Enantioselective photo-organocatalytic intramolecular [2+2]-photocycloaddition of quinolones.
The research involving photo-organocatalysis, photoredox, and electro-organocatalysis processes is revised in this chapter. Modern synthetic processes enable the formation of large arrays of organic molecules with precise control over their three-dimensional structure, which is important in a variety of fields ranging from pharmaceutical to materials science. Photochemical reactions may have a substantial impact on these fields by affording direct access to specific structural motifs that are difficult to construct otherwise. The conjugate structural feature shown by most of the photo-organocatalysts seems to enable the production of free radicals or radical ions in an easy fashion. Electro-organocatalysis has also received recent interest from both academia and industry. In this chapter, we mainly review recent remarkable advancements in organocatalysis involving photo-, photoredox, and electrochemical processes with particular emphasis on asymmetric protocols.
- sustainable chemistry
In general, organocatalysts are divided into two main classes according to the interaction, covalent or non-covalent (H-bonding, proton transfer, ion pair formation), with the organic substrate within the catalytic cycle. In this context, an organocatalyst reacts with an organic molecule in order to form a stable organic compound or a labile intermediate. At this stage, the activation induced by the organocatalyst enables the attack of the second reagent to form a second adduct that releases the desired product with the concomitant regeneration of the organocatalyst.
Most of the common organocatalysts used for carbon-carbon bond formation reactions are based in chiral and achiral secondary amines, while reagents are electrophiles such as aldehydes, ketones, or α,β-unsaturated carbonyls. For these cases, the selected organocatalysts normally promote the generation of either an iminium ion or an enamine.
Photocatalysis, where an electronically excited species acts as the catalyst, has gained increasing interest over the last years, with different organic transformations under such conditions being reported.
Recently, the catalytic activation of organic molecules by visible light photoredox catalysis that works under stereochemical control and provides chiral molecules in an asymmetric fashion has been largely reported. Generically, this approach relies on the ability of metal complexes and organic dyes to engage in single-electron transfer (SET) processes with organic substrates upon photoexcitation with visible light. Most common visible light photocatalysts are based on polypyridyl complexes of ruthenium, for example, tris(2,2′-bipyridine)ruthenium(II) or [Ru(bpy)3]2+, and iridium. These complexes absorb light in the visible region of the electromagnetic spectrum to give stable, long-living photoexcited states. The lifetime of the excited species is sufficiently long that it may engage in bimolecular electron transfer reactions in competition with deactivation pathways. Although these species are poor single-electron oxidants and reductants in the ground state, excitation of an electron affords excited states that are very potent single-electron transfer reagents. The ability of [Ru(bpy)3]2+ and related complexes to function as visible light photocatalysts has been recognized and currently applied to the electrolysis of water and the reduction in carbon dioxide to methane. These photocatalysts have also been employed in organic transformations including asymmetric approaches. Much of the excitement around visible light photoredox organocatalysis is due to the ability to achieve unique, if not exotic bond constructions that are not possible using the established protocols. For instance, photoredox organocatalysis can perform under overall redox neutral reactions where both oxidants and reductants are transiently generated in the same reaction vessel. This approach stands in contrast to methods requiring stoichiometric chemical oxidants and reductants, which are often incompatible with each other, as well as to electrochemical approaches, which are not amenable to redox neutral transformations.
Electro-organocatalysis has also received recent interest from both academia and industry. Electron transfer is one of the most important processes in organic chemistry in which one electron is added to or removed from an electroactive substrate. Such an electron transfer is reversible only when the resulting species are stable under those conditions. In other cases, an electron transfer generates subsequent chemical processes such as bond dissociation and bond formation. In general, radical cations and radical anions can be generated by electrochemical electron transfer reactions. Carbocations, carbon-free radicals, and carbanions can also be generated by subsequent bond dissociation or bond-forming processes. Several organic synthetic transformations especially carbon-carbon bond formation reactions, oxidation, and reduction processes (electrocatalytic processes) have been reported.
