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Synlett 2024; 35(20): 2273-2288
DOI: 10.1055/s-0043-1775382
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Special Issue to Celebrate the 75th Birthday of Prof. B. C. Ranu

Photo- and Electrochemical Organic Transformations Involving Radical Pathway: A Retrospection of Our Green-Chemistry-Inspired Synthetic Endeavours

Goutam Brahmachari  ∗

The author gratefully acknowledges the generous financial support provided by funding agencies, including SERB, New Delhi (Grant No. CRG/2022/000275) and CSIR, New Delhi (Grant No. 02/0464/23/EMR-II).
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Dedicated to Professor Brindaban C. Ranu on the occasion of his 75th Birthday

Abstract

This account summarises our recent efforts (2020 to mid-2024) in designing and developing a handful of promising organic transformations for accessing several diversely functionalized biologically relevant organic scaffolds by following the green-chemistry principles with a particular focus on the application of low-energy visible light and electrochemistry. Mechanistic studies of each of these reactions established the involvement of a radical pathway.

1 Introduction

2 Green-Inspired Organic Transformations

2.1 Visible-Light-Driven Organic Synthesis

2.1.1 Synthesis of Functionalized Dihydrofuro[3,2-c]chromenones

2.1.2 Synthesis of Functionalized 2-(Aryl/alkylamino)-3-(aryl/alkylselanyl)naphthalene-1,4-diones and 2-(Arylamino)-3-(arylthio)naphthalene-1,4-diones

2.1.3 Synthesis of Functionalized 6-(Arylthio/arylseleno)benzo[a]phenazin-5-ols

2.1.4 Synthesis of Functionalized 3-(Alkyl/benzylthio)-4-hydroxy-2H-chromen-2-ones

2.1.5 Synthesis of Functionalized 2-Hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxamides and 2-Hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates

2.1.6 Synthesis of Functionalized 2-Hydroxyphenylated α-Ketoamides

2.2 Electrochemical Organic Synthesis

2.2.1 Synthesis of 3-Selenylated/Sulfenylated Derivatives of 2-Amino-1,4-naphthoquinones

2.2.2 Synthesis of Functionalized 6-(Arylthio/Arylseleno)benzo[a]phenazin-5-ols

2.2.3 Synthesis of Functionalized Alkyl 2-Hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates

3 Conclusions


#

Key words

photochemistry - visible light - electrochemistry - electrosynthesis - radical mechanistic pathway - green chemistry

Biographical Sketch

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Goutam Brahmachari, Ph.D., D.Sc., FRSC, is currently working as a full professor of organic chemistry at the Department of Chemistry, Visva-Bharati (a Central University), Santiniketan, India. With more than 25 years of experience in teaching and research, he has produced about 270 scientific publications, including original research papers, review articles, books, and invited book chapters in synthetic organic chemistry and natural products chemistry. He has authored or edited 27 books and 52 book chapters from leading scientific publishers. He is the founder series editor of the Elsevier book series Natural Product Drug Discovery. Professor Brahmachari is an elected fellow of the Royal Society of Chemistry and a recipient of the CRSI (Chemical Research Society of India) Bronze Medal-2021 (for his contribution to research in chemistry), the Dr. Basudev Banerjee Memorial Award 2021 from the Indian Chemical Society (for his contribution to the field of chemical sciences), the INSA (Indian National Science Academy) Teachers Award 2019, and the Dr. Kalam Best Teaching Faculty Award 2017. Professor Brahmachari featured in the world ranking of the top 2% of scientists (organic chemistry category) in 2020–2023, the AD Scientific World Ranking of Scientists in 2022–2024, and as a ScholarGPS Highly Ranked Scholar 2024 (lifetime; securing a position in the top 0.05% of all scholars worldwide).

1

Introduction

Green chemistry guidelines, as proposed by Anastas and Warner in 1998,[1] help chemists in developing and assessing how green a synthesis, compound, process, or technology is. Green or sustainable chemistry has already created a stir among chemical researchers as a part of the intriguing challenge of developing a sustainable chemical enterprise to minimize human exposure to harmful chemicals and to reduce environmental impact while enhancing scientific progress. Notably, the last two and half decades have seen a massive interest in green chemistry research. As a result, several methodologies/concepts, such as solvent-free synthesis, organic reactions in aqueous media, greener organic reagents, the development of heterogeneous catalysts and ionic liquids, waste management/recycling strategies, and the application of energy-efficient green tools involving the use of ultrasonication, microwave irradiation, ball-milling, visible light, or electrosynthetic techniques have emerged. Green energy tools are currently in extensive use. The application of such tools bears the potential to address not only the most challenging concerns relating to energy consumption in chemical manufacturing, but also to implement a plethora of organic transformations that would not be feasible in conventional processes.[2]

As part of our ongoing research endeavours, we have also been deeply involved in green chemistry research during the last few years, focusing on designing and developing new approaches for biologically promising organic molecules. The present account aims to offer an overview of our recent research works (2020 to mid-2024) in this direction, highlighting the application of low-energy visible light/sunlight and electrochemistry in implementing a handful of organic transformations of interest involving a radical pathway.


