45. Chemical Modifications to Enhance the Drug Properties of a VIP Receptor Antagonist (ANT) Peptide

Christina Lester, Jian-Ming Li, Tenzin Passang, Yuou Wang, Edmund K. Waller, and Simon B. Blakey. Int. J. Mol. Sci. 2024, 25, 4391. DOI: 10.3390/ijms25084391

Antagonist peptides (ANTs) of vasoactive intestinal polypeptide receptors (VIP-Rs) are shown to enhance T cell activation and proliferation in vitro, as well as improving T cell-dependent anti-tumor response in acute myeloid leukemia (AML) murine models. However, peptide therapeutics often suffer from poor metabolic stability and exhibit a short half-life/fast elimination in vivo. In this study, we describe efforts to enhance the drug properties of ANTs via chemical modifications. The lead antagonist (ANT308) is derivatized with the following modifications: N-terminus acetylation, peptide stapling, and PEGylation. Acetylated ANT308 exhibits diminished T cell activation in vitro, indicating that N-terminus conservation is critical for antagonist activity. The replacement of residues 13 and 17 with cysteine to accommodate a chemical staple results in diminished survival using the modified peptide to treat mice with AML. However, the incorporation of the constraint increases survival and reduces tumor burden relative to its unstapled counterpart. Notably, PEGylation has a significant positive effect, with fewer doses of PEGylated ANT308 needed to achieve comparable overall survival and tumor burden in leukemic mice dosed with the parenteral ANT308 peptide, suggesting that polyethylene glycol (PEG) incorporation enhances longevity, and thus the antagonist activity of ANT308.

44. Photoredox-Driven Three-Component Coupling of Aryl Halides, Olefins, and O2

Mark C. Maust and Simon B. Blakey. ACS Catal. 2024, ASAP. DOI: 10.1021/acscatal.3c05988 

Modern organic synthesis requires methodologies that bring together abundant feedstock chemicals in a mild and efficient manner. To aid in this effort, we have developed a multicomponent radical hydroxyarylation reaction that utilizes aryl halides, olefins, and O2 as the reaction components. Crucial to this advance was an oxidative, rather than a reductive, approach to aryl radical generation, which enables reaction tolerance to O2. This methodology displays a broad functional group tolerance with a variety of functionalized aryl halides and a broad array of olefins. Development of this methodology enables rapid access to biologically relevant hydroxyaryl products from simple, commercially available starting materials. 

43. Enantioselective Aziridination of Unactivated Terminal Alkenes Using a Planar Chiral Rh(III) Indenyl Catalyst

Patrick Gross, Hoyoung Im, David Laws III, Bohyun Park, Hu-Hyun Baik, and Simon B. Blakey. J. Am. Chem. Soc. 2024, ASAP. DOI: 10.1021/jacs.3c10637 

Chiral aziridines are important structural motifs found in natural products and various target molecules. They serve as versatile building blocks for the synthesis of chiral amines. While advances in catalyst design have enabled robust methods for enantioselective aziridination of activated olefins, simple and abundant alkyl-substituted olefins pose a significant challenge. In this work, we introduce a novel approach utilizing a planar chiral rhodium indenyl catalyst to facilitate the enantioselective aziridination of unactivated alkenes. This transformation exhibits a remarkable degree of functional group tolerance and displays excellent chemoselectivity favoring unactivated alkenes over their activated counterparts, delivering a wide range of enantioenriched high-value chiral aziridines. Computational studies unveil a stepwise aziridination mechanism in which alkene migratory insertion plays a central role. This process results in the formation of a strained four-membered metallacycle and serves as both the enantio- and rate-determining steps in the overall reaction. 

42. Synthesis, stereochemical assignment, and enantioselective catalytic activity of late transition metal planar chiral complexes

David Laws III, Christopher D. Poff, Ethan M. Heyboer, and Simon B. Blakey. Chem. Soc. Rev. 2023, 52, 9, 6003-6030. DOI: 10.1039/D3CS00325F 

Planar chirality is an important form of molecular chirality that can be utilized to induce enantioselectivity when incorporated into transition metal catalysts. However, due to synthetic constraints, the use of late transition metal planar chiral complexes to conduct enantioselective transformations has been limited. Additionally, the published methods surrounding the stereochemical assignment of planar chiral compounds are sometimes conflicting, making proper assignment difficult. This review aims to provide clarity on the methods available to assign planar chirality and provide an overview on the synthesis and use of late transition metal planar chiral complexes as enantioselective catalysts. 

41. Defluoroalkylation of Trifluoromethylarenes with Hydrazones: Rapid Access to Benzylic Difluoroarylethylamines

Cecilia M. Hendy, Cameron J. Pratt, Nathan T. Jui, and Simon B. Blakey Org. Lett. 2023, 25, 9, 1397–1402. DOI: 10.1021/acs.orglett.3c00126 

Here, we report an efficient and modular approach toward the formation of difluorinated arylethylamines from simple aldehyde-derived N,N-dialkylhydrazones and trifluoromethylarenes (CF3-arenes). This method relies on selective C–F bond cleavage via reduction of the CF3-arene. We show that a diverse set of CF3-arenes and CF3-heteroarenes react smoothly with a range of aryl and alkyl hydrazones. The β-difluorobenzylic hydrazine product can be selectively cleaved to form the corresponding benzylic difluoroarylethylamines. 

