Co-reporter:Gang Lu, Richard Y. Liu, Yang Yang, Cheng Fang, Daniel S. Lambrecht, Stephen L. Buchwald, and Peng Liu
Journal of the American Chemical Society November 22, 2017 Volume 139(Issue 46) pp:16548-16548
Publication Date(Web):October 24, 2017
DOI:10.1021/jacs.7b07373
The current understanding of ligand effects in transition metal catalysis is mostly based on the analysis of catalyst–substrate through-bond and through-space interactions, with the latter commonly considered to be repulsive in nature. The dispersion interaction between the ligand and the substrate, a ubiquitous type of attractive noncovalent interaction, is seldom accounted for in the context of transition-metal-catalyzed transformations. Herein we report a computational model to quantitatively analyze the effects of different types of catalyst–substrate interactions on reactivity. Using this model, we show that in the copper(I) hydride (CuH)-catalyzed hydroamination of unactivated olefins, the substantially enhanced reactivity of copper catalysts based on bulky bidentate phosphine ligands originates from the attractive ligand–substrate dispersion interaction. These computational findings are validated by kinetic studies across a range of hydroamination reactions using structurally diverse phosphine ligands, revealing the critical role of bulky P-aryl groups in facilitating this process.
Co-reporter:Brett P. Fors and Stephen L. Buchwald
Journal of the American Chemical Society November 17, 2010 Volume 132(Issue 45) pp:15914-15917
Publication Date(Web):October 27, 2010
DOI:10.1021/ja108074t
An alternative approach to catalyst development, which led to a Pd catalyst based on two biarylphosphine ligands for C−N cross-coupling reactions, is reported. By effectively being able to take the form of multiple catalysts this system manifests the best properties that catalysts based on either of the two ligands exhibit separately and displays the highest reactivity and substrate scope of any system that has been reported to date for these reactions.
Co-reporter:Wenjun Zhao, Hong Geun Lee, Stephen L. Buchwald, and Jacob M. Hooker
Journal of the American Chemical Society May 31, 2017 Volume 139(Issue 21) pp:7152-7152
Publication Date(Web):May 15, 2017
DOI:10.1021/jacs.7b02761
A practical procedure for 11CN-labeling of unprotected peptides has been developed. The method was shown to be highly chemoselective for cysteine over other potentially nucleophilic residues, and the radiolabeled products were synthesized and purified in less than 15 min. Appropriate for biomedical applications, the method could be used on an extremely small scale (20 nmol) with a high radiochemical yield. The success of the protocol stems from the use of a Pd-reagent based on a dihaloarene, which enables direct “nucleophile–nucleophile” coupling of the peptide and [11C]cyanide by temporal separation of nucleophile addition.
Co-reporter:Haoxuan Wang, Jeffrey C. Yang, and Stephen L. Buchwald
Journal of the American Chemical Society June 28, 2017 Volume 139(Issue 25) pp:8428-8428
Publication Date(Web):June 8, 2017
DOI:10.1021/jacs.7b04816
This report details a general and enantioselective means for the synthesis of alkyl-substituted aziridines. This protocol offers a direct route for the synthesis of alkyl-substituted chiral aziridines from achiral starting materials. Readily accessed allylic hydroxylamine esters undergo copper hydride-catalyzed intramolecular hydroamination with a high degree of regio- and enantiocontrol to afford the aziridine products in good to excellent yields in highly enantioenriched form. The utility of the products derived from this method is further demonstrated through derivatization of the chiral aziridine products to obtain a diverse array of functionalized enantioenriched amines.
Co-reporter:Bryan T. Ingoglia and Stephen L. Buchwald
Organic Letters June 2, 2017 Volume 19(Issue 11) pp:
Publication Date(Web):May 12, 2017
DOI:10.1021/acs.orglett.7b01082
In this report, we describe the application of palladium-based oxidative addition complexes (OACs) as effective precatalysts for C–N, C–O, and C–F cross-coupling reactions with a variety of (hetero)arenes. These complexes offer a convenient alternative to previously developed classes of precatalysts, particularly in the case of the bulkiest biarylphosphine ligands, for which palladacycle-based precatalysts do not readily form. The precatalysts described herein are easily prepared and stable to long-term storage under air.
Co-reporter:Michael W. Gribble Jr., Michael T. Pirnot, Jeffrey S. Bandar, Richard Y. Liu, and Stephen L. Buchwald
Journal of the American Chemical Society February 15, 2017 Volume 139(Issue 6) pp:2192-2192
Publication Date(Web):January 24, 2017
DOI:10.1021/jacs.6b13029
We report a highly enantioselective CuH-catalyzed Markovnikov hydrosilylation of vinylarenes and vinyl heterocycles. This method has a broad scope and enables both the synthesis of isolable silanes and the conversion of crude products to chiral alcohols. Density functional theory calculations support a mechanism proceeding by hydrocupration followed by σ-bond metathesis with a hydrosilane.
Co-reporter:Hu Zhang and Stephen L. Buchwald
Journal of the American Chemical Society August 23, 2017 Volume 139(Issue 33) pp:11590-11590
Publication Date(Web):July 28, 2017
DOI:10.1021/jacs.7b06630
We report a Pd-catalyzed stereospecific α-arylation of optically pure 2,3-epoxy-1,1,1-trifluoropropane (TFPO). This method allows for the direct and reliable preparation of optically pure 2-CF3-2-(hetero)aryloxiranes, which are precursors to many CF3-substituted tertiary alcohols. The use of continuous-flow methods has allowed the deprotonation of TFPO and subsequent zincation at higher temperature compared to that under traditional batch conditions.
Co-reporter:Anthony J. Rojas, Bradley L. Pentelute, and Stephen L. Buchwald
Organic Letters August 18, 2017 Volume 19(Issue 16) pp:
Publication Date(Web):August 4, 2017
DOI:10.1021/acs.orglett.7b01911
We report the use of a sulfonated biarylphosphine ligand (sSPhos) to promote the chemoselective modification of cysteine containing proteins and peptides with palladium reagents in aqueous medium. The use of sSPhos allowed for the isolation of several air-stable and water-soluble mono- and bis-palladium reagents, which were used in an improved protocol for the rapid S-arylation of cysteines under benign and physiologically relevant conditions. The cosolvent-free aqueous conditions were applied to the conjugation of a variety of biomolecules with affinity tags, heterocycles, fluorophores, and functional handles. Additionally, bis-palladium reagents were used to perform macrocyclization of peptides bearing two cysteine residues.
Co-reporter:Dr. Esben P. K. Olsen;Dr. Pedro L. Arrechea; Dr. Stephen L. Buchwald
Angewandte Chemie 2017 Volume 129(Issue 35) pp:10705-10708
Publication Date(Web):2017/08/21
DOI:10.1002/ange.201705525
AbstractBy using mechanistic insight, a new ligand (EPhos) for the palladium-catalyzed C−N cross-coupling between primary amines and aryl halides has been developed. Employing an isopropoxy group at the C3-position favors the C-bound isomer of the ligand-supported palladium(II) complexes and leads to significantly improved reactivity. The use of a catalyst system based on EPhos with NaOPh as a mild homogeneous base proved to be very effective in the formation of 4-arylaminothiazoles and highly functionalized 2-arylaminooxazoles. Previously, these were not readily accessible using palladium catalysis.
Co-reporter:Dr. Stig D. Friis;Dr. Michael T. Pirnot;Lauren N. Dupuis; Dr. Stephen L. Buchwald
Angewandte Chemie 2017 Volume 129(Issue 25) pp:7348-7352
Publication Date(Web):2017/06/12
DOI:10.1002/ange.201703400
AbstractWe report an efficient means of sp2–sp3 cross coupling for a variety of terminal monosubstituted olefins with aryl electrophiles using Pd and CuH catalysis. In addition to its applicability to a range of aryl bromide substrates, this process was also suitable for electron-deficient aryl chlorides, furnishing higher yields than the corresponding aryl bromides in these cases. The optimized protocol does not require the use of a glovebox and employs air-stable Cu and Pd complexes as precatalysts. A reaction on 10 mmol scale further highlighted the practical utility of this protocol. Employing a similar protocol, a series of cyclic alkenes were also examined. Cyclopentene was shown to undergo efficient coupling under these conditions. Lastly, deuterium-labeling studies indicate that deuterium scrambling does not take place in this sp2-sp3 cross coupling, implying that β-hydride elimination is not a significant process in this transformation.
Co-reporter:Dr. Esben P. K. Olsen;Dr. Pedro L. Arrechea; Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2017 Volume 56(Issue 35) pp:10569-10572
Publication Date(Web):2017/08/21
DOI:10.1002/anie.201705525
AbstractBy using mechanistic insight, a new ligand (EPhos) for the palladium-catalyzed C−N cross-coupling between primary amines and aryl halides has been developed. Employing an isopropoxy group at the C3-position favors the C-bound isomer of the ligand-supported palladium(II) complexes and leads to significantly improved reactivity. The use of a catalyst system based on EPhos with NaOPh as a mild homogeneous base proved to be very effective in the formation of 4-arylaminothiazoles and highly functionalized 2-arylaminooxazoles. Previously, these were not readily accessible using palladium catalysis.
Co-reporter:Dr. Stig D. Friis;Dr. Michael T. Pirnot;Lauren N. Dupuis; Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2017 Volume 56(Issue 25) pp:7242-7246
Publication Date(Web):2017/06/12
DOI:10.1002/anie.201703400
AbstractWe report an efficient means of sp2–sp3 cross coupling for a variety of terminal monosubstituted olefins with aryl electrophiles using Pd and CuH catalysis. In addition to its applicability to a range of aryl bromide substrates, this process was also suitable for electron-deficient aryl chlorides, furnishing higher yields than the corresponding aryl bromides in these cases. The optimized protocol does not require the use of a glovebox and employs air-stable Cu and Pd complexes as precatalysts. A reaction on 10 mmol scale further highlighted the practical utility of this protocol. Employing a similar protocol, a series of cyclic alkenes were also examined. Cyclopentene was shown to undergo efficient coupling under these conditions. Lastly, deuterium-labeling studies indicate that deuterium scrambling does not take place in this sp2-sp3 cross coupling, implying that β-hydride elimination is not a significant process in this transformation.
Co-reporter:Anthony J. Rojas;Chi Zhang;Ekaterina V. Vinogradova;Nathan H. Buchwald;John Reilly;Bradley L. Pentelute
Chemical Science (2010-Present) 2017 vol. 8(Issue 6) pp:4257-4263
Publication Date(Web):2017/05/30
DOI:10.1039/C6SC05454D
Macrocyclic peptides are important therapeutic candidates due to their improved physicochemical properties in comparison to their linear counterparts. Here we detail a method for a divergent macrocyclisation of unprotected peptides by crosslinking two cysteine residues with bis-palladium organometallic reagents. These synthetic intermediates are prepared in a single step from commercially available aryl bis-halides. Two bioactive linear peptides with cysteine residues at i, i + 4 and i, i + 7 positions, respectively, were cyclised to introduce a diverse array of aryl and bi-aryl linkers. These two series of macrocyclic peptides displayed similar linker-dependent lipophilicity, phospholipid affinity, and unique volume of distributions. Additionally, one of the bioactive peptides showed target binding affinity that was predominantly affected by the length of the linker. Collectively, this divergent strategy allowed rapid and convenient access to various aryl linkers, enabling the systematic evaluation of the effect of appending unit on the medicinal properties of macrocyclic peptides.
Co-reporter:Paula Ruiz-Castillo and Stephen L. Buchwald
Chemical Reviews 2016 Volume 116(Issue 19) pp:12564-12649
Publication Date(Web):September 30, 2016
DOI:10.1021/acs.chemrev.6b00512
Pd-catalyzed cross-coupling reactions that form C–N bonds have become useful methods to synthesize anilines and aniline derivatives, an important class of compounds throughout chemical research. A key factor in the widespread adoption of these methods has been the continued development of reliable and versatile catalysts that function under operationally simple, user-friendly conditions. This review provides an overview of Pd-catalyzed N-arylation reactions found in both basic and applied chemical research from 2008 to the present. Selected examples of C–N cross-coupling reactions between nine classes of nitrogen-based coupling partners and (pseudo)aryl halides are described for the synthesis of heterocycles, medicinally relevant compounds, natural products, organic materials, and catalysts.
Co-reporter:Aaron C. Sather and Stephen L. Buchwald
Accounts of Chemical Research 2016 Volume 49(Issue 10) pp:2146
Publication Date(Web):September 22, 2016
DOI:10.1021/acs.accounts.6b00247
Aromatic fluorides are prevalent in both agrochemical and pharmaceutical agents. However, methods for their rapid and general preparation from widely available starting materials are limited. Traditional approaches such as the Balz–Schiemann and Halex reactions require harsh conditions that limit functional group tolerance and substrate scope. The use of transition metals to affect C–F bond formation has provided some useful alternatives, but a broadly applicable method remains elusive. In contrast to the widespread use of Pd0/PdII catalysis for aryl–Z bond formation (Z = C, N, O), the analogous C–F cross-coupling process was unknown until fairly recently. In large part, this is due to the challenging Ar–F reductive elimination from Pd(II) intermediates. We have discovered that certain biaryl monophosphine ligands are uniquely capable of promoting this transformation. In this Account, we describe the discovery and development of a Pd-catalyzed C–F cross-coupling process and the systematic developments that made this once hypothetical reaction possible.Key to these developments was the discovery of an unusual in situ ligand modification process in which a molecule of substrate is incorporated into the ligand scaffold and the identity of the modifying group is crucial to the outcome of the reaction. This prompted the synthesis of a variety of “premodified” ligands and the identification of one that led to an expanded substrate scope, including (hetero)aryl triflates and bromides. Contemporaneously, a new Pd(0) precatalyst was also discovered that avoids the need to reduce Pd(II) in situ, a process that was often inefficient and led to the formation of byproducts.The use of inexpensive but hygroscopic sources of fluoride necessitates a reaction setup inside of a N2-filled glovebox, limiting the practicality of the method. Thus, a preformed wax capsule was designed to isolate the catalyst and reagents from the atmosphere and permit benchtop storage and setup. This new technology thus removes the requirement to employ a glovebox for the aromatic fluorination process and other air-sensitive protocols.In every catalyst system that we have studied to date, we observed the formation of regioisomeric fluoride side products. Through deuterium labeling studies it was found that they likely arise from a deprotonation event resulting in the formation of HF and a Pd–benzyne intermediate. Through an investigation of the mechanism of this undesired pathway, a new ligand was designed that substantially reduces the formation of the aryl fluoride regioisomer and even allows room-temperature Ar–F reductive elimination from a Pd(II) intermediate.
Co-reporter:Yang Yang, Ian B. Perry, and Stephen L. Buchwald
Journal of the American Chemical Society 2016 Volume 138(Issue 31) pp:9787-9790
Publication Date(Web):July 25, 2016
DOI:10.1021/jacs.6b06299
The copper-catalyzed intermolecular enantioselective addition of styrenes to imines has been achieved under mild conditions at ambient temperature. This process features the use of styrenes as latent carbanion equivalents via the intermediacy of catalytically generated benzylcopper derivatives, providing an effective means for accessing highly enantiomerically enriched amines bearing contiguous stereocenters. Mechanistic studies shed light on the origin of the preferential styrene hydrocupration in the presence of an imine with the Ph-BPE-derived copper catalyst.
Co-reporter:Pedro Luis Arrechea and Stephen L. Buchwald
Journal of the American Chemical Society 2016 Volume 138(Issue 38) pp:12486-12493
Publication Date(Web):August 25, 2016
DOI:10.1021/jacs.6b05990
Kinetic studies conducted under both catalytic and stoichiometric conditions were employed to investigate the reductive elimination of RuPhos (2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl) based palladium amido complexes. These complexes were found to be the resting state in Pd-catalyzed cross-coupling reactions for a range of aryl halides and diarylamines. Hammett plots demonstrated that Pd(II) amido complexes derived from electron-deficient aryl halides or electron-rich diarylamines undergo faster rates of reductive elimination. A Hammett study employing SPhos (2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl) and analogues of SPhos demonstrated that electron donation of the “lower” aryl group is key to the stability of the amido complex with respect to reductive elimination. The rate of reductive elimination of an amido complex based on a BrettPhos-RuPhos hybrid ligand (2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,6′-diisopropoxybiphenyl) demonstrated that the presence of the 3-methoxy substituent on the “upper” ring of the ligand slows the rate of reductive elimination. These studies indicate that reductive elimination occurs readily for more nucleophilic amines such as N-alkyl anilines, N,N-dialkyl amines, and primary aliphatic amines using this class of ligands.
Co-reporter:Stig D. Friis; Michael T. Pirnot
Journal of the American Chemical Society 2016 Volume 138(Issue 27) pp:8372-8375
Publication Date(Web):June 27, 2016
DOI:10.1021/jacs.6b04566
Detailed in this Communication is the enantioselective synthesis of 1,1-diarylalkanes, a structure found in a range of pharmaceutical drug agents and natural products, through the employment of copper(I) hydride and palladium catalysis. Judicious choice of ligand for both Cu and Pd enabled this hydroarylation protocol to work for an extensive array of aryl bromides and styrenes, including β-substituted vinylarenes and six-membered heterocycles, under relatively mild conditions.
Co-reporter:Jeffrey S. Bandar; Erhad Ascic
Journal of the American Chemical Society 2016 Volume 138(Issue 18) pp:5821-5824
Publication Date(Web):April 27, 2016
DOI:10.1021/jacs.6b03086
A new method for the enantioselective reductive coupling of aryl alkenes with activated carboxylic acid derivatives via copper hydride catalysis is described. Dual catalytic cycles are proposed, with a relatively fast enantioselective hydroacylation cycle followed by a slower diastereoselective ketone reduction cycle. Symmetrical aryl carboxyclic anhydrides provide access to enantioenriched α-substituted ketones or alcohols with excellent stereoselectivity and functional group tolerance.
Co-reporter:Yi-Ming Wang
Journal of the American Chemical Society 2016 Volume 138(Issue 15) pp:5024-5027
Publication Date(Web):April 4, 2016
DOI:10.1021/jacs.6b02527
The enantioselective, intermolecular hydroallylation of vinylarenes employing allylic phosphate electrophiles has been achieved through a copper hydride catalyzed process. The protocol described herein can be applied to a diverse set of vinylarene substrates and allows for the installation of the parent allyl group as well as a range of 2-substituted allylic fragments.
