Advances in Visible-Light-Mediated Carbonylative Reactions ...

catalysts

Review

Advances in Visible-Light-Mediated Carbonylative Reactionsvia Carbon Monoxide (CO) Incorporation

Vinayak Botla 1, Aleksandr Voronov 1, Elena Motti 1, Carla Carfagna 2, Raffaella Mancuso 3 , Bartolo Gabriele 3

and Nicola Della Ca’ 1,*

��

Citation: Botla, V.; Voronov, A.;

Motti, E.; Carfagna, C.; Mancuso, R.;

Gabriele, B.; Della Ca’, N. Advances

in Visible-Light-Mediated

Carbonylative Reactions via Carbon

Monoxide (CO) Incorporation.

Catalysts 2021, 11, 918. https://

doi.org/10.3390/catal11080918

Academic Editor: Ekaterina

A. Kozlova

Received: 26 June 2021

Accepted: 27 July 2021

Published: 29 July 2021

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1 Department of Chemistry, Life Sciences and Environmental Sustainability (SCVSA), University of Parma,Parco Area delle Scienze, 17/A, 43124 Parma, Italy; [email protected] (V.B.);[email protected] (A.V.); [email protected] (E.M.)

2 Department of Industrial Chemistry “T. Montanari”, University of Bologna, 40136 Bologna, Italy;[email protected]

3 Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and ChemicalTechnologies, University of Calabria, Via P. Bucci 12/C, 87036 Arcavacata di Rende Cosenza, Italy;[email protected] (R.M.); [email protected] (B.G.)

* Correspondence: [email protected]; Tel.:+39-0521-905676

Abstract: The abundant and inexpensive carbon monoxide (CO) is widely exploited as a C1 source forthe synthesis of both fine and bulk chemicals. In this context, photochemical carbonylation reactionshave emerged as a powerful tool for the sustainable synthesis of carbonyl-containing compounds(esters, amides, ketones, etc.). This review aims at giving a general overview on visible light-promotedcarbonylation reactions in the presence of metal (Palladium, Iridium, Cobalt, Ruthenium, Copper)and organocatalysts as well, highlighting the main features of the presented protocols and providinguseful insights on the reaction mechanisms.

Keywords: carbon monoxide; carbonylation; photochemical reactions; visible light; carbonyl-containing compounds

1. Introduction

Carbon monoxide (CO) is largely used in the chemical industry for manufacturingbulk chemicals (i.e., methanol, acetic acid) and fine chemicals (i.e., ibuprofen) and is fre-quently employed as an inexpensive and readily available C1 source in a wide range ofcarbonylative transformations for the synthesis of high-value-added carbonyl-containingcompounds, such as acids, esters, amides and ketones [1–6]. The carbonyl unit is ubiqui-tous in a myriad of bioactive molecules, such as natural products, pharmaceuticals andagrochemicals, as well as materials. It can be also manipulated and transformed into aseries of other functional groups, including amines, alcohols and olefins. In the era ofsustainability, the development of economically improved and environmentally friendlycatalytic protocols is highly recommended. In recent years, visible-light photocatalysis hasreceived much attention from the synthetic chemists’ community since, unlike traditionalthermal and catalytic reactions, it enables unprecedented reaction pathways, high selec-tivities and mild reaction conditions [7–10]. The combination of carbon monoxide-basedcarbonylation strategy with the advantages that come from the application of photocataly-sis can potentially lead to a highly sustainable process [11–15]. However, the first reportsdisplayed problems connected with a limited generality, poor selectivity and/or efficiency,high pressure of carbon monoxide or high energy of light irradiation [16–23]. Over thelast two decades, new and more performing catalytic systems allowed to solve in partthese issues. The present review will cover the major advances in the area of visible light-mediated catalyzed carbonylations from 2000, with a focus on CO-based carbonylationmethodologies. Sometimes, for a better and more general overview, less recent reportswill be mentioned. The review is organized into different sections; each one is related to a

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different metal, and one section is dedicated to metal-free protocols, which include the useof organic photocatalysts.

1.1. Visible-Light-Promoted Palladium-Catalyzed Carbonylations

The major achievements in the area of visible-light-driven photocatalysis have beenreached with palladium, thanks to its superior versatility. One of the first reports was re-lated to the synthesis of unsymmetrical ketones, which were readily accessed by means of apalladium-catalyzed cross-coupling reaction of iodoalkanes and 9-alkyl-9-borabicyclo[3.3.l]nonane derivatives (9-alkyl-9-BBN) under atmospheric pressure of CO (Scheme 1) [24]. Thepresence of K3PO4 was essential, while the reaction was significantly accelerated by theirradiation of light. Alkyl halides bearing β hydrogens often lead to competitive pathwaysin traditional cross-coupling reactions, such as the formation of alkenes by β–hydrideelimination. In this case, various primary, secondary and tertiary alkyl iodides affordedunsymmetrical ketones in moderate to good yields. Different functional groups (i.e., acetal,nitrile, carbomethoxy groups) were well tolerated on both iodoalkanes and 9-alkyl-9-BBNunder the optimized reaction conditions. Selected examples are shown in Scheme 1.

Catalysts 2021, 11, x FOR PEER REVIEW 2 of 34

methodologies. Sometimes, for a better and more general overview, less recent reports will be mentioned. The review is organized into different sections; each one is related to a different metal, and one section is dedicated to metal-free protocols, which include the use of organic photocatalysts.

1.1. Visible-Light-Promoted Palladium-Catalyzed Carbonylations The major achievements in the area of visible-light-driven photocatalysis have been

reached with palladium, thanks to its superior versatility. One of the first reports was related to the synthesis of unsymmetrical ketones, which were readily accessed by means of a palladium-catalyzed cross-coupling reaction of iodoalkanes and 9-alkyl-9-borabicy-clo[3.3.l]nonane derivatives (9-alkyl-9-BBN) under atmospheric pressure of CO (Scheme 1) [24]. The presence of K3PO4 was essential, while the reaction was significantly acceler-ated by the irradiation of light. Alkyl halides bearing β hydrogens often lead to competi-tive pathways in traditional cross-coupling reactions, such as the formation of alkenes by β–hydride elimination. In this case, various primary, secondary and tertiary alkyl iodides afforded unsymmetrical ketones in moderate to good yields. Different functional groups (i.e., acetal, nitrile, carbomethoxy groups) were well tolerated on both iodoalkanes and 9-alkyl-9-BBN under the optimized reaction conditions. Selected examples are shown in Scheme 1.

hv, 3% Pd(PPh3)4

K3PO4, C6H6r.t., 24h

R1-I R1 R2

O

OCO2Me

O

OO O

OMe

OMe

O

O

CO2Me

AcO

O

50%

65%

73%

76%67%

BR2

CO(1atm)

R1 = primary, secondary andtertiary alkyl groups

R2 = primary alkyl groups

50–76%

Selected examples:

H

H

10

1991 Suzuki

- 1 atm of CO- Alkyl iodides with hydrogens- hv: 100 W tungsten lightFeatures:

5 7

Proposed mechanism:

Pd(PPh3)4CO

Pd(CO)(PPh3)3- PPh3 I

hv

- 2PPh3Pd(CO)(PPh3)

II

IIR1 I + R1PdXSET

III

R1COPdX

IV

CO 9-R2-9-BBN

R1COPdR2

V

base

R1COR2 + Pd(0)L2 L = CO, PPh3

L

L

L

LL

9 examples

Scheme 1. The synthesis of ketones from iodoalkanes, 9-alkyl-9-BBN derivatives and CO via a light-accelerated Pd-catalyzed reaction.

The reaction is supposed to proceed through a free radical mechanism at the oxida-tive addition step [25]. Firstly, Pd(PPh3)4 likely converts to the low reactive Pd(CO)(PPh3)3

Scheme 1. The synthesis of ketones from iodoalkanes, 9-alkyl-9-BBN derivatives and CO via alight-accelerated Pd-catalyzed reaction.

The reaction is supposed to proceed through a free radical mechanism at the oxidativeaddition step [25]. Firstly, Pd(PPh3)4 likely converts to the low reactive Pd(CO)(PPh3)3complex I under CO atmosphere. In the presence of light irradiation, complex I undergoes

Catalysts 2021, 11, 918 3 of 35

dissociation of ligands to give the unsaturated palladium species II. The latter enablesan electron transfer to the alkyl iodide with the formation of a radical pair (Pd(I)X + R˙)that could provide the oxidative intermediate RPdX (III). The migration of the alkyl groupto a coordinated CO molecule affords complex RCOPdX IV. Then, the base facilitatesthe transfer of the R2 group from 9-R2-9-BBN to palladium providing V, which yieldsthe ketone and a palladium(0) species through a reductive elimination step (Scheme 1,proposed mechanism).

Based on their previous studies [25], Miyaura and co-workers developed a palladium-catalyzed three-component reaction between iodoalkenes, carbon monoxide and 9-alkyl-or 9-aryl-9-BBN derivatives to obtain cyclized unsymmetrical ketones under photoirra-diation conditions (Scheme 2) [26]. Analogously to the previously reported mechanism(Scheme 1), the iodoalkenes provided cyclized ketones via radical cyclization, carbonmonoxide insertion and coupling with 9-R2-9-BBN derivatives. Iodoalkynes led to thecorresponding cyclized unsaturated ketones as a 1:1 mixture of E and Z isomers. Interest-ingly, iodocycloalkenes resulted in the formation of cis-fused bicyclic alkanes starting fromtrans iodides as well (Scheme 2). This, together with the predominance of 5-memberedover the 6-membered annulation mode, can further confirm the radical nature of thereaction pathway.


complex I under CO atmosphere. In the presence of light irradiation, complex I undergoes dissociation of ligands to give the unsaturated palladium species II. The latter enables an electron transfer to the alkyl iodide with the formation of a radical pair (Pd(I)X + R˙) that could provide the oxidative intermediate RPdX (III). The migration of the alkyl group to a coordinated CO molecule affords complex RCOPdX IV. Then, the base facilitates the transfer of the R2 group from 9-R2-9-BBN to palladium providing V, which yields the ke-tone and a palladium(0) species through a reductive elimination step (Scheme 1, proposed mechanism).

Based on their previous studies [25], Miyaura and co-workers developed a palla-dium-catalyzed three-component reaction between iodoalkenes, carbon monoxide and 9-alkyl- or 9-aryl-9-BBN derivatives to obtain cyclized unsymmetrical ketones under pho-toirradiation conditions (Scheme 2) [26]. Analogously to the previously reported mecha-nism (Scheme 1), the iodoalkenes provided cyclized ketones via radical cyclization, carbon monoxide insertion and coupling with 9-R2-9-BBN derivatives. Iodoalkynes led to the cor-responding cyclized unsaturated ketones as a 1:1 mixture of E and Z isomers. Interest-ingly, iodocycloalkenes resulted in the formation of cis-fused bicyclic alkanes starting from trans iodides as well (Scheme 2). This, together with the predominance of 5-mem-bered over the 6-membered annulation mode, can further confirm the radical nature of the reaction pathway.

Scheme 2. The synthesis of ketones from iodoalkenes, 9-R2-9-BBN derivatives and CO via a light-accelerated Pd-catalyzed reaction.

Palladium-catalyzed photochemical carbonylation reactions aimed at the synthesis of ketones, α,β-unsaturated ketones, esters, lactones and carbamoylacetates have been ex-tensively studied by lhyong Ryu and co-workers [15,27,28]. The initial idea was to insert carbon monoxide on an alkyliodide by homolytic cleavage of the C–I bond. The idea has been successfully realized under irradiation and metal-free conditions (vide infra, Section 1.6) [29].

The combination of palladium catalysis with irradiation conditions was crucial for the carbonylation-cyclization-carbonylation sequence reported in 2002 by Ryu and co-workers [30]. A variety of 4-alkenyl iodides were efficiently converted to the desired ke-tones in the presence of alcohol, Pd(PPh3)4 (5 mol %), Et3N, DMAP (5–10 mol %) under irradiation (500 W xenon lamp, 185–2600 nm, Pyrex) and 40 atm of CO pressure (Scheme 3). When the transformation was performed with diethyl amine in place of alcohol, the triply carbonylated α,δ-diketo amides were obtained as the major product. Alkyl bro-mides gave promising but lower yields if compared with the corresponding iodides. This

Scheme 2. The synthesis of ketones from iodoalkenes, 9-R2-9-BBN derivatives and CO via a light-accelerated Pd-catalyzed reaction.

Palladium-catalyzed photochemical carbonylation reactions aimed at the synthesisof ketones, α,β-unsaturated ketones, esters, lactones and carbamoylacetates have beenextensively studied by lhyong Ryu and co-workers [15,27,28]. The initial idea was toinsert carbon monoxide on an alkyliodide by homolytic cleavage of the C–I bond. Theidea has been successfully realized under irradiation and metal-free conditions (vide infra,Section 1.6) [29].

The combination of palladium catalysis with irradiation conditions was crucial forthe carbonylation-cyclization-carbonylation sequence reported in 2002 by Ryu and co-workers [30]. A variety of 4-alkenyl iodides were efficiently converted to the desiredketones in the presence of alcohol, Pd(PPh3)4 (5 mol %), Et3N, DMAP (5–10 mol %) underirradiation (500 W xenon lamp, 185–2600 nm, Pyrex) and 40 atm of CO pressure (Scheme 3).When the transformation was performed with diethyl amine in place of alcohol, the triplycarbonylated α,δ-diketo amides were obtained as the major product. Alkyl bromides

Catalysts 2021, 11, 918 4 of 35

gave promising but lower yields if compared with the corresponding iodides. This free-radical-based methodology complements the traditional palladium-catalyzed carbonylativereactions that are extensively employed for aromatic and vinylic halides [31].


free-radical-based methodology complements the traditional palladium-catalyzed car-bonylative reactions that are extensively employed for aromatic and vinylic halides [31].

Scheme 3. Pd-catalyzed/light-induced Cyclizative Carbonylation to esters and amides.

The efficiency of the reaction was improved by the presence of palladium catalysts; however, the stereoselectivity observed with cyclic substrates was identical with those found in palladium-free radical carbonylation sequences. The interplay of organometallic species and radicals can be explained by the mechanism depicted in Scheme 4. As previ-ously observed [25], the palladium(0) species can be active in the C–I bond cleavage providing the radical pair Pd(I)I and alkyl radical I. The high pressure of carbon monoxide favors the formation of the acyl radical II, which undergoes cyclization and further CO insertion to IV. Then, intermediate IV can recombine with the Pd(I)I species leading to V, which affords the desired product by reaction with an alcohol.

