Showing papers on "Alkylation published in 2017"
TL;DR: This Review summarizes transition-metal-catalyzed alkylations of various carbon-hydrogen bonds (addition of C-H bonds across olefins) using regular ole fins or 1,3-dienes up to May 2016.
Abstract: Alkylation reactions represent an important organic transformation to form C–C bonds. In addition to conventional approaches with alkyl halides or sulfonates as alkylating agents, the use of unactivated olefins for alkylations has become attractive from both cost and sustainability viewpoints. This Review summarizes transition-metal-catalyzed alkylations of various carbon–hydrogen bonds (addition of C–H bonds across olefins) using regular olefins or 1,3-dienes up to May 2016. According to the mode of activation, the Review is divided into two sections: alkylation via C–H activation and alkylation via olefin activation.
745 citations
TL;DR: A polarity-match-based selective sp3 C–H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis is described, which should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.
Abstract: The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp3)-C(sp2) coupling, there is a growing demand for C-H alkylation reactions, wherein sp3 C-H bonds are replaced with sp3 C-alkyl groups. Here we describe a polarity-match-based selective sp3 C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl-alkyl fragment coupling. The sp3 C-H alkylation is highly selective for the α-C-H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.
338 citations
TL;DR: A deaminative strategy for the visible-light-mediated generation of alkyl radicals from redox-activated primary amine precursors is described and the broad synthetic potential of this protocol was demonstrated by the alkylation of a number of heteroarenes under mild conditions.
Abstract: A deaminative strategy for the visible-light-mediated generation of alkyl radicals from redox-activated primary amine precursors is described. Abundant and inexpensive primary amine feedstocks, including amino acids, were converted in a single step into redox-active pyridinium salts and subsequently into alkyl radicals by reaction with an excited-state photocatalyst. The broad synthetic potential of this protocol was demonstrated by the alkylation of a number of heteroarenes under mild conditions.
244 citations
TL;DR: A photoredox-catalyzed C–H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported.
Abstract: A photoredox-catalyzed C–H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild oxidant, conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable tool for late-stage derivatization. The reported method addresses the three major limitations of previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts. Additionally, a number of unprecedented, complex alkyl radicals are used, thereby increasing the chemical space accessible to Minisci chemistry. To showcase the application in late-stage functionalization, quinine and camptothecin analogues were synthesized. Finally, NMR studies were conducted to provide a rationalization for the heteroaryl activation that permits the use of a single equivalent of radical precursor and also leads to enhanced regioselectivity. Thus, by 1H and 13C NMR a distinct heteroaryl species was observed in the presence of acid catalyst and BF3.
200 citations
TL;DR: In this article, the direct visible light-mediated C-H alkylation of heteroarenes using aliphatic carboxylic acids is reported, which enables the rapid conversion of abundant feedstock materials into medically relevant “drug-like” moieties.
Abstract: The direct visible light-mediated C–H alkylation of heteroarenes using aliphatic carboxylic acids is reported. This mild method proceeds at low catalyst loadings (0.5 mol %) and has a high functional group tolerance and a broad substrate scope. Notably, functionalization of (iso)quinoline, pyridine, phthalazine, benzothiazole, and other heterocyclic derivatives with both cyclic and acyclic primary, secondary, and tertiary carboxylic acids as well as amino and fatty acids proceeded under the standard conditions at room temperature. This protocol enables the rapid conversion of abundant feedstock materials into medically relevant “drug-like” moieties.
198 citations
TL;DR: A mechanism that enables direct aldehyde C-H functionalization has been achieved via the synergistic merger of photoredox, nickel, and hydrogen atom transfer catalysis and has been successfully applied to the expedient synthesis of the medicinal agent haloperidol.
