Introduction

The historical challenges of using radicals in synthetic chemistry is well documented . Traditional approaches for radical generation relied on hazardous reagents and harsh conditions, resulting in low reaction efficiency and undesired byproduct formation . As a consequence, the utility of radicals in organic synthesis remained limited for many years and in the past, they were perceived as fleeting reaction intermediates.

Recent progress in photoredox catalysis , electrochemistry , and the use of transition-metal (TM) catalysts in radical cross-coupling reactions have dramatically expanded the use of radicals in synthesis, leading to their strategic incorporation as "synthons" in modern organic chemistry, with complementary reactivity to more common polar reaction manifolds . The utility of radicals has also been expanded through the recent development of transformations involving radical-polar crossover, which incorporate both radical and ionic bond-forming steps into a single synthetic operation .

The success of radical reactions is intimately linked to the mechanisms of their initiation and the radical progenitor employed. Amongst the many progenitors that are available, carboxylic acids are one of the most extensively used, owing to their structural diversity and widespread commercial availability . Carboxylic acids 1 can generate radicals under oxidative conditions, as in classical decarboxylative halogenation reactions (Hunsdiecker reaction) that proceed via a radical mechanism . More recent approaches have leveraged photoinduced ligand-to-metal charge transfer to generate radicals from aliphatic and aromatic carboxylic acids.

However, more broadly used approaches involve carefully designed activated esters. Barton esters 2 emerged in the early 1980s (Scheme 1) and have found applications in a number of functional group interconversions mediated by radical chain decarboxylation . However, their widespread use in synthesis, especially in complex molecular settings, suffers from significant disadvantages. These include thermal and photochemical instability, as evidenced by their low N–O bond dissociation energy (BDE ≈ 42 kcal/mol) , the reliance on toxic tin hydrides as reductants and the undesired radical recombination with reactive 2-pyridylthiyl radicals that leads to (alkylthio)pyridine byproducts . More recently, N-hydroxyphthalimide (NHPI) esters (3) have emerged as convenient alternatives to Barton esters (Scheme 1) due in part to their ease of synthesis and greater stability (N–O BDE ≈ 75 kcal/mol) . Their use as radical precursors was first described by Okada and colleagues in 1988 , who showed that C(sp3)-centered radicals were successfully generated by subjecting NHPI esters to light irradiation in the presence of the photoreductant 1,6-bis(dimethylamino)pyrene (BDMAP). Following their initial discovery, multiple studies have shown their versatility as radical progenitors under thermal, photochemical, and electrochemical conditions .

Scheme 1: Comparison between Barton and NHPI ester radical precursors.

Due to their propensity towards single-electron reduction, NHPI esters, and similar derivatives such as N-hydroxytetrachlorophthalimide (TCNHPI) esters, are collectively referred to as "redox-active esters" (RAEs). The versatility of RAEs stems, in part, to the sensitivity of their reduction half peak potentials (Ep/2) to their environment. For instance, a recent study by Cornella and co-workers, showed that RAEs derived from phenylacetic acid exhibited varying reduction half peak potentials (Ep/2) ranging from −2.0 V for the NHPI ester 4 to −1.2 V for the corresponding TCNHPI ester 5 (measured in MeCN vs Fc0/Fc+, see Scheme 2A) . Based solely on their redox potentials, single-electron reduction of RAEs is only possible in the presence of a sufficiently strong reducing agent. However, the reduction of RAEs can also be facilitated through the formation of charge transfer complexes with a donor species 6 or via LUMO lowering activation with Brønsted and Lewis acids 7 (Scheme 2B), collectively offering a number of variables to influence their reactivity.

Scheme 2: Overview of the mechanisms and activation modes involved in radical generation from RAEs.

