Showing papers on "Alkylation published in 2008"
TL;DR: The conceptual basis and utility of the latest, "fourth-generation" palladium catalyst for the coupling of amines and related reagents with aryl halides is described and the effects of electronic properties on C-C and C-N bond-forming reductive elimination are similar.
Abstract: Many active pharmaceuticals, herbicides, conducting polymers, and components of organic light-emitting diodes contain arylamines. For many years, this class of compound was prepared via classical methods, such as nitration, reduction and reductive alkylation, copper-mediated chemistry at high temperatures, addition to benzyne intermediates, or direct nucleophilic substitution on particularly electron-poor aromatic or heteroaromatic halides. However, during the past decade, palladium-catalyzed coupling reactions of amines with aryl halides have largely supplanted these earlier methods. Successive generations of catalysts have gradually improved the scope and efficiency of the palladium-catalyzed reaction. This Account describes the conceptual basis and utility of our latest, "fourth-generation" palladium catalyst for the coupling of amines and related reagents with aryl halides. In the past five years, we have developed these catalysts using the lessons learned from previous generations of catalysts developed in our group and in other laboratories. The ligands on the fourth-generation catalyst combine the chelating properties of the aromatic bisphosphines of the second-generation systems with the steric properties and strong electron donation of the hindered alkylphosphines of the third-generation systems. The currently most reactive catalyst in this class is generated from palladium and a sterically hindered version of the Josiphos family of ligands that possesses a ferrocenyl-1-ethyl backbone, a hindered di-tert-butylphosphino group, and a hindered dicyclohexylphosphino group. This system catalyzes the coupling of aryl chlorides, bromides, and iodides with primary amines, N-H imines, and hydrazones in high yield. The reaction has broad scope, high functional group tolerance, and nearly perfect selectivity for monoarylation. It also requires the lowest levels of palladium that have been used for C-N coupling. In addition, this latest catalyst has dramatically improved the coupling of thiols with haloarenes to form C-S bonds. Using ligands that lacked one or more of the structural elements of the most active catalyst, we examined the effects of individual structural elements of the Josiphos ligand on catalyst activity. This set of studies showed that each one of these elements contributes to the high reactivity and selectivity of the catalyst containing the hindered, bidentate Josiphos ligand. Finally, we examined the effect of electronic properties on the rates of reductive elimination to distinguish between the effect of the properties of the M-N sigma-bond and the nitrogen electron pair. We have found that the effects of electronic properties on C-C and C-N bond-forming reductive elimination are similar. Because the amido ligands contain an electron pair, while the alkyl ligands do not, we have concluded that the major electronic effect is transmitted through the sigma-bond.
1,535 citations
TL;DR: The relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods are emphasized and researchers will better understand the details of the aforementioned Rh-catalyzed C-H bond functionalization reactions, resulting in the design of more efficient and robust catalysts, expanded substrate scope, and new transformations.
Abstract: Nitrogen heterocycles are present in many compounds of enormous practical importance, ranging from pharmaceutical agents and biological probes to electroactive materials. Direct functionalization of nitrogen heterocycles through C−H bond activation constitutes a powerful means of regioselectively introducing a variety of substituents with diverse functional groups onto the heterocycle scaffold. Working together, our two groups have developed a family of Rh-catalyzed heterocycle alkylation and arylation reactions that are notable for their high level of functional-group compatibility. This Account describes our work in this area, emphasizing the relevant mechanistic insights that enabled synthetic advances and distinguished the resulting transformations from other methods. We initially discovered an intramolecular Rh-catalyzed C-2 alkylation of azoles by alkenyl groups. That reaction provided access to a number of di-, tri-, and tetracyclic azole derivatives. We then developed conditions that exploited mic...
860 citations
TL;DR: In this paper, a catalytic system consisting of [Cp ∗ IrCl 2 ] 2 /NaHCO 3 for the N-alkylation of amines with primary and secondary alcohols as alkylating reagents has been developed.