Co-reporter:Sean M. Smith and Stephen L. Buchwald
Organic Letters 2016 Volume 18(Issue 9) pp:2180-2183
Publication Date(Web):April 15, 2016
DOI:10.1021/acs.orglett.6b00799
The regioselective amination of substituted di- and trichloropyrimidines affording the 2-substituted products is reported. While aryl- and heteroarylamines require the use of a dialkylbiarylphosphine-derived palladium catalyst for high efficiency, more nucleophilic dialkylamines produce 2-aminopyrimidines under noncatalyzed SNAr conditions. The key is the use of 5-trimethylsilyl-2,4-dichloropyrimidine as a surrogate for the parent dichloropyrimidine. For more challenging cases, the 2-chloro-4-thiomethoxy analogues were prepared and exclusively afford the desired 2-aminated-4-thiomethoxypyrimidine products.
Co-reporter:Sandra M. King and Stephen L. Buchwald
Organic Letters 2016 Volume 18(Issue 16) pp:4128-4131
Publication Date(Web):August 8, 2016
DOI:10.1021/acs.orglett.6b02082
A general method for the N-arylation of amino acid esters with aryl triflates is described. Both α- and β-amino acid esters, including methyl, tert-butyl, and benzyl esters, are viable substrates. Reaction optimization was carried out by design of experiment (DOE) analysis using JMP software. The mild reaction conditions, which use t-BuBrettPhos Pd G3 or G4 precatalyst, result in minimal racemization of the amino acid ester. This method is the first synthetic application of the t-BuBrettPhos Pd G4 precatalyst. Mechanistic studies show that the observed erosion in enantiomeric excess is due to racemization of the amino acid ester starting material and not of the product.
Co-reporter:Emily B. Corcoran;Michael T. Pirnot;Shishi Lin;Spencer D. Dreher;Daniel A. DiRocco;Ian W. Davies;David W. C. MacMillan
Science 2016 Volume 353(Issue 6296) pp:279-283
Publication Date(Web):15 Jul 2016
DOI:10.1126/science.aag0209
A light approach to C-N bond formation
The need to form C-N bonds arises frequently in drug discovery research. One versatile approach involves the attachment of the C and N fragments to a Pd catalyst. This approach needs a bulky ligand to “crowd” the fragments together off the metal center. Corcoran et al. present a complementary approach that uses Ni in place of Pd. Instead of the bulky ligand, they used a light-activated cocatalyst that strips an electron from the Ni to accelerate the bond formation. A screen involving elaborately substituted reagents confirmed the utility of this approach in cases that challenge the traditional Pd coupling.
Science, this issue p. 279
Co-reporter:Yang Yang;Peng Liu;Gang Lu;Ian B. Perry
Science 2016 Volume 353(Issue 6295) pp:144-150
Publication Date(Web):08 Jul 2016
DOI:10.1126/science.aaf7720
Olefins enlisted to attack ketones
The reaction of C=O groups in ketones with organometallic compounds is a common method to form carbon-carbon bonds. One drawback to this approach, however, is that the organometallics, such as magnesium-derived Grignard reagents, are difficult to handle and susceptible to side reactions. Yang et al. present an alternative method, whereby a copper catalyst activates stable olefins (C=C double bonds) to attack ketones at room temperature. An added silane functions as a reducing agent, and a chiral phosphine ligand renders the reaction highly enantioselective.
Science, this issue p. 144
Co-reporter:Dr. Michael T. Pirnot;Dr. Yi-Ming Wang;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2016 Volume 55( Issue 1) pp:48-57
Publication Date(Web):
DOI:10.1002/anie.201507594
Abstract
Over the past few years, CuH-catalyzed hydroamination has been discovered and developed as a robust and conceptually novel approach for the synthesis of enantioenriched secondary and tertiary amines. The success in this area of research was made possible through the large body of precedent in copper(I) hydride catalysis and the well-explored use of hydroxylamine esters as electrophilic amine sources in related copper-catalyzed processes. This Minireview details the background, advances, and mechanistic investigations in CuH-catalyzed hydroamination.
Co-reporter:Jeffrey C. Yang;Dawen Niu;Bram P. Karsten;Fabio Lima ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2016 Volume 55( Issue 7) pp:2531-2535
Publication Date(Web):
DOI:10.1002/anie.201509922
Abstract
A general, efficient method for C−N cross-coupling has been developed using N,N-dimethyloctanamide as a catalytic cosolvent for biphasic continuous-flow applications. The described method was used to generate a variety of biarylamines and was integrated into a two-step sequence which converted phenols into biarylamines via either triflates or tosylates. Additionally, the method was applied to a three-step synthesis of imatinib, the API of Gleevec, in good yield without the need of solvent switches.
Co-reporter:Dr. Vasudev R. Bhonde;Dr. Brian T. O'Neill;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2016 Volume 55( Issue 5) pp:1849-1853
Publication Date(Web):
DOI:10.1002/anie.201509341
Abstract
The development of a palladacyclic precatalyst supported by a new biaryl(dialkyl)phosphine ligand (VPhos) in combination with octanoic acid/sodium octanoate as a simple and effective surfactant system provided an improved catalyst system for the rapid construction of a broad spectrum of alkylated scaffolds from alkyl zinc reagents generated in situ.
Co-reporter:Jeffrey C. Yang;Dawen Niu;Bram P. Karsten;Fabio Lima ;Dr. Stephen L. Buchwald
Angewandte Chemie 2016 Volume 128( Issue 7) pp:2577-2581
Publication Date(Web):
DOI:10.1002/ange.201509922
Abstract
A general, efficient method for C−N cross-coupling has been developed using N,N-dimethyloctanamide as a catalytic cosolvent for biphasic continuous-flow applications. The described method was used to generate a variety of biarylamines and was integrated into a two-step sequence which converted phenols into biarylamines via either triflates or tosylates. Additionally, the method was applied to a three-step synthesis of imatinib, the API of Gleevec, in good yield without the need of solvent switches.
Co-reporter:Dr. Vasudev R. Bhonde;Dr. Brian T. O'Neill;Dr. Stephen L. Buchwald
Angewandte Chemie 2016 Volume 128( Issue 5) pp:1881-1885
Publication Date(Web):
DOI:10.1002/ange.201509341
Abstract
The development of a palladacyclic precatalyst supported by a new biaryl(dialkyl)phosphine ligand (VPhos) in combination with octanoic acid/sodium octanoate as a simple and effective surfactant system provided an improved catalyst system for the rapid construction of a broad spectrum of alkylated scaffolds from alkyl zinc reagents generated in situ.
Co-reporter:Dr. Michael T. Pirnot;Dr. Yi-Ming Wang;Dr. Stephen L. Buchwald
Angewandte Chemie 2016 Volume 128( Issue 1) pp:48-57
Publication Date(Web):
DOI:10.1002/ange.201507594
Abstract
In den vergangenen Jahren wurde die CuH-katalysierte Hydroaminierung entdeckt und als robuster und konzeptionell neuer Synthesezugang zu enantiomerenangereicherten sekundären und tertiären Aminen entwickelt. Der Erfolg auf diesem Gebiet wurde möglich durch zahlreiche frühere Beispiele für die Katalyse mit Kupfer(I)hydrid und die gut untersuchte Verwendung von Hydroxylaminestern als elektrophile Aminquellen in ähnlichen kupferkatalysierten Reaktionen. Dieser Kurzaufsatz beschreibt Hintergrund, Fortschritte und mechanistische Untersuchungen der CuH-katalysierten Hydroaminierung.
Co-reporter:Aaron C. Sather; Hong Geun Lee; Valentina Y. De La Rosa; Yang Yang; Peter Müller
Journal of the American Chemical Society 2015 Volume 137(Issue 41) pp:13433-13438
Publication Date(Web):September 28, 2015
DOI:10.1021/jacs.5b09308
A new biaryl monophosphine ligand (AlPhos, L1) allows for the room-temperature Pd-catalyzed fluorination of a variety of activated (hetero)aryl triflates. Furthermore, aryl triflates and bromides that are prone to give mixtures of regioisomeric aryl fluorides with Pd-catalysis can now be converted to the desired aryl fluorides with high regioselectivity. Analysis of the solid-state structures of several Pd(II) complexes, as well as density functional theory (DFT) calculations, shed light on the origin of the enhanced reactivity observed with L1.
Co-reporter:Yi-Ming Wang; Nicholas C. Bruno; Ángel L. Placeres; Shaolin Zhu
Journal of the American Chemical Society 2015 Volume 137(Issue 33) pp:10524-10527
Publication Date(Web):August 9, 2015
DOI:10.1021/jacs.5b07061
The enantioselective, intramolecular hydroalkylation of halide-tethered styrenes has been achieved through a copper hydride-catalyzed process. This approach allowed for the synthesis of enantioenriched cyclobutanes, cyclopentanes, indanes, and six-membered N- and O-heterocycles. This protocol was applied to the synthesis of the commercial serotonin reuptake inhibitor (−)-paroxetine.
Co-reporter:Daniel T. Cohen; Chi Zhang; Bradley L. Pentelute
Journal of the American Chemical Society 2015 Volume 137(Issue 31) pp:9784-9787
Publication Date(Web):July 30, 2015
DOI:10.1021/jacs.5b05447
Herein we report an umpolung strategy for the bioconjugation of selenocysteine in unprotected peptides. This mild and operationally simple approach takes advantage of the electrophilic character of an oxidized selenocysteine (Se–S bond) to react with a nucleophilic arylboronic acid to provide the arylated selenocysteine within hours. This reaction is amenable to a wide range of boronic acids with different biorelevant functional groups and is unique to selenocysteine. Experimental evidence indicates that under oxidative conditions the arylated derivatives are more stable than the corresponding alkylated selenocysteine.
Co-reporter:Dawen Niu
Journal of the American Chemical Society 2015 Volume 137(Issue 30) pp:9716-9721
Publication Date(Web):July 5, 2015
DOI:10.1021/jacs.5b05446
The CuH-catalyzed hydroamination of alkenes and alkynes using a silane and an amine transfer reagent represents a simple strategy to access chiral amine products. We have recently reported methods to prepare chiral amines with high efficiency and stereoselectivity using this approach. However, the current technology is limited to the synthesis of trialkylamines from dialkylamine transfer reagents (R2NOBz). When monoalkylamine transfer reagents [RN(H)OBz] were used for the synthesis of chiral secondary amines, competitive, nonproductive consumption of these reagents by the CuH species resulted in poor yields. In this paper, we report the design of a modified type of amine transfer reagent that addresses this limitation. This effort has enabled us to develop a CuH-catalyzed synthesis of chiral secondary amines using a variety of amine coupling partners, including those derived from amino acid esters, carbohydrates, and steroids. Mechanistic investigations indicated that the modified amine transfer reagents are less susceptible to direct reaction with CuH.
Co-reporter:Rong Zhu
Journal of the American Chemical Society 2015 Volume 137(Issue 25) pp:8069-8077
Publication Date(Web):June 12, 2015
DOI:10.1021/jacs.5b04821
A versatile method for the rapid synthesis of diverse enantiomerically enriched lactones has been developed based on Cu-catalyzed enantioselective radical oxyfunctionalization of alkenes. The scope of this strategy encompasses a series of enantioselective difunctionalization reactions: oxyazidation, oxysulfonylation, oxyarylation, diacyloxylation, and oxyalkylation. These reactions provide straightforward access to a wide range of useful chiral lactone building blocks containing tetrasubstituted stereogenic centers, which are hard to access traditionally.
Co-reporter:Paula Ruiz-Castillo; Donna G. Blackmond
Journal of the American Chemical Society 2015 Volume 137(Issue 8) pp:3085-3092
Publication Date(Web):February 4, 2015
DOI:10.1021/ja512903g
We report the Pd-catalyzed arylation of very hindered α,α,α-trisubstituted primary amines. Kinetics-based mechanistic analysis and rational design have led to the development of two biarylphosphine ligands that allow the transformation to proceed with excellent efficiency. The process was effective in coupling a wide range of functionalized aryl and heteroaryl halides under mild conditions.
Co-reporter:Hong Geun Lee; Phillip J. Milner; Michael S. Placzek; Stephen L. Buchwald;Jacob M. Hooker
Journal of the American Chemical Society 2015 Volume 137(Issue 2) pp:648-651
Publication Date(Web):January 7, 2015
DOI:10.1021/ja512115s
A new radiosynthetic protocol for the preparation of [11C]aryl nitriles has been developed. This process is based on the direct reaction of in situ prepared L·Pd(Ar)X complexes (L = biaryl phosphine) with [11C]HCN. The strategy is operationally simple, exhibits a remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity compared to previously reported systems. With this procedure, a variety of [11C]nitrile-containing pharmaceuticals were prepared with high radiochemical efficiency.
Co-reporter:Jeffrey S. Bandar; Michael T. Pirnot
Journal of the American Chemical Society 2015 Volume 137(Issue 46) pp:14812-14818
Publication Date(Web):November 1, 2015
DOI:10.1021/jacs.5b10219
Enantioselective copper(I) hydride (CuH)-catalyzed hydroamination has undergone significant development over the past several years. To gain a general understanding of the factors governing these reactions, kinetic and spectroscopic studies were performed on the CuH-catalyzed hydroamination of styrene. Reaction profile analysis, rate order assessment, and Hammett studies indicate that the turnover-limiting step is regeneration of the CuH catalyst by reaction with a silane, with a phosphine-ligated copper(I) benzoate as the catalyst resting state. Spectroscopic, electrospray ionization mass spectrometry, and nonlinear effect studies are consistent with a monomeric active catalyst. With this insight, targeted reagent optimization led to the development of an optimized protocol with an operationally simple setup (ligated copper(II) precatalyst, open to air) and short reaction times (<30 min). This improved protocol is amenable to a diverse range of alkene and alkyne substrate classes.
Co-reporter:Erhad Ascic
Journal of the American Chemical Society 2015 Volume 137(Issue 14) pp:4666-4669
Publication Date(Web):March 31, 2015
DOI:10.1021/jacs.5b02316
A diastereo- and enantioselective CuH-catalyzed method for the preparation of highly functionalized indolines is reported. The mild reaction conditions and high degree of functional group compatibility as demonstrated with substrates bearing heterocycles, olefins, and substituted aromatic groups, renders this technique highly valuable for the synthesis of a variety of cis-2,3-disubstituted indolines in high yield and enantioeselectivity.
Co-reporter:James R. Colombe, J. Robb DeBergh, and Stephen L. Buchwald
Organic Letters 2015 Volume 17(Issue 12) pp:3170-3173
Publication Date(Web):June 11, 2015
DOI:10.1021/acs.orglett.5b01540
A method for the preparation of aryl and heteroaryl sulfonamides using 2,4,6-trichlorophenyl chlorosulfate (TCPC) is described. The reaction of 2-pyridylzinc reagents with TCPC resulted in 2,4,6-trichlorophenyl (TCP) pyridine-2-sulfonates, and the parent pyridine-2-sulfonate was shown to react with amines. Less electron-rich aryl- and heteroarylzinc reagents reacted with TCPC to afford sulfonyl chlorides that were converted in situ to sulfonamides.
Co-reporter:Daniel T. Cohen and Stephen L. Buchwald
Organic Letters 2015 Volume 17(Issue 2) pp:202-205
Publication Date(Web):January 2, 2015
DOI:10.1021/ol5032359
A mild, efficient, and low-temperature palladium-catalyzed cyanation of (hetero)aryl halides and triflates is reported. Previous palladium-catalyzed cyanations of (hetero)aryl halides have required higher temperatures to achieve good catalytic activity. This current reaction allows the cyanation of a general scope of (hetero)aryl halides and triflates at 2–5 mol % catalyst loadings with temperatures ranging from rt to 40 °C. This mild method was applied to the synthesis of lersivirine, a reverse transcriptase inhibitor.
Co-reporter:Phillip J. Milner, Yang Yang, and Stephen L. Buchwald
Organometallics 2015 Volume 34(Issue 19) pp:4775-4780
Publication Date(Web):August 20, 2015
DOI:10.1021/acs.organomet.5b00631
A thorough investigation of the challenging Pd-catalyzed fluorination of five-membered heteroaryl bromides is presented. Crystallographic studies and density functional theory (DFT) calculations suggest that the challenging step of this transformation is C–F reductive elimination of five-membered heteroaryl fluorides from Pd(II) complexes. On the basis of these studies, we have found that various heteroaryl bromides bearing phenyl groups in the ortho position can be effectively fluorinated under catalytic conditions. Highly activated 2-bromoazoles, such as 8-bromocaffeine, are also viable substrates for this reaction.
Co-reporter:Nathaniel H. Park;Ekaterina V. Vinogradova;Dr. David S. Surry ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2015 Volume 54( Issue 28) pp:8259-8262
Publication Date(Web):
DOI:10.1002/anie.201502626
Abstract
In Pd-catalyzed CN cross-coupling reactions, α-branched secondary amines are difficult coupling partners and the desired products are often produced in low yields. In order to provide a robust method for accessing N-aryl α-branched tertiary amines, new catalysts have been designed to suppress undesired side reactions often encountered when these amine nucleophiles are used. These advances enabled the arylation of a wide array of sterically encumbered amines, highlighting the importance of rational ligand design in facilitating challenging Pd-catalyzed cross-coupling reactions.
Co-reporter:Nootaree Niljianskul;Dr. Shaolin Zhu ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2015 Volume 54( Issue 5) pp:1638-1641
Publication Date(Web):
DOI:10.1002/anie.201410326
Abstract
The synthesis of α-aminosilanes by a highly enantio- and regioselective copper-catalyzed hydroamination of vinylsilanes is reported. The system employs Cu-DTBM-SEGPHOS as the catalyst, diethoxymethylsilane as the stoichiometric reductant, and O-benzoylhydroxylamines as the electrophilic nitrogen source. This hydroamination reaction is compatible with differentially substituted vinylsilanes, thus providing access to amino acid mimics and other valuable chiral organosilicon compounds.
Co-reporter:Dr. Shi-Liang Shi ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2015 Volume 54( Issue 5) pp:1646-1650
Publication Date(Web):
DOI:10.1002/anie.201410471
Abstract
The synthesis of 3,3-difluoro-2-oxindoles through a robust and efficient palladium-catalyzed CH difluoroalkylation is described. This process generates a broad range of difluorooxindoles from readily prepared starting materials. The use of BrettPhos as the ligand was crucial for high efficiency. Preliminary mechanistic studies suggest that oxidative addition is the rate-determining step for this process.
Co-reporter:Dr. Mao Chen;Saki Ichikawa ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2015 Volume 54( Issue 1) pp:263-266
Publication Date(Web):
DOI:10.1002/anie.201409595
Abstract
A general, rapid, and efficient method for the copper-catalyzed Finkelstein reaction of (hetero)aromatics has been developed using continuous flow to generate a variety of aryl iodides. The described method can tolerate a broad spectrum of functional groups, including N-H and O-H groups. Additionally, in lieu of isolation, the aryl iodide solutions were used in two distinct multistep continuous-flow processes (amidation and Mg–I exchange/nucleophilic addition) to demonstrate the flexibility of this method.