Scheme 4. The proposed mechanism for the Pd-catalyzed/Light-induced Cyclizative Carbonylation to ketones and amides.

Based on their previous report [30], Ryu and co-workers reported a general method for the synthesis of esters and amides [32] and, in particular, described the acceleration effect of light-induced atom transfer carbonylation reactions obtained in the presence of Pd(0) complexes and Mn2(CO)10. Therefore, for example, when 1-iodooctane was caused to react with CO and ethanol under photoirradiation conditions (Xenon lamp, 185–2600 nm), ethyl nonanoate was obtained in a moderate yield of 54% even with prolonged reac-tion time (50 h). However, the same reaction in the presence of Pd(PPh3)4 (5 mol %) af-forded the expected ethyl ester in 87% yield after 16 h (Scheme 5a). Under similar condi-tions, the synthesis of a precursor of the (-)-Hinokinin was efficiently achieved (Scheme 5b).


The efficiency of the reaction was improved by the presence of palladium catalysts;however, the stereoselectivity observed with cyclic substrates was identical with thosefound in palladium-free radical carbonylation sequences. The interplay of organometallicspecies and radicals can be explained by the mechanism depicted in Scheme 4. As pre-viously observed [25], the palladium(0) species can be active in the C–I bond cleavageproviding the radical pair Pd(I)I and alkyl radical I. The high pressure of carbon monoxidefavors the formation of the acyl radical II, which undergoes cyclization and further COinsertion to IV. Then, intermediate IV can recombine with the Pd(I)I species leading to V,which affords the desired product by reaction with an alcohol.


free-radical-based methodology complements the traditional palladium-catalyzed car-bonylative reactions that are extensively employed for aromatic and vinylic halides [31].


The efficiency of the reaction was improved by the presence of palladium catalysts; however, the stereoselectivity observed with cyclic substrates was identical with those found in palladium-free radical carbonylation sequences. The interplay of organometallic species and radicals can be explained by the mechanism depicted in Scheme 4. As previ-ously observed [25], the palladium(0) species can be active in the C–I bond cleavage providing the radical pair Pd(I)I and alkyl radical I. The high pressure of carbon monoxide favors the formation of the acyl radical II, which undergoes cyclization and further CO insertion to IV. Then, intermediate IV can recombine with the Pd(I)I species leading to V, which affords the desired product by reaction with an alcohol.

Scheme 4. The proposed mechanism for the Pd-catalyzed/Light-induced Cyclizative Carbonylation to ketones and amides.

Based on their previous report [30], Ryu and co-workers reported a general method for the synthesis of esters and amides [32] and, in particular, described the acceleration effect of light-induced atom transfer carbonylation reactions obtained in the presence of Pd(0) complexes and Mn2(CO)10. Therefore, for example, when 1-iodooctane was caused to react with CO and ethanol under photoirradiation conditions (Xenon lamp, 185–2600 nm), ethyl nonanoate was obtained in a moderate yield of 54% even with prolonged reac-tion time (50 h). However, the same reaction in the presence of Pd(PPh3)4 (5 mol %) af-forded the expected ethyl ester in 87% yield after 16 h (Scheme 5a). Under similar condi-tions, the synthesis of a precursor of the (-)-Hinokinin was efficiently achieved (Scheme 5b).

Scheme 4. The proposed mechanism for the Pd-catalyzed/Light-induced Cyclizative Carbonylationto ketones and amides.

Based on their previous report [30], Ryu and co-workers reported a general methodfor the synthesis of esters and amides [32] and, in particular, described the accelerationeffect of light-induced atom transfer carbonylation reactions obtained in the presence ofPd(0) complexes and Mn2(CO)10. Therefore, for example, when 1-iodooctane was caused to

Catalysts 2021, 11, 918 5 of 35

react with CO and ethanol under photoirradiation conditions (Xenon lamp, 185–2600 nm),ethyl nonanoate was obtained in a moderate yield of 54% even with prolonged reactiontime (50 h). However, the same reaction in the presence of Pd(PPh3)4 (5 mol %) affordedthe expected ethyl ester in 87% yield after 16 h (Scheme 5a). Under similar conditions, thesynthesis of a precursor of the (-)-Hinokinin was efficiently achieved (Scheme 5b).


Scheme 5. Palladium tetrakis-accelerated photo-irradiated atom transfer carbonylation of alkyl io-dides to esters (a), lactones (b) and amides (c).

The atom transfer carbonylation of secondary and tertiary alkyl iodides proceeded smoothly, affording moderate to high yields of esters in a shorter reaction time (6.5 h). In this case, the use of Mn2(CO)10 in place of Pd(PPh3)4 was found to be even more effective. The selective synthesis of the corresponding amides was again achieved in the presence of Mn2(CO)10 (Scheme 5c), while a palladium(0) precursor led to mixtures of amides and ketoamides. Later, highly functionalized linear ester and lactone derivatives were ob-tained by means of four and three-component photocatalytic methodologies, respectively, under similar reaction conditions [33].

In 2010, a three-component approach for the synthesis of alkynyl ketones was pro-posed by the Ryu research group [34]. This new methodology, which is an alternative to the acylation of alkynyl organometallic reagents with acid chlorides, is based on the reac-tion of alkyl iodides, CO and terminal alkynes in the presence of a palladium catalyst and xenon light, under mild reaction condition (Scheme 6).

Scheme 6. The synthesis of alkynyl ketones via a Pd-catalyzed/light-induced three-component cross-coupling reaction.

Remarkably, the source of light, the palladium catalyst (PdCl2(PPh3)2) and the aque-ous medium proved to be crucial for this transformation. Various substituents on the alkyl iodide, such as chloro, methyl ester and ether (TBS) groups, were well tolerated under

Scheme 5. Palladium tetrakis-accelerated photo-irradiated atom transfer carbonylation of alkyliodides to esters (a), lactones (b) and amides (c).

The atom transfer carbonylation of secondary and tertiary alkyl iodides proceededsmoothly, affording moderate to high yields of esters in a shorter reaction time (6.5 h). Inthis case, the use of Mn2(CO)10 in place of Pd(PPh3)4 was found to be even more effective.The selective synthesis of the corresponding amides was again achieved in the presenceof Mn2(CO)10 (Scheme 5c), while a palladium(0) precursor led to mixtures of amides andketoamides. Later, highly functionalized linear ester and lactone derivatives were obtainedby means of four and three-component photocatalytic methodologies, respectively, undersimilar reaction conditions [33].

In 2010, a three-component approach for the synthesis of alkynyl ketones was pro-posed by the Ryu research group [34]. This new methodology, which is an alternative to theacylation of alkynyl organometallic reagents with acid chlorides, is based on the reaction ofalkyl iodides, CO and terminal alkynes in the presence of a palladium catalyst and xenonlight, under mild reaction condition (Scheme 6).

Catalysts 2021, 11, 918 6 of 35


Scheme 5. Palladium tetrakis-accelerated photo-irradiated atom transfer carbonylation of alkyl io-dides to esters (a), lactones (b) and amides (c).

The atom transfer carbonylation of secondary and tertiary alkyl iodides proceeded smoothly, affording moderate to high yields of esters in a shorter reaction time (6.5 h). In this case, the use of Mn2(CO)10 in place of Pd(PPh3)4 was found to be even more effective. The selective synthesis of the corresponding amides was again achieved in the presence of Mn2(CO)10 (Scheme 5c), while a palladium(0) precursor led to mixtures of amides and ketoamides. Later, highly functionalized linear ester and lactone derivatives were ob-tained by means of four and three-component photocatalytic methodologies, respectively, under similar reaction conditions [33].

In 2010, a three-component approach for the synthesis of alkynyl ketones was pro-posed by the Ryu research group [34]. This new methodology, which is an alternative to the acylation of alkynyl organometallic reagents with acid chlorides, is based on the reac-tion of alkyl iodides, CO and terminal alkynes in the presence of a palladium catalyst and xenon light, under mild reaction condition (Scheme 6).

Scheme 6. The synthesis of alkynyl ketones via a Pd-catalyzed/light-induced three-component cross-coupling reaction.

Remarkably, the source of light, the palladium catalyst (PdCl2(PPh3)2) and the aque-ous medium proved to be crucial for this transformation. Various substituents on the alkyl iodide, such as chloro, methyl ester and ether (TBS) groups, were well tolerated under

Scheme 6. The synthesis of alkynyl ketones via a Pd-catalyzed/light-induced three-componentcross-coupling reaction.

Remarkably, the source of light, the palladium catalyst (PdCl2(PPh3)2) and the aqueousmedium proved to be crucial for this transformation. Various substituents on the alkyliodide, such as chloro, methyl ester and ether (TBS) groups, were well tolerated understandard conditions, while aryl, as well as alkyl fragments, can be efficiently employedin the alkyne partner. Once again, this methodology, which starts from a variety of alkyliodides, is complementary to the transition metal-catalyzed coupling reactions, which aremainly restricted to the use of aryl and vinyl halides [31].

Later, Ryu and co-workers reported versatile four-component coupling reactions lead-ing to functionalized esters using α-substituted iodoalkanes, alkenes, CO and alcoholsunder photoirradiation conditions (500 W xenon lamp), 45 atm of CO pressure in the pres-ence of PdCl2(PPh3)2 (5 mol %) as catalyst (Scheme 7a) [35]. Several electron-withdrawinggroups were tolerated (EWG = COOR, CN, PhSO2) on the iodoalkane coupling partner,and both terminal and internal alkenes gave satisfactory results. When alkenyl alcoholswere employed in place of alkene/ROH mixture, lactone derivatives were obtained viaintramolecular esterification (Scheme 7b).


standard conditions, while aryl, as well as alkyl fragments, can be efficiently employed in the alkyne partner. Once again, this methodology, which starts from a variety of alkyl iodides, is complementary to the transition metal-catalyzed coupling reactions, which are mainly restricted to the use of aryl and vinyl halides [31].

Later, Ryu and co-workers reported versatile four-component coupling reactions leading to functionalized esters using α-substituted iodoalkanes, alkenes, CO and alco-hols under photoirradiation conditions (500 W xenon lamp), 45 atm of CO pressure in the presence of PdCl2(PPh3)2 (5 mol %) as catalyst (Scheme 7a) [35]. Several electron-with-drawing groups were tolerated (EWG = COOR, CN, PhSO2) on the iodoalkane coupling partner, and both terminal and internal alkenes gave satisfactory results. When alkenyl alcohols were employed in place of alkene/ROH mixture, lactone derivatives were ob-tained via intramolecular esterification (Scheme 7b).

Scheme 7. Pd-catalyzed/Light-induced four and three-component coupling reactions to esters (a) and lactones (b).

The same research group has also reported a novel synthetic method of car-bamoylacetates from α-iodoacetate, carbon monoxide and amines under 15 W black light conditions in the presence of PdCl2(PPh3)2 as the catalyst [36]. The methodology was re-stricted to the use of α-iodo ethyl acetate, while a wide variety of amines, including pri-mary and secondary amines as well as aryl, heteroaryl and aliphatic amines, were em-ployed (Scheme 8).


Catalysts 2021, 11, 918 7 of 35

The same research group has also reported a novel synthetic method of carbamoylac-etates from α-iodoacetate, carbon monoxide and amines under 15 W black light conditionsin the presence of PdCl2(PPh3)2 as the catalyst [36]. The methodology was restrictedto the use of α-iodo ethyl acetate, while a wide variety of amines, including primaryand secondary amines as well as aryl, heteroaryl and aliphatic amines, were employed(Scheme 8).


standard conditions, while aryl, as well as alkyl fragments, can be efficiently employed in the alkyne partner. Once again, this methodology, which starts from a variety of alkyl iodides, is complementary to the transition metal-catalyzed coupling reactions, which are mainly restricted to the use of aryl and vinyl halides [31].

Later, Ryu and co-workers reported versatile four-component coupling reactions leading to functionalized esters using α-substituted iodoalkanes, alkenes, CO and alco-hols under photoirradiation conditions (500 W xenon lamp), 45 atm of CO pressure in the presence of PdCl2(PPh3)2 (5 mol %) as catalyst (Scheme 7a) [35]. Several electron-with-drawing groups were tolerated (EWG = COOR, CN, PhSO2) on the iodoalkane coupling partner, and both terminal and internal alkenes gave satisfactory results. When alkenyl alcohols were employed in place of alkene/ROH mixture, lactone derivatives were ob-tained via intramolecular esterification (Scheme 7b).


The same research group has also reported a novel synthetic method of car-bamoylacetates from α-iodoacetate, carbon monoxide and amines under 15 W black light conditions in the presence of PdCl2(PPh3)2 as the catalyst [36]. The methodology was re-stricted to the use of α-iodo ethyl acetate, while a wide variety of amines, including pri-mary and secondary amines as well as aryl, heteroaryl and aliphatic amines, were em-ployed (Scheme 8).

Scheme 8. Palladium-catalyzed/light-induced synthesis of carbamoyl acetates.

A mechanism based on the combined action of radical species and organometallicintermediates was proposed (Scheme 9). The acetate radical I is initially formed throughthe cleavage of the C–I bond, which can be promoted by single-electron transfer fromthe photo-excited Pd complex. The subsequent coupling between I and Pd(I)I leads toan α-pallado ester II, which undergoes aminocarbonylation to carbamoyl esters with theregeneration of Pd(0) (Scheme 9).


Scheme 8. Palladium-catalyzed/light-induced synthesis of carbamoyl acetates.

A mechanism based on the combined action of radical species and organometallic intermediates was proposed (Scheme 9). The acetate radical I is initially formed through the cleavage of the C–I bond, which can be promoted by single-electron transfer from the photo-excited Pd complex. The subsequent coupling between I and Pd(I)I leads to an α-pallado ester II, which undergoes aminocarbonylation to carbamoyl esters with the re-generation of Pd(0) (Scheme 9).

Scheme 9. A plausible reaction mechanism.