274 citations
248 citations
TL;DR: In the past two decades, the asymmetric additions of organometallic reagents to the CdN double bonds of imines in the presence of a stoichiometric or catalytic amount of a chiral ligand have been developed as a new technology for the synthesis of optically active amines, including alkaloids.
Abstract: The catalytic asymmetric addition reactions of organometallic reagents to CdN double bonds of imines are fundamentally important processes, which provide convenient and versatile routes to optically active amines bearing a stereogenic center at the R-position. Optically active R-branched amines are important chiral building blocks, and are abundantly present in biologically active compounds, such as methoxyphenamine (a 2-adrenergic antagonist for treatment of asthma), rivastigmine (an AcCh esterase inhibitor for treatment of Alzheimer’s disease), tamsulosin (a selective R1-adrenergic antagonist to improve urinary trouble due to prostatic hyperplasia), and repaglinide (a blocker of ATP-dependent K channels in cells used as a hypoglycemic agent) (Figure 1). Asymmetric addition to CdN double bonds has been achieved based on the use of a chiral auxiliaries or chiral ligands. In 1982, Takahashi and co-workers reported the pioneering work of a chiral auxiliary-controlled asymmetric addition of organolithium reagents to imines 1 derived from aldehydes and valinol or phenylglycinol (Scheme 1). The chiral auxiliary strategy is still an important technology from a practical point of view because separation of the diastereomeric products prior to cleavage of the chiral auxiliary provides enantiomerically pure products. In the past two decades, the asymmetric additions of organometallic reagents to the CdN double bonds of imines in the presence of a stoichiometric or catalytic amount of a chiral ligand have been developed as a new technology for the synthesis of optically active amines, including alkaloids. The ligandinduced enantioselective synthesis has the potential for direct recovery and reuse of the unchanged chiral ligands. In 1990, Tomioka and co-workers reported the first chiral ligandcontrolled asymmetric addition reaction of organometallic compounds to CdN double bonds of imines with organolithium reagents activated by a chiral amino ether ligand 5 (Scheme 2). Even with 5 mol % of ligand 5, enantiomerically enriched amine 6 was produced, though with moderate ee, opening up the door to catalytic asymmetric addition reactions of organometallic reagents to a CdN double bond of an imine. Denmark and co-workers also showed the excellent ability of asymmetric induction of (-)-sparteine and bisoxazoline ligands and the catalytic use of these ligands for addition of organolithium reagents to imines (Scheme 3). In 1992, Soai and co-workers reported the first catalytic asymmetric addition reaction of a dialkylzinc reagent to a CdN double bond. In the presence of chiral amino alcohol 11, addition of dialkylzinc reagents to N-(diphenylphosphinoyl) imines proceeded with high enantioselectivity (Scheme 4). Surprisingly good enantioselectivity was observed even with 10 mol % of the amino alcohol, although the chemical yield was not satisfactory. Since these early examples, considerable energetic approaches toward the catalytic asymmetric addition of organometallic reagents to CdN double bonds of imines have appeared. Among these, chiral π-allylpalladium-catalyzed allylation with allylstannane or allylsilane, and rhodiumMOP-based phosphine-catalyzed arylation with arylstannanes showed impressive early success. A key concept is catalytic generation of reactive organometal-chiral ligand complexes from corresponding less reactive organometallic reagents in situ. Excellent feature articles have been published on this exciting topic. However, in great contrast to the chiral amino alcohol catalyzed asymmetric alkylation of aldehydes with organozinc reagents, which has become a very effective and general method, the catalytic asymmetric * To whom correspondence should be addressed. Tel: 81-(0)75-753-4553. Fax: 81-(0)75-753-4604. E-mail: tomioka@pharm.kyoto-u.ac.jp. Chem. Rev. 2008, 108, 2874–2886 2874
243 citations
TL;DR: The first catalytic direct alkylation of allylic C-H bonds via Pd(II)-catalysis is described in the absence of base, and polysubstituted cyclic compounds can be constructed by the intramolecular direct allylicAlkylation.