Co-reporter:Nathaniel H. Park;Ekaterina V. Vinogradova;Dr. David S. Surry ;Dr. Stephen L. Buchwald
Angewandte Chemie 2015 Volume 127( Issue 28) pp:8377-8380
Publication Date(Web):
DOI:10.1002/ange.201502626
Abstract
In Pd-catalyzed CN cross-coupling reactions, α-branched secondary amines are difficult coupling partners and the desired products are often produced in low yields. In order to provide a robust method for accessing N-aryl α-branched tertiary amines, new catalysts have been designed to suppress undesired side reactions often encountered when these amine nucleophiles are used. These advances enabled the arylation of a wide array of sterically encumbered amines, highlighting the importance of rational ligand design in facilitating challenging Pd-catalyzed cross-coupling reactions.
Co-reporter:Nootaree Niljianskul;Dr. Shaolin Zhu ;Dr. Stephen L. Buchwald
Angewandte Chemie 2015 Volume 127( Issue 5) pp:1658-1661
Publication Date(Web):
DOI:10.1002/ange.201410326
Abstract
The synthesis of α-aminosilanes by a highly enantio- and regioselective copper-catalyzed hydroamination of vinylsilanes is reported. The system employs Cu-DTBM-SEGPHOS as the catalyst, diethoxymethylsilane as the stoichiometric reductant, and O-benzoylhydroxylamines as the electrophilic nitrogen source. This hydroamination reaction is compatible with differentially substituted vinylsilanes, thus providing access to amino acid mimics and other valuable chiral organosilicon compounds.
Co-reporter:Dr. Shi-Liang Shi ;Dr. Stephen L. Buchwald
Angewandte Chemie 2015 Volume 127( Issue 5) pp:1666-1670
Publication Date(Web):
DOI:10.1002/ange.201410471
Abstract
The synthesis of 3,3-difluoro-2-oxindoles through a robust and efficient palladium-catalyzed CH difluoroalkylation is described. This process generates a broad range of difluorooxindoles from readily prepared starting materials. The use of BrettPhos as the ligand was crucial for high efficiency. Preliminary mechanistic studies suggest that oxidative addition is the rate-determining step for this process.
Co-reporter:Dr. Mao Chen;Saki Ichikawa ;Dr. Stephen L. Buchwald
Angewandte Chemie 2015 Volume 127( Issue 1) pp:265-268
Publication Date(Web):
DOI:10.1002/ange.201409595
Abstract
A general, rapid, and efficient method for the copper-catalyzed Finkelstein reaction of (hetero)aromatics has been developed using continuous flow to generate a variety of aryl iodides. The described method can tolerate a broad spectrum of functional groups, including N-H and O-H groups. Additionally, in lieu of isolation, the aryl iodide solutions were used in two distinct multistep continuous-flow processes (amidation and Mg–I exchange/nucleophilic addition) to demonstrate the flexibility of this method.
Co-reporter:Stephen L. Buchwald;Peng Liu;Shi-Liang Shi;Yang Yang;Dawen Niu
Science 2015 Volume 349(Issue 6243) pp:62-66
Publication Date(Web):03 Jul 2015
DOI:10.1126/science.aab3753
Elaborate amines from commodity olefins
Fine spatial control over the formation of carbon-nitrogen bonds is essential to the synthesis of many pharmaceutical and agrochemical compounds. Yang et al. synthesized a copper catalyst that shows exceptional discrimination between similar substituents in the addition of N-H bonds across the C-C double bonds of simple olefins. In particular, the catalyst favors one of two mirror-image products that differ in the relative orientations of methyl and ethyl groups. This selectivity fosters the use of readily available commodity olefins in the preparation of complex chiral amines.
Science, this issue p. 62
Co-reporter:Phillip J. Milner ; Tom Kinzel ; Yong Zhang
Journal of the American Chemical Society 2014 Volume 136(Issue 44) pp:15757-15766
Publication Date(Web):October 9, 2014
DOI:10.1021/ja509144r
Isotopic labeling has been used to determine that a portion of the desired product in the Pd-catalyzed fluorination of electron-rich, non-ortho-substituted aryl triflates results from direct C–F cross-coupling. In some cases, formation of a Pd-aryne intermediate is responsible for producing undesired regioisomers. The generation of the Pd-aryne intermediate occurs primarily via ortho-deprotonation of a L·Pd(Ar)OTf (L = biaryl monophosphine) species by CsF and thus competes directly with the transmetalation step of the catalytic cycle. Deuterium labeling studies were conducted with a variety of aryl triflates.
Co-reporter:Shaolin Zhu
Journal of the American Chemical Society 2014 Volume 136(Issue 45) pp:15913-15916
Publication Date(Web):October 22, 2014
DOI:10.1021/ja509786v
Enantioselective synthesis of β-chiral amines has been achieved via copper-catalyzed hydroamination of 1,1-disubstituted alkenes with hydroxylamine esters in the presence of a hydrosilane. This mild process affords a range of structurally diverse β-chiral amines, including β-deuterated amines, in excellent yields with high enantioselectivities. Furthermore, catalyst loading as low as 0.4 mol% could be employed to deliver product in undiminished yield and selectivity, demonstrating the practicality of this method for large-scale synthesis.
Co-reporter:Ye Zhu
Journal of the American Chemical Society 2014 Volume 136(Issue 12) pp:4500-4503
Publication Date(Web):March 12, 2014
DOI:10.1021/ja501560x
A palladium-catalyzed asymmetric arylation of 9-aminofluorene-derived imines using a chiral dialkylbiaryl phosphine as the supporting ligand has been developed. This transformation allows for enantioselective access to a diverse range of α-branched benzylamines.
Co-reporter:Hong Geun Lee ; Phillip J. Milner
Journal of the American Chemical Society 2014 Volume 136(Issue 10) pp:3792-3795
Publication Date(Web):February 21, 2014
DOI:10.1021/ja5009739
On the basis of mechanism-driven reaction design, a Pd-catalyzed nucleophilic fluorination of aryl bromides and iodides has been developed. The method exhibits a broad substrate scope, especially with respect to nitrogen-containing heteroaryl bromides, and proceeds with minimal formation of the corresponding reduction products. A facilitated ligand modification process was shown to be critical to the success of the reaction.
Co-reporter:Johannes B. Ernst, Nicholas E. S. Tay, Nathan T. Jui, and Stephen L. Buchwald
Organic Letters 2014 Volume 16(Issue 14) pp:3844-3846
Publication Date(Web):June 27, 2014
DOI:10.1021/ol501531q
A direct method for the regioselective construction of benzimidazolones is reported wherein a single palladium catalyst is employed to couple monosubstituted urea substrates with differentially substituted 1,2-dihaloaromatic systems. In this method, the catalyst is able to promote a cascade of two discrete chemoselective C–N bond-forming processes that allows the highly selective and predictable formation of complex heterocycles from simple, readily available starting materials.
Co-reporter:Mingjuan Su, Naoyuki Hoshiya, and Stephen L. Buchwald
Organic Letters 2014 Volume 16(Issue 3) pp:832-835
Publication Date(Web):January 13, 2014
DOI:10.1021/ol4035947
An efficient method for the palladium-catalyzed amination of unprotected bromoimidazoles and bromopyrazoles is presented. The transformation is facilitated by the use of our newly developed Pd precatalyst based on the bulky biarylphosphine ligand tBuBrettPhos (L4). The mild reaction conditions employed allow for the preparation of a broad scope of aminoimidazoles and aminopyrazoles in moderate to excellent yields.
Co-reporter:Nathaniel H. Park, Georgiy Teverovskiy, and Stephen L. Buchwald
Organic Letters 2014 Volume 16(Issue 1) pp:220-223
Publication Date(Web):November 27, 2013
DOI:10.1021/ol403209k
A new air-stable nickel precatalyst for C–N cross-coupling is reported. The developed catalyst system displays a greatly improved substrate scope for C–N bond formation to include both a wide range of aryl and heteroaryl electrophiles and aryl, heteroaryl, and alkylamines. The catalyst system is also compatible with a weak base, allowing the amination of substrates containing base-sensitive functional groups.
Co-reporter:Stig D. Friis, Troels Skrydstrup, and Stephen L. Buchwald
Organic Letters 2014 Volume 16(Issue 16) pp:4296-4299
Publication Date(Web):August 4, 2014
DOI:10.1021/ol502014b
A palladacyclic precatalyst is employed to cleanly generate a highly active XantPhos-ligated Pd-catalyst. Its use in low temperature aminocarbonylations of (hetero)aryl bromides provides access to a range of challenging products in good to excellent yields with low catalyst loading and only a slight excess of CO. Some products are unattainable by traditional carbonylative coupling.
Co-reporter:Yang Yang, Katrin Niedermann, Chong Han, and Stephen L. Buchwald
Organic Letters 2014 Volume 16(Issue 17) pp:4638-4641
Publication Date(Web):August 25, 2014
DOI:10.1021/ol502230p
The highly selective palladium-catalyzed Negishi coupling of secondary alkylzinc reagents with heteroaryl halides is described. The development of a series of biarylphosphine ligands has led to the identification of an improved catalyst for the coupling of electron-deficient heterocyclic substrates. Preparation and characterization of oxidative addition complex (L)(Ar)PdBr provided insight into the unique reactivity of catalysts based on CPhos-type ligands in facilitating challenging reductive elimination processes.
Co-reporter:Hong Geun Lee, Phillip J. Milner, Michael T. Colvin, Loren Andreas, Stephen L. Buchwald
Inorganica Chimica Acta 2014 Volume 422() pp:188-192
Publication Date(Web):1 October 2014
DOI:10.1016/j.ica.2014.06.008
•Solid state NMR spectra of [(1,5-cyclooctadiene)(1·Pd)2].•Reactivity of [(1,5-cyclooctadiene)(1·Pd)2] with CDCl3.•X-ray structure of Pd(0) species [(N-phenylmaleimide)Pd·1].•Synthesis and reactivity of [(1,5-cyclooctadiene)(L·Pd)2] complexes (L = 6–8).•Synthesis and reactivity of [(1,5-cyclooctadiene)(15·Pd)].The structure of the stable Pd(0) precatalyst [(1,5-cyclooctadiene)(L·Pd)2] (L = AdBrettPhos) for the Pd-catalyzed fluorination of aryl triflates has been further studied by solid state NMR and X-ray cystrallography of the analogous N-phenylmaleimide complex. The reactivity of this complex with CDCl3 to form a dearomatized complex is also presented. In addition, studies suggest that related bulky biaryl phosphine ligands form similar complexes, although the smaller ligand BrettPhos forms a monomeric [(1,5-cyclooctadiene)(L·Pd)] species instead.Graphical abstractThe graphical abstract shows the reactivity modes of the [L·Pd(1,5-COD)] species studied in this work. They can react with CDCl3 or aryl halides to produce Pd(II) species, or with electron-deficient alkenes to produce new olefin-bound Pd(0) species.
Co-reporter:Yang Yang ;Dr. Stephen L. Buchwald
Angewandte Chemie 2014 Volume 126( Issue 33) pp:8821-8825
Publication Date(Web):
DOI:10.1002/ange.201402449
Abstract
A copper-based catalytic technique for the regioselective ortho CH cyanation of vinylarenes has been developed. This method provides an effective means for the selective functionalization of vinylarene derivatives. A copper-catalyzed cyanative dearomatization mechanism is proposed to account for the regiochemical course of this reaction.
Co-reporter:Ekaterina V. Vinogradova;Dr. Peter Müller ;Dr. Stephen L. Buchwald
Angewandte Chemie 2014 Volume 126( Issue 12) pp:3189-3192
Publication Date(Web):
DOI:10.1002/ange.201310897
Abstract
Hypervalent iodine λ3-benziodoxoles are common electrophilic transfer reagents known for their enhanced stability compared to their non-cyclic analogues. Herein we present data showing that chlorobenziodoxole reacts with two different thiolate nucleophiles (thiocyanate and trifluoromethylthiolate), resulting in the formation of stable thioperoxy complexes rather than the expected benziodoxole derivatives. We further report a revised structure for the earlier described electrophilic trifluoromethylthiolation reagent (1), which was previously believed to contain the benziodoxole framework. Our findings, which are based on a combination of analytical techniques, including the recently introduced crystalline sponge method for X-ray analysis, unambiguously demonstrate that 1 is a thioperoxy compound both in solution and the solid state.
Co-reporter:Chi Wai Cheung and Stephen L. Buchwald
The Journal of Organic Chemistry 2014 Volume 79(Issue 11) pp:5351-5358
Publication Date(Web):April 24, 2014
DOI:10.1021/jo500662s
A method for the hydroxylation of aryl and heteroaryl halides, promoted by a catalyst based on a biarylphosphine ligand tBuBrettPhos (L5) and its corresponding palladium precatalyst (1), is described. The reactions allow the cross-coupling of both potassium and cesium hydroxides with (hetero)aryl halides to afford a variety of phenols and hydroxylated heteroarenes in high to excellent yield.
Co-reporter:Nicholas C. Bruno, Nootaree Niljianskul, and Stephen L. Buchwald
The Journal of Organic Chemistry 2014 Volume 79(Issue 9) pp:4161-4166
Publication Date(Web):April 11, 2014
DOI:10.1021/jo500355k
A series of phosphine-ligated palladium precatalysts based on N-methyl- and N-phenyl-2-aminobiphenyl have been developed. Substitution at the nitrogen center prevents the presence of traces of aminobiphenyls that contain a free −NH2 group from contaminating cross-coupling products. These precatalysts produce N-substituted carbazoles upon activation, which cannot consume starting materials. These precatalysts were efficiently generated from 2-aminobiphenyl with minimal purification and found to be highly effective in Suzuki–Miyaura and C–N cross-coupling reactions.
Co-reporter:Yang Yang ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2014 Volume 53( Issue 33) pp:8677-8681
Publication Date(Web):
DOI:10.1002/anie.201402449
Abstract
A copper-based catalytic technique for the regioselective ortho CH cyanation of vinylarenes has been developed. This method provides an effective means for the selective functionalization of vinylarene derivatives. A copper-catalyzed cyanative dearomatization mechanism is proposed to account for the regiochemical course of this reaction.
Co-reporter:Ekaterina V. Vinogradova;Dr. Peter Müller ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2014 Volume 53( Issue 12) pp:3125-3128
Publication Date(Web):
DOI:10.1002/anie.201310897
Abstract
Hypervalent iodine λ3-benziodoxoles are common electrophilic transfer reagents known for their enhanced stability compared to their non-cyclic analogues. Herein we present data showing that chlorobenziodoxole reacts with two different thiolate nucleophiles (thiocyanate and trifluoromethylthiolate), resulting in the formation of stable thioperoxy complexes rather than the expected benziodoxole derivatives. We further report a revised structure for the earlier described electrophilic trifluoromethylthiolation reagent (1), which was previously believed to contain the benziodoxole framework. Our findings, which are based on a combination of analytical techniques, including the recently introduced crystalline sponge method for X-ray analysis, unambiguously demonstrate that 1 is a thioperoxy compound both in solution and the solid state.
Co-reporter:Shaolin Zhu ; Nootaree Niljianskul
Journal of the American Chemical Society 2013 Volume 135(Issue 42) pp:15746-15749
Publication Date(Web):October 9, 2013
DOI:10.1021/ja4092819
A highly enantio- and regioselective copper-catalyzed hydroamination reaction of alkenes has been developed using diethoxymethylsilane and esters of hydroxylamines. The process tolerates a wide variety of substituted styrenes, including trans-, cis-, and β,β-disubstituted styrenes, to yield α-branched amines. In addition, aliphatic alkenes coupled to generate exclusively the anti-Markovnikov hydroamination products.
Co-reporter:J. Robb DeBergh ; Nootaree Niljianskul
Journal of the American Chemical Society 2013 Volume 135(Issue 29) pp:10638-10641
Publication Date(Web):July 9, 2013
DOI:10.1021/ja405949a
A palladium-catalyzed method for the preparation of sulfonamides is described. The process exhibits significant functional group tolerance and allows for the preparation of a number of arylsulfonyl chlorides and sulfonamides under mild conditions.
Co-reporter:Yang Yang
Journal of the American Chemical Society 2013 Volume 135(Issue 29) pp:10642-10645
Publication Date(Web):July 9, 2013
DOI:10.1021/ja405950c
An orthogonal set of catalyst systems has been developed for the Suzuki–Miyaura coupling of 3,3-disubstituted and 3-monosubstituted allylboronates with (hetero)aryl halides. These methods allow for the highly selective preparation of either the α- or the γ-isomeric coupling product.
Co-reporter:M. Alexander Düfert ; Kelvin L. Billingsley
Journal of the American Chemical Society 2013 Volume 135(Issue 34) pp:12877-12885
Publication Date(Web):August 2, 2013
DOI:10.1021/ja4064469
The Suzuki-Miyaura cross-coupling of unprotected, nitrogen-rich heterocycles using precatalysts P1 or P2 is reported. The procedure allows for the reaction of variously substituted indazole, benzimidazole, pyrazole, indole, oxindole, and azaindole halides under mild conditions in good to excellent yields. Additionally, the mechanism behind the inhibitory effect of unprotected azoles on Pd-catalyzed cross-coupling reactions is described based on evidence gained through experimental, crystallographic, and theoretical investigations.
Co-reporter:Nicholas C. Bruno, Matthew T. Tudge and Stephen L. Buchwald
Chemical Science 2013 vol. 4(Issue 3) pp:916-920
Publication Date(Web):20 Aug 2012
DOI:10.1039/C2SC20903A
A series of easily prepared, phosphine-ligated palladium precatalysts based on the 2-aminobiphenyl scaffold have been prepared. The role of the precatalyst-associated labile halide (or pseudohalide) in the formation and stability of the palladacycle has been examined. It was found that replacing the chloride in the previous version of the precatalyst with a mesylate leads to a new class of precatalysts with improved solution stability and that are readily prepared from a wider range of phosphine ligands. The differences between the previous version of precatalyst and that reported here are explored. In addition, the reactivity of the latter is examined in a range of C–C and C–N bond forming reactions.
Co-reporter:James R. Colombe, Sebastian Bernhardt, Christos Stathakis, Stephen L. Buchwald, and Paul Knochel
Organic Letters 2013 Volume 15(Issue 22) pp:5754-5757
Publication Date(Web):October 24, 2013
DOI:10.1021/ol402798z
In search of alternatives to unstable or unreliable 2-pyridylboron reagents, we have explored two new varieties of solid, moderately air-stable 2-pyridylzinc reagents. Both reagents can be manipulated in air and are competent nucleophiles in Negishi cross-coupling reactions.
