Photochemical processes enabled by the direct excitation of organic intermediates

Resumen

The emerging field of photoredox catalysis has led to the development of new transformations due to the ability to generate radical intermediates under mild conditions. Traditionally, this relies on the use of a photocatalyst, which efficiently absorbs light and induces a single electron transfer (SET). However, the chemical reactivity of electronically excited molecules differs fundamentally from that in the ground state and new type of transformations could be unlocks. Recently, the Melchiorre group has been exploring the potential of some organic molecules and organocatalytic intermediates to directly reach an electronically excited-state upon visible-light absorption, to then switch on novel catalytic functions that are unavailable to the ground-state organocatalysis. In this regard, I focused on the development of a photochemical organocatalytic strategy for the direct enantioselective Mannichtype reaction of 2-alkylbenzophenones and cyclic benzoxathiazine-2,2-diones. This chemistry exploits the light-triggered enolization of 2-alkylbenzophenones to generate transient hydroxy-o-quinodimethanes intermediates. These reactive electronrich species, commonly called photoenols are sufficiently long-lived to productively engage in chemical reaction, mainly acting as dienes in [4+2]-cycloadditions with electron-poor olefins. Since the early discovery of these highly reactive intermediates, a variety of new transformations has been developed and recent studies demonstrated that the chemistry of the hydroxy-oquinodimethanes is not limited to cycloaddition-type manifolds, but it can be expanded to develop intermolecular addition processes. However, enantioselective catalytic transformations involving the photoenol intermediate have remained elusive until that organocatalysis has provided suitable tools to stereoselectively trap this fleeting intermediate. Specifically, we considered cyclic imines as suitable candidates for the interception of the photoenol intermeidate. Despite no literature precedent existed even for the racemic version of this reaction, we were motivated by the notion that imines are i) primed to organocatalytic activations, especially through non-covalent interaction, and ii) can generally participate in hetero-Diels Alder processes or in a 1,2 addition reaction. We started the optimization process reacting 2-alkylbenzophenones and cyclic benzoxathiazine-2,2-diones in the presence of a variety of H-bond chiral organocatalysts. The screening identified the dimeric cinchona alkaloid derivative (DHQ)2PHAL as the best candidate for promoting the transformation. After the evaluation of all the reaction parameters, we started to evaluate de generality of our reaction and the mechanism. Overall, we demonstrated that the photoenols, these fleeting intermediates can be stereoselectively intercepted by cyclic imines upon activation with a chiral organocatalyst derived from natural cinchona alkaloids. The developed method uses mild conditions and easily available substrates and catalyst, affording enantioenriched chiral amines that are difficult to synthesize by other approaches. In the second part of my doctoral studies, a photochemical cascade process that combines the excited-state reactivity of in situ formed chiral iminium intermediate and ground-state reactivity of enamine was developed. We demonstrated that selective photo-excitation of chiral iminium-ions, key intermediates in thermal asymmetric organocatalytic processes, turns them into strong oxidants (E*red ~ +2.4V). These could trigger the formation of radicals through SET oxidative fragmentation of a variety of organic substrates. We reasoned that, if the ground-state nucleophilic reactivity of enamine intermediate could be exploited to trigger a following process, this might form the basis for implementing a photochemical enantioselective cascade process. This new strategy would bring a conceptually new approach to organocascade catalysis, opening new opportunities for reaction design while combinin the fields of enantioselective photochemical radical reactions and classic polar ground-state organocatalysis. We envisioned that cyclopropanols could serve as suitable substrates for the proposed cascade sequence. Cyclopropanols can undergo a single-electron oxidation process, thus acting as single-electron donors (D) in the reaction with the excited iminium ion. Removal of one electron from the HOMO orbital results in the formation of unstable oxycyclopropyl radical cations. Such intermediates, because of the release of strain energy, have a strong tendency to undergo rapid ring-opening giving the 􀈕- ketoradical cations. This dystonic radical species possesses two distinct and ambivalent reactivity: a radical character and an electrophilic character. We hypothesized that this intermediate can satisfy our purpose to implement a photochemical organocatalytic cascade process. The SET event furnishes the 5􀊌-electron 􀈕-enaminyl radical intermediate, along with the 􀈕- ketoradical cations. Stereocontrolled radical coupling with the chiral 􀈕-enaminyl radical would then forge the first stereogenic center. The resulting ground-state enamine intermediate would then be well poised to promote an aldol cyclization step by reacting with the newly formed electrophilic ketone. Hydrolysis of the resulting intermediate releases the catalyst while affording the he cyclopentanols bearing three contiguous stereocenters. We started the optimization process reacting cinnamaldehyde, gem-difluorinated diarylprolinol silylether catalyst and TFA (trifluoroacetic acid) to promote the formation of the chiral iminium ion. The racemic 1,1,2,2-tetra-substituted cyclopropanol was selected as potential radical precursor. The experiments were conducted in CH3CN under irradiation by a single high-power (HP) LED (􀈜max = 415 nm). Pleasingly, we found that the cyclopentanol product was generated with high stereoselectivity. After the optimization of the reaction conditions, we demonstrated the generality of the photochemical cascade process. Mechanistic investigations revealed the origin of the asymmetric amplification and provided mechanistic information that could be pertinent for the development of new cascade processes. In summary, we have developed an enantioselective cascade process that combines the excited-state and ground-state reactivity of chiral organocatalytic intermediates. This transformation demonstrates the possibility of effectively merging a stereocontrolled radical pattern with a classical ionic process in a cascade sequence. Moreover, the photo-organocatalytic cascade reaction leads to stereochemically complex cyclopentanols, with high yield and excellent selectivity. In the third part of the PhD studies, a new photochemical strategy for the borylation of alkyl halides using bis(catecholato)diboron as the boron source was taken under investigation. This method exploits the ability of a nucleophilic dithiocarbonyl anion organocatalyst (DTC catalyst) to activate alkyl electrophiles by displacing a variety of leaving groups via an SN2 pathway generating in situ a photon-absorbing intermediate that upon visible light absorption affords radical through homolytic cleavage of the weak C-S bond. The radical generated can be intercepted by bis(catecholato)diboron and afford the alkyl boronic esters product. The nucleophilic organic catalyst can activate alkyl electrophiles such as benzylic and allylic chlorides, bromides, and mesylates, which were inert to or unsuitable for previously reported metal-free borylation protocols. This catalytic method to generate radicals does not rely on the redox properties of the substrates. Therefore, it grants access to alkyl boronic esters from readily available but difficult to reduce electrophiles. In contrast with the other strategies developed, the organic catalyst contain a chromophore unit that is essential for the photoactivation of the substrate.