Highly Enantioselective Synthesis of Propargyl Amide with Vicinal Stereocenters through Ir-Catalyzed Hydroalkynylation

Chiral propargyl amines are valuable synthetic intermediates for the preparation of biologically active compounds and functionalized amines. Catalytic methods to access propargyl amines containing vicinal stereocenters with high diastereoselectivity are particularly rare. We report an unprecedented strategy for the synthesis of enantioenriched propargyl amines with two stereogenic centres. An iridium complex, ligated by a phosphoramidite ligand, catalyzes the hydroalkynylation of β,β-disubstituted enamides to afford propargyl amides in a highly regio-, diastereo-, and enantioselective fashion. Stereodivergent synthesis of all four possible stereoisomers was achieved using this strategy.     

Silver-mediated aminophosphinoylation of propargyl alcohols with aromatic amines and H-phosphine oxides leading to α-aminophosphine oxides

A new silver mediated aminophosphinoylation of propargyl alcohols with aromatic amines and Hphosphine oxides for the construction of a-aminophosphine oxides has been developed.The C-N and C-P bond could be efficiently formed in one pot operation via sequential C-C and C-O bond cleavage of propargylic alcohols.This present methodology,which not only provides a simple and alternative strategy for the synthesis of α-aminophosphine oxides,but also opens a new window for the cleavage reactions of propargyl alcohols via dealkynalation coupling.     

A Facile Synthesis of 2‐Imino‐4‐methylene‐1,3‐dithiolanes

A one‐pot synthesis of 2‐imino‐4‐methylidene‐1,3‐dithiolanes via a three‐component reaction of propargyl bromide (=3‐bromoprop‐1‐yne), primary amines, and carbon disulfide (CS₂) is described.     

Cu(I)‐Catalyzed Regioselective and Highly Efficient One‐Pot Synthesis of Novel 1,2,3‐Triazoles Decorated with Pyridine and Heterocyclic Amines

An efficient one‐pot synthesis of 1,2,3‐triazoles via the three‐component coupling reaction between propargyl bromide, secondary amines, and 3‐azidopyridine in the presence of CuI as catalyst has been presented. The reaction is highly regioselective and afforded novel 1,4‐disubstituted‐1,2,3‐triazoles in excellent yields by the [3 + 2] Huisgen cycloaddition reaction. This method avoids isolation and handling of terminal acetylenes. The ease of purification has made this methodology clean and safe for the synthesis of 1,2,3‐triazoles with a broad scope.     

Propargyl Amine Synthesis Catalysed by Gold and Copper Thin Films by Using Microwave‐Assisted Continuous‐Flow Organic Synthesis (MACOS)

An effective multi‐component reaction (MCR) protocol has been developed for the construction of propargyl amines from aldehydes, amines and terminal alkynes by using microwave‐assisted continuous‐flow organic synthesis (MACOS). The process is catalysed by thin films of either copper or gold that achieve temperatures in excess of 900 °C when irradiated with low levels of microwave power. The process works equally well for premixed solutions of the three starting materials, or as three separate streams, which improves the combinatorial efficiency of the method. The process tolerates a wide variety of functional groups and heterocycles, and conversion over these diverse substrates ranges from 70–90 %.     

Copper‐Catalyzed Synthesis of 1,1‐Diborylalkanes through Regioselective Dihydroboration of Terminal Alkynes

The copper‐catalyzed sequential hydroboration of terminal alkynes with pinacolborane to prepare 1,1‐diborylalkanes directly from alkynes was studied. Protected propargyl amines, propargyl alcohol derivatives, and simple alkynes regioselectively produced the desired 1,1‐diborylalkanes in good yields with a copper/xantphos catalyst.     

Asymmetric Synthesis of Chiral 1,4‐Enynes through Organocatalytic Alkenylation of Propargyl Alcohols with Trialkenylboroxines

A highly enantioselective synthesis of 1,4‐enynes is described that proceeds through an organocatalytic reaction between propargyl alcohols and trialkenylboroxines. Our strategy relies on acid‐mediated generation of the carbocationic intermediate from propargyl alcohols followed by enantioselective alkenylation with trialkenylboroxines. A range of chiral 1,4‐enynes were obtained in moderate to good yields with high levels of enantioselectivity. Use of a highly acidic chiral N‐triflyl phosphoramide catalyst, which has two distant Lewis basic oxygen atoms, was found to be crucial for both high reactivity and selectivity in the present reaction.     