Co-reporter:Hong Geun Lee, Phillip J. Milner, and Stephen L. Buchwald
Organic Letters 2013 Volume 15(Issue 21) pp:5602-5605
Publication Date(Web):October 18, 2013
DOI:10.1021/ol402859k
The stable Pd(0) species [(1,5-cyclooctadiene)(L·Pd)2] (L = AdBrettPhos) has been prepared and successfully evaluated as a precatalyst for the fluorination of aryl triflates derived from biologically active and heteroaryl phenols, challenging substrates for our previously reported catalyst system. Additionally, this precatalyst activates at room temperature under neutral conditions, generates 1,5-cyclooctadiene as the only byproduct, and leads to overall cleaner reaction profiles.
Co-reporter:Chi Wai Cheung and Stephen L. Buchwald
Organic Letters 2013 Volume 15(Issue 15) pp:3998-4001
Publication Date(Web):July 24, 2013
DOI:10.1021/ol401796v
A general method for the Pd-catalyzed coupling of methanol with (hetero)aryl halides is described. The reactions proceed under mild conditions with a wide range of aryl and heteroaryl halides to give methyl aryl ethers in high yield.
Co-reporter:Chi Wai Cheung, David S. Surry, and Stephen L. Buchwald
Organic Letters 2013 Volume 15(Issue 14) pp:3734-3737
Publication Date(Web):July 1, 2013
DOI:10.1021/ol401612c
A method for the Pd-catalyzed arylation of ammonia with a wide range of aryl and heteroaryl halides, including challenging five-membered heterocyclic substrates, is described. Excellent selectivity for monoarylation of ammonia to primary arylamines was achieved under mild conditions or at rt by the use of bulky biarylphosphine ligands (L6, L7, and L4) as well as their corresponding aminobiphenyl palladacycle precatalysts (3a, 3b, and 3c). As this process requires neither the use of a glovebox nor high pressures of ammonia, it should be widely applicable.
Co-reporter:Nicholas C. Bruno and Stephen L. Buchwald
Organic Letters 2013 Volume 15(Issue 11) pp:2876-2879
Publication Date(Web):May 15, 2013
DOI:10.1021/ol401208t
A series of palladacyclic precatalysts that incorporate electron-rich di-tert-butylphosphino biaryl ligands is reported. These precatalysts are easily prepared, and their use provides a general means of employing bulky ligands in palladium-catalyzed cross-coupling reactions. The application of these palladium sources to various C–N and C–O bond-forming processes is also described.
Co-reporter:Ekaterina V. Vinogradova, Nathaniel H. Park, Brett P. Fors, and Stephen L. Buchwald
Organic Letters 2013 Volume 15(Issue 6) pp:1394-1397
Publication Date(Web):February 26, 2013
DOI:10.1021/ol400369n
An efficient synthesis of aryl carbamates was achieved by introducing alcohols into the reaction of palladium-catalyzed cross-coupling of ArX (X = Cl, OTf) with sodium cyanate. The use of aryl triflates as electrophilic components in this transformation allowed for an expanded substrate scope for direct synthesis of aryl isocyanates. This methodology provides direct access to major carbamate protecting groups, S-thiocarbamates, and diisocyanate precursors to polyurethane materials.
Co-reporter:Yang Yang;Nathan J. Oldenhuis ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2013 Volume 52( Issue 2) pp:615-619
Publication Date(Web):
DOI:10.1002/anie.201207750
Co-reporter:Dr. Todd D. Senecal;Dr. Wei Shu ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2013 Volume 52( Issue 38) pp:10035-10039
Publication Date(Web):
DOI:10.1002/anie.201304188
Co-reporter:Dr. Andrew DeAngelis;Dr. Dong-Hui Wang ;Dr. Stephen L. Buchwald
Angewandte Chemie 2013 Volume 125( Issue 12) pp:3518-3521
Publication Date(Web):
DOI:10.1002/ange.201208544
Co-reporter:Dr. Mao Chen ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2013 Volume 52( Issue 15) pp:4247-4250
Publication Date(Web):
DOI:10.1002/anie.201300615
Co-reporter:Dr. Andrew DeAngelis;Dr. Dong-Hui Wang ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2013 Volume 52( Issue 12) pp:3434-3437
Publication Date(Web):
DOI:10.1002/anie.201208544
Co-reporter:Rong Zhu ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2013 Volume 52( Issue 48) pp:12655-12658
Publication Date(Web):
DOI:10.1002/anie.201307790
Co-reporter:Dr. Nathan T. Jui ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2013 Volume 52( Issue 44) pp:11624-11627
Publication Date(Web):
DOI:10.1002/anie.201306007
Co-reporter:Dr. Mao Chen ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2013 Volume 52( Issue 44) pp:11628-11631
Publication Date(Web):
DOI:10.1002/anie.201306094
Co-reporter:Rong Zhu ;Dr. Stephen L. Buchwald
Angewandte Chemie 2013 Volume 125( Issue 48) pp:12887-12890
Publication Date(Web):
DOI:10.1002/ange.201307790
Co-reporter:Dr. Nathan T. Jui ;Dr. Stephen L. Buchwald
Angewandte Chemie 2013 Volume 125( Issue 44) pp:11838-11841
Publication Date(Web):
DOI:10.1002/ange.201306007
Co-reporter:Dr. Mao Chen ;Dr. Stephen L. Buchwald
Angewandte Chemie 2013 Volume 125( Issue 44) pp:11842-11845
Publication Date(Web):
DOI:10.1002/ange.201306094
Co-reporter:Dr. Todd D. Senecal;Dr. Wei Shu ;Dr. Stephen L. Buchwald
Angewandte Chemie 2013 Volume 125( Issue 38) pp:10219-10223
Publication Date(Web):
DOI:10.1002/ange.201304188
Co-reporter:Dr. Mao Chen ;Dr. Stephen L. Buchwald
Angewandte Chemie 2013 Volume 125( Issue 15) pp:4341-4344
Publication Date(Web):
DOI:10.1002/ange.201300615
Co-reporter:Yang Yang;Nathan J. Oldenhuis ;Dr. Stephen L. Buchwald
Angewandte Chemie 2013 Volume 125( Issue 2) pp:643-647
Publication Date(Web):
DOI:10.1002/ange.201207750
Co-reporter:Xiao Wang and Stephen L. Buchwald
The Journal of Organic Chemistry 2013 Volume 78(Issue 7) pp:3429-3433
Publication Date(Web):February 11, 2013
DOI:10.1021/jo400115r
By utilizing Rh catalysts ligated by the P-chirogenic ligands QuinoxP* and DuanPhos, 3,3,3-trifluoroprop-1-en-2-yl acetate could be hydroformylated and subsequently oxidized to yield enantiomerically pure 2-trifluoromethyllactic acid.
Co-reporter:Rong Zhu
Journal of the American Chemical Society 2012 Volume 134(Issue 30) pp:12462-12465
Publication Date(Web):July 17, 2012
DOI:10.1021/ja305840g
A mild, versatile, and convenient method for the efficient oxytrifluoromethylation of unactivated alkenes based on a copper-catalyzed oxidative difunctionalization strategy has been developed. This methodology provides access to a variety of classes of synthetically useful CF3-containing building blocks from simple starting materials.
Co-reporter:Natalia Chernyak
Journal of the American Chemical Society 2012 Volume 134(Issue 30) pp:12466-12469
Publication Date(Web):July 19, 2012
DOI:10.1021/ja305660a
Anilines and ethyl vinyl ether can be used as precursors for a process that is the synthetic equivalent of the α-arylation of acetaldehyde enolate. The reaction manifests a high level of functional group compatibility, allowing the ready preparation of a number of synthetically valuable compounds.
Co-reporter:Ekaterina V. Vinogradova ; Brett P. Fors
Journal of the American Chemical Society 2012 Volume 134(Issue 27) pp:11132-11135
Publication Date(Web):June 20, 2012
DOI:10.1021/ja305212v
An efficient method for palladium-catalyzed cross-coupling of aryl chlorides and triflates with sodium cyanate is reported. The protocol allows for the synthesis of unsymmetrical N,N′-di- and N,N,N′-trisubstituted ureas in one pot and is tolerant of a wide range of functional groups. Insight into the mechanism of aryl isocyanate formation was gleaned through studies of the transmetalation and reductive elimination steps of the reaction, including the first demonstration of reductive elimination from an arylpalladium isocyanate complex to produce an aryl isocyanate.
Co-reporter:Phillip J. Milner ; Thomas J. Maimone ; Mingjuan Su ; Jiahao Chen ; Peter Müller
Journal of the American Chemical Society 2012 Volume 134(Issue 48) pp:19922-19934
Publication Date(Web):November 15, 2012
DOI:10.1021/ja310351e
A series of monoligated L·PdII(Ar)X complexes (L = dialkyl biaryl phosphine) have been prepared and studied in an effort to better understand an unusual dearomative rearrangement previously documented in these systems. Experimental and theoretical evidence suggest a concerted process involving the unprecedented PdII-mediated insertion of an aryl group into an unactivated arene.
Co-reporter:Matthias A. Oberli and Stephen L. Buchwald
Organic Letters 2012 Volume 14(Issue 17) pp:4606-4609
Publication Date(Web):August 15, 2012
DOI:10.1021/ol302063g
Conditions for the Suzuki–Miyaura coupling of lithium triisopropyl borates are reported, as well as a procedure for a one-pot lithiation, borylation, and subsequent Suzuki–Miyaura coupling of various heterocycles with aryl halides. These borate species are much more stable toward protodeboronation than the corresponding boronic acids and can conveniently be stored on benchtop at room temperature.
Co-reporter:Meredeth A. McGowan, Camille Z. McAvoy, and Stephen L. Buchwald
Organic Letters 2012 Volume 14(Issue 14) pp:3800-3803
Publication Date(Web):July 5, 2012
DOI:10.1021/ol301700y
A method for the Pd-catalyzed N-arylation of both aryl and alkyl amidines with a wide range of aryl bromides, chlorides, and triflates is described. The reactions proceed in short reaction times and with excellent selectivity for monoarylation. A one-pot synthesis of quinazoline derivatives, via addition of an aldehyde to the crude reaction mixture following Pd-catalyzed N-arylation, is also demonstrated.
Co-reporter:Luca Salvi, Nicole R. Davis, Siraj Z. Ali, and Stephen L. Buchwald
Organic Letters 2012 Volume 14(Issue 1) pp:170-173
Publication Date(Web):December 19, 2011
DOI:10.1021/ol202955h
A new bulky biarylphosphine ligand (L8) has been developed that allows the Pd-catalyzed C–O cross-coupling of a wide range of aryl halides and phenols under milder conditions than previously possible. A direct correlation between the size of the ligand substituents in the 2′, 4′, and 6′ positions of the nonphosphine containing ring and the reactivity of the derived catalyst system was observed. Specifically, the rate of coupling increased with the size of these substituents.
Co-reporter:Naoyuki Hoshiya
Advanced Synthesis & Catalysis 2012 Volume 354( Issue 10) pp:2031-2037
Publication Date(Web):
DOI:10.1002/adsc.201200398
Abstract
Improved processes for the preparation of biphenyl-based phosphine ligands t-BuBrettPhos, RockPhos, and BrettPhos are presented. The new methods, featuring the use of Grignard reagents and catalytic amounts of copper, are superior to the previous methods, which require the use of tert-butyllithium and stoichiometric amounts of copper. Specifically, the use of less dangerous reagents provides a safer process, while the use of catalytic amounts of copper allows for the isolation of pure products in high yield. These improvements are particularly significant for the large-scale preparation of these ligands.
Co-reporter:Laurent Pellegatti and Stephen L. Buchwald
Organic Process Research & Development 2012 Volume 16(Issue 8) pp:1442-1448
Publication Date(Web):July 22, 2012
DOI:10.1021/op300168z
The Vilsmeier reagent is used in the preparation of a wide variety of heterocycles, such as pyrazoles, via formation of β-chloroacrolein intermediates. However, use of this extremely reactive reagent on large scale requires special precautions to avoid potentially dangerous exotherms. This article describes the safe preparation at room temperature of the Vilsmeier reagent under flow conditions for the formation of β-chloroacroleins and 3-formylchromones, as well as the use of these in multistep, continuous flow processes for the syntheses of β-acrylonitriles and polysubstituted pyrazoles.
Co-reporter:Rong Zhu ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2012 Volume 51( Issue 8) pp:1926-1929
Publication Date(Web):
DOI:10.1002/anie.201108129
Co-reporter:Mingjuan Su ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2012 Volume 51( Issue 19) pp:4710-4713
Publication Date(Web):
DOI:10.1002/anie.201201244
Co-reporter:Alexander M. Spokoyny, Calvin D. Lewis, Georgiy Teverovskiy, and Stephen L. Buchwald
Organometallics 2012 Volume 31(Issue 24) pp:8478-8481
Publication Date(Web):November 30, 2012
DOI:10.1021/om301116x
We have prepared the first examples of B9-connected trivalent aryl and alkyl phosphinoborane species via Pd-catalyzed phosphination of 9-iodo-meta-carborane. Our studies highlight the unique electronic features of the B9-connected meta-carboranyl moiety as compared to its C1-based analogue. This work suggests that the B9-functionalized meta-carboranyl substituent in these ligands exhibits more electron-releasing character than any other known carbon-based substituent, ultimately laying the foundation for a new class of phosphine ligands with extremely electron-rich character.
Co-reporter:Dr. Andrew T. Parsons;Todd D. Senecal ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2012 Volume 51( Issue 12) pp:2947-2950
Publication Date(Web):
DOI:10.1002/anie.201108267
Co-reporter:Dr. Satoshi Ueda ;Dr. Stephen L. Buchwald
Angewandte Chemie 2012 Volume 124( Issue 41) pp:10510-10513
Publication Date(Web):
DOI:10.1002/ange.201204710
Co-reporter:Dr. Wei Shu ;Dr. Stephen L. Buchwald
Angewandte Chemie 2012 Volume 124( Issue 22) pp:5451-5454
Publication Date(Web):
DOI:10.1002/ange.201202221
Co-reporter:Mingjuan Su ;Dr. Stephen L. Buchwald
Angewandte Chemie 2012 Volume 124( Issue 19) pp:4788-4791
Publication Date(Web):
DOI:10.1002/ange.201201244
Co-reporter:Dr. Andrew T. Parsons;Todd D. Senecal ;Dr. Stephen L. Buchwald
Angewandte Chemie 2012 Volume 124( Issue 12) pp:3001-3004
Publication Date(Web):
DOI:10.1002/ange.201108267
Co-reporter:Rong Zhu ;Dr. Stephen L. Buchwald
Angewandte Chemie 2012 Volume 124( Issue 8) pp:1962-1965
Publication Date(Web):
DOI:10.1002/ange.201108129
Co-reporter:Satoshi Ueda, Siraj Ali, Brett P. Fors, and Stephen L. Buchwald
The Journal of Organic Chemistry 2012 Volume 77(Issue 5) pp:2543-2547
Publication Date(Web):February 7, 2012
DOI:10.1021/jo202537e
A new biarylphosphine ligand, Me3(OMe)tBuXPhos (L3), was designed as a surrogate for Me4tBuXPhos (L1). The Me3(OMe)tBuXPhos could be prepared in a chromatography-free manner from inexpensive and readily available 2,3,6-trimethylphenol. Comparative studies demonstrated that a catalyst based on Me3(OMe)tBuXPhos displayed the same reactivity as a catalyst based on Me4tBuXPhos for Pd-catalyzed C–N and C–O bond-forming processes.
Co-reporter:Dr. Satoshi Ueda ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2012 Volume 51( Issue 41) pp:10364-10367
Publication Date(Web):
DOI:10.1002/anie.201204710
Co-reporter:Dr. Wei Shu ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2012 Volume 51( Issue 22) pp:5355-5358
Publication Date(Web):
DOI:10.1002/anie.201202221
Co-reporter:Chi Wai Cheung and Stephen L. Buchwald
The Journal of Organic Chemistry 2012 Volume 77(Issue 17) pp:7526-7537
Publication Date(Web):July 30, 2012
DOI:10.1021/jo301332s
A copper(II)-catalyzed oxidative cyclization of enamides to oxazoles via vinylic C–H bond functionalization at room temperature is described. Various 2,5-disubstituted oxazoles bearing aryl, vinyl, alkyl, and heteroaryl substituents could be synthesized in moderate to high yields. This reaction protocol is complementary to our previously reported iodine-mediated cyclization of enamides to afford 2,4,5-trisubstituted oxazoles.
Co-reporter:Timothy Noël and Stephen L. Buchwald
Chemical Society Reviews 2011 vol. 40(Issue 10) pp:5010-5029
Publication Date(Web):08 Aug 2011
DOI:10.1039/C1CS15075H
Until recently, cross-coupling reactions have been exclusively performed in batch processes. With the advent of microfluidics, significant effort has been devoted to develop a wide variety of continuous-flow techniques to facilitate organic synthesis. In this critical review, we attempt to give an overview of the different continuous-flow methodologies that have been developed and utilized for cross-coupling reactions. In addition, we attempt to point out the advantages of continuous-flow when compared with their batch counterparts (246 references).
Co-reporter:Dmitry Tsvelikhovsky
Journal of the American Chemical Society 2011 Volume 133(Issue 36) pp:14228-14231
Publication Date(Web):August 12, 2011
DOI:10.1021/ja206229y
A general and highly efficient protocol for the synthesis of dibenzodiazepines and their structural analogues is reported. In the presence of catalytic quantities of palladium, readily accessible precursors are cross-coupled with ammonia and then spontaneously undergo an intramolecular condensation to form the corresponding dibenzodiazepines in one step. This new strategy is applicable to the construction of a wide variety of dibenzooxazepines and other structurally related heterocycles.
Co-reporter:Sophie Rousseaux ; Jorge García-Fortanet ; Miguel Angel Del Aguila Sanchez
Journal of the American Chemical Society 2011 Volume 133(Issue 24) pp:9282-9285
Publication Date(Web):May 25, 2011
DOI:10.1021/ja203644q
The palladium-catalyzed arylative dearomatization of phenols to yield spirocyclohexadienone products in good to excellent yields has been developed. Preliminary results demonstrate that the formation of the spirocyclic all-carbon quaternary center can be accomplished with high levels of enantiocontrol (up to 91% ee).
Co-reporter:Xiao Wang
Journal of the American Chemical Society 2011 Volume 133(Issue 47) pp:19080-19083
Publication Date(Web):October 28, 2011
DOI:10.1021/ja2092689
The first method for the highly enantioselective rhodium-catalyzed hydroformylation of 1,1-disubstituted olefins has been developed. By employing either of the P-chirogenic phosphine ligands BenzP* and QuinoxP*, linear aldehydes with β-chirality can be prepared in a highly enantioselective fashion with good chemo- and regioselectivities.