# 2

Green-Inspired Organic Transformations

2.1

Visible-Light-Driven Organic Synthesis

2.1.1

Synthesis of Functionalized Dihydrofuro[3,2-c]chromenones

A visible-light-induced highly efficient and practical protocol for synthesizing a new series of diversely functionalized dihydrofuro[3,2-c]chromenones 2 was developed by Mandal and Brahmachari[3] through intramolecular C(sp3)–H cross-dehydrogenative oxygenation within the warfarin framework of warfarin analogues 1 in dimethyl sulfoxide (DMSO) solvent upon irradiating the reaction mixture with either blue light (Method A) or direct sunlight (Method B) at ambient temperature (28–30 °C) in the presence of rose bengal as a photosensitizer, ammonium thiocyanate as an additive, and molecular oxygen (Scheme [1]). The furochromenone derivatives 2 were isolated in moderate to good yields ranging from 52 to 77% in Method A and 51 to 75% in Method B within three to four hours. Among O-heterocycles, furochromenones occupy a significant position and are ubiquitously abundant in bioactive natural and synthetic analogues, with potential applications in medicinal, agricultural, and materials sciences.[4]

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Scheme 1 Photochemical synthesis of functionalized dihydrofuro[3,2-c]chromenones 2

The present method accomplished a visible-light-promoted intramolecular C–O bond formation through direct C–H functionalization at ambient temperature. In recent times, intramolecular C–O bond formation has acquired great importance because the strategy offers an open platform for accessing diverse O-heterocycles, which are significant in medicinal and industrial fields.[5] Although this particular research area of forming C–O bonds through intramolecular C–H functionalization is rapidly developing, it is still less explored and, categorically, intramolecular cross-dehydrogenative C(sp3)–O coupling is rarely reported. The present method offers several benefits, including abundant sunlight or low-energy visible-light sources, energy-efficient mild reaction conditions, metal-free synthesis, molecular oxygen as the oxidant, low-cost and nontoxic rose bengal as a photosensitizer, and moderate to good yields.

This photochemical reaction follows a radical pathway, as evidenced by the results of radical-scavenging experiments (Scheme [2]). All three radical scavengers examined (TEMPO, p-benzoquinone, and DDQ) were found to inhibit the transformation; the reaction was also found to be inhibited by DABCO, a well-known singlet-oxygen quencher, supporting the generation in situ of singlet oxygen in the process.

Based on their experimental observations,[4] the investigators suggested a plausible mechanism for this organic transformation, as shown in Scheme [3]. Upon irradiation with blue light/direct sunlight, one molecule of activated rose bengal (RB*) photosensitizer participates in generating singlet oxygen (1O2) from its triplet state (3O2), and another molecule takes up an electron from the thiocyanate ion (SCN–), thereby giving rise to the photocatalyst radical anion (RB∙–) and a thiocyanate radical (∙SCN). The photocatalyst radical anion gives up its extra electron to singlet oxygen through a single electron transfer (SET) process. It then enters the catalytic cycle, forming a peroxide radical anion (O2 ∙–) that snatches a hydrogen radical from the tautomeric O–H bond of 1′ through a hydrogen atom transfer (HAT) process, with formation of an enoloxy radical 3 and a hydroperoxide (HO2 –) ion. Next, a thiocyanate intermediate 4 (nonisolable) is produced through C–S coupling between the radicals 3 and the thiocyanate radical (∙SCN). The C4-hydroxy proton within 4 is then abstracted by the hydroperoxide (HO2 –) ion to form H2O2 (detected by KI/starch colour reaction), and the enolate ion generated in situ undergoes an intramolecular nucleophilic substitution reaction, removing the thiocyanate ion and thereby yielding the desired O-heterocycle 2 through a thermodynamically feasible 5-exo-tet process (Scheme [3]).[4]

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Scheme 2 Radical-scavenging experiments
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Scheme 3 Suggested mechanism

# 2.1.2

Synthesis of Functionalized 2-(Aryl/alkylamino)-3-(aryl/alkylselanyl)naphthalene-1,4-diones and 2-(Arylamino)-3-(arylthio)naphthalene-1,4-diones

