JBCS

INTRODUCTION

Organometallic Chemistry: brief overview of the field

The birth of organometallic chemistry can be attributed to the year of 1760, when in a military pharmacy in Paris, Cadet de Gassicourt was interested in preparing invisible inks from common ores containing cobalt, smaltite and cobaltite. However, these ores also typically contained arsenic. In the process, arsenic trioxide was generated as a by-product. The pyrolysis of this oxide, in the presence of potassium acetate produces cacodyl oxide and tetramethyldiarsine, among other products:¹ As₂O₃ + AcOK → [(AsMe₂)₂O] + [Me₂As-AsMe₂] + ... Bunsen also worked with this mixture (which was used to be known as "Cadet's fuming arsenical liquid") and he was the responsible for providing the definitive characterization of cacodyl oxide.²

In 1827, Zeise reported for the first time the preparation of a metal π complex K[PtCl₃(η²-C₂H₄)].H₂O, that could be obtained from the treatment of PtCl₂ with boiling EtOH, followed by treatment with an aqueous solution of KCl.³ The composition of this salt and the nature of the bond between the Pt center and the ethylene ligand was a matter of debate at the time,⁴ which could be solved only years later, based on the studies of Birnbaum⁵ and Dewar⁶/Chatt and Ducanson.⁷ Birnbaum showed that the Zeise's salt could be directly prepared from the reaction of ethylene with H₂PtCl₆. Chatt and Ducanson explained that the surprisingly strong bond between Pt and the ethylene ligand can be understood as a consequence of the donation of π-electrons from the ethylene ligand to Pt, while the back-donation from d electrons of the Pt center to the ethylene π* orbital creates a linkage stronger than what could be anticipated. (This concept can be also readily applied to metal carbonyls, and with slight modifications, to aromatic complexes.)

In 1850s, Edward Frankland (a former student of Bunsen) prepared a number of air-sensitive metal-alkyl complexes, including ZnEt₂,⁸ HgEt₂,⁹ SnEt₄,^8,10 and EtLi,¹¹ with the zinc and mercury compounds being immediately employed for the synthesis of a variety of other main-group organometallic compounds. In this context, in 1863, Friedel and Crafts reacted ZnR₂ with SiCl₄ to prepare organochlorosilanes R_nSiCl_4-n.¹² Later, in 1868, Schützenberger reported the first metal-carbonyl complexes [Pt(CO)₂Cl₂] and [Pt(CO)Cl₂]₂;¹³ and in 1890, Mond was able to isolate the first binary metal-carbonyl compound, Ni(CO)₄;¹⁴ then being followed in 1891 by the almost simultaneous reports of [Fe(CO)₅], by Mond¹⁵ and Berthelot.¹⁶

Earlier, in 1828, the serendipitous preparation of urea from ammonium cyanate reported by Wöhler¹⁷ (a former student of Berzelius) attracted the attention of many chemists, thus representing a key historical event that triggered the rapid development of organic synthesis. In this context, important early examples referring to the use of metals or organometallic compounds in organic synthesis included the preparation of alkanes from alkyl halides and sodium, as reported by Wurtz in 1855,¹⁸ and the Cu-promoted dimerization of terminal alkynes, as reported by Glaser in 1869.¹⁹ At the end of the nineteenth century, in 1894, Phillips described the oxidation of ethylene to acetaldehyde, promoted by an aqueous solution containing stoichiometric amounts of a Pd salt.²⁰ In 1899, Barbier described part of his studies using organometallic reagents of type RMX that could be formed in situ from alkyl halides RX and a metal M (M = Mg, Zn) as nucleophiles in 1,2-additions to carbonyl compounds,^21,22 then being followed in 1900 by his student Victor Grignard, whose studies focused on the use of organomagnesium halides (RMgX) as strong bases and nucleophiles.^23,24 The french chemist Paul Sabatier (a former student of Berthelot) was the first to differentiate homogeneous from heterogeneous catalysis. He studied the hydrogenation of olefins to alkanes in the presence of heterogeneous Nickel catalysts.²⁵ As a consequence of these contributions, Grignard and Sabatier were awarded the Nobel Prize, approximately a decade later, in 1912.

Continuing on with the early advancements of the twentieth century, Ullman showed that Cu can promote the dimerization of arylbromides²⁶ and the coupling of amines with aryl halides.^27,28 In 1909, Wilhelm Ostwald was awarded the Nobel Prize for his contributions to the understanding of fundamental concepts related to catalysis, chemical equilibria and rates of reactions, which placed him as the founder of physical-chemistry.²⁹ Ostwald had several pulpils, among them, Van't Hoff (Nobel Prize in 1901), Arrhenius (Nobel Prize in 1903), and Nernst (Nobel Prize in 1920). In 1917, Schlenk reported the first isolation of organolithium compounds (e.g. MeLi, EtLi and PhLi) by reacting Li with the corresponding dialkyl- or diarylmercury compounds.³⁰ Later, in 1930, Ziegler would describe the ready preparation of such compounds, by reacting Li with the corresponding alkyl- or aryl halides.^31,32

In 1918, Haber and Bosch were recognized with the Nobel Prize for the catalytic hydrogenation of N₂ to produce NH₃.³³ Since early developments, little has changed until today. A key event in the process development included the use of an α-Fe catalyst,³⁴ developed at BASF by Alwin Mittasch in the beginning of the 20^th century.^35,36 The industrial process derived from this transformation paved the way for a revolution in the production of fertilizers. Indeed, ca. 80% of the ammonia produced in the world (>130 megatons)³⁷ is used in the production of fertilizers. Today, it is yet considered one of the greatest achievements of mankind in chemistry.