2. Recent approaches in photo-organocatalysis
2.1. Asymmetric Photo-Organocatalysis
In the area of catalytic reactions, tremendous improvement has been made in the last decades, mostly upon the discovery of efficient transition metal catalysts. According to the variety of reactions, accessible, metal-catalyzed and enantioselective reactions have become significant tools in organic synthesis . However, some disadvantages remain, such as the high cost and toxicity of the transition metal catalysts, employed and in some cases the problems that their residues, mainly in pharmaceutical products, can cause. Nonetheless, this transition metal catalysis will certainly continue to have an impact in synthetic organic chemistry in the future . Alternatively, over the last years, a metal-free approach known as organocatalysis has reached a level of reliability that has allowed researchers to combine this procedure with other powerful techniques for molecule activation based on photochemical processes promoted by visible light. This green strategy has allowed previously unachievable synthetic issues to be solved and has rapidly progressed with application in both symmetric and asymmetric reactions (e.g., nucleophilic substitutions, Michael additions, cycloadditions, and aldol reactions) . Generically, the organic catalysts can be categorized into two main classes according to the covalent or non-covalent (
Homogeneous catalytic asymmetric transformations utilizing visible light photocatalysis include chiral and racemic photocatalysts with chiral organocatalysts, chiral Brønsted acids, or chiral Lewis acids . In photo-organocatalytic processes, there are two main reaction models: the photocatalyst (PC) can act through an electron transfer (ET) process that causes an one-electron oxidation/reduction in the organic substrate R-X (Scheme 1, route a) or through hydrogen atom transfer (HAT, route b) from a hydrogen donor R-H . Most of the photo-organocatalysts are aromatic ketones, dyes, and (chiral) secondary amines, while R substrates are electrophiles, typically aldehydes, ketones, or α,β-unsaturated carbonyls [5, 6]. Furthermore, photosensitization is known as an energy transfer between the excited photocatalyst (PC*) and substrate, which creates an excited state (R-Y*, from quenching of PC*), that is able to initiate a chemical reaction (route c). Sensitization can occurs by energy or electron transfer processes. The catalyst is transformed to act as a photosensitizer via photo-induced electron transfer (PET), hence leading the resulting photo-organocatalytic reaction to occur under stereoselective control .
Nowadays, a possible alternative can be considered in the photochemical activation step, in which the complexation of an organic reagent R-Z is controlled by a distinct, photostable chiral catalyst (route d) .
The aim of this subchapter was to point out the effective tools that the stereoselective ground-state processes offer to enantioselective photochemistry. The catalysts control the photoactivation of the substrates by inducing the transient formation of photon-absorbing chiral electron donor-acceptor (EDA) complexes. In addition, high stereocontrol in synthetically relevant intermolecular carbon-carbon bond-forming reactions driven by visible light can be provided by the inherent chirality of the catalysts.
