Zinc(II)-catalyzed redox cross-dehydrogenative coupling of propargylic amines and terminal alkynes for synthesis of N-tethered 1,6-enynes

The zinc(II)-catalyzed redox cross-dehydrogenative coupling (CDC) of propargylic amines and terminal alkynes proceeds to afford N-tethered 1,6-enynes. In the current CDC reaction, a C(sp)-C(sp(3)) bond is formed between the carbon adjacent to the nitrogen atom in the propargylic amine and the terminal carbon of the alkyne with reduction of the C-C triple bond of the propargylic amine, which acts as an internal oxidant.     

Enantioselective Palladium‐Catalyzed Carbonylative Carbocyclization of Enallenes via Cross‐Dehydrogenative Coupling with Terminal Alkynes: Efficient Construction of α‐Chirality of Ketones

An enantioselective Pd^II/Brønsted acid‐catalyzed carbonylative carbocyclization of enallenes ending with a cross‐dehydrogenative coupling (CDC) with a terminal alkyne was developed. VAPOL phosphoric acid was found as the best co‐catalyst among the examined 28 chiral acids, for inducing the enantioselectivity of α‐chiral ketones. As a result, a number of chiral cyclopentenones were easily synthesized in good to excellent enantiomeric ratio with good yields.     

Zinc‐Catalyzed Dehydrogenative Cross‐Coupling of Terminal Alkynes with Aldehydes: Access to Ynones

Because of the lack of redox ability, zinc has seldom been used as a catalyst in dehydrogenative cross‐coupling reactions. Herein, a novel zinc‐catalyzed dehydrogenative C(sp²)? H/C(sp)? H cross‐coupling of terminal alkynes with aldehydes was developed, and provides a simple way to access ynones from readily available materials under mild reaction conditions. Good reaction selectivity can be achieved with a 1:1 ratio of terminal alkyne and aldehyde. Various terminal alkynes and aldehydes are suitable in this transformation.     

Directing‐Group‐mediated C−H‐Alkynylations

C?C triple bonds are amongst the most versatile functional groups in synthetic chemistry. Complementary to the Sonogashira coupling the direct metal‐catalyzed alkynylation of C?H bonds has emerged as a highly promising approach in recent years. To guarantee a high regioselectivity suitable directing groups (DGs) are necessary to guide the transition metal (TM) into the right place. In this Focus Review we present the current developments in DG‐mediated C(sp²)?H and C(sp³)?H modifications with terminal alkynes under oxidative conditions and with electrophilic alkynylation reagents. We will discuss further modifications of the alkyne, in particular subsequent cyclizations to carbo‐ and heterocycles and modifications of the DG in the presence of the alkyne.     

Synthesis of steroidal dendrimers modified by ‘click’ chemistry with PAMAM dendrons as unimolecular micelles

Novel Fréchet–PAMAM hybrid dendrimers linked by triazole units as unimolecular micelles with a hydrophobic core surrounded by a hydrophilic shell were prepared. The dendritic cores with 3 and 6 alkyne terminal groups were synthesized from 1,3,5-tribromomethyl-benzene (tBrMeB), in one case by direct coupling with 17α-ethynylestradiol (EE); in the second one the tBrMeB was reacted with bis(hydroxymethyl) phenol followed by chlorination of the hydroxyl groups and subsequent coupling to EE. With this strategy, the core can be grown by further substitutions of bis(hydroxymethyl) phenol over the halogenated terminals as Fréchet dendrimer. The hydrophilic shells used were PAMAM type dendrons of 0.5 and 1.5 generations with azide as focal point and tert-butyl ester as end groups. The unimolecular micelles were obtained by cycloaddition between an azide in the selected dendron and the alkyne terminal in the hydrophobic core to obtain a 1,4-disubstituted 1,2,3-triazole. Once the coupling was achieved, the tert-butyl ester groups were hydrolyzed in trifluoroacetic acid and the corresponding dendrimers with carboxylic acid as end groups were completely soluble in phosphate buffer solutions of pH 7.0, 7.4, and 8.0. All hybrid dendrimers were characterized by High Resolution Mass Spectrometry, ¹H and ¹³C NMR, and FTIR.     

