Keary Engle

Keary Engle
The Scripps Research Institute | scripps · Department of Chemistry

PhD, DPhil

About

98
Publications
6,386
Reads
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14,477
Citations
Citations since 2016
70 Research Items
8475 Citations
201620172018201920202021202202004006008001,0001,200
201620172018201920202021202202004006008001,0001,200
201620172018201920202021202202004006008001,0001,200
201620172018201920202021202202004006008001,0001,200
Additional affiliations
September 2013 - May 2015
California Institute of Technology
Position
  • NIH Postdoctoral Fellow
October 2011 - April 2013
University of Oxford
Position
  • PhD Student
August 2008 - June 2011
The Scripps Research Institute
Position
  • PhD Student

Publications

Publications (98)
Preprint
Full-text available
A unique family of N,N,π,C-palladacycles are synthesized from 8-aminoquinoline-coupled nopol derivatives through directed 1,2-migratory insertion of in situ generated arylpalladium(II) species followed by β-carbon elimination. These palladacycles have exceptional stability under air and moisture at room temperature, enabling successful isola-tion a...
Article
An asymmetric 1,2-dicarbofunctionalization of unactivated alkenes with aryl iodides and aryl/alkenylboronic esters under nickel/bioxazoline catalysis is disclosed. A wide array of aryl and alkenyl nucleophiles are tolerated, furnishing the products in good yield and with high enantioselectivity. In addition to terminal alkenes, 1,2-disubstituted in...
Preprint
Full-text available
An asymmetric 1,2-dicarbofunctionalization of unactivated alkenes with aryl iodides and aryl/alkenylboronic esters under nickel/bioxazoline catalysis is disclosed. A wide array of aryl and alkenyl nucleophiles are tolerated, furnishing the products in good yield and with high enantioselectivity. In addition to terminal alkenes, 1,2-disubstituted in...
Preprint
Full-text available
The catalytic enantioselective synthesis of α-chiral alkenes and alkynes represents a powerful strategy for rapid generation of molecular complexity. Herein, we report a transient directing group facilitated site-selective palladium-catalyzed reductive Heck-type hydroalkenylation and hydroalkynylation of alkenylaldehyes using alkenyl and alkynyl br...
Article
Full-text available
The controlled isomerization and functionalization of alkenes is a cornerstone achievement in organometallic catalysis that is now widely used throughout industry. In particular, the addition of CO and H2 to an alkene, also known as the oxo-process, is used in the production of linear aldehydes from crude alkene feedstocks. In these catalytic react...
Article
Full-text available
We report a regioselective, nickel-catalyzed syn-1,2-carbosulfenylation of non-conjugated alkenyl carbonyl compounds with alkyl/arylzinc nucleophiles and tailored N-S electrophiles. This method allows the simultaneous installation of a variety of C(sp3) and S(Ar) (or Se(Ar)) groups onto unactivated alkenes, which complements previously developed 1,...
Preprint
Full-text available
The site-selective palladium-catalyzed three-component coupling of unactivated alkenyl carbonyl compounds, aryl- or alkenylboronic acids, and N-fluorobenzenesulfonimide is described herein. Tuning of the steric environment on the bidentate directing auxiliary is proposed to facilitate challenging C(sp3)–F reductive elimination from a Pd(IV) interme...
Preprint
Full-text available
A flurry of recent research has centered on harnessing the power of nickel catalysis in organic synthesis. These efforts have been bolstered by contemporaneous synthesis, characterization, and optimization of well-defined nickel (pre)catalysts with diverse structure and reactivity. In this report, we present the development of ten different bench-s...
Preprint
Full-text available
We report a redox-neutral catalytic coupling of nitroalkanes and unactivated alkenes that proceeds by a directed carbopalladation mechanism. The reaction is uniquely enabled by the combination of PdI2 as the precatalyst and HFIP solvent. Structurally complex nitroalkane products, including nitro-containing carbo- and heterocycles, are prepared unde...
