Copper-mediated synthesis of N-vinyl ynamides from N-vinyl carbamates

Ynamides are versatile 3-atoms building blocks for organic synthesis as they participate in a variety of ionic, radical and pericyclic processes. Converting ynamides into 5-atom building blocks, such as the yet unreported N-vinyl ynamides, would open new avenues in this fascinating chemistry. We describe herein our efforts towards such goal and demonstrate that the cross-coupling between N-vinyl carbamates and bromo-alkynes using copper(I) thiophene carboxylate, 1,10-phenanthroline and tBuOK in DMSO is a reactive system with an improved profile compared to the classical ynamides syntheses. The advantages and limitations of this copper-mediated reaction are discussed.     

Synthesis of alpha-keto-imides via oxidation of ynamides

A de novo preparation of alpha-keto-imides via ynamide oxidation is described. With a number of alkyne oxidation conditions screened, a highly efficient RuO2-NaIO4 mediated oxidation and a DMDO oxidation have been identified to tolerate a wide range of ynamide types. In addition to accessing a wide variety of alpha-keto-imides, the RuO2-NaIO4 protocol provides a novel entry to the vicinal tricarbonyl motif via oxidation of push-pull ynamides, and imido acylsilanes from silyl-substituted ynamides. Chemoselective oxidation of ynamides containing olefins can be achieved by using DMDO, while the RuO2-NaIO4 protocol is not effective. These studies provide further support for the synthetic utility of ynamides.     

Copper-catalyzed aerobic oxidative amidation of terminal alkynes: efficient synthesis of ynamides

A copper-catalyzed method for the preparation of ynamides has been identified that proceeds via aerobic oxidative coupling of terminal alkynes with various nitrogen nucleophiles, including cyclic carbamates, amides and ureas, and N-alkyl-arylsulfonamides and indoles.     

Click chemistry with ynamides

A series of diversely 1-substituted 4-amino 1,2,3-triazoles were synthesized by [3+2] cycloaddition between azides and ynamides. This copper catalyzed process represents the first examples of a ‘click reaction’ employing ynamides and should expand the scope of the ynamide chemistry both synthetically and industrially. Various azides (even highly functionalized) were allowed to react with N-benzyl, N-tosyl ynamide to give the corresponding triazole adducts in high yield and with very high levels of regioselectivity.     

Palladium-catalyzed hydroacyloxylation of ynamides

In the presence of substoichiometric Pd(OAc)(2), carboxylic acids undergo highly regio- and stereoselective additions to ynamides to provide α-acyloxyenamides.     

A sequential metal-catalyzed C-N bond formation in the synthesis of 2-amido-indoles

A sequential metal-catalyzed C-N bond formation employing ortho-haloaryl acetylenic bromides is described. The initial amidation is highly selective for C (sp)-N bond formation, leading to o-haloaryl-substituted ynamides that can be useful building blocks, while the overall sequence provides a facile construction of 2-amido-indoles.     

Oxoarylation of ynamides with N-aryl hydroxamic acids

Ynamides are electron-rich alkynes with unique reactivities and act as flexible building blocks in organic synthesis. Therefore, the investigation for transformation of ynamides with exceptional selectivity and efficiency is attractive and interesting. Herein, we report an oxoarylation of ynamides with N-aryl hydroxamic acids. In the presence of catalytic Cu(OTf)₂, both the terminal and internal ynamides could undergo an addition/[3,3] sigmatropic rearrangement cascade with N-aryl hydroxamic acids to achieve oxoarylation, along with providing selective entry to (ortho-amino)arylacetamides and oxindoles. Moreover, deuterium-labelling reaction and gram-scale reaction were conducted to probe the mechanism and showcase the scalability.     

The first stereoselective Ficini-Claisen rearrangement using chiral ynamides

The first asymmetric Ficini-Claisen rearrangement using chiral ynamides is described. At relatively low temperatures, the Ficini-Claisen rearrangement can be efficiently promoted by p-nitrobenzenesulfonic acid leading to high diastereoselectivity for a range of different allylic alcohols and chiral ynamides. [reaction: see text]     

N-allyl-N-sulfonyl ynamides as synthetic precursors to amidines and vinylogous amidines. An unexpected N-to-C 1,3-sulfonyl shift in nitrile synthesis

A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements, leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these ynamides.     

Synthesis of chiral allenes from ynamides through a highly stereoselective Saucy-Marbet rearrangement

A highly stereoselective Saucy-Marbet rearrangement using chiral ynamides and propargyl alcohols is described here. This rearrangement can be catalyzed by para-nitrobenzenesulfonic acid and leads to high diastereoselectivities for a range of different chiral propargyl alcohols and ynamides in a stereochemically intriguing matched, mismatched or indifferent manner. The stereoselective Saucy-Marbet rearrangement of ynamides provides an excellent entry to highly substituted chiral homo allenyl alcohols.     