Facile Synthesis of Pyridines from Propargyl Amines: Concise Total Synthesis of Suaveoline Alkaloids

A general and efficient protocol was developed for the synthesis of polysubstituted pyridines from propargyl amines and unsaturated carbonyl compounds through a tandem condensation/alkyne isomerization/6π 3‐azatriene electrocyclization sequence. This process was found to be applicable to a wide range of readily available substrates (30 examples, up to 95 % yield) and could be readily performed on a preparative (20 g) scale. By taking advantage of this method for late‐stage pyridine incorporation, we successfully completed the collective total synthesis of suveoline, norsuveoline, and macrophylline.     

Copper(I)‐Catalyzed Three‐Component Reaction of Terminal Propargyl Alcohols,Aldehydes, and Amines: Synthesis of 3‐Amino‐2‐pyrones and 2,5‐Dihydrofurans

A novel copper(I)‐catalyzed three‐component reaction for the efficient synthesis of 3‐amino‐2‐pyrones and 2,5‐dihydrofurans from propargyl alcohols, aldehydes, and amines has been developed. The starting materials are easily available and the scope of this method is broad. Through mechanistic studies, it is believed that the three‐component reaction consists of an A³‐coupling to propargylic amine, alkyne–allene isomerization, and intramolecular cyclization of the allenol to form a furan. In case of using ethyl glyoxalate as the aldehyde, a ring‐opening, lactonization, and isomerization process affords the 3‐amino‐2‐pyrones.     

Copper(I)‐Catalyzed Three‐Component Reaction of Terminal Propargyl Alcohols,Aldehydes, and Amines: Synthesis of 3‐Amino‐2‐pyrones and 2,5‐Dihydrofurans

A novel copper(I)‐catalyzed three‐component reaction for the efficient synthesis of 3‐amino‐2‐pyrones and 2,5‐dihydrofurans from propargyl alcohols, aldehydes, and amines has been developed. The starting materials are easily available and the scope of this method is broad. Through mechanistic studies, it is believed that the three‐component reaction consists of an A³‐coupling to propargylic amine, alkyne–allene isomerization, and intramolecular cyclization of the allenol to form a furan. In case of using ethyl glyoxalate as the aldehyde, a ring‐opening, lactonization, and isomerization process affords the 3‐amino‐2‐pyrones.     

Designing poly(amido amine) dendrimers containing core diversities by click chemistry of the propargyl focal point poly(amido amine) dendrons

General, fast, efficient, and inexpensive methods for the synthesis of poly (amido amine) (PAMAM) dendrimers having core diversities were elaborated. In all syntheses, the major step involved an inexpensive 1,3‐dipolar cycloaddition reaction between an alkyne and an azide in the presence of Cu(I) species, which is known as the best example of click chemistry. The propargyl‐functionalized PAMAM dendrons are obtained by the divergent approach using propargylamine as an alkyne‐focal point. Three core building blocks, 1,3,5‐tris(azidomethyl)benzene, N,N,N′,N′‐tetra(azidopropylamidoethyl)‐1,2‐diaminoethane, and 4,4′‐(3,5‐bis(azidopropyloxy)benzyloxy)bisphenyl, were designed and synthesized to serve as the azide functionalities for dendrimer growth via click reactions with the alkyne‐dendrons. These three building blocks were employed together with the propargyl‐functionalized PAMAM dendrons in a convergent strategy to synthesize three kinds of PAMAM dendrimers with different core units. This novel and pivotal strategy using an efficient click methodology provides the fast and efficient synthesis of the PAMAM dendrimers with the tailed made core units. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 1083–1097, 2008     

Cu(I)‐catalyzed Green Synthesis of Propargyl Amines Decorated with Carbazole Moiety by A3 ‐Coupling

A series of novel N ‐alkylcarbazol–propargylamine hybrids were designed and synthesized by Cu^IBr ‐catalyzed A³ ‐coupling of N ‐octylcarbazol‐3‐carbaldehyde, amines, and alkynes. The tri‐substituted propargyl amines decorated with carbazole moiety were obtained under solvent‐free conditions in good to moderate yields. Furthermore, the scope of the method was studied, which was found to be applicable to primary aliphatic and aromatic amines. Also, a large variety of substituents both on alkynes and anilines are well tolerated.     