Preprint
Full-text available
We report a redox-neutral catalytic coupling of nitroalkanes and unactivated alkenes that proceeds by a directed carbopalladation mechanism. The reaction is uniquely enabled by the combination of PdI2 as the precatalyst and HFIP solvent. Structurally complex nitroalkane products, including nitro-containing carbo- and heterocycles, are prepared unde...
Preprint
Full-text available
A versatile method to access differentially substituted 1,3- and 1,4-diamines via a nickel-catalyzed three-component 1,2-carboamination of alkenyl amines with aryl/alkenylboronic ester nucleophiles and N–O electrophiles is reported. The reaction proceeds efficiently with free primary and secondary amines without needing a directing auxiliary or pro...
Preprint
Full-text available
A multi-component approach to structurally complex organosulfur products is described via the nickel-catalyzed 1,2-carbosulfenylation of unactivated alkenes with organoboron nucleophiles and tailored organosulfur electrophiles. Key to the development of this transformation is the identification of a modular N-alkyl-N-(arylsulfenyl)arenesulfonamide...
Preprint
Full-text available
In this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti-selective carbo- or heteroannulation with non-conjugated alkenyl amides under Pd catalysis. Detailed optimization of reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other c...
Preprint
In this study, we systematically evaluate different ambiphilic organohalides for their ability to participate in anti-selective carbo- or heteroannulation with non-conjugated alkenyl amides under Pd catalysis. Detailed optimization of reaction conditions has led to protocols for synthesizing tetrahydropyridines, tetralins, pyrrolidines, and other c...
Article
The synthesis of polysubstituted alkenes represents a formidable challenge in organic synthesis. Over the years, many advances have been made for this purpose, yet challenges persist in terms of selectivity, scope, and efficiency. Palladium-catalyzed methods for alkene synthesis are attractive within this field given that cross-coupling is particul...
Article
Full-text available
We report a full account of our research on nickel-catalyzed Markovnikov-selective hydroarylation and hydroalkenylation of non-conjugated alkenes, which has yielded a toolkit of methods that proceed under mild conditions with alkenyl sulfonamide, ketone, and amide substrates. Regioselectivity is controlled through catalyst coordination to the nativ...
Preprint
A tungsten-catalyzed hydroboration of unactivated alkenes at distal C(sp3)–H bonds aided by native directing groups is described herein. The method is characterized by its simplicity, exquisite regio- and chemoselectivity and wide substrate scope, offering a complementary site-selectivity pattern to other metal-catalyzed borylation reactions and ch...
Article
The vicinal fluorofunctionalization of alkenes represents an expedient strategy for converting feedstock olefins into valuable fluorinated molecules and as such has garnered significant attention from the synthetic community; however, current methods remain limited in terms of scope and selectivity. Here we report the site-selective palladium-catal...
Article
We report a direct and modular method to access non-conjugated alkenyl amides containing the 8-aminoquinoline (AQ) directing auxiliary and related groups via cross-metathesis. In this way, readily available, AQ-containing, terminal β,γ-unsaturated amides can be coupled with various terminal alkenes to furnish internal alkene products that are other...
Article
Electron-deficient olefin (EDO) ligands are known to promote a variety of nickel-catalyzed cross-coupling reactions, presumably by accelerating the reductive elimination step and preventing undesired β-hydride elimination. While there is a growing body of experimental and computational evidence elucidating the beneficial effects of EDO ligands, sig...
Chapter
The transition-metal catalyzed difunctionalization of unsaturated organics is a powerful bond-forming strategy in organic chemistry. Installing combinations of amino-, oxo-, carbo-, and halo-groups across a carbon–carbon double or triple bond allows for rapid build-up of molecular complexity in a highly selective and efficient fashion. This chapter...
Article
Full-text available
2,3-Dihydrobenzofurans and indolines are common substructures in medicines and natural products. Herein, we describe a method that enables direct access to these core structures from non-conjugated alkenyl amides and ortho-iodoanilines/phenols. Under palladium(II) catalysis this [3 + 2] heteroannulation proceeds in an anti-selective fashion and tol...