Abstract: A mechanism that enables direct aldehyde C–H functionalization has been achieved via the synergistic merger of photoredox, nickel, and hydrogen atom transfer catalysis. This mild, operationally simple protocol transforms a wide variety of commercially available aldehydes, along with aryl or alkyl bromides, into the corresponding ketones in excellent yield. This C–H abstraction coupling technology has been successfully applied to the expedient synthesis of the medicinal agent haloperidol.
193 citations
TL;DR: Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized intermediate, providing a deeper understanding of the factors governing the reactivity of these radical forebears, proving its applicability.
Abstract: Under oxidative conditions, 1,4-dihydropyridines (DHPs) undergo a homolytic cleavage, forming exclusively a Csp3-centered radical that can engage in the C–H alkylation of heterocyclic bases and 1,4-quinones. DHPs are readily prepared from aldehydes, and considering that aldehydes normally require harsh reaction conditions to take part in such transformations, with mixtures of alkylated and acylated products often being obtained, this net decarbonylative alkylation approach becomes particularly useful. The present method takes place under mild reaction conditions and requires only persulfate as a stoichiometric oxidant, making the procedure suitable for the late-stage C–H alkylation of complex molecules. Notably, structurally complex pharmaceutical agents could be functionalized or prepared with this protocol, such as the antimalarial Atovaquone and antitheilerial Parvaquone, thus evidencing its applicability. Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized i...
181 citations
TL;DR: An ionic cobalt-PNP complex is developed for the efficient α-alkylation of ketones with primary alcohols for the first time and was successfully applied to the greener synthesis of quinoline derivatives while using 2-aminobenzyl alcohol as an alkylating reagent.
166 citations
TL;DR: A direct and highly stereoselective synthesis of small peptides with enantiopure α-alkyl or α,α-dialkyl α-amino acids residues incorporated at specific sites was accomplished using this dual catalyst system.
Abstract: We report a stereoselective and site-specific allylic alkylation of Schiff base activated amino acids and small peptides via a Pd/Cu dual catalysis. A range of noncoded α,α-dialkyl α-amino acids were easily synthesized in high yields and with excellent enantioselectivities (up to >99% ee). Furthermore, a direct and highly stereoselective synthesis of small peptides with enantiopure α-alkyl or α,α-dialkyl α-amino acids residues incorporated at specific sites was accomplished using this dual catalyst system.
162 citations
TL;DR: Mechanistic studies suggest that an IrII /IrIII redox catalytic cycle is responsible for the observed reactivity.
Abstract: An iridium photoredox catalyst in combination with either a stoichiometric amount of Bronsted acid or a catalytic amount of Lewis acid is capable of catalyzing regioselective alkylation of N-heteroarenes with N-(acyloxy)phthalimides at room temperature under irradiation. A broad range of N-heteroarenes can be alkylated using a variety of secondary, tertiary, and quaternary carboxylates. Mechanistic studies suggest that an IrII /IrIII redox catalytic cycle is responsible for the observed reactivity.
159 citations
TL;DR: In this article, an efficient and selective nickel-catalyzed mono-alkylation of various primary alcohols with aryl and heteroaryl amines together with diols and amino alcohol derivatives was developed.
Abstract: Herein, we developed an efficient and selective nickel-catalyzed monoalkylation of various primary alcohols with aryl and heteroaryl amines together with diols and amino alcohol derivatives. Notably, the catalytic protocol consisting of an earth-abundant and non-precious NiBr2/L1 system enables the transformations in the presence of hydroxyl, alkene, nitrile, and nitro functionalities. As a highlight, we have demonstrated the alkylation of diamine, intramolecular cyclization to N-heterocycles, and functionalization of complex vitamin E, an (±)-α-tocopherol derivative. Preliminary mechanistic studies revealed the participation of a benzylic C–H bond in the rate-determining step.
TL;DR: A novel visible-light photoredox system with Pd(PPh3 )4 as the sole catalyst for the realization of the first direct cross-coupling of C(sp3 )-H bonds in N-aryl tetrahydroisoquinolines with unactivated alkyl bromides, which features broad substrate scope, good functional-group tolerance, and facile generation of quaternary centers.