Upon reduction, RAEs give rise to a radical anion 8 with a weakened N–O bond (BDE < 70 kcal/mol) . While fragmentation of 8 affords a radical species 9 in a constructive step towards initiating the radical reaction, a principal competing step is back-electron transfer (BET) to return the closed shell starting materials (Scheme 2B). A recent study showed comparable rates for fragmentation (8 ± 5 × 105 s−1) and BET (3.15 to 2.06 × 105 s−1) when employing catalytic IrIII excited state reductants with moderate reducing potentials (E1/2red[IrIV/*IrIII] ≈ −1.13 V vs Fc0/Fc+ in MeCN) . This suggests that in the absence of a sufficiently strong driving force, BET and fragmentation compete to influence the resulting concentration of radicals. In such instances, opting for a stronger catalytic reductant or utilizing a stoichiometric electron donor can greatly improve the efficiency of radical generation. On the other hand, additional factors such as the ability of Brønsted and Lewis acid additives to promote the fragmentation step can be considered. Importantly, the diverse mechanisms in which RAEs engage in radical reactions can be exploited to modulate the reactivity of the resulting substrate radicals. For example, under net-reductive conditions, the radical intermediates are typically terminated via hydrogen atom transfer (HAT) or sequential electron transfer and proton transfer (ET/PT) steps. Alternatively, redox-neutral transformations can be envisioned using catalytic reductants, which can enable a complementary scope of downstream functionalizations (Scheme 2B).

In this perspective, we present an overview of the diverse mechanisms that have been proposed for radical based transformations initiating from NHPI esters. The discussion is organized into four sections: (i) mechanisms under photochemical conditions, (ii) initiation by metal catalysis and stoichiometric reductants, (iii) N-heterocyclic carbene (NHC)-catalyzed radical relay, and (iv) mechanisms under electrochemical activation.

By discussing selected literature examples, we illustrate how the activation mode of NHPI esters, and the reactivity of the resulting radical species, can vary depending upon the choice of catalytic or stoichiometric electron donors, the presence of a TM catalyst, the formation of a charge-transfer complex, and the overall reaction conditions. While we hope that this discussion will spur the continued development of NHPI esters in complexity-generating transformations, it is not comprehensive, and we refer readers to recently published review articles for additional discussion .

Discussion Mechanism under photochemical conditions

In this section we provide a summary of the various conditions and activation modes employed in radical reactions of NHPI esters using visible-light irradiation. Upon absorption of light, an excited photocatalyst (*PC) engages in single-electron transfer (SET) with either donor (D) or acceptor (A) molecules (Scheme 3) . Accordingly, a reductive quenching mechanism (path a) will operate when an excited photocatalyst effects the one-electron oxidation of a sacrificial donor giving rise to a strongly reducing catalytic species (PCn−1). On the other hand, in an oxidative quenching mechanism (path b) the excited photocatalyst directly induces the one-electron reduction of an acceptor substrate. Alternatively, the photocatalyst can mediate the formation of an electronically excited substrate (*S) through an energy transfer (EnT) mechanism (path c).

Scheme 3: Common mechanisms in photocatalysis.

In addition to these mechanistic blueprints, the formation of charge-transfer complexes involving NHPI esters, as well as examples of photoinduced transition metal-catalyzed activation will be discussed. Depending on the specific activation mechanism, both net reductive and redox neutral transformations can be implemented.

Photocatalytic reductive quenching mechanism

Among the most common reactions of NHPI esters are radical additions to electron-deficient olefins under net-reductive conditions, often referred to as Giese type addition reactions (Scheme 4A). In 1991, Okada and co-workers reported the addition of alkyl radicals to α,β-unsaturated ketones, by subjecting NHPI esters to visible-light irradiation in the presence of the photocatalyst [Ru(bpy)3]Cl2 and the reductant 1-benzyl-1,4-dihydronicotinamide (BNAH) . Two decades later, in 2012 the Overman group demonstrated the utility of this transformation in the total synthesis of (–)-aplyviolene, involving the diastereoselective coupling of a tertiary radical and an enone acceptor . Further developments of this chemistry resulted in the general use of NHPI esters for the construction of quaternary carbons via conjugate addition of 3° radicals . In general, this transformation operates under a reductive quenching photocatalytic cycle, requiring a stoichiometric reductant (Scheme 4A). Both TM complexes, and organic dyes such as eosin Y , have been employed as suitable photocatalysts (Scheme 4B). Under visible light irradiation the photocatalyst (PC) is excited into its corresponding excited state (*PC), where it can be reduced by a suitable electron donor such as DIPEA or Hantzsch ester to generate the reduced form of the photocatalyst (PC•–) (Scheme 4A). This strong reducing agent mediates the one-electron reduction of the NHPI ester 10, forming radical anion intermediate 11. Fragmentation of 11 via N–O bond homolysis and decarboxylation forms the key tertiary radical 12 with concomitant formation of phthalimidyl anion (–Nphth) and CO2. Radical 12 undergoes intermolecular addition to the olefin acceptor 13 to form radical intermediate 14. Finally, under reductive conditions radical 14 can undergo hydrogen atom transfer (HAT) or sequential electron transfer and proton transfer (ET/PT) to form the conjugate addition product 15.

