Hydroamination Of Alkynes Research Articles

Indium(III)-Catalyzed Synthesis of Pyrroles and Benzo[g]indoles by Intramolecular Cyclization of Homopropargyl Azides.

Pyrroles, privileged structural motifs in drug and material science, have been synthesized by indium(III)-catalyzed intramolecular cyclization of homopropargyl azides. This methodology exhibits a broad substrate scope, providing substituted pyrroles and bispyrroles in good yields. Furthermore, an atom-economical sequential method for the synthesis of benzo[g]indoles has been discovered from azido-diynes using InCl3 as catalyst. The method involves two successive intramolecular indium-catalyzed 5-endo-dig alkyne hydroamination and a hydroarylation reactions with 6-endo-dig regioselectivity.

Increasing the Donor Strength of Alkenylphosphines by Twisting the C=C Double Bond.

Electron-rich phosphines play a crucial role in transition metal-based homogeneous catalysis. While alkyl groups have traditionally been employed to increase the phosphine donor strength, recent studies have shown that zwitterionic functional groups such as phosphorus ylides can result in a further enhancement. Herein we report the concept of twisting a C=C double bond to introduce a zwitterionic substituent by the synthesis and application of N-heterocyclic olefin phosphines with a sulfonyl substituent (sNHOP). This sulfonyl group enables the twisting of the olefin moiety due to steric and electronic stabilization of the carbanionic center. The resulting zwitterionic structure leads to a significant increase of the donor strength of the sNHOP ligands compared to conventional NHOP systems with a planar N-heterocyclic olefin moiety. The potential of this new ligand platform for catalysis is demonstrated by its application in the gold-catalyzed hydroamination and cyclo-isomerization of alkynes. Here, the ligands outperform the original NHOP ligands suggesting favorable properties for future catalysis applications.

Gold-catalysed amine synthesis by reductive hydroamination of alkynes with nitroarenes.

Amines are the most pivotal class of organic motifs in pharmaceutical compounds. Here we provide a blueprint for a general synthesis of amines by catalyst differentiation enabled by triple Au-H/Au+/Au-H relay catalysis. The parent catalyst is differentiated into a set of catalytically active species to enable triple cascade catalysis, where each catalytic species is specifically tuned for one catalytic cycle. This strategy enables the synthesis of biorelevant amine motifs by reductive hydroamination of alkynes with nitroarenes. Using this triple cascade approach, we have achieved exceptional functional group tolerance, enabling the use of bulk chemical feedstocks as coupling partners for the amination of both simple and complex alkynes (>100 examples), including those derived from pharmaceuticals, peptides and natural products (>30 examples). The isolation and full crystallographic characterization of gold hydride and hydride-bridged gold complexes has garnered insights into the catalyst differentiation process of fundamental organometallic gold hydride complexes.

Doubly Stereoconvergent Propargylic Alkylation of α-Cyanocarbonyls: Enantioselective Construction of Vicinal Stereocenters.

An asymmetric propargylic alkylation of α-cyanocarbonyls is developed for the first time under cooperative Cu(I) and organocatalysis. With ethynyl benzoxazinanones as the propargylic electrophile, this decarboxylative doubly stereoconvergent reaction evades alkyne hydroamination to furnish acyclic α-propargylic cyanocarbonyls, bearing vicinal tertiary and quaternary stereocenters, with high diastereo- and enantioselectivity (up to >20:1 dr and 99.5:0.5 er).