Analysis of Density‐Dependent Binding of Glycans by Lectins Using Carbohydrate Microarrays

To investigate the density‐dependent binding of glycans by lectins using carbohydrate microarrays, a number of C‐terminal hydrazide‐conjugated neoglycopeptides with various valences and different spatial arrangements of the sugar ligands were prepared on a solid support. The synthetic strategy includes (1) assembly of alkyne‐linked peptides possessing C‐terminal hydrazide on a solid support, (2) coupling of azide‐linked, unprotected sugars to the alkyne‐linked peptides on the solid support utilizing click chemistry, and (3) release of the neoglycopeptides from the solid support. By using this synthetic methodology, sixty five neoglycopeptides with a valency ranging from 1 to 4 and different spatial arrangements of the carbohydrate ligands were generated. Carbohydrate microarrays were constructed by immobilizing the prepared neoglycopeptides on epoxide‐derivatized glass slides and were used to analyze the density‐dependent binding of glycans by lectins. The results of binding property determinations show that lectin binding is highly dependent on the surface glycan density.     

Palladium‐Catalyzed Cross‐Dehydrogenative Functionalization of C(sp2)H Bonds

The catalytic cross‐dehydrogenative coupling (CDC) reaction has received intense attention in recent years. The attractive feature of this coupling process is the formation of a C? C bond from two C? H moieties under oxidative conditions. In this Focus Review, recent advances in the palladium‐catalyzed CDC reactions of C(sp²)? H bond are summarized, with a focus on the period from 2011 to early 2013.     

Total Synthesis,Stereochemical Assignment,and Biological Activity of Chamuvarinin and Structural Analogues

A highly stereocontrolled synthesis of (+)‐chamuvarinin has been completed in 1.5 % overall yield over 20 steps. The key fragment coupling reactions were the addition of alkyne 8 to aldehyde 7 (under Felkin–Anh control), followed by the two step activation/cyclization to close the C20–C23 2,5‐cis‐substituted tetrahydrofuran ring and a Julia–Kocienski olefination at C8–C9 to introduce the terminal butenolide. The inherent flexibility of our coupling strategy led to a streamlined synthesis with 17 steps in the longest sequence (2.2 % overall yield), in which the key bond couplings are reversed. In addition, a series of structural analogues of chamuvarinin have been prepared and screened for activity against HeLa cancer cell lines and both the bloodstream and insect forms of Trypanosoma brucei, the parasitic agent responsible for African sleeping sickness.     

NMR Spectroscopic Observation of a Metal‐Free Acetylide Anion

A metal‐free acetylide was observed by using NMR spectroscopy. Metal‐free acetylides are closely related to reactive intermediates (carbanions) in solution; therefore, they have been regarded as unobservable species. However, we generated this highly reactive and unstable species through the deprotonation of phenylacetylene by using the strong nonmetallic phosphazene base tBu‐P4. In the presence of tBu‐P4, the J coupling between the ethynyl carbon and hydrogen nuclei (¹J_C,H) of phenylacetylene disappeared; this indicates the deprotonation of the alkyne terminal. Furthermore, a large low‐field shift (approximately 90 ppm) of the alkyne carbon resonance was observed. We concluded that we have observed a metal‐free carbanion with a formal charge on an sp‐hybridized carbon atom for the first time.     

Highlight: Stereoselective Cross‐Dehydrogenative Coupling Reactions Based on Sp3 C―H Activation to Give Chiral Heterocyclic Compounds

Stereoselective cross‐dehydrogenative coupling (CDC) reactions based on sp³ C—H activation for functionalization of heterocycles were introduced. It is an efficient, economical and convenient strategy for functionalization of heterocycles.     

‘Clickable’ cyclopentadienyl iron carbonyl complexes for bioorthogonal conjugation of mid‐infrared labels to a model protein and PAMAM dendrimer

Owing to the intrinsic limitations of the conventional bioconjugation methods involving native nucleophilic functions of proteins, we sought to develop alternative approaches to introduce metallocarbonyl infrared labels onto proteins on the basis of the [3 + 2] dipolar azide‐alkyne cycloaddition (AAC). To this end, two cyclopentadienyl iron dicarbonyl (Fp) complexes carrying a terminal or a strained alkyne handle were synthesized. Their reactivity was examined towards a model protein and poly (amidoamine) (PAMAM) dendrimer, both carrying azido groups. While the copper (I)‐catalysed azide‐alkyne cycloaddition (CuAAC) proceeded smoothly with the terminal alkyne metallocarbonyl derivative, labelling by strain‐promoted azide‐alkyne cycloaddition (SPAAC) was less successful in terms of final coupling ratios. Infrared spectral characterization of the bioconjugates showed the presence of two bands in the 2000 cm^?1 region, owing to the stretching vibration modes of the carbonyl ligands of the Fp entities.     