Scheme 4: A) Giese-type radical addition of NHPI esters mediated by a reductive quenching photocatalytic cycle. B) Examples of common photocatalysts.

With this mechanistic blueprint as a backdrop, Phipps and co-workers developed an enantioselective Minisci-type addition, under dual photoredox and chiral Brønsted acid catalysis (Scheme 5A). In their proposed mechanism, the activation of the NHPI ester radical precursor was proposed to occur via a reductive quenching mechanism. However, since the overall transformation is redox-neutral, no stoichiometric reductant was employed. Instead, fluorescence-quenching studies suggested that the reductive quenching of the iridium excited state (*IrIII) was taking place "off-cycle" via oxidation of the chiral phosphate co-catalyst (Scheme 5B). This event leads to the generation of a potent IrII reductant that begins the photocatalytic cycle by reducing 16 into radical anion 17 while regenerating the ground state of the IrIII photocatalyst. After fragmentation, α-amino radical 18 was proposed to undergo addition to the heterocyclic radical acceptor 19 through a ternary transition state 20 involving hydrogen bonding interactions with the chiral phosphate co-catalyst. Notably, a follow-up report revealed that the radical addition is reversible, and that the selectivity determining step involves the deprotonation of 21 to provide radical intermediate 22 . Finally, the iridium excited state (*IrIII) formed under blue light irradiation oxidizes 22 to form product 23 and the corresponding reduced IrII complex, beginning a new photocatalytic cycle.

Scheme 5: A) Minisci-type radical addition of NHPI esters. B) Reaction mechanism involving an “off-cycle” reductive quenching.

Photocatalytic oxidative quenching mechanism

The activation of NHPI esters under a photocatalytic oxidative quenching mechanism was reported for the first time by Glorius and co-workers in 2017 . This activation mode was applied in the functionalization of styrenes using an Ir-photocatalyst and a diverse range of nucleophiles that are H-bond donors (Scheme 6A). Stern–Volmer analysis revealed that quenching of the photocatalyst’s excited state by the NHPI ester occurred only in presence of a hydrogen bond donor such as water (H2O) or methanol (MeOH). This supported the hypothesis that activation of NHPI esters towards photoinduced electron transfer can occur through hydrogen bonding. In the proposed mechanism (Scheme 6B), hydrogen bonded complex 24 undergoes single electron reduction via oxidative quenching of the excited state *IrIII, resulting in the formation of radical anion 25 (presumably H-bonded to H2O) and the corresponding IrIV complex. Radical intermediate 9 formed upon fragmentation of 25, adds to the styrene acceptor forming radical 26. Finally, a radical-polar crossover event between 26 and the IrIV complex regenerates the IrIII ground state while delivering cation 27 that is then trapped by the oxygen-nucleophile to form the oxyalkylation product 28.

Scheme 6: Activation of NHPI esters through hydrogen-bonding in an oxidative quenching photocatalytic cycle.

Li and co-workers described the activation of NHPI esters towards SET using a Lewis acid catalyst, allowing for the functionalization of styrene radical acceptors with nucleophiles that do not necessarily engage in hydrogen-bonding interactions, such as electron-rich (hetero)arenes (Scheme 7A). Cyclic voltammetry measurements of a model NHPI ester showed a shift in its reduction potential from –1.79 V to –1.51 V (vs SCE in MeCN) in the presence of In(OTf)3. As such, it was hypothesized that the Lewis acid lowers the LUMO of the NHPI ester via interaction with the oxygen lone pair in the phthalimide moiety (Scheme 7B). Thus, the excited state reductant *IrIII reduces the activated substrate 29 to form the stabilized radical anion 30. Fragmentation into radical 9, followed by radical addition to styrene gives benzyl radical intermediate 26. Turn-over of the catalytic cycle through radical-polar crossover affords cation 27 that delivers functionalized product 31 upon nucleophilic addition.