In 2022, Nayek and Brahmachari[6] unearthed an alternative synthetic strategy for accessing a diverse series of 2-(aryl/alkyl/amino)-3-(phenyl/methylselanyl)naphthalene-1,4-diones 7 and 2-(arylamino)-3-(arylthio)naphthalene-1,4-diones 9, involving a regioselective C(sp2)–H selenylation or sulfenylation of substituted 2-amino-1,4-naphthoquinones 5 through an oxidative cross-coupling between the substrate molecules 5 and diversely substituted diselenides 6 or disulfides 8 in DMSO medium under photoirradiation by either white LEDs (Method A) or sunlight (Method B) without the aid of an external photosensitizer and in the presence of caesium carbonate as the base under an oxygen atmosphere at ambient temperature (Scheme [4]). The protocol furnished moderate to good yields (42–91%) of the targeted selenylated and sulfenylated compounds within a reasonable timeframe (3–8 h). During the photochemical process, in situ generated deprotonated species of the 2-amino-1,4-naphthoquinone substrates in the basic reaction medium act as visible-light-absorbing self-photosensitizers.[6]

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Scheme 4 Visible-light-mediated, self-sensitized, regioselective oxidative C(sp2–H) bond selenylation/sulfenylation of substituted 2-amino-1,4-naphthoquinones 5

Radical-scavenging experiments (Scheme [5]) supported a radical mechanistic pathway for this photochemical transformation and the involvement of singlet oxygen (1O2) formed in situ.

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Scheme 5 Radical-scavenging experiments. BHT = butylated hydroxytoluene.

As a result, the investigators offered the plausible mechanism shown in Scheme [6].[6] The 2-amino-1,4-naphthoquinone molecule 5 first undergoes tautomerization to form the tautomer 5′ in DMSO medium, and the enolic proton of this tautomer is abstracted by the base under the reaction conditions (pH 11.91 for the model entry), thereby generating an activated anionic species 5′′ with a delocalized negative charge on irradiation with visible light (acts as a self-sensitizer; λmax 571 nm for the model entry). This activated anionic species 5′′ then transfers its extra energy to diselenide/disulfide 6/8, when homolytic cleavage of the X–X bond takes place, thereby generating an aryl/alkyl selenium/sulfur radical (R′X∙ radical 10/11) and another anionic species 14. The in situ generated R′X∙ radical 10/11 is then oxidized to the electrophilic cationic species R′X+ 12/13 by giving up its extra electron to molecular triplet oxygen (3O2) through an SET process to produce a superoxide radical anion (3O2 ∙–). Cyclic voltammetric studies of the starting compound [the model entry, 2-(phenylamino)naphthalene-1,4-dione (5a)] showed a pair of cathodic peaks at –1.30 and –0.95 V (vs Ag/Ag+), whereas diphenyl diselenide (6a) and diphenyl disulfide (8a) showed anodic peaks at +1.52 and +1.74 V (vs Ag/Ag+), respectively, in their cyclic voltammograms, supporting this assumption. Therefore, the superoxide radical anion takes up a proton from the HCO3 – ion in the reaction mixture, producing a hydroperoxide radical (HO2 ∙), and eventually producing hydrogen peroxide and oxygen. In the next step, the anionic species 14 undergoes nucleophilic attack at the Se+/S+ centre of the in situ generated electrophile R′X+ 12/13 through C-3, thereby forming adduct 15, which then aromatizes to afford the desired selenylated/sulfenylated product 7/9 (Scheme [6]).[6]

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Scheme 6 Proposed mechanism

Organochalcogenides are regarded as exciting structural motifs due to their multifaceted and valuable properties as functional and fluorescent materials,[7] organic synthons,[8] pharmaceuticals,[9] and agrochemicals,[10] among many others.[11] The present method offers a new series of organosulfides and organoselenides, starting from biologically potent naphthoquinone derivatives.[12] The notable advantages of this synthetic strategy are the avoidance of any external photoredox catalysts, metal-free synthesis, the use of molecular oxygen as an oxidant, visible light/sunlight as an energy source, a broad substrate scope, moderate to good yields, a high regioselectivity, reasonable reaction times, and ecofriendliness. Abundant and cost-free sunlight can be exploited effectively as an ecofriendly energy source to perform this chalcogenation reaction in the daytime; however, white LEDs are essential in the absence of adequate sunlight.[6]


# 2.1.3

Synthesis of Functionalized 6-(Arylthio/arylseleno)benzo[a]phenazin-5-ols

In another work, Brahmachari and his group[13] accomplished, for the first time, a photocatalyst-free visible-light-induced regioselective and cross-dehydrogenative C(sp2)–H bond sulfenylation and selenylation of substituted benzo[a]phenazin-5-ols 16 to access diversely functionalized 6-(arylthio/arylseleno)benzo[a]phenazin-5-ols 18/18′ by irradiating a mixture of a benzo[a]phenazin-5-ol 16 and an arylthiol 17 or diphenyl diselenide (6a) dissolved in DMSO with either white LEDs (2 × 9 W; Method A) or open sunlight (Method B) in the presence of caesium carbonate as a base under an oxygen atmosphere at ambient temperature (Scheme [7]).