Article
1,2-Diarylation of alkenyl sulfonamides with aryl iodides and aryl boronic esters under nickel catalysis is reported. The developed method tolerates coupling partners with disparate electronic properties and substitution patterns. Di- and trisubstituted alkenes as well as alkenes distal from the directing group are all accommodated. Control experim...
Article
Full-text available
We report a series of palladium(II)-catalyzed, intramolecular alkene hydrofunctionalization reactions with carbon, nitrogen, and oxygen nucleophiles to form five- and six-membered carbo- and heterocycles. In these reactions, the presence of a proximal bidentate directing group controls the cyclization pathway, dictating the ring size that is genera...
Article
A novel 4,4‐disubstituted Pyrox ligand overrides innate regioselectivity trends in the Ni‐catalyzed hydroarylation and alkenylation of alkenyl carboxylic acids. This method enables regiodivergent entry to β‐ and γ‐functionalized aliphatic acids. Abstract A nickel‐catalyzed regiodivergent hydroarylation and hydroalkenylation of unactivated alkenyl...
Article
Full-text available
Nickel-catalyzed three-component alkene difunctionalization has rapidly emerged as a powerful tool for forging multiple C–C bonds in a single step. Building upon the powerful modes of bond construction in traditional two-component cross-coupling, various research groups have demonstrated the versatility of nickel in enabling catalytic 1,2-dicarbofu...
Article
Full-text available
Enantioenriched α-aminoboronic acids play a unique role in medicinal chemistry and have emerged as privileged pharmacophores in proteasome inhibitors. Additionally, they represent synthetically useful chiral building blocks in organic synthesis. Recently, CuH-catalysed asymmetric alkene hydrofunctionalization has become a powerful tool to construct...
Article
Through the combined action of palladium catalysts and chiral phosphoric acids (CPAs) a variety of catalytic asymmetric reactions have been realized during the past decade, including allylation, alkene functionalization, and...
Article
Full-text available
The conventional oxidative Heck reaction between aryl boronic acids and alkenes typically involved the PdII/Pd0/PdII catalytic cycle incorporating an external oxidant and often suffered C=C bond isomerization for internal alkyl-substituted alkenes via chain-walking. Herein, we demonstrate that the regioselectivity (γ-selectivity vs. δ-selectivity)...
Article
The copper-catalyzed hydroboration of benzylidenecyclopropanes, conveniently accessed in one step from readily available benzaldehydes, is reported. Under otherwise identical reaction conditions, two distinct phosphine ligands grant access to different products by either suppressing or promoting cyclopropane opening via β-carbon elimination. Comput...
Article
During the past decade, many research groups have described catalytic methods for 1,2‐carboboration, allowing access to structurally complex organoboronates from alkenes. Various transition metals, especially copper, palladium, and nickel, have been widely used in these reactions. This review summarizes advances in this field, with a special focus...
Article
The Mizoroki-Heck reaction is one of the most studied palladium-catalyzed cross-coupling reactions, representing a powerful method for forming C-C bonds between diverse substrates with broad functional group compatibility. However, the reductive variant has received considerably less attention. In this Review, we summarize distinct mechanistic aspe...
Article
A nickel-catalyzed conjunctive cross-coupling of simple alkenyl amides with aryl iodides and aryl boronic esters is reported. The reaction is enabled by an electron-deficient olefin (EDO) ligand, dimethyl fumarate, and delivers the desired 1,2-diarylated products with excellent regiocontrol. Under optimized conditions, a wide range of amides derive...
Article
We report a regioselective, nickel-catalyzed syn -1,2-carboamination of non-conjugated alkenyl carbonyl compounds with O -benzoyl hydroxylamine (N–O) electrophiles and aryl/alkylzinc nucleophiles to afford β- and γ-amino acid derivatives. This method enables preparation of products containing structurally diverse tertiary amine motifs, including he...
