Atom-Economical Cross-Coupling of Internal and Terminal Alkynes to Access 1,3-Enynes

Selective carbon–carbon (C–C) bond formation in chemical synthesis generally requires pre-functionalized building blocks. However, the requisite pre-functionalization steps undermine the efficiency of multi-step synthetic sequences, which is particularly problematic in large-scale applications, such as in the commercial production of pharmaceuticals. Herein, we describe a selective and catalytic method for synthesizing 1,3-enynes without pre-functionalized building blocks. This method is facilitated by a tailored P,N-ligand that enables regioselective coupling and suppresses secondary <i>E</i>/<i>Z</i>-isomerization of the product. The transformation enables several classes of unactivated internal acceptor alkynes to be coupled with terminal donor alkynes to deliver 1,3-enynes in a highly regio- and stereoselective manner. The scope of compatible acceptor alkynes includes propargyl alcohols, (homo)propargyl amine derivatives, and (homo)propargyl carboxamides. The reaction is scalable and can operate effectively with 0.5 mol% catalyst loading. The products are versatile intermediates that can participate in various downstream transformations. We also present preliminary mechanistic experiments that are consistent with a redox-neutral Pd(II) catalytic cycle.

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5-Iodo-1H-1,2,3-triazoles as Versatile Building Blocks

Synthesis ◽

10.1055/s-0039-1690858 ◽

2020 ◽

Vol 52 (13) ◽

pp. 1874-1896 ◽

Cited By ~ 3

Author(s):

Irina A. Balova ◽

Natalia A. Danilkina ◽

Anastasia I. Govdi

Keyword(s):

Bond Formation ◽

Cross Coupling ◽

Building Blocks ◽

Terminal Alkynes ◽

Direct Arylation ◽

Halogen Exchange ◽

The Creation ◽

Radiolabeled Compounds ◽

Synthetic Approaches ◽

Synthetic Application

Copper-catalyzed azide–alkyne cycloaddition is a useful tool for the synthesis of both 1,2,3-triazoles and 5-iodo-1H-1,2,3-triazoles starting from either terminal alkynes or iodoalkynes. 5-Iodotriazoles have been recognized as very useful building blocks for the synthesis of diverse 1,4,5-trisubstituted 1,2,3-triazoles. Synthetic application of 5-iodo-1,2,3-triazoles through the creation of a new C–C, C–heteroatom, or C–D(T) bond along with the application areas of both iodotriazoles and products of their modification including radiolabeled compounds are discussed.1 Introduction2 Synthetic Approaches to 5-Iodo-1H-1,2,3-triazoles3 5-Iodotriazoles in C–C Bond Formation3.1 Intermolecular C–C Cross-Coupling3.2 Intramolecular Cross-Coupling: Direct Arylation and C–I/C–I Homocoupling3.3 Other Transformations4 5-Iodotriazoles in Radiolabeling, Halogen Exchange, and Heterocoupling Reactions5 Summary

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Palladium-catalyzed denitrative Sonogashira-type cross-coupling of nitrobenzenes with terminal alkynes

Chemical Communications ◽

10.1039/c9cc08663c ◽

2020 ◽

Vol 56 (5) ◽

pp. 790-793 ◽

Cited By ~ 8

Author(s):

Boya Feng ◽

Yudong Yang ◽

Jingsong You

Keyword(s):

Bond Formation ◽

Coupling Reaction ◽

Cross Coupling ◽

Terminal Alkynes ◽

Cross Coupling Reaction ◽

Palladium Catalyzed

Described herein is a palladium-catalyzed cross-coupling reaction between nitroarenes and terminal alkynes, offering a facile method for C(sp2)–C(sp) bond formation.

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Selective Manganese-Catalyzed Dimerization and Cross-Coupling of Terminal Alkynes

10.26434/chemrxiv.14204210 ◽

2021 ◽

Author(s):

Stefan Weber ◽

Luis F. Veiros ◽

Karl Kirchner

Keyword(s):

