Co-reporter:Álvaro Gutiérrez-Bonet, Camille Remeur, Jennifer K. Matsui, and Gary A. Molander
Journal of the American Chemical Society September 6, 2017 Volume 139(Issue 35) pp:12251-12251
Publication Date(Web):August 23, 2017
DOI:10.1021/jacs.7b05899
Under oxidative conditions, 1,4-dihydropyridines (DHPs) undergo a homolytic cleavage, forming exclusively a Csp3-centered radical that can engage in the C–H alkylation of heterocyclic bases and 1,4-quinones. DHPs are readily prepared from aldehydes, and considering that aldehydes normally require harsh reaction conditions to take part in such transformations, with mixtures of alkylated and acylated products often being obtained, this net decarbonylative alkylation approach becomes particularly useful. The present method takes place under mild reaction conditions and requires only persulfate as a stoichiometric oxidant, making the procedure suitable for the late-stage C–H alkylation of complex molecules. Notably, structurally complex pharmaceutical agents could be functionalized or prepared with this protocol, such as the antimalarial Atovaquone and antitheilerial Parvaquone, thus evidencing its applicability. Mechanistic studies revealed a likely radical chain process via the formation of a dearomatized intermediate, providing a deeper understanding of the factors governing the reactivity of these radical forebears.
Co-reporter:Javad Amani, Rauful Alam, Shorouk Badir, and Gary A. Molander
Organic Letters May 5, 2017 Volume 19(Issue 9) pp:
Publication Date(Web):April 26, 2017
DOI:10.1021/acs.orglett.7b00989
An electrophilic, imide-based, visible-light-promoted photoredox/Ni-catalyzed cross-coupling reaction for the synthesis of aliphatic ketones has been developed. This protocol proceeds through N–C(O) bond activation, made possible through the lower activation energy for metal insertion into this bond due to delocalization of the lone pair of electrons on the nitrogen by electron-withdrawing groups. The operationally simple and mild cross-coupling reaction is performed at ambient temperature and exhibits tolerance for a variety of functional groups.
Co-reporter:Brandon A. Vara, Niki R. Patel, and Gary A. Molander
ACS Catalysis June 2, 2017 Volume 7(Issue 6) pp:3955-3955
Publication Date(Web):May 9, 2017
DOI:10.1021/acscatal.7b00772
Alkyl xanthate esters are perhaps best known for their use in deoxygenation chemistry. However, their use in cross-coupling chemistry has not been productive, which is due, in part, to inadequate xanthate activation strategies. Herein, we report the use of O-benzyl xanthate esters, readily derived from alcohols, as radical pronucleophiles in Csp3–Csp2 cross-couplings under Ni/photoredox dual catalysis. Xanthate (C–O) cleavage is found to be reliant on photogenerated (sec-butyl) radical activators to form new carbon-centered radicals primed for nickel-catalyzed cross-couplings. Mechanistic experiments support the fact that the key radical components are formed independently, and relative rates are carefully orchestrated, such that no cross reactivity is observed.Keywords: alkyl xanthate esters; carbon-centered radicals; cross-coupling; metal-catalyzed reactions; selective radical generation;
Co-reporter:Javad Amani and Gary A. Molander
Organic Letters July 7, 2017 Volume 19(Issue 13) pp:
Publication Date(Web):June 12, 2017
DOI:10.1021/acs.orglett.7b01588
An efficient and mild method for acyl–Csp3 bond formation based on the direct conversion of carboxylic acids has been established. This protocol is enabled by the synergistic, Ir-photoredox/nickel catalytic cross-coupling of in situ activated carboxylic acids and alkyltrifluoroborates. This versatile method is amenable to the cross-coupling of structurally diverse carboxylic acids with various potassium alkyltrifluoroborates, affording the corresponding ketones with high yields. In this operationally simple cross-coupling protocol, aliphatic ketones are obtained in one step from bench stable, readily available carboxylic acids.
Co-reporter:David N. Primer and Gary A. Molander
Journal of the American Chemical Society July 26, 2017 Volume 139(Issue 29) pp:9847-9847
Publication Date(Web):July 18, 2017
DOI:10.1021/jacs.7b06288
The construction of quaternary centers is a common challenge in the synthesis of complex materials and natural products. Current cross-coupling strategies that can be generalized for setting these centers are sparse and, when known, are typically predicated on the use of reactive organometallic reagents. To address this shortcoming a new, photoredox-Ni dual catalytic strategy for the cross-coupling of tertiary organoboron reagents with aryl halides is reported. In addition to details on the cross-coupling scope and limitations, full screening efforts and mechanistic experiments are communicated.
Co-reporter:Jennifer K. Matsui and Gary A. Molander
Organic Letters February 3, 2017 Volume 19(Issue 3) pp:
Publication Date(Web):January 12, 2017
DOI:10.1021/acs.orglett.6b03448
Utilizing photoredox/nickel dual catalysis, diverse flavanones have been synthesized by coupling novel 2-trifluoroboratochromanone building blocks with aryl and heteroaryl bromide partners. The newly reported trifluoroboratochromanones can be easily accessed from the corresponding chromones on multigram scale. This represents a general route for accessing natural and unnatural flavanones that were previously formed through a synthetically more restrictive ring closure route from chalcone precursors.
Co-reporter:Gary A. Molander, Sarah L. J. Trice, and Spencer D. Dreher
Journal of the American Chemical Society December 22, 2010 Volume 132(Issue 50) pp:17701-17703
Publication Date(Web):November 24, 2010
DOI:10.1021/ja1089759
Although much current research focuses on developing new boron reagents and identifying robust catalytic systems for the cross-coupling of these reagents, the fundamental preparations of the nucleophilic partners (i.e., boronic acids and derivatives) has been studied to a lesser extent. Most current methods to access boronic acids are indirect and require harsh conditions or expensive reagents. A simple and efficient palladium-catalyzed, direct synthesis of arylboronic acids from the corresponding aryl chlorides using an underutilized reagent, tetrahydroxydiboron B2(OH)4, is reported. To ensure preservation of the carbon−boron bond, the boronic acids were efficiently converted to the trifluoroborate derivatives in good to excellent yields without the use of a workup or isolation. Further, the intermediate boronic acids can be easily converted to a wide range of useful boronates. Finally, a two-step, one-pot method was developed to couple two aryl chlorides efficiently in a Suzuki−Miyaura-type reaction.
Co-reporter:Rauful Alam and Gary A. Molander
The Journal of Organic Chemistry December 15, 2017 Volume 82(Issue 24) pp:13728-13728
Publication Date(Web):November 27, 2017
DOI:10.1021/acs.joc.7b02589
An operationally simple, mild, redox-neutral method for the cross-coupling of α-hydroxyalkyltrifluoroborates is reported. Utilizing an Ir photocatalyst, α-hydroxyalkyl radicals are generated from the single-electron oxidation of the trifluoroborates, and these radicals are subsequently engaged in a nickel-catalyzed C–C bond-forming reaction with aryl halides. The process is highly selective, functional group tolerant, and step economical, which allows the direct synthesis of secondary benzylic alcohol motifs.
Co-reporter:Kingson Lin, Rebecca J. Wiles, Christopher B. Kelly, Geraint H. M. Davies, and Gary A. Molander
ACS Catalysis August 4, 2017 Volume 7(Issue 8) pp:5129-5129
Publication Date(Web):July 7, 2017
DOI:10.1021/acscatal.7b01773
The chemoselective functionalization of polyfunctional aryl linchpins is crucial for rapid diversification. Although well-explored for Csp2 and Csp nucleophiles, the chemoselective introduction of Csp3 groups remains notoriously difficult and is virtually undocumented using Ni catalysts. To fill this methodological gap, a “haloselective” cross-coupling process of arenes bearing two halogens, I and Br, using ammonium alkylbis(catecholato)silicates, has been developed. Utilizing Ni/photoredox dual catalysis, Csp3–Csp2 bonds can be forged selectively at the iodine-bearing carbon of bromo(iodo)arenes. The described high-yielding, base-free strategy accommodates various protic functional groups. Selective electrophile activation enables installation of a second Csp3 center and can be done without the need for purification of the intermediate monoalkylated product.Keywords: bromo(iodo)arenes; cross-coupling; hypervalent silicon; nickel/photoredox dual catalysis; selective functionalization;
Co-reporter:Jennifer K. Matsui, Simon B. Lang, Drew R. Heitz, and Gary A. Molander
ACS Catalysis April 7, 2017 Volume 7(Issue 4) pp:2563-2563
Publication Date(Web):March 14, 2017
DOI:10.1021/acscatal.7b00094
Photoredox catalysis has experienced a revitalized interest from the synthesis community during the past decade. For example, photoredox/Ni dual catalysis protocols have been developed to overcome several inherent limitations of palladium-catalyzed cross-couplings by invoking a single-electron transmetalation pathway. This Perspective highlights advances made by our laboratory since the inception of the photoredox/Ni cross-coupling of benzyltrifluoroborates with aryl bromides. In addition to broadening the scope of trifluoroborate coupling partners, research using readily oxidized hypervalent silicates as radical precursors that demonstrate functional group compatibility is highlighted. The pursuit of electrophilic coupling partners beyond (hetero)aryl bromides has also led to the incorporation of several new classes of C(sp2)-hybridized substrates into light-mediated cross-coupling. Advances to expand the radical toolbox by utilizing feedstock chemicals (e.g., aldehydes) to access radicals that were previously inaccessible from trifluoroborates and silicates are also emphasized. Additionally, several organic photocatalysts have been investigated as replacements for their expensive iridium- and ruthenium-based counterparts. Lastly, the net C–H functionalization of the radical partner in an effort to improve atom economy is presented. An underlying theme in all of these studies is the value of generating radicals in a catalytic manner, rather than stoichiometrically.Keywords: catalysis; cross-coupling; dual catalysis; nickel; photoredox; radicals;
Co-reporter:Jennifer K. Matsui;David N. Primer
Chemical Science (2010-Present) 2017 vol. 8(Issue 5) pp:3512-3522
Publication Date(Web):2017/05/03
DOI:10.1039/C7SC00283A
A photoredox-catalyzed C–H functionalization of heteroarenes using a variety of primary, secondary, and tertiary alkyltrifluoroborates is reported. Using Fukuzumi's organophotocatalyst and a mild oxidant, conditions amenable for functionalizing complex heteroaromatics are described, providing a valuable tool for late-stage derivatization. The reported method addresses the three major limitations of previously reported photoredox-mediated Minisci reactions: (1) use of superstoichiometric amounts of a radical precursor, (2) capricious regioselectivity, and (3) incorporation of expensive photocatalysts. Additionally, a number of unprecedented, complex alkyl radicals are used, thereby increasing the chemical space accessible to Minisci chemistry. To showcase the application in late-stage functionalization, quinine and camptothecin analogues were synthesized. Finally, NMR studies were conducted to provide a rationalization for the heteroaryl activation that permits the use of a single equivalent of radical precursor and also leads to enhanced regioselectivity. Thus, by 1H and 13C NMR a distinct heteroaryl species was observed in the presence of acid catalyst and BF3.