In 1938, as a consequence of his period in Mülheim (Ruhr area, Germany), when he was working with Franz Fischer and Hanz Tropsch, Roelen patented the first homogeneous hydroformylation reaction of olefins in the presence of synthesis gas (CO + H₂) and HCo(CO)₄ as catalyst.³⁸ In 1939, Meerwein reported a Cu-mediated arylation process of electron-poor olefins with diazonium salts,³⁹ and almost ten years later, in 1948, Reppe described the first Ni-catalyzed formal [2+2+2]-cycloaddition of alkynes leading to arenes.^40,41 Shortly after, Pauson⁴² and Wilkinson⁴³ were involved in the first reports of Ferrocene,⁴⁴ while Gilman reported the generation of cuprates from the reaction of alkyl lithium compounds with copper halides.^45,46 In 1955, Ziegler and Natta independently described strategies to polymerize ethylene using a combination of Ti and Al complexes,⁴⁷ which would years later be recognized by the Nobel Prize.⁴⁸ In the following year, in 1956, Hodgkin reported the structure of vitamin B₁₂, the first biomolecule known at that time containing a metal-carbon bond.⁴⁹ In 1959, van der Kerk reported the reduction of alkylhalides using Bu₃SnH,^50,51 which was then demonstrated to involve a radical chain mechanism.⁵² Later, this reactivity was further explored in other transformations, such as the Barton-McCombie deoxygenation⁵³ and the Barton decarboxylation.⁵⁴ Also in 1959, Smidt reported the Pd-catalyzed oxidation of olefins using O₂ and H₂O (Wacker oxidation);^55,56 and in 1965, Tsuji reported for the first time the use of Pd salts to promote the allylic alkylation of diethylmalonate.⁵⁷ In 1973⁵⁸ and in the following years, this strategy received several contributions from the Trost group, including numerous asymmetric catalytic protocols and elements of catalyst design. Among the contributions toward the development of Pd-catalyzed asymmetric allylic alkylation protocols (Pd-AAA), a powerful ligand, known today as the Trost ligand, would appear years later, in 1992.⁵⁹

In 1966, Wilkinson described the preparation and use of RhCl(PPh₃)₃ as an efficient catalyst for hydrogenation reactions.⁶⁰ In the following year, Calderon reported early examples and coined the term "olefin cross metathesis",⁶¹ then being followed by Penella in 1968, who reported that alkyne metathesis was also a feasible transformation, as it became evident from the conversion of 2-pentyne to a mixture of 2-butyne and 3-hexyne, in the presence of WO₃ on silica.⁶² Also in 1968, Heck reported a Pd-promoted cross-coupling transformatin between olefins and organomercurials.⁶³ This Pd-based stoichiometric version would be improved in 1971 by the contribution of Mizoroki, who described that the same olefinic product could be accessed from a Pd-catalyzed cross-coupling reaction replacing organomercurials by aryl halides.⁶⁴ In 1969, Shilov reported a Pt-catalyzed transformation for a Pt-promoted oxidation of alkanes to the corresponding alcohols.⁶⁵ A year later, Chauvin would accurately describe the involvement of metallocyclobutanes as key intermediates in the mechanism of olefin metathesis.^66,67 After the seminal contribution of Heck and Mizoroki to the field of cross-coupling reactions, several other variants followed involving organic halides and an organometallic transmetallating species. In 1972, Corriu⁶⁸ and Kumada⁶⁹ reported the Ni-catalyzed cross-coupling of Grignard reagents; in 1975, Sonogashira reported on the Pd-catalyzed cross-coupling of terminal alkynes;⁷⁰ in 1976-77, Negishi reported the Pd- or Ni-catalyzed cross-coupling of alanes or organozinc reagents with alkenyl/aryl halides;⁷¹ Migita⁷² and Stille⁷³ reported on the Pd-catalyzed cross-coupling of stannanes; and in 1979, Suzuki reported the Pd-catalyzed cross-coupling of boronic acids.⁷⁴ During this period, other important achievements in organometallic chemistry also included the Nobel Prize in 1973 awarded to Fischer and Wilkinson, for their contributions to the chemistry of sandwich compounds;⁷⁵ the work of Mortreux and Blanchard involving the metathesis of alkynes employing a Mo(CO)₆/resorcinol catalytic system;⁷⁶ the work of Kagan in 1977 describing the use of SmI₂ as a SET reducing agent;^77,78 and the report of Crabtree in 1979 demonstrating that an Ir complex containing a cyclooctene ligand could lead to cyclooctadiene via a dehydrogenation process.⁷⁹

While in 1981, Schrock reported the first well-defined catalyst for alkyne metathesis, a W(VI) alkylidyne complex;⁸⁰ in 1983, Sauvage described a new strategy to assemble interlocked molecules (catenanes) by means of Cu-based templates;⁸¹ and in 1989, Kulinkovich reported a Ti-catalyzed preparation of cyclopropanol derivatives employing carboxylic acids.⁸² During this period, asymmetric synthesis was gaining momentum; and a number of new transformations have appeared, including Noyori protocol for Rh- or Ru-BINAP catalyzed hydrogenation of olefins;⁸³ Narasaka⁸⁴ and Seebach⁸⁴ reports on the use of Ti-TADDOL complexes in Diels-Alder cycloadditions and 1,2-additions of Grignard or organolithium reagents to aldehydes; Sharpless dihydroxylation of olefins,⁸⁶ and Jacobsen⁸⁷ and Katsuki⁸⁸ protocols for the epoxidation of olefins.

