SnAP reagents for the one-step synthesis of medium-ring saturated N-heterocycles from aldehydes

Abstract

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

“…The tolerance of these conditions towards heterocyclic carboxaldehydes containing heteroatoms in the ortho-position (6e-6h) is noteworthy as no product was observed with the previously reported stoichometric conditions using 1.0 equiv Cu(OTf)2. [3][4][5][6] The catalytic conditions were unfortunately not applicable to the formation of larger rings, such as diazepanes, which work well under stoichiometric conditions. Ketones also did not prove to be viable substrates under these conditions and afforded the desired spirocycles in low yields.…”

“…This operationally simple process provides facile, one-step access to C-substituted thiomorpholines, [3] morpholines, piperazines, [4] diazepanes and other medium-ring heterocycles [ 5 ] and spirocyclic structures ( Figure 1). [ 6 ] Many of these SnAP reagents are now commercially available and SnAP chemistry is finding widespread use in industry.…”

“…The need for stoichiometric copper is also at odds with our current mechanistic hypothesis, which postulates an overall redox neutral reaction. [3,5] We attributed the need for stoichiometric copper to product inhibition -a common obstacle for metal catalyzed reactions in which the products are more basic than the starting materials. [ 7 ] Second, aldehydes with proximal heteroatoms do not undergo cyclization.…”

Recent contributions to the Diversity-Oriented Synthesis (DOS) mediated by iminium ions through multicomponent Mannich-type reactions

“…69,70 In fact, an exhaustive searching of the literature revealed that very few synthetic approaches for non-fused 1,4-oxazepanes have been reported. [71][72][73] Because of the potential synthetic utility of the γ-aminoalcohols described in Tables 2 and 3 of our previous sections 4 and 5, we envisioned two alternative and straightforward routes for the synthesis of diversely substituted 1,4-oxazepanes 36 via an intramolecular etherification reaction of N-tethered bis-alcohols type 24 and 31 as the key intermediates for these processes. 74 Initially, we planned a three-component Mannich-type reaction/intramolecular etherification sequence under catalyst-free conditions in order to construct the 1,4-oxazepane framework type 36, (Scheme 13).…”

Catalytic Asymmetric Synthesis of α‐Arylpyrrolidines and Benzo‐fused Nitrogen Heterocycles

“…[28] In these cases,wefound that the use of L3 and dimethoxy(methyl)silane (DMMS) not only improved the enantioselectivity,b ut also led to higher yields. Successful construction of the enantioenriched tetraisohydroquinoline led us to examine dibenzo-fused nitrogen heterocycles with medium ring sizes, [32] since many compounds with these structural elements are found in pharmaceuticals and bioactive alkaloids (Scheme 2A). [30] For example,t he synthesis of a-phenylpiperidine 5 resulted in alower yield (Scheme 1A)than the corresponding a-phenylpyrrolidine 2a (45 %v s. 95 %).…”