Inspired by the work of Suzuki and Miyaura [24,26], the same research group re-ported a PdCl2(PPh3)2-catalyzed light-promoted synthesis of alkyl aryl ketones via car-bonylative cross-coupling reaction of alkyl iodides, CO and arylboronic acids.[37] Basic conditions (K2CO3), 45 atm of CO and the presence of water were essential for the success of the reaction (Scheme 10). Primary, secondary and tertiary alkyl iodides were success-fully coupled with CO and a series of substituted arylboronic acids, bearing both electron-withdrawing and electron-donating groups. The mechanism can likely pass through the formation of an acylpalladium complex via carbonylation of the alkyl radical I, which is generated by the action of Pd(0) and light from the alkyl iodide (Scheme 11). The transmetalation of an arylboronic acid with the acylpalladium intermediate III leads to the corresponding acyl(aryl)palladium species, which undergoes reductive elimination to the desired alkyl aryl ketone and Pd(0) (Scheme 11).

Scheme 9. A plausible reaction mechanism.

Catalysts 2021, 11, 918 8 of 35

Inspired by the work of Suzuki and Miyaura [24,26], the same research group reporteda PdCl2(PPh3)2-catalyzed light-promoted synthesis of alkyl aryl ketones via carbonylativecross-coupling reaction of alkyl iodides, CO and arylboronic acids [37]. Basic conditions(K2CO3), 45 atm of CO and the presence of water were essential for the success of thereaction (Scheme 10). Primary, secondary and tertiary alkyl iodides were successfullycoupled with CO and a series of substituted arylboronic acids, bearing both electron-withdrawing and electron-donating groups. The mechanism can likely pass through theformation of an acylpalladium complex via carbonylation of the alkyl radical I, whichis generated by the action of Pd(0) and light from the alkyl iodide (Scheme 11). Thetransmetalation of an arylboronic acid with the acylpalladium intermediate III leads to thecorresponding acyl(aryl)palladium species, which undergoes reductive elimination to thedesired alkyl aryl ketone and Pd(0) (Scheme 11).


Scheme 10. The synthesis of alky aryl ketones via a Pd-catalyzed/light-induced three-component cross-coupling reaction.

Scheme 11. The proposed reaction pathway.

Impressively, this protocol was also applied to the four-component coupling reaction between ethyl iodoacetate, 1-octene, CO and phenylboronic acid to give the correspond-ing functionalized ketone derivative in 62% yield under the standard optimized condi-tions (Scheme 12a). The analogous cyclizative double-carbonylation reaction, where 5-iodo-1-pentene replace the couple iodo alkyl/alkene, took place, leading to the aryl ketone with a cyclopentanone moiety, in 57% yield (Scheme 12b).

Scheme 10. The synthesis of alky aryl ketones via a Pd-catalyzed/light-induced three-componentcross-coupling reaction.






Catalysts 2021, 11, 918 9 of 35

Impressively, this protocol was also applied to the four-component coupling reactionbetween ethyl iodoacetate, 1-octene, CO and phenylboronic acid to give the correspondingfunctionalized ketone derivative in 62% yield under the standard optimized conditions(Scheme 12a). The analogous cyclizative double-carbonylation reaction, where 5-iodo-1-pentene replace the couple iodo alkyl/alkene, took place, leading to the aryl ketone with acyclopentanone moiety, in 57% yield (Scheme 12b).





Scheme 12. The synthesis of diketones via Pd-catalyzed/light-induced cross-coupling reactions.

More recently, a similar approach was employed to synthesize aromatic β-keto estersfrom α-iodoesters, CO and arylboronic acids under lower CO pressures (10 atm) [38].Taking advantage of this strategy, Li and co-workers developed a protocol to synthesizearyl ketones from aryl iodides and aryl boronic acids by carbonylative Suzuki–Miyauracoupling using DMF as CO surrogate. In this case, TiO2 was found essential in the in situgeneration of CO from DMF and also in the reduction of Pd(II) to Pd(0) species, as it wasable to start the catalytic cycle [39].

A carbonylative Mizoroki–Heck reaction was also developed under palladium cataly-sis and photo-induced conditions [40]. The reaction of alkyl iodides, CO and aryl alkenesleading to α,β-unsaturated ketones was carried out in the presence of Pd(PPh3)4 as acatalyst and DBU as a base under irradiation of a xenon lamp (500 W) (Scheme 13).



More recently, a similar approach was employed to synthesize aromatic β-keto esters from α-iodoesters, CO and arylboronic acids under lower CO pressures (10 atm) [38]. Tak-ing advantage of this strategy, Li and co-workers developed a protocol to synthesize aryl ketones from aryl iodides and aryl boronic acids by carbonylative Suzuki–Miyaura cou-pling using DMF as CO surrogate. In this case, TiO2 was found essential in the in situ generation of CO from DMF and also in the reduction of Pd(II) to Pd(0) species, as it was able to start the catalytic cycle [39].

A carbonylative Mizoroki–Heck reaction was also developed under palladium catal-ysis and photo-induced conditions [40]. The reaction of alkyl iodides, CO and aryl alkenes leading to α,β-unsaturated ketones was carried out in the presence of Pd(PPh3)4 as a cata-lyst and DBU as a base under irradiation of a xenon lamp (500 W) (Scheme 13).

Scheme 13. The synthesis of ketones via the Pd-catalyzed/light-induced carbonylative Mizoroki–Heck reaction.

In this approach, alkyl radicals (I) were formed from alkyl iodides via single-electron transfer (SET) and underwent a sequential addition to CO and alkenes to give β-keto rad-icals (III). It is proposed that DBU would abstract a proton in α to the carbonyl to form radical anions (IV), giving α,β-unsaturated ketones via SET (Scheme 14).


Recently, Odell and co-workers have developed a Pd(PPh3)4-catalyzed carbonylative Suzuki–Miyaura coupling of unactivated alkyl halides with aryl boronic acids by means


Catalysts 2021, 11, 918 10 of 35

In this approach, alkyl radicals (I) were formed from alkyl iodides via single-electrontransfer (SET) and underwent a sequential addition to CO and alkenes to give β-ketoradicals (III). It is proposed that DBU would abstract a proton in α to the carbonyl to formradical anions (IV), giving α,β-unsaturated ketones via SET (Scheme 14).



More recently, a similar approach was employed to synthesize aromatic β-keto esters from α-iodoesters, CO and arylboronic acids under lower CO pressures (10 atm) [38]. Tak-ing advantage of this strategy, Li and co-workers developed a protocol to synthesize aryl ketones from aryl iodides and aryl boronic acids by carbonylative Suzuki–Miyaura cou-pling using DMF as CO surrogate. In this case, TiO2 was found essential in the in situ generation of CO from DMF and also in the reduction of Pd(II) to Pd(0) species, as it was able to start the catalytic cycle [39].

A carbonylative Mizoroki–Heck reaction was also developed under palladium catal-ysis and photo-induced conditions [40]. The reaction of alkyl iodides, CO and aryl alkenes leading to α,β-unsaturated ketones was carried out in the presence of Pd(PPh3)4 as a cata-lyst and DBU as a base under irradiation of a xenon lamp (500 W) (Scheme 13).


In this approach, alkyl radicals (I) were formed from alkyl iodides via single-electron transfer (SET) and underwent a sequential addition to CO and alkenes to give β-keto rad-icals (III). It is proposed that DBU would abstract a proton in α to the carbonyl to form radical anions (IV), giving α,β-unsaturated ketones via SET (Scheme 14).


Recently, Odell and co-workers have developed a Pd(PPh3)4-catalyzed carbonylative Suzuki–Miyaura coupling of unactivated alkyl halides with aryl boronic acids by means


Recently, Odell and co-workers have developed a Pd(PPh3)4-catalyzed carbonylativeSuzuki–Miyaura coupling of unactivated alkyl halides with aryl boronic acids by meansof visible-light irradiation with low CO pressure (2–3 atm) at room temperature for thesynthesis of aryl alkyl ketones [41]. This methodology features the use of solid CO-sourceinstead of gaseous CO, readily available LED lights and a double-chamber system, onefor the CO generation and the other for the palladium-catalyzed reaction (Scheme 15).Under the optimized conditions, various alkyl iodides and bromides reacted with CO anddifferently substituted aryl boronic acids to provide the desired ketones with moderate togood yields. The same protocol was successfully applied for the synthesis of a precursor ofmelperone, an antipsychotic drug.


of visible-light irradiation with low CO pressure (2–3 atm) at room temperature for the synthesis of aryl alkyl ketones [41]. This methodology features the use of solid CO-source instead of gaseous CO, readily available LED lights and a double-chamber system, one for the CO generation and the other for the palladium-catalyzed reaction (Scheme 15). Under the optimized conditions, various alkyl iodides and bromides reacted with CO and differently substituted aryl boronic acids to provide the desired ketones with moderate to good yields. The same protocol was successfully applied for the synthesis of a precursor of melperone, an antipsychotic drug.

Scheme 15. The synthesis of alkyl aryl ketones via the Pd-catalyzed/light-induced carbonylative Suzuki–Miyaura coupling.

Based on control experiments, the authors verified the crucial role of the visible light as well as of the palladium catalyst. Moreover, the addition of TEMPO completely pre-vented the product formation while, at the same time, the R-TEMPO adduct was detected.

A recent report by Arndtsen’s group has brought a breakthrough in the area of pal-ladium-catalyzed carbonylation reactions. A new palladium-catalyzed/light-induced methodology for the synthesis of a broad array of carbonylated compounds (acid chlo-rides, esters, amides and ketones) starting from aryl/alkyl iodides and bromides has been reported (Scheme 16) [42]. Compared to previous protocols, this method features high versatility, high functional group tolerance, an impressive reaction scope and mild reac-tion conditions. In particular, this protocol is compatible with aldehydes, protected amines, esters, nitriles, thioethers and heterocyclic substrates on aryl iodides and bro-mides. The synthesis of β-amino acid derivatives was achieved with high efficiency. In addition, electron-rich arenes and heteroarenes were successfully employed in place of nitrogen or oxygen nucleophiles. The importance of palladium catalyst and visible light in this radical reaction has been consistently demonstrated, and, in particular, mechanistic studies revealed that light acts as two different roles in this transformation, enabling, to-gether with the palladium catalytic system, both the oxidative addition and reductive elimination steps.

Scheme 15. The synthesis of alkyl aryl ketones via the Pd-catalyzed/light-induced carbonylativeSuzuki–Miyaura coupling.

Catalysts 2021, 11, 918 11 of 35

Based on control experiments, the authors verified the crucial role of the visible light aswell as of the palladium catalyst. Moreover, the addition of TEMPO completely preventedthe product formation while, at the same time, the R-TEMPO adduct was detected.

A recent report by Arndtsen’s group has brought a breakthrough in the area ofpalladium-catalyzed carbonylation reactions. A new palladium-catalyzed/light-inducedmethodology for the synthesis of a broad array of carbonylated compounds (acid chlo-rides, esters, amides and ketones) starting from aryl/alkyl iodides and bromides hasbeen reported (Scheme 16) [42]. Compared to previous protocols, this method featureshigh versatility, high functional group tolerance, an impressive reaction scope and mildreaction conditions. In particular, this protocol is compatible with aldehydes, protectedamines, esters, nitriles, thioethers and heterocyclic substrates on aryl iodides and bro-mides. The synthesis of β-amino acid derivatives was achieved with high efficiency. Inaddition, electron-rich arenes and heteroarenes were successfully employed in place ofnitrogen or oxygen nucleophiles. The importance of palladium catalyst and visible lightin this radical reaction has been consistently demonstrated, and, in particular, mechanis-tic studies revealed that light acts as two different roles in this transformation, enabling,together with the palladium catalytic system, both the oxidative addition and reductiveelimination steps.


Scheme 16. The general synthesis of carbonylated compounds via the palladium-catalyzed/light-induced carbonylative approach.

Recently, the palladium-catalyzed aminocarbonylation of aliphatic and aromatic io-dides under visible-light irradiation has been reported by Sardana and co-workers [43]. The methodology, based on the employment of COgen (9-methyl-9H-fluorene-9-carbonyl chloride, 1 equiv) in a two-chamber system, can be extended to the synthesis of [14C]-am-ides starting from the corresponding 14Cogen. Despite the moderate yields, tertiary am-ides and C-14-labeled pharmaceutical products were successfully accessed.

Oxalamides represent a class of relevant compounds frequently found in bioactive and pharmaceutical molecules [44] and used as a ligand in asymmetric catalysis [45]. Wu and co-workers have recently developed a novel, highly sustainable visible-light-induced palladium-catalyzed method for the synthesis of oxalamides from amines and carbon monoxide [46]. The versatile and green methodology relies on the use of visible light in combination with palladium/BINAP catalysts (Scheme 17) without any oxidant or base. In addition, the protocol features high selectivity (no urea byproducts were detected) and the possibility to reuse the Pd complex without loss of efficiency. Notably, in some cases, the presence of methylene blue as photosensitizer led to a significant improvement in the yield.

Scheme 16. The general synthesis of carbonylated compounds via the palladium-catalyzed/light-induced carbonylative approach.

Recently, the palladium-catalyzed aminocarbonylation of aliphatic and aromatic io-dides under visible-light irradiation has been reported by Sardana and co-workers [43].The methodology, based on the employment of COgen (9-methyl-9H-fluorene-9-carbonylchloride, 1 equiv) in a two-chamber system, can be extended to the synthesis of [14C]-amides starting from the corresponding 14Cogen. Despite the moderate yields, tertiaryamides and C-14-labeled pharmaceutical products were successfully accessed.

Oxalamides represent a class of relevant compounds frequently found in bioactiveand pharmaceutical molecules [44] and used as a ligand in asymmetric catalysis [45]. Wuand co-workers have recently developed a novel, highly sustainable visible-light-induced

Catalysts 2021, 11, 918 12 of 35

palladium-catalyzed method for the synthesis of oxalamides from amines and carbonmonoxide [46]. The versatile and green methodology relies on the use of visible light incombination with palladium/BINAP catalysts (Scheme 17) without any oxidant or base. Inaddition, the protocol features high selectivity (no urea byproducts were detected) and thepossibility to reuse the Pd complex without loss of efficiency. Notably, in some cases, thepresence of methylene blue as photosensitizer led to a significant improvement in the yield.


Scheme 17. The general photocatalytic synthesis of oxalamides via the palladium-catalyzed dehy-drogenative carbonylation of amines.