Co-reporter:Brandon A. Vara;Matthieu Jouffroy
Chemical Science (2010-Present) 2017 vol. 8(Issue 1) pp:530-535
Publication Date(Web):2016/12/19
DOI:10.1039/C6SC03236B
The attractive field of iterative cross-coupling has seen numerous advances, although almost exclusively in the union of sp2-hybridized partners. Conspicuously absent from this useful synthetic manifold is the inclusion of sp3-hybridized pronucleophiles that can undergo transmetalation under mild conditions. Described here is the use of primary and secondary ammonium alkylsilicates, which undergo facile C(sp3)–C(sp2) cross-coupling with borylated aryl bromide partners under photoredox/nickel dual catalysis conditions. This operationally simple procedure allows the production of alkylated small molecules possessing boronate ester (BPin, Bneopentyl, BMIDA) functional handles. Because of the extremely mild reaction conditions and the innocuous byproduct generated upon fragmentative oxidation of silicates, the corresponding borylated compounds were isolated in good to excellent yields. Aryl bromides bearing unprotected boronic acids are also generally tolerated for the first time and prove useful in multistep syntheses. Unlike many previously reported photoredox/Ni dual cross-couplings, the C(sp3)–C(sp2) bonds were forged using a transition metal-free photocatalyst, allowing a substantial increase in sustainability as well as a cost reduction. Because the developed Ni-catalyzed cross-coupling does not require discrete boron speciation control, as in many popular orthogonal Pd-based methods, this protocol represents a significant advance in atom- and step-economy.
Co-reporter:Geraint H. M. Davies, Zhao-Zhao Zhou, Matthieu Jouffroy, and Gary A. Molander
The Journal of Organic Chemistry 2017 Volume 82(Issue 1) pp:549-555
Publication Date(Web):December 14, 2016
DOI:10.1021/acs.joc.6b02574
The azaborine motif provides a mimic of aromatic systems through replacement of a C═C bond with a B–N bond. In particular, 2,1-borazaronaphthalenes, accessible through robust methods of synthesis and subsequent functionalization, afford an ideal platform to use for a variety of applications. However, the scope of substructures for this archetype has been limited by the lack of nitrogen-containing heteroaryls that can be incorporated within them. In this study, modified reaction conditions were developed to provide access to a wider range of substructures.
Co-reporter:Javad Amani and Gary A. Molander
The Journal of Organic Chemistry 2017 Volume 82(Issue 3) pp:
Publication Date(Web):January 17, 2017
DOI:10.1021/acs.joc.6b02897
Visible light photoredox/nickel dual catalysis has been employed in the cross-coupling of acyl chlorides with potassium alkyltrifluoroborates. This protocol, based on single-electron-mediated alkyl transfer, circumvents the restriction of using reactive alkylmetallic nucleophiles in transition-metal-catalyzed acylation and achieves a mild and efficient method for the synthesis of unsymmetrical alkyl ketones. In this approach, a variety of acyl chlorides have been successfully coupled with structurally diverse potassium alkyltrifluoroborates, generating the corresponding ketones with good yields.
Co-reporter:John C. Tellis, Christopher B. Kelly, David N. Primer, Matthieu Jouffroy, Niki R. Patel, and Gary A. Molander
Accounts of Chemical Research 2016 Volume 49(Issue 7) pp:1429
Publication Date(Web):July 5, 2016
DOI:10.1021/acs.accounts.6b00214
ConspectusThe important role of transition metal-catalyzed cross-coupling in expanding the frontiers of accessible chemical territory is unquestionable. Despite empowering chemists with Herculean capabilities in complex molecule construction, contemporary protocols are not without their Achilles’ heel: Csp3–Csp2/sp3 coupling. The underlying challenge in sp3 cross-couplings is 2-fold: (i) methods employing conventional, bench-stable precursors are universally reliant on extreme reaction conditions because of the high activation barrier of transmetalation; (ii) circumvention of this barrier invariably relies on use of more reactive precursors, thereby sacrificing functional group tolerance, operational simplicity, and broad applicability. Despite the ubiquity of this problem, the nature of the transmetalation step has remained unchanged from the seminal reports of Negishi, Suzuki, Kumada, and Stille, thus suggesting that the challenges in Csp3–Csp2/sp3 coupling result from inherent mechanistic constraints in the traditional cross-coupling paradigm. Rather than submitting to the limitations of this conventional approach, we envisioned that a process rooted in single-electron reactivity could furnish the same key metalated intermediate posited in two-electron transmetalation, while demonstrating entirely complementary reactivity patterns.Inspired by literature reports on the susceptibility of organoboron reagents toward photochemical, single-electron oxidative fragmentation, realization of a conceptually novel open shell transmetalation framework was achieved in the facile coupling of benzylic trifluoroborates with aryl halides via cooperative visible-light activated photoredox and Ni cross-coupling catalysis. Following this seminal study, we disclosed a suite of protocols for the cross-coupling of secondary alkyl, α-alkoxy, α-amino, and α-trifluoromethylbenzyltrifluoroborates. Furthermore, the selective cross-coupling of Csp3 organoboron moieties in the presence of Csp2 organoboron motifs was also demonstrated, highlighting the nuances of this approach to transmetalation. Computational modeling of the reaction mechanism uncovered useful details about the intermediates and transition-state structures involved in the nickel catalytic cycle. Most notably, a unique dynamic kinetic resolution process, characterized by radical homolysis/recombination equilibrium of a NiIII intermediate, was discovered. This process was ultimately found to be responsible for stereoselectivity in an enantioselective variant of these cross-couplings.Prompted by the intrinsic limitations of organotrifluoroborates, we sought other radical feedstocks and quickly identified alkylbis(catecholato)silicates as viable radical precursors for Ni/photoredox dual catalysis. These hypervalent silicate species have several notable benefits, including more favorable redox potentials that allow extension to primary alkyl systems incorporating unprotected amines as well as compatibility with less expensive Ru-based photocatalysts. Additionally, these reagents exhibit an amenability to alkenyl halide cross-coupling while simultaneously expanding the aryl halide scope. In the process of exploring these reagents, we serendipitously discovered a method to effect thioetherification of aryl halides via a H atom transfer mechanism. This latter discovery emphasizes that this robust cross-coupling paradigm is “blind” to the origins of the radical, opening opportunities for a wealth of new discoveries. Taken together, our studies in the area of photoredox/nickel dual catalysis have validated single-electron transmetalation as a powerful platform for enabling conventionally challenging Csp3–Csp2 cross-couplings. More broadly, these findings represent the power of rational design in catalysis and the strategic use of mechanistic knowledge and manipulation for the development of new synthetic methods.
Co-reporter:Drew R. Heitz, John C. Tellis, and Gary A. Molander
Journal of the American Chemical Society 2016 Volume 138(Issue 39) pp:12715-12718
Publication Date(Web):September 21, 2016
DOI:10.1021/jacs.6b04789
An iridium photocatalyst and visible light facilitate a room temperature, nickel-catalyzed coupling of (hetero)aryl bromides with activated α-heterosubstituted or benzylic C(sp3)–H bonds. Mechanistic investigations on this unprecedented transformation have uncovered the possibility of an unexpected mechanism hypothesized to involve a Ni–Br homolysis event from an excited-state nickel complex. The resultant bromine radical is thought to abstract weak C(sp3)–H bonds to generate reactive alkyl radicals that can be engaged in Ni-catalyzed arylation. Evidence suggests that the iridium photocatalyst facilitates nickel excitation and bromine radical generation via triplet–triplet energy transfer.
Co-reporter:Matthieu Jouffroy, Christopher B. Kelly, and Gary A. Molander
Organic Letters 2016 Volume 18(Issue 4) pp:876-879
Publication Date(Web):February 8, 2016
DOI:10.1021/acs.orglett.6b00208
Hypervalent alkylsilicates represent new and readily accessible precursors for the generation of alkyl radicals under photoredox conditions. Alkyl radicals generated from such silicates serve as effective hydrogen atom abstractors from thiols, furnishing thiyl radicals. The reactive sulfur species generated in this manner can be funneled into a nickel-mediated cross-coupling cycle employing aromatic bromides to furnish thioethers. The serendipitous discovery of this reaction and its utilization for the thioetherification of various aryl and heteroaryl bromides with a diverse array of thiols is described. The S–H selective H atom abstraction event enables a wide range of functional groups, including those bearing protic moieties, to be tolerated.
Co-reporter:Javad Amani, Esmat Sodagar, and Gary A. Molander
Organic Letters 2016 Volume 18(Issue 4) pp:732-735
Publication Date(Web):February 1, 2016
DOI:10.1021/acs.orglett.5b03705
A visible-light, single-electron-transfer (SET), photoredox cross-coupling for the synthesis of α-alkoxyketones has been developed. In this method, various aliphatic and aromatic acyl chlorides were successfully coupled with structurally diverse potassium alkoxymethyltrifluoroborates, producing the corresponding α-alkoxyketones with high yields. In this operationally simple and mild cross-coupling protocol, the desired ketones are obtained in one step from bench stable starting materials by a bond connection that is unique to both alkylboron chemistry and photoredox/Ni catalysis.
Co-reporter:Niki R. Patel, Christopher B. Kelly, Matthieu Jouffroy, and Gary A. Molander
Organic Letters 2016 Volume 18(Issue 4) pp:764-767
Publication Date(Web):February 1, 2016
DOI:10.1021/acs.orglett.6b00024
Single-electron transmetalation via photoredox/nickel dual catalysis provides the opportunity for the construction of Csp3–Csp2 bonds through the transfer of alkyl radicals under very mild reaction conditions. A general procedure for the cross-coupling of primary and secondary (bis-catecholato)alkylsilicates with alkenyl halides is presented. The developed method allows not only alkenyl bromides and iodides but also previously underexplored alkenyl chlorides to be employed.