Preprint
We report a regioselective, nickel-catalyzed syn -1,2-carboamination of non-conjugated alkenyl carbonyl compounds with O -benzoyl hydroxylamine (N–O) electrophiles and aryl/alkylzinc nucleophiles to afford β- and γ-amino acid derivatives. This method enables preparation of products containing structurally diverse tertiary amine motifs, including he...
Article
Full-text available
Chemists' ability to synthesize structurally complex, high-value organic molecules from simple starting materials is limited by methods to selectively activate and functionalize strong alkyl C(sp3) covalent bonds. Recent activity has focused on the activation of abundant C-O, C-N and C-C bonds via a mechanistic paradigm of oxidative addition of a l...
Article
Full-text available
A catalytic γ-selective syn -hydroarylation of alkenyl carbonyl compounds using arylboronic acids has been developed using a substrate directivity approach with a palladium(II) catalyst. This method tolerates a wide range of...
Article
Full-text available
A nickel-catalyzed conjunctive cross-coupling of non-conjugated alkenes, alkyl halides, and alkylzinc reagents is reported. Regioselectivity is controlled by chelation of a removable bidentate 8-aminoquinoline directing group. Under optimized conditions, a wide range of 1,2-dialkylated products can be accessed in moderate to excellent yields. To th...
Article
Rational design of second-generation ruthenium olefin metathesis catalysts with desired initiation rates can be enabled by a computational model that depends on a single thermodynamic parameter. Using a computational model with no assumption about the specific initiation mechanism, the initiation kinetics of a spectrum of second-generation rutheniu...
Article
Small molecules containing cyclopropane–heteroatom linkages are commonly needed in medicinal chemistry campaigns, yet are problematic to prepare using existing methods. To address this issue, a scalable Chan–Lam cyclopropylation reaction using potassium cyclopropyl trifluoroborate has been developed. With phenol nucleophiles, the reaction effects O...
Preprint
A nickel-catalyzed conjunctive cross-coupling of non-conjugated alkenes, alkyl halides, and alkylzinc reagents is reported. Regioselectivity is controlled by chelation of a removable bidentate 8-aminoquinoline directing group. Under optimized conditions, a wide range of 1,2-dialkylated products can be accessed in moderate to excellent yields. To th...
Article
Removable tridentate directing groups inspired by pincer ligands have been designed to stabilize otherwise kinetically and thermodynamically disfavored 6-membered alkyl palladacycle intermediates. This family of directing groups enables regioselective remote hydrocarbofunctionalization of several synthetically useful alkene-containing substrate cla...
Article
A nickel-catalyzed conjunctive cross-coupling between non-conjugated alkenes, aryl iodides, and alkylzinc reagents is reported. Excellent regiocontrol is achieved utilizing an 8-aminoquinoline directing group that can be readily cleaved to unmask net β,γ-dicarbofunctionalized carboxylic acid products. Under optimized conditions, both terminal and i...
Article
A selective N-alkylation reaction of 2-pyridones and related heterocycles via intermolecular alkene hydroamination is reported. The reaction utilizes palladium(II) acetate as a catalyst and employs a bidentate directing group to dictate the regioselectivity for both unactivated terminal and internal alkenes. High functional group tolerance is obser...
Article
A regioselective anti-hydrochlorination of unactivated alkynes is reported. The reaction utilizes in situ generated HCl as the source of both the Cl– and H⁺ and is catalyzed by palladium(II) acetate, with loadings as low as 25 ppm. Removable picolinamide and 8-aminoquinoline bidentate directing groups are used to control the regioselectivity of the...
Article
A palladium(II)-catalyzed 1,2-dicarbofunctionalization reaction of unactivated alkenes has been developed, wherein a cleavable bidentate directing group is used to control regioselectivity and stabilize the putative alkylpalladium(II) intermediate. Under the optimized reaction conditions, a broad range of nucleophiles and electrophiles were found t...
