Direct Nucleophilic Addition to N‐Alkoxyamides

While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long‐standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N‐alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N‐alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N‐alkoxy group formed a five‐membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL‐H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter‐ and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered α‐trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five‐ and six‐membered lactams, and macrolactams.     

Direct Metal‐Free Entry to Aminocyclobutenes or Aminocyclobutenols from Ynamides: Synthetic Applications

The [2+2] cycloaddition of ynamides with the highly polarized reagent Tf₂C=CH₂ has been developed to regioselectively afford bis(triflyl)aminocyclobutenes in the absence of catalyst under mild conditions. Incidentally, with the ynamides bearing electron‐rich aromatic rings at the C‐terminal, an interesting reactivity switch was observed; a cyclization/hydroxylation sequence yielded 2‐amino‐3‐(triflyl)cyclobut‐2‐enols. Aminocyclobutene construction with addition of alcohols resulted in the formation of aminocyclobutenyl ethers through a cyclization/hydroalkoxylation process. Moreover, the utility of functionalized aminocyclobutenes as precursors for further elaboration was demonstrated with the preparation of α‐amino‐β,γ‐unsaturated ketones and 3‐(triflyl)buta‐1,3‐dien‐2‐amines through 4 π‐electrocyclic ring opening.     

Synthesis of (±)‐Lasubine II Using N‐Methoxyamines

The synthesis of (±)‐lasubine II has been achieved through a three‐component allylation capitalizing on the unique properties of N‐methoxyamines. This reaction enabled the installation of all the carbon atoms of lasubine II in a single operation. The N‐methoxy group was efficiently used for the subsequent nitrone formation. A single‐step cyclization of isoxazolidines or N‐methoxyamines to form functionalized piperidine rings was also developed.     

Chemoselective Reductive Nucleophilic Addition to Tertiary Amides,Secondary Amides,and N‐Methoxyamides

As the complexity of targeted molecules increases in modern organic synthesis, chemoselectivity is recognized as an important factor in the development of new methodologies. Chemoselective nucleophilic addition to amide carbonyl centers is a challenge because classical methods require harsh reaction conditions to overcome the poor electrophilicity of the amide carbonyl group. We have successfully developed a reductive nucleophilic addition of mild nucleophiles to tertiary amides, secondary amides, and N‐methoxyamides that uses the Schwartz reagent [Cp₂ZrHCl]. The reaction took place in a highly chemoselective fashion in the presence of a variety of sensitive functional groups, such as methyl esters, which conventionally require protection prior to nucleophilic addition. The reaction will be applicable to the concise synthesis of complex natural alkaloids from readily available amide groups.     

Dehydrogenative N‐Incorporation: A Direct Approach to Quinoxaline N‐Oxides under Mild Conditions

An efficient method for the synthesis of quinoxaline N‐oxides proceeds by the dehydrogenative N‐incorporation of simple imines by C(sp²)? H and C(sp³)? H bond functionalization. The overall transformation involves the cleavage of three C? H bonds. The reaction is easily handled and proceeds under mild conditions. Simple and readily available tert‐butyl nitrite (TBN) was employed as the NO source.     

A Multicomponent Conjugation Strategy to Unique N‐Steroidal Peptides: First Evidence of the Steroidal Nucleus as a β‐Turn Inducer in Acyclic Peptides

Constraining small peptides into specific secondary structures has been a major challenge in peptide ligand design. So far, the major solution for decreasing the conformational flexibility in small peptides has been cyclization. An alternative is the use of topological templates, which are able to induce and/or stabilize peptide secondary structures by means of covalent attachment to the peptide. Herein a multicomponent strategy and structural analysis of a new type of peptidosteroid architecture having the steroid as N‐substituent of an internal amide bond is reported. The approach comprises the one‐pot conjugation of two peptide chains (or amino acid derivatives) to aminosteroids by means of the Ugi reaction to give a unique family of N‐steroidal peptides. The conjugation efficiency of a variety of peptide sequences and steroidal amines, as well as their consecutive head‐to‐tail cyclization to produce chimeric cyclopeptide–steroid conjugates, that is, macrocyclic lipopeptides, was assessed. Determination of the three‐dimensional structure of an acyclic N‐steroidal peptide in solution proved that the bulky, rigid steroidal template is capable of both increasing significantly the conformational rigidity, even in a peptide sequence as short as five amino acid residues, and inducing a β‐turn secondary structure even in the all‐s‐trans isomer. This report provides the first evidence of the steroid skeleton as β‐turn inducer in linear peptide sequences.     

N‐Heterocyclic Carbene‐Catalysed Direct Synthesis of Cyano Esters via Cyanation‐Esterification Reaction of α‐Keto Esters

The cyanation‐esterification reaction of α‐keto esters catalysed by N‐heterocyclic carbenes (NHCs) is developed. Under the catalysis of 10 mol% 1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene, aromatic and aliphatic α‐keto esters reacted with ethyl cyanoformate or acetyl cyanide to produce the corresponding cyano esters with a tetrasubstituted carbon center in high yields.     