Co-reporter:Thomas J. Maimone ; Phillip J. Milner ; Tom Kinzel ; Yong Zhang ; Michael K. Takase
Journal of the American Chemical Society 2011 Volume 133(Issue 45) pp:18106-18109
Publication Date(Web):October 14, 2011
DOI:10.1021/ja208461k
A mechanistic investigation of the Pd-catalyzed conversion of aryl triflates to fluorides is presented. Studies reveal that C–F reductive elimination from a LPdII(aryl)F complex (L = t-BuBrettPhos or RockPhos) does not occur when the aryl group is electron rich. Evidence is presented that a modified phosphine, generated in situ, serves as the actual supporting ligand during catalysis with such substrates. A preliminary study of the reactivity of a LPdII(aryl)F complex based on this modified ligand is reported.
Co-reporter:Satoshi Ueda ; Mingjuan Su
Journal of the American Chemical Society 2011 Volume 134(Issue 1) pp:700-706
Publication Date(Web):November 29, 2011
DOI:10.1021/ja2102373
The completely N1-selective Pd-catalyzed arylation of unsymmetric imidazoles with aryl halides and triflates is described. This study showed that imidazoles have a strong inhibitory effect on the in situ formation of the catalytically active Pd(0)–ligand complex. The efficacy of the N-arylation reaction was improved drastically by the use of a preactivated solution of Pd2(dba)3 and L1. From these findings, it is clear that while imidazoles can prevent binding of L1 to Pd, once the ligand is bound to the metal, these heterocycles do not displace it. The utility of the present catalytic system was demonstrated by the regioselective synthesis of the clinically important tyrosine kinase inhibitor nilotinib.
Co-reporter:David S. Surry and Stephen L. Buchwald
Chemical Science 2011 vol. 2(Issue 1) pp:27-50
Publication Date(Web):09 Sep 2010
DOI:10.1039/C0SC00331J
Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This perspective attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations.
Co-reporter:Timothy Noël, John R. Naber, Ryan L. Hartman, Jonathan P. McMullen, Klavs F. Jensen and Stephen L. Buchwald
Chemical Science 2011 vol. 2(Issue 2) pp:287-290
Publication Date(Web):03 Dec 2010
DOI:10.1039/C0SC00524J
A continuous-flow palladium-catalyzed amination reaction was made possible through efficient handling of solids via acoustic irradiation. Various diarylamines were obtained with reaction times ranging from 20 s to 10 min.
Co-reporter:Wei Shu and Stephen L. Buchwald
Chemical Science 2011 vol. 2(Issue 12) pp:2321-2325
Publication Date(Web):07 Sep 2011
DOI:10.1039/C1SC00409C
A general and efficient condition for palladium-catalyzed Heck alkynylation in batch was developed using a novel precatalyst. In addition, the first general and efficient continuous-flow protocol for the coupling of alkynes with aryl bromides in the absence of copper was reported.
Co-reporter:Debabrata Maiti, Brett P. Fors, Jaclyn L. Henderson, Yoshinori Nakamura and Stephen L. Buchwald
Chemical Science 2011 vol. 2(Issue 1) pp:57-68
Publication Date(Web):09 Sep 2010
DOI:10.1039/C0SC00330A
We report our studies on the use of two catalyst systems, based on the ligands BrettPhos and RuPhos, which provide the widest scope for Pd-catalyzed C–N cross-coupling reactions to date. Often low catalyst loadings and short reaction times can be used with functionalized aryl and heteroaryl coupling partners. The reactions are highly robust and can be set up and performed without the use of a glovebox. These catalysts should find wide application in the synthesis of complex molecules including pharmaceuticals, natural products and functional materials.
Co-reporter:Jun Pan, Xinyan Wang, Yong Zhang, and Stephen L. Buchwald
Organic Letters 2011 Volume 13(Issue 18) pp:4974-4976
Publication Date(Web):August 24, 2011
DOI:10.1021/ol202098h
A facile Pd-catalyzed conversion of aryl and vinyl triflates to aryl and vinyl halides (bromides and chlorides) is described. This method allows convenient access to a variety of aryl, heteroaryl, and vinyl halides in good to excellent yields and with greatly simplified conditions relative to our previous report.
Co-reporter:Simon Breitler, Nathan J. Oldenhuis, Brett P. Fors, and Stephen L. Buchwald
Organic Letters 2011 Volume 13(Issue 12) pp:3262-3265
Publication Date(Web):May 23, 2011
DOI:10.1021/ol201210t
A facile synthesis of unsymmetrical N,N′-diarylureas is described. The utilization of the Pd-catalyzed arylation of ureas enables the synthesis of an array of diarylureas in good to excellent yields from benzylurea via a one-pot arylation–deprotection protocol, followed by a second arylation.
Co-reporter:Eun Jin Cho and Stephen L. Buchwald
Organic Letters 2011 Volume 13(Issue 24) pp:6552-6555
Publication Date(Web):November 23, 2011
DOI:10.1021/ol202885w
A method for the palladium-catalyzed trifluoromethylation of cyclohexenyl sulfonates has been developed. Various cyclohexenyl triflates and nonaflates underwent trifluoromethylation under mild reaction conditions using a catalyst system composed of Pd(dba)2 or [(allyl)PdCl]2 and the monodentate biaryl phosphine ligand tBuXPhos. The trifluoromethyl anion (CF3–) or its equivalent for the process was generated in situ from TMSCF3 in combination with KF or TESCF3 in combination with RbF.
Co-reporter:Dr. Pengfei Li ; Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 28) pp:6396-6400
Publication Date(Web):
DOI:10.1002/anie.201102401
Co-reporter:Dr. Wei Shu;Dr. Laurent Pellegatti;Dr. Matthias A. Oberli ;Dr. Stephen L. Buchwald
Angewandte Chemie 2011 Volume 123( Issue 45) pp:10853-10857
Publication Date(Web):
DOI:10.1002/ange.201105223
Co-reporter:Dr. Andrew T. Parsons ;Dr. Stephen L. Buchwald
Angewandte Chemie 2011 Volume 123( Issue 39) pp:9286-9289
Publication Date(Web):
DOI:10.1002/ange.201104053
Co-reporter:Dr. Timothy Noël;Dr. Thomas J. Maimone;Dr. Stephen L. Buchwald
Angewandte Chemie 2011 Volume 123( Issue 38) pp:9062-9065
Publication Date(Web):
DOI:10.1002/ange.201104652
Co-reporter:Dr. Satoshi Ueda;Mingjuan Su ;Dr. Stephen L. Buchwald
Angewandte Chemie 2011 Volume 123( Issue 38) pp:9106-9109
Publication Date(Web):
DOI:10.1002/ange.201103882
Co-reporter:Dr. Jun Pan;Mingjuan Su ;Dr. Stephen L. Buchwald
Angewandte Chemie 2011 Volume 123( Issue 37) pp:
Publication Date(Web):
DOI:10.1002/ange.201102880
Co-reporter:Georgiy Teverovskiy;Dr. David S. Surry ;Dr. Stephen L. Buchwald
Angewandte Chemie 2011 Volume 123( Issue 32) pp:7450-7452
Publication Date(Web):
DOI:10.1002/ange.201102543
Co-reporter:Dr. Wei Shu;Dr. Laurent Pellegatti;Dr. Matthias A. Oberli ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 45) pp:10665-10669
Publication Date(Web):
DOI:10.1002/anie.201105223
Co-reporter:Dr. Andrew T. Parsons ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 39) pp:9120-9123
Publication Date(Web):
DOI:10.1002/anie.201104053
Co-reporter:Dr. Timothy Noël;Dr. Thomas J. Maimone;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 38) pp:8900-8903
Publication Date(Web):
DOI:10.1002/anie.201104652
Co-reporter:Dr. Satoshi Ueda;Mingjuan Su ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 38) pp:8944-8947
Publication Date(Web):
DOI:10.1002/anie.201103882
Co-reporter:Dr. Jun Pan;Mingjuan Su ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 37) pp:
Publication Date(Web):
DOI:10.1002/anie.201102880
Co-reporter:Georgiy Teverovskiy;Dr. David S. Surry ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 32) pp:7312-7314
Publication Date(Web):
DOI:10.1002/anie.201102543
Co-reporter:Dr. Timothy Noël;Dr. Simon Kuhn;Andrew J. Musacchio;Dr. Klavs F. Jensen;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 26) pp:5943-5946
Publication Date(Web):
DOI:10.1002/anie.201101480
Co-reporter:Dr. Pengfei Li ; Stephen L. Buchwald
Angewandte Chemie 2011 Volume 123( Issue 28) pp:6520-6524
Publication Date(Web):
DOI:10.1002/ange.201102401
Co-reporter:Dr. Xiaoxing Wu;Dr. Brett P. Fors ;Dr. Stephen L. Buchwald
Angewandte Chemie 2011 Volume 123( Issue 42) pp:10117-10121
Publication Date(Web):
DOI:10.1002/ange.201104361
Co-reporter:Dr. Xiaoxing Wu;Dr. Brett P. Fors ;Dr. Stephen L. Buchwald
Angewandte Chemie International Edition 2011 Volume 50( Issue 42) pp:9943-9947
Publication Date(Web):
DOI:10.1002/anie.201104361
Co-reporter:Eun Jin Cho;Todd D. Senecal;Tom Kinzel;Yong Zhang;Donald A. Watson
Science 2010 Vol 328(5986) pp:1679-1681
Publication Date(Web):25 Jun 2010
DOI:10.1126/science.1190524
Co-reporter:Xiaoqiang Shen ; Gavin O. Jones ; Donald A. Watson ; Brijesh Bhayana
Journal of the American Chemical Society 2010 Volume 132(Issue 32) pp:11278-11287
Publication Date(Web):July 22, 2010
DOI:10.1021/ja104297g
We report efficient syntheses of axially chiral biaryl amides in yields ranging from 80−92%, and with enantioselectivity in the range 88−94% ee employing an asymmetric Suzuki−Miyaura process with Pd(OAc)2 and KenPhos as ligand. These studies demonstrate that electron-rich and electron-deficient o-halobenzamides can be efficiently coupled with 2-methyl-1-naphthylboronic acid and 2-ethoxy-1-naphthylboronic acid. The yields and selectivities of the reactions are independent of the nature of halogen substituent on the benzamide coupling partner. Our investigations demonstrate that axially chiral heterocyclic and biphenyl compounds can also be synthesized with this methodology. We also report computational studies used to determine the origin of stereoselectivity during the selectivity-determining reductive elimination step of the related coupling of tolyl boronic acid with naphthylphosphonate bromide that was reported in a previous publication (J. Am. Chem. Soc. 2000, 122, 12051−12052). These studies indicate that the stereoselectivity arises from a combination of weak -(C)H··O interactions as well as steric interactions between the tolyl and naphthylphosphonate addends in the transition state for C−C coupling.
Co-reporter:Thomas J. Maimone
Journal of the American Chemical Society 2010 Volume 132(Issue 29) pp:9990-9991
Publication Date(Web):July 6, 2010
DOI:10.1021/ja1044874
An efficient Pd catalyst for the O-arylation of ethyl acetohydroximate with aryl chlorides, bromides, and iodides has been developed. Ethyl acetohydroximate serves as an efficient hydroxylamine equivalent for C−O cross-coupling, thereby allowing for the preparation of O-arylhydroxylamines from simple aryl halides. Short reaction times and broad substrate scope, including heteroaryl coupling partners, allow access to O-arylhydroxylamines that would be difficult to prepare in a single step by traditional methods. Moreover, the O-arylated products so formed can be directly transformed into substituted benzofurans in a single operation.
Co-reporter:Gavin O. Jones ; Peng Liu ; K. N. Houk
Journal of the American Chemical Society 2010 Volume 132(Issue 17) pp:6205-6213
Publication Date(Web):April 13, 2010
DOI:10.1021/ja100739h
Computational investigations of ligand-directed selectivities in Ullmann-type coupling reactions of methanol and methylamine with iodobenzene by β-diketone- and 1,10-phenanthroline-ligated CuI complexes are reported. Density functional theory calculations using several functionals were performed on both the nucleophile formation and aryl halide activation steps of these reactions. The origin of ligand-directed selectivities in N- versus O-arylation reactions as described in a previous publication (J. Am. Chem. Soc. 2007, 129, 3490−3491) were studied and explained. The selectivities observed experimentally are derived not from initial CuI(nucleophile) complex formation but from the subsequent steps involving aryl halide activation. The arylation may occur via single-electron transfer (SET) or iodine atom transfer (IAT), depending on the electron-donating abilities of the ligand and nucleophile. Mechanisms involving either oxidative addition/reductive elimination or σ-bond metathesis are disfavored. SET mechanisms are favored in reactions promoted by the β-diketone ligand; N-arylation is predicted to be favored in these cases, in agreement with experimental results. The phenanthroline ligand promotes O-arylation reactions via IAT mechanisms in preference to N-arylation reactions, which occur via SET mechanisms; this result is also in agreement with experimental results.
Co-reporter:Dmitry Tsvelikhovsky
Journal of the American Chemical Society 2010 Volume 132(Issue 40) pp:14048-14051
Publication Date(Web):September 21, 2010
DOI:10.1021/ja107511g
The Pd-catalyzed condensation of 2-bromostyrene and 2-chloroaniline derivatives yields stable diphenylamine intermediates, which are selectively converted to five-, six-, or seven-membered heteroaromatics (indoles, carbazoles, acridines, and dibenzazepines). The selectivity of these intramolecular transformations is uniquely ligand-controlled and offers efficient routes to four important classes of heterocycles from a common precursor.
Co-reporter:Xiaoqiang Shen ; Alan M. Hyde
Journal of the American Chemical Society 2010 Volume 132(Issue 40) pp:14076-14078
Publication Date(Web):September 21, 2010
DOI:10.1021/ja107481a
The palladium-catalyzed conversion of aryl and vinyl triflates to aryl and vinyl halides (bromides and chlorides) has been developed using dialkylbiaryl phosphine ligands. A variety of aryl, heteroaryl, and vinyl halides can be prepared via this method in good to excellent yields.
Co-reporter:David S. Surry and Stephen L. Buchwald
Chemical Science 2010 vol. 1(Issue 1) pp:13-31
Publication Date(Web):12 May 2010
DOI:10.1039/C0SC00107D
The utility of copper-mediated cross-coupling reactions has been significantly increased by the development of mild reaction conditions and the ability to employ catalytic amounts of copper. The use of diamine-based ligands has been important in these advances and in this perspective we discuss these systems, including the choice of reaction conditions and applications in the synthesis of pharmaceuticals, natural products and designed materials.
Co-reporter:Jaclyn L. Henderson, Sarah M. McDermott, and Stephen L. Buchwald
Organic Letters 2010 Volume 12(Issue 20) pp:4438-4441
Publication Date(Web):September 22, 2010
DOI:10.1021/ol101928m
Simple and efficient procedures for the Pd-catalyzed cross-coupling of primary and secondary amines with halo-7-azaindoles(pyrrolo[2,3-b]pyridine) are presented. Previously, no general method was available to ensure the highly selective reaction of the heteroaryl halide in the presence of the unprotected azaindole N-H. Using palladium precatalysts recently reported by our group, such reactions are easily accomplished under mild conditions that can be applied to cross-coupling reactions with a wide array of aliphatic and aromatic amines.
Co-reporter:Jaclyn L. Henderson and Stephen L. Buchwald
Organic Letters 2010 Volume 12(Issue 20) pp:4442-4445
Publication Date(Web):September 22, 2010
DOI:10.1021/ol101929v
The Pd-catalyzed amination of unprotected benzo-fused heterocycles is reported, which allows for greater flexibility and efficiency in the modification of this important class of molecules. The generality of these simple and efficient procedures is demonstrated through the synthesis of a wide variety of structural types.
Co-reporter:Karin Dooleweerdt, Brett P. Fors and Stephen L. Buchwald
Organic Letters 2010 Volume 12(Issue 10) pp:2350-2353
Publication Date(Web):April 26, 2010
DOI:10.1021/ol100720x
A catalyst, based on a biarylphosphine ligand, for the Pd-catalyzed cross-coupling reactions of amides and aryl mesylates is described. This system allows an array of aryl and heteroaryl mesylates to be transformed into the corresponding N-aryl amides in moderate to excellent yields.
Co-reporter:Brett P. Fors
Advanced Synthesis & Catalysis 2010 Volume 352( Issue 18) pp:3119-3120
Publication Date(Web):
DOI:10.1002/adsc.201000905
No abstract is available for this article.
Co-reporter:Xiaoqiang Shen Dr. ;StephenL. Buchwald Dr.
Angewandte Chemie 2010 Volume 122( Issue 3) pp:574-577
Publication Date(Web):
DOI:10.1002/ange.200905402
Co-reporter:Xiaoqiang Shen Dr. ;StephenL. Buchwald Dr.
Angewandte Chemie International Edition 2010 Volume 49( Issue 3) pp:564-567
Publication Date(Web):
DOI:10.1002/anie.200905402
Co-reporter:RyanL. Hartman;JohnR. Naber;StephenL. Buchwald ;KlavsF. Jensen
Angewandte Chemie 2010 Volume 122( Issue 5) pp:911-915
Publication Date(Web):
DOI:10.1002/ange.200904634
Co-reporter:Jonathan P. McMullen;Dr. Matthew T. Stone; Stephen L. Buchwald; Klavs F. Jensen
Angewandte Chemie 2010 Volume 122( Issue 39) pp:7230-7234
Publication Date(Web):
DOI:10.1002/ange.201002590
Co-reporter:John R. Naber ; Stephen L. Buchwald
Angewandte Chemie 2010 Volume 122( Issue 49) pp:9659-9664
Publication Date(Web):
DOI:10.1002/ange.201004425
Co-reporter:John R. Naber ; Stephen L. Buchwald
Angewandte Chemie International Edition 2010 Volume 49( Issue 49) pp:9469-9474
Publication Date(Web):
DOI:10.1002/anie.201004425
Co-reporter:Jonathan P. McMullen;Dr. Matthew T. Stone; Stephen L. Buchwald; Klavs F. Jensen
Angewandte Chemie International Edition 2010 Volume 49( Issue 39) pp:7076-7080
Publication Date(Web):
DOI:10.1002/anie.201002590
Co-reporter:RyanL. Hartman;JohnR. Naber;StephenL. Buchwald ;KlavsF. Jensen
Angewandte Chemie International Edition 2010 Volume 49( Issue 5) pp:899-903
Publication Date(Web):
DOI:10.1002/anie.200904634
Co-reporter:Brett P. Fors
Journal of the American Chemical Society 2009 Volume 131(Issue 36) pp:12898-12899
Publication Date(Web):August 19, 2009
DOI:10.1021/ja905768k
An efficient Pd catalyst for the transformation of aryl chlorides, triflates, and nonaflates to nitroaromatics has been developed. This reaction proceeds under weakly basic conditions and displays a broad scope and excellent functional group compatibility. Moreover, this method allows for the synthesis of aromatic nitro compounds that cannot be accessed efficiently via other nitration protocols. Mechanistic insight into the transmetalation step of the catalytic process is also reported.