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Scheme 7 Photosensitizer-free, visible-light-mediated, regioselective cross-dehydrogenative C(sp2)–H sulfenylation or selenylation of substituted benzo[a]phenazin-5-ols 16

Interestingly, in this reaction the in situ generated deprotonated intermediates of the staring benzo[a]phenazin-5-ol molecules in basic solution behave as self-photosensitizers in implementing the photochemical transformation. The isolated phenazine derivatives 18/18′ were obtained in good to excellent yields (79–93%).

Based on detailed experimental observations (Scheme [8]), a plausible mechanism was proposed for this visible-light-induced transformation, as outlined in Scheme [9].[13] The carbanionic counterpart 16′′ of phenoxide ion 16′, developed upon deprotonation of the benzo[a]phenazin-5-ol substrate 16 in basic solution, is activated by visible-light irradiation, and the activated species, in turn, reduces molecular oxygen through an SET process. The superoxide radical anion (O2 ∙–) thus generated takes up an electron from the nonbonded electron-pair on the S-atom of thiol 17 to form a peroxide anion (O2 2–) and the thiol radical cation 17′. These species interact through abstraction of a proton from 17′ by the peroxide anion (O2 2–) to produce a hydroperoxide ion (HO2 –) and a thiol radical 17′′. On the other hand, the activated carbanion counterpart 16′′, upon transfer of its extra electron, becomes a C6-centred 2°-carbon radical 19, which recombines with the thiol radical 16′′ to form adduct 20 through C–S coupling. Finally, adduct 20 tautomerizes to form the desired product 18.

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Scheme 8 Radical-scavenging experiments
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Scheme 9 Proposed mechanism

The present method provides a new series of organosulfides and organoselenides starting from biologically potent phenazine derivatives,[14] for the first time. This protocol appears to be advantageous to similar reported methods,[15] particularly with regard to its mild and energy-efficient reaction conditions, metal-free synthesis, good to excellent yields, short reaction times, scalability, and ecofriendliness.


# 2.1.4

Synthesis of Functionalized 3-(Alkyl/benzylthio)-4-hydroxy-2H-chromen-2-ones

Organosulfur compounds are not only vital structural parts of many essential amino acids (e.g., cysteine, cystine, or methionine), peptides (e.g., glutathione), hormones (e.g., insulin), enzymes and coenzymes, and vitamins (e.g., thiamine, pantothenic acid, lipoic acid, biotin),[16] but also find potential applications in several pharmaceutical and medicinal entities, agrochemicals, and other valuable materials with multifaceted uses.[16] Most synthetic drives have reported the construction of C–S bonds through transition-metal-catalysed cross-couplings of thiols with organohalides. These reactions have several shortcomings, particularly the need for highly sensitive and costly metal catalysts/ligands/additives, high catalyst loadings, and harsh reaction conditions.[17] Under this purview, in 2021, our group reported a photochemical method[18] for synthesizing a new series of pharmaceutically interesting functionalized coumarin thioethers 23 through a cross-dehydrogenative coupling reaction between the C(sp2)–H bond of 4-hydroxycoumarins 21 at C-3 and the S–H bond of alkyl/benzyl thiols 22 in acetonitrile solvent, with either white LEDs (Method A) or direct sunlight (Method B) as a visible-light energy source and with rose bengal as a triplet photosensitizer for molecular oxygen (O2) at ambient temperature (28–30 °C) (Scheme [10]). The thioethers 23 were isolated in moderate to good yields, ranging from 48 to 92% within two to four hours using Method A, and from 46 to 91% within four to eight hours using Method B.

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Scheme 10 Photochemical synthesis of diversely substituted coumarin thioethers 23

The results of the radical-scavenging experiments (Scheme [11]) suggested the involvement of a radical pathway in the mechanism of this visible-light-induced transformation.