40. Synthesis of Ribosomally Synthesized and Post-Translationally Modified Peptides Containing C–C Cross-Links

David Laws III, Eleda V Plouch, and Simon B. Blakey J. Nat. Prod. 2022, 85, 10, 2519–2539. DOI: 10.1021/acs.jnatprod.2c00508 

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are known for their macrocyclic structures, which impart unique biological activity. One rapidly emerging subclass of RiPP natural products contains macrocyclic C–C cross-links between two amino acid side chains. These linkages, often biosynthetically formed by a single rSAM or P450 enzyme, introduce significant structural and synthetic complexity to the molecules. While nature utilizes elegant mechanisms to produce C–C cross-linked RiPPs, synthetic tools are only able to access a portion of these biologically relevant natural products. This review provides an overview of the structures in this subclass as well as a discussion on their chemical syntheses. 

39. Switchable Regioselective 6-endo or 5-exo Radical Cyclization via Photoredox Catalysis

Mark C. Maust, Cecilia M. Hendy, Nathan T. Jui, and Simon B. Blakey. J. Am. Chem. Soc. 2022, 144, 9, 3776-3781. DOI: 10.1021/jacs.2c00192 

Controlling the regioselectivity of radical cyclizations to favor the 6-endo mode over its kinetically preferred 5-exo counterpart is difficult without introducing substrate prefunctionalization. To address this challenge, we have developed a simple method for reagent controlled regioselective radical cyclization of halogenated N-heterocycles onto pendant olefins. Radical generation occurs under mild photoredox conditions with control of the regioselectivity governed by the rate of hydrogen atom transfer (HAT). Utilizing a polarity-matched thiol-based HAT agent promotes the highly selective formation of the 5-exo cyclization product. Conversely, limiting the solubility of the HAT reagent Hantzsch ester (HEH) leads to selective formation of the thermodynamically favored 6-endo product. This occurs through an initial 5-exo cyclization, with the resulting alkyl radical intermediate undergoing neophyl rearrangement to form the 6-endo product. Development of this switchable catalysis strategy allows for two modes of divergent reactivity to form either the 6-endo or 5-exo product, generating fused N-heteroaromatic/saturated ring systems. 

Simple synthetic routes for heteroatom‐containing polycyclic aromatic hydrocarbons (H‐PAHs) with alkyl and aryl substitution were demonstrated. Three H‐PAHs including heteroatom containing rubicenes (H‐rubicenes), angular‐benzothiophenes (ABTs), and indenothiophene (IDTs) were successfully synthesized through two key steps including polysubstituted olefins formation and cyclization. Specifically, ABT and H‐rubicenes were comprehensively investigated by single‐crystal X‐ray diffraction, NMR, UV‐vis absorption, cyclic voltammetry, transient absorption and single crystal OFET measurements.

37. Recent Advances in Oxidative Allylic C–H Functionalization via Group IX-Metal Catalysis

Amaan M. Kazerouni, Quincy A. McKoy, and Simon B. Blakey Chem. Commun. 2020, 56, 13287-13300. DOI: 10.1039/D0CC05554A

Allylic substitution, pioneered by the work of Tsuji and Trost, has been an invaluable tool in the synthesis of complex molecules for decades. An attractive alternative to allylic substitution is the direct functionalization of allylic C-H bonds of unactivated alkenes, thereby avoiding the need for prefunctionalization. Significant early advances in allylic C–H functionalization were made using palladium catalysis. However, Pd-catalyzed reactions are generally limited to the functionalization of terminal olefins with stabilized nucleophiles. Insights from Li, Cossy, and Tanaka demonstrated the utility of RhCpx catalysts for allylic functionalization. Since these initial reports, a number of key intermolecular Rh- and Ir-catalyzed allylic C–H functionalization reactions have been reported offering significant complementarity to the Pd-catalyzed reactions. Herein, we report a summary of recent advances in intermolecular allylic C-H functionalization via group IX-metal π-allyl complexes. Mechanistic understanding driving the development of new catalysts is highlighted, and the potential for future developments is discussed.

36. Allylic C–H Functionalization via Group 9 π-Allyl Intermediates

Taylor A. F. Nelson,[†] Michael R. Hollerbach,[†] and Simon B. Blakey Dalton Trans. 2020, 49, 13928-13935. DOI: 10.1039/D0DT02313B [†]Equally contributing authors

Allylic C–H functionalization catalysed by group 9 Cp* transition-metal complexes has recently gained significant attention. These reactions have expanded allylic C–H functionalization to include di- and trisubstituted olefins, and a broad range of coupling partners. More specifically, several catalytic C–N, C–O, and C–C bond forming allylic C–H functionalization reactions have been reported, proceeding via MCp*-π-allyl intermediates. Herein we present an overview of these reactions by mechanistic paradigm. We also place this information in context of recent advances, as well as, limitations that remain for this class of reactions.

