Download PDF
Synlett 2022; 33(02): 116-128
DOI: 10.1055/a-1403-4613
account
EuCheMS Organic Division Young Investigator Workshop

Unlocking the Synthetic Potential of Light-Excited Aryl Ketones: Applications in Direct Photochemistry and Photoredox Catalysis

Javier Mateos 
,
Sara Cuadros
,
Alberto Vega-Peñaloza
,
Luca Dell’Amico  ∗

This work was supported by the Università degli Studi di Padova (University of Padova) (P-DiSC#11BIRD2020-UNIPD) and the Fondazione Cassa di Risparmio di Padova e Rovigo (CariParo Foundation) (Synergy, Progetti di Eccellenza 2018) (L.D). S.C. thanks the DiMED at UniPD for a postdoctoral fellowship.
› Further Information
 
 PDF Download Permissions and Reprints All articles of this category


Abstract

In this Account, we summarize the contributions of our group to the field of photochemistry and photocatalysis. Our work deals with the development of novel synthetic methods based on the exploitation of photoexcited aryl ketones. The application of new technologies, such as microfluidic photoreactors (MFPs), has enhanced the synthetic performance and scalability of several photochemical methods, e.g., Paternò–Büchi and photoenolization/Diels–Alder processes, while opening the way to unprecedented reactivity. In addition, careful mechanistic analysis of the developed methods has been instrumental in disclosing a new family of powerful organic photocatalysts that can mediate several thermodynamically extreme photoredox processes.

1 Introduction

1.1 Shining Light on Aryl Ketones: From the Historical Background to Recent Synthetic Applications

1.2 Preliminary Mechanistic Considerations

2 Synthetic Transformations Driven by Triplet State Benzophenones

3 Synthetic Transformations Driven by Triplet State o-Alkyl-Substituted Benzophenones

4 The Evolution of Aryl-Ketone-Derived Products: Applications in Organophotoredox Catalysis

5 Conclusions and Future Directions


#

Key words

synthetic photochemistry - photoredox catalysis - microfluidic photoreactions - carbonyl compounds - ketones

Biographical Sketches

Zoom Image

Alberto Vega-Peñaloza (left) graduated in pharmaceutical chemistry at Universidad Michoacana (Mexico). He obtained his Ph.D. at the CINVESTAV (Mexico) under the supervision of Prof. Eusebio Juaristi. In 2014 he joined the group of Prof. Paolo Melchiorre at ICIQ in Spain as a postdoctoral researcher. In 2018 he was awarded the Seal of Excellence UniPD grant by the University of Padova (Italy). His research involves the development of novel photocatalytic systems to provide sustainable synthetic methods.


Sara Cuadros (second from left) is from Benidorm (Spain) and she graduated from the University of Alicante with distinction (2014). Sara obtained her M.Sc. and Ph.D. degrees working in the field of enantioselective photochemistry under the supervision of Prof. Paolo Melchiorre at the ICIQ in Spain. She is currently a postdoctoral researcher at the DiSC – DiMED at Padova University (UniPD). Her research focuses on the synthesis of novel positron emission tomography (PET) radioligands for functional imaging.


Luca Dell’Amico (second from right) completed his Ph.D. in organic chemistry at the University of Parma (Italy) under the supervision of Prof. Franca Zanardi in 2014. He spent a research period at the Center for Catalysis, Århus University (Denmark), working with Prof. Karl Anker Jørgensen. From 2014 to 2016 he was a Marie Curie COFUND fellow in the group of Prof. Paolo Melchiorre at ICIQ, Tarragona (Spain). In 2017 he started his independent career at Padova University (Italy). He was awarded the G. Ciamician Medal 2019 and the Thieme Chemistry Journals Award 2020. His research focuses on the development and mechanistic understanding of new photochemical processes.


Javier Mateos (right) was born in Vilafranca del Penedès, a small village close to Barcelona. After obtaining his M.Sc. degree in organic chemistry under the supervision of Prof. Antoni Riera, Javier moved to the University of Padova to pursue his doctoral studies under the supervision of Dr. Luca Dell’Amico. His research involves the development of new photochemical processes on the basis of a rational approach.

1

Introduction

1.1

Shining Light on Aryl Ketones: From the Historical Background to Recent Synthetic Applications

The carbonyl system is one of the most prevalent functional groups in Nature. It is present in several classes of organic compounds and macromolecules that are essential in biological processes. Under classical two-electron polar conditions, the carbonyl group is prone to undergo addition, reduction or reductive amination, among other remarkable transformations.[1] Also, it can act both as a pronucleophile (when α-enolizable positions are present) or as an electrophile in aldol-based chemistry.[2] This broad reactivity is routinely exploited for the formation of new C–C and C–heteroatom bonds within small building blocks and more complex organic molecules. Carbonyl substrates have also shown great synthetic potential in the photochemical domain. Their electronically excited states offer new reactivity pathways that cannot be accessed through classical thermal activation,[3] thus introducing new synthetic strategies and unprecedented disconnections for the construction of complex molecular targets (Scheme [1], right).

Zoom Image
Scheme 1 The classical ground state reactivities of the carbonyl groups in aryl ketones 1 and 2 gives access to tertiary alcohols 3, secondary alcohols 4, and amines 5. The reactivities of the excited states of 1 and 2 enables the formation of a diverse class of molecular scaffolds, such as oxetanes 7, tetrahydronaphthalenols 8 and functionalized benzophenones 9. Nu: nucleophile; A: acceptor.