Synthesis of N‐Arylated 1,2‐Dihydroheteroaromatics Through the Three‐Component Reaction of Arynes with N‐Heteroaromatics and Terminal Alkynes or Ketones

The reaction of benzynes with N‐heteroaromatics including quinolines, isoquinolines, and pyridines and various terminal alkynes or ketones with an α‐hydrogen in the presence of KF and 18‐crown‐6 in THF at room temperature for 8 h gave various N‐arylated 1,2‐dihydroheteroaromatics in good to moderate yields. Some of these product structures are found in various naturally occurring and biologically active heterocyclic compounds. The reaction involves an unusual multiple construction of new C? C, C? N, and C? H bonds and the cleavage of a C? H bond in one pot. It is likely that the three‐component coupling proceeds through the nucleophilic addition of quinoline to benzyne, which generates a zwitterionic species. The latter then attracts a proton from terminal alkyne (or ketone) to generate an N‐arylated quinolinium cation and an acetylide anion. Further reaction of these two ions provides the final substituted 1,2‐dihydroquinolines. In the reaction, the terminal alkyne acts first as a proton donor and then as a nucleophile. The application of a three‐component coupling reaction product, 1,2‐dihydro‐2‐pyridinyl alkyne in a stereospecific [4+2] Diels–Alder cycloaddition reaction with N‐phenyl maleimide to give an isoquinuclidine derivative, an important core present in various natural products, is demonstrated.     

Catalyst‐Free Three‐Component Tandem CDC Cyclization: Convenient Access to Isoindolinones from Aromatic Acid,Amides, and DMSO by a Pummerer‐Type Rearrangement

A catalyst‐free multicomponent CDC reaction is rarely reported, especially for the intermolecular tandem CDC cyclization, which represents an important strategy for constructing cyclic compounds. Herein, a three‐component tandem CDC cyclization by a Pummerer‐type rearrangement to afford biologically relevant isoindolinones from aromatic acids, amides, and DMSO, is described. This intermolecular tandem reaction undergoes a C(sp²)?H/C(sp³)?H cross‐dehydrogenative coupling, C?N bond formation, and intramolecular amidation. A notable feature of this novel protocol is avoiding a catalyst and additive (apart from oxidant).     

Studies on Cu-catalyzed asymmetric alkynylation of tetrahydroisoquinoline derivatives

Enantioselective C–C bond formations between the sp³ C–H bond of prochiral CH₂ and terminal alkynes via the cross-dehydrogenative coupling (CDC) reaction were studied. Efficient asymmetric syntheses of alkynyl tetrahydroisoquinoline derivatives were achieved by using a catalytic amount of CuOTf together with PyBox chiral ligand. When dihydroisoquinolinium salts were used as electrophiles, the combination of CuBr/QUINAP provided the best results for asymmetric syntheses of alkynyl tetrahydroisoquinoline derivatives. The factors influencing the enantioselectivity were studied.     

CuI–Zn(OAc)2 catalyzed C(sp2)–H activation for the synthesis of pyridocoumarins through an uncommon CuI–CuIII switching mechanism: A fast,solvent-free,combo-catalytic,ball milling approach

CuI–Zn(OAc)₂ catalyzed, a fast, solvent-free synthetic protocol has been developed for the oxidative C–C and C–N coupling via C(sp²)–H activation. In this work, an aldehyde, terminal alkyne and 3-aminocoumarin were coupled together to form pyridocoumarin framework through a greener ball milling process under very mild condition. In contrast to the frequently used imine-alkyne cyclization reactions, this uncommon mild Cu^I–Cu^III switching combo-catalysis is expected to proceed through the formation of a flexible propargylic amine intermediate, which leads to a rapid C(sp²)–H activation for cyclization involving transient Cu^III species. The in-situ formation of transient Cu^III species was confirmed through ultraviolet–visible spectroscopy (UV–Vis), electrospray ionization mass spectrometry (ESI-MS), and X-ray photoelectron spectroscopy (XPS) analyses of the reaction mixture.     