Based on control and EPR experiments, the authors propose that the active L2Pd(0)* species I is first generated in situ from L2Pd(II)Cl2 in the presence of the amine under vis-ible-light irradiation (Scheme 18). Then, after a SET process with the amine, a nitrogen-radical and a Pd(I)-radical species II are generated. The reaction of CO with the nitrogen radical leads to an acyl radical, which recombines with II delivering intermediate III. The latter undergoes a ligand exchange to provide complex IV and molecular hydrogen, which was detected by gas GC. The insertion of another CO molecule provides a bis(car-bamoyl)palladium intermediate V, which undergoes a reductive elimination step to give the expected oxamide and a Pd(0) species.

Scheme 18. The proposed reaction mechanism.

In 2016, Lei et al. disclosed a new intramolecular oxidative carbonylation of enamides as a mild and environmentally friendly protocol for the synthesis of 1,3-oxazin-6-ones. Oxygen was employed as a terminal oxidant, avoiding the need for stoichiometric amounts of metal salts, such as Cu(II) salts [47]. The success of the strategy relies on the combination of palladium and photoredox catalysis and, in particular, Pd(OAc)2 and Ru(bpy)3Cl2 were both used in catalytic amounts together with Xantphos as phosphine


Based on control and EPR experiments, the authors propose that the active L2Pd(0)*species I is first generated in situ from L2Pd(II)Cl2 in the presence of the amine undervisible-light irradiation (Scheme 18). Then, after a SET process with the amine, a nitrogen-radical and a Pd(I)-radical species II are generated. The reaction of CO with the nitrogenradical leads to an acyl radical, which recombines with II delivering intermediate III.The latter undergoes a ligand exchange to provide complex IV and molecular hydro-gen, which was detected by gas GC. The insertion of another CO molecule provides abis(carbamoyl)palladium intermediate V, which undergoes a reductive elimination step togive the expected oxamide and a Pd(0) species.



Based on control and EPR experiments, the authors propose that the active L2Pd(0)* species I is first generated in situ from L2Pd(II)Cl2 in the presence of the amine under vis-ible-light irradiation (Scheme 18). Then, after a SET process with the amine, a nitrogen-radical and a Pd(I)-radical species II are generated. The reaction of CO with the nitrogen radical leads to an acyl radical, which recombines with II delivering intermediate III. The latter undergoes a ligand exchange to provide complex IV and molecular hydrogen, which was detected by gas GC. The insertion of another CO molecule provides a bis(car-bamoyl)palladium intermediate V, which undergoes a reductive elimination step to give the expected oxamide and a Pd(0) species.


In 2016, Lei et al. disclosed a new intramolecular oxidative carbonylation of enamides as a mild and environmentally friendly protocol for the synthesis of 1,3-oxazin-6-ones. Oxygen was employed as a terminal oxidant, avoiding the need for stoichiometric amounts of metal salts, such as Cu(II) salts [47]. The success of the strategy relies on the combination of palladium and photoredox catalysis and, in particular, Pd(OAc)2 and Ru(bpy)3Cl2 were both used in catalytic amounts together with Xantphos as phosphine


Catalysts 2021, 11, 918 13 of 35

In 2016, Lei et al. disclosed a new intramolecular oxidative carbonylation of enamidesas a mild and environmentally friendly protocol for the synthesis of 1,3-oxazin-6-ones.Oxygen was employed as a terminal oxidant, avoiding the need for stoichiometric amountsof metal salts, such as Cu(II) salts [47]. The success of the strategy relies on the combinationof palladium and photoredox catalysis and, in particular, Pd(OAc)2 and Ru(bpy)3Cl2 wereboth used in catalytic amounts together with Xantphos as phosphine ligand (Scheme 19).The generality of the reaction was demonstrated as both electron-withdrawing and electron-donating groups, including heteroaromatic rings (furan and thiophene), were well toleratedunder the optimized conditions. The authors suggest that the photocatalyst is exclusivelyinvolved in the reoxidation of palladium, as described in Scheme 20. Firstly, taking advan-tage of the amide group, a Pd catalyzed alkenyl C–H activation affords a vinylpalladiumcomplex I. Then, a molecule of CO coordinates and inserts, leading to the acylpalladiumintermediate II. Subsequently, DABCO enables the formation of complex III, and, finally, areductive elimination step delivers the oxazinone product and Pd(0) species. Re-oxidationof palladium(0) can be exerted by the excited Ru(II)* leading to Pd(II)L, which restart a newcatalytic cycle, and Ru(I), which, in its turn, can be oxidized back to Ru(II) by molecularoxygen. The generated superoxide anion may also oxidize the Pd(0) species by electrontransfer. The presence of KI was found to improve the efficiency of this transformation,likely through coordination of palladium(II) species, while Ac2O was suggested to reducethe possible formation of inactive palladium(0) species under the CO atmosphere.


ligand (Scheme 19). The generality of the reaction was demonstrated as both electron-withdrawing and electron-donating groups, including heteroaromatic rings (furan and thiophene), were well tolerated under the optimized conditions. The authors suggest that the photocatalyst is exclusively involved in the reoxidation of palladium, as described in Scheme 20. Firstly, taking advantage of the amide group, a Pd catalyzed alkenyl C–H ac-tivation affords a vinylpalladium complex I. Then, a molecule of CO coordinates and in-serts, leading to the acylpalladium intermediate II. Subsequently, DABCO enables the for-mation of complex III, and, finally, a reductive elimination step delivers the oxazinone product and Pd(0) species. Re-oxidation of palladium(0) can be exerted by the excited Ru(II)* leading to Pd(II)L, which restart a new catalytic cycle, and Ru(I), which, in its turn, can be oxidized back to Ru(II) by molecular oxygen. The generated superoxide anion may also oxidize the Pd(0) species by electron transfer. The presence of KI was found to im-prove the efficiency of this transformation, likely through coordination of palladium(II) species, while Ac2O was suggested to reduce the possible formation of inactive palla-dium(0) species under the CO atmosphere.

Scheme 19. Visible-light-promoted Pd/Ru-catalyzed intramolecular oxidative carbonylation of en-amides to 1,3-oxazin-6-ones.

Scheme 19. Visible-light-promoted Pd/Ru-catalyzed intramolecular oxidative carbonylation ofenamides to 1,3-oxazin-6-ones.

Catalysts 2021, 11, 918 14 of 35Catalysts 2021, 11, x FOR PEER REVIEW 14 of 34


1.2. Visible-Light-Promoted Iridium-Catalyzed Carbonylations Amides are ubiquitous in both natural and synthetic compounds, including pharma-

ceutical products. Odell and co-workers have recently developed a visible light-mediated fac-Ir(ppy)3 catalyzed amino carbonylation of unactivated alkyl iodides under mild reac-tion conditions [48]. The desired amides are produced in moderate to excellent yields through a two-chamber system (H-tube), where the CO is released ex situ from Mo(CO)6) (Scheme 21). Secondary and tertiary iodides can be successfully aminocarbonylated with a wide range of amine nucleophiles, whereas primary iodides provide satisfactory results in combination with hindered amines only. Remarkably, a dealkylative-aminocarbonyla-tion pathway occurs when alkyl halides react with tertiary amines. The reaction mecha-nism starts with the reductive dehalogenation of an alkyl halide (R–X) to give the alkyl radical I, followed by CO insertion with the formation of an acyl radical intermediate II. The latter is either quenched by the starting alkyl iodide to produce an acyl iodide III or oxidized to an acylium ion IV. The nucleophilic attack of the amine on the acyl iodide or the acylium ion affords the final amide (Scheme 22).


1.2. Visible-Light-Promoted Iridium-Catalyzed Carbonylations

Amides are ubiquitous in both natural and synthetic compounds, including pharma-ceutical products. Odell and co-workers have recently developed a visible light-mediatedfac-Ir(ppy)3 catalyzed amino carbonylation of unactivated alkyl iodides under mild re-action conditions [48]. The desired amides are produced in moderate to excellent yieldsthrough a two-chamber system (H-tube), where the CO is released ex situ from Mo(CO)6)(Scheme 21). Secondary and tertiary iodides can be successfully aminocarbonylated with awide range of amine nucleophiles, whereas primary iodides provide satisfactory results incombination with hindered amines only. Remarkably, a dealkylative-aminocarbonylationpathway occurs when alkyl halides react with tertiary amines. The reaction mechanismstarts with the reductive dehalogenation of an alkyl halide (R–X) to give the alkyl radical I,followed by CO insertion with the formation of an acyl radical intermediate II. The latter iseither quenched by the starting alkyl iodide to produce an acyl iodide III or oxidized to anacylium ion IV. The nucleophilic attack of the amine on the acyl iodide or the acylium ionaffords the final amide (Scheme 22).

A variety of acetate-containing 2,3-dihydrobenzofurans have been synthesized byPolyzos et al. through a visible light-mediated Ir-catalyzed radical carbonylation pro-cess under continuous flow conditions [49]. Overcoming the traditional limitations ofboth Pd-catalyzed alkoxycarbonylation reactions and classical radical-free carbonyla-tion processes in terms of regioselectivity, the pressure of CO and sustainability [50],alkenyl-tethered arenediazonium salts underwent a versatile and stereoselective (exclu-sive 5-exo-dig cyclization) cyclization and alkoxycarbonylation cascade to a wide rangeof 2,3-dihydrobenzofuran derivatives in the presence of [Ir(dtbbpy)(ppy)2]PF6 as cata-lyst under blue LEDs (14 W) at room temperature (Scheme 23). Electron-donating andelectron-withdrawing substituents on the arenediazonium salt moiety were nicely toleratedunder the standard conditions. Regardless of steric bulk, alkyl alcohols were successfullyemployed as coupling partners to produce the desired esters in moderate to good yields.This continuous flow methodology also features a very short reaction time (200 s), moder-

Catalysts 2021, 11, 918 15 of 35

ate CO pressures (25 atm) and a straightforward scale-up. Interestingly, the commercialRu(bpy)3Cl2·6H2O was found to be slightly less efficient in this transformation.


R1 I HNR2R3

Chamber 1: Ir(ppy)3,TBA, Hantzsch ester

Blue LEDs, r.t.

Chamber 2:Mo(CO)6, DBU, 70 °C

R1

O

NR3

R2

O

NO

N

62%72%

2016 Odell

- 1–2 atm of ex situ generated CO- Secondary and primary alkyl iodides

- hv: blue LEDsFeatures:

- mild reaction conditions

R1 = secondary and tertiary alkyl groups,primary (limited to hindered amines)

11 -HSD1 inhibitor

up to 90%

Selected examples:

O

N

67%

O

NBu

Bu48% (from TBA)

33 examples

Scheme 21. Visible light-mediated fac-Ir(ppy)3-catalyzed aminocarbonylation of alkyl iodides.


A variety of acetate-containing 2,3-dihydrobenzofurans have been synthesized by Polyzos et al. through a visible light-mediated Ir-catalyzed radical carbonylation process under continuous flow conditions [49]. Overcoming the traditional limitations of both Pd-catalyzed alkoxycarbonylation reactions and classical radical-free carbonylation processes in terms of regioselectivity, the pressure of CO and sustainability [50], alkenyl-tethered arenediazonium salts underwent a versatile and stereoselective (exclusive 5-exo-dig cy-clization) cyclization and alkoxycarbonylation cascade to a wide range of 2,3-dihydroben-zofuran derivatives in the presence of [Ir(dtbbpy)(ppy)2]PF6 as catalyst under blue LEDs (14 W) at room temperature (Scheme 23). Electron-donating and electron-withdrawing substituents on the arenediazonium salt moiety were nicely tolerated under the standard conditions. Regardless of steric bulk, alkyl alcohols were successfully employed as cou-pling partners to produce the desired esters in moderate to good yields. This continuous flow methodology also features a very short reaction time (200 s), moderate CO pressures (25 atm) and a straightforward scale-up. Interestingly, the commercial Ru(bpy)3Cl2·6H2O was found to be slightly less efficient in this transformation.



R1 I HNR2R3

Chamber 1: Ir(ppy)3,TBA, Hantzsch ester

Blue LEDs, r.t.

Chamber 2:Mo(CO)6, DBU, 70 °C

R1

O

NR3

R2

O

NO

N

62%72%

2016 Odell

- 1–2 atm of ex situ generated CO- Secondary and primary alkyl iodides

- hv: blue LEDsFeatures:

- mild reaction conditions

R1 = secondary and tertiary alkyl groups,primary (limited to hindered amines)

11 -HSD1 inhibitor

up to 90%

Selected examples:

O

N

67%

O

NBu

Bu48% (from TBA)

33 examples



A variety of acetate-containing 2,3-dihydrobenzofurans have been synthesized by Polyzos et al. through a visible light-mediated Ir-catalyzed radical carbonylation process under continuous flow conditions [49]. Overcoming the traditional limitations of both Pd-catalyzed alkoxycarbonylation reactions and classical radical-free carbonylation processes in terms of regioselectivity, the pressure of CO and sustainability [50], alkenyl-tethered arenediazonium salts underwent a versatile and stereoselective (exclusive 5-exo-dig cy-clization) cyclization and alkoxycarbonylation cascade to a wide range of 2,3-dihydroben-zofuran derivatives in the presence of [Ir(dtbbpy)(ppy)2]PF6 as catalyst under blue LEDs (14 W) at room temperature (Scheme 23). Electron-donating and electron-withdrawing substituents on the arenediazonium salt moiety were nicely tolerated under the standard conditions. Regardless of steric bulk, alkyl alcohols were successfully employed as cou-pling partners to produce the desired esters in moderate to good yields. This continuous flow methodology also features a very short reaction time (200 s), moderate CO pressures (25 atm) and a straightforward scale-up. Interestingly, the commercial Ru(bpy)3Cl2·6H2O was found to be slightly less efficient in this transformation.



Scheme 23. Visible light-mediated [Ir(dtbbpy)(ppy)2]PF6-catalyzed cyclizative alkoxycarbonylation of alkenyl-tethered arenediazonium salts under continuous flow conditions.

The mechanism is supposed to start with the homolytic cleavage of the C–N bond of the allyloxy-tethered arenediazonium salt by single-electron transfer from the photocata-lyst in its excited state (PC*), with the generation of an aryl radical I and the oxidized photocatalyst PC•+ (Scheme 24). An intramolecular radical alkene addition provides the primary alkyl radical II, which, after CO insertion, gives the acyl radical III. Oxidation of the acyl radical by the oxidized photocatalyst PC•+ results in the formation of an acylium ion IV and the regeneration of the photocatalyst PC. Lastly, the reaction of IV with alcohol leads to the final product.