In 2016, our group began a research program dealing with the development of novel light-driven methods that enable the sustainable formation of synthetically relevant organic building blocks from simple ketones. To increase the synthetic potential of such methods, we relied on the use of microfluidic photoreactors (MFPs), which provide important advantages compared to the use of conventional in-batch photochemical conditions (Figure [1]).[4] In fact, the use of MFP setups offers an enhanced and more uniform irradiation of the reaction mixture, thanks to the large surface-to-volume ratio of the microchannel.[5] As a result, the reaction time of several light-driven reactions can be shortened, often avoiding the formation of undesired by-products as well as product decomposition by over-irradiation. Moreover, photochemical processes carried out in MFPs are readily amenable to large-scale synthesis since the reactants can be continuously pumped into the photoreactor.[4d] [e] Other beneficial features of MFP setups include: (i) fast mixing of the reactants, which provides a uniform concentration of the starting materials along the microchannel; (ii) favorable heat dissipation, (iii) more efficient mass transfer in biphasic (liquid–liquid or gas–liquid) reactions, and (iv) enhanced safety of the overall chemical process.

Zoom Image
Figure 1 A simplified scheme of a microfluidic photoreactor (MFP) setup, and the advantages over common in-batch reaction conditions

Our initial investigations within this research frame focused on the use of aryl ketones as light-absorbing substrates (1 and 2 in Scheme [1]). Under the classical polar domain, the reactivity of aryl ketones 1 or 2 is virtually identical, leading to: (i) tertiary alcohols 3, (ii) secondary alcohols 4, or (iii) amines 5 (Scheme [1], left). On the other hand, under photochemical conditions, the substitution pattern on the aromatic rings plays a crucial role, largely impacting on both the product outcome and the reaction mechanism.[6] In fact, the incorporation of a methyl group at the ortho-position of 1 leads to a whole change in reactivity, and therefore to a different family of product scaffolds (Scheme [1], right). Specifically, in the presence of the alkene 6, the electronically excited aryl ketone 1* undergoes [2+2]-cycloaddition affording the oxetane 7. In sharp contrast, the excitation of 2 by light irradiation triggers the rapid formation of the enolic species 2′, which can then undergo (i) [4+2]-cycloadditions with 6 leading to the valuable carbocyclic scaffold 8, or (ii) vinylogous nucleophilic additions with a suitable acceptor, giving access to the functionalized benzophenone 9.

In this Account, we assess the contributions from our group and those of other laboratories related to the use of excited aryl ketones for the construction of relevant molecular targets and pharmacophoric cores. Subsequently, we describe how these findings have inspired and guided further evolution of the field towards innovative applications in photoredox catalysis, unlocking previously inaccessible light-driven transformations.


# 1.2

Preliminary Mechanistic Considerations

The understanding of the reaction mechanisms in which both ground and excited state ketones are involved is a key element in developing new classes of chemical transformations (Scheme [2]). The ground state reactivity of diaryl ketones is explained by means of the polarity difference between the carbon and oxygen atom in the C=O bond. The C atom, where a positive charge density is located, is prone to react with nucleophilic species. In particular, the addition of the nucleophile (Nu) to the C=O bond occurs through the overlap between the most energetic electron pair (HOMO) of the Nu and the empty π* orbital of the carbonyl compound (LUMO) (Scheme [2], left). This addition occurs in a given trajectory, known as the Bürgi–Dunitz angle.[7] In such an event, the initial planar geometry is lost forming a tetrahedral intermediate. The relative structural arrangements of the reagents determine the final reaction outcome. Several synthetic strategies point to an increase in the HOMO–LUMO interaction by moving the orbitals energetically closer. In line with this assumption, carbonyl compounds can be activated by lowering the LUMO energy by means of coordination with Lewis acids or by protonation with Brønsted acids.[8]

Zoom Image
Scheme 2 Explanation of the reactivity of diaryl ketones in the ground and excited states. Nu: nucleophile.

The importance of the anti-bonding π* orbital in carbonyl compounds is not limited to the ground state reactivity. After excitation with light, this MO (molecular orbital) is pivotal in controlling the reaction outcome, being connected to the amphoteric character of S1 (Scheme [2], right). In this excited state, one electron lies in the π* orbital, generating an electron-rich π system. On the other hand, the semi-occupied np orbital of the oxygen atom has an electrophilic nature, thus reversing the original polarity of the carbonyl, without the need of any chemical modification.[2] Finally, via efficient inter-system crossing (ISC) of the S1 state, a long-lived triplet state T1 is produced with an analogous charge distribution. This is a key reactive intermediate in most of the photochemical transformations involving aromatic ketones.[9] The photophysical characterization of this fleeting intermediate (T1 ) has been instrumental to the comprehension of the reaction mechanisms.[6]

What makes aromatic ketones so special under photochemical conditions? To answer this question, we need to consider the electronic transitions for both aromatic and aliphatic ketones (Figure [2]). These types of substrates have two non-bonding lone pairs on the oxygen atom occupying two non-degenerate np and ns orbitals. The np lone pair (grey orbital in Figure [2]) is higher in energy than the bonding π-MO (pale blue orbital in Figure [2]) situated on the electronegative oxygen atom.[9b] Therefore, the first electronic transition is attributed to the promotion of an electron from the np orbital to the first anti-bonding π* orbital (orange orbital in Figure [2, a] and b) to reach the first singlet state S1 (1nπ* transition, Figure [2, a] and b). This transition is common for both aromatic and aliphatic carbonyl compounds. Nevertheless, the excitation of diaryl ketones (Figure [2, a]) efficiently generates the triplet manifold with a negligible energy loss. This fact is in sharp contrast with the aliphatic counterparts (Figure [2, b]), making aromatic ketones and benzophenones, in particular, excellent reagents for light-triggered reactions.