Co-reporter:Rahman Karimi-Nami, John C. Tellis, and Gary A. Molander
Organic Letters 2016 Volume 18(Issue 11) pp:2572-2575
Publication Date(Web):May 24, 2016
DOI:10.1021/acs.orglett.6b00911
Protecting-group-independent cross-coupling of α-alkoxyalkyl- and α-acyloxyalkyltrifluoroborates with aryl and heteroaryl bromides is achieved through application of photoredox/nickel dual catalysis. Reactions occur under exceptionally mild conditions, with outstanding functional group compatibility and excellent observed tolerance of heteroarenes. This method offers expedient access to protected secondary benzylic alcohol motifs bearing benzyl, pivaloyl, and N,N-diisopropylcarbamoyl protecting groups.
Co-reporter:Matthieu Jouffroy, Geraint H. M. Davies, and Gary A. Molander
Organic Letters 2016 Volume 18(Issue 7) pp:1606-1609
Publication Date(Web):March 17, 2016
DOI:10.1021/acs.orglett.6b00466
A highly effective method for derivatizing 2,1-borazaronaphthalene cores using ammonium alkylbis(catecholato)silicates via photoredox/nickel dual catalysis is reported. By forging Csp3–Csp2 bonds via this approach, alkyl fragments with various functional groups can be introduced to the azaborine core, affording previously inaccessible heterocyclic isosteres in good to excellent yields. The base-free, room-temperature conditions outlined allow sensitive functional group tolerance, even permitting the cross-coupling of unprotected primary and secondary amines.
Co-reporter:John C. Tellis, Javad Amani, and Gary A. Molander
Organic Letters 2016 Volume 18(Issue 12) pp:2994-2997
Publication Date(Web):June 6, 2016
DOI:10.1021/acs.orglett.6b01357
The first cross-coupling of secondary alkyl β-trifluoroboratoketones and -esters has been achieved through application of photoredox/nickel dual catalysis. Although the related β-trifluoroboratoamides have been effectively cross-coupled via Pd-catalysis, the corresponding ketones and esters had proven recalcitrant prior to this report. Reactions occur under mild conditions, and a variety of functional groups and sterically and electronically diverse reaction partners are tolerated.
Co-reporter:Dr. Mirna ElKhatib;Dr. Ricardo Augusto Massarico Serafim; Gary A. Moler
Angewandte Chemie International Edition 2016 Volume 55( Issue 1) pp:254-258
Publication Date(Web):
DOI:10.1002/anie.201506147
Abstract
Direct access to complex, enantiopure benzylamine architectures using a synergistic iridium photoredox/nickel cross-coupling dual catalysis strategy has been developed. New C(sp3)C(sp2) bonds are forged starting from abundant and inexpensive natural amino acids.
Co-reporter:Dr. Mirna ElKhatib;Dr. Ricardo Augusto Massarico Serafim; Gary A. Moler
Angewandte Chemie 2016 Volume 128( Issue 1) pp:262-266
Publication Date(Web):
DOI:10.1002/ange.201506147
Abstract
Direct access to complex, enantiopure benzylamine architectures using a synergistic iridium photoredox/nickel cross-coupling dual catalysis strategy has been developed. New C(sp3)C(sp2) bonds are forged starting from abundant and inexpensive natural amino acids.
Co-reporter:Dr. DaWeon Ryu;David N. Primer;John C. Tellis ;Dr. Gary A. Moler
Chemistry - A European Journal 2016 Volume 22( Issue 1) pp:120-123
Publication Date(Web):
DOI:10.1002/chem.201504079
Abstract
Novel methods for the incorporation of fluorinated subunits into organic frameworks are important in pharmaceutical, agrochemical, and materials science applications. Herein, the first method for the cross-coupling of benzylic α-trifluoromethylated alkylboron reagents with (hetero)aryl bromides is achieved through application of a photoredox/nickel dual catalytic system. The harsh conditions and high temperatures required by conventional Suzuki-coupling protocols are avoided by exploitation of an odd-electron pathway that permits room temperature transmetalation of these recalcitrant reagents. This method represents the first direct and general route for the synthesis of unsymmetrical 1,1-diaryl-2,2,2-trifluoroethanes, thereby providing efficient access to a previously unexplored chemical space.
Co-reporter:Drew R. Heitz, Komal Rizwan, and Gary A. Molander
The Journal of Organic Chemistry 2016 Volume 81(Issue 16) pp:7308-7313
Publication Date(Web):June 23, 2016
DOI:10.1021/acs.joc.6b01207
Iridium- and ruthenium-free approaches to protected allylic amines and alkyl nitriles under photoredox conditions are reported. An inexpensive organic dye, eosin Y, catalyzes coupling of Boc-protected potassium α-aminomethyltrifluoroborates with a variety of substituted alkenyl sulfones through an α-aminomethyl radical addition–elimination pathway. Allylic and homoallylic amines were formed in moderate yields with high E/Z selectivity. The mechanistic approach was extended using tosyl cyanide as a radical trap, enabling the conversion of alkyltrifluoroborates to nitriles via a Fukuzumi acridinium-catalyzed process.
Co-reporter:Niki R. Patel and Gary A. Molander
The Journal of Organic Chemistry 2016 Volume 81(Issue 16) pp:7271-7275
Publication Date(Web):June 3, 2016
DOI:10.1021/acs.joc.6b00800
Photoredox/nickel dual catalysis via single electron transmetalation allows coupling of Csp3–Csp2 hybridized centers under mild conditions. A procedure for the coupling of electron-deficient aryl triflates, -tosylates, and -mesylates with alkylbis(catecholato)silicates is presented. This method represents the first example of the use of phenol derivatives as electrophilic coupling partners in photoredox/nickel dual catalysis.
Co-reporter:Geraint H. M. Davies and Gary A. Molander
The Journal of Organic Chemistry 2016 Volume 81(Issue 9) pp:3771-3779
Publication Date(Web):April 12, 2016
DOI:10.1021/acs.joc.6b00435
The azaborine motif provides a unique opportunity to develop core isosteres by inserting B–N units in place of C═C bonds within aromatic scaffolds, creating new pseudoaromatic building blocks that retain comparable structural features. Previous synthetic routes to the 1,3,2-benzodiazaborole core have used organoboron dichlorides and boronic acids as the boron precursors. The transformation developed herein utilizes entirely bench stable starting materials, including organotrifluoroborates, enabling a wider array of substrate analogues under facile reaction conditions. Furthermore, physical, structural, and electronic properties of these compounds were explored computationally to understand the influence of the B–N replacement on the structure, aromaticity, and isosteric viability of these analogues.
Co-reporter:Osvaldo Gutierrez; John C. Tellis; David N. Primer; Gary A. Molander;Marisa C. Kozlowski
Journal of the American Chemical Society 2015 Volume 137(Issue 15) pp:4896-4899
Publication Date(Web):April 2, 2015
DOI:10.1021/ja513079r
The cross-coupling of sp3-hybridized organoboron reagents via photoredox/nickel dual catalysis represents a new paradigm of reactivity for engaging alkylmetallic reagents in transition-metal-catalyzed processes. Reported here is an investigation into the mechanistic details of this important transformation using density functional theory. Calculations bring to light a new reaction pathway involving an alkylnickel(I) complex generated by addition of an alkyl radical to Ni(0) that is likely to operate simultaneously with the previously proposed mechanism. Analysis of the enantioselective variant of the transformation reveals an unexpected manifold for stereoinduction involving dynamic kinetic resolution (DKR) of a Ni(III) intermediate wherein the stereodetermining step is reductive elimination. Furthermore, calculations suggest that the DKR-based stereoinduction manifold may be responsible for stereoselectivity observed in numerous other stereoconvergent Ni-catalyzed cross-couplings and reductive couplings.
Co-reporter:David N. Primer; Idris Karakaya; John C. Tellis
Journal of the American Chemical Society 2015 Volume 137(Issue 6) pp:2195-2198
Publication Date(Web):February 4, 2015
DOI:10.1021/ja512946e
Single-electron-mediated alkyl transfer affords a novel mechanism for transmetalation, enabling cross-coupling under mild conditions. Here, general conditions are reported for cross-coupling of secondary alkyltrifluoroborates with an array of aryl bromides mediated by an Ir photoredox catalyst and a Ni cross-coupling catalyst.
Co-reporter:Matthieu Jouffroy; David N. Primer
Journal of the American Chemical Society 2015 Volume 138(Issue 2) pp:475-478
Publication Date(Web):December 24, 2015
DOI:10.1021/jacs.5b10963
Single-electron transmetalation is recognized as an enabling technology for the mild transfer of alkyl groups to transition metal catalysts in cross-coupling reactions. Hypercoordinate silicates represent a new and improved class of radical precursors because of their low oxidation potentials and the innocuous byproducts generated upon oxidation. Herein, we report the cross-coupling of secondary and primary ammonium alkylsilicates with (hetero)aryl bromides in good to excellent yields. The base-free conditions have exceptional protic group tolerance on both partners, permitting the cross-coupling of unprotected primary and secondary amines.
Co-reporter:Idris Karakaya, David N. Primer, and Gary A. Molander
Organic Letters 2015 Volume 17(Issue 13) pp:3294-3297
Publication Date(Web):June 16, 2015
DOI:10.1021/acs.orglett.5b01463
Single-electron transmetalation has emerged as an enabling paradigm for the cross-coupling of Csp3 hybridized organotrifluoroborates. Cross-coupling of α-alkoxymethyltrifluoroborates with aryl and heteroaryl bromides has been demonstrated by employing dual catalysis with a combination of an iridium photoredox catalyst and a Ni cross-coupling catalyst. The resulting method enables the alkoxymethylation of diverse (hetero)arenes under mild, room-temperature conditions.
Co-reporter:Javad Amani and Gary A. Molander
Organic Letters 2015 Volume 17(Issue 14) pp:3624-3627
Publication Date(Web):July 6, 2015
DOI:10.1021/acs.orglett.5b01750
To develop a method for the synthesis of a class of azaborines, potassium 2-(trifluoroboratomethyl)-2,1-borazaronaphthalenes have been synthesized to serve as nucleophilic building blocks. In palladium-catalyzed cross-coupling reactions with (hetero)aryl chlorides they serve to produce a variety of pseudobenzylic (hetero)aryl substituted azaborines. Potassium 2-(trifluoroboratomethyl)-2,1-borazaronaphthalenes are crystalline solids that are more stable than 2-(chloromethyl)-2,1-borazaronaphthalenes and have a broader substrate scope in cross-coupling reactions compared to their pseudobenzylic chloride counterparts.