Scheme 24. A plausible reaction pathway.

In 2020, Polyzos and co-workers reported an Ir-catalyzed visible-light-promoted ami-nocarbonylation of alkyl and aryl halides with CO and amines under continuous flow conditions (Scheme 25) [51]. The iridium-based photocatalyst ([Ir(ppy)2(dtbbpy)]PF6) was used in combination with DIPEA (N,N-diisopropylethylamine) as a sacrificial reductant and under blue LED (54 W) irradiation. A large variety of aryl halides (I, Br, Cl) and alkyl

Scheme 23. Visible light-mediated [Ir(dtbbpy)(ppy)2]PF6-catalyzed cyclizative alkoxycarbonylationof alkenyl-tethered arenediazonium salts under continuous flow conditions.

The mechanism is supposed to start with the homolytic cleavage of the C–N bondof the allyloxy-tethered arenediazonium salt by single-electron transfer from the photo-catalyst in its excited state (PC*), with the generation of an aryl radical I and the oxidizedphotocatalyst PC•+ (Scheme 24). An intramolecular radical alkene addition provides theprimary alkyl radical II, which, after CO insertion, gives the acyl radical III. Oxidation ofthe acyl radical by the oxidized photocatalyst PC•+ results in the formation of an acyliumion IV and the regeneration of the photocatalyst PC. Lastly, the reaction of IV with alcoholleads to the final product.


Scheme 23. Visible light-mediated [Ir(dtbbpy)(ppy)2]PF6-catalyzed cyclizative alkoxycarbonylation of alkenyl-tethered arenediazonium salts under continuous flow conditions.

The mechanism is supposed to start with the homolytic cleavage of the C–N bond of the allyloxy-tethered arenediazonium salt by single-electron transfer from the photocata-lyst in its excited state (PC*), with the generation of an aryl radical I and the oxidized photocatalyst PC•+ (Scheme 24). An intramolecular radical alkene addition provides the primary alkyl radical II, which, after CO insertion, gives the acyl radical III. Oxidation of the acyl radical by the oxidized photocatalyst PC•+ results in the formation of an acylium ion IV and the regeneration of the photocatalyst PC. Lastly, the reaction of IV with alcohol leads to the final product.


In 2020, Polyzos and co-workers reported an Ir-catalyzed visible-light-promoted ami-nocarbonylation of alkyl and aryl halides with CO and amines under continuous flow conditions (Scheme 25) [51]. The iridium-based photocatalyst ([Ir(ppy)2(dtbbpy)]PF6) was used in combination with DIPEA (N,N-diisopropylethylamine) as a sacrificial reductant and under blue LED (54 W) irradiation. A large variety of aryl halides (I, Br, Cl) and alkyl


Catalysts 2021, 11, 918 17 of 35

In 2020, Polyzos and co-workers reported an Ir-catalyzed visible-light-promotedaminocarbonylation of alkyl and aryl halides with CO and amines under continuous flowconditions (Scheme 25) [51]. The iridium-based photocatalyst ([Ir(ppy)2(dtbbpy)]PF6) wasused in combination with DIPEA (N,N-diisopropylethylamine) as a sacrificial reductantand under blue LED (54 W) irradiation. A large variety of aryl halides (I, Br, Cl) and alkyliodides (primary, secondary and tertiary) reacted successfully with CO and an array of alkyland aryl amines to provide the expected amides in good to high yields. The continuous flowsystem was assembled from commercially available components, featuring operationalsimplicity, high applicability, improved safety and easy scalability.


iodides (primary, secondary and tertiary) reacted successfully with CO and an array of alkyl and aryl amines to provide the expected amides in good to high yields. The contin-uous flow system was assembled from commercially available components, featuring op-erational simplicity, high applicability, improved safety and easy scalability.

Scheme 25. Visible light-mediated [Ir(dtbbpy)(ppy)2]PF6-catalyzed aminocarbonylation of aryl and alkyl halides under continuous flow conditions.

Ynones represent an important motif present in bioactive compounds and are useful intermediates in the synthesis of heterocycles [52]. Alternative to the previously described Ryu’s method [34], Lu and Xiao et al. have recently developed an efficient protocol for the synthesis of ynones through a visible-light-induced photocatalytic decarboxylative car-bonylative alkynylation of carboxylic acids in the presence of carbon monoxide (CO) at room temperature [53]. The decarboxylative alkynylation reaction was carried out using ethynylbenziodoxolones (EBX) as the alkynylating agent, carboxylic acid, in the presence of Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst and Cs2CO3 as a base (Scheme 26). A range of aliphatic carboxylic acids gave the corresponding ynones in good to excellent yields under mild conditions but extremely high pressure of CO. Mechanistically, it is proposed that the excited photocatalyst Ir(III)*, generated from Ir(III) under visible-light irradiation, is able to oxidize the substrate with the formation of an alkyl radical I (Scheme 27). Then, the latter, after CO insertion, gives rise to an acyl radical II, which undergoes radical addition to the alkylating agent affording the radical intermediate III. The subse-quent radical elimination reaction yields the desired ynone and the benziodoxolonyl rad-ical IV. Finally, radical IV is reduced to ortho-iodobenzoate by Ir(II), which, in turn, is oxidized to Ir(III) for a new catalytic cycle.

Scheme 25. Visible light-mediated [Ir(dtbbpy)(ppy)2]PF6-catalyzed aminocarbonylation of aryl and alkyl halides undercontinuous flow conditions.

Ynones represent an important motif present in bioactive compounds and are usefulintermediates in the synthesis of heterocycles [52]. Alternative to the previously describedRyu’s method [34], Lu and Xiao et al. have recently developed an efficient protocol forthe synthesis of ynones through a visible-light-induced photocatalytic decarboxylativecarbonylative alkynylation of carboxylic acids in the presence of carbon monoxide (CO) atroom temperature [53]. The decarboxylative alkynylation reaction was carried out usingethynylbenziodoxolones (EBX) as the alkynylating agent, carboxylic acid, in the presence ofIr[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst and Cs2CO3 as a base (Scheme 26). A rangeof aliphatic carboxylic acids gave the corresponding ynones in good to excellent yieldsunder mild conditions but extremely high pressure of CO. Mechanistically, it is proposedthat the excited photocatalyst Ir(III)*, generated from Ir(III) under visible-light irradiation,is able to oxidize the substrate with the formation of an alkyl radical I (Scheme 27). Then,the latter, after CO insertion, gives rise to an acyl radical II, which undergoes radicaladdition to the alkylating agent affording the radical intermediate III. The subsequent

Catalysts 2021, 11, 918 18 of 35

radical elimination reaction yields the desired ynone and the benziodoxolonyl radical IV.Finally, radical IV is reduced to ortho-iodobenzoate by Ir(II), which, in turn, is oxidized toIr(III) for a new catalytic cycle.


Scheme 26. Visible light-promoted photo-catalyzed decarboxylative carbonylative alkynylation of carboxylic acids to ynones.


More recently, the same research group developed a visible-light-driven photocata-lyzed synthesis of α,β-unsaturated ketones starting from alkyl Katritzky salts as a source of radicals [54]. In the context of a more general reactivity, a limited number of alkyl Kat-ritzky salts reacted with 1,1-diphenylethylene in the presence of [Ir(4-Fppy)2(bpy)]PF6 and DABCO in MeCN under CO atmosphere and blue LEDs irradiation, leading to α,β-un-saturated ketones (Scheme 28). In the proposed reaction mechanism, the excited photo-catalyst Ir(III)* is supposed to reduced alkyl Katritzky salts through a SET process (Scheme 29). The generated radicals I inserts one molecule of CO with the formation of an acyl radical II, which reacts with 1,1-diphenylethylene yielding the radical species III. In-termediate III is then reduced by the photocatalyst Ir(IV) with the formation of the cati-onic intermediate IV, which, lastly, undergoes a DABCO-mediated deprotonation step to deliver the final ketone.

Scheme 26. Visible light-promoted photo-catalyzed decarboxylative carbonylative alkynylation of carboxylic acidsto ynones.


Scheme 26. Visible light-promoted photo-catalyzed decarboxylative carbonylative alkynylation of carboxylic acids to ynones.


More recently, the same research group developed a visible-light-driven photocata-lyzed synthesis of α,β-unsaturated ketones starting from alkyl Katritzky salts as a source of radicals [54]. In the context of a more general reactivity, a limited number of alkyl Kat-ritzky salts reacted with 1,1-diphenylethylene in the presence of [Ir(4-Fppy)2(bpy)]PF6 and DABCO in MeCN under CO atmosphere and blue LEDs irradiation, leading to α,β-un-saturated ketones (Scheme 28). In the proposed reaction mechanism, the excited photo-catalyst Ir(III)* is supposed to reduced alkyl Katritzky salts through a SET process (Scheme 29). The generated radicals I inserts one molecule of CO with the formation of an acyl radical II, which reacts with 1,1-diphenylethylene yielding the radical species III. In-termediate III is then reduced by the photocatalyst Ir(IV) with the formation of the cati-onic intermediate IV, which, lastly, undergoes a DABCO-mediated deprotonation step to deliver the final ketone.


More recently, the same research group developed a visible-light-driven photocat-alyzed synthesis of α,β-unsaturated ketones starting from alkyl Katritzky salts as a sourceof radicals [54]. In the context of a more general reactivity, a limited number of alkylKatritzky salts reacted with 1,1-diphenylethylene in the presence of [Ir(4-Fppy)2(bpy)]PF6and DABCO in MeCN under CO atmosphere and blue LEDs irradiation, leading to α,β-unsaturated ketones (Scheme 28). In the proposed reaction mechanism, the excited pho-tocatalyst Ir(III)* is supposed to reduced alkyl Katritzky salts through a SET process

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(Scheme 29). The generated radicals I inserts one molecule of CO with the formation ofan acyl radical II, which reacts with 1,1-diphenylethylene yielding the radical species III.Intermediate III is then reduced by the photocatalyst Ir(IV) with the formation of thecationic intermediate IV, which, lastly, undergoes a DABCO-mediated deprotonation stepto deliver the final ketone.


Scheme 28. Visible light-promoted Ir-catalyzed carbonylative alkyl-Heck-type reactions to α,β-un-saturated ketones.


1.3. Visible-Light-Promoted Cobalt-Catalyzed Carbonylations Cobalt salts have been found to efficiently catalyze the carbonylation of alkenes,

chloro and bromoalkanes under UV irradiation [55–59]. The first report on visible-light-mediated cobalt-catalyzed carbonylation reaction appeared in 2012, when Jia, Yin and col-leagues, based on their previous findings [60], developed a Co(OAc)2-catalyzed alkoxycar-bonylation of aryl bromides under visible-light irradiation and mild conditions (Scheme 30) [61]. The use of a strong base (NaOMe) and an organic sensitizer (PhCOPh) was es-sential to the reaction’s success. Aryl bromides with a chloro substituent behaved better than tolyl bromides; however, a selectivity higher than 99% was always observed.

Scheme 28. Visible light-promoted Ir-catalyzed carbonylative alkyl-Heck-type reactions to α,β-unsaturated ketones.


Scheme 28. Visible light-promoted Ir-catalyzed carbonylative alkyl-Heck-type reactions to α,β-un-saturated ketones.


1.3. Visible-Light-Promoted Cobalt-Catalyzed Carbonylations Cobalt salts have been found to efficiently catalyze the carbonylation of alkenes,

chloro and bromoalkanes under UV irradiation [55–59]. The first report on visible-light-mediated cobalt-catalyzed carbonylation reaction appeared in 2012, when Jia, Yin and col-leagues, based on their previous findings [60], developed a Co(OAc)2-catalyzed alkoxycar-bonylation of aryl bromides under visible-light irradiation and mild conditions (Scheme 30) [61]. The use of a strong base (NaOMe) and an organic sensitizer (PhCOPh) was es-sential to the reaction’s success. Aryl bromides with a chloro substituent behaved better than tolyl bromides; however, a selectivity higher than 99% was always observed.


1.3. Visible-Light-Promoted Cobalt-Catalyzed Carbonylations

Cobalt salts have been found to efficiently catalyze the carbonylation of alkenes, chloroand bromoalkanes under UV irradiation [55–59]. The first report on visible-light-mediatedcobalt-catalyzed carbonylation reaction appeared in 2012, when Jia, Yin and colleagues,based on their previous findings [60], developed a Co(OAc)2-catalyzed alkoxycarbonylationof aryl bromides under visible-light irradiation and mild conditions (Scheme 30) [61]. Theuse of a strong base (NaOMe) and an organic sensitizer (PhCOPh) was essential to thereaction’s success. Aryl bromides with a chloro substituent behaved better than tolylbromides; however, a selectivity higher than 99% was always observed.


Scheme 30. Visible-light-mediated cobalt-catalyzed alkoxycarbonylation of aryl bromides.

Recently, Alexanian et al. reported the visible-light-promoted aminocarbonylation of (hetero) aryl/vinyl bromides and chlorides using an inexpensive cobalt catalyst (Co2(CO)8) in conjunction with tetramethylpiperidine (TMP) (Scheme 31) [62].

Scheme 31. Visible-light-mediated cobalt-catalyzed aminocarbonylation of bromo and chloroaryls.

Aryl bromides having both electron-rich and electron-deficient groups, as well as vi-nyl bromides, were well tolerated. In addition, bromo heteroaryls, such as pyridines, fu-rans, quinolines and indoles, also performed nicely in this reaction. Aryl chlorides with electron-deficient groups gave the expected amides in satisfactory to good yields. A wide variety of primary and secondary aliphatic amines, including amino acids, gave the cor-responding amides in moderate to high yields. Preliminary mechanistic investigations were consistent with the first formation of a cobaltate anion [Co(CO)4]− (I) as an active catalyst and the subsequent generation of an electron donor–acceptor complex (EDA) II (Scheme 32). The intermediacy of the visible light leads to the corresponding excited spe-cies III. Then, a single-electron transfer produces two radical species (IV), which recom-bines, leading to a (hetero)aryl or vinyl cobalt species V. Finally, migratory insertion of


Recently, Alexanian et al. reported the visible-light-promoted aminocarbonylation of(hetero) aryl/vinyl bromides and chlorides using an inexpensive cobalt catalyst (Co2(CO)8)in conjunction with tetramethylpiperidine (TMP) (Scheme 31) [62].