Zoom Image
Figure 2 Electronic transitions of carbonyl compounds in (a) aromatic ketones, and (b) aliphatic ketones. ISC: inter-system crossing; IC: interconical system.

Commonly, the ISC process of carbonyl compounds to the T1 state is fast and efficient (estimated kISC ~10–11 s–1)[9] when the π,π* state (T2 ) is energetically close to the singlet state (S1 ). This is the case for aryl ketones in which the 3(π,π*) T2 state is stabilized (Figure [2, a]). The ISC process is more favorable if it involves a change in orbital type (spin-orbit coupling). This change takes place in the S1 (n,π*) → T2 (π,π*) transition of aromatic ketones (Figure [2, a]). Subsequently, the reactive T1 state is reached via interconical system (IC). Contrarily, alkyl ketones have an S1 state with a longer lifetime. This is because the energy gap between S1 and T2 is higher (Figure [2, b]). Therefore, the ISC rates are slower and inefficient with respect to diaryl ketones.[9]


#
# 2

Synthetic Transformations Driven by Triplet State Benzophenones

The photochemical [2+2]-cycloaddition of an alkene to an excited carbonyl compound is known as the Paternò–­Büchi (PB) reaction.[9] [10] [11] This transformation was historically established with the use of UV-light sources and exploits the excited state reactivity of carbonyl compounds to generate functionalized oxetanes 7. Over the years, the mechanism of the PB reaction has been the subject of intense debates.[12] It is now well known that its regio- and stereoselective outcome is highly dependent on the spin multiplicity of the excited carbonyl substrate (see Scheme [1]).[13] In fact, aromatic ketone 1 reacts with alkene 6 through the n,π* triplet state (1*-T1 ), generating the triplet 1,4-biradical intermediate I (Scheme [3, a]). This latter species must undergo a spin change to reach the singlet energy surface required for the subsequent radical recombination leading to 7. Importantly, the lifetime of the triplet biradical I (1–10 ns)[9c] is long enough to allow the rotation of the C2–C3 bond, which results in the formation of cis- and trans-isomers, with low diastereocontrol. On the other hand, aliphatic carbonyl compounds 11, react mainly through the n,π* single state (11*-S1 in Scheme [3, b]). In this scenario, the addition of the excited carbonyl substrate 11* to the alkene 6 proceeds in a concerted manner,[14] or through the initial generation of a short-lived singlet biradical intermediate II that rapidly cyclizes to form the oxetane 12. This alternative mechanistic pathway ensures higher levels of diastereoselectivity.

Zoom Image
Scheme 3 Mechanism and diastereoselective outcome of the ­Paternò–Büchi reaction with (a) aromatic ketones, and (b) aliphatic ­ycarbonyls. ISC: inter-system crossing.

The electronic properties of the alkene also influence the regio- and diastereoselectivity of the process. The reactivity towards the amphoteric nπ* excited state of the carbonyl group is controlled by the relative positions of the alkene HOMO and LUMO. On the one hand, electron-rich alkenes 6′ preferentially interact with the electrophilic half-filled n-orbital of the excited carbonyl. In this case, the approach of the oxygen atom is predicted to happen perpendicularly to the π-plane (Scheme [4, a]). This interaction leads to the formation of the C–O bond and therefore, to the diradical species III. On the other hand, electron-deficient alkenes 6′′ tend to react with either the oxygen or the carbon atom of the carbonyl function in 1 (Scheme [4, b]). The π systems of both reagents interact to form the exciplex IV, which is stabilized by charge transfer.[10] In this case, the cy­cloaddition process occurs in a quasi-concerted manner, through the formation of a fleeting diradical that immediately evolves to yield the oxetane product 7′′. Due to the fast radical recombination occurring in the emerging diradical intermediate, the stereochemical information is generally preserved in the case of exciplex formation. Nevertheless, these pathways do not exclude mechanisms involving photoinduced electron transfer (PET). The formation of radical ion pairs involving electron-poor carbonyl compounds and electron-rich alkenes has been also observed.[15] Usually, the PB reactions involving a PET process are more selective in stereo- and regiochemical meanings than those involving diradical intermediates.[13]

Zoom Image
Scheme 4 The reactivity of an excited carbonyl compound with (a) electron-rich, and (b) electron-poor alkenes. EDG: electron-donating group; EWG: electron-withdrawing group.

The success of the PB reaction in organic synthesis is due to the high relevance of the oxetane scaffold, which is produced in a one-step process with complete atom economy. In fact, oxetanes are promising structural modules in drug discovery,[16] which are arduous to prepare by polar means due to the high ring strain. Even though the PB reaction is one of the most direct ways to synthetize oxetanes, this reaction has some disadvantages. For instance, this transformation may compete with hydrogen atom transfer (HAT) processes and Norrish type I reactions (α-cleavage of the carbonyl moiety).[9] Further limitations of the reported PB-based methods are posed by the lack of generality and selectivity, leading to high substrate-dependency and poor regio- and diastereocontrol.[10] [11] [12] In addition, its implementation in large-scale synthesis has often been hampered by the need for UV-light sources (Hg or Xe lamps) that require specific reaction setups.