Facile synthesis of unusual glycosyl carbamates and amino acid glycosides from propargyl 1,2-orthoesters as glycosyl donors

Propargyl 1,2-O-orthoesters are exploited for the synthesis of 1,2-trans O-glycosides of protected amino acids. N-Fmoc- and N-Cbz protected serine/threonine - benzyl/methyl esters reacted well with glucosyl-, galactosyl-, mannosyl- and lactosyl- derived propargyl 1,2-orthoesters affording respective 1,2-trans glycosides in good yields under AuBr(3)/4 ? MS Powder/CH(2)Cl(2)/rt. t-Boc serine derivative gave serine 1,2-orthoester and glycosyl carbamate. Optimized conditions enabled preparation of new glycosyl carbamates from N-Boc protected amines in a single step using gold catalysts and propargyl 1,2-orthoesters in excellent yields.     

Direct access to CF3-propargyl amines and conversion to difluoromethyl imines

Trifluoromethyl aldimines reacted with acetylides in toluene at −78 °C to provide propargyl amines in good yields. From a chiral trifluoromethyl aldimine, the propargyl amines were obtained with excellent diastereoselectivities (de >98%). Trifluoromethyl propargyl amines could be further converted into difluoromethyl imines under basic conditions.     

Highly Enantioselective Aza‐Michael Reaction between Alkyl Amines and β‐Trifluoromethyl β‐Aryl Nitroolefins

The aza‐Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza‐Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N‐heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza‐Michael reaction between primary alkyl amines and β‐trifluoromethyl β‐aryl nitroolefins. In contrast to classical conjugate‐addition reactions, a strategy of HOMO‐raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).     

2-Amino homopropargyl alcohols from the highly regioselective Ag2CO3-catalyzed nucleophilic openings of alkynyl epoxides by amines

The nucleophilic ring opening of propargyl epoxides by amines based on a silver catalyst is presented. The reaction takes place under mild conditions and features a high regioselectivity to provide an effective method for the synthesis of 2-amino homopropargyl alcohols in moderate to high yields.     

Tandem amine propargylation-Sonogashira reactions: new three-component coupling leading to functionalized substituted propargylic amines

Three-component coupling reactions of propargyl halides, amines, and organic halides in the presence of palladium-copper catalysis produced efficiently highly functionalized propargylic amines in good to excellent yields at room temperature. Extension to the synthesis of 2-(dialkylaminomethyl)benzo[b]furan or indole derivatives is described.     

An Efficient Synthesis of a (−)‐Physostigmine's Library for Identifying Potential Anti‐Alzheimer's Agents

An efficient route for the synthesis of (?)‐physostigmine analogs 1a – 1g and 2a – 2k is described. Analogs 1a – 1g were synthesized via copper(I)‐catalyzed cycloaddition between the optically pure azide 10 and a variety of alkynes. Similarly, analogs 2a – 2k were prepared through ‘three‐component Huisgen cycloaddition’ using various amines, propargyl bromine, and 10 in H₂O. Facile preparation of 10 via MacMillan's organocatalysis has made it possible to generate a great diversity of natural product‐like compounds that can be screened for anti‐Alzheimer's effects.     

One-pot sequential diprop-2-ynylation and cycloaddition: An efficient synthesis of novel N,N-bis(1,2,3-triazol-4-yl) methylarylamines starting from primary amines

Abstract

A facile, one-pot synthesis strategy for the tertiary arylamines bearing N,N-bis(1,2,3-triazol-4-yl)methyl structure has been developed by sequential diprop-2-ynylation of primary amines with propargyl bromide in the presence of calcium hydride in DMF and [3?+?2] “click” cycloaddition with organic azides promoted by cupric acetate in the mixed DMF-H₂O media. This protocol provides some features, such as high efficiency and regioselectivity, easy operation, and moderate to good product yield (56–84%) with a wide substrate scope under mild conditions.     

Ruthenium‐Catalyzed Functionalization of Pyrroles and Indoles with Propargyl Alcohols

Several ruthenium‐catalyzed atom‐economic transformations of propargyl alcohols with pyrroles or indoles leading to alkylated, propargylated, or annulated heteroaromatics are reported. The mechanistically distinct reactions are catalyzed by a single ruthenium(0) complex containing a redox‐coupled dienone ligand. The mode of activation regarding the propargyl alcohols determines the reaction pathway and depends on the alcohols’ substitution pattern. Secondary substrates form alkenyl complexes by a 1,2‐hydrogen shift, whereas the transformation of tertiary substrates involves allenylidene intermediates. 1‐Vinyl propargyl alcohols are converted by a cascade allylation/cyclization sequence. The environmentally benign processes are of broad scope and allow the selective synthesis of highly functionalized pyrroles and indoles generating water as the only waste product.