Photoredox catalyzed C(sp3)C(sp) coupling of dihydropyridines and alkynylbenziodoxolones

A visible light mediated deformylative alkynylation of aldehydes is presented. Under photo irradiation, 1,4-dihydropyridine (DHP), derived from an aldehyde, generated a C(sp³)- radical which couples with an alkynylbenziodoxolone to generate an alkyl substituted alkyne coupling product. This strategy is mild and easy to operate, a wide range of functional groups were tolerated, and 16 examples of products with 35–86% yields were obtained.     

Pyridine‐Enhanced Head‐to‐Tail Dimerization of Terminal Alkynes by a Rhodium–N‐Heterocyclic‐Carbene Catalyst

A general regioselective rhodium‐catalyzed head‐to‐tail dimerization of terminal alkynes is presented. The presence of a pyridine ligand (py) in a Rh–N‐heterocyclic‐carbene (NHC) catalytic system not only dramatically switches the chemoselectivity from alkyne cyclotrimerization to dimerization but also enhances the catalytic activity. Several intermediates have been detected in the catalytic process, including the π‐alkyne‐coordinated Rh^I species [RhCl(NHC)(η²‐HC?CCH₂Ph)(py)] ( 3 ) and [RhCl(NHC){η²‐C(tBu)?C(E)CH?CHtBu}(py)] ( 4 ) and the Rh^III–hydride–alkynyl species [RhClH{? C?CSi(Me)₃}(IPr)(py)₂] ( 5 ). Computational DFT studies reveal an operational mechanism consisting of sequential alkyne C? H oxidative addition, alkyne insertion, and reductive elimination. A 2,1‐hydrometalation of the alkyne is the more favorable pathway in accordance with a head‐to‐tail selectivity.     

A simple catalyst system for the palladium-catalyzed coupling of aryl halides with terminal alkynes

A convenient catalyst system consisting of Pd(OAc)₂, PPh₃, K₃PO₄ and DMSO was found to be effective for the coupling reaction of aryl halides with terminal alkynes as well as the deacetonative coupling reaction using a 4-aryl-2-methylbut-3-yn-2-ol as a terminal alkyne precursor. An iminophosphine as a ligand worked more effectively for some combination of substrates than triphenylphosphine.     

One‐Pot Tandem Photoredox and Cross‐Coupling Catalysis with a Single Palladium Carbodicarbene Complex

The combination of conventional transition‐metal‐catalyzed coupling (2 e^? process) and photoredox catalysis (1 e^? process) has emerged as a powerful approach to catalyze difficult cross‐coupling reactions under mild reaction conditions. Reported is a palladium carbodicarbene (CDC) complex that mediates both a Suzuki–Miyaura coupling and photoredox catalysis for C?N bond formation upon visible‐light irradiation. These two catalytic pathways can be combined to promote both conventional transition‐metal‐catalyzed coupling and photoredox catalysis to mediate C?H arylation under ambient conditions with a single catalyst in an efficient one‐pot process.     

Rhodium(II)‐Catalyzed Annulation of Azavinyl Carbenes Through Ring‐Expansion of 1,3,5‐Trioxane: Rapid Access to Nine‐Membered 1,3,5,7‐Trioxazonines

The rhodium(II)‐catalyzed denitrogenative coupling of N‐alkylsulfonyl 1,2,3‐triazoles with 1,3,5‐trioxane led to nine‐membered‐ringed trioxazonines in moderate‐to‐good yields. 1,3,5‐Trioxane, acting as an oxygen nucleophile, reacted with the α‐aza‐vinylcarbene intermediate, giving rise to ylide formation, which was probably the key step in the reaction. Triazoles that contained aryl substituents with various electronic and steric features on the C4 carbon atom were well‐tolerated. The synthesis of trioxazonine derivatives was achieved through a one‐pot, two‐step procedure from 1‐mesylazide and a terminal alkyne by combining Cu^I‐catalyzed 1,3‐dipolar cycloaddition and rhodium‐catalyzed transformations.