Dft Calculations ◽

Precious Metal ◽

Bond Cleavage ◽

Cross Coupling ◽

Metal Catalyst ◽

Catalyst Loading ◽

Terminal Alkynes ◽

Migratory Insertion ◽

Earth Abundant ◽

First Time

<div>For the first time, an efficient manganese-catalyzed dimerization of terminal alkynes to afford 1,3-enynes is described. This reaction is atom economic, implementing an inexpensive, earth abundant non-precious metal catalyst. The pre-catalyst is the bench-stable alkyl bisphosphine Mn(I) complex fac-[Mn(dippe)(CO)3(CH2CH2CH3)]. The catalytic process is initiated by migratory insertion of a CO ligand into the Mn-alkyl bond to yield an acyl intermediate which undergoes rapid C-H bond cleavage of the alkyne forming an active Mn(I) acetylide catalyst [Mn(dippe)(CO)2(C≡CPh)(η2-HC≡CPh)] together with liberated butanal. A range of aromatic and aliphatic terminal alkynes were efficiently and selectively converted into head-to-head Z-1,3-enynes and head-to-tail gem-1,3-enynes, respectively, in good to excellent yields. Moreover, cross-coupling of aromatic and aliphatic alkynes yields selectively head-to-tail gem-1,3-enynes. In all cases, the reactions were performed at 70 °C with a catalyst loading of 1-2 mol %. A mechanism based on DFT calculations is presented.</div><div><br></div>

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Concise syntheses of GB22, GB13 and himgaline by cross-coupling and complete reduction

10.26434/chemrxiv-2021-8nlfl ◽

2021 ◽

Author(s):

Eleanor Landwehr ◽

Meghan Baker ◽

Takuya Oguma ◽

Hannah Burdge ◽

Takahiro Kawajiri ◽

...

Keyword(s):

Chemical Synthesis ◽

Cross Coupling ◽

Building Blocks ◽

Class Iii ◽

Stereoselective Reduction ◽

Complete Reduction ◽

Variable Distribution ◽

High Fraction

Class III neuroactive metabolites from the bark of Galbu-limima belgraveana occur in variable distribution and are not easily procured by chemical synthesis. Here we decrease the synthetic burden of himgaline to nearly one-third of the prior best (7–9 vs. 19–31 steps) by cross-coupling high fraction aromatic (FAr) building blocks followed by com-plete, stereoselective reduction to high-fraction sp3 (Fsp3) products. This short entry into GB alkaloid space allows its extensive exploration and biological interrogation.

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Selective Manganese-Catalyzed Dimerization and Cross-Coupling of Terminal Alkynes

10.26434/chemrxiv.14204210.v1 ◽

2021 ◽

Author(s):

Stefan Weber ◽

Luis F. Veiros ◽

Karl Kirchner

Keyword(s):

Dft Calculations ◽

Precious Metal ◽

Bond Cleavage ◽

Cross Coupling ◽

Metal Catalyst ◽

Catalyst Loading ◽

Terminal Alkynes ◽

Migratory Insertion ◽

Earth Abundant ◽

First Time

<div>For the first time, an efficient manganese-catalyzed dimerization of terminal alkynes to afford 1,3-enynes is described. This reaction is atom economic, implementing an inexpensive, earth abundant non-precious metal catalyst. The pre-catalyst is the bench-stable alkyl bisphosphine Mn(I) complex fac-[Mn(dippe)(CO)3(CH2CH2CH3)]. The catalytic process is initiated by migratory insertion of a CO ligand into the Mn-alkyl bond to yield an acyl intermediate which undergoes rapid C-H bond cleavage of the alkyne forming an active Mn(I) acetylide catalyst [Mn(dippe)(CO)2(C≡CPh)(η2-HC≡CPh)] together with liberated butanal. A range of aromatic and aliphatic terminal alkynes were efficiently and selectively converted into head-to-head Z-1,3-enynes and head-to-tail gem-1,3-enynes, respectively, in good to excellent yields. Moreover, cross-coupling of aromatic and aliphatic alkynes yields selectively head-to-tail gem-1,3-enynes. In all cases, the reactions were performed at 70 °C with a catalyst loading of 1-2 mol %. A mechanism based on DFT calculations is presented.</div><div><br></div>

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Biocatalytic oxidative cross-coupling reactions for biaryl bond formation

10.33774/chemrxiv-2021-v0bv6-v2 ◽

2021 ◽

Author(s):

Lara Zetzsche ◽

Jessica Yazarians ◽

Suman Chakrabarty ◽

Meagan Hinze ◽

April Lukowski ◽

...