Recently, Alexanian et al. reported the visible-light-promoted aminocarbonylation of (hetero) aryl/vinyl bromides and chlorides using an inexpensive cobalt catalyst (Co2(CO)8) in conjunction with tetramethylpiperidine (TMP) (Scheme 31) [62].


Aryl bromides having both electron-rich and electron-deficient groups, as well as vi-nyl bromides, were well tolerated. In addition, bromo heteroaryls, such as pyridines, fu-rans, quinolines and indoles, also performed nicely in this reaction. Aryl chlorides with electron-deficient groups gave the expected amides in satisfactory to good yields. A wide variety of primary and secondary aliphatic amines, including amino acids, gave the cor-responding amides in moderate to high yields. Preliminary mechanistic investigations were consistent with the first formation of a cobaltate anion [Co(CO)4]− (I) as an active catalyst and the subsequent generation of an electron donor–acceptor complex (EDA) II (Scheme 32). The intermediacy of the visible light leads to the corresponding excited spe-cies III. Then, a single-electron transfer produces two radical species (IV), which recom-bines, leading to a (hetero)aryl or vinyl cobalt species V. Finally, migratory insertion of


Aryl bromides having both electron-rich and electron-deficient groups, as well asvinyl bromides, were well tolerated. In addition, bromo heteroaryls, such as pyridines,furans, quinolines and indoles, also performed nicely in this reaction. Aryl chlorideswith electron-deficient groups gave the expected amides in satisfactory to good yields. Awide variety of primary and secondary aliphatic amines, including amino acids, gave thecorresponding amides in moderate to high yields. Preliminary mechanistic investigationswere consistent with the first formation of a cobaltate anion [Co(CO)4]− (I) as an activecatalyst and the subsequent generation of an electron donor–acceptor complex (EDA) II

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(Scheme 32). The intermediacy of the visible light leads to the corresponding excited speciesIII. Then, a single-electron transfer produces two radical species (IV), which recombines,leading to a (hetero)aryl or vinyl cobalt species V. Finally, migratory insertion of CO affordsintermediate VI, which undergoes displacement of the amine delivering the amide and theactive catalyst.


CO affords intermediate VI, which undergoes displacement of the amine delivering the amide and the active catalyst.


1.4. Visible-Light-Promoted Rutenium-Catalyzed Carbonylations Carboxylic acids are ubiquitous in a wide range of bioactive molecules and industri-

ally relevant compounds and represent a versatile, functional group in organic synthesis. Bousquet et al. have recently reported a ruthenium-catalyzed visible-light-promoted syn-thesis of benzoic acids starting from aryl diazonium salts, carbon monoxide (10–50 atm) and water under mild conditions (Scheme 33) [63]. The reaction displays a good functional group tolerance and generality. Notably, satisfactory results were achieved directly start-ing from anilines through the in situ generation of aryl diazonium salts, avoiding in this way their isolation. The proposed reaction pathway starts with the generation of an aryl radical (I) by SET with the excited Ru(II)* (Scheme 34). Next, the insertion of CO on the aryl radical gives rise to an acyl radical (II), which is oxidized by the Ru(III) species to an acylium ion III. The Ru(II) is regenerated, and the acylium ion reacts with water deliver-ing the desired carboxylic acid.

Scheme 33. The Ru-catalyzed synthesis of carboxylic acids via hydroxycarbonylation of aryl diazo-nium salts under irradiation conditions.


1.4. Visible-Light-Promoted Rutenium-Catalyzed Carbonylations

Carboxylic acids are ubiquitous in a wide range of bioactive molecules and industriallyrelevant compounds and represent a versatile, functional group in organic synthesis.Bousquet et al. have recently reported a ruthenium-catalyzed visible-light-promotedsynthesis of benzoic acids starting from aryl diazonium salts, carbon monoxide (10–50 atm)and water under mild conditions (Scheme 33) [63]. The reaction displays a good functionalgroup tolerance and generality. Notably, satisfactory results were achieved directly startingfrom anilines through the in situ generation of aryl diazonium salts, avoiding in this waytheir isolation. The proposed reaction pathway starts with the generation of an aryl radical(I) by SET with the excited Ru(II)* (Scheme 34). Next, the insertion of CO on the aryl radicalgives rise to an acyl radical (II), which is oxidized by the Ru(III) species to an acylium ionIII. The Ru(II) is regenerated, and the acylium ion reacts with water delivering the desiredcarboxylic acid.

Catalysts 2021, 11, 918 22 of 35


CO affords intermediate VI, which undergoes displacement of the amine delivering the amide and the active catalyst.


1.4. Visible-Light-Promoted Rutenium-Catalyzed Carbonylations Carboxylic acids are ubiquitous in a wide range of bioactive molecules and industri-

ally relevant compounds and represent a versatile, functional group in organic synthesis. Bousquet et al. have recently reported a ruthenium-catalyzed visible-light-promoted syn-thesis of benzoic acids starting from aryl diazonium salts, carbon monoxide (10–50 atm) and water under mild conditions (Scheme 33) [63]. The reaction displays a good functional group tolerance and generality. Notably, satisfactory results were achieved directly start-ing from anilines through the in situ generation of aryl diazonium salts, avoiding in this way their isolation. The proposed reaction pathway starts with the generation of an aryl radical (I) by SET with the excited Ru(II)* (Scheme 34). Next, the insertion of CO on the aryl radical gives rise to an acyl radical (II), which is oxidized by the Ru(III) species to an acylium ion III. The Ru(II) is regenerated, and the acylium ion reacts with water deliver-ing the desired carboxylic acid.

Scheme 33. The Ru-catalyzed synthesis of carboxylic acids via hydroxycarbonylation of aryl diazo-nium salts under irradiation conditions. Scheme 33. The Ru-catalyzed synthesis of carboxylic acids via hydroxycarbonylation of aryl diazo-nium salts under irradiation conditions.


Scheme 34. The proposed reaction mechanism for the hydroxycarbonylation reaction.

1.5. Visible-Light-Promoted Copper-Catalyzed Carbonylations To the best of our knowledge, the first and only example of copper-catalyzed pho-

toinduced carbonylation reaction has been recently reported by Chen and co-workers [64] and is aimed at the synthesis of cyano-tethered amides by aminocarbonylation of oxime esters with amines and CO under mild conditions (Scheme 35). A number of cycloketone oxime esters and alkyl/aryl amines were evaluated, and a high level of functional group tolerance was found. Larger than four-membered rings, such as cyclopentanone and cy-clohexanone oxime esters, did not lead to the expected products. For this aminocarbonyl-ation reaction, the authors proposed a visible light-mediated Cu(I)/Cu(II)/Cu(III)-based catalytic cycle (Scheme 36). The first step is a single-electron transfer between the photo-excited LnCu(I)–NHPh complex (II)* or, alternatively, the ground state LnCu(I)–NHPh species (I) and the oxime, leading to an iminyl radical III and the oxidized LnCu(II)–NHPh complex (IV). Then, III undergoes a selective β–C–C bond cleavage to form the alkyl rad-ical V, which can react with Cu(II)-complex IV producing a Cu(III) organometallic species VI. The latter, after sequential coordination and insertion of CO, leads to an acyl copper intermediate (VII or VIII), providing the final amide by reductive elimination and regen-erating the active Cu(I) catalyst.


1.5. Visible-Light-Promoted Copper-Catalyzed Carbonylations

To the best of our knowledge, the first and only example of copper-catalyzed photoin-duced carbonylation reaction has been recently reported by Chen and co-workers [64] andis aimed at the synthesis of cyano-tethered amides by aminocarbonylation of oxime esterswith amines and CO under mild conditions (Scheme 35). A number of cycloketone oximeesters and alkyl/aryl amines were evaluated, and a high level of functional group tolerancewas found. Larger than four-membered rings, such as cyclopentanone and cyclohexanoneoxime esters, did not lead to the expected products. For this aminocarbonylation reaction,the authors proposed a visible light-mediated Cu(I)/Cu(II)/Cu(III)-based catalytic cycle(Scheme 36). The first step is a single-electron transfer between the photoexcited LnCu(I)–NHPh complex (II)* or, alternatively, the ground state LnCu(I)–NHPh species (I) and theoxime, leading to an iminyl radical III and the oxidized LnCu(II)–NHPh complex (IV).Then, III undergoes a selective β–C–C bond cleavage to form the alkyl radical V, whichcan react with Cu(II)-complex IV producing a Cu(III) organometallic species VI. The latter,after sequential coordination and insertion of CO, leads to an acyl copper intermediate (VIIor VIII), providing the final amide by reductive elimination and regenerating the activeCu(I) catalyst.

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1.5. Visible-Light-Promoted Copper-Catalyzed Carbonylations To the best of our knowledge, the first and only example of copper-catalyzed pho-

toinduced carbonylation reaction has been recently reported by Chen and co-workers [64] and is aimed at the synthesis of cyano-tethered amides by aminocarbonylation of oxime esters with amines and CO under mild conditions (Scheme 35). A number of cycloketone oxime esters and alkyl/aryl amines were evaluated, and a high level of functional group tolerance was found. Larger than four-membered rings, such as cyclopentanone and cy-clohexanone oxime esters, did not lead to the expected products. For this aminocarbonyl-ation reaction, the authors proposed a visible light-mediated Cu(I)/Cu(II)/Cu(III)-based catalytic cycle (Scheme 36). The first step is a single-electron transfer between the photo-excited LnCu(I)–NHPh complex (II)* or, alternatively, the ground state LnCu(I)–NHPh species (I) and the oxime, leading to an iminyl radical III and the oxidized LnCu(II)–NHPh complex (IV). Then, III undergoes a selective β–C–C bond cleavage to form the alkyl rad-ical V, which can react with Cu(II)-complex IV producing a Cu(III) organometallic species VI. The latter, after sequential coordination and insertion of CO, leads to an acyl copper intermediate (VII or VIII), providing the final amide by reductive elimination and regen-erating the active Cu(I) catalyst.

Scheme 35. The Cu-catalyzed synthesis of amides via aminocarbonylation of oximes under visible-light irradiation.


Scheme 35. The Cu-catalyzed synthesis of amides via aminocarbonylation of oximes under visible-light irradiation.


1.6. Visible-Light-Promoted Metal-Free Carbonylations The major achievements in visible-light-mediated carbonylation reactions were ob-

tained under transition-metal catalysis. The requirement of transition-metal catalysts of-ten in connection with organic ligands is undoubtedly expensive, and the removal of their traces from the final products is necessary, particularly in the synthesis of pharmaceutical compounds. Metal-free photocatalytic protocols can overcome the above-mentioned drawbacks and may represent attractive greener and more sustainable alternatives.

In 1997, the efficient conversion of alkyl iodides to the corresponding esters was achieved under photoirradiation conditions in the absence of catalysts (Scheme 37) [29]. The presence of hydrogens in the β position on the alkyl iodides results in the formation of positional isomers via the β-elimination pathway under conventional transition metal-catalyzed carbonylation conditions [65]. This radical protocol allows the selective alkoxycarbonylation at the carbon attached to the halogen, and, for this reason, a wide range of aliphatic iodides, including tertiary ones, can be efficiently employed (Scheme 37, selected examples). High pressure of CO (from 20 to 55 atm) and the presence of an or-ganic (triethylamine) or inorganic base (K2CO3, KOH) were essential to the reaction out-come. Mechanistically, by irradiation, the homolytic cleavage of the C–I bond produces an alkyl radical species that reacts with the carbon monoxide, providing an acyl radical intermediate. In the presence of another molecule of alkyl iodide, an acyl iodide is then generated, and, after reaction with R2OH, the corresponding ester is produced (Scheme 37, proposed mechanism). Remarkably, the reaction can be extended to the synthesis of am-ides using amines in place of alcohols [28].


1.6. Visible-Light-Promoted Metal-Free Carbonylations

The major achievements in visible-light-mediated carbonylation reactions were ob-tained under transition-metal catalysis. The requirement of transition-metal catalysts oftenin connection with organic ligands is undoubtedly expensive, and the removal of theirtraces from the final products is necessary, particularly in the synthesis of pharmaceuti-cal compounds. Metal-free photocatalytic protocols can overcome the above-mentioneddrawbacks and may represent attractive greener and more sustainable alternatives.

In 1997, the efficient conversion of alkyl iodides to the corresponding esters wasachieved under photoirradiation conditions in the absence of catalysts (Scheme 37) [29].

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The presence of hydrogens in the β position on the alkyl iodides results in the forma-tion of positional isomers via the β-elimination pathway under conventional transitionmetal-catalyzed carbonylation conditions [65]. This radical protocol allows the selectivealkoxycarbonylation at the carbon attached to the halogen, and, for this reason, a widerange of aliphatic iodides, including tertiary ones, can be efficiently employed (Scheme 37,selected examples). High pressure of CO (from 20 to 55 atm) and the presence of an organic(triethylamine) or inorganic base (K2CO3, KOH) were essential to the reaction outcome.Mechanistically, by irradiation, the homolytic cleavage of the C–I bond produces an alkylradical species that reacts with the carbon monoxide, providing an acyl radical intermedi-ate. In the presence of another molecule of alkyl iodide, an acyl iodide is then generated,and, after reaction with R2OH, the corresponding ester is produced (Scheme 37, proposedmechanism). Remarkably, the reaction can be extended to the synthesis of amides usingamines in place of alcohols [28].


Scheme 37. The catalyst-free synthesis of esters via radical alkoxycarbonylation of alkyl iodides un-der irradiation conditions.

The first example of radical alkoxycarboxylation of aryldiazonium salts using CO gas through visible-light-induced photoredox catalysis has been reported in 2015 by the Xiao research group (Scheme 38) [66]. A wide variety of arylcarboxylic acid esters, bearing both electron-donating and electron-withdrawing groups, were obtained in good to excellent yields at room temperature. The generality of the alcohol coupling partner, including the use of chiral alcohols, was also demonstrated. Notably, terminal alkynes, which are known to be good acceptors in radical reactions, remained untouched. Sensitive func-tional groups (such as iodo, bromo) in traditional transition metal-catalyzed alkoxycar-bonylation reactions were compatible in this process, thus allowing further synthetic ma-nipulations. Remarkably, a low loading of an organic dye (fluorescein) is employed as a photocatalyst, and a low energy visible light (16 W blue LEDs) is enough to promote the reaction. However, high pressure of CO (80 atm) proved to be crucial for the success of the reaction.