With the aim to develop new synthetic strategies to efficiently generate complex compounds embodying features of natural molecules, our group started investigating the use of indoles under a dearomatization–PB process. The effective realization of this process would allow the construction of biorelevant three-dimensional indolinic scaffolds from available planar aromatic feedstocks.[17] We initiated our attempts by testing different indole substrates in the presence of benzophenone (1a) (Scheme [5]).[18] Irradiation at 365 nm of an equimolar mixture of 1a and 13a furnished the strained fused oxetane 14a in 55% yield. Moreover, 15a was also detected in 25% yield as a result of the competitive HAT pathway. In this photoreductive process, an excited carbonyl compound undergoes intermolecular hydrogen abstraction to form a ketyl radical, which subsequently recombines to form either alcohols or diols. Under these conditions, we observed the formation of pinacol dimer 15a, consuming large amounts of 1a and rendering difficult the purification of the desired product 14a. An extensive screening of the reaction parameters was unsuccessful and the formation of the undesired by-product 15a could not be minimized.

Zoom Image
Scheme 5 Reaction optimization of the PB process under visible-light irradiation. Light sources: 365 nm (9 W bulb); 405 nm (60 W LEDs).[18]

The selective irradiation of a reaction mixture in a controlled manner is known to avoid the formation of undesired side products.[19] In fact, the keystone was found to be the use of a light source at the borderline of the absorption of benzophenone (1a). This greatly reduced the amount of the 1a-T1 state produced in the reaction mixture, thus driving the process towards the desired reactivity with the indole 13a. Indeed, by using a selective 405 nm LED, we obtained the oxetoindolinic product 14a in quantitative yield (>98%) in a reaction time of only 7 hours (Scheme [5]).

To prove our hypothesis on the selective formation of 14a, we performed a three-dimensional analysis of the excitation/emission spectra of 1a (Figure [3]). As expected, excitation at 365 nm resulted in the generation of an intense emission signal (orange region), indicating the formation of a high concentration of the T1 ketone excited state. This increases the possibilities for the reactive triplet ketone to undergo a HAT process. We also demonstrated that excitation at 405 nm results in the generation of the T1 excited state, although in a much-reduced amount (green region, Figure [3]). In light of these data, we confirmed that the controlled formation of T1 can channel the reactivity towards the desired PB pathway.

Zoom Image
Figure 3 Emission 3D-matrix of benzophenone (1a) in acetone under the optimized reaction conditions[18]

With the optimum conditions in hand, we synthetized more than 35 highly functionalized fused oxetoindolinic polycycles, which were obtained in a rapid and selective manner (for selected examples, see Scheme [6]). These products were prepared from simple and available indole derivatives and diverse aromatic ketones in high yields (up to >98%) and with excellent regio- and diastereocontrol (up to >20:1).[18] Prochiral benzil derivatives also reacted in a highly diastereoselective manner under 465 nm irradiation to give products 14f and 14h. In this way, we generated dearomatized products embodying three contiguous all-substituted stereocenters. Furthermore, bioactive molecules such as N-protected tryptophan, tryptamine, and melatonin, were successfully used as starting materials. These results highlight the synthetic potential of this PB method.

Zoom Image
Scheme 6 Selected reaction scope of the developed visible-light PB process. Ace: acetone. Light sources: 405 nm (60 W LEDs); 465 nm (24W LEDs).[18]

Moreover, the application of microfluidic photoreactors allowed us to implement the PB method with superior performance and scalability (Scheme [7]). We performed a large-scale microfluidic synthesis of 14a, which was obtained with improved productivity with respect to the batch setup (>98% yield and 0.066 mmol∙h–1 in flow vs >98% yield and 0.008 mmol∙h–1 in batch) (entries 1 vs 2).

Encouraged by these results, we next wondered if oxindole-derived enol ethers could also participate in the microfluidic PB process.[20] This transformation allows simultaneous functionalization at C3 and C2 of the oxindole core. Irradiation at 405 nm of the oxindole-derived silyl enol ether 13i in the presence of benzophenone (1a), under MFP conditions, afforded the corresponding product 16a in >98% yield and with high site-, regio- and diastereocontrol (Scheme [7], entry 4). Remarkably, the reaction time was significantly reduced in comparison to the batch reaction conditions (entry 3). Interestingly, 16a was produced in a 0.313 mmol·h–1 productivity rate. As shown in Scheme [8], there is a significant tolerance for structural and electronic variation on the oxindole enol ether and benzophenones. Indoles bearing additional reactive π-systems delivered the corresponding indole products 16g and 16h with full site-selectivity.

Zoom Image
Scheme 7 Microfluidic visible-light PB reaction of indole 13a and oxindole enol ether 13i and a comparison with the in-batch results. Light source: 405 nm (60 W LEDs).[18] [20]
Zoom Image
Scheme 8 Selected reaction scope of the visible-light PB reaction of oxindole enol ethers 13 and benzophenones 1 under MFP conditions. PG: protecting group. Light source: 405 nm (60 W LEDs).[20]

To understand the observed site-selectivity, we performed a competition experiment in the presence of furan (17) (Scheme [9]). We used 2 equivalents of benzophenone (1a) and 1 equivalent of 13i and 17. After 12 minutes, product 16a was formed in 63% yield along with traces of 18, thus indicating the superior reactivity of 13i, despite its sterically hindered nature.

Zoom Image
Scheme 9 A competition experiment in the presence of furan (17). Light source: 405 nm (60 W LEDs).[20]

Given the versatility of the method, we then exploited the synthetic potential of the PB-microfluidic protocol for the gram-scale functionalization of oxindoles. Specifically, we implemented an in-flow process starting from the simple 3-benzyloxindole precursor 19 (Scheme [10]). In this case, 19 was mixed in situ with the silylating agent (TBSOTf) and triethylamine (NEt3). The crude solution was then used in the following PB reaction in the presence of different aromatic ketones (1a or 1b) and irradiated in two parallel MFPs with a residence time of 12 minutes in an overall reaction time of 19.4 hours. This protocol furnished 16a and 16h on gram scale, up to 1.02 g and 1.18 g, respectively. Interestingly, the PB reaction was shown to be almost insensitive to the presence of the base and silylating agent, demonstrating the robustness of the method.