Abstract: The first catalytic direct alkylation of allylic C−H bonds via Pd(II)-catalysis is described in the absence of base. Polysubstituted cyclic compounds can also be constructed by the intramolecular direct allylic alkylation.
227 citations
TL;DR: The compound [IrCl(2)Cp*(I(nBu))] showed to be highly effective in the cross-coupling reactions of amines and alcohols, providing high yields in the production of unsymmetrical ethers and N-alkylated amines.
Abstract: A comparative study on the catalytic activity of a series of [IrCl 2 Cp*(NHC)] complexes in several C-O and C-N coupling processes implying hydrogen-borrowing mechanisms has been performed. The compound [IrCl 2 Cp*(I nBu )] (Cp* = pentamethyl cyclopentadiene; I nBU =1,3-di-n-butylimidazolylidene) showed to be highly effective in the cross-coupling reactions of amines and alcohols, providing high yields in the production of unsymmetrical ethers and N-alkylated amines. A remarkable feature is that the processes were carried out in the absence of base, phosphine, or any other external additive. A comparative study with other known catalysts, such as Shvo's catalyst, is also reported.
222 citations
TL;DR: The first electrophilic Pd(II)-catalyzed allylic C H alkylation is reported, providing a novel method for formation of sp3-sp3 C C bonds directly from C H bonds.
Abstract: The first electrophilic Pd(II)-catalyzed allylic C—H alkylation is reported, providing a novel method for formation of sp3−sp3 C—C bonds directly from C—H bonds. A wide range of aromatic and heteroaromatic linear (E)-α-nitro-arylpentenoates are obtained as single olefin isomers in excellent yields directly from terminal olefin substrates and methyl nitroacetate. The use of DMSO as a π-acidic ligand was found to be crucial for promoting functionalization of the π-allylPd intermediate. Products from this reaction are valuable synthetic intermediates and are readily transformed to amino esters via selective reduction and optically enriched α,α-disubstituted amino acid precursors via asymmetric conjugate addition.
221 citations
TL;DR: An organocatalytic domino Michael addition/alkylation reaction between aliphatic aldehydes and (E)-5-iodo- 1-nitropent-1-ene (B) involving enamine–enamine activation and a novel cyclic g-amino acid was easily synthesized from the domino product in two steps.
Abstract: The development of asymmetric reactions using small organic molecules as catalysts, which are often nontoxic, environmentally friendly, and stable under aerobic and aqueous reaction conditions, has attracted much attention in recent years. Domino reactions provide an efficient means to construct complex molecules in a single process, while minimizing the number of manual operations and the generation of chemical waste and easing purification. Organocatalytic domino reactions can combine these advantages, and many interesting reactions have been developed during the past few years. The asymmetric secondary-amine-catalyzed Michael addition of aldehydes and ketones to nitroalkenes is a direct entry to g-nitroaldehydes and -ketones, which has been applied by our group in organocatalytic triple-cascade reactions. In 2004, List and Vignola reported the first catalytic asymmetric intramolecular a-alkylation of aldehydes. Asymmetric organocatalytic domino reactions consisting of a Michael addition and an alkylation have been recently developed to form enantioenriched and highly functionalized cyclopropane and cyclopentane derivatives. These reactions involve iminium–enamine activation and utilize a,b-unsaturated aldehydes and bromomalonates or bromo-b-ketoesters. We envisaged aldehydes A and the wiodonitroalkene B as potential substrates for a domino reaction made up of Michael addition and intramolecular alkylation, leading to either the cyclopentanecarbaldehydesC or the classical Michael-initiated ring-closure (MIRC) products D (Scheme 1). While the MIRC compounds D are not observed, the cyclic g-nitro-substituted aldehydes C are synthetically useful compounds, which may be converted into cyclic g-amino acids containing an all-carbon-substituted quaternary stereogenic center considered as a challenging task. g-Aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system of mammals, and many of its derivatives show biological activity. For example, Gabapentin, Pregabalin, and Vigabatrin have been commercialized as drugs to treat neurological disorders. Thus, the efficient stereoselective synthesis of gamino acids is of great interest, and many asymmeric auxiliary-based and metal-catalyzed methods have been developed. Recently, organocatalytic asymmetric syntheses of acyclic