In 1991, Arduengo reported the first stable, isolable NHC;⁸⁹ Larock introduced a convenient Pd-catalyzed indole synthesis starting from 2-iodoanilines and internal alkynes;⁹⁰ and Schrock reported a highly active Mo catalyst for ring-opening alkene metathesis polymerization.⁹¹ In 1992, Shibasaki introduced the use of lanthanides-BINOL as powerful Lewis acid catalysts for a nitroaldol⁹² and other transformations.⁹³ In 1993, Grubbs introduced a Ru catalyst for olefin metathesis (later called of first generation, it contained two tricyclohexylphosphine ligands).⁹⁴ In 1999, a second generation Ru catalyst was developed, in which one of the phosphine ligands of the first generation catalyst had been replaced by a NHC ligand.⁹⁵ Because these catalysts are not air sensitive, and generally exhibit a high functional group tolerance, they have allowed a significant extension of the scope of this transformation.⁹⁶ Due to the previous contributions of Schrock, Grubbs and Chauvin to the development of olefin metathesis, they were recognized with the Nobel Prize in 2005.⁹⁷

In 1993, Keck also reported an asymmetric allylation method of aldehydes employing allyltributylstannane and a Ti-BINOL catalytic system;⁹⁸ in 1994, Hartwig⁹⁹ and Buchwald¹⁰⁰ reported simultaneously and independently Pd-catalyzed cross-coupling strategies between aryl halides and tin amides. Later, this Pd-catalyzed C-N cross-coupling strategy was further improved to become a powerful method employed in several domains, such as in the synthesis of heterocycles, ligands and catalysts, in medicinal chemistry, in process chemistry and in chemical biology applications.¹⁰¹ In this context, some years later (1998), Buchwald and his group have also introduced a family of dialkylbiaryl phosphine ligands of superbe activity for Pd-catalyzed Suzuki cross-coupling reactions.^102,103 Nevertheless, these ligands got increased popularity over the years for being also competent in numerous other cross-coupling transformations.¹⁰⁴

In 1995, Jacobsen reported on the stereoselective ring-opening of epoxides,¹⁰⁵ and Herrmann described the use of an NHC ligand in a Pd-catalyzed Heck reaction.¹⁰⁶ In 1996, Sharpless reported an extension of his previous work, this time describing a protocol for the enantioselective catalytic aminohydroxylation of olefins.¹⁰⁷

Approaching the 21^st century, C-H functionalization strategies received more attention. This synthetic interest can be highlighted by the reports of Periana in 1998, when his group described a Pt-based protocol to oxidize methane;¹⁰⁸ in 2005, Sames demonstrated a C-H functionalization process via a redox-neutral approach, consisting of Lewis acid-catalyzed 1,5-H shift/cyclization sequence for the preparation of spirocycles (Lewis acids employed: Sc(OTf)₃, PtCl₄, BF₃.OEt₂);^109,110 and in 2006, Bohle and Li described a CuBr-catalyzed cross-dehydrogenative coupling of amines with nucleophiles, such as nitroalkanes and malonates, among others.^111,112 These studies were accompanied by other impressive contributions in the following years, including: White selective oxidations using Fe(PDP) as catalyst (2007),¹¹³ Yu protocol for the Pd-catalyzed directing-group guided meta-selective functionalization of arenes (2012)¹¹⁴ and the highly seletive Rh-catalyzed protocols for the functionalization of linear alkanes using aryldiazoacetates, as reported by Davies (2016).^115,116

Since the beginning of the 21^st century, asymmetric catalysis has been also undergoing continuous developments. The importance of the field was further brought to the spotlight by the Nobel Prize in Chemistry of 2001, when Knowles, Noyori and Sharpless were recognized for their contributions.¹¹⁷ In the following years, new developments included the use of a chiral counter-ion for enantioselective Au(I)-catalyzed intramolecular cyclization of allenes, as reported by Toste in 2007;¹¹⁸ the synergistic combination of an aminocatalyst and a Ru photocatalyst to promote a highly stereoselective photochemical protocol for the α-alkylation of aldehydes, as reported by MacMillan in 2008;¹¹⁹ TADDOL-derived phosphoramidite ligands for Au(I) asymmetric catalysis reported by Fürstner in 2010;¹²⁰ the use of a NHC ligand in a heterogeneous, enantioselective Pd-catalyzed α-arylation of ketones, as reported by Glorius in 2010;¹²¹ the development of chiral Cp ligands for the Rh-catalyzed enantioselective synthesis of 3,4-dihydroisoquinolin-1(2H)-ones, as reported by Cramer in 2012;¹²² the development of a pyrrolidine/pyridine bifunctional aminocatalyst/ligand for the Rh-catalyzed asymmetric α-alkylation of ketones using ethylene, as reported by Dong in 2014;¹²³ and the development of chiral-at-metal photoredox catalysts, as reported by Meggers, also in 2014.¹²⁴ During the past years, significant achievements have been made also involving other metal-promoted transformations. Representative examples include the Cu-catalyzed Huisguen [3+2] cycloaddition between terminal alkynes and azides,¹²⁵ reported independenly and simultaneously by Meldal¹²⁶ and by Fokin and Sharpless¹²⁷ (this transformation became a canonical representative of click chemistry);¹²⁸ the development of "Turbo Grignard" as highly reactive Grignard reagents, with practical handling and high functional group tolerance, as described by Knochel;^129,130 the Pd-catalyzed reductive carbonylation of arylbromides, as described by Beller (2006), which was the first example of such a reaction to be employed in industry;¹³¹ the development of bench-stable alkyne metathesis precatalysts, as described by Fürstner;¹³² C(sp²)-C(sp³) photochemically-promoted cross-coupling reactions, promoted by the synergistic combination of a Ni-catalyst and an Ir-photoredox catalyst, as described by Molander,¹³³ and Doyle and MacMillan;¹³⁴ a Ni-catalyzed carboxylation of alkyl bromides, as reported by Martin;¹³⁵ a Rh-catalyzed hydrogenation of perfluorinated arenes, as reported by Glorius;¹³⁶ the Ni-catalyzed decarboxylative cross-coupling reaction involving redox-active esters and alkenylzinc halides, as described by Baran,¹³⁷ and the Ni-catalyzed electrochemically promoted cross-coupling of aryl halides with amines, as described by Neurock, Minteer and Baran.¹³⁸ This brief presentation of selected achievements in the history of metal-promoted transformations has been chronologically ordered in Figure 1.