Zoom Image
Scheme 10 A gram-scale, two-step synthesis of indolinic products 16a and 16h. Light source: 405 nm (60 W LEDs).[20]

From a mechanistic perspective, the reaction proceeds through a classical radical combination between the benzophenone T1 excited state and the C2–C3 double bond of the indole. However, in the case of benzil derivatives a photoinduced electron transfer (PET) can also be operative. The PET, which is kinetically favored with respect to the radical combination between the half-filled π* orbital of the aryl ketone and the half-filled π orbital of the alkene, usually results in increased regio- and diastereoselectivity.[13] Thus, a PET process will account for the excellent regio- and diasterocontrol observed. Despite these preliminary observations, an in-depth mechanistic analysis is needed to better understand the exact nature of this transformation.


# 3

Synthetic Transformations Driven by Triplet State o-Alkyl-Substituted Benzophenones

In contrast with the photoreactivity of benzophenone, the light-excitation of ortho-alkyl aryl ketones 2-S0 (Scheme [11]) triggers the rapid formation of highly reactive hydroxy-ortho-quinodimethanes (2′).[21] These intermediates are also known as photoenols. Since the discovery of this photochemical process in 1961,[22] diverse independent studies have characterized all the transient species leading to 2′.[23] The mechanism of photoenolization is initiated by the absorption of a photon by the carbonyl group in 2, producing an electronically excited singlet state 2*-S1 . This state is generally of nπ* character and rapidly decays to a triplet nπ* state (2*-T1 ) by an ISC process. Next, the half-filled nP orbital of the 2*-T1 state is prone to undergo a 1,5-HAT from the C–H σ-orbital, leading to the formation of the conjugated 1,4-biradical (Z)-V (Norrish-type II reactivity). This latter species is in fast equilibrium with its conformer (E)-V, and both can relax to the corresponding ground state (Z)-2′ and (E)-2′ enols through a second ISC process. While (Z)-2′ returns faster to the starting ketone 2 through an intramolecular 1,5-sigmatropic rearrangement, the (E)-2′ enol requires an intermolecular proton transfer mediated by a molecule of acid or solvent. This fact confers a higher lifetime to the (E)-2′ photoenol (τ = 1–10–6 s),[21] thus being the principal species involved in subsequent chemical trapping events.[24]

Zoom Image
Scheme 11 Principal transient species involved in the photoenolization mechanism of diaryl ketones 2. HAT: hydrogen atom transfer. ISC: inter-system crossing. 2*-S1 not shown.

The reactive photoenol (E)-2′ has been traditionally exploited as a diene in [4+2]-cycloaddition reactions with dienophiles 20, giving access to biologically relevant tetrahydronaphthalenol derivatives 8 (Scheme [12], left pathway).[25] [26] More recently, it has been disclosed that the use of other types of electrophiles, such as α,β-unsaturated carbonyl compounds,[27] activated imines,[28] α-fluoroketones[29] or CO2,[30] can lead to the exclusive formation of functionalized benzophenones 9 (Scheme [12], right pathway).[31] Overall, the photoenolization process enables straightforward access to a versatile intermediate 2′ that can be exploited in alternative synthetic scenarios, including natural product synthesis,[25`] [b] [c] [d] macromolecule linkages[32] and polymer chemistry.[33]

Zoom Image
Scheme 12 The two main reactivity patterns of photoenols (2′) lead to the formation of tetrahydronaphthalenol cores 8, or functionalized benzophenone scaffolds 9. EWG: electron-withdrawing group; X = NH, O, CH2COR, where R = H or alkyl. Colored spheres represent unspecified functionalities.

Our next efforts were focused on the implementation of 2-methylbenzophenone-driven reactions under a MFP setup. We proved that the productivity rate and product selectivity of these photochemical processes are highly increased compared to conventional in-batch procedures.[34] Specifically, the MFP system[35] was evaluated in the trapping of the photoenol derived from 2-methylbenzophenone (2-MBP) (2a) with different acceptors (Scheme [13]). Under the optimal conditions described in Scheme [13], we could access different tetrahydronaphthalenol-based scaffolds 8 and functionalized benzophenones 9, with considerably improved productivity rates. For example, the cycloaddition product 8a was obtained in quantitative yield (<98%), as a single diastereoisomer, and only after 16 minutes of residence time. In contrast, the same photochemical process carried out in batch required 500 minutes to obtain up to 92% yield, which entails a productivity rate 13.6 times lower than the corresponding in-flow methodology. On the other hand, the use of the commercially available Togni reagent I as an acceptor[27a] enabled the formation of 9a in an excellent yield (95%), after 8 minutes. This result outcompetes the corresponding batch process by a 4-fold enhancement (0.143 mmol∙h–1 in flow vs 0.035 mmol∙h–1 in batch). The MFP setup also proved to be effective for light-driven carboxylation to give 9b. In this case, the benzophenone 9b was formed under a CO2 atmosphere in a yield as high as 98% after 60 minutes of residence time. The original in-batch protocol[30] furnished the same product in lower yields (75% yield) and with inferior productivity rates (0.003 mmol∙h–1).