Abstract: Reported herein is a novel visible-light photoredox system with Pd(PPh3 )4 as the sole catalyst for the realization of the first direct cross-coupling of C(sp3 )-H bonds in N-aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra- and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp3 )-C(sp3 ) and C(sp2 )-C(sp3 ) bonds in moderate to excellent yields. These redox-neutral reactions feature broad substrate scope (>60 examples), good functional-group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible-light photocatalyst and radicals are involved in the process.
TL;DR: Several organocalcium compounds prepared can alkylate benzene by displacing a hydride, with no need for a more conventionally reactive leaving group such as chloride (see the Perspective by Mulvey).
Abstract: The electrophilic aromatic substitution of a C–H bond of benzene is one of the archetypal transformations of organic chemistry. In contrast, the electron-rich π-system of benzene is highly resistant to reactions with electron-rich and negatively charged organic nucleophiles. Here, we report that this previously insurmountable electronic repulsion may be overcome through the use of sufficiently potent organocalcium nucleophiles. Calcium n -alkyl derivatives—synthesized by reaction of ethene, but-1-ene, and hex-1-ene with a dimeric calcium hydride—react with protio and deutero benzene at 60°C through nucleophilic substitution of an aromatic C–D/H bond. These reactions produce the n- alkyl benzenes with regeneration of the calcium hydride. Density functional theory calculations implicate an unstabilized Meisenheimer complex in the C–H activation transition state.
TL;DR: Vinyl boronates react with electron-deficient alkyl iodides in the presence of visible light to give boronic esters in which two new C-C bonds have been created.
Abstract: Vinyl boronates react with electron-deficient alkyl iodides in the presence of visible light to give boronic esters in which two new C–C bonds have been created. The reaction occurs by radical addition of an electron-deficient alkyl radical to the vinyl boronate followed by electron transfer with another molecule of alkyl iodide, continuing the chain, and triggering a 1,2-metalate rearrangement. In a number of cases, the use of a photoredox catalyst enhances yields significantly. The scope of the radical precursor includes α-iodo ketones, esters, nitriles, primary amides, α-fluorinated halo-acetates and perfluoroalkyl iodides.
TL;DR: Visible light photoredox catalysis enables direct γ- C(sp3)-H alkylation of saturated aliphatic carbonyl compounds using Electron-deficient alkenes as coupling partners in this reaction.
Abstract: Visible light photoredox catalysis enables direct γ- C(sp3)–H alkylation of saturated aliphatic carbonyl compounds. Electron-deficient alkenes are used as the coupling partners in this reaction. Distinguished site selectivity is controlled by the predominant 1,5-hydrogen atom transfer of an amidyl radical generated in situ.
TL;DR: A remote-selective C−H alkylation reaction of arenes using an in situ generated spiropalladacycle has been shown to furnish benzofurans and indoles without the need for a directing group.
Abstract: Existing methods for C–H activation depend on pre-installed directing groups, the removal of which poses a practical limitation on the use of these reactions in synthesis. Now, a remote-selective C−H alkylation reaction of arenes using an in situ generated spiropalladacycle has been shown to furnish benzofurans and indoles without the need for a directing group.
TL;DR: An operationally simple, mild, redox-neutral method for the photoredox alkylation of imines is reported, which is highly selective, metal-free, and does not require a large excess of the alkylating reagent or the use of acidic additives.
Abstract: An operationally simple, mild, redox-neutral method for the photoredox alkylation of imines is reported. Utilizing an inexpensive organic photoredox catalyst, alkyl radicals are readily generated from the single-electron oxidation of ammonium alkyl bis(catecholato)silicates and are subsequently engaged in a C-C bond-forming reaction with imines. The process is highly selective, metal-free, and does not require a large excess of the alkylating reagent or the use of acidic additives.