35. Designing a Planar Chiral Rhodium Indenyl Catalyst for Regio- and Enantioselective Allylic C–H Amidation

Caitlin M. B. Farr,[†] Amaan M. Kazerouni,[†] Bohyun Park,[†] Christopher D. Poff,[†] Joonghee Won, Kimberly R. Sharp, Mu-Hyun Baik, and Simon B. Blakey J. Am. Chem. Soc. 2020, 142, 13996-14004. DOI: 10.1021/jacs.0c07305 [†]Equally contributing authors

Highlighted in Some Items of Interest to Process R&D Chemists and Engineers. Org. Process Res. Dev. 2020, 24, 1549–1557. DOI: 10.1021/acs.oprd.0c00381

Chiral variants of group IX Cp and Cp* catalysts are well established and catalyze a broad range of reactions with high levels of enantioselectivity. Enantiocontrol in these systems results from ligand design that focuses on appropriate steric blocking. Herein we report the development of a new planar chiral indenyl rhodium complex for enantioselective C–H functionalization catalysis. The ligand design is based on establishing electronic asymmetry in the catalyst, to control enantioselectivity during the reactions. The complex is easily synthesized from commercially available starting materials and is capable of catalyzing the asymmetric allylic C–H amidation of unactivated olefins, delivering a wide range of high-value enantioenriched allylic amide products in good yields with excellent regio- and enantioselectivity. Computational studies suggest that C–H cleavage is rate and enantio-determining, while reductive C–N coupling from the RhV-nitrenoid intermediate is regio-determining.

34. The Mechanism of Rhodium Catalyzed Allylic C–H Amination

Robert J. Harris, Jiyong Park, Taylor A. F. Nelson, Nafees Iqbal, Daniel C. Salgueiro, John Bacsa, Cora E. MacBeth, Mu-Hyun Baik, and Simon B. Blakey J. Am. Chem. Soc. 2020, 142, 5842-5851. DOI: 10.1021/jacs.0c01069

Highlighted in Some Items of Interest to Process R&D Chemists and Engineers. Org. Process Res. Dev. 2020, 24, 874–883. DOI: 10.1021/acs.oprd.0c00197

Herein, the mechanism of catalytic allylic C–H amination reactions promoted by Cp*Rh complexes is reported. Reaction kinetics experiments, stoichiometric studies, and DFT calculations demonstrate that the allylic C–H activation to generate a Cp*Rh(π–allyl) complex is viable under mild reaction conditions. The role of external oxidants in the catalytic cycle is elucidated. Quantum mechanical calculations, stoichiometric reactions, and cyclic voltammetry experiments concomitantly support an oxidatively induced reductive elimination process of the allyl fragment with an acetate ligand proceeding through a Rh(IV) intermediate. Stoichiometric oxidation and bulk electrolysis of the proposed π–allyl intermediate are also reported to support these analyses. Lastly, evidence supporting the amination of an allylic acetate intermediate is presented. We show that Cp*Rh(III)2+ behaves as a Lewis acid catalyst to complete the allylic amination reaction.

33. C–H Functionalization Approach for the Synthesis of Chiral C2 Symmetric 1,5-Cyclooctadienes Ligands

Bowen Zhang, Michael R. Hollerbach, Simon B. Blakey, Huw M. L. Davies Org. Lett., 2019, 21, 9864-9868. DOI: 10.1021/acs.orglett.9b03764

Chiral cyclooctadiene (COD) derivatives are readily prepared by rhodium-catalyzed allylic C–H functionalization of COD. Either mono- or difunctionalization of COD is possible generating the products in high yield, diastereoselectivity and enantioselectivity. The double C–H functionalization generates C2-symmetric COD derivatives with four new stereogenic centers in >99% ee, which can be readily converted to a series of chiral COD ligands. Preliminary evaluations revealed that the COD ligands can be used in rhodium-catalyzed asymmetric arylation of cyclohex-2-enone, leading to the conjugate addition products in up to 76% ee.

32. Regioselective Cp*Ir(III)-Catalyzed Allylic C–H Sulfamidation of Allylbenzene Derivatives

Amaan M. Kazerouni,[†] Taylor A. F. Nelson,[†] Steven W. Chen, Kimberly R. Sharp, Simon B. Blakey J. Org. Chem., 2019, 84, 13179-13185 DOI: 10.1021/acs.joc.9b01816. [†]Equally contributing authors

(Special Issue: C–H Bond Functionalization)

In this study we report the development of the regioselective Cp*Ir(III)-catalyzed allylic C–H sulfamidation of allylbenzene derivatives, using azides as the nitrogen source. The reaction putatively proceeds through a Cp*Ir(III)-π-allyl intermediate and demonstrates exclusive regioselectivity for the branched position of the π-allyl. The reaction performs well on electron-rich and electron-deficient allylbenzene derivatives and is tolerant of a wide range of functional groups, including carbamates, esters, and ketones. The proposed mechanism for this reaction proceeds via C–N reductive elimination from a Cp*Ir(V) nitrenoid complex at the branched position of the π-allyl.

31. Rh(III) and Ir(III)Cp* Complexes Provide Complementary Regioselectivity Profiles in Intermolecular Allylic C-H Amidation Reactions

Jacob S. Burman, Robert J. Harris, Caitlin M. B. Farr, John Bacsa, and Simon B. Blakey ACS Catal., 2019, 9, 5474–5479 DOI: 10.1021/acscatal.9b01338

An efficient regioselective allylic C–H amidation of mono-, di-, and trisubstituted olefins has been developed. Specifically, the combination of dioxazolone reagents with RhCp* and IrCp* catalysts is reported to promote reactions with complementary regioselectivites to those previously observed in Pd-catalyzed and Ag-promoted Rh-catalyzed reactions. We report that catalyst matching with substrate class is essential for selective reactions. RhCp* complexes are required for high conversion and selectivities with β-alkylstyrene substrates, and IrCp* complexes are necessary in the context of unactivated terminal olefins.