Co-reporter:Komal Rizwan, Idris Karakaya, Drew Heitz, Muhammad Zubair, Nasir Rasool, Gary A. Molander
Tetrahedron Letters 2015 Volume 56(Issue 49) pp:6839-6842
Publication Date(Web):9 December 2015
DOI:10.1016/j.tetlet.2015.10.080
A practical protocol for the synthesis of N-arylated methyl 2-aminothiophene-3-carboxylate has been developed via Chan–Lam cross-coupling. The desired products were synthesized by cross-coupling of methyl 2-aminothiophene-3-carboxylate with both arylboronic acids and potassium aryltrifluoroborate salts in moderate to good yields. A broad range of functional groups was well tolerated.
Co-reporter:Gary A. Molander, Sarah L.J. Trice, Brittany Tschaen
Tetrahedron 2015 Volume 71(Issue 35) pp:5758-5764
Publication Date(Web):2 September 2015
DOI:10.1016/j.tet.2015.04.026
A modified Pd-catalyzed method of forming aryl- and heteroarylboron species and a two-step, one-pot borylation/Suzuki-Miyaura cross coupling using the atom economical tetrahydroxydiboron (bis-boronic acid, BBA) is reported. By using ethylene glycol as an additive, the new method results in increased yields, lower BBA loading, faster reaction times, and a broader reaction scope, including previously problematic substrates such as heterocycles.
Co-reporter:Yohei Yamashita;John C. Tellis
PNAS 2015 Volume 112 (Issue 39 ) pp:12026-12029
Publication Date(Web):2015-09-29
DOI:10.1073/pnas.1509715112
Orthogonal reactivity modes offer substantial opportunities for rapid construction of complex small molecules. However, most
strategies for imparting orthogonality to cross-coupling reactions rely on differential protection of reactive sites, greatly
reducing both atom and step economies. Reported here is a strategy for orthogonal cross-coupling wherein a mechanistically
distinct activation mode for transmetalation of sp3-hybridized organoboron reagents enables C-C bond formation in the presence of various protected and unprotected sp2-hybridized organoborons. This manifold has the potential for broad application, because orthogonality is inherent to the
activation mode itself. The diversification potential of this platform is shown in the rapid elaboration of a trifunctional
lynchpin through various transition metal-catalyzed processes without nonproductive deprotection or functional group manipulation
steps.
Co-reporter:Gary A. Molander, Kaitlin M. Traister, and Brian T. O’Neill
The Journal of Organic Chemistry 2015 Volume 80(Issue 5) pp:2907-2911
Publication Date(Web):February 25, 2015
DOI:10.1021/acs.joc.5b00135
A method has been developed for the introduction of nonaromatic heterocyclic structures onto aryl and heteroaryl bromides using alkyl tosylates in a reductive cross-coupling manifold. This protocol offers an improvement over previous methods by utilizing alkyl tosylate coupling partners that are bench-stable, crystalline solids that can be prepared from inexpensive, commercially available alcohols.
Co-reporter:Gary A. Molander, Javad Amani, and Steven R. Wisniewski
Organic Letters 2014 Volume 16(Issue 22) pp:6024-6027
Publication Date(Web):November 3, 2014
DOI:10.1021/ol5030508
The synthesis of 2-(chloromethyl)-2,1-borazaronaphthalene has provided an opportunity to expand dramatically the functionalization of the azaborines. This azaborinyl building block can serve as the electrophile in palladium-catalyzed cross-coupling reactions to form sp3–sp and sp3–sp2 bonds. The cross-coupling reactions of 2-(chloromethyl)-2,1-borazaronaphthalene with potassium (hetero)aryl- and alkenyltrifluoroborates as well as terminal alkynes provides access to a variety of novel azaborines, allowing a library of pseudobenzylic substituted azaborines to be prepared from one common starting material.
Co-reporter:Gary A. Molander, Steven R. Wisniewski, and Kaitlin M. Traister
Organic Letters 2014 Volume 16(Issue 14) pp:3692-3695
Publication Date(Web):June 30, 2014
DOI:10.1021/ol501495d
Conditions have been developed for the reductive cross-coupling of 3-bromo-2,1-borazaronaphthalenes with primary and secondary alkyl iodides. This method allows direct alkylation of azaborine cores, providing efficient access to functionalized isosteres of naphthalene derivatives.
Co-reporter:Klaus M. Bjerglund, Troels Skrydstrup, and Gary A. Molander
Organic Letters 2014 Volume 16(Issue 7) pp:1888-1891
Publication Date(Web):March 17, 2014
DOI:10.1021/ol5003362
The carbonylative Suzuki–Miyaura reaction between aryl bromides and arylboronic acid equivalents is herein reported, using base-free conditions and a limited excess of carbon monoxide generated ex situ from stable CO-precursors. Under these conditions, unsymmetrical biaryl ketones were obtained in modest to excellent yields. This method was adapted to the synthesis of the triglyceride and cholesterol regulator drug, fenofibrate, and its 13C-labeled derivative in good yields from the appropriate CO-precursor.
Co-reporter:Gary A. Molander and O. Andreea Argintaru
Organic Letters 2014 Volume 16(Issue 7) pp:1904-1907
Publication Date(Web):March 25, 2014
DOI:10.1021/ol500408a
A general method for the alkenylation of alkyl electrophiles using nearly stoichiometric amounts of the air- and moisture-stable potassium organotrifluoroborates has been developed. Various functional groups were tolerated on both the nucleophilic and electrophilic partner. Reactions of highly substituted E- and Z-alkenyltrifluoroborates, as well as vinyl- and propenyltrifluoroborates, were successful, and no loss of stereochemistry or regiochemistry was observed.
Co-reporter:Gary A. Molander, Steven R. Wisniewski, and Javad Amani
Organic Letters 2014 Volume 16(Issue 21) pp:5636-5639
Publication Date(Web):October 15, 2014
DOI:10.1021/ol502708z
One major synthetic route to the synthesis of benzyl amines, ethers, and esters is the nucleophilic substitution of a benzylic halide. To develop a method for the facile synthesis and functionalization of the isosteric azaborines, 2-chloromethyl-2,1-borazaronaphthalene has been synthesized in one step to afford a similar common precursor to a benzylic halide. This B–N isostere has been shown to be an effective building block by serving as an electrophile in substitution reactions with a large variety of nucleophiles.
Co-reporter:Mirna El Khatib and Gary A. Molander
Organic Letters 2014 Volume 16(Issue 18) pp:4944-4947
Publication Date(Web):September 10, 2014
DOI:10.1021/ol5024689
An effective protocol toward the O-arylation of β-hydroxy-α-amino acid substrates serine and threonine has been developed via Chan–Lam cross-coupling. This Cu(II)-catalyzed transformation involves benign open-flask conditions that are well-tolerated with a variety of protected (Boc-, Cbz-, Tr-, and Fmoc-) serine and threonine derivatives and various potassium organotrifluoroborates and boronic acids.
Co-reporter: Gary A. Moler;DaWeon Ryu
Angewandte Chemie International Edition 2014 Volume 53( Issue 51) pp:14181-14185
Publication Date(Web):
DOI:10.1002/anie.201408191
Abstract
The usefulness of embedded CF3 substituents within organic substructures necessitates the development of diverse methods for incorporating this functional group. A recently reported route to α-trifluoromethylated alkylboron compounds by an α-transfer mechanism has now been extended to the synthesis of unprecedented, vicinally ditrifluoromethylated alkylboron compounds in a diastereoselective fashion. The utility of these products is highlighted by conversion of the CB bond into other functional groups.
Co-reporter: Gary A. Moler;DaWeon Ryu
Angewandte Chemie 2014 Volume 126( Issue 51) pp:14405-14409
Publication Date(Web):
DOI:10.1002/ange.201408191
Abstract
The usefulness of embedded CF3 substituents within organic substructures necessitates the development of diverse methods for incorporating this functional group. A recently reported route to α-trifluoromethylated alkylboron compounds by an α-transfer mechanism has now been extended to the synthesis of unprecedented, vicinally ditrifluoromethylated alkylboron compounds in a diastereoselective fashion. The utility of these products is highlighted by conversion of the CB bond into other functional groups.
Co-reporter:Gary A. Molander and Steven R. Wisniewski
The Journal of Organic Chemistry 2014 Volume 79(Issue 17) pp:8339-8347
Publication Date(Web):August 18, 2014
DOI:10.1021/jo501638q
Unlike their B-alkyl counterparts, brominated N-alkyl B-aryl 2,1-borazaronaphthalenes undergo a self-arylation reaction in the presence of a catalytic amount of palladium and base, in which the azaborine serves as both the electrophile and the nucleophile. The products of the self-arylation are air- and moisture-stable 2,1-borazaronaphthols, previously only observed in basic alcoholic solvents. The steric encumbrance of the azaborine appears to prevent formation of the corresponding boron acid anhydride, allowing access to a family of 2,1-borazaronaphthol derivatives.
Co-reporter:Gary A. Molander, Steven R. Wisniewski, and Elham Etemadi-Davan
The Journal of Organic Chemistry 2014 Volume 79(Issue 22) pp:11199-11204
Publication Date(Web):October 30, 2014
DOI:10.1021/jo502260x
Conditions have been developed for the palladium-catalyzed cross-coupling of 3-bromo-2,1-borazaronaphthalenes with potassium alkenyltrifluoroborates. Twenty-seven alkenyl-substituted azaborines have been synthesized through this method, providing access to a family of 2,1-borazaronaphthalenes with alkenyl substitution at the C3 position.
Co-reporter:Steven R. Wisniewski, Courtney L. Guenther, O. Andreea Argintaru, and Gary A. Molander
The Journal of Organic Chemistry 2014 Volume 79(Issue 1) pp:365-378
Publication Date(Web):December 11, 2013
DOI:10.1021/jo402616w
Azaborines are an important class of compounds with applications in both medicinal chemistry and materials science. The first borazaronaphthalene, 2-chloro-2,1-borazaronaphthalene, was reported in 1959; however, access to more highly functionalized substructures has been limited because of the harsh reaction conditions required to displace the chloride on boron. A convergent approach has been developed to synthesize disubstituted 2,1-borazaronaphthalenes from N-substituted 2-aminostyrenes and potassium organotrifluoroborates, where the potassium organotrifluoroborate is converted to the active R–BX2 species (X = Cl or F) in situ by addition of a fluorophile. Starting from aryl-, heteroaryl-, alkynyl-, alkenyl-, and alkyltrifluoroborates, a library of highly functionalized 2,1-borazaronaphthalenes were synthesized in one step under mild, transition-metal-free conditions.