TL;DR: A redox-neutral and catalyst-free protocol to engender alkyl radicals in the context of trifluoromethylation and general alkylation of arenes, via the Norrish type I concept, accommodates various functional groups and delivers the product in good yields.
Abstract: The Minisci alkylation is useful to functionalize aromatics via alkyl radical addition. Current approaches to prepare alkyl radicals follow either oxidative or reductive pathways from various functional groups. Developing new strategy beyond these traditional methods remains elusive yet highly significant. In this article, we present a redox-neutral and catalyst-free protocol to engender alkyl radicals in the context of trifluoromethylation and general alkylation of arenes. This protocol, via the Norrish type I concept to produce alkyl radicals, accommodates various functional groups and delivers the product in good yields. This method identified a series of compounds as the trifluoromethylation and alkylation reagents assisted by light. It is expected that these compounds can find potential applications in other radical-involved reactions.
TL;DR: A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn2 (CO)10 , to generateAlkyl radicals from alkyl iodides has been developed and is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs.
Abstract: A visible-light-driven Minisci protocol that employs an inexpensive earth-abundant metal catalyst, decacarbonyldimanganese Mn2 (CO)10 , to generate alkyl radicals from alkyl iodides has been developed. This Minisci protocol is compatible with a wide array of sensitive functional groups, including oxetanes, sugar moieties, azetidines, tert-butyl carbamates (Boc-group), cyclobutanes, and spirocycles. The robustness of this protocol is demonstrated on the late-stage functionalization of complex nitrogen-containing drugs. Photophysical and DFT studies indicate a light-initiated chain reaction mechanism propagated by . Mn(CO)5 . The rate-limiting step is the iodine abstraction from an alkyl iodide by . Mn(CO)5 .
TL;DR: The remote C6-selective C–H alkylation of indole derivatives enabled by dual cyclometalation/redox ruthenium catalysis is reported, showing that the C6 position was the most reactive vacant C-H site toward potential functionalization.
Abstract: The site-selective functionalization of an indole template offers exciting possibilities for the derivatization of molecules with useful biological properties. Herein, we report the remote C6-selective C–H alkylation of indole derivatives enabled by dual cyclometalation/redox ruthenium catalysis. Remote alkylation was achieved using N-pyrimidinyl indoles with an ancillary ester directing group at the C3 position. This ancillary directing group proved pivotal to reactivity at C6, with yields up to 92% achieved. A one-pot procedure to install this directing group followed by remote C6 functionalization has also been reported; both processes are shown to proceed via ruthenium redox catalysis. Computationally calculated Fukui indices elucidated that the C6 position was the most reactive vacant C–H site toward potential functionalization. When this investigation was coupled with deuterium incorporation studies, a C2-cyclometalation/remote σ-activation pathway was deduced.
TL;DR: The synergistic merger of three catalytic processes-photoredox, enamine and hydrogen-atom transfer (HAT) catalysis-enables an enantioselective α-aldehyde alkylation reaction that employs simple olefins as coupling partners that allows the production of high-value molecules from feedstock chemicals in one step while consuming only photons.
Abstract: Although the α-alkylation of ketones has already been established, the analogous reaction using aldehyde substrates has proven surprisingly elusive. Despite the structural similarities between the two classes of compounds, the sensitivity and unique reactivity of the aldehyde functionality has typically required activated substrates or specialized additives. Here, we show that the synergistic merger of three catalytic processes-photoredox, enamine and hydrogen-atom transfer (HAT) catalysis-enables an enantioselective α-aldehyde alkylation reaction that employs simple olefins as coupling partners. Chiral imidazolidinones or prolinols, in combination with a thiophenol, iridium photoredox catalyst and visible light, have been successfully used in a triple catalytic process that is temporally sequenced to deliver a new hydrogen and electron-borrowing mechanism. This multicatalytic process enables both intra- and intermolecular aldehyde α-methylene coupling with olefins to construct both cyclic and acyclic products, respectively. With respect to atom and step-economy ideals, this stereoselective process allows the production of high-value molecules from feedstock chemicals in one step while consuming only photons.