30. Chemistry Unbound: Designing a New Four-Year Undergraduate Curriculum

Tracy L. McGill, Leah C. Williams, Douglas R. Mulford, Simon B. Blakey, Robert J. Harris, James T. Kindt, David G. Lynn, Patricia A. Marstellar, Frank E. McDonald, Nichole L. Powell J. Chem. Educ. 2019, 96, 35-46 DOI: 10.1021/acs.jchemed.8b00585

This article describes the process of designing a new four-year curriculum at Emory University. Acknowledging the limitations of traditional curricula and pedagogy, the major goals of this reform effort include an emphasis on core ideas and scientific practices rather than content and historical course boundaries in order to convey the excitement, relevance, and interdisciplinary nature of 21st century chemistry to undergraduate students.

29. Intermolecular Allylic C-H Etherification of Internal Olefins

Taylor A. F. Nelson, Simon B. Blakey Angew. Chem. Int. Ed. 2018, 57, 14911-14915. DOI:10.1002/anie.201809863

In the top 10% of  ACIE papers downloaded in 2019

Herein we report on the development of an oxidative allylic C−H etherification reaction, utilizing internal olefins and alcohols as simple precursors. Key advances include the use of RhCp* complexes to promote the allylic C−H functionalization of internal olefins and the compatibility of the oxidative conditions with oxidatively sensitive alcohols, enabling the direct etherification reaction. Preliminary mechanistic studies, consistent with C−H functionalization as the rate determining step, are presented.

28. Model Studies for the Total Synthesis of 11-Demethoxymyrtoidine and Myrtoidine

Amaan M. Kazerouni, Danny E. Mancheno, Simon B. Blakey Heterocycles, 2019, 99, 389-403 DOI: 10.3987/COM-18-S(F)32

(Special Issue Honoring Tohru Fukuyama).

The malagasy alkaloids, isolated in the 1990s from Madagascan shrub Strychnos myrtoides, are a family of strychnos alkaloids whose members have been reported to potentiate chloroquine activity against resistant strains of Plasmodium falciparum malaria. 11-Demethoxymyrtoidine, myrtoidine, and malagashanine were identified as the major components of the shrub used by local populations to treat malaria. Herein we report our studies on model systems to construct the EF dihydropyran lactone moiety present in 11-demethoxymyrtoidine and myrtoidine, and initial studies toward the application of these strategies to the total synthesis of these alkaloids.

27. The Direct Acylation Polymerization (DarP) of Well-Defined Alternating Copolymers Based on 5,6-Dicyano[2,1,3]benzothiadiazole (DCBT)

Qinqin Shi, Wesley Tatum, Junxiang Zhang, Colleen Scott, T, Christine K. Luscombe, Seth R. Marder, Simon B. Blakey Asian J. Org. Chem. 2018, 7, 1419; DOI:10.3390/molecules22030922

Alternating donor–acceptor copolymers are important materials with readily tunable optical and electronic properties. Direct arylation polymerization (DArP) is emerging as an attractive synthetic methodology for the synthesis of these polymers, avoiding the use of prefunctionalized building blocks. However, challenges remain in achieving well‐defined structure, high molecular weight, and impurity‐free polymers. Herein, a study to synthesize three well‐defined donor–acceptor copolymers through DArP is presented. Comparison of 1H NMR and 13C NMR, as well as optical and electrochemical properties analysis for the polymers and corresponding oligomers provides evidence for the regioregular structure of the polymers. On the basis of the chemical structure of poly(IIDCBT) and the solution electrochemical studies we surmised poly(IIDCBT) could potentially be an electron transport material for organic field‐effect transistors (OFETs), and we determined an electron mobility of 1.2×10−3 cm2 V−1 s−1 for this material.

26. Recent Developments in C-H Activation for Materials Science in the Center for Selective C-H Activation

Junxiang Zhang, Lauren J. Kang, Timothy C. Parker, Simon B. Blakey, Christine K. Luscombe, Seth R. Marder Molecules 2018, 23, 922; DOI:10.1002/ajoc.201800232

A method for catalytic intermolecular allylic C−H amination of trans ‐disubstituted olefins is reported. The reaction is efficient for a range of common nitrogen nucleophiles bearing one electron‐withdrawing group, and proceeds under mild reaction conditions. Good levels of regioselectivity are observed for a wide range of electronically diverse trans ‐β‐alkyl styrene substrates.