Zoom Image
Scheme 13 Photoenolization and chemical trapping of 2-MBP (2a) performed in a MFP setup, and a comparison with the results obtained using the in-batch process A: acceptor. Light source: 365 nm (9 W bulb).[34]
Zoom Image
Scheme 14 (a) In-batch and MFP studies of the photoreaction of 2-MBP (2a) with the coumarin derivative 22a. (b) Selected examples of the microfluidic light-driven benzylation of coumarins. Light source: 365 nm (9 W bulb).[34]

An additional advantage of the use of MFP systems in photochemical reactions is the high degree of control over the product selectivity. This aspect was especially relevant when light-absorbing coumarins 22 were used as trapping agents of the photoenols derived from 2a (Scheme [14, a]). It is known that coumarins can dimerize through a photochemical [2+2] cycloaddition process. The absorption of coumarin derivatives at λ > 320 nm leads to the formation of cyclobutane derivatives (exemplified with 24a) as complex mixtures of regio- and stereoisomers.[36] Indeed, irradiation at 365 nm of a reaction mixture containing ethyl 3-coumarincarboxylate (22a) and 2-methylbenzophenone (2a) furnished both the unprecedented 4-benzylated chromanone 23a and the [2+2]-cycloaddition product 24a in low yields (26% and 17%, respectively) and in a 1.5:1 ratio (Scheme [14, a]). Remarkably, the same reaction performed under MFP conditions yielded the desired product 23a in 75% yield after 27 minutes, with the detection of only 5% of the photo-dimerization product 24a (ratio 23a/24a = 15:1). This result highlighted the ability of the MFP system to greatly outcompete the in-batch procedure in terms of product selectivity and established an innovative photochemical protocol for the direct assembly of benzylated chromanones 23. The generality of the new microfluidic photo-benzylation of coumarins was then evaluated by varying the substitution pattern on both aromatic rings of 2a, as well as on the coumarin scaffold. During these studies, we accessed an array of benzylated chromanones (selected examples 23b–e in Scheme [14, b]) in good yields (50–93%) and complete diastereoselectivity (dr > 20:1).[34]

Due to our interest in providing new and accessible photochemical microfluidic procedures for the construction of medicinally relevant scaffolds, we next investigated the light-promoted [4+2]-cycloaddition between 2-MBPs 2 with 3-unsubstituted coumarins 25 and chromones 27, respectively (Scheme [15]).[37] The resulting cycloaddition products, naphthochromenes 26 and benzoxanthenes 28, are valuable tetracyclic structures that are found in the main core of some biologically active compounds.[38] Our motivation to develop this photochemical transformation under MFP conditions was also fostered by the absence of diastereoselective methods for the construction of tetrahydronaphthochromenones 26. In addition, the reported synthesis of benzoxanthene scaffolds 28 required the use of high temperatures (i.e., 250 °C), leading to mixtures of regio- and diastereoisomers in moderate yields.[39] Gratifyingly, the use of the MFP setup enabled the formation of a variety of tetracyclic products 26 and 28 with high synthetic performances (40 to >98% yield for 26, and 41–72% yield for 28) and complete diastereoselectivities (>20:1 dr). Notably, the in-batch photochemical [4+2]-cycloaddition between 2-MBP 2a and coumarin 25a (i.e., 25 in Scheme [15], where R′ = H) furnished only traces of the desired product 26a (i.e., 26, where R = R′ = H and Ar = Ph).

Zoom Image
Scheme 15 Microfluidic light-driven [4+2]-cycloaddition of 2-MBPs 2 with coumarins 25 and chromones 27, leading to tetrahydronaphthochromenone 26 and benzoxanthene 28 scaffolds, respectively. Light source: 365 nm (9 W bulb).[37]

These results highlight the importance of the use of microfluidic methods for the excitation of carbonyl compounds to enable previously inaccessible photochemical transformations. Finally, by using two MFP setups operating in parallel, we obtained up to 948 mg of 26a within only 14 hours, and an overall productivity rate of 0.196 mmol·h–1. This further highlights the advantages of using MFPs as a key-enabling technology for the development of synthetically useful light-driven transformations.


# 4

The Evolution of Aryl-Ketone-Derived Products: Applications in Organophotoredox Catalysis

After the development of new light-driven methods exploiting diaryl ketones as reactive substrates, we explored the applications of the obtained products as novel modular photoredox catalysts.[40] We first investigated the physicochemical and photoredox properties of the naphthochromenone (NTC) scaffold as a potential organic photocatalyst (PC).[41]

The efficient generation of the tetracyclic scaffold 26 (Scheme [15]) from 2-MBPs 2 and coumarins 25 allowed us to prepare the NTC core 29 in a simple and scalable manner (Scheme [16, a]). The formation of NTCs consists of a simple two-step procedure: the initial MFP photoenolization reaction was followed by a one-pot elimination/aromatization sequence. This strategy furnished 12 diversely functionalized NTCs 29 in up to 82% yield (2.20 g scale).

Zoom Image
Scheme 16 (a) Preparation of NTC cores from 2-MBPs 2 and coumarins 25. (b) Key properties of the NTC photocatalysts.