 

 

Photoredox catalysis

Photocatalysis can be defined as the "change in the rate of a chemical reaction or its initiation under the action of ultraviolet, visible or infrared radiation in the presence of a substance - the photocatalyst - that absorbs light and is involved in the chemical transformation of the reacting partners."¹³⁹ The ability of Nature to transform the sun energy into chemical energy has inspired chemists for more than a century.¹⁴⁰ An example of an important photochemical transformation promoted by Nature is photosynthesis, which uses sunlight to convert carbon dioxide and water into glucose and oxygen.¹⁴¹ Among the wavelenghts that can be harvested from the full electromagnetic spectrum, the visible region can be considered particularly strategic in organic synthesis. The reason for this is that the UV region is associated with photons of high energy, which can be generally absorbed by organic molecules, but often implicates in unselective, or unpredictable competitive reaction pathways. The IR region is associated to photons of quite low energy and have been only rarely employed in synthesis. In contrast, although most of the organic molecules cannot absorb in the visible region,^142,143 numerous metal photocatalysts and dyes can. As a consequence, general mechanisms of electron¹⁴⁴ or energy¹⁴⁵ transfers can be explored, thus allowing the development of new, mild and more sustainable synthetic methods.

Photoredox catalysts and fundamental principles

Most common photoredox catalysts are represented by metal complexes of Ru or Ir carrying polyheteroaromatic rings as ligands¹⁴⁶ (although other metals complexes have been also reported)¹⁴⁷ or dyes,¹⁴⁸ which are highly conjugated organic molecules also absorbing in the visible region (Figure 2).

 

 

The polyunsaturated rings present in these catalysts are chromophores that absorb the low-energy radiation associated to the visible region and promote the excitation of an electron to a higher energy orbital, thus resulting in the formation of an excited state that is both a better reducing and oxidazing agent. In the case of the metal complexes, this electronic excitation typically takes part from the metal to an electron-poor ligand (dπ_metal → π*_ligand), and it is called a metal to ligand charge transfer (MLCT). The singlet state of higher energy can undergo intersystem crossing (ISC) to create a triplet excited state, which has a longer lifetime, due to the spin-forbidden relaxation to the ground state.¹⁴⁶

To a better understanding of how these electronic processes occur, the photocatalyst Ru(bpy)₃²⁺ can be used to demonstrate these properties in greater detail. The metal species Ru²⁺ has 6 electrons in its d orbitals (dπ⁶) and the polypyridine ligands have low-lying π* orbitals, thus becoming electron-acceptor orbitals. Upon absorption of a photon, an electron transfer has sufficient energy to occur from a dπ orbital of the metal to the π* orbital of the ligand. This electron transfer event converts [Ru^II(bpy)₃]²⁺ to [Ru^III(bpy)₂(bpy)^·⊝]²⁺. As a consequence, the lower energy triplet state of *[Ru(bpy)₃]²⁺ can act either as an oxidant or a reductant, depending on the reacting partner present in the reaction mixture¹⁴⁶ (Scheme 1).

 

 

Electron transfer events might occur from a donor molecule (D) to the excited state of the photocatalyst via a reductive quenching cycle; or from the excited catalyst to an acceptor molecule (A), via an oxidative quenching cycle (Scheme 2). In the oxidative quenching cycle, the electron transfer event occurs from the π* orbital of the complex (that is singly occupied after excitation, cf. Scheme 1) to A, thus forming Ru(bpy)³⁺₃; while in the reductive quenching cycle, D gives an electron to the orbital dπ of the metal (that is singly occupied after excitation, cf. Scheme 1) to produce Ru(bpy)⁺₃.^144,146 Because every oxidative or reductive quenching cycle needs a donor and an acceptor molecule to proceed, there are some important elements of design that must be present. Some protocols do contain both donor and acceptor partners directly implicated in the desired transformation. However, it is also possible to design a photoredox catalytic cycle employing one of these elements as sacrificial agents. For instance, sacrificial donors include amines, such as Et₃N, E_1/2(Et₃N^·⊕/Et₃N) = +1.15 V; or thioethers, such as benzylmethylsulfide. E_1/2(BnSMe^·⊕/BnSMe) = +1.25 V, or other electron-rich molecules, such as anisole E_1/2(PhOMe^·⊕/PhOMe) = +1.76 V). Examples of sacrificial acceptors include dicyanobenzenes, e.g. E_1/2(1,4-C₆H₄(CN)₂/1,4-C₆H₄(CN)₂^·⊝) = -1.64 V,¹⁴⁹ aryldiazonium salts, e.g. E_1/2(PhN₂BF₄/Ph·) = -0.16 V¹⁵⁰ or molecular oxygen E_1/2(O₂/O₂^·⊝) = -1.25 V.¹⁵¹

 

 

The knowledge of the redox potentials of all involved molecules in either of these catalytic cycles is important to establish whether the envisioned overall transformation is thermodynamically favored. This is a necessary condition but is not sufficient, as kinetics also play a role. Concerning thermodynamics, in the case of [Ru(bpy)₃]²⁺, the excited photocatalyst, having E_1/2(Ru^*II/Ru^I) = +0.77 V, is a better oxidant than its ground state, having E_1/2(Ru^II/Ru^I) = -1.33 V. In the same manner, its excited state *Ru(bpy)₃²⁺ is a better reducing agent, cf. E_1/2(Ru^III/Ru^*II) = -0.81 V than its ground state [Ru(bpy)₃]²⁺, cf. E_1/2(Ru^III/Ru^II) = +1.29 V. The redox potential and some photophysical properties of some common photocatalysts are presented in Table 1.¹⁴⁶

 

 

The different metals and ligands employed when synthesizing photocatalysts produce distinctive redox potentials.^146,152 The presence of electron donating heteroarenes typically afford more strongly reducing species, while the presence of electron withdrawing heteroarenes typically produce stronger oxidants. For instance, considering the redox potential of Ru^III/Ru^II, it is possible to note that when two pyrazole ligands are present, they make the oxidative power of the corresponding complex Ru(bpy)₂(pz)₂⁺ to be lower, cf. E_1/2(Ru^III/Ru^II) = +0.30 V than the one of Ru(bpy)₃Cl₂, cf. E_1/2(Ru^III/Ru^II) = +1.26 V. Following the same trend, the use of strongly π-acceptor ligands, such as 2,2'-bipyrazine, makes the oxidizing power of Ru(bpz)_³⁺3to be even more elevated, cf. E_1/2(Ru^III/Ru^II) = +1.86 V. These effects are a consequence of the reactivity of the Ru center upon MLCT events: more the Ru center is deficient in electrons, the stronger it is as an oxidizing agent. Extending this analysis to different substitutents on pyridine ligands; donor groups will destabilize the radical anion generated upon MLCT; while electronwithdrawing groups will stabilize them. Therefore, EDG on pyridine ligands will render the corresponding photocatalysts stronger reducing agents, while EWG groups will promote the opposite effect, that is, to generate weaker reducing agents^146,152,153 (Figure 3).