24. Intermediate-Sized Conjugated Donor Molecules for Organic Solar Cells: Comparison of Benzodithiophene and Benzobisthiazole-Based Cores

Siyuan Zhang, Junxiang Zhang, Maged Abdelsamie, Qinqin Shi, Yadong Zhang, Timothy C. Parker, Evgheni V. Jucov, Tatiana V. Timofeeva, Aram Amassian, Guillermo C. Bazan, Simon B. Blakey, Stephen Barlow, and Seth R. Marder Chem. Mater. 2017, 29, 7880; DOI:10.1021/acs.chemmater.7b02665

Two intermediate-sized donor molecules, BBTz-X and BDT-X, have been synthesized by the Stille coupling between 4-(4,4-bis(2-ethylhexyl)-6-(trimethylstannyl)-4H-silolo[3,2-b:4,5-b′]dithiophen-2-yl)-7-(5′-hexyl-[2,2′-bithiophen]-5-yl)-[1,2,5]thiadiazolo[3,4-c]pyridine and either 4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)-2,6-diiodobenzo[1,2-d:4,5-d′]bis(thiazole) or 2,6-dibromo-4,8-bis(5-(2-ethylhexyl)thiophen-2-yl)benzo[1,2-b:4,5-b′]dithiophene, respectively. Both oxidation and reduction potentials for BBTz-X are anodically shifted relative to those for BDT-X, but the oxidation potential is more sensitive to the identity of the core; this is consistent with what is seen for DFT-calculated HOMO and LUMO energies and with a slightly blue-shifted absorption maximum for BBTz-X. Although DFT calculations, along with crystal structures of related compounds, suggest more planar molecular structures for BBTz-X than for BDT-X, film structures and the effects of various annealing processes on these films, as revealed by GIWAXS, are similar. The performance of BDT-X:PC61BM bulk-heterojunction solar cells is more sensitive to annealing conditions than that of BBTz-X:PC61BM cells, but under appropriate conditions, both yield power conversion efficiencies of >7%.

23. Synthesis and C−H Functionalization Chemistry of Thiazole-Semicoronenediimides (TsCDIs) and -Coronenediimides (TCDIs)

Qinqin Shi, Eric S. Andreansky, Seth R. Marder, Simon B. Blakey, J. Org. Chem. 2017, 82, 10139; DOI:10.1021/acs.joc.7b01604

Coronenediimide (CDI) derivatives have a planar structure, a reasonably high electron affinity, and a rigid and extended delocalized π-system. Therefore, this core and variants thereof may be promising building blocks for the synthesis of electron transport materials. Herein, we have synthesized thiazole-semicoronenediimides (TsCDIs) and -coronenediimides (TCDIs) by a two-step process from a perylenediimide (PDI) precursor. Conditions for C–H arylation and heteroarylation of the thiazole moiety of this core were developed and were successfully used for the synthesis of dimer, triad, and polymeric materials. The optical and electrochemical properties of these materials and their monomers were examined as a function of side-chain modification and π-extension. With their broad optical absorption and low reduction potentials, these materials could be candidates as organic semiconductors for applications in OFETs and as nonfullerene acceptors.

Mattogrossine is an indole alkaloid isolated from Strychnos mattogrossensis that contains an unusual tetrahydrofuran ring with a concomitant hemiacetal in its structure. While tetrahydrofuran intermediates have been used in the synthesis of other strychnos alkaloids, no investigations have been performed into the synthesis of alkaloids containing this structure. We have developed an oxocarbenium-ion-initiated cascade annulation that provides us access to the ABCD ring structure of mattogrossine.

21. Total Synthesis of Malagashanine: A Chloroquine Potentiating Indole Alkaloid with Unusual Stereochemistry 

Aidi Kong, Danny E. Mancheno, Nadege, Boudet, Ricardo Delgado, Eric S. Andreansky, Simon B. Blakey, Chem. Sci. 2017, 8, 697 DOI: 10.1039/c6sc03578g

Highlighted in Synfacts, 2016, 12(12), 1229, DOI: 10.1055/s-0036-1589453

The first total synthesis of malagashanine, a chloroquine potentiating indole alkaloid, is presented. A highly stereoselective cascade annulation reaction was developed to generate the tetracyclic core of the Malagasy alkaloids. This chemistry is likely to be broadly applicable to the synthesis of other members of this stereochemically unique family of natural products.

The akuammiline alkaloids are a family of indole monoterpene natural products known for their polycyclic cage-like structures. An iminium ion cascade annulation approach was developed, simultaneously synthesizing both the C and D rings of these natural products by annulation onto a protected indole ring. This reaction allowed the synthesis of a key tetracyclic intermediate toward these natural products. This tetracycle was used for the synthesis of the pentacyclic methanoquinolizidine core present in such alkaloids as akuammiline and strictamine as well as the pentacyclic furoindoline core found in pseudoakuammigine.

19. KOtBu-Initiated Aryl C-H Iodination: A Powerful Tool for the Synthesis of High Electron Affinity Compounds

Qinqin Shi, Siyuan Zhang, Junxiang Zhang, Victoria F. Oswald, Aram Amassian, Seth R. Marder, Simon B. Blakey J. Am. Chem. Soc. 2016, 138, 3946-3949. DOI: 10.1021/jacs.5b12259

Highlighted in Synfacts, 2016, 12(06), 0587, DOI: 10.1055/s-0035-1562147

An efficient iodination reaction of electron-deficient heterocycles is described. The reaction utilizes KOtBu as an initiator and likely proceeds by a radical anion propagation mechanism. This new methodology is particularly effective for functionalization of building blocks for electron transport materials. Its utility is demonstrated with the synthesis of a new perylenediimide–thiazole non-fullerene acceptor capable of delivering a power conversion efficiency of 4.5% in a bulk-heterojunction organic solar cell.