Co-reporter:Alexander M. Taylor ; Ryan A. Altman
Journal of the American Chemical Society 2009 Volume 131(Issue 29) pp:9900-9901
Publication Date(Web):July 6, 2009
DOI:10.1021/ja903880q
The enantioselective α-arylation and α-vinylation of oxindoles catalyzed by Pd and a biarylmonophosphine ligand with both axial and phosphorus-based chirogenicity is reported. The resultant quaternary carbon stereocenters are formed in high enantiomeric excess, and the conditions tolerate a range of substitution on both the oxindole and the aryl/vinyl coupling partners.
Co-reporter:Debabrata Maiti
Journal of the American Chemical Society 2009 Volume 131(Issue 47) pp:17423-17429
Publication Date(Web):November 9, 2009
DOI:10.1021/ja9081815
O- or N-arylated aminophenol products constitute a common structural motif in various potentially useful therapeutic agents and/or drug candidates. We have developed a complementary set of Cu- and Pd-based catalyst systems for the selective O- and N-arylation of unprotected aminophenols using aryl halides. Selective O-arylation of 3- and 4-aminophenols is achieved with copper-catalyzed methods employing picolinic acid or CyDMEDA, trans-N,N′-dimethyl-1,2-cyclohexanediamine, respectively, as the ligand. The selective formation of N-arylated products of 3- and 4-aminophenols can be obtained with BrettPhos precatalyst, a biarylmonophosphine-based palladium catalyst. 2-Aminophenol can be selectively N-arylated with CuI, although no system for the selective O-arylation could be found. Coupling partners with diverse electronic properties and a variety of functional groups can be selectively transformed under these conditions.
Co-reporter:Jacqueline D. Hicks ; Alan M. Hyde ; Alberto Martinez Cuezva
Journal of the American Chemical Society 2009 Volume 131(Issue 46) pp:16720-16734
Publication Date(Web):November 3, 2009
DOI:10.1021/ja9044357
We report the efficient N-arylation of acyclic secondary amides and related nucleophiles with aryl nonaflates, triflates, and chlorides. This method allows for easy variation of the aromatic component in tertiary aryl amides. A new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was found to be uniquely effective for this amidation. The critical aspects of the ligand were explored through synthetic, mechanistic, and computational studies. Systematic variation of the ligand revealed the importance of (1) a methoxy group on the aromatic carbon of the “top ring” ortho to the phosphorus and (2) two highly electron-withdrawing P-bound 3,5-(bis)trifluoromethylphenyl groups. Computational studies suggest the electron-deficient nature of the ligand is important in facilitating amide binding to the LPd(II)(Ph)(X) intermediate.
Co-reporter:Jorge García-Fortanet ; Florian Kessler
Journal of the American Chemical Society 2009 Volume 131(Issue 19) pp:6676-6677
Publication Date(Web):April 23, 2009
DOI:10.1021/ja9025193
An intramolecular enantioselective metal-catalyzed dearomatization reaction is described. This procedure allows the dearomatization of naphthalene derivatives through an electrophilic aromatic substitution-type reaction on a Pd(II) intermediate. The high yields and enantioselectivities achieved make this procedure a valuable method for synthetic chemists.
Co-reporter:Chong Han
Journal of the American Chemical Society 2009 Volume 131(Issue 22) pp:7532-7533
Publication Date(Web):May 14, 2009
DOI:10.1021/ja902046m
An efficient palladium-catalyzed process has been developed for Negishi coupling of secondary alkylzinc halides with a wide range of aryl bromides and activated aryl chlorides. A palladium catalyst composed of a new biaryldialkylphosphine ligand, CPhos, effectively promotes the rate of the reductive elimination step relative to the rate of the undesired β-hydride elimination. The broad substrate scope and excellent ratio of the desired secondary to the undesired primary coupling product make this method a powerful and reliable tool for C(sp3)−C(sp2) bond formation.
Co-reporter:Mark R. Biscoe and Stephen L. Buchwald
Organic Letters 2009 Volume 11(Issue 8) pp:1773-1775
Publication Date(Web):March 18, 2009
DOI:10.1021/ol900295u
Simple, efficient procedures for the monoarylation of acetate esters and aryl methyl ketones using aryl chlorides are presented. Previously, no general method was available to ensure the highly selective monoarylation of these classes of substrates using aryl chlorides. Using palladium precatalysts recently reported by our group, these reactions are easily accomplished under mild conditions that tolerate a wide array of heterocyclic substrates.
Co-reporter:Alan M. Hyde and Stephen L. Buchwald
Organic Letters 2009 Volume 11(Issue 12) pp:2663-2666
Publication Date(Web):May 18, 2009
DOI:10.1021/ol9007102
Methods for the construction of quaternary carbon centers are of great interest to synthetic chemists due to their presence in natural products. Development of the Pd-catalyzed arylation of butenolides with high selectivity for the γ-position allows for a facile construction of quaternary centers. The preparation of a wide variety of γ-aryl butenolides containing a number of functional groups is outlined. An application of this chemistry for a one-pot synthesis of a tricyclic tetrahydroisoquinolinone is demonstrated.
Co-reporter:Brijesh Bhayana, Brett P. Fors and Stephen L. Buchwald
Organic Letters 2009 Volume 11(Issue 17) pp:3954-3957
Publication Date(Web):August 10, 2009
DOI:10.1021/ol9015892
A catalyst system for the Suzuki−Miyaura cross-coupling reactions of aryl and vinyl tosylates and mesylates has been developed. This catalyst displays excellent functional group tolerance and allows the coupling of heteroarylboronic acids with aryl tosylates and mesylates to be performed in high yields. Moreover, reactions employing alkylboronic acids, as well as heteroaryl, vinyl, and allylic pinacol boronate esters, were conducted with high efficiencies.
Co-reporter:Brett P. Fors, Karin Dooleweerdt, Qingle Zeng, Stephen L. Buchwald
Tetrahedron 2009 65(33) pp: 6576-6583
Publication Date(Web):
DOI:10.1016/j.tet.2009.04.096
Co-reporter:Donald A. Watson;Mingjuan Su;Georgiy Teverovskiy;Yong Zhang;Jorge García-Fortanet;Tom Kinzel
Science 2009 Volume 325(Issue 5948) pp:1661-1664
Publication Date(Web):25 Sep 2009
DOI:10.1126/science.1178239
Facile Fluorination
Fluorine atoms have become a useful substituent in pharmaceuticals. However, they remain challenging to introduce synthetically because present methods for carbon-fluorine bond formation require either corrosive conditions or somewhat exotic, and thus expensive, reagents. A sticking point has been the failure of traditional palladium catalysts to couple aryl groups with coordinated fluoride. Watson et al. (p. 1661, published online 13 August; see the Perspective by Gouverneur) show that pairing palladium with a well-designed phosphine ligand produces a versatile catalyst for aryl fluorination using simple fluoride salts. The method tolerates a range of functional groups and should facilitate efficient syntheses of multiple fluoroaromatic targets.
Co-reporter:Ruben Martin and Stephen L. Buchwald
Accounts of Chemical Research 2008 Volume 41(Issue 11) pp:1461
Publication Date(Web):July 12, 2008
DOI:10.1021/ar800036s
The cores of many types of polymers, ligands, natural products, and pharmaceuticals contain biaryl or substituted aromatic structures, and efficient methods of synthesizing these structures are crucial to the work of a broad spectrum of organic chemists. Recently, Pd-catalyzed carbon−carbon bond-forming processes, particularly the Suzuki−Miyaura cross-coupling reaction (SMC), have risen in popularity for this purpose. The SMC has many advantages over other methods for constructing these moieties, including mild conditions, high tolerance toward functional groups, the commercial availability and stability of its reagents, and the ease of handling and separating byproducts from its reaction mixtures. Until 1998, most catalysts for the SMC employed triarylphosphine ligands. More recently, new bulky and electron-rich phosphine ligands, which can dramatically improve the efficiency and selectivity of such cross-coupling reactions, have been introduced. In the course of our studies on carbon−nitrogen bond-forming reactions, we found that the use of electron-rich and bulky phosphines enhanced the rate of both the oxidative addition and reductive elimination processes; this was the beginning of our development of a new family of ligands, the dialkylbiarylphosphines L1−L12. These ligands can be used for a wide variety of palladium-catalyzed carbon−carbon, carbon−nitrogen, and carbon−oxygen bond-forming processes as well as serving as supporting ligands for a number of other reactions. The enhanced reactivity of these catalysts has expanded the scope of cross-coupling partners that can be employed in the SMC. With use of such dialkylbiarylphosphine ligands, the coupling of unactivated aryl chlorides, aryl tosylates, heteroaryl systems, and very hindered substrate combinations have become routine. The utility of these ligands has been successfully demonstrated in a wide number of synthetic applications, including industrially relevant processes. In this Account, we provide an overview of the use and impact of dialkylbiarylphosphine ligands in the SMC. We discuss our studies on the mechanistic framework of the reaction, which have allowed us to rationally modify the ligand structures in order to tune their properties. We also describe selected applications in the synthesis of natural products and new materials to illustrate the utility of these dialkylbiarylphosphine ligands in various “real-world” synthetic applications.
Co-reporter:JohnR. Naber ;StephenL. Buchwald
Advanced Synthesis & Catalysis 2008 Volume 350( Issue 7-8) pp:957-961
Publication Date(Web):
DOI:10.1002/adsc.200800032
Abstract
A highly active catalyst system based upon a biaryl monophosphine ligand, XPhos, for the palladium-catalyzed Stille reaction has been developed. This method allows for the coupling of aryl chlorides with a range of tributylarylstannanes to produce the corresponding biaryl compounds in good to excellent yields (61–98%) in short reaction times (4 h). Palladium(II) acetate [Pd(OAc)2] and XPhos in a 1:1.1 ratio were milled into a fine powder that was used as pre-catalyst for these reactions.
Co-reporter:Jorge García-Fortanet Dr. ;StephenL. Buchwald Dr.
Angewandte Chemie International Edition 2008 Volume 47( Issue 42) pp:8108-8111
Publication Date(Web):
DOI:10.1002/anie.200803809
Co-reporter:Gordon Brasche Dr. ;StephenL. Buchwald Dr.
Angewandte Chemie International Edition 2008 Volume 47( Issue 10) pp:1932-1934
Publication Date(Web):
DOI:10.1002/anie.200705420
Co-reporter:KelvinL. Billingsley ;StephenL. Buchwald Dr.
Angewandte Chemie International Edition 2008 Volume 47( Issue 25) pp:4695-4698
Publication Date(Web):
DOI:10.1002/anie.200801465
Co-reporter:DavidS. Surry Dr. ;StephenL. Buchwald Dr.
Angewandte Chemie International Edition 2008 Volume 47( Issue 34) pp:6338-6361
Publication Date(Web):
DOI:10.1002/anie.200800497
Abstract
Palladium-catalyzed amination reactions of aryl halides have undergone rapid development in the last 12 years, largely driven by the implementation of new classes of ligands. Biaryl phosphanes have proven to provide especially active catalysts in this context. This Review discusses the application of these catalysts in CN cross-coupling reactions in the synthesis of heterocycles and pharmaceuticals, in materials science, and in natural product synthesis.
Co-reporter:Jorge García-Fortanet Dr. ;StephenL. Buchwald Dr.
Angewandte Chemie 2008 Volume 120( Issue 42) pp:8228-8231
Publication Date(Web):
DOI:10.1002/ange.200803809
Co-reporter:DavidS. Surry Dr. ;StephenL. Buchwald Dr.
Angewandte Chemie 2008 Volume 120( Issue 34) pp:6438-6461
Publication Date(Web):
DOI:10.1002/ange.200800497
Abstract
In den vergangenen 12 Jahren erfuhr die palladiumkatalysierte Aminierung von Arylhalogeniden eine rasche Entwicklung, die durch die Einführung neuer Ligandenklassen vorangetrieben wurde. Biarylphosphane liefern in diesem Zusammenhang besonders reaktive Katalysatoren. Dieser Aufsatz behandelt Anwendungen solcher Katalysatoren zur C-N-Kreuzkupplung in der Synthese von Heterocyclen und Pharmazeutika, in den Materialwissenschaften und in der Naturstoffsynthese.
Co-reporter:KelvinL. Billingsley ;StephenL. Buchwald Dr.
Angewandte Chemie 2008 Volume 120( Issue 25) pp:4773-4776
Publication Date(Web):
DOI:10.1002/ange.200801465
Co-reporter:Gordon Brasche Dr. ;StephenL. Buchwald Dr.
Angewandte Chemie 2008 Volume 120( Issue 10) pp:1958-1960
Publication Date(Web):
DOI:10.1002/ange.200705420
Co-reporter:
Nature Protocols 2007 2(10) pp:
Publication Date(Web):2007-10-04
DOI:10.1038/nprot.2007.364
The N-aryl amine moiety can be found in many compounds with interesting biological activities1, 2 (Fig. 1). One traditional approach to the preparation of these structures is the copper (Cu)-mediated coupling of the heterocycle with an aryl iodide3. However, the range of functional groups tolerated by the long-established Goldberg and Ullmann reactions are severely restricted by the harsh conditions often required (exposure of substrates to high temperatures, typically 150–200 °C, for extended periods using stoichiometric quantities of a Cu compound)3. Recently, our group and other groups have developed new N- and O-based bidentate ligands for Cu (I), which have greatly increased the reactivity of the Cu-catalysts, thus allowing for reactions to proceed at significantly lower reaction temperatures—room temperature (RT) up to 110 °C—with weak inorganic bases and only catalytic quantities of a Cu precursor. Subsequently, the cross-coupled products can be obtained in higher yields, and the scope of functional groups that are tolerated in these reactions has been greatly expanded (Fig. 2)4, 5.Cu-catalysts provide excellent catalytic systems for the N-arylation amides6, 7, primary and secondary cyclic alkyl amines8, 9, and N–H-containing heterocycles10, 11, 12 with aryl iodides and bromides. These reactions typically require the use of 1–5 mol% of a Cu(I) salt in conjunction with 5–20 mol% of the N- and/or O-based chelating ligand (Fig. 3), a stoichiometric quantity of a weak base (K3PO4, K2CO3 or Cs2CO3) and a suitable solvent [toluene (PhMe), 1,4-dioxane, acetonitrile (MeCN), N-methylpyrrolidinone (NMP), N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO)] at room temperature to 110 °C to effect the desired transformation.The detailed protocols describe reaction setup, two methods for assaying crude reaction mixtures via thin layer chromatography (TLC) and gas chromatography (GC), reaction workup and purification of products. Although these reactions are moderately sensitive to oxygen, the catalyst precursors and other reagents employed in these reactions are generally stable enough to be handled in the air. These Cu-catalyzed amination reactions of aryl halides are very sensitive toward the choice and quality of base and solvent employed. Further, subtle changes in the structure of an amine or aryl halide may necessitate the optimization of reaction conditions. For purposes of this protocol, reactions are performed on 1-mmol scale; however, this technology has been used to provide product on a 100-g scale21.Steps 1–5, 20 min; Step 6, 20 min to 24 h; Steps 7–9, 4–8 hTroubleshooting advice can be found in Table 1 (see also Fig. 11).Using the general amidation procedure Cu(I) (20 mg, 0.10 mmol, 10 mol%), cyclohexanecarboxamide (127 mg, 0.999 mmol), 5-bromopyrimidine (190 mg, 1.20 mmol), and K3PO4 (425 mg, 2.00 mmol), N,N′-dimethylethylenediamine, 1 (8.9 mg, 0.10 mmol, 10 mol%) and 1,4-dioxane (1 ml) were reacted at 110 °C for 15 h. Flash chromatography on silica gel (ethyl acetate) provided 178 mg (87%) of cyclohexanecarboxylic acid pyrimidin-5-yl-amide7 as a white solid. 1H NMR (CDCl3, 300 MHz): δ 9.02 (s, 2H), 8.97 (s, 1H), 7.40 (br s, 1H), 2.32 (tt, J = 3.6, 11.4 Hz, 1H), 2.10-1.20 (m, 10H). 13C NMR (75 MHz, CDCl3): δ 176.1, 153.5, 147.9, 134.5, 46.0, 29.6, 25.52, 25.49. IR (neat, cm−1): 3234, 1673, 1579, 1532, 1429. Anal. Calcd. for C11H15N3O: C 64.37, H 7.37. Found: C 64.55, H 7.16. m.p. 164–165 °C.According to the general procedure, 1,2-difluoro-4-iodo-benzene (240 mg, 1.0 mmol) was allowed to react with 2-(1-methyl-pyrrolidin-2-yl)-ethylamine (192 mg, 1.5 mmol), Cu(I) (10 mg, 0.05 mmol, 5 mol%), 2-isobutyrylcyclohexanone, 4, (34 mg, 0.2 mmol, 20 mol%), Cs2CO3 (650 mg, 2 mmol), DMF (0.5 ml) for 1 h at ambient temperature (18–22 °C). Flash chromatography on silica gel (CH2Cl2 (saturated with NH3)/MeOH, 50:1) provided 3,4-difluoro-N-(2-(1-methylpyrrolidin-2-yl)ethyl)aniline10 as a yellow oil (235 mg, 98%). 1H NMR (CDCl3, 400 MHz) δ: 6.91 (m, 1H, ArH), 6.36-6.31 (m, 1H, ArH), 6.21 (m, 1H, ArH), 4.32 (br s, 1H, NH), 3.08-3.02 (m, 3H, overlapping CH2 and CH), 2.31 (s, 3H, CH3), 2.22-2.09 (m, 2H, CH2), 1.97-1.75 (m, 2H, CH2), 1.73-1.40 (m, 4H, CH2) ppm. 13C NMR (CDCl3) δ: 151.2 (d, JHF = 224 Hz), 146.1, 143.1 (d, JHF = 234 Hz), 117.7, 108.1, 101.3, 64.9, 57.6, 42.1, 41.0, 32.2, 30.3, 22.6 ppm. IR (neat, cm−1): 3423, 3268, 2948, 2786, 1630, 1605, 1522, 1458, 1339, 1221, 1256, 1174, 1109, 827, 797, 771.The general procedure was followed using Cu2O (3.6 mg, 0.025 mmol, 5.0 mol% Cu), 6 (18 mg, 0.075 mmol, 7.5 mol%), PEG (200 mg), Cs2CO3 (0.45 g, 1.4 mmol), 4-fluoroiodobenzene (222 mg, 1.00 mmol), 2-phenylimidazole (173 mg, 1.2 mmol) with butyronitrile (0.3 ml) as solvent for 24 h at 110 °C. Flash chromatography (hexane/ethyl acetate, 3:1) provided 1-(4-fluoro-phenyl)-2-phenyl-1H-imidazole12 as a white solid (211 mg, 89%). 1H NMR (300 MHz, CDCl3) δ: 7.36-7.30 (m, 2H), 7.24-7.16 (m, 4H), 7.15-7.09 (m, 2H), 7.06 (s, 1H), 7.03-6.96 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 163.5, 160.2, 134.5, 129.0, 128.5, 128.4, 128.2, 127.6, 127.5, 116.5, 116.2. IR (KBr disc, cm−1) 1509, 1501, 1466, 1414, 1303, 1285, 1233, 1212, 1151, 1128, 1091, 1068, 970, 915, 840, 775, 747, 715, 697. Anal. Calcd. for C15H11N2F: C 75.62, H 4.65. Found: C 75.39, H 4.62. m.p. 112–114 °C.
