BuOLi, Et₃N, and triethylbenzylammonium chloride (TEBAC) in THF at 30 °C. A series of commercially available chiral ligands were first screened (Fig. 2). Only (R, R)-DIOP (L1), (R)-DTBM-SegPhos (L3) and (R)-MOP (L4) provided the desired product 3aa with poor enantioselectivity and other ligands such as (R, R)-Ph-BPE (L2), (R, S)-Josiphos (L5) and (S, S)-ⁱPr-FOXAP (L6) showed low reactivity. We next turned to systematically investigate Sadphos, such as Wei-Phos,¹⁶ Xiao-Phos,^15d,17 Ming-Phos,^15a,18 Xu-Phos,^15b,19 Xiang-Phos²⁰ and PC-Phos^15c,21 (Fig. 2). To our delight, PC1 delivered 3aa in 32% yield and 85.5 : 14.5 er. Inspired by this result, we further screened PC2–PC5 which vary in the substituent of phenyl, but unfortunately none of them showed better results. Surprisingly, the reactivity of this reaction could be greatly improved with our recently developed GF-Phos GF1, delivering 71% yield. When steric hindered tert-butyl groups were introduced on the phenyl group (GF2), the product 3aa was obtained in 77% yield with 91.5 : 8.5 er. After screening different palladium catalysts and solvents (Open in a separate windowFig. 2Screened chiral ligands.Optimization of reaction conditions^a