Showing papers on "Alkylation published in 2013"

Photochemical activity of a key donor–acceptor complex can drive stereoselective catalytic α-alkylation of aldehydes

Abstract: Asymmetric catalytic variants of sunlight-driven photochemical processes hold extraordinary potential for the sustainable preparation of chiral molecules. However, the involvement of short-lived electronically excited states inherent to any photochemical reaction makes it challenging for a chiral catalyst to dictate the stereochemistry of the products. Here, we report that readily available chiral organic catalysts, with well-known utility in thermal asymmetric processes, can also confer a high level of stereocontrol in synthetically relevant intermolecular carbon-carbon bond-forming reactions driven by visible light. A unique mechanism of catalysis is proposed, wherein the catalyst is involved actively in both the photochemical activation of the substrates (by inducing the transient formation of chiral electron donor-acceptor complexes) and the stereoselectivity-defining event. We use this approach to enable transformations that are extremely difficult under thermal conditions, such as the asymmetric α-alkylation of aldehydes with alkyl halides, the formation of all-carbon quaternary stereocentres and the control of remote stereochemistry.

meta-Selective C-H bond alkylation with secondary alkyl halides

Abstract: Ruthenium catalysts enabled C–H bond functionalizations on arenes with challenging secondary alkyl halides. Particularly, ruthenium(II) biscarboxylate complexes proved to be the key to success for direct alkylations with excellent levels of unusual meta-selectivity. The direct alkylations occurred under mild reaction conditions with ample scope and tolerated valuable functional groups. Detailed mechanistic studies were performed, including various competition experiments as well as reactions with isotopically labeled substrates. These studies provided strong support for an initial reversible cyclometalation. The cycloruthenation thereby activates the arene for a subsequent remote electrophilic-type substitution with the secondary alkyl halides. Independently prepared cycloruthenated complexes were found to be catalytically active provided that a carboxylate ligand was present, thereby highlighting the key importance of carboxylate assistance for effective meta-selective C–H bond alkylations.

Nickel-Catalyzed Direct Alkylation of C–H Bonds in Benzamides and Acrylamides with Functionalized Alkyl Halides via Bidentate-Chelation Assistance

Abstract: The alkylation of the ortho C–H bonds in benzamides and acrylamides containing an 8-aminoquinoline moiety as a bidentate directing group with unactivated alkyl halides using nickel complexes as catalysts is described. The reaction shows high functional group compatibility. In reactions of meta-substituted aromatic amides, the reaction proceeds in a highly selective manner at the less hindered C–H bond.

Palladium-Catalyzed Picolinamide-Directed Alkylation of Unactivated C(sp3)–H Bonds with Alkyl Iodides

Abstract: We report an efficient method for the alkylation of γ-C(sp3)–H bonds of picolinamide-protected aliphatic amine substrates with primary alkyl iodides via palladium catalysis. Ag2CO3 and dibenzyl phosphate, (BnO)2PO2H, are critical promoters of this reaction. These reactions provide a convenient and straightforward method for the preparation of high-value N-containing products from readily available amine and alkyl iodide precursors.

Directed Amination of Non‐Acidic Arene CH Bonds by a Copper–Silver Catalytic System

Abstract: New methods for direct arylation, alkylation, and oxygenation of sp2 carbon-hydrogen bonds in directing-group containing benzenes have resulted in efficient synthetic routes to functionalized arenes.[1] In contrast, direct amination reactions that do not proceed via nitrenoid intermediates[2] are relatively rare. In most cases, palladium catalysis is used for aminations.[3a-p] Furthermore, majority of publications describe intramolecular C-N bond formation.[3a-i] Typically, protected amines or hydroxylamine derivatives are used to install nitrogen moiety. Simple amine coupling partners are employed only rarely. Several deprotonative, copper-catalyzed thiazole and oxazole aminations have been reported.[4b,c,e] Yu has reported a method for palladium-catalyzed benzamide amination by employing a removable auxiliary.[3k] We disclose here a method for an auxiliary-assisted amination of non-acidic benzamide β-C–H bonds and benzylamine derivative γ-C–H bonds that is catalyzed by copper(II) acetate.

Recent Advances in Iridium-Catalyzed Alkylation of C–H and N–H Bonds

Abstract: Over the past few years, iridium complexes have been widely used in the direct functionalization of unactivated bonds. In the presence of iridium catalysts, inactive C–H and N–H bonds have been transformed into C–C and N–C bonds in dehydrative alkylation using alcohols, allylation using allyl carbonates, and alkylation using alkenes. Enantioselective variants of some reactions have also been reported.