g-amino acids have been reported. Herein we report an organocatalytic domino Michael addition/alkylation reaction between aliphatic aldehydes and (E)-5-iodo-1-nitropent-1-ene (B) involving enamine–enamine activation. The process is highly stereoselective and leads to the g-nitroaldehydes C, which contain an all-carbonsubstituted quaternary stereogenic center. Furthermore, a novel cyclic g-amino acid was easily synthesized from the domino product in two steps. Diphenylprolinol silyl ether 1 shows good catalytic activity and gives excellent levels of asymmetric induction in the Michael addition of aldehydes to nitroalkenes. Therefore, we initially investigated its use as a catalyst in the reaction between propanal (4a) and nitroolefins bearing different leaving groups in the w position (OMs, Br, I; Ms= mesyl). In the case of the bromo and mesylate derivatives, the initial Michael addition occurred in good yield (70–80%); however, the desired cyclopentane product 6a was not formed. Using the w-iodonitroalkene 5 the domino reaction occurred and cyclopentane 6a was obtained in a low yield of 20% (entry 1, Table 1). Although the diastereoselectivity was only moderate (d.r. 70:30), the enantiomeric excess was excellent (trans : 94% ee, cis : 95% ee). Encouraged by this initial result, we undertook a detailed optimization study. Scheme 1. Secondary-amine-catalyzed domino reaction consisting of a Michael addition and an intramolecular alkylation proceeding by tandem enamine–enamine activation.
195 citations
TL;DR: A new series of thiophene containing triarylmethane derivatives were synthesized from the Friedel-Crafts alkylation of diarylcarbinols followed by incorporation of amino alkyl chains and showed the activity in the range of 3.12-12.5 microg/mL in vitro.
181 citations
TL;DR: The catalytic enantioselective and atom economic Friedel−Crafts alkylation of pyrroles with nitroalkenes under mild reaction conditions using a dinuclear zinc catalyst is reported.
Abstract: The catalytic enantioselective and atom economic Friedel−Crafts alkylation of pyrroles with nitroalkenes under mild reaction conditions using a dinuclear zinc catalyst is reported. The versatility of the reaction is demonstrated by the conversion of a number of differentially substituted nitroalkenes with differentially substituted pyrroles. Tandem addition reactions to form 2,5-disubstituted pyrroles are also demsonstrated. All pyrrole alkylations have been carried out without using N-protecting groups, which also enhances the efficiency by which substituted pyrroles may be synthesized. The reactions result in good yields and excellent enantioselectivities.
TL;DR: An efficient multi-gram scale synthesis protocol of a variety of P,N ligands is described in this article, where the synthesis is achieved in a two-step reaction, first the amine is deprotonated and subsequently the chlorophosphine is added to yield the corresponding P-N ligand.
Abstract: An efficient multi-gram scale synthesis protocol of a variety of P,N ligands is described. The synthesis is achieved in a two-step reaction. First, the amine is deprotonated and subsequently the chlorophosphine is added to yield the corresponding P,N ligand. Deprotonation of the amine is normally achieved with n-BuLi at low temperature, but for the preparation of ligands with a 2,2′-dipyridylamino backbone and phosphines with a high steric demand KH has to be employed in combination with reaction temperatures of 110 °C for the salt metathesis step. The reaction of two equivalents of a selected P,N ligand with one equivalent of the iridium complex [IrCl(cod)]2 (cod=1,5-cyclooctadiene) affords P,N ligand-coordinated iridium complexes in quantitative yield. X-Ray single crystal structure analysis of one of these complexes reveals a monomeric five-coordinated structure in the solid state. The iridium complexes were used to form catalysts for the N-alkylation of aromatic amines with alcohols. The catalyst system was optimized by studying 8 different P,N ligands, 9 different solvents and 14 different bases. Systematic variation of the substrate to base and the amine to alcohol ratios as well as the catalyst loading led to optimized catalytic reaction conditions. The substrate scope of the developed catalytic protocol was shown by synthesizing 20 different amines of which 12 could be obtained in isolated yields higher than 90%. A new efficient catalyst system for the selective monoalkylation of primary aromatic and heteroaromatic amines with primary aromatic, heteroaromatic as well as aliphatic alcohols has been established. The reaction proceeds with rather moderate catalyst loadings.