The group of Bach focuses on catalytic processes, which allow previously unknown transformations employing both photochemical and conventional techniques. Their published papers concern photoredox organocatalysis, such as the first highly enantioselective (up to 90%
Four years later, the same group tested the intramolecular [2+2] photocycloaddition of prochiral 4-(3′-butenyloxy) quinolone to the desired products (Scheme 2) . The previously characterized chiral organocatalyst-benzophenone
This photo-organocatalytic transformation was provided by applying a chiral, hydrogen-bonding template with an attached catalytically active sensitizing unit (benzophenone or xanthone). In all cases, it was possible to obtain high yields (78–99%) and enantioselectivities (83–94%
|Entry||Substrate||Catalyst (mol%)||Yield (%)a|
In parallel, the group of Bach proposed an immobilization of earlier mentioned chiral photo-organocatalysts and their use in intramolecular [2+2] photocycloaddition of 4-allyloxyquinolone (Scheme 3) . Under irradiation with light, the immobilized templates
In different experiments, the group of Bach also investigated enantioselective photochemical reactions resorting on chiral Lewis acids as catalysts . They reported the AlBr3-activated chiral cationic oxazaborolidine catalyst for enantioselective intramolecular [2+2] photocycloaddition reactions of 4-alkenyl-substituted coumarins (78%
More recently, Vallavoju et al.  reported intramolecular [2+2] photocycloadditions of 4-alkenyl-substituted coumarins promoted by various atropisomeric binaphthyl-derived thioureas as photo-organocatalysts (Scheme 4). Thiourea catalysts are simple, environmentally benign, sustainable, and inexpensively synthesized from ‘chiral pool’, as well as easy to modulate and to handle. The photocatalytic cycle involves the formation of both static and dynamic complexes (exciplex formation) between the photo-organocatalyst and the reactive substrate, which are stabilized by hydrogen bonding. The corresponding products were achieved with high enantioselectivities (77–96%
Melchiorre and co-workers presented the catalytic approach using a chiral organic catalyst with hydrogen-bonding motifs to bind a specific substrate selectively in synthetically relevant intermolecular carbon-carbon bond-forming reactions driven by visible light . In the asymmetric α-alkylation of aldehydes with alkyl halides, the commercially available diarylprolinol silyl ether catalysts 
In 2014, the authors describe the first light-driven enantioselective organocatalytic alkylation of unmodified ketones with alkyl halides . This correlates to the previously established mechanism, in which the chiral enamines are the key intermediates in ground-state organocatalytic asymmetric processes. A variety of chiral primary amines (20 mol%) to activate cyclohexanone towards benzylation with 2,4-dinitrobenzyl bromide were studied. A chiral secondary amine did not show any ability to catalyze the photochemical alkylation; nevertheless, the primary amines displayed promising (entries 4 and 5) or even excellent (entry 6) reactivity, but insufficient enantioselectivity. The primary cinchona-based amine catalyst
Last year, the group of Melchiorre reported the photo-organocatalytic enantioselective α- and γ-alkylation of aldehydes and enals with bromomalonates by a fluorescent light bulb without the need of any external photoredox catalyst . The preliminary studies involved butanal and diethyl bromomalonate (Table 2) as substrates for this photo-organocatalytic reaction. The results showed that using the aminocatalyst
In parallel, the same group of researchers investigated the phase transfer catalyzed, enantioselective perfluoroalkylation and trifluoromethylation of cyclic β-ketoesters under visible light irradiation . The photo-organocatalytic approach is again caused by the photochemical activity of EDA complexes generated
The above presented strategies of enantioselective photo-organocatalytic processes have a great potential for the sustainable preparation of chiral molecules, a rapidly developing area of modern chemical research.
In parallel to the efforts performed in the field of asymmetric photo-organocatalysis, some attempts were also performed in the non-enantioselective processes.
Non-asymmetric photocatalysis has gained a great deal of attention during the last decades [23, 24], and a remarkable and interesting case was recently described by the already cited group of Melchiorre, in which an aromatic aldehyde was involved in the intermolecular atom transfer radical additions (ATRA) of a variety of haloalkanes to alkenes, one of the essential carbon-carbon bond-forming processes in organic chemistry . In an ATRA reaction, the addition of an organic halide across a carbon-carbon double-bond yields a new C─C and C─X bond (X = halogen) in a single operation. Once more, organic compounds known to be capable of high photoreactivity  could alternatively be used as an energy transfer photocatalyst. It is important to note that for the first time, aromatic aldehydes have been used as photo-organocatalysts in an effective and valuable process . Recent exciting findings by Melchiorre and co-workers have also shown the metal-free photo-organocatalysis which allows the direct alkylation of 2- and 3-substituted 1
3. Recent approaches in photoredox organocatalysis
The term photoredox organocatalysis has its origin in the work by Nicewicz and MacMillan in 2008. They reported the enantioselective α-alkylation of aldehydes using [Ru(bpy)3]Cl2 as a photoredox catalyst. This complex, alongside many others such as [Ir(ppy)2(dtb-bpy)]PF6 and
Scheme 7 depicts the most popular dyes investigated in photoredox catalysis procedures.