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Scheme 11 Radical-scavenging experiments

The investigators offered a possible mechanistic pathway for this photochemical process, as shown in Scheme [12].[18] Initially, rose bengal (RB), a triplet sensitizer, is activated (RB*) upon irradiation with visible light; this, in turn, converts singlet oxygen (1O2) into triplet oxygen (3O2). Another molecule of the activated rose bengal species (RB*) takes up an electron from thiol 22 through an SET process to furnish the thiol radical cation 22′ and the photocatalyst radical anion RB∙–. This photocatalyst radical anion returns to RB upon transferring its extra electron to the excited singlet oxygen (1O2), thereby generating a superoxide radical anion (O2 ∙–). This highly active superoxide radical anion snatches the labile enolic hydrogen atom from the 4-hydroxycoumarin molecule 21 through a HAT process to form the enoloxy radical intermediate 21′ and a hydroperoxide ion (HO2 –) that eventually generates hydrogen peroxide (H2O2) upon abstracting the labile proton (H+) from the thiol radical cation 22′. The less-stable enoloxy radical 21′ rapidly undergoes photoinduced homolytic cleavage of its C3–C4 π-bond, followed by intramolecular radical recombination between the C-4 and oxygen radicals, leading to the generation of the relatively more stable C3-centred radical intermediate 21′′. The secondary carbon radical 21′′ thus formed then rapidly undergoes a radical-recombination reaction with the S-centred thiol radical 22′′ to form adduct 24, which tautomerizes to afford the desired product 23 (Scheme [12]).

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Scheme 12 Proposed mechanism

The major advantages of this present protocol include its use of commercially available low-cost starting materials, abundant sunlight or a low-energy visible-light source, a cheap and ecofriendly photosensitizer, and molecular oxygen as an oxidant, along with its broad substrate scope, metal-free synthesis, good yields with high atom-economy, and energy efficiency.


# 2.1.5

Synthesis of Functionalized 2-Hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxamides and 2-Hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates

2,2-Disubstituted benzofuran-3(2H)-ones with a hydroxy function at the C-2 position are frequent motifs in naturally occurring bioactive compounds,[19] and are reported to possess numerous pharmaceutical properties that include antibiotic, antioxidant, antipsychotic, antidiabetic, anticancer, and anti-HIV activities, among many more.[20] We developed, for the first time, a visible light (white LEDs)-induced straightforward and efficient protocol for the synthesis of 2-hydroxybenzofuran-3(2H)-ones containing either an ester or an amide functionality at the same position, thereby accessing a new series of pharmaceutically interesting functionalized 2-hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxamides 26 and 2-hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates 28 from the corresponding reaction between 4-hydroxycoumarins 21 and amines 25 in 1,4-dioxane or between 4-hydroxycoumarins 21 and alcohols 27 in the absence of any added solvent, making good use of singlet oxygen in the presence of rose bengal as the photosensitizer at ambient temperature (25–28 °C) (Scheme [13]).[21] The carboxamides 26 were isolated in moderate to good yields, ranging from 51 to 86%, within 0.8 to 3.5 hours, whereas the carboxylates 28 were obtained in yields of 64 to 88% within 4 to 20 hours. The notable advantages of this photochemical transformation of a 4-hydroxy-α-benzopyrone motif into a 2-hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxamide/carboxylate scaffold are its use of commercially available low-cost starting materials, a low-energy visible-light source, and a cheap and ecofriendly photosensitizer, along with its broad substrate scope, insertion of molecular oxygen, metal-free synthesis, good to excellent yields, and energy efficiency.

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Scheme 13 Visible-light-induced synthesis of 2,2-disubstituted benzofuran-3(2H)-ones 26 and 28
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Scheme 14 Radical-scavenging experiments

Based on their radical-scavenging experiments (Scheme [14]), which indicated the involvement of radical intermediates and the in situ generation of singlet oxygen during the reaction, the authors suggested a possible mechanism for this rose bengal (RB)-photosensitized transformation, as depicted in Scheme [15].[21] Upon irradiation with white visible light, rose bengal becomes activated (RB*) and, in turn, transfers its extra energy to the ground-state triplet oxygen (3O2), thereby converting it into its singlet state (1O2). The in situ generated singlet oxygen then undergoes a rapid [2+2]-cycloaddition across the enolic double bond of the tautomer 21′ of 4-hydroxycoumarin 21 to form a dioxetane intermediate 29, which furnishes a radical species 30 upon homolytic cleavage of both bonds a and b . In the next step, the formation of a hydroperoxide intermediate 31 is expected to occur, due to the participation of 30 in radical-recombination processes, both intramolecularly (leading to a five-membered furan ring) and intermolecularly with the alkoxy/aminoalkyl and hydrogen radicals generated in situ from the alcohol 27 or amines 25 under the reaction conditions. Finally, hydroperoxide 31 affords the desired product 26/28 on removal of a water molecule (Scheme [15]).