TL;DR: A new challenging strategy for the asymmetric intermolecular enamine-catalyzed formal a-alkylation of aldehydes is reported, founded upon the use of a reagent 1 (Scheme 1), which, because of the presence of the Canizzaro or Tischenko reactions, is considered valuable.
Abstract: Catalysis with chiral secondary amines (asymmetric aminocatalysis) has become a well-established and powerful synthetic tool for modern synthetic chemistry. The impressive level of scientific competition and high quality research generated in this area have opened up new synthetic opportunities that were considered inaccessible only a few years ago. Even reactions that had been considered impossible became a reality through aminocatalysis. One of the best validations of this approach is the development of the catalytic, asymmetric direct a-alkylation of aldehydes. This highly challenging and valuable C C bond-forming strategy was completely unknown before the advent of asymmetric aminocatalysis. In 2004, Vignola and List presented the first catalytic asymmetric intramolecular a-alkylation of haloaldehydes under enamine catalysis. They demonstrated the ability of proline-derived catalysts to overcome the classical drawbacks associated with the stoichiometric alkylation of preformed aldehyde enolates, such as the tendency toward aldol condensation and the Canizzaro or Tischenko reactions. However, extension of their aminocatalytic strategy to an intermolecular version failed because of deactivation of the amine catalyst by N-alkylation with the alkyl halide. Thus, chemists started to search for different aminocatalytic strategies to accomplish the challenging goal of an intermolecular formal aldehyde a-alkylation. In 2006, Ibrahem and C2rdova reported a non-asymmetric catalytic intermolecular a-allylic alkylation of aldehydes by combination of transition-metal and enamine catalysis. More recently, MacMillan and co-workers exploited a new aminocatalytic activation concept, based on radical intermediates, to solve the synthetic problems of the catalytic asymmetric aallylation, arylation, enolation, and vinylation of unmodified aldehydes. Herein, we report a new challenging strategy for the asymmetric intermolecular enamine-catalyzed formal a-alkylation of aldehydes. The novel approach is founded upon the use of a reagent 1 (Scheme 1), which, because of the presence
TL;DR: The utility of the catalytic asymmetric protocols is illustrated through conversion of the enantiomerically enriched alkylation products to a range of cyclic and acyclic compounds bearing an N-substituted quaternary carbon stereogenic center.
Abstract: Catalytic enantioselective alkylations of three classes of ketoimines are reported. Reactions are promoted in the presence 0.5–10 mol % of a Zr salt and a chiral ligand that contains two inexpensive amino acids (valine and phenylalanine) and involve Me2Zn or Et2Zn as alkylating agents. Requisite aryl- and alkyl-substituted α-ketoimine esters, accessed readily and in >80% yield on gram scale through a two-step sequence from the corresponding ketones, undergo alkylation to afford quaternary α-amino esters in 79–97% ee. Aryl-substituted trifluoroketoimines are converted to the corresponding amines by reactions with Me2Zn, catalyzed by a chiral complex that bears a modified N-terminus. The utility of the catalytic asymmetric protocols is illustrated through conversion of the enantiomerically enriched alkylation products to a range of cyclic and acyclic compounds bearing an N-substituted quaternary carbon stereogenic center.
TL;DR: In this article, a three-step reaction pathway consisting of Ir-catalyzed alcohol dehydrogenation to aldehyde, amine-aldehyde condensation to imine, and then Ir-caralyzed imine hydrogenation to amine was studied.