The photoactivation reveals the ability of the photosensitizer to absorb in the visible domain and to act both as a strong oxidant in the excited state S* and as an efficient reductant in its semi-reduced form S•–. In Scheme 8, a comparison between the general photoredox catalytic cycles of ruthenium-based catalysts and a photo-organocatalyst,
3.1. Asymmetric photoredox organocatalysis
One of the most explored aspects investigated in the field of enantioselective photoredox catalysis has been the use of organic dyes as photocatalysts. In the seminal work by Zeitler
Using the same conditions adapted to a microreactor flow regime, smaller reaction times were obtained with comparable results . Rose Bengal was also applied as photoredox catalyst in this type of reaction (Table 3, entries 3–9). Again, imidazolinone
On the other hand, asymmetric α-amination of aldehydes has also been accomplished by means of photoredox chemistry . By using an amine substrate bearing ODNs, photolabile groups that simultaneously work as the photoredox catalyst and also release the reactive carbamyl reagent that couples with the
Wallentin et al.  reported the photocatalyzed decarboxylative reduction in several classes of biologically relevant enantio-enriched 1-aryl-2,2,2-trifluoroethyl-substituted amino acids (see Table 5). A plausible redox-coupled hydrogen shuttle mechanism was proposed by using one of the strongest oxidizing organic dyes mesityl acridinium (Mes-Acr+BF4−,
A stereoselective radical cascade cyclization of polyprenoids through a photocatalytic mechanism has been reported yielding polyenes in moderate to very high yields with excellent diastereoselectivities (d.r. > 19:1) in HFIP and using Eosin Y as the photoredox catalyst (Table 6) . The methodology was based on the cyclization by terminal OH groups of a large substrate array of aliphatic alcohols, phenols, or enols, which was tolerable to electron-rich or electron-poor substituents. In addition, the cyclization of 1,3-diketones required the use of LiBr as a weak Lewis acid. Stern-Volmer analysis reinforced that these reactions proceeded
The photoredox catalyst 2,4,6-
Over the last years, several publications involving non-asymmetric photoredox organocatalytic synthetic transformations mediated by metal-free organic photoredox catalysis under mild conditions have been reported .
From the industrial point of view, it is important to focus the recent developments on selective photocatalytic transformations of benzene, in particular the oxidation of benzene to phenol , alkoxylation of benzene , and monofluorination of benzene with fluoride and oxygen . As an alternative to inorganic catalysts, the selective oxidation of benzene to phenol can be made under visible light irradiation of 2,3-dichloro-5,6-dicyano-
Photocatalytic [2+2] cycloaddition of dioxygen to tetraphenylethylene (TPE)
Eosin Y as a well-known low-cost organic dye that absorbs green light (characteristic peak at 539 nm) has been extensively investigated as photoredox catalyst for different organic transformations [42–49].