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Scheme 15 Suggested mechanism

# 2.1.6

Synthesis of Functionalized 2-Hydroxyphenylated α-Ketoamides

The α-ketoamide structural motif is prevalent in numerous natural products,[22] biologically potent molecules,[23] and marketed drugs.[24] α-Ketoamides also find wide applications as useful synthons for many organic transformations, such as intramolecular arylations and β-lactam formation.[25] As a result, researchers have recently developed a handful of synthetic methods to access this valuable class of organic compounds by following several strategies that have particular merits but which are also associated with undesired shortcomings.[26] Recently, Brahmachari and Karmakar[27] developed a new and effective synthetic strategy to access a diverse series of biologically interesting 2-hydroxyphenylated α-ketoamides 32 through visible-light [white LED (Method A) or direct sunlight (Method B)]-induced photocatalytic decarboxylative amidation of 4-hydroxycoumarins 21 on treatment with secondary amines 31 in the presence of potassium tert-butoxide (t-BuOK) in DMSO, using molecular oxygen as the oxygen source at ambient temperature (28–30 °C) (Scheme [16]). The α-ketoamides 32 were isolated in moderate to good yields, ranging from 51 to 69%, within 1.5 to 2 hours in Method A and 44 to 65% within 2 to 6 hours in Method B. Notable advantages of this method include its mild reaction conditions at ambient temperature, energy efficiency by making use of direct sunlight or a low-energy visible-light source, metal-free synthesis, use of low-cost substrates and nontoxic rose bengal photosensitizer, and moderate to good yields within a reasonable timeframe. The current strategy of photochemical degradative amidation of the 4-hydroxycoumarin scaffold is the first report of this intriguing chemistry in which a hydroxy group is installed at the C-2 position of the phenyl ring of the α-ketoamide skeleton, thereby imparting the inherently good biological properties of phenolics.[28]

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Scheme 16 Photochemical synthesis of functionalized 2-hydroxyphenylated α-ketoamides 32

Based on their experimental observations (Scheme [17]), the investigators outlined a plausible mechanism for this photocatalytic transformation (Scheme [18]). An activated molecule of rose bengal (RB*) first produces a radical amine cation 31′ by abstracting an electron from amine 31 through an SET process. The resulting photocatalyst radical anion (RB∙–) in turn generates a superoxide radical anion (O2 ∙–) by transferring its extra electron to the singlet oxygen (1O2) generated in situ by another molecule of activated rose bengal photosensitizer. This reactive O2 ∙– species then, through an SET process, rapidly grabs an electron from the enolate of the 4-hydroxycoumarin molecule 21, formed by removal of the enolic proton by the tert-butoxide base, to produce the enoloxy radical 21′ and peroxide ion (O2 2–). This peroxide ion abstracts a proton from the amine radical cation 31′ to yield a hydroperoxide anion (HO2 –) and an amine radical 31′′. The next step is the formation of adduct 33 upon C–N cross-coupling of radicals 21′ and 31′′. Now, the acidic methine proton at C-3 of adduct 33 is abstracted by the superoxide anion, thereby forming H2O2 and the corresponding enolate species, which, in turn, undergoes [2+2]-cycloaddition with a singlet oxygen molecule to generate the dioxetane intermediate 34. Dioxetane 34 generates radical species 35 through homolytic cleavage of bonds a and b ; radical 35 then emergently recombines to form intermediate 36, which undergoes rapid decarboxylation to afford the desired product 32 (Scheme [18]).[27]

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Scheme 17 Radical-scavenging experiments
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Scheme 18 Suggested mechanism

#
# 2.2

Electrochemical Organic Synthesis

2.2.1

Synthesis of 3-Selenylated/Sulfenylated Derivatives of 2-Amino-1,4-naphthoquinones

Apart from the photochemical synthetic route,[6] our group recently unearthed an electrochemical process for regioselective C(sp2)–H selenylation or sulfenylation of biologically promising 2-amino-1,4-naphthoquinones 5 for easy access to a diverse series of 2-(aryl/alkyl/benzylamino)-3-(phenyl/methylselanyl)naphthalene-1,4-diones 7 or 2-(aryl/benzyl amino)-3-(aryl/ heteroarylthio)naphthalene-1,4-diones 9 by using low-cost and readily available potassium iodide as both an electrolyte and a redox mediator in acetonitrile under ambient conditions (Scheme [19]).[29] The key advantages of this method are its broad substrate scope; the avoidance of transition-metal catalysts, oxidants, or high temperatures; good to excellent yields; short reaction times (minutes); scalability; and ecofriendliness. This is the first report of selenylation of 2-amino-1,4-naphthoquinone derivatives. The Faraday efficiencies of the overall electrochemical reactions were calculated to be optimal (36.56–83.38%).

