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Saturated heterocycles have long been considered as privileged elements for the preparation of bioactive molecules. Increasing recognition of problems associated with aromatic pharmacophores, such as poor solubility, bioavailability, or pharmacokinetics have further enhanced their importance. Despite this, their implementation in drug discovery has been challenging due to the often long, laborious synthetic routes required for their preparation. To directly access a variety of fully saturated N-heterocycles in one-step, we introduced SnAP (Stannyl Amine Protocol) reagents, which convert aldehydes and ketones into morpholines, piperazines, diazepanes, thiomorpholines, spiro- and other N-heterocycles.
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This page is a summary of: SnAP Reagents for the Synthesis of Piperazines and Morpholines, Organic Letters, February 2014, American Chemical Society (ACS),
DOI: 10.1021/ol500210z.
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Resources
SnAP Reagents for the Transformation of Aldehydes into Substituted Thiomorpholines - An Alternative to Cross-Coupling with Saturated Heterocycles
SnAP Reagents for the Synthesis of Thiomorpholines
Bespoke SnAP Reagents for the Synthesis of C‑Substituted Spirocyclic and Bicyclic Saturated N‑Heterocycles
SnAP Reagents for the Synthesis of Spirocycles and Bicycles
Reagent Assembles Ring Motifs Common In Drugs
ACS Meeting News Highlighted in C&EN News
Commercially available SnAP reagents
SnAP reagents are commercially available through Sigma Aldrich
Sigma Aldrich SnAP Review
Review on commercially available SnAP reagents in Aldrichimica Acta.
SnAP Reagents - eROS
SnAP Reagents - eROS
Silicon Amine Reagents for the Photocatalytic Synthesis of Piperazines from Aldehydes and Ketones
Silicon Amine Reagents for the Photocatalytic Synthesis of Piperazines from Aldehydes and Ketones
Continuous Flow Synthesis of Morpholines and Oxazepanes with Silicon Amine Protocol (SLAP) Reagents and Lewis Acid Facilitated Photoredox Catalysis
Photocatalytic coupling of aldehydes and silicon amine protocol (SLAP) reagents enables the simple, scalable synthesis of substituted morpholines, oxazepanes, thiomorpholines, and thiazepanes under continuous flow conditions. Key to the success of this process is the combination of an inexpensive organic photocatalyst (TPP) and a Lewis acid additive, which form an amine radical cation that is easily reduced to complete the catalytic cycle. Di- and trisubstituted SLAP reagents are formed in one step by an iron-catalyzed aminoetherification of olefins.
SnAP Reagents for the Synthesis of Piperazines and Morpholines
Substituted piperazines and morpholines are valuable structural motifs in biologically active compounds, but are not easily prepared by contemporary cross-coupling approaches. In this report, we introduce SnAP reagents for the transformation of aldehydes into N-unprotected piperazines and morpholines. This approach offers simple, mild conditions compatible with aromatic, heteroaromatic, aliphatic, and glyoxylic aldehydes and provides mono- and disubstituted N-heterocycles in a single step.
SnAP reagents for the one-step synthesis of medium-ring saturated N-heterocycles from aldehydes
Interest in saturated N-heterocycles as scaffolds for the synthesis of bioactive molecules is increasing. Reliable and predictable synthetic methods for the preparation of these compounds, especially medium-sized rings, are limited. We describe the development of SnAP (Sn amino protocol) reagents for the transformation of aldehydes into seven-, eight- and nine-membered saturated N-heterocycles. This process occurs under mild, room-temperature conditions and offers exceptional substrate scope and functional-group tolerance. Air- and moisture-stable SnAP reagents are prepared on a multigram scale from inexpensive starting materials by simple reaction sequences. These new reagents and processes allow widely available aryl, heteroaryl and aliphatic aldehydes to be converted into diverse N-heterocycles, including diazepanes, oxazepanes, diazocanes, oxazocanes and hexahydrobenzoxazonines, by a single synthetic operation.
Catalytic Synthesis of N-Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents
Commercially available SnAP (stannyl amine protocol) reagents allow the transformation of aldehydes and ketones into a variety of N-unprotected heterocycles. By identifying new ligands and reaction conditions, a robust catalytic variant that expands the substrate scope to previously inaccessible heteroaromatic substrates and new substitution patterns was realized. It also establishes the basis for a catalytic enantioselective process through the use of chiral ligands.
SnAP-eX Reagents for the Synthesis of Exocyclic 3-Amino- and 3-Alkoxypyrrolidines and Piperidines from Aldehydes
SnAP-eX (tin amine protocol, exocyclic heteroatoms) reagents allow the single-step transformation of aldehydes and ketones into 2,3-disubstituted pyrrolidines and piperidines containing exocyclic amine or alkoxy groups. These saturated N-heterocycles are of importance in modern drug discovery approaches and are prepared in moderate yields using an operationally simple protocol that is compatible with a range of functional groups and heterocyclic aldehydes.
Copper Promoted Oxidative Coupling of SnAP Hydrazines and Aldehydes to Form Chiral 1,4,5-Oxadiazepanes and 1,2,5-Triazepanes
SnAP (Sn (tin) amine protocol) hydrazine reagents and aldehydes undergo oxidative, copper mediated coupling to form substituted 1,4,5-oxadiazepanes and 1,2,5-triazepanes. Unlike all prior reactions involving SnAP reagents, the SnAP hydrazine reagents undergo a molecular oxygen-assisted oxidative cyclization. The air- and moisture tolerant transformation accommodates a broad range of groups including electron-rich, electron-poor aromatic, heteroaromatic, and aliphatic aldehydes and is amenable to gram scale synthesis. These unusual, chiral heterocycles have unexpectedly large optical rotations, which may find use in optical materials.
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