18. Ir(III)-bis(imidazolinyl)phenyl Catalysts for Enantioselective C-H Functionalization with Ethyl Diazoacetate

Nina M. Weldy, Andrew G. Schafer, Clayton P. Owens, Cameron J. Herting, Adrian Varela-Alvarez, Chen, S.; Zachary Niemeyer, Djamaladdin G. Musaev, Matthew S. Sigman, Huw M. L. Davies, and Simon B. Blakey Chem. Sci. 2016, 7, 3142. DOI 10.1039/C6SC00190D

Highlighted in Synfacts, 2016, 12(08), 0817, DOI: 10.1055/s-0035-1562660

The intermolecular enantioselective C–H functionalization with acceptor-only metallocarbenes is reported using a new family of Ir(III)-bis(imidazolinyl)phenyl catalysts, developed based on the interplay of experimental and computational insights. The reaction is tolerant of a variety of diazoacetate precursors and is found to be heavily influenced by the steric and electronic properties of the substrate. Phthalan and dihydrofuran derivatives are functionalized in good yields and excellent enantioselectivities.

17. Cobalt Catalyzed sp3 C–H Amination Utilizing Aryl Azides

Omar Villanueva, Nina M. Weldy, Simon B. Blakey, Cora E. MacBeth Chem. Sci. 2015, 6, 6672-6675. DOI: 10.1039/C5SC01162K

A dinuclear Co(II) complex supported by a modular, tunable redox-active ligand system is capable of selective C–H amination to form indolines from aryl azides in good yields at low (1 mol%) catalyst loading. The reaction is tolerant of medicinally relevant heterocycles, such as pyridine and indole, and can be used to form 5-, 6-, and 7-membered rings. The synthetic versatility obtained using low loadings of an earth abundant transition metal complex represents a significant advance in catalytic C–H amination technology.

16. Ir-Catalyzed Enantioselective Group Transfer Reactions

Andrew G. Schafer and Simon B. Blakey Chem. Soc. Rev. 2015, 44, 5969-5980. DOI: 10.1039/C5CS00354G

Recently, several novel iridium complexes have been shown to catalyse group transfer reactions in a highly selective fashion. Rhodium complexes, and in particular dirhodium tetracarboxylate salts, have proven to be a remarkably useful class of catalysts for these reactions through several decades of development. Recent results suggest that iridium may offer opportunities to address challenges in this chemistry and provide complementary reactivity patterns. This tutorial review outlines the recent developments in Ir-catalyzed enantioselective group transfer chemistry with highlights on examples which display this unique reactivity.

15. Expanding the Carbene C–H Insertion Toolbox

Daniel Morton and Simon B. Blakey Chem. Cat. Chem. 2015, 7, 577. DOI: 10.1002/cctc.201402945

Two recent discoveries demonstrate significant advances in the controlled generation and C-H insertion chemistry of the previously inaccessible donor–donor and alkyl–alkyl classes of metallocarbenes. These discoveries lay the groundwork for broad reaction development with these versatile reactive species. EDG=Electron‐donating group; EWG=Electron‐withdrawing group; M=Transition metal.

14. A C-H Functionalization Protocol for the Direct Synthesis of Benzobisthiazole Derivatives

Jennifer L. Bon, Daijun Feng, Seth R. Marder, and Simon B. Blakey J. Org. Chem. 2014, 79, 7766,  DOI: 10.1021/jo501416j

Benzobisthiazole and thiazolothiazole derivatives are useful components in a variety of organic electronics devices resulting from their absorption, electroluminescence, and charge-transport properties. A convenient synthesis of these molecules via palladium/copper cocatalyzed C–H bond functionalization is described. Reaction conditions were optimized in a bromobenzene/benzobisthiazole system that allowed for the one-pot functionalization of both thioimidate positions of benzobisthiazole. The extension of this methodology to the synthesis of cruciform architectures and the functionalization of thiazolothiazole is also described.

13. Iridium(III)-bis(oxazolinyl)phenyl Catalysts for Enantioselective C-H Functionalization

Clayton P. Owens, Adrian Varela-Álvarez, Vyacheslav Boyarskikh, Djamaladdin G. Musaev, Huw M. L. Davies, and Simon B. Blakey Chem. Sci. 2013, 4, 2590. DOI: 10.1039/C3SC50886B

Recently, a small number of diverse iridium complexes have been shown to catalyze unusual atom transfer C–H functionalization reactions. To further our understanding and enhance the utility of iridium complexes for C–H functionalization, we report the design and synthesis of a family of iridium(III)-bis(oxazolinyl)phenyl complexes. The ability to tune the ligand environment around the metal in these systems is exploited to design complexes with the ability to catalyze the asymmetric insertion of donor/acceptor iridium carbenoids into activated C–H bonds. Low catalyst loadings (0.5 mol%) routinely lead to excellent reaction yields (51–99%) and enantioselectivities (83–99%). Density functional theory calculations provide compelling evidence that in these complexes the carbene binds to the iridium cis to the phenyl group of the bis(oxazolinyl)phenyl ligand. This finding is vital for understanding the observed stereochemical induction and is of particular significance in the field of enantioselective transition metal-catalysed atom transfer reactions utilizing oxazoline–X–oxazoline tridentate ligands, as previously employed stereochemical models for these ligand sets are based on the assumption that reactive ligands and Lewis bases bind trans to the central X ligand.