 

 

The energy distance (Δ₀) between t_2g and e_g increases with the increase of the period (of the periodic table) of the metal employed, as well as the ion charge. Therefore, Ir³⁺ catalysts are generally more stable than Ru²⁺ catalysts and can hold numerous ligands of type LX, thus rendering more efficient charge transfers between the metal and the ligand (Figure 4).¹⁴⁶

 

 

Early examples

An initial example in this field can be dated back to as early as 1978, when Kellogg and co-workers reported the RuCl₂(bpy)₃‑photomediated reduction of sulfonium ion 1, in the presence of 1,4-dihydropyridine 2, to afford the corresponding reduced compound 3 and dimethylsulfide 4¹⁵⁴ (Scheme 3a). Then, other reports from the groups of Fukuzumi and Tanaka,¹⁵⁵ and Pac¹⁵⁶ described similar catalytic systems, which allowed the reduction of electron-poor olefins, aromatic ketones and benzyl halides. Some years later, in 1984, Cano-Yelo and Deronzier described the first photoredox catalyzed reaction using aryldiazonium salts as terminal oxidants for the conversion of benzyl alcohols to the corresponding aldehydes.¹⁵⁷ They have also reported a photocatalyzed Pschorr reaction using Ru(bpy)₃Cl₂ for the conversion of (Z)-2styrylbenzenediazonium salt 6 to the corresponding phenanthrene 7 in quantitative yield (Scheme 3b).¹⁵⁸

 

 

In 1991, Okada and co-workers demonstrated that N-(acyloxy) phthalimides 8 could serve as a convenient source for alkyl radicals R¹-CH₂· (Scheme 3c). This radical can participate in Michael additions with electron-poor olefins leading to ketones 9,¹⁵⁹ chlorinated products 10,¹⁶⁰ phenylselenated compounds 11¹⁶¹ or reduced compounds 12.^162,163

Despite these initial efforts, examples in this field remained relatively scarce until the beginning of the 21^st century. It was only in 2008, with the landmak work of Nicewicz and MacMillan,¹¹⁹ that catalytic photoredox transformations started to attract the attention of the synthetic organic chemistry community (Figure 5).¹⁶⁴

 

 

Among the most important developments made so far in the field of photoredox catalysis, its merger with metal catalysis has often allowed the development of new powerful protocols, which take advantage of the best of the two worlds: allow the access to highly reactive radical intermediates, as well as generate metal intermediates that can be more easily interconverted between different oxidation states. This review aims to present the most representative developments in this intersection, while critically presenting their reactivity profiles, scope and limitations.

Merging photoredox catalysis and metal catalysis

The synergistic combination of photoredox catalysis with metal catalysis has appeared as a versatile strategy for the development of new synthetic methods. The use of photoredox catalysts allows the mild generation of radical species, which in the presence of metal catalysts, can afford the coupling with non-traditional partners. Overall, photoredox catalysis can modulate oxidation states of the organometallic complexes employed, thus facilitating individual steps of a number of catalytic cycles.¹⁶⁵

Applications employing Pd

The combination of photoredox catalysis and metal catalysis has been accomplished for the first time in 2007, by Osawa and co-workers.¹⁶⁶ The use of Ru(bpy)²⁺₃and visible light has been observed to accelerate the Sonogashira cross-coupling between aryl halides 13 and terminal alkynes 14, in the presence of Pd(MeCN)₂Cl₂ as catalyst, to afford the corresponding internal alkynes 15. The authors remarked that the excited photoredox catalyst has facilitated the oxidative addition step, but more details of the mechanism were not provided (Scheme 4).

 

 

In 2011, Sanford and co-workers have investigated the arylation of C(sp²)-H of 2-arylpyridines 16 and aryldiazonium salts 17, in the presence of Pd(OAc)₂ and Ru(bpy)₃Cl₂.6H₂O as catalysts, under blue light irradiation.¹⁶⁷ In contrast to previous arylation protocols employing strong oxidants and/or high temperatures,¹⁶⁸ here, the use of a photoredox catalyst allowed the same transformation in the absence of any oxidant and at rt.¹⁶⁷

In the proposed mechanism, a paladacycle 20 is formed upon a metallation-deprotonation step involving starting substrate 16 and the Pd catalyst. Simultaneously, the excited photoredox catalyst *Ru reduces the aryldiazonium salt 17 (via a SET process) to afford the aryl radical 19. The aryl radical 19 inserts into the palladium intermediate 20 to form Pd(III) species 21. Subsequent Ru(III)-promoted oxidation of this intermediate leads to Pd(IV) 22, which then undergoes reductive elimination to produce the observed arylated products 18, while regenerating a Pd(II) species¹⁶⁷ (Scheme 5).

 

 

Years later, Rueping and co-workers reported a photoredox-catalyzed C-H functionalization protocol starting from aromatic enamines 23 in the presence of a Pd catalyst to produce indoles 24, while employing molecular oxygen as the terminal oxidant.¹⁶⁹ The reported scope for this transformation included 15 examples, with yields varying from 57 to 95% (Scheme 6a).

