Rapid Photoassisted Access to N,O,S‐Polyheterocycles with Benzoazocine and Hydroquinoline Cores: Intramolecular Cycloadditions of Photogenerated Azaxylylenes

Abstract

o-Azaxylylenes have been known for half a century, [1] but remained in relative synthetic obscurity until a decade ago, when Corey and Steinhagen reported their first preparation under simple mild conditions by base-induced elimination of hydrogen chloride from derivatives of o-chloromethylaniline. [2] It was noted that "Surprisingly, simplest method possible for o-azaxylylene production … has never been reported."Synthetically useful reactions of o-xylylenes (i.e. allcarbon o-quinodimethanes) are plentiful, [3] and their generation from aromatic o-alkyl ketones by an intramolecular photoinduced hydrogen abstraction is well documented. [4] Given this fact, it was surprising to us that the equally simple photogeneration of o-azaxylylenes from o-aminoketones by an excited-state intramolecular proton transfer (ESIPT) [5] has never been utilized in synthetic chemistry.It is conceivable that such implementation was attempted but failed due to the fast back proton transfer successfully competing with bimolecular cycloadditions. Intramolecular proton transfers from one heteroatom to another (and back) are fast; a typical example is the much studied photophysics of salicylaldehyde or o-hydroxyacetophenone, although the elusive tautomeric form is not impossible to characterize. [6] We, however, found that the intramolecular cycloaddition reactions of o-azaxylylenes photogenerated by excited-state proton transfer can successfully compete with the back proton transfer. Herein, we report the first example of [4 + 2] and [4 + 4] cycloaddition reactions of photogenerated azaxylylenes with unsaturated pendant groups; this reaction offers expeditious access to a diverse array of N,S,O-polyheterocycles with mostly unprecedented topologies (Scheme 1).As the azaxylylenes are expected to act as acceptors in the inverse-electron-demand cycloaddition reactions, we synthesized photoactive azaxylylene precursors 1 and 4 by coupling o-aminoketones with furan-or thiophenepropionic acid chlorides. [7] These o-acylamido precursors have broad UV Scheme 1. Photogeneration of azaxylylenes and their intramolecular photocyclizations. Scheme 2.[4+2] and [4 + 4] cycloadditions of photogenerated azaxylylenes to the furan and thiophene pendant groups. 5' a denotes the minor hydroxy epimer in the thiophene [4 + 2] cycloadduct. Yields of the isolated products are shown.

A Highly Enantio‐ and Diastereoselective Synthesis of Spirocyclic Dihydroquinolones via Domino Michael Addition‐Lactamization of ortho‐Quinone Methide Imines

“…ortho ‐Quinone methide imines ( o ‐QMIs) have recently been identified as very powerful synthetic intermediates en route to various benzannulated nitrogen heterocycles . Generated either through thermolysis, photolysis or acid/base‐catalyzed elimination of the requisite substrates, they react with electron‐rich dienophiles in [4+2]‐cycloadditions or with nucleophiles via conjugate addition reactions and in both cases benefit from restoration of aromaticity. More recently, some catalytic, enantioselective protocols have been developed in this context which employ chiral transition metal complexes,, N ‐heterocyclic carbenes,, and squaramide‐, or thiourea‐based hydrogen bond donors, respectively.…”

Synthesis of a crystallochromic indolizine dye by a base- and catalyst-free photochemical route

“…Although azonia-photoenols are not known, at least aza-photoenols have been generated and subsequently trapped with dienophils. 17 However, in the case of pyridinium substrates 1a-d, the resonance structure of a pyridinium ylide, e.g. 1a Y , should also be considered that contributes significantly to the overall electron density and thus to the reactivity.…”

Visible‐Light‐Driven Aza‐ortho‐quinone Methide Generation for the Synthesis of Indoles in a Multicomponent Reaction

“…[2] In contrast to the chemistry of o-QMs, which can be formed from ar ange of precursors, [3] the chemistry of aza-o-QMs has yet to be fully investigated as there are no general methods for their convenient generation.Tr aditional methods for the in situ formation of aza-o-QMs mainly rely on pyrolysis, [4] UV photolysis, [5] as well as base [6] or Brønsted acid [7] promoted 1,4-elimination or tautomerization. This process enables an efficient multicomponent reaction of 2-vinylanilines,h alides,a nd sulfur ylides,a nd has aw ide substrate scope and good functional group tolerance.…”

“…Tr aditional methods for the in situ formation of aza-o-QMs mainly rely on pyrolysis, [4] UV photolysis, [5] as well as base [6] or Brønsted acid [7] promoted 1,4-elimination or tautomerization. In practice,pyrolysis and UV photochemical processes are rarely exploited in organic synthesis owing to the requirement of unstable precursors or their limited substrate scope and functional-group tolerance.B rønsted base and acid mediated 1,4-elimination reactions of orthochloromethyl anilines [8] and ortho-amino benzhydryl alcohols [9] have recently attracted renewed interest in organic synthesis as powerful and benign methods for aza-o-QM generation.…”