Keyword(s):

Asymmetric Catalysis ◽

Bond Formation ◽

Cross Coupling ◽

Building Blocks ◽

Coupling Reactions ◽

Cytochrome P450 Enzymes ◽

Cross Coupling Reactions ◽

Site Selectivity ◽

Valuable Compounds ◽

Selective Process

Despite their varied purposes, many indispensable molecules in medicine, materials, and asymmetric catalysis share a biaryl core. The necessity of joining arene building blocks to access these valuable compounds has inspired multiple approaches for biaryl bond formation and challenged chemists to develop increasingly concise and robust methods for this task. Oxidative coupling of two C–H bonds offers an efficient strategy for the formation of a biaryl C–C bond, however, fundamental challenges remain in controlling the reactivity and selectivity for uniting a given pair of substrates. Biocatalytic oxidative cross-coupling reactions have the potential to overcome limitations inherent to small molecule- mediated methods by providing a paradigm with catalyst-controlled selectivity. In this article, we disclose a strategy for biocatalytic cross-coupling through oxidative C–C bond formation using cytochrome P450 enzymes. We demonstrate the ability to catalyze cross-coupling reactions on a panel of phenolic substrates using natural P450 catalysts. Moreover, we engineer a P450 to possess the desired reactivity, site- selectivity, and atroposelectivity by transforming a low-yielding, unselective reaction into a highly efficient and selective process. This streamlined method for constructing sterically hindered biaryl bonds provides a programmable platform for assembling molecules with catalyst-controlled reactivity and selectivity.

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Fluorous Phases and Compressed Carbon Dioxide as Alternative Solvents for Chemical Synthesis: A Comparison

Green Chemistry Using Liquid and Supercritical Carbon Dioxide ◽

10.1093/oso/9780195154832.003.0009 ◽

2004 ◽

Author(s):

Walter Leitner

Keyword(s):

Carbon Dioxide ◽

Chemical Synthesis ◽

High Throughput Screening ◽

Large Scale ◽

Ecological Impact ◽

Reaction Medium ◽

Building Blocks ◽

Liquid Phases ◽

Synthetic Procedure ◽

Reaction Media

The principal goal of basic research in chemical synthesis is the development of efficient tools for functional group transformations and for the assembly of building blocks during the construction of molecules with increasing complexity. Traditionally, new approaches in this area have focused on the quest for new reaction pathways, reagents, or catalysts. Comparably less effort has been devoted to utilize the reaction medium as a strategic parameter, although the use of solvents is often crucial in synthetically useful transformations. The first choice for a solvent during the development of a synthetic procedure is usually an organic liquid, which is selected on the basis of its protic or aprotic nature, its polarity, and the temperature range in which the reaction is expected to proceed. Once the desired transformation is achieved, yield and selectivity are further optimized in the given medium by variation of temperature, concentration, and related process parameters. At the end of the reaction, the solvent must be removed quantitatively from the product using conventional workup techniques like aqueous extraction, distillation, or chromatography. If the synthetic procedure becomes part of a large-scale application, the solvent can sometimes be recycled, but at least parts of it will ultimately end up in the waste stream of the process. Increasing efforts to develop chemical processes with minimized ecological impact and to reduce the emission of potentially hazardous or toxic organic chemicals have stimulated a rapidly growing interest to provide alternatives to this classical approach of synthesis in solution. At the same time, researchers have started to realize that the design and utilization of multifunctional reaction media can add a new dimension to the development of synthetic chemistry. In particular, efficient protocols for phase separations and recovery of reagents and catalysts are urgently required to provide innovative flow schemes for environmentally benign processes or for high-throughput screening procedures. Fluorous liquid phases and supercritical carbon dioxide (sc CO2) have received particular attention among the various reaction media that are discussed as alternatives to classical organic solvents. The aim of this chapter is to compare these two media directly and to critically evaluate their potential for synthetic organic chemistry.

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Pd-catalyzed cross-coupling of terminal alkynes with ene-yne-ketones: access to conjugated enynes via metal carbene migratory insertion

Chemical Communications ◽

10.1039/c5cc03559g ◽

2015 ◽

Vol 51 (56) ◽

pp. 11233-11235 ◽

Cited By ~ 40

Author(s):

Ying Xia ◽

Zhen Liu ◽

Rui Ge ◽

Qing Xiao ◽

Yan Zhang ◽

...

Keyword(s):

Bond Formation ◽

Cross Coupling ◽

Terminal Alkynes ◽

Conjugated Enynes ◽

Migratory Insertion ◽

Insertion Process

Pd-catalyzed oxidative cross-coupling of terminal alkynes with ene-yne-ketones has been developed, in which the ene-yne-ketones are served as carbene precursors and metal carbene migratory insertion process is the key step for C–C bond formation.

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