 

 

In 2015, Wang and co-workers have demonstrated that it was possible to perform a decarboxylative C-H acylation of phenylamides 25 using α-ketocarboxylic acids 26 in the presence of eosin Y and Pd(OAc)₂ as catalysts to afford the desired compounds 27 (Scheme 6b).¹⁷⁰ In this same context, Tunge and co-workers reported a photoredox co-catalyzed decarboxylative Tsuji-Trost reaction converting allyl esters 28 to allylic compounds 29 (Scheme 6c).¹⁷¹

Applications employing Cu

Trifluoromethylation strategies are important because the CF₃ group can increase the metabolic stability of drugs, improve its permeability into membranes and favor protein-ligands interactions.¹⁷² In this context, Sanford and co-workers reported a protocol employing photoredox catalysis and Cu catalysis for the reaction of boronic acids 30 with CF₃I 31 to afford the corresponding trifluoromethyl arenes 32.¹⁷³ In the proposed mechanism, the trifluoromethyl radical 33 is generated from the Ru(I)-promoted reduction of CF₃I, followed by addition of the resulting radical 33 to the Cu(II)X₂ complex to generate Cu(III) intermediate 34. Then, this new Cu(III) species 34 undergoes transmetallation with the boronic acid 30 to afford a new Cu(III) species 35. Finally, reductive elimination of 35 produces the corresponding trifluoromethylated arene 32. An electron transfer between the oxidant, excited *Ru²⁺, and the Cu(I)X allows the turnover of both catalytic cycles (Scheme 7).

 

 

In 2015, Kobayashi and co-workers presented a photoredox catalyzed Cham-Lam coupling strategy between anilines 36 and boronic acids 30 to afford the corresponding diarylamines 37.^174,175 In this context, boronic acids 30 carrying electronwithdrawing groups could be used and the authors proposed that the role of the photoredox catalyst was to promote the efficient oxidation of Cu(II) to Cu(III) species, which could then undergo reductive elimination to produce the N-C coupling leading to amines 37, while also generating Cu(I) intermediates. Finally, oxidation of Cu(I) intermediates by air is proposed to regenerate the Cu(II) species (Scheme 8a).

 

 

Another method that uses a Cu-catalyst in the presence of a photoredox catalyst has been established by MacMillan and co-workers.¹⁷⁶ A decarboxylative trifluoromethylation of aliphatic carboxylic acids 38 in the presence of Togni reagent 39 allowed the formation of C(sp³)-CF₃ bonds for the corresponding trifluoromethyl compounds 40. Several examples were reported, including the use of natural products and pharmaceutical drugs (Scheme 8b).

Applications employing Ni

Metal catalysis employing Ni has presented solutions to some challenging cross-coupling reactions involving C(sp³). Their success is owned to the ability of promoting oxidative additions with alkyl halides, rather than undergoing β-hydride eliminations, which are fairly common to other metals, such as Pd.¹⁷⁷

The first photoredox catalyzed transformations merged with Ni catalysis have been reported by Molander and co-workers;¹⁷⁸ and Doyle, MacMillan and co-workers,¹⁷⁹ simultaneously and independently in 2014. The work of the Molander group described a C(sp²)-C(sp³) coupling between aryl radicals generated from a SET process involving potassium organotrifluoroborates 41, aryl bromides 13 and an excited photoredox catalyst *Ir(III), in the presence of Ni(cod)₂ catalyst¹⁷⁸ (Scheme 9).

 

 

MacMillan and Doyle reported a decarboxylative coupling between carboxylic acids, such as 43, and aryl halides 13 for the formation of the corresponding arylated amines 44. In the proposed mechanism, the Ir(III) photoredox catalyst is excited by visible light to generate *Ir(III), which is a good oxidant. After the deprotonation of the α-aminoacid by the base, the oxidation of the substrate is promoted by *Ir(III) to afford an alkyl radical 45. Simultaneously, the initial catalyst NiL_n undergoes oxidative addition with the aryl halide 13 to produce Ni(II)-intermediate 46, which rapidly intercepts the alkyl radical 45 to form organometallic complex Ni(III) 47. Finally, reductive elimination from 47 generates the C-C bond of the final arylated compound 44 and the Ni(I) intermediate 48, which undergoes a SET promoted by the Ir(II)-photocatalyst species, thus regenerating both starting catalysts, NiL_n and Ir(III)¹⁷⁹ (Scheme 10).

 

 

In 2016, MacMillan, Fu and co-workers reported an efficient method for the decarboxylative enantioselective arylation of aminoacids employing aryl halides, by means of photoredox catalysis merged with Ni-catalysis. The corresponding arylated amines have been obtained in good yields and > 82% ee.¹⁸¹ In addition, extension of this work to the use of vinyl halides,¹⁸¹ and alkyl halides was also demonstrated (Scheme 11).¹⁸²

 

 

In the same context, MacMillan and co-workers have also described asynergistic combination of Ir(III)/Ni(0) catalysts, acting in the presence of (Me₃Si)₃SiH (TTMSS), for the C(sp²)-C(sp³) coupling between aryl halides 13 and alkyl bromides 56 to produce the corresponding arylated compounds 57.¹⁸³ The mechanism of this transformation is believed to proceed via the generation of bromine radical 58 from a SET between the excited photocatalyst *Ir(III) and a bromide anion, followed by hydrogen abstration from (Me₃Si)₃SiH to produce the corresponding silicon radical 59. Then, the silicon radical 59 reacts with the alkyl bromide 56 to generate an alkyl radical 60, which adds to the Ni(II) species 61 (derived from the oxidative addition of aryl bromide 13 and Ni(0)L_n) to afford the Ni(III) intermediate 62. Finally, reductive elimination leads to Ni(I) species 63, which undergoes a single electron reduction from Ir(II)-photocatalyst to simultaneously regenerate Ir(III) and Ni(0) catalysts, as discussed in some of the previous protocols (Scheme 12).