Co-reporter:Mnaza Noreen, Nasir Rasool, Mirna El Khatib, and Gary A. Molander
The Journal of Organic Chemistry 2014 Volume 79(Issue 15) pp:7243-7249
Publication Date(Web):July 14, 2014
DOI:10.1021/jo501323z
A mild, practical protocol has been developed for the Suzuki cross-coupling of unprotected thienylsulfonamides from air- and bench-stable organotrifluoroborates in the absence of a protecting group on the sulfonamide nitrogen. The developed synthetic method can be applied to the preparation of various arylated and heteroarylated thienylsulfonamides under conditions that are tolerant of a broad range of functional groups.
Co-reporter:Gary A. Molander and Steven R. Wisniewski
The Journal of Organic Chemistry 2014 Volume 79(Issue 14) pp:6663-6678
Publication Date(Web):July 1, 2014
DOI:10.1021/jo5011894
Despite their potential applications in both medicinal chemistry and materials science, there have been limited reports on the functionalization of 2,1-borazaronaphthalenes since their discovery in 1959. To access new chemical space and build molecular complexity, the Suzuki–Miyaura cross-coupling of brominated 2,1-borazaronaphthalenes has been investigated. The palladium-catalyzed cross-coupling proceeds with an array of potassium (hetero)aryltrifluoroborates in high yield with low catalyst loadings under mild reaction conditions. By the use of a high-yielding bromination of various 2,1-borazaronaphthalenes to generate electrophilic azaborine species, a library of 3-(hetero)aryl and 3,6-diaryl-2,1-borazaronaphthalenes has been synthesized.
Co-reporter:Gary A. Molander, Kaitlin M. Traister, and Brian T. O’Neill
The Journal of Organic Chemistry 2014 Volume 79(Issue 12) pp:5771-5780
Publication Date(Web):June 3, 2014
DOI:10.1021/jo500905m
Reductive cross-coupling allows the direct C–C bond formation between two organic halides without the need for preformation of an organometallic reagent. A method has been developed for the reductive cross-coupling of nonaromatic, heterocyclic bromides with aryl or heteroaryl bromides. The developed conditions use an air-stable Ni(II) source in the presence of a diamine ligand and a metal reductant to allow late-stage incorporation of saturated heterocyclic rings onto aryl halides in a functional-group tolerant manner.
Co-reporter:John C. Tellis;David N. Primer
Science 2014 Volume 345(Issue 6195) pp:433-436
Publication Date(Web):25 Jul 2014
DOI:10.1126/science.1253647
A bright outlook for carbon coupling
In contemporary organic chemistry, it is straightforward to forge bonds between unsaturated carbons (i.e., carbons already engaged in double bonds) using cross-coupling catalysis. The protocol runs into some trouble, however, if one or both starting carbon centers are saturated (purely single-bonded). Tellis et al. and Zuo et al. independently found that combining a second, light-activated catalyst with a nickel cross-coupling catalyst could achieve selective coupling of saturated and unsaturated reagents (see the Perspective by Lloyd-Jones and Ball). Their methods rely on single-electron transfer from the light-activated catalyst to the saturated carbon, thereby enhancing its reactivity more effectively than the twoelectron mechanisms prevailing in traditional protocols.
Science, this issue p. 433, p. 437; see also p. 381
Co-reporter:Gary A. Molander, Thiago Barcellos, and Kaitlin M. Traister
Organic Letters 2013 Volume 15(Issue 13) pp:3342-3345
Publication Date(Web):June 14, 2013
DOI:10.1021/ol401377q
A protocol for the stereocontrolled synthesis of (E)- and (Z)-β,γ-unsaturated esters and amides is reported. 2-Chloroacetates as well as secondary and tertiary 2-chloroacetamides were successfully employed as electrophiles in the Suzuki–Miyaura cross-coupling reaction with potassium (E)- and (Z)-alkenyltrifluoroborates, affording the corresponding products in high yield.
Co-reporter:Gary A. Molander and Kaitlin M. Traister
Organic Letters 2013 Volume 15(Issue 19) pp:5052-5055
Publication Date(Web):September 16, 2013
DOI:10.1021/ol402391z
The synthesis of β,γ-alkynyl esters and amides using air-stable potassium alkynyltrifluoroborates as nucleophilic partners in a mild Suzuki–Miyaura cross-coupling reaction has been achieved. Propargyl esters and amides were obtained in high yields using a low catalyst loading, and the substrate scope of the reaction has been significantly improved over previous methods.
Co-reporter:Gary A. Molander and Livia N. Cavalcanti
Organic Letters 2013 Volume 15(Issue 12) pp:3166-3169
Publication Date(Web):June 11, 2013
DOI:10.1021/ol401402d
Isoxazolidines have proven to be important substrates in synthetic organic chemistry. Limited examples in the literature that provide trifluoromethylated versions of these compounds have prompted us to investigate a 1,3-dipolar cycloaddition route providing access to N-functionalized isoxazolidines containing a trifluoromethyl group. Thus, a 1,3-dipolar cycloaddition of nitrosoarenes, (trifluoromethyl)diazomethane, and alkenes was developed. The starting materials can be synthesized from easy to handle and accessible reagents. The reaction proved to be tolerant of a variety of electron-deficient alkenes and nitrosoarenes.
Co-reporter:Marc Presset, Daniel Oehlrich, Frederik Rombouts, and Gary A. Molander
Organic Letters 2013 Volume 15(Issue 7) pp:1528-1531
Publication Date(Web):March 15, 2013
DOI:10.1021/ol400307d
Potassium vinyltrifluoroborate was found to be an efficient partner with benzamide derivatives for Rh(III)-catalyzed annulations. 4-Trifluoroboratotetrahydroisoquinolones were generated under mild conditions, affording a regioisomerically complementary substitution pattern to other alkenes in related reactions. These new boron-containing building blocks were derivatized by N-arylations, retaining the boron substituent for further elaboration.
Co-reporter:Nicolas Fleury-Brégeot, Daniel Oehlrich, Frederik Rombouts, and Gary A. Molander
Organic Letters 2013 Volume 15(Issue 7) pp:1536-1539
Publication Date(Web):March 14, 2013
DOI:10.1021/ol400320q
A robust and efficient protocol for the introduction of the dioxolanylethyl moiety onto various aryl and heteroaryl halides has been developed, providing cross-coupling yields up to 93%. Copper-catalyzed borylation of 2-(2-bromoethyl)-1,3-dioxolane with bis(pinacolato)diboron followed by treatment with potassium bifluoride provides the key organotrifluoroborate reagent.
Co-reporter:Brittany A. Tschaen, Jason R. Schmink, and Gary A. Molander
Organic Letters 2013 Volume 15(Issue 3) pp:500-503
Publication Date(Web):January 15, 2013
DOI:10.1021/ol303298g
Aliphatic and aromatic aldehydes are successfully converted into their corresponding esters using Pd(OAc)2 and XPhos. This approach utilizes a hydrogen transfer protocol: concomitant reduction of acetone to isopropanol provides an inexpensive and sustainable approach that mitigates the need for other oxidants.
Co-reporter:Gary A. Molander and Inji Shin
Organic Letters 2013 Volume 15(Issue 10) pp:2534-2537
Publication Date(Web):May 6, 2013
DOI:10.1021/ol401021x
Sulfamates were studied as the electrophilic partners in the palladium-catalyzed Suzuki–Miyaura cross-coupling reaction with potassium Boc-protected primary and secondary aminomethyltrifluoroborates. A broad range of substrates was successfully coupled to provide the desired products. Complex molecules containing a new carbon–carbon bond and an aminomethyl moiety could be prepared through this developed method.
Co-reporter:Gary A. Moler;Steven R. Wisniewski;Mona Hosseini-Sarvari
Advanced Synthesis & Catalysis 2013 Volume 355( Issue 14-15) pp:3037-3057
Publication Date(Web):
DOI:10.1002/adsc.201300640
Co-reporter:Gary A. Molander, Livia N. Cavalcanti, and Carolina García-García
The Journal of Organic Chemistry 2013 Volume 78(Issue 13) pp:6427-6439
Publication Date(Web):June 18, 2013
DOI:10.1021/jo401104y
Arylboronic acids are gaining increased importance as reagents and target structures in a variety of useful applications. Recently, the palladium-catalyzed synthesis of arylboronic acids employing the atom-economical tetrahydroxydiboron (BBA) reagent has been reported. The high cost associated with palladium, combined with several limitations of both palladium- and copper-catalyzed processes, prompted us to develop an alternative method. Thus, the nickel-catalyzed borylation of aryl and heteroaryl halides and pseudohalides using tetrahydroxydiboron (BBA) has been formulated. The reaction proved to be widely functional group tolerant and applicable to a number of heterocyclic systems. To the best of our knowledge, the examples presented here represent the only effective Ni-catalyzed Miyaura borylations conducted at room temperature.
Co-reporter:Gary A. Molander, DaWeon Ryu, Mona Hosseini-Sarvari, Rammohan Devulapally, and Dave G. Seapy
The Journal of Organic Chemistry 2013 Volume 78(Issue 13) pp:6648-6656
Publication Date(Web):June 25, 2013
DOI:10.1021/jo4009589
The synthesis of potassium trifluoro(N-methylheteroaryl)borates and their use in cross-coupling reactions with various aryl and heteroaryl halides to construct N-methyl heteroaryl-substituted aromatic and heteroaromatic compounds are reported.
Co-reporter:Marc Presset, Nicolas Fleury-Brégeot, Daniel Oehlrich, Frederik Rombouts, and Gary A. Molander
The Journal of Organic Chemistry 2013 Volume 78(Issue 9) pp:4615-4619
Publication Date(Web):April 17, 2013
DOI:10.1021/jo4005519
Copper-catalyzed borylation of a variety of organic halides with bis(pinacolato)diboron allows the preparation of diverse potassium organotrifluoroborates. The reactions are mild and general, providing access to a variety of interesting, boron-containing building blocks, including those containing piperidine, pyrrole, azetidine, tetrahydropyran, and oxetane substructures. Representative Minisci reactions are reported for select examples.
Co-reporter:Gary A. Molander, Kaitlin M. Traister, and Thiago Barcellos
The Journal of Organic Chemistry 2013 Volume 78(Issue 8) pp:4123-4131
Publication Date(Web):April 9, 2013
DOI:10.1021/jo400488q
A method has been developed for the Pd-catalyzed synthesis of α-(hetero)aryl esters and amides through a Suzuki–Miyaura cross-coupling reaction. This method avoids the use of strong base, does not necessitate inert or low temperature formation of reagents, and does not require the use of a large excess of organometallic reagent. Utilization of organotrifluoroborate salts as nucleophilic partners allows a variety of functional groups and heterocyclic compounds to be tolerated.