Stereoselective Synthesis of β-Alkylated α-Amino Acids via Palladium-Catalyzed Alkylation of Unactivated Methylene C(sp3)–H Bonds with Primary Alkyl Halides

Abstract: We report a new set of reactions based on the Pd-catalyzed alkylation of methylene C(sp3)–H bonds of aliphatic quinolyl carboxamides with α-haloacetate and methyl iodide and applications in the stereoselective synthesis of various β-alkylated α-amino acids. These reactions represent the first generally applicable method for the catalytic alkylation of unconstrained and unactivated methylene C–H bonds with high synthetic relevance. When applied with simple isotope-enriched reagents, they also provide a convenient and powerful means to site-selectively incorporate isotopes into the carbon scaffolds of amino acid compounds.

Synthesis of 6‐Alkylated Phenanthridine Derivatives Using Photoredox Neutral Somophilic Isocyanide Insertion

Abstract: Isocyanides have been important building blocks in synthetic chemistry since the discovery of the Ugi reaction and related multicomponent reactions. Isocyanides are isoelectronic with carbon monoxide, and thus it is not surprising that isocyanides can undergo insertion reactions (also named imidoylative reactions) to provide N-containing heterocycles which are ubiquitous in pharmaceuticals and biologically active molecules. As depicted in Scheme 1a, palladium-catalyzed isocyanide insertion and somophilic isocyanide insertion represent two typical strategies currently reported for isocyanide insertion reactions. While the palladium-catalyzed isocyanide insertions often require high reaction temperatures and have the tendency to undergo multiple consecutive insertions, the use of isocyanides as somophiles for insertion reactions holds promise for practical synthetic applications under mild reaction conditions. As a convenient approach to generate somophiles, photoredox catalysis, which usually introduces alkenes, alkynes, and aromatic rings as radical acceptors, has been widely used in the synthetic community to construct C C bonds since 2008. However, none of the reported work has employed photoredox catalysis to initiate isocyanide insertion. We consider photoredox-catalyzed isocyanide insertions to be a new synthetic protocol which circumvents the use of stoichiometric oxidants and harsh reaction conditions. As part of our ongoing work on photoredox neutral catalysis, we report herein the first example of photoredox neutral, somophilic isocyanide insertions, which provide 6-alkylated phenanthridine derivatives under mild reaction conditions. Our design of photoredox netural isocyanide insertions is shown in Scheme 1 b. The biphenyl isocyanide 1, which incorporates an isocyanide group and a somophile (phenyl ring) into the same molecule, is selected to react with an alkyl radical RC. It is envisaged that the alkyl radical RC can be generated from an alkyl bromide (2) assisted by an excitedstate photocatalyst. The radical RC adds to 1 to give the imidoyl radical I, which subsequently undergoes intramolecular homolytic aromatic substitution (HAS), oxidation, and deprotonation to afford the phenanthridine 3. Since the intramolecular HAS is faster than intermolecular radical couplings, multiple isocyanide insertions and double alkylation are avoided in this process. The stoichiometric amount of external oxidants can also be avoided because of the overall redox neutral process. It is noteworthy that the phenanthridine framework can be found in a variety of natural products possessing many important biological properties, thus making this strategy more attractive. This design was first examined using 2-isocyanobiphenyl (1a) and ethyl 2-bromopropanoate (2a) as model substrates (Table 1). The complex [fac-Ir(ppy)3] (A) was chosen as the photocatalyst because of its superior oxidation capacity in the excited state. When a solution of 1a and 2a in CH2Cl2 was irradiated with a 3 W blue LED in the presence of A and Na2HPO4 for 10 hours, the desired phenanthridine 3a was isolated in 25 % yield (Table 1, entry 1). Using CH3CN, Scheme 1. Typical isocyanide insertions and our design.

Palladium-catalyzed C-H activation/cross-coupling of pyridine N-oxides with nonactivated secondary alkyl bromides.

Abstract: An unexpected C–H activation/C–C cross-coupling reaction has been found to occur between pyridine N-oxides and general nonactivated secondary and even tertiary alkyl bromides. It provides a practically useful approach for the synthesis of alkylated pyridine derivatives. Experimental observations indicated that the C–Br cleavage step involves a radical-type process. Thus, the title reaction provides a rather extraordinary example of Pd-catalyzed cross-coupling of secondary and tertiary aliphatic electrophiles.