 

 

In 2017, another protocol reported by the MacMillan group involved the combination of three types of catalysis: metallic, photoredox and organocatalyis. Using this approach, aldehydes 64 could be arylated with aryl halides 13 to the corresponding ketones 65 (Scheme 13).¹⁸⁴ Because the excited complex *Ir(III) is a strong oxidant, E_1/2(Ir*^III/Ir^II) = +1.21 V, it can remove one electron from quinuclidine to generate the corresponding radical cation 66. In the presence of the aldehyde 64, the radical cation of quinuclidine 66 abstracts a hydrogen atom to form the corresponding acyl radical 67. Upon oxidative addition of the catalyst NiBr₂ with aryl halide 13, which produces intermediate 69, it undergoes addition of the radical 67 to generate the Ni(III) species 70. Then, reductive elimination and single electron reduction of the resulting Ni(I) catalyst 71 produces the observed ketones 65 and regenerates both catalytic species Ni(0) and Ir(III). This reactivity has been demonstrated for several aryl bromides and some vinyl and alkyl bromides. In this context, aromatic, linear, branched and cyclic aldehydes can be also employed (Scheme 13).

 

 

Coupling reactions involving C-X (X = heteroatom) have been also investigated by means of the merger of Ni catalysis with photoredox catalysis. The formation of C-N bonds has been reported by the groups of Jamison,¹⁸⁵ Oderinde and Johannes,¹⁸⁶ Buchwald and MacMillan¹⁸⁷ and Molander¹⁸⁸ (Scheme 14). The work of Jamison involves the conversion of iodoacetanilides 72 and alkenes 73 to indolines 74. Stoichiometric studies and cyclic voltammetry of the Ni complexes indicate that the oxidation of Ni(II) to Ni(III), which is promoted by the photoredox catalyst, is necessary for the C-N coupling, thus avoiding the formation of Heck-type products via a competitive β-elimination event¹⁸⁵ (Scheme 14a).

 

 

In 2016, Oderinde, Johannes and co-workers reported the formation of C-N bonds by the coupling of anilines 36 with aryl iodides 13 to afford diarylamines 37. The Ir(III) photoredox catalyst is responsible for oxidizing the employed amine, and then to reduce the Ni(II) catalyst to Ni(I). This methodology is efficient and can tolerate several functional groups, such as alcohols, fluorides, chlorides, aldehydes, ketones, carbamates, eters, cyanides, ethers, thioethers, alkynes, among others¹⁸⁶ (Scheme 14b).

The formation of a C-N bond has been also described by Buchwald and MacMillan for the preparation of heteroaromatic amines 77 starting from aryl bromides 75 and amines 76 in the presence of a Ni(II) catalyst and an Ir(III) photoredox catalyst. In collaboration with Merck, the coupling between 18 drug candidates containing halides and piperidine derivatives has been tested. Among these tests, most of them (78%) presented the coupled product, therefore demonstrating the power of this strategy¹⁸⁷ (Scheme 14c).

Recently, Molander reported a strategy of aminomethylation employing arylbromides 75 and a silylmethylamines 78 to produce the corresponding products 79 via a synergistic combination of Ni catalysis/photoredox catalysis. The relatively low redox potential of silylated methylamines allows the formation of α-amino radicals that can be engaged in cross-coupling transformations with numerous aryl halides¹⁸⁸ (Scheme 14d).

In 2015, MacMillan and co-workers reported the coupling between alcohols 80 and aryl bromides 13 for the formation of C-O bonds in ethers 81. The *Ir(III) species oxidizes the Ni(II) catalyst 83 to Ni(III) intermediate 84. Then, reductive elimination leads to the Ni(I) species 85, while generating cross-coupled product 81. Then, intermediate 85 is reduced by an Ir(II) species to to afford L_nNi(0), thus turning over both catalytic cycles¹⁸⁹ (Scheme 15).

 

 

Aiming at the formation of C-S bonds, Oderinde, Johannes and co-workers reported in 2016 a thioetherification of aryl iodides 13 involving a sulfur radical formed from the oxidation of thiols 86 using an Ir(III) photoredox catalyst. The generated Ir(II) reduced the Ni(II) species to Ni(I) and cyclic voltammetry experiments supported the porposed mechanism (Scheme 16).¹⁹⁰

 

 

In the same year, Molander also reported a thietherification process of aryl bromides 13. Following this strategy, a sulfur radical is generated from a hydrogen atom transfer from the alkyl radical resulting from the oxidation of isobutyl bis(catecolate)silicate 88 by the excited species *Ru(II) and a thiol 86. This sulfur radical reacts with the Ni catalyst and the aryl bromide 13 to afford the corresponding arylthioether 87 (Scheme 16b).¹⁹¹ It was possible to use primary, secondary or tertiary thiols in this transformation; and high selectivity was observed for the C-S coupling in the presence of a variety of functional groups.

Recently, Gutierrez, Molander and co-workers reported a method involving Ni catalysis and a Ru photoredox catalyst for the construction of aryl and heteroaryl sulfones 90, starting from aryl halides 13 and sulfinate salts 89 (Scheme 16c).¹⁹² A sulfonyl radical is formed from the oxidation promoted by the *Ru(II) species (thus generating a Ru(I) species) and adds to the Ni(0) species, thus generating a Ni(I) complex, that undergoes an oxidative addition in the presence of the aryl halide 13. Finally, the resulting Ni(III) species undergoes reductive elimination to afford the sulfone 90 and generates a Ni(I) catalyst, that is finally reduced by the previously formed Ru(I) species to regenerate both Ni(0) and Ru(II) catalysts.