Setting a trap: Described is the development of a metallonitrene‐initiated alkyne oxidation cascade with intermolecular trapping of the reactive intermediate with a variety of allyl ethers to provide α‐oxyimine products in which new C-N, C-O, and C-C bonds have all been generated (see Scheme; tfacam=trifluoroacetamide).

11. Insight into Mechanistic Features of Ruthenium(II)-Pybox-Catalyzed C–H Amination

Djamaladdin G. Musaev, and Simon B. Blakey, Organometallics 2012, 31, 4950. DOI: 10.1021/om300153q

The mechanisms and controlling factors of intra- and intermolecular C–H bond amination catalyzed by cationic bis-imido complex [(Pybox)Ru(NSO3CH2CH2CH2R)2Cl]+ (1_R, where R = H, Ph) were elaborated at the density functional level. It was shown that the cis_1_Ph isomer is slightly (2.7 (2.9) [3.6] kcal/mol) lower in energy than trans_1_Ph, and trans_1_Phcis_1_Ph isomerization proceeds via formation of the mono-imido complex cis-[(Pybox)Ru(Imd)Cl]+ with a 31.0 (17.0) [9.0] kcal/mol energy barrier. The intramolecular α-, β-, and γ-C–H bond amination processes in trans_1_R are kinetically and thermodynamically feasible, while the required energy barrier decreases via α > β > γ for R = H, Ph. These reactions proceed via a C–H bond insertion pathway, except for the γ-C–H bond amination in trans_1_Ph, which proceeds via an H atom transfer mechanism. The H to Ph substitution on the Cγ atom of the imido ligand only slightly reduces the required energy barriers for α- and β-C–H bond amination in trans_1_R. However, it dramatically reduces the γ-C–H bond amination barrier and switches the mechanism of the reaction from C–H bond insertion to H atom transfer. This dramatic effect is a result of the better electron-withdrawing nature of the Ph ring. Thus, by replacing the R ligand, located at the γ (as well as β) C position, one may control the rate (barrier height), mechanism, and product distribution of the C–H bond amination in trans_1_R. The cis_1_Ph isomer is found to be slightly less reactive than the trans_1_Ph isomer. The intermolecular methane C–H bond amination by trans_1_R cannot compete with the intramolecular reactions in trans_1_R. The intermolecular process becomes feasible only for CβH3CαH2Ph. The intermolecular C–H amination of the substrate CβH3CαH2Ph by cis_1_Ph seems as feasible as that for the trans_1_Ph isomer. Involvement of the monoimido intermediate of the bis-imido complex 1_Ph in intra- and intermolecular C–H amination is highly unlikely.

10. Intramolecular Olefin Diamination for the Stereoselective Synthesis of 3-Aminopiperidines

Aidi Kong, and Simon B. Blakey Synthesis 2012, 44, 1190-1198. DOI: 10.1055/s-0031-1290591

(Special issue on Hypervalent Iodine Oxidants)

A general method for the direct intramolecular diamination of terminal olefins is presented. The reaction, mediated by hypervalent iodine oxidants, produces substituted 3-aminopiperidine scaffolds with high regio- and stereoselectivity, rendering this process relevant to both medicinal chemistry and natural products synthesis.

9. Synthesis of Ruthenium(II) 2,6-Bis(imino)pyridyl Complexes for C-H Amination of Sulfamate Esters

Jennifer L. Bon and Simon B. Blakey Heterocycles 2012, 84, 1313-1323. DOI: 10.3987/COM-11-S(P)64 

(Special Issue honoring Prof. Albert Padwa on his 75th birthday)

A family of ruthenium(II) 2,6-bis(imino)pyridyl complexes have been developed as a novel catalyst framework for C-H amination. Their synthesis and evaluation is herein described. The reactivity of these catalysts is heavily dependent upon the electronics of the ligand. These complexes are capable of functionalizing the benzylic protons of sulfamate esters with good conversion.

8. Rhodium Catalyzed Allene Amination: A Facile Entry into 2‑Amidoallylcations for Unusual [3+3] Annulation Reactions

Armin H. Stoll, and Simon B. Blakey Chem. Sci. 2011, 2, 112-116. DOI: 10.1039/C0SC00375A

The interaction of a sulfamate ester derived metallonitrene with an allene generates a versatile intermediate with 2-amidoallylcation like reactivity. In this article we outline reactivity patterns for this novel dipolar species, demonstrating both [3 + 2] reactions with benzaldehyde, and unusual [3 + 3] annulation reactions with a variety of nitrones.

7. Copper-Catalyzed Olefin Aminoacetoxylation

Danny E. Mancheno, Aaron R. Thornton, Armin H. Stoll, Aidi Kong, and Simon B. Blakey Org. Lett. 2010, 13, 4110-4113. DOI: 10.1021/ol101702w

A new catalyst system for intramolecular olefin aminoacetoxylation is described. In contrast to previously reported palladium- and copper-catalyzed systems, the conditions outlined in this communication favor piperdine formation with terminal olefin substrates and induce cyclization with traditionally less reactive disubstituted olefins.