Scope and Limitations of Auxiliary-Assisted, Palladium-Catalyzed Arylation and Alkylation of sp2 and sp3 C–H Bonds

Abstract: The scope of palladium-catalyzed, auxiliary-assisted direct arylation and alkylation of sp2 and sp3 C–H bonds of amine and carboxylic acid derivatives has been investigated. The method employs a palladium acetate catalyst, substrate, aryl, alkyl, benzyl, or allyl halide, and inorganic base in tert-amyl alcohol or water solvent at 100–140 °C. Aryl and alkyl iodides as well as benzyl and allyl bromides are competent reagents in this transformation. The picolinic acid auxiliary is used for amine γ-functionalization, and the 8-aminoquinoline auxiliary is used for carboxylic acid β-functionalization. Some optimization of base, additives, and solvent is required for achieving best results.

Transition‐Metal‐Catalyzed Alkylations of Amines with Alkyl Halides: Photoinduced, Copper‐Catalyzed Couplings of Carbazoles

Abstract: N-alkylations of carbazoles with a variety of secondary and hindered primary alkyl iodides can be achieved by using a simple precatalyst (CuI) under mild conditions (0 °C) in the presence of a Bronsted base; at higher temperature (30 °C), secondary alkyl bromides also serve as suitable coupling partners. A Li[Cu(carbazolide)_2] complex has been crystallographically characterized, and it may serve as an intermediate in the catalytic cycle.

Pd(II)-catalyzed alkylation of unactivated C(sp3)–H bonds: efficient synthesis of optically active unnatural α-amino acids

Abstract: A palladium-catalyzed alkylation of primary and secondary C(sp3)–H bonds with alkyl iodides and/or bromides for the synthesis of optically active unnatural α-amino acids (α-AAs) is described. This process is scalable and tolerates a variety of functional groups with complete retention of chirality, providing an efficient new strategy for the synthesis of various unnatural α-amino acid derivatives.

Ruthenium-catalyzed ortho-C–H bond alkylation of aromatic amides with α,β-unsaturated ketones via bidentate-chelation assistance

Abstract: A new chelation assisted reaction using a removable 8-aminoquinoline bidentate directing group that permits the ruthenium-catalyzed ortho-C–H bond alkylation of aromatic amides with various α,β-unsaturated ketones under straightforward conditions has been developed. This methodology represents the first efficient utilization of enones in the ortho directed ruthenium-catalyzed addition of C–H bonds to C–C double bonds. The reaction offers a broad scope and a high functional group tolerance.

Construction of Vicinal Tertiary and All-Carbon Quaternary Stereocenters via Ir-Catalyzed Regio-, Diastereo-, and Enantioselective Allylic Alkylation and Applications in Sequential Pd Catalysis

Abstract: Highly congested vicinal stereocenters comprised of tertiary and all-carbon quaternary centers were generated via Ir-catalyzed asymmetric allylic alkylation of β-ketoesters. These catalytic reactions proceed in excellent yields with a broad scope on either reaction partner and with outstanding regio-, diastereo-, and enantiocontrol. Implementation of a subsequent Pd-catalyzed alkylation affords dialkylated products with pinpoint stereochemical control of both chiral centers.

Heterogeneous Ni Catalysts for N-Alkylation of Amines with Alcohols

Abstract: Nickel nanoparticles loaded onto various supports (Ni/MOx) have been prepared and studied for the N-alkylation of amines with alcohols. Among the catalysts, Ni/θ-Al2O3 prepared by in situ H2-reduction of NiO/θ-Al2O3 shows the highest activity, and it acts as reusable heterogeneous catalyst for the alkylation of anilines and aliphatic amines with various alcohols (benzyl and aliphatic alcohols) under additive free conditions. Primary amines are converted into secondary amines and secondary amines into tertiary amines. For the reaction of aniline with an aliphatic alcohol the catalyst shows higher turnover number (TON) than precious metal-based state-of-the-art catalysts. Mechanistic studies suggest that the reaction proceeds through a hydrogen-borrowing mechanism. The activity of Ni catalysts depends on the nature of support materials; acid–base bifunctional supports give higher activity than basic or acidic supports, indicating that acid–base sites on supports are necessary. The presence of basic (pyridin...