Co-reporter:O. Andreea Argintaru;DaWeon Ryu;Ioana Aron ; Gary A. Moler
Angewandte Chemie 2013 Volume 125( Issue 51) pp:13901-13905
Publication Date(Web):
DOI:10.1002/ange.201308036
Co-reporter:O. Andreea Argintaru;DaWeon Ryu;Ioana Aron ; Gary A. Moler
Angewandte Chemie International Edition 2013 Volume 52( Issue 51) pp:13656-13660
Publication Date(Web):
DOI:10.1002/anie.201308036
Co-reporter:Marc Presset, Daniel Oehlrich, Frederik Rombouts, and Gary A. Molander
The Journal of Organic Chemistry 2013 Volume 78(Issue 24) pp:12837-12843
Publication Date(Web):November 19, 2013
DOI:10.1021/jo4023233
Copper-mediated trifluoromethylation of unsaturated organotrifluoroborates with the Langlois reagent (NaSO2CF3) and TBHP allows the introduction of trifluoromethyl groups into a variety of organic substructures. The reactions are easy to set up, the conditions are mild and general, and the process provides access to trifluoromethylated alkynes, alkenes, arenes, and heteroarenes in fair to good yields.
Co-reporter:Gary A. Molander ; Sarah L. J. Trice ; Steven M. Kennedy ; Spencer D. Dreher ;Matthew T. Tudge
Journal of the American Chemical Society 2012 Volume 134(Issue 28) pp:11667-11673
Publication Date(Web):July 6, 2012
DOI:10.1021/ja303181m
The Suzuki-Miyaura reaction has become one of the more useful tools for synthetic organic chemists. Until recently, there did not exist a direct way to make the most important component in the coupling reaction, namely the boronic acid. Current methods to make boronic acids often employ harsh or wasteful reagents to prepare boronic acid derivatives and require additional steps to afford the desired boronic acid. The scope of the previously reported palladium-catalyzed, direct boronic acid synthesis is unveiled, which includes a wide array of synthetically useful aryl electrophiles. It makes use of the newly available second generation Buchwald XPhos preformed palladium catalyst and bis-boronic acid. For ease of isolation and to preserve the often sensitive C–B bond, all boronic acids were readily converted to their more stable trifluoroborate counterparts.
Co-reporter:Gary A. Molander ;Steven R. Wisniewski
Journal of the American Chemical Society 2012 Volume 134(Issue 40) pp:16856-16868
Publication Date(Web):October 1, 2012
DOI:10.1021/ja307861n
Potassium 1-(alkoxy/acyloxy)alkyltrifluoroborates have been synthesized through a copper-catalyzed diboration of aldehydes and subsequent conversion of the resulting potassium 1-(hydroxy)alkyltrifluoroborates. The palladium-catalyzed Suzuki–Miyaura reaction employing the potassium 1-(benzyloxy)alkyltrifluoroborates with aryl and heteroaryl chlorides provides access to protected secondary alcohols in high yields. The β-hydride elimination pathway is avoided through use of the benzyl protecting group, which is proposed to stabilize the diorganopalladium intermediate by coordination of the arene to the metal center. This cross-coupling is stereospecific with complete retention of stereochemistry.
Co-reporter:Virginie Colombel, Marc Presset, Daniel Oehlrich, Frederik Rombouts, and Gary A. Molander
Organic Letters 2012 Volume 14(Issue 7) pp:1680-1683
Publication Date(Web):March 9, 2012
DOI:10.1021/ol300215p
Solid-supported organotrifluoroborates were prepared in high yields by ion exchange with Amberlyst resins. The reactivity of solid supported aryltrifluoroborates was evaluated in Suzuki–Miyaura couplings with numerous aryl bromide partners. Electron-rich and -poor substituents were tolerated on both substrates, providing yields up to 90%. Examples of alkyl-, alkenyl-, alkynyl-, and heteroaryltrifluoborates were also successfully cross-coupled to aryl halides.
Co-reporter:Gary A. Molander and Inji Shin
Organic Letters 2012 Volume 14(Issue 17) pp:4458-4461
Publication Date(Web):August 29, 2012
DOI:10.1021/ol301955s
Seven potassium Boc-protected secondary aminomethyltrifluoroborates were prepared in a standardized two-step process. The Suzuki–Miyaura cross-coupling reaction was studied with this new class of nucleophiles, and a large variety of aryl and hetaryl chlorides provided the desired products in good to excellent yields, thereby allowing easy access to secondary aminomethyl substructures.
Co-reporter:Gary A. Molander and Kehinde Ajayi
Organic Letters 2012 Volume 14(Issue 16) pp:4242-4245
Publication Date(Web):August 8, 2012
DOI:10.1021/ol301956p
A library of benzimidazole-substituted potassium organotrifluoroborates was prepared via the condensation of various potassium formyl-substituted aryl- and heteroaryltrifluoroborates with aromatic 1,2-diamines under oxidative conditions. The efficient Suzuki–Miyaura cross-coupling of products thus formed to various aryl and heteroaryl bromides was achieved in good yields. The method allows the facile preparation of benzimidazole-containing triaromatic products in two steps from simple potassium formyl substituted aryl- or heteroaryltrifluoroborates.
Co-reporter:Gary A. Molander, Sarah L. J. Trice, and Steven M. Kennedy
Organic Letters 2012 Volume 14(Issue 18) pp:4814-4817
Publication Date(Web):September 4, 2012
DOI:10.1021/ol302124j
The palladium-catalyzed borylation of aryl and heteroaryl halides with a novel borylating agent, tetrakis(dimethylamino)diboron [(Me2N)2B–B(NMe2)2], is reported. The method is complementary to the previously reported method utilizing bis-boronic acid (BBA) in that certain substrates perform better under one set of optimized reaction conditions than the other. Because tetrakis(dimethylamino)diboron is the synthetic precursor to both BBA and bis(pinacolato)diboron (B2Pin2), the new method represents a more atom-economical and efficient approach to current borylation methods.
Co-reporter:Laura Iannazzo ;Gary A. Moler
European Journal of Organic Chemistry 2012 Volume 2012( Issue 26) pp:4923-4926
Publication Date(Web):
DOI:10.1002/ejoc.201200767
Abstract
Several alkyl- and vinylsilanes were prepared through the copper(I)-catalyzed conjugate silylation of α,β-unsaturated compounds. Optimal reaction conditions were first investigated to realize the conjugate addition of a nucleophilic silicon species to poorly electrophilic acceptors such as phenylvinyl sulfone by cleavage of the Si–Si bond of a disilane reagent. The scope of this reaction was extended to various electrophiles bearing different electron-withdrawing groups and afforded the desired substituted alkyl- and vinylsilanes. Among the wide range of commercially available disilanes, the reactivities of alkyl-, aryl-, and ethoxydisilane were also examined.
Co-reporter:Rammohan Devulapally, Nicolas Fleury-Brégeot, Gary A. Molander, Dave G. Seapy
Tetrahedron Letters 2012 Volume 53(Issue 9) pp:1051-1055
Publication Date(Web):29 February 2012
DOI:10.1016/j.tetlet.2011.12.062
Potassium imidomethyltrifluoroborate salts were efficiently synthesized. Potassium phthalimidomethyltrifluoroborate was successfully used in Suzuki–Miyaura-like cross-coupling reactions with a variety of aryl chlorides.
Co-reporter:Virginie Colombel, Frederik Rombouts, Daniel Oehlrich, and Gary A. Molander
The Journal of Organic Chemistry 2012 Volume 77(Issue 6) pp:2966-2970
Publication Date(Web):March 6, 2012
DOI:10.1021/jo202686p
Efficient Csp3–Csp3 Suzuki couplings have been developed with both potassium cyclopropyl- and alkoxymethyltrifluoroborates. Moderate to good yields have been achieved in the cross-coupling of potassium cyclopropyltrifluoroborate with benzyl chlorides possessing electron-donating or electron-withdrawing substituents. Benzyl chloride was also successfully cross-coupled to potassium alkoxymethyltrifluoroborates derived from primary, secondary, and tertiary alcohols.
Co-reporter:Dr. Nicolas Fleury-Brégeot;Dr. Jessica Raushel;Dr. Deidre L. Srock;Dr. Spencer D. Dreher; Gary A. Moler
Chemistry - A European Journal 2012 Volume 18( Issue 31) pp:9564-9570
Publication Date(Web):
DOI:10.1002/chem.201200831
Abstract
Ammoniomethyl trifluoroborates are very powerful reagents that can be used to access biologically relevant aryl- and heteroaryl-methylamine motifs via Suzuki–Miyaura cross-couplings. Until now, this method was limited to the production of tertiary and primary amines. The synthesis of a large array of secondary ammoniomethyltrifluoroborates has been achieved through a one step nucleophilic substitution reaction on the potassium bromomethyltrifluoroborate. Smooth cross-coupling conditions have been designed, based on the use of an aminobiphenyl palladium precatalyst, to couple these trifluoroborates efficiently with aryl bromides. This strategy offers a new way to access biologically relevant motifs and allows, with the previously developed methods, access to all three classes of aminomethylarenes.
Co-reporter:Nicolas Fleury-Brégeot, Marc Presset, Floriane Beaumard, Virginie Colombel, Daniel Oehlrich, Frederik Rombouts, and Gary A. Molander
The Journal of Organic Chemistry 2012 Volume 77(Issue 22) pp:10399-10408
Publication Date(Web):November 6, 2012
DOI:10.1021/jo3021665
The introduction of an alkoxyethyl moiety onto aromatic substructures has remained a long-standing challenge for synthetic organic chemists. The main reasons are the inherent instability of alkoxyethylmetallic species and the lack of general procedures to access them. A new method utilizing a cross-coupling strategy based on the exceptional properties of organotrifluoroborates has been developed, and the method allows an easy and efficient installation of this unit on a broad range of aryl and heteroaryl bromides.
Co-reporter:Gary A. Molander, Sarah L. J. Trice, and Steven M. Kennedy
The Journal of Organic Chemistry 2012 Volume 77(Issue 19) pp:8678-8688
Publication Date(Web):September 20, 2012
DOI:10.1021/jo301642v
The use of bis-boronic acid for the direct synthesis of boronic acids has greatly facilitated the two-step, one-pot borylation/Suzuki cross-coupling reaction between aryl and heteroaryl halides. With use of Buchwald’s second-generation XPhos preformed catalyst, high yields of cross-coupled products were obtained for most substrates. The method also allows an efficient two-step, one-pot synthesis, providing access to three distinct cross-coupled products after column chromatography. The method also provides a rapid and convenient route to teraryl compounds.