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Scheme 19 Electrochemical synthesis of 3-selenylated/sulfenylated derivatives of 2-amino-1,4-naphthoquinones 5

Based on the results of control experiments (Scheme [20]) and cyclic voltammetric studies, a possible mechanism for this electrochemical transformation was suggested (Scheme [21]). At the anode surface, iodide (I–) ions are oxidized to iodine radicals that undergo a radical-coupling reaction with a selenium/sulfur radical (R′X∙) species 37/38 to form an R′XI intermediate 39/40, which, in turn, undergoes a heterolytic cleavage of the X–I bond to generate a strongly electrophilic R′X+ (41/42). In the next step, the tautomeric form 5′ of 5 rapidly undergoes nucleophilic attack at the Se+/S+ centre of the in situ generated electrophile R′X+ (41/42) at C-3, thereby forming adduct 43, which then aromatizes to afford the desired selenylated/sulfenylated product 7/9. At the cathode surface, hydrogen is liberated upon the reduction of the free protons (Scheme [21]).

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Scheme 20 Radical-scavenging experiments
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Scheme 21 Proposed mechanism

# 2.2.2

Synthesis of Functionalized 6-(Arylthio/Arylseleno)benzo[a]phenazin-5-ols

Brahmachari and his group[13] also explored an electrochemical synthetic route to the title compounds. Functionalized 6-(arylthio/arylseleno)benzo[a]phenazin-5-ols 18/18′ were prepared in good to excellent yields within short reaction times through regioselective C(sp2)–S/Se cross-coupling of benzo[a]phenazin-5-ols 16 with an aryl thiol 17 or diphenyl diselenide (6a) on passing a direct current of 18 mA at a constant voltage of 7.0 V through the reaction mixture dissolved in DMSO under ambient conditions, exploiting the effective use of potassium iodide salt as both electrolyte and catalyst (Scheme [22]).

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Scheme 22 Electrochemical C(sp2)–H bond sulfenylation/selenylation of benzo[a]phenazin-5-ols 16

The electrosynthetic process follows a radical pathway, as evidenced by radical-scavenging experiments (Scheme [23]), and the method avoids using any metal catalysts and external oxidants.

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Scheme 23 Radical-scavenging experiments

A possible mechanistic pathway is shown in Scheme [24]. Iodide (I–) ions release electrons at the anode surface to generate molecular iodine (I2), which is then nucleophilically attacked by the substrate molecule 16 through its C-6 carbon atom to give an iodo intermediate 44. Upon homolytic cleavage of the intermediate 44 at its C(6)–I bond, a C(6)-centred secondary carbon radical 45 is formed; this recombines with a thiol radical to form adduct 20 through intermolecular C–S coupling. Adduct 20, in turn, aromatizes to furnish the desired product 18 through tautomerization. At the cathode surface, hydrogen is liberated upon the reduction of the free protons. The iodide (I–) ions thus regenerated maintain the catalytic cycle. KI, therefore, acts as both the electrolyte salt and as a catalyst.

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Scheme 24 Suggested mechanism

# 2.2.3

Synthesis of Functionalized Alkyl 2-Hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates

Very recently, our group[30] successfully explored an alternative and practical electrosynthetic strategy for preparing a broad spectrum of diversely substituted alkyl 2-hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates 28 through an electrorearrangement/difunctionalization of 4-hydroxycoumarins 21 with alcohols 27 in an undivided electrochemical cell, by passing a constant direct current in the presence of lithium difluoro(oxalato)borate (LiC2O4BF2) as an electrolyte in acetonitrile under an oxygen atmosphere at ambient temperature (25–28 °C) (Scheme [25]). A total of 55 diverse derivatives of the title compounds were prepared in good to excellent yields, ranging from 59 to 87%, within two to six hours. The present electrochemical method is significantly more advantageous than the previously reported photochemical conversion[21] in terms of its yield, reaction time, substrate scope, functional-group tolerance, operational simplicity, and scalability.

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Scheme 25 Electrochemical synthesis of functionalized 2-hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates 28

Based on the results of detailed control experiments (Scheme [26]), coupled with cyclic voltammetric studies of the reaction components, the investigators proposed a tentative mechanism for the electrochemistry-promoted transformation, as depicted in Scheme [27]. The alcohol molecule 2 preferentially gives up an electron to the anode surface to produce an alcohol radical cation 27′. Meanwhile, the 4-hydroxycoumarin molecule 21 undergoes tautomerism in the reaction mixture to produce its tautomer 21′, which immediately undergoes a homolytic cleavage at the enolic double bond to generate a diradical species 46. The in situ generated radical species 27′ and 46 (trapped by BHT; as detected by HRMS) then produce an adduct 47 through a heterocoupling reaction; this then undergoes a homolytic cleavage of its C(O)–C(OR2) bond to form another radical species 48. Again, it was assumed that the triplet-state molecular oxygen (3O2) is first oxidized at the anode surface, followed by reduction at the cathode surface, thereby changing its spin state from a triplet state to a singlet state. At this stage, the triradical species 48 participates simultaneously in both an intramolecular homo radical coupling and intramolecular hetero radical coupling with the in situ generated singlet-state oxygen (1O2) to form a benzofuranone intermediate 49, which then affords the desired product 28 through elimination of a hydroxy radical (HO∙). This hydroxy radical collapses to hydrogen and oxygen gases under the electrochemical conditions. At the cathode surface, hydrogen is liberated upon reduction of the free protons (Scheme [27]).

