Ammonia-promoted one-pot tetrazolopiperidinone synthesis by Ugi reaction

Ammonia in the tetrazole Ugi variation together with α-amino acid methyl ester-derived isocyanides provides tetrazolopiperidinones in good to high yields in one pot. The scope and limitations of this reaction were investigated by performing >70 reactions. The scaffold is useful to fill high-throughput screening decks and in structure-based drug design

Two cycles with one catch : hydrazine in Ugi 4-CR and its postcyclizations

Isocyanide-based multicomponent reactions (IMCR) are by far the most versatile reactions that can construct relatively complex molecules by one-pot synthesis. More importantly, the development of post IMCR modifications significantly improves the scaffold's diversity. Here, we describe the use of N-Boc protected hydrazine together with a-amino acid derived isocyanides in the Ugi tetrazole reaction and its post cyclization under both acidic and basic conditions. The cyclization in acidic conditions was conducted in a one pot fashion, which give 7-aminotetrazolopyrazinone (6) and tetrazolotriazepinone (7) cyclic products. The post cyclization under basic condition could selectively afford Boc-protected 7-aminotetrazolopyrazinone (8) products in yield of 38-87%

Fourfold symmetric MCR's via the tetraisocyanide 1,3-diisocyano-2,2-bis(isocyanomethyl)propane

Oligoisocyanides are attractive synthetic targets, however, only a few are known. Here, we describe the smallest stable tetraisocyanide possible, the 1,3-diisocyano-2,2-bis(isocyano-methyl)propane (1) with S4 symmetry. Its four-step synthesis, structure, and reactivity in unprecedented symmetric fourfold Ugi 4CR and fourfold Passerini 3CR are described. Exhibiting high functional group tolerance and moderate to high yields, we foresee multiple applications of 1,3-diisocyano-2,2-bis(isocyanomethyl)propane, for example in MOFs, COFs, dendrimers, or artificial organs

Multicomponent Reaction Based Synthesis of 1-Tetrazolylimidazo[1,5- a]pyridines

A series of unprecedented tetrazole-linked imidazo[1,5- a]pyridines are synthesized from simple and readily available building blocks. The reaction sequence involves an azido-Ugi-deprotection reaction followed by an acetic anhydride-mediated N-acylation-cyclization process to afford the target heterocycle. Furthermore, the scope of the methodology was extended to diverse R3-substitutions by employing commercial anhydrides, acid chlorides, and acids as an acyl component. The scope for the postmodification reactions are explored and the usefulness of the synthesis is exemplified by an improved three-step synthesis of a guanylate cyclase stimulator

Access to isoquinolin-2(1H)-yl-acetamides and isoindolin-2-yl-acetamides from a common MCR precursor

We achieved a divergent synthesis of isoquinolin-2(1H)-yl-acetamides (16 examples, up to 90% yields) and regioselective isoindolin-2-yl-acetamides (14 examples, up to 93% yields) in moderate to good yields by reacting various substituted ethanones or terminal alkynes with Ugi-4CR intermediates via an ammonia-Ugi-4CR/Copper(I)-catalyzed annulation sequence reaction. The same intermediate thus gives 2D distant but 3D closely related scaffolds, which can be of high interest in exploiting chemistry space on a receptor. The scopes and limitations of these efficient sequence reactions are described, as well as gram-scale synthesis

Copper-catalyzed modular assembly of polyheterocycles

Easy operation, readily accessible starting materials, and short syntheses of the privileged scaffold indeno[1,2-c]isoquinolinone were achieved by an multicomponent reaction (MCR)-based protocol via an ammonia-Ugi-four component reaction (4CR)/copper-catalyzed annulation sequence. The optimization and scope and limitations of this short and general sequence are described. The methodology allows an efficient construction of a wide variety of indenoisoquinolinones in just two steps

De Novo Assembly of Highly Substituted Morpholines and Piperazines

The morpholine and piperazine with their remarkable physical and biochemical properties are popular heterocycles in organic and medicinal chemistry used in rational property design. However, in the majority of cases these rings are added to an existing molecule in a building block approach thus limiting their substitution pattern and diversity. Here we introduce a versatile de novo synthesis of the morpholine and piperazine rings using multicomponent reaction chemistry. The large scale amenable building blocks can be further substituted at up to four positions, making this a very versatile scaffold synthesis strategy. Our methods thus fulfill the increasing demand for novel building block design and nontraditional scaffolds which previously were not accessibl

Dimethyl dl-2,3-dibenzyl-2,3-diisothio­cyanatosuccinate

The title compound, C22H20N2O4S2, has approximate mol­ecular twofold symmetry. In the crystal, the presence of C—H⋯π inter­actions leads to the formation of zigzag chains along [001]

Concise synthesis of tetrazole macrocycle

A concise two step synthesis of tetrazole containing macrocycles from readily accessible starting materials is presented. The first step comprises a chemoselective amidation of amino acid derived isocyanocarboxylicacid esters with unprotected symmetrical diamines to afford diverse α-isocyano-ω-amines. In the second step, the α-isocyano-ω-amines undergo an Ugi tetrazole reaction to close the macrocycle. Advantageously, this strategy allows short access to 11–19-membered macrocycles in which substituents can be independently varied at three different positions