The relevance of NTCs as versatile PCs does not only rely on their straightforward preparation, but also on their excellent properties as light-harvesting molecules. The optimal compromise between its ground and excited state properties makes 29 an ideal and recoverable alternative to some of the commonly used metal-based PCs (Scheme [16, b]). While looking at the ground state, the absorption in the cross-border region between UV and visible light (390–420 nm) infers a high excited state energy (up to 3.22 eV) accessible under visible-light irradiation. This characteristic prevents the use of highly energetic light sources (e.g., Hg lamps), preserving the products stability and favoring the use of readily available irradiation setups (e.g., LEDs, CFL bulbs). Further, NTCs benefit from balanced oxidation and reduction potentials in the ground state (Eox and Ered up to 1.86 V and –1.89 V vs SCE), as well as in the excited state (E*ox and E*red up to –1.77 V and 1.65 V vs SCE), allowing their use in a wide range of photoredox reactions, under both reductive and oxidative quenching mechanisms. This bimodal action is a valuable PC property that only few organic dyes can exhibit.[42]

Zoom Image
Scheme 17 Example of a reductive quenching mediated Povarov-type reaction using NTCs as organic photoredox catalysts. Selected examples and proposed mechanism showcasing the modularity of the PC scaffold. Light source: 400 nm (24 W LEDs).

In order to demonstrate the utility of NTCs we evaluated their catalytic performances with respect to reported synthetically relevant photoreactions.[43] On the one hand, their use in reductive quenching cycles was demonstrated in three different reactions. Firstly, we evaluated the light-triggered Povarov-type cycloaddition (Scheme [17]). In this case NTCs outcompeted a Ru-based photocatalyst as well as eosin Y. The use of N,N-dimethylaniline 30, with a high oxidation potential (Eox = 1.33 V vs SCE), and maleimide 31 in the presence of 3 mol% of the photocatalyst furnished 32 in yields of up to 70%. When PC 29a or 29b (E*red = 1.28 and 1.21 V vs SCE, respectively) were used, product 32 was obtained in moderate yields. These results proved the importance of tuning the PC oxidative properties by rational structural variations. As a matter of fact, the presence of electron-donating groups (EDG) at position 3 decreased the excited state oxidative power, whereas the introduction of electron-withdrawing groups (EWG) made NTC* a better oxidant.

The effect of the E*red value of the PC is showcased in the proposed reaction mechanism (Scheme [17], bottom). After excitation of the PC, its excited state is reduced by 30 producing the corresponding NTC radical anion (NTC•− , blue circle) and 30•+ . This latter species is deprotonated to form the α-aminoradical VI that reacts with 31. After ring closure, VIII is quenched by superoxide (formed after oxygen reduction with NTC•− , triggering the formation of 32 and hydrogen peroxide as the sole by-product.

Zoom Image
Scheme 18 Example of an oxidative-quenching-mediated dechlorination reaction using NTCs as organic photoredox catalysts. Selected examples and proposed mechanism showcasing the versatility of the PC scaffold. Light source: 400 nm (24 W LEDs).

On the other hand, we demonstrated the use of NTCs under oxidative quenching cycles. In this case, dehalogenations of aryl halides and benzyl halides were efficiently developed.[43e] Additionally, the unprecedented dechlorination reaction of p-CN benzyl chloride was also accessible (Scheme [18]). This transformation involved the photoreduction of 33 (Ered = –1.81 V vs SCE) in the presence of 3 mol% of the NTC under 400 nm LED irradiation. The use of visible light for the reduction of aryl and benzyl halides is a definite advancement in the field, being that these reactions are usually performed with more energetic UV irradiation.[44] Once again, the modularity of the PC scaffold allowed us to obtain 34 in high yield. Moving from 29a (E*ox = –1.27 V vs SCE), which furnished 34 in 15% yield, to the more reducing 29b and 29d (E*ox = –1.50 V and –1.64 V vs SCE, respectively), enabled a yield of up to 51% to be obtained. The observed trend confirms the importance of the modulation at position 3 of the NTC scaffold to directly impact the E*ox value of the PC.

In the reported reaction mechanism (Scheme [18] bottom), the NTC* is quenched by 33 producing the corresponding NTC radical cation (NTC•+ , red circle), and the benzyl radical IX. The benzylic radical species undergo a HAT process with the Hantzsch ester, whilst the NTC ground state is restored with the use of a tertiary amine (Bu3N).


# 5

Conclusions and Future Directions

The photochemistry of ketones, and more in general of carbonyl compounds, is an attractive field of research, able to disclose new synthetic paradigms for the construction of C–C and C–heteroatom bonds. The excited state reactivity of ketones allows the construction of unprecedented molecular scaffolds that are often difficult or impossible to synthesize by other means. In this Account, we have described our recent efforts on the capitalization of this concept. Despite the excited state of ketones having been extensively studied over the past century, the rational and critical understanding of their reactivity principles is still crucial for the development of new and efficient synthetic methods. The application of new technologies, such as the use of MFP setups as well as more efficient and selective light irradiation sources, has been crucial to support the evolution of the field towards improved sustainability and synthetic performance.

Since the establishment of our group in 2016, we have exploited the advent of novel technologies for the development of milder and more general light-triggered processes. Thus, historical photoreactions such as the Paternò–Büchi reaction or the photoenolization/Diels–Alder process have been revisited, maximizing safety and productivity. Through careful selection of the light sources and fine-tuning of the microfluidic photoreactors, we have explored new mechanistic avenues departing from the excited states of aryl ketones. We have finally developed and applied new organic PCs to several thermodynamically extreme photoredox processes, realizing that the careful assessment of the structure–property relationships is the keystone for the identification of new reactivity pathways. This observation prompted us to undertake new research on the accurate study of the relationships occurring between PC photochemical and redox properties and its structural arrangement. Current interests of our group also include the implementation of novel microfluidic photoredox processes for the direct functionalization of bioactive molecules.