Scheme 7: SET activation of RAE facilitated by a Lewis acid catalyst.

The Doyle and Knowles groups reported the use of NHPI esters as radical precursors in the context of a radical redox annulation method (Scheme 8A). This transformation occurs through an oxidative quenching photocatalytic cycle employing Ir-based photoreductants and a Brønsted acid additive. While the interaction between the RAE 32 and diphenyl phosphoric acid involves hydrogen bonding, in analogy to the Glorius proposal, it is thought that the substrate activation occurs through proton-coupled electron transfer (PCET), forming neutral radical species 33 and the corresponding phosphate conjugate base (Scheme 8B). The hypothesis is supported by an observed increase in the luminescence quenching of *Ir(p-CF3-ppy)3 by 32 in the presence of diphenyl phosphoric acid, as quantified by the Stern–Volmer constant (Ksv = 1146 M−1 with acid vs Ksv = 603 M−1 without acid). The reaction mechanism continues with the fragmentation of 33 into radical 34. From radical 34 the annulation reaction initiates via intermolecular radical addition, resulting in the formation of intermediate 35. After oxidation of 35 to 36, the photocatalyst is regenerated and product 37 is formed through intramolecular nucleophilic cyclization facilitated by the phosphate base. Importantly, the activation of NHPI esters through PCET may also play a role in transformations mediated by the cyanoarene-based donor–acceptor photocatalyst 4CzIPN, which typically requires the use of strong H+ donors such as trifluoroacetic acid . While many reports, including Okada’s original work, have suggested that a proton donor can accelerate the fragmentation rate of RAEs , specific values comparing the fragmentation rate constants or the N–O bond dissociation energies of radical anions and neutral radicals derived from RAEs are not available in the literature.

Scheme 8: PCET activation of NHPI esters in the context of a radical-redox annulation.

Lumb and co-workers recently published a study on the conversion of biaryl-derived NHPI esters into spirocyclic cyclohexadienones through a photocatalytic radical-mediated dearomatization, with H2O serving as the nucleophile (Scheme 9A). Despite the presence of H2O in the reaction, the reduction of 38 to its corresponding radical anion 39 could occur without the need for hydrogen-bonding (Scheme 9B). Cyclic voltammetry measurements of NHPI ester 38 displayed a reduction half peak potential (Ep/2) of −1.17 V (vs SCE in MeCN) indicating that the single-electron reduction of 38 by a suitably strong reductant, such as *Ir(ppy)3 (E1/2red[IrIV/*IrIII] = −1.73 V vs SCE in MeCN) would be thermodynamically favorable. Indeed, Stern–Volmer photoquenching experiments confirmed that 38 effectively quenched *Ir(ppy)3 under anhydrous conditions. Consequently, the SET reduction of 38, followed by fragmentation of 39 yielded α-oxy radical intermediate 40. Subsequently, the spirocyclization of 40 induced the dearomatization of the methoxy-substituted aromatic ring, forming intermediate 41, which was then oxidized to cation 42, thereby completing the photocatalytic cycle. The reaction proceeded by regioselective nucleophilic addition of H2O, accompanied by the loss of MeOH to deliver spirocycle 43. Notably, the dearomative spirocyclization of biaryl-derived NHPI esters has found application in the total synthesis of natural products, including the plant metabolite denobilone A and the highly oxidized dibenzocyclooctadiene lignans heteroclitin J and kadsulignan E .

Scheme 9: Activation enabled by a strong excited-state reductant catalyst and its application in the dearomative spirocyclization of biaryls.