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Scheme 26 Radical-scavenging experiments
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Scheme 27 Proposed mechanism

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Conclusions

In this account, we have outlined our green-chemistry-driven sincere efforts in designing and developing fruitful synthetic strategies for accessing a handful of different series of diversely functionalized organic scaffolds of biological interest, as reported in the last five years (2020 to mid-2024). The synthetic protocols involve the judicious application of low-energy visible light, abundantly available sunlight, or a low-powered electric current in an undivided electrochemical cell. These organic transformations all follow a radical pathway, as evidenced by detailed mechanistic studies. All these green-chemistry-driven synthetic methods are associated with many advantages and benefits, including operational simplicity, good to excellent yields, mild reaction conditions, energy efficiency, reasonable reaction times, inexpensive starting materials, and large-scale synthetic applicability in most cases. Besides, certain interesting chemistries have also been explored in these transformations.

The chemical fraternity, at present, is deeply involved in attaining a sustainable future that is crucial for our survival. Synthetic organic chemists are primarily concerned with chemical compounds/materials and their synthetic processes on which the material basis of a sustainable society is largely dependent. Hence, the design of chemical products and processes should follow principles that make them conducive to life. Fruitful applications of green-chemistry approaches and engineering have yielded many ecofriendly and efficient chemical processes for value-added chemicals and new chemistries. Recent research has confirmed that microbial enzymatic, electrochemical, and photocatalytic methods occupy a niche in this toolbox. The author hopes this account will motivate young minds and experts working in this domain.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgments

The author thanks his co-workers for their dedicated involvement and support in the various phases of this work.


Corresponding Author

Goutam Brahmachari
Laboratory of Natural Products and Organic Synthesis, Department of Chemistry, Visva-Bharati (a Central University)
Santiniketan-731 235, West Bengal
India   

Publication History

Received: 22 May 2024

Accepted after revision: 19 June 2024

Article published online:
08 July 2024

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Scheme 1 Photochemical synthesis of functionalized dihydrofuro[3,2-c]chromenones 2
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Scheme 2 Radical-scavenging experiments
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Scheme 3 Suggested mechanism
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Scheme 4 Visible-light-mediated, self-sensitized, regioselective oxidative C(sp2–H) bond selenylation/sulfenylation of substituted 2-amino-1,4-naphthoquinones 5
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Scheme 5 Radical-scavenging experiments. BHT = butylated hydroxytoluene.
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Scheme 6 Proposed mechanism
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Scheme 7 Photosensitizer-free, visible-light-mediated, regioselective cross-dehydrogenative C(sp2)–H sulfenylation or selenylation of substituted benzo[a]phenazin-5-ols 16
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Scheme 8 Radical-scavenging experiments
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Scheme 9 Proposed mechanism
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Scheme 10 Photochemical synthesis of diversely substituted coumarin thioethers 23
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Scheme 11 Radical-scavenging experiments
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Scheme 12 Proposed mechanism
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Scheme 13 Visible-light-induced synthesis of 2,2-disubstituted benzofuran-3(2H)-ones 26 and 28
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Scheme 14 Radical-scavenging experiments
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Scheme 15 Suggested mechanism
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Scheme 16 Photochemical synthesis of functionalized 2-hydroxyphenylated α-ketoamides 32
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Scheme 17 Radical-scavenging experiments
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Scheme 18 Suggested mechanism
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Scheme 19 Electrochemical synthesis of 3-selenylated/sulfenylated derivatives of 2-amino-1,4-naphthoquinones 5
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Scheme 20 Radical-scavenging experiments
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Scheme 21 Proposed mechanism
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Scheme 22 Electrochemical C(sp2)–H bond sulfenylation/selenylation of benzo[a]phenazin-5-ols 16
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Scheme 23 Radical-scavenging experiments
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Scheme 24 Suggested mechanism
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Scheme 25 Electrochemical synthesis of functionalized 2-hydroxy-3-oxo-2,3-dihydrobenzofuran-2-carboxylates 28
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Scheme 26 Radical-scavenging experiments
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Scheme 27 Proposed mechanism