Bespoke SnAP Reagents for the Synthesis of C-Substituted Spirocyclic and Bicyclic Saturated N-Heterocycles

Abstract

The precise placement of C-substituents on bicyclic and spirocyclic N-heterocycles is readily achieved by the combination of aldehydes and new SnAP reagents. The substituted SnAP reagents are readily prepared from simple starting materials and couple with a variety of aromatic and heteroaromatic aldehydes at room temperature under operationally simple conditions to deliver substituted morpholine and piperazine products.

Catalytic Synthesis of N‐Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents

“…Thet olerance of these conditions towards heterocyclic carboxaldehydes with heteroatoms in the ortho position (6e-6h)i sn oteworthy as no product was observed under the previously reported stoichiometric conditions with one equivalent of Cu(OTf) 2 . [3][4][5][6] Thecatalytic conditions were unfortunately not applicable to the formation of larger rings,such as diazepanes,which were easily obtained under the stoichiometric conditions.K etones also did not prove to be viable substrates under these conditions and afforded the desired spirocycles in low yields.…”

ChemInform Abstract: Evaluating New Chemistry to Drive Molecular Discovery: Fit for Purpose?

“…[6,7,25a] However, the impact of as caffold on the three-dimensionality of its derivatives is often not obvious by simple inspection. [23] A) Exemplar reaction of benzaldehyde with aSnAP reagent. [27] We analyzed the diversity of molecular shapes that may be Bode's approach to nitrogen-containing heterocycles using SnAP reagents.…”

“…Theability to elaborate diverse,novel scaffolds for library enrichment in asynthetically efficient manner is asignificant challenge.B ode and co-workers have developed SnAP reagents that enable the synthesis of structurally diverse heterocycles from aldehydes or ketones (Figure 4). [23] As an example,condensation of the amino-substituted stannane 2a with benzaldehyde gives the corresponding morpholine 3a ( Figure 4A). Arange of SnAP reagents (many commercially available) has been described, each leading to distinctive heterocyclic scaffolds.T he potential value of the products as building blocks for drug discovery has been noted.…”

“…[27] We analyzed the diversity of molecular shapes that may be Bode's approach to nitrogen-containing heterocycles using SnAP reagents. [23] A) Exemplar reaction of benzaldehyde with aSnAP reagent. B) Additionalscaffolds that have been, or might be, prepared from benzaldehyde using the approach.C )Mean molecular properties of virtual libraries derived from scaffolds 3 after one decoration reaction.…”

Catalytic Synthesis of N‐Unprotected Piperazines, Morpholines, and Thiomorpholines from Aldehydes and SnAP Reagents

“…An advantage of SnAP chemistry is the ability to incorporate various substituents into the reagents themselves, facilitating the synthesis of substituted N‐heterocycles, often as single diastereomers 3. 4, 6b To date, we have explored substitution at every position except for that adjacent to the tributyltin moiety. To complete the study on ring substitution, we investigated the use of α‐bis‐substituted SnAP reagents 7 and 9 , which would afford two adjacent stereocenters upon ring closure.…”