We believe that an interdisciplinary approach involving the exploitation of new technologies in combination with the better understanding of the reaction mechanisms of the photochemical transformations will generate unprecedented solutions and new perspectives in the field of photocatalysis.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We want to take the opportunity to thank all the people involved in our research projects for their invaluable support and contributions: Prof. Marcella Bonchio, Prof. Andrea Sartorel, Prof. Tommaso Carofiglio, Prof. Mirco Natali, Prof. Nadia Marino, Dr. Francesco Rigodanza, Tommaso Bortolato, and Pietro Franceschi, as well as all the former group members: Dr. Xavier Companyo, Dr. Suva Paria, Dr. Alessio Cherubini-Celli, Philip Andreetta, Edoardo Carletti, Michela Marcon, Alessio Calcatelli, and Nicholas Meneghini.


Corresponding Author

Luca Dell’Amico
Department of Chemical Sciences, University of Padova
Via Marzolo 1, 35131, Padova
Italy   

Publication History

Received: 16 February 2021

Accepted after revision: 02 March 2021

Accepted Manuscript online:
02 March 2021

Article published online:
12 April 2021

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany


   Permissions and Reprints All articles of this category
Zoom Image
Zoom Image
Scheme 1 The classical ground state reactivities of the carbonyl groups in aryl ketones 1 and 2 gives access to tertiary alcohols 3, secondary alcohols 4, and amines 5. The reactivities of the excited states of 1 and 2 enables the formation of a diverse class of molecular scaffolds, such as oxetanes 7, tetrahydronaphthalenols 8 and functionalized benzophenones 9. Nu: nucleophile; A: acceptor.
Zoom Image
Figure 1 A simplified scheme of a microfluidic photoreactor (MFP) setup, and the advantages over common in-batch reaction conditions
Zoom Image
Scheme 2 Explanation of the reactivity of diaryl ketones in the ground and excited states. Nu: nucleophile.
Zoom Image
Figure 2 Electronic transitions of carbonyl compounds in (a) aromatic ketones, and (b) aliphatic ketones. ISC: inter-system crossing; IC: interconical system.
Zoom Image
Scheme 3 Mechanism and diastereoselective outcome of the ­Paternò–Büchi reaction with (a) aromatic ketones, and (b) aliphatic ­ycarbonyls. ISC: inter-system crossing.
Zoom Image
Scheme 4 The reactivity of an excited carbonyl compound with (a) electron-rich, and (b) electron-poor alkenes. EDG: electron-donating group; EWG: electron-withdrawing group.
Zoom Image
Scheme 5 Reaction optimization of the PB process under visible-light irradiation. Light sources: 365 nm (9 W bulb); 405 nm (60 W LEDs).[18]
Zoom Image
Figure 3 Emission 3D-matrix of benzophenone (1a) in acetone under the optimized reaction conditions[18]
Zoom Image
Scheme 6 Selected reaction scope of the developed visible-light PB process. Ace: acetone. Light sources: 405 nm (60 W LEDs); 465 nm (24W LEDs).[18]
Zoom Image
Scheme 7 Microfluidic visible-light PB reaction of indole 13a and oxindole enol ether 13i and a comparison with the in-batch results. Light source: 405 nm (60 W LEDs).[18] [20]
Zoom Image
Scheme 8 Selected reaction scope of the visible-light PB reaction of oxindole enol ethers 13 and benzophenones 1 under MFP conditions. PG: protecting group. Light source: 405 nm (60 W LEDs).[20]
Zoom Image
Scheme 9 A competition experiment in the presence of furan (17). Light source: 405 nm (60 W LEDs).[20]
Zoom Image
Scheme 10 A gram-scale, two-step synthesis of indolinic products 16a and 16h. Light source: 405 nm (60 W LEDs).[20]
Zoom Image
Scheme 11 Principal transient species involved in the photoenolization mechanism of diaryl ketones 2. HAT: hydrogen atom transfer. ISC: inter-system crossing. 2*-S1 not shown.
Zoom Image
Scheme 12 The two main reactivity patterns of photoenols (2′) lead to the formation of tetrahydronaphthalenol cores 8, or functionalized benzophenone scaffolds 9. EWG: electron-withdrawing group; X = NH, O, CH2COR, where R = H or alkyl. Colored spheres represent unspecified functionalities.
Zoom Image
Scheme 13 Photoenolization and chemical trapping of 2-MBP (2a) performed in a MFP setup, and a comparison with the results obtained using the in-batch process A: acceptor. Light source: 365 nm (9 W bulb).[34]
Zoom Image
Scheme 14 (a) In-batch and MFP studies of the photoreaction of 2-MBP (2a) with the coumarin derivative 22a. (b) Selected examples of the microfluidic light-driven benzylation of coumarins. Light source: 365 nm (9 W bulb).[34]
Zoom Image
Scheme 15 Microfluidic light-driven [4+2]-cycloaddition of 2-MBPs 2 with coumarins 25 and chromones 27, leading to tetrahydronaphthochromenone 26 and benzoxanthene 28 scaffolds, respectively. Light source: 365 nm (9 W bulb).[37]
Zoom Image
Scheme 16 (a) Preparation of NTC cores from 2-MBPs 2 and coumarins 25. (b) Key properties of the NTC photocatalysts.
Zoom Image
Scheme 17 Example of a reductive quenching mediated Povarov-type reaction using NTCs as organic photoredox catalysts. Selected examples and proposed mechanism showcasing the modularity of the PC scaffold. Light source: 400 nm (24 W LEDs).
Zoom Image
Scheme 18 Example of an oxidative-quenching-mediated dechlorination reaction using NTCs as organic photoredox catalysts. Selected examples and proposed mechanism showcasing the versatility of the PC scaffold. Light source: 400 nm (24 W LEDs).