4. Recent approaches in electro-organocatalysis
As described in the previous sections, the electron transfer (ET) process is a crucial step in the organic chemistry field on which many organic reactions rely in order to occur [50, 51]. Essentially, an electron transfer process is based on the removal (or addition) of at least one electron from (or to) the electroactive substrate. This process is considered reversible only when the obtained products are stable under those experimental conditions. An electron transfer can generate intermediates which subsequently undergo chemical processes such as bond dissociation and bond formation. Basically, electroctrochemical techniques can be applied to establish the electrochemical oxidation and reduction mechanisms, that is the electron transfer reaction (formation and determination of the intermediates) and subsequent chemical reaction associated with the electrochemical generated process (formation of the reaction products). Thus, those formed intermediates are radical cations (or radical anions), and they can be generated by electrosynthetic processes using organic compounds. Carbon-free radicals (carbocations and carbanions) can also be generated by subsequent bond dissociation or bond formation process. Several electro-organic synthetic transformations, especially carbon-carbon, carbon-nitrogen, and carbon-phosphorous bond formation reactions, as well as oxidation and reduction processes have been reported . Electrochemical processes are considered ‘green’ procedures for those synthetic transformations. The main advantage of the electrosynthetic approach is that electrons flow as current and are regard as one inexpensive reactant, thus making the route more environmentally friendly. Moreover, reactions take place in low-temperature conditions, reducing the local consumption of energy and the risk of corrosion, material failure, and accidental release. Finally, it is important to highlight that electrodes can be regarded as heterogeneous catalysts that are easily separated from the products. The low or even almost inexistent volatility of the reaction media is another factor to be taken into account. Therefore, electro-organocatalysis constitutes a valuable tool for the organic chemist with numerous applications in both academia [53, 54] and industry .
The electro-organocatalysis field can be divided into two main branches, depicted in Scheme 11(A) direct electrolysis, in which the redox process occurs between the electrode surface and the reactant without the addition of other compounds and (B) ‘indirect electrolysis’ where the redox process occurs between the electrode surface and an external redox catalyst (or ‘mediator’) which then performs the ET with the reactive species) .
4.1. Direct electro-organocatalysis'
In the direct electro-organocatalysis process, the electron transfer (ET) step occurs at the electrode surface. Due to its heterogeneous nature, the catalyst recycling can be performed easily by separating it from the reaction media after the formation of the desired organic product.
'Direct electro-organocatalysis' or electro-organic synthesis has recently gained increasing attention, which can be attributed to their sustainable and ‘green’ features when compared to the traditional ones.
In the literature, there are few reports concerning bond formation and bond dissociation reactions. Gallardo and co-workers reported the formation of C─C [52, 57, 58], C─N , C─P , and C─S  bonds by an electrochemical approach of nucleophilic aromatic substitution reactions (SNAr). The proposed new route for the electrochemical processes consists on the reaction between an electron-deficient, aromatic compound and a nucleophile, leading to the formation of a σ-complex or Meisenheimer complex intermediate. Then, this species undergoes an oxidation that leads to the departure of the leaving group (heteroatom radical [NASX] and/or hydride, two electrons and a proton [NASH]). This procedure was similarly conducted with other nucleophiles (hydride, cyanide, fluoride, methoxy, ethanethiolate, and n-butylamine) and aromatic compounds as starting materials. In addition, preparative electrolysis was also employed as means to promote the oxidation of the intermediate produced in the first step of the process [52, 58].
This technique allows determination, characterization, and quantification of the type and number of electrochemically produced complexes present in the reaction media. It is also possible to assess if the reaction was successful once most classical SNAr reactions give lower yields.
The main drawbacks of the electrochemical approach are the use of solvent and the amount of tetraalkylammonium salt as electrolyte, which consequently have to be separated from the desired product. The use of ionic liquids (ILs) in particular room temperature ionic liquid (RTIL) as solvents may address this specific problem. They are considered non-flammable, non-volatile, and thermally stable over a wide range of temperatures, as well as good solvents for organic and inorganic compounds. In addition, they may be applied concomitantly as solvent and as electrolyte thereby enhancing the ‘green’ aspect of these procedures.
Gallardo and co-workers  adapted the electrochemical approach of nucleophilic aromatic substitution reactions to this 'greener' alternative family of solvents. The authors described the investigation of the electrocatalytic process as well as regioselectivity effects induced by the solvation properties of the RTILs (1-butyl-3-methylimidazolium [BMIM] combined with tetrafluoroborate [BF4], hexafluorophosphate [PF6], bis(trifluoromethylsulfonyl)imide [NTf2], and acetate [AcO] as anions).
The use of electrochemical techniques such as cyclic voltammetry (CV) and controlled potential electrolysis allows the evaluation of the nature and stability of the electrochemically generated intermediate on the solvent, as well as the extension of the reaction.