Advancing the design of heterogeneous catalyst: Copper-montmorillonite for regioselective alkyne hydroamination

Transition metal catalysts supported on natural materials offer promising avenues for sustainable organic synthesis. In this study, we present the synthesis, characterisation, and catalytic performance of copper nanoparticles supported on montmorillonite K10 (CuMK10) as a heterogeneous catalyst for hydroamination reactions. CuMK10, synthesised through a robust and established nanoparticle synthesis methodology, demonstrates remarkable catalytic efficiency and selectivity in the synthesis of imines via hydroamination of terminal alkynes. The catalyst exhibits exceptional regioselectivity, predominantly yielding Markovnikov products, demonstrating its potential as a versatile tool in organic synthesis. Moreover, CuMK10 shows favourable reusability, offering economic benefits and practical utility due to its ease of recovery and reuse. Comprehensive structural and mechanistic studies provide insights into the catalyst's performance, paving the way for the development of efficient and environmentally benign catalytic systems.

Alkyne Hydroamination Inhibited by Vinylidene Deactivation

Alkyne Hydroamination Inhibited by Vinylidene Deactivation

Influence of Ylide Functionalization on the Catalytic Performance of Ferrocenyldiphosphines in Au(I)‐Catalyzed Hydroaminations and Hydrohydrazinations

Ylide‐functionalized phosphines (YPhos) have been shown to yield highly active gold catalysts owing to their high donor capacity. To examine the impact of ylide functionalization on a given ligand structure, a series of ferrocenyl diphosphines functionalized with no, one or two ylide moieties and their corresponding bimetallic gold complexes were prepared. The complexes feature an anti‐conformation of the two phosphine moieties, guaranteeing the presence of two independent metal centers. Comparative studies of the complexes in the hydroamination and hydrohydrazination of alkynes revealed a significant increase in catalytic activity for each newly introduced ylide group. The di‐YPhos ligands were revealed to be the most active precatalysts, functioning effectively even at 0.1 or 0.2 mol% catalyst loading. This catalytic efficiency was demonstrated for a series of alkynes, amines and hydrazines.

Modeling Complex Ligands for High Oxidation State Catalysis: Titanium Hydroamination with Unsymmetrical Ligands.

A method for modeling high oxidation state catalysts is used on precatalysts with unsymmetrical and symmetrical bidentate ligands to get a more detailed understanding of how changes to ancillary ligands affect the hydroamination of alkynes catalyzed by titanium. To model the electronic donor ability, the ligand donor parameter (LDP) was used, and to model the steric effects, percent buried volume (% Vbur) was employed. For the modeling study, 7 previously unpublished unsymmetrical Ti(XX')(NMe2)2 precatalysts were prepared, where XX' is a chelating ligand with pyrrolyl/indolyl linkages. The rates of these unsymmetrical and 10 previously reported symmetrical precatalysts were used with the model kobs = a + b(LDP)1 + c(LDP)2 + d(% Vbur)1 + e(% Vbur)2, where a-e were found through least-squares refinement. The model suggests that (1) the two attachment points of the bidentate ligand XX' are in different environments on the metal (e.g., axial and equatorial in a trigonal bipyramidal or square pyramidal structure), (2) the position of the unsymmetrical ligand on the metal is determined by the electronics of the ligand rather than the sterics, and (3) that one side of the chelating ligand's electronics strongly influences the rate, while the other side's sterics more strongly influences the rate. From these studies, we were able to generate catalysts fitting to this model with rate constants larger than the fastest symmetrical catalyst tested.

Copper(I) complexes of 1,2-bis(diphenylphosphino)benzene as efficient catalysts for alkyne hydroamination and azide-alkyne cycloaddition