The interaction of a sulfamate ester derived metallonitrene with an allene generates a versatile intermediate with 2-amidoallylcation-like reactivity, capable of rearranging to give highly substituted iminocyclopropanes or acting as a novel dipolar species engaging external dipolarophiles. 

A new cascade annulation reaction has been developed to access the core structures of a novel family of strychnos alkaloids with a unique stereochemical arrangement. The new annulation cascade is facilitated by the development of a robust reaction sequence to access extremely sensitive N ‐acyliminium ions. 

The reaction of a sulfamate ester derived rhodium nitrenoid species with an alkyne produces a versatile intermediate, capable of cascading into a wide variety of secondary transformations. The nature of the intermediate has been probed by reactivity studies, and the synthetic utility of the cascade process, which facilitates the construction of complex heterocyclic structures from remarkably simple acyclic precursors, is highlighted.

3. Synthesis and Reactivity of an Unprecedented Os(VIII) Alkylidene

Veronique I. Martin, Simon B. Blakey Tetrahedron Lett., 2008, 49, 6800-6803. DOI: 10.1016/j.tetlet.2008.09.064

The synthesis of a family of Os(VIII) alkylidene complexes, the highest oxidation state alkylidenes known to date, and their reactivity toward small organic molecules are reported.

2. Enantioselective C–H Amination Using Cationic Ru(II)-pybox Catalysts

Erika E. Milczek, Nadège Boudét, and Simon B. Blakey Angew. Chem., Int. Ed., 2008, 47, 6825-6828. DOI: 10.1002/anie.200801445 

Highlighted in Synfacts, 2008, 11, 1184. DOI: 10.1055/s-0028-1083423

The whole “pybox” and dice : Highly enantioselective amination reactions of both allylic and benzylic C-H bonds are catalyzed by cationic ruthenium(II)–pybox complexes (see structure). A novel mode of stereocontrol, which is induced by the versatile pybox ligand, is proposed to account for the excellent enantioselectivity in these reactions. Boc=tert ‐butoxycarbonyl, pybox=pyridine bisoxazoline.

1. Catalytic Metallonitrene/Alkyne Metathesis: A Powerful Cascade Process for the Synthesis of Nitrogen-Containing Molecules

Aaron R. Thornton, and Simon B. Blakey J. Am. Chem. Soc., 2008, 130, 5020-5021. DOI: 10.1021/ja7111788

Highlighted in Synfacts, 2008, 7, 691. DOI: 10.1055/s-0036-1589453

A conceptually novel metallonitrene/alkyne metathesis cascade reaction has been developed for the construction of nitrogen-containing compounds from simple alkyne starting materials. Rhodium(II) tetracarboxylate salts are efficient catalysts for this reaction, in which an electrophilic rhodium nitrene is trapped by an alkyne, resulting in the formation of a new C–N bond and the generation of a reactive metallocarbene for cascade reaction. The reaction is tolerant of both alkyl and aryl substituents on the alkyne, and proceeds at room temperature in a variety of common solvents. The modular nature of the reaction allows for the rapid construction of congested bicyclic systems from remarkably simple alkyne starting materials.


C–N Bond Formation by C–H Functionalization via Metal-Catalyzed Nitrene Insertion

Mace Weldy, N.; Blakey, S. B in “Science of Synthesis”, Wiley VCH, 2015 In press

Enantioselective C-H Amination 

Boudét, N.; Blakey, S. In “Chiral Amine Synthesis, Methods, Developments and Applications”, T. C. Nugent Ed.; Wiley-VCH: Weinheim, 2010, p 377-396


6. Total Synthesis of Aplyronine C

Paterson, I.; Fink, S. J.; Lee, L. Y. W.; Atkinson, S. J.; Blakey, S. B. Org. Lett. 2013, 15, 3118. DOI: 10.1021/ol401327r

5. Total Synthesis of Diazonamide A

Knowles, R. R.; Carpenter, J.; Blakey, S. B.; Kayano, A.; Mangion, I. K.; Sinz, C. J.; MacMillan, D. W. C. M. Chem. Sci. 2011, 2, 308. DOI: 10.1039/C0SC00577K

4. The First Suzuki Cross-Couplings of Aryltrimethylammonium Salts 

Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 6046. DOI: 10.1021/ja034908b

3. Studies in marine macrolide synthesis: stereocontrolled synthesis of a C21-C34subunit of the aplyronines

Paterson, I.; Blakey, S. B.; Cowden, C. J. Tetrahedron Lett. 2002, 43, 6005. DOI: 10.1016/S0040-4039(02)01217-0

2. cis-1,2-Dihydrocatechols in Chemical Synthesis: First synthesis of L-ascorbic acid (vitamin C) from a non-carbohydrate source 

Banwell, M.; Blakey, S.; Harfoot, G.; Longmore, R. Aust. J. Chem. 1999, 52, 137. DOI: 10.1071/C98157

1. First synthesis of L-ascorbic acid (vitamin C) from a non-carbohydrate source

Banwell, M.; Blakey, S.; Harfoot, G.; Longmore, R. J. Chem. Soc., Perkin Trans. 1, 1998, 3141. DOI: 10.1039/A806062B