Activation via charge-transfer complex formation

Under conditions where oxidative quenching is not thermodynamically favorable, the single electron reduction of RAEs can proceed via an alternative mechanism. For example, in the transformation of NHPI ester 44 into spirocycle 45 catalyzed by [Ir(ppy)2(dtbbpy)][PF]6, Reiser and co-workers observed that the excited state of this Ir-catalyst (E1/2red[IrIV/*IrIII] = −0.96 V vs SCE) would not promote the reduction of 44 (−1.25 V vs SCE) (Scheme 10). Interestingly, the role of H-bonding in substrate activation was not considered. To explain the observed transformation, it was suggested that the IrIII-photocatalyst acted as a photosensitizer in an energy-transfer (EnT) mechanism. This proposal was supported by fluorescence quenching measurements, as well as the direct excitation of 44 by UV irradiation, resulting in the formation of 45 in a 45% yield. According to this hypothesis, NHPI ester 44 would adopt a favorable conformation (46) for π-stacking between the furan and phthalimide rings, before EnT from *IrIII leads to the formation of an excited charge-transfer complex 47. This species would undergo intramolecular electron transfer (IET) giving rise to intermediate 48, which upon fragmentation would form radical 49. Intramolecular radical addition into the radical cation of the furan ring would then form cation 50 before nucleophilic capture by H2O leads to product 45.

Scheme 10: Proposed formation of an intramolecular charge-transfer complex in the synthesis of (spiro)anellated furans.

In 2020, the Wang group reported the functionalization of enamides employing radicals derived from NHPI esters in combination with indole nucleophiles (Scheme 11A). This transformation occurred under light irradiation either in the presence or absence of a RuII photoredox catalyst. It was found that the chiral lithium phosphate catalyst (R)-TRIP-Li played a crucial role in accelerating the reaction rate. Following an in-depth analysis of the mechanism, the authors proposed that (R)-TRIP-Li has the capability to engage enamide 51 through H-bonding and NHPI ester 3 through Li-promoted Lewis acid activation, acting as a pocket that facilitates the formation of charge-transfer complex 52 (Scheme 11B). This complex can be excited either by direct irradiation at 390 nm or through RuII-mediated EnT under blue light irradiation (456 nm). Following excitation, SET from the enamide to the active ester forms intermediate 53, which undergoes fragmentation and radical recombination to afford intermediate 54. At this stage, the indole nucleophile substitutes the phthalimidyl anion within the chiral pocket of the phosphate catalyst to form complex 55, before enantioselective addition to the iminium ion affords product 56.

Scheme 11: Formation of a charge-transfer complex between enamides and NHPI esters enabled by a chiral phosphate catalyst.

NHPI esters can also engage in π–π interactions with electron-rich species to generate charge-transfer complexes that can absorb light in the visible region. These species are referred to in the literature as electron donor–acceptor (EDA) complexes and undergo photoexcitation in the absence of an exogenous photoredox catalyst. When excited by visible light, an intra-complex SET from the donor substrate D to the NHPI ester acceptor takes place, generating radical ion pair 57. Subsequently, this ion pair undergoes fragmentation, forming the corresponding substrate radical 9, which can participate in diverse chemical transformations (Scheme 12).

Scheme 12: Activation of NHPI ester through the formation of photoactive EDA-complexes.

Different donor molecules are known to form EDA complexes with NHPI esters. For example, the NHPI ester derived from pivalic acid 58 and Hantzsch ester HE form EDA complex 59 which participates in radical mediated hydroalkylation reactions (Scheme 13A). In the presence of electron deficient olefin 60, classic Giese-type addition takes place under photocatalyst-free conditions, affording product 61 . On the other hand, reaction with 1,7-enyne 62 affords dihydroquinolinone product 63 via a cascade radical addition/cyclization process . In both transformations, HE serves a dual role by activating the NHPI ester through EDA complex formation and providing a hydrogen atom to terminate the radical reaction. The proposed mechanism of the hydroalkylation cascade is depicted in Scheme 13B. Upon excitation of complex 59 with blue light, intra-complex SET takes place from the HE to the NHPI ester, leading to the formation of tert-butyl radical 64 and radical cation 65. Addition of radical 64 to enyne 62 followed by 6-exo-dig cyclization yields radical intermediate 66. Finally, species 65 acts as a hydrogen atom donor, delivering product 63 while forming pyridine 67 as a byproduct.