This paper reports the synthesis of a small group of three copper(I) complexes using 1,2-bis(diphenylphosphino)benzene, abbreviated as dppbz, and their utilization as catalyst for CN bond formation reactions. Reaction of dppbz has been carried out with three different copper(I) sources. While reaction with [Cu(CH3CN)4]ClO4 affords [CuI(dppbz)2]ClO4 (complex 1), that with CuI and CuSCN affords di-copper complexes [{CuI(dppbz)I}2] and [{CuI(dppbz)(SCN)}2] (complexes 2 and 3) respectively. Bulk characterization on the complexes has been done by elemental (C, H, N) analysis, magnetic susceptibility measurement, and spectroscopic (IR, NMR and UV–vis) methods. Crystal structures of all three complexes have been determined. In [CuI(dppbz)2]ClO4, copper(I) is having a highly distorted tetrahedral CuP4 core. In [{CuI(dppbz)I}2] and [{CuI(dppbz)(SCN)}2], the tetrahedral CuP2I2 and CuP2SN cores are relatively less distorted. These copper complexes have been found to serve as efficient catalyst precursors for two types of CN bond formation reactions, viz. hydroamination and click reaction. Hydroamination of aryl alkynes with aryl amines has afforded selectively imine products of a single type (Markownikov product) in good yields under relatively mild condition. However, similar hydroamination with benzyl amines or alkyl amines has afforded selectively anti-Markownikov imine products. Click reaction between aryl alkynes and aryl azides yielding the cycloaddition products has also been brought about successfully with remarkable catalytic efficiency.

Hydroamination of alkynes catalyzed by NHC-Gold(I) complexes: the non-monotonic effect of substituted arylamines on the catalyst activity.

Imines are valuable key compounds for synthesizing several nitrogen-containing molecules used in biological and industrial fields. They have been obtained, as highly regioselective Markovnikov products, by reacting several alkynes with arylamines in the presence of three new N-Heterocyclic carbene gold(I) complexes (3b, 4b, and 6b) together with the known 1-2b and 7b gold complexes as well as silver complexes 1-2a. Gold(I) complexes were investigated by means of NMR, mass spectroscopy, elemental analysis, and X-ray crystallographic studies. Accurate screening of co-catalysts and solvents led to identifying the best reaction conditions and the most active catalyst (2b) in the model hydroamination of phenylacetylene with aniline. Complex 2b was then tested in the hydroamination of alkynes with a wide variety of arylamines yielding a lower percentage of product when arylamines with both electron-withdrawing and electron-donating substituents were involved. Computational studies on the rate-determining step of hydroamination were conducted to shed light on the significantly different yields observed when reacting arylamines with different substituents.

Recent Advances in Domino Synthesis of Fused Polycyclic N‐Heterocycles Based on Intramolecular Alkyne Hydroamination under Copper Catalysis

Comprehensive SummaryFused polycyclic N‐heterocycles are very important scaffolds in biomedicinal chemistry and materials science. Intramolecular alkyne hydroamination is a powerful method for the construction of N‐heterocycles. In the last two decades, copper‐catalyzed domino reactions based on intramolecular alkyne hydroamination has emerged as a robust strategy for assembling various fused polycyclic N‐heterocycles. Great progress has been achieved in this area. This short review covers the advances made in copper‐catalyzed domino synthesis of fused polycyclic N‐heterocycles based on the strategy from 2008 to 2023, and will hopefully serve as an inspiration towards the exploration of new copper‐catalyzed versions of the transformation. The domino transformations are introduced and discussed from five aspects according to the different key processes involved in these reactions.

Double Hydroamination of Terminal Alkynes over Beta Zeolite‐Supported CuO Catalyst

AbstractAn effective and novel heterogeneous beta zeolite supported CuO (Cuβ) catalyzed double hydroamination of alkynes for the synthesis of 2,3‐dihydroquinazolin‐4(1H)‐ones has been achieved in a solvent‐free condition. Cuβ zeolite was synthesized by impregnation method. The synthesized Cuβ was characterized by X‐ray diffraction, Fourier transformation infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, and X‐ray photoelectron spectroscopy. Pure Hβ (18 % yield) or Nano CuO (44 % yield) displayed poor catalytic activity, whereas 1 % Cuβ (96 % yield) showed higher catalytic activity for double hydroamination of alkynes due to the synergistic effect of CuO and Hβ zeolite in the reaction. The new protocol offers an appealing approach to a number of di‐substituted quinazolinones with decent to excellent yields. The catalyst has been successfully recycled for up to 5 consecutive cycles.