In addition, other similar photochemically-promoted cross-coupling reactions leading to the preparation of other sulfones have been also reported by Rueping¹⁹³ and Manolikakes.¹⁹⁴

Molander and co-workers explored the interplay between Ni catalysis and photoredox catalysis to react aryl bromides 13 with SH-containing biomolecules 91 to afford the corresponding cross-coupled products 92, in the absence of any protecting groups. The mechanism of this transformation is proposed to proceed by the generation of a sulfur radical 93 from a hydrogen atom transfer event between the biomolecule 91 and the alkyl radical 43, which in turn is derived from the *Ru(II)-promoted oxidation of the silicon reagent 88. Then, the thioradical 93 adds to the Ni(0) catalyst 95 to form the Ni(I) species 96. This intermediate undergoes oxidative addition with the starting aryl halide 13 to produce the Ni(III) intermediate 97. Finally, reductive elimination leads to the formation of the cross-coupled product 92, while producing Ni(I) catalyst 98. This catalytic species is reduced by the Ru(I) photoredox catalyst to regenerate both the Ni(0) catalyst 95 and the Ru(II) photoredox catalyst (Scheme 17).¹⁹⁵ This method can be performed in gram-scale and the scope of this transformation has been demonstrated to the use of L-glutathione, Tiopronin, D-penicillamine, biological probes, and pharmaceuticals.

 

 

In 2018, MacMillan and co-workers reported a protocol for a decarboxylative hydroalkylation of internal alkynes 99 using carboxylic acids 100, in order to produce the corresponding trisubstituted alkenes 101. Accordingly, this transformation involves the *Ir(III)-promoted oxidation of carboxylic acids 100, followed by a decarboxylation event to generate the corresponding alkyl radical 102. Upon generation of the alkyl radical 102, *Ir(III) is reduced to Ir(II), which is then oxidized back to Ir(III) by transferring one electron to Ni(II) species 103, thus forming a Ni(I) intermediate 104. The generated alkyl radical 102 adds onto the Ni(I) intermediate 104 to afford the corresponding Ni(II) species 105. Subsequently, 1,2-insertion onto the internal alkyne 99 leads to Ni(II) intermediate 106, which undergoes protodemetallation to produce the desired trisubstituted alkene 101 and Ni(II) catalyst 103. Finally, a SET involving Ir(II) photocatalyst and Ni(II) intermediate 103 regenerates Ni(I) starting catalyst species 104 (Scheme 18). Control experiments have shown that the observed regioselectivity of the 1,2-migration involving Ni intermediate 105 and alkyne 99 depends on the size of the groups envolved.¹⁹⁶

 

 

Applications employing Au

Oxidative additions between Au(I) and aryl halides are challenging¹⁹⁷ and the redox pair Au(I)/Au(III) is generally not easily interconverted.¹⁹⁸ Among some of the catalytic cycles reported for cross-coupling reactions involving gold, this challenging redox interconversion can be performed in the presence of an oxidizing agent or a photoredox catalyst. The merger of Au catalysis with photoredox catalysis has been reported by the first time by Glorius and co-workers in 2013.¹⁹⁹ They employed aryldiazonium salts 17 as the source of aryl radicals 19, that were generated for the intramolecular oxy/aminoarylation of alkenes. The excited photoredox catalyst *Ru(II) reduces the aryldiazonium salt 17 to produce aryl radicals 19, while Au(I) catalyst 109 promotes an intramolecular cyclization event of starting substrate 107, leading to organogold intermediate 110. The Au(I) intermediate 110 reacts with aryl radical 19 to afford Au(II) intermediate 111, which upon an electron transfer event converting Ru(III) into starting Ru(II), generates Au(III) intermediate 112. Finally, reductive elimination of 112 leads to the cross coupled product 108 and regenerates the Au(I) catalyst 109 (Scheme 19). Remarkably, the formation of Au(III)-Ar complexes, such as 112, typically produces a fast reductive elimination, thus avoiding protodeauration compounds and a potentially competing homodimerization pathway.

 

 

In contrast to the use of strong oxidizing agents employed in stoichiometric amounts for other gold-catalyzed cross-coupling protocols,²⁰⁰ the merger with photocatalysis allows the use of mild conditions, based on an overall neutral redox conditions.

Inspired by the early work of Sanford,¹⁶⁷ Glorius and Toste have demonstrated that aryl radicals 19 generated by photoredox catalysis from aryldiazonium salts 17 could be employed in gold-catalyzed reactions in a variety of transformations, such as arylation of alkynes 113 or 119;^201,202 H-phosphonates 115;²⁰³ in arylative-ring-expansions using substrates 117;²⁰⁴ arylation-hydration sequences usig alkynes 99 and α-arylation within Meyer-Shuster rearrangements of propargyl alcohols 121²⁰⁵ (Scheme 20).

 

 

Although the synergistic combination of metal catalysis and photoredox catalysis has been mainly composed of contributions employing Cu, Pd, Ni and Au as metal catalysts, other protocols involving Co,²⁰⁶ Ru,²⁰⁷ and Rh²⁰⁸ have been also reported for C-H functionalization processes, C-C and C-O couplings and oxidation reactions.

 

CONCLUSIONS

Since 2011, the synergism involving photoredox catalysis and metal catalysis has been used as a powerful strategy for the development of new synthetic technologies. In this context, advantages and disadvantages generally involve low catalyst loadings and potential toxicity issues associated to the use of metals, or sustainability aspects when rare metals are employed, respectively. Metal catalysis is a well-established field, which did not cease to evolve over the years. Nevertheless, the involvement of SET processes has allowed the development of new cross coupling protocols, most remarkably due to the involvement of new oxidation states of key catalytic intermediates (which are not as easily generated by other strategies). It is likely that the merger of both catalytic strategies will become increasingly important in the next years. It is possible to anticipate that new reactivity profiles will continue to be unlocked, proceeding via mild reaction conditions and significantly contributing to the broad advancement of organic synthesis.

Although economic aspects are always important to be taken into account, looking at the great number of publications appearing every year in the field of photoredox catalysis and metal catalysis in general; and the price of most common promoters, such as classical photoredox catalysts or Ni catalysts, their values do not seem to be a dominant barrier here for the advancement of this chemistry. Creativity and understanding the reactivity aspects underpinning these fields are far more important ingredients for the development of useful new protocols.

 

ACKNOWLEDGMENTS

The authors acknowledge Fapesp for a PhD Fellowship to A. A. G. F. (2017/22164-6) and a Research Grant to I. D. J. (2017/24017-0).

 

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