Scheme 37. The catalyst-free synthesis of esters via radical alkoxycarbonylation of alkyl iodidesunder irradiation conditions.

The first example of radical alkoxycarboxylation of aryldiazonium salts using CO gasthrough visible-light-induced photoredox catalysis has been reported in 2015 by the Xiaoresearch group (Scheme 38) [66]. A wide variety of arylcarboxylic acid esters, bearing bothelectron-donating and electron-withdrawing groups, were obtained in good to excellentyields at room temperature. The generality of the alcohol coupling partner, includingthe use of chiral alcohols, was also demonstrated. Notably, terminal alkynes, which areknown to be good acceptors in radical reactions, remained untouched. Sensitive functionalgroups (such as iodo, bromo) in traditional transition metal-catalyzed alkoxycarbonylationreactions were compatible in this process, thus allowing further synthetic manipulations.

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Remarkably, a low loading of an organic dye (fluorescein) is employed as a photocatalyst,and a low energy visible light (16 W blue LEDs) is enough to promote the reaction. However,high pressure of CO (80 atm) proved to be crucial for the success of the reaction.


Scheme 37. The catalyst-free synthesis of esters via radical alkoxycarbonylation of alkyl iodides un-der irradiation conditions.

The first example of radical alkoxycarboxylation of aryldiazonium salts using CO gas through visible-light-induced photoredox catalysis has been reported in 2015 by the Xiao research group (Scheme 38) [66]. A wide variety of arylcarboxylic acid esters, bearing both electron-donating and electron-withdrawing groups, were obtained in good to excellent yields at room temperature. The generality of the alcohol coupling partner, including the use of chiral alcohols, was also demonstrated. Notably, terminal alkynes, which are known to be good acceptors in radical reactions, remained untouched. Sensitive func-tional groups (such as iodo, bromo) in traditional transition metal-catalyzed alkoxycar-bonylation reactions were compatible in this process, thus allowing further synthetic ma-nipulations. Remarkably, a low loading of an organic dye (fluorescein) is employed as a photocatalyst, and a low energy visible light (16 W blue LEDs) is enough to promote the reaction. However, high pressure of CO (80 atm) proved to be crucial for the success of the reaction.

Scheme 38. Visible light-induced fluorescein-catalyzed alkoxycarboxylation of aryldiazonium salts.

This radical alkoxycarboxylation protocol was applicable to other radical carboxyla-tion cascade reactions. For example, when benzenediazonium salts, bearing the allyl or thepropargyl function at the ortho position, were caused to react under standard reaction con-ditions, the corresponding methyl 2-(2,3-dihydrobenzofuran-3-yl)acetate (Scheme 39a) andmethyl 2-(benzofuran-3-yl)acetate (Scheme 39b) were obtained in satisfactory yields. Mech-anistic studies suggested that the reaction might proceed via carbon radical intermediatesI formed by single-electron reduction of the substrate with the fluorescein photocatalystin its excited state. The reactive intermediate I might be able to trap the CO moleculedelivering the benzoyl radical II, which is oxidized by the dye radical cation (Dye·+) withconcomitant restoring of the active photocatalyst. The resulting cation III could be directlytrapped by various alcohols leading to a wide range of alkyl benzoates (Scheme 40).



This radical alkoxycarboxylation protocol was applicable to other radical carboxyla-tion cascade reactions. For example, when benzenediazonium salts, bearing the allyl or the propargyl function at the ortho position, were caused to react under standard reaction conditions, the corresponding methyl 2-(2,3-dihydrobenzofuran-3-yl)acetate (Scheme 39a) and methyl 2-(benzofuran-3-yl)acetate (Scheme 39b) were obtained in satisfactory yields. Mechanistic studies suggested that the reaction might proceed via carbon radical intermediates I formed by single-electron reduction of the substrate with the fluorescein photocatalyst in its excited state. The reactive intermediate I might be able to trap the CO molecule delivering the benzoyl radical II, which is oxidized by the dye radical cation (Dye·+) with concomitant restoring of the active photocatalyst. The resulting cation III could be directly trapped by various alcohols leading to a wide range of alkyl benzoates (Scheme 40).

Scheme 39. Fluorescein-catalyzed radical addition/alkoxycarboxylation reaction sequences from alkene (a) and alkyne (b) derivatives.

Scheme 40. The proposed mechanism for the fluorescein-catalyzed visible light-induced alkoxycar-boxylation of aryldiazonium salts.

A very similar approach was developed in the same period by Jacobi von Wangelin’s group. Alkyl benzoates were efficiently obtained from arene diazonium salts, carbon monoxide and alcohols under visible-light irradiation and in the presence of eosin Y as the catalyst (Scheme 41) [67]. Under metal and base-free conditions, a variety of function-alities were well tolerated both on the substrates and on various functionalized additives. Interestingly, tertiary esters, which are difficult to obtain by conventional esterification

Scheme 39. Fluorescein-catalyzed radical addition/alkoxycarboxylation reaction sequences fromalkene (a) and alkyne (b) derivatives.

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This radical alkoxycarboxylation protocol was applicable to other radical carboxyla-tion cascade reactions. For example, when benzenediazonium salts, bearing the allyl or the propargyl function at the ortho position, were caused to react under standard reaction conditions, the corresponding methyl 2-(2,3-dihydrobenzofuran-3-yl)acetate (Scheme 39a) and methyl 2-(benzofuran-3-yl)acetate (Scheme 39b) were obtained in satisfactory yields. Mechanistic studies suggested that the reaction might proceed via carbon radical intermediates I formed by single-electron reduction of the substrate with the fluorescein photocatalyst in its excited state. The reactive intermediate I might be able to trap the CO molecule delivering the benzoyl radical II, which is oxidized by the dye radical cation (Dye·+) with concomitant restoring of the active photocatalyst. The resulting cation III could be directly trapped by various alcohols leading to a wide range of alkyl benzoates (Scheme 40).

Scheme 39. Fluorescein-catalyzed radical addition/alkoxycarboxylation reaction sequences from alkene (a) and alkyne (b) derivatives.


A very similar approach was developed in the same period by Jacobi von Wangelin’s group. Alkyl benzoates were efficiently obtained from arene diazonium salts, carbon monoxide and alcohols under visible-light irradiation and in the presence of eosin Y as the catalyst (Scheme 41) [67]. Under metal and base-free conditions, a variety of function-alities were well tolerated both on the substrates and on various functionalized additives. Interestingly, tertiary esters, which are difficult to obtain by conventional esterification


A very similar approach was developed in the same period by Jacobi von Wangelin’sgroup. Alkyl benzoates were efficiently obtained from arene diazonium salts, carbonmonoxide and alcohols under visible-light irradiation and in the presence of eosin Y as thecatalyst (Scheme 41) [67]. Under metal and base-free conditions, a variety of functional-ities were well tolerated both on the substrates and on various functionalized additives.Interestingly, tertiary esters, which are difficult to obtain by conventional esterificationprocedures due to their steric hindrance, can also be prepared in excellent yields. More-over, the industrially relevant intermediate, 2-ethylhexyl benzoate, has been obtained in58% yield from PhN2BF4, 2-ethylhexanol and CO under standard conditions.


procedures due to their steric hindrance, can also be prepared in excellent yields. Moreo-ver, the industrially relevant intermediate, 2-ethylhexyl benzoate, has been obtained in 58% yield from PhN2BF4, 2-ethylhexanol and CO under standard conditions.

Scheme 41. The synthesis of benzoates through visible light-driven eosin Y-catalyzed alkoxycar-bonylation of arene diazonium salts.

The mechanistic investigations, including the observation of benzoyl-TEMPO ad-duct, support the sequential reduction (SET), carbonylation, and oxidation (SET) to aroy-lium cations, which undergo rapid addition to alcohols (Scheme 40, Dye = Eosin Y).

From the pioneering work of Heck on palladium-catalyzed aminocarbonylation of aryl iodides [68], several efforts have been accomplished for the synthesis of aromatic am-ides [69,70] through radical carbonylative pathways as well [66,67,71]. Recently, the first example of catalyst-free photo-induced aminocarbonylation of aryl iodides with CO and amines has been reported by Ryu and co-workers [72]. A wide variety of amides, includ-ing hetero aromatic amides, has been obtained in good yields under mild reaction condi-tions (Scheme 42).

Scheme 42. Photo-induced aminocarbonylation of aryl iodides with primary and secondary amines.

The aryl radical I, generated by a photo-induced cleavage of the starting aryl iodide, might react with CO leading to the corresponding acyl radical II (Scheme 43). The nucle-ophilic addition of an amine to the latter gives a zwitterionic radical intermediate III. Fi-nally, electron transfer to the aryl iodide would provide the aryl radical I and the expected amide.

Scheme 41. The synthesis of benzoates through visible light-driven eosin Y-catalyzed alkoxycarbony-lation of arene diazonium salts.

The mechanistic investigations, including the observation of benzoyl-TEMPO adduct,support the sequential reduction (SET), carbonylation, and oxidation (SET) to aroyliumcations, which undergo rapid addition to alcohols (Scheme 40, Dye = Eosin Y).

From the pioneering work of Heck on palladium-catalyzed aminocarbonylation ofaryl iodides [68], several efforts have been accomplished for the synthesis of aromaticamides [69,70] through radical carbonylative pathways as well [66,67,71]. Recently, the firstexample of catalyst-free photo-induced aminocarbonylation of aryl iodides with CO andamines has been reported by Ryu and co-workers [72]. A wide variety of amides, including

Catalysts 2021, 11, 918 27 of 35

hetero aromatic amides, has been obtained in good yields under mild reaction conditions(Scheme 42).


procedures due to their steric hindrance, can also be prepared in excellent yields. Moreo-ver, the industrially relevant intermediate, 2-ethylhexyl benzoate, has been obtained in 58% yield from PhN2BF4, 2-ethylhexanol and CO under standard conditions.

Scheme 41. The synthesis of benzoates through visible light-driven eosin Y-catalyzed alkoxycar-bonylation of arene diazonium salts.

The mechanistic investigations, including the observation of benzoyl-TEMPO ad-duct, support the sequential reduction (SET), carbonylation, and oxidation (SET) to aroy-lium cations, which undergo rapid addition to alcohols (Scheme 40, Dye = Eosin Y).

From the pioneering work of Heck on palladium-catalyzed aminocarbonylation of aryl iodides [68], several efforts have been accomplished for the synthesis of aromatic am-ides [69,70] through radical carbonylative pathways as well [66,67,71]. Recently, the first example of catalyst-free photo-induced aminocarbonylation of aryl iodides with CO and amines has been reported by Ryu and co-workers [72]. A wide variety of amides, includ-ing hetero aromatic amides, has been obtained in good yields under mild reaction condi-tions (Scheme 42).


The aryl radical I, generated by a photo-induced cleavage of the starting aryl iodide, might react with CO leading to the corresponding acyl radical II (Scheme 43). The nucle-ophilic addition of an amine to the latter gives a zwitterionic radical intermediate III. Fi-nally, electron transfer to the aryl iodide would provide the aryl radical I and the expected amide.


The aryl radical I, generated by a photo-induced cleavage of the starting aryl io-dide, might react with CO leading to the corresponding acyl radical II (Scheme 43). Thenucleophilic addition of an amine to the latter gives a zwitterionic radical intermediateIII. Finally, electron transfer to the aryl iodide would provide the aryl radical I and theexpected amide.


Scheme 43. The proposed mechanistic pathway for the catalyst-free photo-induced aminocarbonyl-ation of aryl iodides.

Inspired by Xiao [66] and Wangelin [67] independent reports, the Eosin-Y-catalyzed synthesis of indol-3-yl aryl ketones from indoles, CO and aryldiazonium salts has been recently reported by Gu and Li (Scheme 44) [73]. This protocol features high versatility, high functional group tolerance and mild reaction conditions except for the high pressure of CO required (70 atm).

Scheme 44. The photo-induced synthesis of indol-3-yl aryl ketones from indoles, CO and aryldia-zonium salts.

The synthesis of indol-3-yl aryl ketones was achieved also by Li, Liang and col-leagues, starting from arylsulfonyl chlorides in place of aryldiazonium salts under very similar photocatalytic conditions (Scheme 45) [74]. Notably, the methodology demon-strated wide applicability with both electron-rich and electron-deficient functional groups at reduced reaction time if compared with Gu and Li’s protocol [73]. The proposed path-way starts with the reduction of the arylsulfonyl chloride by a single-electron transfer process (SET) to produce an aryl radical I and the Eosin radical cation [Eosin˙+] (Scheme 46). Then, the aryl radical I reacts with CO, delivering an acyl radical II, which is oxidized

Scheme 43. The proposed mechanistic pathway for the catalyst-free photo-induced aminocarbonyla-tion of aryl iodides.

Catalysts 2021, 11, 918 28 of 35

Inspired by Xiao [66] and Wangelin [67] independent reports, the Eosin-Y-catalyzedsynthesis of indol-3-yl aryl ketones from indoles, CO and aryldiazonium salts has beenrecently reported by Gu and Li (Scheme 44) [73]. This protocol features high versatility,high functional group tolerance and mild reaction conditions except for the high pressureof CO required (70 atm).


Scheme 43. The proposed mechanistic pathway for the catalyst-free photo-induced aminocarbonyl-ation of aryl iodides.

Inspired by Xiao [66] and Wangelin [67] independent reports, the Eosin-Y-catalyzed synthesis of indol-3-yl aryl ketones from indoles, CO and aryldiazonium salts has been recently reported by Gu and Li (Scheme 44) [73]. This protocol features high versatility, high functional group tolerance and mild reaction conditions except for the high pressure of CO required (70 atm).

Scheme 44. The photo-induced synthesis of indol-3-yl aryl ketones from indoles, CO and aryldia-zonium salts.

The synthesis of indol-3-yl aryl ketones was achieved also by Li, Liang and col-leagues, starting from arylsulfonyl chlorides in place of aryldiazonium salts under very similar photocatalytic conditions (Scheme 45) [74]. Notably, the methodology demon-strated wide applicability with both electron-rich and electron-deficient functional groups at reduced reaction time if compared with Gu and Li’s protocol [73]. The proposed path-way starts with the reduction of the arylsulfonyl chloride by a single-electron transfer process (SET) to produce an aryl radical I and the Eosin radical cation [Eosin˙+] (Scheme 46). Then, the aryl radical I reacts with CO, delivering an acyl radical II, which is oxidized

Scheme 44. The photo-induced synthesis of indol-3-yl aryl ketones from indoles, CO and aryldiazo-nium salts.