Despite the successful reports on SNAr reactions, the ‘direct electrolysis’ approach requires the application of high potentials in order for the electrosynthetic process to occur. To address this issue, the redox process can be applied to organocatalysts which then lead to yield the desired products in the indirect electrocatalysis fashion.
4.2. Indirect electro-organocatalysis
In the indirect electro-organocatalysis process, the electron transfer (ET) step is shifted from a heterogeneous process occurring at the electrode surface (as described earlier as ‘direct electrolysis’) to homogeneous process that can provide an electrochemically generated substance which acts as a so-called organocatalyst (or ‘mediator’). Usually triarylamines, triarylimidazoles and
In order to explore and generalize this methodology, analogous organocatalysts with modified aromatic rings were also reported by the authors. The desired products were formed in good yields .
4.3. Asymmetric electro-organocatalysis
In this specific case of the ‘indirect electro-organocatalysis’, particular conditions of solvent and catalyst are employed in order to enhance the enantioselectivity of the formed products. It is considered as safer and ‘green route’ towards enantioselective reactions by combining asymmetric organocatalysis with electrochemistry. The selected organocatalysts are stable, stereoselective organic compounds that can undergo the electrosynthetic process under unsuitable conditions for conventional catalysts. Asymmetric electro-organocatalysis methodologies have been successfully employed to produce several optically active compounds with application in life sciences. Scheme 12 depicts the direct intermolecular α-arylation of aldehydes to produce meta-alkylated anilines using electron-rich aromatic compounds .
The described methodology for the regio- and stereoselective electroorganocatalyzed production of the
In 2005, Schäfer and co-workers  reported the reaction of enamines and mediated anodic oxidation of carbohydrates in the presence of 2,2,6,6-tetramethylpiperidine-1-oxoammonium cation ([TEMPO]) as organocatalyst. These species reacted with selected enaminoesters to form intermediate imidazolium cations, which selectively oxidize the primary hydroxy groups of trisaccharides at the anode to give tricarboxylic acid sugars in 50–80% yields. The relative stability of the electrogenerated TEMPO cation in acetonitrile enables it to react as a selective oxidant, electrophile, and also catalyst.
Enantioselective α-oxyamination of aldehydes has been reported by the group of H.-J. Jang using a
An asymmetric electro-organocatalysis method for enantioselective α-alkylation of aldehydes with xanthene has also been devised by the group of Jang et al. . Scheme 15 depicts the best results using a chiral imidazole as organocatalyst, which was chosen from a plethora of differently substituted imidazole-based compounds . According to electrochemical studies and control experiments, the reaction is probable to occur through the formation of an enamine intermediate. DFT calculations suggested that xanthene adds to the opposite side of the phenyl ring of the radical intermediate blue to stereochemical hindrance issues, thus enhancing the stereoselectivity of the reaction.
In 2014, Xu and co-workers  published an electrochemical intramolecular aminooxygenation reaction of unactivated alkenes based on the addition of N-centered radicals to alkenes (generated from electrochemical oxidation) followed by trapping of the cyclized radical intermediate with TEMPO. This process allowed the preparation of different aminooxygenation products in high yields and excellent trans-selectivity for cyclic systems (d.r. up to > 20:1).
Very recent, Xu and collaborators  reported the first electrocatalytic method using ferrocene as a cheap redox catalyst to produce amidyl radicals from N-arylamides. The conventional methods for oxidative generation of amidyl radicals from N─H amides need to use a stoichiometric quantity of expensive noble-metal catalysts or strong oxidants. In this case, the authors showed an efficient radical-generating process based on intramolecular olefin hydroamidation reaction.
This work was supported by Fundação para a Ciência e a Tecnologia through projects (PEst-C/LA0006/2013) one contract under principal investigator FCT (L.C. Branco) and one postdoctoral fellowships (Hugo Cruz—SFRH/BPD/102705/2014).