Scheme 13: A) EDA complex-mediated radical hydroalkylation reactions of NHPI esters. B) Proposed mechanism for the hydroalkylation cascade.

A similar mechanism would in principle account for EDA-complex-mediated Giese-type additions. However, an alternative radical chain mechanism has been discussed in the literature (Scheme 14). In this instance, chain initiation takes place through photoinduced SET, enabled by EDA complex formation between the reductant N-(n-butyl)-1,4-dihydronicotinamide (BuNAH) and an NHPI ester (complex 68). This process delivers substrate radical 9 and nicotinyl radical 69 following proton transfer to the phthalimidyl anion. Then, addition of 9 to α,β-unsaturated ester 70 yields radical intermediate 71. At this stage, HAT mediated by another equivalent of BuNAH delivers product 72, with concomitant formation of radical 69. Finally, aromatization of 69 via SET to NHPI ester 3, generates pyridinium 73 as a byproduct, while propagating the radical chain reaction.

Scheme 14: Proposed radical chain mechanism initiated by EDA-complex formation.

Aggarwal and co-workers discovered the photoinduced decarboxylative borylation of NHPI esters mediated by bis(catecholato)diboron (B2cat2) (Scheme 15A). UV–vis absorption measurements showed that a mixture of a model NHPI ester with B2cat2 in dimethylacetamide (DMA) formed a new charge-transfer band in the visible region (>390 nm), which was attributed to the formation of EDA complex 74 (Scheme 15B). Under blue light irradiation, EDA complex 74 triggered a radical chain process initiated by B–B bond cleavage, forming boryl-NHPI ester radical 75 and boryl radical 76. Subsequent decarboxylation of 75 yields carbon-centered radical 9 and boryl-phthalimide byproduct 77. Meanwhile DMA-ligated B2cat2 78 is formed upon dimerization of radical 76. Reaction between radical 9 and species 78 affords boronic ester 79 while returning boryl radical 76. Finally, chain propagation takes place via reaction of 76 with another equivalent of the NHPI ester 3.

Scheme 15: A) Photoinduced decarboxylative borylation. B) Proposed radical chain mechanism.

The Baran lab has recently published a complementary electrochemical method, wherein the activation of complex 74 takes place through SET under constant current electrolysis . The Glorius and Y. Fu groups have independently proposed the formation of analogous charge-transfer complexes involving NHPI esters, bis(pinacolato)diboron (B2pin2), and Lewis bases (pyridine or isonicotinate tert-butyl ester) in C(sp2)-borylation methods under photochemical and thermal conditions, respectively .

The activation of NHPI esters through EDA complex formation is also possible by employing a catalytic donor species, which enables a range of redox neutral transformations. In 2019, Shang and Fu initially demonstrated this approach by utilizing catalytic amounts of triphenylphosphine (PPh3) and sodium iodide (NaI) . Upon formation of EDA complex 80, radical addition to silyl enol ether 81 was promoted under blue light irradiation, affording acetophenone product 82 (Scheme 16A). Additionally, Minisci-type additions were carried out in the presence of protonated quinoline radical acceptor 83, affording product 84 (Scheme 16A). Mechanistically, this activation mode involves an intra-complex SET that forms the Ph3P–NaI radical cation species 85 and the corresponding radical anion 86. Decarboxylative fragmentation of 86 forms radical 9, which upon radical addition to 84 and deprotonation yields radical 87. Finally, oxidation of 87 mediated by 85 delivers the Minisci addition product 84 while regenerating PPh3 and NaI (Scheme 16B).

Scheme 16: A) Activation of NHPI esters mediated by PPh3/NaI. B) Proposed catalytic cycle involving EDA-complex formation.

The Ohmiya group has developed a series of light-mediated decarboxylative transformations of NHPI esters using a phenothiazine-based organophotoredox catalyst PTH1. This type of catalyst is believed to facilitate SET to NHPI esters through the formation of EDA complexes. Interestingly, upon addition of RAE 58 to a solution of PTH1, a noticeable red shift in the UV–vis absorption spectra of PTH1 was observed, suggesting the formation of a charge transfer complex of the type 88 (Scheme 17A). tert-Butyl radical (64), along with additional 2° and 3° alkyl radicals, resulting from these EDA complexes were harnessed in C(sp3)-heteroatom bond forming reactions , and in the difunctionalization of styrenes (Scheme 17B).

