Aqueous Amine-Tolerant [2+2] Photocycloadditions of Unactivated Olefins

Abstract

The Kochi−Salomon reaction is the only photochemical [2+2] cycloaddition capable of combining two electronically unactivated olefins into a cyclobutane. Yet, the reaction has remained largely unexplored and suffers many drawbacks, most notably an intolerance to Lewis/Brønsted basic amines and amides. Since these groups are ubiquitous in biologically active pharmaceuticals, an amine-tolerant Kochi−Salomon reaction would greatly facilitate rapid exploration of novel drug scaffolds. Herein, we disclose a transformation that is run in water with the most widely available Cu(II) salts and mineral acids. Furthermore, we apply this methodology to synthesize a variety of amine-containing cyclobutanes, including known and novel pharmacological analogues.

Iron-Catalyzed Synthesis of Conformationally Restricted Bicyclic N-Heterocycles via [2+2]-Cycloaddition: Exploring Ring Expansion─Mechanistic Insights and Challenges

“…Notably, even p-chlorophenylsulfonates underwent conversion, yielding 10, indicating that the [2 + 2]-cycloaddition reaction is faster than the conceivably competitive Ar−Cl oxidative addition. Additionally, tert-butyloxycarbonyl (Boc) (11), benzyl (12), and trifluoroacetyl (13) all underwent full conversion under the same conditions. Interestingly, N-Bocprotected diallylamines underwent conversion more slowly than their tosyl analogues, but the catalyst loadings could be lowered to 0.5 mol %.…”

“…10 significant improvement was subsequently reported by Burns and Mansson, where the [2 + 2]-cyclization of diallylamines could be achieved under photolytic conditions employing simple copper salts in water media (Figure 2a). 11 However, since the Kochi−Salomon reaction relies on the formation of an alkene-copper intermediate which can be activated by UV light, using this method for substrates that have longer unconjugated chains would be challenging, as the absorption wavelengths for such copper-diene complexes are not compatible with standard UV reactors. In such cases, the use of non-photocatalytic methods is a promising alternative (Figure 2b).…”

“…Recently, Yoon and co-workers reported a modification of the Kochi–Salomon reaction using silver activated copper photocatalysts to give azabicyclo[3.2.0]­heptanes from unactivated dienes . A further significant improvement was subsequently reported by Burns and Mansson, where the [2 + 2]-cyclization of diallylamines could be achieved under photolytic conditions employing simple copper salts in water media (Figure a) . However, since the Kochi–Salomon reaction relies on the formation of an alkene-copper intermediate which can be activated by UV light, using this method for substrates that have longer unconjugated chains would be challenging, as the absorption wavelengths for such copper-diene complexes are not compatible with standard UV reactors.…”

Direct Alkylative Reductive Amination using 1-Allylsilatrane

“…1,2 Access to heterocycles of various ring sizes ranging from azetidines (four) and pyrrolidines (five) to piperidine and quinoline analogues (six) demonstrates the versatile utility of this particular scaffold. [3][4][5][6][7] Homoallylic amines are typically prepared via the allylation of imine substrates in the presence of a Lewis acid catalyst. Examples of allyl nucleophiles include allylstannanes and allylic organometallics, 8 however these reagents can suffer from air and moisture sensitivity.…”

A Metal-Free Cyclobutadiene Reagent for Intermolecular [4 + 2] Cycloadditions

“…Nevertheless, these complexes have demonstrated cyclobutadiene’s utility in the synthesis of natural products, cubanes, and other highly strained hydrocarbons . We have recently developed other synthetic approaches to prepare ladderene hydrocarbons and ladderene polymers, and realized the potential of cyclobutadiene for preparing such scaffolds.…”