Co-reporter:Gary A. Molander and Livia N. Cavalcanti
The Journal of Organic Chemistry 2012 Volume 77(Issue 9) pp:4402-4413
Publication Date(Web):April 24, 2012
DOI:10.1021/jo300551m
Organotrifluoroborates have emerged as an alternative to toxic and air- and moisture-sensitive organometallic species for the synthesis of functionalized aryl and heteroaryl compounds. It has been shown that the trifluoroborate moiety can be easily converted into a variety of different substituents in a late synthetic stage. In this paper, we disclose a mild, selective, and convenient method for the ipso-nitrosation of organotrifluoroborates using nitrosonium tetrafluoroborate (NOBF4). Aryl- and heteroaryltrifluoroborates were converted into the corresponding nitroso products in good to excellent yields. This method proved to be tolerant of a broad range of functional groups.
Co-reporter:Gary A. Molander and Inji Shin
Organic Letters 2011 Volume 13(Issue 15) pp:3956-3959
Publication Date(Web):July 6, 2011
DOI:10.1021/ol2014768
Potassium Boc-protected aminomethyltrifluoroborate, a primary aminomethyl equivalent, was synthesized successfully through a “one-pot” process. With this trifluoroborate, Suzuki–Miyaura cross-coupling reactions were investigated with a variety of both aryl and hetaryl chlorides in good to excellent yields.
Co-reporter:Gary A. Molander, Nicolas Fleury-Brégeot, and Marie-Aude Hiebel
Organic Letters 2011 Volume 13(Issue 7) pp:1694-1697
Publication Date(Web):March 2, 2011
DOI:10.1021/ol200202g
Sulfonamidomethyltrifluoroborates were successfully synthesized and cross-coupled with a wide range of aryl and heteroaryl chlorides, allowing the construction of a sulfonamidomethyl aryl linkage through a new disconnection, thus offering a new way to access such structurally interesting motifs.
Co-reporter:Gary A. Molander, Frédéric Cadoret
Tetrahedron Letters 2011 Volume 52(Issue 17) pp:2199-2202
Publication Date(Web):27 April 2011
DOI:10.1016/j.tetlet.2010.11.162
We describe herein our progress toward the synthesis of halicyclamine A, which possesses very interesting biological activities and has never been synthesized. For this purpose, we proposed a stereoselective Diels–Alder reaction as a key step for the establishment of the stereogenic triad of the bis(piperidinyl) core of this molecule. A series of NMR studies was then conducted to establish the correct stereochemical assignment subsequent to the Diels–Alder reaction.
Co-reporter:Gary A. Molander and Laura Iannazzo
The Journal of Organic Chemistry 2011 Volume 76(Issue 21) pp:9182-9187
Publication Date(Web):October 6, 2011
DOI:10.1021/jo201840n
An efficient, palladium-catalyzed Hiyama cross-coupling reaction of aryltrifluorosilanes with aryl chlorides has been developed. A wide variety of functionalized biaryl derivatives were isolated in good to excellent yields. The scope of this reaction has also been extended to heteroaryl chlorides, affording the corresponding heterobiaryl compounds in high yields.
Co-reporter:Gary A. Molander, Floriane Beaumard, and Terren K. Niethamer
The Journal of Organic Chemistry 2011 Volume 76(Issue 19) pp:8126-8130
Publication Date(Web):September 2, 2011
DOI:10.1021/jo2015246
C–O activation of mesylates by a palladium catalyst and subsequent cross-coupling with potassium cyclopropyltrifluoroborate have been achieved with high yield. Both electron-enriched and electron-deficient aryl mesylates are suitable electrophilic partners for the Suzuki–Miyaura reaction. The scope was successfully extended to heteroaryl mesylates with yields up to 94%.
Co-reporter:Gary A. Molander and Livia N. Cavalcanti
The Journal of Organic Chemistry 2011 Volume 76(Issue 17) pp:7195-7203
Publication Date(Web):August 3, 2011
DOI:10.1021/jo201313a
A mild and metal-free method for the chlorodeboronation of organotrifluoroborates using trichloroisocyanuric acid (TCICA) was developed. Aryl-, heteroaryl-, alkenyl-, alkynyl-, and alkyltrifluoroborates were converted into the corresponding chlorinated products in good yields. This method proved to be tolerant of a broad range of functional groups.
Co-reporter:Jessica Raushel, Deidre L. Sandrock, Kanth V. Josyula, Deborah Pakyz, and Gary A. Molander
The Journal of Organic Chemistry 2011 Volume 76(Issue 8) pp:2762-2769
Publication Date(Web):March 15, 2011
DOI:10.1021/jo2001066
A reinvestigation into the chemical composition of potassium aminomethyltrifluoroborates is reported. These trifluoroborato salts have been reassigned as zwitterionic ammoniomethyltrifluoroborates. Minor adjustments to the previously disclosed reaction conditions are reported that permit a similar level of activity as nucleophiles in Suzuki−Miyaura cross-coupling reactions.
Co-reporter:Deidre L. Sandrock ; Ludivine Jean-Gérard ; Cheng-yi Chen ; Spencer D. Dreher
Journal of the American Chemical Society 2010 Volume 132(Issue 48) pp:17108-17110
Publication Date(Web):November 15, 2010
DOI:10.1021/ja108949w
The stereospecific cross-coupling of enantioenriched nonbenzylic secondary alkyl boron compounds has been achieved. The high selectivity toward product formation over an undesired β-H elimination pathway is achieved via an intramolecular coordination of an ancillary carbonyl to the metal center in the diorganopalladium intermediate.
Co-reporter:Gary A. Molander, O. Andreea Argintaru, Ioana Aron, and Spencer D. Dreher
Organic Letters 2010 Volume 12(Issue 24) pp:5783-5785
Publication Date(Web):November 19, 2010
DOI:10.1021/ol102717x
A method for the cross-coupling of alkyl electrophiles with various potassium aryl- and heteroaryltrifluoroborates has been developed. Nearly stoichiometric amounts of organoboron species could be employed to cross-couple a large variety of challenging heteroaryl nucleophiles. Several functional groups were tolerated on both the electrophilic and the nucleophilic partners. Chemoselective reactivity of C(sp3)−Br bonds in the presence of C(sp2)−Br bonds was achieved.
Co-reporter:Gary A. Molander and Marie-Aude Hiebel
Organic Letters 2010 Volume 12(Issue 21) pp:4876-4879
Publication Date(Web):September 29, 2010
DOI:10.1021/ol102039c
Amidomethyltrifluoroborates were successfully synthesized in a one-pot fashion and used in cross-coupling reactions with a wide variety of aryl and heteroaryl chlorides.
Co-reporter:Gary A. Molander, Inji Shin, and Ludivine Jean-Gérard
Organic Letters 2010 Volume 12(Issue 19) pp:4384-4387
Publication Date(Web):September 10, 2010
DOI:10.1021/ol101865e
Enantiomerically enriched potassium β-trifluoroboratoamides were synthesized as air-stable solids in greater than 95:5 dr using pseudoephedrine as the chiral auxiliary. With these chiral nucleophiles, Suzuki−Miyaura cross-coupling reactions were carried out with various aryl- and hetaryl chlorides in good to excellent yields. Moreover, the diastereoselectivities were preserved throughout the Suzuki−Miyaura cross-coupling reactions.
Co-reporter:Gary A. Molander and Floriane Beaumard
Organic Letters 2010 Volume 12(Issue 18) pp:4022-4025
Publication Date(Web):August 17, 2010
DOI:10.1021/ol101592r
A general method based on nickel-catalyzed C−O activation of various phenol derivatives with potassium (hetero)aryltrifluoroborates has been developed. A large number of heterobiaryls can be easily obtained with yields up to 99% using methanesulfonate cross-coupling partners.
Co-reporter:Young Ae Cho, Dong-Su Kim, Hong Ryul Ahn, Belgin Canturk, Gary A. Molander and Jungyeob Ham
Organic Letters 2009 Volume 11(Issue 19) pp:4330-4333
Publication Date(Web):September 8, 2009
DOI:10.1021/ol901669k
Potassium azidoaryltrifluoroborates have been prepared from the corresponding haloaryltrifluoroborates in 73−98% yields. Also, we successfully cross-coupled the azido-functionalized organotrifluoroborates and carried out a one-pot sequential cross-coupling/1,3-dipolar cycloaddition and a one-pot cross-coupling/azide reduction process.
Co-reporter:Gary A. Molander, Wilma Febo-Ayala and Ludivine Jean-Gérard
Organic Letters 2009 Volume 11(Issue 17) pp:3830-3833
Publication Date(Web):August 10, 2009
DOI:10.1021/ol901395c
A library of oxazoline-substituted potassium organotrifluoroborates was prepared via the condensation of various potassium formyl-substituted aryl- and heteroaryltrifluoroborates with tosylmethyl isocyanide under basic conditions. The efficient Suzuki−Miyaura cross-coupling of products thus formed to various aryl bromides was achieved in good yields. The method allows the facile preparation of oxazole-containing triaromatic products in two steps from simple potassium formyl-substituted aryl- or heteroaryltrifluoroborates.
Co-reporter:Gary A. Molander and Deidre L. Sandrock
Organic Letters 2009 Volume 11(Issue 11) pp:2369-2372
Publication Date(Web):May 7, 2009
DOI:10.1021/ol900822j
Previous studies of orthogonally reactive dibora species led to the discovery of a unique reactivity pattern associated with potassium vinyltrifluoroborate. Upon hydroboration, the vinyltrifluoroborate generates a 1,2-diboraethane, which is distinct from the 1,1-dibora intermediates generated when traditional alkenyldialkylboron species undergo hydroboration. The 1,2-dianion equivalent thus generated can be envisioned as a building block for the linkage of two different electrophiles via palladium-catalyzed Suzuki−Miyaura cross-couplings.
Co-reporter:GaryA. Moler ;Belgin Canturk
Angewandte Chemie International Edition 2009 Volume 48( Issue 49) pp:9240-9261
Publication Date(Web):
DOI:10.1002/anie.200904306
Abstract
Monocoordinated palladium catalysts derived from sterically hindered, electron-rich phosphines or N-heterocyclic carbenes have revolutionized the Suzuki–Miyaura coupling reaction. The emergence of organotrifluoroborates has provided important new perspectives for the organoboron component of these reactions. In combination, these two components prove to be extraordinarily powerful partners for cross-coupling reactions.