Scheme 17: A) Radical generation facilitated by EDA complex formation between PTH1 catalyst and NHPI esters. B) Selected scope of PTH1-catalyzed decarboxylative transformations.

The catalytic cycle for the styrene difunctionalization reaction is depicted in Scheme 18. First, EDA complex 88 consisting of RAE 58 and the PTH1 catalyst is formed. Under blue light irradiation, intra-complex SET leads to the formation of PTH radical cation species 89 and the radical anion 90 with the corresponding charges balanced by the LiBF4 additive. Notably, it was suggested that LiBF4 could also facilitate the reduction of the NHPI ester substrate, potentially by the coordination of Li cation to the phthalimide moiety. Next, fragmentation of 90 yields tert-butyl radical 64, which then adds to styrene 91 affording radical intermediate 92. At this stage, recombination of intermediates 89 and 92 may occur via SET followed by addition or through radical–radical coupling, affording benzylsulfonium intermediate 93. Finally, nucleophilic substitution with alcohol 94 in the presence of lithium phthalimide 95 leads to product 96 and turns over the catalytic cycle. Importantly, species 93 can be detected by high resolution mass spectrometry, when the reaction is carried out without nucleophile and using stoichiometric amounts of PTH1.

Scheme 18: Proposed catalytic cycle for the difunctionalization of styrenes.

H. Fu and co-workers reported that the combination of NHPI esters and cesium carbonate (Cs2CO3) gave rise to a new absorption band in the visible region, suggesting the formation of a photoactive charge-transfer complex . This activation mode was initially employed in a decarboxylative coupling reaction with aryl thiols . Further studies showed that 4-(trifluoromethyl)thiophenol (97) could act as a catalytic reductant in the aminodecarboxylation reaction of NHPI esters derived from α-amino acids (Scheme 19). Accordingly, visible light irradiation of a mixture consisting of N-Boc-alanine NHPI ester 98 and Cs2CO3 in DMF resulted in the generation of the excited charge transfer complex 99. Subsequent SET mediated by the thiol catalyst followed by fragmentation afforded α-amino radical 100, which was then oxidized by the resulting thiol-radical species, regenerating the thiol catalyst while forming an iminium intermediate 101. Finally, nucleophilic addition of phthalimide anion 102 afforded the amination product 103.

Scheme 19: Formation of a charge-transfer complex between NHPI esters and Cs2CO3 enables decarboxylative amination.

Bosque and Bach reported the use of 3-acetoxyquinuclidine (q-Ac) as a catalytic donor for the activation of TCNHPI esters derived from α-amino acids (Scheme 20). Treatment of N-Boc-proline-derived TCNHPI ester 104 with q-OAc in MeCN resulted in the formation of a yellow solution, which upon blue light irradiation provided the aminodecarboxylation product 105 in 69% yield. It was hypothesized that the reaction involved the formation of EDA complex 106 that led to the formation of α-amino radical 107 through photoinduced SET followed by fragmentation. Subsequent oxidation of 107 by radical cation q-Ac•+ afforded iminium ion 108 before nucleophilic addition of the in situ-generated tetrachlorophthalimyl anion (–TCPhth) led to the formation of aminal product 105. Of note, the aminodecarboxylation reaction proved unsuccessful when employing alternative photocatalysts such as Ru(bpy)3Cl2 or eosin Y, underscoring the distinctive ability of q-OAc to activate TCNHPI esters via EDA complex formation.

Scheme 20: 3-Acetoxyquinuclidine as catalytic donor in the activation of TCNHPI esters.

Photoinduced transition metal-catalyzed mechanisms

The in situ formation of photoactive catalysts can be achieved by combining simple transition metal (TM) salts with suitable ligands. These TM catalysts are fundamentally distinct from traditional Ru- and Ir-based photoredox catalysts, as they play a dual role, by engaging in photoinduced electron transfer processes with the substrate and participating in the key bond-forming/breaking steps via substrate–TM interactions . This paradigm has been employed in the activation of NHPI esters under photoinduced copper (Cu) and palladium (Pd) catalysis.