Co-reporter:Ryan A Altman;Brett P Fors;Stephen L Buchwald
Nature Protocols 2007 2(11) pp:
Publication Date(Web):2007-11-08
DOI:10.1038/nprot.2007.414
The N-aryl amine moiety can be found in many compounds with interesting biological1, 2 or physical3 functions (Fig. 1).Traditionally, N-substituted anilines have been prepared by benzyne chemistry4, by reductive amination5, by an arene nitration/reduction sequence5, by nucleophilic aromatic substitution of an activated aryl halide6 and by traditional Ullmann and Goldberg reactions of amines with aryl iodides7. The harsh conditions required by these methods (strong acid or base, high reaction temperatures, use of stoichiometric metal reagents) and the inherent problems in achieving high regioselectivity make these methods ill-suited to achieve the desired reactivity with some substrates. Additionally, employing these strategies makes it difficult to rapidly and directly assemble multiple analogs of a given substrate (core structure) in a simple fashion using mild conditions.These limitations have led to the development of new complementary methods based on metal-catalyzed cross-coupling reactions between amines and aryl halides. These new Cu-8, 9 and Pd-based10 methodologies allow for the rapid, direct and efficient preparation of a wide variety of N-aryl compounds under conditions that are mild enough to tolerate sensitive functional groups.Interestingly, the Pd- and Cu-based catalyst systems are often complementary to each other as each metal encompasses a somewhat orthogonal substrate scope. Pd-catalysts have, for instance, proven more efficient in the N-arylation of anilines, diaryl amines, primary and secondary alkyl amines with aryl bromides, chlorides11 and sulfonate esters12 under generally mild conditions13 (Fig. 2), while more limited success has been achieved for the N-arylation of N-containing heterocycles14, 15. In contrast, Cu-catalysts provide excellent systems for the N-arylation of amides16, 17, primary and secondary cyclic alkyl amines18, 19 and N–H-containing heterocycles20, 21, 22 with aryl iodides and bromides.Steps 1–5: 20 minStep 6: 5 min to 24 hSteps 7–9: 4 hTroubleshooting advice can be found in Table 1.
Co-reporter:
Nature Protocols 2007 2(12) pp:
Publication Date(Web):2007-12-06
DOI:10.1038/nprot.2007.411
Many compounds containing the (hetero)biaryl motif display interesting biological1, 2, 3 and physical4 properties (Fig. 1). Metal-catalyzed cross-coupling reactions between two sp2-hybridized C atoms have become invaluable tools for the formation of unsymmetrically substituted biaryl compounds5. These cross-coupling reactions involve the reaction of an electrophilic aryl halide with an organometallic nucleophile, including organoboron (Suzuki–Miyaura), organolithium/magnesium (Kumada–Corriu), organotin (Stille), organozinc (Negishi) and organosilicon (Hiyama) reagents (Fig. 2). Arylboronic acids are frequently employed in cross-coupling reactions, as they are compatible with a wide variety of functional groups, air and water stable, non-toxic and commercially available. In addition, the removal of the inorganic boron-containing side products is relatively easy.Traditionally, the Suzuki–Miyaura reaction was limited to the cross-coupling reaction of aryl and vinyl iodides and bromides with arylboronic acids to produce unhindered biaryl and vinyl-aryl structures6. However, recently designed catalyst systems, which employ highly active and highly stable ligands, have broadened the scope of the reaction to include the use of inexpensive, stable and widely commercially available aryl chlorides in conjunction with arylboronic acids to prepare highly functionalized biaryl compounds7, 8. One class of these new ligands is our biarylmonophosphine ligands such as SPhos9, 10 1, which provides a highly active and highly stable catalyst (Fig. 3). These systems can be used in the cross-coupling of substrates at extremely low catalyst loading (down to 0.0005 mol% palladium), at room temperature (RT, up to 100°C) and/or in short reaction times (<15 min), making this process applicable to both laboratory- and process-scale applications. The cross-coupling of vinyl10 and heteroaryl11, 12 substrate combinations has also been demonstrated. Tri- and tetra-ortho-substituted biaryl bonds can be formed, as well as biaryl compounds containing sensitive functional groups10. Moreover, the successful cross-coupling of aryl sulfonate esters has extended the scope of electrophiles to include those arenes that can be derived from a corresponding phenol13.One example of this C–C bond-forming process using SPhos as a ligand describes the preparation of a tri-ortho-substituted biaryl (Fig. 4). In the second example, the use of the SPhos ligand allows Suzuki–Miyaura reaction of an aryl chloride to proceed at RT (Fig. 5). In the third example, the cross-coupling of an aryl chloride is performed at a low catalyst loading. In this case, the catalyst is pre-activated in a separate reaction vessel, before adding the catalyst solution to the reaction mixture (Fig. 6). The final example details a modified set of conditions for the preparation of heteroaryl-heteroaryl C–C bonds (Fig. 7)12, 13.An amended version of the general procedure can also be adapted to successfully cross-couple moisture-sensitive organozinc14 and Grignard15 reagents with aryl bromides and chlorides using RuPhos (3) and DavePhos (4), respectively. In addition, the coupling reactions of water-soluble substrate combinations can be accomplished using a sulfonated version of SPhos (5)16. Practitioners are encouraged to seek out these original documents for further experimental details about these procedures.Steps 1–5: 20 minStep 6: 5 min–24 hSteps 7–9: 4 hSee Table 1 for Troubleshooting guidance.
Co-reporter:Kelvin L. Billingsley;Timothy E. Barder;Stephen L. Buchwald Dr.
Angewandte Chemie 2007 Volume 119(Issue 28) pp:
Publication Date(Web):11 JUN 2007
DOI:10.1002/ange.200701551
Von Chlorid zu Boronat: Biarylmonophosphan-Palladium-Katalysatoren zeichnen sich durch hohe Aktivität bei der Borylierung von Aryl- und Heteroarylchloriden aus (siehe Schema). Symmetrische und unsymmetrische Biaryle können auch direkt aus zwei Arylchloriden hergestellt werden, ohne dass die Boronatester-Zwischenprodukte isoliert werden müssen. Rechnungen geben Einblicke in die Rolle des Biarylphosphan-Liganden und der Base KOAc im Katalysezyklus.
Co-reporter:Rubén Martín Dr.;Stephen L. Buchwald Dr.
Angewandte Chemie 2007 Volume 119(Issue 38) pp:
Publication Date(Web):23 AUG 2007
DOI:10.1002/ange.200703009
Breites Produktspektrum: Es wurde ein Katalysatorsystem entwickelt, das effizient die Titelreaktion vermittelt (siehe Schema). Seine hohe Aktivität ermöglicht die Synthese hoch funktionalisierter Verbindungen mit unterschiedlichsten Substitutionsmustern unter sehr milden Bedingungen.
Co-reporter:Mark R. Biscoe Dr.;Timothy E. Barder Dr.;Stephen L. Buchwald Dr.
Angewandte Chemie 2007 Volume 119(Issue 38) pp:
Publication Date(Web):6 AUG 2007
DOI:10.1002/ange.200702122
Elektronischer Einfluss: Die Korrelierung der Bindungskonstanten von Aminen an isoliertes [SPhosPd(Ph)Cl] mit dem pKS-Wert der Aminkomplexe zeigt, dass die Selektivität der katalytischen Arylierung von Aminen durch die elektronischen Eigenschaften des Amins beeinflusst wird. Die Selektivitäten von C-N-Kreuzkupplungen mit neutralen Aminen lassen sich durch Verwendung von Lithiumamiden umkehren. SPhos=2-Dicyclohexylphosphanyl-2′,6′-dimethoxy-1,1′-biphenyl.
Co-reporter:Nan Zheng Dr.;Kevin W. Anderson Dr.;Xiaohua Huang Dr.;Hanh Nho Nguyen Dr.;Stephen L. Buchwald Dr.
Angewandte Chemie 2007 Volume 119(Issue 39) pp:
Publication Date(Web):23 AUG 2007
DOI:10.1002/ange.200702542
Äußerst tolerant: Mit einem Katalysatorsystem aus [Pd2(dba)3] und XPhos oder RuPhos gelingt die effiziente, regioselektive Synthese von N-Arylbenzimidazolen ausgehend von ortho-Halogenaniliden (siehe Schema) in Gegenwart vielfältiger funktioneller Gruppen. dba=trans,trans-Dibenzylidenaceton.
Co-reporter:Joseph R. Martinelli Dr.;Thomas P. Clark Dr.;Donald A. Watson Dr.;Rachel H. Munday Dr.;Stephen L. Buchwald Dr.
Angewandte Chemie 2007 Volume 119(Issue 44) pp:
Publication Date(Web):27 SEP 2007
DOI:10.1002/ange.200702943
Kein Druck, kein Stress: Ein allgemein anwendbares, mildes System für die Pd-katalysierte Carbonylierng von Arylchloriden zu den entsprechenden Amiden wurde entwickelt. Der Katalysator enthält einen einfachen, luftstabilen und kommerziell erhältlichen Liganden und arbeitet bei 1 atm CO-Druck (siehe Schema, Cy=Cyclohexyl). Entscheidend ist der Zusatz von Natriumphenoxid, dessen Rolle durch In-situ-IR-Spektroskopie untersucht wurde.
Co-reporter:Kelvin L. Billingsley;Timothy E. Barder;Stephen L. Buchwald Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 28) pp:
Publication Date(Web):11 JUN 2007
DOI:10.1002/anie.200701551
From chloride to boronate: Catalysts comprising palladium and biaryl monophosphine ligands provide highly active systems for the borylation of aryl and heteroaryl chlorides (see scheme). Symmetrical and unsymmetrical biaryl products can also be prepared directly from two aryl chlorides without isolation of the intermediate boronate esters. Computational studies provide insight into the roles of the biaryl phosphine ligand and the KOAc base in the catalytic cycle.
Co-reporter:Rubén Martín Dr.;Stephen L. Buchwald Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 38) pp:
Publication Date(Web):23 AUG 2007
DOI:10.1002/anie.200703009
Wide scope: A catalyst system able to efficiently perform the title reaction is described (see scheme). The high level of activity achieved allows for the synthesis of highly functionalized compounds with a wide variety of substitution patterns under very mild conditions.
Co-reporter:Mark R. Biscoe Dr.;Timothy E. Barder Dr.;Stephen L. Buchwald Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 38) pp:
Publication Date(Web):6 AUG 2007
DOI:10.1002/anie.200702122
Electronic influence: Correlation between the relative binding constants of amines to isolated [SPhosPd(Ph)Cl] (SPhos=2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl) and the pKa of the amine complexes shows that the selectivity in the catalytic arylation of amines is influenced by the electronic properties of the amine. Selectivities observed in CN cross-coupling reactions using neutral amines can be reversed using lithium amides.
Co-reporter:Nan Zheng Dr.;Kevin W. Anderson Dr.;Xiaohua Huang Dr.;Hanh Nho Nguyen Dr.;Stephen L. Buchwald Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 39) pp:
Publication Date(Web):23 AUG 2007
DOI:10.1002/anie.200702542
Highly tolerated: A catalytic method employing [Pd2(dba)3] and XPhos or RuPhos permits the efficient synthesis of N-aryl benzimidazoles in regioisomerically pure form starting from ortho-haloanilides (see scheme), and tolerates a wide range of functional groups. dba=trans,trans-dibenzylideneacetone.
Co-reporter:Joseph R. Martinelli Dr.;Thomas P. Clark Dr.;Donald A. Watson Dr.;Rachel H. Munday Dr.;Stephen L. Buchwald Dr.
Angewandte Chemie International Edition 2007 Volume 46(Issue 44) pp:
Publication Date(Web):27 SEP 2007
DOI:10.1002/anie.200702943
No pressure, no worries: A general, functional-group-tolerant, mild system for the Pd-catalyzed carbonylation of aryl chlorides to the corresponding amides has been developed. The catalyst operates at 1 atm CO using an inexpensive, air-stable, and commercially available ligand (see scheme, Cy=cyclohexyl). Sodium phenoxide is a critical additive in this transformation; its role has been studied using in situ IR spectroscopy.
Co-reporter:AlanM. Hyde ;StephenL. Buchwald Dr.
Angewandte Chemie 2007 Volume 120( Issue 1) pp:183-186
Publication Date(Web):
DOI:10.1002/ange.200704529
Co-reporter:AlanM. Hyde ;StephenL. Buchwald Dr.
Angewandte Chemie International Edition 2007 Volume 47( Issue 1) pp:177-180
Publication Date(Web):
DOI:10.1002/anie.200704529
Co-reporter:Stephen L. Buchwald;Christelle Mauger;Gerard Mignani;Ulrich Scholz
Advanced Synthesis & Catalysis 2006 Volume 348(Issue 1-2) pp:
Publication Date(Web):19 JAN 2006
DOI:10.1002/adsc.200505158
The palladium-catalyzed coupling of amines and aryl halides or aryl alcohol derivatives has matured from an exotic small-scale transformation into a very general, efficient and robust reaction during the last ten years. This article reports several applications of this method from an industrial vantage point, including ligand synthesis, synthesis of arylpiperazines, arylhydrazines and diarylamines. Much emphasis in placed on issues of scale-up and safety to underline the potential of CN couplings as solutions for industrial-scale synthetic problems.
Co-reporter:Stephen L. Buchwald;Christelle Mauger;Gerard Mignani;Ulrich Scholz
Advanced Synthesis & Catalysis 2006 Volume 348(Issue 1-2) pp:
Publication Date(Web):19 JAN 2006
DOI:10.1002/adsc.200690000
The cover picture shows a typical vessel for industrial scale-up of chemical reactions, in this case for the synthesis of dialkylphosphinobiphenyl ligands. These ligands are important catalyst components for the amination of aryl halides. For more details, see the Review by Stephen L. Buchwald, Christelle Mauger, Gerard Mignani, and Ulrich Scholz on pages 23 – 39.
Co-reporter:Eric R. Strieter,Stephen L. Buchwald
Angewandte Chemie International Edition 2006 45(6) pp:925-928
Publication Date(Web):
DOI:10.1002/anie.200502927
Co-reporter:Kelvin L. Billingsley, Kevin W. Anderson,Stephen L. Buchwald
Angewandte Chemie International Edition 2006 45(21) pp:3484-3488
Publication Date(Web):
DOI:10.1002/anie.200600493
Co-reporter:Carlos H. Burgos Dr.;Timothy E. Barder;Xiaohua Huang Dr. Dr.
Angewandte Chemie International Edition 2006 Volume 45(Issue 26) pp:
Publication Date(Web):30 MAY 2006
DOI:10.1002/anie.200601253
A variety of diaryl ethers were synthesized by the Pd-catalyzed reaction of (hetero)aryl halides and phenols. These reactions were achieved through the use of two new di-tert-butylphosphino biaryl ligands that overcome several limitations of previously described methods.
Co-reporter:Kevin W. Anderson;Rachel E. Tundel;Takashi Ikawa;Ryan A. Altman Dr.
Angewandte Chemie International Edition 2006 Volume 45(Issue 39) pp:
Publication Date(Web):6 SEP 2006
DOI:10.1002/anie.200601612
A good alternative: Highly reactive catalysts based on palladium and dialkylbiarylphosphino ligands provide unprecedented reactivity and selectivity in CN bond-forming processes. The bulky monophosphine catalyst system Pd/1 was effective for the reaction of aryl/heteroaryl halides bearing primary amides and 2-aminoheterocycles (see scheme; dba=dibenzylideneacetone, R=CONH2, NH2), thus showing that monodentate phosphines are viable alternatives to, and sometimes superior to, chelating ligands.
Co-reporter:Rubén Martín Dr.;Marta Rodríguez Rivero Dr. Dr.
Angewandte Chemie International Edition 2006 Volume 45(Issue 42) pp:
Publication Date(Web):29 SEP 2006
DOI:10.1002/anie.200602917
Working in tandem: Highly functionalized pyrroles and pyrazoles can be synthesized from a domino Cu-catalyzed CN coupling/hydroamidation sequence. The scope and the generality of the method is noteworthy as a wide variety of substituents, either in the alkene or alkyne counterparts, are well tolerated.
Co-reporter:Eric R. Strieter Dr. Dr.
Angewandte Chemie 2006 Volume 118(Issue 6) pp:
Publication Date(Web):28 DEC 2005
DOI:10.1002/ange.200502927
Die strukturellen Grundlagen der unterschiedlichen Katalysatoraktivität von Systemen mit 2′-substituierten und 2′,6′-disubstituierten Biarylmonophosphanliganden bei Pd-katalysierten C-N-Verknüpfungen wurden untersucht. Mit 2′,6′-disubstituierten Liganden wird die Bildung von Palladacyclen verhindert und eine optimale Katalysatoraktivität erzielt. (tAm=tert-Amyl, dppe=1,2-Bis(diphenylphosphanyl)ethan).
Co-reporter:Kelvin L. Billingsley;Kevin W. Anderson Dr.
Angewandte Chemie 2006 Volume 118(Issue 21) pp:
Publication Date(Web):26 APR 2006
DOI:10.1002/ange.200600493
Ein Muster an Aktivität: Pd-Katalysatoren mit sperrigen (Dialkylphosphanyl)biaryl-Liganden erwiesen sich als sehr stabil und aktiv in Suzuki-Miyaura-Reaktionen von Heteroarylhalogeniden mit Heteroarylboronsäuren oder -estern (z. B. 3- oder 4-Pyridin-, Indol- oder N-geschützte Pyrrolderivaten). Das Katalysatorsystem wird durch stark basische Aminopyridine oder Aminopyrimidine nicht inhibiert.
Co-reporter:Carlos H. Burgos Dr.;Timothy E. Barder;Xiaohua Huang Dr. Dr.
Angewandte Chemie 2006 Volume 118(Issue 26) pp:
Publication Date(Web):30 MAY 2006
DOI:10.1002/ange.200601253
Eine Vielzahl an Diarylethern war durch die Pd-katalysierte Reaktion von (Hetero)arylhalogeniden mit Phenolen zugänglich. Diese Reaktionen wurden durch den Einsatz zweier neuer Di-tert-butylphosphanylbiaryl-Liganden möglich, die mehrere Einschränkungen bekannter Methoden hinfällig machen.