The synthesis of indol-3-yl aryl ketones was achieved also by Li, Liang and colleagues,starting from arylsulfonyl chlorides in place of aryldiazonium salts under very similarphotocatalytic conditions (Scheme 45) [74]. Notably, the methodology demonstrated wideapplicability with both electron-rich and electron-deficient functional groups at reducedreaction time if compared with Gu and Li’s protocol [73]. The proposed pathway startswith the reduction of the arylsulfonyl chloride by a single-electron transfer process (SET)to produce an aryl radical I and the Eosin radical cation [Eosin˙+] (Scheme 46). Then, thearyl radical I reacts with CO, delivering an acyl radical II, which is oxidized to an acyliumintermediate III by the Eosin radical cation [Eosin·+]. The active photocatalytic species isindeed regenerated while the acylium ion undergoes nucleophilic attack by the indolylspecies, leading to the final product.

It has been demonstrated that not only indoles but also (hetero)arenes might serveas a platform to trap benzylidyneoxonium cations [75]. Under very similar reactionconditions [67,73], a wide variety of unsymmetrical aryl and heteroaryl ketones weresuccessfully obtained from (hetero)arenes, CO and aryldiazonium salts in the presence ofEosin Y and green LEDs (Scheme 47). Interestingly, the electronic nature of the diazoniumsalt has little influence on the reaction, while electron-rich (hetero)arenes gave the bestresults. Based on control experiments and in agreement with the previous reports [67], theproposed mechanism is shown in Scheme 48. Under irradiation conditions, the excitedphotocatalyst (Eosin Y*) is generated. Then, the electron-deficient phenyl diazonium salt isreduced to I by Eosin Y* through a single-electron transfer (SET). The aryl radical speciesI react with CO, providing the acyl radical II, which is oxidized by Eosin Y·+ to cationicintermediate III. Finally, benzylidyneoxonium III is trapped by the arene (or heteroarene)derivative, delivering the desired ketone.

Catalysts 2021, 11, 918 29 of 35


to an acylium intermediate III by the Eosin radical cation [Eosin·+]. The active photocata-lytic species is indeed regenerated while the acylium ion undergoes nucleophilic attack by the indolyl species, leading to the final product.

Scheme 45. The photo-induced synthesis of indol-3-yl aryl ketones from indoles, CO and aryl sul-fonyl chlorides.

Scheme 46. The proposed mechanism for the Eosin-catalyzed visible-light-promoted indolylcarbox-ylation of aryl sulfonyl chlorides.

It has been demonstrated that not only indoles but also (hetero)arenes might serve as a platform to trap benzylidyneoxonium cations [75]. Under very similar reaction condi-tions [67,73], a wide variety of unsymmetrical aryl and heteroaryl ketones were success-fully obtained from (hetero)arenes, CO and aryldiazonium salts in the presence of Eosin Y and green LEDs (Scheme 47). Interestingly, the electronic nature of the diazonium salt has little influence on the reaction, while electron-rich (hetero)arenes gave the best results. Based on control experiments and in agreement with the previous reports [67], the pro-posed mechanism is shown in Scheme 48. Under irradiation conditions, the excited pho-tocatalyst (Eosin Y*) is generated. Then, the electron-deficient phenyl diazonium salt is reduced to I by Eosin Y* through a single-electron transfer (SET). The aryl radical species I react with CO, providing the acyl radical II, which is oxidized by Eosin Y·+ to cationic intermediate III. Finally, benzylidyneoxonium III is trapped by the arene (or heteroarene) derivative, delivering the desired ketone.

Scheme 45. The photo-induced synthesis of indol-3-yl aryl ketones from indoles, CO and arylsulfonyl chlorides.


to an acylium intermediate III by the Eosin radical cation [Eosin·+]. The active photocata-lytic species is indeed regenerated while the acylium ion undergoes nucleophilic attack by the indolyl species, leading to the final product.

Scheme 45. The photo-induced synthesis of indol-3-yl aryl ketones from indoles, CO and aryl sul-fonyl chlorides.

Scheme 46. The proposed mechanism for the Eosin-catalyzed visible-light-promoted indolylcarbox-ylation of aryl sulfonyl chlorides.

It has been demonstrated that not only indoles but also (hetero)arenes might serve as a platform to trap benzylidyneoxonium cations [75]. Under very similar reaction condi-tions [67,73], a wide variety of unsymmetrical aryl and heteroaryl ketones were success-fully obtained from (hetero)arenes, CO and aryldiazonium salts in the presence of Eosin Y and green LEDs (Scheme 47). Interestingly, the electronic nature of the diazonium salt has little influence on the reaction, while electron-rich (hetero)arenes gave the best results. Based on control experiments and in agreement with the previous reports [67], the pro-posed mechanism is shown in Scheme 48. Under irradiation conditions, the excited pho-tocatalyst (Eosin Y*) is generated. Then, the electron-deficient phenyl diazonium salt is reduced to I by Eosin Y* through a single-electron transfer (SET). The aryl radical species I react with CO, providing the acyl radical II, which is oxidized by Eosin Y·+ to cationic intermediate III. Finally, benzylidyneoxonium III is trapped by the arene (or heteroarene) derivative, delivering the desired ketone.

Scheme 46. The proposed mechanism for the Eosin-catalyzed visible-light-promoted indolylcarboxy-lation of aryl sulfonyl chlorides.


Scheme 47. The photo-induced synthesis of unsymmetrical aryl ketones from (hetero)arenes, CO and aryldiazonium salts.

Scheme 48. The proposed mechanism for the photo-induced synthesis of indol-3-yl aryl ketones from indoles, CO and aryldiazonium salts.

Recently, the first example of photocatalyzed oxidative carbonylation of organosili-cates to unsymmetrical ketones has been reported by Fukuyama, Ollivier, Ryu, Fen-sterbank and co-workers [76]. This metal-free procedure is based on the use of an inex-pensive organic dye, 4CzIPN, which, in combination with the blue led, is able to catalyze the reaction of alkyl bis(catecholato)silicates, CO (80 atm) and activated olefins to produce a wide range of ketones (Scheme 49). Notably, primary, secondary and tertiary alkyl rad-icals generated by the photocatalyzed oxidation of organosilicates underwent efficient carbonylation with CO under standard conditions. Interestingly, 1,4-dicarbonyl com-pounds were efficiently accessed through this protocol, while allyl sulfones were success-fully employed as radical acceptors in this three-component reaction.

Scheme 47. The photo-induced synthesis of unsymmetrical aryl ketones from (hetero)arenes, COand aryldiazonium salts.


Scheme 47. The photo-induced synthesis of unsymmetrical aryl ketones from (hetero)arenes, CO and aryldiazonium salts.

Scheme 48. The proposed mechanism for the photo-induced synthesis of indol-3-yl aryl ketones from indoles, CO and aryldiazonium salts.

Recently, the first example of photocatalyzed oxidative carbonylation of organosili-cates to unsymmetrical ketones has been reported by Fukuyama, Ollivier, Ryu, Fen-sterbank and co-workers [76]. This metal-free procedure is based on the use of an inex-pensive organic dye, 4CzIPN, which, in combination with the blue led, is able to catalyze the reaction of alkyl bis(catecholato)silicates, CO (80 atm) and activated olefins to produce a wide range of ketones (Scheme 49). Notably, primary, secondary and tertiary alkyl rad-icals generated by the photocatalyzed oxidation of organosilicates underwent efficient carbonylation with CO under standard conditions. Interestingly, 1,4-dicarbonyl com-pounds were efficiently accessed through this protocol, while allyl sulfones were success-fully employed as radical acceptors in this three-component reaction.

Scheme 48. The proposed mechanism for the photo-induced synthesis of indol-3-yl aryl ketonesfrom indoles, CO and aryldiazonium salts.

Recently, the first example of photocatalyzed oxidative carbonylation of organosili-cates to unsymmetrical ketones has been reported by Fukuyama, Ollivier, Ryu, Fensterbankand co-workers [76]. This metal-free procedure is based on the use of an inexpensive or-ganic dye, 4CzIPN, which, in combination with the blue led, is able to catalyze the reactionof alkyl bis(catecholato)silicates, CO (80 atm) and activated olefins to produce a wide rangeof ketones (Scheme 49). Notably, primary, secondary and tertiary alkyl radicals generatedby the photocatalyzed oxidation of organosilicates underwent efficient carbonylation withCO under standard conditions. Interestingly, 1,4-dicarbonyl compounds were efficientlyaccessed through this protocol, while allyl sulfones were successfully employed as radicalacceptors in this three-component reaction.


Scheme 49. The synthesis of unsymmetrical ketones via 4CzIPN-catalyzed radical carbonylations.

Mechanistic studies reveal that, initially, the photocatalyst is excited under visible-light irradiation. Then, the alkyl bis(catecholato)silicate undergoes oxidation by the ex-cited 4CzIPN* through a single-electron-transfer (SET) process, leading to the formation of the alkyl radical species I and the reduced organocatalyst [4CzIPN]ˉ. The alkyl radical I reacts with CO to generate the acyl radical II, which, in turn, adds to the activated alkene affording the radical intermediate III. Catalyst [4CzIPN]ˉ converts III into the carbanionic species IV by reduction (SET), and, in this way, the photocatalyst is able to restart a new catalytic cycle. Finally, the base (KH2PO4) provides the proton for the formation of the final product (Scheme 50).

Scheme 50. Proposed mechanism for the 4CzIPN-catalyzed carbonylative synthesis of ketones from organosilicates, CO and activated alkenes.

More recently, the same authors have developed a visible-light-driven photocata-lyzed aminocarbonylation of alkyl bis(catecholato)silicates with amines under similar re-action conditions [77]. In this approach, the CCl4 was used as a mediator in order to pro-mote the formation of acyl chloride, which is intermediate in the formation of the corre-sponding amides.

2. Conclusions In this review, the major advances in the field of visible-light-induced catalyzed and

un-catalyzed carbon monoxide-based carbonylation reactions have been described. The use of visible light in carbonylation chemistry has led to valuable and more sustainable


Mechanistic studies reveal that, initially, the photocatalyst is excited under visible-light irradiation. Then, the alkyl bis(catecholato)silicate undergoes oxidation by the excited4CzIPN* through a single-electron-transfer (SET) process, leading to the formation of thealkyl radical species I and the reduced organocatalyst [4CzIPN]−. The alkyl radical Ireacts with CO to generate the acyl radical II, which, in turn, adds to the activated alkeneaffording the radical intermediate III. Catalyst [4CzIPN]− converts III into the carbanionicspecies IV by reduction (SET), and, in this way, the photocatalyst is able to restart a newcatalytic cycle. Finally, the base (KH2PO4) provides the proton for the formation of the finalproduct (Scheme 50).



Mechanistic studies reveal that, initially, the photocatalyst is excited under visible-light irradiation. Then, the alkyl bis(catecholato)silicate undergoes oxidation by the ex-cited 4CzIPN* through a single-electron-transfer (SET) process, leading to the formation of the alkyl radical species I and the reduced organocatalyst [4CzIPN]ˉ. The alkyl radical I reacts with CO to generate the acyl radical II, which, in turn, adds to the activated alkene affording the radical intermediate III. Catalyst [4CzIPN]ˉ converts III into the carbanionic species IV by reduction (SET), and, in this way, the photocatalyst is able to restart a new catalytic cycle. Finally, the base (KH2PO4) provides the proton for the formation of the final product (Scheme 50).

Scheme 50. Proposed mechanism for the 4CzIPN-catalyzed carbonylative synthesis of ketones from organosilicates, CO and activated alkenes.

More recently, the same authors have developed a visible-light-driven photocata-lyzed aminocarbonylation of alkyl bis(catecholato)silicates with amines under similar re-action conditions [77]. In this approach, the CCl4 was used as a mediator in order to pro-mote the formation of acyl chloride, which is intermediate in the formation of the corre-sponding amides.

2. Conclusions In this review, the major advances in the field of visible-light-induced catalyzed and

un-catalyzed carbon monoxide-based carbonylation reactions have been described. The use of visible light in carbonylation chemistry has led to valuable and more sustainable

Scheme 50. Proposed mechanism for the 4CzIPN-catalyzed carbonylative synthesis of ketones fromorganosilicates, CO and activated alkenes.

More recently, the same authors have developed a visible-light-driven photocat-alyzed aminocarbonylation of alkyl bis(catecholato)silicates with amines under similarreaction conditions [77]. In this approach, the CCl4 was used as a mediator in order topromote the formation of acyl chloride, which is intermediate in the formation of thecorresponding amides.

Catalysts 2021, 11, 918 32 of 35

2. Conclusions

In this review, the major advances in the field of visible-light-induced catalyzed andun-catalyzed carbon monoxide-based carbonylation reactions have been described. Theuse of visible light in carbonylation chemistry has led to valuable and more sustainablealternatives for the synthesis of carbonyl-containing compounds. Mild reaction condi-tions, such as room temperature, are routinely applied. However, the use of low COpressure is less frequent, and many improvements are expected from this point of view.The employment of greener reaction media and the application of continuous flow con-ditions can be beneficial to this chemistry. The use of CO surrogates, so attractive inconventional carbonylation reactions, can lead to several advantages in photocatalyticcarbonylation reactions. The research in this field should be focused on discovering moreefficient photocatalysts, possibly in combination with co-catalysts or additives, in order toincrease both turnover number and turnover frequency (TON and TOF) and to improve theindustrial attractiveness of these carbonylative methodologies. Heterogeneous systems, al-though sometimes hardly compatible, should be considered to improve the sustainability ofthese processes.

Despite the increasing number of high-impact publications in the field, this is, un-doubtedly, an underdeveloped area, and the real potential of this highly sustainable car-bonylation strategy still needs to be discovered. We hope that this contribution might helpother researchers in developing even more attractive visible-light-driven carbonylationprotocols in the coming years.

Author Contributions: Conceptualization, N.D.C.; writing—original draft preparation, V.B., R.M.,E.M. and A.V.; writing—review and editing, N.D.C., B.G., C.C.; supervision, N.D.C. All authors haveread and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Acknowledgments: V.B. and N.D. acknowledge European Union for Marie Skłodowska-CurieIndividual Fellowship grant No. 894026.

Conflicts of Interest: The authors declare no conflict of interest.

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