TL;DR: A highly site-selective modification of peptides/proteins with aldehydes or carbohydrates under mild conditions was achieved.
Abstract: We report an efficient, highly selective modification on the N-terminal amines of peptides and proteins using aldehyde derivatives via reductive alkylation. After modification of a library of unprotected peptides XYSKEASAL (X varies over 20 natural amino acids) by benzaldehyde at room temperature, pH 6.1 resulted in excellent N-terminal selectivity (α-amino/e-amino: >99 : 1) and high reaction conversion for 19 out of the 20 peptides. Under similar conditions, highly selective N-terminal modifications were achieved with a variety of aldehydes. Furthermore, N-termini of native peptides and proteins could be selectively modified under the same conditions to introduce bioorthogonal functional groups. Using human insulin as an example, we further demonstrated that preserving the positive charge in the N-terminus using reductive alkylation instead of acylation leads to a 5-fold increase in bioactivity. In summary, our reported method provides a universal strategy for site-selective N-terminal functionalization in native peptides and proteins.
TL;DR: It is reported herein that primary aliphatic amines can be cleanly mono-alkylated by unactivated secondary alkyl iodides in the presence of visible light and a copper catalyst.
Abstract: Although the alkylation of an amine by an alkyl halide serves as a “textbook example” of a nucleophilic substitution reaction, the selective mono-alkylation of aliphatic amines by unactivated, hindered halides persists as a largely unsolved challenge in organic synthesis. We report herein that primary aliphatic amines can be cleanly mono-alkylated by unactivated secondary alkyl iodides in the presence of visible light and a copper catalyst. The method operates under mild conditions (–10 °C), displays good functional-group compatibility, and employs commercially available catalyst components. A trapping experiment with TEMPO is consistent with C–N bond formation via an alkyl radical in an out-of-cage process.
TL;DR: Differences of more than 9-fold in numbers of identified methionine-containing peptide spectral matches for in-gel digested samples were observed between iodine- and noniodine- containing alkylation reagents, as one of the major factors for the differences.
TL;DR: A new organocatalytic strategy is described in which in-situ generated aza-para-quinone methides are employed as the alkylating reagent, and the intermolecular C-N bond formation with various indole and carbazole nucleophiles proceeded efficiently under mild conditions with excellent enantioselectivity and functional-group compatibility.
Abstract: Catalytic asymmetric N-alkylation of indoles and carbazoles represents a family of important but underdeveloped reactions. Herein, we describe a new organocatalytic strategy in which in situ generated aza-para-quinone methides are employed as the alkylating reagent. With the proper choice of a chiral phosphoric acid and an N-protective group, the intermolecular C−N bond formation with various indole and carbazole nucleophiles proceeded efficiently under mild conditions with excellent enantioselectivity and functional-group compatibility. Control experiments and kinetic studies provided important insight into the reaction mechanism.
TL;DR: This report addresses the challenge of coupling a carbamate nucleophile with an unactivated secondary alkyl electrophile to generate a substituted carbamate, a process that has not been achieved effectively in the absence of a catalyst; the product carbamates can serve as useful intermediates in organic synthesis as well as bioactive compounds in their own right.
Abstract: Despite the long history of SN2 reactions between nitrogen nucleophiles and alkyl electrophiles, many such substitution reactions remain out of reach. In recent years, efforts to develop transition-metal catalysts to address this deficiency have begun to emerge. In this report, we address the challenge of coupling a carbamate nucleophile with an unactivated secondary alkyl electrophile to generate a substituted carbamate, a process that has not been achieved effectively in the absence of a catalyst; the product carbamates can serve as useful intermediates in organic synthesis as well as bioactive compounds in their own right. Through the design and synthesis of a new copper-based photoredox catalyst, bearing a tridentate carbazolide/bisphosphine ligand, that can be activated upon irradiation by blue-LED lamps, we can achieve the coupling of a range of primary carbamates with unactivated secondary alkyl bromides at room temperature. Our mechanistic observations are consistent with the new copper complex se...