Enantio-, Diastereo-, and Regioselective Iridium-Catalyzed Asymmetric Allylic Alkylation of Acyclic β-Ketoesters

Abstract: The first regio-, diastereo-, and enantioselective allylic alkylation of acyclic β-ketoesters to form vicinal tertiary and all-carbon quaternary stereocenters is reported. Critical to the successful development of this method was the employment of iridium catalysis in concert with N-aryl-phosphoramidite ligands. Broad functional group tolerance is observed at the keto-, ester-, and α-positions of the nucleophile. Various transformations demonstrating the utility of this method for rapidly accessing complex enantioenriched compounds are reported.

Cobalt-catalyzed C-H bond functionalizations with aryl and alkyl chlorides.

Abstract: Inexpensive cobalt catalysts derived from N-heterocylic carbenes (NHC) allowed efficient catalytic CH bond arylations on heteroaryl-substituted arenes with widely available aryl chlorides, which set the stage for the preparation of sterically hindered tri-ortho-substituted biaryls. Likewise, challenging direct alkylations with β-hydrogen-containing primary and even secondary alkyl chlorides proceeded on pyridyl- and pyrimidyl-substituted arenes and heteroarenes. The cobalt-catalyzed CH bond functionalizations occurred efficiently at ambient reaction temperature with excellent levels of site-selectivities and ample scope. Mechanistic studies highlighted that electron-deficient aryl chlorides reacted preferentially, while the arenes kinetic CH bond acidity was found to largely govern their reactivity.

Highly Enantioselective Construction of Trifluoromethylated All-Carbon Quaternary Stereocenters via Nickel-Catalyzed Friedel–Crafts Alkylation Reaction

Abstract: A highly enantioselective Friedel–Crafts alkylation reaction of indoles with β-CF3-β-disubstituted nitroalkenes was achieved using a Ni(ClO4)2–bisoxazoline complex as a catalyst, which afforded indole-bearing chiral compounds with trifluoromethylated all-carbon quaternary stereocenters in good yields with excellent enantioselectivities (up to 97% ee). The transformation of one of the products into first a trifluoromethylated tryptamine and then a trifluoromethylated tetrahydro-β-carboline by sequential nitro reduction and Pictet–Spengler cyclization were realized with complete preservation of enantiopurity.

Pd-catalyzed asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols: the role of the chiral phosphoric acid in C-O bond cleavage and stereocontrol.

Abstract: The combination of a palladium complex with a chiral phosphoramidite ligand and a chiral phosphoric acid enables the first highly efficient asymmetric allylic alkylation of pyrazol-5-ones with allylic alcohols, affording multiply functionalized heterocyclic products in high yields with excellent enantioselectivities that would be of great potential in the synthesis of pharmaceutically interesting molecules.

Highly Enantioselective Friedel-Crafts Alkylation/N-Hemiacetalization Cascade Reaction with Indoles

Abstract: The method allows the preparation of a broad spectrum of diversely functionalized polycyclic indole skeletons with generally high enantioselectivity.

Rhodium(III)-catalyzed azacycle-directed intermolecular insertion of arene C-H bonds into α-diazocarbonyl compounds.

Abstract: Cp*Rh(III)-catalyzed intermolecular C–C couplings between activated α-diazocarbonyl compounds and arenes bearing a range of azacyclic directing groups have been achieved. This catalytic alkylation reaction operates under mild conditions with good functional group tolerance.

Palladium-catalyzed intramolecular ipso-Friedel-Crafts alkylation of phenols and indoles: rearomatization-assisted oxidative addition.