Co-reporter:Spencer D. Dreher, Siang-Ee Lim, Deidre L. Sandrock and Gary A. Molander
The Journal of Organic Chemistry 2009 Volume 74(Issue 10) pp:3626-3631
Publication Date(Web):March 9, 2009
DOI:10.1021/jo900152n
Parallel microscale experimentation was used to develop general conditions for the Suzuki−Miyaura cross-coupling of diversely functionalized primary alkyltrifluoroborates with a variety of aryl chlorides. These conditions were found to be amenable to coupling with aryl bromides, iodides, and triflates as well. The conditions that were previously identified through similar techniques to promote the cross-coupling of secondary alkyltrifluoroborates with aryl chlorides were not optimal for the primary alkyltrifluoroborates, thus demonstrating the value of parallel experimentation to develop novel, substrate specific results.
Co-reporter:GaryA. Moler ;Belgin Canturk
Angewandte Chemie 2009 Volume 121( Issue 49) pp:9404-9425
Publication Date(Web):
DOI:10.1002/ange.200904306
Abstract
Einfach koordinierte katalytische Palladiumkomplexe mit sperrigen, elektronenreichen Phosphan- oder N-heterocyclischen Carbenliganden haben die Suzuki-Miyaura-Kupplung revolutioniert. Weitere interessante Perspektiven für diese Reaktionen ergaben sich durch die Einführung von Organotrifluorboraten als Organoborkomponenten. Die Kombination dieser beiden Neuerungen führte zu einem außerordentlich leistungsfähigen Kreuzkupplungsverfahren.
Co-reporter:Gary A. Molander ; Sarah L. J. Trice ;Spencer D. Dreher
Journal of the American Chemical Society () pp:
Publication Date(Web):November 24, 2010
DOI:10.1021/ja1089759
Although much current research focuses on developing new boron reagents and identifying robust catalytic systems for the cross-coupling of these reagents, the fundamental preparations of the nucleophilic partners (i.e., boronic acids and derivatives) has been studied to a lesser extent. Most current methods to access boronic acids are indirect and require harsh conditions or expensive reagents. A simple and efficient palladium-catalyzed, direct synthesis of arylboronic acids from the corresponding aryl chlorides using an underutilized reagent, tetrahydroxydiboron B2(OH)4, is reported. To ensure preservation of the carbon−boron bond, the boronic acids were efficiently converted to the trifluoroborate derivatives in good to excellent yields without the use of a workup or isolation. Further, the intermediate boronic acids can be easily converted to a wide range of useful boronates. Finally, a two-step, one-pot method was developed to couple two aryl chlorides efficiently in a Suzuki−Miyaura-type reaction.
Co-reporter:Gary A. Molander ;Inji Shin
Organic Letters () pp:
Publication Date(Web):May 31, 2012
DOI:10.1021/ol301221p
Palladium-catalyzed Suzuki–Miyaura cross-coupling reactions were studied with potassium Boc-protected aminomethyltrifluoroborate through C–O activation of various mesylate derivatives to afford the corresponding products in moderate to good yields.
Co-reporter:Jennifer K. Matsui, David N. Primer and Gary A. Molander
Chemical Science (2010-Present) 2017 - vol. 8(Issue 5) pp:
Publication Date(Web):
DOI:10.1039/C7SC00283A
Co-reporter:Brandon A. Vara, Matthieu Jouffroy and Gary A. Molander
Chemical Science (2010-Present) 2017 - vol. 8(Issue 1) pp:NaN535-535
Publication Date(Web):2016/09/09
DOI:10.1039/C6SC03236B
The attractive field of iterative cross-coupling has seen numerous advances, although almost exclusively in the union of sp2-hybridized partners. Conspicuously absent from this useful synthetic manifold is the inclusion of sp3-hybridized pronucleophiles that can undergo transmetalation under mild conditions. Described here is the use of primary and secondary ammonium alkylsilicates, which undergo facile C(sp3)–C(sp2) cross-coupling with borylated aryl bromide partners under photoredox/nickel dual catalysis conditions. This operationally simple procedure allows the production of alkylated small molecules possessing boronate ester (BPin, Bneopentyl, BMIDA) functional handles. Because of the extremely mild reaction conditions and the innocuous byproduct generated upon fragmentative oxidation of silicates, the corresponding borylated compounds were isolated in good to excellent yields. Aryl bromides bearing unprotected boronic acids are also generally tolerated for the first time and prove useful in multistep syntheses. Unlike many previously reported photoredox/Ni dual cross-couplings, the C(sp3)–C(sp2) bonds were forged using a transition metal-free photocatalyst, allowing a substantial increase in sustainability as well as a cost reduction. Because the developed Ni-catalyzed cross-coupling does not require discrete boron speciation control, as in many popular orthogonal Pd-based methods, this protocol represents a significant advance in atom- and step-economy.
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![Potassium Trifluoro(1-{[(2-methyl-2-propanyl)oxy]carbonyl}-3-azet Idinyl)borate(1-)](http://img.cochemist.com/ccimg/1430300/1430219-73-0.png)
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![POTASSIUM;TRIFLUORO-[(1R,2R)-2-METHYLCYCLOHEXYL]BORANUIDE](http://img.cochemist.com/ccimg/1041700/1041642-14-1.png)
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![Potassium Trifluoro[(2-methoxyethoxy)methyl]borate(1-)](http://img.cochemist.com/ccimg/910300/910251-13-7_b.png)
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![1-[4-[2-(BENZENESULFONYL)ETHENYL]PHENYL]ETHANONE](http://img.cochemist.com/ccimg/721500/721427-01-6_b.png)
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![Pyridine, 2-[(4R)-4-(1,1-dimethylethyl)-4,5-dihydro-2-oxazolyl]-](/data/chemimg/3721600/242482-28-6.png)
![Pyridine, 2-[(4R)-4-(1,1-dimethylethyl)-4,5-dihydro-2-oxazolyl]-](/data/chemimg/3721600/242482-28-6_b.png)
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![Benzonitrile, 2-[(1,1-dimethylethyl)thio]-](http://img.cochemist.com/ccimg/184200/184169-45-7.png)
![Benzonitrile, 2-[(1,1-dimethylethyl)thio]-](http://img.cochemist.com/ccimg/184200/184169-45-7_b.png)
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![Benzene, [(cyclohexylidenemethyl)sulfonyl]-](http://img.cochemist.com/ccimg/90100/90020-44-3_b.png)
![Benzene, 1-methoxy-4-[(1E)-2-(phenylsulfonyl)ethenyl]-](http://img.cochemist.com/ccimg/87900/87891-80-3.png)
![Benzene, 1-methoxy-4-[(1E)-2-(phenylsulfonyl)ethenyl]-](http://img.cochemist.com/ccimg/87900/87891-80-3_b.png)
![Ethanone, 1-[4-(3-methoxypropyl)phenyl]-](http://img.cochemist.com/ccimg/83900/83811-57-8.png)
![Ethanone, 1-[4-(3-methoxypropyl)phenyl]-](http://img.cochemist.com/ccimg/83900/83811-57-8_b.png)
![Benzene, [(2-phenyl-2-propenyl)sulfonyl]-](http://img.cochemist.com/ccimg/74900/74866-37-8.png)
![Benzene, [(2-phenyl-2-propenyl)sulfonyl]-](http://img.cochemist.com/ccimg/74900/74866-37-8_b.png)
![Methanesulfonamide, N-[(4-methylphenyl)methylene]-](http://img.cochemist.com/ccimg/65600/65501-32-8.png)
![Methanesulfonamide, N-[(4-methylphenyl)methylene]-](http://img.cochemist.com/ccimg/65600/65501-32-8_b.png)
![Methanesulfonamide, N-[(4-methoxyphenyl)methylene]-](http://img.cochemist.com/ccimg/65600/65501-30-6.png)
![Methanesulfonamide, N-[(4-methoxyphenyl)methylene]-](http://img.cochemist.com/ccimg/65600/65501-30-6_b.png)
![Propanoic acid, 3,3',3''-[1,2,3-propanetriyltris(oxy)]tris-, trimethyl ester](http://img.cochemist.com/ccimg/64400/64310-21-0.png)
![Propanoic acid, 3,3',3''-[1,2,3-propanetriyltris(oxy)]tris-, trimethyl ester](http://img.cochemist.com/ccimg/64400/64310-21-0_b.png)
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![Ethanone, 1-[4-[[(4-methylphenyl)sulfonyl]oxy]phenyl]-](http://img.cochemist.com/ccimg/64200/64101-67-3_b.png)
![Ethanone, 1-[4-[3-(acetyloxy)propyl]phenyl]-](http://img.cochemist.com/ccimg/58900/58810-86-9.png)
![Ethanone, 1-[4-[3-(acetyloxy)propyl]phenyl]-](http://img.cochemist.com/ccimg/58900/58810-86-9_b.png)
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![Phenol, 4-[(4-chlorophenyl)methyl]-](http://img.cochemist.com/ccimg/52900/52890-73-0_b.png)
![PYRIDINE, 2-[2-(4-METHOXYPHENYL)ETHYL]-](http://img.cochemist.com/ccimg/46800/46739-62-2.png)
![PYRIDINE, 2-[2-(4-METHOXYPHENYL)ETHYL]-](http://img.cochemist.com/ccimg/46800/46739-62-2_b.png)
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![Benzene, 1,1'-[(phenylsulfonyl)ethenylidene]bis-](http://img.cochemist.com/ccimg/26200/26189-62-8_b.png)
![Benzenesulfonamide, N-[(4-methylphenyl)methylene]-](http://img.cochemist.com/ccimg/24900/24865-82-5.png)
![Benzenesulfonamide, N-[(4-methylphenyl)methylene]-](http://img.cochemist.com/ccimg/24900/24865-82-5_b.png)
![Bicyclo[2.2.1]heptane, 2-(4-methoxyphenyl)-, (1R,2R,4S)-rel-](/data/chemimg/1163200/24739-56-8.png)
![Bicyclo[2.2.1]heptane, 2-(4-methoxyphenyl)-, (1R,2R,4S)-rel-](/data/chemimg/1163200/24739-56-8_b.png)
![Benzene, 1-nitro-4-[2-(phenylsulfonyl)ethenyl]-, (E)-](http://img.cochemist.com/ccimg/18500/18462-38-9.png)
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