TL;DR: In this article, a series of five different (p-cymene)Ru(NHC) complexes have been obtained and fully characterized, and the crystal structure of two of the new complexes has been determined by X-ray diffraction methods.
TL;DR: In this paper, the reaction of 1,2,4-trimethyltriazolium tetrafluoroborate ([LH2](BF4)2] with several metal precursors provides a series of homo- and heterodimetallic compounds of Rh and Ir.
TL;DR: Highly regio- and enantioselective Ir-catalyzed Friedel-Crafts type allylic alkylation of indoles have been realized using [Ir(COD)Cl]2/phosphoramidite ligand 1a, affording the branched products with up to >97/3 brANChed-linear ratio and 92% ee.
TL;DR: In this paper, a catalytic catalytic intramolecular ortho-alkylation of aromatic imines containing alkenyl groups tethered at the meta position relative to the imine directing group has been achieved using [RhCl(coe)2]2 and chiral phosphoramidite ligands.
Abstract: Highly enantioselective catalytic intramolecular ortho-alkylation of aromatic imines containing alkenyl groups tethered at the meta position relative to the imine directing group has been achieved using [RhCl(coe)2]2 and chiral phosphoramidite ligands. Cyclization of substrates containing 1,1- and 1,2-disubstituted as well as trisubstituted alkenes were achieved with enantioselectivities >90% ee for each substrate class. Cyclization of substrates with Z-alkene isomers proceeded much more efficiently than substrates with E-alkene isomers. This further enabled the highly stereoselective intramolecular alkylation of certain substrates containing Z/E-alkene mixtures via a Rh-catalyzed alkene isomerization with preferential cyclization of the Z-isomer.
TL;DR: In this paper, the amination of secondary alcohols to give tertiary amines in the presence of different in situ generated ruthenium catalysts has been investigated in detail.
TL;DR: Layered HNbMoO6 was found to function as a strong solid acid catalyst, exceeding the activity of zeolites and ion-exchange resins for Friedel-Crafts alkylation and has high catalytic activity for esterification of hydrocarboxylic acid and hydration.
Abstract: Layered HNbMoO6 was found to function as a strong solid acid catalyst, exceeding the activity of zeolites and ion-exchange resins for Friedel−Crafts alkylation. HNbMoO6 also exhibited high catalytic activity for esterification of hydrocarboxylic acid and hydration. The catalytic performance of layered HNbMoO6 is attributed to the intercalation of reactants into the interlayer and the development of strong acidity.
TL;DR: In this paper, a Friedel-Crafts reaction of 4,7-dihydroindoles with β,γ-unsaturated α-keto esters by a chiral N-triflyl phosphoramide was realized.
Abstract: A highly efficient Friedel-Crafts reaction of 4,7-dihydroindoles with β,γ-unsaturated α-keto esters by a chiral N-triflyl phosphoramide was realized, affording the 2-substituted 4,7-dihydroindoles with up to 98% ee for a wide range of substrates. The Friedel-Crafts alkylation together with a subsequent oxidation of the product with p-benzoquinone led to a 2-alkylated indole derivative in 98% ee.
TL;DR: An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield.
Abstract: An asymmetric total synthesis of (-)-incarvillateine, a natural product having potent analgesic properties, has been achieved in 11 steps and 15.4% overall yield. The key step is a rhodium-catalyzed intramolecular alkylation of an olefinic C-H bond to set two stereocenters. Additionally, this transformation produces an exocyclic, tetrasubstituted alkene through which the bicyclic piperidine moiety can readily be accessed.
TL;DR: In this paper, the use of combinations of amino acids, amines, K 2CO3 or Cs2CO3 and CuSO4/Cu for catalysing green cascade reactions was investigated.
TL;DR: The asymmetric Friedel-Crafts alkylation of electron-rich N-containing heterocycles with nitroalkenes under catalysis of diphenylamine-tethered bis(oxazoline) and bis(thiazoline)-Zn(II) complexes was investigated and the origin of the enantioselectivity was attributed to the NH-pi interaction between the catalyst and the incoming aromatic system in the transition state.
