Divergent Dendrimer Synthesis via the Passerini Three‐Component Reaction and Olefin Cross‐Metathesis

The combination of the Passerini reaction and olefin cross‐metathesis is shown to be a very useful approach for the divergent synthesis of dendrimers. Castor oil‐derived platform chemicals, such as 10‐undecenoic acid and 10‐undecenal, are reacted in a Passerini reaction with an unsaturated isocyanide to obtain a core unit having three terminal double bonds. Subsequent olefin cross‐metathesis with tert‐butyl acrylate, followed by hydrogenation of the double bonds and hydrolysis of the tert‐butyl ester, leads to an active core unit bearing three carboxylic acid groups as reactive sites. Iterative steps of the Passerini reaction with 10‐undecenal and 10‐isocyanodec‐1‐ene for branching, and olefin cross‐metathesis with tert‐butyl acrylate, followed by hydrogenation and hydrolysis allow the synthesis of a third‐generation dendrimer. All steps of the synthesis are carefully characterized by NMR, GPC, MS, and IR.

     

A Scalable and High‐Yield Strategy for the Synthesis of Sequence‐Defined Macromolecules

The efficient synthesis of a sequence‐defined decamer, its characterization, and its straightforward dimerization through self‐metathesis are described. For this purpose, a monoprotected AB monomer was designed and used to synthesize a decamer bearing ten different and selectable side chains by iterative Passerini three‐component reaction (P‐3CR) and subsequent deprotection. The highly efficient procedure provided excellent yields and allows for the multigram‐scale synthesis of such perfectly defined macromolecules. An olefin was introduced at the end of the synthesis, allowing the self‐metathesis reaction of the resulting decamer to provide a sequence‐defined 20‐mer with a molecular weight of 7046.40 g mol^?1. The obtained oligomers were carefully characterized by NMR and IR spectroscopy, GPC and GPC coupled to ESI‐MS, and mass spectrometry (FAB and orbitrap ESI‐MS).     

A One‐Pot O‐Phosphinative Passerini/Pudovik Reaction: Efficient Synthesis of Highly Functionalized α‐(Phosphinyloxy)amide Derivatives

A one‐pot O‐phosphinative Passerini/Pudovik reaction has been developed, based on reacting aldehydes, isocyanides, and phosphinic acids followed by the addition of second aldehydes to form the corresponding α‐(phosphinyloxy)amide derivatives. This is the first reported instance of a Passerini‐type, isocyanide‐based multicomponent reaction using a phosphinic acid instead of a carboxylic acid. The nucleophilicity of the phosphinate group allows a subsequent catalytic Pudovik‐type reaction, affording the highly functionalized α‐(phosphinyloxy)amide derivative in high yield. A wide range of aldehydes and isocyanides are applicable to this reaction.     

Catalytic Three‐Component Domino Reaction for the Preparation of Trisubstituted Oxazoles

Multicomponent reactions are attractive for assembling functionalized heterocyclic compounds. To this end, an efficient gold‐catalyzed three‐component domino reaction to form oxazoles directly from imines, alkynes, and acid chlorides is presented. The reaction proceeds in a single synthetic step by using a gold(III)–N,N′‐ethylenebis(salicylimine) (salen) catalyst to give trisubstituted oxazoles in up to 96 % yield. The substrate scope, a mechanistic study exploring the role of the gold catalyst, and the synthetic applications of the oxazole products are discussed.     

A Metal‐Free Three‐Component Reaction for the Regioselective Synthesis of 1,4,5‐Trisubstituted 1,2,3‐Triazoles

A metal‐free three‐component reaction to synthesize 1,4,5‐trisubstituted 1,2,3‐triazoles from readily available building blocks, such as aldehydes, nitroalkanes, and organic azides, is described. The process is enabled by an organocatalyzed Knoevenagel condensation of the formyl group with the nitro compound, which is followed by the 1,3‐dipolar cycloaddition of the azide to the activated alkene. The reaction features an excellent substrate scope, and the products are obtained with high yield and regioselectivity. This method can be utilized for the synthesis of fused triazole heterocycles and materials with several triazole moieties.     

A Three‐Component Enantioselective Cyclization Reaction Catalyzed by an Unnatural Amino Acid Derivative

A new diastereo‐ and enantioselective three‐component cyclization reaction is described. The reaction takes place between a ketone, a carboxylic acid, and a nitroalkene to yield a bicyclic octahydro‐2H‐indol‐2‐one scaffold possessing three chiral centers. This reaction involves a rearrangement of the nitro group under simple thermal conditions. A plausible mechanism is proposed for this new reaction based on DFT calculations and isotope‐labeling experiments. A new concise enantioselective synthesis of the alkaloid (+)‐pancracine is presented as an example of the potential of this novel organocatalytic cyclization reaction in the synthesis of natural products.     

Three‐Component Asymmetric Mannich Reaction Catalyzed by a Lewis Acid with Rhodium‐Centered Chirality

A highly efficient direct asymmetric three‐component Mannich reaction of an N ‐acylpyrazole, an aldehyde and a primary or secondary amine, was enabled by a rhodium‐based Lewis‐acid catalyst with metal‐centered chirality. Excellent enantioselectivities were achieved for a variety of substrates at a typical catalyst loading of merely 0.5 mol % (23 examples, up to 98 % ee ).     

Three‐Component Synthesis of Highly Functionalized 5‐Acetyloxazoles

By a flexible three‐component synthesis, alkoxy‐substituted enamides are easily available from lithiated alkoxyallenes, nitriles and carboxylic acids (see scheme). The treatment of these versatile intermediates with trifluoroacetic acid provided 5‐acetyloxazoles in moderate to good yields. Different substituents are possible at C‐2 and C‐5 and the 5‐acetyl group is a suitable handle for further synthetic transformations.

     

Titanocene(III)‐Catalyzed Three‐Component Reaction of Secondary Amides,Aldehydes, and Electrophilic Alkenes

An umpolung Mannich‐type reaction of secondary amides, aliphatic aldehydes, and electrophilic alkenes has been disclosed. This reaction features the one‐pot formation of C? N and C? C bonds by a titanocene‐catalyzed radical coupling of the condensation products, from secondary amides and aldehydes, with electrophilic alkenes. N‐substituted γ‐amido‐acid derivatives and γ‐amido ketones can be efficiently prepared by the current method. Extension to the reaction between ketoamides and electrophilic alkenes allows rapid assembly of piperidine skeletons with α‐amino quaternary carbon centers. Its synthetic utility has been demonstrated by a facile construction of the tricyclic core of marine alkaloids such as cylindricine C and polycitorol A.     

Rhodium(III)‐Catalyzed Three‐Component Reaction of Imines,Alkynes, and Aldehydes through CH Activation

An efficient rhodium(III)‐catalyzed tandem three‐component reaction of imines, alkynes and aldehydes through C?H activation has been developed. High stereo‐ and regioselectivity, as well as good yields were obtained in most cases. The simple and atom‐economical approach offers a broad scope of substrates, providing polycyclic skeletons with potential biological properties.