Co-reporter:Rubén Martín Dr.;Marta Rodríguez Rivero Dr. Dr.
Angewandte Chemie 2006 Volume 118(Issue 42) pp:
Publication Date(Web):29 SEP 2006
DOI:10.1002/ange.200602917
Eins nach dem anderen: Hoch funktionalisierte Pyrrole und Pyrazole wurden mit einer Dominosequenz aus kupferkatalysierter C-N-Kupplung und Hydroamidierung synthetisiert. Die Anwendungsbreite der Methode ist beachtlich: Doppel- wie Dreifachbindung können verschiedenartige Substituenten tragen.
Co-reporter:Kevin W. Anderson;Rachel E. Tundel;Takashi Ikawa;Ryan A. Altman Dr.
Angewandte Chemie 2006 Volume 118(Issue 39) pp:
Publication Date(Web):6 SEP 2006
DOI:10.1002/ange.200601612
Eine gute Alternative: Hoch reaktive Palladium-Dialkylbiarylphosphanyl-Katalysatoren ergeben bislang unerreichte Reaktivitäten und Selektivitäten bei der C-N-Verknüpfung. Der voluminöse Monophosphan-Katalysator Pd/1 eignet sich zur Umsetzung von Halogen(het)arenen, die primäre Amide tragen, und 2-Aminoheterocyclen (siehe Schema; dba=Dibenzylidenaceton, R=CONH2, NH2). Einzähnige Phosphane können Chelatliganden also ebenbürtig, manchmal gar überlegen sein.
Co-reporter:Kevin W. Anderson,Stephen L. Buchwald
Angewandte Chemie International Edition 2005 44(38) pp:6173-6177
Publication Date(Web):
DOI:10.1002/anie.200502017
Co-reporter:Matthew P. Rainka, Jacqueline E. Milne,Stephen L. Buchwald
Angewandte Chemie International Edition 2005 44(38) pp:6177-6180
Publication Date(Web):
DOI:10.1002/anie.200501890
Co-reporter:Matthew P. Rainka;Jacqueline E. Milne
Angewandte Chemie 2005 Volume 117(Issue 38) pp:
Publication Date(Web):30 AUG 2005
DOI:10.1002/ange.200501890
In nur sechs Stufen gelang die Totalsynthese von Eupomatilon-3 in 48 % Gesamtausbeute dank der Entwicklung einer dynamischen kinetischen Racematspaltung, mit der ein racemisches α,β-ungesättigtes Butenolid in hoher Ausbeute und mit hohem Enantiomeren- und Diastereomerenüberschuss reduktiv umgewandelt werden kann. Diese kupferkatalysierte Racematspaltung wurde bei mehreren α,β-ungesättigten γ-Arylbutenoliden angewendet.
Co-reporter:Kevin W. Anderson Dr.
Angewandte Chemie 2005 Volume 117(Issue 38) pp:
Publication Date(Web):12 AUG 2005
DOI:10.1002/ange.200502017
Amphiphile Phosphanliganden (siehe Strukturen) lieferten bei palladiumkatalysierten Suzuki-Miyaura- und Sonogashira-Kupplungen in Wasser oder Zweiphasensystemen aus Wasser und einem organischen Solvens ausgezeichnete Ausbeuten an funktionalisierten Biarylen bzw. Arylalkinen.
Co-reporter:Stephen L. Buchwald
Advanced Synthesis & Catalysis 2004 Volume 346(Issue 13-15) pp:
Publication Date(Web):16 DEC 2004
DOI:10.1002/adsc.200404335
Co-reporter:Shawn D. Walker Dr.;Timothy E. Barder;Joseph R. Martinelli Dr.
Angewandte Chemie 2004 Volume 116(Issue 14) pp:
Publication Date(Web):24 MAR 2004
DOI:10.1002/ange.200353615
Eine beispiellose Anwendungsbreite, Reaktivität und Stabilität zeichnen einen neuen Kupplungskatalysator aus. Dies wurde mit effizienten Synthesen sterisch gehinderter (Hetero-)Biaryle (siehe Bild) durch milde und schnelle Kupplungen von Alkylboronsäurederivaten mit Arylchloriden, auch bei Raumtemperatur, belegt.
Co-reporter:Shawn D. Walker Dr.;Timothy E. Barder;Joseph R. Martinelli Dr.
Angewandte Chemie International Edition 2004 Volume 43(Issue 14) pp:
Publication Date(Web):24 MAR 2004
DOI:10.1002/anie.200353615
Unprecedented scope, reactivity, and stability are displayed by a new catalyst system. This was demonstrated with general and efficient syntheses of sterically hindered (hetero)biaryls (see examples shown), mild coupling reactions of alkyl boron derivatives, and rapid coupling reactions of aryl chlorides at room temperature.
Co-reporter:Yimon Aye;Matthew P. Rainka
PNAS 2004 Volume 101 (Issue 16 ) pp:5821-5823
Publication Date(Web):2004-04-20
DOI:10.1073/pnas.0307764101
A chiral copper-hydride catalyst for the asymmetric conjugate reduction of α,β-unsaturated carbonyl compounds has been used
for the reduction of substrates containing β-nitrogen substituents. A new set of reaction conditions has allowed for a variety
of β-azaheterocyclic acid derivatives to be synthesized in excellent yields and with high degrees of enantioselectivity. In
addition, the effect that the nature of the nitrogen substituent has on the rate of the conjugate reduction reaction has been
explored.
Co-reporter:Dmitri Gelman
Angewandte Chemie 2003 Volume 115(Issue 48) pp:
Publication Date(Web):10 DEC 2003
DOI:10.1002/ange.200353015
Geringere Katalysatormenge bei niedrigerer Temperatur – dies sind nur zwei der Vorteile der hier vorgestellten Methode zur Pd-katalysierten Kupplung von Arylchloriden mit Alkinen (siehe Schema). Im Unterschied zu etablierten Methoden werden hier nicht nur bessere Ergebnisse ohne Kupfer als Cokatalysator erzielt, sondern Kupfer inhibiert sogar die Produktbildung.
Co-reporter:Dmitri Gelman
Angewandte Chemie International Edition 2003 Volume 42(Issue 48) pp:
Publication Date(Web):10 DEC 2003
DOI:10.1002/anie.200353015
Less catalyst, lower temperature, and greater generality are the advantages of the new general protocol over those previously described for the palladium-catalyzed coupling of aryl chlorides and alkynes (see scheme). Better results are obtained without a copper cocatalyst, which has been found to inhibit product formation in the coupling reaction of aryl chlorides with terminal alkynes.
Co-reporter:Jaesook Yun
Chirality 2000 Volume 12(Issue 5‐6) pp:476-478
Publication Date(Web):19 MAY 2000
DOI:10.1002/(SICI)1520-636X(2000)12:5/6<476::AID-CHIR31>3.0.CO;2-B
The efficient kinetic resolution of 2,5-disubstituted pyrrolines was accomplished by employing hydrosilylation with a chiral catalyst, (EBTHI)TiF2 (EBTHI = ethylenebis(tetrahydroindenyl)). An interesting isomerization reaction of the cyclic imines catalyzed by the same chiral catalyst was also discovered. Chirality 12:476–478, 2000. © 2000 Wiley-Liss, Inc.
Co-reporter:John P. Wolfe
Angewandte Chemie International Edition 1999 Volume 38(Issue 16) pp:
Publication Date(Web):6 AUG 1999
DOI:10.1002/(SICI)1521-3773(19990816)38:16<2413::AID-ANIE2413>3.0.CO;2-H
A unique combination of steric and electronic properties appears to determine the effectiveness of phosphanyl-substituted biphenyls as ligands in palladium-catalyzed aminations and Suzuki coupling of aryl chlorides at room temperature [Eq. (1)]. The oxidative addition step is greatly accelerated, and transmetalation (or Pd−N bond formation) and reductive elimination processes are facilitated. Use of these ligands allows for Suzuki coupling at very low catalyst loadings (as little as 10−6 mol % Pd). R″=cyclohexyl, tert-butyl.
Co-reporter:John P. Wolfe;Stephen L. Buchwald
Angewandte Chemie 1999 Volume 111(Issue 16) pp:
Publication Date(Web):6 AUG 1999
DOI:10.1002/(SICI)1521-3757(19990816)111:16<2570::AID-ANGE2570>3.0.CO;2-S
Die Kombination sterischer und elektronischer Eigenschaften scheint die Effektivität Phosphanyl-substituierter Biphenyle als Liganden in Pd-katalysierten Aminierungen und Suzuki-Kupplungen von Arylchloriden bei Raumtemperatur zu bedingen [Gl. (1)]. Die oxidative Addition wird dabei stark beschleunigt, die Transmetallierung (oder Pd-N-Bindungsbildung) und die reduktive Eliminierung werden erleichtert. Mit diesen Liganden können Suzuki-Kupplungen bei sehr geringen Katalysatorkonzentrationen (bis zu 10−6 Mol-%) durchgeführt werden. R″ = Cyclohexyl, tert-Butyl.
Co-reporter:Christoph Gürtler
Chemistry - A European Journal 1999 Volume 5(Issue 11) pp:
Publication Date(Web):29 OCT 1999
DOI:10.1002/(SICI)1521-3765(19991105)5:11<3107::AID-CHEM3107>3.0.CO;2-#
Trisubstituted olefins are easily accessible under mild reaction conditions using a new catalyst system consisting of dicyclohexylamine or methyl(dicyclohexyl)amine and a phase-transfer catalyst (see equation). The choice of the base was found to be crucial for the stereoselectivity and the rate of Heck type arylation reactions.
Co-reporter:Xavier Verdaguer;Udo E. W. Lange
Angewandte Chemie International Edition 1998 Volume 37(Issue 8) pp:
Publication Date(Web):17 DEC 1998
DOI:10.1002/(SICI)1521-3773(19980504)37:8<1103::AID-ANIE1103>3.0.CO;2-M
Slow addition of a primary amine to the reaction mixture greatly increases the scope of the titanium-catalyzed asymmetric reduction of imines 1. An important added feature of this method is that chiral secondary amines 2 can be obtained in much higher optical purity (up to 99 % ee) than would be predicted from the E:Z ratios of the starting imines 1.
Co-reporter:Xavier Verdaguer;Udo E. W. Lange;Stephen L. Buchwald
Angewandte Chemie 1998 Volume 110(Issue 8) pp:
Publication Date(Web):12 MAR 1999
DOI:10.1002/(SICI)1521-3757(19980420)110:8<1174::AID-ANGE1174>3.0.CO;2-8
Durch die langsame Zugabe primärer Amine zur Reaktionsmischung wird die Anwendungsbreite der titankatalysierten asymmetrischen Reduktion von Iminen 1 deutlich erweitert. Bemerkenswerterweise liefert diese Methode chirale sekundäre Amine 2 in einer viel höheren optischen Reinheit (bis zu 99% ee), als man aufgrund der (E):(Z)-Verhältnisse der Iminsubstrate 1 erwarten würde.
Co-reporter:Shelley Bower;Dr. Kristina A. Kreutzer; Dr. Stephen L. Buchwald
Angewandte Chemie 1996 Volume 108(Issue 13‐14) pp:
Publication Date(Web):31 JAN 2006
DOI:10.1002/ange.19961081338
Co-reporter:Tom Kinzel ; Yong Zhang
Journal of the American Chemical Society () pp:
Publication Date(Web):
DOI:10.1021/ja1073799
Boronic acids which quickly deboronate under basic conditions, such as polyfluorophenylboronic acid and five-membered 2-heteroaromatic boronic acids, are especially challenging coupling partners for Suzuki−Miyaura reactions. Nevertheless, being able to use these substrates is highly desirable for a number of applications. Having found that monodentate biarylphosphine ligands can promote these coupling processes, we developed a precatalyst that forms the catalytically active species under conditions where boronic acid decomposition is slow. With this precatalyst, Suzuki−Miyaura reactions of a wide range of (hetero)aryl chlorides, bromides, and triflates with polyfluorophenyl, 2-furan, 2-thiophene, and 2-pyrroleboronic acids and their analogues proceed at room temperature or 40 °C in short reaction times to give the desired products in excellent yields.
Co-reporter:Brett P. Fors
Journal of the American Chemical Society () pp:
Publication Date(Web):October 27, 2010
DOI:10.1021/ja108074t
An alternative approach to catalyst development, which led to a Pd catalyst based on two biarylphosphine ligands for C−N cross-coupling reactions, is reported. By effectively being able to take the form of multiple catalysts this system manifests the best properties that catalysts based on either of the two ligands exhibit separately and displays the highest reactivity and substrate scope of any system that has been reported to date for these reactions.
Co-reporter:Meredeth A. McGowan ; Jaclyn L. Henderson
Organic Letters () pp:
Publication Date(Web):March 6, 2012
DOI:10.1021/ol300178j
A method for the Pd-catalyzed coupling of 2-aminothiazole derivatives with aryl bromides and triflates is described. Significantly, for this class of nucleophiles, the coupling exhibits a broad substrate scope and proceeds with a reasonable catalyst loading. Furthermore, an interesting effect of acetic acid as an additive is uncovered that facilitates catalyst activation.
Co-reporter:Anthony J. Rojas, Chi Zhang, Ekaterina V. Vinogradova, Nathan H. Buchwald, John Reilly, Bradley L. Pentelute and Stephen L. Buchwald
Chemical Science (2010-Present) 2017 - vol. 8(Issue 6) pp:NaN4263-4263
Publication Date(Web):2017/03/24
DOI:10.1039/C6SC05454D
Macrocyclic peptides are important therapeutic candidates due to their improved physicochemical properties in comparison to their linear counterparts. Here we detail a method for a divergent macrocyclisation of unprotected peptides by crosslinking two cysteine residues with bis-palladium organometallic reagents. These synthetic intermediates are prepared in a single step from commercially available aryl bis-halides. Two bioactive linear peptides with cysteine residues at i, i + 4 and i, i + 7 positions, respectively, were cyclised to introduce a diverse array of aryl and bi-aryl linkers. These two series of macrocyclic peptides displayed similar linker-dependent lipophilicity, phospholipid affinity, and unique volume of distributions. Additionally, one of the bioactive peptides showed target binding affinity that was predominantly affected by the length of the linker. Collectively, this divergent strategy allowed rapid and convenient access to various aryl linkers, enabling the systematic evaluation of the effect of appending unit on the medicinal properties of macrocyclic peptides.
Co-reporter:David S. Surry and Stephen L. Buchwald
Chemical Science (2010-Present) 2011 - vol. 2(Issue 1) pp:NaN50-50
Publication Date(Web):2010/09/09
DOI:10.1039/C0SC00331J
Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This perspective attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations.
Co-reporter:Debabrata Maiti, Brett P. Fors, Jaclyn L. Henderson, Yoshinori Nakamura and Stephen L. Buchwald
Chemical Science (2010-Present) 2011 - vol. 2(Issue 1) pp:NaN68-68
Publication Date(Web):2010/09/09
DOI:10.1039/C0SC00330A
We report our studies on the use of two catalyst systems, based on the ligands BrettPhos and RuPhos, which provide the widest scope for Pd-catalyzed C–N cross-coupling reactions to date. Often low catalyst loadings and short reaction times can be used with functionalized aryl and heteroaryl coupling partners. The reactions are highly robust and can be set up and performed without the use of a glovebox. These catalysts should find wide application in the synthesis of complex molecules including pharmaceuticals, natural products and functional materials.
Co-reporter:Nicholas C. Bruno, Matthew T. Tudge and Stephen L. Buchwald
Chemical Science (2010-Present) 2013 - vol. 4(Issue 3) pp:NaN920-920
Publication Date(Web):2012/08/20
DOI:10.1039/C2SC20903A
A series of easily prepared, phosphine-ligated palladium precatalysts based on the 2-aminobiphenyl scaffold have been prepared. The role of the precatalyst-associated labile halide (or pseudohalide) in the formation and stability of the palladacycle has been examined. It was found that replacing the chloride in the previous version of the precatalyst with a mesylate leads to a new class of precatalysts with improved solution stability and that are readily prepared from a wider range of phosphine ligands. The differences between the previous version of precatalyst and that reported here are explored. In addition, the reactivity of the latter is examined in a range of C–C and C–N bond forming reactions.
Co-reporter:Timothy Noël, John R. Naber, Ryan L. Hartman, Jonathan P. McMullen, Klavs F. Jensen and Stephen L. Buchwald
Chemical Science (2010-Present) 2011 - vol. 2(Issue 2) pp:NaN290-290
Publication Date(Web):2010/12/03
DOI:10.1039/C0SC00524J
A continuous-flow palladium-catalyzed amination reaction was made possible through efficient handling of solids via acoustic irradiation. Various diarylamines were obtained with reaction times ranging from 20 s to 10 min.
Co-reporter:Wei Shu and Stephen L. Buchwald
Chemical Science (2010-Present) 2011 - vol. 2(Issue 12) pp:NaN2325-2325
Publication Date(Web):2011/09/07
DOI:10.1039/C1SC00409C
A general and efficient condition for palladium-catalyzed Heck alkynylation in batch was developed using a novel precatalyst. In addition, the first general and efficient continuous-flow protocol for the coupling of alkynes with aryl bromides in the absence of copper was reported.
Co-reporter:David S. Surry and Stephen L. Buchwald
Chemical Science (2010-Present) 2010 - vol. 1(Issue 1) pp:NaN31-31
Publication Date(Web):2010/05/12
DOI:10.1039/C0SC00107D
The utility of copper-mediated cross-coupling reactions has been significantly increased by the development of mild reaction conditions and the ability to employ catalytic amounts of copper. The use of diamine-based ligands has been important in these advances and in this perspective we discuss these systems, including the choice of reaction conditions and applications in the synthesis of pharmaceuticals, natural products and designed materials.
Co-reporter:Timothy Noël and Stephen L. Buchwald
Chemical Society Reviews 2011 - vol. 40(Issue 10) pp:NaN5029-5029
Publication Date(Web):2011/08/08
DOI:10.1039/C1CS15075H
Until recently, cross-coupling reactions have been exclusively performed in batch processes. With the advent of microfluidics, significant effort has been devoted to develop a wide variety of continuous-flow techniques to facilitate organic synthesis. In this critical review, we attempt to give an overview of the different continuous-flow methodologies that have been developed and utilized for cross-coupling reactions. In addition, we attempt to point out the advantages of continuous-flow when compared with their batch counterparts (246 references).
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methanone](http://img.cochemist.com/ccimg/52800/52742-32-2.png)
methanone](http://img.cochemist.com/ccimg/52800/52742-32-2_b.png)