Iridium-catalyzed reductive hydroamination of terminal alkynes in water

Herein, we report an efficient one-pot iridium-catalyzed reductive hydroamination of terminal alkynes with amines. A variety of primary amines and secondary amines are amenable to this catalytic system, leading to the complicated aliphatic amines in excellent yields. More broadly, this straightforward and convenient transformation do not just employ inexpensive and easy to handle HCO2H as reducing agent, but also employs H2O as reaction media, which makes this strategy be in accordance with green and sustainable chemistry principles.

Regio‐ and Z‐Selective Alkyne Hydroamination and Hydrophenoxylation using Tetrafluoro‐λ6‐Sulfanyl Alkynes under Superbasic, Naked Anion Conditions

AbstractAlkyne hydroamination is an effective approach for the production of enamines and enamine‐containing N‐heterocycles. However, stereoselectivity control is a considerable challenge in this reaction because of the electronic repulsion between an incoming nitrogen lone pair and the alkyne π‐system. Herein, we propose a methodology involving β‐regio‐ and Z‐selective alkyne hydroamination by using tetrafluoro‐λ6‐sulfanyl (SF4) alkynes under superbasic, naked anion conditions. The reaction is compatible with a wide variety of N‐heterocycles, including indoles, carbazoles, pyrazoles, and imidazoles, and selectively furnishes SF4‐linked Z‐vinyl enamines with β‐regioselectively. Moreover, the method can be extended to the β‐ and Z‐controlled, base‐mediated alkyne hydrophenoxylation with phenols to provide SF4‐linked Z‐vinyl ethers in high yields. As the SF4 unit has attracted attention as a bioisostere for alkynes, p‐benzenes, bicyclo[1.1.1]pentyl (BCP) groups, and cubanes in medicinal chemistry, this chemistry represents an effective approach to creating novel drug candidates incorporating SF4‐containing molecules.

Regio- and Z-Selective Alkyne Hydroamination and Hydrophenoxylation using Tetrafluoro-λ6 -Sulfanyl Alkynes under Superbasic, Naked Anion Conditions.

Alkyne hydroamination is an effective approach for the production of enamines and enamine-containing N-heterocycles. However, stereoselectivity control is a considerable challenge in this reaction because of the electronic repulsion between an incoming nitrogen lone pair and the alkyne π-system. Herein, we propose a methodology involving β-regio- and Z-selective alkyne hydroamination by using tetrafluoro-λ6 -sulfanyl (SF4 ) alkynes under superbasic, naked anion conditions. The reaction is compatible with a wide variety of N-heterocycles, including indoles, carbazoles, pyrazoles, and imidazoles, and selectively furnishes SF4 -linked Z-vinyl enamines with β-regioselectively. Moreover, the method can be extended to the β- and Z-controlled, base-mediated alkyne hydrophenoxylation with phenols to provide SF4 -linked Z-vinyl ethers in high yields. As the SF4 unit has attracted attention as a bioisostere for alkynes, p-benzenes, bicyclo[1.1.1]pentyl (BCP) groups, and cubanes in medicinal chemistry, this chemistry represents an effective approach to creating novel drug candidates incorporating SF4 -containing molecules.

Anti-Markovnikov Intermolecular Hydroamination of Alkenes and Alkynes: A Mechanistic View.

Hydroamination, the addition of an N-H bond across a C-C multiple bond, is a reaction with a great synthetic potential. Important advances have been made in the last decades concerning catalysis of these reactions. However, controlling the regioselectivity in the amine addition toward the formation of anti-Markovnikov products (addition to the less substituted carbon) still remains a challenge, particularly in intermolecular hydroaminations of alkenes and alkynes. The goal of this review is to collect the systems in which intermolecular hydroamination of terminal alkynes and alkenes with anti-Markovnikov regioselectivity has been achieved. The focus will be placed on the mechanistic aspects of such reactions, to discern the step at which regioselectivity is decided and to unravel the factors that favor the anti-Markovnikov regioselectivity. In addition to the processes entailing direct addition of the amine to the C-C multiple bond, alternative pathways, involving several reactions to accomplish anti-Markovnikov regioselectivity (formal hydroamination processes), will also be discussed in this review. The catalysts gathered embrace most of the metal groups of the Periodic Table. Finally, a section discussing radical-mediated and metal-free approaches, as well as heterogeneous catalyzed processes, is also included.