Abstract: Spirocyclohexadienones are recognized as versatile intermediates for complex molecule syntheses. Functionalization of the cyclohexadienone unit provides efficient and rapid access to multicyclic molecular frameworks. A number of natural product syntheses have been achieved using spirocyclohexadienones as key intermediates. The development of an innovative method for synthesizing spirocyclohexadienones is therefore in high demand because of its potential impact on synthetic organic chemistry. Dearomatization of phenols is one of the most straightforward approaches to the synthesis of spirocyclohexadienones. Among such methods, transition-metal-catalyzed intramolecular nucleophilic dearomatization of phenols has attracted recent attention. 4] Key to the success of this dearomatization process is whether the intramolecular C alkylation can be preferentially promoted over the competitive intermolecular O alkylation. We recently demonstrated that the present chemoselectivity issue was successfully controlled in a palladium-catalyzed intramolecular ipso-Friedel–Crafts allylic alkylation of para-substituted phenols with an allylic carbonate unit to give spiro[4.5]cyclohexa-dienones in excellent yield. Reaction of propargyl carbonates with a palladium catalyst provides an equilibrium mixture of h-allenylpalladium(II) complexes and h-propargyl-palladium(II) complexes. Various catalytic transformations have been developed based on the electrophilic reactivity of these palladium complexes. We envisioned that these complexes would be adaptable to palladium-catalyzed intramolecular nucleophilic dearomatization of phenols, thus providing novel access to functionalized spirocyclohexadienones (Scheme 1). Moreover, the use of indole variants in the same catalytic process would result in the formation of aza-spirocycles. Herein, we report a novel synthetic method for spirocyclic molecules based on palladium-catalyzed intramolecular ipsoFriedel–Crafts alkylation of phenols and indoles. Mechanistic studies revealed that the reaction proceeds through an unprecedented rearomatization-assisted oxidative addition. Our studies began with the model substrate 1 a (Table 1). We first examined the reaction using 5 mol% [Pd(dba)2] and 12 mol% PPh3 in CH2Cl2, which are the

Cobalt-catalyzed ortho alkylation of aromatic imines with primary and secondary alkyl halides

Abstract: We report here cobalt–N-heterocyclic carbene catalytic systems for the ortho alkylation of aromatic imines with alkyl chlorides and bromides, which allows the introduction of a variety of primary and secondary alkyl groups at room temperature. The stereochemical outcomes of the reaction of secondary alkyl halides suggest that the present reaction involves single-electron transfer from a cobalt species to the alkyl halide to generate the corresponding alkyl radical. A cycloalkylated product obtained by this method can be transformed into unique spirocycles through manipulation of the directing and cycloalkyl groups.

Ligand-accelerated ortho-C-H alkylation of arylcarboxylic acids using alkyl boron reagents.

Abstract: A protocol for the Pd(II)-catalyzed ortho-C–H alkylation of phenylacetic and benzoic acids using alkylboron reagents is disclosed. Monoprotected amino acid ligands (MPAA) were found to significantly promote reactivity. Both potassium alkyltrifluoroborates and alkylboronic acids were compatible coupling partners. The possibility of a radical alkyl transfer to Pd(II) was also investigated.

Enantioconvergent cross-couplings of racemic alkylmetal reagents with unactivated secondary alkyl electrophiles: catalytic asymmetric Negishi α-alkylations of N-Boc-pyrrolidine.

Abstract: Although enantioconvergent alkyl–alkyl couplings of racemic electrophiles have been developed, there have been no reports of the corresponding reactions of racemic nucleophiles. Herein we describe Negishi cross-couplings of racemic α-zincated N-Boc-pyrrolidine with unactivated secondary halides, thus providing a one-pot, catalytic asymmetric method for the synthesis of a range of 2-alkylpyrrolidines (an important family of target molecules) from N-Boc-pyrrolidine, a commercially available precursor. Preliminary mechanistic studies indicated that two of the most straightforward mechanisms for enantioconvergence (dynamic kinetic resolution of the organometallic coupling partner and a simple β-hydride elimination/β-migratory insertion pathway) are unlikely to be operative.

Osmium Catalyst for the Borrowing Hydrogen Methodology: α-Alkylation of Arylacetonitriles and Methyl Ketones

Abstract: Complex [Os(η6-p-cymene)(OH)(IPr)]OTf is an efficient catalyst precursor for the α-alkylation of arylacetonitriles and methyl ketones with alcohols, which works with turnover frequencies between 675 and 176 h–1 for nitriles and between 194 and 28 h–1 for ketones.

Construction of Vicinal All-Carbon Quaternary Stereocenters by Catalytic Asymmetric Alkylation Reaction of 3-Bromooxindoles with 3-Substituted Indoles: Total Synthesis of (+)-Perophoramidine

Abstract: Highly congested vicinal all-carbon quaternary stereocenters were generated via catalytic asymmetric alkylation reaction of 3-bromooxindoles with 3-substituted indoles. These catalytic reactions proceeded in excellent yields with a broad scope on either reaction partner, and with outstanding diastereo- and enantiocontrol. The newly developed method led to the total synthesis of (+)-perophoramidine in a highly efficient manner.