Abstract: The asymmetric Friedel-Crafts alkylation of electron-rich N-containing heterocycles with nitroalkenes under catalysis of diphenylamine-tethered bis(oxazoline) and bis(thiazoline)-Zn(II) complexes was investigated. In the reaction of indole derivatives, the complex of ligand 4 f with trans-diphenyl substitutions afforded better results than previously published ligand 4 e with cis-diphenyl substitutions. Excellent yields (up to greater than 99 %) and enantioselectivities (up to 97 %) were achieved in most cases. The complex of ligand 4 d bearing tert-butyl groups gave the best results in the reactions of pyrrole. Moderate to good yields (up to 91 %) and enantioselectivities (up to 91 %) were achieved in most cases. The origin of the enantioselectivity was attributed to the NH-pi interaction between the catalyst and the incoming aromatic system in the transition state. Such an interaction was confirmed through comparison of the enantioselectivity and the absolute configuration of the products in the reactions catalyzed by designed ligands.
TL;DR: Analysis by solid-phase catalysis/circular dichroism high-throughput screening of a copper-catalyzed Henry reaction revealed that ligand L25, comprising a (S,S)-diphenylethylenediamine-derived imidazoline, (S)-phenylethylamine, and dibromophenol, was highly efficient, thus providing the adduct of nitromethane and benzaldehyde in 95 % ee.
Abstract: A library of imidazoline-aminophenol ligands was synthesized on solid supports. After immobilization of chiral chloromethylimidazolines 1 and 2 onto the polystyrylsulfonyl chloride, nucleophilic substitution with (R)- or (S)-phenylethylamine (3 and 4) provided four combinations of polymer-supported imidazoline-amine ligands. Further reductive alkylation using salicylaldehydes 7-10 provided a series of imidazoline-aminophenol ligands (L9-L24). Analysis by solid-phase catalysis/circular dichroism high-throughput screening of a copper-catalyzed Henry reaction revealed that ligand L25, comprising a (S,S)-diphenylethylenediamine-derived imidazoline, (S)-phenylethylamine, and dibromophenol, was highly efficient, thus providing the adduct of nitromethane and benzaldehyde in 95 % ee. The combination of stereogenic centers was crucial in promoting the highly stereoselective reactions. The unique reaction sphere of L25 was also examined in a Friedel-Crafts alkylation of indole and nitroalkene to give the adduct in up to 83 % ee.
TL;DR: Nickel nanoparticles have been found to activate primary alcohols used for the α-alkylation of ketones or in indirect aza-Wittig reactions as mentioned in this paper, and a reaction mechanism is proposed on the basis of some deuteration experiments.
TL;DR: It is shown that alpha,alpha-disubstituted pseudoephedrine amide enolates can be generated in a highly stereocontrolled fashion by conjugate addition of an alkyllithium reagent to the s-cis-conformer of an alpha-alkyl-alpha,beta-unsaturated pseudoephernylbutyramides that undergo alkylation in the same sense as those formed by direct deprotonation.
Abstract: Protocols for the stereodefined formation of α,α-disubstituted enolates of pseudoephedrine amides are presented followed by the implementation of these in diastereoselective alkylation reactions. Direct alkylation of α,α-disubstituted pseudoephedrine amide substrates is demonstrated to be both efficient and diastereoselective across a range of substrates, as exemplified by alkylation of the diastereomeric pseudoephedrine α-methylbutyramides, where both substrates are found to undergo stereospecific replacement of the α-C−H bond with α-C−alkyl, with retention of stereochemistry. This is shown to arise by sequential stereospecific enolization and alkylation reactions, with the alkyl halide attacking a common π-face of the E- and Z-enolates, proposed to be opposite the pseudoephedrine alkoxide side chain. Pseudoephedrine α-phenylbutyramides are found to undergo highly stereoselective but not stereospecific α-alkylation reactions, which evidence suggests is due to facile enolate isomerization. Also, we show t...