Article
Reactions that forge carbon–carbon (C–C) bonds are the bedrock of organic synthesis, widely used across the chemical sciences. We report a transformation that enables C–C bonds to be constructed from two classes of commonly available starting materials, alkenes and carbon–hydrogen (C–H) bonds. The reaction employs a palladium(II) catalyst and utili...
Article
Olefin metathesis reactions with 3E-1,3-dienes using Z-selective cyclometalated ruthenium benzylidene catalysts are described. In particular, a procedure for employing 3E-1,3-dienes in Z-selective homodimerization and cross-metathesis with terminal alkenes is detailed. The reaction takes advantage of the pronounced chemoselectivity of a recently re...
Article
Hydrogen-bonding with fluoride is a key interaction encountered when analyzing the mode of action of 5’-fluoro-5’-deoxyadenosine synthase, the only known enzyme capable of catalyzing the formation of a C–F bond from F–. Further understanding of the effect of hydrogen-bonding on the structure and reactivity of complexed fluoride is therefore importa...
Article
A palladium(II)-catalyzed regioselective syn-hydroarylation reaction of homopropargyl amines has been developed, wherein selectivity is controlled by a cleavable bidentate directing group. Under the optimized reaction conditions, both dialkyl and alkylaryl alkyne substrates were found to undergo hydroarylation with high selectivity. The products of...
Conference Paper
A series of second-generation ruthenium olefin metathesis catalysts was investigated using a combination of reaction kinetics, X-ray crystallog., NMR spectroscopy, and DFT calcns. in order to det. the relationship between the structure of the chelating ortho-alkoxybenzylidene and the obsd. initiation rate. Included in this series were twenty new ca...
Conference Paper
A method for olefin metathesis between 3(E)-1,3-dienes and terminal olefins is described. The method employs a recently reported ruthenium-based catalyst contg. a cyclometalated NHC ligand and takes advantage of its pronounced selectivity for terminal olefins in the presence of internal E-olefins. A wide variety of functional groups can be tolerate...
Article
Ruthenium benzylidene complexes are well known as olefin metathesis catalysts. Several reports have demonstrated the ability of these catalysts to also facilitate atom transfer radical (ATR) reactions, such as atom transfer radical addition (ATRA) and atom transfer radical polymerization (ATRP). However, while the mechanism of olefin metathesis wit...
Article
If organic molecules were trees, then the numerous carbon-hydrogen bonds within them would be leaves. A catalyst that targets one 'leaf' out of many similar other ones looks set to be a huge leap for synthetic chemistry. See Letter p.230
Article
A directed, regiocontrolled hydroamination of unactivated terminal and internal alkenes is reported. The reaction is catalyzed by palladium(II) acetate and is compatible with a variety of nitrogen nucleophiles. A removable bidentate directing group is used to control the regiochemistry, prevent β-hydride elimination, and stabilize the nucleopallada...
Chapter
Mono-N-protected amino acid (MPAA)-accelerated ortho-C–H olefination reaction tolerates a range of electron-donating and -withdrawing substituents on the aryl group of the phenylacetic acid. This work demonstrates the essential role that the ligand plays in developing practical Pd(II)-catalyzed C–H functionalization reactions that are reliable in p...
Conference Paper
Since the first report of ruthenium- based catalysts in atom transfer radical addn. (ATRA, also called Kharasch addn.) and atom transfer radical polymn. (ATRP) , this area of research has attracted widespread interest. Well- defined ruthenium benzylidene complexes, commonly used as olefin metathesis catalysts, have also been reported to catalyze AT...
Article
It has long been known that transition metals are capable of interacting with, cleaving, and mediating the functionalization of activated and unactivated carbon–hydrogen (C–H) bonds. Broadly speaking, a basic underlying principle in the fields of inorganic and organometallic chemistry is that the primary and secondary coordination spheres around a...
Data
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and...
Article
A simple protocol for preparation of benzofurans from o-fluorobenzenes via in situ generated N-alkyl- and -arylimines is developed.