Transition metal-free oxidation of ynamides for synthesis of α-keto-imides

Transition metal-free double oxidation of triple bonds in ynamides for synthesis of α-keto-imides is described. The successful key was combination of NIS and DMSO under atmospheric air in CPME solvent, and the reaction quickly proceeds at 0 °C within 1 h. Although the yields and substrate generality are moderate, yet the prototype protocol avoids the use of expensive, moisture-sensitive, toxic, and explosive additives, which make it potentially and significantly greener than current alternatives.     

Highly stereoselective synthesis of novel alpha-haloenamides via a mild and efficient hydrohalogenation of ynamides

A highly stereoselective preparation of novel chiral (E)-alpha-haloenamides under mild conditions utilizing magnesium halide salts is described. This unexpected mild and efficient hydrohalogenation reaction highlights another synthetic utility of ynamides. [reaction: see text]     

Synthesis of carbazoles by dehydro Diels-Alder reactions of ynamides

A new approach to carbazoles and benzannulated carbazoles by means of intramolecular dehydro Diels-Alder of ynamides is reported. N-(o-Ethynyl)aryl ynamides and N-(o-ethynyl) arylynamides were prepared in a few steps starting from o-iodoaniline. Thermal cycloaddition of N-(o-ethynyl)aryl ynamides and N-(o-ethynyl) arylynamides affords carbazoles and benzannulated and heteroannulated carbazoles in moderate-to-good yields.     

Ruthenium-catalyzed [2+2] cycloadditions of bicyclic alkenes and ynamides

Ruthenium-catalyzed [2+2] cycloadditions between bicyclic alkenes and ynamides were investigated. The ynamide moiety was found to be compatible with the ruthenium-catalyzed cycloaddition conditions giving the corresponding cyclobutene cycloadducts in moderate to good yields (up to 97%). Diastereoselective cycloaddition utilizing chiral cyclic ynamides were also examined and a low to moderate level of asymmetric induction was observed.     

Copper sulfate-pentahydrate-1,10-phenanthroline catalyzed amidations of alkynyl bromides. Synthesis of heteroaromatic amine substituted ynamides

A practical cross-coupling of amides with alkynyl bromides using catalytic CuSO(4).5H(2)O and 1,10-phenanthroline is described here. This catalytic protocol is more environmentally friendly than the use of CuCN or copper halides and provides a general entry for syntheses of ynamides including various new sulfonyl and heteroaromatic amine substituted ynamides. Given the interest in ynamides, this N-alkynylation of amides should be significant for the future of ynamides in organic synthesis.     

Radical cyclization of ynamides into six- or eight-membered rings. Application to the synthesis of a protoberberine analog

A straightforward formation of six- and eight-membered rings via the radical cyclization of specifically designed ynamides is reported. This strategy provides a protoberberine analog in only three steps by a radical cyclization cascade.     

Regioselective TfOH-mediated hydroamidation of ynamides with nitriles

A new TfOH-mediated reaction of ynamides with nitriles as nucleophiles has been developed. The reaction works efficiently under mild reaction conditions to afford a new class of α-acylaminoenamides readily via the intermediacy of keteniminium ion. The reaction displays generality and a broad substrates scope. Additionally, the α-acylaminoenamides could be transformed to highly substituted pyridine, 4-aminopyrimidine or isoquinoline cores.     

BF_3-promoted annulation of azonaphthalenes and ynamides for synthesis of benzo[e]indoles

A novel BF₃-promoted [3+2] annulation of azonaphthalenes and ynamides is described.This protocol provides a modular and efficient entry to functionalized amino benzo[e]indole derivatives smoothly.     

Regio- and stereoselective synthesis of 2-amino-1,3-diene derivatives by ruthenium-catalyzed coupling of ynamides and ethylene

A ruthenium-catalyzed hydrovinylation-type cross-coupling of ynamides and ethylene proceeds via ruthenacyclopentene to give 2-aminobuta-1,3-diene derivatives in a highly regioselective manner. It was also demonstrated that 2-aminobuta-1,3-diene derivatives reacted with various dienophiles or singlet oxygen to give a cyclic enamide derivative.     

Sonogashira cross-couplings of ynamides. Syntheses of urethane- and sulfonamide-terminated conjugated phenylacetylenic systems

[reaction: see text] The first successful Sonogashira coupling of ynamides with aryl and vinyl iodides is described here. This study resolves the problem of the competing pathway involving homocoupling of ynamides and provides a practical entry to novel urethane- or sulfonamide-terminated conjugated acetylenic systems. An interesting tandem hydrohalogenation and Sonogashira coupling was also observed to give an en-ynamide.