Potassium t‐Butoxide‐Promoted Metal‐Free Synthesis of Pyrazino[1,2‐a]indoles via Direct Amidation and Intramolecular Hydroamination Reaction

AbstractA library of pyrazino[1,2‐a]indoles has been synthesized via direct amidation and alkyne hydroamination reactions of the molecule produced by indole‐2‐carboxylic acid and propargyl bromide. The noteworthy features of the present strategy are short reaction time, excellent yields and a broad substrate scope. This cascade reaction also occurred under transition metal‐free and ambient conditions as well as operational simplicity.

Synthesis of Ti Complexes Supported by an ortho-terphenoxide Ligand and their Applications in Alkyne Hydroamination Catalysis.

The synthesis of a series of Ti complexes of an aryl-linked bis-phenoxide ligand, 3,3''-di-tert-butyl-5,5''-dimethyl-[1,1':2',1''-terphenyl]-2,2''-bis(olate), (TPO)H2, is reported. This ortho-linked terphenyl ligand builds on previously reported meta- and para- linked terphenyl based ligands, completing the isomeric series of terphenoxide ligands. The 4-coordinate (TPO)Ti(NMe2)2 is an active catalyst for alkyne hydroamination with a variety of arylamines, revealing good regioselectivity in reactions with unsymmetric alkynes. Terminal alkynes such as phenylacetylene undergo additional insertion reactions with the key azatitanacyclobutene intermediates, providing further evidence that Ti aryloxide complexes are susceptible to this further reactivity.

On the Edge of the Known: Extremely Electron-Rich (Di)Carboranyl Phosphines.

The syntheses of the first B9-connected carboranylphosphines (B9-Phos) featuring two carboranyl moieties as well as access to B9-Phos ligands with bulky electron-donating substituents, previously deemed unattainable, is reported. The electrochemical properties of the B9-Phos ligands were investigated, revealing the ability of the mesityl derivatives to form stabilized phosphoniumyl radical cations. The B9-Phos ligands display an extremely electron-releasing character surpassing that of alkyl phosphines and commonly used N-heterocyclic carbenes. This is demonstrated by their very small Tolman electronic parameters (TEPs) as well as extremely low P-Se coupling constants. Cone angles and buried volumes attest to the high steric demand exerted by the (di)carboranyl phosphines. The dicarboranyl phosphine AuI complexes show superior catalytic performance in the hydroamination of alkynes compared to the monocarboranyl phosphine analogs.

One-Pot Sequential Hydroamination Protocol for N-Heterocycle Synthesis: One Method To Access Five Different Classes of Tri-Substituted Pyridines

Tri-substituted pyridines are important scaffolds that can be found in a plethora of commercially available drugs. A one-pot general method for the selective synthesis of less explored/challenging patterns of tri-substituted pyridines is described. Hydroamination of alkynes with commercially available N-triphenylsilylamine generates N-silylenamines. These in situ generated N-silylenamines, upon reaction with α,β-unsaturated carbonyl compounds and subsequent oxidation, furnish 25 examples of selectively substituted 2,4,5-, 2,3,4-, 3,4,5-, 2,3,5-, and 2,3,6-trisubstituted pyridines in up to 78% yield. The reaction features high functional group compatibility providing an expeditious and general approach for the assembly of selectively substituted tri-substituted pyridine derivatives. The robustness and practicality of the reaction have been demonstrated in a gram-scale reaction.