TL;DR: A borrowing-hydrogen reaction between amines and alcohols is an atom-economic way to prepare alkylamines, ideally with water as the sole byproduct as discussed by the authors.
Abstract: A borrowing-hydrogen reaction between amines and alcohols is an atom-economic way to prepare alkylamines, ideally with water as the sole byproduct. Herein, nickel catalysts are used for direct N-alkylation of hydrazides and arylamines using racemic alcohols. Moreover, a nickel catalyst of (S)-binapine was used for an asymmetric N-alkylation of benzohydrazide with racemic benzylic alcohols.
TL;DR: A pyrimidine-based template effective for the formation of β-aryl aldehydes and ketones, using allyl alcohols, by meta-C-H activation of benzylsulfonyl esters is described and new functionalizations at the meta-position of an arene have also been successfully implemented in benzylphosphonate, phenethyl carbonyl, and phenethylsulfonate scaffolds.
Abstract: To expand the scope of meta-functionalization, a pyrimidine-based template effective for the formation of β-aryl aldehydes and ketones, using allyl alcohols, by meta-C−H activation of benzylsulfonyl esters is described. In addition, α,β-unsaturated aldehydes were generated by in situ olefination and deprotection of allyl benzyl ethers. These new functionalizations at the meta-position of an arene have also been successfully implemented in benzylphosphonate, phenethyl carbonyl, and phenethylsulfonyl ester scaffolds. Key to these successful new functionalizations is the creation of an electropositive palladium center by accepting the electron cloud from the metal to the energetically low-lying π-orbitals of pyrimidine ring, and it favors coordination of allyl alcohol to the metal center.
TL;DR: An unprecendented direct alkylation of unfunctionalized allylic/benzylic sp3 C–H bonds via photoredox induced radical cation deprotonation is disclosed.
Abstract: Despite notable recent efforts, a catalytic and convenient strategy for the direct alkylation of unactivated allylic or benzylic sp3 C–H bonds remains a formidable challenge facing the synthesis community. We herein report an unprecedented allylic/benzylic alkylation using only an organo-photoredox catalyst, which enables coupling of a broad scope of alkenes/arenes and electron-deficient alkenes in an atom- and redox-economic manner. A photoredox induced alkene/arene radical cation deprotonation is proposed to smoothly generate the key allylic and benzylic radical intermediates. It represents the first C–C bond formation via radical cation deprotonation under visible light conditions. The resulting products can be easily scaled up and directly converted to γ,δ-unsaturated or α,β-diaryl-acids, -esters, -amides, -pyrazoles, -isoxazoles, as well as lactones, which enables this mild and selective sp3 C–H alkylation to rapidly access complex bioactive molecules.
TL;DR: This work reports on the first cobalt-catalyzed alkylation of secondary alcohols with primary alcohols, and Mechanistic studies indicate that the reaction follows the borrowing hydrogen or hydrogen autotransfer concept.
Abstract: Alcohols are promising sustainable starting materials because they can be obtained from abundant and indigestible biomass. The substitution of expensive noble metals in catalysis by earth abundant 3d metals, such as Mn, Fe, or Co, (nonprecious or base metals) is a related key concept with respect to sustainability. Here, we report on the first cobalt-catalyzed alkylation of secondary alcohols with primary alcohols. Easy-to-synthesize and easy-to-activate PN5 P-pincer-ligand-stabilized Co complexes developed in our laboratory mediate the reaction most efficiently. The catalysis is applicable to a broad substrate scope and proceeds under relatively mild conditions. We have even demonstrated the coupling of a variety of purely aliphatic alcohols with a base or nonprecious metal catalyst. Mechanistic studies indicate that the reaction follows the borrowing hydrogen or hydrogen autotransfer concept.