Efficient Synthesis of Dimeric Oxazoles,Piperidines and Tetrahydroisoquinolines from N‐Substituted 2‐Oxazolones

A mild and practical method for the construction of heterocycles from N‐substituted 2‐oxazolones through cascade, BF₃?Et₂O/H₂O‐catalyzed reactions involving iminium ion generation and trapping by external or internal olefinic and aryl moieties is described. Mechanistic and computational studies revealed the strong protic acid HBF₄ as the initiating catalyst for these cascade reactions. Providing access to novel molecular diversity, these processes may facilitate chemical biology studies, drug discovery efforts and natural products synthesis.     

N‐Substituted Azacalixphyrins: Synthesis,Properties, and Self‐Assembly

Pre‐ and postintroduction of substituents with respect to the macrocyclization step leads to previously unknown N‐substituted azacalixphyrins. The stepwise synthetic approach has been studied in detail to highlight the key role of the N‐substituents of the precursors and/or intermediates in terms of reactivity. Based on a combined experimental and theoretical investigation, the relationship between the properties of the macrocycles and their degree of substitution is rationalized. Depending on the nature of the N‐substituents, the formation of supramolecular ribbon‐like structures could also be observed, as demonstrated by combined TEM, SEM, AFM, and FTIR experiments.     

Cyclization of Zincated α‐N‐Homoallylamino Nitriles: A New Entry to Enantiopure 2,3‐Methanopyrrolidines

Stereoselective cyclization of zincated α‐N‐homoallylamino nitriles has been developed. Following treatment with lithium diisopropylamide (LDA) and transmetalation with zinc bromide, α‐N‐(1‐phenylethyl)‐N‐homoallylamino nitriles lead to 2,3‐methanopyrrolidines in moderate to good yields (up to 66 %) and excellent selectivities (up to >98:2). With substrates derived from α‐branched homoallylic amines, a stereospecific inversion of the homoallylic stereogenic center was observed. To account for this, a mechanistic rationale involving the formation of zincioiminium ions from zincated α‐amino nitriles is put forward. 2,3‐Methanopyrrolidines should then arise from a sequence involving an aza‐Cope rearrangement providing a configurationally stable (2‐azoniaallyl)zinc species that then undergoes a [3+2] cycloaddition reaction.     

Copper‐Catalyzed Reductive N‐Alkylation of Amides with N‐Tosylhydrazones Derived from Ketones

A CuI‐catalyzed reductive coupling of ketone‐derived N‐tosylhydrazones with amides is presented. Under the optimized conditions, an array of N‐tosylhydrazones derived from aryl–alkyl and diaryl ketones could couple effectively with a wide variety of (hetero)aryl as well as aliphatic amides to afford the N‐alkylated amides in high yields. The method represents the very few examples for reliably accessing secondary and tertiary amides through a reductive N‐alkylation protocol.     

Insertion of Nitriles into Zirconocene 1‐aza‐1,3‐diene Complexes: Chemoselective Synthesis of N–H and N‐Substituted Pyrroles

The direct insertion of nitriles into zirconocene‐1‐aza‐1,3‐diene complexes provides an efficient, chemoselective, and controllable synthesis of N‐H and N‐substituted pyrroles upon acidic aqueous work‐up. The outcome of the reaction (that is, the formation of N‐H or N‐substituted pyrroles) results from the different cyclization patterns, which depend on the relative stability and reactivity of the enamine–imine tautomers formed by hydrolysis of the diazazirconacycles.     

Direct Acyl Substitution of Carboxylic Acids: A Chemoselective O‐ to N‐Acyl Migration in the Traceless Staudinger Ligation

A chlorophosphite‐modified, Staudinger‐like acylation of azides involving a highly chemoselective, direct nucleophilic acyl substitution of carboxylic acids is described. The reaction provides the corresponding amides with analytical purity in 32–97 % yield after a simple aqueous workup without the need for a pre‐activation step. The use of chlorophosphites as dual carboxylic acid–azide activating agents enables the formation of acyl C? N bonds in the presence of a wide range of nucleophilic and electrophilic functional groups, including amines, alcohols, amides, aldehydes, and ketones. The coupling of carboxylic acids and azides for the formation of alkyl amides, sulfonyl amides, lactams, and dipeptides is described.     

Synthesis of Substituted 2‐Amino‐1,3‐oxazoles via Copper‐Catalyzed Oxidative Cyclization of Enamines and N,N‐Dialkyl Formamides

A facile synthesis of 2‐amino‐1,3‐oxazoles via Cu^I‐catalyzed oxidative cyclization of enamines and N ,N ‐dialkyl formamides has been developed. The reaction proceeds through an oxidative C−N bond formation, followed by an intramolecular C(sp²)−H bond functionalization/C−O cyclization in one pot. This protocol provides direct access to useful 2‐amino‐1,3‐oxazoles and features protecting‐group‐free nitrogen sources, readily available starting materials, a broad substrate scope and mild reaction conditions.