In 2017, Peters and Fu reported a Cu-catalyzed decarboxylative C(sp3)–N coupling employing NHPI esters as dual reagents (Scheme 21A). The combination of CuCN and the ligands xantphos and neocuproine in a 2:3:1 ratio resulted in the formation of a light absorbing species with an absorption band in the 380–460 nm range. Thus, it was hypothesized that CuI catalytic species 109 would give rise to photoexcited complex 110 under blue light irradiation (Scheme 21B). Complex 110 and NHPI ester 3 would then engage in SET likely through an inner sphere mechanism, providing phthalimide ligated CuII intermediate 111 and carboxyl radical 112. At this stage, the resulting radical species 9 would recombine with 111 to form CuIII complex 113. Alternatively, reaction of 3 with the photoexcited CuI complex through oxidative addition (OA) followed by decarboxylation could directly lead to intermediate 113 (Scheme 21B, blue arrow). However, radical clock experiments support the intermediacy of free radicals, indicating the involvement of the SET pathway (Scheme 21C). Eventually, reductive elimination of 113 afforded product 114 while regenerating the catalytic species 109. It is worth nothing that further transformations of NHPI esters under photoinduced Cu catalysis have been reported in recent years, including decarboxylative alkynylations and the C(sp3)–H alkylation of α-amino acids .

Scheme 21: A) Photoinduced Cu-catalyzed decarboxylative amination. B) Proposed catalytic cycle. C) Radical clock experiment supporting the intermediacy of radicals.

The ability of NHPI esters to act as dual reagents was also investigated by Glorius and co-workers in the context of a photoinduced Pd-catalyzed aminoalkylation of 1,4-dienes (Scheme 22A). The study showed that a photoexcited Pd0 species formed upon blue-light irradiation of Pd(Ph3)4, was able to promote the activation of NHPI esters via SET (Scheme 22B). The photoinduced electron transfer process between the Pd-photocatalyst and RAE 58 was proposed to form a hybrid alkyl PdI-radical species 115 which could then react with 1,4-butadiene (116) to form hybrid allyl PdI complex 117. Subsequently, it was suggested that the species 117 would lead to the formation of a π-allylpalladium intermediate 118 through radical recombination. Ultimately, nucleophilic attack by the phthalimidyl anion would generate the aminoalkylation product 119, completing the catalytic cycle. In addition to this aminoalkylation method, the synthetic utility of radical intermediates derived from NHPI esters under photoinduced Pd-catalysis has been demonstrated in Heck-type couplings and in the desaturation of aliphatic carboxylic acids .

Scheme 22: A) Photoinduced Pd-catalyzed aminoalkylation of 1,4-dienes. B) Proposed catalytic cycle.

Initiation by metal catalysts and stoichiometric reductants

The activation of NHPI esters under transition metal catalysis without the need of light is also feasible, and generally, two types of coupling reactions can be envisioned. On one hand, the decarboxylative cross-coupling (DCC) of NHPI esters with organometallic reagents, resembling classic Kumada, Negishi, and Suzuki couplings, has been enabled by nickel (Ni), cobalt (Co), iron (Fe), and copper (Cu) catalysts (Scheme 23A). The typical mechanism begins by transmetallation of the organometallic coupling partner 120 to the TM catalyst (Scheme 23B). The resulting organometallic intermediate 121 can act as a reducing agent, transferring an electron to RAE 10 to form radical anion 11 and the corresponding oxidized metal complex 122. Following fragmentation, the ensuing alkyl radical 12 is captured by intermediate 122, resulting in the formation of complex 123. At this point, the metal center has undergone a two-electron oxidation, making it well-suited for reductive elimination yielding the cross-coupling product 124.

Scheme 23: A) TM-catalyzed decarboxylative coupling of NHPI esters and organometallic reagents. B) Representative catalytic cycle.

Under these catalytic conditions, various TM-catalyzed decarboxylative functionalizations employing RAEs have been established (Scheme 24). Baran and co-work